2	32033249	However, asbestos has been historically shown to cause pleural malignant mesothelioma and lung cancer by inhalation exposure.	('asbestos', 'Var', (9, 17))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('pleural malignant mesothelioma', 'Phenotype', 'HP:0100002', (55, 85))	('cause', 'Reg', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (63, 85))	('pleural malignant mesothelioma and lung cancer', 'Disease', 'MESH:C562839', (55, 101))
59	32033249	This suggests that MWCNTs, at lower concentrations, and do not exhibit cytotoxicity, may promote bone formation.	('promote', 'PosReg', (89, 96))	('cytotoxicity', 'Disease', (71, 83))	('MWCNTs', 'Chemical', '-', (19, 25))	('rat', 'Species', '10116', (43, 46))	('MWCNTs', 'Var', (19, 25))	('bone formation', 'biological_process', 'GO:0001503', ('97', '111'))	('bone formation', 'CPA', (97, 111))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))
100	32033249	PEGylated SWCNTs showed prolonged blood circulation half-life and stability in serum.	('PEGylated', 'Var', (0, 9))	('prolonged blood circulation', 'Phenotype', 'HP:0011028', (24, 51))	('blood', 'MPA', (34, 39))	('SWCNTs', 'Chemical', '-', (10, 16))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('blood circulation', 'biological_process', 'GO:0008015', ('34', '51'))
135	32033249	The production of antioxidant glutathione also decreased with impure SWCNTs.	('decreased', 'NegReg', (47, 56))	('production of antioxidant glutathione', 'MPA', (4, 41))	('SWCNTs', 'Chemical', '-', (69, 75))	('impure', 'Var', (62, 68))	('glutathione', 'Chemical', 'MESH:D005978', (30, 41))
140	32033249	In addition, when inflammatory cytokines in the culture medium were measured with a cytometric bead array flex set system, the greatest amount of IL-6 and IL-8 were produced in the order of gelatin, DPPC, and CMC in the same manner as the amount of MWCNTs uptake into the cells.	('IL-6', 'molecular_function', 'GO:0005138', ('146', '150'))	('IL-8', 'Gene', '20309', (155, 159))	('CMC', 'Chemical', '-', (209, 212))	('IL-8', 'molecular_function', 'GO:0005153', ('155', '159'))	('MWCNTs', 'Chemical', '-', (249, 255))	('uptake', 'biological_process', 'GO:0098657', ('256', '262'))	('uptake', 'biological_process', 'GO:0098739', ('256', '262'))	('DPPC', 'Var', (199, 203))	('IL-6', 'Gene', (146, 150))	('IL-6', 'Gene', '16193', (146, 150))	('DPPC', 'Chemical', 'MESH:C081581', (199, 203))	('IL-8', 'Gene', (155, 159))
156	32033249	Although, there were models that showed mesothelioma in the lung (Figure 5a) in the group receiving MWCNTs, there was no significant difference in the incidence of tumor with the vehicle group.	('MWCNTs', 'Var', (100, 106))	('tumor', 'Disease', (164, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mesothelioma', 'Disease', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('MWCNTs', 'Chemical', '-', (100, 106))
309	30272283	It has previously been demonstrated that mitochondria or activation of the death receptor pathway converge to induce the activation of caspases, which are the final executioners of cell death.	('cell death', 'biological_process', 'GO:0008219', ('181', '191'))	('mitochondria', 'Var', (41, 53))	('death receptor pathway', 'Pathway', (75, 97))	('mitochondria', 'cellular_component', 'GO:0005739', ('41', '53'))	('caspases', 'Gene', (135, 143))	('activation', 'PosReg', (121, 131))	('caspases', 'Gene', '841;12370;842;12371', (135, 143))
320	30272283	4A and B, treatment with increasing doses of curcumin resulted in significant downregulation of PI3K, p-Akt, p-mTOR and p-p70S6K; however, no significant differences were detected with regards to the total expression levels of Akt, mTOR and p70S6K.	('p-p70S6K', 'Var', (120, 128))	('p70S6K', 'Var', (241, 247))	('downregulation', 'NegReg', (78, 92))	('PI3K', 'Pathway', (96, 100))	('curcumin', 'Chemical', 'MESH:D003474', (45, 53))	('p-mTOR', 'MPA', (109, 115))	('p-Akt', 'Pathway', (102, 107))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))
325	30272283	The mean tumor volumes in mice treated with cisplatin and a high dose of curcumin were 58 and 72 mm3, respectively, whereas the tumor volumes in mice treated with the solvent and a low dose of curcumin were 161 and 120 mm3 on day 25.	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cisplatin', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (145, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('curcumin', 'Chemical', 'MESH:D003474', (193, 201))	('curcumin', 'Chemical', 'MESH:D003474', (73, 81))	('mice', 'Species', '10090', (26, 30))
346	30272283	In the present study, cleaved caspase-3 expression was significantly upregulated by cisplatin treatment, whereas cleaved caspase-3, -8 and -9 expression was not detected following curcumin treatment.	('expression', 'MPA', (40, 50))	('cisplatin', 'Var', (84, 93))	('cleaved', 'MPA', (22, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('upregulated', 'PosReg', (69, 80))	('curcumin', 'Chemical', 'MESH:D003474', (180, 188))
378	29520212	Reactive oxygen species may play an important role in the mechanism of carcinogenesis; therefore, genetic variability in antioxidative defence may modify an individual's susceptibility to this cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('antioxidative defence', 'MPA', (121, 142))	('cancer', 'Disease', (193, 199))	('carcinogenesis', 'Disease', (71, 85))	('genetic variability', 'Var', (98, 117))	('susceptibility', 'MPA', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('modify', 'Reg', (147, 153))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))
380	29520212	In total, 150 cases with malignant mesothelioma and 122 controls with no asbestos-related disease were genotyped for NQO1, CAT, SOD2 and hOGG1 polymorphisms.	('NQO1', 'Gene', (117, 121))	('malignant mesothelioma', 'Disease', (25, 47))	('hOGG1', 'Gene', '4968', (137, 142))	('NQO1', 'Gene', '1728', (117, 121))	('SOD2', 'Gene', '6648', (128, 132))	('SOD2', 'Gene', (128, 132))	('CAT', 'molecular_function', 'GO:0004096', ('123', '126'))	('polymorphisms', 'Var', (143, 156))	('asbestos', 'Chemical', 'MESH:D001194', (73, 81))	('CAT', 'Gene', (123, 126))	('CAT', 'Gene', '847', (123, 126))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (25, 47))	('SOD2', 'molecular_function', 'GO:0004784', ('128', '132'))	('hOGG1', 'Gene', (137, 142))	('NQO1', 'molecular_function', 'GO:0003955', ('117', '121'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (25, 47))
383	29520212	NQO1 rs1800566 was significantly associated with increased malignant mesothelioma risk, OR 1.73 (95% CI 1.02-2.96).	('OR 1.73', 'Gene', (88, 95))	('malignant mesothelioma', 'Disease', (59, 81))	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (59, 81))	('rs1800566', 'Var', (5, 14))	('NQO1', 'Gene', (0, 4))	('rs1800566', 'Mutation', 'rs1800566', (5, 14))	('OR 1.73', 'Gene', '401637', (88, 95))	('NQO1', 'Gene', '1728', (0, 4))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (59, 81))
384	29520212	Although there was no independent association between either CAT rs1001179 or hOGG1 rs1052133 polymorphism and malignant mesothelioma, interaction between both polymorphisms showed a protective effect, ORint 0.27 (95% CI 0.10-0.77).	('rs1001179', 'Mutation', 'rs1001179', (65, 74))	('hOGG1', 'Gene', (78, 83))	('malignant mesothelioma', 'Disease', (111, 133))	('CAT', 'Gene', '847', (61, 64))	('rs1001179', 'Var', (65, 74))	('rs1052133', 'Var', (84, 93))	('CAT', 'molecular_function', 'GO:0004096', ('61', '64'))	('CAT', 'Gene', (61, 64))	('rs1052133', 'Mutation', 'rs1052133', (84, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (111, 133))	('hOGG1', 'Gene', '4968', (78, 83))	('interaction', 'Interaction', (135, 146))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (111, 133))
385	29520212	Our findings suggest a role of both genetic variability in antioxidative defence and repair as well as the impact of gene-gene interactions in the development of malignant mesothelioma.	('malignant mesothelioma', 'Disease', (162, 184))	('interactions', 'Interaction', (127, 139))	('genetic variability', 'Var', (36, 55))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (162, 184))	('antioxidative defence', 'MPA', (59, 80))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (162, 184))
399	29520212	CAT helps to maintain the oxidative balance by catalysing H2O2 to H2O and O2  Numerous polymorphisms of CAT gene (CAT) have been described, rs1001179 being the most commonly studied one.	('rs1001179', 'Mutation', 'rs1001179', (140, 149))	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('CAT', 'Gene', '847', (114, 117))	('CAT', 'molecular_function', 'GO:0004096', ('0', '3'))	('H2O', 'Chemical', 'MESH:D014867', (58, 61))	('rs1001179', 'Var', (140, 149))	('H2O', 'Chemical', 'MESH:D014867', (66, 69))	('O2', 'Chemical', '-', (74, 76))	('O2', 'Chemical', '-', (60, 62))	('CAT', 'Gene', '847', (0, 3))	('CAT', 'molecular_function', 'GO:0004096', ('104', '107'))	('CAT', 'molecular_function', 'GO:0004096', ('114', '117'))	('CAT', 'Gene', (0, 3))	('CAT', 'Gene', (104, 107))	('CAT', 'Gene', '847', (104, 107))	('oxidative balance', 'MPA', (26, 43))	('CAT', 'Gene', (114, 117))
404	29520212	The most common polymorphism is rs4880, resulting in C to T substitution at position 201 (c.201C>T), which causes the change of alanine to valine at position 16 (p.Ala16Val).	('C to T substitution at position 201', 'Mutation', 'c.201C>T', (53, 88))	('alanine to valine at position 16', 'MPA', (128, 160))	('p.Ala16Val', 'Mutation', 'rs4880', (162, 172))	('alanine to valine at position 16', 'Mutation', 'rs4880', (128, 160))	('rs4880', 'Var', (32, 38))	('rs4880', 'Mutation', 'rs4880', (32, 38))	('c.201C>T', 'Mutation', 'c.201C>T', (90, 98))	('change', 'Reg', (118, 124))	('c.201C>T', 'Var', (90, 98))
406	29520212	HOGG1 catalyses the repair of 8-oxoguanine that may result from ROS damage to the DNA.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (30, 42))	('damage', 'Var', (68, 74))	('HOGG1', 'Gene', '4968', (0, 5))	('ROS', 'Gene', (64, 67))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('result from', 'Reg', (52, 63))	('HOGG1', 'Gene', (0, 5))
407	29520212	In rs1052133 polymorphism, C replaces G in exon 7, causing the substitution of serine with cysteine in codon 326 (p.Ser326Cys).	('rs1052133', 'Var', (3, 12))	('C replaces', 'Var', (27, 37))	('causing', 'Reg', (51, 58))	('serine with cysteine in codon 326', 'Mutation', 'rs1052133', (79, 112))	('p.Ser326Cys', 'Mutation', 'rs1052133', (114, 125))	('substitution', 'Var', (63, 75))	('serine with cysteine', 'MPA', (79, 99))	('Ser', 'cellular_component', 'GO:0005790', ('116', '119'))	('rs1052133', 'Mutation', 'rs1052133', (3, 12))
408	29520212	Although a changed structure of the polymorphic enzyme has not been proved, several studies have shown the association between hOGG1 Ser326Cys polymorphism and lung cancer risk.	('hOGG1', 'Gene', '4968', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Ser326Cys', 'Var', (133, 142))	('hOGG1', 'Gene', (127, 132))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('Ser326Cys', 'SUBSTITUTION', 'None', (133, 142))	('Ser', 'cellular_component', 'GO:0005790', ('133', '136'))	('association', 'Interaction', (107, 118))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
410	29520212	The most frequently studied single nucleotide polymorphism (SNP), rs1800566, results in C to T change (c.609C>T), which causes proline to serine substitution (p.Pro187Ser).	('Ser', 'cellular_component', 'GO:0005790', ('167', '170'))	('proline', 'Chemical', 'MESH:D011392', (127, 134))	('c.609C>T', 'Var', (103, 111))	('causes', 'Reg', (120, 126))	('rs1800566', 'Mutation', 'rs1800566', (66, 75))	('rs1800566', 'Var', (66, 75))	('C to T', 'MPA', (88, 94))	('serine', 'Chemical', 'MESH:D012694', (138, 144))	('results', 'Reg', (77, 84))	('c.609C>T', 'Mutation', 'rs1800566', (103, 111))	('p.Pro187Ser', 'Mutation', 'rs1800566', (159, 170))	('proline to serine substitution', 'MPA', (127, 157))
411	29520212	Some studies found this polymorphism to be associated with an increased risk of several malignant diseases: lung cancer, colorectal cancer, breast cancer and bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('lung cancer', 'Disease', (108, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (158, 172))	('bladder cancer', 'Disease', (158, 172))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('bladder cancer', 'Phenotype', 'HP:0009725', (158, 172))	('breast cancer', 'Disease', (140, 153))	('malignant diseases', 'Disease', (88, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('associated', 'Reg', (43, 53))	('malignant diseases', 'Disease', 'MESH:D009369', (88, 106))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('polymorphism', 'Var', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
413	29520212	Nevertheless, the interaction between asbestos exposure and genetic susceptibility due to genetic polymorphism of antioxidant enzymes has been shown for asbestosis.	('asbestosis', 'Disease', (153, 163))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('interaction', 'Interaction', (18, 29))	('asbestos', 'Chemical', 'MESH:D001194', (153, 161))	('asbestosis', 'Disease', 'MESH:D001195', (153, 163))	('genetic polymorphism', 'Var', (90, 110))
416	29520212	This study aimed to investigate whether functional polymorphisms in NQO1, CAT, SOD2 and hOGG1 genes influence the risk of MM, to investigate the interactions between genetic variability in antioxidative and DNA repair mechanisms and to investigate the interactions between asbestos exposure and the investigated polymorphisms in MM patients.	('interactions', 'Interaction', (252, 264))	('patients', 'Species', '9606', (332, 340))	('NQO1', 'Gene', '1728', (68, 72))	('polymorphisms', 'Var', (51, 64))	('SOD2', 'Gene', (79, 83))	('SOD2', 'molecular_function', 'GO:0004784', ('79', '83'))	('NQO1', 'molecular_function', 'GO:0003955', ('68', '72'))	('NQO1', 'Gene', (68, 72))	('CAT', 'Gene', (74, 77))	('interactions', 'Interaction', (145, 157))	('investigate', 'Reg', (129, 140))	('DNA repair', 'biological_process', 'GO:0006281', ('207', '217'))	('asbestos', 'Chemical', 'MESH:D001194', (273, 281))	('CAT', 'molecular_function', 'GO:0004096', ('74', '77'))	('SOD2', 'Gene', '6648', (79, 83))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('hOGG1', 'Gene', '4968', (88, 93))	('influence', 'Reg', (100, 109))	('hOGG1', 'Gene', (88, 93))	('CAT', 'Gene', '847', (74, 77))
430	29520212	Real-time polymerase chain reaction (PCR) based TaqMan assays were used for the analysis of NQO1 rs1800566, CAT rs1001179, SOD2 rs4880 and hOGG1 rs1052133 polymorphisms as recommended by the manufacturer (Thermo Fisher Scientific, SNP genotyping assay C_2091255_30, C_11468118_10, C_8709053_10 and C_3095552_1_, respectively).	('rs4880', 'Mutation', 'rs4880', (128, 134))	('rs4880', 'Var', (128, 134))	('rs1800566', 'Mutation', 'rs1800566', (97, 106))	('NQO1', 'Gene', '1728', (92, 96))	('NQO1', 'molecular_function', 'GO:0003955', ('92', '96'))	('C_11468118_10', 'Var', (266, 279))	('rs1001179', 'Mutation', 'rs1001179', (112, 121))	('CAT', 'molecular_function', 'GO:0004096', ('108', '111'))	('C_2091255_30', 'Var', (252, 264))	('NQO1', 'Gene', (92, 96))	('rs1052133', 'Mutation', 'rs1052133', (145, 154))	('hOGG1', 'Gene', '4968', (139, 144))	('CAT', 'Gene', '847', (108, 111))	('SOD2', 'molecular_function', 'GO:0004784', ('123', '127'))	('hOGG1', 'Gene', (139, 144))	('C_3095552_1_', 'Var', (298, 310))	('rs1001179', 'Var', (112, 121))	('SOD2', 'Gene', (123, 127))	('rs1800566', 'Var', (97, 106))	('C_8709053_10', 'Var', (281, 293))	('rs1052133', 'Var', (145, 154))	('SOD2', 'Gene', '6648', (123, 127))	('CAT', 'Gene', (108, 111))
443	29520212	Minor allele frequencies were 13.9% for NQO1 rs1800566, 22.4% for CAT rs1001179, 52.5% for SOD2 rs4880 and 18.8% for hOGG1 rs1052133.	('rs4880', 'Mutation', 'rs4880', (96, 102))	('hOGG1', 'Gene', '4968', (117, 122))	('SOD2', 'Gene', '6648', (91, 95))	('CAT', 'Gene', (66, 69))	('hOGG1', 'Gene', (117, 122))	('rs1052133', 'Mutation', 'rs1052133', (123, 132))	('rs1001179', 'Mutation', 'rs1001179', (70, 79))	('NQO1', 'Gene', '1728', (40, 44))	('rs1800566', 'Var', (45, 54))	('CAT', 'Gene', '847', (66, 69))	('NQO1', 'molecular_function', 'GO:0003955', ('40', '44'))	('rs1052133', 'Var', (123, 132))	('NQO1', 'Gene', (40, 44))	('CAT', 'molecular_function', 'GO:0004096', ('66', '69'))	('rs1800566', 'Mutation', 'rs1800566', (45, 54))	('rs1001179', 'Var', (70, 79))	('SOD2', 'molecular_function', 'GO:0004784', ('91', '95'))	('SOD2', 'Gene', (91, 95))	('rs4880', 'Var', (96, 102))
449	29520212	The interaction between CAT rs1001179 and hOGG1 rs1052133 had a protective effect on the risk of MM (ORint = 0.27; 95% CI = 0.10-0.77; p = 0.014).	('hOGG1', 'Gene', '4968', (42, 47))	('rs1052133', 'Mutation', 'rs1052133', (48, 57))	('rs1052133', 'Var', (48, 57))	('CAT', 'molecular_function', 'GO:0004096', ('24', '27'))	('rs1001179', 'Var', (28, 37))	('hOGG1', 'Gene', (42, 47))	('CAT', 'Gene', '847', (24, 27))	('CAT', 'Gene', (24, 27))	('rs1001179', 'Mutation', 'rs1001179', (28, 37))
455	29520212	According to the free radical hypothesis of aging, ROS and RNS can drive the accumulation of cell and DNA damage leading to carcinogenesis and cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('ROS', 'Var', (51, 54))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('RNS', 'Chemical', 'MESH:D026361', (59, 62))	('aging', 'biological_process', 'GO:0007568', ('44', '49'))	('carcinogenesis', 'Disease', (124, 138))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
463	29520212	Another important finding of the current study indicates a higher risk of MM among subjects with the NQO1 rs1800566 T allele.	('NQO1', 'Gene', (101, 105))	('rs1800566 T', 'Var', (106, 117))	('NQO1', 'Gene', '1728', (101, 105))	('NQO1', 'molecular_function', 'GO:0003955', ('101', '105'))	('rs1800566', 'Mutation', 'rs1800566', (106, 115))
464	29520212	According to the available literature, the association between NQO1 polymorphisms and MM has not been investigated yet.	('NQO1', 'Gene', '1728', (63, 67))	('NQO1', 'molecular_function', 'GO:0003955', ('63', '67'))	('polymorphisms', 'Var', (68, 81))	('NQO1', 'Gene', (63, 67))
465	29520212	However, some studies have found an increased risk of lung cancer, colorectal cancer and bladder cancer among the carriers of the polymorphic allele.	('polymorphic allele', 'Var', (130, 148))	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
469	29520212	Even though there was no association between CAT rs1001179 or hOGG1 rs1052133 alone and MM, one of the key findings of this study was that the interactions between CAT rs1001179 and hOGG1 rs1052133 have a protective effect on the risk of MM.	('rs1001179', 'Mutation', 'rs1001179', (168, 177))	('interactions', 'Interaction', (143, 155))	('hOGG1', 'Gene', '4968', (182, 187))	('hOGG1', 'Gene', '4968', (62, 67))	('rs1001179', 'Mutation', 'rs1001179', (49, 58))	('CAT', 'Gene', '847', (164, 167))	('rs1052133', 'Mutation', 'rs1052133', (68, 77))	('CAT', 'Gene', (164, 167))	('CAT', 'molecular_function', 'GO:0004096', ('45', '48'))	('hOGG1', 'Gene', (182, 187))	('CAT', 'Gene', '847', (45, 48))	('CAT', 'Gene', (45, 48))	('CAT', 'molecular_function', 'GO:0004096', ('164', '167'))	('hOGG1', 'Gene', (62, 67))	('rs1052133', 'Mutation', 'rs1052133', (188, 197))	('rs1052133', 'Var', (188, 197))
472	29520212	We have also previously reported slightly increased risk of asbestosis among the carriers of the CAT rs1001179 TT genotype.	('CAT', 'Gene', (97, 100))	('rs1001179', 'Mutation', 'rs1001179', (101, 110))	('asbestosis', 'Disease', 'MESH:D001195', (60, 70))	('asbestosis', 'Disease', (60, 70))	('rs1001179 TT', 'Var', (101, 113))	('CAT', 'molecular_function', 'GO:0004096', ('97', '100'))	('CAT', 'Gene', '847', (97, 100))
473	29520212	have observed an association between hOGG1 Ser326Cys polymorphism and higher DNA damage levels in healthy young population.	('hOGG1', 'Gene', (37, 42))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('higher DNA damage levels', 'MPA', (70, 94))	('Ser326Cys', 'Var', (43, 52))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('Ser326Cys', 'SUBSTITUTION', 'None', (43, 52))	('hOGG1', 'Gene', '4968', (37, 42))
481	29520212	In conclusion, our study showed for the first time that NQO1 polymorphism influences the risk of MM both independently and after adjustment by smoking.	('influences', 'Reg', (74, 84))	('NQO1', 'Gene', (56, 60))	('NQO1', 'Gene', '1728', (56, 60))	('polymorphism', 'Var', (61, 73))	('NQO1', 'molecular_function', 'GO:0003955', ('56', '60'))
482	29520212	Another key observation is the protective effect of the interaction between CAT rs1001179 and hOGG1 rs1052133 polymorphisms, indicating the importance of interaction between antioxidative and DNA repair mechanisms.	('CAT', 'Gene', (76, 79))	('CAT', 'Gene', '847', (76, 79))	('rs1052133', 'Mutation', 'rs1052133', (100, 109))	('rs1052133', 'Var', (100, 109))	('rs1001179', 'Mutation', 'rs1001179', (80, 89))	('hOGG1', 'Gene', '4968', (94, 99))	('interaction', 'Interaction', (56, 67))	('CAT', 'molecular_function', 'GO:0004096', ('76', '79'))	('rs1001179', 'Var', (80, 89))	('DNA repair', 'biological_process', 'GO:0006281', ('192', '202'))	('hOGG1', 'Gene', (94, 99))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))
484	28062663	A population-based analysis of germline BAP1 mutations in melanoma Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma.	('basal cell carcinoma', 'Disease', (217, 237))	('meningioma', 'Disease', 'MESH:D008577', (180, 190))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('BRCA1 associated protein-1', 'Gene', '8314', (92, 118))	('linked to', 'Reg', (140, 149))	('BAP1', 'Gene', (40, 44))	('BAP1', 'Gene', (120, 124))	('renal cell carcinoma', 'Disease', (192, 212))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (217, 237))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('meningioma', 'Disease', (180, 190))	('mesothelioma', 'Disease', (166, 178))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('meningioma', 'Phenotype', 'HP:0002858', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('BRCA1 associated protein-1', 'Gene', (92, 118))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (217, 237))	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', '8314', (40, 44))	('BAP1', 'Gene', '8314', (120, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))	('melanoma', 'Disease', (58, 66))
487	28062663	A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified.	('S98R', 'Mutation', 'rs371168635', (19, 23))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('66', '89'))	('S98R', 'Var', (19, 23))	('abolished', 'NegReg', (51, 60))	('BAP1 deubiquitinase', 'Enzyme', (61, 80))	('activity', 'MPA', (81, 89))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('66', '89'))
488	28062663	Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('uveal melanoma', 'Disease', (258, 272))	('BAP1-associated', 'Gene', (167, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (258, 272))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Disease', (183, 190))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 219))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('S98R', 'Var', (64, 68))	('meningioma', 'Disease', (238, 248))	('meningioma', 'Phenotype', 'HP:0002858', (238, 248))	('mesothelioma', 'Disease', (221, 233))	('renal cell carcinoma', 'Disease', (199, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('S98R', 'Mutation', 'rs371168635', (64, 68))	('cancers', 'Disease', (12, 19))	('meningioma', 'Disease', 'MESH:D008577', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (258, 272))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))
489	28062663	Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation.	('melanomas', 'Disease', (77, 86))	('BAP1', 'Gene', (144, 148))	('variants', 'Var', (59, 67))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('loss-of-function', 'NegReg', (42, 58))	('BAP1', 'Gene', (37, 41))	('mutation', 'Var', (149, 157))
490	28062663	The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants.	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('missense mutations', 'Var', (70, 88))	('germline mutations', 'Var', (25, 43))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
493	28062663	Additionally, studies in melanoma-prone families have found inactivating variants in CDKN2A and CDK4, and more recently, activating variants in the promoter of TERT.	('TERT', 'Gene', '7015', (160, 164))	('CDKN2A', 'Gene', (85, 91))	('CDK4', 'Gene', (96, 100))	('CDKN2A', 'Gene', '1029', (85, 91))	('variants', 'Var', (132, 140))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('TERT', 'Gene', (160, 164))	('melanoma', 'Disease', (25, 33))	('CDK4', 'Gene', '1019', (96, 100))
494	28062663	Loss-of-function variants in the protection of telomeres 1 (POT1) gene, and other members of the shelterin complex, have also been found.	('Loss-of-function', 'NegReg', (0, 16))	('variants', 'Var', (17, 25))	('POT1', 'Gene', '25913', (60, 64))	('POT1', 'Gene', (60, 64))	('shelterin complex', 'cellular_component', 'GO:0070187', ('97', '114'))
495	28062663	Collectively, these findings indicate that strong and weakly penetrant variants influencing the same genes or biological pathways may contribute to disease development in familial and sporadic melanoma, respectively.	('variants', 'Var', (71, 79))	('familial', 'Disease', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('contribute', 'Reg', (134, 144))	('sporadic melanoma', 'Disease', (184, 201))	('biological pathways', 'Pathway', (110, 129))	('sporadic melanoma', 'Disease', 'MESH:D008545', (184, 201))	('weakly penetrant variants', 'Var', (54, 79))
499	28062663	Subsequently, it was recognised that germline BAP1 mutations are associated with a risk of disparate cancers such as lung cancer, meningioma, mesothelioma, and renal cell carcinoma, with a recent pan-cancer analysis revealing that BAP1 is significantly enriched for somatic truncating mutations across a range of tumour types.	('mutations', 'Var', (51, 60))	('meningioma', 'Disease', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (117, 128))	('meningioma', 'Phenotype', 'HP:0002858', (130, 140))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 180))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('associated with', 'Reg', (65, 80))	('BAP1', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('meningioma', 'Disease', 'MESH:D008577', (130, 140))	('tumour', 'Disease', 'MESH:D009369', (313, 319))	('tumour', 'Disease', (313, 319))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('renal cell carcinoma', 'Disease', (160, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('mesothelioma', 'Disease', (142, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('germline', 'Var', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (200, 206))
500	28062663	Intriguingly, while germline loss of Bap1 in the mouse results in embryonic lethality, somatic loss has been associated with the development of a myelodysplastic syndrome, a disease not normally associated with loss of BAP1 in humans.	('associated', 'Reg', (109, 119))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (146, 170))	('mouse', 'Species', '10090', (49, 54))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('loss', 'Var', (29, 33))	('myelodysplastic syndrome', 'Disease', (146, 170))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (146, 170))	('humans', 'Species', '9606', (227, 233))	('Bap1', 'Gene', '104416', (37, 41))	('loss', 'NegReg', (95, 99))	('Bap1', 'Gene', (37, 41))
501	28062663	Thus, mutation of BAP1, either somatically or in the germline, is associated with a range of cancers, and the biological effects of BAP1 loss are likely to manifest through a range of downstream pathways.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('mutation', 'Var', (6, 14))	('associated', 'Reg', (66, 76))	('BAP1', 'Gene', (132, 136))	('BAP1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'NegReg', (137, 141))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
502	28062663	Wiesner et al first reported a characteristic clinical and histopathological appearance of melanocytic lesions in two families with inherited BAP1 mutations, and showed somatic loss of the wildtype allele in these tumours.	('mutations', 'Var', (147, 156))	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('melanocytic lesions', 'Disease', 'MESH:D009508', (91, 110))	('melanocytic lesions', 'Disease', (91, 110))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('tumours', 'Disease', (214, 221))	('loss', 'NegReg', (177, 181))	('BAP1', 'Gene', (142, 146))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))
503	28062663	The mutation carriers in that study developed multiple, pink melanocytic lesions from the second decade, which had an innocuous clinical appearance but were quite remarkable at a histopathological level.	('melanocytic lesions', 'Disease', 'MESH:D009508', (61, 80))	('mutation', 'Var', (4, 12))	('melanocytic lesions', 'Disease', (61, 80))
506	28062663	One report however, described cytological findings typical of melanocytic lesions from germline BAP1 mutation carriers, including the presence of both epithelioid and naevoid-like cells except that there was no sparing of the dermo-epidermal junction.	('BAP1', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('melanocytic lesions', 'Disease', 'MESH:D009508', (62, 81))	('melanocytic lesions', 'Disease', (62, 81))
508	28062663	Notably, similar histological appearances have been recorded for tumours with either somatic or germline BAP1 mutations.	('mutations', 'Var', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('BAP1', 'Gene', (105, 109))	('tumours', 'Disease', (65, 72))
509	28062663	Here we report germline mutations of the BAP1 gene in a sample of 1977 melanoma patients and 754 controls ascertained from the UK population as part of the Leeds Melanoma Case-Control Study.	('patients', 'Species', '9606', (80, 88))	('BAP1', 'Gene', (41, 45))	('Melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('Melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('Melanoma', 'Disease', (162, 170))	('germline mutations', 'Var', (15, 33))
510	28062663	We also performed an evaluation of cancer incidence in BAP1 variant carriers and their families, and estimated the degree to which the histopathological features of primary tumours predict germline BAP1 variant status.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BAP1', 'Gene', (55, 59))	('primary tumours', 'Disease', 'MESH:D009369', (165, 180))	('variant', 'Var', (60, 67))	('primary tumours', 'Disease', (165, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
513	28062663	Nine of the variants present in cases were predicted to be deleterious by either the SIFT or PolyPhen-2 algorithms (Table 1).	('SIFT', 'Disease', 'None', (85, 89))	('SIFT', 'Disease', (85, 89))	('variants', 'Var', (12, 20))
514	28062663	To do this, we generated cDNA constructs in a pcDNA3.1 expression vector, each carrying a different BAP1 missense or frameshift variant and transfected these into BAP1-null H226 cells (Supplementary Material, Fig.	('H226', 'CellLine', 'CVCL:J621', (173, 177))	('missense', 'Var', (105, 113))	('BAP1', 'Gene', (100, 104))	('frameshift', 'Var', (117, 127))
515	28062663	All protein-changing variants in both cases and controls were tested with the exception of R728H found in a control, the missense alleles E406A, T613M and T613A, and the splice acceptor variant Chr3: 52442623 C/T (in intron 3-4), which were found in cases and identified in a second round of sequencing (Table 1, Fig.	('R728H', 'Var', (91, 96))	('T613A', 'Mutation', 'rs749728488', (155, 160))	('T613M', 'Var', (145, 150))	('E406A', 'Mutation', 'rs535695655', (138, 143))	('T613M', 'Mutation', 'rs35448940', (145, 150))	('T613A', 'Var', (155, 160))	('E406A', 'Var', (138, 143))	('52442623 C/T', 'Mutation', 'g.52442623C>T', (200, 212))	('R728H', 'Mutation', 'rs773230722', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
516	28062663	A truncating frameshift mutant that disrupts BAP1 at codon 618 (Chr3: 52437191 -/A, P618fs) produced two bands inconsistent with the expected size shift seen with the WT BAP1 cDNA construct.	('P618fs', 'Var', (84, 90))	('disrupts', 'NegReg', (36, 44))	('P618fs', 'Mutation', 'p.P618fsX', (84, 90))	('BAP1', 'Gene', (45, 49))
519	28062663	In addition to the frameshift mutation, we also identified a missense variant (S98R) falling into the UCH domain that completely abolished deubiquitinase activity (Figs 1 and 2).	('S98R', 'Var', (79, 83))	('deubiquitinase activity', 'MPA', (139, 162))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('139', '162'))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('139', '162'))	('S98R', 'Mutation', 'rs371168635', (79, 83))	('falling', 'Phenotype', 'HP:0002527', (85, 92))	('abolished', 'NegReg', (129, 138))
522	28062663	Group 1 alleles were found in 3/1,977 cases (and 0/754 controls); these three definite loss-of-function variants were S98R, a frameshift and a splice acceptor variant (Fig.	('frameshift', 'Var', (126, 136))	('S98R', 'Mutation', 'rs371168635', (118, 122))	('loss-of-function', 'NegReg', (87, 103))	('S98R', 'Var', (118, 122))
523	28062663	This study therefore suggests that complete loss-of-function germline BAP1 mutations underlie susceptibility to cutaneous melanoma in ~0.2% of the population-ascertained melanoma cases in the UK.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BAP1', 'Gene', (70, 74))	('cutaneous melanoma', 'Disease', (112, 130))	('mutations', 'Var', (75, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('loss-of-function', 'NegReg', (44, 60))
524	28062663	Even when variants defined by SIFT and PolyPhen-2 as possibly damaging or deleterious are also considered (n = 9, discussed below) the overall frequency of BAP1 mutations remains low (<1%) (Table 1).	('BAP1', 'Gene', (156, 160))	('SIFT', 'Disease', (30, 34))	('mutations', 'Var', (161, 170))	('SIFT', 'Disease', 'None', (30, 34))
525	28062663	Previous reports have defined a spectrum of malignancies associated with loss-of-function germline variants of BAP1.	('malignancies', 'Disease', (44, 56))	('variants', 'Var', (99, 107))	('loss-of-function', 'NegReg', (73, 89))	('BAP1', 'Gene', (111, 115))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))
531	28062663	Thus, all three of the probands had pedigrees consistent with the described germline cancer predisposition syndrome associated with loss-of-function BAP1 alleles.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('BAP1', 'Gene', (149, 153))	('loss-of-function', 'NegReg', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('alleles', 'Var', (154, 161))
532	28062663	In addition to the three families with clear loss-of-function BAP1 mutations described, there were six families with BAP1 variants that were predicted to be deleterious by SIFT/PolyPhen-2 (Group 2 [pedigrees 4-9], Table 1).	('SIFT', 'Disease', 'None', (172, 176))	('SIFT', 'Disease', (172, 176))	('BAP1', 'Gene', (117, 121))	('variants', 'Var', (122, 130))
533	28062663	3D), carrying the R150C variant, had a history of melanoma, BCC and lymphoma and had first-degree relatives, each with a history of one of the following cancers: BCC, leukaemia and uterine cancer.	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('lymphoma', 'Disease', (68, 76))	('R150C', 'Mutation', 'rs548946316', (18, 23))	('lymphoma', 'Disease', 'MESH:D008223', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('leukaemia', 'Disease', (167, 176))	('uterine cancer', 'Phenotype', 'HP:0010784', (181, 195))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Disease', (189, 195))	('R150C', 'Var', (18, 23))	('BCC', 'Disease', (60, 63))	('leukaemia', 'Disease', 'MESH:D007938', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (50, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('BCC', 'Disease', (162, 165))
534	28062663	3E), in which the proband carried an R548H missense mutation, there was a case of stomach cancer in a first-degree relative and of uterine cancer in a second-degree relative.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('uterine cancer', 'Phenotype', 'HP:0010784', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('R548H missense', 'Var', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('R548H', 'Mutation', 'rs779877855', (37, 42))	('stomach cancer', 'Disease', 'MESH:D013274', (82, 96))	('stomach cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('stomach cancer', 'Disease', (82, 96))	('cancer', 'Disease', (139, 145))
537	28062663	Of the remaining three individuals with predicted hazardous BAP1 mutations, each carrying either A130V, S292C or Y418C missense mutations, there was limited information available for family history and thus their pedigrees are not shown.	('A130V', 'Var', (97, 102))	('Y418C missense mutations', 'Var', (113, 137))	('S292C', 'Var', (104, 109))	('Y418C', 'Mutation', 'rs773947541', (113, 118))	('A130V', 'Mutation', 'rs1211721310', (97, 102))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))	('S292C', 'Mutation', 'p.S292C', (104, 109))
540	28062663	3) had features reported in the literature as being suggestive of the atypical melanocytic tumours of germline BAP1 mutation carriers (Fig.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('melanocytic tumours', 'Disease', 'MESH:D009508', (79, 98))	('mutation', 'Var', (116, 124))	('melanocytic tumours', 'Disease', (79, 98))	('germline', 'Gene', (102, 110))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
541	28062663	Here, we discuss in detail the melanocytic lesions identified in the three probands carrying confirmed loss-of-function variants (Fig.	('melanocytic lesions', 'Disease', 'MESH:D009508', (31, 50))	('loss-of-function', 'NegReg', (103, 119))	('variants', 'Var', (120, 128))	('melanocytic lesions', 'Disease', (31, 50))
543	28062663	This melanoma had a Breslow thickness of 1.5mm, without evidence of ulceration, and it resembled the reported features of melanocytic lesions found in BAP1 mutation carriers, being distinctly dermal in silhouette and composed of pleomorphic, epithelioid melanocytes.	('BAP1', 'Gene', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('melanocytic lesions', 'Disease', (122, 141))	('melanocytic lesions', 'Disease', 'MESH:D009508', (122, 141))	('mutation', 'Var', (156, 164))
547	28062663	Given that the majority of published melanoma cases in BAP1 families consist of epithelioid rather than spindled melanocytes, this histopathological appearance would be unlikely to alert a pathologist to the presence of a BAP1 mutation, not being remarkably different from melanomas seen among BAP1 wild-type individuals.	('melanomas', 'Disease', (273, 282))	('BAP1', 'Gene', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (273, 282))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('melanomas', 'Disease', 'MESH:D008545', (273, 282))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('mutation', 'Var', (227, 235))	('BAP1', 'Gene', (222, 226))
550	28062663	Such changes have previously been reported in a range of melanocytic lesions and are not known to be unique to BAP1 mutant tumours, although they have been reported to be prominent within melanocytic lesions from BAP1 syndrome families.	('BAP1 syndrome', 'Disease', 'MESH:D013577', (213, 226))	('reported', 'Reg', (34, 42))	('melanocytic lesions', 'Disease', 'MESH:D009508', (57, 76))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('melanocytic lesions', 'Disease', (57, 76))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('melanocytic lesions', 'Disease', 'MESH:D009508', (188, 207))	('melanocytic lesions', 'Disease', (188, 207))	('BAP1', 'Gene', (111, 115))	('tumours', 'Disease', (123, 130))	('mutant', 'Var', (116, 122))	('BAP1 syndrome', 'Disease', (213, 226))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
551	28062663	In summary, two of these three probands had a melanoma that demonstrated some features of a pathogenic germline BAP1 mutation and were most prominent in the proband in family 1.	('BAP1', 'Gene', (112, 116))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('mutation', 'Var', (117, 125))
553	28062663	The median age at diagnosis of melanoma was 57 years in cases carrying no variant or a benign variant in BAP1, compared to 49 years in cases within the 'predicted deleterious' group (Table 1).	('variant', 'Var', (94, 101))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('BAP1', 'Gene', (105, 109))
554	28062663	There were very few cases of mesothelioma or meningioma within the cohort, so these data are based upon small numbers, but statistical analysis revealed that cases were more likely to carry a deleterious BAP1 variant compared to no variant if there was a history of meningioma or mesothelioma in the proband or their pedigree (Table 2; P = 0.02, OR = 58.3 (95% CI 1.1-670.5) and P = 3 x 10-6, OR = 233 (95% CI 26.7-1660.1), respectively).	('mesothelioma or meningioma', 'Disease', (29, 55))	('meningioma or mesothelioma', 'Disease', 'MESH:D008654', (266, 292))	('variant', 'Var', (209, 216))	('mesothelioma or meningioma', 'Disease', 'MESH:D008654', (29, 55))	('meningioma', 'Phenotype', 'HP:0002858', (266, 276))	('meningioma or mesothelioma', 'Disease', (266, 292))	('meningioma', 'Phenotype', 'HP:0002858', (45, 55))	('BAP1', 'Gene', (204, 208))
555	28062663	It was notable that no cases with a predicted deleterious variant had a personal or family history of ocular melanoma.	('ocular melanoma', 'Phenotype', 'HP:0007716', (102, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('variant', 'Var', (58, 65))	('ocular melanoma', 'Disease', (102, 117))	('ocular melanoma', 'Disease', 'MESH:D008545', (102, 117))
556	28062663	Interestingly, cases with the 'BAP-like phenotype (in the family)' were more likely to carry a predicted deleterious variant compared to none (Table 2; P = 0.006, OR 8.2 (95% CI 1.6-38.4)).	('variant', 'Var', (117, 124))	("'BAP-like", 'Disease', (30, 39))	('BAP', 'Chemical', '-', (31, 34))
558	28062663	The presence of suggestive histological features ('BAP-like histology present (in the proband's melanoma)'), however, was not significantly predictive of a predicted deleterious BAP1 variant compared to no variant (Table 2; P = 0.1).	('variant', 'Var', (183, 190))	('BAP', 'Chemical', '-', (51, 54))	('BAP1', 'Gene', (178, 182))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('BAP', 'Chemical', '-', (178, 181))
560	28062663	Whilst two out of three of probands with a loss-of-function BAP1 variant had BAP-like histology in the proband's melanoma, none of the remaining six cases classified as 'predicted deleterious' had such features (not shown).	('BAP-like histology', 'MPA', (77, 95))	('loss-of-function', 'NegReg', (43, 59))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('BAP', 'Chemical', '-', (77, 80))	('variant', 'Var', (65, 72))	('BAP', 'Chemical', '-', (60, 63))	('BAP1', 'Gene', (60, 64))
561	28062663	It is possible that some variants that were not identified as loss-of-function alleles by functional testing (deubiquitinase assays), may still impair BAP1 function and predispose to cancer types associated with the BAP1 syndrome phenotype.	('impair', 'NegReg', (144, 150))	('variants', 'Var', (25, 33))	('cancer', 'Disease', (183, 189))	('BAP1 syndrome', 'Disease', 'MESH:D013577', (216, 229))	('BAP1', 'Gene', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('110', '124'))	('function', 'MPA', (156, 164))	('BAP1 syndrome', 'Disease', (216, 229))	('predispose to', 'Reg', (169, 182))
562	28062663	Germline mutations in BAP1 are rare, being present in <1% of the population-ascertained melanoma cases in the UK.	('Germline mutations', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('BAP1', 'Gene', (22, 26))
563	28062663	It has been noted that high-penetrance variants found in melanoma-prone families can also contribute to sporadic disease, for example, germline mutations of CDKN2A have been identified in around 2% of cases in European and Australian cohorts.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('CDKN2A', 'Gene', (157, 163))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('sporadic disease', 'Disease', 'MESH:D004421', (104, 120))	('sporadic disease', 'Disease', (104, 120))	('CDKN2A', 'Gene', '1029', (157, 163))	('contribute', 'Reg', (90, 100))	('identified', 'Reg', (174, 184))	('variants', 'Var', (39, 47))
564	28062663	As such, we sought to determine the contribution of BAP1 variants to sporadic melanoma, and here we present the most comprehensive such analysis to-date.	('sporadic melanoma', 'Disease', (69, 86))	('BAP1', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('sporadic melanoma', 'Disease', 'MESH:D008545', (69, 86))	('variants', 'Var', (57, 65))
565	28062663	We sequenced 1,977 melanoma cases and 754 controls, identifying a total of 30 BAP1 variants.	('variants', 'Var', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('BAP1', 'Gene', (78, 82))
567	28062663	The close relatives of the 9 probands carrying these predicted deleterious variants were an estimated 8 times more likely to report a cancer previously associated with BAP1 germline variants than among probands without a BAP1 variant allele (Table 2); however, most of this increase is due to the 3 families with loss-of-function mutations who all reported a family history of BAP1-associated cancers (mesothelioma, renal cancer).	('loss-of-function', 'NegReg', (313, 329))	('cancer', 'Disease', (422, 428))	('cancer', 'Disease', 'MESH:D009369', (393, 399))	('variants', 'Var', (75, 83))	('cancers', 'Disease', 'MESH:D009369', (393, 400))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('renal cancer', 'Phenotype', 'HP:0009726', (416, 428))	('cancer', 'Disease', (134, 140))	('BAP1', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('BAP1-associated', 'Gene', (377, 392))	('mesothelioma, renal cancer', 'Disease', 'MESH:D007680', (402, 428))	('cancers', 'Phenotype', 'HP:0002664', (393, 400))	('cancer', 'Disease', (393, 399))	('cancers', 'Disease', (393, 400))	('mutations', 'Var', (330, 339))	('variants', 'Var', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
569	28062663	Overall, less than ~0.2% of melanoma cases had identifiable loss-of-function BAP1 variants.	('variants', 'Var', (82, 90))	('melanoma', 'Disease', (28, 36))	('BAP1', 'Gene', (77, 81))	('loss-of-function', 'NegReg', (60, 76))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
570	28062663	3A-C), their family histories of cancer were suggestive of a deleterious BAP1 variant, although the reported cancers most strongly associated with the mutation were mesotheliomas, meningiomas and BCC rather than the uveal melanomas in which germline BAP1 mutations were first reported (Fig.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('meningiomas', 'Disease', 'MESH:D008577', (180, 191))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('BAP1', 'Gene', (73, 77))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('meningiomas', 'Phenotype', 'HP:0002858', (180, 191))	('meningiomas', 'Disease', (180, 191))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('uveal melanomas', 'Disease', 'MESH:C536494', (216, 231))	('mesotheliomas', 'Disease', (165, 178))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('associated', 'Reg', (131, 141))	('variant', 'Var', (78, 85))	('mutation', 'Var', (151, 159))	('BCC', 'Disease', (196, 199))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mesotheliomas', 'Disease', 'MESH:D008654', (165, 178))	('meningioma', 'Phenotype', 'HP:0002858', (180, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (216, 230))	('uveal melanomas', 'Disease', (216, 231))	('uveal melanomas', 'Phenotype', 'HP:0007716', (216, 231))
571	28062663	The remaining six probands with BAP1 variants predicted to be deleterious by SIFT or PolyPhen-2 had equivocal pedigrees.	('variants', 'Var', (37, 45))	('SIFT', 'Disease', 'None', (77, 81))	('SIFT', 'Disease', (77, 81))	('BAP1', 'Gene', (32, 36))
572	28062663	We examined the cancer history in BAP1 variant carrier cases, comparing groups with predicted deleterious variants, benign variants, and no variants.	('carrier', 'molecular_function', 'GO:0005215', ('47', '54'))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('BAP1', 'Gene', (34, 38))	('cancer', 'Disease', (16, 22))	('variant', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
573	28062663	The presence of a predicted deleterious variant was associated with several observations (Table 2): particularly a personal history of mesothelioma and a family history of BCC, meningioma, mesothelioma or cutaneous melanoma.	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('meningioma', 'Disease', (177, 187))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('meningioma', 'Phenotype', 'HP:0002858', (177, 187))	('mesothelioma', 'Disease', (189, 201))	('variant', 'Var', (40, 47))	('associated', 'Reg', (52, 62))	('cutaneous melanoma', 'Disease', (205, 223))	('meningioma', 'Disease', 'MESH:D008577', (177, 187))	('BCC', 'Disease', (172, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (205, 223))	('mesothelioma', 'Disease', (135, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (205, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('presence', 'Var', (4, 12))
574	28062663	The presence of a 'BAP-like phenotype' in the family history highlights the importance of taking the extended pedigree into account when assessing the risk of carrying a deleterious BAP1 variant.	('variant', 'Var', (187, 194))	('BAP1', 'Gene', (182, 186))	("'BAP-like", 'Disease', (18, 27))	('BAP', 'Chemical', '-', (19, 22))	('BAP', 'Chemical', '-', (182, 185))
575	28062663	1B) suggesting that weaker alleles, or variants that may influence BAP1 beyond its role as a deubiquitinase, may underlie some of the cancer incidence in mutation carriers.	('influence', 'Reg', (57, 66))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('underlie', 'Reg', (113, 121))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('93', '107'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('variants', 'Var', (39, 47))	('BAP1', 'Gene', (67, 71))
576	28062663	Also of note was the observation that none of the cases with predicted deleterious variants had a personal or family history of ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('variants', 'Var', (83, 91))	('ocular melanoma', 'Disease', (128, 143))	('ocular melanoma', 'Disease', 'MESH:D008545', (128, 143))	('ocular melanoma', 'Phenotype', 'HP:0007716', (128, 143))
577	28062663	Primary melanomas in 2/3 probands with clear loss of function mutations demonstrated some of the histopathological features described in melanocytic lesions associated with a BAP1 mutation (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('BAP1', 'Gene', (175, 179))	('Primary melanomas', 'Disease', (0, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('loss of function', 'NegReg', (45, 61))	('melanocytic lesions', 'Disease', (137, 156))	('Primary melanomas', 'Disease', 'MESH:D008545', (0, 17))	('melanocytic lesions', 'Disease', 'MESH:D009508', (137, 156))	('mutation', 'Var', (180, 188))	('mutations', 'Var', (62, 71))
579	28062663	None of the remaining six probands with BAP1 variants, predicted to be deleterious by SIFT or PolyPhen-2, had suggestive histology and importantly, similar histological changes were seen in a significant proportion of melanoma patients without a germline BAP1 mutation.	('SIFT', 'Disease', (86, 90))	('variants', 'Var', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('SIFT', 'Disease', 'None', (86, 90))	('BAP1', 'Gene', (40, 44))	('patients', 'Species', '9606', (227, 235))
580	28062663	Our study therefore suggests that in the absence of a family history of cancers such as mesothelioma, or meningioma, the presence of histological changes described in BAP1 mutated families is a poor predictor of a germline BAP1 mutation.	('mutation', 'Var', (228, 236))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('meningioma', 'Disease', (105, 115))	('meningioma', 'Phenotype', 'HP:0002858', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', (223, 227))	('meningioma', 'Disease', 'MESH:D008577', (105, 115))	('BAP1', 'Gene', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mesothelioma', 'Disease', (88, 100))	('mutated', 'Var', (172, 179))	('germline', 'Var', (214, 222))
581	28062663	The term 'BAPomas' is sometimes coined by pathologists to denote melanocytic lesions with consistent histology that occur within families with germline BAP1 mutations, which have either benign behaviour or are of uncertain malignant potential.	('BAP', 'Chemical', '-', (10, 13))	('BAP', 'Chemical', '-', (152, 155))	('mutations', 'Var', (157, 166))	('behaviour', 'biological_process', 'GO:0007610', ('193', '202'))	('BAP1', 'Gene', (152, 156))	('melanocytic lesions', 'Disease', 'MESH:D009508', (65, 84))	('melanocytic lesions', 'Disease', (65, 84))
582	28062663	We hope that this work presents a framework for considering the management of individuals found to carry germline BAP1 mutations in the context of sporadic melanoma.	('sporadic melanoma', 'Disease', (147, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('sporadic melanoma', 'Disease', 'MESH:D008545', (147, 164))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
585	28062663	We transfected pcDNA3.1 constructs containing BAP1 variants into H226 lung cancer cells and measured deubiquitinase activity using a HA-Ub-VME activity probe, as described previously.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('101', '124'))	('deubiquitinase activity', 'MPA', (101, 124))	('variants', 'Var', (51, 59))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('101', '124'))	('BAP1', 'Gene', (46, 50))	('H226', 'CellLine', 'CVCL:J621', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
594	28062663	We used the phenotypes of all BAP1 variant carrier cases to explore the influence of BAP1 alleles on cancer presentation.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('BAP1', 'Gene', (30, 34))	('cancer', 'Disease', (101, 107))	('carrier', 'molecular_function', 'GO:0005215', ('43', '50'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('variant', 'Var', (35, 42))
595	28062663	Cases carrying confirmed loss-of-function alleles were classified into group 1 (n = 3) and those carrying variants predicted to be hazardous by SIFT and/or PolyPhen-2 were classified as group 2 (n = 6).	('SIFT', 'Disease', (144, 148))	('alleles', 'Var', (42, 49))	('SIFT', 'Disease', 'None', (144, 148))	('loss-of-function', 'NegReg', (25, 41))
596	28062663	Cases carrying variants predicted to be benign by SIFT and PolyPhen-2 (n = 14, as one case carries variants at both 3:52440269 and 3:52437206) were classified as group 3 and those carrying variants of uncertain significance (n = 86, as one case carries variants at both 3:52436441 and 3:52437424) were classified as group 4.	('3:52437424', 'Var', (285, 295))	('3:52437206', 'Var', (131, 141))	('variants', 'Var', (99, 107))	('3:52436441', 'Var', (270, 280))	('SIFT', 'Disease', (50, 54))	('3:52440269', 'Var', (116, 126))	('SIFT', 'Disease', 'None', (50, 54))
597	28062663	The rest of the melanoma patient cohort who did not carry a variant were grouped together and defined as 'None' (n = 1,868).	('variant', 'Var', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('patient', 'Species', '9606', (25, 32))
606	28062663	The Fisher's exact test was used to assess the association between the reported history of cancer and BAP1 variant categories (Tables 1 and 2, Supplementary Material, Fig.	('BAP1', 'Gene', (102, 106))	('variant', 'Var', (107, 114))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
628	26805818	MV6401 (pyropheophorbide derivative), a second generation PS, has been shown to cause a biphasic response in the vasculature, which includes constriction of the vessels followed by necrosis, thereby delaying tumour growth and proliferation.	('necrosis', 'Disease', (181, 189))	('MV6401', 'Var', (0, 6))	('biphasic response', 'MPA', (88, 105))	('MV6401', 'Chemical', 'MESH:C453421', (0, 6))	('tumour growth', 'Disease', 'MESH:D006130', (208, 221))	('constriction', 'cellular_component', 'GO:0005702', ('141', '153'))	('delaying', 'NegReg', (199, 207))	('necrosis', 'Disease', 'MESH:D009336', (181, 189))	('necrosis', 'biological_process', 'GO:0070265', ('181', '189'))	('necrosis', 'biological_process', 'GO:0008219', ('181', '189'))	('constriction', 'CPA', (141, 153))	('necrosis', 'biological_process', 'GO:0019835', ('181', '189'))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('necrosis', 'biological_process', 'GO:0008220', ('181', '189'))	('tumour growth', 'Disease', (208, 221))	('pyropheophorbide', 'Chemical', '-', (8, 24))	('necrosis', 'biological_process', 'GO:0001906', ('181', '189'))	('cause', 'Reg', (80, 85))
672	26805818	Although reporting of symptom control and quality of life was poor, PDT appeared to significantly reduce hemoptysis, dyspnea and coughing as compared to baseline.	('cough', 'Phenotype', 'HP:0012735', (129, 134))	('hemoptysis', 'Phenotype', 'HP:0002105', (105, 115))	('PDT', 'Var', (68, 71))	('coughing', 'Phenotype', 'HP:0012735', (129, 137))	('dyspnea', 'Disease', 'MESH:D004417', (117, 124))	('hemoptysis', 'Disease', (105, 115))	('reduce', 'NegReg', (98, 104))	('cough', 'Disease', (129, 134))	('dyspnea', 'Phenotype', 'HP:0002094', (117, 124))	('hemoptysis', 'Disease', 'MESH:D006469', (105, 115))	('dyspnea', 'Disease', (117, 124))	('cough', 'Disease', 'MESH:D003371', (129, 134))
712	26805818	Thymoma patients treated with PDT also experienced better local control of disease than their non-PDT counterparts.	('local control of disease', 'CPA', (58, 82))	('PDT', 'Var', (30, 33))	('Thymoma', 'Phenotype', 'HP:0100522', (0, 7))	('Thymoma', 'Disease', (0, 7))	('Thymoma', 'Disease', 'MESH:D013945', (0, 7))	('patients', 'Species', '9606', (8, 16))
807	23211021	We observed that the serum starvation-induced activation of p53 is ATM-dependent because it was inhibited by Ku-55933, a specific inhibitor of ATM  (Figure  2A).	('activation', 'PosReg', (46, 56))	('ATM', 'Gene', '472', (67, 70))	('Ku-55933', 'Chemical', 'MESH:C495818', (109, 117))	('Ku-55933', 'Var', (109, 117))	('p53', 'Gene', (60, 63))	('inhibited', 'NegReg', (96, 105))	('ATM', 'Gene', (143, 146))	('p53', 'Gene', '7157', (60, 63))	('ATM', 'Gene', '472', (143, 146))	('ATM', 'Gene', (67, 70))
822	23211021	While serum starvation strongly inhibited the phosphorylating of S6, ATM inhibitor Ku55933 and AMPK inhibitor Compound C did not show any effect on the S6 phosphorylation (Figure  2G), suggesting that ATM inhibitor (Ku55933) and AMPK inhibitor (Compound C) were quite target-specific and do not interfere activity of mTOR signaling.	('AMPK', 'molecular_function', 'GO:0050405', ('95', '99'))	('Ku55933', 'Chemical', 'MESH:C495818', (216, 223))	('AMPK', 'molecular_function', 'GO:0004691', ('229', '233'))	('signaling', 'biological_process', 'GO:0023052', ('322', '331'))	('ATM', 'Gene', '472', (69, 72))	('Ku55933', 'Var', (216, 223))	('AMPK', 'molecular_function', 'GO:0047322', ('229', '233'))	('AMPK', 'molecular_function', 'GO:0004691', ('95', '99'))	('phosphorylating', 'MPA', (46, 61))	('AMPK', 'Gene', '5563', (229, 233))	('mTOR', 'Gene', (317, 321))	('AMPK', 'Gene', '5563', (95, 99))	('ATM', 'Gene', '472', (201, 204))	('AMPK', 'molecular_function', 'GO:0047322', ('95', '99'))	('ATM', 'Gene', (69, 72))	('AMPK', 'molecular_function', 'GO:0050405', ('229', '233'))	('AMPK', 'Gene', (229, 233))	('mTOR', 'Gene', '2475', (317, 321))	('phosphorylation', 'biological_process', 'GO:0016310', ('155', '170'))	('inhibited', 'NegReg', (32, 41))	('AMPK', 'Gene', (95, 99))	('Ku55933', 'Chemical', 'MESH:C495818', (83, 90))	('ATM', 'Gene', (201, 204))
861	23211021	One of the potential reasons for ATM/Chk2/p53 activation by serum starvation may be due to a temporary loss of coordination between the cell proliferation driven by oncogenic mutations and the paracrine growth factors-stimulated cell growth, thus resulting in cellular stress.	('p53', 'Gene', (42, 45))	('Chk2', 'Gene', '11200', (37, 41))	('p53', 'Gene', '7157', (42, 45))	('Chk2', 'Gene', (37, 41))	('activation', 'PosReg', (46, 56))	('cellular stress', 'MPA', (260, 275))	('ATM', 'Gene', (33, 36))	('ATM', 'Gene', '472', (33, 36))	('mutations', 'Var', (175, 184))	('coordination', 'MPA', (111, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('cell proliferation', 'CPA', (136, 154))	('cell growth', 'biological_process', 'GO:0016049', ('229', '240'))	('loss', 'NegReg', (103, 107))
868	23211021	Although Ser15 phosphorylation generally stabilizes the p53 protein, Ser15-phosphorylation-unrelated p53 stabilization has also been reported and potential mechanisms include acetylation and methylation.	('Ser', 'cellular_component', 'GO:0005790', ('9', '12'))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('p53', 'Gene', (56, 59))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('Ser15', 'Chemical', '-', (69, 74))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('Ser15', 'Chemical', '-', (9, 14))	('Ser15', 'Var', (9, 14))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('methylation', 'biological_process', 'GO:0032259', ('191', '202'))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))
869	23211021	However, an acetylation-dependent mechanism was excluded because of the absence of change of the Lys373 and Lys320 acetylation status of p53 under starvation condition (data not shown).	('Lys320', 'Chemical', '-', (108, 114))	('Lys373', 'Var', (97, 103))	('Lys320', 'Var', (108, 114))	('Lys373', 'Chemical', '-', (97, 103))	('p53', 'Gene', (137, 140))	('p53', 'Gene', '7157', (137, 140))
896	23211021	Ku55933 and Compound C (Merck) were used at concentrations of 5 muM and 20 muM, respectively.	('muM', 'Gene', (64, 67))	('Ku55933', 'Chemical', 'MESH:C495818', (0, 7))	('Ku55933', 'Var', (0, 7))	('muM', 'Gene', '56925', (75, 78))	('muM', 'Gene', '56925', (64, 67))	('muM', 'Gene', (75, 78))
961	22666659	AG 2037 is a GARFT inhibitor being evaluated for its activity in NSCLC and colorectal cancer (Webber et al.,).	('colorectal cancer', 'Disease', (75, 92))	('GARFT', 'Gene', (13, 18))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('AG 2037', 'Var', (0, 7))	('GARFT', 'Gene', '2618', (13, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('NSCLC', 'Disease', (65, 70))
996	22666659	A possible explanation of absence of significant benefit from using EGFR-TKIs could be due to the absence of activating somatic mutation in EGFR-TKI domain that is strongly predictive of response to EGFR-TKIs (Cortese et al.,).	('EGFR', 'Gene', (140, 144))	('EGFR', 'Gene', (199, 203))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('EGFR', 'Gene', '1956', (68, 72))	('mutation', 'Var', (128, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('EGFR', 'Gene', '1956', (140, 144))	('EGFR', 'Gene', '1956', (199, 203))
1006	22666659	Mesothelial cell transfected with SV40 or only with SV40 Tag antigen releases great amount of VEGF proteins and mRNA that leads to cell line proliferation.	('VEGF', 'Gene', (94, 98))	('leads to', 'Reg', (122, 130))	('cell line proliferation', 'CPA', (131, 154))	('mRNA', 'MPA', (112, 116))	('VEGF', 'Gene', '7422', (94, 98))	('SV40', 'Var', (34, 38))
1007	22666659	The inactivation of VEGF signal transduction pathway abolished this proliferation.	('inactivation', 'Var', (4, 16))	('signal transduction', 'biological_process', 'GO:0007165', ('25', '44'))	('VEGF', 'Gene', '7422', (20, 24))	('abolished', 'NegReg', (53, 62))	('VEGF', 'Gene', (20, 24))
1048	22666659	In vitro and in vivo experiments demonstrated that STI-571 can cause MPM cell apoptosis and death through inhibition of the AKT/PI3K pathway and that it can also enhances MPM sensitivity to gemcitabine or pemetrexed (Bertino et al.,).	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('pemetrexed', 'Chemical', 'MESH:D000068437', (205, 215))	('MPM cell apoptosis', 'CPA', (69, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('AKT', 'Gene', '207', (124, 127))	('AKT', 'Gene', (124, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (190, 201))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('STI-571', 'Var', (51, 58))	('death', 'CPA', (92, 97))	('inhibition', 'NegReg', (106, 116))	('MPM sensitivity to gemcitabine', 'MPA', (171, 201))	('STI-571', 'Chemical', 'MESH:D000068877', (51, 58))	('enhances', 'PosReg', (162, 170))
1057	22666659	Therefore, both histone and non-histone protein-mediated effects of HDAC inhibitors are thought to be responsible for their anticancer effects (Deroanne et al.,).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('histone', 'MPA', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('non-histone protein-mediated', 'MPA', (28, 56))	('HDAC', 'Gene', (68, 72))	('HDAC', 'Gene', '9734', (68, 72))	('inhibitors', 'Var', (73, 83))	('cancer', 'Disease', (128, 134))
1073	22666659	High levels of VEGF and FGF2 or co-expression of TGFbeta, VEGF, FGF1, and FGF2 have been found to be associated with a poor outcome.	('FGF2', 'Gene', (74, 78))	('VEGF', 'Gene', (58, 62))	('FGF2', 'Gene', '2247', (24, 28))	('FGF1', 'Gene', '2246', (64, 68))	('TGFbeta', 'Gene', (49, 56))	('VEGF', 'Gene', (15, 19))	('FGF2', 'Gene', (24, 28))	('VEGF', 'Gene', '7422', (58, 62))	('FGF2', 'Gene', '2247', (74, 78))	('associated', 'Reg', (101, 111))	('FGF1', 'Gene', (64, 68))	('VEGF', 'Gene', '7422', (15, 19))	('TGFbeta', 'Gene', '7040', (49, 56))	('co-expression', 'Var', (32, 45))
1103	22666659	The results of this study showed that mice treated with low-dose radiation and SS1P or high-dose radiation and SS1P had a statistically significant prolongation in time to tumor doubling or tripling compared with control, SS1P or radiation alone treated mice.	('SS1P', 'Chemical', 'MESH:C474515', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('SS1P', 'Var', (111, 115))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('mice', 'Species', '10090', (254, 258))	('SS1P', 'Chemical', 'MESH:C474515', (222, 226))	('SS1P', 'Chemical', 'MESH:C474515', (79, 83))	('tripling', 'CPA', (190, 198))	('prolongation', 'PosReg', (148, 160))
1116	22666659	Laboratory studies show that MORAb-009 kills mesothelin expressing cell lines via antibody dependent cellular cytoxicity (ADCC) and in addition it inhibits the binding of mesothelin to CA-125.	('antibody', 'cellular_component', 'GO:0019814', ('82', '90'))	('ADCC', 'biological_process', 'GO:0001788', ('122', '126'))	('antibody', 'molecular_function', 'GO:0003823', ('82', '90'))	('toxicity', 'Disease', (112, 120))	('binding', 'molecular_function', 'GO:0005488', ('160', '167'))	('CA-125', 'Protein', (185, 191))	('MORAb-009', 'Chemical', 'MESH:C526187', (29, 38))	('antibody', 'cellular_component', 'GO:0042571', ('82', '90'))	('MORAb-009', 'Var', (29, 38))	('binding', 'Interaction', (160, 167))	('mesothelin', 'Protein', (171, 181))	('antibody', 'cellular_component', 'GO:0019815', ('82', '90'))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('inhibits', 'NegReg', (147, 155))
1121	22666659	The engineered vector CRS-100, has deletions of the two genes that encode the virulence determinants actA and internalin B (inlB), which results in a greater than 1000-fold decrease in virulence compared to the wild type Lm.	('decrease', 'NegReg', (173, 181))	('virulence', 'biological_process', 'GO:0016032', ('78', '87'))	('virulence', 'biological_process', 'GO:0009406', ('185', '194'))	('Lm', 'Species', '1639', (221, 223))	('virulence', 'biological_process', 'GO:0009405', ('78', '87'))	('virulence', 'biological_process', 'GO:0009405', ('185', '194'))	('deletions', 'Var', (35, 44))	('virulence', 'MPA', (185, 194))	('CRS', 'Chemical', 'MESH:D002857', (22, 25))	('virulence', 'biological_process', 'GO:0016032', ('185', '194'))	('virulence', 'biological_process', 'GO:0009406', ('78', '87'))
1169	22666659	A large retrospective uncontrolled series reports that P/D might prolong survival as compared to EPP and that a less invasive procedure might hence be preferable in selected patients, provided it is standardized (Flores et al.,).	('patients', 'Species', '9606', (174, 182))	('survival', 'MPA', (73, 81))	('prolong', 'PosReg', (65, 72))	('P/D', 'Var', (55, 58))
1277	30967648	New results from the Cancer Genome Atlas Research Project have identified genetic mutations that are common among 12 different types of cancer, including carcinomas, adenocarcinomas and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (186, 195))	('Cancer', 'Disease', (21, 27))	('cancer', 'Disease', (136, 142))	('melanomas', 'Disease', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('carcinomas', 'Disease', (171, 181))	('common', 'Reg', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('carcinomas', 'Disease', (154, 164))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Disease', 'MESH:D009369', (171, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('mutations', 'Var', (82, 91))	('adenocarcinomas', 'Disease', 'MESH:D000230', (166, 181))	('carcinomas', 'Disease', 'MESH:D009369', (154, 164))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('adenocarcinomas', 'Disease', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
1298	30967648	Usually this occurs by mutations in the CDKN2A gen.	('mutations', 'Var', (23, 32))	('occurs by', 'Reg', (13, 22))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))
1331	29774102	In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression.	('Ang', 'Gene', '11727', (26, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('angiogenesis', 'biological_process', 'GO:0001525', ('66', '78'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('disrupting', 'Var', (15, 25))	('limits', 'NegReg', (46, 52))	('halts', 'NegReg', (83, 88))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('Ang', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('mesothelioma', 'Disease', (53, 65))
1353	29774102	Overall, the Balbc-AB1 mesothelioma model is characterized by elevated host- and tumor-derived Ang-2, lower Ang-1 tumor content and increased vascularity and higher Tie-2 expression by endothelial cells compared to the C57BL-AE17 model.	('host- and', 'MPA', (71, 80))	('expression', 'MPA', (171, 181))	('lower', 'NegReg', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Ang-1', 'Gene', (108, 113))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Balbc-AB1', 'Var', (13, 22))	('higher', 'PosReg', (158, 164))	('tumor', 'Disease', (114, 119))	('vascularity', 'CPA', (142, 153))	('increased', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Tie-2', 'Protein', (165, 170))	('mesothelioma', 'Disease', (23, 35))	('elevated', 'PosReg', (62, 70))	('tumor', 'Disease', (81, 86))
1414	29774102	To investigate whether angiopoietins or the inhibitor, impact tumor cell growth, 3x103 tumor cells were seeded on 96-well plates and 24h later were treated with 300-1000 ng/ml Ang-1 or Ang-2 and 1-100 mug/ml Murine Tek-deltaFc or vehicle for 24h.	('Tek', 'Gene', '21687', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('impact tumor', 'Disease', 'MESH:D004834', (55, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('impact tumor', 'Disease', (55, 67))	('mug', 'molecular_function', 'GO:0043739', ('201', '204'))	('Tek', 'Gene', (215, 218))	('Ang-2', 'Var', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('Murine', 'Species', '10090', (208, 214))
1419	29774102	Four days upon tumor cell implantation, when pleural tumors are already evident animals were divided into two groups, receiving either Murine Tek-deltaFc or vehicle.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('pleural tumors', 'Disease', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('pleural tumors', 'Disease', 'MESH:D010997', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Tek', 'Gene', (142, 145))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Murine', 'Var', (135, 141))	('Tek', 'Gene', '21687', (142, 145))	('Murine', 'Species', '10090', (135, 141))
1435	29774102	Mesothelioma tumor tissue sections were stained for Ang-1 (ab8451) and -2 (ab153934) (Abcam, Cambridge, UK) and staining was evaluated by an experienced pathologist.	('Mesothelioma tumor', 'Disease', 'MESH:D008654', (0, 18))	('ab8451', 'Var', (59, 65))	('Mesothelioma tumor', 'Disease', (0, 18))	('ab153934', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('Mesothelioma tumor', 'Phenotype', 'HP:0100001', (0, 18))
1524	23411061	Overall, the suicide gene therapy was well-tolerated with minimal side effects and no dose-limiting toxicity.	('toxicity', 'Disease', 'MESH:D064420', (100, 108))	('toxicity', 'Disease', (100, 108))	('suicide gene therapy', 'Var', (13, 33))
1592	23103606	To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A.	('9571', 'Var', (330, 334))	('13473A', 'Var', (339, 345))	('MPM', 'Chemical', '-', (156, 159))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (134, 154))	('men', 'Species', '9606', (268, 271))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (161, 169))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (124, 154))	('malignant pleural mesothelioma', 'Disease', (124, 154))	('tumour', 'Disease', (104, 110))
1820	12569381	In human malignant mesothelioma, p53 is generally not mutated, but may be inactivated by SV40 early region T antigen (SV40 Tag).	('human', 'Species', '9606', (3, 8))	('malignant mesothelioma', 'Disease', (9, 31))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (9, 31))	('SV40', 'Var', (89, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (9, 31))	('inactivated', 'NegReg', (74, 85))
1822	12569381	Here, we investigated the function of the cell cycle checkpoints in six human mesothelioma cell lines (HMCLs) by studying the cell distribution in the different phases of the cell cycle by flow cytometry, and expression of cell cycle proteins, p53, p21WAF1/CIP1 and p27KIP1.	('cell cycle', 'biological_process', 'GO:0007049', ('223', '233'))	('cell cycle', 'biological_process', 'GO:0007049', ('42', '52'))	('p53', 'Gene', (244, 247))	('p53', 'Gene', '7157', (244, 247))	('p21WAF1/CIP1', 'Gene', (249, 261))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('human', 'Species', '9606', (72, 77))	('cell cycle', 'biological_process', 'GO:0007049', ('175', '185'))	('HMCLs', 'Chemical', '-', (103, 108))	('p21WAF1/CIP1', 'Gene', '1026', (249, 261))	('mesothelioma', 'Disease', (78, 90))	('p27KIP1', 'Var', (266, 273))
1826	12569381	Lack of arrest in G1 was not related to p53 mutation or binding to SV40 Tag, except in one HMCL presenting a missense mutation at codon 248.	('mutation', 'Var', (44, 52))	('p53', 'Gene', (40, 43))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('HM', 'CellLine', 'CVCL:M679', (91, 93))	('p53', 'Gene', '7157', (40, 43))
1836	12569381	This has been carried out following gene transfer, either by the overexpression of p53 (Giuliano et al, 2000), by the expression of regulators of p53 levels such as p14ARF (Yang et al, 2000) or by the expression of antisense transcripts to Tag (Waheed et al, 1999).	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('p14ARF', 'Gene', (165, 171))	('antisense', 'Var', (215, 224))	('overexpression', 'PosReg', (65, 79))	('p14ARF', 'Gene', '1029', (165, 171))
1872	12569381	The following antibodies were used: primary mouse monoclonal antibodies against human p21WAF1/CIP1, p27KIP1, p53 (D01) and SV40 Tag (Ab-1), all from Santa Cruz.	('mouse', 'Species', '10090', (44, 49))	('p21WAF1/CIP1', 'Gene', '1026', (86, 98))	('human', 'Species', '9606', (80, 85))	('p27KIP1', 'Var', (100, 107))	('p53', 'Gene', (109, 112))	('SV40 Tag', 'Var', (123, 131))	('p53', 'Gene', '7157', (109, 112))	('p21WAF1/CIP1', 'Gene', (86, 98))
1896	12569381	p27KIP1 protein expression was markedly lowered in a dose-dependent manner in the HMCLs that did not arrest in G1 (RV and BT) (data not shown).	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('lowered', 'NegReg', (40, 47))	('HMCLs', 'Chemical', '-', (82, 87))	('protein', 'Protein', (8, 15))	('p27KIP1', 'Var', (0, 7))
1900	12569381	In this study, we investigated cell cyle control in HMCLs exposed to gamma-radiation by flow cytometry, and characterised their p53 status through analysis of p53 mutation status and Tag SV40 expression.	('p53', 'Gene', '7157', (128, 131))	('p53', 'Gene', (128, 131))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('HMCLs', 'Chemical', '-', (52, 57))	('mutation', 'Var', (163, 171))
1907	12569381	The inhibitor of the cyclin E- (cyclin-dependent kinase) (CDK2) p27KIP1, of which accumulation is observed in response to antiproliferative signals, does not appear to be involved in the response of MM cells to gamma-radiation.	('p27KIP1', 'Var', (64, 71))	('cyclin', 'molecular_function', 'GO:0016538', ('32', '38'))	('rat', 'Species', '10116', (133, 136))	('CDK2', 'Gene', (58, 62))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('CDK2', 'Gene', '1017', (58, 62))	('cyclin', 'molecular_function', 'GO:0016538', ('21', '27'))
1908	12569381	This result agrees with the literature findings showing that p27KIP1 degradation, because of the phosphorylation and ubiquitination of the protein, occurs in cells that are not in G1 phase (Desdouets et al, 2000).	('degradation', 'MPA', (69, 80))	('rat', 'Species', '10116', (32, 35))	('p27KIP1', 'Var', (61, 68))	('degradation', 'biological_process', 'GO:0009056', ('69', '80'))	('ubiquitination', 'MPA', (117, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('phosphorylation', 'MPA', (97, 112))	('G1 phase', 'biological_process', 'GO:0051318', ('180', '188'))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
1910	12569381	We believe that this is the first report of such a point mutation in a characterised human mesothelioma cell line.	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('point mutation', 'Var', (51, 65))	('mesothelioma', 'Disease', (91, 103))	('human', 'Species', '9606', (85, 90))
1916	12569381	p53 is likely to be inactivated by mutation in BT, but no mutation was found in RV.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (35, 43))
1931	12569381	Abrogation of p53 by E6 transfection results in loss of G1 control, but not G2 in human colon carcinoma cells (Wouters et al, 1999).	('loss', 'NegReg', (48, 52))	('colon carcinoma', 'Disease', (88, 103))	('G1 control', 'MPA', (56, 66))	('colon carcinoma', 'Disease', 'MESH:D015179', (88, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('p53', 'Gene', (14, 17))	('E6 transfection', 'Var', (21, 36))	('p53', 'Gene', '7157', (14, 17))	('Abrogation', 'NegReg', (0, 10))	('human', 'Species', '9606', (82, 87))
1932	12569381	Our results are consistent with these observations since HMCLs defective in p53 either by mutation (BT) or by failure of p21WAF1/CIP1 induction (RV) arrested in the G2/M phase.	('failure', 'NegReg', (110, 117))	('HMCLs', 'Chemical', '-', (57, 62))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('p21WAF1/CIP1', 'Gene', '1026', (121, 133))	('defective', 'NegReg', (63, 72))	('M phase', 'biological_process', 'GO:0000279', ('168', '175'))	('mutation', 'Var', (90, 98))	('p21WAF1/CIP1', 'Gene', (121, 133))
1935	12569381	From another source, in HMCLs with p53 deficiency, an enhancement of the amount of p53 by transfection with an adenovirus carrying human p14(ARF) cDNA has been found to reduce cell proliferation and enhance apoptosis (Yang et al, 2000).	('deficiency', 'Var', (39, 49))	('p53', 'Gene', (35, 38))	('p53', 'Gene', (83, 86))	('apoptosis', 'CPA', (207, 216))	('enhance', 'PosReg', (199, 206))	('cell proliferation', 'CPA', (176, 194))	('ARF', 'Disease', (141, 144))	('p14', 'Gene', '1029', (137, 140))	('rat', 'Species', '10116', (188, 191))	('enhancement', 'PosReg', (54, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('p14', 'Gene', (137, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('176', '194'))	('ARF', 'Disease', 'MESH:D058186', (141, 144))	('reduce', 'NegReg', (169, 175))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', '7157', (83, 86))	('HMCLs', 'Chemical', '-', (24, 29))	('human', 'Species', '9606', (131, 136))
1943	33537296	In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('MPM', 'Disease', (109, 112))	('contributes', 'Reg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Notch pathway', 'Pathway', (32, 45))	('humans', 'Species', '9606', (3, 9))	('dysregulation', 'Var', (15, 28))
1953	33537296	These alterations include dysregulated activity of growth factors and their specific receptors, apoptosis inhibition, alteration of cellular and circulating microRNAs and remodeling of intracellular calcium homeostasis and Ca2+-dependent pathways.	('Ca2+-dependent pathways', 'Pathway', (223, 246))	('Ca2+', 'Chemical', 'MESH:D000069285', (223, 227))	('growth', 'Protein', (51, 57))	('alteration', 'Reg', (118, 128))	('intracellular', 'cellular_component', 'GO:0005622', ('185', '198'))	('homeostasis', 'biological_process', 'GO:0042592', ('207', '218'))	('activity', 'MPA', (39, 47))	('apoptosis', 'CPA', (96, 105))	('calcium', 'Chemical', 'MESH:D002118', (199, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('inhibition', 'NegReg', (106, 116))	('dysregulated', 'Var', (26, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
1955	33537296	Furthermore, mutations in specific genes have been associated to the development of MPM, such as germline mutations/inactivations discovered in the tumor suppressor gene BRCA1-associated protein 1 (BAP1) in cases with a family history of cancer.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MPM', 'Disease', (84, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('148', '164'))	('tumor', 'Disease', (148, 153))	('BAP1', 'Gene', '8314', (198, 202))	('BRCA1-associated protein 1', 'Gene', '8314', (170, 196))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('BAP1', 'Gene', (198, 202))	('BRCA1-associated protein 1', 'Gene', (170, 196))	('mutations', 'Var', (13, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('148', '164'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations/inactivations', 'Var', (106, 129))
1958	33537296	Patients with untreated diabetes and T2DM have an increased cancer risk, attributed mostly to the growth-promoting effect of chronic elevated plasma glucose and insulin levels.	('diabetes', 'Disease', (24, 32))	('glucose', 'Chemical', 'MESH:D005947', (149, 156))	('T2DM', 'Var', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('elevated', 'PosReg', (133, 141))	('insulin', 'molecular_function', 'GO:0016088', ('161', '168'))	('elevated plasma glucose', 'Phenotype', 'HP:0003074', (133, 156))	('cancer', 'Disease', (60, 66))	('diabetes', 'Disease', 'MESH:D003920', (24, 32))	('insulin', 'Gene', (161, 168))	('Patients', 'Species', '9606', (0, 8))	('untreated diabetes', 'Phenotype', 'HP:0005978', (14, 32))	('insulin', 'Gene', '3630', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
1960	33537296	The interest in potential anti-neoplastic and cancer preventive properties of metformin is based on numerous clinical studies that showed a significantly reduced incidence of neoplastic diseases and cancer mortality in diabetic patients treated with metformin compared to diabetic patients treated with other antidiabetic drugs.	('cancer mortality', 'Disease', (199, 215))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('diabetic', 'Disease', 'MESH:D003920', (272, 280))	('cancer', 'Disease', (199, 205))	('diabetic', 'Disease', (272, 280))	('metformin', 'Var', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('metformin', 'Chemical', 'MESH:D008687', (250, 259))	('patients', 'Species', '9606', (228, 236))	('cancer mortality', 'Disease', 'MESH:D003643', (199, 215))	('neoplastic diseases', 'Disease', (175, 194))	('cancer', 'Disease', (46, 52))	('patients', 'Species', '9606', (281, 289))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('diabetic', 'Disease', 'MESH:D003920', (219, 227))	('metformin', 'Chemical', 'MESH:D008687', (78, 87))	('diabetic', 'Disease', 'MESH:D003920', (313, 321))	('diabetic', 'Disease', (219, 227))	('reduced', 'NegReg', (154, 161))	('diabetic', 'Disease', (313, 321))	('neoplastic diseases', 'Disease', 'MESH:D009386', (175, 194))
1995	33537296	For immunoblotting analysis, the PVDF membranes were blocked with 5% non-fat milk and incubated overnight at 4 C with following primary antibodies: anti-cleaved Notch1 (Val1744) (1:1000), anti-pRPS6 (Ser240/244) (1:1000), anti-Noxa (1:1000), anti-Bcl2 (1:1000), anti-caspase-3 (1:1000), anti-caspase-8 (1:1000), anti-caspase-9 (1:1000), anti-PARP (1:1000) (all purchased from Cell Signaling Technology, Danvers, MA, United States), anti-Notch1 (C-20) (1:500) (Santa Cruz Biotechnology, Inc., Dallas, TX, United States) and anti-beta actin (1:10000) (Sigma-Aldrich).	('RPS6', 'Gene', '6194', (194, 198))	('Notch1', 'Gene', (161, 167))	('Notch1', 'Gene', '4851', (161, 167))	('Ser', 'cellular_component', 'GO:0005790', ('200', '203'))	('caspase-8', 'Gene', '841', (292, 301))	('Notch1', 'Gene', (437, 443))	('Noxa', 'Gene', '5366', (227, 231))	('PVDF', 'Chemical', 'MESH:C024865', (33, 37))	('Notch1', 'Gene', '4851', (437, 443))	('caspase-3', 'Gene', '836', (267, 276))	('Bcl2', 'Gene', (247, 251))	('Signaling', 'biological_process', 'GO:0023052', ('381', '390'))	('Bcl2', 'Gene', '596', (247, 251))	('caspase-9', 'Gene', '842', (317, 326))	('caspase-3', 'Gene', (267, 276))	('PARP', 'Gene', '142', (342, 346))	('Noxa', 'Gene', (227, 231))	('RPS6', 'Gene', (194, 198))	('anti-beta', 'Var', (523, 532))	('PARP', 'Gene', (342, 346))	('caspase-8', 'Gene', (292, 301))	('Bcl2', 'molecular_function', 'GO:0015283', ('247', '251'))	('caspase-9', 'Gene', (317, 326))
2041	33537296	Epidemiological evidence show that diabetes is strongly associated with cancer and retrospective analyses have shown that metformin, a drug used to treat T2DM, possesses antineoplastic properties since it increases survival in diabetic patients affected by several types of tumors with less toxicity compared to existing anti-cancer drugs.	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Disease', (72, 78))	('metformin', 'Var', (122, 131))	('diabetes', 'Disease', 'MESH:D003920', (35, 43))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('metformin', 'Chemical', 'MESH:D008687', (122, 131))	('cancer', 'Disease', (326, 332))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('toxicity', 'Disease', 'MESH:D064420', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (274, 280))	('diabetes', 'Disease', (35, 43))	('toxicity', 'Disease', (291, 299))	('diabetic', 'Disease', 'MESH:D003920', (227, 235))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('increases', 'PosReg', (205, 214))	('diabetic', 'Disease', (227, 235))	('survival', 'CPA', (215, 223))
2046	33537296	Our results are in agreement with previous investigations reporting similar effects of metformin in other tumor cell lines and show, for the first time, that metformin arrests cell growth and induces apoptosis in MPM cells.	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('induces', 'Reg', (192, 199))	('cell growth', 'biological_process', 'GO:0016049', ('176', '187'))	('metformin', 'Var', (158, 167))	('cell growth', 'CPA', (176, 187))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('metformin', 'Chemical', 'MESH:D008687', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('metformin', 'Chemical', 'MESH:D008687', (87, 96))	('arrests', 'NegReg', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('apoptosis', 'CPA', (200, 209))	('tumor', 'Disease', (106, 111))
2048	33537296	These results suggest that metformin induces an up-regulation of Noxa, which per se entailed significant cell death (Figure 2), as demonstrated in some systems and this increase is accompanied by cytochrome c release and subsequent caspase activation.	('cell death', 'CPA', (105, 115))	('cytochrome c', 'Gene', '54205', (196, 208))	('cytochrome c', 'molecular_function', 'GO:0045155', ('196', '208'))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('196', '208'))	('metformin', 'Var', (27, 36))	('caspase activation', 'biological_process', 'GO:0006919', ('232', '250'))	('Noxa', 'Gene', '5366', (65, 69))	('caspase', 'Gene', '841;842', (232, 239))	('cell death', 'biological_process', 'GO:0008219', ('105', '115'))	('cytochrome c', 'Gene', (196, 208))	('Noxa', 'Gene', (65, 69))	('metformin', 'Chemical', 'MESH:D008687', (27, 36))	('activation', 'PosReg', (240, 250))	('up-regulation', 'PosReg', (48, 61))	('caspase', 'Gene', (232, 239))
2049	33537296	In order to demonstrate that metformin induces a caspases-depend cell death, experiments with various peptide inhibitors, either directed against individual caspases, or the zVAD-fmk broad-spectrum inhibitor will be performed.	('metformin', 'Chemical', 'MESH:D008687', (29, 38))	('caspases', 'Gene', '841;842', (49, 57))	('caspases', 'Gene', (157, 165))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('caspases', 'Gene', (49, 57))	('cell death', 'CPA', (65, 75))	('metformin', 'Var', (29, 38))	('zVAD-fmk', 'Chemical', 'MESH:C096713', (174, 182))	('caspases', 'Gene', '841;842', (157, 165))	('induces', 'Reg', (39, 46))
2051	33537296	In addition, the employment of caspase inhibitors in breast cancer cells, revealed that metformin induces both caspase-dependent and poly(ADPribose) polymerase-dependent cell death.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('caspase', 'Gene', '841;842', (31, 38))	('cell death', 'biological_process', 'GO:0008219', ('170', '180'))	('caspase', 'Gene', '841;842', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('caspase', 'Gene', (31, 38))	('metformin', 'Var', (88, 97))	('caspase', 'Gene', (111, 118))	('breast cancer', 'Disease', (53, 66))
2069	33537296	As shown in Figure 4A and Supplementary Figure 2, MMP89 cells have Notch1 basal level significantly higher compared to IST-Mes-2 cells.	('MMP89', 'Var', (50, 55))	('Notch1', 'Gene', (67, 73))	('higher', 'PosReg', (100, 106))	('IST-Mes', 'Chemical', '-', (119, 126))	('MMP', 'molecular_function', 'GO:0004235', ('50', '53'))	('Notch1', 'Gene', '4851', (67, 73))
2075	33537296	Additionally, as with GSIs, there is concern with the side effect profile of metformin: even though clinical trials have revealed a low incidence of dose limiting toxicity with metformin in combination with a wide variety of chemotherapy regimens, metformin is well known for causing gastrointestinal problems.	('gastrointestinal problems', 'Disease', (284, 309))	('metformin', 'Chemical', 'MESH:D008687', (177, 186))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('GSIs', 'Chemical', '-', (22, 26))	('gastrointestinal problems', 'Phenotype', 'HP:0011024', (284, 309))	('metformin', 'Var', (248, 257))	('toxicity', 'Disease', 'MESH:D064420', (163, 171))	('metformin', 'Chemical', 'MESH:D008687', (248, 257))	('causing', 'Reg', (276, 283))	('toxicity', 'Disease', (163, 171))
2076	33537296	Our study, by showing that Notch1 inhibitors could act downstream or in parallel to metformin in inhibiting viability proliferation and inducing apoptosis of MPM cells, provides new data on a novel therapeutic strategy based on the combination of these two agents to treat MPM.	('inducing', 'Reg', (136, 144))	('metformin', 'Chemical', 'MESH:D008687', (84, 93))	('Notch1', 'Gene', (27, 33))	('MPM', 'Disease', (273, 276))	('inhibitors', 'Var', (34, 44))	('Notch1', 'Gene', '4851', (27, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('viability proliferation', 'CPA', (108, 131))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('inhibiting', 'NegReg', (97, 107))	('apoptosis', 'CPA', (145, 154))
2080	33537296	Nevertheless, in breast cancer, metformin has been reported to reduce the levels of M2 macrophages in favor of M1 and this has been explained on the basis of cytokines production by cancer cells induced by metformin.	('metformin', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (182, 188))	('reduce', 'NegReg', (63, 69))	('levels of M2 macrophages', 'MPA', (74, 98))	('metformin', 'Chemical', 'MESH:D008687', (206, 215))
2082	33537296	This treatment could be especially relevant for heterozygous carriers of germline BAP1 mutation more at risk of MPM development due to high levels of M2 in pleural fluid.	('BAP1', 'Gene', (82, 86))	('MPM development', 'Disease', (112, 127))	('germline', 'Var', (73, 81))	('BAP1', 'Gene', '8314', (82, 86))	('mutation', 'Var', (87, 95))	('pleural fluid', 'Phenotype', 'HP:0002202', (156, 169))
2097	32181989	Anaplastic lymphoma kinase (ALK) was first discovered in 1994 in anaplastic large cell lymphoma (ALCL).1 Subsequent studies have found that inflammatory myofibroblastic tumors and neuroblastomas are associated with ALK gene mutations.2 In 2007, Soda et al.	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('neuroblastomas', 'Phenotype', 'HP:0003006', (180, 194))	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (65, 95))	('neuroblastomas', 'Disease', (180, 194))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (140, 175))	('ALK', 'Gene', (28, 31))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('neuroblastomas', 'Disease', 'MESH:D009447', (180, 194))	('cell lymphoma', 'Phenotype', 'HP:0012191', (82, 95))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (153, 175))	('lymphoma', 'Disease', (11, 19))	('ALK', 'Gene', '238', (215, 218))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lymphoma', 'Disease', 'MESH:D008223', (11, 19))	('inflammatory myofibroblastic tumors', 'Disease', (140, 175))	('ALK', 'Gene', (215, 218))	('mutations.2', 'Var', (224, 235))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('lymphoma', 'Disease', (87, 95))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('ALCL', 'Phenotype', 'HP:0012193', (97, 101))	('lymphoma', 'Disease', 'MESH:D008223', (87, 95))
2110	32181989	Preliminary clinical trial results have been reported in the 2017 European Society for Medical Oncology Asia Congress.11  Adult patients (aged 18-65) with a locally advanced or metastatic malignancy harboring a genetic alteration in ALK, who had disease progression despite underlying standard chemotherapy or had no effective standard therapy, were included in this study.	('genetic alteration', 'Var', (211, 229))	('Oncology', 'Phenotype', 'HP:0002664', (95, 103))	('malignancy', 'Disease', (188, 198))	('ALK', 'Gene', (233, 236))	('patients', 'Species', '9606', (128, 136))	('malignancy', 'Disease', 'MESH:D009369', (188, 198))	('ALK', 'Gene', '238', (233, 236))
2141	32181989	ALK positivity in patients with mesothelioma was confirmed by immunohistochemistry.	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('positivity', 'Var', (4, 14))	('ALK', 'Gene', (0, 3))	('mesothelioma', 'Disease', (32, 44))	('patients', 'Species', '9606', (18, 26))	('ALK', 'Gene', '238', (0, 3))
2153	32181989	Grade 3 elevated alkaline phosphatase and glutamyl transpeptidase (>2.0-5.0 x upper normal [ULN]) occurred in a patient who was treated with CT-707450 mg once a day.	('elevated', 'PosReg', (8, 16))	('patient', 'Species', '9606', (112, 119))	('phosphatase', 'molecular_function', 'GO:0016791', ('26', '37'))	('elevated alkaline phosphatase', 'Phenotype', 'HP:0003155', (8, 37))	('glutamyl transpeptidase', 'Enzyme', (42, 65))	('CT-707450', 'Chemical', '-', (141, 150))	('alkaline phosphatase', 'MPA', (17, 37))	('CT-707450 mg', 'Var', (141, 153))
2172	32181989	Patient 2010 had a temporal lobe metastasis, and the metastasis was significantly reduced after taking CT-707600 mg once a day for one week.	('CT-707600 mg', 'Var', (103, 115))	('reduced', 'NegReg', (82, 89))	('temporal lobe metastasis', 'CPA', (19, 43))	('Patient', 'Species', '9606', (0, 7))	('CT-707600', 'Chemical', '-', (103, 112))
2188	32181989	The kinase inhibition studies of four ALK mutant kinases expressed by eukaryotic insect expression systems revealed that CT-707 more effectively inhibits four common crizotinib-resistant ALK kinase mutants, including ALK L1196M, ALK F1174L, ALK G1296S, and ALK R1275Q in vitro.	('ALK', 'Gene', (229, 232))	('ALK', 'Gene', '238', (38, 41))	('crizotinib', 'Chemical', 'MESH:D000077547', (166, 176))	('ALK', 'Gene', '238', (187, 190))	('R1275Q', 'Mutation', 'rs113994087', (261, 267))	('ALK', 'Gene', (38, 41))	('ALK', 'Gene', (187, 190))	('ALK', 'Gene', '238', (241, 244))	('L1196M', 'Var', (221, 227))	('ALK', 'Gene', '238', (257, 260))	('ALK', 'Gene', (257, 260))	('ALK', 'Gene', (241, 244))	('L1196M', 'Mutation', 'rs1057519784', (221, 227))	('G1296S', 'Mutation', 'p.G1296S', (245, 251))	('R1275Q', 'Var', (261, 267))	('ALK', 'Gene', '238', (217, 220))	('G1296S', 'Var', (245, 251))	('F1174L', 'Mutation', 'rs863225281', (233, 239))	('F1174L', 'Var', (233, 239))	('ALK', 'Gene', (217, 220))	('CT-707', 'Chemical', '-', (121, 127))	('ALK', 'Gene', '238', (229, 232))	('inhibits', 'NegReg', (145, 153))
2198	32181989	In conclusion, the results of this study suggest that CT-707 is effective in Chinese patients with tumors harboring ALK rearrangements.	('rearrangements', 'Var', (120, 134))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('CT-707', 'Chemical', '-', (54, 60))	('ALK', 'Gene', (116, 119))	('patients', 'Species', '9606', (85, 93))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('ALK', 'Gene', '238', (116, 119))	('CT-707', 'Var', (54, 60))
2391	21412769	Until 1999, under ICD-9, MM death was coded as ICD-163 (malignant neoplasm of the pleura) or ICD 162 (malignant tumor of the trachea bronchus and lung) or ICD 199 (malignant neoplasm without specification of site).	('malignant neoplasm', 'Disease', (56, 74))	('malignant tumor of the trachea bronchus', 'Disease', 'MESH:C557675', (102, 141))	('neoplasm', 'Phenotype', 'HP:0002664', (174, 182))	('malignant neoplasm', 'Disease', 'MESH:D009369', (164, 182))	('malignant neoplasm', 'Disease', 'MESH:D009369', (56, 74))	('MM death', 'Disease', (25, 33))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MM death', 'Disease', 'MESH:D003643', (25, 33))	('neoplasm of the pleura', 'Disease', 'MESH:D054363', (66, 88))	('tumor of the trachea', 'Phenotype', 'HP:0100551', (112, 132))	('malignant neoplasm', 'Disease', (164, 182))	('malignant tumor of the trachea bronchus', 'Disease', (102, 141))	('neoplasm of the pleura', 'Disease', (66, 88))	('neoplasm of the pleura', 'Phenotype', 'HP:0100527', (66, 88))	('ICD 162', 'Var', (93, 100))
2400	21412769	However, it is accepted that chrysotile can cause lung cancer in man and MM in rats, and some authors have proposed that even if chrysotile is less potent than amphiboles, it is a known carcinogen that accounts for about 95% of the asbestos used worldwide, and therefore chrysotile is the main cause of MM.	('lung cancer', 'Disease', (50, 61))	('chrysotile', 'Var', (29, 39))	('cause', 'Reg', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('rats', 'Species', '10116', (79, 83))	('man', 'Species', '9606', (65, 68))	('asbestos', 'Chemical', 'MESH:D001194', (232, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
2435	21412769	By eliminating mesothelial cells that have accumulated asbestos-induced mutations without promoting inflammation, apoptosis may be regarded as a protective mechanism against the development of MM.	('inflammation', 'Disease', (100, 112))	('mutations', 'Var', (72, 81))	('men', 'Species', '9606', (185, 188))	('inflammation', 'biological_process', 'GO:0006954', ('100', '112'))	('asbestos', 'Chemical', 'MESH:D001194', (55, 63))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))
2439	21412769	A recent study from Japan proposed that ferruginous bodies that often form around amphibole asbestos contain high concentrations of radium, a finding that led the authors to suggest that ionizing radiation from these bodies may cause DNA damage and cancer, including MM.	('cause', 'Reg', (228, 233))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('DNA damage', 'CPA', (234, 244))	('cancer', 'Disease', (249, 255))	('ionizing radiation', 'Var', (187, 205))	('DNA', 'cellular_component', 'GO:0005574', ('234', '237'))	('asbestos', 'Chemical', 'MESH:D001194', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
2442	21412769	The hepatocyte growth/scatter factor (HGF) and its receptor tyrosine kinase c-Met are highly expressed in most MM, especially those containing SV40; HGF activation is mediated through a PI3K/ERK5/Fra-1 feedback pathway.	('Fra-1', 'Gene', (196, 201))	('Fra-1', 'Gene', '8061', (196, 201))	('hepatocyte', 'MPA', (4, 14))	('HGF', 'Gene', (38, 41))	('c-Met', 'Gene', (76, 81))	('SV40', 'Species', '1891767', (143, 147))	('c-Met', 'Gene', '4233', (76, 81))	('HGF', 'Gene', (149, 152))	('ERK', 'molecular_function', 'GO:0004707', ('191', '194'))	('SV40', 'Var', (143, 147))	('HGF', 'Gene', '3082', (149, 152))	('HGF', 'Gene', '3082', (38, 41))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))
2504	21412769	In human MM biopsies, SV40 has been shown to bind and inactivate p53 and pRb, and to activate c-met, IGF-I and other oncogenes.	('pRb', 'Gene', (73, 76))	('activate', 'PosReg', (85, 93))	('inactivate', 'NegReg', (54, 64))	('human', 'Species', '9606', (3, 8))	('c-met', 'Gene', (94, 99))	('SV40', 'Species', '1891767', (22, 26))	('SV40', 'Var', (22, 26))	('c-met', 'Gene', '4233', (94, 99))	('p53', 'Protein', (65, 68))	('bind', 'Interaction', (45, 49))	('IGF-I', 'Gene', (101, 106))	('oncogenes', 'Gene', (117, 126))
2506	21412769	Other studies found that only a low percentage, 5-6%, of MM contained SV40 and suggested that both the low incidence and the low amunt of SV40 present argued against a pathogenic role.	('SV40', 'Species', '1891767', (138, 142))	('SV40', 'Var', (70, 74))	('contained', 'Reg', (60, 69))	('SV40', 'Species', '1891767', (70, 74))
2508	21412769	Among the 8 women, 3 contained SV40.	('SV40', 'Var', (31, 35))	('women', 'Species', '9606', (12, 17))	('SV40', 'Species', '1891767', (31, 35))	('contained', 'Reg', (21, 30))
2517	21412769	Although it is well accepted that SV40 causes MM in animals and data unequivocally show that SV40 acts as a co-factor for asbestos carcinogenesis, the role of SV40 in causing human MM is controversial.	('causes', 'Reg', (39, 45))	('human', 'Species', '9606', (175, 180))	('SV40', 'Species', '1891767', (93, 97))	('SV40', 'Species', '1891767', (159, 163))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (122, 145))	('SV40', 'Species', '1891767', (34, 38))	('asbestos carcinogenesis', 'Disease', (122, 145))	('SV40', 'Var', (34, 38))
2562	21412769	Multivariate analysis of 78 MM patients indicated that high levels of ER beta was an independent protective factor of all-cause mortality (HR= 0.2; 95% CI, 0.05-0.6), although only 4 out of 19 women (21.1%) and 8 out of 59 men (13.6%) were classified as having high levels.	('men', 'Species', '9606', (223, 226))	('all-cause', 'Disease', (118, 127))	('ER beta', 'Gene', (70, 77))	('high levels', 'Var', (55, 66))	('women', 'Species', '9606', (193, 198))	('patients', 'Species', '9606', (31, 39))	('ER beta', 'Gene', '2100', (70, 77))	('men', 'Species', '9606', (195, 198))
2698	20591913	FISH assay development for the detection of p16/CDKN2A deletion in malignant pleural mesothelioma To develop a fluorescence in-situ hybridisation (FISH) assay for detecting p16/CDKN2A deletion on paraffin tissue sections for use as an ancillary test to distinguish reactive from malignant mesothelial proliferations.	('CDKN2A', 'Gene', (177, 183))	('p16', 'Gene', (44, 47))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (77, 97))	('p16', 'Gene', '1029', (173, 176))	('CDKN2A', 'Gene', '1029', (177, 183))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (77, 97))	('pleural mesothelioma', 'Disease', (77, 97))	('CDKN2A', 'Gene', (48, 54))	('p16', 'Gene', '1029', (44, 47))	('deletion', 'Var', (55, 63))	('p16', 'Gene', (173, 176))	('CDKN2A', 'Gene', '1029', (48, 54))	('paraffin', 'Chemical', 'MESH:D010232', (196, 204))
2699	20591913	Dual-colour FISH for p16/CDKN2A and chromosome 9 (CEP-9) was performed on 11 benign mesothelial proliferations and 54 malignant pleural mesothelioma (MPM) cases to establish cut-off values for p16/CDKN2A deletion.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (118, 148))	('deletion', 'Var', (204, 212))	('p16', 'Gene', '1029', (193, 196))	('CDKN2A', 'Gene', (197, 203))	('malignant pleural mesothelioma', 'Disease', (118, 148))	('p16', 'Gene', (21, 24))	('CDKN2A', 'Gene', '1029', (197, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (128, 148))	('CDKN2A', 'Gene', (25, 31))	('p16', 'Gene', (193, 196))	('CEP', 'molecular_function', 'GO:0047849', ('50', '53'))	('p16', 'Gene', '1029', (21, 24))	('CDKN2A', 'Gene', '1029', (25, 31))
2700	20591913	Cut-off values for p16/CDKN2A deletion were calculated based on FISH signalling patterns obtained from the benign controls (mean percent nuclei plus three standard deviations).	('p16', 'Gene', (19, 22))	('CDKN2A', 'Gene', (23, 29))	('deletion', 'Var', (30, 38))	('p16', 'Gene', '1029', (19, 22))	('CDKN2A', 'Gene', '1029', (23, 29))	('signalling', 'biological_process', 'GO:0023052', ('69', '79'))
2701	20591913	Hemizygous deletion was defined as >44% of nuclei showing the hemizygous (one p16/CDKN2A, two CEP-9 signals) or >15% of nuclei showing the monosomy (one p16/CDKN2A, one CEP-9 signal) deletion patterns.	('p16', 'Gene', (153, 156))	('p16', 'Gene', (78, 81))	('p16', 'Gene', '1029', (153, 156))	('CDKN2A', 'Gene', (82, 88))	('CEP', 'molecular_function', 'GO:0047849', ('169', '172'))	('CDKN2A', 'Gene', (157, 163))	('CDKN2A', 'Gene', '1029', (82, 88))	('p16', 'Gene', '1029', (78, 81))	('CEP', 'molecular_function', 'GO:0047849', ('94', '97'))	('CDKN2A', 'Gene', '1029', (157, 163))	('deletion', 'Var', (183, 191))
2703	20591913	P16/CDKN2A deletion was detected in 61% (33/54) of MPM cases.	('detected', 'Reg', (24, 32))	('P16', 'Gene', (0, 3))	('CDKN2A', 'Gene', '1029', (4, 10))	('P16', 'Gene', '1029', (0, 3))	('deletion', 'Var', (11, 19))	('CDKN2A', 'Gene', (4, 10))	('MPM', 'Disease', (51, 54))
2704	20591913	Among the equivocal biopsies, four showed homozygous and one showed hemizygous p16/CDKN2A deletion.	('deletion', 'Var', (90, 98))	('p16', 'Gene', '1029', (79, 82))	('CDKN2A', 'Gene', '1029', (83, 89))	('p16', 'Gene', (79, 82))	('CDKN2A', 'Gene', (83, 89))
2705	20591913	Age over 60 years, asbestos exposure and p16/CDKN2A deletion were associated with a worse prognosis.	('p16', 'Gene', (41, 44))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('CDKN2A', 'Gene', (45, 51))	('deletion', 'Var', (52, 60))	('p16', 'Gene', '1029', (41, 44))	('CDKN2A', 'Gene', '1029', (45, 51))
2706	20591913	FISH for p16/CDKN2A deletion is a useful test for confirming the diagnosis of MPM.	('MPM', 'Disease', (78, 81))	('CDKN2A', 'Gene', (13, 19))	('p16', 'Gene', '1029', (9, 12))	('deletion', 'Var', (20, 28))	('CDKN2A', 'Gene', '1029', (13, 19))	('p16', 'Gene', (9, 12))
2712	20591913	Deletion involving the 9p21 locus, the site of the cyclin-dependent kinase inhibitor 2A/p16 gene (p16/CDKN2A), frequently occurs in mesothelioma.	('p16', 'Gene', (88, 91))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('68', '84'))	('p16', 'Gene', (98, 101))	('occurs', 'Reg', (122, 128))	('CDKN2A', 'Gene', (102, 108))	('p16', 'Gene', '1029', (88, 91))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('51', '84'))	('mesothelioma', 'Disease', (132, 144))	('CDKN2A', 'Gene', '1029', (102, 108))	('p16', 'Gene', '1029', (98, 101))	('mesothelioma', 'Disease', 'MESH:D008654', (132, 144))	('Deletion', 'Var', (0, 8))
2713	20591913	Homozygous deletion has been reported in 22-74% of mesotheliomas.	('Homozygous deletion', 'Var', (0, 19))	('mesotheliomas', 'Disease', (51, 64))	('reported', 'Reg', (29, 37))	('mesotheliomas', 'Disease', 'MESH:D008654', (51, 64))
2714	20591913	The objectives of this study were to: (a) develop a FISH assay for clinical use in the diagnosis of MPM, by establishing cut-off values for the detection of p16/CDKN2A deletion on formalin-fixed paraffin-embedded (FFPE) material; and (b) test the assay on tissue sections from equivocal cases with known clinical outcome.	('formalin', 'Chemical', 'MESH:D005557', (180, 188))	('paraffin', 'Chemical', 'MESH:D010232', (195, 203))	('p16', 'Gene', (157, 160))	('CDKN2A', 'Gene', (161, 167))	('MPM', 'Disease', (100, 103))	('deletion', 'Var', (168, 176))	('p16', 'Gene', '1029', (157, 160))	('CDKN2A', 'Gene', '1029', (161, 167))
2730	20591913	As monosomy pattern could be interpreted as hemizygous deletion, hemizygous p16/CDKN2A deletion was defined as >44% of nuclei showing 1SpO/1SpG or >15% of nuclei showing 1SpO/2SpG (table 2).	('CDKN2A', 'Gene', '1029', (80, 86))	('1SpO/1SpG', 'Var', (134, 143))	('p16', 'Gene', '1029', (76, 79))	('p16', 'Gene', (76, 79))	('deletion', 'Var', (87, 95))	('CDKN2A', 'Gene', (80, 86))
2731	20591913	To mitigate uncertainty from artifactual loss of signals due to nuclear sectioning, a cut-off of >10% for 0SpO/1-2SpG was defined for homozygous deletion (table 2).	('artifactual loss', 'Disease', 'MESH:D015431', (29, 45))	('artifactual loss', 'Disease', (29, 45))	('deletion', 'Var', (145, 153))
2732	20591913	Using this cut-off, homozygous p16/CDKN2A deletion was detected in 23/54 (43%) of MPM cases (table 3, figure 1).	('p16', 'Gene', '1029', (31, 34))	('CDKN2A', 'Gene', '1029', (35, 41))	('detected', 'Reg', (55, 63))	('MPM', 'Disease', (82, 85))	('p16', 'Gene', (31, 34))	('deletion', 'Var', (42, 50))	('CDKN2A', 'Gene', (35, 41))
2735	20591913	P16/CDKN2A deletion shows 61% sensitivity and 100% specificity for MPM.	('MPM', 'Disease', (67, 70))	('P16', 'Gene', (0, 3))	('CDKN2A', 'Gene', (4, 10))	('P16', 'Gene', '1029', (0, 3))	('deletion', 'Var', (11, 19))	('CDKN2A', 'Gene', '1029', (4, 10))
2736	20591913	Four cases showed homozygous p16/CDKN2A deletion (mean 49%, range 16-75%) and one showed hemizygous (1SpO/2SpG) deletion.	('p16', 'Gene', (29, 32))	('CDKN2A', 'Gene', (33, 39))	('deletion', 'Var', (40, 48))	('CDKN2A', 'Gene', '1029', (33, 39))	('p16', 'Gene', '1029', (29, 32))
2741	20591913	Correlation of patient characteristics and p16/CDKN2A FISH status with clinical outcome showed that age >=60 (35% vs 20% survival at 2 years; p=0.026), asbestos exposure (39% vs 17% survival at 2 years; p=0.039) and p16/CDKN2A deletion by FISH (50% vs 17% survival at 2 years; p=0.039) were significantly associated with reduced survival on univariate analysis (figure 2).	('p16', 'Gene', (43, 46))	('patient', 'Species', '9606', (15, 22))	('CDKN2A', 'Gene', (47, 53))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('p16', 'Gene', (216, 219))	('reduced', 'NegReg', (321, 328))	('CDKN2A', 'Gene', '1029', (47, 53))	('p16', 'Gene', '1029', (43, 46))	('CDKN2A', 'Gene', (220, 226))	('survival', 'MPA', (329, 337))	('deletion', 'Var', (227, 235))	('p16', 'Gene', '1029', (216, 219))	('CDKN2A', 'Gene', '1029', (220, 226))
2742	20591913	There was no association between p16/CDKN2A deletion status and any of the clinical parameters.	('p16', 'Gene', (33, 36))	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('deletion status', 'Var', (44, 59))	('p16', 'Gene', '1029', (33, 36))
2743	20591913	We demonstrate that FISH for p16/CDKN2A deletion can be a clinically useful marker to confirm a diagnosis of malignancy, particularly in biopsies with limited material that lack definitive evidence of invasion.	('p16', 'Gene', (29, 32))	('CDKN2A', 'Gene', (33, 39))	('malignancy', 'Disease', (109, 119))	('deletion', 'Var', (40, 48))	('CDKN2A', 'Gene', '1029', (33, 39))	('p16', 'Gene', '1029', (29, 32))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))
2744	20591913	Moreover, we determined cut-off values for homozygous and hemizygous p16/CDKN2A deletion by FISH on routine FFPE tissue sections and tested our assay using equivocal cases.	('deletion', 'Var', (80, 88))	('CDKN2A', 'Gene', '1029', (73, 79))	('p16', 'Gene', (69, 72))	('p16', 'Gene', '1029', (69, 72))	('CDKN2A', 'Gene', (73, 79))
2745	20591913	Using the established criteria, we show that hemizygous deletion alone may occur in mesothelioma and is, in and of itself, sufficient for the diagnosis of malignancy.	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('malignancy', 'Disease', 'MESH:D009369', (155, 165))	('malignancy', 'Disease', (155, 165))	('hemizygous deletion', 'Var', (45, 64))	('mesothelioma', 'Disease', (84, 96))	('occur', 'Reg', (75, 80))
2746	20591913	The establishment of cut-off values for detecting deletions in FFPE material requires special consideration because sectioning creates truncation artifacts; therefore cut-offs need to be higher than in samples containing intact nuclei, and criteria for deletion must account for this artifactual loss of signals.	('artifactual loss', 'Disease', (284, 300))	('truncation', 'MPA', (135, 145))	('deletions', 'Var', (50, 59))	('artifactual loss', 'Disease', 'MESH:D015431', (284, 300))
2747	20591913	Our overall rate of p16/CDKN2A deletion in MPM was 61%; 43% homozygous and 18% hemizygous.	('p16', 'Gene', (20, 23))	('CDKN2A', 'Gene', (24, 30))	('deletion', 'Var', (31, 39))	('MPM', 'Gene', (43, 46))	('CDKN2A', 'Gene', '1029', (24, 30))	('p16', 'Gene', '1029', (20, 23))
2748	20591913	Half of the homozygous deletion samples included a concurrent hemizygous pattern suggesting genetic tumour progression.	('tumour', 'Disease', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('deletion', 'Var', (23, 31))
2749	20591913	Alternatively, haploid deficiency by hemizygous deletion in combination with other oncogenic events could be sufficient for malignant transformation.	('malignant transformation', 'CPA', (124, 148))	('haploid deficiency', 'Disease', (15, 33))	('haploid deficiency', 'Disease', 'MESH:D007153', (15, 33))	('hemizygous deletion', 'Var', (37, 56))
2750	20591913	Using FISH on 32 cytological specimens (whole cell nuclei), Illei et al identified homozygous p16/CDKN2A deletion in 85.7% (6/7) of cases with malignant cytology and 100% (6/6) with suspicious cytology; no deletion was detected in 19 cytologically negative specimens.	('deletion', 'Var', (105, 113))	('p16', 'Gene', '1029', (94, 97))	('CDKN2A', 'Gene', (98, 104))	('p16', 'Gene', (94, 97))	('CDKN2A', 'Gene', '1029', (98, 104))
2751	20591913	They subsequently reported FISH on freshly imprinted tumour cells of 95 MPM and showed homozygous p16/CDKN2A deletion in 74% of cases and hemizygous loss in five cases (5%).	('p16', 'Gene', (98, 101))	('deletion', 'Var', (109, 117))	('tumour', 'Disease', (53, 59))	('CDKN2A', 'Gene', (102, 108))	('p16', 'Gene', '1029', (98, 101))	('CDKN2A', 'Gene', '1029', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
2753	20591913	More recently, a study that combined FFPE whole sections and tissue microarray (TMA) cores identified homozygous p16/CDKN2A deletion in 67% (35/52) of MPM and 25% (5/20) of peritoneal mesotheliomas.	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (173, 197))	('p16', 'Gene', (113, 116))	('CDKN2A', 'Gene', '1029', (117, 123))	('p16', 'Gene', '1029', (113, 116))	('peritoneal mesotheliomas', 'Disease', 'MESH:D008654', (173, 197))	('MPM', 'Disease', (151, 154))	('CDKN2A', 'Gene', (117, 123))	('deletion', 'Var', (124, 132))	('peritoneal mesotheliomas', 'Disease', (173, 197))
2754	20591913	In these latter two studies, homozygous p16/CDKN2A deletion was defined by the same cut-off used by Illei et al, but without the rationale to justify the use of this cut-off in tissue sections.	('p16', 'Gene', (40, 43))	('CDKN2A', 'Gene', (44, 50))	('p16', 'Gene', '1029', (40, 43))	('CDKN2A', 'Gene', '1029', (44, 50))	('deletion', 'Var', (51, 59))
2756	20591913	P16/CDKN2A deletion was associated with a worse outcome, with a 50% two-year survival for lack of p16/CDKN2A deletion versus 17% survival for patients with the deletion.	('p16', 'Gene', (98, 101))	('deletion', 'Var', (109, 117))	('P16', 'Gene', (0, 3))	('CDKN2A', 'Gene', (102, 108))	('lack', 'NegReg', (90, 94))	('CDKN2A', 'Gene', '1029', (4, 10))	('P16', 'Gene', '1029', (0, 3))	('p16', 'Gene', '1029', (98, 101))	('CDKN2A', 'Gene', '1029', (102, 108))	('deletion', 'Var', (11, 19))	('patients', 'Species', '9606', (142, 150))	('CDKN2A', 'Gene', (4, 10))
2757	20591913	This is consistent with previous studies identifying loss of p16/CDKN2A as a poor prognostic indicator.	('CDKN2A', 'Gene', '1029', (65, 71))	('CDKN2A', 'Gene', (65, 71))	('p16', 'Gene', (61, 64))	('loss', 'Var', (53, 57))	('p16', 'Gene', '1029', (61, 64))
2759	20591913	In conclusion, FISH for p16/CDKN2A deletion on FFPE sections is a clinically relevant confirmatory test for diagnosing MPM.	('p16', 'Gene', '1029', (24, 27))	('MPM', 'Disease', (119, 122))	('p16', 'Gene', (24, 27))	('CDKN2A', 'Gene', (28, 34))	('deletion', 'Var', (35, 43))	('CDKN2A', 'Gene', '1029', (28, 34))
2760	20591913	Establishing cut-off values for p16/CDKN2A deletion using appropriate controls is essential to fluorescence in situ hybridisation (FISH) assay development on paraffin sections.	('paraffin', 'Chemical', 'MESH:D010232', (158, 166))	('CDKN2A', 'Gene', (36, 42))	('deletion', 'Var', (43, 51))	('p16', 'Gene', '1029', (32, 35))	('CDKN2A', 'Gene', '1029', (36, 42))	('p16', 'Gene', (32, 35))
2761	20591913	Detection of hemizygous p16/CDKN2A deletion alone is supportive of the diagnosis of malignant pleural mesothelioma.	('p16', 'Gene', '1029', (24, 27))	('p16', 'Gene', (24, 27))	('CDKN2A', 'Gene', (28, 34))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (94, 114))	('deletion', 'Var', (35, 43))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (84, 114))	('CDKN2A', 'Gene', '1029', (28, 34))	('malignant pleural mesothelioma', 'Disease', (84, 114))
2762	20591913	Presence of p16/CDKN2A deletion by FISH is associated with a worse prognosis in malignant pleural mesothelioma (MPM).	('deletion', 'Var', (23, 31))	('p16', 'Gene', '1029', (12, 15))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (90, 110))	('malignant pleural mesothelioma', 'Disease', (80, 110))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (80, 110))	('p16', 'Gene', (12, 15))
2781	28168071	Mesothelioma is caused by a mutation of mesothelial cells that make up the lining of organs as lung, pericardium, peritoneum, and testicles.	('mutation', 'Var', (28, 36))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('caused by', 'Reg', (16, 25))
2802	26467803	Despite the import of asbestos into the UK having been banned for two decades, Health and Safety Executive data for 2012 shows that MPM caused 2535 deaths in England, Wales and Scotland.	('MPM', 'Var', (132, 135))	('death', 'Disease', 'MESH:D003643', (148, 153))	('asbestos', 'Chemical', 'MESH:D001194', (22, 30))	('death', 'Disease', (148, 153))
2888	23868066	Polyubiquitinated RIPK1 then serves as a docking site for the downstream kinases that activate the canonical nuclear factor-kappaB (NF-kappaB, RelA/p50) signaling pathway.	('NF-kappaB', 'Gene', (132, 141))	('p50', 'Gene', '4790', (148, 151))	('Polyubiquitinated', 'Var', (0, 17))	('RelA', 'Gene', (143, 147))	('RIPK1', 'Gene', (18, 23))	('RelA', 'Gene', '5970', (143, 147))	('activate', 'PosReg', (86, 94))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))	('NF-kappaB', 'Gene', '4790', (132, 141))	('RIPK1', 'Gene', '8737', (18, 23))	('p50', 'Gene', (148, 151))
2890	23868066	Thus, by ubiquitinating RIPK1, cIAP1 and cIAP2 act as positive regulators of the generally antiapoptotic, pro-inflammatory canonical NF-kappaB signaling pathway and at the same time inhibit caspase 8 activation in response to ligation of TNFR1.	('NF-kappaB', 'Gene', '4790', (133, 142))	('caspase 8', 'Gene', '841', (190, 199))	('TNFR1', 'Gene', '7132', (238, 243))	('RIPK1', 'Gene', (24, 29))	('NF-kappaB', 'Gene', (133, 142))	('cIAP1', 'Gene', (31, 36))	('cIAP1', 'Gene', '329', (31, 36))	('caspase 8', 'Gene', (190, 199))	('ubiquitinating', 'Var', (9, 23))	('activation', 'MPA', (200, 210))	('inhibit', 'NegReg', (182, 189))	('cIAP2', 'Gene', (41, 46))	('TNFR1', 'Gene', (238, 243))	('cIAP2', 'Gene', '330', (41, 46))	('ligation', 'MPA', (226, 234))	('signaling pathway', 'biological_process', 'GO:0007165', ('143', '160'))	('RIPK1', 'Gene', '8737', (24, 29))
2893	23868066	Moreover, FLIP is the product of an NFkappaB target gene (CFLAR) and therefore is upregulated following TNFR1 ligation.	('ligation', 'Var', (110, 118))	('TNFR1', 'Gene', '7132', (104, 109))	('NFkappaB', 'Gene', '4790', (36, 44))	('CFLAR', 'Gene', '8837', (58, 63))	('upregulated', 'PosReg', (82, 93))	('CFLAR', 'Gene', (58, 63))	('TNFR1', 'Gene', (104, 109))	('FLIP', 'MPA', (10, 14))	('NFkappaB', 'Gene', (36, 44))
2895	23868066	Under certain conditions Complex II can induce cell death through an non-apoptotic, programmed necrosis pathway, which is dependent on RIPK1 and 3.	('Complex II', 'molecular_function', 'GO:0008177', ('25', '35'))	('non-apoptotic', 'Pathway', (69, 82))	('programmed necrosis', 'biological_process', 'GO:0070266', ('84', '103'))	('cell death', 'CPA', (47, 57))	('Complex', 'Var', (25, 32))	('necrosis', 'Disease', (95, 103))	('RIPK1 and 3', 'Gene', '8737;11035', (135, 146))	('necrosis', 'Disease', 'MESH:D009336', (95, 103))	('cell death', 'biological_process', 'GO:0008219', ('47', '57'))
2933	23868066	Indeed, we found that FLIP silencing did not promote formation of complex IIb formation either in response to SMC or TNFalpha treatment (Supplementary Figure 4C).	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('TNFalpha', 'Gene', (117, 125))	('SMC', 'cellular_component', 'GO:0016029', ('110', '113'))	('TNFalpha', 'Gene', '7124', (117, 125))	('formation', 'biological_process', 'GO:0009058', ('53', '62'))	('FLIP silencing', 'Var', (22, 36))
2936	23868066	To further prove that it is FLIP's recruitment to complex IIb that modulates sensitivity to AT-IAP/TNFalpha, we utilized a FLIP mutant (F114A) that cannot interact with the critical adapter protein in the complex, FADD (Figure 4c).	('TNFalpha', 'Gene', (99, 107))	('IAP', 'Gene', '961', (95, 98))	('F114A', 'Mutation', 'p.F114A', (136, 141))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('TNFalpha', 'Gene', '7124', (99, 107))	('IAP', 'Gene', (95, 98))	('modulates', 'Reg', (67, 76))	('F114A', 'Var', (136, 141))
2937	23868066	When endogenous FLIP(L) and FLIP(S) proteins were depleted with a 5'-UTR-targeting siRNA (Supplementary Figure 4D), an exogenously expressed wild-type FLIP(S) protein was able to completely rescue the cell death induced by AT-IAP/TNFalpha treatment, however, the exogenously expressed F114A FLIP(S) mutant failed to rescue the cell death phenotype (Figure 4d), indicating that FLIP(S) must be able to interact with FADD to inhibit cell death induced by AT-IAP/TNFalpha.	('TNFalpha', 'Gene', (460, 468))	('IAP', 'Gene', (456, 459))	('inhibit', 'NegReg', (423, 430))	('TNFalpha', 'Gene', (230, 238))	('cell death', 'CPA', (431, 441))	('cell death', 'biological_process', 'GO:0008219', ('201', '211'))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('TNFalpha', 'Gene', '7124', (460, 468))	('F114A', 'Var', (285, 290))	('TNFalpha', 'Gene', '7124', (230, 238))	('cell death', 'biological_process', 'GO:0008219', ('327', '337'))	('cell death', 'biological_process', 'GO:0008219', ('431', '441'))	('IAP', 'Gene', '961', (226, 229))	('cell death', 'CPA', (201, 211))	('F114A', 'Mutation', 'p.F114A', (285, 290))	('IAP', 'Gene', '961', (456, 459))	('IAP', 'Gene', (226, 229))
2944	23868066	However, these results demonstrate that although cisplatin can induce downregulation of FLIP(S) in some MPM cell lines, it has little effect on FLIP(L) expression.	('downregulation', 'NegReg', (70, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('FLIP(S', 'Gene', (88, 94))	('cisplatin', 'Var', (49, 58))
2954	23868066	Consistent with FLIP downregulation being necessary for SAHA treatment to promote AT-IAP/TNFalpha-induced cell death, overexpression of either FLIP(S) or FLIP(L) blocked the effects of SAHA and AT-IAP/TNFalpha cotreatment on cell death (Figure 7b).	('FLIP', 'Var', (154, 158))	('TNFalpha', 'Gene', (89, 97))	('SAHA', 'Chemical', '-', (185, 189))	('IAP', 'Gene', '961', (197, 200))	('TNFalpha', 'Gene', '7124', (89, 97))	('cell death', 'biological_process', 'GO:0008219', ('225', '235'))	('IAP', 'Gene', (197, 200))	('downregulation', 'NegReg', (21, 35))	('TNFalpha', 'Gene', (201, 209))	('IAP', 'Gene', (85, 88))	('SAHA', 'Chemical', '-', (56, 60))	('IAP', 'Gene', '961', (85, 88))	('TNFalpha', 'Gene', '7124', (201, 209))	('cell death', 'biological_process', 'GO:0008219', ('106', '116'))
2965	23868066	Thus, the central tenet of our approach was that inhibition of IAP function would divert microenvironment-derived, pro-inflammatory signaling from activating pro-tumorigenic NF-kappaB-driven responses towards apoptosis-promoting and anti-inflammatory signaling phenotypes.	('IAP', 'Gene', (63, 66))	('divert', 'NegReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('microenvironment-derived', 'MPA', (89, 113))	('activating', 'PosReg', (147, 157))	('NF-kappaB', 'Gene', '4790', (174, 183))	('tumor', 'Disease', (162, 167))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))	('NF-kappaB', 'Gene', (174, 183))	('apoptosis', 'biological_process', 'GO:0097194', ('209', '218'))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('inhibition', 'Var', (49, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('209', '218'))	('IAP', 'Gene', '961', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
2999	23868066	REN cell lines overexpressing FLIP(L) and FLIP(S) were generated as previously described.	('REN', 'Gene', '5972', (0, 3))	('FLIP', 'Var', (30, 34))	('REN', 'Gene', (0, 3))
3041	22569537	Staining for anti-EAAT1 and anti-GS antibodies was positive in H2052, H513, MS-1, 211H and H290, and negative in H28 and LP9.	('H290', 'CellLine', 'CVCL:A555', (91, 95))	('GS', 'Gene', '2752', (33, 35))	('EAAT1', 'Gene', (18, 23))	('EAAT1', 'Gene', '6507', (18, 23))	('H513', 'CellLine', 'CVCL:A570', (70, 74))	('LP9', 'CellLine', 'CVCL:E109', (121, 124))	('H2052', 'Var', (63, 68))
3049	22569537	Western blot analysis showed that EAAT1 protein expression was high in H2052, MS-1, 211H, H513 and H290, but low in H28 and LP9.	('H290', 'CellLine', 'CVCL:A555', (99, 103))	('low', 'NegReg', (109, 112))	('EAAT1', 'Gene', (34, 39))	('EAAT1', 'Gene', '6507', (34, 39))	('expression', 'MPA', (48, 58))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('H2052', 'Var', (71, 76))	('LP9', 'CellLine', 'CVCL:E109', (124, 127))	('H513', 'CellLine', 'CVCL:A570', (90, 94))	('high', 'PosReg', (63, 67))
3099	22043159	According to the literature, the main positive MM markers include HBME-1, 34betaE12, calretinin, WT-1 and vimentin, and the negative markers mainly include TTF-1 and villin.	('vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('34betaE12', 'Var', (74, 83))	('vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('HBME-1', 'CellLine', 'CVCL:U718', (66, 72))	('calretinin', 'Gene', '794', (85, 95))	('TTF-1', 'Gene', '7080', (156, 161))	('TTF-1', 'Gene', (156, 161))	('WT-1 and vimentin', 'Gene', '7490;7431', (97, 114))	('calretinin', 'Gene', (85, 95))	('HBME-1', 'Gene', (66, 72))
3126	18662397	The effects of these mutations and additional effects from environmental risk factors have begun to explain how malignant mesothelioma cells form malignant tumors.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (112, 134))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (112, 134))	('malignant mesothelioma', 'Disease', (112, 134))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('malignant tumors', 'Disease', (146, 162))	('malignant tumors', 'Disease', 'MESH:D018198', (146, 162))	('mutations', 'Var', (21, 30))
3132	18662397	Epigenetic methods may also contribute to TSG inactivation.	('TSG', 'Gene', '57045', (42, 45))	('contribute', 'Reg', (28, 38))	('inactivation', 'NegReg', (46, 58))	('Epigenetic methods', 'Var', (0, 18))	('TSG', 'Gene', (42, 45))
3138	18662397	The most well-known mechanism is the inactivation of p53's upstream regulator p14ARF.	('p53', 'Gene', (53, 56))	('inactivation', 'Var', (37, 49))	('p14ARF', 'Gene', (78, 84))	('p14ARF', 'Gene', '1029', (78, 84))
3139	18662397	With the loss of p14ARF, the cell loses its ability to inhibit MDM2.	('loses', 'NegReg', (34, 39))	('ability', 'MPA', (44, 51))	('p14ARF', 'Gene', (17, 23))	('loss', 'Var', (9, 13))	('MDM2', 'Gene', '4193', (63, 67))	('MDM2', 'Gene', (63, 67))	('inhibit', 'NegReg', (55, 62))	('p14ARF', 'Gene', '1029', (17, 23))
3145	18662397	Homozygous deletion of p16/CDKN2A has been reported in >70% of malignant mesotheliomas, and has been associated with poor prognosis.	('p16', 'Gene', (23, 26))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (63, 86))	('malignant mesotheliomas', 'Disease', (63, 86))	('CDKN2A', 'Gene', (27, 33))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (63, 86))	('p16', 'Gene', '1029', (23, 26))	('Homozygous deletion', 'Var', (0, 19))	('reported', 'Reg', (43, 51))	('CDKN2A', 'Gene', '1029', (27, 33))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (63, 85))
3151	18662397	found that the re-expression of merlin in two human malignant mesothelioma cell lines significantly decreased cell motility and invasion.	('re-expression', 'Var', (15, 28))	('cell motility', 'biological_process', 'GO:0048870', ('110', '123'))	('malignant mesothelioma', 'Disease', (52, 74))	('merlin', 'Gene', '4771', (32, 38))	('human', 'Species', '9606', (46, 51))	('decreased', 'NegReg', (100, 109))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (52, 74))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (52, 74))	('merlin', 'Gene', (32, 38))
3154	18662397	While the loss of TSGs allows the cell to grow in light of aberrant changes in cellular DNA and function, it is the activation of oncogenes that inspires cell growth and proliferation.	('loss', 'Var', (10, 14))	('TSG', 'Gene', (18, 21))	('cell growth', 'biological_process', 'GO:0016049', ('154', '165'))	('function', 'MPA', (96, 104))	('rat', 'Species', '10116', (177, 180))	('changes', 'Reg', (68, 75))	('proliferation', 'CPA', (170, 183))	('cell growth', 'CPA', (154, 165))	('TSG', 'Gene', '57045', (18, 21))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))
3167	18662397	SV40tag is known to inhibit protein phosphatase 2A (PP2A).	('SV40tag', 'Var', (0, 7))	('protein', 'Protein', (28, 35))	('inhibit', 'NegReg', (20, 27))	('PP2A', 'Gene', '5524', (52, 56))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('28', '50'))	('PP2A', 'Gene', (52, 56))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('phosphatase 2A', 'Gene', (36, 50))	('phosphatase 2A', 'Gene', '5524', (36, 50))
3174	18662397	It is interesting that activating mutations in the GSK3beta phosphorylation sites of beta-catenin have not been detected since mutations in the p53 and pRb tumor suppressors also do not appear to play an important role in MPM pathogenesis as discussed above.	('beta-catenin', 'Gene', '1499', (85, 97))	('pRb', 'Gene', (152, 155))	('GSK3beta', 'Gene', '2932', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('MPM', 'Disease', (222, 225))	('pRb', 'Gene', '5925', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('pathogenesis', 'biological_process', 'GO:0009405', ('226', '238'))	('tumor', 'Disease', (156, 161))	('beta-catenin', 'Gene', (85, 97))	('mutations', 'Var', (127, 136))	('GSK3beta', 'Gene', (51, 59))	('GSK', 'molecular_function', 'GO:0050321', ('51', '54'))	('p53', 'Gene', (144, 147))
3176	18662397	For example, an increase in disheveled expression has been observed in patient samples and mesothelioma cell lines, and a lack of staining in some mesotheliomas for the C-terminus of APC has led to the hypothesis that inactivating mutations of APC may be involved.	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('mesotheliomas', 'Disease', (147, 160))	('mesothelioma', 'Disease', (147, 159))	('disheveled expression', 'MPA', (28, 49))	('APC', 'Phenotype', 'HP:0005227', (244, 247))	('APC', 'Disease', 'MESH:D011125', (244, 247))	('increase', 'PosReg', (16, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('APC', 'Phenotype', 'HP:0005227', (183, 186))	('inactivating mutations', 'Var', (218, 240))	('APC', 'cellular_component', 'GO:0005680', ('183', '186'))	('APC', 'cellular_component', 'GO:0005680', ('244', '247'))	('mesothelioma', 'Disease', (91, 103))	('APC', 'Disease', 'MESH:D011125', (183, 186))	('APC', 'Disease', (244, 247))	('patient', 'Species', '9606', (71, 78))	('APC', 'Disease', (183, 186))	('mesotheliomas', 'Disease', 'MESH:D008654', (147, 160))
3180	18662397	Lastly, SV40tag may also be involved in the activation of the Wnt pathway, in addition to its role of ERK activation.	('Wnt pathway', 'Pathway', (62, 73))	('ERK', 'molecular_function', 'GO:0004707', ('102', '105'))	('ERK', 'Gene', '5594', (102, 105))	('involved', 'Reg', (28, 36))	('ERK', 'Gene', (102, 105))	('SV40tag', 'Var', (8, 15))
3198	18662397	The use of antisense oligonucleotides (ODN) to inhibit the production of both VEGF and VEGF-C slowed mesothelioma cell growth.	('VEGF-C', 'Gene', (87, 93))	('VEGF', 'Gene', '7422', (78, 82))	('VEGF', 'Gene', (78, 82))	('inhibit', 'NegReg', (47, 54))	('oligonucleotides', 'Chemical', 'MESH:D009841', (21, 37))	('VEGF', 'Gene', '7422', (87, 91))	('mesothelioma', 'Disease', (101, 113))	('production', 'MPA', (59, 69))	('cell growth', 'biological_process', 'GO:0016049', ('114', '125'))	('slowed', 'NegReg', (94, 100))	('VEGF-C', 'Gene', '7424', (87, 93))	('antisense', 'Var', (11, 20))	('VEGF', 'Gene', (87, 91))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
3199	18662397	In addition, antibodies to VEGF receptor (VEGFR-2) and VEGF-C receptor (VEGFR-3) had a synergistic effect in inhibiting mesothelioma cell growth.	('inhibiting', 'NegReg', (109, 119))	('VEGF-C', 'Gene', (55, 61))	('VEGF', 'Gene', '7422', (27, 31))	('VEGFR-3', 'Gene', (72, 79))	('VEGF-C', 'Gene', '7424', (55, 61))	('EGF receptor', 'Gene', (28, 40))	('VEGF', 'Gene', (27, 31))	('VEGF', 'Gene', '7422', (42, 46))	('VEGF', 'Gene', (42, 46))	('VEGFR-2', 'Gene', '3791', (42, 49))	('mesothelioma', 'Disease', (120, 132))	('VEGF', 'Gene', '7422', (55, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('VEGF', 'Gene', '7422', (72, 76))	('cell growth', 'biological_process', 'GO:0016049', ('133', '144'))	('VEGF', 'Gene', (55, 59))	('VEGFR-3', 'Gene', '2324', (72, 79))	('antibodies', 'Var', (13, 23))	('VEGF', 'Gene', (72, 76))	('EGF receptor', 'Gene', '1956', (28, 40))	('VEGFR-2', 'Gene', (42, 49))
3201	18662397	Production and release of VEGF was greater in SV40Tag-positive MPM cells than in MPM cells that did not show evidence of SV40 infection.	('greater', 'PosReg', (35, 42))	('SV40 infection', 'Disease', (121, 135))	('Production', 'MPA', (0, 10))	('VEGF', 'Gene', (26, 30))	('SV40Tag-positive', 'Var', (46, 62))	('SV40 infection', 'Disease', 'MESH:D007239', (121, 135))	('VEGF', 'Gene', '7422', (26, 30))
3202	18662397	It appears that this effect is mediated through more than just SV40Tag, since mesothelial cells transfected with the full length SV40 genome produced higher levels of VEGF as compared to cells transfected with SV40Tag only.	('SV40 genome', 'Var', (129, 140))	('higher', 'PosReg', (150, 156))	('VEGF', 'Gene', '7422', (167, 171))	('VEGF', 'Gene', (167, 171))
3219	18662397	The activation of telomerase allows MPM cells to escape this mechanism of cell death and to perpetuate mutations that might have otherwise been discarded in the normal process of "cell aging."	('mutations', 'Var', (103, 112))	('cell death', 'biological_process', 'GO:0008219', ('74', '84'))	('death', 'Disease', 'MESH:D003643', (79, 84))	('telomerase', 'Protein', (18, 28))	('death', 'Disease', (79, 84))	('activation', 'PosReg', (4, 14))
3222	18662397	Asbestos induces mutations in mesothelial cells.	('induces', 'Reg', (9, 16))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('mutations', 'Var', (17, 26))
3234	18662397	In addition, polymorphisms in some genes of important free radical scavenging enzymes such as mitochondrial manganese superoxide dismutase (MnSOD), glutathione-S-transferase M1 and mEH have been associated with MPM.	('associated', 'Reg', (195, 205))	('manganese superoxide dismutase', 'Gene', '6648', (108, 138))	('MPM', 'Disease', (211, 214))	('mEH', 'molecular_function', 'GO:0033961', ('181', '184'))	('polymorphisms', 'Var', (13, 26))	('glutathione-S-transferase M1', 'Gene', '2946', (148, 176))	('mEH', 'Gene', '13849', (181, 184))	('manganese superoxide dismutase', 'Gene', (108, 138))	('MnSOD', 'Gene', '6648', (140, 145))	('mEH', 'Gene', (181, 184))	('glutathione-S-transferase M1', 'Gene', (148, 176))	('MnSOD', 'Gene', (140, 145))
3259	18662397	Briefly, SV40Tag can bind to and inhibit p53 and pRb TSGs, and SV40tag has been shown to inhibit PP2A, which may lead to the activation of Wnt and ERK signaling pathways.	('PP2A', 'Gene', (97, 101))	('pRb', 'Gene', (49, 52))	('ERK', 'Gene', (147, 150))	('activation', 'PosReg', (125, 135))	('inhibit', 'NegReg', (33, 40))	('pRb', 'Gene', '5925', (49, 52))	('PP2A', 'Gene', '5524', (97, 101))	('ERK', 'Gene', '5594', (147, 150))	('SV40tag', 'Var', (63, 70))	('TSG', 'Gene', (53, 56))	('SV40Tag', 'Var', (9, 16))	('inhibit', 'NegReg', (89, 96))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('p53', 'Protein', (41, 44))	('bind', 'Interaction', (21, 25))	('TSG', 'Gene', '57045', (53, 56))
3267	18662397	10 out of 11 tumors with detectable SV40Tag expression also stained positively for activated Akt.	('Akt', 'Gene', (93, 96))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('stained', 'Reg', (60, 67))	('SV40Tag', 'Var', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('Akt', 'Gene', '207', (93, 96))
3269	18662397	expressed SV40Tag and SV40tag in human mesothelial and fibroblast cells, cells that had been treated with asbestos showed a larger number of transformed foci as compared to cells that only expressed SV40.	('SV40tag', 'Var', (22, 29))	('SV40Tag', 'Var', (10, 17))	('human', 'Species', '9606', (33, 38))	('transformed foci', 'CPA', (141, 157))	('asbestos', 'Chemical', 'MESH:D001194', (106, 114))
3270	18662397	Not only does the above data supply strong mechanistic support for the role of SV40 infection in MPM pathogenesis, but in vitro experiments have also demonstrated a high susceptibility of mesothelial cells to develop stable infections by SV40 as compared to human fibroblasts, which quickly lyse after only semipermissive infection.	('SV40 infection', 'Disease', (79, 93))	('human', 'Species', '9606', (258, 263))	('infection', 'Disease', 'MESH:D007239', (84, 93))	('infection', 'Disease', (224, 233))	('SV40 infection', 'Disease', 'MESH:D007239', (79, 93))	('infection', 'Disease', 'MESH:D007239', (224, 233))	('SV40', 'Var', (238, 242))	('pathogenesis', 'biological_process', 'GO:0009405', ('101', '113'))	('rat', 'Species', '10116', (157, 160))	('infection', 'Disease', (84, 93))	('infection', 'Disease', (322, 331))	('infection', 'Disease', 'MESH:D007239', (322, 331))
3279	18662397	In a study by Manfredi et al., SV40Tag DNA was not detectable in tumor tissue of 69 mesothelioma patients.	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('SV40Tag DNA', 'Var', (31, 42))	('mesothelioma', 'Disease', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('patients', 'Species', '9606', (97, 105))
3280	18662397	SV40Tag protein was also undetectable in tumor samples and mesothelioma cell lines by immunohistochemistry.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('mesothelioma', 'Disease', (59, 71))	('SV40Tag', 'Var', (0, 7))	('tumor', 'Disease', (41, 46))	('protein', 'Protein', (8, 15))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('undetectable', 'NegReg', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
3301	18662397	It is unclear if the time lag between asbestos exposure and diagnosis reflects a slow-growing tumor after early genetic mutations, or if the accumulation of genetic changes reaches a threshold of malignant transformation since the late stage of diagnosis makes it difficult to determine the temporality of various genetic and molecular events.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (120, 129))
3306	29524617	In addition, other promising targeted therapies including ADI-PEG20 focusing on argininosuccinate synthase 1 deficient tumors and Tazemetostat, an EZH2 inhibitor of BAP1 deficient tumors are currently being explored.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('deficient tumors', 'Disease', 'MESH:D009369', (109, 125))	('EZH2', 'Gene', '2146', (147, 151))	('argininosuccinate synthase 1', 'Gene', (80, 108))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('EZH2', 'Gene', (147, 151))	('Tazemetostat', 'Chemical', 'MESH:C000593333', (130, 142))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('ADI-PEG20', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('deficient tumors', 'Disease', (109, 125))	('deficient tumors', 'Disease', (170, 186))	('argininosuccinate synthase 1', 'Gene', '445', (80, 108))	('deficient tumors', 'Disease', 'MESH:D009369', (170, 186))
3346	29524617	The role of heredity in familial MPM predisposition, even without occupational asbestos exposure, has finally been proven by the discovery of germline BAP1 mutations, and supported by murine modeling.	('asbestos', 'Chemical', 'MESH:D001194', (79, 87))	('BAP1', 'Gene', (151, 155))	('familial MPM', 'Disease', (24, 36))	('mutations', 'Var', (156, 165))	('murine', 'Species', '10090', (184, 190))
3352	29524617	Furthermore, frequent germline mutations in other genes associated with DNA repair have been identified in asbestos-exposed individuals who developed MPM, suggesting theses pathways to be associated with MPM predisposition.	('associated', 'Reg', (188, 198))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('MPM', 'Disease', (204, 207))	('germline mutations', 'Var', (22, 40))	('MPM', 'Disease', (150, 153))	('asbestos', 'Chemical', 'MESH:D001194', (107, 115))	('identified', 'Reg', (93, 103))	('DNA repair', 'biological_process', 'GO:0006281', ('72', '82'))
3353	29524617	Interestingly common germline BAP1 variants appear to mediate the risk of developing renal cell carcinoma and lung cancer, and possibly also MPM.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (85, 105))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('BAP1', 'Gene', (30, 34))	('variants', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('renal cell carcinoma', 'Disease', (85, 105))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('MPM', 'Disease', (141, 144))
3354	29524617	When mesothelioma develops in carriers of germline BAP1 mutations, these malignancies have a much better prognosis, and survival of 5 or more years is commonly seen.	('mutations', 'Var', (56, 65))	('BAP1', 'Gene', (51, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (5, 17))	('germline', 'Var', (42, 50))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('malignancies', 'Disease', (73, 85))	('mesothelioma', 'Disease', (5, 17))
3357	29524617	In 2017 it was reported that these patients show distinctive clinical, pathologic and genetic features, such as: higher likelihood of a past history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('deletion', 'Var', (229, 237))	('breast cancer', 'Disease', (188, 201))	('CDKN2A', 'Gene', (222, 228))	('patients', 'Species', '9606', (249, 257))	('CDKN2A', 'Gene', '1029', (222, 228))	('patients', 'Species', '9606', (35, 43))	('lower', 'NegReg', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
3367	29524617	In 87 evaluable patients (44 nintedanib, 43 placebo), nintedanib improved progression-free survival (PFS) by 3.7 months as compared with placebo (p=0.01), most notably in those with epithelioid histology (4 months PFS, p=0.006).	('improved', 'PosReg', (65, 73))	('patients', 'Species', '9606', (16, 24))	('nintedanib', 'Var', (54, 64))	('nintedanib', 'Chemical', 'MESH:C530716', (29, 39))	('nintedanib', 'Chemical', 'MESH:C530716', (54, 64))	('progression-free survival', 'CPA', (74, 99))
3371	29524617	CTLA-4 inhibition enhances T-cell activation and increases antitumor efficacy in other cancers.	('cancers', 'Disease', (87, 94))	('T-cell activation', 'CPA', (27, 44))	('tumor', 'Disease', (63, 68))	('CTLA-4', 'Gene', (0, 6))	('T-cell activation', 'biological_process', 'GO:0042110', ('27', '44'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('increases', 'PosReg', (49, 58))	('inhibition', 'Var', (7, 17))	('CTLA-4', 'Gene', '1493', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('enhances', 'PosReg', (18, 26))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
3419	29524617	No dose-limiting toxicities were encountered, and only nine reported adverse events were related to ADI-PEG20, most commonly rash.	('rash', 'Phenotype', 'HP:0000988', (125, 129))	('toxicities', 'Disease', 'MESH:D064420', (17, 27))	('rash', 'Disease', 'MESH:D005076', (125, 129))	('ADI-PEG20', 'Var', (100, 109))	('rash', 'Disease', (125, 129))	('toxicities', 'Disease', (17, 27))
3425	29524617	Hippo pathway dysregulation leads to constitutive activation of YAP1/TAZ transcriptional coactivators and enhances malignant phenotypes of MM cells.	('Hippo', 'Gene', (0, 5))	('YAP1', 'Gene', '10413', (64, 68))	('activation', 'PosReg', (50, 60))	('dysregulation', 'Var', (14, 27))	('TAZ', 'Gene', '6901', (69, 72))	('enhances', 'PosReg', (106, 114))	('TAZ', 'Gene', (69, 72))	('malignant phenotypes of MM cells', 'CPA', (115, 147))	('YAP1', 'Gene', (64, 68))
3436	29524617	Other promising therapeutic candidates include the monopolar spindle 1 kinase, a kinase of the spindle assembly checkpoint that controls cell division and cell fate; the mTOR/PI3K/AKT axis for the aggressive subset of MPM harboring simultaneous inactivating mutations of the genes LATS2 and NF2; the sialylated protein HEG1 which can be targeted by a specific monoclonal antibody; and targeting of MYC which is upregulated in MPM cells.	('HEG1', 'Gene', (319, 323))	('spindle', 'cellular_component', 'GO:0005819', ('61', '68'))	('mTOR', 'Gene', (170, 174))	('spindle assembly checkpoint', 'biological_process', 'GO:0071173', ('95', '122'))	('HEG1', 'Gene', '57493', (319, 323))	('MYC', 'Gene', (398, 401))	('antibody', 'cellular_component', 'GO:0019814', ('371', '379'))	('mTOR', 'Gene', '2475', (170, 174))	('AKT', 'Gene', (180, 183))	('monopolar spindle 1 kinase', 'Gene', (51, 77))	('protein', 'cellular_component', 'GO:0003675', ('311', '318'))	('antibody', 'molecular_function', 'GO:0003823', ('371', '379'))	('NF2', 'Gene', '4771', (291, 294))	('MYC', 'Gene', '4609', (398, 401))	('inactivating mutations', 'Var', (245, 267))	('antibody', 'cellular_component', 'GO:0042571', ('371', '379'))	('monopolar spindle 1 kinase', 'Gene', '7272', (51, 77))	('NF2', 'Gene', (291, 294))	('AKT', 'Gene', '207', (180, 183))	('spindle', 'cellular_component', 'GO:0005819', ('95', '102'))	('cell division', 'biological_process', 'GO:0051301', ('137', '150'))	('PI3K', 'molecular_function', 'GO:0016303', ('175', '179'))	('LATS2', 'Gene', (281, 286))	('LATS2', 'Gene', '26524', (281, 286))	('antibody', 'cellular_component', 'GO:0019815', ('371', '379'))
3446	29524617	A recently published comprehensive review on quality of life (QoL) in MPM showed that QoL was generally better for patients undergoing P/D compared to EPP.	('MPM', 'Disease', (70, 73))	('patients', 'Species', '9606', (115, 123))	('QoL', 'MPA', (86, 89))	('P/D', 'Var', (135, 138))	('better', 'Reg', (104, 110))
3456	29524617	Of note, carriers of germline BAP1 mutations may have a high risk of developing a second malignancy when treated with radiation therapy.	('malignancy', 'Disease', (89, 99))	('BAP1', 'Gene', (30, 34))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))	('mutations', 'Var', (35, 44))
3484	29193587	injection of iron saccharate, an in situ depositable form of iron, induced MM, in which the homozygous deletion of Cdkn2a/2b was observed in the sarcomatoid subtype.19 The same genetic alteration is observed in most (92.6%) of the asbestos-induced peritoneal MM in rats.20 Homozygous deletion of CDKN2A (p16 INK4A) is one of the most common genetic alterations in human MM.21, 22 Moreover, we observed that repeated administration of nitrilotriacetate, an iron chelator to increase the catalytic activity of iron, significantly shortened the period of asbestos-induced MM carcinogenesis, confirming the involvement of iron in this carcinogenesis.20 Therefore, we hypothesized that iron removal may reduce free radical generation even after exposure to asbestos fibers.	('free radical generation', 'MPA', (705, 728))	('iron', 'Chemical', 'MESH:D007501', (508, 512))	('asbestos', 'Chemical', 'MESH:D001194', (752, 760))	('iron', 'Chemical', 'MESH:D007501', (681, 685))	('CDKN2A', 'Gene', '25163', (296, 302))	('MM carcinogenesis', 'Disease', 'MESH:D063646', (569, 586))	('reduce', 'NegReg', (698, 704))	('CDKN2A', 'Gene', (296, 302))	('rat', 'Species', '10116', (24, 27))	('rat', 'Species', '10116', (722, 725))	('p16', 'Gene', (304, 307))	('iron', 'Chemical', 'MESH:D007501', (13, 17))	('iron', 'Chemical', 'MESH:D007501', (618, 622))	('INK4A', 'Gene', '25163', (308, 313))	('asbestos', 'Chemical', 'MESH:D001194', (552, 560))	('deletion', 'Var', (284, 292))	('MM carcinogenesis', 'Disease', (569, 586))	('rats', 'Species', '10116', (265, 269))	('rat', 'Species', '10116', (189, 192))	('catalytic activity', 'molecular_function', 'GO:0003824', ('486', '504'))	('iron', 'Chemical', 'MESH:D007501', (61, 65))	('Cdkn2a', 'Gene', (115, 121))	('Cdkn2a', 'Gene', '1029', (115, 121))	('human', 'Species', '9606', (364, 369))	('iron', 'Chemical', 'MESH:D007501', (456, 460))	('asbestos', 'Chemical', 'MESH:D001194', (231, 239))	('rat', 'Species', '10116', (353, 356))	('sarcomatoid subtype', 'Disease', (145, 164))	('rat', 'Species', '10116', (265, 268))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (145, 164))	('rat', 'Species', '10116', (424, 427))	('p16', 'Gene', '25163', (304, 307))	('INK4A', 'Gene', (308, 313))
3487	29193587	Phlebotomy has been applied in Japan to patients with chronic active hepatitis C16, 17, 28, 29 and polycythemia vera.30 We found that phlebotomy significantly decreased the tumor weight, modestly prolonged survival, and reduced the fraction of the sarcomatoid subtype.	('polycythemia vera', 'Disease', 'MESH:D011087', (99, 116))	('phlebotomy', 'Var', (134, 144))	('sarcomatoid subtype', 'Disease', (248, 267))	('reduced', 'NegReg', (220, 227))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('hepatitis', 'Phenotype', 'HP:0012115', (69, 78))	('survival', 'CPA', (206, 214))	('polycythemia vera', 'Disease', (99, 116))	('patients', 'Species', '9606', (40, 48))	('polycythemia', 'Phenotype', 'HP:0001901', (99, 111))	('prolonged', 'PosReg', (196, 205))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('chronic active hepatitis C', 'Disease', 'MESH:D019698', (54, 80))	('decreased', 'NegReg', (159, 168))	('chronic active hepatitis', 'Phenotype', 'HP:0200120', (54, 78))	('chronic active hepatitis C', 'Disease', (54, 80))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (248, 267))
3497	29193587	For adult rats, (body weight x 60) x (1/12) x (18/12) x (120/40) = 22.5 x body weight mL/month   6 x body weight mL/time every week (calculated as 40 days of turnover), or (body weight x 60) x (1/12) x (18/12) x (120/60) = 15 x body weight mL/month   8 x body weight mL/time every other week (calculated as 60 days of turnover).	('rats', 'Species', '10116', (10, 14))	('body', 'Var', (17, 21))	('body', 'Var', (173, 177))
3517	29193587	There are several variants in the epithelioid or sarcomatoid subtypes of MM.2 In our model, MMs were present with one or more variants, and we regarded them as a variant when they occupied >10% of the tumor area with H&E staining.	('variants', 'Var', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('MM.2', 'Gene', (73, 77))	('tumor', 'Disease', (201, 206))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (49, 68))	('sarcomatoid subtype', 'Disease', (49, 68))
3530	29193587	The serum iron level was measured at 20, 30, 40, 50, and 60 weeks, showing lower levels in the Phleb-4 group than in the NT group during the whole period (P < .05; Figure 1E,F).	('serum iron level', 'MPA', (4, 20))	('lower', 'NegReg', (75, 80))	('iron', 'Chemical', 'MESH:D007501', (10, 14))	('Phleb-4', 'Var', (95, 102))	('levels', 'MPA', (81, 87))	('NT', 'Chemical', '-', (121, 123))
3535	29193587	Alternatively, the survival fraction at week 103 of male Phleb-2 + Phleb-4 rats (7 alive and 12 dead) was significantly higher (P = .032; Fisher's exact test) than that of male NT rats (0 alive and 10 dead).	('Phleb-2 + Phleb-4', 'Var', (57, 74))	('rats', 'Species', '10116', (75, 79))	('higher', 'PosReg', (120, 126))	('rats', 'Species', '10116', (180, 184))	('survival fraction', 'CPA', (19, 36))	('NT', 'Chemical', '-', (177, 179))
3544	29193587	The tumor weight was significantly lower in male Phleb-4 rats (P = .039; Figure 4B) than in male NT rats.	('tumor', 'Disease', (4, 9))	('NT', 'Chemical', '-', (97, 99))	('rats', 'Species', '10116', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('lower', 'NegReg', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rats', 'Species', '10116', (57, 61))	('Phleb-4', 'Var', (49, 56))
3551	29193587	Regarding histological variants, we observed more cases in the phlebotomy group with variant histology, especially the osteosarcomatoid variant (Figure S1i) belonging to the sarcomatoid subtype (Table S2).	('osteosarcomatoid', 'Disease', (119, 135))	('osteosarcomatoid', 'Disease', 'None', (119, 135))	('variant', 'Var', (85, 92))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (174, 193))	('sarcomatoid subtype', 'Disease', (174, 193))	('osteosarcomatoid variant', 'Phenotype', 'HP:0002669', (119, 143))
3571	29193587	Phlebotomy reduced serum 8-OHdG in the Phleb-2 group but not in the Phleb-4 group, which might be affected by the acute inflammatory changes associated with repeated phlebotomy.	('reduced', 'NegReg', (11, 18))	('repeated phlebotomy', 'Phenotype', 'HP:0004419', (157, 176))	('8-OHdG', 'Chemical', 'MESH:C067134', (25, 31))	('Phleb-2', 'Var', (39, 46))	('serum 8-OHdG', 'MPA', (19, 31))
3604	28111991	NCRDs can significantly impact various aspects of patient outcomes.	('impact', 'Reg', (24, 30))	('NCRDs', 'Var', (0, 5))	('patient', 'Species', '9606', (50, 57))
3730	24497793	proposed the following criteria for malignant glomangiosarcoma: tumors with a deep location and a size of more than 2 cm, or atypical mitotic figures or marked atypia with mitotic activity.	('malignant glomangiosarcoma', 'Disease', 'MESH:D009369', (36, 62))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('atypia', 'Disease', 'None', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('malignant glomangiosarcoma', 'Disease', (36, 62))	('atypia', 'Disease', (160, 166))	('atypical', 'Var', (125, 133))
3799	16925806	Tumor suppressor gene alterations in patients with malignant mesothelioma due to environmental asbestos exposure in Turkey Environmental asbestos exposure can cause the grave lung and pleura malignancies with a high mortality rate, and it is also associated with increased rate of other organ malignancies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignant mesothelioma', 'Disease', (51, 73))	('pleura malignancies', 'Disease', (184, 203))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('Tumor suppressor', 'Gene', '7248', (0, 16))	('cause', 'Reg', (159, 164))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (51, 73))	('men', 'Species', '9606', (130, 133))	('malignancies', 'Disease', (191, 203))	('patients', 'Species', '9606', (37, 45))	('malignancies', 'Disease', 'MESH:D009369', (293, 305))	('men', 'Species', '9606', (88, 91))	('asbestos', 'Chemical', 'MESH:D001194', (137, 145))	('malignancies', 'Disease', (293, 305))	('pleura malignancies', 'Disease', 'MESH:D054363', (184, 203))	('asbestos', 'Chemical', 'MESH:D001194', (95, 103))	('Tumor suppressor', 'Gene', (0, 16))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (51, 73))	('alterations', 'Var', (22, 33))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('0', '16'))
3804	16925806	Loss of Heterozygosity (LOH) was determined at D6S275 in one patient, at D6S301 in another, at D6S474 in 2, at ARG1 in 2, at D6S1038 in 2 and at D6S1008 in 3 patients.	('D6S1008', 'Var', (145, 152))	('Heterozygosity', 'MPA', (8, 22))	('patient', 'Species', '9606', (61, 68))	('D6S275', 'Chemical', '-', (47, 53))	('D6S1008', 'Chemical', '-', (145, 152))	('D6S301', 'Chemical', '-', (73, 79))	('patient', 'Species', '9606', (158, 165))	('ARG1', 'Gene', (111, 115))	('D6S275', 'Var', (47, 53))	('D6S1038', 'Var', (125, 132))	('Loss', 'NegReg', (0, 4))	('D6S474', 'Var', (95, 101))	('D6S1038', 'Chemical', '-', (125, 132))	('patients', 'Species', '9606', (158, 166))	('ARG1', 'Gene', '383', (111, 115))	('D6S301', 'Var', (73, 79))	('D6S474', 'Chemical', '-', (95, 101))
3834	16925806	DNA samples obtained by being used to primers such as D6S251, D6S275, D6S301, D6S474, D6S1039, ARG1, D6S1038, D6S441 and D6S1008 primers on the long arm (q) of chromosome 6, and D9S169, D9S126 and D9S171 primers on the short arm (p) of chromosome 9 were amplified by PCR.	('D6S441', 'Var', (110, 116))	('ARG1', 'Gene', '383', (95, 99))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('D6S275', 'Chemical', '-', (62, 68))	('short arm', 'Phenotype', 'HP:0009824', (219, 228))	('D6S474', 'Chemical', '-', (78, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('236', '246'))	('chromosome', 'cellular_component', 'GO:0005694', ('160', '170'))	('D6S1008', 'Var', (121, 128))	('D6S301', 'Chemical', '-', (70, 76))	('D9S169', 'Var', (178, 184))	('D6S1039', 'Chemical', '-', (86, 93))	('D6S1038', 'Var', (101, 108))	('D6S1008', 'Chemical', '-', (121, 128))	('D9S126', 'Chemical', '-', (186, 192))	('ARG1', 'Gene', (95, 99))	('D6S1039', 'Var', (86, 93))	('D6S301', 'Var', (70, 76))	('D9S126', 'Var', (186, 192))	('D6S275', 'Var', (62, 68))	('D6S474', 'Var', (78, 84))	('D6S1038', 'Chemical', '-', (101, 108))	('D6S251', 'Var', (54, 60))	('D9S171', 'Var', (197, 203))
3836	16925806	Conditions for the amplification of D6S251, D6S1038, D6S441, D9S126 and D9S169 primers consisted of an initial denaturation for 3 min at 94 C, followed by 32 cycles: 30 sec at 94 C, 30 sec at 53 C and 30 sec at 72 C, and then by a 3 min extension at 72 C. Conditions for the amplification of D6S275, D6S301, D6S474, D6S1039, ARG1, D6S1008 and D9S171 primers consisted of an initial denaturation for 3 min at 94 C followed by 32 cycles: 30 sec at 94 C, 30 sec at 55 C and 30 sec at 72 C, and then by a 3 min extension at 72 C. PCR products were diluted 1:1 with a 95% formamide gel-loading buffer.	('D6S441', 'Var', (53, 59))	('D6S275', 'Chemical', '-', (292, 298))	('ARG1', 'Gene', '383', (325, 329))	('D6S1008', 'Chemical', '-', (331, 338))	('D6S251', 'Var', (36, 42))	('D6S474', 'Chemical', '-', (308, 314))	('formamide', 'Chemical', 'MESH:C031066', (567, 576))	('D9S126', 'Chemical', '-', (61, 67))	('D6S301', 'Chemical', '-', (300, 306))	('D9S171', 'Var', (343, 349))	('D9S126', 'Var', (61, 67))	('D6S1039', 'Chemical', '-', (316, 323))	('ARG1', 'Gene', (325, 329))	('D6S301', 'Var', (300, 306))	('D6S1038', 'Var', (44, 51))	('D6S1039', 'Var', (316, 323))	('D6S1008', 'Var', (331, 338))	('D6S474', 'Var', (308, 314))	('D6S275', 'Var', (292, 298))	('D6S1038', 'Chemical', '-', (44, 51))	('D9S169', 'Var', (72, 78))
3844	16925806	Of the 13 cases of which pleural effusion and blood genomic DNA were compared, 7 (54%) showed allelic loss in 6q.	('pleural effusion', 'Disease', 'MESH:D010996', (25, 41))	('pleural effusion', 'Phenotype', 'HP:0002202', (25, 41))	('pleural effusion', 'Disease', (25, 41))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('allelic loss', 'Var', (94, 106))
3846	16925806	The boundaries of the most centromeric region of deletion, SRO1, were defined by marker D6S251 proximally and by D6S249 distally.	('SRO1', 'Chemical', '-', (59, 63))	('D6S249', 'Var', (113, 119))	('deletion', 'Var', (49, 57))	('D6S251', 'Var', (88, 94))
3847	16925806	Allelic losses affecting SRO1 were detected in 1 of 13 (8%) MPMs analyzed.	('SRO1', 'Gene', (25, 29))	('Allelic losses', 'Var', (0, 14))	('SRO1', 'Chemical', '-', (25, 29))
3849	16925806	The distance between D6S301 and D6S474 was ~8 cM, and D6S301 was localized to 6q16.3-21.	('D6S301', 'Var', (54, 60))	('D6S474', 'Var', (32, 38))	('D6S301', 'Chemical', '-', (54, 60))	('D6S301', 'Var', (21, 27))	('D6S474', 'Chemical', '-', (32, 38))	('D6S301', 'Chemical', '-', (21, 27))
3850	16925806	The 3rd minimally deleted region, SRO3 was defined by an interstitial deletion in 4 of 13 cases (31%).	('deletion', 'Var', (70, 78))	('SRO3', 'Gene', (34, 38))	('SRO3', 'Chemical', '-', (34, 38))
3851	16925806	SRO3 was flanked by D6S1039 proximally and by D6S1038 distally.	('SRO3', 'Chemical', '-', (0, 4))	('D6S1039', 'Chemical', '-', (20, 27))	('D6S1038', 'Var', (46, 53))	('D6S1038', 'Chemical', '-', (46, 53))	('D6S1039', 'Var', (20, 27))
3852	16925806	A 4th discrete region of deletion, SRO4, was defined proximally by the terminal deletion in cases 2, 6 and 10, and distally by deletion in none.	('SRO4', 'Chemical', '-', (35, 39))	('deletion', 'Var', (80, 88))	('SRO4', 'Gene', (35, 39))
3853	16925806	SRO4 lies between D6S441 and D6S1008, a region of ~13 cM.	('D6S1008', 'Var', (29, 36))	('D6S441', 'Var', (18, 24))	('D6S1008', 'Chemical', '-', (29, 36))	('SRO4', 'Chemical', '-', (0, 4))
3854	16925806	On the basis of the position of markers adjacent to D6S441 and D6S1008, SRO4 was probably located within band 6q25.	('D6S1008', 'Var', (63, 70))	('D6S1008', 'Chemical', '-', (63, 70))	('SRO4', 'Chemical', '-', (72, 76))	('SRO4', 'Gene', (72, 76))	('D6S441', 'Var', (52, 58))
3863	16925806	No LOH case was determined with D9S171, D9S126 and D9S169 markers on 9p (Table 3).	('D9S169 markers', 'Var', (51, 65))	('D9S126', 'Var', (40, 46))	('D9S171', 'Var', (32, 38))	('D9S126', 'Chemical', '-', (40, 46))
3872	16925806	Although there is no common specific chromosomal alteration in MPM patients, inactivation and/or loss of TSG caused by frequent cytogenetic deletions of MPM are thought to be responsible in neoplastic development and progression of mesothelial cells.	('loss', 'NegReg', (97, 101))	('patients', 'Species', '9606', (67, 75))	('neoplastic development', 'CPA', (190, 212))	('TSG', 'Gene', (105, 108))	('deletions', 'Var', (140, 149))	('men', 'Species', '9606', (208, 211))	('MPM', 'Gene', (153, 156))	('TSG', 'Gene', '57045', (105, 108))	('responsible', 'Reg', (175, 186))	('inactivation', 'Var', (77, 89))
3873	16925806	Complex profiles of characteristic somatic-genetic alterations of MPM show that tumorigenesis of this malignancy is a multi-directional and multi-step period.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('alterations', 'Var', (51, 62))	('malignancy', 'Disease', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('malignancy', 'Disease', 'MESH:D009369', (102, 112))	('MPM', 'Gene', (66, 69))
3875	16925806	Loss of function of one or more TSG, determined by LOH at 6q, is interpreted as an important genetic change which contributes development of this malignancy.	('LOH at', 'Var', (51, 57))	('TSG', 'Gene', (32, 35))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('Loss of function', 'NegReg', (0, 16))	('TSG', 'Gene', '57045', (32, 35))	('men', 'Species', '9606', (133, 136))	('malignancy', 'Disease', (146, 156))	('contributes', 'PosReg', (114, 125))
3879	16925806	Allelic losses for SRO1 were detected in 1 of 13 (8%).	('Allelic losses', 'Var', (0, 14))	('SRO1', 'Gene', (19, 23))	('SRO1', 'Chemical', '-', (19, 23))
3880	16925806	SRO2 was also deleted in 3 of 13 cases (23%).	('SRO2', 'Chemical', '-', (0, 4))	('SRO2', 'Gene', (0, 4))	('deleted', 'Var', (14, 21))
3881	16925806	SRO3 was defined by an interstitial deletion in 4 of 13 cases (31%), whereas SRO4 was defined in 3 cases (23%).	('SRO4', 'Chemical', '-', (77, 81))	('SRO3', 'Chemical', '-', (0, 4))	('SRO3', 'Disease', (0, 4))	('deletion', 'Var', (36, 44))
3883	16925806	Although some important TSG losses in 6q and 9p, which may have an important effect in the development of this malignity, have been reported, the presence of TSG losses at 6q in the early stages of MPM and 9p in advanced stage of MPM are stressed.	('TSG', 'Gene', '57045', (158, 161))	('TSG', 'Gene', '57045', (24, 27))	('losses', 'Var', (162, 168))	('MPM', 'Disease', (198, 201))	('TSG', 'Gene', (158, 161))	('men', 'Species', '9606', (98, 101))	('TSG', 'Gene', (24, 27))
3887	16925806	Three or 4 SRO sites of genomic loss from 6q have also been described in other malignancy types, such as breast cancer, ovary cancer, and Non-Hodgkin's lymphoma.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('malignancy', 'Disease', (79, 89))	('ovary cancer', 'Disease', (120, 132))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (142, 160))	('genomic loss', 'Var', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	("Non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (138, 160))	('ovary cancer', 'Phenotype', 'HP:0100615', (120, 132))	('ovary cancer', 'Disease', 'MESH:D010051', (120, 132))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('described', 'Reg', (60, 69))	('breast cancer', 'Disease', (105, 118))	("Non-Hodgkin's lymphoma", 'Disease', (138, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
3888	16925806	In DNA analysis, deletions of interferon locus at 9p21-p22 were also detected in acute lymphoblastic leukemia, glioma, melanoma, lung cancer and bladder cancer.	('detected', 'Reg', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('p22', 'Gene', '11261', (55, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('acute lymphoblastic leukemia', 'Disease', (81, 109))	('glioma', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('deletions', 'Var', (17, 26))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (81, 109))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (81, 109))	('lung cancer', 'Disease', (129, 140))	('p22', 'Gene', (55, 58))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (87, 109))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
3890	16925806	LOH at p53 TSG accelerates tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('accelerates', 'PosReg', (15, 26))	('TSG', 'Gene', '57045', (11, 14))	('LOH', 'Var', (0, 3))	('tumor', 'Disease', (27, 32))	('p53', 'Gene', '7157', (7, 10))	('TSG', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p53', 'Gene', (7, 10))
3929	32423432	Personality has been associated with depressive symptoms in chronic illnesses and reduced emotional HRQoL in heart failure patients.	('depressive symptoms', 'Disease', (37, 56))	('depressive symptoms', 'Phenotype', 'HP:0000716', (37, 56))	('depressive symptoms', 'Disease', 'MESH:D000275', (37, 56))	('patients', 'Species', '9606', (123, 131))	('heart failure', 'Phenotype', 'HP:0001635', (109, 122))	('emotional HRQoL in heart failure', 'Disease', 'MESH:D006333', (90, 122))	('emotional HRQoL in heart failure', 'Disease', (90, 122))	('Personality', 'Var', (0, 11))	('reduced', 'NegReg', (82, 89))
3939	32423432	In addition, we estimated neuroticism and trait anxiety to be associated with decreased HRQoL and QoL scores.	('anxiety', 'Disease', (48, 55))	('anxiety', 'Phenotype', 'HP:0000739', (48, 55))	('neuroticism', 'Var', (26, 37))	('decreased HRQoL and QoL', 'Disease', 'MESH:D002303', (78, 101))	('anxiety', 'Disease', 'MESH:D001007', (48, 55))
4233	26962828	For lung adenocarcinoma-mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set.	('kallikrein-12', 'Gene', '43849', (83, 96))	('CA15-3', 'Gene', (71, 77))	('lung adenocarcinoma-mesothelioma discrimination', 'Disease', 'MESH:D000077192', (4, 51))	('lung adenocarcinoma-mesothelioma discrimination', 'Disease', (4, 51))	('kallikrein', 'molecular_function', 'GO:0004293', ('83', '93'))	('kallikrein-12', 'Gene', (83, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('CA19-9', 'Var', (63, 69))	('kallikrein', 'molecular_function', 'GO:0003807', ('83', '93'))	('CA15-3', 'Gene', '4582', (71, 77))
4276	26962828	In the second comparison, a classification tree which sequentially included the proteins CA19-9, CA15-3, MMP-3, and kallikrein-12 (Figure 2B) yielded a sensitivity of 83% (95% CI 64.2-94.2%) and a specificity of 89.7% (95% CI 73-98%) for separating 29 lung adenocarcinomas from 29 mesotheliomas.	('CA15-3', 'Gene', (97, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (252, 271))	('kallikrein', 'molecular_function', 'GO:0003807', ('116', '126'))	('kallikrein-12', 'Gene', (116, 129))	('CA19-9', 'Var', (89, 95))	('lung adenocarcinomas', 'Disease', (252, 272))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (252, 272))	('MMP-3', 'Gene', '4314', (105, 110))	('kallikrein', 'molecular_function', 'GO:0004293', ('116', '126'))	('MMP-3', 'Gene', (105, 110))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (252, 272))	('kallikrein-12', 'Gene', '43849', (116, 129))	('mesotheliomas', 'Disease', 'MESH:D008654', (281, 294))	('CA15-3', 'Gene', '4582', (97, 103))	('mesotheliomas', 'Disease', (281, 294))	('MMP-3', 'molecular_function', 'GO:0004248', ('105', '110'))
4279	26962828	We established a score system as follows: MMP-9 < 15.5 ng/mL (3 points), chondroitin sulfate >1.25 ng/mL (3 points), cathepsin-B <0.42 ng/mL (2 points), and C-reactive protein <12.5 mg/L (1 point).	('MMP-9', 'Gene', '4318', (42, 47))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('chondroitin sulfate', 'MPA', (73, 92))	('MMP-9', 'Gene', (42, 47))	('MMP-9', 'molecular_function', 'GO:0004229', ('42', '47'))	('cathepsin-B', 'Gene', (117, 128))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (73, 92))	('cathepsin-B', 'Gene', '1508', (117, 128))	('C-reactive protein', 'Gene', (157, 175))	('C-reactive protein', 'Gene', '1401', (157, 175))	('<0.42', 'Var', (129, 134))
4281	26962828	Similarly, 20 lung adenocarcinomas and 20 mesotheliomas were tested for the expression of the pleural fluid proteins CA19-9, CA15-3, kallikrein-12, and MMP-3.	('mesotheliomas', 'Disease', (42, 55))	('CA19-9', 'Var', (117, 123))	('kallikrein-12', 'Gene', (133, 146))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (14, 34))	('mesotheliomas', 'Disease', 'MESH:D008654', (42, 55))	('kallikrein', 'molecular_function', 'GO:0003807', ('133', '143'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('pleural fluid', 'Phenotype', 'HP:0002202', (94, 107))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('kallikrein', 'molecular_function', 'GO:0004293', ('133', '143'))	('CA15-3', 'Gene', '4582', (125, 131))	('lung adenocarcinomas', 'Disease', (14, 34))	('MMP-3', 'Gene', (152, 157))	('MMP-3', 'molecular_function', 'GO:0004248', ('152', '157'))	('pleural', 'Disease', 'MESH:D010995', (94, 101))	('pleural', 'Disease', (94, 101))	('CA15-3', 'Gene', (125, 131))	('kallikrein-12', 'Gene', '43849', (133, 146))	('MMP-3', 'Gene', '4314', (152, 157))
4282	26962828	The last was dismissed by the following best scoring model, which had an AUC of 0.94 (95% CI 0.88-1) (Figure 3B): CA19-9 >=13.3 U/mL (3 points), kallikrein-12 <55 ng/mL (2 points), and CA15-3 >110 U/mL (1 point).	('kallikrein-12', 'Gene', '43849', (145, 158))	('kallikrein', 'molecular_function', 'GO:0003807', ('145', '155'))	('kallikrein', 'molecular_function', 'GO:0004293', ('145', '155'))	('CA15-3', 'Gene', '4582', (185, 191))	('CA15-3', 'Gene', (185, 191))	('CA19-9 >=13.3', 'Var', (114, 127))	('kallikrein-12', 'Gene', (145, 158))
4287	26962828	In particular, patients who scored 2 points, in which 1 point each was assigned to both pleural fluid cathepsin-B concentrations <0.31 ng/mL and age >=50 years, were most likely to have lymphomas rather than TB (sensitivity 72.2%, 95% CI 46.5-90.3%; specificity 100%, 95% CI 89.7-100%; LR positive 25.3, 95% CI 3.6-178.2; LR negative 0.28, 95% CI 0.13-0.59; and AUC 0.94, 95% CI 0.88-0.99).	('pleural', 'Disease', (88, 95))	('cathepsin-B', 'Gene', (102, 113))	('patients', 'Species', '9606', (15, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (186, 194))	('pleural fluid', 'Phenotype', 'HP:0002202', (88, 101))	('lymphomas', 'Disease', (186, 195))	('cathepsin-B', 'Gene', '1508', (102, 113))	('lymphomas', 'Disease', 'MESH:D008223', (186, 195))	('lymphomas', 'Phenotype', 'HP:0002665', (186, 195))	('pleural', 'Disease', 'MESH:D010995', (88, 95))	('<0.31', 'Var', (129, 134))
4303	26962828	In a recent meta-analysis of 49 studies, pleural fluid CA15-3 and CA19-9 exhibited 50.7% and 37.6% pooled sensitivities, respectively, and 98% specificities for diagnosing malignant effusions.	('pleural', 'Disease', 'MESH:D010995', (41, 48))	('pleural fluid', 'Phenotype', 'HP:0002202', (41, 54))	('pleural', 'Disease', (41, 48))	('malignant effusions', 'Disease', (172, 191))	('CA19-9', 'Var', (66, 72))	('CA15-3', 'Gene', '4582', (55, 61))	('CA15-3', 'Gene', (55, 61))
4306	26962828	Significantly higher levels of CA15-3 (138.6 U/mL vs 21.3 U/mL) and CA19-9 (516.6 U/mL vs 181.5 U/mL) were found in 128 lung adenocarcinoma cases than in 18 mesotheliomas.	('lung adenocarcinoma', 'Disease', (120, 139))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('CA19-9', 'Var', (68, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('CA15-3', 'Gene', '4582', (31, 37))	('CA15-3', 'Gene', (31, 37))	('mesotheliomas', 'Disease', 'MESH:D008654', (157, 170))	('higher', 'PosReg', (14, 20))	('mesotheliomas', 'Disease', (157, 170))
4327	26462016	The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA.	('growth', 'CPA', (4, 10))	('metastasis', 'CPA', (32, 42))	('eIF6 shRNA', 'Var', (90, 100))	('Enzastaurin', 'Chemical', 'MESH:C504878', (65, 76))	('reduced', 'NegReg', (47, 54))
4328	26462016	Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells.	('affects', 'Reg', (50, 57))	('manipulation', 'Var', (37, 49))	('metabolic status', 'MPA', (62, 78))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (82, 104))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (82, 104))	('malignant mesothelioma', 'Disease', (82, 104))	('eIF6', 'Gene', (32, 36))
4333	26462016	Furthermore, mutations of ribosome-associated factors have been described in sporadic cancer, i.e.	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ribosome', 'cellular_component', 'GO:0005840', ('26', '34'))	('ribosome-associated', 'Gene', (26, 45))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('described', 'Reg', (64, 73))	('cancer', 'Disease', (86, 92))
4348	26462016	In contrast, cancer cells with mutations in the RAS pathway are resistant to mTORc1 inhibition, demonstrating the existence of either alternative initiation factors or pathways converging on translation which control tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mTORc1', 'cellular_component', 'GO:0031931', ('77', '83'))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mTORc1', 'Gene', (77, 83))	('translation', 'biological_process', 'GO:0006412', ('191', '202'))	('mTORc1', 'Gene', '382056', (77, 83))
4349	26462016	eIF6 is an initiation factor driven by RACK1-PKCbetaII axis, independently from mTORc1.	('mTORc1', 'cellular_component', 'GO:0031931', ('80', '86'))	('mTORc1', 'Gene', (80, 86))	('eIF6', 'Var', (0, 4))	('RACK1', 'Gene', (39, 44))	('mTORc1', 'Gene', '382056', (80, 86))	('RACK1', 'Gene', '10399', (39, 44))
4350	26462016	In general, eIF6 is rate limiting for tumor onset and progression.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('eIF6', 'Var', (12, 16))
4352	26462016	In a mouse model of Myc-driven lymphomagenesis, eIF6 heterozygous mice survive much longer, even more than one year, when compared to the 4-months life expectancy of wt mice.	('lymphoma', 'Disease', (31, 39))	('mice', 'Species', '10090', (66, 70))	('lymphoma', 'Disease', 'MESH:D008223', (31, 39))	('eIF6', 'Var', (48, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('mice', 'Species', '10090', (169, 173))	('mouse', 'Species', '10090', (5, 10))
4353	26462016	eIF6 phosphorylation of Ser235 has been reported in several tumor cells.	('phosphorylation', 'MPA', (5, 20))	('tumor', 'Disease', (60, 65))	('Ser235', 'Chemical', '-', (24, 30))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('eIF6', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reported', 'Reg', (40, 48))	('Ser', 'cellular_component', 'GO:0005790', ('24', '27'))	('Ser235', 'Gene', (24, 30))
4362	26462016	We found that eIF6 is overexpressed and hyperactivated in mesotheliomas and that inhibition of its expression or phosphorylation delays tumor progression.	('delays tumor', 'Disease', 'MESH:D009369', (129, 141))	('hyperactivated in mesotheliomas', 'Disease', (40, 71))	('delays tumor', 'Disease', (129, 141))	('inhibition', 'Var', (81, 91))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('hyperactivated in mesotheliomas', 'Disease', 'MESH:D008654', (40, 71))	('overexpressed', 'PosReg', (22, 35))	('eIF6', 'Protein', (14, 18))
4377	26462016	Strikingly, high eIF6/high PRKCB expression correlated with lower survival, p <= 0.005 (Figure 1D).	('PRKCB', 'Gene', (27, 32))	('survival', 'MPA', (66, 74))	('high', 'Var', (12, 16))	('PRKCB', 'Gene', '5579', (27, 32))	('expression', 'MPA', (33, 43))	('lower', 'NegReg', (60, 65))
4390	26462016	In summary eIF6 depletion caused a significant protein synthesis reduction (Figure 3B) and led to a slight decrease of polysomes accompanied by 80S increase, as shown in Figure 3C.	('protein synthesis reduction', 'Disease', 'MESH:C536766', (47, 74))	('increase', 'PosReg', (148, 156))	('depletion', 'Var', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('protein synthesis', 'biological_process', 'GO:0006412', ('47', '64'))	('polysomes', 'MPA', (119, 128))	('protein synthesis reduction', 'Disease', (47, 74))	('decrease', 'NegReg', (107, 115))	('eIF6', 'Gene', (11, 15))
4397	26462016	We analysed MPM cells growth at 24, 48 and 72 hours after plating and upon eIF6 depletion (Figure 4A, REN cells; Supplementary Figure S4, MM98, sarcomatous, MSTO-211H, biphasic).	('sarcomatous', 'Disease', (144, 155))	('MSTO-211H', 'Chemical', '-', (157, 166))	('depletion', 'Var', (80, 89))	('sarcomatous', 'Disease', 'MESH:D018316', (144, 155))
4404	26462016	In conclusion, both shRNA for eIF6 or Enzastaurin treatment slightly reduce proliferation in cultured REN cells, in vitro.	('reduce', 'NegReg', (69, 75))	('eIF6', 'Var', (30, 34))	('Enzastaurin', 'Chemical', 'MESH:C504878', (38, 49))	('proliferation in cultured REN cells', 'CPA', (76, 111))
4415	26462016	These findings may be in agreement with the protective role of eIF6 depletion and/or inactivation by Enzastaurin in neo-angiogenesis and metastasis development.	('inactivation', 'Var', (85, 97))	('angiogenesis', 'biological_process', 'GO:0001525', ('120', '132'))	('depletion', 'Var', (68, 77))	('eIF6', 'Gene', (63, 67))	('Enzastaurin', 'Chemical', 'MESH:C504878', (101, 112))
4420	26462016	We show that eIF6 is highly expressed and activated in malignant mesotheliomas, and that inhibition of either its activity or phosphorylation reduces tumor burden and tumor growth.	('activity', 'MPA', (114, 122))	('eIF6', 'Gene', (13, 17))	('inhibition', 'Var', (89, 99))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('reduces', 'NegReg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('malignant mesotheliomas', 'Disease', (55, 78))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (55, 78))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('activated', 'PosReg', (42, 51))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (55, 77))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (167, 172))
4437	26462016	Emu-Myc/ eIF6+/- mice have increased survival, up to 1 year and do not show overt negative phenotypes.	('Emu-Myc/ eIF6+/-', 'Var', (0, 16))	('increased', 'PosReg', (27, 36))	('survival', 'CPA', (37, 45))	('mice', 'Species', '10090', (17, 21))
4438	26462016	Even in the p53-/- genotype, where p53 deletion further accelerates lymphomagenesis due to suppression of apoptosis, eIF6 depletion delays tumor development.	('lymphoma', 'Disease', (68, 76))	('p53', 'Gene', (35, 38))	('lymphoma', 'Disease', 'MESH:D008223', (68, 76))	('apoptosis', 'CPA', (106, 115))	('deletion', 'Var', (39, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('delays tumor', 'Disease', 'MESH:D009369', (132, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('delays tumor', 'Disease', (132, 144))	('accelerates', 'PosReg', (56, 67))
4440	26462016	The phosphorylation of Ser235 residue on eIF6 is necessary for transformation and cancer development.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Ser235', 'Chemical', '-', (23, 29))	('Ser235 residue', 'Var', (23, 37))	('transformation', 'CPA', (63, 77))	('eIF6', 'Gene', (41, 45))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Ser', 'cellular_component', 'GO:0005790', ('23', '26'))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
4443	26462016	We previously showed that inhibition of eIF6 phosphorylation by genetic inactivation of Ser235 is a way to block eIF6 activity.	('Ser', 'cellular_component', 'GO:0005790', ('88', '91'))	('genetic inactivation', 'Var', (64, 84))	('activity', 'MPA', (118, 126))	('eIF6', 'Protein', (40, 44))	('eIF6', 'Protein', (113, 117))	('block', 'NegReg', (107, 112))	('inhibition', 'NegReg', (26, 36))	('Ser235', 'Gene', (88, 94))	('phosphorylation', 'MPA', (45, 60))	('Ser235', 'Chemical', '-', (88, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))
4455	26462016	These data suggested that a similar event might occur in cancer cells, namely eIF6 favors a glycolytic switch.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('eIF6', 'Var', (78, 82))	('cancer', 'Disease', (57, 63))	('glycolytic switch', 'MPA', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
4458	26462016	Our data are in agreement with the observation that mutation of eIF6 Ser235 to Ala greatly reduces cancer growth in vivo, more efficiently than in vitro.	('Ser235 to Ala', 'Mutation', 'p.S235A', (69, 82))	('eIF6', 'Gene', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('reduces', 'NegReg', (91, 98))	('mutation', 'Var', (52, 60))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
4460	26462016	In conclusion, we suggest that modulation of eIF6 levels and activity may lead to a therapeutical avenue in tumor therapy, especially where eIF4E inhibition by rapalogs is not effective, as in malignant mesothelioma.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('modulation', 'Var', (31, 41))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (193, 215))	('lead to', 'Reg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignant mesothelioma', 'Disease', (193, 215))	('eIF4E', 'Gene', '1977', (140, 145))	('tumor', 'Disease', (108, 113))	('eIF4E', 'Gene', (140, 145))	('activity', 'MPA', (61, 69))	('eIF4', 'cellular_component', 'GO:0008304', ('140', '144'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (193, 215))
4572	23128478	We found increased cell migration in the mesothelioma cell lines MSTO-211H and TUM1 following in vitro shRNA-mediated knockdown of CD9 expression.	('CD9', 'Gene', (131, 134))	('MSTO-211H', 'Chemical', '-', (65, 74))	('knockdown', 'Var', (118, 127))	('TUM1', 'Gene', '4357', (79, 83))	('mesothelioma', 'Disease', (41, 53))	('cell migration', 'biological_process', 'GO:0016477', ('19', '33'))	('increased', 'PosReg', (9, 18))	('TUM1', 'Gene', (79, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('cell migration in', 'CPA', (19, 36))
4576	23128478	Patients with CD9 expression showed higher 1- and 2-year survival rates (63 and 25%) compared to the patients without CD9 expression (39 and 11%).	('Patients', 'Species', '9606', (0, 8))	('CD9 expression', 'Var', (14, 28))	('higher', 'PosReg', (36, 42))	('patients', 'Species', '9606', (101, 109))
4577	23128478	Univariate analysis revealed that patients with CD9 expression demonstrated a more favorable survival (P=0.0025) along with other clinicopathological factors, including age younger than 60 years, IMIG stage I-II, epithelioid histology, EM-D and patients who underwent extrapleural pneumonectomy or received chemotherapy.	('patients', 'Species', '9606', (245, 253))	('survival', 'CPA', (93, 101))	('patients', 'Species', '9606', (34, 42))	('CD9', 'Gene', (48, 51))	('expression', 'Var', (52, 62))	('favorable', 'PosReg', (83, 92))
4578	23128478	Multivariate analysis identified CD9 expression as an independent prognostic factor with a hazard ratio (HR) of 1.99 in the analysis of all mesotheliomas (P=0.0261) and an HR of 2.60 in the analysis of EMs (P=0.0376).	('expression', 'Var', (37, 47))	('mesotheliomas', 'Disease', 'MESH:D008654', (140, 153))	('CD9', 'Gene', (33, 36))	('mesotheliomas', 'Disease', (140, 153))
4581	23128478	In malignancies, its expression usually suppresses tumor progression and metastasis by inhibition of tumor proliferation and survival.	('inhibition', 'NegReg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('suppresses', 'NegReg', (40, 50))	('tumor', 'Disease', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (3, 15))	('malignancies', 'Disease', (3, 15))	('survival', 'CPA', (125, 133))	('expression', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
4627	23128478	Among the patients receiving best supportive care, patients with CD9 expression had higher survival (mean survival time 8 months) compared to those without CD9 expression (mean survival time, 2.5 months) (P=0.0376).	('survival', 'MPA', (91, 99))	('CD9 expression', 'Var', (65, 79))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (10, 18))	('higher', 'PosReg', (84, 90))
4628	23128478	A similar result was found among the patients treated with chemotherapy alone with a mean survival time of 16.2 months for patients with CD9 expression and 9.7 months for patients without CD9 expression (P=0.0037) (Fig.	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (123, 131))	('CD9', 'Gene', (137, 140))	('patients', 'Species', '9606', (171, 179))	('expression', 'Var', (141, 151))
4633	23128478	The tetraspanin superfamily proteins (TM4SF) mainly CD9, CD63, CD82, CD151 and CD81 have been implicated in cell migration, proliferation and tumor cell metastasis.	('CD81', 'Gene', '975', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CD82', 'Gene', (63, 67))	('tumor', 'Disease', (142, 147))	('CD63', 'Gene', '967', (57, 61))	('cell migration', 'biological_process', 'GO:0016477', ('108', '122'))	('implicated', 'Reg', (94, 104))	('cell migration', 'CPA', (108, 122))	('CD151', 'Gene', '977', (69, 74))	('CD9', 'Var', (52, 55))	('CD82', 'Gene', '3732', (63, 67))	('CD63', 'Gene', (57, 61))	('CD81', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CD151', 'Gene', (69, 74))
4636	23128478	In this migration assay experiment using MSTO-211H cells, we found a decrease in CD9 expression after CD9-shRNA transfection which led to increased cell migration compared to control-shRNA-transfected cells.	('expression', 'MPA', (85, 95))	('MSTO-211H', 'Chemical', '-', (41, 50))	('increased', 'PosReg', (138, 147))	('transfection', 'Var', (112, 124))	('cell migration', 'biological_process', 'GO:0016477', ('148', '162'))	('CD9', 'Gene', (81, 84))	('cell migration', 'CPA', (148, 162))	('decrease', 'NegReg', (69, 77))
4649	23128478	Patients with CD9 expression had higher survival compared to those without CD9 expression in patients receiving best supportive care or patients treated with chemotherapy.	('higher', 'PosReg', (33, 39))	('survival', 'MPA', (40, 48))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (136, 144))	('CD9', 'Gene', (14, 17))	('patients', 'Species', '9606', (93, 101))	('expression', 'Var', (18, 28))
4663	23028939	In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells.	('SphK1', 'Gene', (88, 93))	('H2461', 'CellLine', 'CVCL:A536', (155, 160))	('elevated', 'PosReg', (44, 52))	('levels', 'MPA', (53, 59))	('SphK1', 'Gene', (63, 68))	('H2461', 'Var', (155, 160))	('protein expression', 'MPA', (94, 112))	('SphK2', 'Gene', '56848', (73, 78))	('SphK2', 'Gene', (73, 78))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
4677	23028939	S1P, generated intracellularly either by SphK1 or SphK2, is transported out of the cells where it acts as ligand for five G protein coupled S1P1-5 receptors and regulates several vital cellular processes such as growth and differentiation, survival, cytoskeletal rearrangements and motility, angiogenesis, and immune defense.	('growth', 'CPA', (212, 218))	('SphK2', 'Gene', '56848', (50, 55))	('SphK2', 'Gene', (50, 55))	('angiogenesis', 'biological_process', 'GO:0001525', ('292', '304'))	('motility', 'CPA', (282, 290))	('SphK1', 'Var', (41, 46))	('survival', 'CPA', (240, 248))	('cytoskeletal rearrangements', 'CPA', (250, 277))	('S1P1-5', 'Gene', '1901;9294;1903;8698;53637', (140, 146))	('regulates', 'Reg', (161, 170))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('angiogenesis', 'CPA', (292, 304))	('immune defense', 'CPA', (310, 324))	('ligand', 'molecular_function', 'GO:0005488', ('106', '112'))	('S1P1-5', 'Gene', (140, 146))
4688	23028939	Given the positive role of SphK1 in cancer, we hypothesized that high expression of SphK1 may play an important role in the development of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('high expression', 'Var', (65, 80))	('mesothelioma', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('SphK1', 'Gene', (84, 89))
4692	23028939	H2691 (epithelioid), H2461 (epithelioid), H513 (epithelioid), H2596 (sarcomatoid), H2373 (sarcomatoid), and non-malignant mesothelial cells (Met5A) were obtained from the American Type Culture Collection.	('sarcomatoid', 'Disease', (69, 80))	('sarcomatoid', 'Disease', (90, 101))	('H2461', 'Var', (21, 26))	('H2373', 'Var', (83, 88))	('H2373', 'CellLine', 'CVCL:A533', (83, 88))	('H513', 'Var', (42, 46))	('Met5A', 'Chemical', '-', (141, 146))	('sarcomatoid', 'Disease', 'MESH:C538614', (90, 101))	('sarcomatoid', 'Disease', 'MESH:C538614', (69, 80))	('H2596', 'Var', (62, 67))	('H2596', 'CellLine', 'CVCL:A546', (62, 67))	('H2461', 'CellLine', 'CVCL:A536', (21, 26))
4705	23028939	After 3 h post-transfection, 1 ml of fresh complete Medium 199 containing 10% FBS for Met5A or RPMI1640 with 10% FBS for mesothelioma cell lines was added and cells were cultured for an additional 48 h for analysis of SphK1 and SphK2 by Western blotting.	('SphK1', 'Gene', (218, 223))	('SphK2', 'Gene', '56848', (228, 233))	('RPMI1640', 'Var', (95, 103))	('Met5A', 'Chemical', '-', (86, 91))	('mesothelioma', 'Disease', (121, 133))	('RPMI1640', 'Chemical', '-', (95, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('SphK2', 'Gene', (228, 233))
4748	23028939	In comparison, siSphK1 transduced cells when treated with Sph (5 microM) did not reveal any increase in [32 P]S1P generation and the increased production of S1P in presence of sphingosine was only inhibited by siSphK1 but not siSphK2 ( Fig.	('Sph', 'Chemical', 'MESH:D013110', (228, 231))	('siSphK1', 'Var', (210, 217))	('SphK2', 'Gene', (228, 233))	('Sph', 'Chemical', 'MESH:D013110', (58, 61))	('Sph', 'Chemical', 'MESH:D013110', (212, 215))	('Sph', 'Chemical', 'MESH:D013110', (17, 20))	('[32 P]S1P generation', 'MPA', (104, 124))	('sphingosine', 'Chemical', 'MESH:D013110', (176, 187))	('SphK2', 'Gene', '56848', (228, 233))
4775	23028939	Hematoxylin and eosin stained histology sections show the presence of dose dependent increase in granulamatous inflammation (early mesothelioma like symptom) in C57BL/6 mice which were exposed to MWNT, compared to PBS injected mice ( Fig.	('inflammation', 'biological_process', 'GO:0006954', ('111', '123'))	('PBS', 'Chemical', 'MESH:D007854', (214, 217))	('MWNT', 'Var', (196, 200))	('granulamatous inflammation', 'Disease', 'MESH:D007249', (97, 123))	('granulamatous inflammation', 'Phenotype', 'HP:0002955', (97, 123))	('mice', 'Species', '10090', (227, 231))	('mesothelioma', 'Disease', (131, 143))	('granulamatous inflammation', 'Disease', (97, 123))	('mice', 'Species', '10090', (169, 173))	('eosin', 'Chemical', 'MESH:D004801', (16, 21))	('Hematoxylin', 'Chemical', 'MESH:D006416', (0, 11))	('increase', 'PosReg', (85, 93))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))
4777	23028939	Semi-quantification of granulamatous inflammation by Image analyzer confirmed attenuation of MWNT-mediated inflammation in SphK1 deficient mouse [Relative area of the granulomas (mm2): wild type mice- sham,0; 50 microg, 19055; 3 mg, 38197; SphK1-/- mice - sham, 0; 50 microg, 4483; 3 mg, 15988].	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('attenuation', 'NegReg', (78, 89))	('granulamatous inflammation', 'Phenotype', 'HP:0002955', (23, 49))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('granulomas', 'Disease', (167, 177))	('mice', 'Species', '10090', (195, 199))	('SphK1', 'Gene', (123, 128))	('inflammation', 'Disease', (37, 49))	('mice', 'Species', '10090', (249, 253))	('granulomas', 'Phenotype', 'HP:0032252', (167, 177))	('deficient', 'Var', (129, 138))	('inflammation', 'Disease', (107, 119))	('MWNT-mediated', 'MPA', (93, 106))	('mouse', 'Species', '10090', (139, 144))	('granulamatous inflammation', 'Disease', (23, 49))	('granulamatous inflammation', 'Disease', 'MESH:D007249', (23, 49))	('granulomas', 'Disease', 'MESH:D006099', (167, 177))	('inflammation', 'biological_process', 'GO:0006954', ('37', '49'))	('inflammation', 'biological_process', 'GO:0006954', ('107', '119'))
4785	23028939	Finally, using a mouse model, we demonstrated that abrogation of SphK1 resulted in significantly reduced MWNT-induced peritoneal granulomas.	('abrogation', 'Var', (51, 61))	('mouse', 'Species', '10090', (17, 22))	('SphK1', 'Gene', (65, 70))	('reduced', 'NegReg', (97, 104))	('peritoneal granulomas', 'Disease', 'MESH:D010534', (118, 139))	('peritoneal granulomas', 'Disease', (118, 139))	('granulomas', 'Phenotype', 'HP:0032252', (129, 139))
4796	23028939	Although the levels of SphK1 are detectable in Met5A control cells, knocking down SphK1 in these cells had no discernable effect on cell proliferation thereby suggesting that SphK1's growth promoting role may be specific to mesothelioma cancer cells.	('SphK1', 'Gene', (82, 87))	('knocking down', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cell proliferation', 'CPA', (132, 150))	('mesothelioma cancer', 'Disease', (224, 243))	('mesothelioma cancer', 'Disease', 'MESH:D008654', (224, 243))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (224, 243))	('growth', 'MPA', (183, 189))	('Met5A', 'Chemical', '-', (47, 52))
4802	23028939	Further investigation into the mechanism underlying the role of SphK1 in mesothelial cell proliferation revealed that abrogation of SpkK1 expression results in a dramatic loss in CDK2 phosphorylation ( Fig.	('CDK2', 'Gene', (179, 183))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('abrogation', 'Var', (118, 128))	('CDK2', 'Gene', '1017', (179, 183))	('phosphorylation', 'biological_process', 'GO:0016310', ('184', '199'))	('CDK', 'molecular_function', 'GO:0004693', ('179', '182'))	('loss', 'NegReg', (171, 175))	('phosphorylation', 'MPA', (184, 199))	('SpkK1', 'Gene', (132, 137))
4803	23028939	As CDK2 activity is required for early cell cycle progression, it is not surprising that DNA replication is arrested in SphK1 knockdown H2691 cells.	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('SphK1', 'Gene', (120, 125))	('CDK2', 'Gene', (3, 7))	('DNA replication', 'biological_process', 'GO:0006260', ('89', '104'))	('CDK2', 'Gene', '1017', (3, 7))	('CDK', 'molecular_function', 'GO:0004693', ('3', '6'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('knockdown', 'Var', (126, 135))
4820	23028939	We also demonstrated specificity by clearly showing that abrogation of SphK1 in H2691 cell resulted in marked reduction in p300 (CBP) and PCAF transcripts but not that of MYST2 ( Fig.	('SphK1', 'Gene', (71, 76))	('p300', 'Gene', (123, 127))	('reduction', 'NegReg', (110, 119))	('MYST2', 'Gene', (171, 176))	('PCAF', 'Gene', '8850', (138, 142))	('p300', 'Gene', '2033', (123, 127))	('CBP', 'molecular_function', 'GO:0008140', ('129', '132'))	('MYST2', 'Gene', '11143', (171, 176))	('abrogation', 'Var', (57, 67))	('PCAF', 'Gene', (138, 142))	('CBP', 'Gene', (129, 132))	('CBP', 'Gene', '1387', (129, 132))
4835	23028939	Here, we observed inflamed granulamatous tissue lining the diaphragm of mice exposed to MWNT that was significantly suppressed in SphK1 knockout mice ( Fig.	('suppressed', 'NegReg', (116, 126))	('SphK1', 'Gene', (130, 135))	('knockout', 'Var', (136, 144))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (145, 149))
4868	21037025	In tumor xenograft studies combination treatment with MORAb-009 plus chemotherapy led to a greater reduction in the growth of mesothelin expressing tumors than either MORAb-009 or chemotherapy alone.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (3, 8))	('growth', 'MPA', (116, 122))	('tumor', 'Disease', (148, 153))	('MORAb-009', 'Chemical', 'MESH:C526187', (54, 63))	('reduction', 'NegReg', (99, 108))	('MORAb-009', 'Chemical', 'MESH:C526187', (167, 176))	('mesothelin', 'Protein', (126, 136))	('MORAb-009', 'Var', (54, 63))	('tumors', 'Disease', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
4876	21037025	Other eligibility criteria included a life expectancy >= 3 months; Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; adequate bone marrow, hepatic, and renal function (absolute neutrophil count >= 1.5 x 109/L; platelet count >= 100 x 109/L; hemoglobin >= 9 g/dL; serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase <= 5 x upper limit of normal; serum bilirubin <= 2.0 mg/dL; serum creatinine <= 2.0 mg/dL) determined <= 2 weeks before starting therapy.	('AST', 'Gene', '26503', (311, 314))	('alanine transaminase', 'MPA', (317, 337))	('aspartate transaminase', 'Gene', '26503', (287, 309))	('serum bilirubin', 'MPA', (399, 414))	('>= 100 x 109/L', 'Var', (243, 257))	('alkaline phosphatase', 'MPA', (348, 368))	('aspartate transaminase', 'Gene', (287, 309))	('AST', 'Gene', (311, 314))	('phosphatase', 'molecular_function', 'GO:0016791', ('357', '368'))	('Oncology', 'Phenotype', 'HP:0002664', (87, 95))	('serum creatinine', 'MPA', (429, 445))	('ALT', 'molecular_function', 'GO:0004021', ('339', '342'))
4950	21037025	The mean Cmax of MORAb-009 at the MTD (200 mg/m2) is significantly higher than the concentration of MORAb-009 required for ADCC against mesothelin expressing cell lines or to inhibit the mesothelin CA125 interaction in vitro.	('MORAb-009', 'Chemical', 'MESH:C526187', (17, 26))	('higher', 'PosReg', (67, 73))	('Cmax', 'MPA', (9, 13))	('MORAb-009', 'Var', (17, 26))	('MORAb-009', 'Chemical', 'MESH:C526187', (100, 109))	('ADCC', 'biological_process', 'GO:0001788', ('123', '127'))	('CA125', 'Gene', (198, 203))	('inhibit', 'NegReg', (175, 182))	('CA125', 'Gene', '94025', (198, 203))
4956	21037025	These results suggest that MORAb-009 can potentially inhibit the interaction between mesothelin and CA125 and therefore inhibit heterotypic adhesion and intra-cavitary metastasis in patients with mesothelioma and ovarian cancer.	('mesothelioma and ovarian cancer', 'Disease', 'MESH:D010051', (196, 227))	('inhibit', 'NegReg', (53, 60))	('MORAb-009', 'Chemical', 'MESH:C526187', (27, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (213, 227))	('interaction', 'Interaction', (65, 76))	('MORAb-009', 'Var', (27, 36))	('heterotypic adhesion', 'MPA', (128, 148))	('CA125', 'Gene', '94025', (100, 105))	('intra-cavitary metastasis', 'CPA', (153, 178))	('inhibit', 'NegReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('patients', 'Species', '9606', (182, 190))	('mesothelin', 'Protein', (85, 95))	('CA125', 'Gene', (100, 105))
5053	29150040	This combination of massive malignant effusion and malignant pleural rind will distort the respiratory mechanics by preventing normal chest wall excursion and enhancing the ventilation perfusion mismatch.	('malignant', 'Var', (51, 60))	('distort', 'Reg', (79, 86))	('ventilation perfusion mismatch', 'MPA', (173, 203))	('preventing', 'NegReg', (116, 126))	('normal chest wall excursion', 'MPA', (127, 154))	('respiratory mechanics', 'MPA', (91, 112))	('malignant effusion', 'Disease', (28, 46))	('enhancing', 'PosReg', (159, 168))	('malignant effusion', 'Disease', 'MESH:D016066', (28, 46))
5122	29150040	The overall survival at 1 year was in fact similar between the 2 groups (52% vs 57%, respectively), but surgical complications and pulmonary complications (including prolonged air leak) were significantly more prevalent in the VATS-PP group.	('pulmonary complications', 'Disease', 'MESH:D008171', (131, 154))	('surgical complications', 'CPA', (104, 126))	('more prevalent', 'PosReg', (205, 219))	('pulmonary complications', 'Phenotype', 'HP:0006532', (131, 154))	('pulmonary complications', 'Disease', (131, 154))	('VATS-PP', 'Var', (227, 234))
5140	29150040	It is believed that PDT can directly kill cancer cells, destroy the tumor neovasculature, and induce a tumor-directed immune response.	('tumor', 'Disease', (68, 73))	('tumor neovasculature', 'Disease', 'MESH:D009369', (68, 88))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PDT', 'Var', (20, 23))	('tumor', 'Disease', (103, 108))	('destroy', 'NegReg', (56, 63))	('immune response', 'biological_process', 'GO:0006955', ('118', '133'))	('tumor neovasculature', 'Disease', (68, 88))	('induce', 'Reg', (94, 100))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
5341	31366157	Frequent mutations in BAP1 (BRCA-associated protein 1) have been reported in many types of cancer including uveal melanoma, renal cancer and MM.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('mutations', 'Var', (9, 18))	('renal cancer', 'Disease', (124, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (124, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('reported', 'Reg', (65, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('renal cancer', 'Disease', 'MESH:D007680', (124, 136))	('BAP1', 'Gene', '8314', (22, 26))	('BRCA-associated protein 1', 'Gene', (28, 53))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('BAP1', 'Gene', (22, 26))	('BRCA-associated protein 1', 'Gene', '8314', (28, 53))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
5342	31366157	A recent study proposed that germline BAP1 mutations are linked with cancer syndrome which is associated with familiar cases of MM in the above-mentioned Cappadocian villages.	('cancer syndrome', 'Disease', 'MESH:D009369', (69, 84))	('BAP1', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (43, 52))	('linked', 'Reg', (57, 63))	('germline', 'Var', (29, 37))	('BAP1', 'Gene', '8314', (38, 42))	('cancer syndrome', 'Disease', (69, 84))
5414	30223066	Next, we summarize the incidence data and potential mechanisms of sexual dimorphism in ten human cancer types with higher incidence ratios of at least 2-fold.	('cancer', 'Disease', (97, 103))	('sexual', 'Var', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
5463	30223066	Although neither ERbeta nor GPER1 is expressed in normal liver and liver tumors from rodents and humans, one recent study showed that global but not liver-specific ablation of Gper1 accelerated hepatocarcinogenesis.	('GPER1', 'Gene', (28, 33))	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('liver tumors', 'Disease', (67, 79))	('humans', 'Species', '9606', (97, 103))	('GPER1', 'Gene', '2852', (28, 33))	('Gper1', 'Gene', '2852', (176, 181))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (194, 214))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ERbeta', 'Gene', '2100', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('accelerated', 'PosReg', (182, 193))	('ablation', 'Var', (164, 172))	('Gper1', 'Gene', (176, 181))	('ERbeta', 'Gene', (17, 23))	('hepatocarcinogenesis', 'Disease', (194, 214))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))
5467	30223066	Li et al found that both of the ERalpha-mediated protection and AR-mediated facilitation of hepatic tumorigenesis in mice depended on Foxa1/2, while deficiency of Foxa1 and Foxa2 in the mouse liver would reverse the protective role of ERalpha and the detrimental role of AR for HCC; and genetic variants that affected the binding of FOXA2 and ERalpha were associated with the increased incidence of HCC in patients.	('Foxa1', 'Gene', (163, 168))	('FOXA2', 'Gene', (333, 338))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (117, 121))	('men', 'Species', '9606', (256, 259))	('deficiency', 'Var', (149, 159))	('HCC', 'Disease', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('binding', 'Interaction', (322, 329))	('HCC', 'Disease', 'MESH:D006528', (399, 402))	('HCC', 'Phenotype', 'HP:0001402', (278, 281))	('associated', 'Reg', (356, 366))	('Foxa1/2', 'Gene', '15375;15376', (134, 141))	('Foxa1', 'Gene', '15375', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('genetic variants', 'Var', (287, 303))	('Foxa1', 'Gene', (134, 139))	('mouse', 'Species', '10090', (186, 191))	('HCC', 'Disease', 'MESH:D006528', (278, 281))	('HCC', 'Disease', (399, 402))	('Foxa2', 'Gene', '15376', (173, 178))	('patients', 'Species', '9606', (406, 414))	('HCC', 'Phenotype', 'HP:0001402', (399, 402))	('binding', 'molecular_function', 'GO:0005488', ('322', '329'))	('Foxa1/2', 'Gene', (134, 141))	('Foxa2', 'Gene', (173, 178))	('Foxa1', 'Gene', '15375', (163, 168))	('FOXA2', 'Gene', '15376', (333, 338))	('ERalpha', 'Gene', (343, 350))
5483	30223066	For example, estrogen signaling, through ERalpha or a splicing variant of ERalpha, promoted the growth of gastric cancer cells whereas ERbeta-mediated estrogen signaling inhibited the growth of gastric cancer cells and genetic variants in the ESR2 gene were highly associated with survival in patients with locally advanced gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ERbeta', 'Gene', (135, 141))	('associated with', 'Reg', (265, 280))	('genetic variants', 'Var', (219, 235))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('inhibited', 'NegReg', (170, 179))	('gastric cancer', 'Disease', (324, 338))	('estrogen', 'Chemical', 'MESH:D004967', (151, 159))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('growth', 'MPA', (184, 190))	('ESR2', 'Gene', '2100', (243, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (324, 338))	('gastric cancer', 'Disease', (194, 208))	('estrogen', 'Chemical', 'MESH:D004967', (13, 21))	('ESR2', 'Gene', (243, 247))	('gastric cancer', 'Disease', (106, 120))	('growth', 'MPA', (96, 102))	('promoted', 'PosReg', (83, 91))	('splicing variant', 'Var', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('gastric cancer', 'Disease', 'MESH:D013274', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (324, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('splicing', 'biological_process', 'GO:0045292', ('54', '62'))	('ERbeta', 'Gene', '2100', (135, 141))	('patients', 'Species', '9606', (293, 301))	('ERalpha', 'Gene', (74, 81))
5489	30223066	The evidence of estrogen signaling in the growth of kidney cancer cells is limited, e.g., ESR1 polymorphism was associated with the risk of kidney cancer; GPER1 promoted the growth and metastasis of kidney cancer cells; and AR-mediated androgen signaling promoted the growth of kidney cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('kidney cancer', 'Disease', (140, 153))	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('GPER1', 'Gene', '2852', (155, 160))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('kidney cancer', 'Disease', 'MESH:D007680', (199, 212))	('kidney cancer', 'Disease', 'MESH:D007680', (278, 291))	('metastasis of kidney cancer', 'Disease', 'MESH:D009362', (185, 212))	('GPER1', 'Gene', (155, 160))	('signaling', 'biological_process', 'GO:0023052', ('245', '254'))	('growth', 'CPA', (174, 180))	('ESR1', 'Gene', '2099', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (199, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (278, 291))	('metastasis of kidney cancer', 'Disease', (185, 212))	('estrogen', 'Chemical', 'MESH:D004967', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('kidney cancer', 'Disease', (278, 291))	('ESR1', 'Gene', (90, 94))	('polymorphism', 'Var', (95, 107))	('kidney cancer', 'Disease', 'MESH:D007680', (140, 153))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('androgen', 'Chemical', 'MESH:D000728', (236, 244))	('promoted', 'PosReg', (255, 263))	('growth', 'CPA', (268, 274))	('promoted', 'PosReg', (161, 169))	('associated', 'Reg', (112, 122))	('kidney cancer', 'Phenotype', 'HP:0009726', (140, 153))
5638	29540358	These changes may have impacted the outcome for mesothelioma, too.	('changes', 'Var', (6, 13))	('impacted', 'Reg', (23, 31))	('mesothelioma', 'Disease', (48, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))
5680	28460459	In some cases, mesothelin expression has been associated with increased tumor aggressiveness and poor clinical outcome, however, its impact on the clinical outcome of malignant pleural mesothelioma patients has not been extensively evaluated.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (72, 92))	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('malignant pleural mesothelioma', 'Disease', (167, 197))	('patients', 'Species', '9606', (198, 206))	('expression', 'Var', (26, 36))	('mesothelin', 'Protein', (15, 25))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('tumor aggressiveness', 'Disease', (72, 92))	('associated', 'Reg', (46, 56))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (177, 197))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (167, 197))
5683	28460459	Although the mechanism(s) and/or tumor biological significances were unclear, high mesothelin expression was associated with KRAS gene mutation in lung adenocarcinoma.	('associated', 'Reg', (109, 119))	('KRAS', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('high', 'PosReg', (78, 82))	('KRAS', 'Gene', '3845', (125, 129))	('mesothelin', 'Protein', (83, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor', 'Disease', (33, 38))	('expression', 'MPA', (94, 104))	('mutation', 'Var', (135, 143))	('lung adenocarcinoma', 'Disease', (147, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))
5714	28460459	Multivariable Cox hazards regression analysis revealed diffuse membranous mesothelin expression in mesothelioma tumor cells to be a favorable prognostic factor (HR, 0.36; 95% CI, 0.21-0.64; P < 0.001) (Table 4).	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mesothelioma tumor', 'Disease', (99, 117))	('diffuse', 'Var', (55, 62))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (99, 117))
5717	28460459	Arbitrary selected 75 colorectal tumors were analyzed for BRAF, KRAS, and NRAS gene mutations.	('NRAS', 'Gene', (74, 78))	('KRAS', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (84, 93))	('NRAS', 'Gene', '4893', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal tumors', 'Disease', (22, 39))	('colorectal tumors', 'Disease', 'MESH:D015179', (22, 39))	('BRAF', 'Gene', '673', (58, 62))	('KRAS', 'Gene', '3845', (64, 68))	('BRAF', 'Gene', (58, 62))
5750	28460459	In case of lung adenocarcinoma high-level of mesothelin expression is associated with aggressiveness, poor prognosis and KRAS gene mutation status.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (11, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', '3845', (121, 125))	('high-level', 'Var', (31, 41))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (11, 30))	('associated', 'Reg', (70, 80))	('expression', 'MPA', (56, 66))	('aggressiveness', 'Disease', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('lung adenocarcinoma', 'Disease', (11, 30))
5751	28460459	Based on these observations, in the present study, gene mutation analyses were performed in colorectal adenocarcinomas since they commonly harbor KRAS mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('KRAS', 'Gene', (146, 150))	('harbor', 'Reg', (139, 145))	('KRAS', 'Gene', '3845', (146, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colorectal adenocarcinomas', 'Disease', (92, 118))	('mutations', 'Var', (151, 160))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (92, 118))
5752	28460459	Among 75 arbitrarily selected colorectal adenocarcinomas, 20 and 31 tumors carried BRAF and RAS mutations, respectively.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (30, 56))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('RAS', 'Gene', (92, 95))	('carried', 'Reg', (75, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('colorectal adenocarcinomas', 'Disease', (30, 56))	('BRAF', 'Gene', '673', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('BRAF', 'Gene', (83, 87))	('mutations', 'Var', (96, 105))
5792	27323398	Furthermore, in a large group of human MPM samples it results that CYP19A1 was expressed as a cytoplasmic protein and its expression was significantly associated with poor survival of patients.	('expression', 'MPA', (122, 132))	('CYP19A1', 'Var', (67, 74))	('patients', 'Species', '9606', (184, 192))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('associated', 'Reg', (151, 161))	('poor', 'NegReg', (167, 171))	('MPM', 'Chemical', '-', (39, 42))	('human', 'Species', '9606', (33, 38))
5799	27323398	Interestingly, exemestane induces cell death in MSTO-211H (MSTO) by PI3K and cAMP inhibition, pathways involved in the action of GPR30.	('cAMP', 'Gene', (77, 81))	('cAMP', 'Gene', '820', (77, 81))	('cell death', 'CPA', (34, 44))	('exemestane', 'Chemical', 'MESH:C056516', (15, 25))	('MSTO', 'Chemical', '-', (59, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('GPR30', 'Gene', (129, 134))	('MSTO', 'Chemical', '-', (48, 52))	('inhibition', 'NegReg', (82, 92))	('GPR30', 'Gene', '2852', (129, 134))	('cell death', 'biological_process', 'GO:0008219', ('34', '44'))	('PI3K', 'Var', (68, 72))	('MSTO-211H', 'CellLine', 'CVCL:1430', (48, 57))
5818	27323398	This allows us to highlight a significant difference (P < 0.05) between patients with low, intermediate and high E2compared to patients without E2 that the Kaplan-Meier survival plot would neglect.	('patients', 'Species', '9606', (127, 135))	('low', 'Var', (86, 89))	('E2compared', 'Gene', (113, 123))	('patients', 'Species', '9606', (72, 80))
5834	27323398	Using RNAi silencing and G15, a selective GPR30 antagonist, it is possible to demonstrate the involvement of GPR30 in cell proliferation.	('silencing', 'Var', (11, 20))	('GPR30', 'Gene', '2852', (42, 47))	('G15', 'Gene', (25, 28))	('RNAi', 'biological_process', 'GO:0016246', ('6', '10'))	('G15', 'Gene', '10181', (25, 28))	('involvement', 'Reg', (94, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('cell proliferation', 'CPA', (118, 136))	('GPR30', 'Gene', (109, 114))	('GPR30', 'Gene', '2852', (109, 114))	('GPR30', 'Gene', (42, 47))
5873	27323398	When the cohort of patients was divided according to the E2 levels, we noted that median survival times for patients low, intermediate and high E2 levels were significantly less than the patients without E2 levels (P < 0.05), 27 months for negative E2 levels and about 14 for others (Figure 2A).	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (19, 27))	('less', 'NegReg', (173, 177))	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (139, 143))
5975	22607910	However, IMRT can be associated with increased toxicity, including fatal pneumonitis, if radiation exposure to the remaining lung is not carefully restricted.	('IMRT', 'Var', (9, 13))	('toxicity', 'Disease', 'MESH:D064420', (47, 55))	('pneumonitis', 'Disease', (73, 84))	('toxicity', 'Disease', (47, 55))	('pneumonitis', 'Disease', 'MESH:D011014', (73, 84))
5976	22607910	A report compiling data on 663 patients with MPM managed surgically suggested that those who underwent EPP had an inferior survival compared to patients who had P/D.	('EPP', 'Var', (103, 106))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (31, 39))	('man', 'Species', '9606', (49, 52))	('inferior', 'NegReg', (114, 122))
6045	22607910	Additionally, while the decision between EPP and P/D remains controversial, a multi-institutional retrospective analysis reported improved survival among patients receiving P/D compared to those receiving EPP.	('patients', 'Species', '9606', (154, 162))	('P/D', 'Var', (173, 176))	('survival', 'MPA', (139, 147))	('improved', 'PosReg', (130, 138))
6067	22607910	Thus, IMRT after other treatment modalities appears to improve progression free and overall survival in these patients.	('overall survival', 'CPA', (84, 100))	('improve', 'PosReg', (55, 62))	('IMRT', 'Var', (6, 10))	('progression free', 'CPA', (63, 79))	('patients', 'Species', '9606', (110, 118))
6077	22082164	However, functionalization of CNTs to modulate aspect ratio, biodegradability and to remove residual metals could allow for safe design of CNTs for use in drug delivery in certain circumstances.	('biodegradability', 'MPA', (61, 77))	('rat', 'Species', '10116', (54, 57))	('metal', 'Chemical', 'MESH:D008670', (101, 106))	('aspect ratio', 'MPA', (47, 59))	('modulate', 'Var', (38, 46))
6116	22082164	These metals are well known to cause pulmonary diseases in humans including pulmonary fibrosis, asthma or cancer.	('asthma', 'Disease', 'MESH:D001249', (96, 102))	('pulmonary fibrosis', 'Disease', (76, 94))	('asthma', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('metals', 'Var', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('pulmonary diseases', 'Disease', (37, 55))	('asthma', 'Phenotype', 'HP:0002099', (96, 102))	('cancer', 'Disease', (106, 112))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (76, 94))	('cause', 'Reg', (31, 36))	('pulmonary diseases', 'Disease', 'MESH:D008171', (37, 55))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (76, 94))	('humans', 'Species', '9606', (59, 65))	('metal', 'Chemical', 'MESH:D008670', (6, 11))
6125	22082164	More recent work by these investigators suggested that SWCNT also can exacerbate murine allergic airway inflammation via enhanced activation of Th2 immunity and increased oxidative stress, and that this exacerbation may be partly through the inappropriate activation of antigen-presenting cells, including dendritic cells.	('allergic airway inflammation', 'Disease', 'MESH:D004342', (88, 116))	('exacerbate', 'PosReg', (70, 80))	('Th2', 'Gene', '15111', (144, 147))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (161, 187))	('oxidative stress', 'Phenotype', 'HP:0025464', (171, 187))	('allergic airway inflammation', 'Phenotype', 'HP:0002099', (88, 116))	('murine', 'Species', '10090', (81, 87))	('enhanced activation', 'PosReg', (121, 140))	('SWCNT', 'Var', (55, 60))	('oxidative stress', 'MPA', (171, 187))	('increased', 'PosReg', (161, 170))	('allergic airway inflammation', 'Disease', (88, 116))	('inflammation', 'biological_process', 'GO:0006954', ('104', '116'))	('Th2', 'Gene', (144, 147))
6132	22082164	Moreover, pulmonary exposure to nanometals exacerbates airway hyper-responsiveness in mice.	('nanometals', 'Var', (32, 42))	('mice', 'Species', '10090', (86, 90))	('exacerbates', 'PosReg', (43, 54))	('hyper-responsiveness', 'Disease', 'MESH:D012130', (62, 82))	('hyper-responsiveness', 'Disease', (62, 82))	('metal', 'Chemical', 'MESH:D008670', (36, 41))
6138	22082164	SWCNTs or MWCNTs have been shown to exacerbate lung inflammation, pulmonary vascular permeability and lung expression of proinflammatory cytokines induced by LPS.	('LPS', 'Var', (158, 161))	('lung expression of proinflammatory cytokines', 'MPA', (102, 146))	('pulmonary vascular permeability', 'CPA', (66, 97))	('inflammation', 'biological_process', 'GO:0006954', ('52', '64'))	('lung inflammation', 'Disease', 'MESH:D011014', (47, 64))	('exacerbate', 'PosReg', (36, 46))	('MWCNTs', 'Chemical', '-', (10, 16))	('lung inflammation', 'Disease', (47, 64))
6139	22082164	Pre-exposure to LPS also exacerbates the fibrogenic potential of MWCNT delivered to the lungs of rats.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('fibrogenic potential', 'CPA', (41, 61))	('rats', 'Species', '10116', (97, 101))	('LPS', 'Var', (16, 19))	('exacerbates', 'PosReg', (25, 36))	('MWCNT', 'Chemical', '-', (65, 70))
6141	22082164	The precise mechanism through which LPS enhances CNT-induced lung fibrosis remains to be elucidated.	('enhances', 'PosReg', (40, 48))	('lung fibrosis', 'Phenotype', 'HP:0002206', (61, 74))	('lung fibrosis', 'Disease', 'MESH:D005355', (61, 74))	('LPS', 'Var', (36, 39))	('lung fibrosis', 'Disease', (61, 74))
6150	22082164	As mentioned previously in the discussion of immune cell reactions, inhaled MWCNTs have been reported to cause systemic immunosuppression and splenic oxidative stress.	('MWCNTs', 'Chemical', '-', (76, 82))	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('systemic immunosuppression', 'CPA', (111, 137))	('cause', 'Reg', (105, 110))	('inhaled MWCNTs', 'Var', (68, 82))	('splenic', 'MPA', (142, 149))
6155	22082164	SWCNTs have been shown to cause fragmented centrosomes, multiple mitotic spindle poles, anaphase bridges and aneuploid chromosome number in cultured primary or immortalized human airway epithelial cell types.	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('cause', 'Reg', (26, 31))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('65', '80'))	('anaphase', 'biological_process', 'GO:0051322', ('88', '96'))	('anaphase bridges', 'CPA', (88, 104))	('human', 'Species', '9606', (173, 178))	('SWCNTs', 'Var', (0, 6))	('multiple mitotic spindle poles', 'CPA', (56, 86))	('fragmented centrosomes', 'CPA', (32, 54))	('aneuploid chromosome number', 'CPA', (109, 136))
6163	22082164	Therefore, increased or decreased toxicity due to modification of CNTs depends on the specific type of functionalization.	('modification', 'Var', (50, 62))	('decreased', 'NegReg', (24, 33))	('toxicity', 'Disease', (34, 42))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))
6212	33374980	Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM) Malignant pleural mesothelioma (MPM) is characterized by the lack of effective long-term treatments and highly prevalent drug resistance.	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (144, 174))	('drug resistance', 'biological_process', 'GO:0009315', ('265', '280'))	('Malignant pleural mesothelioma', 'Disease', (144, 174))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (154, 174))	('Decrease', 'NegReg', (45, 53))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (107, 137))	('STAT3', 'Gene', '6774', (39, 44))	('drug resistance', 'biological_process', 'GO:0042493', ('265', '280'))	('Inhibitors', 'Var', (0, 10))	('drug resistance', 'Phenotype', 'HP:0020174', (265, 280))	('Growth', 'MPA', (54, 60))	('Immune Response', 'biological_process', 'GO:0006955', ('72', '87'))	('STAT3', 'Gene', (39, 44))	('Induce', 'PosReg', (65, 71))	('Decrease Growth', 'Phenotype', 'HP:0001510', (45, 60))	('Immune Response Genes', 'Gene', (72, 93))	('Malignant Pleural Mesothelioma', 'Disease', (107, 137))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (117, 137))
6216	33374980	Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options.	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (0, 30))	('Malignant pleural mesothelioma', 'Disease', (0, 30))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (10, 30))	('aggressive cancer', 'Disease', 'MESH:D009369', (43, 60))	('mutations', 'Var', (89, 98))	('aggressive cancer', 'Disease', (43, 60))	('loss-of-function', 'NegReg', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
6221	33374980	Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response.	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('cell cycle', 'biological_process', 'GO:0007049', ('107', '117'))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', (142, 145))	('cell cycle progression', 'CPA', (107, 129))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('gene expression', 'MPA', (48, 63))	('modulation', 'Var', (34, 44))
6222	33374980	Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2).	('immune response', 'biological_process', 'GO:0006955', ('188', '203'))	('pyrimethamine', 'Var', (97, 110))	('modulation', 'MPA', (127, 137))	('upregulation', 'PosReg', (215, 227))	('immune', 'MPA', (188, 194))	('ICOSLG', 'Gene', (231, 237))	('atovaquone', 'Chemical', 'MESH:D053626', (82, 92))	('pyrimethamine', 'Chemical', 'MESH:D011739', (97, 110))	('immunoregulatory genes', 'Gene', (141, 163))	('enhance', 'PosReg', (177, 184))
6229	33374980	MPM itself is characterized by mutations in tumor suppressor genes, which are not directly related to STAT3 activation.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MPM', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))
6230	33374980	Our previous data suggest that STAT3 can also be infrequently activated in MPM by EPHA2 mutations with oncogenic characteristics.	('EPHA2', 'Gene', (82, 87))	('MPM', 'Disease', (75, 78))	('mutations', 'Var', (88, 97))	('STAT3', 'MPA', (31, 36))	('EPHA2', 'Gene', '1969', (82, 87))
6234	33374980	STAT3 was readily detected in all of these models, and there was variable phosphorylation of STAT3 at Tyr705 as an indicator of activation, but not necessarily STAT3 dependency, with the highest in the H2804 cell line.	('activation', 'PosReg', (128, 138))	('phosphorylation', 'MPA', (74, 89))	('Tyr705', 'Chemical', '-', (102, 108))	('H2804', 'CellLine', 'CVCL:U998', (202, 207))	('Tyr705', 'Var', (102, 108))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))
6240	33374980	Indeed, expression of activated STAT3 increased growth of these cells in the absence of epidermal growth factor (EGF) (52% increased growth versus control LP9.EV; p < 0.05), indicating a central role of this protein in the biology of these cells (Figure 1B).	('increased', 'PosReg', (123, 132))	('epidermal growth factor', 'Gene', '1950', (88, 111))	('EGF', 'Gene', (113, 116))	('activated STAT3', 'Gene', (22, 37))	('EGF', 'Gene', '1950', (113, 116))	('growth', 'MPA', (48, 54))	('LP9', 'CellLine', 'CVCL:E109', (155, 158))	('epidermal growth factor', 'Gene', (88, 111))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('88', '111'))	('EGF', 'molecular_function', 'GO:0005154', ('113', '116'))	('increased', 'PosReg', (38, 47))	('expression', 'Var', (8, 18))
6241	33374980	In additional control experiments, we also show that the modest growth of LP9 cells is only affected by STAT3 knockdown in the presence of EGF (Figure 1C).	('knockdown', 'Var', (110, 119))	('LP9', 'CellLine', 'CVCL:E109', (74, 77))	('EGF', 'Gene', (139, 142))	('STAT3', 'Gene', (104, 109))	('EGF', 'Gene', '1950', (139, 142))	('EGF', 'molecular_function', 'GO:0005154', ('139', '142'))
6259	33374980	We found that atovaquone, pyrimethamine, and nifuroxazide all led to differential effects on MSTO-211H cells compared to nontransformed LP9 cells in 3D culture (Figure S7A,B), even though the same concentrations were toxic in monolayer culture settings (Figure 2A).	('MSTO-211H', 'Gene', (93, 102))	('pyrimethamine', 'Chemical', 'MESH:D011739', (26, 39))	('LP9', 'CellLine', 'CVCL:E109', (136, 139))	('rat', 'Species', '10116', (204, 207))	('nifuroxazide', 'Chemical', 'MESH:C013150', (45, 57))	('pyrimethamine', 'Var', (26, 39))	('effects', 'Reg', (82, 89))	('atovaquone', 'Chemical', 'MESH:D053626', (14, 24))
6266	33374980	Similar to atovaquone, pyrimethamine also significantly reduced tumor growth (p < 0.05), but, as expected from the in vitro data, the changes were smaller (Figure S7C).	('tumor', 'Disease', (64, 69))	('pyrimethamine', 'Chemical', 'MESH:D011739', (23, 36))	('reduced', 'NegReg', (56, 63))	('atovaquone', 'Chemical', 'MESH:D053626', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('pyrimethamine', 'Var', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
6284	33374980	However, atovaquone and pyrimethamine treatments were associated with a significant change (q < 0.25) in the HALLMARK_IL6_JAK_STAT3 gene expression signature in H28 cells.	('HALLMARK_IL6_JAK_STAT3', 'MPA', (109, 131))	('JAK', 'molecular_function', 'GO:0004713', ('122', '125'))	('change', 'Reg', (84, 90))	('IL6', 'molecular_function', 'GO:0005138', ('118', '121'))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('pyrimethamine', 'Chemical', 'MESH:D011739', (24, 37))	('atovaquone', 'Chemical', 'MESH:D053626', (9, 19))	('pyrimethamine', 'Var', (24, 37))
6288	33374980	Overall, the results support the notion that targeting the STAT3 pathway through drugs such as atovaquone and pyrimethamine not only inhibits tumor growth but may also decrease the immunosuppressive microenvironment in MPM.	('pyrimethamine', 'Chemical', 'MESH:D011739', (110, 123))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('atovaquone', 'Chemical', 'MESH:D053626', (95, 105))	('tumor', 'Disease', (142, 147))	('pyrimethamine', 'Var', (110, 123))	('immunosuppressive microenvironment', 'MPA', (181, 215))	('decrease', 'NegReg', (168, 176))	('MPM', 'Disease', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('STAT3 pathway', 'Pathway', (59, 72))	('inhibits', 'NegReg', (133, 141))
6290	33374980	Since inhibition of STAT3 is well-tolerated in normal tissue, this approach has the potential to have a high therapeutic index.	('STAT3', 'Gene', (20, 25))	('rat', 'Species', '10116', (38, 41))	('inhibition', 'Var', (6, 16))
6294	33374980	Due to the abundance of mutations in tumor suppressors, distinct mechanisms of activation are likely, including loss of expression of phosphatases and other negative regulators of this signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('expression', 'MPA', (120, 130))	('phosphatases', 'Protein', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (24, 33))	('activation', 'PosReg', (79, 89))	('signaling pathway', 'biological_process', 'GO:0007165', ('185', '202'))	('loss of', 'NegReg', (112, 119))
6307	33374980	Mutations in CDKN2A, encoding for p16INK4A and p14ARF, regulators of cell cycle and apoptosis through Rb and p53, are common in MPM and render cells resistant to apoptotic stimuli.	('p14ARF', 'Gene', (47, 53))	('CDKN2A', 'Gene', (13, 19))	('p16INK4A', 'Gene', (34, 42))	('cell cycle', 'biological_process', 'GO:0007049', ('69', '79'))	('Mutations', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('CDKN2A', 'Gene', '1029', (13, 19))	('p14ARF', 'Gene', '1029', (47, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('p16INK4A', 'Gene', '1029', (34, 42))
6311	33374980	Pyrimethamine, at least in breast cancer cells, is sufficient to induce an immune-stimulatory effect by inducing tumor infiltration of CD8+ T-cells with elevated Lamp1.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (113, 118))	('inducing', 'PosReg', (104, 112))	('rat', 'Species', '10116', (125, 128))	('Pyrimethamine', 'Chemical', 'MESH:D011739', (0, 13))	('Pyrimethamine', 'Var', (0, 13))	('immune-stimulatory effect', 'MPA', (75, 100))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('Lamp1', 'Gene', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('Lamp1', 'Gene', '3916', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
6314	33374980	STAT3 inhibitors induced cell cycle arrest and reduced growth; it is not known how interleukin-8 influences the MPM tumor microenvironment in vivo, but interleukin-8 has the potential to retain antigen-presenting dendritic cells in the tumor.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('25', '42'))	('growth', 'CPA', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (236, 241))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('arrest', 'Disease', (36, 42))	('tumor', 'Disease', (116, 121))	('reduced', 'NegReg', (47, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))	('interleukin-8', 'Var', (152, 165))
6343	33374980	Our results suggest that STAT3 is likely to induce localized immune suppression, and both STAT3 inhibitors, atovaquone and pyrimethamine, resulted in the modulation of genes predicted to enhance an immune response.	('atovaquone', 'Chemical', 'MESH:D053626', (108, 118))	('pyrimethamine', 'Var', (123, 136))	('STAT3', 'Gene', (90, 95))	('modulation', 'Reg', (154, 164))	('genes', 'Gene', (168, 173))	('pyrimethamine', 'Chemical', 'MESH:D011739', (123, 136))	('enhance', 'PosReg', (187, 194))	('STAT3', 'Var', (25, 30))	('resulted in', 'Reg', (138, 149))	('immune response', 'biological_process', 'GO:0006955', ('198', '213'))
6530	27813512	Genomic Profiling of Malignant Peritoneal Mesothelioma Reveals Recurrent Alterations in Epigenetic Regulatory Genes BAP1, SETD2, and DDX3X Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis.	('Malignant Peritoneal Mesothelioma', 'Disease', (21, 54))	('BAP1', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (139, 161))	('Malignant mesothelioma', 'Disease', (139, 161))	('SETD2', 'Gene', '29072', (122, 127))	('SETD2', 'Gene', (122, 127))	('Alterations', 'Var', (73, 84))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (139, 161))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('Malignant Peritoneal Mesothelioma', 'Disease', 'MESH:C562839', (21, 54))	('Peritoneal Mesothelioma', 'Phenotype', 'HP:0100003', (31, 54))	('DDX3', 'Gene', '1654', (133, 137))	('cancer', 'Disease', (172, 178))	('DDX3', 'Gene', (133, 137))	('BAP1', 'Gene', '8314', (116, 120))
6534	27813512	The most frequent genetic alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13 cases, with an additional 2 cases demonstrating monoallelic loss of BAP1.	('biallelic inactivation', 'Var', (41, 63))	('BAP1', 'Gene', '8314', (173, 177))	('BAP1', 'Gene', '8314', (71, 75))	('BAP1', 'Gene', (173, 177))	('BAP1', 'Gene', (71, 75))
6537	27813512	While these genes are known to be recurrently mutated in pleural mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of pleural tumors.	('mesotheliomas', 'Disease', (123, 136))	('mesotheliomas', 'Disease', (65, 78))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (57, 77))	('BAP1', 'Gene', (185, 189))	('peritoneal tumors', 'Disease', (157, 174))	('mesotheliomas', 'Disease', 'MESH:D008654', (123, 136))	('mesotheliomas', 'Disease', 'MESH:D008654', (65, 78))	('peritoneal tumors', 'Disease', 'MESH:D010534', (157, 174))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (57, 78))	('harboring', 'Reg', (175, 184))	('pleural tumors', 'Disease', (224, 238))	('pleural tumors', 'Disease', 'MESH:D010997', (224, 238))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (112, 135))	('BAP1', 'Gene', '8314', (185, 189))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (57, 78))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (112, 136))	('pleural mesotheliomas', 'Disease', (57, 78))	('alterations', 'Var', (190, 201))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
6538	27813512	Together, these findings demonstrate the importance of epigenetic modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and suggest opportunities for targeted therapies.	('epigenetic modifiers', 'Var', (55, 75))	('BAP1', 'Gene', '8314', (86, 90))	('SETD2', 'Gene', '29072', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('DDX3X', 'Gene', '1654', (103, 108))	('SETD2', 'Gene', (92, 97))	('tumor', 'Disease', (124, 129))	('BAP1', 'Gene', (86, 90))	('DDX3X', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
6544	27813512	These include deletion of the CDKN2A tumor suppressor gene (>60% of cases) that encodes the cell cycle kinase inhibitor protein p16INK4a, mutation of the NF2 tumor suppressor gene (20-40% of cases) that encodes the cytoskeletal scaffolding protein Merlin, and mutation or deletion of the BAP1 tumor suppressor gene (20-30% of cases) that encodes a deubiquitinating enzyme originally identified as a BRCA1 interacting protein..	('p16INK4a', 'Gene', '1029', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('mutation', 'Var', (260, 268))	('CDKN2A', 'Gene', '1029', (30, 36))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('348', '371'))	('mutation', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('deletion', 'Var', (14, 22))	('Merlin', 'Gene', '4771', (248, 254))	('NF2', 'Gene', '4771', (154, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('293', '309'))	('BAP1', 'Gene', '8314', (288, 292))	('p16INK4a', 'Gene', (128, 136))	('NF2', 'Gene', (154, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('103', '119'))	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('CDKN2A', 'Gene', (30, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('293', '309'))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('protein', 'cellular_component', 'GO:0003675', ('417', '424'))	('deletion', 'Var', (272, 280))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('BAP1', 'Gene', (288, 292))	('Merlin', 'Gene', (248, 254))
6546	27813512	Inactivating mutations in two epigenetic regulatory genes, DDX3X and SETD2, were identified in a 4% and 8% of pleural mesotheliomas, respectively.	('Inactivating mutations', 'Var', (0, 22))	('SETD2', 'Gene', '29072', (69, 74))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (110, 130))	('DDX3X', 'Gene', (59, 64))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (110, 131))	('SETD2', 'Gene', (69, 74))	('identified', 'Reg', (81, 91))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (110, 131))	('DDX3X', 'Gene', '1654', (59, 64))	('pleural mesotheliomas', 'Disease', (110, 131))
6547	27813512	In addition to these somatic mutations found in sporadic mesotheliomas, germline mutation of BAP1 has been identified in rare patients with malignant mesothelioma as part of the BAP1 tumor predisposition syndrome (OMIM 603089), which in addition to mesothelioma includes increased incidence of uveal melanoma, meningioma, renal cell carcinoma, and other tumors.	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (48, 70))	('BAP1', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (354, 359))	('renal cell carcinoma', 'Disease', (322, 342))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (322, 342))	('patients', 'Species', '9606', (126, 134))	('mesothelioma', 'Disease', (249, 261))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (48, 70))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('BAP1', 'Gene', '8314', (93, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (249, 261))	('tumors', 'Phenotype', 'HP:0002664', (354, 360))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (140, 162))	('sporadic mesotheliomas', 'Disease', (48, 70))	('meningioma', 'Disease', (310, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('meningioma', 'Phenotype', 'HP:0002858', (310, 320))	('mesothelioma', 'Disease', (57, 69))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('mutation', 'Var', (81, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (294, 308))	('tumor', 'Disease', (183, 188))	('malignant mesothelioma', 'Disease', (140, 162))	('BAP1', 'Gene', (93, 97))	('tumors', 'Disease', (354, 360))	('uveal melanoma', 'Disease', (294, 308))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (322, 342))	('BAP1', 'Gene', '8314', (178, 182))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (140, 162))	('mesothelioma', 'Disease', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('meningioma', 'Disease', 'MESH:D008577', (310, 320))	('mesothelioma', 'Disease', 'MESH:D008654', (150, 162))	('tumors', 'Disease', 'MESH:D009369', (354, 360))	('uveal melanoma', 'Phenotype', 'HP:0007716', (294, 308))
6548	27813512	Given the frequent genetic inactivation of CDKN2A and BAP1 in malignant pleural mesothelioma, several recent studies have assessed the sensitivity and specificity of either fluorescence in situ hybridization (FISH) or imunohistochemistry against these two genes/proteins as helpful diagnostic markers to distinguish malignant mesothelioma from benign mesothelial proliferations and metastatic carcinoma in pleural fluid.	('pleural fluid', 'Phenotype', 'HP:0002202', (406, 419))	('carcinoma in pleural fluid', 'Disease', 'MESH:D010997', (393, 419))	('malignant mesothelioma', 'Disease', (316, 338))	('genetic inactivation', 'Var', (19, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('CDKN2A', 'Gene', (43, 49))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (62, 92))	('CDKN2A', 'Gene', '1029', (43, 49))	('carcinoma in pleural fluid', 'Disease', (393, 419))	('BAP1', 'Gene', '8314', (54, 58))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (316, 338))	('malignant pleural mesothelioma', 'Disease', (62, 92))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (316, 338))	('BAP1', 'Gene', (54, 58))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (72, 92))
6551	27813512	Indeed, one study performed FISH on mesotheliomas from different sites of origin and found chromosome 9p21 deletion much more commonly in pleural than peritoneal tumors (85% versus 36%), whereas 5p15 and 7p12 gains were more common in peritoneal than pleural tumors.	('pleural tumors', 'Disease', (251, 265))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('chromosome', 'Var', (91, 101))	('pleural than peritoneal tumors', 'Disease', (138, 168))	('pleural tumors', 'Disease', 'MESH:D010997', (251, 265))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('mesotheliomas', 'Disease', 'MESH:D008654', (36, 49))	('pleural than peritoneal tumors', 'Disease', 'MESH:D010997', (138, 168))	('deletion', 'Var', (107, 115))	('mesotheliomas', 'Disease', (36, 49))
6552	27813512	A recent genome-wide analysis of 12 peritoneal mesotheliomas found BAP1 alterations (either deletions or truncating mutations) in 7 cases, but failed to identify alterations in CDKN2A or NF2 that are common in pleural mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (218, 231))	('CDKN2A', 'Gene', (177, 183))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (36, 60))	('truncating mutations', 'Var', (105, 125))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (210, 231))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (36, 59))	('NF2', 'Gene', '4771', (187, 190))	('mesotheliomas', 'Disease', (47, 60))	('CDKN2A', 'Gene', '1029', (177, 183))	('NF2', 'Gene', (187, 190))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (210, 230))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (210, 231))	('BAP1', 'Gene', '8314', (67, 71))	('mesotheliomas', 'Disease', 'MESH:D008654', (47, 60))	('pleural mesotheliomas', 'Disease', (210, 231))	('alterations', 'Reg', (72, 83))	('mesotheliomas', 'Disease', (218, 231))	('deletions', 'Var', (92, 101))	('BAP1', 'Gene', (67, 71))
6575	27813512	BAP1 alterations were identified in 11 of 13 tumors (85%).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BAP1', 'Gene', (0, 4))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (5, 16))	('BAP1', 'Gene', '8314', (0, 4))
6576	27813512	Of these 11 cases, three had somatic BAP1 mutations accompanied by loss of heterozygosity (one with a frameshift mutation, p.D362fs; one with a splice site mutation, c.68-1G>A; and one with a missense mutation, p.L97Q).	('BAP1', 'Gene', '8314', (37, 41))	('p.D362fs', 'Var', (123, 131))	('loss', 'NegReg', (67, 71))	('BAP1', 'Gene', (37, 41))	('p.L97Q', 'Mutation', 'p.L97Q', (211, 217))	('c.68-1G>A', 'Var', (166, 175))	('heterozygosity', 'MPA', (75, 89))	('mutations', 'Var', (42, 51))	('p.D362fs', 'Mutation', 'p.D362fsX', (123, 131))	('c.68-1G>A', 'Mutation', 'c.68-1G>A', (166, 175))
6577	27813512	One case had two somatic BAP1 mutations (p.H669D and p.86_87del).	('BAP1', 'Gene', (25, 29))	('p.H669D', 'Var', (41, 48))	('p.86_87del', 'Var', (53, 63))	('p.H669D', 'Mutation', 'p.H669D', (41, 48))	('p.86_87del', 'Mutation', 'p.86_87del', (53, 63))	('BAP1', 'Gene', '8314', (25, 29))
6580	27813512	The final case had a germline frameshift mutation in BAP1 (p.L573fs) that was accompanied by loss of heterozygosity in the tumor.	('p.L573fs', 'Mutation', 'rs869025212', (59, 67))	('tumor', 'Disease', (123, 128))	('germline frameshift', 'Var', (21, 40))	('BAP1', 'Gene', '8314', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('BAP1', 'Gene', (53, 57))
6581	27813512	Of the 9 cases with biallelic BAP1 alterations, two cases also demonstrated inactivating frameshift mutations (p.V2345fs and p.Q1152fs) in the epigenetic regulatory gene SETD2 with accompanying loss of heterozygosity.	('p.V2345fs', 'Mutation', 'p.V2345fsX', (111, 120))	('p.Q1152fs', 'Mutation', 'p.Q1152fsX', (125, 134))	('BAP1', 'Gene', (30, 34))	('alterations', 'Var', (35, 46))	('SETD2', 'Gene', (170, 175))	('p.Q1152fs', 'Var', (125, 134))	('SETD2', 'Gene', '29072', (170, 175))	('BAP1', 'Gene', '8314', (30, 34))	('p.V2345fs', 'Var', (111, 120))
6582	27813512	One of these tumors also harbored a truncating mutation (p.L1051fs) in the ARID1A gene, which encodes a subunit of the Swi/Snf chromatin remodeling complex.	('p.L1051fs', 'Var', (57, 66))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('127', '147'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('127', '155'))	('ARID1A', 'Gene', '8289', (75, 81))	('ARID1A', 'Gene', (75, 81))	('p.L1051fs', 'Mutation', 'p.L1051fsX', (57, 66))
6583	27813512	In addition, two other cases with biallelic BAP1 alteration demonstrated mutations in another epigenetic regulatory gene, DDX3X.	('DDX3X', 'Gene', (122, 127))	('BAP1', 'Gene', '8314', (44, 48))	('biallelic', 'Var', (34, 43))	('alteration', 'Var', (49, 59))	('DDX3X', 'Gene', '1654', (122, 127))	('mutations', 'Var', (73, 82))	('BAP1', 'Gene', (44, 48))
6584	27813512	Three tumors harbored inactivating mutations in the NF2 tumor suppressor gene (p.Q428*, p.F47fs, and p.L176fs) including both of the two cases with heterozygous BAP1 loss and one case without BAP1 alteration or chromosome 3p loss.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAP1', 'Gene', (161, 165))	('BAP1', 'Gene', (192, 196))	('inactivating', 'Reg', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('p.F47fs', 'Var', (88, 95))	('p.Q428*', 'Mutation', 'p.Q428*', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('p.Q428*', 'Var', (79, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('211', '221'))	('tumor', 'Disease', (56, 61))	('tumors', 'Disease', (6, 12))	('BAP1', 'Gene', '8314', (161, 165))	('NF2', 'Gene', '4771', (52, 55))	('BAP1', 'Gene', '8314', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (6, 11))	('p.L176fs', 'Var', (101, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('loss', 'NegReg', (166, 170))	('p.F47fs', 'Mutation', 'p.F47fsX', (88, 95))	('NF2', 'Gene', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('p.L176fs', 'Mutation', 'p.L176fsX', (101, 109))
6587	27813512	The two tumors without BAP1 alteration occurred in the oldest (age 85) and youngest (age 19) patients in this cohort and each demonstrated a solitary genetic alteration, NF2 truncating mutation with loss of heterozygosity in the 85 year old and TERT promoter mutation in the 19 year old.	('BAP1', 'Gene', (23, 27))	('loss of', 'NegReg', (199, 206))	('NF2', 'Gene', '4771', (170, 173))	('TERT', 'Gene', '7015', (245, 249))	('truncating mutation', 'Var', (174, 193))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('BAP1', 'Gene', '8314', (23, 27))	('NF2', 'Gene', (170, 173))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('TERT', 'Gene', (245, 249))	('patients', 'Species', '9606', (93, 101))
6588	27813512	The one case of peritoneal mesothelioma with mixed epithelioid and sarcomatoid morphology was the only case found to harbor homozygous deletion of CDKN2A and focal high-level amplification of the MET oncogene in addition to a structural rearrangement involving BAP1.	('deletion', 'Var', (135, 143))	('mesothelioma', 'Disease', (27, 39))	('BAP1', 'Gene', '8314', (261, 265))	('sarcomatoid morphology', 'Disease', (67, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('BAP1', 'Gene', (261, 265))	('sarcomatoid morphology', 'Disease', 'MESH:C538614', (67, 89))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (16, 39))	('CDKN2A', 'Gene', (147, 153))	('sarcomatoid morphology', 'Phenotype', 'HP:0100242', (67, 89))	('CDKN2A', 'Gene', '1029', (147, 153))
6592	27813512	Moreover, BAP1 loss was seen uniformly throughout all tumor cells in each case, suggesting that BAP1 inactivation is an early or initiating event in mesothelial tumorigenesis.	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('loss', 'NegReg', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inactivation', 'Var', (101, 113))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (161, 166))	('BAP1', 'Gene', '8314', (96, 100))	('BAP1', 'Gene', '8314', (10, 14))
6597	27813512	While CDKN2A deletion is very common in pleural mesotheliomas, it was only seen in one of 13 peritoneal mesotheliomas, which was the only case with a sarcomatoid component.	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (40, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (48, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (104, 117))	('sarcomatoid component', 'Disease', 'MESH:C538614', (150, 171))	('mesotheliomas', 'Disease', (48, 61))	('mesotheliomas', 'Disease', (104, 117))	('pleural mesotheliomas', 'Disease', (40, 61))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (40, 60))	('deletion', 'Var', (13, 21))	('common', 'Reg', (30, 36))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (93, 116))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (93, 117))	('CDKN2A', 'Gene', (6, 12))	('CDKN2A', 'Gene', '1029', (6, 12))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (40, 61))	('sarcomatoid component', 'Disease', (150, 171))
6598	27813512	In contrast, BAP1 inactivation/loss is much more common in peritoneal than pleural mesotheliomas.	('BAP1', 'Gene', (13, 17))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (75, 96))	('common', 'Reg', (49, 55))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (75, 95))	('pleural mesotheliomas', 'Disease', (75, 96))	('inactivation/loss', 'Var', (18, 35))	('inactivation/loss', 'NegReg', (18, 35))	('peritoneal', 'Disease', (59, 69))	('BAP1', 'Gene', '8314', (13, 17))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (75, 96))
6599	27813512	DDX3X and SETD2 mutations appear to be present in a small subset (5-15%) of both pleural and peritoneal mesotheliomas.	('pleural and peritoneal mesotheliomas', 'Disease', 'MESH:D010997', (81, 117))	('mutations', 'Var', (16, 25))	('SETD2', 'Gene', '29072', (10, 15))	('DDX3X', 'Gene', (0, 5))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (93, 116))	('SETD2', 'Gene', (10, 15))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (93, 117))	('present', 'Reg', (39, 46))	('DDX3X', 'Gene', '1654', (0, 5))
6600	27813512	A recent array comparative genomic hybridization study on 33 malignant peritoneal mesotheliomas identified focal deletions affecting BAP1 (61% of cases), NF2 (21% of cases), and CDKN2A (33% of cases), providing additional support for our conclusion that similar genetic alterations drive peritoneal mesothelioma but at different frequency compared to pleural mesothelioma.	('CDKN2A', 'Gene', (178, 184))	('BAP1', 'Gene', '8314', (133, 137))	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('malignant peritoneal mesotheliomas', 'Disease', (61, 95))	('mesothelioma', 'Disease', (359, 371))	('CDKN2A', 'Gene', '1029', (178, 184))	('mesothelioma', 'Disease', 'MESH:D008654', (359, 371))	('BAP1', 'Gene', (133, 137))	('pleural mesothelioma', 'Disease', (351, 371))	('NF2', 'Gene', '4771', (154, 157))	('deletions', 'Var', (113, 122))	('NF2', 'Gene', (154, 157))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (288, 311))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (71, 95))	('mesothelioma', 'Disease', (299, 311))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (71, 94))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (351, 371))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (351, 371))	('mesothelioma', 'Disease', 'MESH:D008654', (299, 311))	('malignant peritoneal mesotheliomas', 'Disease', 'MESH:C562839', (61, 95))
6603	27813512	Finally, our genomic profiling of malignant peritoneal mesothelioma has identified recurrent mutations in the epigenetic regulatory genes BAP1, SETD2, and DDX3X.	('malignant peritoneal mesothelioma', 'Disease', (34, 67))	('BAP1', 'Gene', '8314', (138, 142))	('mutations', 'Var', (93, 102))	('DDX3X', 'Gene', '1654', (155, 160))	('BAP1', 'Gene', (138, 142))	('SETD2', 'Gene', '29072', (144, 149))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (34, 67))	('SETD2', 'Gene', (144, 149))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (44, 67))	('DDX3X', 'Gene', (155, 160))
6605	27813512	Emerging preclinical evidence suggests that inhibitors of epigenetic modifiers including histone deacetylases and the histone methyltransferase EZH2 may be efficacious in the treatment of mesothelioma.	('mesothelioma', 'Disease', (188, 200))	('inhibitors', 'Var', (44, 54))	('EZH2', 'Gene', (144, 148))	('EZH2', 'Gene', '2146', (144, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (188, 200))	('histone', 'Protein', (89, 96))
6606	27813512	Those mesotheliomas harboring inactivating events affecting both BAP1 and other transcriptional regulators such as SETD2, DDX3X, and ARID1A likely define a molecular subgroup with altered transcriptional programs that may respond favorably to these agents, compared to those mesotheliomas lacking these alterations.	('ARID1A', 'Gene', '8289', (133, 139))	('SETD2', 'Gene', (115, 120))	('mesotheliomas', 'Disease', 'MESH:D008654', (6, 19))	('ARID1A', 'Gene', (133, 139))	('mesotheliomas', 'Disease', (6, 19))	('BAP1', 'Gene', '8314', (65, 69))	('mesotheliomas', 'Disease', 'MESH:D008654', (275, 288))	('transcriptional programs', 'MPA', (188, 212))	('mesotheliomas', 'Disease', (275, 288))	('BAP1', 'Gene', (65, 69))	('altered', 'Reg', (180, 187))	('DDX3X', 'Gene', (122, 127))	('SETD2', 'Gene', '29072', (115, 120))	('respond', 'MPA', (222, 229))	('DDX3X', 'Gene', '1654', (122, 127))	('inactivating events', 'Var', (30, 49))
6607	27813512	cabozantinib) for the subset of peritoneal mesotheliomas harboring MET amplification, as well as small molecule inhibition of WEE1 (e.g.	('cabozantinib', 'Chemical', 'MESH:C558660', (0, 12))	('mesotheliomas', 'Disease', (43, 56))	('inhibition', 'NegReg', (112, 122))	('WEE1', 'Gene', '7465', (126, 130))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (32, 55))	('mesotheliomas', 'Disease', 'MESH:D008654', (43, 56))	('WEE1', 'Gene', (126, 130))	('MET amplification', 'Var', (67, 84))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (32, 56))
6608	27813512	AZD1775) for the subset of tumors harboring SETD2 inactivation, a synthetic lethality that was recently reported in renal cell carcinoma and osteosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('SETD2', 'Gene', '29072', (44, 49))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('SETD2', 'Gene', (44, 49))	('osteosarcoma', 'Disease', (141, 153))	('renal cell carcinoma', 'Disease', (116, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (141, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('inactivation', 'Var', (50, 62))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))
6617	24142973	The crude mortality rates for lung cancer were higher in Fengtian than in Taiwan for all age groups and both genders.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('higher', 'PosReg', (47, 53))	('Fengtian', 'Var', (57, 65))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))
6677	24142973	Yang et al have reported that the destruction of nephrite can release asbestiform fibres and that nephrite carvers have an increased risk of pulmonary fibrosis.	('nephrite', 'Chemical', '-', (98, 106))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (141, 159))	('pulmonary fibrosis', 'Disease', (141, 159))	('destruction', 'Var', (34, 45))	('nephrite', 'Chemical', '-', (49, 57))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (141, 159))	('nephrite', 'Var', (98, 106))	('release asbestiform fibres', 'MPA', (62, 88))
6808	33509252	Beyond this "classical" pathway, ADCs can induce tumor cell death through the so-called bystander effect, which occurs when the cytotoxic warhead diffuses across the cell membrane to neighboring cells, thus inducing their apoptosis.	('ADCs', 'Var', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cell membrane', 'cellular_component', 'GO:0005886', ('164', '177'))	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('induce', 'Reg', (42, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('apoptosis', 'CPA', (222, 231))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('tumor', 'Disease', (49, 54))	('inducing', 'Reg', (207, 215))
6821	33509252	Conversely, conjugation into ADC hides the cytotoxic drug in the bloodstream to convey it directly into tumor cells, thus significantly reducing toxicity of these potent agents.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('reducing', 'NegReg', (136, 144))	('conjugation', 'biological_process', 'GO:0000746', ('12', '23'))	('tumor', 'Disease', (104, 109))	('ADC', 'Gene', (29, 32))	('conjugation', 'Var', (12, 23))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('toxicity', 'Disease', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
6827	33509252	Maytansinoids (DM1 and DM4) are synthetic derivatives of maytansine that also act by inhibiting microtubule polymerization.	('Maytansinoids', 'Chemical', '-', (0, 13))	('DM1', 'Gene', (15, 18))	('microtubule', 'cellular_component', 'GO:0005874', ('96', '107'))	('inhibiting', 'NegReg', (85, 95))	('DM1', 'Gene', '28509', (15, 18))	('microtubule polymerization', 'MPA', (96, 122))	('microtubule polymerization', 'biological_process', 'GO:0046785', ('96', '122'))	('DM4', 'Chemical', 'MESH:D008453', (23, 26))	('DM4', 'Var', (23, 26))	('maytansine', 'Chemical', 'MESH:D008453', (57, 67))
6843	33509252	Given the rarity of these mutations, their role as oncogenic drivers has been questioned for many years, and only recent studies proved their tumorigenic role along with their sensitivity to anti-HER2 agents.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('HER2', 'Gene', (196, 200))	('mutations', 'Var', (26, 35))	('HER2', 'Gene', '2064', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
6844	33509252	Bladder cancer has the highest prevalence of HER2 mutations (9-18%), followed by uterine cervix (6%), colorectal (5.8%), lung (4%) and breast cancer (4%).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('uterine cervix', 'Disease', (81, 95))	('lung', 'Disease', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('uterine cervix', 'Phenotype', 'HP:0030160', (81, 95))	('colorectal', 'Disease', (102, 112))	('HER2', 'Gene', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('HER2', 'Gene', '2064', (45, 49))	('breast cancer', 'Disease', (135, 148))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', (142, 148))
6849	33509252	Trastuzumab deruxtecan (DS-8201a; T-DXd) is an anti-HER2 ADC in which trastuzumab is conjugated with DXd, a novel topoisomerase I inhibitor payload.	('topoisomerase', 'molecular_function', 'GO:0003918', ('114', '127'))	('deruxtecan', 'Chemical', '-', (12, 22))	('HER2', 'Gene', '2064', (52, 56))	('DS-8201a', 'Var', (24, 32))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('topoisomerase', 'molecular_function', 'GO:0003917', ('114', '127'))	('HER2', 'Gene', (52, 56))
6856	33509252	In preclinical studies, T-DXd showed antitumor activity across a wide range of HER2-expressing tumor models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('HER2', 'Gene', '2064', (79, 83))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('T-DXd', 'Var', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('HER2', 'Gene', (79, 83))	('tumor', 'Disease', (95, 100))
6866	33509252	This gap has mainly been attributed to tumor heterogeneity of HER2-expression in GC/GEJC, eventual co-occurrence of HER2 amplification with other oncogenic mutations and to mechanisms of primary and secondary resistance to anti-HER2 treatments.	('amplification', 'Var', (121, 134))	('HER2', 'Gene', '2064', (62, 66))	('HER2', 'Gene', (228, 232))	('GC/GEJC', 'Disease', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('HER2', 'Gene', '2064', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('HER2', 'Gene', (116, 120))	('co-occurrence', 'Reg', (99, 112))	('tumor', 'Disease', (39, 44))	('HER2', 'Gene', '2064', (116, 120))	('HER2', 'Gene', (62, 66))
6868	33509252	The trial met its primary endpoint, with an ORR of 51% in patients in the T-DXd group, as compared to 14% in the control arm (P < 0.001).	('met', 'Gene', (10, 13))	('T-DXd', 'Var', (74, 79))	('met', 'Gene', '79811', (10, 13))	('patients', 'Species', '9606', (58, 66))
6878	33509252	Noteworthy, many other anti-HER2 ADCs are under evaluation, including A166, XMT-1522, MEDI-4276, ARX788, RC48-ADC, BAT8001 and PF-06804103.	('HER2', 'Gene', '2064', (28, 32))	('PF-06804103', 'Var', (127, 138))	('BAT8001', 'Var', (115, 122))	('HER2', 'Gene', (28, 32))	('A166', 'Var', (70, 74))
6907	33509252	This ADC is characterized by a high drug-to-antibody ratio (7.5-8), allowed by the significantly better toxicity profile of SN-38 than irinotecan, its prodrug.	('SN-38', 'Chemical', 'MESH:D000077146', (124, 129))	('antibody', 'cellular_component', 'GO:0042571', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019814', ('44', '52'))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('antibody', 'molecular_function', 'GO:0003823', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019815', ('44', '52'))	('toxicity', 'Disease', (104, 112))	('better', 'PosReg', (97, 103))	('SN-38', 'Var', (124, 129))	('irinotecan', 'Chemical', 'MESH:D000077146', (135, 145))
6930	33509252	The TROPiCS-03 (NCT03964727) is a multi-cohort, open-label, phase 2 study that is currently open to enrollment for patients with metastatic solid tumors, presently NSCLC (adenocarcinoma and squamous cell carcinoma), head and neck squamous cell carcinoma, and endometrial cancer, all selected for Trop-2 overexpression by a validated IHC assay.	('met', 'Gene', (129, 132))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (225, 253))	('neck', 'cellular_component', 'GO:0044326', ('225', '229'))	('Trop-2', 'Gene', '4070', (296, 302))	('endometrial cancer', 'Phenotype', 'HP:0012114', (259, 277))	('met', 'Gene', '79811', (263, 266))	('met', 'Gene', (263, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('Trop-2', 'Gene', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('solid tumors', 'Disease', (140, 152))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('endometrial cancer', 'Disease', (259, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('endometrial cancer', 'Disease', 'MESH:D016889', (259, 277))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (216, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('NSCLC', 'Disease', (164, 169))	('patients', 'Species', '9606', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('NCT03964727', 'Var', (16, 27))	('overexpression', 'PosReg', (303, 317))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 213))	('neck squamous cell carcinoma', 'Disease', (225, 253))	('met', 'Gene', '79811', (129, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
6951	33509252	SAR408701 is an ADC in which an anti-CEACAM5 antibody is conjugated to DM4, a maytansinoid cytotoxic agent.	('SAR408701', 'Chemical', '-', (0, 9))	('CEACAM5', 'Gene', (37, 44))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('CEACAM5', 'Gene', '1048', (37, 44))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('conjugated', 'Interaction', (57, 67))	('DM4', 'Chemical', 'MESH:D008453', (71, 74))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('SAR408701', 'Var', (0, 9))
6956	33509252	Given the manageable tolerability profile, SAR408701 was then subsequently investigated in three expansion cohorts, enrolling patients with CRC, lung cancers (both small-cell lung cancer and non-squamous NSCLC) and GC.	('small-cell lung cancer', 'Disease', 'MESH:D055752', (164, 186))	('small-cell lung cancer', 'Disease', (164, 186))	('non-squamous NSCLC', 'Disease', (191, 209))	('CRC', 'Disease', (140, 143))	('patients', 'Species', '9606', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('lung cancers', 'Disease', 'MESH:D008175', (145, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('lung cancers', 'Disease', (145, 157))	('SAR408701', 'Var', (43, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('SAR408701', 'Chemical', '-', (43, 52))	('lung cancers', 'Phenotype', 'HP:0100526', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (191, 209))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('CR', 'Chemical', '-', (140, 142))
6957	33509252	Most promising data came from the non-squamous NSCLC cohort, where a high antitumor activity was shown particularly in patients with high expression of CEACAM5 (>= 50%; ORR 20.3%, SD 42.2%), while responses were reduced in moderate expressors (1-49%; ORR 7.1%).	('high expression', 'Var', (133, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (34, 52))	('tumor', 'Disease', (78, 83))	('CEACAM5', 'Gene', (152, 159))	('non-squamous NSCLC', 'Disease', (34, 52))	('CEACAM5', 'Gene', '1048', (152, 159))
6958	33509252	Accordingly, subsequent development of SAR408701 was mainly focused on patients with CEACAM5-positive non-squamous NSCLC, and three ongoing trials are investigating it as monotherapy (CARMEN-LC03), in association with ramucirumab (CARMEN-LC04) or as first-line therapy in combination with PD-1 (CARMEN-LC05) are ongoing (Table 2).	('ramucirumab', 'Chemical', 'MESH:C543333', (218, 229))	('CEACAM5', 'Gene', '1048', (85, 92))	('CEACAM5', 'Gene', (85, 92))	('patients', 'Species', '9606', (71, 79))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (102, 120))	('PD-1', 'Gene', '5133', (289, 293))	('PD-1', 'Gene', (289, 293))	('SAR408701', 'Var', (39, 48))	('non-squamous NSCLC', 'Disease', (102, 120))	('SAR408701', 'Chemical', '-', (39, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
6959	33509252	Of note, despite the high expression of CEACAM5 by colorectal cancer cells, development of SAR408701 was discontinued in this subtype because of its low sensitivity to microtubule-inhibitors payload.	('SAR408701', 'Chemical', '-', (91, 100))	('CEACAM5', 'Gene', '1048', (40, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('sensitivity to microtubule-inhibitors payload', 'MPA', (153, 198))	('microtubule', 'cellular_component', 'GO:0005874', ('168', '179'))	('colorectal cancer', 'Disease', (51, 68))	('SAR408701', 'Var', (91, 100))	('CEACAM5', 'Gene', (40, 47))
6979	33509252	A phase I trial then investigated this ADC in EGFR-mutated NSCLC progressing to first generation EGFR-TKIs and negative for T790M mutation, or after osimertinib failure.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', '1956', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('EGFR', 'Gene', (97, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('EGFR', 'Gene', (46, 50))	('T790M mutation', 'Var', (124, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('osimertinib failure', 'Disease', (149, 168))	('NSCLC', 'Disease', (59, 64))	('T790M', 'Mutation', 'rs121434569', (124, 129))	('osimertinib failure', 'Disease', 'MESH:D006333', (149, 168))
6982	33509252	Antitumor activity was seen regardless of the specific mechanism of resistance to EGFR-TKI (EGFR mutations, amplifications of non-EGFR mutations/fusions).	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', (82, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('amplifications', 'Var', (108, 122))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
7006	33509252	Others anti-mesothelin ADCs, like DMOT4039A, RC88 and BMS-986148, are under clinical evaluation (Table 2).	('DMOT4039A', 'Var', (34, 43))	('mesothelin', 'Gene', '10232', (12, 22))	('mesothelin', 'Gene', (12, 22))	('MS', 'Chemical', 'MESH:C000607289', (55, 57))
7010	33509252	Physiologically, c-Met is primarily implicated in processes of cell motility occurring during embryogenesis and wound repair, while its pathological activation throughout mutation, amplification or overexpression has been detected in different cancer types.	('activation', 'PosReg', (149, 159))	('embryogenesis', 'biological_process', 'GO:0009790', ('94', '107'))	('mutation', 'Var', (171, 179))	('c-Met', 'Gene', '4233', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('embryogenesis', 'biological_process', 'GO:0009793', ('94', '107'))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('implicated', 'Reg', (36, 46))	('cell motility', 'biological_process', 'GO:0048870', ('63', '76'))	('cell motility', 'CPA', (63, 76))	('embryogenesis', 'biological_process', 'GO:0009792', ('94', '107'))	('cancer', 'Disease', (244, 250))	('c-Met', 'Gene', (17, 22))
7011	33509252	Aberrations of c-Met have been described as both primary events, leading to cancer cell transformation, and secondary events, responsible for cancer progression and treatment resistance.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('c-Met', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('c-Met', 'Gene', '4233', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (76, 82))	('leading to', 'Reg', (65, 75))	('cancer', 'Disease', (142, 148))
7028	33509252	Conversely, data from LUNG-MAP sub-study S1400K evaluating teliso-V in squamous NSCLC in ICI-refractory or ICI-naive patients were disappointing, with a ORR of 9% (2/23) and 7 high-grade events (3 G5 and 4 G3), leading to S1400K closure.	('S1400K', 'Mutation', 'p.S1400K', (222, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('squamous NSCLC', 'Disease', (71, 85))	('MAP', 'molecular_function', 'GO:0004239', ('27', '30'))	('S1400K', 'Mutation', 'p.S1400K', (41, 47))	('squamous NSCLC', 'Disease', 'MESH:D002294', (71, 85))	('S1400K', 'Var', (222, 228))	('patients', 'Species', '9606', (117, 125))
7029	33509252	A phase II study (NCT03539536) investigating teliso-V in both squamous and non-squamous (EGFR mutated and wt) c-Met-positive NSCLC is open to enrollment, with data expected in 2021.	('mutated', 'Var', (94, 101))	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', (125, 130))	('c-Met', 'Gene', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('c-Met', 'Gene', '4233', (110, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('EGFR', 'Gene', '1956', (89, 93))
7081	33509252	Centyrins are small (~ 10 kDa) cysteine-free scaffolds based on the type-III fibronectin domain of human Tenascin C. These alternative scaffolds possess excellent biophysical properties, which allow for mutation and conjugation at one or even multiple positions and are easily internalized by tumor.	('Tenascin C', 'Gene', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('conjugation', 'MPA', (216, 227))	('Tenascin C', 'Gene', '3371', (105, 115))	('Tenascin C', 'cellular_component', 'GO:0090733', ('105', '115'))	('mutation', 'Var', (203, 211))	('tumor', 'Disease', (293, 298))	('conjugation', 'biological_process', 'GO:0000746', ('216', '227'))	('cysteine', 'Chemical', 'MESH:D003545', (31, 39))	('human', 'Species', '9606', (99, 104))
7087	33509252	Trastuzumab deruxtecan has been associated with development of grade 5 interstitial lung diseases (ILDs) across several tumor types, while maytansinoids or auristatins-based ADCs have been linked to high-grade ocular or neurological toxicities, not always reversible.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('auristatins', 'Chemical', 'MESH:C543533', (156, 167))	('neurological toxicities', 'Disease', 'MESH:D009422', (220, 243))	('ILDs', 'Phenotype', 'HP:0006530', (99, 103))	('deruxtecan', 'Var', (12, 22))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (71, 96))	('associated with', 'Reg', (32, 47))	('lung diseases', 'Disease', 'MESH:D008171', (84, 97))	('ILD', 'Disease', 'MESH:D017563', (99, 102))	('lung diseases', 'Phenotype', 'HP:0002088', (84, 97))	('tumor', 'Disease', (120, 125))	('ILD', 'Phenotype', 'HP:0006530', (99, 102))	('maytansinoids', 'Chemical', '-', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('lung diseases', 'Disease', (84, 97))	('ILD', 'Disease', (99, 102))	('deruxtecan', 'Chemical', '-', (12, 22))	('lung disease', 'Phenotype', 'HP:0002088', (84, 96))	('neurological toxicities', 'Disease', (220, 243))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('interstitial lung diseases', 'Phenotype', 'HP:0006530', (71, 97))
7210	33383846	Moreover, using the functional enrichment tool FunRich and the Catalogue Of Somatic Mutations In Cancer (COSMIC) data, the network of the LOX family was shown to be associated with endometrium (78.9% of the network proteins), prostate (62.3%), ovary (74.7%), and skin (71.1%) cancers (Supplementary Table S5).	('endometrium', 'Disease', (181, 192))	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('Mutations', 'Var', (84, 93))	('LOX', 'Gene', '4015', (138, 141))	('ovary', 'Disease', (244, 249))	('associated', 'Reg', (165, 175))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('skin', 'Disease', (263, 267))	('cancers', 'Disease', (276, 283))	('LOX', 'Gene', (138, 141))	('prostate', 'Disease', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('ovary', 'Disease', 'MESH:D010051', (244, 249))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer', 'Disease', (97, 103))
7228	33383846	"Epithelial-mesenchymal transition" (37% of proteins annotated, 12.6-fold-enrichment) and "Integrin cell surface interactions" (22%, 19.4-fold-enrichment) were the most significantly enriched pathways in the mesothelioma subnetwork (Supplementary Table S11A) but not in the ovarian cancer subnetwork (Supplementary Table S11B), which suggests that the changes in LOX and LOXL interactome associated with cancer might depend on the cancer type.	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('ovarian cancer', 'Disease', 'MESH:D010051', (274, 288))	('cancer', 'Disease', (431, 437))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('S11A', 'Var', (253, 257))	('LOXL', 'Gene', (371, 375))	('S11A', 'SUBSTITUTION', 'None', (253, 257))	('ovarian cancer', 'Disease', (274, 288))	('LOX', 'Gene', '4015', (363, 366))	('mesothelioma', 'Disease', (208, 220))	('S11B', 'Var', (321, 325))	('LOX', 'Gene', '4015', (371, 374))	('ovarian cancer', 'Phenotype', 'HP:0100615', (274, 288))	('cancer', 'Disease', 'MESH:D009369', (431, 437))	('mesothelioma', 'Disease', 'MESH:D008654', (208, 220))	('cancer', 'Disease', (404, 410))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('cancer', 'Disease', (282, 288))	('LOX', 'Gene', (363, 366))	('LOX', 'Gene', (371, 374))	('S11B', 'SUBSTITUTION', 'None', (321, 325))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('LOXL', 'Gene', '84695', (371, 375))	('enriched', 'Reg', (183, 191))
7283	33383846	The class "Cancer-Related-Condition" (C8278) is defined as "A disorder either associated with an increased risk for malignant transformation (e.g., intraepithelial neoplasia, leukoplakia, dysplastic nevus, myelodysplastic syndrome) or that develops as a result of the presence of an existing malignant neoplasm (e.g., paraneoplastic syndrome)".	('paraneoplastic syndrome', 'Disease', (318, 341))	('C8278', 'Var', (38, 43))	('leukoplakia', 'Disease', 'MESH:D007971', (175, 186))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('leukoplakia', 'Disease', (175, 186))	('nevus', 'Phenotype', 'HP:0003764', (199, 204))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (188, 204))	('malignant transformation', 'CPA', (116, 140))	('myelodysplastic syndrome', 'Disease', (206, 230))	('dysplastic nevus', 'Disease', (188, 204))	('dysplastic nevus', 'Disease', 'MESH:D004416', (188, 204))	('malignant neoplasm', 'Disease', 'MESH:D009369', (292, 310))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (318, 341))	('Cancer', 'Disease', (11, 17))	('malignant neoplasm', 'Disease', (292, 310))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (148, 173))	('associated', 'Reg', (78, 88))	('neoplasia', 'Disease', 'MESH:D009369', (164, 173))	('neoplasia', 'Disease', (164, 173))	('Cancer', 'Disease', 'MESH:D009369', (11, 17))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (206, 230))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (206, 230))	('neoplasm', 'Phenotype', 'HP:0002664', (302, 310))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))
7288	33383846	Further binding assays will be performed to increase the coverage of the LOX interactome with proteins containing domains found in the known partners of LOX and LOXLs (e.g., the triple helix), and to determine the influence of mutations reported in cancer patients on the interaction network, and on the functional network in order to refine our understanding of the role of LOX and LOXLs in cancer.	('cancer', 'Disease', (392, 398))	('LOX', 'Gene', '4015', (73, 76))	('LOX', 'Gene', (375, 378))	('cancer', 'Disease', (249, 255))	('LOX', 'Gene', '4015', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('LOX', 'Gene', '4015', (383, 386))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('LOX', 'Gene', (161, 164))	('LOX', 'Gene', (73, 76))	('LOXL', 'Gene', '84695', (161, 165))	('LOX', 'Gene', (153, 156))	('LOX', 'Gene', (383, 386))	('binding', 'molecular_function', 'GO:0005488', ('8', '15'))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('LOXL', 'Gene', '84695', (383, 387))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('mutations', 'Var', (227, 236))	('LOXL', 'Gene', (161, 165))	('LOX', 'Gene', '4015', (375, 378))	('patients', 'Species', '9606', (256, 264))	('LOXL', 'Gene', (383, 387))	('LOX', 'Gene', '4015', (161, 164))
7304	33383846	Table S11A,B: Enrichment analysis of the subnetworks of the LOX family in mesothelioma (A) and ovarian serous cystadenocarcinoma (B) using FunRich.	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (95, 128))	('ovarian serous cystadenocarcinoma', 'Disease', (95, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('S11A', 'Var', (6, 10))	('S11A', 'SUBSTITUTION', 'None', (6, 10))	('LOX', 'Gene', '4015', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (95, 128))	('LOX', 'Gene', (60, 63))	('mesothelioma', 'Disease', (74, 86))
7365	31470859	Hallmarks of mesothelioma are epithelial cuboidal cells with microvilli, basement membranes, filaments and desmosomes.The criteria for malignancy are nuclear pleomorphism, mitotic activity and stromal invasion.	('stromal invasion', 'CPA', (193, 209))	('malignancy', 'Disease', 'MESH:D009369', (135, 145))	('men', 'Species', '9606', (97, 100))	('men', 'Species', '9606', (77, 80))	('malignancy', 'Disease', (135, 145))	('mitotic activity', 'CPA', (172, 188))	('microvilli', 'cellular_component', 'GO:0005902', ('61', '71'))	('Hallmarks of mesothelioma', 'Disease', (0, 25))	('nuclear pleomorphism', 'Var', (150, 170))	('Hallmarks of mesothelioma', 'Disease', 'MESH:D008654', (0, 25))
7368	31470859	Epithelial membrane antigen and factor VIII are strongly suggestive for the diagnosis of MM; mesothelioma-related markers include calretinin, thrombomodulin, CK5/6 (pleural), WT1 (Wilms tumour antibody), D2-40, CK7 (tunica vaginalis), CD20 +, and calretinin +.	('pleural', 'Disease', 'MESH:D010995', (165, 172))	('pleural', 'Disease', (165, 172))	('CK7', 'Gene', '3855', (211, 214))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('antibody', 'cellular_component', 'GO:0019815', ('193', '201'))	('calretinin', 'Gene', (130, 140))	('CD20', 'Gene', '54474', (235, 239))	('membrane', 'cellular_component', 'GO:0016020', ('11', '19'))	('Epithelial membrane antigen', 'Gene', (0, 27))	('Wilms tumour', 'Disease', (180, 192))	('CK5/6', 'Gene', '3852', (158, 163))	('antibody', 'cellular_component', 'GO:0019814', ('193', '201'))	('calretinin', 'Gene', (247, 257))	('calretinin', 'Gene', '794', (130, 140))	('MM', 'Disease', (89, 91))	('WT1', 'Gene', (175, 178))	('thrombomodulin', 'Gene', (142, 156))	('Epithelial membrane antigen', 'Gene', '4582', (0, 27))	('thrombomodulin', 'Gene', '7056', (142, 156))	('Wilms tumour', 'Phenotype', 'HP:0002667', (180, 192))	('CK5/6', 'Gene', (158, 163))	('antibody', 'molecular_function', 'GO:0003823', ('193', '201'))	('WT1', 'Gene', '7490', (175, 178))	('CK7', 'Gene', (211, 214))	('mesothelioma', 'Disease', (93, 105))	('Wilms tumour', 'Disease', 'MESH:D009396', (180, 192))	('antibody', 'cellular_component', 'GO:0042571', ('193', '201'))	('D2-40', 'Var', (204, 209))	('calretinin', 'Gene', '794', (247, 257))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('CD20', 'Gene', (235, 239))
7417	31470859	Jean (Jean 2012) hypothesized that NF2 regulates cell growth function, and its inactivation could be related to tumour progression and patient survival.	('regulates', 'Reg', (39, 48))	('patient', 'Species', '9606', (135, 142))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('NF2', 'Gene', (35, 38))	('cell growth function', 'CPA', (49, 69))	('inactivation', 'Var', (79, 91))	('tumour', 'Disease', (112, 118))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('NF2', 'Gene', '4771', (35, 38))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('related', 'Reg', (101, 108))
7418	31470859	We are deepening the study of these new cases, all with ascertained exposure to asbestos, to understand whether there are specific DNA copy number changes in MMTVT and investigating the relative genes involved to define whether they are or are not the same as those reported in pleural MM, particularly in relation to asbestos exposure, and whether they might be useful in elucidating tumorigenesis and predicting prognosis.	('pleural MM', 'Disease', (278, 288))	('MMTVT', 'Chemical', '-', (158, 163))	('changes', 'Var', (147, 154))	('MMTVT', 'Gene', (158, 163))	('asbestos', 'Chemical', 'MESH:D001194', (318, 326))	('asbestos', 'Chemical', 'MESH:D001194', (80, 88))	('pleural MM', 'Disease', 'MESH:D010995', (278, 288))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))
7449	22748269	In mice, liposomal BLP25 induces a cellular immune response characterised by antigen-specific T-cell proliferation and production of interferon-gamma, indicating a T helper type 1 response.	('cellular immune response', 'biological_process', 'GO:0002443', ('35', '59'))	('production of interferon-gamma', 'MPA', (119, 149))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('94', '114'))	('cellular immune response', 'biological_process', 'GO:0002449', ('35', '59'))	('liposomal', 'Var', (9, 18))	('mice', 'Species', '10090', (3, 7))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('133', '149'))	('cellular immune', 'MPA', (35, 50))	('BLP25', 'Gene', (19, 24))	('cellular immune response', 'biological_process', 'GO:0002456', ('35', '59'))
7453	22748269	Although not significant, median overall survival (the primary objective) was increased by 4 2 months for patients who received liposomal BLP25 (n=88; 17 2 vs 13 0 months, hazard ratio [HR] 0 745, 95% CI 0 533-1 042).	('liposomal', 'Var', (128, 137))	('BLP25', 'Gene', (138, 143))	('overall survival', 'MPA', (33, 49))	('increased', 'PosReg', (78, 87))	('patients', 'Species', '9606', (106, 114))
7469	22748269	In preclinical studies, antisense inhibition of TGF-beta2 led to inhibition of cellular TGF-beta2 expression and increased immunogenicity of cancer cells.	('inhibition', 'NegReg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('TGF-beta2', 'Gene', '7042', (88, 97))	('TGF-beta2', 'Gene', (88, 97))	('TGF-beta2', 'Gene', '7042', (48, 57))	('increased', 'PosReg', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('antisense inhibition', 'Var', (24, 44))	('cancer', 'Disease', (141, 147))	('TGF-beta2', 'Gene', (48, 57))	('expression', 'MPA', (98, 108))
7471	22748269	In a randomised, dose-variable, phase 2 trial, 75 NSCLC patients with stages II, IIIA, IIIB, and IV disease were randomly assigned to receive one of three doses (1 25x107, 2 5x107, or 5 0x107 cells per injection intra dermally) of belagenpumatucel-L on a monthly or alternate month schedule to a maximum of 16 doses.	('IIIA', 'Disease', (81, 85))	('patients', 'Species', '9606', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('IV disease', 'Disease', 'MESH:D020432', (97, 107))	('IV disease', 'Disease', (97, 107))	('NSCLC', 'Disease', (50, 55))	('1 25x107', 'Var', (162, 170))	('IIIB', 'Disease', (87, 91))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
7490	22748269	By contrast, seven of the eight patients who received recombinant MAGE A3 with adjuvant had a substantial increase in serum anti-MAGE A3 antibodies, suggesting the importance of adjuvant for the development of immunity to MAGE A3.	('MAGE A3', 'Gene', (66, 73))	('patients', 'Species', '9606', (32, 40))	('recombinant', 'Var', (54, 65))	('MAGE A3', 'Gene', '4102', (66, 73))	('MAGE A3', 'Gene', (129, 136))	('MAGE A3', 'Gene', '4102', (129, 136))	('increase', 'PosReg', (106, 114))	('MAGE A3', 'Gene', (222, 229))	('MAGE A3', 'Gene', '4102', (222, 229))
7503	22748269	Ipilimumab was associated with increased toxic effects; 41 patients (58%) in the concurrent group, 35 (52%) in the sequential group, and 18 (42%) in the chemotherapy only group had grade 3 or 4 adverse events.	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('patients', 'Species', '9606', (59, 67))	('Ipilimumab', 'Var', (0, 10))	('toxic', 'MPA', (41, 46))
7509	22748269	CTLA-4 and PD-1 blockage are both associated with immune-related adverse events from uncontrolled T-cell lymphoproliferation, although these toxic effects are less frequent and milder for PD-1 inhibition than for CTLA-4 inhibition.	('PD-1', 'Gene', '5133', (188, 192))	('PD-1', 'Gene', (188, 192))	('CTLA-4', 'Gene', (0, 6))	('immune-related', 'Disease', (50, 64))	('CTLA-4', 'Gene', '1493', (213, 219))	('blockage', 'Var', (16, 24))	('CTLA-4', 'Gene', '1493', (0, 6))	('PD-1', 'Gene', (11, 15))	('PD-1', 'Gene', '5133', (11, 15))	('CTLA-4', 'Gene', (213, 219))
7514	22748269	PF-3512676 (formerly known as CpG 7909) is a synthetic TLR9-activating oligodeoxynucleotide that mimics the natural ligand of TLR9 (unmethylated CpG motifs), thereby inducing a cascade of immune reactions, potentially promoting an antitumour immune response.	('immune response', 'biological_process', 'GO:0006955', ('242', '257'))	('TLR9', 'Gene', '54106', (126, 130))	('TLR9', 'Gene', '54106', (55, 59))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (71, 91))	('inducing', 'PosReg', (166, 174))	('tumour', 'Disease', (235, 241))	('ligand', 'molecular_function', 'GO:0005488', ('116', '122'))	('PF-3512676', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('promoting', 'PosReg', (218, 227))	('cascade', 'MPA', (177, 184))	('TLR9', 'Gene', (126, 130))	('TLR9', 'Gene', (55, 59))	('PF', 'Chemical', 'MESH:C002997', (0, 2))
7515	22748269	In mouse lung cancer models, PF-3512676 has single-agent activity, and a combination of PF-3512676 and paclitaxel improves survival compared with either treatment alone, without additive toxic eff ects.	('survival', 'CPA', (123, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('mouse', 'Species', '10090', (3, 8))	('improves', 'PosReg', (114, 122))	('PF', 'Chemical', 'MESH:C002997', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('PF', 'Chemical', 'MESH:C002997', (88, 90))	('PF-3512676', 'Var', (29, 39))	('PF-3512676', 'Var', (88, 98))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('combination', 'Interaction', (73, 84))
7517	22748269	In a phase 2 randomised controlled study, 111 chemotherapy-naive patients who received a combination of taxane and PF-3512676 had higher response rates (38% vs 19%; p=0 043) and a trend towards improved overall survival (12 3 vs 6 8 months; p=0 188), compared with patients who received chemotherapy alone.	('taxane', 'Chemical', 'MESH:C080625', (104, 110))	('overall', 'MPA', (203, 210))	('higher', 'PosReg', (130, 136))	('PF', 'Chemical', 'MESH:C002997', (115, 117))	('response', 'MPA', (137, 145))	('PF-3512676', 'Var', (115, 125))	('patients', 'Species', '9606', (265, 273))	('patients', 'Species', '9606', (65, 73))	('improved', 'PosReg', (194, 202))
7550	22748269	In human mesothelioma cell lines, peptide epitopes from WT1 induce CD4 and cytotoxic CD8 WT1-specifi c T-cell responses.	('induce', 'PosReg', (60, 66))	('WT1', 'Gene', (89, 92))	('CD8', 'Gene', (85, 88))	('human', 'Species', '9606', (3, 8))	('CD8', 'Gene', '925', (85, 88))	('CD4', 'Gene', (67, 70))	('peptide', 'Var', (34, 41))	('mesothelioma', 'Disease', (9, 21))	('WT1', 'Gene', '7490', (56, 59))	('CD4', 'Gene', '920', (67, 70))	('WT1', 'Gene', (56, 59))	('cytotoxic', 'CPA', (75, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (9, 21))	('WT1', 'Gene', '7490', (89, 92))
7573	22748269	The deletion of these coding sequences in mice causes a more than 1000-times attenuation of virulence.	('virulence', 'biological_process', 'GO:0016032', ('92', '101'))	('virulence', 'biological_process', 'GO:0009406', ('92', '101'))	('mice', 'Species', '10090', (42, 46))	('attenuation', 'NegReg', (77, 88))	('virulence', 'biological_process', 'GO:0009405', ('92', '101'))	('virulence', 'MPA', (92, 101))	('deletion', 'Var', (4, 12))
7574	22748269	However, uptake of CRS-207 by macrophages and phagocytic cells in the liver and spleen is retained and results in a local inflammatory response and activation and recruitment of immune effector cells, such as natural killer and T cells, to the liver.	('CRS', 'Chemical', 'MESH:D002857', (19, 22))	('local inflammatory response', 'CPA', (116, 143))	('activation', 'PosReg', (148, 158))	('uptake', 'biological_process', 'GO:0098739', ('9', '15'))	('inflammatory response', 'biological_process', 'GO:0006954', ('122', '143'))	('recruitment', 'CPA', (163, 174))	('uptake', 'biological_process', 'GO:0098657', ('9', '15'))	('CRS-207', 'Var', (19, 26))	('results in', 'Reg', (103, 113))
7577	22748269	In preclinical studies, CRS-207 elicited mesothelin-specific cellular immunity in mice and in non-human primates and was efficacious in tumour-bearing mice.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (151, 155))	('CRS-207', 'Var', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('CRS', 'Chemical', 'MESH:D002857', (24, 27))	('tumour', 'Disease', (136, 142))	('elicited', 'Reg', (32, 40))	('human', 'Species', '9606', (98, 103))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('mesothelin-specific cellular immunity', 'CPA', (41, 78))
7588	22748269	Some of the non-specif c immunotherapies assessed for NSCLC include PF-3512676, a TLR9 agonist, agents based on mycobacterial adjuvant, and talactoferrin.	('PF-3512676', 'Var', (68, 78))	('TLR9', 'Gene', (82, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('PF', 'Chemical', 'MESH:C002997', (68, 70))	('NSCLC', 'Disease', (54, 59))	('TLR9', 'Gene', '54106', (82, 86))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
7603	29698884	Pathology demonstrated an epithelioid necrotic intrahepatic mesothelioma that stained positive for calretinin, CK AE1/AE3, WT-1, D2-40 and CK7.	('positive', 'Reg', (86, 94))	('D2-40', 'Var', (129, 134))	('calretinin', 'Protein', (99, 109))	('epithelioid necrotic intrahepatic mesothelioma', 'Disease', (26, 72))	('CK AE1/AE3', 'Var', (111, 121))	('epithelioid necrotic intrahepatic mesothelioma', 'Disease', 'MESH:D008654', (26, 72))
7641	29698884	The tumor stained positive for calretinin, CK AE1/AE3, WT-1, D2-40 and CK7 (Fig.	('tumor', 'Disease', (4, 9))	('CK AE1/AE3', 'Var', (43, 53))	('calretinin', 'Protein', (31, 41))	('CK7', 'Var', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('D2-40', 'Var', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
7679	28670467	The cumulative probability of survival after 2 years of follow-up was 80% for subjects with high ERbeta expression versus 31% for subjects with negative of low ERbeta expression (p = 0.02, log-rank test).	('ERbeta', 'Gene', '2100', (160, 166))	('high', 'Var', (92, 96))	('ERbeta', 'Gene', (97, 103))	('ERbeta', 'Gene', (160, 166))	('ERbeta', 'Gene', '2100', (97, 103))
7695	28670467	Conversely, ERbeta knockdown in ER-positive cells conferred a more invasive phenotype, increased anchorage independent growth and elevated EGFR-coupled signal transduction pathways.	('increased', 'PosReg', (87, 96))	('ERbeta', 'Gene', '2100', (12, 18))	('anchorage independent growth', 'CPA', (97, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('knockdown', 'Var', (19, 28))	('EGFR', 'Gene', '1956', (139, 143))	('ERbeta', 'Gene', (12, 18))	('invasive phenotype', 'CPA', (67, 85))	('elevated', 'PosReg', (130, 138))	('more', 'PosReg', (62, 66))	('ER', 'Gene', '2099', (32, 34))	('ER', 'Gene', '2099', (12, 14))	('EGFR', 'Gene', (139, 143))	('signal transduction', 'biological_process', 'GO:0007165', ('152', '171'))
7699	28670467	Another study has described carbonic anhydrase IX positivity, proposed to serve as a surrogate marker of hypoxia, to be predominant in epithelioid MPMs, while not expressed in sarcomatoid and sarcomatoid areas of biphasic MPMs.	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('carbonic anhydrase IX', 'Gene', (28, 49))	('epithelioid', 'Disease', (135, 146))	('sarcomatoid and sarcomatoid areas of biphasic MPMs', 'Disease', 'MESH:C538614', (176, 226))	('carbonic anhydrase IX', 'Gene', '768', (28, 49))	('positivity', 'Var', (50, 60))
7708	28670467	We showed that KB9520 acted as a chemosensitizer through activation of ERbeta, increasing the antitumorigenic efficacy of cisplatin or the cisplatin/pemetrexed combination.	('KB9520', 'Var', (15, 21))	('ERbeta', 'Gene', '2100', (71, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('activation', 'PosReg', (57, 67))	('ERbeta', 'Gene', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('increasing', 'PosReg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('pemetrexed', 'Chemical', 'MESH:D000068437', (149, 159))	('KB9520', 'Chemical', '-', (15, 21))
7709	28670467	Treatment with KB9520 in combination with cisplatin/pemetrexed in vivo had greater efficacy than either treatment alone and caused a significantly reduced tumor burden compared with vehicle-treated animals.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('KB9520', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('pemetrexed', 'Chemical', 'MESH:D000068437', (52, 62))	('men', 'Species', '9606', (5, 8))	('efficacy', 'MPA', (83, 91))	('men', 'Species', '9606', (109, 112))	('reduced', 'NegReg', (147, 154))	('KB9520', 'Chemical', '-', (15, 21))
7710	28670467	Importantly, KB9520 had no cytotoxic effect per se and reduced cisplatin toxicity in ERbeta-expressing non malignant mesothelial cells.	('ERbeta', 'Gene', '2100', (85, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('reduced', 'NegReg', (55, 62))	('KB9520', 'Chemical', '-', (13, 19))	('ERbeta', 'Gene', (85, 91))	('KB9520', 'Var', (13, 19))	('toxicity', 'Disease', (73, 81))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))
7711	28670467	Thus, KB9520 may increase the sensitivity of MPM tumors to the standard of care in patients and perhaps result in higher response rates, without adding toxicity.	('sensitivity', 'MPA', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('MPM tumors', 'Disease', (45, 55))	('response rates', 'MPA', (121, 135))	('KB9520', 'Chemical', '-', (6, 12))	('toxicity', 'Disease', 'MESH:D064420', (152, 160))	('toxicity', 'Disease', (152, 160))	('KB9520', 'Var', (6, 12))	('increase', 'PosReg', (17, 25))	('MPM tumors', 'Disease', 'MESH:D009369', (45, 55))	('higher', 'PosReg', (114, 120))
7717	26807072	In this study, serum presence of mesothelioma-specific protein transcript variants of ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2 (ENOX2), a recently identified marker of malignancy, were investigated using the ONCOblot tissue of origin cancer detection test.	('cancer', 'Disease', (268, 274))	('malignancy', 'Disease', 'MESH:D009369', (202, 212))	('ENOX2', 'Gene', '10495', (162, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2', 'Gene', '10495', (86, 160))	('malignancy', 'Disease', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('exchanger', 'molecular_function', 'GO:0015297', ('149', '158'))	('ENOX2', 'Gene', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('variants', 'Var', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('mesothelioma', 'Disease', (33, 45))
7718	26807072	Sequential serum samples collected from asbestos-exposed individuals prior to the development of frank mesothelioma were assayed for ENOX2 presence by 2-D gel immunoblot analysis to determine how long in advance of clinical symptoms mesothelioma-specific ENOX2 transcript variants could be detected.	('variants', 'Var', (272, 280))	('mesothelioma', 'Disease', (233, 245))	('ENOX2', 'Gene', '10495', (133, 138))	('ENOX2', 'Gene', (255, 260))	('mesothelioma', 'Disease', (103, 115))	('asbestos', 'Chemical', 'MESH:D001194', (40, 48))	('frank mesothelioma', 'Disease', 'MESH:D008654', (97, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (233, 245))	('frank mesothelioma', 'Disease', (97, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))	('ENOX2', 'Gene', (133, 138))	('ENOX2', 'Gene', '10495', (255, 260))
7719	26807072	Two mesothelioma-specific ENOX2 protein transcript variants were detected in the serum of asbestos-exposed individuals 4-10 years prior to clinical diagnosis of malignant mesothelioma (average 6.2 years).	('mesothelioma', 'Disease', (171, 183))	('detected', 'Reg', (65, 73))	('ENOX2', 'Gene', (26, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (161, 183))	('mesothelioma', 'Disease', (4, 16))	('asbestos', 'Chemical', 'MESH:D001194', (90, 98))	('variants', 'Var', (51, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (161, 183))	('ENOX2', 'Gene', '10495', (26, 31))	('malignant mesothelioma', 'Disease', (161, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))
7720	26807072	Either one or both ENOX2 protein transcript variants indicative of malignant mesothelioma were absent in 14 of 15 subjects diagnosed with benign pleural plaques either with or without accompanying asbestosis.	('asbestosis', 'Disease', 'MESH:D001195', (197, 207))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (67, 89))	('ENOX2', 'Gene', '10495', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('asbestosis', 'Disease', (197, 207))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (67, 89))	('malignant mesothelioma', 'Disease', (67, 89))	('pleura', 'Disease', (145, 151))	('absent', 'NegReg', (95, 101))	('variants', 'Var', (44, 52))	('ENOX2', 'Gene', (19, 24))	('pleura', 'Disease', 'MESH:D054363', (145, 151))
7721	26807072	In a population of asbestos-exposed subjects who eventually developed malignant mesothelioma, ENOX2 protein transcript variants characteristic of malignant mesothelioma were present in serum 4-10 years in advance of clinical symptoms.	('ENOX2', 'Gene', '10495', (94, 99))	('malignant mesothelioma', 'Disease', (70, 92))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (146, 168))	('malignant mesothelioma', 'Disease', (146, 168))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (70, 92))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('ENOX2', 'Gene', (94, 99))	('variants', 'Var', (119, 127))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (146, 168))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))
7730	26807072	The test is based on the discovery that there are cancer-specific transcript variants of ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2 (ENOX2) and consists of 2-D gel electrophoretic separation of serum proteins followed by immunoblot analysis with an ENOX2-specific recombinant antibody.	('exchanger', 'molecular_function', 'GO:0015297', ('152', '161'))	('variants', 'Var', (77, 85))	('antibody', 'cellular_component', 'GO:0019814', ('308', '316'))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('ENOX2', 'Gene', (165, 170))	('antibody', 'molecular_function', 'GO:0003823', ('308', '316'))	('antibody', 'cellular_component', 'GO:0019815', ('308', '316'))	('ENOX2', 'Gene', '10495', (281, 286))	('antibody', 'cellular_component', 'GO:0042571', ('308', '316'))	('ENOX2', 'Gene', '10495', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2', 'Gene', '10495', (89, 163))	('ENOX2', 'Gene', (281, 286))
7732	26807072	At least 20 tissue of origin specific patterns of ENOX2 transcript variants have been described (and/or combinations of isoforms) indicative of the cancer tissue of origin.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ENOX2', 'Gene', '10495', (50, 55))	('variants', 'Var', (67, 75))	('ENOX2', 'Gene', (50, 55))
7734	26807072	ENOX2 transcript variants of specific molecular weights and isoelectric points (pIs) are produced uniquely by patients with cancer.	('cancer', 'Disease', (124, 130))	('variants', 'Var', (17, 25))	('ENOX2', 'Gene', (0, 5))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ENOX2', 'Gene', '10495', (0, 5))	('pIs', 'Chemical', '-', (80, 83))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
7735	26807072	Identification of cancer presence by detecting ENOX2 transcript variants produces a low incidence of both false positives and false negatives (>1 % for subjects with clinically confirmed cancers), as they are molecular signature molecules produced specifically by cancer cells and are absent from non-cancer cells.	('ENOX2', 'Gene', '10495', (47, 52))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('non-cancer', 'Disease', 'MESH:D009369', (297, 307))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('variants', 'Var', (64, 72))	('false', 'biological_process', 'GO:0071877', ('126', '131'))	('false', 'biological_process', 'GO:0071877', ('106', '111'))	('non-cancer', 'Disease', (297, 307))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('ENOX2', 'Gene', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancer', 'Disease', (187, 193))	('cancers', 'Disease', (187, 194))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('false', 'biological_process', 'GO:0071878', ('106', '111'))	('false', 'biological_process', 'GO:0071878', ('126', '131'))
7738	26807072	Therefore, the present study was undertaken to determine if cancer-specific ENOX2 transcript variants might serve as biomarkers to detect the presence of malignant mesothelioma in advance of clinical symptoms.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (154, 176))	('ENOX2', 'Gene', '10495', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (154, 176))	('variants', 'Var', (93, 101))	('cancer', 'Disease', (60, 66))	('ENOX2', 'Gene', (76, 81))	('malignant mesothelioma', 'Disease', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
7755	26807072	Overall, both of the mesothelioma-specific ENOX2 transcript variants were detected 4-10 years in advance of clinical symptoms and with an average of 6.2 +- 2.6 years in advance of clinical symptoms (Fig.	('mesothelioma', 'Disease', (21, 33))	('ENOX2', 'Gene', (43, 48))	('ENOX2', 'Gene', '10495', (43, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('variants', 'Var', (60, 68))
7790	26807072	Within the ONCOblot test, the presence of only the high molecular weight mesothelioma-specific ENOX2 transcript variant would be identified as 'not in the database' as no malignancy characterized to date produces a single ENOX2 transcript variant with a similar molecular weight and pI as this ENOX2 transcript variant.	('ENOX2', 'Gene', (95, 100))	('ENOX2', 'Gene', (294, 299))	('mesothelioma', 'Disease', (73, 85))	('ENOX2', 'Gene', '10495', (222, 227))	('variant', 'Var', (239, 246))	('ENOX2', 'Gene', '10495', (95, 100))	('ENOX2', 'Gene', '10495', (294, 299))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('ENOX2', 'Gene', (222, 227))	('malignancy', 'Disease', (171, 181))
7798	26807072	The presence of one of the mesothelioma-associated ENOX2 transcript variants may reflect this interaction.	('variants', 'Var', (68, 76))	('mesothelioma', 'Disease', (27, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('ENOX2', 'Gene', (51, 56))	('ENOX2', 'Gene', '10495', (51, 56))
7802	26807072	In a population of asbestos-exposed subjects who eventually developed malignant mesothelioma, ENOX2 transcript variants characteristic of malignant mesothelioma were present in serum 4-10 years in advance of clinical symptoms.	('ENOX2', 'Gene', '10495', (94, 99))	('malignant mesothelioma', 'Disease', (70, 92))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (70, 92))	('variants', 'Var', (111, 119))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (138, 160))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('ENOX2', 'Gene', (94, 99))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (138, 160))	('malignant mesothelioma', 'Disease', (138, 160))
7806	26807072	Serum samples were analyzed for the presence of ENOX2 protein transcript variants by using the ONCOblot Tissue of Origin Cancer Detection Test as described.	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('variants', 'Var', (73, 81))	('ENOX2', 'Gene', (48, 53))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Cancer', 'Disease', (121, 127))	('protein', 'Protein', (54, 61))	('Cancer', 'Disease', 'MESH:D009369', (121, 127))	('ENOX2', 'Gene', '10495', (48, 53))
7810	26807072	The two reference serum proteins, serotransferrin and alpha-fetuin are detected on western blots because they both share a similar five amino acid sequence within the antibody combining site shared by all ENOX2 protein transcript variants.	('antibody', 'cellular_component', 'GO:0019815', ('167', '175'))	('variants', 'Var', (230, 238))	('serotransferrin', 'Gene', (34, 49))	('serotransferrin', 'Gene', '7018', (34, 49))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('ENOX2', 'Gene', '10495', (205, 210))	('antibody', 'cellular_component', 'GO:0019814', ('167', '175'))	('antibody', 'molecular_function', 'GO:0003823', ('167', '175'))	('antibody', 'cellular_component', 'GO:0042571', ('167', '175'))	('ENOX2', 'Gene', (205, 210))
7812	26807072	Each transcript variant of ENOX2 migrates to a specific location defined by the two reference proteins and has a specific location (molecular weight and pI) on the blot that correlates to the known tissue of origin determined from banked sera samples collected from individuals with a clinically confirmed diagnosis of cancer (Table 1).	('variant', 'Var', (16, 23))	('sera', 'molecular_function', 'GO:0004617', ('238', '242'))	('cancer', 'Disease', (319, 325))	('ENOX2', 'Gene', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('ENOX2', 'Gene', '10495', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
7813	26807072	The protein chemistry differences that underlie the molecular weight and pI differences that distinguish tissue-specific ENOX2 transcript variants result from alternative splicing of the ENOX2 mRNA.	('alternative splicing', 'MPA', (159, 179))	('ENOX2', 'Gene', '10495', (187, 192))	('protein chemistry', 'MPA', (4, 21))	('variants', 'Var', (138, 146))	('splicing', 'biological_process', 'GO:0045292', ('171', '179'))	('result from', 'Reg', (147, 158))	('ENOX2', 'Gene', (121, 126))	('ENOX2', 'Gene', (187, 192))	('ENOX2', 'Gene', '10495', (121, 126))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
7814	26807072	Each of the protein transcript variants share a common exon 5 which contains the ENOX2-specific antibody-combining site including the amino acid sequence EEMTE.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('variants', 'Var', (31, 39))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('ENOX2', 'Gene', '10495', (81, 86))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('ENOX2', 'Gene', (81, 86))
7815	26807072	The different tissues of origin provide for non-overlapping patterns of ENOX2 protein transcript variants each with a characteristic number of protein transcript variants, molecular weights and pIs.	('ENOX2', 'Gene', '10495', (72, 77))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('variants', 'Var', (97, 105))	('ENOX2', 'Gene', (72, 77))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('pIs', 'Chemical', '-', (194, 197))	('protein', 'Protein', (78, 85))
7842	26448888	Family history was significant for breast cancer and BRCA1 mutation positivity in two siblings; the patient's own BRCA status was unknown.	('BRCA', 'Gene', '672', (53, 57))	('positivity', 'Var', (68, 78))	('mutation positivity', 'Var', (59, 78))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA', 'Gene', (53, 57))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('patient', 'Species', '9606', (100, 107))	('BRCA', 'Gene', '672', (114, 118))	('BRCA1', 'Gene', '672', (53, 58))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('BRCA', 'Gene', (114, 118))	('BRCA1', 'Gene', (53, 58))
7855	26448888	In this reported case, there were clinical findings concerning both primary mammary carcinoma (clinically palpable breast mass, family history of breast cancer and BRCA1 mutation, and recent benign pleural biopsy) and malignant mesothelioma (history of asbestos exposure and pleural thickening).	('pleural thickening', 'Phenotype', 'HP:0031944', (275, 293))	('BRCA1', 'Gene', '672', (164, 169))	('mammary carcinoma', 'Disease', 'MESH:D015674', (76, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (218, 240))	('BRCA1', 'Gene', (164, 169))	('breast mass', 'Phenotype', 'HP:0032408', (115, 126))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('malignant mesothelioma', 'Disease', (218, 240))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('asbestos', 'Chemical', 'MESH:D001194', (253, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('mammary carcinoma', 'Disease', (76, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (218, 240))	('mutation', 'Var', (170, 178))
7892	25575875	Of 61 patients recruited, 7 patients (23%) developed a PTM in the radiotherapy arm, compared with 3 patients (10%) in the control arm.	('developed', 'Reg', (43, 52))	('PTM', 'Disease', (55, 58))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (6, 14))	('PTM', 'biological_process', 'GO:0043687', ('55', '58'))	('patients', 'Species', '9606', (28, 36))	('radiotherapy', 'Var', (66, 78))
7968	25147801	The presence of syndecan-1 on mesothelioma cells is associated with favourable prognosis, while high levels of syndecan-1 in breast cancer indicate poor prognosis.	('syndecan', 'molecular_function', 'GO:0015023', ('16', '24'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('syndecan', 'molecular_function', 'GO:0015023', ('111', '119'))	('breast cancer', 'Disease', (125, 138))	('presence', 'Var', (4, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
8011	17710208	Recent preclinical evidence suggests that inhibition of pdgfr signalling augments the antitumour and anti-angiogenic effects of vegfr inhibitors.	('vegf', 'Gene', (128, 132))	('pdgfr', 'Gene', (56, 61))	('vegf', 'Gene', '7422', (128, 132))	('pdgfr', 'Gene', '5159', (56, 61))	('signalling', 'biological_process', 'GO:0023052', ('62', '72'))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('inhibition', 'Var', (42, 52))	('anti-angiogenic effects', 'CPA', (101, 124))	('augments', 'NegReg', (73, 81))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
8123	17620119	The Tags of SV40, BKV and JCV strongly cross-react with the same antisera, while a less strong cross-reactivity is observed in most structural antigenic determinants of the viral proteins, named VP1, 2 and 3.	('SV40', 'Species', '1891767', (12, 16))	('cross-react', 'Reg', (39, 50))	('SV40', 'Var', (12, 16))	('Tag', 'Gene', (4, 7))	('Tag', 'Gene', '404663', (4, 7))
8127	17620119	In monkeys, initial lytic infection by SV40 is controlled by the immune system.	('SV40', 'Species', '1891767', (39, 43))	('lytic infection', 'Disease', (20, 35))	('lytic infection', 'Disease', 'MESH:D007239', (20, 35))	('SV40', 'Var', (39, 43))
8138	17620119	Analysis of SV40 deletion mutants revealed that tag is not essential for lytic infection in culture.	('tag', 'Gene', (48, 51))	('SV40', 'Species', '1891767', (12, 16))	('SV40', 'Gene', (12, 16))	('deletion mutants', 'Var', (17, 33))	('lytic infection', 'Disease', (73, 88))	('tag', 'Gene', '404663', (48, 51))	('lytic infection', 'Disease', 'MESH:D007239', (73, 88))
8144	17620119	Human mesothelial cells do not support the lytic infection efficiently and are transformed at a high rate (1,000 times higher than that of human fibroblasts) by SV40 or Tag alone, and release SV40 virions as a result of the persistent infection.	('Human', 'Species', '9606', (0, 5))	('Tag', 'Gene', '404663', (169, 172))	('lytic infection', 'Disease', 'MESH:D007239', (43, 58))	('SV40', 'Species', '1891767', (161, 165))	('SV40', 'Species', '1891767', (192, 196))	('persistent infection', 'Phenotype', 'HP:0031035', (224, 244))	('human', 'Species', '9606', (139, 144))	('SV40', 'Var', (192, 196))	('Tag', 'Gene', (169, 172))	('lytic infection', 'Disease', (43, 58))	('SV40', 'Var', (161, 165))
8150	17620119	SV40 Tag may also lead to transformation by inducing mutations to the cellular genome or numerical and structural alterations of chromosomes, such as gaps, breaks, dicentric and ring chromosomes, chromatid exchanges, deletions, duplications and translocations.	('translocations', 'CPA', (245, 259))	('breaks', 'CPA', (156, 162))	('Tag', 'Gene', (5, 8))	('chromatid', 'cellular_component', 'GO:0005694', ('196', '205'))	('Tag', 'Gene', '404663', (5, 8))	('duplications', 'CPA', (228, 240))	('mutations', 'Var', (53, 62))	('chromatid exchanges', 'CPA', (196, 215))	('deletions', 'CPA', (217, 226))	('chromatid', 'cellular_component', 'GO:0005695', ('196', '205'))	('inducing', 'Reg', (44, 52))	('SV40', 'Species', '1891767', (0, 4))	('lead to', 'Reg', (18, 25))	('gaps', 'CPA', (150, 154))
8159	17620119	SV40 is highly oncogenic in rodents and when inoculated subcutaneously, intracerebrally or intravenously in newborn hamsters induces soft tissue sarcomas, osteosarcomas, ependymomas and choroid plexus papillomas, and neoplasms of the hematopoietic system, such as lymphocytic leukemia, histiocytic lymphomas and rarely, B-cell lymphomas.	('B-cell lymphomas', 'Disease', (320, 336))	('lymphomas', 'Disease', (327, 336))	('osteosarcomas', 'Disease', (155, 168))	('choroid plexus papillomas', 'Disease', 'MESH:D020288', (186, 211))	('leukemia', 'Phenotype', 'HP:0001909', (276, 284))	('papillomas', 'Phenotype', 'HP:0012740', (201, 211))	('ependymomas', 'Disease', (170, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (327, 335))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (320, 336))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (264, 284))	('osteosarcomas', 'Phenotype', 'HP:0002669', (155, 168))	('induces', 'Reg', (125, 132))	('neoplasms', 'Phenotype', 'HP:0002664', (217, 226))	('choroid plexus papillomas', 'Disease', (186, 211))	('lymphomas', 'Disease', 'MESH:D008223', (298, 307))	('lymphomas', 'Phenotype', 'HP:0002665', (298, 307))	('soft', 'Disease', (133, 137))	('neoplasms of the hematopoietic system', 'Disease', (217, 254))	('lymphomas', 'Disease', 'MESH:D008223', (327, 336))	('choroid plexus papillomas', 'Phenotype', 'HP:0200022', (186, 211))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('lymphomas', 'Phenotype', 'HP:0002665', (327, 336))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (133, 153))	('neoplasms of the hematopoietic system', 'Disease', 'MESH:D019337', (217, 254))	('lymphocytic leukemia', 'Disease', (264, 284))	('ependymoma', 'Phenotype', 'HP:0002888', (170, 180))	('lymphoma', 'Phenotype', 'HP:0002665', (298, 306))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('sarcomas', 'Disease', 'MESH:D012509', (160, 168))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (320, 336))	('ependymomas', 'Disease', 'MESH:D004806', (170, 181))	('osteosarcomas', 'Disease', 'MESH:D012516', (155, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('lymphomas', 'Disease', (298, 307))	('sarcomas', 'Disease', (145, 153))	('SV40', 'Species', '1891767', (0, 4))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcomas', 'Disease', (160, 168))	('SV40', 'Var', (0, 4))
8160	17620119	Moreover, direct inoculation of SV40 into the pleural space induces malignant mesothelioma in 100% of the injected hamsters.	('induces', 'Reg', (60, 67))	('SV40', 'Species', '1891767', (32, 36))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (68, 90))	('SV40', 'Var', (32, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (68, 90))	('malignant mesothelioma', 'Disease', (68, 90))
8162	17620119	SV40-transgenic mice, like rodents experimentally inoculated with the virus, develop ependymomas and choroid plexus papillomas, as well as other neoplasms.	('papillomas', 'Phenotype', 'HP:0012740', (116, 126))	('ependymomas', 'Disease', (85, 96))	('SV40-transgenic', 'Var', (0, 15))	('choroid plexus papillomas', 'Phenotype', 'HP:0200022', (101, 126))	('neoplasms', 'Disease', (145, 154))	('transgenic mice', 'Species', '10090', (5, 20))	('ependymoma', 'Phenotype', 'HP:0002888', (85, 95))	('develop', 'PosReg', (77, 84))	('choroid plexus papillomas', 'Disease', 'MESH:D020288', (101, 126))	('neoplasms', 'Disease', 'MESH:D009369', (145, 154))	('SV40', 'Species', '1891767', (0, 4))	('ependymomas', 'Disease', 'MESH:D004806', (85, 96))	('choroid plexus papillomas', 'Disease', (101, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (145, 154))
8168	17620119	Inactivated vaccines against adenoviruses and hepatitis A virus also exposed humans to SV40, although the amount of infectious SV40 was almost certainly lower then that administered with OPV or live respiratory syncytial virus.	('SV40', 'Var', (87, 91))	('humans', 'Species', '9606', (77, 83))	('exposed', 'Reg', (69, 76))	('SV40', 'Species', '1891767', (127, 131))	('hepatitis', 'Phenotype', 'HP:0012115', (46, 55))	('respiratory syncytial virus', 'Species', '12814', (199, 226))	('lower', 'NegReg', (153, 158))	('SV40', 'Species', '1891767', (87, 91))
8172	17620119	Shah et al., detected antibodies to SV40 in children born after 1964, when IPV was free of SV40, as well as in people born before 1954.	('SV40', 'Species', '1891767', (36, 40))	('antibodies', 'Var', (22, 32))	('people', 'Species', '9606', (111, 117))	('SV40', 'Gene', (36, 40))	('SV40', 'Species', '1891767', (91, 95))	('children', 'Species', '9606', (44, 52))	('detected', 'Reg', (13, 21))
8197	17620119	Other studies have examined seroprevalence for SV40 in cancer patients compared with controls using viral-like-particle (VLP)- based assays, which detect antibodies that are specific to the major capsid protein VP1 of SV40, BKV, and JCV.	('VLP', 'cellular_component', 'GO:0000943', ('121', '124'))	('SV40', 'Species', '1891767', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('SV40', 'Species', '1891767', (218, 222))	('SV40', 'Var', (218, 222))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Disease', (55, 61))
8200	17620119	Carter et al., using recombinant SV40 VP1 virus-like particles (VLPs) as antigen in an ELISA test, detected antibodies to SV40 in 6,6% of human sera, whereas SV40 reactivity in the same sera disappeared after serum pre-adsorption with BKV and JCV VLPs.	('SV40', 'Species', '1891767', (33, 37))	('human', 'Species', '9606', (138, 143))	('SV40', 'Species', '1891767', (122, 126))	('sera', 'molecular_function', 'GO:0004617', ('144', '148'))	('SV40', 'Gene', (122, 126))	('sera', 'molecular_function', 'GO:0004617', ('186', '190'))	('SV40', 'Species', '1891767', (158, 162))	('antibodies', 'Var', (108, 118))	('pre', 'molecular_function', 'GO:0003904', ('215', '218'))	('detected', 'Reg', (99, 107))
8216	17620119	Finally, SV40, as with other tumor viruses, tends to establish long-term persistent infection, as compared with the self-limited infection typical of most common viruses.	('SV40', 'Species', '1891767', (9, 13))	('SV40', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor viruses', 'Disease', (29, 42))	('tumor viruses', 'Disease', 'MESH:D009369', (29, 42))	('persistent infection', 'Phenotype', 'HP:0031035', (73, 93))
8222	17620119	SV40 DNA was localized to renal tubular epithelial cell nuclei in renal biopsies of patients with focal segmental glomerulosclerosis as determined by in situ hybridization.	('patients', 'Species', '9606', (84, 92))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (98, 132))	('SV40 DNA', 'Var', (0, 8))	('renal tubular epithelial cell nuclei', 'Phenotype', 'HP:0031198', (26, 62))	('focal segmental glomerulosclerosis', 'Disease', (98, 132))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (114, 132))	('SV40', 'Species', '1891767', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('5', '8'))	('focal segmental glomerulosclerosis', 'Disease', 'MESH:D005923', (98, 132))
8224	17620119	One study reported that SV40 and BKV sequences have been co-detected in the kidneys of patients with post-transplantation interstitial nephritis thus suggesting that SV40 may cooperate in the etiopathogenesis of this chronic disease.	('SV40', 'Species', '1891767', (166, 170))	('interstitial nephritis', 'Phenotype', 'HP:0001970', (122, 144))	('SV40', 'Var', (166, 170))	('cooperate', 'Reg', (175, 184))	('nephritis', 'Phenotype', 'HP:0000123', (135, 144))	('interstitial nephritis', 'Disease', 'MESH:D009395', (122, 144))	('patients', 'Species', '9606', (87, 95))	('BKV', 'Protein', (33, 36))	('SV40', 'Species', '1891767', (24, 28))	('interstitial nephritis', 'Disease', (122, 144))	('SV40', 'Gene', (24, 28))
8226	17620119	Other studies showed that SV40 DNA sequences from the viral regulatory region were detected and identified in the allografts of immunocompromised pediatric renal transplant recipients and in the native kidneys of a young adult lung transplant patient with polyomavirus nephropathy.	('polyomavirus nephropathy', 'Disease', (256, 280))	('patient', 'Species', '9606', (243, 250))	('SV40 DNA', 'Var', (26, 34))	('SV40', 'Species', '1891767', (26, 30))	('nephropathy', 'Phenotype', 'HP:0000112', (269, 280))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('polyomavirus nephropathy', 'Disease', 'MESH:D007674', (256, 280))
8254	17620119	Indeed, many reports indicate that different SV40 strains and variants are distributed throughout the human population and consequently in human specimens.	('variants', 'Var', (62, 70))	('human', 'Species', '9606', (139, 144))	('SV40', 'Species', '1891767', (45, 49))	('SV40', 'Gene', (45, 49))	('human', 'Species', '9606', (102, 107))
8255	17620119	Variations in the Tag-C gene region have frequently been detected in human tumor associated sequences.	('human', 'Species', '9606', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Variations', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Tag', 'Gene', (18, 21))	('Tag', 'Gene', '404663', (18, 21))	('tumor', 'Disease', (75, 80))
8257	17620119	In contrast, the SV40 regulatory region may contain large insertions, deletions or duplications, and rearrangements have been observed to occur within individual infected monkeys and during the passage of SV40 in certain cultured cells.	('SV40', 'Species', '1891767', (205, 209))	('SV40', 'Species', '1891767', (17, 21))	('SV40', 'Gene', (17, 21))	('duplications', 'Var', (83, 95))	('deletions', 'Var', (70, 79))
8265	17620119	In addition, the presence of SV40 sequences in people born before and after the introduction of SV40-contaminated vaccine suggests that (i) SV40 is spreading by horizontal infection and probably (ii) other unidentified sources of SV40 infection may exist.	('SV40', 'Species', '1891767', (29, 33))	('SV40', 'Gene', (29, 33))	('SV40 infection', 'Disease', 'MESH:D007239', (230, 244))	('SV40', 'Species', '1891767', (140, 144))	('people', 'Species', '9606', (47, 53))	('SV40', 'Species', '1891767', (230, 234))	('SV40', 'Var', (140, 144))	('SV40', 'Species', '1891767', (96, 100))	('SV40 infection', 'Disease', (230, 244))
8274	17620119	Therefore, in human cells SV40 could initiate the tumorigenic process by hitting the cell genome, then it could become dispensable and lost in the progression phase of the tumor, when the accumulation of genetic alterations renders the presence of viral transforming functions unnecessary.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('human', 'Species', '9606', (14, 19))	('tumor', 'Disease', (172, 177))	('SV40', 'Species', '1891767', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SV40', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (50, 55))
8275	17620119	Immunoselection may even be exerted against persistently SV40-infected cells, while genetically mutated and uninfected cells may have a proliferative advantage and become the prevalent population in the tumor tissue.	('tag', 'Gene', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('SV40', 'Species', '1891767', (57, 61))	('SV40-infected', 'Var', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tag', 'Gene', '404663', (155, 158))
8285	17620119	Suggestive data are available on the role of SV40 Tag in the pathogenesis of human mesothelioma: (i) its ability to bind in vivo p53 and RB family proteins in human mesothelioma samples; (ii) activation of Notch-1, a gene promoting cell cycle progression and cell proliferation, in primary human mesothelial cells; (iii) induction of apoptosis in mesothelioma cells transfected with antisense DNA to the SV40 early region gene; (iv) the presence of SV40 Tag-specific cytotoxic T lymphocytes in sera of patients affected by mesothelioma; and (v) the poorer prognosis of mesotheliomas harboring SV40 early region sequences compared to SV40-negative mesotheliomas.	('Tag', 'Gene', (50, 53))	('mesotheliomas', 'Disease', 'MESH:D008654', (569, 582))	('SV40', 'Species', '1891767', (404, 408))	('cell cycle', 'biological_process', 'GO:0007049', ('232', '242'))	('mesothelioma', 'Disease', (569, 581))	('SV40', 'Species', '1891767', (593, 597))	('Tag', 'Gene', '404663', (50, 53))	('Notch-1', 'Gene', (206, 213))	('mesothelioma', 'Disease', (83, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (569, 581))	('p53', 'Gene', (129, 132))	('Tag', 'Gene', (454, 457))	('mesotheliomas', 'Disease', 'MESH:D008654', (647, 660))	('SV40', 'Species', '1891767', (45, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('Tag', 'Gene', '404663', (454, 457))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('321', '343'))	('SV40', 'Species', '1891767', (633, 637))	('SV40', 'Species', '1891767', (449, 453))	('human', 'Species', '9606', (159, 164))	('DNA', 'cellular_component', 'GO:0005574', ('393', '396'))	('mesothelioma', 'Disease', (523, 535))	('patients', 'Species', '9606', (502, 510))	('mesothelioma', 'Disease', 'MESH:D008654', (523, 535))	('human', 'Species', '9606', (77, 82))	('sera', 'molecular_function', 'GO:0004617', ('494', '498'))	('cell proliferation', 'biological_process', 'GO:0008283', ('259', '277'))	('mesotheliomas', 'Disease', (569, 582))	('mesothelioma', 'Disease', (165, 177))	('SV40 early region sequences', 'Var', (593, 620))	('mesothelioma', 'Disease', (347, 359))	('pathogenesis', 'biological_process', 'GO:0009405', ('61', '73'))	('Notch-1', 'Gene', '4851', (206, 213))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('mesothelioma', 'Disease', (647, 659))	('p53', 'Gene', '7157', (129, 132))	('mesotheliomas', 'Disease', (647, 660))	('mesothelioma', 'Disease', 'MESH:D008654', (347, 359))	('human', 'Species', '9606', (290, 295))	('mesothelioma', 'Disease', 'MESH:D008654', (647, 659))
8310	31788004	High levels of GLI-1 expression is significantly associated with worst overall survival in two independent cohorts of patients [ and analysis of mesothelioma TCGA  data using Progene2 ].	('GLI-1', 'Gene', (15, 20))	('High levels', 'Var', (0, 11))	('mesothelioma', 'Disease', (145, 157))	('overall survival', 'MPA', (71, 87))	('patients', 'Species', '9606', (118, 126))	('worst', 'NegReg', (65, 70))	('GLI-1', 'Gene', '2735', (15, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))
8312	31788004	Interestingly, a recent pan-cancer analysis revealed that not only GLI-1 (p = 0.019584614) but also GLI-2 (p = 0.035063475) and SHH (p = 0.003447888) high expression have prognostic value in mesothelioma TCGA.	('mesothelioma', 'Disease', 'MESH:D008654', (191, 203))	('GLI-1', 'Gene', '2735', (67, 72))	('GLI-2', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('GLI-1', 'Gene', (67, 72))	('SHH', 'Gene', (128, 131))	('high', 'Var', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mesothelioma', 'Disease', (191, 203))	('cancer', 'Disease', (28, 34))	('GLI-2', 'Gene', '2736', (100, 105))	('SHH', 'Gene', '6469', (128, 131))
8314	31788004	Oncoprint analysis  of TCGA data ( Figure 1A ) shows that few mesothelioma patients bear PTCH1 truncation mutations or SUFU deep deletions and there is a statistically significant co-occurrence between alterations of several components of Hh signaling ( Figure 1B ).	('SUFU', 'Gene', '51684', (119, 123))	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('PTCH1', 'Gene', (89, 94))	('mesothelioma', 'Disease', (62, 74))	('patients', 'Species', '9606', (75, 83))	('truncation mutations', 'Var', (95, 115))	('PTCH1', 'Gene', '5727', (89, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('SUFU', 'Gene', (119, 123))
8327	31788004	Patients with PTCH1 driver mutations should respond to Smo inhibitors.	('mutations', 'Var', (27, 36))	('Patients', 'Species', '9606', (0, 8))	('PTCH1', 'Gene', '5727', (14, 19))	('PTCH1', 'Gene', (14, 19))
8332	31788004	Patients with Hh-ligand independent mutations may benefit from alternative therapeutic strategies.	('Hh-ligand', 'Protein', (14, 23))	('Patients', 'Species', '9606', (0, 8))	('ligand', 'molecular_function', 'GO:0005488', ('17', '23'))	('mutations', 'Var', (36, 45))
8346	29587439	MM is a very aggressive tumor associated with asbestos exposure, and genetic alterations in NF2 that abrogate merlin's functional activity are found in about 40% of MMs, indicating the importance of NF2 inactivation in MM development and progression.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('genetic alterations', 'Var', (69, 88))	('functional activity', 'MPA', (119, 138))	('rat', 'Species', '10116', (81, 84))	('very aggressive tumor', 'Disease', (8, 29))	('asbestos', 'Chemical', 'MESH:D001194', (46, 54))	('MMs', 'Disease', (165, 168))	('very aggressive tumor', 'Disease', 'MESH:D000326', (8, 29))	('NF2', 'Gene', (92, 95))
8347	29587439	In this review, we summarize the current knowledge of molecular events triggered by NF2/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas.	('deficient mesotheliomas', 'Disease', (226, 249))	('mesothelioma', 'Disease', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (236, 248))	('mesothelioma', 'Disease', (142, 154))	('NF2/merlin', 'Gene', (84, 94))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('inactivation', 'Var', (95, 107))	('deficient mesotheliomas', 'Disease', 'MESH:D008654', (226, 249))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('lead to', 'Reg', (115, 122))
8348	29587439	Mutations in the neurofibromatosis type 2 (NF2) gene are responsible for neurofibromatosis 2, a dominantly inherited familial cancer syndrome characterized by the formation of bilateral vestibular schwannomas and meningiomas.	('bilateral vestibular schwannomas', 'Phenotype', 'HP:0009589', (176, 208))	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (17, 41))	('vestibular schwannomas', 'Phenotype', 'HP:0009588', (186, 208))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (117, 141))	('neurofibromatosis 2', 'Gene', (73, 92))	('neurofibromatosis type 2', 'Disease', (17, 41))	('bilateral vestibular schwannomas', 'Disease', (176, 208))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('bilateral vestibular schwannomas', 'Disease', 'MESH:D009464', (176, 208))	('responsible', 'Reg', (57, 68))	('meningiomas', 'Disease', 'MESH:D008577', (213, 224))	('meningioma', 'Phenotype', 'HP:0002858', (213, 223))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (73, 90))	('schwannomas', 'Phenotype', 'HP:0100008', (197, 208))	('meningiomas', 'Phenotype', 'HP:0002858', (213, 224))	('schwannoma', 'Phenotype', 'HP:0100008', (197, 207))	('familial cancer syndrome', 'Disease', (117, 141))	('meningiomas', 'Disease', (213, 224))	('NF2', 'Gene', (43, 46))	('neurofibromatosis 2', 'Gene', '4771', (73, 92))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (17, 34))
8349	29587439	Besides sporadic schwannomas and meningiomas, frequent biallelic inactivation of NF2 was also found in malignant mesothelioma (MM), a very aggressive tumor which is not associated with the NF2 cancer syndrome.	('cancer syndrome', 'Disease', (193, 208))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('malignant mesothelioma', 'Disease', (103, 125))	('meningioma', 'Phenotype', 'HP:0002858', (33, 43))	('very aggressive tumor', 'Disease', 'MESH:D000326', (134, 155))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (103, 125))	('schwannomas', 'Phenotype', 'HP:0100008', (17, 28))	('schwannoma', 'Phenotype', 'HP:0100008', (17, 27))	('biallelic inactivation', 'Var', (55, 77))	('meningiomas', 'Disease', 'MESH:D008577', (33, 44))	('found', 'Reg', (94, 99))	('meningiomas', 'Phenotype', 'HP:0002858', (33, 44))	('schwannomas', 'Disease', 'MESH:D009442', (17, 28))	('cancer syndrome', 'Disease', 'MESH:D009369', (193, 208))	('meningiomas', 'Disease', (33, 44))	('very aggressive tumor', 'Disease', (134, 155))	('schwannomas', 'Disease', (17, 28))	('NF2', 'Gene', (81, 84))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (103, 125))
8350	29587439	Tumors carrying NF2 mutations are also observed, albeit infrequently, in multiple organs such as the breast, the prostate, the liver, and the kidney, indicating a significant role of NF2 in the development of various human malignancies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('human', 'Species', '9606', (217, 222))	('observed', 'Reg', (39, 47))	('NF2', 'Gene', (16, 19))	('malignancies', 'Disease', 'MESH:D009369', (223, 235))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('malignancies', 'Disease', (223, 235))	('mutations', 'Var', (20, 29))
8355	29587439	Thus, heterozygous NF2+/- mice had a higher sensitivity to asbestos, which resulted in an increased risk of malignant mesothelioma formation compared to wild-type NF2+/+ mice.	('sensitivity', 'MPA', (44, 55))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (108, 130))	('asbestos', 'Chemical', 'MESH:D001194', (59, 67))	('malignant mesothelioma', 'Disease', (108, 130))	('higher', 'PosReg', (37, 43))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('NF2+/-', 'Var', (19, 25))	('mice', 'Species', '10090', (170, 174))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (108, 130))	('mice', 'Species', '10090', (26, 30))
8356	29587439	A direct injection of the Adeno-Cre virus into the pleural cavity of adult mice resulted in a conditional knockout of oncosuppressor genes, which further demonstrated that the loss of NF2, together with Tp53 or Ink4a/Arf, frequently causes the development of mesothelioma which closely mimicked human MM.	('Ink4a/Arf', 'Gene', (211, 220))	('human', 'Species', '9606', (295, 300))	('mesothelioma', 'Disease', 'MESH:D008654', (259, 271))	('Tp53', 'Gene', (203, 207))	('mice', 'Species', '10090', (75, 79))	('loss', 'Var', (176, 180))	('causes', 'Reg', (233, 239))	('NF2', 'Gene', (184, 187))	('Tp53', 'Gene', '22059', (203, 207))	('rat', 'Species', '10116', (161, 164))	('mesothelioma', 'Disease', (259, 271))	('Ink4a/Arf', 'Gene', '12578', (211, 220))
8357	29587439	It was also shown that the restoration of NF2 expression in NF2-deficient mesothelioma cells significantly inhibited their growth.	('restoration', 'Var', (27, 38))	('NF2', 'Gene', (42, 45))	('NF2-deficient mesothelioma', 'Disease', (60, 86))	('rat', 'Species', '10116', (32, 35))	('NF2-deficient mesothelioma', 'Disease', 'MESH:C537392', (60, 86))	('expression', 'MPA', (46, 56))	('inhibited', 'NegReg', (107, 116))	('growth', 'CPA', (123, 129))
8358	29587439	These in vitro and in vivo data strongly support the role of NF2 inactivation in mesothelioma development.	('inactivation', 'Var', (65, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('NF2', 'Gene', (61, 64))	('mesothelioma', 'Disease', (81, 93))
8368	29587439	Alanine substitution in, or deletion of, this region produces unique merlin mutants, which have dominant-negative activity and result in an excessive proliferation of wing epithelial cells in flies and a loss of contact inhibition in mammalian cells.	('Alanine substitution', 'Var', (0, 20))	('Alanine', 'Chemical', 'MESH:D000409', (0, 7))	('loss', 'NegReg', (204, 208))	('contact inhibition', 'CPA', (212, 230))	('mutants', 'Var', (76, 83))	('merlin', 'Gene', (69, 75))	('rat', 'Species', '10116', (157, 160))	('mammalian', 'Species', '9606', (234, 243))	('deletion', 'Var', (28, 36))	('excessive', 'PosReg', (140, 149))	('contact inhibition', 'biological_process', 'GO:0060242', ('212', '230'))
8369	29587439	Although a C-terminal phosphorylation site, threonine 576, critical for the conformational change in ERM proteins, is also conserved in merlin; the Thr576Ala substitution does not affect merlin's ability to suppress cell growth and motility.	('suppress', 'NegReg', (207, 215))	('cell growth', 'biological_process', 'GO:0016049', ('216', '227'))	('Thr576Ala', 'Var', (148, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('cell growth', 'CPA', (216, 227))	('threonine', 'Chemical', 'MESH:D013912', (44, 53))	('Thr576Ala', 'SUBSTITUTION', 'None', (148, 157))
8370	29587439	Aside from this, the phosphorylation of merlin at serine 518 abrogates its growth inhibition activity.	('growth inhibition activity', 'CPA', (75, 101))	('merlin', 'Protein', (40, 46))	('phosphorylation', 'MPA', (21, 36))	('abrogates', 'NegReg', (61, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('serine 518', 'Var', (50, 60))	('serine', 'Chemical', 'MESH:D012694', (50, 56))
8371	29587439	Merlin phosphorylation at Ser518 was frequently observed in mesothelioma cells expressing full-length merlin.	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('Ser518', 'Chemical', '-', (26, 32))	('at Ser518', 'Var', (23, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('7', '22'))	('Merlin', 'Gene', '4771', (0, 6))	('Merlin', 'Gene', (0, 6))	('mesothelioma', 'Disease', (60, 72))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('observed', 'Reg', (48, 56))
8372	29587439	Moreover, CPI-17, a cellular inhibitor of myosin phosphatase targeting subunit 1 (MYPT1-PP1delta), was increased in mesothelioma cells with full-length NF2 compared to normal pleura or mesothelioma with truncated NF2.	('mesothelioma', 'Disease', (116, 128))	('CPI-17', 'Gene', '94274', (10, 16))	('MYPT1', 'Gene', '4659', (82, 87))	('increased', 'PosReg', (103, 112))	('mesothelioma', 'Disease', (185, 197))	('phosphatase', 'molecular_function', 'GO:0016791', ('49', '60'))	('NF2', 'Gene', (152, 155))	('pleura or mesothelioma', 'Disease', (175, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('CPI-17', 'Gene', (10, 16))	('MYPT1', 'Gene', (82, 87))	('full-length', 'Var', (140, 151))	('pleura or mesothelioma', 'Disease', 'MESH:D008654', (175, 197))
8374	29587439	These findings suggest that merlin can be inactivated not only by mutations but also through posttranslational modifications occurring in mesothelioma cells.	('mutations', 'Var', (66, 75))	('mesothelioma', 'Disease', (138, 150))	('inactivated', 'NegReg', (42, 53))	('merlin', 'Protein', (28, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))
8375	29587439	The Ser518 phosphorylation in merlin is independently catalyzed by distinct protein kinases such as p21-activated kinase (PAK) and protein kinase A (PKA).	('merlin', 'Gene', (30, 36))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('phosphorylation', 'MPA', (11, 26))	('Ser', 'cellular_component', 'GO:0005790', ('4', '7'))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('PKA', 'cellular_component', 'GO:0005952', ('149', '152'))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('PKA', 'molecular_function', 'GO:0004691', ('149', '152'))	('Ser518', 'Chemical', '-', (4, 10))	('Ser518', 'Var', (4, 10))
8376	29587439	PAK causes a phosphorylation-dependent inactivation of merlin and promotes the loss of contact inhibition of proliferation, whereas PKA, in addition to Ser518, also phosphorylates Ser10 that is not conserved in ERM proteins, which results in increased cell migration.	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('PKA', 'cellular_component', 'GO:0005952', ('132', '135'))	('PKA', 'molecular_function', 'GO:0004691', ('132', '135'))	('rat', 'Species', '10116', (260, 263))	('Ser', 'cellular_component', 'GO:0005790', ('180', '183'))	('phosphorylation-dependent', 'MPA', (13, 38))	('increased', 'PosReg', (242, 251))	('cell migration', 'biological_process', 'GO:0016477', ('252', '266'))	('contact inhibition', 'MPA', (87, 105))	('Ser10', 'Var', (180, 185))	('merlin', 'Protein', (55, 61))	('Ser518', 'Chemical', '-', (152, 158))	('Ser', 'cellular_component', 'GO:0005790', ('152', '155'))	('contact inhibition', 'biological_process', 'GO:0060242', ('87', '105'))	('rat', 'Species', '10116', (116, 119))	('inactivation', 'NegReg', (39, 51))	('loss', 'NegReg', (79, 83))	('Ser10', 'Chemical', '-', (180, 185))	('cell migration', 'CPA', (252, 266))
8377	29587439	Another protein kinase, AKT, phosphorylates merlin at Thr230 and Ser315, which appears to stimulate ubiquitin-dependent protein degradation.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('AKT', 'Gene', (24, 27))	('Ser', 'cellular_component', 'GO:0005790', ('65', '68'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('ubiquitin-dependent protein degradation', 'biological_process', 'GO:0006511', ('100', '139'))	('Thr230', 'Chemical', '-', (54, 60))	('Ser315', 'Chemical', '-', (65, 71))	('AKT', 'Gene', '207', (24, 27))	('ubiquitin', 'molecular_function', 'GO:0031386', ('100', '109'))	('Ser315', 'Var', (65, 71))	('stimulate', 'PosReg', (90, 99))	('ubiquitin-dependent protein degradation', 'MPA', (100, 139))
8378	29587439	Given the data on ERM proteins, Ser518 phosphorylation in merlin has been suggested to change its conformation from a 'closed' to an 'open' state.	('Ser518', 'Chemical', '-', (32, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('merlin', 'Gene', (58, 64))	('Ser518 phosphorylation', 'Var', (32, 54))	('change', 'Reg', (87, 93))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('conformation', 'MPA', (98, 110))
8379	29587439	Instead, phosphorylation was shown to rather strengthen the head-to-tail folding in merlin.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('head-to-tail folding', 'CPA', (60, 80))	('phosphorylation', 'Var', (9, 24))	('merlin', 'Disease', (84, 90))	('strengthen', 'PosReg', (45, 55))	('rat', 'Species', '10116', (38, 41))
8381	29587439	Cumulatively, these findings suggest that the phosphorylation at Ser518 would inactivate merlin without the accompanying dynamic conformational change observed in ERM proteins.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('Ser518', 'Var', (65, 71))	('Ser518', 'Chemical', '-', (65, 71))	('Ser', 'cellular_component', 'GO:0005790', ('65', '68'))	('phosphorylation', 'Var', (46, 61))	('inactivate', 'NegReg', (78, 88))	('merlin', 'Protein', (89, 95))
8382	29587439	In addition to a frequent loss of the 22q12 region, which is the locus of the NF2 gene, mutations within the entire NF2 coding region are common for mesothelioma (Figure 1B).	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('NF2', 'Gene', (116, 119))	('common', 'Reg', (138, 144))	('mutations', 'Var', (88, 97))	('mesothelioma', 'Disease', (149, 161))
8384	29587439	Therefore, nonsense mutations in NF2, even those occurring close to the C-terminus, are suggested to produce functional defects and are responsible for mesothelioma development.	('nonsense mutations', 'Var', (11, 29))	('responsible', 'Reg', (136, 147))	('mesothelioma', 'Disease', (152, 164))	('NF2', 'Gene', (33, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('functional', 'MPA', (109, 119))
8385	29587439	In contrast, the impact of missense mutations that cause amino acid substitutions is less understood, and it is unclear as to how and to what extent individual mutations affect merlin tumor-suppressive function.	('merlin', 'Protein', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('affect', 'Reg', (170, 176))	('missense mutations', 'Var', (27, 45))	('tumor', 'Disease', (184, 189))	('amino acid substitutions', 'Var', (57, 81))
8386	29587439	Although the pathogenic activity of several missense mutants identified in tumors have been studied, further investigation is required for a complete understanding of the effect produced by merlin mutations on tumor progression.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutations', 'Var', (197, 206))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('merlin', 'Gene', (190, 196))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
8387	29587439	Regarding gene mutation frequency in MM, gene alterations in NF2 are considered to be the second most common after those in BAP1.	('BAP1', 'Gene', '8314', (124, 128))	('rat', 'Species', '10116', (50, 53))	('BAP1', 'Gene', (124, 128))	('common', 'Reg', (102, 108))	('gene alterations', 'Var', (41, 57))	('NF2', 'Gene', (61, 64))
8389	29587439	An expression analysis of 211 malignant plural mesothelioma samples suggested that among the subtypes, sarcomatoid tumors had the highest NF2 mutation rate, while epithelioid tumors had the lowest NF2 mutation rate (Figure 1D).	('malignant plural mesothelioma', 'Disease', (30, 59))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('epithelioid tumors', 'Disease', (163, 181))	('NF2', 'Gene', (138, 141))	('malignant plural mesothelioma', 'Phenotype', 'HP:0100001', (30, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (103, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('malignant plural mesothelioma', 'Disease', 'MESH:C562839', (30, 59))	('epithelioid tumors', 'Disease', 'MESH:D012509', (163, 181))	('rat', 'Species', '10116', (151, 154))	('sarcomatoid tumors', 'Disease', (103, 121))	('mutation', 'Var', (142, 150))	('rat', 'Species', '10116', (210, 213))	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
8391	29587439	These data suggest that NF2 inactivation might be involved in the epithelial-mesenchymal transition during metastasis, and that the development of sarcomatoid mesotheliomas is characterized by a poorer overall survival compared to the epithelioid subtype.	('sarcomatoid mesotheliomas', 'Disease', 'MESH:C538614', (147, 172))	('NF2', 'Gene', (24, 27))	('sarcomatoid mesotheliomas', 'Disease', (147, 172))	('inactivation', 'Var', (28, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('involved', 'Reg', (50, 58))	('poorer', 'NegReg', (195, 201))	('overall', 'MPA', (202, 209))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('66', '99'))
8396	29587439	Although the localization of the wild-type or the mutant merlin in mesothelial and mesothelioma cells is not defined, we have observed exogenously expressed full-length V5-tagged merlin both at the plasma membrane and in the cytoplasm of merlin-negative mesothelioma cells.	('cytoplasm', 'cellular_component', 'GO:0005737', ('225', '234'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('198', '213'))	('mesothelioma', 'Disease', (254, 266))	('merlin', 'Gene', (179, 185))	('mesothelioma', 'Disease', (83, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (254, 266))	('mutant', 'Var', (50, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('merlin', 'Gene', (57, 63))	('localization', 'biological_process', 'GO:0051179', ('13', '25'))
8400	29587439	Alternatively, Hippo pathway inactivation induces an accumulation of underphosphorylated YAP and TAZ in the nucleus and their association with DNA-binding TEAD (TEA Domain Transcription Factor) family proteins, which upregulates the transcription of multiple oncogenic genes.	('YAP', 'Protein', (89, 92))	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('nucleus', 'cellular_component', 'GO:0005634', ('108', '115'))	('association', 'Interaction', (126, 137))	('transcription', 'MPA', (233, 246))	('underphosphorylated', 'MPA', (69, 88))	('DNA-binding', 'molecular_function', 'GO:0003677', ('143', '154'))	('transcription', 'biological_process', 'GO:0006351', ('233', '246'))	('upregulates', 'PosReg', (217, 228))	('TAZ', 'Gene', '6901', (97, 100))	('Hippo', 'Gene', (15, 20))	('TAZ', 'Gene', (97, 100))	('inactivation', 'Var', (29, 41))	('accumulation', 'PosReg', (53, 65))
8401	29587439	Along with NF2 mutations, gene alterations are also frequently observed in Hippo pathway components, including LATS1/2, SAV1, and LIM-domain containing protein AJUBA, a Drosophila djub homolog and LATS1/2 binding partner.	('alterations', 'Var', (31, 42))	('AJUBA', 'Gene', '32351', (160, 165))	('NF2', 'Gene', (11, 14))	('Drosophila', 'Species', '7227', (169, 179))	('SAV1', 'Gene', '60485', (120, 124))	('binding', 'molecular_function', 'GO:0005488', ('205', '212'))	('rat', 'Species', '10116', (35, 38))	('mutations', 'Var', (15, 24))	('Hippo pathway', 'Pathway', (75, 88))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('AJUBA', 'Gene', (160, 165))	('SAV1', 'Gene', (120, 124))	('observed', 'Reg', (63, 71))
8402	29587439	have shown that the expression of constitutively active YAP Ser127Ala mutants in immortalized mesothelial cells promotes their growth in vitro, as well as tumor formation after their transplantation in mice.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('promotes', 'PosReg', (112, 120))	('growth', 'CPA', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mice', 'Species', '10090', (202, 206))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('tumor', 'Disease', (155, 160))	('formation', 'biological_process', 'GO:0009058', ('161', '170'))	('YAP', 'Gene', (56, 59))	('Ser127Ala', 'Var', (60, 69))	('Ser127Ala', 'SUBSTITUTION', 'None', (60, 69))
8403	29587439	Conversely, YAP knockdown inhibits cell growth, motility, and invasion in mesothelioma cells with activated YAP, but did not show any effects in cells without YAP activation.	('inhibits', 'NegReg', (26, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('motility', 'CPA', (48, 56))	('knockdown', 'Var', (16, 25))	('cell growth', 'biological_process', 'GO:0016049', ('35', '46'))	('YAP', 'Gene', (12, 15))	('invasion', 'CPA', (62, 70))	('mesothelioma', 'Disease', (74, 86))	('cell growth', 'CPA', (35, 46))
8408	29587439	The interaction between merlin and DCAF1 depends on merlin activation, since neither the Ser518Asp phosphomimetic mutant, nor the Ser64Ala mutant, which lacks tumor-suppressor activity, bind to CRL4DCAF1.	('interaction', 'Interaction', (4, 15))	('DCAF1', 'Gene', '9730', (35, 40))	('bind', 'Interaction', (186, 190))	('Ser518Asp', 'SUBSTITUTION', 'None', (89, 98))	('Ser518Asp', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Ser64Ala', 'SUBSTITUTION', 'None', (130, 138))	('Ser64Ala', 'Var', (130, 138))	('DCAF1', 'Gene', '9730', (198, 203))	('tumor', 'Disease', (159, 164))	('DCAF1', 'Gene', (35, 40))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('DCAF1', 'Gene', (198, 203))	('Ser', 'cellular_component', 'GO:0005790', ('130', '133'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))
8410	29587439	It was shown that LATS1/2 are functional targets of CRL4DCAF1 and that in tumors with mutated NF2, such as mesothelioma, activated CRL4 induces LATS1/2 ubiquitination to promote their degradation and YAP/TAZ activation, thus stimulating oncogenesis (Figure 2, shown in purple).	('oncogenesis', 'biological_process', 'GO:0007048', ('237', '248'))	('mutated', 'Var', (86, 93))	('mesothelioma', 'Disease', (107, 119))	('degradation', 'biological_process', 'GO:0009056', ('184', '195'))	('CRL4', 'Gene', (52, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('CRL4', 'Gene', (131, 135))	('TAZ', 'Gene', '6901', (204, 207))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('TAZ', 'Gene', (204, 207))	('NF2', 'Gene', (94, 97))	('tumors', 'Disease', (74, 80))	('ubiquitination', 'MPA', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('activation', 'MPA', (208, 218))	('stimulating', 'PosReg', (225, 236))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('LATS1/2', 'Protein', (144, 151))	('CRL4', 'Gene', '55540', (52, 56))	('CRL4', 'Gene', '55540', (131, 135))	('degradation', 'MPA', (184, 195))	('oncogenesis', 'CPA', (237, 248))	('induces', 'PosReg', (136, 143))	('promote', 'PosReg', (170, 177))
8412	29587439	tested whether CRL4DCAF1 inhibition with NEDD8-activating enzyme (NAE) inhibitor MLN4924 could suppress the growth of tumor cells carrying NF2 mutations.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MLN4924', 'Chemical', 'MESH:C539933', (81, 88))	('growth', 'CPA', (108, 114))	('suppress', 'NegReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('NEDD8', 'Gene', '4738', (41, 46))	('NEDD8', 'Gene', (41, 46))	('tumor', 'Disease', (118, 123))	('NAE', 'Chemical', '-', (66, 69))	('MLN4924', 'Var', (81, 88))	('NF2', 'Gene', (139, 142))	('mutations', 'Var', (143, 152))
8413	29587439	MLN4924 alone caused only a moderate inhibition of mesothelioma cell growth, but the combination of MLN4924 and GDC-0980, an mechanistic target of rapamycin/phosphatidylinositol 3-kinase (mTOR/PI3K) inhibitor, strongly suppressed cell proliferation.	('rat', 'Species', '10116', (242, 245))	('cell proliferation', 'CPA', (230, 248))	('rat', 'Species', '10116', (32, 35))	('MLN4924', 'Var', (100, 107))	('GDC-0980', 'Gene', (112, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('230', '248'))	('mesothelioma', 'Disease', (51, 63))	('suppressed', 'NegReg', (219, 229))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('GDC-0980', 'Chemical', 'MESH:C569670', (112, 120))	('mTOR', 'Gene', (188, 192))	('PI3K', 'molecular_function', 'GO:0016303', ('193', '197'))	('mTOR', 'Gene', '2475', (188, 192))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('rapamycin', 'Chemical', 'MESH:D020123', (147, 156))	('MLN4924', 'Chemical', 'MESH:C539933', (100, 107))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (157, 177))
8423	29587439	Furthermore, it was demonstrated that the concurrent loss of Tp53 and tuberous sclerosis 1 (TSC1), a negative regulator of Rheb-mTORC1 signaling, induces the development of peritoneal mesothelioma in mice.	('tuberous sclerosis 1', 'Gene', '64930', (70, 90))	('peritoneal mesothelioma', 'Disease', (173, 196))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (173, 196))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('TSC1', 'Gene', (92, 96))	('Tp53', 'Gene', '22059', (61, 65))	('mTORC1', 'cellular_component', 'GO:0031931', ('128', '134'))	('tuberous sclerosis 1', 'Gene', (70, 90))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (173, 196))	('induces', 'Reg', (146, 153))	('mice', 'Species', '10090', (200, 204))	('loss', 'Var', (53, 57))	('rat', 'Species', '10116', (27, 30))	('mTORC1', 'Gene', '382056', (128, 134))	('Tp53', 'Gene', (61, 65))	('mTORC1', 'Gene', (128, 134))
8425	29587439	These findings suggest that mTOR activation caused by merlin inactivation plays a significant role in mesothelioma development (Figure 2, shown in orange).	('inactivation', 'Var', (61, 73))	('mTOR', 'Gene', '2475', (28, 32))	('mesothelioma', 'Disease', (102, 114))	('mTOR', 'Gene', (28, 32))	('activation', 'PosReg', (33, 43))	('merlin', 'Protein', (54, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))
8430	29587439	On the other hand, no activating mutations in the MTOR, nor the RHEB genes, have been identified in mesothelioma cells to date, although such mutations were shown to cause the hyper-activation of mTORC1 observed in mesothelioma.	('mTORC1', 'cellular_component', 'GO:0031931', ('196', '202'))	('mutations', 'Var', (142, 151))	('RHEB', 'Gene', '6009', (64, 68))	('MTOR', 'Gene', (50, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (215, 227))	('mTORC1', 'Gene', '382056', (196, 202))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('MTOR', 'Gene', '2475', (50, 54))	('mTORC1', 'Gene', (196, 202))	('mesothelioma', 'Disease', (215, 227))	('hyper-activation', 'MPA', (176, 192))	('RHEB', 'Gene', (64, 68))
8436	29587439	Recurrent mutations in the TRAF7 gene are observed in mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('TRAF7', 'Gene', '84231', (27, 32))	('observed', 'Reg', (42, 50))	('mutations', 'Var', (10, 19))	('mesothelioma', 'Disease', (54, 66))	('TRAF7', 'Gene', (27, 32))
8439	29587439	Interestingly, TRAF7 and NF2 mutations are mutually exclusive in malignant pleural mesothelioma as well as in meningioma, suggesting that merlin and TRAF7 may use a common signal transduction pathway.	('meningioma', 'Phenotype', 'HP:0002858', (110, 120))	('NF2', 'Gene', (25, 28))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (75, 95))	('TRAF7', 'Gene', (15, 20))	('TRAF7', 'Gene', (149, 154))	('meningioma', 'Disease', 'MESH:D008577', (110, 120))	('mutations', 'Var', (29, 38))	('malignant pleural mesothelioma', 'Disease', (65, 95))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (65, 95))	('TRAF7', 'Gene', '84231', (149, 154))	('signal transduction', 'biological_process', 'GO:0007165', ('172', '191'))	('TRAF7', 'Gene', '84231', (15, 20))	('meningioma', 'Disease', (110, 120))
8445	29587439	A recent study on the pharmacological effects of FAK inhibitors has demonstrated a significant correlation between E-cadherin mRNA levels and VS-4718 in merlin-negative mesothelioma, suggesting that E-cadherin may serve as a promising biomarker for predicting the response to FAK inhibitors in mesothelioma, which should be tested in clinical settings.	('VS-4718', 'Var', (142, 149))	('FAK', 'Gene', '5747', (276, 279))	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('mesothelioma', 'Disease', 'MESH:D008654', (294, 306))	('FAK', 'molecular_function', 'GO:0004717', ('49', '52'))	('rat', 'Species', '10116', (75, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('FAK', 'molecular_function', 'GO:0004717', ('276', '279'))	('E-cadherin', 'Gene', (199, 209))	('E-cadherin', 'Gene', '999', (199, 209))	('mesothelioma', 'Disease', (169, 181))	('FAK', 'Gene', (49, 52))	('E-cadherin', 'Gene', '999', (115, 125))	('FAK', 'Gene', '5747', (49, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('mesothelioma', 'Disease', (294, 306))	('E-cadherin', 'Gene', (115, 125))	('FAK', 'Gene', (276, 279))
8451	29587439	By preventing the interaction between YAP and TEAD, CIL56 strongly inhibited esophageal adenocarcinoma cell growth both in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('inhibited', 'NegReg', (67, 76))	('CIL56', 'Var', (52, 57))	('interaction', 'Interaction', (18, 29))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('preventing', 'NegReg', (3, 13))	('CIL56', 'Chemical', '-', (52, 57))
8470	29587439	Recently, it was reported that mesothelioma cells with NF2 and/or LATS2 mutations were more sensitive to fluvastatin compared to those with BAP1 mutations, whereas merlin-negative breast cancer cells showed sensitivity to simvastatin.	('mutations', 'Var', (72, 81))	('BAP1', 'Gene', (140, 144))	('NF2', 'Gene', (55, 58))	('sensitive to fluvastatin', 'MPA', (92, 116))	('simvastatin', 'Chemical', 'MESH:D019821', (222, 233))	('mesothelioma', 'Disease', (31, 43))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('fluvastatin', 'Chemical', 'MESH:D000077340', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('LATS2', 'Gene', (66, 71))	('breast cancer', 'Disease', (180, 193))	('LATS2', 'Gene', '26524', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('BAP1', 'Gene', '8314', (140, 144))
8474	29587439	However, a recent study showed that celecoxib failed to prevent the generation of schwannomas in a genetically engineered mouse model of NF2 inactivation, although COX-2 expression was increased in tumors that developed in these mice.	('rat', 'Species', '10116', (72, 75))	('celecoxib', 'Chemical', 'MESH:D000068579', (36, 45))	('schwannomas', 'Disease', 'MESH:D009442', (82, 93))	('expression', 'MPA', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inactivation', 'Var', (141, 153))	('schwannomas', 'Disease', (82, 93))	('schwannoma', 'Phenotype', 'HP:0100008', (82, 92))	('schwannomas', 'Phenotype', 'HP:0100008', (82, 93))	('tumors', 'Disease', (198, 204))	('COX-2', 'Gene', (164, 169))	('mice', 'Species', '10090', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('increased', 'PosReg', (185, 194))	('mouse', 'Species', '10090', (122, 127))	('NF2', 'Gene', (137, 140))	('COX-2', 'Gene', '5743', (164, 169))
8484	29587439	For example, is the activation of YAP via the inactivation of the Hippo signaling pathway enough for mesothelioma formation?	('Hippo signaling pathway', 'Pathway', (66, 89))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('66', '89'))	('YAP', 'Disease', (34, 37))	('mesothelioma', 'Disease', (101, 113))	('activation', 'PosReg', (20, 30))	('inactivation', 'Var', (46, 58))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
8491	29416614	We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice.	('extracellular signaling regulated kinase 5', 'Gene', '5598', (30, 72))	('reduced', 'NegReg', (203, 210))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('mesothelioma', 'Disease', (107, 119))	('human', 'Species', '9606', (153, 158))	('tumor', 'Disease', (211, 216))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('ERK5', 'Gene', (139, 143))	('ERK5', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mesothelioma', 'Disease', (159, 171))	('ERK', 'molecular_function', 'GO:0004707', ('74', '77'))	('mesothelioma', 'Disease', 'MESH:D008654', (159, 171))	('silenced', 'Var', (144, 152))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('extracellular signaling regulated kinase 5', 'Gene', (30, 72))	('extracellular', 'cellular_component', 'GO:0005576', ('30', '43'))	('pathogenesis', 'biological_process', 'GO:0009405', ('120', '132'))	('mice', 'Species', '10090', (245, 249))
8492	29416614	Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (142, 160))	('inhibition', 'Var', (109, 119))	('ERK', 'molecular_function', 'GO:0004707', ('25', '28'))	('XMD8-92', 'Chemical', 'MESH:C568790', (42, 49))	('mesothelioma tumorigenesis', 'Disease', (142, 168))	('ERK', 'Gene', (123, 126))	('slow down', 'NegReg', (132, 141))	('ERK', 'Gene', '5595;5594;5595', (123, 126))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('ERK', 'Gene', (25, 28))	('ERK', 'Gene', '5595;5594;5595', (25, 28))	('mesothelioma tumorigenesis', 'Disease', 'MESH:D008654', (142, 168))
8497	29416614	We found XMD8-92 attenuated naive and chemotherapeutic-induced inflammasome priming and activation in mesothelioma cells.	('mesothelioma', 'Disease', (102, 114))	('XMD8-92', 'Var', (9, 16))	('activation', 'PosReg', (88, 98))	('attenuated', 'NegReg', (17, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('XMD8-92', 'Chemical', 'MESH:C568790', (9, 16))
8509	29416614	Our previous results were generated by genetic manipulations of ERK5 in immune-deficient mice and in the present study we moved our research to the next step by using a specific small molecule inhibitor of ERK5 on mesothelioma tumor growth in immune competent mice.	('mice', 'Species', '10090', (260, 264))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (214, 232))	('mice', 'Species', '10090', (89, 93))	('manipulations', 'Var', (47, 60))	('inhibitor', 'NegReg', (193, 202))	('ERK5', 'Gene', (206, 210))	('mesothelioma tumor', 'Disease', (214, 232))	('ERK', 'molecular_function', 'GO:0004707', ('206', '209'))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (214, 232))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
8511	29416614	Briefly, XMD8-92 is a selective inhibitor of ERK5 phosphorylation that does not exert any effects on close family member MEK5 or ERK1/2.	('XMD8-92', 'Var', (9, 16))	('phosphorylation', 'MPA', (50, 65))	('MEK5', 'Gene', (121, 125))	('MEK5', 'Gene', '5607', (121, 125))	('XMD8-92', 'Chemical', 'MESH:C568790', (9, 16))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('ERK1', 'molecular_function', 'GO:0004707', ('129', '133'))	('ERK1/2', 'Gene', '5595;5594', (129, 135))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('ERK5', 'Protein', (45, 49))	('ERK1/2', 'Gene', (129, 135))
8532	29416614	A trend of decrease in levels of pERK5 was observed in 3 cell lines after high doses of XMD8-92 treatment (Figure 1C).	('decrease', 'NegReg', (11, 19))	('XMD8-92', 'Chemical', 'MESH:C568790', (88, 95))	('XMD8-92', 'Var', (88, 95))	('levels', 'MPA', (23, 29))
8535	29416614	Furthermore, XMD8-92 was also significantly effective in killing mesothelioma cells grown as a 3-D spheroid model (Figure 2B, 2C).	('XMD8-92', 'Chemical', 'MESH:C568790', (13, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('XMD8-92', 'Var', (13, 20))	('mesothelioma', 'Disease', (65, 77))
8536	29416614	In H2373 cells, combining doxorubicin and XMD8-92 lead to a greater decrease in cell growth (Figure 2B), however, this additive effect was not observed with the cisplatin/XMD8-92 combination.	('doxorubicin', 'Chemical', 'MESH:D004317', (26, 37))	('XMD8-92', 'Chemical', 'MESH:C568790', (171, 178))	('decrease', 'NegReg', (68, 76))	('H2373', 'CellLine', 'CVCL:A533', (3, 8))	('XMD8-92', 'Chemical', 'MESH:C568790', (42, 49))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('doxorubicin', 'Var', (26, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('XMD8-92', 'Var', (42, 49))	('cell growth', 'CPA', (80, 91))
8543	29416614	While not significant, total cell numbers were reduced in PLF of the XMD8-92 group.	('XMD8-92', 'Chemical', 'MESH:C568790', (69, 76))	('XMD8-92', 'Var', (69, 76))	('reduced', 'NegReg', (47, 54))	('total cell numbers', 'CPA', (23, 41))
8544	29416614	Neutrophil numbers were significantly decreased in PLF of the XMD8-92 group as compared to controls (Figure 3A).	('Neutrophil numbers', 'CPA', (0, 18))	('decreased', 'NegReg', (38, 47))	('XMD8-92', 'Chemical', 'MESH:C568790', (62, 69))	('XMD8-92', 'Var', (62, 69))
8545	29416614	Furthermore, levels of pro-inflammatory (IL-6) and angiogenic (VEGF) cytokine levels were also significantly reduced in PLF of XMD8-92 treated mice as compared to saline or vehicle treated mice (Figure 3A).	('VEGF', 'Gene', (63, 67))	('IL-6', 'molecular_function', 'GO:0005138', ('41', '45'))	('reduced', 'NegReg', (109, 116))	('XMD8-92 treated', 'Var', (127, 142))	('mice', 'Species', '10090', (189, 193))	('XMD8-92', 'Chemical', 'MESH:C568790', (127, 134))	('VEGF', 'Gene', '22339', (63, 67))	('saline', 'Chemical', 'MESH:D012965', (163, 169))	('IL-6', 'Gene', (41, 45))	('IL-6', 'Gene', '16193', (41, 45))	('PLF', 'Var', (120, 123))	('mice', 'Species', '10090', (143, 147))
8546	29416614	In the xenograft model, where human mesothelioma cells (Hmeso) were injected intrapleurally into nude-SCID mice and one week post cell injection XMD8-92 was administered IP daily, XMD8-92 showed effects on tumor reduction (Figure 3B) as compared to vehicle control.	('pleural', 'Disease', (82, 89))	('human', 'Species', '9606', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('XMD8-92', 'Var', (180, 187))	('SCID', 'Disease', (102, 106))	('tumor', 'Disease', (206, 211))	('Hmeso', 'Chemical', '-', (56, 61))	('SCID', 'Disease', 'MESH:D053632', (102, 106))	('XMD8-92', 'Chemical', 'MESH:C568790', (145, 152))	('mice', 'Species', '10090', (107, 111))	('reduction', 'NegReg', (212, 221))	('mesothelioma', 'Disease', (36, 48))	('pleural', 'Disease', 'MESH:D010995', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('XMD8-92', 'Chemical', 'MESH:C568790', (180, 187))
8547	29416614	The effect of XMD8-92 on intrapleural tumors was less remarkable than in the intraperitoneal model (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('intrapleural tumors', 'Disease', 'MESH:D009369', (25, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('intrapleural tumors', 'Disease', (25, 44))	('XMD8-92', 'Chemical', 'MESH:C568790', (14, 21))	('XMD8-92', 'Var', (14, 21))
8550	29416614	NLRP3 levels were decreased by XMD8-92 in H2373 at 24 and 48 h but increased in Hmeso cells at all time points, an interesting observation that needs detailed investigation (Figure 4A, 4B).	('H2373', 'CellLine', 'CVCL:A533', (42, 47))	('decreased', 'NegReg', (18, 27))	('NLRP3', 'Gene', (0, 5))	('XMD8-92', 'Chemical', 'MESH:C568790', (31, 38))	('increased', 'PosReg', (67, 76))	('NLRP3', 'Gene', '114548', (0, 5))	('XMD8-92', 'Var', (31, 38))	('Hmeso', 'Chemical', '-', (80, 85))
8556	29416614	As shown in Figure 5B, XMD8-92 significantly inhibited asbestos-induced IL-1beta release in mesothelial cells.	('IL-1', 'molecular_function', 'GO:0005149', ('72', '76'))	('XMD8-92', 'Chemical', 'MESH:C568790', (23, 30))	('asbestos', 'Chemical', 'MESH:D001194', (55, 63))	('XMD8-92', 'Var', (23, 30))	('IL-1beta', 'Gene', '3553', (72, 80))	('inhibited', 'NegReg', (45, 54))	('IL-1beta', 'Gene', (72, 80))
8564	29416614	XMD8-92 showed cytotoxicity in mesothelioma cells using mono layers as well as in a 3-D spheroid model.	('cytotoxicity', 'Disease', (15, 27))	('mesothelioma', 'Disease', (31, 43))	('XMD8-92', 'Chemical', 'MESH:C568790', (0, 7))	('cytotoxicity', 'Disease', 'MESH:D064420', (15, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('XMD8-92', 'Var', (0, 7))
8567	29416614	Although Hmeso mesothelioma cells showed increased toxicity with XMD8-92 as compared to H2373 cells in a mono layer and in a 3-D model, we did not see the similar combined response with doxorubicin and XMD8-92 in this cell line.	('doxorubicin', 'Chemical', 'MESH:D004317', (186, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('XMD8-92', 'Chemical', 'MESH:C568790', (202, 209))	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('toxicity', 'Disease', (51, 59))	('XMD8-92', 'Chemical', 'MESH:C568790', (65, 72))	('XMD8-92', 'Var', (65, 72))	('H2373', 'CellLine', 'CVCL:A533', (88, 93))	('mesothelioma', 'Disease', (15, 27))	('Hmeso', 'Chemical', '-', (9, 14))
8570	29416614	Inhibition of ERK5 resulted in significantly decreased colony formation, supporting an earlier observation we reported with mesothelioma cells where ERK5 was inhibited by shRNA.	('ERK5', 'Gene', (149, 153))	('ERK', 'molecular_function', 'GO:0004707', ('149', '152'))	('formation', 'biological_process', 'GO:0009058', ('62', '71'))	('decreased', 'NegReg', (45, 54))	('mesothelioma', 'Disease', (124, 136))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('inhibited', 'NegReg', (158, 167))	('Inhibition', 'Var', (0, 10))	('ERK5', 'Gene', (14, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('colony formation', 'CPA', (55, 71))
8571	29416614	Previously, XMD8-92 was reported to inhibit EGF-induced ERK5 phosphorylation in multiple tumor cell lines.	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('XMD8-92', 'Var', (12, 19))	('ERK5', 'Protein', (56, 60))	('inhibit', 'NegReg', (36, 43))	('EGF-induced', 'Protein', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('EGF', 'molecular_function', 'GO:0005154', ('44', '47'))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('XMD8-92', 'Chemical', 'MESH:C568790', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
8573	29416614	Furthermore, XMD8-92 attenuated constitutive ERK5 phosphorylation in 3 out of 4 mesothelioma cell lines tested.	('attenuated', 'NegReg', (21, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('XMD8-92', 'Chemical', 'MESH:C568790', (13, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('XMD8-92', 'Var', (13, 20))	('constitutive ERK5 phosphorylation', 'MPA', (32, 65))	('mesothelioma', 'Disease', (80, 92))
8576	29416614	Findings of these studies demonstrated that XMD8-92 could inhibit mesothelioma growth in both models, more so in the peritoneal model than in the pleural model.	('XMD8-92', 'Var', (44, 51))	('mesothelioma', 'Disease', (66, 78))	('pleural', 'Disease', 'MESH:D010995', (146, 153))	('pleural', 'Disease', (146, 153))	('inhibit', 'NegReg', (58, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('XMD8-92', 'Chemical', 'MESH:C568790', (44, 51))
8581	29416614	For example, our previous in vitro experiments showed that ERK5 silenced mesothelioma cells retained more drug inside of the cells.	('mesothelioma', 'Disease', (73, 85))	('ERK5', 'Gene', (59, 63))	('ERK', 'molecular_function', 'GO:0004707', ('59', '62'))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('silenced', 'Var', (64, 72))	('more', 'PosReg', (101, 105))	('drug', 'MPA', (106, 110))
8586	29416614	Furthermore, another important finding from this experiment is that XMD8-92 is capable of inhibiting mesothelioma tumor growth in both immune-compromised as well as immune-competent mice.	('XMD8-92', 'Chemical', 'MESH:C568790', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (101, 119))	('XMD8-92', 'Var', (68, 75))	('mice', 'Species', '10090', (182, 186))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (101, 119))	('mesothelioma tumor', 'Disease', (101, 119))	('inhibiting', 'NegReg', (90, 100))
8588	29416614	In addition to tumor weight and volume, XMD8-92 also inhibited total cell numbers in PLF as well as neutrophil counts.	('inhibited', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('XMD8-92', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('neutrophil counts', 'CPA', (100, 117))	('tumor', 'Disease', (15, 20))	('XMD8-92', 'Chemical', 'MESH:C568790', (40, 47))
8589	29416614	have also reported reduced neutrophil infiltration in response to tetradecanoyl phorbol acetate (TPA), at the epidermis of ERK5 deleted mice.	('mice', 'Species', '10090', (136, 140))	('TPA', 'molecular_function', 'GO:0031299', ('97', '100'))	('tetradecanoyl phorbol acetate', 'Chemical', 'MESH:D013755', (66, 95))	('response to tetradecanoyl phorbol acetate', 'MPA', (54, 95))	('neutrophil', 'CPA', (27, 37))	('ERK5', 'Gene', (123, 127))	('deleted', 'Var', (128, 135))	('TPA', 'Chemical', 'MESH:D013755', (97, 100))	('reduced', 'NegReg', (19, 26))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))
8599	29416614	To demonstrate this, mesothelioma cells were treated with XMD8-92, with or without chemotherapeutics and inflammasome priming and activation was assessed.	('XMD8-92', 'Chemical', 'MESH:C568790', (58, 65))	('mesothelioma', 'Disease', (21, 33))	('XMD8-92', 'Var', (58, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))
8601	29416614	In Hmeso cells, NLRP3 transcript levels were increased with XMD8-92 treatment in a time-dependent manner, whereas, all other parameters were decreased by XMD8-92.	('XMD8-92', 'Chemical', 'MESH:C568790', (154, 161))	('XMD8-92 treatment', 'Var', (60, 77))	('NLRP3', 'Gene', (16, 21))	('increased', 'PosReg', (45, 54))	('NLRP3', 'Gene', '114548', (16, 21))	('Hmeso', 'Chemical', '-', (3, 8))	('transcript levels', 'MPA', (22, 39))	('XMD8-92', 'Chemical', 'MESH:C568790', (60, 67))
8603	29416614	In addition, doxorubicin-induced inflammasome activation in this cell line was not effectively or significantly attenuated by XMD8-92 (data not shown).	('doxorubicin-induced', 'MPA', (13, 32))	('XMD8-92', 'Chemical', 'MESH:C568790', (126, 133))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('inflammasome activation', 'MPA', (33, 56))	('XMD8-92', 'Var', (126, 133))
8605	29416614	XMD8-92 inhibited doxorubicin-induced activation of the NLRP3 inflammasome in H2373 mesothelioma cells as depicted by the absence of caspase-1 p20 and IL-1beta in the medium after XMD8-92 treatment.	('NLRP3', 'Gene', '114548', (56, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('p20', 'Gene', '51673', (143, 146))	('p20', 'Gene', (143, 146))	('IL-1', 'molecular_function', 'GO:0005149', ('151', '155'))	('doxorubicin', 'Chemical', 'MESH:D004317', (18, 29))	('XMD8-92', 'Chemical', 'MESH:C568790', (0, 7))	('IL-1beta', 'Gene', '3553', (151, 159))	('activation', 'PosReg', (38, 48))	('H2373', 'CellLine', 'CVCL:A533', (78, 83))	('XMD8-92', 'Chemical', 'MESH:C568790', (180, 187))	('caspase-1', 'Gene', '834', (133, 142))	('inhibited', 'NegReg', (8, 17))	('IL-1beta', 'Gene', (151, 159))	('caspase-1', 'Gene', (133, 142))	('absence', 'NegReg', (122, 129))	('NLRP3', 'Gene', (56, 61))	('XMD8-92', 'Var', (0, 7))	('mesothelioma', 'Disease', (84, 96))
8611	29416614	The observed effects of combination drug on 3D spheroid model of MM in the present study could partly be attributed to the inhibition of drug-induced caspase-1 activation by XMD8-92.	('XMD8-92', 'Chemical', 'MESH:C568790', (174, 181))	('caspase-1', 'Gene', '834', (150, 159))	('activation', 'PosReg', (160, 170))	('XMD8-92', 'Var', (174, 181))	('caspase-1', 'Gene', (150, 159))	('inhibition', 'NegReg', (123, 133))
8612	29416614	Regardless of these in vitro findings in Hmeso cells, XMD8-92 inhibited in vivo Hmeso mesothelioma tumor growth, suggesting involvement of other pathways and signaling molecules.	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (86, 104))	('Hmeso', 'Chemical', '-', (80, 85))	('XMD8-92', 'Var', (54, 61))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('Hmeso', 'Chemical', '-', (41, 46))	('mesothelioma tumor', 'Disease', (86, 104))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (86, 104))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('XMD8-92', 'Chemical', 'MESH:C568790', (54, 61))
8613	29416614	The fact that neutrophil counts were lower in PLF after XMD8-92 treatment (Figure 3A) also suggests that the inflammasome may be inhibited in these mice, as inflammasome knockout mice have been shown to have a lower number of neutrophils in bronchoalveolar lavage fluid (BALF) after asbestos inhalation.	('mice', 'Species', '10090', (179, 183))	('neutrophil counts', 'CPA', (14, 31))	('mice', 'Species', '10090', (148, 152))	('lower', 'NegReg', (210, 215))	('asbestos', 'Chemical', 'MESH:D001194', (283, 291))	('XMD8-92', 'Chemical', 'MESH:C568790', (56, 63))	('lower number of neutrophils', 'Phenotype', 'HP:0001875', (210, 237))	('lower', 'NegReg', (37, 42))	('XMD8-92', 'Var', (56, 63))
8658	29416614	This dose of XMD8-92 was derived from a published report and found to have no toxicity in mice.	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('toxicity', 'Disease', (78, 86))	('XMD8-92', 'Chemical', 'MESH:C568790', (13, 20))	('mice', 'Species', '10090', (90, 94))	('XMD8-92', 'Var', (13, 20))
8707	28196068	The main change that has occurred over the past 20 years is the current availability of reliable immunohistochemical mesothelial markers such as calretinin, CK5/6, D240, mesothelin and WT1, as well as more specific glandular markers, for example, TTF1 (lung), PAX8 (gynaecological tract, kidney, thyroid).	('TTF1', 'Gene', (247, 251))	('PAX8', 'Gene', (260, 264))	('WT1', 'Gene', '7490', (185, 188))	('mesothelin', 'Gene', (170, 180))	('TTF1', 'Gene', '7270', (247, 251))	('mesothelin', 'Gene', '10232', (170, 180))	('CK5/6', 'Gene', '3852', (157, 162))	('WT1', 'Gene', (185, 188))	('CK5/6', 'Gene', (157, 162))	('D240', 'Var', (164, 168))	('PAX8', 'Gene', '7849', (260, 264))
8728	26981775	Here, we describe the efficacy of NIR-PIT, using hYP218 as the antibody within the APC to target a mesothelin expressing A431/H9 cell.	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('NIR', 'Gene', (34, 37))	('A431/H9', 'CellLine', 'CVCL:0037', (121, 128))	('APC', 'cellular_component', 'GO:0005680', ('83', '86'))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('hYP218', 'Chemical', '-', (49, 55))	('hYP218', 'Var', (49, 55))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('NIR', 'Gene', '57741', (34, 37))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))
8730	26981775	The hYP218-IR700 showed specific binding to cells and cell-specific killing was observed in vitro.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('hYP218', 'Chemical', '-', (4, 10))	('binding', 'Interaction', (33, 40))	('cell-specific killing', 'CPA', (54, 75))	('hYP218-IR700', 'Var', (4, 16))
8731	26981775	After implanting A431/H9 cells in an athymic nude mouse, tumor-bearing mice were treated with the following regimen of NIR-PIT; 100 mug of hYP218-IR700 i.v., NIR light was administered at 50 J/cm2 on day 1 after injection and 100 J/cm2 of light on day 2 after injection.	('mice', 'Species', '10090', (71, 75))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('NIR', 'Gene', '57741', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NIR', 'Gene', '57741', (119, 122))	('NIR', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('hYP218-IR700', 'Var', (139, 151))	('mouse', 'Species', '10090', (50, 55))	('hYP218', 'Chemical', '-', (139, 145))	('tumor', 'Disease', (57, 62))	('A431/H9', 'CellLine', 'CVCL:0037', (17, 24))	('NIR', 'Gene', (158, 161))
8732	26981775	The hYP218-IR700 showed high tumor accumulation and a high tumor-background ratio (TBR).	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('hYP218-IR700', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('hYP218', 'Chemical', '-', (4, 10))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TBR', 'Chemical', '-', (83, 86))
8735	26981775	Furthermore, NIR-PIT with hYP218-IR700 is a promising candidate for the treatment of mesothelin-expressing tumors that could be readily translated to humans.	('hYP218', 'Chemical', '-', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('humans', 'Species', '9606', (150, 156))	('NIR', 'Gene', '57741', (13, 16))	('NIR', 'Gene', (13, 16))	('hYP218-IR700', 'Var', (26, 38))
8740	26981775	Recently, a humanized non-Region I antibody (hYP218) with high binding affinity for the C-terminus (residues 487-581) of mesothelin has been reported.	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('binding', 'Interaction', (63, 70))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('hYP218', 'Chemical', '-', (45, 51))	('hYP218', 'Var', (45, 51))	('residues 487-581', 'Var', (100, 116))	('human', 'Species', '9606', (12, 17))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
8745	26981775	In this study, we investigated hYP218-IR700 as a candidate APC to be used in NIR-PIT.	('hYP218-IR700', 'Var', (31, 43))	('NIR', 'Gene', '57741', (77, 80))	('hYP218', 'Chemical', '-', (31, 37))	('NIR', 'Gene', (77, 80))	('APC', 'cellular_component', 'GO:0005680', ('59', '62'))
8747	26981775	NIR-PIT was performed using hYP218-IR700 in vitro and in a tumor-bearing mouse model in vivo.	('tumor', 'Disease', (59, 64))	('NIR', 'Gene', (0, 3))	('hYP218-IR700', 'Var', (28, 40))	('hYP218', 'Chemical', '-', (28, 34))	('mouse', 'Species', '10090', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NIR', 'Gene', '57741', (0, 3))
8749	26981775	After a 6 h incubation with hYP218-IR700, A431/H9 cells showed a high fluorescence signal, which was confirmed with flow cytometry and fluorescence microscopy (Figure 1B and 1C).	('hYP218-IR700', 'Var', (28, 40))	('A431/H9', 'CellLine', 'CVCL:0037', (42, 49))	('hYP218', 'Chemical', '-', (28, 34))	('fluorescence signal', 'MPA', (70, 89))
8750	26981775	On the other hand, mesothelin negative A431 cells did not show an increase in fluorescence signal after hYP218-IR700 incubation.	('fluorescence signal', 'MPA', (78, 97))	('hYP218', 'Chemical', '-', (104, 110))	('A431', 'CellLine', 'CVCL:0037', (39, 43))	('hYP218-IR700', 'Var', (104, 116))
8751	26981775	Additionally, this increase in fluorescence signal was blocked by adding excess hYP218, indicating that hYP218-IR700 specifically binds to the mesothelin on A431/H9 cells.	('hYP218-IR700', 'Var', (104, 116))	('hYP218', 'Chemical', '-', (104, 110))	('hYP218', 'Chemical', '-', (80, 86))	('binds', 'Interaction', (130, 135))	('A431/H9', 'CellLine', 'CVCL:0037', (157, 164))
8757	26981775	The fluorescence intensity and TBR of hYP218-IR700 in A431/H9 tumors decreased gradually over days (Figure 2).	('H9 tumors', 'Disease', 'MESH:D009369', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('fluorescence intensity', 'MPA', (4, 26))	('hYP218-IR700', 'Var', (38, 50))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('decreased', 'NegReg', (69, 78))	('hYP218', 'Chemical', '-', (38, 44))	('TBR', 'MPA', (31, 34))	('H9 tumors', 'Disease', (59, 68))	('A431/H9', 'CellLine', 'CVCL:0037', (54, 61))	('TBR', 'Chemical', '-', (31, 34))
8758	26981775	Similarly, the fluorescence intensity and TBR of hYP218-IR700 in the liver decreased gradually over days (Figure 2).	('hYP218-IR700', 'Var', (49, 61))	('liver decreased', 'Phenotype', 'HP:0001410', (69, 84))	('TBR', 'MPA', (42, 45))	('hYP218', 'Chemical', '-', (49, 55))	('fluorescence intensity', 'MPA', (15, 37))	('TBR', 'Chemical', '-', (42, 45))	('decreased', 'NegReg', (75, 84))
8762	26981775	One day after injection of hYP218-IR700, tumors showed higher fluorescence intensity than the tumors with no APC.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('hYP218-IR700', 'Var', (27, 39))	('APC', 'cellular_component', 'GO:0005680', ('109', '112'))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('fluorescence intensity', 'MPA', (62, 84))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('hYP218', 'Chemical', '-', (27, 33))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('higher', 'PosReg', (55, 61))
8764	26981775	The IR700 fluorescence did not change for up to two days in tumors receiving hYP218-IR700 but not NIR light (Figure 3B).	('hYP218', 'Chemical', '-', (77, 83))	('NIR', 'Gene', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NIR', 'Gene', '57741', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('hYP218-IR700', 'Var', (77, 89))	('IR700', 'MPA', (4, 9))	('tumors', 'Disease', (60, 66))
8772	26981775	However, no damage was observed in A431/H9 tumors 24 h after hYP218-IR700 injection without NIR light exposure (Figure 4C).	('NIR', 'Gene', (92, 95))	('A431/H9', 'CellLine', 'CVCL:0037', (35, 42))	('hYP218', 'Chemical', '-', (61, 67))	('hYP218-IR700 injection', 'Var', (61, 83))	('H9 tumors', 'Disease', (40, 49))	('NIR', 'Gene', '57741', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('H9 tumors', 'Disease', 'MESH:D009369', (40, 49))
8780	26981775	The conjugated hYP218-IR700, achieved adequate tumor TBRs as shown in Figure 2, indicating that it may be practical for clinical application during surgical or endoscopic procedures because of its high TBR on the mesothelin expressing tumors.	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('TBRs', 'Chemical', '-', (53, 57))	('TBR', 'Chemical', '-', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('TBR', 'Chemical', '-', (202, 205))	('hYP218-IR700', 'Var', (15, 27))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('mesothelin', 'Protein', (213, 223))	('tumors', 'Disease', (235, 241))	('hYP218', 'Chemical', '-', (15, 21))
8782	26981775	Our results showed that hYP218 bound to mesothelin specifically and was internalized homogenously within 6 hours of incubation in mesothelin expressing cancer cells.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('hYP218', 'Chemical', '-', (24, 30))	('bound', 'Interaction', (31, 36))	('hYP218', 'Var', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
8784	26981775	The conjugate hYP218-IR700 proved to be an effective agent for treating a mesothelin expressing tumor model with NIR-PIT.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('hYP218-IR700', 'Var', (14, 26))	('tumor', 'Disease', (96, 101))	('NIR', 'Gene', '57741', (113, 116))	('hYP218', 'Chemical', '-', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('NIR', 'Gene', (113, 116))
8785	26981775	NIR-PIT with hYP218-IR700 led to rapid cell death in vitro and significant tumor growth reduction and survival improvement in vivo.	('hYP218-IR700', 'Var', (13, 25))	('tumor growth reduction', 'Disease', 'MESH:D006130', (75, 97))	('NIR', 'Gene', (0, 3))	('improvement', 'PosReg', (111, 122))	('survival', 'CPA', (102, 110))	('hYP218', 'Chemical', '-', (13, 19))	('cell death', 'biological_process', 'GO:0008219', ('39', '49'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor growth reduction', 'Disease', (75, 97))	('NIR', 'Gene', '57741', (0, 3))
8786	26981775	Thus, hYP218-IR700 could be an effective platform for NIR-PIT in mesothelin expressing tumors.	('hYP218-IR700', 'Var', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NIR', 'Gene', '57741', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('hYP218', 'Chemical', '-', (6, 12))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('NIR', 'Gene', (54, 57))
8815	26981775	The conjugated, hYP218-IR700 and NIR-PIT can be an effective treatment of a mesothelin expressing animal tumor model.	('mesothelin expressing', 'Disease', (76, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('hYP218-IR700', 'Var', (16, 28))	('NIR', 'Gene', '57741', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('NIR', 'Gene', (33, 36))	('tumor', 'Disease', (105, 110))	('hYP218', 'Chemical', '-', (16, 22))
8837	26981775	The cytotoxic effects of NIR-PIT with hYP218-IR700 were determined by flow cytometric Propidium Iodide (PI) (Life Technologies, Carlsbad, CA) staining, which can detect compromised cell membranes.	('Propidium Iodide', 'Chemical', 'MESH:D011419', (86, 102))	('hYP218-IR700', 'Var', (38, 50))	('NIR', 'Gene', (25, 28))	('hYP218', 'Chemical', '-', (38, 44))	('NIR', 'Gene', '57741', (25, 28))
8851	26981775	To examine the therapeutic effect of in vivo NIR-PIT on A431/H9 cells, tumor bearing mice were randomized into 4 groups of at least 10 animals per group for the following treatments: (1) no treatment (control); (2) 100 mug of hYP218-IR700 i.v., no NIR light exposure (APC i.v.	('NIR', 'Gene', '57741', (45, 48))	('mice', 'Species', '10090', (85, 89))	('APC', 'cellular_component', 'GO:0005680', ('268', '271'))	('NIR', 'Gene', '57741', (248, 251))	('NIR', 'Gene', (45, 48))	('hYP218', 'Chemical', '-', (226, 232))	('A431/H9', 'CellLine', 'CVCL:0037', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('NIR', 'Gene', (248, 251))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mug', 'molecular_function', 'GO:0043739', ('219', '222'))	('tumor', 'Disease', (71, 76))	('hYP218-IR700', 'Var', (226, 238))
8852	26981775	only); (3) NIR light exposure only, NIR light was administered at 50 J/cm2 on day 1 and 100 J/cm2 on day 2 (NIR light only); (4) 100 mug of hYP218-IR700 i.v., NIR light was administered at 50 J/cm2 on day 1 after injection and 100 J/cm2 on day 2 after injection (NIR-PIT).	('NIR', 'Gene', '57741', (159, 162))	('NIR', 'Gene', '57741', (108, 111))	('hYP218', 'Chemical', '-', (140, 146))	('NIR', 'Gene', (11, 14))	('NIR', 'Gene', '57741', (36, 39))	('NIR', 'Gene', (108, 111))	('NIR', 'Gene', (159, 162))	('NIR', 'Gene', '57741', (263, 266))	('mug', 'molecular_function', 'GO:0043739', ('133', '136'))	('NIR', 'Gene', (36, 39))	('NIR', 'Gene', (263, 266))	('hYP218-IR700', 'Var', (140, 152))	('NIR', 'Gene', '57741', (11, 14))
8950	21983936	Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis.	('chromatin', 'cellular_component', 'GO:0000785', ('100', '109'))	('mitotic count', 'CPA', (163, 176))	('atypical', 'Var', (192, 200))	('patients', 'Species', '9606', (31, 39))	('nuclear atypia', 'CPA', (74, 88))
9001	21983936	For the purpose of survival analysis, tumors were classified into the following two groups by median MIB-1 labeling index (10.0%): low <10.0%, and high >=10.0%.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('low <10.0%', 'Var', (131, 141))	('MIB-1', 'Gene', (101, 106))	('MIB-1', 'Gene', '57534', (101, 106))
9015	21983936	For chromatin pattern, patients with coarse granular chromatin had the worst median overall survival (n = 96, 11 months), followed by fine granular (n = 112, 19 months) and homogeneous (n = 24, 25 months) (Figure 2b).	('patients', 'Species', '9606', (23, 31))	('chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('overall survival', 'MPA', (84, 100))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('worst', 'NegReg', (71, 76))	('coarse granular chromatin', 'Var', (37, 62))
9016	21983936	Patients with large nucleoli had the worst median overall survival (n = 55, 11 months), followed by distinct (n = 122, 16 months) and indistinct (n = 55, 25 months) (Figure 2c).	('overall survival', 'MPA', (50, 66))	('Patients', 'Species', '9606', (0, 8))	('large nucleoli', 'Var', (14, 28))
9017	21983936	Mitotic count ranged from 0 to 64 per 10 HPF (median, 3.0; mean +- s.d., 5.0 +- 6.9), and patients with high mitotic counts had the worst median overall survival (n = 81, 10 months), followed by intermediate (n = 76, 17 months) and low mitotic counts (n = 75, 31 months) (Figure 2d).	('overall survival', 'MPA', (145, 161))	('patients', 'Species', '9606', (90, 98))	('high mitotic counts', 'Var', (104, 123))
9029	21983936	Patients with high mitotic count had the worst median overall survival (n = 56, 11 months), followed by intermediate (n = 68, 18 months) and low (n = 74, 31 months) (P < 0.001).	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (54, 70))	('high mitotic count', 'Var', (14, 32))
9039	21983936	Furthermore, patients with high MIB-1 labeling index (n = 88) had significantly worse median overall survival (12 months) than low MIB-1 labeling index (n = 70, 23 months) (P < 0.001; Figure 5a).	('MIB-1', 'Gene', '57534', (131, 136))	('MIB-1', 'Gene', '57534', (32, 37))	('overall survival', 'MPA', (93, 109))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))	('worse', 'NegReg', (80, 85))	('MIB-1', 'Gene', (131, 136))	('MIB-1', 'Gene', (32, 37))
9040	21983936	Among patients who underwent complete resection, patients with high MIB-1 labeling index (n = 68) had shorter median time to recurrence (16 months) than low MIB-1 labeling index (n = 55, 25 months) (P = 0.048; Figure 5b).	('shorter', 'NegReg', (102, 109))	('MIB-1', 'Gene', (157, 162))	('MIB-1', 'Gene', (68, 73))	('MIB-1', 'Gene', '57534', (157, 162))	('MIB-1', 'Gene', '57534', (68, 73))	('patients', 'Species', '9606', (6, 14))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))
9061	21983936	In this study, we observed similar results for diffuse malignant pleural mesothelioma patients with atypical mitoses but observed mitotic count as being a stronger prognostic factor.	('mitotic', 'Var', (130, 137))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (65, 85))	('malignant pleural mesothelioma', 'Disease', (55, 85))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (55, 85))	('patients', 'Species', '9606', (86, 94))
9109	23009708	The DNA integrity index, represented by the ratio of the longer to shorter (ALU 247bp/ALU 115bp) fragments, was calculated for each individual sample (pleural effusion and serum) by dividing the ALU247 DNA quantity (ng/mL) by the ALU 115 DNA quantity (ng/mL).	('pleural effusion', 'Phenotype', 'HP:0002202', (151, 167))	('pleural effusion', 'Disease', 'MESH:D010996', (151, 167))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('pleural effusion', 'Disease', (151, 167))	('ALU247 DNA', 'Var', (195, 205))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('DNA', 'cellular_component', 'GO:0005574', ('238', '241'))
9169	23009708	An alternative approach to distinguish malignant from benign effusions has been to evaluate the utility of quantitative and qualitative tumour-specific alterations, such as microsatellite alterations in effusion DNA.	('effusion', 'Disease', 'MESH:D010996', (203, 211))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('effusion', 'Disease', (61, 69))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('effusion', 'Disease', (203, 211))	('tumour', 'Disease', (136, 142))	('microsatellite alterations', 'Var', (173, 199))	('effusion', 'Disease', 'MESH:D010996', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
9170	23009708	studied patients with malignant (n=26) and benign (n=22) effusions and found that microsatellite instability and loss of heterozygosity in DNA from pleural fluid and blood were not diagnostically useful.	('effusion', 'Disease', (57, 65))	('pleural', 'Disease', 'MESH:D010995', (148, 155))	('loss', 'Var', (113, 117))	('effusion', 'Disease', 'MESH:D010996', (57, 65))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('microsatellite instability', 'MPA', (82, 108))	('pleural', 'Disease', (148, 155))	('DNA', 'Gene', (139, 142))	('pleural fluid', 'Phenotype', 'HP:0002202', (148, 161))	('patients', 'Species', '9606', (8, 16))
9240	11875695	Patients had to be between 18 years and 75 years with a WHO performance status of 0 to 2, have an adequate haematological (hemoglobin >9.5 g dl-1, granulocyte count >=2x109 l-1, platelet count >=100x109 l-1), hepatic (bilirubin <=25 mumol l-1) and renal (creatinine clearance >=60 ml min-1) function.	('min-1', 'Gene', '966', (284, 289))	('min-1', 'Gene', (284, 289))	('creatinine', 'Chemical', 'MESH:D003404', (255, 265))	('>=2x109 l-1', 'Var', (165, 176))	('Patients', 'Species', '9606', (0, 8))	('bilirubin', 'Chemical', 'MESH:D001663', (218, 227))
9252	11875695	Gemcitabine was omitted on day 8 in case of a leukocyte count below 1x109 l-1 or a platelet count below 50x109 l-1.	('platelet', 'MPA', (83, 91))	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('below 50x109', 'Var', (98, 110))
9412	30609805	The SMAD-2 phosphorylation event induces some transcription factors such as SNAIL-1, which in turn promotes E-cadherin downregulation and, consequently, the start of EMT.	('E-cadherin', 'Gene', (108, 118))	('SMAD-2', 'Gene', (4, 10))	('E-cadherin', 'Gene', '999', (108, 118))	('SNAIL-1', 'Gene', '6615', (76, 83))	('EMT', 'biological_process', 'GO:0001837', ('166', '169'))	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('downregulation', 'NegReg', (119, 133))	('EMT', 'CPA', (166, 169))	('promotes', 'PosReg', (99, 107))	('SMAD-2', 'Gene', '4087', (4, 10))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('phosphorylation', 'Var', (11, 26))	('induces', 'Reg', (33, 40))	('SNAIL-1', 'Gene', (76, 83))
9416	30609805	Our results confirm phosphorylation of GSK-3beta drives SNAIL-1 accumulation in the nucleus (Figure 7B), thus inhibiting E-cadherin expression.	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('nucleus', 'cellular_component', 'GO:0005634', ('84', '91'))	('inhibiting', 'NegReg', (110, 120))	('GSK-3beta', 'Gene', (39, 48))	('GSK-3beta', 'Gene', '2932', (39, 48))	('cadherin', 'molecular_function', 'GO:0008014', ('123', '131'))	('E-cadherin', 'Gene', (121, 131))	('E-cadherin', 'Gene', '999', (121, 131))	('phosphorylation', 'Var', (20, 35))	('GSK', 'molecular_function', 'GO:0050321', ('39', '42'))	('SNAIL-1', 'Gene', '6615', (56, 63))	('SNAIL-1', 'Gene', (56, 63))
9423	30609805	carried out a study on A549 epithelioma cells using crocidolite asbestos, and the authors demonstrated that crocidolite is able to induce EMT through a mechanism involving the Mitogen-activated protein kinase/Extracellular signal-regulated kinase (MAPK/Erk) signaling pathway.	('crocidolite', 'Var', (108, 119))	('A549 epithelioma', 'Disease', 'MESH:D002277', (23, 39))	('Erk', 'Gene', '5594', (253, 256))	('EMT', 'CPA', (138, 141))	('MAPK', 'molecular_function', 'GO:0004707', ('248', '252'))	('Extracellular', 'cellular_component', 'GO:0005576', ('209', '222'))	('A549 epithelioma', 'Disease', (23, 39))	('crocidolite asbestos', 'Disease', 'MESH:D001195', (52, 72))	('EMT', 'biological_process', 'GO:0001837', ('138', '141'))	('crocidolite', 'Chemical', 'MESH:D017638', (52, 63))	('crocidolite asbestos', 'Disease', (52, 72))	('crocidolite', 'Chemical', 'MESH:D017638', (108, 119))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('Erk', 'Gene', (253, 256))	('signaling pathway', 'biological_process', 'GO:0007165', ('258', '275'))	('induce', 'PosReg', (131, 137))	('Erk', 'molecular_function', 'GO:0004707', ('253', '256'))
9442	30609805	We observed the accumulation of SNAIL-1 into the nucleus of MeT-5A cells incubated with asbestos fibers as a consequence of the phosphorylation and inactivation of GSK-3beta, thus allowing SNAIL-1 to translocate into the nucleus and to repress E-cadherin transcription.	('inactivation', 'Var', (148, 160))	('SNAIL-1', 'Gene', '6615', (32, 39))	('SNAIL-1', 'Gene', (32, 39))	('GSK-3beta', 'Gene', (164, 173))	('E-cadherin', 'Gene', '999', (244, 254))	('E-cadherin', 'Gene', (244, 254))	('allowing', 'Reg', (180, 188))	('transcription', 'biological_process', 'GO:0006351', ('255', '268'))	('GSK', 'molecular_function', 'GO:0050321', ('164', '167'))	('accumulation', 'PosReg', (16, 28))	('cadherin', 'molecular_function', 'GO:0008014', ('246', '254'))	('nucleus', 'cellular_component', 'GO:0005634', ('221', '228'))	('asbestos', 'Chemical', 'MESH:D001194', (88, 96))	('SNAIL-1', 'Gene', '6615', (189, 196))	('SNAIL-1', 'Gene', (189, 196))	('translocate into', 'MPA', (200, 216))	('nucleus', 'cellular_component', 'GO:0005634', ('49', '56'))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('repress', 'NegReg', (236, 243))	('GSK-3beta', 'Gene', '2932', (164, 173))
9485	28099801	In a rat model of pancreatic carcinomatosis, HFR-eNP identification of tumor is validated against gold-standard histopathological analysis to reveal that HFR-eNPs possess high specificity (99%) and sensitivity (92%) for tumors, in particular, sub-centimeter and microscopic sub-millimeter tumors, with an overall accuracy of 95%.	('tumor', 'Disease', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('pancreatic carcinomatosis', 'Disease', (18, 43))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('sub-centimeter', 'Var', (243, 257))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', (289, 294))	('HFR-eNPs', 'Gene', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumors', 'Disease', (220, 226))	('rat', 'Species', '10116', (5, 8))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumors', 'Disease', (289, 295))	('pancreatic carcinomatosis', 'Disease', 'MESH:D002277', (18, 43))
9507	28099801	Herein, we report the (1) synthesis of HFR-eNPs with varying incorporations of conjugated rhodamine; (2) amplification of rhodamine fluorescence via loading in the HFR-eNPs; (3) facile visualization via an inexpensive, hand-held UV lamp of HFR-eNP localization to mesothelial (MSTO-211H), ovarian (OVCAR-3), and pancreatic (Panc1 cancer stem cell; Panc1-CSC) peritoneal tumors following intraperitoneal injection; (4) impact of nanoparticle surface charge and expansile property on localization; (5) specificity and sensitivity of HFR-eNP localization to PDAC-PC tumors while sparing adjacent normal mesothelium, microvasculature, and organs; (6) HFR-eNP localization to sub-millimeter peritoneal tumors; (7) localization of HFR-eNPs to tumor cell clusters with high expression of lactate dehydrogenase-A (LDH-A); and (8) proof-of-principle, intraoperative image-guided resection of sub-millimeter pancreatic tumors in a PDAC-PC xenograft rat model.	('pancreatic tumors', 'Phenotype', 'HP:0002894', (898, 915))	('localization', 'biological_process', 'GO:0051179', ('709', '721'))	('synthesis', 'biological_process', 'GO:0009058', ('26', '35'))	('tumors', 'Phenotype', 'HP:0002664', (563, 569))	('tumors', 'Disease', 'MESH:D009369', (909, 915))	('PDAC-PC', 'Chemical', '-', (921, 928))	('tumors', 'Phenotype', 'HP:0002664', (697, 703))	('rat', 'Species', '10116', (850, 853))	('localization', 'biological_process', 'GO:0051179', ('539', '551'))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('lactate dehydrogenase-A', 'Gene', (781, 804))	('rhodamine', 'Chemical', 'MESH:D012235', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (737, 742))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (563, 568))	('localization', 'biological_process', 'GO:0051179', ('248', '260'))	('tumor', 'Disease', (909, 914))	('lactate dehydrogenase-A', 'Gene', '3939', (781, 804))	('tumor', 'Phenotype', 'HP:0002664', (697, 702))	('rhodamine', 'Chemical', 'MESH:D012235', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (370, 376))	('tumors', 'Disease', (563, 569))	('pancreatic', 'Disease', 'MESH:D010195', (898, 908))	('tumors', 'Disease', (697, 703))	('tumor', 'Disease', 'MESH:D009369', (909, 914))	('pancreatic', 'Disease', 'MESH:D010195', (312, 322))	('pancreatic tumors', 'Disease', 'MESH:D010190', (898, 915))	('localization', 'biological_process', 'GO:0051179', ('482', '494'))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('pancreatic tumors', 'Disease', (898, 915))	('sub-millimeter', 'Var', (883, 897))	('tumors', 'Phenotype', 'HP:0002664', (909, 915))	('tumors', 'Disease', (370, 376))	('tumors', 'Disease', 'MESH:D009369', (563, 569))	('Panc1', 'CellLine', 'CVCL:0480', (324, 329))	('Panc1', 'CellLine', 'CVCL:0480', (348, 353))	('tumors', 'Disease', 'MESH:D009369', (697, 703))	('pancreatic', 'Disease', (898, 908))	('rat', 'Species', '10116', (68, 71))	('peritoneal tumors', 'Disease', (686, 703))	('pancreatic', 'Disease', (312, 322))	('tumor', 'Phenotype', 'HP:0002664', (909, 914))	('tumor', 'Disease', (737, 742))	('LDH-A', 'Gene', (806, 811))	('cancer', 'Disease', (330, 336))	('tumors', 'Disease', (909, 915))	('tumor', 'Disease', (563, 568))	('tumors', 'Disease', 'MESH:D009369', (370, 376))	('tumor', 'Disease', (697, 702))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('localization', 'biological_process', 'GO:0051179', ('655', '667'))	('peritoneal tumors', 'Disease', 'MESH:D010534', (686, 703))	('peritoneal tumors', 'Disease', (359, 376))	('rat', 'Species', '10116', (939, 942))	('tumor', 'Disease', 'MESH:D009369', (737, 742))	('tumor', 'Disease', 'MESH:D009369', (563, 568))	('PDAC-PC', 'Chemical', '-', (555, 562))	('tumor', 'Disease', 'MESH:D009369', (697, 702))	('peritoneal tumors', 'Disease', 'MESH:D010534', (359, 376))	('tumor', 'Disease', (370, 375))
9515	28099801	Interestingly, the fluorescence intensity/AUC for 0.02 and 0.2% HFR-eNPs is significantly greater than that of equivalent concentrations of free rhodamine (Figure 1e).	('rhodamine', 'Chemical', 'MESH:D012235', (145, 154))	('HFR-eNPs', 'Var', (64, 72))	('greater', 'PosReg', (90, 97))	('rat', 'Species', '10116', (129, 132))	('0.02', 'Var', (50, 54))	('fluorescence intensity/AUC', 'MPA', (19, 45))
9519	28099801	Interestingly, PLGA-NPs covalently labeled with rhodamine do not produce a significant increase in fluorescence compared to free rhodamine (Figure 1e).	('rhodamine', 'Var', (48, 57))	('fluorescence', 'MPA', (99, 111))	('rhodamine', 'Chemical', 'MESH:D012235', (129, 138))	('rhodamine', 'Chemical', 'MESH:D012235', (48, 57))
9531	28099801	The HFR-PEG-eNPs appeared to be completely absent from the peritoneal cavity, consistent with the PEG surface functionalization reducing cellular uptake and affording a more rapid clearance of the particles from the peritoneal cavity.	('PEG surface functionalization', 'Var', (98, 127))	('cellular uptake', 'CPA', (137, 152))	('PEG', 'Chemical', 'MESH:D011092', (8, 11))	('uptake', 'biological_process', 'GO:0098739', ('146', '152'))	('HFR-PEG-eNPs', 'Chemical', '-', (4, 16))	('clearance', 'CPA', (180, 189))	('reducing', 'NegReg', (128, 136))	('uptake', 'biological_process', 'GO:0098657', ('146', '152'))	('PEG', 'Chemical', 'MESH:D011092', (98, 101))	('more', 'PosReg', (169, 173))
9551	28099801	This deduction is supported by the detection of HFR-eNPs within cells rather than distributed in the extracellular matrix surrounding tumor cells (Figure 6a).	('rat', 'Species', '10116', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('HFR-eNPs', 'Var', (48, 56))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('101', '121'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
9601	28099801	Mice received intraperitoneal injections of 5 x 106 MSTO-211H or 1 x 106 OVCAR-3 cells, yielding established tumors within 2-4 weeks.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('MSTO-211H', 'Var', (52, 61))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
9617	28099801	HFR-eNPs were injected IP and, 24 h later, animals were anesthetized using isoflurane and underwent laparotomy in sterile manner to evaluate the potential for HFR-eNP image-guided surgical resection/elimination of peritoneal tumors, especially sub-millimeter tumors.	('sub-millimeter', 'Var', (244, 258))	('peritoneal tumors', 'Disease', 'MESH:D010534', (214, 231))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('isoflurane', 'Chemical', 'MESH:D007530', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('peritoneal tumors', 'Disease', (214, 231))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumors', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('tumors', 'Disease', (225, 231))
9630	28587822	In cancer cells with the HR repair pathway deficiency due to BRCA1 and BRCA2 mutation, inhibition of PARP will lead to DNA breaks unrepaired and cause cell death eventually.	('BRCA1', 'Gene', (61, 66))	('deficiency', 'NegReg', (43, 53))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('mutation', 'Var', (77, 85))	('DNA breaks', 'MPA', (119, 129))	('BRCA2', 'Gene', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('cancer', 'Disease', (3, 9))	('cell death', 'CPA', (151, 161))	('cause', 'Reg', (145, 150))	('PARP', 'Gene', (101, 105))	('PARP', 'Gene', '11545', (101, 105))	('BRCA2', 'Gene', '12190', (71, 76))	('lead', 'Reg', (111, 115))	('BRCA1', 'Gene', '12189', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
9646	28587822	Different from the previous F-18 labeled agents, we would like to modify this molecule with introduction of Cu-64, a PET isotope with favorable characteristics (T1/2 = 12.7 h, beta+ 17.4%, Emax = 0.656 MeV, beta- 39%, Emax = 0.573 MeV).	('Cu-64', 'Chemical', '-', (108, 113))	('F-18', 'Chemical', '-', (28, 32))	('beta+ 17.4', 'Var', (176, 186))	('beta- 39%', 'Var', (207, 216))
9647	28587822	Compared with F-18 (T1/2 = 109 min), there is a longer physical half-life for Cu-64 which allow more time for time-sensitive operations.	('Cu-64', 'Var', (78, 83))	('Cu-64', 'Chemical', '-', (78, 83))	('F-18', 'Chemical', '-', (14, 18))	('physical half-life', 'MPA', (55, 73))
9740	20664588	Splenocytes were stained with the following monoclonal antibodies: Ly6C (FITC), F4/80 (FITC), MHCII (PE), CD11c (PE-Texas red), CD11b (PerCP-Cy5.5), CD31 (PE-Cy7), CD206 (Alexa 647), Ly6G (Alexa Fluor 700), Gr-1 (APC-Cy7) and a fixable live/dead marker in DAPI (Invitrogen, Breda, The Netherlands).	('CD11c', 'Gene', '16411', (106, 111))	('Texas red', 'Chemical', 'MESH:C034657', (116, 125))	('APC', 'cellular_component', 'GO:0005680', ('213', '216'))	('Ly6C', 'Gene', '17067', (67, 71))	('Gr-1', 'Gene', '546644', (207, 211))	('PerCP-Cy5', 'Chemical', '-', (135, 144))	('Gr-1', 'Gene', (207, 211))	('Ly6C', 'Gene', (67, 71))	('CD11b', 'Var', (128, 133))	('CD31', 'Gene', '18613', (149, 153))	('FITC', 'Chemical', '-', (73, 77))	('DAPI', 'Chemical', 'MESH:C007293', (256, 260))	('MHCII', 'Gene', (94, 99))	('Cy7', 'Chemical', '-', (217, 220))	('PE', 'Chemical', '-', (155, 157))	('Ly6G', 'Gene', '546644', (183, 187))	('F4/80', 'Gene', '13733', (80, 85))	('Alexa Fluor 700', 'Chemical', '-', (189, 204))	('MHCII', 'Gene', '111364', (94, 99))	('PE', 'Chemical', '-', (101, 103))	('Cy7', 'Chemical', '-', (158, 161))	('Ly6G', 'Gene', (183, 187))	('Alexa 647', 'Chemical', 'MESH:C569686', (171, 180))	('FITC', 'Chemical', '-', (87, 91))	('CD31', 'Gene', (149, 153))	('CD206', 'Gene', '17533', (164, 169))	('CD11c', 'Gene', (106, 111))	('F4/80', 'Gene', (80, 85))	('PE', 'Chemical', '-', (113, 115))	('CD206', 'Gene', (164, 169))
9811	20664588	Expression of the markers F4/80 and MHCII was found on MO-MDSC and Gr-1low-MDSC, but not on PMN-MDSC.	('MHCII', 'Gene', '111364', (36, 41))	('Gr-1', 'Gene', '546644', (67, 71))	('MO-MDSC', 'Var', (55, 62))	('PMN', 'biological_process', 'GO:0034727', ('92', '95'))	('Gr-1', 'Gene', (67, 71))	('MHCII', 'Gene', (36, 41))	('F4/80', 'Gene', (26, 31))	('F4/80', 'Gene', '13733', (26, 31))
9827	20664588	The proportion of macrophages in the spleen of ZA-treated mice was significantly lower compared with PBS-treated mice (P=0.0091).	('lower', 'NegReg', (81, 86))	('ZA-treated', 'Var', (47, 57))	('ZA', 'Chemical', 'MESH:D000077211', (47, 49))	('mice', 'Species', '10090', (58, 62))	('mice', 'Species', '10090', (113, 117))	('PBS', 'Chemical', 'MESH:D007854', (101, 104))
9854	20664588	We and others have shown that depleting TAMs with liposome-encapsulated clodronate inhibits tumour growth and prolongs survival.	('depleting', 'Var', (30, 39))	('prolongs', 'PosReg', (110, 118))	('survival', 'CPA', (119, 127))	('tumour growth', 'Disease', 'MESH:D006130', (92, 105))	('inhibits', 'NegReg', (83, 91))	('clodronate', 'Chemical', 'MESH:D004002', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('TAMs', 'Chemical', '-', (40, 44))	('tumour growth', 'Disease', (92, 105))
9978	19830126	Histologically, the tumor was epithelioid type (Figure 1B) with T4N0, stage IV (IMIG staging).	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('T4N0', 'Var', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
10174	32123850	The reduced expression of SV40 TAg in crocidolite plus clinoptilolite-treated mice might be caused by the amelioration of mesothelial cell transformation and thus a reduction in the initiation of mesothelioma.	('initiation of mesothelioma', 'Disease', (182, 208))	('crocidolite', 'Chemical', 'MESH:D017638', (38, 49))	('mesothelial cell transformation', 'CPA', (122, 153))	('reduced', 'NegReg', (4, 11))	('clinoptilolite', 'Chemical', 'MESH:C083175', (55, 69))	('reduction', 'NegReg', (165, 174))	('initiation of mesothelioma', 'Disease', 'MESH:D008654', (182, 208))	('expression', 'MPA', (12, 22))	('amelioration', 'PosReg', (106, 118))	('SV40 TAg', 'Var', (26, 34))	('mice', 'Species', '10090', (78, 82))
10191	32123850	Mouse peritoneal macrophages exposed to Fe3+ in culture showed a marked decline in survival rate and an enhanced capacity for lipid peroxidation.46 The electrical activity of macrophages may be compromised by the presence of Fe3+ derived from aberrant metabolic function or foreign sources such as asbestos, and this probably extends to the immune system generally.	('compromised', 'NegReg', (194, 205))	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('electrical activity', 'MPA', (152, 171))	('Fe3+', 'Var', (225, 229))	('Mouse', 'Species', '10090', (0, 5))	('asbestos', 'Chemical', 'MESH:D001194', (298, 306))	('Fe3+', 'Chemical', '-', (225, 229))	('Fe3+', 'Chemical', '-', (40, 44))
10214	28600498	Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease.	('Deregulation', 'Var', (0, 12))	('metabolism', 'biological_process', 'GO:0008152', ('121', '131'))	('cancer', 'Disease', (192, 198))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (132, 162))	('Malignant pleural mesothelioma', 'Disease', (132, 162))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('human', 'Species', '9606', (186, 191))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (142, 162))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (26, 56))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (36, 56))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('malignant pleural mesothelioma', 'Disease', (26, 56))
10217	28600498	Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively.	('miR-151a', 'Gene', '442893', (169, 177))	('hypoxia', 'Disease', (193, 200))	('miR-151a', 'Gene', (169, 177))	('related', 'Reg', (182, 189))	('hypoxia', 'Disease', 'MESH:D000860', (193, 200))	('metabolism', 'biological_process', 'GO:0008152', ('212', '222'))	('Let-7c-5p', 'Var', (155, 164))
10219	28600498	Their abnormal expression has been linked to multiple human diseases, including cancer.	('abnormal', 'Var', (6, 14))	('linked', 'Reg', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (54, 59))	('cancer', 'Disease', (80, 86))
10223	28600498	From the published literature it seems established that miRNAs deregulated in MPM target genes fundamental for the development and progression of the disease, such as CDKN2A, NF2, JUN, HGF, and PDGFA .	('PDGFA', 'Gene', '5154', (194, 199))	('CDKN2A', 'Gene', (167, 173))	('HGF', 'Gene', (185, 188))	('CDKN2A', 'Gene', '1029', (167, 173))	('NF2', 'Gene', '4771', (175, 178))	('JUN', 'Disease', (180, 183))	('HGF', 'Gene', '3082', (185, 188))	('deregulated', 'Var', (63, 74))	('MPM', 'Gene', (78, 81))	('NF2', 'Gene', (175, 178))	('PDGFA', 'Gene', (194, 199))
10237	28600498	We identified a 2-miRNA signature based on Let-7c-5p and miR-151a-5p expression levels.	('miR-151a', 'Gene', (57, 65))	('Let-7c-5p', 'Var', (43, 52))	('miR-151a', 'Gene', '442893', (57, 65))
10239	28600498	The OS rates were significantly lower in the patient group with the high-risk score (P = 0.004 by the log-rank test; Fig.	('OS rates', 'MPA', (4, 12))	('patient', 'Species', '9606', (45, 52))	('high-risk', 'Var', (68, 77))	('lower', 'NegReg', (32, 37))
10242	28600498	Taken together, these results show that the classifier based on Let-7c-5p and miR-151a-5p expression levels has great potential as prognostic tool.	('miR-151a', 'Gene', '442893', (78, 86))	('miR-151a', 'Gene', (78, 86))	('Let-7c-5p', 'Var', (64, 73))
10264	28600498	Altogether, the "miRNomic" approach allows highlighting a list of deregulated miRNAs, which could act as tumour suppressor or oncogene according to their target mRNAs.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('miRNAs', 'Gene', (78, 84))	('tumour', 'Disease', (105, 111))	('deregulated', 'Var', (66, 77))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
10271	28600498	While the earlier studies suggested a prognostic value for single miRNAs (miR-29c*, miR-17-5p and miR-30c-5p), subsequent works attempted to increase the accuracy of the survival analysis using a combination of multiple miRNAs (four-miRNA classifier or six-miRNA score).	('miR-29c', 'Gene', (74, 81))	('miR-29c', 'Gene', '407026', (74, 81))	('miR-30c-5p', 'Var', (98, 108))	('miR-17-5p', 'Gene', '406952', (84, 93))	('miR-17-5p', 'Gene', (84, 93))
10272	28600498	In line with this approach, we proposed here a 2-miRNA signature (Let-7c-5p plus miR-151a-5p) relating to overall survival, whose prognostic value was also validated in the TCGA mesothelioma dataset and in an independent set of fresh frozen MPM samples.	('Let-7c-5p', 'Var', (66, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('miR-151a', 'Gene', '442893', (81, 89))	('miR-151a', 'Gene', (81, 89))	('overall survival', 'MPA', (106, 122))	('mesothelioma', 'Disease', (178, 190))
10273	28600498	Our study showed some discrepancies compared to the literature data, where general poor overlap among studies could be at least partially ascribed to different microarray platforms (for example, miR-29c* and miR-652-3p probes were not included in the Nanostring platform), to subtle different statistical analyses in the calculation of the survival curves and, as acknowledged before, to the intrinsic heterogeneity of MPM.	('miR-29c', 'Gene', '407026', (195, 202))	('miR-29c', 'Gene', (195, 202))	('miR-652-3p', 'Var', (208, 218))
10274	28600498	Nonetheless, our results were consistent with data provided recently about an eight-miRNA signature in bladder cancer, reporting an association between a high expression of Let-7c-5p and a poor outcome.	('Let-7c-5p', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('association', 'Interaction', (132, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('bladder cancer', 'Disease', (103, 117))
10275	28600498	At a similar extent, high levels of miR-151 correlated with adverse effects on survival rate in prostate cancer.	('high levels', 'Var', (21, 32))	('miR-151', 'Gene', '442893', (36, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('miR-151', 'Gene', (36, 43))	('survival rate', 'CPA', (79, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
10276	28600498	In fact, Let-7c-5p plays a protective role against cerebral ischemia injury in mice, while miR-151a-5p regulates energy metabolism reducing ATP production via mitochondrial dysfunction.	('cerebral ischemia', 'Phenotype', 'HP:0002637', (51, 68))	('miR-151a', 'Gene', '442893', (91, 99))	('Let-7c-5p', 'Var', (9, 18))	('miR-151a', 'Gene', (91, 99))	('metabolism', 'biological_process', 'GO:0008152', ('120', '130'))	('cerebral ischemia injury', 'Disease', (51, 75))	('cerebral ischemia injury', 'Disease', 'MESH:D002545', (51, 75))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (159, 184))	('energy metabolism reducing ATP production', 'MPA', (113, 154))	('mice', 'Species', '10090', (79, 83))	('ATP', 'Chemical', 'MESH:D000255', (140, 143))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (159, 184))	('mitochondrial dysfunction', 'Disease', (159, 184))	('regulates', 'Reg', (103, 112))
10280	28600498	This could explain their association with the overall survival that we observed here, since their high expression could promote the hypoxic microenvironment very well known to activate many signalling pathways involved in tumour initiation, progression and maintenance of MPM.	('high expression', 'Var', (98, 113))	('promote', 'PosReg', (120, 127))	('activate', 'PosReg', (176, 184))	('tumour initiation', 'Disease', 'MESH:D009369', (222, 239))	('hypoxic', 'Disease', (132, 139))	('hypoxic', 'Disease', 'MESH:D000860', (132, 139))	('signalling', 'biological_process', 'GO:0023052', ('190', '200'))	('tumour initiation', 'Disease', (222, 239))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('signalling pathways', 'Pathway', (190, 209))
10298	28600498	The miRNA panel detects 800 endogenous miRNAs, five housekeeping transcripts [actin beta (NM_001101.2), beta-2 microglobulin (NM_004048.2), GAPDH (NM_002046.3), RPL19 (NM_000981.3), and RPLP0 (NM_001002.3)], six positive and eight negative controls (proprietary spike-in controls).	('GAPDH', 'Gene', (140, 145))	('RPLP0', 'Gene', '6175', (186, 191))	('NM_001101.2', 'Var', (90, 101))	('beta-2 microglobulin', 'Gene', (104, 124))	('RPLP0', 'Gene', (186, 191))	('NM_000981.3', 'Var', (168, 179))	('NM_002046.3', 'Var', (147, 158))	('RPL19', 'Gene', '6143', (161, 166))	('GAPDH', 'Gene', '2597', (140, 145))	('beta-2 microglobulin', 'Gene', '567', (104, 124))	('RPL19', 'Gene', (161, 166))	('NM_004048.2', 'Var', (126, 137))
10417	31289611	Our data suggest that in MPM, the downregulation of miR-15/16 is due to transcriptional repression by c-Myc, primarily via control of the miR-15b/16-2 locus, while miR-193a-3p loss is due to genomic deletion.	('miR-15', 'Chemical', '-', (52, 58))	('miR-15b', 'Gene', (138, 145))	('loss', 'NegReg', (176, 180))	('downregulation', 'NegReg', (34, 48))	('miR-15', 'Chemical', '-', (138, 144))	('miR-15b', 'Gene', '406949', (138, 145))	('MPM', 'Disease', (25, 28))	('miR-15/16', 'Gene', (52, 61))	('deletion', 'Var', (199, 207))	('c-Myc', 'Gene', '4609', (102, 107))	('transcriptional repression', 'MPA', (72, 98))	('miR-193a', 'Gene', (164, 172))	('c-Myc', 'Gene', (102, 107))	('miR-193a', 'Gene', '406968', (164, 172))
10431	31289611	Despite the association of the MIR193A gene promoter with CpG islands and its confirmed silencing by methylation in NSCLC and acute myeloid leukemia (AML), methylation was excluded as a predominant cause of its downregulation in MPM cell lines and the causes for its reduction in MPM remain unknown.	('methylation', 'Var', (101, 112))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (126, 148))	('AML', 'Disease', 'MESH:D015470', (150, 153))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('silencing', 'NegReg', (88, 97))	('AML', 'Disease', (150, 153))	('acute myeloid leukemia', 'Disease', (126, 148))	('MIR193A', 'Gene', (31, 38))	('association', 'Interaction', (12, 23))	('AML', 'Phenotype', 'HP:0004808', (150, 153))	('MIR193A', 'Gene', '406968', (31, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (132, 148))	('NSCLC', 'Disease', (116, 121))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (126, 148))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))
10435	31289611	Allelic loss of the MIR193A gene was observed in the majority of MPM cell lines tested (Figure 1C), suggesting that heterozygous deletion of the MIR193A region is a key contributor to downregulation of miR-193a-3p in MPM.	('downregulation', 'NegReg', (184, 198))	('deletion', 'Var', (129, 137))	('MIR193A', 'Gene', (20, 27))	('MIR193A', 'Gene', '406968', (145, 152))	('MIR193A', 'Gene', '406968', (20, 27))	('miR-193a', 'Gene', (202, 210))	('MIR193A', 'Gene', (145, 152))	('miR-193a', 'Gene', '406968', (202, 210))
10438	31289611	In contrast, negligible changes in expression were observed for miR-15a, miR-15b and miR-16 in most cells, however, the expression of miR-15/16 is partially affected by decitabine treatment in H2052 and H2452, suggesting some regulation by DNA methylation in these cell lines (Figure 2A), whereas miR-193a-3p expression was only slightly altered.	('miR-15', 'Chemical', '-', (73, 79))	('miR-15a', 'Gene', '406948', (64, 71))	('miR-16', 'Gene', (85, 91))	('regulation', 'biological_process', 'GO:0065007', ('226', '236'))	('miR-15', 'Chemical', '-', (64, 70))	('miR-15', 'Chemical', '-', (134, 140))	('miR-15/16', 'Gene', (134, 143))	('expression', 'MPA', (120, 130))	('affected', 'Reg', (157, 165))	('H2052', 'Var', (193, 198))	('miR-16', 'Gene', '51573', (85, 91))	('miR-15b', 'Gene', '406949', (73, 80))	('miR-15a', 'Gene', (64, 71))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('H2052', 'CellLine', 'CVCL:1518', (193, 198))	('miR-15b', 'Gene', (73, 80))	('regulation', 'Reg', (226, 236))	('miR-193a', 'Gene', (297, 305))	('DNA methylation', 'biological_process', 'GO:0006306', ('240', '255'))	('H2452', 'Var', (203, 208))	('miR-193a', 'Gene', '406968', (297, 305))	('decitabine', 'Chemical', 'MESH:D000077209', (169, 179))
10442	31289611	Since pri-miR-15a/16-1 and pri-miR-15b/16-2 are transcribed from the promoters of their host genes DLEU2 and SMC4 respectively, we hypothesized that a transcriptional defect at these loci would affect both pri-miRNA and host gene expression.	('SMC4', 'Gene', (109, 113))	('miR-15b', 'Gene', (31, 38))	('miR-15a', 'Gene', (10, 17))	('DLEU2', 'Gene', (99, 104))	('gene expression', 'biological_process', 'GO:0010467', ('225', '240'))	('affect', 'Reg', (194, 200))	('defect', 'Var', (167, 173))	('expression', 'MPA', (230, 240))	('miR-15a', 'Gene', '406948', (10, 17))	('miR-15b', 'Gene', '406949', (31, 38))	('DLEU2', 'Gene', '8847', (99, 104))	('SMC4', 'Gene', '10051', (109, 113))	('SMC', 'cellular_component', 'GO:0016029', ('109', '112'))	('transcriptional', 'MPA', (151, 166))
10444	31289611	We next investigated the potential role of the oncogenic transcription factor Myc in miR-15/16 inhibition, as it has been shown to suppress miRNA expression and is upregulated in MPM partly due to increased copy number of the MYC gene.	('copy number', 'Var', (207, 218))	('Myc', 'Gene', '4609', (78, 81))	('MYC', 'Gene', (226, 229))	('Myc', 'Gene', (78, 81))	('transcription factor', 'molecular_function', 'GO:0000981', ('57', '77'))	('suppress', 'NegReg', (131, 139))	('upregulated', 'PosReg', (164, 175))	('transcription', 'biological_process', 'GO:0006351', ('57', '70'))	('MYC', 'Gene', '4609', (226, 229))	('increased', 'PosReg', (197, 206))	('miRNA expression', 'MPA', (140, 156))	('miR-15', 'Chemical', '-', (85, 91))
10447	31289611	Myc knockdown led to upregulation of miR-16 levels in MSTO (2-fold) and H28 (1.7-fold) compared to control transfected cells.	('knockdown', 'Var', (4, 13))	('Myc', 'Gene', '4609', (0, 3))	('Myc', 'Gene', (0, 3))	('miR-16', 'Gene', (37, 43))	('upregulation', 'PosReg', (21, 33))	('miR-16', 'Gene', '51573', (37, 43))
10449	31289611	As seen in Figure 4C, levels of pri-miR-15b were increased by 10.7-fold and 2.7-fold in MSTO and H28 respectively following transfection with Myc siRNA while co-transcribed SMC4 was elevated by 5.9-fold in MSTO and 8.1-fold in H28 (Figure 4D).	('SMC4', 'Gene', (173, 177))	('miR-15b', 'Gene', '406949', (36, 43))	('SMC', 'cellular_component', 'GO:0016029', ('173', '176'))	('increased', 'PosReg', (49, 58))	('miR-15b', 'Gene', (36, 43))	('Myc', 'Gene', '4609', (142, 145))	('levels', 'MPA', (22, 28))	('transfection', 'Var', (124, 136))	('Myc', 'Gene', (142, 145))	('SMC4', 'Gene', '10051', (173, 177))
10451	31289611	As Myc knockdown increased miR-15/16 expression, and these miRNAs inhibit MPM growth in vitro and in vivo , we tested the effect of Myc knockdown in MPM cell line growth.	('increased', 'PosReg', (17, 26))	('miR-15/16', 'Protein', (27, 36))	('miR-15', 'Chemical', '-', (27, 33))	('Myc', 'Gene', '4609', (3, 6))	('Myc', 'Gene', (3, 6))	('Myc', 'Gene', '4609', (132, 135))	('expression', 'MPA', (37, 47))	('inhibit', 'NegReg', (66, 73))	('Myc', 'Gene', (132, 135))	('tested', 'Reg', (111, 117))	('MPM growth', 'CPA', (74, 84))	('knockdown', 'Var', (7, 16))
10452	31289611	Consistent with the effects of Myc on miR-15/16 expression, Myc knockdown significantly reduced proliferation of MSTO cells (Figure 4E).	('Myc', 'Gene', (60, 63))	('miR-15', 'Chemical', '-', (38, 44))	('Myc', 'Gene', '4609', (31, 34))	('proliferation of MSTO cells', 'CPA', (96, 123))	('Myc', 'Gene', (31, 34))	('knockdown', 'Var', (64, 73))	('reduced', 'NegReg', (88, 95))	('Myc', 'Gene', '4609', (60, 63))
10453	31289611	Given the increase of miR-15b/16-2 and miR-15a/16-1 expression following Myc knockdown, we set out to determine the effect of Myc upregulation.	('miR-15b', 'Gene', '406949', (22, 29))	('Myc', 'Gene', '4609', (126, 129))	('miR-15b', 'Gene', (22, 29))	('Myc', 'Gene', (126, 129))	('knockdown', 'Var', (77, 86))	('expression', 'MPA', (52, 62))	('miR-15a', 'Gene', '406948', (39, 46))	('Myc', 'Gene', '4609', (73, 76))	('miR-15a', 'Gene', (39, 46))	('Myc', 'Gene', (73, 76))	('increase', 'PosReg', (10, 18))
10467	31289611	Copy number alterations in the 13q14 chromosomal region, where miR-15a/16-1 reside, were identified in more than 50% of B-cell chronic lymphocytic leukemia (B-CLL) tumors resulting in loss of mature miRNA expression.	('-cell chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (121, 155))	('miR-15a', 'Gene', (63, 70))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (127, 155))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('loss', 'NegReg', (184, 188))	('lymphocytic leukemia (B-CLL) tumors', 'Disease', 'MESH:D015448', (135, 170))	('Copy number alterations', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mature miRNA expression', 'MPA', (192, 215))	('chromosomal region', 'cellular_component', 'GO:0098687', ('37', '55'))	('miR-15a', 'Gene', '406948', (63, 70))
10470	31289611	Our data are somewhat consistent with these findings; using CNV analysis, we found heterozygous loss of MIR15A/16-1 in H2452 and H2052 but not in the other MPM cell lines tested.	('MIR15A', 'Gene', '406948', (104, 110))	('MIR15A', 'Gene', (104, 110))	('H2452', 'Var', (119, 124))	('H2052', 'Var', (129, 134))	('H2052', 'CellLine', 'CVCL:1518', (129, 134))
10473	31289611	In comparison, the majority of cell lines were found to have deletion of one allele of the MIR193A locus, therefore attributing loss of mature miR-193a-3p expression to genomic deletion of its coding region in MPM.	('MIR193A', 'Gene', (91, 98))	('loss', 'NegReg', (128, 132))	('MIR193A', 'Gene', '406968', (91, 98))	('deletion', 'Var', (177, 185))	('deletion', 'Var', (61, 69))	('expression', 'MPA', (155, 165))	('miR-193a', 'Gene', '406968', (143, 151))	('miR-193a', 'Gene', (143, 151))
10474	31289611	Epigenetic changes frequently modulate miRNA expression in cancer.	('miRNA expression', 'MPA', (39, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('modulate', 'Reg', (30, 38))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('Epigenetic changes', 'Var', (0, 18))
10475	31289611	Family members miR-34b and miR-34c are inactivated due to CpG methylation in patients with colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (149, 170))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('ovarian', 'Disease', (124, 131))	('urothelial', 'Disease', (133, 143))	('miR-34b', 'Gene', '407041', (15, 22))	('methylation', 'Var', (62, 73))	('renal cell carcinomas', 'Disease', (149, 170))	('ovarian', 'Disease', 'MESH:D010051', (124, 131))	('CpG', 'Gene', (58, 61))	('colorectal', 'Disease', 'MESH:D015179', (91, 101))	('soft tissue sarcomas', 'Disease', (175, 195))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (149, 170))	('miR-34b', 'Gene', (15, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('mammary', 'Disease', (115, 122))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (175, 195))	('patients', 'Species', '9606', (77, 85))	('miR-34c', 'Gene', '407042', (27, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('miR-34c', 'Gene', (27, 34))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (175, 195))	('pancreatic', 'Disease', 'MESH:D010195', (103, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('pancreatic', 'Disease', (103, 113))	('colorectal', 'Disease', (91, 101))
10478	31289611	Instead, miR-193a-3p loss in MPM cell lines appears to be the result of genomic deletion.	('miR-193a', 'Gene', (9, 17))	('loss', 'NegReg', (21, 25))	('deletion', 'Var', (80, 88))	('miR-193a', 'Gene', '406968', (9, 17))
10482	31289611	Collectively, this data suggests that epigenetic modifications are not a predominant cause of the substantial reduction of miR-15a, 15b and 16 expression in MPM cell lines and tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('reduction', 'NegReg', (110, 119))	('expression', 'MPA', (143, 153))	('epigenetic modifications', 'Var', (38, 62))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('miR-15a', 'Gene', '406948', (123, 130))	('miR-15a', 'Gene', (123, 130))
10484	31289611	Recently, DNA copy number analysis revealed frequent genomic amplification of the MYC gene in MPM tumor samples and cell lines.	('MPM tumor', 'Disease', (94, 103))	('MPM tumor', 'Disease', 'MESH:D009369', (94, 103))	('MYC', 'Gene', '4609', (82, 85))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('genomic amplification', 'Var', (53, 74))	('MYC', 'Gene', (82, 85))
10499	31289611	Previously, we and others have shown that restoring expression levels of the miR-15/16 family results in similar cellular consequences to Myc knockdown, so it is likely that increased miR-15/16 expression contributes to the effects on proliferation seen following Myc silencing.	('silencing', 'Var', (268, 277))	('miR-15', 'Chemical', '-', (184, 190))	('Myc', 'Gene', '4609', (264, 267))	('expression', 'MPA', (52, 62))	('proliferation', 'MPA', (235, 248))	('Myc', 'Gene', '4609', (138, 141))	('Myc', 'Gene', (138, 141))	('expression', 'MPA', (194, 204))	('miR-15/16', 'Gene', (184, 193))	('Myc', 'Gene', (264, 267))	('miR-15', 'Chemical', '-', (77, 83))	('increased', 'PosReg', (174, 183))
10501	31289611	For example, tumor-specific inactivation of Myc expression was shown to reverse immune evasion by preventing the Myc-induced transcriptional activation of PD-L1 and CD47.	('Myc', 'Gene', (113, 116))	('tumor', 'Disease', (13, 18))	('CD47', 'Gene', (165, 169))	('Myc', 'Gene', (44, 47))	('immune evasion', 'biological_process', 'GO:0042783', ('80', '94'))	('PD-L1', 'Gene', '29126', (155, 160))	('preventing', 'NegReg', (98, 108))	('reverse immune evasion', 'MPA', (72, 94))	('inactivation', 'Var', (28, 40))	('immune evasion', 'biological_process', 'GO:0051842', ('80', '94'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Myc', 'Gene', '4609', (44, 47))	('PD-L1', 'Gene', (155, 160))	('CD47', 'Gene', '961', (165, 169))	('Myc', 'Gene', '4609', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
10528	31289611	The effect of Myc knockdown on the proliferation of MPM cell lines was carried out using SYBR Green-based cell proliferation assays as described.	('knockdown', 'Var', (18, 27))	('Myc', 'Gene', '4609', (14, 17))	('Myc', 'Gene', (14, 17))	('SYBR Green', 'Chemical', '-', (89, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
10612	30801908	Cell proliferation did not change significantly in tumors treated with intact NZ-12 (0 MBq), whereas 3.70 MBq of 90Y-labeled NZ-12 reduced cell proliferation (Ki-67-positive cells) in a time-dependent way (Figure 5), and the reduction was statistically significant on days 3 and 7 compared with untreated tumors and tumors treated with intact NZ-12 (0 MBq).	('NZ-12', 'Chemical', '-', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('reduced', 'NegReg', (131, 138))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('NZ-12', 'Chemical', '-', (125, 130))	('rat', 'Species', '10116', (151, 154))	('90Y', 'Chemical', 'MESH:C000615496', (113, 116))	('3.70 MBq', 'Var', (101, 109))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumors', 'Disease', (316, 322))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('rat', 'Species', '10116', (12, 15))	('NZ-12', 'Gene', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))	('tumors', 'Disease', (305, 311))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NZ-12', 'Chemical', '-', (343, 348))	('tumors and tumors', 'Disease', 'MESH:D009369', (305, 322))	('tumors', 'Disease', (51, 57))	('cell proliferation', 'CPA', (139, 157))	('tumors', 'Disease', 'MESH:D009369', (305, 311))
10626	30801908	By replacing 111In with a therapeutic radionuclide 90Y, 3.70 MBq of 90Y-labeled NZ-12 showed a stronger tumor growth suppression effect and prolonged survival with statistically significant differences compared with giving intact NZ-12 and 3.70 MBq of 90Y-labeled control antibody, whereas 1.85 MBq of 90Y-labeled NZ-12 had no significant effect.	('90Y', 'Chemical', 'MESH:C000615496', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('antibody', 'molecular_function', 'GO:0003823', ('272', '280'))	('antibody', 'cellular_component', 'GO:0042571', ('272', '280'))	('stronger', 'PosReg', (95, 103))	('90Y-labeled', 'Var', (68, 79))	('survival', 'CPA', (150, 158))	('NZ-12', 'Gene', (80, 85))	('NZ-12', 'Chemical', '-', (314, 319))	('radionuclide', 'Chemical', 'MESH:D011868', (38, 50))	('antibody', 'cellular_component', 'GO:0019815', ('272', '280'))	('prolonged', 'PosReg', (140, 149))	('90Y', 'Chemical', 'MESH:C000615496', (302, 305))	('tumor', 'Disease', (104, 109))	('90Y', 'Chemical', 'MESH:C000615496', (252, 255))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('111In', 'Chemical', 'MESH:C000615551', (13, 18))	('NZ-12', 'Chemical', '-', (230, 235))	('antibody', 'cellular_component', 'GO:0019814', ('272', '280'))	('90Y', 'Chemical', 'MESH:C000615496', (68, 71))	('NZ-12', 'Chemical', '-', (80, 85))	('3.70 MBq', 'Var', (56, 64))
10637	30801908	However, 90Y-labeled NZ-12 suppressed tumor growth and, therefore, further efforts as described below, may improve the therapeutic effect to achieve complete remission in malignant mesothelioma patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (171, 193))	('patients', 'Species', '9606', (194, 202))	('NZ-12', 'Gene', (21, 26))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (171, 193))	('suppressed', 'NegReg', (27, 37))	('90Y', 'Chemical', 'MESH:C000615496', (9, 12))	('NZ-12', 'Chemical', '-', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('malignant mesothelioma', 'Disease', (171, 193))	('improve', 'PosReg', (107, 114))	('therapeutic effect', 'MPA', (119, 137))	('90Y-labeled', 'Var', (9, 20))
10644	30801908	Some chemotherapeutic agents such as pemetrexed and gemcitabine have radiosensitizing effects.52, 53 Pemetrexed is recommended as first-line chemotherapy for malignant mesothelioma5 and is the first candidate as a radiosensitizer with RIT against mesothelioma.	('mesothelioma', 'Disease', (247, 259))	('Pemetrexed', 'Var', (101, 111))	('mesothelioma', 'Disease', (168, 180))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (158, 180))	('gemcitabine', 'Chemical', 'MESH:C056507', (52, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (247, 259))	('mesothelioma', 'Disease', 'MESH:D008654', (168, 180))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (101, 111))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (158, 180))	('malignant mesothelioma', 'Disease', (158, 180))	('pemetrexed', 'Chemical', 'MESH:D000068437', (37, 47))
10646	30801908	Taken together, the triple combination of 90Y-labeled NZ-12, pemetrexed, and intact NZ-12 has the potential to induce cytotoxic effects and suppress tumor growth for a long time.	('90Y', 'Chemical', 'MESH:C000615496', (42, 45))	('pemetrexed', 'Chemical', 'MESH:D000068437', (61, 71))	('NZ-12', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cytotoxic effects', 'CPA', (118, 135))	('NZ-12', 'Gene', (54, 59))	('induce', 'PosReg', (111, 117))	('NZ-12', 'Gene', (84, 89))	('tumor', 'Disease', (149, 154))	('90Y-labeled', 'Var', (42, 53))	('suppress', 'NegReg', (140, 148))	('NZ-12', 'Chemical', '-', (84, 89))
10676	29207669	We analyzed 5 different models (Table 2, Figure 1): MPM vs. HC (model 1), MPM vs. AEx (model 2), MPM vs. ARD (model 3), MPM vs. AEx+ARD (model 4) and ARD vs. AEx (model 5).	('MPM vs.', 'Var', (74, 81))	('ARD', 'Disease', 'None', (150, 153))	('ARD', 'Disease', (132, 135))	('ARD', 'Disease', (105, 108))	('ARD', 'Disease', (150, 153))	('AEx', 'Chemical', '-', (158, 161))	('ARD', 'Disease', 'None', (132, 135))	('ARD', 'molecular_function', 'GO:0010309', ('105', '108'))	('AEx', 'Chemical', '-', (82, 85))	('ARD', 'molecular_function', 'GO:0010309', ('132', '135'))	('ARD', 'molecular_function', 'GO:0010309', ('150', '153'))	('AEx', 'Chemical', '-', (128, 131))	('ARD', 'Disease', 'None', (105, 108))
10742	29209316	We have recently shown that C1q can promote tumor by encouraging their adhesion, migration, and proliferation in addition to angiogenesis and metastasis.	('angiogenesis', 'CPA', (125, 137))	('C1q', 'Var', (28, 31))	('promote', 'PosReg', (36, 43))	('proliferation', 'CPA', (96, 109))	('metastasis', 'CPA', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('adhesion', 'CPA', (71, 79))	('migration', 'CPA', (81, 90))	('encouraging', 'PosReg', (53, 64))	('tumor', 'Disease', (44, 49))	('angiogenesis', 'biological_process', 'GO:0001525', ('125', '137'))	('C1q', 'cellular_component', 'GO:0062167', ('28', '31'))
10746	29209316	C1q bound to HA was able to induce adhesion and proliferation of mesothelioma cells (MES) via enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation; however, it did not activate the complement cascade.	('JNK', 'Gene', '5599', (122, 125))	('complement cascade', 'biological_process', 'GO:0006956', ('185', '203'))	('JNK', 'molecular_function', 'GO:0004705', ('122', '125'))	('proliferation', 'CPA', (48, 61))	('enhancement', 'PosReg', (94, 105))	('C1q', 'Var', (0, 3))	('HA', 'Chemical', 'MESH:D006820', (13, 15))	('mesothelioma', 'Disease', (65, 77))	('p38', 'Gene', (131, 134))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('phosphorylation', 'MPA', (135, 150))	('MES', 'Chemical', '-', (85, 88))	('SAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('SAPK', 'Gene', (117, 121))	('adhesion', 'CPA', (35, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('SAPK', 'Gene', '5601', (117, 121))	('ERK1/2', 'Gene', (109, 115))	('ERK1/2', 'Gene', '5595;5594', (109, 115))	('p38', 'Gene', '5594', (131, 134))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('ERK1', 'molecular_function', 'GO:0004707', ('109', '113'))	('induce', 'PosReg', (28, 34))	('JNK', 'Gene', (122, 125))
10747	29209316	Consistent with the modular organization of the globular domain, we demonstrated that C1q may bind to HA through ghA module, whereas it may interact with human MES through the ghC.	('C1q', 'Var', (86, 89))	('human', 'Species', '9606', (154, 159))	('ghC', 'Chemical', '-', (176, 179))	('HA', 'Chemical', 'MESH:D006820', (102, 104))	('bind', 'Interaction', (94, 98))	('ghA', 'Chemical', '-', (113, 116))	('C1q', 'cellular_component', 'GO:0062167', ('86', '89'))	('MES', 'Chemical', '-', (160, 163))	('interact', 'Interaction', (140, 148))
10748	29209316	In conclusion, C1q highly expressed in MPM binds to HA and enhances the tumor growth promoting cell adhesion and proliferation.	('binds', 'Interaction', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('C1q', 'cellular_component', 'GO:0062167', ('15', '18'))	('cell adhesion', 'biological_process', 'GO:0007155', ('95', '108'))	('tumor', 'Disease', (72, 77))	('HA', 'Chemical', 'MESH:D006820', (52, 54))	('C1q', 'Var', (15, 18))	('enhances', 'PosReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
10763	29209316	We found that C1q can bind to HA and acquires protumorigenic properties, leading to heightened adhesion, migration and proliferation of human mesothelioma cells (MES).	('human', 'Species', '9606', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('C1q', 'Var', (14, 17))	('heightened', 'PosReg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HA', 'Chemical', 'MESH:D006820', (30, 32))	('tumor', 'Disease', (49, 54))	('adhesion', 'CPA', (95, 103))	('MES', 'Chemical', '-', (162, 165))	('mesothelioma', 'Disease', (142, 154))	('C1q', 'cellular_component', 'GO:0062167', ('14', '17'))	('bind', 'Interaction', (22, 26))	('migration', 'CPA', (105, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('proliferation', 'CPA', (119, 132))
10767	29209316	Poly-l-lysine, bovine serum albumin (BSA) and all reagents were from Sigma-Aldrich.	('Poly-l-lysine', 'Chemical', '-', (0, 13))	('serum albumin', 'Gene', '213', (22, 35))	('serum albumin', 'Gene', (22, 35))	('Poly-l-lysine', 'Var', (0, 13))	('bovine', 'Species', '9913', (15, 21))
10810	29209316	C1q was allowed to bind (25 microg/ml) to HA in PBS + 0.5% BSA, 0.7 mM CaCl2, and 0.7 mM MgCl2, overnight at 4 C. 1 x 105 mesothelial cells or MES, labeled with the fluorescent dye FAST DiI (Molecular Probes, Invitrogen), were re-suspended in HESF (Life Technologies) containing 0.1% BSA (HESF + 0.1% BSA; Sigma), preincubated with 10 microM of ERK (#SCH772984, Selleckchem), JNK (#SP600125, SIGMA-Aldrich), or p38 (#SB203580, Selleckchem) inhibitors for 30 min at RT and then added to a 96-well plate (wells were coated as described above) for 35 min at 37 C in 5% v/v CO2 incubator.	('ERK', 'Gene', '5594', (345, 348))	('MgCl2', 'Chemical', 'MESH:D015636', (89, 94))	('FAST', 'molecular_function', 'GO:0033867', ('181', '185'))	('ERK', 'Gene', (345, 348))	('p38', 'Gene', '5594', (411, 414))	('ERK', 'molecular_function', 'GO:0004707', ('345', '348'))	('#SP600125', 'Var', (381, 390))	('HA', 'Chemical', 'MESH:D006820', (42, 44))	('PBS', 'Chemical', 'MESH:D007854', (48, 51))	('JNK', 'molecular_function', 'GO:0004705', ('376', '379'))	('MES', 'Chemical', '-', (143, 146))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('JNK', 'Gene', (376, 379))	('CaCl2', 'Chemical', 'MESH:D002122', (71, 76))	('JNK', 'Gene', '5599', (376, 379))	('CO2', 'Chemical', '-', (570, 573))	('inhibitors', 'Var', (440, 450))	('DiI', 'Chemical', '-', (186, 189))	('p38', 'Gene', (411, 414))
10813	29209316	5 x 103 MES were re-suspended in HESF + 0.1% BSA medium and seeded to a 96-well plate, which was earlier coated with C1q, HA or C1q + HA, as described above.	('C1q + HA', 'Var', (128, 136))	('C1q', 'Var', (117, 120))	('MES', 'Chemical', '-', (8, 11))	('C1q', 'cellular_component', 'GO:0062167', ('117', '120'))	('HA', 'Chemical', 'MESH:D006820', (134, 136))	('C1q', 'cellular_component', 'GO:0062167', ('128', '131'))	('HA', 'Chemical', 'MESH:D006820', (122, 124))
10833	29209316	C1q was also diffusely present in the tumor stroma and associated with the cell membrane of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor stroma', 'Disease', 'MESH:D009369', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor stroma', 'Disease', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (92, 97))	('cell membrane', 'cellular_component', 'GO:0005886', ('75', '88'))
10843	29209316	As shown in Figures 4C,D, only C1q bound to IgG, and not HA-bound C1q, induced complement activation, and therefore, C4 deposition and C9-neoantigen formation.	('complement activation', 'MPA', (79, 100))	('C1q', 'Var', (31, 34))	('C4 deposition', 'MPA', (117, 130))	('induced', 'Reg', (71, 78))	('C1q', 'cellular_component', 'GO:0062167', ('66', '69'))	('complement activation', 'biological_process', 'GO:0006956', ('79', '100'))	('bound', 'Interaction', (35, 40))	('C1q', 'cellular_component', 'GO:0062167', ('31', '34'))	('HA', 'Chemical', 'MESH:D006820', (57, 59))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('C9-neoantigen formation', 'MPA', (135, 158))
10864	29209316	In contrast, MES showed greater adherence to HA; HA-bound-C1q was able to enhance MES adhesion considerably compared to HA alone (Figure 6B).	('HA-bound-C1q', 'Var', (49, 61))	('MES adhesion', 'CPA', (82, 94))	('HA', 'Chemical', 'MESH:D006820', (45, 47))	('C1q', 'cellular_component', 'GO:0062167', ('58', '61'))	('HA', 'Chemical', 'MESH:D006820', (49, 51))	('MES', 'Chemical', '-', (82, 85))	('MES', 'Chemical', '-', (13, 16))	('HA', 'Chemical', 'MESH:D006820', (120, 122))	('adherence', 'MPA', (32, 41))	('enhance', 'PosReg', (74, 81))
10866	29209316	The analysis of the adherent MES by phase-contrast optical microscopy revealed that a high proportion of the cells seeded on to C1q or HA-bound-C1q were spread out, in contrast to the round morphology exhibited by those attached to HA or BSA (Figure 6C).	('C1q', 'Var', (128, 131))	('C1q', 'cellular_component', 'GO:0062167', ('144', '147'))	('HA', 'Chemical', 'MESH:D006820', (135, 137))	('HA', 'Chemical', 'MESH:D006820', (232, 234))	('MES', 'Chemical', '-', (29, 32))	('spread out', 'CPA', (153, 163))	('C1q', 'cellular_component', 'GO:0062167', ('128', '131'))
10872	29209316	We investigated whether C1q might contribute to tumor growth by stimulating the proliferation of MES.	('tumor', 'Disease', (48, 53))	('stimulating', 'PosReg', (64, 75))	('C1q', 'Var', (24, 27))	('proliferation', 'CPA', (80, 93))	('MES', 'Chemical', '-', (97, 100))	('C1q', 'cellular_component', 'GO:0062167', ('24', '27'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
10876	29209316	C1q (60%) was found to be more effective than HA (~20%), in effecting migration (Figure 8B).	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('migration', 'CPA', (70, 79))	('effecting', 'Reg', (60, 69))	('HA', 'Chemical', 'MESH:D006820', (46, 48))
10878	29209316	In fact, the percentage of the cell migration due to HA + C1q was comparable to that observed with C1q alone.	('C1q', 'cellular_component', 'GO:0062167', ('58', '61'))	('cell migration', 'biological_process', 'GO:0016477', ('31', '45'))	('HA + C1q', 'Var', (53, 61))	('C1q', 'cellular_component', 'GO:0062167', ('99', '102'))	('cell migration', 'CPA', (31, 45))	('HA', 'Chemical', 'MESH:D006820', (53, 55))
10880	29209316	As shown in the graph in Figure 8C, the fluorogenic units of the MES on HA treated with H2O2 was double, compared to the untreated cells.	('MES', 'Chemical', '-', (65, 68))	('fluorogenic units', 'MPA', (40, 57))	('HA', 'Chemical', 'MESH:D006820', (72, 74))	('H2O2', 'Chemical', 'MESH:D006861', (88, 92))	('H2O2', 'Var', (88, 92))
10888	29209316	In a murine model of melanoma, C1q was found to promote cancer cell adhesion, migration and proliferation.	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('C1q', 'Var', (31, 34))	('proliferation', 'CPA', (92, 105))	('murine', 'Species', '10090', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cell adhesion', 'biological_process', 'GO:0007155', ('63', '76'))	('C1q', 'cellular_component', 'GO:0062167', ('31', '34'))	('migration', 'CPA', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('promote', 'PosReg', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
10889	29209316	Thus, as a pro-tumorigenic soluble factor, C1q can promote tumor progression by facilitating cancer cell seeding and angiogenesis.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (59, 64))	('facilitating', 'PosReg', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('angiogenesis', 'biological_process', 'GO:0001525', ('117', '129'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('C1q', 'cellular_component', 'GO:0062167', ('43', '46'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (15, 20))	('promote', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('C1q', 'Var', (43, 46))	('soluble', 'cellular_component', 'GO:0005625', ('27', '34'))	('angiogenesis', 'CPA', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
10892	29209316	In this study, we particularly focused our attention on the interaction between C1q and HA and its implication on adhesion and proliferation of MPM cells.	('C1q', 'cellular_component', 'GO:0062167', ('80', '83'))	('proliferation', 'CPA', (127, 140))	('adhesion', 'CPA', (114, 122))	('C1q', 'Var', (80, 83))	('interaction', 'Interaction', (60, 71))	('HA', 'Chemical', 'MESH:D006820', (88, 90))
10894	29209316	C1q was also diffusely present in the tumor stroma and associated with the cell membrane of tumor cells mainly of the epithelioid histotype.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor stroma', 'Disease', 'MESH:D009369', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor stroma', 'Disease', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (92, 97))	('cell membrane', 'cellular_component', 'GO:0005886', ('75', '88'))
10903	29209316	The interaction of C1q with synovial HA in rheumatoid arthritis has been previously reported; however, C1q binds synovial antibodies that are covalently coupled to HA.	('binds', 'Interaction', (107, 112))	('C1q', 'Var', (103, 106))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (43, 63))	('C1q', 'cellular_component', 'GO:0062167', ('103', '106'))	('HA', 'Chemical', 'MESH:D006820', (37, 39))	('arthritis', 'Phenotype', 'HP:0001369', (54, 63))	('C1q', 'cellular_component', 'GO:0062167', ('19', '22'))	('rheumatoid arthritis', 'Disease', (43, 63))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (43, 63))	('HA', 'Chemical', 'MESH:D006820', (164, 166))
10906	29209316	Since LMW-HA, but not HMW-HA, can stimulate a number of biological processes, it is likely that C1q can interfere with several functions mediated by HA, such as angiogenesis and inflammation.	('LMW-HA', 'Var', (6, 12))	('inflammation', 'biological_process', 'GO:0006954', ('178', '190'))	('HA', 'Chemical', 'MESH:D006820', (10, 12))	('C1q', 'cellular_component', 'GO:0062167', ('96', '99'))	('stimulate', 'PosReg', (34, 43))	('angiogenesis', 'CPA', (161, 173))	('HA', 'Chemical', 'MESH:D006820', (149, 151))	('angiogenesis', 'biological_process', 'GO:0001525', ('161', '173'))	('inflammation', 'Disease', 'MESH:D007249', (178, 190))	('inflammation', 'Disease', (178, 190))	('biological processes', 'CPA', (56, 76))	('interfere', 'NegReg', (104, 113))	('functions', 'MPA', (127, 136))	('HA', 'Chemical', 'MESH:D006820', (26, 28))	('C1q', 'Var', (96, 99))
10911	29209316	Here, we demonstrated that the effects mediated by C1q-bound-HA were different from that observed for HA or C1q alone in terms of the number of adhering cells as well as morphology indicating that the presence of C1q can considerably modify the tumor microenvironment.	('HA', 'Chemical', 'MESH:D006820', (102, 104))	('presence', 'Var', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('C1q', 'cellular_component', 'GO:0062167', ('213', '216'))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('HA', 'Chemical', 'MESH:D006820', (61, 63))	('tumor', 'Disease', (245, 250))	('modify', 'Reg', (234, 240))	('C1q', 'Var', (213, 216))	('C1q', 'cellular_component', 'GO:0062167', ('51', '54'))	('C1q', 'cellular_component', 'GO:0062167', ('108', '111'))
10913	29209316	Among various C1q receptors gC1qR, also called HA-binding protein-1, is an interesting molecule for its ability to bind both the gC1q domain of C1q and HA.	('bind', 'Interaction', (115, 119))	('C1q', 'cellular_component', 'GO:0062167', ('144', '147'))	('gC1q domain', 'Var', (129, 140))	('gC1qR', 'Gene', (28, 33))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('gC1qR', 'Gene', '708', (28, 33))	('C1q', 'cellular_component', 'GO:0062167', ('14', '17'))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('HA', 'Chemical', 'MESH:D006820', (152, 154))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
10917	29209316	Since ghA is the preferential binder to HA, the gC1q domain can act as a bridging molecule for anchoring the tumor cells to the ECM.	('gC1q domain', 'Var', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ghA', 'Chemical', '-', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('anchoring', 'molecular_function', 'GO:0043495', ('95', '104'))	('HA', 'Chemical', 'MESH:D006820', (40, 42))	('tumor', 'Disease', (109, 114))
10918	29209316	C1q-bound-HA was able to promote the growth and the migration of MES in vitro confirming our previous results, obtained with B16/F10 murine cells and C1q bound to fibronectin.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q-bound-HA', 'Var', (0, 12))	('migration of MES', 'CPA', (52, 68))	('MES', 'Chemical', '-', (65, 68))	('fibronectin', 'Gene', (163, 174))	('HA', 'Chemical', 'MESH:D006820', (10, 12))	('C1q', 'cellular_component', 'GO:0062167', ('150', '153'))	('promote', 'PosReg', (25, 32))	('murine', 'Species', '10090', (133, 139))	('C1q', 'Var', (150, 153))	('growth', 'CPA', (37, 43))	('fibronectin', 'Gene', '14268', (163, 174))
10922	29209316	That C1q can act as a tumor promoting factor in MPM confirms our recent data.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('C1q', 'cellular_component', 'GO:0062167', ('5', '8'))	('C1q', 'Var', (5, 8))	('tumor', 'Disease', (22, 27))	('MPM', 'Disease', (48, 51))
10926	29209316	have reported that C1q, via its gC1q domain, induced apoptosis in an ovarian cancer cell line SKOV3 via TNF-alpha induced apoptosis pathway involving upregulation of Bax and Fas.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('ovarian cancer', 'Disease', (69, 83))	('apoptosis', 'CPA', (53, 62))	('gC1q domain', 'Var', (32, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('apoptosis pathway', 'Pathway', (122, 139))	('upregulation', 'PosReg', (150, 162))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('Bax', 'Gene', (166, 169))	('Bax', 'Gene', '581', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('C1q', 'cellular_component', 'GO:0062167', ('19', '22'))	('SKOV3', 'CellLine', 'CVCL:0532', (94, 99))	('TNF-alpha', 'Gene', '7124', (104, 113))	('TNF-alpha', 'Gene', (104, 113))	('C1q', 'Var', (19, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))
10929	29209316	The presence of C1q or C1 in soluble phase or bound to the ECM can provide different stimuli to the tumor cells present in the microenvironment.	('C1q', 'cellular_component', 'GO:0062167', ('16', '19'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('C1q', 'Var', (16, 19))	('stimuli', 'MPA', (85, 92))	('soluble', 'cellular_component', 'GO:0005625', ('29', '36'))
10930	29209316	In conclusion, C1q is abundantly present in mesothelioma tissue, interacts with HA, and interferes with adhesion, migration and proliferation of MES.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('C1q', 'cellular_component', 'GO:0062167', ('15', '18'))	('adhesion', 'CPA', (104, 112))	('MES', 'Chemical', '-', (145, 148))	('migration', 'CPA', (114, 123))	('HA', 'Chemical', 'MESH:D006820', (80, 82))	('C1q', 'Var', (15, 18))	('proliferation', 'CPA', (128, 141))	('interferes', 'NegReg', (88, 98))	('mesothelioma', 'Disease', (44, 56))	('interacts', 'Reg', (65, 74))
10960	27803412	Moreover, these malignant cells were immunohistochemically identical to the samples collected previously from the pericardium, showing positivity for calretinin, WT1, AE1/AE3, and CAM5.2, and negativity for CEA and TTF-1.	('AE1', 'Gene', (167, 170))	('calretinin', 'Gene', '794', (150, 160))	('CEA', 'Gene', (207, 210))	('AE3', 'Gene', '6508', (171, 174))	('CEA', 'Gene', '5670', (207, 210))	('positivity', 'Var', (135, 145))	('TTF-1', 'Gene', (215, 220))	('WT1', 'Gene', '7490', (162, 165))	('WT1', 'Gene', (162, 165))	('calretinin', 'Gene', (150, 160))	('TTF-1', 'Gene', '7270', (215, 220))	('AE1', 'Gene', '6521', (167, 170))	('AE3', 'Gene', (171, 174))
11005	23788952	Transient alleviation occurred after introduction of NSAIDs and clarithromycin, followed however by recurrent rises in temperature, paroxysmal and persistent cough, and malaise after a few days.	('paroxysmal', 'Disease', (132, 142))	('malaise', 'Disease', (169, 176))	('clarithromycin', 'Chemical', 'MESH:D017291', (64, 78))	('recurrent rises in temperature', 'Phenotype', 'HP:0001954', (100, 130))	('clarithromycin', 'Var', (64, 78))	('rises', 'PosReg', (110, 115))	('malaise', 'Phenotype', 'HP:0012378', (169, 176))	('cough', 'Disease', 'MESH:D003371', (158, 163))	('persistent cough', 'Phenotype', 'HP:0031245', (147, 163))	('temperature', 'MPA', (119, 130))	('cough', 'Phenotype', 'HP:0012735', (158, 163))	('cough', 'Disease', (158, 163))
11151	29467873	Overexpression of Survivin is associated with tumour progression and poor prognosis in many types of human malignancies, including MM.	('associated', 'Reg', (30, 40))	('tumour', 'Disease', (46, 52))	('human', 'Species', '9606', (101, 106))	('malignancies', 'Disease', 'MESH:D009369', (107, 119))	('Overexpression', 'Var', (0, 14))	('Survivin', 'Protein', (18, 26))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('malignancies', 'Disease', (107, 119))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
11154	29467873	Several studies have determined that germline mutations in the gene for BAP1 predispose individuals to developing various tumours, including MM, cutaneous melanocytic tumours, uveal melanoma, lung adenocarcinoma, and meningioma.	('BAP1', 'Gene', '8314', (72, 76))	('meningioma', 'Disease', (217, 227))	('meningioma', 'Phenotype', 'HP:0002858', (217, 227))	('tumours', 'Disease', (122, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('uveal melanoma', 'Disease', (176, 190))	('germline mutations', 'Var', (37, 55))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('BAP1', 'Gene', (72, 76))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', (167, 174))	('lung adenocarcinoma', 'Disease', (192, 211))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('meningioma', 'Disease', 'MESH:D008577', (217, 227))	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('cutaneous melanocytic tumours', 'Disease', 'MESH:D009508', (145, 174))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (192, 211))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (192, 211))	('predispose', 'Reg', (77, 87))	('cutaneous melanocytic tumours', 'Disease', (145, 174))
11155	29467873	These studies suggest that germline mutations in BAP1 result in a 'tumour predisposition syndrome' linking BAP1 to many other cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('BAP1', 'Gene', '8314', (107, 111))	('result in', 'Reg', (54, 63))	('tumour', 'Disease', (67, 73))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('germline mutations', 'Var', (27, 45))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('BAP1', 'Gene', '8314', (49, 53))
11159	29467873	Several different alterations in the BAP1 gene have been described, including large deletions of exons leading to loss of the N-terminal region, or to premature protein termination, focal deletions, frameshift mutations due to insertions or deletions, splice site mutations, and base substitutions leading to nonsense and missense mutations.	('premature protein termination', 'MPA', (151, 180))	('nonsense', 'MPA', (309, 317))	('missense mutations', 'Var', (322, 340))	('frameshift mutations', 'Var', (199, 219))	('splice site mutations', 'Var', (252, 273))	('focal', 'Disease', (182, 187))	('loss', 'NegReg', (114, 118))	('deletions', 'Var', (188, 197))	('insertions', 'Var', (227, 237))	('BAP1', 'Gene', '8314', (37, 41))	('leading', 'Reg', (298, 305))	('deletions', 'Var', (241, 250))	('BAP1', 'Gene', (37, 41))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('base substitutions', 'Var', (279, 297))	('the N-terminal region', 'MPA', (122, 143))	('deletions', 'Var', (84, 93))
11160	29467873	Truncating mutations frequently result in loss of the nuclear localization signal and/or the C-terminal protein-binding domain, while missense mutations interfere with the ubiquitin hydrolase function of BAP1.	('interfere', 'NegReg', (153, 162))	('ubiquitin', 'molecular_function', 'GO:0031386', ('172', '181'))	('nuclear localization signal', 'MPA', (54, 81))	('Truncating mutations', 'Var', (0, 20))	('protein-binding', 'molecular_function', 'GO:0005515', ('104', '119'))	('missense mutations', 'Var', (134, 152))	('ubiquitin hydrolase function', 'MPA', (172, 200))	('BAP1', 'Gene', '8314', (204, 208))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('C-terminal protein-binding domain', 'MPA', (93, 126))	('localization', 'biological_process', 'GO:0051179', ('62', '74'))	('BAP1', 'Gene', (204, 208))	('loss', 'NegReg', (42, 46))
11161	29467873	As the detection of these alterations in BAP1 has been made possible in recent years using immunohistochemistry (IHC), immunohistochemical detection of BAP1 loss has also been reported to be useful in distinguishing MM from RMH.	('BAP1', 'Gene', (41, 45))	('BAP1', 'Gene', '8314', (152, 156))	('alterations', 'Var', (26, 37))	('RMH', 'Disease', (224, 227))	('BAP1', 'Gene', (152, 156))	('loss', 'NegReg', (157, 161))	('BAP1', 'Gene', '8314', (41, 45))
11162	29467873	Several studies indicate that the loss of nuclear BAP1 expression as assessed by IHC is closely correlated with genetic alterations in BAP1.	('BAP1', 'Gene', '8314', (135, 139))	('genetic alterations', 'Var', (112, 131))	('BAP1', 'Gene', '8314', (50, 54))	('expression', 'MPA', (55, 65))	('BAP1', 'Gene', (135, 139))	('BAP1', 'Gene', (50, 54))	('loss', 'NegReg', (34, 38))
11179	29467873	Although various studies have reported the usefulness of Ki-67 IHC in differentiating EM from RMH, it is not routinely utilized for the confirmation of mesothelioma due to its low sensitivity and specificity.	('Ki-67', 'Var', (57, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('RMH', 'Disease', (94, 97))	('mesothelioma', 'Disease', (152, 164))
11180	29467873	However, the diagnostic accuracy of the combination of Ki-67 and BAP1 was 94.8%, which was almost the same as that of the combination of Survivin and BAP1.	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (150, 154))	('combination', 'Interaction', (40, 51))	('Ki-67', 'Var', (55, 60))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (150, 154))
11281	32944962	Nuclear BAP1 staining is more common in sarcomatoid disease [11, 15, 18], consistent with studies describing biphasic cases with BAP1 nuclear positivity in the sarcomatoid component and negativity in the epithelioid component [9, 18, 25].	('sarcomatoid disease', 'Disease', (40, 59))	('sarcomatoid disease', 'Disease', 'MESH:C538614', (40, 59))	('common', 'Reg', (30, 36))	('nuclear positivity', 'Var', (134, 152))	('sarcomatoid component', 'Disease', (160, 181))	('BAP1', 'Gene', (129, 133))	('sarcomatoid component', 'Disease', 'MESH:C538614', (160, 181))	('sarcomatoid disease', 'Phenotype', 'HP:0100242', (40, 59))
11282	32944962	The significance of cytoplasmic BAP1 immunostaining is thought to represent either a mutation in the ubiquitin C-terminal hydrolase (UCH) domain [6, 17, 28], deleted/inactivated NLS2 [6, 29], or a non-specific reaction of the antibody (either classified as BAP1 loss or removed from the dataset) [10, 11, 12, 13, 14, 18, 25].	('NLS2', 'Gene', (178, 182))	('UCH', 'Gene', (133, 136))	('antibody', 'cellular_component', 'GO:0019815', ('226', '234'))	('antibody', 'cellular_component', 'GO:0019814', ('226', '234'))	('NLS2', 'Gene', '29968', (178, 182))	('antibody', 'molecular_function', 'GO:0003823', ('226', '234'))	('ubiquitin C-terminal hydrolase', 'Gene', (101, 131))	('ubiquitin C-terminal hydrolase', 'molecular_function', 'GO:0036459', ('101', '131'))	('antibody', 'cellular_component', 'GO:0042571', ('226', '234'))	('deleted/inactivated', 'Var', (158, 177))	('UCH', 'Gene', '7345', (133, 136))	('ubiquitin C-terminal hydrolase', 'Gene', '7345', (101, 131))
11287	32944962	Four cases exhibited mutations specifically in the NLS1 domain, of which three demonstrated cytoplasmic and one nuclear BAP1 staining.	('NLS1', 'Gene', (51, 55))	('exhibited', 'Reg', (11, 20))	('NLS1', 'Gene', '84879', (51, 55))	('mutations', 'Var', (21, 30))
11296	32944962	Many solid tumors, such as non-small cell lung cancer, are driven by specific mutations in oncogenes, leading to the development and successful use of targeted sequencing panels to select targeted therapies and predict survival of cancer patients [51].	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('driven by', 'Reg', (59, 68))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (27, 53))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', (47, 53))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('solid tumors', 'Disease', (5, 17))
11297	32944962	Our finding that single-pattern cytoplasmic BAP1 is associated with improved survival of patients with non-epithelioid MPM suggests that BAP1 IHC may also be useful as a prognostic biomarker, as has been suggested for glioma [52].	('BAP1', 'Gene', (137, 141))	('glioma', 'Disease', (218, 224))	('single-pattern cytoplasmic', 'Var', (17, 43))	('survival', 'MPA', (77, 85))	('glioma', 'Disease', 'MESH:D005910', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('improved', 'PosReg', (68, 76))	('BAP1', 'Gene', (44, 48))
11415	32290540	From this point of view, a new frontier can be represented by the use of the comet assay since inhaled asbestos may induce oxidative stress and biochemical changes in lipids, proteins, DNA and RNA.	('biochemical changes', 'MPA', (144, 163))	('lipids', 'MPA', (167, 173))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('lipids', 'Chemical', 'MESH:D008055', (167, 173))	('oxidative stress', 'MPA', (123, 139))	('DNA', 'MPA', (185, 188))	('induce', 'Reg', (116, 122))	('RNA', 'cellular_component', 'GO:0005562', ('193', '196'))	('proteins', 'Protein', (175, 183))	('inhaled', 'Var', (95, 102))
11429	31138176	CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure Deletion of the CDKN2A locus is centrally involved in the development of several malignancies.	('CDKN2A', 'Gene', '1029', (121, 127))	('CDKN2A', 'Gene', '1029', (0, 6))	('p16', 'Gene', (23, 26))	('involved', 'Reg', (147, 155))	('asbestos', 'Chemical', 'MESH:D001194', (87, 95))	('malignant pleural mesothelioma', 'Disease', (41, 71))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (41, 71))	('Deletion', 'Var', (105, 113))	('men', 'Species', '9606', (170, 173))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (51, 71))	('p16', 'Gene', '1029', (23, 26))	('CDKN2A', 'Gene', (0, 6))	('malignancies', 'Disease', 'MESH:D009369', (186, 198))	('CDKN2A', 'Gene', (121, 127))	('malignancies', 'Disease', (186, 198))
11433	31138176	Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear.	('p16', 'Gene', '1029', (28, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('Copy number alterations', 'Var', (0, 23))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('p16', 'Gene', (28, 31))	('19p13', 'Gene', (44, 49))	('accumulate', 'PosReg', (77, 87))	('lung cancer', 'Disease', (91, 102))
11438	31138176	We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed).	('abnormal copy number', 'Var', (17, 37))	('high pulmonary asbestos', 'Disease', 'MESH:D001195', (85, 108))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MPM tumor', 'Disease', 'MESH:D009369', (51, 60))	('high pulmonary asbestos', 'Disease', (85, 108))	('associated', 'Reg', (67, 77))	('CDKN2A', 'Gene', (41, 47))	('MPM tumor', 'Disease', (51, 60))
11445	31138176	Alterations of CDKN2A locus and its corresponding protein expression are involved in numerous malignancies.	('CDKN2A', 'Gene', (15, 21))	('Alterations', 'Var', (0, 11))	('numerous malignancies', 'Disease', 'MESH:D009369', (85, 106))	('numerous malignancies', 'Disease', (85, 106))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('involved', 'Reg', (73, 81))
11446	31138176	In non-small cell lung cancer linked with asbestos exposure CDKN2A has been shown to be inactivated, mainly via deletions.	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('deletions', 'Var', (112, 121))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('CDKN2A', 'Gene', (60, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('inactivated', 'NegReg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
11450	31138176	In MPM, deletion of CDKN2A is the most frequently detected chromosomal change and the most common cause for p16 protein inactivation (reviewed in).	('cause', 'Reg', (98, 103))	('p16', 'Gene', '1029', (108, 111))	('CDKN2A', 'Gene', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('p16', 'Gene', (108, 111))	('inactivation', 'NegReg', (120, 132))	('deletion', 'Var', (8, 16))
11451	31138176	Hypermethylation of CDKN2A as a cause of loss of p16 expression in MPM has been reported in a minority of cases.	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (49, 52))	('CDKN2A', 'Gene', (20, 26))	('expression', 'MPA', (53, 63))	('p16', 'Gene', '1029', (49, 52))	('loss', 'NegReg', (41, 45))
11452	31138176	The frequency of CDKN2A deletion in MPM have most often been shown to range from 61 to 88% in primary tumors, few studies, however, showing deletion only in one-fifth of cases.	('MPM', 'Disease', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN2A', 'Gene', (17, 23))	('deletion', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
11459	31138176	In MPM, the asbestos-related genomic changes reported mainly consist of copy number alterations such as deletions in 14q11.2-q21, 6q, 17p, and 22q and DNA methylation changes.	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('asbestos', 'Chemical', 'MESH:D001194', (12, 20))	('DNA', 'MPA', (151, 154))	('14q11.2-q21', 'Gene', (117, 128))	('DNA methylation', 'biological_process', 'GO:0006306', ('151', '166'))	('17p', 'CPA', (134, 137))	('MPM', 'Disease', (3, 6))	('22q', 'CPA', (143, 146))	('deletions', 'Var', (104, 113))
11460	31138176	As we have earlier shown in lung cancer asbestos exposure-related accumulation of copy number alterations in 2p16, 9q33.1 and 19p13, we also studied the same loci in MPM.	('lung cancer asbestos', 'Disease', 'MESH:D008175', (28, 48))	('copy number alterations', 'Var', (82, 105))	('p16', 'Gene', '1029', (110, 113))	('accumulation', 'PosReg', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('p16', 'Gene', (110, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('lung cancer asbestos', 'Disease', (28, 48))
11497	31138176	To measure the degree of agreement with CDKN2A abnormality and p16 staining we calculated Cohen's Kappa (kappa) Coefficient.	('abnormality', 'Var', (47, 58))	('p16', 'Gene', '1029', (63, 66))	('p16', 'Gene', (63, 66))	('men', 'Species', '9606', (30, 33))
11498	31138176	MPM tumors from 92 patients having either low (<=0.5 x 106 f/g), high (>=1.0 x 106 f/g), including very high (>= 5.0 x 106 f/g), or unknown pulmonary asbestos fiber counts (unknown exposure) were studied for p16 immunoreactivity and CDKN2A copy number.	('<=0.5', 'Var', (47, 52))	('patients', 'Species', '9606', (19, 27))	('unknown pulmonary asbestos', 'Disease', (132, 158))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MPM tumors', 'Disease', (0, 10))	('p16', 'Gene', '1029', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('unknown pulmonary asbestos', 'Disease', 'MESH:D001195', (132, 158))	('>=', 'Var', (110, 112))	('MPM tumors', 'Disease', 'MESH:D009369', (0, 10))	('>=1.0 x 106 f/g', 'Var', (71, 86))	('p16', 'Gene', (208, 211))
11508	31138176	Positivity of p16 in stromal cells was even more predominant among the very highly exposed when compared with MPM with low exposure (p = 0.018, Chi-Square) (Table 2).	('p16', 'Gene', '1029', (14, 17))	('p16', 'Gene', (14, 17))	('Positivity', 'Var', (0, 10))
11514	31138176	Abnormal DNA copy number of CDKN2A in MPM tumor cells associated with patients' high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed) (Table 2, Fig.	('patients', 'Species', '9606', (70, 78))	('MPM tumor', 'Disease', 'MESH:D009369', (38, 47))	('high pulmonary asbestos', 'Disease', (80, 103))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('CDKN2A', 'Gene', (28, 34))	('Abnormal', 'Var', (0, 8))	('high pulmonary asbestos', 'Disease', 'MESH:D001195', (80, 103))	('MPM tumor', 'Disease', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (54, 64))
11518	31138176	When the relation of CDKN2A abnormality and p16 staining status was observed in individual MPM tumors, low exposure group tumors with abnormal CDKN2A always were negative for p16 staining and vice versa, yet the case numbers were small (Kappa coefficient 1.000) (Additional file 3).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('p16', 'Gene', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('p16', 'Gene', (175, 178))	('MPM tumors', 'Disease', 'MESH:D009369', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('p16', 'Gene', '1029', (44, 47))	('CDKN2A', 'Gene', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('negative', 'NegReg', (162, 170))	('p16', 'Gene', '1029', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (95, 101))	('abnormal', 'Var', (134, 142))	('MPM tumors', 'Disease', (91, 101))
11522	31138176	Mean signal counts of the loci and centromeres #2, #9, #10 and #15 suggested that copy numbers in 2p16, 9q33.1, and 19p13 and centromeres of chromosomes 2, 9, 10, and 15 in majority of MPM were diploid or close to diploid (Additional file 1).	('p16', 'Gene', '1029', (99, 102))	('p16', 'Gene', (99, 102))	('MPM', 'Gene', (185, 188))	('copy', 'Var', (82, 86))
11525	31138176	In mouse studies, MM formation through asbestos exposure has shown a significant role of alterations in Cdkn2a/Arf and deletion of CDKN2A is the most frequently detected chromosomal change in human MPM.	('mouse', 'Species', '10090', (3, 8))	('human', 'Species', '9606', (192, 197))	('MM formation', 'CPA', (18, 30))	('deletion', 'Var', (119, 127))	('Cdkn2a', 'Gene', '12578', (104, 110))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('asbestos', 'Chemical', 'MESH:D001194', (39, 47))	('alterations', 'Var', (89, 100))	('Cdkn2a', 'Gene', (104, 110))	('CDKN2A', 'Gene', (131, 137))
11540	31138176	Accordingly, a majority (84.1%) of our MPM cases showed a CDKN2A copy number abnormality, either HD or hemizygous deletion or monosomy.	('HD', 'Disease', 'MESH:D006816', (97, 99))	('monosomy', 'Var', (126, 134))	('CDKN2A', 'Gene', (58, 64))	('hemizygous deletion', 'Var', (103, 122))	('copy number abnormality', 'Var', (65, 88))
11545	31138176	We showed that abnormal copy number of CDKN2A in MPM tumor cells associated with high pulmonary asbestos fiber count but not with age or MPM histologic type.	('MPM tumor', 'Disease', (49, 58))	('CDKN2A', 'Gene', (39, 45))	('high pulmonary asbestos', 'Disease', 'MESH:D001195', (81, 104))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('associated', 'Reg', (65, 75))	('MPM tumor', 'Disease', 'MESH:D009369', (49, 58))	('abnormal copy number', 'Var', (15, 35))	('high pulmonary asbestos', 'Disease', (81, 104))
11547	31138176	In their study, p16 alterations (deletion or methylation) were more common in cases with lower pulmonary asbestos (fiber counts by a method different than ours) although p16 deletions were more common in heavy exposed group.	('alterations', 'Var', (20, 31))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('p16', 'Gene', '1029', (16, 19))	('p16', 'Gene', '1029', (170, 173))	('pulmonary asbestos', 'Disease', (95, 113))	('pulmonary asbestos', 'Disease', 'MESH:D001195', (95, 113))	('methylation', 'Var', (45, 56))	('p16', 'Gene', (16, 19))	('p16', 'Gene', (170, 173))
11549	31138176	In other earlier studies, exposure data obtained from work history evaluation, CDKN2A deletion and asbestos exposure did not associate with each other.	('asbestos', 'Chemical', 'MESH:D001194', (99, 107))	('CDKN2A', 'Gene', (79, 85))	('deletion', 'Var', (86, 94))
11552	31138176	This is the first report indicating a correlation between the CDKN2A deletion status and the p16 protein levels in MPM patients having low asbestos exposure.	('correlation', 'Interaction', (38, 49))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('p16', 'Gene', '1029', (93, 96))	('patients', 'Species', '9606', (119, 127))	('CDKN2A', 'Gene', (62, 68))	('p16', 'Gene', (93, 96))	('asbestos', 'Chemical', 'MESH:D001194', (139, 147))	('deletion', 'Var', (69, 77))
11553	31138176	Earlier, somewhat discrepant results about the relationship and correlation of the CDKN2A deletion status and the p16 levels in MPM has been reported.	('deletion', 'Var', (90, 98))	('CDKN2A', 'Gene', (83, 89))	('p16', 'Gene', '1029', (114, 117))	('p16', 'Gene', (114, 117))
11554	31138176	Immunoreactivity for the proteins p14, p15, p16 and MTAP, all encoded from DNA in 9p21, has been studied and compared with FISH result of 9p21.	('p16', 'Gene', (44, 47))	('p14', 'Var', (34, 37))	('p15', 'Var', (39, 42))	('MTAP', 'Gene', '4507', (52, 56))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('p16', 'Gene', '1029', (44, 47))	('MTAP', 'Gene', (52, 56))
11557	31138176	Nevertheless, the correlation between the CDKN2A deletion status and p16 protein levels was shown here for the first time, interestingly only in the low exposure group MPM.	('p16', 'Gene', (69, 72))	('CDKN2A', 'Gene', (42, 48))	('deletion', 'Var', (49, 57))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('p16', 'Gene', '1029', (69, 72))
11559	31138176	Our studies here on locus specific DNA copy numbers and on the centromeres of chromosomes 2, 9, 10 and 15 suggested that asbestos exposure related accumulation of alterations in 2p16, 9q33 and 19p13 that we earlier have showed in lung cancer was not comparable in MPM.	('alterations', 'Var', (163, 174))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('9q33', 'Gene', (184, 188))	('lung cancer', 'Disease', (230, 241))	('p16', 'Gene', (179, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('19p13', 'Gene', (193, 198))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('p16', 'Gene', '1029', (179, 182))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))
11560	31138176	Abnormal signals, even if being infrequent may suggest that in asbestos-exposed patients these genomic regions gained disintegration due to exposure-induced DNA damage, reflected as increased locus copy number variation in single MPM individuals.	('asbestos', 'Chemical', 'MESH:D001194', (63, 71))	('increased', 'PosReg', (182, 191))	('patients', 'Species', '9606', (80, 88))	('gained', 'PosReg', (111, 117))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('locus copy number variation', 'Var', (192, 219))	('disintegration', 'MPA', (118, 132))
11562	31138176	Although 2p changes were not reported using comparative genomic hybridization in primary MPM tumors, another study on MPM cell lines have shown gains in 2p16.2-p12, 2p11.2-q11.2, and 19p13.13, depending on the cell passage.	('MPM tumors', 'Disease', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p16', 'Gene', (154, 157))	('p12', 'Gene', '56655', (160, 163))	('MPM tumors', 'Disease', 'MESH:D009369', (89, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('p16', 'Gene', '1029', (154, 157))	('19p13.13', 'Var', (183, 191))	('2p11.2-q11.2', 'Var', (165, 177))	('p12', 'Gene', (160, 163))	('gains', 'PosReg', (144, 149))
11564	31138176	Additionally, abnormal copy number of CDKN2A in MPM tumor cells associated with high pulmonary asbestos fiber count, again suggesting a biological difference between mesotheliomas depending on the degree of asbestos exposure.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('associated', 'Reg', (64, 74))	('MPM tumor', 'Disease', 'MESH:D009369', (48, 57))	('high pulmonary asbestos', 'Disease', (80, 103))	('mesotheliomas', 'Disease', 'MESH:D008654', (166, 179))	('asbestos', 'Chemical', 'MESH:D001194', (207, 215))	('mesotheliomas', 'Disease', (166, 179))	('abnormal copy number', 'Var', (14, 34))	('asbestos', 'Chemical', 'MESH:D001194', (95, 103))	('CDKN2A', 'Gene', (38, 44))	('high pulmonary asbestos', 'Disease', 'MESH:D001195', (80, 103))	('MPM tumor', 'Disease', (48, 57))
11570	31138176	The patients are deceased, consent from them was not required (Dnro 39/13/03/00/09; Dnro 105/13/03/00/2013, Dnro TTL/2/2016; Dnro THL/1055/5.05.01/2013; Dnro 5929/06.01.03.01/2013).	('TTL', 'Gene', (113, 116))	('TTL', 'Gene', '150465', (113, 116))	('patients', 'Species', '9606', (4, 12))	('THL', 'Chemical', '-', (130, 133))	('Dnro', 'Var', (125, 129))
11585	30723653	Immunohistochemical analyses demonstrated that these cells were positive for AE1/AE3, calretinin, D2-40, WT-1, mesothelin, HEG1, CD146, EMA, MTAP, p16, and p53, and negative for CEA, TTF-1, desmin, and BAP1 and Ki67 index was 5%.	('p16', 'Gene', (147, 150))	('TTF-1', 'Gene', (183, 188))	('CD146', 'Gene', '4162', (129, 134))	('CD146', 'Gene', (129, 134))	('calretinin', 'Gene', '794', (86, 96))	('CEA', 'Gene', (178, 181))	('D2-40', 'Var', (98, 103))	('p16', 'Gene', '1029', (147, 150))	('CEA', 'Gene', '5670', (178, 181))	('desmin', 'Gene', '1674', (190, 196))	('desmin', 'cellular_component', 'GO:0045098', ('190', '196'))	('AE3', 'Gene', (81, 84))	('HEG1', 'Gene', (123, 127))	('BAP1', 'Gene', '8314', (202, 206))	('p53', 'Gene', '7157', (156, 159))	('HEG1', 'Gene', '57493', (123, 127))	('AE1', 'Gene', '6521', (77, 80))	('TTF-1', 'Gene', '7270', (183, 188))	('MTAP', 'Gene', (141, 145))	('BAP1', 'Gene', (202, 206))	('AE3', 'Gene', '6508', (81, 84))	('calretinin', 'Gene', (86, 96))	('MTAP', 'Gene', '4507', (141, 145))	('p53', 'Gene', (156, 159))	('desmin', 'Gene', (190, 196))	('desmin', 'cellular_component', 'GO:0045100', ('190', '196'))	('AE1', 'Gene', (77, 80))
11595	30723653	Immunohistochemical analyses demonstrated that these cells were positive for AE1/AE3, calretinin, D2-40, WT-1, mesothelin, HEG1, CD146, MTAP, and p53, and negative for CEA, TTF-1, and claudin-4 and Ki67 index was 8%.	('claudin-4', 'Gene', (184, 193))	('p53', 'Gene', (146, 149))	('CD146', 'Gene', '4162', (129, 134))	('CD146', 'Gene', (129, 134))	('calretinin', 'Gene', '794', (86, 96))	('D2-40', 'Var', (98, 103))	('claudin-4', 'Gene', '1364', (184, 193))	('TTF-1', 'Gene', (173, 178))	('MTAP', 'Gene', (136, 140))	('AE3', 'Gene', (81, 84))	('HEG1', 'Gene', (123, 127))	('CEA', 'Gene', (168, 171))	('MTAP', 'Gene', '4507', (136, 140))	('CEA', 'Gene', '5670', (168, 171))	('positive', 'Reg', (64, 72))	('HEG1', 'Gene', '57493', (123, 127))	('AE1', 'Gene', '6521', (77, 80))	('AE3', 'Gene', '6508', (81, 84))	('calretinin', 'Gene', (86, 96))	('p53', 'Gene', '7157', (146, 149))	('AE1', 'Gene', (77, 80))	('TTF-1', 'Gene', '7270', (173, 178))
11623	26443804	Recombinant Immunotoxin with T Cell Epitope Mutations that Greatly Reduce Immunogenicity for Treatment of Mesothelin Expressing Tumors SS1P is a recombinant immunotoxin (RIT) that targets mesothelin.	('Mesothelin', 'Gene', '10232', (106, 116))	('SS1P', 'Chemical', 'MESH:C474515', (135, 139))	('Immunogenicity', 'MPA', (74, 88))	('Mesothelin', 'Gene', (106, 116))	('RIT', 'Chemical', '-', (170, 173))	('SS1P', 'Gene', (135, 139))	('Tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Mutations', 'Var', (44, 53))	('Tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Tumors', 'Disease', (128, 134))	('Tumors', 'Disease', 'MESH:D009369', (128, 134))
11626	26443804	LMB-T20 was more active than SS1P when tested on 4 different mesothelin expressing cell lines as well as on cells obtained from patients with mesothelioma.	('LMB-T20', 'Chemical', '-', (0, 7))	('SS1P', 'Chemical', 'MESH:C474515', (29, 33))	('LMB-T20', 'Var', (0, 7))	('mesothelioma', 'Disease', (142, 154))	('patients', 'Species', '9606', (128, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('active', 'MPA', (17, 23))
11635	26443804	When SS1P was evaluated in clinical trials, it had low anti-tumor activity as a single agent and in most patients could only be given for a single cycle of three doses before neutralizing antibodies developed.	('patients', 'Species', '9606', (105, 113))	('SS1P', 'Chemical', 'MESH:C474515', (5, 9))	('SS1P', 'Var', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('low', 'NegReg', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
11639	26443804	The antibodies involved in the immunogenicity response against SS1P are mostly high affinity IgGs reacting with PE38, the toxin portion of the RIT.	('SS1P', 'Chemical', 'MESH:C474515', (63, 67))	('PE38', 'Var', (112, 116))	('SS1P', 'Gene', (63, 67))	('RIT', 'Chemical', '-', (143, 146))
11644	26443804	SS1P, SS1P-LR-GGS and LMB-T20 are composed of the heavy-chain Fv fused to PE38 or PE24 toxin, with a disulfide-linkage to the light-chain Fv (VL).	('disulfide', 'Chemical', 'MESH:D004220', (101, 110))	('PE38', 'Var', (74, 78))	('heavy-chain', 'Protein', (50, 61))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('SS1P', 'Chemical', 'MESH:C474515', (6, 10))	('LMB-T20', 'Chemical', '-', (22, 29))
11653	26443804	Identity of all cell lines was confirmed by short tandem repeat (STR) testing within the past 12 months and all cell lines were tested negative for mycoplasma.	('mycoplasma', 'Disease', 'MESH:D009175', (148, 158))	('mycoplasma', 'Disease', (148, 158))	('short tandem repeat', 'Var', (44, 63))
11688	26443804	PE38 is made up of two domains; domain II (amino acids 253-364) involved in toxin processing, and domain III (amino acids 395-613) contains the ADP ribosylation activity.	('ADP', 'Chemical', 'MESH:D000244', (144, 147))	('involved', 'Reg', (64, 72))	('ADP ribosylation activity', 'MPA', (144, 169))	('amino acids 395-613', 'Var', (110, 129))	('amino acids 253-364', 'Var', (43, 62))
11689	26443804	We previously showed that modifying SS1P by deletion of the majority of domain II and retaining the 11 amino acid furin cleavage site followed by a GGS spacer results in a RIT (SS1-LR-GGS) (Fig.	('SS1P', 'Chemical', 'MESH:C474515', (36, 40))	('deletion', 'Var', (44, 52))	('amino acid furin', 'Chemical', '-', (103, 119))	('SS1', 'Gene', '3123', (177, 180))	('SS1', 'Gene', '3123', (36, 39))	('RIT', 'Chemical', '-', (172, 175))	('SS1', 'Gene', (177, 180))	('SS1', 'Gene', (36, 39))
11691	26443804	To construct LMB-T20 we introduced six mutations (R427A, F443A, L477H, R494A, R505A and L552E) into SS1-LR-GGS (Fig.	('R427A', 'Var', (50, 55))	('LMB-T20', 'Chemical', '-', (13, 20))	('F443A', 'Mutation', 'p.F443A', (57, 62))	('F443A', 'Var', (57, 62))	('R494A', 'Mutation', 'p.R494A', (71, 76))	('SS1', 'Gene', '3123', (100, 103))	('L552E', 'Var', (88, 93))	('L477H', 'Mutation', 'p.L477H', (64, 69))	('R505A', 'Mutation', 'p.R505A', (78, 83))	('SS1', 'Gene', (100, 103))	('L477H', 'Var', (64, 69))	('R494A', 'Var', (71, 76))	('R505A', 'Var', (78, 83))	('L552E', 'Mutation', 'p.L552E', (88, 93))	('R427A', 'Mutation', 'p.R427A', (50, 55))
11692	26443804	These mutations were previously shown to reduce T cell epitopes in an immunotoxin targeting CD22.	('CD22', 'Gene', (92, 96))	('T cell epitopes', 'MPA', (48, 63))	('CD22', 'Gene', '933', (92, 96))	('reduce T cell', 'Phenotype', 'HP:0005403', (41, 54))	('reduce', 'NegReg', (41, 47))	('mutations', 'Var', (6, 15))
11694	26443804	To quantify the decrease in T cell epitope content and to determine if the changes in six amino acids that diminish the T cell epitope content could have affected the processing of the protein antigen (LMB-T20) or produced new T cell epitopes, we mapped the T cell epitopes in LMB-T20 and compared the results to the epitopes in SS1P.	('LMB-T20', 'Chemical', '-', (202, 209))	('LMB-T20', 'Chemical', '-', (277, 284))	('changes', 'Var', (75, 82))	('processing', 'MPA', (167, 177))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('LMB-T20', 'Gene', (277, 284))	('affected', 'Reg', (154, 162))	('SS1P', 'Chemical', 'MESH:C474515', (329, 333))
11696	26443804	After 14 days of in vitro expansion, the cells that were stimulated with SS1P were re-stimulated with 111 peptides spanning the sequence of PE38 and the cells that were stimulated with LMB-T20 were re-stimulated with 76 peptides spanning the entire sequence of LMB-T20.	('PE38', 'Var', (140, 144))	('LMB-T20', 'Chemical', '-', (185, 192))	('LMB-T20', 'Chemical', '-', (261, 268))	('SS1P', 'Var', (73, 77))	('SS1P', 'Chemical', 'MESH:C474515', (73, 77))
11699	26443804	However, in cells that were stimulated with LMB-T20 there was an 81% reduction in the total response (p>0.0001 in 2-way ANOVA) from a total of 105 positive responses to SS1P to a total of 25 responses to LMB-T20.	('SS1P', 'Chemical', 'MESH:C474515', (169, 173))	('LMB-T20', 'Chemical', '-', (204, 211))	('LMB-T20', 'Chemical', '-', (44, 51))	('reduction', 'NegReg', (69, 78))	('LMB-T20', 'Var', (44, 51))
11701	26443804	To evaluate the ability of LMB-T20 to induce a T cell response, we directly stimulated PBMC from 12 donors (with various DRB1 HLA haplotypes) with SS1P, LMB-T20 or KLH in ELISpot plates.	('DRB1', 'Gene', (121, 125))	('DRB1', 'Gene', '3123', (121, 125))	('LMB-T20', 'Chemical', '-', (27, 34))	('LMB-T20', 'Chemical', '-', (153, 160))	('SS1P', 'Chemical', 'MESH:C474515', (147, 151))	('LMB-T20', 'Var', (153, 160))	('SS1P', 'Var', (147, 151))	('donor', 'Species', '9606', (100, 105))
11704	26443804	SS1P also produced a strong T cell response, which was significantly greater than the no protein control for both IFNgamma and IL-2 (p<0.0001 and 0.001 respectively in Freidman test with Dunn's multiple comparisons) with a median of 702 IFNgamma SFC/1x106 and 226 IL-2 SFC/1x106 in SS1P stimulated cells and a median of 10 IFNgamma SFC/1x106 and 19 IL-2 SFC/1x106 in the no protein control.	('IFNgamma SFC/1x106', 'Gene', (237, 255))	('IFNgamma SFC/1x106', 'Gene', (323, 341))	('IFNgamma', 'Gene', (237, 245))	('SS1P', 'Var', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('374', '381'))	('IFNgamma', 'Gene', '3458', (237, 245))	('IFNgamma', 'Gene', (323, 331))	('T cell response', 'MPA', (28, 43))	('IFNgamma', 'Gene', '3458', (323, 331))	('greater', 'PosReg', (69, 76))	('IL-2', 'Gene', (264, 268))	('SS1P', 'Chemical', 'MESH:C474515', (282, 286))	('IFNgamma', 'Gene', (114, 122))	('IL-2', 'Gene', (349, 353))	('IL-2', 'Gene', (127, 131))	('IFNgamma', 'Gene', '3458', (114, 122))	('IL-2', 'molecular_function', 'GO:0005134', ('127', '131'))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('IL-2', 'molecular_function', 'GO:0005134', ('349', '353'))	('IL-2', 'Gene', '3558', (264, 268))	('IL-2', 'molecular_function', 'GO:0005134', ('264', '268'))	('IFNgamma SFC/1x106', 'Gene', '3439', (323, 341))	('IFNgamma SFC/1x106', 'Gene', '3439', (237, 255))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('IL-2', 'Gene', '3558', (349, 353))	('IL-2', 'Gene', '3558', (127, 131))
11712	26443804	We found that LMB-T20 was very cytotoxic to all five cell lines and almost as active as SS1-LR-GGS that has no mutations in domain III.	('SS1', 'Gene', (88, 91))	('cytotoxic', 'CPA', (31, 40))	('LMB-T20', 'Chemical', '-', (14, 21))	('LMB-T20', 'Var', (14, 21))	('SS1', 'Gene', '3123', (88, 91))
11717	26443804	We found that LMB-T20 was more active than SS1P in cytotoxicity assays on all four patient derived lines (Supplementary Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('LMB-T20', 'Chemical', '-', (14, 21))	('SS1P', 'Chemical', 'MESH:C474515', (43, 47))	('LMB-T20', 'Var', (14, 21))	('cytotoxicity', 'Disease', (51, 63))	('patient', 'Species', '9606', (83, 90))
11726	26443804	We observed a significant delay in tumor growth starting on day 9 (p<0.05 in Mann Whitney test) in the mice treated with LMB-T20.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('delay', 'NegReg', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mice', 'Species', '10090', (103, 107))	('LMB-T20', 'Chemical', '-', (121, 128))	('tumor', 'Disease', (35, 40))	('LMB-T20', 'Var', (121, 128))
11730	26443804	On day 55, a significant difference between the treatment groups was observed (p<0.03 Mann Whitney test), with an average tumor size of 110mm3 for tumors treated with LMB-T20 and 168mm3 for tumors treated with vehicle.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('LMB-T20', 'Var', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (190, 196))	('LMB-T20', 'Chemical', '-', (167, 174))	('tumor', 'Disease', (122, 127))
11732	26443804	Mice that were inoculated with patients cells NCI-Meso21 had a better anti-tumor response compared to NCI-Meso16.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('patients', 'Species', '9606', (31, 39))	('better', 'PosReg', (63, 69))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NCI-Meso21', 'Var', (46, 56))	('tumor', 'Disease', (75, 80))
11734	26443804	Mice were treated daily starting day 88 intravenously with 5mg/kg of LMB-T20 or vehicle and a significant decrease in tumor size was observed as early as day 90, in which the average tumor size in LMB-T20 treated mice was 87mm3 while the vehicle treated tumors grew to 120mm3 (p<0.008 Mann Whitney test).	('tumors', 'Disease', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('LMB-T20', 'Chemical', '-', (69, 76))	('mice', 'Species', '10090', (213, 217))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('decrease', 'NegReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (183, 188))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('LMB-T20', 'Chemical', '-', (197, 204))	('LMB-T20', 'Var', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
11741	26443804	T cell activation assays show that LMB-T20 has greatly decreased immunogenicity compared with its parent SS1P that contains a 38-kDa form of the toxin.	('SS1P', 'Chemical', 'MESH:C474515', (105, 109))	('LMB-T20', 'Chemical', '-', (35, 42))	('LMB-T20', 'Var', (35, 42))	('decreased', 'NegReg', (55, 64))	('immunogenicity', 'MPA', (65, 79))	('T cell activation', 'biological_process', 'GO:0042110', ('0', '17'))
11742	26443804	Despite this very large decrease in immunogenicity, LMB-T20 is significantly more active than SS1P in killing mesothelin expressing cancer cell lines and in inducing regressions of mesothelin-expressing tumors in mice.	('SS1P', 'Chemical', 'MESH:C474515', (94, 98))	('immunogenicity', 'MPA', (36, 50))	('cancer', 'Disease', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('mice', 'Species', '10090', (213, 217))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('LMB-T20', 'Chemical', '-', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('regressions', 'CPA', (166, 177))	('LMB-T20', 'Var', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('inducing', 'Reg', (157, 165))
11820	31692820	Although vimentine is always positive in sarcomas, whereas cytokeratins are weakly and focally expressd, a vascular tumor should be suspected when diffuse and intense vimentin positivity with negativity of mesothelioma markers (ex.	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('mesothelioma', 'Disease', (206, 218))	('vimentin', 'cellular_component', 'GO:0045098', ('167', '175'))	('sarcomas', 'Disease', (41, 49))	('vimentin', 'Gene', '7431', (9, 17))	('negativity', 'Var', (192, 202))	('vimentin', 'Gene', (9, 17))	('vascular tumor', 'Disease', 'MESH:D019043', (107, 121))	('positivity', 'Var', (176, 186))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('vimentin', 'Gene', '7431', (167, 175))	('vascular tumor', 'Disease', (107, 121))	('vascular tumor', 'Phenotype', 'HP:0100742', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('vimentin', 'cellular_component', 'GO:0045099', ('167', '175'))	('vimentin', 'Gene', (167, 175))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
11841	29988936	Patients and families with germline BAP1 mutation are predisposed to familial cancers including UM, mesothelioma, cutaneous melanoma (CM), renal cell carcinoma (RCC), and others.	('CM', 'Phenotype', 'HP:0012056', (134, 136))	('renal cell carcinoma', 'Disease', (139, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('BAP1', 'Gene', '8314', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('mutation', 'Var', (41, 49))	('Patients', 'Species', '9606', (0, 8))	('RCC', 'Disease', (161, 164))	('predisposed', 'Reg', (54, 65))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('familial cancers', 'Disease', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('familial cancers', 'Disease', 'MESH:D009369', (69, 85))	('BAP1', 'Gene', (36, 40))	('CM', 'Disease', 'MESH:D009202', (134, 136))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mesothelioma', 'Disease', (100, 112))	('cutaneous melanoma', 'Disease', (114, 132))	('germline', 'Var', (27, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (139, 159))
11842	29988936	Clinicians should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (119, 123))	('patients', 'Species', '9606', (155, 163))	('BAP1', 'Gene', '8314', (59, 63))	('BAP1', 'Gene', (119, 123))
11843	29988936	The ability of BAP1 gene mutation to cause multiple tumor types and high penetrance in carriers suggests that this gene has an important role for influencing cancer cell growth.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutation', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('multiple tumor', 'Disease', (43, 57))	('multiple tumor', 'Disease', 'MESH:D009369', (43, 57))	('BAP1', 'Gene', '8314', (15, 19))	('cancer', 'Disease', (158, 164))	('cell growth', 'biological_process', 'GO:0016049', ('165', '176'))	('BAP1', 'Gene', (15, 19))	('cause', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
11844	29988936	With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving BAP1 and other gene mutations, it is possible to improve the outcome of this malignant cancer.	('BAP1', 'Gene', (130, 134))	('improve', 'PosReg', (179, 186))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (150, 159))	('BAP1', 'Gene', '8314', (130, 134))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
11858	29988936	Therefore, patients with BAP1 germline mutation are at risk for several malignant tumors and should be counseled regarding cancer risk for patient and family members as well as routinely monitored.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (82, 88))	('BAP1', 'Gene', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('germline mutation', 'Var', (30, 47))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (123, 129))	('risk', 'Reg', (55, 59))	('patients', 'Species', '9606', (11, 19))	('BAP1', 'Gene', '8314', (25, 29))	('patient', 'Species', '9606', (139, 146))
11879	29988936	Genetic assessment and chromosome microarray on the L and W families disclosed alteration in chromosome region 3p21 in both mesothelioma and UM cases.	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('mesothelioma', 'Disease', (124, 136))	('alteration', 'Var', (79, 89))	('chromosome region', 'cellular_component', 'GO:0098687', ('93', '110'))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))
11881	29988936	Since then, mutations in BAP1 gene has been confirmed in mesothelioma, UM, CM, and RCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('mesothelioma', 'Disease', (57, 69))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('BAP1', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('confirmed', 'Reg', (44, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('CM', 'Disease', 'MESH:D009202', (75, 77))	('BAP1', 'Gene', '8314', (25, 29))	('CM', 'Phenotype', 'HP:0012056', (75, 77))
11886	29988936	recognized that germline BAP1 mutation was associated with a benign atypical skin melanocytic tumor.	('germline', 'Var', (16, 24))	('BAP1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (30, 38))	('associated', 'Reg', (43, 53))	('BAP1', 'Gene', '8314', (25, 29))	('skin melanocytic tumor', 'Disease', (77, 99))	('skin melanocytic tumor', 'Disease', 'MESH:D012878', (77, 99))
11889	29988936	Unlike Spitz nevus, MBAIT nearly always demonstrate B-Raf Proto-Oncogene (BRAF) mutation.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutation', 'Var', (80, 88))	('nevus', 'Phenotype', 'HP:0003764', (13, 18))	('B-Raf Proto-Oncogene', 'Gene', '673', (52, 72))	('B-Raf Proto-Oncogene', 'Gene', (52, 72))
11892	29988936	Instead of the term MBAITs, some employ the term "BAPomas" to describe this precursor skin lesion that occurs within families having germline BAP1 mutation.	('germline', 'Var', (133, 141))	('BAP1', 'Gene', '8314', (142, 146))	('skin lesion', 'Disease', 'MESH:D012871', (86, 97))	('mutation', 'Var', (147, 155))	('skin lesion', 'Disease', (86, 97))	('BAP1', 'Gene', (142, 146))
11894	29988936	reported 174 patients with germline BAP1 mutation and found that 130 (75%) developed at least one of the five main tumors, including UM (31%), MMe (22%), MBAIT (18%), CM (13%), and RCC (10%).	('MMe', 'Disease', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('MBAIT', 'Disease', (154, 159))	('patients', 'Species', '9606', (13, 21))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('BAP1', 'Gene', '8314', (36, 40))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('mutation', 'Var', (41, 49))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('CM', 'Phenotype', 'HP:0012056', (167, 169))	('MMe', 'Phenotype', 'HP:0100001', (143, 146))	('developed', 'PosReg', (75, 84))	('BAP1', 'Gene', (36, 40))	('RCC', 'Disease', (181, 184))	('RCC', 'Disease', 'MESH:C538614', (181, 184))
11906	29988936	The survival rate in persons with BAP1-related MMe may be significantly longer compared to sporadic MMe as several reports have documented that patients with germline BAP1 mutation showed a sevenfold longer overall survival compared to those with sporadic MMe.	('BAP1', 'Gene', (34, 38))	('persons', 'Species', '9606', (21, 28))	('MMe', 'Phenotype', 'HP:0100001', (256, 259))	('overall', 'MPA', (207, 214))	('mutation', 'Var', (172, 180))	('patients', 'Species', '9606', (144, 152))	('BAP1', 'Gene', '8314', (167, 171))	('MMe', 'Phenotype', 'HP:0100001', (47, 50))	('longer', 'PosReg', (200, 206))	('MMe', 'Phenotype', 'HP:0100001', (100, 103))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', (167, 171))
11912	29988936	Several different alterations in the BAP1 gene have been described, including large deletions of exons leading to loss of the N-terminal region, focal deletions, frameshift mutations due to insertions or deletions, splice site mutations, and base substitutions leading to non-sense and missense mutations.	('focal deletions', 'Var', (145, 160))	('base substitutions', 'Var', (242, 260))	('non-sense', 'MPA', (272, 281))	('loss', 'NegReg', (114, 118))	('splice site mutations', 'Var', (215, 236))	('frameshift mutations', 'Var', (162, 182))	('BAP1', 'Gene', '8314', (37, 41))	('insertions', 'Var', (190, 200))	('missense mutations', 'Var', (286, 304))	('deletions', 'Var', (204, 213))	('BAP1', 'Gene', (37, 41))	('the N-terminal region', 'MPA', (122, 143))	('deletions', 'Var', (84, 93))
11913	29988936	In various tumors, including RCC, mesothelioma, metastasizing UM, and non-small cell lung cancer, the BAP1 gene is commonly lost by chromosomal deletion, and more than 70% of reported germline BAP1 mutations are truncation.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RCC', 'Disease', (29, 32))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('BAP1', 'Gene', '8314', (102, 106))	('mesothelioma', 'Disease', (34, 46))	('mutations', 'Var', (198, 207))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('lost', 'NegReg', (124, 128))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (70, 96))	('truncation', 'Var', (212, 222))	('BAP1', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('BAP1', 'Gene', '8314', (193, 197))	('non-small cell lung cancer', 'Disease', (70, 96))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('tumors', 'Disease', (11, 17))	('BAP1', 'Gene', (193, 197))
11915	29988936	1), while missense mutations affect the ubiquitin hydrolase function of BAP1.	('ubiquitin hydrolase function', 'MPA', (40, 68))	('BAP1', 'Gene', '8314', (72, 76))	('affect', 'Reg', (29, 35))	('missense mutations', 'Var', (10, 28))	('BAP1', 'Gene', (72, 76))	('ubiquitin', 'molecular_function', 'GO:0031386', ('40', '49'))
11916	29988936	In fact, for reasons that are unclear, all four main cancers of BAP1-TPDS have been observed with all classes of mutations.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('observed', 'Reg', (84, 92))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BAP1', 'Gene', '8314', (64, 68))	('BAP1', 'Gene', (64, 68))
11917	29988936	Therefore, available data suggest no distinct genotype-phenotype correlation between location or type of the mutations and the type of cancers in patients.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (146, 154))
11921	29988936	This cancer syndrome follows an AD inheritance pattern, and each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant; however, penetrance appears to be incomplete, and the types of BAP1-related tumors can vary among different members of the same family.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', '8314', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('BAP1', 'Gene', (226, 230))	('cancer syndrome', 'Disease', 'MESH:D009369', (5, 20))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('BAP1', 'Gene', (138, 142))	('variant', 'Var', (154, 161))	('cancer syndrome', 'Disease', (5, 20))	('BAP1', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('child', 'Species', '9606', (65, 70))	('BAP1', 'Gene', '8314', (226, 230))
11923	29988936	Newer evidence suggests that penetrance of BAP1 mutation is fairly high, and more than 80% of gene carriers are ultimately affected by at least one type of cancer.	('BAP1', 'Gene', (43, 47))	('cancer', 'Disease', (156, 162))	('affected', 'Reg', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutation', 'Var', (48, 56))
11925	29988936	The proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown.	('caused', 'Reg', (28, 34))	('BAP1', 'Gene', '8314', (18, 22))	('variant', 'Var', (59, 66))	('BAP1', 'Gene', (18, 22))
11928	29988936	Also, the mutational load in UM tumors is low.	('mutational', 'Var', (10, 20))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
11929	29988936	Therefore, recurrent mutations in genes and chromosomal abnormalities in UM are likely to be specific for tumor progression rather than random event.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (44, 69))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('chromosomal abnormalities', 'Disease', (44, 69))	('tumor', 'Disease', (106, 111))	('mutations', 'Var', (21, 30))
11930	29988936	The association between deletion in chromosome 3 (monosomy 3) and metastatic death in UM was first described by Prescher et al and later confirmed by our team in Philadelphia in a large cohort of 1059 patients.	('patients', 'Species', '9606', (201, 209))	('death', 'Disease', 'MESH:D003643', (77, 82))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('death', 'Disease', (77, 82))	('Philadelphia', 'Disease', 'MESH:D010677', (162, 174))	('Philadelphia', 'Disease', (162, 174))	('deletion', 'Var', (24, 32))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
11932	29988936	This finding indicates that greater tumor size is correlated with greater single-chromosome mutational profile.	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('single-chromosome mutational', 'Var', (74, 102))	('tumor', 'Disease', (36, 41))
11934	29988936	The GEP of class 1A and 1B tumors resembles normal uveal melanocytes and low-grade uveal melanocytic tumors with 2 and 21% 5-years metastatic risk respectively, whereas the GEP of class 2 tumors is associated with a 72% 5-year metastatic risk, has correlated with chromosome 3 alterations, and has shown reduced expression of melanocytic genes.	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('reduced', 'NegReg', (304, 311))	('expression', 'MPA', (312, 322))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('1B tumors', 'Disease', 'MESH:C565748', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('uveal melanocytic tumors', 'Disease', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (83, 107))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('1B tumors', 'Disease', (24, 33))	('tumors', 'Disease', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('melanocytic genes', 'Gene', (326, 343))	('tumors', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', (27, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('264', '274'))	('alterations', 'Var', (277, 288))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (83, 107))	('metastatic', 'CPA', (227, 237))
11935	29988936	Several gene mutations in UM have been described, and these do not resemble other melanoma subtypes such as CM.	('CM', 'Disease', 'MESH:D009202', (108, 110))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CM', 'Phenotype', 'HP:0012056', (108, 110))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('mutations', 'Var', (13, 22))
11938	29988936	GNAQ/GNA11 mutations do not have known prognostic value, and they can be found in benign nevi and occur in similar frequencies in metastatic and non-metastatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (5, 10))	('benign nevi', 'Disease', (82, 93))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('occur', 'Reg', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
11939	29988936	Mutations in other driver genes are likely to arise later in tumor development and have greater importance for patient outcome (Fig.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patient', 'Species', '9606', (111, 118))	('tumor', 'Disease', (61, 66))
11940	29988936	BAP1 mutation is associated with monosomy 3 or class 2 GEP tumors and impart poor survival.	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('monosomy 3', 'Disease', (33, 43))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
11941	29988936	The frequency of somatic BAP1 mutation in primary UM has been estimated to be approximately 40% which closely resembles chromosome 3 status and strongly correlates with metastatic disease in UM.	('BAP1', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('BAP1', 'Gene', '8314', (25, 29))	('metastatic disease', 'Disease', (169, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))	('correlates with', 'Reg', (153, 168))
11944	29988936	Mutations in this gene have not been detected in disomy 3 of UM, but other mutations including those in EIF1AX (48%) and/or SF3B1 (29%) genes have been identified.	('EIF1AX', 'Gene', (104, 110))	('SF3B1', 'Gene', '23451', (124, 129))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', (124, 129))	('EIF1AX', 'Gene', '1964', (104, 110))
11949	29988936	In the presence of BAP1 germline mutations, the risk for UM occurrence in carriers is estimated at up to 29%.	('BAP1', 'Gene', '8314', (19, 23))	('germline mutations', 'Var', (24, 42))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('BAP1', 'Gene', (19, 23))
11950	29988936	The prevalence of germline BAP1 mutations rate among the unselected population of UM cases is about 2-3%.	('BAP1', 'Gene', (27, 31))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('mutations', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (27, 31))
11951	29988936	It is predicted that germline BAP1 mutations are present in about 22% of FUM families overall.	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (30, 34))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('mutations', 'Var', (35, 44))
11954	29988936	Conversely, with additional family history of CM, MMe, and RCC, the chance of BAP1 germline mutations can be approximately 50%.	('MMe', 'Phenotype', 'HP:0100001', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('BAP1', 'Gene', '8314', (78, 82))	('CM', 'Disease', 'MESH:D009202', (46, 48))	('germline mutations', 'Var', (83, 101))	('CM', 'Phenotype', 'HP:0012056', (46, 48))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('BAP1', 'Gene', (78, 82))
11957	29988936	showed that FUM families without BAP1 mutation have lower rate of RCC and MMe compared to those with BAP1 mutations.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('MMe', 'CPA', (74, 77))	('BAP1', 'Gene', '8314', (101, 105))	('MMe', 'Phenotype', 'HP:0100001', (74, 77))	('BAP1', 'Gene', '8314', (33, 37))	('lower', 'NegReg', (52, 57))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('BAP1', 'Gene', (101, 105))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))
11958	29988936	Despite AD pattern inheritance of BAP1 gene mutations, FUM is indeed uncommon, and it rarely involve more than 2-3 family members.	('BAP1', 'Gene', (34, 38))	('FUM', 'Disease', (55, 58))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
11960	29988936	While BAP1 is the most frequent known genetic cause of FUM, evidence shows less than 25% of families are positive for germline BAP1 mutations.	('BAP1', 'Gene', (127, 131))	('BAP1', 'Gene', (6, 10))	('mutations', 'Var', (132, 141))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', '8314', (6, 10))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
11962	29988936	Patients with germline BAP1 mutations and UM are implicated in this hereditary cancer syndrome (BAP1-TPDS).	('BAP1', 'Gene', (23, 27))	('hereditary cancer syndrome', 'Disease', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', '8314', (23, 27))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (68, 94))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (96, 100))	('mutations', 'Var', (28, 37))	('implicated', 'Reg', (49, 59))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
11966	29988936	Ciliary body involvement is more often noted in patients with BAP1 mutations (75% vs 21.6%).	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('Ciliary', 'Disease', (0, 7))	('patients', 'Species', '9606', (48, 56))
11968	29988936	Metastatic disease developed more frequently in BAP1 germline mutations group compared to the control group (71% vs 18%).	('BAP1', 'Gene', '8314', (48, 52))	('germline mutations', 'Var', (53, 71))	('BAP1', 'Gene', (48, 52))	('Metastatic disease', 'Disease', 'MESH:C538445', (0, 18))	('Metastatic disease', 'Disease', (0, 18))
11969	29988936	Generally, BAP1 germline mutation is associated with a 4-fold increased risk of metastasis and poor survival in patients.	('metastasis', 'CPA', (80, 90))	('poor survival', 'CPA', (95, 108))	('BAP1', 'Gene', '8314', (11, 15))	('germline mutation', 'Var', (16, 33))	('patients', 'Species', '9606', (112, 120))	('BAP1', 'Gene', (11, 15))
11972	29988936	In UM patients with germline BAP1 gene mutation, the mean survival is 4.74 years in comparison with 9.97 years in patients with normal BAP1 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('BAP1', 'Gene', '8314', (135, 139))	('germline', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (29, 33))	('patients', 'Species', '9606', (6, 14))	('BAP1', 'Gene', (135, 139))	('patients', 'Species', '9606', (114, 122))	('BAP1', 'Gene', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
11973	29988936	Patients at high risk for harboring germline BAP1 mutations are offered BAP1 sequencing and genetic counseling.	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (72, 76))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', (72, 76))	('Patients', 'Species', '9606', (0, 8))	('germline', 'Var', (36, 44))	('BAP1', 'Gene', '8314', (45, 49))
11975	29988936	Genetic assessment and testing for BAP1 mutations should be taken into account for patients with two or more of primary tumors (UM, RCC, MMe, and CM) in themselves or first-degree relatives.	('primary tumors', 'Disease', 'MESH:D009369', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('CM', 'Phenotype', 'HP:0012056', (146, 148))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('BAP1', 'Gene', '8314', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('mutations', 'Var', (40, 49))	('CM', 'Disease', 'MESH:D009202', (146, 148))	('BAP1', 'Gene', (35, 39))	('MMe', 'Phenotype', 'HP:0100001', (137, 140))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('primary tumors', 'Disease', (112, 126))	('MMe', 'Disease', (137, 140))
11977	29988936	Germline BAP1 mutation test should be advised when a patient is diagnosed with UM at an early age (younger than 30 years) or one of the following is present in the patients or first relatives: (1) history of two UM cases or more in a family, (2) patients with UM and history of at least one other primary tumor (CM, RCC, and MMe) in themselves, (3) patients with UM and history of at least 2 other primary tumors in first- or second-degree relatives (there is controversy about exclusion of families with only multiple CM cases, given its frequency in the general population).	('patients', 'Species', '9606', (246, 254))	('CM', 'Phenotype', 'HP:0012056', (312, 314))	('MMe', 'Phenotype', 'HP:0100001', (325, 328))	('BAP1', 'Gene', (9, 13))	('tumor', 'Disease', (305, 310))	('patient', 'Species', '9606', (246, 253))	('primary tumors', 'Disease', (398, 412))	('patient', 'Species', '9606', (349, 356))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('CM', 'Disease', 'MESH:D009202', (519, 521))	('tumor', 'Disease', (406, 411))	('patients', 'Species', '9606', (164, 172))	('UM', 'Phenotype', 'HP:0007716', (363, 365))	('patient', 'Species', '9606', (53, 60))	('CM', 'Disease', 'MESH:D009202', (312, 314))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('patient', 'Species', '9606', (164, 171))	('primary tumors', 'Disease', 'MESH:D009369', (398, 412))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('RCC', 'Phenotype', 'HP:0005584', (316, 319))	('RCC', 'Disease', (316, 319))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('patients', 'Species', '9606', (349, 357))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('BAP1', 'Gene', '8314', (9, 13))	('CM', 'Phenotype', 'HP:0012056', (519, 521))	('mutation', 'Var', (14, 22))	('UM', 'Phenotype', 'HP:0007716', (260, 262))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('RCC', 'Disease', 'MESH:C538614', (316, 319))	('UM', 'Phenotype', 'HP:0007716', (212, 214))
11978	29988936	Also, germline BAP1 mutations should be suspected when a patient has multifocal UM.	('patient', 'Species', '9606', (57, 64))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
11980	29988936	Once the germline BAP1 pathogenic variant has been identified in a family, all family members should be informed about the details of this syndrome.	('BAP1', 'Gene', '8314', (18, 22))	('pathogenic', 'Reg', (23, 33))	('variant', 'Var', (34, 41))	('BAP1', 'Gene', (18, 22))
11986	29988936	If a UM is found in BAP1 mutation carriers, it should be managed as a high-risk tumor, and the ocular oncologist should monitor for systemic metastasis, including magnetic resonance imaging (MRI) of the abdomen and liver every 3-6 months and chest X-ray every 6-12 months.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BAP1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutation', 'Var', (25, 33))	('tumor', 'Disease', (80, 85))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('BAP1', 'Gene', '8314', (20, 24))
11987	29988936	The discovery of GNAQ/11 and BAP1 mutations in UM provides an opportunity for targeted therapy of metastatic disease.	('metastatic disease', 'Disease', (98, 116))	('GNAQ', 'Gene', (17, 21))	('BAP1', 'Gene', '8314', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('GNAQ', 'Gene', '2776', (17, 21))
11989	29988936	Therapeutic targeting of BAP1 mutation poses a different challenge.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))
11994	29988936	About 80% of UM have oncogenic mutations for GNAQ or GNA11 genes, and it appears to be early or perhaps an initiating event for malignant transformation because these mutations can be found in nevus as well and do not correlate with survival.	('oncogenic', 'CPA', (21, 30))	('mutations', 'Var', (31, 40))	('GNA11', 'Gene', (53, 58))	('nevus', 'Phenotype', 'HP:0003764', (193, 198))	('GNA11', 'Gene', '2767', (53, 58))	('GNAQ', 'Gene', (45, 49))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('GNAQ', 'Gene', '2776', (45, 49))
11995	29988936	On the contrary, BAP1 inactivation mutation is a late event in tumor progression, beyond which metastasis and death await.	('tumor', 'Disease', (63, 68))	('inactivation mutation', 'Var', (22, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (17, 21))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', (17, 21))
11996	29988936	One strategy is to inhibit downstream signaling molecules that are activated by GNAQ/11 mutations.	('inhibit', 'NegReg', (19, 26))	('mutations', 'Var', (88, 97))	('GNAQ', 'Gene', '2776', (80, 84))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('GNAQ', 'Gene', (80, 84))
11997	29988936	These include mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) that is shown to be upregulated in GNAQ/GNA11 mutated tumors.	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('mutated', 'Var', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('GNAQ', 'Gene', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('MEK', 'Gene', (93, 96))	('MEK', 'Gene', '5609', (93, 96))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('GNA11', 'Gene', (138, 143))	('upregulated', 'PosReg', (118, 129))	('tumors', 'Disease', (152, 158))	('mitogen-activated', 'Enzyme', (14, 31))	('GNA11', 'Gene', '2767', (138, 143))	('extracellular', 'cellular_component', 'GO:0005576', ('54', '67'))	('GNAQ', 'Gene', '2776', (133, 137))
11999	29988936	Clinician should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.	('BAP1', 'Gene', (58, 62))	('patients', 'Species', '9606', (154, 162))	('mutation', 'Var', (63, 71))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (118, 122))	('BAP1', 'Gene', '8314', (58, 62))
12002	29988936	With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving GNAQ/GNA11, BAP1, EIF1AX, SF3B1 mutations and epigenetic mechanisms, it is possible to improve the outcome of this malignant cancer.	('GNA11', 'Gene', '2767', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('mutations', 'Var', (162, 171))	('EIF1AX', 'Gene', '1964', (148, 154))	('EIF1AX', 'Gene', (148, 154))	('BAP1', 'Gene', '8314', (142, 146))	('improve', 'PosReg', (217, 224))	('SF3B1', 'Gene', '23451', (156, 161))	('GNAQ', 'Gene', (130, 134))	('BAP1', 'Gene', (142, 146))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('GNA11', 'Gene', (135, 140))	('GNAQ', 'Gene', '2776', (130, 134))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('SF3B1', 'Gene', (156, 161))	('epigenetic', 'Var', (176, 186))
12197	25006323	In case of LHP malignancies, the most probable carcinogens were pure benzene (27.5%), impurity of benzene in a mixture (56.9%), and ionizing radiation (8.0%).	('pure', 'molecular_function', 'GO:0034023', ('64', '68'))	('benzene', 'Chemical', 'MESH:D001554', (98, 105))	('LHP malignancies', 'Disease', (11, 27))	('LHP malignancies', 'Disease', 'MESH:D009369', (11, 27))	('benzene', 'Chemical', 'MESH:D001554', (69, 76))	('impurity', 'Var', (86, 94))
12419	32608142	A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (257, 280))	('Malignant Mesothelioma', 'Disease', (51, 73))	('Aurora kinase A', 'Gene', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Alisertib', 'Chemical', 'MESH:C550258', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (31, 38))	('malignant pleural or peritoneal mesothelioma', 'Disease', 'MESH:C562839', (236, 280))	('MLN8237', 'Var', (31, 38))	('patients', 'Species', '9606', (209, 217))	('tumor', 'Disease', (169, 174))	('Aurora kinase A', 'Gene', '6790', (93, 108))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (51, 73))	('disease', 'Disease', (140, 147))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (51, 73))	('malignant pleural or peritoneal mesothelioma', 'Disease', (236, 280))
12420	32608142	In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.	('alisertib', 'Chemical', 'MESH:C550258', (107, 116))	('gain', 'PosReg', (42, 46))	('MYC', 'Gene', '4609', (26, 29))	('gene amplification', 'Var', (50, 68))	('MYC', 'Gene', (26, 29))	('copy-number', 'Var', (30, 41))	('patient', 'Species', '9606', (170, 177))
12425	32608142	Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number.	('copy number', 'Var', (152, 163))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('MYC', 'Gene', (148, 151))	('toxicity', 'Disease', (104, 112))	('MYC', 'Gene', '4609', (148, 151))
12443	32608142	An additional secondary endpoint related to MYC copy number identified between two and five patients with tumors bearing MYC copy number gain/amplification, depending on FISH criteria, but there was no correlation with response, duration of response, or survival in this small data set.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('MYC', 'Gene', '4609', (44, 47))	('tumors', 'Disease', (106, 112))	('MYC', 'Gene', (121, 124))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('patients', 'Species', '9606', (92, 100))	('gain/amplification', 'PosReg', (137, 155))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MYC', 'Gene', (44, 47))	('copy number', 'Var', (125, 136))	('MYC', 'Gene', '4609', (121, 124))
12452	32608142	Alisertib, also known as MLN8237, is a selective small molecule inhibitor of Aurora A kinase that has shown modest antitumor activity in a number of clinical settings [7].	('tumor', 'Disease', (119, 124))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('MLN8237', 'Var', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
12456	32608142	Overexpression of Aurora kinases and/or MYC is common in malignant mesothelioma, and in vitro inhibition of Aurora kinases leads to cell growth arrest in mesothelioma cell line models [2, 4, 12, 13, 14].	('malignant mesothelioma', 'Disease', 'MESH:C562839', (57, 79))	('MYC', 'Gene', '4609', (40, 43))	('mesothelioma', 'Disease', (154, 166))	('growth arrest', 'Disease', 'MESH:D006323', (137, 150))	('growth arrest', 'Disease', (137, 150))	('cell growth', 'biological_process', 'GO:0016049', ('132', '143'))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (57, 79))	('malignant mesothelioma', 'Disease', (57, 79))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('growth arrest', 'Phenotype', 'HP:0001510', (137, 150))	('MYC', 'Gene', (40, 43))	('inhibition', 'Var', (94, 104))	('mesothelioma', 'Disease', (67, 79))
12471	32608142	Using four different FISH criteria for positivity, between two and five patient tumors were determined to have MYC copy number gain/amplification.	('copy number', 'Var', (115, 126))	('MYC', 'Gene', '4609', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MYC', 'Gene', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('patient', 'Species', '9606', (72, 79))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('gain/amplification', 'PosReg', (127, 145))
12487	30250045	Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser893 and Ser900.	('lectin', 'molecular_function', 'GO:0005530', ('31', '37'))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))	('Ser', 'cellular_component', 'GO:0005790', ('232', '235'))	('Ser900', 'Var', (243, 249))	('O-linked glycan', 'Chemical', '-', (190, 205))	('core', 'cellular_component', 'GO:0019013', ('183', '187'))	('Ser893', 'Chemical', '-', (232, 238))	('Ser', 'cellular_component', 'GO:0005790', ('243', '246'))	('soluble', 'cellular_component', 'GO:0005625', ('58', '65'))	('Ser', 'cellular_component', 'GO:0005790', ('127', '130'))	('Ser893', 'Var', (232, 238))	('Ser900', 'Chemical', '-', (243, 249))	('serine', 'Chemical', 'MESH:D012694', (215, 221))	('Ser897', 'Chemical', '-', (127, 133))
12507	30250045	Further, the epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan (disialyl T)-modified serine residues, Ser893 and Ser900.	('Ser897', 'Chemical', '-', (31, 37))	('core', 'cellular_component', 'GO:0019013', ('87', '91'))	('Ser', 'cellular_component', 'GO:0005790', ('160', '163'))	('Ser893', 'Var', (149, 155))	('Ser900', 'Var', (160, 166))	('disialyl T', 'Chemical', '-', (111, 121))	('Ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('Ser', 'cellular_component', 'GO:0005790', ('149', '152'))	('Ser900', 'Chemical', '-', (160, 166))	('serine', 'Chemical', 'MESH:D012694', (132, 138))	('O-linked glycan', 'Chemical', '-', (94, 109))	('Ser893', 'Chemical', '-', (149, 155))
12509	30250045	SKM9-2's recognition of glycan modification in this specific region of HEG1 could be useful for the precise detection and diagnosis of malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (135, 157))	('malignant mesothelioma', 'Disease', (135, 157))	('glycan', 'Chemical', 'MESH:D011134', (24, 30))	('glycan', 'Var', (24, 30))	('HEG1', 'Gene', (71, 75))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (135, 157))
12510	30250045	The SKM9-2 epitope was investigated using HEG1 deletion mutants transfected in HEK293T cells.	('deletion mutants', 'Var', (47, 63))	('HEG1', 'Gene', (42, 46))	('HEK293T', 'CellLine', 'CVCL:0063', (79, 86))
12514	30250045	A fused protein including most of the extracellular domain, which was deleted from Cys1089 to Phe1481 in HEG1, was recognized by SKM9-2 (named as Ex1-7), but proteins without the exon 7 region, deleted from Ser305 (Ex1-3) or Ile530 (Ex1-5), were not detected (Fig.	('Ser', 'cellular_component', 'GO:0005790', ('207', '210'))	('Cys1089', 'Var', (83, 90))	('Phe1481', 'Chemical', '-', (94, 101))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('Ex1-5', 'Gene', (233, 238))	('Ex1-3', 'Gene', '122786', (215, 220))	('extracellular', 'cellular_component', 'GO:0005576', ('38', '51'))	('Cys1089', 'Chemical', '-', (83, 90))	('Ex1-7', 'Gene', (146, 151))	('Ex1-5', 'Gene', '122786', (233, 238))	('Phe1481', 'Var', (94, 101))	('Ile530', 'Chemical', '-', (225, 231))	('Ser305', 'Chemical', '-', (207, 213))	('Ex1-3', 'Gene', (215, 220))	('Ex1-7', 'Gene', '122786', (146, 151))
12516	30250045	Two fused proteins including the region from Asp877 to Ser1085 (named as 7.5 and 7.6) were recognized by SKM9-2, but proteins with sequences beginning after Gln926 were not detected (7.7-7.9).	('Ser1085', 'Var', (55, 62))	('Asp877', 'Var', (45, 51))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('Asp877', 'Chemical', '-', (45, 51))	('Gln926', 'Chemical', '-', (157, 163))	('Ser1085', 'Chemical', '-', (55, 62))
12517	30250045	Therefore, the epitope of SKM9-2 was confined to the region from Asp877 to Glu925.	('Glu925', 'Var', (75, 81))	('SKM9-2', 'Gene', (26, 32))	('Asp877', 'Var', (65, 71))	('Glu925', 'Chemical', '-', (75, 81))	('Asp877', 'Chemical', '-', (65, 71))
12522	30250045	2a, truncation up to Glu892 on the N-terminal side did not affect SKM9-2 reactivity (7.62, and 7.621-7.623); whereas, the truncation on C-terminal side decreased SKM9-2 reactivity.	('Glu892', 'Chemical', '-', (21, 27))	('SKM9-2 reactivity', 'MPA', (162, 179))	('decreased', 'NegReg', (152, 161))	('truncation', 'Var', (122, 132))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('Glu892', 'Var', (21, 27))
12523	30250045	The Thr903-deleted mutant (7.626) was weakly recognized by SKM9-2 and a shorter peptide (7.627) was not bound (Fig.	('weakly', 'NegReg', (38, 44))	('7.626', 'Var', (27, 32))	('Thr903', 'Chemical', '-', (4, 10))	('Thr903-deleted', 'Var', (4, 18))
12527	30250045	3a, alanine substitution for Ser893, Lys894, Pro896, Ser897, Val899, or Ser900 resulted in the loss of recognition by SKM9-2.	('alanine substitution for Ser893', 'Var', (4, 35))	('recognition', 'MPA', (103, 114))	('Ser900', 'Chemical', '-', (72, 78))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Lys894', 'Var', (37, 43))	('Ser897', 'Var', (53, 59))	('Ser900', 'Var', (72, 78))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('loss', 'NegReg', (95, 99))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('Pro896', 'Var', (45, 51))	('alanine substitution for Ser893', 'SUBSTITUTION', 'None', (4, 35))	('Val899', 'Var', (61, 67))
12528	30250045	The replacement of Glu904 did not affect SKM9-2 binding.	('Glu904', 'Var', (19, 25))	('Glu904', 'Chemical', '-', (19, 25))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('binding', 'Interaction', (48, 55))
12529	30250045	The alanine-substituted mutant of Thr903 in the presence of Glu904 was recognized by SKM9-2, unlike the results of Thr903 deletion (7.626) in Fig.	('alanine-substituted', 'Var', (4, 23))	('Thr903', 'Chemical', '-', (115, 121))	('Glu904', 'Var', (60, 66))	('alanine', 'Chemical', 'MESH:D000409', (4, 11))	('Glu904', 'Chemical', '-', (60, 66))	('Thr903', 'Chemical', '-', (34, 40))	('Thr903', 'Gene', (34, 40))
12537	30250045	These results indicate that, in the SKM9-2 epitope region, three Ser/Thr residues (Ser893, Ser900, and Thr903), but not Ser895 and Ser897, are modified with O-linked glycans, which are probably core 1 or sialylated core 1 variants.	('Ser897', 'Chemical', '-', (131, 137))	('Ser', 'Chemical', 'MESH:D012694', (91, 94))	('Thr', 'Chemical', 'MESH:D013912', (69, 72))	('O-linked glycans', 'Protein', (157, 173))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))	('O-linked glycans', 'Chemical', '-', (157, 173))	('core', 'cellular_component', 'GO:0019013', ('215', '219'))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('Ser', 'cellular_component', 'GO:0005790', ('131', '134'))	('Ser', 'Chemical', 'MESH:D012694', (83, 86))	('Ser', 'Chemical', 'MESH:D012694', (131, 134))	('modified', 'Reg', (143, 151))	('core', 'cellular_component', 'GO:0019013', ('194', '198'))	('Ser', 'Chemical', 'MESH:D012694', (65, 68))	('Ser895', 'Chemical', '-', (120, 126))	('Ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('Ser900', 'Chemical', '-', (91, 97))	('Thr903', 'Chemical', '-', (103, 109))	('Ser893', 'Chemical', '-', (83, 89))	('Ser', 'Chemical', 'MESH:D012694', (120, 123))	('Ser', 'cellular_component', 'GO:0005790', ('65', '68'))	('Ser893', 'Var', (83, 89))	('Thr', 'Chemical', 'MESH:D013912', (103, 106))
12539	30250045	Alanine substitutions for Ser895 and Thr903 increased the affinity to SKM9-2 primarily through incremental changes to the association rate constants (SKMepmin1, 2, and 3).	('changes', 'Reg', (107, 114))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('association', 'Interaction', (122, 133))	('Alanine substitutions for Ser895 and Thr903', 'Mutation', 'p.S,T895,903A', (0, 43))	('Thr903', 'Var', (37, 43))	('Alanine substitutions for Ser895', 'Var', (0, 32))	('increased', 'PosReg', (44, 53))	('affinity', 'MPA', (58, 66))	('SKM9-2', 'Gene', (70, 76))	('Alanine substitutions for Ser895', 'SUBSTITUTION', 'None', (0, 32))
12541	30250045	Further alanine substitution for Ser893, Ser897, or Ser900 decreased the affinity of SKM9-2 in contrast to SKMepmin3 (SKMepmin4, 6, and 8).	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('Ser', 'cellular_component', 'GO:0005790', ('52', '55'))	('Ser897', 'Var', (41, 47))	('decreased', 'NegReg', (59, 68))	('Ser', 'cellular_component', 'GO:0005790', ('41', '44'))	('Ser900', 'Var', (52, 58))	('alanine substitution for Ser893', 'SUBSTITUTION', 'None', (8, 39))	('alanine substitution for Ser893', 'Var', (8, 39))	('affinity', 'MPA', (73, 81))
12542	30250045	The substitution for Ser897, or Ser900 increased the dissociation rate (SKMepmin6 and 8).	('dissociation rate', 'MPA', (53, 70))	('Ser897', 'Var', (21, 27))	('Ser', 'cellular_component', 'GO:0005790', ('21', '24'))	('increased', 'PosReg', (39, 48))	('Ser900', 'Chemical', '-', (32, 38))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('Ser897', 'Chemical', '-', (21, 27))	('Ser900', 'Var', (32, 38))
12543	30250045	The SKM9-2 binding affinity was restored by threonine substitution at position 893 or 900 (SKMepmin5 and 9), whereas the binding ability was further reduced by the replacement of Ser897 with Thr (SKMepmin7).	('binding', 'Interaction', (11, 18))	('Ser897 with Thr', 'Mutation', 'p.S897T', (179, 194))	('Ser897', 'Var', (179, 185))	('threonine substitution', 'Var', (44, 66))	('binding', 'molecular_function', 'GO:0005488', ('11', '18'))	('Ser', 'cellular_component', 'GO:0005790', ('179', '182'))	('SKM9-2', 'Gene', (4, 10))	('binding', 'Interaction', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('restored', 'PosReg', (32, 40))	('threonine', 'Chemical', 'MESH:D013912', (44, 53))
12544	30250045	In conjunction with the results of alanine substitution, as shown in Figs 3, 5, SKM9-2 binding requires the O-linked glycan modification of Ser893 and Ser900 and non-glycosylated Ser897.	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('alanine', 'Chemical', 'MESH:D000409', (35, 42))	('Ser897', 'Chemical', '-', (179, 185))	('Ser900', 'Chemical', '-', (151, 157))	('Ser900', 'Var', (151, 157))	('Ser', 'cellular_component', 'GO:0005790', ('140', '143'))	('O-linked glycan', 'Protein', (108, 123))	('binding', 'Interaction', (87, 94))	('O-linked glycan', 'Chemical', '-', (108, 123))	('Ser893', 'Chemical', '-', (140, 146))	('Ser', 'cellular_component', 'GO:0005790', ('151', '154'))	('Ser', 'cellular_component', 'GO:0005790', ('179', '182'))	('Ser893', 'Var', (140, 146))	('SKM9-2', 'Gene', (80, 86))
12545	30250045	Ser895 and Thr903 are not important for the SKM9-2 binding.	('Thr903', 'Var', (11, 17))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('binding', 'Interaction', (51, 58))	('Ser895', 'Chemical', '-', (0, 6))	('Thr903', 'Chemical', '-', (11, 17))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
12556	30250045	Jacalin recognized the desialylated SKMepmin3 with Neuraminidase A, but not the deglycosylated SKMepmin3 (Fig.	('desialylated', 'Var', (23, 35))	('Neuraminidase', 'Gene', (51, 64))	('Neuraminidase', 'Gene', '4758', (51, 64))
12564	30250045	Taken together, the results suggest that SKM9-2 recognizes the peptide sequence of HEG1 (893-SKSPSLVSLPT-903) modified with disialyl T at the positions of Ser893 and Ser900, and that SKM9-2 does not bind to the peptide without glycosylation.	('Ser893', 'Chemical', '-', (155, 161))	('HEG1', 'Gene', (83, 87))	('glycosylation', 'biological_process', 'GO:0070085', ('227', '240'))	('Ser893', 'Var', (155, 161))	('Ser900', 'Chemical', '-', (166, 172))	('disialyl T', 'Chemical', '-', (124, 134))	('disialyl T', 'MPA', (124, 134))	('Ser', 'cellular_component', 'GO:0005790', ('166', '169'))	('Ser900', 'Var', (166, 172))	('Ser', 'cellular_component', 'GO:0005790', ('155', '158'))
12573	30250045	Therefore, SKM9-2 would recognize the HEG1 peptide sequences (893-SKSPSLVSLPT-903) containing two disialyl T antigens at the positions of Ser893 and Ser900, but not Ser897, in mesothelioma cells as well (Fig.	('disialyl T', 'Chemical', '-', (98, 108))	('Ser893', 'Var', (138, 144))	('Ser900', 'Chemical', '-', (149, 155))	('Ser', 'cellular_component', 'GO:0005790', ('165', '168'))	('Ser900', 'Var', (149, 155))	('mesothelioma', 'Disease', (176, 188))	('Ser', 'cellular_component', 'GO:0005790', ('149', '152'))	('Ser', 'cellular_component', 'GO:0005790', ('138', '141'))	('Ser897', 'Chemical', '-', (165, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (176, 188))	('Ser893', 'Chemical', '-', (138, 144))
12574	30250045	mAb against an O-linked glycosylated region in a mucin-like protein is often an excellent tool for the detection of a disease.	('mucin', 'Gene', '100508689', (49, 54))	('mAb', 'Var', (0, 3))	('mucin', 'Gene', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))
12579	30250045	An alteration in carbohydrate chain synthesis in the tumor cells can cause the expression of an aberrant mucin, wherein the core peptide is not sufficiently modified by O-linked glycans.	('mucin', 'Gene', (105, 110))	('carbohydrate', 'Chemical', 'MESH:D002241', (17, 29))	('expression', 'MPA', (79, 89))	('synthesis', 'biological_process', 'GO:0009058', ('36', '45'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('alteration', 'Var', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('O-linked glycans', 'Chemical', '-', (169, 185))	('cause', 'Reg', (69, 74))	('core', 'cellular_component', 'GO:0019013', ('124', '128'))	('mucin', 'Gene', '100508689', (105, 110))	('tumor', 'Disease', (53, 58))	('carbohydrate chain synthesis', 'MPA', (17, 45))
12580	30250045	The aberrant mucin with hypoglycosylation can become a tumor antigen.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mucin', 'Gene', (13, 18))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', (55, 60))	('tumor antigen', 'molecular_function', 'GO:0008222', ('55', '68'))	('mucin', 'Gene', '100508689', (13, 18))
12584	30250045	The product of the major peak, showing high SKM9-2 binding activity and quantity, was identified as a peptide containing two disialyl T antigens at the positions of Ser893 and Ser900 (Fig.	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('Ser900', 'Chemical', '-', (176, 182))	('binding', 'Interaction', (51, 58))	('disialyl T', 'Chemical', '-', (125, 135))	('Ser900', 'Var', (176, 182))	('Ser', 'cellular_component', 'GO:0005790', ('165', '168'))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('Ser893', 'Chemical', '-', (165, 171))
12598	30250045	The substitution of threonine for Ser900 increased the dissociation rate between SKM9-2 and its epitope peptide (SKMepmin9 in Fig.	('Ser900', 'Var', (34, 40))	('increased', 'PosReg', (41, 50))	('threonine for Ser900', 'Mutation', 'p.S900T', (20, 40))	('Ser', 'cellular_component', 'GO:0005790', ('34', '37'))	('SKM9-2', 'Gene', (81, 87))	('dissociation rate', 'MPA', (55, 72))	('substitution', 'Var', (4, 16))
12601	30250045	On the contrary, threonine substitution for Ser893 hardly influenced the association and dissociation rates (SKMepmin5 in Fig.	('association', 'Interaction', (73, 84))	('threonine substitution for Ser893', 'Mutation', 'p.SUBSTITUTION,S893T', (17, 50))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('threonine substitution', 'Var', (17, 39))	('dissociation', 'MPA', (89, 101))	('Ser893', 'Var', (44, 50))
12602	30250045	5), while alanine substitution decreased the association rate (SKMepmin4 in Fig.	('association', 'MPA', (45, 56))	('alanine', 'Chemical', 'MESH:D000409', (10, 17))	('alanine substitution', 'Var', (10, 30))	('decreased', 'NegReg', (31, 40))
12605	30250045	In contrast, SKMepmin4 had a similar dissociation constant to SKMepmin1 without substitution, despite the same alanine substitution for Ser893 (Fig.	('alanine substitution', 'Var', (111, 131))	('alanine substitution for Ser893', 'Mutation', 'p.SUBSTITUTION,S893A', (111, 142))	('Ser', 'cellular_component', 'GO:0005790', ('136', '139'))	('dissociation', 'MPA', (37, 49))	('Ser893', 'Var', (136, 142))
12606	30250045	This discrepancy may be due to two more substitutions, S895A and T903A, in SKMepmin4.	('S895A', 'Mutation', 'p.S895A', (55, 60))	('SKMepmin4', 'Gene', (75, 84))	('T903A', 'Var', (65, 70))	('S895A', 'Var', (55, 60))	('T903A', 'Mutation', 'rs1333272547', (65, 70))
12607	30250045	SKMepmin3, containing S895A and T903A, can bind to SKM9-2 more strongly than SKMepmin1 (Fig.	('T903A', 'Var', (32, 37))	('strongly', 'PosReg', (63, 71))	('S895A', 'Var', (22, 27))	('T903A', 'Mutation', 'rs1333272547', (32, 37))	('S895A', 'Mutation', 'p.S895A', (22, 27))	('bind', 'Interaction', (43, 47))
12608	30250045	The alanine substitution at positions 895 and 903 may induce the conformational change of amino acid residues in the epitope, as well as the glycan modification at position 893.	('alanine substitution', 'Var', (4, 24))	('conformational change', 'MPA', (65, 86))	('alanine', 'Chemical', 'MESH:D000409', (4, 11))	('glycan', 'Chemical', 'MESH:D011134', (141, 147))	('amino acid residues', 'MPA', (90, 109))	('induce', 'Reg', (54, 60))
12610	30250045	This may be due to protease resistance by the surrounding glycans and/or loss of antigen activity by cleavage at Lys894 in the epitope.	('loss', 'NegReg', (73, 77))	('cleavage', 'Var', (101, 109))	('Lys894', 'Var', (113, 119))	('glycans', 'Chemical', 'MESH:D011134', (58, 65))	('Lys894', 'Chemical', '-', (113, 119))	('antigen', 'Protein', (81, 88))	('activity', 'MPA', (89, 97))
12613	30250045	The glycan of Thr903 may be larger than those on the other glycosylation sites because the molecular size of T903A mutant was clearly smaller than the size of the other mutants (Fig.	('smaller', 'NegReg', (134, 141))	('glycosylation', 'biological_process', 'GO:0070085', ('59', '72'))	('glycan', 'Chemical', 'MESH:D011134', (4, 10))	('molecular size', 'MPA', (91, 105))	('T903A', 'Var', (109, 114))	('T903A', 'Mutation', 'rs1333272547', (109, 114))	('Thr903', 'Chemical', '-', (14, 20))
12617	30250045	The substitution of alanine for Thr903 did not suppress SKM9-2 binding (Fig.	('SKM9-2', 'Protein', (56, 62))	('binding', 'Interaction', (63, 70))	('Thr903', 'Var', (32, 38))	('alanine', 'Var', (20, 27))	('suppress', 'NegReg', (47, 55))	('substitution', 'Var', (4, 16))	('alanine for Thr903', 'Mutation', 'p.T903A', (20, 38))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
12618	30250045	Further elongation of the glycan at Thr903 could potentially interfere with the approach of SKM9-2 to the epitope in HEG1 and may influence the detection of mesothelioma with SKM9-2.	('mesothelioma', 'Disease', (157, 169))	('interfere', 'NegReg', (61, 70))	('influence', 'Reg', (130, 139))	('HEG1', 'Gene', (117, 121))	('Thr903', 'Chemical', '-', (36, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (157, 169))	('approach', 'Interaction', (80, 88))	('Thr903', 'Var', (36, 42))	('epitope', 'MPA', (106, 113))	('glycan', 'Chemical', 'MESH:D011134', (26, 32))
12628	30250045	For analyses of N-terminal truncation, we inserted mutants into pFLAG-CMV1 (Sigma-Aldrich Japan K.K., Tokyo, Japan).	('pFLAG-CMV1', 'Gene', (64, 74))	('mutants', 'Var', (51, 58))	('N', 'Chemical', 'MESH:D009584', (16, 17))
12629	30250045	For analyses of C-terminal deletion lacking the transmembrane domain, we used mutants that were fused with a GPI-anchor protein, SLURP1-gpi, in pcDNA3.1(+) (Thermo Fisher Scientific) (Supplementary Dataset).	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('deletion', 'Var', (27, 35))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('SLURP1', 'Gene', (129, 135))	('GPI', 'Chemical', 'MESH:D017261', (109, 112))	('mutants', 'Var', (78, 85))	('transmembrane', 'cellular_component', 'GO:0016021', ('48', '61'))	('transmembrane', 'cellular_component', 'GO:0044214', ('48', '61'))	('SLURP1', 'Gene', '57152', (129, 135))
12678	26334320	3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis.	('caspase', 'Gene', (197, 204))	('3-MA', 'Chemical', 'MESH:C025946', (17, 21))	('ATG5', 'Gene', (24, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('apoptotic potential', 'CPA', (85, 104))	('simvastatin', 'Chemical', 'MESH:D019821', (123, 134))	('E64D', 'SUBSTITUTION', 'None', (55, 59))	('enhanced', 'PosReg', (72, 80))	('rapamycin', 'Chemical', 'MESH:D020123', (144, 153))	('LY294002', 'Chemical', 'MESH:C085911', (158, 166))	('bafilomycin A', 'Chemical', 'MESH:C057620', (36, 49))	('pemetrexed', 'Chemical', 'MESH:D000068437', (108, 118))	('caspase', 'Gene', '841;842', (197, 204))	('E64D', 'Var', (55, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('ATG5', 'Gene', '9474', (24, 28))	('3-Methyladenine', 'Chemical', 'MESH:C025946', (0, 15))
12690	26334320	Additionally, inhibition of the intrinsic apoptosis pathway has been shown to suppress the cytotoxicity of pemetrexed.	('intrinsic apoptosis', 'biological_process', 'GO:0097193', ('32', '51'))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('pemetrexed', 'Chemical', 'MESH:D000068437', (107, 117))	('suppress', 'NegReg', (78, 86))	('inhibition', 'Var', (14, 24))	('cytotoxicity', 'Disease', (91, 103))	('intrinsic apoptosis pathway', 'Pathway', (32, 59))
12707	26334320	Annexin V staining showed that combination treatment significantly enhances apoptosis compared to either drug alone in MSTO-211H and A549 cells (Figure 1C).	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('combination', 'Var', (31, 42))	('enhances', 'PosReg', (67, 75))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('MSTO-211H', 'Chemical', '-', (119, 128))	('A549', 'CellLine', 'CVCL:0023', (133, 137))
12716	26334320	In non-treated control cells, a diffuse pattern of GFP fluorescence was observed in the cytoplasm; however, MSTO-211H and A549 cells treated with both pemetrexed and simvastatin displayed markedly more LC3-positive GFP punctae in compared to cells treated with pemetrexed or simvastatin alone (Figure 2B).	('simvastatin', 'Chemical', 'MESH:D019821', (166, 177))	('MSTO-211H', 'Chemical', '-', (108, 117))	('more', 'PosReg', (197, 201))	('LC3', 'Gene', '84557', (202, 205))	('LC3', 'Gene', (202, 205))	('simvastatin', 'Chemical', 'MESH:D019821', (275, 286))	('pemetrexed', 'Var', (151, 161))	('cytoplasm', 'cellular_component', 'GO:0005737', ('88', '97'))	('pemetrexed', 'Chemical', 'MESH:D000068437', (151, 161))	('pemetrexed', 'Chemical', 'MESH:D000068437', (261, 271))	('simvastatin', 'Var', (166, 177))	('A549', 'CellLine', 'CVCL:0023', (122, 126))
12719	26334320	GFP generation showed that autophagic induction was significantly increased by pemetrexed and simvastatin combination compared to individual treatment with either drug (Figure 2C).	('combination', 'Var', (106, 117))	('increased', 'PosReg', (66, 75))	('pemetrexed', 'Chemical', 'MESH:D000068437', (79, 89))	('autophagic induction', 'CPA', (27, 47))	('simvastatin', 'Chemical', 'MESH:D019821', (94, 105))	('simvastatin', 'Gene', (94, 105))
12727	26334320	Therefore, we investigated whether suppression of mTOR function by rapamycin or LY294002 alters apoptosis induced by the pemetrexed and simvastatin cotreatment.	('LY294002', 'Chemical', 'MESH:C085911', (80, 88))	('simvastatin', 'Chemical', 'MESH:D019821', (136, 147))	('mTOR', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (50, 54))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('LY294002', 'Var', (80, 88))	('apoptosis', 'CPA', (96, 105))	('pemetrexed', 'Chemical', 'MESH:D000068437', (121, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
12730	26334320	Following similar protocols, we next demonstrated that pemetrexed, simvastatin, and LY294002 cotreatment also increased LC3-II levels (Figure 4C).	('LC3', 'Gene', '84557', (120, 123))	('LY294002', 'Chemical', 'MESH:C085911', (84, 92))	('LC3', 'Gene', (120, 123))	('increased', 'PosReg', (110, 119))	('LY294002', 'Var', (84, 92))	('pemetrexed', 'Chemical', 'MESH:D000068437', (55, 65))	('increased LC3', 'Phenotype', 'HP:0003141', (110, 123))	('simvastatin', 'Chemical', 'MESH:D019821', (67, 78))
12731	26334320	Annexin V staining showed that rapamycin or LY294002 activation of pemetrexed and simvastatin-induced autophagy results in significantly attenuated apoptosis compared to combination treatment in MSTO-211H and A549 cells (Figure 4B and 4D).	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('MSTO-211H', 'Chemical', '-', (195, 204))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('activation', 'PosReg', (53, 63))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('simvastatin', 'Chemical', 'MESH:D019821', (82, 93))	('LY294002', 'Var', (44, 52))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('autophagy', 'CPA', (102, 111))	('apoptosis', 'CPA', (148, 157))	('rapamycin', 'Chemical', 'MESH:D020123', (31, 40))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('pemetrexed', 'Chemical', 'MESH:D000068437', (67, 77))	('A549', 'CellLine', 'CVCL:0023', (209, 213))	('attenuated', 'NegReg', (137, 147))
12732	26334320	Together, these findings indicate that AKT-mediated inhibition of mTOR by rapamycin or LY294002 attenuates apoptosis induced by pemetrexed and simvastatin combination in malignant mesothelioma and NSCLC cells.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('rapamycin', 'Chemical', 'MESH:D020123', (74, 83))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('AKT', 'Gene', (39, 42))	('mTOR', 'Gene', (66, 70))	('NSCLC', 'Disease', (197, 202))	('apoptosis', 'CPA', (107, 116))	('inhibition', 'NegReg', (52, 62))	('mTOR', 'Gene', '2475', (66, 70))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (170, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('LY294002', 'Var', (87, 95))	('attenuates', 'NegReg', (96, 106))	('AKT', 'Gene', '207', (39, 42))	('pemetrexed', 'Chemical', 'MESH:D000068437', (128, 138))	('malignant mesothelioma', 'Disease', (170, 192))	('simvastatin', 'Chemical', 'MESH:D019821', (143, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (170, 192))	('LY294002', 'Chemical', 'MESH:C085911', (87, 95))
12733	26334320	To investigate the relationship between pemetrexed and simvastatin-induced apoptosis and autophagy, cells were cotreated with pemetrexed and simvastatin using one of the four autophagic inhibitors: (i) 3-methyladenine (3-MA), a class III PI3 kinase inhibitor; (ii) ATG5 siRNA, an inhibitor of ATG5-12 formation; (iii) bafilomycin A, a specific lysomal vacuolar-type H+-ATPase pump inhibitor that blocks the fusion of autophagosomes and lysosomes; and (iv) E64D/pepstatin A, an inhibitor of lysosomal enzymes.	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('ATG5', 'Gene', '9474', (265, 269))	('autophagy', 'biological_process', 'GO:0006914', ('89', '98'))	('ATG5', 'Gene', '9474', (293, 297))	('3-MA', 'Chemical', 'MESH:C025946', (219, 223))	('ATG5', 'Gene', (265, 269))	('E64D', 'Var', (456, 460))	('E64D', 'SUBSTITUTION', 'None', (456, 460))	('fusion', 'CPA', (407, 413))	('ATG5', 'Gene', (293, 297))	('formation', 'biological_process', 'GO:0009058', ('301', '310'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('242', '258'))	('pemetrexed', 'Chemical', 'MESH:D000068437', (126, 136))	('pemetrexed', 'Chemical', 'MESH:D000068437', (40, 50))	('autophagy', 'biological_process', 'GO:0016236', ('89', '98'))	('simvastatin', 'Chemical', 'MESH:D019821', (141, 152))	('simvastatin', 'Chemical', 'MESH:D019821', (55, 66))	('bafilomycin A', 'Chemical', 'MESH:C057620', (318, 331))	('blocks', 'NegReg', (396, 402))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
12739	26334320	ATG5 silencing accelerated apoptosis and decreased autophagy flux, as was indicated by both an increase in the cleaved forms of caspase 3 and PARP and a decrease in LC3-II levels compared to cells expressing control scrambled siRNA (Figure 5C).	('ATG5', 'Gene', '9474', (0, 4))	('cleaved forms', 'MPA', (111, 124))	('autophagy flux', 'CPA', (51, 65))	('accelerated', 'PosReg', (15, 26))	('decreased', 'NegReg', (41, 50))	('LC3', 'Gene', (165, 168))	('silencing', 'Var', (5, 14))	('caspase 3', 'Gene', (128, 137))	('caspase 3', 'Gene', '836', (128, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('ATG5', 'Gene', (0, 4))	('apoptosis', 'CPA', (27, 36))	('autophagy', 'biological_process', 'GO:0016236', ('51', '60'))	('decrease', 'NegReg', (153, 161))	('LC3', 'Gene', '84557', (165, 168))	('PARP', 'Gene', '142', (142, 146))	('increase', 'PosReg', (95, 103))	('PARP', 'Gene', (142, 146))	('autophagy', 'biological_process', 'GO:0006914', ('51', '60'))
12743	26334320	We next demonstrated that the protease inhibitors E64D/pepstatin A caused the accumulation of LC3-II (Figure 5G).	('E64D', 'Var', (50, 54))	('LC3', 'Gene', '84557', (94, 97))	('LC3', 'Gene', (94, 97))	('E64D', 'SUBSTITUTION', 'None', (50, 54))	('accumulation', 'PosReg', (78, 90))
12744	26334320	Bafilomycin A or E64D/pepstatin A inhibition of pemetrexed and simvastatin-induced autophagy also increased the proportion of apoptotic MSTO-211H and A549 cells (Figure 5F and 5H).	('E64D', 'SUBSTITUTION', 'None', (17, 21))	('autophagy', 'CPA', (83, 92))	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('apoptotic MSTO-211H', 'CPA', (126, 145))	('E64D', 'Var', (17, 21))	('Bafilomycin A', 'Chemical', 'MESH:C057620', (0, 13))	('pemetrexed', 'Chemical', 'MESH:D000068437', (48, 58))	('inhibition', 'NegReg', (34, 44))	('increased', 'PosReg', (98, 107))	('simvastatin', 'Chemical', 'MESH:D019821', (63, 74))	('MSTO-211H', 'Chemical', '-', (136, 145))	('autophagy', 'biological_process', 'GO:0016236', ('83', '92'))	('autophagy', 'biological_process', 'GO:0006914', ('83', '92'))
12748	26334320	Furthermore, mice co-injected with pemetrexed and simvastatin had significantly smaller tumor volumes compared to the groups receiving either pemetrexed or simvastatin alone (Figure 6B and 6C).	('mice', 'Species', '10090', (13, 17))	('simvastatin', 'Chemical', 'MESH:D019821', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('pemetrexed', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('pemetrexed', 'Chemical', 'MESH:D000068437', (35, 45))	('smaller', 'NegReg', (80, 87))	('simvastatin', 'Var', (50, 61))	('tumor', 'Disease', (88, 93))	('simvastatin', 'Chemical', 'MESH:D019821', (156, 167))	('pemetrexed', 'Chemical', 'MESH:D000068437', (142, 152))
12761	26334320	In the present study, MSTO-211H and A549 cells cotreated with the autophagy inhibitors 3-MA, bafilomycin A, and E64d/pepstatin A displayed markedly increased expression of cleaved PARP, caspase-3, -8, and -9, suggesting that autophagy serves a protective role.	('3-MA', 'Chemical', 'MESH:C025946', (87, 91))	('PARP', 'Gene', '142', (180, 184))	('increased', 'PosReg', (148, 157))	('autophagy', 'biological_process', 'GO:0016236', ('225', '234'))	('expression', 'MPA', (158, 168))	('autophagy', 'biological_process', 'GO:0016236', ('66', '75'))	('bafilomycin A', 'Chemical', 'MESH:C057620', (93, 106))	('E64d', 'Chemical', 'MESH:C108192', (112, 116))	('E64d/pepstatin', 'Var', (112, 126))	('autophagy', 'biological_process', 'GO:0006914', ('225', '234'))	('MSTO-211H', 'Chemical', '-', (22, 31))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('autophagy', 'biological_process', 'GO:0006914', ('66', '75'))	('pepstatin A', 'Chemical', 'MESH:C031375', (117, 128))	('PARP', 'Gene', (180, 184))	('caspase-3, -8, and -9', 'Gene', '836;841;842', (186, 207))
12767	26334320	We found that pretreatment with bafilomycin A and E64d/pepstatin A, which blocks later autophagosomal degradation, increased the formation of LC3-II in MSTO-211H and A549 cells after combination treatment of pemetrexed and simvastatin.	('MSTO-211H', 'Chemical', '-', (152, 161))	('degradation', 'biological_process', 'GO:0009056', ('102', '113'))	('E64d', 'Chemical', 'MESH:C108192', (50, 54))	('increased', 'PosReg', (115, 124))	('simvastatin', 'Chemical', 'MESH:D019821', (223, 234))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('LC3', 'Gene', '84557', (142, 145))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('LC3', 'Gene', (142, 145))	('pepstatin A', 'Chemical', 'MESH:C031375', (55, 66))	('E64d/pepstatin', 'Var', (50, 64))	('bafilomycin A', 'Chemical', 'MESH:C057620', (32, 45))	('formation', 'MPA', (129, 138))	('pemetrexed', 'Chemical', 'MESH:D000068437', (208, 218))
12768	26334320	Autophagy-associated genes are under the control of mTOR, and the inhibition of mTOR by rapamycin or LY294002 enhances autophagy.	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('mTOR', 'Gene', (52, 56))	('autophagy', 'biological_process', 'GO:0016236', ('119', '128'))	('mTOR', 'Gene', '2475', (52, 56))	('autophagy', 'biological_process', 'GO:0006914', ('119', '128'))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('mTOR', 'Gene', (80, 84))	('rapamycin', 'Chemical', 'MESH:D020123', (88, 97))	('mTOR', 'Gene', '2475', (80, 84))	('LY294002', 'Var', (101, 109))	('inhibition', 'Var', (66, 76))	('Autophagy-associated', 'Gene', (0, 20))	('enhances', 'PosReg', (110, 118))	('LY294002', 'Chemical', 'MESH:C085911', (101, 109))	('autophagy', 'CPA', (119, 128))
12773	26334320	Consistent with these results, inhibition of autophagy can enhance the anti-cancer effects of pemetrexed and simvastatin and, thus, could be therapeutically targeted to improve the efficacy of these combination therapies.	('simvastatin', 'Chemical', 'MESH:D019821', (109, 120))	('autophagy', 'CPA', (45, 54))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('enhance', 'PosReg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibition', 'Var', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('improve', 'PosReg', (169, 176))	('cancer', 'Disease', (76, 82))	('pemetrexed', 'Chemical', 'MESH:D000068437', (94, 104))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
12830	25932953	It has been suggested that tumour heterogeneity, as a consequence of genetic instability and niche factors within the tumour, is a major cause of resistance to treatment in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumour', 'Disease', (118, 124))	('cancer', 'Disease', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('cause', 'Reg', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Disease', (27, 33))	('patients', 'Species', '9606', (180, 188))	('genetic instability', 'Var', (69, 88))
12909	25932953	CD24 knock-down also significantly suppressed proliferation of Ist-Mes-2 cells, as documented in Fig 6D.	('knock-down', 'Var', (5, 15))	('Mes', 'Chemical', 'MESH:C004550', (67, 70))	('proliferation', 'CPA', (46, 59))	('CD24', 'Gene', (0, 4))	('suppressed', 'NegReg', (35, 45))
12916	25932953	We next tested the effect of CD24 knock-down on the propensity of MM cells to form tumours, such that mock-transfected and CD24- Ist-Mes-2 cells were grafted in NOD/SCID mice and tumour growth kinetics evaluated by USI.	('tested', 'Reg', (8, 14))	('tumours', 'Disease', (83, 90))	('tumour growth', 'Disease', (179, 192))	('NOD', 'Gene', (161, 164))	('knock-down', 'Var', (34, 44))	('SCID', 'Disease', (165, 169))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour growth', 'Disease', 'MESH:D006130', (179, 192))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('NOD', 'Gene', '1822', (161, 164))	('SCID', 'Disease', 'MESH:D053632', (165, 169))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('mice', 'Species', '10090', (170, 174))	('Mes', 'Chemical', 'MESH:C004550', (133, 136))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
12921	25932953	DeltaPsim,i was found lower in CD24- cells and higher in sphere cells (Fig 8C), which was also the case for superoxide generation (Fig 8D), glucose uptake (Fig 8I), and lactate production (Fig 8E), while SDH activity was not altered (Fig 7G) and SQR activity was increased in sphere cells (Fig 7H).	('lactate', 'Chemical', 'MESH:D019344', (169, 176))	('superoxide', 'Chemical', 'MESH:D013481', (108, 118))	('higher', 'PosReg', (47, 53))	('lactate production', 'MPA', (169, 187))	('superoxide generation', 'MPA', (108, 129))	('glucose uptake', 'MPA', (140, 154))	('DeltaPsim', 'MPA', (0, 9))	('SDH', 'Gene', '6390', (204, 207))	('CD24-', 'Var', (31, 36))	('glucose uptake', 'biological_process', 'GO:0046323', ('140', '154'))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))	('lower', 'NegReg', (22, 27))	('SDH', 'Gene', (204, 207))
12930	25932953	Knocking down CD24 did not significantly affect the IC50 values for 5FU, tamoxifen and alpha-TOS.	('5FU', 'Chemical', 'MESH:D005472', (68, 71))	('tamoxifen', 'Chemical', 'MESH:D013629', (73, 82))	('alpha-TOS', 'Chemical', 'MESH:D024502', (87, 96))	('CD24', 'Gene', (14, 18))	('Knocking', 'Var', (0, 8))
12947	25932953	We found that CD24- cells lost their propensity to form spheres in SFM and that when grafted in NOD/SCID mice, their rate of tumour progression was >50% lower than that of their mock-transfected counterparts.	('lost', 'NegReg', (26, 30))	('NOD', 'Gene', (96, 99))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('CD24- cells', 'Var', (14, 25))	('SCID', 'Disease', (100, 104))	('lower', 'NegReg', (153, 158))	('propensity', 'MPA', (37, 47))	('NOD', 'Gene', '1822', (96, 99))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('SCID', 'Disease', 'MESH:D053632', (100, 104))	('tumour', 'Disease', (125, 131))	('mice', 'Species', '10090', (105, 109))
12948	25932953	The loss of sphere-forming capacity and efficacy of tumour formation for CD24- MM cells can be linked to their loss of several other stemness markers, including CD47, EpCAM and OCT4, as shown for the tumour tissue.	('tumour', 'Disease', (200, 206))	('loss', 'NegReg', (111, 115))	('CD47', 'Gene', (161, 165))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('OCT4', 'Gene', (177, 181))	('EpCAM', 'Gene', (167, 172))	('CD24- MM', 'Var', (73, 81))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('tumour', 'Disease', (52, 58))	('sphere-forming capacity', 'CPA', (12, 35))	('loss', 'NegReg', (4, 8))	('EpCAM', 'Gene', '4072', (167, 172))	('CD47', 'Gene', '961', (161, 165))
12949	25932953	Further, the lower proliferative capacity of CD24- cells can be reconciled with lower level of pEGFR and pERK1/2, a component of the MAP kinase pathway, compared to parental and sphere cells.	('ERK1/2', 'Gene', (106, 112))	('ERK1/2', 'Gene', '5595;5594', (106, 112))	('proliferative capacity', 'CPA', (19, 41))	('lower', 'NegReg', (13, 18))	('EGFR', 'Gene', (96, 100))	('MAP', 'molecular_function', 'GO:0004239', ('133', '136'))	('CD24- cells', 'Var', (45, 56))	('lower', 'NegReg', (80, 85))	('EGFR', 'Gene', '1956', (96, 100))
12968	25932953	We further document that MM stemness is dependent on CD24, whose knock-down compromises the stem-like properties of the cells including efficient tumour progression.	('MM stemness', 'Disease', (25, 36))	('tumour', 'Disease', (146, 152))	('CD24', 'Gene', (53, 57))	('knock-down', 'Var', (65, 75))	('compromises', 'NegReg', (76, 87))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('MM stemness', 'Disease', 'MESH:D020295', (25, 36))	('stem-like properties of the cells', 'CPA', (92, 125))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
13032	20396658	Immunohistochemical stains showed positivity for Pancytokeratin and negative reactivity for CEA and CD-15 (Leu-M 1).	('CD-15', 'Gene', '2526', (100, 105))	('positivity', 'Var', (34, 44))	('CEA', 'Gene', (92, 95))	('CD-15', 'Gene', (100, 105))	('CEA', 'Gene', '1084', (92, 95))	('Pancytokeratin', 'Protein', (49, 63))
13088	31529678	BRAF mutation that was found in our patient may also help since it is commonly found in thyroid carcinoma, but not in primary pleural processes such as mesothelioma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (88, 105))	('patient', 'Species', '9606', (36, 43))	('BRAF', 'Gene', '673', (0, 4))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (88, 105))	('thyroid carcinoma', 'Disease', (88, 105))	('mesothelioma', 'Disease', (152, 164))	('found', 'Reg', (79, 84))	('BRAF', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('mutation', 'Var', (5, 13))
13122	26184317	High GLI1 gene expression was associated with shorter overall survival in MPM patients.	('High', 'Var', (0, 4))	('gene expression', 'biological_process', 'GO:0010467', ('10', '25'))	('GLI1', 'Gene', '2735', (5, 9))	('MPM', 'Disease', (74, 77))	('overall survival', 'MPA', (54, 70))	('patients', 'Species', '9606', (78, 86))	('expression', 'MPA', (15, 25))	('GLI1', 'Gene', (5, 9))	('shorter', 'NegReg', (46, 53))
13132	26184317	A study using a panel of seven MPM cell lines demonstrated a missense mutation in the SUFU gene, leading to T411M amino acid change, coupled with three base pair (CTG) insertions in the SMO gene, resulting in an additional amino acid 23L_24GinsL in the signal peptide region in one cell line.	('amino acid', 'MPA', (223, 233))	('CTG', 'Chemical', '-', (163, 166))	('T411M', 'Mutation', 'rs368020224', (108, 113))	('SMO', 'Gene', '6608', (186, 189))	('SUFU', 'Gene', (86, 90))	('SMO', 'Gene', (186, 189))	('rat', 'Species', '10116', (53, 56))	('SUFU', 'Gene', '51684', (86, 90))	('missense mutation', 'Var', (61, 78))	('T411M', 'Var', (108, 113))
13133	26184317	The 3-bp insertion in SMO was also detected in one MPM patient out of 14 patients analyzed.	('3-bp', 'Var', (4, 8))	('SMO', 'Gene', '6608', (22, 25))	('SMO', 'Gene', (22, 25))	('patient', 'Species', '9606', (73, 80))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (73, 81))
13134	26184317	Transfection of a SUFU cDNA harboring the T411M missense mutation suppressed Gli-reporter gene downregulation as observed with wild-type SUFU, although it is unclear whether such results were observed with similar levels of SUFU protein expressed.	('T411M missense', 'Var', (42, 56))	('SUFU', 'Gene', '51684', (137, 141))	('SUFU', 'Gene', (224, 228))	('downregulation', 'NegReg', (95, 109))	('SUFU', 'Gene', '51684', (224, 228))	('SUFU', 'Gene', (18, 22))	('Gli', 'Gene', (77, 80))	('SUFU', 'Gene', '51684', (18, 22))	('suppressed', 'NegReg', (66, 76))	('T411M', 'Mutation', 'rs368020224', (42, 47))	('protein', 'cellular_component', 'GO:0003675', ('229', '236'))	('Gli', 'Gene', '2735', (77, 80))	('SUFU', 'Gene', (137, 141))
13135	26184317	Deletion of PTCH1 exons 8-23 was observed in another cell line.	('PTCH1', 'Gene', '5727', (12, 17))	('PTCH1', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
13136	26184317	Deletion of chromosome 9q22.32, containing the PTCH1 gene, is observed in medulloblastoma and basal cell carcinoma (reviewed in) and various other cancers, consistent with the loss of tumor suppressor function.	('PTCH1', 'Gene', (47, 52))	('medulloblastoma', 'Phenotype', 'HP:0002885', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (94, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PTCH1', 'Gene', '5727', (47, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))	('tumor', 'Disease', (184, 189))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cancers', 'Disease', (147, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('medulloblastoma and basal cell carcinoma', 'Disease', 'MESH:D008527', (74, 114))	('observed', 'Reg', (62, 70))	('Deletion', 'Var', (0, 8))
13137	26184317	The functional impact of the insertion in the SMO gene still remains to be investigated.	('insertion', 'Var', (29, 38))	('SMO', 'Gene', '6608', (46, 49))	('SMO', 'Gene', (46, 49))
13152	26184317	Nevertheless, it should be noted that a small group of MPM patients may harbor mutations of the pathway.	('MPM', 'Disease', (55, 58))	('patients', 'Species', '9606', (59, 67))	('harbor', 'Reg', (72, 78))	('mutations', 'Var', (79, 88))
13222	24361865	In silico digestions of mesothelin (UniProt entry #Q13421), osteopontin (#P10451), and CA125 (#Q8WXI7) were performed to predict a suitable pH interval that would include peptides from these proteins in the range of the IPG-HiRIEF strip.	('CA125', 'Gene', (87, 92))	('#P10451', 'Var', (73, 80))	('peptides', 'MPA', (171, 179))	('mesothelin', 'Gene', '10232', (24, 34))	('osteopontin', 'Gene', '6696', (60, 71))	('CA125', 'Gene', '94025', (87, 92))	('osteopontin', 'Gene', (60, 71))	('mesothelin', 'Gene', (24, 34))	('IPG', 'Chemical', '-', (220, 223))	('peptides', 'Chemical', 'MESH:D010455', (171, 179))
13253	24361865	2A), and two mesothelioma patients showed a different distribution than the bulk of the patients (M115a and M115b in Figs.	('mesothelioma', 'Disease', (13, 25))	('M115b', 'Var', (108, 113))	('patients', 'Species', '9606', (88, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('patients', 'Species', '9606', (26, 34))
13254	24361865	Proteins clustering around the L118a lung cancer sample were uploaded to the DAVID database, and significant BioCarta pathways were involved in the complement system and in prothrombin-activated coagulation.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('L118a', 'Var', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('involved', 'Reg', (132, 140))	('coagulation', 'biological_process', 'GO:0050817', ('195', '206'))
13255	24361865	Proteins separating the two M115 mesothelioma patients from the rest were involved in the glycolysis pathway, the complement and coagulation cascades, and response to hypoxia-induced stress.	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('patients', 'Species', '9606', (46, 54))	('glycolysis', 'biological_process', 'GO:0006096', ('90', '100'))	('response to hypoxia', 'biological_process', 'GO:0001666', ('155', '174'))	('M115', 'Var', (28, 32))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('glycolysis pathway', 'Pathway', (90, 108))	('coagulation', 'biological_process', 'GO:0050817', ('129', '140'))	('mesothelioma', 'Disease', (33, 45))	('involved', 'Reg', (74, 82))
13270	24361865	Patients with high apolipoprotein C-I levels (>5.33 mug/ml) also had a mean survival time that was 5.5 months longer (10 months compared with low expressing patients' survival of 4.5 months; p value = 0.02) with a reciprocal hazard ratio of 2.30 (1.4-9.0).	('apolipoprotein', 'molecular_function', 'GO:0005319', ('19', '33'))	('mug', 'molecular_function', 'GO:0043739', ('52', '55'))	('patients', 'Species', '9606', (157, 165))	('apolipoprotein C-I', 'Gene', '341', (19, 37))	('Patients', 'Species', '9606', (0, 8))	('apolipoprotein C-I', 'Gene', (19, 37))	('>5.33 mug/ml', 'Var', (46, 58))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('19', '33'))	('longer', 'PosReg', (110, 116))
13296	24361865	As a consequence, lung cancer patients with high levels of galectin 1 have a worse prognosis than those expressing lower levels.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('galectin 1', 'Gene', (59, 69))	('patients', 'Species', '9606', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('galectin 1', 'Gene', '3956', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('high levels', 'Var', (44, 55))	('galectin', 'molecular_function', 'GO:0001577', ('59', '67'))
13310	24361865	As already stated, the expression of galectin 1 affects the immune system and is prognostic for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('galectin', 'molecular_function', 'GO:0001577', ('37', '45'))	('galectin 1', 'Gene', '3956', (37, 47))	('galectin 1', 'Gene', (37, 47))	('lung cancer', 'Disease', (96, 107))	('prognostic', 'Reg', (81, 91))	('expression', 'Var', (23, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('affects', 'Reg', (48, 55))	('immune', 'CPA', (60, 66))
13316	24361865	Furthermore, bladder cancer patients with high levels of the aldo-keto reductase 1B10 after chemotherapy had significantly lower disease-free survival rates.	('disease-free survival rates', 'CPA', (129, 156))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (13, 27))	('lower', 'NegReg', (123, 128))	('high levels', 'Var', (42, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (13, 27))	('bladder cancer', 'Disease', (13, 27))	('patients', 'Species', '9606', (28, 36))
13355	19096314	HDAC inhibitors have been documented to enhance the susceptibility of mesothelioma cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) .	('TRAIL', 'Gene', (154, 159))	('HDAC', 'Gene', '9734', (0, 4))	('necrosis', 'biological_process', 'GO:0008219', ('103', '111'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('97', '118'))	('ligand', 'molecular_function', 'GO:0005488', ('146', '152'))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('HDAC', 'Gene', (0, 4))	('mesothelioma cell', 'Disease', (70, 87))	('susceptibility', 'MPA', (52, 66))	('necrosis', 'biological_process', 'GO:0008220', ('103', '111'))	('necrosis', 'biological_process', 'GO:0070265', ('103', '111'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('necrosis', 'biological_process', 'GO:0019835', ('103', '111'))	('inhibitors', 'Var', (5, 15))	('necrosis', 'biological_process', 'GO:0001906', ('103', '111'))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (97, 152))	('mesothelioma cell', 'Disease', 'MESH:D008654', (70, 87))	('enhance', 'PosReg', (40, 47))	('TRAIL', 'Gene', '8743', (154, 159))
13614	20838437	In contrast, lovastatin treatment alone inhibited AKT, S6K1 and 4EPB1 phosphorylation and the combination of lovastatin and KRN633 induced a dramatic inhibition of the AKT pathway in this MM derived cell line (Figure 5).	('lovastatin', 'Chemical', 'MESH:D008148', (13, 23))	('KRN633', 'Chemical', 'MESH:C508488', (124, 130))	('inhibited', 'NegReg', (40, 49))	('AKT', 'Gene', '207', (50, 53))	('combination', 'Var', (94, 105))	('AKT', 'Gene', '207', (168, 171))	('inhibition', 'NegReg', (150, 160))	('phosphorylation', 'MPA', (70, 85))	('AKT', 'Gene', (50, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('KRN633', 'Gene', (124, 130))	('S6K1 and 4', 'Gene', '6198', (55, 65))	('AKT', 'Gene', (168, 171))	('lovastatin', 'Chemical', 'MESH:D008148', (109, 119))
13617	20838437	KRN633 inhibits VEGFR 1, 2 and 3 with similar kinetics while ZM323881 is highly selective for VEGFR-2.	('VEGFR 1', 'Gene', (16, 23))	('KRN633', 'Var', (0, 6))	('inhibits', 'NegReg', (7, 15))	('ZM323881', 'Chemical', 'MESH:C478783', (61, 69))	('VEGFR 1', 'Gene', '2321', (16, 23))	('ZM323881', 'Var', (61, 69))	('KRN633', 'Chemical', 'MESH:C508488', (0, 6))
13618	20838437	With both MM derived cell lines and in HUVEC, increases in the concentration of the VEGFR-TKIs, KRN633 and ZM323881, resulted in a dose dependent decrease of MTT activity (Figure 6A).	('ZM323881', 'Var', (107, 115))	('concentration', 'MPA', (63, 76))	('VEGFR', 'Gene', (84, 89))	('MTT', 'Chemical', 'MESH:C070243', (158, 161))	('KRN633', 'Var', (96, 102))	('increases', 'PosReg', (46, 55))	('MTT activity', 'MPA', (158, 170))	('HUVEC', 'CellLine', 'CVCL:2959', (39, 44))	('VEGFR', 'Gene', '3791', (84, 89))	('ZM323881', 'Chemical', 'MESH:C478783', (107, 115))	('KRN633', 'Chemical', 'MESH:C508488', (96, 102))	('decrease', 'NegReg', (146, 154))
13631	20838437	Employing the MTT cell viability assay, we demonstrated that while the siControl treatments (50 nM 48 hrs, followed by 48 hrs lovastatin treatment) had no effect on lovastatin treatments (1 and 5 microM) compared to reagent alone, siVEGFR-2 (50 nM 48 hrs, followed by 48 hrs lovastatin treatment) significantly enhanced lovastatin-induced cytotoxicity in H2052 and H28 MM cells (Figure 6D).	('enhanced', 'PosReg', (311, 319))	('lovastatin', 'Chemical', 'MESH:D008148', (165, 175))	('lovastatin', 'Chemical', 'MESH:D008148', (275, 285))	('lovastatin-induced', 'MPA', (320, 338))	('H2052', 'CellLine', 'CVCL:1518', (355, 360))	('cytotoxicity', 'Disease', (339, 351))	('lovastatin', 'Chemical', 'MESH:D008148', (320, 330))	('MTT', 'Chemical', 'MESH:C070243', (14, 17))	('H28 MM', 'CellLine', 'CVCL:4D15', (365, 371))	('siVEGFR-2', 'Var', (231, 240))	('cytotoxicity', 'Disease', 'MESH:D064420', (339, 351))	('lovastatin', 'Chemical', 'MESH:D008148', (126, 136))
13632	20838437	In our previous study, we demonstrated that the targeting of HMG-CoA reductase, which results in mevalonate depletion, can inhibit the function of the EGFR.	('mevalonate', 'Chemical', 'MESH:D008798', (97, 107))	('EGFR', 'Gene', (151, 155))	('mevalonate depletion', 'MPA', (97, 117))	('inhibit', 'NegReg', (123, 130))	('HMG-CoA reductase', 'Gene', (61, 78))	('targeting', 'Var', (48, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('results in', 'Reg', (86, 96))	('function', 'MPA', (135, 143))	('EGFR', 'Gene', '1956', (151, 155))
13654	20838437	Inhibition of HMG-CoA reductase has been evaluated as an anti-cancer therapeutic approach owing to its ability to inhibit tumor cell proliferation, induce tumor specific apoptosis and inhibit cell motility and metastasis in several tumor models.	('cell motility', 'biological_process', 'GO:0048870', ('192', '205'))	('inhibit', 'NegReg', (184, 191))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (122, 127))	('metastasis', 'Disease', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Disease', (62, 68))	('tumor', 'Disease', (232, 237))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('metastasis', 'Disease', 'MESH:D009362', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))	('inhibit', 'NegReg', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('induce', 'PosReg', (148, 154))
13718	30132292	Tumor sequencing revealed a PDGFRA D842V mutation, which is known to be imatinib-resistant.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PDGFRA', 'Gene', '5156', (28, 34))	('PDGFRA', 'Gene', (28, 34))	('D842V', 'Mutation', 'rs121908585', (35, 40))	('imatinib', 'Chemical', 'MESH:D000068877', (72, 80))	('revealed', 'Reg', (17, 25))	('D842V', 'Var', (35, 40))
13736	25364818	Altered Protease-Activated Receptor-1 Expression and Signaling in a Malignant Pleural Mesothelioma Cell Line, NCI-H28, with Homozygous Deletion of the beta-Catenin Gene Protease activated receptors (PARs) are G-protein coupled receptors that are activated by an unique proteolytic mechanism.	('Protease-Activated Receptor-1', 'Gene', '2149', (8, 37))	('Expression', 'MPA', (38, 48))	('Deletion', 'Var', (135, 143))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (78, 98))	('Signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('Protease-Activated Receptor-1', 'Gene', (8, 37))	('beta-Catenin', 'Gene', (151, 163))	('Signaling', 'MPA', (53, 62))	('beta-Catenin', 'Gene', '1499', (151, 163))	('NCI-H28', 'CellLine', 'CVCL:1555', (110, 117))	('Malignant Pleural Mesothelioma', 'Disease', (68, 98))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (68, 98))
13752	25364818	Although asbestos exposure has a pivotal role in initiating both cellular and molecular events which lead to MM development other factors such as genetic and epigenetic alterations contribute to its pathogenesis.	('contribute', 'Reg', (181, 191))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('epigenetic alterations', 'Var', (158, 180))	('pathogenesis', 'biological_process', 'GO:0009405', ('199', '211'))	('MM development', 'Disease', (109, 123))
13754	25364818	Numerous evidences link aberrant GPCR expression and activation to several types of human malignancies.	('malignancies', 'Disease', (90, 102))	('activation', 'PosReg', (53, 63))	('aberrant', 'Var', (24, 32))	('GPCR expression', 'Protein', (33, 48))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))
13790	25364818	Met-5A cells were grown in Medium 199 supplemented with 10% FBS, 1% penicillin/streptomycin (100 units/ml/100 microg/ml), hydrocortisone (400 nM), EGF (3.3 nM) and human recombinant insulin (870 nM).	('streptomycin', 'Chemical', 'MESH:D013307', (79, 91))	('FBS', 'Disease', 'MESH:D005198', (60, 63))	('human', 'Species', '9606', (164, 169))	('insulin', 'molecular_function', 'GO:0016088', ('182', '189'))	('400', 'Var', (138, 141))	('EGF', 'Gene', (147, 150))	('insulin', 'Gene', (182, 189))	('penicillin', 'Chemical', 'MESH:D010406', (68, 78))	('FBS', 'Disease', (60, 63))	('insulin', 'Gene', '3630', (182, 189))	('hydrocortisone', 'Chemical', 'MESH:D006854', (122, 136))	('EGF', 'Gene', '1950', (147, 150))	('EGF', 'molecular_function', 'GO:0005154', ('147', '150'))
13829	25364818	In this MPM cell line, apart from a homozygous deletion of the beta-catenin gene (CTNNB1) a down-regulation of thrombomodulin expression by an epigenetic mechanism has been described.	('beta-catenin', 'Gene', (63, 75))	('thrombomodulin', 'Gene', (111, 125))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('thrombomodulin', 'Gene', '7056', (111, 125))	('CTNNB1', 'Gene', (82, 88))	('beta-catenin', 'Gene', '1499', (63, 75))	('deletion', 'Var', (47, 55))	('down-regulation', 'NegReg', (92, 107))	('CTNNB1', 'Gene', '1499', (82, 88))
13843	25364818	However, the pattern of the proliferative response was quite different in NCI-H28 cells compared to that of Met-5A cells.	('proliferative response', 'CPA', (28, 50))	('NCI-H28', 'Var', (74, 81))	('NCI-H28 cells', 'CellLine', 'CVCL:1555', (74, 87))
13854	25364818	First, we investigated PAR1-activated Gq signaling by analyzing intracellular Ca2+ mobilization after cell stimulation with either thrombin or the selective PAR1-AP.	('intracellular', 'cellular_component', 'GO:0005622', ('64', '77'))	('PAR1-AP', 'Var', (157, 164))	('thrombin', 'Gene', (131, 139))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('thrombin', 'Gene', '2147', (131, 139))	('Ca2+', 'Chemical', 'MESH:D000069285', (78, 82))	('intracellular Ca2+ mobilization', 'MPA', (64, 95))
13861	25364818	In the presence of SCH 79797, the inhibitory effect of thrombin was reduced indicating that PAR1 mediates the effect.	('thrombin', 'Gene', (55, 63))	('thrombin', 'Gene', '2147', (55, 63))	('SCH 79797', 'Chemical', 'MESH:C415424', (19, 28))	('reduced', 'NegReg', (68, 75))	('SCH 79797', 'Var', (19, 28))
13863	25364818	In the presence of SCH 79797, the inhibition curve was upwards shifted and the maximal inhibition at 100 nM was only 42% indicating that the inhibitory effect of cAMP accumulation is partially mediated by PAR1.	('cAMP', 'Gene', '820', (162, 166))	('SCH 79797', 'Var', (19, 28))	('cAMP', 'Gene', (162, 166))	('SCH 79797', 'Chemical', 'MESH:C415424', (19, 28))
13864	25364818	Various concentrations of the selective PAR1-AP did not cause any inhibition of isoproterenol stimulated cAMP production in both Met-5A and NCI-H28 cells (Figure 4.D) demonstrating the functional selectivity of this peptide agonist.	('isoproterenol', 'Chemical', 'MESH:D007545', (80, 93))	('NCI-H28 cells', 'CellLine', 'CVCL:1555', (140, 153))	('cAMP', 'Gene', (105, 109))	('PAR1-AP', 'Var', (40, 47))	('cAMP', 'Gene', '820', (105, 109))
13865	25364818	Next, we examined PAR1-activated G12/13 signaling by measuring RhoA activation after cell stimulation with either thrombin or PAR1-AP.	('RhoA', 'Gene', (63, 67))	('thrombin', 'Gene', (114, 122))	('PAR1-AP', 'Var', (126, 133))	('RhoA', 'Gene', '387', (63, 67))	('G12/13', 'Gene', '10672', (33, 39))	('thrombin', 'Gene', '2147', (114, 122))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('G12/13', 'Gene', (33, 39))
13868	25364818	Similarly to thrombin, PAR1-AP induced a modest increase of RhoA activation in NCI-H28 cells (Figure 5.B).	('PAR1-AP', 'Var', (23, 30))	('thrombin', 'Gene', '2147', (13, 21))	('RhoA', 'Gene', (60, 64))	('NCI-H28 cells', 'CellLine', 'CVCL:1555', (79, 92))	('RhoA', 'Gene', '387', (60, 64))	('thrombin', 'Gene', (13, 21))	('increase', 'PosReg', (48, 56))
13873	25364818	Using a single time point (5 min) we examined the effect of various thrombin concentrations ranging from 0.01 to 100 nM and found that a maximal response was induced by 0.1 nM thrombin in Met-5A cells while higher thrombin concentrations reduced pERK1/2 (Figure 6).	('thrombin', 'Gene', (176, 184))	('thrombin', 'Gene', (214, 222))	('thrombin', 'Gene', '2147', (176, 184))	('thrombin', 'Gene', (68, 76))	('thrombin', 'Gene', '2147', (214, 222))	('0.1 nM', 'Var', (169, 175))	('thrombin', 'Gene', '2147', (68, 76))
13895	25364818	have shown that MPM cell lines, which express tissue factor and PAR1 generate large tumors in mouse thoracic cavity thus indicating that activation of PAR1 promotes MPM cell growth.	('activation', 'Var', (137, 147))	('PAR1', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cell growth', 'biological_process', 'GO:0016049', ('169', '180'))	('PAR1', 'Gene', (151, 155))	('mouse', 'Species', '10090', (94, 99))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('promotes', 'PosReg', (156, 164))
13904	25364818	However, the proliferative response was slightly less marked than that observed with thrombin suggesting that either thrombin is also acting through other receptors or PAR1 activation by proteolytic cleavage elicits a cellular response which is not completely identical to that induced by a "free" synthetic peptide agonist.	('thrombin', 'Gene', (117, 125))	('thrombin', 'Gene', '2147', (85, 93))	('activation', 'PosReg', (173, 183))	('thrombin', 'Gene', '2147', (117, 125))	('cellular response', 'MPA', (218, 235))	('PAR1', 'Gene', (168, 172))	('elicits', 'Reg', (208, 215))	('thrombin', 'Gene', (85, 93))	('proteolytic cleavage', 'Var', (187, 207))
13913	25364818	It is interesting to note that the selective PAR1-AP did not cause any major inhibition of cAMP accumulation.	('cAMP', 'Gene', (91, 95))	('PAR1-AP', 'Var', (45, 52))	('cAMP', 'Gene', '820', (91, 95))
13922	25364818	The recruitment of caveolin-1 at cell junctions is greatly facilitated by the presence of beta-catenin in the cadherin/catenin complex.	('cadherin', 'Gene', (110, 118))	('cadherin', 'Gene', '1003', (110, 118))	('caveolin-1', 'Gene', '857', (19, 29))	('beta-catenin', 'Gene', (90, 102))	('facilitated', 'PosReg', (59, 70))	('beta-catenin', 'Gene', '1499', (90, 102))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('presence', 'Var', (78, 86))	('catenin complex', 'cellular_component', 'GO:0016342', ('119', '134'))	('caveolin-1', 'Gene', (19, 29))	('recruitment', 'MPA', (4, 15))
13923	25364818	In NCI-H28 cells, a homozygous deletion of the beta-catenin gene (CTNNB1) has been demonstrated suggesting that in these cells caveolin-1 is not completely associated to the plasma membrane.	('beta-catenin', 'Gene', '1499', (47, 59))	('CTNNB1', 'Gene', '1499', (66, 72))	('caveolin-1', 'Gene', '857', (127, 137))	('plasma membrane', 'cellular_component', 'GO:0005886', ('174', '189'))	('NCI-H28 cells', 'CellLine', 'CVCL:1555', (3, 16))	('CTNNB1', 'Gene', (66, 72))	('deletion', 'Var', (31, 39))	('beta-catenin', 'Gene', (47, 59))	('caveolin-1', 'Gene', (127, 137))
13932	25364818	In order to exclude a role of beta-catenin in recruiting PAR1 to the plasma membrane, we performed both rescue and deletion experiments and evaluated cell surface receptor expression by ELISA.	('beta-catenin', 'Gene', '1499', (30, 42))	('deletion', 'Var', (115, 123))	('cell surface', 'cellular_component', 'GO:0009986', ('150', '162'))	('cell surface receptor', 'Gene', (150, 171))	('cell surface receptor', 'Gene', '57126', (150, 171))	('beta-catenin', 'Gene', (30, 42))	('plasma membrane', 'cellular_component', 'GO:0005886', ('69', '84'))
13943	21701776	In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent.	('tumor', 'Disease', (109, 114))	('mesothelioma', 'Disease', (96, 108))	('TGFBI', 'Gene', (263, 268))	('mesothelioma', 'Disease', 'MESH:D008654', (301, 313))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutants', 'Var', (160, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('mutants', 'Var', (284, 291))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TGFBI', 'Gene', (144, 149))	('mesothelioma', 'Disease', (301, 313))	('overexpression', 'PosReg', (269, 283))
13954	21701776	Mutations in p53 have only been observed in a few cases, while Cyclin D1 has been shown to be overexpressed and transforming growth factor (TGF) and other inflammatory cytokines were increased in mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (196, 209))	('transforming growth factor', 'MPA', (112, 138))	('mesotheliomas', 'Disease', (196, 209))	('Cyclin', 'molecular_function', 'GO:0016538', ('63', '69'))	('increased', 'PosReg', (183, 192))	('p53', 'Gene', '7157', (13, 16))	('overexpressed', 'PosReg', (94, 107))	('Mutations', 'Var', (0, 9))	('Cyclin D1', 'Gene', '595', (63, 72))	('p53', 'Gene', (13, 16))	('Cyclin D1', 'Gene', (63, 72))
13956	21701776	Mutations or altered expression of this gene is believed to be responsible for the pathogenesis of human corneal dystrophy, angiogenesis, osteogenesis and inflammation.	('osteogenesis', 'biological_process', 'GO:0001503', ('138', '150'))	('inflammation', 'Disease', (155, 167))	('corneal dystrophy', 'Phenotype', 'HP:0001131', (105, 122))	('corneal dystrophy', 'Disease', (105, 122))	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('corneal dystrophy', 'Disease', 'MESH:D003317', (105, 122))	('expression', 'MPA', (21, 31))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (99, 104))	('osteogenesis', 'Disease', 'MESH:D010013', (138, 150))	('inflammation', 'biological_process', 'GO:0006954', ('155', '167'))	('responsible', 'Reg', (63, 74))	('altered', 'Var', (13, 20))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('osteogenesis', 'Disease', (138, 150))
13988	21701776	Antibodies to EGF receptor, p85, phosphor-AKT, pan-AKT, phosphor-mTOR, mTOR, phosphor-p70S6, p-70S6, phosphor-4EBP1, 4EBP1, and beta-actin were obtained from Cell Signaling Technology.	('4EBP1', 'Gene', (117, 122))	('4EBP1', 'Gene', (110, 115))	('AKT', 'Gene', '207', (42, 45))	('mTOR', 'Gene', (65, 69))	('beta-actin', 'Gene', '728378', (128, 138))	('p-70S6', 'Var', (93, 99))	('EGF', 'molecular_function', 'GO:0005154', ('14', '17'))	('4EBP1', 'Gene', '1978', (117, 122))	('mTOR', 'Gene', '2475', (65, 69))	('4EBP1', 'Gene', '1978', (110, 115))	('AKT', 'Gene', (51, 54))	('mTOR', 'Gene', (71, 75))	('EGF receptor', 'Gene', '1956', (14, 26))	('beta-actin', 'Gene', (128, 138))	('AKT', 'Gene', (42, 45))	('mTOR', 'Gene', '2475', (71, 75))	('Signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('EGF receptor', 'Gene', (14, 26))	('AKT', 'Gene', '207', (51, 54))
13997	21701776	Meanwhile, the mesothelioma cell line H28 which does not express endogenous TGFBI, was transfected with ectopic TGFBI.	('mesothelioma', 'Disease', (15, 27))	('TGFBI', 'Gene', (76, 81))	('ectopic', 'Var', (104, 111))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))
13999	21701776	We then chose 5AT1, which has undetectable TGFBI and the scrambled RNA transfected cell line 5ATE for most of the studies in this report; so as to H28V, the empty vector transfected cell line, and TGFBI expressing H28T7 were selected in the parallel study.	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('H28V', 'Var', (147, 151))	('H28V', 'SUBSTITUTION', 'None', (147, 151))	('H28T7', 'CellLine', 'CVCL:1555', (214, 219))	('H28T7', 'Var', (214, 219))
14000	21701776	Conceivably, parental H28 and vector carrying H28V cell lines that do not express endogenous TGFBI, grew more rapidly than their counterparts H28T6 and H28T7 (Fig.	('H28V', 'SUBSTITUTION', 'None', (46, 50))	('H28T7', 'CellLine', 'CVCL:1555', (152, 157))	('H28V', 'Var', (46, 50))	('H28T6', 'CellLine', 'CVCL:1555', (142, 147))	('TGFBI', 'Gene', (93, 98))	('grew', 'CPA', (100, 104))
14001	21701776	2C, the expressions of c-myc, cyclin-D1 and phosphor-Rb were all up-regulated in both 5AT1 and H28V, compared with their corresponding TGFBI-expressing controls 5ATE and H28T7, respectively; quantitative data show 2-4-fold increases in Fig.	('up-regulated', 'PosReg', (65, 77))	('cyclin', 'molecular_function', 'GO:0016538', ('30', '36'))	('5AT1', 'Var', (86, 90))	('cyclin-D1', 'Gene', (30, 39))	('cyclin-D1', 'Gene', '595', (30, 39))	('H28V', 'Var', (95, 99))	('H28V', 'SUBSTITUTION', 'None', (95, 99))	('H28T7', 'CellLine', 'CVCL:1555', (170, 175))	('phosphor-Rb', 'Gene', (44, 55))	('expressions', 'MPA', (8, 19))	('c-myc', 'Gene', '4609', (23, 28))	('c-myc', 'Gene', (23, 28))
14002	21701776	2E, ablation of TGFBI significantly increased the anchorage-independent growth in 5AT1 and 5AT2, versus 5ATN and 5ATE; a similar effect was also observed in the H28T7 and H28V cell lines (data not shown).	('anchorage-independent growth', 'CPA', (50, 78))	('TGFBI', 'Gene', (16, 21))	('H28V', 'Var', (171, 175))	('increased', 'PosReg', (36, 45))	('ablation', 'Var', (4, 12))	('H28V', 'SUBSTITUTION', 'None', (171, 175))	('H28T7', 'CellLine', 'CVCL:1555', (161, 166))
14003	21701776	In a separate study in our group, H28T7 had a remarkably suppressed tumorigenic potential upon inoculation into immune-deficient nude mice when compared with H28V cells (data not shown).	('tumor', 'Disease', (68, 73))	('H28T7', 'CellLine', 'CVCL:1555', (34, 39))	('nude mice', 'Species', '10090', (129, 138))	('H28T7', 'Var', (34, 39))	('H28V', 'Var', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('H28V', 'SUBSTITUTION', 'None', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppressed', 'NegReg', (57, 67))
14007	21701776	Similarly, H28T7 showed a slower and less dramatic response in AKT phosphorylation upon EGF stimulation than H28V (Fig.	('EGF', 'molecular_function', 'GO:0005154', ('88', '91'))	('H28V', 'Var', (109, 113))	('EGF', 'Gene', (88, 91))	('AKT', 'Gene', (63, 66))	('H28T7', 'CellLine', 'CVCL:1555', (11, 16))	('H28V', 'SUBSTITUTION', 'None', (109, 113))	('EGF', 'Gene', '1950', (88, 91))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('H28T7', 'Var', (11, 16))	('AKT', 'Gene', '207', (63, 66))
14008	21701776	These data strongly indicate that the absence of TGFBI potentiates the activation of Akt upon growth factor stimulation.	('Akt', 'Gene', '207', (85, 88))	('Akt', 'Gene', (85, 88))	('absence', 'Var', (38, 45))	('TGFBI', 'Gene', (49, 54))	('potentiates', 'PosReg', (55, 66))
14010	21701776	Therefore, we next examined the phosphorylation status of Ser2448 in mTOR, an indicator of its activation, in these four cell lines.	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('mTOR', 'Gene', (69, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('Ser2448', 'Var', (58, 65))	('Ser2448', 'Chemical', '-', (58, 65))	('mTOR', 'Gene', '2475', (69, 73))
14013	21701776	Consistently, a similar effect with slightly different pattern on mTOR phosphorylation was documented in H28V versus H28T7 cells (Fig.	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('H28V', 'Var', (105, 109))	('H28V', 'SUBSTITUTION', 'None', (105, 109))	('H28T7', 'CellLine', 'CVCL:1555', (117, 122))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))
14019	21701776	In H28V cells, both S6K and 4EBP1 are markedly phosphorylated in response to EGF treatment, higher than in H28T7 cells, with S6K exhibiting a more transient response as compared with 5AT1; while that of 4EBP1 showed a similar pattern in these two sets of cells (Fig.	('4EBP1', 'Gene', (203, 208))	('4EBP1', 'Gene', (28, 33))	('EGF', 'Gene', (77, 80))	('S6K', 'Var', (125, 128))	('higher', 'PosReg', (92, 98))	('S6K and 4EBP1', 'Gene', '6198', (20, 33))	('S6K', 'Mutation', 'p.S6K', (20, 23))	('H28T7', 'CellLine', 'CVCL:1555', (107, 112))	('EGF', 'Gene', '1950', (77, 80))	('H28V', 'Var', (3, 7))	('EGF', 'molecular_function', 'GO:0005154', ('77', '80'))	('H28V', 'SUBSTITUTION', 'None', (3, 7))	('4EBP1', 'Gene', '1978', (28, 33))	('S6K', 'Mutation', 'p.S6K', (125, 128))	('4EBP1', 'Gene', '1978', (203, 208))
14021	21701776	5A and B, the phosphorylations of Akt, mTOR, S6K and 4EBP1 were all enhanced in TGFBI-deficient cell lines versus TGFBI-expressing cell lines, i.e., 5AT1 versus 5ATE, and H28V versus H28T7.	('enhanced', 'PosReg', (68, 76))	('S6K and 4EBP1', 'Gene', '6198', (45, 58))	('TGFBI-deficient', 'Gene', (80, 95))	('5AT1', 'Var', (149, 153))	('H28V', 'Var', (171, 175))	('mTOR', 'Gene', (39, 43))	('Akt', 'Gene', '207', (34, 37))	('mTOR', 'Gene', '2475', (39, 43))	('H28V', 'SUBSTITUTION', 'None', (171, 175))	('H28T7', 'CellLine', 'CVCL:1555', (183, 188))	('Akt', 'Gene', (34, 37))	('phosphorylations', 'MPA', (14, 30))
14023	21701776	After establishing that Akt/mTOR pathway was up-regulated in TGFB-deficient cells, we asked whether the absence of TGFBI indeed affected protein synthesis in cell culture, which would be ultimately translated into a perceived functional molecule.	('mTOR', 'Gene', '2475', (28, 32))	('up-regulated', 'PosReg', (45, 57))	('mTOR', 'Gene', (28, 32))	('TGFB', 'Gene', '7040', (115, 119))	('TGFB', 'Gene', (61, 65))	('TGFB', 'Gene', '7040', (61, 65))	('protein synthesis', 'MPA', (137, 154))	('absence', 'Var', (104, 111))	('Akt', 'Gene', '207', (24, 27))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('TGFB', 'Gene', (115, 119))	('affected', 'Reg', (128, 136))	('protein synthesis', 'biological_process', 'GO:0006412', ('137', '154'))	('Akt', 'Gene', (24, 27))
14024	21701776	6, both 5AT1 and H28V, cells without TGFBI have significantly enhanced protein synthesis rate compared with their TGFBI-expressing counterparts, establishing that TGFBI plays a suppressive role in protein synthesis.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('protein synthesis rate', 'MPA', (71, 93))	('enhanced', 'PosReg', (62, 70))	('H28V', 'Var', (17, 21))	('protein synthesis', 'biological_process', 'GO:0006412', ('197', '214'))	('H28V', 'SUBSTITUTION', 'None', (17, 21))	('protein synthesis', 'biological_process', 'GO:0006412', ('71', '88'))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
14043	21701776	2D), which corresponds to our previous observations in different type of tumorigenic cells expressing exogenous TGFBI, strongly suggesting that loss of TGFBI expression may adapt the cells to receive survival signals irrespective of the unfavorable environment, and potentially gain the ability to undergo tumorigenic transformation.	('loss', 'Var', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('gain', 'PosReg', (278, 282))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('adapt', 'Reg', (173, 178))	('tumor', 'Disease', (306, 311))	('tumor', 'Disease', (73, 78))	('TGFBI', 'Gene', (152, 157))
14048	21701776	Mesothelioma cells treated with PI3K inhibitor LY294002 was found to have a synergistic effect on inhibiting cell proliferation and inducing apoptosis when combined with cisplatin, a cell division interfering drug.	('cell proliferation', 'CPA', (109, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('LY294002', 'Chemical', 'MESH:C085911', (47, 55))	('cell division', 'biological_process', 'GO:0051301', ('183', '196'))	('inducing', 'Reg', (132, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('LY294002', 'Var', (47, 55))	('apoptosis', 'CPA', (141, 150))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('inhibiting', 'NegReg', (98, 108))
14056	21701776	With growth factor receptor stimulation, p85 binds to the phosphorylated tyrosine sites on the cytoplasmic domain of the activated receptor through its SH2 domain and then releases the inhibition of PI3K.	('inhibition', 'MPA', (185, 195))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('binds', 'Interaction', (45, 50))	('releases', 'PosReg', (172, 180))	('p85', 'Var', (41, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))
14060	21701776	However, recent studies suggested that TGFBI expression actually increased the metastatic ability of a colon cancer and ovarian cancer cell line.	('increased', 'PosReg', (65, 74))	('colon cancer', 'Disease', (103, 115))	('TGFBI', 'Gene', (39, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('metastatic ability of a', 'CPA', (79, 102))	('ovarian cancer', 'Disease', (120, 134))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colon cancer', 'Disease', 'MESH:D015179', (103, 115))	('expression', 'Var', (45, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
14067	23978876	Downregulation of gremlin-1 expression by siRNA-mediated silencing in a mesothelioma cell line inhibited cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('Downregulation', 'NegReg', (0, 14))	('expression', 'MPA', (28, 38))	('inhibited', 'NegReg', (95, 104))	('mesothelioma', 'Disease', (72, 84))	('gremlin-1', 'Gene', (18, 27))	('silencing', 'Var', (57, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('cell proliferation', 'CPA', (105, 123))
14092	23978876	The final filtered list contained four proteins: cytokeratin-9 (Swiss-Prot: P35527), fibrillin-2 (Swiss-Prot: P35556), cytokeratin-2a (Swiss-Prot: P35908) and APOBEC1-binding protein 2 (Swiss-Prot: Q9UBS4).	('cytokeratin-9', 'Gene', (49, 62))	('fibrillin', 'molecular_function', 'GO:0001511', ('85', '94'))	('APOBEC1-binding protein 2', 'Gene', '51726', (159, 184))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('APOBEC1-binding protein 2', 'Gene', (159, 184))	('Swiss-Prot', 'Var', (135, 145))	('fibrillin-2', 'Gene', (85, 96))	('fibrillin-2', 'Gene', '2201', (85, 96))	('APOBEC', 'cellular_component', 'GO:0030895', ('159', '165'))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('fibrillin', 'cellular_component', 'GO:0001527', ('85', '94'))	('cytokeratin-9', 'Gene', '3857', (49, 62))
14132	23978876	To determine whether lack of gremlin induces apoptosis, H2052 cells were cultured on coverslips, transfected with siRNAs and analyzed with TUNEL assay 3 days after transfection (Figure 6d).	('gremlin', 'Gene', '26585', (29, 36))	('lack', 'Var', (21, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('gremlin', 'Gene', (29, 36))
14135	23978876	These results suggest that although lack of gremlin impaired cell proliferation, it did not induce apoptosis.	('impaired', 'NegReg', (52, 60))	('gremlin', 'Gene', '26585', (44, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('gremlin', 'Gene', (44, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('lack', 'Var', (36, 40))	('cell proliferation', 'CPA', (61, 79))
14137	23978876	Gremlin-1 silencing increased BMP-dependent reporter activity in H2052 cells (Figure 7a) as well as the expression of a BMP target gene Id1 (inhibitor of differentiation/DNA binding 1, Figure 7b), suggesting that endogenous gremlin-1 regulates BMP activity negatively.	('increased', 'PosReg', (20, 29))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('BMP', 'Gene', (120, 123))	('BMP', 'Gene', (244, 247))	('Gremlin-1', 'Gene', (0, 9))	('BMP', 'Gene', '649', (30, 33))	('Id1', 'Gene', (136, 139))	('Id1', 'Gene', '3397', (136, 139))	('BMP', 'Gene', '649', (120, 123))	('BMP', 'Gene', (30, 33))	('DNA binding', 'molecular_function', 'GO:0003677', ('170', '181'))	('BMP', 'Gene', '649', (244, 247))	('silencing', 'Var', (10, 19))
14140	23978876	H2052 cells were found to have high basal level of phospho-Akt (S473), which was not altered in gremlin-1-silenced cells (Figures 7d-f).	('H2052', 'Var', (0, 5))	('Akt', 'Gene', '207', (59, 62))	('Akt', 'Gene', (59, 62))
14143	23978876	Further, increased levels of p53 phosphorylation (S46 and S392) were reflected in increased mRNA expression levels of p21 (Cip1/Waf1) in H2052 cells (Figure 7h).	('Cip1', 'Gene', '1026', (123, 127))	('mRNA expression levels', 'MPA', (92, 114))	('S46', 'Var', (50, 53))	('p21', 'Gene', '1026', (118, 121))	('p21', 'Gene', (118, 121))	('increased', 'PosReg', (9, 18))	('p53', 'Gene', (29, 32))	('Cip1', 'Gene', (123, 127))	('S392', 'Var', (58, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('increased', 'PosReg', (82, 91))	('p53', 'Gene', '7157', (29, 32))	('Waf1', 'Gene', (128, 132))	('Waf1', 'Gene', '1026', (128, 132))
14153	23978876	Slug protein levels also showed a dramatic difference between H2052 and H2452 cells (Figure 8d).	('H2052', 'Var', (62, 67))	('Slug', 'Gene', '6591', (0, 4))	('Slug', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('H2452', 'CellLine', 'CVCL:1553', (72, 77))
14154	23978876	Silencing of gremlin-1 by siRNA transfection significantly reduced slug mRNA and protein expressions in H2052 cells (Figure 8e and i).	('reduced', 'NegReg', (59, 66))	('slug', 'Gene', (67, 71))	('gremlin-1', 'Gene', (13, 22))	('slug', 'Gene', '6591', (67, 71))	('Silencing', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
14206	23978876	Silencing of gremlin-1 expression led to reduced slug mRNA and protein levels.	('slug', 'Gene', '6591', (49, 53))	('reduced', 'NegReg', (41, 48))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('gremlin-1', 'Gene', (13, 22))	('Silencing', 'Var', (0, 9))	('slug', 'Gene', (49, 53))
14213	23978876	This indicates that blocking gremlin-1 function may be beneficial in mesothelioma especially when combined with chemotherapy.	('blocking', 'Var', (20, 28))	('mesothelioma', 'Disease', (69, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('gremlin-1', 'Gene', (29, 38))	('function', 'MPA', (39, 47))
14272	23414396	However, the average robust sandwich variance estimates based on dfbetas residuals were systematically lower than the empirical variance of the parameter estimates, which resulted in too narrow confidence intervals (CI) and low coverage probabilities.	('dfbetas', 'Chemical', '-', (65, 72))	('dfbetas', 'Gene', (65, 72))	('residuals', 'Var', (73, 82))	('lower', 'NegReg', (103, 108))
14274	23414396	The Cox proportional hazards model specifies the hazard function as where lambda0 is the baseline hazard, x(t) is the vector of observed covariate values at time t and beta is the vector of unknown regression parameters.	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('lambda0', 'Var', (74, 81))
14324	23414396	Indeed, missmodeling the covariates has already been shown to induce bias in sandwich variance estimator based on dfbetas of unweighted Cox model for nested case-control analysis.	('missmodeling', 'Var', (8, 20))	('Cox', 'Gene', '1351', (136, 139))	('Cox', 'Gene', (136, 139))	('dfbetas', 'Chemical', '-', (114, 121))	('bias', 'MPA', (69, 73))
14368	29534192	The dose-specific mesothelioma risk to age 50 estimated from these data is 0.00032% per f/mg [95% confidence interval (CI) 0.00026%, 0.00040%)] for men and 0.00019% per f/mg (95% CI 0.00014%, 0.00024%) for women (P < 0.002).	('0.00032%', 'Var', (75, 83))	('men', 'Species', '9606', (148, 151))	('0.00019%', 'Var', (156, 164))	('mesothelioma', 'Disease', (18, 30))	('men', 'Species', '9606', (208, 211))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('women', 'Species', '9606', (206, 211))
14379	29534192	Average lung burdens in men born 1940-54 (Table 2) reflect the ranking of occupational and environmental relative risks seen in our case-control study (154 f/mg in carpenters, 88 f/mg in plumbers, electricians and decorators, 60 f/mg in other high-risk occupations (including shipbuilding and lagging), 49 f/mg in medium-risk (mainly factory) work and 30 f/mg in general construction).	('f/mg', 'Var', (156, 160))	('men', 'Species', '9606', (24, 27))	('lung burdens', 'MPA', (8, 20))	('men', 'Species', '9606', (98, 101))
14387	29534192	Therefore we believe that the female estimate of the risk per f/mg (0.00019% by age 50, lifetime risk 0.010%) provides a more reliable indication of future mesothelioma rates in both sexes from recent exposure, which is predominantly environmental.	('mesothelioma', 'Disease', (156, 168))	('men', 'Species', '9606', (241, 244))	('mesothelioma', 'Disease', 'MESH:D008654', (156, 168))	('f/mg', 'Var', (62, 66))
14471	28191281	Apart from domestic, environmental, and occupational exposure to asbestos or other carcinogenic mineral fibers, mesotheliomas can also be caused by inherited BAP1 germline mutations.	('asbestos', 'Chemical', 'MESH:D001194', (65, 73))	('carcinogenic mineral fibers', 'Disease', 'MESH:C537337', (83, 110))	('BAP1', 'Gene', (158, 162))	('carcinogenic mineral fibers', 'Disease', (83, 110))	('BAP1', 'Gene', '8314', (158, 162))	('caused by', 'Reg', (138, 147))	('mesotheliomas', 'Disease', 'MESH:D008654', (112, 125))	('germline', 'Var', (163, 171))	('mesotheliomas', 'Disease', (112, 125))
14472	28191281	Moreover carriers of germline BAP1 mutations are at increased risk of mesothelioma when exposed to asbestos, including low doses that usually are not sufficient to cause cancer.	('asbestos', 'Chemical', 'MESH:D001194', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('BAP1', 'Gene', (30, 34))	('cancer', 'Disease', (170, 176))	('mesothelioma', 'Disease', (70, 82))	('risk', 'Reg', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('BAP1', 'Gene', '8314', (30, 34))	('mutations', 'Var', (35, 44))
14482	28191281	Genomic aberrations include aneuploidies, point mutations, as well as numerous chromosomal rearrangements that result in deletions, amplification, inversions and translocations.	('point mutations', 'Var', (42, 57))	('result', 'Reg', (111, 117))	('deletions', 'Var', (121, 130))	('aneuploidies', 'Disease', (28, 40))	('aneuploidies', 'Disease', 'MESH:D000782', (28, 40))	('numerous chromosomal rearrangements', 'Phenotype', 'HP:0040012', (70, 105))	('inversions', 'Var', (147, 157))	('amplification', 'MPA', (132, 145))	('translocations', 'Var', (162, 176))
14494	28191281	In normoxic conditions, hydroxylated HIF-1alpha is ubiquitinated by von-Hippel-Lindau E3 ubiquitin ligase and degraded by the proteasome.	('proteasome', 'molecular_function', 'GO:0004299', ('126', '136'))	('proteasome', 'cellular_component', 'GO:0000502', ('126', '136'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('89', '98'))	('degraded', 'NegReg', (110, 118))	('HIF-1alpha', 'Gene', (37, 47))	('von-Hippel-Lindau', 'Disease', 'MESH:D006623', (68, 85))	('ubiquitinated', 'MPA', (51, 64))	('hydroxylated', 'Var', (24, 36))	('von-Hippel-Lindau', 'Disease', (68, 85))	('E3 ubiquitin ligase', 'Protein', (86, 105))	('HIF-1alpha', 'Gene', '3091', (37, 47))
14515	28191281	It is an established endogenous marker of hypoxia, and particularly overexpressed in VHL mutated clear cell renal cell carcinomas, mesotheliomas, kidney, as well as other hypoxic solid tumors.	('hypoxic solid tumors', 'Disease', (171, 191))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 128))	('mesotheliomas', 'Disease', 'MESH:D008654', (131, 144))	('hypoxia', 'Disease', (42, 49))	('VHL', 'Disease', 'MESH:D006623', (85, 88))	('overexpressed', 'PosReg', (68, 81))	('clear cell renal cell carcinoma', 'Disease', (97, 128))	('cell renal cell carcinomas', 'Disease', 'MESH:C538614', (103, 129))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (97, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (108, 129))	('cell renal cell carcinomas', 'Disease', (103, 129))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (97, 128))	('mutated', 'Var', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('VHL', 'Disease', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('mesotheliomas', 'Disease', (131, 144))	('hypoxic solid tumors', 'Disease', 'MESH:D009369', (171, 191))	('kidney', 'Disease', (146, 152))
14542	28191281	A tumor suppressor gene most commonly deleted or mutated in mesotheliomas (~60% of cases) is BRCA1 associated protein-1 (BAP1), a C-terminal family of deubiquitinating enzymes (DUBs) linked to DNA damage repair regulation.	('BRCA1 associated protein-1', 'Gene', '8314', (93, 119))	('mutated', 'Var', (49, 56))	('BAP1', 'Gene', '8314', (121, 125))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('2', '18'))	('BRCA1 associated protein-1', 'Gene', (93, 119))	('BAP1', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('regulation', 'biological_process', 'GO:0065007', ('211', '221'))	('tumor', 'Disease', (2, 7))	('mesotheliomas', 'Disease', 'MESH:D008654', (60, 73))	('mesotheliomas', 'Disease', (60, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('2', '18'))
14544	28191281	Although BAP1's crystal structure has been solved, a therapeutic drug for patients carrying mutations of BAP1 has not been developed.	('patients', 'Species', '9606', (74, 82))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', '8314', (9, 13))	('mutations', 'Var', (92, 101))	('BAP1', 'Gene', (9, 13))	('BAP1', 'Gene', (105, 109))
14545	28191281	Moreover, cell cycle related genes often found mutated in pleural mesothelioma and regulated by hypoxic stress are cyclin-dependent kinases (such as ~15-45% incidence in deletions of CDKN1,2A).	('cyclin', 'molecular_function', 'GO:0016538', ('115', '121'))	('hypoxic stress', 'Disease', (96, 110))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (58, 78))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (58, 78))	('cell cycle', 'biological_process', 'GO:0007049', ('10', '20'))	('deletions', 'Var', (170, 179))	('CDKN1,2A', 'Gene', '1026;1029', (183, 191))	('hypoxic stress', 'Disease', 'MESH:D004194', (96, 110))	('pleural mesothelioma', 'Disease', (58, 78))
14548	28191281	Interestingly, BAP1 inactivation is associated with carbonic anhydrase 9 (CA-IX) expression.	('CA-IX', 'Gene', (74, 79))	('inactivation', 'Var', (20, 32))	('carbonic anhydrase 9', 'Gene', '768', (52, 72))	('BAP1', 'Gene', '8314', (15, 19))	('CA-IX', 'Gene', '768', (74, 79))	('associated', 'Reg', (36, 46))	('BAP1', 'Gene', (15, 19))	('carbonic anhydrase 9', 'Gene', (52, 72))	('expression', 'MPA', (81, 91))
14549	28191281	Additionally, two important genes consistently found mutated or inactivated in pleural mesotheliomas are neurofibromin or merlin (NF2, with ~ 45% incidence of aberration), a negative regulator of E3 ubiquitin ligase, and the Large Tumor Suppressor kinase 1/2 (LATS1/2, with ~ 30% incidence of aberration), two components of the Hippo pathway.	('NF2', 'Gene', (130, 133))	('LATS1/2', 'Gene', (260, 267))	('mutated', 'Var', (53, 60))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (79, 99))	('merlin', 'Gene', (122, 128))	('neurofibromin', 'Gene', '4763', (105, 118))	('Large Tumor Suppressor kinase 1/2', 'Gene', (225, 258))	('Large Tumor Suppressor kinase 1/2', 'Gene', '9113;26524', (225, 258))	('inactivated', 'NegReg', (64, 75))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('231', '247'))	('neurofibromin', 'Gene', (105, 118))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (79, 100))	('merlin', 'Gene', '4771', (122, 128))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('231', '247'))	('NF2', 'Gene', '4771', (130, 133))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (79, 100))	('Tumor', 'Phenotype', 'HP:0002664', (231, 236))	('pleural mesotheliomas', 'Disease', (79, 100))	('LATS1/2', 'Gene', '9113;26524', (260, 267))	('ubiquitin', 'molecular_function', 'GO:0031386', ('199', '208'))
14553	28191281	The homologous and non-homologous recombination as well as mismatch are inhibited under hypoxia, increasing unrepaired replication errors and double stranded breaks.	('homologous recombination', 'biological_process', 'GO:0035825', ('23', '47'))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('hypoxia', 'Disease', (88, 95))	('mismatch', 'Var', (59, 67))	('double stranded breaks', 'CPA', (142, 164))	('unrepaired', 'MPA', (108, 118))	('homologous', 'CPA', (4, 14))	('increasing', 'PosReg', (97, 107))
14557	28191281	A CHEK1 inhibitor, LY2606369, is currently used in clinical trials for breast cancer patients with BRCA1/2 mutations and could be re-purposed for treating pleural mesothelioma malignancy.	('mesothelioma malignancy', 'Phenotype', 'HP:0100001', (163, 186))	('breast cancer', 'Disease', (71, 84))	('CHEK1', 'Gene', (2, 7))	('pleural mesothelioma malignancy', 'Disease', (155, 186))	('mutations', 'Var', (107, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pleural mesothelioma malignancy', 'Disease', 'MESH:C562839', (155, 186))	('patients', 'Species', '9606', (85, 93))	('BRCA1/2', 'Gene', (99, 106))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (155, 175))	('CHEK1', 'Gene', '1111', (2, 7))	('LY2606369', 'Chemical', '-', (19, 28))	('BRCA1/2', 'Gene', '672;675', (99, 106))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
14559	28191281	Thus, co-targeting DNA damage genes in addition to chemotherapy may improve patient survival.	('improve', 'PosReg', (68, 75))	('co-targeting', 'Var', (6, 18))	('patient survival', 'CPA', (76, 92))	('patient', 'Species', '9606', (76, 83))	('DNA damage genes', 'Gene', (19, 35))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
14561	28191281	Additionally, there are many microRNAs identified to date to be associated with poor survival in mesotheliomas (miR-210, mir-126, miR-125a-5p, miR-484, miR-320, and let-7a, miR-29c, miR-16, miR-31, miR-34, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, and miR-429, and miR-193, miR-200, and miR-192 with diagnostic confidence).	('miR', 'Gene', '220972', (267, 270))	('miR', 'Gene', (245, 248))	('miR', 'Gene', (198, 201))	('miR', 'Gene', '220972', (235, 238))	('miR-16', 'Gene', (182, 188))	('miR-429', 'Gene', (267, 274))	('miR-203', 'Gene', '406986', (245, 252))	('miR-200c', 'Gene', '406985', (235, 243))	('mesotheliomas', 'Disease', (97, 110))	('miR-205', 'Gene', '406988', (254, 261))	('miR-31', 'Gene', (190, 196))	('miR-200b', 'Gene', '406984', (225, 233))	('miR', 'Gene', '220972', (289, 292))	('miR-200a', 'Gene', '406983', (215, 223))	('let-7a', 'Var', (165, 171))	('miR', 'Gene', '220972', (280, 283))	('miR', 'Gene', '220972', (225, 228))	('miR', 'Gene', (267, 270))	('miR-29c', 'Gene', (173, 180))	('miR-34', 'Gene', (198, 204))	('miR', 'Gene', (235, 238))	('miR-200c', 'Gene', (235, 243))	('miR', 'Gene', '220972', (130, 133))	('mesotheliomas', 'Disease', 'MESH:D008654', (97, 110))	('miR-16', 'Gene', '51573', (182, 188))	('miR-192', 'Gene', (302, 309))	('miR', 'Gene', (289, 292))	('miR-205', 'Gene', (254, 261))	('miR', 'Gene', '220972', (152, 155))	('mir-126', 'Gene', '406913', (121, 128))	('miR', 'Gene', '220972', (215, 218))	('miR', 'Gene', (280, 283))	('miR-429', 'Gene', '554210', (267, 274))	('miR', 'Gene', (190, 193))	('miR', 'Gene', (225, 228))	('miR-141', 'Gene', '406933', (206, 213))	('miR-31', 'Gene', '407035', (190, 196))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', '220972', (182, 185))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', '220972', (254, 257))	('miR-210', 'Gene', '406992', (112, 119))	('miR-141', 'Gene', (206, 213))	('miR', 'Gene', '220972', (302, 305))	('miR', 'Gene', (152, 155))	('miR-200a', 'Gene', (215, 223))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', (215, 218))	('mir-126', 'Gene', (121, 128))	('miR-484', 'Gene', '619553', (143, 150))	('miR', 'Gene', '220972', (245, 248))	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', '220972', (190, 193))	('miR-200b', 'Gene', (225, 233))	('poor', 'NegReg', (80, 84))	('miR', 'Gene', (112, 115))	('miR', 'Gene', (182, 185))	('miR-203', 'Gene', (245, 252))	('miR', 'Gene', (143, 146))	('miR-192', 'Gene', '406967', (302, 309))	('miR', 'Gene', (206, 209))	('miR', 'Gene', (254, 257))	('miR-210', 'Gene', (112, 119))	('miR-34', 'Gene', '407040', (198, 204))	('miR-484', 'Gene', (143, 150))	('miR', 'Gene', (302, 305))	('miR', 'Gene', (173, 176))	('miR-29c', 'Gene', '407026', (173, 180))
14570	28191281	For instance, inhibiting the UPR (with MG132 and PSI) results in apoptosis and inhibition of invasion in malignant pleural mesothelioma cells.	('malignant pleural mesothelioma', 'Disease', (105, 135))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (105, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (115, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('apoptosis', 'CPA', (65, 74))	('PSI', 'Disease', (49, 52))	('inhibition', 'NegReg', (79, 89))	('inhibiting', 'NegReg', (14, 24))	('invasion', 'CPA', (93, 101))	('PSI', 'Disease', 'None', (49, 52))	('MG132', 'Var', (39, 44))	('MG132', 'Chemical', 'MESH:C072553', (39, 44))
14755	33319489	Results: In mesothelioma cell lines, VER-155008 (5.0 muM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (139, 145))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('128', '145'))	('arrest', 'Disease', (139, 145))	('inhibited', 'NegReg', (66, 75))	('VER-155008', 'Var', (37, 47))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))
14758	33319489	This plasmid produces light chain 3 (LC3) protein bound to green fluorescent protein (GFP), and LC3DeltaG protein, an internal control, bound to red fluorescent protein (RFP).	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('red fluorescent protein', 'Gene', '5987', (145, 168))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('bound', 'Interaction', (50, 55))	('light chain 3', 'Gene', '84557', (22, 35))	('LC3DeltaG', 'Var', (96, 105))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('light chain 3', 'Gene', (22, 35))	('red fluorescent protein', 'Gene', (145, 168))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('bound', 'Interaction', (136, 141))	('LC3', 'Gene', (37, 40))
14766	33319489	8  Because macroautophagy is also induced by epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), which are molecular target drugs for NSCLC patients with sensitive EGFR mutations, autophagy is expected to be a new therapeutic target in the treatment of NSCLC independent of EGFR expression.	('patients', 'Species', '9606', (163, 171))	('epidermal growth factor receptor', 'Gene', (45, 77))	('macroautophagy', 'CPA', (11, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('297', '301'))	('autophagy', 'biological_process', 'GO:0016236', ('203', '212'))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('45', '68'))	('EGFR', 'Gene', (187, 191))	('epidermal growth factor receptor', 'Gene', '1956', (45, 77))	('macroautophagy', 'biological_process', 'GO:0016236', ('11', '25'))	('induced', 'Reg', (34, 41))	('autophagy', 'biological_process', 'GO:0006914', ('203', '212'))	('mutations', 'Var', (192, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (276, 281))	('autophagy', 'CPA', (203, 212))
14770	33319489	15   In NSCLC, high serum HSP70 levels are associated with an increased risk of developing, 16  and the early stages of carcinogenesis are associated with high HSP70 expression.	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('expression', 'MPA', (166, 176))	('carcinogenesis', 'Disease', (120, 134))	('HSP70', 'Protein', (160, 165))	('associated', 'Reg', (139, 149))	('high', 'Var', (155, 159))
14771	33319489	17  Furthermore, high HSP70 levels are related to the suppression of chemosensitivity and the effects of TKIs on prostate carcinoma, fibrosarcoma and chronic myeloid leukemia.	('fibrosarcoma', 'Disease', (133, 145))	('prostate carcinoma', 'Disease', 'MESH:D011471', (113, 131))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (150, 174))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (150, 174))	('chronic myeloid leukemia', 'Disease', (150, 174))	('effects', 'Reg', (94, 101))	('chemosensitivity', 'CPA', (69, 85))	('TKIs', 'Gene', (105, 109))	('high', 'Var', (17, 21))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (158, 174))	('fibrosarcoma', 'Disease', 'MESH:D005354', (133, 145))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (133, 145))	('HSP70', 'Protein', (22, 27))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('suppression', 'NegReg', (54, 65))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (113, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('prostate carcinoma', 'Disease', (113, 131))
14782	33319489	The primary antibodies were as follows: HSP70/HSC70 (W27) (sc-24), p-AKT1/2/3 (C-11) (sc-514032), GFP (B-2) (sc-9996) and beta-actin (C4) (sc-47778) from Santa Cruz Biotechnology (USA); AKT (pan) (11E7) rabbit mAb (4685), and LC3A (D50G8) XP rabbit mAb (4599) from Cell Signaling Technology (USA); and anti-LAMP2A (ab18528) from Abcam (UK).	('AKT1/2/3', 'Gene', (69, 77))	('LC3A', 'Gene', (226, 230))	('HSC', 'cellular_component', 'GO:0035301', ('46', '49'))	('anti-LAMP2A', 'Var', (302, 313))	('LC3A', 'Gene', '84557', (226, 230))	('Signaling', 'biological_process', 'GO:0023052', ('270', '279'))	('HSC70', 'Gene', '3312', (46, 51))	('AKT1/2/3', 'Gene', '207;208;10000', (69, 77))	('HSC70', 'Gene', (46, 51))
14801	33319489	35  In this study, phosphorylation of p38, ERK and JNK was facilitated following cisplatin treatment, but AKT was not affected, and HSP70 knockdown inhibited phosphorylation leading to augmentation of apoptosis.	('phosphorylation', 'MPA', (19, 34))	('facilitated', 'PosReg', (59, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('knockdown', 'Var', (138, 147))	('phosphorylation', 'MPA', (158, 173))	('ERK', 'Gene', (43, 46))	('p38', 'Gene', '1432', (38, 41))	('JNK', 'molecular_function', 'GO:0004705', ('51', '54'))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('apoptosis', 'CPA', (201, 210))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('augmentation', 'PosReg', (185, 197))	('ERK', 'Gene', '2048', (43, 46))	('JNK', 'Gene', (51, 54))	('JNK', 'Gene', '5599', (51, 54))	('HSP70', 'Protein', (132, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('inhibited', 'NegReg', (148, 157))	('p38', 'Gene', (38, 41))
14808	32290283	We found that S100A4, along with 12 other biomarkers, differentiated neoplastic from preneoplastic mesothelial cell lines, and invasive vs. non-invasive tumor cells in vitro, and MM tumors in vivo.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('non-invasive tumor', 'Disease', (140, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('MM tumors', 'Disease', 'MESH:D009369', (179, 188))	('non-invasive tumor', 'Disease', 'MESH:D009361', (140, 158))	('MM tumors', 'Disease', (179, 188))	('S100A4', 'Var', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
14810	32290283	Finally, S100A4 was the most significantly increased biomarker in liver metastases vs. primary tumor, and in the spleen colonized by MM cells.	('tumor', 'Disease', (95, 100))	('liver metastases', 'Disease', (66, 82))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('liver metastases', 'Disease', 'MESH:D009362', (66, 82))	('increased', 'PosReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('S100A4', 'Var', (9, 15))
14813	32290283	Moreover, in the context of a pre-metastatic niche, S100A4 production serves as a link between inflammation and tumor metastasis, and is indicative of poor prognosis.	('pre', 'molecular_function', 'GO:0003904', ('30', '33'))	('tumor metastasis', 'Disease', 'MESH:D009362', (112, 128))	('tumor metastasis', 'Disease', (112, 128))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('S100A4 production', 'Var', (52, 69))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('inflammation', 'Disease', (95, 107))	('inflammation', 'biological_process', 'GO:0006954', ('95', '107'))
14822	32290283	In this study, our aim was to determine whether S100A4, one of the most important biomarkers for invasiveness, previously identified in a list of 137 proteins, was involved in all stages of MM pathogenesis, including tumorigenesis, EMT, invasion, and colonization of host organs, and whether it presented a comparable evolution during the whole process when used alone or when combined with other proteins of interest.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('colonization', 'CPA', (251, 263))	('involved', 'Reg', (164, 172))	('EMT', 'CPA', (232, 235))	('EMT', 'biological_process', 'GO:0001837', ('232', '235'))	('S100A4', 'Var', (48, 54))	('pathogenesis', 'biological_process', 'GO:0009405', ('193', '205'))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('invasion', 'CPA', (237, 245))
14841	32290283	This role of S100A4 in human MM invasiveness is also consistent with the observation of a decreased survival probability for patients with renal cancer and high S100A4 expression (Supplementary Figure S5).	('patients', 'Species', '9606', (125, 133))	('renal cancer', 'Disease', 'MESH:D007680', (139, 151))	('expression', 'MPA', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('decreased', 'NegReg', (90, 99))	('survival', 'CPA', (100, 108))	('MM invasiveness', 'Disease', 'MESH:D009361', (29, 44))	('S100A4', 'Gene', (161, 167))	('renal cancer', 'Disease', (139, 151))	('human', 'Species', '9606', (23, 28))	('renal cancer', 'Phenotype', 'HP:0009726', (139, 151))	('high', 'Var', (156, 160))	('MM invasiveness', 'Disease', (29, 44))
14845	32290283	For this purpose, M5-T1 liver metastases were collected from two groups of rats that differed in the number/extent of secondary organs affected by M5-T1 cell invasion.	('M5-T1', 'Var', (147, 152))	('liver metastases', 'Disease', (24, 40))	('liver metastases', 'Disease', 'MESH:D009362', (24, 40))	('rats', 'Species', '10116', (75, 79))
14857	32290283	Comparison of the abundances for other proteins of the S100 family demonstrated that five proteins were detected in the spleen tissue (S100A11, S100A6, S100A8, S100A9, and S100A4, in increasing order of abundance), S100A9 being the only one that increased (Figure 6B).	('S100A8', 'Gene', (152, 158))	('S100A8', 'Gene', '116547', (152, 158))	('S100A6', 'Gene', (144, 150))	('rat', 'Species', '10116', (74, 77))	('S100A9', 'Var', (160, 166))	('S100A11', 'Gene', '445415', (135, 142))	('S100A9', 'Var', (215, 221))	('S100A4', 'Var', (172, 178))	('S100A6', 'Gene', '85247', (144, 150))	('S100A11', 'Gene', (135, 142))
14859	32290283	Analysis of changes in abundance between the different stages for the eight markers identified above plus S100A9 revealed a comparable evolution for S100A4, Tubulin-specific chaperone A (TBCA), and, to a lesser extent Annexin A2 (ANXA2), the former still being the most sensitive to invasion by M5-T1 tumor cells (Figure 6C).	('ANXA2', 'Gene', (230, 235))	('S100A4', 'Var', (149, 155))	('Annexin A2', 'Gene', (218, 228))	('Tubulin-specific chaperone A', 'Gene', '366995', (157, 185))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('ANXA2', 'Gene', '56611', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Disease', (301, 306))	('Tubulin-specific chaperone A', 'Gene', (157, 185))	('Annexin A2', 'Gene', '56611', (218, 228))
14863	32290283	Although AHNAK mesothelioma-associated gene mutation was recently found in a rare type of human MM, its role in MM pathogenesis is still under investigation.	('mutation', 'Var', (44, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('pathogenesis', 'biological_process', 'GO:0009405', ('115', '127'))	('human', 'Species', '9606', (90, 95))	('mesothelioma', 'Disease', (15, 27))
14872	32290283	This finding is interesting as it corroborates our data on the increased abundance of S100A6 that accompanied the increased abundance of S100A4 in all three invasive MM tumors versus the non-invasive MM tumor.	('abundance', 'MPA', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('increased', 'PosReg', (63, 72))	('S100A6', 'Gene', '85247', (86, 92))	('invasive MM tumors versus the non-invasive MM tumor', 'Disease', 'MESH:D009361', (157, 208))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('S100A4', 'Var', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('rat', 'Species', '10116', (41, 44))	('S100A6', 'Gene', (86, 92))
14875	32290283	The presence of HIF-1 could also explain the parallel rise in Vegfa expression in these cell lines, and the highest invasiveness of M5-T1 tumor, in agreement with the statement that its presence in tumor microenvironment could foster the expression of VEGF, among others.	('tumor', 'Disease', (138, 143))	('expression', 'MPA', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('Vegfa', 'Gene', '83785', (62, 67))	('invasiveness', 'CPA', (116, 128))	('foster', 'PosReg', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('VEGF', 'Gene', (252, 256))	('HIF-1', 'Gene', (16, 21))	('Vegfa', 'Gene', (62, 67))	('rise', 'PosReg', (54, 58))	('tumor', 'Disease', (198, 203))	('presence', 'Var', (4, 12))	('expression', 'MPA', (238, 248))	('VEGF', 'Gene', '83785', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
14887	32290283	Besides the dramatic changes observed for S100A4, S100A9 was the only member of this family that was detected neither in cells nor in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('S100A9', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
14889	32290283	S100A4 and S100A9 show common molecular interactions, both being associated with inflammation and in vivo tumor progression, reducing overall survival for the patient.	('S100A9', 'Var', (11, 17))	('inflammation', 'biological_process', 'GO:0006954', ('81', '93'))	('associated', 'Reg', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('reducing', 'NegReg', (125, 133))	('inflammation', 'Disease', (81, 93))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('S100A4', 'Var', (0, 6))	('overall survival', 'MPA', (134, 150))	('patient', 'Species', '9606', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('interactions', 'Interaction', (40, 52))	('tumor', 'Disease', (106, 111))
14895	32290283	Other than S100A4, our study also led us to identify several other potential markers of interest for MM, including annexin A5, as its serum level in patients with colon cancer is related to lymph node metastasis and tumor grades, while investigations of its role and action in hepatocarcinoma malignancy has revealed that its knockdown suppressed the expression of key molecules in the integrin and MEK-ERK pathways (mitogen-activated protein kinases-extracellular signal-regulated kinases).	('integrin', 'Pathway', (386, 394))	('suppressed', 'NegReg', (336, 346))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('expression', 'MPA', (351, 361))	('hepatocarcinoma malignancy', 'Disease', (277, 303))	('tumor', 'Disease', (216, 221))	('colon cancer', 'Disease', (163, 175))	('patients', 'Species', '9606', (149, 157))	('related', 'Reg', (179, 186))	('MEK', 'Gene', '5609', (399, 402))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('protein', 'cellular_component', 'GO:0003675', ('435', '442'))	('ERK', 'Gene', '5594', (403, 406))	('ERK', 'molecular_function', 'GO:0004707', ('403', '406'))	('MEK', 'Gene', (399, 402))	('knockdown', 'Var', (326, 335))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('extracellular', 'cellular_component', 'GO:0005576', ('451', '464'))	('ERK', 'Gene', (403, 406))	('annexin A5', 'Gene', (115, 125))	('annexin A5', 'Gene', '308', (115, 125))	('hepatocarcinoma malignancy', 'Disease', 'MESH:D009369', (277, 303))	('colon cancer', 'Disease', 'MESH:D015179', (163, 175))
14898	32290283	Interestingly, the continuous rise in LMNA in F4-T2, F5-T1, and M5-T1 tumors is consistent with an increased tumor invasiveness and the involvement of EMT at the invasive tumor front.	('rise', 'PosReg', (30, 34))	('invasive tumor', 'Disease', (162, 176))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor invasiveness', 'Disease', 'MESH:D009361', (109, 127))	('invasive tumor', 'Disease', 'MESH:D009361', (162, 176))	('LMNA', 'Gene', '60374', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('increased', 'PosReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('LMNA', 'Gene', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor invasiveness', 'Disease', (109, 127))	('F4-T2', 'Var', (46, 51))	('F5-T1', 'Var', (53, 58))	('M5-T1', 'Var', (64, 69))	('EMT', 'CPA', (151, 154))
15153	29652548	CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-gamma activating receptors on immune-effector cells.	('CA125', 'Gene', '94025', (0, 5))	('CD32a', 'Gene', (358, 363))	('CD16a', 'Gene', (348, 353))	('CD32a', 'Gene', '2212', (358, 363))	('mesothelioma', 'Disease', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('bind', 'Interaction', (217, 221))	('perturbation', 'Var', (313, 325))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('suppress', 'NegReg', (263, 271))	('CA125', 'Gene', (184, 189))	('immune-effector mediated killing', 'CPA', (272, 304))	('amatuximab', 'Chemical', 'MESH:C526187', (17, 27))	('CA125', 'Gene', (0, 5))	('CD16a', 'Gene', '2214', (348, 353))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('CA125', 'Gene', '94025', (184, 189))	('suppresses', 'NegReg', (6, 16))	('Fc-gamma', 'Protein', (364, 372))
15166	29652548	This trial found that a pre-specified subgroup of patients treated with farletuzumab plus standard-of-care (SOC) carboplatin/taxane with baseline serum CA125 levels no greater than 3X the upper limit of normal (<= 3X ULN) demonstrated clinical improvements in both progression free survival (PFS) (hazard ratio [HR] 0.49, p = 0.0028) and overall survival (OS) (HR 0.44, p = 0.0108) as compared to patients treated with SOC and placebo.	('pre', 'molecular_function', 'GO:0003904', ('24', '27'))	('CA125', 'Gene', (152, 157))	('taxane', 'Chemical', 'MESH:C080625', (125, 131))	('patients', 'Species', '9606', (397, 405))	('carboplatin', 'Chemical', 'MESH:D016190', (113, 124))	('patients', 'Species', '9606', (50, 58))	('overall survival', 'CPA', (338, 354))	('farletuzumab', 'Var', (72, 84))	('farletuzumab', 'Chemical', 'MESH:C527484', (72, 84))	('SOC', 'biological_process', 'GO:0031578', ('108', '111'))	('no greater', 'Var', (165, 175))	('CA125', 'Gene', '94025', (152, 157))	('progression free survival', 'CPA', (265, 290))	('improvements', 'PosReg', (244, 256))	('OS', 'Chemical', '-', (356, 358))	('SOC', 'biological_process', 'GO:0031578', ('419', '422'))
15201	29652548	2A, sCA125 was effective in suppressing the ADCC activity on mesothelin-positive tumor cell lines similar to that shown for farletuzumab.	('sCA125', 'Var', (4, 10))	('mesothelin', 'Gene', (61, 71))	('sCA125', 'Chemical', '-', (4, 10))	('ADCC', 'biological_process', 'GO:0001788', ('44', '48'))	('ADCC activity', 'MPA', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('farletuzumab', 'Chemical', 'MESH:C527484', (124, 136))	('suppressing', 'NegReg', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mesothelin', 'Gene', '10232', (61, 71))	('tumor', 'Disease', (81, 86))
15229	29652548	reported that patients from the Phase 2 study, same as those tested in this study, with amatuximab Cmin levels > 32.9 mug/mL for PFS and > 38 mug/mL for OS had statistically improved outcomes as compared to those with levels below that value (log rank test 6.52 x 10-5 and 0.0202, respectively).	('amatuximab', 'Chemical', 'MESH:C526187', (88, 98))	('> 32.9', 'Var', (111, 117))	('OS', 'Chemical', '-', (153, 155))	('PFS', 'Disease', (129, 132))	('mug', 'molecular_function', 'GO:0043739', ('118', '121'))	('outcomes', 'MPA', (183, 191))	('patients', 'Species', '9606', (14, 22))	('improved', 'PosReg', (174, 182))	('mug', 'molecular_function', 'GO:0043739', ('142', '145'))
15269	29652548	shRNA Mission Lentiviral particles were employed to knockdown CA125/MUC16 expression.	('CA125', 'Gene', (62, 67))	('expression', 'MPA', (74, 84))	('MUC16', 'Gene', '94025', (68, 73))	('knockdown', 'Var', (52, 61))	('CA125', 'Gene', '94025', (62, 67))	('expression', 'Species', '29278', (74, 84))	('MUC16', 'Gene', (68, 73))
15416	25781025	2 patients in the ZA arm of this study showed a reduction in tumour volume by modified RECIST of >10%, although this does not meet the above criteria for a partial response.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('modified RECIST', 'Var', (78, 93))	('patients', 'Species', '9606', (2, 10))	('tumour', 'Disease', (61, 67))	('ZA', 'Chemical', 'MESH:D000077211', (18, 20))	('reduction', 'NegReg', (48, 57))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
15424	25781025	However, despite this and data from other cancer types also suggesting Zoledronic Acid supresses circulating VEGF levels, we failed to show any treatment effect of ZA on the blood biomarkers tested.	('Zoledronic', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ZA', 'Chemical', 'MESH:D000077211', (164, 166))	('supresses', 'NegReg', (87, 96))	('VEGF', 'Gene', (109, 113))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Zoledronic Acid', 'Chemical', 'MESH:D000077211', (71, 86))	('VEGF', 'Gene', '7422', (109, 113))
15479	25089223	He was discharged from the hospital on postoperative day 8 with no postoperative complications but does suffer from minimal high-frequency hearing loss as a result of the cisplatin.	('hearing loss', 'Disease', (139, 151))	('hearing', 'biological_process', 'GO:0007605', ('139', '146'))	('cisplatin', 'Var', (171, 180))	('hearing loss', 'Disease', 'MESH:D034381', (139, 151))	('high-frequency', 'MPA', (124, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('hearing loss', 'Phenotype', 'HP:0000365', (139, 151))
15545	23946800	The tumor cells in the present case were positive for CK, CAM5.2, SMA, CK19, CR and CD34, while the markers for bcl-2, PLAP, CD117, S-100, CD20, CD79a, CD45RO, CD15, CD30 were negative.	('tumor', 'Disease', (4, 9))	('PLAP', 'Gene', '250', (119, 123))	('CK19', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CAM5.2', 'Var', (58, 64))	('CD20', 'Gene', (139, 143))	('CK19', 'Gene', '3880', (71, 75))	('CR', 'Gene', '794', (77, 79))	('CD15', 'Gene', (160, 164))	('CD34', 'Gene', '947', (84, 88))	('bcl-2', 'Gene', '596', (112, 117))	('positive', 'Reg', (41, 49))	('CD117', 'Gene', '3815', (125, 130))	('CD20', 'Gene', '54474', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD15', 'Gene', '2526', (160, 164))	('CD30', 'Gene', (166, 170))	('CD117', 'Gene', (125, 130))	('CD79a', 'Gene', '973', (145, 150))	('bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('CD30', 'Gene', '943', (166, 170))	('PLAP', 'Gene', (119, 123))	('CD34', 'Gene', (84, 88))	('bcl-2', 'Gene', (112, 117))	('CD79a', 'Gene', (145, 150))
15565	22891886	Three forms of CNT exist, depending on the number of the walls: single-walled carbon nanotubes (SWCNT), double-walled carbon nanotubes (DWCNT), and multi-walled carbon nanotubes (MWCNT).	('carbon', 'Chemical', 'MESH:D002244', (78, 84))	('carbon', 'Chemical', 'MESH:D002244', (161, 167))	('DWCNT', 'Chemical', '-', (136, 141))	('MWCNT', 'Chemical', '-', (179, 184))	('double-walled carbon', 'Var', (104, 124))	('carbon', 'Chemical', 'MESH:D002244', (118, 124))	('SWCNT', 'Chemical', '-', (96, 101))	('single-walled', 'Var', (64, 77))	('multi-walled', 'Var', (148, 160))
15572	22891886	Several animal studies demonstrated that exposure to MWCNT induces inflammatory granulomas and substantial interstitial lung fibrosis in the lungs.	('interstitial lung fibrosis', 'Disease', (107, 133))	('granuloma', 'Phenotype', 'HP:0032252', (80, 89))	('lung fibrosis', 'Phenotype', 'HP:0002206', (120, 133))	('induces', 'Reg', (59, 66))	('MWCNT', 'Var', (53, 58))	('granulomas', 'Phenotype', 'HP:0032252', (80, 90))	('MWCNT', 'Chemical', '-', (53, 58))	('granulomas', 'Disease', (80, 90))	('interstitial lung fibrosis', 'Disease', 'MESH:D017563', (107, 133))	('granulomas', 'Disease', 'MESH:D006099', (80, 90))	('interstitial lung', 'Phenotype', 'HP:0006530', (107, 124))
15573	22891886	Animal studies using intraperitoneal (IP) exposure also showed that MWCNT induced inflammatory granulomas and mesothelioma to a degree similar to asbestos fibers.	('granulomas', 'Disease', (95, 105))	('granulomas', 'Disease', 'MESH:D006099', (95, 105))	('asbestos', 'Chemical', 'MESH:D001194', (146, 154))	('induced', 'Reg', (74, 81))	('mesothelioma', 'Disease', (110, 122))	('granuloma', 'Phenotype', 'HP:0032252', (95, 104))	('MWCNT', 'Var', (68, 73))	('granulomas', 'Phenotype', 'HP:0032252', (95, 105))	('MWCNT', 'Chemical', '-', (68, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))
15578	22891886	It was also demonstrated that MWCNT-induced mesothelioma is accompanied by homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos.	('mesothelioma', 'Disease', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('MWCNT-induced', 'Var', (30, 43))	('asbestos', 'Chemical', 'MESH:D001194', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('tumor', 'Disease', (108, 113))	('MWCNT', 'Chemical', '-', (30, 35))	('Cdkn2a', 'Gene', (98, 104))	('Cdkn2a', 'Gene', '1029', (98, 104))	('mesotheliomas', 'Disease', 'MESH:D008654', (143, 156))	('mesothelioma', 'Disease', (44, 56))	('deletion', 'Var', (86, 94))	('mesotheliomas', 'Disease', (143, 156))
15584	22891886	In contrast, morphometric analysis of lung tissue from the study by indicated that MWCNT-induced interstitial fibrosis increased significantly at day 28 and progressed through 56 days post-exposure.	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (97, 118))	('MWCNT', 'Chemical', '-', (83, 88))	('MWCNT-induced', 'Var', (83, 96))	('interstitial fibrosis', 'Disease', (97, 118))	('interstitial fibrosis', 'Disease', 'MESH:D005355', (97, 118))
15595	22891886	An alteration of TGF-beta expression was associated with increased human cancer incidence, including lung cancer.	('expression', 'MPA', (26, 36))	('cancer', 'Disease', (73, 79))	('TGF-beta', 'Gene', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('alteration', 'Var', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (106, 112))	('TGF-beta', 'Gene', '7040', (17, 25))	('increased', 'PosReg', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('human', 'Species', '9606', (67, 72))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
15604	22891886	The finding of an association would justify further long term studies to determine the temporal association between MWCNT-induced gene alterations and the development of pre-cancerous lesions and/or tumors in the mouse lung.	('mouse', 'Species', '10090', (213, 218))	('cancerous lesions', 'Disease', 'MESH:D009062', (174, 191))	('tumors', 'Disease', (199, 205))	('cancerous lesions', 'Disease', (174, 191))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('MWCNT-induced gene', 'Gene', (116, 134))	('alterations', 'Var', (135, 146))	('MWCNT', 'Chemical', '-', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('pre', 'molecular_function', 'GO:0003904', ('170', '173'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
15629	22891886	Following purification of labeled cRNAs, 825 ng of Cy3- and Cy5-labeled cRNAs were combined and hybridized for 17 hr at 65 C in an Agilent hybridization oven.	('Cy3', 'Chemical', '-', (51, 54))	('Cy5', 'Chemical', 'MESH:C085321', (60, 63))	('Cy5-labeled', 'Var', (60, 71))	('Cy3-', 'Var', (51, 55))
15679	22891886	These results indicate that human lung tumors with the MWCNT-induced gene expression patterns were more likely to be aggressive and had shorter overall survival compared with those with unexposed gene expression patterns.	('lung tumor', 'Phenotype', 'HP:0100526', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('aggressive', 'CPA', (117, 127))	('MWCNT-induced gene expression patterns', 'Var', (55, 93))	('human', 'Species', '9606', (28, 33))	('MWCNT', 'Chemical', '-', (55, 60))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('lung tumors', 'Phenotype', 'HP:0100526', (34, 45))	('lung tumors', 'Disease', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gene expression', 'biological_process', 'GO:0010467', ('196', '211'))	('shorter', 'NegReg', (136, 143))	('overall survival', 'CPA', (144, 160))	('lung tumors', 'Disease', 'MESH:D008175', (34, 45))
15709	22891886	The characteristic histopathological changes of MWCNT-induced mesotheliomas were hobnail appearance to large tumors along with high mitotic rate cells and central necrosis due to a high grade of malignant mesothelioma, indicating that characteristic carcinogenic mechanisms were involved.	('carcinogenic', 'Disease', (250, 262))	('MWCNT-induced', 'Var', (48, 61))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('necrosis', 'biological_process', 'GO:0008219', ('163', '171'))	('carcinogenic', 'Disease', 'MESH:D063646', (250, 262))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (195, 217))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('necrosis', 'biological_process', 'GO:0008220', ('163', '171'))	('mesotheliomas', 'Disease', (62, 75))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))	('malignant mesothelioma', 'Disease', (195, 217))	('necrosis', 'biological_process', 'GO:0070265', ('163', '171'))	('MWCNT', 'Chemical', '-', (48, 53))	('necrosis', 'biological_process', 'GO:0019835', ('163', '171'))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (195, 217))	('mesotheliomas', 'Disease', 'MESH:D008654', (62, 75))	('necrosis', 'biological_process', 'GO:0001906', ('163', '171'))	('necrosis', 'Disease', (163, 171))
15741	22891886	In terms of genotoxic effects of MWCNT and asbestos, it was demonstrated that MWCNT interact with cellular biomolecules, such as the centrosomes and mitotic spindles, as well as the motor proteins that separate the chromosomes during cell division, leading to monopolar divisions of chromosomes.	('interact', 'Reg', (84, 92))	('MWCNT', 'Var', (78, 83))	('monopolar divisions of chromosomes', 'CPA', (260, 294))	('MWCNT', 'Chemical', '-', (33, 38))	('leading to', 'Reg', (249, 259))	('MWCNT', 'Chemical', '-', (78, 83))	('cell division', 'biological_process', 'GO:0051301', ('234', '247'))	('asbestos', 'Chemical', 'MESH:D001194', (43, 51))
15742	22891886	The resulting aneuplody was proposed as a major molecular mechanism involved in potential MWCNT-induced carcinogenesis.	('aneuplody', 'Var', (14, 23))	('carcinogenesis', 'Disease', (104, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('MWCNT', 'Chemical', '-', (90, 95))
15757	22891886	Disruption of the MMP activities plays a key role in the development of pulmonary diseases, including lung cancer.	('MMP', 'molecular_function', 'GO:0004235', ('18', '21'))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('pulmonary diseases', 'Disease', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('pulmonary diseases', 'Disease', 'MESH:D008171', (72, 90))	('MMP', 'Gene', (18, 21))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('MMP', 'Gene', '4318;4321;4323', (18, 21))	('Disruption', 'Var', (0, 10))
15761	22891886	DNA methylation changes of two genes, EYA 4 and DAPK1, are associated with lung cancer development.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DAPK1', 'Gene', '1612', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EYA 4', 'Gene', (38, 43))	('methylation changes', 'Var', (4, 23))	('associated with', 'Reg', (59, 74))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('DAPK1', 'Gene', (48, 53))	('EYA 4', 'Gene', '2070', (38, 43))
15763	22891886	In the present study, the lung tissue specimens were collected from the mice exposed to MWCNT from 1 to 56 days post-exposure, which was not sufficient for mice to develop lung cancer.	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('MWCNT', 'Var', (88, 93))	('MWCNT', 'Chemical', '-', (88, 93))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
15769	22891886	The ability of MWCNT-induced gene sets to correlate with carcinogenesis of lung cancer patients provides justification for a further long term study to determine the temporal association between MWCNT-induced gene alterations and development of pre-cancerous lesions and/or tumor in the mouse lung.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancerous lesions', 'Disease', (249, 266))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('MWCNT', 'Chemical', '-', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('pre', 'molecular_function', 'GO:0003904', ('245', '248'))	('carcinogenesis of lung cancer', 'Disease', (57, 86))	('alterations', 'Var', (214, 225))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('cancerous lesions', 'Disease', 'MESH:D009062', (249, 266))	('mouse', 'Species', '10090', (287, 292))	('tumor', 'Disease', (274, 279))	('carcinogenesis of lung cancer', 'Disease', 'MESH:D063646', (57, 86))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('MWCNT', 'Chemical', '-', (195, 200))
15792	22891886	The selection of 16 genes that were changed at two time points was aimed to identify genes that were consistently changed by MWCNT, and these gene expression changes were not transient or reversible over the time course up to 56 days post exposure.	('MWCNT', 'Chemical', '-', (125, 130))	('changed', 'Reg', (114, 121))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('MWCNT', 'Var', (125, 130))
15795	22891886	Our genome-wide expression studies show that the MWCNT-induced gene alterations (in more than 3,000 significant genes) have implications on multiple diseases and disorders, including inflammation, fibrosis, and cardiovascular disease, among many others (will be discussed in a separate manuscript).	('multiple diseases and disorders', 'Disease', 'MESH:D000015', (140, 171))	('inflammation', 'biological_process', 'GO:0006954', ('183', '195'))	('inflammation', 'Disease', (183, 195))	('implications', 'Reg', (124, 136))	('MWCNT', 'Chemical', '-', (49, 54))	('cardiovascular disease', 'Disease', 'MESH:D002318', (211, 233))	('man', 'Species', '9606', (241, 244))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))	('alterations', 'Var', (68, 79))	('cardiovascular disease', 'Disease', (211, 233))	('man', 'Species', '9606', (286, 289))	('fibrosis', 'Disease', 'MESH:D005355', (197, 205))	('fibrosis', 'Disease', (197, 205))	('MWCNT-induced', 'Gene', (49, 62))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (211, 233))
15797	22891886	Although the current animal study did not observe tumor formation in response to MWCNT exposure and the analyzed human samples were not previously exposed to MWCNT, the similarity between the genomic characteristics induced by NWCNT exposure in mice and those associated with human lung cancer initiation and progression suggests a significant association between MWCNT-induced gene alterations and clinical phenotypes in human lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('MWCNT', 'Chemical', '-', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('human', 'Species', '9606', (113, 118))	('lung cancer', 'Disease', (428, 439))	('human', 'Species', '9606', (422, 427))	('alterations', 'Var', (383, 394))	('human', 'Species', '9606', (276, 281))	('patients', 'Species', '9606', (440, 448))	('tumor', 'Disease', (50, 55))	('lung cancer initiation', 'Disease', (282, 304))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('lung cancer', 'Disease', 'MESH:D008175', (428, 439))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('MWCNT', 'Chemical', '-', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (428, 439))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('lung cancer initiation', 'Disease', 'MESH:D008175', (282, 304))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (245, 249))	('MWCNT', 'Chemical', '-', (364, 369))
15799	22891886	To provide further support for this application, a 1 year evaluation after a 2 week inhalation of MWCNT is currently being conducted in our lab to correlate time-dependent alterations in gene expression with development of pre-cancerous lesions and/or tumor formation.	('cancerous lesions', 'Disease', 'MESH:D009062', (227, 244))	('formation', 'biological_process', 'GO:0009058', ('258', '267'))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancerous lesions', 'Disease', (227, 244))	('pre', 'molecular_function', 'GO:0003904', ('223', '226'))	('MWCNT', 'Chemical', '-', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('gene expression', 'biological_process', 'GO:0010467', ('187', '202'))	('tumor', 'Disease', (252, 257))	('gene expression', 'MPA', (187, 202))	('alterations', 'Var', (172, 183))
15843	22761781	Regardless of subtype, the majority of MM tumors expressed nuclear FOXM1 in 50% or more of the cells (Fig.	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('MM tumors', 'Disease', 'MESH:D009369', (39, 48))	('MM tumors', 'Disease', (39, 48))	('nuclear FOXM1', 'Var', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
15879	22761781	However, these immunoreactive species were maintained when heated to 95 C for more than 10 min in SDS sample buffer with dithiothreitol (DTT), indicating the modified species of PRX3 are resistant to denaturation by detergents or reduction by DTT.	('PRX3', 'Gene', (178, 182))	('DTT', 'Chemical', 'MESH:D004229', (243, 246))	('SDS', 'Chemical', 'MESH:D012967', (98, 101))	('modified', 'Var', (158, 166))	('DTT', 'Chemical', 'MESH:D004229', (137, 140))	('dithiothreitol', 'Chemical', 'MESH:D004229', (121, 135))	('PRX3', 'Gene', '10935', (178, 182))
15914	22761781	The mechanism by which disruption of PRX3 activity and increased levels of mitochondrial oxidants inhibit FOXM1 expression is not known.	('activity', 'MPA', (42, 50))	('disruption', 'Var', (23, 33))	('PRX3', 'Gene', '10935', (37, 41))	('increased', 'PosReg', (55, 64))	('FOXM1', 'Gene', (106, 111))	('inhibit', 'NegReg', (98, 105))	('PRX3', 'Gene', (37, 41))	('levels of mitochondrial oxidants', 'MPA', (65, 97))	('expression', 'MPA', (112, 122))
15920	22761781	There are a large number of studies that have targeted perturbations in ROS metabolism as a therapeutic strategy in cancer, and induction of intolerable levels of oxidative stress generally appears to be a more effective strategy than blocking oxidant production.	('perturbations', 'Var', (55, 68))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (163, 179))	('metabolism', 'biological_process', 'GO:0008152', ('76', '86'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
15927	22761781	TS covalently binds TipAS with a 1:1 stoichiometry, and the peptide harboring the modified cysteine peptide is increased in MW by 1664 Da, in excellent agreement with the MW of TS.	('increased', 'PosReg', (111, 120))	('TS', 'Chemical', 'MESH:D013883', (0, 2))	('modified', 'Var', (82, 90))	('cysteine', 'Chemical', 'MESH:D003545', (91, 99))	('TipAS', 'Species', '162890', (20, 25))	('men', 'Species', '9606', (157, 160))	('TS', 'Chemical', 'MESH:D013883', (177, 179))
15942	22761781	Inhibition of PRX3 expression in breast cancer cells induces cell cycle arrest and impairs cell proliferation.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('PRX3', 'Gene', (14, 18))	('arrest', 'Disease', (72, 78))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('61', '78'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('Inhibition', 'Var', (0, 10))	('PRX3', 'Gene', '10935', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('impairs', 'NegReg', (83, 90))	('cell proliferation', 'CPA', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))	('induces', 'Reg', (53, 60))
15980	22761781	Assays for RNA expression were done in triplicate using Assay On Demand (Applied Biosystems) for FOXM1 (Hs01073586_m1) and HPRT (Hs02800695_m1).	('HPRT', 'Gene', '3251', (123, 127))	('Hs02800695_m1', 'Var', (129, 142))	('HPRT', 'Gene', (123, 127))	('HPRT', 'molecular_function', 'GO:0004422', ('123', '127'))	('Hs01073586_m1', 'Var', (104, 117))	('RNA', 'cellular_component', 'GO:0005562', ('11', '14'))
16253	28951802	HRs were adjusted for age group (25-34 years, 35-44 years, 45-54 years, and 55-74 years), province of residence and education (no high school diploma, high school with/without trade certificate, postsecondary nonuniversity diploma, or university degree).	('no', 'Var', (127, 129))	('diploma', 'Disease', (223, 230))	('diploma', 'Disease', (142, 149))	('diploma', 'Disease', 'None', (142, 149))	('diploma', 'Disease', 'None', (223, 230))
16306	28951802	Occupational risk factors for kidney cancer are not well understood, but exposure to cadmium is known to cause renal disease, and evidence suggests that it may cause cancer even at lower levels of exposure found among environmentally exposed individuals.	('renal disease', 'Disease', 'MESH:D007674', (111, 124))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (166, 172))	('cause', 'Reg', (160, 165))	('cause', 'Reg', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (37, 43))	('kidney cancer', 'Disease', (30, 43))	('kidney cancer', 'Phenotype', 'HP:0009726', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cadmium', 'Var', (85, 92))	('renal disease', 'Disease', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('exposure', 'Var', (73, 81))	('cadmium', 'Chemical', 'MESH:D002104', (85, 92))	('renal disease', 'Phenotype', 'HP:0000112', (111, 124))	('kidney cancer', 'Disease', 'MESH:D007680', (30, 43))
16349	26883190	Finally, mesothelioma cell lines expressing high CD74 levels had a low tumorigenic potential after xenogeneic implantation in athymic nude mice.	('high CD74 levels', 'Var', (44, 60))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('nude mice', 'Species', '10090', (134, 143))	('mesothelioma', 'Disease', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('low', 'NegReg', (67, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (9, 21))
16364	26883190	In murine models of human colorectal adenoma and metastatic breast cancer, inhibition of MIF expression by genetic deletion or RNA interference decreased tumor progression and metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('tumor', 'Disease', (154, 159))	('decreased', 'NegReg', (144, 153))	('RNA interference', 'MPA', (127, 143))	('colorectal adenoma', 'Disease', (26, 44))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Disease', (60, 73))	('inhibition', 'NegReg', (75, 85))	('RNA interference', 'biological_process', 'GO:0016246', ('127', '143'))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('human', 'Species', '9606', (20, 25))	('expression', 'Protein', (93, 103))	('colorectal adenoma', 'Disease', 'MESH:D015179', (26, 44))	('genetic deletion', 'Var', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MIF', 'Gene', (89, 92))
16365	26883190	A reduction of tumor growth was also observed in sub-cutaneous human neuroblastoma and prostate cancer xenografts, after inhibition of MIF expression by MIF antisens transfection or RNA interference or after treatment with anti-MIF antibodies or MIF inhibitors.	('neuroblastoma and prostate cancer', 'Disease', 'MESH:D011471', (69, 102))	('RNA interference', 'biological_process', 'GO:0016246', ('182', '198'))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('neuroblastoma', 'Phenotype', 'HP:0003006', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MIF', 'Gene', (135, 138))	('antisens transfection', 'Var', (157, 178))	('sub-cutaneous', 'Disease', (49, 62))	('reduction', 'NegReg', (2, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('RNA', 'cellular_component', 'GO:0005562', ('182', '185'))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('tumor', 'Disease', (15, 20))	('MIF', 'Gene', (153, 156))	('expression', 'MPA', (139, 149))	('RNA', 'MPA', (182, 185))	('inhibition', 'NegReg', (121, 131))
16368	26883190	We also demonstrated that high levels of CD74 were an independent prognostic factor for prolonged overall survival in MPM patients.	('MPM', 'Disease', (118, 121))	('high', 'Var', (26, 30))	('CD74', 'Protein', (41, 45))	('patients', 'Species', '9606', (122, 130))	('overall', 'MPA', (98, 105))	('prolonged', 'PosReg', (88, 97))
16380	26883190	We compared physiological characteristics, such as cell multiplication, cell proliferation and apoptosis of MeT5A cells with JL-1 and H28 MPM cell lines chosen in regard to their MIF/CD74 expressions and MIF secreting levels.	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('MIF/CD74', 'Var', (179, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('H28', 'Gene', '15061', (134, 137))	('H28', 'Gene', (134, 137))
16385	26883190	The population doubling time of MeT5A (18.9 +- 4.5 h (n = 4)) was the lowest one compared to that of H28 (29.1 +- 2.7 h (n = 7; P < 0.01)) and JL-1 (41.0 +- 9.1 h (n = 6; P < 0.01)).	('MeT5A', 'Var', (32, 37))	('H28', 'Gene', (101, 104))	('H28', 'Gene', '15061', (101, 104))
16397	26883190	Human MPM cell line H28 (expressing high level of CD74 and secreting high level of MIF) showed a high level of multiplication and proliferation rate associated with a low level of apoptosis rate.	('multiplication', 'CPA', (111, 125))	('Human', 'Species', '9606', (0, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('CD74', 'Var', (50, 54))	('proliferation rate', 'CPA', (130, 148))	('H28', 'Gene', '15061', (20, 23))	('H28', 'Gene', (20, 23))
16402	26883190	Multiplication rate of MIF siRNA treated-cells was reduced of 39% and 40% for H28 and H2052 respectively, compared to that of NC siRNA treated cells (Figure 5C, 61 +- 17% and 60 +- 34% for H28 and H2052 respectively, n = 6-7, P < 0.01).	('MIF siRNA treated-cells', 'Var', (23, 46))	('H28', 'Gene', (189, 192))	('H2052', 'Var', (86, 91))	('reduced', 'NegReg', (51, 58))	('H28', 'Gene', '15061', (78, 81))	('Multiplication', 'CPA', (0, 14))	('H28', 'Gene', (78, 81))	('H28', 'Gene', '15061', (189, 192))
16403	26883190	This reduction in cell multiplication was explained by a reduction of 13% of cell proliferation of MIF siRNA-treated H28 cells (Figure 5D, 87 +- 24%, n = 5 for H28 cells; 120 +- 34%, n = 6 for H2052 cells) and an increase of 213% and 334% of cell apoptosis for H28 and H2052 (Figure 5E, 213 +- 86% and 334 +- 278% for H28 and H2052, n = 7-13, P < 0.05).	('H28', 'Gene', '15061', (117, 120))	('H28', 'Gene', (261, 264))	('H28', 'Gene', (117, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('cell apoptosis', 'CPA', (242, 256))	('reduction', 'NegReg', (5, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('reduction', 'NegReg', (57, 66))	('H28', 'Gene', '15061', (160, 163))	('H28', 'Gene', (160, 163))	('cell multiplication', 'CPA', (18, 37))	('H28', 'Gene', '15061', (318, 321))	('H28', 'Gene', (318, 321))	('H28', 'Gene', '15061', (261, 264))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('MIF', 'Var', (99, 102))	('cell proliferation', 'CPA', (77, 95))
16406	26883190	Multiplication rate of H28 and H2052 transfected with CD74 siRNA was reduced of 29% and 49% respectively, compared to that of NC siRNA treated cells (Figure 5C, 71% +- 20%, n = 6, P < 0.05 for H28; 51 +- 26%, n = 7; P < 0.01 for H2052).	('H28', 'Gene', '15061', (193, 196))	('CD74 siRNA', 'Var', (54, 64))	('reduced', 'NegReg', (69, 76))	('H28', 'Gene', (193, 196))	('H28', 'Gene', '15061', (23, 26))	('H28', 'Gene', (23, 26))	('Multiplication', 'CPA', (0, 14))
16407	26883190	CD74 siRNA-treated H28 and H2052 cells showed a decrease in cell proliferation compared to NC siRNA treated cells (Figure 5D; 37 +- 29%, n = 5, P < 0.05 for H28; and 59 +- 33%, n = 6 for H2052) and an increase in cell apoptosis (Figure 5E; 245 +- 143%, n = 4 for H28 and 427 +- 389%, n = 7 for H2052; P < 0.05).	('CD74', 'Var', (0, 4))	('cell proliferation', 'CPA', (60, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('H28', 'Gene', '15061', (263, 266))	('H28', 'Gene', '15061', (19, 22))	('H28', 'Gene', (19, 22))	('cell apoptosis', 'CPA', (213, 227))	('H28', 'Gene', (263, 266))	('decrease', 'NegReg', (48, 56))	('H28', 'Gene', '15061', (157, 160))	('H28', 'Gene', (157, 160))
16436	26883190	We also demonstrated that high expression of CD74 was an independent prognostic factor for prolonged overall survival in MPM patients.	('CD74', 'Gene', (45, 49))	('prolonged', 'PosReg', (91, 100))	('overall survival', 'MPA', (101, 117))	('high', 'Var', (26, 30))	('MPM', 'Disease', (121, 124))	('patients', 'Species', '9606', (125, 133))
16453	26883190	In contrast, other studies showed that MIF can activate the AMPK pathway, leading in some cancers to a decrease in cell proliferation, cell viability and in their metastatic potential.	('cancers', 'Disease', (90, 97))	('metastatic potential', 'CPA', (163, 183))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('115', '133'))	('cell viability', 'CPA', (135, 149))	('AMPK', 'molecular_function', 'GO:0050405', ('60', '64'))	('AMPK', 'molecular_function', 'GO:0004691', ('60', '64'))	('MIF', 'Var', (39, 42))	('cell proliferation', 'CPA', (115, 133))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('AMPK', 'molecular_function', 'GO:0047322', ('60', '64'))	('decrease', 'NegReg', (103, 111))	('AMPK pathway', 'Pathway', (60, 72))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
16462	26883190	syngeneic implantations of murine mesothelioma cells deleted or not in MIF or CD74 expression into wild-type or MIF-deficient or CD74-deficient mice and study tumor development, tumor angiogenesis and identify the inflammatory cells recruited by the host.	('tumor', 'Disease', (178, 183))	('mice', 'Species', '10090', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('MIF-deficient or CD74-deficient', 'Disease', (112, 143))	('MIF-deficient or CD74-deficient', 'Disease', 'MESH:D007153', (112, 143))	('mesothelioma', 'Disease', (34, 46))	('MIF', 'Gene', (71, 74))	('tumor', 'Disease', (159, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('murine', 'Species', '10090', (27, 33))	('deleted', 'Var', (53, 60))	('CD74', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
16464	26883190	Decreasing MIF or CD74 expression in H28 and H2052 MPM cells reduced multiplication rate of the tumor cells due to a reduction in proliferation and an increase in apoptosis.	('H2052', 'Var', (45, 50))	('apoptosis', 'CPA', (163, 172))	('reduction', 'NegReg', (117, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('Decreasing', 'NegReg', (0, 10))	('H2052 MPM', 'CellLine', 'CVCL:1518', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('CD74', 'Gene', (18, 22))	('tumor', 'Disease', (96, 101))	('H28', 'Gene', '15061', (37, 40))	('H28', 'Gene', (37, 40))	('proliferation', 'CPA', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('increase', 'PosReg', (151, 159))	('MIF', 'Protein', (11, 14))	('reduced', 'NegReg', (61, 68))	('expression', 'MPA', (23, 33))
16483	26883190	The membranes were saturated for 1 h at room temperature (RT) in a 10 mmol/l Tris-HCl buffer (pH 7.4) containing 150 mmol/l NaCl, 0.1% (v/v) Tween-20, and 5% (w/v) milk (TBS/T/milk), and then incubated overnight at 4 C with rabbit polyclonal primary antibodies diluted in TBS/T/milk at 1/1000 for GAPDH (#2118, Cell Signaling Technology), 1/200 for CXCR4 (ab2074, Abcam), 1/1000 for CD74 (HPA010592, Sigma) and 1/1000 for MIF (BR47, from the Roger lab, Lausanne, Switzerland).	('Signaling', 'biological_process', 'GO:0023052', ('316', '325'))	('CXCR4', 'Gene', '7852', (349, 354))	('CD74', 'Var', (383, 387))	('CXCR4', 'Gene', (349, 354))	('GAPDH', 'Gene', '2597', (297, 302))	('Tris-HCl', 'Chemical', '-', (77, 85))	('NaCl', 'Chemical', 'MESH:D012965', (124, 128))	('CXCR4', 'molecular_function', 'GO:0038147', ('349', '354'))	('rabbit', 'Species', '9986', (224, 230))	('GAPDH', 'Gene', (297, 302))
16487	26883190	4 mum thick mesothelioma tumor sections from formalin fixed paraffin embedded samples were analysed by immunohistochemistry using anti-MIF (gift of Thierry Roger, Lausanne), anti-CD74 (HPA010592, Sigma) and anti-CD44 antibodies (HPA005785, Sigma) using the Ventana Discovery automated staining system (Ventana Medical Systems, Tucson, AZ, USA).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('anti-CD74', 'Var', (174, 183))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (12, 30))	('anti-MIF', 'Var', (130, 138))	('paraffin', 'Chemical', 'MESH:D010232', (60, 68))	('mesothelioma tumor', 'Disease', (12, 30))	('anti-CD44', 'Var', (207, 216))	('formalin', 'Chemical', 'MESH:D005557', (45, 53))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (12, 30))
16490	26883190	Detection of anti-MIF, anti-CD74 and anti-CD44 antibodies were performed using the rabbit OmniMap kit (760-149).	('anti-CD44', 'Gene', (37, 46))	('rabbit', 'Species', '9986', (83, 89))	('anti-CD74', 'Var', (23, 32))	('anti-CD44', 'Var', (37, 46))
16526	25264933	Chronic nose-only inhalation bioassays indicated that RCF exposure in rats increased the incidence of lung cancer and similar exposures resulted in mesothelioma in hamsters, but these studies may have been compromised by overload.	('resulted in', 'Reg', (136, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('mesothelioma', 'Disease', (148, 160))	('rats', 'Species', '10116', (70, 74))	('exposure', 'Var', (58, 66))	('hamster', 'Species', '10034', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('RCF', 'Gene', (54, 57))	('increased', 'PosReg', (75, 84))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('cancer', 'Disease', (107, 113))
16594	22216185	Two pathways control eIF4F: 1) mTORc1 phosphorylates and inactivates 4E-BPs, leading to eIF4F formation; 2) the Ras-Mnk cascade phosphorylates eIF4E.	('eIF4F', 'Gene', (88, 93))	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('eIF4F', 'Gene', '1981', (88, 93))	('mTORc1', 'cellular_component', 'GO:0031931', ('31', '37'))	('4E-BPs', 'Protein', (69, 75))	('mTORc1', 'Gene', (31, 37))	('leading to', 'Reg', (77, 87))	('eIF4F', 'Gene', (21, 26))	('Mnk', 'Gene', '538', (116, 119))	('mTORc1', 'Gene', '382056', (31, 37))	('eIF4', 'cellular_component', 'GO:0008304', ('143', '147'))	('eIF4E', 'Gene', '1977', (143, 148))	('eIF4F', 'cellular_component', 'GO:0016281', ('21', '26'))	('eIF4F', 'Gene', '1981', (21, 26))	('eIF4F', 'cellular_component', 'GO:0016281', ('88', '93'))	('Mnk', 'Gene', (116, 119))	('inactivates', 'Var', (57, 68))	('eIF4E', 'Gene', (143, 148))
16596	22216185	Translation is rapidly abrogated by phosphorylation of eIF2alpha.	('Translation', 'MPA', (0, 11))	('eIF2', 'cellular_component', 'GO:0005850', ('55', '59'))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('phosphorylation', 'Var', (36, 51))	('eIF2alpha', 'Gene', (55, 64))	('abrogated', 'NegReg', (23, 32))	('eIF2alpha', 'Gene', '83939', (55, 64))
16600	22216185	In spite of this, mTORc1 inhibition reduces eIF4F complex formation, and depresses translocation of TOP mRNAs on polysomes.	('eIF4F', 'Gene', (44, 49))	('As', 'Chemical', 'MESH:C015001', (107, 109))	('eIF4F', 'Gene', '1981', (44, 49))	('mTORc1', 'cellular_component', 'GO:0031931', ('18', '24'))	('mTORc1', 'Gene', (18, 24))	('inhibition', 'Var', (25, 35))	('reduces', 'NegReg', (36, 43))	('depresses', 'NegReg', (73, 82))	('mTORc1', 'Gene', '382056', (18, 24))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('eIF4F', 'cellular_component', 'GO:0016281', ('44', '49'))	('translocation of TOP mRNAs on polysomes', 'MPA', (83, 122))
16601	22216185	Downregulation of eIF4E and overexpression of 4E-BP1 induce rapamycin sensitivity, suggesting that disruption of eIF4F complex, due to eIF4E modulation, competes with its recycling to ribosomes.	('competes', 'NegReg', (153, 161))	('eIF4E', 'Gene', (135, 140))	('eIF4F', 'Gene', (113, 118))	('eIF4F', 'Gene', '1981', (113, 118))	('Downregulation', 'NegReg', (0, 14))	('eIF4F', 'cellular_component', 'GO:0016281', ('113', '118'))	('disruption', 'Var', (99, 109))	('eIF4', 'cellular_component', 'GO:0008304', ('135', '139'))	('4E-BP1', 'Gene', (46, 52))	('eIF4E', 'Gene', '1977', (18, 23))	('rapamycin', 'Chemical', 'MESH:D020123', (60, 69))	('induce', 'Reg', (53, 59))	('rapamycin sensitivity', 'MPA', (60, 81))	('eIF4', 'cellular_component', 'GO:0008304', ('18', '22'))	('recycling to ribosomes', 'MPA', (171, 193))	('4E-BP1', 'Gene', '1978', (46, 52))	('eIF4E', 'Gene', '1977', (135, 140))	('eIF4E', 'Gene', (18, 23))
16605	22216185	The net result of eIF2alpha phosphorylation is a block in general initiation.	('phosphorylation', 'Var', (28, 43))	('eIF2', 'cellular_component', 'GO:0005850', ('18', '22'))	('eIF2alpha', 'Gene', (18, 27))	('block', 'NegReg', (49, 54))	('general initiation', 'MPA', (58, 76))	('eIF2alpha', 'Gene', '83939', (18, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))
16610	22216185	4E-binding proteins (4E-BPs) are inhibitory factors preventing eIF4F formation by binding eIF4E and replacing eIF4G.	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('eIF4', 'cellular_component', 'GO:0008304', ('110', '114'))	('eIF4', 'cellular_component', 'GO:0008304', ('90', '94'))	('eIF4E', 'Gene', (90, 95))	('eIF4F', 'Gene', (63, 68))	('eIF4G', 'Gene', (110, 115))	('eIF4F', 'Gene', '1981', (63, 68))	('eIF4G', 'Gene', '1981', (110, 115))	('eIF4F', 'cellular_component', 'GO:0016281', ('63', '68'))	('binding', 'molecular_function', 'GO:0005488', ('3', '10'))	('binding', 'Interaction', (82, 89))	('replacing', 'Var', (100, 109))	('eIF4E', 'Gene', '1977', (90, 95))
16621	22216185	Although the exact mechanism by which eIF4E phosphorylation affects translation is unclear, it may increase affinity of eIF4E for the mRNA cap structure and for eIF4G.	('affinity', 'Interaction', (108, 116))	('eIF4E', 'Gene', (38, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('eIF4G', 'Gene', '1981', (161, 166))	('affects', 'Reg', (60, 67))	('eIF4E', 'Gene', '1977', (120, 125))	('translation', 'biological_process', 'GO:0006412', ('68', '79'))	('eIF4', 'cellular_component', 'GO:0008304', ('161', '165'))	('phosphorylation', 'Var', (44, 59))	('eIF4', 'cellular_component', 'GO:0008304', ('120', '124'))	('translation', 'MPA', (68, 79))	('increase', 'PosReg', (99, 107))	('eIF4E', 'Gene', '1977', (38, 43))	('eIF4', 'cellular_component', 'GO:0008304', ('38', '42'))	('eIF4E', 'Gene', (120, 125))	('cap', 'Chemical', '-', (139, 142))	('mRNA', 'Protein', (134, 138))	('eIF4G', 'Gene', (161, 166))
16623	22216185	Recently, others and we described the relative insensitivity of several cancer cell lines and patients to the action of rapalogues; the insensitivity was linked to mutations in the Ras pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Ras pathway', 'Pathway', (181, 192))	('linked', 'Reg', (154, 160))	('mutations', 'Var', (164, 173))	('cancer', 'Disease', (72, 78))
16628	22216185	eIF6 depletion results in impaired translation, upon insulin stimulation.	('insulin', 'Gene', (53, 60))	('depletion', 'Var', (5, 14))	('insulin', 'Gene', '3630', (53, 60))	('eIF6', 'Gene', '3692', (0, 4))	('eIF6', 'Gene', (0, 4))	('impaired', 'NegReg', (26, 34))	('translation', 'biological_process', 'GO:0006412', ('35', '46'))	('insulin', 'molecular_function', 'GO:0016088', ('53', '60'))	('translation', 'MPA', (35, 46))
16661	22216185	Coadministration of rapamycin and U0126 led to the complete dephosphorylation of ERK1/2, but not of eIF4E.	('eIF4E', 'Gene', (100, 105))	('U0126', 'Chemical', 'MESH:C113580', (34, 39))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('U0126', 'Var', (34, 39))	('rapamycin', 'Chemical', 'MESH:D020123', (20, 29))	('eIF4', 'cellular_component', 'GO:0008304', ('100', '104'))	('dephosphorylation', 'MPA', (60, 77))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))	('ERK1/2', 'Gene', (81, 87))	('eIF4E', 'Gene', '1977', (100, 105))	('dephosphorylation', 'biological_process', 'GO:0016311', ('60', '77'))
16666	22216185	mTOR kinase inhibition was performed with PP242, an inhibitor that targets the ATP binding domain, blocking both mTORc1 and mTORc2 signalling.	('ATP binding', 'molecular_function', 'GO:0005524', ('79', '90'))	('mTOR', 'Gene', '2475', (124, 128))	('mTORc1', 'Gene', '382056', (113, 119))	('PP242', 'Chemical', 'MESH:C572919', (42, 47))	('mTORc2', 'cellular_component', 'GO:0031932', ('124', '130'))	('mTOR', 'Gene', (124, 128))	('signalling', 'biological_process', 'GO:0023052', ('131', '141'))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('mTOR', 'Gene', (113, 117))	('mTORc2', 'Gene', '74343', (124, 130))	('mTOR', 'Gene', '2475', (113, 117))	('mTORc1', 'cellular_component', 'GO:0031931', ('113', '119'))	('PP242', 'Var', (42, 47))	('mTORc2', 'Gene', (124, 130))	('mTOR', 'Gene', '2475', (0, 4))	('blocking', 'NegReg', (99, 107))	('mTOR', 'Gene', (0, 4))	('mTORc1', 'Gene', (113, 119))
16667	22216185	We treated cells with PP242 and tested the phosphorylation of mTORc1 and mTORCc2 downstream effectors.	('mTOR', 'Gene', '2475', (73, 77))	('mTOR', 'Gene', '2475', (62, 66))	('tested', 'Reg', (32, 38))	('mTOR', 'Gene', (73, 77))	('mTOR', 'Gene', (62, 66))	('phosphorylation', 'MPA', (43, 58))	('PP242', 'Var', (22, 27))	('mTORc1', 'Gene', (62, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('mTORc1', 'Gene', '382056', (62, 68))	('mTORc1', 'cellular_component', 'GO:0031931', ('62', '68'))	('PP242', 'Chemical', 'MESH:C572919', (22, 27))
16669	22216185	Then we measured methionine incorporation in REN cells treated with different concentration of PP242, both at the EC50 of the compound and 100 times more concentrated.	('methionine incorporation', 'MPA', (17, 41))	('REN', 'Gene', '5972', (45, 48))	('REN', 'Gene', (45, 48))	('PP242', 'Var', (95, 100))	('methionine', 'Chemical', 'MESH:D008715', (17, 27))	('PP242', 'Chemical', 'MESH:C572919', (95, 100))
16670	22216185	Surprisingly, methionine incorporation was unaffected by PP242 treatment (Fig.	('methionine', 'Chemical', 'MESH:D008715', (14, 24))	('PP242', 'Chemical', 'MESH:C572919', (57, 62))	('PP242', 'Var', (57, 62))	('methionine incorporation', 'MPA', (14, 38))
16675	22216185	The effect of Mnk/MAPK inhibition was subtle; U0126 did not affect 4E-BP1 binding to eIF4E, but caused a minimal decrease of eIF4G binding (Fig.	('Mnk', 'Gene', (14, 17))	('decrease', 'NegReg', (113, 121))	('eIF4', 'cellular_component', 'GO:0008304', ('125', '129'))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('eIF4E', 'Gene', '1977', (85, 90))	('4E-BP1', 'Gene', (67, 73))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('eIF4G', 'Gene', (125, 130))	('eIF4G', 'Gene', '1981', (125, 130))	('binding', 'Interaction', (131, 138))	('eIF4', 'cellular_component', 'GO:0008304', ('85', '89'))	('Mnk', 'Gene', '538', (14, 17))	('eIF4E', 'Gene', (85, 90))	('eIF4G binding', 'molecular_function', 'GO:0031370', ('125', '138'))	('4E-BP1', 'Gene', '1978', (67, 73))	('U0126', 'Var', (46, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
16676	22216185	mTORc1 and mTORc2 inhibition by PP242 strongly affects the cap complex assembly of initiation factors (Fig.	('inhibition', 'NegReg', (18, 28))	('mTORc2', 'Gene', '74343', (11, 17))	('PP242', 'Var', (32, 37))	('cap', 'Chemical', '-', (59, 62))	('mTORc1', 'Gene', (0, 6))	('affects', 'Reg', (47, 54))	('initiation', 'Protein', (83, 93))	('mTORc2', 'Gene', (11, 17))	('mTORc1', 'Gene', '382056', (0, 6))	('mTORc1', 'cellular_component', 'GO:0031931', ('0', '6'))	('mTORc2', 'cellular_component', 'GO:0031932', ('11', '17'))	('PP242', 'Chemical', 'MESH:C572919', (32, 37))	('cap complex assembly', 'MPA', (59, 79))
16681	22216185	Briefly, we found a slight decrease in polysomal distribution of TOP mRNA in cells treated with rapamycin and PP242 (Fig.	('polysomal distribution', 'MPA', (39, 61))	('decrease', 'NegReg', (27, 35))	('PP242', 'Chemical', 'MESH:C572919', (110, 115))	('TOP', 'Protein', (65, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (96, 105))	('PP242', 'Var', (110, 115))
16692	22216185	The overexpression of 4E-BP1 wt or mutated did not affect caspase 3 activation (Fig.	('mutated', 'Var', (35, 42))	('caspase 3', 'Gene', (58, 67))	('activation', 'MPA', (68, 78))	('caspase 3', 'Gene', '836', (58, 67))	('4E-BP1', 'Gene', (22, 28))	('4E-BP1', 'Gene', '1978', (22, 28))
16697	22216185	So far we have shown that REN cells have an impairment of cap complex formation, but not global reduction of translation, upon mTOR inhibition.	('cap', 'Chemical', '-', (58, 61))	('cap complex formation', 'MPA', (58, 79))	('REN', 'Gene', (26, 29))	('translation', 'biological_process', 'GO:0006412', ('109', '120'))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('inhibition', 'Var', (132, 142))	('REN', 'Gene', '5972', (26, 29))
16727	22216185	A more intriguing possibility exists: it was recently shown that mTOR inactivation in the heart led to 4E-BP upregulation.	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('upregulation', 'PosReg', (109, 121))	('inactivation', 'Var', (70, 82))	('4E-BP', 'MPA', (103, 108))
16731	22216185	Moreover, when we blocked TOR kinase activity with PP242, leading to a complete inhibition of both mTORc1 and mTORc2, even at 100 microM, where PP242 has been reported to aspecifically block PI3K/Akt pathway, the global rate of translation was not affected, after short term treatment.	('inhibition', 'NegReg', (80, 90))	('mTORc1', 'cellular_component', 'GO:0031931', ('99', '105'))	('PP242', 'Chemical', 'MESH:C572919', (51, 56))	('TOR', 'Gene', '6097', (26, 29))	('Akt', 'Gene', (196, 199))	('mTORc1', 'Gene', (99, 105))	('PP242', 'Chemical', 'MESH:C572919', (144, 149))	('mTORc1', 'Gene', '382056', (99, 105))	('Akt', 'Gene', '207', (196, 199))	('translation', 'biological_process', 'GO:0006412', ('228', '239'))	('TOR', 'Gene', (26, 29))	('mTORc2', 'cellular_component', 'GO:0031932', ('110', '116'))	('block', 'NegReg', (185, 190))	('PP242', 'Var', (51, 56))	('TOR', 'Gene', '6097', (111, 114))	('kinase activity', 'molecular_function', 'GO:0016301', ('30', '45'))	('mTORc2', 'Gene', '74343', (110, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('191', '195'))	('PP242', 'Var', (144, 149))	('TOR', 'Gene', '6097', (100, 103))	('TOR', 'Gene', (111, 114))	('mTORc2', 'Gene', (110, 116))	('TOR', 'Gene', (100, 103))
16732	22216185	We previously found that the sensitivity of the translational apparatus to pharmacological inhibition with Everolimus, a rapamycin analogue, was linked to mutations in the Ras pathway.	('Everolimus', 'Chemical', 'MESH:D000068338', (107, 117))	('mutations', 'Var', (155, 164))	('linked', 'Reg', (145, 151))	('Ras pathway', 'Pathway', (172, 183))	('rapamycin', 'Chemical', 'MESH:D020123', (121, 130))
16734	22216185	Even if ERK1/2 was constitutively activated in REN cells, the inhibition of either this pathway trough U0126 drug or Mnk1 inhibition, had a modest role on the general level of translation.	('REN', 'Gene', '5972', (47, 50))	('U0126', 'Chemical', 'MESH:C113580', (103, 108))	('translation', 'biological_process', 'GO:0006412', ('176', '187'))	('ERK1/2', 'Gene', (8, 14))	('ERK1', 'molecular_function', 'GO:0004707', ('8', '12'))	('inhibition', 'NegReg', (122, 132))	('ERK1/2', 'Gene', '5595;5594', (8, 14))	('U0126', 'Var', (103, 108))	('Mnk1', 'Gene', (117, 121))	('REN', 'Gene', (47, 50))	('Mnk1', 'Gene', '8569', (117, 121))
16737	22216185	This interpretation is backed up by the observation that increasing 4E-BP1 or lowering eIF4E results in a more rapid inhibition of translation by rapamycin; 2) in principle, oncogenic activation by Ras, PI3K or Myc may alter by a transcriptional mechanism the sensitivity of the translational machinery to pharmacological inhibition.	('eIF4E', 'Gene', (87, 92))	('translation', 'biological_process', 'GO:0006412', ('131', '142'))	('4E-BP1', 'Gene', '1978', (68, 74))	('lowering', 'NegReg', (78, 86))	('PI3K', 'Var', (203, 207))	('eIF4', 'cellular_component', 'GO:0008304', ('87', '91'))	('alter', 'Reg', (219, 224))	('PI3K', 'molecular_function', 'GO:0016303', ('203', '207'))	('4E-BP1', 'Gene', (68, 74))	('eIF4E', 'Gene', '1977', (87, 92))	('Myc', 'Gene', '4609', (211, 214))	('Myc', 'Gene', (211, 214))	('rapamycin', 'Chemical', 'MESH:D020123', (146, 155))	('sensitivity', 'MPA', (260, 271))
16743	22216185	In consideration of the data that we presented, showing that inhibition of signaling pathways may not always affect translation of cancer cells, it may be more fruitful to directly inhibit the association of initiation factors.	('cancer', 'Disease', (131, 137))	('inhibition', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('translation', 'biological_process', 'GO:0006412', ('116', '127'))	('affect', 'Reg', (109, 115))	('association', 'Interaction', (193, 204))	('inhibit', 'NegReg', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
16853	32690771	Immune-competent mice with subcutaneously or orthotopically growing KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist).	('Trp53', 'Gene', (79, 84))	('mice', 'Species', '10090', (17, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('tumors', 'Disease', (113, 119))	('Pdx-1', 'Gene', '18609', (92, 97))	('PDAC', 'Chemical', '-', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('KrasG12D/+', 'Var', (68, 78))	('Trp53', 'Gene', '22059', (79, 84))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('mesothelioma', 'Disease', (221, 233))	('Pdx-1', 'Gene', (92, 97))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PDAC', 'Phenotype', 'HP:0006725', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))
16855	32690771	Extensive analysis of the TME showed that anti-CD40 monotherapy did improve CD8 +T cell infiltration, but these essential effector cells displayed hallmarks of exhaustion, including PD-1, TIM-3 and NKG2A.	('NKG2A', 'Gene', '16641', (198, 203))	('TIM-3', 'Gene', (188, 193))	('CD8', 'Gene', (76, 79))	('improve', 'PosReg', (68, 75))	('TIM-3', 'Gene', '171285', (188, 193))	('PD-1', 'Gene', '18566', (182, 186))	('PD-1', 'Gene', (182, 186))	('NKG2A', 'Gene', (198, 203))	('anti-CD40', 'Var', (42, 51))	('CD8', 'Gene', '925', (76, 79))
16893	32690771	Higher frequencies of intratumoral CD4+ and CD8+T cells were noted, paralleling the delayed tumor growth observed after vaccination (figure 1G).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('delayed tumor', 'Disease', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD4+', 'Var', (35, 39))	('tumor', 'Disease', (92, 97))	('delayed tumor', 'Disease', 'MESH:D009369', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
16905	32690771	The lack of increased T-cell infiltration found in established tumors in the presence of a systemic immune response suggested that the PDAC TME might physically obstruct T cells from infiltrating the tumor.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('T cells', 'CPA', (170, 177))	('increased T-cell', 'Phenotype', 'HP:0100828', (12, 28))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('PDAC', 'Var', (135, 139))	('tumor', 'Disease', (200, 205))	('obstruct', 'NegReg', (161, 169))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('PDAC', 'Chemical', '-', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('immune response', 'biological_process', 'GO:0006955', ('100', '115'))
16908	32690771	Interestingly, alphaCD40 combined with DC vaccination resulted in significant tumor growth control when compared with untreated mice while monotherapy DC or alphaCD40 did not (online supplementary figure S6b).	('alphaCD40', 'Chemical', '-', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('alphaCD40', 'Chemical', '-', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Disease', (78, 83))	('alphaCD40', 'Var', (15, 24))
16909	32690771	alphaCD40 monotherapy was able to induce systemic and intratumoral responses (online supplementary figure S6c-f).	('alphaCD40', 'Var', (0, 9))	('tumor', 'Disease', (59, 64))	('alphaCD40', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
16912	32690771	In this experimental setup, tumor growth and survival of mice treated with monotherapy DC vaccination or alphaCD40 also did not significantly differ from untreated tumor-bearing mice (figure 3B-D and online supplementary figure S8).	('alphaCD40', 'Var', (105, 114))	('mice', 'Species', '10090', (57, 61))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (28, 33))	('mice', 'Species', '10090', (178, 182))	('alphaCD40', 'Chemical', '-', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
16915	32690771	Antitumoral efficacy was retained in alphaCD4 and isotype-treated mice receiving DC vaccination and alphaCD40 (figure 3E-G).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (66, 70))	('alphaCD40', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('alphaCD40', 'Chemical', '-', (100, 109))
16920	32690771	Interim peripheral blood analysis demonstrated that both monotherapy DC vaccination and alphaCD40 treatment induced higher frequencies of CD69+, Ki-67+ and PD-1 +T cells.	('alphaCD40', 'Gene', (88, 97))	('higher', 'PosReg', (116, 122))	('alphaCD40', 'Chemical', '-', (88, 97))	('Ki-67', 'Gene', (145, 150))	('CD69+', 'Var', (138, 143))	('PD-1', 'Gene', '18566', (156, 160))	('PD-1', 'Gene', (156, 160))	('Ki-67', 'Gene', '17345', (145, 150))
16922	32690771	Combination therapy induced higher frequencies of CD69+, Ki-67+ and PD-1+ for both CD4+ and CD8+T cells.	('PD-1', 'Gene', '18566', (68, 72))	('CD8', 'Gene', (92, 95))	('CD69+', 'Var', (50, 55))	('CD8', 'Gene', '925', (92, 95))	('Ki-67', 'Gene', '17345', (57, 62))	('Ki-67', 'Gene', (57, 62))	('PD-1', 'Gene', (68, 72))
16927	32690771	The enrichment of effector memory T-cell frequencies was less prominent after single DC vaccination and subsequent alphaCD40 treatment (online supplementary figure S6d), promoting the role of multiple vaccinations.	('alphaCD40', 'Var', (115, 124))	('alphaCD40', 'Chemical', '-', (115, 124))	('promoting', 'PosReg', (170, 179))	('memory', 'biological_process', 'GO:0007613', ('27', '33'))
16936	32690771	In line with these findings, gene-set enrichment analysis (GSEA) revealed that gene transcripts associated with T-cell exhaustion were significantly enriched in tumors of alphaCD40 therapy treated mice compared with combination therapy treated animals (online supplementary figure S14a).	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('alphaCD40', 'Chemical', '-', (171, 180))	('alphaCD40 therapy', 'Var', (171, 188))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mice', 'Species', '10090', (197, 201))	('GSEA', 'Chemical', '-', (59, 63))
16940	32690771	Furthermore, we also found lower expression of genes related to various collagen markers and 'M2' phenotype macrophages after alphaCD40 therapy indicating TME remodeling.	('alphaCD40', 'Var', (126, 135))	('collagen', 'molecular_function', 'GO:0005202', ('72', '80'))	('lower', 'NegReg', (27, 32))	('alphaCD40', 'Chemical', '-', (126, 135))	('expression of genes', 'MPA', (33, 52))
16943	32690771	Strikingly, high mRNA expression of genes related to glycolysis were detected in tumors after combination therapy as compared with alphaCD40 monotherapy (figure 6A).	('tumors', 'Disease', (81, 87))	('high', 'PosReg', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('combination therapy', 'Var', (94, 113))	('glycolysis', 'biological_process', 'GO:0006096', ('53', '63'))	('mRNA expression', 'MPA', (17, 32))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('alphaCD40', 'Chemical', '-', (131, 140))
16944	32690771	A glycolysis GSEA indeed revealed higher activity in the combination therapy treated mice compared with alphaCD40 treated mice (online supplementary figure S14b).	('mice', 'Species', '10090', (85, 89))	('alphaCD40', 'Chemical', '-', (104, 113))	('mice', 'Species', '10090', (122, 126))	('higher', 'PosReg', (34, 40))	('glycolysis', 'biological_process', 'GO:0006096', ('2', '12'))	('GSEA', 'Chemical', '-', (13, 17))	('combination', 'Var', (57, 68))	('activity', 'MPA', (41, 49))
16945	32690771	Combination therapy was also able to significantly upregulate expression of Vegfa, adm and Flt1 compared with alphaCD40 treated mice (online supplementary figure S13).	('alphaCD40', 'Chemical', '-', (110, 119))	('Flt1', 'Gene', '14254', (91, 95))	('Combination', 'Var', (0, 11))	('expression', 'MPA', (62, 72))	('Vegfa', 'Gene', '22339', (76, 81))	('mice', 'Species', '10090', (128, 132))	('adm', 'Gene', (83, 86))	('Flt1', 'Gene', (91, 95))	('Vegfa', 'Gene', (76, 81))	('upregulate', 'PosReg', (51, 61))
16955	32690771	Recently, targeting NKG2A on T cells has been described as a novel approach to promote antitumor immunity and has been linked to T-cell dysfunction.	('NKG2A', 'Gene', (20, 25))	('NKG2A', 'Gene', '16641', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promote', 'PosReg', (79, 86))	('targeting', 'Var', (10, 19))	('T-cell dysfunction', 'Phenotype', 'HP:0005435', (129, 147))	('tumor', 'Disease', (91, 96))	('linked', 'Reg', (119, 125))	('T-cell dysfunction', 'Disease', (129, 147))
16956	32690771	Interestingly, alphaCD40 induced the highest numbers of NKG2A+CD8+TILs compared with combination therapy arm (figure 6B).	('alphaCD40', 'Chemical', '-', (15, 24))	('NKG2A', 'Gene', (56, 61))	('CD8', 'Gene', (62, 65))	('CD8', 'Gene', '925', (62, 65))	('NKG2A', 'Gene', '16641', (56, 61))	('alphaCD40', 'Var', (15, 24))
16957	32690771	Moreover, although alphaCD40 therapy increased TIL numbers, the frequencies of proliferating TILs were lower compared with untreated mice suggesting that this is not explained by local expansion, but enhanced infiltration (figure 6C).	('mice', 'Species', '10090', (133, 137))	('alphaCD40', 'Chemical', '-', (19, 28))	('alphaCD40 therapy', 'Var', (19, 36))	('lower', 'NegReg', (103, 108))	('infiltration', 'CPA', (209, 221))	('TIL', 'CPA', (47, 50))	('increased', 'PosReg', (37, 46))	('enhanced', 'PosReg', (200, 208))
16969	32690771	alphaCD40 therapy may, therefore, also activate endogenous DCs that present tumor antigens and contribute to a monotherapy effect.	('endogenous DCs', 'MPA', (48, 62))	('monotherapy', 'MPA', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('alphaCD40', 'Chemical', '-', (0, 9))	('alphaCD40 therapy', 'Var', (0, 17))	('present', 'MPA', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('activate', 'PosReg', (39, 47))
16970	32690771	Also, Schoenberger and Bennett et al demonstrated that CD40-activated APCs might replace the requirement for CD4 +T helper-mediated licensing, thereby lowering the threshold for CD8 +effector T-cell priming.	('APCs', 'Gene', '20219', (70, 74))	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('lowering', 'NegReg', (151, 159))	('CD40-activated', 'Var', (55, 69))	('APCs', 'Gene', (70, 74))
16971	32690771	Alternatively, CD40 ligation may also license delivered DCs, thereby enhancing their capacity to prime CD8 +T cells.	('CD40 ligation', 'Var', (15, 28))	('enhancing', 'PosReg', (69, 78))	('delivered DCs', 'MPA', (46, 59))	('CD8', 'Gene', (103, 106))	('CD8', 'Gene', '925', (103, 106))
16972	32690771	Indeed, when bone marrow-derived DCs were treated with alphaCD40, increased IL-12 production could be detected (online supplementary figure S18).	('IL-12', 'molecular_function', 'GO:0005143', ('76', '81'))	('increased', 'PosReg', (66, 75))	('IL-12 production', 'MPA', (76, 92))	('alphaCD40', 'Chemical', '-', (55, 64))	('alphaCD40', 'Var', (55, 64))	('IL-12 production', 'biological_process', 'GO:0032615', ('76', '92'))	('increased IL-12 production', 'Phenotype', 'HP:0030783', (66, 92))
16973	32690771	Furthermore, alphaCD40 therapy can also directly modulate the TME: targeting CD40 on macrophages can lead to phenotypic polarization from immunosuppressive 'M2' into inflammatory 'M1' macrophages, the latter being tumoricidal and capable of ablating tumor stroma.	('targeting', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('lead to', 'Reg', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (214, 219))	('tumor stroma', 'Disease', (250, 262))	('alphaCD40', 'Chemical', '-', (13, 22))	('CD40', 'Gene', (77, 81))	('tumor stroma', 'Disease', 'MESH:D009369', (250, 262))	('tumor', 'Disease', (250, 255))	('phenotypic polarization', 'MPA', (109, 132))
16974	32690771	In line with this thought, our mRNA expression data and histochemical staining on tumors confirmed decreased collagen content after alphaCD40 mono and combination therapy (figure 6A).	('alphaCD40', 'Chemical', '-', (132, 141))	('collagen', 'molecular_function', 'GO:0005202', ('109', '117'))	('decreased', 'NegReg', (99, 108))	('combination', 'Var', (151, 162))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('decreased collagen content', 'Phenotype', 'HP:0030095', (99, 125))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('alphaCD40', 'Var', (132, 141))	('collagen content', 'MPA', (109, 125))
16975	32690771	Also, lower expression of mRNA levels related to M2 macrophages was found in tumors of mice treated with alphaCD40 (figure 6A).	('tumors', 'Disease', (77, 83))	('alphaCD40', 'Var', (105, 114))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('lower', 'NegReg', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mice', 'Species', '10090', (87, 91))	('mRNA levels', 'MPA', (26, 37))	('alphaCD40', 'Chemical', '-', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'MPA', (12, 22))
16977	32690771	It has been found that CSF-1 inhibition leads to desmoplasia depletion and sensitizes pancreatic cancer to immune checkpoint blockade therapy.	('desmoplasia depletion', 'MPA', (49, 70))	('CSF-1', 'Gene', (23, 28))	('CSF-1', 'molecular_function', 'GO:0005011', ('23', '28'))	('pancreatic cancer', 'Disease', (86, 103))	('sensitizes', 'Reg', (75, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CSF-1', 'Gene', '12977', (23, 28))	('leads to', 'Reg', (40, 48))	('inhibition', 'Var', (29, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
16978	32690771	We were able to show lower Csf1 mRNA levels in tumors after alphaCD40 therapy and combination therapy (figure 6A).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('alphaCD40 therapy', 'Var', (60, 77))	('lower', 'NegReg', (21, 26))	('alphaCD40', 'Chemical', '-', (60, 69))	('Csf1', 'Gene', '12977', (27, 31))	('Csf1', 'molecular_function', 'GO:0005011', ('27', '31'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Csf1', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('combination', 'Var', (82, 93))
16979	32690771	A recently reported combination therapy involving alphaCD40 and alphaPD-1 therapy showed promising results in preclinical PDAC models, and demonstrated that therapy reprograms the TME resulting in the increase of DCs and decrease of granulocytic-MDSCs.	('PDAC', 'Chemical', '-', (122, 126))	('increase', 'PosReg', (201, 209))	('alphaCD40', 'Chemical', '-', (50, 59))	('PD-1', 'Gene', '18566', (69, 73))	('granulocytic-MDSCs', 'MPA', (233, 251))	('PD-1', 'Gene', (69, 73))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))	('alphaCD40', 'Var', (50, 59))	('DCs', 'MPA', (213, 216))	('decrease', 'NegReg', (221, 229))
16990	32690771	In addition, KLRG1hiIL7rlo CD8 +T cells have previously been described as dysfunctional.	('dysfunctional', 'Disease', 'MESH:D009461', (74, 87))	('KLRG1hiIL7rlo', 'Var', (13, 26))	('CD8', 'Gene', (27, 30))	('CD8', 'Gene', '925', (27, 30))	('dysfunctional', 'Disease', (74, 87))
16991	32690771	We found that monotherapy with alphaCD40 induced higher expression of Klrg1 but not Il7r, whereas DC vaccination increased the levels of both Klrg1 and Il7r.	('Klrg1', 'Gene', (70, 75))	('Il7r', 'Gene', (84, 88))	('Il7r', 'Gene', '16197', (84, 88))	('Klrg1', 'Gene', '50928', (142, 147))	('Klrg1', 'Gene', '50928', (70, 75))	('Il7r', 'molecular_function', 'GO:0004917', ('84', '88'))	('alphaCD40', 'Var', (31, 40))	('expression', 'MPA', (56, 66))	('Il7r', 'molecular_function', 'GO:0004917', ('152', '156'))	('Il7r', 'Gene', '16197', (152, 156))	('alphaCD40', 'Chemical', '-', (31, 40))	('higher', 'PosReg', (49, 55))	('Il7r', 'Gene', (152, 156))	('Klrg1', 'Gene', (142, 147))
16994	32690771	We found that combination DC and alphaCD40 therapy indeed induced higher Cxcr5 expression in the tumor compared with other groups.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('alphaCD40', 'Chemical', '-', (33, 42))	('Cxcr5', 'Gene', '12145', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('alphaCD40', 'Var', (33, 42))	('higher', 'PosReg', (66, 72))	('Cxcr5', 'Gene', (73, 78))
16995	32690771	Flow cytometry analysis confirmed the reduced expression of various inhibitory markers on CD8 +TILs derived from combination therapy-treated mice compared with alphaCD40-treated mice.	('alphaCD40', 'Chemical', '-', (160, 169))	('reduced', 'NegReg', (38, 45))	('mice', 'Species', '10090', (178, 182))	('CD8', 'Gene', (90, 93))	('mice', 'Species', '10090', (141, 145))	('expression', 'MPA', (46, 56))	('CD8', 'Gene', '925', (90, 93))	('combination', 'Var', (113, 124))
17005	32690771	Currently, several studies with combination strategies incorporating CD40 agonists in PDAC patients are ongoing and recruiting (NCT03214250; NCT02588443; NCT03329950).	('patients', 'Species', '9606', (91, 99))	('NCT03214250;', 'Var', (128, 140))	('PDAC', 'Chemical', '-', (86, 90))	('CD40', 'Protein', (69, 73))	('PDAC', 'Disease', (86, 90))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))
17012	32690771	All mouse experiments were controlled by the animal welfare committee (IvD) of the Leiden University Medical Center (Leiden) or Erasmus University Medical Center (Rotterdam) and approved by the national central committee of animal experiments (CCD) under the permit numbers AVD116002015271 and AVD101002017867, in accordance with the Dutch Act on Animal Experimentation and European Union (EU) Directive 2010/63/EU.	('mouse', 'Species', '10090', (4, 9))	('AVD', 'cellular_component', 'GO:0044754', ('274', '277'))	('AVD', 'cellular_component', 'GO:0044754', ('294', '297'))	('CCD', 'Disease', 'MESH:D002973', (244, 247))	('AVD116002015271', 'Var', (274, 289))	('CCD', 'Disease', (244, 247))	('AVD101002017867', 'Var', (294, 309))
17055	31443309	Additionally, the process of pathogenesis is greatly affected by activating mutations of EGFR, KRAS, PIK3CA, BRAF, MET, EML4/ALK and RET, which correlate with an increased incidence of MPE.	('ALK', 'Gene', '238', (125, 128))	('activating', 'PosReg', (65, 75))	('ALK', 'Gene', (125, 128))	('PIK3CA', 'Gene', (101, 107))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('RET', 'Gene', '5979', (133, 136))	('MPE', 'Disease', (185, 188))	('affected', 'Reg', (53, 61))	('EGFR', 'Gene', (89, 93))	('KRAS', 'Gene', '3845', (95, 99))	('PIK3CA', 'Gene', '5290', (101, 107))	('EML4', 'Gene', (120, 124))	('mutations', 'Var', (76, 85))	('pathogenesis', 'biological_process', 'GO:0009405', ('29', '41'))	('RET', 'Gene', (133, 136))	('EML4', 'Gene', '27436', (120, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('KRAS', 'Gene', (95, 99))	('MET', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (89, 93))
17116	31443309	In the last decade, researchers used genome analysis of tumor cells and discovered that tumors which have activating mutations EGFR, KRAS, PIK3CA, BRAF, MET, EML4/ALK and RET are connected to increased MPE formation.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EML4', 'Gene', (158, 162))	('ALK', 'Gene', '238', (163, 166))	('RET', 'Gene', (171, 174))	('activating', 'PosReg', (106, 116))	('EML4', 'Gene', '27436', (158, 162))	('PIK3CA', 'Gene', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ALK', 'Gene', (163, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('MPE formation', 'MPA', (202, 215))	('tumor', 'Disease', (88, 93))	('EGFR', 'Gene', (127, 131))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (56, 61))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('KRAS', 'Gene', '3845', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('RET', 'Gene', '5979', (171, 174))	('increased', 'PosReg', (192, 201))	('PIK3CA', 'Gene', '5290', (139, 145))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('KRAS', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('EGFR', 'Gene', '1956', (127, 131))
17117	31443309	KRAS mutations are common for distant metastases and EGFR mutations for tumors which metastasize via direct infiltration.	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('common', 'Reg', (19, 25))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('metastases', 'Disease', (38, 48))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
17118	31443309	Mutations in the primary tumor differ from metastases in MPE.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('metastases', 'Disease', (43, 53))	('Mutations', 'Var', (0, 9))	('metastases', 'Disease', 'MESH:D009362', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
17131	31443309	The most common biological markers are EGFR mutations and Alk translocations.	('Alk', 'Gene', '238', (58, 61))	('Alk', 'Gene', (58, 61))	('common', 'Reg', (9, 15))	('mutations', 'Var', (44, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
17145	31443309	According to this, we can divide BC into four types: Luminal A (positive PR and ER), luminal B (positive PR, ER and HER2), triple-negative (PR-, ER- and HER2-negative), as well as HER2 positive (PR- and ER-negative, positive HER2).	('PR-', 'Var', (195, 198))	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', (225, 229))	('HER2', 'Gene', (153, 157))	('HER2', 'Gene', '2064', (180, 184))	('HER2', 'Gene', '2064', (225, 229))	('HER2', 'Gene', '2064', (153, 157))	('HER2', 'Gene', (116, 120))	('HER2', 'Gene', '2064', (116, 120))
17175	31443309	The proposed pathophysiological mechanisms of action are: (a) Direct infiltration of the pleural space; (b) lymphatic obstruction with infiltration of pulmonal and mediastinal lymph nodes and; (c) obstruction of the ductus thoracicus, which leads to the formation of a chylothorax.	('formation', 'biological_process', 'GO:0009058', ('254', '263'))	('pleural', 'Disease', (89, 96))	('lymphatic', 'Disease', (108, 117))	('leads to', 'Reg', (241, 249))	('chylothorax', 'Disease', (269, 280))	('lymphatic obstruction', 'Phenotype', 'HP:0001004', (108, 129))	('pleural', 'Disease', 'MESH:D010995', (89, 96))	('obstruction', 'Var', (197, 208))	('chylothorax', 'Phenotype', 'HP:0010310', (269, 280))
17291	31443309	Patients with a mutant EGFR in NSCLC respond to EGFR-tyrosine kinase inhibitors.	('respond', 'Reg', (37, 44))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('NSCLC', 'Disease', (31, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('EGFR', 'Gene', (48, 52))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('EGFR', 'Gene', '1956', (23, 27))	('Patients', 'Species', '9606', (0, 8))	('mutant', 'Var', (16, 22))	('EGFR', 'Gene', (23, 27))
17292	31443309	Unfortunately, most patients who initially had mutant EGFR in NSCLC without pleural effusion develop resistance to the prescribed therapy within a year.	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('NSCLC', 'Disease', (62, 67))	('resistance', 'MPA', (101, 111))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('EGFR', 'Gene', '1956', (54, 58))	('pleural effusion', 'Disease', 'MESH:D010996', (76, 92))	('patients', 'Species', '9606', (20, 28))	('pleural effusion', 'Phenotype', 'HP:0002202', (76, 92))	('pleural effusion', 'Disease', (76, 92))	('EGFR', 'Gene', (54, 58))	('mutant', 'Var', (47, 53))
17295	31443309	The presence of MPE in advanced cancer is associated with a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('presence', 'Var', (4, 12))	('MPE', 'Gene', (16, 19))
17410	28756416	In this case, using a more conservative estimate, the total burden dropped to 67.6% of the original estimate with the $C50 000 value and to 51.5% with the $C25 000 value.	('$C2', 'Gene', (155, 158))	('dropped', 'NegReg', (67, 74))	('burden', 'MPA', (60, 66))	(' $C50 000 value', 'Var', (117, 132))	('$C2', 'Gene', '717', (155, 158))
17448	27635089	In-vitro, RG7787 plus nab-Paclitaxel led to decreased cell viability compared to either agent alone.	('nab', 'Chemical', '-', (22, 25))	('Paclitaxel', 'Chemical', 'MESH:D017239', (26, 36))	('RG7787', 'Var', (10, 16))	('cell viability', 'CPA', (54, 68))	('decreased', 'NegReg', (44, 53))
17452	27635089	RG7787 plus nab-Paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response.	('tumor', 'Disease', (158, 163))	('nab', 'Chemical', '-', (12, 15))	('human', 'Species', '9606', (58, 63))	('serum mesothelin levels', 'MPA', (117, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RG7787', 'Var', (0, 6))	('mesothelioma', 'Disease', (64, 76))	('Paclitaxel', 'Chemical', 'MESH:D017239', (16, 26))
17460	27635089	In clinical trials SS1P was well tolerated and the dose-limiting toxicity was pleuritis.	('pleuritis', 'Disease', 'MESH:D010998', (78, 87))	('SS1P', 'Chemical', 'MESH:C474515', (19, 23))	('toxicity', 'Disease', 'MESH:D064420', (65, 73))	('SS1P', 'Var', (19, 23))	('toxicity', 'Disease', (65, 73))	('rat', 'Species', '10116', (37, 40))	('pleuritis', 'Phenotype', 'HP:0002102', (78, 87))	('pleuritis', 'Disease', (78, 87))
17463	27635089	Having shown proof of principle anti-tumor efficacy with SS1P, our group has now focused on developing anti-mesothelin immunotoxins that are inherently less immunogenic so there is no need to use immunosuppressive drugs.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('SS1P', 'Chemical', 'MESH:C474515', (57, 61))	('SS1P', 'Var', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
17465	27635089	PE24 is a modified Pseudomonas exotoxin A in which part of domain II of PE toxin has been deleted, as well as seven bulky hydrophilic resides in domain III of PE toxin have been mutated to alanine to silence B cell epitopes.	('PE24', 'Gene', (0, 4))	('B cell epitopes', 'MPA', (208, 223))	('alanine', 'Chemical', 'MESH:D000409', (189, 196))	('mutated', 'Var', (178, 185))
17466	27635089	Structurally RG7787 differs from SS1P since it consists of an anti-mesothelin Fab rather than Fv and is linked to PE24 rather than PE38 and has a molecular size of 72 kDa compared to SS1P's molecular size of 62 kDa.	('SS1P', 'Chemical', 'MESH:C474515', (183, 187))	('SS1P', 'Chemical', 'MESH:C474515', (33, 37))	('anti-mesothelin Fab', 'Protein', (62, 81))	('rat', 'Species', '10116', (119, 122))	('rat', 'Species', '10116', (82, 85))	('RG7787', 'Var', (13, 19))
17468	27635089	RG7787 also can be given at much higher doses to mice than SS1P and also causes decreased vascular leak in a rat vascular leak model.	('decreased vascular leak', 'Disease', (80, 103))	('decreased vascular leak', 'Disease', 'MESH:D019559', (80, 103))	('vascular leak', 'Phenotype', 'HP:0030005', (90, 103))	('mice', 'Species', '10090', (49, 53))	('rat', 'Species', '10116', (109, 112))	('vascular leak', 'Phenotype', 'HP:0030005', (113, 126))	('SS1P', 'Chemical', 'MESH:C474515', (59, 63))	('RG7787', 'Var', (0, 6))
17474	27635089	More importantly we show that treatment of mesothelioma patient derived tumor xenografts with RG7787 plus nab-Paclitaxel results in remarkable anti-tumor efficacy in three different tumor models.	('mesothelioma', 'Disease', (43, 55))	('RG7787', 'Var', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (182, 187))	('patient', 'Species', '9606', (56, 63))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (148, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('nab', 'Chemical', '-', (106, 109))	('Paclitaxel', 'Chemical', 'MESH:D017239', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
17475	27635089	These results suggest that treatment with RG7787 and nab-Paclitaxel could be effective in patients with mesothelioma.	('nab', 'Chemical', '-', (53, 56))	('mesothelioma', 'Disease', (104, 116))	('RG7787', 'Var', (42, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('patients', 'Species', '9606', (90, 98))	('Paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))
17503	27635089	In NOD-SCID mice bearing NCI-Meso29 tumors the second course of therapy consisted of either single dose of nab-Paclitaxel; single dose of RG7787; or single dose of RG7787 given the day after nab-Paclitaxel administration.	('nab', 'Chemical', '-', (191, 194))	('Paclitaxel', 'Chemical', 'MESH:D017239', (195, 205))	('NCI-Meso29 tumors', 'Disease', 'MESH:D009369', (25, 42))	('rat', 'Species', '10116', (214, 217))	('Paclitaxel', 'Chemical', 'MESH:D017239', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('RG7787', 'Var', (164, 170))	('mice', 'Species', '10090', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('nab', 'Chemical', '-', (107, 110))	('NCI-Meso29 tumors', 'Disease', (25, 42))
17515	27635089	The mesothelin sites/cell for NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 were 249x103, 41x103, 346x103 and 44x103 respectively (Figure 1a).	('NCI-Meso16', 'Chemical', '-', (30, 40))	('249x103', 'Var', (85, 92))	('41x103', 'Var', (94, 100))	('346x103', 'Var', (102, 109))
17521	27635089	As shown in Figure 2a the combination of RG7787 and nab-Paclitaxel resulted in decreased cell viability compared to untreated cells, RG7787 or nab-Paclitaxel alone treated cells for all three cell lines.	('nab', 'Chemical', '-', (52, 55))	('nab-Paclitaxel', 'Var', (52, 66))	('decreased', 'NegReg', (79, 88))	('Paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('Paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('nab', 'Chemical', '-', (143, 146))	('RG7787', 'Var', (41, 47))	('cell viability', 'CPA', (89, 103))
17524	27635089	The percent decrease in cell viability in the RG7787 plus nab-Paclitaxel treated cells was statistically significant compared to either RG7787 or nab-Paclitaxel treated cells.	('cell viability', 'CPA', (24, 38))	('RG7787', 'Var', (46, 52))	('Paclitaxel', 'Chemical', 'MESH:D017239', (62, 72))	('nab', 'Chemical', '-', (58, 61))	('decrease', 'NegReg', (12, 20))	('nab', 'Chemical', '-', (146, 149))	('Paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))
17531	27635089	The fraction of NCI-Meso21 cells undergoing apoptosis with RG7787 plus nab-Paclitaxel was numerically greater than seen with RG7787 or nab-Paclitaxel alone but this difference was not statistically significant.	('greater', 'PosReg', (102, 109))	('Paclitaxel', 'Chemical', 'MESH:D017239', (75, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('nab', 'Chemical', '-', (135, 138))	('nab', 'Chemical', '-', (71, 74))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('Paclitaxel', 'Chemical', 'MESH:D017239', (139, 149))	('RG7787', 'Var', (59, 65))
17532	27635089	Similarly, for NCI-Meso29 cells the percent increase in apoptotic cells when treated with RG7787 and nab-Paclitaxel was significant compared to nab-Paclitaxel alone treated cells (p=0.028) but not compared to RG7787 alone treated cells (p=0.449).	('nab', 'Chemical', '-', (101, 104))	('apoptotic cells', 'CPA', (56, 71))	('NCI-Meso29 cells', 'CellLine', 'CVCL:0320', (15, 31))	('nab', 'Chemical', '-', (144, 147))	('Paclitaxel', 'Chemical', 'MESH:D017239', (148, 158))	('Paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('RG7787', 'Var', (90, 96))
17543	27635089	In the RG7787 group there was stabilization of tumor growth while the mice were receiving treatment but then rapidly increased in size.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RG7787', 'Var', (7, 13))	('tumor', 'Disease', (47, 52))
17545	27635089	However, in mice that received both RG7787 and nab-Paclitaxel there was complete tumor regression by day 68 in all mice and 5 of 7 mice had no tumor regrowth when the experiment was terminated on day 142 (Figure 4a).	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('RG7787', 'Var', (36, 42))	('mice', 'Species', '10090', (12, 16))	('nab', 'Chemical', '-', (47, 50))	('Paclitaxel', 'Chemical', 'MESH:D017239', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', (81, 86))
17549	27635089	As shown in Figure 4b, these tumors grow slowly, but treatment with RG7787 alone initially led to tumor shrinkage followed by a stabilization in tumor size, while as treatment with nab-Paclitaxel resulted in tumor stasis followed by slow growth by day 100.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('nab', 'Chemical', '-', (181, 184))	('tumor', 'Disease', (98, 103))	('tumor stasis', 'Disease', 'MESH:D014647', (208, 220))	('Paclitaxel', 'Chemical', 'MESH:D017239', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (208, 213))	('tumors', 'Disease', (29, 35))	('slow growth', 'Phenotype', 'HP:0001510', (233, 244))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor stasis', 'Disease', (208, 220))	('shrinkage', 'NegReg', (104, 113))	('RG7787', 'Var', (68, 74))	('tumor', 'Disease', (29, 34))
17552	27635089	The NCI-Meso29 tumor cells were grown in NOD-SCID mice and our initial experiments showed that these mice are very sensitive to combination treatment with RG7787 and nab-Paclitaxel at the doses that were used to treat athymic mice (data not shown).	('Paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('RG7787', 'Var', (155, 161))	('mice', 'Species', '10090', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('NCI-Meso29 tumor', 'Disease', 'MESH:D009369', (4, 20))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (50, 54))	('nab', 'Chemical', '-', (166, 169))	('combination', 'Interaction', (128, 139))	('NCI-Meso29 tumor', 'Disease', (4, 20))
17555	27635089	However, treatment with RG7787 plus nab-Paclitaxel led to marked tumor shrinkage, which was statistically significant, compared to nab-Paclitaxel alone treated mice (p<0.05).	('nab', 'Chemical', '-', (36, 39))	('nab', 'Chemical', '-', (131, 134))	('Paclitaxel', 'Chemical', 'MESH:D017239', (40, 50))	('tumor', 'Disease', (65, 70))	('mice', 'Species', '10090', (160, 164))	('Paclitaxel', 'Chemical', 'MESH:D017239', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('RG7787 plus', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
17557	27635089	There was decrease in mesothelin positive tumor cells in both the RG7787 and nab-Paclitaxel group but much more in the combination group.	('Paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('tumor', 'Disease', (42, 47))	('nab', 'Chemical', '-', (77, 80))	('decrease', 'NegReg', (10, 18))	('mesothelin', 'Protein', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('RG7787', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
17564	27635089	In mice with NCI-Meso16 tumors, the serum mesothelin levels increased in the control group and decreased in the RG7787 and nab-paclitaxel group and became undetectable in the combination group.	('decreased', 'NegReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('NCI-Meso16 tumors', 'Disease', (13, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('NCI-Meso16 tumors', 'Disease', 'MESH:D009369', (13, 30))	('nab', 'Chemical', '-', (123, 126))	('mice', 'Species', '10090', (3, 7))	('RG7787', 'Var', (112, 118))	('serum mesothelin levels', 'MPA', (36, 59))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('increased', 'PosReg', (60, 69))
17568	27635089	In this manuscript we demonstrate anti-tumor efficacy for the combination of RG7787 and nab-Paclitaxel against primary mesothelioma cell lines grown in vitro and sustained tumor regressions in three patient derived mesothelioma tumor xenograft models each with different growth kinetics.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (172, 177))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (215, 233))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('patient', 'Species', '9606', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mesothelioma', 'Disease', (215, 227))	('mesothelioma', 'Disease', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mesothelioma', 'Disease', 'MESH:D008654', (215, 227))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('rat', 'Species', '10116', (29, 32))	('RG7787', 'Var', (77, 83))	('tumor', 'Disease', (39, 44))	('mesothelioma tumor', 'Disease', (215, 233))	('nab', 'Chemical', '-', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (111, 131))	('tumor', 'Disease', (228, 233))	('Paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (215, 233))
17571	27635089	Our results show that in vitro RG7787 is 2 to 9 fold more cytotoxic than SS1P against three of the four primary mesothelioma cell lines tested.	('cytotoxic', 'CPA', (58, 67))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (104, 124))	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('to 9', 'Species', '1214577', (43, 47))	('RG7787', 'Var', (31, 37))	('SS1P', 'Chemical', 'MESH:C474515', (73, 77))	('mesothelioma', 'Disease', (112, 124))
17572	27635089	We have previously shown increased anti-tumor efficacy of SS1P with gemcitabine and cisplatin, drugs that are commonly used to treat mesothelioma.	('increased', 'PosReg', (25, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('SS1P', 'Chemical', 'MESH:C474515', (58, 62))	('mesothelioma', 'Disease', (133, 145))	('SS1P', 'Var', (58, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (68, 79))
17573	27635089	Although RG7787 given in combination with these chemotherapy drugs could have increased activity, for our initial studies we focused on combination of RG7787 with nab-Paclitaxel since our prior studies have shown remarkable synergy between immunotoxins and taxanes in different tumor models.	('taxanes', 'Chemical', 'MESH:D043823', (257, 264))	('Paclitaxel', 'Chemical', 'MESH:D017239', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', (278, 283))	('activity', 'MPA', (88, 96))	('RG7787', 'Var', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('nab', 'Chemical', '-', (163, 166))
17575	27635089	Nab-Paclitaxel is an albumin bound paclitaxel that has distinct pharmacologic properties compared to paclitaxel including greater uptake by and retention within tumor, which could make it efficacious to treat solid tumors.	('greater', 'PosReg', (122, 129))	('solid tumors', 'Disease', (209, 221))	('uptake', 'MPA', (130, 136))	('paclitaxel', 'Chemical', 'MESH:D017239', (35, 45))	('Nab-Paclitaxel', 'Var', (0, 14))	('retention', 'biological_process', 'GO:0051235', ('144', '153'))	('Paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('retention within tumor', 'Disease', 'MESH:D001929', (144, 166))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('uptake', 'biological_process', 'GO:0098739', ('130', '136'))	('solid tumors', 'Disease', 'MESH:D009369', (209, 221))	('uptake', 'biological_process', 'GO:0098657', ('130', '136'))	('retention within tumor', 'Disease', (144, 166))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
17576	27635089	Results of recent clinical trials have shown nab-Paclitaxel to be effective against several human cancers but it has not been evaluated in patients with mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('patients', 'Species', '9606', (139, 147))	('nab-Paclitaxel', 'Var', (45, 59))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('Paclitaxel', 'Chemical', 'MESH:D017239', (49, 59))	('cancers', 'Disease', (98, 105))	('nab', 'Chemical', '-', (45, 48))	('mesothelioma', 'Disease', (153, 165))	('human', 'Species', '9606', (92, 97))
17578	27635089	Our in-vitro studies also showed that combination therapy with RG7787 plus nab-Paclitaxel resulted in increased cytotoxicity against all three mesothelioma cell lines tested in-vitro.	('mesothelioma', 'Disease', (143, 155))	('cytotoxicity', 'Disease', (112, 124))	('nab', 'Chemical', '-', (75, 78))	('Paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('combination', 'Interaction', (38, 49))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('increased', 'PosReg', (102, 111))	('RG7787', 'Var', (63, 69))
17582	27635089	Also these tumors had variable tumor mesothelin expression with NCI-Meso16 and NCI-Meso29 having an H-score of 230 and 290 respectively, which was in keeping with high mesothelin expression present on tumor cells grown in culture.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (31, 36))	('expression', 'MPA', (48, 58))	('NCI-Meso29', 'Var', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('NCI-Meso16', 'Chemical', '-', (64, 74))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
17585	27635089	In the case of NCI-Meso29 tumors, marked reduction in tumors of mice treated with RG7787 plus nab-paclitaxel was observed even though these mice received reduced doses of both nab-Paclitaxel and RG7787.	('reduction in tumors', 'Disease', 'MESH:D009369', (41, 60))	('mice', 'Species', '10090', (140, 144))	('NCI-Meso29 tumors', 'Disease', (15, 32))	('NCI-Meso29 tumors', 'Disease', 'MESH:D009369', (15, 32))	('reduction in tumors', 'Disease', (41, 60))	('Paclitaxel', 'Chemical', 'MESH:D017239', (180, 190))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('RG7787', 'Var', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('nab', 'Chemical', '-', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('nab', 'Chemical', '-', (176, 179))	('mice', 'Species', '10090', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
17587	27635089	We also show that in these tumor xenograft models treatment with nab-Paclitaxel plus RG7787 resulted in reduced mesothelin expression by tumor cells, decreased proliferative index as well as increased apoptosis.	('Paclitaxel', 'Chemical', 'MESH:D017239', (69, 79))	('mesothelin', 'Protein', (112, 122))	('rat', 'Species', '10116', (167, 170))	('reduced', 'NegReg', (104, 111))	('tumor', 'Disease', (27, 32))	('proliferative index', 'CPA', (160, 179))	('apoptosis', 'CPA', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('decreased', 'NegReg', (150, 159))	('tumor', 'Disease', (137, 142))	('nab-Paclitaxel', 'Var', (65, 79))	('RG7787', 'Var', (85, 91))	('nab', 'Chemical', '-', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('increased', 'PosReg', (191, 200))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
17593	27635089	Patients with tumor mesothelin positivity but without increased mesothelin levels in the serum could still benefit from mesothelin directed therapies but serum mesothelin levels cannot be used as biomarker of tumor response in these patients.	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (209, 214))	('benefit', 'PosReg', (107, 114))	('positivity', 'Var', (31, 41))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('patients', 'Species', '9606', (233, 241))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
17598	27635089	In summary, our results validate the use of serum mesothelin as a biomarker of tumor response, and show marked anti-tumor efficacy of RG7787 plus nab-Paclitaxel against human mesothelioma primary cell lines as well as tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mesothelioma', 'Disease', (175, 187))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('RG7787', 'Var', (134, 140))	('human', 'Species', '9606', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', (116, 121))	('nab', 'Chemical', '-', (146, 149))	('Paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))
17602	27635089	In this study we show that RG7787 is very active against primary mesothelioma cell lines.	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('RG7787', 'Var', (27, 33))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (57, 77))	('mesothelioma', 'Disease', (65, 77))
17613	22564432	Direct exposure of cells to H2O2 produced similar effects on Ca2+ and ROS, and these effects were prevented by the same inhibitors.	('H2O2', 'Chemical', 'MESH:D006861', (28, 32))	('H2O2', 'Var', (28, 32))	('ROS', 'MPA', (70, 73))	('Ca2+', 'MPA', (61, 65))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))
17622	22564432	We have previously shown that ascorbate, which is known to produce H2O2, exerts anti-tumour properties on mesothelioma through a stronger oxidative stress in MMe cells compared to normal mesothelial cells.	('oxidative stress', 'MPA', (138, 154))	('stronger', 'PosReg', (129, 137))	('mesothelioma', 'Disease', (106, 118))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('H2O2', 'Chemical', 'MESH:D006861', (67, 71))	('H2O2', 'Var', (67, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (138, 154))	('MMe', 'Phenotype', 'HP:0100001', (158, 161))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('ascorbate', 'Chemical', 'MESH:D001205', (30, 39))
17634	22564432	In line with these findings, it has been shown that EGCG can also inhibit cancer cell growth through pro-oxidant activities, and also in this respect, normal cells have been reported to be less sensitive than tumours to the action of EGCG.	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('pro-oxidant activities', 'MPA', (101, 123))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumours', 'Disease', 'MESH:D009369', (209, 216))	('tumours', 'Disease', (209, 216))	('cancer', 'Disease', (74, 80))	('EGCG', 'Chemical', 'MESH:C045651', (234, 238))	('inhibit', 'NegReg', (66, 73))	('EGCG', 'Chemical', 'MESH:C045651', (52, 56))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('EGCG', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
17638	22564432	This mechanism involves the induction of T-channel opening by H2O2, followed by [Ca2+]i homeostasis impairment, induction of intracellular ROS and eventually cell apoptosis or necrosis, depending on the intensity of the stimulus.	('H2O2', 'Chemical', 'MESH:D006861', (62, 66))	('necrosis', 'biological_process', 'GO:0008220', ('176', '184'))	('intracellular ROS', 'MPA', (125, 142))	('necrosis', 'Disease', (176, 184))	('necrosis', 'biological_process', 'GO:0070265', ('176', '184'))	('induction', 'Reg', (112, 121))	('necrosis', 'biological_process', 'GO:0019835', ('176', '184'))	('H2O2', 'Var', (62, 66))	('homeostasis impairment', 'Disease', 'MESH:D001523', (88, 110))	('necrosis', 'biological_process', 'GO:0001906', ('176', '184'))	('homeostasis impairment', 'Disease', (88, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('intracellular', 'cellular_component', 'GO:0005622', ('125', '138'))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('T-channel opening', 'MPA', (41, 58))	('homeostasis', 'biological_process', 'GO:0042592', ('88', '99'))	('cell apoptosis', 'CPA', (158, 172))	('necrosis', 'biological_process', 'GO:0008219', ('176', '184'))	('necrosis', 'Disease', 'MESH:D009336', (176, 184))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))
17662	22564432	Fmax and Fmin are maximum and minimum fluorescence intensities obtained by fluo 3 calibration after cell exposure to 500 muM A23187 for a few minutes, followed by addition of 20 mM EDTA.	('fluo 3', 'Chemical', 'MESH:C059715', (75, 81))	('A23187', 'Var', (125, 131))	('mum', 'Gene', (22, 25))	('muM', 'Gene', '56925', (121, 124))	('mum', 'Gene', '56925', (22, 25))	('muM', 'Gene', (121, 124))	('mum', 'Gene', '56925', (34, 37))	('fluorescence intensities', 'MPA', (38, 62))	('A23187', 'Chemical', 'MESH:D000001', (125, 131))	('mum', 'Gene', (34, 37))	('rat', 'Species', '10116', (87, 90))	('EDTA', 'Chemical', 'MESH:D004492', (181, 185))
17682	22564432	The rate of LDH release showed a non-linear, dose-dependent increase in the range 5-500 muM EGCG (Fig.	('muM', 'Gene', (88, 91))	('EGCG', 'Chemical', 'MESH:C045651', (92, 96))	('EGCG', 'Var', (92, 96))	('rate', 'MPA', (4, 8))	('increase', 'PosReg', (60, 68))	('muM', 'Gene', '56925', (88, 91))	('rat', 'Species', '10116', (4, 7))	('LDH', 'Protein', (12, 15))
17694	22564432	In addition, EGCG is known to disrupt cell Ca2+ homeostasis.	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('EGCG', 'Var', (13, 17))	('homeostasis', 'biological_process', 'GO:0042592', ('48', '59'))	('cell Ca2+ homeostasis', 'MPA', (38, 59))	('disrupt', 'NegReg', (30, 37))
17696	22564432	Confocal imaging showed that EGCG induces a progressive and sustained [Ca2+]i rise, indicating Ca2+ homeostasis disruption (Fig.	('EGCG', 'Chemical', 'MESH:C045651', (29, 33))	('EGCG', 'Var', (29, 33))	('cat', 'Gene', (88, 91))	('homeostasis', 'biological_process', 'GO:0042592', ('100', '111'))	('Ca2+ homeostasis disruption', 'MPA', (95, 122))	('[Ca2+]i', 'MPA', (70, 77))	('rise', 'PosReg', (78, 82))	('cat', 'Gene', '847', (88, 91))
17706	22564432	Similar to what was observed with Ca2+, EGCG induced a sustained rise in ROS production, which was abolished by exogenous CAT, and, most intriguingly, also by cell loading with the cell-permeant Ca2+ chelator BAPTA-AM or by cell preincubation with mibefradil (Fig.	('EGCG', 'Chemical', 'MESH:C045651', (40, 44))	('mibefradil', 'Chemical', 'MESH:D020748', (248, 258))	('rise', 'PosReg', (65, 69))	('EGCG', 'Var', (40, 44))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (209, 217))	('CAT', 'Gene', '847', (122, 125))	('ROS production', 'MPA', (73, 87))	('CAT', 'molecular_function', 'GO:0004096', ('122', '125'))	('CAT', 'Gene', (122, 125))
17711	22564432	These experiments confirmed that EGCG induces a significant increase of [Ca2+]i and ROS in REN cells, whereas in contrast in mesothelial cells the variation of [Ca2+]i was barely significant, and the ROS increase was significantly lower than in REN cells (Table 2).	('EGCG', 'Chemical', 'MESH:C045651', (33, 37))	('ROS increase', 'Phenotype', 'HP:0025464', (200, 212))	('EGCG', 'Var', (33, 37))	('ROS', 'MPA', (84, 87))	('increase', 'PosReg', (60, 68))	('[Ca2+]i', 'MPA', (72, 79))	('ROS', 'Chemical', 'MESH:D017382', (200, 203))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
17713	22564432	Confocal imaging revealed that H2O2 induced a sustained [Ca2+]i rise, which was abolished by addition of DTT or mibefradil.	('H2O2', 'Chemical', 'MESH:D006861', (31, 35))	('H2O2', 'Var', (31, 35))	('[Ca2+]i rise', 'MPA', (56, 68))	('DTT', 'Chemical', 'MESH:D004229', (105, 108))	('mibefradil', 'Chemical', 'MESH:D020748', (112, 122))
17716	22564432	We therefore targeted these channels by siRNA-mediated knock-down of the CACNA1H gene, encoding for the Cav3.2 alpha1H protein.	('CACNA1H', 'Gene', (73, 80))	('knock-down', 'Var', (55, 65))	('Cav3.2', 'Gene', (104, 110))	('CACNA1H', 'Gene', '8912', (73, 80))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('Cav3.2', 'Gene', '8912', (104, 110))	('targeted', 'Reg', (13, 21))
17735	22564432	Such a view was fully confirmed by our results, showing that exogenous catalase can block or strongly reduce the anti-proliferative effects of EGCG, and moreover that it hampers the induction of cell apoptosis and necrosis, as revealed by LDH and caspase 3 assays.	('catalase', 'Gene', '847', (71, 79))	('necrosis', 'biological_process', 'GO:0001906', ('214', '222'))	('hampers', 'NegReg', (170, 177))	('EGCG', 'Chemical', 'MESH:C045651', (143, 147))	('block', 'NegReg', (84, 89))	('anti-proliferative effects', 'MPA', (113, 139))	('caspase 3', 'Gene', (247, 256))	('caspase 3', 'Gene', '836', (247, 256))	('necrosis', 'Disease', 'MESH:D009336', (214, 222))	('reduce', 'NegReg', (102, 108))	('necrosis', 'Disease', (214, 222))	('necrosis', 'biological_process', 'GO:0008219', ('214', '222'))	('rat', 'Species', '10116', (125, 128))	('EGCG', 'Gene', (143, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('necrosis', 'biological_process', 'GO:0008220', ('214', '222'))	('cell apoptosis', 'CPA', (195, 209))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('exogenous', 'Var', (61, 70))	('necrosis', 'biological_process', 'GO:0070265', ('214', '222'))	('catalase', 'Gene', (71, 79))	('necrosis', 'biological_process', 'GO:0019835', ('214', '222'))
17746	22564432	The data of DHR 123 fluorescence showed that also ROS production within cells depends on extracellular H2O2 induced by EGCG.	('H2O2', 'Chemical', 'MESH:D006861', (103, 107))	('extracellular', 'cellular_component', 'GO:0005576', ('89', '102'))	('DHR', 'Chemical', '-', (12, 15))	('EGCG', 'Chemical', 'MESH:C045651', (119, 123))	('EGCG', 'Var', (119, 123))	('extracellular H2O2', 'MPA', (89, 107))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('ROS production', 'MPA', (50, 64))
17759	22564432	Consistent with the above findings, Cav3.2 siRNA was also able to lower LDH release and drastically modify the pattern of caspase 3 activation by EGCG.	('EGCG', 'Var', (146, 150))	('Cav3.2', 'Gene', (36, 42))	('Cav3.2', 'Gene', '8912', (36, 42))	('lower', 'NegReg', (66, 71))	('LDH release', 'MPA', (72, 83))	('activation', 'MPA', (132, 142))	('EGCG', 'Chemical', 'MESH:C045651', (146, 150))	('caspase 3', 'Gene', (122, 131))	('caspase 3', 'Gene', '836', (122, 131))	('modify', 'Reg', (100, 106))
17764	22564432	The mechanism can be summarized as follows: EGCG induces H2O2 release at the outside of cells; H2O2 acts by inducing T-channel opening at the plasma membrane; Ca2+ leakage into the cytosol causes [Ca2+]i rise and triggers ROS production; Ca2+ and ROS cooperate in inducing either apoptosis or necrosis, depending on damage.	('necrosis', 'biological_process', 'GO:0001906', ('293', '301'))	('ROS production', 'MPA', (222, 236))	('ROS', 'Chemical', 'MESH:D017382', (247, 250))	('inducing', 'Reg', (264, 272))	('H2O2', 'Var', (95, 99))	('necrosis', 'Disease', 'MESH:D009336', (293, 301))	('plasma membrane', 'cellular_component', 'GO:0005886', ('142', '157'))	('necrosis', 'Disease', (293, 301))	('EGCG', 'Var', (44, 48))	('necrosis', 'biological_process', 'GO:0008219', ('293', '301'))	('ROS', 'Chemical', 'MESH:D017382', (222, 225))	('apoptosis', 'CPA', (280, 289))	('T-channel opening at the', 'MPA', (117, 141))	('EGCG', 'Chemical', 'MESH:C045651', (44, 48))	('inducing', 'Reg', (108, 116))	('Ca2+ leakage', 'MPA', (159, 171))	('H2O2', 'Chemical', 'MESH:D006861', (57, 61))	('necrosis', 'biological_process', 'GO:0008220', ('293', '301'))	('apoptosis', 'biological_process', 'GO:0097194', ('280', '289'))	('apoptosis', 'biological_process', 'GO:0006915', ('280', '289'))	('rat', 'Species', '10116', (256, 259))	('[Ca2+]i', 'MPA', (196, 203))	('induces', 'Reg', (49, 56))	('rise', 'PosReg', (204, 208))	('cytosol', 'cellular_component', 'GO:0005829', ('181', '188'))	('necrosis', 'biological_process', 'GO:0070265', ('293', '301'))	('H2O2', 'Chemical', 'MESH:D006861', (95, 99))	('triggers', 'Reg', (213, 221))	('necrosis', 'biological_process', 'GO:0019835', ('293', '301'))
17765	22564432	Hence, our data have demonstrated for the first time that EGCG can selectively inhibit the proliferation of MMe cells and moreover that T-type Ca2+ channels are involved in the mechanism of action of the green tea polyphenol.	('inhibit', 'NegReg', (79, 86))	('involved', 'Reg', (161, 169))	('proliferation of MMe cells', 'CPA', (91, 117))	('T-type Ca2+ channels', 'MPA', (136, 156))	('rat', 'Species', '10116', (98, 101))	('polyphenol', 'Chemical', 'MESH:D059808', (214, 224))	('EGCG', 'Chemical', 'MESH:C045651', (58, 62))	('EGCG', 'Var', (58, 62))	('rat', 'Species', '10116', (28, 31))	('MMe', 'Phenotype', 'HP:0100001', (108, 111))
17905	19900274	Immunohistochemistry showed positivity with Vimentin, CAM 5.2 and CD10 and focally with SMA and Calretinin.	('Vimentin', 'cellular_component', 'GO:0045099', ('44', '52'))	('CD10', 'Gene', '4311', (66, 70))	('Calretinin', 'Gene', (96, 106))	('CD10', 'molecular_function', 'GO:0004245', ('66', '70'))	('positivity', 'Var', (28, 38))	('Vimentin', 'Gene', (44, 52))	('SMA', 'Gene', (88, 91))	('Calretinin', 'Gene', '794', (96, 106))	('Vimentin', 'cellular_component', 'GO:0045098', ('44', '52'))	('CAM 5.2', 'Gene', (54, 61))	('SMA', 'Gene', '6606', (88, 91))	('Vimentin', 'Gene', '7431', (44, 52))	('CD10', 'Gene', (66, 70))
18025	33538989	Loss of BAP1 expression and CDKN2A/p16 deletion may allow discrimination of MPM from benign pleural lesions.	('MPM', 'Disease', (76, 79))	('p16', 'Gene', '1029', (35, 38))	('expression', 'MPA', (13, 23))	('deletion', 'Var', (39, 47))	('BAP1', 'Gene', '8314', (8, 12))	('p16', 'Gene', (35, 38))	('Loss', 'NegReg', (0, 4))	('CDKN2A', 'Gene', (28, 34))	('pleural lesions', 'Disease', 'MESH:D010995', (92, 107))	('BAP1', 'Gene', (8, 12))	('CDKN2A', 'Gene', '1029', (28, 34))	('pleural lesions', 'Disease', (92, 107))	('pleural lesions', 'Phenotype', 'HP:0002102', (92, 107))
18027	33538989	A proportion of MPM patients carry germline mutations in cancer susceptibility genes, especially those with young age and family history of cancer supporting genetic testing for selected MPM patients [IIIA].	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patients', 'Species', '9606', (191, 199))	('MPM', 'Disease', (16, 19))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('germline mutations', 'Var', (35, 53))
18028	33538989	MPM are dominated by the inactivation of tumor suppressor genes (BAP1, CDKN2A, NF2, TP53, LATS2 and SETD2) and generally have low tumor mutation burden.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('BAP1', 'Gene', (65, 69))	('NF2', 'Gene', '4771', (79, 82))	('SETD2', 'Gene', '29072', (100, 105))	('TP53', 'Gene', (84, 88))	('tumor', 'Disease', (130, 135))	('NF2', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('low tumor', 'Disease', 'MESH:D009800', (126, 135))	('CDKN2A', 'Gene', (71, 77))	('tumor', 'Disease', (41, 46))	('inactivation', 'Var', (25, 37))	('TP53', 'Gene', '7157', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('low tumor', 'Disease', (126, 135))	('BAP1', 'Gene', '8314', (65, 69))	('CDKN2A', 'Gene', '1029', (71, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('LATS2', 'Gene', (90, 95))	('LATS2', 'Gene', '26524', (90, 95))	('SETD2', 'Gene', (100, 105))
18029	33538989	Germline mutations has been reported in 12% of patients with MPM, but in higher proportion for MPM with early onset or family history.	('Germline mutations', 'Var', (0, 18))	('patients', 'Species', '9606', (47, 55))	('reported', 'Reg', (28, 36))	('MPM', 'Disease', (61, 64))
18056	33538989	Although initial studies suggested that VATS-PP might be superior option to talc pleurodesis, the MesoVATS randomized controlled trial demonstrated no survival advantage with VATS-PP in patients with pleural effusion, which increased length of hospital stay compared with talc pleurodesis.	('pleural effusion', 'Disease', 'MESH:D010996', (200, 216))	('pleural effusion', 'Disease', (200, 216))	('VATS-PP', 'Var', (175, 182))	('pleural effusion', 'Phenotype', 'HP:0002202', (200, 216))	('patients', 'Species', '9606', (186, 194))
18057	33538989	To date, only one prospective, randomized trial, the Mesothelioma and Radical Surgery (MARS) trial, has evaluated the added benefit of performing EPP versus no EPP in the setting of trimodal therapy.	('EPP', 'Chemical', '-', (160, 163))	('EPP', 'Chemical', '-', (146, 149))	('EPP', 'Var', (146, 149))	('Mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('Mesothelioma', 'Disease', (53, 65))
18060	33538989	An ongoing randomized clinical trial (MARS 2) should determine whether P/D or EPD after induction chemotherapy leads to superior outcomes compared with chemotherapy alone.	('MARS 2', 'Gene', (38, 44))	('P/D', 'Var', (71, 74))	('MARS 2', 'Gene', '92935', (38, 44))	('EPD', 'Var', (78, 81))
18098	33538989	Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of enhancer of zeste-homolog 2 (EZH2).	('EZH2', 'Gene', (122, 126))	('EZH2', 'Gene', '2146', (122, 126))	('inactivation', 'Var', (34, 46))	('sensitizes', 'Reg', (47, 57))	('enhancer of zeste-homolog 2', 'Gene', '2146', (93, 120))	('BAP1', 'Gene', '8314', (29, 33))	('inhibition', 'NegReg', (79, 89))	('enhancer of zeste-homolog 2', 'Gene', (93, 120))	('BAP1', 'Gene', (29, 33))
18136	31929500	Immunohistochemical staining showed that mesothelial cells in the mass presented as strongly positive for calretinin (Figure 2) and were focally positive for epithelial membrane antigen (EMA), CK903 (high-molecular keratin), and vimentin.	('calretinin', 'Gene', (106, 116))	('vimentin', 'cellular_component', 'GO:0045099', ('229', '237'))	('vimentin', 'Gene', '7431', (229, 237))	('vimentin', 'cellular_component', 'GO:0045098', ('229', '237'))	('vimentin', 'Gene', (229, 237))	('calretinin', 'Gene', '794', (106, 116))	('EMA', 'Gene', (187, 190))	('mesothelial cells', 'CPA', (41, 58))	('membrane', 'cellular_component', 'GO:0016020', ('169', '177'))	('positive', 'Reg', (93, 101))	('EMA', 'Gene', '4582', (187, 190))	('positive', 'Reg', (145, 153))	('CK903', 'Var', (193, 198))
18178	31929500	However, the presence of calretinin, as in our case, is much more likely in WDPM and occurs in a smaller percentage of cases of serous papillary carcinoma (Table 2).	('calretinin', 'Gene', (25, 35))	('serous papillary carcinoma', 'Disease', (128, 154))	('likely', 'Reg', (66, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('calretinin', 'Gene', '794', (25, 35))	('presence', 'Var', (13, 21))	('WDPM', 'Disease', (76, 80))	('serous papillary carcinoma', 'Disease', 'MESH:D002291', (128, 154))
18180	31929500	In addition, the lack of D2-40 or CK5/6 would indicate serous papillary carcinoma over WDPM.	('serous papillary carcinoma', 'Disease', (55, 81))	('CK5/6', 'Gene', (34, 39))	('D2-40', 'Protein', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lack', 'Var', (17, 21))	('CK5/6', 'Gene', '3852', (34, 39))	('serous papillary carcinoma', 'Disease', 'MESH:D002291', (55, 81))
18182	31929500	If a more limited diagnostic immunostain panel had been chosen in the current case, especially considering the patient's clinical course, the ER, PAX-8, and BAP1 positivity in particular may have led an investigator toward a diagnosis of a PSC, potentially significantly affecting clinical care.	('PAX-8', 'Gene', '7849', (146, 151))	('BAP1', 'Gene', (157, 161))	('PAX-8', 'Gene', (146, 151))	('positivity', 'Var', (162, 172))	('affecting', 'Reg', (271, 280))	('led', 'Reg', (196, 199))	('patient', 'Species', '9606', (111, 118))	('BAP1', 'Gene', '8314', (157, 161))	('PSC', 'Disease', 'MESH:D002291', (240, 243))	('PSC', 'Disease', (240, 243))
18223	29804728	We identified that patients who responded (CR and PR) to front-line therapy with cisplatin or cisplatin and pemetrexed had a significantly longer OS (HR 0.34, 95% CI 0.24-0.49; median 20.6 months, 95% CI: 15.3-not reached) than patients who did not respond (SD or PD) to treatment (median 9.4 months, 95% CI: 8.1-11.0; P<.001; Figure 1A).	('SD', 'Disease', 'MESH:D029461', (258, 260))	('patients', 'Species', '9606', (19, 27))	('PR', 'Chemical', '-', (50, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('OS', 'Chemical', '-', (146, 148))	('cisplatin', 'Var', (81, 90))	('patients', 'Species', '9606', (228, 236))	('CR', 'Chemical', '-', (43, 45))	('pemetrexed', 'Chemical', 'MESH:D000068437', (108, 118))	('PD', 'Disease', 'MESH:D010300', (264, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('cisplatin', 'Var', (94, 103))
18246	29804728	Additionally, targeted therapies may result in dramatic reductions of tumor burden, but these responses may be short lived and may not always correlate with survival benefits.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('targeted therapies', 'Var', (14, 32))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('reductions', 'NegReg', (56, 66))
18292	28978091	In order to inhibit CXCR4, we selected AMD3100 in this study.	('AMD3100', 'Var', (39, 46))	('inhibit', 'NegReg', (12, 19))	('CXCR4', 'Gene', '7852', (20, 25))	('CXCR4', 'molecular_function', 'GO:0038147', ('20', '25'))	('CXCR4', 'Gene', (20, 25))	('AMD3100', 'Chemical', 'MESH:C088327', (39, 46))
18293	28978091	The exposure of both cell lines to AMD3100 24 hours before the migration assays almost fully reversed the detected phenotype of photon-induced migration and significantly inhibited the previously radiation-enhanced migration through collagen I/IV-coated membranes of both H28 and H226 cells after exposition to photon radiation with 2 Gy (H28: p=0.024 and p=0.016; H226: p<0.001 and p=0.001, respectively).	('H28', 'Chemical', '-', (272, 275))	('AMD3100', 'Chemical', 'MESH:C088327', (35, 42))	('AMD3100', 'Var', (35, 42))	('inhibited', 'NegReg', (171, 180))	('migration', 'CPA', (215, 224))	('H28', 'Chemical', '-', (339, 342))	('collagen', 'molecular_function', 'GO:0005202', ('233', '241'))
18342	28978091	For FACS analysis, PE-labeled anti-human CXCR4 antibody (555974), PE-labeled anti-human beta1 antibody (556049), PE-labeled anti-human alpha3 antibody (556025), PE-labeled anti-human alpha5 antibody (555617), and isotope controls corresponding to these antibodies were purchased from BD Bioscience (Heidelberg, Germany).	('antibody', 'molecular_function', 'GO:0003823', ('190', '198'))	('CXCR4', 'Gene', (41, 46))	('antibody', 'cellular_component', 'GO:0019815', ('142', '150'))	('human', 'Species', '9606', (35, 40))	('antibody', 'cellular_component', 'GO:0019815', ('47', '55'))	('antibody', 'cellular_component', 'GO:0042571', ('190', '198'))	('beta1', 'Gene', '10678', (88, 93))	('human', 'Species', '9606', (177, 182))	('antibody', 'cellular_component', 'GO:0019815', ('94', '102'))	('antibody', 'cellular_component', 'GO:0019814', ('142', '150'))	('antibody', 'cellular_component', 'GO:0019814', ('47', '55'))	('555974', 'Var', (57, 63))	('antibody', 'cellular_component', 'GO:0019815', ('190', '198'))	('CXCR4', 'molecular_function', 'GO:0038147', ('41', '46'))	('556049', 'Var', (104, 110))	('antibody', 'molecular_function', 'GO:0003823', ('142', '150'))	('antibody', 'cellular_component', 'GO:0019814', ('94', '102'))	('antibody', 'molecular_function', 'GO:0003823', ('47', '55'))	('antibody', 'cellular_component', 'GO:0042571', ('142', '150'))	('antibody', 'cellular_component', 'GO:0019814', ('190', '198'))	('antibody', 'cellular_component', 'GO:0042571', ('47', '55'))	('beta1', 'Gene', (88, 93))	('antibody', 'molecular_function', 'GO:0003823', ('94', '102'))	('CXCR4', 'Gene', '7852', (41, 46))	('human', 'Species', '9606', (129, 134))	('antibody', 'cellular_component', 'GO:0042571', ('94', '102'))	('556025', 'Var', (152, 158))	('human', 'Species', '9606', (82, 87))
18384	25210967	In addition to asbestos exposure, risk factors for the development of MM include erionite exposure, simian virus 40, and germline BAP1 mutations.	('BAP1', 'Gene', '8314', (130, 134))	('BAP1', 'Gene', (130, 134))	('mutations', 'Var', (135, 144))
18385	25210967	Between 1980 and 1995, the authors of that study used the International Classification of Diseases, 9th revision (ICD-9), codes 163.0, 163.1, 163.8, and 163.9, and all cases of pleural neoplasm were considered to be cases of mesothelioma.	('pleural neoplasm', 'Phenotype', 'HP:0100527', (177, 193))	('neoplasm', 'Phenotype', 'HP:0002664', (185, 193))	('codes 163.0', 'Var', (122, 133))	('mesothelioma', 'Disease', (225, 237))	('pleural neoplasm', 'Disease', 'MESH:D010997', (177, 193))	('pleural neoplasm', 'Disease', (177, 193))
18393	25210967	The p16INK4a protein is a cyclin-dependent kinase inhibitor and plays a role in the hyperphosphorylation of the retinoblastoma protein.	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('84', '104'))	('p16INK4a', 'Var', (4, 12))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('43', '59'))	('retinoblastoma', 'Disease', 'MESH:D012175', (112, 126))	('retinoblastoma', 'Disease', (112, 126))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (112, 126))	('hyperphosphorylation', 'MPA', (84, 104))	('plays', 'Reg', (64, 69))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('26', '59'))	('protein', 'Protein', (13, 20))
18394	25210967	In contrast, the p14ARF protein inhibits the degradation of p53 through its interaction with murine double minute 2 protein (MDM2).	('degradation', 'MPA', (45, 56))	('double minute 2 protein', 'Gene', (100, 123))	('murine', 'Species', '10090', (93, 99))	('protein', 'Protein', (24, 31))	('degradation', 'biological_process', 'GO:0009056', ('45', '56'))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('double minute 2 protein', 'Gene', '17246', (100, 123))	('interaction', 'Interaction', (76, 87))	('p53', 'Protein', (60, 63))	('inhibits', 'NegReg', (32, 40))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('p14ARF', 'Var', (17, 23))
18396	25210967	Approximately 70% of all cases of epithelial MM and nearly 100% of all cases of biphasic or sarcomatoid MM show changes in p16 INK4a and p14  ARF.	('biphasic or sarcomatoid MM', 'Disease', 'MESH:C538614', (80, 106))	('p14  ARF', 'Protein', (137, 145))	('changes', 'Reg', (112, 119))	('biphasic or sarcomatoid MM', 'Disease', (80, 106))	('p16', 'Var', (123, 126))
18398	25210967	Germline BAP1 mutations have recently been detected in families with a high incidence of MM, characterizing a syndrome that predisposes to MM, uveal melanoma, and, possibly, other cancers.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('uveal melanoma', 'Disease', (143, 157))
18399	25210967	In individuals suspected of having BAP1 cancer syndrome, early diagnosis is essential to prevent the onset of diseases associated with BAP1 mutations.	('cancer syndrome', 'Disease', 'MESH:D009369', (40, 55))	('cancer syndrome', 'Disease', (40, 55))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
18401	25210967	Monoallelic mutations are common in various types of cancer; however, homozygous PTEN mutations are frequently found in advanced cancers, such as endometrial cancer and glioblastoma.	('found', 'Reg', (111, 116))	('mutations', 'Var', (86, 95))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('endometrial cancer', 'Disease', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PTEN', 'Gene', (81, 85))	('endometrial cancer', 'Phenotype', 'HP:0012114', (146, 164))	('endometrial cancer', 'Disease', 'MESH:D016889', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
18452	25210967	Todavia, a delecao completa de PTEN associada com TP53 com mutacao foi associada a uma forma mais grave de cancer de prostata.	('uma forma mais grave de cancer de prostata', 'Disease', (83, 125))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Var', (50, 54))	('uma forma mais grave de cancer de prostata', 'Disease', 'MESH:D005862', (83, 125))
18476	22613358	There is emerging evidence supporting the role of BAP1 mutations in the pathogenesis of these two neoplasias.	('neoplasias', 'Disease', (98, 108))	('mutations', 'Var', (55, 64))	('BAP1', 'Gene', '8314', (50, 54))	('neoplasias', 'Phenotype', 'HP:0002664', (98, 108))	('BAP1', 'Gene', (50, 54))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))	('neoplasias', 'Disease', 'MESH:D009369', (98, 108))
18528	22613358	All cases were found to have a BAP1 mutation.	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))
18530	22613358	Mutations in BAP1 are infrequent in the general population but high in mesothelioma (20.1%) and uveal melanoma (44.1%).	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', (13, 17))	('uveal melanoma', 'Disease', (96, 110))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('BAP1', 'Gene', '8314', (13, 17))	('high', 'Reg', (63, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
18532	22613358	In that study, the authors found germline BAP1 mutations in 2 of 26 patients diagnosed with mesothelioma and both patients were previously diagnosed with uveal melanoma.	('BAP1', 'Gene', '8314', (42, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (68, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('patients', 'Species', '9606', (114, 122))	('mesothelioma', 'Disease', (92, 104))
18533	22613358	Three of their four patients with uveal melanoma and BAP1 mutations subsequently developed mesothelioma.	('mutations', 'Var', (58, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('developed', 'Reg', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', '8314', (53, 57))	('mesothelioma', 'Disease', (91, 103))	('patients', 'Species', '9606', (20, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', (34, 48))	('BAP1', 'Gene', (53, 57))
18536	22613358	Clinicians should be aware of this entity since individuals who carry germline BAP1 mutations may be at increased risk of developing metachronously both OM and DMPM.	('DMPM', 'Disease', (160, 164))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('germline', 'Var', (70, 78))	('OM', 'Phenotype', 'HP:0007716', (153, 155))	('DMPM', 'Chemical', '-', (160, 164))
18537	22613358	Patients found with BAP1 mutations and their families should be closely monitored for the development of any or both of these malignancies for the possibility of early detection and intervention.	('mutations', 'Var', (25, 34))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('BAP1', 'Gene', (20, 24))	('malignancies', 'Disease', (126, 138))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (20, 24))
18542	22613358	Genetic testing for BAP1 mutations in this patient and his family is currently in progress and the results will be the subject of another publication.	('mutations', 'Var', (25, 34))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', (20, 24))	('patient', 'Species', '9606', (43, 50))
18549	21364680	Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity.	('caspase-3/7', 'Gene', '836;840', (177, 188))	('caspase-3/7', 'Gene', (177, 188))	('fragmentation', 'MPA', (54, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('increased', 'PosReg', (161, 170))	('caspase-8 and -9', 'Gene', '841;842', (71, 87))	('Acquisition', 'Var', (0, 11))	('activity', 'MPA', (189, 197))
18556	21364680	Granzyme B is a protease that can cleave caspase-3 and -7 and cleave Bid with subsequent activation of the mitochondrial pathway.	('cleave', 'Reg', (34, 40))	('cleave', 'Var', (62, 68))	('mitochondrial pathway', 'Pathway', (107, 128))	('Granzyme B', 'Gene', '3002', (0, 10))	('caspase-3 and -7', 'Gene', '836;840', (41, 57))	('activation', 'PosReg', (89, 99))	('Bid', 'Gene', (69, 72))	('Bid', 'Gene', '637', (69, 72))	('Granzyme B', 'Gene', (0, 10))
18574	21364680	It cannot be excluded that these changes may affect caspase activity, as well as, for example, accumulation and intra-cellular trapping of cisplatin.	('affect', 'Reg', (45, 51))	('accumulation', 'MPA', (95, 107))	('changes', 'Var', (33, 40))	('caspase activity', 'molecular_function', 'GO:0030693', ('52', '68'))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('caspase activity', 'molecular_function', 'GO:0004197', ('52', '68'))	('intra-cellular trapping', 'MPA', (112, 135))	('activity', 'MPA', (60, 68))	('caspase', 'Enzyme', (52, 59))	('caspase activity', 'molecular_function', 'GO:0097153', ('52', '68'))
18577	21364680	Previously, we have shown that acquisition of cisplatin-resistance resulted in a higher basal caspase-3/7 activity, an earlier cisplatin-induced increase in caspase-3/7 activity, but no significant changes in basal levels of nuclear DNA fragmentation.	('caspase-3/7', 'Gene', (94, 105))	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('cisplatin-resistance', 'Var', (46, 66))	('higher', 'PosReg', (81, 87))	('activity', 'MPA', (169, 177))	('activity', 'MPA', (106, 114))	('caspase-3/7', 'Gene', '836;840', (157, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('caspase-3/7', 'Gene', '836;840', (94, 105))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('233', '250'))	('caspase-3/7', 'Gene', (157, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
18597	21364680	We therefore concluded that acquisition of cisplatin-resistance increased the basal effector caspase activity, but did not change the final response of the effector caspases-3 and -7 to cisplatin exposure.	('caspases-3 and -7', 'Gene', '836;840', (165, 182))	('effector caspase activity', 'molecular_function', 'GO:0004207', ('84', '109'))	('cisplatin', 'Chemical', 'MESH:D002945', (186, 195))	('effector caspase activity', 'molecular_function', 'GO:0097200', ('84', '109'))	('activity', 'MPA', (101, 109))	('cisplatin-resistance', 'Var', (43, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('increased', 'PosReg', (64, 73))	('acquisition', 'Var', (28, 39))	('effector caspase activity', 'molecular_function', 'GO:0030693', ('84', '109'))
18599	21364680	To determine whether the basal changes in effector caspase contents were consistent findings after in vitro acquisition of cisplatin resistance, we used western blotting to screen the H1299 and H1299res cells for caspase-3, caspase-7 and DFF45/DFF35 contents under control conditions (Figure 1e).	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('caspase-3', 'Gene', '836', (213, 222))	('H1299', 'CellLine', 'CVCL:0060', (184, 189))	('caspase-7', 'Gene', (224, 233))	('H1299res', 'Var', (194, 202))	('H1299', 'CellLine', 'CVCL:0060', (194, 199))	('caspase-7', 'Gene', '840', (224, 233))	('DFF45', 'Gene', '1676', (238, 243))	('caspase-3', 'Gene', (213, 222))	('DFF45', 'Gene', (238, 243))	('H1299', 'Var', (184, 189))
18600	21364680	As in the P31res1.2 cells, full-length caspase-3 protein was increased in H1299res cells, but it was again not possible to detect any caspase-3 fragments by western blotting.	('P31', 'Gene', '55850', (10, 13))	('P31', 'Gene', (10, 13))	('caspase-3', 'Gene', (39, 48))	('H1299res', 'Var', (74, 82))	('H1299', 'CellLine', 'CVCL:0060', (74, 79))	('full-length', 'MPA', (27, 38))	('caspase-3', 'Gene', (134, 143))	('increased', 'PosReg', (61, 70))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('caspase-3', 'Gene', '836', (134, 143))	('caspase-3', 'Gene', '836', (39, 48))
18601	21364680	In contrast to the P31res1.2 cells (data not shown), the H1299res cells had increased content of DFF45/DFF35, as well as increased caspase-7 and caspase-7 fragmentation (Figure 1e).	('caspase-7', 'Gene', '840', (131, 140))	('increased', 'PosReg', (76, 85))	('increased', 'PosReg', (121, 130))	('DFF45', 'Gene', '1676', (97, 102))	('content', 'MPA', (86, 93))	('H1299res', 'Var', (57, 65))	('H1299', 'CellLine', 'CVCL:0060', (57, 62))	('DFF45', 'Gene', (97, 102))	('caspase-7', 'Gene', (145, 154))	('caspase-7', 'Gene', (131, 140))	('caspase-7', 'Gene', '840', (145, 154))	('P31', 'Gene', '55850', (19, 22))	('P31', 'Gene', (19, 22))
18602	21364680	Thus, similar to the P31res1.2 cells, the H1299res cells appear to have increased basal expression of effector caspase-3 subsequent to the in vitro acquired cisplatin-resistance.	('caspase-3', 'Gene', (111, 120))	('increased', 'PosReg', (72, 81))	('P31', 'Gene', (21, 24))	('caspase-3', 'Gene', '836', (111, 120))	('H1299res', 'Var', (42, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('H1299', 'CellLine', 'CVCL:0060', (42, 47))	('expression', 'MPA', (88, 98))	('P31', 'Gene', '55850', (21, 24))
18603	21364680	However, the H1299res cells also had increased basal expression and fragmentation of caspase-7 that was not found in the P31res1.2 cells.	('caspase-7', 'Gene', (85, 94))	('basal expression', 'MPA', (47, 63))	('caspase-7', 'Gene', '840', (85, 94))	('P31', 'Gene', '55850', (121, 124))	('P31', 'Gene', (121, 124))	('H1299res', 'Var', (13, 21))	('increased', 'PosReg', (37, 46))	('fragmentation', 'MPA', (68, 81))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))
18615	21364680	To determine whether the basal changes in activator caspase contents were consistent findings after in vitro acquisition of cisplatin resistance, we used western blotting to screen the H1299 and H1299res cells for caspase-8 (not shown) and caspase-9 contents (Figure 2c) under control conditions.	('caspase-9', 'Gene', '842', (240, 249))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('H1299', 'Var', (185, 190))	('H1299', 'CellLine', 'CVCL:0060', (185, 190))	('caspase-8', 'Gene', (214, 223))	('caspase-8', 'Gene', '841', (214, 223))	('caspase-9', 'Gene', (240, 249))	('H1299', 'CellLine', 'CVCL:0060', (195, 200))	('H1299res', 'Var', (195, 203))
18616	21364680	In contrast to the P31 and P31res1.2 cells (Figure 2a), no fragments of caspase-8 were identified in the H1299 or H1299res cells (not shown).	('H1299res', 'Var', (114, 122))	('H1299', 'CellLine', 'CVCL:0060', (114, 119))	('P31', 'Gene', '55850', (27, 30))	('H1299', 'Var', (105, 110))	('caspase-8', 'Gene', (72, 81))	('P31', 'Gene', (27, 30))	('caspase-8', 'Gene', '841', (72, 81))	('H1299', 'CellLine', 'CVCL:0060', (105, 110))	('P31', 'Gene', '55850', (19, 22))	('P31', 'Gene', (19, 22))
18617	21364680	However, as in the P31res1.2 cells (Figure 2a), the H1299res cells had increased caspase-9 content and increased fragmentation of caspase-9, compared with the parental H1299 cells (Figure 2c).	('caspase-9', 'Gene', '842', (81, 90))	('caspase-9', 'Gene', '842', (130, 139))	('increased', 'PosReg', (103, 112))	('H1299res', 'Var', (52, 60))	('caspase-9', 'Gene', (130, 139))	('fragmentation', 'MPA', (113, 126))	('caspase-9', 'Gene', (81, 90))	('increased', 'PosReg', (71, 80))	('P31', 'Gene', '55850', (19, 22))	('H1299', 'CellLine', 'CVCL:0060', (168, 173))	('P31', 'Gene', (19, 22))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))
18636	21364680	Although additional studies are necessary to fully characterize the H1299 and H1299res cells regarding caspase activity, the results indicate that in vitro acquisition of cisplatin-resistance results in similar changes in basal caspase-3 and caspase-9 expression and fragmentation.	('changes', 'Reg', (211, 218))	('caspase activity', 'molecular_function', 'GO:0030693', ('103', '119'))	('caspase-3', 'Gene', (228, 237))	('caspase-9', 'Gene', (242, 251))	('caspase activity', 'molecular_function', 'GO:0004197', ('103', '119'))	('H1299', 'CellLine', 'CVCL:0060', (78, 83))	('H1299res', 'Var', (78, 86))	('caspase-3', 'Gene', '836', (228, 237))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))	('caspase-9', 'Gene', '842', (242, 251))	('expression', 'MPA', (252, 262))	('fragmentation', 'CPA', (267, 280))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('caspase activity', 'molecular_function', 'GO:0097153', ('103', '119'))
18654	21364680	They both have similar efficiency in cleavage of, for example, DEVD-AFC and PARP, whereas caspase-3 is more efficient in the proteolysis of caspase-9 and XIAP.	('cleavage', 'MPA', (37, 45))	('XIAP', 'Gene', '331', (154, 158))	('PARP', 'Gene', '142', (76, 80))	('caspase-3', 'Gene', (90, 99))	('proteolysis', 'biological_process', 'GO:0006508', ('125', '136'))	('caspase-9', 'Gene', '842', (140, 149))	('caspase-3', 'Gene', '836', (90, 99))	('caspase-9', 'Gene', (140, 149))	('PARP', 'Gene', (76, 80))	('DEVD-AFC', 'Var', (63, 71))	('XIAP', 'Gene', (154, 158))
18655	21364680	Caspase-3-mediated fragmentation of caspase-9 occurs at Asp330 and results in a 37-kDa fragment, the most abundant fragment in the P31res1.2 cells.	('caspase-9', 'Gene', '842', (36, 45))	('Caspase-3', 'Gene', (0, 9))	('Asp330', 'Chemical', '-', (56, 62))	('results in', 'Reg', (67, 77))	('Asp330', 'Var', (56, 62))	('37-kDa fragment', 'MPA', (80, 95))	('P31', 'Gene', '55850', (131, 134))	('caspase-9', 'Gene', (36, 45))	('fragmentation', 'Var', (19, 32))	('P31', 'Gene', (131, 134))	('Caspase-3', 'Gene', '836', (0, 9))
18659	21364680	However, caspase-3-mediated fragmentation of caspase-8 is reported to result in 41 and 43 kDa fragments, such as those found in this study.	('fragmentation', 'Var', (28, 41))	('caspase-3', 'Gene', (9, 18))	('caspase-8', 'Gene', (45, 54))	('caspase-8', 'Gene', '841', (45, 54))	('result', 'Reg', (70, 76))	('caspase-3', 'Gene', '836', (9, 18))
18665	21364680	Thus, acquisition of cisplatin-resistance may cause resistance to caspase activation and activity, particularly through the caspase 9-mediated pathway.	('resistance', 'MPA', (52, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('caspase', 'Enzyme', (66, 73))	('activation', 'PosReg', (74, 84))	('acquisition', 'Var', (6, 17))	('caspase 9', 'Gene', (124, 133))	('cause', 'Reg', (46, 51))	('caspase activation', 'biological_process', 'GO:0006919', ('66', '84'))	('caspase 9', 'Gene', '842', (124, 133))	('activity', 'MPA', (89, 97))
18736	15702125	The SMR for pleural cancer was 3427.7 for <1 year of exposure, 7659.3 for 1 to <5 years, 2978.6 for 5 to <10 years and 2129.9 for >=10 years.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pleural cancer', 'Disease', (12, 26))	('pleural cancer', 'Disease', 'MESH:D010995', (12, 26))	('2978.6', 'Var', (89, 95))
18740	15702125	Between 15 and 25 years since first employment, the SMR were 1599.4 for peritoneal cancer and 2910.2 for pleural and peritoneal mesothelioma combined; corresponding values increased to 2062.9 and 3593.0 for latency of 25 to <35 years, and to 5360.6 and 4480.7 for latency >=35 years.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (117, 140))	('men', 'Species', '9606', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('2910.2', 'Var', (94, 100))	('pleural and peritoneal mesothelioma', 'Disease', 'MESH:D010997', (105, 140))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
18847	31609087	A novel intraperitoneal therapy for gastric cancer with DFP-10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model In advanced gastric cancer, peritoneal dissemination is a life-threatening mode of metastasis.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('gastric cancer', 'Disease', (36, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('DFP-10825', 'Chemical', 'MESH:D007531', (56, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('DFP-10825', 'Var', (56, 65))	('thymidylate synthase', 'Gene', '22171', (103, 123))	('RNAi', 'biological_process', 'GO:0016246', ('76', '80'))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('thymidylate synthase', 'Gene', (103, 123))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
18849	31609087	The treatment with DFP-10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer-bearing mice via intraperitoneal administration.	('mice', 'Species', '10090', (127, 131))	('DFP-10825', 'Chemical', 'MESH:D007531', (19, 28))	('ovarian cancer', 'Disease', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('human', 'Species', '9606', (98, 103))	('tumor', 'Disease', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('DFP-10825', 'Var', (19, 28))
18858	31609087	Our current study indicates that DFP-10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('improve', 'PosReg', (81, 88))	('patients', 'Species', '9606', (105, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('DFP-10825', 'Chemical', 'MESH:D007531', (33, 42))	('DFP-10825', 'Var', (33, 42))	('gastric cancer', 'Disease', (145, 159))
18859	31609087	Intraperitoneal DFP-10825 showed effective antitumor activity in peritoneally disseminated human gastric cancer-bearing mice.	('DFP-10825', 'Var', (16, 25))	('gastric cancer', 'Disease', (97, 111))	('mice', 'Species', '10090', (120, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (47, 52))	('DFP-10825', 'Chemical', 'MESH:D007531', (16, 25))	('human', 'Species', '9606', (91, 96))
18860	31609087	As an alternative treatment regimen, DFP-10825 has the potential to improve the outcomes of patients with peritoneally disseminated gastric cancer.	('improve', 'PosReg', (68, 75))	('gastric cancer', 'Disease', (132, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('patients', 'Species', '9606', (92, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('DFP-10825', 'Chemical', 'MESH:D007531', (37, 46))	('DFP-10825', 'Var', (37, 46))
18866	31609087	The model mice were treated with either DFP-10825 or S-1.	('DFP-10825', 'Chemical', 'MESH:D007531', (40, 49))	('mice', 'Species', '10090', (10, 14))	('S-1', 'Gene', (53, 56))	('S-1', 'Gene', '70247', (53, 56))	('DFP-10825', 'Var', (40, 49))
18868	31609087	In contrast, the intraperitoneal treatment with DFP-10825 showed superior therapeutic effects without any systemic adverse events.	('therapeutic effects', 'CPA', (74, 93))	('DFP-10825', 'Var', (48, 57))	('DFP-10825', 'Chemical', 'MESH:D007531', (48, 57))
18869	31609087	The present study shows that intraperitoneal delivery of DFP-10825 could be a feasible therapeutic approach to treat peritoneally disseminated gastric cancer.	('DFP-10825', 'Var', (57, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('gastric cancer', 'Disease', (143, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('DFP-10825', 'Chemical', 'MESH:D007531', (57, 66))
18884	31609087	The development of a MKN45 peritoneally disseminated mouse model was confirmed by a >1.5 g decrease in body weight from Day 0 to Day 7 post-tumor implantation.	('body weight', 'CPA', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('decrease in body weight', 'Phenotype', 'HP:0004325', (91, 114))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('MKN45', 'Var', (21, 26))	('mouse', 'Species', '10090', (53, 58))	('decrease', 'NegReg', (91, 99))	('tumor', 'Disease', (140, 145))
18901	31609087	The levels of significance were set at *P < .05, **P < .01 vs. control, # P < .05 vs S-1 treatment, and $$ P < .01 vs 2.5 microg TS shRNA.	('TS', 'Gene', '22171', (129, 131))	('S-1', 'Gene', '70247', (85, 88))	(' $$ P <', 'Var', (103, 110))	('S-1', 'Gene', (85, 88))
18903	31609087	The intraperitoneal injection of DFP-10825 prolonged the survival times of the mice, compared with the untreated control mice (Figure 1A).	('mice', 'Species', '10090', (79, 83))	('mice', 'Species', '10090', (121, 125))	('survival times', 'CPA', (57, 71))	('prolonged', 'PosReg', (43, 52))	('DFP-10825', 'Var', (33, 42))	('DFP-10825', 'Chemical', 'MESH:D007531', (33, 42))
18904	31609087	The body weight of the treated mice gradually decreased with each dose of DFP-10825, and yet, it was comparable to that of the untreated control mice (Figure 1B).	('body weight', 'CPA', (4, 15))	('mice', 'Species', '10090', (31, 35))	('decreased', 'NegReg', (46, 55))	('mice', 'Species', '10090', (145, 149))	('DFP-10825', 'Var', (74, 83))	('DFP-10825', 'Chemical', 'MESH:D007531', (74, 83))
18906	31609087	The suppressive effect that DFP-10825 exerted on tumor growth was compared with that of conventional standard chemotherapy for gastric cancer, S-1.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('DFP-10825', 'Var', (28, 37))	('DFP-10825', 'Chemical', 'MESH:D007531', (28, 37))	('tumor', 'Disease', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', (127, 141))	('S-1', 'Gene', (143, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('suppressive', 'NegReg', (4, 15))	('S-1', 'Gene', '70247', (143, 146))
18911	31609087	On the other hand, in DFP-10825-treated mice, the intraperitoneal luciferase activity increased slowly, and at each time point, with the exception of the earliest point, the luciferase activity was smaller than that for either the S-1-treated or the control mice (Figure 2A,B).	('luciferase activity', 'molecular_function', 'GO:0047712', ('174', '193'))	('activity', 'MPA', (185, 193))	('S-1', 'Gene', (231, 234))	('luciferase', 'Enzyme', (174, 184))	('luciferase activity', 'molecular_function', 'GO:0050248', ('66', '85'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('66', '85'))	('DFP-10825', 'Chemical', 'MESH:D007531', (22, 31))	('smaller', 'NegReg', (198, 205))	('luciferase activity', 'molecular_function', 'GO:0050397', ('174', '193'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('174', '193'))	('mice', 'Species', '10090', (258, 262))	('S-1', 'Gene', '70247', (231, 234))	('DFP-10825-treated', 'Var', (22, 39))	('activity', 'MPA', (77, 85))	('mice', 'Species', '10090', (40, 44))	('luciferase activity', 'molecular_function', 'GO:0047077', ('66', '85'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('174', '193'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('66', '85'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('66', '85'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('174', '193'))
18912	31609087	Body weights of the mice treated with both S-1 and DFP-10825 gradually decreased, but were comparable to that of the untreated control mice (Figure 2C).	('mice', 'Species', '10090', (20, 24))	('DFP-10825', 'Chemical', 'MESH:D007531', (51, 60))	('S-1', 'Gene', (43, 46))	('S-1', 'Gene', '70247', (43, 46))	('DFP-10825', 'Var', (51, 60))	('mice', 'Species', '10090', (135, 139))	('Body weights', 'CPA', (0, 12))	('decreased', 'NegReg', (71, 80))
18914	31609087	To further confirm the tumor growth suppression effect of DFP-10825, we next prepared a peritoneally disseminated gastric cancer model with another cell line, NCI-N87 human gastric carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('gastric carcinoma', 'Disease', (173, 190))	('gastric cancer', 'Disease', (114, 128))	('tumor growth suppression', 'Disease', (23, 47))	('tumor growth suppression', 'Disease', 'MESH:D006130', (23, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('DFP-10825', 'Chemical', 'MESH:D007531', (58, 67))	('DFP-10825', 'Var', (58, 67))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (173, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('gastric carcinoma', 'Disease', 'MESH:D013274', (173, 190))	('human', 'Species', '9606', (167, 172))
18924	31609087	In the DFP-10825-treated mice, the luciferase activity was somewhat decreased during the treatment period (Day 7-Day 21) and then began to increase.	('decreased', 'NegReg', (68, 77))	('mice', 'Species', '10090', (25, 29))	('luciferase activity', 'molecular_function', 'GO:0045289', ('35', '54'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('35', '54'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('35', '54'))	('DFP-10825', 'Chemical', 'MESH:D007531', (7, 16))	('DFP-10825-treated', 'Var', (7, 24))	('activity', 'MPA', (46, 54))	('increase', 'PosReg', (139, 147))	('luciferase activity', 'molecular_function', 'GO:0047077', ('35', '54'))	('luciferase', 'Enzyme', (35, 45))	('luciferase activity', 'molecular_function', 'GO:0047712', ('35', '54'))
18925	31609087	For the DFP-10825-treated mice, however, the luciferase activity at Day 45 was much smaller than that of both the untreated mice and the S-1-treated mice.	('luciferase activity', 'molecular_function', 'GO:0047077', ('45', '64'))	('activity', 'MPA', (56, 64))	('luciferase', 'Enzyme', (45, 55))	('mice', 'Species', '10090', (124, 128))	('luciferase activity', 'molecular_function', 'GO:0045289', ('45', '64'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('45', '64'))	('mice', 'Species', '10090', (26, 30))	('S-1', 'Gene', (137, 140))	('mice', 'Species', '10090', (149, 153))	('luciferase activity', 'molecular_function', 'GO:0050248', ('45', '64'))	('S-1', 'Gene', '70247', (137, 140))	('luciferase activity', 'molecular_function', 'GO:0050397', ('45', '64'))	('DFP-10825', 'Chemical', 'MESH:D007531', (8, 17))	('DFP-10825-treated', 'Var', (8, 25))	('smaller', 'NegReg', (84, 91))
18928	31609087	These results indicate that the intraperitoneal injection of DFP-10825 showed a superior tumor growth suppressive effect without severe side effects in yet another gastric cancer peritoneally disseminated mouse model.	('DFP-10825', 'Var', (61, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('mouse', 'Species', '10090', (205, 210))	('gastric cancer', 'Disease', (164, 178))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('DFP-10825', 'Chemical', 'MESH:D007531', (61, 70))
18935	31609087	Interestingly, DFP-10825 containing either Alexa750-labeled TS shRNA or DiR was selectively accumulated in the peritoneally disseminated tumor masses without accumulation in any abdominal organs.	('TS', 'Gene', '22171', (60, 62))	('tumor', 'Disease', (137, 142))	('DiR', 'Chemical', 'MESH:C574020', (72, 75))	('accumulated', 'PosReg', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Alexa750-labeled', 'Var', (43, 59))	('DFP-10825', 'Chemical', 'MESH:D007531', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
18936	31609087	These results indicate that intraperitoneally injected DFP-10825 was retained in the peritoneal cavity for extended periods of time and was selectively accumulated in the peritoneally disseminated tumors, which efficiently delivered TS shRNA to the disseminated tumors and resulted in TS shRNA-mediated RNAi.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('TS', 'Gene', '22171', (285, 287))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('resulted in', 'Reg', (273, 284))	('tumors', 'Disease', (262, 268))	('TS', 'Gene', '22171', (233, 235))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('RNAi', 'biological_process', 'GO:0016246', ('303', '307'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('DFP-10825', 'Var', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('delivered', 'Reg', (223, 232))	('DFP-10825', 'Chemical', 'MESH:D007531', (55, 64))	('tumors', 'Disease', (197, 203))
18939	31609087	Thus far, however, neither systemic chemotherapy nor intraperitoneal chemotherapy has shown promising clinical benefits.6, 23, 24 In the current study, we showed that intraperitoneal injection of DFP-10825 induced desired tumor growth suppression in two different types of peritoneally disseminated gastric cancer models (MKN45 and NCI-N87) (Figures 2A,B and 3A) and increased the survival time of a MKN45 peritoneally disseminated gastric cancer model (Figure 1A) without severe side effects (Figures 1B, 2C and 3B).	('gastric cancer', 'Disease', 'MESH:D013274', (299, 313))	('tumor growth suppression', 'Disease', (222, 246))	('tumor growth suppression', 'Disease', 'MESH:D006130', (222, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (432, 446))	('DFP-10825', 'Chemical', 'MESH:D007531', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('DFP-10825', 'Var', (196, 205))	('survival time', 'CPA', (381, 394))	('gastric cancer', 'Phenotype', 'HP:0012126', (299, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('gastric cancer', 'Disease', (432, 446))	('increased', 'PosReg', (367, 376))	('gastric cancer', 'Disease', 'MESH:D013274', (432, 446))	('gastric cancer', 'Disease', (299, 313))
18944	31609087	DFP-10825 is an RNAi therapeutic composed of TS shRNA conjugated with cationic liposomes that has downregulated TS in cancer xenograft models.11, 30 Accordingly, DFP-10825 should be a feasible approach to control the malignancy of metastatic advanced gastric cancer and would meet the Japanese Gastric Cancer Treatment Guidelines.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('gastric cancer', 'Phenotype', 'HP:0012126', (251, 265))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (294, 308))	('TS', 'Gene', '22171', (112, 114))	('RNAi', 'biological_process', 'GO:0016246', ('16', '20'))	('DFP-10825', 'Chemical', 'MESH:D007531', (162, 171))	('gastric cancer', 'Disease', (251, 265))	('Cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', (259, 265))	('cancer', 'Disease', (118, 124))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('gastric cancer', 'Disease', 'MESH:D013274', (251, 265))	('TS', 'Gene', '22171', (45, 47))	('DFP-10825', 'Chemical', 'MESH:D007531', (0, 9))	('malignancy', 'Disease', (217, 227))	('DFP-10825', 'Var', (162, 171))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
18946	31609087	Such a long retention of DFP-10825 in the body cavity was also observed following intrathecal injection into a malignant pleural mesothelioma xenograft model.11 In addition, interestingly, a current study showed a selective accumulation of DFP-10825 in peritoneally disseminated tumors (Figure 4B), although the mechanism behind such selective tumor accumulation remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('DFP-10825', 'Var', (240, 249))	('tumors', 'Disease', (279, 285))	('malignant pleural mesothelioma', 'Disease', (111, 141))	('pleural mesothelioma xenograft', 'Disease', 'MESH:D008654', (121, 151))	('accumulation', 'PosReg', (224, 236))	('tumor', 'Disease', (344, 349))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('DFP-10825', 'Chemical', 'MESH:D007531', (240, 249))	('tumor', 'Disease', (279, 284))	('retention', 'biological_process', 'GO:0051235', ('12', '21'))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (111, 141))	('pleural mesothelioma xenograft', 'Disease', (121, 151))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('DFP-10825', 'Chemical', 'MESH:D007531', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (121, 141))
18952	31609087	We recently reported that DFP-10825 also induced tumor growth suppression in a malignant pleural mesothelioma xenograft model11 and in a peritoneal disseminated ovarian cancer xenograft model.30 In the current study, DFP-10825 also showed a superior suppressive effect on tumor growth in a peritoneally disseminated gastric cancer xenograft model (Figures 1, 2, 3).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('DFP-10825', 'Var', (217, 226))	('malignant pleural mesothelioma', 'Disease', (79, 109))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor growth suppression', 'Disease', 'MESH:D006130', (49, 73))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (89, 109))	('gastric cancer', 'Disease', (316, 330))	('tumor', 'Disease', (272, 277))	('pleural mesothelioma xenograft', 'Disease', 'MESH:D008654', (89, 119))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('gastric cancer', 'Disease', 'MESH:D013274', (316, 330))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (79, 109))	('DFP-10825', 'Chemical', 'MESH:D007531', (217, 226))	('tumor', 'Disease', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('tumor growth suppression', 'Disease', (49, 73))	('ovarian cancer', 'Disease', (161, 175))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('DFP-10825', 'Chemical', 'MESH:D007531', (26, 35))	('suppressive', 'NegReg', (250, 261))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('gastric cancer', 'Phenotype', 'HP:0012126', (316, 330))	('pleural mesothelioma xenograft', 'Disease', (89, 119))
18957	31609087	DFP-10825 might be a reliable alternative to the traditional chemotherapeutic regimen via suppression of tumor growth without severe adverse effects, which should achieve a higher therapeutic index.	('suppression', 'NegReg', (90, 101))	('DFP-10825', 'Var', (0, 9))	('DFP-10825', 'Chemical', 'MESH:D007531', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
18961	31609087	These results strongly indicate that intraperitoneal treatment with DFP-10825 would provide a new therapeutic approach that could improve the outcomes for patients with advanced gastric cancer.	('improve', 'PosReg', (130, 137))	('DFP-10825', 'Var', (68, 77))	('DFP-10825', 'Chemical', 'MESH:D007531', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric cancer', 'Disease', (178, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (178, 192))	('patients', 'Species', '9606', (155, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))
19035	29120491	The ICARuS (Intraperitoneal Chemotherapy After cytoreductive Surgery) trial , at Memorial Sloan Kettering Cancer Center (MSKCC), seeks to determine the benefit of HIPEC with MMC versus early, post-operative, normothermic IP chemotherapy (EPIC) with floxuridine after optimal CRS in patients with appendiceal and colorectal cancers.	('appendiceal', 'Disease', (296, 307))	('colorectal cancers', 'Disease', 'MESH:D015179', (312, 330))	('appendiceal', 'Disease', 'MESH:D001063', (296, 307))	('floxuridine', 'Chemical', 'MESH:D005467', (249, 260))	('Cancer', 'Disease', (106, 112))	('colorectal cancers', 'Disease', (312, 330))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('patients', 'Species', '9606', (282, 290))	('MMC', 'Chemical', 'MESH:D016685', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))	('MMC', 'Var', (174, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (312, 329))
19097	29120491	Carolinas Medical Center plans to similarly investigate the surgical outcomes and clinicopathological results of treating patients with T1-T3, resectable pancreatic ductal adenocarcinoma with pancreaticoduodenectomy and HIPEC with gemcitabine, in conjunction with perioperative systemic therapy .	('pancreatic ductal adenocarcinoma', 'Disease', (154, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (154, 186))	('patients', 'Species', '9606', (122, 130))	('T1-T3', 'Var', (136, 141))	('gemcitabine', 'Chemical', 'MESH:C056507', (231, 242))
19178	30687679	However, asbestos fibers had been found even in lungs of affected subjects exposed to very low doses of asbestos (or not supposed to be exposed at all), suggesting that even very few fibers, in a hypersusceptible individual, might cause mesothelioma.	('asbestos', 'Chemical', 'MESH:D001194', (104, 112))	('mesothelioma', 'Disease', (237, 249))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('fibers', 'Var', (183, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('cause', 'Reg', (231, 236))
19249	30627323	We found that mesothelioma tumor growth was markedly attenuated by heparanase gene silencing and by heparanase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (14, 32))	('gene silencing', 'Var', (78, 92))	('heparanase', 'Protein', (67, 77))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (14, 32))	('mesothelioma tumor', 'Disease', (14, 32))	('attenuated', 'NegReg', (53, 63))	('gene silencing', 'biological_process', 'GO:0016458', ('78', '92'))
19257	30627323	Cleavage of HS by heparanase leads to disassembly of the ECM, thereby promoting cell dissemination associated with tumor metastasis, angiogenesis and inflammation.	('Cleavage', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('heparanase', 'Protein', (18, 28))	('angiogenesis', 'biological_process', 'GO:0001525', ('133', '145'))	('promoting', 'PosReg', (70, 79))	('angiogenesis', 'CPA', (133, 145))	('HS', 'Chemical', 'MESH:D006497', (12, 14))	('disassembly', 'CPA', (38, 49))	('inflammation', 'Disease', 'MESH:D007249', (150, 162))	('inflammation', 'biological_process', 'GO:0006954', ('150', '162'))	('tumor metastasis', 'Disease', 'MESH:D009362', (115, 131))	('inflammation', 'Disease', (150, 162))	('cell dissemination', 'CPA', (80, 98))	('tumor metastasis', 'Disease', (115, 131))
19259	30627323	Notably, cancer patients exhibiting high levels of heparanase had a significantly shorter postoperative survival time than patients whose tumors exhibit low levels of heparanase.	('cancer', 'Disease', (9, 15))	('high levels of heparanase', 'Phenotype', 'HP:0410342', (36, 61))	('postoperative survival time', 'CPA', (90, 117))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('high', 'Var', (36, 40))	('shorter', 'NegReg', (82, 89))
19262	30627323	This notion is reinforced by preclinical studies revealing a marked inhibition of tumor growth in mice treated with heparanase-inhibitors (i.e., roneparstat, pixatimod) and neutralizing antibodies.	('neutralizing', 'Var', (173, 185))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('heparanase-inhibitors', 'Protein', (116, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'NegReg', (68, 78))	('pixatimod', 'Chemical', '-', (158, 167))	('roneparstat', 'Chemical', '-', (145, 156))	('tumor', 'Disease', (82, 87))	('mice', 'Species', '10090', (98, 102))
19265	30627323	Applying extensive pre-clinical mouse models, Barash, Lapidot et al show that mesothelioma tumor growth is markedly attenuated by heparanase-inhibiting compounds (Figure 1), heparanase gene silencing, and by inoculation of mesothelioma cells into heparanase null mice.	('mesothelioma tumor', 'Disease', (78, 96))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (78, 96))	('gene', 'Var', (185, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('mesothelioma', 'Disease', (223, 235))	('heparanase-inhibiting', 'MPA', (130, 151))	('gene silencing', 'biological_process', 'GO:0016458', ('185', '199'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mouse', 'Species', '10090', (32, 37))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (78, 96))	('heparanase', 'Protein', (174, 184))	('mesothelioma', 'Disease', 'MESH:D008654', (223, 235))	('mice', 'Species', '10090', (263, 267))	('pre', 'molecular_function', 'GO:0003904', ('19', '22'))	('attenuated', 'NegReg', (116, 126))	('mesothelioma', 'Disease', (78, 90))
19266	30627323	Clinically, patients with high heparanase immunostaining or H-score survived less than patients with low levels of heparanase (Figure 1D).	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('heparanase', 'Protein', (31, 41))	('less', 'NegReg', (77, 81))	('survived', 'CPA', (68, 76))	('patients', 'Species', '9606', (87, 95))
19269	30627323	Notably, the heparanase inhibitor PG545 (= pixatimod, a highly sulfated tetra-saccharide bound to a lipophilic cholestanol aglycone) appeared more effective than cisplatin, a common chemotherapeutics in mesothelioma, in restraining tumor growth, closely associating with a profoundly prolonged survival of mesothelioma-bearing mice (Figure 1B).	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('tetra', 'Species', '42554', (72, 77))	('cholestanol', 'Chemical', 'MESH:D004083', (111, 122))	('mesothelioma', 'Disease', (203, 215))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('pixatimod', 'Chemical', '-', (43, 52))	('PG545', 'Var', (34, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (306, 318))	('PG545', 'Chemical', 'MESH:C557899', (34, 39))	('mice', 'Species', '10090', (327, 331))	('aglycone', 'Chemical', '-', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('mesothelioma', 'Disease', 'MESH:D008654', (203, 215))	('mesothelioma', 'Disease', (306, 318))	('prolonged', 'PosReg', (284, 293))	('tumor', 'Disease', (232, 237))	('restraining', 'NegReg', (220, 231))
19310	29900099	Specific primary antibodies were diluted in blocking buffer as follows: 1:2000 for anti-S100A11, anti-CLIC3, and anti-SSA1 and 1:500 anti-gamma-enolase.	('S100A11', 'Gene', (88, 95))	('gamma-enolase', 'Gene', (138, 151))	('gamma-enolase', 'Gene', '2026', (138, 151))	('CLIC3', 'Gene', '9022', (102, 107))	('CLIC3', 'Gene', (102, 107))	('anti-SSA1', 'Var', (113, 122))	('S100A11', 'Gene', '6282', (88, 95))
19344	29900099	In fact, the nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2), the cytokine IL-6 and the tumour suppressor TP53 were significantly activated in B-PM, while were turned off in E-PM.	('Nrf2', 'Gene', (68, 72))	('IL-6', 'Gene', (88, 92))	('tumour', 'Disease', (101, 107))	('NFE2L2', 'Gene', '4780', (58, 64))	('IL-6', 'Gene', '3569', (88, 92))	('nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (13, 56))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('activated', 'PosReg', (143, 152))	('NFE2L2', 'Gene', (58, 64))	('IL-6', 'molecular_function', 'GO:0005138', ('88', '92'))	('B-PM', 'Var', (156, 160))	('TP53', 'Gene', '7157', (119, 123))	('Nrf2', 'Gene', '4780', (68, 72))	('TP53', 'Gene', (119, 123))	('nuclear factor erythroid 2-related factor 2', 'Gene', (13, 56))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
19351	29900099	demonstrated the importance of Nrf2 in cytoprotection, survival, and drug resistance on MSTO-211H, a biphasic cell line, suggesting the targeting of Nrf2 as a promising strategy for overcoming resistance to chemotherapeutics in MPM.	('Nrf2', 'Gene', (149, 153))	('drug resistance', 'biological_process', 'GO:0009315', ('69', '84'))	('overcoming', 'PosReg', (182, 192))	('targeting', 'Var', (136, 145))	('drug resistance', 'Phenotype', 'HP:0020174', (69, 84))	('Nrf2', 'Gene', '4780', (31, 35))	('drug resistance', 'biological_process', 'GO:0042493', ('69', '84'))	('Nrf2', 'Gene', '4780', (149, 153))	('Nrf2', 'Gene', (31, 35))
19367	29362358	Proteins of the S100 family are small molecules (ranging from 9 to 14 kDa) with two EF-hands and in humans, the family is composed of 20 different members (S100A1-S100A16, S100beta, S100G, S100P, and S100Z).	('S100A16', 'Gene', '140576', (163, 170))	('S100', 'Gene', '6285', (172, 176))	('S100', 'Gene', '6285', (163, 167))	('S100', 'Gene', (172, 176))	('S100', 'Gene', (163, 167))	('S100beta', 'Gene', (172, 180))	('S100P', 'Var', (189, 194))	('S100Z', 'Gene', '170591', (200, 205))	('S100Z', 'Gene', (200, 205))	('S100G', 'Gene', '795', (182, 187))	('S100', 'Gene', '6285', (200, 204))	('S100', 'Gene', (200, 204))	('humans', 'Species', '9606', (100, 106))	('S100', 'Gene', '6285', (16, 20))	('S100beta', 'Gene', '6285', (172, 180))	('S100', 'Gene', (16, 20))	('S100', 'Gene', '6285', (189, 193))	('S100G', 'Gene', (182, 187))	('S100', 'Gene', '6285', (182, 186))	('S100A16', 'Gene', (163, 170))	('S100', 'Gene', (189, 193))	('S100', 'Gene', (182, 186))	('S100P', 'SUBSTITUTION', 'None', (189, 194))	('S100', 'Gene', '6285', (156, 160))	('S100', 'Gene', (156, 160))
19370	29362358	Namely, in the cytoplasmic compartment, S100A11 inhibits the growth of normal human keratinocytes in response to high Ca2+ or transforming growth factor beta.	('inhibits', 'NegReg', (48, 56))	('growth of normal human keratinocytes', 'CPA', (61, 97))	('Ca2+', 'Chemical', 'MESH:D000069285', (118, 122))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('126', '157'))	('S100A11', 'Var', (40, 47))	('human', 'Species', '9606', (78, 83))	('response to high Ca2+', 'MPA', (101, 122))
19377	29362358	All examined MPM cell lines except for MSTO-211H commonly secreted S100A11, whereas no secretion was observed in normal mesothelial cell lines.	('MSTO-211H', 'Chemical', '-', (39, 48))	('secreted', 'Reg', (58, 66))	('secretion', 'biological_process', 'GO:0046903', ('87', '96'))	('S100A11', 'Var', (67, 74))
19378	29362358	MPM cell lines were classified into three categories based on the secretion level of S100A11: High (YUMC44, H290, and H28), Low (HP-1, H2452, and H2052), and None (MSTO-211H).	('H2052', 'Var', (146, 151))	('secretion', 'biological_process', 'GO:0046903', ('66', '75'))	('S100A11', 'Gene', (85, 92))	('H290', 'Var', (108, 112))	('H28', 'Var', (118, 121))	('H2452', 'CellLine', 'CVCL:1553', (135, 140))	('H290', 'CellLine', 'CVCL:A555', (108, 112))	('H2052', 'CellLine', 'CVCL:1518', (146, 151))	('HP-1', 'Var', (129, 133))	('secretion', 'MPA', (66, 75))	('MSTO-211H', 'Chemical', '-', (164, 173))	('H2452', 'Var', (135, 140))	('YUMC44', 'Var', (100, 106))
19385	29362358	We found that cellular growth of "Low" cells (H2452 and H2052) was both highly suppressed by an anti-S100A11 antibody with a final concentration of 100 ng/ml in culture media (Fig.	('H2052', 'Var', (56, 61))	('antibody', 'molecular_function', 'GO:0003823', ('107', '115'))	('suppressed', 'NegReg', (79, 89))	('anti-S100A11', 'Var', (96, 108))	('H2052', 'CellLine', 'CVCL:1518', (56, 61))	('antibody', 'cellular_component', 'GO:0042571', ('107', '115'))	('cellular growth', 'biological_process', 'GO:0016049', ('14', '29'))	('cellular growth', 'CPA', (14, 29))	('antibody', 'cellular_component', 'GO:0019815', ('107', '115'))	('H2452', 'CellLine', 'CVCL:1553', (46, 51))	('antibody', 'cellular_component', 'GO:0019814', ('107', '115'))
19390	29362358	By the western blot analysis approach, we found that Cyclin D but not Cyclin B was significantly induced with time dependency after the addition of S100A11 in MPM cultures (H2452 and H2052) (Fig.	('Cyclin D', 'Gene', (53, 61))	('H2052', 'Var', (183, 188))	('Cyclin', 'molecular_function', 'GO:0016538', ('53', '59'))	('S100A11', 'Var', (148, 155))	('H2052', 'CellLine', 'CVCL:1518', (183, 188))	('induced', 'PosReg', (97, 104))	('Cyclin', 'molecular_function', 'GO:0016538', ('70', '76'))	('H2452', 'Var', (173, 178))	('H2452', 'CellLine', 'CVCL:1553', (173, 178))
19393	29362358	To gain insight into the intracellular signaling events induced by the neutralization of extracellular S100A11, we investigated the key molecules regarding to cancer progression.	('cancer', 'Disease', (159, 165))	('neutralization', 'Var', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('intracellular', 'cellular_component', 'GO:0005622', ('25', '38'))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('S100A11', 'Gene', (103, 110))	('extracellular', 'cellular_component', 'GO:0005576', ('89', '102'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
19394	29362358	MPM cells were cultured with the anti-S100A11 antibody (1 mug/ml), S100A11 recombinant protein (100 ng/ml), or mouse control IgG (1 mug/ml).	('S100A11', 'Gene', (67, 74))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('mug', 'molecular_function', 'GO:0043739', ('58', '61'))	('antibody', 'cellular_component', 'GO:0019815', ('46', '54'))	('mouse', 'Species', '10090', (111, 116))	('IgG (1', 'cellular_component', 'GO:0071735', ('125', '131'))	('antibody', 'cellular_component', 'GO:0019814', ('46', '54'))	('antibody', 'molecular_function', 'GO:0003823', ('46', '54'))	('antibody', 'cellular_component', 'GO:0042571', ('46', '54'))	('anti-S100A11', 'Var', (33, 45))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
19395	29362358	As a result, we found that the treatment with the anti-S100A11 antibody significantly suppressed the constitutive phosphorylation of endogenous STAT3 in H2452 and H2052 cells.	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('H2052', 'CellLine', 'CVCL:1518', (163, 168))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('suppressed', 'NegReg', (86, 96))	('STAT3', 'Gene', '6774', (144, 149))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('anti-S100A11', 'Var', (50, 62))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('H2452', 'CellLine', 'CVCL:1553', (153, 158))	('STAT3', 'Gene', (144, 149))
19398	29362358	The addition of S100A11 recombinant protein in turn activated the downstream proteins, STAT3, AKT, and MAPK (Supplementary Fig.	('AKT', 'Gene', '207', (94, 97))	('MAPK', 'Pathway', (103, 107))	('STAT3', 'Gene', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('MAPK', 'molecular_function', 'GO:0004707', ('103', '107'))	('AKT', 'Gene', (94, 97))	('S100A11', 'Var', (16, 23))	('activated', 'PosReg', (52, 61))	('STAT3', 'Gene', '6774', (87, 92))
19401	29362358	We investigated the antitumor effect of the validated anti-S100A11 neutralizing antibody on the MPM in a xenograft mouse model, using H2452 and H290 cells.	('anti-S100A11', 'Var', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('H2452', 'CellLine', 'CVCL:1553', (134, 139))	('antibody', 'cellular_component', 'GO:0042571', ('80', '88'))	('tumor', 'Disease', (24, 29))	('H290', 'CellLine', 'CVCL:A555', (144, 148))	('antibody', 'cellular_component', 'GO:0019815', ('80', '88'))	('mouse', 'Species', '10090', (115, 120))	('antibody', 'molecular_function', 'GO:0003823', ('80', '88'))	('antibody', 'cellular_component', 'GO:0019814', ('80', '88'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
19402	29362358	We subcutaneously injected tumor cells and the anti-S100A11 antibody, and evaluated the effect of the antibody on the tumorigenic potential.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('anti-S100A11', 'Var', (47, 59))	('antibody', 'molecular_function', 'GO:0003823', ('60', '68'))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('antibody', 'cellular_component', 'GO:0042571', ('102', '110'))	('tumor', 'Disease', (27, 32))	('antibody', 'cellular_component', 'GO:0019814', ('60', '68'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('antibody', 'cellular_component', 'GO:0042571', ('60', '68'))	('antibody', 'cellular_component', 'GO:0019815', ('102', '110'))	('tumor', 'Disease', (118, 123))	('antibody', 'cellular_component', 'GO:0019815', ('60', '68'))	('antibody', 'cellular_component', 'GO:0019814', ('102', '110'))	('antibody', 'molecular_function', 'GO:0003823', ('102', '110'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
19403	29362358	3a, b, the tumor growth in the antibody-administered group was significantly suppressed, compared to those of the control group.	('suppressed', 'NegReg', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('antibody-administered', 'Var', (31, 52))	('tumor', 'Disease', (11, 16))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
19404	29362358	To reveal the mechanisms involved in the anticancer activity induced by neutralization of extracellular S100A11, we carried out gene expression microarray analysis.	('extracellular', 'cellular_component', 'GO:0005576', ('90', '103'))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('S100A11', 'Gene', (104, 111))	('cancer', 'Disease', (45, 51))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('neutralization', 'Var', (72, 86))
19410	29362358	We found that blockage of RAGE signaling suppressed the phosphorylation of STAT3 and MAPK induced by S100A11 stimulation (Fig.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('blockage', 'Var', (14, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('RAGE', 'Gene', (26, 30))	('MAPK', 'Gene', (85, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('STAT3', 'Gene', '6774', (75, 80))	('suppressed', 'NegReg', (41, 51))	('STAT3', 'Gene', (75, 80))	('phosphorylation', 'MPA', (56, 71))	('RAGE', 'Gene', '177', (26, 30))	('S100A11', 'Gene', (101, 108))
19415	29362358	6, the level of S100A11 was remarkably elevated in pleural effusion obtained from MPM patients when compared to that obtained from BA patients as a benchmark (P = 0.014).	('MPM', 'Var', (82, 85))	('pleural effusion', 'Disease', 'MESH:D010996', (51, 67))	('pleural effusion', 'Phenotype', 'HP:0002202', (51, 67))	('pleural effusion', 'Disease', (51, 67))	('BA', 'Chemical', '-', (131, 133))	('patients', 'Species', '9606', (134, 142))	('elevated', 'PosReg', (39, 47))	('level', 'MPA', (7, 12))	('S100A11', 'Var', (16, 23))	('patients', 'Species', '9606', (86, 94))
19418	29362358	Additionally, in a mouse xenograft model, tumorigenesis of MPM cells was markedly inhibited by an anti-S100A11 antibody.	('tumor', 'Disease', (42, 47))	('anti-S100A11', 'Var', (98, 110))	('antibody', 'cellular_component', 'GO:0019815', ('111', '119'))	('inhibited', 'NegReg', (82, 91))	('antibody', 'cellular_component', 'GO:0019814', ('111', '119'))	('antibody', 'molecular_function', 'GO:0003823', ('111', '119'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mouse', 'Species', '10090', (19, 24))	('antibody', 'cellular_component', 'GO:0042571', ('111', '119'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
19422	29362358	Therefore, S100A11 might act sometimes as an oncogene, and sometimes as a suppressor gene, and have a key role in the progression of malignant tumors based on the balance of its ambivalent effect, which may be different depending on cancer types.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('malignant tumors', 'Disease', (133, 149))	('S100A11', 'Var', (11, 18))	('malignant tumors', 'Disease', 'MESH:D018198', (133, 149))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('role', 'Reg', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
19424	29362358	We found that RAGE-positive MPM cells constitutively express and secrete S100A11, the S100A11-RAGE axis is greatly involved in sustained phosphorylation of downstream effector molecules, STAT3, MAPK, and PI3K-AKT, and the blockage of S100A11-RAGE connection using either sRAGE or S100A11 neutralizing antibody effectively inhibits cell growth of MPM cells.	('RAGE', 'Gene', '177', (14, 18))	('phosphorylation', 'MPA', (137, 152))	('RAGE', 'Gene', '177', (94, 98))	('blockage', 'Var', (222, 230))	('S100A11', 'Gene', (73, 80))	('antibody', 'cellular_component', 'GO:0019814', ('301', '309'))	('RAGE', 'Gene', (242, 246))	('MAPK', 'molecular_function', 'GO:0004707', ('194', '198'))	('PI3K', 'molecular_function', 'GO:0016303', ('204', '208'))	('RAGE', 'Gene', (272, 276))	('cell growth of MPM cells', 'CPA', (331, 355))	('RAGE', 'Gene', '177', (242, 246))	('AKT', 'Gene', (209, 212))	('antibody', 'molecular_function', 'GO:0003823', ('301', '309'))	('inhibits', 'NegReg', (322, 330))	('antibody', 'cellular_component', 'GO:0042571', ('301', '309'))	('RAGE', 'Gene', '177', (272, 276))	('STAT3', 'Gene', (187, 192))	('STAT3', 'Gene', '6774', (187, 192))	('AKT', 'Gene', '207', (209, 212))	('RAGE', 'Gene', (14, 18))	('antibody', 'cellular_component', 'GO:0019815', ('301', '309'))	('involved', 'Reg', (115, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('RAGE', 'Gene', (94, 98))	('cell growth', 'biological_process', 'GO:0016049', ('331', '342'))	('S100A11', 'Gene', (280, 287))
19425	29362358	For the S100A11-mediated growth upregulation, Cyclin D and Bcl-2 might be critically relevant.	('Bcl-2', 'molecular_function', 'GO:0015283', ('59', '64'))	('growth', 'CPA', (25, 31))	('upregulation', 'PosReg', (32, 44))	('S100A11-mediated', 'Var', (8, 24))	('Cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))	('Bcl-2', 'Gene', (59, 64))	('Bcl-2', 'Gene', '596', (59, 64))
19433	29362358	Although "High" cells (H290 and H28) displayed resistance to the S100A11 antibody at lower concentration (100 ng/ml), the effect of S100A11 antibody was shown when much higher concentration of it (1 mug/ml) was used.	('H290', 'CellLine', 'CVCL:A555', (23, 27))	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('antibody', 'cellular_component', 'GO:0042571', ('138', '146'))	('S100A11', 'Var', (65, 72))	('resistance', 'MPA', (47, 57))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('antibody', 'cellular_component', 'GO:0019814', ('138', '146'))	('S100A11', 'Var', (132, 139))	('antibody', 'cellular_component', 'GO:0019815', ('138', '146'))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('antibody', 'molecular_function', 'GO:0003823', ('138', '146'))	('mug', 'molecular_function', 'GO:0043739', ('197', '200'))
19443	29362358	MSTO-211H, MeT-5A, N87 cell lines, seven lung cancer cell lines (HCC827, H1975, H1993, H1299, H460, H2170, and H157), three breast cancer cell lines (MCF-7, BT474, and SK-BR-3), and three colorectal cancer cell lines (Sw480, HT29, and DLD-1) were purchased from the American Type Culture Collection (Manassas, VA, USA).	('H1299', 'CellLine', 'CVCL:0060', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('H460', 'CellLine', 'CVCL:0459', (94, 98))	('H2170', 'Var', (100, 105))	('SK-BR-3', 'CellLine', 'CVCL:0033', (168, 175))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('MCF-7', 'CellLine', 'CVCL:0031', (150, 155))	('H2170', 'CellLine', 'CVCL:1535', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('HT29', 'CellLine', 'CVCL:0320', (225, 229))	('Sw480', 'CellLine', 'CVCL:0546', (218, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('HCC827', 'CellLine', 'CVCL:2063', (65, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('breast cancer', 'Disease', (124, 137))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('H1975', 'CellLine', 'CVCL:1511', (73, 78))	('lung cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('H1993', 'CellLine', 'CVCL:1512', (80, 85))	('MSTO-211H', 'Chemical', '-', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))
19464	29362358	Each cell line (5 x 106 cells) suspended in 200 microL RPMI-1640 media and Matrigel Basement Membrane Matrix (Corning, NY, USA, catalog #354234) was subcutaneously injected into the backs of the mice either with 1 microg/ml anti-S100A11 antibody (proteintech Group) or mouse IgG-isotype control (two tumors per mouse).	('RPMI-1640', 'Chemical', '-', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('antibody', 'cellular_component', 'GO:0019815', ('237', '245'))	('mice', 'Species', '10090', (195, 199))	('antibody', 'cellular_component', 'GO:0019814', ('237', '245'))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('tumors', 'Disease', (300, 306))	('anti-S100A11', 'Var', (224, 236))	('mouse', 'Species', '10090', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('Basement Membrane', 'cellular_component', 'GO:0005604', ('84', '101'))	('antibody', 'molecular_function', 'GO:0003823', ('237', '245'))	('antibody', 'cellular_component', 'GO:0042571', ('237', '245'))	('mouse', 'Species', '10090', (311, 316))
19475	22734486	Viability of MSTO-211H and H28 cells were decreased, and apoptotic cell death was increased in MSTO-211H as a result of cafestol and kahweol treatment.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('57', '77'))	('Viability', 'CPA', (0, 9))	('decreased', 'NegReg', (42, 51))	('apoptotic cell death', 'CPA', (57, 77))	('H28', 'CellLine', 'CVCL:1555', (27, 30))	('MSTO-211H', 'CellLine', 'CVCL:1430', (95, 104))	('cafestol', 'Chemical', 'MESH:C053400', (120, 128))	('MSTO-211H', 'CellLine', 'CVCL:1430', (13, 22))	('increased', 'PosReg', (82, 91))	('kahweol', 'Chemical', 'MESH:C053401', (133, 140))	('MSTO-211H', 'Var', (95, 104))
19546	22734486	The cells treated with 10-40 muM Mith A demonstrated decrease in cell viability (Figure 3A) and induction of nuclear condensation and fragmentation (Figure 3B).	('muM', 'Gene', (29, 32))	('Mith', 'Var', (33, 37))	('decrease', 'NegReg', (53, 61))	('cell viability', 'CPA', (65, 79))	('Mith A', 'Chemical', 'MESH:C066851', (33, 39))	('muM', 'Gene', '56925', (29, 32))	('nuclear condensation', 'CPA', (109, 129))
19547	22734486	Sp1 expression and the expression of Sp1 regulatory proteins (Cyclin D1, Mcl-1, and Survivin) were significantly downregulated by Mith A as well.	('Survivin', 'Gene', (84, 92))	('Sp1', 'Gene', (0, 3))	('Cyclin D1', 'Gene', (62, 71))	('downregulated', 'NegReg', (113, 126))	('Mith A', 'Var', (130, 136))	('expression', 'MPA', (4, 14))	('Mcl-1', 'Gene', '4170', (73, 78))	('Cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('Mith A', 'Chemical', 'MESH:C066851', (130, 136))	('Cyclin D1', 'Gene', '595', (62, 71))	('Mcl-1', 'Gene', (73, 78))	('expression', 'MPA', (23, 33))
19567	22734486	In previous studies, we confirmed the role of Sp1 in cell proliferation and apoptosis of MSTO-211H cells by RNA interference with small interfering Sp1.	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('cell proliferation', 'CPA', (53, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('small interfering', 'Var', (130, 147))	('Sp1', 'Gene', (148, 151))	('RNA interference', 'biological_process', 'GO:0016246', ('108', '124'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (89, 98))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('RNA interference', 'MPA', (108, 124))
19672	33625287	A slight but prolonged survival effect was observed in the group administered 100 mug/head compared with the group administered 10 mug/head and the PBS group (Fig.	('mug', 'molecular_function', 'GO:0043739', ('82', '85'))	('survival effect', 'CPA', (23, 38))	('100 mug/head', 'Var', (78, 90))	('mug', 'molecular_function', 'GO:0043739', ('131', '134'))	('prolonged', 'PosReg', (13, 22))	('PBS', 'Chemical', 'MESH:D007854', (148, 151))
19674	33625287	JMAM-1 concentrations used for dose-response analyses were 0.001, 0.005, 0.025, 0.1, 0.4, and 2 muM.	('0.1', 'Var', (80, 83))	('0.025', 'Var', (73, 78))	('JMAM-1', 'Chemical', '-', (0, 6))	('0.005', 'Var', (66, 71))	('0.001', 'Var', (59, 64))
19679	33625287	Furthermore, mitotic counts were significantly higher in CD10-positive tumors than in CD10-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CD10-positive', 'Var', (57, 70))	('mitotic counts', 'CPA', (13, 27))	('higher', 'PosReg', (47, 53))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CD10', 'molecular_function', 'GO:0004245', ('86', '90'))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('CD10', 'molecular_function', 'GO:0004245', ('57', '61'))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
19686	33625287	JMAM-1 mAb has an inhibitory effect on cell proliferation, and even Kaplan-Meier estimates showed a life-prolonging effect of JMAM-1 mAb compared with that of control PBS.	('life-prolonging', 'CPA', (100, 115))	('PBS', 'Chemical', 'MESH:D007854', (167, 170))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('JMAM-1', 'Chemical', '-', (126, 132))	('JMAM-1', 'Chemical', '-', (0, 6))	('cell proliferation', 'CPA', (39, 57))	('JMAM-1 mAb', 'Var', (126, 136))
19691	33625287	YAP protein is involved in the proliferation of MPM cells, whereas suppressing CDK7 reduces YAP protein as well as suppresses the infiltration and metastasis of MM.	('suppresses', 'NegReg', (115, 125))	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('YAP', 'Gene', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('CDK7', 'Gene', '1022', (79, 83))	('YAP', 'Gene', '10413', (92, 95))	('YAP', 'Gene', '10413', (0, 3))	('reduces', 'NegReg', (84, 91))	('suppressing', 'Var', (67, 78))	('CDK7', 'Gene', (79, 83))	('YAP', 'Gene', (92, 95))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
19785	32533757	For detection of SNVs, indels, and SVs, the Enrichment v3.0.0 (using Isaac aligner) and Variant Studio v3.0 app of the Illumina Base Space Sequence Hub were used.	('a', 'Gene', '351', (89, 90))	('a', 'Gene', '351', (126, 127))	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (72, 73))	('indels', 'Var', (23, 29))	('a', 'Gene', '351', (135, 136))	('a', 'Gene', '351', (108, 109))	('a', 'Gene', '351', (84, 85))	('SNVs', 'Var', (17, 21))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (75, 76))	('a', 'Gene', '351', (92, 93))
19807	32533757	This analysis identified SNVs, including single nucleotide insertions and deletions (indels) in 8 loci, that is, ADAMTS7, BRCA1, BRCA2, CSMD3, FAT3, NF1, RAD51C, and TP53, in at least one patient (Fig.	('BRCA2', 'Gene', '675', (129, 134))	('BRCA1', 'Gene', '672', (122, 127))	('NF1', 'Gene', (149, 152))	('deletions', 'Var', (74, 83))	('BRCA1', 'Gene', (122, 127))	('FAT3', 'Gene', (143, 147))	('a', 'Gene', '351', (70, 71))	('a', 'Gene', '351', (189, 190))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (7, 8))	('TP53', 'Gene', '7157', (166, 170))	('patient', 'Species', '9606', (188, 195))	('FAT3', 'Gene', '120114', (143, 147))	('a', 'Gene', '351', (162, 163))	('single nucleotide insertions', 'Var', (41, 69))	('RAD51C', 'Gene', '5889', (154, 160))	('CSMD3', 'Gene', '114788', (136, 141))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (106, 107))	('BRCA2', 'Gene', (129, 134))	('ADAMTS7', 'Gene', '11173', (113, 120))	('RAD', 'biological_process', 'GO:1990116', ('154', '157'))	('TP53', 'Gene', (166, 170))	('RAD51C', 'Gene', (154, 160))	('CSMD3', 'Gene', (136, 141))	('ADAMTS7', 'Gene', (113, 120))	('NF1', 'Gene', '4763', (149, 152))	('a', 'Gene', '351', (175, 176))
19809	32533757	In addition, we found larger deletions, duplications, translocations, and inversions at the BRCA2, ERN1, and/or NF1 loci.	('a', 'Gene', '351', (3, 4))	('ERN1', 'Gene', '2081', (99, 103))	('a', 'Gene', '351', (70, 71))	('a', 'Gene', '351', (62, 63))	('a', 'Gene', '351', (56, 57))	('BRCA2', 'Gene', (92, 97))	('NF1', 'Gene', '4763', (112, 115))	('NF1', 'Gene', (112, 115))	('inversions', 'Var', (74, 84))	('ERN1', 'Gene', (99, 103))	('a', 'Gene', '351', (23, 24))	('a', 'Gene', '351', (46, 47))	('a', 'Gene', '351', (105, 106))	('deletions', 'Var', (29, 38))	('a', 'Gene', '351', (85, 86))	('BRCA2', 'Gene', '675', (92, 97))
19821	32533757	As the C122G mutation renders p53 nonfunctional [51], it is likely that a new subclone arose by loss of the mutated allele.	('A', 'Gene', '351', (0, 1))	('C122G', 'SUBSTITUTION', 'None', (7, 12))	('a', 'Gene', '351', (87, 88))	('a', 'Gene', '351', (69, 70))	('a', 'Gene', '351', (72, 73))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (45, 46))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('a', 'Gene', '351', (116, 117))	('a', 'Gene', '351', (16, 17))	('C122G', 'Var', (7, 12))
19833	32533757	As shown in Table 1, we found the same SNVs in spheroids from ascites and OCMI cells, that is, in RAD51D in OCMI38 (T99A; 14% in spheroids; 49% in OCMI cells), in ADAMTS7 in OC122 (N1071S and Y1078fs; 17 and 18% in spheroids; 14 and 17% in OCMI cells), and in TP53 (R248W; 93% in spheroids; 96% in OCMI cells).	('Y1078fs', 'FRAMESHIFT', 'None', (192, 199))	('OC', 'Phenotype', 'HP:0025318', (108, 110))	('N1071S', 'Var', (181, 187))	('OC', 'Gene', '632', (298, 300))	('spheroids', 'Chemical', '-', (215, 224))	('a', 'Gene', '351', (229, 230))	('OC', 'Gene', '632', (147, 149))	('spheroids', 'Chemical', '-', (47, 56))	('T99A', 'Var', (116, 120))	('A', 'Gene', '351', (163, 164))	('ascites', 'Phenotype', 'HP:0001541', (62, 69))	('a', 'Gene', '351', (253, 254))	('A', 'Gene', '351', (99, 100))	('TP53', 'Gene', (260, 264))	('OC', 'Phenotype', 'HP:0025318', (147, 149))	('RAD51D', 'Gene', '5892', (98, 104))	('OC', 'Gene', '632', (74, 76))	('a', 'Gene', '351', (70, 71))	('a', 'Gene', '351', (62, 63))	('RAD', 'biological_process', 'GO:1990116', ('98', '101'))	('a', 'Gene', '351', (204, 205))	('OC', 'Gene', '632', (240, 242))	('OC', 'Phenotype', 'HP:0025318', (74, 76))	('T99A', 'SUBSTITUTION', 'None', (116, 120))	('ADAMTS7', 'Gene', '11173', (163, 170))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (188, 189))	('a', 'Gene', '351', (13, 14))	('spheroids', 'Chemical', '-', (280, 289))	('OC', 'Phenotype', 'HP:0025318', (240, 242))	('spheroids', 'Chemical', '-', (129, 138))	('OC', 'Gene', '632', (174, 176))	('ascites', 'Disease', (62, 69))	('ADAMTS7', 'Gene', (163, 170))	('OC', 'Phenotype', 'HP:0025318', (174, 176))	('N1071S', 'SUBSTITUTION', 'None', (181, 187))	('R248W', 'Var', (266, 271))	('A', 'Gene', '351', (165, 166))	('TP53', 'Gene', '7157', (260, 264))	('Y1078fs', 'Var', (192, 199))	('A', 'Gene', '351', (119, 120))	('RAD51D', 'Gene', (98, 104))	('R248W', 'SUBSTITUTION', 'None', (266, 271))	('a', 'Gene', '351', (35, 36))	('ascites', 'Disease', 'MESH:D001201', (62, 69))	('OC', 'Gene', '632', (108, 110))	('a', 'Gene', '351', (88, 89))
19834	32533757	The TP53 SNV in spheroids from patient 122 (C277G) was not detected in OCMI122 cells, in contrast to the ADAMTS7-mutated allele.	('TP53', 'Gene', (4, 8))	('ADAMTS7', 'Gene', '11173', (105, 112))	('a', 'Gene', '351', (121, 122))	('a', 'Gene', '351', (52, 53))	('spheroids', 'Chemical', '-', (16, 25))	('a', 'Gene', '351', (94, 95))	('C277G', 'Var', (44, 49))	('patient', 'Species', '9606', (31, 38))	('TP53', 'Gene', '7157', (4, 8))	('a', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (116, 117))	('C277G', 'SUBSTITUTION', 'None', (44, 49))	('OC', 'Phenotype', 'HP:0025318', (71, 73))	('ADAMTS7', 'Gene', (105, 112))	('OC', 'Gene', '632', (71, 73))
19837	32533757	A similar situation seems to exist for patient OC38, where an NF1 deletion was found in metastases with a frequency of 10-32%, but was not detectable in OCMI38 cells (not shown), whereas the same RAD51D mutation was detected in all samples with the highest frequency in cultured cells (10-32% in metastases and spheroids; 49% in OCMI38 cells).	('OC', 'Gene', '632', (329, 331))	('a', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (302, 303))	('metastases', 'Disease', 'MESH:D009362', (296, 306))	('a', 'Gene', '351', (104, 105))	('NF1', 'Gene', (62, 65))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('OC', 'Phenotype', 'HP:0025318', (329, 331))	('OC', 'Gene', '632', (153, 155))	('a', 'Gene', '351', (40, 41))	('metastases', 'Disease', (296, 306))	('a', 'Gene', '351', (213, 214))	('RAD51D', 'Gene', (196, 202))	('metastases', 'Disease', (88, 98))	('a', 'Gene', '351', (206, 207))	('a', 'Gene', '351', (14, 15))	('OC', 'Phenotype', 'HP:0025318', (153, 155))	('a', 'Gene', '351', (7, 8))	('a', 'Gene', '351', (94, 95))	('a', 'Gene', '351', (228, 229))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (59, 60))	('patient', 'Species', '9606', (39, 46))	('a', 'Gene', '351', (307, 308))	('a', 'Gene', '351', (76, 77))	('a', 'Gene', '351', (299, 300))	('a', 'Gene', '351', (132, 133))	('a', 'Gene', '351', (91, 92))	('a', 'Gene', '351', (233, 234))	('RAD51D', 'Gene', '5892', (196, 202))	('OC', 'Gene', '632', (47, 49))	('RAD', 'biological_process', 'GO:1990116', ('196', '199'))	('spheroids', 'Chemical', '-', (311, 320))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (184, 185))	('NF1', 'Gene', '4763', (62, 65))	('A', 'Gene', '351', (197, 198))	('OC', 'Phenotype', 'HP:0025318', (47, 49))	('deletion', 'Var', (66, 74))
19838	32533757	The C277G SNV in TP53 in OCMI122 cells is a loss-of-function mutation [51], which might explain its low frequency in some metastases and its loss in the OCMI122 cell population.	('a', 'Gene', '351', (64, 65))	('a', 'Gene', '351', (133, 134))	('OC', 'Phenotype', 'HP:0025318', (25, 27))	('a', 'Gene', '351', (42, 43))	('OC', 'Phenotype', 'HP:0025318', (153, 155))	('a', 'Gene', '351', (125, 126))	('OC', 'Gene', '632', (25, 27))	('a', 'Gene', '351', (128, 129))	('metastases', 'Disease', (122, 132))	('a', 'Gene', '351', (171, 172))	('C277G', 'Var', (4, 9))	('loss-of-function', 'NegReg', (44, 60))	('C277G', 'SUBSTITUTION', 'None', (4, 9))	('OC', 'Gene', '632', (153, 155))	('a', 'Gene', '351', (92, 93))	('TP53', 'Gene', '7157', (17, 21))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('TP53', 'Gene', (17, 21))
19839	32533757	In contrast, the R248W SNV found in OC137 spheroids (Table 1) is a known hot spot driver mutation in HGSC [54], and accordingly, mutated (stabilized) p53 protein was found in OCMI137 cells as opposed to OCMI38 cells with wild-type TP53 (Fig.	('OC', 'Gene', '632', (36, 38))	('R248W', 'Var', (17, 22))	('TP53', 'Gene', '7157', (231, 235))	('a', 'Gene', '351', (65, 66))	('R248W', 'SUBSTITUTION', 'None', (17, 22))	('p53', 'Gene', '7157', (150, 153))	('a', 'Gene', '351', (8, 9))	('OC', 'Phenotype', 'HP:0025318', (36, 38))	('a', 'Gene', '351', (189, 190))	('p53', 'Gene', (150, 153))	('a', 'Gene', '351', (116, 117))	('a', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (140, 141))	('a', 'Gene', '351', (54, 55))	('OC', 'Gene', '632', (175, 177))	('a', 'Gene', '351', (163, 164))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('a', 'Gene', '351', (132, 133))	('TP53', 'Gene', (231, 235))	('spheroids', 'Chemical', '-', (42, 51))	('protein', 'Protein', (154, 161))	('OC', 'Phenotype', 'HP:0025318', (203, 205))	('OC', 'Phenotype', 'HP:0025318', (175, 177))	('OC', 'Gene', '632', (203, 205))	('a', 'Gene', '351', (112, 113))
19879	32533757	To this end, we evaluated the data from the PRECOG and KM Plotter meta-analyses [49, 50] and The Cancer Genome Atlas (TCGA) dataset [43], which consistently revealed a strong association of high CALB2 or PDPN expression with a short relapse-free survival (RFS) and overall survival of HGSC, while no significant link of survival to the epithelial markers EPCAM, MUC16, and PAX8 (included for comparison) was observed (Fig.	('a', 'Gene', '351', (89, 90))	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('A', 'Gene', '351', (196, 197))	('expression', 'MPA', (209, 219))	('a', 'Gene', '351', (166, 167))	('a', 'Gene', '351', (73, 74))	('a', 'Gene', '351', (396, 397))	('a', 'Gene', '351', (279, 280))	('PDPN', 'Gene', (204, 208))	('a', 'Gene', '351', (71, 72))	('EPCAM', 'Gene', (355, 360))	('a', 'Gene', '351', (308, 309))	('high', 'Var', (190, 194))	('a', 'Gene', '351', (181, 182))	('a', 'Gene', '351', (127, 128))	('a', 'Gene', '351', (31, 32))	('RFS', 'Disease', 'MESH:D005198', (256, 259))	('A', 'Gene', '351', (121, 122))	('MUC16', 'Gene', (362, 367))	('a', 'Gene', '351', (261, 262))	('a', 'Gene', '351', (269, 270))	('a', 'Gene', '351', (125, 126))	('a', 'Gene', '351', (348, 349))	('a', 'Gene', '351', (252, 253))	('a', 'Gene', '351', (236, 237))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('A', 'Gene', '351', (374, 375))	('a', 'Gene', '351', (21, 22))	('PAX8', 'Gene', (373, 377))	('CALB2', 'Gene', '794', (195, 200))	('a', 'Gene', '351', (69, 70))	('A', 'Gene', '351', (111, 112))	('CALB2', 'Gene', (195, 200))	('A', 'Gene', '351', (358, 359))	('a', 'Gene', '351', (225, 226))	('a', 'Gene', '351', (369, 370))	('PDPN', 'Gene', '10630', (204, 208))	('PAX8', 'Gene', '7849', (373, 377))	('a', 'Gene', '351', (98, 99))	('Cancer', 'Disease', (97, 103))	('RFS', 'Disease', (256, 259))	('a', 'Gene', '351', (161, 162))	('a', 'Gene', '351', (18, 19))	('EPCAM', 'Gene', '4072', (355, 360))	('a', 'Gene', '351', (51, 52))	('a', 'Gene', '351', (344, 345))	('a', 'Gene', '351', (33, 34))	('a', 'Gene', '351', (114, 115))	('MUC16', 'Gene', '94025', (362, 367))	('a', 'Gene', '351', (326, 327))	('a', 'Gene', '351', (405, 406))	('a', 'Gene', '351', (175, 176))
19884	32533757	While high CALB2 or PDPN expression in several other carcinomas, including breast cancer, was associated with a poor prognosis, the OS of other cancers, in particular hematologic malignancies, showed the opposite association.	('carcinomas', 'Disease', (53, 63))	('a', 'Gene', '351', (78, 79))	('a', 'Gene', '351', (157, 158))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('a', 'Gene', '351', (213, 214))	('PDPN', 'Gene', (20, 24))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (110, 111))	('high', 'Var', (6, 10))	('a', 'Gene', '351', (94, 95))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('a', 'Gene', '351', (61, 62))	('a', 'Gene', '351', (54, 55))	('a', 'Gene', '351', (219, 220))	('a', 'Gene', '351', (83, 84))	('a', 'Gene', '351', (164, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('a', 'Gene', '351', (100, 101))	('a', 'Gene', '351', (170, 171))	('carcinomas', 'Disease', 'MESH:D009369', (53, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('a', 'Gene', '351', (91, 92))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('a', 'Gene', '351', (44, 45))	('a', 'Gene', '351', (185, 186))	('breast cancer', 'Disease', (75, 88))	('PDPN', 'Gene', '10630', (20, 24))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('a', 'Gene', '351', (145, 146))	('malignancies', 'Disease', (179, 191))	('CALB2', 'Gene', '794', (11, 16))	('CALB2', 'Gene', (11, 16))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
19892	32533757	8), indicating that the loss of calretinin expression did not induce cell death in these cells.	('loss', 'Var', (24, 28))	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('a', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (9, 10))	('a', 'Gene', '351', (76, 77))	('calretinin', 'Gene', (32, 42))	('a', 'Gene', '351', (33, 34))	('calretinin', 'Gene', '794', (32, 42))
19903	32533757	Likewise, ADAMTS8 was altered by SNVs in the majority of patients (6/10; in 3 cases simultaneously at 2 different sites), while 8 other loci were affected in a smaller subset of patients (1-5 out of 10).	('a', 'Gene', '351', (179, 180))	('a', 'Gene', '351', (79, 80))	('a', 'Gene', '351', (158, 159))	('a', 'Gene', '351', (58, 59))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (146, 147))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (178, 186))	('SNVs', 'Var', (33, 37))	('ADAMTS8', 'Gene', '11095', (10, 17))	('a', 'Gene', '351', (162, 163))	('ADAMTS8', 'Gene', (10, 17))	('a', 'Gene', '351', (19, 20))	('a', 'Gene', '351', (46, 47))	('a', 'Gene', '351', (22, 23))	('a', 'Gene', '351', (99, 100))
19926	32533757	On the one hand, genetic alterations of TP53 are considered one of the earliest events driving HGSC tumorigenesis [56], which is consistent with our observation of TP53 SNVs in 90% of the patients, including both hot spot and inactivating mutations and indels.	('a', 'Gene', '351', (25, 26))	('tumor', 'Disease', (100, 105))	('a', 'Gene', '351', (72, 73))	('patients', 'Species', '9606', (188, 196))	('TP53', 'Gene', '7157', (40, 44))	('a', 'Gene', '351', (222, 223))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('TP53', 'Gene', (164, 168))	('a', 'Gene', '351', (189, 190))	('a', 'Gene', '351', (228, 229))	('a', 'Gene', '351', (30, 31))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('a', 'Gene', '351', (155, 156))	('indels', 'Var', (253, 259))	('rat', 'Species', '10116', (29, 32))	('a', 'Gene', '351', (45, 46))	('TP53', 'Gene', (40, 44))	('a', 'Gene', '351', (12, 13))	('a', 'Gene', '351', (249, 250))	('a', 'Gene', '351', (242, 243))	('TP53', 'Gene', '7157', (164, 168))	('a', 'Gene', '351', (233, 234))
19928	32533757	One possible explanation for this observation could be the loss of variant alleles with nonessential functions in metastasis formation, such as the inactivating C277G TP53 variant in patient OC122, which appears to be absent from a large fraction of tumor cells even within the same metastasis (Fig.	('a', 'Gene', '351', (120, 121))	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (286, 287))	('a', 'Gene', '351', (279, 280))	('TP53', 'Gene', '7157', (167, 171))	('patient', 'Species', '9606', (183, 190))	('a', 'Gene', '351', (71, 72))	('tumor', 'Disease', (250, 255))	('a', 'Gene', '351', (40, 41))	('a', 'Gene', '351', (150, 151))	('a', 'Gene', '351', (117, 118))	('a', 'Gene', '351', (141, 142))	('a', 'Gene', '351', (204, 205))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('a', 'Gene', '351', (173, 174))	('OC', 'Gene', '632', (191, 193))	('a', 'Gene', '351', (155, 156))	('OC', 'Phenotype', 'HP:0025318', (191, 193))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('C277G', 'Var', (161, 166))	('a', 'Gene', '351', (19, 20))	('C277G', 'SUBSTITUTION', 'None', (161, 166))	('a', 'Gene', '351', (218, 219))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('a', 'Gene', '351', (75, 76))	('a', 'Gene', '351', (98, 99))	('TP53', 'Gene', (167, 171))	('a', 'Gene', '351', (240, 241))	('a', 'Gene', '351', (68, 69))	('a', 'Gene', '351', (233, 234))	('a', 'Gene', '351', (184, 185))	('a', 'Gene', '351', (176, 177))	('a', 'Gene', '351', (208, 209))	('a', 'Gene', '351', (289, 290))	('a', 'Gene', '351', (230, 231))
19933	32533757	Several lines of evidence suggest that the increase in calretinin and podoplanin expression is relevant to peritoneal dissemination: (a) A similar pattern of upregulated mesenchymal and mesothelial genes was identified in metastatic lesions compared with spheroids from ascites; (b) immunostaining revealed calretinin staining in a subset of cancer cells in HGSC metastases with preference for the invasive tumor front; (c) a high expression of CALB2 or PDPN is strongly associated with a short RFS and OS; and (d) CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I.	('a', 'Gene', '351', (343, 344))	('PDPN', 'Gene', '10630', (454, 458))	('calretinin', 'Gene', (307, 317))	('a', 'Gene', '351', (302, 303))	('a', 'Gene', '351', (48, 49))	('cancer', 'Disease', (342, 348))	('a', 'Gene', '351', (477, 478))	('a', 'Gene', '351', (588, 589))	('a', 'Gene', '351', (56, 57))	('a', 'Gene', '351', (245, 246))	('RFS', 'Disease', 'MESH:D005198', (495, 498))	('podoplanin', 'Gene', '10630', (70, 80))	('a', 'Gene', '351', (308, 309))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('a', 'Gene', '351', (270, 271))	('a', 'Gene', '351', (507, 508))	('a', 'Gene', '351', (134, 135))	('a', 'Gene', '351', (165, 166))	('calretinin', 'Gene', '794', (55, 65))	('inhibited', 'NegReg', (592, 601))	('CALB2', 'Gene', '794', (445, 450))	('a', 'Gene', '351', (126, 127))	('a', 'Gene', '351', (548, 549))	('a', 'Gene', '351', (182, 183))	('collagen', 'molecular_function', 'GO:0005202', ('641', '649'))	('a', 'Gene', '351', (499, 500))	('CALB2', 'Gene', (445, 450))	('silencing', 'Var', (521, 530))	('CALB2', 'Gene', '794', (515, 520))	('a', 'Gene', '351', (205, 206))	('a', 'Gene', '351', (228, 229))	('a', 'Gene', '351', (401, 402))	('calretinin', 'Gene', '794', (307, 317))	('a', 'Gene', '351', (291, 292))	('ascites', 'Disease', (270, 277))	('podoplanin', 'Gene', (70, 80))	('a', 'Gene', '351', (195, 196))	('A', 'Gene', '351', (137, 138))	('CALB2', 'Gene', (515, 520))	('invasive tumor', 'Disease', (398, 412))	('PDPN', 'Gene', (454, 458))	('a', 'Gene', '351', (179, 180))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('A', 'Gene', '351', (446, 447))	('A', 'Gene', '351', (516, 517))	('a', 'Gene', '351', (330, 331))	('a', 'Gene', '351', (606, 607))	('a', 'Gene', '351', (100, 101))	('a', 'Gene', '351', (115, 116))	('RFS', 'Disease', (495, 498))	('a', 'Gene', '351', (76, 77))	('a', 'Gene', '351', (225, 226))	('a', 'Gene', '351', (369, 370))	('a', 'Gene', '351', (148, 149))	('a', 'Gene', '351', (424, 425))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (36, 37))	('a', 'Gene', '351', (487, 488))	('invasive tumor', 'Disease', 'MESH:D009361', (398, 412))	('metastases', 'Disease', 'MESH:D009362', (363, 373))	('a', 'Gene', '351', (559, 560))	('a', 'Gene', '351', (621, 622))	('a', 'Gene', '351', (645, 646))	('calretinin', 'Gene', (55, 65))	('ascites', 'Disease', 'MESH:D001201', (270, 277))	('a', 'Gene', '351', (471, 472))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (320, 321))	('metastases', 'Disease', (363, 373))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('spheroids', 'Chemical', '-', (255, 264))	('a', 'Gene', '351', (366, 367))	('a', 'Gene', '351', (144, 145))	('ascites', 'Phenotype', 'HP:0001541', (270, 277))
19962	32533757	We did not observe direct effects of CALB2 silencing on cell viability, although a fraction of OCMI cells died after detaching from the culture dish.	('CALB2', 'Gene', '794', (37, 42))	('a', 'Gene', '351', (120, 121))	('OC', 'Gene', '632', (95, 97))	('a', 'Gene', '351', (63, 64))	('CALB2', 'Gene', (37, 42))	('a', 'Gene', '351', (72, 73))	('a', 'Gene', '351', (111, 112))	('silencing', 'Var', (43, 52))	('died', 'Disease', (106, 110))	('OC', 'Phenotype', 'HP:0025318', (95, 97))	('died', 'Disease', 'MESH:D003643', (106, 110))	('a', 'Gene', '351', (81, 82))	('a', 'Gene', '351', (85, 86))
19980	32533757	Intriguingly, high CALB2 or PDPN expression was strongly associated with a poor clinical outcome, and calretinin expression was observed at the invasive tumor edges of HGSC metastases.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (63, 64))	('a', 'Gene', '351', (103, 104))	('a', 'Gene', '351', (73, 74))	('expression', 'MPA', (33, 43))	('PDPN', 'Gene', (28, 32))	('calretinin', 'Gene', '794', (102, 112))	('a', 'Gene', '351', (125, 126))	('a', 'Gene', '351', (86, 87))	('high', 'Var', (14, 18))	('invasive tumor', 'Disease', (144, 158))	('a', 'Gene', '351', (179, 180))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('a', 'Gene', '351', (45, 46))	('invasive tumor', 'Disease', 'MESH:D009361', (144, 158))	('a', 'Gene', '351', (98, 99))	('CALB2', 'Gene', '794', (19, 24))	('a', 'Gene', '351', (147, 148))	('CALB2', 'Gene', (19, 24))	('metastases', 'Disease', (173, 183))	('PDPN', 'Gene', '10630', (28, 32))	('a', 'Gene', '351', (176, 177))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('a', 'Gene', '351', (57, 58))	('calretinin', 'Gene', (102, 112))
19981	32533757	Furthermore, silencing of CALB2 inhibited the adhesion of detached HGSC cells to a collagen type I matrix.	('CALB2', 'Gene', '794', (26, 31))	('inhibited', 'NegReg', (32, 41))	('a', 'Gene', '351', (87, 88))	('CALB2', 'Gene', (26, 31))	('a', 'Gene', '351', (100, 101))	('collagen', 'molecular_function', 'GO:0005202', ('83', '91'))	('a', 'Gene', '351', (46, 47))	('a', 'Gene', '351', (61, 62))	('a', 'Gene', '351', (81, 82))	('silencing', 'Var', (13, 22))
20013	32438515	For instance, profiling molecular alterations and mutations in tumors allows identification of the molecular targets suitable for specific treatments and subsequent development of drug treatments specific to an individual patient.	('men', 'Species', '9606', (144, 147))	('mutations', 'Var', (50, 59))	('patient', 'Species', '9606', (222, 229))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('men', 'Species', '9606', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('alterations', 'Var', (34, 45))	('men', 'Species', '9606', (172, 175))
20038	32438515	The cutoff level for an aberrant ALK, RET, and ROS1 FISH was >=15% of cells with a split-apart signal.	('ROS1', 'Gene', (47, 51))	('ALK', 'Gene', (33, 36))	('RET', 'Gene', '5979', (38, 41))	('ROS1', 'Gene', '6098', (47, 51))	('aberrant', 'Var', (24, 32))	('ALK', 'Gene', '238', (33, 36))	('RET', 'Gene', (38, 41))
20060	32438515	None of the patients had copy number alterations or MSI high status.	('MSI', 'Gene', (52, 55))	('patients', 'Species', '9606', (12, 20))	('copy number alterations', 'Var', (25, 48))	('MSI', 'Gene', '5928', (52, 55))
20098	32438515	performed a comprehensive genomic analysis of pleural MM and identified frequent mutations in BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51.	('DDX51', 'Gene', '317781', (157, 162))	('CFAP45', 'Gene', '25790', (137, 143))	('pleural MM', 'Disease', (46, 56))	('mutations', 'Var', (81, 90))	('CFAP45', 'Gene', (137, 143))	('BAP1', 'Gene', '8314', (94, 98))	('DDX3X', 'Gene', (118, 123))	('NF2', 'Gene', '4771', (100, 103))	('TP53', 'Gene', (105, 109))	('SETD2', 'Gene', (111, 116))	('NF2', 'Gene', (100, 103))	('RYR', 'cellular_component', 'GO:1990425', ('131', '134'))	('pleural MM', 'Disease', 'MESH:D010995', (46, 56))	('DDX3X', 'Gene', '1654', (118, 123))	('SETDB1', 'Gene', (145, 151))	('ULK2', 'Gene', '9706', (125, 129))	('BAP1', 'Gene', (94, 98))	('SETD2', 'Gene', '29072', (111, 116))	('SETDB1', 'Gene', '9869', (145, 151))	('RYR2', 'Gene', (131, 135))	('ULK2', 'Gene', (125, 129))	('RYR2', 'Gene', '6262', (131, 135))	('TP53', 'Gene', '7157', (105, 109))	('DDX51', 'Gene', (157, 162))
20099	32438515	They found that recurrent gene fusions and splice alterations were frequently the underlying reasons for the inactivation of NF2, BAP1, and SETD2.19 Particularly, inactivation of the tumor suppressor genes NF2 and BAP1 is frequently observed in MM, possibly playing a pivotal role in the tumorigenesis.	('BAP1', 'Gene', (130, 134))	('SETD2', 'Gene', '29072', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('NF2', 'Gene', '4771', (206, 209))	('inactivation', 'Var', (163, 175))	('BAP1', 'Gene', '8314', (214, 218))	('NF2', 'Gene', (206, 209))	('NF2', 'Gene', '4771', (125, 128))	('BAP1', 'Gene', (214, 218))	('tumor', 'Disease', (288, 293))	('NF2', 'Gene', (125, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('183', '199'))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Disease', (183, 188))	('BAP1', 'Gene', '8314', (130, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('183', '199'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('SETD2', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))
20144	31032152	The presence of certain autoimmune antibodies has also been associated with certain malignancies without any underlying rheumatologic processes.	('malignancies', 'Disease', (84, 96))	('autoimmune antibodies', 'Phenotype', 'HP:0002960', (24, 45))	('presence', 'Var', (4, 12))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('associated', 'Reg', (60, 70))
20191	31032152	In 2010, a study published in Saudi Arabia evaluated patients with positive anti-dsDNA antibodies to explore potentially non SLE-related etiologies.	('patients', 'Species', '9606', (53, 61))	('SLE', 'Disease', 'MESH:D008180', (125, 128))	('SLE', 'Disease', (125, 128))	('SLE', 'Phenotype', 'HP:0002725', (125, 128))	('anti-dsDNA', 'Gene', (76, 86))	('antibodies', 'Var', (87, 97))
20199	31032152	Typically, anti-histone antibodies are associated with drug-induced lupus erythematosus (DILE).	('lupus erythematosus', 'Phenotype', 'HP:0002725', (68, 87))	('anti-histone', 'Protein', (11, 23))	('antibodies', 'Var', (24, 34))	('associated', 'Reg', (39, 49))	('drug-induced lupus erythematosus', 'Disease', 'MESH:D008180', (55, 87))	('drug-induced lupus erythematosus', 'Disease', (55, 87))
20226	31032152	Anti-dsDNA antibodies and AHA could potentially be considered false positives or attributed to malignancy.	('AHA', 'Disease', (26, 29))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('false', 'biological_process', 'GO:0071877', ('62', '67'))	('antibodies', 'Var', (11, 21))	('Anti-dsDNA', 'Disease', (0, 10))	('malignancy', 'Disease', (95, 105))	('false', 'biological_process', 'GO:0071878', ('62', '67'))
20339	30914057	While the initial 2011 report of frequent somatic inactivation in PlM of the gene encoding the ubiquitin carboxyl-terminal hydrolase BAP1 was followed by the finding that PeM shows a similar high prevalence of BAP1 alterations, PeM also shows some genetic differences, notably a lower prevalence of losses of other tumor suppressors:CDKN2A and NF2:than PlM.	('PeM', 'Phenotype', 'HP:0100003', (228, 231))	('BAP1', 'Gene', (210, 214))	('BAP1', 'Gene', '8314', (210, 214))	('NF2', 'Gene', (344, 347))	('alterations', 'Var', (215, 226))	('CDKN2A', 'Gene', (333, 339))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('PlM', 'Phenotype', 'HP:0100002', (353, 356))	('BAP1', 'Gene', '8314', (133, 137))	('ubiquitin', 'molecular_function', 'GO:0031386', ('95', '104'))	('PlM', 'Phenotype', 'HP:0100002', (66, 69))	('CDKN2A', 'Gene', '1029', (333, 339))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('PeM', 'Phenotype', 'HP:0100003', (171, 174))	('NF2', 'Gene', '4771', (344, 347))	('inactivation', 'Var', (50, 62))	('BAP1', 'Gene', (133, 137))	('tumor', 'Disease', (315, 320))
20340	30914057	Somatic BAP1 mutations are also seen not infrequently in carcinomas of the kidney and intrahepatic bile ducts and in ocular melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('ocular melanomas', 'Phenotype', 'HP:0025534', (117, 133))	('ocular melanomas', 'Disease', 'MESH:D008545', (117, 133))	('BAP1', 'Gene', '8314', (8, 12))	('ocular melanomas', 'Disease', (117, 133))	('carcinomas of the kidney and intrahepatic bile', 'Disease', 'MESH:D002780', (57, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
20364	30914057	In this respect, the proximity of BAP1 and PBRM1 and their frequent co-inactivation (or co-haploinsufficiency) in PeM might represent a confounding factor in these analyses as recent studies in other cancers have demonstrated that loss of PBRM1 is associated with increased T cell infiltration and response to ICI therapy.	('PeM', 'Phenotype', 'HP:0100003', (114, 117))	('PBRM1', 'Gene', (43, 48))	('haploinsufficiency', 'Disease', 'MESH:D058495', (91, 109))	('T cell infiltration', 'CPA', (274, 293))	('BAP1', 'Gene', (34, 38))	('increased', 'PosReg', (264, 273))	('PBRM1', 'Gene', '55193', (239, 244))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('increased T cell', 'Phenotype', 'HP:0100828', (264, 280))	('response', 'CPA', (298, 306))	('cancers', 'Disease', (200, 207))	('PBRM1', 'Gene', '55193', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('loss', 'Var', (231, 235))	('haploinsufficiency', 'Disease', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('BAP1', 'Gene', '8314', (34, 38))	('PBRM1', 'Gene', (239, 244))
20369	30914057	ICI Immune checkpoint inhibitor PeM Peritoneal mesothelioma PlM Pleural mesothelioma TMB Tumor mutational burden ML and MZ wrote the manuscript.	('Tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Pleural mesothelioma', 'Phenotype', 'HP:0100002', (64, 84))	('PlM', 'Phenotype', 'HP:0100002', (60, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('PeM', 'Phenotype', 'HP:0100003', (32, 35))	('Peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (36, 59))	('mesothelioma', 'Disease', (72, 84))	('ML', 'Disease', 'MESH:C537366', (113, 115))	('Pleural mesothelioma', 'Disease', 'MESH:D008654', (64, 84))	('Pleural mesothelioma', 'Disease', (64, 84))	('mutational', 'Var', (95, 105))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('mesothelioma', 'Disease', (47, 59))	('TMB', 'Chemical', '-', (85, 88))
20373	24154601	We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells.	('mesothelin', 'Gene', (141, 151))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (200, 216))	('advanced mesothelioma', 'Disease', 'MESH:D008654', (97, 118))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mesothelin', 'Gene', '10232', (141, 151))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('pentostatin', 'Chemical', 'MESH:D015649', (184, 195))	('SS1P', 'Chemical', 'MESH:C474515', (164, 168))	('SS1P', 'Var', (164, 168))	('advanced mesothelioma', 'Disease', (97, 118))
20381	24154601	SS1P is a recombinant immunotoxin consisting of an anti-mesothelin variable fragment linked to PE38, a portion of Pseudomonas exotoxin A, and it is cytotoxic to mesothelin-expressing cell lines.	('PE38', 'Var', (95, 99))	('mesothelin', 'Gene', (56, 66))	('mesothelin', 'Gene', '10232', (161, 171))	('mesothelin', 'Gene', '10232', (56, 66))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('mesothelin', 'Gene', (161, 171))	('SS1P', 'Gene', (0, 4))
20386	24154601	In these phase 1 trials, SS1P showed only minor antitumor activity, with none of the 36 patients with mesothelioma having an objective partial tumor response.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mesothelioma', 'Disease', (102, 114))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (52, 57))	('patients', 'Species', '9606', (88, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('SS1P', 'Chemical', 'MESH:C474515', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('SS1P', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
20412	24154601	Rapid reduction in the size of tumors in the neck, chest, abdomen, and pelvis was noted after only two cycles of SS1P (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('neck', 'cellular_component', 'GO:0044326', ('45', '49'))	('SS1P', 'Var', (113, 117))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SS1P', 'Chemical', 'MESH:C474515', (113, 117))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('reduction', 'NegReg', (6, 15))
20413	24154601	Continued tumor response was observed after cycle 4, when further treatment was discontinued because of development of anti-SS1P antibodies.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('anti-SS1P', 'Var', (119, 128))	('anti-SS1P', 'Gene', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SS1P', 'Chemical', 'MESH:C474515', (124, 128))
20417	24154601	Although marked tumor reductions were seen on CT scan after two cycles of SS1P (Fig.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SS1P', 'Var', (74, 78))	('reductions', 'NegReg', (22, 32))	('SS1P', 'Chemical', 'MESH:C474515', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))
20431	24154601	3B), showed a significant increase in tumor metabolic activity with a SULpeak/cm3 of 660 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SULpeak/cm3 of 660', 'Var', (70, 88))	('increase', 'PosReg', (26, 34))
20451	24154601	Pentostatin and cyclophosphamide produced lymphopenia without much myelosuppression.	('myelosuppression', 'Disease', (67, 83))	('lymphopenia', 'Phenotype', 'HP:0001888', (42, 53))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (16, 32))	('Pentostatin', 'Chemical', 'MESH:D015649', (0, 11))	('lymphopenia', 'Disease', 'MESH:D008231', (42, 53))	('cyclophosphamide', 'Var', (16, 32))	('myelosuppression', 'Disease', 'MESH:D001855', (67, 83))	('lymphopenia', 'Disease', (42, 53))
20459	24154601	These results suggest that in addition to the two patients (patients 4 and 11) who developed antibodies at the end of cycle 1, two other patients (patients 7 and 10) developed anti-SS1P antibodies before receiving cycle 2, accounting for low serum SS1P levels in these patients.	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (60, 68))	('serum SS1P levels', 'MPA', (242, 259))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (147, 155))	('SS1P', 'Chemical', 'MESH:C474515', (181, 185))	('low', 'NegReg', (238, 241))	('anti-SS1P', 'Var', (176, 185))	('SS1P', 'Chemical', 'MESH:C474515', (248, 252))	('patients', 'Species', '9606', (269, 277))
20461	24154601	The serum levels of SS1P were 100-fold higher than the concentration (1 ng/ml) at which cytotoxic activity was observed against mesothelin-expressing human tumor cells.	('human', 'Species', '9606', (150, 155))	('higher', 'PosReg', (39, 45))	('mesothelin', 'Gene', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mesothelin', 'Gene', '10232', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('SS1P', 'Chemical', 'MESH:C474515', (20, 24))	('tumor', 'Disease', (156, 161))	('SS1P', 'Var', (20, 24))	('serum levels', 'MPA', (4, 16))
20523	26680231	Of particular note, MexTAg mesothelioma development was not dependent on cdkn2 deletion.	('mesothelioma', 'Disease', (27, 39))	('cdkn2', 'Gene', '1029', (73, 78))	('MexTAg', 'Chemical', '-', (20, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('cdkn2', 'Gene', (73, 78))	('deletion', 'Var', (79, 87))
20538	26680231	Mutations in the tumour suppressors p53 and retinoblastoma (RB) family and the oncogenic ras family occur at a considerably lower frequency in mesothelioma compared to other cancer types.	('mesothelioma', 'Disease', (143, 155))	('retinoblastoma', 'Phenotype', 'HP:0009919', (44, 58))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('RB', 'Phenotype', 'HP:0009919', (60, 62))	('p53', 'Gene', (36, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Mutations', 'Var', (0, 9))	('RB', 'Gene', (60, 62))	('tumour', 'Disease', (17, 23))	('p53', 'Gene', '22060', (36, 39))	('retinoblastoma', 'Disease', 'MESH:D012175', (44, 58))	('retinoblastoma', 'Disease', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
20547	26680231	The lines, denoted high TAg (hiTAg), intermediate TAg (intTAg) and single TAg (sTAg) have 100, 32 or single copy of the TAg transgene, respectively.	('TAg', 'Gene', '404663', (74, 77))	('TAg', 'Gene', (58, 61))	('TAg', 'Gene', '404663', (24, 27))	('TAg', 'Gene', (120, 123))	('TAg', 'Gene', '404663', (50, 53))	('TAg', 'Gene', '404663', (58, 61))	('TAg', 'Gene', (31, 34))	('TAg', 'Gene', '404663', (120, 123))	('TAg', 'Gene', (24, 27))	('TAg', 'Gene', '404663', (31, 34))	('TAg', 'Gene', (80, 83))	('TAg', 'Gene', (50, 53))	('single copy', 'Var', (101, 112))	('TAg', 'Gene', (74, 77))	('TAg', 'Gene', '404663', (80, 83))
20548	26680231	All of the high copy MexTAg mice rapidly develop mesothelioma after asbestos exposure compared to approximately 20-30 % of wild-type mice which develop mesothelioma over a much longer time span.	('mice', 'Species', '10090', (133, 137))	('asbestos', 'Chemical', 'MESH:D001194', (68, 76))	('develop', 'PosReg', (41, 48))	('mesothelioma', 'Disease', (49, 61))	('mice', 'Species', '10090', (28, 32))	('MexTAg', 'Chemical', '-', (21, 27))	('mesothelioma', 'Disease', (152, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (49, 61))	('high copy', 'Var', (11, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))
20604	26680231	However, as the frequency of deletion of these genes is around 20-50 % of human mesotheliomas, we would not logically expect to find a deletion in the sample size of 6 tumours used in this study.	('human', 'Species', '9606', (74, 79))	('deletion', 'Var', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('mesotheliomas', 'Disease', 'MESH:D008654', (80, 93))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('mesotheliomas', 'Disease', (80, 93))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('tumours', 'Disease', (168, 175))
20610	26680231	It was noted earlier that p16 expression levels were higher in TAg tumours and TAg mesothelial cells compared to wild type mesotheliomas, due to deletion of the cdkN2A locus in the latter samples.	('higher', 'PosReg', (53, 59))	('cdkN2A', 'Gene', (161, 167))	('TAg', 'Gene', (63, 66))	('p16 expression levels', 'MPA', (26, 47))	('cdkN2A', 'Gene', '12578', (161, 167))	('TAg', 'Gene', (79, 82))	('TAg tumours', 'Disease', (63, 74))	('type mesotheliomas', 'Disease', 'MESH:D008654', (118, 136))	('type mesotheliomas', 'Disease', (118, 136))	('TAg', 'Gene', '404663', (63, 66))	('TAg tumours', 'Disease', 'MESH:C566904', (63, 74))	('TAg', 'Gene', '404663', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('deletion', 'Var', (145, 153))
20643	26680231	This is reflective of human mesothelioma whereby deletion of the cdkn2 locus on chromosome 9p21.3 encoding the cyclin dependent kinase inhibitors p16 and p15 is common (up to 80 % of mesothelioma cases) and is thought to be a primary driver of mesothelioma development.	('p21', 'Gene', '12575', (92, 95))	('cdkn2', 'Gene', (65, 70))	('mesothelioma', 'Disease', (244, 256))	('mesothelioma', 'Disease', (28, 40))	('mesothelioma', 'Disease', (183, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('mesothelioma', 'Disease', 'MESH:D008654', (244, 256))	('deletion', 'Var', (49, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('human', 'Species', '9606', (22, 27))	('cdkn2', 'Gene', '1029', (65, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('p21', 'Gene', (92, 95))
20644	26680231	Loss of p16 leads to an inability of the cell to phosphorylate RB and activation of the E2F family of transcription factors and increased cell proliferation.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('E2F family of transcription factors', 'Pathway', (88, 123))	('increased', 'PosReg', (128, 137))	('rat', 'Species', '10116', (150, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('p16', 'Gene', (8, 11))	('cell proliferation', 'CPA', (138, 156))	('inability', 'NegReg', (24, 33))	('RB', 'Phenotype', 'HP:0009919', (63, 65))	('Loss', 'Var', (0, 4))	('activation', 'PosReg', (70, 80))
20648	26680231	Thus implying the changes in gene expression observed in the TAg positive mesotheliomas mimic deletion of p16.	('deletion', 'Var', (94, 102))	('TAg', 'Gene', (61, 64))	('p16', 'Gene', (106, 109))	('TAg', 'Gene', '404663', (61, 64))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('mesotheliomas', 'Disease', 'MESH:D008654', (74, 87))	('mesotheliomas', 'Disease', (74, 87))	('changes', 'Reg', (18, 25))	('gene expression', 'MPA', (29, 44))
20650	26680231	The similarities of MexTAg mesotheliomas at both molecular and functional levels with WT mouse mesotheliomas and their lack of dependence on deletion of p16, suggests that additional, as yet unidentified, genetic changes are required downstream of p16 loss for mesothelioma development.	('mesothelioma', 'Disease', (27, 39))	('deletion', 'Var', (141, 149))	('p16', 'Gene', (153, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('mesotheliomas', 'Disease', 'MESH:D008654', (27, 40))	('mesotheliomas', 'Disease', (27, 40))	('mesothelioma', 'Disease', (261, 273))	('MexTAg', 'Chemical', '-', (20, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('p16', 'Gene', (248, 251))	('loss', 'NegReg', (252, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (261, 273))	('WT', 'Disease', 'MESH:C536751', (86, 88))	('mesotheliomas', 'Disease', 'MESH:D008654', (95, 108))	('mesotheliomas', 'Disease', (95, 108))	('mouse', 'Species', '10090', (89, 94))	('mesothelioma', 'Disease', (95, 107))
20662	26680231	While this could be a consequence of large T antigen, activation of this particular cell signalling cascade, has previously been associated with mesothelioma.	('T antigen', 'Protein', (43, 52))	('associated', 'Reg', (129, 139))	('large', 'Var', (37, 42))	('activation', 'PosReg', (54, 64))	('mesothelioma', 'Disease', (145, 157))	('signalling cascade', 'biological_process', 'GO:0007165', ('89', '107'))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))
20663	26680231	However, mutations in MAP kinase pathway genes, including RAS and PIK3CA are very rare in human mesothelioma.	('MAP', 'molecular_function', 'GO:0004239', ('22', '25'))	('RAS', 'Gene', (58, 61))	('mesothelioma', 'Disease', (96, 108))	('mutations', 'Var', (9, 18))	('PIK3CA', 'Gene', (66, 72))	('human', 'Species', '9606', (90, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('PIK3CA', 'Gene', '5290', (66, 72))
20732	26253127	The authors suggest that performing SPECT or SPECT/TC imaging would improve the sensitivity of diagnosis with the planar images of SRS and propose that the images with Ga 68 peptide may offer better results in localizing ectopic ACTH-producing tumors than those peformed with In 111 octreotide.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('ACTH', 'Gene', (229, 233))	('improve', 'PosReg', (68, 75))	('octreotide', 'Chemical', 'MESH:D015282', (283, 293))	('ACTH', 'Gene', '5443', (229, 233))	('sensitivity', 'MPA', (80, 91))	('Ga 68 peptide', 'Var', (168, 181))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('SRS', 'Chemical', '-', (131, 134))
20739	26253127	Although most patients with ectopic ACTH secretion have plasma levels that are considerably greater than normal, there are also reports of cases with normal or mildly elevated ACTH; these cases generally have a gradual progression and are associated to poorly aggressive carcinoid tumors.	('associated', 'Reg', (239, 249))	('ACTH', 'Gene', (36, 40))	('plasma levels', 'MPA', (56, 69))	('aggressive carcinoid tumors', 'Disease', 'MESH:D002276', (260, 287))	('ACTH secretion', 'biological_process', 'GO:0051458', ('36', '50'))	('ACTH', 'Gene', '5443', (36, 40))	('ACTH', 'Gene', '5443', (176, 180))	('mildly elevated ACTH', 'Phenotype', 'HP:0008180', (160, 180))	('carcinoid', 'Phenotype', 'HP:0100570', (271, 280))	('ectopic', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('elevated ACTH', 'Phenotype', 'HP:0003154', (167, 180))	('aggressive carcinoid tumors', 'Disease', (260, 287))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('greater', 'PosReg', (92, 99))	('ACTH', 'Gene', (176, 180))	('patients', 'Species', '9606', (14, 22))
20747	23867514	PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer.	('Renal Cell Carcinoma', 'Disease', (36, 56))	('renal cancer', 'Disease', (165, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('BAP1', 'Gene', (10, 14))	('renal cancer', 'Phenotype', 'HP:0009726', (165, 177))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('renal cancer', 'Disease', 'MESH:D007680', (165, 177))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (36, 56))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('mutated', 'Var', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('BAP1', 'Gene', '8314', (10, 14))
20756	23867514	We discovered that PBRM1 mutations tend to anti-correlate with BAP1 mutations in ccRCC, and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('mutations', 'Var', (25, 34))	('RCC', 'Disease', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BAP1', 'Gene', (63, 67))	('tumors', 'Disease', (121, 127))	('anti-correlate', 'NegReg', (43, 57))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('associated', 'Reg', (162, 172))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (68, 77))	('PBRM1', 'Gene', (19, 24))
20760	23867514	The following year, the same group reported frequent VHL mutations in sporadic ccRCC.	('VHL', 'Disease', (53, 56))	('VHL', 'Disease', 'MESH:D006623', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('mutations', 'Var', (57, 66))
20771	23867514	Thus, with a single deletion, renal cells lose one copy of 4 tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('deletion', 'Var', (20, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Disease', (61, 66))	('lose', 'NegReg', (42, 46))
20774	23867514	Meta-analyses show that the frequency of SETD2 mutations in ccRCC is twice as high in tumors with PBRM1 mutations.	('PBRM1', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (104, 113))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SETD2', 'Gene', '29072', (41, 46))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('SETD2', 'Gene', (41, 46))
20776	23867514	Mutations acquired early during the process of tumorigenesis are ubiquitous, whereas those acquired at very late stages are private, with shared mutations in between.	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
20777	23867514	VHL and PBRM1 mutations may be acquired early, whereas BAP1 and SETD2 mutations may occur later.	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('BAP1', 'Gene', (55, 59))	('SETD2', 'Gene', '29072', (64, 69))	('VHL', 'Disease', (0, 3))	('SETD2', 'Gene', (64, 69))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
20778	23867514	In some ccRCC, there are different mutations in SETD2 and this convergence may be explained by cooperation between PBRM1 and SETD2.	('mutations', 'Var', (35, 44))	('SETD2', 'Gene', '29072', (48, 53))	('SETD2', 'Gene', '29072', (125, 130))	('SETD2', 'Gene', (48, 53))	('RCC', 'Disease', (10, 13))	('SETD2', 'Gene', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
20779	23867514	The finding that PBRM1 and BAP1 mutations are largely exclusive and that tumors with these mutations exhibit different biology and are associated with markedly different overall survival (OS) set the foundation for the first molecular genetic classification of sporadic ccRCC.	('RCC', 'Disease', (272, 275))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('BAP1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PBRM1', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('associated', 'Reg', (135, 145))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (272, 275))
20781	23867514	Exome sequencing of 7 ccRCC and matched normal tissues by the Sanger Institute identified truncating mutations in PBRM1 (Polybromo 1) in 4 tumors.	('RCC', 'Disease', (24, 27))	('Polybromo 1', 'Gene', '55193', (121, 132))	('Polybromo 1', 'Gene', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('truncating mutations', 'Var', (90, 110))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('PBRM1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
20783	23867514	The PBRM1 gene is located on chromosome 3p21 and in 38 tumors examined, PBRM1 mutations were uniformly associated with loss of heterozygosity (LOH).	('p21', 'Gene', (41, 44))	('p21', 'Gene', '644914', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (78, 87))	('PBRM1', 'Gene', (72, 77))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('loss', 'NegReg', (119, 123))
20784	23867514	PBRM1 mutations occurred most often together with VHL mutations and nearly all of the PBRM1-mutant tumors that Varela et al., examined (36/38) exhibited a hypoxia signature, including some cases without a detectable VHL mutation.	('VHL', 'Disease', (50, 53))	('PBRM1-mutant', 'Var', (86, 98))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('VHL', 'Disease', (216, 219))	('PBRM1', 'Gene', (0, 5))	('VHL', 'Disease', 'MESH:D006623', (216, 219))	('PBRM1-mutant', 'Gene', (86, 98))	('hypoxia', 'Disease', 'MESH:D000860', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('hypoxia', 'Disease', (155, 162))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('VHL', 'Disease', 'MESH:D006623', (50, 53))	('mutations', 'Var', (6, 15))	('exhibited', 'Reg', (143, 152))
20785	23867514	These data suggest that PBRM1 mutations are often associated with loss of VHL.	('loss', 'NegReg', (66, 70))	('PBRM1', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('associated', 'Reg', (50, 60))	('VHL', 'Disease', (74, 77))	('VHL', 'Disease', 'MESH:D006623', (74, 77))
20788	23867514	PBRM1 mutation in ccRCC was initially reported to portend aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (58, 72))	('aggressiveness', 'Disease', (58, 72))	('PBRM1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (58, 72))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('portend', 'PosReg', (50, 57))	('RCC', 'Disease', (20, 23))
20789	23867514	However, more recent reports suggest that PBRM1 mutations are found in tumors at similar rates regardless of stage, and PBRM1 mutations appear not to adversely impact patient survival.	('impact', 'Reg', (160, 166))	('PBRM1', 'Gene', (120, 125))	('patient', 'Species', '9606', (167, 174))	('PBRM1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
20801	23867514	The importance of bromodomains and BAH domains for BAF180 tumor suppressor function is highlighted by their being frequent targets of missense mutations in renal cancer.	('BAF180', 'Gene', (51, 57))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BAF180', 'Gene', '55193', (51, 57))	('missense mutations', 'Var', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('renal cancer', 'Disease', (156, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('renal cancer', 'Disease', 'MESH:D007680', (156, 168))	('renal cancer', 'Phenotype', 'HP:0009726', (156, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
20802	23867514	While these domains are highly structured and missense mutations may inactivate BAF180 by disrupting folding and protein stability, there is precedent for a missense mutation in a bromodomain not affecting BAF180 levels.	('missense mutations', 'Var', (46, 64))	('BAF180', 'Gene', '55193', (80, 86))	('BAF180', 'Gene', '55193', (206, 212))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('folding', 'MPA', (101, 108))	('protein stability', 'CPA', (113, 130))	('inactivate', 'NegReg', (69, 79))	('disrupting', 'NegReg', (90, 100))	('missense mutation', 'Var', (157, 174))	('BAF180', 'Gene', (80, 86))	('BAF180', 'Gene', (206, 212))
20803	23867514	Should other such mutations be found, the data would suggest that each bromodomain may be required for BAF180 tumor suppressor function.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAF180', 'Gene', '55193', (103, 109))	('mutations', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('BAF180', 'Gene', (103, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
20806	23867514	In addition, ARID1A and ARID1B, which encode the putative targeting subunits of the BAF complex, are also mutated in renal cancer (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/ and http://cancergenome.nih.gov/).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (138, 144))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1B', 'Gene', '57492', (24, 30))	('renal cancer', 'Disease', (117, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (158, 164))	('renal cancer', 'Disease', 'MESH:D007680', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('mutated', 'Var', (106, 113))	('ARID1A', 'Gene', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (123, 129))	('ARID1B', 'Gene', (24, 30))
20807	23867514	These mutations are not exclusive with PBRM1 mutations, suggesting that mutations in these genes may cooperate in tumorigenesis.	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('cooperate', 'Reg', (101, 110))	('PBRM1', 'Gene', (39, 44))
20809	23867514	In addition, the catalytic subunits, and in particular BRG1, which forms part of both the BAF and PBAF complexes, are targeted by mutation in ccRCC (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/ and http://cancergenome.nih.gov/).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('BRG1', 'Gene', '6597', (55, 59))	('mutation', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('RCC', 'Disease', (144, 147))	('BRG1', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
20810	23867514	Other subunits mutated in ccRCC include BAF170, BAF60A and BAF47.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('BAF47', 'Gene', '6598', (59, 64))	('BAF170', 'Gene', '6601', (40, 46))	('BAF47', 'Gene', (59, 64))	('BAF60A', 'Gene', '6602', (48, 54))	('mutated', 'Var', (15, 22))	('BAF170', 'Gene', (40, 46))	('BAF60A', 'Gene', (48, 54))	('RCC', 'Disease', (28, 31))
20812	23867514	The mutation of other subunits suggests that SWI/SNF function is important, but it is conceivable that BAF180 may be implicated in other processes.	('implicated', 'Reg', (117, 127))	('BAF180', 'Gene', '55193', (103, 109))	('mutation', 'Var', (4, 12))	('BAF180', 'Gene', (103, 109))
20820	23867514	Conversely, mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone.	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PBRM1', 'Gene', (25, 30))	('SETD2', 'Gene', (35, 40))	('SETD2', 'Gene', '29072', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
20822	23867514	Interestingly, mutations in SETD2 in tumors are associated with loss of DNA methylation at non-promoter regions.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('mutations', 'Var', (15, 24))	('DNA methylation at non-promoter regions', 'MPA', (72, 111))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('loss', 'NegReg', (64, 68))	('SETD2', 'Gene', '29072', (28, 33))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('tumors', 'Disease', (37, 43))	('SETD2', 'Gene', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
20823	23867514	A greater understanding of the cooperativity between PBRM1 and SETD2 mutations may identify opportunities for therapeutic intervention.	('SETD2', 'Gene', '29072', (63, 68))	('mutations', 'Var', (69, 78))	('SETD2', 'Gene', (63, 68))	('PBRM1', 'Gene', (53, 58))
20829	23867514	Smarca4+/- mice develop mammary tumors, albeit at low penetrance.	('mammary', 'Disease', (24, 31))	('mice', 'Species', '10090', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Smarca4+/-', 'Var', (0, 10))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
20832	23867514	In addition, conditional biallelic inactivation of Smarcb1 in lymphocytes causes lymphoma with 100% penetrance and a short latency.	('lymphoma', 'Disease', (81, 89))	('causes', 'Reg', (74, 80))	('biallelic inactivation', 'Var', (25, 47))	('lymphoma', 'Disease', 'MESH:D008223', (81, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('Smarcb1', 'Gene', (51, 58))
20834	23867514	PBRM1 knockdown in 4/5 RCC cell lines increased proliferation and the cell line with discrepant results was PBRM1-deficient.	('PBRM1-deficient', 'Disease', (108, 123))	('proliferation', 'CPA', (48, 61))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('knockdown', 'Var', (6, 15))	('increased', 'PosReg', (38, 47))	('PBRM1-deficient', 'Disease', 'MESH:D007153', (108, 123))
20835	23867514	The development of therapies exploiting the loss of PBRM1 in renal cancer will be facilitated by a greater understanding of the molecular mechanism of BAF180 tumor suppressor action.	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('PBRM1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('loss', 'Var', (44, 48))	('BAF180', 'Gene', (151, 157))	('renal cancer', 'Disease', (61, 73))	('BAF180', 'Gene', '55193', (151, 157))
20841	23867514	A screen in Drosophila for suppressors of a PcG mutant identified the orthologue of BRM/BRG1 in flies, brm.	('PcG', 'Gene', (44, 47))	('mutant', 'Var', (48, 54))	('PcG', 'Gene', '40358', (44, 47))	('Drosophila', 'Species', '7227', (12, 22))	('BRG1', 'Gene', (88, 92))	('BRG1', 'Gene', '6597', (88, 92))
20842	23867514	Heterozygous mutations (or deficiencies) in brm suppressed homeotic transformations (alterations in body patterning) induced by a polycomb loss-of-function mutation.	('brm', 'Gene', (44, 47))	('polycomb', 'Gene', (130, 138))	('body patterning', 'CPA', (100, 115))	('polycomb', 'Gene', '40358', (130, 138))	('suppressed', 'NegReg', (48, 58))	('homeotic transformations', 'CPA', (59, 83))	('loss-of-function', 'NegReg', (139, 155))	('mutation', 'Var', (156, 164))
20843	23867514	These data suggest that the derepression of gene expression induced by a polycomb gene mutation involves BRM/BRG1 and nucleosome remodeling.	('gene expression', 'MPA', (44, 59))	('BRG1', 'Gene', (109, 113))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('polycomb', 'Gene', (73, 81))	('nucleosome', 'cellular_component', 'GO:0000786', ('118', '128'))	('derepression', 'PosReg', (28, 40))	('BRG1', 'Gene', '6597', (109, 113))	('polycomb', 'Gene', '40358', (73, 81))	('mutation', 'Var', (87, 95))
20844	23867514	Loss of SMARCB1, frequently observed in malignant rhabdoid tumors, results in PRC2-dependent repression of p16.	('SMARCB1', 'Gene', '6598', (8, 15))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (40, 65))	('SMARCB1', 'Gene', (8, 15))	('p16', 'Gene', '1029', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PRC2-dependent repression', 'MPA', (78, 103))	('p16', 'Gene', (107, 110))	('malignant rhabdoid tumors', 'Disease', (40, 65))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
20846	23867514	Furthermore, PRC2 appears to play a critical role in tumorigenesis following Smarcb1 inactivation.	('inactivation', 'Var', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Smarcb1', 'Gene', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
20847	23867514	Lymphoma development in mice with conditional biallelic inactivation of Smarcb1 is suppressed by simultaneous inactivation of Ezh2, which encodes the catalytic subunit of PRC2.	('mice', 'Species', '10090', (24, 28))	('Smarcb1', 'Gene', (72, 79))	('Ezh2', 'Gene', (126, 130))	('inactivation', 'Var', (110, 122))	('Ezh2', 'Gene', '14056', (126, 130))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))	('biallelic inactivation', 'Var', (46, 68))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('suppressed', 'NegReg', (83, 93))	('Lymphoma', 'Disease', (0, 8))
20851	23867514	Whether loss of PBRM1 would similarly activate EZH2 and sensitize RCC to EZH2 inhibitors remains to be determined.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('EZH2', 'Gene', '2146', (47, 51))	('EZH2', 'Gene', (47, 51))	('EZH2', 'Gene', '2146', (73, 77))	('activate', 'PosReg', (38, 46))	('EZH2', 'Gene', (73, 77))	('loss', 'Var', (8, 12))	('RCC', 'Disease', (66, 69))	('PBRM1', 'Gene', (16, 21))
20853	23867514	In addition, the preferential mutation of PBRM1 over SMARCB1 in ccRCC further suggests that they are not equivalent.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('SMARCB1', 'Gene', '6598', (53, 60))	('mutation', 'Var', (30, 38))	('PBRM1', 'Gene', (42, 47))	('SMARCB1', 'Gene', (53, 60))	('RCC', 'Disease', (66, 69))
20856	23867514	Knock-down of EZH2 reduces cell proliferation, and causes apoptosis in a subset of RCC cell lines.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('EZH2', 'Gene', (14, 18))	('cell proliferation', 'CPA', (27, 45))	('Knock-down', 'Var', (0, 10))	('EZH2', 'Gene', '2146', (14, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('causes', 'Reg', (51, 57))	('apoptosis', 'CPA', (58, 67))	('reduces', 'NegReg', (19, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
20858	23867514	Of note, the one cell line that did not undergo apoptosis in response to EZH2 knock-down, 769-P, is BAP1 mutant.	('knock-down', 'Var', (78, 88))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('BAP1', 'Gene', (100, 104))	('EZH2', 'Gene', '2146', (73, 77))	('EZH2', 'Gene', (73, 77))	('mutant', 'Var', (105, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
20864	23867514	Assuming a fixed mutation rate per nucleotide, given the size of the coding sequence, SMARCC1 would be expected to be mutated by chance at 70% of the frequency of PBRM1.	('SMARCC1', 'Gene', (86, 93))	('mutated', 'Var', (118, 125))	('SMARCC1', 'Gene', '6599', (86, 93))
20865	23867514	However, SMARCC1 mutations in ccRCC are exceedingly rare (0 mutations in 459 ccRCC sequenced; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('SMARCC1', 'Gene', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('SMARCC1', 'Gene', '6599', (9, 16))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (12, 15))	('RCC', 'Disease', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
20866	23867514	These data suggest that mutations in SMARCC1 and PBRM1 are non-equivalent, and raise the possibility that SMARCC1 mutations would be detrimental for ccRCC.	('mutations', 'Var', (114, 123))	('detrimental', 'NegReg', (133, 144))	('SMARCC1', 'Gene', (37, 44))	('RCC', 'Disease', (40, 43))	('SMARCC1', 'Gene', '6599', (37, 44))	('SMARCC1', 'Gene', (106, 113))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('SMARCC1', 'Gene', '6599', (106, 113))	('PBRM1', 'Gene', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('mutations', 'Var', (24, 33))
20869	23867514	The lack of mutations in SMARCC1 raise the possibility that SMARCC1 may be required for ccRCC survival.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('SMARCC1', 'Gene', (60, 67))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('mutations', 'Var', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('SMARCC1', 'Gene', '6599', (60, 67))	('SMARCC1', 'Gene', (25, 32))	('SMARCC1', 'Gene', '6599', (25, 32))	('RCC', 'Disease', (28, 31))	('RCC', 'Disease', (90, 93))
20870	23867514	Interestingly, inactivation of another SWI/SNF gene, Smarca4 (encoding Brg1) abrogates lymphomas arising from biallelic loss of Smarcb1.	('Smarcb1', 'Gene', (128, 135))	('lymphomas', 'Disease', 'MESH:D008223', (87, 96))	('Smarca4', 'Gene', (53, 60))	('abrogates', 'NegReg', (77, 86))	('lymphomas', 'Disease', (87, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('inactivation', 'Var', (15, 27))
20871	23867514	Thus, inactivation of SWI/SNF complexes may be a viable approach for cancer therapy.	('inactivation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('SWI/SNF complexes', 'Protein', (22, 39))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
20872	23867514	SWI/SNF complexes may be broadly required for cell survival, but in the case of ccRCC with 3p deletions, the loss of one SMARCC1 allele may sensitize tumor cells to this approach.	('RCC', 'Disease', (124, 127))	('SMARCC1', 'Gene', '6599', (121, 128))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('loss', 'Var', (109, 113))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sensitize', 'Reg', (140, 149))	('tumor', 'Disease', (150, 155))	('SMARCC1', 'Gene', (121, 128))
20874	23867514	While the function of BAF180 at the kinetochore is not well understood, mutations in kinetochore components may sensitize cells to microtubule-destabilizing drugs.	('mutations', 'Var', (72, 81))	('BAF180', 'Gene', (22, 28))	('BAF180', 'Gene', '55193', (22, 28))	('sensitize', 'Reg', (112, 121))	('microtubule', 'cellular_component', 'GO:0005874', ('131', '142'))	('kinetochore', 'cellular_component', 'GO:0000776', ('85', '96'))	('kinetochore', 'cellular_component', 'GO:0000776', ('36', '47'))
20875	23867514	BRCA1 associated protein-1 (BAP1) was identified in a yeast two-hybrid screen for proteins that interacted with the RING finger of BRCA1.	('BRCA1', 'Gene', (0, 5))	('yeast', 'Species', '4932', (54, 59))	('BRCA1', 'Gene', '672', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('RING finger', 'Var', (116, 127))	('BRCA1', 'Gene', (131, 136))	('BRCA1', 'Gene', '672', (0, 5))
20880	23867514	An analysis of multiple lung cancer cell lines identified a cell line with biallelic inactivation suggesting that BAP1 may be a two-hit tumor suppressor gene.	('multiple lung cancer', 'Disease', (15, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('multiple lung cancer', 'Disease', 'MESH:D008175', (15, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('BAP1', 'Gene', (114, 118))	('biallelic inactivation', 'Var', (75, 97))	('tumor', 'Disease', (136, 141))
20881	23867514	In NCI-H226, where BAP1 suppresses cell proliferation, ectopic BAP1 expression also inhibited tumor formation in xenografts.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAP1', 'Gene', (63, 67))	('tumor', 'Disease', (94, 99))	('cell proliferation', 'CPA', (35, 53))	('suppresses', 'NegReg', (24, 34))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('ectopic', 'Var', (55, 62))	('NCI-H226', 'CellLine', 'CVCL:1544', (3, 11))	('inhibited', 'NegReg', (84, 93))
20882	23867514	BAP1 mutations in tumors were first identified in a search for metastasis-related genes in uveal melanoma (UM).	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('uveal melanoma', 'Disease', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
20883	23867514	Loss of chromosome 3 is the most important cytogenetic predictor of UM metastases, and Harbour et al., embarked on exome sequencing of two metastatic UM with chromosome 3 loss.	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('metastases', 'Disease', (71, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('loss', 'NegReg', (171, 175))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('Loss', 'Var', (0, 4))
20884	23867514	BAP1 sequencing of a larger UM cohort showed BAP1 mutations in 84% of metastasizing UM, but in 4% of non-metastasizing tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('BAP1', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (50, 59))	('tumors', 'Disease', (119, 125))	('metastasizing UM', 'Disease', (70, 86))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
20885	23867514	In non-metastasizing tumors, BAP1 localized to the nucleus and BAP1 knockdown in a UM cell line caused epithelioid changes and cell rounding, reproducing features observed in metastasizing UM.	('caused', 'Reg', (96, 102))	('UM', 'Phenotype', 'HP:0007716', (189, 191))	('BAP1', 'Gene', (63, 67))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('nucleus', 'cellular_component', 'GO:0005634', ('51', '58'))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('epithelioid changes', 'CPA', (103, 122))	('knockdown', 'Var', (68, 77))	('BAP1', 'Gene', (29, 33))	('cell rounding', 'CPA', (127, 140))
20886	23867514	A year later, BAP1 mutations were reported in 23% of malignant pleural mesotheliomas (MPMs).	('malignant pleural mesotheliomas', 'Disease', (53, 84))	('BAP1', 'Gene', (14, 18))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (63, 84))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (53, 84))	('mutations', 'Var', (19, 28))
20888	23867514	However, other investigators have postulated an inverse relationship between BAP1 and NF2 mutations.	('NF2', 'Gene', (86, 89))	('mutations', 'Var', (90, 99))	('NF2', 'Gene', '4771', (86, 89))	('inverse', 'NegReg', (48, 55))	('BAP1', 'Gene', (77, 81))
20893	23867514	In addition, BAP1 was found to be mutated in 1/10 ccRCC cell lines examined.	('RCC', 'Disease', (52, 55))	('BAP1', 'Gene', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('mutated', 'Var', (34, 41))
20895	23867514	Two tumors had mutations in BAP1 and subsequent analyses of BAP1 in 168 matched ccRCC/normal pairs identified 22 tumors with additional mutations.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', (4, 10))	('BAP1', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
20897	23867514	Overall, BAP1 loss (either by mutation or IHC) was observed in 15% of ccRCC (25/168).	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (9, 13))	('loss', 'NegReg', (14, 18))
20899	23867514	BAP1 mutation rates increase as a function of stage suggesting that BAP1 may be implicated in ccRCC progression.	('RCC', 'Disease', (96, 99))	('BAP1', 'Gene', (0, 4))	('implicated', 'Reg', (80, 90))	('mutation', 'Var', (5, 13))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
20901	23867514	Interestingly, mutations in BAP1 and PBRM1 in ccRCC tend to be mutually exclusive.	('PBRM1', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', (48, 51))
20902	23867514	First, whereas BAP1 mutations in tumors are associated with high Fuhrman grade and mTORC1 activation, PBRM1 mutations are associated with low grade and a lack of mTORC1 activation.	('BAP1', 'Gene', (15, 19))	('activation', 'PosReg', (90, 100))	('mutations', 'Var', (108, 117))	('mTORC1', 'Gene', (162, 168))	('PBRM1', 'Gene', (102, 107))	('mTORC1', 'Gene', '382056', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('high Fuhrman grade', 'MPA', (60, 78))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mTORC1', 'Gene', '382056', (162, 168))	('mTORC1', 'cellular_component', 'GO:0031931', ('83', '89'))	('tumors', 'Disease', (33, 39))	('mTORC1', 'cellular_component', 'GO:0031931', ('162', '168'))	('mutations', 'Var', (20, 29))	('mTORC1', 'Gene', (83, 89))
20903	23867514	In addition, BAP1 and PBRM1 mutations in ccRCC are associated with characteristic and non-overlapping gene expression signatures.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('BAP1', 'Gene', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutations', 'Var', (28, 37))	('PBRM1', 'Gene', (22, 27))
20904	23867514	Finally, the outcomes of patients with ccRCCs mutated for BAP1 and PBRM1 is quite different.	('BAP1', 'Gene', (58, 62))	('mutated', 'Var', (46, 53))	('patients', 'Species', '9606', (25, 33))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('PBRM1', 'Gene', (67, 72))
20905	23867514	Thus, these data suggest that BAP1 and PBRM1 mutations define two different molecular subtypes of ccRCC, with different biology and outcomes.	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', (30, 34))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('PBRM1', 'Gene', (39, 44))
20906	23867514	Kaplan-Meier analyses of patients with BAP1- and PBRM1-mutated tumors showed that BAP1 mutation was associated with a significantly worse OS than that PBRM1 mutation (median OS of 4.6 years; 95% CI 2.1-7.2 vs. 10.6 years; 95% CI 9.8-11.5) corresponding to a hazard ratio (HR) of 2.7 (95% CI 0.99-7.6, p=0.044).	('BAP1', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutation', 'Var', (87, 95))
20911	23867514	Somatically-acquired mutations in BAP1 have been identified at low frequencies (<2%) in tumors from other sites including breast, lung, uterus, large bowel, ovary and prostate (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('BAP1', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate', 'Disease', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('bowel', 'Disease', 'MESH:D015212', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('breast', 'Disease', (122, 128))	('ovary', 'Disease', (157, 162))	('cancer', 'Disease', (204, 210))	('uterus', 'Disease', (136, 142))	('ovary', 'Disease', 'MESH:D010051', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('large bowel', 'Phenotype', 'HP:0002037', (144, 155))	('mutations', 'Var', (21, 30))	('bowel', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('lung', 'Disease', (130, 134))
20912	23867514	During their studies, Harbour et al., discovered a BAP1 frameshift mutation in the germline of a patient with UM suggesting that BAP1 mutations may also predispose to familial UM.. BAP1 was subsequently found to be mutated in affected individuals of two families with a syndrome of autosomal dominant inheritance characterized by uveal and cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (340, 359))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (340, 359))	('BAP1', 'Gene', (181, 185))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('cutaneous melanomas', 'Disease', (340, 359))	('melanomas', 'Phenotype', 'HP:0002861', (350, 359))	('mutated', 'Var', (215, 222))	('melanoma', 'Phenotype', 'HP:0002861', (350, 358))	('patient', 'Species', '9606', (97, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (340, 358))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
20913	23867514	The estimated frequency of germline BAP1 mutations in patients with familial cutaneous melanoma is <1%, but this percentage is higher for families with both cutaneous and uveal melanoma.	('mutations', 'Var', (41, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('patients', 'Species', '9606', (54, 62))	('cutaneous', 'Disease', (157, 166))	('familial cutaneous melanoma', 'Disease', (68, 95))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('uveal melanoma', 'Disease', (171, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))	('BAP1', 'Gene', (36, 40))	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
20917	23867514	Germline BAP1 mutations were also discovered in families with a high incidence of mesothelioma.	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('discovered', 'Reg', (34, 44))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
20918	23867514	Families with germline BAP1 mutations exhibit a variety of other tumors including lung and breast cancers.	('lung', 'Disease', (82, 86))	('BAP1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('exhibit', 'Reg', (38, 45))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('germline', 'Var', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancers', 'Phenotype', 'HP:0003002', (91, 105))	('breast cancers', 'Disease', 'MESH:D001943', (91, 105))	('breast cancers', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mutations', 'Var', (28, 37))
20922	23867514	During our search for somatically-acquired BAP1 mutations in ccRCC, a germline BAP1 missense variant was discovered in one patient who was found to have familial RCC suggesting that BAP1 mutations may predispose to renal cancer as well.	('RCC', 'Disease', (63, 66))	('BAP1', 'Gene', (43, 47))	('renal cancer', 'Disease', 'MESH:D007680', (215, 227))	('RCC', 'Disease', (162, 165))	('patient', 'Species', '9606', (123, 130))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('BAP1', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('familial RCC', 'Disease', 'MESH:C538614', (153, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (215, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('renal cancer', 'Disease', (215, 227))	('predispose to', 'Reg', (201, 214))	('mutations', 'Var', (48, 57))	('familial RCC', 'Disease', (153, 165))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
20923	23867514	A study of 83 families with an unexplained predisposition to renal cancer revealed a novel missense mutation in BAP1 that cosegregated with the ccRCC phenotype in one family.	('BAP1', 'Gene', (112, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cosegregated', 'Reg', (122, 134))	('renal cancer', 'Disease', (61, 73))	('missense mutation', 'Var', (91, 108))
20928	23867514	In additional studies of 32 unrelated individuals with familial RCC, no more BAP1 mutations were found.	('familial RCC', 'Disease', (55, 67))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', (77, 81))	('familial RCC', 'Disease', 'MESH:C538614', (55, 67))
20931	23867514	The risk of RCC was markedly increased compared to the general population suggesting that BAP1 was a RCC-predisposing gene and that RCC should be added to the list of tumors associated with germline mutations in BAP1.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('germline mutations', 'Var', (190, 208))	('BAP1', 'Gene', (212, 216))	('RCC', 'Disease', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
20939	23867514	BAP1 mutations target residues across the protein, although the UCH domain appears to be targeted particularly frequently (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('UCH', 'Gene', (64, 67))	('BAP1', 'Gene', (0, 4))	('target', 'Reg', (15, 21))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (150, 156))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('UCH', 'Gene', '7345', (64, 67))
20940	23867514	Mapping of missense mutations not affecting protein levels to a BAP1 structure model suggests that BAP1 tumor suppressor function requires not only ubiquitin binding, but also an intramolecular interaction between the UCH and ULD domains.	('ULD', 'Disease', (226, 229))	('UCH', 'Gene', '7345', (218, 221))	('BAP1', 'Gene', (99, 103))	('ubiquitin binding', 'molecular_function', 'GO:0043130', ('148', '165'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('UCH', 'Gene', (218, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('missense', 'Var', (11, 19))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('interaction', 'Interaction', (194, 205))	('ubiquitin', 'MPA', (148, 157))	('binding', 'Interaction', (158, 165))	('ULD', 'Disease', 'MESH:D020194', (226, 229))
20947	23867514	PR-DUB deubiquitylates H2AK119ub1 (K118 in Drosophila), and despite that, at face value, this would antagonize PRC1, PR-DUB seemingly synergizes with PRC1.	('antagonize', 'NegReg', (100, 110))	('H2AK119ub1', 'Var', (23, 33))	('K118', 'Chemical', '-', (35, 39))	('Drosophila', 'Species', '7227', (43, 53))
20950	23867514	Calypso mutant fly embryos failed to suppress HOX genes leading to homeotic transformations characteristic of mutations in PcG genes.	('PcG', 'Gene', (123, 126))	('mutations', 'Var', (110, 119))	('PcG', 'Gene', '40358', (123, 126))	('HOX', 'Gene', (46, 49))	('HOX', 'Gene', '42536', (46, 49))	('homeotic transformations', 'CPA', (67, 91))
20951	23867514	As expected, Calypso/ASX complexes bound to HOX genes by ChIP and calypso and Asx mutant embryos exhibited global increases in H2Aub1 levels.	('ASX', 'Gene', '36612', (21, 24))	('Asx', 'Gene', '36612', (78, 81))	('HOX', 'Gene', '42536', (44, 47))	('H2Aub1 levels', 'MPA', (127, 140))	('bound', 'Interaction', (35, 40))	('increases', 'PosReg', (114, 123))	('ASX', 'Gene', (21, 24))	('HOX', 'Gene', (44, 47))	('Asx', 'Gene', (78, 81))	('calypso', 'Gene', (66, 73))	('mutant', 'Var', (82, 88))
20953	23867514	As Drosophila Calypso, human BAP1 deubiquitylates H2AK119ub1.	('Drosophila Calypso', 'Disease', (3, 21))	('Drosophila Calypso', 'Disease', 'None', (3, 21))	('human', 'Species', '9606', (23, 28))	('deubiquitylates', 'MPA', (34, 49))	('H2AK119ub1', 'Var', (50, 60))
20954	23867514	Furthermore, depletion of BAP1 in uveal melanoma cells increases global H2AK119ub1 levels.	('BAP1', 'Gene', (26, 30))	('global H2AK119ub1 levels', 'MPA', (65, 89))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('depletion', 'Var', (13, 22))	('increases', 'PosReg', (55, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Disease', (34, 48))
20963	23867514	Mutation in the Kelch domain of HCF-1 (P134S) disrupts binding to HBM-containing proteins, and also markedly impairs BAP1 binding.	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('impairs', 'NegReg', (109, 116))	('Mutation', 'Var', (0, 8))	('BAP1', 'Protein', (117, 121))	('HBM-containing proteins', 'Protein', (66, 89))	('binding', 'Interaction', (55, 62))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('disrupts', 'NegReg', (46, 54))	('HCF-1', 'Gene', (32, 37))	('P134S', 'Mutation', 'p.P134S', (39, 44))	('P134S', 'Var', (39, 44))
20972	23867514	Postnatal systemic Bap1 inactivation (using an inducible Cre from a ubiquitously expressed locus) led to the development of myelodysplasia with thrombocytopenia and anemia.	('anemia', 'Phenotype', 'HP:0001903', (165, 171))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (144, 160))	('systemic Bap1', 'Gene', (10, 23))	('inactivation', 'Var', (24, 36))	('thrombocytopenia', 'Disease', (144, 160))	('myelodysplasia', 'Phenotype', 'HP:0002863', (124, 138))	('anemia', 'Disease', (165, 171))	('anemia', 'Disease', 'MESH:D000740', (165, 171))	('myelodysplasia', 'Disease', 'MESH:D009190', (124, 138))	('thrombocytopenia', 'Disease', 'MESH:D013921', (144, 160))	('myelodysplasia', 'Disease', (124, 138))
20973	23867514	Thrombocytopenia developed as early as one week after Bap1 inactivation.	('inactivation', 'Var', (59, 71))	('Thrombocytopenia', 'Disease', (0, 16))	('Thrombocytopenia', 'Phenotype', 'HP:0001873', (0, 16))	('Bap1', 'Gene', (54, 58))	('Thrombocytopenia', 'Disease', 'MESH:D013921', (0, 16))
20979	23867514	In atypical Spitz tumors, which uncommonly have mutations in BRAF, BRAFV600E mutations tend to co-occur with BAP1 mutations.	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', (61, 65))	('BRAFV600E', 'Mutation', 'rs113488022', (67, 76))	('mutations', 'Var', (77, 86))	('Spitz tumors', 'Disease', 'MESH:D018332', (12, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('BAP1', 'Gene', (109, 113))	('Spitz tumors', 'Disease', (12, 24))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
20980	23867514	Among 32 tumors examined, 9 had lost BAP1 expression and 8 of them had mutations in BRAF.	('BRAF', 'Gene', '673', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('expression', 'MPA', (42, 52))	('BRAF', 'Gene', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (71, 80))	('BAP1', 'Protein', (37, 41))	('tumors', 'Disease', (9, 15))	('lost', 'NegReg', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
20981	23867514	In contrast, only one tumor out of 23 without BAP1 expression had a BRAF mutation (p<0.0001).	('BRAF', 'Gene', '673', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('BRAF', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('mutation', 'Var', (73, 81))
20984	23867514	BAP1 reintroduction into two different BAP1-deficient ccRCC cell lines reduced cell growth.	('RCC', 'Disease', (56, 59))	('BAP1', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('BAP1-deficient', 'Gene', (39, 53))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('reintroduction', 'Var', (5, 19))	('reduced', 'NegReg', (71, 78))	('cell growth', 'CPA', (79, 90))
20986	23867514	Mammalian BAP1 deubiquitylates H2AK119ub1, and BAP1 reintroduction into BAP1-deficient ccRCC cell lines affected global levels of H2AK119ub1.	('Mammalian', 'Species', '9606', (0, 9))	('H2AK119ub1', 'MPA', (130, 140))	('RCC', 'Disease', (89, 92))	('affected', 'Reg', (104, 112))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('global levels', 'MPA', (113, 126))	('reintroduction', 'Var', (52, 66))	('BAP1', 'Gene', (47, 51))
21001	23867514	In experiments performed with BAP1-deficient and reconstituted ccRCC cell lines, BAP1 reintroduction reduced the sensitivity of two different cell lines to radiation and the PARP inhibitor olaparib.	('PARP', 'Gene', '1302', (174, 178))	('reintroduction', 'Var', (86, 100))	('BAP1', 'Gene', (81, 85))	('PARP', 'Gene', (174, 178))	('olaparib', 'Chemical', 'MESH:C531550', (189, 197))	('reduced', 'NegReg', (101, 108))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('sensitivity', 'MPA', (113, 124))	('RCC', 'Disease', (65, 68))
21003	23867514	Interestingly, atypical Spitz tumors with BAP1 mutations commonly exhibit a lymphocytic infiltrate.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Spitz tumors', 'Disease', 'MESH:D018332', (24, 36))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('Spitz tumors', 'Disease', (24, 36))	('lymphocytic infiltrate', 'CPA', (76, 98))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
21006	23867514	Valproic acid seemingly counteracted the effects of BAP1 knockdown on H2AK119ub1.	('BAP1', 'Gene', (52, 56))	('Valproic acid', 'Chemical', 'MESH:D014635', (0, 13))	('knockdown', 'Var', (57, 66))
21007	23867514	As determined by the development of dendrites, valproic acid also induced differentiation of tumor cells with BAP1 mutations and shifted the gene expression signature to a more differentiated type.	('valproic acid', 'Chemical', 'MESH:D014635', (47, 60))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('BAP1', 'Gene', (110, 114))	('induced', 'Reg', (66, 73))	('differentiation', 'CPA', (74, 89))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
21012	23867514	The development and evaluation of candidate compounds may be facilitated by the availability of tumorgraft models of renal cancer that reproduce the treatment responsiveness of human RCC, and the availability of mice bearing tumors with BAP1 and PBRM1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PBRM1', 'Gene', (246, 251))	('mice', 'Species', '10090', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('RCC', 'Disease', (183, 186))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('BAP1', 'Gene', (237, 241))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('mutations', 'Var', (252, 261))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('human', 'Species', '9606', (177, 182))	('tumors', 'Disease', (225, 231))	('tumorgraft models of renal cancer', 'Disease', 'MESH:D007680', (96, 129))	('tumorgraft models of renal cancer', 'Disease', (96, 129))
21099	21738614	Additionally, out of ten natural health products (NHPs) assessed during an initial scoping review of the literature for this project, vitamin A had the greatest volume and quality of evidence around its use in lung cancers.	('lung cancers', 'Disease', (210, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('vitamin', 'Var', (134, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('lung cancers', 'Disease', 'MESH:D008175', (210, 222))	('lung cancers', 'Phenotype', 'HP:0100526', (210, 222))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('vitamin A', 'Chemical', 'MESH:D014801', (134, 143))
21184	21738614	Lippman found no significant effects overall, however, lung cancer recurrence and all cause mortality were significantly increased in current smokers receiving isotretinoin compared to placebo, HR 3.11 (95% CI 1.00-9.71) and 4.39 (1.11-17.29) respectively.	('isotretinoin', 'Chemical', 'MESH:D015474', (160, 172))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('increased', 'PosReg', (121, 130))	('isotretinoin', 'Var', (160, 172))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('all cause mortality', 'CPA', (82, 101))
21211	21738614	13CRA was found to decrease elimination of paclitaxel and increase the AUC of the metabolite 6-alfa-hydroxytaxol.	('AUC of the metabolite 6-alfa-hydroxytaxol', 'MPA', (71, 112))	('increase', 'PosReg', (58, 66))	('elimination of paclitaxel', 'MPA', (28, 53))	('decrease', 'NegReg', (19, 27))	('13CRA', 'Var', (0, 5))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('13CRA', 'Chemical', 'MESH:D015474', (0, 5))	('6-alfa-hydroxytaxol', 'Chemical', '-', (93, 112))
21222	21738614	This inconsistency has been confirmed, for instance, in studies of selenium comparing chemoprevention in both complex- or single- carcinogen lung cancer models, wherein selenium was able to prevent lung tumors induced by NNK, but not those caused by exposure to tobacco smoke.	('NNK', 'Chemical', 'MESH:C016583', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('lung tumors', 'Disease', (198, 209))	('lung tumors', 'Phenotype', 'HP:0100526', (198, 209))	('NNK', 'Var', (221, 224))	('carcinogen lung cancer', 'Disease', 'MESH:D008175', (130, 152))	('selenium', 'Chemical', 'MESH:D012643', (169, 177))	('selenium', 'Chemical', 'MESH:D012643', (67, 75))	('tobacco', 'Species', '4097', (262, 269))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung tumors', 'Disease', 'MESH:D008175', (198, 209))	('carcinogen lung cancer', 'Disease', (130, 152))	('prevent', 'NegReg', (190, 197))
21231	21738614	A biomarker study was conducted in a small subgroup of the CARET population to determine the effect of supplementation on target tissue levels: bronchoalveolar lavage showed that while tissue levels of beta carotene increased significantly with supplementation, retinol levels did not; serum levels increased for both.	('beta carotene', 'MPA', (202, 215))	('retinol', 'Chemical', 'MESH:D014801', (262, 269))	('beta carotene', 'Chemical', 'MESH:D019207', (202, 215))	('supplementation', 'Var', (245, 260))
21242	21738614	Also, while CBPs have been shown to impair mitochondrial function, preliminary evidence suggests that retinol may be an essential response modifier and cofactor of mitochondrial energy production.	('retinol', 'Chemical', 'MESH:D014801', (102, 109))	('mitochondrial function', 'MPA', (43, 65))	('impair', 'NegReg', (36, 42))	('CBPs', 'Var', (12, 16))
21247	21738614	In trials conducted in high risk populations comprised of smokers and asbestos workers (n = 2), there were significant increases in lung cancer risk associated with beta carotene supplementation: in the ATBC trial, RR 1.17 (95% CI 1.02 - 1.34), and in the CARET trial 1.36 (1.07 - 1.72).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('beta carotene', 'Protein', (165, 178))	('increases in lung cancer', 'Disease', 'MESH:D008175', (119, 143))	('increases in lung cancer', 'Disease', (119, 143))	('supplementation', 'Var', (179, 194))	('beta carotene', 'Chemical', 'MESH:D019207', (165, 178))	('ATBC', 'Chemical', '-', (203, 207))
21277	33567673	Homozygous deletion of the p16 gene and tumor invasion into fatty tissue are considered the most reliable features of a malignant tumor.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('malignant tumor', 'Disease', 'MESH:D009369', (120, 135))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('p16', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Homozygous deletion', 'Var', (0, 19))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (130, 135))	('malignant tumor', 'Disease', (120, 135))	('p16', 'Gene', '1029', (27, 30))
21282	33567673	Despite the advent of molecular methods, tumor morphology remains the best indicator of an aggressive disease course, as the presence of sarcomatoid differentiation worsens the prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('prognosis', 'MPA', (177, 186))	('tumor', 'Disease', (41, 46))	('presence', 'Var', (125, 133))	('aggressive disease', 'Disease', 'MESH:D001523', (91, 109))	('sarcomatoid', 'Disease', 'MESH:C538614', (137, 148))	('aggressive disease', 'Disease', (91, 109))	('worsens', 'NegReg', (165, 172))	('sarcomatoid', 'Disease', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
21291	33567673	The cell lines have previously been characterized as epithelioid (MeT-5a and Mero-25), sarcomatoid (DM-3) or biphasic (M-14-K, JL-1, STAV-AB, STAV-FCS, ZL34).	('sarcomatoid', 'Disease', (87, 98))	('Mero-25', 'Chemical', '-', (77, 84))	('STAV-AB', 'Chemical', '-', (133, 140))	('ZL34', 'Chemical', '-', (152, 156))	('sarcomatoid', 'Disease', 'MESH:C538614', (87, 98))	('M-14-K', 'Var', (119, 125))
21307	33567673	DM-3, STAV-FCS and JL-1 had well-spread MT ends, whereas M-14-K, STAV-AB and ZL34 had fewer and smaller EB3 positive speckles (Figure S2) In the normal Met-5a cell line, the EB3 clusters had the appearance of arrowheads, similar to focal adhesions.	('ZL34', 'Chemical', '-', (77, 81))	('EB3', 'Gene', (104, 107))	('fewer', 'NegReg', (86, 91))	('smaller', 'NegReg', (96, 103))	('EB3', 'Gene', '22924', (104, 107))	('STAV-AB', 'Chemical', '-', (65, 72))	('M-14-K', 'Var', (57, 63))	('EB3', 'Gene', (174, 177))	('EB3', 'Gene', '22924', (174, 177))
21309	33567673	Taken together, this shows that the microtubules in M-14-K and ZL34 are more prone to be under dynamic instability, which could indicate an increased migratory state.	('M-14-K', 'Var', (52, 58))	('microtubules', 'Protein', (36, 48))	('migratory', 'CPA', (150, 159))	('ZL34', 'Chemical', '-', (63, 67))	('prone', 'Reg', (77, 82))	('increased', 'PosReg', (140, 149))	('ZL34', 'Gene', (63, 67))
21326	33567673	Four cell lines had equal amount of nuclear YAP: (38 +- 3% in Met-5a, 40 +- 4% in Mero-25, 40 +- 6% in M-14-K and 38 +- 13% in STAV-AB (Figure 7B).	('M-14-K', 'Var', (103, 109))	('YAP', 'Gene', '10413', (44, 47))	('Mero-25', 'Chemical', '-', (82, 89))	('STAV-AB', 'Chemical', '-', (127, 134))	('YAP', 'Gene', (44, 47))
21329	33567673	In addition, the nuclear perimeter and aspect ratio were higher in ZL34 cells (Figure 7D,E).	('ZL34', 'Var', (67, 71))	('aspect ratio', 'CPA', (39, 51))	('higher', 'PosReg', (57, 63))	('nuclear perimeter', 'CPA', (17, 34))	('ZL34', 'Chemical', '-', (67, 71))
21335	33567673	The ZL34 cells (175 +- 15) were particularly efficient in passing through the Matrigel compared to M-14-K (48 +- 19), STAV-AB (33 +- 12) and Met-5a (30 +- 23) (Figure 8C).	('ZL34', 'Var', (4, 8))	('passing through the Matrigel', 'CPA', (58, 86))	('ZL34', 'Chemical', '-', (4, 8))	('STAV-AB', 'Chemical', '-', (118, 125))
21337	33567673	The analysis, showed in Figure 1E, showed that MeT-5a and Mero-25 were clearly epithelioid with marked cortical actin arcs and that DM-3 had a clear sarcomatoid phenotype with prominent stress fibers.	('Mero-25', 'Gene', (58, 65))	('MeT-5a', 'Var', (47, 53))	('clear sarcomatoid', 'Disease', 'MESH:C538614', (143, 160))	('cortical actin arcs', 'CPA', (103, 122))	('Mero-25', 'Chemical', '-', (58, 65))	('clear sarcomatoid', 'Disease', (143, 160))	('stress fibers', 'CPA', (186, 199))	('arcs', 'molecular_function', 'GO:0002948', ('118', '122'))
21338	33567673	Both STAV-AB and M-14-K have previously been considered to be of the epithelioid type, but their actin organization is markedly different from MeT-5a and Mero-25 cell lines.	('STAV-AB', 'Chemical', '-', (5, 12))	('different', 'Reg', (128, 137))	('M-14-K', 'Var', (17, 23))	('Mero-25', 'Chemical', '-', (154, 161))
21339	33567673	M-14-K grow in colonies, like epithelial cells, but are more elongated and have more stress fibers than MeT-5a and Mero-25.	('M-14-K', 'Var', (0, 6))	('stress fibers', 'CPA', (85, 98))	('more', 'PosReg', (56, 60))	('more', 'PosReg', (80, 84))	('Mero-25', 'Chemical', '-', (115, 122))
21346	33567673	In MeT-5a, Mero-25, M-14-K, JL-1 STAV-AB and STAV-AB, the vimentin filaments were wrapped around the perinuclear area.	('vimentin', 'Gene', (58, 66))	('STAV-AB', 'Chemical', '-', (33, 40))	('Mero-25', 'Var', (11, 18))	('STAV-AB', 'Var', (45, 52))	('MeT-5a', 'Var', (3, 9))	('vimentin', 'cellular_component', 'GO:0045099', ('58', '66'))	('STAV-AB', 'Chemical', '-', (45, 52))	('vimentin', 'cellular_component', 'GO:0045098', ('58', '66'))	('Mero-25', 'Chemical', '-', (11, 18))	('M-14-K', 'Var', (20, 26))	('vimentin', 'Gene', '7431', (58, 66))
21351	33567673	This way, Met-5a, Mero-25, M-14-K and, to some extent, also STAV-AB, had epithelial cell-like characteristics.	('Mero-25', 'Chemical', '-', (18, 25))	('STAV-AB', 'Chemical', '-', (60, 67))	('M-14-K', 'Var', (27, 33))	('Mero-25', 'Var', (18, 25))	('Met-5a', 'Var', (10, 16))	('epithelial cell-like characteristics', 'CPA', (73, 109))
21354	33567673	We detected essentially two different types of organizations: In Mero-25, M-14-K, JL-1, STAV-FCS and DM-3 cells, the microtubules were abundant all the way to the cell periphery.	('Mero-25', 'Chemical', '-', (65, 72))	('microtubules', 'MPA', (117, 129))	('cell periphery', 'cellular_component', 'GO:0005938', ('163', '177'))	('abundant', 'PosReg', (135, 143))	('cell periphery', 'cellular_component', 'GO:0071944', ('163', '177'))	('M-14-K', 'Var', (74, 80))
21355	33567673	In MeT-5a, STAV-AB and ZL34 the microtubules accumulated at the perinuclear area and much fewer microtubules could be seen at the cell periphery.	('ZL34', 'Chemical', '-', (23, 27))	('STAV-AB', 'Var', (11, 18))	('MeT-5a', 'Var', (3, 9))	('microtubules', 'MPA', (32, 44))	('cell periphery', 'cellular_component', 'GO:0005938', ('130', '144'))	('STAV-AB', 'Chemical', '-', (11, 18))	('cell periphery', 'cellular_component', 'GO:0071944', ('130', '144'))	('accumulated', 'PosReg', (45, 56))
21357	33567673	In contrast, M-14-K and ZL34 had less acetylated microtubules indicative of a higher dynamic capacity, which is in line with ZL34 being highly efficient in wound closure and in invasion.	('M-14-K', 'Var', (13, 19))	('less', 'NegReg', (33, 37))	('ZL34', 'Chemical', '-', (24, 28))	('higher', 'PosReg', (78, 84))	('dynamic capacity', 'MPA', (85, 101))	('ZL34', 'Chemical', '-', (125, 129))	('acetylated microtubules', 'MPA', (38, 61))	('ZL34', 'Var', (125, 129))	('wound closure', 'CPA', (156, 169))
21360	33567673	Several lines of evidence have indicated roles for the Hippo pathway in MM, and a common mechanism appears to be linked to inactivation of the NF2 gene, which encodes a protein called Merlin.	('inactivation', 'Var', (123, 135))	('NF2', 'Gene', (143, 146))	('NF2', 'Gene', '4771', (143, 146))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('roles', 'Reg', (41, 46))	('Merlin', 'Gene', '4771', (184, 190))	('Hippo pathway', 'Pathway', (55, 68))	('Merlin', 'Gene', (184, 190))
21368	33567673	Yes, there is a clear correlation for some of the cell lines: ZL34 efficiently migrated in the wound closure assay and in the Matrigel invasion assay, whereas DM-3 had a very low invasive capacity.	('ZL34', 'Chemical', '-', (62, 66))	('ZL34', 'Var', (62, 66))	('Matrigel invasion assay', 'CPA', (126, 149))
21439	31743489	It has been suggested that important barriers to participation in cancer clinical trials are mistrust and lack of knowledge of clinical trials.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mistrust', 'Var', (93, 101))	('cancer', 'Disease', (66, 72))
21526	31477126	The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7.	('MWCNT-7', 'Chemical', '-', (133, 140))	('increased', 'PosReg', (72, 81))	('bronchiolo-alveolar cell hyperplasia', 'Disease', (17, 53))	('bronchiolo-alveolar cell hyperplasia', 'Disease', 'MESH:D002282', (17, 53))	('0.50 mg', 'Var', (125, 132))	('0.50 mg', 'Var', (109, 116))
21624	31477126	There was a significant increase in pleural mesothelial cell hyperplasia and a non-significant increase in pleural mesotheliomas in rats treated with 0.25 mg and 0.50 mg POT fibers and 0.50 mg MWCNT-7 fibers; the untreated, vehicle control, and r-nTiO2 treated rats did not develop either mesothelial cell hyperplasia or mesotheliomas (see Table 1).	('increase', 'PosReg', (24, 32))	('r-nTiO2', 'Chemical', '-', (245, 252))	('mesothelial cell hyperplasia or mesotheliomas', 'Disease', (289, 334))	('0.50 mg', 'Var', (162, 169))	('increase', 'PosReg', (95, 103))	('mesothelial cell hyperplasia or mesotheliomas', 'Disease', 'MESH:D018301', (289, 334))	('rats', 'Species', '10116', (132, 136))	('rats', 'Species', '10116', (261, 265))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (107, 128))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (107, 128))	('pleural mesothelial cell hyperplasia', 'Disease', 'MESH:D018301', (36, 72))	('0.25', 'Var', (150, 154))	('MWCNT-7', 'Chemical', '-', (193, 200))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (107, 127))	('pleural mesothelial cell hyperplasia', 'Disease', (36, 72))	('pleural mesotheliomas', 'Disease', (107, 128))
21628	31477126	We also observed a significant induction of type II epithelial cell hyperplasia in the 0.50 mg POT and MWCNT-7 groups; however, the development of lung tumors was not increased in these groups (see Table 1).	('lung tumors', 'Disease', 'MESH:D008175', (147, 158))	('lung tumor', 'Phenotype', 'HP:0100526', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('0.50 mg', 'Var', (87, 94))	('type II epithelial cell hyperplasia', 'Disease', 'MESH:D017573', (44, 79))	('MWCNT-7', 'Chemical', '-', (103, 110))	('lung tumors', 'Phenotype', 'HP:0100526', (147, 158))	('lung tumors', 'Disease', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('type II epithelial cell hyperplasia', 'Disease', (44, 79))
21662	31477126	The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT and MWCNT-7 treated rats indicates that POT and MWCNT-7 fibers are highly likely to be carcinogenic in the lung of male rats.	('MWCNT-7', 'Chemical', '-', (119, 126))	('carcinomas', 'Disease', (78, 88))	('MWCNT-7', 'Var', (163, 170))	('type II epithelial cell hyperplasia', 'Disease', (17, 52))	('rats', 'Species', '10116', (235, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('carcinogenic', 'Disease', 'MESH:D063646', (202, 214))	('carcinogenic', 'Disease', (202, 214))	('MWCNT-7', 'Chemical', '-', (163, 170))	('type II epithelial cell hyperplasia', 'Disease', 'MESH:D017573', (17, 52))	('rats', 'Species', '10116', (135, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('carcinomas', 'Disease', 'MESH:D002277', (78, 88))
21681	31477126	2018 and Abdelgied et al., 2019 the PCNA index at 4 weeks and at 1 year in the lung and pleura of rats treated with POT or MWCNT-7 fibers, but not r-nTiO2, was significantly higher than that of the control groups.	('rats', 'Species', '10116', (98, 102))	('MWCNT-7', 'Chemical', '-', (123, 130))	('higher', 'PosReg', (174, 180))	('PCNA', 'molecular_function', 'GO:0003892', ('36', '40'))	('r-nTiO2', 'Chemical', '-', (147, 154))	('MWCNT-7', 'Var', (123, 130))	('PCNA', 'Gene', '25737', (36, 40))	('PCNA', 'Gene', (36, 40))
21683	31477126	Thus, the DNA damaging ROS and RNS could have damaged the DNA of dividing cells, allowing replication of damaged DNA before it was repaired, resulting in fixation of mutations in the DNA of the daughter cells.	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('mutations', 'Var', (166, 175))	('RNS', 'Chemical', 'MESH:D011886', (31, 34))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('fixation', 'MPA', (154, 162))	('ROS', 'Chemical', '-', (23, 26))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))
21724	24222919	The Cytotoxic Effect of Magainin II on the MDA-MB-231 and M14K Tumour Cell Lines Many studies have highlighted the tumoricidal properties of some natural peptides known to have antimicrobial virtues.	('M14K', 'SUBSTITUTION', 'None', (58, 62))	('peptides', 'Chemical', 'MESH:D010455', (154, 162))	('M14K', 'Var', (58, 62))	('tumoricidal properties', 'CPA', (115, 137))	('Cytotoxic', 'Disease', 'MESH:D064420', (4, 13))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (43, 53))	('Cytotoxic', 'Disease', (4, 13))	('Tumour', 'Phenotype', 'HP:0002664', (63, 69))
21726	24222919	Relying on the literature, the purpose of our in vitro research was to assess the tumoricidal potential of magainin II on a series of tumour cell lines, namely, MDA-MB-231 (breast adenocarcinoma) and M14K (human mesothelioma).	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (173, 194))	('mesothelioma', 'Disease', (212, 224))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (161, 171))	('human', 'Species', '9606', (206, 211))	('M14K', 'SUBSTITUTION', 'None', (200, 204))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('M14K', 'Var', (200, 204))	('tumoricidal potential', 'CPA', (82, 103))	('breast adenocarcinoma', 'Disease', (173, 194))	('tumour', 'Disease', (134, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (212, 224))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (173, 194))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
21733	24222919	Nevertheless, all forms of cancer are characterized by abnormal cell proliferation caused by different inherited or environment-induced genetic mutations.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('caused', 'Reg', (83, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (144, 153))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (55, 82))
21738	24222919	Relying on the literature, the purpose of our in vitro research was to assess the tumoricidal potential of the cytotoxic peptide magainin II on a series of tumour cell lines, namely, MDA-MB-231 (breast adenocarcinoma) and M14K (human mesothelioma).	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (195, 216))	('tumour', 'Disease', (156, 162))	('mesothelioma', 'Disease', (234, 246))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (195, 216))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (183, 193))	('M14K', 'SUBSTITUTION', 'None', (222, 226))	('mesothelioma', 'Disease', 'MESH:D008654', (234, 246))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('M14K', 'Var', (222, 226))	('human', 'Species', '9606', (228, 233))	('breast adenocarcinoma', 'Disease', (195, 216))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
21739	24222919	a cationic peptide (Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Asn-Ser) with an alpha-helix-like amphiphilic structure targets certain cell membranes directly, where it forms permeable ion channels that lead to depolarization and irreversible cytolysis and eventually to cell death.	('Gly', 'Chemical', 'MESH:D005998', (88, 91))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('Ser', 'Chemical', 'MESH:D012694', (48, 51))	('Gly', 'Chemical', 'MESH:D005998', (68, 71))	('cytolysis', 'biological_process', 'GO:0019835', ('284', '293'))	('cell death', 'biological_process', 'GO:0008219', ('312', '322'))	('Gly', 'Chemical', 'MESH:D005998', (20, 23))	('Ser', 'Chemical', 'MESH:D012694', (108, 111))	('ion channels', 'molecular_function', 'GO:0022831', ('226', '238'))	('lead', 'Reg', (244, 248))	('Gly', 'Chemical', 'MESH:D005998', (28, 31))	('Ser', 'cellular_component', 'GO:0005790', ('108', '111'))	('forms', 'Reg', (210, 215))	('depolarization', 'MPA', (252, 266))	('Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Asn-Ser', 'Var', (20, 111))
21754	24222919	We analysed the cytotoxicity of the peptide chosen for our study in relation to two adherent tumour cell lines: MDA-MB-231 (breast adenocarcinoma) and M14K (human mesothelioma).	('tumour', 'Disease', (93, 99))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (124, 145))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('mesothelioma', 'Disease', (163, 175))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (124, 145))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('M14K', 'SUBSTITUTION', 'None', (151, 155))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('cytotoxicity', 'Disease', (16, 28))	('M14K', 'Var', (151, 155))	('human', 'Species', '9606', (157, 162))	('breast adenocarcinoma', 'Disease', (124, 145))
21780	24222919	Both the M14K adherent line cells (Figure 4(a)) and the K562 suspension line cells (Figure 4(b)) proliferated in 250 mL flasks in order to obtain a sufficient number of cells (4 x 106 cells for M14K and 1 x 107 cells for K562).	('proliferated', 'CPA', (97, 109))	('M14K', 'SUBSTITUTION', 'None', (9, 13))	('M14K', 'Var', (9, 13))	('M14K', 'SUBSTITUTION', 'None', (194, 198))	('M14K', 'Var', (194, 198))	('K562', 'CellLine', 'CVCL:0004', (56, 60))	('K562', 'CellLine', 'CVCL:0004', (221, 225))
21784	24222919	In addition to this in vitro experimental model, another objective of this study was to assess the cytotoxic potential of magainin II on the MDA-MB-231 and M14K tumour cell lines.	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('M14K', 'SUBSTITUTION', 'None', (156, 160))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('M14K', 'Var', (156, 160))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (141, 151))	('tumour', 'Disease', (161, 167))
21792	24222919	M14K Is an Adherent Human Mesothelioma Cell Line.	('M14K', 'Var', (0, 4))	('Human', 'Species', '9606', (20, 25))	('Mesothelioma', 'Disease', (26, 38))	('Mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('M14K', 'SUBSTITUTION', 'None', (0, 4))
21795	24222919	Among the 3 histological subtypes of mesothelioma, our experiment used the M14K mesothelial epithelial cell line.	('mesothelioma', 'Disease', (37, 49))	('M14K', 'Var', (75, 79))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('M14K', 'SUBSTITUTION', 'None', (75, 79))
21796	24222919	The evolution of the M14K cells after 72 h of incubation with magainin II was similar to that of the MDA-MB-231 cells, meaning that cytostasis exceeded 50% when a 120 muM concentration of magainin II was used (Table 3).	('cytostasis', 'MPA', (132, 142))	('muM', 'Gene', (167, 170))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (101, 111))	('M14K', 'SUBSTITUTION', 'None', (21, 25))	('M14K', 'Var', (21, 25))	('muM', 'Gene', '56925', (167, 170))
21798	24222919	Therefore, when incubated with magainin II, cell viability was equally low in the MDA-MB-231 tumour cell line and in the M14K tumour cell line.	('low', 'NegReg', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (82, 92))	('tumour', 'Disease', (93, 99))	('M14K', 'SUBSTITUTION', 'None', (121, 125))	('M14K', 'Var', (121, 125))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('cell viability', 'CPA', (44, 58))
21809	24222919	The objectives of our research were fulfilled by the assessment, by means of the MTT technique, of the in vitro cytotoxic effect determining the cytostasis process in various types of cells (MDA-MB-231 and M14K cell lines), depending on the type and concentrations of cytotoxic peptide used.	('M14K', 'Var', (206, 210))	('MTT', 'Chemical', 'MESH:C070243', (81, 84))	('cytostasis process', 'MPA', (145, 163))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (191, 201))	('M14K', 'SUBSTITUTION', 'None', (206, 210))
21827	21139925	is a 53-year-old G3P3003 menstruating female who presented to her gynecologist with a complaint of intermittent urinary urgency.	('urinary urgency', 'Phenotype', 'HP:0000012', (112, 127))	('G3P3003', 'Var', (17, 24))	('intermittent urinary urgency', 'Disease', (99, 127))	('men', 'Species', '9606', (25, 28))
21960	18560526	After stratifying asbestos burden data into tertiles of low burden (0-99 ABs/g lung), moderate burden (100-1,099 ABs/g lung), and high burden (> 1,099 ABs/g lung), we found an association of fiber burden with survival among these groups that approached statistical significance (Figure 3; log-rank p = 0.06).	('ABs', 'Phenotype', 'HP:0011002', (151, 154))	('asbestos', 'Chemical', 'MESH:D001194', (18, 26))	('> 1,099 ABs/g', 'Var', (143, 156))	('100-1,099 ABs/g', 'Var', (103, 118))	('ABs', 'Phenotype', 'HP:0011002', (73, 76))	('association', 'Interaction', (176, 187))	('ABs', 'Phenotype', 'HP:0011002', (113, 116))
22083	15138470	Furthermore, it is possible that such changes in metabolism may have an adverse effect on outcomes for patients with SCLC irrespective of treatment.	('metabolism', 'MPA', (49, 59))	('SCLC', 'Gene', '7864', (117, 121))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('SCLC', 'Gene', (117, 121))	('metabolism', 'biological_process', 'GO:0008152', ('49', '59'))	('men', 'Species', '9606', (143, 146))	('patients', 'Species', '9606', (103, 111))	('changes', 'Var', (38, 45))
22121	30874891	Incidence of overall cancer (defined as ICD-10 codes C00-C97 [excluding C44] and D00-D09 [excluding D04]) and specific cancer incidences in Gortschitztal valley in comparison to the rates in the region of Carinthia, between 1983 and 2012 were computed.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('C00-C97', 'Var', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('D00-D09', 'Var', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
22132	30874891	For females, the incidences of all malignancies were greater in St. Veit East than in St. Veit West (25/30 years) and similar to the average for Carinthia (St. Veit East greater than Carinthia in 14 years).	('St. Veit East', 'Var', (64, 77))	('malignancies', 'Disease', 'MESH:D009369', (35, 47))	('greater', 'PosReg', (53, 60))	('malignancies', 'Disease', (35, 47))
22138	30874891	For kidney cancer, the incidence rates in St. Veit East and West were both above the average for Carinthia, with St. Veit West having a higher incidence rate than St. Veit East.	('kidney cancer', 'Disease', 'MESH:D007680', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('kidney cancer', 'Disease', (4, 17))	('St. Veit West', 'Var', (113, 126))	('Carinthia', 'Disease', (97, 106))	('kidney cancer', 'Phenotype', 'HP:0009726', (4, 17))
22139	30874891	Thyroid cancer incidence rate was higher in St. Veit East, compared to St. Veit West and Carinthia overall.	('cancer', 'Disease', (8, 14))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (0, 14))	('higher', 'PosReg', (34, 40))	('St. Veit East', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
22168	30316293	In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival.	('p53', 'Gene', (31, 34))	('FEN1', 'Gene', (84, 88))	('patients', 'Species', '9606', (162, 170))	('SIAH1', 'Gene', (192, 197))	('p53', 'Gene', '7157', (31, 34))	('MMP2', 'molecular_function', 'GO:0004228', ('93', '97'))	('p53', 'Gene', (187, 190))	('p53', 'Gene', '7157', (187, 190))	('MMP2', 'Gene', (93, 97))	('patients', 'Species', '9606', (3, 11))	('FEN1', 'Gene', '2237', (84, 88))	('SIAH1', 'Gene', '6477', (192, 197))	('correlated', 'Reg', (209, 219))	('MMP2', 'Gene', '4313', (93, 97))	('mutated', 'Var', (179, 186))
22174	30316293	Here we employ a combination of computer simulation techniques along with data from both mesothelioma cells and from mesothelioma patients to identify genes that are correlated with both patient survival and disease stage.	('patient', 'Species', '9606', (130, 137))	('mesothelioma', 'Disease', (89, 101))	('correlated', 'Reg', (166, 176))	('mesothelioma', 'Disease', (117, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('patients', 'Species', '9606', (130, 138))	('genes', 'Var', (151, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('patient', 'Species', '9606', (187, 194))
22184	30316293	Genomic and transcriptomic analysis of MPM patients has shown the existence of aberrations in the p53 network, for instance mutations in the ARF pathway, which regulates p53.	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (43, 51))	('p53', 'Gene', (170, 173))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (170, 173))	('ARF pathway', 'Pathway', (141, 152))	('p53', 'Gene', '7157', (98, 101))
22189	30316293	Thus, intensive investigation of the TP53 signaling is carried out (more than 91,000 published articles related to p53 as of September 2018) and detailed understanding of the alterations that occur in its network when this tumor suppressor is mutated is needed to improve the outcomes of the TP53-network based therapies.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('223', '239'))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('mutated', 'Var', (243, 250))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('223', '239'))
22221	30316293	These groups were wild-type p53 treated, or not treated with chemotherapy, and mutant p53 treated or not treated with chemotherapy.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (86, 89))	('p53', 'Gene', '7157', (28, 31))	('mutant', 'Var', (79, 85))	('p53', 'Gene', (86, 89))
22229	30316293	In not treated with chemotherapy patients carrying wild-type p53 the highest negative correlation with survival was observed for MMP2 (- 0.521), which is a matrix metallopeptidase involved in cell migration and metastasis (Table 4 and Additional file 9: Table S9).	('MMP2', 'molecular_function', 'GO:0004228', ('129', '133'))	('patients', 'Species', '9606', (33, 41))	('negative', 'NegReg', (77, 85))	('MMP2', 'Gene', '4313', (129, 133))	('cell migration', 'biological_process', 'GO:0016477', ('192', '206'))	('MMP2', 'Gene', (129, 133))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('wild-type', 'Var', (51, 60))
22230	30316293	Finally, in the not treated with chemotherapy p53 mutated group of patients the highest negative correlation with survival was observed with SIAH1 (- 0.702) gene.	('negative', 'NegReg', (88, 96))	('SIAH1', 'Gene', '6477', (141, 146))	('patients', 'Species', '9606', (67, 75))	('p53', 'Gene', (46, 49))	('SIAH1', 'Gene', (141, 146))	('mutated', 'Var', (50, 57))	('p53', 'Gene', '7157', (46, 49))
22232	30316293	Negative correlation with survival in patients expressing either wild type or mutant p53 was observed for five genes namely the E2F1, FOXM1, PRC1, HSP90AB1 and AURKA.	('E2F1', 'Gene', '1869', (128, 132))	('E2F1', 'Gene', (128, 132))	('HSP90AB1', 'Gene', (147, 155))	('patients', 'Species', '9606', (38, 46))	('HSP90AB1', 'Gene', '3326', (147, 155))	('PRC1', 'Gene', (141, 145))	('PRC1', 'Gene', '9055', (141, 145))	('FOXM1', 'Gene', (134, 139))	('Negative', 'NegReg', (0, 8))	('AURKA', 'Gene', '6790', (160, 165))	('FOXM1', 'Gene', '2305', (134, 139))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('mutant', 'Var', (78, 84))	('AURKA', 'Gene', (160, 165))
22249	30316293	In order to determine which pathways are modulated by these genes we used KEGG, the biological biochemical image database (BBID) and Biocarta databases (Additional file 15: Table S14).	('genes', 'Var', (60, 65))	('S14', 'Gene', '6208', (179, 182))	('S14', 'Gene', (179, 182))
22267	30316293	In mesothelioma inactivation of the p53 network is frequent (> 70%) through p53 and the CDKN2A locus alterations.	('CDKN2A', 'Gene', (88, 94))	('alterations', 'Var', (101, 112))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('mesothelioma', 'Disease', (3, 15))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('CDKN2A', 'Gene', '1029', (88, 94))	('inactivation', 'Var', (16, 28))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))
22272	30316293	We mimicked in vivo mutations or loss of function of p53 using various in silico simulations and predicted the effects on gene signaling pathways and cellular fate caused by perturbations of DNA damage input (ON or OFF).	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('cellular fate', 'CPA', (150, 163))	('effects', 'Reg', (111, 118))	('gene signaling pathways', 'Pathway', (122, 145))	('loss of function', 'NegReg', (33, 49))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('mutations', 'Var', (20, 29))	('DNA damage input', 'MPA', (191, 207))
22294	30316293	In patients with mutant p53 that have not been treated with chemotherapy 19 genes were identified with significant negative correlation to survival (Table 4).	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('patients', 'Species', '9606', (3, 11))	('negative', 'NegReg', (115, 123))	('mutant', 'Var', (17, 23))
22296	30316293	Although there are no drugs directly targeting SIAH1, 6 already approved drugs that target its interaction partners UBE2N and 9 that target STAT3 could be tested in mesothelioma patients carrying mutated p53.	('mesothelioma', 'Disease', (165, 177))	('patients', 'Species', '9606', (178, 186))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '7157', (204, 207))	('SIAH1', 'Gene', '6477', (47, 52))	('UBE2N', 'Gene', (116, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('UBE2N', 'Gene', '7334', (116, 121))	('STAT3', 'Gene', '6774', (140, 145))	('mutated', 'Var', (196, 203))	('STAT3', 'Gene', (140, 145))	('SIAH1', 'Gene', (47, 52))	('tested', 'Reg', (155, 161))
22297	30316293	There are several genes identified in both p53 wild type and mutant cases including the E2F1 transcription factor that is a master regulator of cell cycle, FOXM1 that is a member of forkhead family of transcription factors that control proliferation, and PRC1 involved in control of cytokinesis and chromosomal stability.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('PRC1', 'Gene', (255, 259))	('PRC1', 'Gene', '9055', (255, 259))	('transcription factor', 'molecular_function', 'GO:0000981', ('93', '113'))	('transcription', 'biological_process', 'GO:0006351', ('201', '214'))	('cell cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('FOXM1', 'Gene', '2305', (156, 161))	('E2F1', 'Gene', '1869', (88, 92))	('E2F1', 'Gene', (88, 92))	('FOXM1', 'Gene', (156, 161))	('cytokinesis', 'biological_process', 'GO:0000910', ('283', '294'))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))
22327	30316293	Patients were split into 4 groups: treated with chemotherapy patients with TP53 wild-type (n = 27), not treated with chemotherapy patients with TP53 wild-type (n = 26), treated with chemotherapy patients with TP53 mutant (n = 1) and not treated with chemotherapy patients with TP53 mutant (n = 17).	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('TP53', 'Gene', (209, 213))	('patients', 'Species', '9606', (263, 271))	('patients', 'Species', '9606', (61, 69))	('mutant', 'Var', (214, 220))	('patients', 'Species', '9606', (130, 138))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (195, 203))	('TP53', 'Gene', '7157', (209, 213))	('TP53', 'Gene', '7157', (277, 281))	('TP53', 'Gene', (277, 281))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
22459	27169472	Changes in RR resulted in a significant change in LRx, FEN and FEF for both sexes.	('change', 'Reg', (40, 46))	('FEN', 'MPA', (55, 58))	('LR', 'Gene', '4035', (50, 52))	('Changes', 'Var', (0, 7))	('FEF', 'MPA', (63, 66))
22496	26193793	We postulated that the dichotomy in response to CTLA4 blockade could be leveraged for increasing treatment efficacy, by visualizing the immunotherapy-induced response in the regressing tumour as a complex, modular network of interacting gene products.	('blockade', 'Var', (54, 62))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('CTLA4', 'Gene', (48, 53))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Disease', (185, 191))
22504	26193793	We treated mice with anti-CTLA4 or PBS, surgically removed one of the tumours 7 days after treatment administration, at which time regressor and progressor tumours are macroscopically identical.	('anti-CTLA4', 'Var', (21, 31))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('PBS', 'Chemical', 'MESH:D007854', (35, 38))	('mice', 'Species', '10090', (11, 15))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('tumours', 'Disease', (70, 77))
22525	26193793	In vivo validation experiments showed a significant enhancement of treatment efficacy when ATRA was co-administered with CTLA-4 blockade, with long-term cures in the majority of mice (Fig.	('CTLA-4', 'Gene', (121, 127))	('enhancement', 'PosReg', (52, 63))	('mice', 'Species', '10090', (178, 182))	('ATRA', 'Chemical', 'MESH:D014212', (91, 95))	('treatment', 'MPA', (67, 76))	('blockade', 'Var', (128, 136))	('CTLA-4', 'Gene', '12477', (121, 127))
22536	26193793	We internally validated the relevance of these hubs, within the same tumour model, that modification of these hubs indeed changed the response rate to anti-CTLA4.	('tumour', 'Disease', (69, 75))	('response rate', 'MPA', (134, 147))	('modification', 'Var', (88, 100))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('changed', 'Reg', (122, 129))
22557	26193793	In responding animals, tumours consistently started regressing on day 7 after administration of anti-CTLA4; before this time point tumours of responding and non-responding mice were identical in size (Fig.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('anti-CTLA4', 'Var', (96, 106))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('tumours', 'Disease', (131, 138))	('mice', 'Species', '10090', (172, 176))	('tumours', 'Disease', (23, 30))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
22560	26193793	Tumors from 4 different experiments were used, in which the mice were treated on day 5 or 6 with 200 mug anti-CTLA4.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mug', 'molecular_function', 'GO:0043739', ('101', '104'))	('Tumors', 'Disease', (0, 6))	('anti-CTLA4', 'Var', (105, 115))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (60, 64))
22593	26193793	We observed substantial toxicity when we treated mice simultaneously with VX-680 and anti-CTLA4 (sterile inflammation of the peritoneal cavity leading to bowel obstruction as found by macroscopic and microscopic examination; there was no sign of colitis, data not shown).	('colitis', 'Phenotype', 'HP:0002583', (246, 253))	('bowel obstruction', 'Disease', 'MESH:D015212', (154, 171))	('bowel obstruction', 'Phenotype', 'HP:0005214', (154, 171))	('colitis', 'Disease', 'MESH:D003092', (246, 253))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('mice', 'Species', '10090', (49, 53))	('toxicity', 'Disease', (24, 32))	('bowel obstruction', 'Disease', (154, 171))	('anti-CTLA4', 'Var', (85, 95))	('colitis', 'Disease', (246, 253))	('VX-680', 'Var', (74, 80))	('inflammation', 'biological_process', 'GO:0006954', ('105', '117'))
22697	24910640	In contrast to many other types of solid tumor, mesotheliomas generally lack mutations of the fundamental tumor suppressor genes, p53 and RB.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mesotheliomas', 'Disease', 'MESH:D008654', (48, 61))	('mesotheliomas', 'Disease', (48, 61))	('p53', 'Gene', '7157', (130, 133))	('lack', 'NegReg', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (77, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('solid tumor', 'Disease', (35, 46))	('men', 'Species', '9606', (99, 102))	('p53', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (106, 111))	('solid tumor', 'Disease', 'MESH:D009369', (35, 46))
22701	24910640	The more commonly noted losses occur on the short arms of chromosomes 1 (notably 1p21-p22), 3 (notably 3p21.3), and 9 (notably 9p14/p16), and on the long arms of chromosomes 6 (notably 6q14-q21, 6q16.6-q21, 6q21-q23.2, and 6q25), 15 (notably 15q11.1-q15), and both arms of chromosome 22 (Pisick and Salgia,; Pass et al.,).	('p22', 'Gene', '11331', (86, 89))	('3p21.3', 'Var', (103, 109))	('p16', 'Gene', '1029', (132, 135))	('chromosome', 'cellular_component', 'GO:0005694', ('273', '283'))	('losses', 'NegReg', (24, 30))	('p16', 'Gene', (132, 135))	('Pisick and Salgia', 'Disease', 'None', (288, 305))	('p22', 'Gene', (86, 89))	('short arms', 'Phenotype', 'HP:0009824', (44, 54))
22705	24910640	These authors identified a slightly wider range of associated chromosomal alterations including losses at 1p, 3p, 4q, 6q, 13p, 14q, and 22q, and gains at 1q, 5p, 7p, 8q, and 17q and noted that more specific mutations on chromosome 22 (e.g., deletions at the neurofibromatosis 2 locus, 22q12), chromosome 9 (e.g., INK4 genes, specifically deletions at cyclin-dependent kinase inhibitor genes CDKN2A and CDKN2B at 9p21.3), and chromosome 17 (TP53 gene deletion at 17p13.1, though less common) have been associated with mesothelioma in recent reports.	('p13', 'Gene', (464, 467))	('chromosome', 'cellular_component', 'GO:0005694', ('425', '435'))	('associated', 'Reg', (501, 511))	('deletions', 'Var', (338, 347))	('chromosome', 'cellular_component', 'GO:0005694', ('220', '230'))	('TP53', 'Gene', (440, 444))	('p13', 'Gene', '440926', (464, 467))	('mutations', 'Var', (207, 216))	('CDKN2A', 'Gene', (391, 397))	('deletions', 'Var', (241, 250))	('deletion', 'Var', (450, 458))	('CDKN2B', 'Gene', (402, 408))	('mesothelioma', 'Disease', (517, 529))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (258, 275))	('mesothelioma', 'Disease', 'MESH:D008654', (517, 529))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('368', '384'))	('INK4', 'Gene', '1029', (313, 317))	('CDKN2B', 'Gene', '1030', (402, 408))	('CDKN2A', 'Gene', '1029', (391, 397))	('neurofibromatosis', 'Disease', 'MESH:C537392', (258, 275))	('TP53', 'Gene', '7157', (440, 444))	('INK4', 'Gene', (313, 317))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('351', '384'))	('neurofibromatosis', 'Disease', (258, 275))	('chromosome', 'cellular_component', 'GO:0005694', ('293', '303'))
22706	24910640	However, these mutations occur with several other cancer types (Jean et al.,).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (15, 24))	('occur', 'Reg', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
22707	24910640	They noted a new association between mesotheliomas and increased microRNA expression of certain types (MiR-31, -141, -192, -193, -200a-c, -203, -205, and -429); greater DNA methylation at certain loci, and increases in markers of telomere length maintenance mechanisms were also reportedly associated with mesotheliomas (Ivanov et al.,; Jean et al.,).	('methylation', 'Var', (173, 184))	('MiR-31', 'Gene', (103, 109))	('greater', 'PosReg', (161, 168))	('MiR-31', 'Gene', '407035', (103, 109))	('increases', 'PosReg', (206, 215))	('increased', 'PosReg', (55, 64))	('mesotheliomas', 'Disease', 'MESH:D008654', (306, 319))	('associated', 'Reg', (290, 300))	('mesotheliomas', 'Disease', (306, 319))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('DNA methylation', 'biological_process', 'GO:0006306', ('169', '184'))	('telomere', 'cellular_component', 'GO:0000781', ('230', '238'))	('mesotheliomas', 'Disease', 'MESH:D008654', (37, 50))	('mesotheliomas', 'Disease', (37, 50))	('telomere', 'cellular_component', 'GO:0005696', ('230', '238'))	('microRNA expression', 'MPA', (65, 84))	('DNA', 'MPA', (169, 172))
22710	24910640	First, there is recent evidence suggesting that telomere status and telomere maintenance mechanisms tied to P53, ATRX and DAXX mutations may be helpful in distinguishing more aggressive mesotheliomas (Durant,; Gocha et al.,; Tallet et al.,).	('ATRX', 'Gene', '546', (113, 117))	('DAXX', 'Gene', (122, 126))	('telomere', 'cellular_component', 'GO:0000781', ('68', '76'))	('telomere', 'cellular_component', 'GO:0000781', ('48', '56'))	('aggressive mesotheliomas', 'Disease', 'MESH:D008654', (175, 199))	('telomere', 'cellular_component', 'GO:0005696', ('48', '56'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('68', '88'))	('aggressive mesotheliomas', 'Disease', (175, 199))	('P53', 'Gene', (108, 111))	('DAXX', 'Gene', '1616', (122, 126))	('mutations', 'Var', (127, 136))	('telomere', 'cellular_component', 'GO:0005696', ('68', '76'))	('P53', 'Gene', '7157', (108, 111))	('ATRX', 'Gene', (113, 117))
22712	24910640	Second, the mutations leading to telomere lengthening and survival of clonally expanding mesothelioma cells using ALT mechanisms are reported to form ALT-associated promyelocytic bodies that may be akin to micronuclei observed in tumor cells and blood polynucleated lymphocytes with exposure to asbestos (Dopp et al.,; Bolognesi et al.,; Martini et al.,).	('telomere', 'Gene', (33, 41))	('tumor', 'Disease', (230, 235))	('ALT', 'Gene', (150, 153))	('mesothelioma', 'Disease', (89, 101))	('ALT', 'Gene', '76282', (114, 117))	('mutations', 'Var', (12, 21))	('telomere', 'cellular_component', 'GO:0005696', ('33', '41'))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('ALT', 'Gene', '76282', (150, 153))	('ALT', 'molecular_function', 'GO:0004021', ('150', '153'))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('ALT', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('ALT', 'molecular_function', 'GO:0004021', ('114', '117'))	('asbestos', 'Chemical', 'MESH:D001194', (295, 303))	('telomere', 'cellular_component', 'GO:0000781', ('33', '41'))
22714	24910640	And fourth, germline mutations in nuclear deubiquitinase BRCA1-associated protein 1 (BAP1) have been observed in familial clusters of mesothelioma not necessarily linked to asbestos (Testa et al.,) and in a fraction of pleural mesotheliomas in other case series (Bott et al.,; Jean et al.,; Tallet et al.,).	('BAP1', 'Gene', (85, 89))	('observed', 'Reg', (101, 109))	('mesothelioma', 'Disease', (134, 146))	('germline mutations', 'Var', (12, 30))	('linked', 'Reg', (163, 169))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (219, 240))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('42', '56'))	('mesothelioma', 'Disease', (227, 239))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (219, 240))	('asbestos', 'Chemical', 'MESH:D001194', (173, 181))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (219, 239))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('BRCA1-associated protein 1', 'Gene', '8314', (57, 83))	('BAP1', 'Gene', '8314', (85, 89))	('pleural mesotheliomas', 'Disease', (219, 240))	('BRCA1-associated protein 1', 'Gene', (57, 83))
22728	24910640	GCTs can arise from germ cell tissues in the testes, the prostate, and other tissue locations (extragonadal GCT) as a result of a mutation and abnormal migration of germ cells during embryonic development (Blossom et al.,; Sarma et al.,).	('GCTs', 'Disease', (0, 4))	('result of', 'Reg', (118, 127))	('mutation', 'Var', (130, 138))	('men', 'Species', '9606', (200, 203))	('GCTs', 'Phenotype', 'HP:0100728', (0, 4))	('abnormal migration', 'Phenotype', 'HP:0002269', (143, 161))	('arise', 'Reg', (9, 14))
22751	24910640	Indeed, PSC in many ways can mimic epithelioid mesothelioma, but unlike mesothelioma, PSC is linked to hereditary and sporadic mutations of two breast cancer susceptibility genes (BRCA-1 and BRCA-2).	('BRCA-1', 'Gene', '672', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('epithelioid mesothelioma', 'Disease', (35, 59))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('linked', 'Reg', (93, 99))	('mesothelioma', 'Disease', (72, 84))	('BRCA-2', 'Gene', '675', (191, 197))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (35, 59))	('BRCA-2', 'Gene', (191, 197))	('PSC', 'Disease', (86, 89))	('mutations', 'Var', (127, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('mesothelioma', 'Disease', (47, 59))	('BRCA-1', 'Gene', (180, 186))	('PSC', 'Disease', (8, 11))
22752	24910640	Primary epithelial cancers of the fallopian tubes (particularly the fimbria) appear to be linked to more aggressive and early-onset PSC in women with the BRCA-1 mutation (Sobol et al.,; Zweemer et al.,; Aziz et al.,; Paley et al.,; Levine et al.,; Piek et al.,; Finch et al.,; Medeiros et al.,; Kindelberger et al.,), while ovarian surface epithelium tumors have been linked to both BRCA-1 and BRCA-2 mutations (Werness et al.,; Colgan et al.,; Piura et al.,; Risch et al.,; Agoff et al.,; Brose et al.,; Geisler et al.,; Hilton et al.,; Cass et al.,).	('BRCA-2', 'Gene', (394, 400))	('Primary epithelial cancers of the fallopian tubes', 'Disease', 'MESH:D005185', (0, 49))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('linked', 'Reg', (368, 374))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('BRCA-1', 'Gene', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('BRCA-1', 'Gene', '672', (154, 160))	('mutation', 'Var', (161, 169))	('BRCA-1', 'Gene', (383, 389))	('BRCA-1', 'Gene', '672', (383, 389))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('Primary epithelial cancers of the fallopian tubes', 'Disease', (0, 49))	('mutations', 'Var', (401, 410))	('women', 'Species', '9606', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('fimbria', 'cellular_component', 'GO:0009289', ('68', '75'))	('BRCA-2', 'Gene', '675', (394, 400))	('tumors', 'Disease', (351, 357))	('ovarian surface epithelium tumors', 'Phenotype', 'HP:0025318', (324, 357))
22753	24910640	More advanced PSC tumors originating from ovarian surface epithelium or tubal fimbria epithelium are subject to genomic instability, loss of WT-1 gene expression, and the presence of both BRCA and p53 mutations, sometimes making the site or origin difficult to distinguish in more advanced stages of the disease (Schorge et al.,; Piek et al.,; Kindelberger et al.,; Lee et al.,; Gilks et al.,).	('mutations', 'Var', (201, 210))	('fimbria', 'cellular_component', 'GO:0009289', ('78', '85'))	('gene expression', 'biological_process', 'GO:0010467', ('146', '161'))	('loss', 'NegReg', (133, 137))	('p53', 'Gene', (197, 200))	('PSC tumors', 'Disease', 'MESH:D015209', (14, 24))	('p53', 'Gene', '7157', (197, 200))	('WT-1', 'Gene', (141, 145))	('BRCA', 'Gene', '672', (188, 192))	('PSC tumors', 'Disease', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('presence', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('BRCA', 'Gene', (188, 192))	('WT-1', 'Gene', '7490', (141, 145))
22756	24910640	Three familial genetic syndromes associated with excess ovarian cancer risk have been identified: certain BRCA-1 or BRCA-2 mutations result in Breast Ovarian Cancer Syndrome, Site-Specific Ovarian Cancer Syndrome, and Hereditary Non-Polyposis Colon Cancer (or Lynch II Syndrome) which are associated with mutations in DNA mismatch repair genes in affected families (Muto,).	('excess ovarian cancer', 'Disease', 'MESH:D010051', (49, 70))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (150, 164))	('Lynch II Syndrome', 'Disease', 'MESH:D055847', (260, 277))	('mismatch repair', 'biological_process', 'GO:0006298', ('322', '337'))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (189, 203))	('Lynch II Syndrome', 'Disease', (260, 277))	('Cancer', 'Phenotype', 'HP:0002664', (249, 255))	('BRCA-1', 'Gene', (106, 112))	('BRCA-1', 'Gene', '672', (106, 112))	('Breast Ovarian Cancer', 'Disease', (143, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('Non-Polyposis Colon Cancer', 'Disease', (229, 255))	('Non-Polyposis Colon Cancer', 'Disease', 'MESH:D015179', (229, 255))	('Site-Specific Ovarian Cancer Syndrome', 'Disease', 'MESH:D010051', (175, 212))	('Breast Ovarian Cancer', 'Disease', 'MESH:D010051', (143, 164))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Site-Specific Ovarian Cancer Syndrome', 'Disease', (175, 212))	('familial genetic syndromes', 'Disease', (6, 32))	('excess ovarian cancer', 'Disease', (49, 70))	('familial genetic syndromes', 'Disease', 'MESH:D030342', (6, 32))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BRCA-2', 'Gene', '675', (116, 122))	('DNA', 'cellular_component', 'GO:0005574', ('318', '321'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('result in', 'Reg', (133, 142))	('Colon Cancer', 'Phenotype', 'HP:0003003', (243, 255))	('mutations', 'Var', (123, 132))	('BRCA-2', 'Gene', (116, 122))
22765	24910640	Many congenital heart defects are related to trisomies of chromosomes 13, 15, 18, and 21, and deletions in chromosome 22 (22q11.2) are thought to play a major role in congenital heart disorders of the conotruncus and the brachial arches (Kumar et al.,).	('congenital heart defects', 'Phenotype', 'HP:0001627', (5, 29))	('congenital heart defects', 'Disease', (5, 29))	('brachial arches', 'Disease', (221, 236))	('congenital heart disorders', 'Disease', 'MESH:D006330', (167, 193))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('heart defects', 'Phenotype', 'HP:0030680', (16, 29))	('congenital heart disorders', 'Phenotype', 'HP:0001627', (167, 193))	('trisomies', 'Var', (45, 54))	('deletions', 'Var', (94, 103))	('congenital heart disorders', 'Disease', (167, 193))	('22q11.2', 'Gene', (122, 129))	('congenital heart defects', 'Disease', 'MESH:D006330', (5, 29))	('brachial arches', 'Disease', 'MESH:D020968', (221, 236))	('conotruncus', 'Disease', (201, 212))
22777	24910640	Indeed, Sandberg provides a summary of specific chromosomal translocations corresponding to a variety of soft tissue sarcomas including synovial sarcoma where:the translocation is the sole cytogenetic anomaly, indicating the probable causative role of this translocation in the genesis of these tumors.	('tumors', 'Disease', (295, 301))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (105, 125))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('synovial sarcoma', 'Disease', (136, 152))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('anomaly', 'Disease', (201, 208))	('translocation', 'Var', (163, 176))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (105, 125))	('soft tissue sarcomas', 'Disease', (105, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('anomaly', 'Disease', 'MESH:D000014', (201, 208))	('synovial sarcoma', 'Disease', 'MESH:D013584', (136, 152))
22779	24910640	The available evidence suggests that the specific type of translocation may be related to the aggressiveness of the synovial sarcoma and its prognosis.	('translocation', 'Var', (58, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('aggressiveness of the synovial sarcoma', 'Disease', 'MESH:D013584', (94, 132))	('related', 'Reg', (79, 86))	('aggressiveness of the synovial sarcoma', 'Disease', (94, 132))	('aggressiveness', 'Phenotype', 'HP:0000718', (94, 108))
22785	24910640	Certain inherited disorders produce multiple cancers that are prone to develop chromosomal instability and present at a late stage with histological features that mimic disseminated mesothelioma (Hawley and Pandolfi,).	('inherited disorders', 'Disease', (8, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mesothelioma', 'Disease', (182, 194))	('inherited disorders', 'Disease', 'MESH:D030342', (8, 27))	('multiple cancers', 'Disease', (36, 52))	('chromosomal instability', 'Var', (79, 102))	('chromosomal instability', 'Phenotype', 'HP:0040012', (79, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('multiple cancers', 'Disease', 'MESH:D009369', (36, 52))
22787	24910640	Both syndromes are known to have diagnostic genetic mutations in somatic cells that identify the syndrome and overt clinical outcome which consists of multiple, but often survivable, cancers in affected subjects and their blood relatives.	('mutations', 'Var', (52, 61))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancers', 'Disease', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
22793	24910640	Late stage tumors of MEN-1 patients have been associated with chromosomal instability that may plausibly lead to local tissue invasion and conversion to mixed neoplastic cell types including soft tissue sarcomas that may mimic mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (227, 240))	('soft tissue sarcomas', 'Disease', (191, 211))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('MEN-1', 'Gene', '4221', (21, 26))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (191, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (191, 210))	('chromosomal instability', 'Var', (62, 85))	('chromosomal instability', 'Phenotype', 'HP:0040012', (62, 85))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (191, 211))	('MEN-1', 'Gene', (21, 26))	('patients', 'Species', '9606', (27, 35))	('local tissue invasion', 'CPA', (113, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('lead to', 'Reg', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('mesotheliomas', 'Disease', (227, 240))	('tumors', 'Disease', (11, 17))	('tissue invasion', 'biological_process', 'GO:0001404', ('119', '134'))
22794	24910640	Thus, it is suggested that persons with characteristic prior cancers and/or ZES and distal gastrectomy who present with apparent mesothelioma should be tested for the somatic cell mutation (11q13) of the MEN-1 tumor suppressor gene, in addition to testing for other translocations that may be diagnostic for various types of soft tissue sarcoma that may be relevant to the tumor/site (Sandberg,).	('tumor suppressor', 'biological_process', 'GO:0051726', ('210', '226'))	('mesothelioma', 'Disease', (129, 141))	('MEN-1', 'Gene', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (325, 344))	('tumor', 'Disease', (210, 215))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('sarcoma', 'Disease', 'MESH:D012509', (337, 344))	('sarcoma', 'Disease', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (373, 378))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('persons', 'Species', '9606', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('11q13', 'Var', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (373, 378))	('ZES', 'Phenotype', 'HP:0002044', (76, 79))	('MEN-1', 'Gene', '4221', (204, 209))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('210', '226'))
22797	24910640	Also, late stage tumors in HNPCC patients are associated with chromosomal instability that may plausibly lead to local tissue invasion and conversion to mixed neoplastic cell types including soft tissue sarcomas that may mimic mesotheliomas.	('tumors', 'Disease', (17, 23))	('mesotheliomas', 'Disease', 'MESH:D008654', (227, 240))	('soft tissue sarcomas', 'Disease', (191, 211))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (191, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (191, 210))	('chromosomal instability', 'Var', (62, 85))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('chromosomal instability', 'Phenotype', 'HP:0040012', (62, 85))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (191, 211))	('local tissue invasion', 'CPA', (113, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('lead to', 'Reg', (105, 112))	('HNPCC', 'Gene', (27, 32))	('HNPCC', 'Gene', '4436', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('patients', 'Species', '9606', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('mesotheliomas', 'Disease', (227, 240))	('tissue invasion', 'biological_process', 'GO:0001404', ('119', '134'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
22798	24910640	Thus, persons with characteristic prior cancers who present with apparent mesothelioma should be tested for the somatic cell mutations of HNPCC, in addition to testing for other translocations that may be diagnostic for various types of soft tissue sarcoma that may be relevant to the tumor/site (Sandberg,).	('mutations', 'Var', (125, 134))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('HNPCC', 'Gene', (138, 143))	('tumor', 'Disease', (285, 290))	('persons', 'Species', '9606', (6, 13))	('cancers', 'Disease', (40, 47))	('sarcoma', 'Disease', 'MESH:D012509', (249, 256))	('sarcoma', 'Disease', (249, 256))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (237, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('HNPCC', 'Gene', '4436', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mesothelioma', 'Disease', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
22867	22208720	Primary pleural angiosarcoma as a mimicker of mesothelioma: a case report **VS** Primary pleural angiosarcoma is a rare and clinically aggressive tumor.	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('Primary pleural angiosarcoma', 'Disease', (81, 109))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Primary pleural angiosarcoma', 'Disease', 'MESH:D006394', (81, 109))	('Primary pleural angiosarcoma', 'Disease', (0, 28))	('aggressive tumor', 'Disease', 'MESH:D001523', (135, 151))	('angiosarcoma', 'Phenotype', 'HP:0200058', (97, 109))	('mesothelioma', 'Disease', (46, 58))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('Primary pleural angiosarcoma', 'Disease', 'MESH:D006394', (0, 28))	('**VS', 'Var', (74, 78))	('aggressive tumor', 'Disease', (135, 151))
22871	22208720	However, frequent epithelioid feature and immunoreactivity to cytokeratin in primary pleural angiosarcoma further complicate the pathologic diagnosis.	('epithelioid feature', 'CPA', (18, 37))	('primary pleural angiosarcoma', 'Disease', (77, 105))	('primary pleural angiosarcoma', 'Disease', 'MESH:D006394', (77, 105))	('angiosarcoma', 'Phenotype', 'HP:0200058', (93, 105))	('cytokeratin', 'Protein', (62, 73))	('immunoreactivity', 'Var', (42, 58))
22942	22208720	The diagnostic pitfalls include mesotheliomatous growth pattern with diffuse pleural involvement, biphasic histomorphologic pattern and immunoreactivity to cytokeratin.	('pleural involvement', 'Disease', (77, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('growth pattern', 'biological_process', 'GO:0040007', ('49', '63'))	('immunoreactivity', 'Var', (136, 152))	('biphasic', 'Disease', (98, 106))	('pleural involvement', 'Disease', 'MESH:D010995', (77, 96))	('mesothelioma', 'Disease', (32, 44))	('growth pattern', 'biological_process', 'GO:0007150', ('49', '63'))
22951	32922794	Four months later, she consented to a surgical pleural biopsy under general anesthesia to obtain larger tissue samples, which included typical proliferating polygonal cells positive for CAM5.2, calretinin, WT-1, D2-40, CK5/6, epithelial membrane antigen, and glucose transporter-1 and negative for carcinoembryonic antigen, BerEP4, and MOC31.	('CK5/6, epithelial membrane antigen', 'Gene', '3852', (219, 253))	('calretinin', 'Gene', '794', (194, 204))	('carcinoembryonic antigen', 'Gene', '1084', (298, 322))	('she', 'Gene', '126669', (19, 22))	('glucose transporter-1', 'Gene', '6513', (259, 280))	('glucose transporter-1', 'Gene', (259, 280))	('calretinin', 'Gene', (194, 204))	('she', 'Gene', (19, 22))	('carcinoembryonic antigen', 'Gene', (298, 322))	('membrane', 'cellular_component', 'GO:0016020', ('237', '245'))	('CAM5.2', 'Gene', (186, 192))	('D2-40', 'Var', (212, 217))
22979	32922794	Even though she had no history of asbestos exposure, malignant pleural mesothelioma was suspected based on CT scan findings and an abnormally high concentration of hyaluronic acid (2,030,000 ng/mL) in the pleural fluids.	('abnormally high concentration of hyaluronic acid', 'Phenotype', 'HP:0031210', (131, 179))	('she', 'Gene', '126669', (12, 15))	('she', 'Gene', (12, 15))	('2,030,000', 'Var', (181, 190))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (53, 83))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (63, 83))	('asbestos', 'Chemical', 'MESH:D001194', (34, 42))	('pleural fluid', 'Phenotype', 'HP:0002202', (205, 218))	('malignant pleural mesothelioma', 'Disease', (53, 83))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (164, 179))
22986	32922794	The atypical cells were positive for CAM5.2, calretinin, WT-1, D2-40, and CK 5/6, but negative for carcinoembryonic antigen (CEA), thyroid transcription factor-1 (TTF-1), and claudin 4 expression.	('claudin 4', 'Gene', '1364', (175, 184))	('expression', 'MPA', (185, 195))	('calretinin', 'Gene', (45, 55))	('CEA', 'Gene', (125, 128))	('CK 5/6', 'Gene', (74, 80))	('thyroid transcription factor-1', 'Gene', '7080', (131, 161))	('negative', 'NegReg', (86, 94))	('transcription factor', 'molecular_function', 'GO:0000981', ('139', '159'))	('CEA', 'Gene', '1084', (125, 128))	('carcinoembryonic antigen', 'Gene', (99, 123))	('calretinin', 'Gene', '794', (45, 55))	('TTF-1', 'Gene', '7080', (163, 168))	('TTF-1', 'Gene', (163, 168))	('carcinoembryonic antigen', 'Gene', '1084', (99, 123))	('thyroid transcription factor-1', 'Gene', (131, 161))	('CAM5.2', 'Var', (37, 43))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('claudin 4', 'Gene', (175, 184))	('CK 5/6', 'Gene', '3852', (74, 80))
23032	30349006	Remarkably, Calypso also regulates Asx monoubiquitination and transgenic flies expressing monoubiquitination-defective Asx mutant exhibit developmental defects.	('Asx', 'Gene', (35, 38))	('Asx', 'Gene', '36612', (119, 122))	('regulates', 'Reg', (25, 34))	('developmental defects', 'CPA', (138, 159))	('Asx', 'Gene', '36612', (35, 38))	('Asx', 'Gene', (119, 122))	('mutant', 'Var', (123, 129))
23036	30349006	BAP1 is a tumor suppressor inactivated in numerous cancers, and ablation of this gene in mice also results in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Disease', (10, 15))	('ablation', 'Var', (64, 72))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('results in', 'Reg', (99, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('numerous cancers', 'Disease', 'MESH:D009369', (42, 58))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('numerous cancers', 'Disease', (42, 58))
23042	30349006	Although PR-DUB deubiquitinates monoubiquitinated histone H2A on K118 (H2AK119 in vertebrates, hereafter H2Aub), the functional significance of this deubiquitination event remains unclear, as mutation of K118 of H2A does not impact the repression of Ubx.	('histone', 'Protein', (50, 57))	('H2Aub', 'Chemical', '-', (105, 110))	('mutation', 'Var', (192, 200))	('H2A', 'Gene', (58, 61))	('H2A', 'Gene', (212, 215))	('K118', 'Var', (204, 208))	('Ubx', 'Chemical', '-', (250, 253))	('deubiquitination', 'biological_process', 'GO:0016579', ('149', '165'))	('repression', 'MPA', (236, 246))	('H2A', 'Gene', '8337', (58, 61))	('H2A', 'Gene', '8337', (71, 74))	('H2A', 'Gene', '8337', (105, 108))	('monoubiquitinated', 'MPA', (32, 49))	('H2A', 'Gene', (71, 74))	('H2A', 'Gene', (105, 108))	('H2A', 'Gene', '8337', (212, 215))	('K118', 'Var', (65, 69))
23051	30349006	Interestingly, deletion of the DEUBAD domain results in the disruption of BAP1/ASXLs interaction and leads to decreased ASXL2, but not ASXL1, protein levels.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('ASXL1', 'Gene', (135, 140))	('BAP1/ASXLs', 'Protein', (74, 84))	('deletion', 'Var', (15, 23))	('disruption', 'NegReg', (60, 70))	('decreased', 'NegReg', (110, 119))	('interaction', 'Interaction', (85, 96))	('ASXL1', 'Gene', '171023', (135, 140))	('ASXL2', 'MPA', (120, 125))
23056	30349006	Moreover, expression of a monoubiquitination-defective Asx mutant alters Drosophila development.	('Asx', 'Gene', (55, 58))	('mutant', 'Var', (59, 65))	('expression', 'Species', '29278', (10, 20))	('Asx', 'Gene', '36612', (55, 58))	('alters', 'Reg', (66, 72))	('Drosophila development', 'CPA', (73, 95))	('monoubiquitination-defective', 'MPA', (26, 54))	('Drosophila', 'Species', '7227', (73, 83))
23063	30349006	To identify the regions/domains of ASXL2 required for its monoubiquitination, we used ASXL2 deletion mutants lacking known domains (ASXL2DeltaASXN, ASXL2DeltaDEUBAD, and ASXL2DeltaPHD) that we overexpressed with GFP-Ub and Flag-BAP1 and found that the DEUBAD domain is necessary for ASXL2 monoubiquitination (Fig.	('deletion mutants', 'Var', (92, 108))	('ASXL2', 'Gene', (86, 91))	('mutants', 'Var', (101, 108))	('PHD', 'Disease', 'MESH:D011547', (180, 183))	('ASXL2 monoubiquitination', 'MPA', (283, 307))	('PHD', 'Disease', (180, 183))
23066	30349006	To validate the MS data, we generated lysine to arginine mutants of Myc-DEUBAD, and identified the K370 residue as the key BAP1-dependent monoubiquitination site (Fig.	('lysine to arginine', 'Var', (38, 56))	('Myc-DEUBAD', 'Gene', (68, 78))	('K370', 'Var', (99, 103))	('arginine', 'Chemical', 'MESH:D001120', (48, 56))	('lysine', 'Chemical', 'MESH:D008239', (38, 44))
23067	30349006	Note that an upper band shift of BAP1 is observed following expression of Myc-DEUBAD K370R suggesting its potential modification.	('upper band shift', 'MPA', (13, 29))	('K370R', 'Var', (85, 90))	('BAP1', 'Gene', (33, 37))	('expression', 'Species', '29278', (60, 70))	('K370R', 'Mutation', 'p.K370R', (85, 90))
23069	30349006	MS analysis revealed a major ubiquitination site within ASXL1 DEUBAD and further validated K351 as the main site of monoubiquitination (Supplementary Fig.	('ASXL1', 'Gene', (56, 61))	('K351', 'Chemical', 'MESH:C036089', (91, 95))	('ubiquitination', 'MPA', (29, 43))	('ASXL1', 'Gene', '171023', (56, 61))	('K351', 'Var', (91, 95))
23071	30349006	We noted that ASXL3 was also found in proteomics studies to be ubiquitinated on K350 which corresponds to the highly conserved monoubiquitination site of ASXL2 DEUBAD (Supplementary Fig.	('ASXL3', 'Gene', '80816', (14, 19))	('ASXL3', 'Gene', (14, 19))	('K350', 'Var', (80, 84))	('K350', 'Chemical', '-', (80, 84))
23075	30349006	The upper band was abolished following expression of Myc-V5-DEUBAD K325R mutant (K370 in human ASXL2).	('human', 'Species', '9606', (89, 94))	('K325R', 'Chemical', '-', (67, 72))	('K325R', 'Var', (67, 72))	('abolished', 'NegReg', (19, 28))	('expression', 'Species', '29278', (39, 49))
23076	30349006	Co-transfection of Myc-V5-DEUBAD or K325R mutant with HA-Ub further validated the monoubiquitination of Asx DEUBAD.	('HA-Ub', 'Chemical', '-', (54, 59))	('K325R', 'Chemical', '-', (36, 41))	('K325R', 'Var', (36, 41))	('Asx', 'Gene', (104, 107))	('monoubiquitination', 'MPA', (82, 100))	('Asx', 'Gene', '36612', (104, 107))	('HA-Ub', 'Gene', (54, 59))
23078	30349006	Calypso also promoted the monoubiquitination of the wildtype (WT) DEUBAD, but not its corresponding K325R mutant (Supplementary Fig.	('promoted', 'PosReg', (13, 21))	('K325R', 'Chemical', '-', (100, 105))	('K325R', 'Var', (100, 105))	('monoubiquitination', 'MPA', (26, 44))
23079	30349006	Interestingly, we also found that overexpression of BAP1 or Calypso in HEK293T cells promoted the monoubiquitination of the DEUBAD of Asx and ASXL2 on K325 and K370, respectively (Supplementary Fig.	('expression', 'Species', '29278', (38, 48))	('Asx', 'Gene', (134, 137))	('K370', 'Var', (160, 164))	('HEK293T', 'CellLine', 'CVCL:0063', (71, 78))	('K325', 'Var', (151, 155))	('monoubiquitination', 'MPA', (98, 116))	('promoted', 'PosReg', (85, 93))	('Asx', 'Gene', '36612', (134, 137))
23080	30349006	Finally, we sought to test whether a similar mechanism of DEUBAD monoubiquitination, involving UCH37, could be observed for INO80G and RPN13.	('DEUBAD monoubiquitination', 'MPA', (58, 83))	('UCH37', 'Gene', (95, 100))	('INO80G', 'Gene', (124, 130))	('UCH37', 'Gene', '51377', (95, 100))	('RPN13', 'Var', (135, 140))	('INO80G', 'Gene', '4798', (124, 130))
23083	30349006	Although we observed additional upper bands for RPN13 and INO80G that can suggest DEUBAD ubiquitination, these patterns did not change upon expression of UCH37 (Supplementary Fig.	('expression', 'Species', '29278', (140, 150))	('UCH37', 'Gene', (154, 159))	('DEUBAD ubiquitination', 'MPA', (82, 103))	('RPN13', 'Var', (48, 53))	('INO80G', 'Gene', '4798', (58, 64))	('UCH37', 'Gene', '51377', (154, 159))	('INO80G', 'Gene', (58, 64))
23087	30349006	To define whether these interactions are necessary for DEUBAD monoubiquitination, we used several Flag-BAP1 deletion mutants targeting the UCH, CC1 and CTD that we expressed with the DEUBAD of ASXL2 (Fig.	('CC1', 'Gene', (144, 147))	('Flag-BAP1', 'Gene', (98, 107))	('mutants', 'Var', (117, 124))	('CC1', 'Gene', '9821', (144, 147))	('deletion mutants', 'Var', (108, 124))
23088	30349006	Deletion of CC1 or CTD resulted in a strong decrease of DEUBAD monoubiquitination (Fig.	('CC1', 'Gene', '9821', (12, 15))	('decrease', 'NegReg', (44, 52))	('DEUBAD monoubiquitination', 'MPA', (56, 81))	('CC1', 'Gene', (12, 15))	('Deletion', 'Var', (0, 8))
23089	30349006	Importantly, a cancer-associated mutation of BAP1 in its CTD, BAP1DeltaR666-H669, that abrogates its interaction with ASXL1 and ASXL2, also failed in promoting DEUBAD monoubiquitination (Fig.	('ASXL1', 'Gene', '171023', (118, 123))	('BAP1', 'Gene', (45, 49))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('ASXL1', 'Gene', (118, 123))	('DEUBAD monoubiquitination', 'MPA', (160, 185))	('interaction', 'Interaction', (101, 112))	('failed', 'NegReg', (140, 146))	('promoting', 'PosReg', (150, 159))	('BAP1DeltaR666-H669', 'Var', (62, 80))	('abrogates', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
23091	30349006	Of note, expression of the UCH domain often results in an additional upper band suggesting its modification (Fig.	('expression', 'Var', (9, 19))	('modification', 'Reg', (95, 107))	('UCH domain', 'Gene', (27, 37))	('upper band', 'MPA', (69, 79))	('expression', 'Species', '29278', (9, 19))	('results in', 'Reg', (44, 54))
23093	30349006	However, monoubiquitination of DEUBAD was induced to a similar extent by WT BAP1 or a catalytically inactive (C91S) mutant (Fig.	('monoubiquitination', 'MPA', (9, 27))	('C91S', 'Mutation', 'p.C91S', (110, 114))	('induced', 'Reg', (42, 49))	('C91S', 'Var', (110, 114))
23094	30349006	Based on the structure of UCHL-5 in complex with Ub, we generated several point mutants within the Ub-binding interface of BAP1 and tested their impact on DEUBAD monoubiquitination.	('BAP1', 'Gene', (123, 127))	('UCHL-5', 'Gene', '51377', (26, 32))	('UCHL-5', 'Gene', (26, 32))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('DEUBAD monoubiquitination', 'MPA', (155, 180))	('mutants', 'Var', (80, 87))	('tested', 'Reg', (132, 138))
23102	30349006	Interestingly, the protein levels of WT HA-ASXL2 were, in general, lower than the corresponding K370R mutant (Fig.	('HA', 'Chemical', 'MESH:C034124', (40, 42))	('K370R', 'Mutation', 'p.K370R', (96, 101))	('protein levels', 'MPA', (19, 33))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('lower', 'NegReg', (67, 72))	('K370R', 'Var', (96, 101))
23103	30349006	3c, d), and proteasome inhibition with MG132 stabilized ASXL2 up to the levels of the K370R mutant (Fig.	('K370R', 'Var', (86, 91))	('stabilized ASXL2', 'MPA', (45, 61))	('proteasome', 'molecular_function', 'GO:0004299', ('12', '22'))	('proteasome', 'cellular_component', 'GO:0000502', ('12', '22'))	('K370R', 'Mutation', 'p.K370R', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (39, 44))
23105	30349006	As expected, the protein levels of ASXL2 K370R mutant showed a less pronounced decrease than the non-ubiquitinated form (Fig.	('K370R', 'Var', (41, 46))	('ASXL2', 'MPA', (35, 40))	('K370R', 'Mutation', 'p.K370R', (41, 46))	('decrease', 'NegReg', (79, 87))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('protein levels', 'MPA', (17, 31))
23107	30349006	To further substantiate these results, we generated U-2 OS cells stably expressing Flag-HA-BAP1 with either GFP-DEUBAD of ASXL2 or the corresponding K370R mutant.	('K370R', 'Var', (149, 154))	('HA', 'Chemical', 'MESH:C034124', (88, 90))	('K370R', 'Mutation', 'p.K370R', (149, 154))	('Flag-HA-BAP1', 'Gene', (83, 95))	('U-2 OS', 'CellLine', 'CVCL:0042', (52, 58))
23109	30349006	Consistent with the data obtained with ASXL2, we found that protein levels of GFP-DEUBAD K370R mutant were significantly higher than the WT form (Fig.	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('K370R', 'Var', (89, 94))	('protein levels', 'MPA', (60, 74))	('higher', 'PosReg', (121, 127))	('K370R', 'Mutation', 'p.K370R', (89, 94))
23110	30349006	Note the upper band of BAP1, suggestive of its modification, observed following expression of DEUBAD K370R.	('expression', 'Species', '29278', (80, 90))	('BAP1', 'Gene', (23, 27))	('K370R', 'Var', (101, 106))	('K370R', 'Mutation', 'p.K370R', (101, 106))
23112	30349006	We also observed that MG132 treatment leads to a strong increase in the protein levels of unmodified GFP-DEUBAD which become comparable to the levels of the corresponding K370R mutant (Fig.	('increase', 'PosReg', (56, 64))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('K370R', 'Var', (171, 176))	('MG132', 'Var', (22, 27))	('K370R', 'Mutation', 'p.K370R', (171, 176))	('MG132', 'Chemical', 'MESH:C072553', (22, 27))	('protein levels', 'MPA', (72, 86))
23114	30349006	We also included K48R and K48 only mutants.	('K48R', 'Var', (17, 21))	('K48R', 'Mutation', 'rs115108034', (17, 21))	('K48 only', 'Var', (26, 34))
23115	30349006	We observed that the monoubiquitination signal of the DEUBAD domain was increased when this domain is co-expressed with Ub mutants that cannot assemble degradation-inducing Ub chains (HA-Ub K48R and HA-Ub K0) (Fig.	('HA-Ub', 'Chemical', '-', (199, 204))	('HA-Ub K0', 'Var', (199, 207))	('HA-Ub K48R', 'Var', (184, 194))	('increased', 'PosReg', (72, 81))	('degradation', 'biological_process', 'GO:0009056', ('152', '163'))	('monoubiquitination signal', 'MPA', (21, 46))	('HA-Ub', 'Chemical', '-', (184, 189))	('Ub K0', 'Chemical', '-', (202, 207))	('K48R', 'Mutation', 'rs115108034', (190, 194))	('mutants', 'Var', (123, 130))
23117	30349006	We also observed that protein levels of full length ASXL2 were higher following co-expression of Myc-ASXL2 with K48R and K0 mutants (Fig.	('K48R', 'Mutation', 'rs115108034', (112, 116))	('K48R', 'Var', (112, 116))	('expression', 'Species', '29278', (83, 93))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('protein levels of', 'MPA', (22, 39))	('higher', 'PosReg', (63, 69))
23119	30349006	First, we assembled a library of siRNA targeting human DUBs (Supplementary Table 1), and conducted a loss-of-function screen in U-2 OS cells stably expressing Flag-HA-BAP1 and GFP-DEUBAD of ASXL2.	('human', 'Species', '9606', (49, 54))	('HA', 'Chemical', 'MESH:C034124', (164, 166))	('Flag-HA-BAP1', 'Var', (159, 171))	('GFP-DEUBAD', 'Var', (176, 186))	('loss-of-function', 'NegReg', (101, 117))	('U-2 OS', 'CellLine', 'CVCL:0042', (128, 134))
23123	30349006	Moreover, the upper bands of DEUBAD were completely abrogated for the K370R mutant, thus further demonstrating that this monoubiquitination site can be subjected to polyubiquitination (Fig.	('abrogated', 'NegReg', (52, 61))	('DEUBAD', 'MPA', (29, 35))	('K370R', 'Var', (70, 75))	('K370R', 'Mutation', 'p.K370R', (70, 75))
23128	30349006	In further dissecting the mechanism of catalysis in vitro, we found that UBE2E3 monoubiquitinates recombinant DEUBAD either alone or in complex with BAP1, and mutation of K370 abolishes DEUBAD monoubiquitination (Fig.	('UBE2E3', 'Gene', (73, 79))	('DEUBAD monoubiquitination', 'MPA', (186, 211))	('mutation', 'Var', (159, 167))	('UBE2E3', 'Gene', '10477', (73, 79))	('abolishes', 'NegReg', (176, 185))
23130	30349006	Hence, we used recombinant protein products of several BAP1 mutants in an in vitro reaction with defined components, and demonstrated that its enzymatic activity and ability to bind Ub do not impact UBE2E3-mediated DEUBAD monoubiquitination (Fig.	('UBE2E3', 'Gene', '10477', (199, 205))	('BAP1', 'Gene', (55, 59))	('bind', 'Interaction', (177, 181))	('mutants', 'Var', (60, 67))	('UBE2E3', 'Gene', (199, 205))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
23138	30349006	We confirmed that UBE2E3 and UBE2E2 knockdown resulted in a substantial increase of DEUBAD protein levels above that of the non-target siRNA control (Fig.	('increase', 'PosReg', (72, 80))	('UBE2E3', 'Gene', (18, 24))	('UBE2E2', 'Gene', (29, 35))	('knockdown', 'Var', (36, 45))	('UBE2E2', 'Gene', '7325', (29, 35))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('UBE2E3', 'Gene', '10477', (18, 24))	('DEUBAD protein levels', 'MPA', (84, 105))
23142	30349006	Also, combined knockdown of UBE2Es resulted in increased GFP-DEUBAD protein to a similar level to that of the DEUBAD K370R (Fig.	('UBE2', 'Gene', '7318', (28, 32))	('K370R', 'Mutation', 'p.K370R', (117, 122))	('knockdown', 'Var', (15, 24))	('UBE2', 'Gene', (28, 32))	('increased GFP', 'Phenotype', 'HP:0012214', (47, 60))	('increased', 'PosReg', (47, 56))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('GFP-DEUBAD protein', 'MPA', (57, 75))
23144	30349006	Interestingly, expression of UBE2Es with BAP1 resulted in decreased protein levels of the non-ubiquitinated form of the DEUBAD while a slight increase of its monoubiquitinated form was observed.	('monoubiquitinated form', 'MPA', (158, 180))	('protein levels of the non-ubiquitinated form', 'MPA', (68, 112))	('expression', 'Var', (15, 25))	('increase', 'PosReg', (142, 150))	('UBE2', 'Gene', '7318', (29, 33))	('BAP1', 'Gene', (41, 45))	('decreased', 'NegReg', (58, 67))	('expression', 'Species', '29278', (15, 25))	('UBE2', 'Gene', (29, 33))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))
23151	30349006	Thus, we evaluated whether knockdown of UbcD2 would affect the monoubiquitination state of Asx DEUBAD in S2 cells.	('knockdown', 'Var', (27, 36))	('Asx', 'Gene', '36612', (91, 94))	('UbcD2', 'Gene', '34487', (40, 45))	('S2', 'CellLine', 'CVCL:Z232', (105, 107))	('UbcD2', 'Gene', (40, 45))	('Asx', 'Gene', (91, 94))	('affect', 'Reg', (52, 58))
23153	30349006	First, we transduced U-2 OS cells stably expressing Flag-HA-BAP1 with lentiviral expressing constructs for GFP-DEUBAD (ASXL2) or the corresponding K370R mutant form and validated that these factors are co-expressed (Supplementary Fig.	('HA', 'Chemical', 'MESH:C034124', (57, 59))	('K370R', 'Mutation', 'p.K370R', (147, 152))	('Flag-HA-BAP1', 'Gene', (52, 64))	('U-2 OS', 'CellLine', 'CVCL:0042', (21, 27))	('K370R', 'Var', (147, 152))
23154	30349006	Of note, as expected, co-expression of BAP1 with DEUBAD or ASXL2 resulted in elevated levels of both proteins.	('co-expression', 'Var', (22, 35))	('expression', 'Species', '29278', (25, 35))	('elevated', 'PosReg', (77, 85))	('levels of both proteins', 'MPA', (86, 109))	('BAP1', 'Gene', (39, 43))
23156	30349006	Expression of GFP-DEUBAD, but not the K370R mutant, resulted in a strong reduction of H2Aub levels (Fig.	('K370R', 'Mutation', 'p.K370R', (38, 43))	('H2Aub', 'Chemical', '-', (86, 91))	('GFP-DEUBAD', 'Var', (14, 24))	('Expression', 'Species', '29278', (0, 10))	('reduction', 'NegReg', (73, 82))	('H2Aub levels', 'MPA', (86, 98))
23159	30349006	Moreover, the same results were observed using ASXL2 since the expression of the WT form, but not the corresponding K370R mutant, induced a strong decrease of H2Aub levels (Fig.	('expression', 'Species', '29278', (63, 73))	('decrease', 'NegReg', (147, 155))	('H2Aub', 'Chemical', '-', (159, 164))	('K370R', 'Var', (116, 121))	('H2Aub levels', 'MPA', (159, 171))	('K370R', 'Mutation', 'p.K370R', (116, 121))
23160	30349006	Next, we co-expressed Flag-DEUBAD or Flag-HA-DEUBAD K370R with Myc-BAP1 in presence or absence of HA-Ub in HEK293T cells and purified the monoubiquitinated (Flag-DEUBAD-Ub) versus the unmodified form of DEUBAD (Flag-HA-DEUBAD K370R) in complex with BAP1 (Fig.	('K370R', 'Mutation', 'p.K370R', (226, 231))	('K370R', 'Var', (52, 57))	('monoubiquitinated', 'MPA', (138, 155))	('HA', 'Chemical', 'MESH:C034124', (98, 100))	('K370R', 'Mutation', 'p.K370R', (52, 57))	('HA', 'Chemical', 'MESH:C034124', (216, 218))	('HA', 'Chemical', 'MESH:C034124', (42, 44))	('HA-Ub', 'Chemical', '-', (98, 103))	('HEK293T', 'CellLine', 'CVCL:0063', (107, 114))
23163	30349006	Remarkably, expression of the Drosophila Asx DEUBAD in S2 cells results in decreased H2Aub levels, while an increase of this modification was observed following expression of the corresponding K325R mutant suggesting a dominant negative effect (Fig.	('Asx', 'Gene', (41, 44))	('expression', 'Species', '29278', (161, 171))	('K325R', 'Var', (193, 198))	('K325R', 'Chemical', '-', (193, 198))	('Drosophila', 'Species', '7227', (30, 40))	('expression', 'Species', '29278', (12, 22))	('Asx', 'Gene', '36612', (41, 44))	('S2', 'CellLine', 'CVCL:Z232', (55, 57))	('H2Aub levels', 'MPA', (85, 97))	('H2Aub', 'Chemical', '-', (85, 90))	('decreased', 'NegReg', (75, 84))
23166	30349006	Early studies reported that loss of function mutations of Calypso or Asx resulted in derepression of the Ubx locus in Drosophila embryos and imaginal discs.	('Drosophila', 'Species', '7227', (118, 128))	('Calypso', 'Gene', (58, 65))	('mutations', 'Var', (45, 54))	('derepression', 'MPA', (85, 97))	('Ubx locus', 'Gene', (105, 114))	('Asx', 'Gene', (69, 72))	('loss of function', 'NegReg', (28, 44))	('Ubx', 'Chemical', '-', (105, 108))	('Asx', 'Gene', '36612', (69, 72))
23172	30349006	8a, 1', 2'), expression of Asx K325R mutant led to increased levels of H2Aub, suggesting that it dominantly interfere with the catalytic activity of the endogenous Calypso/Asx complex (Fig.	('Asx', 'Gene', (27, 30))	('Asx', 'Gene', (172, 175))	('expression', 'Species', '29278', (13, 23))	('H2Aub', 'Protein', (71, 76))	('increased', 'PosReg', (51, 60))	('K325R', 'Chemical', '-', (31, 36))	('catalytic activity', 'MPA', (127, 145))	('levels', 'MPA', (61, 67))	('catalytic activity', 'molecular_function', 'GO:0003824', ('127', '145'))	('Asx', 'Gene', '36612', (27, 30))	('Asx', 'Gene', '36612', (172, 175))	('H2Aub', 'Chemical', '-', (71, 76))	('interfere with', 'NegReg', (108, 122))	('K325R', 'Var', (31, 36))
23174	30349006	This effect does not seem to be the consequence of ectopic cell death as the signal for activated Caspase-3 remained essentially similar between WT and mutant Asx (Supplementary Fig.	('Asx', 'Gene', (159, 162))	('mutant', 'Var', (152, 158))	('cell death', 'biological_process', 'GO:0008219', ('59', '69'))	('Asx', 'Gene', '36612', (159, 162))
23176	30349006	We also note that WT and K325R Asx transgenes are expressed at comparable levels (Supplementary Fig.	('Asx', 'Gene', '36612', (31, 34))	('Asx', 'Gene', (31, 34))	('K325R', 'Var', (25, 30))	('K325R', 'Chemical', '-', (25, 30))
23180	30349006	Taken together, our results suggest that the Asx K325R mutant exerts a dominant negative effect over the endogenous Asx leading to increased levels of H2Aub and developmental defects in Drosophila.	('Asx', 'Gene', (116, 119))	('levels', 'MPA', (141, 147))	('Asx', 'Gene', (45, 48))	('developmental defects in Drosophila', 'Disease', 'MESH:D003147', (161, 196))	('increased', 'PosReg', (131, 140))	('H2Aub', 'Chemical', '-', (151, 156))	('developmental defects in Drosophila', 'Disease', (161, 196))	('Asx', 'Gene', '36612', (116, 119))	('K325R', 'Chemical', '-', (49, 54))	('H2Aub', 'Protein', (151, 156))	('Asx', 'Gene', '36612', (45, 48))	('K325R', 'Var', (49, 54))	('negative', 'NegReg', (80, 88))
23183	30349006	In U-2 OS cells, expression of ASXL2 K370R resulted in reduced cell proliferation as determined by colony forming ability assays (Fig.	('colony forming ability assays', 'CPA', (99, 128))	('expression', 'Species', '29278', (17, 27))	('reduced', 'NegReg', (55, 62))	('K370R', 'Var', (37, 42))	('cell proliferation', 'CPA', (63, 81))	('U-2 OS', 'CellLine', 'CVCL:0042', (3, 9))	('K370R', 'Mutation', 'p.K370R', (37, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
23185	30349006	While the majority of U-2 OS cell population transduced with empty vector or ASXL2 progressed to M phase, cells expressing the ASXL2 K370R were significantly delayed in their progression from G1 to M (Fig.	('U-2 OS', 'CellLine', 'CVCL:0042', (22, 28))	('M phase', 'CPA', (97, 104))	('delayed', 'NegReg', (158, 165))	('K370R', 'Var', (133, 138))	('K370R', 'Mutation', 'p.K370R', (133, 138))	('M phase', 'biological_process', 'GO:0000279', ('97', '104'))
23186	30349006	Expression of ASXL2 K370R also resulted in decreased cell proliferation in IMR90 normal human fibroblasts (Fig.	('K370R', 'Mutation', 'p.K370R', (20, 25))	('IMR90', 'CellLine', 'CVCL:0347', (75, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('Expression', 'Species', '29278', (0, 10))	('K370R', 'Var', (20, 25))	('human', 'Species', '9606', (88, 93))	('cell proliferation', 'CPA', (53, 71))	('decreased', 'NegReg', (43, 52))
23188	30349006	These results predict that depletion of ASXL2 itself would phenocopy the overexpression of ASXL2 K370R.	('K370R', 'Var', (97, 102))	('K370R', 'Mutation', 'p.K370R', (97, 102))	('expression', 'Species', '29278', (77, 87))	('depletion', 'MPA', (27, 36))
23197	30349006	Since we found that BAP1 activity is tightly regulated by UBE2Es-mediated ASXL2 monoubiquitination, we analyzed protein expression of these proteins in malignant mesothelioma, a cancer characterized by a high frequency of BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (227, 236))	('UBE2', 'Gene', (58, 62))	('expression', 'Species', '29278', (120, 130))	('analyzed', 'Reg', (103, 111))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (152, 174))	('malignant mesothelioma', 'Disease', (152, 174))	('UBE2', 'Gene', '7318', (58, 62))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('BAP1', 'Gene', (222, 226))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (152, 174))	('activity', 'MPA', (25, 33))
23199	30349006	Changes of UBE2Es expression is expected to impact BAP1 and ASXL2 expression.	('ASXL2', 'Gene', (60, 65))	('UBE2', 'Gene', '7318', (11, 15))	('BAP1', 'Gene', (51, 55))	('UBE2', 'Gene', (11, 15))	('expression', 'Species', '29278', (66, 76))	('impact', 'Reg', (44, 50))	('expression', 'Species', '29278', (18, 28))	('expression', 'MPA', (66, 76))	('Changes', 'Var', (0, 7))
23200	30349006	In turn, loss of BAP1 function by inactivating mutations, might also impact the expression of UBE2Es, as part of a potential feedback loop.	('UBE2', 'Gene', '7318', (94, 98))	('UBE2', 'Gene', (94, 98))	('loss', 'NegReg', (9, 13))	('expression', 'Species', '29278', (80, 90))	('expression', 'MPA', (80, 90))	('impact', 'NegReg', (69, 75))	('function', 'MPA', (22, 30))	('inactivating mutations', 'Var', (34, 56))	('BAP1', 'Gene', (17, 21))
23201	30349006	We studied BAP1, ASXL2, and UBE2Es expression in 10 human malignant mesothelioma biopsies containing wild-type BAP1 and in 10 human mesothelioma biopsies containing mutated BAP1, as determined in previous studies.	('malignant mesothelioma', 'Disease', (58, 80))	('mesothelioma', 'Disease', (68, 80))	('UBE2', 'Gene', '7318', (28, 32))	('human', 'Species', '9606', (126, 131))	('mesothelioma', 'Disease', 'MESH:D008654', (132, 144))	('expression', 'Species', '29278', (35, 45))	('UBE2', 'Gene', (28, 32))	('human', 'Species', '9606', (52, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (58, 80))	('mesothelioma', 'Disease', (132, 144))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (58, 80))	('BAP1', 'Gene', (173, 177))	('mutated', 'Var', (165, 172))
23202	30349006	Applying a logistic regression model with BAP1 status (WT vs. mutant) as the outcome, the best predictors were UBE2E3 (p = 0.04) and ASXL2 (p = 0.04).	('UBE2E3', 'Gene', (111, 117))	('UBE2E3', 'Gene', '10477', (111, 117))	('mutant', 'Var', (62, 68))
23208	30349006	Consistent with this model, ubiquitination of lysine 370 of ASXL2 plays a dual role in promoting protein stability (in the presence of interaction with BAP1) or inducing protein degradation (in the absence of interaction with BAP1).	('ASXL2', 'Gene', (60, 65))	('inducing', 'Reg', (161, 169))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('ubiquitination', 'MPA', (28, 42))	('promoting', 'PosReg', (87, 96))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('protein degradation', 'biological_process', 'GO:0030163', ('170', '189'))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('protein stability', 'MPA', (97, 114))	('lysine 370', 'Var', (46, 56))	('protein degradation', 'MPA', (170, 189))	('interaction', 'Interaction', (135, 146))
23209	30349006	Indeed, mutation of K370 results in increased protein levels of DEUBAD or ASXL2, and expression of chain elongation-defective Ub mutants, as well as the inhibition of the proteasome-associated DUB PSMD14, result in both stronger monoubiquitination and the apparition of additional ubiquitinated species of DEUBAD.	('chain elongation-defective', 'CPA', (99, 125))	('expression', 'MPA', (85, 95))	('inhibition', 'NegReg', (153, 163))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('proteasome', 'cellular_component', 'GO:0000502', ('171', '181'))	('monoubiquitination', 'MPA', (229, 247))	('stronger', 'PosReg', (220, 228))	('increased', 'PosReg', (36, 45))	('protein levels of DEUBAD', 'MPA', (46, 70))	('proteasome', 'molecular_function', 'GO:0004299', ('171', '181'))	('K370', 'Var', (20, 24))	('mutation', 'Var', (8, 16))	('mutants', 'Var', (129, 136))	('PSMD14', 'Gene', (197, 203))	('PSMD14', 'Gene', '10213', (197, 203))	('expression', 'Species', '29278', (85, 95))	('apparition of additional ubiquitinated species', 'MPA', (256, 302))
23212	30349006	In contrast, UBE2Es expression did not have a noticeable effect on ASXL2 alone, but increased its monoubiquitination and protein levels following co-expression with BAP1.	('expression', 'Var', (20, 30))	('expression', 'Species', '29278', (149, 159))	('UBE2', 'Gene', '7318', (13, 17))	('increased', 'PosReg', (84, 93))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('UBE2', 'Gene', (13, 17))	('expression', 'Species', '29278', (20, 30))
23223	30349006	Thus, although Asx K325R appears to act as a dominant-negative allele on the endogenous DUB complex, its effect is possibly not strong enough to displace all endogenous complexes repressing Ubx in wing imaginal discs.	('K325R', 'Var', (19, 24))	('K325R', 'Chemical', '-', (19, 24))	('Asx', 'Gene', '36612', (15, 18))	('Ubx', 'Chemical', '-', (190, 193))	('Asx', 'Gene', (15, 18))	('displace', 'NegReg', (145, 153))
23224	30349006	The crumpled wing phenotype is likely to be caused by a slight dominant negative effect of Asx K325R on endogenous Asx.	('crumpled wing phenotype', 'CPA', (4, 27))	('Asx', 'Gene', '36612', (91, 94))	('K325R', 'Chemical', '-', (95, 100))	('K325R', 'Var', (95, 100))	('Asx', 'Gene', (115, 118))	('Asx', 'Gene', (91, 94))	('negative', 'NegReg', (72, 80))	('Asx', 'Gene', '36612', (115, 118))
23227	30349006	It is also interesting to note that expression of the Asx K325R mutant might interfere with the en-Gal4 gene itself and this might explain the patchy expression of GFP in the discs.	('Gal4', 'Gene', '3960', (99, 103))	('Asx', 'Gene', '36612', (54, 57))	('interfere', 'NegReg', (77, 86))	('expression', 'Species', '29278', (150, 160))	('K325R', 'Chemical', '-', (58, 63))	('Gal4', 'Gene', (99, 103))	('K325R', 'Var', (58, 63))	('expression', 'Species', '29278', (36, 46))	('Asx', 'Gene', (54, 57))	('explain', 'Reg', (131, 138))	('expression', 'MPA', (36, 46))
23228	30349006	While this will require other studies, our results, nonetheless, show that expression of Asx K325R resulted in distinct Drosophila phenotypes suggesting the importance of Asx monoubiquitination in vivo.	('resulted in', 'Reg', (99, 110))	('Drosophila', 'Species', '7227', (120, 130))	('Asx', 'Gene', '36612', (89, 92))	('Drosophila phenotypes', 'CPA', (120, 141))	('K325R', 'Chemical', '-', (93, 98))	('Asx', 'Gene', '36612', (171, 174))	('expression', 'Species', '29278', (75, 85))	('K325R', 'Var', (93, 98))	('Asx', 'Gene', (89, 92))	('Asx', 'Gene', (171, 174))
23229	30349006	Here, we found that depletion of E2 enzymes responsible for ASXL2 monoubiquitination as well as expression of monoubiquitination-defective ASXL2 mutant reduces cell proliferation in several cell types suggesting the importance of this modification for normal cell cycle progression.	('expression', 'Species', '29278', (96, 106))	('cell proliferation in several cell types', 'CPA', (160, 200))	('mutant', 'Var', (145, 151))	('cell cycle', 'biological_process', 'GO:0007049', ('259', '269'))	('reduces', 'NegReg', (152, 159))	('ASXL2', 'Gene', (139, 144))	('depletion', 'MPA', (20, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))
23232	30349006	Indeed, a cancer mutation of BAP1 CTD found in melanoma, that abrogate BAP1-ASXL2 interaction and DUB activity toward histone H2Aub results in highly reduced DEUBAD monoubiquitination.	('H2Aub', 'Chemical', '-', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mutation', 'Var', (17, 25))	('BAP1-ASXL2 interaction', 'MPA', (71, 93))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('abrogate', 'NegReg', (62, 70))	('reduced', 'NegReg', (150, 157))	('activity', 'MPA', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('DEUBAD monoubiquitination', 'MPA', (158, 183))	('cancer', 'Disease', (10, 16))
23233	30349006	In addition, all BAP1 domains and motifs, including UCH, CC1, and CTD involved in catalysis as well as DEUBAD domains of ASXLs are targeted by cancer mutations (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CC1', 'Gene', '9821', (57, 60))	('targeted', 'Reg', (131, 139))	('mutations', 'Var', (150, 159))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CC1', 'Gene', (57, 60))	('BAP1', 'Gene', (17, 21))
23234	30349006	11b, c), Finally, we found that a positive BAP1 nuclear staining in mesothelioma tumors, indicative of wild-type BAP1, correlated with positive staining for ASXL2 and UBE2Es, particularly UBE2E2 and UBE2E3, while negative nuclear staining, indicative of BAP1 mutation correlated with negative or reduced (focal) staining for these same proteins.	('BAP1', 'Gene', (43, 47))	('reduced', 'NegReg', (296, 303))	('UBE2E3', 'Gene', '10477', (199, 205))	('staining', 'MPA', (144, 152))	('UBE2', 'Gene', '7318', (188, 192))	('UBE2E2', 'Gene', (188, 194))	('UBE2E2', 'Gene', '7325', (188, 194))	('BAP1', 'Gene', (254, 258))	('positive', 'PosReg', (34, 42))	('UBE2', 'Gene', (167, 171))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (68, 87))	('UBE2', 'Gene', (199, 203))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (68, 87))	('UBE2', 'Gene', (188, 192))	('positive', 'PosReg', (135, 143))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('staining', 'MPA', (312, 320))	('mesothelioma tumors', 'Disease', (68, 87))	('UBE2', 'Gene', '7318', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('UBE2E3', 'Gene', (199, 205))	('ASXL2', 'MPA', (157, 162))	('UBE2', 'Gene', '7318', (199, 203))	('mutation', 'Var', (259, 267))
23235	30349006	These findings suggest that deregulation of the UBE2E-ASXL2/BAP1 Ub signaling axis might participate to mesothelioma development.	('UBE2', 'Gene', '7318', (48, 52))	('deregulation', 'Var', (28, 40))	('UBE2', 'Gene', (48, 52))	('mesothelioma', 'Disease', (104, 116))	('participate', 'Reg', (89, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
23247	30349006	DEUBAD (ASXL2) (K289R, K340R, K365R, K370R, K390R, K391R) and DEUBAD (ASXL1) (K351R, K353R, K362R) point mutations constructs were generated by site direct mutagenesis using Q5 DNA Polymerase (CAT#M0491L) (New England Biolabs) in pENTR D-Topo DEUBAD (ASXL2) and pENTR D-Topo DEUBAD (ASXL1) respectively.	('ASXL1', 'Gene', '171023', (283, 288))	('K365R', 'Mutation', 'p.K365R', (30, 35))	('K289R', 'Var', (16, 21))	('mutagenesis', 'biological_process', 'GO:0006280', ('156', '167'))	('K353R', 'Mutation', 'p.K353R', (85, 90))	('K362R', 'Mutation', 'p.K362R', (92, 97))	('CAT', 'Gene', (193, 196))	('K351R', 'Mutation', 'p.K351R', (78, 83))	('ASXL1', 'Gene', (70, 75))	('K365R', 'Var', (30, 35))	('K340R', 'Mutation', 'rs893110546', (23, 28))	('K353R', 'Var', (85, 90))	('ASXL1', 'Gene', (283, 288))	('K370R', 'Var', (37, 42))	('D-Topo', 'Chemical', '-', (236, 242))	('K289R', 'Mutation', 'rs1431986163', (16, 21))	('K390R', 'Var', (44, 49))	('K362R', 'Var', (92, 97))	('D-Topo', 'Chemical', '-', (268, 274))	('M0491L', 'Mutation', 'p.M0491L', (197, 203))	('K340R', 'Var', (23, 28))	('K391R', 'Mutation', 'rs1490646627', (51, 56))	('K351R', 'Var', (78, 83))	('CAT', 'Gene', '847', (193, 196))	('CAT', 'molecular_function', 'GO:0004096', ('193', '196'))	('K391R', 'Var', (51, 56))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('K390R', 'Mutation', 'p.K390R', (44, 49))	('K370R', 'Mutation', 'p.K370R', (37, 42))	('ASXL1', 'Gene', '171023', (70, 75))
23248	30349006	Mammalian expression vectors of DEUBAD (ASXL1) and DEUBAD (ASXL2) mutant forms were generated in pDEST-Myc vector by recombination using LR clonase kit (CAT#11791020) (ThermoFisher Scientific).	('Mammalian', 'Species', '9606', (0, 9))	('CAT', 'Gene', '847', (153, 156))	('ASXL1', 'Gene', '171023', (40, 45))	('mutant', 'Var', (66, 72))	('CAT', 'Gene', (153, 156))	('ASXL1', 'Gene', (40, 45))	('expression vectors', 'Species', '29278', (10, 28))	('CAT', 'molecular_function', 'GO:0004096', ('153', '156'))
23249	30349006	MBP-DEUBAD (ASXL2) K370R was generated by recombination of pENTR D-Topo DEUBAD (ASXL2) K370R into pDEST-MBP vector.	('MBP', 'Gene', '4155', (0, 3))	('K370R', 'Mutation', 'p.K370R', (87, 92))	('MBP', 'Gene', '4155', (104, 107))	('D-Topo', 'Chemical', '-', (65, 71))	('K370R', 'Mutation', 'p.K370R', (19, 24))	('MBP', 'Gene', (0, 3))	('MBP', 'Gene', (104, 107))	('K370R', 'Var', (87, 92))
23250	30349006	DEUBAD (ASXL3) 240-280 a.a and DEUBAD (ASXL3) K350R 240-280 a.a were generated by gene synthesis (Biobasic Inc.) and then subcloned into pENTR D-Topo vector.	('K350R 240-280 a.a', 'Var', (46, 63))	('D-Topo', 'Chemical', '-', (143, 149))	('synthesis', 'biological_process', 'GO:0009058', ('87', '96'))	('ASXL3', 'Gene', '80816', (8, 13))	('ASXL3', 'Gene', '80816', (39, 44))	('ASXL3', 'Gene', (8, 13))	('ASXL3', 'Gene', (39, 44))	('K350R', 'Mutation', 'rs774483962', (46, 51))
23251	30349006	Myc-DEUBAD (ASXL3) and Myc-DEUBAD (ASXL3) K350R were generated by recombination of pENTR D-Topo DEUBAD (ASXL2) vectors into pDEST-Myc vector.	('ASXL3', 'Gene', (12, 17))	('K350R', 'Var', (42, 47))	('ASXL3', 'Gene', '80816', (35, 40))	('ASXL3', 'Gene', (35, 40))	('K350R', 'Mutation', 'rs774483962', (42, 47))	('ASXL3', 'Gene', '80816', (12, 17))	('D-Topo', 'Chemical', '-', (89, 95))
23258	30349006	pRK5-HA-Ubiquitin-K48, pRK5-HA-Ubiquitin-K48R, pRK5-HA-Ubiquitin-K63, pRK5-HA-Ubiquitin-K0, and pCDNA-HA-UCH37 were purchased from Addgene (#17605, #17604, #17606, #17603, and # 19415).	('Ubiquitin', 'molecular_function', 'GO:0031386', ('31', '40'))	('Ubi', 'Gene', (78, 81))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('78', '87'))	('pRK', 'molecular_function', 'GO:0008974', ('47', '50'))	('pRK', 'molecular_function', 'GO:0008974', ('70', '73'))	('UCH37', 'Gene', '51377', (105, 110))	('HA', 'Chemical', 'MESH:C034124', (102, 104))	('HA', 'Chemical', 'MESH:C034124', (52, 54))	('HA-Ub', 'Chemical', '-', (5, 10))	('#17606', 'Var', (156, 162))	('Ubi', 'Gene', '38456', (8, 11))	('HA-Ub', 'Chemical', '-', (28, 33))	('HA', 'Chemical', 'MESH:C034124', (75, 77))	('HA', 'Chemical', 'MESH:C034124', (5, 7))	('HA-Ub', 'Chemical', '-', (52, 57))	('HA', 'Chemical', 'MESH:C034124', (28, 30))	('Ubi', 'Gene', '38456', (55, 58))	('HA-Ub', 'Chemical', '-', (75, 80))	('UCH37', 'Gene', (105, 110))	('Ubi', 'Gene', '38456', (31, 34))	('pRK', 'molecular_function', 'GO:0008974', ('23', '26'))	('K48R', 'Mutation', 'rs115108034', (41, 45))	('Ubi', 'Gene', '38456', (78, 81))	('pRK', 'molecular_function', 'GO:0008974', ('0', '3'))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('8', '17'))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('55', '64'))	('Ubi', 'Gene', (8, 11))	('CD', 'Disease', 'MESH:D006223', (97, 99))	('Ubi', 'Gene', (55, 58))	('Ubi', 'Gene', (31, 34))
23259	30349006	BAP1 Ub binding mutants, Y33A/I226A/F228A, L8A/F168A/N229A, and L35A/I214A/F228A/L230A were generated using gene synthesis (BioBasic) and then subcloned into a modified pENTR D-Topo plasmid (Life Technologies).	('I214A', 'Var', (69, 74))	('F228A', 'Mutation', 'p.F228A', (75, 80))	('F228A', 'Mutation', 'p.F228A', (36, 41))	('I226A', 'SUBSTITUTION', 'None', (30, 35))	('N229A', 'Var', (53, 58))	('BAP1 Ub', 'Gene', (0, 7))	('F168A', 'Var', (47, 52))	('F168A', 'SUBSTITUTION', 'None', (47, 52))	('Y33A', 'SUBSTITUTION', 'None', (25, 29))	('L35A', 'Var', (64, 68))	('binding', 'molecular_function', 'GO:0005488', ('8', '15'))	('I226A', 'Var', (30, 35))	('Y33A', 'Var', (25, 29))	('synthesis', 'biological_process', 'GO:0009058', ('113', '122'))	('L230A', 'Mutation', 'p.L230A', (81, 86))	('N229A', 'SUBSTITUTION', 'None', (53, 58))	('L35A', 'SUBSTITUTION', 'None', (64, 68))	('I214A', 'SUBSTITUTION', 'None', (69, 74))	('D-Topo', 'Chemical', '-', (175, 181))
23260	30349006	Mammalian and bacterial expression constructs of Flag-BAP1 mutants were generated by recombination of pENTR BAP1 into pDEST-Flag or pDEST-His expression vectors respectively.	('Mammalian', 'Species', '9606', (0, 9))	('expression', 'Species', '29278', (24, 34))	('mutants', 'Var', (59, 66))	('His', 'Chemical', 'MESH:D006639', (138, 141))	('expression', 'Species', '29278', (142, 152))	('pENTR BAP1', 'Gene', (102, 112))	('Flag-BAP1', 'Gene', (49, 58))	('expression vectors', 'Species', '29278', (142, 160))
23267	30349006	pENTR-DEUBAD (Asx) WT was generated by gene synthesis of the Drosophila DEUBAD (Asx) domain (185-352aa) (ThermoFisher Scientific) into modified pENTR D-Topo.	('Asx', 'Gene', '36612', (80, 83))	('Asx', 'Gene', (14, 17))	('185-352aa', 'Var', (93, 102))	('Drosophila', 'Species', '7227', (61, 71))	('synthesis', 'biological_process', 'GO:0009058', ('44', '53'))	('Asx', 'Gene', (80, 83))	('Asx', 'Gene', '36612', (14, 17))	('D-Topo', 'Chemical', '-', (150, 156))
23269	30349006	pENTR-DEUBAD (Asx) K325R was generated by site-directed mutagenesis using Q5 High-Fidelity DNA Polymerase into pENTR-DEUBAD (Asx) WT.	('K325R', 'Var', (19, 24))	('Asx', 'Gene', '36612', (125, 128))	('K325R', 'Chemical', '-', (19, 24))	('Asx', 'Gene', (14, 17))	('Asx', 'Gene', (125, 128))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('Asx', 'Gene', '36612', (14, 17))	('mutagenesis', 'biological_process', 'GO:0006280', ('56', '67'))
23270	30349006	Myc-V5-DEUBAD (Asx) WT, Myc-V5-DEUBAD (Asx) K325R and 3xFlag-Calypso WT were generated by PCR using their respective pENTR vectors as templates and then subcloned into pActin5C vector for ubiquitous expression in S2 cells.	('expression', 'Species', '29278', (199, 209))	('Asx', 'Gene', '36612', (15, 18))	('K325R', 'Var', (44, 49))	('K325R', 'Chemical', '-', (44, 49))	('Asx', 'Gene', '36612', (39, 42))	('Asx', 'Gene', (15, 18))	('Asx', 'Gene', (39, 42))	('S2', 'CellLine', 'CVCL:Z232', (213, 215))
23287	30349006	U-2 OS, IMR90 or LF1 cells were transfected using Lipofectamine RNAimax (Life technologies) (CAT#13778150) with 200 pmol of either ON-TARGET plus Non-targeting pool (D-001810) or with a pool of siRNA sequences purchased from Sigma-Aldrich targeting UBE2E1 (pool of 2 oligonucleotides, SASI_Hs01_00147125, SASI_Hs01_00335491) UBE2E2 (pool of 2 oligonucleotides, SASI_Hs01_00102040, SASI_Hs01_00102041), UBE2E3 (pool of 2 oligonucleotides, SASI_Hs01_00107204, SASI_Hs01_00107206), ASXL2 (pool of 3 oligonucleotides SASI_Hs01_00202197, SASI_Hs01_00202200, SASI_Hs01_00202201), PSMD14 (pool of 2 oligonucleotides, SASI_Hs01_00024447, SASI_Hs01_00024446), UCH37 (pool of 2 oligonucleotides, SASI_Hs01_00142742, SASI_Hs01_00142743).	('oligonucleotides', 'Chemical', 'MESH:D009841', (496, 512))	('CAT', 'Gene', (93, 96))	('oligonucleotides', 'Chemical', 'MESH:D009841', (267, 283))	('IMR90', 'CellLine', 'CVCL:0347', (8, 13))	('Lipofectamine', 'Chemical', 'MESH:C086724', (50, 63))	('oligonucleotides', 'Chemical', 'MESH:D009841', (343, 359))	('UCH37', 'Gene', '51377', (651, 656))	('PSMD14', 'Gene', (574, 580))	('SASI_Hs01_00202197', 'Var', (513, 531))	('U-2 OS', 'CellLine', 'CVCL:0042', (0, 6))	('CAT', 'Gene', '847', (93, 96))	('UBE2E3', 'Gene', (402, 408))	('SASI_Hs01_00202201', 'Var', (553, 571))	('CAT', 'molecular_function', 'GO:0004096', ('93', '96'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (668, 684))	('UBE2E3', 'Gene', '10477', (402, 408))	('PSMD14', 'Gene', '10213', (574, 580))	('UCH37', 'Gene', (651, 656))	('SASI_Hs01_00024447', 'Var', (610, 628))	('UBE2E1', 'Gene', (249, 255))	('oligonucleotides', 'Chemical', 'MESH:D009841', (420, 436))	('SASI_Hs01_00142743', 'Var', (706, 724))	('UBE2E1', 'Gene', '7324', (249, 255))	('UBE2E2', 'Gene', (325, 331))	('oligonucleotides', 'Chemical', 'MESH:D009841', (592, 608))	('SASI_Hs01_00024446', 'Var', (630, 648))	('UBE2E2', 'Gene', '7325', (325, 331))
23288	30349006	ON-TARGETplus SMARTpool UBE2O siRNA (pool of 4 oligonucleotides, J-008979-08, J-008979-07, J-008979-06, J-008979-05) was purchased from Dharmacon (L-008979-00-0050).	('J-008979-08', 'Var', (65, 76))	('J-008979-07', 'Var', (78, 89))	('J-008979-06', 'Var', (91, 102))	('oligonucleotides', 'Chemical', 'MESH:D009841', (47, 63))	('UBE2O', 'Gene', '63893', (24, 29))	('UBE2O', 'Gene', (24, 29))	('J-008979-05', 'Var', (104, 115))
23303	30349006	The dilutions for primary antibodies are as follow: H2Aub (1/200), UBX (1/200), Flag M2 (1/200), cleaved Caspase-3 (1/200).	('Caspase-3', 'Protein', (105, 114))	('cleaved', 'MPA', (97, 104))	('H2Aub', 'Chemical', '-', (52, 57))	('UBX (1/200', 'Gene', '55968', (67, 77))	('H2Aub', 'Var', (52, 57))
23323	30349006	His-BAP1, His-BAP1 C91S, MBP-DEUBAD (ASXL2) (WT and K370R) and His-tagged UBE2E2 and UBE2E3 proteins were purified from bacteria as described above.	('MBP', 'Gene', '4155', (25, 28))	('UBE2E3', 'Gene', '10477', (85, 91))	('His', 'Chemical', 'MESH:D006639', (0, 3))	('C91S', 'Mutation', 'p.C91S', (19, 23))	('K370R', 'Mutation', 'p.K370R', (52, 57))	('His', 'Chemical', 'MESH:D006639', (10, 13))	('His', 'Chemical', 'MESH:D006639', (63, 66))	('C91S', 'Var', (19, 23))	('UBE2E3', 'Gene', (85, 91))	('MBP', 'Gene', (25, 28))	('UBE2E2', 'Gene', (74, 80))	('His-BAP1 C91S', 'Var', (10, 23))	('UBE2E2', 'Gene', '7325', (74, 80))
23347	30349006	The deubiquitination reactions were done using monoubiquitinated-Flag-DEUBAD (ASXL2) WT-HA-Ub or Flag-HA-DEUBAD (ASXL2) K370R each in complex with BAP1.	('HA', 'Chemical', 'MESH:C034124', (88, 90))	('HA', 'Chemical', 'MESH:C034124', (102, 104))	('K370R', 'Var', (120, 125))	('deubiquitination', 'biological_process', 'GO:0016579', ('4', '20'))	('K370R', 'Mutation', 'p.K370R', (120, 125))	('deubiquitination', 'MPA', (4, 20))	('HA-Ub', 'Chemical', '-', (88, 93))
23352	30349006	U-2 OS, IMR90, LF1 and 3T3L1 cell lines stably expressing Myc-GFP, Myc-ASXL2 WT and Myc-ASXL2 K370R were generated by transduction using lentiviral pLenti-CMV expression constructs.	('IMR90', 'CellLine', 'CVCL:0347', (8, 13))	('Myc-ASXL2', 'Var', (84, 93))	('transduction', 'biological_process', 'GO:0009293', ('118', '130'))	('expression', 'Species', '29278', (159, 169))	('K370R', 'Mutation', 'p.K370R', (94, 99))	('U-2 OS', 'CellLine', 'CVCL:0042', (0, 6))	('L1', 'CellLine', 'CVCL:S918', (26, 28))	('Myc-GFP', 'Gene', (58, 65))
23378	30349006	A BAP1 model lacking a large loop region and the NLS was generated by SWISS Model, and this was followed by substitution of amino acid differences superimposed on the UCH37 structure using Coot.	('lacking', 'NegReg', (13, 20))	('UCH37', 'Gene', (167, 172))	('UCH37', 'Gene', '51377', (167, 172))	('substitution', 'Var', (108, 120))
23427	30363152	Those receiving cisplatin and pemetrexed had a significantly longer median overall survival (12.1 versus 9.3 months), longer time to progression (5.7 versus 3.9 months) and greater objective response rate (41 versus 17%).	('longer', 'PosReg', (61, 67))	('pemetrexed', 'Chemical', 'MESH:D000068437', (30, 40))	('cisplatin', 'Var', (16, 25))	('overall survival', 'MPA', (75, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('objective', 'MPA', (181, 190))
23498	30109162	ALK-positive mesotheliomas have also been identified by immunohistochemistry in rare case and confirmed ALK rearrangement by fluorescence in situ hybridization.	('mesotheliomas', 'Disease', 'MESH:D008654', (13, 26))	('mesotheliomas', 'Disease', (13, 26))	('ALK', 'Gene', '238', (104, 107))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (104, 107))	('rearrangement', 'Var', (108, 121))	('ALK', 'Gene', '238', (0, 3))
23501	30109162	Molecular prognostic factors like chromosomal alterations of the CDKN2A locus 9p21.3 in which a homozygous deletion by FISH is a marker of malignancy and poor prognosis with shorter survival and shorter time to relapse.	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('malignancy', 'Disease', (139, 149))	('CDKN2A', 'Gene', (65, 71))	('deletion', 'Var', (107, 115))	('shorter', 'NegReg', (174, 181))
23502	30109162	Germline BAP1 mutations, observed in 1%-2% of mesotheliomas appear to confer a favorable prognosis on the overall survival.	('BAP1', 'Gene', '8314', (9, 13))	('mesotheliomas', 'Disease', 'MESH:D008654', (46, 59))	('mesotheliomas', 'Disease', (46, 59))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
23677	21159167	Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox.	('MEK1/2', 'Gene', '5604;5605', (10, 16))	('U0126', 'Chemical', 'MESH:C113580', (28, 33))	('MEK1/2', 'Gene', (10, 16))	('Dox', 'Chemical', 'MESH:D004317', (156, 159))	('sensitizes', 'Reg', (133, 143))	('ERK1', 'molecular_function', 'GO:0004707', ('122', '126'))	('MEK1', 'molecular_function', 'GO:0004708', ('10', '14'))	('inhibition', 'Var', (103, 113))	('ERK1 and 2', 'Gene', '5595;5594', (122, 132))
23678	21159167	U0126 significantly modulated endogenous expression of several important drug resistance (BCL2, ABCB1, ABCC3), prosurvival (BCL2), DNA repair (BRCA1, BRCA2), hormone receptor (AR, ESR2, PPARgamma) and drug metabolism (CYP3A4) genes newly identified in MM cells.	('BCL2', 'molecular_function', 'GO:0015283', ('90', '94'))	('hormone receptor', 'Gene', '3164', (158, 174))	('BCL2', 'molecular_function', 'GO:0015283', ('124', '128'))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('drug metabolism', 'biological_process', 'GO:0017144', ('201', '216'))	('CYP3A4', 'molecular_function', 'GO:0033780', ('218', '224'))	('ABCB1', 'Gene', (96, 101))	('ESR2', 'Gene', '2100', (180, 184))	('BRCA2', 'Gene', (150, 155))	('ABCB1', 'Gene', '5243', (96, 101))	('endogenous expression', 'MPA', (30, 51))	('drug resistance', 'biological_process', 'GO:0009315', ('73', '88'))	('drug resistance', 'biological_process', 'GO:0042493', ('73', '88'))	('ESR2', 'Gene', (180, 184))	('hormone receptor', 'Gene', (158, 174))	('ABCC3', 'Gene', (103, 108))	('PPARgamma', 'Gene', '5468', (186, 195))	('drug resistance', 'Phenotype', 'HP:0020174', (73, 88))	('BCL2', 'Gene', (90, 94))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('DNA repair', 'biological_process', 'GO:0006281', ('131', '141'))	('BRCA2', 'Gene', '675', (150, 155))	('CYP3A4', 'Gene', '1576', (218, 224))	('BRCA1', 'Gene', '672', (143, 148))	('BRCA1', 'Gene', (143, 148))	('U0126', 'Var', (0, 5))	('ABCC3', 'Gene', '8714', (103, 108))	('modulated', 'Reg', (20, 29))	('CYP3A4', 'Gene', (218, 224))	('PPARgamma', 'Gene', (186, 195))
23685	21159167	For example, abnormal activation of the Raf/MEK/extracellular signal-regulated (ERK) pathway occurs in many human cancers, including MM, due to mutations in upstream membrane receptors, Ras and B-Raf, as well as mutations in genes regulating Raf activity that reportedly induces chemoresistance to doxorubicin (Dox) and paclitaxel in breast cancer cells.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('B-Raf', 'Gene', (194, 199))	('cancers', 'Disease', (114, 121))	('extracellular', 'cellular_component', 'GO:0005576', ('48', '61'))	('membrane', 'cellular_component', 'GO:0016020', ('166', '174'))	('Raf', 'Gene', '22882', (242, 245))	('Ras', 'Gene', (186, 189))	('breast cancer', 'Disease', 'MESH:D001943', (334, 347))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (334, 347))	('mutations', 'Var', (144, 153))	('MEK', 'Gene', '5609', (44, 47))	('Raf', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('paclitaxel', 'Chemical', 'MESH:D017239', (320, 330))	('mutations', 'Var', (212, 221))	('MEK', 'Gene', (44, 47))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('ERK', 'Gene', '5594', (80, 83))	('B-Raf', 'Gene', '673', (194, 199))	('Dox', 'Chemical', 'MESH:D004317', (311, 314))	('Raf', 'Gene', (196, 199))	('Raf', 'Gene', '22882', (40, 43))	('Raf', 'Gene', (242, 245))	('chemoresistance', 'CPA', (279, 294))	('doxorubicin', 'Chemical', 'MESH:D004317', (298, 309))	('ERK', 'Gene', (80, 83))	('activation', 'PosReg', (22, 32))	('induces', 'Reg', (271, 278))	('human', 'Species', '9606', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (334, 347))	('Raf', 'Gene', '22882', (196, 199))
23704	21159167	Subsequent karyotype analysis of the Hmeso line by Dr. Joseph Testa demonstrated that the cells were human and possessed several deletions common in mesothelioma lines.	('deletions', 'Var', (129, 138))	('mesothelioma lines', 'Disease', 'MESH:D008654', (149, 167))	('mesothelioma lines', 'Disease', (149, 167))	('rat', 'Species', '10116', (75, 78))	('human', 'Species', '9606', (101, 106))
23711	21159167	Human MM cells (transfected or untransfected) were treated with different concentrations of Dox with and without U0126 or U0124 for 24 h, and cell viability was measured in cells using the colorimetric MTS Assay, CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega) as per the manufacturer's recommendations.	('Human', 'Species', '9606', (0, 5))	('U0124', 'Chemical', '-', (122, 127))	('rat', 'Species', '10116', (259, 262))	('U0126', 'Var', (113, 118))	('rat', 'Species', '10116', (81, 84))	('U0124', 'Var', (122, 127))	('Cell Proliferation', 'biological_process', 'GO:0008283', ('247', '265'))	('Dox', 'Chemical', 'MESH:D004317', (92, 95))	('U0126', 'Chemical', 'MESH:C113580', (113, 118))
23717	21159167	Confluent HMESO cells were transfected with either ERK1 or ERK2, or scrambled control Sure Silencing Plasmids (4 sh sequences for each gene were used) from SA Biosciences (Frederick, MD), using Lipofectamine 2000 (Invitrogen, Carlsbad, CA).	('ERK2', 'molecular_function', 'GO:0004707', ('59', '63'))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (194, 212))	('ERK1', 'Var', (51, 55))	('HMESO', 'Chemical', '-', (10, 15))	('ERK2', 'Gene', (59, 63))	('ERK1', 'molecular_function', 'GO:0004707', ('51', '55'))
23748	21159167	Pre-treatment of human MM cells with the MEK1/2 inhibitor U0126 (20 muM for 1 h) resulted in attenuation of Dox-induced ERK1/2 activation in all MM lines, whereas the inactive analog, U0124 (20 muM for 1 h), had no significant effects on Dox-induced ERK phosphorylation (Figure 1C).	('muM', 'Gene', (68, 71))	('activation', 'MPA', (127, 137))	('ERK', 'Gene', (250, 253))	('muM', 'Gene', '56925', (194, 197))	('muM', 'Gene', (194, 197))	('attenuation', 'NegReg', (93, 104))	('Dox', 'Chemical', 'MESH:D004317', (108, 111))	('ERK1', 'molecular_function', 'GO:0004707', ('120', '124'))	('human', 'Species', '9606', (17, 22))	('ERK', 'molecular_function', 'GO:0004707', ('250', '253'))	('ERK', 'Gene', '5594', (120, 123))	('U0124', 'Chemical', '-', (184, 189))	('U0126', 'Chemical', 'MESH:C113580', (58, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('254', '269'))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('U0126', 'Var', (58, 63))	('ERK', 'Gene', (120, 123))	('MEK1/2', 'Gene', '5604;5605', (41, 47))	('MEK1/2', 'Gene', (41, 47))	('ERK', 'Gene', '5594', (250, 253))	('Dox', 'Chemical', 'MESH:D004317', (238, 241))	('MEK1', 'molecular_function', 'GO:0004708', ('41', '45'))	('muM', 'Gene', '56925', (68, 71))	('Dox-induced', 'MPA', (108, 119))
23751	21159167	As shown in Figure 2A (grey bars), treatment with U0126 and Dox resulted in significantly more cell killing in all 3 MM lines evaluated as compared to Dox or U0126 alone.	('cell killing', 'CPA', (95, 107))	('U0126', 'Var', (50, 55))	('U0126', 'Chemical', 'MESH:C113580', (50, 55))	('Dox', 'Chemical', 'MESH:D004317', (60, 63))	('cell killing', 'biological_process', 'GO:0001906', ('95', '107'))	('more', 'PosReg', (90, 94))	('Dox', 'Chemical', 'MESH:D004317', (151, 154))	('U0126', 'Chemical', 'MESH:C113580', (158, 163))
23752	21159167	In HMESO and MO cells, U0126 alone also had a significant effect on reducing cell viability, suggesting the possible role of endogenous ERK1/2 activation in cell survival.	('U0126', 'Var', (23, 28))	('reducing', 'NegReg', (68, 76))	('ERK1', 'molecular_function', 'GO:0004707', ('136', '140'))	('HMESO', 'Chemical', '-', (3, 8))	('U0126', 'Chemical', 'MESH:C113580', (23, 28))	('cell viability', 'CPA', (77, 91))
23758	21159167	Exposure of both MM cell lines to the MEK1/2 inhibitor (U0126, 20 muM for 24 h) resulted in significantly altered levels of some of these genes (BCL2, cFOS, BRCA1, AR, ESR2, CYP3A4, PPARgamma, BRCA2, ABCC3) (Table 1 and Additional Table 1), suggesting a role of ERK1 or 2 in their regulation.	('altered', 'Reg', (106, 113))	('muM', 'Gene', '56925', (66, 69))	('BRCA2', 'Gene', (193, 198))	('ESR2', 'Gene', '2100', (168, 172))	('muM', 'Gene', (66, 69))	('ESR2', 'Gene', (168, 172))	('PPARgamma', 'Gene', '5468', (182, 191))	('CYP3A4', 'Gene', '1576', (174, 180))	('ERK1', 'molecular_function', 'GO:0004707', ('262', '266'))	('ABCC3', 'Gene', (200, 205))	('BRCA2', 'Gene', '675', (193, 198))	('CYP3A4', 'Gene', (174, 180))	('CYP3A4', 'molecular_function', 'GO:0033780', ('174', '180'))	('PPARgamma', 'Gene', (182, 191))	('ABCC3', 'Gene', '8714', (200, 205))	('BCL2', 'Gene', (145, 149))	('BRCA1', 'Gene', '672', (157, 162))	('BCL2', 'molecular_function', 'GO:0015283', ('145', '149'))	('regulation', 'biological_process', 'GO:0065007', ('281', '291'))	('MEK1', 'molecular_function', 'GO:0004708', ('38', '42'))	('levels', 'MPA', (114, 120))	('BRCA1', 'Gene', (157, 162))	('U0126', 'Chemical', 'MESH:C113580', (56, 61))	('U0126', 'Var', (56, 61))	('MEK1/2', 'Gene', '5604;5605', (38, 44))	('MEK1/2', 'Gene', (38, 44))
23759	21159167	As the small molecule inhibitor, U0126, abrogated both ERK1 and ERK2 activation, we created stably inhibited (short hairpin, sh) ERK1 and ERK2 HMESO and PPMMill lines to determine if ERKs had similar or unique roles in Dox chemoresistance.	('U0126', 'Var', (33, 38))	('ERK2', 'Gene', (64, 68))	('ERKs', 'Gene', (183, 187))	('ERKs', 'Gene', '5595;5594;26413;50689;116590;5595;26417;50689', (183, 187))	('ERK1', 'molecular_function', 'GO:0004707', ('129', '133'))	('HMESO', 'Chemical', '-', (143, 148))	('ERK1', 'molecular_function', 'GO:0004707', ('55', '59'))	('abrogated', 'NegReg', (40, 49))	('U0126', 'Chemical', 'MESH:C113580', (33, 38))	('ERK1', 'Gene', (55, 59))	('ERK2', 'molecular_function', 'GO:0004707', ('138', '142'))	('ERK2', 'molecular_function', 'GO:0004707', ('64', '68'))	('Dox', 'Chemical', 'MESH:D004317', (219, 222))
23763	21159167	Although significantly increased Dox-induced cell killing was observed after inhibition of either ERK1 or ERK2, the shERK2 cell lines showed significantly ( p <= 0.05) greater cell killing as compared to the shERK1 lines from both MMs (Figure 2B).	('ERK1', 'molecular_function', 'GO:0004707', ('98', '102'))	('inhibition', 'Var', (77, 87))	('greater', 'PosReg', (168, 175))	('ERK2', 'Gene', (106, 110))	('ERK1', 'Gene', (98, 102))	('cell killing', 'biological_process', 'GO:0001906', ('176', '188'))	('ERK2', 'molecular_function', 'GO:0004707', ('106', '110'))	('Dox', 'Chemical', 'MESH:D004317', (33, 36))	('Dox-induced cell killing', 'CPA', (33, 57))	('increased', 'PosReg', (23, 32))	('cell killing', 'CPA', (176, 188))	('cell killing', 'biological_process', 'GO:0001906', ('45', '57'))
23765	21159167	To show that inhibition of ERK1 or ERK2 increases Dox-induced toxicity by causing greater intracellular accumulation of Dox, we performed flow cytometry experiments on stably transfected HMESO lines treated with Dox (0.5 or 5.0 muM for 1 h or 5 h).	('ERK2', 'molecular_function', 'GO:0004707', ('35', '39'))	('ERK1', 'molecular_function', 'GO:0004707', ('27', '31'))	('intracellular accumulation of Dox', 'MPA', (90, 123))	('Dox', 'Chemical', 'MESH:D004317', (120, 123))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('inhibition', 'Var', (13, 23))	('Dox', 'Chemical', 'MESH:D004317', (50, 53))	('intracellular', 'cellular_component', 'GO:0005622', ('90', '103'))	('muM', 'Gene', '56925', (228, 231))	('toxicity', 'Disease', (62, 70))	('ERK1', 'Gene', (27, 31))	('HMESO', 'Chemical', '-', (187, 192))	('ERK2', 'Gene', (35, 39))	('increases', 'PosReg', (40, 49))	('Dox', 'Chemical', 'MESH:D004317', (212, 215))	('muM', 'Gene', (228, 231))	('greater', 'PosReg', (82, 89))
23788	21159167	We studied 4 different MM lines for Dox responses after ERK1/2 manipulation either with an inhibitor (U0126) or by shRNA approaches.	('Dox responses', 'MPA', (36, 49))	('ERK1/2', 'Gene', (56, 62))	('Dox', 'Chemical', 'MESH:D004317', (36, 39))	('manipulation', 'Var', (63, 75))	('U0126', 'Chemical', 'MESH:C113580', (102, 107))	('ERK1', 'molecular_function', 'GO:0004707', ('56', '60'))
23798	21159167	BRCA2 was also endogenously upregulated in MM cells and ERK1/2 inhibition decreased expression of this gene (Table 1), consistent with already published work that ERK1/2 activation inhibits replication of prostate cells via upregulation of BRCA2 .	('BRCA2', 'Gene', '675', (0, 5))	('BRCA2', 'Gene', '675', (240, 245))	('ERK1', 'molecular_function', 'GO:0004707', ('163', '167'))	('inhibits', 'NegReg', (181, 189))	('replication of prostate cells', 'CPA', (190, 219))	('BRCA2', 'Gene', (0, 5))	('upregulated', 'PosReg', (28, 39))	('BRCA2', 'Gene', (240, 245))	('inhibition', 'Var', (63, 73))	('decreased', 'NegReg', (74, 83))	('upregulation', 'PosReg', (224, 236))	('ERK1', 'molecular_function', 'GO:0004707', ('56', '60'))	('expression', 'MPA', (84, 94))
23801	21159167	We also report for the first time the upregulation of a cytochrome P450 enzyme gene, CYP3A4, related to drug metabolism in the ME-26 epithelioid cell line that was decreased 3-fold after addition of U0126.	('CYP3A4', 'Gene', (85, 91))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('56', '71'))	('decreased', 'NegReg', (164, 173))	('CYP3A4', 'Gene', '1576', (85, 91))	('U0126', 'Var', (199, 204))	('CYP3A4', 'molecular_function', 'GO:0033780', ('85', '91'))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('56', '71'))	('upregulation', 'PosReg', (38, 50))	('U0126', 'Chemical', 'MESH:C113580', (199, 204))	('drug metabolism', 'biological_process', 'GO:0017144', ('104', '119'))
23809	21159167	Inhibition of ABC genes by ERK1 or 2 inhibition may be responsible for the increased accumulation of Dox observed in shERK1 and shERK2 MM cells (Figure 3).	('ERK1', 'molecular_function', 'GO:0004707', ('27', '31'))	('inhibition', 'Var', (37, 47))	('ABC', 'Gene', (14, 17))	('Dox', 'MPA', (101, 104))	('Dox', 'Chemical', 'MESH:D004317', (101, 104))	('ABC', 'Gene', '10058', (14, 17))	('increased accumulation', 'PosReg', (75, 97))	('ERK1', 'Gene', (27, 31))
23815	21159167	Further, we demonstrate that blocking ERK1 and ERK2 enhances the chemotherapeutic potential of Dox in a murine xenograft model.	('enhances', 'PosReg', (52, 60))	('ERK2', 'Gene', (47, 51))	('ERK1', 'molecular_function', 'GO:0004707', ('38', '42'))	('Dox', 'Chemical', 'MESH:D004317', (95, 98))	('rat', 'Species', '10116', (19, 22))	('murine', 'Species', '10090', (104, 110))	('ERK1', 'Gene', (38, 42))	('ERK2', 'molecular_function', 'GO:0004707', ('47', '51'))	('blocking', 'Var', (29, 37))	('chemotherapeutic potential of Dox', 'MPA', (65, 98))
23823	21159167	Hillegass), NIH (P30CA006927) an appropriation from the Commonwealth of Pennsylvania (J.R. Testa), and the Vermont Cancer Center/Lake Champlain Cancer Research Organization (A. Shukla).	('Cancer Center/Lake Champlain Cancer', 'Disease', (115, 150))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer Center/Lake Champlain Cancer', 'Disease', 'MESH:D009369', (115, 150))	('P30CA006927', 'Var', (17, 28))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))
23861	19133112	Thus, preoperative diagnostics including physical examination, laboratory parameters, tumor markers (CA19-9, CEA, CA125, CA72-4), computed tomography of the chest, abdomen and pelvis with intravenous and oral/rectal contrast and endoscopy with or without endoluminal ultrasonography (colorectal and gastric cancer) are indispensable (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CA125', 'Gene', (114, 119))	('CA19-9', 'Var', (101, 107))	('tumor', 'Disease', (86, 91))	('CA72-4', 'Var', (121, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (299, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('CEA', 'Gene', (109, 112))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (284, 313))	('CA125', 'Gene', '94025', (114, 119))	('CEA', 'Gene', '5670', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
23881	19133112	Bowel morbidity was associated with electroevaporation or excision of tumor nodes on the small bowel surface.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('electroevaporation', 'Var', (36, 54))	('tumor', 'Disease', (70, 75))	('excision', 'Var', (58, 66))	('Bowel morbidity', 'Disease', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
23882	19133112	In conclusion, morbitity rates after CRS and HIPEC are relatively high but comparable to other major gastrointestinal surgery.	('CRS', 'Disease', (37, 40))	('major gastrointestinal surgery', 'Phenotype', 'HP:0004798', (95, 125))	('HIPEC', 'Var', (45, 50))	('CRS', 'Disease', 'MESH:D003398', (37, 40))
23892	19133112	Moreover, low PCI as well as P1/P2 using the Japanese classification or stage I/II using the Lyon classification indicating limited extent of peritoneal tumor dissemination were associated with better prognosis.	('low', 'Var', (10, 13))	('tumor dissemination', 'Disease', (153, 172))	('tumor dissemination', 'Disease', 'MESH:D009103', (153, 172))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
23975	30825033	While we did not have formal guidelines to help decide for or against repeat CRS-HIPEC, our data suggest that we were more likely to perform repeat CRS-HIPEC in patients having primary appendix histology, non-high-grade tumors, and longer PFS following initial CRS-HIPEC.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('primary appendix', 'Disease', (177, 193))	('tumors', 'Disease', (220, 226))	('patients', 'Species', '9606', (161, 169))	('non-high-grade', 'Var', (205, 219))
23977	30171198	Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age.	('TRAF7', 'Gene', '84231', (119, 124))	('CDC42', 'Gene', (129, 134))	('papillary mesothelioma', 'Disease', (155, 177))	('mesothelial neoplasm', 'Disease', (193, 213))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (20, 42))	('women', 'Species', '9606', (270, 275))	('TRAF7', 'Gene', (119, 124))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (155, 177))	('mesothelial neoplasm', 'Disease', 'MESH:D018301', (193, 213))	('neoplasm', 'Phenotype', 'HP:0002664', (205, 213))	('mutations', 'Var', (106, 115))	('papillary mesothelioma', 'Disease', (20, 42))
23982	30171198	We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma.	('TRAF7', 'Gene', (80, 85))	('BAP1', 'Gene', '8314', (135, 139))	('ALK', 'Gene', (172, 175))	('SETD2', 'Gene', (161, 166))	('NF2', 'Gene', '4771', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('CDKN2A', 'Gene', (146, 152))	('missense mutations', 'Var', (47, 65))	('NF2', 'Gene', (141, 144))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (197, 219))	('SETD2', 'Gene', '29072', (161, 166))	('CDC42', 'Gene', (89, 94))	('BAP1', 'Gene', (135, 139))	('tumors', 'Disease', (23, 29))	('CDKN2A', 'Gene', '1029', (146, 152))	('DDX3X', 'Gene', (154, 159))	('malignant mesothelioma', 'Disease', (197, 219))	('TRAF7', 'Gene', '84231', (80, 85))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (197, 219))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('ALK', 'Gene', '238', (172, 175))	('DDX3X', 'Gene', '1654', (154, 159))
23983	30171198	We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors.	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('adenomatoid tumors', 'Disease', (268, 286))	('TRAF7', 'Gene', '84231', (158, 163))	('pathogenesis', 'biological_process', 'GO:0009405', ('200', '212'))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (268, 286))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (241, 263))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (58, 75))	('adenomatoid tumor', 'Disease', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('mesothelial neoplasm', 'Disease', (36, 56))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (268, 285))	('TRAF7', 'Gene', (158, 163))	('mesothelial neoplasm', 'Disease', 'MESH:D018301', (36, 56))	('tumor of the genital tract', 'Phenotype', 'HP:0010787', (70, 96))	('missense mutations', 'Var', (132, 150))	('papillary mesothelioma', 'Disease', (241, 263))
23984	30171198	To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutations', 'Var', (129, 138))	('human', 'Species', '9606', (86, 91))	('GTP', 'Chemical', 'MESH:D006160', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('papillary mesothelioma', 'Disease', (50, 72))	('CDC42', 'Gene', (146, 151))	('tumor', 'Disease', (92, 97))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (50, 72))
23988	30171198	Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.	('malignant mesothelioma', 'Disease', (204, 226))	('mutations', 'Var', (129, 138))	('TRAF7', 'Gene', '84231', (142, 147))	('papillary mesothelioma', 'Disease', (61, 83))	('CDC42', 'Gene', (152, 157))	('distinguish', 'Reg', (175, 186))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (204, 226))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (61, 83))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (204, 226))	('TRAF7', 'Gene', (142, 147))
23994	30171198	Well-differentiated papillary mesothelioma express markers typical of mesothelial cells including calretinin, WT1, D2-40, and cytokeratin 5/6.	('calretinin', 'Gene', '794', (98, 108))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (20, 42))	('D2-40', 'Var', (115, 120))	('WT1', 'Gene', '7490', (110, 113))	('cytokeratin 5/6', 'Gene', '3852', (126, 141))	('WT1', 'Gene', (110, 113))	('cytokeratin 5/6', 'Gene', (126, 141))	('calretinin', 'Gene', (98, 108))	('papillary mesothelioma', 'Disease', (20, 42))
24009	30171198	Pathologic review of all tumor samples was performed to confirm the diagnosis by a group of expert gynecologic pathologists (J.T.R., K.G., C.Z., and D.A.S.).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('K.G.', 'Var', (133, 137))	('C.Z.', 'Var', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
24038	30171198	This identified somatic missense mutations in the TRAF7 gene or CDC42 gene in all ten cases (Figures 1-2, Supplementary Table 2).	('missense mutations', 'Var', (24, 42))	('TRAF7', 'Gene', (50, 55))	('CDC42', 'Gene', (64, 69))	('men', 'Species', '9606', (112, 115))	('TRAF7', 'Gene', '84231', (50, 55))
24039	30171198	Mutations in TRAF7 and CDC42 were mutually exclusive, with seven cases that harbored TRAF7 mutations and were CDC42 wildtype, while the remaining three cases harbored CDC42 mutations and were TRAF7 wildtype (Figure 3).	('CDC42', 'Gene', (23, 28))	('TRAF7', 'Gene', '84231', (192, 197))	('TRAF7', 'Gene', '84231', (13, 18))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (91, 100))	('TRAF7', 'Gene', (85, 90))	('TRAF7', 'Gene', (13, 18))	('TRAF7', 'Gene', (192, 197))	('TRAF7', 'Gene', '84231', (85, 90))
24040	30171198	These TRAF7 and CDC42 missense mutations were verified to be somatic (i.e.	('TRAF7', 'Gene', (6, 11))	('missense mutations', 'Var', (22, 40))	('CDC42', 'Gene', (16, 21))	('TRAF7', 'Gene', '84231', (6, 11))
24042	30171198	Snapshots of the TRAF7 and CDC42 mutations are shown in Supplementary Figure 2.	('men', 'Species', '9606', (62, 65))	('TRAF7', 'Gene', '84231', (17, 22))	('mutations', 'Var', (33, 42))	('CDC42', 'Gene', (27, 32))	('TRAF7', 'Gene', (17, 22))
24045	30171198	Similar to the TRAF7 mutations observed in these tumor types, the TRAF7 mutations in well-differentiated papillary mesothelioma were all missense mutations that clustered in the WD40 repeats at the C-terminus of the protein (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TRAF7', 'Gene', (15, 20))	('missense mutations', 'Var', (137, 155))	('TRAF7', 'Gene', '84231', (66, 71))	('tumor', 'Disease', (49, 54))	('papillary mesothelioma', 'Disease', (105, 127))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('TRAF7', 'Gene', '84231', (15, 20))	('TRAF7', 'Gene', (66, 71))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (105, 127))
24046	30171198	In five of the seven cases harboring TRAF7 mutations, a single missense mutation was present.	('mutations', 'Var', (43, 52))	('TRAF7', 'Gene', '84231', (37, 42))	('TRAF7', 'Gene', (37, 42))
24047	30171198	WDPM #3 harbored a focal amplification of the TRAF7 gene on chromosome 16p13 and two TRAF7 missense mutations (p.N520D and p.G536S) that were either present in trans (on opposite alleles) or within separate tumor subclones.	('p.N520D', 'Var', (111, 118))	('TRAF7', 'Gene', (46, 51))	('p.G536S', 'Mutation', 'p.G536S', (123, 130))	('amplification', 'PosReg', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('TRAF7', 'Gene', '84231', (46, 51))	('TRAF7', 'Gene', (85, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('tumor', 'Disease', (207, 212))	('p.N520D', 'Mutation', 'p.N520D', (111, 118))	('p.G536S', 'Var', (123, 130))	('TRAF7', 'Gene', '84231', (85, 90))
24048	30171198	WDPM #4 harbored three TRAF7 missense mutations (p.G536S, p.Q539H, and p.Y621D; Supplementary Figure 2).	('p.Q539H', 'Mutation', 'p.Q539H', (58, 65))	('men', 'Species', '9606', (86, 89))	('p.Y621D', 'Var', (71, 78))	('TRAF7', 'Gene', (23, 28))	('p.G536S', 'Mutation', 'p.G536S', (49, 56))	('p.Q539H', 'Var', (58, 65))	('p.Y621D', 'Mutation', 'p.Y621D', (71, 78))	('TRAF7', 'Gene', '84231', (23, 28))	('p.G536S', 'Var', (49, 56))
24049	30171198	The p.G536S and p.Q539H mutations were present either in trans or within separate subclones, while the p.Y621D mutation was too distant to phase.	('p.Q539H', 'Var', (16, 23))	('p.G536S', 'Var', (4, 11))	('p.Y621D', 'Mutation', 'p.Y621D', (103, 110))	('p.G536S', 'Mutation', 'p.G536S', (4, 11))	('p.Q539H', 'Mutation', 'p.Q539H', (16, 23))	('p.Y621D', 'Var', (103, 110))
24050	30171198	In addition to the recurrent TRAF7 mutations found in well-differentiated papillary mesothelioma, the presence of a focal amplification in one case and multiple mutations in two cases indicates a strong selection pressure for the acquisition of TRAF7 alterations during the development of well-differentiated papillary mesothelioma.	('alterations', 'Var', (251, 262))	('TRAF7', 'Gene', (245, 250))	('TRAF7', 'Gene', (29, 34))	('papillary mesothelioma', 'Disease', (74, 96))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (309, 331))	('TRAF7', 'Gene', '84231', (245, 250))	('TRAF7', 'Gene', '84231', (29, 34))	('papillary mesothelioma', 'Disease', (309, 331))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (74, 96))	('men', 'Species', '9606', (281, 284))	('mutations', 'Var', (35, 44))
24051	30171198	The variant allele frequencies for the TRAF7 mutations ranged from 4-45%.	('mutations', 'Var', (45, 54))	('TRAF7', 'Gene', (39, 44))	('TRAF7', 'Gene', '84231', (39, 44))
24052	30171198	Cases with the highest TRAF7 variant allele frequencies had genomic DNA isolated from areas histologically visualized to contain a high tumor cell content, whereas cases with lower allele frequencies had genomic DNA that was isolated from tissue visualized to contain a lesser tumor to normal cell content.	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('TRAF7', 'Gene', (23, 28))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('variant', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TRAF7', 'Gene', '84231', (23, 28))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', (136, 141))
24053	30171198	These data suggest that TRAF7 mutations were likely heterozygous and clonal (i.e.	('mutations', 'Var', (30, 39))	('TRAF7', 'Gene', '84231', (24, 29))	('TRAF7', 'Gene', (24, 29))
24056	30171198	Two well-differentiated papillary mesothelioma cases harbored the identical p.Q61R mutation in CDC42, while a third case harbored p.P34Q mutation.	('p.P34Q', 'Var', (130, 136))	('CDC42', 'Gene', (95, 100))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (24, 46))	('p.P34Q', 'Mutation', 'p.P34Q', (130, 136))	('p.Q61R', 'Mutation', 'rs866591162', (76, 82))	('p.Q61R', 'Var', (76, 82))	('papillary mesothelioma', 'Disease', (24, 46))
24057	30171198	Similar to the TRAF7 mutations, the variant allele frequencies for the CDC42 mutations (ranging from 20-38%) indicated that these are also likely to be clonal heterozygous alterations in well-differentiated papillary mesothelioma and are probably early or initiating genetic events in those well-differentiated papillary mesothelioma lacking TRAF7 alterations.	('CDC42', 'Gene', (71, 76))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (311, 333))	('TRAF7', 'Gene', (15, 20))	('TRAF7', 'Gene', (342, 347))	('papillary mesothelioma', 'Disease', (207, 229))	('papillary mesothelioma', 'Disease', (311, 333))	('mutations', 'Var', (77, 86))	('TRAF7', 'Gene', '84231', (15, 20))	('TRAF7', 'Gene', '84231', (342, 347))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (207, 229))
24058	30171198	The p.Q61R mutation is located within a GTP binding domain, whereas the p.P34Q mutation is located within the effector domain (Figure 5a).	('p.P34Q', 'Mutation', 'p.P34Q', (72, 78))	('p.Q61R', 'Mutation', 'rs866591162', (4, 10))	('GTP binding', 'molecular_function', 'GO:0005525', ('40', '51'))	('p.Q61R', 'Var', (4, 10))	('p.P34Q', 'Var', (72, 78))	('GTP', 'Chemical', 'MESH:D006160', (40, 43))
24060	30171198	Recurrent mutations in the CDC42 gene have not been previously reported in any human tumor type to the best of our knowledge, and the p.Q61R and p.P34Q variants in CDC42 are not present in the COSMIC database.	('tumor', 'Disease', (85, 90))	('p.P34Q', 'Mutation', 'p.P34Q', (145, 151))	('human', 'Species', '9606', (79, 84))	('p.Q61R', 'Mutation', 'rs866591162', (134, 140))	('p.Q61R', 'Var', (134, 140))	('CDC42', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p.P34Q', 'Var', (145, 151))
24061	30171198	However, the p.Q61 residue of CDC42 located in the highly conserved GTP binding domain is the equivalent residue to p.Q61 in the NRAS, HRAS, and KRAS proteins, which is a mutational hotspot with thousands of confirmed somatic mutations in human cancers present in the COSMIC database.	('GTP', 'Chemical', 'MESH:D006160', (68, 71))	('CDC42', 'Gene', (30, 35))	('p.Q61', 'Var', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('KRAS', 'Gene', (145, 149))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('NRAS', 'Gene', (129, 133))	('p.Q61', 'Var', (13, 18))	('cancers', 'Disease', (245, 252))	('HRAS', 'Gene', '3265', (135, 139))	('GTP binding', 'molecular_function', 'GO:0005525', ('68', '79'))	('NRAS', 'Gene', '4893', (129, 133))	('HRAS', 'Gene', (135, 139))	('KRAS', 'Gene', '3845', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('human', 'Species', '9606', (239, 244))
24066	30171198	Additionally, the TRAF7 and CDC42 mutations were the solitary somatic alterations identified in these two cases, indicating that these well-differentiated papillary mesothelioma did not acquire accompanying genetic alterations among the assayed genes to explain the multifocal growth.	('TRAF7', 'Gene', '84231', (18, 23))	('papillary mesothelioma', 'Disease', (155, 177))	('CDC42', 'Gene', (28, 33))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (155, 177))	('TRAF7', 'Gene', (18, 23))	('mutations', 'Var', (34, 43))
24068	30171198	While five cases contained additional somatic nonsynonymous mutations in addition to TRAF7 or CDC42, all of these additional mutations are considered variants of unknown significance, as they do not affect genes known to be important in mesothelioma tumorigenesis and are not mutations that have been previously seen before in human cancers (COSMIC database, version 84 release).	('mutations', 'Var', (125, 134))	('mesothelioma', 'Disease', (237, 249))	('cancers', 'Phenotype', 'HP:0002664', (333, 340))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cancers', 'Disease', (333, 340))	('human', 'Species', '9606', (327, 332))	('cancers', 'Disease', 'MESH:D009369', (333, 340))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('TRAF7', 'Gene', (85, 90))	('CDC42', 'Gene', (94, 99))	('tumor', 'Disease', (250, 255))	('TRAF7', 'Gene', '84231', (85, 90))
24069	30171198	The complete list of somatic single nucleotide variants and insertions/deletions identified in the well-differentiated papillary mesothelioma cohort is shown in Supplementary Table 2.	('papillary mesothelioma', 'Disease', 'MESH:D008654', (119, 141))	('single nucleotide variants', 'Var', (29, 55))	('insertions/deletions', 'Var', (60, 80))	('papillary mesothelioma', 'Disease', (119, 141))	('men', 'Species', '9606', (167, 170))
24071	30171198	Chromosomal copy number analysis revealed trisomy 7 and focal amplification of chromosome 16p13.3 containing the TRAF7 gene in WDPM #3 (Supplementary Table 3).	('men', 'Species', '9606', (142, 145))	('trisomy', 'Var', (42, 49))	('TRAF7', 'Gene', (113, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))	('TRAF7', 'Gene', '84231', (113, 118))
24072	30171198	All tumors lacked identifiable mutations, deletions, or rearrangements involving the BAP1, CDKN2A, NF2, DDX3X, SETD2, TP53, and ALK genes known to be recurrently altered in pleural or peritoneal malignant mesotheliomas.	('DDX3X', 'Gene', (104, 109))	('CDKN2A', 'Gene', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('rearrangements', 'Var', (56, 70))	('lacked', 'NegReg', (11, 17))	('TP53', 'Gene', (118, 122))	('malignant mesotheliomas', 'Disease', (195, 218))	('men', 'Species', '9606', (65, 68))	('DDX3X', 'Gene', '1654', (104, 109))	('CDKN2A', 'Gene', '1029', (91, 97))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (195, 217))	('deletions', 'Var', (42, 51))	('BAP1', 'Gene', '8314', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SETD2', 'Gene', (111, 116))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (195, 218))	('ALK', 'Gene', '238', (128, 131))	('NF2', 'Gene', '4771', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (118, 122))	('SETD2', 'Gene', '29072', (111, 116))	('ALK', 'Gene', (128, 131))	('NF2', 'Gene', (99, 102))	('BAP1', 'Gene', (85, 89))	('tumors', 'Disease', (4, 10))	('pleural', 'Disease', 'MESH:D010995', (173, 180))	('pleural', 'Disease', (173, 180))	('peritoneal malignant mesotheliomas', 'Phenotype', 'HP:0100003', (184, 218))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (195, 218))
24073	30171198	The BAP1 tumor suppressor gene has emerged as a frequent target of inactivating mutations, deletions, or rearrangements in malignant mesothelioma, particularly in peritoneal cases where genetic alterations and associated loss of nuclear BAP1 immunostaining are seen in greater than 80% of cases according to multiple case series.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (123, 145))	('men', 'Species', '9606', (114, 117))	('genetic alterations', 'Var', (186, 205))	('inactivating mutations', 'Var', (67, 89))	('BAP1', 'Gene', '8314', (237, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('deletions', 'Var', (91, 100))	('tumor', 'Disease', (9, 14))	('BAP1', 'Gene', '8314', (4, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', (237, 241))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (123, 145))	('peritoneal', 'Disease', (163, 173))	('loss', 'NegReg', (221, 225))	('BAP1', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('malignant mesothelioma', 'Disease', (123, 145))	('rearrangements', 'Var', (105, 119))
24077	30171198	We previously demonstrated that tumor-derived TRAF7 mutations induce activation of NF-kB signaling and cause increased expression of L1 cell adhesion molecule (L1CAM), a known transcriptional target of NF-kB that has emerged as a reliable surrogate marker for tumors with activated NF-kB signaling.	('tumor', 'Disease', (260, 265))	('TRAF7', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('NF-kB signaling', 'Pathway', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('136', '158'))	('increased', 'PosReg', (109, 118))	('L1CAM', 'Gene', '3897', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('L1 cell adhesion molecule', 'Gene', '3897', (133, 158))	('tumors', 'Disease', (260, 266))	('expression', 'MPA', (119, 129))	('L1CAM', 'Gene', (160, 165))	('signaling', 'biological_process', 'GO:0023052', ('288', '297'))	('L1 cell adhesion molecule', 'Gene', (133, 158))	('TRAF7', 'Gene', '84231', (46, 51))	('tumor', 'Disease', (32, 37))	('mutations', 'Var', (52, 61))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cell adhesion', 'biological_process', 'GO:0007155', ('136', '149'))	('activation', 'PosReg', (69, 79))
24078	30171198	Here we find strong membranous staining for L1CAM protein in all nine of the well-differentiated papillary mesothelioma cases in this cohort with tissue available for immunohistochemical evaluation (Figure 6), which include both TRAF7 and CDC42 mutant cases.	('papillary mesothelioma', 'Disease', (97, 119))	('TRAF7', 'Gene', (229, 234))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('L1CAM', 'Gene', (44, 49))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (97, 119))	('protein', 'Protein', (50, 57))	('mutant', 'Var', (245, 251))	('TRAF7', 'Gene', '84231', (229, 234))	('L1CAM', 'Gene', '3897', (44, 49))	('CDC42', 'Gene', (239, 244))	('well-differentiated', 'Disease', (77, 96))
24079	30171198	This was comparable to the L1CAM expression we previously documented in adenomatoid tumors of the genital tract harboring TRAF7 mutations (n=8), whereas no appreciable L1CAM staining was seen in normal mesothelial cells lining organs of the peritoneal cavity (n=7), nor was staining seen in malignant peritoneal mesotheliomas (n=7) or multilocular peritoneal inclusion cysts (n=6).	('men', 'Species', '9606', (62, 65))	('TRAF7', 'Gene', '84231', (122, 127))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (301, 325))	('L1CAM', 'Gene', '3897', (168, 173))	('malignant peritoneal mesotheliomas', 'Disease', (291, 325))	('mutations', 'Var', (128, 137))	('L1CAM', 'Gene', '3897', (27, 32))	('tumors of the genital tract', 'Phenotype', 'HP:0010787', (84, 111))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('adenomatoid tumors of the genital tract', 'Disease', 'MESH:D018254', (72, 111))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (301, 324))	('TRAF7', 'Gene', (122, 127))	('L1CAM', 'Gene', (168, 173))	('multilocular peritoneal inclusion cysts', 'Disease', (335, 374))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('adenomatoid tumors of the genital tract', 'Disease', (72, 111))	('L1CAM', 'Gene', (27, 32))	('malignant peritoneal mesotheliomas', 'Disease', 'MESH:C562839', (291, 325))
24080	30171198	Similar to adenomatoid tumors of the genital tract, these data suggest that well-differentiated papillary mesothelioma are also characterized by activated NF-kB signaling, which in well-differentiated papillary mesothelioma can be due to either TRAF7 or CDC42 mutation.	('activated', 'PosReg', (145, 154))	('TRAF7', 'Gene', (245, 250))	('adenomatoid tumors of the genital tract', 'Disease', 'MESH:D018254', (11, 50))	('papillary mesothelioma', 'Disease', (201, 223))	('CDC42', 'Gene', (254, 259))	('mutation', 'Var', (260, 268))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (96, 118))	('adenomatoid tumors of the genital tract', 'Disease', (11, 50))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('NF-kB signaling', 'MPA', (155, 170))	('TRAF7', 'Gene', '84231', (245, 250))	('tumors of the genital tract', 'Phenotype', 'HP:0010787', (23, 50))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (201, 223))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('papillary mesothelioma', 'Disease', (96, 118))
24081	30171198	Our study identifies mutually exclusive somatic mutations of TRAF7 and CDC42 in all cases of well-differentiated papillary mesothelioma of the peritoneum.	('CDC42', 'Gene', (71, 76))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (113, 135))	('TRAF7', 'Gene', (61, 66))	('papillary mesothelioma', 'Disease', (113, 135))	('TRAF7', 'Gene', '84231', (61, 66))	('mutations', 'Var', (48, 57))
24083	30171198	Beyond TRAF7 or CDC42 mutation, all tumors had relatively simple genomes with few, if any, additional somatic mutations or chromosomal copy number alterations.	('mutation', 'Var', (22, 30))	('TRAF7', 'Gene', '84231', (7, 12))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('TRAF7', 'Gene', (7, 12))	('CDC42', 'Gene', (16, 21))
24084	30171198	The presence of a solitary pathogenic alteration in either TRAF7 or CDC42 in all cases of well-differentiated papillary mesothelioma is in keeping with the low grade nature of these neoplasms.	('neoplasms', 'Disease', (182, 191))	('TRAF7', 'Gene', '84231', (59, 64))	('papillary mesothelioma', 'Disease', (110, 132))	('neoplasm', 'Phenotype', 'HP:0002664', (182, 190))	('CDC42', 'Gene', (68, 73))	('neoplasms', 'Disease', 'MESH:D009369', (182, 191))	('alteration', 'Var', (38, 48))	('TRAF7', 'Gene', (59, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (182, 191))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (110, 132))
24085	30171198	We recently identified that adenomatoid tumors of the genital tract are genetically defined by somatic missense mutations in the TRAF7 gene that similarly localize in the WD40 repeats at the C-terminus of the protein.	('TRAF7', 'Gene', (129, 134))	('adenomatoid tumors of the genital tract', 'Disease', 'MESH:D018254', (28, 67))	('missense mutations', 'Var', (103, 121))	('adenomatoid tumors of the genital tract', 'Disease', (28, 67))	('tumors of the genital tract', 'Phenotype', 'HP:0010787', (40, 67))	('TRAF7', 'Gene', '84231', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
24090	30171198	Of note though is that a subset of well-differentiated papillary mesothelioma lack TRAF7 mutations and instead harbor CDC42 mutations, whereas all 31 of the adenomatoid tumors of the genital tract harbored TRAF7 mutations and lacked CDC42 mutations in our initial study.	('harbored', 'Reg', (197, 205))	('mutations', 'Var', (124, 133))	('papillary mesothelioma', 'Disease', (55, 77))	('TRAF7', 'Gene', '84231', (83, 88))	('TRAF7', 'Gene', '84231', (206, 211))	('tumors of the genital tract', 'Phenotype', 'HP:0010787', (169, 196))	('adenomatoid tumors of the genital tract', 'Disease', 'MESH:D018254', (157, 196))	('adenomatoid tumors of the genital tract', 'Disease', (157, 196))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (55, 77))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('mutations', 'Var', (89, 98))	('mutations', 'Var', (212, 221))	('CDC42', 'Gene', (118, 123))	('lack', 'NegReg', (78, 82))	('TRAF7', 'Gene', (83, 88))	('TRAF7', 'Gene', (206, 211))
24093	30171198	However, while TRAF7 mutations have not been reported in any cases of malignant peritoneal mesothelioma, they were reportedly seen in a small number of malignant pleural mesotheliomas in one recent study (5 of 216 cases, 2%).	('seen', 'Reg', (126, 130))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (70, 103))	('malignant pleural mesotheliomas', 'Disease', (152, 183))	('TRAF7', 'Gene', (15, 20))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (80, 103))	('malignant peritoneal mesothelioma', 'Disease', (70, 103))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (162, 183))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (152, 183))	('TRAF7', 'Gene', '84231', (15, 20))	('mutations', 'Var', (21, 30))
24094	30171198	Two of the five TRAF7-mutant tumors harbored additional BAP1 and TP53 mutations, one harbored additional NF2 mutation, and two lacked additional pathogenic alterations.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (56, 60))	('TRAF7', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('BAP1', 'Gene', (56, 60))	('NF2', 'Gene', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('harbored', 'Reg', (36, 44))	('tumors', 'Disease', (29, 35))	('TRAF7', 'Gene', '84231', (16, 21))	('NF2', 'Gene', '4771', (105, 108))
24095	30171198	Whether these cases represent misclassified well-differentiated papillary mesothelioma of the pleural cavity is one possibility, which would be supported by the presence of solitary TRAF7 mutations.	('papillary mesothelioma of the pleural', 'Disease', (64, 101))	('TRAF7', 'Gene', '84231', (182, 187))	('mesothelioma of the pleural cavity', 'Phenotype', 'HP:0100002', (74, 108))	('mutations', 'Var', (188, 197))	('TRAF7', 'Gene', (182, 187))	('papillary mesothelioma of the pleural', 'Disease', 'MESH:D008654', (64, 101))
24096	30171198	Another consideration is that these cases represent well-differentiated papillary mesothelioma that underwent malignant transformation, which would be supported by the presence of TRAF7 mutation combined with other pathogenic alterations such as BAP1 or NF2.	('BAP1', 'Gene', (246, 250))	('papillary mesothelioma', 'Disease', (72, 94))	('NF2', 'Gene', (254, 257))	('presence', 'Reg', (168, 176))	('TRAF7', 'Gene', '84231', (180, 185))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (72, 94))	('BAP1', 'Gene', '8314', (246, 250))	('NF2', 'Gene', '4771', (254, 257))	('TRAF7', 'Gene', (180, 185))	('mutation', 'Var', (186, 194))
24097	30171198	Or a third explanation is that TRAF7 mutation can be selected for during tumor development in a small subset of de novo malignant mesotheliomas without progression from a well-differentiated papillary mesothelioma-like precursor.	('TRAF7', 'Gene', (31, 36))	('men', 'Species', '9606', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (120, 143))	('mutation', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('papillary mesothelioma', 'Disease', (191, 213))	('TRAF7', 'Gene', '84231', (31, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (120, 142))	('tumor', 'Disease', (73, 78))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (191, 213))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (120, 143))	('malignant mesotheliomas', 'Disease', (120, 143))
24098	30171198	Further investigation of patients with malignant mesotheliomas harboring TRAF7 mutation is required to understand the biologic nature of these tumors.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (39, 61))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('TRAF7', 'Gene', (73, 78))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('TRAF7', 'Gene', '84231', (73, 78))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (39, 62))	('patients', 'Species', '9606', (25, 33))	('mutation', 'Var', (79, 87))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (39, 62))	('malignant mesotheliomas', 'Disease', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
24099	30171198	In addition to well-differentiated papillary mesothelioma and adenomatoid tumors of the genital tract, TRAF7 mutations are also common in meningiomas and perineuriomas.	('papillary mesothelioma', 'Disease', (35, 57))	('common', 'Reg', (128, 134))	('TRAF7', 'Gene', '84231', (103, 108))	('adenomatoid tumors of the genital tract', 'Disease', 'MESH:D018254', (62, 101))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors of the genital tract', 'Phenotype', 'HP:0010787', (74, 101))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (35, 57))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('adenomatoid tumors of the genital tract', 'Disease', (62, 101))	('meningiomas', 'Phenotype', 'HP:0002858', (138, 149))	('meningiomas and perineuriomas', 'Disease', 'MESH:D010524', (138, 167))	('mutations', 'Var', (109, 118))	('TRAF7', 'Gene', (103, 108))
24100	30171198	However, the mechanisms by which TRAF7 mutations contribute to tumor development are not well described.	('tumor', 'Disease', (63, 68))	('TRAF7', 'Gene', (33, 38))	('men', 'Species', '9606', (76, 79))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TRAF7', 'Gene', '84231', (33, 38))	('contribute', 'Reg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
24102	30171198	We have previously shown that expression of tumor-derived mutant isoforms but not wildtype TRAF7 in cultured human cells causes increased phosphorylation of the p65/RELA subunit of NF-kB, a modification associated with activation, and also upregulation of L1CAM expression, a downstream transcriptional target of NF-kB.	('mutant', 'Var', (58, 64))	('human', 'Species', '9606', (109, 114))	('L1CAM', 'Gene', '3897', (256, 261))	('increased', 'PosReg', (128, 137))	('p65', 'Gene', (161, 164))	('p65', 'Gene', '5970', (161, 164))	('RELA', 'Gene', (165, 169))	('TRAF7', 'Gene', (91, 96))	('L1CAM', 'Gene', (256, 261))	('RELA', 'Gene', '5970', (165, 169))	('phosphorylation', 'MPA', (138, 153))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('TRAF7', 'Gene', '84231', (91, 96))	('tumor', 'Disease', (44, 49))	('NF-kB', 'Gene', (181, 186))	('upregulation', 'PosReg', (240, 252))
24103	30171198	Similar to the robust expression of L1CAM seen in adenomatoid tumors harboring TRAF7 mutations, here we show that well-differentiated papillary mesothelioma are also characterized by robust L1CAM expression, indicative of active NF-kB signaling.	('papillary mesothelioma', 'Disease', 'MESH:D008654', (134, 156))	('TRAF7', 'Gene', '84231', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('L1CAM', 'Gene', (190, 195))	('L1CAM', 'Gene', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (196, 206))	('mutations', 'Var', (85, 94))	('L1CAM', 'Gene', '3897', (190, 195))	('TRAF7', 'Gene', (79, 84))	('adenomatoid tumors', 'Disease', (50, 68))	('papillary mesothelioma', 'Disease', (134, 156))	('signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (50, 68))	('L1CAM', 'Gene', '3897', (36, 41))
24104	30171198	Robust L1CAM expression was observed in both TRAF7 and CDC42 mutant well-differentiated papillary mesothelioma, indicating that CDC42 mutations may potentially be an alternative mechanism of driving NF-kB signaling in TRAF7 wildtype mesothelial neoplasms.	('TRAF7', 'Gene', '84231', (45, 50))	('TRAF7', 'Gene', '84231', (218, 223))	('mesothelial neoplasms', 'Disease', (233, 254))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (88, 110))	('L1CAM', 'Gene', '3897', (7, 12))	('signaling', 'biological_process', 'GO:0023052', ('205', '214'))	('mesothelial neoplasms', 'Disease', 'MESH:D018301', (233, 254))	('mutations', 'Var', (134, 143))	('CDC42', 'Gene', (128, 133))	('TRAF7', 'Gene', (45, 50))	('papillary mesothelioma', 'Disease', (88, 110))	('TRAF7', 'Gene', (218, 223))	('NF-kB signaling', 'MPA', (199, 214))	('mutant', 'Var', (61, 67))	('CDC42', 'Gene', (55, 60))	('L1CAM', 'Gene', (7, 12))	('neoplasms', 'Phenotype', 'HP:0002664', (245, 254))	('expression', 'MPA', (13, 23))	('driving', 'Reg', (191, 198))	('neoplasm', 'Phenotype', 'HP:0002664', (245, 253))
24108	30171198	We are currently investigating which of these functions of CDC42 are abrogated by mutations to drive well-differentiated papillary mesothelioma tumorigenesis.	('tumor', 'Disease', (144, 149))	('CDC42', 'Gene', (59, 64))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (121, 143))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('papillary mesothelioma', 'Disease', (121, 143))
24109	30171198	Given the presence of heterozygous missense mutations that localize within the GTP binding and effector domains, we anticipate that these are likely to be oncogenic, gain-of-function mutations, as opposed to tumor suppressive, loss-of-function variants.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('GTP', 'Chemical', 'MESH:D006160', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('GTP binding', 'molecular_function', 'GO:0005525', ('79', '90'))	('missense mutations', 'Var', (35, 53))	('tumor', 'Disease', (208, 213))	('gain-of-function', 'PosReg', (166, 182))
24112	30171198	Why CDC42 mutations are selected for during mesothelioma development, but not any of the other Ras family GTPases is an interesting question that remains to be answered.	('GTP', 'Chemical', 'MESH:D006160', (106, 109))	('CDC42', 'Gene', (4, 9))	('men', 'Species', '9606', (64, 67))	('mutations', 'Var', (10, 19))	('mesothelioma', 'Disease', (44, 56))
24113	30171198	In summary, we have characterized the genetic landscape of well-differentiated papillary mesothelioma of the peritoneum that revealed mutually exclusive mutations in TRAF7 and CDC42, along with an absence of genetic alterations that are common in malignant mesothelioma such as BAP1, NF2, CDKN2A, DDX3X, SETD2, TP53, and ALK.	('TRAF7', 'Gene', (166, 171))	('SETD2', 'Gene', (304, 309))	('mutations', 'Var', (153, 162))	('CDC42', 'Gene', (176, 181))	('ALK', 'Gene', '238', (321, 324))	('TP53', 'Gene', '7157', (311, 315))	('CDKN2A', 'Gene', (289, 295))	('SETD2', 'Gene', '29072', (304, 309))	('ALK', 'Gene', (321, 324))	('NF2', 'Gene', '4771', (284, 287))	('malignant mesothelioma', 'Disease', (247, 269))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (79, 101))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (247, 269))	('BAP1', 'Gene', (278, 282))	('NF2', 'Gene', (284, 287))	('CDKN2A', 'Gene', '1029', (289, 295))	('DDX3X', 'Gene', (297, 302))	('TRAF7', 'Gene', '84231', (166, 171))	('papillary mesothelioma', 'Disease', (79, 101))	('TP53', 'Gene', (311, 315))	('DDX3X', 'Gene', '1654', (297, 302))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (247, 269))	('BAP1', 'Gene', '8314', (278, 282))
24122	30354850	loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g.	('adenocarcinoma', 'Disease', 'MESH:D000230', (183, 197))	('mesothelioma', 'Disease', (134, 146))	('mesothelioma', 'Disease', (165, 177))	('rat', 'Species', '10116', (160, 163))	('p16', 'Gene', '1029', (70, 73))	('deletion', 'Var', (74, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))	('rat', 'Species', '10116', (60, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('adenocarcinoma', 'Disease', (183, 197))	('p16', 'Gene', (70, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('loss', 'NegReg', (0, 4))
24126	30354850	Molecular testing must include, at least, mutations of epidermal growth-factor receptor and BRAF V600E, translocations of rat osteosarcoma and anaplastic lymphoma kinase, and expression of programmed death ligand 1.	('osteosarcoma', 'Disease', (126, 138))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('mutations', 'Var', (42, 51))	('anaplastic lymphoma kinase', 'Gene', '266802', (143, 169))	('translocations', 'Var', (104, 118))	('programmed death ligand 1', 'Gene', (189, 214))	('V600E', 'Mutation', 'rs113488022', (97, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('BRAF', 'Gene', (92, 96))	('epidermal growth-factor receptor', 'Gene', '24329', (55, 87))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (143, 162))	('epidermal growth-factor', 'molecular_function', 'GO:0005154', ('55', '78'))	('BRAF', 'Gene', '114486', (92, 96))	('anaplastic lymphoma kinase', 'Gene', (143, 169))	('epidermal growth-factor receptor', 'Gene', (55, 87))	('programmed death ligand 1', 'Gene', '29126', (189, 214))	('rat', 'Species', '10116', (122, 125))	('ligand', 'molecular_function', 'GO:0005488', ('206', '212'))
24144	30354850	The score consisted of age >= 75 years (3 points), albumin gradient > 1.2 g/dl (3 points), bilateral effusions on chest radiograph (2 points), PF lactate dehydrogenase < 250 U/l (2 points) and protein gradient > 2.5 g/dl (1 point).	('< 250', 'Var', (168, 173))	('protein gradient', 'MPA', (193, 209))	('albumin gradient', 'MPA', (51, 67))	('PF', 'Phenotype', 'HP:0002202', (143, 145))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('PF lactate dehydrogenase', 'MPA', (143, 167))	('effusion', 'Disease', 'MESH:D010996', (101, 109))	('effusion', 'Disease', (101, 109))
24159	30354850	The presence of free, unstimulated interferon-gamma in PF had a respective sensitivity and specificity of 89% and 97%, with an AUC of 0.99, in a meta-analysis of 22 studies which included 2883 patients.	('patients', 'Species', '9606', (193, 201))	('PF', 'Phenotype', 'HP:0002202', (55, 57))	('interferon-gamma', 'Gene', '3458', (35, 51))	('presence', 'Var', (4, 12))	('interferon-gamma', 'Gene', (35, 51))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('35', '51'))
24206	30354850	If BAP1 is intact or a sarcomatoid mesothelioma is suspected, fluorescence in situ hybridization (FISH) for homozygous deletion of p16 should be tested.	('sarcomatoid mesothelioma', 'Disease', (23, 47))	('BAP1', 'Gene', '8314', (3, 7))	('deletion', 'Var', (119, 127))	('BAP1', 'Gene', (3, 7))	('p16', 'Gene', '1029', (131, 134))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (23, 47))	('p16', 'Gene', (131, 134))
24207	30354850	Deletions of p16 are identified in up to 80% of pleural mesotheliomas (sarcomatoid subtype 90-100%, epithelioid and biphasic subtypes 70%).	('identified', 'Reg', (21, 31))	('p16', 'Gene', (13, 16))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (48, 69))	('sarcomatoid', 'Disease', (71, 82))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (48, 69))	('p16', 'Gene', '1029', (13, 16))	('Deletions', 'Var', (0, 9))	('pleural mesotheliomas', 'Disease', (48, 69))	('sarcomatoid', 'Disease', 'MESH:C538614', (71, 82))
24208	30354850	Neither BAP1 loss nor p16 deletions occur in reactive mesothelial cells.	('deletions', 'Var', (26, 35))	('BAP1', 'Gene', '8314', (8, 12))	('p16', 'Gene', '1029', (22, 25))	('loss', 'NegReg', (13, 17))	('BAP1', 'Gene', (8, 12))	('p16', 'Gene', (22, 25))
24220	30354850	The discovery of driver mutations and rearrangements for which targeted therapies are available have led to the recommendation of molecular testing as the standard approach to non-small cell lung cancer (NSCLC) patients.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('non-small cell lung cancer', 'Disease', (176, 202))	('patients', 'Species', '9606', (211, 219))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (176, 202))	('NSCLC', 'Disease', (204, 209))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (176, 202))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('mutations', 'Var', (24, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (180, 202))
24221	30354850	This should include, at minimum, testing for mutations in the genes encoding epidermal growth-factor receptor (EGFR) and BRAF (V600E), and for translocations in the genes encoding anaplastic lymphoma kinase (ALK) and rat osteosarcoma (ROS1) in patients with nonsquamous NSCLC.	('anaplastic lymphoma kinase', 'Gene', (180, 206))	('BRAF', 'Gene', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('ROS1', 'Gene', '25346', (235, 239))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (180, 199))	('BRAF', 'Gene', '114486', (121, 125))	('patients', 'Species', '9606', (244, 252))	('NSCLC', 'Disease', (270, 275))	('anaplastic lymphoma kinase', 'Gene', '266802', (180, 206))	('V600E', 'Var', (127, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('osteosarcoma', 'Phenotype', 'HP:0002669', (221, 233))	('translocations', 'Var', (143, 157))	('ROS1', 'Gene', (235, 239))	('EGFR', 'Gene', (111, 115))	('epidermal growth-factor receptor', 'Gene', '24329', (77, 109))	('epidermal growth-factor', 'molecular_function', 'GO:0005154', ('77', '100'))	('ALK', 'Gene', (208, 211))	('mutations', 'Var', (45, 54))	('testing', 'Reg', (33, 40))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('osteosarcoma', 'Disease', 'MESH:D012516', (221, 233))	('osteosarcoma', 'Disease', (221, 233))	('rat', 'Species', '10116', (217, 220))	('ALK', 'Gene', '266802', (208, 211))	('epidermal growth-factor receptor', 'Gene', (77, 109))
24223	30354850	While subjects with targetable mutations should receive tyrosine kinase inhibitors, those with a PD-L1 status > 50% are candidates for immune-checkpoint inhibitors.	('tyrosine kinase inhibitors', 'MPA', (56, 82))	('mutations', 'Var', (31, 40))	('PD-L1', 'Gene', (97, 102))	('PD-L1', 'Gene', '29126', (97, 102))
24225	30354850	Moreover, the concordance between the primary tumor and pleural metastases concerning mutational alterations is very high.	('rat', 'Species', '10116', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutational alterations', 'Var', (86, 108))	('tumor', 'Disease', (46, 51))	('pleural metastases', 'Disease', 'MESH:D009362', (56, 74))	('pleural metastases', 'Disease', (56, 74))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
24228	30354850	ICC is the test of choice for ALK, ROS1 (in this case, positive results should be subsequently confirmed by FISH) and PD-L1 alterations, but it is not appropriate for EGFR and BRAF mutation testing.	('ALK', 'Gene', (30, 33))	('PD-L1', 'Gene', (118, 123))	('ALK', 'Gene', '266802', (30, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('alterations', 'Var', (124, 135))	('BRAF', 'Gene', '114486', (176, 180))	('PD-L1', 'Gene', '29126', (118, 123))	('ROS1', 'Gene', (35, 39))	('ROS1', 'Gene', '25346', (35, 39))	('rat', 'Species', '10116', (128, 131))	('BRAF', 'Gene', (176, 180))
24229	30354850	Instead, polymerase-chain-reaction-based or next-generation sequencing techniques are employed for EGFR mutations (including T790M mutations that confer resistance to EGFR-targeted kinase inhibitors), which can even be convincingly evaluated on circulating cell-free DNA from PF supernatants.	('EGFR', 'Gene', (99, 103))	('DNA', 'cellular_component', 'GO:0005574', ('267', '270'))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('rat', 'Species', '10116', (53, 56))	('PF', 'Phenotype', 'HP:0002202', (276, 278))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('T790M', 'Mutation', 'rs121434569', (125, 130))	('T790M', 'Var', (125, 130))
24233	30354850	Specifically, the presence of a mutation in KRAS may identify patients who will not benefit from further molecular testing, owing to the low probability of overlapping targetable alterations.	('rat', 'Species', '10116', (183, 186))	('patients', 'Species', '9606', (62, 70))	('KRAS', 'Gene', (44, 48))	('KRAS', 'Gene', '3845', (44, 48))	('mutation', 'Var', (32, 40))
24248	30354850	There is enough evidence for testing the loss of BAP1 by ICC and p16 deletion by FISH methodologies when differentiation between mesothelioma and reactive benign mesothelial cells is a concern, though these markers are not yet widely employed.	('p16', 'Gene', '1029', (65, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('ICC', 'Gene', (57, 60))	('BAP1', 'Gene', (49, 53))	('p16', 'Gene', (65, 68))	('deletion', 'Var', (69, 77))	('mesothelioma', 'Disease', (129, 141))	('BAP1', 'Gene', '8314', (49, 53))
24286	30333914	As shown in Figure 3A, no statistically significant difference was observed in any group, however, macroscopic analysis showed that amatuximab treated mice had a reduced number of gross tumor masses (Figure 3B) and developed sherbet-like aggregates (Figure 3C) in all cases, despite having not formed any aggregates in other groups (Table 1).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('amatuximab', 'Var', (132, 142))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('sherbet-like aggregates', 'CPA', (225, 248))	('reduced', 'NegReg', (162, 169))	('tumor', 'Disease', (186, 191))	('developed', 'PosReg', (215, 224))	('amatuximab', 'Chemical', 'MESH:C526187', (132, 142))
24304	30333914	This effect along with broader tumor cell killing can be further enhanced using amatuximab in combination with GEM, an agent approved for the treatment of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('GEM', 'Chemical', 'MESH:C056507', (111, 114))	('tumor', 'Disease', (31, 36))	('enhanced', 'PosReg', (65, 73))	('pancreatic cancer', 'Disease', (155, 172))	('cell killing', 'biological_process', 'GO:0001906', ('37', '49'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('amatuximab', 'Chemical', 'MESH:C526187', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('amatuximab', 'Var', (80, 90))
24510	22427768	In addition there is the Helwan factory, which was built in 1927 and started to produce asbestos articles in 1948, long before the discovery, in 1960, that asbestos can cause mesothelioma.	('mesothelioma', 'Disease', (175, 187))	('asbestos', 'Var', (156, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('asbestos', 'Chemical', 'MESH:D001194', (156, 164))	('asbestos', 'Chemical', 'MESH:D001194', (88, 96))	('cause', 'Reg', (169, 174))
24607	23691382	reported on a 25-year-old woman, who had undergone chemotherapy, partial excision of tumor followed by radiotherapy of mesothelioma of the pleura, presented three months later with painless widespread subcutaneous nodules, histologically being diagnosed as metastases of mesothelioma of the pleura.	('metastases of mesothelioma of the pleura', 'Disease', 'MESH:D009362', (257, 297))	('woman', 'Species', '9606', (26, 31))	('partial excision', 'Var', (65, 81))	('subcutaneous nodules', 'Phenotype', 'HP:0001482', (201, 221))	('pain', 'Phenotype', 'HP:0012531', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('metastases of mesothelioma of the pleura', 'Disease', (257, 297))
24623	23432995	Their data are not inconsistent with our hypothesis that EGCG may induce mesothelioma cell death via oxidative stress.	('cell death', 'biological_process', 'GO:0008219', ('86', '96'))	('EGCG', 'Chemical', 'MESH:C045651', (57, 61))	('oxidative stress', 'MPA', (101, 117))	('mesothelioma cell death', 'Disease', (73, 96))	('EGCG', 'Var', (57, 61))	('induce', 'PosReg', (66, 72))	('mesothelioma cell death', 'Disease', 'MESH:D008654', (73, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (101, 117))
24624	23432995	Although we had no data concerning H2O2-dependent T-type Ca2+ channel opening, we tested our idea that EGCG might induce autophagy in the present study.	('autophagy', 'biological_process', 'GO:0016236', ('121', '130'))	('autophagy', 'CPA', (121, 130))	('autophagy', 'biological_process', 'GO:0006914', ('121', '130'))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('induce', 'PosReg', (114, 120))	('EGCG', 'Chemical', 'MESH:C045651', (103, 107))	('EGCG', 'Var', (103, 107))
24627	23432995	Several reports have suggested that inhibition of autophagy restores chemosensitivity and augmentes tumor cell death .	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('autophagy', 'biological_process', 'GO:0016236', ('50', '59'))	('augmentes tumor cell death', 'Disease', 'MESH:D003643', (90, 116))	('inhibition', 'Var', (36, 46))	('chemosensitivity', 'CPA', (69, 85))	('restores', 'PosReg', (60, 68))	('autophagy', 'biological_process', 'GO:0006914', ('50', '59'))	('autophagy', 'CPA', (50, 59))	('augmentes tumor cell death', 'Disease', (90, 116))	('cell death', 'biological_process', 'GO:0008219', ('106', '116'))
24634	23432995	EGCG reduced the cell viability in a dose-dependent manner (Figure 1).	('cell viability', 'CPA', (17, 31))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('reduced', 'NegReg', (5, 12))	('EGCG', 'Var', (0, 4))
24652	23432995	The EHMES-10 cells were treated with EGCG (100, 250 and 500 muM) for 24 hr, and were incubated with 2 mug/ml JC-1 for 30 min.	('muM', 'Gene', (60, 63))	('EGCG', 'Chemical', 'MESH:C045651', (37, 41))	('EGCG', 'Var', (37, 41))	('muM', 'Gene', '56925', (60, 63))	('mug', 'molecular_function', 'GO:0043739', ('102', '105'))	('EHMES-10', 'CellLine', 'CVCL:M208', (4, 12))
24654	23432995	These results suggest that EGCG decreased mitochondrial membrane potential.	('mitochondrial membrane potential', 'MPA', (42, 74))	('EGCG', 'Chemical', 'MESH:C045651', (27, 31))	('EGCG', 'Var', (27, 31))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('42', '64'))	('decreased', 'NegReg', (32, 41))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (32, 74))
24658	23432995	These data suggest that EGCG led to the production of superoxide in the mitochondria of EHMES-10 cells.	('mitochondria', 'cellular_component', 'GO:0005739', ('72', '84'))	('production of superoxide in the mitochondria', 'MPA', (40, 84))	('superoxide', 'Chemical', 'MESH:D013481', (54, 64))	('EHMES-10', 'CellLine', 'CVCL:M208', (88, 96))	('EGCG', 'Var', (24, 28))	('EGCG', 'Chemical', 'MESH:C045651', (24, 28))
24662	23432995	Tempol (1 mM) also significantly inhibited the cell death induced by 200 muM EGCG or 300 muM EGCG (Figure 4B), but not that induced by 50 muM or 100 muM EGCG.	('EGCG', 'Var', (93, 97))	('muM', 'Gene', '56925', (89, 92))	('muM', 'Gene', (89, 92))	('cell death', 'CPA', (47, 57))	('EGCG', 'Chemical', 'MESH:C045651', (153, 157))	('EGCG', 'Chemical', 'MESH:C045651', (77, 81))	('muM', 'Gene', '56925', (138, 141))	('muM', 'Gene', '56925', (149, 152))	('EGCG', 'Var', (77, 81))	('muM', 'Gene', '56925', (73, 76))	('muM', 'Gene', (73, 76))	('muM', 'Gene', (149, 152))	('muM', 'Gene', (138, 141))	('Tempol', 'Chemical', 'MESH:C001803', (0, 6))	('EGCG', 'Chemical', 'MESH:C045651', (93, 97))	('inhibited', 'NegReg', (33, 42))	('cell death', 'biological_process', 'GO:0008219', ('47', '57'))
24666	23432995	ACC-meso, Y-meso and EHMES-10 cells were treated with EGCG (50, 250 and 200 muM, respectively) for 3, 6, 9 and 12hr.	('EGCG', 'Chemical', 'MESH:C045651', (54, 58))	('ACC-meso', 'Chemical', '-', (0, 8))	('muM', 'Gene', '56925', (76, 79))	('muM', 'Gene', (76, 79))	('Y-meso', 'Chemical', '-', (10, 16))	('EHMES-10', 'CellLine', 'CVCL:M208', (21, 29))	('50', 'Var', (60, 62))
24668	23432995	EGCG increased the LC3-II expression levels at 3 and 6 hr after treatment (Figure 5A and 5B).	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('increased', 'PosReg', (5, 14))	('EGCG', 'Var', (0, 4))	('LC3', 'Gene', '84557', (19, 22))	('LC3', 'Gene', (19, 22))
24695	23432995	In fact, as shown in Figure 3B, EGCG did decrease the mitochondrial membrane potential.	('EGCG', 'Chemical', 'MESH:C045651', (32, 36))	('EGCG', 'Var', (32, 36))	('decrease', 'NegReg', (41, 49))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('54', '76'))	('mitochondrial membrane potential', 'MPA', (54, 86))
24744	23229133	The antineoplastic activity of cisplatin is rather complex and in light of the published reports it appears that cisplatin may activate several parallel pathways leading to cell cycle arrest and apoptosis depending on the treatment conditions, cell type or concentration.	('activate', 'PosReg', (127, 135))	('arrest', 'Disease', 'MESH:D006323', (184, 190))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('173', '190'))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('cisplatin', 'Var', (113, 122))	('apoptosis', 'CPA', (195, 204))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (173, 190))	('arrest', 'Disease', (184, 190))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))
24769	23229133	PCR primers were as follows: survivin (NM_001168) forward (5'-cttgaaagtggcaccagagg-3'), reverse (5'-ggaccaccgcatct ctacat-3'); XIAP (NM_001167) forward (5'-ggggttcagtttcaa gga-3'), reverse (5'-cgccttagctgctcttcagt-3'); IAP1 (NM_001165) forward (5'-cctggatagtctactaactgcct-3'), reverse (5'-gcttct tcagagagtttctgaa-3'); IAP2 (NM_001160) forward (5'-cagaat tggcaagagctggt-3'), reverse (5'-attcgagctgcatgtgtct-3'); HPRT1 (NM_000194) forward (5'-tgacactggcaaaacaatgca-3'), reverse (5'-ggtccttttcaccagcaagct-3') and GAPDH (NM_002046) forward (5'-accacagtccatgccatcac-3'), reverse (5'-tccaccacc ctgttgctgta-3').	('NM_002046', 'Var', (517, 526))	('IAP2', 'Gene', (318, 322))	('XIAP', 'Gene', '331', (127, 131))	('HPRT1', 'Gene', '3251', (411, 416))	('IAP2', 'Gene', '329', (318, 322))	('HPRT1', 'Gene', (411, 416))	('IAP1', 'Gene', (219, 223))	('HPRT', 'molecular_function', 'GO:0004422', ('411', '415'))	('GAPDH', 'Gene', '2597', (510, 515))	('GAPDH', 'Gene', (510, 515))	('XIAP', 'Gene', (127, 131))	('IAP1', 'Gene', '330', (219, 223))
24785	23229133	Interestingly, at 100 mug/ml in both JU77 and ONE58 cisplatin inhibited the function of mitochondria to the same extent as the positive control FCCP (a protonophore that dissipates the H+ gradient across the inner membrane of mitochondria) whereas a lesser effect was seen in LO68 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('mug', 'molecular_function', 'GO:0043739', ('22', '25'))	('ONE58', 'Var', (46, 51))	('function of mitochondria', 'MPA', (76, 100))	('JU77', 'Var', (37, 41))	('LO68', 'Chemical', '-', (276, 280))	('inhibited', 'NegReg', (62, 71))	('FCCP', 'Chemical', 'MESH:D002259', (144, 148))	('membrane', 'cellular_component', 'GO:0016020', ('214', '222'))	('mitochondria', 'cellular_component', 'GO:0005739', ('88', '100'))	('mitochondria', 'cellular_component', 'GO:0005739', ('226', '238'))
24799	23229133	Since some authors have reported that cisplatin can downregulate IAP expression in tumour cells we also examined the mRNA levels of IAPs by real-time PCR following 3, 6 and 24 h of treatment with 10 mug/ml cisplatin but we did not see any significant changes in IAP expression in MM cells (data not shown).	('tumour', 'Disease', (83, 89))	('IAP', 'Gene', (262, 265))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('IAP', 'Gene', '84061', (132, 135))	('mug', 'molecular_function', 'GO:0043739', ('199', '202'))	('IAP', 'Gene', (132, 135))	('cisplatin', 'Var', (38, 47))	('IAP', 'Gene', '84061', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('IAP', 'Gene', '84061', (262, 265))	('downregulate', 'NegReg', (52, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('IAP', 'Gene', (65, 68))
24806	23229133	Experiments in JU77, LO68 and ONE58 showed that knockdown of XIAP had little effect upon the sensitivity of these cell lines to cisplatin (Fig.	('XIAP', 'Gene', '331', (61, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('sensitivity', 'MPA', (93, 104))	('XIAP', 'Gene', (61, 65))	('LO68', 'Chemical', '-', (21, 25))	('knockdown', 'Var', (48, 57))
24831	23229133	The XIAP protein knockdown achieved by us was at a level consistent with similar studies in other cell types which showed effects upon viability and drug sensitization.	('sensitization', 'biological_process', 'GO:0046960', ('154', '167'))	('XIAP', 'Gene', '331', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('knockdown', 'Var', (17, 26))	('XIAP', 'Gene', (4, 8))
24834	23229133	We achieved a 40-60% knockdown of this protein, however, as with XIAP, there was no effect upon cisplatin sensitivity.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('XIAP', 'Gene', (65, 69))	('XIAP', 'Gene', '331', (65, 69))	('knockdown', 'Var', (21, 30))
24835	23229133	Several previous studies have examined the functional effects of inhibition of survivin in mesothelioma cell lines finding enhanced caspase activation and apoptotic morphology in response to cisplatin.	('enhanced', 'PosReg', (123, 131))	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('survivin', 'Protein', (79, 87))	('caspase', 'CPA', (132, 139))	('apoptotic morphology', 'CPA', (155, 175))	('response to cisplatin', 'biological_process', 'GO:0072718', ('179', '200'))	('activation', 'PosReg', (140, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('mesothelioma', 'Disease', (91, 103))	('inhibition', 'Var', (65, 75))	('caspase activation', 'biological_process', 'GO:0006919', ('132', '150'))
24843	19603014	Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('protein translation', 'biological_process', 'GO:0006412', ('83', '102'))	('cap', 'Chemical', '-', (69, 72))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('dysregulation', 'Var', (52, 65))	('cap-dependent protein translation', 'MPA', (69, 102))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))
24850	19603014	Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1A37/A46) were resistant to IGF-I-mediated growth, motility, and colony formation.	('IGF-I', 'Gene', '3479', (98, 103))	('formation', 'biological_process', 'GO:0009058', ('142', '151'))	('colony formation', 'CPA', (135, 151))	('motility', 'CPA', (121, 129))	('IGF-I', 'Gene', (98, 103))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('4E-BP1', 'Var', (49, 55))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('resistant', 'CPA', (85, 94))
24870	19603014	Deranged cap-dependent protein translation is implicated in tumourigenesis in multiple tumour types (Jacobson et al, 2006), including mesothelioma (Patel et al, 2007).	('multiple tumour', 'Disease', (78, 93))	('tumour', 'Disease', (87, 93))	('mesothelioma', 'Disease', (134, 146))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('protein translation', 'biological_process', 'GO:0006412', ('23', '42'))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('implicated', 'Reg', (46, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('tumour', 'Disease', (60, 66))	('Deranged', 'Var', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('cap', 'Chemical', '-', (9, 12))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('multiple tumour', 'Disease', 'MESH:D009369', (78, 93))	('cap-dependent protein translation', 'MPA', (9, 42))
24874	19603014	4E-BP1 blocks the interaction between eIF4E and the scaffolding protein eIF4G, inhibiting the formation of the active eIF4F complex and suppressing cap-mediated translation.	('eIF4G', 'Gene', '1981', (72, 77))	('eIF4F', 'Gene', (118, 123))	('eIF4', 'cellular_component', 'GO:0008304', ('38', '42'))	('cap-mediated translation', 'MPA', (148, 172))	('suppressing', 'NegReg', (136, 147))	('eIF4F', 'cellular_component', 'GO:0016281', ('118', '123'))	('eIF4F', 'Gene', '1977', (118, 123))	('inhibiting', 'NegReg', (79, 89))	('4E-BP1', 'Var', (0, 6))	('cap', 'Chemical', '-', (148, 151))	('eIF4E', 'Gene', (38, 43))	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('translation', 'biological_process', 'GO:0006412', ('161', '172'))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('eIF4G', 'Gene', (72, 77))	('interaction', 'Interaction', (18, 29))	('formation of the active', 'MPA', (94, 117))	('eIF4E', 'Gene', '1977', (38, 43))	('eIF4', 'cellular_component', 'GO:0008304', ('72', '76'))
24879	19603014	Furthermore, a dominant active 4E-BP1 results in the repression of translation and disrupts IGF-I-mediated motility and proliferation of mesothelioma cells.	('repression', 'NegReg', (53, 63))	('translation', 'MPA', (67, 78))	('IGF-I', 'Gene', (92, 97))	('IGF-I', 'Gene', '3479', (92, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('disrupts', 'NegReg', (83, 91))	('translation', 'biological_process', 'GO:0006412', ('67', '78'))	('4E-BP1', 'Var', (31, 37))	('rat', 'Species', '10116', (127, 130))	('mesothelioma', 'Disease', (137, 149))
24883	19603014	The medium used for H513, H2052, H2373, H2461, and H2596 was RPMI (Gibco, Invitrogen, Carlsbad, CA, USA), containing 10% calf serum (Biofluids, Rockville, MD, USA).	('calf', 'Species', '9913', (121, 125))	('H513', 'CellLine', 'CVCL:A570', (20, 24))	('RPMI', 'Chemical', '-', (61, 65))	('H2052', 'Var', (26, 31))	('H2461', 'CellLine', 'CVCL:A536', (40, 45))	('H2052', 'CellLine', 'CVCL:1518', (26, 31))	('H2596', 'Var', (51, 56))	('H2373', 'Var', (33, 38))	('H2373', 'CellLine', 'CVCL:A533', (33, 38))	('H2461', 'Var', (40, 45))
24887	19603014	Cells were washed twice with phosphate-buffered saline (PBS) and grown in a serum-free medium (SFM) for 14-16 h. Also added at this time to the appropriate plates was the PI3K inhibitor, LY294002 (Promega, Madison, WI, USA) (20 muM), or the MAPK kinase (MAPKK or MEK) inhibitor, U0126 (Promega) (10 muM).	('MEK', 'Gene', '5609', (263, 266))	('PBS', 'Chemical', '-', (56, 59))	('muM', 'Gene', '56925', (299, 302))	('U0126', 'Chemical', 'MESH:C113580', (279, 284))	('LY294002', 'Var', (187, 195))	('muM', 'Gene', '56925', (228, 231))	('muM', 'Gene', (299, 302))	('phosphate-buffered saline', 'Chemical', '-', (29, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('171', '175'))	('MAPK', 'molecular_function', 'GO:0004707', ('241', '245'))	('MAPKK', 'molecular_function', 'GO:0004708', ('254', '259'))	('LY294002', 'Chemical', 'MESH:C085911', (187, 195))	('muM', 'Gene', (228, 231))	('MEK', 'Gene', (263, 266))
24894	19603014	Blots were probed separately with either rabbit alpha-eIF4GI antibody (kindly provided by Nahum Sonenberg, McGill University Montreal, Quebec, Canada) at a 1 : 2500 dilution, rabbit alpha-IGF1R antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) at a 1 : 1000 dilution, rabbit alpha-phospho-IGF1R antibody (Cell Signaling, Danvers, MA, USA) at a 1 : 1000 dilution, rabbit alpha-Akt antibody (Cell Signaling) at a 1 : 1000 dilution, rabbit alpha-phospho-Akt (ser473) antibody (Cell Signaling) at a 1 : 1000 dilution, rabbit alpha-MAPK antibody (Cell Signaling) at a 1 : 1000 dilution, rabbit alpha-phospho-MAPK (Thr202/Tyr204) antibody (Cell Signaling) at a 1 : 1000 dilution, rabbit alpha-4E-BP1 antibody (Abcam Inc., Cambridge, MA, USA) at a 1 : 2500 dilution, alpha-phospho-4E-BP1 (ser65) antibody (Cell Signaling) at a 1 : 1000 dilution, alpha-eIF4E antibody (BD Biosciences, San Jose, CA, USA) at a 1 : 500 dilution, mouse alpha-actin (Sigma) at a 1 : 10 000 dilution, or rat alpha-HA antibody (Roche) at a 1 : 2000 dilution to detect the haemagglutinin-tagged HA-4E-BP1A37/A46 proteins.	('antibody', 'cellular_component', 'GO:0019815', ('476', '484'))	('antibody', 'cellular_component', 'GO:0019815', ('544', '552'))	('ser', 'cellular_component', 'GO:0005790', ('468', '471'))	('Akt', 'Gene', '207', (388, 391))	('rabbit', 'Species', '9986', (686, 692))	('antibody', 'cellular_component', 'GO:0019815', ('307', '315'))	('antibody', 'molecular_function', 'GO:0003823', ('706', '714'))	('Signaling', 'biological_process', 'GO:0023052', ('407', '416'))	('antibody', 'cellular_component', 'GO:0019814', ('194', '202'))	('antibody', 'cellular_component', 'GO:0019814', ('392', '400'))	('Signaling', 'biological_process', 'GO:0023052', ('559', '568'))	('eIF4G', 'Gene', (54, 59))	('antibody', 'cellular_component', 'GO:0019814', ('61', '69'))	('MAPK', 'molecular_function', 'GO:0004707', ('539', '543'))	('antibody', 'cellular_component', 'GO:0019814', ('801', '809'))	('Signaling', 'biological_process', 'GO:0023052', ('651', '660'))	('rabbit', 'Species', '9986', (526, 532))	('antibody', 'cellular_component', 'GO:0042571', ('706', '714'))	('antibody', 'molecular_function', 'GO:0003823', ('636', '644'))	('rabbit', 'Species', '9986', (375, 381))	('antibody', 'cellular_component', 'GO:0019815', ('999', '1007'))	('antibody', 'molecular_function', 'GO:0003823', ('863', '871'))	('rabbit', 'Species', '9986', (280, 286))	('rat', 'Species', '10116', (22, 25))	('antibody', 'cellular_component', 'GO:0019814', ('476', '484'))	('HA-4E-BP1A37/A46', 'Var', (1075, 1091))	('antibody', 'cellular_component', 'GO:0042571', ('636', '644'))	('antibody', 'cellular_component', 'GO:0042571', ('863', '871'))	('rabbit', 'Species', '9986', (175, 181))	('antibody', 'cellular_component', 'GO:0019814', ('544', '552'))	('antibody', 'cellular_component', 'GO:0019814', ('307', '315'))	('antibody', 'molecular_function', 'GO:0003823', ('392', '400'))	('Akt', 'Gene', (463, 466))	('rabbit', 'Species', '9986', (41, 47))	('Signaling', 'biological_process', 'GO:0023052', ('322', '331'))	('antibody', 'molecular_function', 'GO:0003823', ('194', '202'))	('eIF4G', 'Gene', '1981', (54, 59))	('antibody', 'molecular_function', 'GO:0003823', ('61', '69'))	('antibody', 'cellular_component', 'GO:0042571', ('392', '400'))	('antibody', 'molecular_function', 'GO:0003823', ('801', '809'))	('antibody', 'cellular_component', 'GO:0042571', ('61', '69'))	('antibody', 'cellular_component', 'GO:0019815', ('706', '714'))	('antibody', 'cellular_component', 'GO:0042571', ('194', '202'))	('Akt', 'Gene', '207', (463, 466))	('antibody', 'molecular_function', 'GO:0003823', ('476', '484'))	('antibody', 'cellular_component', 'GO:0019814', ('999', '1007'))	('antibody', 'cellular_component', 'GO:0042571', ('801', '809'))	('antibody', 'molecular_function', 'GO:0003823', ('544', '552'))	('eIF4E', 'Gene', (857, 862))	('antibody', 'cellular_component', 'GO:0019815', ('636', '644'))	('rat', 'Species', '10116', (986, 989))	('antibody', 'cellular_component', 'GO:0019815', ('863', '871'))	('eIF4', 'cellular_component', 'GO:0008304', ('54', '58'))	('eIF4', 'cellular_component', 'GO:0008304', ('857', '861'))	('antibody', 'molecular_function', 'GO:0003823', ('307', '315'))	('Signaling', 'biological_process', 'GO:0023052', ('816', '825'))	('rabbit', 'Species', '9986', (594, 600))	('Signaling', 'biological_process', 'GO:0023052', ('491', '500'))	('antibody', 'cellular_component', 'GO:0042571', ('476', '484'))	('antibody', 'cellular_component', 'GO:0042571', ('544', '552'))	('eIF4E', 'Gene', '1977', (857, 862))	('antibody', 'cellular_component', 'GO:0042571', ('307', '315'))	('rabbit', 'Species', '9986', (442, 448))	('antibody', 'molecular_function', 'GO:0003823', ('999', '1007'))	('mouse', 'Species', '10090', (931, 936))	('antibody', 'cellular_component', 'GO:0019814', ('706', '714'))	('antibody', 'cellular_component', 'GO:0019815', ('392', '400'))	('antibody', 'cellular_component', 'GO:0019815', ('194', '202'))	('ser', 'cellular_component', 'GO:0005790', ('794', '797'))	('antibody', 'cellular_component', 'GO:0019815', ('61', '69'))	('Akt', 'Gene', (388, 391))	('antibody', 'cellular_component', 'GO:0042571', ('999', '1007'))	('antibody', 'cellular_component', 'GO:0019814', ('636', '644'))	('antibody', 'cellular_component', 'GO:0019814', ('863', '871'))	('MAPK', 'molecular_function', 'GO:0004707', ('615', '619'))	('antibody', 'cellular_component', 'GO:0019815', ('801', '809'))
24902	19603014	Cells were seeded as triplicate sets into 96-well plates with 6000 cells per well for H2373, H2373 empty vector, and H2373 4E-BP1A37/A46, and with 3000 cells per well for H2461, H2461 empty vector, and H2461 4E-BP1A37/A46.	('H2461', 'CellLine', 'CVCL:A536', (202, 207))	('H2461', 'Var', (202, 207))	('H2373', 'Var', (117, 122))	('H2373', 'CellLine', 'CVCL:A533', (86, 91))	('H2373', 'CellLine', 'CVCL:A533', (117, 122))	('H2373', 'Var', (93, 98))	('H2373', 'CellLine', 'CVCL:A533', (93, 98))	('H2373', 'Var', (86, 91))	('H2461', 'CellLine', 'CVCL:A536', (171, 176))	('H2461', 'CellLine', 'CVCL:A536', (178, 183))	('H2461', 'Var', (171, 176))
24907	19603014	Another set of five nude mice were injected with 0.5 ml of PBS containing H2596 cells (2.6 x 107) stably transfected with pACTAG neo or pACTAG neo/HA-4E-BP1A37/A46 into the left or right flank, respectively.	('PBS', 'Chemical', '-', (59, 62))	('pACTAG neo/HA-4E-BP1A37/A46', 'Var', (136, 163))	('pACTAG neo', 'Gene', (122, 132))	('nude mice', 'Species', '10090', (20, 29))
24911	19603014	Increased IGF1R phosphorylation lasted for up to 300 min in two cell lines (H2461, H513), but drifted back to baseline levels in the remaining mesothelioma cells (H2373, H2052, and H2596) and control LP9 mesothelial cells.	('mesothelioma', 'Disease', (143, 155))	('H2052', 'Var', (170, 175))	('Increased IGF1R', 'Phenotype', 'HP:0030269', (0, 15))	('H2461', 'CellLine', 'CVCL:A536', (76, 81))	('H513', 'CellLine', 'CVCL:A570', (83, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('IGF1R', 'Gene', (10, 15))	('H2052', 'CellLine', 'CVCL:1518', (170, 175))	('H2373', 'Var', (163, 168))	('H2373', 'CellLine', 'CVCL:A533', (163, 168))	('phosphorylation', 'MPA', (16, 31))	('LP9', 'CellLine', 'CVCL:E109', (200, 203))
24916	19603014	Sequential phosphorylation of 4E-BP1 leads to slower electrophoretic migration, with the gamma, beta, and alpha isoforms corresponding, respectively, to hyper-, intermediate, and hypophosphorylation.	('slower', 'NegReg', (46, 52))	('rat', 'Species', '10116', (72, 75))	('electrophoretic migration', 'MPA', (53, 78))	('intermediate', 'MPA', (161, 173))	('hyper-', 'MPA', (153, 159))	('4E-BP1', 'Var', (30, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('hypophosphorylation', 'MPA', (179, 198))
24921	19603014	Akt inhibition with LY294002 strongly diminished the phosphorylation of Akt and its downstream target 4E-BP1 in all five mesothelioma cell lines and control LP9 cells (Figure 1A and B).	('LY294002', 'Var', (20, 28))	('Akt', 'Gene', '207', (72, 75))	('Akt', 'Gene', (72, 75))	('diminished', 'NegReg', (38, 48))	('LP9', 'CellLine', 'CVCL:E109', (157, 160))	('inhibition', 'NegReg', (4, 14))	('LY294002', 'Chemical', 'MESH:C085911', (20, 28))	('Akt', 'Gene', '207', (0, 3))	('mesothelioma', 'Disease', (121, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('Akt', 'Gene', (0, 3))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
24922	19603014	Although MAPK inhibition with U0126 did suppress the phosphorylation of MAPK, it did not suppress 4E-BP1 phosphorylation as expected (Figure 1A and B).	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('MAPK', 'molecular_function', 'GO:0004707', ('9', '13'))	('MAPK', 'Enzyme', (9, 13))	('U0126', 'Var', (30, 35))	('suppress', 'NegReg', (40, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('U0126', 'Chemical', 'MESH:C113580', (30, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))	('phosphorylation', 'MPA', (53, 68))	('MAPK', 'Protein', (72, 76))	('inhibition', 'NegReg', (14, 24))
24924	19603014	Finally, the level of eIF4G, the scaffolding component of the eIF4F complex necessary for the initiation of translation, was not affected by IGF-I stimulation and was mildly decreased upon LY294002 treatment in three of the five mesothelioma cell lines (H2052, H513, and H2596) and LP9 cells (Figure 1A).	('IGF-I', 'Gene', (141, 146))	('translation', 'biological_process', 'GO:0006412', ('108', '119'))	('decreased', 'NegReg', (174, 183))	('eIF4F', 'Gene', '1977', (62, 67))	('LP9', 'CellLine', 'CVCL:E109', (282, 285))	('mesothelioma', 'Disease', 'MESH:D008654', (229, 241))	('LY294002', 'Var', (189, 197))	('H2052', 'CellLine', 'CVCL:1518', (254, 259))	('H513', 'CellLine', 'CVCL:A570', (261, 265))	('eIF4F', 'Gene', (62, 67))	('eIF4F', 'cellular_component', 'GO:0016281', ('62', '67'))	('LY294002', 'Chemical', 'MESH:C085911', (189, 197))	('eIF4', 'cellular_component', 'GO:0008304', ('22', '26'))	('IGF-I', 'Gene', '3479', (141, 146))	('eIF4G', 'Gene', (22, 27))	('mesothelioma', 'Disease', (229, 241))	('eIF4G', 'Gene', '1981', (22, 27))
24926	19603014	It is possible that treatment with LY249002 decreased eIF4G levels by inducing caspase-mediated cleavage (Prevot et al, 2003).	('eIF4G', 'Gene', '1981', (54, 59))	('inducing', 'Reg', (70, 78))	('caspase-mediated cleavage', 'MPA', (79, 104))	('LY249002', 'Var', (35, 43))	('eIF4', 'cellular_component', 'GO:0008304', ('54', '58'))	('LY249002', 'Chemical', '-', (35, 43))	('eIF4G', 'Gene', (54, 59))	('decreased', 'NegReg', (44, 53))
24934	19603014	The effect on cap-dependent translation of activating 4E-BP1 by blocking the PI3K/Akt/mTOR-signalling pathway with LY249002 was also examined using the cap-affinity assay.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('LY249002', 'Chemical', '-', (115, 123))	('mTOR', 'Gene', '2475', (86, 90))	('Akt', 'Gene', '207', (82, 85))	('mTOR', 'Gene', (86, 90))	('cap', 'Chemical', '-', (14, 17))	('signalling pathway', 'biological_process', 'GO:0007165', ('91', '109'))	('cap', 'Chemical', '-', (152, 155))	('blocking', 'NegReg', (64, 72))	('LY249002', 'Var', (115, 123))	('Akt', 'Gene', (82, 85))	('activating', 'PosReg', (43, 53))	('translation', 'biological_process', 'GO:0006412', ('28', '39'))
24935	19603014	In all mesothelioma cell lines, LY249002 treatment resulted in a decrease in the eIF4G/eIF4E ratio in IGF-I-stimulated cells than in cells treated with only IGF-I (Figure 2B).	('IGF-I', 'Gene', '3479', (157, 162))	('eIF4', 'cellular_component', 'GO:0008304', ('81', '85'))	('IGF-I', 'Gene', '3479', (102, 107))	('eIF4E', 'Gene', (87, 92))	('LY249002', 'Chemical', '-', (32, 40))	('IGF-I', 'Gene', (102, 107))	('mesothelioma', 'Disease', (7, 19))	('eIF4', 'cellular_component', 'GO:0008304', ('87', '91'))	('IGF-I', 'Gene', (157, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (7, 19))	('decrease', 'NegReg', (65, 73))	('rat', 'Species', '10116', (93, 96))	('eIF4G', 'Gene', '1981', (81, 86))	('LY249002', 'Var', (32, 40))	('eIF4E', 'Gene', '1977', (87, 92))	('eIF4G', 'Gene', (81, 86))
24937	19603014	In addition, the level of eIF4E-bound 4E-BP1 increased in IGF-I stimulated cells treated with LY249002 (Figure 1A), consistent with the suppression of cap-dependent translation.	('LY249002', 'Chemical', '-', (94, 102))	('increased', 'PosReg', (45, 54))	('cap', 'Chemical', '-', (151, 154))	('4E-BP1', 'Protein', (38, 44))	('eIF4E', 'Gene', '1977', (26, 31))	('IGF-I', 'Gene', '3479', (58, 63))	('eIF4', 'cellular_component', 'GO:0008304', ('26', '30'))	('eIF4E', 'Gene', (26, 31))	('LY249002', 'Var', (94, 102))	('IGF-I', 'Gene', (58, 63))	('translation', 'biological_process', 'GO:0006412', ('165', '176'))
24938	19603014	If cap-mediated translation contributes to the malignant phenotype, then repressing its activity should repress the malignant potential of mesothelioma cells.	('translation', 'biological_process', 'GO:0006412', ('16', '27'))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('cap', 'Chemical', '-', (3, 6))	('repress', 'NegReg', (104, 111))	('malignant phenotype', 'MPA', (47, 66))	('activity', 'MPA', (88, 96))	('repressing', 'Var', (73, 83))	('cap-mediated', 'MPA', (3, 15))	('mesothelioma', 'Disease', (139, 151))
24940	19603014	The 4E-BP1A37/A46 construct has substituted alanine for threonine at residues 37 and 46, the first two sites of sequential phosphorylation that render 4E-BP1 incapable of phosphorylation and consequently dominantly active (Gingras et al, 2001).	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('phosphorylation', 'MPA', (171, 186))	('incapable', 'NegReg', (158, 167))	('4E-BP1', 'Var', (151, 157))	('cap', 'Chemical', '-', (160, 163))	('active', 'MPA', (215, 221))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('alanine for threonine at residues 37', 'Mutation', 'p.T37A', (44, 80))
24941	19603014	To assess the ability of 4E-BP1A37/A46 to interfere with the assembly of the eIF4F initiation complex, a cap-analogue capture of eIF4E and its binding partners was used, followed by immunoblot analysis.	('eIF4F', 'Gene', (77, 82))	('eIF4E', 'Gene', '1977', (129, 134))	('assembly', 'MPA', (61, 69))	('4E-BP1A37/A46', 'Var', (25, 38))	('eIF4', 'cellular_component', 'GO:0008304', ('129', '133'))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('eIF4E', 'Gene', (129, 134))	('eIF4F', 'Gene', '1977', (77, 82))	('eIF4F', 'cellular_component', 'GO:0016281', ('77', '82'))	('interfere', 'NegReg', (42, 51))	('cap', 'Chemical', '-', (118, 121))	('cap', 'Chemical', '-', (105, 108))
24945	19603014	For each cell line, the association of eIF4G to eIF4E was repressed when cells expressed 4E-BP1A37/A46 compared with cells transfected with an empty vector (Figure 3A, lower panel).	('4E-BP1A37/A46', 'Var', (89, 102))	('eIF4', 'cellular_component', 'GO:0008304', ('39', '43'))	('association', 'Interaction', (24, 35))	('eIF4', 'cellular_component', 'GO:0008304', ('48', '52'))	('eIF4G', 'Gene', '1981', (39, 44))	('eIF4E', 'Gene', '1977', (48, 53))	('eIF4G', 'Gene', (39, 44))	('eIF4E', 'Gene', (48, 53))
24946	19603014	Formation of the eIF4F initiation complex was inhibited in cells expressing 4E-BP1A37/A46 by 66.7% (H2373) to 51% (H2461) (Figure 3B).	('eIF4F', 'cellular_component', 'GO:0016281', ('17', '22'))	('H2461', 'CellLine', 'CVCL:A536', (115, 120))	('H2373', 'CellLine', 'CVCL:A533', (100, 105))	('eIF4F', 'Gene', (17, 22))	('4E-BP1A37/A46', 'Var', (76, 89))	('eIF4F', 'Gene', '1977', (17, 22))	('inhibited', 'NegReg', (46, 55))	('Formation', 'MPA', (0, 9))
24948	19603014	The level of the mutually exclusive cap-bound proteins (eIF4G and 4E-BP1) indicates that ectopically expressed 4E-BP1A37/A46 strongly diminishes the activation of the cap-dependent complex.	('4E-BP1A37/A46', 'Var', (111, 124))	('activation', 'MPA', (149, 159))	('cap', 'Chemical', '-', (167, 170))	('cap-dependent', 'Interaction', (167, 180))	('eIF4G and 4E-BP1', 'Gene', '1981;1978', (56, 72))	('cap', 'Chemical', '-', (36, 39))	('eIF4', 'cellular_component', 'GO:0008304', ('56', '60'))	('diminishes', 'NegReg', (134, 144))
24956	19603014	4E-BP1A37/A46 expression resulted in diminished proliferation.	('proliferation', 'CPA', (48, 61))	('4E-BP1A37/A46 expression', 'Var', (0, 24))	('diminished', 'NegReg', (37, 47))	('rat', 'Species', '10116', (55, 58))
24957	19603014	In a similar manner, 4E-BP1A37/A46 expression decreased mesothelioma cell motility after IGF-I stimulation (Figure 6), although the results did not reach statistical significance.	('IGF-I', 'Gene', '3479', (89, 94))	('mesothelioma cell motility', 'Disease', 'MESH:D008654', (56, 82))	('mesothelioma cell motility', 'Disease', (56, 82))	('4E-BP1A37/A46', 'Var', (21, 34))	('cell motility', 'biological_process', 'GO:0048870', ('69', '82'))	('decreased', 'NegReg', (46, 55))	('IGF-I', 'Gene', (89, 94))
24959	19603014	In contrast, the migration of H2461 cells expressing 4E-BP1A37/A46 did not increase in response to IGF-I stimulation.	('IGF-I', 'Gene', '3479', (99, 104))	('IGF-I', 'Gene', (99, 104))	('rat', 'Species', '10116', (20, 23))	('H2461', 'CellLine', 'CVCL:A536', (30, 35))	('4E-BP1A37/A46', 'Var', (53, 66))
24962	19603014	To demonstrate the relationship between cap-mediated translation and in vivo tumour formation, H2596 or H2373 cells ectopically expressing 4E-BP1A37/A46 or empty vector were injected into nude mice.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('H2373', 'CellLine', 'CVCL:A533', (104, 109))	('nude mice', 'Species', '10090', (188, 197))	('translation', 'biological_process', 'GO:0006412', ('53', '64'))	('4E-BP1A37/A46', 'Var', (139, 152))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('rat', 'Species', '10116', (10, 13))	('cap', 'Chemical', '-', (40, 43))
24964	19603014	Expression of 4E-BP1A37/A46 caused a marked suppression of tumour growth in these mesothelioma xenografts (Figure 7B).	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('tumour growth', 'Disease', (59, 72))	('4E-BP1A37/A46', 'Var', (14, 27))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour growth', 'Disease', 'MESH:D006130', (59, 72))	('suppression', 'NegReg', (44, 55))
24965	19603014	H2373 cells expressing 4E-BP1A37/A46 produced tumours that were one-third the size of parental controls.	('H2373', 'CellLine', 'CVCL:A533', (0, 5))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumours', 'Disease', (46, 53))	('4E-BP1A37/A46', 'Var', (23, 36))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
24966	19603014	H2596 cells expressing 4E-BP1A37/A46 did not produce tumours in any mice.	('mice', 'Species', '10090', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('4E-BP1A37/A46', 'Var', (23, 36))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
24969	19603014	These results show that suppression of aberrant cap-dependent translation in mesothelioma cells abrogates tumour growth.	('tumour growth', 'Disease', (106, 119))	('mesothelioma', 'Disease', (77, 89))	('suppression', 'NegReg', (24, 35))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('tumour growth', 'Disease', 'MESH:D006130', (106, 119))	('cap', 'Chemical', '-', (48, 51))	('aberrant', 'Var', (39, 47))	('translation', 'biological_process', 'GO:0006412', ('62', '73'))	('abrogates', 'NegReg', (96, 105))
24972	19603014	Enhanced cap-mediated translation in cancer often occurs after either an overexpression of eIF4E, phosphorylation of eIF4E, or an inactivation of the 4E-BP1 repressor protein.	('eIF4E', 'Gene', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('phosphorylation', 'MPA', (98, 113))	('inactivation', 'Var', (130, 142))	('eIF4E', 'Gene', '1977', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('cancer', 'Disease', (37, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('translation', 'biological_process', 'GO:0006412', ('22', '33'))	('eIF4', 'cellular_component', 'GO:0008304', ('117', '121'))	('eIF4E', 'Gene', (91, 96))	('cap-mediated translation', 'MPA', (9, 33))	('eIF4E', 'Gene', '1977', (117, 122))	('cap', 'Chemical', '-', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('eIF4', 'cellular_component', 'GO:0008304', ('91', '95'))	('overexpression', 'PosReg', (73, 87))	('Enhanced', 'PosReg', (0, 8))
24981	19603014	Activation of IGF1R is associated with an increase in both mesothelioma cell proliferation and motility (Hoang et al, 2004b).	('mesothelioma cell proliferation and motility', 'Disease', 'MESH:D008654', (59, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('Activation', 'Var', (0, 10))	('IGF1R', 'Gene', (14, 19))	('increase', 'PosReg', (42, 50))
24986	19603014	IGF1R inhibitors are currently in clinical testing and seem to have potent in vitro activity against mesothelioma cells (Whitson et al, 2006).	('mesothelioma', 'Disease', (101, 113))	('inhibitors', 'Var', (6, 16))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))	('IGF1R', 'Gene', (0, 5))
25003	29100460	The fibrous mineral erionite, carbon nanotubes, genetic mutations, radiation and Simian Virus 40 have also been linked to mesothelioma.	('carbon', 'Chemical', 'MESH:D002244', (30, 36))	('mesothelioma', 'Disease', (122, 134))	('Simian Virus 40', 'Gene', (81, 96))	('Simian Virus 40', 'Species', '1891767', (81, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('linked', 'Reg', (112, 118))	('genetic mutations', 'Var', (48, 65))
25009	29100460	Survival is influenced by histological subtype (epithelioid, biphasic, sarcomatoid) as epithelioid patients survive on average 9 months longer than sarcomatoid patients.	('patients', 'Species', '9606', (160, 168))	('sarcomatoid', 'Disease', (148, 159))	('sarcomatoid', 'Disease', (71, 82))	('patients', 'Species', '9606', (99, 107))	('sarcomatoid', 'Disease', 'MESH:C538614', (71, 82))	('sarcomatoid', 'Disease', 'MESH:C538614', (148, 159))	('epithelioid', 'Var', (87, 98))
25055	29100460	MiR-31 is another downregulated miRNA in MPM caused by co-deletion of the miR-31 and CDKN2A genes from chromosome 9p21.	('miR', 'Gene', (32, 35))	('miR', 'Gene', (74, 77))	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('miR', 'Gene', '220972', (74, 77))	('co-deletion', 'Var', (55, 66))	('MiR-31', 'Gene', (0, 6))	('MiR-31', 'Gene', '407035', (0, 6))	('miR-31', 'Gene', '407035', (74, 80))	('CDKN2A', 'Gene', (85, 91))	('downregulated', 'NegReg', (18, 31))	('CDKN2A', 'Gene', '1029', (85, 91))	('MPM', 'Disease', (41, 44))	('miR-31', 'Gene', (74, 80))	('miR', 'Gene', '220972', (32, 35))
25057	29100460	Aberrant PPP6C activity is associated with resistance to chemotherapy and radiotherapy.	('PPP6C', 'Gene', (9, 14))	('Aberrant', 'Var', (0, 8))	('resistance to chemotherapy', 'CPA', (43, 69))	('PPP6C', 'Gene', '5537', (9, 14))	('associated', 'Reg', (27, 37))	('activity', 'MPA', (15, 23))
25071	29100460	The same laboratory has recently published results demonstrating that miR-16 is also a regulator of programmed death ligand 1 (PD-L1) in MPM and may therefore contribute to immune system evasion.	('miR-16', 'Var', (70, 76))	('MPM', 'Disease', (137, 140))	('ligand', 'molecular_function', 'GO:0005488', ('117', '123'))	('programmed death ligand 1', 'Gene', (100, 125))	('PD-L1', 'Gene', (127, 132))	('programmed death ligand 1', 'Gene', '29126', (100, 125))	('contribute', 'Reg', (159, 169))	('immune system evasion', 'MPA', (173, 194))	('PD-L1', 'Gene', '29126', (127, 132))
25073	29100460	The absence of miR-34b/c in MPM cells is caused by methylation and restoring miR-34b/c reverses malignant features such as migration, invasion, motility and resistance to radiotherapy.	('miR-34b', 'Gene', (77, 84))	('malignant', 'CPA', (96, 105))	('miR-34b', 'Gene', (15, 22))	('reverses', 'NegReg', (87, 95))	('miR-34b', 'Gene', '407041', (15, 22))	('miR-34b', 'Gene', '407041', (77, 84))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('invasion', 'CPA', (134, 142))	('methylation', 'Var', (51, 62))	('migration', 'CPA', (123, 132))	('resistance to radiotherapy', 'CPA', (157, 183))	('motility', 'CPA', (144, 152))
25074	29100460	In normal mesothelial cells, reducing miR-34 induced cell proliferation, migration and invasion by up-regulating oncogenes such as C-MET and Bcl-2.	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('migration', 'CPA', (73, 82))	('miR-34', 'Gene', '407040', (38, 44))	('Bcl-2', 'Gene', '596', (141, 146))	('Bcl-2', 'Gene', (141, 146))	('Bcl-2', 'molecular_function', 'GO:0015283', ('141', '146'))	('C-MET', 'Gene', '4233', (131, 136))	('up-regulating', 'PosReg', (99, 112))	('C-MET', 'Gene', (131, 136))	('invasion', 'CPA', (87, 95))	('cell proliferation', 'CPA', (53, 71))	('reducing', 'Var', (29, 37))	('miR-34', 'Gene', (38, 44))
25084	29100460	MiR-145 is also downregulated in MPM cell lines and tumours and restoring miR-145 reduced proliferation, migration and invasion in vitro and inhibited tumour growth in mice.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumours', 'Disease', (52, 59))	('proliferation', 'CPA', (90, 103))	('tumour growth', 'Disease', (151, 164))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mice', 'Species', '10090', (168, 172))	('miR-145', 'Gene', (74, 81))	('tumour growth', 'Disease', 'MESH:D006130', (151, 164))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('restoring', 'Var', (64, 73))	('reduced', 'NegReg', (82, 89))	('inhibited', 'NegReg', (141, 150))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
25097	29100460	STMN1 is highly expressed in many malignancies and reducing STMN1 consistently inhibits cell growth, motility, invasion and the formation of metastasis in vivo.	('STMN1', 'Gene', (0, 5))	('inhibits', 'NegReg', (79, 87))	('malignancies', 'Disease', 'MESH:D009369', (34, 46))	('STMN1', 'Gene', '3925', (60, 65))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('motility', 'CPA', (101, 109))	('cell growth', 'CPA', (88, 99))	('malignancies', 'Disease', (34, 46))	('reducing', 'Var', (51, 59))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('invasion', 'CPA', (111, 119))	('formation of metastasis', 'CPA', (128, 151))	('STMN1', 'Gene', (60, 65))	('STMN1', 'Gene', '3925', (0, 5))
25118	29100460	Therefore, loss of miR-205 correlated with a mesenchymal phenotype and a more aggressive tumour.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('miR-205', 'Gene', (19, 26))	('loss', 'Var', (11, 15))	('aggressive tumour', 'Disease', 'MESH:D001523', (78, 95))	('mesenchymal phenotype', 'CPA', (45, 66))	('miR-205', 'Gene', '406988', (19, 26))	('aggressive tumour', 'Disease', (78, 95))
25149	29100460	Santarelli and colleagues chose to analyse miR-126 as a potential biomarker for MPM in these groups and found that miR-126 could differentiate asbestos exposed from healthy individuals with a sensitivity of 60% and specificity of 74% and from MPM with a sensitivity of 73% and specificity of 73%.	('asbestos', 'Chemical', 'MESH:D001194', (143, 151))	('differentiate', 'Reg', (129, 142))	('miR-126', 'Var', (115, 122))
25164	29100460	A combination of miR-126 and miR-21 could complement the cytological assessment of PE to differentiate MPM from RM with a sensitivity of 86% and a specificity of 87%.	('MPM', 'Disease', (103, 106))	('miR-21', 'Gene', '406991', (29, 35))	('miR-126', 'Var', (17, 24))	('miR-21', 'Gene', (29, 35))	('PE', 'Phenotype', 'HP:0002202', (83, 85))
25183	29100460	MiR-34a was chosen as its aberrant expression has been associated with numerous malignancies and a liposomal nanoparticle formulated synthetic miR-34 (MRX34) recently entered a phase I trial.	('miR-34', 'Gene', '407040', (143, 149))	('aberrant', 'Var', (26, 34))	('numerous malignancies', 'Disease', (71, 92))	('numerous malignancies', 'Disease', 'MESH:D009369', (71, 92))	('MRX34', 'Gene', (151, 156))	('associated', 'Reg', (55, 65))	('MiR-34a', 'Gene', (0, 7))	('MRX34', 'Gene', '11141', (151, 156))	('MiR-34a', 'Gene', '407040', (0, 7))	('miR-34', 'Gene', (143, 149))
25187	29100460	The inhibitory effects were suggested to be caused by miR-34a regulating c-MET and AXL signalling.	('AXL', 'Gene', (83, 86))	('c-MET', 'Gene', (73, 78))	('signalling', 'biological_process', 'GO:0023052', ('87', '97'))	('miR-34a', 'Var', (54, 61))	('AXL', 'Gene', '558', (83, 86))	('regulating', 'Reg', (62, 72))	('c-MET', 'Gene', '4233', (73, 78))
25188	29100460	The delay in the induction of apoptosis seen in some of the cell lines following miR-34a overexpression was likely due to the activation of ERK1/2 and AKT.	('AKT', 'Gene', (151, 154))	('activation', 'PosReg', (126, 136))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('17', '39'))	('ERK1', 'molecular_function', 'GO:0004707', ('140', '144'))	('AKT', 'Gene', '207', (151, 154))	('miR-34a', 'Gene', (81, 88))	('ERK1/2', 'Gene', '5595;5594', (140, 146))	('ERK1/2', 'Gene', (140, 146))	('overexpression', 'Var', (89, 103))
25197	29100460	The re-expression of these miRNA in mesothelioma cells influences functions such as proliferation, migration, invasion, apoptosis, autophagy, methylation and chemoresistance.	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('apoptosis', 'CPA', (120, 129))	('miR', 'Gene', '220972', (27, 30))	('autophagy', 'CPA', (131, 140))	('miR', 'Gene', (27, 30))	('methylation', 'CPA', (142, 153))	('influences', 'Reg', (55, 65))	('autophagy', 'biological_process', 'GO:0016236', ('131', '140'))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('chemoresistance', 'CPA', (158, 173))	('migration', 'CPA', (99, 108))	('mesothelioma', 'Disease', (36, 48))	('re-expression', 'Var', (4, 17))	('invasion', 'CPA', (110, 118))	('autophagy', 'biological_process', 'GO:0006914', ('131', '140'))
25208	28186988	Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibited', 'NegReg', (47, 56))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('tumor', 'Disease', (103, 108))	('motility', 'CPA', (76, 84))	('mice', 'Species', '10090', (162, 166))	('HMGB1', 'Gene', (41, 46))	('MM cell growth', 'CPA', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('targeting', 'Var', (31, 40))	('reduced', 'NegReg', (95, 102))	('prolonged', 'PosReg', (129, 138))	('survival', 'CPA', (139, 147))
25218	28186988	In addition, we recently discovered that BAP1 germline mutations play a critical role in MM pathogenesis.	('BAP1', 'Gene', (41, 45))	('pathogenesis', 'biological_process', 'GO:0009405', ('92', '104'))	('germline mutations', 'Var', (46, 64))	('BAP1', 'Gene', '8314', (41, 45))
25250	28186988	As previously reported, we observed an increase in RAGE expression in cells treated with HMGB1, while in cells pretreated with EP, HMGB1-induced RAGE mRNA levels were significantly lower (Supplementary Figure 1B).	('RAGE', 'Gene', '101669765', (145, 149))	('Supplementary Figure 1B', 'Disease', (188, 211))	('lower', 'NegReg', (181, 186))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (188, 211))	('increase', 'PosReg', (39, 47))	('RAGE', 'Gene', (51, 55))	('RAGE', 'Gene', '101669765', (51, 55))	('HMGB1', 'Var', (89, 94))	('RAGE', 'Gene', (145, 149))	('EP', 'Chemical', 'MESH:C046522', (127, 129))
25296	28186988	Disruption of the HMGB1-RAGE autocrine loop of activation may reasonably explain the anti-tumor activity that we observed in MM using both in vitro and in vivo models.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('RAGE', 'Gene', '101669765', (24, 28))	('RAGE', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Disruption', 'Var', (0, 10))
25516	20508851	Splenocytes obtained from tumor-bearing mice were stained for CD3, CD4, CD8, and CD25.	('CD3', 'Gene', (62, 65))	('CD25', 'Var', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('CD3', 'Gene', '12501', (62, 65))	('CD8', 'Gene', (72, 75))	('CD4', 'Var', (67, 70))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Disease', (26, 31))	('CD8', 'Gene', '925', (72, 75))
25522	20508851	The mesothelioma mouse model described in our previous study was used to examine the presence of CD4+CD25+Foxp3+ T cells in tumor progression.	('CD4+CD25+Foxp3+', 'Var', (97, 112))	('mouse', 'Species', '10090', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mesothelioma', 'Disease', (4, 16))	('tumor', 'Disease', (124, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
25532	20508851	Stainings confirmed that mouse tumor tissue obtained from AB1 inoculated mice contained significant amounts of Foxp3+ regulatory T cells, consisting with previous findings in human mesothelioma tissue.	('human', 'Species', '9606', (175, 180))	('Foxp3+', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mesothelioma', 'Disease', (181, 193))	('tumor', 'Disease', (31, 36))	('mouse', 'Species', '10090', (25, 30))	('mice', 'Species', '10090', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (181, 193))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
25537	20508851	Also the CD4+CD25+Foxp3+ Tregs were increased in the lymph nodes from 8.9% to 11.5% of the total CD4+ T cell population in tumor-bearing mice (Figure 1(d)).	('tumor', 'Disease', (123, 128))	('CD4+CD25+Foxp3+', 'Var', (9, 24))	('increased', 'PosReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mice', 'Species', '10090', (137, 141))
25538	20508851	In the splenocytes from tumor-inoculated mice, the presence of Foxp3+ Tregs increased to 11% compared to 9% in the control group treated with PBS alone (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Foxp3+', 'Var', (63, 69))	('tumor', 'Disease', (24, 29))	('increased', 'PosReg', (76, 85))	('mice', 'Species', '10090', (41, 45))	('to 9', 'Species', '1214577', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PBS', 'Chemical', '-', (142, 145))
25554	20508851	In contrast to the significant increase in the proportions of total CD3+ T cells, we observed a significant reduction in the fractions of Foxp3+ T cells (Figures 3(a) and 3(b)).	('CD3', 'Gene', (68, 71))	('reduction', 'NegReg', (108, 117))	('CD3', 'Gene', '12501', (68, 71))	('Foxp3+ T', 'Var', (138, 146))
25560	20508851	Mice that received CTX had an increased survival, as seen in our earlier experiments, compared to untreated mice.	('CTX', 'Var', (19, 22))	('mice', 'Species', '10090', (108, 112))	('Mice', 'Species', '10090', (0, 4))	('increased', 'PosReg', (30, 39))	('survival', 'CPA', (40, 48))
25585	20508851	Like in human mesothelioma biopsies, a growing AB1 tumor in vivo contains significant amounts of CD4+CD25+Foxp3+ regulatory Tcells, which were previously shown to promote tumor progression in other cancer models.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('CD4+CD25+Foxp3+', 'Var', (97, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', (198, 204))	('mesothelioma', 'Disease', (14, 26))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('AB1', 'Gene', (47, 50))	('mesothelioma', 'Disease', 'MESH:D008654', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('human', 'Species', '9606', (8, 13))	('promote', 'PosReg', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
25589	20508851	Reports dating from the 1980s have shown that under some conditions low-dose CTX can potentiate antitumor immunity in mouse models.	('CTX', 'Gene', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('potentiate', 'PosReg', (85, 95))	('tumor', 'Disease', (100, 105))	('mouse', 'Species', '10090', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('low-dose', 'Var', (68, 76))
25593	20508851	CD4+CD25+Foxp3+ regulatory T cells comprise between 5 and 10% of the total CD4+ population in the blood of mice, and are important in controlling tolerance to self-antigens and thereby maintain immune system homeostasis.	('CD4+CD25+Foxp3+', 'Gene', (0, 15))	('mice', 'Species', '10090', (107, 111))	('homeostasis', 'biological_process', 'GO:0042592', ('208', '219'))	('CD4+CD25+Foxp3+', 'Var', (0, 15))	('maintain immune system', 'Phenotype', 'HP:0002721', (185, 207))	('maintain', 'Reg', (185, 193))
25598	20508851	Our findings suggest that CTX may also potentiate the immunogenicity of DC-immunotherapy in mesothelioma patients.	('immunogenicity', 'MPA', (54, 68))	('patients', 'Species', '9606', (105, 113))	('CTX', 'Var', (26, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('mesothelioma', 'Disease', (92, 104))	('potentiate', 'PosReg', (39, 49))
25606	18256831	Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IL-2', 'molecular_function', 'GO:0005134', ('98', '102'))	('IL-2', 'molecular_function', 'GO:0005134', ('52', '56'))	('tumor', 'Disease', (69, 74))	('IL-2', 'Gene', (52, 56))	('IL-2 release', 'MPA', (98, 110))	('insertion', 'Var', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
25731	18256831	Nine months after treatment, the daily doses of 5 x 103, 2 x 104, 2 x 105, 5 x 105, 1 x 106, 2 x 106 U IL-2 had induced complete tumor regression in 82, 81, 56, 15, 44, and 35% of the animals, respectively.	('IL-2', 'molecular_function', 'GO:0005134', ('103', '107'))	('5 x 103', 'Var', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('5 x 105', 'Var', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
25773	18256831	TUR causes tumor cell damage, which may induce tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('TUR', 'Var', (0, 3))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', (47, 52))	('induce', 'PosReg', (40, 46))
25916	18256831	It is remarkable that IL-2 induced tumor regression is very quick in the case of (very) fast growing tumors like SL2 lymphoma and P815 mastocytoma.	('P815', 'Var', (130, 134))	('SL2 lymphoma', 'Disease', 'MESH:D008223', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mastocytoma', 'Disease', (135, 146))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('IL-2', 'molecular_function', 'GO:0005134', ('22', '26'))	('tumor', 'Disease', (35, 40))	('SL2 lymphoma', 'Disease', (113, 125))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('mastocytoma', 'Disease', 'MESH:D034801', (135, 146))	('tumors', 'Disease', (101, 107))
25964	18256831	This is clear as deficiency of IL-2 leads to autoimmunity.	('IL-2', 'molecular_function', 'GO:0005134', ('31', '35'))	('autoimmunity', 'Disease', 'MESH:D001327', (45, 57))	('deficiency', 'Var', (17, 27))	('IL-2', 'Gene', (31, 35))	('leads to', 'Reg', (36, 44))	('autoimmunity', 'Phenotype', 'HP:0002960', (45, 57))	('autoimmunity', 'Disease', (45, 57))
25978	18256831	Pro-inflammatory cytokines (IFN-gamma, IL-5) are more increased after local IL-2 therapy than anti-inflammatory cytokines.	('IL-5', 'Gene', (39, 43))	('IFN-gamma', 'Gene', (28, 37))	('IL-5', 'molecular_function', 'GO:0005137', ('39', '43'))	('local', 'Var', (70, 75))	('increased', 'PosReg', (54, 63))	('therapy', 'Var', (81, 88))	('IL-2', 'Gene', (76, 80))	('IFN-gamma', 'Gene', '3458', (28, 37))	('IL-2', 'molecular_function', 'GO:0005134', ('76', '80'))	('IL-5', 'Gene', '3567', (39, 43))
25982	18256831	Nevertheless, the immune system must be involved as local IL-2 treatment causes systemic immunity, that resides in CD3+ lymphocytes or CD4+ and CD8+ lymphocytes.	('IL-2', 'molecular_function', 'GO:0005134', ('58', '62'))	('CD8', 'Gene', (144, 147))	('systemic immunity', 'MPA', (80, 97))	('CD4', 'Gene', (135, 138))	('treatment', 'Var', (63, 72))	('CD8', 'Gene', '925', (144, 147))	('CD4', 'Gene', '920', (135, 138))	('causes', 'Reg', (73, 79))
26099	29966799	Galinpepimut-S showed a trend toward an improved median progression-free survival (PFS) (11.4 versus 5.7 months, hazard ratio [HR] = 0.69, p = 0.3) and median OS (21.4 versus 16.6 months, HR = 0.52, p = 0.14) over the placebo control arm.	('OS', 'Chemical', '-', (159, 161))	('progression-free survival', 'CPA', (56, 81))	('improved', 'PosReg', (40, 48))	('rat', 'Species', '10116', (120, 123))	('Galinpepimut-S', 'Var', (0, 14))
26103	29966799	The primary end point was modulation of p-SrcTyr419 in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('modulation', 'Reg', (26, 36))	('tumor', 'Disease', (55, 60))	('p-SrcTyr419', 'Var', (40, 51))
26115	29966799	There are currently ongoing trials in the neoadjuvant setting in which immunotherapies are being used in window of opportunity trials (NCT02592551 and NCT02707666) and in combination with neoadjuvant chemotherapy-atezolizumab (SWOG 1619; NCT03228537).	('NCT02592551', 'Var', (135, 146))	('NCT02707666', 'Var', (151, 162))	('atezolizumab', 'Chemical', 'MESH:C000594389', (213, 225))
26137	29966799	Median PFS was also increased in the CPB arm: 9.2 versus 7.3 months (HR = 0.61, p < 0.001).	('increased', 'PosReg', (20, 29))	('CPB', 'Chemical', '-', (37, 40))	('CPB', 'Var', (37, 40))	('PFS', 'MPA', (7, 10))
26141	29966799	Thus, CPB provided a significantly longer survival in MPM with acceptable toxicity, making this triplet a potential treatment paradigm for these patients, and it was included in the 2016 National Comprehensive Cancer Network guidelines.	('patients', 'Species', '9606', (145, 153))	('survival', 'MPA', (42, 50))	('toxicity', 'Disease', (74, 82))	('men', 'Species', '9606', (121, 124))	('CPB', 'Var', (6, 9))	('MPM', 'Disease', (54, 57))	('Cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Cancer', 'Disease', (210, 216))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('longer', 'PosReg', (35, 41))	('MPM', 'Chemical', '-', (54, 57))	('Cancer', 'Disease', 'MESH:D009369', (210, 216))	('CPB', 'Chemical', '-', (6, 9))
26145	29966799	A trend toward improved OS also favored nintedanib (HR = 0.77, 95% CI: 0.46-1.29, p = .319).	('nintedanib', 'Chemical', 'MESH:C530716', (40, 50))	('nintedanib', 'Var', (40, 50))	('improved', 'PosReg', (15, 23))	('OS', 'Chemical', '-', (24, 26))
26146	29966799	Neutropenia was the most frequent grade 3 or higher AE (43.2% with nintedanib versus 12.2% with placebo); the rates of febrile neutropenia were low (4.5% in the nintedanib group versus 0% in the placebo group).	('rat', 'Species', '10116', (110, 113))	('nintedanib', 'Var', (67, 77))	('neutropenia', 'Disease', 'MESH:D009503', (127, 138))	('Neutropenia', 'Disease', 'MESH:D009503', (0, 11))	('neutropenia', 'Phenotype', 'HP:0001875', (127, 138))	('nintedanib', 'Chemical', 'MESH:C530716', (67, 77))	('Neutropenia', 'Phenotype', 'HP:0001875', (0, 11))	('nintedanib', 'Var', (161, 171))	('neutropenia', 'Disease', (127, 138))	('nintedanib', 'Chemical', 'MESH:C530716', (161, 171))	('Neutropenia', 'Disease', (0, 11))
26147	29966799	AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus in 17.1% of those in the placebo group.	('AEs', 'Chemical', 'MESH:C045560', (0, 3))	('AEs', 'Disease', (0, 3))	('nintedanib', 'Chemical', 'MESH:C530716', (72, 82))	('nintedanib', 'Var', (72, 82))
26151	29966799	However, SWOG0905, which was a phase I/II trial that combined cediranib (a VEGFR inhibitor) with CP, reported a median PFS time of 8.6 months and a median OS time of 16.2 months.	('PFS', 'MPA', (119, 122))	('cediranib', 'Chemical', 'MESH:C500926', (62, 71))	('OS', 'Chemical', '-', (155, 157))	('SWOG0905', 'Var', (9, 17))	('VEGFR', 'Gene', (75, 80))	('combined', 'Interaction', (53, 61))	('VEGFR', 'Gene', '3791', (75, 80))
26228	29966799	Another source of hope might come from the arginine dependence that is exhibited by argininosuccinate synthetase 1 tumors such as mesothelioma, and the good results of pegylated arginine deiminase alone or in combination with CP in the phase I TRAP trial.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('mesothelioma', 'Disease', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('arginine', 'Chemical', 'MESH:D001120', (178, 186))	('argininosuccinate synthetase 1', 'Gene', (84, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('pegylated', 'Var', (168, 177))	('argininosuccinate synthetase 1', 'Gene', '445', (84, 114))
26238	29966799	Lastly, even though MPM cells show a relatively low mutational load that can affect the sensitivity to immunotherapy, there is no doubt that the genetics, gene-driven metabolism, and immune characteristics of this tumor are likely to unravel translational implications within the next few years.	('mutational', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('affect', 'Reg', (77, 83))	('tumor', 'Disease', (214, 219))	('sensitivity to immunotherapy', 'MPA', (88, 116))	('metabolism', 'biological_process', 'GO:0008152', ('167', '177'))	('MPM', 'Chemical', '-', (20, 23))
26288	27543099	More virulent and resistant strains leading to multi drug resistant and extended drug resistant tuberculosis have made it extremely difficult to diagnose a co infection or coexisting pathology.	('multi drug', 'Var', (47, 57))	('infection', 'Disease', (159, 168))	('infection', 'Disease', 'MESH:D007239', (159, 168))	('extended drug resistant', 'Var', (72, 95))
26343	25830670	 BAP1 Missense Mutation c.2054 A>T (p.E685V) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site in a Human Mesothelioma Cell Line BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela noma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma.	('cancers', 'Phenotype', 'HP:0002664', (225, 232))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (299, 325))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (331, 349))	('cancers', 'Disease', (225, 232))	('cancer', 'Disease', (225, 231))	('uveal mela noma', 'Disease', (244, 259))	('cholangiocarcinoma', 'Disease', (331, 349))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (1, 5))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('168', '184'))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (331, 349))	('uveal mela', 'Phenotype', 'HP:0025358', (244, 254))	('Mesothelioma', 'Disease', (135, 147))	('mesothelioma', 'Disease', (279, 291))	('malignant pleural mesothelioma', 'Disease', (261, 291))	('Mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('168', '184'))	('mesothelioma', 'Disease', 'MESH:D008654', (279, 291))	('clear cell renal carcinoma', 'Disease', (299, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('Disrupts', 'NegReg', (56, 64))	('Splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('p.E685V', 'Mutation', 'p.E685V', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (168, 173))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('BAP1', 'Gene', (158, 162))	('c.2054 A>T', 'Var', (24, 34))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (299, 325))	('uveal mela noma', 'Disease', 'MESH:D017241', (244, 259))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Human', 'Species', '9606', (129, 134))	('Normal Splicing', 'MPA', (65, 80))	('renal carcinoma', 'Phenotype', 'HP:0005584', (310, 325))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (271, 291))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (261, 291))	('BAP1', 'Gene', '8314', (1, 5))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('c.2054 A>T', 'Mutation', 'c.2054A>T', (24, 34))
26344	25830670	Here we report mRNA splicing analysis on a homozygous substitution mutation, BAP1 c. 2054 A&T (p.Glu685Val), identified in an MPM cell line derived from a mesothelioma patient.	('mRNA splicing', 'biological_process', 'GO:0006371', ('15', '28'))	('mRNA splicing', 'biological_process', 'GO:0000374', ('15', '28'))	('patient', 'Species', '9606', (168, 175))	('c. 2054 A&', 'Var', (82, 92))	('mRNA splicing', 'biological_process', 'GO:0000373', ('15', '28'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('15', '28'))	('p.Glu685Val', 'Mutation', 'p.E685V', (95, 106))	('mRNA splicing', 'biological_process', 'GO:0000372', ('15', '28'))	('BAP1', 'Gene', (77, 81))	('mRNA splicing', 'biological_process', 'GO:0000394', ('15', '28'))
26345	25830670	The BAP1 c. 2054 A&T mutation introduced a new 5' splice site (GU), which resulted in the deletion of 4 base pairs and presumably protein truncation; 2) a variety of alternative splicing products that led to retention of different introns: introns 14-16; introns 15-16; intron 14 and intron 16; 3) partial intron 14 and 15 retentions caused by activation of alternative 3' splice acceptor sites (AG) in the introns.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('GU', 'Chemical', 'MESH:D019791', (63, 65))	('BAP1 c.', 'Gene', (4, 11))	('splicing', 'biological_process', 'GO:0045292', ('178', '186'))	('retention', 'biological_process', 'GO:0051235', ('208', '217'))	('the', 'Var', (86, 89))
26346	25830670	These data support the conclusion that BAP1 c.2054 A&T (p.E685V) variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing.	('through', 'NegReg', (121, 128))	('p.E685V', 'Var', (56, 63))	('and', 'Reg', (98, 101))	('of normal', 'MPA', (140, 149))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('c.2054 A&', 'Var', (44, 53))	('p.E685V', 'SUBSTITUTION', 'None', (56, 63))	('c.2054 A&T', 'Mutation', 'c.2054A>T', (44, 54))	('BAP1', 'Gene', (39, 43))
26347	25830670	BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal melanoma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (112, 132))	('uveal mela', 'Phenotype', 'HP:0025358', (86, 96))	('cholangiocarcinoma', 'Disease', (172, 190))	('malignant pleural mesothelioma', 'Disease', (102, 132))	('clear cell renal carcinoma', 'Disease', (140, 166))	('BAP1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('deleted', 'Var', (48, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('uveal melanoma', 'Disease', (86, 100))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (140, 166))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (172, 190))	('renal carcinoma', 'Phenotype', 'HP:0005584', (151, 166))
26348	25830670	It has been proposed that BAP1 germline mutations define a new familial cancer syndrome.	('BAP1', 'Gene', (26, 30))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (63, 87))	('familial cancer syndrome', 'Disease', (63, 87))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('germline mutations', 'Var', (31, 49))
26354	25830670	Because of this functional complexity, BAP1 germline mutations predispose individuals to the aggressive tumor phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('predispose', 'Reg', (63, 73))	('germline mutations', 'Var', (44, 62))	('aggressive tumor', 'Disease', 'MESH:D001523', (93, 109))	('aggressive tumor', 'Disease', (93, 109))	('BAP1', 'Gene', (39, 43))
26355	25830670	It is relatively straightforward to interpret germline BAP1 truncating mutations (nonsense mutation, small insertions/deletions) and alterations of a canonical dinucleotide splice donor/acceptor sequences that affect the GU-AG rules.	('donor', 'Species', '9606', (180, 185))	('affect', 'Reg', (210, 216))	('GU-AG rules', 'MPA', (221, 232))	('truncating mutations', 'Var', (60, 80))	('BAP1', 'Gene', (55, 59))	('alterations', 'Var', (133, 144))
26356	25830670	Here we report a homozygous substitution mutation, BAP1 c. 2054 A>T (p.Glu685Val) in exon 16 in an MPM cell line, HMeso01A, identified through BAP1 full gene sequencing analysis.	('HMeso01A', 'CellLine', 'CVCL:5760', (114, 122))	('2054 A>T', 'SUBSTITUTION', 'None', (59, 67))	('BAP1', 'Gene', (51, 55))	('p.Glu685Val', 'SUBSTITUTION', 'None', (69, 80))	('p.Glu685Val', 'Var', (69, 80))	('2054 A>T', 'Var', (59, 67))
26358	25830670	Three commonly used programs were used to predict the potential effects of amino acid substitutions on protein structure and activity: PolyPhen (Polymorphism Phenotyping, http://genetics.bwh.harvard.edu/pph2/), SIFT (Sorting Intolerant from Tolerant, http://sift.jcvi.org/), and MutationTaster (http://www.mutationtaster.org/).	('substitutions', 'Var', (86, 99))	('pph', 'molecular_function', 'GO:0033978', ('203', '206'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('activity', 'MPA', (125, 133))	('pph', 'molecular_function', 'GO:0004238', ('203', '206'))	('SIFT', 'Disease', (211, 215))	('effects', 'Reg', (64, 71))	('SIFT', 'Disease', 'None', (211, 215))	('protein', 'MPA', (103, 110))
26360	25830670	BAP1 full gene sequencing identified a homozygous missense mutation, c. 2054A>T Glu685Val, in cell line HMeso01A that was derived from a malignant pleural mesothelioma patient.	('2054A>T', 'Var', (72, 79))	('Glu685Val', 'SUBSTITUTION', 'None', (80, 89))	('Glu685Val', 'Var', (80, 89))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (147, 167))	('2054A>T', 'SUBSTITUTION', 'None', (72, 79))
26362	25830670	Control RNAs were extracted from four individuals seen at Memorial Sloan Kettering Cancer Center who do not carry the c.2054A>T mutation.	('c.2054A>T', 'Var', (118, 127))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('c.2054A>T', 'Mutation', 'c.2054A>T', (118, 127))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
26366	25830670	Multi-species comparative genomic analysis was used to identify sequence homology at the BAP1 c.2054 A>T (p.E685V) mutation site in ten distantly related species: human, chimpanzee, mouse, rat, dog, cat, rabbit, chicken, xenopus and zebrafish.	('zebrafish', 'Species', '7955', (233, 242))	('BAP1', 'Gene', (89, 93))	('dog', 'Species', '9615', (194, 197))	('rabbit', 'Species', '9986', (204, 210))	('mouse', 'Species', '10090', (182, 187))	('cat', 'molecular_function', 'GO:0004096', ('199', '202'))	('xenopus', 'Species', '8355', (221, 228))	('chimpanzee', 'Species', '9598', (170, 180))	('chicken', 'Species', '9031', (212, 219))	('p.E685V', 'SUBSTITUTION', 'None', (106, 113))	('p.E685V', 'Var', (106, 113))	('c.2054 A>T', 'Var', (94, 104))
26367	25830670	Given the fact that the BAP1 c.2054 A>T (p.E685V) mutation affects the 3rd nucleotide from the end of exon 16 (-3 position) and the -3 base pair is involved in the U1snRNP binding and initiation of spliceosome assembly, we used Sroogle and NNSplice to predict its potential effects on normal mRNA splicing.	('spliceosome', 'cellular_component', 'GO:0005681', ('198', '209'))	('U1snRNP binding', 'molecular_function', 'GO:1990446', ('164', '179'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('292', '305'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('292', '305'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('292', '305'))	('mRNA splicing', 'biological_process', 'GO:0000374', ('292', '305'))	('BAP1', 'Gene', (24, 28))	('mRNA splicing', 'biological_process', 'GO:0000372', ('292', '305'))	('mRNA splicing', 'biological_process', 'GO:0000394', ('292', '305'))	('3rd nucleotide from the end', 'MPA', (71, 98))	('U1snRNP', 'cellular_component', 'GO:0005685', ('164', '171'))	('affects', 'Reg', (59, 66))	('p.E685V', 'SUBSTITUTION', 'None', (41, 48))	('spliceosome assembly', 'biological_process', 'GO:0000245', ('198', '218'))	('mRNA splicing', 'MPA', (292, 305))	('effects', 'Reg', (274, 281))	('p.E685V', 'Var', (41, 48))	('c.2054 A>T', 'Var', (29, 39))
26368	25830670	To evaluate the effect of the BAP1 c.2054 A>T (p.E685V) mutation on RNA splicing, we amplified BAP1 cDNA from four BAP1 wild type patients and the mutant c.2054 A>T HMeso01A cell line that was derived from a malignant pleural mesothelioma patient.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (218, 238))	('c.2054 A>T', 'Var', (154, 164))	('p.E685V', 'SUBSTITUTION', 'None', (47, 54))	('BAP1 cDNA', 'Gene', (95, 104))	('p.E685V', 'Var', (47, 54))	('RNA', 'cellular_component', 'GO:0005562', ('68', '71'))	('RNA splicing', 'biological_process', 'GO:0008380', ('68', '80'))
26369	25830670	Taken together, we were unable to detect any correctly spliced mRNA transcripts in the MPM cell line, HMeso01A, that harbors the missense mutation BAP1 c.2054 A>T (p.Glu685Val).	('p.Glu685Val', 'Var', (164, 175))	('BAP1', 'Gene', (147, 151))	('p.Glu685Val', 'SUBSTITUTION', 'None', (164, 175))	('c.2054 A>T', 'Var', (152, 162))
26370	25830670	Bioinformatic analysis predicts that the BAP1 missense mutation c.2054 A>T (p.Glu685Val) is most likely damaging because it alters a highly conserved amino acid.	('p.Glu685Val', 'SUBSTITUTION', 'None', (76, 87))	('c.2054 A>T', 'Var', (64, 74))	('BAP1', 'Gene', (41, 45))	('p.Glu685Val', 'Var', (76, 87))	('alters', 'Reg', (124, 130))
26373	32690542	Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('cancer syndrome', 'Disease', (145, 160))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('malignancies', 'Disease', 'MESH:D009369', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mesothelioma', 'Disease', (313, 325))	('malignancies', 'Disease', (240, 252))	('BAP1', 'Gene', '8314', (102, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (313, 325))	('Cancer', 'Disease', (75, 81))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (331, 362))	('BAP1', 'Gene', (199, 203))	('cutaneous melanoma', 'Disease', (293, 311))	('Human', 'Species', '9606', (69, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (293, 311))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (293, 311))	('Mutations', 'Var', (56, 65))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', '8314', (140, 144))	('developed', 'Reg', (218, 227))	('BAP1', 'Gene', (102, 106))	('clear-cell renal cell carcinoma', 'Disease', (331, 362))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutant', 'Var', (204, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (342, 362))	('cancer syndrome', 'Disease', 'MESH:D009369', (145, 160))	('BAP1', 'Gene', (140, 144))	('BAP1', 'Gene', (51, 55))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (331, 362))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('BAP1', 'Gene', '8314', (199, 203))
26374	32690542	These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('biallelic', 'Var', (103, 112))	('cancer', 'Disease', (6, 12))	('BAP1', 'Gene', (113, 117))
26377	32690542	BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutated', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
26383	32690542	Because of the powerful tumor suppressor activity of BAP1 and of its role in modulating "gene-environment" (GxE) interactions in cancer, an increasing number of researchers are investigating the biological mechanisms and medical implications of inherited and acquired BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Disease', (24, 29))	('BAP1', 'Gene', (268, 272))	('cancer', 'Disease', (129, 135))	('mutations', 'Var', (273, 282))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('BAP1', 'Gene', (53, 57))
26385	32690542	It is an important component of the pathologic diagnosis of mesothelioma and early-detection clinical trials have been established at the NCI and elsewhere for carriers of germline BAP1 mutations (NCT03830229), including trials targeting BAP1 (NCT03207347, NCT03531840).	('NCT03830229', 'Var', (197, 208))	('BAP1', 'Gene', (181, 185))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('mutations (NCT03830229', 'Var', (186, 208))	('NCT03207347', 'Var', (244, 255))	('NCT03531840', 'Var', (257, 268))	('mesothelioma', 'Disease', (60, 72))
26386	32690542	Here we review current understanding of how BAP1 suppresses tumorigenesis and how BAP1 status can inform diagnosis, prognosis, targeted therapy, and cancer prevention in patients with cancer with hereditary and acquired BAP1 mutations.	('cancer', 'Disease', (184, 190))	('patients', 'Species', '9606', (170, 178))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (225, 234))	('BAP1', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('suppresses', 'NegReg', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('BAP1', 'Gene', (44, 48))
26387	32690542	Moreover, we discuss some puzzling questions, such as why germline BAP1 mutations are associated with mesothelioma of low aggressiveness, but very aggressive uveal melanoma.	('mutations', 'Var', (72, 81))	('mesothelioma of low aggressiveness', 'Disease', 'MESH:D008654', (102, 136))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('associated', 'Reg', (86, 96))	('aggressive uveal melanoma', 'Disease', (147, 172))	('mesothelioma of low aggressiveness', 'Disease', (102, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (147, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('BAP1', 'Gene', (67, 71))
26391	32690542	The investigators proposed that GxE interactions caused the mesothelioma epidemic among genetically predisposed families, challenging the dogma that mesothelioma was an example of a malignancy caused exclusively by exposure to carcinogenic fibers.	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('interactions', 'Var', (36, 48))	('malignancy', 'Disease', 'MESH:D009369', (182, 192))	('malignancy', 'Disease', (182, 192))	('caused', 'Reg', (49, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('carcinogenic fibers', 'Disease', (227, 246))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (227, 246))	('mesothelioma', 'Disease', (149, 161))	('mesothelioma', 'Disease', (60, 72))
26397	32690542	Both tumors have a high frequency of 3p deletions, and, by sequencing 3p, Carbone and colleagues discovered that the individuals affected by mesothelioma, uveal melanoma, or breast cancer in both families carried truncating BAP1 mutations, a condition they named the "BAP1 cancer syndrome".	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('uveal melanoma', 'Disease', (155, 169))	('BAP1', 'Gene', (224, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer syndrome', 'Disease', (273, 288))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('breast cancer', 'Disease', (174, 187))	('mutations', 'Var', (229, 238))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('truncating', 'Var', (213, 223))	('carried', 'Reg', (205, 212))	('tumors', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer syndrome', 'Disease', 'MESH:D009369', (273, 288))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('mesothelioma', 'Disease', (141, 153))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
26398	32690542	A parallel study by Weisner and colleagues reported that BAP1 germline mutations were causally linked to benign melanocytic tumors developing at a young age, which were initially identified as atypical Spitz tumors.	('Spitz tumors', 'Disease', 'MESH:D018332', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('germline', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Spitz tumors', 'Disease', (202, 214))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('linked to', 'Reg', (95, 104))	('BAP1', 'Gene', (57, 61))	('benign melanocytic tumors', 'Disease', 'MESH:D009369', (105, 130))	('benign melanocytic tumors', 'Disease', (105, 130))
26416	32690542	Studying primary fibroblast cell cultures derived from skin-punch biopsies of individuals from two separate families carrying heterozygous BAP1 mutations (BAP1+/-), and wild-type BAP1 (BAP1+/+) control fibroblasts (matched for sex and age from individuals from the same families), it was found that BAP1 localizes to the endoplasmic reticulum (ER), where it deubiquitylates and thus stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; ref.).	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('321', '342'))	('IP3R3', 'Gene', '3710', (444, 449))	('deubiquitylates', 'MPA', (358, 373))	('IP3R3', 'Gene', (444, 449))	('BAP1', 'Gene', (299, 303))	('stabilizes', 'MPA', (383, 393))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))
26428	32690542	The transcriptional repression of ATF3 and CHOP is dependent upon the deubiquitinylation of H2A (at K119) by BAP1.	('transcriptional', 'MPA', (4, 19))	('H2A', 'Protein', (92, 95))	('CHOP', 'Gene', (43, 47))	('at K119', 'Var', (97, 104))	('K119', 'Chemical', 'MESH:C118156', (100, 104))	('deubiquitinylation', 'MPA', (70, 88))	('ATF3', 'Gene', '467', (34, 38))	('dependent', 'Reg', (51, 60))	('BAP1', 'Gene', (109, 113))	('ATF3', 'Gene', (34, 38))	('CHOP', 'Gene', '1649', (43, 47))
26429	32690542	By engineering a knock-in mouse model expressing the catalytically inactive C91A Bap1 mutant, He and colleagues showed that the loss of function of BAP1 has a proapoptotic effect in mouse embryonic stem cells, fibroblasts, liver, and pancreas, but not in melanocytes and mesothelial cells, the cells that give rise to the cancer types most commonly associated with BAP1 mutations in humans.	('proapoptotic effect', 'MPA', (159, 178))	('Bap1', 'Gene', (81, 85))	('humans', 'Species', '9606', (383, 389))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('mouse', 'Species', '10090', (182, 187))	('mutant', 'Var', (86, 92))	('loss', 'Var', (128, 132))	('cancer', 'Disease', (322, 328))	('C91A', 'Var', (76, 80))	('BAP1', 'Gene', (148, 152))	('C91A', 'SUBSTITUTION', 'None', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('BAP1', 'Gene', (365, 369))	('mouse', 'Species', '10090', (26, 31))	('mutations', 'Var', (370, 379))	('Bap1', 'Gene', '104416', (81, 85))
26436	32690542	Moreover, using a genetically engineered inducible Bap1 knockout murine model, it has been demonstrated that the deletion of Bap1 altered several metabolic pathways.	('Bap1', 'Gene', '104416', (125, 129))	('deletion', 'Var', (113, 121))	('Bap1', 'Gene', (51, 55))	('Bap1', 'Gene', (125, 129))	('metabolic pathways', 'Pathway', (146, 164))	('altered', 'Reg', (130, 137))	('murine', 'Species', '10090', (65, 71))	('Bap1', 'Gene', '104416', (51, 55))
26440	32690542	In 2010, Harbour and colleagues reported that 26 of 31 metastasizing uveal melanomas carried inactivating somatic BAP1 mutations, and one of the patients also carried a germline BAP1 mutation.	('patients', 'Species', '9606', (145, 153))	('inactivating', 'MPA', (93, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('metastasizing uveal melanomas', 'Disease', 'MESH:D009362', (55, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('metastasizing uveal melanomas', 'Disease', (55, 84))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
26441	32690542	In 2011, Carbone's team reported that germline BAP1 mutations predisposed to mesothelioma and uveal melanoma, the BAP1 cancer syndrome.	('mutations', 'Var', (52, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('predisposed', 'Reg', (62, 73))	('mesothelioma', 'Disease', (77, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('uveal melanoma', 'Disease', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('germline', 'Var', (38, 46))	('cancer syndrome', 'Disease', 'MESH:D009369', (119, 134))	('cancer syndrome', 'Disease', (119, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BAP1', 'Gene', (47, 51))
26442	32690542	In 2012, Brugarolas and colleagues reported that 15% of ccRCCs carried somatic BAP1 mutations, and subsequently found that some patients also had inactivating germline mutations.	('carried', 'Reg', (63, 70))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('RCC', 'Disease', (58, 61))	('patients', 'Species', '9606', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
26444	32690542	Numerous studies have now confirmed and expanded on the direct link of BAP1 germline mutations to a cancer syndrome characterized by a predisposition to mesothelioma, uveal melanoma, and less frequently cutaneous melanoma, as well as ccRCC, which are the core cancer types in the BAP1 cancer syndrome.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer syndrome', 'Disease', 'MESH:D009369', (285, 300))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('uveal melanoma', 'Disease', (167, 181))	('mesothelioma', 'Disease', (153, 165))	('cancer syndrome', 'Disease', 'MESH:D009369', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('cancer', 'Disease', (285, 291))	('BAP1', 'Gene', (71, 75))	('cutaneous melanoma', 'Disease', (203, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (203, 221))	('cancer syndrome', 'Disease', (285, 300))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (260, 266))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('mutations', 'Var', (85, 94))	('link', 'Reg', (63, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer syndrome', 'Disease', (100, 115))	('RCC', 'Disease', (236, 239))	('core', 'cellular_component', 'GO:0019013', ('255', '259'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
26445	32690542	Although the term "mutations" has been widely used to encompass different types of genetic damage, most BAP1-mutant families carry truncating BAP1 mutations.	('mutations', 'Var', (147, 156))	('BAP1-mutant', 'Gene', (104, 115))	('truncating', 'MPA', (131, 141))	('BAP1', 'Gene', (142, 146))	('genetic damage', 'Disease', 'MESH:D030342', (83, 97))	('genetic damage', 'Disease', (83, 97))
26452	32690542	Recently, Badhai and colleagues reported that the combined deletion in the mesothelial cell lineage of Bap1, Nf2, and Cdkn2ab caused mesothelioma in 100% of mice.	('Bap1', 'Gene', '104416', (103, 107))	('Nf2', 'Gene', (109, 112))	('mice', 'Species', '10090', (157, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('Nf2', 'Gene', '18016', (109, 112))	('Bap1', 'Gene', (103, 107))	('Cdkn2ab', 'Gene', (118, 125))	('deletion', 'Var', (59, 67))	('mesothelioma', 'Disease', (133, 145))	('caused', 'Reg', (126, 132))
26453	32690542	Bap1 deletion alone caused mesothelioma in 5% of unexposed mice, and combined Nf2 and Cdkn2ab deletion alone did not.	('mesothelioma', 'Disease', (27, 39))	('Bap1', 'Gene', '104416', (0, 4))	('deletion', 'Var', (5, 13))	('mice', 'Species', '10090', (59, 63))	('Bap1', 'Gene', (0, 4))	('Nf2', 'Gene', (78, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('Nf2', 'Gene', '18016', (78, 81))	('caused', 'Reg', (20, 26))
26454	32690542	In summary, inherited BAP1 mutations cause cancer in mice and in humans, and cancer incidence increases upon exposure to asbestos or other carcinogenic fibers and when other mutations are present.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('carcinogenic fibers', 'Disease', (139, 158))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (139, 158))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('humans', 'Species', '9606', (65, 71))	('cause', 'Reg', (37, 42))	('mice', 'Species', '10090', (53, 57))	('BAP1', 'Gene', (22, 26))
26455	32690542	However, the spontaneous development of mesotheliomas in Bap1+/- mice not exposed to asbestos, and the development of multiple cancer types in carriers of BAP1 mutations (Fig.	('Bap1', 'Gene', (57, 61))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (160, 169))	('mice', 'Species', '10090', (65, 69))	('BAP1', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('carriers', 'Reg', (143, 151))	('cancer', 'Disease', (127, 133))	('Bap1', 'Gene', '104416', (57, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (40, 53))	('mesotheliomas', 'Disease', (40, 53))
26456	32690542	2B), including tumor types that have not been associated with known carcinogens, suggests that BAP1 mutations also drive tumor growth independently of genotoxic stress, perhaps by favoring the accumulation of age-related DNA damage.	('mutations', 'Var', (100, 109))	('genotoxic stress', 'Disease', 'MESH:D000079225', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BAP1', 'Gene', (95, 99))	('genotoxic stress', 'Disease', (151, 167))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('favoring', 'PosReg', (180, 188))	('tumor', 'Disease', (121, 126))	('DNA damage', 'MPA', (221, 231))	('tumor', 'Disease', (15, 20))	('DNA', 'cellular_component', 'GO:0005574', ('221', '224'))	('accumulation', 'MPA', (193, 205))	('drive', 'PosReg', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
26458	32690542	However, patients with uveal melanoma with germline BAP1 mutations always have an initiating mutation in the G-alpha-q (Gq) pathway, suggesting that additional genetic variants play a critical role in the development of uveal melanoma.	('patients', 'Species', '9606', (9, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('initiating', 'Reg', (82, 92))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('G-alpha-q', 'Gene', (109, 118))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', (23, 37))	('Gq', 'Chemical', '-', (120, 122))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('mutation', 'Var', (93, 101))	('G-alpha-q', 'Gene', '2776', (109, 118))
26461	32690542	Carriers of germline BAP1 mutations often develop multiple cancers during their lifetime.	('BAP1', 'Gene', (21, 25))	('multiple cancers', 'Disease', (50, 66))	('develop', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('multiple cancers', 'Disease', 'MESH:D009369', (50, 66))
26463	32690542	The fact that most BAP1-associated cancers arise in middle-age and older individuals, and that the penetrance for any particular cancer type is less than 100%, suggests that genomic aberrations in addition to BAP1 loss are required for cancer formation, for example, mutations in the Gq signaling pathway.	('BAP1', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Gq', 'Chemical', '-', (284, 286))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Gq signaling pathway', 'Pathway', (284, 304))	('signaling pathway', 'biological_process', 'GO:0007165', ('287', '304'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('formation', 'biological_process', 'GO:0009058', ('243', '252'))	('cancer', 'Disease', (236, 242))	('mutations', 'Var', (267, 276))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('BAP1-associated', 'Gene', (19, 34))	('loss', 'NegReg', (214, 218))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
26464	32690542	The first cancer in which somatic (i.e., acquired) BAP1 mutations were found to be common was uveal melanoma, where these mutations are present in approximately 45% of primary tumors and are highly correlated with the poor prognosis class 2 transcriptional signature and metastatic phenotype (ref.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BAP1', 'Gene', (51, 55))	('uveal melanoma', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('correlated', 'Reg', (198, 208))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
26466	32690542	Other cancers in which acquired somatic BAP1 mutations are common include mesothelioma (60%-70% of them; ref.)	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('mesothelioma', 'Disease', (74, 86))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('BAP1', 'Gene', (40, 44))
26469	32690542	The parallel between the tumor types developing most frequently in carriers of germline BAP1 mutations and the tumor types that most frequently contain somatic BAP1 mutations underscores the increased susceptibility of uveal, mesothelial, and kidney cells to BAP1 loss.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (25, 30))	('germline', 'Var', (79, 87))	('tumor', 'Disease', (111, 116))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('BAP1', 'Gene', (88, 92))
26470	32690542	Somatic BAP1 mutations are also present in other malignancies, although at lower rates: thymic carcinoma (13%), cholangiocarcinoma (7%), cutaneous melanoma (5%), basal cell carcinoma (4%), and others (ref.	('carcinoma', 'Disease', 'MESH:D009369', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('carcinoma', 'Disease', (121, 130))	('malignancies', 'Disease', (49, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))	('BAP1', 'Gene', (8, 12))	('cholangiocarcinoma', 'Disease', (112, 130))	('carcinoma', 'Disease', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (162, 182))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (13, 22))	('carcinoma', 'Disease', (173, 182))	('basal cell carcinoma', 'Disease', (162, 182))	('carcinoma', 'Disease', 'MESH:D009369', (95, 104))	('cutaneous melanoma', 'Disease', (137, 155))
26472	32690542	The role of BAP1 as a two-hit tumor suppressor gene is underscored by the fact that in humans they are accompanied by monoallelic loss of 3p, or by biallelic deletions of the BAP1 locus (LOH), including broad deletions of 3p21, narrow deletions of several exons, or loss of the entire BAP1 allele.	('humans', 'Species', '9606', (87, 93))	('BAP1', 'Gene', (175, 179))	('3p21', 'Protein', (222, 226))	('narrow deletions', 'Var', (228, 244))	('loss', 'NegReg', (266, 270))	('BAP1', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('loss', 'NegReg', (130, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
26473	32690542	Initial studies underestimated the frequency of BAP1 mutations in mesothelioma as 22% to 23%.	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('mesothelioma', 'Disease', (66, 78))
26474	32690542	A subsequent study using a comprehensive integrated genomic approach that included Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), copy-number analysis, and cDNA sequencing, combined with IHC and DNA methylation analyses in mesothelioma biopsies, found that >60% carried biallelic somatic BAP1 mutations.	('mesothelioma', 'Disease', (252, 264))	('DNA methylation', 'biological_process', 'GO:0006306', ('224', '239'))	('mutations', 'Var', (322, 331))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('BAP1', 'Gene', (317, 321))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))
26475	32690542	This is because of the frequent occurrence of minute BAP1 deletions in the range of 250 to 3,000 kb, which are not reliably detected by targeted NGS (tNGS), by whole-exome sequencing (WES), or by Sanger sequencing, but are instead detected by MLPA.	('deletions', 'Var', (58, 67))	('tNGS', 'Chemical', '-', (150, 154))	('BAP1', 'Gene', (53, 57))
26476	32690542	These findings were supported by a study in which high-density aCGH to detect deletions larger than 250 bp, and tNGS to detect nucleotide level mutations, resulted in a much higher prevalence of BAP1 mutations in human mesothelioma biopsies than either technique alone (~50%).	('human', 'Species', '9606', (213, 218))	('BAP1', 'Gene', (195, 199))	('mutations', 'Var', (200, 209))	('mesothelioma', 'Disease', (219, 231))	('tNGS', 'Chemical', '-', (112, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))
26478	32690542	Additional studies confirmed that BAP1 is the most frequently mutated gene in mesothelioma; however, studies that relied only on tNGS or WES invariably underestimated the true incidence of BAP1 mutations.	('tNGS', 'Chemical', '-', (129, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('BAP1', 'Gene', (189, 193))	('mutations', 'Var', (194, 203))	('mesothelioma', 'Disease', (78, 90))
26479	32690542	Similarly, Harbour and colleagues used an integrated DNA/RNA-sequencing approach and a customized bioinformatics pipeline to improve the detection of BAP1 mutations in uveal melanoma, identifying BAP1 mutations in approximately 45% of uveal melanomas, twice the rate detected by previous NGS approaches.	('BAP1', 'Gene', (196, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('mutations', 'Var', (201, 210))	('uveal melanomas', 'Disease', (235, 250))	('BAP1', 'Gene', (150, 154))	('uveal melanomas', 'Phenotype', 'HP:0007716', (235, 250))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('uveal melanomas', 'Disease', 'MESH:C536494', (235, 250))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (241, 250))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
26481	32690542	A detailed analysis of 3p deletions in sporadic mesotheliomas revealed that deletions are not contiguous but rather preferentially occur in BAP1 and in some nearby genes (SETD2, PBRM1, and SMARCC1), alternating with segments showing oscillating copy-number changes along the 3p21 chromosome, findings suggestive of chromothripsis.	('chromothripsis', 'Disease', 'MESH:D000072837', (315, 329))	('deletions', 'Var', (76, 85))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (39, 61))	('deletions', 'Var', (26, 35))	('BAP1', 'Gene', (140, 144))	('SETD2', 'Gene', '29072', (171, 176))	('sporadic mesotheliomas', 'Disease', (39, 61))	('PBRM1', 'Gene', (178, 183))	('SETD2', 'Gene', (171, 176))	('occur', 'Reg', (131, 136))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (39, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('280', '290'))	('chromothripsis', 'Disease', (315, 329))	('SMARCC1', 'Gene', (189, 196))	('SMARCC1', 'Gene', '6599', (189, 196))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (39, 61))
26482	32690542	The occurrence of chromothripsis in mesothelioma may be favored by BAP1 inactivation, and it has been confirmed by mate-pair sequencing (MPseq) analyses and by WES.	('favored', 'PosReg', (56, 63))	('chromothripsis in mesothelioma', 'Disease', (18, 48))	('inactivation', 'Var', (72, 84))	('chromothripsis in mesothelioma', 'Disease', 'MESH:D000072837', (18, 48))	('BAP1', 'Gene', (67, 71))
26491	32690542	Negative BAP1 nuclear staining by IHC, regardless of cytoplasmic staining, is found in about 60% to 70% of mesotheliomas and is a reliable, rapid, and economical approach to identify biallelic BAP1 inactivating mutations.	('biallelic', 'Var', (183, 192))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', (107, 120))	('Negative', 'NegReg', (0, 8))	('inactivating mutations', 'Var', (198, 220))	('BAP1', 'Gene', (193, 197))
26492	32690542	In most tumor cells showing no nuclear staining (e.g., mutated BAP1), there is also no staining in the cytoplasm (Fig.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutated', 'Var', (55, 62))	('BAP1', 'Gene', (63, 67))	('cytoplasm', 'cellular_component', 'GO:0005737', ('103', '112'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
26499	32690542	The two discordant samples had missense mutations in the catalytic domain (p.Gly13Val and p.Phe170Leu).	('p.Phe170Leu', 'SUBSTITUTION', 'None', (90, 101))	('p.Phe170Leu', 'Var', (90, 101))	('p.Gly13Val', 'SUBSTITUTION', 'None', (75, 85))	('p.Gly13Val', 'Var', (75, 85))
26500	32690542	In addition, Western blot analyses of an IHC-negative sample with wild-type BAP1 failed to reveal detectable BAP1 protein, suggesting that BAP1 may have been inactivated through mutations eluding detection by conventional Sanger sequencing, as described in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('mutations', 'Var', (178, 187))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('mesothelioma', 'Disease', (257, 269))
26503	32690542	Baumann and colleagues reported that the presence of germ line BAP1 mutations strikingly increased the 5-year survival rate of patients with mesothelioma by 7-fold [47% (95% confidence interval [CI], 24-67) vs. 6.7% (95% CI, 6.2-7.3)], indicating that mesothelioma is less aggressive when it occurs in the context of the BAP1 cancer syndrome.	('mesothelioma', 'Disease', (252, 264))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('patients', 'Species', '9606', (127, 135))	('cancer syndrome', 'Disease', 'MESH:D009369', (326, 341))	('cancer syndrome', 'Disease', (326, 341))	('mesothelioma', 'Disease', (141, 153))	('mutations', 'Var', (68, 77))	('increased', 'PosReg', (89, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
26504	32690542	In these individuals, normal cells contain 50% of the BAP1 protein, whereas tumor cells show biallelic BAP1 mutations and thus do not contain a biologically functional BAP1 protein.	('mutations', 'Var', (108, 117))	('protein', 'Protein', (59, 66))	('BAP1', 'Gene', (103, 107))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('BAP1 protein', 'Protein', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
26508	32690542	Most subjects (43/79) carried germline BAP1 mutations; 12 of 79 carried germline mutations in other tumor suppressors; and 5 of 79 carried mutations in BAP1 and also in other cancer-related genes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mutations', 'Reg', (139, 148))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', (39, 43))
26510	32690542	An analysis conducted at the University of Chicago on the germline DNA of 198 patients with mesothelioma using targeted capture and NGS of 85 cancer susceptibility genes revealed that 12% of patients within this cohort carried pathogenic germline mutations; BAP1 was the most commonly mutated gene.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (191, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('germline mutations', 'Var', (238, 256))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (78, 86))	('BAP1', 'Gene', (258, 262))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('pathogenic', 'Reg', (227, 237))	('mesothelioma', 'Disease', (92, 104))	('cancer', 'Disease', (142, 148))
26511	32690542	A similar survey conducted at the NCI on a cohort of 385 patients using a panel of 73 genes involved in DNA repair and tumor suppression demonstrated that 12% of them carried germline mutations (mostly germline BAP1 mutations).	('tumor', 'Disease', (119, 124))	('patients', 'Species', '9606', (57, 65))	('germline mutations', 'Var', (175, 193))	('germline BAP1 mutations', 'Var', (202, 225))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carried', 'Reg', (167, 174))	('DNA repair', 'biological_process', 'GO:0006281', ('104', '114'))
26512	32690542	The presence of inherited mutations significantly increased median overall survival compared with patients without these mutations (7.9 years vs. 2.4 years, P = 0.001; ref.).	('mutations', 'Var', (26, 35))	('overall survival', 'MPA', (67, 83))	('increased', 'PosReg', (50, 59))	('patients', 'Species', '9606', (98, 106))
26513	32690542	Together, these studies validate the prognostic significance of germline mutations that confer a significantly improved survival to patients with mesothelioma (Fig.	('improved', 'PosReg', (111, 119))	('germline mutations', 'Var', (64, 82))	('mesothelioma', 'Disease', (146, 158))	('mesothelioma', 'Disease', 'MESH:D008654', (146, 158))	('survival', 'MPA', (120, 128))	('patients', 'Species', '9606', (132, 140))
26514	32690542	The improved survival was also observed among patients who, in addition to mesothelioma, developed other aggressive malignancies, which, rather than an exception, is the norm among those carrying germline BAP1 mutations.	('improved', 'PosReg', (4, 12))	('aggressive malignancies', 'Disease', (105, 128))	('mutations', 'Var', (210, 219))	('patients', 'Species', '9606', (46, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('aggressive malignancies', 'Disease', 'MESH:D009369', (105, 128))	('mesothelioma', 'Disease', (75, 87))
26516	32690542	Because almost all BAP1-mutated cancers contain biallelic BAP1 mutations, regardless of whether they are sporadic or occur in carriers of germline mutations, the markedly improved prognosis of mesotheliomas occurring in carriers of germline BAP1 mutations does not seem to be related only to the mutation in the tumor cells.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('BAP1', 'Gene', (241, 245))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('mutations', 'Var', (246, 255))	('mesotheliomas', 'Disease', 'MESH:D008654', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (312, 317))	('mesotheliomas', 'Disease', (193, 206))	('biallelic', 'Var', (48, 57))	('improved', 'PosReg', (171, 179))	('BAP1-mutated', 'Gene', (19, 31))
26517	32690542	Therefore, the improved prognosis of mesothelioma and other cancer types in carriers of germline BAP1 mutations may be influenced by the microenvironment and/or the immune system.	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('influenced', 'Reg', (119, 129))	('cancer', 'Disease', (60, 66))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('improved', 'PosReg', (15, 23))	('mesothelioma', 'Disease', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
26519	32690542	In contrast to mesothelioma, a study of 8 patients with uveal melanoma with germline BAP1 mutations found an increased risk of metastasis (p.003) compared with uveal melanoma patients with wild-type BAP1 in their germline, confirming that BAP1 mutations induce a metastatic phenotype.	('mutations', 'Var', (90, 99))	('p.0', 'SUBSTITUTION', 'None', (139, 142))	('metastasis', 'CPA', (127, 137))	('induce', 'Reg', (254, 260))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutations', 'Var', (244, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('p.0', 'Var', (139, 142))	('uveal melanoma', 'Disease', (160, 174))	('mesothelioma', 'Disease', (15, 27))	('patients', 'Species', '9606', (42, 50))	('BAP1', 'Gene', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('patients', 'Species', '9606', (175, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))
26521	32690542	Somatic BAP1 mutations in the tumor biopsy are the strongest known risk factor for uveal melanoma metastatic death.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('uveal melanoma metastatic death', 'Disease', (83, 114))	('uveal melanoma metastatic death', 'Disease', 'MESH:C536494', (83, 114))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('BAP1', 'Gene', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))
26522	32690542	These phenotypic differences among cancer types associated with BAP1 mutations suggest that there are cell type- and context-dependent differences in the role of BAP1 in biology and cancer.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('BAP1', 'Gene', (64, 68))
26523	32690542	It is not yet clear whether germline BAP1 mutations are associated with improved survival in RCC.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('improved', 'PosReg', (72, 80))	('germline', 'Var', (28, 36))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
26524	32690542	Mesotheliomas with acquired BAP1 mutations are mostly of the epithelial type and may have a slightly improved prognosis of a few months compared with mesotheliomas of similar histologic type with wild-type BAP1; however, some studies did not support this finding.	('mesotheliomas', 'Disease', (150, 163))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('improved', 'PosReg', (101, 109))	('Mesotheliomas', 'Disease', 'MESH:D008654', (0, 13))	('Mesotheliomas', 'Disease', (0, 13))	('mesotheliomas', 'Disease', 'MESH:D008654', (150, 163))
26525	32690542	Intriguingly, the opposite correlation with survival was observed in uveal melanoma, ccRCC, and cholangiocarcinoma, where somatic biallelic BAP1 mutations were associated with a metastatic phenotype and poor prognosis.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('BAP1', 'Gene', (140, 144))	('uveal melanoma', 'Disease', (69, 83))	('mutations', 'Var', (145, 154))	('biallelic', 'Var', (130, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('cholangiocarcinoma', 'Disease', (96, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('metastatic', 'CPA', (178, 188))	('associated', 'Reg', (160, 170))
26526	32690542	In uveal melanoma, detection of BAP1 mutations directly by sequencing, or indirectly via the class 2 transcriptional signature or other methods, is now a routine part of patient care, with high-risk patients stratified for increased surveillance and clinical trial entry.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('patient', 'Species', '9606', (199, 206))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (32, 36))	('patients', 'Species', '9606', (199, 207))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('patient', 'Species', '9606', (170, 177))
26528	32690542	Brugarolas and colleagues found that ccRCCs with somatic BAP1 mutations were associated with high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('associated', 'Reg', (77, 87))
26531	32690542	To determine whether BAP1 and PBRM1 directly affect tumor grade, mice were generated with targeted inactivation of Bap1 or Pbrm1 in the kidney using the same Cre driver.	('affect', 'Reg', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (65, 69))	('Bap1', 'Gene', '104416', (115, 119))	('Pbrm1', 'Gene', (123, 128))	('Pbrm1', 'Gene', '66923', (123, 128))	('Bap1', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inactivation', 'Var', (99, 111))
26532	32690542	Inactivation of Bap1 or Pbrm1, along with Vhl, which is uniformly inactivated in ccRCC, led to the development of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('Bap1', 'Gene', (16, 20))	('Vhl', 'Gene', (42, 45))	('led to', 'Reg', (88, 94))	('Pbrm1', 'Gene', (24, 29))	('Pbrm1', 'Gene', '66923', (24, 29))	('Bap1', 'Gene', '104416', (16, 20))	('Vhl', 'Gene', '7428', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('Inactivation', 'Var', (0, 12))
26538	32690542	Following VHL inactivation, which is the signature and initiating event in ccRCC, a mutation of the second copy of BAP1 or PBRM1 likely leads to tumors of different grade and prognosis.	('leads to', 'Reg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('PBRM1', 'Gene', (123, 128))	('RCC', 'Disease', (77, 80))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('BAP1', 'Gene', (115, 119))	('VHL', 'Gene', (10, 13))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('VHL', 'Gene', '7428', (10, 13))	('mutation', 'Var', (84, 92))
26539	32690542	A fourth tumor suppressor gene in the same 3p region, SETD2, is also mutated in ccRCC and is associated with poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('SETD2', 'Gene', '29072', (54, 59))	('mutated', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SETD2', 'Gene', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('tumor', 'Disease', (9, 14))	('RCC', 'Disease', (82, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))
26540	32690542	Whereas mutations in BAP1 and PBRM1 tend to be mutually exclusive, mutations in PBRM1 and SETD2 appear to cooperate and are found at higher-than-expected frequencies.	('SETD2', 'Gene', (90, 95))	('PBRM1', 'Gene', (30, 35))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (67, 76))	('PBRM1', 'Gene', (80, 85))	('SETD2', 'Gene', '29072', (90, 95))
26545	32690542	The incorporation of the active metabolite of gemcitabine into DNA causes replication arrest and apoptosis, making this drug one of the most used chemotherapeutic agents against several cancers, including mesothelioma, for which it is approved as second-line treatment.	('incorporation', 'Var', (4, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('arrest', 'Disease', (86, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('mesothelioma', 'Disease', (205, 217))	('gemcitabine', 'Chemical', 'MESH:C056507', (46, 57))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('apoptosis', 'CPA', (97, 106))
26547	32690542	Upon treatment with this agent or with hydroxyurea, the viability of mesothelioma spheroids expressing nonfunctional C91A BAP1 was significantly higher compared with wild-type BAP1 counterparts.	('BAP1', 'Gene', (122, 126))	('C91A', 'Var', (117, 121))	('viability', 'CPA', (56, 65))	('hydroxyurea', 'Chemical', 'MESH:D006918', (39, 50))	('mesothelioma spheroids', 'Disease', 'MESH:D008654', (69, 91))	('C91A', 'SUBSTITUTION', 'None', (117, 121))	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (69, 91))	('mesothelioma spheroids', 'Disease', (69, 91))	('higher', 'PosReg', (145, 151))
26553	32690542	This combined therapy is the standard of care for BRAFV600E-mutant human melanoma.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('BRAFV600E-mutant', 'Var', (50, 66))	('human', 'Species', '9606', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
26555	32690542	In addition, a large study in more than 100 cases of metastatic RCC demonstrated that BAP1 mutational status did not correlate with clinical benefit upon rapalog therapy, despite the significantly higher aggressiveness of RCC in carriers of BAP1 mutations.	('aggressiveness of RCC', 'Disease', (204, 225))	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('aggressiveness of RCC', 'Disease', 'MESH:C538614', (204, 225))	('higher', 'PosReg', (197, 203))	('rapalog', 'Chemical', '-', (154, 161))	('BAP1', 'Gene', (241, 245))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (246, 255))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Disease', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
26561	32690542	The BAP1-deficient developmental phenotype could be rescued using SAHA or specific depletion of HDAC4.	('BAP1-deficient developmental', 'Disease', 'MESH:D007805', (4, 32))	('depletion', 'Var', (83, 92))	('HDAC4', 'Gene', '9759', (96, 101))	('BAP1-deficient developmental', 'Disease', (4, 32))	('HDAC4', 'Gene', (96, 101))
26564	32690542	In the context of mutations in BRCA1 or BRCA2 genes in patients with breast, ovary, prostate, or pancreatic cancers, PARP inhibitors have shown antitumor activity, and three agents are currently in the clinic.	('PARP', 'Gene', '142', (117, 121))	('pancreatic cancers', 'Disease', (97, 115))	('PARP', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreatic cancers', 'Disease', 'MESH:D010190', (97, 115))	('breast', 'Disease', (69, 75))	('BRCA2', 'Gene', (40, 45))	('prostate', 'Disease', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('ovary', 'Disease', (77, 82))	('BRCA2', 'Gene', '675', (40, 45))	('BRCA1', 'Gene', '672', (31, 36))	('tumor', 'Disease', (148, 153))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (97, 115))	('BRCA1', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations', 'Var', (18, 27))
26569	32690542	A BAP1 mutant by alternative splicing resulting in a 54-bp deletion increased sensitivity to the PARP inhibitor olaparib.	('PARP', 'Gene', '142', (97, 101))	('olaparib', 'Chemical', 'MESH:C531550', (112, 120))	('mutant', 'Var', (7, 13))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('PARP', 'Gene', (97, 101))	('deletion', 'Var', (59, 67))	('increased', 'PosReg', (68, 77))	('BAP1', 'Gene', (2, 6))
26570	32690542	A recent study on HR defects in a cohort of patients with mesothelioma showed both in vitro and by digital gene-expression analysis that loss of BAP1 increased sensitivity to PARP inhibitors.	('patients', 'Species', '9606', (44, 52))	('gene-expression', 'biological_process', 'GO:0010467', ('107', '122'))	('PARP', 'Gene', (175, 179))	('mesothelioma', 'Disease', (58, 70))	('HR defects', 'Disease', 'MESH:D000014', (18, 28))	('PARP', 'Gene', '142', (175, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('loss', 'Var', (137, 141))	('increased', 'PosReg', (150, 159))	('BAP1', 'Gene', (145, 149))	('HR defects', 'Disease', (18, 28))
26571	32690542	Presently, two ongoing clinical trials are testing the hypothesis that BAP1 mutations increase sensitivity to PARP inhibitors in mesothelioma (NCT03207347, NCT03531840).	('increase', 'PosReg', (86, 94))	('mutations', 'Var', (76, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('PARP', 'Gene', (110, 114))	('mesothelioma', 'Disease', (129, 141))	('BAP1', 'Gene', (71, 75))	('PARP', 'Gene', '142', (110, 114))
26573	32690542	We propose that these results may indicate that the increased resistance to cell death caused by BAP1 mutations in tumor cells over-come whatever increased DNA damage may be induced by PARP inhibitors in these same cells, making them resistant to this therapy.	('increased', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('PARP', 'Gene', (185, 189))	('tumor', 'Disease', (115, 120))	('DNA damage', 'MPA', (156, 166))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('resistance', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PARP', 'Gene', '142', (185, 189))
26587	32690542	Moreover, based on the structural rearrangements induced by chromothripsis, which may be favored by BAP1 mutations, Mansfield and colleagues predicted and validated in vitro the expression of altered peptides that may act as neoantigens and thus potentially increase mesothelioma immunogenicity and responsiveness to immunotherapy.	('chromothripsis', 'Disease', 'MESH:D000072837', (60, 74))	('BAP1', 'Gene', (100, 104))	('increase mesothelioma immunogenicity', 'Disease', (258, 294))	('mutations', 'Var', (105, 114))	('chromothripsis', 'Disease', (60, 74))	('increase mesothelioma immunogenicity', 'Disease', 'MESH:D008654', (258, 294))	('peptides', 'Protein', (200, 208))	('altered', 'Var', (192, 199))
26591	32690542	In addition, depletion or pharmacologic inhibition of EZH2 in BAP1-deficient Xenopus embryos did not rescue a neural crest developmental phenotype.	('EZH2', 'Gene', (54, 58))	('BAP1-deficient Xenopus embryos', 'Disease', (62, 92))	('depletion', 'Var', (13, 22))	('neural crest developmental phenotype', 'CPA', (110, 146))	('BAP1-deficient Xenopus embryos', 'Disease', 'MESH:D020964', (62, 92))
26593	32690542	Although the BAP1 cancer syndrome and the driving role of acquired BAP1 mutations in human cancer were discovered less than a decade ago, much progress has been made to elucidate critical mechanisms of BAP1 activities (Fig.	('mutations', 'Var', (72, 81))	('cancer syndrome', 'Disease', (18, 33))	('cancer syndrome', 'Disease', 'MESH:D009369', (18, 33))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('human', 'Species', '9606', (85, 90))	('BAP1', 'Gene', (67, 71))
26595	32690542	Therefore, reduced levels of BAP1, as observed in carriers of heterozygous BAP1 mutations, increase the amount of genetic damage that occurs spontaneously as cells divide, or that occurs in response to exposure to environmental carcinogens.	('genetic damage', 'Disease', (114, 128))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('increase', 'PosReg', (91, 99))	('genetic damage', 'Disease', 'MESH:D030342', (114, 128))
26596	32690542	Moreover, BAP1 loss favors tumor growth by inducing a Warburg effect (i.e., aerobic glycolysis) that provides the metabolic building blocks to support cell division and at the same time helps cancer cells to grow in a hypoxic environment.	('grow', 'CPA', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell division', 'biological_process', 'GO:0051301', ('151', '164'))	('tumor', 'Disease', (27, 32))	('BAP1', 'Gene', (10, 14))	('Warburg', 'MPA', (54, 61))	('cancer', 'Disease', (192, 198))	('loss', 'Var', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('favors', 'PosReg', (20, 26))	('helps', 'PosReg', (186, 191))	('inducing', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('84', '94'))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
26598	32690542	Therefore, the combined nuclear and cytoplasmic BAP1 activities account for the very high incidence of cancer in carriers of germline BAP1 mutations (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
26601	32690542	All published data support the notion that BAP1 is a potent tumor suppressor, as almost all carriers of pathogenic germline BAP1 mutations developed one or more cancers during their lifetime.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BAP1', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('developed', 'Reg', (139, 148))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
26602	32690542	LOH for BAP1 is observed in 100% of human tumors developing in carriers of germline BAP1 mutations, as well as in sporadic mesotheliomas with somatic BAP1 mutations, underscoring the potent tumor suppressor activity of BAP1.	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (114, 136))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (89, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (114, 135))	('sporadic mesotheliomas', 'Disease', (114, 136))	('tumor', 'Disease', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('BAP1', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (190, 195))	('BAP1', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (155, 164))	('tumors', 'Disease', (42, 48))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (114, 136))	('human', 'Species', '9606', (36, 41))
26603	32690542	Intriguingly, LOH for BAP1 is not always observed in tumors developing in mice carrying germline Bap1 mutations.	('Bap1', 'Gene', '104416', (97, 101))	('Bap1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mice', 'Species', '10090', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
26604	32690542	This critical question shall be addressed in the coming years to understand why germline BAP1 mutations cause or are present as somatic mutations more frequently in mesothelioma, uveal melanoma, and ccRCC, rather than in other cancer types.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('BAP1', 'Gene', (89, 93))	('mesothelioma', 'Disease', (165, 177))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('cancer', 'Disease', (227, 233))	('cause', 'Reg', (104, 109))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
26605	32690542	This information will help to design more effective preventive and therapeutic strategies for patients carrying germline BAP1 mutations or cancers with somatic BAP1 mutations.	('germline', 'Var', (112, 120))	('patients', 'Species', '9606', (94, 102))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('BAP1', 'Gene', (121, 125))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (126, 135))	('mutations', 'Var', (165, 174))
26606	32690542	An additional question that will be addressed in coming years is why BAP1 mutations have phenotypic and prognostic implications that are cell type- and context-dependent: Germline mutations confer a better prognosis in mesothelioma, whereas somatic mutations induce a worse prognosis in uveal melanoma and ccRCC.	('better', 'PosReg', (199, 205))	('mesothelioma', 'Disease', (219, 231))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (287, 301))	('uveal melanoma', 'Disease', (287, 301))	('uveal melanoma', 'Disease', 'MESH:C536494', (287, 301))	('RCC', 'Disease', 'MESH:C538614', (308, 311))	('RCC', 'Disease', (308, 311))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))
26607	32690542	The difference in survival is quite significant, with median survival of 5 to 7 years for mesothelioma developing in carriers of heterozygous BAP1 mutations compared with 1-year median survival in sporadic mesotheliomas, cancers characteristically resistant to therapy.	('mutations', 'Var', (147, 156))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('mesothelioma', 'Disease', (206, 218))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (197, 218))	('cancers', 'Disease', (221, 228))	('sporadic mesotheliomas', 'Disease', (197, 219))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('BAP1', 'Gene', (142, 146))	('mesothelioma', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
26610	32690542	Adding to this puzzle, in sporadic mesotheliomas acquired biallelic BAP1 mutations are frequent, yet these mesotheliomas are not associated with significantly improved survival.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (26, 47))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', 'MESH:D008654', (35, 48))	('mesotheliomas', 'Disease', (107, 120))	('mesotheliomas', 'Disease', (35, 48))	('sporadic mesotheliomas', 'Disease', (26, 48))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (26, 48))	('biallelic', 'Var', (58, 67))	('BAP1', 'Gene', (68, 72))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (26, 48))	('mutations', 'Var', (73, 82))
26611	32690542	These findings in the same tumor type suggest that the improved survival in carriers of germline BAP1 mutations may be linked to the microenvironment, the immune system, and maybe in part to early diagnosis, as family members are being enrolled in early-detection screening programs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('improved', 'PosReg', (55, 63))	('tumor', 'Disease', (27, 32))	('survival', 'MPA', (64, 72))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
26613	32690542	What if germline BAP1 mutations render the host capable to fight mesothelioma growth by affecting the tumor microenvironment?	('affecting', 'Reg', (88, 97))	('mesothelioma', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('fight', 'CPA', (59, 64))	('BAP1', 'Gene', (17, 21))
26614	32690542	BAP1 mutations may influence the response to immunotherapy by increasing the propensity to chromothripsis, by deregulating the expression of genes that modulate immune checkpoints, and by promoting a proinflammatory tumor microenvironment.	('tumor', 'Disease', (216, 221))	('influence', 'Reg', (19, 28))	('BAP1', 'Gene', (0, 4))	('expression of', 'MPA', (127, 140))	('deregulating', 'Reg', (110, 122))	('mutations', 'Var', (5, 14))	('chromothripsis', 'Disease', (91, 105))	('increasing', 'PosReg', (62, 72))	('proinflammatory', 'MPA', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('response to immunotherapy', 'MPA', (33, 58))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('promoting', 'PosReg', (188, 197))	('chromothripsis', 'Disease', 'MESH:D000072837', (91, 105))
26615	32690542	By studying patients and mice with germline BAP1 mutations, we may learn how to treat mesotheliomas and maybe other cancers more effectively.	('patients', 'Species', '9606', (12, 20))	('mice', 'Species', '10090', (25, 29))	('mutations', 'Var', (49, 58))	('mesotheliomas', 'Disease', 'MESH:D008654', (86, 99))	('mesotheliomas', 'Disease', (86, 99))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BAP1', 'Gene', (44, 48))
26616	32690542	For example, the role of metformin, a drug that reprograms cell metabolism by restraining aerobic glycolysis and promoting mitochondrial respiration, could be explored in the existing mouse models carrying heterozygous Bap1 mutations and in xenografts of BAP1-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('Bap1', 'Gene', (219, 223))	('respiration', 'biological_process', 'GO:0045333', ('137', '148'))	('restraining', 'NegReg', (78, 89))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('mouse', 'Species', '10090', (184, 189))	('respiration', 'biological_process', 'GO:0007585', ('137', '148'))	('metabolism', 'biological_process', 'GO:0008152', ('64', '74'))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('mutations', 'Var', (224, 233))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('aerobic glycolysis', 'MPA', (90, 108))	('promoting', 'PosReg', (113, 122))	('mitochondrial respiration', 'MPA', (123, 148))	('glycolysis', 'biological_process', 'GO:0006096', ('98', '108'))	('Bap1', 'Gene', '104416', (219, 223))
26618	32690542	Family members of carriers of germline BAP1 mutations should be tested for BAP1 mutations, and those found to carry mutations should be enrolled in early-detection clinical trials (NCT03830229) that can help identify malignancies at an early stage, when they can be cured by surgery (uveal melanoma, RCC, cutaneous melanoma, etc.	('BAP1', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (300, 303))	('RCC', 'Disease', (300, 303))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (284, 298))	('uveal melanoma', 'Disease', 'MESH:C536494', (284, 298))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('mutations', 'Var', (44, 53))	('cutaneous melanoma', 'Disease', (305, 323))	('uveal melanoma', 'Disease', (284, 298))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (305, 323))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (305, 323))	('malignancies', 'Disease', (217, 229))	('BAP1', 'Gene', (39, 43))
26620	32690542	Moreover, BAP1 mutant carriers should limit exposure to diagnostic and therapeutic ionizing radiation that in these individuals may carry a higher cancer risk than in the population at large.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('BAP1', 'Gene', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('mutant', 'Var', (15, 21))
26642	28694705	Lymphoma patients found to have MPE on initial diagnosis have a higher risk of disease recurrence postchemotherapy.	('patients', 'Species', '9606', (9, 17))	('disease', 'Disease', (79, 86))	('MPE', 'Var', (32, 35))	('PE', 'Chemical', '-', (33, 35))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('Lymphoma', 'Disease', (0, 8))
26700	28694705	IPCs have been shown significantly to improve validated dyspnea and quality of life scores (Medical Research Council, European Organisation for Research and Treatment of Cancer Lung Cancer 13 and Core Quality of Life 30 questionnaires) at 2 weeks with persistent and improved scores at 14 weeks.	('IPCs', 'Var', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Lung Cancer', 'Phenotype', 'HP:0100526', (177, 188))	('dyspnea', 'Disease', 'MESH:D004417', (56, 63))	('Cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Cancer Lung Cancer', 'Disease', (170, 188))	('Cancer Lung Cancer', 'Disease', 'MESH:D009369', (170, 188))	('improve', 'PosReg', (38, 45))	('IPC', 'Chemical', '-', (0, 3))	('dyspnea', 'Phenotype', 'HP:0002094', (56, 63))	('quality', 'MPA', (68, 75))	('dyspnea', 'Disease', (56, 63))
26752	28694705	Predic-tors of 30-day mortality included tumor type, specifically primary lung and gastrointestinal cancers, pleural protein levels <3.6 g/dL, hemoglobin <11 g/dL, and serum leukocytes >9x109/L.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lung and gastrointestinal cancers', 'Disease', 'MESH:D004067', (74, 107))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('>9x109/L', 'Var', (185, 193))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('hemoglobin', 'MPA', (143, 153))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('pleural', 'Disease', 'MESH:D010995', (109, 116))	('pleural', 'Disease', (109, 116))
26793	28694705	When treatment was compared in patients with limited survival (less than 14 weeks), at a willingness-to-pay threshold of $30,000 ($43,000) per QALY, IPCs were cost-effective compared to talc pleurodesis approximately 95% of the time.	('IPCs', 'Var', (149, 153))	('patients', 'Species', '9606', (31, 39))	('talc pleurodesis', 'Disease', 'None', (186, 202))	('talc pleurodesis', 'Disease', (186, 202))	('IPC', 'Chemical', '-', (149, 152))
26904	27599565	In addition, the use of p16 FISH promises to yield observations in mesothelioma pathology useful for distinguishing it from benign pleuritic.	('p16', 'Var', (24, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('mesothelioma', 'Disease', (67, 79))
26933	25941579	ONCOS-102 is a serotype 5 adenovirus that features a chimeric capsid for enhanced gene delivery to cancer cells and a 24 bp deletion in Rb binding site of E1A for cancer cell restricted replication, and is armed with GM-CSF, a potent inducer of antitumor immunity (6).	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('ONCOS-102', 'Chemical', '-', (0, 9))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (249, 254))	('enhanced', 'PosReg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('replication', 'MPA', (186, 197))	('gene delivery', 'MPA', (82, 95))	('deletion', 'Var', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('cancer', 'Disease', (163, 169))
26952	25941579	A prominent post-treatment induction of MAGE-A3-specific (peptide p271-279 FLWGPRALV) CD8+ T-cells in PBMCs was seen 29 d after treatment initiation suggesting that intratumoral treatment with ONCOS-102 elicits systemic tumor specific immunity despite the presence of viral antigens (Fig.	('elicits', 'PosReg', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('ONCOS-102', 'Chemical', '-', (193, 202))	('MAGE-A3', 'Gene', '4102', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('men', 'Species', '9606', (183, 186))	('tumor', 'Disease', (220, 225))	('peptide p271-279 FLWGPRALV', 'Var', (58, 84))	('MAGE-A3', 'Gene', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CD8', 'Gene', (86, 89))	('tumor', 'Disease', (170, 175))	('men', 'Species', '9606', (22, 25))	('CD8', 'Gene', '925', (86, 89))	('men', 'Species', '9606', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
26961	25941579	The patient had not received additional treatments after the trial before the last imaging, suggesting that the tumor-specific immune response elicited by ONCOS-102-treatment was robust enough to partially eradicate the tumor load.	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('men', 'Species', '9606', (45, 48))	('immune response', 'biological_process', 'GO:0006955', ('127', '142'))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('men', 'Species', '9606', (170, 173))	('ONCOS-102-treatment', 'Var', (155, 174))	('ONCOS-102', 'Chemical', '-', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
27099	22351743	After binding to cell surface mesothelin via the Fv, PE38 is internalized into the cell, undergoes processing and kills the cell due to inhibition of protein synthesis by ADP ribosylation and inactivation of elongation factor 2.	('binding', 'molecular_function', 'GO:0005488', ('6', '13'))	('cell surface', 'cellular_component', 'GO:0009986', ('17', '29'))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('binding', 'Interaction', (6, 13))	('protein synthesis', 'biological_process', 'GO:0006412', ('150', '167'))	('processing', 'MPA', (99, 109))	('ADP ribosylation', 'MPA', (171, 187))	('inhibition', 'NegReg', (136, 146))	('protein synthesis', 'MPA', (150, 167))	('elongation factor 2', 'Gene', '1938', (208, 227))	('elongation factor 2', 'Gene', (208, 227))	('PE38', 'Var', (53, 57))	('inactivation', 'NegReg', (192, 204))	('undergoes', 'Reg', (89, 98))
27102	22351743	Preclinical studies have shown marked anti-tumor synergy when SS1P is combined with several commonly used chemotherapeutic agents such as paclitaxel, gemcitbaine or cisplatin.	('SS1P', 'Var', (62, 66))	('gemcitbaine', 'Chemical', '-', (150, 161))	('tumor synergy', 'Disease', (43, 56))	('paclitaxel', 'Chemical', 'MESH:D017239', (138, 148))	('combined', 'Interaction', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('SS1P', 'Chemical', 'MESH:C474515', (62, 66))	('tumor synergy', 'Disease', 'MESH:D009369', (43, 56))
27103	22351743	Although, the combination of SS1P with chemotherapeutic agents did not result in synergy in cell culture there was a marked increase in anti-tumor activity with the combination in tumor xenograft models.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('increase', 'PosReg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('SS1P', 'Chemical', 'MESH:C474515', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('SS1P', 'Var', (29, 33))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (180, 185))
27104	22351743	Using a mesothelin expressing cell line, A431-K5, grown as a tumor xenograft in athymic nude mice, treatment with SS1P plus paclitaxel resulted in increased anti-tumor activity with durable complete tumor regressions compared to treatment with paclitaxel or SS1P alone.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('A431', 'CellLine', 'CVCL:0037', (41, 45))	('increased', 'PosReg', (147, 156))	('SS1P', 'Var', (114, 118))	('nude mice', 'Species', '10090', (88, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (244, 254))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('SS1P', 'Chemical', 'MESH:C474515', (114, 118))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('SS1P', 'Chemical', 'MESH:C474515', (258, 262))	('tumor', 'Disease', (61, 66))
27112	22351743	Based on these preclinical studies the combination of SS1P with chemotherapy is being evaluated in clinical trials involving mesothelin expressing cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('SS1P', 'Chemical', 'MESH:C474515', (54, 58))	('SS1P', 'Var', (54, 58))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Disease', (147, 154))
27159	22351743	In all of these patients, treatment with MORAb-009 led to a marked increase in serum CA-125 levels even in patients who had normal CA-125 levels at baseline.	('serum CA-125 levels', 'MPA', (79, 98))	('MORAb-009', 'Chemical', 'MESH:C526187', (41, 50))	('MORAb-009', 'Var', (41, 50))	('patients', 'Species', '9606', (16, 24))	('increase', 'PosReg', (67, 75))	('increase in serum CA', 'Phenotype', 'HP:0003072', (67, 87))	('patients', 'Species', '9606', (107, 115))
27173	22351743	These deletions result in a 1000-fold decrease in virulence compared to the wild-type Lm.	('virulence', 'biological_process', 'GO:0009406', ('50', '59'))	('virulence', 'biological_process', 'GO:0009405', ('50', '59'))	('virulence', 'MPA', (50, 59))	('deletions', 'Var', (6, 15))	('decrease', 'NegReg', (38, 46))	('Lm', 'Species', '1639', (86, 88))	('virulence', 'biological_process', 'GO:0016032', ('50', '59'))
27180	22351743	Based on the tolerability and immune activation, CRS-207 may be an attractive agent to treat mesothelin-expressing cancers either alone or in combination with other agents.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('CRS-207', 'Var', (49, 56))	('cancers', 'Disease', (115, 122))	('CRS', 'Chemical', 'MESH:D002857', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
27183	22351743	The primary endpoint of this clinical trial is to determine if administration of CRS-207 will improve overall survival compared to GVAX alone.	('GVAX', 'Chemical', '-', (131, 135))	('improve', 'PosReg', (94, 101))	('overall survival', 'MPA', (102, 118))	('CRS', 'Chemical', 'MESH:D002857', (81, 84))	('CRS-207', 'Var', (81, 88))
27228	22351743	AdMSLNCRAd5/3 treatment resulted in significant tumor growth inhibition and improved overall survival of these mice compared to no virus administration or wild-type adenovirus administration.	('tumor', 'Disease', (48, 53))	('improved', 'PosReg', (76, 84))	('mice', 'Species', '10090', (111, 115))	('AdMSLNCRAd5/3', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('overall survival', 'CPA', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
27361	31798327	Over the last two decades of identifying new mutations in oncogenes, gene suppressors, and genes responsible for genomic stability, the pathway of tumour formation could not be fully explained.	('mutations', 'Var', (45, 54))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('oncogenes', 'Gene', (58, 67))	('tumour', 'Disease', (147, 153))
27370	31798327	Depending on the genes that they influence, miRNAs can function either as "oncomirs", activators of carcinogenic transformation, or as suppressor miRNA, which are inhibitors of oncogenes.	('N', 'Chemical', 'MESH:D009584', (47, 48))	('miRNAs', 'Var', (44, 50))	('carcinogenic transformation', 'Disease', (100, 127))	('carcinogenic transformation', 'Disease', 'MESH:D002472', (100, 127))	('N', 'Chemical', 'MESH:D009584', (149, 150))
27400	31798327	In unicellular organisms, miRNA can also inhibit translation.	('translation', 'biological_process', 'GO:0006412', ('49', '60'))	('inhibit', 'NegReg', (41, 48))	('miRNA', 'Var', (26, 31))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('translation', 'MPA', (49, 60))
27405	31798327	The oncogenic effect of miRNAs is provided through the silencing of expression, or the deletion of mRNA, of oncogenes inhibitors, as well as the silencing of suppressor gene amplification or the up-regulation of their expression in neoplastic cells.	('silencing', 'NegReg', (55, 64))	('silencing', 'Var', (145, 154))	('suppressor gene', 'Gene', (158, 173))	('expression', 'MPA', (68, 78))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('regulation', 'biological_process', 'GO:0065007', ('198', '208'))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('expression', 'MPA', (218, 228))	('deletion', 'Var', (87, 95))	('mRNA', 'Gene', (99, 103))	('up-regulation', 'PosReg', (195, 208))
27408	31798327	This indicates a strong association between abnormal expression of miRNA and the development and progression of cancer.	('development', 'CPA', (81, 92))	('progression of', 'CPA', (97, 111))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('miRNA', 'Protein', (67, 72))	('abnormal', 'Var', (44, 52))	('expression', 'MPA', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('N', 'Chemical', 'MESH:D009584', (70, 71))
27409	31798327	Fragile sites of the genome are areas on chromosomes that are susceptible to frequent mutations, such as loss of genetic material or fragment rearrangement, abnormalities that are often observed in cancer cells.	('fragment rearrangement', 'Var', (133, 155))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('loss of genetic', 'Var', (105, 120))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
27414	31798327	Increasing evidence indicate the association between altered miRNA expression and tumour progression and survival.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('miRNA', 'Protein', (61, 66))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('tumour', 'Disease', (82, 88))	('altered', 'Var', (53, 60))	('survival', 'CPA', (105, 113))
27423	31798327	The presence of MPE in patients diagnosed with lung cancer is an unfavourable prognostic factor.	('MPE', 'Disease', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('MPE', 'Disease', 'MESH:D016066', (16, 19))	('lung cancer', 'Disease', (47, 58))	('patients', 'Species', '9606', (23, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('presence', 'Var', (4, 12))
27433	31798327	linked the high expression of miRNA-100 and a low miRNA-93, miRNA-134, miRNA-151, and miRNA-345 with poor survival rate.	('low', 'NegReg', (46, 49))	('N', 'Chemical', 'MESH:D009584', (53, 54))	('miRNA-345', 'Var', (86, 95))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('miRNA-93', 'Gene', '407051', (50, 58))	('miRNA-151', 'Var', (71, 80))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('miRNA-134', 'Var', (60, 69))	('miRNA-100', 'Gene', (30, 39))	('miRNA-93', 'Gene', (50, 58))	('expression', 'MPA', (16, 26))
27445	31798327	In this study, nine miRNAs (miRNA-200c-3p, miRNA-200b-3p, miRNA-200a-3p, miRNA-429 and miRNA-141-3p, miRNA-205-5p, miRNA-483-5p, miRNA-375, and miRNA-203a-3p) were the most frequently observed in APE, when compared with TPE or NPE.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('miRNA-141-3p', 'Var', (87, 99))	('miRNA-203', 'Gene', (144, 153))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('miRNA-429', 'Var', (73, 82))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('miRNA-200c-3p', 'Var', (28, 41))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('miRNA-200b-3p', 'Var', (43, 56))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('miRNA-205-5p', 'Var', (101, 113))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('miRNA-200a-3p', 'Var', (58, 71))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('miRNA-483-5p', 'Var', (115, 127))	('miRNA-375', 'Gene', (129, 138))	('miRNA-203', 'Gene', '406986', (144, 153))	('APE', 'Disease', (196, 199))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('miRNA-375', 'Gene', '494324', (129, 138))	('N', 'Chemical', 'MESH:D009584', (118, 119))
27447	31798327	These two groups differed from each other only in three miRNAs (miRNA-148a-3p, miRNA-451a, and miRNA-150-5p).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('miRNA-451a', 'Var', (79, 89))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('miRNA-150-5p', 'Var', (95, 107))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('miRNA-148a-3p', 'Var', (64, 77))
27451	31798327	Within the exosomes from the biopsy of lung tumours, 12 miRNAs were overexpressed: miRNA-17, miRNA-21, miR-106, miR-146, miR-155, miR-191, miR-192, miRNA-203, miRNA-205, miRNA-210, miRNA-212, and miRNA-214.	('N', 'Chemical', 'MESH:D009584', (173, 174))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('miR-155', 'Gene', '406947', (121, 128))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('miRNA-203', 'Gene', '406986', (148, 157))	('miR-191', 'Gene', '406966', (130, 137))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('miR-191', 'Gene', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('miR-106', 'Gene', (103, 110))	('miR-192', 'Gene', (139, 146))	('overexpressed', 'PosReg', (68, 81))	('miRNA-214', 'Gene', '406996', (196, 205))	('miRNA-17', 'Gene', '406952', (83, 91))	('miR-146', 'Var', (112, 119))	('miRNA-21', 'Gene', '406991', (196, 204))	('miRNA-214', 'Gene', (196, 205))	('miRNA-21', 'Gene', '406991', (181, 189))	('miRNA-17', 'Gene', (83, 91))	('miRNA-203', 'Gene', (148, 157))	('miRNA-21', 'Gene', '406991', (93, 101))	('miRNA-21', 'Gene', (196, 204))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('miRNA-21', 'Gene', (181, 189))	('lung tumours', 'Disease', (39, 51))	('miR-106', 'Gene', '406899', (103, 110))	('miRNA-21', 'Gene', (93, 101))	('N', 'Chemical', 'MESH:D009584', (199, 200))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('miR-192', 'Gene', '406967', (139, 146))	('miRNA-21', 'Gene', '406991', (170, 178))	('miRNA-21', 'Gene', (170, 178))	('lung tumours', 'Disease', 'MESH:D008175', (39, 51))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('miR-155', 'Gene', (121, 128))	('miRNA-205', 'Var', (159, 168))
27460	31798327	There is a proven association between altered profiles of miRNA and the presence of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('altered', 'Var', (38, 45))	('profiles', 'MPA', (46, 54))	('mesothelioma', 'Disease', (84, 96))	('miRNA', 'Protein', (58, 63))
27463	31798327	linked the decreased level of miRNA-17-5p, miRNA-30c, and miRNA-31 with a positive result for sarcomatoid carcinoma.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('level', 'MPA', (21, 26))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('miRNA-17', 'Gene', (30, 38))	('decreased', 'NegReg', (11, 20))	('miRNA-30c', 'Var', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (94, 115))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (94, 115))	('miRNA-31', 'Var', (58, 66))	('sarcomatoid carcinoma', 'Disease', (94, 115))	('miRNA-17', 'Gene', '406952', (30, 38))
27468	31798327	In another study, it was suggested that a combination of six miRNAs (miRNA-21-5p, miRNA-23a-3p, miRNA-30e-5p, miRNA-221-3p, miRNA-222-3p, and miRNA-31-5p) provides approximately 90% accuracy for survival prediction of patients after surgically-resected mesothelioma.	('miRNA-31-5p', 'Var', (142, 153))	('miRNA-23a-3p', 'Var', (82, 94))	('miRNA-21', 'Gene', (69, 77))	('patients', 'Species', '9606', (218, 226))	('mesothelioma', 'Disease', 'MESH:D008654', (253, 265))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('miRNA-222', 'Gene', '407007', (124, 133))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('miRNA-222', 'Gene', (124, 133))	('miRNA-30e-5p', 'Var', (96, 108))	('miRNA-221-3p', 'Var', (110, 122))	('miRNA-21', 'Gene', '406991', (69, 77))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('mesothelioma', 'Disease', (253, 265))
27470	31798327	A significant upregulation of multiple miRNAs (including miRNA-484, miRNA-320, let-7a, and miRNA-125a-5p) was discovered in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion, suggesting a potential diagnostic and therapeutic role.	('let-7a', 'Gene', (79, 85))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (134, 154))	('pleural effusion', 'Disease', 'MESH:D010996', (191, 207))	('miRNA-320', 'Var', (68, 77))	('pleural effusion', 'Disease', (191, 207))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (124, 154))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('pleural effusion', 'Phenotype', 'HP:0002202', (191, 207))	('miRNA-125a-5p', 'Var', (91, 104))	('miRNA-484', 'Var', (57, 66))	('malignant pleural mesothelioma', 'Disease', (124, 154))	('upregulation', 'PosReg', (14, 26))	('N', 'Chemical', 'MESH:D009584', (94, 95))
27479	31798327	reported that mainly miRNA-126 was down-regulated, whereas miRNA-19a, miRNA-19b, miRNA-21, miRNA-25, and miRNA-126 were over-expressed in malignant mesothelioma cell lines versus the mesothelial cell line.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('miRNA-21', 'Gene', '406991', (81, 89))	('miRNA-21', 'Gene', (81, 89))	('N', 'Chemical', 'MESH:D009584', (108, 109))	('miRNA-126', 'Gene', '406913', (105, 114))	('miRNA-126', 'Gene', (21, 30))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (138, 160))	('over-expressed', 'PosReg', (120, 134))	('miRNA-19a', 'Gene', '406979', (59, 68))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('miRNA-25', 'Var', (91, 99))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('miRNA-126', 'Gene', (105, 114))	('miRNA-126', 'Gene', '406913', (21, 30))	('mesothelioma', 'Disease', (148, 160))	('miRNA-19b', 'Gene', (70, 79))	('down-regulated', 'NegReg', (35, 49))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('miRNA-19a', 'Gene', (59, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))	('N', 'Chemical', 'MESH:D009584', (94, 95))
27482	31798327	The microRNA profile was also used for discriminating between mesothelioma and lung adenocarcinoma, with results showing that miRNA-130 was significantly higher in mesotheliomas when compared with lung adenocarcinomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (164, 177))	('mesothelioma', 'Disease', (164, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (197, 216))	('miRNA-130', 'Var', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (197, 217))	('higher', 'PosReg', (154, 160))	('lung adenocarcinomas', 'Disease', (197, 217))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (79, 98))	('lung adenocarcinoma', 'Disease', (79, 98))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (197, 217))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (197, 216))	('mesotheliomas', 'Disease', (164, 177))	('mesothelioma', 'Disease', (62, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))
27485	31798327	Eleven miRNAs were significantly upregulated in MPM compared to BAPE and included miRNA-484, miRNA-320, let-7a, miRNA-744, miRNA-20a, miRNA-193b, let-7d miRNA-125a-5p, miRNA-92a, miRNA-155, and miRNA-152.	('let-7d', 'Gene', (146, 152))	('N', 'Chemical', 'MESH:D009584', (197, 198))	('miRNA-744', 'Var', (112, 121))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('miRNA-155', 'Gene', '406947', (179, 188))	('MPM', 'Disease', 'MESH:C562839', (48, 51))	('MPM', 'Disease', (48, 51))	('N', 'Chemical', 'MESH:D009584', (115, 116))	('N', 'Chemical', 'MESH:D009584', (156, 157))	('miRNA-20a', 'Gene', (123, 132))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('miRNA-484', 'Var', (82, 91))	('miRNA-155', 'Gene', (179, 188))	('miRNA-20a', 'Gene', '406982', (123, 132))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('upregulated', 'PosReg', (33, 44))	('let-7a', 'Var', (104, 110))	('let-7d', 'Gene', '406886', (146, 152))	('miRNA-125a-5p', 'Var', (153, 166))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('N', 'Chemical', 'MESH:D009584', (182, 183))	('miRNA-193b', 'Var', (134, 144))	('miRNA-320', 'Var', (93, 102))
27515	30510965	Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1.	('immune suppression', 'CPA', (48, 66))	('PDL1', 'Gene', '29126', (183, 187))	('E-MpMs', 'Var', (15, 21))	('Tregs', 'CPA', (94, 99))	('PDL1', 'Gene', (183, 187))	('expression', 'MPA', (118, 128))	('PD1', 'Gene', (175, 178))
27526	30510965	Our data indicate that the immune contexture differs among the MpM variants with the Th1-related features present in the E-MpM variants but progressively weakened in the more aggressive forms of the E-MpM histotypes and completely lost in S-MpM, subtypes displaying enhanced expression of the transcriptional repressor EZH2.	('variants', 'Var', (127, 135))	('EZH2', 'Gene', (319, 323))	('EZH2', 'Gene', '2146', (319, 323))	('Th1', 'Gene', '51497', (85, 88))	('variants', 'Var', (67, 75))	('weakened', 'NegReg', (154, 162))	('lost', 'NegReg', (231, 235))	('Th1', 'Gene', (85, 88))
27558	30510965	Taken together, these findings indicate that the inflammatory T cell profile segregates with E-MpMs and their progressive phase and that Th1-related features are progressively impaired in the more aggressive forms of Pro- or HG-E-MpMs and in S-MpMs which displayed enhanced positivity for EZH2 expression in their tumour cells (Table 1).	('tumour', 'Disease', (314, 320))	('Th1', 'Gene', (137, 140))	('impaired', 'NegReg', (176, 184))	('EZH2', 'Gene', '2146', (289, 293))	('enhanced', 'PosReg', (265, 273))	('Th1', 'Gene', '51497', (137, 140))	('EZH2', 'Gene', (289, 293))	('tumour', 'Phenotype', 'HP:0002664', (314, 320))	('HG-E-MpMs', 'Var', (225, 234))	('tumour', 'Disease', 'MESH:D009369', (314, 320))
27567	30510965	Unlike the antitumour cytokines, the IL6, IL10, and TGFB1 genes, encoding for immunosuppressive factors, were expressed by all of the E-MpM cases, which suggest the presence of an immunosuppression network.	('IL6', 'Gene', (37, 40))	('E-MpM', 'Var', (134, 139))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('IL10', 'Gene', (42, 46))	('IL10', 'Gene', '3586', (42, 46))	('TGFB1', 'Gene', '7040', (52, 57))	('IL6', 'molecular_function', 'GO:0005138', ('37', '40'))	('tumour', 'Disease', (15, 21))	('TGFB1', 'Gene', (52, 57))	('IL10', 'molecular_function', 'GO:0005141', ('42', '46'))	('IL6', 'Gene', '3569', (37, 40))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
27571	30510965	The presence of IL6 and TGFB1 creates a cytokine microenvironment potentially favouring Th17 conversion.	('TGFB1', 'Gene', '7040', (24, 29))	('TGFB1', 'Gene', (24, 29))	('Th1', 'Gene', '51497', (88, 91))	('IL6', 'molecular_function', 'GO:0005138', ('16', '19'))	('Th1', 'Gene', (88, 91))	('IL6', 'Gene', (16, 19))	('IL6', 'Gene', '3569', (16, 19))	('presence', 'Var', (4, 12))	('favouring', 'PosReg', (78, 87))
27591	30510965	The immunodecorated cells in the E-MpMs and Pro-E-MpMs had a fibrovascular pattern, whereas those in the HG-E-MpM and S-MpMs had a diffuse pattern: i.e., they were closely intermingled with tumoural cells in a patternless arrangement (Figure 5(a)).	('fibrovascular pattern', 'MPA', (61, 82))	('E-MpMs', 'Var', (33, 39))	('tumoural', 'Disease', 'MESH:D009369', (190, 198))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumoural', 'Disease', (190, 198))
27593	30510965	Moreover, we have previously found an association between CD209+ tumour-associated macrophages (TAM) and an ongoing T cell response in a tumoural setting.	('tumour', 'Disease', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('T cell response', 'CPA', (116, 131))	('tumour', 'Disease', (137, 143))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumoural', 'Disease', 'MESH:D009369', (137, 145))	('tumoural', 'Disease', (137, 145))	('CD209+', 'Var', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
27601	30510965	IHC analysis showed that these areas were positive for CD209, CD14, and the tumour marker WT1 (Figure 6(a)), whereas they were negative for the lineage-specific marker CD45 (data not shown).	('CD45', 'Gene', (168, 172))	('CD45', 'Gene', '5788', (168, 172))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('WT1', 'Gene', '7490', (90, 93))	('CD14', 'Gene', (62, 66))	('WT1', 'Gene', (90, 93))	('CD209', 'Var', (55, 60))	('CD14', 'Gene', '929', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))
27613	30510965	The impaired T cell immunity was associated with clear signs of immunosuppression and the presence of IL10 and TGFB1 cytokines in all of the E-MpM variants, albeit at different levels and with the clear prevalence of the first.	('variants', 'Var', (147, 155))	('TGFB1', 'Gene', '7040', (111, 116))	('TGFB1', 'Gene', (111, 116))	('IL10', 'molecular_function', 'GO:0005141', ('102', '106'))	('presence', 'Reg', (90, 98))	('IL10', 'Gene', (102, 106))	('IL10', 'Gene', '3586', (102, 106))	('impaired T', 'Disease', (4, 14))	('impaired T', 'Disease', 'MESH:D009422', (4, 14))	('cytokines', 'MPA', (117, 126))
27618	30510965	Consistently, mouse peritoneal cavities are inhabited by anti-inflammatory lymphocytes specifically enriched in a subset of CD5+ B cells (also called CD5+ B1a cells) that express CD20, CD43, IgMhi, and IgDlo and have tolerogenic functions.	('IgDlo', 'Gene', (202, 207))	('mouse', 'Species', '10090', (14, 19))	('tolerogenic functions', 'CPA', (217, 238))	('CD43', 'Gene', '20737', (185, 189))	('CD43', 'Gene', (185, 189))	('CD20', 'Var', (179, 183))
27620	30510965	Mouse B1a and Bregs and human Bregs share a high capacity to produce IL10, a cytokine we found to be expressed in all of the E-MpM variants, and so it is entirely possible that the onset of IL10-driven immune suppression is an intrinsic characteristic of the peritoneum that protects the milieu against inflammation.	('inflammation', 'biological_process', 'GO:0006954', ('303', '315'))	('IL10', 'Gene', (69, 73))	('IL10', 'Gene', '3586', (69, 73))	('inflammation', 'Disease', (303, 315))	('human', 'Species', '9606', (24, 29))	('IL10', 'molecular_function', 'GO:0005141', ('190', '194'))	('IL10', 'Gene', (190, 194))	('E-MpM', 'Gene', (125, 130))	('IL10', 'Gene', '3586', (190, 194))	('variants', 'Var', (131, 139))	('Mouse', 'Species', '10090', (0, 5))	('IL10', 'molecular_function', 'GO:0005141', ('69', '73'))	('inflammation', 'Disease', 'MESH:D007249', (303, 315))
27622	30510965	We have previously described cells with a similar phenotype (e.g., CD14+, CD163+, and CD209+) as infiltrating post-imatinib-treated fibrosarcomatous dermatofibrosarcoma protuberans, and these same myeloid components have been also found in human renal carcinomas.	('CD14', 'Gene', '929', (67, 71))	('CD209+', 'Var', (86, 92))	('imatinib', 'Chemical', 'MESH:D000068877', (115, 123))	('renal carcinomas', 'Disease', (246, 262))	('human', 'Species', '9606', (240, 245))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('renal carcinomas', 'Phenotype', 'HP:0005584', (246, 262))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (132, 180))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', (132, 180))	('CD163', 'Gene', '9332', (74, 79))	('renal carcinomas', 'Disease', 'MESH:C538614', (246, 262))	('CD14', 'Gene', (67, 71))	('CD163', 'Gene', (74, 79))
27623	30510965	In these settings and in MpMs, the presence of CD209+ macrophages is associated with heavy T cell infiltration, thus suggesting that these macrophage phenotypes may be the result of interplay between T cells and cells of the myeloid lineage, as has been found in mice.	('CD209+', 'Var', (47, 53))	('T cell infiltration', 'CPA', (91, 110))	('mice', 'Species', '10090', (263, 267))
27625	30510965	Although human CD209+ macrophages have been described as having enhanced phagocytosis in the context of sepsis and are thus probably associated with enhanced protective immunity, we did not detect any IL12 mRNA expression (the key cytokine qualifying M1 antitumour macrophages) in E-MpMs.	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('phagocytosis', 'CPA', (73, 85))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('phagocytosis', 'biological_process', 'GO:0006909', ('73', '85'))	('human', 'Species', '9606', (9, 14))	('IL12', 'molecular_function', 'GO:0005143', ('201', '205'))	('sepsis', 'Phenotype', 'HP:0100806', (104, 110))	('sepsis', 'Disease', (104, 110))	('CD209+', 'Var', (15, 21))	('enhanced', 'PosReg', (149, 157))	('IL12', 'Gene', (201, 205))	('tumour', 'Disease', (258, 264))	('sepsis', 'Disease', 'MESH:D018805', (104, 110))	('enhanced', 'PosReg', (64, 72))
27636	30510965	Untreated or naive MpMs therefore do not seem to be promising targets for PD1/PDL1 inhibitors, but other checkpoint inhibitors may be active.	('PDL1', 'Gene', '29126', (78, 82))	('PDL1', 'Gene', (78, 82))	('inhibitors', 'Var', (83, 93))
27638	30510965	In conclusion, we found that the MpM variants include different entities in terms of their immune contexture, and our data suggest that, as in other solid tumour, the nature of TME of MpMs might be linked to the epigenetic modifier EZH2.	('EZH2', 'Gene', '2146', (232, 236))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('variants', 'Var', (37, 45))	('EZH2', 'Gene', (232, 236))	('tumour', 'Disease', (155, 161))
27642	30510965	The administration of drug silencing tumoural EZH2 (currently explored as monotherapy in the NTC022899195 clinical trial in malignant mesothelioma patients), given to favour lymphocyte recruitment and constrain immune suppression, might be an option to be tested in combination with immune-based approaches such as blockage of ICIs.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (124, 146))	('malignant mesothelioma', 'Disease', (124, 146))	('tumoural EZH2', 'Disease', (37, 50))	('drug silencing', 'Var', (22, 36))	('patients', 'Species', '9606', (147, 155))	('NTC', 'cellular_component', 'GO:0000974', ('93', '96'))	('lymphocyte recruitment', 'CPA', (174, 196))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (124, 146))	('tumoural EZH2', 'Disease', 'MESH:D009369', (37, 50))
27674	25377015	It is now recognised that pleurodesis with non-graded talc (still the only type of talc preparation available in many countries) can result in acute respiratory distress syndrome.	('pleurodesis', 'Disease', 'None', (26, 37))	('pleurodesis', 'Disease', (26, 37))	('acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (143, 178))	('acute respiratory distress syndrome', 'Disease', (143, 178))	('talc', 'Chemical', 'MESH:D013627', (83, 87))	('respiratory distress', 'Phenotype', 'HP:0002098', (149, 169))	('result in', 'Reg', (133, 142))	('acute respiratory distress syndrome', 'Phenotype', 'HP:0011948', (143, 178))	('talc', 'Chemical', 'MESH:D013627', (54, 58))	('non-graded', 'Var', (43, 53))
27804	25024722	At that time, immumohistochemical staining showed p53(+, focal), EMA(+), CK5/CK6(+), D2-40(+), HBME-1(+), and WT-1(-).	('CK5', 'Gene', '3852', (73, 76))	('D2-40(+', 'Var', (85, 92))	('EMA', 'Gene', (65, 68))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('EMA', 'Gene', '4582', (65, 68))	('CK5', 'Gene', (73, 76))	('HBME-1', 'CellLine', 'CVCL:U718', (95, 101))
27821	25024722	Mutations in p53 are common in malignancies, and mutations in p53 lead to a prolonged half-life and accumulation of high amounts of the protein.	('mutations', 'Var', (49, 58))	('malignancies', 'Disease', 'MESH:D009369', (31, 43))	('accumulation', 'PosReg', (100, 112))	('high amounts of the protein', 'MPA', (116, 143))	('half-life', 'MPA', (86, 95))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('Mutations', 'Var', (0, 9))	('prolonged', 'PosReg', (76, 85))	('malignancies', 'Disease', (31, 43))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', '7157', (13, 16))
27826	25024722	The carcinogenic effect of SV40 is mediated by its tag antigen, which leads to inactivation of tumor suppressor gene production, such as that of p53 and Rb.	('inactivation', 'NegReg', (79, 91))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('carcinogenic', 'Disease', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('SV40', 'Species', '1891767', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SV40', 'Var', (27, 31))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
28027	32664515	SDC1 overexpression leads to nuclear accumulation of FGF-2, which confirms the functional role of SDC1 in the nuclear transport.	('FGF-2', 'Gene', (53, 58))	('FGF-2', 'Gene', '2247', (53, 58))	('SDC1', 'Gene', (98, 102))	('SDC1', 'Gene', '6382', (98, 102))	('SDC1', 'Gene', (0, 4))	('nuclear accumulation', 'MPA', (29, 49))	('SDC1', 'Gene', '6382', (0, 4))	('nuclear transport', 'biological_process', 'GO:0051169', ('110', '127'))	('overexpression', 'Var', (5, 19))
28037	32664515	The effects of transfection and silencing on the cellular content of SDC1 were always controlled by FACS analysis of each cell harvest.	('silencing', 'Var', (32, 41))	('SDC1', 'Gene', (69, 73))	('SDC1', 'Gene', '6382', (69, 73))
28065	32664515	Co-staining was then performed with a combination of antibodies against SDC1 (1:500, rabbit monoclonal anti-SDC1, ab128936, Abcam, Cambridge, UK) and either EWSR1 (1:200, rat monoclonal anti-EWSR1/EWS, ab252829, Abcam) or FUS (1:200, mouse monoclonal anti-TLS/FUS, ab154141, Abcam, Cambridge, UK) in 0.1% BSA in PBST.	('EWS', 'Gene', '2130', (197, 200))	('SDC1', 'Gene', (72, 76))	('EWS', 'Gene', '2130', (157, 160))	('PBST', 'Chemical', '-', (312, 316))	('TLS', 'Gene', (256, 259))	('EWS', 'Gene', (191, 194))	('SDC1', 'Gene', (108, 112))	('EWSR1', 'Gene', '2130', (191, 196))	('EWSR1', 'Gene', '2130', (157, 162))	('FUS', 'Gene', (260, 263))	('FUS', 'Gene', (222, 225))	('EWS', 'Gene', (197, 200))	('TLS', 'Gene', '2521', (256, 259))	('SDC1', 'Gene', '6382', (72, 76))	('EWS', 'Gene', (157, 160))	('1:500', 'Var', (78, 83))	('FUS', 'Gene', '2521', (260, 263))	('EWS', 'Gene', '2130', (191, 194))	('FUS', 'Gene', '2521', (222, 225))	('SDC1', 'Gene', '6382', (108, 112))	('EWSR1', 'Gene', (191, 196))	('EWSR1', 'Gene', (157, 162))
28094	32664515	The total amount of RNA, normalized to DNA content, was significantly lower in SDC1 knockdown cells compared to control cells (p = 0.0379), as shown in Figure 4 in the left image.	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('knockdown', 'Var', (84, 93))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('lower', 'NegReg', (70, 75))	('SDC1', 'Gene', (79, 83))	('SDC1', 'Gene', '6382', (79, 83))
28097	32664515	The knockdown of SDC1 had no significant effect on total RNA levels (p = 0.212), as shown in Figure 4b in the left image, while the overexpression of SDC1 resulted in decreased levels of Actin RNA (p = 0.0364), as shown in Figure 4b in the right image, compared to the controls.	('RNA levels', 'MPA', (57, 67))	('Actin RNA', 'MPA', (187, 196))	('SDC1', 'Gene', (17, 21))	('SDC1', 'Gene', '6382', (17, 21))	('SDC1', 'Gene', (150, 154))	('SDC1', 'Gene', '6382', (150, 154))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('RNA', 'cellular_component', 'GO:0005562', ('193', '196'))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (167, 176))
28123	32664515	When the amounts of SDC1 are altered, this hampers the respective functions, regardless of if SDC1 is up- or downregulated, and it seems that the effects of SDC1 on these functions are regulatory, rather than simple stimulation or blocking.	('functions', 'MPA', (66, 75))	('SDC1', 'Gene', (157, 161))	('SDC1', 'Gene', '6382', (157, 161))	('SDC1', 'Gene', (20, 24))	('SDC1', 'Gene', '6382', (20, 24))	('hampers', 'NegReg', (43, 50))	('altered', 'Var', (29, 36))	('SDC1', 'Gene', '6382', (94, 98))	('SDC1', 'Gene', (94, 98))
28124	32664515	A similar "bell shaped" dose-response effect of varying the expression of SDC1 has been demonstrated with a number of genes and pathways.	('expression', 'MPA', (60, 70))	('SDC1', 'Gene', '6382', (74, 78))	('SDC1', 'Gene', (74, 78))	('varying', 'Var', (48, 55))
28142	31817531	Correspondingly, patients with high B cells but low neutrophils gene expression signature showed longer median overall survival of 500 days (HR = 2.29, p-value = 0.009).	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('overall survival', 'MPA', (111, 127))	('high B cells', 'Var', (31, 43))	('patients', 'Species', '9606', (17, 25))	('low neutrophil', 'Phenotype', 'HP:0001875', (48, 62))	('longer', 'PosReg', (97, 103))	('low neutrophils', 'Phenotype', 'HP:0001875', (48, 63))
28184	31817531	Consistent with the NLR prognostic result, patients with high a S100A12/CD45 ratio had a significantly shorter medOS (p-value = 0.035, Supplementary Figure S3A).	('CD45', 'Gene', (72, 76))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (43, 51))	('shorter', 'NegReg', (103, 110))	('S100A12', 'Gene', '6283', (64, 71))	('S100A12', 'Gene', (64, 71))	('CD45', 'Gene', '5788', (72, 76))	('medOS', 'MPA', (111, 116))
28185	31817531	Even though the survival analysis of CD20/CD45 did not reach significance, we still observed the same survival trend of BLR that patients with high CD20/CD45 ratio had a longer medOS (385 days versus 236 days, Supplementary Figure S3B).	('CD20', 'Gene', (37, 41))	('patients', 'Species', '9606', (129, 137))	('CD45', 'Gene', (153, 157))	('high', 'Var', (143, 147))	('CD45', 'Gene', '5788', (42, 46))	('CD20', 'Gene', '54474', (148, 152))	('CD20', 'Gene', (148, 152))	('CD45', 'Gene', '5788', (153, 157))	('CD20', 'Gene', '54474', (37, 41))	('medOS', 'MPA', (177, 182))	('longer', 'PosReg', (170, 176))	('CD45', 'Gene', (42, 46))
28187	31817531	In line with the survival analysis result of combined BLR/NLR data, patients with high B cells (B+) and low neutrophils (N-) gene signature had the longest medOS of 500 days (compared with the rest of the patients: p-value = 0.009, HR = 2.29, Figure 5B), and the corresponding immune gene signature was also independent of risk categories (tumor entities) according to multivariate Cox regression analysis (p-value of immune gene signature was < 0.05).	('patients', 'Species', '9606', (205, 213))	('tumor entities', 'Disease', 'MESH:D009369', (340, 354))	('high B cells', 'Var', (82, 94))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('low neutrophils', 'Phenotype', 'HP:0001875', (104, 119))	('low neutrophil', 'Phenotype', 'HP:0001875', (104, 118))	('tumor entities', 'Disease', (340, 354))
28198	31817531	This was further corroborated by transcriptional analysis of digitalized NanoString mRNA expression showing that a signature of high B cells and low neutrophil gene expressions correlated with better survival outcomes of patients.	('low neutrophil', 'Phenotype', 'HP:0001875', (145, 159))	('patients', 'Species', '9606', (221, 229))	('survival outcomes', 'CPA', (200, 217))	('low', 'NegReg', (145, 148))	('high', 'Var', (128, 132))	('better', 'PosReg', (193, 199))
28354	26824986	Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood.	('Malignant pleural mesothelioma', 'Disease', (140, 170))	('malignancy', 'Disease', 'MESH:D009369', (185, 195))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (118, 139))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (150, 170))	('pleural mesotheliomas', 'Disease', (118, 139))	('loss', 'NegReg', (70, 74))	('malignancy', 'Disease', (185, 195))	('mesotheliomas Malignant', 'Phenotype', 'HP:0100001', (126, 149))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (118, 138))	('SETDB1', 'Gene', '9869', (88, 94))	('mutations', 'Var', (95, 104))	('SETDB1', 'Gene', (88, 94))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (118, 139))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (140, 170))
28356	26824986	We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura.	('primary cancers', 'Disease', 'MESH:D009369', (102, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('primary lung cancer', 'Disease', 'MESH:D008175', (228, 247))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('patient', 'Species', '9606', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MPM', 'Disease', (79, 82))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('primary cancers', 'Disease', (102, 117))	('primary lung cancer', 'Disease', (228, 247))
28357	26824986	We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM.	('loss', 'NegReg', (86, 90))	('R282W', 'Var', (26, 31))	('TP53', 'Gene', '7157', (39, 43))	('R282W', 'Mutation', 'rs28934574', (26, 31))	('TP53', 'Gene', (39, 43))
28358	26824986	We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing.	('patient', 'Species', '9606', (61, 68))	('patients', 'Species', '9606', (94, 102))	('inactivating', 'Reg', (23, 35))	('SETDB1', 'Gene', '9869', (36, 42))	('mutations', 'Var', (43, 52))	('patient', 'Species', '9606', (94, 101))	('SETDB1', 'Gene', (36, 42))
28360	26824986	The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM.	('MPM', 'Disease', (108, 111))	('SETDB1', 'Gene', '9869', (13, 19))	('SETDB1', 'Gene', (13, 19))	('inactivating mutations', 'Var', (20, 42))
28377	26824986	Final pathology revealed a T1N0M0 lung adenocarcinoma in the left lower lobe and pleural biopsies indicated sarcomatoid pleural mesothelioma, which stained positive for calretinin (Figure 1B) and was staged as T3N0M0 because there was no evidence of venous, arterial, lymphovascular, or perineural invasion.	('calretinin', 'Gene', '794', (169, 179))	('sarcomatoid pleural mesothelioma', 'Disease', 'MESH:C538614', (108, 140))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (120, 140))	('calretinin', 'Gene', (169, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (34, 53))	('positive', 'Reg', (156, 164))	('lung adenocarcinoma', 'Disease', (34, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (34, 53))	('sarcomatoid pleural mesothelioma', 'Disease', (108, 140))	('T1N0M0', 'Var', (27, 33))
28383	26824986	One key mutation identified was R282W in the TP53 tumor suppressor gene.	('TP53', 'Gene', (45, 49))	('R282W', 'Var', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('R282W', 'Mutation', 'rs28934574', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('TP53', 'Gene', '7157', (45, 49))	('tumor', 'Disease', (50, 55))
28384	26824986	R282W is a structural mutation that renders the DNA-binding domain of p53 unstable and is a common TP53 cancer-related mutation, but has not been described in MPM.	('TP53', 'Gene', (99, 103))	('DNA-binding', 'molecular_function', 'GO:0003677', ('48', '59'))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('DNA-binding domain', 'MPA', (48, 66))	('R282W', 'Var', (0, 5))	('TP53', 'Gene', '7157', (99, 103))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('R282W', 'Mutation', 'rs28934574', (0, 5))
28385	26824986	We also identified a nonsense mutation, Y249X, of SETDB1, a histone methyltransferase.	('histone methyltransferase', 'Gene', '56979', (60, 85))	('SETDB1', 'Gene', '9869', (50, 56))	('Y249X', 'Mutation', 'p.Y249X', (40, 45))	('Y249X', 'Var', (40, 45))	('histone methyltransferase', 'Gene', (60, 85))	('SETDB1', 'Gene', (50, 56))
28387	26824986	A frameshift mutation (V132fs) producing a premature stop codon in SETDB1 was also described in the ACCMESO1 mesothelioma cell line (Cancer Cell Line Encyclopedia (CCLE) database), which suggests a potential role of SETDB1 in MPM development.	('SETDB1', 'Gene', '9869', (216, 222))	('mesothelioma', 'Disease', 'MESH:D008654', (109, 121))	('Cancer Cell Line Encyclopedia', 'Disease', (133, 162))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('SETDB1', 'Gene', '9869', (67, 73))	('SETDB1', 'Gene', (216, 222))	('premature stop codon', 'MPA', (43, 63))	('V132fs', 'Mutation', 'p.V132fsX', (23, 29))	('V132fs', 'Var', (23, 29))	('mesothelioma', 'Disease', (109, 121))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (133, 162))	('SETDB1', 'Gene', (67, 73))
28388	26824986	Interestingly, most mutations identified in the MPM patient were highly enriched for the mutant allele, suggesting a homozygous alteration or deletion of wild-type allele when minimal contamination of normal pleura in the MPM is considered (Figure 2A).	('deletion', 'Var', (142, 150))	('patient', 'Species', '9606', (52, 59))	('mutations', 'Var', (20, 29))
28389	26824986	Analyses of allelic fraction between wild-type and variants in MPM tumor (Fig 3A, upper panel), as well as tumor allelic log ratio to normal (Fig 3A, lower panel) using all variants in exome sequencing, including known SNPs, revealed that this MPM showed genome-wide allelic loss or loss of heterozygosity (LOH).	('MPM tumor', 'Disease', 'MESH:D009369', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('variants', 'Var', (51, 59))	('loss of', 'NegReg', (283, 290))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('MPM tumor', 'Disease', (63, 72))	('loss', 'NegReg', (275, 279))
28393	26824986	However, a major driver mutation, G12C, in the KRAS oncogene, might have been involved in the development of this AAH.	('G12C', 'Var', (34, 38))	('involved', 'Reg', (78, 86))	('G12C', 'Mutation', 'rs121913530', (34, 38))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))
28396	26824986	Among the mutations validated by exome and targeted sequencing in MPM tumor samples, we found that SETDB1 had a nonsense mutation (Y249X).	('Y249X', 'Mutation', 'p.Y249X', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Y249X', 'Var', (131, 136))	('MPM tumor', 'Disease', 'MESH:D009369', (66, 75))	('SETDB1', 'Gene', '9869', (99, 105))	('MPM tumor', 'Disease', (66, 75))	('SETDB1', 'Gene', (99, 105))
28397	26824986	Because another inactivating frameshift mutation (V132fs) was reported in the mesothelioma cell line ACCMESO1, we analyzed mutations of SETDB1 for this whole coding region by targeted deep sequencing of the whole coding exons of SETDB1 in 77 additional primary MPM tissues, for a total sample of 78 MPM tissues from 69 MPM patients.	('SETDB1', 'Gene', (136, 142))	('patients', 'Species', '9606', (323, 331))	('V132fs', 'Var', (50, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('SETDB1', 'Gene', '9869', (229, 235))	('SETDB1', 'Gene', '9869', (136, 142))	('V132fs', 'Mutation', 'p.V132fsX', (50, 56))	('SETDB1', 'Gene', (229, 235))	('mesothelioma', 'Disease', (78, 90))
28401	26824986	Ten matched normal pleural samples were available from 69 mesothelioma patients and sequenced to find any SETDB1 variant, but none were identified.	('SETDB1', 'Gene', (106, 112))	('mesothelioma', 'Disease', (58, 70))	('patients', 'Species', '9606', (71, 79))	('variant', 'Var', (113, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('SETDB1', 'Gene', '9869', (106, 112))
28402	26824986	Finally, to determine whether SETDB1 mutation was correlated with overall survival of MPM patients, we divided 69 MPM patients based on SETDB1 mutation status.	('SETDB1', 'Gene', (30, 36))	('SETDB1', 'Gene', (136, 142))	('mutation', 'Var', (37, 45))	('SETDB1', 'Gene', '9869', (136, 142))	('SETDB1', 'Gene', '9869', (30, 36))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (118, 126))
28405	26824986	Loss of p53 may lead tumor cells to be more vulnerable to unrepaired genomic instability in response to DNA damage or stress.	('p53', 'Gene', (8, 11))	('tumor', 'Disease', (21, 26))	('p53', 'Gene', '7157', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
28407	26824986	Chromothripsis is strongly linked to TP53 germline or somatic mutations.	('linked', 'Reg', (27, 33))	('germline', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))	('Chromothripsis', 'Disease', (0, 14))	('TP53', 'Gene', (37, 41))
28408	26824986	Although we could not clearly define or classify the genome-wide allelic loss phenomenon as a chromothripsis or similar event because of the limited number of variants identified in exome sequencing analysis, we could assume that bi-allelic inactivation of the TP53 tumor suppressor gene via R282W mutation and LOH played a critical role in the genomic abnormality observed in our MPM case.	('TP53', 'Gene', '7157', (261, 265))	('chromothripsis', 'Disease', (94, 108))	('R282W', 'Mutation', 'rs28934574', (292, 297))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('R282W mutation', 'Var', (292, 306))	('TP53', 'Gene', (261, 265))	('chromothripsis', 'Disease', 'MESH:D000072837', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor suppressor', 'biological_process', 'GO:0051726', ('266', '282'))	('MPM', 'Disease', (381, 384))	('tumor', 'Disease', (266, 271))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('266', '282'))
28410	26824986	Because TP53 mutation is important for genomic instability such as chromothripsis, and R282W is a key mutation altering function of p53, it would be meaningful to further examine the relationship between TP53 R282W and a genome-wide loss in MPM.	('R282W', 'Mutation', 'rs28934574', (87, 92))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('chromothripsis', 'Disease', (67, 81))	('MPM', 'Disease', (241, 244))	('TP53', 'Gene', '7157', (204, 208))	('R282W', 'Var', (209, 214))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('TP53', 'Gene', (204, 208))	('chromothripsis', 'Disease', 'MESH:D000072837', (67, 81))	('loss', 'NegReg', (233, 237))	('R282W', 'Mutation', 'rs28934574', (209, 214))
28411	26824986	We believe this is the first report of genome-wide allelic loss in a patient who developed multiple primary cancers including MPM.	('multiple primary cancers', 'Disease', (91, 115))	('allelic loss', 'Var', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MPM', 'Disease', (126, 129))	('patient', 'Species', '9606', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('multiple primary cancers', 'Disease', 'MESH:D009369', (91, 115))
28413	26824986	Another notable finding in this study was the high frequency of SETDB1 mutations in MPM.	('SETDB1', 'Gene', (64, 70))	('mutations', 'Var', (71, 80))	('SETDB1', 'Gene', '9869', (64, 70))
28415	26824986	We identified a somatic SETDB1 mutation by exome sequencing, validated it by targeted deep sequencing analysis, and sequenced 77 additional MPM samples using another targeted deep sequencing panel of SETDB1 three times, which we believe clearly rules out a technical artifact of sequencing.	('SETDB1', 'Gene', '9869', (200, 206))	('SETDB1', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('SETDB1', 'Gene', (200, 206))	('SETDB1', 'Gene', '9869', (24, 30))
28419	26824986	In contrast, our coverage range of SETDB1 targeted deep sequencing was up to 40,000X:a difference that could explain why we detected the SETDB1 mutation.	('SETDB1', 'Gene', '9869', (35, 41))	('SETDB1', 'Gene', (137, 143))	('mutation', 'Var', (144, 152))	('SETDB1', 'Gene', (35, 41))	('SETDB1', 'Gene', '9869', (137, 143))
28424	26824986	Our finding that SETDB1 had a nonsense mutation (Y249X) and the fact that another inactivating frameshift mutation (V132fs) was reported in the mesothelioma cell line ACCMESO1, led us to hypothesize that truncating mutations such as nonsense and frameshift mutations are frequent in MPM.	('Y249X', 'Mutation', 'p.Y249X', (49, 54))	('Y249X', 'Var', (49, 54))	('SETDB1', 'Gene', (17, 23))	('mesothelioma', 'Disease', (144, 156))	('MPM', 'Disease', (283, 286))	('frameshift mutations', 'Var', (246, 266))	('V132fs', 'Mutation', 'p.V132fsX', (116, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('nonsense', 'Var', (233, 241))	('SETDB1', 'Gene', '9869', (17, 23))
28426	26824986	Interestingly, while all predicted loss-of-function mutations except one are located in the N-terminal, missense and in-frame deletion mutations affecting single amino acid residues are located in the SET domain of SETDB1 (Figure 5).	('mutations', 'Var', (52, 61))	('loss-of-function', 'NegReg', (35, 51))	('SETDB1', 'Gene', (215, 221))	('SETDB1', 'Gene', '9869', (215, 221))
28427	26824986	Although SETDB1 has been suggested to have an oncogenic impact in lung cancer based on transcription level or expression data, our results suggest that at least some of the identified SETDB1 somatic mutations are probably loss of function mutations.	('SETDB1', 'Gene', '9869', (184, 190))	('loss of function', 'NegReg', (222, 238))	('SETDB1', 'Gene', '9869', (9, 15))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('SETDB1', 'Gene', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('SETDB1', 'Gene', (9, 15))	('mutations', 'Var', (199, 208))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
28428	26824986	Functional validation and characterization should be performed to prove this, but the different mutation spectrum suggests the location of somatic mutations on the SETDB1 functional domains may be important for oncogenic effect or tumor suppression.	('mutations', 'Var', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('oncogenic effect', 'CPA', (211, 227))	('SETDB1', 'Gene', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('SETDB1', 'Gene', '9869', (164, 170))
28429	26824986	Exome sequencing in eight primary cultured cells from different subtypes of mesothelioma found that genes involved in histone modification and regulation mechanisms, such as BAP1, SETD2, USP49, and PRMT6, were mutated, suggesting somatic inactivation of histone modifier genes is important for mesothelioma development.	('mutated', 'Var', (210, 217))	('PRMT6', 'Gene', (198, 203))	('USP', 'molecular_function', 'GO:0051748', ('187', '190'))	('mesothelioma', 'Disease', 'MESH:D008654', (294, 306))	('BAP1', 'Gene', (174, 178))	('regulation', 'biological_process', 'GO:0065007', ('143', '153'))	('histone modification', 'biological_process', 'GO:0016570', ('118', '138'))	('mesothelioma', 'Disease', (76, 88))	('USP49', 'Gene', (187, 192))	('USP49', 'Gene', '25862', (187, 192))	('PRMT6', 'Gene', '55170', (198, 203))	('SETD2', 'Gene', '29072', (180, 185))	('mesothelioma', 'Disease', (294, 306))	('SETD2', 'Gene', (180, 185))	('BAP1', 'Gene', '8314', (174, 178))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
28431	26824986	These results are consistent with our finding that mutations of SETDB1, histone methyltransferase, are frequent in MPM, suggesting that histone modifier genes, including SETDB1, are potentially important in MPM.	('histone methyltransferase', 'Gene', '56979', (72, 97))	('SETDB1', 'Gene', (64, 70))	('MPM', 'Disease', (115, 118))	('mutations', 'Var', (51, 60))	('SETDB1', 'Gene', '9869', (170, 176))	('histone methyltransferase', 'Gene', (72, 97))	('SETDB1', 'Gene', '9869', (64, 70))	('SETDB1', 'Gene', (170, 176))	('frequent', 'Reg', (103, 111))
28433	26824986	In summary, we identified genome-wide allelic loss in a patient who had MPM and two additional primary cancers, results which suggest that careful analysis in exome sequencing is needed to detect genome-wide deletion in MPM samples with or without multiple primary cancers.	('deletion', 'Var', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('loss', 'NegReg', (46, 50))	('multiple primary cancers', 'Disease', 'MESH:D009369', (248, 272))	('primary cancers', 'Disease', 'MESH:D009369', (257, 272))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('allelic', 'Var', (38, 45))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('multiple primary cancers', 'Disease', (248, 272))	('primary cancers', 'Disease', (95, 110))	('patient', 'Species', '9606', (56, 63))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('primary cancers', 'Disease', 'MESH:D009369', (95, 110))	('MPM', 'Disease', (72, 75))
28434	26824986	The high frequency of mutations in SETDB1 that we found suggests that this and other histone-related genes are important in MPM.	('SETDB1', 'Gene', '9869', (35, 41))	('SETDB1', 'Gene', (35, 41))	('mutations', 'Var', (22, 31))	('MPM', 'Disease', (124, 127))
28442	26824986	To validate the identified mutations from the exome sequencing of the patient who had MPM and two other primary cancers, we designed a customized Ampliseq panel (Life Technologies) to sequence six mutation candidates (KANK4, GBP4, SETDB1, ACTB, GOT1, and NOD2).	('mutations', 'Var', (27, 36))	('KANK4', 'Gene', (218, 223))	('SETDB1', 'Gene', '9869', (231, 237))	('MPM', 'Disease', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('primary cancers', 'Disease', (104, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('GBP4', 'Gene', '115361', (225, 229))	('patient', 'Species', '9606', (70, 77))	('ACTB', 'Gene', '60', (239, 243))	('ACTB', 'Gene', (239, 243))	('SETDB1', 'Gene', (231, 237))	('KANK4', 'Gene', '163782', (218, 223))	('GOT1', 'Gene', (245, 249))	('NOD2', 'Gene', (255, 259))	('GOT1', 'Gene', '2805', (245, 249))	('primary cancers', 'Disease', 'MESH:D009369', (104, 119))	('NOD2', 'Gene', '64127', (255, 259))	('GBP4', 'Gene', (225, 229))
28446	26824986	Sanger sequencing as described previously was done to validate TP53 R282W and RAPGEF6 T325S mutations in the sample from the MPM patient who had additional primary cancers.	('T325S', 'Mutation', 'p.T325S', (86, 91))	('R282W', 'Mutation', 'rs28934574', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('T325S', 'Var', (86, 91))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('RAPGEF6', 'Gene', '51735', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('primary cancers', 'Disease', (156, 171))	('RAPGEF6', 'Gene', (78, 85))	('primary cancers', 'Disease', 'MESH:D009369', (156, 171))	('patient', 'Species', '9606', (129, 136))
28447	26824986	We divided 69 MPM patients into SETDB1 wild-type (n=62) and mutant (n=7) groups.	('SETDB1', 'Gene', '9869', (32, 38))	('patients', 'Species', '9606', (18, 26))	('mutant', 'Var', (60, 66))	('MPM', 'Disease', (14, 17))	('SETDB1', 'Gene', (32, 38))
28448	26226841	Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology.	('mesothelioma', 'Disease', 'MESH:D008654', (211, 223))	('pleural effusion', 'Phenotype', 'HP:0002202', (164, 180))	('pleural effusions', 'Disease', (164, 181))	('mesotheliomas', 'Disease', 'MESH:D008654', (137, 150))	('effusion', 'Disease', 'MESH:D010996', (260, 268))	('mesothelioma', 'Disease', (137, 149))	('mesotheliomas', 'Disease', (137, 150))	('effusion', 'Disease', 'MESH:D010996', (172, 180))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('BAP1', 'Gene', '8314', (22, 26))	('effusion', 'Disease', 'MESH:D010996', (105, 113))	('pleural effusions', 'Disease', 'MESH:D010996', (164, 181))	('Loss of expression', 'Var', (0, 18))	('mesothelioma', 'Disease', (89, 101))	('effusion', 'Disease', (260, 268))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('effusion', 'Disease', (172, 180))	('pleural effusions', 'Phenotype', 'HP:0002202', (164, 181))	('BAP1', 'Gene', (22, 26))	('effusion', 'Disease', (105, 113))	('mesothelioma in effusion', 'Disease', (89, 113))	('mesothelioma', 'Disease', (211, 223))	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (89, 113))
28460	26226841	We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology.	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (104, 128))	('expression', 'MPA', (30, 40))	('BAP1', 'Gene', (25, 29))	('mesothelioma in effusion', 'Disease', (104, 128))	('BAP1', 'Gene', '8314', (25, 29))	('loss', 'Var', (17, 21))
28465	26226841	The discovery of germline BAP1 mutations in families with high incidences of mesothelioma and other neoplasms has led to the recent recognition of the BAP1 tumor predisposition syndrome (OMIM #614327), which is inherited in an autosomal dominant manner and is characterised by uveal melanoma, mesothelioma, cutaneous melanocytic lesions, renal cell carcinoma, basal cell carcinoma, and possibly intrahepatic cholangiocarcinoma.	('mesothelioma', 'Disease', (77, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (395, 426))	('intrahepatic cholangiocarcinoma', 'Disease', (395, 426))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (408, 426))	('tumor', 'Disease', (156, 161))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('cutaneous melanocytic lesions', 'Disease', (307, 336))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (360, 380))	('mutations', 'Var', (31, 40))	('neoplasms', 'Disease', 'MESH:D009369', (100, 109))	('mesothelioma', 'Disease', (293, 305))	('uveal melanoma', 'Disease', 'MESH:C536494', (277, 291))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (338, 358))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('uveal melanoma', 'Disease', (277, 291))	('mesothelioma', 'Disease', 'MESH:D008654', (293, 305))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (360, 380))	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (307, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (417, 426))	('neoplasms', 'Disease', (100, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (277, 291))	('BAP1', 'Gene', '8314', (26, 30))	('renal cell carcinoma', 'Disease', (338, 358))	('BAP1', 'Gene', '8314', (151, 155))	('basal cell carcinoma', 'Disease', (360, 380))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (338, 358))
28471	26226841	These observations suggest a genetic predisposition to developing mesothelioma, and have led to the discovery of the association between germline BAP1 mutation and mesothelioma.	('BAP1', 'Gene', '8314', (146, 150))	('mesothelioma', 'Disease', (164, 176))	('association', 'Interaction', (117, 128))	('mutation', 'Var', (151, 159))	('BAP1', 'Gene', (146, 150))	('mesothelioma', 'Disease', (66, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))
28472	26226841	Furthermore recent studies have identified an association between somatic BAP1 inactivation and mesothelioma, with double-hit inactivation of BAP1 reported in approximately half of all mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (185, 198))	('mesotheliomas', 'Disease', (185, 198))	('mesothelioma', 'Disease', (96, 108))	('mesothelioma', 'Disease', (185, 197))	('inactivation', 'Var', (79, 91))	('BAP1', 'Gene', '8314', (142, 146))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (142, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', (74, 78))
28480	26226841	Given the high rate of BAP1 double-hit inactivation in mesothelioma and its correlation with loss of BAP1 expression as determined by immunohistochemistry in tissue specimens, we sought to investigate whether loss of expression of BAP1 as determined in cell-block preparations from pleural effusion specimens could be used to support a diagnosis of mesothelioma.	('mesothelioma', 'Disease', (349, 361))	('BAP1', 'Gene', (23, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (349, 361))	('mesothelioma', 'Disease', (55, 67))	('BAP1', 'Gene', '8314', (101, 105))	('pleural effusion', 'Disease', 'MESH:D010996', (282, 298))	('BAP1', 'Gene', '8314', (231, 235))	('pleural effusion', 'Phenotype', 'HP:0002202', (282, 298))	('pleural effusion', 'Disease', (282, 298))	('BAP1', 'Gene', '8314', (23, 27))	('BAP1', 'Gene', (101, 105))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('BAP1', 'Gene', (231, 235))	('double-hit', 'Var', (28, 38))
28512	26226841	Loss of immunohistochemical staining for BAP1 in the presence of an internal positive control in non-neoplastic cells has been proven to be a reliable marker of BAP1 double-hit inactivation in tissue samples from mesothelioma and uveal melanoma.	('BAP1', 'Gene', (161, 165))	('mesothelioma', 'Disease', (213, 225))	('BAP1', 'Gene', (41, 45))	('double-hit', 'Var', (166, 176))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('Loss', 'NegReg', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (230, 244))	('mesothelioma', 'Disease', 'MESH:D008654', (213, 225))	('uveal melanoma', 'Disease', 'MESH:C536494', (230, 244))	('BAP1', 'Gene', '8314', (161, 165))	('uveal melanoma', 'Disease', (230, 244))	('BAP1', 'Gene', '8314', (41, 45))
28513	26226841	Given that double-hit inactivation of BAP1 has been reported as a key driver event in approximately half of all mesotheliomas, loss of immunohistochemical staining for BAP1 is an attractive ancillary marker for mesothelioma with the potential to be highly specific, albeit not particularly sensitive.	('mesothelioma', 'Disease', 'MESH:D008654', (211, 223))	('BAP1', 'Gene', '8314', (168, 172))	('BAP1', 'Gene', (38, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('BAP1', 'Gene', (168, 172))	('BAP1', 'Gene', '8314', (38, 42))	('mesothelioma', 'Disease', (211, 223))	('loss', 'Var', (127, 131))	('mesotheliomas', 'Disease', 'MESH:D008654', (112, 125))	('mesotheliomas', 'Disease', (112, 125))	('mesothelioma', 'Disease', (112, 124))
28525	26226841	Therefore, because BAP1 immunohistochemistry may be difficult to interpret with certainty in pleural effusion specimens, loss of BAP1 expression even when interpreted by experienced observers, can only be used to support a diagnosis of mesothelioma in the appropriate clinical and morphological context and is not completely definitive when interpreted in isolation.	('mesothelioma', 'Disease', (236, 248))	('mesothelioma', 'Disease', 'MESH:D008654', (236, 248))	('loss', 'Var', (121, 125))	('BAP1', 'Gene', '8314', (19, 23))	('pleural effusion', 'Disease', 'MESH:D010996', (93, 109))	('BAP1', 'Gene', '8314', (129, 133))	('pleural effusion', 'Disease', (93, 109))	('pleural effusion', 'Phenotype', 'HP:0002202', (93, 109))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', (129, 133))
28528	26226841	Therefore, in addition to supporting a diagnosis of mesothelioma over reactive mesothelial change in the appropriate context, loss of expression of BAP1 can also be used to support a malignancy as being mesothelial rather than epithelial.	('loss of expression', 'Var', (126, 144))	('BAP1', 'Gene', '8314', (148, 152))	('malignancy', 'Disease', 'MESH:D009369', (183, 193))	('mesothelioma', 'Disease', (52, 64))	('BAP1', 'Gene', (148, 152))	('malignancy', 'Disease', (183, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
28612	30282530	Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in an SD rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated with antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque and rete ovarii proliferative ovarian lesions in various aged rat strains.	('gallbladder mucinous hyperplasia', 'Disease', 'MESH:D005705', (215, 247))	('antisense', 'Var', (403, 412))	('intestinal leiomyositis', 'Disease', 'MESH:D007410', (174, 197))	('choriocarcinoma', 'Disease', 'MESH:D002822', (448, 463))	('seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (71, 101))	('necrosis', 'biological_process', 'GO:0008219', ('151', '159'))	('rat', 'Species', '10116', (144, 147))	('rat', 'Species', '10116', (546, 549))	('choriocarcinoma', 'Disease', (448, 463))	('rats', 'Species', '10116', (105, 109))	('rat', 'Species', '10116', (302, 305))	('rhesus macaque', 'Species', '9544', (469, 483))	('myositis', 'Phenotype', 'HP:0100614', (189, 197))	('necrosis', 'biological_process', 'GO:0008220', ('151', '159'))	('rete ovarii proliferative ovarian lesions', 'Disease', 'MESH:D010049', (488, 529))	('renal tubule cytoplasmic vacuolation', 'Phenotype', 'HP:0001922', (320, 356))	('mice', 'Species', '10090', (385, 389))	('rat', 'Species', '10116', (507, 510))	('rat', 'Species', '10116', (277, 280))	('necrosis', 'biological_process', 'GO:0070265', ('151', '159'))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (448, 463))	('necrosis', 'biological_process', 'GO:0019835', ('151', '159'))	('degeneration/necrosis', 'Disease', (138, 159))	('beagle dog', 'Species', '9615', (203, 213))	('degeneration/necrosis', 'Disease', 'MESH:D009336', (138, 159))	('necrosis', 'biological_process', 'GO:0001906', ('151', '159'))	('rat', 'Species', '10116', (169, 172))	('gallbladder mucinous hyperplasia', 'Disease', (215, 247))	('rat', 'Species', '10116', (105, 108))	('ovarian lesions', 'Phenotype', 'HP:0100615', (514, 529))	('carcinoma', 'Phenotype', 'HP:0030731', (454, 463))	('rete ovarii proliferative ovarian lesions', 'Disease', (488, 529))	('intestinal leiomyositis', 'Disease', (174, 197))
28616	30282530	Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in Hsd:Sprague Dawley (SD) rats, ameloblast and odontoblast degeneration/necrosis with dentin matrix alteration in an SD rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters (Lutra lutra), renal tubule cytoplasmic vacuolation with basophilic granules in CRL:CD1(ICR) mice treated with antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque (Macaca mulatta) and rete ovarii proliferative ovarian lesions in various aged rat strains.	('rete ovarii proliferative ovarian lesions', 'Disease', 'MESH:D010049', (586, 627))	('rat', 'Species', '10116', (207, 210))	('Macaca mulatta', 'Species', '9544', (566, 580))	('rat', 'Species', '10116', (644, 647))	('intestinal leiomyositis', 'Disease', (228, 251))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (529, 544))	('seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (71, 101))	('dentin matrix alteration', 'Phenotype', 'HP:0011060', (189, 213))	('gallbladder mucinous hyperplasia', 'Disease', 'MESH:D005705', (269, 301))	('rats', 'Species', '10116', (129, 133))	('rat', 'Species', '10116', (223, 226))	('intestinal leiomyositis', 'Disease', 'MESH:D007410', (228, 251))	('mice', 'Species', '10090', (466, 470))	('antisense oligonucleotide therapy', 'Var', (484, 517))	('necrosis', 'biological_process', 'GO:0008219', ('175', '183'))	('myositis', 'Phenotype', 'HP:0100614', (243, 251))	('rat', 'Species', '10116', (356, 359))	('necrosis', 'biological_process', 'GO:0001906', ('175', '183'))	('degeneration/necrosis', 'Disease', (162, 183))	('degeneration/necrosis', 'Disease', 'MESH:D009336', (162, 183))	('rat', 'Species', '10116', (331, 334))	('Lutra lutra', 'Species', '9657', (374, 385))	('Sprague', 'Species', '10116', (109, 116))	('ovarian lesions', 'Phenotype', 'HP:0100615', (612, 627))	('rete ovarii proliferative ovarian lesions', 'Disease', (586, 627))	('necrosis', 'biological_process', 'GO:0008220', ('175', '183'))	('rat', 'Species', '10116', (605, 608))	('choriocarcinoma', 'Disease', 'MESH:D002822', (529, 544))	('renal tubule cytoplasmic vacuolation', 'Phenotype', 'HP:0001922', (388, 424))	('beagle dog', 'Species', '9615', (257, 267))	('choriocarcinoma', 'Disease', (529, 544))	('rat', 'Species', '10116', (129, 132))	('rhesus macaque', 'Species', '9544', (550, 564))	('necrosis', 'biological_process', 'GO:0070265', ('175', '183'))	('carcinoma', 'Phenotype', 'HP:0030731', (535, 544))	('rat', 'Species', '10116', (168, 171))	('necrosis', 'biological_process', 'GO:0019835', ('175', '183'))	('gallbladder mucinous hyperplasia', 'Disease', (269, 301))
28629	30282530	Seminiferous tubule dysgenesis is characterized in experimental studies as a developmental malformation seen microscopically as aberrant or misshapen seminiferous tubules.	('Seminiferous tubule dysgenesis', 'Disease', (0, 30))	('misshapen', 'Var', (140, 149))	('men', 'Species', '9606', (84, 87))	('Seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (0, 30))	('men', 'Species', '9606', (57, 60))
28662	30282530	However, in utero phthalate exposure does cause a disorder of embryonic germ cells that manifests as multinucleated gonocytes in the neonatal rat.	('multinucleated gonocytes', 'CPA', (101, 125))	('phthalate', 'Var', (18, 27))	('cause', 'Reg', (42, 47))	('disorder of embryonic germ cells', 'Phenotype', 'HP:0012862', (50, 82))	('phthalate', 'Chemical', 'MESH:C032279', (18, 27))	('rat', 'Species', '10116', (142, 145))
28709	30282530	All cases were zebrafish (wild-type, mutant and transgenic) that presented from the same facility.	('transgenic', 'Var', (48, 58))	('mutant', 'Var', (37, 43))	('zebrafish', 'Species', '7955', (15, 24))
28822	30282530	The voting choices and results were: (1) delayed organogenesis, deformed yolk sac, eye abnormalities, pigmentation defects (2%); (2) stunted growth, axial skeletal deformities, craniofacial deformities, underdeveloped swim bladder (32%); (3) both 1 & 2 (66%) and (4) none of the above (0%).	('axial skeletal deformities', 'Phenotype', 'HP:0009121', (149, 175))	('stunted growth', 'Phenotype', 'HP:0001510', (133, 147))	('craniofacial deformities', 'Phenotype', 'HP:0004484', (177, 201))	('pigmentation defects', 'Disease', (102, 122))	('eye abnormalities', 'Phenotype', 'HP:0000478', (83, 100))	('stunted growth', 'CPA', (133, 147))	('pigmentation defects', 'Phenotype', 'HP:0001000', (102, 122))	('organogenesis', 'biological_process', 'GO:0048513', ('49', '62'))	('eye abnormalities', 'Disease', 'MESH:D005124', (83, 100))	('sac', 'cellular_component', 'GO:0035003', ('78', '81'))	('sac', 'biological_process', 'GO:0071173', ('78', '81'))	('craniofacial deformities', 'Disease', 'MESH:D019465', (177, 201))	('deformed', 'Var', (64, 72))	('yolk', 'cellular_component', 'GO:0060417', ('73', '77'))	('axial skeletal deformities', 'Disease', 'MESH:D009139', (149, 175))	('eye abnormalities', 'Disease', (83, 100))	('pigmentation defects', 'Disease', 'MESH:D010859', (102, 122))	('craniofacial deformities', 'Disease', (177, 201))	('delayed organogenesis', 'CPA', (41, 62))	('axial skeletal deformities', 'Disease', (149, 175))	('pigmentation', 'biological_process', 'GO:0043473', ('102', '114'))	('skeletal deformities', 'Phenotype', 'HP:0000924', (155, 175))
28876	30282530	Commonly used strains include New Zealand White (NZW), New Zealand Red (NZR), NZW x NZR F1 crosses, Dutch Belted (for ocular studies requiring a pigmented iris), and Watanabe (atherosclerosis).	('crosses', 'Var', (91, 98))	('atherosclerosis', 'Disease', (176, 191))	('Zealand Red', 'Chemical', 'MESH:C523279', (59, 70))	('pigmented iris', 'Disease', (145, 159))	('pigmented iris', 'Disease', 'MESH:D007499', (145, 159))	('atherosclerosis', 'Disease', 'MESH:D050197', (176, 191))	('atherosclerosis', 'Phenotype', 'HP:0002621', (176, 191))
28923	30282530	While the majority of the lesion was negative for CD10, there were rare foci of CD10 positivity which were negative for hCG and pancytokeratin (Figure 8F).	('positivity', 'Var', (85, 95))	('CD10', 'molecular_function', 'GO:0004245', ('80', '84'))	('CD10', 'Gene', (80, 84))	('CD10', 'Gene', '24590', (80, 84))	('CD10', 'Gene', '24590', (50, 54))	('CD10', 'Gene', (50, 54))	('hCG', 'Gene', '93659', (120, 123))	('CD10', 'molecular_function', 'GO:0004245', ('50', '54'))	('rat', 'Species', '10116', (137, 140))	('hCG', 'Gene', (120, 123))
28929	30282530	Trophoblastic tumors are rare neoplasms in domestic and laboratory animal species, and in non-human primates have been reported in the uterus and ovary In humans, most occur following a normal or ectopic pregnancy, abortion, or molar pregnancy.	('Trophoblastic tumors', 'Disease', (0, 20))	('molar pregnancy', 'CPA', (228, 243))	('domestic', 'Species', '9825', (43, 51))	('neoplasms', 'Phenotype', 'HP:0002664', (30, 39))	('ectopic pregnancy', 'Phenotype', 'HP:0031456', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('humans', 'Species', '9606', (155, 161))	('neoplasms', 'Disease', 'MESH:D009369', (30, 39))	('rat', 'Species', '10116', (60, 63))	('ectopic', 'Var', (196, 203))	('human', 'Species', '9606', (94, 99))	('neoplasms', 'Disease', (30, 39))	('Trophoblastic tumors', 'Disease', 'MESH:D014328', (0, 20))	('human', 'Species', '9606', (155, 160))	('abortion', 'Disease', 'MESH:D000031', (215, 223))	('abortion', 'Disease', (215, 223))	('Trophoblastic tumors', 'Phenotype', 'HP:0031502', (0, 20))
29113	27660729	Immunohistochemistry showed that the malignant cells expressed CAM 5.2 (strong, diffuse), AE1/AE3 (strong, diffuse), D2-40 (patchy, strong), and CK5/6 (patchy, weak) and lacked CK7, CK20, TTF-1, p63, WT-1, calretinin, MOC-31, Ber-Ep4, and S100 reactivity.	('CAM 5.2', 'Gene', (63, 70))	('CK7', 'Gene', (177, 180))	('TTF-1', 'Gene', '7270', (188, 193))	('AE1', 'Gene', '6521', (90, 93))	('calretinin', 'Gene', '794', (206, 216))	('lacked', 'NegReg', (170, 176))	('AE3', 'Gene', '6508', (94, 97))	('WT-1', 'Gene', '7490', (200, 204))	('S100 reactivity', 'MPA', (239, 254))	('CK5/6', 'Gene', (145, 150))	('MOC-31', 'MPA', (218, 224))	('Ber', 'biological_process', 'GO:0006284', ('226', '229'))	('CK7', 'Gene', '3855', (177, 180))	('AE1', 'Gene', (90, 93))	('TTF-1', 'Gene', (188, 193))	('CK20', 'Gene', (182, 186))	('WT-1', 'Gene', (200, 204))	('calretinin', 'Gene', (206, 216))	('D2-40', 'Var', (117, 122))	('p63', 'Gene', (195, 198))	('CK20', 'Gene', '54474', (182, 186))	('AE3', 'Gene', (94, 97))	('p63', 'Gene', '8626', (195, 198))	('CK5/6', 'Gene', '3852', (145, 150))
29140	27660729	When evaluating suspected skeletal tumors based on thoracic imaging, variants of malignant pleural mesotheliomas must always be considered in the differential diagnosis of a chest wall lesion, even in relatively young individuals with no history of asbestos exposure.	('skeletal tumors', 'Phenotype', 'HP:0010622', (26, 41))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (91, 111))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (91, 112))	('chest wall lesion', 'Disease', (174, 191))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('variants', 'Var', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('malignant pleural mesotheliomas', 'Disease', (81, 112))	('asbestos', 'Chemical', 'MESH:D001194', (249, 257))	('skeletal tumors', 'Disease', (26, 41))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (81, 112))	('skeletal tumors', 'Disease', 'MESH:D009369', (26, 41))	('skeletal tumor', 'Phenotype', 'HP:0010622', (26, 40))
29150	27403364	The epithelioid portion showed IHC reactivity for pan cytokeratin, CK5/6, D2-40, and calretinin and the small cell portion marked with CD99, pan cytokeratin, WT1, FLI1, S100, CD200, MyoD1, and CD15.	('CK5/6', 'Gene', (67, 72))	('D2-40', 'Var', (74, 79))	('CD15', 'Gene', '2526', (193, 197))	('calretinin', 'Gene', '794', (85, 95))	('CD99', 'Gene', (135, 139))	('S100', 'Gene', (169, 173))	('S100', 'Gene', '6271', (169, 173))	('pan cytokeratin', 'Protein', (50, 65))	('WT1', 'Gene', (158, 161))	('MyoD1', 'Gene', (182, 187))	('FLI1', 'Gene', (163, 167))	('CD99', 'Gene', '4267', (135, 139))	('WT1', 'Gene', '7490', (158, 161))	('CD200', 'Gene', (175, 180))	('MyoD1', 'Gene', '4654', (182, 187))	('CK5/6', 'Gene', '3852', (67, 72))	('FLI1', 'Gene', '2313', (163, 167))	('CD200', 'Gene', '4345', (175, 180))	('calretinin', 'Gene', (85, 95))	('CD15', 'Gene', (193, 197))
29168	27403364	Here we describe a patient's tumor with histopathological and immunohistochemical features of a mixture of a small cell malignancy and an epithelioid mesothelioma that had multiple complex chromosomal abnormalities on microarray, including the loss of 11p15.5-p11.12 and 22q12.1-q13.33 regions.	('loss', 'Var', (244, 248))	('p11', 'Gene', (260, 263))	('epithelioid mesothelioma', 'Disease', (138, 162))	('malignancy', 'Disease', (120, 130))	('patient', 'Species', '9606', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (189, 214))	('chromosomal abnormalities', 'Disease', (189, 214))	('p11', 'Gene', '6281', (260, 263))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (138, 162))	('tumor', 'Disease', (29, 34))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))
29187	27403364	An array of comparative genome hybridization (a-CGH) was performed on formalin-fixed paraffin embedded (FFPE) slides to investigate the possibility of monosomy 22 or deletion of the EWSR1 gene region.	('paraffin', 'Chemical', 'MESH:D010232', (85, 93))	('EWSR1', 'Gene', (182, 187))	('deletion', 'Var', (166, 174))	('monosomy 22', 'Var', (151, 162))	('EWSR1', 'Gene', '2130', (182, 187))	('formalin', 'Chemical', 'MESH:D005557', (70, 78))
29189	27403364	The losses of chromosome regions 11p13 and 22q12 implies a loss of the WT1 and EWSR1 genes, respectively, and confirms that the single intact signal seen on FISH was caused by deletion of the EWSR1 gene region.	('deletion', 'Var', (176, 184))	('caused by', 'Reg', (166, 175))	('EWSR1', 'Gene', (79, 84))	('WT1', 'Gene', (71, 74))	('p13', 'Gene', (35, 38))	('loss', 'NegReg', (59, 63))	('EWSR1', 'Gene', '2130', (192, 197))	('EWSR1', 'Gene', '2130', (79, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('14', '24'))	('p13', 'Gene', '440926', (35, 38))	('EWSR1', 'Gene', (192, 197))	('WT1', 'Gene', '7490', (71, 74))	('22q12', 'Gene', (43, 48))	('losses', 'NegReg', (4, 10))
29206	27403364	Some have hypothesized that calretinin positivity in DSRCTs may be related to focal mesothelial differentiation within a DSRCT or enveloping of mesothelial cells by a surrounding DSRCT.	('calretinin', 'Gene', (28, 38))	('related', 'Reg', (67, 74))	('focal mesothelial differentiation', 'CPA', (78, 111))	('calretinin', 'Gene', '794', (28, 38))	('positivity', 'Var', (39, 49))
29207	27403364	Additionally, mesotheliomas generally show immunopositivity for CK5/6, CK7, and HBME-1 and are negative for desmin.	('desmin', 'cellular_component', 'GO:0045098', ('108', '114'))	('HBME-1', 'Gene', (80, 86))	('CK7', 'Gene', (71, 74))	('mesotheliomas', 'Disease', 'MESH:D008654', (14, 27))	('desmin', 'cellular_component', 'GO:0045100', ('108', '114'))	('mesotheliomas', 'Disease', (14, 27))	('HBME-1', 'CellLine', 'CVCL:U718', (80, 86))	('desmin', 'Gene', (108, 114))	('CK7', 'Gene', '3855', (71, 74))	('CK5/6', 'Gene', '3852', (64, 69))	('CK5/6', 'Gene', (64, 69))	('immunopositivity', 'Var', (43, 59))	('desmin', 'Gene', '1674', (108, 114))
29214	27403364	In our case, the papillary or large cell population showed a staining pattern characteristic for mesothelioma with calretinin, cytokeratin, and CD99 positivity, while the small cell component was positive for CD99, WT1, FLI-1, and cytokeratin.	('FLI-1', 'Gene', (220, 225))	('calretinin', 'Gene', (115, 125))	('CD99', 'Gene', (144, 148))	('CD99', 'Gene', (209, 213))	('mesothelioma', 'Disease', (97, 109))	('positivity', 'Var', (149, 159))	('FLI-1', 'Gene', '2313', (220, 225))	('calretinin', 'Gene', '794', (115, 125))	('CD99', 'Gene', '4267', (209, 213))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('WT1', 'Gene', '7490', (215, 218))	('WT1', 'Gene', (215, 218))	('CD99', 'Gene', '4267', (144, 148))
29234	27403364	Molecular variants of the EWS-WT1 fusion have been reported in up to 5% of DSRCTs, but the clinicopathological significance of these variants is not known.	('DSRCTs', 'Disease', (75, 81))	('reported', 'Reg', (51, 59))	('variants', 'Var', (10, 18))	('EWS-WT1', 'Gene', '7490', (26, 33))	('EWS-WT1', 'Gene', (26, 33))
29235	27403364	The most common type of variation is additional exons, usually from EWS, which combine to produce a different-sized fusion transcript detectable by RT-PCR.	('produce', 'Reg', (90, 97))	('variation', 'Var', (24, 33))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))
29240	27403364	suggested that the EWS-WT1 (-KTS) isoform differentially experiences a gain of function mutation and transforms the fusion product into an oncogene that is not seen with EWS-WT1 (+KTS) isoforms.	('EWS-WT1', 'Gene', (19, 26))	('mutation', 'Var', (88, 96))	('gain of function', 'PosReg', (71, 87))	('EWS-WT1', 'Gene', '7490', (170, 177))	('EWS-WT1', 'Gene', '7490', (19, 26))	('EWS-WT1', 'Gene', (170, 177))
29242	27403364	Loss of p53 is also seen in retinoblastoma and sarcomas and was lost in our patient's tumor as part of the loss of 17p13.3-11.2 noted on a-CGH.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcomas', 'Disease', (47, 55))	('p53', 'Gene', (8, 11))	('tumor', 'Disease', (86, 91))	('retinoblastoma', 'Phenotype', 'HP:0009919', (28, 42))	('loss', 'Var', (107, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('p13', 'Gene', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Loss', 'NegReg', (0, 4))	('p13', 'Gene', '440926', (117, 120))	('patient', 'Species', '9606', (76, 83))	('retinoblastoma', 'Disease', 'MESH:D012175', (28, 42))	('retinoblastoma', 'Disease', (28, 42))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))
29248	27403364	One cell each in that case did show a del(22)(q12) and del(11)(p13).	('del(22)(q12', 'Var', (38, 49))	('p13', 'Gene', '440926', (63, 66))	('p13', 'Gene', (63, 66))
29250	27403364	Recurrent changes identified by karyotype included monosomy of chromosomes 4 and 22, polysomy of chromosomes 5, 7, and 20, and losses of 1p21-p22, 3p21, 6q15-q21, 9p21-p22, 11p11-p13, 13q, 14q, and 22q12.	('p13', 'Gene', (179, 182))	('polysomy', 'CPA', (85, 93))	('p22', 'Gene', '1778', (142, 145))	('p13', 'Gene', '440926', (179, 182))	('p22', 'Gene', (168, 171))	('p21', 'Gene', (164, 167))	('p21', 'Gene', '644914', (164, 167))	('p21', 'Gene', (148, 151))	('monosomy', 'Var', (51, 59))	('p21', 'Gene', '644914', (148, 151))	('13q', 'CPA', (184, 187))	('p11', 'Gene', '6281', (175, 178))	('14q', 'Disease', (189, 192))	('losses', 'NegReg', (127, 133))	('p22', 'Gene', (142, 145))	('p21', 'Gene', (138, 141))	('p11', 'Gene', (175, 178))	('p22', 'Gene', '1778', (168, 171))	('22q12', 'Gene', (198, 203))	('p21', 'Gene', '644914', (138, 141))	('6q15-q21', 'Var', (153, 161))
29251	27403364	Tumors subjected to a-CGH revealed the most frequent losses to be 1p11-p22, 3p21, 4q31.1-qter, 6q14, 6q22, 6q24, 6q25-qter, 8p12-p21, 8p21-qter, 9p21, 13q12-q14, 14q24-qter, 15q11.1-q21, and 22q13.	('p22', 'Gene', '1778', (71, 74))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('4q31.1-qter', 'Var', (82, 93))	('p11', 'Gene', '6281', (67, 70))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p11', 'Gene', (67, 70))	('6q25-qter', 'Var', (113, 122))	('Tumors', 'Disease', (0, 6))	('p21', 'Gene', (135, 138))	('p21', 'Gene', (77, 80))	('p21', 'Gene', '644914', (135, 138))	('p21', 'Gene', '644914', (77, 80))	('6q24', 'Var', (107, 111))	('13q12-q14', 'Var', (151, 160))	('22q13', 'Var', (191, 196))	('p22', 'Gene', (71, 74))	('6q14', 'Var', (95, 99))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('losses', 'NegReg', (53, 59))	('6q22', 'Var', (101, 105))	('p21', 'Gene', (146, 149))	('15q11.1-q21', 'Var', (174, 185))	('p21', 'Gene', '644914', (146, 149))	('p21', 'Gene', (129, 132))	('14q24-qter', 'Var', (162, 172))	('p21', 'Gene', '644914', (129, 132))
29256	27403364	The loss of 22q12.1-q13.33, along with several other shared losses found using a-CGH, seems to support a link between the primitive-appearing DSRCTs and mesotheliomas.	('primitive-appearing DSRCTs', 'Disease', (122, 148))	('mesotheliomas', 'Disease', 'MESH:D008654', (153, 166))	('mesotheliomas', 'Disease', (153, 166))	('loss', 'Var', (4, 8))
29259	27403364	The biphasic nature was confirmed with immunostaining, the mesothelial area marked with calretinin, WT1, D2-40, CK7, and CK5/6, while the small cell areas were positive for Golgi MyoD1, CD99, CD200, FLI1, and WT1.	('MyoD1', 'Gene', '4654', (179, 184))	('FLI1', 'Gene', (199, 203))	('WT1', 'Gene', (209, 212))	('WT1', 'Gene', '7490', (100, 103))	('CD99', 'Gene', '4267', (186, 190))	('WT1', 'Gene', '7490', (209, 212))	('FLI1', 'Gene', '2313', (199, 203))	('CK5/6', 'Gene', (121, 126))	('CK7', 'Gene', (112, 115))	('calretinin', 'Gene', (88, 98))	('D2-40', 'Var', (105, 110))	('mesothelial area', 'CPA', (59, 75))	('CK7', 'Gene', '3855', (112, 115))	('calretinin', 'Gene', '794', (88, 98))	('MyoD1', 'Gene', (179, 184))	('CD200', 'Gene', (192, 197))	('WT1', 'Gene', (100, 103))	('Golgi', 'cellular_component', 'GO:0005794', ('173', '178'))	('CD200', 'Gene', '4345', (192, 197))	('CK5/6', 'Gene', '3852', (121, 126))	('CD99', 'Gene', (186, 190))
29266	26689197	MTA1 promotes metastasis of MPM via suppression of E-cadherin Metastasis-associated gene 1(MTA1) has been identified as an oncogene in many tumors, and aberrant MTA1 expression has been linked to carcinogenesis and metastasis.	('aberrant', 'Var', (152, 160))	('carcinogenesis', 'Disease', (196, 210))	('promotes', 'PosReg', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Metastasis-associated gene 1(MTA1', 'Gene', '9112', (62, 95))	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('carcinogenesis', 'Disease', 'MESH:D063646', (196, 210))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', (140, 146))	('metastasis', 'CPA', (14, 24))	('MTA1', 'Gene', (91, 95))	('MTA1', 'Gene', (161, 165))	('suppression', 'NegReg', (36, 47))	('MTA1', 'Gene', '9112', (91, 95))	('MTA1', 'Gene', '9112', (161, 165))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('linked', 'Reg', (186, 192))	('MTA1', 'Gene', (0, 4))	('MTA1', 'Gene', '9112', (0, 4))
29269	26689197	Stable clone with knock-down of MTA1 was generated with shRNA via lentivirus technology in MPM cell lines.	('knock-down', 'Var', (18, 28))	('MTA1', 'Gene', '9112', (32, 36))	('MTA1', 'Gene', (32, 36))
29292	26689197	MSTO-211H and H2452 were origin from the patients with mesothelioma and cultured in RPMI 1640 medium supplemented with 10 % fetal bovine serum (Invitrogen, Carlsbad, CA), while 293 T were origin from human embryonic kidney cells and cultured in DMEM high glucose medium supplemented with 10 % fetal bovine serum.	('293 T', 'CellLine', 'CVCL:0063', (177, 182))	('embryonic kidney', 'Disease', (206, 222))	('mesothelioma', 'Disease', (55, 67))	('RPMI 1640 medium', 'Chemical', '-', (84, 100))	('H2452', 'Var', (14, 19))	('patients', 'Species', '9606', (41, 49))	('bovine', 'Species', '9913', (299, 305))	('embryonic kidney', 'Disease', 'MESH:D007674', (206, 222))	('DMEM', 'Chemical', '-', (245, 249))	('human', 'Species', '9606', (200, 205))	('bovine', 'Species', '9913', (130, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('high glucose', 'Phenotype', 'HP:0003074', (250, 262))	('glucose', 'Chemical', 'MESH:D005947', (255, 262))	('MSTO-211H', 'Var', (0, 9))
29300	26689197	Proteins were fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to polyvinylidene fluoride (PVDF) membrane, blocked in 4 % dry milk at room temperature for 1 hour, and immunostained with primary antibodies at 4  C over-night using anti-MTA1 (1:2000, Abcam, Cambridge, MA), anti-E-cadherin (1:1000; Abcam, Cambridge, MA), and anti-GAPDH (1:1000, Kangchen,China).	('1:1000;', 'Var', (327, 334))	('anti-E-cadherin', 'Var', (310, 325))	('cadherin', 'molecular_function', 'GO:0008014', ('317', '325'))	('MTA1', 'Gene', (273, 277))	('polyacrylamide', 'Chemical', 'MESH:C016679', (53, 67))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (30, 52))	('MTA1', 'Gene', '9112', (273, 277))	('membrane', 'cellular_component', 'GO:0016020', ('135', '143'))	('PVDF', 'Chemical', 'MESH:C024865', (129, 133))	('polyvinylidene fluoride', 'Chemical', 'MESH:C024865', (104, 127))
29309	26689197	Total RNA was extracted from MSTO-211H, MSTO-211H-shMTA1, H2452 and H2452-shMTA and reverse transcribed to cDNA.	('MTA1', 'Gene', '9112', (52, 56))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('H2452', 'Var', (58, 63))	('H2452-shMTA', 'Var', (68, 79))	('MTA1', 'Gene', (52, 56))
29324	26689197	2d and f. Moreover, We found that MTA1 silencing could not affect cell proliferation (Fig.	('cell proliferation', 'CPA', (66, 84))	('MTA1', 'Gene', (34, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('silencing', 'Var', (39, 48))	('MTA1', 'Gene', '9112', (34, 38))
29326	26689197	We found E-cadherin was up-regulated most after MTA1 silenced in both MSTO-211H and H2452 (Fig.	('E-cadherin', 'Protein', (9, 19))	('MTA1', 'Gene', '9112', (48, 52))	('silenced', 'Var', (53, 61))	('MTA1', 'Gene', (48, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('11', '19'))	('up-regulated', 'PosReg', (24, 36))
29337	26689197	Additionally, our findings indicated that MPM patients with a high expression level of MTA1 had a significantly shorter overall survival compared with patients with a low expression level of MTA1 and 10 months median survival compared with 19 months median survival after operation (p < 0.01, Fig.	('MTA1', 'Gene', (191, 195))	('high expression level', 'Var', (62, 83))	('patients', 'Species', '9606', (46, 54))	('MTA1', 'Gene', '9112', (87, 91))	('MTA1', 'Gene', '9112', (191, 195))	('patients', 'Species', '9606', (151, 159))	('overall survival', 'MPA', (120, 136))	('MTA1', 'Gene', (87, 91))	('MPM', 'Disease', (42, 45))	('shorter', 'NegReg', (112, 119))
29352	26689197	In particular, repressing the gene expression of E-cadherin could notably promote the EMT which is considered as a primary reason of tumor metastasis.	('E-cadherin', 'Protein', (49, 59))	('tumor metastasis', 'Disease', 'MESH:D009362', (133, 149))	('tumor metastasis', 'Disease', (133, 149))	('promote', 'PosReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('repressing', 'Var', (15, 25))	('gene expression', 'Var', (30, 45))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))	('EMT', 'CPA', (86, 89))
29353	26689197	According to our study, the poor prognosis of patients with high MTA1expression was correlated with E-cadherin, the very classical metastasis suppressor.	('E-cadherin', 'Protein', (100, 110))	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))	('MTA1', 'Gene', (65, 69))	('MTA1', 'Gene', '9112', (65, 69))
29376	33114048	Another important example is the combination of BRAF and MEK inhibition with dabrafenib and trametinib or vemurafenib and cobimetinib for the treatment of melanoma harboring a BRAF V600E mutation.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('men', 'Species', '9606', (147, 150))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('MEK', 'Gene', '5609', (57, 60))	('dabrafenib', 'Chemical', 'MESH:C561627', (77, 87))	('V600E', 'Var', (181, 186))	('V600E', 'Mutation', 'rs113488022', (181, 186))	('BRAF', 'Gene', '673', (176, 180))	('trametinib', 'Chemical', 'MESH:C560077', (92, 102))	('cobimetinib', 'Chemical', 'MESH:C574276', (122, 133))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('vemurafenib', 'Chemical', 'MESH:D000077484', (106, 117))	('melanoma', 'Disease', (155, 163))	('MEK', 'Gene', (57, 60))	('BRAF', 'Gene', (176, 180))
29377	33114048	For the treatment of non-small cell lung cancer (NSCLC), molecularly targeted agents are already an integral part of therapeutic algorithms, including the inhibitors of the epidermal growth factor receptor (EGFR), including erlotinib, gefitinib, and osimertinib.	('NSCLC', 'Disease', (49, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('epidermal growth factor receptor', 'Gene', (173, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('erlotinib', 'Chemical', 'MESH:D000069347', (224, 233))	('osimertinib', 'Chemical', '-', (250, 261))	('epidermal growth factor receptor', 'Gene', '1956', (173, 205))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (21, 47))	('gefitinib', 'Chemical', 'MESH:D000077156', (235, 244))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('173', '196'))	('EGFR', 'Gene', (207, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (25, 47))	('lung cancer', 'Disease', (36, 47))	('inhibitors', 'Var', (155, 165))	('men', 'Species', '9606', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('EGFR', 'Gene', '1956', (207, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
29429	33114048	In total, 397 tumor samples (71.7%) were tested with the 50-gene panel and 166 specimens (28.3%) were analyzed with the 161-gene panel.	('tumor', 'Disease', (14, 19))	('50-gene', 'Var', (57, 64))	('men', 'Species', '9606', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tested', 'Reg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
29432	33114048	The inter- and intratumoral genomic profile was heterogeneous and mutations were seen in 123 different genes tested with the 161-gene panel (see Figure 1 and Table 3).	('tumoral', 'Disease', (20, 27))	('tumoral', 'Disease', 'MESH:D009369', (20, 27))	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
29464	33114048	However, the Chi-squared test chi2 revealed, after exclusion of gender-specific cancer diseases, five different genetic mutations that are significantly more common in men than in women: CDKN2A (p = 0.04), CTNNB1 (p = 0.002), KIT (p = 0.0005), SLX4 (p = 0.034), and VHL (p = 0.046).	('CTNNB1', 'Gene', '1499', (206, 212))	('SLX4', 'Gene', '84464', (244, 248))	('women', 'Species', '9606', (180, 185))	('CDKN2A', 'Gene', (187, 193))	('CDKN2A', 'Gene', '1029', (187, 193))	('SLX4', 'Gene', (244, 248))	('VHL', 'Gene', (266, 269))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CTNNB1', 'Gene', (206, 212))	('VHL', 'Gene', '7428', (266, 269))	('KIT', 'molecular_function', 'GO:0005020', ('226', '229'))	('KIT', 'Gene', '3815', (226, 229))	('mutations', 'Var', (120, 129))	('cancer diseases', 'Disease', (80, 95))	('men', 'Species', '9606', (182, 185))	('KIT', 'Gene', (226, 229))	('cancer diseases', 'Disease', 'MESH:D009369', (80, 95))	('men', 'Species', '9606', (168, 171))
29475	33114048	Moreover, we detected a broad variety of mutations highlighting the well-known tumoral heterogeneity in cancer diseases.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer diseases', 'Disease', (104, 119))	('detected', 'Reg', (13, 21))	('tumoral', 'Disease', (79, 86))	('tumoral', 'Disease', 'MESH:D009369', (79, 86))	('cancer diseases', 'Disease', 'MESH:D009369', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
29498	33114048	H.T., M.U., R.M.M., G.W.P.	('H.T', 'Disease', 'MESH:D000848', (0, 3))	('H.T', 'Disease', (0, 3))	('M.U.', 'Var', (6, 10))
29499	33114048	performed the experiments; H.T., M.U., R.M.M., L.M., G.W.P.	('H.T', 'Disease', 'MESH:D000848', (27, 30))	('H.T', 'Disease', (27, 30))	('R.M.M.', 'Var', (39, 45))	('men', 'Species', '9606', (20, 23))
29550	32581053	The following Taqman assays have been used: IL34 (Hs01050926_m1), CSF1 (Hs00174164_m1), 18S (Hs03928990_g1), ACTB (Hs01060665_g1), CLTC (Hs00964504_m1), GAPDH (Hs02758991_g1) and TBP (Hs00427620_m1).	('CLTC', 'Gene', '1213', (131, 135))	('Hs00427620_m1', 'Var', (184, 197))	('IL34', 'Gene', '146433', (44, 48))	('GAPDH', 'Gene', '2597', (153, 158))	('CSF1', 'molecular_function', 'GO:0005011', ('66', '70'))	('Hs00174164_m1', 'Var', (72, 85))	('CLTC', 'Gene', (131, 135))	('Hs01050926_m1', 'Var', (50, 63))	('GAPDH', 'Gene', (153, 158))	('Hs02758991_g1', 'Var', (160, 173))	('ACTB', 'Gene', (109, 113))	('TBP', 'Gene', (179, 182))	('ACTB', 'Gene', '60', (109, 113))	('CSF1', 'Gene', (66, 70))	('Hs01060665_g1', 'Var', (115, 128))	('IL34', 'Gene', (44, 48))	('TBP', 'Gene', '6908', (179, 182))	('Hs03928990_g1', 'Var', (93, 106))	('CSF1', 'Gene', '1435', (66, 70))	('Hs00964504_m1', 'Var', (137, 150))
29578	32581053	Figure 1D shows that, in MPM samples, M-CSF levels were significantly higher in IL-34 positive PE compared with IL-34 negative PE.	('M-CSF', 'Gene', (38, 43))	('IL-34', 'Gene', (112, 117))	('M-CSF', 'Gene', '1435', (38, 43))	('IL-34', 'Gene', '146433', (112, 117))	('higher', 'PosReg', (70, 76))	('IL-34', 'Gene', (80, 85))	('positive', 'Var', (86, 94))	('IL-34', 'Gene', '146433', (80, 85))
29585	32581053	We found IL-34 score to be an independent prognostic factor in our MPM cohort (online supplementary figure S2), whereas histologic subtype and M-CSF did not reach significance (p=0.243 and p=0.218, respectively).	('MPM', 'Disease', (67, 70))	('IL-34', 'Gene', '146433', (9, 14))	('M-CSF', 'Gene', '1435', (143, 148))	('M-CSF', 'Gene', (143, 148))	('score', 'Var', (15, 20))	('IL-34', 'Gene', (9, 14))
29589	32581053	Moreover, CSF1 expression was associated with the infiltration of the tumor by immune cells of the monocytic lineage determined by the MCP-Counter tool on transcriptomic data (figure 2C).	('expression', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('infiltration', 'CPA', (50, 62))	('tumor', 'Disease', (70, 75))	('CSF1', 'Gene', (10, 14))	('CSF1', 'Gene', '1435', (10, 14))	('MCP', 'molecular_function', 'GO:0004298', ('135', '138'))	('CSF1', 'molecular_function', 'GO:0005011', ('10', '14'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('associated with', 'Reg', (30, 45))
29597	32581053	Interestingly, we observed that overexpression of IL34 in primary MPM cells was strongly associated with genetic alterations, consisting mainly in biallelic deletions of the CDKN2A gene and weakly with mutations in the NF2 gene, whereas CSF1 expression was independent of the mutational status (figure 3C-F).	('genetic', 'Disease', (105, 112))	('associated', 'Reg', (89, 99))	('overexpression', 'PosReg', (32, 46))	('CSF1', 'molecular_function', 'GO:0005011', ('237', '241'))	('NF2', 'Gene', (219, 222))	('IL34', 'Gene', '146433', (50, 54))	('CDKN2A', 'Gene', (174, 180))	('NF2', 'Gene', '4771', (219, 222))	('CDKN2A', 'Gene', '1029', (174, 180))	('CSF1', 'Gene', (237, 241))	('CSF1', 'Gene', '1435', (237, 241))	('biallelic', 'Var', (147, 156))	('IL34', 'Gene', (50, 54))
29598	32581053	No other significant association was found between IL34 or CSF1 expression and genetic alterations in BAP1, LATS2 or TP53 genes or with C1/C2 subtypes of the molecular classification.	('IL34', 'Gene', '146433', (51, 55))	('BAP1', 'Gene', (102, 106))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('IL34', 'Gene', (51, 55))	('CSF1', 'Gene', (59, 63))	('CSF1', 'molecular_function', 'GO:0005011', ('59', '63'))	('CSF1', 'Gene', '1435', (59, 63))	('BAP1', 'Gene', '8314', (102, 106))	('LATS2', 'Gene', (108, 113))	('LATS2', 'Gene', '26524', (108, 113))	('genetic alterations', 'Var', (79, 98))
29604	32581053	MCTSs were dissociated and cells were labeled with antibodies anti-CCR2, anti-HLA-DR, anti-CD14 and anti-CD163 to determine the M1-like or M2-like phenotype.	('CCR', 'molecular_function', 'GO:0043880', ('67', '70'))	('CD163', 'Gene', (105, 110))	('CD14', 'Gene', (91, 95))	('CCR2', 'Gene', (67, 71))	('MCTSs', 'Chemical', '-', (0, 5))	('CD14', 'Gene', '929', (91, 95))	('anti-HLA-DR', 'Var', (73, 84))	('CCR2', 'Gene', '729230', (67, 71))	('CD163', 'Gene', '9332', (105, 110))
29611	32581053	Expressions of all these macrophage markers were higher in MCTS made of Meso 34+ monocytes than in MCTS containing only Meso 34 cells (figure 4D).	('higher', 'PosReg', (49, 55))	('Meso 34+ monocytes', 'Var', (72, 90))	('MCTS', 'Chemical', '-', (99, 103))	('MCTS', 'Chemical', '-', (59, 63))	('Expressions', 'MPA', (0, 11))
29615	32581053	The profile of cytokines expressed in MCTS supernatants was similar to the one of M2 macrophages: absence of IL-12, presence of high amount of IL-6, IP-10 and presence of IL-10.	('IP-10', 'Gene', '3627', (149, 154))	('absence', 'NegReg', (98, 105))	('IL-10', 'Gene', (171, 176))	('presence', 'Reg', (159, 167))	('IL-6', 'Gene', (143, 147))	('IP-10', 'Gene', (149, 154))	('IL-6', 'Gene', '3569', (143, 147))	('IL-12', 'molecular_function', 'GO:0005143', ('109', '114'))	('presence', 'Var', (116, 124))	('IL-6', 'molecular_function', 'GO:0005138', ('143', '147'))	('IL-10', 'Gene', '3586', (171, 176))	('IL-10', 'molecular_function', 'GO:0005141', ('171', '176'))	('MCTS', 'Chemical', '-', (38, 42))
29618	32581053	Figure 5A shows that treatment with GW2580 reduced the expression of macrophage markers MAFB, CD14, CD163 and IL10 by approximately 50%.	('IL10', 'Gene', (110, 114))	('IL10', 'Gene', '3586', (110, 114))	('MAFB', 'Gene', '9935', (88, 92))	('GW2580', 'Chemical', 'MESH:C506269', (36, 42))	('CD163', 'Gene', '9332', (100, 105))	('expression', 'MPA', (55, 65))	('CD163', 'Gene', (100, 105))	('CD14', 'Gene', (94, 98))	('IL10', 'molecular_function', 'GO:0005141', ('110', '114'))	('reduced', 'NegReg', (43, 50))	('CD14', 'Gene', '929', (94, 98))	('MAFB', 'Gene', (88, 92))	('GW2580', 'Var', (36, 42))
29633	32581053	High expressions of M-CSF and presence of IL-34 in PE were associated with a shorter survival of patients with MPM.	('M-CSF', 'Gene', (20, 25))	('M-CSF', 'Gene', '1435', (20, 25))	('IL-34', 'Gene', (42, 47))	('IL-34', 'Gene', '146433', (42, 47))	('presence', 'Var', (30, 38))	('survival', 'MPA', (85, 93))	('shorter', 'NegReg', (77, 84))	('patients', 'Species', '9606', (97, 105))
29635	32581053	In primary MPM cell lines, but also in MPM cell lines established from PE of patients, we observed an overexpression of IL34 compared with normal mesothelial cells, particularly in MPM cells with an alteration of CDKN2A.	('IL34', 'Gene', (120, 124))	('alteration', 'Var', (199, 209))	('overexpression', 'PosReg', (102, 116))	('CDKN2A', 'Gene', (213, 219))	('patients', 'Species', '9606', (77, 85))	('CDKN2A', 'Gene', '1029', (213, 219))	('IL34', 'Gene', '146433', (120, 124))
29654	32581053	We observed a higher expression of IL34 in MPM cells with a biallelic deletion of CDKN2A.	('IL34', 'Gene', '146433', (35, 39))	('CDKN2A', 'Gene', (82, 88))	('expression', 'MPA', (21, 31))	('CDKN2A', 'Gene', '1029', (82, 88))	('IL34', 'Gene', (35, 39))	('biallelic deletion', 'Var', (60, 78))	('higher', 'PosReg', (14, 20))
29655	32581053	The link with the NF2 mutation status was weaker and could be due to the fact that most of NF2-mutated MPM primary cell lines also show a CDKN2A biallelic deletion.	('CDKN2A', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (138, 144))	('NF2', 'Gene', (18, 21))	('biallelic deletion', 'Var', (145, 163))	('NF2', 'Gene', (91, 94))	('NF2', 'Gene', '4771', (18, 21))	('NF2', 'Gene', '4771', (91, 94))
29656	32581053	In the chromosomal region 9p21.3, frequently deleted in MPM, the locus of the gene coding for miR31 can also be found close to the CDKN2A and CDKN2B loci.	('CDKN2B', 'Gene', (142, 148))	('CDKN2A', 'Gene', '1029', (131, 137))	('miR31', 'Gene', (94, 99))	('MPM', 'Gene', (56, 59))	('CDKN2B', 'Gene', '1030', (142, 148))	('deleted', 'Var', (45, 52))	('miR31', 'Gene', '407035', (94, 99))	('chromosomal region', 'cellular_component', 'GO:0098687', ('7', '25'))	('CDKN2A', 'Gene', (131, 137))
29659	32581053	Thus, it would be interesting to study miR-31 expression in our cells to evaluate the possible relation with IL34 expression and with the deletion of CDKN2A.	('miR-31', 'Gene', '407035', (39, 45))	('CDKN2A', 'Gene', (150, 156))	('IL34', 'Gene', '146433', (109, 113))	('CDKN2A', 'Gene', '1029', (150, 156))	('miR-31', 'Gene', (39, 45))	('deletion', 'Var', (138, 146))	('IL34', 'Gene', (109, 113))
29671	32581053	The inhibition of the cytotoxic activity of a CD8+ T cell clone by Mo-MCTS, as observed in cytotoxic assays, provides new pieces of evidence which reinforced our hypothesis.	('CD8', 'Gene', '925', (46, 49))	('cytotoxic activity', 'CPA', (22, 40))	('Mo-MCTS', 'Chemical', '-', (67, 74))	('CD8', 'Gene', (46, 49))	('Mo-MCTS', 'Var', (67, 74))	('inhibition', 'NegReg', (4, 14))
29673	32581053	Indeed, we showed that the use of GW2580, which reduced the formation of M2-like macrophages as demonstrated by the expression of specific cellular markers and cytokines, restored the cytotoxic activity of CD8+ T cells.	('expression', 'MPA', (116, 126))	('GW2580', 'Var', (34, 40))	('formation of M2-like macrophages', 'MPA', (60, 92))	('restored', 'PosReg', (171, 179))	('reduced', 'NegReg', (48, 55))	('CD8', 'Gene', (206, 209))	('CD8', 'Gene', '925', (206, 209))	('GW2580', 'Chemical', 'MESH:C506269', (34, 40))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('cytotoxic activity', 'CPA', (184, 202))
29677	32581053	Thanks to our Mo-MCTS model, which represents an intermediate and simple model to replace some in vivo experiments and to develop new anti-immunosuppressive agents, we highlighted the efficacy of blocking CSF-1R to inhibit M2 macrophage differentiation from monocyte and to restore human CD8+ effector T cell function.	('CSF-1R', 'Gene', (205, 211))	('restore', 'PosReg', (274, 281))	('blocking', 'Var', (196, 204))	('CD8', 'Gene', '925', (288, 291))	('human', 'Species', '9606', (282, 287))	('Mo-MCTS', 'Chemical', '-', (14, 21))	('inhibit', 'NegReg', (215, 222))	('CSF-1R', 'Gene', '1436', (205, 211))	('macrophage differentiation', 'biological_process', 'GO:0030225', ('226', '252'))	('M2 macrophage differentiation', 'CPA', (223, 252))	('CSF-1', 'molecular_function', 'GO:0005011', ('205', '210'))	('CD8', 'Gene', (288, 291))
29678	32581053	Moreover, inhibition of CSF-1R, rather than blocking one cytokine, could also be beneficial to inhibit the deleterious effect of IL-34 in MPM suggested by patient survival analysis and a previous study.	('IL-34', 'Gene', (129, 134))	('IL-34', 'Gene', '146433', (129, 134))	('CSF-1R', 'Gene', (24, 30))	('inhibit', 'NegReg', (95, 102))	('patient', 'Species', '9606', (155, 162))	('CSF-1R', 'Gene', '1436', (24, 30))	('CSF-1', 'molecular_function', 'GO:0005011', ('24', '29'))	('inhibition', 'Var', (10, 20))	('MPM', 'Disease', (138, 141))
29683	32581053	Thus, inhibition of CSF-1R pathway could be a promising approach to favor the antitumor T cell response in patients with MPM.	('patients', 'Species', '9606', (107, 115))	('CSF-1', 'molecular_function', 'GO:0005011', ('20', '25'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('CSF-1R', 'Gene', (20, 26))	('CSF-1R', 'Gene', '1436', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', (82, 87))	('MPM', 'Disease', (121, 124))	('favor', 'PosReg', (68, 73))
29684	32148838	Remarkable response to nivolumab in sarcomatoid malignant pleural mesothelioma with high PD-L1 We report herein a case of sarcomatoid malignant pleural mesothelioma (MPM) with high PD-L1 expression who was refractory to standard chemotherapy but had a remarkable and sustained response to nivolumab.	('MPM', 'Disease', 'MESH:C562839', (166, 169))	('MPM', 'Disease', (166, 169))	('PD-L1', 'Gene', '29126', (89, 94))	('sarcomatoid malignant pleural mesothelioma', 'Disease', (36, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (23, 32))	('sarcomatoid malignant pleural mesothelioma', 'Disease', (122, 164))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (144, 164))	('PD-L1', 'Gene', (181, 186))	('PD-L1', 'Gene', (89, 94))	('sarcomatoid malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (122, 164))	('sarcomatoid malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (36, 78))	('sarcomatoid malignant', 'Phenotype', 'HP:0100242', (122, 143))	('sarcomatoid malignant', 'Phenotype', 'HP:0100242', (36, 57))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (58, 78))	('PD-L1', 'Gene', '29126', (181, 186))	('nivolumab', 'Chemical', 'MESH:D000077594', (289, 298))	('high', 'Var', (176, 180))
29693	32148838	We report herein a case of a 78-year-old male patient diagnosed with sarcomatoid malignant pleural mesothelioma (MPM) with high PD-L1 expression who was refractory to standard chemotherapy but had a remarkable and sustained response to nivolumab.	('sarcomatoid malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (69, 111))	('patient', 'Species', '9606', (46, 53))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (91, 111))	('PD-L1', 'Gene', (128, 133))	('nivolumab', 'Chemical', 'MESH:D000077594', (236, 245))	('MPM', 'Disease', 'MESH:C562839', (113, 116))	('MPM', 'Disease', (113, 116))	('high', 'Var', (123, 127))	('sarcomatoid malignant', 'Phenotype', 'HP:0100242', (69, 90))	('PD-L1', 'Gene', '29126', (128, 133))	('sarcomatoid malignant pleural mesothelioma', 'Disease', (69, 111))
29803	27342200	NCI-H226 cells were incubated with JMAM mAbs followed by staining with existing Abs already known to bind to mesothelioma [anti-calretinin, anti-podoplanin (D2-40), anti-GLUT-1, anti-CD25 (BC96), anti-CD26 (1F7, 5F8), anti-C-ERC/mesothelin (22A31)].	('mesothelin', 'Gene', (229, 239))	('GLUT-1', 'Gene', (170, 176))	('anti-CD25', 'Var', (178, 187))	('GLUT-1', 'Gene', '6513', (170, 176))	('Abs', 'Gene', '72935', (41, 44))	('CD26', 'Gene', (201, 205))	('Abs', 'Gene', (41, 44))	('mAbs', 'Gene', '72935', (40, 44))	('Abs', 'Gene', '72935', (80, 83))	('mesothelin', 'Gene', '10232', (229, 239))	('Abs', 'Gene', (80, 83))	('calretinin', 'Gene', (128, 138))	('mesothelioma', 'Disease', (109, 121))	('CD26', 'Gene', '1803', (201, 205))	('podoplanin', 'Gene', '10630', (145, 155))	('mesothelioma', 'Disease', 'MESH:D008654', (109, 121))	('mAbs', 'Gene', (40, 44))	('NCI-H226', 'CellLine', 'CVCL:1544', (0, 8))	('calretinin', 'Gene', '794', (128, 138))	('ERC', 'cellular_component', 'GO:0055037', ('225', '228'))	('podoplanin', 'Gene', (145, 155))
29850	27342200	We also developed anti-human CD26 mAbs (clone: 1F7, 5F8) that clearly and reliably detect the denatured CD26 molecule in formalin-fixed paraffin-embedded tissue.	('mAbs', 'Gene', '72935', (34, 38))	('CD26', 'Gene', (29, 33))	('CD26', 'Gene', '1803', (29, 33))	('paraffin', 'Chemical', 'MESH:D010232', (136, 144))	('detect', 'Reg', (83, 89))	('denatured', 'Var', (94, 103))	('CD26', 'Gene', (104, 108))	('CD26', 'Gene', '1803', (104, 108))	('human', 'Species', '9606', (23, 28))	('mAbs', 'Gene', (34, 38))	('formalin', 'Chemical', 'MESH:D005557', (121, 129))
29898	26136339	Recent data have revealed that polyphenols affect different cell signalling pathways and exert their anticancer effects along the different steps of carcinogenesis.	('cell signalling pathways', 'Pathway', (60, 84))	('signalling', 'biological_process', 'GO:0023052', ('65', '75'))	('carcinogenesis', 'Disease', (149, 163))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('affect', 'Reg', (43, 49))	('polyphenols', 'Chemical', 'MESH:D059808', (31, 42))	('polyphenols', 'Var', (31, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
29900	26136339	Several in vitro and in vivo experiments have shown that Cynara scolymus exhibits choleretic, hepatoprotective, antibacterial, antinflammatory, antithrombotic and hypocolesterolemic properties.	('antithrombotic', 'CPA', (144, 158))	('antibacterial', 'MPA', (112, 125))	('hepatoprotective', 'MPA', (94, 110))	('choleretic', 'MPA', (82, 92))	('Cynara', 'Var', (57, 63))	('scolymus', 'Species', '59895', (64, 72))	('antinflammatory', 'MPA', (127, 142))	('hypocolesterolemic', 'Disease', (163, 181))
29959	26136339	Since aberrant activation of the WNT signalling pathway plays a role in mesothelioma tumorigenesis we investigated whether the treatment with the artichoke extract of MPM cell lines modulated the expression of diverse components of this pathway.	('tumor', 'Disease', (85, 90))	('activation', 'PosReg', (15, 25))	('aberrant', 'Var', (6, 14))	('WNT signalling pathway', 'Pathway', (33, 55))	('mesothelioma', 'Disease', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('signalling pathway', 'biological_process', 'GO:0007165', ('37', '55'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('modulated', 'Reg', (182, 191))
29968	26136339	This has further established that cancer is the consequence of a broad array of genetic and epigenetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('epigenetic alterations', 'Var', (92, 114))
29971	26136339	In particular considering cancer development, carcinogenesis process is multistep (that is, it results from accumulated genetic and epigenetic alterations), multipath (that is, multiple functional pathways are involved, such as self-sufficiency in growth signals, insensitivity to anti-growth signals, apoptosis evasion, limitless replicative potential, tissue invasion and metastasis and sustained angiogenesis), and multifocal (both multiclonal - e.g., field cancerization - and clonal expansion leading to intraepithelial spread).	('apoptosis', 'biological_process', 'GO:0006915', ('302', '311'))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('302', '311'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('carcinogenesis', 'Disease', (46, 60))	('multipath', 'Disease', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('self-sufficiency', 'Disease', 'MESH:D012652', (228, 244))	('angiogenesis', 'biological_process', 'GO:0001525', ('399', '411'))	('self-sufficiency', 'Disease', (228, 244))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (461, 467))	('clonal', 'Var', (481, 487))	('multipath', 'Disease', 'None', (157, 166))	('tissue invasion', 'biological_process', 'GO:0001404', ('354', '369'))	('cancer', 'Disease', 'MESH:D009369', (461, 467))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (233, 254))
29995	26136339	Interestingly artichoke leaf extracts reduced DNA damage of HMC cells upon cisplatin treatment, thereby suggesting that its co-treatment with either cisplatin or pemetrexed not only potentiates their antitumoral effects but might also confers selectivity toward tumor cells.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('DNA damage', 'MPA', (46, 56))	('reduced', 'NegReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (262, 267))	('cisplatin', 'Var', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('tumor', 'Disease', (204, 209))	('potentiates', 'PosReg', (182, 193))	('pemetrexed', 'Chemical', 'MESH:D000068437', (162, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
30073	17090323	In contrast, neither the presence of SV40 DNA in tumor samples nor a previous vaccination exposure had any detectable influence on the cancer mortality rate in neither in males (asbestos-corrected rates) nor in females.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('SV40 DNA', 'Var', (37, 45))	('cancer', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('SV40', 'Species', '1891767', (37, 41))	('tumor', 'Disease', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('asbestos', 'Chemical', 'MESH:D001194', (178, 186))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
30088	17090323	SV40 DNA was subsequently detected in human brain and bone tumors as well as lymphoma samples (reviewed in).	('bone tumor', 'Phenotype', 'HP:0010622', (54, 64))	('bone tumors', 'Phenotype', 'HP:0010622', (54, 65))	('lymphoma', 'Disease', (77, 85))	('bone tumors', 'Disease', 'MESH:D001859', (54, 65))	('lymphoma', 'Disease', 'MESH:D008223', (77, 85))	('human', 'Species', '9606', (38, 43))	('SV40 DNA', 'Var', (0, 8))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('SV40', 'Species', '1891767', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('5', '8'))	('bone tumors', 'Disease', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
30089	17090323	Intriguingly, SV40 causes the same tumor types in hamsters.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('SV40', 'Species', '1891767', (14, 18))	('SV40', 'Var', (14, 18))
30090	17090323	The most important step in the process of carcinogenesis is the inactivation of tumor suppressor p53 and members of the retinoblastoma family of proteins through the SV40 large T antigen.	('inactivation', 'Var', (64, 76))	('SV40', 'Species', '1891767', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('SV40', 'Var', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('retinoblastoma', 'Disease', (120, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))
30091	17090323	In addition, other tumor suppressor genes become methylated and are shut down.	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('methylated', 'Var', (49, 59))	('tumor', 'Disease', (19, 24))
30092	17090323	These gene modifications have not only been observed in vitro, but also in an analogous fashion in SV40-positive lymphoma samples.	('lymphoma', 'Disease', 'MESH:D008223', (113, 121))	('modifications', 'Var', (11, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('SV40', 'Species', '1891767', (99, 103))	('lymphoma', 'Disease', (113, 121))
30093	17090323	However, it is important to note that SV40 DNA was not detected in several studies of tumor samples from particular populations, whereas it was readily detectable in appropriate control samples from the USA.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('SV40 DNA', 'Var', (38, 46))	('SV40', 'Species', '1891767', (38, 42))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
30094	17090323	In particular, SV40 DNA was not detected in mesothelioma, brain tumor and bone tumor samples from Austria, Finland and Turkey, countries which apparently had never used contaminated polio vaccines.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('brain tumor', 'Phenotype', 'HP:0030692', (58, 69))	('bone tumor', 'Phenotype', 'HP:0010622', (74, 84))	('SV40', 'Species', '1891767', (15, 19))	('bone tumor', 'Disease', (74, 84))	('contaminated polio', 'Phenotype', 'HP:0020090', (169, 187))	('brain tumor', 'Disease', (58, 69))	('brain tumor', 'Disease', 'MESH:D001932', (58, 69))	('bone tumor', 'Disease', 'MESH:D001859', (74, 84))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('SV40 DNA', 'Var', (15, 23))	('Turkey', 'Species', '9103', (119, 125))	('mesothelioma', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
30102	17090323	The authors stated that these results point to the possibility that exposure to SV40 could have led to antibody responses that declined over the decades, probably due to lack of virus replication, and that SV40 seems not to be a common cause of infection in humans.	('SV40', 'Species', '1891767', (80, 84))	('antibody', 'cellular_component', 'GO:0019814', ('103', '111'))	('SV40', 'Var', (80, 84))	('antibody', 'cellular_component', 'GO:0042571', ('103', '111'))	('antibody', 'molecular_function', 'GO:0003823', ('103', '111'))	('exposure', 'Var', (68, 76))	('lack', 'NegReg', (170, 174))	('antibody', 'cellular_component', 'GO:0019815', ('103', '111'))	('SV40', 'Species', '1891767', (206, 210))	('humans', 'Species', '9606', (258, 264))	('antibody responses', 'CPA', (103, 121))
30110	17090323	All abstracts were checked for valid results on SV40 DNA in human tissue samples or for information about past poliomyelitis virus vaccination programs in European countries.	('poliomyelitis virus vaccination', 'Disease', (111, 142))	('SV40', 'Var', (48, 52))	('poliomyelitis virus vaccination', 'Disease', 'MESH:D011051', (111, 142))	('SV40', 'Species', '1891767', (48, 52))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('human', 'Species', '9606', (60, 65))
30137	17090323	However, whether SV40 DNA had been detected in tumor samples from a particular country or not, had no effect on pleural cancer mortality rates at either cut-off level, neither in males (asbestos-corrected rates) nor in females (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('SV40 DNA', 'Var', (17, 25))	('asbestos', 'Chemical', 'MESH:D001194', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('SV40', 'Species', '1891767', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('pleural cancer', 'Disease', (112, 126))	('pleural cancer', 'Disease', 'MESH:D010995', (112, 126))	('tumor', 'Disease', (47, 52))
30142	17090323	In males, the mean asbestos-corrected mortality rate was 0.77/100 000 (n = 7) in countries with SV40-contaminated vaccines and 0.83/100 000 (n = 3) in countries without SV40-contaminated vaccines (P = 0.700).	('SV40', 'Species', '1891767', (169, 173))	('SV40', 'Species', '1891767', (96, 100))	('SV40-contaminated', 'Var', (96, 113))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('asbestos-corrected mortality', 'Disease', (19, 47))
30163	17090323	Incidentally, these were the same countries in which molecular genetic studies failed to detect SV40 DNA in a representative large number of tumor samples.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('SV40 DNA', 'Var', (96, 104))	('tumor', 'Disease', (141, 146))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('SV40', 'Species', '1891767', (96, 100))
30199	17090323	However, the results of this study, the negative SV40 DNA reports, and the serologic data argue against a major role of SV40 in mesothelioma carcinogenesis.	('mesothelioma carcinogenesis', 'Disease', (128, 155))	('SV40', 'Species', '1891767', (120, 124))	('SV40', 'Var', (120, 124))	('SV40', 'Species', '1891767', (49, 53))	('mesothelioma carcinogenesis', 'Disease', 'MESH:D063646', (128, 155))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
30205	32080953	Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity.	('anthophyllite', 'Chemical', 'MESH:C025965', (43, 56))	('associated', 'Reg', (78, 88))	('talc', 'Chemical', 'MESH:D013627', (140, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('carcinogenic', 'Disease', 'MESH:D063646', (182, 194))	('carcinogenic', 'Disease', (182, 194))	('anthophyllite', 'Var', (43, 56))	('tremolite', 'Chemical', 'MESH:C005846', (112, 121))	('mesothelioma', 'Disease', (94, 106))
30304	32080953	After incubation with tremolite for 24 hours, the release of intracellular LDH was increased significantly in the MeT5A cells but not in the RAW264.7 cells, whereas anthophyllite did not induce an increase in LDH (Figure 4E,F).	('RAW264.7', 'CellLine', 'CVCL:0493', (141, 149))	('increased', 'PosReg', (83, 92))	('MeT5A', 'Var', (114, 119))	('anthophyllite', 'Chemical', 'MESH:C025965', (165, 178))	('tremolite', 'Chemical', 'MESH:C005846', (22, 31))	('intracellular', 'cellular_component', 'GO:0005622', ('61', '74'))	('release of intracellular LDH', 'MPA', (50, 78))
30308	32080953	Anthophyllite caused granulomatous inflammation based on foreign body reaction, leading to focal fibrosis of the serosal surface in a limited manner (Figure 5).	('Anthophyllite', 'Chemical', 'MESH:C025965', (0, 13))	('granulomatous inflammation', 'Disease', (21, 47))	('inflammation', 'biological_process', 'GO:0006954', ('35', '47'))	('fibrosis', 'Disease', 'MESH:D005355', (97, 105))	('fibrosis', 'Disease', (97, 105))	('granulomatous inflammation', 'Phenotype', 'HP:0002955', (21, 47))	('granulomatous inflammation', 'Disease', 'MESH:D007249', (21, 47))	('Anthophyllite', 'Var', (0, 13))
30336	32080953	32  Taken together, these findings indicate that length of carcinogenic fiber might start from less than 4 mum, because Stanton's hypothesis was established on the basis of the correlation coefficients of tumor probability and the following 5 fiber length categories: 0.1-1, 1-4, 4-8, 8-64, and longer than 64 mum.	('mum', 'Gene', '56925', (310, 313))	('mum', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mum', 'Gene', (310, 313))	('carcinogenic', 'Disease', 'MESH:D063646', (59, 71))	('0.1-1', 'Var', (268, 273))	('carcinogenic', 'Disease', (59, 71))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mum', 'Gene', '56925', (107, 110))
30355	32080953	40  The homozygous deletion of Cdkn2a/2b was not observed in the epithelioid subtype (EM) (0/6), but it was observed in the sarcomatoid subtype (SM) (4/5) in our study 36  and EM (1/5) in another study 41  when iron saccharate was used for rat MM carcinogenesis.	('iron saccharate', 'Chemical', 'MESH:D000077605', (211, 226))	('sarcomatoid', 'Disease', (124, 135))	('deletion', 'Var', (19, 27))	('rat', 'Species', '10116', (222, 225))	('MM carcinogenesis', 'Disease', (244, 261))	('sarcomatoid', 'Disease', 'MESH:C538614', (124, 135))	('MM carcinogenesis', 'Disease', 'MESH:D063646', (244, 261))	('Cdkn2a', 'Gene', '25163', (31, 37))	('Cdkn2a', 'Gene', (31, 37))	('rat', 'Species', '10116', (240, 243))
30357	32080953	42  Here, the coexistence of homozygous (5/8) or hemizygous deletions (3/8) of Cdkn2a/2b loci were observed in the cases of tremolite-induced MM (Figure 7A), as they were after MWCNT injections, 20  whereas the majority of the genetic disruption to Cdkn2a/2b was homozygous deletion by crocidolite (8/9), amosite (9/9), and chrysotile (8/9).	('genetic disruption', 'Var', (227, 245))	('tremolite', 'Chemical', 'MESH:C005846', (124, 133))	('Cdkn2a', 'Gene', '25163', (249, 255))	('deletion', 'Var', (274, 282))	('amosite', 'Chemical', 'MESH:D017639', (305, 312))	('Cdkn2a', 'Gene', (249, 255))	('MWCNT', 'Chemical', '-', (177, 182))	('crocidolite', 'Chemical', 'MESH:D017638', (286, 297))	('Cdkn2a', 'Gene', '25163', (79, 85))	('Cdkn2a', 'Gene', (79, 85))
30365	27748850	Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer.	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('presence', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('associated', 'Reg', (116, 126))
30386	27748850	There is also increasing evidence to indicate that specific non-ionising radiation may be linked to the risk of cancer caused by lethal mutations.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lethal mutations', 'Var', (129, 145))	('cancer', 'Disease', (112, 118))
30400	27748850	It is widely accepted that benzene can cause hematological diseases, such as acute myeloid leukemia, acute and chronic lymphocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma and aplastic anemia.	('myeloma and aplastic anemia', 'Disease', 'MESH:D000741', (174, 201))	('benzene', 'Chemical', 'MESH:D001554', (27, 34))	('hematological diseases', 'Disease', 'MESH:D006402', (45, 67))	('cause', 'Reg', (39, 44))	('acute myeloid leukemia', 'Disease', (77, 99))	('hematological diseases', 'Disease', (45, 67))	('benzene', 'Var', (27, 34))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (119, 139))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (141, 163))	('anemia', 'Phenotype', 'HP:0001903', (195, 201))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (145, 163))	('aplastic anemia', 'Phenotype', 'HP:0001915', (186, 201))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (111, 139))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (83, 99))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (77, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	("non-Hodgkin's lymphoma", 'Disease', (141, 163))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (77, 99))	('lymphocytic leukemia', 'Disease', (119, 139))	('multiple myeloma', 'Phenotype', 'HP:0006775', (165, 181))
30401	27748850	Apart from the fact that benzene can cause cancer of blood components, in animal studies, benzene has also been reported to induce mammary cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('induce', 'Reg', (124, 130))	('benzene', 'Var', (25, 32))	('benzene', 'Chemical', 'MESH:D001554', (25, 32))	('benzene', 'Chemical', 'MESH:D001554', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('benzene', 'Var', (90, 97))	('cause', 'Reg', (37, 42))	('cancer', 'Disease', (139, 145))
30407	27748850	ROS can also affect critical kinases and signal transduction pathways [mitogen-activated protein kinse (MAPK) family, p38-MAPK, nuclear factor (NF)-kappaB and signal transducer and activator of transcription 3 (STAT3)], involved both in cellular proliferation and apoptosis.	('ROS', 'Var', (0, 3))	('signal transduction', 'biological_process', 'GO:0007165', ('41', '60'))	('signal transducer and activator of transcription 3', 'Gene', '6774', (159, 209))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('critical kinases', 'Pathway', (20, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('STAT3', 'Gene', '6774', (211, 216))	('p38', 'Gene', (118, 121))	('mitogen-activated protein', 'Pathway', (71, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('STAT3', 'Gene', (211, 216))	('transcription', 'biological_process', 'GO:0006351', ('194', '207'))	('signal transduction pathways', 'Pathway', (41, 69))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('p38', 'Gene', '1432', (118, 121))	('affect', 'Reg', (13, 19))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
30415	27748850	There also data to suggest an association between exposure to benzene, epigenetic alterations and an increased susceptibility to develop several diseases, such as cancer and inflammatory diseases.	('inflammatory diseases', 'Disease', 'MESH:D007249', (174, 195))	('epigenetic alterations', 'Var', (71, 93))	('benzene', 'Chemical', 'MESH:D001554', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('inflammatory diseases', 'Disease', (174, 195))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
30419	27748850	Further elucidation of the mechanisms through which benzene alters gene expression is required in order to better comprehend the toxic potential of this pollutant and to identify more appropriate preventative measures, particularly for occupationally-exposed subjects.	('alters', 'Reg', (60, 66))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('benzene', 'Chemical', 'MESH:D001554', (52, 59))	('benzene', 'Var', (52, 59))	('gene expression', 'MPA', (67, 82))
30427	27748850	These modifications can alter cancer immunosurveillance and can compromise any of the 3 Es of cancer immunoediting: elimination, equilibrium and escape.	('modifications', 'Var', (6, 19))	('equilibrium', 'CPA', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('elimination', 'CPA', (116, 127))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('compromise', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('alter', 'Reg', (24, 29))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
30428	27748850	Moreover, pesticides may promote cancerogenesisby, inducing innate immune dysfunctions, leading to chronic inflammation.	('inflammation', 'Disease', (107, 119))	('leading to', 'Reg', (88, 98))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('innate immune dysfunctions', 'MPA', (60, 86))	('inducing', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('promote', 'PosReg', (25, 32))	('inflammation', 'biological_process', 'GO:0006954', ('107', '119'))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('pesticides', 'Var', (10, 20))
30440	27748850	It has also been observed that organochlorine pesticides possess carcinogenicity and can induce liver cancer.	('induce', 'Reg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('liver cancer', 'Phenotype', 'HP:0002896', (96, 108))	('liver cancer', 'Disease', 'MESH:D006528', (96, 108))	('liver cancer', 'Disease', (96, 108))	('organochlorine', 'Chemical', 'MESH:D006843', (31, 45))	('carcinogenic', 'Disease', 'MESH:D063646', (65, 77))	('carcinogenic', 'Disease', (65, 77))	('organochlorine pesticides', 'Var', (31, 56))
30480	27748850	It has also been demonstrated that low levels of p27 are associated with stathmin upregulation, determining an aggressive phenotype of tumor cells.	('stathmin', 'Gene', '3925', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('stathmin', 'Gene', (73, 81))	('p27', 'Gene', '3429', (49, 52))	('tumor', 'Disease', (135, 140))	('p27', 'Gene', (49, 52))	('upregulation', 'PosReg', (82, 94))	('low levels', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
30501	26860323	EBRT increased the risk of mesothelioma (any site; HR 1.34, 95% CI 1.04-1.77).	('EBRT', 'Chemical', '-', (0, 4))	('EBRT', 'Var', (0, 4))	('mesothelioma', 'Disease', (27, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))
30566	26860323	We observed an increased risk of mesothelioma in any site among EBRT patients compared to nonirradiated subjects (fully adjusted HR = 1.34, 95% CI 1.04-1.74) and the estimate was higher after a minimum latency period of 10 years (fully adjusted HR = 1.58, 95% CI 1.10-2.26).	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('EBRT', 'Chemical', '-', (64, 68))	('patients', 'Species', '9606', (69, 77))	('EBRT', 'Var', (64, 68))	('mesothelioma', 'Disease', (33, 45))
30576	26860323	Our analysis demonstrated that EBRT is a risk factor for mesothelioma.	('EBRT', 'Chemical', '-', (31, 35))	('mesothelioma', 'Disease', (57, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('EBRT', 'Var', (31, 35))
30820	25553247	Patients with NSCLC, SCLC or mesothelioma, who were suitable for platinum-based chemotherapy, were eligible for inclusion into the study if they fulfilled the following criteria: age>18 years, histologically or cytologically confirmed NSCLC, SCLC or mesothelioma; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2; adequate organ function defined as an absolute neutrophil count >1.5x109/L, white cell count >3x109/L, platelet count >100x109/L, serum creatinine <=1.25 upper level of normal, creatinine clearance >50 mL/min (EDTA) or >60 mL/min (Cockroft and Gault formula) for cisplatin or >40 mL/min for carboplatin; estimated life expectancy of at least 12 weeks.	('mesothelioma', 'Disease', 'MESH:D008654', (250, 262))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('Oncology', 'Phenotype', 'HP:0002664', (287, 295))	('SCLC', 'Gene', '7864', (15, 19))	('SCLC', 'Gene', (15, 19))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('SCLC', 'Gene', '7864', (21, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (604, 613))	('SCLC', 'Gene', (21, 25))	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('NSCLC', 'Disease', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('NSCLC', 'Disease', (235, 240))	('SCLC', 'Gene', (236, 240))	('SCLC', 'Gene', '7864', (236, 240))	('>100x109/L', 'Var', (459, 469))	('SCLC', 'Gene', '7864', (242, 246))	('SCLC', 'Gene', (242, 246))	('creatinine clearance', 'MPA', (518, 538))	('carboplatin', 'Chemical', 'MESH:D016190', (632, 643))	('mesothelioma', 'Disease', (250, 262))	('mesothelioma', 'Disease', (29, 41))
30959	24567297	H28 cells showed a significant increase in apoptosis and death when treated with MSCTRAIL compared with either rTRAIL (3.6+-0.1% vs 11.3+-0.7%, p=0.007) or inactivated MSCTRAIL (3.4+-0.1% vs 11.3+-0.7%, p=0.001) (figure 2A,D).	('apoptosis', 'CPA', (43, 52))	('rTRAIL', 'Gene', (111, 117))	('rTRAIL', 'Gene', '246775', (111, 117))	('MSCTRAIL', 'Chemical', '-', (81, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('death', 'CPA', (57, 62))	('MSCTRAIL', 'Var', (81, 89))	('MSCTRAIL', 'Chemical', '-', (168, 176))
30961	24567297	In Met5A, there was no significant increase in apoptosis and death when treated with either rTRAIL or MSCTRAIL compared with inactivated MSCTRAIL (1.5+-0.2% and 1.9+-1.1%, respectively, vs 0.8+-0.05%, p=0.283 and p=0.285, respectively) (figure 2C,D).	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('rTRAIL', 'Gene', (92, 98))	('apoptosis', 'CPA', (47, 56))	('MSCTRAIL', 'Chemical', '-', (137, 145))	('MSCTRAIL', 'Chemical', '-', (102, 110))	('rTRAIL', 'Gene', '246775', (92, 98))	('MSCTRAIL', 'Var', (102, 110))
30962	24567297	ONE58, JU77, H2052 and LO68 were also tested and were sensitive to MSCTRAIL (see online supplementary Fig S2A).	('LO68', 'Var', (23, 27))	('JU77', 'Var', (7, 11))	('MSCTRAIL', 'Chemical', '-', (67, 75))	('H2052', 'Var', (13, 18))
30972	24567297	Immunofluorescence confirmed that DiI-labelled MSCs were located within the tumour stroma when delivered both intrapleurally and intravenously (figure 4G-J).	('DiI-labelled', 'Var', (34, 46))	('MSCs', 'molecular_function', 'GO:0043854', ('47', '51'))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('pleural', 'Disease', 'MESH:D010995', (115, 122))	('tumour stroma', 'Disease', (76, 89))	('tumour stroma', 'Disease', 'MESH:D009369', (76, 89))	('pleural', 'Disease', (115, 122))	('DiI', 'Chemical', 'MESH:C024286', (34, 37))
30983	24567297	There was a significant difference in signal 24 h post-MSC injection (p=0.0125; figure 6B), which was maintained throughout the imaging period, suggesting that MSCs incorporate into tumours in greater numbers when delivered intravenously compared with intrapleurally.	('pleural', 'Disease', 'MESH:D010995', (257, 264))	('MSCs', 'Var', (160, 164))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('MSCs', 'molecular_function', 'GO:0043854', ('160', '164'))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('pleural', 'Disease', (257, 264))	('tumours', 'Disease', 'MESH:D009369', (182, 189))	('tumours', 'Disease', (182, 189))
30998	24567297	MSCTRAIL is known to eliminate or reduce tumour growth in other in vivo cancer models,   but has not been assessed in MPM.	('MSCTRAIL', 'Var', (0, 8))	('tumour growth', 'Disease', (41, 54))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour growth', 'Disease', 'MESH:D006130', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MPM', 'Chemical', '-', (118, 121))	('reduce', 'NegReg', (34, 40))	('MSCTRAIL', 'Chemical', '-', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('eliminate', 'NegReg', (21, 30))	('cancer', 'Disease', (72, 78))
31034	32846277	The surgical Peritoneal carcinomatosis Index (PCI) was 6 (Lesion Size score (LS)- 3 in omentum and LS-2 in pouch of douglas, LS-1 in right paracolic gutter) and the adjacent structures- bowel, rectum and bladder were free of tumor.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('surgical Peritoneal carcinomatosis', 'Phenotype', 'HP:0030406', (4, 38))	('Peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (13, 38))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('LS-2', 'Gene', '3053', (99, 103))	('Peritoneal carcinomatosis', 'Disease', (13, 38))	('LS-2', 'Gene', (99, 103))	('LS-1', 'Var', (125, 129))
31075	32283709	In addition, pDNA induces innate immune responses when it contains CpG motifs in its sequence.	('CpG motifs', 'Var', (67, 77))	('innate', 'CPA', (26, 32))	('induces', 'Reg', (18, 25))	('C', 'Chemical', 'MESH:D003596', (67, 68))	('N', 'Chemical', 'MESH:D009584', (15, 16))
31092	32283709	To evaluate the in vivo gene silencing effect of DNAs; including pDNA, dsDNA and iRed, cationic liposomes were used as delivery vehicles to increase the stability of loaded DNAs and to enhance internalization into cells.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('gene', 'Var', (24, 28))	('enhance', 'PosReg', (185, 192))	('internalization', 'MPA', (193, 208))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('stability', 'MPA', (153, 162))	('increase', 'PosReg', (140, 148))	('gene silencing', 'biological_process', 'GO:0016458', ('24', '38'))
31146	32283709	The rank order of in vitro shRNA expression induced by these DNAs was also highly correlated to their in vivo gene-silencing (Figure 3b).	('shRNA', 'Gene', (27, 32))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('DNAs', 'Var', (61, 65))	('gene-silencing', 'biological_process', 'GO:0016458', ('110', '124'))
31187	32283709	For in vivo imaging, the mice were intraperitoneally injected with 100 muL of 7.5 mg/mL D-luciferin and were subsequently anesthetized using isoflurane inhalation.	('muL', 'Gene', (71, 74))	('mice', 'Species', '10090', (25, 29))	('D-luciferin', 'Chemical', 'MESH:C532924', (88, 99))	('muL', 'Gene', '68729', (71, 74))	('D-luciferin', 'Var', (88, 99))	('isoflurane', 'Chemical', 'MESH:D007530', (141, 151))
31238	31963601	Thus, the annual number of MPM deaths in the period 1970-2002 was estimated by applying a correction factor to the number of deaths for pleural cancers (ICD codes: VIII revision: 163.0-163.0; IX revision: 163.0-163.9; X revision: C38.4, C45.0, C45.9) recorded in each year, as proposed by Ferrante and colleagues.	('C38.4', 'Var', (230, 235))	('VIII', 'Gene', '1351', (164, 168))	('VIII', 'Gene', (164, 168))	('deaths for pleural cancers', 'Disease', 'MESH:D003643', (125, 151))	('MPM', 'Disease', (27, 30))	('death', 'Disease', 'MESH:D003643', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('death', 'Disease', 'MESH:D003643', (31, 36))	('MPM', 'Disease', 'MESH:C562839', (27, 30))	('death', 'Disease', (31, 36))	('death', 'Disease', (125, 130))	('deaths for pleural cancers', 'Disease', (125, 151))
31319	30111295	First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies.	('hamartoma', 'Phenotype', 'HP:0010566', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patient', 'Species', '9606', (89, 96))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (31, 54))	('Phosphatase', 'molecular_function', 'GO:0016791', ('280', '291'))	('Phosphatase and Tensin homolog', 'cellular_component', 'GO:1990455', ('280', '310'))	('PTEN-hamartoma', 'Phenotype', 'HP:0004390', (208, 222))	('caused by', 'Reg', (248, 257))	('PHTS', 'Gene', '116372', (239, 243))	('PTEN', 'Gene', (113, 117))	('malignancies', 'Disease', 'MESH:D009369', (372, 384))	('PTEN-hamartoma-tumor-syndrome', 'Disease', (208, 237))	('PTEN', 'Gene', (312, 316))	('malignancies', 'Disease', (372, 384))	('PTEN', 'Gene', (208, 212))	('men', 'Species', '9606', (348, 351))	('mutation', 'Var', (118, 126))	('PTEN', 'Gene', '5728', (113, 117))	('PTEN', 'Gene', '5728', (312, 316))	('malignant peritoneal mesothelioma and oral verrucous carcinoma', 'Disease', 'MESH:C562839', (21, 83))	('PHTS', 'Gene', (239, 243))	('PTEN-hamartoma-tumor-syndrome', 'Disease', 'MESH:D006223', (208, 237))	('PTEN', 'Gene', '5728', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))
31320	30111295	Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('implicated', 'Reg', (33, 43))	('verrucous carcinomas', 'Disease', (115, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (65, 88))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('malignant mesotheliomas', 'Disease', (65, 88))	('verrucous carcinomas', 'Disease', 'MESH:D018289', (115, 135))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (65, 88))	('mutations', 'Var', (13, 22))
31324	30111295	The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion.	('deletion', 'Var', (80, 88))	('PHTS', 'Gene', (26, 30))	('PHTS', 'Gene', '116372', (26, 30))	('PTEN', 'Gene', (75, 79))	('PTEN', 'Gene', '5728', (75, 79))
31330	30111295	The PTEN-hamartoma-tumor-syndrome (PHTS) is a cancer predisposition syndrome with autosomal dominant inheritance, caused by mutations in the PTEN (phosphatase and tensin homolog) tumor suppressor gene.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('PTEN', 'Gene', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('phosphatase', 'molecular_function', 'GO:0016791', ('147', '158'))	('tumor', 'Disease', (19, 24))	('PTEN', 'Gene', (4, 8))	('PHTS', 'Gene', '116372', (35, 39))	('caused by', 'Reg', (114, 123))	('PTEN', 'Gene', '5728', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PTEN-hamartoma-tumor-syndrome', 'Disease', 'MESH:D006223', (4, 33))	('PTEN', 'Gene', '5728', (4, 8))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('147', '177'))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('hamartoma', 'Phenotype', 'HP:0010566', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PHTS', 'Gene', (35, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('mutations', 'Var', (124, 133))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('PTEN-hamartoma', 'Phenotype', 'HP:0004390', (4, 18))	('PTEN-hamartoma-tumor-syndrome', 'Disease', (4, 33))	('tumor', 'Disease', (179, 184))
31333	30111295	Mutations in PTEN impair its function and result in the stimulation of PI3K-AKT signaling, whereas functional PTEN dephosphorylates phosphatidyl-inositolphosphates that inhibit MAP kinase signaling and promote Ca2+ mediated apoptosis.	('PTEN', 'Gene', '5728', (110, 114))	('AKT', 'Gene', '207', (76, 79))	('Ca2+', 'Chemical', 'MESH:D000069285', (210, 214))	('AKT signaling', 'biological_process', 'GO:0043491', ('76', '89'))	('PTEN', 'Gene', '5728', (13, 17))	('Ca2+ mediated apoptosis', 'CPA', (210, 233))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('MAP kinase signaling', 'Pathway', (177, 197))	('Mutations', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('stimulation', 'PosReg', (56, 67))	('MAP', 'molecular_function', 'GO:0004239', ('177', '180'))	('AKT', 'Gene', (76, 79))	('function', 'MPA', (29, 37))	('PTEN', 'Gene', (110, 114))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))	('inhibit', 'NegReg', (169, 176))	('phosphatidyl-inositolphosphates', 'Chemical', 'MESH:D018129', (132, 163))	('promote', 'PosReg', (202, 209))	('impair', 'NegReg', (18, 24))	('PTEN', 'Gene', (13, 17))
31334	30111295	Accordingly, PTEN germline mutations predispose to the development of different cancers and coincide with a highly increased life-time risk for specific malignancies.	('men', 'Species', '9606', (62, 65))	('predispose to', 'Reg', (37, 50))	('malignancies', 'Disease', (153, 165))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('germline', 'Var', (18, 26))	('PTEN', 'Gene', (13, 17))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('PTEN', 'Gene', '5728', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
31344	30111295	Somatic mutations in PTEN have been implicated in the emergence of many different tumor types including pleural mesothelioma, where loss of PTEN was described as a frequent event and associated with a worse prognosis.	('PTEN', 'Gene', '5728', (21, 25))	('loss', 'Var', (132, 136))	('implicated', 'Reg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (104, 124))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (104, 124))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PTEN', 'Gene', (140, 144))	('PTEN', 'Gene', (21, 25))	('tumor', 'Disease', (82, 87))	('pleural mesothelioma', 'Disease', (104, 124))	('PTEN', 'Gene', '5728', (140, 144))
31370	30111295	In this way, we detected various mutations including LRP1B (NM_018557.2:c.2623G > A), EPHA7 (NM_004440.3:c.2812G > A), JAK2 (NM_001322194.1:c.614 + 20C > T), NF1 (NM_001042492.2:c.5764C > T) and one truncating variant in PTEN (NM_001304717.2:c.907C > T) in the VC.	('JAK2', 'Gene', '3717', (119, 123))	('NM_001304717.2:c.907C > T', 'Var', (227, 252))	('PTEN', 'Gene', '5728', (221, 225))	('NF1', 'Gene', (158, 161))	('EPHA7', 'Gene', (86, 91))	('JAK', 'molecular_function', 'GO:0004713', ('119', '122'))	('LRP1B', 'Gene', (53, 58))	('NM_001042492.2', 'Var', (163, 177))	('20C > T', 'Var', (148, 155))	('JAK2', 'Gene', (119, 123))	('NM_001322194.1', 'Var', (125, 139))	('EPHA7', 'Gene', '2045', (86, 91))	('NM_004440.3:c.2812G > A', 'Mutation', 'c.2812G>A', (93, 116))	('NM_018557.2:c.2623G > A', 'Mutation', 'rs768074082', (60, 83))	('NM_001304717.2:c.907C > T', 'Mutation', 'rs121909224', (227, 252))	('LRP1B', 'Gene', '53353', (53, 58))	('NM_001042492.2:c.5764C > T', 'Mutation', 'c.5764C>T', (163, 189))	('PTEN', 'Gene', (221, 225))	('NF1', 'Gene', '4763', (158, 161))	('20C > T', 'SUBSTITUTION', 'None', (148, 155))	('NM_004440.3', 'Var', (93, 104))
31371	30111295	The genetic profile of the thyroid carcinoma revealed two further classical driver mutations, namely KMT2D (NM_003482.3:c.6235-6dupC) and TP53 (NM_000546.5:c.626_627delGA), confirming the diagnosis on a molecular level.	('thyroid carcinoma', 'Disease', (27, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('KMT2D', 'Gene', (101, 106))	('KMT2D', 'Gene', '8085', (101, 106))	('TP53', 'Gene', '7157', (138, 142))	('NM_003482.3:c.6235-6dupC', 'Var', (108, 132))	('NM_000546.5:c.626_627delGA', 'Var', (144, 170))	('TP53', 'Gene', (138, 142))	('NM_003482.3:c.6235-6dupC', 'Mutation', 'c.6235-6dupC', (108, 132))	('c.626_627delGA', 'Var', (156, 170))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (27, 44))	('NM_000546.5:c.626_627delGA', 'Mutation', 'rs1057517840', (144, 170))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (27, 44))
31375	30111295	With regard to the PTEN deletion and its downstream effects, we have analyzed all three tumors by immunohistochemistry (Fig.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('deletion', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
31390	30111295	Since both BAP1 and PTEN inhibit apoptosis in a similar way, increasing the likelihood for pre-malignant cells to survive, it is tempting to speculate that also PTEN mutations may contribute to mesothelioma development in carriers of PTEN mutations, as demonstrated in animal models carrying germline BAP1 mutations with even minimal exposure to asbestos.	('pre', 'molecular_function', 'GO:0003904', ('91', '94'))	('mutations', 'Var', (239, 248))	('BAP1', 'Gene', (11, 15))	('BAP1', 'Gene', '8314', (301, 305))	('mesothelioma', 'Disease', (194, 206))	('asbestos', 'Chemical', 'MESH:D001194', (346, 354))	('PTEN', 'Gene', (234, 238))	('PTEN', 'Gene', (20, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('mutations', 'Var', (166, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('PTEN', 'Gene', (161, 165))	('PTEN', 'Gene', '5728', (234, 238))	('PTEN', 'Gene', '5728', (20, 24))	('BAP1', 'Gene', (301, 305))	('men', 'Species', '9606', (214, 217))	('PTEN', 'Gene', '5728', (161, 165))	('BAP1', 'Gene', '8314', (11, 15))	('contribute', 'Reg', (180, 190))
31397	30111295	Assessing oncogenic somatic mutations in the different tumors, we detected several driver mutations in the VC including JAK2, NF1 and PTEN.	('JAK', 'molecular_function', 'GO:0004713', ('120', '123'))	('mutations', 'Var', (90, 99))	('JAK2', 'Gene', '3717', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('JAK2', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('NF1', 'Gene', (126, 129))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('NF1', 'Gene', '4763', (126, 129))	('PTEN', 'Gene', (134, 138))	('PTEN', 'Gene', '5728', (134, 138))
31399	30111295	We identified also other established driver mutations in the thyroid carcinoma, whereas the analysis of the MPM was unrevealing.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (61, 78))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (61, 78))	('mutations', 'Var', (44, 53))	('thyroid carcinoma', 'Disease', (61, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
31412	32560575	Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described.	('Genetic alterations', 'Var', (0, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('chromatin', 'cellular_component', 'GO:0000785', ('58', '67'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Disease', (23, 28))	('hypoxia', 'Disease', (87, 94))
31413	32560575	Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies.	('SNPs', 'Var', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('promote', 'PosReg', (83, 90))	('DNA', 'Gene', (171, 174))	('detoxification', 'biological_process', 'GO:0098754', ('194', '208'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('malignancies', 'Disease', 'MESH:D009369', (258, 270))	('tumor', 'Disease', (94, 99))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('malignancies', 'Disease', (258, 270))	('interaction', 'Interaction', (140, 151))	('asbestos', 'Chemical', 'MESH:D001194', (126, 134))	('DNA repair', 'biological_process', 'GO:0006281', ('171', '181'))
31414	32560575	The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('mutations', 'Var', (32, 41))	('malignancies', 'Disease', (141, 153))
31431	32560575	The functional roles of BAP1 are partially through its deubiquitinase activity and synergy with other proteins, such as HCFC1, YY1, OGT, ASXL1/2 and FOXK1/2, but the impact of the distinct BAP1 mutations on the function of these complexes is not fully understood.	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('55', '78'))	('ASXL1/2', 'Gene', (137, 144))	('synergy', 'MPA', (83, 90))	('OGT', 'Gene', (132, 135))	('BAP1', 'Gene', '8314', (189, 193))	('OGT', 'Gene', '8473', (132, 135))	('HCFC1', 'Gene', '3054', (120, 125))	('YY1', 'Gene', '7528', (127, 130))	('BAP1', 'Gene', (24, 28))	('ASXL1/2', 'Gene', '171023;55252', (137, 144))	('YY1', 'Gene', (127, 130))	('HCFC1', 'Gene', (120, 125))	('BAP1', 'Gene', (189, 193))	('deubiquitinase activity', 'MPA', (55, 78))	('FOXK1/2', 'Gene', (149, 156))	('FOXK1/2', 'Gene', '221937;3607', (149, 156))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('55', '78'))	('mutations', 'Var', (194, 203))	('BAP1', 'Gene', '8314', (24, 28))
31432	32560575	Germline BAP1 mutations underlie the BAP1 tumor predisposition syndrome, associated with uveal (UM) and cutaneous melanoma (CM), MM, renal cell carcinoma (RCC), non-melanoma skin cancer, meningioma and cholangiocarcinoma as well as other cancers (Figure 2).	('RCC', 'Disease', (155, 158))	('meningioma', 'Phenotype', 'HP:0002858', (187, 197))	('cutaneous melanoma', 'Disease', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('associated', 'Reg', (73, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('melanoma skin cancer', 'Disease', (165, 185))	('melanoma skin cancer', 'Disease', 'MESH:D012878', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('BAP1', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('uveal', 'Disease', (89, 94))	('cancers', 'Disease', (238, 245))	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('BAP1', 'Gene', '8314', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (133, 153))	('mutations', 'Var', (14, 23))	('meningioma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (187, 220))	('CM', 'Phenotype', 'HP:0012056', (124, 126))	('BAP1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('skin cancer', 'Phenotype', 'HP:0008069', (174, 185))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('renal cell carcinoma', 'Disease', (133, 153))	('BAP1', 'Gene', '8314', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
31433	32560575	BAP1 genetic alterations appear typically with one mutant allele in all cells, while the somatic inactivation of the second allele results in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('results in', 'Reg', (131, 141))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (142, 147))	('genetic alterations', 'Var', (5, 24))	('inactivation', 'Var', (97, 109))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
31434	32560575	The gene-environment interaction is suspected to play an important role in cancer susceptibility for BAP1 mutation carriers.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('BAP1', 'Gene', '8314', (101, 105))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (106, 114))	('BAP1', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
31435	32560575	The pathogenic BAP1 variants are known with a high penetration and approximately 85% of the mutation carriers are diagnosed with more than one malignancy.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('variants', 'Var', (20, 28))	('malignancy', 'Disease', (143, 153))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('pathogenic', 'Reg', (4, 14))
31436	32560575	Beside malignancies, individuals with germline BAP1 mutations often present with BAP1-inactivated nevi, previously called melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), that are atypical melanocytes proliferations with spitzoid morphology.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('BAP1', 'Gene', (134, 138))	('BAP1', 'Gene', (81, 85))	('malignancies', 'Disease', 'MESH:D009369', (7, 19))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('present', 'Reg', (68, 75))	('BAP1', 'Gene', '8314', (47, 51))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('malignancies', 'Disease', (7, 19))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', (47, 51))
31437	32560575	BAP1 mutations are infrequent in the general population and there are no homozygotes.	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
31438	32560575	Patients carrying BAP1 genetic variations were shown to have a higher incidence of peritoneal versus pleural MM.	('BAP1', 'Gene', '8314', (18, 22))	('genetic variations', 'Var', (23, 41))	('peritoneal versus pleural MM', 'Disease', (83, 111))	('BAP1', 'Gene', (18, 22))	('Patients', 'Species', '9606', (0, 8))	('peritoneal versus pleural MM', 'Disease', 'MESH:D010534', (83, 111))
31439	32560575	In comparison with sporadic MM, the BAP1 mutated patients tend to have sevenfold longer overall survival even when they have other cancers as well.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('mutated', 'Var', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('longer', 'PosReg', (81, 87))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('overall survival', 'MPA', (88, 104))	('BAP1', 'Gene', '8314', (36, 40))	('patients', 'Species', '9606', (49, 57))	('BAP1', 'Gene', (36, 40))
31441	32560575	Patients with UM and inherited BAP1 mutations present often with a more aggressive and metastatic disease and more advanced tumor staging, and thus worse survival.	('more', 'PosReg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BAP1', 'Gene', '8314', (31, 35))	('aggressive and metastatic disease', 'Disease', 'MESH:C538445', (72, 105))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
31444	32560575	Asbestos fibers are known to induce DNA damage, which is repaired by HR and double-strand breaks repair, MMR and NER, thus individuals with defects in the DNA repair processes are more prone to develop MM.	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('MMR', 'biological_process', 'GO:0006298', ('105', '108'))	('NER', 'biological_process', 'GO:0006289', ('113', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA repair', 'biological_process', 'GO:0006281', ('155', '165'))	('develop', 'PosReg', (194, 201))	('defects', 'Var', (140, 147))
31451	32560575	Hence, TP53 and p53 are crucial for regulating DNA repair and cell division and genetic mutations in this gene may predispose to several malignancies.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('genetic mutations', 'Var', (80, 97))	('TP53', 'Gene', '7157', (7, 11))	('predispose', 'Reg', (115, 125))	('TP53', 'Gene', (7, 11))	('DNA repair', 'biological_process', 'GO:0006281', ('47', '57'))	('cell division', 'biological_process', 'GO:0051301', ('62', '75'))	('p53', 'Gene', (16, 19))	('malignancies', 'Disease', (137, 149))	('p53', 'Gene', '7157', (16, 19))
31459	32560575	They are necessary in order to maintain genomic stability and defects in the MMR may result in microsatellite instability and or malignant diseases, such as hereditary nonpolyposis colon cancer (HNPCC) and cancers of the NHPCC spectrum.	('MMR', 'Gene', (77, 80))	('result in', 'Reg', (85, 94))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (157, 193))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('HNPCC', 'Phenotype', 'HP:0006716', (195, 200))	('defects', 'Var', (62, 69))	('microsatellite instability', 'Disease', 'MESH:D053842', (95, 121))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('NHPCC spectrum', 'Disease', (221, 235))	('microsatellite instability', 'Disease', (95, 121))	('malignant diseases', 'Disease', (129, 147))	('MMR', 'biological_process', 'GO:0006298', ('77', '80'))	('hereditary nonpolyposis colon cancer', 'Disease', (157, 193))	('malignant diseases', 'Disease', 'MESH:D009369', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (157, 193))	('HNPCC', 'Disease', 'None', (195, 200))	('HNPCC', 'Disease', (195, 200))
31461	32560575	An interesting observation is that MPM patients with inherited mutations in these genes tend to have improved survival compared with those with no genetic alteration, mirroring patients with BRCA1- and BRCA2-associated malignancies (Figure 3).	('mutations', 'Var', (63, 72))	('BRCA1', 'Gene', (191, 196))	('BRCA1', 'Gene', '672', (191, 196))	('survival', 'MPA', (110, 118))	('patients', 'Species', '9606', (39, 47))	('BRCA2', 'Gene', '675', (202, 207))	('malignancies', 'Disease', 'MESH:D009369', (219, 231))	('patients', 'Species', '9606', (177, 185))	('improved', 'PosReg', (101, 109))	('malignancies', 'Disease', (219, 231))	('BRCA2', 'Gene', (202, 207))
31462	32560575	Patients with ovarian, breast or prostate cancer who carry germline BRCA1 or BRCA2 mutations are more likely to respond to cisplatin-based chemotherapy and have better prognosis.	('mutations', 'Var', (83, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('ovarian, breast or prostate cancer', 'Disease', 'MESH:D011472', (14, 48))	('BRCA1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA2', 'Gene', (77, 82))	('Patients', 'Species', '9606', (0, 8))	('BRCA2', 'Gene', '675', (77, 82))	('respond to cisplatin-based chemotherapy', 'MPA', (112, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('BRCA1', 'Gene', '672', (68, 73))
31464	32560575	PARPi are proven to be effective for various solid tumors with somatic or germline mutations in HR deficit genes, including breast, prostate, ovarian and pancreatic cancer.	('prostate', 'Disease', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast', 'Disease', (124, 130))	('germline mutations', 'Var', (74, 92))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (142, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('HR deficit', 'Gene', (96, 106))
31466	32560575	The literature suggests that germline mutations in DNA repair and other tumor suppressor genes may be a prognostic biomarker for cisplatin chemotherapy in MPM.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('DNA repair', 'biological_process', 'GO:0006281', ('51', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('tumor', 'Disease', (72, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('DNA repair', 'Gene', (51, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('MPM', 'Disease', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('germline mutations', 'Var', (29, 47))
31471	32560575	Their mutations collectively occur in ~20% of all human cancer types that have been genomically characterized so far.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('occur', 'Reg', (29, 34))	('human', 'Species', '9606', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (56, 62))
31479	32560575	Genetic testing would be of high benefit for MM patients and their relatives, as it would allow early detection and prevention of malignancies in high-risk individuals.	('malignancies', 'Disease', (130, 142))	('patients', 'Species', '9606', (48, 56))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('Genetic', 'Var', (0, 7))
31482	32560575	Most importantly, the patients and their physicians should also be aware of the better survival that mutation-carriers have, as this would have a big impact on their lives and on their treatment considerations and planning.	('mutation-carriers', 'Var', (101, 118))	('impact', 'Reg', (150, 156))	('patients', 'Species', '9606', (22, 30))
31486	32560575	There is no compelling evidence in the two studies that the identified SNPs can cause MM in the absence of asbestos exposure.	('cause', 'Reg', (80, 85))	('asbestos', 'Chemical', 'MESH:D001194', (107, 115))	('SNPs', 'Var', (71, 75))
31493	32560575	SLC7A14 is involved in arginine transport and although this gene has not been previously linked to MM, there are indications of neighboring genes involvement due to identified chromosomal gain in this region.	('involvement', 'Reg', (146, 157))	('chromosomal', 'Var', (176, 187))	('SLC7A14', 'Gene', '57709', (0, 7))	('arginine', 'MPA', (23, 31))	('arginine transport', 'biological_process', 'GO:0015809', ('23', '41'))	('SLC7A14', 'Gene', (0, 7))	('gain', 'PosReg', (188, 192))	('arginine', 'Chemical', 'MESH:D001120', (23, 31))
31496	32560575	Especially the GSTM1 and GSTT1 subfamilies present with homozygous deletion polymorphisms (null genotype) that have been considered as modulators of susceptibility to environmentally induced malignancies.	('GSTM1', 'Gene', '2944', (15, 20))	('GSTM1', 'Gene', (15, 20))	('deletion polymorphisms', 'Var', (67, 89))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('GSTT1', 'Gene', '2952', (25, 30))	('GSTT1', 'Gene', (25, 30))	('malignancies', 'Disease', (191, 203))
31499	32560575	Genetic polymorphisms of EPHX may result in an increase or decrease in enzyme activity, which may promote cancer susceptibility.	('EPHX', 'Gene', '2052', (25, 29))	('promote', 'PosReg', (98, 105))	('enzyme activity', 'molecular_function', 'GO:0003824', ('71', '86'))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('enzyme activity', 'MPA', (71, 86))	('EPHX', 'Gene', (25, 29))	('cancer', 'Disease', (106, 112))	('decrease', 'NegReg', (59, 67))	('Genetic polymorphisms', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
31501	32560575	The most common polymorphism of MnSOD occurs at codon 16 and results in an Alanine (Ala) to Valine amino acid transformation, which alters the protein secondary structure, and thus impairs the transport of the protein into the mitochondria.	('transport', 'biological_process', 'GO:0006810', ('193', '202'))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('common', 'Reg', (9, 15))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('polymorphism', 'Var', (16, 28))	('Ala', 'Chemical', 'MESH:D000409', (75, 78))	('results in', 'Reg', (61, 71))	('MnSOD', 'Gene', '6648', (32, 37))	('protein secondary structure', 'MPA', (143, 170))	('Ala', 'Chemical', 'MESH:D000409', (84, 87))	('impairs', 'NegReg', (181, 188))	('Valine amino acid', 'Chemical', '-', (92, 109))	('MnSOD', 'Gene', (32, 37))	('Alanine', 'Chemical', 'MESH:D000409', (75, 82))	('alters', 'Reg', (132, 138))	('mitochondria', 'cellular_component', 'GO:0005739', ('227', '239'))	('transport of the protein into the mitochondria', 'MPA', (193, 239))
31506	32560575	The low-activity-associated EPHX1 genotype was a risk factor for MM in the Italian, but not in the Finnish population.	('low-activity-associated', 'Var', (4, 27))	('EPHX1', 'Gene', (28, 33))	('EPHX1', 'Gene', '2052', (28, 33))	('risk', 'Reg', (49, 53))
31508	32560575	The nucleotidic change 282C > T within NAT2 was also found to be significantly associated with MPM risk in another Italian study of 50 SNPs within oxidative metabolism enzymes and 75 SNPs in genome stability genes.	('oxidative metabolism', 'biological_process', 'GO:0045333', ('147', '167'))	('MPM', 'Disease', (95, 98))	('NAT2', 'Gene', (39, 43))	('associated with', 'Reg', (79, 94))	('NAT2', 'Gene', '10', (39, 43))	('nucleotidic change 282C > T', 'Var', (4, 31))	('282C > T', 'Mutation', 'rs1041983', (23, 31))
31510	32560575	genotyped 90 MPM patients versus 395 control subjects and found a higher MPM risk for individuals with a GSTM1 null allele and in those with the Ala/Ala genotypes at codon 16 within MnSOD.	('Ala', 'Chemical', 'MESH:D000409', (145, 148))	('Ala', 'Chemical', 'MESH:D000409', (149, 152))	('GSTM1', 'Gene', '2944', (105, 110))	('MnSOD', 'Gene', (182, 187))	('null', 'Var', (111, 115))	('GSTM1', 'Gene', (105, 110))	('patients', 'Species', '9606', (17, 25))	('higher', 'PosReg', (66, 72))	('MPM', 'Disease', (73, 76))	('MnSOD', 'Gene', '6648', (182, 187))
31511	32560575	focused on four DNA repair genes, XRCC1, XRCC3, XPD and OGG1, hypothesizing that deficient DNA repair mechanisms would fail to protect against the oxidative stress induced by asbestos fibers and eventually result in a higher risk of carcinogenesis.	('XRCC1', 'Gene', '7515', (34, 39))	('XPD', 'Gene', (48, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('91', '101'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('XRCC3', 'Gene', (41, 46))	('oxidative stress', 'MPA', (147, 163))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('DNA repair', 'biological_process', 'GO:0006281', ('16', '26'))	('carcinogenesis', 'Disease', (233, 247))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (233, 247))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('XRCC1', 'Gene', (34, 39))	('XPD', 'Gene', '2068', (48, 51))	('XRCC3', 'Gene', '7517', (41, 46))	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))	('OGG1', 'Gene', (56, 60))	('OGG1', 'Gene', '4968', (56, 60))	('deficient', 'Var', (81, 90))	('result in', 'Reg', (206, 215))
31517	32560575	A significant association with MM was noticed for the XRCC1-R399Q Q homozygotes and Q/R heterozygotes versus the R homozygotes and for the XRCC3-T241M T homozygotes and M/T heterozygotes versus the M homozygotes.	('XRCC3', 'Gene', (139, 144))	('R399Q', 'Mutation', 'rs25487', (60, 65))	('XRCC1', 'Gene', (54, 59))	('Q/R', 'Var', (84, 87))	('XRCC3', 'Gene', '7517', (139, 144))	('T241M', 'Mutation', 'rs861539', (145, 150))	('XRCC1', 'Gene', '7515', (54, 59))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('M/T', 'Var', (169, 172))
31538	24848258	Successful targeted therapies that pair small molecule inhibitors with specific activated oncogenes include agents targeting BCR-ABL and EML4-ALK translocations, HER2 gene amplification, and activating mutations in EGFR and B-RAF.	('HER2', 'Gene', '2064', (162, 166))	('activating mutations', 'Var', (191, 211))	('HER2', 'Gene', (162, 166))	('BCR-ABL', 'Gene', (125, 132))	('EML4', 'Gene', (137, 141))	('ALK', 'Gene', '238', (142, 145))	('BCR-ABL', 'Gene', '25', (125, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('215', '219'))	('EML4', 'Gene', '27436', (137, 141))	('B-RAF', 'Gene', '673', (224, 229))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('ALK', 'Gene', (142, 145))	('amplification', 'Var', (172, 185))	('B-RAF', 'Gene', (224, 229))
31539	24848258	Alternatively, identification of a synthetic lethal relationship between a drug target and loss of a tumor suppressor is exemplified by the efficacy of PARP inhibitors in breast cancer bearing BRCA1 or BRCA2 mutations.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('101', '117'))	('tumor suppressor', 'Gene', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer bearing BRCA1', 'Disease', (171, 198))	('tumor suppressor', 'Gene', '7248', (101, 117))	('BRCA2', 'Gene', '675', (202, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('mutations', 'Var', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PARP', 'Gene', '1302', (152, 156))	('tumor suppressor', 'biological_process', 'GO:0051726', ('101', '117'))	('breast cancer bearing BRCA1', 'Disease', 'MESH:D001943', (171, 198))	('PARP', 'Gene', (152, 156))	('BRCA2', 'Gene', (202, 207))
31542	24848258	Germline mutations in NF2 contribute to development of type 2 neurofibromatosis, which is characterized by growth of meningiomas, ependymomas and schwannomas.	('Germline mutations', 'Var', (0, 18))	('NF2', 'Gene', '4771', (22, 25))	('neurofibromatosis', 'Disease', 'MESH:C537392', (62, 79))	('schwannomas', 'Disease', (146, 157))	('schwannoma', 'Phenotype', 'HP:0100008', (146, 156))	('contribute to', 'Reg', (26, 39))	('NF2', 'Gene', (22, 25))	('meningiomas', 'Phenotype', 'HP:0002858', (117, 128))	('schwannomas', 'Disease', 'MESH:D009442', (146, 157))	('neurofibromatosis', 'Disease', (62, 79))	('ependymomas', 'Disease', 'MESH:D004806', (130, 141))	('meningioma', 'Phenotype', 'HP:0002858', (117, 127))	('schwannomas', 'Phenotype', 'HP:0100008', (146, 157))	('meningiomas', 'Disease', (117, 128))	('meningiomas', 'Disease', 'MESH:D008577', (117, 128))	('ependymomas', 'Disease', (130, 141))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (62, 79))
31552	24848258	Therefore, therapeutic targeting of FAK may diminish CSCs in a variety of malignancies including MPM.	('FAK', 'Gene', (36, 39))	('malignancies', 'Disease', (74, 86))	('FAK', 'molecular_function', 'GO:0004717', ('36', '39'))	('diminish', 'NegReg', (44, 52))	('CSCs', 'Disease', (53, 57))	('therapeutic targeting', 'Var', (11, 32))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))	('MPM', 'Disease', (97, 100))
31554	24848258	VS-4718, previously known as PND-1186, is a potent and selective FAK inhibitor (Fig.	('FAK', 'Enzyme', (65, 68))	('FAK', 'molecular_function', 'GO:0004717', ('65', '68'))	('VS-4718', 'Var', (0, 7))	('PND-1186', 'Chemical', 'MESH:C559284', (29, 37))	('VS-4718', 'Chemical', 'MESH:C559284', (0, 7))
31555	24848258	We found that VS-4718 is especially effective against Merlin-negative cell lines of certain cancer types including MPM in vitro and in vivo and have uncovered a mechanism governing sensitivity to the FAK inhibitor.	('MPM', 'Disease', (115, 118))	('VS-4718', 'Chemical', 'MESH:C559284', (14, 21))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('FAK', 'molecular_function', 'GO:0004717', ('200', '203'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('VS-4718', 'Var', (14, 21))
31556	24848258	The preferential inhibitory effect of VS-4718 on CSCs, in addition to eradication of non-CSCs, provides a rationale for clinical use of a FAK inhibitor as a single agent after first-line chemotherapy.	('CSCs', 'Disease', (49, 53))	('VS-4718', 'Chemical', 'MESH:C559284', (38, 45))	('VS-4718', 'Var', (38, 45))	('inhibitory effect', 'MPA', (17, 34))	('FAK', 'molecular_function', 'GO:0004717', ('138', '141'))
31562	24848258	Hence, loss of Merlin correlated with increased sensitivity to the VS-4718 FAK inhibitor in vitro.	('Merlin', 'Protein', (15, 21))	('loss', 'NegReg', (7, 11))	('FAK', 'molecular_function', 'GO:0004717', ('75', '78'))	('VS-4718', 'Var', (67, 74))	('sensitivity', 'MPA', (48, 59))	('VS-4718', 'Chemical', 'MESH:C559284', (67, 74))	('increased', 'PosReg', (38, 47))
31565	24848258	In vivo, in the MDA-MB-231 xenograft model, mice dosed orally twice daily with VS-4718 at 25 mg/kg had significantly smaller tumors (p=0.006) than mice receiving vehicle control after 29 days of treatment.	('mice', 'Species', '10090', (147, 151))	('VS-4718', 'Chemical', 'MESH:C559284', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('smaller', 'NegReg', (117, 124))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (16, 26))	('mice', 'Species', '10090', (44, 48))	('VS-4718', 'Var', (79, 86))
31566	24848258	Moreover, tumor regression was observed in mice treated with 100 mg/kg VS-4718 (p< 0.0001; Fig.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('VS-4718', 'Var', (71, 78))	('tumor', 'Disease', (10, 15))	('VS-4718', 'Chemical', 'MESH:C559284', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
31569	24848258	Final average tumor weights in VS-4718 treated groups were reduced only by ~30% relative to the vehicle control group despite significant inhibition of tumor pFAK-Y397 (p=0.0002; Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('inhibition', 'NegReg', (138, 148))	('reduced', 'NegReg', (59, 66))	('tumor', 'Disease', (14, 19))	('VS-4718', 'Chemical', 'MESH:C559284', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('pFAK-Y397', 'Gene', (158, 167))	('VS-4718', 'Var', (31, 38))
31571	24848258	Thus, we conclude that Merlin-negative cancer cells are especially sensitive to the FAK inhibitor VS-4718 in vitro and in vivo.	('FAK', 'molecular_function', 'GO:0004717', ('84', '87'))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('VS-4718', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('VS-4718', 'Chemical', 'MESH:C559284', (98, 105))	('sensitive', 'Reg', (67, 76))
31572	24848258	NF2 mutations are common in MPM, with approximately 40-50% of tumors exhibiting biallelic inactivation of NF2 leading to absent or low Merlin expression.	('NF2', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('absent', 'NegReg', (121, 127))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('low', 'NegReg', (131, 134))	('NF2', 'Gene', '4771', (0, 3))	('NF2', 'Gene', '4771', (106, 109))	('Merlin', 'Protein', (135, 141))	('expression', 'MPA', (142, 152))	('mutations', 'Var', (4, 13))	('MPM', 'Disease', (28, 31))	('NF2', 'Gene', (106, 109))
31577	24848258	In addition to greater potency of VS-4718, all Merlin-negative cell lines demonstrated a greater magnitude of response, exhibiting cell viability curves that approached zero, suggesting a cytotoxic effect of VS-4718 (Fig.	('VS-4718', 'Chemical', 'MESH:C559284', (34, 41))	('cytotoxic effect', 'CPA', (188, 204))	('VS-4718', 'Var', (208, 215))	('VS-4718', 'Chemical', 'MESH:C559284', (208, 215))
31581	24848258	The VS-4718 EC50 in control MM87/GFP cells was ~300 nM, while in MM87/NF2-GFP cells the EC50 was increased by approximately 3-fold (Fig.	('EC50', 'MPA', (12, 16))	('EC50', 'MPA', (88, 92))	('increased', 'PosReg', (97, 106))	('VS-4718', 'Chemical', 'MESH:C559284', (4, 11))	('NF2', 'Gene', (70, 73))	('MM87', 'CellLine', 'CVCL:D231', (28, 32))	('MM87', 'CellLine', 'CVCL:D231', (65, 69))	('VS-4718', 'Var', (4, 11))	('NF2', 'Gene', '4771', (70, 73))
31582	24848258	This demonstrated that ectopic expression of full-length Merlin reduced sensitivity to the FAK inhibitor VS-4718, consistent with our hypothesis that FAK inhibitor sensitivity in Merlin-negative mesothelioma and breast cancer cells is enhanced by loss of Merlin.	('sensitivity', 'MPA', (164, 175))	('sensitivity to the FAK inhibitor VS-4718', 'MPA', (72, 112))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mesothelioma', 'Disease', (195, 207))	('breast cancer', 'Disease', (212, 225))	('FAK', 'molecular_function', 'GO:0004717', ('91', '94'))	('Merlin', 'Gene', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('FAK', 'molecular_function', 'GO:0004717', ('150', '153'))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('Merlin', 'Gene', (255, 261))	('reduced', 'NegReg', (64, 71))	('VS-4718', 'Chemical', 'MESH:C559284', (105, 112))	('loss', 'Var', (247, 251))	('enhanced', 'PosReg', (235, 243))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
31586	24848258	To extend our observation to an in vivo mesothelioma model, we first tested the efficacy of VS-4718 in a Merlin-negative MPM lung tumor model.	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('MPM lung tumor', 'Disease', (121, 135))	('lung tumor', 'Phenotype', 'HP:0100526', (125, 135))	('VS-4718', 'Var', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('MPM lung tumor', 'Disease', 'MESH:D008175', (121, 135))	('VS-4718', 'Chemical', 'MESH:C559284', (92, 99))	('tested', 'Reg', (69, 75))	('mesothelioma', 'Disease', (40, 52))
31589	24848258	At the end of the VS-4718 treatment on day 21 after initial tail vein injection, the tumor burden in the lungs of VS-4718-treated animals averaged 3.5-fold less than in the lungs of vehicle control-treated animals (p<0.0001; Fig.	('tumor', 'Disease', (85, 90))	('less', 'NegReg', (156, 160))	('VS-4718', 'Chemical', 'MESH:C559284', (18, 25))	('VS-4718-treated', 'Var', (114, 129))	('VS-4718', 'Chemical', 'MESH:C559284', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('VS-4718', 'Var', (18, 25))
31591	24848258	We also tested the effect of VS-4718 in an MM87 intraperitoneal orthotopic xenograft model.	('tested', 'Reg', (8, 14))	('VS-4718', 'Var', (29, 36))	('VS-4718', 'Chemical', 'MESH:C559284', (29, 36))	('MM87', 'CellLine', 'CVCL:D231', (43, 47))
31592	24848258	Animals treated with 25 mg/kg VS-4718 orally twice daily for 2 weeks had small tumors with an average volume of approximately 100 mm3, in contrast to control-treated animals that had large tumors with an average volume of approximately 500 mm3.	('VS-4718', 'Var', (30, 37))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Disease', (79, 85))	('small tumors', 'Disease', (73, 85))	('small tumors', 'Disease', 'MESH:D058405', (73, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('VS-4718', 'Chemical', 'MESH:C559284', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
31595	24848258	pFAK-Y397 was significantly inhibited in the tumors treated with VS-4718 (p=0.016; Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('VS-4718', 'Chemical', 'MESH:C559284', (65, 72))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('inhibited', 'NegReg', (28, 37))	('VS-4718', 'Var', (65, 72))	('pFAK-Y397', 'Gene', (0, 9))
31599	24848258	As a closer approximation of human cancer, we assessed the effect of VS-4718 in mice bearing human MPM patient-derived xenografts (PDX).	('VS-4718', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('MPM', 'Disease', (99, 102))	('VS-4718', 'Chemical', 'MESH:C559284', (69, 76))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('patient', 'Species', '9606', (103, 110))	('mice', 'Species', '10090', (80, 84))	('human', 'Species', '9606', (29, 34))	('cancer', 'Disease', (35, 41))
31601	24848258	FAK autophosphorylation was effectively inhibited in both PDX models treated with 50 mg/kg VS-4718 (Fig.	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('VS-4718', 'Var', (91, 98))	('inhibited', 'NegReg', (40, 49))	('FAK autophosphorylation', 'MPA', (0, 23))	('VS-4718', 'Chemical', 'MESH:C559284', (91, 98))
31602	24848258	Merlin-positive PDX tumors treated with VS-4718 at 50 mg/kg averaged only 23% smaller than control tumors at the end of the study on day 42 (Fig.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('PDX tumors', 'Disease', 'MESH:D009369', (16, 26))	('VS-4718', 'Var', (40, 47))	('Merlin-positive', 'Gene', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('VS-4718', 'Chemical', 'MESH:C559284', (40, 47))	('PDX tumors', 'Disease', (16, 26))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('smaller', 'NegReg', (78, 85))
31603	24848258	In contrast, in the Merlin-negative PDX study, mice treated orally twice daily with 50 mg/kg VS-4718 exhibited 56% tumor growth inhibition on day 35 as compared to vehicle-treated control animals (p=0.0089; Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('VS-4718', 'Chemical', 'MESH:C559284', (93, 100))	('50 mg/kg VS-4718', 'Var', (84, 100))	('mice', 'Species', '10090', (47, 51))	('VS-4718', 'Var', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
31605	24848258	Reduced cell number in response to VS-4718 could potentially result from reduction of cell proliferation and/or induction of apoptosis.	('VS-4718', 'Chemical', 'MESH:C559284', (35, 42))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('112', '134'))	('Reduced', 'NegReg', (0, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('cell proliferation', 'CPA', (86, 104))	('apoptosis', 'CPA', (125, 134))	('VS-4718', 'Var', (35, 42))	('cell number', 'CPA', (8, 19))	('reduction', 'NegReg', (73, 82))
31606	24848258	We therefore assessed effects of VS-4718 on caspase3/7 activity as a marker of apoptosis, and Ki67 positivity as an indicator of cell proliferation in mesothelioma cells.	('positivity', 'Var', (99, 109))	('Ki67', 'Gene', (94, 98))	('activity', 'MPA', (55, 63))	('mesothelioma', 'Disease', (151, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('VS-4718', 'Var', (33, 40))	('caspase3', 'Gene', (44, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('mesothelioma', 'Disease', 'MESH:D008654', (151, 163))	('VS-4718', 'Chemical', 'MESH:C559284', (33, 40))	('caspase3', 'Gene', '836', (44, 52))
31607	24848258	We observed 2-3 fold induction of caspase3/7 activity in response to VS-4718 treatment in a panel of human Merlin-negative MPM cell lines, Mero-41, Mero-48a and Mero-83, with only weak caspase3/7 activation in Merlin-positive Mero-25 and H28 cells (Fig.	('activity', 'MPA', (45, 53))	('VS-4718', 'Var', (69, 76))	('caspase3', 'Gene', '836', (34, 42))	('caspase3', 'Gene', '836', (185, 193))	('VS-4718', 'Chemical', 'MESH:C559284', (69, 76))	('human', 'Species', '9606', (101, 106))	('caspase3', 'Gene', (34, 42))	('caspase3', 'Gene', (185, 193))
31608	24848258	Ki67 staining was markedly reduced in Merlin-negative Mero-48a and Mero-41 cells treated with VS-4718, whereas little reduction in Ki67 staining was observed in Merlin-positive MSTO-211H and H28 cells (Fig.	('VS-4718', 'Var', (94, 101))	('reduced', 'NegReg', (27, 34))	('MSTO-211H', 'CellLine', 'CVCL:1430', (177, 186))	('VS-4718', 'Chemical', 'MESH:C559284', (94, 101))	('Ki67', 'Protein', (0, 4))
31612	24848258	In contrast, after 1 hr of VS-4718 treatment we observed reduced AKT activation (pAKT-S473) in Merlin-negative Mero-41 and Mero-48a cells sustained for 48 hrs, whereas no inhibition of AKT activation was detected in Merlin-positive H28 or MSTO-211H cells (Fig.	('AKT', 'Gene', (185, 188))	('VS-4718', 'Chemical', 'MESH:C559284', (27, 34))	('MSTO-211H', 'CellLine', 'CVCL:1430', (239, 248))	('AKT', 'Gene', (65, 68))	('reduced', 'NegReg', (57, 64))	('AKT', 'Gene', '207', (82, 85))	('AKT', 'Gene', '207', (65, 68))	('AKT', 'Gene', '207', (185, 188))	('VS-4718', 'Var', (27, 34))	('AKT', 'Gene', (82, 85))	('activation', 'PosReg', (69, 79))
31613	24848258	VS-4718 had no effect on ERK1/2 activation in both Merlin-negative and Merlin-positive cells.	('ERK1', 'molecular_function', 'GO:0004707', ('25', '29'))	('ERK1/2', 'Gene', '5595;5594', (25, 31))	('activation', 'PosReg', (32, 42))	('VS-4718', 'Var', (0, 7))	('VS-4718', 'Chemical', 'MESH:C559284', (0, 7))	('ERK1/2', 'Gene', (25, 31))
31621	24848258	We found that activated FAK levels were decreased by approximately 70% upon expression of NF2 (Fig.	('FAK', 'molecular_function', 'GO:0004717', ('24', '27'))	('activated FAK levels', 'MPA', (14, 34))	('NF2', 'Gene', (90, 93))	('NF2', 'Gene', '4771', (90, 93))	('decreased', 'NegReg', (40, 49))	('expression', 'Var', (76, 86))
31626	24848258	While Merlin-positive MSTO-211H cells were only modestly sensitive to VS-4718, exhibiting an EC50 of 11 muM, the N-cadherin blocking antibody increased the potency of VS-4718 by approximately 60-fold resulting in an EC50 of 180 nM (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('115', '123'))	('N-cadherin', 'Gene', (113, 123))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('potency', 'MPA', (156, 163))	('increased', 'PosReg', (142, 151))	('VS-4718', 'Chemical', 'MESH:C559284', (70, 77))	('muM', 'Gene', '56925', (104, 107))	('N-cadherin', 'Gene', '1000', (113, 123))	('EC50', 'MPA', (216, 220))	('MSTO-211H', 'CellLine', 'CVCL:1430', (22, 31))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('muM', 'Gene', (104, 107))	('VS-4718', 'Var', (167, 174))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('VS-4718', 'Chemical', 'MESH:C559284', (167, 174))
31629	24848258	We further hypothesized that reducing cell-ECM interactions through disruption of beta1 integrin activity in Merlin-negative cells would supplant FAK inhibition, decreasing sensitivity to the FAK inhibitor.	('ECM', 'Gene', (43, 46))	('disruption', 'Var', (68, 78))	('activity', 'MPA', (97, 105))	('FAK inhibition', 'MPA', (146, 160))	('FAK', 'molecular_function', 'GO:0004717', ('146', '149'))	('supplant', 'NegReg', (137, 145))	('FAK', 'molecular_function', 'GO:0004717', ('192', '195'))	('sensitivity to the FAK inhibitor', 'MPA', (173, 205))	('beta1 integrin', 'Gene', '3688', (82, 96))	('reducing', 'NegReg', (29, 37))	('ECM', 'Gene', '22915', (43, 46))	('decreasing', 'NegReg', (162, 172))	('beta1 integrin', 'Gene', (82, 96))
31633	24848258	Moreover, blocking of beta1 integrin activity rendered Merlin-negative Mero-41 cells relatively insensitive to further reduction of proliferation by VS-4718, with an EC50 of 12 muM compared to an EC50 of 0.31 muM in the control IgG treated cells (Fig.	('blocking', 'NegReg', (10, 18))	('muM', 'Gene', (209, 212))	('VS-4718', 'Chemical', 'MESH:C559284', (149, 156))	('beta1 integrin', 'Gene', '3688', (22, 36))	('muM', 'Gene', '56925', (177, 180))	('muM', 'Gene', '56925', (209, 212))	('beta1 integrin', 'Gene', (22, 36))	('muM', 'Gene', (177, 180))	('VS-4718', 'Var', (149, 156))
31655	24848258	We next determined whether the FAK inhibitor VS-4718 has an effect on tumor-initiating cells in MPM.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('VS-4718', 'Chemical', 'MESH:C559284', (45, 52))	('tumor', 'Disease', (70, 75))	('MPM', 'Disease', (96, 99))	('FAK', 'molecular_function', 'GO:0004717', ('31', '34'))	('VS-4718', 'Var', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
31657	24848258	VS-4718 treatment reduced the percentage of Aldefluor+ cells in direct contrast with the standard cytotoxic agents, which enriched the Aldefluor+ cell subpopulation (Fig.	('Aldefluor', 'Chemical', '-', (135, 144))	('reduced', 'NegReg', (18, 25))	('Aldefluor', 'Chemical', '-', (44, 53))	('VS-4718', 'Var', (0, 7))	('VS-4718', 'Chemical', 'MESH:C559284', (0, 7))
31658	24848258	Similar effects of VS-4718 on Aldefluor+ CSCs were observed in the Mero-83 and Mero-48a MPM cell lines (Fig.	('Aldefluor+ CSCs', 'MPA', (30, 45))	('Aldefluor', 'Chemical', '-', (30, 39))	('VS-4718', 'Var', (19, 26))	('VS-4718', 'Chemical', 'MESH:C559284', (19, 26))
31659	24848258	Moreover, when used in combination, VS-4718 blocked the enrichment of Aldefluor+ cells by pemetrexed (Fig.	('enrichment of Aldefluor+ cells', 'MPA', (56, 86))	('Aldefluor', 'Chemical', '-', (70, 79))	('VS-4718', 'Var', (36, 43))	('blocked', 'NegReg', (44, 51))	('VS-4718', 'Chemical', 'MESH:C559284', (36, 43))	('pemetrexed', 'Chemical', 'MESH:D000068437', (90, 100))
31663	24848258	In contrast, tumors from animals treated with VS-4718 at 50 mg/kg PO BID showed a marked reduction of ALDH1-positive cells (Fig.	('VS-4718', 'Var', (46, 53))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BID', 'Gene', (69, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('102', '106'))	('ALDH1', 'Gene', (102, 107))	('reduction', 'NegReg', (89, 98))	('VS-4718', 'Chemical', 'MESH:C559284', (46, 53))	('BID', 'Gene', '637', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('ALDH1', 'Gene', '216', (102, 107))
31670	24848258	In contrast, treatment with VS-4718 as a single agent starting on day 16, after cessation of the cisplatin/pemetrexed regimen, substantially delayed tumor regrowth resulting in 77% tumor growth inhibition by day 46 as compared to the cisplatin/pemetrexed arm (p=0.035; Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('tumor', 'Disease', (181, 186))	('VS-4718', 'Chemical', 'MESH:C559284', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('delayed', 'NegReg', (141, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pemetrexed', 'Chemical', 'MESH:D000068437', (107, 117))	('tumor', 'Disease', (149, 154))	('pemetrexed', 'Chemical', 'MESH:D000068437', (244, 254))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('VS-4718', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
31671	24848258	These results demonstrate that a FAK inhibitor can indeed extend the duration of tumor growth inhibition, providing a more durable response when used as a single agent after cisplatin/pemetrexed treatment in a PDX model of mesothelioma.	('pemetrexed', 'Chemical', 'MESH:D000068437', (184, 194))	('mesothelioma', 'Disease', (223, 235))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (223, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('FAK', 'Var', (33, 36))	('tumor', 'Disease', (81, 86))	('FAK', 'molecular_function', 'GO:0004717', ('33', '36'))
31675	24848258	NF2 expression and function can be lost in tumors by a variety of mechanisms, including mutation, chromosome loss and focal deletions.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (88, 96))	('NF2', 'Gene', (0, 3))	('focal deletions', 'Var', (118, 133))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('expression', 'MPA', (4, 14))	('NF2', 'Gene', '4771', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('chromosome loss', 'Var', (98, 113))	('tumors', 'Disease', (43, 49))	('lost', 'NegReg', (35, 39))	('function', 'MPA', (19, 27))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
31676	24848258	NF2 is mutated in approximately 40-50% of MPMs, with lower frequency of mutations in several other cancer types.	('NF2', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('NF2', 'Gene', '4771', (0, 3))	('cancer', 'Disease', (99, 105))	('MPMs', 'Disease', (42, 46))	('mutated', 'Var', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
31677	24848258	Additional promising indications for clinical use of FAK inhibitors may include other tumors with high prevalence of NF2 loss, such as schwannomas, meningiomas and ependymomas resulting from neurofibromatosis type 2 syndrome (89% NF2 mutations) and high-grade malignant meningioma.	('malignant meningioma', 'Disease', (260, 280))	('meningiomas', 'Disease', 'MESH:D008577', (148, 159))	('meningioma', 'Phenotype', 'HP:0002858', (148, 158))	('NF2', 'Gene', '4771', (230, 233))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('neurofibromatosis type 2 syndrome', 'Disease', (191, 224))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (191, 208))	('meningiomas', 'Phenotype', 'HP:0002858', (148, 159))	('schwannomas', 'Disease', 'MESH:D009442', (135, 146))	('NF2', 'Gene', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('meningiomas', 'Disease', (148, 159))	('schwannomas', 'Disease', (135, 146))	('tumors', 'Disease', (86, 92))	('NF2', 'Gene', '4771', (117, 120))	('ependymomas', 'Disease', 'MESH:D004806', (164, 175))	('schwannoma', 'Phenotype', 'HP:0100008', (135, 145))	('loss', 'NegReg', (121, 125))	('NF2', 'Gene', (117, 120))	('meningioma', 'Phenotype', 'HP:0002858', (270, 280))	('malignant meningioma', 'Disease', 'MESH:D008577', (260, 280))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('FAK', 'molecular_function', 'GO:0004717', ('53', '56'))	('mutations', 'Var', (234, 243))	('schwannomas', 'Phenotype', 'HP:0100008', (135, 146))	('ependymomas', 'Disease', (164, 175))	('neurofibromatosis type 2 syndrome', 'Disease', 'MESH:C537392', (191, 224))
31680	24848258	Ectopic expression of Merlin in NF2-/- MPM cells inhibited invasion, decreased FAK Tyr397 phosphorylation and impaired FAK interaction with its binding partners Src and p85.	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('p85', 'Gene', '5296', (169, 172))	('Src', 'Gene', '6714', (161, 164))	('NF2', 'Gene', (32, 35))	('invasion', 'CPA', (59, 67))	('FAK', 'MPA', (119, 122))	('Merlin', 'Gene', (22, 28))	('FAK Tyr397 phosphorylation', 'MPA', (79, 105))	('Tyr397', 'Chemical', '-', (83, 89))	('Ectopic expression', 'Var', (0, 18))	('decreased FAK', 'Phenotype', 'HP:0032341', (69, 82))	('p85', 'Gene', (169, 172))	('interaction', 'Interaction', (123, 134))	('FAK', 'molecular_function', 'GO:0004717', ('119', '122'))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('decreased', 'NegReg', (69, 78))	('FAK', 'molecular_function', 'GO:0004717', ('79', '82'))	('inhibited', 'NegReg', (49, 58))	('impaired', 'NegReg', (110, 118))	('Src', 'Gene', (161, 164))	('binding', 'Interaction', (144, 151))	('NF2', 'Gene', '4771', (32, 35))
31683	24848258	For example, others have suggested that another FAK inhibitor, BI 853520, may be most effective in treatment of tumors with low expression of E-cadherin, another essential mediator of adherens junctions.	('E-cadherin', 'Gene', (142, 152))	('BI 853520', 'Chemical', '-', (63, 72))	('E-cadherin', 'Gene', '999', (142, 152))	('FAK', 'molecular_function', 'GO:0004717', ('48', '51'))	('tumors', 'Disease', (112, 118))	('BI 853520', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
31688	24848258	In murine and human mesothelioma samples, VS-4718 decreased ALDH-positive cells in vitro and in vivo, establishing the FAK inhibitor as an anti-CSC agent in mesothelioma.	('mesothelioma', 'Disease', (157, 169))	('decreased ALDH', 'Phenotype', 'HP:0003282', (50, 64))	('mesothelioma', 'Disease', (20, 32))	('VS-4718', 'Chemical', 'MESH:C559284', (42, 49))	('ALDH-positive cells', 'CPA', (60, 79))	('human', 'Species', '9606', (14, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (157, 169))	('ALDH', 'molecular_function', 'GO:0004030', ('60', '64'))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('decreased', 'NegReg', (50, 59))	('murine', 'Species', '10090', (3, 9))	('VS-4718', 'Var', (42, 49))	('FAK', 'molecular_function', 'GO:0004717', ('119', '122'))
31710	24260583	Targeting Eukaryotic Translation in Mesothelioma Cells with an eIF4E-Specific Antisense Oligonucleotide Aberrant cap-dependent translation is implicated in tumorigenesis in multiple tumor types including mesothelioma.	('translation', 'biological_process', 'GO:0006412', ('127', '138'))	('implicated', 'Reg', (142, 152))	('tumor', 'Disease', (182, 187))	('eIF4', 'cellular_component', 'GO:0008304', ('63', '67'))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mesothelioma', 'Disease', (204, 216))	('Aberrant', 'Var', (104, 112))	('Mesothelioma', 'Disease', (36, 48))	('Oligonucleotide', 'Chemical', 'MESH:D009841', (88, 103))	('Mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('eIF4E', 'Gene', '1977', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('eIF4E', 'Gene', (63, 68))	('cap', 'Chemical', '-', (113, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
31725	24260583	In the cytoplasm, eIF4E is the cap-binding protein component of the eIF4F complex that is also comprised of the RNA helicase eIF4A and the scaffolding protein eIF4G.	('cap', 'Chemical', '-', (31, 34))	('eIF4', 'cellular_component', 'GO:0008304', ('125', '129'))	('eIF4A', 'Gene', (125, 130))	('eIF4F', 'Gene', (68, 73))	('RNA helicase', 'Protein', (112, 124))	('eIF4A', 'Gene', '1973', (125, 130))	('cytoplasm', 'cellular_component', 'GO:0005737', ('7', '16'))	('RNA', 'cellular_component', 'GO:0005562', ('112', '115'))	('eIF4E', 'Var', (18, 23))	('eIF4G', 'Gene', (159, 164))	('eIF4G', 'Gene', '1981', (159, 164))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('eIF4F', 'Gene', '1977', (68, 73))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('eIF4F', 'cellular_component', 'GO:0016281', ('68', '73'))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('eIF4', 'cellular_component', 'GO:0008304', ('18', '22'))	('eIF4', 'cellular_component', 'GO:0008304', ('159', '163'))
31730	24260583	Phosphorylation of 4E-BP1 lessens the affinity of 4E-BP1 for eIF4E allowing eIF4E to bind to eIF4G permitting eIF4F assembly and driving cap-dependent translation.	('cap', 'Chemical', '-', (137, 140))	('eIF4', 'cellular_component', 'GO:0008304', ('76', '80'))	('eIF4F', 'cellular_component', 'GO:0016281', ('110', '115'))	('4E-BP1', 'Gene', (50, 56))	('eIF4G', 'Gene', (93, 98))	('eIF4', 'cellular_component', 'GO:0008304', ('93', '97'))	('4E-BP1', 'Gene', (19, 25))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('eIF4F', 'Gene', (110, 115))	('eIF4E', 'Var', (76, 81))	('permitting', 'PosReg', (99, 109))	('eIF4G', 'Gene', '1981', (93, 98))	('translation', 'biological_process', 'GO:0006412', ('151', '162'))	('lessens', 'NegReg', (26, 33))	('assembly', 'MPA', (116, 124))	('eIF4F', 'Gene', '1977', (110, 115))	('eIF4F assembly', 'biological_process', 'GO:0097010', ('110', '124'))	('4E-BP1', 'Gene', '1978', (50, 56))	('affinity', 'Interaction', (38, 46))	('4E-BP1', 'Gene', '1978', (19, 25))	('eIF4', 'cellular_component', 'GO:0008304', ('61', '65'))	('cap-dependent translation', 'MPA', (137, 162))	('bind', 'Interaction', (85, 89))
31739	24260583	With this in mind therapies that target the deranged cap-dependent translation engendered by eIF4E hyperactivation have been explored.	('eIF4E', 'Gene', (93, 98))	('translation', 'biological_process', 'GO:0006412', ('67', '78'))	('eIF4', 'cellular_component', 'GO:0008304', ('93', '97'))	('hyperactivation', 'Var', (99, 114))	('cap', 'Chemical', '-', (53, 56))	('deranged cap-dependent translation', 'MPA', (44, 78))
31745	24260583	These approaches of directly targeting eIF4F integrity and function by eIF4E antagonism provide evidence of therapeutic efficacy in each cancer studied.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('eIF4', 'cellular_component', 'GO:0008304', ('71', '75'))	('antagonism', 'Var', (77, 87))	('function', 'MPA', (59, 67))	('eIF4F', 'Gene', '1977', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('eIF4F', 'cellular_component', 'GO:0016281', ('39', '44'))	('eIF4E', 'Gene', (71, 76))	('integrity', 'MPA', (45, 54))	('cancer', 'Disease', (137, 143))	('eIF4F', 'Gene', (39, 44))
31779	24260583	In previous work it was shown that cap-mediated translation is enhanced in mesothelioma compared to normal mesothelial (LP9) cells and may be a consequence of Ras signaling pathway, phosphorylation of eIF4E and lower 4EBP1 levels.	('4EBP1 levels', 'MPA', (217, 229))	('enhanced', 'PosReg', (63, 71))	('eIF4E', 'Protein', (201, 206))	('cap-mediated translation', 'MPA', (35, 59))	('LP9', 'CellLine', 'CVCL:E109', (120, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('cap', 'Chemical', '-', (35, 38))	('signaling pathway', 'biological_process', 'GO:0007165', ('163', '180'))	('phosphorylation', 'Var', (182, 197))	('eIF4', 'cellular_component', 'GO:0008304', ('201', '205'))	('lower', 'NegReg', (211, 216))	('translation', 'biological_process', 'GO:0006412', ('48', '59'))	('mesothelioma', 'Disease', (75, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('182', '197'))
31780	24260583	In addition, the importance of deranged cap-dependent translation in mediating the effects of the IGF-I axis in mesothelioma was also established.	('IGF-I', 'Gene', '3479', (98, 103))	('IGF-I', 'Gene', (98, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('cap-dependent translation', 'MPA', (40, 65))	('deranged', 'Var', (31, 39))	('cap', 'Chemical', '-', (40, 43))	('translation', 'biological_process', 'GO:0006412', ('54', '65'))	('mesothelioma', 'Disease', (112, 124))
31782	24260583	These results demonstrate that the malignant phenotype conferred upon mesothelioma by aberrant cap-dependent translation may be abrogated by reduction of eIF4E activity.	('abrogated', 'NegReg', (128, 137))	('eIF4', 'cellular_component', 'GO:0008304', ('154', '158'))	('translation', 'biological_process', 'GO:0006412', ('109', '120'))	('activity', 'MPA', (160, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('eIF4E', 'Protein', (154, 159))	('mesothelioma', 'Disease', (70, 82))	('aberrant', 'Var', (86, 94))	('cap-dependent translation', 'MPA', (95, 120))	('cap', 'Chemical', '-', (95, 98))	('reduction', 'NegReg', (141, 150))
31804	24260583	The decrease in the level of eIF4E bound to the cap-analogue indicates that 4EASO strongly diminishes the levels of the eIF4F translation initiation complex.	('translation initiation', 'biological_process', 'GO:0006413', ('126', '148'))	('eIF4F', 'Gene', (120, 125))	('4EASO', 'Var', (76, 81))	('eIF4', 'cellular_component', 'GO:0008304', ('29', '33'))	('eIF4F', 'cellular_component', 'GO:0016281', ('120', '125'))	('cap', 'Chemical', '-', (48, 51))	('decrease', 'NegReg', (4, 12))	('4EASO', 'Chemical', '-', (76, 81))	('translation initiation complex', 'cellular_component', 'GO:0070992', ('126', '156'))	('eIF4F', 'Gene', '1977', (120, 125))	('diminishes', 'NegReg', (91, 101))
31814	24260583	There was a slight difference noted in the survival of mmASO treated cells compared to untreated cells, however, this difference was not statistically significant.	('mmASO', 'Chemical', '-', (55, 60))	('mmASO treated', 'Var', (55, 68))	('survival', 'CPA', (43, 51))
31815	24260583	Thus, the added efficacy of 4EASO to chemotherapy was more likely due to eIF4E knockdown rather than off target effects of ASO (Figure 5).	('4EASO', 'Chemical', '-', (28, 33))	('eIF4E', 'Gene', (73, 78))	('eIF4', 'cellular_component', 'GO:0008304', ('73', '77'))	('ASO', 'Chemical', 'MESH:D016376', (30, 33))	('ASO', 'Chemical', 'MESH:D016376', (123, 126))	('knockdown', 'Var', (79, 88))
31820	24260583	Hyperactivation of eIF4E increases the activity of the eIF4F translation initiation complex that is believed to result in the increase in translation of a limited pool of oncogenic mRNA transcripts that drives the malignant phenotype.	('eIF4', 'cellular_component', 'GO:0008304', ('19', '23'))	('eIF4F', 'Gene', '1977', (55, 60))	('translation', 'biological_process', 'GO:0006412', ('138', '149'))	('eIF4F', 'cellular_component', 'GO:0016281', ('55', '60'))	('increases', 'PosReg', (25, 34))	('eIF4E', 'Gene', (19, 24))	('Hyperactivation', 'Var', (0, 15))	('activity', 'MPA', (39, 47))	('translation initiation complex', 'cellular_component', 'GO:0070992', ('61', '91'))	('eIF4F', 'Gene', (55, 60))	('translation initiation', 'biological_process', 'GO:0006413', ('61', '83'))	('increase', 'PosReg', (126, 134))	('translation', 'MPA', (138, 149))
31821	24260583	To assess whether 4EASO mediated knockdown of eIF4E would affect the expression of malignancy-related proteins H2373 and H2596 cell lines were treated with 4EASO for 72 hours, lysates prepared and immunoblot analysis performed.	('eIF4', 'cellular_component', 'GO:0008304', ('46', '50'))	('eIF4E', 'Gene', (46, 51))	('knockdown', 'Var', (33, 42))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('4EASO', 'Chemical', '-', (18, 23))	('4EASO', 'Chemical', '-', (156, 161))	('expression', 'MPA', (69, 79))	('H2373', 'CellLine', 'CVCL:A533', (111, 116))	('malignancy', 'Disease', (83, 93))	('H2596', 'CellLine', 'CVCL:A546', (121, 126))	('affect', 'Reg', (58, 64))
31826	24260583	Substantial suppression of Bcl-2 and ODC was seen in H2373 while Bcl-2 was diminished in H2596 following 4EASO treatment (Figure 6).	('ODC', 'Gene', (37, 40))	('Bcl-2', 'MPA', (27, 32))	('suppression', 'NegReg', (12, 23))	('Bcl-2', 'molecular_function', 'GO:0015283', ('27', '32'))	('H2596', 'CellLine', 'CVCL:A546', (89, 94))	('ODC', 'Gene', '4953', (37, 40))	('Bcl-2', 'molecular_function', 'GO:0015283', ('65', '70'))	('H2373', 'Var', (53, 58))	('H2373', 'CellLine', 'CVCL:A533', (53, 58))	('4EASO', 'Chemical', '-', (105, 110))
31829	24260583	The view that deranged activation of cap-dependent translation is oncogenic is strongly recognized.	('translation', 'biological_process', 'GO:0006412', ('51', '62'))	('cap-dependent translation', 'MPA', (37, 62))	('deranged', 'Var', (14, 22))	('cap', 'Chemical', '-', (37, 40))
31832	24260583	Considerable evidence exists for therapeutic strategies that target eIF4E hyperactivation in preclinical models that result in inhibited tumor cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('143', '154'))	('tumor', 'Disease', (137, 142))	('eIF4', 'cellular_component', 'GO:0008304', ('68', '72'))	('inhibited', 'NegReg', (127, 136))	('hyperactivation', 'Var', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('eIF4E', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
31833	24260583	The strategy selected here for suppressing eIF4E hyperactivity was by direct targeting of eIF4E mRNA by specific antisense oligonucleotide (4EASO).	('hyperactivity', 'Disease', (49, 62))	('hyperactivity', 'Phenotype', 'HP:0000752', (49, 62))	('4EASO', 'Chemical', '-', (140, 145))	('eIF4', 'cellular_component', 'GO:0008304', ('90', '94'))	('eIF4E', 'Gene', (90, 95))	('eIF4', 'cellular_component', 'GO:0008304', ('43', '47'))	('suppressing', 'NegReg', (31, 42))	('antisense oligonucleotide', 'Var', (113, 138))	('hyperactivity', 'Disease', 'MESH:D006948', (49, 62))	('mRNA', 'MPA', (96, 100))	('oligonucleotide', 'Chemical', 'MESH:D009841', (123, 138))
31834	24260583	In previous work, the 4EASO was shown to diminish eIF4E levels and induce apoptosis in a panel of human cancer cell lines at nanomolar concentrations.	('apoptosis', 'CPA', (74, 83))	('4EASO', 'Var', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('4EASO', 'Chemical', '-', (22, 27))	('eIF4', 'cellular_component', 'GO:0008304', ('50', '54'))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('diminish', 'NegReg', (41, 49))	('eIF4E levels', 'MPA', (50, 62))	('cancer', 'Disease', (104, 110))	('human', 'Species', '9606', (98, 103))	('induce', 'PosReg', (67, 73))
31835	24260583	The systemic delivery of 4EASO (LY2275796) produced a knockdown in eIF4E, decreased malignancy-related proteins in a dose-dependent manner and prevented tumor growth in breast and prostate xenografts.	('malignancy', 'Disease', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('knockdown', 'Var', (54, 63))	('prevented', 'NegReg', (143, 152))	('LY2275796', 'Chemical', 'MESH:C569652', (32, 41))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('4EASO', 'Chemical', '-', (25, 30))	('eIF4E', 'Gene', (67, 72))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('decreased', 'NegReg', (74, 83))	('LY2275796', 'Var', (32, 41))	('eIF4', 'cellular_component', 'GO:0008304', ('67', '71'))
31844	24260583	Evidence is presented establishing that suppression of eIF4E levels induced by 4EASO treatment is correlated with reduced cell viability, induced apoptosis, disrupted eIF4F complex formation, reduced expression of malignancy related proteins and enhanced chemosensitization of mesothelioma cells.	('eIF4F', 'cellular_component', 'GO:0016281', ('167', '172'))	('reduced', 'NegReg', (114, 121))	('eIF4', 'cellular_component', 'GO:0008304', ('55', '59'))	('suppression', 'NegReg', (40, 51))	('eIF4F', 'Gene', '1977', (167, 172))	('expression', 'MPA', (200, 210))	('malignancy', 'Disease', (214, 224))	('reduced', 'NegReg', (192, 199))	('apoptosis', 'CPA', (146, 155))	('eIF4E', 'Protein', (55, 60))	('enhanced', 'PosReg', (246, 254))	('disrupted', 'NegReg', (157, 166))	('mesothelioma', 'Disease', (277, 289))	('eIF4F', 'Gene', (167, 172))	('4EASO', 'Chemical', '-', (79, 84))	('formation', 'biological_process', 'GO:0009058', ('181', '190'))	('mesothelioma', 'Disease', 'MESH:D008654', (277, 289))	('malignancy', 'Disease', 'MESH:D009369', (214, 224))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('4EASO treatment', 'Var', (79, 94))	('cell viability', 'CPA', (122, 136))
31932	29960000	showed that longer, rigid multiwall carbon nanotubes (~150 nm in diameter, ~8 mum in length) translocated to the parietal pleura and induced inflammation, fibrosis, and focal mesothelial cell proliferation to a greater extent than shorter, thinner agglomerates (~15 nm in diameter, 3 mum in length).	('inflammation', 'Disease', 'MESH:D007249', (141, 153))	('~150', 'Var', (54, 58))	('inflammation', 'Disease', (141, 153))	('fibrosis', 'Disease', 'MESH:D005355', (155, 163))	('fibrosis', 'Disease', (155, 163))	('induced', 'Reg', (133, 140))	('inflammation', 'biological_process', 'GO:0006954', ('141', '153'))	('cell proliferation', 'biological_process', 'GO:0008283', ('187', '205'))	('rat', 'Species', '10116', (255, 258))	('translocated', 'CPA', (93, 105))	('rat', 'Species', '10116', (199, 202))	('carbon', 'Chemical', 'MESH:D002244', (36, 42))	('focal mesothelial cell proliferation', 'CPA', (169, 205))
31935	29960000	A chronic inhalation assay in rats using MWCNT-7 induced lung adenomas and carcinomas at doses of 0.2 and 2 mg/m3 but no mesotheliomas.	('rats', 'Species', '10116', (30, 34))	('lung adenomas and carcinomas', 'Disease', 'MESH:D000236', (57, 85))	('mesotheliomas', 'Disease', 'MESH:D008654', (121, 134))	('mesotheliomas', 'Disease', (121, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('induced', 'Reg', (49, 56))	('MWCNT-7', 'Var', (41, 48))
31986	29960000	A lack or dysfunction of surfactant prevents the proper functioning of the alveoli and leads to severe lung diseases.	('prevents', 'NegReg', (36, 44))	('lung disease', 'Phenotype', 'HP:0002088', (103, 115))	('lung diseases', 'Phenotype', 'HP:0002088', (103, 116))	('dysfunction', 'Var', (10, 21))	('lung diseases', 'Disease', (103, 116))	('leads to', 'Reg', (87, 95))	('lung diseases', 'Disease', 'MESH:D008171', (103, 116))
32046	29960000	This pathogenicity mechanism is based on lysosomal membrane damage induced by hydrophobic long, rigid carbon nanotubes and is consistent with the lower pathogenicity of short or tangled carbon nanotubes summarized in section 2.	('hydrophobic long', 'Var', (78, 94))	('carbon', 'Chemical', 'MESH:D002244', (102, 108))	('lysosomal membrane', 'cellular_component', 'GO:0005765', ('41', '59'))	('carbon', 'Chemical', 'MESH:D002244', (186, 192))	('lysosomal membrane damage', 'MPA', (41, 66))
32157	27570625	DNA, RNA, or chromosomes, which may cause mutations or aneuploidy that may subsequently lead to cancer.	('aneuploidy', 'Disease', (55, 65))	('lead to', 'Reg', (88, 95))	('cause', 'Reg', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Disease', (96, 102))	('RNA', 'cellular_component', 'GO:0005562', ('5', '8'))	('aneuploidy', 'Disease', 'MESH:D000782', (55, 65))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (42, 51))
32162	27570625	Recent evidence indicates that epigenetics, heritable changes in gene expression that are not accompanied by changes in gene sequence, can also serve as a tumor-initiating event.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('changes', 'Reg', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('epigenetics', 'Var', (31, 42))	('tumor', 'Disease', (155, 160))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('gene expression', 'MPA', (65, 80))
32189	27570625	Analysis of CNT genotoxicity by measuring proto-oncogene K-ras mutations, a frequent occurrence in lung tumors, showed a much higher mutation frequency in mice receiving SWCNTs by inhalation (62.5%) compared to inhalation of air (26.7%) or SWCNT aspiration (12.5%).	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('lung tumors', 'Disease', (99, 110))	('SWCNTs', 'Chemical', '-', (170, 176))	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('aspiration', 'Phenotype', 'HP:0002835', (246, 256))	('toxicity', 'Disease', (20, 28))	('mutation', 'MPA', (133, 141))	('higher', 'PosReg', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('lung tumors', 'Phenotype', 'HP:0100526', (99, 110))	('SWCNT', 'Chemical', '-', (240, 245))	('K-ras', 'Gene', (57, 62))	('mice', 'Species', '10090', (155, 159))	('lung tumor', 'Phenotype', 'HP:0100526', (99, 109))	('lung tumors', 'Disease', 'MESH:D008175', (99, 110))	('SWCNT', 'Chemical', '-', (170, 175))
32190	27570625	The specific roles of K-ras mutations in fibrosis and fibrosis-associated malignancies are unclear and need further elucidation for risk assessment and pathologic intervention.	('fibrosis', 'Disease', 'MESH:D005355', (41, 49))	('fibrosis', 'Disease', (41, 49))	('malignancies', 'Disease', (74, 86))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))	('K-ras', 'Gene', (22, 27))	('mutations', 'Var', (28, 37))	('fibrosis', 'Disease', 'MESH:D005355', (54, 62))	('fibrosis', 'Disease', (54, 62))
32213	27570625	A one-year follow-up study found that thin and rigid MWCNTs caused mesothelioma that harbored Cdkn2a/2b homozygous deletions, a common feature in human and rodent mesothelioma, likely due to their ability to pierce and injure mesothelial cells along with macrophage activation.	('Cdkn2a', 'Gene', (94, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('Cdkn2a', 'Gene', '1029', (94, 100))	('macrophage activation', 'biological_process', 'GO:0042116', ('255', '276'))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('MWCNTs', 'Chemical', '-', (53, 59))	('mesothelioma', 'Disease', (163, 175))	('human', 'Species', '9606', (146, 151))	('caused', 'Reg', (60, 66))	('deletions', 'Var', (115, 124))	('mesothelioma', 'Disease', (67, 79))
32218	27570625	A slower tumor onset and lower morbidity rate were observed in MWCNTs with a smaller diameter (40 nm) and more bent structure (curved and narrow), with 80% morbidity after 16 and 23 months, respectively.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('40', 'Var', (95, 97))	('tumor', 'Disease', (9, 14))	('MWCNTs', 'Chemical', '-', (63, 69))
32225	27570625	It was further found that MWCNTs, like asbestos, induced mesothelial hyperplasia, which was associated with macrophage infiltration and inflammation-associated fibrosis, and likely linked to mesothelioma development.	('inflammation', 'Disease', (136, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (191, 203))	('MWCNTs', 'Var', (26, 32))	('MWCNTs', 'Chemical', '-', (26, 32))	('hyperplasia', 'Disease', 'MESH:D006965', (69, 80))	('inflammation', 'Disease', 'MESH:D007249', (136, 148))	('induced', 'Reg', (49, 56))	('mesothelioma', 'Disease', (191, 203))	('asbestos', 'Chemical', 'MESH:D001194', (39, 47))	('fibrosis', 'Disease', 'MESH:D005355', (160, 168))	('fibrosis', 'Disease', (160, 168))	('associated', 'Reg', (92, 102))	('inflammation', 'biological_process', 'GO:0006954', ('136', '148'))	('hyperplasia', 'Disease', (69, 80))
32271	27570625	Increased cell proliferation and invasion were observed in SWCNT- and MWCNT-treated cells, as well as asbestos-treated cells.	('MWCNT', 'Chemical', '-', (70, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('10', '28'))	('invasion', 'CPA', (33, 41))	('cell proliferation', 'CPA', (10, 28))	('SWCNT', 'Chemical', '-', (59, 64))	('MWCNT-treated', 'Var', (70, 83))	('Increased', 'PosReg', (0, 9))	('asbestos', 'Chemical', 'MESH:D001194', (102, 110))
32283	27570625	These cells expressed general stem cell markers such as Nanog, SOX2 and SOX17, as well as unique stem cell surface markers such as high CD133 and low CD24, which may be used for risk assessment and early detection of CNT-induced carcinogenesis.	('SOX2', 'Gene', (63, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (229, 243))	('low', 'Var', (146, 149))	('SOX2', 'Gene', '6657', (63, 67))	('carcinogenesis', 'Disease', (229, 243))	('SOX17', 'Gene', (72, 77))	('high CD133', 'Var', (131, 141))	('CD24', 'Gene', '100133941', (150, 154))	('CD24', 'Gene', (150, 154))	('cell surface', 'cellular_component', 'GO:0009986', ('102', '114'))	('SOX17', 'Gene', '64321', (72, 77))
32309	27405588	Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma Approximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14ARF and the 16INK4A genes.	('deletions', 'Var', (236, 245))	('bisphosphonate', 'Chemical', 'MESH:D004164', (34, 48))	('p14ARF', 'Gene', '1029', (282, 288))	('cytotoxicity', 'Disease', 'MESH:D064420', (101, 113))	('INK4A', 'Gene', '1029', (253, 258))	('mesothelioma', 'Disease', (117, 129))	('INK4A/ARF', 'Gene', (253, 262))	('p14ARF', 'Gene', (282, 288))	('INK4A', 'Gene', (253, 258))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('mesothelioma', 'Disease', (152, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('INK4A', 'Gene', '1029', (299, 304))	('INK4A/ARF', 'Gene', '1029', (253, 262))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('cytotoxicity', 'Disease', (101, 113))	('INK4A', 'Gene', (299, 304))
32311	27405588	We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene.	('p53', 'Gene', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (20, 35))	('bisphosphonate', 'Chemical', 'MESH:D004164', (62, 76))	('infected tumors', 'Disease', (180, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('p53', 'Gene', '7157', (292, 295))	('E1B', 'Gene', '6080', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('deletion', 'Var', (102, 110))	('human', 'Species', '9606', (245, 250))	('E1B', 'Gene', (139, 142))	('p53', 'Gene', (292, 295))	('ZOL', 'Chemical', 'MESH:D000077211', (37, 40))	('tumor', 'Disease', (189, 194))	('mesothelioma', 'Disease', (251, 263))	('augments', 'PosReg', (153, 161))	('infected tumors', 'Disease', 'MESH:D009369', (180, 195))	('p53', 'Gene', '7157', (162, 165))	('E1B', 'Gene', (118, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (251, 263))	('E1B', 'Gene', '6080', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (228, 233))
32321	27405588	Previous analyses showed that approximately 80 % of mesothelioma specimens had a homozygous deletion in the INK4A/ARF locus which encoded p14ARF and the 16INK4A genes, but the p53 genotype was infrequently mutated.	('INK4A', 'Gene', '1029', (155, 160))	('INK4A', 'Gene', '1029', (108, 113))	('INK4A/ARF', 'Gene', (108, 117))	('INK4A', 'Gene', (155, 160))	('INK4A', 'Gene', (108, 113))	('p53', 'Gene', (176, 179))	('p14ARF', 'Gene', '1029', (138, 144))	('deletion', 'Var', (92, 100))	('p53', 'Gene', '7157', (176, 179))	('mesothelioma', 'Disease', (52, 64))	('INK4A/ARF', 'Gene', '1029', (108, 117))	('p14ARF', 'Gene', (138, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
32380	27405588	Cells uninfected or infected with Ad-LacZ as a control however showed a minimal level of polyploidy and the sub-G1 fractions did not increase markedly in both MSTO-211H and NCI-H28 cells with Ad-LacZ.	('NCI-H28 cells', 'CellLine', 'CVCL:1555', (173, 186))	('polyploidy', 'Disease', (89, 99))	('Ad-LacZ', 'Var', (192, 199))	('polyploidy', 'Disease', 'MESH:D011123', (89, 99))
32423	27405588	Previous studies in fact reported that ZOL induced S-phase arrest and that the cell cycle changes were subjected to aberrant signals induced by mutated tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cell cycle', 'CPA', (79, 89))	('mutated', 'Var', (144, 151))	('ZOL', 'Chemical', 'MESH:D000077211', (39, 42))	('S-phase arrest', 'CPA', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('79', '89'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('S-phase', 'biological_process', 'GO:0051320', ('51', '58'))	('tumor', 'Disease', (152, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))
32432	27405588	On the other hand, mesothelioma is often defective of the Hippo pathways due to mutation of the NF/Merlin gene.	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('Merlin', 'Gene', (99, 105))	('Merlin', 'Gene', '4771', (99, 105))	('mutation', 'Var', (80, 88))	('mesothelioma', 'Disease', (19, 31))	('defective', 'NegReg', (41, 50))	('Hippo pathways', 'Pathway', (58, 72))
32435	27405588	ZOL thereby blocks one of the dysfunctional Hippo pathways and combinatory effects of ZOL and Ad-delE1B55 can inhibit a possible cross-talk between NF/Merlin and the p53 pathways in mesothelioma with deletion of both INK4A/ARF and NF/Merlin regions.	('deletion', 'Var', (200, 208))	('E1B', 'Gene', (100, 103))	('INK4A/ARF', 'Gene', '1029', (217, 226))	('ZOL', 'Chemical', 'MESH:D000077211', (86, 89))	('ZOL', 'Chemical', 'MESH:D000077211', (0, 3))	('Merlin', 'Gene', (151, 157))	('Merlin', 'Gene', '4771', (234, 240))	('Hippo pathways', 'Pathway', (44, 58))	('inhibit', 'NegReg', (110, 117))	('blocks', 'NegReg', (12, 18))	('p53', 'Gene', '7157', (166, 169))	('INK4A/ARF', 'Gene', (217, 226))	('cross-talk', 'MPA', (129, 139))	('E1B', 'Gene', '6080', (100, 103))	('mesothelioma', 'Disease', (182, 194))	('p53', 'Gene', (166, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('Merlin', 'Gene', '4771', (151, 157))	('Merlin', 'Gene', (234, 240))
32442	27405588	Down-regulated expression of integrin molecules and enhanced Ad infectivity can be in part attributable to the ZOL-mediated morphological changes, but inhibition of small G proteins also influences several intracellular signal pathways and may augment infectivity, for example, due to facilitated viral release into cytoplasm after binding to the cellular receptors.	('viral release into cytoplasm', 'MPA', (297, 325))	('infectivity', 'MPA', (252, 263))	('intracellular signal pathways', 'Pathway', (206, 235))	('binding', 'Interaction', (332, 339))	('small G proteins', 'Protein', (165, 181))	('binding', 'molecular_function', 'GO:0005488', ('332', '339'))	('augment', 'PosReg', (244, 251))	('intracellular', 'cellular_component', 'GO:0005622', ('206', '219'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('316', '325'))	('viral release', 'biological_process', 'GO:0019076', ('297', '310'))	('inhibition', 'Var', (151, 161))	('influences', 'Reg', (187, 197))	('facilitated', 'PosReg', (285, 296))	('ZOL', 'Chemical', 'MESH:D000077211', (111, 114))
32493	26787751	Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors This first-in-human phase I trial assessed the safety, tolerability, and preliminary anti-tumor activity of apitolisib (GDC-0980), a dual inhibitor of class I phosphatidylinositol-3-(PI3K) and mammalian target of rapamycin (mTOR) kinases.	('phosphatidylinositol-3', 'Chemical', '-', (325, 347))	('GDC-0980', 'Chemical', 'MESH:C569670', (29, 37))	('apitolisib', 'Gene', (274, 284))	('Patients', 'Species', '9606', (130, 138))	('Tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('109', '125'))	('Tumors', 'Disease', (159, 165))	('Mammalian Target of Rapamycin', 'Gene', (79, 108))	('Apitolisib', 'Chemical', '-', (17, 27))	('PI3K', 'molecular_function', 'GO:0016303', ('349', '353'))	('mTOR', 'Gene', (390, 394))	('apitolisib', 'Chemical', '-', (274, 284))	('Tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (256, 261))	('human', 'Species', '9606', (180, 185))	('mTOR', 'Gene', '2475', (390, 394))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('mammalian target of rapamycin', 'Gene', '2475', (359, 388))	('GDC-0980', 'Var', (286, 294))	('GDC-0980', 'Chemical', 'MESH:C569670', (286, 294))	('Tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('mammalian target of rapamycin', 'Gene', (359, 388))	('Mammalian Target of Rapamycin', 'Gene', '2475', (79, 108))
32508	26787751	Other causes of pathway hyperactivation include loss of function of the tumor suppressor PTEN, gain of function mutations in AKT and PDK1, or up-regulation of receptor tyrosine kinases.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PDK1', 'Gene', (133, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('mutations', 'Var', (112, 121))	('PDK1', 'molecular_function', 'GO:0004740', ('133', '137'))	('regulation', 'biological_process', 'GO:0065007', ('145', '155'))	('up-regulation', 'PosReg', (142, 155))	('AKT', 'Gene', (125, 128))	('PDK1', 'Gene', '5163', (133, 137))	('gain of function', 'PosReg', (95, 111))	('tumor', 'Disease', (72, 77))	('receptor tyrosine kinases', 'Enzyme', (159, 184))	('loss of function', 'NegReg', (48, 64))	('PTEN', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('AKT', 'Gene', '207', (125, 128))	('hyperactivation', 'PosReg', (24, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('PTEN', 'Gene', '5728', (89, 93))
32515	26787751	Phase I studies have been reported with other dual PI3K/mTOR inhibitors including BEZ-235, SF1126, BGT226, XL765, and PF-04691502, although the majority of these studies confirmed limited single agent anti-tumor efficacy.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('BGT226', 'Var', (99, 105))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('PF-04691502', 'Var', (118, 129))	('tumor', 'Disease', (206, 211))	('SF1126', 'Var', (91, 97))	('BEZ-235', 'Chemical', 'MESH:C531198', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('SF1126', 'CellLine', 'CVCL:2363', (91, 97))
32517	26787751	Tumor growth inhibition has been demonstrated in multiple xenograft cancer models with PI3K-mutant, PTEN-null, and KRAS-mutant cell lines.	('PTEN', 'Gene', (100, 104))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PTEN', 'Gene', '5728', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('KRAS', 'Gene', (115, 119))	('PI3K-mutant', 'Var', (87, 98))	('KRAS', 'Gene', '3845', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('cancer', 'Disease', (68, 74))	('Tumor growth', 'CPA', (0, 12))
32528	26787751	Hence, this expansion cohort enrolled patients with solid tumors or NHL that harbored a PIK3CA hotspot mutation.	('NHL', 'Disease', (68, 71))	('solid tumors', 'Disease', 'MESH:D009369', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('PIK3CA', 'Gene', '5290', (88, 94))	('NHL', 'Disease', 'MESH:D008228', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('NHL', 'Phenotype', 'HP:0012539', (68, 71))	('solid tumors', 'Disease', (52, 64))	('patients', 'Species', '9606', (38, 46))	('mutation', 'Var', (103, 111))	('PIK3CA', 'Gene', (88, 94))
32529	26787751	SCCHN also qualified if it was positive for human papillomavirus (HPV), in view of the high prevalence of PIK3CA mutations in these tumors.	('HPV', 'Species', '10566', (66, 69))	('human papillomavirus', 'Species', '10566', (44, 64))	('PIK3CA', 'Gene', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PIK3CA', 'Gene', '5290', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (113, 122))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
32535	26787751	The primary outcome measures were the occurrence of DLTs assessed using CTCAE (version 3.0) and defined as the following treatment-related adverse events (AEs) occurring within the first cycle: grade 4 thrombocytopenia, grade 4 neutropenia lasting >=5 days or in association with fever, fasting grade 4 or sustained (>=24 hours) or symptomatic grade 3 hyperglycemia, grade 4 hypercholesterolemia or triglyceridemia for 2 weeks despite lipid-lowering agent, grade 3 liver dysfunction, grade >=2 decrease in diffusion capacity of carbon monoxide (DLCO) as well as any grade >=3 non-hematological AE with the exception of alopecia or poorly managed grade 3 nausea, vomiting or diarrhea.	('liver dysfunction', 'Disease', 'MESH:D017093', (465, 482))	('diarrhea', 'Disease', 'MESH:D003967', (674, 682))	('fever', 'Phenotype', 'HP:0001945', (280, 285))	('grade 3 hyperglycemia', 'Phenotype', 'HP:0025501', (344, 365))	('alopecia', 'Phenotype', 'HP:0001596', (619, 627))	('neutropenia', 'Disease', 'MESH:D009503', (228, 239))	('hyperglycemia', 'Phenotype', 'HP:0003074', (352, 365))	('nausea', 'Disease', 'MESH:D009325', (654, 660))	('AEs', 'Chemical', '-', (155, 158))	('neutropenia', 'Phenotype', 'HP:0001875', (228, 239))	('liver dysfunction', 'Disease', (465, 482))	('vomiting', 'Disease', 'MESH:D014839', (662, 670))	('alopecia', 'Disease', 'MESH:D000505', (619, 627))	('AE', 'Chemical', '-', (594, 596))	('AE', 'Chemical', '-', (155, 157))	('diarrhea', 'Phenotype', 'HP:0002014', (674, 682))	('vomiting', 'Phenotype', 'HP:0002013', (662, 670))	('thrombocytopenia', 'Disease', (202, 218))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (375, 395))	('hyperglycemia', 'Disease', (352, 365))	('AE', 'Chemical', '-', (75, 77))	('alopecia', 'Disease', (619, 627))	('vomiting', 'Disease', (662, 670))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (375, 395))	('grade >=2', 'Var', (484, 493))	('nausea', 'Phenotype', 'HP:0002018', (654, 660))	('grade', 'Var', (457, 462))	('liver dysfunction', 'Phenotype', 'HP:0001410', (465, 482))	('fever', 'Disease', 'MESH:D005334', (280, 285))	('hyperglycemia', 'Disease', 'MESH:D006943', (352, 365))	('fever', 'Disease', (280, 285))	('neutropenia', 'Disease', (228, 239))	('decrease', 'NegReg', (494, 502))	('hypercholesterolemia', 'Disease', (375, 395))	('diarrhea', 'Disease', (674, 682))	('nausea', 'Disease', (654, 660))	('thrombocytopenia', 'Disease', 'MESH:D013921', (202, 218))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (202, 218))
32558	26787751	DNA was extracted for PIK3CA, NRAS, KRAS, BRAF, EGFR, and AKT1 mutational analysis using DxS allele-specific PCR, qRT-PCR assays, or Sanger Sequencing.	('BRAF', 'Gene', '673', (42, 46))	('mutational', 'Var', (63, 73))	('NRAS', 'Gene', '4893', (30, 34))	('EGFR', 'Gene', '1956', (48, 52))	('AKT1', 'Gene', '207', (58, 62))	('PIK3CA', 'Gene', '5290', (22, 28))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('KRAS', 'Gene', (36, 40))	('AKT1', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (36, 40))	('NRAS', 'Gene', (30, 34))	('BRAF', 'Gene', (42, 46))	('PIK3CA', 'Gene', (22, 28))
32559	26787751	The assays targeted eight single nucleotide mutations in four hotspots within the PIK3CA gene found to be common in human cancer and transformed cells in vitro (C420R, E542K, E545K, E545G, E545A, H1047R, H1047L, and H1047Y).	('C420R', 'Var', (161, 166))	('C420R', 'Mutation', 'rs121913272', (161, 166))	('E545K', 'Var', (175, 180))	('PIK3CA', 'Gene', '5290', (82, 88))	('H1047L', 'Var', (204, 210))	('H1047R', 'Var', (196, 202))	('H1047Y', 'Var', (216, 222))	('H1047R', 'Mutation', 'rs121913279', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('E545A', 'Mutation', 'rs121913274', (189, 194))	('E545G', 'Var', (182, 187))	('E545G', 'Mutation', 'rs121913274', (182, 187))	('PIK3CA', 'Gene', (82, 88))	('H1047Y', 'Mutation', 'rs121913281', (216, 222))	('E545A', 'Var', (189, 194))	('human', 'Species', '9606', (116, 121))	('E545K', 'Mutation', 'rs104886003', (175, 180))	('E542K', 'Mutation', 'rs121913273', (168, 173))	('cancer', 'Disease', (122, 128))	('H1047L', 'Mutation', 'rs121913279', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('E542K', 'Var', (168, 173))
32595	26787751	Radiological PD biomarker studies demonstrated decreased FDG-PET tumor uptake in the majority of patients following apitolisib treatment >=16 mg (Figure 2b); three-quarters of patients (9/12) with PIK3CA mutations treated at 40 mg apitolisib QD displayed more than a 25% mean decrease in maximum standardized uptake (SUVmax), among 10 out of 14 (71%) PIK3CA mutation patients who responded from all dose cohorts.	('PIK3CA', 'Gene', (197, 203))	('uptake', 'biological_process', 'GO:0098657', ('309', '315'))	('FDG', 'Chemical', 'MESH:D019788', (57, 60))	('apitolisib', 'Chemical', '-', (116, 126))	('uptake', 'biological_process', 'GO:0098739', ('309', '315'))	('tumor', 'Disease', (65, 70))	('maximum standardized uptake', 'MPA', (288, 315))	('uptake', 'biological_process', 'GO:0098657', ('71', '77'))	('PIK3CA', 'Gene', (351, 357))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PIK3CA', 'Gene', '5290', (197, 203))	('mutations', 'Var', (204, 213))	('PD', 'Disease', 'MESH:D010300', (13, 15))	('uptake', 'biological_process', 'GO:0098739', ('71', '77'))	('patients', 'Species', '9606', (367, 375))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('patients', 'Species', '9606', (97, 105))	('patients', 'Species', '9606', (176, 184))	('apitolisib', 'Chemical', '-', (231, 241))	('decrease', 'NegReg', (276, 284))	('PIK3CA', 'Gene', '5290', (351, 357))
32596	26787751	Furthermore, a comparison of PET responses between patients with steady-state AUC0-24h higher than the median exposure for the RP2D of 40 mg QD to patients below the median (Supplementary Figure 2a) demonstrated that a greater mean reduction in FDG uptake may still be seen with higher exposures (-34% with high vs -18% low exposure compared to median, p=0.028), although there are relatively few data points at low exposures as almost all FDG-PET data were acquired at 30 mg QD or higher.	('FDG', 'Chemical', 'MESH:D019788', (440, 443))	('FDG', 'Chemical', 'MESH:D019788', (245, 248))	('reduction', 'NegReg', (232, 241))	('patients', 'Species', '9606', (147, 155))	('AUC0-24h', 'Var', (78, 86))	('FDG uptake', 'MPA', (245, 255))	('patients', 'Species', '9606', (51, 59))	('uptake', 'biological_process', 'GO:0098739', ('249', '255'))	('uptake', 'biological_process', 'GO:0098657', ('249', '255'))
32606	26787751	Interestingly, evidence of anti-tumor activity was apparent in mesothelioma with 2 PRs in MPM patients by modified RECIST; one partial responder at 8mg QD had a non-hotspot PIK3CA mutation (R88Q) detected on sequencing (Supplementary Table 4).	('PIK3CA', 'Gene', '5290', (173, 179))	('patients', 'Species', '9606', (94, 102))	('MPM', 'Chemical', '-', (90, 93))	('mesothelioma', 'Disease', (63, 75))	('R88Q', 'Var', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('tumor', 'Disease', (32, 37))	('R88Q', 'Mutation', 'rs121913287', (190, 194))	('PIK3CA', 'Gene', (173, 179))
32609	26787751	One PR was confirmed for an E542K SCCHN PIK3CA mutant.	('E542K', 'Mutation', 'rs121913273', (28, 33))	('E542K', 'Var', (28, 33))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))
32610	26787751	Two additional patients (one SCCHN and one ovarian cancer) with unconfirmed PRs also had an E545K PIK3CA mutation (Figure 3b).	('E545K', 'Var', (92, 97))	('patients', 'Species', '9606', (15, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('PIK3CA', 'Gene', (98, 104))	('ovarian cancer', 'Disease', (43, 57))	('PIK3CA', 'Gene', '5290', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SCCHN', 'Disease', (29, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('E545K', 'Mutation', 'rs104886003', (92, 97))
32615	26787751	Of the 14 evaluable patients with PIK3CA mutations, there were 3 PRs (1 confirmed), 8 SD, and 3 PD as best radiological responses (Figure 3b, Supplementary Table 3).	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('SD', 'Disease', 'MESH:D029461', (86, 88))	('PIK3CA', 'Gene', '5290', (34, 40))	('PD', 'Disease', 'MESH:D010300', (96, 98))	('patients', 'Species', '9606', (20, 28))
32620	26787751	Only 2 patients of this cohort had molecular abnormalities detected, one PTEN loss and one PIK3CA mutation (E545A) (Supplementary Table 3) both with SD as their best response.	('PIK3CA', 'Gene', (91, 97))	('E545A', 'Mutation', 'rs121913274', (108, 113))	('molecular abnormalities', 'Disease', (35, 58))	('mutation', 'Var', (98, 106))	('SD', 'Disease', 'MESH:D029461', (149, 151))	('PIK3CA', 'Gene', '5290', (91, 97))	('PTEN loss', 'Disease', (73, 82))	('molecular abnormalities', 'Disease', 'MESH:C567116', (35, 58))	('patients', 'Species', '9606', (7, 15))	('PTEN loss', 'Disease', 'MESH:D006223', (73, 82))
32644	26787751	Significant reductions in SUVmax of >25% were recorded in three quarters of PIK3CA mutant patients and 66% of all patients treated at the RP2D of 40 mg QD.	('reductions', 'NegReg', (12, 22))	('mutant', 'Var', (83, 89))	('SUVmax', 'MPA', (26, 32))	('PIK3CA', 'Gene', (76, 82))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (90, 98))	('PIK3CA', 'Gene', '5290', (76, 82))
32650	26787751	Durable RECIST responses were detected at >=30 mg. Enrichment for PIK3CA mutations doubled the responses to 18.8%.	('PIK3CA', 'Gene', (66, 72))	('doubled', 'PosReg', (83, 90))	('PIK3CA', 'Gene', '5290', (66, 72))	('responses', 'MPA', (95, 104))	('mutations', 'Var', (73, 82))
32651	26787751	The biological background appears to define sensitivity, hence, the presence of a PIK3CA mutation alone may not associate with anti-tumor response, as seen with the contrasting response with the single agent BRAF inhibitors in melanoma and colorectal cancers.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('BRAF', 'Gene', '673', (208, 212))	('melanoma', 'Disease', (227, 235))	('colorectal cancers', 'Disease', 'MESH:D015179', (240, 258))	('PIK3CA', 'Gene', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('BRAF', 'Gene', (208, 212))	('mutation', 'Var', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('colorectal cancers', 'Disease', (240, 258))	('PIK3CA', 'Gene', '5290', (82, 88))	('presence', 'Var', (68, 76))	('tumor', 'Disease', (132, 137))
32657	26787751	Analysis of tumor tissue of the 27 MPM treated at the RP2D detected a much lower rate of PTEN loss (4%, 1/24) and PIK3CA mutations (5%, 1/21) compared to previous studies reporting 30-60% and up to 100%, respectively.	('PIK3CA', 'Gene', '5290', (114, 120))	('MPM', 'Chemical', '-', (35, 38))	('lower', 'NegReg', (75, 80))	('mutations', 'Var', (121, 130))	('PTEN loss', 'Disease', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('PIK3CA', 'Gene', (114, 120))	('PTEN loss', 'Disease', 'MESH:D006223', (89, 98))	('tumor', 'Disease', (12, 17))
32667	26787751	Durable RECIST responses were evident in mesothelioma, some PIK3CA mutant tumors, and SCCHN; the underlying reason for these remains to be elucidated.	('PIK3CA', 'Gene', (60, 66))	('mesothelioma', 'Disease', (41, 53))	('PIK3CA', 'Gene', '5290', (60, 66))	('SCCHN', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('mutant', 'Var', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
32684	26291840	Deletion status of p16 in effusion smear preparation correlates with that of underlying malignant pleural mesothelioma tissue Differentiating malignant pleural mesothelioma (MPM) cells morphologically from reactive mesothelial hyperplasia cells is problematic.	('p16', 'Gene', (19, 22))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (88, 118))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (98, 118))	('Deletion status', 'Var', (0, 15))	('effusion', 'Disease', (26, 34))	('mesothelial hyperplasia', 'Disease', (215, 238))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (98, 118))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (152, 172))	('malignant pleural mesothelioma', 'Disease', (142, 172))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (142, 172))	('p16', 'Gene', '1029', (19, 22))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (152, 172))	('malignant pleural mesothelioma', 'Disease', (88, 118))	('mesothelial hyperplasia', 'Disease', 'MESH:D018301', (215, 238))	('effusion', 'Disease', 'MESH:D010996', (26, 34))
32691	26291840	Moreover, the extent to which p16 was deleted in smears highly correlated with the extent of p16 deletion in tissues.	('p16', 'Gene', (30, 33))	('p16', 'Gene', '1029', (93, 96))	('p16', 'Gene', '1029', (30, 33))	('p16', 'Gene', (93, 96))	('deletion', 'Var', (97, 105))
32692	26291840	The p16 deletion percentages were also similar among smears, tissue surface proliferations, and invasive components.	('p16', 'Gene', '1029', (4, 7))	('p16', 'Gene', (4, 7))	('deletion', 'Var', (8, 16))
32694	26291840	However, the absence of p16 deletion in cytologic smear samples does not preclude MPM.	('MPM', 'Disease', (82, 85))	('deletion', 'Var', (28, 36))	('p16', 'Gene', '1029', (24, 27))	('p16', 'Gene', (24, 27))
32700	26291840	One of the most common genetic alterations is the homozygous deletion (HD) of the 9p21 locus, which includes a cluster of genes such as cyclin-dependent kinase inhibitor 2A (CDKN2A, also known as p16), CDKN2B (also known as p15), p14 ARF, and methylthioadenosine phosphorylase (MTAP).9, 17, 18, 19, 20 Previous studies reported that homozygous deletion of p16 can be detected by FISH in up to 70-80% of MPM cases.	('p16', 'Gene', '1029', (196, 199))	('p16', 'Gene', (356, 359))	('HD', 'Disease', 'MESH:D006816', (71, 73))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('136', '169'))	('p16', 'Gene', (196, 199))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('153', '169'))	('ARF', 'Disease', 'MESH:D058186', (234, 237))	('p16', 'Gene', '1029', (356, 359))	('deletion', 'Var', (344, 352))	('MPM', 'Disease', (403, 406))	('ARF', 'Disease', (234, 237))
32707	26291840	The aim of our study was to establish the correlation between the p16 deletion status of effusion cytology and that of underlying MPM tissues by FISH analysis for MPM cases in which both materials were available.	('deletion', 'Var', (70, 78))	('effusion', 'Disease', 'MESH:D010996', (89, 97))	('effusion', 'Disease', (89, 97))	('p16', 'Gene', (66, 69))	('p16', 'Gene', '1029', (66, 69))
32728	26291840	The deletion status of p16 determined by FISH in cytologic and histologic specimens in each case is summarized in Table 1.	('p16', 'Gene', '1029', (23, 26))	('deletion', 'Var', (4, 12))	('p16', 'Gene', (23, 26))
32731	26291840	Although the atypical mesothelial cells in smears may have contained MPM cells and also some RMC, no significant difference was detected in the proportions of p16 homozygous deletion between effusion smears and MPM tissues.	('p16', 'Gene', '1029', (159, 162))	('deletion', 'Var', (174, 182))	('p16', 'Gene', (159, 162))	('effusion', 'Disease', 'MESH:D010996', (191, 199))	('effusion', 'Disease', (191, 199))
32736	26291840	As shown in Table 3, all five positive cases that included both surface mesothelial proliferations and invasive components in histologic specimens showed similar p16 homozygous deletion rates in all three specimens: effusion smears, surface mesothelial proliferations, and underlying invasive MPM components (%HD-positive cells, 43.5 +- 21.4 [smears], 66.3 +- 16.5 [surface tissues], 68.0 +- 14.7 [invasive tissues]) (Table 3, Fig.	('HD', 'Disease', 'MESH:D006816', (310, 312))	('p16', 'Gene', '1029', (162, 165))	('deletion', 'Var', (177, 185))	('effusion', 'Disease', (216, 224))	('p16', 'Gene', (162, 165))	('effusion', 'Disease', 'MESH:D010996', (216, 224))
32738	26291840	There was a trend toward positive correlation in homozygous p16 deletion MPM cells among the three preparations, although the number of cases was not enough (smears vs surface tissues, Spearman's rho = 0.8000, P = 0.1041; smears vs invasive tissues, rho = 0.8000, P = 0.1041; surface vs invasive tissues, rho = 1.0000, P < 0.0001).	('p16', 'Gene', '1029', (60, 63))	('p16', 'Gene', (60, 63))	('deletion', 'Var', (64, 72))
32747	26291840	Hwang et al.14 revealed that it is possible to diagnose MPM using the detection of p16 deletion in surface mesothelial proliferations, even if tumor invasion was not evident, because the p16 deletion status of mesothelial surface proliferations and that of underlying mesotheliomas are correlated.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('MPM', 'Disease', (56, 59))	('p16', 'Gene', '1029', (83, 86))	('tumor', 'Disease', (143, 148))	('p16', 'Gene', '1029', (187, 190))	('mesotheliomas', 'Disease', 'MESH:D008654', (268, 281))	('mesotheliomas', 'Disease', (268, 281))	('p16', 'Gene', (83, 86))	('p16', 'Gene', (187, 190))	('deletion', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
32749	26291840	Moreover, we also revealed the correlation of p16 deletion status among effusion cytologic smears, surface mesothelial proliferations, and underlying invasive MPM components in five cases.	('p16', 'Gene', '1029', (46, 49))	('correlation', 'Interaction', (31, 42))	('deletion status', 'Var', (50, 65))	('effusion', 'Disease', 'MESH:D010996', (72, 80))	('effusion', 'Disease', (72, 80))	('p16', 'Gene', (46, 49))
32765	26291840	Detection of p16 deletion in smear cytologic samples may permit diagnosis of MPM without additional tissue examination in cases with clinical and radiologic evidence of a diffuse pleural tumor, although the absence of p16 deletion in cytologic smear samples does not preclude MPM.	('MPM', 'Disease', (276, 279))	('pleural tumor', 'Disease', (179, 192))	('MPM', 'Disease', (77, 80))	('p16', 'Gene', (218, 221))	('p16', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('deletion', 'Var', (17, 25))	('p16', 'Gene', '1029', (218, 221))	('p16', 'Gene', '1029', (13, 16))	('pleural tumor', 'Disease', 'MESH:D010997', (179, 192))
32772	19671764	Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects.	('mice', 'Species', '10090', (91, 95))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (58, 90))	('tumor growth', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor growth', 'Disease', 'MESH:D006130', (131, 143))	('panobinostat', 'Var', (147, 159))	('Panobinostat', 'Chemical', 'MESH:D000077767', (0, 12))	('immunodeficiency', 'Phenotype', 'HP:0002721', (74, 90))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (65, 90))	('immunodeficiency', 'Disease', (74, 90))	('immunodeficiency', 'Disease', 'MESH:D007153', (74, 90))	('panobinostat', 'Chemical', 'MESH:D000077767', (147, 159))
32792	19671764	The human mesothelioma cell lines OK-2 (SF151720), OK-4 (SF080125B), OK-5 (SF161815), and OK-6 (SF160520) were provided by the Stehlin Foundation.	('SF080125B', 'Var', (57, 66))	('human', 'Species', '9606', (4, 9))	('mesothelioma', 'Disease', (10, 22))	('SF161815', 'Var', (75, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (10, 22))	('SF151720', 'Var', (40, 48))	('SF160520', 'Var', (96, 104))
32824	19671764	The membranes were subsequently blocked with PBS containing 5% nonfat dry milk, and then probed with primary antibodies overnight at 4 C. The following primary antibodies and dilutions were used: anti-beta-actin (1:10,000; Sigma-Aldrich), anti-Bcl-XL (1:1,000; Santa Cruz Biotechnology), anti-Bid (1:500; Becton Dickinson Pharmingen), anti-p21 (1:1,000; Santa Cruz), anti-Bcl-2 (1:100; Dako Cytomation), anti-acetylated histone H4 (AH4; 1:1,000; Upstate Biotechnology), anti-acetylated histone H3 (AH3; 1:5,000; Upstate Biotechnology), anti-cleaved caspase 3 (1:1,000; Cell Signaling), anti-cleaved caspase 7 (1:1,000; Cell Signaling), anti-poly[ADP-ribose] polymerase (PARP; 1:1,000; Cell Signaling), and anti-alpha-tubulin (1:5,000; Sigma-Aldrich).	('Bcl-2', 'Gene', '596', (372, 377))	('Bid', 'Gene', '637', (293, 296))	('caspase 3', 'Gene', (549, 558))	('caspase 3', 'Gene', '836', (549, 558))	('anti-alpha-tubulin', 'Var', (706, 724))	('Signaling', 'biological_process', 'GO:0023052', ('690', '699'))	('Signaling', 'biological_process', 'GO:0023052', ('574', '583'))	('caspase 7', 'Gene', (599, 608))	('PBS', 'Disease', 'MESH:D011535', (45, 48))	('Signaling', 'biological_process', 'GO:0023052', ('624', '633'))	('p21', 'Gene', (340, 343))	('p21', 'Gene', '644914', (340, 343))	('Bid', 'Gene', (293, 296))	('Bcl-XL', 'Gene', '598', (244, 250))	('PBS', 'Disease', (45, 48))	('Bcl-2', 'molecular_function', 'GO:0015283', ('372', '377'))	('caspase 7', 'Gene', '840', (599, 608))	('Bcl-2', 'Gene', (372, 377))	('Bcl-XL', 'Gene', (244, 250))	('anti-cleaved', 'Var', (586, 598))	('anti-poly[ADP-ribose] polymerase (PARP; 1', 'Gene', '142', (636, 677))
32856	19671764	H69 cells exposed to panobinostat showed accumulation of cells with G2-M DNA content, which was initially coincident with but eventually was superseded by the proportion of nonviable cells (marked by sub-G1 DNA content; Fig.	('G2-M DNA content', 'Var', (68, 84))	('accumulation', 'PosReg', (41, 53))	('panobinostat', 'Chemical', 'MESH:D000077767', (21, 33))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('H69', 'CellLine', 'CVCL:8121', (0, 3))
32866	19671764	Although tumor regression was not observed, panobinostat significantly slowed tumor growth when compared with vehicle control for all four different in vivo models tested, and by an average of almost 60% (P < 0.05).	('slowed', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('panobinostat', 'Var', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('panobinostat', 'Chemical', 'MESH:D000077767', (44, 56))	('tumor', 'Disease', (9, 14))	('tumor growth', 'Disease', (78, 90))	('tumor', 'Disease', (78, 83))	('tumor growth', 'Disease', 'MESH:D006130', (78, 90))
32877	19671764	Compared with the corresponding control tumors, panobinostat resulted in a 53% decrease for H526-derived tumors (Fig.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('panobinostat', 'Chemical', 'MESH:D000077767', (48, 60))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('decrease', 'NegReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('panobinostat', 'Var', (48, 60))	('tumors', 'Disease', (40, 46))
32881	19671764	In contrast to the lack of tumor regression noted in NSCLC and Meso-derived xenografted tumors that were treated under identical conditions and doses, panobinostat resulted in dramatic tumor regression in two of the SCLC-derived tumors, with the size of the BK-T-derived tumors reduced from an average of 296 mm3 at the beginning of the treatment course to 116 mm3 at the end of the experiment, and RG-1-derived tumors decreased from an average of 185 mm3 at the beginning of the treatment course to 86 mm3 at the end of the experiment.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (412, 418))	('tumors', 'Disease', (271, 277))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('SCLC', 'Gene', (54, 58))	('SCLC', 'Gene', '7864', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('men', 'Species', '9606', (485, 488))	('tumor', 'Disease', (185, 190))	('men', 'Species', '9606', (389, 392))	('tumor', 'Disease', (27, 32))	('regression', 'NegReg', (191, 201))	('tumors', 'Disease', (412, 418))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('panobinostat', 'Var', (151, 163))	('men', 'Species', '9606', (531, 534))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('NSCLC', 'Disease', (53, 58))	('men', 'Species', '9606', (342, 345))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (229, 235))	('SCLC', 'Phenotype', 'HP:0030357', (216, 220))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('reduced', 'NegReg', (278, 285))	('tumors', 'Disease', 'MESH:D009369', (412, 418))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('SCLC', 'Gene', (216, 220))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('SCLC', 'Gene', '7864', (216, 220))	('panobinostat', 'Chemical', 'MESH:D000077767', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (412, 417))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('SCLC', 'Phenotype', 'HP:0030357', (54, 58))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (412, 417))
32893	19671764	5, acetylation of histone H3 and H4 was markedly increased by panobinostat treatment, indicating HDAC inhibition.	('HDAC', 'Gene', (97, 101))	('panobinostat', 'Chemical', 'MESH:D000077767', (62, 74))	('panobinostat', 'Var', (62, 74))	('HDAC', 'Gene', '9734', (97, 101))	('increased', 'PosReg', (49, 58))	('acetylation', 'MPA', (3, 14))	('men', 'Species', '9606', (80, 83))	('histone H3', 'Protein', (18, 28))
32894	19671764	Panobinostat was also associated with marked up-regulation of the proapoptotic markers t-Bid, cleaved PARP, cleaved caspase 3, and cleaved caspase 7; a marked decrease of the antiapoptosis factor Bcl-XL; and a small increase in the cyclin-dependent kinase inhibitor p21.	('PARP', 'Gene', (102, 106))	('cyclin-dependent', 'MPA', (232, 248))	('cleaved', 'MPA', (94, 101))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('249', '265'))	('Bid', 'Gene', (89, 92))	('Panobinostat', 'Chemical', 'MESH:D000077767', (0, 12))	('caspase 7', 'Gene', (139, 148))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('Bcl-XL', 'Gene', '598', (196, 202))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('232', '265'))	('decrease', 'NegReg', (159, 167))	('caspase 3', 'Gene', (116, 125))	('Bcl-XL', 'Gene', (196, 202))	('p21', 'Gene', (266, 269))	('caspase 3', 'Gene', '836', (116, 125))	('increase', 'PosReg', (216, 224))	('caspase 7', 'Gene', '840', (139, 148))	('p21', 'Gene', '644914', (266, 269))	('up-regulation', 'PosReg', (45, 58))	('Bid', 'Gene', '637', (89, 92))	('PARP', 'Gene', '142', (102, 106))	('Panobinostat', 'Var', (0, 12))
32925	19671764	However, we also found that panobinostat resulted in increased levels of the proapoptotic factors t-Bid, cleaved PARP, cleaved caspase 3, and cleaved caspase 7, accompanied by the disappearance of Bcl-XL and an increase in levels of the cyclin-dependent kinase (cdk) inhibitor p21.	('caspase 7', 'Gene', (150, 159))	('increased', 'PosReg', (53, 62))	('cleaved', 'MPA', (142, 149))	('levels', 'MPA', (63, 69))	('panobinostat', 'Chemical', 'MESH:D000077767', (28, 40))	('increase', 'PosReg', (211, 219))	('caspase 7', 'Gene', '840', (150, 159))	('PARP', 'Gene', '142', (113, 117))	('Bid', 'Gene', '637', (100, 103))	('PARP', 'Gene', (113, 117))	('caspase 3', 'Gene', (127, 136))	('p21', 'Gene', (277, 280))	('caspase 3', 'Gene', '836', (127, 136))	('p21', 'Gene', '644914', (277, 280))	('Bcl-XL', 'Gene', '598', (197, 203))	('Bcl-XL', 'Gene', (197, 203))	('cyclin', 'molecular_function', 'GO:0016538', ('237', '243'))	('cdk) inhibitor', 'molecular_function', 'GO:0004861', ('262', '276'))	('levels of the cyclin-dependent', 'MPA', (223, 253))	('cleaved', 'MPA', (105, 112))	('panobinostat', 'Var', (28, 40))	('Bid', 'Gene', (100, 103))	('disappearance', 'NegReg', (180, 193))
32931	19671764	This Bcl-2 sensitivity has resulted in SCLC being the primary target for a recent clinical trial using a Bcl-2 antisense oligonucleotide.	('oligonucleotide', 'Chemical', 'MESH:D009841', (121, 136))	('Bcl-2', 'molecular_function', 'GO:0015283', ('5', '10'))	('antisense oligonucleotide', 'Var', (111, 136))	('Bcl-2', 'Gene', (105, 110))	('Bcl-2', 'Gene', (5, 10))	('Bcl-2', 'Gene', '596', (105, 110))	('SCLC', 'Gene', '7864', (39, 43))	('Bcl-2', 'Gene', '596', (5, 10))	('SCLC', 'Gene', (39, 43))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('Bcl-2', 'molecular_function', 'GO:0015283', ('105', '110'))
32938	19671764	In vivo, panobinostat may inhibit angiogenesis or other microenvironment-related mechanisms that contribute to tumor growth and treatment resistance, thereby sensitizing the tumor to etoposide-induced mitotic death and inhibition of tumor growth, as shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor growth', 'Disease', 'MESH:D006130', (111, 123))	('etoposide', 'Chemical', 'MESH:D005047', (183, 192))	('etoposide-induced', 'MPA', (183, 200))	('angiogenesis', 'CPA', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor growth', 'Disease', (233, 245))	('panobinostat', 'Var', (9, 21))	('angiogenesis', 'biological_process', 'GO:0001525', ('34', '46'))	('tumor', 'Disease', (233, 238))	('sensitizing', 'Reg', (158, 169))	('inhibition', 'NegReg', (219, 229))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor growth', 'Disease', (111, 123))	('panobinostat', 'Chemical', 'MESH:D000077767', (9, 21))	('tumor', 'Disease', (111, 116))	('men', 'Species', '9606', (133, 136))	('mitotic death', 'Disease', (201, 214))	('mitotic death', 'Disease', 'MESH:D003643', (201, 214))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor growth', 'Disease', 'MESH:D006130', (233, 245))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('inhibit', 'NegReg', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('men', 'Species', '9606', (68, 71))
32942	19671764	Consequently, it is also possible that panobinostat modulates intracellular components beyond caspase activation, to sensitize cancer cells to killing by etoposide.	('sensitize', 'Reg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('intracellular', 'cellular_component', 'GO:0005622', ('62', '75'))	('panobinostat', 'Var', (39, 51))	('modulates', 'Reg', (52, 61))	('panobinostat', 'Chemical', 'MESH:D000077767', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('caspase activation', 'biological_process', 'GO:0006919', ('94', '112'))	('cancer', 'Disease', (127, 133))	('etoposide', 'Chemical', 'MESH:D005047', (154, 163))
32971	26503962	Solid tumor CAR targets under investigation are altered gene products arising from genetic mutations or altered splicing (EGFRvIII), altered glycosylation patterns (MUC-1), cancer-testis antigen-derived peptides (MAGE), differentiation antigens (CEA), overexpressed antigens in tumors (PSMA, GD2, CA125, Her-2, and mesothelin [MSLN]), or tumor-associated stroma (FAP, VEGFR) (see Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Disease', (278, 284))	('splicing', 'biological_process', 'GO:0045292', ('112', '120'))	('PSMA', 'molecular_function', 'GO:0043275', ('286', '290'))	('tumor', 'Disease', (338, 343))	('glycosylation patterns', 'MPA', (141, 163))	('mesothelin', 'Gene', (315, 325))	('glycosylation', 'biological_process', 'GO:0070085', ('141', '154'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('VEGFR', 'Gene', '3791', (368, 373))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('CA125', 'Gene', (297, 302))	('VEGFR', 'Gene', (368, 373))	('altered', 'Reg', (133, 140))	('mesothelin', 'Gene', '10232', (315, 325))	('splicing', 'MPA', (112, 120))	('tumor', 'Disease', (278, 283))	('FAP', 'Gene', (363, 366))	('CEA', 'Gene', (246, 249))	('PSMA', 'Gene', '2346', (286, 290))	('cancer-testis', 'Disease', 'MESH:D013736', (173, 186))	('Her-2', 'Gene', '2064', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('CEA', 'Gene', '5670', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('MUC-1', 'Gene', (165, 170))	('MUC-1', 'Gene', '4582', (165, 170))	('PSMA', 'Gene', (286, 290))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', (6, 11))	('CA125', 'Gene', '94025', (297, 302))	('CAR', 'cellular_component', 'GO:0005826', ('12', '15'))	('altered', 'Var', (104, 111))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mutations', 'Var', (91, 100))	('Her-2', 'Gene', (304, 309))	('FAP', 'Gene', '2191', (363, 366))	('cancer-testis', 'Disease', (173, 186))
32985	26503962	In contrast, preclinical and clinical studies increasingly show that aberrant MSLN expression plays an active role in both malignant transformation of tumors and tumor aggressiveness by promoting cancer cell proliferation, contributing to local invasion and metastasis, and conferring resistance to apoptosis induced by cytotoxic agents.	('local invasion', 'CPA', (239, 253))	('MSLN', 'Gene', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('malignant transformation', 'CPA', (123, 147))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('resistance to apoptosis', 'CPA', (285, 308))	('promoting', 'PosReg', (186, 195))	('aggressiveness', 'Phenotype', 'HP:0000718', (168, 182))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('contributing', 'PosReg', (223, 235))	('metastasis', 'CPA', (258, 268))	('apoptosis', 'biological_process', 'GO:0097194', ('299', '308'))	('tumors and tumor aggressiveness', 'Disease', 'MESH:D009369', (151, 182))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('apoptosis', 'biological_process', 'GO:0006915', ('299', '308'))	('aberrant', 'Var', (69, 77))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))
32986	26503962	MSLN can act bidirectionally, either by directly activating intracellular pathways via its GPI domain or by interacting with its receptor, CA125/MUC16.	('interacting', 'Interaction', (108, 119))	('GPI', 'Chemical', '-', (91, 94))	('MUC16', 'Gene', (145, 150))	('intracellular pathways', 'Pathway', (60, 82))	('CA125', 'Gene', (139, 144))	('activating', 'PosReg', (49, 59))	('MUC16', 'Gene', '94025', (145, 150))	('MSLN', 'Var', (0, 4))	('intracellular', 'cellular_component', 'GO:0005622', ('60', '73'))	('CA125', 'Gene', '94025', (139, 144))
32988	26503962	In addition, the high-affinity interaction between MSLN and CA125 leads to heterotypic cell adhesion, which facilitates metastasis of ovarian cancer cell lines.	('heterotypic cell adhesion', 'CPA', (75, 100))	('metastasis of ovarian cancer', 'Disease', (120, 148))	('CA125', 'Gene', '94025', (60, 65))	('interaction', 'Interaction', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CA125', 'Gene', (60, 65))	('facilitates', 'PosReg', (108, 119))	('leads to', 'Reg', (66, 74))	('MSLN', 'Var', (51, 55))	('cell adhesion', 'biological_process', 'GO:0007155', ('87', '100'))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (120, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))
32997	26503962	In our series, MSLN expression was found in 90% of epitheloid malignant pleural mesothelioma (n=139), 69% of lung adenocarcinoma (n=1209), 60% of breast (n=314), and 46% of esophageal cancers (n=125).	('epitheloid malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (51, 92))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('MSLN', 'Var', (15, 19))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lung adenocarcinoma', 'Disease', (109, 128))	('breast', 'Disease', (146, 152))	('esophageal cancers', 'Disease', (173, 191))	('epitheloid malignant pleural mesothelioma', 'Disease', (51, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (72, 92))	('esophageal cancers', 'Disease', 'MESH:D004938', (173, 191))	('found', 'Reg', (35, 40))
33007	26503962	Although no objective responses were reported, MSLN-specific CD8 T-cell responses were induced following cyclophosphamide, GVAX, and CRS-207 administration, along with a modest increase in survival.	('CRS-207', 'Var', (133, 140))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (105, 121))	('GVAX', 'Chemical', '-', (123, 127))
33044	26503962	Furthermore, intrapleurally administered MSLN CAR T cells persisted long-term, and eliminated a tumor re-challenge 200 days after the initial tumor eradication.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('a tumor', 'Disease', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CAR', 'cellular_component', 'GO:0005826', ('46', '49'))	('MSLN CAR', 'Var', (41, 49))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('eliminated', 'NegReg', (83, 93))	('a tumor', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
33053	26503962	The antitumoral activity of MSLN CAR T cells in vivo was established by the transient elevation of inflammatory cytokines in the sera, including IL-12, IL-6, G-CSF, MIP-1beta, MCP-1, IL1RA, and RANTES.	('IL1RA', 'Gene', '3554', (183, 188))	('sera', 'molecular_function', 'GO:0004617', ('129', '133'))	('IL1RA', 'Gene', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('MIP', 'molecular_function', 'GO:0004243', ('165', '168'))	('MCP-1', 'Gene', '6347', (176, 181))	('MIP-1beta', 'Gene', '6351', (165, 174))	('G-CSF', 'Gene', '1440', (158, 163))	('G-CSF', 'Gene', (158, 163))	('IL-6', 'molecular_function', 'GO:0005138', ('152', '156'))	('MSLN', 'Var', (28, 32))	('MIP-1beta', 'Gene', (165, 174))	('IL-6', 'Gene', '3569', (152, 156))	('IL1RA', 'molecular_function', 'GO:0005152', ('183', '188'))	('IL-12', 'molecular_function', 'GO:0005143', ('145', '150'))	('CAR', 'cellular_component', 'GO:0005826', ('33', '36'))	('MCP-1', 'Gene', (176, 181))	('tumor', 'Disease', (8, 13))	('MCP', 'molecular_function', 'GO:0004298', ('176', '179'))	('IL-6', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('RANTES', 'Gene', '6352', (194, 200))	('inflammatory cytokines', 'MPA', (99, 121))	('RANTES', 'Gene', (194, 200))	('elevation', 'PosReg', (86, 95))	('elevation of inflammatory cytokines', 'Phenotype', 'HP:0012649', (86, 121))
33062	26503962	The clinical-grade construct that incorporates an iCaspase-9 safety switch:which we will use in upcoming clinical trial of intrapleural MSLN-targeted CAR T-cell therapy (NCT02414269, Table 1), has been shown to be safe in preclinical experiments wherein a single dose of the AP1903 small molecule eliminated intrapleurally administered MSLN CAR T cells at the peak of their proliferation within 4 hours.	('Caspase-9', 'Gene', '842', (51, 60))	('CAR', 'cellular_component', 'GO:0005826', ('341', '344'))	('CAR', 'cellular_component', 'GO:0005826', ('150', '153'))	('Caspase-9', 'Gene', (51, 60))	('eliminated', 'NegReg', (297, 307))	('AP1903', 'Var', (275, 281))
33068	26503962	Potentiation of trafficking by cotransduction of chemokine receptors, such as CCR2 or CCR4, have been demonstrated previously in other preclinical models for T-cell therapy engineered with CARs as well as TCRs.	('Potentiation', 'PosReg', (0, 12))	('CCR2', 'Gene', (78, 82))	('CCR', 'molecular_function', 'GO:0043880', ('86', '89'))	('trafficking', 'MPA', (16, 27))	('CCR', 'molecular_function', 'GO:0043880', ('78', '81'))	('cotransduction', 'Var', (31, 45))	('CCR4', 'Gene', (86, 90))	('CCR4', 'Gene', '1233', (86, 90))	('CCR2', 'Gene', '729230', (78, 82))
33077	26503962	Overexpression of PD-L1 by tumor cells has been shown to induce MSLN CAR T-cell exhaustion.	('MSLN CAR T-cell exhaustion', 'CPA', (64, 90))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CAR', 'cellular_component', 'GO:0005826', ('69', '72'))	('tumor', 'Disease', (27, 32))	('Overexpression', 'Var', (0, 14))	('induce', 'PosReg', (57, 63))	('PD-L1', 'Gene', (18, 23))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (73, 90))	('PD-L1', 'Gene', '29126', (18, 23))
33081	26503962	In one such strategy, T cells are engineered to express an MSLN-specific CAR containing a CD3zeta domain and a folate receptor-specific CAR containing a CD28 costimulation domain (Figure 4B).	('CAR', 'cellular_component', 'GO:0005826', ('136', '139'))	('CD3zeta', 'Gene', '919', (90, 97))	('CD28', 'Gene', '940', (153, 157))	('MSLN-specific', 'Var', (59, 72))	('CD3zeta', 'Gene', (90, 97))	('CAR', 'cellular_component', 'GO:0005826', ('73', '76'))	('CD28', 'Gene', (153, 157))
33091	26503962	These clinical outcomes, combined with the preclinical data obtained with mesothelin CARs, argue favorably for a series of clinical trials targeting breast, lung, mesothelioma, ovarian and pancreatic cancer, which will soon be performed at multiple centers (NCT01355965, NCT01897415, NCT011583686, NCT02159716, NCT02414269, and NCT02465983).	('NCT01897415', 'Var', (271, 282))	('NCT02465983', 'Var', (328, 339))	('mesothelin', 'Gene', '10232', (74, 84))	('NCT02414269', 'Var', (311, 322))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast', 'Disease', (149, 155))	('mesothelioma', 'Disease', (163, 175))	('mesothelin', 'Gene', (74, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (189, 206))	('NCT011583686', 'Var', (284, 296))	('NCT01355965', 'Var', (258, 269))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010190', (177, 206))	('NCT02159716', 'Var', (298, 309))	('lung', 'Disease', (157, 161))
33141	23816056	Natural killer (NK) cells were analyzed using four colours staining with antibodies to CD3-PC7, CD8-PC5, CD16-PE and CD56-FITC.	('CD16', 'Gene', '2214', (105, 109))	('PC7', 'Gene', '9159', (91, 94))	('CD8', 'Gene', (96, 99))	('CD16', 'Gene', (105, 109))	('CD8', 'Gene', '925', (96, 99))	('PC5', 'Gene', (100, 103))	('CD56-FITC', 'Var', (117, 126))	('PC5', 'Gene', '5125', (100, 103))	('PC7', 'Gene', (91, 94))
33151	23816056	This low proportion of NK cells within pleural fluid of patients contrasted with the elevated proportion of NK cells in the peripheral blood of the same patients with median values (IQR) of 18.6% (11.6-33.5), 13.5% (7.8-22.3), 15.1% (9.3-22.5) for METS, BPLAE and MPM groups respectively compared to 9,6% (7.05-14.6) for the healthy control group.	('patients', 'Species', '9606', (56, 64))	('MPM', 'Chemical', '-', (264, 267))	('patients', 'Species', '9606', (153, 161))	('pleural fluid', 'Phenotype', 'HP:0002202', (39, 52))	('to 9', 'Species', '1214577', (297, 301))	('low proportion of NK cells', 'Phenotype', 'HP:0040218', (5, 31))	('MPM', 'Var', (264, 267))	('pleural', 'Disease', 'MESH:D010995', (39, 46))	('METS', 'Disease', (248, 252))	('pleural', 'Disease', (39, 46))
33254	20040979	An association has also been observed between polymorphism in DNA repair genes and asbestos-associated malignant mesothelioma.	('malignant mesothelioma', 'Disease', (103, 125))	('asbestos', 'Chemical', 'MESH:D001194', (83, 91))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (103, 125))	('polymorphism', 'Var', (46, 58))	('DNA repair genes', 'Gene', (62, 78))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (103, 125))	('DNA repair', 'biological_process', 'GO:0006281', ('62', '72'))
33288	33202573	Dysfunction of these kinases can contribute to cancer formation.	('Dysfunction', 'Var', (0, 11))	('contribute', 'Reg', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
33301	33202573	Nowadays, in advanced non-small cell lung cancer, molecular targeted therapy is the standard first-line treatment for patients with identified driver mutations; on the other hand, chemotherapy (platinum-based) is the standard treatment for patients without driver mutation or those with unknown mutation status.	('small cell lung cancer', 'Disease', (26, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('platinum', 'Chemical', 'MESH:D010984', (194, 202))	('small cell lung cancer', 'Disease', 'MESH:D055752', (26, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (26, 48))	('patients', 'Species', '9606', (240, 248))	('mutations', 'Var', (150, 159))	('patients', 'Species', '9606', (118, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (22, 48))
33333	33202573	In a separate work, the prognostic value of AURKA, Ki67, p53, p21, and WAF1 in resected NSCLC tissues showed that positive expressions of AURKA, Ki67, and p53 were unfavorable factors in the prognosis of NSCLC patients.	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('WAF1', 'Gene', (71, 75))	('AURKA', 'Gene', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NSCLC', 'Disease', (204, 209))	('NSCLC', 'Disease', (88, 93))	('WAF1', 'Gene', '1026', (71, 75))	('p53', 'Gene', (57, 60))	('patients', 'Species', '9606', (210, 218))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('Ki67', 'Var', (145, 149))	('p21', 'Gene', '1026', (62, 65))	('p53', 'Gene', '7157', (57, 60))	('p21', 'Gene', (62, 65))
33340	33202573	In corroboration of this observation, silencing of AURKB resensitized NSCLC cells to these chemotherapeutic agents by establishing correct chromosome segregation and restoring p53 expression, which suggests AURKB as a promising therapeutic target in this malignancy.	('restoring', 'PosReg', (166, 175))	('p53', 'Gene', (176, 179))	('malignancy', 'Disease', 'MESH:D009369', (255, 265))	('NSCLC', 'Disease', (70, 75))	('malignancy', 'Disease', (255, 265))	('expression', 'MPA', (180, 190))	('p53', 'Gene', '7157', (176, 179))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('AURKB', 'Gene', (51, 56))	('establishing', 'Reg', (118, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('chromosome segregation', 'biological_process', 'GO:0007059', ('139', '161'))	('silencing', 'Var', (38, 47))
33351	33202573	These EGFR-resistant cells were sensitive to AURKB inhibitor barasertib and S49076, which reduced the levels of pH3:a major product of AURKB mediating G1/S arrest and polyploidy.	('S49076', 'Var', (76, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('S arrest', 'Disease', (154, 162))	('reduced', 'NegReg', (90, 97))	('EGFR', 'Gene', (6, 10))	('S arrest', 'Disease', 'MESH:D006323', (154, 162))	('EGFR', 'Gene', '1956', (6, 10))	('polyploidy', 'Disease', (167, 177))	('levels', 'MPA', (102, 108))	('polyploidy', 'Disease', 'MESH:D011123', (167, 177))
33357	33202573	These findings affirmed that inhibition of AURKA could enhance the potency of chemotherapeutic agents and is capable of reversing the acquired resistance resulting from activated NF-kappaB.	('activated', 'PosReg', (169, 178))	('NF-kappaB', 'Gene', '4790', (179, 188))	('reversing', 'NegReg', (120, 129))	('inhibition', 'Var', (29, 39))	('enhance', 'PosReg', (55, 62))	('NF-kappaB', 'Gene', (179, 188))	('acquired resistance', 'MPA', (134, 153))	('potency of chemotherapeutic agents', 'MPA', (67, 101))	('AURKA', 'Gene', (43, 48))
33360	33202573	However, intriguingly, silencing of p53 in these cells showed high expression of AURKA rendering the cancer cells insensitive to gefitinib-induced apoptosis thus, indicating a role for AURKA in gefitinib resistance.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('silencing', 'Var', (23, 32))	('gefitinib', 'Chemical', 'MESH:D000077156', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (129, 138))	('expression', 'MPA', (67, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('AURKA', 'Gene', (81, 86))
33361	33202573	Accordingly, this study showed that silencing of AURKA in p53-knockdown cancer cells sensitized the A549 cancer cells to gefitinib, which also proved the inhibitory action of p53 in decreasing the ability of AURKA in conferring resistance to gefitinib.	('resistance', 'MPA', (228, 238))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('p53', 'Gene', '7157', (175, 178))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('p53', 'Gene', (175, 178))	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('AURKA', 'Gene', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('silencing', 'Var', (36, 45))	('gefitinib', 'Chemical', 'MESH:D000077156', (242, 251))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('p53', 'Gene', '7157', (58, 61))	('ability', 'MPA', (197, 204))	('sensitized', 'Reg', (85, 95))	('gefitinib', 'Chemical', 'MESH:D000077156', (121, 130))	('decreasing', 'NegReg', (182, 192))	('p53', 'Gene', (58, 61))
33367	33202573	Silencing of AURKB validated this concept, which resulted in a marked increased resistance to paclitaxel, confirming the effect that reduced AURKB expression modulates insensitivity to taxane in human lung cancer cells and, thus, may serve as predictive parameter to taxane response in NSCLC.	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('NSCLC', 'Disease', (286, 291))	('increased', 'PosReg', (70, 79))	('expression', 'MPA', (147, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('Silencing', 'Var', (0, 9))	('modulates', 'Reg', (158, 167))	('taxane', 'Chemical', 'MESH:C080625', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('AURKB', 'Gene', (141, 146))	('lung cancer', 'Disease', (201, 212))	('reduced', 'NegReg', (133, 140))	('human', 'Species', '9606', (195, 200))	('AURKB', 'Gene', (13, 18))	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('resistance to paclitaxel', 'MPA', (80, 104))	('NSCLC', 'Disease', 'MESH:D002289', (286, 291))	('insensitivity to taxane', 'MPA', (168, 191))	('taxane', 'Chemical', 'MESH:C080625', (185, 191))
33373	33202573	The preclinical characterization of the AURKA inhibitor, R763/AS703569 showed that it could inhibit Aurora kinases along with other kinases including FMS-related tyrosine kinase 3 (FLT3) conferring a potent anti-proliferative ability against many cell types having enlarged cell size, endo-reduplication, and apoptosis.	('FMS-related tyrosine kinase 3', 'Gene', (150, 179))	('AS703569', 'Chemical', 'MESH:C000592140', (62, 70))	('anti-proliferative ability', 'CPA', (207, 233))	('Aurora kinases', 'Gene', (100, 114))	('FLT3', 'Gene', '2322', (181, 185))	('inhibit', 'NegReg', (92, 99))	('FMS-related tyrosine kinase 3', 'Gene', '2322', (150, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('309', '318'))	('FMS', 'molecular_function', 'GO:0005011', ('150', '153'))	('apoptosis', 'biological_process', 'GO:0006915', ('309', '318'))	('Aurora kinases', 'Gene', '6790', (100, 114))	('R763/AS703569', 'Var', (57, 70))	('FLT3', 'Gene', (181, 185))
33374	33202573	In vivo, R763/AS703569 was able to inhibit tumor growth in different tumors including lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('AS703569', 'Chemical', 'MESH:C000592140', (14, 22))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lung cancer', 'Disease', (86, 97))	('tumors', 'Disease', (69, 75))	('R763/AS703569', 'Var', (9, 22))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (43, 48))	('inhibit', 'NegReg', (35, 42))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
33381	33202573	Sak and colleagues showed that inhibition of AURKB with low AZD1152-hydroxyquinazoline pyrazol anilide (AZD 1152-HQPA) concentrations concomitant to radiotherapy negatively affects repopulation of NSCLC cell lines, indicating the combined efficacy of AURKB inhibition and irradiation in regrowth of lung cancer cells.	('inhibition', 'NegReg', (31, 41))	('lung cancer', 'Disease', 'MESH:D008175', (299, 310))	('regrowth of lung', 'Phenotype', 'HP:0002089', (287, 303))	('Sak', 'Gene', (0, 3))	('negatively', 'NegReg', (162, 172))	('Sak', 'Gene', '10733', (0, 3))	('AZD 1152-HQPA', 'Chemical', '-', (104, 117))	('lung cancer', 'Disease', (299, 310))	('AZD1152-hydroxyquinazoline', 'Var', (60, 86))	('AURKB', 'Gene', (45, 50))	('repopulation', 'CPA', (181, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (299, 310))	('NSCLC', 'Disease', (197, 202))	('AZD1152-hydroxyquinazoline pyrazol anilide', 'Chemical', '-', (60, 102))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('affects', 'Reg', (173, 180))
33382	33202573	In another study, varying concentrations of AZD 1152-HQPA conferred a reduction in cell viability and ensued apoptotic cell death in four malignant mesothelioma cell lines, but without considerable effect on the level of AURKB expression at the translational level.	('reduction', 'NegReg', (70, 79))	('AZD 1152-HQPA', 'Var', (44, 57))	('cell viability', 'CPA', (83, 97))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (138, 160))	('death', 'Disease', 'MESH:D003643', (124, 129))	('AZD 1152-HQPA', 'Chemical', '-', (44, 57))	('death', 'Disease', (124, 129))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('109', '129'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (138, 160))	('malignant mesothelioma', 'Disease', (138, 160))
33383	33202573	AZD 1152, another selective inhibitor of AURKB, was also able to inhibit the growth of different human cancer xenografts including that of the lung, via suppression of histone H3 phosphorylation, accumulation of 4N DNA in cells and increased proportion of polyploid cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('179', '194'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('suppression', 'NegReg', (153, 164))	('accumulation', 'PosReg', (196, 208))	('inhibit', 'NegReg', (65, 72))	('AZD 1152', 'Chemical', 'MESH:C520647', (0, 8))	('human', 'Species', '9606', (97, 102))	('histone H3', 'Protein', (168, 178))	('increased', 'PosReg', (232, 241))	('growth', 'CPA', (77, 83))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('AZD', 'Var', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('215', '218'))
33386	33202573	found that dual inhibition of survivin by an antisense oligonucleotides and AURKB inhibitor ZM447439 synergistically radiosensitized mesothelioma cells by promoting mitotic cell arrest in mesothelioma cells after irradiation.	('mesothelioma', 'Disease', (188, 200))	('antisense oligonucleotides', 'Var', (45, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('promoting', 'PosReg', (155, 164))	('inhibition', 'NegReg', (16, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (188, 200))	('mitotic cell arrest', 'Disease', 'MESH:D006323', (165, 184))	('oligonucleotides', 'Chemical', 'MESH:D009841', (55, 71))	('ZM447439', 'Chemical', 'MESH:C474722', (92, 100))	('mesothelioma', 'Disease', (133, 145))	('mitotic cell arrest', 'Disease', (165, 184))	('survivin', 'Protein', (30, 38))
33387	33202573	S49076, a MET/AXL/FGFR inhibitor has been shown to negate AURKB activity and improve the anti-tumor efficacy of radiotherapy.	('improve', 'PosReg', (77, 84))	('AXL', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MET', 'Gene', '79811', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MET', 'Gene', (10, 13))	('negate', 'NegReg', (51, 57))	('tumor', 'Disease', (94, 99))	('activity', 'MPA', (64, 72))	('AXL', 'Gene', '558', (14, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('S49076', 'Var', (0, 6))	('AURKB', 'Protein', (58, 63))
33388	33202573	S49076 could exert its cytotoxic action at low doses on Met-dependent cells, GTL16 and U87-MG, via MET inhibition, whereas it restrained the growth of MET-independent lung adenocarcinoma cells H441, H460, and A549 at higher but clinically relevant doses by targeting AURKB.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (167, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (167, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('Met', 'Gene', (56, 59))	('MET', 'Gene', '79811', (99, 102))	('MET', 'Gene', (151, 154))	('targeting', 'Reg', (257, 266))	('cytotoxic action', 'CPA', (23, 39))	('AURKB', 'Protein', (267, 272))	('Met', 'Gene', '79811', (56, 59))	('lung adenocarcinoma', 'Disease', (167, 186))	('MET', 'Gene', (99, 102))	('MET', 'Gene', '79811', (151, 154))	('H460', 'CellLine', 'CVCL:0459', (199, 203))	('growth', 'MPA', (141, 147))	('S49076', 'Var', (0, 6))	('restrained', 'NegReg', (126, 136))	('A549', 'CellLine', 'CVCL:0023', (209, 213))	('inhibition', 'NegReg', (103, 113))
33389	33202573	Additionally, S49076 was able to improve the efficacy of radiotherapy in both MET-dependent and -independent cell lines under in vitro and in vivo conditions.	('improve', 'PosReg', (33, 40))	('MET', 'Gene', (78, 81))	('radiotherapy', 'CPA', (57, 69))	('MET', 'Gene', '79811', (78, 81))	('S49076', 'Var', (14, 20))
33391	33202573	Likewise, HOl-07 [(E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene) indolin-2-one] has been found to specifically inhibit AURKB in lung cancer cells in vitro and A549 xenografts via inhibition of histone H3-Ser 10 phosphorylation in a dose- and time-dependent manner.	('phosphorylation', 'biological_process', 'GO:0016310', ('229', '244'))	('histone', 'Protein', (211, 218))	('Ser', 'cellular_component', 'GO:0005790', ('222', '225'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('HOl-07', 'Var', (10, 16))	('inhibition', 'NegReg', (197, 207))	('inhibit', 'NegReg', (129, 136))	('(E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene) indolin-2-one', 'Chemical', '-', (18, 96))	('A549', 'CellLine', 'CVCL:0023', (177, 181))	('lung cancer', 'Disease', (146, 157))	('AURKB', 'Protein', (137, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('Ser', 'Chemical', 'MESH:D012694', (222, 225))
33392	33202573	Notably, silencing of AURKB profoundly reduced the sensitivity of tumor cells to HOl-07 that further attested the inhibitory activity of HOl-07 to AURKB.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('AURKB', 'Gene', (22, 27))	('tumor', 'Disease', (66, 71))	('silencing', 'Var', (9, 18))	('sensitivity', 'MPA', (51, 62))	('reduced', 'NegReg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
33395	33202573	The major component of rice bran oil, 24-methylenecyloartanyl ferulate (24-mCAF) was found capable of inhibiting cell proliferation and activating apoptosis in A549 lung cancer cells through an upregulation of the Myc binding protein 1A (MYBBP1A), a tumor suppressor that represses cancer development.	('activating', 'PosReg', (136, 146))	('MYBBP1A', 'Gene', '10514', (238, 245))	('cancer', 'Disease', (170, 176))	('inhibiting', 'NegReg', (102, 112))	('MYBBP1A', 'Gene', (238, 245))	('rice', 'Species', '4530', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('A549', 'CellLine', 'CVCL:0023', (160, 164))	('tumor', 'Disease', (250, 255))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('cell proliferation', 'CPA', (113, 131))	('mCAF', 'Gene', (75, 79))	('lung cancer', 'Disease', (165, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('250', '266'))	('24-methylenecyloartanyl ferulate', 'Chemical', '-', (38, 70))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('apoptosis', 'CPA', (147, 156))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('cancer', 'Disease', (282, 288))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('24-methylenecyloartanyl', 'Var', (38, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('250', '266'))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('upregulation', 'PosReg', (194, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('mCAF', 'Gene', '104272', (75, 79))
33400	33202573	Likewise, ZM447439, an Aurora kinase inhibitor, has shown effective inhibition of both AURKA and AURKB activities via reduction in histone H3 phosphorylation, resulting in decreased cell growth in mesothelioma cell lines.	('AURKB', 'Protein', (97, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('ZM447439', 'Chemical', 'MESH:C474722', (10, 18))	('histone H3 phosphorylation', 'MPA', (131, 157))	('activities', 'MPA', (103, 113))	('cell growth', 'biological_process', 'GO:0016049', ('182', '193'))	('reduction', 'NegReg', (118, 127))	('decreased', 'NegReg', (172, 181))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('30', '46'))	('ZM447439', 'Var', (10, 18))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('AURKA', 'Protein', (87, 92))	('inhibition', 'NegReg', (68, 78))	('mesothelioma', 'Disease', (197, 209))
33403	33202573	In vitro assays showed that GSK 1070916 conferred a dose-dependent inhibition of histone H3 phosphorylation, a specific substrate of AURKB and conveyed anti-tumor effects in ten human tumor xenografts, including lung cancer.	('tumor', 'Disease', (157, 162))	('GSK', 'molecular_function', 'GO:0050321', ('28', '31'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibition', 'NegReg', (67, 77))	('histone H3', 'Protein', (81, 91))	('lung cancer', 'Disease', (212, 223))	('human', 'Species', '9606', (178, 183))	('GSK 1070916', 'Var', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('GSK 1070916', 'Chemical', 'MESH:C544308', (28, 39))
33419	33202573	The predictive potential of c-Myc expression and cell cycle mutations as biomarkers for alisertib efficacy is encouraging, but necessitates further validation.	('c-Myc', 'Gene', (28, 33))	('cell cycle', 'CPA', (49, 59))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('alisertib', 'Chemical', 'MESH:C550258', (88, 97))	('c-Myc', 'Gene', '4609', (28, 33))	('mutations', 'Var', (60, 69))
33427	33202573	AT9283, an inhibitor of AURKA and AURKB, has been assessed in a phase I dose escalation study in patients with advanced solid tumors including NSCLC.	('tumors', 'Disease', (126, 132))	('NSCLC', 'Disease', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('AT9283', 'Var', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('patients', 'Species', '9606', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
33428	33202573	AT9283 was generally tolerated with toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue, and alopecia.	('myelosuppression, gastrointestinal disturbance', 'Disease', 'MESH:D005767', (77, 123))	('fatigue', 'Disease', 'MESH:D005221', (125, 132))	('alopecia', 'Disease', (138, 146))	('AT9283', 'Var', (0, 6))	('alopecia', 'Phenotype', 'HP:0001596', (138, 146))	('fatigue', 'Disease', (125, 132))	('fatigue', 'Phenotype', 'HP:0012378', (125, 132))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
33465	26894330	In the special cases of electron contamination errors, a ranking of "Low-Mid" was assigned because it only had a nonnegligible (2.1%) effect on one of the five clinical plans analyzed (the scalp plan).	('scalp plan', 'Phenotype', 'HP:0010541', (189, 199))	('errors', 'Var', (47, 53))	('electron contamination', 'MPA', (24, 46))	('scalp plan', 'Disease', 'MESH:C538225', (189, 199))	('scalp plan', 'Disease', (189, 199))
33469	26894330	In general the clinical effect was minimal and within fractions of a percent, with the exception of the V20Gy in the untreated left lung in the mesothelioma case which saw a change of more than 6% its original value.	('mesothelioma', 'Disease', (144, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('V20Gy', 'Var', (104, 109))
33470	26894330	Upon calculation of the percent depth-dose curves and dose profiles, a difference of up to 20% is observable in the surface dose in the PDD for changes of 70 mm in .	('PDD', 'Disease', (136, 139))	('changes', 'Var', (144, 151))	('PDD', 'Disease', 'MESH:D003966', (136, 139))
33471	26894330	The MLC DLG is entered separately from the AAA beam modeling algorithm, hence errors in the DLG were the least likely to be detected by the TPS.	('errors', 'Var', (78, 84))	('MLC', 'Gene', (4, 7))	('MLC', 'Gene', '23209', (4, 7))
33473	26894330	The most sensitive plans to errors in transmission factor were the head and neck plan and scalp plan.	('scalp plan', 'Disease', 'MESH:C538225', (90, 100))	('scalp plan', 'Phenotype', 'HP:0010541', (90, 100))	('scalp plan', 'Disease', (90, 100))	('neck', 'cellular_component', 'GO:0044326', ('76', '80'))	('errors', 'Var', (28, 34))
33479	26894330	10 shows that the OAR TLDs are more sensitive to errors in flattening filter material and MLC transmission factor.	('errors', 'Var', (49, 55))	('MLC', 'Gene', (90, 93))	('MLC', 'Gene', '23209', (90, 93))
33487	28929108	Indeed, exposure to MWCNT has been shown to induce lung cancer and even mesothelioma, but contradictory results also exist.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('induce', 'PosReg', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('mesothelioma', 'Disease', (72, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('MWCNT', 'Var', (20, 25))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('MWCNT', 'Chemical', '-', (20, 25))
33489	28929108	It was found that MWCNT did not affect MeT-5A cell proliferation at 10 mug/cm2 within 72 h treatment, but under the same condition, MWCNT induced genotoxicity and perturbed cell motility.	('cell motility', 'CPA', (173, 186))	('MWCNT', 'Chemical', '-', (18, 23))	('cell motility', 'biological_process', 'GO:0048870', ('173', '186'))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('perturbed', 'NegReg', (163, 172))	('toxicity', 'Disease', (150, 158))	('MWCNT', 'Var', (132, 137))	('MWCNT', 'Chemical', '-', (132, 137))	('rat', 'Species', '10116', (58, 61))	('mug', 'molecular_function', 'GO:0043739', ('71', '74'))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
33494	28929108	Indeed, many publications have shown that MWCNT could induce mesothelioma in rodents and exhibit genotoxic effects in various cell systems.	('genotoxic effects', 'CPA', (97, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (61, 73))	('MWCNT', 'Chemical', '-', (42, 47))	('MWCNT', 'Var', (42, 47))	('mesothelioma', 'Disease', (61, 73))	('induce', 'PosReg', (54, 60))
33495	28929108	For example, MWCNT caused genotoxic injury in different cell lines, leading to the induction of high mobility group box-1 protein (HMGB1), reactive oxygen species (ROS), or hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutations.	('reactive', 'MPA', (139, 147))	('hypoxanthine-guanine phosphoribosyl transferase', 'Gene', (173, 220))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (139, 162))	('HPRT', 'Gene', '3251', (222, 226))	('hypoxanthine-guanine phosphoribosyl transferase', 'Gene', '3251', (173, 220))	('mutations', 'Var', (228, 237))	('HPRT', 'Gene', (222, 226))	('HMGB1', 'Gene', (131, 136))	('high mobility group box-1', 'Gene', '3146', (96, 121))	('genotoxic injury', 'Disease', (26, 42))	('MWCNT', 'Var', (13, 18))	('HPRT', 'molecular_function', 'GO:0004422', ('222', '226'))	('MWCNT', 'Chemical', '-', (13, 18))	('HMGB1', 'Gene', '3146', (131, 136))	('genotoxic injury', 'Disease', 'MESH:D058186', (26, 42))	('high mobility group box-1', 'Gene', (96, 121))	('ROS', 'Chemical', 'MESH:D017382', (164, 167))
33497	28929108	Furthermore, fully characterized MWCNT were able to induce epithelial-mesenchymal transition (EMT) in human bronchial epithelial cells (BEAS-2B), and a neoplastic-like transformation was demonstrated by increased cell proliferation, anchorage-independent growth, invasion, and angiogenesis in human lung epithelial cells (SAECs) at occupationally relevant concentrations.	('BEAS-2B', 'CellLine', 'CVCL:0168', (136, 143))	('epithelial-mesenchymal transition', 'CPA', (59, 92))	('angiogenesis', 'biological_process', 'GO:0001525', ('277', '289'))	('increased', 'PosReg', (203, 212))	('cell proliferation', 'biological_process', 'GO:0008283', ('213', '231'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('59', '92'))	('neoplastic-like transformation', 'CPA', (152, 182))	('anchorage-independent growth', 'CPA', (233, 261))	('rat', 'Species', '10116', (363, 366))	('human', 'Species', '9606', (102, 107))	('invasion', 'CPA', (263, 271))	('cell proliferation', 'CPA', (213, 231))	('angiogenesis', 'CPA', (277, 289))	('MWCNT', 'Chemical', '-', (33, 38))	('human', 'Species', '9606', (293, 298))	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('rat', 'Species', '10116', (194, 197))	('rat', 'Species', '10116', (225, 228))	('MWCNT', 'Var', (33, 38))	('induce', 'PosReg', (52, 58))
33498	28929108	Moreover, it was reported that MWCNT could cause lung cancer and mesothelioma in rats in vivo and induce DNA damage in rat lung cells and DNA damage lasted even 90 days after exposure.	('MWCNT', 'Var', (31, 36))	('induce', 'Reg', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cause', 'Reg', (43, 48))	('MWCNT', 'Chemical', '-', (31, 36))	('mesothelioma', 'Disease', (65, 77))	('rats', 'Species', '10116', (81, 85))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('rat', 'Species', '10116', (81, 84))	('rat', 'Species', '10116', (119, 122))	('DNA damage', 'MPA', (105, 115))	('lung cancer', 'Disease', (49, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
33502	28929108	For instance, no induction of DNA damage was observed in A549 and BEAS-2B cells after NM-401, NM-402, and NM403 MWCNT treatments by the comet assay.	('NM-401', 'Var', (86, 92))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('NM403 MWCNT', 'Var', (106, 117))	('BEAS-2B', 'CellLine', 'CVCL:0168', (66, 73))	('MWCNT', 'Chemical', '-', (112, 117))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('NM-402', 'Var', (94, 100))	('comet', 'Species', '302767', (136, 141))
33537	28929108	As shown in Figure 1(a), the cell viability was suppressed significantly at concentrations >= 20 mug/cm2 throughout the 24 h period compared with control cells.	('>= 20 mug/cm2', 'Var', (91, 104))	('rat', 'Species', '10116', (83, 86))	('suppressed', 'NegReg', (48, 58))	('cell viability', 'CPA', (29, 43))	('mug', 'molecular_function', 'GO:0043739', ('97', '100'))
33542	28929108	M-MeT-5A cells showed a significant increase in cell proliferation rate above controls at 48 and 72 hours after seeding (Figure 2(b)).	('rat', 'Species', '10116', (67, 70))	('cell proliferation rate', 'CPA', (48, 71))	('increase', 'PosReg', (36, 44))	('rat', 'Species', '10116', (60, 63))	('M-MeT-5A', 'Var', (0, 8))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
33551	28929108	As shown in Figure 5, MWCNT caused a decreased trend of cell invasion within 72 h exposure, and at 30 days, it was decreased to 44% compared to that of control MeT-5A cells (P < 0.05).	('MWCNT', 'Var', (22, 27))	('cell invasion', 'CPA', (56, 69))	('decreased', 'NegReg', (115, 124))	('MWCNT', 'Chemical', '-', (22, 27))	('decreased', 'NegReg', (37, 46))
33571	28929108	It has been reported that MWCNT-induced formation of polyploidization and aneuploidization may be attributed to the cell morphology changes.	('MWCNT', 'Chemical', '-', (26, 31))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('aneuploidization', 'Var', (74, 90))	('polyploidization', 'MPA', (53, 69))
33572	28929108	In our earlier study, MWCNT caused increased expression of actin as well as actin filament remodeling in A549 cells, which may be another reason for the morphology change.	('increased', 'PosReg', (35, 44))	('actin filament', 'cellular_component', 'GO:0005884', ('76', '90'))	('MWCNT', 'Var', (22, 27))	('MWCNT', 'Chemical', '-', (22, 27))	('expression', 'MPA', (45, 55))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('actin', 'MPA', (76, 81))	('actin', 'Protein', (59, 64))
33589	28929108	Likewise, 3 months of MWCNT exposure to MeT-5A cells also resulted in increased invasion capacity in our study.	('invasion capacity', 'CPA', (80, 97))	('MWCNT', 'Chemical', '-', (22, 27))	('MeT-5A', 'Var', (40, 46))	('increased', 'PosReg', (70, 79))
33595	28929108	Knockdown of Annexin 1 expression resulted in a significant reduction in invasion in colorectal adenocarcinoma epithelial cells SKCO-15.	('colorectal adenocarcinoma', 'Disease', (85, 110))	('Knockdown', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (85, 110))	('Annexin 1', 'Gene', (13, 22))	('reduction', 'NegReg', (60, 69))	('invasion', 'CPA', (73, 81))	('Annexin 1', 'Gene', '301', (13, 22))	('SKCO-15', 'CellLine', 'CVCL:A337', (128, 135))
33596	28929108	Similarly, in our study, downregulated Annexin 1 decreased cell migration in MeT-5A cells.	('rat', 'Species', '10116', (67, 70))	('Annexin 1', 'Gene', (39, 48))	('cell migration', 'CPA', (59, 73))	('Annexin 1', 'Gene', '301', (39, 48))	('decreased', 'NegReg', (49, 58))	('downregulated', 'Var', (25, 38))	('cell migration', 'biological_process', 'GO:0016477', ('59', '73'))
33600	28929108	Annexin 5 knockdown also resulted in significantly reduced proliferation, migration, invasion, and in situ lymph node adhesion potentials of hepatocarcinoma Hca-F cells in proportion to its knockdown extent.	('proliferation', 'CPA', (59, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('reduced', 'NegReg', (51, 58))	('Annexin 5', 'Protein', (0, 9))	('rat', 'Species', '10116', (77, 80))	('rat', 'Species', '10116', (66, 69))	('in situ lymph node adhesion potentials', 'CPA', (99, 137))	('migration', 'CPA', (74, 83))	('invasion', 'CPA', (85, 93))	('knockdown', 'Var', (10, 19))	('Hca-F', 'CellLine', 'CVCL:D015', (157, 162))	('hepatocarcinoma', 'Disease', (141, 156))	('hepatocarcinoma', 'Disease', 'None', (141, 156))
33602	28929108	Loss of Annexin 6 suppresses the invasiveness and motility of breast cancer (BC) and BC cells, while enhancing the anchorage-independent cell growth of BC cells.	('BC', 'Phenotype', 'HP:0003002', (77, 79))	('Annexin 6', 'Gene', (8, 17))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Annexin 6', 'Gene', '309', (8, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('anchorage-independent cell growth', 'CPA', (115, 148))	('enhancing', 'PosReg', (101, 110))	('cell growth', 'biological_process', 'GO:0016049', ('137', '148'))	('invasiveness and motility of breast cancer', 'Disease', 'MESH:D001943', (33, 75))	('suppresses', 'NegReg', (18, 28))	('Loss', 'Var', (0, 4))	('BC', 'Phenotype', 'HP:0003002', (152, 154))
33609	28929108	The cellular responses of MeT-5A to short-term and long-term MWCNT treatments are different, and after long-term exposure, MeT-5A cells exhibit certain characteristics related to carcinogenic potential.	('carcinogenic', 'Disease', 'MESH:D063646', (179, 191))	('MeT-5A', 'Var', (123, 129))	('carcinogenic', 'Disease', (179, 191))	('MWCNT', 'Chemical', '-', (61, 66))
33742	27401493	The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 including variants (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions.	('SSX1', 'Gene', '6756', (37, 41))	('fusions', 'Var', (132, 139))	('SSX4', 'Gene', (113, 117))	('SS18', 'Gene', '6760', (59, 63))	('SSX1', 'Gene', (37, 41))	('SS18', 'Gene', (32, 36))	('SSX2', 'Gene', '6757', (64, 68))	('variants', 'Var', (79, 87))	('SS18', 'Gene', '6760', (108, 112))	('SSX2', 'Gene', (64, 68))	('SS18', 'Gene', (59, 63))	('SS18', 'Gene', '6760', (32, 36))	('SS18', 'Gene', (108, 112))	('SSX4', 'Gene', '6759', (113, 117))
33749	27401493	SSs are characterized by the t(X;18)(p11.2;q11.2) translocation, which leads to SS18-SSX gene fusion, and extremely rare neoplasms harbor SS18L1-SSX1, resulting from t(X;20).	('neoplasms', 'Disease', (121, 130))	('SSX', 'Gene', (85, 88))	('SS18L1', 'Gene', '26039', (138, 144))	('SSX', 'Gene', '6757', (145, 148))	('SSs', 'Disease', (0, 3))	('SS18', 'Gene', '6760', (138, 142))	('t(X;20', 'Var', (166, 172))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (29, 49))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('SSX', 'Gene', (145, 148))	('leads to', 'Reg', (71, 79))	('SS18', 'Gene', (80, 84))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('SS18L1', 'Gene', (138, 144))	('SSX1', 'Gene', '6756', (145, 149))	('SSX1', 'Gene', (145, 149))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('SSX', 'Gene', '6757', (85, 88))	('SS18', 'Gene', '6760', (80, 84))	('SS18', 'Gene', (138, 142))
33821	27401493	The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions.	('SSX1', 'Gene', '6756', (37, 41))	('SS18', 'Gene', '6760', (59, 63))	('SSX1', 'Gene', (37, 41))	('SS18', 'Gene', (32, 36))	('fusions', 'Var', (113, 120))	('SS18', 'Gene', '6760', (89, 93))	('SSX2', 'Gene', (64, 68))	('SS18', 'Gene', (89, 93))	('SS18', 'Gene', (59, 63))	('SSX4', 'Gene', '6759', (94, 98))	('SS18', 'Gene', '6760', (32, 36))	('SSX4', 'Gene', (94, 98))	('SSX2', 'Gene', '6757', (64, 68))
33831	27401493	Log-rank analyses on the prognostic parameters were as follows: gender (chi2 = 1.25, p = 0.246 > 0.05), age (>=37 vs. <37; chi2 = 0.064, p = 0.800 > 0.05), tumor size (>=5 cm vs. <5 cm; chi2 = 0.56, p = 0.454 > 0.05), FNCLCC grade (chi2 = 0.17, p = 0.685 > 0.05), fusion gene types (SS18-SSX1 vs. SS18-SSX2; chi2 = 0.10, p = 0.756 > 0.05), mitotic rate (>=10/10 HPFs vs. <10/10 HPFs; chi2 = 0.01, p = 0.925 > 0.05), tumor resection (yes vs. no; chi2 = 5.13, p = 0.024 < 0.05) and tumor residual status (yes vs. no; chi2 = 8.55, p = 0.004 < 0.05).	('SSX2', 'Gene', (302, 306))	('SS18', 'Gene', (297, 301))	('SSX2', 'Gene', '6757', (302, 306))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (480, 485))	('SS18', 'Gene', '6760', (283, 287))	('tumor', 'Disease', (416, 421))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (480, 485))	('FNCLCC grade', 'CPA', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('>=10/10 HPFs', 'Var', (354, 366))	('SS18', 'Gene', '6760', (297, 301))	('SSX1', 'Gene', '6756', (288, 292))	('SSX1', 'Gene', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (480, 485))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('SS18', 'Gene', (283, 287))	('mitotic rate', 'CPA', (340, 352))
33836	27401493	The mean age of patients with PPMSS in this study was somewhat lower than that reported in the largest series (37.8 years vs. 42 years) and much lower than that of the Japanese series (37.8 years vs. 58 years).	('lower', 'NegReg', (145, 150))	('PPMSS', 'Var', (30, 35))	('patients', 'Species', '9606', (16, 24))	('lower', 'NegReg', (63, 68))
33856	27401493	This finding has not been described in PPMSSs, although it has been reported in soft tissue SSs, and the presence of aneuploidy or amplificon of chromosome 18q might account for this event.	('amplificon', 'Var', (131, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))	('aneuploidy', 'Disease', 'MESH:D000782', (117, 127))	('aneuploidy', 'Disease', (117, 127))
33939	22918238	Amplification of the YAP gene locus 11q22 has been reported in many types of human cancers including malignant mesothelioma, ependymoma, hepatocellular carcinomas, and esophageal squamous cell carcinomas.	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('ependymoma', 'Disease', (125, 135))	('reported', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (137, 162))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (101, 123))	('YAP', 'Gene', (21, 24))	('ependymoma', 'Phenotype', 'HP:0002888', (125, 135))	('hepatocellular carcinomas', 'Disease', (137, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (179, 203))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('ependymoma', 'Disease', 'MESH:D004806', (125, 135))	('esophageal squamous cell carcinomas', 'Disease', (168, 203))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (168, 203))	('malignant mesothelioma', 'Disease', (101, 123))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (101, 123))	('human', 'Species', '9606', (77, 82))	('Amplification', 'Var', (0, 13))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (137, 162))	('cancers', 'Disease', (83, 90))
33941	22918238	A genetic characteristic of MM tumors is the deletion or mutation of tumor suppressor genes, such as p16INK4a/p14ARF and NF2.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('NF2', 'Gene', (121, 124))	('p14ARF', 'Gene', (110, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('p16INK4a', 'Gene', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('MM tumors', 'Disease', 'MESH:D009369', (28, 37))	('deletion', 'Var', (45, 53))	('mutation', 'Var', (57, 65))	('MM tumors', 'Disease', (28, 37))	('p16INK4a', 'Gene', '1029', (101, 109))	('p14ARF', 'Gene', '1029', (110, 116))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (31, 36))	('NF2', 'Gene', '4771', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
33942	22918238	Although several other cancer cell types have also been reported to have homologous somatic mutations of the NF2 gene, MM has an extremely high mutational frequency in this pathway.	('NF2', 'Gene', '4771', (109, 112))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutations', 'Var', (92, 101))	('NF2', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
33943	22918238	The fact is that at least 75% of MM cases have a mutation in the NF2 pathway and components of the Hippo signaling pathway, Salvador1 and LATS2, indicates that this type of tumor greatly relies on the inactivation of this pathway for oncogenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('NF2', 'Gene', (65, 68))	('Hippo signaling pathway', 'Pathway', (99, 122))	('mutation', 'Var', (49, 57))	('NF2', 'Gene', '4771', (65, 68))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('LATS2', 'Gene', (138, 143))	('LATS2', 'Gene', '26524', (138, 143))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('99', '122'))	('oncogenesis', 'biological_process', 'GO:0007048', ('234', '245'))
33947	22918238	A disturbance in the NF2-Hippo signaling cascade may lead to dysregulation of the monitoring system, thereby leading to occurrence of MM.	('NF2', 'Gene', (21, 24))	('lead to', 'Reg', (53, 60))	('NF2', 'Gene', '4771', (21, 24))	('Hippo signaling cascade', 'biological_process', 'GO:0035329', ('25', '48'))	('dysregulation', 'MPA', (61, 74))	('leading to occurrence', 'Reg', (109, 130))	('disturbance', 'Var', (2, 13))
33965	22918238	The ratios of mice with emaciation at the time of death were 7/8 with the control, 3/8 with shCTGF #1 cells, and 1/8 with shCTGF #2 cells (p < 0.05 vs. control).	('death', 'Disease', 'MESH:D003643', (50, 55))	('death', 'Disease', (50, 55))	('mice', 'Species', '10090', (14, 18))	('shCTGF', 'Var', (92, 98))	('rat', 'Species', '10116', (4, 7))
33969	22918238	The cause of death of shCTGF tumor-bearing mice may be different from that of control tumor-bearing mice because a feature of their last stage was not emaciation but an unexpected hydroperitoneum and occasional systemic edema.	('mice', 'Species', '10090', (43, 47))	('edema', 'Disease', 'MESH:D004487', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (86, 91))	('death', 'Disease', 'MESH:D003643', (13, 18))	('mice', 'Species', '10090', (100, 104))	('death', 'Disease', (13, 18))	('shCTGF', 'Var', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('edema', 'Disease', (220, 225))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('edema', 'Phenotype', 'HP:0000969', (220, 225))
33981	22918238	Furthermore, we also found a strong link between CTGF expression in MM cells and the deposition of ECM proteins in both MM cell lines implanted into mice and patient tissue specimens.	('deposition of ECM proteins', 'MPA', (85, 111))	('CTGF', 'Gene', (49, 53))	('expression', 'Var', (54, 64))	('patient', 'Species', '9606', (158, 165))	('mice', 'Species', '10090', (149, 153))
33989	22918238	Our data indicated that the knockdown of CTGF suppresses MM cell growth and proliferation both in vitro and in vivo in the mouse model.	('rat', 'Species', '10116', (83, 86))	('CTGF', 'Gene', (41, 45))	('mouse', 'Species', '10090', (123, 128))	('suppresses', 'NegReg', (46, 56))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('MM cell growth', 'CPA', (57, 71))	('knockdown', 'Var', (28, 37))
33994	22918238	Our previous analysis using human MM tissues showed that these two pathways are not perfectly linked to direct CTGF expression, suggesting that besides TGF-beta signaling and defects in Hippo signaling, there are additional unknown mechanisms that participate in CTGF regulation.	('human', 'Species', '9606', (28, 33))	('TGF-beta signaling', 'MPA', (152, 170))	('regulation', 'biological_process', 'GO:0065007', ('268', '278'))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('Hippo signaling', 'MPA', (186, 201))	('Hippo signaling', 'biological_process', 'GO:0035329', ('186', '201'))	('defects', 'Var', (175, 182))
33995	22918238	We demonstrated that the TGF-beta pathway and disturbances in the Hippo signaling pathway synergistically promote MM cell growth.	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('66', '89'))	('promote', 'PosReg', (106, 113))	('MM cell growth', 'CPA', (114, 128))	('cell growth', 'biological_process', 'GO:0016049', ('117', '128'))	('TGF-beta pathway', 'Pathway', (25, 41))	('Hippo signaling pathway', 'Pathway', (66, 89))	('rat', 'Species', '10116', (10, 13))	('disturbances', 'Var', (46, 58))
34048	19843662	All assays included either PBS/3% BSA or a healthy volunteer sample as a negative control, and serum from a patient with ovarian carcinoma as positive control on the same ELISA plate.	('PBS/3', 'Var', (27, 32))	('ovarian carcinoma', 'Disease', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('PBS', 'Chemical', 'MESH:D007854', (27, 30))	('patient', 'Species', '9606', (108, 115))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (121, 138))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (121, 138))
34144	29386699	SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('SFRP2', 'Gene', '6423', (0, 5))	('SFRP2', 'Gene', (0, 5))	('tumour', 'Disease', (16, 22))	('SFRP2', 'Gene', (154, 159))	('SFRP1', 'Gene', (144, 149))	('SFRP5', 'Gene', (10, 15))	('epigenetic alterations', 'Var', (198, 220))	('reduced', 'NegReg', (118, 125))	('expression', 'MPA', (126, 136))	('asbestos', 'Chemical', 'MESH:D001194', (93, 101))	('SFRP5', 'Gene', '6425', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('SFRP2', 'Gene', '6423', (154, 159))	('SFRP1', 'Gene', '6422', (144, 149))
34145	29386699	Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients.	('SFRP2', 'Gene', (95, 100))	('SFRP5', 'Gene', '6425', (105, 110))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('methylated', 'Var', (84, 94))	('patient', 'Species', '9606', (55, 62))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('patient', 'Species', '9606', (159, 166))	('patients', 'Species', '9606', (159, 167))	('SFRP5', 'Gene', (105, 110))	('SFRP2', 'Gene', '6423', (95, 100))
34155	29386699	The mechanism by which asbestos-induced chronic inflammation progresses to MPM carcinogenesis may be through epigenetic changes.	('MPM carcinogenesis', 'Disease', (75, 93))	('MPM carcinogenesis', 'Disease', 'MESH:D063646', (75, 93))	('chronic inflammation', 'Disease', (40, 60))	('epigenetic changes', 'Var', (109, 127))	('inflammation', 'biological_process', 'GO:0006954', ('48', '60'))	('chronic inflammation', 'Disease', 'MESH:D007249', (40, 60))	('asbestos', 'Chemical', 'MESH:D001194', (23, 31))	('progresses', 'PosReg', (61, 71))
34156	29386699	A relationship between inflammation and promoter DNA hypermethylation has been documented in many forms of cancer, including MPM.	('inflammation', 'biological_process', 'GO:0006954', ('23', '35'))	('inflammation', 'Disease', 'MESH:D007249', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('inflammation', 'Disease', (23, 35))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('49', '69'))	('promoter DNA hypermethylation', 'Var', (40, 69))	('cancer', 'Disease', (107, 113))	('MPM', 'Disease', (125, 128))
34157	29386699	Dysregulation of epigenetic transcriptional control, as well as aberrant promoter DNA methylation and histone modifications in particular, is a fundamental feature of human malignancies.	('histone', 'MPA', (102, 109))	('malignancies', 'Disease', (173, 185))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('promoter DNA', 'MPA', (73, 85))	('malignancies', 'Disease', 'MESH:D009369', (173, 185))	('transcriptional control', 'biological_process', 'GO:0006355', ('28', '51'))	('epigenetic transcriptional control', 'MPA', (17, 51))	('human', 'Species', '9606', (167, 172))	('aberrant', 'Var', (64, 72))
34159	29386699	Global DNA methylation has been investigated in MPM, and a number of genes were found to be methylated at varying frequencies, with the extent of methylation correlating with self-reported asbestos exposure and burden of asbestos fibres in the lung.	('asbestos', 'Chemical', 'MESH:D001194', (189, 197))	('DNA methylation', 'biological_process', 'GO:0006306', ('7', '22'))	('correlating', 'Reg', (158, 169))	('asbestos', 'Chemical', 'MESH:D001194', (221, 229))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('methylation', 'Var', (146, 157))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
34162	29386699	Methylation-induced silencing of tumour suppressor-like miRs has been observed in MPM, suggesting that aberrant DNA methylation is involved in MPM carcinogenesis.	('MPM carcinogenesis', 'Disease', 'MESH:D063646', (143, 161))	('tumour', 'Disease', (33, 39))	('MPM carcinogenesis', 'Disease', (143, 161))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('aberrant', 'Var', (103, 111))	('MPM', 'Disease', (82, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('112', '127'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('silencing', 'NegReg', (20, 29))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('involved', 'Reg', (131, 139))
34169	29386699	Silencing of SFRP4 and SRFP5 has been linked to pemetrexed and cisplatin resistance, two drugs used in standard MPM treatment.	('pemetrexed', 'Disease', (48, 58))	('linked', 'Reg', (38, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('SRFP5', 'Gene', (23, 28))	('pemetrexed', 'Chemical', 'MESH:D000068437', (48, 58))	('SFRP4', 'Gene', '6424', (13, 18))	('SFRP4', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('cisplatin resistance', 'Disease', (63, 83))
34170	29386699	Epigenetic silencing of the Wnt pathway is well characterized in colon cancer, a cancer known to be related to chronic inflammation.	('colon cancer', 'Disease', (65, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', (81, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('inflammation', 'biological_process', 'GO:0006954', ('119', '131'))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('Wnt', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('chronic inflammation', 'Disease', (111, 131))	('Wnt', 'Gene', '89780', (28, 31))	('chronic inflammation', 'Disease', 'MESH:D007249', (111, 131))
34171	29386699	Recently, it was shown that the downregulation of SFRP gene family members in gastric and colorectal cancer is mediated by methylation silencing.	('downregulation', 'NegReg', (32, 46))	('gastric', 'Disease', (78, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('methylation silencing', 'Var', (123, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SFRP gene', 'Gene', (50, 59))	('colorectal cancer', 'Disease', (90, 107))
34200	29386699	Primers for the amplification of methylated SFRP DNA via MSP were optimized using ddPCR EvaGreen (Bio-Rad) according to the manufacturer's recommendations.	('SFRP DNA', 'Gene', (44, 52))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('Rad', 'Gene', (102, 105))	('Rad', 'Gene', '6236', (102, 105))	('methylated', 'Var', (33, 43))	('Rad', 'biological_process', 'GO:1990116', ('102', '105'))
34215	29386699	Investigating the DNA methylation status of SFRP2 and SFRP5 in MPM cells lines revealed that SFRP2 and SFRP5 were consistently methylated and became unmethylated when treated with decitabine (Figure 1(b)).	('SFRP2', 'Gene', (44, 49))	('decitabine', 'Chemical', 'MESH:D000077209', (180, 190))	('SFRP5', 'Gene', (103, 108))	('methylated', 'Var', (127, 137))	('SFRP5', 'Gene', '6425', (54, 59))	('SFRP2', 'Gene', '6423', (93, 98))	('SFRP2', 'Gene', (93, 98))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('SFRP5', 'Gene', '6425', (103, 108))	('SFRP5', 'Gene', (54, 59))	('SFRP2', 'Gene', '6423', (44, 49))
34241	29386699	Our results for promoter methylation of SFRP2 and SFRP5 in MPM suggested that they are downregulated in MPM by hypermethylation and thus may have tumour suppressor potential in MPM.	('SFRP2', 'Gene', (40, 45))	('tumour', 'Disease', (146, 152))	('hypermethylation', 'Var', (111, 127))	('SFRP5', 'Gene', '6425', (50, 55))	('promoter methylation', 'MPA', (16, 36))	('downregulated', 'NegReg', (87, 100))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('SFRP2', 'Gene', '6423', (40, 45))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('MPM', 'Disease', (177, 180))	('SFRP5', 'Gene', (50, 55))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
34249	29386699	We were able to detect methylated DNA from SFRP2 and SFRP5 with both showing a distinctive cut-off between patient and healthy normal plasma (Figure 4(c)).	('methylated', 'Var', (23, 33))	('SFRP2', 'Gene', (43, 48))	('SFRP5', 'Gene', '6425', (53, 58))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('detect', 'Reg', (16, 22))	('SFRP5', 'Gene', (53, 58))	('SFRP2', 'Gene', '6423', (43, 48))	('patient', 'Species', '9606', (107, 114))
34252	29386699	Although we have demonstrated that methylated SFRPs can be detected in plasma of MPM patients, the small sample size means that we are not able to make a definitive conclusion about whether we can use this finding as a diagnostic marker for MPM.	('SFRPs', 'Gene', (46, 51))	('MPM', 'Disease', (81, 84))	('MPM', 'Disease', (241, 244))	('patients', 'Species', '9606', (85, 93))	('methylated', 'Var', (35, 45))
34269	27516891	Upon the diagnosis of stage III c-T3N2M0 sarcomatoid malignant pleural mesothelioma, the patient underwent left extra-pleural pneumonectomy.	('patient', 'Species', '9606', (89, 96))	('sarcomatoid malignant', 'Phenotype', 'HP:0100242', (41, 62))	('sarcomatoid malignant pleural mesothelioma', 'Disease', (41, 83))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (63, 83))	('sarcomatoid malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (41, 83))	('c-T3N2M0', 'Var', (32, 40))
34302	23890748	Intrapleural treatment of orthotopic MPM xenografts resulted in a significant reduction in tumor burden one week after treatment and an improvement in survival.	('MPM', 'Var', (37, 40))	('survival', 'CPA', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('reduction', 'NegReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('improvement', 'PosReg', (136, 147))	('tumor', 'Disease', (91, 96))
34304	23890748	Our results suggest GLV-1h153 is a promising therapeutic agent for MPM and warrants further investigation.	('MPM', 'Disease', (67, 70))	('GLV-1h153', 'Var', (20, 29))	('GLV-1h153', 'Chemical', '-', (20, 29))
34315	23890748	GLV-1h68 is a replication-competent oncolytic vaccinia virus with interruptions in thymidine kinase, hemagglutinin, and F14.5L that confer tumor selectivity and decrease virulence to normal host cells.	('hemagglutinin', 'Protein', (101, 114))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('virulence', 'biological_process', 'GO:0009406', ('170', '179'))	('GLV-1h68', 'Species', '502057', (0, 8))	('vaccinia virus', 'Species', '10245', (46, 60))	('virulence', 'biological_process', 'GO:0009405', ('170', '179'))	('thymidine kinase', 'MPA', (83, 99))	('decrease', 'NegReg', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('virulence', 'biological_process', 'GO:0016032', ('170', '179'))	('F14.5L', 'Gene', (120, 126))	('virulence to normal host cells', 'MPA', (170, 200))	('interruptions', 'Var', (66, 79))
34321	23890748	In this paper, we report that GLV-1h153, a novel vaccinia virus carrying hNIS, kills mesothelioma in vitro, confers improved 30-day survival in an orthotopic model of malignant pleural mesothelioma, and facilitates PET imaging for real-time tracking of viral therapy.	('mesothelioma', 'Disease', (85, 97))	('malignant pleural mesothelioma', 'Disease', (167, 197))	('mesothelioma', 'Disease', (185, 197))	('GLV-1h153', 'Chemical', '-', (30, 39))	('30-day survival', 'CPA', (125, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('GLV-1h153', 'Var', (30, 39))	('hNIS', 'Gene', (73, 77))	('hNIS', 'Gene', '6528', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('kills', 'NegReg', (79, 84))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (177, 197))	('vaccinia virus', 'Species', '10245', (49, 63))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (167, 197))	('improved', 'PosReg', (116, 124))
34324	23890748	Mesothelioma cells were maintained in RPMI with 10% fetal calf serum with penicillin (100,000 U/L) and streptomycin (100mg/L), and incubated in a 5% C02 humidified incubator at 37 degrees.	('streptomycin', 'Chemical', 'MESH:D013307', (103, 115))	('penicillin', 'Chemical', 'MESH:D010406', (74, 84))	('C02', 'Chemical', '-', (149, 152))	('calf', 'Species', '9913', (58, 62))	('RPMI', 'Chemical', '-', (38, 42))	('100,000 U/L', 'Var', (86, 97))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
34344	23890748	Cells were subsequently infected with GLV-1h153 at an MOI of 1.0 or mock-infected with media for 24 hours.	('mock-infected', 'Disease', 'MESH:D007239', (68, 81))	('GLV-1h153', 'Var', (38, 47))	('GLV-1h153', 'Chemical', '-', (38, 47))	('mock-infected', 'Disease', (68, 81))
34370	23890748	In order to determine the efficacy of intrapleural treatment with GLV-1h153 on prolonging survival in a mouse model of MPM, mice with established tumor burden were quantitatively randomized into treatment groups (n = 6).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mouse', 'Species', '10090', (104, 109))	('tumor', 'Disease', (146, 151))	('mice', 'Species', '10090', (124, 128))	('GLV-1h153', 'Chemical', '-', (66, 75))	('GLV-1h153', 'Var', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
34377	23890748	Mesothelioma cell lines of all histologic subtypes demonstrated sensitivity to the cytotoxic effect of GLV-1h153.	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('GLV-1h153', 'Var', (103, 112))	('GLV-1h153', 'Chemical', '-', (103, 112))
34379	23890748	The epithelial mesothelioma cell line H-MESO demonstrated particular sensitivity with an MOI of 0.1 resulting in near 80% cell kill at 5 days post-infection.	('epithelial mesothelioma', 'Disease', (4, 27))	('cell kill', 'CPA', (122, 131))	('MOI', 'Var', (89, 92))	('epithelial mesothelioma', 'Disease', 'MESH:D008654', (4, 27))
34385	23890748	Treatment with 1x105 PFUs of GLV-1h153 resulted in a progressive and significant reduction in tumor burden for the duration of the survival study.	('GLV-1h153', 'Chemical', '-', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('GLV-1h153', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('reduction', 'NegReg', (81, 90))
34389	23890748	All mice (n = 6 per group) treated with intrapleural injection of 1x104 or 1x105 PFUs of GLV-1h153 were alive 1 month after tumor establishment.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mice', 'Species', '10090', (4, 8))	('GLV-1h153', 'Chemical', '-', (89, 98))	('tumor', 'Disease', (124, 129))	('1x105 PFUs', 'Var', (75, 85))	('GLV-1h153', 'Gene', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
34391	23890748	H-Meso, MSTO-211H, JMN and VAMT cells infected for 24 hours with GLV-1h153 followed by one hour of incubation with carrier-free 131I all demonstrated significantly increased radiouptake compared to uninfected controls as measured by gamma scintigraphy (Figure 7A).	('VAMT', 'Chemical', '-', (27, 31))	('131I', 'Chemical', 'MESH:C000614965', (128, 132))	('carrier', 'molecular_function', 'GO:0005215', ('115', '122'))	('GLV-1h153', 'Chemical', '-', (65, 74))	('radiouptake', 'MPA', (174, 185))	('GLV-1h153', 'Var', (65, 74))	('increased', 'PosReg', (164, 173))
34394	23890748	These results demonstrate that GLV-1h153 facilitates transport of radio-iodine via specific, blockable, hNIS mediated transport.	('facilitates', 'PosReg', (41, 52))	('radio-iodine', 'Chemical', 'MESH:C000614965', (66, 78))	('transport', 'biological_process', 'GO:0006810', ('53', '62'))	('transport of radio-iodine', 'MPA', (53, 78))	('hNIS', 'Gene', (104, 108))	('hNIS', 'Gene', '6528', (104, 108))	('GLV-1h153', 'Chemical', '-', (31, 40))	('GLV-1h153', 'Var', (31, 40))	('transport', 'biological_process', 'GO:0006810', ('118', '127'))
34397	23890748	The two mice that had received intrapleural GLV-1h153 demonstrated clear 131I uptake in pleural tumor burden (Figure 7B) while no such signal was evident on the PBS treated control animal.	('uptake', 'biological_process', 'GO:0098739', ('78', '84'))	('131I uptake', 'MPA', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('GLV-1h153', 'Chemical', '-', (44, 53))	('131I', 'Chemical', 'MESH:C000614965', (73, 77))	('PBS', 'Chemical', 'MESH:D007854', (161, 164))	('GLV-1h153', 'Var', (44, 53))	('pleural tumor', 'Disease', (88, 101))	('pleural tumor', 'Disease', 'MESH:D010997', (88, 101))	('mice', 'Species', '10090', (8, 12))	('uptake', 'biological_process', 'GO:0098657', ('78', '84'))
34412	23890748	Most recently, we have demonstrated that GLV-1h153 can treat orthotopic TNBC underline tumors, prevent metastasis, and facilitate 131I imaging of positive surgical margins after resection.	('TNBC', 'Disease', 'None', (72, 76))	('prevent', 'NegReg', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TNBC', 'Disease', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('131I imaging', 'MPA', (130, 142))	('GLV-1h153', 'Chemical', '-', (41, 50))	('tumors', 'Disease', (87, 93))	('131I', 'Chemical', 'MESH:C000614965', (130, 134))	('GLV-1h153', 'Var', (41, 50))	('facilitate', 'PosReg', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('metastasis', 'CPA', (103, 113))
34413	23890748	The present work describes encouraging results utilizing GLV-1h153 to treat malignant pleural mesothelioma while providing real-time, hNIS mediated imaging of viral delivery.	('GLV-1h153', 'Var', (57, 66))	('GLV-1h153', 'Chemical', '-', (57, 66))	('hNIS', 'Gene', (134, 138))	('hNIS', 'Gene', '6528', (134, 138))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (86, 106))	('malignant pleural mesothelioma', 'Disease', (76, 106))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (76, 106))
34414	23890748	In vitro work presented here demonstrate the ability of GLV-1h153 to efficiently infect, replicate within, and kill mesothelioma cells of epithelial, bi-phasic, sarcomatoid and mixed histologic subtypes.	('mesothelioma', 'Disease', (116, 128))	('kill', 'CPA', (111, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('sarcomatoid', 'Disease', 'MESH:C538614', (161, 172))	('replicate', 'CPA', (89, 98))	('GLV-1h153', 'Var', (56, 65))	('GLV-1h153', 'Chemical', '-', (56, 65))	('sarcomatoid', 'Disease', (161, 172))
34418	23890748	Conversely, the epithelial H-Meso cell line demonstrated particular sensitivity to viral oncolysis with doses as low as MOI 0.1 resulting in complete eradication which may reflect the favorable tumor characteristics observed in this subtype clinically.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('eradication', 'MPA', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('MOI 0.1', 'Var', (120, 127))
34441	23890748	Intrapleural treatment with GLV-1h153 prolongs survival and provides a non-invasive means to track oncolytic viral therapy in an orthotopic mouse model of malignant pleural mesothelioma.	('mouse', 'Species', '10090', (140, 145))	('survival', 'CPA', (47, 55))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (165, 185))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (155, 185))	('GLV-1h153', 'Chemical', '-', (28, 37))	('malignant pleural mesothelioma', 'Disease', (155, 185))	('GLV-1h153', 'Var', (28, 37))	('prolongs', 'PosReg', (38, 46))
34571	31823764	MDSCs are associated with tumor progression in mouse models of mesothelioma, and MDSCs are believed to be associated with mesotheliomas in human patients.	('patients', 'Species', '9606', (145, 153))	('mesothelioma', 'Disease', (122, 134))	('MDSCs', 'Var', (0, 5))	('mesothelioma', 'Disease', (63, 75))	('associated', 'Reg', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('human', 'Species', '9606', (139, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('mesotheliomas', 'Disease', 'MESH:D008654', (122, 135))	('tumor', 'Disease', (26, 31))	('mesotheliomas', 'Disease', (122, 135))	('mouse', 'Species', '10090', (47, 52))
34886	28331795	Amyloid can also produce single or multiple nodules, which are sometimes a manifestation of an underlying myeloma; and diffuse septal amyloid, where amyloid is laid down along alveolar walls, producing a physiologic, imaging, and at first glance, pathologic impression of an interstitial lung disease.	('interstitial lung disease', 'Disease', 'MESH:D017563', (275, 300))	('myeloma', 'Disease', 'MESH:D009101', (106, 113))	('interstitial lung disease', 'Disease', (275, 300))	('myeloma', 'Disease', (106, 113))	('lung disease', 'Phenotype', 'HP:0002088', (288, 300))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (275, 300))	('man', 'Species', '9606', (75, 78))	('Amyloid', 'Var', (0, 7))
34951	24401838	These GEMM-ESCs contain the same genetic modifications as present in the original model plus the newly introduced genetic modification, for instance a frequently observed point mutation in a tumor suppressor gene or a transgene with conditional expression of an oncogene that is often amplified or otherwise overexpressed in a particular tumor type.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor suppressor', 'biological_process', 'GO:0051726', ('191', '207'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('191', '207'))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('point mutation', 'Var', (171, 185))
34962	24401838	In these protocols, culture media containing fetal bovine serum (FBS) and feeder cells are replaced by defined N2B27 medium supplemented with two inhibitors (2i): the MEK1 inhibitor, PD0325901, which effectively blocks MEK/ERK signaling thereby preventing ESC differentiation, and the GSK3 inhibitor, CHIR99021, which acts as a Wnt agonist thereby stimulating growth of ESCs.	('MEK', 'Gene', (167, 170))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('blocks', 'NegReg', (212, 218))	('GSK3', 'Gene', '56637', (285, 289))	('MEK1', 'Gene', (167, 171))	('bovine', 'Species', '9913', (51, 57))	('stimulating', 'PosReg', (348, 359))	('MEK', 'Gene', '17242', (219, 222))	('FBS', 'Disease', (65, 68))	('GSK', 'molecular_function', 'GO:0050321', ('285', '288'))	('FBS', 'Disease', 'MESH:D005198', (65, 68))	('PD0325901', 'Var', (183, 192))	('GSK3', 'Gene', (285, 289))	('MEK1', 'molecular_function', 'GO:0004708', ('167', '171'))	('MEK', 'Gene', (219, 222))	('MEK', 'Gene', '17242', (167, 170))	('MEK1', 'Gene', '26395', (167, 171))	('ESC', 'Disease', (256, 259))	('ESCs', 'Disease', (370, 374))	('preventing', 'NegReg', (245, 255))	('PD0325901', 'Chemical', 'MESH:C506614', (183, 192))	('ERK', 'molecular_function', 'GO:0004707', ('223', '226'))	('growth', 'CPA', (360, 366))
34968	24401838	ESC clones from either C57BL/6J (clone 1.4) or FVB/n (clone 1.3) showed robust expression of Nanog, Oct4 and Sox2 in the majority of cells (Fig 1A and B).	('Nanog', 'Gene', (93, 98))	('Sox2', 'Gene', '20674', (109, 113))	('Oct4', 'Gene', (100, 104))	('Sox2', 'Gene', (109, 113))	('Nanog', 'Gene', '71950', (93, 98))	('Oct4', 'Gene', '18999', (100, 104))	('C57BL/6J', 'Var', (23, 31))
34972	24401838	The increase in coat color contribution came at a price, as the number of liveborn chimeras relative to the total number of implanted embryos was lower for the morula injections than for the blastocyst injections (Fig 1E and F and supplementary Table S1).	('coat color', 'MPA', (16, 26))	('lower', 'NegReg', (146, 151))	('blastocyst', 'Disease', (191, 201))	('blastocyst', 'Disease', 'MESH:D020964', (191, 201))	('morula', 'Var', (160, 166))	('liveborn chimeras', 'CPA', (74, 91))
34974	24401838	In case of FVB/n or mixed FVB/n;129/Ola ESC clones we used more fail-safe blastocyst injections (C57BL/6N).	('mixed', 'Var', (20, 25))	('blastocyst', 'Disease', 'MESH:D020964', (74, 84))	('blastocyst', 'Disease', (74, 84))
34978	24401838	ESCs were also derived from Nf2F/F ;Trp53F/F ;Cdkn2a*/* mice, which carry:in addition to conditional Nf2 and Trp53 alleles:a homozygous mutation in Cdkn2a that results in loss of p16Ink4a expression but retention of the alternative reading frame protein p19Arf (Krimpenfort et al,).	('Cdkn2a', 'Gene', '12578', (46, 52))	('retention', 'biological_process', 'GO:0051235', ('203', '212'))	('Nf2', 'Gene', (28, 31))	('loss', 'NegReg', (171, 175))	('Cdkn2a', 'Gene', '12578', (148, 154))	('Trp53', 'Gene', '22059', (109, 114))	('Nf2', 'Gene', '18016', (101, 104))	('Cdkn2a', 'Gene', (46, 52))	('p19Arf', 'Gene', '12578', (254, 260))	('Trp53', 'Gene', (109, 114))	('Nf2', 'Gene', '18016', (28, 31))	('Cdkn2a', 'Gene', (148, 154))	('Trp53', 'Gene', '22059', (36, 41))	('mutation', 'Var', (136, 144))	('Trp53', 'Gene', (36, 41))	('p16Ink4a', 'Gene', (179, 187))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('expression', 'MPA', (188, 198))	('p19', 'cellular_component', 'GO:0070743', ('254', '257'))	('p16Ink4a', 'Gene', '12578', (179, 187))	('mice', 'Species', '10090', (56, 60))	('p19Arf', 'Gene', (254, 260))	('Nf2', 'Gene', (101, 104))
34992	24401838	All NSCLC chimeras developed multiple lesions in the lung ranging from adenomatous or bronchioalveolar hyperplasia to bronchioalveolar adenomas, adenocarcinomas and papillary carcinomas (supplementary Fig S2B and C).	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('chimeras', 'Var', (10, 18))	('adenocarcinomas and papillary carcinomas', 'Disease', 'MESH:D000231', (145, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('adenomatous or bronchioalveolar hyperplasia to bronchioalveolar adenomas', 'Disease', 'MESH:D000236', (71, 143))	('SCLC', 'Phenotype', 'HP:0030357', (5, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('developed', 'Reg', (19, 28))	('NSCLC', 'Disease', (4, 9))
34996	24401838	Combined, these data illustrate that tumor induction in chimeras is as efficient as in animals carrying the conditional lesions in all of their cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('chimeras', 'Var', (56, 64))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('rat', 'Species', '10116', (27, 30))
35004	24401838	Assessment of the genomic integrity of these targeted clones by array comparative genomic hybridization (aCGH) revealed three types of genomic aberrations, either small copy number variations (CNVs) in the 0.2-1.0 megabase (Mb) range, loss of the Y-chromosome or trisomy of entire chromosomes (supplementary Fig S5C and D, Tables S3 and S4).	('Y-chromosome', 'CPA', (247, 259))	('rat', 'Species', '10116', (75, 78))	('loss', 'NegReg', (235, 239))	('trisomy of entire chromosomes', 'CPA', (263, 292))	('rat', 'Species', '10116', (147, 150))	('small copy number variations', 'Var', (163, 191))	('Y-chromosome', 'cellular_component', 'GO:0000806', ('247', '259'))
35013	24401838	The majority of the invCAG-Luc;Rb1F/F ;Trp53F/F chimeras developed SCLC with similar latency as presented earlier (Figs 4A-C and 2E).	('Trp53', 'Gene', '22059', (39, 44))	('chimeras', 'Var', (48, 56))	('Trp53', 'Gene', (39, 44))	('SCLC', 'Gene', '7864', (67, 71))	('SCLC', 'Phenotype', 'HP:0030357', (67, 71))	('SCLC', 'Gene', (67, 71))
35024	24401838	Tumors of small cell lung cancer patients often show amplifications of genomic regions coding for either MYCL1, c-MYC or NMYC (Iwakawa et al,).	('c-MYC', 'Gene', '4609', (112, 117))	('MYCL1', 'Gene', '4610', (105, 110))	('patients', 'Species', '9606', (33, 41))	('NMYC', 'Gene', '4613', (121, 125))	('Tumors of small cell lung cancer', 'Disease', (0, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('MYCL1', 'Gene', (105, 110))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('c-MYC', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Tumors of small cell lung cancer', 'Disease', 'MESH:D055752', (0, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('NMYC', 'Gene', (121, 125))	('amplifications', 'Var', (53, 67))
35042	24401838	In practice, ESCs derived from C57BL/6J strains were injected into FVB/n morulae, whereas ESCs from FVB/n;129/Ola or FVB/n strains were injected into C57BL/6N blastocysts.	('blastocysts', 'Disease', 'MESH:D020964', (159, 170))	('C57BL/6J', 'Var', (31, 39))	('blastocysts', 'Disease', (159, 170))
35056	24401838	In our experience 70-100% chimeras give a quite consistent reproducible tumor phenotype when the penetrance is high.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('chimeras', 'Var', (26, 34))
35111	24401838	DNA (500 ng) was labeled with either Cy5 or Cy3 using the NimbleGen Dual-Color DNA Labeling Kit (NimbleGen).	('Cy5', 'Var', (37, 40))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('Cy3', 'Chemical', '-', (44, 47))	('Cy5', 'Chemical', 'MESH:C085321', (37, 40))	('Cy3', 'Var', (44, 47))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
35221	33318203	Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma We found that the probability of carrying heterozygous germline BLM mutations is significantly higher among mesothelioma patients than in the general population.	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('BLM', 'Gene', (22, 25))	('mutations', 'Var', (26, 35))	('susceptibility to', 'MPA', (45, 62))	('mesothelioma', 'Disease', (76, 88))	('BLM', 'Gene', (153, 156))	('mutations', 'Var', (157, 166))	('mesothelioma', 'Disease', (197, 209))	('higher', 'PosReg', (184, 190))	('BLM', 'Gene', '641', (22, 25))	('patients', 'Species', '9606', (210, 218))	('BLM', 'Gene', '641', (153, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
35222	33318203	In vitro and in vivo experiments suggest that heterozygous BLM mutations increase susceptibility to mesothelioma.	('BLM', 'Gene', (59, 62))	('mesothelioma', 'Disease', (100, 112))	('mutations', 'Var', (63, 72))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))
35227	33318203	We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R).	('c.569_570del', 'Mutation', 'c.569_570del', (127, 139))	('c.968A>G', 'Mutation', 'rs146504061', (186, 194))	('mesothelioma', 'Disease', (96, 108))	('p.R191Kfs*4', 'Mutation', 'p.R191KfsX4', (141, 152))	('BLM+/-', 'Gene', (32, 38))	('p.K323R', 'Mutation', 'rs146504061', (196, 203))	('c.968A>G;', 'Var', (186, 195))	('p.R191Kfs*4', 'Var', (141, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('c.569_570del; p.R191Kfs*4', 'Var', (127, 152))	('Turkey', 'Species', '9103', (119, 125))
35228	33318203	Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected.	('mutations', 'Var', (42, 51))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('mesothelioma', 'Disease', (62, 74))	('developed', 'Reg', (52, 61))
35229	33318203	Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (37, 58))	('pathogenic', 'Reg', (114, 124))	('patients', 'Species', '9606', (23, 31))	('sporadic mesothelioma', 'Disease', 'MESH:D008654', (37, 58))	('sporadic mesothelioma', 'Disease', (37, 58))	('Cancer', 'Disease', (86, 92))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('germline', 'Var', (125, 133))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))
35230	33318203	Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency).	('BLM+/- mutations', 'Var', (71, 87))	('mesothelioma', 'Disease', (41, 53))	('c.968A>G', 'Mutation', 'rs146504061', (270, 278))	('patients', 'Species', '9606', (54, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('higher', 'PosReg', (103, 109))	('c.968A>G', 'Var', (270, 278))
35231	33318203	Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-alpha release.	('cell death', 'biological_process', 'GO:0008219', ('205', '215'))	('BLM', 'Gene', (118, 121))	('genomic instability', 'CPA', (163, 182))	('BLM levels', 'MPA', (144, 154))	('human', 'Species', '9606', (73, 78))	('TNF-alpha release', 'MPA', (229, 246))	('promoted', 'PosReg', (220, 228))	('promote', 'PosReg', (155, 162))	('death', 'Disease', 'MESH:D003643', (210, 215))	('death', 'Disease', (210, 215))	('reduced', 'Var', (136, 143))	('mice', 'Species', '10090', (53, 57))
35240	33318203	In 2011, we discovered that carriers of heterozygous germline BRCA1-associated protein-1 (BAP1) mutations (BAP1+/-) developed mesothelioma and uveal melanoma, findings expanded and confirmed by us and by multiple research teams (reviewed in refs.).	('BRCA1-associated protein-1', 'Gene', '8314', (62, 88))	('mesothelioma', 'Disease', (126, 138))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('BAP1', 'Gene', (90, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('BRCA1-associated protein-1', 'Gene', (62, 88))	('developed', 'PosReg', (116, 125))	('mutations', 'Var', (96, 105))
35241	33318203	Moreover, heterozygous germline Bap1 mutations (Bap1+/-) significantly increased susceptibility to asbestos-induced mesothelioma in mice, evidence of GxE.	('asbestos', 'Chemical', 'MESH:D001194', (99, 107))	('mesothelioma', 'Disease', (116, 128))	('Bap1', 'Gene', '104416', (48, 52))	('Bap1', 'Gene', (48, 52))	('Bap1', 'Gene', '104416', (32, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('mutations', 'Var', (37, 46))	('mice', 'Species', '10090', (132, 136))	('increased', 'PosReg', (71, 80))	('Bap1', 'Gene', (32, 36))	('susceptibility', 'MPA', (81, 95))
35242	33318203	Reduced BAP1 levels impair DNA repair as well as different forms of cell death and induce metabolic alterations that together favor cancer development and growth.	('cancer', 'Disease', (132, 138))	('impair', 'NegReg', (20, 26))	('growth', 'CPA', (155, 161))	('metabolic alterations', 'CPA', (90, 111))	('cell death', 'biological_process', 'GO:0008219', ('68', '78'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DNA repair', 'CPA', (27, 37))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('favor', 'PosReg', (126, 131))	('BAP1', 'Gene', (8, 12))	('Reduced', 'Var', (0, 7))	('death', 'Disease', 'MESH:D003643', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('death', 'Disease', (73, 78))	('DNA repair', 'biological_process', 'GO:0006281', ('27', '37'))
35243	33318203	Recent studies revealed that mesothelioma may also develop among carriers of germline mutations of additional tumor-suppressor genes that cause well-defined cancer syndromes, including MLH1 and MLH3 (Lynch syndrome), TP53 (Li-Fraumeni syndrome), and BRCA1-2 (Breast and Ovarian Cancer syndrome).	('TP53', 'Gene', '7157', (217, 221))	('BRCA1-2', 'Gene', '672;675', (250, 257))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('Li-Fraumeni syndrome', 'Disease', (223, 243))	('BRCA1-2', 'Gene', (250, 257))	('Breast and Ovarian Cancer syndrome', 'Disease', 'MESH:D061325', (259, 293))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (270, 284))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (223, 243))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Cancer', 'Phenotype', 'HP:0002664', (278, 284))	('mutations', 'Var', (86, 95))	('cancer syndromes', 'Disease', (157, 173))	('MLH3', 'Gene', (194, 198))	('Lynch syndrome', 'Disease', (200, 214))	('TP53', 'Gene', (217, 221))	('develop', 'Reg', (51, 58))	('cause', 'Reg', (138, 143))	('MLH1', 'Gene', (185, 189))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('cancer syndromes', 'Disease', 'MESH:D009369', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', (110, 115))	('Lynch syndrome', 'Disease', 'MESH:D003123', (200, 214))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('MLH1', 'Gene', '4292', (185, 189))	('mesothelioma', 'Disease', (29, 41))	('MLH3', 'Gene', '27030', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
35244	33318203	When all germline mutations are combined, it has been estimated that about 12% of mesotheliomas occur in carriers of heterozygous germline mutations of BAP1, the most frequent mutation among patients with mesothelioma, or of other tumor suppressors.	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('patients', 'Species', '9606', (191, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('mutations', 'Var', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('mesothelioma', 'Disease', (205, 217))	('BAP1', 'Gene', (152, 156))	('mesotheliomas', 'Disease', 'MESH:D008654', (82, 95))	('mesotheliomas', 'Disease', (82, 95))
35245	33318203	Some of these mutations may sensitize the host to asbestos carcinogenesis, according to a GxE scenario.	('asbestos carcinogenesis', 'Disease', (50, 73))	('mutations', 'Var', (14, 23))	('sensitize', 'Reg', (28, 37))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (50, 73))
35248	33318203	We are investigating genetic variants that may increase cancer risk upon exposure to carcinogens to implement preventive strategies.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('variants', 'Var', (29, 37))	('increase', 'PosReg', (47, 55))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
35249	33318203	Biallelic mutations of the Bloom syndrome gene (BLM) cause Bloom syndrome, an autosomal-recessive tumor predisposition syndrome characterized by pre- and postnatal growth deficiency, photosensitivity, type 2 diabetes, and greatly increased risk of developing various types of cancers.	('Biallelic mutations', 'Var', (0, 19))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (201, 216))	('photosensitivity', 'Phenotype', 'HP:0000992', (183, 199))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('diabetes', 'Disease', (208, 216))	('autosomal-recessive tumor', 'Disease', 'None', (78, 103))	('BLM', 'Gene', (48, 51))	('cause', 'Reg', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('pre', 'molecular_function', 'GO:0003904', ('145', '148'))	('growth deficiency', 'Phenotype', 'HP:0001510', (164, 181))	('cancers', 'Disease', (276, 283))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('autosomal-recessive tumor', 'Disease', (78, 103))	('Bloom syndrome', 'Disease', (59, 73))	('diabetes', 'Disease', 'MESH:D003920', (208, 216))	('postnatal growth deficiency', 'Disease', (154, 181))	('postnatal growth deficiency', 'Disease', 'MESH:D006130', (154, 181))	('postnatal growth deficiency', 'Phenotype', 'HP:0008897', (154, 181))
35250	33318203	In patients affected by Bloom syndrome, the absence of the BLM protein causes chromosomal instability, increased number of sister chromatid exchanges, and increased numbers of micronuclei.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (78, 101))	('increased', 'PosReg', (103, 112))	('absence', 'Var', (44, 51))	('increased', 'PosReg', (155, 164))	('chromosomal instability', 'CPA', (78, 101))	('chromatid', 'cellular_component', 'GO:0005695', ('130', '139'))	('BLM protein', 'Protein', (59, 70))	('Bloom syndrome', 'Disease', (24, 38))	('patients', 'Species', '9606', (3, 11))	('increased number of sister chromatid exchanges', 'Phenotype', 'HP:0040012', (103, 149))	('chromatid', 'cellular_component', 'GO:0005694', ('130', '139'))	('causes', 'Reg', (71, 77))	('micronuclei', 'CPA', (176, 187))
35252	33318203	Impaired DNA repair together with altered apoptosis resulted in increased cancer incidence.	('DNA repair', 'biological_process', 'GO:0006281', ('9', '19'))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Disease', (74, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('increased', 'PosReg', (64, 73))	('Impaired', 'Var', (0, 8))
35253	33318203	BLM+/- mutation carriers do not show an obvious phenotype; however, some studies have suggested that carriers of these mutations may have an increased cancer risk.	('mutations', 'Var', (119, 128))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))
35254	33318203	Mice carrying Blm+/- mutations are prone to develop a higher rate of malignancies in the presence of contributing factors, such as concurrent heterozygous mutations of the adenomatous polyposis coli (Apc) gene, or upon infection with murine leukemia virus.	('adenomatous polyposis coli', 'Gene', '11789', (172, 198))	('adenomatous polyposis coli', 'Gene', (172, 198))	('Blm+/- mutations', 'Var', (14, 30))	('infection', 'Disease', (219, 228))	('Apc', 'Gene', (200, 203))	('Apc', 'Gene', '11789', (200, 203))	('infection', 'Disease', 'MESH:D007239', (219, 228))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('Apc', 'cellular_component', 'GO:0005680', ('200', '203'))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('develop', 'PosReg', (44, 51))	('murine leukemia virus', 'Species', '11786', (234, 255))	('Mice', 'Species', '10090', (0, 4))	('malignancies', 'Disease', (69, 81))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (172, 198))
35263	33318203	Two patients from the same family (mother and son) carried the heterozygous BLM mutation chr15:91293067_91293068, c.569_570delAG; p.R191Kfs*4 (Fig.	('c.569_570delAG', 'Mutation', 'c.569_570delAG', (114, 128))	('BLM', 'Gene', (76, 79))	('c.569_570delAG; p.R191Kfs*4', 'Var', (114, 141))	('p.R191Kfs*4', 'Mutation', 'p.R191KfsX4', (130, 141))	('patients', 'Species', '9606', (4, 12))	('p.R191Kfs*4', 'Var', (130, 141))
35265	33318203	The findings in the Turkish family prompted us to test the germline of 29 mesothelioma patients, 28 from the United States and 1 from Turkey, with a family history of mesothelioma in 2 or more family members, who had tested negative for BAP1 mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('patients', 'Species', '9606', (87, 95))	('BAP1', 'Gene', (237, 241))	('mutations', 'Var', (242, 251))	('test', 'Reg', (50, 54))	('mesothelioma', 'Disease', (74, 86))	('mesothelioma', 'Disease', (167, 179))	('Turkey', 'Species', '9103', (134, 140))
35266	33318203	Sanger sequencing of the entire BLM gene revealed that 1 of 29, a 57-y-old US female (family 2), carried a rare heterozygous missense mutation c.968A>G; p.K323R of the BLM gene (rs146504061, allele frequency in the general population, gnomAD T = 0.00039; Fig.	('c.968A>G; p.K323R', 'Var', (143, 160))	('p.K323R', 'Var', (153, 160))	('p.K323R', 'Mutation', 'rs146504061', (153, 160))	('c.968A>G', 'Mutation', 'rs146504061', (143, 151))	('rs146504061', 'Mutation', 'rs146504061', (178, 189))	('rs146504061', 'Var', (178, 189))	('BLM', 'Gene', (168, 171))
35271	33318203	We tested the hypothesis that BLM mutations might be unusually frequent among patients with mesothelioma in a cohort of 122 patients with pleural and peritoneal mesothelioma treated at the US National Cancer Institute (NCI) for whom germline DNA was available.	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mesothelioma', 'Disease', (161, 173))	('Cancer', 'Disease', (201, 207))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('patients', 'Species', '9606', (124, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (78, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('BLM', 'Gene', (30, 33))	('frequent', 'Reg', (63, 71))	('pleural and peritoneal mesothelioma', 'Disease', 'MESH:D010534', (138, 173))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (150, 173))	('mutations', 'Var', (34, 43))	('mesothelioma', 'Disease', (92, 104))
35272	33318203	WES revealed that 5 of 122 patients, 2 with pleural mesothelioma and 3 with peritoneal mesothelioma, carried pathogenic BLM mutations, with a CADD score >20 (Table 1).	('pleural mesothelioma', 'Disease', 'MESH:D008654', (44, 64))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (44, 64))	('mutations', 'Var', (124, 133))	('pleural mesothelioma', 'Disease', (44, 64))	('mesothelioma', 'Disease', (87, 99))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (76, 99))	('mesothelioma', 'Disease', (52, 64))	('patients', 'Species', '9606', (27, 35))	('pathogenic', 'Reg', (109, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('BLM', 'Gene', (120, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
35278	33318203	In summary, 7 of 155 unrelated patients with mesothelioma carried germline pathogenic BLM+/- mutations (SI Appendix, Fig.	('mutations', 'Var', (93, 102))	('mesothelioma', 'Disease', (45, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('patients', 'Species', '9606', (31, 39))	('BLM+/-', 'Gene', (86, 92))
35279	33318203	S1D), a highly significant incidence (P = 6.7E-10) compared to the expected frequency of pathogenic BLM mutations in the general population of 1 in 900, and as high as the 1-in-100 incidence among people of Ashkenazi Jewish ancestry, who carry a specific set of mutations that were not found in any of our patients, as none of them were of Ashkenazi Jewish ancestry.	('people', 'Species', '9606', (197, 203))	('mutations', 'Var', (104, 113))	('BLM', 'Gene', (100, 103))	('patients', 'Species', '9606', (306, 314))
35280	33318203	Moreover, two of seven apparently unrelated BLM-mutated mesothelioma patients carried the same missense mutation c.968A>G, statistically significant (P = 0.0017) given an allele frequency of 0.00039.	('c.968A>G', 'Mutation', 'rs146504061', (113, 121))	('mesothelioma', 'Disease', (56, 68))	('patients', 'Species', '9606', (69, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))	('c.968A>G', 'Var', (113, 121))
35281	33318203	In summary, the probability of finding heterozygous germline BLM mutations is much greater among mesothelioma patients than in the general population.	('mesothelioma', 'Disease', (97, 109))	('BLM', 'Gene', (61, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('patients', 'Species', '9606', (110, 118))	('mutations', 'Var', (65, 74))
35283	33318203	The powerful activity of heterozygous germline BAP1 mutations to facilitate asbestos-induced transformation and cause mesothelioma has been linked to the alterations in the mechanisms that regulate DNA repair and cell death caused by decreased BAP1 protein levels.	('mutations', 'Var', (52, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('cause', 'Reg', (112, 117))	('death', 'Disease', 'MESH:D003643', (218, 223))	('death', 'Disease', (218, 223))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('decreased', 'NegReg', (234, 243))	('cell death', 'biological_process', 'GO:0008219', ('213', '223'))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('asbestos', 'Chemical', 'MESH:D001194', (76, 84))	('facilitate', 'PosReg', (65, 75))	('asbestos-induced', 'Disease', (76, 92))	('DNA repair', 'biological_process', 'GO:0006281', ('198', '208'))	('mesothelioma', 'Disease', (118, 130))	('protein', 'Protein', (249, 256))	('BAP1', 'Gene', (47, 51))
35284	33318203	Since BLM is also involved in DNA repair and chromosome segregation, as well as apoptosis, we investigated if similar mechanisms might regulate GxE in carriers of heterozygous germline BLM mutations, making them more susceptible to asbestos carcinogenesis.	('BLM', 'Gene', (185, 188))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('DNA repair', 'biological_process', 'GO:0006281', ('30', '40'))	('chromosome segregation', 'biological_process', 'GO:0007059', ('45', '67'))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('GxE', 'MPA', (144, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (232, 255))	('susceptible', 'Reg', (217, 228))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('asbestos carcinogenesis', 'Disease', (232, 255))	('mutations', 'Var', (189, 198))
35286	33318203	We investigated if Blm heterozygosity increases genomic instability in murine mesothelial cells exposed to asbestos.	('increases', 'PosReg', (38, 47))	('murine', 'Species', '10090', (71, 77))	('asbestos', 'Chemical', 'MESH:D001194', (107, 115))	('Blm', 'Gene', (19, 22))	('genomic instability', 'MPA', (48, 67))	('heterozygosity', 'Var', (23, 37))
35296	33318203	Moreover, silencing of BLM induced a significant increase in the viability of HM cells upon crocidolite exposure, expressed as percentage of viable cells compared with vehicle-exposed cells (scrambled, 24.2 +- 5.3%; siBLM-pool, 44.1 +- 10.9%; P < 0.01; Fig.	('crocidolite', 'Chemical', 'MESH:D017638', (92, 103))	('increase', 'PosReg', (49, 57))	('viability', 'CPA', (65, 74))	('BLM', 'Gene', (23, 26))	('HM', 'CellLine', 'CVCL:M679', (78, 80))	('silencing', 'Var', (10, 19))
35301	33318203	S2D) but partially protected mesothelioma cells from apoptosis, regardless of the cell line or the stimulus used: H2O2 (SI Appendix, Fig.	('apoptosis', 'CPA', (53, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('H2O2', 'Chemical', 'MESH:D006861', (114, 118))	('H2O2', 'Var', (114, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('mesothelioma', 'Disease', (29, 41))
35303	33318203	We next tested whether BLM silencing influences in vitro transformation of HM cells.	('tested', 'Reg', (8, 14))	('silencing', 'Var', (27, 36))	('HM', 'CellLine', 'CVCL:M679', (75, 77))	('BLM', 'Gene', (23, 26))	('influences', 'Reg', (37, 47))
35308	33318203	Silencing of BLM protected human THP-1 cells differentiated into macrophages from crocidolite-induced apoptosis (Fig.	('crocidolite', 'Chemical', 'MESH:D017638', (82, 93))	('THP-1', 'CellLine', 'CVCL:0006', (33, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('human', 'Species', '9606', (27, 32))	('BLM', 'Gene', (13, 16))	('crocidolite-induced apoptosis', 'Disease', (82, 111))	('Silencing', 'Var', (0, 9))
35309	33318203	Moreover, BLM silencing caused increased release of TNF-alpha, both in vehicle-treated macrophages (scrambled, 2,125.3 +- 132.6 pg/mL; siBLM-pool, 2,968.5 +- 215.2 pg/mL; P < 0.01) and in macrophages exposed to crocidolite (scrambled, 24,30.7 +- 145.4 pg/mL; siBLM-pool, 2,737.8 +- 87.8; P < 0.05; Fig.	('silencing', 'Var', (14, 23))	('increased', 'PosReg', (31, 40))	('release', 'MPA', (41, 48))	('crocidolite', 'Chemical', 'MESH:D017638', (211, 222))	('TNF-alpha', 'Protein', (52, 61))	('BLM', 'Gene', (10, 13))
35310	33318203	We tested whether heterozygous Blm deletion might make mice more susceptible to asbestos carcinogenesis.	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (80, 103))	('asbestos carcinogenesis', 'Disease', (80, 103))	('mice', 'Species', '10090', (55, 59))	('deletion', 'Var', (35, 43))	('susceptible', 'Reg', (65, 76))	('Blm', 'Gene', (31, 34))
35314	33318203	We observed a significant increase in the percentage of M1 macrophages (CD45+; F4/80+, CD86+, CD206-) in Blm+/- mice compared to WT littermates (P = 0.015; Fig.	('CD45', 'Gene', (72, 76))	('CD45', 'Gene', '19264', (72, 76))	('CD206', 'Gene', (94, 99))	('CD206', 'Gene', '17533', (94, 99))	('CD86', 'Gene', (87, 91))	('CD86', 'Gene', '12524', (87, 91))	('M1 macrophages', 'CPA', (56, 70))	('increase', 'PosReg', (26, 34))	('mice', 'Species', '10090', (112, 116))	('F4/80+', 'Var', (79, 85))
35315	33318203	We also observed a nonsignificant reduction of M0 macrophages (P = 0.0848; CD45+, F480+, CD86-, CD206-; SI Appendix, Fig.	('CD206', 'Gene', '17533', (96, 101))	('CD206', 'Gene', (96, 101))	('CD86', 'Gene', (89, 93))	('F480+', 'Var', (82, 87))	('M0 macrophages', 'CPA', (47, 61))	('CD45', 'Gene', '19264', (75, 79))	('CD86', 'Gene', '12524', (89, 93))	('reduction', 'NegReg', (34, 43))	('CD45', 'Gene', (75, 79))
35326	33318203	The incidence of mesothelioma was higher in Blm+/- mice (21 of 25 mice developed MM, 84.0%; P = 0.0453) compared with WT littermates (13 of 23 mice developed MM, 56.5%; Fig.	('mesothelioma', 'Disease', (17, 29))	('mice', 'Species', '10090', (51, 55))	('mice', 'Species', '10090', (66, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))	('Blm+/-', 'Var', (44, 50))	('mice', 'Species', '10090', (143, 147))
35327	33318203	Moreover, Blm+/- mice had a significantly shorter mesothelioma-free survival (median survival, 334 d; P = 0.0264) compared to WT littermates (median survival, 362 d; Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('mice', 'Species', '10090', (17, 21))	('Blm+/-', 'Var', (10, 16))	('shorter', 'NegReg', (42, 49))	('mesothelioma', 'Disease', (50, 62))
35328	33318203	Chronic inflammation leading to intestinal occlusion was the cause of death in 3 of 25 (12.0%) Blm+/- mice, compared to 10 of 23 (43.5%) WT mice (for 2 WT mice, tissues were not available for histology; 1 Blm+/- mouse died of lymphoma).	('mice', 'Species', '10090', (102, 106))	('mice', 'Species', '10090', (140, 144))	('inflammation', 'Disease', (8, 20))	('lymphoma', 'Disease', (226, 234))	('inflammation', 'Disease', 'MESH:D007249', (8, 20))	('died', 'Disease', (218, 222))	('intestinal occlusion', 'Phenotype', 'HP:0005214', (32, 52))	('lymphoma', 'Disease', 'MESH:D008223', (226, 234))	('died', 'Disease', 'MESH:D003643', (218, 222))	('lymphoma', 'Phenotype', 'HP:0002665', (226, 234))	('mice', 'Species', '10090', (155, 159))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('Blm+/-', 'Var', (95, 101))	('intestinal occlusion', 'Disease', (32, 52))	('inflammation', 'biological_process', 'GO:0006954', ('8', '20'))	('mouse', 'Species', '10090', (212, 217))
35330	33318203	There are conflicting conclusions in the literature as to whether carriers of heterozygous BLM mutations have an increased cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('BLM', 'Gene', (91, 94))	('cancer', 'Disease', (123, 129))	('mutations', 'Var', (95, 104))
35332	33318203	We discovered that 7 of 155 unrelated mesothelioma patients carried pathogenic heterozygous germline BLM mutations.	('mesothelioma', 'Disease', (38, 50))	('mutations', 'Var', (105, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (38, 50))	('patients', 'Species', '9606', (51, 59))
35333	33318203	For 2 of these 7, we had a family pedigree: both patients had relatives who had developed mesothelioma carrying the same BLM mutations as in the proband.	('mutations', 'Var', (125, 134))	('BLM', 'Gene', (121, 124))	('mesothelioma', 'Disease', (90, 102))	('patients', 'Species', '9606', (49, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
35334	33318203	The germline c.968A>G mutation found in family 2 was also present in one apparently unrelated mesothelioma patient (Table 1).	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('c.968A>G', 'Mutation', 'rs146504061', (13, 21))	('mesothelioma', 'Disease', (94, 106))	('patient', 'Species', '9606', (107, 114))	('c.968A>G', 'Var', (13, 21))
35335	33318203	This significant finding (P = 0.0017), given a 0.00039 mutation probability, together with the high CADD score, supports the pathogenic contributory effect of this mutation to mesothelioma.	('0.00039 mutation', 'Var', (47, 63))	('mesothelioma', 'Disease', (176, 188))	('mesothelioma', 'Disease', 'MESH:D008654', (176, 188))
35336	33318203	Mesothelial cells from Blm+/- mice accumulated a higher percentage of micronuclei when exposed to asbestos, and silencing BLM in HM cells exposed to asbestos delayed H2A.X phosphorylation.	('mice', 'Species', '10090', (30, 34))	('asbestos', 'Chemical', 'MESH:D001194', (149, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('micronuclei', 'CPA', (70, 81))	('silencing', 'Var', (112, 121))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('HM', 'CellLine', 'CVCL:M679', (129, 131))	('BLM', 'Gene', (122, 125))
35339	33318203	Moreover, silencing of BLM protected HM cells and macrophages from asbestos-induced apoptosis and protected mesothelioma cells from cell death induced by H2O2 and ceramide.	('mesothelioma', 'Disease', (108, 120))	('death', 'Disease', 'MESH:D003643', (137, 142))	('cell death', 'biological_process', 'GO:0008219', ('132', '142'))	('death', 'Disease', (137, 142))	('HM', 'CellLine', 'CVCL:M679', (37, 39))	('BLM', 'Gene', (23, 26))	('cell', 'CPA', (132, 136))	('asbestos', 'Chemical', 'MESH:D001194', (67, 75))	('ceramide', 'Chemical', 'MESH:D002518', (163, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('H2O2', 'Chemical', 'MESH:D006861', (154, 158))	('silencing', 'Var', (10, 19))
35345	33318203	These findings indicate that asbestos exposure increases the risk of mesothelioma in carriers of heterozygous BLM mutations.	('BLM', 'Gene', (110, 113))	('mutations', 'Var', (114, 123))	('mesothelioma', 'Disease', (69, 81))	('asbestos', 'Chemical', 'MESH:D001194', (29, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))
35346	33318203	Since four of nine patients did not report exposure, heterozygous BLM mutations may also increase the risk of mesothelioma per se.	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (19, 27))	('mesothelioma', 'Disease', (110, 122))	('heterozygous', 'Var', (53, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('BLM', 'Gene', (66, 69))	('increase', 'PosReg', (89, 97))
35347	33318203	We found that carriers of germline BLM mutations are at increased risk of mesothelioma because: 1) the probability of finding heterozygous pathogenic germline BLM mutations is significantly higher among mesothelioma patients than in the general population (P = 6.7E-10); 2) in affected families, mesothelioma only developed in individuals who inherited the BLM mutation; and 3) the incidence of mesothelioma was higher in Blm+/- mice exposed to asbestos.	('mutation', 'Var', (361, 369))	('BLM', 'Gene', (35, 38))	('mesothelioma', 'Disease', (395, 407))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('mesothelioma', 'Disease', (203, 215))	('mice', 'Species', '10090', (429, 433))	('mesothelioma', 'Disease', (296, 308))	('asbestos', 'Chemical', 'MESH:D001194', (445, 453))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (216, 224))	('mesothelioma', 'Disease', 'MESH:D008654', (395, 407))	('mesothelioma', 'Disease', 'MESH:D008654', (203, 215))	('mesothelioma', 'Disease', 'MESH:D008654', (296, 308))	('BLM', 'Gene', (357, 360))	('mesothelioma', 'Disease', (74, 86))	('developed', 'Reg', (314, 323))
35350	33318203	In summary, we identified a mesothelioma family in Turkey with heterozygous germline BLM mutations.	('mesothelioma', 'Disease', (28, 40))	('mutations', 'Var', (89, 98))	('Turkey', 'Species', '9103', (51, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))
35351	33318203	This led us to investigate BLM in US mesothelioma families: the combined findings indicated that carriers of heterozygous germline BLM mutations are at increased risk of developing mesothelioma.	('mesothelioma', 'Disease', (181, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('BLM', 'Gene', (131, 134))	('mutations', 'Var', (135, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (181, 193))	('mesothelioma', 'Disease', (37, 49))
35352	33318203	We validated these findings in a Blm heterozygous mutant mouse model and elucidated mechanisms in tissue culture.	('mouse', 'Species', '10090', (57, 62))	('mutant', 'Var', (50, 56))	('Blm', 'Gene', (33, 36))
35353	33318203	Exposure prevention measures may be warranted for BLM mutant carriers; for example, they may decide not to travel to areas where asbestos and other carcinogenic fibers are abundantly present in the environment and avoid work in trades associated with a risk of exposure to asbestos.	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('BLM', 'Gene', (50, 53))	('carcinogenic', 'Disease', 'MESH:D063646', (148, 160))	('asbestos', 'Chemical', 'MESH:D001194', (273, 281))	('mutant', 'Var', (54, 60))	('carcinogenic', 'Disease', (148, 160))
35368	30773744	Importantly, malignant mesothelioma is considered to be a "disease of gene loss" rather than being associated with driver mutations.3 Genetic analyses have clarified the depletions and/or loss-of-functional mutations of CDKN2A, NF2, BAP1 genes, and both p53-dependent DNA repair pathway and PI3K/Akt/mTOR signal transduction are involved in mesothelioma development.	('mTOR', 'Gene', '2475', (300, 304))	('BAP1', 'Gene', (233, 237))	('mTOR', 'Gene', (300, 304))	('p53-dependent DNA', 'Pathway', (254, 271))	('NF2', 'Gene', (228, 231))	('CDKN2A', 'Gene', '1029', (220, 226))	('mutations', 'Var', (207, 216))	('Akt', 'Gene', '207', (296, 299))	('mesothelioma', 'Disease', (341, 353))	('BAP1', 'Gene', '8314', (233, 237))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (13, 35))	('CDKN2A', 'Gene', (220, 226))	('NF2', 'Gene', '4771', (228, 231))	('Akt', 'Gene', (296, 299))	('loss-of-functional', 'NegReg', (188, 206))
35369	30773744	Alterations in CDKN2A locus with inactivation of p16 (INK4a) are reported in more than a half of malignant mesothelioma patients.	('malignant mesothelioma', 'Disease', (97, 119))	('INK4a', 'Gene', '1029', (54, 59))	('reported', 'Reg', (65, 73))	('CDKN2A', 'Gene', (15, 21))	('Alterations', 'Var', (0, 11))	('p16', 'Gene', (49, 52))	('patients', 'Species', '9606', (120, 128))	('inactivation', 'NegReg', (33, 45))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (97, 119))	('p16', 'Gene', '1029', (49, 52))	('INK4a', 'Gene', (54, 59))
35374	30773744	Nagai et al reported that MWCNTs directly pierce mesothelial plasma and nuclear membranes, whereas asbestos fibers are internalized by mesothelial cells via encapsulation by vesicular membranous structures.4 For a typical instance, MWNT-7, one of the fibrous straight MWCNTs, induces polyploidy without specific genetic mutations.	('induces', 'Reg', (276, 283))	('MWNT-7', 'Var', (232, 238))	('polyploidy', 'Disease', (284, 294))	('pierce', 'NegReg', (42, 48))	('polyploidy', 'Disease', 'MESH:D011123', (284, 294))
35375	30773744	Animal experiments have shown that MWNT-7 exposure results in the development of pre-neoplastic hyperplasia, adenomas, and bronchioloalveolar carcinoma in the concentration-dependent manner.1 MWCNTs which remain in the cytoplasm and uncovered by membranes are expected to injure chromosomes during mitosis as compared with asbestos.4 Indeed, there are multiple machineries underlying chromosomal instability bringing about carcinogenesis; faulty sister chromatid cohesion, defective centrosome duplication, telomere dysfunction, hyperactive or hypoactive spindle assembly checkpoint, and overly stable attachments of microtubules to chromosomes.5 The long latency of malignant mesothelioma, with decades-long chronic inflammation accompanied by the aberrant microenvironment rich in ROS and subsequently oxidative DNA damage, may advocate a multifactorial mechanism of disease progression including epigenetic modifications and loss-of-tumor suppressor genes such as p16 and p19 (Figure 1).	('adenomas', 'Disease', 'MESH:D000236', (109, 117))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('446', '471'))	('inflammation', 'biological_process', 'GO:0006954', ('717', '729'))	('adenomas', 'Disease', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (936, 941))	('hyperactive', 'Disease', (529, 540))	('centrosome', 'cellular_component', 'GO:0005813', ('483', '493'))	('hyperactive', 'Disease', 'MESH:D006948', (529, 540))	('bronchioloalveolar carcinoma', 'Disease', (123, 151))	('neoplastic hyperplasia', 'Disease', 'MESH:D006965', (85, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('neoplastic hyperplasia', 'Disease', (85, 107))	('p19', 'cellular_component', 'GO:0070743', ('975', '978'))	('loss-of-tumor', 'NegReg', (928, 941))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('936', '952'))	('mitosis', 'biological_process', 'GO:0000278', ('298', '305'))	('neoplastic hyperplasia', 'Phenotype', 'HP:0002664', (85, 107))	('mitosis', 'Disease', (298, 305))	('p19', 'Gene', (975, 978))	('bronchioloalveolar carcinoma', 'Disease', 'MESH:D002282', (123, 151))	('tumor suppressor', 'biological_process', 'GO:0051726', ('936', '952'))	('centrosome duplication', 'biological_process', 'GO:0051298', ('483', '505'))	('telomere dysfunction', 'Disease', (507, 527))	('DNA', 'cellular_component', 'GO:0005574', ('814', '817'))	('spindle', 'cellular_component', 'GO:0005819', ('555', '562'))	('mitosis', 'Disease', 'None', (298, 305))	('chromatid', 'cellular_component', 'GO:0005694', ('453', '462'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (384, 407))	('epigenetic modifications', 'Var', (899, 923))	('p16', 'Gene', (967, 970))	('telomere dysfunction', 'Disease', 'MESH:C536801', (507, 527))	('pre', 'molecular_function', 'GO:0003904', ('81', '84'))	('spindle assembly checkpoint', 'biological_process', 'GO:0071173', ('555', '582'))	('chromatid', 'cellular_component', 'GO:0005695', ('453', '462'))	('telomere', 'cellular_component', 'GO:0000781', ('507', '515'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (667, 689))	('cytoplasm', 'cellular_component', 'GO:0005737', ('219', '228'))	('telomere', 'cellular_component', 'GO:0005696', ('507', '515'))
35437	29053631	Also in 2001, the JSOH set the reference values for occupational exposure at 0.15 f/mL for chrysotile and 0.03 f/mL for non-chrysotile asbestos, which corresponded to 10-3 individual excess lifetime risks of mesothelioma and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('chrysotile asbestos', 'Disease', (124, 143))	('chrysotile asbestos', 'Disease', 'MESH:D001195', (124, 143))	('0.03 f/mL', 'Var', (106, 115))	('mesothelioma and lung cancer', 'Disease', 'MESH:D008175', (208, 236))
35616	25653696	Another study shows combination therapy of pemetrexed and cisplatin increases median survival, delays progression and improves response rate compared to pemetrexed alone or cisplatin alone therapy.	('pemetrexed', 'Chemical', 'MESH:D000068437', (43, 53))	('increases', 'PosReg', (68, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('median survival', 'MPA', (78, 93))	('combination', 'Var', (20, 31))	('progression', 'MPA', (102, 113))	('response', 'MPA', (127, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('pemetrexed', 'Chemical', 'MESH:D000068437', (153, 163))	('improves', 'PosReg', (118, 126))
35630	24591784	Other risk factors include SV40 virus, genetic alterations, and exposure to radiotherapy generally for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genetic alterations', 'Var', (39, 58))	('SV40', 'Gene', (27, 31))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
35999	29980753	In turn activated PARP-1 induces PARylation of multiple proteins and promotes cell necrosis through ATP depletion.	('PAR', 'Gene', (18, 21))	('necrosis', 'biological_process', 'GO:0070265', ('83', '91'))	('ATP depletion', 'MPA', (100, 113))	('cell necrosis', 'CPA', (78, 91))	('necrosis', 'biological_process', 'GO:0008219', ('83', '91'))	('necrosis', 'biological_process', 'GO:0019835', ('83', '91'))	('PAR', 'Gene', '69597', (33, 36))	('induces', 'Reg', (25, 32))	('proteins', 'Protein', (56, 64))	('promotes', 'PosReg', (69, 77))	('PAR', 'Gene', (33, 36))	('necrosis', 'biological_process', 'GO:0008220', ('83', '91'))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('activated', 'Var', (8, 17))	('necrosis', 'biological_process', 'GO:0001906', ('83', '91'))	('PAR', 'Gene', '69597', (18, 21))
36004	29980753	We therefore determined the impact of RAPTA-T on VEGF released by MSTO211H cells in culture, and we found that RAPTA-T (400 muM) caused a two-fold drop in VEGF-A levels (Fig S1D).	('drop', 'NegReg', (147, 151))	('RAPTA-T', 'Chemical', 'MESH:C534678', (111, 118))	('RAPTA-T (400 muM', 'Var', (111, 127))	('RAPTA-T', 'Chemical', 'MESH:C534678', (38, 45))	('VEGF-A levels', 'MPA', (155, 168))
36025	29980753	Abnormal blood vessel function contributes to elevated IFP in tumors, which in turn adds to a decreased transcapillary transport and impairs drug delivery throughout tumors.	('IFP', 'MPA', (55, 58))	('elevated', 'PosReg', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('transport', 'biological_process', 'GO:0006810', ('119', '128'))	('tumors', 'Disease', (62, 68))	('transcapillary transport', 'MPA', (104, 128))	('drug delivery', 'MPA', (141, 154))	('impairs', 'NegReg', (133, 140))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('decreased', 'NegReg', (94, 103))	('Abnormal blood vessel', 'Phenotype', 'HP:0002597', (0, 21))	('Abnormal', 'Var', (0, 8))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
36032	29980753	Pericyte coverage was significantly enhanced in RAPTA-T (50 mg kg-1) treated tumors compared to controls (34.6 +- 19.2 vs 21.5 +- 16.3% alpha-SMA-positive vessels, respectively, Fig.	('tumors', 'Disease', (77, 83))	('50 mg', 'Var', (57, 62))	('RAPTA-T', 'Chemical', 'MESH:C534678', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('RAPTA-T', 'Gene', (48, 55))	('alpha-SMA', 'Gene', '11475', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('alpha-SMA', 'Gene', (136, 145))	('enhanced', 'PosReg', (36, 44))
36049	29980753	Interestingly, while RAPTA-T treatment alone had no significant effect on tumor growth by day 21 compared to control, there was a significant decrease in tumor growth of the RAPTA-T combination with cisplatin compared to cisplatin alone (333 +- 88 vs 164 +- 65 mm3 at day 21, respectively, p < 0.005, Fig S5).	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('combination', 'Var', (182, 193))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('decrease', 'NegReg', (142, 150))	('tumor', 'Disease', (74, 79))	('RAPTA-T', 'Chemical', 'MESH:C534678', (21, 28))	('RAPTA-T', 'Chemical', 'MESH:C534678', (174, 181))	('RAPTA-T', 'Gene', (174, 181))	('tumor', 'Disease', (154, 159))
36052	29980753	We initially confirmed that vascular stabilization under the form of enhanced pericyte coverage occurred in MSTO211H tumors (Fig S4B,C).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('enhanced', 'PosReg', (69, 77))	('vascular stabilization', 'CPA', (28, 50))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('MSTO211H', 'Var', (108, 116))
36099	29980753	We further confirmed the beneficial vascular transport conditions created by RAPTA-T in an orthotopic mesothelioma model by pre-treating with RAPTA-T followed by lipoplatin, and demonstrated improved tumor regression for a longer period of time in tumors pre-treated with RAPTA-T compared to tumors that did not receive the pre-treatment (Fig.	('RAPTA-T', 'Chemical', 'MESH:C534678', (142, 149))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('RAPTA-T', 'Chemical', 'MESH:C534678', (77, 84))	('RAPTA-T', 'Var', (272, 279))	('tumors', 'Disease', (248, 254))	('improved', 'PosReg', (191, 199))	('vascular transport', 'MPA', (36, 54))	('beneficial', 'PosReg', (25, 35))	('vascular transport', 'biological_process', 'GO:0010232', ('36', '54'))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumor', 'Disease', (248, 253))	('tumors', 'Disease', (292, 298))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('pre', 'molecular_function', 'GO:0003904', ('324', '327'))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mesothelioma', 'Disease', (102, 114))	('lipoplatin', 'Chemical', 'MESH:C503131', (162, 172))	('RAPTA-T', 'Chemical', 'MESH:C534678', (272, 279))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('pre', 'molecular_function', 'GO:0003904', ('124', '127'))	('tumor', 'Disease', (292, 297))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('pre', 'molecular_function', 'GO:0003904', ('255', '258'))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
36152	29980753	Pericytes were stained by anti-alpha-SMA (1:100, 1A4, Dako, Glostrup, Denmark) antibody for 40 min at room temperature, followed by secondary antibodies donkey anti-mouse Alexa488 (1:800) and goat anti-rat Alexa568 (1:1000).	('mouse', 'Species', '10090', (165, 170))	('alpha-SMA', 'Gene', (31, 40))	('alpha-SMA', 'Gene', '11475', (31, 40))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))	('donkey', 'Species', '9793', (153, 159))	('goat', 'Species', '9925', (192, 196))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('rat', 'Species', '10116', (112, 115))	('Alexa568', 'Chemical', 'MESH:C000607448', (206, 214))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('1:100', 'Var', (42, 47))	('rat', 'Species', '10116', (202, 205))	('Alexa488', 'Chemical', '-', (171, 179))
36286	22043235	The first involved silencing E-Cadherin using siRNA.	('Cadherin', 'molecular_function', 'GO:0008014', ('31', '39'))	('silencing', 'Var', (19, 28))	('E-Cadherin', 'Gene', (29, 39))	('E-Cadherin', 'Gene', '999', (29, 39))
36315	31929796	Between MSTO-211H and NCI-H2452, three phosphosites (CD3Z, EGFR, and GSK3ss) showed a higher phosphorylation and four phosphosites (EFS, ENOG, EPHA7, and PTN6) showed lower phosphorylation levels in NCI-H2452 cells.	('lower', 'NegReg', (167, 172))	('phosphorylation levels', 'MPA', (173, 195))	('CD3Z', 'Gene', (53, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('173', '188'))	('EGFR', 'Gene', (59, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('CD3Z', 'Gene', '919', (53, 57))	('EPHA7', 'Gene', (143, 148))	('MSTO-211H', 'Var', (8, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('higher', 'PosReg', (86, 92))	('phosphorylation', 'MPA', (93, 108))	('EPHA7', 'Gene', '2045', (143, 148))	('GSK', 'molecular_function', 'GO:0050321', ('69', '72'))	('EGFR', 'Gene', '1956', (59, 63))
36316	31929796	Especially, high phosphorylation of ESR1, LAT, PTN12, and PTN6 showed the strongest apoptosis-preventing effect.	('PTN6', 'Gene', (58, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('high', 'Var', (12, 16))	('ESR1', 'Gene', '2099', (36, 40))	('phosphorylation', 'MPA', (17, 32))	('apoptosis-preventing effect', 'CPA', (84, 111))	('PTN12', 'Gene', (47, 52))	('LAT', 'Gene', (42, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('ESR1', 'Gene', (36, 40))	('LAT', 'Gene', '27040', (42, 45))
36318	31929796	In the cell cycle pathway, GSK3B, CDK2, and CDK1 are reduced by cisplatin in each cell line, and in cancer pathways, cisplatin reduces phosphorylation of GSK3B, AKT1, PDGFRa/b, PLCG1/2, and CDK2.	('CDK1', 'Gene', '983', (44, 48))	('CDK1', 'Gene', (44, 48))	('GSK3B', 'Protein', (154, 159))	('CDK2', 'Gene', '1017', (34, 38))	('PLCG1/2', 'Gene', '5335;5336', (177, 184))	('CDK2', 'Gene', (34, 38))	('cell cycle', 'biological_process', 'GO:0007049', ('7', '17'))	('phosphorylation', 'MPA', (135, 150))	('cisplatin', 'Var', (117, 126))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('reduces', 'NegReg', (127, 134))	('CDK2', 'Gene', '1017', (190, 194))	('PDGFRa', 'Gene', '5156', (167, 173))	('cell', 'Pathway', (7, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('reduced', 'NegReg', (53, 60))	('GSK3B', 'Gene', (27, 32))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('PDGFRa', 'Gene', (167, 173))	('GSK', 'molecular_function', 'GO:0050321', ('154', '157'))	('CDK2', 'Gene', (190, 194))	('CDK', 'molecular_function', 'GO:0004693', ('190', '193'))	('AKT1', 'Gene', (161, 165))	('PLCG1/2', 'Gene', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CDK', 'molecular_function', 'GO:0004693', ('34', '37'))
36326	31929796	Phosphorylation of proteins driving cell cycle control showed major changes during therapy (CDK1, CDK2, EPHA1, EPHA2, EPHA7, ENO2, PTK2B, FER, FES, FRK, KIT, PDGFRB, and KDR).	('KIT', 'molecular_function', 'GO:0005020', ('153', '156'))	('Phosphorylation of', 'MPA', (0, 18))	('CDK', 'molecular_function', 'GO:0004693', ('92', '95'))	('changes', 'Reg', (68, 75))	('cell cycle control', 'biological_process', 'GO:1901987', ('36', '54'))	('PTK2B', 'Var', (131, 136))	('EPHA1', 'Var', (104, 109))	('ENO2', 'Gene', '2026', (125, 129))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('proteins', 'Protein', (19, 27))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))	('FRK', 'Gene', '2444', (148, 151))	('CDK2', 'Gene', (98, 102))	('ENO2', 'Gene', (125, 129))	('FRK', 'Gene', (148, 151))
36328	31929796	Figures -), NCI-H2052 cells showed a 2.5-3-fold decrease in kinase activity of FGFR1, FES, and ALK due to cisplatin treatment, with a high specificity score (2, dark red) for the respective phosphosites.	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('cisplatin', 'Var', (106, 115))	('FGFR1', 'Gene', (79, 84))	('kinase activity', 'MPA', (60, 75))	('decrease', 'NegReg', (48, 56))	('FGFR1', 'Gene', '2260', (79, 84))	('kinase activity', 'molecular_function', 'GO:0016301', ('60', '75'))
36339	31929796	found the activating transcription factor 3 (ATF3) as an important regulator of cisplatin cytotoxicity, being activated in platin-sensitive lung cancer cells due to cisplatin treatment.	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('transcription factor', 'molecular_function', 'GO:0000981', ('21', '41'))	('activating transcription factor 3', 'Gene', (10, 43))	('ATF3', 'Gene', (45, 49))	('ATF3', 'Gene', '467', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('cisplatin', 'Var', (165, 174))	('activating transcription factor 3', 'Gene', '467', (10, 43))	('activated', 'PosReg', (110, 119))
36422	29163783	We found CD4+ and CD8+ T cells, B cells, macrophages, natural killer cells, dendritic cells and tumor cells in the fluids.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CD', 'Chemical', 'MESH:D002104', (9, 11))	('B cells', 'CPA', (32, 39))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('CD4+', 'Var', (9, 13))	('CD', 'Chemical', 'MESH:D002104', (18, 20))	('CD8+', 'Var', (18, 22))
36424	29163783	Moreover, we identified two MPM effusion-related factors with clinical value: CD4+ T cells were significantly correlated with better response to chemotherapy, while the percentage of PD-L1+ podoplanin (PDPN)+ tumor cells is a significant prognostic factor for worse outcome.	('tumor', 'Disease', (209, 214))	('better', 'PosReg', (126, 132))	('CD', 'Chemical', 'MESH:D002104', (78, 80))	('CD4+ T cells', 'Var', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
36441	29163783	The latter two are upcoming immune checkpoints that are gaining more attention due to interesting preclinical results in different tumor types and ongoing clinical trials testing specific blocking antibodies (NCT01968109; NCT02817633).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('int', 'Gene', (86, 89))	('int', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('NCT01968109', 'Var', (209, 220))	('int', 'Gene', '27152', (86, 89))	('int', 'Gene', '27152', (42, 45))
36451	29163783	Predominant cells were CD3+CD4+ T cells, CD64+ macrophages and CD11c+ or CD303+ dendritic cells (DCs) with percentages up to 51.7%, 38.8% and 43.4% of viable cells, respectively.	('CD64', 'Gene', '2209', (41, 45))	('CD', 'Chemical', 'MESH:D002104', (73, 75))	('CD11c+', 'Var', (63, 69))	('CD', 'Chemical', 'MESH:D002104', (27, 29))	('CD', 'Chemical', 'MESH:D002104', (23, 25))	('CD3+CD4+', 'Var', (23, 31))	('CD64', 'Gene', (41, 45))	('CD303+', 'Var', (73, 79))	('CD', 'Chemical', 'MESH:D002104', (41, 43))	('CD', 'Chemical', 'MESH:D002104', (63, 65))
36455	29163783	The immune checkpoints PD-1, LAG-3 and TIM-3 were expressed on CD3+CD4+ T cells, CD3+CD8+ T cells and on NK cells in both fluid types.	('CD3+CD4+ T', 'Var', (63, 73))	('TIM-', 'Gene', '26762', (39, 43))	('CD', 'Chemical', 'MESH:D002104', (67, 69))	('int', 'Gene', (18, 21))	('1, LAG-', 'Gene', '3925', (26, 33))	('CD', 'Chemical', 'MESH:D002104', (81, 83))	('CD', 'Chemical', 'MESH:D002104', (85, 87))	('TIM-', 'Gene', (39, 43))	('CD3+CD8+ T', 'Var', (81, 91))	('int', 'Gene', '27152', (18, 21))	('CD', 'Chemical', 'MESH:D002104', (63, 65))
36456	29163783	PD-1 expression was found in all samples on CD8+ T cells and in ten samples on CD4+ T cells and/or NK cells.	('CD', 'Chemical', 'MESH:D002104', (79, 81))	('amp', 'Gene', (69, 72))	('expression', 'MPA', (5, 15))	('PD-1', 'Gene', (0, 4))	('CD8+ T cells', 'Var', (44, 56))	('CD', 'Chemical', 'MESH:D002104', (44, 46))	('amp', 'Gene', '353', (34, 37))	('found', 'Reg', (20, 25))	('amp', 'Gene', '353', (69, 72))	('amp', 'Gene', (34, 37))
36457	29163783	Positivity of LAG-3 was seen in nine samples on CD4+ T cells, in seven samples on CD8+ T cells and in eight samples on NK cells.	('CD4+ T cells', 'Var', (48, 60))	('amp', 'Gene', '353', (109, 112))	('amp', 'Gene', (38, 41))	('amp', 'Gene', (72, 75))	('CD', 'Chemical', 'MESH:D002104', (82, 84))	('LAG-', 'Gene', (14, 18))	('CD', 'Chemical', 'MESH:D002104', (48, 50))	('amp', 'Gene', (109, 112))	('amp', 'Gene', '353', (38, 41))	('LAG-', 'Gene', '3925', (14, 18))	('amp', 'Gene', '353', (72, 75))
36458	29163783	Expression of TIM-3 was observed in all samples on CD4+ T cells and NK cells and in nine samples on CD8+ T cells (Figure 1).	('TIM-', 'Gene', (14, 18))	('amp', 'Gene', (41, 44))	('amp', 'Gene', (90, 93))	('CD', 'Chemical', 'MESH:D002104', (100, 102))	('amp', 'Gene', '353', (41, 44))	('TIM-', 'Gene', '26762', (14, 18))	('observed', 'Reg', (24, 32))	('amp', 'Gene', '353', (90, 93))	('CD4+ T cells', 'Var', (51, 63))	('CD', 'Chemical', 'MESH:D002104', (51, 53))
36459	29163783	Figure 1 and Table 2 depict the distributions and proportions of PD-1, LAG-3 and TIM-3 expression on CD3+CD4+ and CD3+CD8+ T cells and NK cells.	('CD3+CD8+', 'Var', (114, 122))	('CD', 'Chemical', 'MESH:D002104', (114, 116))	('CD', 'Chemical', 'MESH:D002104', (101, 103))	('CD', 'Chemical', 'MESH:D002104', (118, 120))	('CD', 'Chemical', 'MESH:D002104', (105, 107))	('TIM-', 'Gene', '26762', (81, 85))	('1, LAG-', 'Gene', '3925', (68, 75))	('TIM-', 'Gene', (81, 85))
36461	29163783	PD-1 positivity varied in each cell type, ranging from 9% to 61.9% for the CD4+ T cells, 11.4% to 66.4% for the CD8+ T cells and 3.28% to 64.3 % for the NK cells.	('CD4+ T', 'Var', (75, 81))	('CD', 'Chemical', 'MESH:D002104', (75, 77))	('PD-1', 'Gene', (0, 4))	('CD', 'Chemical', 'MESH:D002104', (112, 114))	('CD8+ T', 'Var', (112, 118))
36470	29163783	Highest PD-L1 expression was found on the PDPN+ tumor cells in both fluid types, with a median expression of 19.4% PD-L1+ cells and a range of 20 up to 14524 on a per cell basis (Table 3).	('PDPN+', 'Var', (42, 47))	('tumor', 'Disease', (48, 53))	('PD-L1', 'Gene', (8, 13))	('expression', 'MPA', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
36471	29163783	Similar to the immune checkpoints, there is a broad range of PD-L1 positivity between and within the fluid types.	('PD-L1', 'Gene', (61, 66))	('int', 'Gene', '27152', (29, 32))	('int', 'Gene', (29, 32))	('positivity', 'Var', (67, 77))
36496	29163783	While PD-L1 expression in MPM tissue samples has already been reported to be associated with decreased overall survival, as far as we know we are the first to report this for MPM fluid samples.	('overall survival', 'MPA', (103, 119))	('amp', 'Gene', '353', (186, 189))	('amp', 'Gene', (38, 41))	('expression', 'Var', (12, 22))	('amp', 'Gene', (186, 189))	('decreased', 'NegReg', (93, 102))	('PD-L1', 'Gene', (6, 11))	('amp', 'Gene', '353', (38, 41))
36521	29163783	Our results also confirm the presence of CD4+ T cells, CD8+ T cells and macrophages in pleural effusions of MPM patients.	('CD8+ T cells', 'CPA', (55, 67))	('CD', 'Chemical', 'MESH:D002104', (55, 57))	('CD4+', 'Var', (41, 45))	('patients', 'Species', '9606', (112, 120))	('pleural effusions of MPM', 'Disease', (87, 111))	('pleural effusions of MPM', 'Disease', 'MESH:D010996', (87, 111))	('pleural effusions', 'Phenotype', 'HP:0002202', (87, 104))	('CD', 'Chemical', 'MESH:D002104', (41, 43))
36529	29163783	In the evaluated patient population of cisplatin/pemetrexed-treated patients who developed effusions over time, we observed that the percentage of CD3+CD4+ T cells is significantly correlated with the patients' response to chemotherapy.	('patients', 'Species', '9606', (201, 209))	('patient', 'Species', '9606', (68, 75))	('patient', 'Species', '9606', (17, 24))	('patients', 'Species', '9606', (68, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('pemetrexed', 'Chemical', 'MESH:D000068437', (49, 59))	('CD', 'Chemical', 'MESH:D002104', (151, 153))	('correlated', 'Reg', (181, 191))	('patient', 'Species', '9606', (201, 208))	('CD', 'Chemical', 'MESH:D002104', (147, 149))	('CD3+CD4+ T cells', 'Var', (147, 163))
36543	29163783	All the antibodies were purchased from Becton Dickinson (BD Biosciencesa), except for the live/dead stains and the CD8 mAb (Life TechnologiesTM), the CD303 mAb (Biolegenda, California, USA) and the PDPN mAb (eBiosciencea, Vienna, Austria).	('CD', 'Chemical', 'MESH:D002104', (115, 117))	('BD Biosciencesa', 'Disease', (57, 72))	('CD', 'Chemical', 'MESH:D002104', (150, 152))	('BD Biosciencesa', 'Disease', 'MESH:D001528', (57, 72))	('CD303', 'Var', (150, 155))	('eBiosciencea', 'Disease', 'None', (208, 220))	('eBiosciencea', 'Disease', (208, 220))
36558	19130460	A Possible Association Between Aprotinin and Improved Survival After Radical Surgery for Mesothelioma Aprotinin has been used to decrease blood loss with complicated cardiac surgery but has not been investigated in extrapleural pneumonectomy, an operation that does not use cardiopulmonary bypass.	('blood loss', 'Disease', 'MESH:D006473', (138, 148))	('decrease', 'NegReg', (129, 137))	('rat', 'Species', '10116', (249, 252))	('blood loss', 'Disease', (138, 148))	('Aprotinin', 'Var', (102, 111))	('Mesothelioma', 'Disease', (89, 101))	('Mesothelioma', 'Disease', 'MESH:D008654', (89, 101))
36563	19130460	The mean blood loss was 769 mL with aprotinin versus 1832 mL with placebo (P = .05; Wilcoxon test).	('blood loss', 'Disease', (9, 19))	('blood loss', 'Disease', 'MESH:D006473', (9, 19))	('aprotinin', 'Var', (36, 45))
36572	19130460	Recently, its use was called into question by a controversial but influential study, which suggested that aprotinin used in the setting of coronary revascularization was associated with a doubling of the rate of renal failure requiring dialysis, a 55% increase in myocardial infarction or heart failure, and a 181% increase in stroke or encephalopathy.	('myocardial infarction', 'Disease', (264, 285))	('renal failure', 'Phenotype', 'HP:0000083', (212, 225))	('myocardial infarction', 'Phenotype', 'HP:0001658', (264, 285))	('encephalopathy', 'Disease', 'MESH:D001927', (337, 351))	('renal failure', 'Disease', 'MESH:D051437', (212, 225))	('myocardial infarction', 'Disease', 'MESH:D009203', (264, 285))	('renal failure', 'Disease', (212, 225))	('aprotinin', 'Var', (106, 115))	('stroke', 'Phenotype', 'HP:0001297', (327, 333))	('increase', 'PosReg', (252, 260))	('increase', 'PosReg', (315, 323))	('stroke', 'Disease', 'MESH:D020521', (327, 333))	('heart failure', 'Disease', 'MESH:D006333', (289, 302))	('encephalopathy', 'Phenotype', 'HP:0001298', (337, 351))	('heart failure', 'Phenotype', 'HP:0001635', (289, 302))	('rat', 'Species', '10116', (204, 207))	('stroke', 'Disease', (327, 333))	('encephalopathy', 'Disease', (337, 351))	('heart failure', 'Disease', (289, 302))
36573	19130460	Studies also have demonstrated that aprotinin decreases blood loss during liver transplantation and major orthopedic surgery, although the mechanism of blood conservation in these models may differ from that in cardiac surgery, because cardiopulmonary bypass is not used for these surgeries.	('decreases blood loss', 'Disease', (46, 66))	('decreases blood loss', 'Disease', 'MESH:D006473', (46, 66))	('rat', 'Species', '10116', (25, 28))	('aprotinin', 'Var', (36, 45))
36577	19130460	Nonetheless, despite uncertainty over the exact mechanism, aprotinin decreases hemorrhage in these widely disparate models.	('decreases hemorrhage', 'Disease', (69, 89))	('rat', 'Species', '10116', (111, 114))	('decreases hemorrhage', 'Disease', 'MESH:D006470', (69, 89))	('aprotinin', 'Var', (59, 68))
36583	19130460	Because there was little experimental evidence that aprotinin would be helpful in the setting of EPP, which does not use cardiopulmonary bypass, we undertook an investigator-initiated, prospective, randomized, controlled, double-blind study of the estimated blood loss (EBL) in patients undergoing EPP who received aprotinin versus patients who received placebo.	('blood loss', 'Disease', (258, 268))	('patients', 'Species', '9606', (332, 340))	('patients', 'Species', '9606', (278, 286))	('aprotinin', 'Var', (315, 324))	('EPP', 'Var', (298, 301))	('blood loss', 'Disease', 'MESH:D006473', (258, 268))
36622	19130460	The plot in Figure 1 indicates that aprotinin was associated with a decrease in blood loss (P = .05, Wilcoxon test), with mean loss of 769 mL (95% confidence interval [95% CI], 243-1295 mL) in the aprotinin group (3 inoperable patients were excluded) and a mean loss of 1832 mL (95% CI, 633-3030 mL) in the placebo group (1 intraoperative death was excluded).	('blood loss', 'Disease', 'MESH:D006473', (80, 90))	('decrease', 'NegReg', (68, 76))	('intraoperative death', 'Disease', (324, 344))	('intraoperative death', 'Disease', 'MESH:D003643', (324, 344))	('aprotinin', 'Var', (197, 206))	('blood loss', 'Disease', (80, 90))	('aprotinin', 'Var', (36, 45))	('loss', 'NegReg', (127, 131))	('patients', 'Species', '9606', (227, 235))
36623	19130460	The frequency of transfusion of blood products also was significantly lower (P < .001; 2-tailed Fisher exact test) in the aprotinin group, in which 2 of 8 patients received transfusions (3 inoperable patients were excluded) compared with 8 of 8 patients in the placebo group (1 intraoperative death was excluded).	('patients', 'Species', '9606', (200, 208))	('intraoperative death', 'Disease', (278, 298))	('patients', 'Species', '9606', (245, 253))	('intraoperative death', 'Disease', 'MESH:D003643', (278, 298))	('transfusion of blood products', 'MPA', (17, 46))	('lower', 'NegReg', (70, 75))	('aprotinin', 'Var', (122, 131))	('patients', 'Species', '9606', (155, 163))
36626	19130460	Excluding the 3 aprotinin patients who underwent a lesser resection or no resection and who, by definition, had persistent disease, recurrent mesothelioma occurred in 4 of 8 patients in the aprotinin group and in 3 of 8 patients in the placebo group.	('aprotinin', 'Var', (190, 199))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (174, 182))	('mesothelioma', 'Disease', (142, 154))	('patients', 'Species', '9606', (220, 228))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))
36642	19130460	On the basis of the observed data on the 18 patients who had covariates available and who were evaluable for overall survival, and accounting for the noted patient covariates with known significant effects on survival, the fitted Bayesian model indicated that the posterior probability that aprotinin was associated with longer survival was Pr(beta9>0 data) = .99.	('patient', 'Species', '9606', (44, 51))	('patients', 'Species', '9606', (44, 52))	('longer', 'PosReg', (321, 327))	('aprotinin', 'Var', (291, 300))	('patient', 'Species', '9606', (156, 163))
36645	19130460	Despite early closure of the study to enrollment because of the FDA ruling, we observed that aprotinin had a statistically significant beneficial effect compared with placebo both in terms of decreasing blood loss and improving overall survival, the latter after accounting for prognostic covariate effects.	('blood loss', 'Disease', (203, 213))	('improving', 'PosReg', (218, 227))	('decreasing', 'NegReg', (192, 202))	('overall survival', 'CPA', (228, 244))	('blood loss', 'Disease', 'MESH:D006473', (203, 213))	('aprotinin', 'Var', (93, 102))
36647	19130460	Therefore, although our dataset was quite small, the magnitude of the beneficial effect associated with aprotinin use suggests that aprotinin still should be considered as a means of decreasing blood loss and lengthening survival in patients who undergo EPP.	('blood loss', 'Disease', 'MESH:D006473', (194, 204))	('survival', 'MPA', (221, 229))	('aprotinin', 'Var', (132, 141))	('blood loss', 'Disease', (194, 204))	('lengthening', 'PosReg', (209, 220))	('patients', 'Species', '9606', (233, 241))	('decreasing', 'NegReg', (183, 193))
36650	19130460	Although our study did not involve a search for the mechanism of survival improvement, it is reasonable to speculate that aprotinin may have improved survival either by preventing tumor progression, perhaps through an effect on the urokinase-type plasminogen activator (uPA), or by stimulating the immune system to oppose cancer progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('urokinase-type plasminogen activator', 'Gene', '5328', (232, 268))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('urokinase-type plasminogen activator', 'Gene', (232, 268))	('uPA', 'Gene', (270, 273))	('preventing', 'NegReg', (169, 179))	('cancer', 'Disease', (322, 328))	('urokinase-type plasminogen activator', 'molecular_function', 'GO:0008243', ('232', '268'))	('tumor', 'Disease', (180, 185))	('uPA', 'Gene', '5328', (270, 273))	('improved', 'PosReg', (141, 149))	('uPA', 'molecular_function', 'GO:0008243', ('270', '273'))	('aprotinin', 'Var', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('survival', 'MPA', (150, 158))
36655	19130460	Similarly, another study demonstrated improved survival in patients who received aprotinin during esophagectomy, although this finding came from a nonrandomized, nonblinded study that was reported only in a meeting abstract.	('improved', 'PosReg', (38, 46))	('rat', 'Species', '10116', (32, 35))	('survival', 'MPA', (47, 55))	('patients', 'Species', '9606', (59, 67))	('aprotinin', 'Var', (81, 90))
36661	19130460	as suggested by the finding of a decrease in basic fibroblast growth factor levels in a mutant rat study model.	('decrease', 'NegReg', (33, 41))	('rat', 'Species', '10116', (95, 98))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('51', '75'))	('mutant', 'Var', (88, 94))	('basic fibroblast growth factor', 'Gene', '54250', (45, 75))	('basic fibroblast growth factor', 'Gene', (45, 75))
36793	24185840	In fact, the daily exposures resulting from clothing activities were indistinguishable from background concentrations of asbestos, reported as ranging between 0.00001 f/cc and 0.0001 f/cc.	('0.00001 f/cc', 'Var', (159, 171))	('0.0001 f/cc', 'Var', (176, 187))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))
36810	20635326	AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny, and spread in multiple mesothelioma cell lines.	('produce', 'Reg', (51, 58))	('spread', 'Reg', (78, 84))	('AdMdk-E1-iresTK', 'Var', (0, 15))	('mesothelioma', 'Disease', (97, 109))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))
36811	20635326	Lytic spread of AdMdk-E1-iresTK mediated efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir.	('mesothelioma', 'Disease', (68, 80))	('Lytic spread', 'CPA', (0, 12))	('enhanced', 'PosReg', (140, 148))	('ganciclovir', 'Chemical', 'MESH:D015774', (180, 191))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('killing', 'CPA', (51, 58))	('AdMdk-E1-iresTK', 'Var', (16, 31))
36812	20635326	Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice.	('MESO4', 'Chemical', '-', (72, 77))	('mesothelioma xenografts', 'Disease', 'MESH:D008654', (93, 116))	('AdMdk-E1-iresTK', 'Var', (26, 41))	('mesothelioma xenografts', 'Disease', (93, 116))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('human', 'Species', '9606', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Disease', (5, 10))	('regression', 'NegReg', (58, 68))
36845	20635326	The primers and TaqMan probe for Mdk (Hs00171064_m1), CAR (Hs00154661_m1) and GAPDH (Hs99999905_m1) were purchased from Applied Biosystems Japan (Taqman gene expression assays).	('gene expression', 'biological_process', 'GO:0010467', ('153', '168'))	('Hs99999905_m1', 'Var', (85, 98))	('CAR', 'cellular_component', 'GO:0005826', ('54', '57'))	('Hs00154661_m1', 'Var', (59, 72))	('GAPDH', 'Gene', '2597', (78, 83))	('GAPDH', 'Gene', (78, 83))	('Hs00171064_m1', 'Var', (38, 51))	('CAR', 'Gene', '1525', (54, 57))	('CAR', 'Gene', (54, 57))
36847	20635326	These shuttle plasmids were then transformed into Escherichia coli BJ5183-AD (Stratagene) for homologous recombination in order to generate pAdMdk-E1-iresTK (Ad881), pAdCMV-E1-iresTK (Ad883), pAdMdk-TK (Ad884) and pAdCMV-TK (Ad885).	('Escherichia coli', 'Species', '562', (50, 66))	('pAdMdk-E1-iresTK', 'Var', (140, 156))	('Ad884', 'Var', (203, 208))	('BJ5183', 'CellLine', 'CVCL:6573', (67, 73))	('homologous recombination', 'biological_process', 'GO:0035825', ('94', '118'))
36850	20635326	For quantitative analysis of the cytocidal effect of each adenovirus, five sets of 96-well tissue-culture plates containing Met5A, MESO4, or MSTO cells (1 x 104 cells/well) were infected with Ad881, Ad883, Ad884, or Ad885 at MOIs of 0, 0.01, 0.1, 1, 10, or 100.	('MESO4', 'Chemical', '-', (131, 136))	('Ad885', 'Var', (216, 221))	('Ad883', 'Var', (199, 204))	('Ad884', 'Var', (206, 211))	('Ad881', 'Var', (192, 197))
36855	20635326	When tumors reached a diameter of ~5 mm, mice were injected intratumorally with 100 muL of PBS, Ad881 or Ad884 (5 x 108 TU) on Day 0.	('tumors', 'Disease', (5, 11))	('Ad884', 'Var', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('PBS', 'Gene', (91, 94))	('PBS', 'Gene', '1131', (91, 94))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('Ad881', 'Var', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
36857	20635326	In a separate set of experiments, MESO4 cells were grown subcutaneously in nude mice to a diameter of 5-6 mm as above, and five groups of mice (n = 8 per group) were then injected intratumorally with 100 muL of PBS, Ad881 or Ad884 (5 x 108 TU) on Day 0, followed by intraperitoneal administration of either GCV (100 mg/kg/day) or saline (0.9% NaCl) from Day 14 to Day 28 (n = 8 per group).	('tumor', 'Disease', (185, 190))	('NaCl', 'Chemical', 'MESH:D012965', (343, 347))	('GCV', 'Chemical', 'MESH:D015774', (307, 310))	('mice', 'Species', '10090', (138, 142))	('nude mice', 'Species', '10090', (75, 84))	('saline', 'Chemical', 'MESH:D012965', (330, 336))	('PBS', 'Gene', (211, 214))	('PBS', 'Gene', '1131', (211, 214))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('mice', 'Species', '10090', (80, 84))	('MESO4', 'Chemical', '-', (34, 39))	('Ad881', 'Var', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
36860	20635326	This experiment was repeated using MSTO cells, and tumors were injected with 100 muL of PBS, Ad881 or Ad884 (5 x 108 TU) on Day 0 and Day 6, followed by intraperitoneal administration of either GCV or saline from Day 24 to Day 48 (n = 8 per group).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GCV', 'Chemical', 'MESH:D015774', (194, 197))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PBS', 'Gene', (88, 91))	('PBS', 'Gene', '1131', (88, 91))	('saline', 'Chemical', 'MESH:D012965', (201, 207))	('Ad881', 'Var', (93, 98))
36861	20635326	To compare the antitumor efficacy between Mdk-driven Ad 881 and CMV-driven Ad 883, subcutaneous MSTO tumors in nude mice were injected intratumorally with 5 x 108 TU of either Ad881 (n = 4), Ad883 (n = 4) or Ad884 (n = 3), or PBS (n = 3) on Day 0, followed by intraperitoneal administration of GCV from Day 14 to Day 28.	('PBS', 'Gene', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (19, 24))	('Ad884', 'Var', (208, 213))	('nude mice', 'Species', '10090', (111, 120))	('Ad883', 'Var', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('GCV', 'Chemical', 'MESH:D015774', (294, 297))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MSTO tumors', 'Disease', 'MESH:D009369', (96, 107))	('PBS', 'Gene', '1131', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Ad881', 'Var', (176, 181))	('tumor', 'Disease', (101, 106))	('MSTO tumors', 'Disease', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', (140, 145))
36862	20635326	To compare the potential for hepatotoxicity caused by targeted vs. non-targeted adenovirus, 6- to 7-week-old female nude mice were intravenously injected with 5 x 108 TU of Ad881, Ad883, or PBS (n = 3 per group) via tail vein.	('to 7', 'Species', '1214577', (95, 99))	('Ad881', 'Var', (173, 178))	('hepatotoxicity', 'Disease', (29, 43))	('adenovirus, 6', 'Species', '10534', (80, 93))	('nude mice', 'Species', '10090', (116, 125))	('PBS', 'Gene', (190, 193))	('PBS', 'Gene', '1131', (190, 193))	('hepatotoxicity', 'Disease', 'MESH:D056486', (29, 43))	('Ad883', 'Var', (180, 185))
36873	20635326	Similar results were obtained using other mesothelioma cell lines (i.e., MESO1, MSTO, and H2452) (data not shown), indicating that lytic spread of the Ad881 oncolytic adenovirus mediates efficient killing in multiple established mesothelioma cell lines.	('Ad881', 'Var', (151, 156))	('killing', 'CPA', (197, 204))	('mesothelioma', 'Disease', 'MESH:D008654', (229, 241))	('mesothelioma', 'Disease', (42, 54))	('lytic', 'CPA', (131, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('mesothelioma', 'Disease', (229, 241))
36874	20635326	To assess oncolytic adenovirus propagation in mesothelial cells, normal mesothelial cells (NMC), the non-malignant transformed mesothelial cell line Met5A, and the malignant mesothelioma cell lines MESO1, MESO4, and MSTO, were infected with Mdk-driven replication-competent Ad881, CMV-driven replication-competent Ad883, or Mdk-driven replication-defective Ad884 at an MOI of 100.	('MESO4', 'Chemical', '-', (205, 210))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (164, 186))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (164, 186))	('malignant mesothelioma', 'Disease', (164, 186))	('Mdk-driven replication-defective', 'Var', (324, 356))
36875	20635326	In contrast, in malignant mesothelioma cells Ad881 showed much higher levels of virus production compared to Ad883: in MESO1, MESO4, and MSTO cells, Ad881 showed, respectively, 2.6-fold, 51.3-fold, and 21.2-fold higher virus production than Ad883 (Figure 4a).	('Ad881', 'Var', (45, 50))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (16, 38))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (16, 38))	('Ad881', 'Var', (149, 154))	('malignant mesothelioma', 'Disease', (16, 38))	('MESO4', 'Chemical', '-', (126, 131))	('higher', 'PosReg', (212, 218))	('virus production', 'MPA', (219, 235))
36877	20635326	To investigate tumor-specific cytotoxicity, malignant mesothelioma cell lines (MESO1, MESO4, H28, H2052, H2452, and MSTO), Met5A non-malignant transformed mesothelial cells, and untransformed cell lines (NMC and fibroblast), either remained uninfected or were infected with Ad881, Ad883, Ad884, or Ad885 at various MOIs.	('MESO4', 'Chemical', '-', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (44, 66))	('Ad885', 'Var', (298, 303))	('Ad883', 'Var', (281, 286))	('Ad884', 'Var', (288, 293))	('cytotoxicity', 'Disease', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Ad881', 'Var', (274, 279))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (44, 66))	('tumor', 'Disease', (15, 20))	('malignant mesothelioma', 'Disease', (44, 66))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('H2052', 'CellLine', 'CVCL:1518', (98, 103))
36879	20635326	All of the mesothelioma cell lines tested showed cytolysis in a dose-dependent manner by the replication-competent adenoviruses, Ad881 and Ad883, although the sensitivity varied among different cell lines (Figure 5).	('Ad883', 'Var', (139, 144))	('cytolysis', 'biological_process', 'GO:0019835', ('49', '58'))	('mesothelioma', 'Disease', (11, 23))	('Ad881', 'Var', (129, 134))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('cytolysis', 'MPA', (49, 58))
36880	20635326	As expected from the virus propagation assay results, Ad881 showed cytotoxicity at levels comparable to Ad883 in Met5A non-malignant transformed mesothelial cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('cytotoxicity', 'Disease', (67, 79))	('Ad881', 'Var', (54, 59))
36881	20635326	In most malignant mesothelioma cell lines, Mdk-driven Ad881 caused more extensive cell death at lower MOIs than CMV-driven Ad883, which is consistent with the higher level of virus propagation seen in most of these cell lines (Figures 4a and 4b).	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (8, 30))	('cell death', 'CPA', (82, 92))	('malignant mesothelioma', 'Disease', (8, 30))	('Ad881', 'Var', (54, 59))	('cell death', 'biological_process', 'GO:0008219', ('82', '92'))	('Mdk-driven Ad881', 'Var', (43, 59))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (8, 30))
36882	20635326	In contrast, Ad881 showed no apparent CPE in NMC or fibroblasts even at MOI 1000, representing a therapeutic window ranging between 2-5 orders of magnitude for Ad881 cytotoxicity in the various mesothelioma cell lines compared to normal cells.	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('cytotoxicity', 'Disease', 'MESH:D064420', (166, 178))	('mesothelioma', 'Disease', (194, 206))	('Ad881', 'Var', (13, 18))	('cytotoxicity', 'Disease', (166, 178))
36884	20635326	The cytotoxicity of the adenoviruses was assayed by infecting replicate cultures of Met5A, MESO4, and MSTO cells with Ad881, Ad883, Ad884, or Ad885 at various MOIs.	('Ad884', 'Var', (132, 137))	('Ad881', 'Var', (118, 123))	('MESO4', 'Chemical', '-', (91, 96))	('Ad885', 'Var', (142, 147))	('cytotoxicity', 'Disease', (4, 16))	('Ad883', 'Var', (125, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
36886	20635326	As shown in Figure 6, the replication-defective vectors, Ad884 (with an Mdk-driven HSV-TK expression cassette) and Ad885 (with a CMV-driven HSV-TK cassette), showed cytotoxicity only in the presence of GCV.	('Ad884', 'Var', (57, 62))	('cytotoxicity', 'Disease', (165, 177))	('Ad885', 'Var', (115, 120))	('GCV', 'Chemical', 'MESH:D015774', (202, 205))	('cytotoxicity', 'Disease', 'MESH:D064420', (165, 177))
36887	20635326	On the other hand, both the Mdk-driven Ad881 and the CMV-driven Ad883 replication-competent adenoviruses showed time- and dose-dependent cytotoxicity in MESO4 and MSTO cells, in which the Mdk promoter is highly activated.	('MESO4', 'Chemical', '-', (153, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (137, 149))	('Ad881', 'Var', (39, 44))	('cytotoxicity', 'Disease', (137, 149))
36889	20635326	As expected, CMV-driven Ad883 was also cytotoxic to Met5A non-malignant transformed mesothelial cells, even without GCV treatment.	('Ad883', 'Var', (24, 29))	('GCV', 'Chemical', 'MESH:D015774', (116, 119))	('cytotoxic', 'CPA', (39, 48))
36890	20635326	In contrast, Mdk-driven Ad881 did not show significant cytotoxicity in the absence of prodrug, consistent with its inability to propagate at high levels in Met5A cells (Figure 4a), which have low levels of Mdk promoter activity (Figure 1b).	('cytotoxicity', 'Disease', (55, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))	('Ad881', 'Var', (24, 29))
36892	20635326	Athymic nude mice with subcutaneous MESO-4 human malignant mesothelioma xenografts received an intratumoral injection with 5 x 108 TU of either Ad881 or Ad884, or PBS control on Day 0.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('malignant mesothelioma', 'Disease', (49, 71))	('nude mice', 'Species', '10090', (8, 17))	('tumor', 'Disease', (100, 105))	('PBS', 'Gene', (163, 166))	('human', 'Species', '9606', (43, 48))	('PBS', 'Gene', '1131', (163, 166))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (49, 71))	('mesothelioma xenografts', 'Disease', (59, 82))	('Ad881', 'Var', (144, 149))	('mesothelioma xenografts', 'Disease', 'MESH:D008654', (59, 82))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (49, 71))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Ad884', 'Var', (153, 158))
36901	20635326	Tumors treated with replication-defective adenovirus Ad884 showed partial regression (40.9% reduction in tumor volume) only in the presence of GCV, and tumor regrowth was observed (Figure 8a).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (152, 157))	('reduction', 'NegReg', (92, 101))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('GCV', 'Chemical', 'MESH:D015774', (143, 146))	('tumor', 'Disease', (105, 110))	('Ad884', 'Var', (53, 58))
36904	20635326	In the presence of GCV, the Ad881-treated group showed a 64.2% reduction in tumor volume by Day 20, and tumor regrowth was observed thereafter, suggesting that further viral replication and spread was inhibited by suicide gene activation.	('viral replication', 'CPA', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('GCV', 'Chemical', 'MESH:D015774', (19, 22))	('viral replication', 'biological_process', 'GO:0008166', ('168', '185'))	('spread', 'CPA', (190, 196))	('Ad881-treated', 'Var', (28, 41))	('reduction', 'NegReg', (63, 72))	('inhibited', 'NegReg', (201, 210))	('viral replication', 'biological_process', 'GO:0019079', ('168', '185'))	('viral replication', 'biological_process', 'GO:0019058', ('168', '185'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
36906	20635326	Subcutaneous MSTO tumors were established in nude mice, and injected intratumorally with PBS, Ad881 or Ad884 (5 x 108 TU) on Day 0 and Day 6, followed by intraperitoneal administration of either GCV or saline from Day 24 to Day 48.	('nude mice', 'Species', '10090', (45, 54))	('Ad881', 'Var', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (18, 23))	('saline', 'Chemical', 'MESH:D012965', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (74, 79))	('PBS', 'Gene', (89, 92))	('PBS', 'Gene', '1131', (89, 92))	('Subcutaneous MSTO tumors', 'Disease', 'MESH:D013352', (0, 24))	('GCV', 'Chemical', 'MESH:D015774', (195, 198))	('Subcutaneous MSTO tumors', 'Disease', (0, 24))
36907	20635326	Tumors treated with Ad884 showed partial regression (23.2% reduction in tumor volume) only in the presence of GCV, and tumor regrowth was observed (Figure 8b).	('GCV', 'Chemical', 'MESH:D015774', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (119, 124))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (72, 77))	('Ad884', 'Var', (20, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('reduction', 'NegReg', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
36908	20635326	Without GCV treatment, Ad881 yielded significant growth inhibition compared with PBS control, but did not achieve complete tumor regression.	('GCV', 'Chemical', 'MESH:D015774', (8, 11))	('tumor', 'Disease', (123, 128))	('Ad881', 'Var', (23, 28))	('PBS', 'Gene', (81, 84))	('PBS', 'Gene', '1131', (81, 84))	('growth inhibition', 'CPA', (49, 66))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
36910	20635326	Next, we compared the anti-tumor efficacy of targeted Mdk-driven Ad881 vs. non-targeted CMV-driven Ad883 replication-competent adenoviruses in the subcutaneous MSTO tumor model.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Ad881', 'Var', (65, 70))	('tumor', 'Disease', (165, 170))
36911	20635326	Nude mice bearing MSTO tumors established as above were injected intratumorally with PBS, Ad881, Ad883 or Ad884 (5 x 108 TU) on Day 0, followed by intraperitoneal administration of GCV from Day 14 to Day 28.	('MSTO tumors', 'Disease', (18, 29))	('Ad881', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Nude mice', 'Species', '10090', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('PBS', 'Gene', (85, 88))	('PBS', 'Gene', '1131', (85, 88))	('tumor', 'Disease', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('MSTO tumors', 'Disease', 'MESH:D009369', (18, 29))	('GCV', 'Chemical', 'MESH:D015774', (181, 184))
36912	20635326	Prior to GCV administration, Mdk-driven Ad881 but not CMV-driven Ad883 showed significant inhibition of tumor growth compared to the PBS-treated group.	('inhibition', 'NegReg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('GCV', 'Chemical', 'MESH:D015774', (9, 12))	('tumor', 'Disease', (104, 109))	('Mdk-driven Ad881', 'Var', (29, 45))	('PBS', 'Gene', (133, 136))	('PBS', 'Gene', '1131', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
36913	20635326	Additionally, when combined with GCV treatment, Mdk-targeted replication-competent Ad881 yielded a significant reduction in tumor volume (77.1%) in comparison to the non-targeted CMV-driven replication competent control virus Ad883 (21.3%), as well as the Mdk-targeted non-replicating Ad884 (31.2%) (Figure 8c).	('reduction', 'NegReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('GCV', 'Chemical', 'MESH:D015774', (33, 36))	('Mdk-targeted', 'Var', (48, 60))	('Ad881', 'Gene', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
36914	20635326	Tumor regrowth was observed in Ad884- and Ad883- treated groups after GCV discontinuation, but not in the Ad881-treated group.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GCV', 'Chemical', 'MESH:D015774', (70, 73))	('Tumor regrowth', 'CPA', (0, 14))	('Ad884-', 'Var', (31, 37))	('Ad883- treated', 'Var', (42, 56))
36917	20635326	We found that serum ALT levels in mice injected with the non-targeted Ad883 virus were significantly higher (225.5 +- 39.52 U/L) compared to those injected with Mdk-targeted Ad881 (29.70 +- 14.98 U/L) (P = 0.0098).	('mice', 'Species', '10090', (34, 38))	('higher', 'PosReg', (101, 107))	('ALT', 'Gene', (20, 23))	('Ad883', 'Var', (70, 75))	('ALT', 'Gene', '76282', (20, 23))	('non-targeted Ad883', 'Var', (57, 75))	('ALT', 'molecular_function', 'GO:0004021', ('20', '23'))
36918	20635326	Notably, no significant difference was observed in serum ALT values between Ad881-injected mice (29.70 +- 14.98 U/L) and the PBS-injected negative control group (15.43 +- 1.981 U/L) (P = 0.3986).	('mice', 'Species', '10090', (91, 95))	('ALT', 'Gene', (57, 60))	('PBS', 'Gene', (125, 128))	('PBS', 'Gene', '1131', (125, 128))	('ALT', 'molecular_function', 'GO:0004021', ('57', '60'))	('ALT', 'Gene', '76282', (57, 60))	('Ad881-injected', 'Var', (76, 90))
36929	20635326	However, in the MESO4-xenograft mouse model, GCV treatment was associated with a significant reduction of antitumoral efficacy in vivo, compared to the effectiveness of oncolytic virotherapy without GCV (Figure 8a).	('reduction', 'NegReg', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('MESO4', 'Chemical', '-', (16, 21))	('mouse', 'Species', '10090', (32, 37))	('GCV', 'Var', (45, 48))	('GCV', 'Chemical', 'MESH:D015774', (199, 202))	('GCV', 'Chemical', 'MESH:D015774', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
36931	20635326	Although most studies combining oncolytic virotherapy with suicide gene therapy have reported enhancement of therapeutic efficacy, there has been at least one study reporting that intracellular conversion of prodrug to active toxin can result in complete inhibition of oncolytic vaccinia virus replication.	('therapeutic efficacy', 'CPA', (109, 129))	('enhancement', 'PosReg', (94, 105))	('intracellular', 'cellular_component', 'GO:0005622', ('180', '193'))	('oncolytic', 'CPA', (269, 278))	('vaccinia virus', 'Species', '10245', (279, 293))	('inhibition', 'NegReg', (255, 265))	('intracellular', 'Var', (180, 193))
36937	20635326	In this context, it is interesting to note that the survivin-targeted adenovirus gave up to a 5-fold enhancement of infectivity in mesothelioma cell lines with fiber modifications, to increase CAR-independent binding.	('binding', 'Interaction', (209, 216))	('enhancement', 'PosReg', (101, 112))	('infectivity', 'MPA', (116, 127))	('modifications', 'Var', (166, 179))	('increase', 'PosReg', (184, 192))	('CAR', 'cellular_component', 'GO:0005826', ('193', '196'))	('mesothelioma', 'Disease', (131, 143))	('binding', 'molecular_function', 'GO:0005488', ('209', '216'))	('CAR', 'Gene', '1525', (193, 196))	('CAR', 'Gene', (193, 196))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))
37055	32967259	In addition, accumulating evidence indicates that asbestos bans reduce national mesothelioma burdens.	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('national', 'MPA', (71, 79))	('reduce', 'NegReg', (64, 70))	('asbestos', 'Chemical', 'MESH:D001194', (50, 58))	('asbestos', 'Protein', (50, 58))	('bans', 'Var', (59, 63))	('mesothelioma', 'Disease', (80, 92))
37142	30859065	Lab work done on the same day as his clinic visit also revealed an elevated ESR (52mm/hr), CRP (32.7mg/L), a positive ANA (enzyme-linked immunoassay, no titer obtained), double-stranded DNA (15 IU/ml) and rheumatoid factor (16 IU/ml), though he denied any symptoms suggestive of a rash, oral ulcers, joint pains or joint swelling or morning stiffness.	('CRP', 'MPA', (91, 94))	('joint pains or joint swelling or morning stiffness', 'Disease', (300, 350))	('rheumatoid', 'Disease', 'MESH:D001172', (205, 215))	('joint pains or joint swelling or morning stiffness', 'Disease', 'MESH:D018771', (300, 350))	('elevated ESR', 'Phenotype', 'HP:0003565', (67, 79))	('rash', 'Phenotype', 'HP:0000988', (281, 285))	('morning stiffness', 'Phenotype', 'HP:0005197', (333, 350))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('ulcers', 'Disease', (292, 298))	('elevated', 'PosReg', (67, 75))	('rheumatoid', 'Disease', (205, 215))	('rash', 'Disease', (281, 285))	('pains', 'Phenotype', 'HP:0012531', (306, 311))	('oral ulcers', 'Phenotype', 'HP:0000155', (287, 298))	('ulcers', 'Disease', 'MESH:D014456', (292, 298))	('rash', 'Disease', 'MESH:D005076', (281, 285))	('ANA', 'Gene', '10950', (118, 121))	('joint pains', 'Phenotype', 'HP:0002829', (300, 311))	('joint swelling', 'Phenotype', 'HP:0001386', (315, 329))	('ANA', 'Gene', (118, 121))	('double-stranded', 'Var', (170, 185))
37177	30859065	One possibility is that the connection between non-asbestos MPM and autoimmune disease is due to a paraneoplastic processes.	('non-asbestos', 'Var', (47, 59))	('paraneoplastic', 'Disease', 'MESH:D010257', (99, 113))	('asbestos', 'Chemical', 'MESH:D001194', (51, 59))	('autoimmune disease', 'Disease', (68, 86))	('paraneoplastic', 'Disease', (99, 113))	('autoimmune disease', 'Phenotype', 'HP:0002960', (68, 86))	('autoimmune disease', 'Disease', 'MESH:D001327', (68, 86))
37229	29492267	In patients with asbestos exposure, BAPE is a plausible benign cause of an exudative effusion.	('exudative effusion', 'Disease', (75, 93))	('exudative effusion', 'Phenotype', 'HP:0011921', (75, 93))	('patients', 'Species', '9606', (3, 11))	('BAPE', 'Var', (36, 40))	('asbestos', 'Chemical', 'MESH:D001194', (17, 25))	('BAPE', 'Chemical', '-', (36, 40))
37240	27902597	Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma.	('asbestos', 'Chemical', 'MESH:D001194', (158, 166))	('mesothelioma', 'Disease', (175, 187))	('WT1', 'Gene', (98, 101))	('mutation', 'Var', (82, 90))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('involved', 'Reg', (121, 129))	('PM', 'Phenotype', 'HP:0100003', (16, 18))	('variants', 'Var', (61, 69))
37241	27902597	Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('single nucleotide polymorphisms', 'Var', (51, 82))	('DNA repair', 'biological_process', 'GO:0006281', ('86', '96'))	('DNA repair genes', 'Gene', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('higher', 'PosReg', (121, 127))	('cancer', 'Disease', (128, 134))
37253	27902597	Concomitantly, the sequencing of normal genomic DNA (gDNA) allowed the identification of germline genetic variants potentially correlated with an individual risk of developing multiple cancers.	('multiple cancers', 'Disease', (176, 192))	('variants', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('correlated with', 'Reg', (127, 142))	('multiple cancers', 'Disease', 'MESH:D009369', (176, 192))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))
37259	27902597	The immunohistochemistry (IHC) analysis revealed positivity for TTF-1, consistently with the diagnosis of a lung primary tumor.	('TTF-1', 'Gene', (64, 69))	('lung primary tumor', 'Disease', (108, 126))	('TTF-1', 'Gene', '7270', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('positivity', 'Var', (49, 59))	('lung primary tumor', 'Disease', 'MESH:D008175', (108, 126))
37271	27902597	At IHC, expression of CK7, CK5&6, calretinin, and WT-1 was detected in neoplastic cells, whereas no expression of CK20, p63, MOC-31, TTF-1, and napsin-A was reported (Fig.	('p63', 'Gene', (120, 123))	('CK5', 'Species', '2007335', (27, 30))	('CK7', 'Var', (22, 25))	('p63', 'Gene', '8626', (120, 123))	('TTF-1', 'Gene', (133, 138))	('CK5&', 'Var', (27, 31))	('TTF-1', 'Gene', '7270', (133, 138))
37277	27902597	We firstly extracted the somatic mutational signature from all the tumors according to base substitutions, as already described by Alexandrov et al.	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('base substitutions', 'Var', (87, 105))
37278	27902597	This analysis displayed a predominance of C>A transversions in both lung cancers (ADC and SCC) (Fig.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung cancers', 'Disease', 'MESH:D008175', (68, 80))	('lung cancers', 'Phenotype', 'HP:0100526', (68, 80))	('SCC', 'Gene', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('C>A transversions', 'Var', (42, 59))	('SCC', 'Gene', '6317', (90, 93))	('lung cancers', 'Disease', (68, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
37280	27902597	Then, we found that each tumor reported a specific set of somatic variants (358, 405, 28 in ADC, SCC, and PM, respectively; Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('358', 'Var', (76, 79))	('PM', 'Phenotype', 'HP:0100003', (106, 108))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('SCC', 'Gene', '6317', (97, 100))	('ADC', 'Disease', (92, 95))
37282	27902597	Both ADC and SCC showed lung tumor hotspot mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC; http://cancer.sanger.ac.uk/cosmic) database and described in lung cancers: EHHADH (COSM5247826), KRAS (COSM512), OR4K2 (COSM1515038), and TP53 (COSM6549) in ADC; KIAA1324L (COSM396629), NFE2L2 (COSM396629), PEG3 (COSM5284477), POM121L12 (COSM393793), and WAC (COSM5311283) in SCC.	('SCC', 'Gene', (395, 398))	('lung cancers', 'Phenotype', 'HP:0100526', (180, 192))	('OR4K2', 'Gene', (232, 237))	('COSM5247826', 'Var', (202, 213))	('lung tumor', 'Disease', (24, 34))	('COSM393793', 'Var', (357, 367))	('POM121L12', 'Gene', '285877', (346, 355))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('COSM396629', 'Var', (292, 302))	('cancer', 'Disease', (185, 191))	('KRAS', 'Gene', '3845', (216, 220))	('NFE2L2', 'Gene', '4780', (305, 311))	('lung tumor', 'Phenotype', 'HP:0100526', (24, 34))	('TP53', 'Gene', (257, 261))	('KIAA1324L', 'Gene', (281, 290))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('COSM6549', 'Var', (263, 271))	('COSM1515038', 'Var', (239, 250))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('OR4K2', 'Gene', '390431', (232, 237))	('cancer', 'Disease', (126, 132))	('POM121L12', 'Gene', (346, 355))	('KIAA1324L', 'Gene', '222223', (281, 290))	('KRAS', 'Gene', (216, 220))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('NFE2L2', 'Gene', (305, 311))	('SCC', 'Phenotype', 'HP:0002860', (395, 398))	('PEG3', 'Gene', (326, 330))	('COSM5284477', 'Var', (332, 343))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('lung tumor', 'Disease', 'MESH:D008175', (24, 34))	('lung cancers', 'Disease', 'MESH:D008175', (180, 192))	('TP53', 'Gene', '7157', (257, 261))	('COSM5311283', 'Var', (379, 390))	('COSM396629', 'Var', (313, 323))	('SCC', 'Gene', '6317', (13, 16))	('PEG3', 'Gene', '5178', (326, 330))	('SCC', 'Gene', '6317', (395, 398))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('COSM6549', 'CellLine', 'CVCL:C760', (263, 271))	('lung cancers', 'Disease', (180, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('SCC', 'Gene', (13, 16))
37283	27902597	Moreover, both histotypes carried mutations associated with potential therapeutic targets (FLT3 and HGF in ADC; MTOR in SCC), or in a predictor of resistance to EGFR tyrosine kinase inhibitors (KRAS in ADC).	('associated', 'Reg', (44, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))	('EGFR', 'Gene', (161, 165))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('KRAS', 'Gene', (194, 198))	('MTOR', 'Gene', (112, 116))	('HGF', 'Gene', (100, 103))	('FLT3', 'Gene', '2322', (91, 95))	('carried', 'Reg', (26, 33))	('ADC', 'Disease', (107, 110))	('MTOR', 'Gene', '2475', (112, 116))	('HGF', 'Gene', '3082', (100, 103))	('KRAS', 'Gene', '3845', (194, 198))	('FLT3', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (161, 165))	('mutations', 'Var', (34, 43))	('SCC', 'Gene', (120, 123))
37285	27902597	Specifically, ADC was enriched with altered genes belonging to the MAPK pathway (p.Gly12Phe KRAS; c.*76delC MAP2K; c.*30C>T MAP3K4), whereas the mutations observed in SCC mostly affected genes involved in collagen modification, in extracellular matrix organization (p.His1331Gln ADAMTS3; p.Phe486Ser COL19A1; p.Ala75fs LOX; c.93 + 567C>A SPP1; p.Pro947Ser LAMB1; p.Met688Ile A2M), and in the meiotic synapsis pathway (p.Ser1801Gly ATR; p.Gln1747Glu DIDO1; c.1961 + 53A>T SUN1; c.17542-41A>C SYNE1).	('53A>T', 'Var', (465, 470))	('KRAS', 'Gene', (92, 96))	('MAP3K4', 'Gene', '4216', (124, 130))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('231', '264'))	('567C>A', 'SUBSTITUTION', 'None', (331, 337))	('LOX', 'Gene', (319, 322))	('p.His1331Gln', 'Var', (266, 278))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('567C>A', 'Var', (331, 337))	('SPP', 'molecular_function', 'GO:0042499', ('338', '341'))	('p.Met688Ile', 'Mutation', 'p.M688I', (363, 374))	('Ser', 'cellular_component', 'GO:0005790', ('296', '299'))	('p.Ala75fs', 'Mutation', 'p.A75fsX', (309, 318))	('c.*76delC', 'Mutation', 'c.*76delC', (98, 107))	('collagen', 'molecular_function', 'GO:0005202', ('205', '213'))	('MAP3K4', 'Gene', (124, 130))	('p.Pro947Ser', 'Mutation', 'p.P947S', (344, 355))	('53A>T', 'SUBSTITUTION', 'None', (465, 470))	('c.17542-41A>C', 'Mutation', 'c.17542-41A>C', (477, 490))	('c.*30C>T', 'Mutation', 'rs1278357203', (115, 123))	('SCC', 'Gene', '6317', (167, 170))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('231', '251'))	('affected', 'Reg', (178, 186))	('p.Phe486Ser', 'Mutation', 'p.F486S', (288, 299))	('p.Gln1747Glu DIDO1', 'Var', (436, 454))	('p.Gly12Phe', 'Mutation', 'p.G12F', (81, 91))	('p.Ser1801Gly', 'Mutation', 'p.S1801G', (418, 430))	('p.Gln1747Glu', 'Mutation', 'rs763123356', (436, 448))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('synapsis', 'biological_process', 'GO:0007129', ('400', '408'))	('p.Ser1801Gly', 'Var', (418, 430))	('SCC', 'Gene', (167, 170))	('meiotic synapsis pathway', 'Pathway', (392, 416))	('Ser', 'cellular_component', 'GO:0005790', ('420', '423'))	('c.17542-41A>C SYNE1', 'Var', (477, 496))	('p.His1331Gln', 'Mutation', 'p.H1331Q', (266, 278))	('Ser', 'cellular_component', 'GO:0005790', ('352', '355'))	('COL19', 'Species', '2007335', (300, 305))	('MAP2K', 'molecular_function', 'GO:0004708', ('108', '113'))	('MAP3K', 'molecular_function', 'GO:0004709', ('124', '129'))	('KRAS', 'Gene', '3845', (92, 96))	('LOX', 'Gene', '4015', (319, 322))
37286	27902597	Conversely, the PM did not display COSMIC mutations or pathways associated with the carcinogenesis, probably due to the low number of somatic mutations (28); however, among these mutations, we identified 3 novel variants including 2 frameshift variants (p.Glu673fs BAP1; p.Glu1595fs SETD2) and a missense variant (p.Ser71Phe WT1).	('SETD2', 'Gene', '29072', (283, 288))	('BAP1', 'Gene', '8314', (265, 269))	('SETD2', 'Gene', (283, 288))	('p.Glu1595fs', 'Var', (271, 282))	('p.Glu1595fs', 'Mutation', 'p.E1595fsX', (271, 282))	('p.Ser71Phe', 'Mutation', 'p.S71F', (314, 324))	('p.Ser71Phe', 'Var', (314, 324))	('BAP1', 'Gene', (265, 269))	('PM', 'Phenotype', 'HP:0100003', (16, 18))	('Ser', 'cellular_component', 'GO:0005790', ('316', '319'))	('p.Glu673fs', 'Mutation', 'p.E673fsX', (254, 264))
37287	27902597	Germline analysis was also performed in order to discover genetic variants potentially linked to cancer predisposition.	('cancer', 'Disease', (97, 103))	('linked', 'Reg', (87, 93))	('variants', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
37290	27902597	Specifically, 21 out of 74 genetic variants have already been described to confer a high risk of cancer development and 7 of them were homozygous (rs3760413, EME1; rs26279, MSH3; rs8305, POLI; rs373572, RAD18; rs462779, REV3L; rs25487, XRCC1; rs1143634, IL1B) (Table 1).	('IL1B', 'Gene', '3553', (254, 258))	('rs8305', 'Mutation', 'rs8305', (179, 185))	('rs373572', 'Mutation', 'rs373572', (193, 201))	('IL1', 'molecular_function', 'GO:0005149', ('254', '257'))	('rs8305', 'Var', (179, 185))	('cancer', 'Disease', (97, 103))	('MSH3', 'Gene', (173, 177))	('XRCC1', 'Gene', (236, 241))	('MSH3', 'Gene', '4437', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RAD18', 'Gene', (203, 208))	('POLI', 'Gene', '11201', (187, 191))	('EME1', 'Gene', '146956', (158, 162))	('rs1143634', 'Mutation', 'rs1143634', (243, 252))	('rs462779', 'Mutation', 'rs462779', (210, 218))	('RAD', 'biological_process', 'GO:1990116', ('203', '206'))	('REV3L', 'Gene', '5980', (220, 225))	('POLI', 'Gene', (187, 191))	('rs3760413', 'Var', (147, 156))	('rs3760413', 'Mutation', 'rs3760413', (147, 156))	('XRCC1', 'Gene', '7515', (236, 241))	('EME1', 'Gene', (158, 162))	('rs25487', 'Mutation', 'rs25487', (227, 234))	('rs26279', 'Mutation', 'rs26279', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('RAD18', 'Gene', '56852', (203, 208))	('REV3L', 'Gene', (220, 225))	('IL1B', 'Gene', (254, 258))
37291	27902597	Finally, we found 5 single nucleotide polymorphisms (SNPs) (rs1948, CHRNB4; rs1051730, CHRNA3; rs16969968, CHRNA5; rs4950, CHRNB3; rs5320, DBH) involved in the etiology of the nicotine dependence (Table 1).	('CHRNA3', 'Gene', (87, 93))	('nicotine dependence', 'Disease', (176, 195))	('CHRNB3', 'Gene', (123, 129))	('CHRNA5', 'Gene', '1138', (107, 113))	('rs16969968', 'Var', (95, 105))	('rs16969968', 'Mutation', 'rs16969968', (95, 105))	('CHRNA5', 'Gene', (107, 113))	('CHRNB4', 'Gene', '1143', (68, 74))	('involved', 'Reg', (144, 152))	('CHRNB3', 'Gene', '1142', (123, 129))	('nicotine', 'Chemical', 'MESH:D009538', (176, 184))	('rs5320', 'Mutation', 'rs5320', (131, 137))	('CHRNA3', 'Gene', '1136', (87, 93))	('DBH', 'Gene', (139, 142))	('rs1948', 'Var', (60, 66))	('rs4950', 'Var', (115, 121))	('rs1948', 'Mutation', 'rs1948', (60, 66))	('rs1051730', 'Var', (76, 85))	('CHRNB4', 'Gene', (68, 74))	('rs4950', 'Mutation', 'rs4950', (115, 121))	('DBH', 'Gene', '1621', (139, 142))	('rs1051730', 'Mutation', 'rs1051730', (76, 85))	('rs5320', 'Var', (131, 137))
37294	27902597	Although both lung ADC and SCC showed a similar mutational signature, characterized by a prominence of C>A substitutions, they did not share common somatic variants.	('SCC', 'Gene', (27, 30))	('substitutions', 'Var', (107, 120))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('SCC', 'Gene', '6317', (27, 30))	('lung ADC', 'Disease', (14, 22))	('C>A substitutions', 'Var', (103, 120))
37295	27902597	Interestingly, the signature characterized by C>A mutations has been associated with smoke exposure in several cancers including lung ADC and SCC; indeed, cigarettes contain a complex mixture of carcinogenic agents and these compounds could interact with DNA leading to the accumulation of somatic mutations.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('lung ADC', 'Disease', (129, 137))	('somatic mutations', 'CPA', (290, 307))	('cancers', 'Disease', (111, 118))	('mutations', 'Var', (50, 59))	('SCC', 'Gene', (142, 145))	('C>A', 'Gene', (46, 49))	('associated', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinogenic', 'Disease', 'MESH:D063646', (195, 207))	('carcinogenic', 'Disease', (195, 207))	('SCC', 'Phenotype', 'HP:0002860', (142, 145))	('SCC', 'Gene', '6317', (142, 145))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('interact', 'Reg', (241, 249))
37298	27902597	Across 358 altered genes in the ADC, we found 6 (KRAS, MAP2K1, MGAM, NF1, PPP3CA, and TP53) of 38 genes significantly mutated in a cohort of 660 lung ADC.	('NF1', 'Gene', '4763', (69, 72))	('KRAS', 'Gene', '3845', (49, 53))	('MAP2K1', 'Gene', (55, 61))	('PPP3CA', 'Gene', '5530', (74, 80))	('TP53', 'Gene', '7157', (86, 90))	('MAP2K', 'molecular_function', 'GO:0004708', ('55', '60'))	('mutated', 'Var', (118, 125))	('TP53', 'Gene', (86, 90))	('PPP3CA', 'Gene', (74, 80))	('MGAM', 'Gene', '8972', (63, 67))	('NF1', 'Gene', (69, 72))	('MGAM', 'Gene', (63, 67))	('MAP2K1', 'Gene', '5604', (55, 61))	('KRAS', 'Gene', (49, 53))
37299	27902597	Of note, mutation in PPP3CA co-occurred with an activating KRAS mutation (COSM512) as already described by Campbell et al.	('mutation', 'Var', (9, 17))	('KRAS', 'Gene', '3845', (59, 63))	('activating', 'PosReg', (48, 58))	('PPP3CA', 'Gene', '5530', (21, 27))	('co-occurred', 'Reg', (28, 39))	('PPP3CA', 'Gene', (21, 27))	('KRAS', 'Gene', (59, 63))
37301	27902597	Across the 405 SCC-mutated genes, we found only 1 gene (NFE2L2) of 20 genes recurrent mutated in 484 lung SCC tumors; moreover, mutations in NFE3L2 gene have also been identified in 34% of 178 lung SCC tumors profiled by Cancer Genome Atlas Research Networt.	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('identified', 'Reg', (168, 178))	('mutations', 'Var', (128, 137))	('SCC', 'Gene', '6317', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('lung SCC tumors', 'Disease', (101, 116))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', (106, 109))	('SCC', 'Phenotype', 'HP:0002860', (198, 201))	('lung SCC tumors', 'Disease', 'MESH:D008175', (101, 116))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('NFE2L2', 'Gene', '4780', (56, 62))	('lung SCC tumors', 'Disease', (193, 208))	('SCC', 'Gene', '6317', (15, 18))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('lung SCC tumors', 'Disease', 'MESH:D008175', (193, 208))	('SCC', 'Gene', '6317', (198, 201))	('SCC', 'Gene', (15, 18))	('NFE2L2', 'Gene', (56, 62))	('SCC', 'Gene', (198, 201))	('NFE3L2', 'Gene', (141, 147))
37303	27902597	Specifically, the ADC harbored mutations in genes involved in EGFR signaling pathway, such as 2 novel genetic variants in the 3'UTR regions of MAP3K4 and MAP2K1 genes, and a hotspot mutation in the KRAS codon 12; as it is known, the EGFR signaling pathway is one of the most frequently altered pathways in this histology.	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('62', '84'))	('MAP3K4', 'Gene', (143, 149))	('MAP3K', 'molecular_function', 'GO:0004709', ('143', '148'))	('MAP2K', 'molecular_function', 'GO:0004708', ('154', '159'))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('233', '237'))	('EGFR', 'Gene', (233, 237))	('altered', 'Reg', (286, 293))	('mutations', 'Var', (31, 40))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('233', '255'))	('variants', 'Var', (110, 118))	('MAP2K1', 'Gene', '5604', (154, 160))	('KRAS', 'Gene', '3845', (198, 202))	('MAP2K1', 'Gene', (154, 160))	('EGFR', 'Gene', '1956', (233, 237))	('MAP3K4', 'Gene', '4216', (143, 149))	('EGFR', 'Gene', (62, 66))	('KRAS', 'Gene', (198, 202))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))
37304	27902597	On the contrary, the SCC carried several mutations in genes involved in the extracellular matrix organization, a pathway often deregulated in cancer.	('mutations', 'Var', (41, 50))	('SCC', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('76', '109'))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('76', '96'))	('cancer', 'Disease', (142, 148))
37305	27902597	In particular, we found a novel frameshift deletion (c.221delC; p.Ala75fs) leading to a potential LOX protein destruction.	('p.Ala75fs', 'Mutation', 'p.A75fsX', (64, 73))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('c.221delC; p.Ala75fs', 'Var', (53, 73))	('c.221delC', 'Mutation', 'c.221delC', (53, 62))	('LOX', 'Gene', '4015', (98, 101))	('p.Ala75fs', 'Var', (64, 73))	('LOX', 'Gene', (98, 101))
37308	27902597	Although it is still unclear whether KRAS mutations are actually associated with resistance to EGFR inhibitors in lung cancer, aberrations of HGF signal are apparently involved in resistance to anti-EGFR and anti-VEGF targeted therapies.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('KRAS', 'Gene', (37, 41))	('associated', 'Reg', (65, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('EGFR', 'Gene', '1956', (95, 99))	('aberrations', 'Var', (127, 138))	('involved', 'Reg', (168, 176))	('HGF', 'Gene', '3082', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'Gene', (199, 203))	('lung cancer', 'Disease', (114, 125))	('HGF', 'Gene', (142, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (199, 203))	('VEGF', 'Gene', '7422', (213, 217))	('KRAS', 'Gene', '3845', (37, 41))	('mutations', 'Var', (42, 51))	('VEGF', 'Gene', (213, 217))
37310	27902597	Conversely, in PM, the distribution of base substitutions did not match any specific mutational signature, probably as a consequence of a relatively limited number of observed mutations (28 variants in PM vs >350 in the lung cancer lesions).	('PM', 'Phenotype', 'HP:0100003', (202, 204))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('lung cancer lesions', 'Disease', (220, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('lung cancer lesions', 'Disease', 'MESH:D008175', (220, 239))	('variants', 'Var', (190, 198))	('PM', 'Phenotype', 'HP:0100003', (15, 17))
37312	27902597	We also found an insertion in BAP1, potentially associated with a loss-of-function, and a deletion changing the reading frame in SETD2, a gene found altered in malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', (160, 190))	('SETD2', 'Gene', '29072', (129, 134))	('BAP1', 'Gene', (30, 34))	('reading', 'MPA', (112, 119))	('SETD2', 'Gene', (129, 134))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (160, 190))	('loss-of-function', 'NegReg', (66, 82))	('insertion', 'Var', (17, 26))	('BAP1', 'Gene', '8314', (30, 34))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (170, 190))	('deletion changing', 'Var', (90, 107))
37313	27902597	In addition, we detected a novel mutation in the WT1 transactivation domain (NM_000378.4; c.212C>T; p.Ser71Phe).	('c.212C>T', 'Var', (90, 98))	('p.Ser71Phe', 'Mutation', 'p.S71F', (100, 110))	('p.Ser71Phe', 'Var', (100, 110))	('Ser', 'cellular_component', 'GO:0005790', ('102', '105'))	('transactivation', 'biological_process', 'GO:2000144', ('53', '68'))	('NM_000378.4', 'Var', (77, 88))	('c.212C>T', 'SUBSTITUTION', 'None', (90, 98))
37314	27902597	Mutated WT1 has been already described in mesothelioma; interestingly, Park et al reported a patient with PM that harbored a point mutation within the transactivation domain of WT1 gene, demonstrating that this variant conferred an activation of its transcriptional role.	('PM', 'Phenotype', 'HP:0100003', (106, 108))	('variant', 'Var', (211, 218))	('activation', 'PosReg', (232, 242))	('mesothelioma', 'Disease', (42, 54))	('point mutation within', 'Var', (125, 146))	('patient', 'Species', '9606', (93, 100))	('transactivation', 'biological_process', 'GO:2000144', ('151', '166'))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('transcriptional role', 'MPA', (250, 270))
37316	27902597	These data suggest that the p.Ser71Phe WT1 mutation might be implicated in the PM carcinogenesis process through the WT1 downstream pathway activation.	('WT1 downstream pathway', 'Pathway', (117, 139))	('p.Ser71Phe', 'Mutation', 'p.S71F', (28, 38))	('p.Ser71Phe', 'Var', (28, 38))	('implicated', 'Reg', (61, 71))	('PM', 'Phenotype', 'HP:0100003', (79, 81))	('activation', 'PosReg', (140, 150))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('PM carcinogenesis', 'Disease', (79, 96))
37319	27902597	Notably, the analysis identified 21 genetic variants that were already described; of these, 62% were related to increased lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('variants', 'Var', (44, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('increased lung cancer', 'Disease', 'MESH:D008175', (112, 133))	('increased lung cancer', 'Disease', (112, 133))	('related', 'Reg', (101, 108))
37320	27902597	Among such variants, the association of the p.Glu589Lys in EXO1 gene (rs1047840) with cigarette smoking has been described as conferring a significantly increased lung cancer risk, with a reported odds ratio equal to 1.72.	('EXO1', 'Gene', '9156', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rs1047840', 'Mutation', 'rs1047840', (70, 79))	('increased lung cancer', 'Disease', 'MESH:D008175', (153, 174))	('EXO1', 'Gene', (59, 63))	('association', 'Interaction', (25, 36))	('p.Glu589Lys', 'Var', (44, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('p.Glu589Lys', 'Mutation', 'rs1047840', (44, 55))	('increased lung cancer', 'Disease', (153, 174))	('rs1047840', 'Var', (70, 79))
37326	27902597	On the contrary, the low number of somatic mutations in PM suggests that its development is mainly caused by onset of mutations in driver genes (BAP1 and SETD2) and that other mechanisms, such as microRNA deregulation, might be involved.	('SETD2', 'Gene', '29072', (154, 159))	('PM', 'Phenotype', 'HP:0100003', (56, 58))	('mutations', 'Var', (118, 127))	('SETD2', 'Gene', (154, 159))	('BAP1', 'Gene', '8314', (145, 149))	('BAP1', 'Gene', (145, 149))
37327	27902597	In addition, the novel missense mutation in WT1 gene may also explain the PM development regardless of asbestos exposure.	('WT1', 'Gene', (44, 47))	('PM development', 'CPA', (74, 88))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('explain', 'Reg', (62, 69))	('missense mutation', 'Var', (23, 40))	('PM', 'Phenotype', 'HP:0100003', (74, 76))
37330	26236392	NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy.	('mesothelioma', 'Disease', 'MESH:D008654', (355, 367))	('rs6502867', 'Var', (184, 193))	('patients', 'Species', '9606', (46, 54))	('rs35829419', 'Var', (217, 227))	('rs12150220', 'Var', (150, 160))	('rs2670660', 'Var', (195, 204))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (337, 367))	('rs2670660', 'Mutation', 'rs2670660', (195, 204))	('asbestos', 'Chemical', 'MESH:D001194', (59, 67))	('rs9889625', 'Var', (162, 171))	('asbestos', 'Chemical', 'MESH:D001194', (400, 408))	('rs35829419', 'Mutation', 'rs35829419', (217, 227))	('rs9889625', 'Mutation', 'rs9889625', (162, 171))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (347, 367))	('asbestos', 'Chemical', 'MESH:D001194', (305, 313))	('rs10754558', 'Var', (229, 239))	('mesothelioma', 'Disease', (33, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('rs12150220', 'Mutation', 'rs12150220', (150, 160))	('NLRP3', 'Gene', (10, 15))	('malignant pleural mesothelioma', 'Disease', (337, 367))	('NLRP1', 'Gene', '22861', (0, 5))	('NLRP3', 'Gene', (210, 215))	('NLRP1', 'Gene', (0, 5))	('NLRP3', 'Gene', '114548', (10, 15))	('NLRP3', 'Gene', '114548', (210, 215))	('patients', 'Species', '9606', (375, 383))	('rs6502867', 'Mutation', 'rs6502867', (184, 193))	('rs9900356', 'Mutation', 'rs9900356', (173, 182))	('mesothelioma', 'Disease', (355, 367))	('rs9900356', 'Var', (173, 182))	('rs10754558', 'Mutation', 'rs10754558', (229, 239))
37331	26236392	No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models.	('NLRP3', 'Gene', (43, 48))	('NLRP1', 'Gene', '22861', (33, 38))	('mesothelioma', 'Disease', (93, 105))	('NLRP1', 'Gene', (33, 38))	('NLRP3', 'Gene', '114548', (43, 48))	('polymorphisms', 'Var', (49, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))
37337	26236392	reported an association of rs12150220 NLRP1 polymorphism with mesothelioma in Italian patients the presence of T allele conferred a major risk (OR 1.79) to acquire the disease.	('mesothelioma', 'Disease', (62, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('rs12150220', 'Mutation', 'rs12150220', (27, 37))	('association', 'Interaction', (12, 23))	('NLRP1', 'Gene', '22861', (38, 43))	('rs12150220', 'Var', (27, 37))	('NLRP1', 'Gene', (38, 43))	('patients', 'Species', '9606', (86, 94))
37343	26236392	We genotyped two NLRP3 polymorphisms (rs35829419, cSNP and rs10754558, Tag SNP) and five NLRP1 polymorphisms (rs12150220, cSNP; rs9889625, Tag SNP; rs9900356, Tag SNP; rs6502867, Tag SNP; rs2670660, Tag SNP) using the following Taqman genotyping assays: NLRP3 C__25648615_10, C__26052028_10; NLRP1 C___1600653_10, C___1274455_10, C__29796119_10, C__29222211_20 and C___1600689_10.	('rs6502867', 'Mutation', 'rs6502867', (168, 177))	('NLRP1', 'Gene', (292, 297))	('C__29222211_20', 'Var', (346, 360))	('rs12150220', 'Var', (110, 120))	('rs2670660', 'Mutation', 'rs2670660', (188, 197))	('C___1600653_10', 'Var', (298, 312))	('rs10754558', 'Mutation', 'rs10754558', (59, 69))	('C___1600689_10', 'Var', (365, 379))	('C__26052028_10', 'Var', (276, 290))	('C___1274455_10', 'Var', (314, 328))	('NLRP1', 'Gene', '22861', (89, 94))	('NLRP1', 'Gene', (89, 94))	('rs12150220', 'Mutation', 'rs12150220', (110, 120))	('C__29796119_10', 'Var', (330, 344))	('C__25648615_10', 'Var', (260, 274))	('rs9900356', 'Mutation', 'rs9900356', (148, 157))	('NLRP3', 'Gene', (254, 259))	('NLRP3', 'Gene', (17, 22))	('rs35829419', 'Mutation', 'rs35829419', (38, 48))	('NLRP3', 'Gene', '114548', (17, 22))	('NLRP3', 'Gene', '114548', (254, 259))	('NLRP1', 'Gene', '22861', (292, 297))	('rs9889625', 'Mutation', 'rs9889625', (128, 137))
37345	26236392	Table 1 summarizes the distribution of NLRP1 and NLRP3 polymorphisms genotype counts among the AEM and AENM groups (a graphic representation is also provided as Additional file 1: Figure S1).	('NLRP3', 'Gene', '114548', (49, 54))	('NLRP1', 'Gene', '22861', (39, 44))	('NLRP1', 'Gene', (39, 44))	('AENM', 'Chemical', '-', (103, 107))	('NLRP3', 'Gene', (49, 54))	('polymorphisms', 'Var', (55, 68))
37346	26236392	All markers were in Hardy-Weinberg Equilibrium (HWE) in both AEM and AENM groups with the exception of NLRP1 rs9900356 SNP in AEM group and NLRP3 rs35829419, which was not in HWE in AENM and AEM.	('rs35829419', 'Mutation', 'rs35829419', (146, 156))	('NLRP1', 'Gene', (103, 108))	('NLRP3', 'Gene', (140, 145))	('rs9900356 SNP', 'Var', (109, 122))	('NLRP3', 'Gene', '114548', (140, 145))	('AENM', 'Chemical', '-', (182, 186))	('AENM', 'Chemical', '-', (69, 73))	('rs35829419', 'Var', (146, 156))	('rs9900356', 'Mutation', 'rs9900356', (109, 118))	('NLRP1', 'Gene', '22861', (103, 108))
37348	26236392	We detected two blocks for NLRP1: Haplo1 (rs9900356, rs6502867 and rs9889625; D' = 1) and Haplo2 (rs12150220 and rs2670660; D' = 0.83).	('rs9900356', 'Mutation', 'rs9900356', (42, 51))	('rs9900356', 'Var', (42, 51))	('NLRP1', 'Gene', (27, 32))	('rs12150220', 'Mutation', 'rs12150220', (98, 108))	('rs12150220', 'Var', (98, 108))	('rs6502867', 'Var', (53, 62))	('rs2670660', 'Var', (113, 122))	('rs6502867', 'Mutation', 'rs6502867', (53, 62))	('rs9889625', 'Var', (67, 76))	('NLRP1', 'Gene', '22861', (27, 32))	('rs2670660', 'Mutation', 'rs2670660', (113, 122))	('rs9889625', 'Mutation', 'rs9889625', (67, 76))
37351	26236392	So the association (for both rs12150220 SNP and rs12150220- rs2670660 haplotype) with susceptibility to mesothelioma reported by Girardelli et al.	('rs12150220 SNP', 'Var', (29, 43))	('mesothelioma', 'Disease', (104, 116))	('rs12150220', 'Mutation', 'rs12150220', (48, 58))	('rs12150220- rs2670660', 'Var', (48, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('rs2670660', 'Mutation', 'rs2670660', (60, 69))	('rs12150220', 'Mutation', 'rs12150220', (29, 39))
37355	26236392	The authors suggested a possible functional role for NLRP1 functional SNP rs12150220, indicating the presence of the T allele as able to imbalance NLRP1 production.	('rs12150220', 'Mutation', 'rs12150220', (74, 84))	('rs12150220', 'Var', (74, 84))	('NLRP1', 'Gene', '22861', (53, 58))	('NLRP1', 'Gene', (53, 58))	('imbalance', 'NegReg', (137, 146))	('imbalance', 'Phenotype', 'HP:0002172', (137, 146))	('NLRP1', 'Gene', (147, 152))	('NLRP1', 'Gene', '22861', (147, 152))
37356	26236392	Since no functional data are already available in the literature for rs12150220 variation, we performed an in silico search with SIFT and Polyphen softwares able to predict an eventual detrimental effect of the SNP: both SIFT (0.16) and Polyphen (0.415) predictive values indicate no damaging effect for NLRP1 rs12150220 SNP.	('SIFT', 'Disease', 'None', (129, 133))	('rs12150220', 'Var', (310, 320))	('SIFT', 'Disease', (221, 225))	('NLRP1', 'Gene', '22861', (304, 309))	('SIFT', 'Disease', (129, 133))	('NLRP1', 'Gene', (304, 309))	('SIFT', 'Disease', 'None', (221, 225))	('rs12150220', 'Mutation', 'rs12150220', (69, 79))	('rs12150220', 'Mutation', 'rs12150220', (310, 320))	('rs12150220', 'Var', (69, 79))
37365	25996440	One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('NCI-H226 xenograft tumor', 'Disease', (128, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NCI-H226 xenograft tumor', 'Disease', 'MESH:D009369', (128, 152))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('YP218 Fv-PE38', 'Var', (17, 30))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (80, 100))	('cytotoxicity', 'Disease', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (53, 58))	('mice', 'Species', '10090', (156, 160))	('mesothelioma', 'Disease', (88, 100))
37366	25996440	Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for mesothelin-expressing cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('binding', 'Interaction', (71, 78))	('YP218', 'Var', (44, 49))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('cancer', 'Disease', (114, 120))
37378	25996440	MORAb-009 and SS1P recognize an epitope within the N-terminal Region I (296-390) of mesothelin.	('MORAb-009', 'Chemical', 'MESH:C526187', (0, 9))	('296-390', 'Var', (72, 79))	('SS1', 'Gene', (14, 17))	('SS1', 'Gene', '3123', (14, 17))
37385	25996440	In addition, we generated a humanized YP218 Fv that retained full binding affinity for mesothelin-expressing tumor cells.	('binding affinity', 'Interaction', (66, 82))	('YP218 Fv', 'Var', (38, 46))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('human', 'Species', '9606', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
37396	25996440	To screen for domain-specific Abs, rabbit hybridoma supernatants were incubated with Nunc MaxiSorp 96-well flat-bottomed plates coated with 5 mug ml-1 of full-length mesothelin, Region I (residues 296-390), II (residues 391-486) or III (residues 487-598) fragments (Fig.	('residues 487-598', 'Var', (237, 253))	('rabbit hybridoma', 'Disease', 'MESH:D001480', (35, 51))	('mug', 'molecular_function', 'GO:0043739', ('142', '145'))	('residues 296-390', 'Var', (188, 204))	('residues 391-486', 'Var', (211, 227))	('rabbit hybridoma', 'Disease', (35, 51))
37441	25996440	We screened the 232 clones with an ELISA assay using a panel of mesothelin fragments generated in our lab, including Region I (residues 296-390), II (residues 391-486) and III (residues 487-598), and full-length mouse or human mesothelin.	('residues 296-390', 'Var', (127, 143))	('residues 391-486', 'Var', (150, 166))	('human', 'Species', '9606', (221, 226))	('residues 487-598', 'Var', (177, 193))	('mouse', 'Species', '10090', (212, 217))
37446	25996440	Rabbit mAbs YP3, YP187, YP218, and YP223 bound wild-type mesothelin (both recombinant and secreted by mammalian cells in culture medium) in a dose-dependent manner in the presence of SS1P.	('YP218', 'Var', (24, 29))	('YP223', 'Gene', (35, 40))	('bound', 'Interaction', (41, 46))	('SS1', 'Gene', (183, 186))	('SS1', 'Gene', '3123', (183, 186))	('mammalian', 'Species', '9606', (102, 111))	('Rabbit', 'Species', '9986', (0, 6))
37452	25996440	2e), we wondered whether the YP218 and YP223 mAbs can be used to measure soluble mesothelin in the presence of the SS1P immunotoxin.	('soluble', 'cellular_component', 'GO:0005625', ('73', '80'))	('YP223', 'Var', (39, 44))	('SS1', 'Gene', (115, 118))	('SS1', 'Gene', '3123', (115, 118))
37456	25996440	To evaluate potential use of the new mAbs in immunohistochemistry, fixed patient mesothelioma tissue was stained with YP187, YP223, YP218 and YP3 at an antibody concentration of 0.1 mug ml-1 or less (Fig.	('YP223', 'Var', (125, 130))	('antibody', 'cellular_component', 'GO:0042571', ('152', '160'))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('YP187', 'Var', (118, 123))	('YP218', 'Var', (132, 137))	('patient', 'Species', '9606', (73, 80))	('antibody', 'cellular_component', 'GO:0019815', ('152', '160'))	('mug', 'molecular_function', 'GO:0043739', ('182', '185'))	('YP3', 'Var', (142, 145))	('antibody', 'cellular_component', 'GO:0019814', ('152', '160'))	('antibody', 'molecular_function', 'GO:0003823', ('152', '160'))	('mesothelioma', 'Disease', (81, 93))
37461	25996440	We first compared the cytotoxicity and affinity of YP3 Fv-PE38, YP218 Fv-PE38, YP223 Fv-PE38 and SS1P in vitro with several solid tumor cell lines (Figs.	('YP218 Fv-PE38', 'Var', (64, 77))	('YP223 Fv-PE38', 'Var', (79, 92))	('cytotoxicity', 'Disease', (22, 34))	('YP3 Fv-PE38', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('SS1', 'Gene', '3123', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SS1', 'Gene', (97, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (22, 34))	('tumor', 'Disease', (130, 135))
37463	25996440	We found that the IC50s of SS1P and YP218 Fv-PE38 were inversely correlated with the mesothelin surface expression level, if the outlier, Panc 3.014, was excluded from the analysis (Fig.	('Fv-PE38', 'Gene', (42, 49))	('mesothelin surface expression level', 'MPA', (85, 120))	('50s', 'Species', '1214577', (20, 23))	('SS1', 'Gene', '3123', (27, 30))	('SS1', 'Gene', (27, 30))	('YP218', 'Var', (36, 41))	('correlated', 'Reg', (65, 75))
37469	25996440	The combination of SS1P and YP218 immunotoxins showed an additive effect and no obvious synergistic effect in EKVX (a cell line with low mesothelin expression levels) (Fig.	('EKVX', 'Disease', (110, 114))	('YP218', 'Var', (28, 33))	('SS1', 'Gene', '3123', (19, 22))	('SS1', 'Gene', (19, 22))
37471	25996440	4b), YP218 Fv-PE38 also showed higher affinity than other rabbit anti-mesothelin immunotoxins on most of the cell lines (Supplemental Table 3).	('higher', 'PosReg', (31, 37))	('YP218 Fv-PE38', 'Var', (5, 18))	('rabbit', 'Species', '9986', (58, 64))	('affinity', 'Interaction', (38, 46))
37472	25996440	In light of this, we decided to further compare the cytotoxicity of YP218 Fv-PE38 and SS1P in vitro with four primary cell lines isolated from malignant mesothelioma patients (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (52, 64))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (143, 165))	('SS1', 'Gene', '3123', (86, 89))	('patients', 'Species', '9606', (166, 174))	('SS1', 'Gene', (86, 89))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (143, 165))	('cytotoxicity', 'Disease', (52, 64))	('malignant mesothelioma', 'Disease', (143, 165))	('YP218', 'Var', (68, 73))
37473	25996440	We found that YP218 Fv-PE38 showed greater cytotoxicity than SS1P in NCI-M-19 and comparable cytotoxicity in NCI-M-16 and NCI-M-21, whereas NCI-M-18 was resistant to both immunotoxins.	('NCI-M-21', 'CellLine', 'CVCL:D031', (122, 130))	('SS1', 'Gene', '3123', (61, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('NCI-M-16', 'CellLine', 'CVCL:G225', (109, 117))	('cytotoxicity', 'Disease', (43, 55))	('SS1', 'Gene', (61, 64))	('NCI-M-19', 'CellLine', 'CVCL:B415', (69, 77))	('cytotoxicity', 'Disease', (93, 105))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('YP218 Fv-PE38', 'Var', (14, 27))
37474	25996440	To further analyze its potential value in cancer therapy, we tested YP218 Fv-PE38 in a mouse xenograft model with the NCI-H226 line expressing GFP and luciferase (LMB-H226-GL).	('mouse', 'Species', '10090', (87, 92))	('tested', 'Reg', (61, 67))	('NCI-H226', 'CellLine', 'CVCL:1544', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Fv-PE38', 'Gene', (74, 81))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('LMB-H226-GL', 'CellLine', 'CVCL:J621', (163, 174))	('YP218', 'Var', (68, 73))
37476	25996440	SS1P and YP218 Fv-PE38 were used at the same dosage (0.4 mg kg-1).	('SS1', 'Gene', '3123', (0, 3))	('SS1', 'Gene', (0, 3))	('YP218 Fv-PE38', 'Var', (9, 22))
37478	25996440	Both SS1P and YP218 Fv-PE38 shrank the tumor and their effect was similar (Fig.	('SS1', 'Gene', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('shrank', 'PosReg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('YP218 Fv-PE38', 'Var', (14, 27))	('SS1', 'Gene', '3123', (5, 8))
37479	25996440	Most serum chemistry and blood cell counts in YP218 Fv-PE38 treated group were similar to those of the untreated group and SS1P-treated group (Supplemental Table 4).	('YP218 Fv-PE38', 'Var', (46, 59))	('SS1', 'Gene', '3123', (123, 126))	('SS1', 'Gene', (123, 126))
37482	25996440	These data demonstrated that the YP218 Fv-PE38 immuntoxin had no severe in vivo toxicity in mice.	('YP218 Fv-PE38', 'Var', (33, 46))	('mice', 'Species', '10090', (92, 96))	('toxicity', 'Disease', 'MESH:D064420', (80, 88))	('toxicity', 'Disease', (80, 88))
37510	25996440	An immunotoxin based on the hYP218 Fv had even stronger cytotoxicity than the original rabbit YP218-derived immunotoxin.	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('stronger', 'PosReg', (47, 55))	('rabbit', 'Species', '9986', (87, 93))	('hYP218', 'Chemical', '-', (28, 34))	('hYP218 Fv', 'Var', (28, 37))	('cytotoxicity', 'Disease', (56, 68))
37515	25996440	We showed that the epitopes of YP218, YP223 and SS1P do not overlap each other.	('SS1', 'Gene', '3123', (48, 51))	('YP218', 'Var', (31, 36))	('YP223', 'Var', (38, 43))	('SS1', 'Gene', (48, 51))
37516	25996440	Importantly, a sandwich ELISA combining YP218 and YP223 brought the detection limit of soluble mesothelin (<0.01 nM) to 250-fold lower than the threshold between healthy people and malignant mesothelioma patients (>2.5 nM in serum and >20 nM in plueural effusions).	('patients', 'Species', '9606', (204, 212))	('detection', 'MPA', (68, 77))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (181, 203))	('plueural effusions', 'Disease', 'MESH:D010996', (245, 263))	('lower', 'NegReg', (129, 134))	('people', 'Species', '9606', (170, 176))	('YP223', 'Var', (50, 55))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (181, 203))	('YP218', 'Var', (40, 45))	('malignant mesothelioma', 'Disease', (181, 203))	('soluble', 'cellular_component', 'GO:0005625', ('87', '94'))	('plueural effusions', 'Disease', (245, 263))
37520	25996440	As YP218 Fv-PE38 effectively shrank the NCI-H226 xenograft tumor and demonstrated potent anti-tumor activity in animal testing and primary cell lines, it may prove to be a promising candidate for cancer therapy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('NCI-H226 xenograft tumor', 'Disease', 'MESH:D009369', (40, 64))	('shrank', 'CPA', (29, 35))	('tumor', 'Disease', (94, 99))	('NCI-H226 xenograft tumor', 'Disease', (40, 64))	('YP218 Fv-PE38', 'Var', (3, 16))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
37538	24850840	At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared to the parent strain.	('HLA-A', 'Gene', '3105', (89, 94))	('HLA-A', 'Gene', (89, 94))	('ESKM', 'Var', (24, 28))	('biodistribution', 'MPA', (70, 85))	('transgenic mice', 'Species', '10090', (102, 117))
37543	24850840	We recently reported the first fully human TCRm mAb, called ESK1, that specifically targets RMFPNAPYL (RMF), a peptide derived from Wilms' tumor gene 1 (WT1), presented in the context of HLA-A*02:01 (RMF/A2).	('HLA-A', 'Gene', (187, 192))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (132, 144))	('HLA-A', 'Gene', '3105', (187, 192))	('ESK1', 'Gene', '22137', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('RMFPNAPYL', 'Var', (92, 101))	('human', 'Species', '9606', (37, 42))	('ESK1', 'Gene', (60, 64))	("Wilms' tumor", 'Disease', (132, 144))	("Wilms' tumor", 'Disease', 'MESH:D009396', (132, 144))
37549	24850840	The addition of bisecting N-acetyl-D-glucosamine (GlcNAc) can also significantly enhance ADCC.	('ADCC', 'Disease', (89, 93))	('bisecting N-acetyl-D-glucosamine', 'Var', (16, 48))	('ADCC', 'biological_process', 'GO:0001788', ('89', '93'))	('N-acetyl-D-glucosamine', 'Chemical', 'MESH:D000117', (26, 48))	('GlcNAc', 'Chemical', 'MESH:D000117', (50, 56))	('enhance', 'PosReg', (81, 88))
37550	24850840	However, removal or replacement of the terminal galactose residues present on endogenous IgG reduces complement dependent cytotoxicity (CDC) activity.	('IgG', 'Gene', (89, 92))	('replacement', 'Var', (20, 31))	('reduces', 'NegReg', (93, 100))	('cytotoxicity', 'Disease', (122, 134))	('complement dependent cytotoxicity', 'biological_process', 'GO:0097278', ('101', '134'))	('galactose', 'Chemical', 'MESH:D005690', (48, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (122, 134))
37601	24850840	For human leukemia stem cell studies, cells were stained with the following antibodies, and corresponding fully-stained-minus-one controls: PE-Cy5 anti-human lineage cocktail (BioLegend; anti-CD3, CD14, CD16, CD19, CD20, CD56), FITC-labeled anti-CD38, PE-labeled anti-CD34, PE-Cy7-labeled BB7.2, and APC-labeled ESK1.	('leukemia', 'Disease', (10, 18))	('CD56', 'Gene', '4684', (221, 225))	('leukemia', 'Disease', 'MESH:D007938', (10, 18))	('human', 'Species', '9606', (152, 157))	('CD3', 'Gene', '12501', (268, 271))	('CD14', 'Gene', (197, 201))	('CD3', 'Gene', (192, 195))	('CD19', 'Var', (209, 213))	('CD14', 'Gene', '929', (197, 201))	('CD3', 'Gene', (246, 249))	('CD20', 'Gene', (215, 219))	('APC', 'cellular_component', 'GO:0005680', ('300', '303'))	('FITC', 'Chemical', 'MESH:D016650', (228, 232))	('CD3', 'Gene', '12501', (192, 195))	('CD3', 'Gene', '12501', (246, 249))	('CD20', 'Gene', '931', (215, 219))	('human', 'Species', '9606', (4, 9))	('leukemia', 'Phenotype', 'HP:0001909', (10, 18))	('ESK1', 'Gene', '22137', (312, 316))	('CD3', 'Gene', (268, 271))	('CD56', 'Gene', (221, 225))	('ESK1', 'Gene', (312, 316))
37607	24850840	ESKM had 80% higher affinity for activating human FcgammaRIIIa (158V variant), 3.5-fold higher affinity for the FcgammaRIIIa 158F variant, and 50% reduced affinity for inhibitory FcgammaRIIb.	('human', 'Species', '9606', (44, 49))	('higher', 'PosReg', (88, 94))	('158F variant', 'Var', (125, 137))	('variant', 'Var', (130, 137))	('FcgammaRIIIa', 'Gene', '2214', (112, 124))	('FcgammaRIIIa', 'Gene', '2214', (50, 62))	('158V', 'Var', (64, 68))	('FcgammaRIIIa', 'Gene', (50, 62))	('activating', 'MPA', (33, 43))	('reduced', 'NegReg', (147, 154))	('FcgammaRIIIa', 'Gene', (112, 124))
37615	24850840	Against AML-14 and SET2 acute myeloid leukemia (AML) cell lines, which both bind ~5000 mAb per cell, ESKM mediated higher cell lysis than ESK1 at the highest antibody concentrations, and showed cytolytic efficacy down to doses as low as 100ng/mL (Fig.	('antibody', 'cellular_component', 'GO:0019814', ('158', '166'))	('AML-14', 'Disease', 'MESH:D015470', (8, 14))	('ESKM', 'Var', (101, 105))	('AML', 'Disease', 'MESH:D015470', (8, 11))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (24, 46))	('AML', 'Disease', (8, 11))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (24, 46))	('antibody', 'molecular_function', 'GO:0003823', ('158', '166'))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('higher', 'PosReg', (115, 121))	('antibody', 'cellular_component', 'GO:0042571', ('158', '166'))	('AML-14', 'Disease', (8, 14))	('cytolytic', 'CPA', (194, 203))	('AML', 'Disease', (48, 51))	('lysis', 'biological_process', 'GO:0019835', ('127', '132'))	('mAb', 'Protein', (87, 90))	('SET2', 'Gene', '29072', (19, 23))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (30, 46))	('antibody', 'cellular_component', 'GO:0019815', ('158', '166'))	('ESK1', 'Gene', '22137', (138, 142))	('ESK1', 'Gene', (138, 142))	('acute myeloid leukemia', 'Disease', (24, 46))	('SET2', 'Gene', (19, 23))	('cell lysis', 'CPA', (122, 132))
37617	24850840	Further, ESKM mediated higher specific lysis at nearly all doses tested against 3 HLA-A*02:01+ mesothelioma cell lines: JMN, Meso-37, and Meso-56 (Fig 1D).	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('HLA-A', 'Gene', '3105', (82, 87))	('lysis', 'biological_process', 'GO:0019835', ('39', '44'))	('HLA-A', 'Gene', (82, 87))	('higher', 'PosReg', (23, 29))	('specific lysis', 'MPA', (30, 44))	('ESKM', 'Var', (9, 13))	('mesothelioma', 'Disease', (95, 107))
37621	24850840	These data showed that ESKM was both more potent -as illustrated by its ability to kill cells with lower mAb concentrations and fewer cell surface targets:and more effective than ESK1, as demonstrated by higher specific lysis attained at the highest concentrations.	('ESK1', 'Gene', (179, 183))	('specific lysis', 'MPA', (211, 225))	('ESK1', 'Gene', '22137', (179, 183))	('lysis', 'biological_process', 'GO:0019835', ('220', '225'))	('cell surface', 'cellular_component', 'GO:0009986', ('134', '146'))	('ESKM', 'Var', (23, 27))	('higher', 'PosReg', (204, 210))
37629	24850840	Biweekly 50microg treatment with ESKM was more effective than ESK1 against intraperitoneal JMN, and significantly improved survival over isotype control antibody (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('ESK1', 'Gene', (62, 66))	('improved', 'PosReg', (114, 122))	('survival', 'MPA', (123, 131))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('ESKM', 'Var', (33, 37))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))	('ESK1', 'Gene', '22137', (62, 66))
37630	24850840	Further, ESKM was able to reduce tumor burden during the treatment course, whereas ESK1 merely slowed growth (Supplementary Fig.	('slowed growth', 'Phenotype', 'HP:0001510', (95, 108))	('reduce', 'NegReg', (26, 32))	('slowed', 'NegReg', (95, 101))	('ESK1', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('ESK1', 'Gene', '22137', (83, 87))	('ESKM', 'Var', (9, 13))
37637	24850840	ESKM also significantly reduced initial burden and slowed outgrowth of a patient-derived human pre-B-cell ALL (Fig.	('human', 'Species', '9606', (89, 94))	('reduced', 'NegReg', (24, 31))	('ESKM', 'Var', (0, 4))	('pre', 'molecular_function', 'GO:0003904', ('95', '98'))	('initial burden', 'MPA', (32, 46))	('patient', 'Species', '9606', (73, 80))	('slowed', 'NegReg', (51, 57))	('outgrowth', 'CPA', (58, 67))
37641	24850840	In this same patient ALL sample, ESK bound a lineagelow, CD34+, CD38- population, characterized as a cancer stem cell population in ALL, at nearly the same level as lineage+ populations (Figure 2D and Supplemental Methods).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('patient', 'Species', '9606', (13, 20))	('CD34+', 'Var', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CD38-', 'Var', (64, 69))
37657	24850840	Additionally, increased spleen uptake in transgenic mice appeared to be partly related to strain differences in clearance, as the isotype control antibody also showed 60% increased splenic uptake at 24 hours in transgenic compared to wild-type mice (Fig.	('increased', 'PosReg', (14, 23))	('mice', 'Species', '10090', (244, 248))	('transgenic', 'Species', '10090', (211, 221))	('antibody', 'molecular_function', 'GO:0003823', ('146', '154'))	('spleen uptake', 'CPA', (24, 37))	('uptake', 'biological_process', 'GO:0098657', ('189', '195'))	('increased', 'PosReg', (171, 180))	('antibody', 'cellular_component', 'GO:0042571', ('146', '154'))	('mice', 'Species', '10090', (52, 56))	('uptake', 'biological_process', 'GO:0098739', ('189', '195'))	('transgenic', 'Species', '10090', (41, 51))	('increased spleen', 'Phenotype', 'HP:0001744', (14, 30))	('antibody', 'cellular_component', 'GO:0019815', ('146', '154'))	('uptake', 'biological_process', 'GO:0098657', ('31', '37'))	('antibody', 'cellular_component', 'GO:0019814', ('146', '154'))	('transgenic', 'Var', (211, 221))	('uptake', 'biological_process', 'GO:0098739', ('31', '37'))	('splenic uptake', 'CPA', (181, 195))	('transgenic mice', 'Species', '10090', (41, 56))
37662	24850840	4B) and HSCs (CD150hi, CD48-, LSK) (Fig.	('CD48', 'Gene', (23, 27))	('CD150hi', 'Var', (14, 21))	('CD48', 'Gene', '12506', (23, 27))	('LSK', 'Chemical', '-', (30, 33))
37676	24850840	ESKM was also more effective than ESK1 in vivo, and was able to treat peritoneal mesothelioma in SCID mice, modeling the clinical situation.	('mice', 'Species', '10090', (102, 106))	('SCID', 'Gene', (97, 101))	('ESK1', 'Gene', (34, 38))	('ESKM', 'Var', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (70, 93))	('ESK1', 'Gene', '22137', (34, 38))	('SCID', 'Gene', '19090', (97, 101))	('mesothelioma', 'Disease', (81, 93))
37677	24850840	Further, ESKM significantly slowed leukemia growth of disseminated SET2, an AML cell line with much more aggressive in vivo leukemia growth kinetics than BV173, and a fresh patient-derived pre-B-cell ALL in xenograft models.	('BV173', 'CellLine', 'CVCL:0181', (154, 159))	('AML', 'Disease', (76, 79))	('pre', 'molecular_function', 'GO:0003904', ('189', '192'))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('slowed', 'NegReg', (28, 34))	('leukemia', 'Disease', 'MESH:D007938', (35, 43))	('SET2', 'Gene', '29072', (67, 71))	('leukemia', 'Disease', (124, 132))	('leukemia', 'Disease', (35, 43))	('leukemia', 'Disease', 'MESH:D007938', (124, 132))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('SET2', 'Gene', (67, 71))	('patient', 'Species', '9606', (173, 180))	('AML', 'Disease', 'MESH:D015470', (76, 79))	('ESKM', 'Var', (9, 13))
37692	24850840	Importantly, ESKM did not affect the architecture or cell coverage in the bone marrow, thymus or spleen, where WT1+ HSCs could be expected, and where HLA-A*02:01 expression is highest because the transgene is driven by a lymphoid promoter.	('HLA-A', 'Gene', '3105', (150, 155))	('HLA-A', 'Gene', (150, 155))	('ESKM', 'Var', (13, 17))
37698	24850840	Carriers of CD16-158F are less responsive than CD16-158V/V individuals to human IgG1 therapeutics such as rituximab and trastuzumab.	('rituximab', 'Chemical', 'MESH:D000069283', (106, 115))	('IgG1', 'cellular_component', 'GO:0071735', ('80', '84'))	('CD16-158F', 'Var', (12, 21))	('trastuzumab', 'Chemical', 'MESH:D000068878', (120, 131))	('less', 'NegReg', (26, 30))	('IgG1', 'Gene', (80, 84))	('human', 'Species', '9606', (74, 79))	('responsive', 'MPA', (31, 41))	('IgG1', 'Gene', '16017', (80, 84))
37776	23858317	It is important to remember that endosalpingiosis is positive for B72.3 and also shows nuclear estrogen receptor (ER) and progesteron receptor (PR) positivity.	('positive', 'Reg', (53, 61))	('B72.3', 'Var', (66, 71))	('ER', 'Gene', '2099', (114, 116))	('endosalpingiosis', 'Disease', (33, 49))	('endosalpingiosis', 'Disease', 'MESH:C537064', (33, 49))	('estrogen receptor', 'Gene', (95, 112))	('estrogen receptor', 'Gene', '2099', (95, 112))	('nuclear', 'Protein', (87, 94))
37816	23858317	Low grade serous carcinomas are indolent tumors, and mutations of Kirsten rat sarcoma (KRAS) and vRaf murine sarcoma viral oncogene homolog B1BRAF can be found in the majority of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sarcoma viral', 'Disease', (109, 122))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', (41, 47))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (78, 85))	('sarcoma', 'Disease', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('serous carcinomas', 'Disease', 'MESH:D018284', (10, 27))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('murine', 'Species', '10090', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('B1BRAF', 'Gene', (140, 146))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('serous carcinomas', 'Disease', (10, 27))	('rat', 'Species', '10116', (74, 77))	('sarcoma viral', 'Disease', 'MESH:D001102', (109, 122))
37829	23858317	At the molecular level, these tumors demonstrate chromosomal instability and tumor protein 53(TP53) mutations.	('tumors', 'Disease', (30, 36))	('mutations', 'Var', (100, 109))	('tumor protein 53', 'Gene', '7157', (77, 93))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('rat', 'Species', '10116', (44, 47))	('tumor protein 53', 'Gene', (77, 93))	('chromosomal', 'MPA', (49, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (49, 72))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))
37830	23858317	Peritoneal washings tend to be highly cellular, have larger tissue fragments (sometimes with over 30 cells) with complex architecture, crowded and disorganized cell arrangements, marked nuclear atypia, pleomorphism, macronucleoli and mitoses when compared with low grade serous tumors.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('pleomorphism', 'Var', (202, 214))	('men', 'Species', '9606', (71, 74))	('serous tumors', 'Disease', 'MESH:D018284', (271, 284))	('serous tumors', 'Disease', (271, 284))	('mitoses', 'CPA', (234, 241))	('men', 'Species', '9606', (172, 175))
37832	23858317	Most serous carcinomas are immunoreactive for Wilm's tumor 1 (WT1), CA-125 and PAX8 [Figure 10].	('serous carcinomas', 'Disease', (5, 22))	("Wilm's tumor 1", 'Gene', '7490', (46, 60))	('WT1', 'Gene', '7490', (62, 65))	('PAX8', 'Gene', '7849', (79, 83))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (46, 58))	('WT1', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('PAX8', 'Gene', (79, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	("Wilm's tumor 1", 'Gene', (46, 60))	('CA-125', 'Var', (68, 74))	('serous carcinomas', 'Disease', 'MESH:D018284', (5, 22))
37844	23858317	With that possibility in mind, Landon et al., studied the utility of peritoneal washing for detecting occult primary peritoneal carcinoma in 117 patients with breast cancer 1 (BRCA-1 or BRCA2 mutations.	('patients', 'Species', '9606', (145, 153))	('BRCA-1', 'Gene', (176, 182))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('BRCA-1', 'Gene', '672', (176, 182))	('primary peritoneal carcinoma', 'Phenotype', 'HP:0030406', (109, 137))	('BRCA2', 'Gene', (186, 191))	('carcinoma', 'Disease', 'MESH:D002277', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('carcinoma', 'Disease', (128, 137))	('BRCA2', 'Gene', '675', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (192, 201))
37856	23858317	TP53 mutations have been reported in these tumors, which is only rarely seen in uterine or ovarian MMMT.	('TP53', 'Gene', '7157', (0, 4))	('reported', 'Reg', (25, 33))	('TP53', 'Gene', (0, 4))	('ovarian MMMT', 'Disease', (91, 103))	('mutations', 'Var', (5, 14))	('ovarian MMMT', 'Disease', 'MESH:D010051', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
37869	23858317	Deleted in pancretic cancer (DPC4) or SMAD4 can be a helpful immunostain, since it is positive in ovarian mucinous tumors and negative in approximately 50% of pancreatic tumors.	('pancretic cancer', 'Phenotype', 'HP:0002894', (11, 27))	('Deleted', 'Var', (0, 7))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (159, 176))	('SMAD4', 'Gene', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian mucinous tumors', 'Disease', (98, 121))	('pancretic cancer', 'Disease', 'MESH:D009369', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic tumors', 'Disease', 'MESH:D010190', (159, 176))	('SMAD4', 'Gene', '4089', (38, 43))	('ovarian mucinous tumors', 'Disease', 'MESH:D010051', (98, 121))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('pancreatic tumors', 'Disease', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('DPC4', 'Gene', (29, 33))	('ovarian mucinous tumors', 'Phenotype', 'HP:0031494', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('positive', 'Reg', (86, 94))	('DPC4', 'Gene', '4089', (29, 33))	('pancretic cancer', 'Disease', (11, 27))
37901	23858317	The Call-Exner bodies in fluid appear as small clusters of cells in a rosette pattern with a central hyaline globule that stains green or blue on Pap stain or pink on Diff-Quik.	('Pap', 'Gene', (146, 149))	('stains', 'Var', (122, 128))	('rosette', 'Phenotype', 'HP:0031925', (70, 77))	('hyaline globule', 'Phenotype', 'HP:0025115', (101, 116))	('Pap', 'Gene', '10914', (146, 149))	('Pap', 'molecular_function', 'GO:0043751', ('146', '149'))
37918	23858317	Immunostains for epithelial markers (e.g., B72.3 and BerEP4) help detect and/or confirm the presence of endometrial carcinoma in washings, but will not distinguish these cell groups from benign epithelial entities such as endosalpingiosis.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (104, 125))	('endometrial carcinoma', 'Disease', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('endosalpingiosis', 'Disease', (222, 238))	('endosalpingiosis', 'Disease', 'MESH:C537064', (222, 238))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('B72.3', 'Var', (43, 48))
37951	23858317	At the molecular level neurofibromatosis 2 (NF2) gene alterations have been associated with this tumor.	('NF2', 'Gene', '4771', (44, 47))	('fibroma', 'Phenotype', 'HP:0010614', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('neurofibromatosis 2', 'Gene', '4771', (23, 42))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (23, 40))	('tumor', 'Disease', (97, 102))	('associated', 'Reg', (76, 86))	('NF2', 'Gene', (44, 47))	('alterations', 'Var', (54, 65))	('rat', 'Species', '10116', (58, 61))	('neurofibromatosis 2', 'Gene', (23, 42))
37972	23858317	Although several immunostains have been reported to support a diagnosis of malignant mesothelioma (e.g., epithelial membrane antigen (EMA), glucose transporter-1(GLUT-1), and X-linked inhibitor of apoptosis protein), detection of a homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (p16) on chromosome 9p21 by fluorescence in situ hybridization appears to show the most promising results as a marker for malignancy in mesothelial proliferations.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (75, 97))	('CDKN2A', 'Gene', (297, 303))	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('EMA', 'Gene', (134, 137))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (259, 295))	('GLUT-1', 'Gene', '6513', (162, 168))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('276', '292'))	('GLUT-1', 'Gene', (162, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('p16', 'Gene', (311, 314))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('CDKN2A', 'Gene', '1029', (297, 303))	('p16', 'Gene', '1029', (311, 314))	('malignancy', 'Disease', 'MESH:D009369', (432, 442))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (75, 97))	('deletion', 'Var', (243, 251))	('chromosome', 'cellular_component', 'GO:0005694', ('319', '329'))	('rat', 'Species', '10116', (465, 468))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (259, 295))	('malignancy', 'Disease', (432, 442))	('EMA', 'Gene', '4582', (134, 137))	('malignant mesothelioma', 'Disease', (75, 97))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('259', '292'))	('membrane', 'cellular_component', 'GO:0016020', ('116', '124'))
37998	23858317	DSRCT also exhibits a reciprocal translocation t (11;22) resulting in fusion of the Ewing sarcoma 1 (EWS1) gene on chromosome 22 and WT1 on chromosome 11.	('Ewing sarcoma', 'Disease', (84, 97))	('WT1', 'Gene', (133, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('fusion', 'Var', (70, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('EWS1', 'Gene', (101, 105))	('WT1', 'Gene', '7490', (133, 136))
38030	22147941	These virulence-determinants facilitate cell-to-cell spread and invasion of non-phagocytic cells, and their combined deletion results in 1,000-fold attenuation when compared to wild-type Lm.	('attenuation', 'NegReg', (148, 159))	('virulence', 'biological_process', 'GO:0016032', ('6', '15'))	('cell-to-cell spread', 'CPA', (40, 59))	('Lm', 'Species', '1639', (187, 189))	('invasion of non-phagocytic cells', 'CPA', (64, 96))	('virulence', 'biological_process', 'GO:0009406', ('6', '15'))	('virulence', 'biological_process', 'GO:0009405', ('6', '15'))	('facilitate', 'PosReg', (29, 39))	('deletion', 'Var', (117, 125))
38031	22147941	However, uptake of ANZ-100 by phagocytic cells in the liver and spleen is retained and results in a local pro-inflammatory cytokine response resulting in activation and recruitment of both innate and adaptive effector cells.	('results in', 'Reg', (87, 97))	('activation', 'PosReg', (154, 164))	('uptake', 'biological_process', 'GO:0098739', ('9', '15'))	('ANZ-100', 'Var', (19, 26))	('uptake', 'biological_process', 'GO:0098657', ('9', '15'))	('recruitment', 'CPA', (169, 180))	('local pro-inflammatory cytokine response', 'MPA', (100, 140))	('ANZ-100', 'Chemical', '-', (19, 26))
38035	22147941	CRS-207 has been shown to efficiently deliver mesothelin antigen into both class I and class II antigen processing pathways.	('CRS-207', 'Var', (0, 7))	('class I', 'Pathway', (75, 82))	('class II antigen processing pathways', 'Pathway', (87, 123))	('CRS', 'Chemical', 'MESH:D002857', (0, 3))	('deliver', 'MPA', (38, 45))	('antigen processing', 'biological_process', 'GO:0019882', ('96', '114'))
38039	22147941	In a Phase 1 study, a dose-dependent systemic anti-tumor response was reported to be associated with anti-mesothelin CD8+ T cell responses.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('anti-mesothelin', 'Var', (101, 116))	('tumor', 'Disease', (51, 56))	('CD8', 'Gene', (117, 120))	('CD8', 'Gene', '925', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
38045	22147941	ANZ-100 (LADD; Lm DeltaactA/DeltainlB), Lm strain CERS 382.20, was constructed by deletion of the actA and inlB genes from the Streptomycin resistant wild-type strain DP-L4056.	('Lm', 'Species', '1639', (40, 42))	('ANZ-100', 'Chemical', '-', (0, 7))	('Lm', 'Species', '1639', (15, 17))	('Lm strain', 'Species', '1639', (40, 49))	('deletion', 'Var', (82, 90))	('actA', 'Gene', (98, 102))	('inlB', 'Gene', (107, 111))	('Streptomycin', 'Chemical', 'MESH:D013307', (127, 139))
38065	22147941	Nine subjects (6 with colorectal cancer (CRC), 2 with PDA, 1 with melanoma) with treatment-refractory carcinoma and liver metastases received a single-dose 2-hour infusion at one of three dose levels (1x106, 3x107, 3x108 cfu) of ANZ-100 (Table 1).	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('colorectal cancer', 'Disease', (22, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('carcinoma and liver metastases', 'Disease', 'MESH:D009362', (102, 132))	('PDA', 'Chemical', '-', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('1x106', 'Var', (201, 206))	('3x107', 'Var', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('ANZ-100', 'Gene', (229, 236))	('ANZ-100', 'Chemical', '-', (229, 236))	('PDA', 'Phenotype', 'HP:0006725', (54, 57))
38083	22147941	Cytokines were detected using the Meso Scale Discovery (MSD) platform (Gaithersburg, MD) using frozen serum samples collected before, 4 hours and 24 hours post infusion with ANZ-100 or CRS-207.	('ANZ-100', 'Chemical', '-', (174, 181))	('CRS-207', 'Var', (185, 192))	('CRS', 'Chemical', 'MESH:D002857', (185, 188))	('MSD', 'Disease', 'MESH:D052517', (56, 59))	('MSD', 'Disease', (56, 59))
38119	22147941	Overall review of the safety data from the trial did not identify any significant toxicity with Lm or Lm-mesothelin that was not reversible or unexpected from either previous studies in cynomologus monkeys or based on mechanism of action.	('toxicity', 'Disease', (82, 90))	('Lm-mesothelin', 'Var', (102, 115))	('Lm', 'Species', '1639', (102, 104))	('Lm', 'Species', '1639', (96, 98))	('toxicity', 'Disease', 'MESH:D064420', (82, 90))
38128	22147941	Serum samples were collected prior to and at 2 hours, 6 hours, and daily for 5 days following ANZ-100 administration and analyzed for the presence of MCP-1, MIP-1alpha, MIP-1beta, LT-alpha, IP-10, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IFN-gamma, and TNF-alpha.	('MCP-1', 'Gene', (150, 155))	('IL-4', 'molecular_function', 'GO:0005136', ('219', '223'))	('ANZ-100', 'Chemical', '-', (94, 101))	('MIP-1alpha', 'Gene', (157, 167))	('IL-1', 'molecular_function', 'GO:0005149', ('197', '201'))	('IL-6', 'molecular_function', 'GO:0005138', ('231', '235'))	('IL-5', 'molecular_function', 'GO:0005137', ('225', '229'))	('IL-7', 'molecular_function', 'GO:0005139', ('237', '241'))	('MIP-1beta', 'Var', (169, 178))	('MIP', 'molecular_function', 'GO:0004243', ('169', '172'))	('IL-2', 'molecular_function', 'GO:0005134', ('207', '211'))	('MCP', 'molecular_function', 'GO:0004298', ('150', '153'))	('IL-12p70', 'Var', (256, 264))	('TNF-alpha', 'Gene', (281, 290))	('IL-8', 'molecular_function', 'GO:0005153', ('243', '247'))	('IFN-gamma', 'Gene', '3458', (266, 275))	('IFN-gamma', 'Gene', (266, 275))	('IL-3', 'molecular_function', 'GO:0005135', ('213', '217'))	('IL-10', 'molecular_function', 'GO:0005141', ('249', '254'))	('MIP', 'molecular_function', 'GO:0004243', ('157', '160'))	('IL-12', 'molecular_function', 'GO:0005143', ('256', '261'))
38157	22147941	Another example of transaminitis in the context of immunotherapy is the flares in chronic hepatitis B patients induced by Peg-IFN alpha-2b.	('patients', 'Species', '9606', (102, 110))	('hepatitis', 'Phenotype', 'HP:0012115', (90, 99))	('hepatitis B', 'Disease', 'MESH:D006509', (90, 101))	('Peg-IFN', 'Var', (122, 129))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (82, 99))	('flares', 'Disease', (72, 78))	('hepatitis B', 'Disease', (90, 101))
38167	22147941	In these two first-in-human Phase 1 clinical studies in patients with advanced cancer, ANZ-100 (a live-attenuated Lm strain (Lm DeltaactA/DeltainlB)) and CRS-207 (the Lm DeltaactA/DeltainlB strain engineered to express human mesothelin), were well tolerated with encouraging dose-dependent evidence of immune activation.	('patients', 'Species', '9606', (56, 64))	('Lm', 'Species', '1639', (114, 116))	('Lm strain', 'Species', '1639', (114, 123))	('Lm', 'Species', '1639', (125, 127))	('human', 'Species', '9606', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Lm', 'Species', '1639', (167, 169))	('ANZ-100', 'Gene', (87, 94))	('ANZ-100', 'Chemical', '-', (87, 94))	('human', 'Species', '9606', (22, 27))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('CRS', 'Chemical', 'MESH:D002857', (154, 157))	('CRS-207', 'Var', (154, 161))
38184	20006539	Several reports support a role for SV40 in mesothelioma, while many other reports have questioned or even negated a role for this virus.	('mesothelioma', 'Disease', (43, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('SV40', 'Var', (35, 39))
38185	20006539	A biological rationale for a role for SV40 is that it efficiently induces transformation of mesothelial cells and that asbestos and transforming proteins of the virus synergize to enhance proliferation and survival and to counteract apoptosis of mesothelial cells.	('SV40', 'Var', (38, 42))	('induces', 'Reg', (66, 73))	('survival', 'CPA', (206, 214))	('apoptosis', 'biological_process', 'GO:0006915', ('233', '242'))	('proliferation', 'CPA', (188, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('233', '242'))	('enhance', 'PosReg', (180, 187))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('transformation of mesothelial cells', 'CPA', (74, 109))
38220	20006539	If a polyomavirus is indeed linked to human mesothelioma, it probably is not MCPyV.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('linked', 'Reg', (28, 34))	('human', 'Species', '9606', (38, 43))	('MCPyV', 'Species', '493803', (77, 82))	('polyomavirus', 'Var', (5, 17))	('polyomavirus', 'Species', '36362', (5, 17))	('mesothelioma', 'Disease', (44, 56))
38263	28361969	We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs.	('gene silencing', 'Var', (19, 33))	('suppressed', 'NegReg', (56, 66))	('gene silencing', 'biological_process', 'GO:0016458', ('19', '33'))	('mesothelioma', 'Disease', (101, 113))	('HEG1', 'Gene', (37, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
38287	28361969	Here we show that sialylated HEG1, which we identified as a novel mucin-like membrane protein, is indeed a mesothelioma-related antigen, and that HEG1 expression supports the survival and proliferation of mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('membrane', 'cellular_component', 'GO:0016020', ('77', '85'))	('HEG1', 'Gene', (146, 150))	('survival', 'CPA', (175, 183))	('mucin', 'Gene', '100508689', (66, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('mesothelioma', 'Disease', (107, 119))	('proliferation', 'CPA', (188, 201))	('mucin', 'Gene', (66, 71))	('HEG1', 'Gene', (29, 33))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('mesothelioma', 'Disease', (205, 217))	('supports', 'PosReg', (162, 170))	('sialylated', 'Var', (18, 28))
38302	28361969	These results suggest that SKM9-2 antigen has low expression in non-mesothelioma cells and normal tissues, except in a part of the capillary endothelium, and reactive mesothelial cells.	('SKM9-2', 'Var', (27, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('expression', 'MPA', (50, 60))	('mesothelioma', 'Disease', (68, 80))
38307	28361969	These biochemical properties suggest that SKM9-2 antigen is a heavily sialylated mucin.	('mucin', 'Gene', '100508689', (81, 86))	('SKM9-2', 'Var', (42, 48))	('mucin', 'Gene', (81, 86))
38310	28361969	Suppressing the HEG1 gene with 3 different regions of siRNA (H1097, H2674, and H3671) specifically decreased HEG1 western blot signals (Fig.	('decreased', 'NegReg', (99, 108))	('HEG1 gene', 'Gene', (16, 25))	('H2674', 'Var', (68, 73))	('HEG1 western blot signals', 'MPA', (109, 134))	('H2674', 'CellLine', 'CVCL:Y658', (68, 73))	('H1097', 'Var', (61, 66))	('H3671', 'Var', (79, 84))
38327	28361969	HEG1 of ACC-MESO-4 also had two missense SNPs (Fig.	('ACC-MESO-4', 'Chemical', '-', (8, 18))	('missense SNPs', 'Var', (32, 45))	('ACC-MESO-4', 'Gene', (8, 18))
38344	28361969	Proliferation of mesothelioma cells was suppressed by HEG1 siRNA, but not control siRNA, in a time-dependent manner (Fig.	('HEG1 siRNA', 'Var', (54, 64))	('suppressed', 'NegReg', (40, 50))	('mesothelioma', 'Disease', (17, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))
38348	28361969	The suppression of cell growth by H2674 was also observed on NCI-H2452, another mesothelioma cell line (Fig.	('cell growth', 'biological_process', 'GO:0016049', ('19', '30'))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('suppression', 'NegReg', (4, 15))	('cell growth', 'CPA', (19, 30))	('H2674', 'Var', (34, 39))	('H2674', 'CellLine', 'CVCL:Y658', (34, 39))	('NCI-H2452', 'CellLine', 'CVCL:1553', (61, 70))	('mesothelioma', 'Disease', (80, 92))
38351	28361969	This high specificity makes it possible to provide chimeric antigen receptor therapy that is more potent than tumor vaccine or antibody therapy.	('antibody', 'cellular_component', 'GO:0019815', ('127', '135'))	('antibody', 'cellular_component', 'GO:0019814', ('127', '135'))	('antibody', 'molecular_function', 'GO:0003823', ('127', '135'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('chimeric', 'Var', (51, 59))	('antibody', 'cellular_component', 'GO:0042571', ('127', '135'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
38355	28361969	We showed that sialylated human HEG1 was mainly expressed on the apical membrane, unlike the reported mouse HEG1 observed in the cell-cell junction.	('sialylated', 'Var', (15, 25))	('HEG1', 'Gene', (32, 36))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('129', '147'))	('membrane', 'cellular_component', 'GO:0016020', ('72', '80'))	('mouse', 'Species', '10090', (102, 107))	('human', 'Species', '9606', (26, 31))
38357	28361969	Mesothelioma cells disseminated into pleural effusion also expressed sialylated HEG1 on the cell cluster apical surface, but not at cell-cell junctions (Fig.	('pleural effusion', 'Phenotype', 'HP:0002202', (37, 53))	('expressed', 'Reg', (59, 68))	('HEG1', 'Protein', (80, 84))	('pleural effusion', 'Disease', (37, 53))	('pleural effusion', 'Disease', 'MESH:D010996', (37, 53))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('sialylated', 'Var', (69, 79))
38358	28361969	This HEG1 expression seemed to prevent re-attachment of mesothelioma cells detached from the pleura as well as anti-adhesion effects of membrane-associated mucin.	('pleura', 'Disease', 'MESH:D054363', (93, 99))	('mucin', 'Gene', (156, 161))	('membrane', 'cellular_component', 'GO:0016020', ('136', '144'))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))	('re-attachment', 'CPA', (39, 52))	('expression', 'Var', (10, 20))	('HEG1', 'Gene', (5, 9))	('prevent', 'NegReg', (31, 38))	('mesothelioma', 'Disease', (56, 68))	('anti-adhesion effects', 'MPA', (111, 132))	('mucin', 'Gene', '100508689', (156, 161))	('pleura', 'Disease', (93, 99))
38366	28361969	Functional inhibitors of HEG1 may have anti-mesothelioma activity; a MUC1 inhibitor has been examined for anti-cancer properties.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('inhibitors', 'Var', (11, 21))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('HEG1', 'Gene', (25, 29))	('mesothelioma', 'Disease', (44, 56))	('MUC1', 'Gene', (69, 73))	('MUC1', 'Gene', '4582', (69, 73))
38394	28361969	siRNA against human HEG1 was designed by Enhanced siDirect (http://rnai.co.jp/lsci/license.html); H1097, 5'-GAUCUUUGACGGUCAGUCUGG-3' and 5'-AGACUGACCGUCAAAGAUCGC-3'; H2674, 5'-CCUAUAGCCGUACAGACUACA-3' and 5'-UAGUCUGUACGGCUAUAGGGC-3'; H3671, 5'-GCAAGUCGGGAUACUUUCAGU-3' and 5'-UGAAAGUAUCCCGACUUGCAC-3'.	('human', 'Species', '9606', (14, 19))	('ACG', 'Chemical', 'MESH:C023716', (116, 119))	('ACG', 'Chemical', 'MESH:C023716', (216, 219))	('rnai', 'biological_process', 'GO:0016246', ('67', '71'))	('H1097', 'Var', (98, 103))	('H2674', 'CellLine', 'CVCL:Y658', (166, 171))	('H3671', 'Var', (234, 239))
38401	28361969	Several human HEG1 siRNAs designed by Enhanced siDirect were used; HEG1 siRNA mix 1, a mixture of H1097 and H2674 (1:1); H3059, 5'-GCGAAUGCGUCGCAGACAACA-3' and 5'-UUGUCUGCGACGCAUUCGCCA-3'; and H9106, 5'-CUGGCGUUCUAGUCAGUAAAA-3' and 5'-UUACUGACUAGAACGCCAGAC-3'.	('H3059', 'Var', (121, 126))	('ACG', 'Chemical', 'MESH:C023716', (247, 250))	('ACG', 'Chemical', 'MESH:C023716', (172, 175))	('H9106', 'Var', (193, 198))	('human', 'Species', '9606', (8, 13))	('H2674', 'CellLine', 'CVCL:Y658', (108, 113))
38402	28361969	Four commercially available siRNAs against human HEG1 were also tested: HEG1 siRNA mix 2, sc-78365 (Santa Cruz Biotechnology); S3816, SASI_Hs02_00353816; S3817, SASI_Hs02_00353817; and S3818, SASI_Hs02_00353818 (Sigma-Aldrich Japan K.K.).	('SASI_Hs02_00353817', 'Var', (161, 179))	('human', 'Species', '9606', (43, 48))	('S3818', 'Var', (185, 190))	('S3817', 'Var', (154, 159))	('SASI_Hs02_00353818', 'Var', (192, 210))	('S3816', 'Var', (127, 132))	('SASI_Hs02_00353816', 'Var', (134, 152))
38408	27452468	Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1 Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis.	('ASS1', 'Gene', (142, 146))	('Polyamine Synthesis Pathway', 'Pathway', (18, 45))	('Argininosuccinate synthase 1', 'Gene', '445', (112, 140))	('arginine biosynthesis', 'biological_process', 'GO:0006526', ('180', '201'))	('Polyamine', 'Chemical', 'MESH:D011073', (18, 27))	('Argininosuccinate synthase 1', 'Gene', (112, 140))	('Polyamine Synthesis', 'biological_process', 'GO:0006596', ('18', '37'))	('Loss', 'Var', (75, 79))	('Argininosuccinate Synthase', 'Gene', (83, 109))	('arginine', 'Chemical', 'MESH:D001120', (180, 188))	('Argininosuccinate Synthase', 'Gene', '445', (83, 109))	('ASS1', 'Gene', '445', (142, 146))
38411	27452468	We have generated a model of ADI-PEG20 resistance in mesothelioma cells.	('ADI-PEG20 resistance', 'Var', (29, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (29, 38))	('mesothelioma', 'Disease', (53, 65))
38412	27452468	This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter.	('ASS1', 'Gene', (53, 57))	('ASS1', 'Gene', '445', (53, 57))	('demethylation', 'Var', (62, 75))	('ASS1', 'Gene', (83, 87))	('demethylation', 'biological_process', 'GO:0070988', ('62', '75'))	('ASS1', 'Gene', '445', (83, 87))
38417	27452468	have generated a model of ADI-PEG20 resistance in mesothelioma cells.	('ADI-PEG20 resistance', 'Var', (26, 46))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (26, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('mesothelioma', 'Disease', (50, 62))
38423	27452468	As a versatile amino acid, arginine has connections to a number of metabolic pathways pertinent to tumorigenesis, including nitric oxide, creatine, and polyamine synthesis.	('connections', 'Reg', (40, 51))	('tumor', 'Disease', (99, 104))	('nitric oxide', 'Chemical', 'MESH:D009569', (124, 136))	('creatine', 'Chemical', 'MESH:D003401', (138, 146))	('creatine', 'MPA', (138, 146))	('metabolic pathways', 'Pathway', (67, 85))	('arginine', 'Chemical', 'MESH:D001120', (27, 35))	('polyamine synthesis', 'biological_process', 'GO:0006596', ('152', '171'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('polyamine', 'Chemical', 'MESH:D011073', (152, 161))	('nitric oxide', 'MPA', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('arginine', 'Var', (27, 35))	('polyamine synthesis', 'MPA', (152, 171))
38426	27452468	For example, in lymphoma, myxofibrosarcoma, nasopharyngeal carcinoma, bladder cancer, hepatocellular carcinoma, and malignant pleural mesothelioma (MPM), methylation of the ASS1 promoter appears to mediate ASS1 repression, whereas in melanoma, the interplay between c-Myc and HIF1alpha controls ASS1 levels.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (86, 110))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (116, 146))	('lymphoma', 'Disease', 'MESH:D008223', (16, 24))	('ASS1', 'Gene', '445', (295, 299))	('c-Myc', 'Gene', '4609', (266, 271))	('myxofibrosarcoma', 'Disease', (26, 42))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (44, 68))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('mediate', 'Reg', (198, 205))	('repression', 'NegReg', (211, 221))	('hepatocellular carcinoma', 'Disease', (86, 110))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (126, 146))	('ASS1', 'Gene', '445', (173, 177))	('ASS1', 'Gene', (173, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))	('HIF1alpha', 'Gene', '3091', (276, 285))	('malignant pleural mesothelioma', 'Disease', (116, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('methylation', 'Var', (154, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (16, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('HIF1alpha', 'Gene', (276, 285))	('nasopharyngeal carcinoma', 'Disease', (44, 68))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('myxofibrosarcoma', 'Disease', 'None', (26, 42))	('melanoma', 'Disease', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 110))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (44, 68))	('controls', 'Reg', (286, 294))	('ASS1', 'Gene', (295, 299))	('ASS1', 'Gene', '445', (206, 210))	('c-Myc', 'Gene', (266, 271))	('ASS1', 'Gene', (206, 210))	('lymphoma', 'Disease', (16, 24))
38430	27452468	Approximately 50% of MPMs do not express ASS1, making ADI-PEG20 an attractive personalized therapeutic strategy that has shown significant activity in a randomized phase II trial.	('ADI-PEG20', 'Var', (54, 63))	('ASS1', 'Gene', (41, 45))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (54, 63))	('ASS1', 'Gene', '445', (41, 45))
38442	27452468	Ju77R cells had a 20-fold increase in ASS1 mRNA (Figure 1B) and the corresponding protein (Figure 1C) and increased levels of ASL (Figures 1C and 1D).	('ASS1', 'Gene', (38, 42))	('levels of ASL', 'MPA', (116, 129))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('increase', 'PosReg', (26, 34))	('increased levels of ASL', 'Phenotype', 'HP:0031956', (106, 129))	('protein', 'MPA', (82, 89))	('increased', 'PosReg', (106, 115))	('ASS1', 'Gene', '445', (38, 42))	('Ju77R', 'Var', (0, 5))
38444	27452468	Previously, we demonstrated that expression of ASS1 in mesothelioma is regulated by methylation at CpG islands in the ASS1 promoter, which represses transcription.	('methylation', 'Var', (84, 95))	('mesothelioma', 'Disease', (55, 67))	('ASS1', 'Gene', (118, 122))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('represses', 'NegReg', (139, 148))	('ASS1', 'Gene', (47, 51))	('ASS1', 'Gene', '445', (118, 122))	('ASS1', 'Gene', '445', (47, 51))	('transcription', 'MPA', (149, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('expression', 'MPA', (33, 43))	('regulated by', 'Reg', (71, 83))	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))
38449	27452468	The cell line most sensitive to ADI-PEG20, MSTO-211H (MSTO), had 10% overall promoter methylation, compared to 2% for the most resistant cell line, H226.	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (32, 41))	('promoter methylation', 'MPA', (77, 97))	('H226', 'CellLine', 'CVCL:J621', (148, 152))	('ADI-PEG20', 'Var', (32, 41))
38450	27452468	Thus, it is possible that 10% methylation represents a threshold for methylation-induced transcriptional silencing of the ASS1 gene in MPM cells.	('methylation', 'Var', (30, 41))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('silencing', 'NegReg', (105, 114))	('methylation-induced', 'Var', (69, 88))	('ASS1', 'Gene', (122, 126))	('transcriptional', 'MPA', (89, 104))	('ASS1', 'Gene', '445', (122, 126))
38456	27452468	Altogether, our data suggest that re-expression of ASS1 in the Ju77R cells is via demethylation of the ASS1 promoter and not through regulation by c-Myc.	('c-Myc', 'Gene', (147, 152))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('demethylation', 'Var', (82, 95))	('ASS1', 'Gene', (51, 55))	('ASS1', 'Gene', '445', (51, 55))	('ASS1', 'Gene', (103, 107))	('c-Myc', 'Gene', '4609', (147, 152))	('demethylation', 'biological_process', 'GO:0070988', ('82', '95'))	('ASS1', 'Gene', '445', (103, 107))
38459	27452468	The metabolomic analysis showed that the levels of the acetylated polyamines N1-acetylspermidine and N1-acetylspermine were significantly lower in the ASS1-deficient Ju77S cells in comparison to the ASS1-proficient Ju77R cells (Figure 2A).	('N1-acetylspermine', 'MPA', (101, 118))	('acetylated polyamines N1-acetylspermidine', 'MPA', (55, 96))	('polyamines', 'Chemical', 'MESH:D011073', (66, 76))	('lower', 'NegReg', (138, 143))	('Ju77S', 'Var', (166, 171))	('N1-acetylspermine', 'Chemical', 'MESH:C029452', (101, 118))	('N1-acetylspermidine', 'Chemical', 'MESH:C017988', (77, 96))	('ASS1', 'Gene', (151, 155))	('ASS1', 'Gene', (199, 203))	('ASS1', 'Gene', '445', (151, 155))	('ASS1', 'Gene', '445', (199, 203))	('levels', 'MPA', (41, 47))
38464	27452468	It has previously been shown that levels of SSAT1 can influence polyamine levels by depleting spermidine and spermine with an increase in N1-acetylspermidine, which is subsequently oxidatively degraded to putrescine.	('levels', 'Var', (34, 40))	('spermidine', 'Chemical', 'MESH:D013095', (94, 104))	('N1-acetylspermidine', 'Chemical', 'MESH:C017988', (138, 157))	('spermine', 'MPA', (109, 117))	('spermidine', 'MPA', (94, 104))	('polyamine', 'Chemical', 'MESH:D011073', (64, 73))	('depleting', 'NegReg', (84, 93))	('SSAT1', 'Gene', (44, 49))	('N1-acetylspermidine', 'MPA', (138, 157))	('spermine', 'Chemical', 'MESH:D013096', (109, 117))	('polyamine levels', 'MPA', (64, 80))	('spermidine', 'Chemical', 'MESH:D013095', (147, 157))	('increase', 'PosReg', (126, 134))	('SSAT1', 'Gene', '6303', (44, 49))	('putrescine', 'Chemical', 'MESH:D011700', (205, 215))	('influence', 'Reg', (54, 63))
38467	27452468	The basal levels of putrescine and spermine were similar in both cell lines; however, there was a trend toward decreased baseline spermidine levels in Ju77S cells (Figure 2C).	('spermine', 'Chemical', 'MESH:D013096', (35, 43))	('baseline spermidine levels', 'MPA', (121, 147))	('putrescine', 'Chemical', 'MESH:D011700', (20, 30))	('decreased', 'NegReg', (111, 120))	('Ju77S', 'Var', (151, 156))	('spermidine', 'Chemical', 'MESH:D013095', (130, 140))
38469	27452468	However, upon ADI-PEG20 treatment, putrescine and spermine levels were significantly reduced in Ju77S cells but not in Ju77R cells (p < 0.05; Figures 2D and 2E).	('Ju77S', 'Var', (96, 101))	('ADI-PEG20', 'Var', (14, 23))	('putrescine', 'Chemical', 'MESH:D011700', (35, 45))	('spermine', 'Chemical', 'MESH:D013096', (50, 58))	('reduced', 'NegReg', (85, 92))	('putrescine', 'MPA', (35, 45))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (14, 23))	('spermine levels', 'MPA', (50, 65))
38478	27452468	As expected, we observed a significant decrease in arginine levels (Figure 3A) and a subsequent significant increase in citrulline levels (Figure 3B) after ADI-PEG20 treatment in plasma from ASS1-deficient mesothelioma patients.	('increase', 'PosReg', (108, 116))	('citrulline', 'Chemical', 'MESH:D002956', (120, 130))	('decrease', 'NegReg', (39, 47))	('citrulline levels', 'MPA', (120, 137))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (156, 165))	('ASS1-deficient mesothelioma', 'Disease', (191, 218))	('arginine', 'Chemical', 'MESH:D001120', (51, 59))	('ADI-PEG20', 'Var', (156, 165))	('patients', 'Species', '9606', (219, 227))	('arginine levels', 'MPA', (51, 66))	('ASS1-deficient mesothelioma', 'Disease', 'MESH:D008654', (191, 218))
38483	27452468	These data strongly support our in vitro data that polyamine levels are decreased upon ADI-PEG20 treatment in ASS1-deficient cells.	('ASS1', 'Gene', (110, 114))	('polyamine levels', 'MPA', (51, 67))	('decreased', 'NegReg', (72, 81))	('ADI-PEG20', 'Var', (87, 96))	('polyamine', 'Chemical', 'MESH:D011073', (51, 60))	('ASS1', 'Gene', '445', (110, 114))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (87, 96))
38484	27452468	Significantly, we show that ADI-PEG20 treatment can modulate polyamine levels both in vitro and in vivo, thus suggesting that polyamine disruption may be an additional mechanism of action of this therapeutic.	('polyamine', 'Chemical', 'MESH:D011073', (61, 70))	('polyamine', 'Chemical', 'MESH:D011073', (126, 135))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (28, 37))	('ADI-PEG20', 'Var', (28, 37))	('polyamine levels', 'MPA', (61, 77))	('modulate', 'Reg', (52, 60))
38489	27452468	Ju77S cells have increased expression of the arginine transporters SLC7A2 and SLC3A2, indicating an increased reliance on arginine transport from the extracellular environment (Figure 4A).	('increased', 'PosReg', (17, 26))	('Ju77S', 'Var', (0, 5))	('SLC7A2', 'Gene', '6542', (67, 73))	('arginine', 'Chemical', 'MESH:D001120', (122, 130))	('SLC3A2', 'Gene', (78, 84))	('reliance', 'MPA', (110, 118))	('expression', 'MPA', (27, 37))	('arginine transporters', 'MPA', (45, 66))	('arginine', 'Chemical', 'MESH:D001120', (45, 53))	('SLC7A2', 'Gene', (67, 73))	('arginine transport', 'biological_process', 'GO:0015809', ('122', '140'))	('extracellular', 'cellular_component', 'GO:0005576', ('150', '163'))	('SLC3A2', 'Gene', '6520', (78, 84))
38512	27452468	We have generated a model of resistance to arginine deprivation in MPM cells that is characterized by demethylation of the ASS1 promoter and re-expression of ASS1.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('demethylation', 'biological_process', 'GO:0070988', ('102', '115'))	('demethylation', 'Var', (102, 115))	('ASS1', 'Gene', (123, 127))	('ASS1', 'Gene', '445', (123, 127))	('ASS1', 'Gene', '445', (158, 162))	('ASS1', 'Gene', (158, 162))
38516	27452468	Future studies will determine whether combinatorial treatment with ADI-PEG20 and DFMO can overcome the generation of resistance to arginine deprivation by simultaneously targeting two compensatory metabolic pathways.	('DFMO', 'Gene', (81, 85))	('ADI-PEG20', 'Var', (67, 76))	('generation of resistance to arginine deprivation', 'MPA', (103, 151))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (67, 76))	('DFMO', 'Chemical', 'MESH:D000518', (81, 85))	('compensatory metabolic pathways', 'Pathway', (184, 215))	('targeting', 'Reg', (170, 179))	('arginine', 'Chemical', 'MESH:D001120', (131, 139))
38520	27452468	Inhibition of heme oxygenation is synthetically lethal in fumarate hydratase-deficient hereditary leiomyomatosis and renal-cell cancer (HLRCC) cells.	('fumarate hydratase', 'Gene', '2271', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Inhibition', 'Var', (0, 10))	('fumarate hydratase', 'Gene', (58, 76))	('heme', 'Chemical', 'MESH:D006418', (14, 18))	('hydratase-deficient hereditary leiomyomatosis and renal-cell cancer', 'Disease', 'MESH:C535516', (67, 134))
38523	27452468	Advances in high-throughput genomic technologies have greatly increased our understanding of the genetics of tumor cells and have identified numerous mutations in metabolic enzymes, including isocitrate dehydrogenase 1, fumarate hydratase, and succinate dehydrogenase, in a range of tumor types.	('increased', 'PosReg', (62, 71))	('isocitrate dehydrogenase 1', 'Enzyme', (192, 218))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('succinate dehydrogenase', 'Enzyme', (244, 267))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('fumarate hydratase', 'Gene', '2271', (220, 238))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (283, 288))	('mutations', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('fumarate hydratase', 'Gene', (220, 238))	('tumor', 'Disease', (109, 114))
38528	27452468	Polyamines affect numerous processes in carcinogenesis, including increasing cell proliferation, modulating apoptosis, and increasing expression of genes affecting tumor invasion and metastasis.	('Polyamines', 'Var', (0, 10))	('tumor', 'Disease', (164, 169))	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('expression', 'MPA', (134, 144))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('carcinogenesis', 'Disease', (40, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('increasing', 'PosReg', (123, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('increasing', 'PosReg', (66, 76))	('modulating', 'Reg', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('apoptosis', 'CPA', (108, 117))	('cell proliferation', 'CPA', (77, 95))	('affect', 'Reg', (11, 17))
38530	27452468	In addition, numerous studies have shown that polyamines have the ability to regulate expression of a number of oncogenes.	('polyamines', 'Var', (46, 56))	('regulate', 'Reg', (77, 85))	('oncogenes', 'Gene', (112, 121))	('expression', 'MPA', (86, 96))	('polyamines', 'Chemical', 'MESH:D011073', (46, 56))
38532	27452468	In addition to uncovering a dependence on polyamine synthesis in ASS1-deficient tumor cells, our results point to a potential mechanism of resistance to ADI-PEG20, with demethylation driving ASS1 upregulation.	('demethylation', 'Var', (169, 182))	('ASS1', 'Gene', '445', (65, 69))	('demethylation', 'biological_process', 'GO:0070988', ('169', '182'))	('ASS1', 'Gene', (191, 195))	('resistance', 'MPA', (139, 149))	('ASS1-deficient tumor', 'Disease', (65, 85))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (153, 162))	('ASS1', 'Gene', '445', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ASS1-deficient tumor', 'Disease', 'MESH:D009369', (65, 85))	('polyamine', 'Chemical', 'MESH:D011073', (42, 51))	('polyamine synthesis', 'biological_process', 'GO:0006596', ('42', '61'))	('upregulation', 'PosReg', (196, 208))	('ADI-PEG20', 'Var', (153, 162))	('ASS1', 'Gene', (65, 69))
38535	27452468	Moreover, ASS1 re-expression is likely to modulate sensitivity to alternative drugs and drug combinations, the study of which is possible by the availability of the Ju77S and Ju77R cell lines.	('re-expression', 'Var', (15, 28))	('sensitivity', 'MPA', (51, 62))	('ASS1', 'Gene', (10, 14))	('modulate', 'Reg', (42, 50))	('ASS1', 'Gene', '445', (10, 14))
38546	27452468	After blocking for 1 hr in 1 x Tris-buffered saline/5% non-fat dried milk, membranes were incubated overnight at 4 C in primary antibody, including anti-ASS1 (HPA020934, Sigma-Aldrich), anti-ASL (HPA016646, Sigma-Aldrich), anti-c-Myc (#5650, Cell Signaling Technology [CST]), anti-vinculin (#4650, CST), and anti-beta-actin-HRP (#4970, CST).	('#4650', 'Var', (291, 296))	('#5650', 'Var', (235, 240))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('vinculin', 'Gene', '7414', (281, 289))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('beta-actin', 'Gene', (313, 323))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('Tris-buffered saline', 'Chemical', '-', (31, 51))	('HPA020934', 'Var', (159, 168))	('HPA016646', 'Var', (196, 205))	('c-Myc', 'Gene', (228, 233))	('#4970', 'Var', (329, 334))	('Cell Signaling Technology', 'CPA', (242, 267))	('Signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('vinculin', 'Gene', (281, 289))	('ASS1', 'Gene', (153, 157))	('c-Myc', 'Gene', '4609', (228, 233))	('ASS1', 'Gene', '445', (153, 157))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('beta-actin', 'Gene', '728378', (313, 323))
38585	25749175	HIPEC appears to increase survival but can typically be used to treat only peritoneal mesothelioma.	('increase', 'PosReg', (17, 25))	('survival', 'CPA', (26, 34))	('mesothelioma', 'Disease', (86, 98))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (75, 98))	('HIPEC', 'Var', (0, 5))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
38616	25749175	While HIOC + EPP appears to double mean survival compared with EPP alone, the mean survival for pleural mesothelioma treated with HIOC + EPP is far less than that reported for peritoneal mesothelioma treated with HIPEC + cytoreductive surgery, which suggests a difference in the natural history of pleural versus peritoneal mesothelioma regardless of treatment.	('less', 'NegReg', (148, 152))	('pleural versus peritoneal mesothelioma regardless', 'Disease', 'MESH:D010997', (298, 347))	('pleural versus peritoneal mesothelioma regardless', 'Disease', (298, 347))	('HIOC + EPP', 'Var', (130, 140))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (176, 199))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (313, 336))	('mesothelioma', 'Disease', (104, 116))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (96, 116))	('mesothelioma', 'Disease', (187, 199))	('mesothelioma', 'Disease', (324, 336))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (96, 116))	('pleural mesothelioma', 'Disease', (96, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('men', 'Species', '9606', (356, 359))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (324, 336))
38645	25749175	Genetic predisposition is complex in that genes can affect 1) tumorogenesis, 2) the ability to spread and metastasize, 3) immune surveillance that aborts tumor growth and development, and 4) response to chemotherapy.	('ability', 'CPA', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('men', 'Species', '9606', (178, 181))	('aborts tumor', 'Disease', (147, 159))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('genes', 'Var', (42, 47))	('aborts tumor', 'Disease', 'MESH:D000031', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('affect', 'Reg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (154, 159))
38669	20482802	Given the established roles of NFkappaB in angiogenesis, cell invasion, oncogenesis, proliferation, and inhibition of apoptosis, inhibition of this important transcription factor is widely regarded as an attractive strategy of cancer therapy and a primary mechanism of bortezomib anti-tumor activity in MM cells.	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('104', '127'))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('angiogenesis', 'biological_process', 'GO:0001525', ('43', '55'))	('inhibition', 'Var', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', (285, 290))	('angiogenesis', 'CPA', (43, 55))	('NFkappaB', 'Gene', (31, 39))	('oncogenesis', 'biological_process', 'GO:0007048', ('72', '83'))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('NFkappaB', 'Gene', '4790', (31, 39))	('oncogenesis', 'CPA', (72, 83))	('bortezomib', 'Chemical', 'MESH:D000069286', (269, 279))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('transcription factor', 'molecular_function', 'GO:0000981', ('158', '178'))	('cell invasion', 'CPA', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
38671	20482802	Beyond NFkappaB inhibition, bortezomib also induces the intracellular unfolded protein response (UPR) and stabilizes the expression of the proapoptotic genes p53, Bim, or noxa, indirectly contributing to bortezomib anti-tumor activity.	('intracellular', 'cellular_component', 'GO:0005622', ('56', '69'))	('tumor', 'Disease', (220, 225))	('expression', 'MPA', (121, 131))	('bortezomib', 'Var', (28, 38))	('noxa', 'Gene', (171, 175))	('NFkappaB', 'Gene', (7, 15))	('p53', 'Gene', '7157', (158, 161))	('Bim', 'Gene', '10018', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('intracellular unfolded protein response', 'MPA', (56, 95))	('bortezomib', 'Chemical', 'MESH:D000069286', (204, 214))	('Bim', 'Gene', (163, 166))	('p53', 'Gene', (158, 161))	('induces', 'Reg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('bortezomib', 'Chemical', 'MESH:D000069286', (28, 38))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('noxa', 'Gene', '5366', (171, 175))	('contributing', 'Reg', (188, 200))	('NFkappaB', 'Gene', '4790', (7, 15))
38677	20482802	Further investigation demonstrated that inhibition of PSMB5 expression partially restored bortezomib sensitivity in resistant cells.	('PSMB5', 'Gene', '5693', (54, 59))	('restored', 'PosReg', (81, 89))	('inhibition', 'Var', (40, 50))	('bortezomib sensitivity', 'MPA', (90, 112))	('PSMB5', 'Gene', (54, 59))	('bortezomib', 'Chemical', 'MESH:D000069286', (90, 100))
38694	20482802	Several recent reports on acute myeloid leukemia, lymphoma, and MM described increased PSMB5 RNA and protein expression in bortezomib-adapted cells, and inhibition of PSMB5 expression partially restored bortezomib sensitivity in resistant cells, indicating that PSMB5 over expression is important for bortezomib resistance in cancer.	('bortezomib sensitivity', 'MPA', (203, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('increased', 'PosReg', (77, 86))	('inhibition', 'Var', (153, 163))	('restored', 'NegReg', (194, 202))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (26, 48))	('bortezomib', 'Chemical', 'MESH:D000069286', (301, 311))	('PSMB5', 'Gene', '5693', (167, 172))	('PSMB5', 'Gene', '5693', (262, 267))	('PSMB5', 'Gene', '5693', (87, 92))	('cancer', 'Disease', (326, 332))	('PSMB5', 'Gene', (167, 172))	('lymphoma', 'Disease', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('PSMB5', 'Gene', (262, 267))	('PSMB5', 'Gene', (87, 92))	('bortezomib', 'Chemical', 'MESH:D000069286', (203, 213))	('myeloid leukemia', 'Disease', (32, 48))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (32, 48))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('bortezomib', 'Chemical', 'MESH:D000069286', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('RNA', 'cellular_component', 'GO:0005562', ('93', '96'))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('myeloid leukemia', 'Disease', 'MESH:D007951', (32, 48))
38705	20482802	TPPII upregulation has been reported in some lymphoma cells resistant to the proteasome inhibitor tri-leucine-vinyl-sulphone (NLVS), and inhibition of TPPII function using the specific inhibitor AAF-CMK either directly induces apoptosis or indirectly induces NLVS-mediated cell death.	('apoptosis', 'biological_process', 'GO:0006915', ('227', '236'))	('proteasome', 'cellular_component', 'GO:0000502', ('77', '87'))	('lymphoma', 'Disease', (45, 53))	('lymphoma', 'Disease', 'MESH:D008223', (45, 53))	('TPPII', 'Gene', '7174', (151, 156))	('CMK', 'Gene', '51727', (199, 202))	('tri-leucine-vinyl-sulphone', 'Chemical', '-', (98, 124))	('induces', 'Reg', (251, 258))	('inhibition', 'Var', (137, 147))	('apoptosis', 'CPA', (227, 236))	('upregulation', 'PosReg', (6, 18))	('TPPII', 'Gene', (0, 5))	('induces', 'PosReg', (219, 226))	('CMK', 'Gene', (199, 202))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('TPPII', 'Gene', (151, 156))	('proteasome', 'molecular_function', 'GO:0004299', ('77', '87'))	('TPPII', 'Gene', '7174', (0, 5))	('cell death', 'biological_process', 'GO:0008219', ('273', '283'))	('apoptosis', 'biological_process', 'GO:0097194', ('227', '236'))
38722	20482802	Since CHOP is a pro-apoptotic transcriptional factor during ER stress and UPR, we tested whether siRNA knockdown of CHOP expression could protect I-45-BTZ-R cells from bortezomib-induced cell death.	('cell death', 'biological_process', 'GO:0008219', ('187', '197'))	('CHOP', 'Gene', '1649', (116, 120))	('CHOP', 'Gene', '1649', (6, 10))	('bortezomib', 'Chemical', 'MESH:D000069286', (168, 178))	('BTZ', 'Gene', '22794', (151, 154))	('tested', 'Reg', (82, 88))	('CHOP', 'Gene', (116, 120))	('BTZ', 'Gene', (151, 154))	('CHOP', 'Gene', (6, 10))	('I', 'Chemical', 'MESH:D007455', (146, 147))	('knockdown', 'Var', (103, 112))
38725	20482802	In addition, our data also demonstrated that siRNA-mediated knockdown of CHOP gene expression also partially protected parental I-45 cells from bortezomib-induced cell death (data not shown).	('I', 'Chemical', 'MESH:D007455', (128, 129))	('bortezomib', 'Chemical', 'MESH:D000069286', (144, 154))	('protected', 'NegReg', (109, 118))	('CHOP', 'Gene', '1649', (73, 77))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('cell death', 'biological_process', 'GO:0008219', ('163', '173'))	('knockdown', 'Var', (60, 69))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('CHOP', 'Gene', (73, 77))	('bortezomib-induced', 'MPA', (144, 162))
38731	20482802	Strong expression of the noxa protein was also detected in I-45 cells after treatment with bortezomib, while noxa expression was barely detectable in I-45-BTZ-R cells subjected to the same treatment (Figure 6).	('bortezomib', 'Chemical', 'MESH:D000069286', (91, 101))	('noxa', 'Gene', '5366', (25, 29))	('BTZ', 'Gene', (155, 158))	('bortezomib', 'Var', (91, 101))	('noxa', 'Gene', (109, 113))	('expression', 'MPA', (7, 17))	('I', 'Chemical', 'MESH:D007455', (150, 151))	('I', 'Chemical', 'MESH:D007455', (59, 60))	('noxa', 'Gene', '5366', (109, 113))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('BTZ', 'Gene', '22794', (155, 158))	('noxa', 'Gene', (25, 29))
38745	20482802	A missense point mutation has been reported in a highly conserved PSMB5 bortezomib-binding pocket and that siRNA-mediated reduction of PSMB5 expression restored bortezomib sensitivity in the bortezomib-resistant cell line.	('bortezomib', 'Chemical', 'MESH:D000069286', (191, 201))	('missense point mutation', 'Var', (2, 25))	('PSMB5', 'Gene', (66, 71))	('PSMB5', 'Gene', (135, 140))	('bortezomib', 'Chemical', 'MESH:D000069286', (161, 171))	('PSMB5', 'Gene', '5693', (66, 71))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('reduction', 'NegReg', (122, 131))	('restored', 'PosReg', (152, 160))	('expression', 'MPA', (141, 151))	('PSMB5', 'Gene', '5693', (135, 140))	('bortezomib', 'Chemical', 'MESH:D000069286', (72, 82))	('bortezomib sensitivity', 'MPA', (161, 183))
38796	21435101	SeV/DeltaF/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells.	('SeV', 'Species', '11191', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SeV/DeltaF/FIR', 'Var', (0, 14))	('tumor', 'Disease', (107, 112))	('reduced', 'NegReg', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell viability', 'CPA', (37, 51))
38798	21435101	In addition, SeV/DeltaF/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H.	('SeV', 'Species', '11191', (13, 16))	('MSTO-211H', 'CellLine', 'CVCL:1430', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SeV/DeltaF/FIR', 'Var', (13, 27))	('tumor', 'Disease', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
38799	21435101	Moreover, combination therapy with SeV/DeltaF/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model.	('improvement', 'PosReg', (110, 121))	('SeV', 'Species', '11191', (35, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor reduction', 'Disease', 'MESH:D007022', (90, 105))	('survival rate', 'CPA', (125, 138))	('SeV/DeltaF/FIR', 'Var', (35, 49))	('tumor reduction', 'Disease', (90, 105))
38800	21435101	Combination therapy with SeV/DeltaF/FIR plus cisplatin has therapeutic potential against HMPM.	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('SeV', 'Species', '11191', (25, 28))	('SeV/DeltaF/FIR', 'Var', (25, 39))	('HMPM', 'Disease', (89, 93))
38801	21435101	SeV/DeltaF/FIR plus cisplatin will be an attractive modality against HMPM in the future.	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('SeV', 'Species', '11191', (0, 3))	('HMPM', 'Disease', (69, 73))	('SeV/DeltaF/FIR', 'Var', (0, 14))
38820	21435101	Monolayer cells were washed twice with phosphate-buffered saline (PBS) and overlaid with serum-free medium containing SeV/DeltaF/GFP at a multiplicity of infection (MOI) of 0, 10, 100 and 1000.	('SeV/DeltaF/GFP', 'Var', (118, 132))	('infection', 'Disease', (154, 163))	('infection', 'Disease', 'MESH:D007239', (154, 163))	('SeV', 'Species', '11191', (118, 121))	('PBS', 'Chemical', '-', (66, 69))	('phosphate-buffered saline', 'Chemical', '-', (39, 64))
38824	21435101	In brief, the synthetic peptide C+KVVAEVYDQERFDNSDLSA (C+541-559; numbers indicate the amino acids of PUF60) was used as the immunization antigen.	('C+KVVAEVYDQERFDNSDLSA', 'Var', (32, 53))	('PUF60', 'Gene', (102, 107))	('PUF60', 'Gene', '22827', (102, 107))	('C+541-559;', 'Var', (55, 65))
38828	21435101	In brief, 3 x 103 cells/well from 211H, H2452, H226 and Met5A cell lines were seeded in 96-well plates and infected with SeV/DeltaF/GFP and SeV/DeltaF/FIR at 10, 100 and 1000 MOI.	('SeV', 'Species', '11191', (140, 143))	('SeV/DeltaF/FIR', 'Var', (140, 154))	('SeV', 'Species', '11191', (121, 124))	('infected', 'Disease', 'MESH:D007239', (107, 115))	('SeV/DeltaF/GFP', 'Var', (121, 135))	('infected', 'Disease', (107, 115))
38834	21435101	Calculated CI was used to ascertain the presence of synergism (CI < 1), an additive effect (CI = 1) or antagonism (CI > 1) between SeV/DeltaF/FIR and cisplatin.	('SeV/DeltaF/FIR', 'Var', (131, 145))	('additive', 'Interaction', (75, 83))	('synergism', 'MPA', (52, 61))	('SeV', 'Species', '11191', (131, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('antagonism', 'Interaction', (103, 113))
38843	21435101	SeV/DeltaF/FIR at 100 MOI significantly reduced the number of viable cancer cells (Movie S1) compared with SeV/DeltaF/GFP and the control (PBS; Fig.	('SeV', 'Species', '11191', (0, 3))	('SeV/DeltaF/FIR', 'Var', (0, 14))	('PBS', 'Chemical', '-', (139, 142))	('SeV', 'Species', '11191', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('reduced', 'NegReg', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
38849	21435101	1B,C), all the mesothelioma cells (211H, H2452 and H226) were more efficiently killed by SeV/DeltaF/FIR than SeV/DeltaF/GFP in a dose-dependent manner; however, this was not the case against the immortalized non-tumor mesothelial cells (Met5A; Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('SeV/DeltaF/FIR', 'Var', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mesothelioma', 'Disease', (15, 27))	('SeV', 'Species', '11191', (89, 92))	('SeV', 'Species', '11191', (109, 112))	('tumor', 'Disease', (212, 217))
38852	21435101	To determine whether SeV/DeltaF/FIR also induces apoptosis in HMPM cells, we examined the expression levels of FIR, c-Myc, caspase-3 and caspase-9 after SeV/DeltaF/FIR transduction (Fig.	('SeV', 'Species', '11191', (21, 24))	('SeV/DeltaF/FIR', 'Var', (21, 35))	('induces', 'Reg', (41, 48))	('transduction', 'biological_process', 'GO:0009293', ('168', '180'))	('SeV', 'Species', '11191', (153, 156))	('c-Myc', 'Gene', '4609', (116, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('c-Myc', 'Gene', (116, 121))
38853	21435101	As expected, SeV/DeltaF/FIR transduction increased FIR expression and decreased expressions of c-Myc and proforms of caspase-3 and caspase-9, but increased cleaved caspase-3 and caspase-9 expressions compared with SeV/DeltaF/GFP in all HMPM cells examined (Fig.	('expressions', 'MPA', (188, 199))	('c-Myc', 'Gene', (95, 100))	('FIR', 'Protein', (51, 54))	('SeV', 'Species', '11191', (13, 16))	('increased', 'PosReg', (41, 50))	('caspase-9', 'Gene', (131, 140))	('increased', 'PosReg', (146, 155))	('SeV/DeltaF/FIR transduction', 'Var', (13, 40))	('transduction', 'biological_process', 'GO:0009293', ('28', '40'))	('cleaved caspase-3', 'MPA', (156, 173))	('decreased', 'NegReg', (70, 79))	('expressions', 'MPA', (80, 91))	('c-Myc', 'Gene', '4609', (95, 100))	('SeV', 'Species', '11191', (214, 217))	('caspase-9', 'Enzyme', (178, 187))
38854	21435101	2C) indicated that SeV/DeltaF/FIR transduction induced apoptotic cells.	('SeV/DeltaF/FIR transduction', 'Var', (19, 46))	('transduction', 'biological_process', 'GO:0009293', ('34', '46'))	('apoptotic cells', 'CPA', (55, 70))	('induced', 'Reg', (47, 54))	('SeV', 'Species', '11191', (19, 22))
38857	21435101	If SeV/DeltaF/FIR can increase cisplatin cytotoxicity, combination therapy with SeV/DeltaF/FIR might reduce the dosage of cisplatin required for HMPM treatment.	('reduce', 'NegReg', (101, 107))	('SeV', 'Species', '11191', (3, 6))	('dosage of cisplatin', 'MPA', (112, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('SeV/DeltaF/FIR', 'Var', (3, 17))	('increase', 'PosReg', (22, 30))	('cytotoxicity', 'Disease', (41, 53))	('SeV', 'Species', '11191', (80, 83))	('SeV/DeltaF/FIR', 'Var', (80, 94))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
38859	21435101	SeV/DeltaF/FIR plus cisplatin caused a leftward shift of the dose response curve determined by the MTS assay (Fig.	('leftward shift', 'CPA', (39, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('SeV', 'Species', '11191', (0, 3))	('SeV/DeltaF/FIR', 'Var', (0, 14))
38863	21435101	Interestingly, the mice treated with the combination of SeV/DeltaF/FIR plus cisplatin only gained bodyweight on day 29 after tumor implantation (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('bodyweight', 'MPA', (98, 108))	('SeV', 'Species', '11191', (56, 59))	('SeV/DeltaF/FIR', 'Var', (56, 70))	('gained', 'PosReg', (91, 97))	('mice', 'Species', '10090', (19, 23))	('gained bodyweight', 'Phenotype', 'HP:0004324', (91, 108))
38865	21435101	SeV/DeltaF/FIR transduction induced acidophilic cells on HE staining that were revealed to be apoptotic by TUNEL assay (Fig.	('SeV', 'Species', '11191', (0, 3))	('transduction', 'biological_process', 'GO:0009293', ('15', '27'))	('HE', 'Chemical', '-', (57, 59))	('SeV/DeltaF/FIR transduction', 'Var', (0, 27))	('induced', 'Reg', (28, 35))	('acidophilic', 'MPA', (36, 47))
38877	21435101	However, when the viral amount was reduced to 1 x 107 CIU/body (10 MOI), SeV/DeltaF/FIR did not show a significant tumor reduction effect compared with SeV/DeltaF/GFP (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SeV', 'Species', '11191', (73, 76))	('SeV', 'Species', '11191', (152, 155))	('SeV/DeltaF/FIR', 'Var', (73, 87))	('tumor reduction', 'Disease', 'MESH:D007022', (115, 130))	('tumor reduction', 'Disease', (115, 130))
38878	21435101	During these experiments, no mouse died immediately after SeV/DeltaF/FIR or SeV/DeltaF/GFP injection.	('SeV', 'Species', '11191', (58, 61))	('died', 'Disease', 'MESH:D003643', (35, 39))	('died', 'Disease', (35, 39))	('SeV/DeltaF/FIR', 'Var', (58, 72))	('SeV', 'Species', '11191', (76, 79))	('mouse', 'Species', '10090', (29, 34))	('SeV/DeltaF/GFP', 'Var', (76, 90))
38879	21435101	In this study, we showed that SeV/DeltaF/FIR induced a significant antitumor effect on HMPM cells in a dose-dependent manner in vitro and in vivo.	('SeV/DeltaF/FIR', 'Var', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('SeV', 'Species', '11191', (30, 33))
38880	21435101	In addition, we identified the anti-tumor effect of SeV/DeltaF/FIR plus cisplatin against tumor growth without significant side-effects in an orthotopic xenograft mesothelioma mouse model.	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mouse', 'Species', '10090', (176, 181))	('mesothelioma', 'Disease', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SeV', 'Species', '11191', (52, 55))	('SeV/DeltaF/FIR', 'Var', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
38881	21435101	Sendai virus has a high gene transduction capacity, and SeV/DeltaF/GFP showed high transduction efficiency in three different HMPM cell lines (Fig.	('Sendai virus', 'Species', '11191', (0, 12))	('transduction', 'MPA', (83, 95))	('gene transduction capacity', 'MPA', (24, 50))	('SeV', 'Species', '11191', (56, 59))	('transduction', 'biological_process', 'GO:0009293', ('83', '95'))	('SeV/DeltaF/GFP', 'Var', (56, 70))	('transduction', 'biological_process', 'GO:0009293', ('29', '41'))
38882	21435101	In the present study, SeV/DeltaF/FIR activated caspase-3 and caspase-9 and decreased c-Myc expression in three different HMPM cell lines (Fig.	('c-Myc', 'Gene', (85, 90))	('caspase-3', 'Enzyme', (47, 56))	('activated', 'PosReg', (37, 46))	('decreased', 'NegReg', (75, 84))	('SeV', 'Species', '11191', (22, 25))	('c-Myc', 'Gene', '4609', (85, 90))	('caspase-9', 'Enzyme', (61, 70))	('SeV/DeltaF/FIR', 'Var', (22, 36))
38883	21435101	In addition, histological observations indicated that SeV/DeltaF/FIR suppressed tumor growth by apoptosis (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SeV/DeltaF/FIR', 'Var', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('apoptosis', 'CPA', (96, 105))	('suppressed', 'NegReg', (69, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('SeV', 'Species', '11191', (54, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
38892	21435101	Thus, FIR might alter cisplatin sensitivity by P89 and/or c-Myc suppression because the synergistic effect of SeV/DeltaF/FIR plus cisplatin is quite evident (Figs 2E,3C, Table 2).	('cisplatin sensitivity', 'MPA', (22, 43))	('alter', 'Reg', (16, 21))	('c-Myc', 'Gene', (58, 63))	('SeV', 'Species', '11191', (110, 113))	('SeV/DeltaF/FIR', 'Var', (110, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('suppression', 'NegReg', (64, 75))	('P89', 'Var', (47, 50))	('c-Myc', 'Gene', '4609', (58, 63))
38894	21435101	As SeV/DeltaF/FIR targets c-Myc, SeV/DeltaF/FIR is expected to have a greater influence on cancer cells than normal cells.	('SeV', 'Species', '11191', (3, 6))	('SeV', 'Species', '11191', (33, 36))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('c-Myc', 'Gene', '4609', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SeV/DeltaF/FIR', 'Var', (33, 47))	('c-Myc', 'Gene', (26, 31))
38895	21435101	As expected, SeV/DeltaF/FIR had less toxicity in non-tumor immortalized mesothelial cells (Met5A), which indicated low c- Myc expression (Fig.	('toxicity', 'Disease', (37, 45))	('SeV', 'Species', '11191', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SeV/DeltaF/FIR', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('c- Myc', 'Gene', '4609', (119, 125))	('c- Myc', 'Gene', (119, 125))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))	('low', 'NegReg', (115, 118))
38897	21435101	In conclusion, our data clearly indicate that SeV/DeltaF/FIR has significant therapeutic potential against HMPM.	('HMPM', 'Disease', (107, 111))	('SeV', 'Species', '11191', (46, 49))	('SeV/DeltaF/FIR', 'Var', (46, 60))
38898	21435101	Furthermore, combination therapy with SeV/DeltaF/FIR plus cisplatin significantly enhanced the antitumor effect in vitro and in vivo.	('tumor', 'Disease', (99, 104))	('enhanced', 'PosReg', (82, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('SeV', 'Species', '11191', (38, 41))	('SeV/DeltaF/FIR', 'Var', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
38931	32517259	In order to evaluate the mechanisms associated with the response of MPM to chemotherapy, the viability of different cell lines (M14K, M38K, ZL34 and H28) in response to the VPA HDAC inhibitor and/or the doxorubicin anthracyclin was compared.	('M14K', 'SUBSTITUTION', 'None', (128, 132))	('M14K', 'Var', (128, 132))	('anthracyclin', 'Chemical', '-', (215, 227))	('HDAC', 'Gene', (177, 181))	('HDAC', 'Gene', '9734', (177, 181))	('M38K', 'Var', (134, 138))	('VPA', 'Chemical', 'MESH:D014635', (173, 176))	('doxorubicin', 'Chemical', 'MESH:D004317', (203, 214))	('MPM', 'Chemical', '-', (68, 71))	('M38K', 'SUBSTITUTION', 'None', (134, 138))
38934	32517259	In contrast to M14K, M38K and ZL34, H28 cells were unresponsive to VPA and doxorubicin (Supplementary Materials Figure S2).	('M38K', 'SUBSTITUTION', 'None', (21, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (75, 86))	('M14K', 'SUBSTITUTION', 'None', (15, 19))	('M14K', 'Var', (15, 19))	('VPA', 'Chemical', 'MESH:D014635', (67, 70))	('M38K', 'Var', (21, 25))
38936	32517259	Cell cycle analysis confirmed that a combination of doxorubicin (100 nM) and VPA (2 mM) was able to significantly induce apoptosis in M14K cells but not in H28 cells (Figure 1a).	('VPA', 'Chemical', 'MESH:D014635', (77, 80))	('induce', 'PosReg', (114, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('M14K', 'SUBSTITUTION', 'None', (134, 138))	('apoptosis', 'CPA', (121, 130))	('M14K', 'Var', (134, 138))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('doxorubicin', 'Chemical', 'MESH:D004317', (52, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
38942	32517259	Of note, the multidrug resistance pathway was enriched neither in M14K nor in H28 cells (Supplementary Materials Figure S3).	('M14K', 'SUBSTITUTION', 'None', (66, 70))	('multidrug resistance pathway', 'Pathway', (13, 41))	('M14K', 'Var', (66, 70))
38949	32517259	Similarly, an increase in apoptosis was also observed in the chemosensitive M14K cells when TGFalpha expression was reduced (Figure 2a).	('TGFalpha', 'Gene', (92, 100))	('M14K', 'SUBSTITUTION', 'None', (76, 80))	('apoptosis', 'CPA', (26, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('M14K', 'Var', (76, 80))	('reduced', 'NegReg', (116, 123))
38950	32517259	Conversely, increasing the expression of TGFalpha led to a significant decrease in the apoptosis induced by doxorubicin-VPA in M14K cells (Figure 2b).	('increasing', 'PosReg', (12, 22))	('decrease', 'NegReg', (71, 79))	('TGFalpha', 'Gene', (41, 49))	('expression', 'MPA', (27, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'MPA', (87, 96))	('M14K', 'SUBSTITUTION', 'None', (127, 131))	('M14K', 'Var', (127, 131))	('doxorubicin-VPA', 'Chemical', '-', (108, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
38954	32517259	The apoptotic response was measured in three mesothelioma cell lines (M14K, H28 and ZL34).	('M14K', 'SUBSTITUTION', 'None', (70, 74))	('mesothelioma', 'Disease', (45, 57))	('apoptotic response', 'CPA', (4, 22))	('M14K', 'Var', (70, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))
38956	32517259	In particular, both EGFR TKIs could synergize with doxorubicin-VPA to significantly enhance apoptosis in chemoresistant H28 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'CPA', (92, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('EGFR TKIs', 'Var', (20, 29))	('doxorubicin-VPA', 'Chemical', '-', (51, 66))	('enhance', 'PosReg', (84, 91))
38962	32517259	The toxicity of CUDC-101 was evaluated by assessing the metabolic activity in H28, M14K and ZL34 cells (see dose response in the MTS assay in Supplementary Materials Figure S5).	('M14K', 'SUBSTITUTION', 'None', (83, 87))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('M14K', 'Var', (83, 87))	('CUDC-101', 'Chemical', 'MESH:C549566', (16, 24))	('metabolic activity', 'MPA', (56, 74))	('toxicity', 'Disease', (4, 12))
38964	32517259	As expected, the phosphorylation of HER2 and EGFR, as well as the phosphorylation of EGFR downstream proteins (AKT and STAT1), were inhibited by CUDC-101 in H28 cells (Figure 4a).	('AKT', 'Gene', '207', (111, 114))	('inhibited', 'NegReg', (132, 141))	('EGFR', 'Gene', (85, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('STAT1', 'Gene', '6772', (119, 124))	('EGFR', 'Gene', (45, 49))	('CUDC-101', 'Chemical', 'MESH:C549566', (145, 153))	('phosphorylation', 'MPA', (17, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('phosphorylation', 'MPA', (66, 81))	('HER2', 'Protein', (36, 40))	('CUDC-101', 'Var', (145, 153))	('AKT', 'Gene', (111, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('STAT1', 'Gene', (119, 124))
38966	32517259	As a single agent, CUDC-101 was unable to induce apoptosis but synergized with doxorubicin to significantly increase apoptosis in three MPM cell lines (H28, M14K and ZL34) (Figure 4b).	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('CUDC-101', 'Chemical', 'MESH:C549566', (19, 27))	('increase', 'PosReg', (108, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('apoptosis', 'MPA', (117, 126))	('M14K', 'SUBSTITUTION', 'None', (157, 161))	('MPM', 'Chemical', '-', (136, 139))	('M14K', 'Var', (157, 161))
38973	32517259	In the epithelial M14K subtype, tumor growth was almost completely inhibited.	('M14K', 'SUBSTITUTION', 'None', (18, 22))	('M14K', 'Var', (18, 22))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
38977	32517259	As expected, the stratification of survival rates revealed that patients with partial/complete response with low TGFalpha expression survived for longer compared to those with stable/progressive diseases (Kaplan-Meier in Supplementary Materials Figure S8).	('TGFalpha', 'Gene', (113, 121))	('expression', 'MPA', (122, 132))	('patients', 'Species', '9606', (64, 72))	('progressive disease', 'Disease', 'MESH:D018450', (183, 202))	('progressive disease', 'Disease', (183, 202))	('low', 'Var', (109, 112))
38987	32517259	Conversely, the overexpression of TGFalpha reduced the chemosensitivity of M14K cells.	('overexpression', 'PosReg', (16, 30))	('TGFalpha', 'Gene', (34, 42))	('M14K', 'SUBSTITUTION', 'None', (75, 79))	('reduced', 'NegReg', (43, 50))	('M14K', 'Var', (75, 79))
38988	32517259	Our data show that EGFR inhibitors improve the therapeutic response to VPA and doxorubicin.	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('inhibitors', 'Var', (24, 34))	('improve', 'PosReg', (35, 42))	('EGFR', 'Gene', (19, 23))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('VPA', 'Chemical', 'MESH:D014635', (71, 74))
38994	32517259	Furthermore, the effect of MET or COX-2 inhibitors was improved by anti-EGFR TKIs in vitro.	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('improved', 'PosReg', (55, 63))	('anti-EGFR', 'Var', (67, 76))	('effect', 'MPA', (17, 23))	('COX-2', 'Gene', '4513', (34, 39))	('COX-2', 'Gene', (34, 39))
39012	32517259	As observed in the mouse model, it is predicted that a combination of doxorubicin, VPA and EGFR/HER2 inhibitors may also benefit relapsing or unresponsive mesothelioma patients, providing that toxicity issues are controlled.	('inhibitors', 'Var', (101, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('EGFR/HER2', 'Gene', (91, 100))	('mouse', 'Species', '10090', (19, 24))	('mesothelioma', 'Disease', (155, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('benefit', 'PosReg', (121, 128))	('toxicity', 'Disease', 'MESH:D064420', (193, 201))	('VPA', 'Chemical', 'MESH:D014635', (83, 86))	('patients', 'Species', '9606', (168, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('VPA', 'Protein', (83, 86))	('toxicity', 'Disease', (193, 201))
39018	32517259	Human (NCI-H2452, H28, M14K, M38K, MSTO-211H, SPC111, SPC212, ZL5, ZL34 and ZL55) and murine mesothelioma cells (AB12, see Vandermeers et al.)	('Human', 'Species', '9606', (0, 5))	('SPC', 'molecular_function', 'GO:0009004', ('46', '49'))	('murine', 'Species', '10090', (86, 92))	('M38K', 'Var', (29, 33))	('ZL5', 'Gene', (76, 79))	('ZL5', 'Gene', '106633808', (76, 79))	('mesothelioma', 'Disease', (93, 105))	('NCI-H2452', 'CellLine', 'CVCL:1553', (7, 16))	('M14K', 'SUBSTITUTION', 'None', (23, 27))	('M38K', 'SUBSTITUTION', 'None', (29, 33))	('M14K', 'Var', (23, 27))	('SPC', 'molecular_function', 'GO:0009004', ('54', '57'))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('SPC212', 'CellLine', 'CVCL:D312', (54, 60))	('ZL5', 'Gene', (62, 65))	('ZL5', 'Gene', '106633808', (62, 65))
39019	32517259	were cultured in RPMI 1640 (or in DMEM for M14K and M38K), supplemented with 10% fetal calf serum (FCS), 2 mM L-glutamine and antibiotics (penicillin-streptomycin).	('M38K', 'SUBSTITUTION', 'None', (52, 56))	('M14K', 'Var', (43, 47))	('M14K', 'SUBSTITUTION', 'None', (43, 47))	('M38K', 'Var', (52, 56))
39025	32517259	RNA was isolated from M14K and H28 cells using the RNeasy Mini Kit (QIAGEN, Hilden, Germany) and then treated with DNase with a DNA-free DNA Removal Kit (Thermo Fisher Scientific, Waltham, MA, USA).	('Kit', 'Gene', (149, 152))	('Kit', 'Gene', '3815', (63, 66))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('Kit', 'Gene', '3815', (149, 152))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('M14K', 'SUBSTITUTION', 'None', (22, 26))	('M14K', 'Var', (22, 26))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('Kit', 'Gene', (63, 66))
39047	32517259	Blotted proteins were labeled overnight at 4  C with primary antibodies: phospho-EGF Receptor (Tyr1068 D7A5), phospho-HER2/ERBB2 (Tyr1248), HER2/ERBB2 (D8F12), acetyl-Histone H3 (Lys9/Lys14) and heat-shock protein 90 (from Cell Signaling Technology, Danvers, MA, USA) and phospho-STAT1 (Tyr701) and phospho-AKT (Thr308) (from Abcam, Cambridge, UK).	('EGF', 'molecular_function', 'GO:0005154', ('81', '84'))	('EGF', 'Gene', (81, 84))	('AKT', 'Gene', (307, 310))	('shock', 'Phenotype', 'HP:0031273', (200, 205))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('EGF', 'Gene', '1950', (81, 84))	('Signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('Tyr1068 D7A5', 'Var', (95, 107))	('ERBB2', 'Gene', '2064', (123, 128))	('heat-shock protein 90', 'Gene', (195, 216))	('ERBB2', 'Gene', (123, 128))	('Tyr1248', 'Var', (130, 137))	('STAT1', 'Gene', (280, 285))	('heat-shock protein 90', 'Gene', '3320', (195, 216))	('ERBB2', 'Gene', (145, 150))	('ERBB2', 'Gene', '2064', (145, 150))	('AKT', 'Gene', '207', (307, 310))	('STAT1', 'Gene', '6772', (280, 285))
39059	32517259	Figure S1: Metabolic activity of MPM cell lines in the presence of doxorubicin and/or VPA, Figure S2: Apoptosis of MPM cell lines in the presence of doxorubicin and/or VPA, Figure S3: Enrichment plot of multidrug resistance pathway gene set using GSEA on the transcriptomic data of M14K and H28 cells, Figure S4: VPA + doxorubicin induced apoptosis upon transduction with a second TGFalpha shRNA, Figure S5: Metabolic activity of MPM cell lines in the presence of CUDC-101, Figure S6: Immunoblotting intensity ratios, Figure S7: Original immunoblots, Figure S8: Stratification of survival rates based on response to treatment and TGFalpha expression, Table S1: Genes differentially expressed in M14K and H28 cells with a log2 fold change > 6, Table S2: Levels of VPA-doxorubicin-induced apoptosis and TGF-alpha expression in 10 MPM cell lines.	('doxorubicin', 'Chemical', 'MESH:D004317', (319, 330))	('TGF-alpha', 'Gene', (801, 810))	('apoptosis', 'biological_process', 'GO:0097194', ('787', '796'))	('apoptosis', 'biological_process', 'GO:0006915', ('787', '796'))	('M14K', 'Var', (695, 699))	('VPA', 'Chemical', 'MESH:D014635', (313, 316))	('doxorubicin', 'Chemical', 'MESH:D004317', (149, 160))	('apoptosis', 'biological_process', 'GO:0097194', ('339', '348'))	('VPA', 'Chemical', 'MESH:D014635', (168, 171))	('apoptosis', 'biological_process', 'GO:0006915', ('339', '348'))	('M14K', 'Var', (282, 286))	('MPM', 'Chemical', '-', (115, 118))	('M14K', 'SUBSTITUTION', 'None', (695, 699))	('VPA', 'Chemical', 'MESH:D014635', (763, 766))	('M14K', 'SUBSTITUTION', 'None', (282, 286))	('MPM', 'Chemical', '-', (430, 433))	('doxorubicin', 'Chemical', 'MESH:D004317', (767, 778))	('MPM', 'Chemical', '-', (828, 831))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('CUDC-101', 'Chemical', 'MESH:C549566', (464, 472))	('VPA', 'Chemical', 'MESH:D014635', (86, 89))	('TGF-alpha', 'Gene', '7039', (801, 810))	('MPM', 'Chemical', '-', (33, 36))	('transduction', 'biological_process', 'GO:0009293', ('354', '366'))
39100	30965570	Loss of WT1 results in reduced cardiomyocyte mass, pericardial hemorrhage, thinning of the myocardial wall, and embryonic lethality.	('embryonic lethality', 'Disease', (112, 131))	('thinning of the myocardial wall', 'CPA', (75, 106))	('pericardial hemorrhage', 'Disease', (51, 73))	('embryonic lethality', 'Disease', 'MESH:D020964', (112, 131))	('pericardial hemorrhage', 'Phenotype', 'HP:0001698', (51, 73))	('pericardial hemorrhage', 'Disease', 'MESH:D006470', (51, 73))	('WT1', 'Gene', (8, 11))	('reduced', 'NegReg', (23, 30))	('Loss', 'Var', (0, 4))	('cardiomyocyte mass', 'CPA', (31, 49))
39101	30965570	Mutations in the WT1 gene have also been associated with pulmonary dysplasia, hypoplastic lung malformation, diaphragmatic hernia, decreased mesothelial cell entry into the lung, and mesothelioma.	('pulmonary dysplasia', 'Disease', (57, 76))	('hypoplastic lung malformation', 'Disease', 'MESH:D000014', (78, 107))	('hernia', 'Disease', 'MESH:D006547', (123, 129))	('diaphragmatic hernia', 'Phenotype', 'HP:0000776', (109, 129))	('associated', 'Reg', (41, 51))	('hypoplastic lung', 'Phenotype', 'HP:0002089', (78, 94))	('hypoplastic lung malformation', 'Disease', (78, 107))	('hernia', 'Phenotype', 'HP:0100790', (123, 129))	('WT1', 'Gene', (17, 20))	('decreased', 'NegReg', (131, 140))	('mesothelioma', 'Disease', (183, 195))	('Mutations', 'Var', (0, 9))	('lung malformation', 'Phenotype', 'HP:0002088', (90, 107))	('pulmonary dysplasia', 'Disease', 'MESH:D008171', (57, 76))	('hernia', 'Disease', (123, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))
39104	30965570	Deletion of WT1 results in loss of hepatic mesothelial expression of the retinoic acid (RA) synthesizing enzyme, RALDH2.	('hepatic mesothelial expression', 'MPA', (35, 65))	('RA', 'Chemical', 'MESH:D014212', (113, 115))	('Deletion', 'Var', (0, 8))	('retinoic acid', 'Chemical', 'MESH:D014212', (73, 86))	('loss', 'NegReg', (27, 31))	('RA', 'Chemical', 'MESH:D014212', (88, 90))	('WT1', 'Gene', (12, 15))
39110	30965570	In the liver, the relationship between RA signaling and WT1 has been explored using the WT1 knockout mouse; loss of WT1 results in loss of hepatic mesothelial expression of RALDH2.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('loss', 'Var', (108, 112))	('hepatic mesothelial expression', 'MPA', (139, 169))	('loss', 'NegReg', (131, 135))	('mouse', 'Species', '10090', (101, 106))	('WT1', 'Gene', (116, 119))	('RA', 'Chemical', 'MESH:D014212', (39, 41))	('RA', 'Chemical', 'MESH:D014212', (173, 175))	('RALDH2', 'Gene', (173, 179))
39114	30965570	Disruption of the expression of IGF2 or its receptors leads to decreased myocardial proliferation in mice.	('decreased myocardial proliferation', 'Disease', 'MESH:D009202', (63, 97))	('IGF2', 'Gene', (32, 36))	('mice', 'Species', '10090', (101, 105))	('decreased myocardial proliferation', 'Disease', (63, 97))	('Disruption', 'Var', (0, 10))
39126	30965570	Mice deficient for FGF9 develop a shortened small intestine due to both decreased mesenchymal proliferation and premature differentiation.	('mesenchymal proliferation', 'CPA', (82, 107))	('rat', 'Species', '10116', (101, 104))	('decreased', 'NegReg', (72, 81))	('FGF9', 'Gene', (19, 23))	('premature differentiation', 'CPA', (112, 137))	('Mice', 'Species', '10090', (0, 4))	('develop a shortened small intestine', 'Phenotype', 'HP:0030889', (24, 59))	('deficient', 'Var', (5, 14))
39215	30965570	In addition, it has been shown that asbestos fibers can also cause necrosis of mesothelial cells resulting in the release of High Molecular Group Binding protein 1 (HMGB1), promoting an inflammatory response and the accumulation of TNF-alpha producing macrophages.	('High Molecular Group Binding protein 1', 'Gene', '3146', (125, 163))	('asbestos fibers', 'Var', (36, 51))	('HMGB1', 'Gene', (165, 170))	('inflammatory response', 'CPA', (186, 207))	('HMGB1', 'Gene', '3146', (165, 170))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('promoting', 'PosReg', (173, 182))	('necrosis', 'biological_process', 'GO:0008219', ('67', '75'))	('accumulation', 'PosReg', (216, 228))	('necrosis', 'biological_process', 'GO:0008220', ('67', '75'))	('release', 'MPA', (114, 121))	('necrosis', 'biological_process', 'GO:0070265', ('67', '75'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('TNF-alpha', 'Gene', '7124', (232, 241))	('High Molecular Group Binding protein 1', 'Gene', (125, 163))	('necrosis', 'biological_process', 'GO:0019835', ('67', '75'))	('TNF-alpha', 'Gene', (232, 241))	('necrosis', 'biological_process', 'GO:0001906', ('67', '75'))	('necrosis', 'Disease', 'MESH:D009336', (67, 75))	('necrosis', 'Disease', (67, 75))	('inflammatory response', 'biological_process', 'GO:0006954', ('186', '207'))
39247	30965570	Malignant mesothelioma has also been associated with recurrent deletions in specific chromosomal regions, including 1p, 3p, 6q, 9p, and 22q.	('deletions', 'Var', (63, 72))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('associated', 'Reg', (37, 47))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))
39248	30965570	The chromosomal deletions 9p21 and the 22q12 are well described as they lead to alterations of known signaling pathways crucial for maintaining cellular integrity through regulation of the cell cycle, cellular growth, and apoptosis during the establishment and progression of mesothelioma.	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('cellular growth', 'biological_process', 'GO:0016049', ('201', '216'))	('cell cycle', 'biological_process', 'GO:0007049', ('189', '199'))	('mesothelioma', 'Disease', 'MESH:D008654', (276, 288))	('apoptosis', 'CPA', (222, 231))	('rat', 'Species', '10116', (84, 87))	('cell cycle', 'CPA', (189, 199))	('men', 'Species', '9606', (252, 255))	('deletions 9p21', 'Var', (16, 30))	('regulation', 'Reg', (171, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))	('mesothelioma', 'Disease', (276, 288))	('cellular growth', 'CPA', (201, 216))	('signaling pathways', 'Pathway', (101, 119))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('regulation', 'biological_process', 'GO:0065007', ('171', '181'))	('alterations', 'Reg', (80, 91))
39249	30965570	The coding region for CDKN2A is located in the 9p21 locus and its deletion leads to loss of p16INK4A, which is a critical cyclin-dependent kinase (CDK) inhibitor.	('p16INK4A', 'Protein', (92, 100))	('CDK) inhibitor', 'molecular_function', 'GO:0004861', ('147', '161'))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('loss', 'NegReg', (84, 88))	('deletion', 'Var', (66, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('122', '128'))
39251	30965570	The loss of p16INK4A is associated with activation of the CDK4 and CDK6 which leads to inactivation of pRB and results in a feed-forward cycle as CDK4 becomes hyperphosphorylated leading to more activation.	('results in', 'Reg', (111, 121))	('CDK4', 'Gene', '12567', (146, 150))	('pRB', 'Gene', '18667', (103, 106))	('inactivation', 'MPA', (87, 99))	('CDK6', 'Gene', (67, 71))	('CDK4', 'Gene', '12567', (58, 62))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('CDK', 'molecular_function', 'GO:0004693', ('146', '149'))	('activation', 'PosReg', (40, 50))	('pRB', 'Gene', (103, 106))	('CDK6', 'Gene', '12571', (67, 71))	('CDK', 'molecular_function', 'GO:0004693', ('67', '70'))	('activation', 'PosReg', (195, 205))	('feed-forward cycle', 'MPA', (124, 142))	('CDK4', 'Gene', (58, 62))	('p16INK4A', 'Gene', (12, 20))	('CDK4', 'Gene', (146, 150))	('loss', 'Var', (4, 8))
39253	30965570	Loss of p14ARF leads to the activation of MDM2 resulting in a destabilization of p53 and eventually its degradation.	('degradation', 'MPA', (104, 115))	('p14ARF', 'Gene', '1029', (8, 14))	('p53', 'Protein', (81, 84))	('activation', 'PosReg', (28, 38))	('MDM2', 'Gene', (42, 46))	('p14ARF', 'Gene', (8, 14))	('destabilization', 'MPA', (62, 77))	('Loss', 'Var', (0, 4))	('degradation', 'biological_process', 'GO:0009056', ('104', '115'))
39255	30965570	The high frequency of deletion of the 9p21 locus observed in patients with mesothelioma is linked with increased malignancy.	('increased malignancy', 'Disease', (103, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('deletion', 'Var', (22, 30))	('patients', 'Species', '9606', (61, 69))	('increased malignancy', 'Disease', 'MESH:D009369', (103, 123))	('9p21', 'Gene', (38, 42))	('mesothelioma', 'Disease', (75, 87))
39259	30965570	The phosphorylation of YAP prevents its entry to the nucleus and leads to its degradation.	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('YAP', 'Gene', '10413', (23, 26))	('leads to', 'Reg', (65, 73))	('entry to the nucleus', 'MPA', (40, 60))	('prevents', 'NegReg', (27, 35))	('nucleus', 'cellular_component', 'GO:0005634', ('53', '60'))	('degradation', 'MPA', (78, 89))	('degradation', 'biological_process', 'GO:0009056', ('78', '89'))	('YAP', 'Gene', (23, 26))	('phosphorylation', 'Var', (4, 19))
39260	30965570	When Merlin is lost following a deletion of the 22q12 region, the cascade of phosphorylation in the Hippo pathways is lost as well, and YAP is able to enter the nucleus where it regulates genes involved in cell proliferation and death.	('nucleus', 'cellular_component', 'GO:0005634', ('161', '168'))	('YAP', 'Gene', (136, 139))	('deletion', 'Var', (32, 40))	('Hippo pathways', 'Pathway', (100, 114))	('lost', 'NegReg', (15, 19))	('Merlin', 'Gene', '4771', (5, 11))	('cell proliferation', 'biological_process', 'GO:0008283', ('206', '224'))	('Merlin', 'Gene', (5, 11))	('cell', 'CPA', (206, 210))	('regulates', 'Reg', (178, 187))	('genes', 'Gene', (188, 193))	('cascade of phosphorylation', 'MPA', (66, 92))	('rat', 'Species', '10116', (218, 221))	('YAP', 'Gene', '10413', (136, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('lost', 'NegReg', (118, 122))	('death', 'Disease', 'MESH:D003643', (229, 234))	('death', 'Disease', (229, 234))
39261	30965570	Studies have also revealed a loss of and/or mutations for several components of the Hippo pathway (e.g., YAP, NF2, LATS2, and RASSF1) in mesothelioma.	('NF2', 'Gene', '4771', (110, 113))	('YAP', 'Gene', '10413', (105, 108))	('NF2', 'Gene', (110, 113))	('Hippo pathway', 'Pathway', (84, 97))	('RASSF1', 'Gene', '11186', (126, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('loss', 'NegReg', (29, 33))	('RASSF1', 'Gene', (126, 132))	('mutations', 'Var', (44, 53))	('YAP', 'Gene', (105, 108))	('LATS2', 'Gene', (115, 120))	('LATS2', 'Gene', '26524', (115, 120))	('mesothelioma', 'Disease', (137, 149))
39262	30965570	Modification of the Hippo pathway appears to be a key event in the carcinogenesis of mesothelioma.	('carcinogenesis of mesothelioma', 'Disease', 'MESH:D063646', (67, 97))	('Modification', 'Var', (0, 12))	('Hippo pathway', 'Pathway', (20, 33))	('carcinogenesis of mesothelioma', 'Disease', (67, 97))
39278	25798586	Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified.	('CDKN2A', 'Gene', '1029', (51, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('LATS2', 'Gene', (59, 64))	('Mutations', 'Var', (0, 9))	('NF2', 'Gene', (46, 49))	('LATS2', 'Gene', '26524', (59, 64))	('CDKN2A', 'Gene', (51, 57))	('mesothelioma', 'Disease', (19, 31))	('NF2', 'Gene', '4771', (46, 49))
39279	25798586	A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease.	('single nucleotide variants', 'Var', (62, 88))	('sarcomatoid', 'Disease', 'MESH:C538614', (143, 154))	('multifocal disease', 'Disease', (169, 187))	('multifocal disease', 'Disease', 'None', (169, 187))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (143, 164))	('sarcomatoid', 'Disease', (143, 154))	('associated', 'Reg', (98, 108))
39291	25798586	Homozygous deletion of the 9p21 region has been described in a subset of body cavity mesotheliomas and can be useful for diagnosis and prognosis.	('mesotheliomas', 'Disease', (85, 98))	('described', 'Reg', (48, 57))	('Homozygous deletion', 'Var', (0, 19))	('9p21', 'Gene', (27, 31))	('mesotheliomas', 'Disease', 'MESH:D008654', (85, 98))
39294	25798586	Germline mutations in BAP1 are known to predispose carriers to mesothelioma, and other malignancies such as uveal melanoma and clear cell renal carcinoma.	('Germline mutations', 'Var', (0, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('renal carcinoma', 'Phenotype', 'HP:0005584', (138, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('mesothelioma', 'Disease', (63, 75))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (127, 153))	('clear cell renal carcinoma', 'Disease', (127, 153))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('predispose', 'Reg', (40, 50))	('BAP1', 'Gene', '8314', (22, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (127, 153))	('malignancies', 'Disease', (87, 99))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('BAP1', 'Gene', (22, 26))
39299	25798586	Whole-genome analyses of pleural mesothelioma have identified a number of single-nucleotide variations (SNVs), as well as gross chromosomal alterations.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (25, 45))	('pleural mesothelioma', 'Disease', (25, 45))	('single-nucleotide variations', 'Var', (74, 102))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (25, 45))
39317	25798586	Whole-genome sequencing (107X tumor and 40X germline depth of coverage) identified a somatic frameshifting mutation in NF2 (Y177fs, COSM23800), as well as somatic SNVs in SOCS3 (N92K), an inhibitor of JAK2 tyrosine kinase; TET3 (R870G), a gene involved in chromatin remodeling; and TFPT (G128W) a promoter of apoptosis (Table 1).	('JAK2', 'Gene', (201, 205))	('NF2', 'Gene', '4771', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Y177fs', 'Mutation', 'p.Y177fsX', (124, 130))	('NF2', 'Gene', (119, 122))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('256', '276'))	('TFPT', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('frameshifting mutation', 'Var', (93, 115))	('chromatin', 'cellular_component', 'GO:0000785', ('256', '265'))	('R870G', 'Mutation', 'p.R870G', (229, 234))	('SOCS3', 'Gene', (171, 176))	('JAK', 'molecular_function', 'GO:0004713', ('201', '204'))	('G128W', 'Mutation', 'p.G128W', (288, 293))	('N92K', 'Mutation', 'p.N92K', (178, 182))	('TFPT', 'Gene', '29844', (282, 286))	('JAK2', 'Gene', '3717', (201, 205))	('SOCS3', 'Gene', '9021', (171, 176))	('TET3', 'Gene', '200424', (223, 227))	('Y177fs', 'Var', (124, 130))	('TET3', 'Gene', (223, 227))	('apoptosis', 'biological_process', 'GO:0097194', ('309', '318'))	('apoptosis', 'biological_process', 'GO:0006915', ('309', '318'))	('tumor', 'Disease', (30, 35))
39333	25798586	Targeted panel sequencing identified a missense mutation in the smoothened gene (SMO V210M, COSM364081), a member of the hedgehog signaling pathway previously implicated in pleural mesothelioma.	('pleural mesothelioma', 'Disease', (173, 193))	('V210M', 'Mutation', 'rs1247135717', (85, 90))	('COSM364081', 'Gene', (92, 102))	('hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('121', '147'))	('SMO', 'Gene', '6608', (81, 84))	('SMO', 'Gene', (81, 84))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (173, 193))	('missense mutation', 'Var', (39, 56))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (173, 193))
39334	25798586	A nonsense mutation in p53 (R213*, COSM10654), and a nonsense mutation in CDKN2A (R58*, COSM12473); the mutation in CDKN2A was identified only in the chemotherapy-resistant right colon nodule.	('R58*', 'Var', (82, 86))	('R58*', 'SUBSTITUTION', 'None', (82, 86))	('CDKN2A', 'Gene', (116, 122))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (116, 122))	('R213*', 'Var', (28, 33))	('COSM10654', 'Var', (35, 44))	('R213*', 'SUBSTITUTION', 'None', (28, 33))	('CDKN2A', 'Gene', '1029', (74, 80))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('COSM12473)', 'Var', (88, 98))
39338	25798586	Additionally, a nonsense mutation in NF2 (R466*, COSM23667) was identified in both samples.	('NF2', 'Gene', '4771', (37, 40))	('R466*', 'SUBSTITUTION', 'None', (42, 47))	('R466*', 'Var', (42, 47))	('NF2', 'Gene', (37, 40))	('COSM23667', 'Var', (49, 58))
39339	25798586	A novel missense mutation in LATS2 (R958H) was identified in both samples, affecting a highly conserved residue of the tumor suppressor protein.	('LATS2', 'Gene', '26524', (29, 34))	('tumor', 'Disease', (119, 124))	('affecting', 'Reg', (75, 84))	('R958H', 'Mutation', 'rs765566250', (36, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('highly conserved residue of the', 'MPA', (87, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('missense mutation', 'Var', (8, 25))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('R958H', 'Var', (36, 41))	('LATS2', 'Gene', (29, 34))
39340	25798586	Another novel missense mutation in NOTCH1 (P2097L) was also identified in both samples affecting a highly conserved region of the cell-surface receptor that has also been previously implicated in mesothelioma by activating the PI3K-mTOR cell-signaling pathway (Table 1).	('mesothelioma', 'Disease', (196, 208))	('P2097L', 'Mutation', 'p.P2097L', (43, 49))	('cell-surface', 'cellular_component', 'GO:0009986', ('130', '142'))	('activating', 'PosReg', (212, 222))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('affecting', 'Reg', (87, 96))	('mTOR', 'Gene', (232, 236))	('implicated', 'Reg', (182, 192))	('mTOR', 'Gene', '2475', (232, 236))	('PI3K', 'molecular_function', 'GO:0016303', ('227', '231'))	('NOTCH1', 'Gene', '4851', (35, 41))	('NOTCH1', 'Gene', (35, 41))	('signaling pathway', 'biological_process', 'GO:0007165', ('242', '259'))	('P2097L', 'Var', (43, 49))
39350	25798586	Comparing patients 1 and 2, similarities include loss-of-function mutations in NF2, a well-characterized tumor suppressor gene that is frequently inactivated in mesotheliomas.	('mutations', 'Var', (66, 75))	('mesotheliomas', 'Disease', (161, 174))	('NF2', 'Gene', (79, 82))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('loss-of-function', 'NegReg', (49, 65))	('NF2', 'Gene', '4771', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('patients', 'Species', '9606', (10, 18))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('mesotheliomas', 'Disease', 'MESH:D008654', (161, 174))
39353	25798586	A single common mutation in the contactin associated protein-like 3B (CNTNAP3B, M1247I, COSM1472297) gene was shared between the two patients; the significance of this is not clear.	('COSM1472297', 'Gene', (88, 99))	('M1247I', 'Var', (80, 86))	('patients', 'Species', '9606', (133, 141))	('CNTNAP3B', 'Gene', '101930090', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('contactin associated protein-like 3B', 'Gene', '101930090', (32, 68))	('contactin associated protein-like 3B', 'Gene', (32, 68))	('M1247I', 'Mutation', 'p.M1247I', (80, 86))	('CNTNAP3B', 'Gene', (70, 78))
39354	25798586	Mutations in this gene have been reported to occur at low frequencies in tumors of the thyroid (0.98% of cases tested), prostate (0.38% of cases), and lung (0.21% of cases).	('tumors of the thyroid', 'Disease', 'MESH:D013959', (73, 94))	('lung', 'Disease', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors of the thyroid', 'Disease', (73, 94))	('prostate', 'Disease', (120, 128))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))
39360	25798586	The chemotherapy-responsive component of the tumor showed sarcomatoid histology and contained 151 unique mutations, while the chemotherapy-resistant component showed an epithelioid histology with 167 unique mutations.	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (58, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('sarcomatoid', 'Disease', 'MESH:C538614', (58, 69))	('mutations', 'Var', (105, 114))	('sarcomatoid', 'Disease', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
39365	25798586	Hypermutation may be defined as a subset of tumors that show an increased rate of mutation as compared to their non-hypermutated counterparts.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('mutation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Hypermutation', 'Var', (0, 13))
39371	25798586	In patient 2, somatic hypermutation was associated with platinum sensitivity and favorable prognosis, similar to findings from studies in other tumor types.	('tumor', 'Disease', (144, 149))	('platinum', 'Chemical', 'MESH:D010984', (56, 64))	('platinum sensitivity', 'CPA', (56, 76))	('somatic hypermutation', 'Var', (14, 35))	('patient', 'Species', '9606', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('associated', 'Reg', (40, 50))
39372	25798586	Other frequently hypermutated cancers are associated with defects in DNA repair machinery, or ongoing mutagenesis by an external carcinogen.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('DNA repair', 'biological_process', 'GO:0006281', ('69', '79'))	('defects', 'NegReg', (58, 65))	('mutagenesis', 'biological_process', 'GO:0006280', ('102', '113'))	('mutagenesis', 'Var', (102, 113))
39376	25798586	This analysis showed a prevalence of C>T transitions at NCG trinucleotide sequences, a mutational signature related to cytosine deamination which is observed in a wide variety of tumor types and not known to be associated with a specific etiology.	('cytosine', 'Chemical', 'MESH:D003596', (119, 127))	('NCG', 'Gene', (56, 59))	('C>T transitions', 'Var', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('trinucleotide', 'Chemical', '-', (60, 73))	('tumor', 'Disease', (179, 184))
39388	25798586	Additional ancillary tests performed outside of routine standard of practice include BAP1, MET and p16 IHC and FISH for 9p21 deletion and MET amplification.	('p16', 'Gene', (99, 102))	('BAP1', 'Gene', (85, 89))	('MET amplification', 'Var', (138, 155))	('p16', 'Gene', '1029', (99, 102))	('9p21', 'Gene', (120, 124))	('BAP1', 'Gene', '8314', (85, 89))
39408	32194667	Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018).	('patients', 'Species', '9606', (60, 68))	('shorter', 'NegReg', (49, 56))	('diffuse luminal/membranous', 'Var', (74, 100))	('MSLN', 'Gene', (115, 119))	('overall survival', 'MPA', (14, 30))
39409	32194667	Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04-4.91; P=0.039) as a potential risk factor.	('Cox', 'Gene', (14, 17))	('diffuse MSLN expression', 'Var', (55, 78))	('Cox', 'Gene', '1351', (14, 17))
39411	32194667	The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MSLN', 'Var', (54, 58))	('colon cancer', 'Disease', (62, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))	('positive', 'PosReg', (36, 44))
39420	32194667	In breast and lung adenocarcinoma, high-level MSLN expression was reported to be associated with poor prognosis.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('breast and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 33))	('MSLN', 'Gene', (46, 50))	('high-level', 'Var', (35, 45))
39421	32194667	In contrast, prolonged survival in patients with MSLN-expressing tumors was noted in ovarian serous and thymic carcinomas as well as malignant pleural mesothelioma.	('ovarian serous', 'Disease', (85, 99))	('malignant pleural mesothelioma', 'Disease', (133, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('prolonged', 'PosReg', (13, 22))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (143, 163))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('thymic carcinomas', 'Disease', 'MESH:D013945', (104, 121))	('MSLN-expressing', 'Var', (49, 64))	('patients', 'Species', '9606', (35, 43))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (133, 163))	('thymic carcinomas', 'Disease', (104, 121))	('ovarian serous', 'Disease', 'MESH:D010051', (85, 99))
39461	32194667	Male CRC patients with diffuse MSLN expression (P=0.010) but not female patients (P=0.312) showed a significantly worse clinical outcome (Fig.	('patients', 'Species', '9606', (9, 17))	('diffuse MSLN expression', 'Var', (23, 46))	('CRC', 'Disease', (5, 8))	('worse', 'NegReg', (114, 119))	('CRC', 'Phenotype', 'HP:0003003', (5, 8))	('CRC', 'Disease', 'MESH:D015179', (5, 8))	('patients', 'Species', '9606', (72, 80))
39466	32194667	Forced expression of MSLN in CW-2 and HCT-116 cells enhanced their proliferation or survival significantly with phospho-ERK accumulation under serum-reduced conditions (Fig.	('ERK', 'molecular_function', 'GO:0004707', ('120', '123'))	('enhanced', 'PosReg', (52, 60))	('ERK', 'Gene', '5594', (120, 123))	('MSLN', 'Var', (21, 25))	('proliferation', 'CPA', (67, 80))	('ERK', 'Gene', (120, 123))	('survival', 'CPA', (84, 92))
39467	32194667	MSLN also enhanced anchorage-independent cell proliferation of colon cancer cells (Fig.	('anchorage-independent cell proliferation', 'CPA', (19, 59))	('enhanced', 'PosReg', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('MSLN', 'Var', (0, 4))	('colon cancer', 'Disease', (63, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))
39468	32194667	CCNA, one of markers for S phase, were upregulated in MSLN-transfected cells (Fig.	('S phase', 'biological_process', 'GO:0051320', ('25', '32'))	('CCNA', 'Gene', '890', (0, 4))	('upregulated', 'PosReg', (39, 50))	('MSLN-transfected', 'Var', (54, 70))	('CCNA', 'Gene', (0, 4))
39469	32194667	Furthermore, transient knock down of MSLN significantly suppressed the proliferation of COLO205 and SW48 cells in both adherent and anchorage-independent conditions with downregulation of CCNA (Fig.	('MSLN', 'Gene', (37, 41))	('CCNA', 'Gene', (188, 192))	('suppressed', 'NegReg', (56, 66))	('knock down', 'Var', (23, 33))	('proliferation', 'CPA', (71, 84))	('downregulation', 'NegReg', (170, 184))	('CCNA', 'Gene', '890', (188, 192))
39484	32194667	Kim et al reported the prognostic role of MSLN in microsatellite unstable CRCs using SP74 antibody; however, this type of association was not confirmed in our cohort (data not shown).	('antibody', 'molecular_function', 'GO:0003823', ('90', '98'))	('antibody', 'cellular_component', 'GO:0042571', ('90', '98'))	('CRC', 'Disease', (74, 77))	('antibody', 'cellular_component', 'GO:0019815', ('90', '98'))	('microsatellite', 'Var', (50, 64))	('MSLN', 'Var', (42, 46))	('antibody', 'cellular_component', 'GO:0019814', ('90', '98'))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('CRC', 'Disease', 'MESH:D015179', (74, 77))
39487	32194667	In cases of breast and lung adenocarcinoma, aberrant high MSLN expression is reported to be associated with poor prognosis.	('aberrant high', 'Var', (44, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('breast and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (12, 42))	('expression', 'MPA', (63, 73))	('MSLN', 'Gene', (58, 62))
39488	32194667	In contrast, prolonged survival in patients with MSLN-expressing tumors was shown in ovarian serous and thymic carcinomas.	('ovarian serous', 'Disease', (85, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('prolonged', 'PosReg', (13, 22))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('thymic carcinomas', 'Disease', 'MESH:D013945', (104, 121))	('MSLN-expressing', 'Var', (49, 64))	('patients', 'Species', '9606', (35, 43))	('thymic carcinomas', 'Disease', (104, 121))	('ovarian serous', 'Disease', 'MESH:D010051', (85, 99))
39489	32194667	Our group also reported diffuse (100% positive cells) MSLN expression as a favorable prognostic factor in malignant pleural mesothelioma patients.	('MSLN', 'Gene', (54, 58))	('malignant pleural mesothelioma', 'Disease', (106, 136))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (116, 136))	('patients', 'Species', '9606', (137, 145))	('diffuse', 'Var', (24, 31))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (106, 136))
39492	32194667	These results indicate that high MSLN expression might be a favorable prognostic marker without tumor biological significance in some tumor types including malignant pleural mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MSLN', 'Protein', (33, 37))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (156, 186))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('malignant pleural mesothelioma', 'Disease', (156, 186))	('high', 'Var', (28, 32))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (166, 186))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
39495	32194667	Our study demonstrated the MSLN-dependent cellular proliferation of colon cancer cells (Figs.	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('MSLN-dependent', 'Var', (27, 41))	('colon cancer', 'Disease', (68, 80))	('cellular proliferation', 'CPA', (42, 64))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
39510	32194667	Additional molecular studies indicated the importance of enhanced cellular proliferation induced by MSLN for worse patient prognosis.	('cellular proliferation', 'CPA', (66, 88))	('patient', 'Species', '9606', (115, 122))	('enhanced', 'PosReg', (57, 65))	('MSLN', 'Var', (100, 104))
39668	31877692	Besides, O-linked and N-linked glycosylation create the most common branches on the tumor cell surface glycocalyx.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('glycocalyx', 'cellular_component', 'GO:0030112', ('103', '113'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('N-linked', 'Var', (22, 30))	('glycosylation', 'biological_process', 'GO:0070085', ('31', '44'))	('cell surface', 'cellular_component', 'GO:0009986', ('90', '102'))	('O-linked', 'Protein', (9, 17))	('tumor', 'Disease', (84, 89))
39675	31877692	Furthermore, taking these notions into consideration, exogenously induced expression of lectin inside the tumor cells could be another effective strategy to promote tumor eradication.	('lectin', 'molecular_function', 'GO:0005530', ('88', '94'))	('lectin', 'Gene', '100136250', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('promote', 'PosReg', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('exogenously', 'Var', (54, 65))	('lectin', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', (165, 170))
39699	31877692	PEG was added in order to prolong the half-life of the vesicles compared to normal liposomes since PEGylation should decrease the reticuloendothelial uptake.	('PEGylation', 'Var', (99, 109))	('PEG', 'Chemical', 'MESH:D011092', (99, 102))	('uptake', 'biological_process', 'GO:0098739', ('150', '156'))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('decrease', 'NegReg', (117, 125))	('reticuloendothelial uptake', 'CPA', (130, 156))	('uptake', 'biological_process', 'GO:0098657', ('150', '156'))
39701	31877692	ESA-immobilized lipid vesicles reached and bonded Colo201, HB4C5, OST, while no interaction was recorded with normal human fibroblasts and MCF10-2A (Table 1).	('ESA', 'Chemical', '-', (0, 3))	('MCF10-2A', 'CellLine', 'CVCL:3743', (139, 147))	('human', 'Species', '9606', (117, 122))	('bonded', 'Interaction', (43, 49))	('Colo201', 'Var', (50, 57))	('OST', 'Disease', 'MESH:D012516', (66, 69))	('OST', 'Disease', (66, 69))	('lipid', 'Chemical', 'MESH:D008055', (16, 21))
39704	31877692	No study directly compared the antitumor activity of the PEGylated vs. the not-PEGylated ESA-vesicles, while only in vivo bioavailability experiments were performed, showing no difference between the two systems.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PEG', 'Chemical', 'MESH:D011092', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumor', 'Disease', (35, 40))	('PEG', 'Chemical', 'MESH:D011092', (57, 60))	('ESA', 'Chemical', '-', (89, 92))	('PEGylated', 'Var', (57, 66))
39719	31877692	Due to congenital or acquired genetic alterations of cancer cells, one or, in the worst case, both pathways are often compromised.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (53, 59))	('genetic alterations', 'Var', (30, 49))
39724	31877692	During post-translational modifications, 53 amino acids are lost and the N-terminal sequence of UPL1 starts at amino acid number 54.	('lost', 'NegReg', (60, 64))	('UPL1', 'Gene', (96, 100))	('post-translational', 'Var', (7, 25))	('N', 'Chemical', 'MESH:D009584', (73, 74))
39780	31877692	OncoVV-TTL was able to replicate inside tumor cells and significantly reduced tumor growth compared to onvoVV-only treated mice (Table 2).	('reduced', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('OncoVV-TTL', 'Var', (0, 10))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (123, 127))
39783	31877692	Ad.FLAG-HddSBL promoted cell death of hepatocellular carcinoma (Hep3B), lung cancer (A549 and H1299), and colorectal carcinoma (SW480) in a tumor-dependent manner, as the different sensitivity of these cell lines to this compound suggests.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('Hep3B', 'CellLine', 'CVCL:0326', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('promoted', 'PosReg', (15, 23))	('H1299', 'CellLine', 'CVCL:0060', (94, 99))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (38, 62))	('cell death', 'CPA', (24, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('hepatocellular carcinoma', 'Disease', (38, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal carcinoma', 'Disease', (106, 126))	('cell death', 'biological_process', 'GO:0008219', ('24', '34'))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (106, 126))	('Ad.FLAG-HddSBL', 'Var', (0, 14))	('lung cancer', 'Disease', (72, 83))	('SW480', 'CellLine', 'CVCL:0546', (128, 133))	('tumor', 'Disease', (140, 145))
39814	31877692	On Hela, MCF-7, and T47D, Hol-18 promoted apoptosis and activated the MAPK-ERK signal, showing once again how this pathway is often involved in marine lectin mechanism of action.	('Hol-18', 'Var', (26, 32))	('promoted', 'PosReg', (33, 41))	('ERK', 'Gene', '5594', (75, 78))	('T47D', 'CellLine', 'CVCL:0553', (20, 24))	('lectin', 'Gene', (151, 157))	('ERK', 'molecular_function', 'GO:0004707', ('75', '78'))	('ERK', 'Gene', (75, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('lectin', 'Gene', '100136250', (151, 157))	('apoptosis', 'CPA', (42, 51))	('lectin', 'molecular_function', 'GO:0005530', ('151', '157'))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('MCF-7', 'CellLine', 'CVCL:0031', (9, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('activated', 'PosReg', (56, 65))	('Hol-18', 'Chemical', '-', (26, 32))	('Hela', 'CellLine', 'CVCL:0030', (3, 7))
39816	31877692	The recombinant oncoVV-AVL is the result of the insertion of the Aphrocallistes vastus lectin (AVL) into an oncolytic VV.	('oncoVV-AVL', 'Disease', (16, 26))	('lectin', 'molecular_function', 'GO:0005530', ('87', '93'))	('insertion', 'Var', (48, 57))	('lectin', 'Gene', (87, 93))	('lectin', 'Gene', '100136250', (87, 93))	('Aphrocallistes vastus', 'Species', '83887', (65, 86))
39820	31877692	The insertion of this lectin in the oncolityc VV allowed its exogenous expression into infected cells.	('lectin', 'Gene', '100136250', (22, 28))	('exogenous expression', 'MPA', (61, 81))	('insertion', 'Var', (4, 13))	('lectin', 'molecular_function', 'GO:0005530', ('22', '28'))	('lectin', 'Gene', (22, 28))
39832	31877692	On K562, it increased p21 and repressed the expression of pRb (retinoblastoma protein), suggesting the ability to block the cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('124', '134'))	('retinoblastoma', 'Disease', 'MESH:D012175', (63, 77))	('retinoblastoma', 'Disease', (63, 77))	('K562', 'CellLine', 'CVCL:0004', (3, 7))	('increased', 'PosReg', (12, 21))	('block', 'NegReg', (114, 119))	('p21', 'Gene', (22, 25))	('cell cycle', 'CPA', (124, 134))	('p21', 'Gene', '644914', (22, 25))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('pRb', 'Gene', (58, 61))	('retinoblastoma', 'Phenotype', 'HP:0009919', (63, 77))	('pRb', 'Gene', '5925', (58, 61))	('K562', 'Var', (3, 7))
39843	31877692	In CVL-mediated activity, the ablation of CTPB restored almost entirely cell viability, while TNFR1 was upregulated and the subunit p65 of the nuclear factor kB (Nf-kB) was downregulated.	('downregulated', 'NegReg', (173, 186))	('CTPB', 'Gene', (42, 46))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('cell viability', 'CPA', (72, 86))	('ablation', 'Var', (30, 38))	('upregulated', 'PosReg', (104, 115))	('TNFR1', 'Gene', (94, 99))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('TNFR1', 'Gene', '7132', (94, 99))
39869	31877692	showed that Lectin hemagglutination activity was inhibited blocking amino groups and in particular t-amino ones, but not tyrosine residues, letting presume that those residues are responsible for the binding with the sugar.	('t-amino ones', 'Var', (99, 111))	('Lectin', 'molecular_function', 'GO:0005530', ('12', '18'))	('sugar', 'Chemical', 'MESH:D000073893', (217, 222))	('tyrosine', 'Chemical', 'MESH:D014443', (121, 129))	('Lectin', 'Gene', '100136250', (12, 18))	('amino groups', 'Var', (68, 80))	('Lectin', 'Gene', (12, 18))	('binding', 'molecular_function', 'GO:0005488', ('200', '207'))	('inhibited', 'NegReg', (49, 58))
39883	31877692	In these cell lines, the phosphorylation of p38 MAPK plays a key role in the pro-apoptotic activity of SBLc since the ablation of this pathway significantly decreases SBLc-mediated activation of caspase-3 and caspase-7 and cleavage of PARP and reduced cell death.	('ablation', 'Var', (118, 126))	('caspase-3', 'Gene', '836', (195, 204))	('cell death', 'CPA', (252, 262))	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('p38', 'Gene', '1432', (44, 47))	('reduced', 'NegReg', (244, 251))	('caspase-7', 'Gene', (209, 218))	('PARP', 'Gene', '142', (235, 239))	('caspase-7', 'Gene', '840', (209, 218))	('p38', 'Gene', (44, 47))	('activation', 'PosReg', (181, 191))	('cleavage', 'MPA', (223, 231))	('caspase-3', 'Gene', (195, 204))	('decreases', 'NegReg', (157, 166))	('PARP', 'Gene', (235, 239))	('cell death', 'biological_process', 'GO:0008219', ('252', '262'))
39896	31877692	This result is particularly interesting since hormonal therapies, and in particular receptor antagonism, represent efficient and usually well-tolerated treatments for breast cancer.	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('antagonism', 'Var', (93, 103))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
39954	31877692	p53 and p73 (the proline 73 polymorphic variant of p53) represent the links between EF2-1 and apoptosis.	('p53', 'Gene', (51, 54))	('proline', 'Chemical', 'MESH:D011392', (17, 24))	('p73', 'Gene', '7161', (8, 11))	('p73', 'Gene', (8, 11))	('p53', 'Var', (0, 3))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))
39957	31877692	DIFBL-FLAG and AJL1-FLAG elicited cytotoxicity in several human liver and lung cancer cell lines (Table 3).	('cytotoxicity', 'Disease', 'MESH:D064420', (34, 46))	('human', 'Species', '9606', (58, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('AJL1-FLAG', 'Var', (15, 24))	('cytotoxicity', 'Disease', (34, 46))	('liver and lung cancer', 'Disease', 'MESH:D008175', (64, 85))	('DIFBL-FLAG', 'Chemical', '-', (0, 10))
40103	23361052	Despite mechanistic studies demonstrating that Axl inhibition can suppress mesothelioma proliferation and invasion in vitro, further research is needed to understand how Axl expression can shape the clinical phenotype of MPM.	('clinical', 'Species', '191496', (199, 207))	('mesothelioma proliferation', 'Disease', 'MESH:D008654', (75, 101))	('suppress', 'NegReg', (66, 74))	('Axl', 'Gene', (170, 173))	('Axl', 'Gene', (47, 50))	('invasion', 'CPA', (106, 114))	('mesothelioma proliferation', 'Disease', (75, 101))	('inhibition', 'Var', (51, 61))	('Axl', 'Gene', '558', (170, 173))	('Axl', 'Gene', '558', (47, 50))
40111	23361052	The European Organisation for Research and Treatment of Cancer Prognostic Score (EPS) was derived as described previously and categorises patients into good vs poor prognostic groups according to male gender, probable or possible histologic diagnosis, sarcomatoid differentiation, PS >=1, and WBC >=8.3 x 109 l-1.	('WBC >=8.3', 'Var', (293, 302))	('EPS', 'Disease', 'MESH:D001480', (81, 84))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('sarcomatoid', 'Disease', (252, 263))	('Cancer', 'Disease', (56, 62))	('PS >=1', 'Var', (281, 287))	('EPS', 'Disease', (81, 84))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('patients', 'Species', '9606', (138, 146))	('sarcomatoid', 'Disease', 'MESH:C538614', (252, 263))
40127	23361052	We also performed an ad hoc subanalysis on a further subgroup of 20 specimens selected from the derivation group based on high (HS>=150) vs low (HS<150) Axl expression levels to investigate whether Axl expression influenced tumour cell senescence.	('HS', 'Var', (128, 130))	('Axl', 'Gene', (153, 156))	('Axl', 'Gene', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('senescence', 'biological_process', 'GO:0010149', ('236', '246'))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('influenced', 'Reg', (213, 223))	('tumour', 'Disease', (224, 230))	('Axl', 'Gene', '558', (153, 156))	('Axl', 'Gene', '558', (198, 201))
40147	23361052	Univariate analyses revealed the following variables to predict for poor OS: low Axl expression (P=0.001), IMIG stage (P=0.05), PS>1 (P<0.001), albumin <35 g l-1 (P<0.001), haemoglobin <12 g l-1 (P<0.001).	('low', 'NegReg', (77, 80))	('IMIG stage', 'CPA', (107, 117))	('Axl', 'Gene', (81, 84))	('PS>1', 'Var', (128, 132))	('albumin', 'MPA', (144, 151))	('Axl', 'Gene', '558', (81, 84))
40148	23361052	Multivariate analysis of survival confirmed reduced Axl expression (P=0.01), PS>1 (P=0.01), haemoglobin <12 g l-1 (P=0.04) and albumin <35 g l-1 (P<0.001) as independent predictors of worse OS (Table 2).	('Axl', 'Gene', '558', (52, 55))	('worse OS', 'Disease', (184, 192))	('reduced', 'NegReg', (44, 51))	('albumin', 'Var', (127, 134))	('Axl', 'Gene', (52, 55))
40150	23361052	In order to further elucidate the mechanism by which Axl expression improves OS in patients with mesothelioma, we performed an ad hoc subgroup analysis on Axl-negative vs Axl overexpressing clinical specimens (n=10 each group) to verify whether hTERT expression, a marker of unlimited proliferative potential, was influenced by Axl expression levels.	('Axl', 'Gene', '558', (171, 174))	('Axl', 'Gene', (53, 56))	('expression', 'Var', (57, 67))	('improves', 'PosReg', (68, 76))	('Axl', 'Gene', (328, 331))	('Axl', 'Gene', '558', (328, 331))	('patients', 'Species', '9606', (83, 91))	('Axl', 'Gene', '558', (155, 158))	('Axl', 'Gene', (171, 174))	('mesothelioma', 'Disease', (97, 109))	('clinical', 'Species', '191496', (190, 198))	('hTERT', 'Gene', '7015', (245, 250))	('Axl', 'Gene', (155, 158))	('Axl', 'Gene', '558', (53, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('hTERT', 'Gene', (245, 250))
40157	23361052	As the aberrant activation of RTKs is crucial to maintain tumour cell proliferation and facilitate evasion from apoptosis, a considerable interest has emerged for RTKs both as tissue biomarkers to predict the biologic aggressiveness of the disease as well as putative therapeutic targets, in a context where the survival benefit that can be offered by currently available treatments is notoriously limited.	('aggressiveness of the disease', 'Disease', 'MESH:D001523', (218, 247))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('activation', 'PosReg', (16, 26))	('aggressiveness', 'Phenotype', 'HP:0000718', (218, 232))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('aberrant', 'Var', (7, 15))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('aggressiveness of the disease', 'Disease', (218, 247))	('tumour', 'Disease', (58, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('evasion from apoptosis', 'MPA', (99, 121))
40160	23361052	The qualification of Axl as a transforming oncogene regulating the proliferation and invasiveness of MPM relies on preclinical studies, where the inhibition of Axl using selective tyrosine kinase inhibitors determined significant antiproliferative effects in vitro.	('Axl', 'Gene', '558', (21, 24))	('Axl', 'Gene', (160, 163))	('clinical', 'Species', '191496', (118, 126))	('Axl', 'Gene', (21, 24))	('antiproliferative effects', 'CPA', (230, 255))	('Axl', 'Gene', '558', (160, 163))	('inhibition', 'Var', (146, 156))
40163	23361052	Unlike other tumours, where Axl overexpression negatively impacts on patients' prognosis, we found that Axl expression exerts a protective effect on patients' survival independent from other validated prognostic factors such as tumour stage, PS, low haemoglobin and hypoalbuminaemia.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumour', 'Disease', (228, 234))	('low haemoglobin', 'Phenotype', 'HP:0001903', (246, 261))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))	('patients', 'Species', '9606', (69, 77))	('expression', 'Var', (108, 118))	('patients', 'Species', '9606', (149, 157))	('Axl', 'Gene', '558', (28, 31))	('tumours', 'Disease', (13, 20))	('hypoalbuminaemia', 'Disease', (266, 282))	('Axl', 'Gene', (28, 31))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('Axl', 'Gene', '558', (104, 107))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('hypoalbuminaemia', 'Phenotype', 'HP:0003073', (266, 282))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('Axl', 'Gene', (104, 107))	('hypoalbuminaemia', 'Disease', 'None', (266, 282))
40170	23361052	It can be further hypothesised that Axl overexpression as a result of copy number gain has in fact been shown to be sufficient to exert oncogenic properties even in absence of its ligand.	('oncogenic properties', 'CPA', (136, 156))	('Axl', 'Gene', (36, 39))	('overexpression', 'PosReg', (40, 54))	('Axl', 'Gene', '558', (36, 39))	('copy number', 'Var', (70, 81))	('gain', 'PosReg', (82, 86))	('ligand', 'molecular_function', 'GO:0005488', ('180', '186'))
40189	23144729	We modulated the expression of syndecan-1 in a human mesothelioma cell line via both overexpression and silencing, and followed the transcriptomic responses with microarray analysis.	('syndecan-1', 'Gene', '6382', (31, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('silencing', 'Var', (104, 113))	('overexpression', 'PosReg', (85, 99))	('syndecan', 'molecular_function', 'GO:0015023', ('31', '39'))	('syndecan-1', 'Gene', (31, 41))	('human', 'Species', '9606', (47, 52))	('modulated', 'Reg', (3, 12))	('mesothelioma', 'Disease', (53, 65))
40192	23144729	Syndecan-1 silencing had less powerful effect on the transcriptome compared to overexpression, which can be explained by the already low initial syndecan-1 level of these cells.	('silencing', 'Var', (11, 20))	('Syndecan-1', 'Gene', (0, 10))	('syndecan-1', 'Gene', '6382', (145, 155))	('syndecan', 'molecular_function', 'GO:0015023', ('145', '153'))	('syndecan-1', 'Gene', (145, 155))	('Syndecan', 'molecular_function', 'GO:0015023', ('0', '8'))	('Syndecan-1', 'Gene', '6382', (0, 10))	('transcriptome', 'MPA', (53, 66))
40195	23144729	Most strikingly, nearly all analyzed pathways related to cell cycle were enriched after syndecan-1 silencing and depleted after syndecan-1 overexpression.	('syndecan-1', 'Gene', '6382', (128, 138))	('syndecan-1', 'Gene', '6382', (88, 98))	('syndecan-1', 'Gene', (128, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('syndecan', 'molecular_function', 'GO:0015023', ('88', '96'))	('enriched', 'Reg', (73, 81))	('syndecan-1', 'Gene', (88, 98))	('silencing', 'Var', (99, 108))	('syndecan', 'molecular_function', 'GO:0015023', ('128', '136'))
40207	23144729	Furthermore, the presence of syndecan-1 implies a better prognosis of malignant mesothelioma.	('malignant mesothelioma', 'Disease', (70, 92))	('syndecan-1', 'Gene', '6382', (29, 39))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (70, 92))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))	('presence', 'Var', (17, 25))	('syndecan', 'molecular_function', 'GO:0015023', ('29', '37'))	('syndecan-1', 'Gene', (29, 39))
40211	23144729	For this purpose we modulated syndecan-1 expression in a human malignant mesothelioma cell line and performed microarray analysis to investigate the effects of syndecan-1 overexpression and silencing on general transcriptional level.	('malignant mesothelioma', 'Disease', (63, 85))	('syndecan', 'molecular_function', 'GO:0015023', ('160', '168'))	('syndecan-1', 'Gene', (30, 40))	('silencing', 'Var', (190, 199))	('human', 'Species', '9606', (57, 62))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (63, 85))	('syndecan-1', 'Gene', '6382', (160, 170))	('syndecan-1', 'Gene', '6382', (30, 40))	('modulated', 'Reg', (20, 29))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (63, 85))	('syndecan', 'molecular_function', 'GO:0015023', ('30', '38'))	('syndecan-1', 'Gene', (160, 170))
40212	23144729	Our previous data show that overexpression of syndecan-1 inhibits proliferation of malignant mesothelioma; in this paper we also investigated the effect of syndecan-1 silencing on the proliferation rate and cell cycle distribution of these cells.	('malignant mesothelioma', 'Disease', (83, 105))	('syndecan', 'molecular_function', 'GO:0015023', ('156', '164'))	('proliferation', 'CPA', (66, 79))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (83, 105))	('syndecan-1', 'Gene', '6382', (156, 166))	('syndecan-1', 'Gene', '6382', (46, 56))	('silencing', 'Var', (167, 176))	('syndecan', 'molecular_function', 'GO:0015023', ('46', '54'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (83, 105))	('syndecan-1', 'Gene', (156, 166))	('inhibits', 'NegReg', (57, 65))	('cell cycle', 'biological_process', 'GO:0007049', ('207', '217'))	('syndecan-1', 'Gene', (46, 56))
40236	23144729	Flow cytometry was performed for confirmation of syndecan-1 modulation on protein level.	('syndecan', 'molecular_function', 'GO:0015023', ('49', '57'))	('syndecan-1', 'Gene', '6382', (49, 59))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('syndecan-1', 'Gene', (49, 59))	('modulation', 'Var', (60, 70))
40244	23144729	Twenty-four and forty-eight hours after syndecan-1 silencing, cells silenced for syndecan-1 or cells transfected with scrambled control siRNA were harvested using 5 mM EDTA and fixed overnight in cold ethanol.	('EDTA', 'Chemical', 'MESH:D004492', (168, 172))	('syndecan-1', 'Gene', (81, 91))	('silencing', 'Var', (51, 60))	('syndecan-1', 'Gene', (40, 50))	('ethanol', 'Chemical', 'MESH:D000431', (201, 208))	('syndecan-1', 'Gene', '6382', (81, 91))	('syndecan-1', 'Gene', '6382', (40, 50))	('syndecan', 'molecular_function', 'GO:0015023', ('81', '89'))	('syndecan', 'molecular_function', 'GO:0015023', ('40', '48'))
40255	23144729	Molecular pathway analysis was performed to reveal possible involvement of genes with specific biological functions following both syndecan-1 overexpression and silencing.	('overexpression', 'PosReg', (142, 156))	('syndecan-1', 'Gene', '6382', (131, 141))	('syndecan', 'molecular_function', 'GO:0015023', ('131', '139'))	('syndecan-1', 'Gene', (131, 141))	('silencing', 'Var', (161, 170))
40265	23144729	Cell proliferation significantly decreased in cells with silenced syndecan-1.	('syndecan-1', 'Gene', '6382', (66, 76))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('syndecan', 'molecular_function', 'GO:0015023', ('66', '74'))	('syndecan-1', 'Gene', (66, 76))	('decreased', 'NegReg', (33, 42))	('silenced', 'Var', (57, 65))	('Cell proliferation', 'CPA', (0, 18))
40266	23144729	Doubling time increased correspondingly from 21.6 hours to 27.9 hours in the syndecan-1 silenced cells compared to the scrambled control (Figure 1B).	('increased', 'PosReg', (14, 23))	('syndecan', 'molecular_function', 'GO:0015023', ('77', '85'))	('Doubling', 'MPA', (0, 8))	('syndecan-1', 'Gene', '6382', (77, 87))	('silenced', 'Var', (88, 96))	('syndecan-1', 'Gene', (77, 87))
40268	23144729	No significant difference was detected in the rate of apoptotic cells in the syndecan-1 silenced cells compared to the scrambled siRNA control (Figure 1D, Table S3).	('syndecan', 'molecular_function', 'GO:0015023', ('77', '85'))	('syndecan-1', 'Gene', '6382', (77, 87))	('silenced', 'Var', (88, 96))	('syndecan-1', 'Gene', (77, 87))
40272	23144729	Fourteen genes were concordantly altered by both syndecan-1 overexpression and silencing.	('syndecan', 'molecular_function', 'GO:0015023', ('49', '57'))	('syndecan-1', 'Gene', '6382', (49, 59))	('overexpression', 'PosReg', (60, 74))	('altered', 'Reg', (33, 40))	('syndecan-1', 'Gene', (49, 59))	('silencing', 'Var', (79, 88))
40273	23144729	ETS-1, TNSF-18, CLIP-4 and FBLN5 were altered in the same direction with syndecan-1 modulation.	('FBLN5', 'Gene', (27, 32))	('TNSF-18', 'Gene', (7, 14))	('CLIP-4', 'Gene', '79745', (16, 22))	('syndecan', 'molecular_function', 'GO:0015023', ('73', '81'))	('syndecan-1', 'Gene', '6382', (73, 83))	('modulation', 'Var', (84, 94))	('FBLN5', 'Gene', '10516', (27, 32))	('CLIP-4', 'Gene', (16, 22))	('syndecan-1', 'Gene', (73, 83))	('ETS-1', 'Gene', (0, 5))	('ETS-1', 'Gene', '2113', (0, 5))
40313	23144729	These networks supported our finding that modulation of syndecan-1 affects the process of cell proliferation and cell cycle at different levels comprising not only growth factors and cell surface receptors but also downstream kinases.	('cell cycle', 'biological_process', 'GO:0007049', ('113', '123'))	('syndecan-1', 'Gene', '6382', (56, 66))	('modulation', 'Var', (42, 52))	('affects', 'Reg', (67, 74))	('syndecan', 'molecular_function', 'GO:0015023', ('56', '64'))	('syndecan-1', 'Gene', (56, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('cell surface', 'cellular_component', 'GO:0009986', ('183', '195'))	('cell cycle', 'CPA', (113, 123))
40314	23144729	Five pathways were significantly altered by both syndecan-1 overexpression and silencing: two interleukin pathways (IL10 and IL6), the HGF pathway and the ERK5 and ERK/MAPK signaling pathways (Figure 8).	('ERK', 'Gene', (155, 158))	('altered', 'Reg', (33, 40))	('IL10', 'molecular_function', 'GO:0005141', ('116', '120'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('168', '182'))	('ERK5', 'Gene', (155, 159))	('syndecan', 'molecular_function', 'GO:0015023', ('49', '57'))	('ERK', 'molecular_function', 'GO:0004707', ('164', '167'))	('overexpression', 'PosReg', (60, 74))	('IL10', 'Gene', (116, 120))	('HGF', 'Gene', '3082', (135, 138))	('interleukin pathways', 'Pathway', (94, 114))	('IL6', 'Gene', '3569', (125, 128))	('ERK', 'Gene', '5594', (164, 167))	('syndecan-1', 'Gene', (49, 59))	('IL10', 'Gene', '3586', (116, 120))	('HGF', 'Gene', (135, 138))	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('ERK5', 'Gene', '5598', (155, 159))	('ERK', 'Gene', '5594', (155, 158))	('syndecan-1', 'Gene', '6382', (49, 59))	('ERK', 'Gene', (164, 167))	('IL6', 'Gene', (125, 128))	('silencing', 'Var', (79, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('168', '172'))	('IL6', 'molecular_function', 'GO:0005138', ('125', '128'))
40316	23144729	From more than 1,600 pathways analyzed, 939 were significantly altered in syndecan-1 overexpressing cells and 234 in syndecan-1 silenced cells.	('syndecan-1', 'Gene', '6382', (117, 127))	('syndecan-1', 'Gene', (74, 84))	('syndecan', 'molecular_function', 'GO:0015023', ('74', '82'))	('altered', 'Reg', (63, 70))	('syndecan-1', 'Gene', (117, 127))	('syndecan-1', 'Gene', '6382', (74, 84))	('overexpressing', 'Var', (85, 99))	('syndecan', 'molecular_function', 'GO:0015023', ('117', '125'))
40321	23144729	Silencing of syndecan-1 highly altered several cell-cycle related pathways along with several cancer-related functional gene sets.	('altered', 'Reg', (31, 38))	('syndecan-1', 'Gene', (13, 23))	('syndecan', 'molecular_function', 'GO:0015023', ('13', '21'))	('cell-cycle related pathways', 'Pathway', (47, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cell-cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('syndecan-1', 'Gene', '6382', (13, 23))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
40322	23144729	The results further expanded the findings from GSEA and IPA analysis: many growth-factor, cytokine and cell cycle related pathways were altered following both syndecan-1 overexpression and silencing (Figure 9A).	('silencing', 'Var', (189, 198))	('syndecan', 'molecular_function', 'GO:0015023', ('159', '167'))	('growth-factor', 'Pathway', (75, 88))	('syndecan-1', 'Gene', '6382', (159, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('103', '113'))	('cell cycle related pathways', 'Pathway', (103, 130))	('syndecan-1', 'Gene', (159, 169))	('GSEA', 'Chemical', '-', (47, 51))	('altered', 'Reg', (136, 143))	('overexpression', 'PosReg', (170, 184))
40323	23144729	Cell-cycle pathways were enriched when syndecan-1 was silenced.	('Cell-cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('syndecan', 'molecular_function', 'GO:0015023', ('39', '47'))	('silenced', 'Var', (54, 62))	('syndecan-1', 'Gene', '6382', (39, 49))	('Cell-cycle pathways', 'Pathway', (0, 19))	('syndecan-1', 'Gene', (39, 49))
40335	23144729	While the inhibition of cell growth was accompanied by a prolonged S phase due to syndecan-1 overexpression, silencing showed accumulation of cells in G0/G1 phase with less cells in G2/M.	('G1 phase', 'biological_process', 'GO:0051318', ('154', '162'))	('accumulation', 'PosReg', (126, 138))	('syndecan', 'molecular_function', 'GO:0015023', ('82', '90'))	('syndecan-1', 'Gene', (82, 92))	('G0/G1 phase', 'CPA', (151, 162))	('S phase', 'biological_process', 'GO:0051320', ('67', '74'))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('10', '35'))	('silencing', 'Var', (109, 118))	('syndecan-1', 'Gene', '6382', (82, 92))	('overexpression', 'PosReg', (93, 107))	('cell growth', 'CPA', (24, 35))
40340	23144729	The finding that both syndecan-1 overexpression and silencing suppressed proliferation may seem paradoxal.	('overexpression', 'PosReg', (33, 47))	('syndecan-1', 'Gene', (22, 32))	('syndecan', 'molecular_function', 'GO:0015023', ('22', '30'))	('silencing', 'Var', (52, 61))	('proliferation', 'CPA', (73, 86))	('syndecan-1', 'Gene', '6382', (22, 32))	('suppressed', 'NegReg', (62, 72))
40342	23144729	In a recent study on HT1080 fibrosarcoma cell line syndecan-1 overexpression promoted proliferation along with the activation of genes driving the G1S transition, whereas in B6FS fibrosarcoma cell line the opposite effect was found.	('genes', 'Gene', (129, 134))	('activation', 'PosReg', (115, 125))	('syndecan-1', 'Gene', '6382', (51, 61))	('promoted', 'PosReg', (77, 85))	('overexpression', 'Var', (62, 76))	('fibrosarcoma', 'Disease', (179, 191))	('proliferation', 'CPA', (86, 99))	('fibrosarcoma', 'Disease', (28, 40))	('syndecan-1', 'Gene', (51, 61))	('HT1080', 'CellLine', 'CVCL:0317', (21, 27))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (179, 191))	('fibrosarcoma', 'Disease', 'MESH:D005354', (179, 191))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (28, 40))	('fibrosarcoma', 'Disease', 'MESH:D005354', (28, 40))	('syndecan', 'molecular_function', 'GO:0015023', ('51', '59'))
40347	23144729	Modulation of syndecan-1 expression significantly enriched the cytokine-cytokine receptor interaction pathway and pathways where ILs were involved.	('Modulation', 'Var', (0, 10))	('enriched', 'Reg', (50, 58))	('syndecan', 'molecular_function', 'GO:0015023', ('14', '22'))	('cytokine-cytokine receptor interaction pathway', 'Pathway', (63, 109))	('syndecan-1', 'Gene', '6382', (14, 24))	('expression', 'MPA', (25, 35))	('pathways', 'Pathway', (114, 122))	('syndecan-1', 'Gene', (14, 24))
40359	23144729	Thus, modulation of growth factors and growth factor receptors was accompanied by a deregulation of ERK/MAPK, JNK and p38/MAPK pathways.	('deregulation', 'Reg', (84, 96))	('JNK', 'Gene', (110, 113))	('modulation', 'Var', (6, 16))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('JNK', 'Gene', '5599', (110, 113))	('JNK', 'molecular_function', 'GO:0004705', ('110', '113'))	('p38', 'Gene', (118, 121))	('ERK', 'Gene', '5594', (100, 103))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('growth', 'Protein', (20, 26))	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('p38', 'Gene', '5594', (118, 121))	('ERK', 'Gene', (100, 103))
40382	23144729	High SULF1 expression was associated with poor prognosis in adenocarcinoma, and silencing of this enzyme inhibited proliferation of pancreatic cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('adenocarcinoma', 'Disease', (60, 74))	('silencing', 'Var', (80, 89))	('High', 'Var', (0, 4))	('inhibited', 'NegReg', (105, 114))	('expression', 'MPA', (11, 21))	('pancreatic cancer', 'Disease', (132, 149))	('proliferation', 'CPA', (115, 128))	('adenocarcinoma', 'Disease', 'MESH:D000230', (60, 74))	('SULF1', 'Gene', '23213', (5, 10))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('SULF1', 'Gene', (5, 10))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))
40398	23144729	These results indicate that syndecan-1 modulation also may interfere with syndecan-1 shedding, a conclusion supported by a very recent concomitant study.	('syndecan', 'molecular_function', 'GO:0015023', ('28', '36'))	('syndecan-1', 'Gene', (74, 84))	('syndecan', 'molecular_function', 'GO:0015023', ('74', '82'))	('interfere', 'NegReg', (59, 68))	('syndecan-1', 'Gene', (28, 38))	('modulation', 'Var', (39, 49))	('syndecan-1', 'Gene', '6382', (74, 84))	('syndecan-1', 'Gene', '6382', (28, 38))
40627	32273321	There was potential for bias from misclassification of occupations and causes of death, but misclassification of lung cancer and COPD as causes of death is likely to have been non-differential with respect to occupation, and therefore to have biased PMRs for those diseases towards the null.	('death', 'Disease', 'MESH:D003643', (81, 86))	('COPD', 'Disease', (129, 133))	('lung cancer', 'Disease', (113, 124))	('biased', 'Reg', (243, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('death', 'Disease', (81, 86))	('death', 'Disease', 'MESH:D003643', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('death', 'Disease', (147, 152))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('misclassification', 'Var', (92, 109))	('COPD', 'Phenotype', 'HP:0006510', (129, 133))	('COPD', 'Disease', 'MESH:D029424', (129, 133))
40642	32273321	Next, we focused on 22 asbestos-exposed job groups with significantly elevated PMRs over the period 1979-2010 for cancer of the pleura (ICD9 163, ICD10 C38.4, C38.8 and C45.0, lower 95% confidence limit >100) (online supplementary table 2).	('elevated', 'PosReg', (70, 78))	('men', 'Species', '9606', (223, 226))	('cancer of the pleura', 'Phenotype', 'HP:0100527', (114, 134))	('cancer of the pleura', 'Disease', 'MESH:D009369', (114, 134))	('cancer of the pleura', 'Disease', (114, 134))	('C38.8', 'Var', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('asbestos', 'Chemical', 'MESH:D001194', (23, 31))	('ICD10 C38.4', 'Var', (146, 157))	('C45.0', 'Var', (169, 174))	('PMRs', 'MPA', (79, 83))
40649	32273321	In a sensitivity analysis, we repeated our calculations for this period, aggregating all deaths from mesotheliomas other than of the peritoneum (C45.2, C45.7 and C45.9) with those from pleural cancer.	('pleural cancer', 'Disease', 'MESH:D009369', (185, 199))	('mesotheliomas', 'Disease', 'MESH:D008654', (101, 114))	('mesotheliomas', 'Disease', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('deaths', 'Disease', 'MESH:D003643', (89, 95))	('deaths', 'Disease', (89, 95))	('C45.7', 'Var', (152, 157))	('pleural cancer', 'Disease', (185, 199))
40713	29669524	Furthermore, PIPAC induces significant histological regression of malignant mesothelioma in the majority of patients.	('PIPAC', 'Var', (13, 18))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (66, 88))	('patients', 'Species', '9606', (108, 116))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (66, 88))	('regression', 'NegReg', (52, 62))	('PIPAC', 'Chemical', '-', (13, 18))	('malignant mesothelioma', 'Disease', (66, 88))
40797	29669524	On an intention-to-treat basis, PIPAC thus caused histological tumor regression in 51.7% of patients (15/29).	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PIPAC', 'Chemical', '-', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PIPAC', 'Var', (32, 37))	('regression', 'NegReg', (69, 79))
41079	31715131	Combining CAR T-cell therapy and CPB may produce a synergistic effect: CAR T cells can provide an infiltrate for immunogenically silent tumors, and CPB can reverse CAR T-cell inhibition and restore functional persistence.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('CPB', 'Chemical', '-', (148, 151))	('CAR', 'cellular_component', 'GO:0005826', ('164', '167'))	('CAR', 'cellular_component', 'GO:0005826', ('71', '74'))	('silent tumors', 'Disease', 'MESH:C566065', (129, 142))	('CPB', 'Chemical', '-', (33, 36))	('CAR', 'cellular_component', 'GO:0005826', ('10', '13'))	('functional persistence', 'MPA', (198, 220))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('CPB', 'Var', (148, 151))	('silent tumors', 'Disease', (129, 142))	('restore', 'PosReg', (190, 197))
41082	31715131	Downregulation or knockout of CTLA-4 causes rampant lymphoproliferation and death from autoimmunity, and in cancer models, CTLA-4 signal blockade leads to tumor regression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Downregulation', 'NegReg', (0, 14))	('CTLA-4', 'Gene', '1493', (30, 36))	('CTLA-4', 'Gene', '1493', (123, 129))	('tumor', 'Disease', (155, 160))	('lymphoproliferation', 'Disease', (52, 71))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('autoimmunity', 'Phenotype', 'HP:0002960', (87, 99))	('CTLA-4', 'Gene', (30, 36))	('knockout', 'Var', (18, 26))	('CTLA-4', 'Gene', (123, 129))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
41088	31715131	Cancer cells can also express PD-L1 innately in response to disruption of the regulatory 3' region of the PD-L1 gene or activation of oncogenic pathways such as PI3K/Akt, EGFR, STAT3, MYC, and cyclin-dependent kinase 5.	('STAT3', 'Gene', '6774', (177, 182))	('Akt', 'Gene', (166, 169))	('cyclin', 'molecular_function', 'GO:0016538', ('193', '199'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cyclin-dependent kinase 5', 'Gene', '1020', (193, 218))	('Akt', 'Gene', '207', (166, 169))	('cyclin-dependent kinase 5', 'Gene', (193, 218))	('activation', 'PosReg', (120, 130))	('MYC', 'Gene', (184, 187))	('disruption', 'Var', (60, 70))	('PD-L1', 'Gene', (30, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('MYC', 'Gene', '4609', (184, 187))	('EGFR', 'Pathway', (171, 175))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('oncogenic pathways', 'Pathway', (134, 152))	('STAT3', 'Gene', (177, 182))	('Cancer', 'Disease', (0, 6))	('PD-L1', 'Gene', (106, 111))
41098	31715131	CPB is under continued investigation and is now part of the standard therapy for advanced melanoma, NSCLC, Merkel cell carcinoma, head and neck squamous cell carcinoma, urothelial and kidney cancers, refractory Hodgkin lymphoma, hepatocellular carcinoma, gastric cancer, and cancers with high microsatellite instability (MSIH).	('melanoma', 'Disease', (90, 98))	('refractory Hodgkin lymphoma', 'Disease', (200, 227))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (139, 167))	('neck', 'cellular_component', 'GO:0044326', ('139', '143'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (229, 253))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('gastric cancer', 'Disease', 'MESH:D013274', (255, 269))	('refractory Hodgkin lymphoma', 'Disease', 'MESH:D006689', (200, 227))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (130, 167))	('kidney cancers', 'Phenotype', 'HP:0009726', (184, 198))	('hepatocellular carcinoma', 'Disease', (229, 253))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('CPB', 'Chemical', '-', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('NSCLC', 'Disease', (100, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (255, 269))	('high microsatellite instability', 'Var', (288, 319))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (107, 128))	('cancers', 'Disease', (275, 282))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (211, 227))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (229, 253))	('urothelial and kidney cancers', 'Disease', 'MESH:D007680', (169, 198))	('neck squamous cell carcinoma', 'Disease', (139, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (219, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('gastric cancer', 'Disease', (255, 269))	('Merkel cell carcinoma', 'Disease', (107, 128))
41105	31715131	Tumors often and to varying degrees express neoantigens within the context of MHC as a result of mutations that generate altered proteins.	('mutations', 'Var', (97, 106))	('express', 'Reg', (36, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('altered', 'Reg', (121, 128))	('neoantigens', 'MPA', (44, 55))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('proteins', 'Protein', (129, 137))
41107	31715131	Patients whose NSCLC tumors had higher levels of nonsynonymous mutations:namely, mutations that result in the production of a different amino acid and, subsequently, a different protein:were more responsive to PD-1 blockade.	('NSCLC tumors', 'Disease', 'MESH:D009369', (15, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('NSCLC tumors', 'Disease', (15, 27))	('Patients', 'Species', '9606', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('production', 'MPA', (110, 120))	('responsive', 'MPA', (196, 206))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
41123	31715131	As the T cell is capable of high-fidelity transgene expression and is a potent antitumor effector, it is an ideal host cell for the CAR.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('host cell', 'cellular_component', 'GO:0043657', ('114', '123'))	('tumor', 'Disease', (83, 88))	('transgene', 'Var', (42, 51))	('CAR', 'cellular_component', 'GO:0005826', ('132', '135'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
41125	31715131	Second- and third-generation CARs, which were designed with one or multiple costimulatory domains (e.g., 4-1BB, CD28, ICOS, and OX40) in addition to the CD3zeta domain, have demonstrated superior antitumor efficacy, which has been associated with enhanced T-cell accumulation, cytokine secretion, cytotoxicity, and long-term persistence.	('CARs', 'Gene', (29, 33))	('4-1BB', 'Gene', (105, 110))	('enhanced', 'PosReg', (247, 255))	('ICOS', 'Gene', (118, 122))	('cytotoxicity', 'Disease', (297, 309))	('cytokine secretion', 'biological_process', 'GO:0050663', ('277', '295'))	('4-1BB', 'Gene', '3604', (105, 110))	('OX40', 'Gene', '7293', (128, 132))	('CARs', 'Gene', '833', (29, 33))	('cytotoxicity', 'Disease', 'MESH:D064420', (297, 309))	('T-cell accumulation', 'CPA', (256, 275))	('tumor', 'Disease', (200, 205))	('CD28', 'Var', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cytokine', 'CPA', (277, 285))	('OX40', 'Gene', (128, 132))	('CD3zeta', 'Gene', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ICOS', 'Gene', '29851', (118, 122))	('CD3zeta', 'Gene', '919', (153, 160))
41151	31715131	Overexpression of PD-L1 and PD-L2 on tumor cells directly inhibits CAR T-cell effector functions, especially after chronic antigen stimulation.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CAR', 'cellular_component', 'GO:0005826', ('67', '70'))	('inhibits', 'NegReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('PD-L2', 'Gene', (28, 33))	('PD-L2', 'Gene', '80380', (28, 33))	('PD-L1', 'Var', (18, 23))	('CAR T-cell effector functions', 'CPA', (67, 96))
41157	31715131	PD-1 blockade enhanced in vitro T-cell proliferation, IFN-gamma production, granzyme B expression, and in vivo activity of CAR T cells.	('blockade', 'Var', (5, 13))	('granzyme B', 'Gene', '100233184', (76, 86))	('PD-1', 'Gene', (0, 4))	('granzyme B', 'Gene', (76, 86))	('enhanced', 'PosReg', (14, 22))	('CAR', 'cellular_component', 'GO:0005826', ('123', '126'))	('T-cell proliferation', 'CPA', (32, 52))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('32', '52'))
41173	31715131	Cy/Flu lymphodepletion significantly increased levels of IL-15 and CAR T-cell expansion, but the addition of pembrolizumab did not further enhance this accumulation or persistence.	('Cy/Flu', 'Var', (0, 6))	('IL-15', 'Gene', (57, 62))	('IL-15', 'Gene', '3600', (57, 62))	('levels', 'MPA', (47, 53))	('cell expansion', 'biological_process', 'GO:0016049', ('73', '87'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (109, 122))	('increased', 'PosReg', (37, 46))	('Cy', 'Chemical', 'MESH:D003545', (0, 2))	('CAR', 'cellular_component', 'GO:0005826', ('67', '70'))	('CAR T-cell expansion', 'CPA', (67, 87))	('IL-15', 'molecular_function', 'GO:0016170', ('57', '62'))
41182	31715131	When co-expressed with an anti-mesothelin CAR T cell, PD-1:CD28 chimera enhanced CAR T-cell effector functions and persistence in vivo, thus leading to durable efficacy and tumor eradication of established tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('chimera', 'Var', (64, 71))	('tumor', 'Disease', (206, 211))	('CD28', 'Gene', (59, 63))	('persistence', 'CPA', (115, 126))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (173, 178))	('enhanced', 'PosReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('CAR', 'cellular_component', 'GO:0005826', ('42', '45'))	('CAR', 'cellular_component', 'GO:0005826', ('81', '84'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('leading to', 'Reg', (141, 151))	('CAR T-cell effector functions', 'CPA', (81, 110))
41186	31715131	Also, off-target cleavage must be identified and limited, and added PD-1 gene editing, in addition to CAR transgene, may produce genotoxicity, with negative effects on T-cell proliferation and effector functions.	('gene editing', 'Var', (73, 85))	('CAR', 'cellular_component', 'GO:0005826', ('102', '105'))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('168', '188'))	('produce', 'Reg', (121, 128))	('genotoxicity', 'Disease', (129, 141))	('T-cell proliferation', 'CPA', (168, 188))	('genotoxicity', 'Disease', 'None', (129, 141))	('PD-1', 'Gene', (68, 72))
41207	31715131	And as with all functional enhancements to a targeted therapy, combination CPB enhances efficacy but risks increasing toxicity.	('CPB', 'Chemical', '-', (75, 78))	('efficacy', 'MPA', (88, 96))	('combination', 'Var', (63, 74))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('toxicity', 'Disease', (118, 126))	('enhances', 'PosReg', (79, 87))
41209	31715131	An optimal solid-tumor antigen target is one whose expression is restricted to expendable cells or, better yet, tumor cells only, such as the mutated form of EGFR expressed on glioblastoma multiforme tumors, or neoantigen peptide: MHC complexes, which have yet to be developed but theoretically could selectively target unique tumor mutations.	('mutated', 'Var', (142, 149))	('glioblastoma multiforme tumors', 'Disease', 'MESH:D005909', (176, 206))	('glioblastoma multiforme tumors', 'Disease', (176, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))	('tumor antigen', 'molecular_function', 'GO:0008222', ('17', '30'))	('tumor', 'Disease', (327, 332))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('EGFR', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
41220	31681580	In multivariable analysis, high gC1qR expression was an independent factor for improved OS in patients treated with NAC.	('NAC', 'cellular_component', 'GO:0005854', ('116', '119'))	('patients', 'Species', '9606', (94, 102))	('gC1qR', 'Gene', (32, 37))	('gC1qR', 'Gene', '708', (32, 37))	('improved', 'PosReg', (79, 87))	('high', 'Var', (27, 31))
41221	31681580	In the No-NAC cohort, high gC1qR expression correlated with lower tumor stage.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('NAC', 'cellular_component', 'GO:0005854', ('10', '13'))	('high', 'Var', (22, 26))	('gC1qR', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))	('gC1qR', 'Gene', '708', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('lower', 'NegReg', (60, 65))
41222	31681580	Moreover, the influence of Ki67 and CD4 T-cell infiltration on OS were more pronounced among patients with high gC1qR expression.	('gC1qR', 'Gene', (112, 117))	('gC1qR', 'Gene', '708', (112, 117))	('CD4', 'Gene', (36, 39))	('high', 'Var', (107, 111))	('CD4', 'Gene', '920', (36, 39))	('patients', 'Species', '9606', (93, 101))
41250	31681580	Patients with mesotheliomas either underwent surgical resection without neoadjuvant chemotherapy (No-NAC cohort) or received NAC (NAC cohort) prior to resection.	('NAC', 'cellular_component', 'GO:0005854', ('101', '104'))	('mesotheliomas', 'Disease', 'MESH:D008654', (14, 27))	('mesotheliomas', 'Disease', (14, 27))	('NAC', 'Var', (125, 128))	('NAC', 'cellular_component', 'GO:0005854', ('125', '128'))	('Patients', 'Species', '9606', (0, 8))	('NAC', 'cellular_component', 'GO:0005854', ('130', '133'))
41303	31681580	High gC1qR expression was associated with better overall survival in patients with epithelioid MPM in both NAC (Figure 2A; median OS, 25 vs. 11 months, p = 0.020) and No-NAC cohorts (Figure 2B; median OS, 18 vs. 16 months, p = 0.023).	('overall survival', 'MPA', (49, 65))	('gC1qR', 'Gene', (5, 10))	('MPM', 'Disease', 'MESH:C562839', (95, 98))	('gC1qR', 'Gene', '708', (5, 10))	('High', 'Var', (0, 4))	('MPM', 'Disease', (95, 98))	('better', 'PosReg', (42, 48))	('NAC', 'cellular_component', 'GO:0005854', ('170', '173'))	('NAC', 'cellular_component', 'GO:0005854', ('107', '110'))	('patients', 'Species', '9606', (69, 77))
41318	31681580	Due to the relationships between gC1qR and Ki-67 expression as well as infiltrating immune cells in the no-NAC cohort, multivariable models were developed separately among patients with low gC1qR expression and high gC1qR expression to quantify differential impact of Ki67 and CD4 based on levels of gC1qR.	('gC1qR', 'Gene', '708', (190, 195))	('low', 'NegReg', (186, 189))	('gC1qR', 'Gene', (33, 38))	('high', 'Var', (211, 215))	('CD4', 'Gene', '920', (277, 280))	('gC1qR', 'Gene', '708', (33, 38))	('NAC', 'cellular_component', 'GO:0005854', ('107', '110'))	('expression', 'MPA', (222, 232))	('expression', 'MPA', (196, 206))	('gC1qR', 'Gene', (216, 221))	('gC1qR', 'Gene', '708', (216, 221))	('gC1qR', 'Gene', (300, 305))	('gC1qR', 'Gene', '708', (300, 305))	('Ki-67', 'Gene', (43, 48))	('patients', 'Species', '9606', (172, 180))	('CD4', 'Gene', (277, 280))	('gC1qR', 'Gene', (190, 195))
41328	31681580	In this surgical patient cohort, high gC1qR expression correlated with better overall survival in patients who received NAC or any post-operative chemotherapy.	('high', 'Var', (33, 37))	('patient', 'Species', '9606', (98, 105))	('patient', 'Species', '9606', (17, 24))	('patients', 'Species', '9606', (98, 106))	('gC1qR', 'Gene', '708', (38, 43))	('overall survival', 'MPA', (78, 94))	('NAC', 'cellular_component', 'GO:0005854', ('120', '123'))	('gC1qR', 'Gene', (38, 43))	('better', 'PosReg', (71, 77))
41341	31681580	In the present study, univariable cox proportional hazard analysis confirmed that in patients who did not receive neoadjuvant chemotherapy, Ki-67 was associated with a higher hazard ratio for death.	('patients', 'Species', '9606', (85, 93))	('death', 'Disease', 'MESH:D003643', (192, 197))	('Ki-67', 'Var', (140, 145))	('death', 'Disease', (192, 197))
41344	31681580	The apparent contradictory association between high gC1qR expression and worse OS in patients with tumors expressing a high Ki-67 index, compared to the overall favorable prognostic influence of high gC1qR expression in patients who undergo chemotherapy or whose tumors express high CD4 lymphocyte infiltration, is not well-understood.	('patients', 'Species', '9606', (220, 228))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('CD4', 'Gene', '920', (283, 286))	('high CD4 lymphocyte infiltration', 'Phenotype', 'HP:0005407', (278, 310))	('worse OS', 'Disease', (73, 81))	('high', 'Var', (47, 51))	('patients', 'Species', '9606', (85, 93))	('CD4', 'Gene', (283, 286))	('gC1qR', 'Gene', '708', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('CD4 lymphocyte infiltration', 'Phenotype', 'HP:0005407', (283, 310))	('gC1qR', 'Gene', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('gC1qR', 'Gene', '708', (200, 205))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', (263, 269))	('gC1qR', 'Gene', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
41349	31681580	Interestingly, in the present study, high gC1qR expression combined with high CD4 staining in patients in the no- NAC cohort was associated with better OS in both univariable and multivariable analysis.	('CD4', 'Gene', '920', (78, 81))	('patients', 'Species', '9606', (94, 102))	('high', 'Var', (37, 41))	('NAC', 'cellular_component', 'GO:0005854', ('114', '117'))	('gC1qR', 'Gene', (42, 47))	('gC1qR', 'Gene', '708', (42, 47))	('CD4', 'Gene', (78, 81))	('better OS', 'Disease', (145, 154))
41354	31681580	Although gC1qR expression was not associated with differences in immune cell infiltration, patients bearing tumors with high gC1qR expression and high CD4 T cell infiltration had better OS than other combinations.	('gC1qR', 'Gene', '708', (9, 14))	('CD4', 'Gene', (151, 154))	('high CD4 T cell infiltration', 'Phenotype', 'HP:0005407', (146, 174))	('CD4', 'Gene', '920', (151, 154))	('patients', 'Species', '9606', (91, 99))	('gC1qR', 'Gene', '708', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('high', 'Var', (120, 124))	('better', 'PosReg', (179, 185))	('high CD4 T cell', 'Phenotype', 'HP:0032219', (146, 161))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('CD4 T cell infiltration', 'Phenotype', 'HP:0005407', (151, 174))	('gC1qR', 'Gene', (125, 130))	('gC1qR', 'Gene', (9, 14))
41356	31681580	The correlation of high gC1qR expression with lower tumor stage, and better OS in patients with epithelioid MPM differs from observations made in a variety of adenocarcinomas, in which increased gC1qR expression was associated with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high', 'Var', (19, 23))	('tumor', 'Disease', (52, 57))	('patients', 'Species', '9606', (82, 90))	('gC1qR', 'Gene', '708', (24, 29))	('gC1qR', 'Gene', (195, 200))	('adenocarcinomas', 'Disease', 'MESH:D000230', (159, 174))	('gC1qR', 'Gene', '708', (195, 200))	('adenocarcinomas', 'Disease', (159, 174))	('gC1qR', 'Gene', (24, 29))	('MPM', 'Disease', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('MPM', 'Disease', 'MESH:C562839', (108, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
41364	31681580	In MPM, CD44-HA interactions modify cell signaling pathways triggering malignant cell migration and metastasis and have been described as a possible docking/signaling molecule for gC1qR.	('modify', 'Reg', (29, 35))	('metastasis', 'Disease', 'MESH:D009362', (100, 110))	('metastasis', 'Disease', (100, 110))	('triggering', 'Reg', (60, 70))	('CD44', 'Gene', (8, 12))	('malignant cell migration', 'CPA', (71, 95))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('signaling molecule', 'molecular_function', 'GO:0048018', ('157', '175'))	('cell migration', 'biological_process', 'GO:0016477', ('81', '95'))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('MPM', 'Disease', 'MESH:C562839', (3, 6))	('MPM', 'Disease', (3, 6))	('interactions', 'Var', (16, 28))	('gC1qR', 'Gene', (180, 185))	('gC1qR', 'Gene', '708', (180, 185))	('cell signaling pathways', 'Pathway', (36, 59))	('CD44', 'Gene', '960', (8, 12))
41379	30226590	Furthermore, inhibition of activated epidermal growth factor (EGFR)-associated survival pathways enhance PDT efficacy.	('EGFR', 'Gene', '1956', (62, 66))	('PDT', 'Disease', (105, 108))	('inhibition', 'Var', (13, 23))	('EGFR', 'Gene', (62, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('enhance', 'PosReg', (97, 104))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('37', '60'))
41387	30226590	FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging.	('fluorescence', 'MPA', (74, 86))	('disassembly', 'MPA', (28, 39))	('activation', 'PosReg', (87, 97))	('FOLR1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('targeting', 'Var', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('MPM tumors', 'Disease', (128, 138))	('MPM tumors', 'Disease', 'MESH:D009369', (128, 138))
41400	30226590	At present, a few photosensitizers have been clinically approved for cancer therapy, including porfimer sodium (Photofrin ) in the USA and m-tetrahydroxyphenylchlorin (Foscan ) in Europe.	('m-tetrahydroxyphenylchlorin', 'Chemical', 'MESH:C072269', (139, 166))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('m-tetrahydroxyphenylchlorin', 'Var', (139, 166))	('clinical', 'Species', '191496', (45, 53))	('Foscan', 'Chemical', 'MESH:C072269', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
41403	30226590	Similarly, Foscan-PDT may cause severe toxicity and even mortality.	('cause', 'Reg', (26, 31))	('Foscan-PDT', 'Var', (11, 21))	('Foscan', 'Chemical', 'MESH:C072269', (11, 17))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('toxicity', 'Disease', (39, 47))
41415	30226590	Another aspect of PDT is that it has been reported to stimulate survival pathways via the nuclear accumulation of activated epidermal growth factor receptor (EGFR).	('nuclear accumulation', 'MPA', (90, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))	('survival', 'CPA', (64, 72))	('EGFR', 'Gene', (158, 162))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('124', '147'))	('epidermal growth factor receptor', 'Gene', (124, 156))	('PDT', 'Var', (18, 21))	('EGFR', 'Gene', '1956', (158, 162))	('stimulate', 'PosReg', (54, 63))	('epidermal growth factor receptor', 'Gene', '1956', (124, 156))
41484	30226590	The PDT efficacy of FPs was investigated in the subcutaneous tumor model using three groups (n=6/ group), as follows: No treatment, light only and FP-PDT at 24 h after i.v.	('men', 'Species', '9606', (126, 129))	('FPs', 'molecular_function', 'GO:0047221', ('20', '23'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (48, 66))	('FP-PDT', 'Var', (147, 153))	('tumor', 'Disease', (61, 66))
41514	30226590	Sections were then drained and incubated at room temperature with the appropriate primary antibodies, under previously optimized conditions: Cleaved caspase-3 (cat.	('Cleaved', 'Var', (141, 148))	('caspase-3', 'Gene', '836', (149, 158))	('cat', 'molecular_function', 'GO:0004096', ('160', '163'))	('caspase-3', 'Gene', (149, 158))
41530	30226590	Notably, 71% of MPM cases expressed both FOLR1 and EGFR (76% of epithelioid and 85% of biphasic cases) (Table IV).	('MPM', 'Disease', (16, 19))	('EGFR', 'Gene', (51, 55))	('FOLR1', 'Var', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('EGFR', 'Gene', '1956', (51, 55))
41547	30226590	Conversely, FP-PDT caused typical initial tumor swelling at day 1 post-treatment, which resolved by day 2, with subsequent inhibition of tumor growth (Fig.	('tumor swelling', 'Disease', 'MESH:D004487', (42, 56))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (137, 142))	('FP-PDT', 'Var', (12, 18))	('men', 'Species', '9606', (76, 79))	('inhibition', 'NegReg', (123, 133))	('tumor swelling', 'Disease', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
41552	30226590	In a previous study, FP-PDT was revealed to achieve complete tumor elimination using optimized dosing in subcutaneous KB tumors; therefore, optimizing the doses in the MPM model is likely to further enhance the efficacy.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('optimizing', 'Var', (140, 150))	('KB tumors', 'Disease', 'MESH:D009072', (118, 127))	('enhance', 'PosReg', (199, 206))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('KB tumors', 'Disease', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
41554	30226590	One contributor to tumor regrowth/recurrence following PDT (in general) is induced activation of cell cycle progression pathways, such as EGFR.	('EGFR', 'Gene', '1956', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cell cycle progression pathways', 'Pathway', (97, 128))	('PDT', 'Var', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EGFR', 'Gene', (138, 142))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('tumor', 'Disease', (19, 24))	('activation', 'PosReg', (83, 93))
41555	30226590	Benzoporphyrin derivative-mediated PDT stimulates EGFR tyrosine phosphorylation and nuclear translocation from the cellular membrane, whereas EGFR inhibition by erlotinib results in a reduction of PDT-mediated EGFR activation.	('nuclear translocation from the cellular membrane', 'MPA', (84, 132))	('stimulates', 'PosReg', (39, 49))	('Benzoporphyrin', 'Chemical', '-', (0, 14))	('tyrosine', 'Chemical', 'MESH:D014443', (55, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('EGFR', 'Gene', (210, 214))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('PDT', 'Var', (35, 38))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('erlotinib', 'Chemical', 'MESH:D000069347', (161, 170))	('EGFR', 'Gene', (50, 54))	('cellular membrane', 'cellular_component', 'GO:0005886', ('115', '132'))	('EGFR', 'Gene', '1956', (210, 214))
41556	30226590	In the MPM in vivo model, IHC demonstrated that EGFR was markedly activated in the region of effective FP-PDT (Fig.	('FP-PDT', 'Var', (103, 109))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('activated', 'PosReg', (66, 75))
41562	30226590	In addition, there was a slight decrease in the viability of H2052 cells treated with FP-PDT (10 J/cm2) and EGFR-TKI, as compared with cells treated with FP-PDT only, even though there was no statistical significance (from 19.0+-1.1 to 12.1+-0.7%; Fig.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('H2052', 'CellLine', 'CVCL:1518', (61, 66))	('FP-PDT (10 J/cm2', 'Var', (86, 102))	('decrease', 'NegReg', (32, 40))
41569	30226590	However, tumors treated with FP-PDT still exhibited high EGFR activation and partial nuclear translocation (Fig.	('FP-PDT', 'Var', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'Gene', '1956', (57, 61))	('tumors', 'Disease', (9, 15))	('EGFR', 'Gene', (57, 61))	('activation', 'PosReg', (62, 72))
41570	30226590	Since nuclear translocation of EGFR is thought to mediate anti-apoptotic signaling, these results suggested that FP-PDT initiated nuclear signaling of EGFR, which resulted in reduced PDT cytotoxicity.	('reduced', 'NegReg', (175, 182))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (151, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('EGFR', 'Gene', (31, 35))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('FP-PDT', 'Var', (113, 119))	('nuclear signaling', 'MPA', (130, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('cytotoxicity', 'Disease', (187, 199))	('PDT', 'MPA', (183, 186))	('EGFR', 'Gene', '1956', (151, 155))
41578	30226590	Likely as a consequence of this, FPs exhibited markedly higher cellular uptake compared with non-targeted porphysomes in vitro, and possessed higher photocytotoxicity in FOLR1-positive MPM cell lines.	('cellular', 'CPA', (63, 71))	('FPs', 'Var', (33, 36))	('uptake', 'biological_process', 'GO:0098739', ('72', '78'))	('uptake', 'biological_process', 'GO:0098657', ('72', '78'))	('cytotoxicity', 'Disease', (154, 166))	('higher', 'PosReg', (56, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))	('FPs', 'molecular_function', 'GO:0047221', ('33', '36'))	('higher', 'PosReg', (142, 148))
41581	30226590	Notably, however, only FPs were internalized into the FOLR1- positive tumor cells and became reactivated for PDT upon disruption of the nanostructure, whereas non-targeted porphysomes remained in the interstitial space and most of them remained photodynamically quenched.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('disruption', 'Var', (118, 128))	('tumor', 'Disease', (70, 75))	('FPs', 'molecular_function', 'GO:0047221', ('23', '26'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
41585	30226590	Although tumor growth in vivo was significantly suppressed by FP-PDT, the tumor recurred and all mice eventually reached the endpoint by 21 days after treatment.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('men', 'Species', '9606', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (97, 101))	('suppressed', 'NegReg', (48, 58))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (74, 79))	('FP-PDT', 'Var', (62, 68))
41587	30226590	Since it has been reported that inhibiting EGFR signaling increases PDT cytotoxicity through a mechanism that involves increased apoptotic cell death, the present study investigated this as a strategy to improve FP-PDT.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('129', '149'))	('increases', 'PosReg', (58, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('apoptotic cell death', 'CPA', (129, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('PDT', 'Disease', (68, 71))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('EGFR', 'Gene', '1956', (43, 47))	('inhibiting', 'Var', (32, 42))	('cytotoxicity', 'Disease', (72, 84))	('EGFR', 'Gene', (43, 47))	('increased', 'PosReg', (119, 128))
41588	30226590	The human-TMA analysis revealed ~89% EGFR positivity and, more importantly, ~70% coexpression of FOLR1 and EGFR in MPM.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('human', 'Species', '9606', (4, 9))	('EGFR', 'Gene', '1956', (107, 111))	('positivity', 'Var', (42, 52))	('EGFR', 'Gene', (107, 111))	('TMA', 'Chemical', '-', (10, 13))	('FOLR1', 'Gene', (97, 102))	('EGFR', 'Gene', '1956', (37, 41))	('coexpression', 'Interaction', (81, 93))	('EGFR', 'Gene', (37, 41))
41590	30226590	Numerous mechanisms may be involved here, including erlotinib-induced increase of photosensitizer accumulation and/or sensitization of the tumor vasculature.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('increase', 'PosReg', (70, 78))	('photosensitizer accumulation', 'MPA', (82, 110))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('erlotinib-induced', 'Var', (52, 69))	('photosensitizer accumulation', 'Phenotype', 'HP:0000992', (82, 110))	('sensitization', 'biological_process', 'GO:0046960', ('118', '131'))	('erlotinib', 'Chemical', 'MESH:D000069347', (52, 61))
41770	25772281	Adjuvant RT was also associated with significantly longer time to local recurrence and local recurrence-free survival when correcting for histology, HIOC, and adjuvant chemotherapy (Table 4).	('HIOC', 'Chemical', '-', (149, 153))	('local recurrence-free survival', 'CPA', (87, 117))	('Adjuvant', 'Var', (0, 8))	('local recurrence', 'CPA', (66, 82))	('longer', 'PosReg', (51, 57))
41810	22065079	PI3K, AKT and the downstream mTOR are involved in cell growth and survival and are often found to be activated in mesothelioma.	('AKT', 'Gene', (6, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('involved', 'Reg', (38, 46))	('mTOR', 'Gene', (29, 33))	('mTOR', 'Gene', '2475', (29, 33))	('mesothelioma', 'Disease', (114, 126))	('AKT', 'Gene', '207', (6, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))	('activated', 'PosReg', (101, 110))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))
41817	22065079	The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma and melanocytic tumors provides researchers with a novel target for prevention and early detection.	('melanocytic tumors', 'Disease', 'MESH:D009508', (133, 151))	('mutations', 'Var', (45, 54))	('cancer syndrome', 'Disease', 'MESH:D009369', (67, 82))	('melanocytic tumors', 'Disease', (133, 151))	('cancer syndrome', 'Disease', (67, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('mesothelioma', 'Disease', (100, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('uveal melanoma', 'Disease', (114, 128))	('BAP1', 'Gene', '8314', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cause', 'Reg', (55, 60))	('BAP1', 'Gene', (40, 44))
41842	22065079	Germline mutations of the BAP1 gene have now been linked to the high incidence of MM in some US families.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', '8314', (26, 30))	('linked to', 'Reg', (50, 59))
41843	22065079	Individuals with heterozygous BAP1 germline mutations are affected by a novel cancer syndrome characterized by very high risk of developing mesothelioma, uveal melanoma, and possibly additional cancers.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('BAP1', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('mesothelioma', 'Disease', (140, 152))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('BAP1', 'Gene', '8314', (30, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('affected', 'Reg', (58, 66))	('cancers', 'Disease', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer syndrome', 'Disease', 'MESH:D009369', (78, 93))	('cancer syndrome', 'Disease', (78, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('germline mutations', 'Var', (35, 53))
41845	22065079	The identification of BAP1 mutant carriers may be facilitated by the detection of melanocytic nevi as described by Wiesner et al and confirmed by genetic testing.	('mutant', 'Var', (27, 33))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('melanocytic nevi', 'Disease', (82, 98))	('BAP1', 'Gene', '8314', (22, 26))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (82, 98))	('BAP1', 'Gene', (22, 26))
41849	22065079	Mutations that abolish the deubiquitinating activity of BAP1 and/or its nuclear localization abolish BAP1 tumor suppressor activity.	('localization', 'biological_process', 'GO:0051179', ('80', '92'))	('BAP1', 'Gene', '8314', (56, 60))	('nuclear localization', 'MPA', (72, 92))	('BAP1', 'Gene', '8314', (101, 105))	('abolish', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('abolish', 'NegReg', (15, 22))	('BAP1', 'Gene', (56, 60))	('BAP1', 'Gene', (101, 105))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('tumor', 'Disease', (106, 111))	('deubiquitinating activity', 'MPA', (27, 52))
41851	22065079	Ventii et al proposed that expression of BAP1 induces early exit out of G1 causing an accumulation of DNA damage and cell death.	('BAP1', 'Gene', (41, 45))	('accumulation', 'PosReg', (86, 98))	('DNA damage', 'MPA', (102, 112))	('cell death', 'biological_process', 'GO:0008219', ('117', '127'))	('expression', 'Var', (27, 37))	('induces', 'Reg', (46, 53))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('BAP1', 'Gene', '8314', (41, 45))
41862	22065079	P16INK4a and p14ARF are frequently inactivated in mesothelioma, and approximately 50% of mesotheliomas contain missense or nonsense mutations in the neurofibromatosis type 2 (NF2) gene.	('mesotheliomas', 'Disease', 'MESH:D008654', (89, 102))	('neurofibromatosis type 2', 'Disease', (149, 173))	('mesothelioma', 'Disease', (89, 101))	('P16INK4a', 'Gene', (0, 8))	('mesotheliomas', 'Disease', (89, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('p14ARF', 'Gene', '1029', (13, 19))	('p14ARF', 'Gene', (13, 19))	('NF2', 'Gene', '4771', (175, 178))	('missense', 'Var', (111, 119))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (149, 166))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('mesothelioma', 'Disease', (50, 62))	('P16INK4a', 'Gene', '1029', (0, 8))	('NF2', 'Gene', (175, 178))	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (149, 173))	('nonsense mutations', 'Var', (123, 141))
41877	22065079	This allows HM that accumulated asbestos-induced genetic damage to survive, divide and propagate genetic aberrations in pre-malignant cells that can give rise to a malignant clone.	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('genetic aberrations', 'Var', (97, 116))	('pre', 'molecular_function', 'GO:0003904', ('120', '123'))	('genetic damage', 'Disease', 'MESH:D030342', (49, 63))	('give rise to', 'Reg', (149, 161))	('genetic damage', 'Disease', (49, 63))	('malignant clone', 'CPA', (164, 179))
41888	22065079	Moreover, the disheveled proteins, also downstream of Wnt, are often over-expressed in mesothelioma and siRNA knockdown of disheveled suppressed mesothelioma growth.	('knockdown', 'Var', (110, 119))	('suppressed', 'NegReg', (134, 144))	('mesothelioma', 'Disease', (87, 99))	('over-expressed', 'PosReg', (69, 83))	('mesothelioma', 'Disease', (145, 157))	('mesothelioma growth', 'Disease', (145, 164))	('mesothelioma growth', 'Disease', 'MESH:D008654', (145, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))
41892	22065079	PI3K, AKT and the downstream mTOR are often found to be activated in mesothelioma, and inhibition of mTOR using rapamycin enhances the apoptosis of mesothelioma cells in vitro, which suggest that mTOR may serve as a target for mesothelioma therapies (Figure 2).	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('mTOR', 'Gene', '2475', (101, 105))	('mesothelioma', 'Disease', (227, 239))	('enhances', 'PosReg', (122, 130))	('mTOR', 'Gene', '2475', (29, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('AKT', 'Gene', (6, 9))	('rapamycin', 'Chemical', 'MESH:D020123', (112, 121))	('AKT', 'Gene', '207', (6, 9))	('mTOR', 'Gene', (196, 200))	('activated', 'PosReg', (56, 65))	('inhibition', 'Var', (87, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', (29, 33))	('mesothelioma', 'Disease', (69, 81))	('mesothelioma', 'Disease', (148, 160))	('mTOR', 'Gene', '2475', (196, 200))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
41920	22065079	Moreover, genetic testing for BAP1 mutations should help us identify among exposed cohorts of those genetically susceptible individuals that have the highest risk of developing mesothelioma.	('BAP1', 'Gene', (30, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (177, 189))	('BAP1', 'Gene', '8314', (30, 34))	('mesothelioma', 'Disease', (177, 189))	('mutations', 'Var', (35, 44))
42078	31537143	On the other hand, tumors act as wounds that fail to heal, wherein proliferating cells that sustain DNA damage and/or mutagenic assault continue to proliferate in a microenvironment that is rich in inflammatory cells, growth factors, and neovasculature, which support their growth.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('rat', 'Species', '10116', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('mutagenic', 'Var', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('rat', 'Species', '10116', (155, 158))
42109	31537143	Persistent gastritis caused by Helicobacter pylori increases the risk of gastric cancer by 75%, whereas hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are strongly associated with the formation of hepatocellular carcinoma.	('Helicobacter pylori', 'Species', '210', (31, 50))	('gastritis caused by Helicobacter pylori', 'Phenotype', 'HP:0005202', (11, 50))	('gastritis', 'Phenotype', 'HP:0005263', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (213, 237))	('associated', 'Reg', (180, 190))	('increases', 'PosReg', (51, 60))	('hepatitis', 'Phenotype', 'HP:0012115', (104, 113))	('gastritis', 'Disease', 'MESH:D005756', (11, 20))	('hepatitis B virus (HBV) and hepatitis C virus (HCV) infections', 'Disease', 'MESH:D006526', (104, 166))	('gastritis', 'Disease', (11, 20))	('hepatocellular carcinoma', 'Disease', (213, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('Helicobacter pylori', 'Var', (31, 50))	('hepatitis', 'Phenotype', 'HP:0012115', (132, 141))	('formation', 'biological_process', 'GO:0009058', ('200', '209'))	('Persistent gastritis', 'Phenotype', 'HP:0005231', (0, 20))	('gastric cancer', 'Disease', (73, 87))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (213, 237))
42205	31537143	In particular, MWNT-7 CNTs have been consistently found to be a strong tumor-inducing agent, both as an initiator and a promoter.	('MWNT-7 CNTs', 'Var', (15, 26))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
42229	31537143	Presumably, accumulated M-MDSC boost immunosuppression, which counteracts immune surveillance of tumor cells, thereby increasing tumor cell survival.	('boost', 'PosReg', (31, 36))	('increasing', 'PosReg', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('M-MDSC', 'Var', (24, 30))	('immunosuppression', 'CPA', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
42230	31537143	Long MWCNTs with diameters of ~50 nm and lengths of larger than 15 mum (85% fibers), which were directly instilled into the pleural cavity, induced mesotheliomas in the pleura of mice, with a similar carcinogenic potential to that of long asbestos; moreover, similarities between long CNT- and asbestos-induced mesotheliomas were noted, including latency, time course of progression, preceding inflammation and oxidative DNA damage, and epigenetic silencing of the tumor suppressor gene Cdkn2a (cyclin-dependent kinase 2a), which encodes p16Ink4a and p19ARF.	('pleural cavity', 'Disease', (124, 138))	('pleural cavity', 'Disease', 'MESH:D010995', (124, 138))	('mesotheliomas in the pleura', 'Disease', 'MESH:D008654', (148, 175))	('inflammation', 'Disease', 'MESH:D007249', (394, 406))	('mesotheliomas', 'Disease', (311, 324))	('mice', 'Species', '10090', (179, 183))	('p19ARF', 'Gene', (551, 557))	('tumor', 'Phenotype', 'HP:0002664', (465, 470))	('p16Ink4a', 'Gene', (538, 546))	('mesotheliomas', 'Disease', 'MESH:D008654', (311, 324))	('mesotheliomas in the pleura', 'Disease', (148, 175))	('inflammation', 'Disease', (394, 406))	('carcinogenic', 'Disease', (200, 212))	('cyclin', 'molecular_function', 'GO:0016538', ('495', '501'))	('p19', 'cellular_component', 'GO:0070743', ('551', '554'))	('tumor suppressor', 'Gene', (465, 481))	('p16Ink4a', 'Gene', '12578', (538, 546))	('mesotheliomas', 'Disease', (148, 161))	('Cdkn2a', 'Gene', '12578', (487, 493))	('inflammation', 'biological_process', 'GO:0006954', ('394', '406'))	('DNA', 'cellular_component', 'GO:0005574', ('421', '424'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('465', '481'))	('carcinogenic', 'Disease', 'MESH:D063646', (200, 212))	('mesotheliomas', 'Disease', 'MESH:D008654', (148, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('465', '481'))	('Cdkn2a', 'Gene', (487, 493))	('epigenetic silencing', 'Var', (437, 457))	('tumor suppressor', 'Gene', '7248', (465, 481))	('mesotheliomas in the pleura', 'Phenotype', 'HP:0100002', (148, 175))	('p19ARF', 'Gene', '12578', (551, 557))
42233	31537143	Inhalation of MWNT-7 nanotubes following tumor initiation with a single injection of methylcholanthrene (MCA) resulted in increased incidences of lung bronchoalveolar adenomas and adenocarcinomas, as well as serosal tumors morphologically consistent with sarcomatoid mesothelioma, in comparison with treatment with MCA alone, thereby establishing MWNT-7 as a strong tumor promoter in the lung (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lung bronchoalveolar adenomas and adenocarcinomas', 'Disease', 'MESH:C538231', (146, 195))	('sarcomatoid mesothelioma', 'Disease', 'MESH:D008654', (255, 279))	('nanotubes', 'Var', (21, 30))	('tumor', 'Disease', (216, 221))	('MCA', 'Chemical', 'MESH:D008748', (105, 108))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (85, 103))	('MWNT-7 nanotubes', 'Var', (14, 30))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('serosal tumors', 'Disease', (208, 222))	('tumor initiation', 'Disease', 'MESH:D009369', (41, 57))	('tumor', 'Disease', (366, 371))	('tumor', 'Disease', (41, 46))	('tumor initiation', 'Disease', (41, 57))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('serosal tumors', 'Disease', 'MESH:D012700', (208, 222))	('sarcomatoid mesothelioma', 'Disease', (255, 279))	('MCA', 'Chemical', 'MESH:D008748', (315, 318))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
42265	31537143	Functionally, NLRP3:IL-1beta pathway is clearly required for the acute inflammatory response, as suppression of the pathway by knocking out the gene encoding IL-1 receptor 1 (IL-1R1) or inhibiting IL-1R1 signaling using anakinra attenuated neutrophilia significantly.	('neutrophilia', 'Phenotype', 'HP:0011897', (240, 252))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('IL-1', 'molecular_function', 'GO:0005149', ('20', '24'))	('IL-1 receptor 1', 'Gene', (158, 173))	('acute inflammatory response', 'biological_process', 'GO:0002526', ('65', '92'))	('IL-1R', 'molecular_function', 'GO:0004908', ('197', '202'))	('suppression', 'NegReg', (97, 108))	('anakinra attenuated neutrophilia', 'Disease', 'MESH:C563010', (220, 252))	('IL-1 receptor 1', 'Gene', '3554', (158, 173))	('knocking out', 'Var', (127, 139))	('inhibiting', 'NegReg', (186, 196))	('IL-1R1', 'Gene', '3554', (197, 203))	('anakinra attenuated neutrophilia', 'Disease', (220, 252))	('IL-1', 'molecular_function', 'GO:0005149', ('158', '162'))	('IL-1R1', 'Gene', '3554', (175, 181))	('IL-1R1', 'Gene', (197, 203))	('IL-1R', 'molecular_function', 'GO:0004908', ('175', '180'))	('IL-1R1', 'Gene', (175, 181))
42266	31537143	On the other hand, knockout (KO) of STAT6 in mice suppressed both the acute inflammation and the fibrotic lesions induced by CNTs in comparison with wild-type mice.	('inflammation', 'Disease', 'MESH:D007249', (76, 88))	('fibrotic lesions', 'Disease', (97, 113))	('suppressed', 'NegReg', (50, 60))	('mice', 'Species', '10090', (45, 49))	('knockout', 'Var', (19, 27))	('inflammation', 'Disease', (76, 88))	('inflammation', 'biological_process', 'GO:0006954', ('76', '88'))	('STAT6', 'Gene', (36, 41))	('mice', 'Species', '10090', (159, 163))	('fibrotic lesions', 'Disease', 'MESH:D051437', (97, 113))
42272	31537143	Knockout of TGF-beta1 in mice is lethal by the age of 2-4 weeks due to excessive inflammatory responses in organs such as the heart and the lung.	('TGF-beta1', 'Gene', (12, 21))	('inflammatory responses', 'CPA', (81, 103))	('Knockout', 'Var', (0, 8))	('mice', 'Species', '10090', (25, 29))
42273	31537143	As such, it is difficult to investigate the effect of TGF-beta1 on organ fibrosis by knocking out or knocking down TGF-beta1 in animals.	('TGF-beta1', 'Gene', (115, 124))	('knocking', 'Var', (101, 109))	('fibrosis', 'Disease', 'MESH:D005355', (73, 81))	('fibrosis', 'Disease', (73, 81))	('knocking out', 'Var', (85, 97))
42278	31537143	On days 7 and 28 post-exposure to MWNT-7, the levels of TGF-beta1 protein in lung tissue and lung macrophages were significantly lower in OPN KO mice than those in wild-type (WT) mice.	('OPN KO', 'Var', (138, 144))	('mice', 'Species', '10090', (179, 183))	('protein', 'Protein', (66, 73))	('TGF-beta1', 'Gene', (56, 65))	('levels', 'MPA', (46, 52))	('mice', 'Species', '10090', (145, 149))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('lower', 'NegReg', (129, 134))
42288	31537143	As an example, OPN was induced by MWNT-7 in cultured mouse primary fibroblastic cells and was at high levels in fibrotic and granulomatous foci in mouse lungs during the chronic stage, i.e., on day 28 and day 56, post-exposure to MWNT-7.	('mouse', 'Species', '10090', (147, 152))	('granuloma', 'Phenotype', 'HP:0032252', (125, 134))	('granulomatous foci', 'Disease', 'MESH:C565785', (125, 143))	('induced', 'Reg', (23, 30))	('OPN', 'Gene', (15, 18))	('mouse', 'Species', '10090', (53, 58))	('granulomatous foci', 'Disease', (125, 143))	('MWNT-7', 'Var', (34, 40))
42323	31537143	Knockout of Timp1 in mice caused significant decreases in fibroblast accumulation, myofibroblast differentiation, collagen fiber deposition, and fibrotic focus formation in lungs exposed to MWNT-7, compared with WT.	('fibroblast accumulation', 'CPA', (58, 81))	('mice', 'Species', '10090', (21, 25))	('formation', 'biological_process', 'GO:0009058', ('160', '169'))	('decreases', 'NegReg', (45, 54))	('collagen', 'molecular_function', 'GO:0005202', ('114', '122'))	('collagen fiber deposition', 'CPA', (114, 139))	('myofibroblast differentiation', 'biological_process', 'GO:0036446', ('83', '112'))	('Knockout', 'Var', (0, 8))	('Timp1', 'Gene', '21857', (12, 17))	('fibrotic focus formation', 'CPA', (145, 169))	('Timp1', 'Gene', (12, 17))	('myofibroblast differentiation', 'CPA', (83, 112))
42325	31537143	Meanwhile, MWNT-7 elicited a significant induction of CD63 and integrin beta1 in lung fibroblasts and the formation of the TIMP1/CD63/integrin beta1 complex on the surface of fibroblasts, which triggered the phosphorylation and activation of Erk1/2 that mediates cell proliferation.	('integrin beta1', 'Gene', '3688', (63, 77))	('Erk1', 'molecular_function', 'GO:0004707', ('242', '246'))	('CD63', 'Gene', '967', (129, 133))	('MWNT-7', 'Var', (11, 17))	('integrin beta1', 'Gene', (134, 148))	('CD63', 'Gene', '967', (54, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('263', '281'))	('phosphorylation', 'biological_process', 'GO:0016310', ('208', '223'))	('integrin beta1', 'Gene', '3688', (134, 148))	('phosphorylation', 'MPA', (208, 223))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('CD63', 'Gene', (129, 133))	('CD63', 'Gene', (54, 58))	('Erk1/2', 'Protein', (242, 248))	('activation', 'MPA', (228, 238))	('rat', 'Species', '10116', (275, 278))	('integrin beta1', 'Gene', (63, 77))
42463	24334762	MDA-MB-231 was originally obtained from American Type Culture Collection (ATCC) and authenticated by the analysis of short tandem repeat sequences performed at MD Anderson Cancer Center, Texas, USA.	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('short tandem repeat sequences', 'Var', (117, 146))	('MDA-MB-231', 'Gene', (0, 10))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (0, 10))
42471	24334762	Tissue arrays were obtained from Cybrdi Inc (Rockville, MD) for breast cancer (CC08-10-001) and HNSCC (CC34-01-001), while melanoma (ME2082b), neuroblastoma (MC602), mesothelioma (T392), and normal tissue (FDA 808b) arrays were obtained from US Biomax, Inc. (Rockville, MD).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('ME2082b', 'Var', (133, 140))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('neuroblastoma', 'Disease', (143, 156))	('melanoma', 'Disease', (123, 131))	('mesothelioma', 'Disease', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('breast cancer', 'Disease', (64, 77))
42540	24334762	As expected CAR.CSPG4+ T lymphocytes secreted significantly more IL-2 than control T cells only in the presence of CSPG4+ tumor cells (Fig.	('CAR', 'cellular_component', 'GO:0005826', ('12', '15'))	('more', 'PosReg', (60, 64))	('IL-2', 'Gene', '3558', (65, 69))	('IL-2', 'molecular_function', 'GO:0005134', ('65', '69'))	('IL-2', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CAR.CSPG4+', 'Var', (12, 22))	('secreted', 'MPA', (37, 45))	('tumor', 'Disease', (122, 127))
42545	24334762	In all three models, CAR.CSPG4+ T lymphocytes inhibited tumor growth significantly better than control T lymphocytes (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('CAR', 'cellular_component', 'GO:0005826', ('21', '24'))	('CAR.CSPG4+ T', 'Var', (21, 33))	('inhibited', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
42546	24334762	By day 30, melanoma tumors reached a volume of 879 mm3 +- 124 mm3 in mice receiving CAR.CSPG4+ T lymphocytes versus 8359 mm3 +- 958 mm3 in mice receiving control T cells (p<0.001) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('melanoma tumors', 'Disease', 'MESH:D008545', (11, 26))	('CAR.CSPG4+ T', 'Var', (84, 96))	('CAR', 'cellular_component', 'GO:0005826', ('84', '87'))	('mice', 'Species', '10090', (69, 73))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma tumors', 'Disease', (11, 26))
42562	24334762	Antitumor effects mediated by CAR.CSPG4+ T cells significantly limit tumor growth in xenograft mouse models of melanoma, HNSCC and breast carcinoma, strongly validating our in vitro findings.	('tumor', 'Disease', (4, 9))	('HNSCC', 'Disease', (121, 126))	('CAR.CSPG4+ T', 'Var', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mouse', 'Species', '10090', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('breast carcinoma', 'Phenotype', 'HP:0003002', (131, 147))	('CAR', 'cellular_component', 'GO:0005826', ('30', '33'))	('HNSCC', 'Phenotype', 'HP:0012288', (121, 126))	('breast carcinoma', 'Disease', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('limit', 'NegReg', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('tumor', 'Disease', (69, 74))	('breast carcinoma', 'Disease', 'MESH:D001943', (131, 147))
42576	30386115	In this regard, paired-box gene 8 negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (115, 132))	('ovarian carcinoma', 'Disease', (115, 132))	('negativity', 'Var', (34, 44))	('paired-box gene 8', 'Protein', (16, 33))	('MPM', 'Disease', (106, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (115, 132))	('MPM', 'Chemical', '-', (106, 109))
42580	30386115	Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment.	('men', 'Species', '9606', (140, 143))	('DDX3X', 'Gene', '1654', (48, 53))	('BAP1', 'Gene', '8314', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('SETD2', 'Gene', '29072', (38, 43))	('Epigenetic modifiers', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', (32, 36))	('SETD2', 'Gene', (38, 43))	('tumor', 'Disease', (82, 87))	('DDX3X', 'Gene', (48, 53))
42640	30386115	One study revealed chromosome 9p21 deletion more frequently in pleural than in peritoneal tumors (85% vs. 36%), whereas 5p15 and 7p12 gains were more common in peritoneal than in pleural tumors.	('peritoneal tumors', 'Disease', (79, 96))	('pleural', 'Disease', 'MESH:D010995', (179, 186))	('pleural tumors', 'Disease', 'MESH:D010997', (179, 193))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('pleural', 'Disease', 'MESH:D010995', (63, 70))	('pleural', 'Disease', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('pleural', 'Disease', (63, 70))	('peritoneal tumors', 'Disease', 'MESH:D010534', (79, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('deletion', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('pleural tumors', 'Disease', (179, 193))
42648	30386115	Therefore, loss of nuclear BAP1 confirm the diagnosis of MPM but does not offer prognostic information.	('loss', 'Var', (11, 15))	('BAP1', 'Gene', (27, 31))	('MPM', 'Disease', (57, 60))	('MPM', 'Chemical', '-', (57, 60))	('BAP1', 'Gene', '8314', (27, 31))
42651	30386115	The combination of homozygous CDKN2A deletion and hemizygous NF2 loss in MPM is an independent prognostic factor, associated with shorter progression-free survival (PFS) and OS.	('loss', 'NegReg', (65, 69))	('MPM', 'Chemical', '-', (73, 76))	('deletion', 'Var', (37, 45))	('NF2', 'Gene', '4771', (61, 64))	('progression-free survival', 'CPA', (138, 163))	('CDKN2A', 'Gene', (30, 36))	('CDKN2A', 'Gene', '1029', (30, 36))	('shorter', 'NegReg', (130, 137))	('NF2', 'Gene', (61, 64))
42652	30386115	In addition, tumor suppressor gene BAP1 mutation can predispose to MPM.	('MPM', 'Disease', (67, 70))	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (13, 18))	('MPM', 'Chemical', '-', (67, 70))	('BAP1', 'Gene', '8314', (35, 39))	('predispose', 'Reg', (53, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('BAP1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))
42653	30386115	An array comparative genomic hybridization study involving 33 MPM patients revealed focal deletions affecting BAP1 and CDKN2A in 61% and 33% of cases, respectively, suggesting that similar genetic alterations drive MPM and pleural mesothelioma but at different frequencies.	('pleural mesothelioma', 'Disease', (223, 243))	('BAP1', 'Gene', '8314', (110, 114))	('drive', 'Reg', (209, 214))	('MPM', 'Disease', (215, 218))	('MPM', 'Chemical', '-', (215, 218))	('BAP1', 'Gene', (110, 114))	('CDKN2A', 'Gene', (119, 125))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (223, 243))	('CDKN2A', 'Gene', '1029', (119, 125))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (223, 243))	('MPM', 'Chemical', '-', (62, 65))	('deletions', 'Var', (90, 99))	('patients', 'Species', '9606', (66, 74))
42656	30386115	It has been suggested that miR-380-5p:a miRNA normally negligibly expressed in telomerase-positive MPM tissues:may interfere with telomerase activity and promotes cell growth impairment and induction of apoptosis in relevant models of MPM.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('190', '212'))	('miR-380-5p', 'Var', (27, 37))	('cell growth', 'biological_process', 'GO:0016049', ('163', '174'))	('activity', 'MPA', (141, 149))	('growth impairment', 'Phenotype', 'HP:0001510', (168, 185))	('promotes', 'PosReg', (154, 162))	('induction', 'Reg', (190, 199))	('apoptosis', 'CPA', (203, 212))	('telomerase', 'Enzyme', (130, 140))	('MPM', 'Chemical', '-', (235, 238))	('MPM', 'Chemical', '-', (99, 102))	('telomerase activity', 'molecular_function', 'GO:0003720', ('130', '149'))	('cell growth impairment', 'CPA', (163, 185))	('interfere', 'NegReg', (115, 124))	('men', 'Species', '9606', (181, 184))
42667	30386115	In this sequence of procedures, postponement of bowel reconstruction following resections until after the chemotherapy perfusion is considered, to reduce the risk of tumor cell seeding at anastomotic sites.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('men', 'Species', '9606', (40, 43))	('postponement', 'Var', (32, 44))
42692	30386115	CRS-HIPEC is considered as the standard first-line treatment for MPM, whereas systemic chemotherapy is the alternative approach for inoperable/unsuitable patients or for those patients who seek non-surgical management.	('patients', 'Species', '9606', (176, 184))	('men', 'Species', '9606', (56, 59))	('patients', 'Species', '9606', (154, 162))	('CRS-HIPEC', 'Var', (0, 9))	('MPM', 'Disease', (65, 68))	('CRS-HIPEC', 'Chemical', '-', (0, 9))	('men', 'Species', '9606', (213, 216))	('MPM', 'Chemical', '-', (65, 68))
42710	30386115	However, there is no consensus in the literature concerning the presence of epidermal growth factor receptor (EGFR) mutations in MPM.	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('epidermal growth factor receptor', 'Gene', (76, 108))	('MPM', 'Chemical', '-', (129, 132))	('mutations', 'Var', (116, 125))	('MPM', 'Gene', (129, 132))	('epidermal growth factor receptor', 'Gene', '1956', (76, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('76', '99'))
42711	30386115	These mutations were identified in 31% of patients diagnosed with MPM, a similar rate to that reported for non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('MPM', 'Chemical', '-', (66, 69))	('identified', 'Reg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('cell lung cancer', 'Disease', (117, 133))	('MPM', 'Disease', (66, 69))	('patients', 'Species', '9606', (42, 50))	('cell lung cancer', 'Disease', 'MESH:D008175', (117, 133))	('mutations', 'Var', (6, 15))
42712	30386115	The presence of EGFR mutations is predictive of optimal cytoreduction:the only surrogate factor that predicts long-term survival :treatment response and improved outcome as compared to the wild-type MPM.	('MPM', 'Chemical', '-', (199, 202))	('men', 'Species', '9606', (135, 138))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
42721	30386115	Furthermore, studies revealed that MORAb-009 blocks the binding of mesothelin to CA-125 and thus could be a promising approach for the prevention of tumor metastasis.	('MORAb-009', 'Chemical', 'MESH:C526187', (35, 44))	('MORAb-009', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mesothelin', 'Protein', (67, 77))	('blocks', 'NegReg', (45, 51))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('tumor metastasis', 'Disease', 'MESH:D009362', (149, 165))	('CA-125', 'Protein', (81, 87))	('tumor metastasis', 'Disease', (149, 165))
42722	30386115	Finally, the recombinant anti-mesothelin immunotoxin SS1(dsFv)PE38 demonstrated preclinical cytotoxic activity and is under clinical investigation.	('PE38', 'Var', (62, 66))	('SS1', 'Gene', '3123', (53, 56))	('SS1', 'Gene', (53, 56))
42730	30386115	In addition, NF2 alterations lead to activation of focal adhesion kinase (FAK) and merlin deficiency predicts sensitivity to FAK inhibitors.	('merlin', 'Gene', '4771', (83, 89))	('NF2', 'Gene', '4771', (13, 16))	('FAK', 'Gene', (74, 77))	('activation', 'PosReg', (37, 47))	('FAK', 'Gene', '5747', (125, 128))	('FAK', 'Gene', '5747', (74, 77))	('sensitivity to', 'MPA', (110, 124))	('focal adhesion', 'cellular_component', 'GO:0005925', ('51', '65'))	('focal adhesion kinase', 'Gene', (51, 72))	('NF2', 'Gene', (13, 16))	('merlin', 'Gene', (83, 89))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('deficiency', 'Var', (90, 100))	('FAK', 'molecular_function', 'GO:0004717', ('74', '77'))	('alterations', 'Var', (17, 28))	('FAK', 'Gene', (125, 128))	('focal adhesion kinase', 'Gene', '5747', (51, 72))
42731	30386115	The genomic profiling of MPM revealed recurrent mutations in the epigenetic regulatory genes BAP1, SETD2, and DDX3X.	('DDX3X', 'Gene', (110, 115))	('BAP1', 'Gene', '8314', (93, 97))	('SETD2', 'Gene', '29072', (99, 104))	('DDX3X', 'Gene', '1654', (110, 115))	('SETD2', 'Gene', (99, 104))	('BAP1', 'Gene', (93, 97))	('MPM', 'Chemical', '-', (25, 28))	('mutations', 'Var', (48, 57))	('MPM', 'Gene', (25, 28))
42733	30386115	Preclinical data suggest that inhibitors of epigenetic modifiers, including histone deacetylases and the histone methyltransferase EZH2, may be therapeutically beneficial in mesothelioma.	('mesothelioma', 'Disease', (174, 186))	('histone', 'Protein', (76, 83))	('inhibitors', 'Var', (30, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (174, 186))	('beneficial', 'PosReg', (160, 170))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))
42734	30386115	Those mesotheliomas that harbor inactivating events affecting both BAP1 and other transcriptional regulators, including SETD2 and DDX3X, probably constitute a molecular subgroup with altered transcriptional programs that may respond therapeutically to these agents.	('mesotheliomas', 'Disease', 'MESH:D008654', (6, 19))	('mesotheliomas', 'Disease', (6, 19))	('SETD2', 'Gene', '29072', (120, 125))	('SETD2', 'Gene', (120, 125))	('DDX3X', 'Gene', (130, 135))	('BAP1', 'Gene', '8314', (67, 71))	('inactivating events', 'Var', (32, 51))	('DDX3X', 'Gene', '1654', (130, 135))	('BAP1', 'Gene', (67, 71))
42736	30386115	Furthermore, in one study ALK rearrangements were identified in 3% of patients with MPM, mostly in younger women.	('ALK', 'Gene', (26, 29))	('patients', 'Species', '9606', (70, 78))	('MPM', 'Disease', (84, 87))	('MPM', 'Chemical', '-', (84, 87))	('ALK', 'Gene', '238', (26, 29))	('men', 'Species', '9606', (39, 42))	('women', 'Species', '9606', (107, 112))	('men', 'Species', '9606', (109, 112))	('rearrangements', 'Var', (30, 44))
42757	30386115	In addition, it has been suggested that cell proliferation biomarkers such as Ki-67 may play a prognostic role in patients with MPM; high Ki-67 in association with a high peritoneal cancer index resulted in a median OS of only 10 months.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('MPM', 'Chemical', '-', (128, 131))	('Ki-67', 'Gene', (138, 143))	('high', 'Var', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (114, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))
42764	30386115	Immunohistochemical loss of nuclear BAP1 is highly specific in the distinction of MPM from benign mesothelial proliferations.	('loss', 'Var', (20, 24))	('BAP1', 'Gene', '8314', (36, 40))	('MPM', 'Disease', (82, 85))	('mica', 'Chemical', 'MESH:C011934', (14, 18))	('MPM', 'Chemical', '-', (82, 85))	('BAP1', 'Gene', (36, 40))
42779	28674496	API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage.	('increased', 'PosReg', (42, 51))	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('induced', 'Reg', (105, 112))	('reactive oxygen species intracellular production', 'MPA', (52, 100))	('API', 'Chemical', 'MESH:D047310', (0, 3))	('increased reactive oxygen species intracellular production', 'Phenotype', 'HP:0025464', (42, 100))	('inhibited', 'NegReg', (4, 13))	('DNA damage', 'MPA', (113, 123))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (52, 75))	('API', 'Var', (0, 3))	('intracellular', 'cellular_component', 'GO:0005622', ('76', '89'))
42796	28674496	Preclinical trials have used a second generation of drugs including inhibitors of mTOR, folate, receptor tyrosine kinase and ciclooxygenase, while clinical trials have been carried out using chemotherapy with proteasome, mTOR and histone deacetylases inhibitors.	('ciclooxygenase', 'Enzyme', (125, 139))	('mTOR', 'Gene', (221, 225))	('mTOR', 'Gene', '2475', (221, 225))	('inhibitors', 'Var', (68, 78))	('tyrosine', 'Chemical', 'MESH:D014443', (105, 113))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('proteasome', 'molecular_function', 'GO:0004299', ('209', '219'))	('proteasome', 'cellular_component', 'GO:0000502', ('209', '219'))
42880	28674496	In addition, the expression of Bcl-2 was down-regulated in MM-F1-treated cells compared to DMSO-treated cells.	('MM-F1-treated', 'Var', (59, 72))	('Bcl-2', 'Gene', (31, 36))	('Bcl-2', 'Gene', '596', (31, 36))	('expression', 'MPA', (17, 27))	('Bcl-2', 'molecular_function', 'GO:0015283', ('31', '36'))	('DMSO', 'Chemical', 'MESH:D004121', (91, 95))	('down-regulated', 'NegReg', (41, 55))
42882	28674496	Furthermore, API increased p53 expression compared to DMSO treatment in MM-F1 (p = 0.001), MM-B1 (p = 0.0063), H-Meso-1 (p = 0.008), and #40a (p = 0.02) cells (Figures 5A,C).	('increased', 'PosReg', (17, 26))	('p53', 'Gene', '7157', (27, 30))	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))	('API', 'Chemical', 'MESH:D047310', (13, 16))	('API', 'Var', (13, 16))	('expression', 'MPA', (31, 41))	('p53', 'Gene', (27, 30))
42888	28674496	The cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) impairs DNA repairs and genomic integrity sustaining apoptosis, and is mainly mediated by activation of caspase 3.	('PARP-1', 'Gene', (48, 54))	('cleavage', 'Var', (4, 12))	('PARP-1', 'Gene', '142', (48, 54))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (16, 46))	('poly (ADP-ribose) polymerase-1', 'Gene', (16, 46))	('apoptosis', 'CPA', (109, 118))	('genomic integrity', 'CPA', (80, 97))	('caspase 3', 'Gene', (160, 169))	('DNA repairs', 'CPA', (64, 75))	('caspase 3', 'Gene', '836', (160, 169))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('impairs', 'NegReg', (56, 63))
42903	28674496	p46 JNK phosphorylation was decreased in MM-B1 and #40a cells (p = 0.005 and p = 0.0033, respectively), while it was increased in MM-B1 (p = 0.0136) and remained unchanged in H-Meso-1 cells, compared to control-treated cells (Figure 8B).	('decreased', 'NegReg', (28, 37))	('p46', 'Var', (0, 3))	('JNK', 'molecular_function', 'GO:0004705', ('4', '7'))	('phosphorylation', 'biological_process', 'GO:0016310', ('8', '23'))	('JNK', 'Gene', (4, 7))	('MM-B1', 'Var', (41, 46))	('JNK', 'Gene', '5599', (4, 7))
42954	28674496	One of the most characterized mechanisms of API is the ability to induce apoptosis through the p53-related pathway.	('API', 'Chemical', 'MESH:D047310', (44, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('API', 'Var', (44, 47))	('induce', 'PosReg', (66, 72))	('apoptosis', 'CPA', (73, 82))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))
42979	28674496	Overall, API-mediated-inhibition of NF-kappaB, and AKT signaling might inhibit pro-survival signals inducing apoptosis in MM cells.	('inhibit', 'NegReg', (71, 78))	('API-mediated-inhibition', 'Var', (9, 32))	('AKT', 'Gene', (51, 54))	('pro-survival signals', 'MPA', (79, 99))	('apoptosis', 'CPA', (109, 118))	('AKT signaling', 'biological_process', 'GO:0043491', ('51', '64'))	('API', 'Chemical', 'MESH:D047310', (9, 12))	('pro-survival', 'biological_process', 'GO:0043066', ('79', '91'))	('NF-kappaB', 'Protein', (36, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('AKT', 'Gene', '207', (51, 54))
42999	24465798	However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity.	('activity', 'MPA', (155, 163))	('inhibit', 'NegReg', (142, 149))	('antisense oligonucleotides', 'Var', (97, 123))	('MSLN', 'Protein', (150, 154))	('oligonucleotides', 'Chemical', 'MESH:D009841', (107, 123))
43003	24465798	In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells.	('decreased', 'NegReg', (68, 77))	('sphere formation', 'CPA', (131, 147))	('rat', 'Species', '10116', (85, 88))	('rat', 'Species', '10116', (92, 95))	('reduced', 'NegReg', (101, 108))	('invasive capacity', 'CPA', (109, 126))	('proliferation rate', 'CPA', (78, 96))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('MSLN-silencing', 'Var', (46, 60))
43004	24465798	Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin.	('increase', 'PosReg', (65, 73))	('MSLN-siRNA', 'Var', (10, 20))	('apoptosis', 'CPA', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('proliferation', 'CPA', (105, 118))	('rat', 'Species', '10116', (112, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('decrease', 'NegReg', (93, 101))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))
43010	24465798	Then, the precursor is cleaved at Arg295 by the endoprotease furin into a ~31 kDa soluble peptide called "megakaryocyte potentiating factor" (from aminoacid Ser34 to Arg286) and a ~40 kDa GPI-anchored membrane-bound glycoprotein (mature mesothelin, MSLN, starting from Glu296).	('Arg295', 'Chemical', '-', (34, 40))	('megakaryocyte potentiating factor"', 'Gene', (106, 140))	('soluble', 'cellular_component', 'GO:0005625', ('82', '89'))	('mesothelin', 'Gene', '10232', (237, 247))	('Glu296', 'Chemical', '-', (269, 275))	('Glu296', 'Var', (269, 275))	('Arg295', 'Var', (34, 40))	('megakaryocyte potentiating factor"', 'Gene', '10232', (106, 140))	('Ser34', 'Chemical', '-', (157, 162))	('mesothelin', 'Gene', (237, 247))	('furin', 'Gene', '5045', (61, 66))	('GPI', 'Chemical', 'MESH:D017261', (188, 191))	('Arg286', 'Chemical', '-', (166, 172))	('furin', 'Gene', (61, 66))
43016	24465798	MSLN could also increase cancer cell survival and proliferation via the activation of the NF-kappaB signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('100', '117'))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('proliferation', 'CPA', (50, 63))	('increase', 'PosReg', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('rat', 'Species', '10116', (57, 60))	('MSLN', 'Var', (0, 4))	('cancer', 'Disease', (25, 31))	('NF-kappaB signaling pathway', 'Pathway', (90, 117))
43025	24465798	Overall, MSLN depletion significantly hampered proliferation and colony-forming capability.	('proliferation', 'CPA', (47, 60))	('MSLN', 'Protein', (9, 13))	('hampered', 'NegReg', (38, 46))	('rat', 'Species', '10116', (54, 57))	('depletion', 'Var', (14, 23))	('colony-forming capability', 'CPA', (65, 90))
43074	24465798	Thus, two different silencing-RNAs (siRNAs) were assayed: siMSLN-1 and siMSLN-2 for MSLN in Mero-14 cells, (Table S2; Figure 1C).	('siMSLN-1', 'Chemical', '-', (58, 66))	('siMSLN-2', 'Var', (71, 79))	('siMSLN-1', 'Var', (58, 66))
43077	24465798	Following the administration of siMSLN-1, a significant reduction (p < 0.05) in the proliferation rate was observed for Mero-14 cells, starting from the third day of treatment, as compared to cells treated with control siRNA (siCtrl), reaching a 86% decrease at day 6 (Figure 2A).	('decrease', 'NegReg', (250, 258))	('rat', 'Species', '10116', (91, 94))	('Mero-14', 'Gene', (120, 127))	('rat', 'Species', '10116', (22, 25))	('proliferation rate', 'CPA', (84, 102))	('siMSLN-1', 'Chemical', '-', (32, 40))	('rat', 'Species', '10116', (98, 101))	('siCtrl', 'Chemical', '-', (226, 232))	('siMSLN-1', 'Var', (32, 40))	('reduction', 'NegReg', (56, 65))
43080	24465798	The silencing of MSLN in Mero-14 cells was also associated with smaller and uniform spheres (mean  =  34.4 microm+-3.11), as compared to the cells treated with siCtrl (mean  =  52.5 microm, +-7.65, p<10-6).	('siCtrl', 'Chemical', '-', (160, 166))	('silencing', 'Var', (4, 13))	('MSLN', 'Gene', (17, 21))	('smaller', 'NegReg', (64, 71))
43082	24465798	Thus, Mero-14 cells following MSLN silencing showed a low proliferation rate and a reduced capacity of forming spheroids.	('rat', 'Species', '10116', (72, 75))	('silencing', 'Var', (35, 44))	('low', 'NegReg', (54, 57))	('reduced', 'NegReg', (83, 90))	('MSLN', 'Gene', (30, 34))	('rat', 'Species', '10116', (65, 68))
43100	24465798	The transient MSLN-silencing caused a decrease in the proliferation rate of the MSLN-overexpressing cell line Mero-14.	('rat', 'Species', '10116', (61, 64))	('decrease', 'NegReg', (38, 46))	('MSLN-silencing', 'Var', (14, 28))	('rat', 'Species', '10116', (68, 71))	('proliferation rate', 'CPA', (54, 72))
43105	24465798	Concerning the cell cycle, a significant increase (50%) of MPM H2373 cells in the S-phase was observed portraying a blockade in progression from S to G2 phase.	('MPM H2373', 'Var', (59, 68))	('H2373', 'CellLine', 'CVCL:A533', (63, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('15', '25'))	('S-phase', 'CPA', (82, 89))	('S-phase', 'biological_process', 'GO:0051320', ('82', '89'))	('G2 phase', 'biological_process', 'GO:0051319', ('150', '158'))	('blockade', 'NegReg', (116, 124))	('increase', 'PosReg', (41, 49))
43110	24465798	By contrast, MSLN silencing was able to promote apoptosis in PC AsPC-1, Capan-1, and Capan-2 cells.	('promote', 'PosReg', (40, 47))	('Capan-1', 'CellLine', 'CVCL:0237', (72, 79))	('silencing', 'Var', (18, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('Capan-2', 'CellLine', 'CVCL:0026', (85, 92))	('MSLN', 'Gene', (13, 17))	('PC AsPC-1', 'CellLine', 'CVCL:0152', (61, 70))	('apoptosis', 'CPA', (48, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
43111	24465798	However, MSLN depletion triggered a marked increase in apoptosis in Mero-14 cells when used in combination with cisplatin, thereby suggesting a synergistic effect.	('MSLN', 'Gene', (9, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('depletion', 'Var', (14, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('apoptosis', 'CPA', (55, 64))
43124	20859946	For example, the selenoenzyme glutathione peroxidase can protect cells from oxidative damage and the seleno-enzymes, glutathione S-transferases, can repair damaged DNA and prevent mutation.	('mutation', 'MPA', (180, 188))	('damaged', 'Var', (156, 163))	('glutathione', 'Chemical', 'MESH:D005978', (117, 128))	('prevent', 'NegReg', (172, 179))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('glutathione', 'Chemical', 'MESH:D005978', (30, 41))
43167	20859946	Induction of cell death by selenium forms was confirmed by reduction of cellular density, loss of cell symmetry and detachment (Figure 3A-D) as well as typical morphological changes of apoptosis including loss of cellular and nuclear membrane integrity, chromatin condensation and cellular blebs (Figure 3F-H and J-L) compared to untreated cells (Figure 3E and I).	('apoptosis', 'biological_process', 'GO:0006915', ('185', '194'))	('loss', 'NegReg', (90, 94))	('detachment', 'CPA', (116, 126))	('cell death', 'CPA', (13, 23))	('loss', 'NegReg', (205, 209))	('cellular blebs', 'CPA', (281, 295))	('cell symmetry', 'CPA', (98, 111))	('chromatin condensation', 'CPA', (254, 276))	('cellular density', 'CPA', (72, 88))	('cell death', 'biological_process', 'GO:0008219', ('13', '23'))	('nuclear membrane', 'cellular_component', 'GO:0031965', ('226', '242'))	('selenium forms', 'Var', (27, 41))	('reduction', 'NegReg', (59, 68))	('selenium', 'Chemical', 'MESH:D012643', (27, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('185', '194'))	('chromatin', 'cellular_component', 'GO:0000785', ('254', '263'))
43198	32438640	Interestingly, inhibition of TGF-beta2 signaling and diacylglycerol O-acyltransferase (DGAT), the last enzyme involved in triglyceride synthesis, led to a significant restoration of DC activity and anticancer immune response.	('TGF-beta2', 'Protein', (29, 38))	('restoration', 'PosReg', (167, 178))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('triglyceride synthesis', 'biological_process', 'GO:0019432', ('122', '144'))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('immune response', 'biological_process', 'GO:0006955', ('209', '224'))	('triglyceride', 'Chemical', 'MESH:D014280', (122, 134))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('cancer', 'Disease', (202, 208))	('diacylglycerol O-acyltransferase', 'Gene', (53, 85))	('DGAT', 'Gene', '13350', (87, 91))	('diacylglycerol O-acyltransferase', 'Gene', '13350', (53, 85))	('DC activity', 'MPA', (182, 193))	('inhibition', 'Var', (15, 25))	('DGAT', 'Gene', (87, 91))
43230	32438640	Inhibition of DGAT1 and DGAT2 enzymes by A922500 and PF-06424439, respectively, led to a dramatic reduction in LD formation in 6.5/CM-exposed DCs (Figure 2B,C).	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('PF-06424439', 'Var', (53, 64))	('A922500', 'Chemical', 'MESH:C542909', (41, 48))	('PF-06424439', 'Chemical', 'MESH:C000603793', (53, 64))	('reduction', 'NegReg', (98, 107))	('DGAT2', 'Gene', (24, 29))	('DGAT2', 'Gene', '67800', (24, 29))	('DGAT1', 'Gene', (14, 19))	('A922500', 'Var', (41, 48))	('DGAT1', 'Gene', '13350', (14, 19))	('LD formation', 'CPA', (111, 123))
43231	32438640	Of note, while both DGAT1 and DGAT2 inhibition inhibited 6.5/CM-induced LD formation, only DGAT2 inhibition reduced basal amounts of LDs (i.e., in the 7.4/CM condition) (Figure 2B,C).	('inhibition', 'Var', (97, 107))	('inhibited', 'NegReg', (47, 56))	('DGAT2', 'Gene', (91, 96))	('DGAT2', 'Gene', (30, 35))	('inhibition', 'Var', (36, 46))	('reduced', 'NegReg', (108, 115))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('DGAT2', 'Gene', '67800', (91, 96))	('DGAT2', 'Gene', '67800', (30, 35))	('DGAT1', 'Gene', (20, 25))	('DGAT1', 'Gene', '13350', (20, 25))	('LD formation', 'CPA', (72, 84))
43232	32438640	We also found that in 6.5/CM-exposed DCs, DGAT2 inhibition more extensively induced cell death than DGAT1 inhibition (Figure S2A).	('DGAT1', 'Gene', '13350', (100, 105))	('death', 'Disease', 'MESH:D003643', (89, 94))	('DGAT2', 'Gene', (42, 47))	('inhibition', 'Var', (48, 58))	('death', 'Disease', (89, 94))	('DGAT1', 'Gene', (100, 105))	('DGAT2', 'Gene', '67800', (42, 47))	('cell death', 'biological_process', 'GO:0008219', ('84', '94'))	('induced', 'Reg', (76, 83))
43244	32438640	We found that at the concentrations of the pharmacological inhibitors used, inhibition of DGAT1 activity reversed CCR7 decline, while only a trend was observed with a DGAT2i (Figure 3B).	('activity', 'MPA', (96, 104))	('DGAT1', 'Gene', '13350', (90, 95))	('DGAT2', 'Gene', (167, 172))	('CCR', 'molecular_function', 'GO:0043880', ('114', '117'))	('DGAT2', 'Gene', '67800', (167, 172))	('decline', 'NegReg', (119, 126))	('inhibition', 'Var', (76, 86))	('CCR7', 'Gene', (114, 118))	('DGAT1', 'Gene', (90, 95))
43246	32438640	A significant decrease in the in vivo migratory potential was observed for DCs pre-exposed to 6.5/CM and importantly, inhibition of TGF-beta signaling reversed this phenotype (Figure 3D).	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('TGF-beta', 'Gene', (132, 140))	('TGF-beta', 'Gene', '21802', (132, 140))	('decrease', 'NegReg', (14, 22))	('pre', 'molecular_function', 'GO:0003904', ('79', '82'))	('inhibition', 'Var', (118, 128))
43249	32438640	A decrease in the expression of this co-stimulatory molecule was however not reversed by SB-431542 (Figure 4A), nor by DGAT inhibition (Figure S4A).	('SB-431542', 'Var', (89, 98))	('decrease', 'NegReg', (2, 10))	('DGAT', 'Gene', '13350', (119, 123))	('DGAT', 'Gene', (119, 123))	('SB-431542', 'Chemical', 'MESH:C459179', (89, 98))	('expression', 'MPA', (18, 28))
43250	32438640	Still, 6.5/CM accounted for a more significant reduction in the MHCII+ CD40+ DC population than that observed upon exposure to pH 6.5-buffered medium (Figure S4B).	('.5-buffered medium', 'Chemical', '-', (131, 149))	('6.5/CM', 'Var', (7, 13))	('MHCII', 'Gene', '111364', (64, 69))	('reduction', 'NegReg', (47, 56))	('CD40', 'Gene', '21939', (71, 75))	('CD40', 'Gene', (71, 75))	('MHCII', 'Gene', (64, 69))
43252	32438640	CD80 and CD86 expressions were not or slightly affected by 6.5/CM, respectively, (Figure S4D,E) and were not influenced by SB-431542 or DGATi (Figure S4D-F).	('CD86', 'Gene', (9, 13))	('CD86', 'Gene', '12524', (9, 13))	('DGAT', 'Gene', '13350', (136, 140))	('CD80', 'Gene', (0, 4))	('6.5/CM', 'Var', (59, 65))	('DGAT', 'Gene', (136, 140))	('SB-431542', 'Chemical', 'MESH:C459179', (123, 132))	('CD80', 'Gene', '12519', (0, 4))
43260	32438640	Mice vaccinated with 6.5/CM-exposed DCs showed a reduction in progression-free survival (p = 0.057, n = 6) (Figure 5B), with relapse occurring in half of the mice post-vaccination (Figure 5C).	('reduction', 'NegReg', (49, 58))	('progression-free survival', 'CPA', (62, 87))	('mice', 'Species', '10090', (158, 162))	('DCs', 'Var', (36, 39))	('Mice', 'Species', '10090', (0, 4))
43264	32438640	We also found that 6.5/CM-based DC vaccination was associated with a decreased CD8+ cytotoxic activity, as reflected by decreased lysosomal-associated membrane protein-1 (LAMP-1) expression in CD8+ splenocytes (Figure 6C and Figure S6C).	('decreased', 'NegReg', (120, 129))	('CD8', 'Gene', '925', (193, 196))	('LAMP-1', 'Gene', (171, 177))	('LAMP-1', 'Gene', '16783', (171, 177))	('expression', 'MPA', (179, 189))	('vaccination', 'Var', (35, 46))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('decreased', 'NegReg', (69, 78))	('DC vaccination', 'Var', (32, 46))	('CD8', 'Gene', (79, 82))	('CD8', 'Gene', '925', (79, 82))	('CD8', 'Gene', (193, 196))	('lysosomal-associated membrane protein-1', 'Gene', '16783', (130, 169))	('lysosomal-associated membrane protein-1', 'Gene', (130, 169))	('membrane', 'cellular_component', 'GO:0016020', ('151', '159'))
43291	32438640	The most likely explanation is that by preventing triglyceride formation, DGAT inhibitors render FA more available for critical DC functions and spare pyruvate that may be used for needed tasks (Figure 7).	('spare', 'NegReg', (145, 150))	('triglyceride formation', 'biological_process', 'GO:0019432', ('50', '72'))	('DGAT', 'Gene', '13350', (74, 78))	('pyruvate', 'Chemical', 'MESH:D019289', (151, 159))	('triglyceride', 'Chemical', 'MESH:D014280', (50, 62))	('preventing', 'NegReg', (39, 49))	('DGAT', 'Gene', (74, 78))	('triglyceride formation', 'MPA', (50, 72))	('inhibitors', 'Var', (79, 89))	('more', 'PosReg', (100, 104))
43318	32438640	In some experiments, DCs were exposed to 5 microM TGF-beta type I receptor inhibitor SB-431542, 15 microM DGAT1 inhibitor A922500, or 10 microM DGAT2 inhibitor PF-06424439; concentrations were chosen based on our previous work in cancer cells.	('PF-06424439', 'Chemical', 'MESH:C000603793', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('DGAT1', 'Gene', (106, 111))	('DGAT2', 'Gene', (144, 149))	('TGF-beta', 'Gene', (50, 58))	('TGF-beta', 'Gene', '21802', (50, 58))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('DGAT2', 'Gene', '67800', (144, 149))	('DGAT1', 'Gene', '13350', (106, 111))	('SB-431542', 'Chemical', 'MESH:C459179', (85, 94))	('A922500', 'Var', (122, 129))	('A922500', 'Chemical', 'MESH:C542909', (122, 129))
43319	32438640	DC maturation was obtained by stimulation with 0.3 microg/mL LPS for 18 h and analyzed with antibodies against CD11c-BV421 (BD Pharm, 565452, San Jose, CA, USA), MHCII (I-A/I-E)-APC (BD Pharm, 565367), CD40-PE (BD Pharm, 553791), CD80-PE (eBioscience, 12-0801, San Diego, CA, USA), CD86-PE (eBioscience, 12-0862), or CCR7-PE (BioLegend 120105).	('APC', 'cellular_component', 'GO:0005680', ('178', '181'))	('CD80', 'Gene', (230, 234))	('CD11c-BV421', 'Var', (111, 122))	('MHCII (I-A/I-E)-APC', 'Gene', (162, 181))	('CCR', 'molecular_function', 'GO:0043880', ('317', '320'))	('CD86', 'Gene', (282, 286))	('MHCII (I-A/I-E)-APC', 'Gene', '111364', (162, 181))	('CD80', 'Gene', '12519', (230, 234))	('CD40', 'Gene', '21939', (202, 206))	('CD86', 'Gene', '12524', (282, 286))	('CD40', 'Gene', (202, 206))
43338	32438640	After washing, isolated CD8+ OT-1 were added (ratio DC/T cell 1:5) and T cell response was analyzed after 48 h. Proliferation of CD3+/CD8+ T cells was analyzed based on dilution of CFSE while for measuring activation, T cells were treated for 4 h with Golgi Stop (BD Pharm, 554715) before exposure to Fixation/Permeabilization Solution (BD Pharm 554715) and staining with phycoerythrin-conjugated interferon gamma (IFNgamma-PE) antibody (BioLegend, 505807).	('antibody', 'cellular_component', 'GO:0019815', ('428', '436'))	('CD8', 'Gene', (134, 137))	('CD3', 'Gene', '12501', (129, 132))	('antibody', 'molecular_function', 'GO:0003823', ('428', '436'))	('CD8', 'Gene', '925', (134, 137))	('BD Pharm 554715', 'Var', (337, 352))	('interferon gamma (IFNgamma-PE', 'Gene', '15978', (397, 426))	('antibody', 'cellular_component', 'GO:0019814', ('428', '436'))	('CD8', 'Gene', (24, 27))	('Golgi', 'cellular_component', 'GO:0005794', ('252', '257'))	('CD8', 'Gene', '925', (24, 27))	('antibody', 'cellular_component', 'GO:0042571', ('428', '436'))	('interferon gamma', 'molecular_function', 'GO:0005133', ('397', '413'))	('CD3', 'Gene', (129, 132))
43354	32318342	In the last 10 years, epigenetic markers, such as DNA methylation and microRNAs (miRNAs), have gained popularity as possible early diagnostic and prognostic biomarkers in cancer research.	('microRNAs', 'Var', (70, 79))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('DNA methylation', 'Var', (50, 65))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
43371	32318342	The BAP1-tumor predisposition syndrome is the most studied genetic condition associated with MPM development and is caused by mutations in the BRCA1-associated protein 1 (BAP1) gene.	('BAP1', 'Gene', (171, 175))	('BRCA1-associated protein 1', 'Gene', '8314', (143, 169))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('BRCA1-associated protein 1', 'Gene', (143, 169))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('caused by', 'Reg', (116, 125))	('tumor', 'Disease', (9, 14))	('BAP1', 'Gene', '8314', (171, 175))	('mutations', 'Var', (126, 135))	('BAP1', 'Gene', '8314', (4, 8))
43373	32318342	In this context, epigenetic markers such as DNA methylation and microRNAs (miRNAs) are emerging as promising biomarkers for several cancer types, including MPM.	('MPM', 'Disease', (156, 159))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DNA methylation', 'Var', (44, 59))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
43374	32318342	While genetic biomarkers may differ from case to case in most cancer patients (i.e., each patient may carry a different mutation within the same gene), different subjects show variable levels of epigenetic biomarkers in a specific target depending on health/disease status.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (120, 128))	('patient', 'Species', '9606', (90, 97))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patient', 'Species', '9606', (69, 76))	('patients', 'Species', '9606', (69, 77))	('epigenetic biomarkers', 'MPA', (195, 216))
43383	32318342	Moreover, aberrant peripheral epigenetic modifications have been frequently observed in early-stage cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('aberrant', 'Var', (10, 18))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (107, 115))	('observed', 'Reg', (76, 84))
43388	32318342	Several studies have been performed to evaluate alterations of DNA methylation in mesothelioma tumor samples, but very few have focused on alteration of DNA methylation in blood as circulating marker.	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('alterations', 'Reg', (48, 59))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (82, 100))	('mesothelioma tumor', 'Disease', (82, 100))	('DNA methylation', 'biological_process', 'GO:0006306', ('63', '78'))	('DNA methylation', 'biological_process', 'GO:0006306', ('153', '168'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (82, 100))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('methylation', 'Var', (67, 78))
43390	32318342	Although the analysis of single gene methylation did not influence prognosis, the combined hypermethylation of the tumor-suppressors RARbeta, DAPK, and RASSF1A was associated with shorter overall survival.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RARbeta', 'Gene', (133, 140))	('RARbeta', 'Gene', '5914', (133, 140))	('tumor', 'Disease', (115, 120))	('overall survival', 'MPA', (188, 204))	('shorter', 'NegReg', (180, 187))	('DAPK', 'Gene', (142, 146))	('hypermethylation', 'Var', (91, 107))	('RASSF1A', 'Gene', (152, 159))	('DAPK', 'Gene', '1612', (142, 146))	('RASSF1A', 'Gene', '11186', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
43392	32318342	Indeed, arginine deprivation is synthetically lethal in cancers, such as mesothelioma, that are argininosuccinate synthetase 1 (ASS1)-negative.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('ASS1', 'Gene', (128, 132))	('argininosuccinate synthetase 1', 'Gene', (96, 126))	('ASS1', 'Gene', '445', (128, 132))	('mesothelioma', 'Disease', (73, 85))	('arginine', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('argininosuccinate synthetase 1', 'Gene', '445', (96, 126))	('arginine', 'Chemical', 'MESH:D001120', (8, 16))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
43396	32318342	The top hypomethylated single-CpG island was detected in FOXK1 gene, an interactor of BAP1, which was found mutated in MPM tissue and constitutionally mutated in familial MPM, as described above.	('mutated', 'Var', (108, 115))	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', (86, 90))	('FOXK1', 'Gene', '221937', (57, 62))	('FOXK1', 'Gene', (57, 62))
43405	32318342	Furthermore, low levels of miR-126 were strongly associated with worse prognosis in MPM patients.	('low levels', 'Var', (13, 23))	('MPM', 'Disease', (84, 87))	('patients', 'Species', '9606', (88, 96))	('miR-126', 'Gene', '406913', (27, 34))	('miR-126', 'Gene', (27, 34))
43410	32318342	We investigated 23 MPM patients and 19 cancer-free subjects with past asbestos exposure, and found a two miRNA (miR-103a-3p and miR-30e-3p) signature able to discriminate the two groups with high sensitivity (95.5%) and specificity (80%).	('discriminate', 'Reg', (158, 170))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('patients', 'Species', '9606', (23, 31))	('miR-103a-3p', 'Chemical', '-', (112, 123))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('miR-30e-3p', 'Var', (128, 138))	('miR-103a-3p', 'Var', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
43411	32318342	The expression of miR-625-3p was significantly higher in plasma/serum of 30 MPM patients and allowed to discriminate between cases and controls (the latter consisting of 14 healthy subjects and 10 subjects with asbestosis), in both the original and in an independent series of patients.	('asbestosis', 'Disease', 'MESH:D001195', (211, 221))	('patients', 'Species', '9606', (80, 88))	('higher', 'PosReg', (47, 53))	('asbestosis', 'Disease', (211, 221))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (277, 285))	('miR-625-3p', 'Var', (18, 28))	('miR-625-3p', 'Chemical', '-', (18, 28))
43412	32318342	miR-625-3p was also found upregulated in tumor samples from 18 MPM patients vs. nonmalignant pleura samples, suggesting a potential connection between circulating miRNAs and the tissue of origin.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('upregulated', 'PosReg', (26, 37))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', (41, 46))	('miR-625-3p', 'Chemical', '-', (0, 10))	('miR-625-3p', 'Var', (0, 10))	('MPM', 'Disease', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
43413	32318342	found reduced miR-132-3p expression levels in the plasma of 22 MPM patients compared to 44 asbestos-exposed controls, with a sensitivity of 86% and a specificity of 61%.	('miR-132-3p', 'Gene', '100302255', (14, 24))	('reduced', 'NegReg', (6, 13))	('patients', 'Species', '9606', (67, 75))	('miR-132-3p', 'Gene', (14, 24))	('MPM', 'Var', (63, 66))	('asbestos', 'Chemical', 'MESH:D001194', (91, 99))
43414	32318342	In order to improve the marker performance, they also measured two miRNAs (miR-126 and miR625-3p) previously reported as possible biomarkers for MPM.	('miR-126', 'Gene', (75, 82))	('miR-126', 'Gene', '406913', (75, 82))	('improve', 'PosReg', (12, 19))	('miR625-3p', 'Var', (87, 96))	('MPM', 'Disease', (145, 148))
43417	32318342	quantified miRNA-16, miRNA-17, miRNA-126, and miRNA-486 in the plasma of 32 MPM patients, 14 subjects with asbestosis, and 15 subjects with other non-neoplastic pulmonary diseases.	('neoplastic pulmonary diseases', 'Disease', 'MESH:D008171', (150, 179))	('patients', 'Species', '9606', (80, 88))	('miRNA-17', 'Gene', (21, 29))	('asbestosis', 'Disease', 'MESH:D001195', (107, 117))	('miRNA-486', 'Var', (46, 55))	('miRNA-16', 'Gene', (11, 19))	('neoplastic pulmonary diseases', 'Disease', (150, 179))	('miRNA-126', 'Gene', '406913', (31, 40))	('miRNA-126', 'Gene', (31, 40))	('miRNA-17', 'Gene', '406952', (21, 29))	('asbestosis', 'Disease', (107, 117))
43425	32318342	Five miRNAs (miR-101, miR-25, miR-26b, miR-335, and miR-433) were upregulated, while two (miR-191, miR-223) were downregulated.	('miR-223', 'Gene', (99, 106))	('miR-25', 'Gene', '407014', (22, 28))	('miR-25', 'Gene', (22, 28))	('miR-191', 'Gene', '406966', (90, 97))	('miR-26b', 'Gene', (30, 37))	('miR-223', 'Gene', '407008', (99, 106))	('upregulated', 'PosReg', (66, 77))	('miR-191', 'Gene', (90, 97))	('miR-26b', 'Gene', '407017', (30, 37))	('miR-433', 'Gene', (52, 59))	('miR-433', 'Gene', '574034', (52, 59))	('miR-335', 'Gene', (39, 46))	('miR-101', 'Var', (13, 20))	('miR-335', 'Gene', '442904', (39, 46))
43426	32318342	miR-29a and miR-516 were expressed exclusively in MPM patients.	('MPM', 'Disease', (50, 53))	('miR-29a', 'Gene', '407021', (0, 7))	('miR-29a', 'Gene', (0, 7))	('patients', 'Species', '9606', (54, 62))	('miR-516', 'Var', (12, 19))
43432	32318342	They analyzed three circulating miRNAs (miR-132-3p, miR-126-3p, and miR-103a-3p), previously reported as differentially expressed among MPM patients and asbestos exposed subjects, using a nested case-control approach.	('miR-103a-3p', 'Chemical', '-', (68, 79))	('miR-103a-3p', 'Var', (68, 79))	('asbestos', 'Chemical', 'MESH:D001194', (153, 161))	('miR-132-3p', 'Gene', '100302255', (40, 50))	('miR-126-3p', 'Gene', '100302148', (52, 62))	('MPM', 'Disease', (136, 139))	('miR-126-3p', 'Gene', (52, 62))	('patients', 'Species', '9606', (140, 148))	('miR-132-3p', 'Gene', (40, 50))
43435	32318342	Just to make some examples, alteration of circulating miR-126 expression has been associated not only with MPM but also with other neoplastic conditions [e.g., NSCLC or colorectal carcinoma ], and with non-neoplastic conditions such as diabetes; in addition, altered expression of circulating miR-103a-3p was associated also with prostate cancer.	('associated', 'Reg', (82, 92))	('associated', 'Reg', (309, 319))	('alteration', 'Var', (28, 38))	('NSCLC', 'Disease', (160, 165))	('miR-126', 'Gene', '406913', (54, 61))	('miR-103a-3p', 'Chemical', '-', (293, 304))	('diabetes', 'Disease', 'MESH:D003920', (236, 244))	('altered', 'Var', (259, 266))	('colorectal carcinoma', 'Disease', (169, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('miR-103a-3p', 'Gene', (293, 304))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (169, 189))	('diabetes', 'Disease', (236, 244))	('MPM', 'Disease', (107, 110))	('expression', 'MPA', (267, 277))	('miR-126', 'Gene', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('prostate cancer', 'Disease', 'MESH:D011471', (330, 345))	('prostate cancer', 'Phenotype', 'HP:0012125', (330, 345))	('prostate cancer', 'Disease', (330, 345))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
43445	32318342	Mesothelin concentration was evaluated in plasma, while miR-103a-3p in the cellular blood fraction.	('Mesothelin', 'Gene', '10232', (0, 10))	('miR-103a-3p', 'Chemical', '-', (56, 67))	('miR-103a-3p', 'Var', (56, 67))	('Mesothelin', 'Gene', (0, 10))
43447	32318342	The combination of mesothelin and miR-103a-3p showed a good sensitivity of 95% and a specificity of 81%.	('mesothelin', 'Gene', (19, 29))	('miR-103a-3p', 'Var', (34, 45))	('mesothelin', 'Gene', '10232', (19, 29))	('miR-103a-3p', 'Chemical', '-', (34, 45))
43453	32318342	The combination of increased expression of miR-625-3p and decreased expression of GAS5 was significantly associated with disease progression (p = 0.0393).	('miR-625-3p', 'Chemical', '-', (43, 53))	('GAS', 'molecular_function', 'GO:0034005', ('82', '85'))	('GAS5', 'Gene', (82, 86))	('expression', 'MPA', (68, 78))	('miR-625-3p', 'Var', (43, 53))	('disease', 'Disease', (121, 128))	('decreased', 'NegReg', (58, 67))	('increased', 'PosReg', (19, 28))	('GAS5', 'Gene', '60674', (82, 86))	('expression', 'MPA', (29, 39))
43465	27680026	Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies.	('TCR', 'cellular_component', 'GO:0042101', ('122', '125'))	('improved', 'PosReg', (55, 63))	('MHC', 'Gene', (72, 75))	('killing', 'CPA', (99, 106))	('MAPK', 'Gene', '5595;5594;5595', (28, 32))	('TCR', 'biological_process', 'GO:0006283', ('122', '125'))	('MHC', 'Gene', '3107', (72, 75))	('MAPK', 'Gene', (28, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('28', '32'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('28', '42'))	('inhibition', 'Var', (14, 24))
43472	27680026	Previously, a genome-wide screen provided evidence that regulators of MHC-II could be identified by RNAi knockdown.	('MHC', 'Gene', (70, 73))	('RNAi', 'biological_process', 'GO:0016246', ('100', '104'))	('knockdown', 'Var', (105, 114))	('RNAi', 'Gene', (100, 104))	('MHC', 'Gene', '3107', (70, 73))
43482	27680026	HEK293T, PC9, SKMEL5, UACC257, SW480, CFPAC1, H827, H1975, H1299, and A549 were obtained from ATCC between the years 2012 and 2016 and were not further validated.	('H1975', 'Var', (52, 57))	('H1975', 'CellLine', 'CVCL:1511', (52, 57))	('SW480', 'Var', (31, 36))	('H827', 'Var', (46, 50))	('H1299', 'Var', (59, 64))	('CFPAC1', 'CellLine', 'CVCL:1119', (38, 44))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('SKMEL5', 'CellLine', 'CVCL:0527', (14, 20))	('PC9', 'Gene', '255738', (9, 12))	('SW480', 'CellLine', 'CVCL:0546', (31, 36))	('PC9', 'Gene', (9, 12))	('A549', 'Var', (70, 74))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('HEK293T', 'Var', (0, 7))	('H1299', 'CellLine', 'CVCL:0060', (59, 64))
43487	27680026	HEK293T were grown in Dulbecco's modified media with 10% FBS and 2 mM L-glutamine.	('FBS', 'Disease', 'MESH:D005198', (57, 60))	('L-glutamine', 'Chemical', 'MESH:D005973', (70, 81))	("Dulbecco's modified media", 'Chemical', '-', (22, 47))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('HEK293T', 'Var', (0, 7))	('FBS', 'Disease', (57, 60))
43509	27680026	Real-time assays were conducted using TaqMan realtime probes (Life Technlogies) for human HLA-A (Hs01058806_g1), B2M (Hs00187842_m1), TAP1 (Hs00388677_m1), TAP2 (Hs00241060_m1), and TBP (Hs00427620_m1) with 50 ng cDNA.	('Hs00241060_m1', 'Var', (162, 175))	('TBP', 'Gene', (182, 185))	('Hs00187842_m1', 'Var', (118, 131))	('TBP', 'Gene', '6908', (182, 185))	('Hs00388677_m1', 'Var', (140, 153))	('Hs00427620_m1', 'Var', (187, 200))	('human', 'Species', '9606', (84, 89))	('HLA-A', 'Gene', '3105', (90, 95))	('HLA-A', 'Gene', (90, 95))	('Hs01058806_g1', 'Var', (97, 110))
43521	27680026	Cells were treated with the indicated drug 24 h after siRNA knockdown for 72 h before assaying for surface HLA-A by flow cytometry.	('HLA-A', 'Gene', '3105', (107, 112))	('knockdown', 'Var', (60, 69))	('HLA-A', 'Gene', (107, 112))	('siRNA', 'Gene', (54, 59))
43542	27680026	EGFR is a receptor tyrosine kinase that binds epidermal growth factor and is frequently found to be activated by mutation in NSCLC.	('mutation', 'Var', (113, 121))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('46', '69'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('binds', 'Interaction', (40, 45))	('activated', 'PosReg', (100, 109))
43545	27680026	We validated each of these genes with independent shRNA knockdown to the gene products and saw significant increases in HLA-A*02:01 by flow cytometry (Fig.	('HLA-A', 'Gene', '3105', (120, 125))	('HLA-A', 'Gene', (120, 125))	('knockdown', 'Var', (56, 65))	('increases', 'PosReg', (107, 116))
43554	27680026	JMN and PC9, a NSCLC cell line with an activating EGFR mutation (del E746-A750), responded to the EGFR inhibitor afatinib, whereas the Meso34 cell line without an EGFR mutation did not respond to afatinib at the same dose, demonstrating selectivity for activation mutations in the MAPK pathway leading to a response to HLA-A upregulation (Supplementary Table 1).	('MAPK', 'Gene', '5595;5594;5595', (281, 285))	('HLA-A', 'Gene', '3105', (319, 324))	('NSCLC', 'Disease', (15, 20))	('activating', 'PosReg', (39, 49))	('EGFR', 'Gene', (50, 54))	('afatinib', 'Chemical', 'MESH:D000077716', (196, 204))	('mutation (del E746-A750', 'Var', (55, 78))	('MAPK', 'Gene', (281, 285))	('EGFR inhibitor', 'MPA', (98, 112))	('PC9', 'Gene', '255738', (8, 11))	('del E746', 'Mutation', 'p.746delE', (65, 73))	('HLA-A', 'Gene', (319, 324))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('afatinib', 'Chemical', 'MESH:D000077716', (113, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('PC9', 'Gene', (8, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('MAPK', 'molecular_function', 'GO:0004707', ('281', '285'))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('responded', 'MPA', (81, 90))
43555	27680026	We detected an effect of MAP kinase pathway inhibition on upregulation of HLA-A in the context of gain-of-function mutations or activation of other targets in the MAP kinase pathway, such as the KRAS G12V mutation in the SW480 and CFPAC-1 cell lines, the RET/PTC1 gene rearrangement in the TPC1 thyroid cell line, and the BRAF V600E mutation seen in the UACC257 and SK-MEL-5 melanoma cell lines (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (375, 383))	('melanoma', 'Disease', (375, 383))	('TPC1', 'Gene', (290, 294))	('G12V', 'Mutation', 'p.G12V', (200, 204))	('TPC1', 'Gene', '53373', (290, 294))	('HLA-A', 'Gene', (74, 79))	('MAP', 'molecular_function', 'GO:0004239', ('25', '28'))	('RET', 'Gene', (255, 258))	('V600E', 'Mutation', 'rs113488022', (327, 332))	('PTC1', 'Gene', '5727', (259, 263))	('melanoma', 'Disease', 'MESH:D008545', (375, 383))	('gain-of-function', 'PosReg', (98, 114))	('BRAF', 'Gene', (322, 326))	('MAP kinase pathway', 'Pathway', (25, 43))	('inhibition', 'NegReg', (44, 54))	('KRAS G12V', 'Var', (195, 204))	('PTC1', 'Gene', (259, 263))	('HLA-A', 'Gene', '3105', (74, 79))	('mutations', 'Var', (115, 124))	('MAP', 'molecular_function', 'GO:0004239', ('163', '166'))	('SW480', 'CellLine', 'CVCL:0546', (221, 226))	('upregulation', 'PosReg', (58, 70))	('CFPAC-1', 'CellLine', 'CVCL:1119', (231, 238))	('RET', 'Gene', '5979', (255, 258))
43562	27680026	Given that many cancers have activating mutations in specific genes in the MAP kinase pathway, we investigated inhibition of the identified hits in cell lines harboring mutations in EGFR, or downstream in Ras.	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('MAP', 'molecular_function', 'GO:0004239', ('75', '78'))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('cancers', 'Disease', (16, 23))	('mutations', 'Var', (169, 178))	('EGFR', 'Gene', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('activating', 'PosReg', (29, 39))	('MAP kinase pathway', 'Pathway', (75, 93))
43563	27680026	We used a panel of NSCLC cell lines with activating mutations in EGFR, such as the delE746-A750 in H827, or L858R/T790M mutation in H1975.	('T790M', 'Mutation', 'rs121434569', (114, 119))	('EGFR', 'Gene', (65, 69))	('activating', 'PosReg', (41, 51))	('L858R', 'SUBSTITUTION', 'None', (108, 113))	('delE746-A750', 'Var', (83, 95))	('L858R', 'Var', (108, 113))	('H1975', 'CellLine', 'CVCL:1511', (132, 137))	('NSCLC', 'Disease', (19, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('H1975', 'Gene', (132, 137))
43564	27680026	The delE746-A750 confers sensitivity to erlotinib, whereas the T790M confers resistance to erlotinib and to other first generation EGFR inhibitors, but is sensitive to afatinib.	('delE746-A750', 'Var', (4, 16))	('sensitivity', 'MPA', (25, 36))	('afatinib', 'Chemical', 'MESH:D000077716', (168, 176))	('erlotinib', 'MPA', (40, 49))	('resistance', 'MPA', (77, 87))	('erlotinib', 'Chemical', 'MESH:D000069347', (40, 49))	('erlotinib', 'Chemical', 'MESH:D000069347', (91, 100))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('T790M', 'Var', (63, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))
43565	27680026	We also used EGFR wild-type NSCLC lines with downstream mutations, such as activating NRAS Q61K in H1299 or KRAS G12S in A549.	('NRAS', 'Gene', (86, 90))	('NSCLC', 'Disease', (28, 33))	('NRAS', 'Gene', '4893', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('A549', 'CellLine', 'CVCL:0023', (121, 125))	('Q61K', 'Mutation', 'rs121913254', (91, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('G12S', 'SUBSTITUTION', 'None', (113, 117))	('H1299', 'CellLine', 'CVCL:0060', (99, 104))	('activating', 'PosReg', (75, 85))	('G12S', 'Var', (113, 117))
43566	27680026	Use of the EGFRi erlotinib and afatinib upregulated surface MHC-I if the cell line had the sensitizing mutation, whereas all responded to trametinib MEKi (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (31, 39))	('erlotinib', 'Chemical', 'MESH:D000069347', (17, 26))	('surface', 'MPA', (52, 59))	('responded', 'MPA', (125, 134))	('MHC', 'Gene', (60, 63))	('mutation', 'Var', (103, 111))	('MHC', 'Gene', '3107', (60, 63))	('trametinib', 'Chemical', 'MESH:C560077', (138, 148))	('upregulated', 'PosReg', (40, 51))
43568	27680026	Expression of the activating EGFR mutation L858R suppressed MHC-I in H1299 NRAS Q61K mutant cell lines (Fig.	('L858R', 'Mutation', 'rs121434568', (43, 48))	('MHC', 'Gene', (60, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))	('suppressed', 'NegReg', (49, 59))	('EGFR', 'Gene', (29, 33))	('H1299 NRAS', 'CellLine', 'CVCL:0060', (69, 79))	('MHC', 'Gene', '3107', (60, 63))	('L858R', 'Var', (43, 48))	('mutation L858R', 'Var', (34, 48))	('Q61K', 'Mutation', 'rs121913254', (80, 84))
43569	27680026	H827 responded more strongly to EGFRi by erlotinib than MEKi by trametinib, despite their similar suppression of pERK, a downstream marker of MEK activity.	('trametinib', 'Chemical', 'MESH:C560077', (64, 74))	('responded', 'MPA', (5, 14))	('erlotinib', 'Var', (41, 50))	('pERK', 'MPA', (113, 117))	('MEK activity', 'molecular_function', 'GO:0004708', ('142', '154'))	('suppression', 'NegReg', (98, 109))	('erlotinib', 'Chemical', 'MESH:D000069347', (41, 50))
43572	27680026	This could be due to activation of parallel signaling pathways in EGFR mutant cancers or differential stimulation of ERK.	('ERK', 'Gene', (117, 120))	('stimulation', 'PosReg', (102, 113))	('EGFR', 'Gene', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('mutant', 'Var', (71, 77))	('cancers', 'Disease', (78, 85))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))	('activation', 'PosReg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ERK', 'Gene', '5594', (117, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
43577	27680026	Both IFNgamma and afatinib (in EGFR mutant H1975 lung cancer cells), and IFNgamma and trametinib (in Braf mutant SK-MEL5 and UACC257 melanoma cells), alone, each increased expression of cell surface HLA molecules, as measured by antibodies to HLA-A*02:01 or pan HLA-A, B, C. The combination of the IFNgamma and the drug had greater effects than either alone, consistent with the involvement of two different pathways.	('Braf', 'Gene', '673', (101, 105))	('trametinib', 'Chemical', 'MESH:C560077', (86, 96))	('HLA-A', 'Gene', '3105', (262, 267))	('HLA-A, B, C', 'Gene', '3105;3106;3107', (262, 273))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('IFNgamma', 'Gene', (5, 13))	('increased', 'PosReg', (162, 171))	('IFNgamma', 'Gene', '3458', (5, 13))	('IFNgamma', 'Gene', (298, 306))	('HLA-A', 'Gene', (243, 248))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('IFNgamma', 'Gene', '3458', (298, 306))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('H1975', 'CellLine', 'CVCL:1511', (43, 48))	('Braf', 'Gene', (101, 105))	('cell surface', 'cellular_component', 'GO:0009986', ('186', '198'))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('HLA-A', 'Gene', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('IFNgamma', 'Gene', '3458', (73, 81))	('IFNgamma', 'Gene', (73, 81))	('afatinib', 'Chemical', 'MESH:D000077716', (18, 26))	('HLA-A', 'Gene', '3105', (243, 248))	('expression', 'MPA', (172, 182))	('lung cancer', 'Disease', (49, 60))	('mutant', 'Var', (36, 42))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('SK-MEL5', 'CellLine', 'CVCL:0527', (113, 120))
43583	27680026	IFNgamma and afatinib (in EGFR mutant lung cancer cells) did not affect HLA-E levels (Supplementary Fig.	('mutant', 'Var', (31, 37))	('lung cancer', 'Disease', (38, 49))	('HLA-E', 'Gene', '3133', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('HLA-E', 'Gene', (72, 77))	('IFNgamma', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('IFNgamma', 'Gene', '3458', (0, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('afatinib', 'Chemical', 'MESH:D000077716', (13, 21))
43584	27680026	Trametinib, in Braf mutant SK-MEL5 melanoma cells, increased cell surface HLA-E molecules, but did not do so in UACC257 cells.	('melanoma', 'Disease', (35, 43))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('SK-MEL5', 'CellLine', 'CVCL:0527', (27, 34))	('increased', 'PosReg', (51, 60))	('Braf', 'Gene', (15, 19))	('Braf', 'Gene', '673', (15, 19))	('HLA-E', 'Gene', (74, 79))	('HLA-E', 'Gene', '3133', (74, 79))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('cell surface', 'cellular_component', 'GO:0009986', ('61', '73'))	('mutant', 'Var', (20, 26))
43590	27680026	Increased cytotoxicity of the Pr20m mAb was also observed with use of the MEKi trametinib in the SK-MEL-5 human melanoma cell line, validating this observation with multiple targets in multiple cell lines (Fig.	('human', 'Species', '9606', (106, 111))	('Pr20m', 'Var', (30, 35))	('trametinib', 'Chemical', 'MESH:C560077', (79, 89))	('cytotoxicity', 'Disease', (10, 22))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (10, 22))
43595	27680026	Indeed, EGFR and MEK inhibition produced an increase in mRNA gene expression of HLA-A along with other key components of the antigen presentation pathway and MHC-I structure, such as TAP1, TAP2, and beta2M, (Fig.	('MEK', 'Gene', (17, 20))	('mRNA gene expression', 'MPA', (56, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('antigen presentation', 'biological_process', 'GO:0019882', ('125', '145'))	('beta2M', 'Gene', (199, 205))	('increase', 'PosReg', (44, 52))	('inhibition', 'Var', (21, 31))	('beta2M', 'Gene', '12010', (199, 205))	('HLA-A', 'Gene', '3105', (80, 85))	('MHC', 'Gene', (158, 161))	('EGFR', 'Gene', (8, 12))	('MHC', 'Gene', '3107', (158, 161))	('HLA-A', 'Gene', (80, 85))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
43608	27680026	STAT1 knockdown had the largest inhibition of upregulation of surface HLA-A after MEKi, suggesting a role for STAT1 in responses to MEKi (Fig.	('STAT1', 'Gene', '6772', (0, 5))	('upregulation', 'PosReg', (46, 58))	('STAT1', 'Gene', (110, 115))	('HLA-A', 'Gene', '3105', (70, 75))	('STAT1', 'Gene', '6772', (110, 115))	('knockdown', 'Var', (6, 15))	('HLA-A', 'Gene', (70, 75))	('STAT1', 'Gene', (0, 5))
43610	27680026	Microarray profiling of the lung bearing tumors from transgenic EGFR L858R, which activates the MAPK pathway, compared to normal lungs, demonstrated suppression of mouse MHC-I and antigen presentation components H2-K/D, and beta2M, thereby confirming the effects of this pathway in vivo (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MAPK', 'Gene', '5595;5594;5595', (96, 100))	('antigen presentation', 'biological_process', 'GO:0019882', ('180', '200'))	('tumors', 'Disease', (41, 47))	('MHC', 'Gene', '3107', (170, 173))	('beta2M', 'Gene', '12010', (224, 230))	('H2-K/D', 'Gene', (212, 218))	('L858R', 'Var', (69, 74))	('suppression', 'NegReg', (149, 160))	('MAPK', 'Gene', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('EGFR', 'Gene', (64, 68))	('mouse', 'Species', '10090', (164, 169))	('H2-K/D', 'Gene', '14972;83772', (212, 218))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('transgenic', 'Species', '10090', (53, 63))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('MHC', 'Gene', (170, 173))	('beta2M', 'Gene', (224, 230))	('L858R', 'Mutation', 'rs121434568', (69, 74))
43612	27680026	Expression of EGFR L858R in the transgenic mice, given doxycycline for > 6 wk, was demonstrated by increased binding of a human EGFR-specific fluorescently labeled mAb (Fig.	('human', 'Species', '9606', (122, 127))	('L858R', 'Mutation', 'rs121434568', (19, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('EGFR', 'Gene', (14, 18))	('doxycycline', 'Chemical', 'MESH:D004318', (55, 66))	('transgenic mice', 'Species', '10090', (32, 47))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('increased', 'PosReg', (99, 108))	('L858R', 'Var', (19, 24))	('binding', 'Interaction', (109, 116))
43614	27680026	The CD45-hEGFR+ population in the lung in the EGFR L858R-expressing mice demonstrated decreased binding of a MHC-I-specific mAb by flow cytometry, when compared to a wild-type mouse which did not express the EGFR L858R mutation (Fig.	('mice', 'Species', '10090', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('binding', 'Interaction', (96, 103))	('hEGFR', 'Gene', '1956', (9, 14))	('mouse', 'Species', '10090', (176, 181))	('L858R', 'Mutation', 'rs121434568', (213, 218))	('L858R-expressing', 'Var', (51, 67))	('MHC', 'Gene', (109, 112))	('decreased', 'NegReg', (86, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('MHC', 'Gene', '3107', (109, 112))	('L858R', 'Mutation', 'rs121434568', (51, 56))	('hEGFR', 'Gene', (9, 14))	('CD45', 'Gene', (4, 8))	('CD45', 'Gene', '19264', (4, 8))
43620	27680026	A second model, of adoptive T cell therapy in combination with MEKi in BRAF mutant murine melanoma, has demonstrated superiority to single agents alone.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('mutant', 'Var', (76, 82))	('BRAF', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('murine', 'Species', '10090', (83, 89))
43632	27680026	These investigations will be complicated by the effects of some of the drugs on the cellular effectors themselves, the variable effects on the cancer cells depending on their specific mutations, the time frames required to upregulate the responses (about 3 days in the experiments here) and the time required for the effects to wash out of the cancer cells and the effectors.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (344, 350))	('mutations', 'Var', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Disease', (143, 149))	('upregulate', 'PosReg', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
43641	27680026	EGFR inhibition can augment MHC-I and MHC-II expression in keratinocytes.	('MHC', 'Gene', (38, 41))	('MHC', 'Gene', (28, 31))	('inhibition', 'Var', (5, 15))	('MHC', 'Gene', '3107', (38, 41))	('MHC', 'Gene', '3107', (28, 31))	('augment', 'NegReg', (20, 27))	('expression', 'MPA', (45, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Protein', (0, 4))
43645	27680026	We characterized these effects on MHC-I in cells with activating mutations in the MAP kinase pathway with various genotypic lesions, such as activating EGFR mutations, BRAF mutations, and RAS mutations.	('activating', 'PosReg', (54, 64))	('RAS', 'Gene', (188, 191))	('MAP kinase pathway', 'Pathway', (82, 100))	('MHC', 'Gene', '3107', (34, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('activating', 'PosReg', (141, 151))	('mutations', 'Var', (173, 182))	('mutations', 'Var', (157, 166))	('MAP', 'molecular_function', 'GO:0004239', ('82', '85'))	('EGFR', 'Gene', (152, 156))	('BRAF', 'Gene', (168, 172))	('MHC', 'Gene', (34, 37))	('mutations', 'Var', (65, 74))
43649	27680026	We further show, in a transgenically engineered mouse model in vivo, that activating this pathway reduces expression of the components of the antigen presentation machinery, along with MHC-I.	('expression of', 'MPA', (106, 119))	('MHC', 'Gene', '3107', (185, 188))	('mouse', 'Species', '10090', (48, 53))	('transgenic', 'Species', '10090', (22, 32))	('components of the antigen presentation machinery', 'MPA', (124, 172))	('antigen presentation', 'biological_process', 'GO:0019882', ('142', '162'))	('activating', 'Var', (74, 84))	('reduces', 'NegReg', (98, 105))	('MHC', 'Gene', (185, 188))
43650	27680026	This gain-of-function experiment is crucial to proving that activation of MAPK can cause decreased MHC-I in vivo.	('MAPK', 'Gene', (74, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('MHC', 'Gene', (99, 102))	('decreased MHC', 'Phenotype', 'HP:0025547', (89, 102))	('MHC', 'Gene', '3107', (99, 102))	('MAPK', 'Gene', '5595;5594;5595', (74, 78))	('activation', 'Var', (60, 70))	('decreased', 'NegReg', (89, 98))
43653	27680026	Our data also suggest that using combination therapy with MAP kinase inhibition can be powerful, not only as a direct cancer therapy to prevent growth, but also indirectly to promote immunotherapy.	('cancer', 'Disease', (118, 124))	('prevent', 'NegReg', (136, 143))	('growth', 'MPA', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('promote', 'PosReg', (175, 182))	('inhibition', 'Var', (69, 79))	('MAP', 'Enzyme', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MAP', 'molecular_function', 'GO:0004239', ('58', '61'))
43659	27680026	Tumors can decrease MHC-I expression, to avoid immune system detection of the rare neoantigens created in tumors by mutations, and increase inhibitory receptor expression.	('expression', 'MPA', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('MHC', 'Gene', '3107', (20, 23))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('increase', 'PosReg', (131, 139))	('MHC', 'Gene', (20, 23))	('Tumors', 'Disease', (0, 6))	('decrease', 'NegReg', (11, 19))	('mutations', 'Var', (116, 125))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('decrease MHC', 'Phenotype', 'HP:0025547', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('inhibitory receptor expression', 'MPA', (140, 170))	('avoid', 'NegReg', (41, 46))
43661	27680026	Many of the recently approved immunotherapies, such as blockade of CTLA-4 or PD-1, release the T cell inhibition promoted by target tumor cells.	('T cell inhibition', 'MPA', (95, 112))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('release', 'PosReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CTLA-4', 'Gene', (67, 73))	('tumor', 'Disease', (132, 137))	('blockade', 'Var', (55, 63))	('PD-1', 'Gene', (77, 81))
43766	23959774	In addition to up-regulating SOD, Libby six-mix also caused increased production of oxidants and a transient decrease in reduced glutathione (GSH), suggesting that Libby six-mix affects human mesothelial cells by altering their oxidative environment.	('decrease', 'NegReg', (109, 117))	('glutathione', 'Chemical', 'MESH:D005978', (129, 140))	('SOD', 'Gene', '6647', (29, 32))	('altering', 'Reg', (213, 221))	('GSH', 'Chemical', 'MESH:D005978', (142, 145))	('production of oxidants', 'MPA', (70, 92))	('affects', 'Reg', (178, 185))	('SOD', 'molecular_function', 'GO:0004784', ('29', '32'))	('SOD', 'Gene', (29, 32))	('Libby', 'Var', (34, 39))	('human', 'Species', '9606', (186, 191))	('increased production of oxidants', 'Phenotype', 'HP:0025464', (60, 92))	('oxidative environment', 'MPA', (228, 249))	('reduced glutathione', 'MPA', (121, 140))	('increased', 'PosReg', (60, 69))
43767	23959774	Yet another study from our group demonstrated that crocidolite asbestos exposure can cause an altered profile of genes in human peritoneal mesothelial cells.	('human', 'Species', '9606', (122, 127))	('altered', 'Reg', (94, 101))	('cause', 'Reg', (85, 90))	('rat', 'Species', '10116', (40, 43))	('profile of genes', 'MPA', (102, 118))	('crocidolite asbestos', 'Var', (51, 71))
43777	23959774	Furthermore, silencing of ERK1, 2 or AKT by siRNA demonstrated that asbestos-induced cell death is ERK1/2 dependent in both cell lines.	('ERK1', 'molecular_function', 'GO:0004707', ('99', '103'))	('ERK1, 2', 'Gene', '5595;5594', (26, 33))	('ERK1', 'molecular_function', 'GO:0004707', ('26', '30'))	('AKT', 'Gene', '207', (37, 40))	('rat', 'Species', '10116', (57, 60))	('AKT', 'Gene', (37, 40))	('ERK1/2', 'Gene', (99, 105))	('asbestos', 'Chemical', 'MESH:D001194', (68, 76))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('silencing', 'Var', (13, 22))
43798	23959774	More recent studies have shown that a significant number of sporadic MM cases exhibit somatic BRCA 1 associated protein (BAP1) mutations while cases of familial MM were found to have germline BAP1 mutations.	('BRCA 1 associated protein', 'Gene', '8315', (94, 119))	('BAP1', 'Gene', '8314', (121, 125))	('BAP1', 'Gene', (192, 196))	('BAP1', 'Gene', (121, 125))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('mutations', 'Var', (127, 136))	('BAP1', 'Gene', '8314', (192, 196))	('BRCA 1 associated protein', 'Gene', (94, 119))
43800	23959774	Together, these studies indicate that genetic factors such as BAP1 mutations contribute to a predisposition to develop MM after asbestos exposure.	('BAP1', 'Gene', '8314', (62, 66))	('develop MM', 'Disease', (111, 121))	('asbestos', 'Chemical', 'MESH:D001194', (128, 136))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
43829	23959774	Mesothelin itself has a pro-proliferative effect on MMs and knocking it down with siMSLN decreases the viability of the MM cell lines.	('MSLN', 'Gene', (84, 88))	('Mesothelin', 'Gene', '10232', (0, 10))	('Mesothelin', 'Gene', (0, 10))	('viability', 'CPA', (103, 112))	('pro-proliferative effect', 'MPA', (24, 48))	('MMs', 'Chemical', 'MESH:D008741', (52, 55))	('knocking', 'Var', (60, 68))	('rat', 'Species', '10116', (35, 38))	('decreases', 'NegReg', (89, 98))	('MSLN', 'Gene', '10232', (84, 88))
43839	23959774	Furthermore, knockdown and inhibition of ERK 1 and 2 has also been demonstrated to reduce tumor growth rates in mouse tumor xenograft studies while increasing the sensitivity of different MM cell lines to Dox.	('increasing', 'PosReg', (148, 158))	('ERK 1', 'molecular_function', 'GO:0004707', ('41', '46'))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ERK 1 and 2', 'Gene', '26417;26413', (41, 52))	('Dox', 'Chemical', 'MESH:D004317', (205, 208))	('tumor', 'Disease', (90, 95))	('rat', 'Species', '10116', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('sensitivity', 'MPA', (163, 174))	('inhibition', 'Var', (27, 37))	('tumor', 'Disease', (118, 123))	('reduce', 'NegReg', (83, 89))	('mouse', 'Species', '10090', (112, 117))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
43840	23959774	The transcription factor, CREB1, has also been found to be constitutively activated in human MM cells and tumors where it conferred protection from apoptotic cell death as evidenced by an increase in Dox-induced cell death after silencing of CREB1 with siCREB.	('CREB', 'Gene', '1385', (242, 246))	('CREB', 'Gene', (26, 30))	('tumors', 'Disease', (106, 112))	('silencing', 'Var', (229, 238))	('CREB', 'Gene', '1385', (255, 259))	('CREB1', 'Gene', '1385', (26, 31))	('transcription factor', 'molecular_function', 'GO:0000981', ('4', '24'))	('increase', 'PosReg', (188, 196))	('rip', 'Gene', '8737', (10, 13))	('human', 'Species', '9606', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('CREB', 'Gene', '1385', (26, 30))	('cell death', 'biological_process', 'GO:0008219', ('212', '222'))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))	('rip', 'Gene', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CREB1', 'Gene', (242, 247))	('CREB', 'Gene', (242, 246))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('CREB', 'Gene', (255, 259))	('CREB1', 'Gene', '1385', (242, 247))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('148', '168'))	('Dox', 'Chemical', 'MESH:D004317', (200, 203))	('apoptotic cell death', 'CPA', (148, 168))	('CREB1', 'Gene', (26, 31))	('Dox-induced cell death', 'MPA', (200, 222))
43841	23959774	Therefore, identifying and employing inhibitors of CREB as part of a multimodal therapeutic approach to the treatment of MM could help improve survival outcomes.	('inhibitors', 'Var', (37, 47))	('CREB', 'Gene', (51, 55))	('CREB', 'Gene', '1385', (51, 55))	('survival outcomes', 'CPA', (143, 160))	('improve', 'PosReg', (135, 142))
43842	23959774	showed that the EphB4 inhibitor, sEphB4-HAS, used alone or in combination with the VEGF inhibitor, Bevacizumab, was effective at reducing tumor volume, angiogenesis and proliferation of cells in subcutaneous mouse xenograft models of human sarcomatoid MM (H2373 MM cells).	('angiogenesis', 'CPA', (152, 164))	('sEphB4-HAS', 'Chemical', '-', (33, 43))	('rat', 'Species', '10116', (176, 179))	('tumor', 'Disease', (138, 143))	('human', 'Species', '9606', (234, 239))	('angiogenesis', 'biological_process', 'GO:0001525', ('152', '164'))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (99, 110))	('proliferation', 'CPA', (169, 182))	('sEphB4-HAS', 'Var', (33, 43))	('sarcomatoid MM', 'Disease', 'MESH:C538614', (240, 254))	('sarcomatoid MM', 'Disease', (240, 254))	('mouse', 'Species', '10090', (208, 213))	('H2373 MM', 'CellLine', 'CVCL:A533', (256, 264))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('reducing', 'NegReg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
43924	22922885	As shown in Table I, the level of EGFR expression in each MPM cell line, in ascending order, is as follows: EHMES-1, MSTO-211H, H2052, EHMES-10 and H28.	('EGFR', 'Gene', (34, 38))	('EHMES-10', 'CellLine', 'CVCL:M208', (135, 143))	('MSTO-211H', 'Var', (117, 126))	('H2052', 'Var', (128, 133))	('H28', 'Var', (148, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('H2052', 'CellLine', 'CVCL:1518', (128, 133))	('MSTO-211H', 'CellLine', 'CVCL:1430', (117, 126))
43944	22922885	To determine the optimal dose of cetuximab for the treatment of SCID mice bearing MSTO-211H, we first determined the survival times of the mice using various amounts of cetuximab (0.5 mg/mouse, 0.05 mg/mouse and 0.005 mg/mouse i.t.	('SCID', 'Disease', (64, 68))	('0.05 mg/mouse', 'Var', (194, 207))	('mouse', 'Species', '10090', (202, 207))	('SCID', 'Disease', 'MESH:D053632', (64, 68))	('MSTO-211H', 'CellLine', 'CVCL:1430', (82, 91))	('mouse', 'Species', '10090', (221, 226))	('0.005 mg/mouse', 'Var', (212, 226))	('mice', 'Species', '10090', (69, 73))	('cetuximab', 'Chemical', 'MESH:D000068818', (169, 178))	('cetuximab', 'Chemical', 'MESH:D000068818', (33, 42))	('mouse', 'Species', '10090', (187, 192))	('mice', 'Species', '10090', (139, 143))
43965	22922885	We demonstrated that the demarcation point of the EGFR expression level to achieve maximum ADCC activity is between EHMES-1 (6.54x103 EGFR molecules/cell) and MSTO-211H (1.42x104 EGFR molecules/cell), both of which are scored as 1+ by IHC.	('EGFR', 'molecular_function', 'GO:0005006', ('179', '183'))	('activity', 'MPA', (96, 104))	('ADCC', 'biological_process', 'GO:0001788', ('91', '95'))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('6.54x103 EGFR', 'Var', (125, 138))	('1.42x104', 'Var', (170, 178))	('ADCC', 'Enzyme', (91, 95))	('MSTO-211H', 'CellLine', 'CVCL:1430', (159, 168))
44052	23516439	PF1038 displayed two different morphologies in early passages (p6) (spindle shaped and rounded cells), but spindle cells were dominant in later passages (p16) (Figure 1).	('spindle', 'cellular_component', 'GO:0005819', ('68', '75'))	('p16', 'Gene', (154, 157))	('spindle', 'cellular_component', 'GO:0005819', ('107', '114'))	('p16', 'Gene', '1029', (154, 157))	('PF1038', 'Var', (0, 6))
44054	23516439	Cells from all six lines [MM04 (p4), MM05 (p5), MM12 (p5), MM13 (p2), MM1081 (p5) and PF1038 (p3)] stained positively for calretinin and cytokeratin 19 by immunocytochemistry (Table 2).	('MM1081', 'Var', (70, 76))	('calretinin', 'Gene', '794', (122, 132))	('MM13', 'Var', (59, 63))	('cytokeratin 19', 'Gene', '3880', (137, 151))	('cytokeratin 19', 'Gene', (137, 151))	('calretinin', 'Gene', (122, 132))	('stained', 'Reg', (99, 106))	('MM05', 'Var', (37, 41))	('MM12', 'Var', (48, 52))
44055	23516439	Growth characteristics were studied at the following passages (p) - MM04 (p11) MM05 (p16), MM12 (p5), MM13 (p9), MM1081 (p6) and PF1038 (p6).	('p16', 'Gene', (85, 88))	('MM13', 'Var', (102, 106))	('MM12', 'Var', (91, 95))	('p11', 'Gene', '6281', (74, 77))	('PF1038', 'Var', (129, 135))	('MM1081', 'Var', (113, 119))	('p16', 'Gene', '1029', (85, 88))	('p11', 'Gene', (74, 77))
44058	23516439	MM12 p10 (biphasic) and MM1081 p4 (epithelioid) both showed polyploidy.	('polyploidy', 'Disease', 'MESH:D011123', (60, 70))	('polyploidy', 'Disease', (60, 70))	('p10', 'Gene', (5, 8))	('p10', 'Gene', '6281', (5, 8))	('MM1081 p4', 'Var', (24, 33))
44059	23516439	A single copy of chromosomes 8, 14 and 22 was observed in two cell lines (MM04 p8 and PF1038 p12) and of chromosome 17 in MM04, MM05p5 and PF1038.	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('p12', 'Gene', '56655', (93, 96))	('p12', 'Gene', (93, 96))	('PF1038', 'Var', (139, 145))
44077	23516439	Monosomy 17, found in three of five cell lines, has been reported previously in mesothelioma, and may be implicated in functional inactivation of the p53 gene due to binding of SV40 Tag protein.	('inactivation', 'NegReg', (130, 142))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('binding', 'molecular_function', 'GO:0005488', ('166', '173'))	('binding', 'Interaction', (166, 173))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('p53', 'Gene', (150, 153))	('protein', 'Protein', (186, 193))	('SV40', 'Var', (177, 181))	('p53', 'Gene', '7157', (150, 153))	('mesothelioma', 'Disease', (80, 92))	('Monosomy 17', 'Var', (0, 11))	('reported', 'Reg', (57, 65))
44078	23516439	Rearrangements involving chromosome 1 were found in all mesothelioma cell lines.	('Rearrangements', 'Var', (0, 14))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('found', 'Reg', (43, 48))	('mesothelioma', 'Disease', (56, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
44079	23516439	Breakpoints and deletions at chromosome 1 regions located near Blym, L-Myc and sci proto-oncogenes have been described in various solid tumours including mesothelioma.	('L-Myc', 'Gene', '4610', (69, 74))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('deletions', 'Var', (16, 25))	('sci', 'Gene', (79, 82))	('mesothelioma', 'Disease', (154, 166))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('solid tumours', 'Disease', 'MESH:D009369', (130, 143))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('L-Myc', 'Gene', (69, 74))	('solid tumours', 'Disease', (130, 143))	('described', 'Reg', (109, 118))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
44080	23516439	Multiple regions of allelic loss from 6q have been reported in mesothelioma, and we observed chromosome 6 rearrangements in one (of five) line.	('reported', 'Reg', (51, 59))	('mesothelioma', 'Disease', (63, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('allelic', 'Var', (20, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('loss', 'NegReg', (28, 32))
44081	23516439	Allelic losses at three known tumour suppressor regions (22q which includes Nf2 marker (NF2CA3), 9p for the p16 gene, and 3p for FHIT gene) and at other areas of 14q and 6q, are also frequent in mesothelioma.	('frequent', 'Reg', (183, 191))	('FHIT', 'Gene', (129, 133))	('Allelic losses', 'Var', (0, 14))	('mesothelioma', 'Disease', (195, 207))	('NF2', 'Gene', '4771', (88, 91))	('p16', 'Gene', '1029', (108, 111))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('FHIT', 'Gene', '2272', (129, 133))	('tumour', 'Disease', (30, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('NF2', 'Gene', (88, 91))	('p16', 'Gene', (108, 111))	('Nf2', 'Gene', (76, 79))	('Nf2', 'Gene', '4771', (76, 79))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
44109	11953832	The integrity of each RNA and oligo-dT-synthesised cDNA sample was confirmed by the amplification of the beta-actin housekeeping gene (Coral et al, 1999).	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('beta-actin', 'Gene', (105, 115))	('amplification', 'Var', (84, 97))	('beta-actin', 'Gene', '728378', (105, 115))	('oligo-dT', 'Chemical', 'MESH:C027903', (30, 38))
44121	11953832	Furthermore, the intensity of RT-PCR products for CTA that were constitutively expressed by MM cells was invariantly higher in 5-AZA-CdR-treated cells (Table 2, Figure 1).	('5-AZA-CdR-treated', 'Var', (127, 144))	('intensity', 'MPA', (17, 26))	('higher', 'PosReg', (117, 123))	('CTA', 'Chemical', '-', (50, 53))	('RT-PCR', 'MPA', (30, 36))
44122	11953832	Consistently, competitive RT-PCR analysis revealed a six to 10-fold increase in MAGE-3 expression in 5-AZA-CdR-treated MPP-89 and MES-OC99 cells, respectively.	('MAGE-3', 'Gene', (80, 86))	('MAGE-3', 'Gene', '4102', (80, 86))	('5-AZA-CdR-treated', 'Var', (101, 118))	('MES', 'Chemical', 'MESH:C004550', (130, 133))	('expression', 'MPA', (87, 97))	('increase', 'PosReg', (68, 76))	('MPP', 'molecular_function', 'GO:0004240', ('119', '122'))
44123	11953832	As expected, no induction of Melan-A/MART-1 expression was observed following 5-AZA-CdR treatment in MM cells (data not shown).	('Melan-A', 'Gene', (29, 36))	('5-AZA-CdR', 'Var', (78, 87))	('MART-1', 'Gene', '2315', (37, 43))	('MART-1', 'Gene', (37, 43))	('Melan-A', 'Gene', '2315', (29, 36))
44126	11953832	Noteworthy, the molecular weight of NY-ESO-1 expressed by 5-AZA-CdR-treated MPP-89 and MES-CM98 MM cells was identical to that of NY-ESO-1 constitutively expressed by HT1080 fibrosarcoma cells utilised as positive control (Figure 1).	('HT1080', 'CellLine', 'CVCL:0317', (167, 173))	('5-AZA-CdR-treated', 'Var', (58, 75))	('fibrosarcoma', 'Disease', (174, 186))	('NY-ESO-1', 'Gene', '246100', (36, 44))	('MPP', 'molecular_function', 'GO:0004240', ('76', '79'))	('NY-ESO-1', 'Gene', (36, 44))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (174, 186))	('fibrosarcoma', 'Disease', 'MESH:D005354', (174, 186))	('NY-ESO-1', 'Gene', '246100', (130, 138))	('MES', 'Chemical', 'MESH:C004550', (87, 90))	('NY-ESO-1', 'Gene', (130, 138))
44135	11953832	The feasibility of this approach is further supported by recent evidences indicating that CTA expression induced by 5-AZA-CdR in melanoma cells is long-lasting (Coral et al, 1999; De Smet et al, 1999), remaining stable throughout cellular replication (De Smet et al, 1999).	('CTA', 'Chemical', '-', (90, 93))	('CTA', 'MPA', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('5-AZA-CdR', 'Var', (116, 125))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))
44136	11953832	We also found that 5-AZA-CdR up-regulates the expression of HLA class I antigens, and of the co-stimulatory molecules intercellular adhesion molecule-1 and leukocyte function-associated antigen-3 on MES-MM98 MM cells (data not shown).	('HLA class I antigens', 'Protein', (60, 80))	('up-regulates', 'PosReg', (29, 41))	('MES-MM98', 'CellLine', 'CVCL:Z508', (199, 207))	('5-AZA-CdR', 'Var', (19, 28))	('MM98 MM', 'CellLine', 'CVCL:H241', (203, 210))	('expression', 'MPA', (46, 56))
44137	11953832	Thus, in vivo administration of 5-AZA-CdR, in addition to induce/up-regulate CTA expression by MM cells, might also enhance their constitutive immunogenicity through the up-regulated expression of distinct components recognised on transformed cells by T lymphocytes.	('induce/up-regulate', 'PosReg', (58, 76))	('constitutive immunogenicity', 'MPA', (130, 157))	('enhance', 'PosReg', (116, 123))	('5-AZA-CdR', 'Var', (32, 41))	('up-regulated', 'PosReg', (170, 182))	('expression', 'MPA', (183, 193))	('CTA', 'Chemical', '-', (77, 80))	('CTA', 'Protein', (77, 80))	('expression', 'MPA', (81, 91))
44174	33166791	Patients in this study were enrolled in either the NivoMes study (NCT02497508) or the INITIATE study (NCT03048474).	('NCT03048474', 'Var', (102, 113))	('NCT02497508', 'Var', (66, 77))	('Patients', 'Species', '9606', (0, 8))
44212	33166791	Using comprehensive immune monitoring, we demonstrate that combining aPD-1 with aCTLA-4 treatment strongly induces memory T-cell proliferation and activation of both CD4 and CD8 T cells.	('CD8', 'Gene', (174, 177))	('aPD-1', 'Var', (69, 74))	('CD8', 'Gene', '925', (174, 177))	('CD4', 'Gene', (166, 169))	('CD4', 'Gene', '920', (166, 169))	('memory T-cell proliferation', 'CPA', (115, 142))	('induces', 'Reg', (107, 114))	('memory T-cell proliferation', 'biological_process', 'GO:0061485', ('115', '142'))	('activation', 'PosReg', (147, 157))
44217	33166791	Survival analysis also showed that PFS was significantly longer in patients with high frequencies of TEMRAs prior to treatment.	('RA', 'Disease', 'MESH:D001172', (104, 106))	('longer', 'PosReg', (57, 63))	('patients', 'Species', '9606', (67, 75))	('PFS', 'MPA', (35, 38))	('high frequencies', 'Var', (81, 97))
44237	33166791	High proportions of TEMRAs that expressed cytokines, prior to treatment, were associated with a better clinical outcome to combination therapy, likely because TEMRAs comprise tumor-specific T cells.	('tumor', 'Disease', (175, 180))	('RA', 'Disease', 'MESH:D001172', (162, 164))	('cytokines', 'Var', (42, 51))	('better', 'PosReg', (96, 102))	('RA', 'Disease', 'MESH:D001172', (23, 25))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
44238	33166791	This also suggests that TEMRAs can only be reactivated upon combined blockade of both aPD-1 and aCTLA-4.	('aPD-1', 'Gene', (86, 91))	('RA', 'Disease', 'MESH:D001172', (27, 29))	('blockade', 'Var', (69, 77))
44243	33166791	Furthermore, prof. dr. Aerts has a patent pending on tumour lysate antigen (EP2938354A1) and is stock owner at Amphera B.V. Immunotherapy.	('tumour', 'Disease', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('EP2938354A1', 'Var', (76, 87))
44341	32977478	This was also regulated by FoxO1, as revealed by overexpression by transfection into sublines or silencing in the original MT-2 line.	('FoxO1', 'Gene', '2308', (27, 32))	('silencing', 'Var', (97, 106))	('MT-2', 'CellLine', 'CVCL:2631', (123, 127))	('MT-2', 'molecular_function', 'GO:0043851', ('123', '127'))	('overexpression', 'PosReg', (49, 63))	('FoxO1', 'Gene', (27, 32))
44354	32977478	Furthermore, changes in the ratio of NADPH to oxidized NADP+ (NADPH/NADP+) also acted to relieve oxidative stress due to asbestos (Figure 3E).	('relieve', 'NegReg', (89, 96))	('oxidative stress', 'MPA', (97, 113))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('NADP+', 'Chemical', 'MESH:D009249', (68, 73))	('NADPH', 'Chemical', 'MESH:D009249', (62, 67))	('changes', 'Var', (13, 20))	('NADP+', 'Chemical', 'MESH:D009249', (55, 60))	('NADPH', 'Chemical', 'MESH:D009249', (37, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))
44428	31662796	Therefore, inhibition of HIF1alpha synthesis or activity can contribute to blocking tumour angiogenesis, glycolysis and tumour-cell growth.	('angiogenesis', 'biological_process', 'GO:0001525', ('91', '103'))	('tumour', 'Disease', (84, 90))	('glycolysis', 'Disease', (105, 115))	('tumour-cell', 'Disease', (120, 131))	('activity', 'MPA', (48, 56))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('synthesis', 'biological_process', 'GO:0009058', ('35', '44'))	('tumour', 'Disease', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('cell growth', 'biological_process', 'GO:0016049', ('127', '138'))	('inhibition', 'Var', (11, 21))	('HIF1alpha', 'Protein', (25, 34))	('glycolysis', 'Disease', 'MESH:C564972', (105, 115))	('blocking', 'NegReg', (75, 83))	('glycolysis', 'biological_process', 'GO:0006096', ('105', '115'))	('tumour-cell', 'Disease', 'MESH:D018295', (120, 131))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
44440	31662796	Based on this, and knowing the oxygenating action of CF, we assumed that it can sensitize cancer cells to standard therapy through HIF1alpha modulation.	('modulation', 'Var', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('oxygen', 'Chemical', 'MESH:D010100', (31, 37))	('CF', 'Gene', '100036221', (53, 55))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('HIF1alpha', 'Protein', (131, 140))
44466	31662796	Oxidation of DCFH-DA by ROS converts the molecule to 2',7'dichlorodihydrofluorescein diacetate (DCF), which is highly fluorescent.	('DCF', 'Chemical', 'MESH:C110400', (13, 16))	('Oxidation', 'Var', (0, 9))	("2',7'dichlorodihydrofluorescein diacetate", 'Chemical', 'MESH:C110400', (53, 94))	('ROS', 'Gene', (24, 27))	('DCFH-DA', 'Gene', (13, 20))	('DCF', 'Chemical', 'MESH:C110400', (96, 99))
44517	31662796	The associations CF + CISP, CF + RT(4) and CISP + RT(4) were more effective at reducing vital cells than single treatment, and a synergistic effect of the treatment was highlighted (Table 1).	('CF', 'Gene', '100036221', (17, 19))	('CF', 'Gene', '100036221', (28, 30))	('vital cells', 'CPA', (88, 99))	('reducing', 'NegReg', (79, 87))	('CISP', 'Chemical', 'MESH:D002945', (43, 47))	('CISP', 'Chemical', 'MESH:D002945', (22, 26))	('CISP + RT', 'Var', (43, 52))
44523	31662796	First, we performed a dose curve, as the different cell lines have various sensitivity thresholds to H2O2, and we chose for the following experiments the dose range of 50-200 mumol/l of H2O2 because it induces stress without killing MSTO cells dramatically.	('stress', 'MPA', (210, 216))	('induces', 'Reg', (202, 209))	('H2O2', 'Var', (186, 190))	('H2O2', 'Chemical', 'MESH:D014867', (101, 105))	('H2O2', 'Chemical', 'MESH:D014867', (186, 190))
44524	31662796	The addition of 50-200mumol/l H2O2 to MSTO cells resulted in enhanced ROS generation, while the cotreatment with NAC attenuates the ROS levels [Figure 5(a)].	('attenuates', 'NegReg', (117, 127))	('enhanced', 'PosReg', (61, 69))	('H2O2', 'Chemical', 'MESH:D014867', (30, 34))	('NAC', 'Gene', '195046', (113, 116))	('ROS generation', 'biological_process', 'GO:1903409', ('70', '84'))	('ROS generation', 'MPA', (70, 84))	('H2O2', 'Var', (30, 34))	('NAC', 'cellular_component', 'GO:0005854', ('113', '116'))	('NAC', 'Gene', (113, 116))
44525	31662796	We detected HIF1alpha at 100 mumol/l and 200 mumol/l of H2O2 but not at 0 mumol/l and 50 mumol/l, while VEGF and PGK1 were detectable from 0 mumol/l to 200 mumol/l of H2O2 [Figure 5(b)].	('PGK1', 'Gene', '18655', (113, 117))	('HIF1alpha', 'Protein', (12, 21))	('H2O2', 'Chemical', 'MESH:D014867', (167, 171))	('H2O2', 'Var', (56, 60))	('VEGF', 'Gene', '22339', (104, 108))	('PGK1', 'Gene', (113, 117))	('PGK', 'molecular_function', 'GO:0004618', ('113', '116'))	('H2O2', 'Chemical', 'MESH:D014867', (56, 60))	('VEGF', 'Gene', (104, 108))	('detected', 'Reg', (3, 11))
44526	31662796	We found an increasing expression of HIF1alpha at 100 mumol/l H2O2 while at 200 mumol/l H2O2 it decreased [Figure 5(b), (c)].	('increasing', 'PosReg', (12, 22))	('H2O2', 'Var', (62, 66))	('H2O2', 'Chemical', 'MESH:D014867', (88, 92))	('HIF1alpha', 'Protein', (37, 46))	('decreased', 'NegReg', (96, 105))	('H2O2', 'Chemical', 'MESH:D014867', (62, 66))	('expression', 'MPA', (23, 33))
44527	31662796	Vice versa PGK1 and VEGF showed greater expression after the addition of 200 mumol/l H2O2 [Figure 5(b), (c)].	('expression', 'MPA', (40, 50))	('H2O2', 'Chemical', 'MESH:D014867', (85, 89))	('VEGF', 'Gene', '22339', (20, 24))	('greater', 'PosReg', (32, 39))	('H2O2', 'Var', (85, 89))	('PGK1', 'Gene', '18655', (11, 15))	('PGK', 'molecular_function', 'GO:0004618', ('11', '14'))	('VEGF', 'Gene', (20, 24))	('PGK1', 'Gene', (11, 15))
44530	31662796	On the other hand, the levels of ROS generated after 200 mumol/l H2O2 and NAC treatment, were comparable with those obtained with 100 micromol/l H2O2 alone [Figure 5(a)].	('NAC', 'Gene', '195046', (74, 77))	('ROS', 'MPA', (33, 36))	('H2O2', 'Chemical', 'MESH:D014867', (65, 69))	('NAC', 'cellular_component', 'GO:0005854', ('74', '77'))	('H2O2', 'Chemical', 'MESH:D014867', (145, 149))	('H2O2', 'Var', (65, 69))	('NAC', 'Gene', (74, 77))
44578	31662796	PGK1 and VEGF expression, proteins with HIF1alpha correlation, were positively regulated by HIF1alpha in CF + RT(4) treatment but not in CF + ST + RT(4) treatment, suggesting a strengthening effect of RT(4) by CF.	('CF', 'Gene', '100036221', (137, 139))	('HIF1alpha', 'Var', (92, 101))	('VEGF', 'Gene', (9, 13))	('CF', 'Gene', '100036221', (210, 212))	('expression', 'MPA', (14, 24))	('PGK', 'molecular_function', 'GO:0004618', ('0', '3'))	('PGK1', 'Gene', '18655', (0, 4))	('positively', 'PosReg', (68, 78))	('CF', 'Gene', '100036221', (105, 107))	('PGK1', 'Gene', (0, 4))	('regulated', 'Reg', (79, 88))	('VEGF', 'Gene', '22339', (9, 13))
44583	31662796	Overexpression of HIF1alpha is associated with advanced disease stages, poor prognosis and treatment resistance among cancer patients, while inhibition of HIF1alpha retards tumour growth in animal models.	('cancer', 'Disease', (118, 124))	('retards tumour', 'Disease', 'MESH:D009369', (165, 179))	('retards tumour', 'Disease', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HIF1alpha', 'Gene', (155, 164))	('HIF1alpha', 'Gene', (18, 27))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('Overexpression', 'Var', (0, 14))	('inhibition', 'Var', (141, 151))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
44633	31662796	Overexpressed PGK1 is one of the extrinsic factors of tumour cell radiosensibility.	('Overexpressed', 'Var', (0, 13))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('PGK', 'molecular_function', 'GO:0004618', ('14', '17'))	('tumour', 'Disease', (54, 60))	('PGK1', 'Gene', '18655', (14, 18))	('PGK1', 'Gene', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
44641	30001711	Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('cancers', 'Disease', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BAP1', 'Gene', (176, 180))	('susceptibility', 'MPA', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('peritoneal mesothelioma', 'Disease', (51, 74))	('mutations', 'Var', (24, 33))	('patient', 'Species', '9606', (88, 95))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('mesothelioma', 'Disease', (209, 221))	('patients', 'Species', '9606', (37, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (51, 74))	('BRCA-1 associated tumor protein 1', 'Gene', '8314', (141, 174))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (51, 74))	('BAP1', 'Gene', '8314', (19, 23))	('BRCA-1 associated tumor protein 1', 'Gene', (141, 174))	('mutations', 'Var', (124, 133))	('patient', 'Species', '9606', (37, 44))	('BAP1', 'Gene', '8314', (176, 180))	('mesothelioma', 'Disease', (62, 74))	('BAP1', 'Gene', (19, 23))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))
44643	30001711	These findings lead us to hypothesize that the mesothelioma occurred in the setting of germline a BAP1 mutation.	('BAP1', 'Gene', (98, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('occurred', 'Reg', (60, 68))	('mutation', 'Var', (103, 111))	('mesothelioma', 'Disease', (47, 59))
44645	30001711	Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma, uveal and cutaneous melanomas, renal cell carcinomas, basal cell and squamous cell carcinomas, as well as, although less frequently, to other cancer types.	('Germline mutations', 'Var', (0, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('BRCA-1 associated tumor protein 1', 'Gene', '8314', (26, 59))	('susceptibility', 'Reg', (76, 90))	('basal cell and squamous cell carcinomas', 'Phenotype', 'HP:0002671', (162, 201))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (139, 160))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('BRCA-1 associated tumor protein 1', 'Gene', (26, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (118, 137))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (118, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('renal cell carcinomas', 'Disease', (139, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (177, 201))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (139, 160))	('basal cell', 'Disease', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (177, 201))	('cutaneous melanomas', 'Disease', (118, 137))	('BAP1', 'Gene', (61, 65))	('cancer', 'Disease', (250, 256))	('uveal', 'Disease', (108, 113))	('mesothelioma', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('squamous cell carcinomas', 'Disease', (177, 201))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
44648	30001711	Similarly to patients with the Li-Fraumeni syndrome, BAP1 mutations are highly penetrant, and so far most carriers of BAP1 mutations have developed one or more malignancies during their lifetime.	('mutations', 'Var', (58, 67))	('malignancies', 'Disease', (160, 172))	('Li-Fraumeni syndrome', 'Disease', (31, 51))	('patients', 'Species', '9606', (13, 21))	('developed', 'Reg', (138, 147))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (31, 51))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))	('BAP1', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))	('BAP1', 'Gene', (53, 57))
44651	30001711	Human cells derived from carriers of germline BAP1 mutations showed reduced ability to repair DNA by homologous recombination and to execute apoptosis following exposure to asbestos, ultraviolet light and irradiation.	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('Human', 'Species', '9606', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('mutations', 'Var', (51, 60))	('homologous recombination', 'biological_process', 'GO:0035825', ('101', '125'))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('asbestos', 'Chemical', 'MESH:D001194', (173, 181))	('BAP1', 'Gene', (46, 50))	('reduced', 'NegReg', (68, 75))	('apoptosis', 'CPA', (141, 150))	('ability', 'MPA', (76, 83))
44653	30001711	Under normal circumstances accumulation of DNA mutations triggers apoptosis, but BAP1 mutant cells have impaired apoptosis because of the reduced Ca2+ mitochondrial levels.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('BAP1', 'Gene', (81, 85))	('reduced', 'NegReg', (138, 145))	('mutant', 'Var', (86, 92))	('Ca2+ mitochondrial levels', 'MPA', (146, 171))	('Ca2+', 'Chemical', 'MESH:D000069285', (146, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
44654	30001711	These mechanisms account for the high rate of cancer, especially those cancers caused by environmental carcinogens in carriers of germline BAP1 mutations.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Disease', (46, 52))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (144, 153))
44655	30001711	Cancers that develop in carriers of germline BAP1 mutations are less aggressive, have a better prognosis and improved survival.	('BAP1', 'Gene', (45, 49))	('Cancers', 'Disease', (0, 7))	('mutations', 'Var', (50, 59))	('aggressive', 'CPA', (69, 79))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('less', 'NegReg', (64, 68))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('improved', 'PosReg', (109, 117))	('germline', 'Var', (36, 44))	('better', 'PosReg', (88, 94))
44656	30001711	Detecting BAP1 mutations in appropriate cancer patients is important since management may be affected.	('BAP1', 'Gene', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
44657	30001711	If a BAP1 mutation is present, then screening and early detection of BAP1-associated cancers can be undertaken.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('mutation', 'Var', (10, 18))	('cancers', 'Disease', (85, 92))	('BAP1', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
44665	30001711	Genetic testing revealed that our patient carried the following inactivating truncating germline BAP1 mutation: chr3.52406884A > G, c.604T > C, p.Trp202Arg.	('p.Trp202Arg', 'Mutation', 'p.W202R', (144, 155))	('chr3.52406884A > G', 'Var', (112, 130))	('p.Trp202Arg', 'Var', (144, 155))	('BAP1', 'Gene', (97, 101))	('c.604T > C', 'Var', (132, 142))	('patient', 'Species', '9606', (34, 41))	('52406884A > G', 'Mutation', 'g.52406884A>G', (117, 130))	('c.604T > C', 'Mutation', 'c.604T>C', (132, 142))
44667	30001711	The identification of a germline BAP1 mutation in this young lady with peritoneal mesothelioma, led to meetings with family members in which we explained the potential advantages and possible disadvantages of genetic testing for BAP1 mutations, consistent with the guidelines of the Consensus report on mesothelioma.	('mesothelioma', 'Disease', (82, 94))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (71, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('peritoneal mesothelioma', 'Disease', (71, 94))	('mesothelioma', 'Disease', (303, 315))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (71, 94))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', (229, 233))	('mesothelioma', 'Disease', 'MESH:D008654', (303, 315))
44671	30001711	Those who had not inherited the mutation were reassured that they did not carry a higher risk of developing mesothelioma or other cancers compared to the general population at large.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('mesothelioma', 'Disease', (108, 120))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutation', 'Var', (32, 40))
44672	30001711	Those who were found to carry germline BAP1 mutations, were informed of the increased risk for mesothelioma and other BAP1-associated cancers, and advised to reduce sun-exposure, minimize radiation exposure, including diagnostic/therapeutic radiation for the increased risk of cancer because of impaired DNA repair and apoptosis, and to avoid trades that could lead to asbestos exposure.	('DNA', 'cellular_component', 'GO:0005574', ('304', '307'))	('DNA repair', 'biological_process', 'GO:0006281', ('304', '314'))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Disease', (277, 283))	('cancers', 'Disease', (134, 141))	('cancer', 'Disease', (134, 140))	('asbestos', 'Chemical', 'MESH:D001194', (369, 377))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('mesothelioma', 'Disease', (95, 107))	('BAP1', 'Gene', (39, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('impaired', 'NegReg', (295, 303))	('germline', 'Var', (30, 38))	('DNA repair', 'CPA', (304, 314))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('apoptosis', 'CPA', (319, 328))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('319', '328'))	('apoptosis', 'biological_process', 'GO:0006915', ('319', '328'))	('mutations', 'Var', (44, 53))	('minimize', 'NegReg', (179, 187))
44673	30001711	Carriers of germline BAP1 mutations have a very high incidence of cancer, most commonly uveal melanoma, malignant mesothelioma, cutaneous melanoma and clear cell renal cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cutaneous melanoma', 'Disease', (128, 146))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (128, 146))	('mutations', 'Var', (26, 35))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('malignant mesothelioma', 'Disease', (104, 126))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('uveal melanoma', 'Disease', (88, 102))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (104, 126))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('clear cell renal cell carcinoma', 'Disease', (151, 182))	('BAP1', 'Gene', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (151, 182))	('cancer', 'Disease', (66, 72))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (104, 126))
44675	30001711	Other malignancies often reported in carriers of germline BAP1 mutations include most types of skin cancers, breast cancer, cholangiocarcinoma, non-small cell lung adenocarcinoma, meningioma, sarcomas, peripheral nerve sheath tumor, and neuroendocrine carcinoma.	('meningioma', 'Disease', 'MESH:D008577', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('BAP1', 'Gene', (58, 62))	('cholangiocarcinoma', 'Disease', (124, 142))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 142))	('neuroendocrine carcinoma', 'Disease', (237, 261))	('mutations', 'Var', (63, 72))	('skin cancers', 'Disease', (95, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('sheath tumor', 'Disease', (219, 231))	('cell lung adenocarcinoma', 'Disease', (154, 178))	('skin cancers', 'Disease', 'MESH:D012878', (95, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cell lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 178))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('breast cancer', 'Disease', (109, 122))	('malignancies', 'Disease', 'MESH:D009369', (6, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('malignancies', 'Disease', (6, 18))	('meningioma', 'Disease', (180, 190))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (237, 261))	('meningioma', 'Phenotype', 'HP:0002858', (180, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcomas', 'Disease', (192, 200))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (237, 261))	('sheath tumor', 'Disease', 'MESH:D010524', (219, 231))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))	('skin cancers', 'Phenotype', 'HP:0008069', (95, 107))
44676	30001711	Carriers of germline BAP1 mutations can also develop characteristic benign melanocytic skin lesions that were initially called as "atypical Spitz tumors", and later when the unique histological and molecular characteristics of these lesions were elucidated, named as "melanocytic BAP1 mutated atypical intradermal tumors" (MBAITs).	('develop', 'PosReg', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('BAP1', 'Gene', (21, 25))	('benign melanocytic skin lesions', 'Disease', 'MESH:D012871', (68, 99))	('intradermal tumors', 'Disease', 'MESH:D018330', (302, 320))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', (314, 320))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('benign melanocytic skin lesions', 'Disease', (68, 99))	('tumors', 'Disease', (146, 152))	('intradermal tumors', 'Disease', (302, 320))
44677	30001711	Peritoneal and pleural mesotheliomas have both been associated with sporadic and germline BAP1 mutations.	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (15, 36))	('pleural mesotheliomas', 'Disease', (15, 36))	('associated', 'Reg', (52, 62))	('BAP1', 'Gene', (90, 94))	('Peritoneal', 'Disease', (0, 10))	('mutations', 'Var', (95, 104))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (15, 36))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (15, 35))
44678	30001711	It has been estimated that only about 1% of mesotheliomas are associated with germline BAP1 mutations.	('mesotheliomas', 'Disease', (44, 57))	('associated', 'Reg', (62, 72))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('mesotheliomas', 'Disease', 'MESH:D008654', (44, 57))
44682	30001711	It is presently unclear if germline BAP1 mutations are sufficient per se to cause mesothelioma, as suggested by the spontaneous development of mesothelioma in mice carrying germline BAP1 mutations, or whether germline BAP1 mutations lower the threshold of asbestos exposure required to cause mesothelioma, as suggested by experiments in which lower amounts of asbestos were required to induce mesothelioma in heterozygous BAP1 mutant mice.	('BAP1', 'Gene', (422, 426))	('mice', 'Species', '10090', (434, 438))	('mutations', 'Var', (223, 232))	('mutations', 'Var', (41, 50))	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('asbestos', 'Chemical', 'MESH:D001194', (360, 368))	('mesothelioma', 'Disease', (143, 155))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('cause', 'Reg', (76, 81))	('mutant', 'Var', (427, 433))	('BAP1', 'Gene', (36, 40))	('asbestos', 'Chemical', 'MESH:D001194', (256, 264))	('mesothelioma', 'Disease', 'MESH:D008654', (393, 405))	('mesothelioma', 'Disease', (292, 304))	('mutations', 'Var', (187, 196))	('mesothelioma', 'Disease', (393, 405))	('mice', 'Species', '10090', (159, 163))	('BAP1', 'Gene', (218, 222))	('mesothelioma', 'Disease', 'MESH:D008654', (292, 304))
44683	30001711	The possibility that germline BAP1 mutations increase susceptibility to low amounts of asbestos:amounts that would not be considered harmful for the population at large:is important, as rural areas continue to be developed exposing some cohort to asbestos and to other carcinogenic mineral fibers.	('BAP1', 'Gene', (30, 34))	('asbestos', 'Chemical', 'MESH:D001194', (87, 95))	('carcinogenic mineral fibers', 'Disease', 'MESH:C537337', (269, 296))	('carcinogenic mineral fibers', 'Disease', (269, 296))	('susceptibility', 'MPA', (54, 68))	('asbestos', 'Chemical', 'MESH:D001194', (247, 255))	('mutations', 'Var', (35, 44))
44687	30001711	Relatively low levels of carcinogenic fibers, as those found in areas with environmental exposure, might increase the risk of developing mesothelioma among carriers of germline BAP1 mutations.	('carriers', 'Reg', (156, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('carcinogenic fibers', 'Disease', (25, 44))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (25, 44))	('BAP1', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))	('mesothelioma', 'Disease', (137, 149))
44688	30001711	The ratio of peritoneal to pleural mesothelioma is significantly higher in carriers of germline BAP1 mutations compared to the rate in the sporadic mesotheliomas.	('sporadic mesotheliomas', 'Disease', (139, 161))	('mutations', 'Var', (101, 110))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (139, 161))	('BAP1', 'Gene', (96, 100))	('peritoneal', 'Disease', (13, 23))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (27, 47))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (27, 47))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (139, 161))	('pleural mesothelioma', 'Disease', (27, 47))	('higher', 'PosReg', (65, 71))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (139, 160))
44689	30001711	In addition, in carriers of BAP1 mutations the majority of peritoneal mesothelioma occurs in women, and have a better prognosis, in contrast to sporadic mesotheliomas.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (59, 82))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (144, 166))	('women', 'Species', '9606', (93, 98))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('carriers', 'Reg', (16, 24))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (144, 165))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (59, 82))	('sporadic mesotheliomas', 'Disease', (144, 166))	('peritoneal mesothelioma', 'Disease', (59, 82))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (144, 166))
44690	30001711	The critical role of normal levels BAP1 in preventing mesothelioma development is highlighted by multiple factors: (1) In families, BAP1 mutations specifically segregate among patients, while individuals who do not inherit the mutation are cancer free; (2) tumors in carriers of germline BAP1 mutations always show loss of heterozygosity, i.e., biallelic BAP1 inactivation; (3) BAP1 is the most common acquired somatic mutation in sporadic mesothelioma.	('patients', 'Species', '9606', (176, 184))	('mesothelioma', 'Disease', (54, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (257, 263))	('mutations', 'Var', (293, 302))	('BAP1', 'Gene', (378, 382))	('mesothelioma', 'Disease', (440, 452))	('BAP1', 'Gene', (355, 359))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (431, 452))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('mesothelioma', 'Disease', 'MESH:D008654', (440, 452))	('cancer', 'Disease', (240, 246))	('BAP1', 'Gene', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('biallelic', 'Var', (345, 354))
44691	30001711	Malignant mesothelioma or other BAP1 associated cancers occurring at a young age, i.e., 50 years old or younger, or occurring in multiple family members:regardless of age:should trigger testing for germline BAP1 mutations.	('germline', 'Var', (198, 206))	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('BAP1', 'Gene', (207, 211))	('BAP1', 'Gene', (32, 36))	('mutations', 'Var', (212, 221))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
44693	30001711	Consensus guidelines suggest that screening for germline BAP1 mutations in mesothelioma patients who are members of families with multiple cases of mesothelioma, melanoma, renal cell carcinoma, cholangiocarcinoma, basal cell carcinoma, can lead to early detection that can be life saving for several of these malignancies, or at least to better therapeutic options when cancers are treated at an early stage.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (214, 234))	('cholangiocarcinoma', 'Disease', (194, 212))	('renal cell carcinoma', 'Disease', (172, 192))	('BAP1', 'Gene', (57, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (194, 212))	('mesothelioma', 'Disease', (75, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (172, 192))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('malignancies', 'Disease', 'MESH:D009369', (309, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('malignancies', 'Disease', (309, 321))	('basal cell carcinoma', 'Disease', (214, 234))	('cancers', 'Disease', 'MESH:D009369', (370, 377))	('mutations', 'Var', (62, 71))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (194, 212))	('lead to', 'Reg', (240, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 192))	('patients', 'Species', '9606', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('mesothelioma', 'Disease', (148, 160))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (214, 234))	('cancers', 'Phenotype', 'HP:0002664', (370, 377))	('cancers', 'Disease', (370, 377))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
44695	30001711	Those studies led to the discovery that inherited germline BAP1 mutations cause a high incidence of mesothelioma and of certain other cancer types in some families.	('BAP1', 'Gene', (59, 63))	('mesothelioma', 'Disease', (100, 112))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cause', 'Reg', (74, 79))	('germline', 'Var', (50, 58))
44696	30001711	The challenge is to identify these cases of mesotheliomas because when mesothelioma and other cancers develop in carriers of germline BAP1 mutations, they often have a better prognosis.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mesothelioma', 'Disease', (71, 83))	('mesotheliomas', 'Disease', (44, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('BAP1', 'Gene', (134, 138))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('germline', 'Var', (125, 133))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('mesothelioma', 'Disease', (44, 56))	('cancers', 'Disease', (94, 101))	('mesotheliomas', 'Disease', 'MESH:D008654', (44, 57))
44698	30001711	This risk cannot be underestimated in carriers of genetic mutations that impair DNA repair and apoptosis, as demonstrated in cancer patients affected by the Li-Fraumeni cancer syndrome who are also monitored preferentially by MRI.	('mutations', 'Var', (58, 67))	('DNA', 'MPA', (80, 83))	('cancer', 'Disease', (169, 175))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('apoptosis', 'CPA', (95, 104))	('Li-Fraumeni cancer syndrome', 'Disease', 'MESH:D016864', (157, 184))	('Li-Fraumeni cancer syndrome', 'Disease', (157, 184))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('impair', 'NegReg', (73, 79))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (132, 140))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
44700	30001711	These unusual findings:young age, family history, no history of exposure to asbestos made us suspect that the mesothelioma in our patient might have a genetic basis and that the patient might carry a germline BAP1 mutation.	('patient', 'Species', '9606', (130, 137))	('mutation', 'Var', (214, 222))	('carry', 'Reg', (192, 197))	('patient', 'Species', '9606', (178, 185))	('asbestos', 'Chemical', 'MESH:D001194', (76, 84))	('mesothelioma', 'Disease', (110, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('germline', 'Var', (200, 208))
44704	30001711	Based on our experience we strongly recommend that mesothelioma occurring at a young age (< 50 years old), or in patients with multiple family members affected by mesothelioma or other cancers associated with germline BAP1 mutations should be tested for BAP1 gene mutations.	('BAP1', 'Gene', (254, 258))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (113, 121))	('germline', 'Var', (209, 217))	('mesothelioma', 'Disease', (51, 63))	('mesothelioma', 'Disease', (163, 175))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('BAP1', 'Gene', (218, 222))	('mutations', 'Var', (223, 232))
44705	30001711	Early recognition of signs and symptoms of peritoneal mesothelioma in patients who carry germline BAP1 mutations can impact outcome and survival.	('BAP1', 'Gene', (98, 102))	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (103, 112))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (43, 66))	('impact', 'Reg', (117, 123))	('peritoneal mesothelioma', 'Disease', (43, 66))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (43, 66))
44706	30001711	BAP1 BRCA-1 associated tumor protein 1 MBAITS melanocytic BAP1 mutated atypical intradermal tumors	('mutated', 'Var', (63, 70))	('BRCA-1 associated tumor protein 1', 'Gene', (5, 38))	('BRCA-1 associated tumor protein 1', 'Gene', '8314', (5, 38))	('intradermal tumors', 'Disease', 'MESH:D018330', (80, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('melanocytic', 'Disease', (46, 57))	('intradermal tumors', 'Disease', (80, 98))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
44738	29238267	A769662 (Abcam, Cambridge, UK) and nutlin-3a (Selleck, Houston, TX, USA) were used to stimulate endogenous the AMPK and the p53 pathways, respectively.	('p53', 'Gene', (124, 127))	('AMPK', 'molecular_function', 'GO:0047322', ('111', '115'))	('endogenous', 'MPA', (96, 106))	('p53', 'Gene', '7157', (124, 127))	('A769662', 'Var', (0, 7))	('A769662', 'Chemical', 'MESH:C512408', (0, 7))	('AMPK', 'molecular_function', 'GO:0050405', ('111', '115'))	('stimulate', 'PosReg', (86, 95))	('AMPK', 'Gene', '5562', (111, 115))	('AMPK', 'Gene', (111, 115))	('AMPK', 'molecular_function', 'GO:0004691', ('111', '115'))
44740	29238267	Cells were transfected with small interfering RNA (si-RNA) duplex targeting cardiac ankyrin repeat protein (CARP) (si-RNA-s502326, s502327, s502328) (Thermo Fisher Scientific, Fremont, CA, USA), insulin-like growth factor binding protein-3 (IGFBP3) (si-RNA-s7227, s7228, s7229) (Thermo Fisher Scientific), or nonspecific si-RNA as a control (Thermo Fisher Scientific) using Lipofectamine RNAiMAX according to the manufacturer's protocol (Thermo Fisher Scientific).	('IGFBP3', 'Gene', (241, 247))	('s7228', 'Var', (264, 269))	('insulin-like growth factor binding protein', 'cellular_component', 'GO:0017052', ('195', '237'))	('RNA', 'cellular_component', 'GO:0005562', ('324', '327'))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('insulin-like growth factor binding', 'molecular_function', 'GO:0005520', ('195', '229'))	('CARP', 'Species', '7962', (108, 112))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('s502327', 'Var', (131, 138))	('IGFBP3', 'Gene', '3486', (241, 247))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('si-RNA-s7227', 'Var', (250, 262))	('RNA', 'cellular_component', 'GO:0005562', ('253', '256'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('si-RNA-s502326', 'Var', (115, 129))	('s502328', 'Var', (140, 147))
44745	29238267	The protein was transferred to a nitrocellulose membrane and was hybridized with antibody against integrin beta-3 (Catalog Number: #13166), AMPK (#2532), phosphorylated AMPK (Thr 172) (#2535), phosphorylated p53 (Ser 15) (#9284) (Cell Signaling, Danvers, MA, USA), plasminogen activator inhibitor (#ab20562), a disintegrin and metalloproteinase with thrombospondin motifs 5 (#ab41037) (Abcam), IGFBP3 (#sc-9028), CARP (sc-30181), beta-2 adrenergic receptor (#sc-569) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), phosphorylated H2AX (Ser 139) (#613401) (BioLegend, San Diego, CA, USA), p53 (Ab-6, Clone DO-1) and tubulin-alpha (Clone DM1A) (Thermo Fisher Scientific) as a control followed by an appropriate second antibody.	('membrane', 'cellular_component', 'GO:0016020', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019815', ('81', '89'))	('p53', 'Gene', '7157', (589, 592))	('p53', 'Gene', '7157', (208, 211))	('AMPK', 'Gene', (140, 144))	('Ser', 'cellular_component', 'GO:0005790', ('537', '540'))	('AMPK', 'Gene', '5562', (169, 173))	('CARP', 'Species', '7962', (413, 417))	('#613401', 'Var', (547, 554))	('antibody', 'molecular_function', 'GO:0003823', ('717', '725'))	('AMPK', 'molecular_function', 'GO:0050405', ('140', '144'))	('Signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('p53', 'Gene', (589, 592))	('AMPK', 'molecular_function', 'GO:0050405', ('169', '173'))	('antibody', 'cellular_component', 'GO:0042571', ('717', '725'))	('p53', 'Gene', (208, 211))	('antibody', 'cellular_component', 'GO:0019814', ('81', '89'))	('AMPK', 'Gene', (169, 173))	('IGFBP3', 'Gene', (394, 400))	('AMPK', 'molecular_function', 'GO:0004691', ('169', '173'))	('Ser', 'cellular_component', 'GO:0005790', ('213', '216'))	('AMPK', 'molecular_function', 'GO:0004691', ('140', '144'))	('AMPK', 'Gene', '5562', (140, 144))	('H2AX', 'Gene', (531, 535))	('antibody', 'molecular_function', 'GO:0003823', ('81', '89'))	('antibody', 'cellular_component', 'GO:0019815', ('717', '725'))	('antibody', 'cellular_component', 'GO:0042571', ('81', '89'))	('IGFBP3', 'Gene', '3486', (394, 400))	('H2AX', 'Gene', '3014', (531, 535))	('AMPK', 'molecular_function', 'GO:0047322', ('140', '144'))	('AMPK', 'molecular_function', 'GO:0047322', ('169', '173'))	('antibody', 'cellular_component', 'GO:0019814', ('717', '725'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
44769	29238267	H28-PEM cells were then treated with three kinds of si-RNA for CARP (s502326, s502327 and s502328) and each kind of si-RNA down-regulated the CARP expression (Fig.	('s502327', 'Var', (78, 85))	('PEM', 'Gene', (4, 7))	('s502328', 'Var', (90, 97))	('CARP', 'Gene', (142, 146))	('expression', 'MPA', (147, 157))	('PEM', 'Gene', '4582', (4, 7))	('down-regulated', 'NegReg', (123, 137))	('s502326', 'Var', (69, 76))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))	('CARP', 'Species', '7962', (63, 67))	('CARP', 'Species', '7962', (142, 146))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))
44775	29238267	We transfected three kinds of si-RNA for IGFBP3 (s7227, s7228, and s7229) into H226-PEM cells and examined the expression levels with their parent cells with ELISA (Additional file 4: Fig.	('H226-PEM', 'CellLine', 'CVCL:J621', (79, 87))	('IGFBP3', 'Gene', (41, 47))	('s7229', 'Var', (67, 72))	('s7228', 'Var', (56, 61))	('IGFBP3', 'Gene', '3486', (41, 47))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))	('s7227', 'Var', (49, 54))
44779	29238267	We then tested the PEM sensitivity of H226-PEM cells treated with the si-RNA and showed that knocking down of IGFBP3 did not improve susceptibility to PEM (Fig.	('tested', 'Reg', (8, 14))	('PEM', 'Gene', (151, 154))	('PEM', 'Gene', '4582', (151, 154))	('H226-PEM', 'CellLine', 'CVCL:J621', (38, 46))	('knocking down', 'Var', (93, 106))	('PEM', 'Gene', '4582', (19, 22))	('IGFBP3', 'Gene', (110, 116))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('PEM', 'Gene', '4582', (43, 46))	('PEM', 'Gene', (19, 22))	('IGFBP3', 'Gene', '3486', (110, 116))	('PEM', 'Gene', (43, 46))
44794	29238267	We used mesothelioma cells with mutated p53 genotype, EHMES-1 and JMN-1B, and mesothelium-derived immortalized Met-5A cells that expressed the SV40 T antigen (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('143', '157'))	('mutated', 'Var', (32, 39))	('SV40 T', 'Var', (143, 149))	('p53', 'Gene', (40, 43))	('mesothelioma', 'Disease', (8, 20))	('p53', 'Gene', '7157', (40, 43))	('JMN-1B', 'CellLine', 'CVCL:M006', (66, 72))
44810	29238267	NCI-H28 and NCI-H226 cells treated with A769662 increased phosphorylated AMPK, but the CARP expression was not induced or rather decreased.	('increased', 'PosReg', (48, 57))	('A769662', 'Var', (40, 47))	('NCI-H226', 'CellLine', 'CVCL:1544', (12, 20))	('A769662', 'Chemical', 'MESH:C512408', (40, 47))	('AMPK', 'molecular_function', 'GO:0050405', ('73', '77'))	('CARP', 'Species', '7962', (87, 91))	('AMPK', 'Gene', '5562', (73, 77))	('AMPK', 'molecular_function', 'GO:0004691', ('73', '77'))	('AMPK', 'Gene', (73, 77))	('AMPK', 'molecular_function', 'GO:0047322', ('73', '77'))
44811	29238267	IGFBP3 was not induced by A769662 either.	('IGFBP3', 'Gene', '3486', (0, 6))	('A769662', 'Var', (26, 33))	('A769662', 'Chemical', 'MESH:C512408', (26, 33))	('IGFBP3', 'Gene', (0, 6))
44830	29238267	EHMES-1 cells mutated p53 genotype increased CARP expression, whereas the expression of JMN-1B cells with the mutated genotype remained unchanged.	('JMN-1B', 'CellLine', 'CVCL:M006', (88, 94))	('increased', 'PosReg', (35, 44))	('mutated', 'Var', (14, 21))	('p53', 'Gene', (22, 25))	('CARP', 'Species', '7962', (45, 49))	('genotype', 'Var', (26, 34))	('p53', 'Gene', '7157', (22, 25))	('CARP expression', 'MPA', (45, 60))
44952	24842043	In our study, 22 patients underwent surgery (9 pleurectomy, 1 pleurodesis, 5 EPP, and 7 P/D) and no mortality occurred.	('7 P/D', 'Var', (86, 91))	('7 P/D', 'SUBSTITUTION', 'None', (86, 91))	('pleurodesis', 'Disease', 'None', (62, 73))	('pleurectomy', 'Disease', (47, 58))	('patients', 'Species', '9606', (17, 25))	('pleurodesis', 'Disease', (62, 73))
44960	24842043	In our study, overall survival time was found to be significantly longer in the patients treated with chemotherapy compared to those who did not receive it (17.6 months and 2.8 months, respectively, p<0.001).	('chemotherapy', 'Var', (102, 114))	('patients', 'Species', '9606', (80, 88))	('longer', 'PosReg', (66, 72))	('overall survival time', 'CPA', (14, 35))
44990	20635390	CA125 is a very large membrane-bound cell surface mucin, with an average molecular weight between 2.5 and 5 million Daltons owing to its extensive glycosylation with both O-linked and N-linked oligosaccharides.	('N-linked oligosaccharides', 'Chemical', '-', (184, 209))	('membrane', 'cellular_component', 'GO:0016020', ('22', '30'))	('mucin', 'Gene', (50, 55))	('cell surface', 'cellular_component', 'GO:0009986', ('37', '49'))	('glycosylation', 'biological_process', 'GO:0070085', ('147', '160'))	('CA125', 'Var', (0, 5))	('glycosylation', 'MPA', (147, 160))	('O-linked', 'Chemical', '-', (171, 179))	('N-linked oligosaccharides', 'Protein', (184, 209))	('mucin', 'Gene', '100508689', (50, 55))	('O-linked', 'Protein', (171, 179))
44992	20635390	CA125 is used as a biomarker in ovarian cancer due to its high expression in ovarian carcinomas and release into the serum.	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (77, 95))	('CA125', 'Var', (0, 5))	('ovarian cancer', 'Disease', (32, 46))	('expression', 'MPA', (63, 73))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (77, 95))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (77, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('release', 'MPA', (100, 107))	('ovarian carcinomas', 'Disease', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))
44993	20635390	A majority (88%) of mesotheliomas are also CA125 positive on the cell membrane.	('mesotheliomas', 'Disease', 'MESH:D008654', (20, 33))	('CA125 positive', 'Var', (43, 57))	('mesotheliomas', 'Disease', (20, 33))	('cell membrane', 'cellular_component', 'GO:0005886', ('65', '78'))
44996	20635390	It has been found that the very abundant N-glycans on CA125, presumably in its TR region, are required for binding to both glycosylated and non-glycosylated mesothelin.	('N-glycans', 'Chemical', '-', (41, 50))	('CA125', 'Var', (54, 59))	('N-glycans', 'Protein', (41, 50))	('binding', 'Interaction', (107, 114))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
45062	20635390	At the end of the third round of selection, more than 90% of clones were mesothelin binders and the HN1 scFv sequence was the only Fv sequence highly enriched in the phage clones tested (Fig.	('mesothelin', 'Protein', (73, 83))	('scFv', 'Gene', '652070', (104, 108))	('scFv', 'Gene', (104, 108))	('clones', 'Var', (61, 67))
45064	20635390	Interestingly, while it is different from its germline sequence (IGKV1-5*03) and contains several somatic mutations in complementarity determining regions (CDR), the VL sequence of HN1 is the same as those with diverse specificities: 2MR (anti-HIV gp41), CAO79111 and CAO19109 (anti-tetanus toxin), CAD 32240 and CAA12399 (antibeta-galactosidase), and AAC98735 (anti-HER3).	('CAO19109', 'Var', (268, 276))	('CAA12399', 'Var', (313, 321))	('CAO79111', 'Var', (255, 263))	('AAC98735', 'Var', (352, 360))	('IGKV1', 'Gene', '3519', (65, 70))	('2MR', 'Var', (234, 237))	('IGKV1', 'Gene', (65, 70))	('CAD 32240', 'Var', (299, 308))	('HER3', 'Gene', (367, 371))	('HER3', 'Gene', '2065', (367, 371))
45144	20635390	The binding of m912 IgG on human cancer cells (OVCAR-3) was reported to require high concentrations of the mAb (625-3125 nM or 90 - 450 mug/mL) and m912 could only induce about 20% (compared to 40% of HN1) specific lysis of cancer cells through ADCC.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('binding', 'Interaction', (4, 11))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('human', 'Species', '9606', (27, 32))	('ADCC', 'biological_process', 'GO:0001788', ('245', '249'))	('lysis', 'biological_process', 'GO:0019835', ('215', '220'))	('m912', 'Var', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mug', 'molecular_function', 'GO:0043739', ('136', '139'))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('m912', 'Var', (15, 19))	('cancer', 'Disease', (224, 230))	('specific lysis', 'CPA', (206, 220))
45152	29613986	Non-epithelioid MPM (bMPM and sMPM) was more likely than eMPM to have calcified pleural plaques (P=0.035).	('Non-epithelioid', 'Var', (0, 15))	('calcified pleural plaques', 'Disease', 'MESH:D010995', (70, 95))	('calcified pleural plaques', 'Disease', (70, 95))
45334	26459178	MTS, chemotaxis, soft agar, ss-galactosidase and Apo-BrdU techniques were used to assess proliferation, migration, clonogenicity, senescence and apoptosis in MPM cells following SP1 knockdown, p53 over-expression, or mithramycin treatment.	('p53', 'Gene', (193, 196))	('migration', 'CPA', (104, 113))	('senescence', 'biological_process', 'GO:0010149', ('130', '140'))	('mithramycin', 'Chemical', 'MESH:D008926', (217, 228))	('p53', 'Gene', '7157', (193, 196))	('SP1', 'Gene', (178, 181))	('senescence', 'CPA', (130, 140))	('chemotaxis', 'biological_process', 'GO:0006935', ('5', '15'))	('over-expression', 'PosReg', (197, 212))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('clonogenicity', 'CPA', (115, 128))	('knockdown', 'Var', (182, 191))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('apoptosis', 'CPA', (145, 154))
45343	26459178	Malignant pleural mesotheliomas (MPM) are highly lethal neoplasms attributable primarily to occupational or environmental exposures to asbestos and other related mineral fibers such as erionite { 3215 /id; 3220 /id;International Agency for Research on Cancer 3221 /id}.	('asbestos', 'Disease', (135, 143))	('neoplasms', 'Disease', 'MESH:D009369', (56, 65))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (10, 31))	('neoplasms', 'Disease', (56, 65))	('Malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (0, 31))	('asbestos', 'Disease', 'MESH:D001195', (135, 143))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (10, 30))	('Malignant pleural mesotheliomas', 'Disease', (0, 31))	('neoplasms', 'Phenotype', 'HP:0002664', (56, 65))	('{ 3215 /id; 3220 /id', 'Var', (194, 214))	('Cancer', 'Phenotype', 'HP:0002664', (252, 258))
45345	26459178	Median overall survival of MPM patients undergoing aggressive multimodality therapy ranges from 14-22 months, depending on tumor stage and histology, extent of surgical resection, and response to chemotherapy { 3216 /id; 3217 /id; 2615 /id}.	('{ 3216 /id; 3217 /id; 2615 /id}', 'Var', (209, 240))	('tumor', 'Disease', (123, 128))	('MPM', 'Disease', (27, 30))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
45346	26459178	For example, rare familial MPMs and approximately 65% of sporadic MPM exhibit mutations involving BRCA1 Associated Protein-1 (BAP1), which encodes a nuclear ubiquitin hydrolase with diverse activities including DNA repair and de-ubiquitination of the repressive histone mark H2AK119Ub { 2623 /id; 3134 /id; 2598 /id; 2593 /id}.	('DNA', 'MPA', (211, 214))	('BAP1', 'Gene', (126, 130))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('de-ubiquitination', 'MPA', (226, 243))	('BRCA1 Associated Protein-1', 'Gene', '8314', (98, 124))	('mutations', 'Var', (78, 87))	('DNA repair', 'biological_process', 'GO:0006281', ('211', '221'))	('BRCA1 Associated Protein-1', 'Gene', (98, 124))	('ubiquitin', 'molecular_function', 'GO:0031386', ('157', '166'))	('BAP1', 'Gene', '8314', (126, 130))
45347	26459178	Additionally, MPMs exhibit recurrent cytogenetic abnormalities including allelic loss of CDKN2A and p14 ARF { 2896 /id} and amplification of MYC and PVT1 oncogenes { 2899 /id}.	('p14 ARF', 'Gene', '1029', (100, 107))	('PVT1', 'Gene', '5820', (149, 153))	('MYC', 'Gene', (141, 144))	('p14 ARF', 'Gene', (100, 107))	('MYC', 'Gene', '4609', (141, 144))	('CDKN2A', 'Gene', (89, 95))	('CDKN2A', 'Gene', '1029', (89, 95))	('PVT1', 'Gene', (149, 153))	('loss', 'NegReg', (81, 85))	('amplification', 'Var', (124, 137))
45350	26459178	SP1 is over-expressed and contributes to the malignant phenotype of a variety of human cancers by up-regulating genes that enhance proliferation, invasion, and metastasis { 2908 /id; 2883 /id}, as well as stemness and chemoresistance { 2399 /id;Saha, 2014 2942 /id; 2943 /id; 2901 /id}.	('stemness', 'Disease', (205, 213))	('cancers', 'Disease', (87, 94))	('stemness', 'Disease', 'MESH:D020295', (205, 213))	('enhance', 'PosReg', (123, 130))	('genes', 'Gene', (112, 117))	('2942 /id; 2943 /id; 2901 /id}', 'Var', (256, 285))	('proliferation', 'CPA', (131, 144))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('metastasis', 'CPA', (160, 170))	('up-regulating', 'PosReg', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('chemoresistance', 'CPA', (218, 233))	('human', 'Species', '9606', (81, 86))	('{ 2399 /id', 'Var', (234, 244))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('invasion', 'CPA', (146, 154))
45367	26459178	Both sham control or SP1 knockdown MES1 and MES7 were transduced with high titer Ad-GFP or Ad-GFP-p53 (Vector labs, CA) for 48 hours.	('MES7', 'Chemical', '-', (44, 48))	('Ad-GFP', 'Var', (81, 87))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))	('MES1', 'Chemical', '-', (35, 39))
45370	26459178	Similar techniques were used to detect senescence in sham control or SP1 knockdown MES1 and MES7 cells 48 hours following transduction with high titer Ad-GFP or Ad-GFP-p53.	('MES7', 'Chemical', '-', (92, 96))	('senescence', 'biological_process', 'GO:0010149', ('39', '49'))	('p53', 'Gene', '7157', (168, 171))	('Ad-GFP', 'Var', (151, 157))	('MES1', 'Chemical', '-', (83, 87))	('transduction', 'biological_process', 'GO:0009293', ('122', '134'))	('senescence', 'MPA', (39, 49))	('p53', 'Gene', (168, 171))	('SP1', 'Gene', (69, 72))
45414	26459178	Immunoblot experiments demonstrated dose dependent increases in  H2AX in MES1 and MES7 cells indicative of DNA damage, which coincided with increases in total p53 as well as acetylated p53-K320, K373, K382 and phosphorylated p53-S15 levels in MES7 cells, and to a lesser extent, MES1 cells following MM exposure (Supplementary Figures S3B, S3C and S3D).	('increases', 'PosReg', (140, 149))	('p53', 'Gene', '7157', (185, 188))	('K382', 'Var', (201, 205))	('p53', 'Gene', '7157', (159, 162))	('phosphorylated', 'MPA', (210, 224))	('p53', 'Gene', (225, 228))	('MES7', 'Chemical', '-', (243, 247))	('p53', 'Gene', (185, 188))	('H2AX', 'Gene', (65, 69))	('p53', 'Gene', (159, 162))	('increases', 'PosReg', (51, 60))	('MES1', 'Chemical', '-', (279, 283))	('MES1', 'Chemical', '-', (73, 77))	('H2AX', 'Gene', '3014', (65, 69))	('MES7', 'Chemical', '-', (82, 86))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('p53', 'Gene', '7157', (225, 228))	('acetylated', 'MPA', (174, 184))	('K373', 'Var', (195, 199))
45417	26459178	ChIP was performed using primers flanking p53 or SP1 response elements to quantitate occupancy of p53, SP1 or RNA Pol II, as well as levels of H3K4Me3 and H3K27Me3 (euchromatin and heterochromatin histone marks, respectively) within the promoter regions of p21, PMAIP1, HDAC4, ROR1, DACT1, and PRDM1.	('ROR1', 'Gene', (277, 281))	('p53', 'Gene', '7157', (42, 45))	('p53', 'Gene', (98, 101))	('H3K4Me3', 'Var', (143, 150))	('p53', 'Gene', (42, 45))	('DACT1', 'Gene', '51339', (283, 288))	('euchromatin', 'cellular_component', 'GO:0000791', ('165', '176'))	('PMAIP1', 'Gene', (262, 268))	('DACT1', 'Gene', (283, 288))	('PRDM1', 'Gene', '639', (294, 299))	('ROR1', 'Gene', '4919', (277, 281))	('heterochromatin', 'cellular_component', 'GO:0000792', ('181', '196'))	('PRDM1', 'Gene', (294, 299))	('PMAIP1', 'Gene', '5366', (262, 268))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('p21', 'Gene', (257, 260))	('p21', 'Gene', '644914', (257, 260))	('H3K27Me3', 'Var', (155, 163))	('p53', 'Gene', '7157', (98, 101))
45422	26459178	MES1 and MES7 cells exhibiting either knockdown of SP1, or respective vector controls, were transduced with adenovirus GFP-p53-WT or control adenovirus.	('SP1', 'Gene', (51, 54))	('MES7', 'Chemical', '-', (9, 13))	('MES1', 'Chemical', '-', (0, 4))	('p53', 'Gene', (123, 126))	('knockdown', 'Var', (38, 47))	('p53', 'Gene', '7157', (123, 126))
45426	26459178	Gene expression profiles were obtained from additional microarray experiments in MPM cells following combined shRNA mediated knockdown of SP1 and adenoviral mediated overexpression of p53 (shSP1/p53-OEX).	('p53', 'Gene', (195, 198))	('SP1', 'Gene', (138, 141))	('p53-OEX', 'Gene', '7157', (195, 202))	('knockdown', 'Var', (125, 134))	('p53', 'Gene', '7157', (195, 198))	('p53-OEX', 'Gene', (195, 202))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
45432	26459178	Knock-down of SP1 had no effect on endogenous levels of p53 in MES1 or MES7 cells (Supplementary Figure S5D), but modestly induced expression of p21 (Figure 4C).	('p53', 'Gene', (56, 59))	('Knock-down', 'Var', (0, 10))	('p21', 'Gene', (145, 148))	('p53', 'Gene', '7157', (56, 59))	('endogenous levels', 'MPA', (35, 52))	('p21', 'Gene', '644914', (145, 148))	('induced', 'Reg', (123, 130))	('expression', 'MPA', (131, 141))	('MES1', 'Chemical', '-', (63, 67))	('MES7', 'Chemical', '-', (71, 75))	('SP1', 'Gene', (14, 17))
45435	26459178	Modulation of other targets such as ROR1 and EZH2 appeared to be determined by SP1 depletion as well as activation of p53.	('activation', 'PosReg', (104, 114))	('EZH2', 'Gene', '2146', (45, 49))	('p53', 'Gene', (118, 121))	('EZH2', 'Gene', (45, 49))	('p53', 'Gene', '7157', (118, 121))	('SP1', 'MPA', (79, 82))	('depletion', 'Var', (83, 92))	('ROR1', 'Gene', '4919', (36, 40))	('ROR1', 'Gene', (36, 40))
45437	26459178	Histochemistry experiments performed at this time point demonstrated that MM mediated dose-dependent increases in ss-galactosidase expression indicative of senescence in MPM cells; similarly, shSP1 and p53-OEX had additive effects on senescent phenotype in MPM cells (Figure 5B; additional data available upon request).	('senescent phenotype', 'CPA', (234, 253))	('ss-galactosidase', 'Enzyme', (114, 130))	('senescence', 'biological_process', 'GO:0010149', ('156', '166'))	('p53-OEX', 'Gene', (202, 209))	('increases', 'PosReg', (101, 110))	('expression', 'MPA', (131, 141))	('shSP1', 'Var', (192, 197))	('p53-OEX', 'Gene', '7157', (202, 209))
45450	26459178	Affymetrix Drug Metabolizing Elimination and Transport (DMET) microarray experiments demonstrated that MM-induced hepatotoxicity correlated with single nucleotide polymorphisms (SNP) in several genes encoding transporter proteins regulating bile flow (Schrump et al, manuscript in preparation).	('hepatotoxicity', 'Disease', (114, 128))	('hepatotoxicity', 'Disease', 'MESH:D056486', (114, 128))	('single nucleotide polymorphisms', 'Var', (145, 176))
45453	26459178	These findings are consistent with recent studies demonstrating that the anti-angiogenic effects of MM in myeloma cells in-vivo are mediated not by inhibition of SP1 signaling, but rather by activation of p53 { 2916 /id}, and that knockdown of p53 significantly attenuates MM-mediated cytotoxicity in endometrial carcinoma cells { 2917 /id}.	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (301, 322))	('cytotoxicity', 'Disease', 'MESH:D064420', (285, 297))	('p53', 'Gene', (244, 247))	('p53', 'Gene', '7157', (244, 247))	('attenuates', 'NegReg', (262, 272))	('myeloma', 'Disease', 'MESH:D009101', (106, 113))	('p53', 'Gene', (205, 208))	('activation', 'PosReg', (191, 201))	('knockdown', 'Var', (231, 240))	('p53', 'Gene', '7157', (205, 208))	('myeloma', 'Disease', (106, 113))	('anti-angiogenic', 'MPA', (73, 88))	('SP1 signaling', 'MPA', (162, 175))	('cytotoxicity', 'Disease', (285, 297))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (301, 322))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('endometrial carcinoma', 'Disease', (301, 322))
45455	26459178	However, our recent studies have demonstrated dramatic cytotoxic effects of MM irrespective of p53 mutation status in lung and esophageal cancer cells { 2399 /id}; these latter observations suggest that p53 activation may not be essential for growth arrest induced by MM in MPM cells.	('growth arrest', 'Disease', (243, 256))	('esophageal cancer', 'Disease', (127, 144))	('growth arrest', 'Disease', 'MESH:D006323', (243, 256))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('mutation', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('growth arrest', 'Phenotype', 'HP:0001510', (243, 256))	('p53', 'Gene', '7157', (203, 206))	('p53', 'Gene', (203, 206))
45460	26459178	Mdm2, which is up-regulated by p53, facilitates proteosomal degradation of SP1, and negatively regulates p53 { 2938 /id; 2939 /id}.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('negatively', 'NegReg', (84, 94))	('Mdm2', 'Gene', (0, 4))	('p53', 'Gene', (105, 108))	('up-regulated', 'PosReg', (15, 27))	('SP1', 'Protein', (75, 78))	('p53', 'Gene', '7157', (105, 108))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('{ 2938 /id; 2939 /id}', 'Var', (109, 130))	('facilitates', 'PosReg', (36, 47))	('proteosomal degradation', 'MPA', (48, 71))	('Mdm2', 'Gene', '4193', (0, 4))
45464	26459178	Experiments are underway to examine these issues, and to ascertain if small molecule mdm2-p53 inhibitors { 3222 /id} or agents which inhibit p21 expression { 1774 /id} can augment MM-mediated apoptosis in MPM cells.	('p53', 'Gene', (90, 93))	('mdm2', 'Gene', (85, 89))	('augment', 'PosReg', (172, 179))	('p21', 'Gene', (141, 144))	('p53', 'Gene', '7157', (90, 93))	('mdm2', 'Gene', '4193', (85, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('p21', 'Gene', '644914', (141, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('inhibitors { 3222 /id}', 'Var', (94, 116))	('MM-mediated apoptosis', 'CPA', (180, 201))
45473	26459178	Experiments described in this manuscript demonstrate that under exposure conditions potentially achievable in clinical settings, mithramycin depletes SP1 and activates p53 signaling to mediate profound growth arrest associated with senescence and subsequent apoptosis of pleural mesothelioma cells in-vitro and in-vivo.	('mithramycin', 'Var', (129, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('258', '267'))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('apoptosis', 'biological_process', 'GO:0006915', ('258', '267'))	('senescence', 'biological_process', 'GO:0010149', ('232', '242'))	('mithramycin', 'Chemical', 'MESH:D008926', (129, 140))	('senescence', 'CPA', (232, 242))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (271, 291))	('p53', 'Gene', '7157', (168, 171))	('growth arrest', 'Phenotype', 'HP:0001510', (202, 215))	('growth arrest', 'Disease', (202, 215))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (271, 291))	('apoptosis', 'CPA', (258, 267))	('pleural mesothelioma', 'Disease', (271, 291))	('depletes SP1', 'MPA', (141, 153))	('growth arrest', 'Disease', 'MESH:D006323', (202, 215))	('activates', 'PosReg', (158, 167))	('p53', 'Gene', (168, 171))
45532	26693247	The ratio E 340/E 380 was calculated every 40 msec to acquire a time-dependent internal Ca2+ sensitive signal.	('Ca2', 'Gene', '760', (88, 91))	('E 340/E 380', 'Var', (10, 21))	('Ca2', 'Gene', (88, 91))
45549	26693247	In addition, the use of the T-type Ca2+ channel inhibitor NNC-55-0396 (Sigma, >=98%, HPLC) reversibly reduced the Ca2+ spike induced by the highest dose of 100 muM oleuropein (Figures 1(c) and 1(d)), suggesting at least a partial involvement of T-type Ca2+ channels.	('muM', 'Gene', (160, 163))	('NNC-55-0396', 'Var', (58, 69))	('Ca2', 'Gene', (35, 38))	('Ca2', 'Gene', '760', (252, 255))	('Ca2', 'Gene', (114, 117))	('Ca2', 'Gene', (252, 255))	('muM', 'Gene', '56925', (160, 163))	('reduced', 'NegReg', (102, 109))	('Ca2', 'Gene', '760', (35, 38))	('Ca2', 'Gene', '760', (114, 117))
45553	26693247	Moreover, NNC-55-0396 also hindered the hydroxytyrosol-induced [Ca2+]i spikes, with 80% inhibition at 10 muM hydroxytyrosol and 65% inhibition at 100 muM hydroxytyrosol (Figures 1(e) and 1(f)).	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (109, 123))	('hindered', 'NegReg', (27, 35))	('muM', 'Gene', (150, 153))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (40, 54))	('inhibition', 'NegReg', (132, 142))	('inhibition', 'NegReg', (88, 98))	('NNC-55-0396', 'Var', (10, 21))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (154, 168))	('Ca2', 'Gene', '760', (64, 67))	('muM', 'Gene', '56925', (105, 108))	('muM', 'Gene', '56925', (150, 153))	('Ca2', 'Gene', (64, 67))	('muM', 'Gene', (105, 108))
45564	26693247	We have also shown that Cav3.2 is responsible for Ca2+ spikes induced by epigallocatechin-3-gallate in MCF-7 breast cancer cells.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('Cav3.2', 'Gene', (24, 30))	('responsible', 'Reg', (34, 45))	('Ca2', 'Gene', '760', (50, 53))	('MCF-7', 'CellLine', 'CVCL:0031', (103, 108))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (73, 99))	('Cav3.2', 'Gene', '8912', (24, 30))	('Ca2', 'Gene', (50, 53))	('epigallocatechin-3-gallate', 'Var', (73, 99))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
45567	26693247	The almost complete inhibition exerted by NNC-55-0396 on hydroxytyrosol at lower dose, compared with the partial inhibition at higher dose, seems to indicate that the effect of olive phenolics mostly involves a T-type Ca2+ channel-dependent mechanism at low doses (<=10 muM).	('NNC-55-0396', 'Var', (42, 53))	('Ca2', 'Gene', '760', (218, 221))	('olive', 'Species', '4146', (177, 182))	('hydroxytyrosol', 'MPA', (57, 71))	('muM', 'Gene', '56925', (270, 273))	('Ca2', 'Gene', (218, 221))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (57, 71))	('muM', 'Gene', (270, 273))
45881	22448326	For example, a study has shown that a combination assay including ADA, interferon-gamma, and nucleic acid amplification for TB will have superior sensitivity and specificity as compared to a single test alone and offers a future promise in the workup of tuberculous effusions.	('ADA', 'Gene', '100', (66, 69))	('ADA', 'molecular_function', 'GO:0008774', ('66', '69'))	('nucleic acid', 'cellular_component', 'GO:0005561', ('93', '105'))	('tuberculous effusions', 'Disease', 'MESH:D010996', (254, 275))	('interferon-gamma', 'Gene', '3458', (71, 87))	('ADA', 'Gene', (66, 69))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('71', '87'))	('interferon-gamma', 'Gene', (71, 87))	('tuberculous effusions', 'Disease', (254, 275))	('nucleic acid amplification', 'Var', (93, 119))
45970	29899672	More recently, detection of p16 deletion by FISH and loss of BAP1 nuclear immunohistochemical expression seem to emerge as promising markers of malignancy in pleural mesothelial proliferations.	('p16', 'Gene', '1029', (28, 31))	('deletion', 'Var', (32, 40))	('malignancy in pleural mesothelial proliferations', 'Disease', 'MESH:D018301', (144, 192))	('BAP1', 'Gene', (61, 65))	('pleural mesothelial proliferations', 'Phenotype', 'HP:0100002', (158, 192))	('p16', 'Gene', (28, 31))	('malignancy in pleural mesothelial proliferations', 'Disease', (144, 192))	('BAP1', 'Gene', '8314', (61, 65))
45979	29899672	In addition to the histologic type and nuclear grade, variables that confer a poor prognostic effect on the overall survival are older age, higher stage, molecular alterations of the CDKN2A locus (9p21.3) and homozygous deletion of p16.	('CDKN2A', 'Gene', (183, 189))	('homozygous deletion', 'Var', (209, 228))	('p16', 'Gene', '1029', (232, 235))	('CDKN2A', 'Gene', '1029', (183, 189))	('molecular alterations', 'Var', (154, 175))	('p16', 'Gene', (232, 235))
45980	29899672	Germline BAP1 mutations appear to give a favorable prognostic effect.	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (9, 13))
46092	25192022	A proposed strategy therefore is a combination of infusion of antibodies against CD40 in order to stimulate the secondary lymph node resident macrophages to migrate into the tumor tissue with IFN-gamma to effectively reprogram tumor-induced M2-like macrophages into activated IL-12 producing M1 cells.	('tumor', 'Disease', (174, 179))	('stimulate', 'PosReg', (98, 107))	('IFN-gamma', 'Gene', (192, 201))	('IFN-gamma', 'Gene', '3458', (192, 201))	('tumor', 'Disease', (227, 232))	('IL-12', 'molecular_function', 'GO:0005143', ('276', '281'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('antibodies', 'Var', (62, 72))	('CD40', 'Gene', '958', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('CD40', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
46303	32705221	The RNAscope probe was as follows: Human Meflin (ISLR) (NM_005545.3, region 275-1322; cat.	('ISLR', 'Gene', '3671', (49, 53))	('cat', 'molecular_function', 'GO:0004096', ('86', '89'))	('Human', 'Species', '9606', (35, 40))	('ISLR', 'Gene', (49, 53))	('NM_005545.3', 'Var', (56, 67))	('Meflin', 'Gene', (41, 47))	('Meflin', 'Gene', '3671', (41, 47))
46304	32705221	ImageJ software was used for obtaining the merged image of alphaSMA + AE1/AE3 and Meflin.	('alphaSMA + AE1/AE3', 'Var', (59, 77))	('Meflin', 'Gene', (82, 88))	('Meflin', 'Gene', '3671', (82, 88))
46308	32705221	Through H&E, IHC staining of alphaSMA + AE1/AE3, and Elastica-Masson staining, a high extent of fibrosis was observed in the reactive pleura present adjacent to mesothelioma (Fig.	('mesothelioma', 'Disease', (161, 173))	('fibrosis', 'Disease', 'MESH:D005355', (96, 104))	('fibrosis', 'Disease', (96, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('reactive pleura', 'Phenotype', 'HP:0002102', (125, 140))	('H&E', 'Chemical', '-', (8, 11))	('of alphaSMA +', 'Var', (26, 39))
46341	32705221	In the present study, CTGF expression was found to be correlated with poor prognosis after surgery irrespective of the tumor stage diagnosed at surgery.	('tumor', 'Disease', (119, 124))	('correlated', 'Reg', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('expression', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CTGF', 'Gene', (22, 26))
46356	32705221	In contrast, IF of alphaSMA/CTGF may be useful for studying the differentiation of CAFs from mesenchymal stem cells and for classifying CAFs (alphaSMA/CTGF-, alphaSMA+/CTGF-, alphaSMA-/CTGF+, and alphaSMA+/CTGF+).	('CAF', 'Gene', '8850', (83, 86))	('CTGF+', 'Gene', (185, 190))	('CAF', 'Gene', (136, 139))	('CTGF+', 'Gene', '1490', (206, 211))	('CTGF+', 'Gene', (206, 211))	('CAF', 'Gene', '8850', (136, 139))	('CAF', 'Gene', (83, 86))	('CTGF+', 'Gene', '1490', (185, 190))	('alphaSMA+/CTGF-', 'Var', (158, 173))
46434	32375654	One of the most effective methods to distinguish MPeM and reactive mesothelial hyperplasia was fluorescence in situ hybridization (FISH), which could be used to analyze the homozygous deletion at site 9p21, which was positive in 67% of pleural mesothelioma, but the positive rate of peritoneal mesothelioma was low, only 25%.	('hyperplasia', 'Disease', (79, 90))	('deletion', 'Var', (184, 192))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (236, 256))	('mesothelioma', 'Disease', (244, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (294, 306))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (236, 256))	('hyperplasia', 'Disease', 'MESH:D006965', (79, 90))	('pleural mesothelioma', 'Disease', (236, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (244, 256))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (283, 306))	('mesothelioma', 'Disease', (294, 306))	('MPeM', 'Chemical', '-', (49, 53))
46491	30259640	By imperfectly base pairing to the 3'UTR of target messenger RNA (mRNA), miRNA can cause mRNA degradation or translational silencing and eventually repress gene expression (Pichler and Calin, 2015; Ventura and Jacks, 2009).	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('mRNA degradation', 'MPA', (89, 105))	('base pairing', 'molecular_function', 'GO:0003676', ('15', '27'))	('translational', 'MPA', (109, 122))	('mRNA degradation', 'biological_process', 'GO:0006402', ('89', '105'))	('gene expression', 'biological_process', 'GO:0010467', ('156', '171'))	('cause', 'Reg', (83, 88))	('repress', 'NegReg', (148, 155))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('gene expression', 'MPA', (156, 171))	('imperfectly base pairing', 'Var', (3, 27))
46492	30259640	Alterations in post-transcriptional regulation by miRNA have been described in different pathological conditions, and in the context of cancer, where miRNA can potentiate or attenuate tumorigenesis by affecting expression of various oncogenes or tumor suppressors, deregulation of miRNA is often a driving factor in cancer development and progression.	('attenuate', 'NegReg', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', '220972', (281, 284))	('tumor', 'Disease', (184, 189))	('affecting', 'Reg', (201, 210))	('cancer', 'Disease', (316, 322))	('post-transcriptional regulation', 'MPA', (15, 46))	('miR', 'Gene', '220972', (150, 153))	('potentiate', 'PosReg', (160, 170))	('miR', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('deregulation', 'Var', (265, 277))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('miR', 'Gene', (281, 284))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', (246, 251))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('oncogenes', 'Protein', (233, 242))	('miR', 'Gene', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('expression', 'MPA', (211, 221))
46496	30259640	Genomic studies have revealed that MM is characterized by frequent mutations in tumor suppressor genes (Yap et al., 2017), making the study of PIAS3 in this cancer highly relevant.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PIAS3', 'Gene', (143, 148))	('Yap', 'Gene', (104, 107))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('cancer', 'Disease', (157, 163))	('PIAS3', 'Gene', '10401', (143, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('Yap', 'Gene', '10413', (104, 107))
46514	30259640	miR candidates were initially selected if they were upregulated in at least one of the MM cells having low PIAS3 protein expression (211H, H2052, and H2452) relative to H28 cells that demonstrate high PIAS3 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('H2452', 'Var', (150, 155))	('PIAS3', 'Gene', '10401', (201, 206))	('H2052', 'Var', (139, 144))	('expression', 'MPA', (121, 131))	('upregulated', 'PosReg', (52, 63))	('PIAS3', 'Gene', (107, 112))	('miR', 'Gene', (0, 3))	('211H', 'Var', (133, 137))	('miR', 'Gene', '220972', (0, 3))	('H2052', 'CellLine', 'CVCL:1518', (139, 144))	('low', 'NegReg', (103, 106))	('PIAS3', 'Gene', (201, 206))	('PIAS3', 'Gene', '10401', (107, 112))
46526	30259640	Viable cells in culture were measured using CellTiter-Glo Luminescence Cell Viability Assay (Promega) at 24, 72, and 100 h after miR-18a inhibitors transfection.	('miR-18a', 'Gene', (129, 136))	('miR-18a', 'Gene', '406953', (129, 136))	('inhibitors transfection', 'Var', (137, 160))	('transfection', 'Var', (148, 160))
46533	30259640	We found that PIAS3 protein is markedly downregulated in three MM cell lines, 211H, H2052, and H2452, compared to H28 MM cells and A549 cells (Fig.	('downregulated', 'NegReg', (40, 53))	('H2452', 'Var', (95, 100))	('protein', 'Protein', (20, 27))	('PIAS3', 'Gene', (14, 19))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('H2052', 'CellLine', 'CVCL:1518', (84, 89))	('H28 MM', 'CellLine', 'CVCL:4D15', (114, 120))	('PIAS3', 'Gene', '10401', (14, 19))
46543	30259640	Specifically, we looked for miRs that were upregulated in MM cells with low PIAS3 protein levels (211H, H2052, and H2452) relative to H28 cells that demonstrate high PIAS3 protein expression.	('PIAS3', 'Gene', '10401', (76, 81))	('upregulated', 'PosReg', (43, 54))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('H2052', 'Var', (104, 109))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('H2052', 'CellLine', 'CVCL:1518', (104, 109))	('PIAS3', 'Gene', (166, 171))	('211H', 'Var', (98, 102))	('PIAS3', 'Gene', (76, 81))	('miR', 'Gene', (28, 31))	('H2452', 'Var', (115, 120))	('miR', 'Gene', '220972', (28, 31))	('low', 'NegReg', (72, 75))	('PIAS3', 'Gene', '10401', (166, 171))
46562	30259640	6A, endogenous miR-18a is significantly decreased by transfecting miR-18a inhibitor in H2452 MM cells.	('miR-18a', 'Gene', (66, 73))	('H2452 MM', 'CellLine', 'CVCL:1553', (87, 95))	('miR-18a', 'Gene', '406953', (15, 22))	('miR-18a', 'Gene', '406953', (66, 73))	('miR-18a', 'Gene', (15, 22))	('transfecting', 'Var', (53, 65))	('decreased', 'NegReg', (40, 49))
46566	30259640	To further investigate downstream effects of elevated PIAS3 expression after miR-18a inhibition, we performed a STAT3 luciferase reporter assay after transfecting miR-18a inhibitors into H2052 MM cells (shown in Fig.	('H2052 MM', 'CellLine', 'CVCL:1518', (187, 195))	('expression', 'MPA', (60, 70))	('PIAS3', 'Gene', (54, 59))	('miR-18a', 'Gene', '406953', (77, 84))	('miR-18a', 'Gene', (163, 170))	('inhibitors', 'Var', (171, 181))	('STAT3', 'Gene', '6774', (112, 117))	('PIAS3', 'Gene', '10401', (54, 59))	('STAT3', 'Gene', (112, 117))	('elevated', 'PosReg', (45, 53))	('miR-18a', 'Gene', (77, 84))	('miR-18a', 'Gene', '406953', (163, 170))
46567	30259640	Compared to the control group, STAT3 luciferase activity was significantly decreased after miR-18a inhibition (P = 0.021), suggesting that miR-18a inhibition suppresses STAT3 transcriptional activity in MM cells.	('STAT3', 'Gene', '6774', (169, 174))	('miR-18a', 'Gene', '406953', (91, 98))	('luciferase activity', 'molecular_function', 'GO:0050397', ('37', '56'))	('miR-18a', 'Gene', '406953', (139, 146))	('STAT3', 'Gene', (31, 36))	('activity', 'MPA', (48, 56))	('luciferase activity', 'molecular_function', 'GO:0050248', ('37', '56'))	('STAT3', 'Gene', (169, 174))	('STAT3', 'Gene', '6774', (31, 36))	('luciferase activity', 'molecular_function', 'GO:0047712', ('37', '56'))	('miR-18a', 'Gene', (91, 98))	('suppresses', 'NegReg', (158, 168))	('miR-18a', 'Gene', (139, 146))	('luciferase activity', 'molecular_function', 'GO:0047077', ('37', '56'))	('inhibition', 'Var', (147, 157))	('luciferase activity', 'molecular_function', 'GO:0045289', ('37', '56'))	('decreased', 'NegReg', (75, 84))
46600	30259640	Because our miR inhibition assay and survival analysis have identified miR-18a as a potential oncogenic miR in MM, targeting miR-18a with antagomirs may represent a novel approach to reduce future mortality in MM.	('miR', 'Gene', (71, 74))	('miR-18a', 'Gene', '406953', (125, 132))	('miR-18a', 'Gene', '406953', (71, 78))	('miR-18a', 'Gene', (125, 132))	('miR', 'Gene', '220972', (71, 74))	('miR-18a', 'Gene', (71, 78))	('miR', 'Gene', '220972', (104, 107))	('targeting', 'Var', (115, 124))	('miR', 'Gene', (104, 107))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))	('miR', 'Gene', '220972', (12, 15))	('reduce', 'NegReg', (183, 189))	('miR', 'Gene', (12, 15))
46603	30259640	Furthermore, inhibition of miR-18a restored PIAS3 expression and was associated with decreased cell viability.	('decreased', 'NegReg', (85, 94))	('miR-18a', 'Gene', (27, 34))	('PIAS3', 'Gene', (44, 49))	('inhibition', 'Var', (13, 23))	('restored', 'PosReg', (35, 43))	('PIAS3', 'Gene', '10401', (44, 49))	('miR-18a', 'Gene', '406953', (27, 34))	('expression', 'MPA', (50, 60))	('cell viability', 'CPA', (95, 109))
46613	29296529	In addition, blocking CD47 inhibited growth and promoted phagocytosis of DMM cell lines by macrophages in vitro.	('blocking', 'Var', (13, 21))	('phagocytosis', 'biological_process', 'GO:0006909', ('57', '69'))	('DMM', 'Chemical', '-', (73, 76))	('growth', 'CPA', (37, 43))	('inhibited', 'NegReg', (27, 36))	('phagocytosis', 'CPA', (57, 69))	('promoted', 'PosReg', (48, 56))	('CD47', 'Gene', (22, 26))
46624	29296529	Recently, loss of expression of BRCA1-associated protein 1 (BAP-1) due to inactivating mutations and/or chromosomal loss has emerged as a marker of malignancy in mesothelial cells that has a sensitivity similar to that of FISH for CDKN2A and an identical 100% specificity, but can be reliably assessed by immunostaining.	('malignancy', 'Disease', (148, 158))	('BAP-1', 'Gene', '8314', (60, 65))	('CDKN2A', 'Gene', (231, 237))	('chromosomal loss', 'Var', (104, 120))	('CDKN2A', 'Gene', '1029', (231, 237))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('BAP-1', 'Gene', (60, 65))	('inactivating mutations', 'Var', (74, 96))	('BRCA1-associated protein 1', 'Gene', '8314', (32, 58))	('BRCA1-associated protein 1', 'Gene', (32, 58))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('loss of expression', 'NegReg', (10, 28))
46640	29296529	These data indicate that DMM cells express the "don't eat me" signalling molecule CD47 and the pro-phagocytic molecule calreticulin.	('DMM', 'Chemical', '-', (25, 28))	('calreticulin', 'Gene', '811', (119, 131))	('CD47', 'Var', (82, 86))	('calreticulin', 'Gene', (119, 131))
46651	29296529	In addition to inhibit phagocytosis of tumour cells by binding to SIRPalpha on macrophages, CD47 signalling has also been shown to stimulate tumour cell proliferation directly by activating the PI3K/Akt pathway.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('Akt', 'Gene', '207', (199, 202))	('PI3K', 'molecular_function', 'GO:0016303', ('194', '198'))	('phagocytosis', 'biological_process', 'GO:0006909', ('23', '35'))	('inhibit', 'NegReg', (15, 22))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('activating', 'Reg', (179, 189))	('SIRPalpha', 'Gene', '140885', (66, 75))	('CD47', 'Var', (92, 96))	('phagocytosis', 'CPA', (23, 35))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('stimulate', 'PosReg', (131, 140))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('tumour', 'Disease', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('binding', 'Interaction', (55, 62))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('tumour', 'Disease', (141, 147))	('Akt', 'Gene', (199, 202))	('SIRPalpha', 'Gene', (66, 75))
46654	29296529	3A), indicating that blocking CD47 directly inhibits DMM cell growth.	('blocking', 'Var', (21, 29))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('DMM', 'Chemical', '-', (53, 56))	('DMM cell growth', 'CPA', (53, 68))	('inhibits', 'NegReg', (44, 52))	('CD47', 'Protein', (30, 34))
46655	29296529	In addition, to investigate if blocking CD47 also increases phagocytosis of DMM cells, we performed a well-established in vitro phagocytosis assay by co-culturing human macrophages with fluorescently labelled ACC-MESO-1 cells (Fig.	('DMM', 'Chemical', '-', (76, 79))	('MESO-1', 'CellLine', 'CVCL:5759', (213, 219))	('phagocytosis', 'biological_process', 'GO:0006909', ('128', '140'))	('blocking', 'Var', (31, 39))	('increases', 'PosReg', (50, 59))	('phagocytosis', 'CPA', (60, 72))	('human', 'Species', '9606', (163, 168))	('CD47', 'Gene', (40, 44))	('phagocytosis', 'biological_process', 'GO:0006909', ('60', '72'))
46656	29296529	Blocking of CD47 resulted in a two-fold increase in the phagocytosis of ACC-MESO-1 cells by macrophages compared to control IgG treatment, as analysed by FACS (Fig.	('Blocking', 'Var', (0, 8))	('increase', 'PosReg', (40, 48))	('phagocytosis', 'biological_process', 'GO:0006909', ('56', '68'))	('MESO-1', 'CellLine', 'CVCL:5759', (76, 82))	('phagocytosis of ACC-MESO-1 cells by', 'CPA', (56, 91))	('CD47', 'Gene', (12, 16))
46657	29296529	These data indicate that blocking CD47 directly inhibits the growth and increases macrophage-mediated phagocytosis of DMM tumour cells.	('CD47', 'Protein', (34, 38))	('inhibits', 'NegReg', (48, 56))	('increases', 'PosReg', (72, 81))	('blocking', 'Var', (25, 33))	('DMM tumour', 'Disease', 'MESH:D009369', (118, 128))	('DMM tumour', 'Disease', (118, 128))	('macrophage-mediated phagocytosis', 'CPA', (82, 114))	('growth', 'CPA', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('phagocytosis', 'biological_process', 'GO:0006909', ('102', '114'))
46675	29296529	Targeting the CD47-SIRPalpha interaction to increase the phagocytosis of tumour cells is currently being investigated in several early-phase clinical trials in haematological malignancies (NCT02641002, NCT02663518, NCT02678338, NCT02953509) and solid tumours (NCT02216409, NCT02890368, NCT02953782).	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('phagocytosis', 'biological_process', 'GO:0006909', ('57', '69'))	('solid tumours', 'Disease', (245, 258))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('tumour', 'Disease', (251, 257))	('NCT02663518', 'Var', (202, 213))	('NCT02953509', 'Var', (228, 239))	('increase', 'PosReg', (44, 52))	('NCT02641002', 'Var', (189, 200))	('NCT02678338', 'Var', (215, 226))	('haematological malignancies', 'Disease', (160, 187))	('SIRPalpha', 'Gene', '140885', (19, 28))	('solid tumours', 'Disease', 'MESH:D009369', (245, 258))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('NCT02953782', 'Var', (286, 297))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('NCT02890368', 'Var', (273, 284))	('tumour', 'Disease', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('SIRPalpha', 'Gene', (19, 28))	('NCT02216409', 'Var', (260, 271))	('haematological malignancies', 'Disease', 'MESH:D019337', (160, 187))
46686	29296529	Importantly, we could demonstrate that blocking CD47 in vitro directly inhibits the growth of DMM cell lines and increases their phagocytosis by macrophages.	('phagocytosis by macrophages', 'CPA', (129, 156))	('DMM', 'Chemical', '-', (94, 97))	('CD47', 'Protein', (48, 52))	('growth', 'CPA', (84, 90))	('phagocytosis', 'biological_process', 'GO:0006909', ('129', '141'))	('increases', 'PosReg', (113, 122))	('inhibits', 'NegReg', (71, 79))	('blocking', 'Var', (39, 47))
46688	29296529	TSP-1, which is overexpressed in malignant mesothelioma, is a well-known ligand for CD47, and ligation of CD47 by TSP-1 was shown to induce vascular smooth muscle cell proliferation.	('vascular smooth muscle cell proliferation', 'CPA', (140, 181))	('TSP-1', 'Gene', (0, 5))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (33, 55))	('TSP-1', 'Gene', '7057', (0, 5))	('TSP-1', 'molecular_function', 'GO:0004277', ('114', '119'))	('induce', 'PosReg', (133, 139))	('ligation', 'Var', (94, 102))	('vascular smooth muscle cell proliferation', 'biological_process', 'GO:1990874', ('140', '181'))	('malignant mesothelioma', 'Disease', (33, 55))	('ligand', 'molecular_function', 'GO:0005488', ('73', '79'))	('TSP-1', 'Gene', '7057', (114, 119))	('CD47', 'Var', (106, 110))	('TSP-1', 'Gene', (114, 119))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (33, 55))	('TSP-1', 'molecular_function', 'GO:0004277', ('0', '5'))
46689	29296529	Although further analysis of the exact mechanism by which CD47 directly promotes tumour cell proliferation in our in vitro cultures was out of the scope of this study, we propose TSP-1 secreted by mesothelioma cells to be a likely candidate mediating this effect in an autocrine manner.	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('TSP-1', 'Gene', (179, 184))	('TSP-1', 'Gene', '7057', (179, 184))	('TSP-1', 'molecular_function', 'GO:0004277', ('179', '184'))	('tumour', 'Disease', (81, 87))	('promotes', 'PosReg', (72, 80))	('mesothelioma', 'Disease', (197, 209))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('CD47', 'Var', (58, 62))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
46708	29296529	DMM cell lines were cultured to 70% confluence, harvested using non-enzymatic cell dissociation buffer (Sigma) and stained for CD47, calreticulin and the respective isotype controls (Table S1) in PBS for 30 min at 4 C. Samples were acquired on a BD LSR II flow cytometer (Becton Dickinson) and were analysed using FlowJo software (TreeStar).	('PBS', 'Chemical', 'MESH:D007854', (196, 199))	('calreticulin', 'Gene', '811', (133, 145))	('CD47', 'Var', (127, 131))	('calreticulin', 'Gene', (133, 145))	('DMM', 'Chemical', '-', (0, 3))
46793	28978143	In particular, their down-modulation has been described in lung cancer linked to a homozygous deletion at 21q21.1, although in our cohort of samples we did not find any CNVs at the miR-99a/let-7c/miR-125b cluster.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('let-7c', 'Gene', (189, 195))	('deletion', 'Var', (94, 102))	('miR-99a', 'Gene', '407055', (181, 188))	('miR', 'Gene', '220972', (196, 199))	('let-7c', 'Gene', '406885', (189, 195))	('miR', 'Gene', (196, 199))	('lung cancer', 'Disease', (59, 70))	('miR', 'Gene', '220972', (181, 184))	('miR', 'Gene', (181, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('miR-99a', 'Gene', (181, 188))	('down-modulation', 'NegReg', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
46795	28978143	Likewise, let-7c is down-regulated in a variety of cancer types such as lung and prostate cancer, melanoma and Wilms' tumors; indeed, lack of let-7c expression is associated with increased cell proliferation in both prostate and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('let-7c', 'Gene', (142, 148))	('let-7c', 'Gene', '406885', (10, 16))	("Wilms' tumors", 'Disease', 'MESH:D009396', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('increased', 'PosReg', (179, 188))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('lack', 'Var', (134, 138))	('let-7c', 'Gene', '406885', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('189', '207'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('prostate and lung cancer', 'Disease', 'MESH:D011471', (216, 240))	("Wilms' tumors", 'Phenotype', 'HP:0002667', (111, 124))	('lung and prostate cancer', 'Disease', 'MESH:D011471', (72, 96))	("Wilms' tumors", 'Disease', (111, 124))	('cell proliferation', 'CPA', (189, 207))	('cancer', 'Disease', (90, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('let-7c', 'Gene', (10, 16))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', (51, 57))
46836	28978143	Specifically, custom FAM-labeled miR-99a/let-7c/miR-125b assay (dHsaCNS694336600) was normalized with two HEX-labeled assays as follows: RBM11 (dHsaCP2506724) targeting the centromere locus on chromosome 21 and AP3B1 (dHsaCP2500348) mapping on 5q14.1 (Bio-Rad).	('dHsaCP2506724', 'Var', (144, 157))	('let-7c', 'Gene', '406885', (41, 47))	('RBM11', 'Gene', '54033', (137, 142))	('Rad', 'biological_process', 'GO:1990116', ('256', '259'))	('Rad', 'Gene', '6236', (256, 259))	('Rad', 'Gene', (256, 259))	('miR-99a', 'Gene', '407055', (33, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('centromere', 'cellular_component', 'GO:0000775', ('173', '183'))	('dHsaCP2500348', 'Var', (218, 231))	('miR', 'Gene', '220972', (33, 36))	('RBM11', 'Gene', (137, 142))	('centromere', 'cellular_component', 'GO:0005698', ('173', '183'))	('AP3B1', 'Gene', (211, 216))	('miR', 'Gene', '220972', (48, 51))	('AP3B1', 'Gene', '8546', (211, 216))	('let-7c', 'Gene', (41, 47))	('miR', 'Gene', (33, 36))	('miR-99a', 'Gene', (33, 40))	('miR', 'Gene', (48, 51))
46849	28704484	Ptac2S increases ZL34 cell death in vivo compared with cisplatin and, in vitro, Ptac2S was more efficacious than cisplatin in inducing apoptosis.	('apoptosis', 'CPA', (135, 144))	('Ptac2S', 'Chemical', '-', (0, 6))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('Ptac2S', 'Chemical', '-', (80, 86))	('Ptac2S', 'Var', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('Ptac2S', 'Var', (80, 86))	('ZL34 cell death', 'CPA', (17, 32))	('cell death', 'biological_process', 'GO:0008219', ('22', '32'))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('ZL34', 'CellLine', 'CVCL:5906', (17, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
46854	28704484	In ZL34 cells, Ptac2S also activated PKC-alpha thus provoking ERK1/2 activation; inhibition of PKC-alpha, or ERK1/2, increased Ptac2S cytotoxicity.	('PKC-alpha', 'Gene', '5578', (37, 46))	('ERK1', 'molecular_function', 'GO:0004707', ('109', '113'))	('increased', 'PosReg', (117, 126))	('PKC-alpha', 'Gene', '5578', (95, 104))	('inhibition', 'Var', (81, 91))	('PKC', 'molecular_function', 'GO:0004697', ('95', '98'))	('ERK1', 'molecular_function', 'GO:0004707', ('62', '66'))	('cytotoxicity', 'Disease', (134, 146))	('ERK1/2', 'Enzyme', (62, 68))	('Ptac2S', 'Chemical', '-', (15, 21))	('PKC', 'molecular_function', 'GO:0004697', ('37', '40'))	('PKC-alpha', 'Gene', (95, 104))	('PKC-alpha', 'Gene', (37, 46))	('cytotoxicity', 'Disease', 'MESH:D064420', (134, 146))	('ZL34', 'CellLine', 'CVCL:5906', (3, 7))	('Ptac2S', 'Chemical', '-', (127, 133))	('provoking', 'Reg', (52, 61))	('activation', 'PosReg', (69, 79))
46855	28704484	Results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, giving a substantial starting point for its further validation.	('malignant mesothelioma', 'Disease', (65, 87))	('Ptac2S', 'Var', (21, 27))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (65, 87))	('Ptac2S', 'Chemical', '-', (21, 27))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (65, 87))
46865	28704484	Notably, in a preclinical model made of hypodermic injection of breast cancer cells, Ptac2S shows up for an anticancer activity higher than cisplatin; in Wistar rats it as well showed increased pharmacokinetics, bio distribution and tolerability in comparison to cisplatin.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('Ptac2S', 'Var', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('bio distribution', 'MPA', (212, 228))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Wistar rats', 'Species', '10116', (154, 165))	('increased', 'PosReg', (184, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pharmacokinetics', 'MPA', (194, 210))	('Ptac2S', 'Chemical', '-', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('higher', 'PosReg', (128, 134))	('breast cancer', 'Disease', (64, 77))
46867	28704484	In principle, this Pt-compound would yield a wider use, since Ptac2S also exerts specific antimetastatic responses in vitro.	('Pt', 'Chemical', 'MESH:D010984', (19, 21))	('Pt', 'Chemical', 'MESH:D010984', (62, 64))	('Ptac2S', 'Var', (62, 68))	('antimetastatic responses', 'CPA', (90, 114))	('Ptac2S', 'Chemical', '-', (62, 68))
46868	28704484	As said, it seems notable to understand whether Ptac2S has also cytotoxic effects on MPM.	('cytotoxic effects', 'CPA', (64, 81))	('MPM', 'Disease', (85, 88))	('Ptac2S', 'Chemical', '-', (48, 54))	('Ptac2S', 'Var', (48, 54))
46871	28704484	Ptac2S was able to activate different transduction pathways with strong pro-apoptotic activity (p38 and PKC-delta), while the PKC-alpha pro-survival pathway activated by cisplatin was not observed.	('Ptac2S', 'Chemical', '-', (0, 6))	('transduction', 'biological_process', 'GO:0009293', ('38', '50'))	('activate', 'PosReg', (19, 27))	('transduction pathways', 'Pathway', (38, 59))	('PKC-alpha', 'Gene', (126, 135))	('PKC', 'molecular_function', 'GO:0004697', ('126', '129'))	('PKC-alpha', 'Gene', '5578', (126, 135))	('PKC', 'molecular_function', 'GO:0004697', ('104', '107'))	('Ptac2S', 'Var', (0, 6))	('PKC-delta', 'Gene', (104, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('PKC-delta', 'Gene', '5580', (104, 113))	('p38', 'Gene', '5594', (96, 99))	('pro-apoptotic activity', 'MPA', (72, 94))	('pro-survival', 'biological_process', 'GO:0043066', ('136', '148'))	('p38', 'Gene', (96, 99))
46872	28704484	Therefore, the higher cytotoxicity of Ptac2S in these cells may be due to the fact that it does not activate PKC-alpha.	('higher', 'PosReg', (15, 21))	('PKC-alpha', 'Gene', '5578', (109, 118))	('Ptac2S', 'Var', (38, 44))	('cytotoxicity', 'Disease', (22, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (22, 34))	('PKC', 'molecular_function', 'GO:0004697', ('109', '112'))	('PKC-alpha', 'Gene', (109, 118))	('Ptac2S', 'Chemical', '-', (38, 44))
46905	28704484	Ptac2S displayed higher anticancer activity than cisplatin toward ZL34 tumours examined, inducing up to 50% growth inhibition.	('Ptac2S', 'Chemical', '-', (0, 6))	('ZL34', 'CellLine', 'CVCL:5906', (66, 70))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('Ptac2S', 'Var', (0, 6))	('tumours', 'Disease', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (28, 34))	('growth inhibition', 'CPA', (108, 125))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
46907	28704484	Mice displayed a significant decrease of tumour mass for each experimental time considered in the Ptac2S groups compared with both control and cisplatin-treated mice (p < 0.05).	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('mice', 'Species', '10090', (161, 165))	('decrease of tumour', 'Disease', 'MESH:D009369', (29, 47))	('tumour mass', 'Disease', (41, 52))	('Ptac2S', 'Var', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('Mice', 'Species', '10090', (0, 4))	('decrease of tumour', 'Disease', (29, 47))	('Ptac2S', 'Chemical', '-', (98, 104))	('tumour mass', 'Disease', 'MESH:C536030', (41, 52))
46912	28704484	Clonogenic assay performed on ZL34 showed that Ptac2S was more cytotoxic than cisplatin (Fig 2B).	('cytotoxic', 'CPA', (63, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('Ptac2S', 'Chemical', '-', (47, 53))	('ZL34', 'CellLine', 'CVCL:5906', (30, 34))	('Ptac2S', 'Var', (47, 53))
46914	28704484	PARP was cleaved in cells treated with 5 muM Ptac2S or with 50 muM cisplatin; however, proteolysis was faster with Ptac2S.	('Ptac2S', 'Chemical', '-', (45, 51))	('proteolysis', 'MPA', (87, 98))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', '56925', (63, 66))	('muM', 'Gene', (41, 44))	('faster', 'PosReg', (103, 109))	('PARP', 'Gene', (0, 4))	('Ptac2S', 'Chemical', '-', (115, 121))	('proteolysis', 'biological_process', 'GO:0006508', ('87', '98'))	('muM', 'Gene', (63, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('Ptac2S', 'Var', (115, 121))	('PARP', 'Gene', '142', (0, 4))
46918	28704484	By RT-PCR we found that Ptac2S up-regulated p53 and BAX mRNA expression, and decreased Bcl-2 mRNA in a time-dependent way (ANOVA p < 0.01, Fig 3B, 3C and 3D).	('Bcl-2', 'Gene', (87, 92))	('up-regulated', 'PosReg', (31, 43))	('Bcl-2', 'Gene', '596', (87, 92))	('Ptac2S', 'Var', (24, 30))	('Bcl-2', 'molecular_function', 'GO:0015283', ('87', '92'))	('BAX', 'Gene', (52, 55))	('BAX', 'Gene', '581', (52, 55))	('Ptac2S', 'Chemical', '-', (24, 30))	('p53', 'MPA', (44, 47))	('decreased', 'NegReg', (77, 86))
46920	28704484	We demonstrated previously that Ptac2S activates the MAPKs signalling pathways in several tumour cell lines, ZL55 cells included and that cisplatin activates ERK1/2 in ZL55 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('signalling', 'biological_process', 'GO:0023052', ('59', '69'))	('ERK1', 'molecular_function', 'GO:0004707', ('158', '162'))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('activates', 'PosReg', (39, 48))	('Ptac2S', 'Chemical', '-', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('MAPKs signalling pathways', 'Pathway', (53, 78))	('Ptac2S', 'Var', (32, 38))	('tumour', 'Disease', (90, 96))
46921	28704484	We showed that whereas Ptac2S activated all three MAPKs in ZL34 cells, in ZL55 cells it activated p38MAPK and JNK1/2 but not ERK1/2 (Fig 4A and ref.).	('Ptac2S', 'Var', (23, 29))	('ERK1', 'molecular_function', 'GO:0004707', ('125', '129'))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('JNK', 'molecular_function', 'GO:0004705', ('110', '113'))	('p38', 'Gene', '5594', (98, 101))	('activated', 'PosReg', (88, 97))	('JNK1/2', 'MPA', (110, 116))	('p38', 'Gene', (98, 101))	('Ptac2S', 'Chemical', '-', (23, 29))	('ZL34', 'CellLine', 'CVCL:5906', (59, 63))
46922	28704484	Pre-incubation with JNK1/2 inhibitor SP600125, or with the p38MAPK inhibitor SB203580, significantly reduced Ptac2S-induced cytotoxicity in both cell lines (Fig 4).	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('p38', 'Gene', (59, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (124, 136))	('SB203580', 'Chemical', 'MESH:C093642', (77, 85))	('JNK', 'molecular_function', 'GO:0004705', ('20', '23'))	('SP600125', 'Chemical', 'MESH:C432165', (37, 45))	('p38', 'Gene', '5594', (59, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('SP600125', 'Var', (37, 45))	('reduced', 'NegReg', (101, 108))	('Ptac2S', 'Chemical', '-', (109, 115))	('cytotoxicity', 'Disease', (124, 136))
46923	28704484	Furthermore, SP600125 markedly inhibited Ptac2S-induced activation of p53 (Fig 4), thus suggesting that JNK1/2 mediates p53 induction.	('p53', 'Protein', (70, 73))	('JNK', 'molecular_function', 'GO:0004705', ('104', '107'))	('SP600125', 'Chemical', 'MESH:C432165', (13, 21))	('activation', 'MPA', (56, 66))	('SP600125', 'Var', (13, 21))	('inhibited', 'NegReg', (31, 40))	('Ptac2S', 'Chemical', '-', (41, 47))
46924	28704484	PD98059, an inhibitor of MEK1/2, the ERK1/2 upstream kinase, significantly increased Ptac2S-induced cytotoxicity, in ZL34 cells (Fig 4).	('ZL34', 'CellLine', 'CVCL:5906', (117, 121))	('MEK1/2', 'Gene', (25, 31))	('PD98059', 'Var', (0, 7))	('ERK1', 'molecular_function', 'GO:0004707', ('37', '41'))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('cytotoxicity', 'Disease', (100, 112))	('MEK1', 'molecular_function', 'GO:0004708', ('25', '29'))	('Ptac2S', 'Chemical', '-', (85, 91))	('increased', 'PosReg', (75, 84))	('MEK1/2', 'Gene', '5604;5605', (25, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))
46925	28704484	Jointly these results indicated that JNK1/2 and p38MAPK are pro-apoptotic pathways whereas ERK1/2, in ZL34 cells, behaves like an anti-apoptotic survival pathway.	('p38', 'Gene', (48, 51))	('JNK1/2', 'Var', (37, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('ERK1', 'molecular_function', 'GO:0004707', ('91', '95'))	('JNK', 'molecular_function', 'GO:0004705', ('37', '40'))	('ZL34', 'CellLine', 'CVCL:5906', (102, 106))	('p38', 'Gene', '5594', (48, 51))
46927	28704484	In the previous study in ZL55 cells, we showed that PKC-epsilon and PKC-delta translocated from the cytosol to the membranes; similarly to what happened with cisplatin, the cells treated with Ptac2S also show the proteolytic activation of PKC-delta.	('PKC-epsilon', 'Gene', '5581', (52, 63))	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('cytosol', 'cellular_component', 'GO:0005829', ('100', '107'))	('proteolytic', 'MPA', (213, 224))	('Ptac2S', 'Var', (192, 198))	('PKC-delta', 'Gene', (239, 248))	('PKC-epsilon', 'Gene', (52, 63))	('PKC', 'molecular_function', 'GO:0004697', ('68', '71'))	('translocated', 'MPA', (78, 90))	('PKC-delta', 'Gene', '5580', (239, 248))	('PKC', 'molecular_function', 'GO:0004697', ('239', '242'))	('PKC-delta', 'Gene', (68, 77))	('Ptac2S', 'Chemical', '-', (192, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))	('PKC-delta', 'Gene', '5580', (68, 77))
46945	28704484	In addition, we showed that Ptac2S was more efficacious than cisplatin in inducing apoptosis in epithelioid ZL55 cells and, in a preclinical model based on injection of ZL55 cells, Ptac2S shows up an anticancer activity higher than that of cisplatin.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('cancer', 'Disease', (204, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('Ptac2S', 'Chemical', '-', (181, 187))	('Ptac2S', 'Chemical', '-', (28, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('Ptac2S', 'Var', (181, 187))	('Ptac2S', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('apoptosis', 'CPA', (83, 92))	('inducing', 'Reg', (74, 82))
46947	28704484	In Ptac2S group mice displayed an important curtailment of tumour volume at each time point compared with both not treated and cisplatin-treated mice (Fig 1).	('Ptac2S', 'Var', (3, 9))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('Ptac2S', 'Chemical', '-', (3, 9))	('mice', 'Species', '10090', (145, 149))	('curtailment', 'NegReg', (44, 55))	('mice', 'Species', '10090', (16, 20))	('tumour', 'Disease', (59, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('tumour', 'Disease', 'MESH:D009369', (59, 65))
46948	28704484	The in vivo effects of Ptac2S (53% reduction of tumour mass) were considerably greater than those of cisplatin (12% reduction).	('Ptac2S', 'Var', (23, 29))	('tumour mass', 'Disease', 'MESH:C536030', (48, 59))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('tumour mass', 'Disease', (48, 59))	('Ptac2S', 'Chemical', '-', (23, 29))	('reduction', 'NegReg', (35, 44))
46951	28704484	suggesting that Ptac2S causes rapid apoptosis onset.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('apoptosis', 'CPA', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('Ptac2S', 'Chemical', '-', (16, 22))	('Ptac2S', 'Var', (16, 22))
46952	28704484	The caspase-7 cleavage pattern was detected earlier in cells treated with Ptac2S compared to cisplatin, and is similar to PARP proteolysis time course, hence supporting the study that shows that the proteolysis of PARP is due to caspase-7.	('PARP', 'Gene', (214, 218))	('Ptac2S', 'Var', (74, 80))	('proteolysis', 'biological_process', 'GO:0006508', ('127', '138'))	('PARP', 'Gene', (122, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('caspase-7', 'Gene', (4, 13))	('PARP', 'Gene', '142', (214, 218))	('caspase-7', 'Gene', '840', (4, 13))	('proteolysis', 'biological_process', 'GO:0006508', ('199', '210'))	('PARP', 'Gene', '142', (122, 126))	('cleavage', 'MPA', (14, 22))	('caspase-7', 'Gene', (229, 238))	('Ptac2S', 'Chemical', '-', (74, 80))	('caspase-7', 'Gene', '840', (229, 238))
46956	28704484	In vivo we also noted a phenotype-dependent sensitivity to Ptac2S (ZL55 tumour size decreased to 38%, whilst ZL34 tumour size decreased to 47%), a result in agreement with the conclusion that patients with sarcomatoid tumours have a poor prognosis.	('Ptac2S', 'Chemical', '-', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('sarcomatoid tumours', 'Disease', (206, 225))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('sarcomatoid tumours', 'Disease', 'MESH:C538614', (206, 225))	('tumour', 'Disease', (218, 224))	('sarcomatoid tumours', 'Phenotype', 'HP:0100242', (206, 225))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('decreased', 'NegReg', (126, 135))	('tumour', 'Disease', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (192, 200))	('ZL34', 'CellLine', 'CVCL:5906', (109, 113))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('decreased', 'NegReg', (84, 93))	('Ptac2S', 'Var', (59, 65))
46958	28704484	However, in both ZL34 and ZL55, Ptac2S induced apoptosis by up-regulating p53 protein and mRNA levels (Fig 3).	('mRNA levels', 'MPA', (90, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('up-regulating', 'PosReg', (60, 73))	('Ptac2S', 'Chemical', '-', (32, 38))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('ZL34', 'CellLine', 'CVCL:5906', (17, 21))	('p53', 'MPA', (74, 77))	('Ptac2S', 'Var', (32, 38))
46959	28704484	Many pathways mediate the apoptosis due to p53, and among these there is one mediated by BAX proteins and by the pro apoptotic components of Bcl-2 protein family.	('BAX', 'Gene', (89, 92))	('Bcl-2', 'Gene', '596', (141, 146))	('apoptosis', 'CPA', (26, 35))	('BAX', 'Gene', '581', (89, 92))	('p53', 'Var', (43, 46))	('Bcl-2', 'Gene', (141, 146))	('Bcl-2', 'molecular_function', 'GO:0015283', ('141', '146'))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
46960	28704484	BAX gene promoter contains several consensus sequences for p53 binding and is heavily trans activated by p53.	('p53', 'Var', (105, 108))	('BAX', 'Gene', (0, 3))	('binding', 'Interaction', (63, 70))	('BAX', 'Gene', '581', (0, 3))	('p53 binding', 'molecular_function', 'GO:0002039', ('59', '70'))
46966	28704484	Albeit in other MPM cell lines are found small levels of Bcl-2 mRNA /protein, in ZL34 MPM cells, treatment with Bcl-2 antisense oligonucleotides reduced apoptosis threshold.	('reduced', 'NegReg', (145, 152))	('Bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('ZL34', 'CellLine', 'CVCL:5906', (81, 85))	('apoptosis threshold', 'CPA', (153, 172))	('Bcl-2', 'molecular_function', 'GO:0015283', ('57', '62'))	('antisense oligonucleotides', 'Var', (118, 144))	('Bcl-2', 'Gene', (112, 117))	('Bcl-2', 'Gene', (57, 62))	('Bcl-2', 'Gene', '596', (112, 117))	('Bcl-2', 'Gene', '596', (57, 62))	('oligonucleotides', 'Chemical', 'MESH:D009841', (128, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))
46969	28704484	As stated above, activated MAPKs are involved in apoptosis also when apoptosis is due to Ptac2S, as shown in human neuroblastoma and breast cancer cells.	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))	('human', 'Species', '9606', (109, 114))	('breast cancer', 'Disease', (133, 146))	('Ptac2S', 'Var', (89, 95))	('neuroblastoma', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('neuroblastoma', 'Phenotype', 'HP:0003006', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Ptac2S', 'Chemical', '-', (89, 95))	('involved', 'Reg', (37, 45))	('neuroblastoma', 'Disease', 'MESH:D009447', (115, 128))
46970	28704484	We have show that Ptac2S causes activation of p38MAPK in ZL55 cells, and in the present paper we also show that Ptac2S causes activation of MAPKs and that p38MAPK and JNK1/2 have a pro-apoptotic role in both ZL34 and ZL55.	('JNK', 'molecular_function', 'GO:0004705', ('167', '170'))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('p38', 'Gene', (155, 158))	('Ptac2S', 'Gene', (112, 118))	('activation', 'PosReg', (32, 42))	('p38', 'Gene', (46, 49))	('Ptac2S', 'Chemical', '-', (18, 24))	('activation', 'PosReg', (126, 136))	('MAPKs', 'Protein', (140, 145))	('Ptac2S', 'Chemical', '-', (112, 118))	('p38', 'Gene', '5594', (155, 158))	('ZL34', 'CellLine', 'CVCL:5906', (208, 212))	('Ptac2S', 'Var', (18, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('158', '162'))	('pro-apoptotic', 'CPA', (181, 194))	('p38', 'Gene', '5594', (46, 49))
46980	28704484	In this report we show that PKC-alpha was activated by Ptac2S in ZL34 cells, starting an antiapoptotic program able to activate a signalling pathway comprehending ERK1/2 (ERK1/2 phosphorylation was blocked by siRNA-PKC-alpha, Fig 5).	('ZL34', 'CellLine', 'CVCL:5906', (65, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('signalling pathway', 'Pathway', (130, 148))	('PKC-alpha', 'Gene', (28, 37))	('ERK1', 'molecular_function', 'GO:0004707', ('163', '167'))	('Ptac2S', 'Chemical', '-', (55, 61))	('PKC-alpha', 'Gene', '5578', (215, 224))	('PKC-alpha', 'Gene', '5578', (28, 37))	('ERK1', 'molecular_function', 'GO:0004707', ('171', '175'))	('PKC', 'molecular_function', 'GO:0004697', ('215', '218'))	('Ptac2S', 'Var', (55, 61))	('antiapoptotic program', 'MPA', (89, 110))	('signalling pathway', 'biological_process', 'GO:0007165', ('130', '148'))	('activate', 'PosReg', (119, 127))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))	('PKC-alpha', 'Gene', (215, 224))
46982	28704484	We conclude by pointing out that Ptac2S is effective in pleural mesothelioma and that these new acquisitions enhance the knowledge of the anti tumour activity of this compound.	('pleural mesothelioma', 'Disease', (56, 76))	('Ptac2S', 'Var', (33, 39))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (56, 76))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('Ptac2S', 'Chemical', '-', (33, 39))	('tumour', 'Disease', (143, 149))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (56, 76))
47064	27560933	There was no pleural thickening on CT imaging and no pleural 18F-FDG uptake on PET imaging in 12 patients with pleural effusion caused by the dysfunction of liver, heart and kidney.	('caused by', 'Reg', (128, 137))	('pleural', 'Disease', (13, 20))	('18F-FDG', 'Chemical', '-', (61, 68))	('dysfunction', 'Var', (142, 153))	('pleural effusion', 'Disease', 'MESH:D010996', (111, 127))	('pleural effusion', 'Phenotype', 'HP:0002202', (111, 127))	('uptake', 'biological_process', 'GO:0098657', ('69', '75'))	('pleural effusion', 'Disease', (111, 127))	('pleural', 'Disease', 'MESH:D010995', (111, 118))	('pleural', 'Disease', 'MESH:D010995', (53, 60))	('pleural', 'Disease', (111, 118))	('pleural', 'Disease', (53, 60))	('uptake', 'biological_process', 'GO:0098739', ('69', '75'))	('pleural thickening', 'Phenotype', 'HP:0031944', (13, 31))	('dysfunction of liver', 'Phenotype', 'HP:0001410', (142, 162))	('pleural', 'Disease', 'MESH:D010995', (13, 20))	('patients', 'Species', '9606', (97, 105))
47142	27088262	ICR (Crl:CD1) and C57BL (C57BL/6J) mice and F344 (F344/DuCrlCrj) rats were from Japan Charles River (Shiga, Japan).	('CD1', 'Gene', '111334', (9, 12))	('CD1', 'Gene', (9, 12))	('rats', 'Species', '10116', (65, 69))	('C57BL', 'Var', (18, 23))	('mice', 'Species', '10090', (35, 39))
47187	27088262	C57BL mice showed an increase in occurrence of mitoses, and A/J mice displayed severe atypia of pleural cells.	('atypia of pleural', 'Disease', 'MESH:D010995', (86, 103))	('atypia of pleural', 'Disease', (86, 103))	('mice', 'Species', '10090', (6, 10))	('C57BL', 'Var', (0, 5))	('mitoses', 'CPA', (47, 54))	('mice', 'Species', '10090', (64, 68))
47236	24815191	Previously we showed that MWCNT translocated from the lung alveoli into the pleural cavity and caused mesothelial proliferation and fibrosis in the visceral pleura.	('mesothelial proliferation', 'CPA', (102, 127))	('fibrosis in the visceral pleura', 'Disease', (132, 163))	('fibrosis in the visceral pleura', 'Disease', 'MESH:D005355', (132, 163))	('caused', 'Reg', (95, 101))	('MWCNT', 'Var', (26, 31))	('MWCNT', 'Chemical', '-', (26, 31))	('rat', 'Species', '10116', (121, 124))
47241	24815191	It was found that MWCNT-L, but not MWCNT-S, translocated into the pleural cavity, deposited in the parietal pleura, and induced fibrosis and patchy parietal mesothelial proliferation lesions.	('patchy parietal mesothelial proliferation lesions', 'Disease', 'MESH:D018301', (141, 190))	('MWCNT-L', 'Chemical', '-', (18, 25))	('fibrosis', 'Disease', (128, 136))	('induced', 'Reg', (120, 127))	('MWCNT-S', 'Chemical', '-', (35, 42))	('patchy parietal mesothelial proliferation lesions', 'Disease', (141, 190))	('MWCNT-L', 'Var', (18, 25))	('fibrosis', 'Disease', 'MESH:D005355', (128, 136))	('parietal pleura', 'Disease', 'MESH:D054363', (99, 114))	('parietal pleura', 'Disease', (99, 114))
47242	24815191	In addition, MWCNT-L induced stronger inflammatory reactions including increased inflammatory cell number and cytokine/chemokine levels in the pleural cavity lavage than MWCNT-S.	('MWCNT-S', 'Chemical', '-', (170, 177))	('MWCNT-L', 'Var', (13, 20))	('increased inflammatory cell', 'Phenotype', 'HP:0012649', (71, 98))	('increased', 'PosReg', (71, 80))	('inflammatory cell number', 'CPA', (81, 105))	('MWCNT-L', 'Chemical', '-', (13, 20))	('inflammatory reactions', 'CPA', (38, 60))	('cytokine/chemokine levels', 'MPA', (110, 135))	('stronger', 'PosReg', (29, 37))
47243	24815191	In contrast, MWCNT-S induced stronger inflammation and higher 8-hydroxydeoxyguanosine level in the lung tissue than MWCNT-L.	('8-hydroxydeoxyguanosine level', 'MPA', (62, 91))	('MWCNT-S', 'Chemical', '-', (13, 20))	('8-hydroxydeoxyguanosine', 'Chemical', 'MESH:C067134', (62, 85))	('inflammation', 'biological_process', 'GO:0006954', ('38', '50'))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('MWCNT-L', 'Chemical', '-', (116, 123))	('higher', 'PosReg', (55, 61))	('MWCNT-S', 'Var', (13, 20))	('stronger', 'PosReg', (29, 37))	('inflammation', 'Disease', (38, 50))
47244	24815191	These results suggest that MWCNT-L has higher risk of causing asbestos-like pleural lesions relevant to mesothelioma development.	('MWCNT-L', 'Chemical', '-', (27, 34))	('pleural lesions', 'Disease', 'MESH:D010995', (76, 91))	('asbestos', 'Chemical', 'MESH:D001194', (62, 70))	('MWCNT-L', 'Var', (27, 34))	('pleural lesions', 'Disease', (76, 91))	('mesothelioma', 'Disease', (104, 116))	('pleural lesions', 'Phenotype', 'HP:0002102', (76, 91))	('causing', 'Reg', (54, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))
47253	24815191	Furthermore, MWCNT administered to the lung has been found to translocate into the pleural cavity and induce inflammation in the pleural cavity and mesothelial cell proliferation in the visceral pleura in mice and rats.	('induce', 'PosReg', (102, 108))	('mesothelial cell proliferation', 'CPA', (148, 178))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('visceral pleura', 'Disease', 'MESH:D054363', (186, 201))	('rat', 'Species', '10116', (214, 217))	('inflammation', 'biological_process', 'GO:0006954', ('109', '121'))	('mice', 'Species', '10090', (205, 209))	('inflammation', 'Disease', (109, 121))	('rat', 'Species', '10116', (172, 175))	('MWCNT', 'Var', (13, 18))	('visceral pleura', 'Disease', (186, 201))	('MWCNT', 'Chemical', '-', (13, 18))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('rats', 'Species', '10116', (214, 218))
47255	24815191	reported that intrapleural injection of long (>15 mum) but not short (<4 mum) MWCNT caused persistent inflammation and fibrosis of the parietal pleura up to 24 weeks post-treatment.	('fibrosis of the parietal pleura', 'Disease', (119, 150))	('fibrosis of the parietal pleura', 'Disease', 'MESH:D005355', (119, 150))	('MWCNT', 'Chemical', '-', (78, 83))	('>15 mum', 'Var', (46, 53))	('inflammation', 'Disease', 'MESH:D007249', (102, 114))	('inflammation', 'Disease', (102, 114))	('inflammation', 'biological_process', 'GO:0006954', ('102', '114'))
47298	24815191	The thickness of the parietal and visceral pleura with deposition of MWCNT-L was 28.75 +- 10.43 mum and 18.92 +- 10.13 mum, respectively, both lesions showing a significant increase compared to those in the rats treated with MWCNT-S (7.28 +- 4.37 mum and 6.16 +- 2.05 mum) or with the dispersing agent, PF68, alone (7.16 +- 4.95 mum and 4.57 +- 1.23 mum; Fig.	('PF68', 'Chemical', 'MESH:D020442', (303, 307))	('visceral pleura', 'Disease', (34, 49))	('MWCNT-L', 'Chemical', '-', (69, 76))	('MWCNT-L', 'Var', (69, 76))	('increase', 'PosReg', (173, 181))	('rats', 'Species', '10116', (207, 211))	('MWCNT-S', 'Chemical', '-', (225, 232))	('visceral pleura', 'Disease', 'MESH:D054363', (34, 49))
47299	24815191	An increase in the thickness of the visceral pleura of the rats treated with MWCNT-S compared with the PF68-treated rats was also observed (Fig.	('PF68', 'Chemical', 'MESH:D020442', (103, 107))	('rats', 'Species', '10116', (116, 120))	('rats', 'Species', '10116', (59, 63))	('MWCNT-S', 'Var', (77, 84))	('visceral pleura', 'Disease', 'MESH:D054363', (36, 51))	('visceral pleura', 'Disease', (36, 51))	('MWCNT-S', 'Chemical', '-', (77, 84))	('increase', 'PosReg', (3, 11))
47308	24815191	In the PCL, the total cell number, composed mostly of macrophages, neutrophils, eosinophils, and lymphocytes, in the MWCNT-L and MWCNT-S treated groups was significantly increased compared with the PF68 group.	('cell number', 'CPA', (22, 33))	('MWCNT-S', 'Chemical', '-', (129, 136))	('MWCNT-L', 'Chemical', '-', (117, 124))	('increased', 'PosReg', (170, 179))	('MWCNT-L', 'Var', (117, 124))	('PF68', 'Chemical', 'MESH:D020442', (198, 202))	('MWCNT-S', 'Var', (129, 136))
47309	24815191	The PCL cell number in the MWCNT-L group was significantly greater than in the MWCNT-S group (Fig.	('MWCNT-L', 'Chemical', '-', (27, 34))	('MWCNT-L', 'Var', (27, 34))	('greater', 'PosReg', (59, 66))	('MWCNT-S', 'Chemical', '-', (79, 86))	('PCL cell number', 'CPA', (4, 19))
47311	24815191	The ratios of cells in the PCL pellets positive for mesothelin/Erc, a mesothelial cell marker, were approximately 1%, indicating that the increased cell number in the pleural cavity of the rats treated with MWCNT-L and MWCNT-S was caused by inflammatory cell effusion, not by mesothelial cell shedding from the mesothelium.	('increased', 'PosReg', (138, 147))	('Erc', 'cellular_component', 'GO:0055037', ('63', '66'))	('Erc', 'Gene', '266806', (63, 66))	('MWCNT-S', 'Chemical', '-', (219, 226))	('rats', 'Species', '10116', (189, 193))	('MWCNT-L', 'Chemical', '-', (207, 214))	('Erc', 'Gene', (63, 66))	('rat', 'Species', '10116', (4, 7))	('MWCNT-L', 'Var', (207, 214))	('cell number', 'CPA', (148, 159))	('rat', 'Species', '10116', (189, 192))	('MWCNT-S', 'Var', (219, 226))	('inflammatory cell effusion', 'Disease', (241, 267))
47313	24815191	Analysis of 20 cytokines and chemokines by Multiplex Suspension Array indicated that the levels of IP-10, RANTES, IL-2, and IL-18 were significantly higher in the MWCNT-L group than the MWCNT-S group (Table 1).	('RANTES', 'Gene', (106, 112))	('RANTES', 'Gene', '81780', (106, 112))	('MWCNT-L', 'Chemical', '-', (163, 170))	('IL-18', 'Gene', (124, 129))	('MWCNT-S', 'Chemical', '-', (186, 193))	('IP-10', 'Gene', '245920', (99, 104))	('IL-2', 'molecular_function', 'GO:0005134', ('114', '118'))	('IL-18', 'Gene', '29197', (124, 129))	('MWCNT-L', 'Var', (163, 170))	('IL-2', 'Gene', (114, 118))	('higher', 'PosReg', (149, 155))	('IL-18', 'molecular_function', 'GO:0045515', ('124', '129'))	('IP-10', 'Gene', (99, 104))	('IL-2', 'Gene', '116562', (114, 118))
47316	24815191	The number of alveolar macrophages was higher in the MWCNT-S group than in the MWCNT-L group.	('MWCNT-S', 'Chemical', '-', (53, 60))	('higher', 'PosReg', (39, 45))	('MWCNT-S', 'Var', (53, 60))	('MWCNT-L', 'Chemical', '-', (79, 86))
47317	24815191	We were unable to quantitatively analyze the alveolar macrophage number, because most of the alveolar macrophages induced by MWCNT-S were degenerative or necrotic.	('alveolar macrophage number', 'Disease', (45, 71))	('alveolar macrophage number', 'Disease', 'MESH:D055501', (45, 71))	('necrotic', 'Disease', 'MESH:D009336', (154, 162))	('MWCNT-S', 'Var', (125, 132))	('rat', 'Species', '10116', (144, 147))	('MWCNT-S', 'Chemical', '-', (125, 132))	('necrotic', 'Disease', (154, 162))	('degenerative', 'NegReg', (138, 150))
47322	24815191	The level of RANTES was significantly higher in the MWCNT-L group than the MWCNT-S group, and the other 10 cytokines were comparable among the PF68, MWCNT-L, and MWCNT-S treated groups (Table 1).	('RANTES', 'Gene', (13, 19))	('MWCNT-L', 'Chemical', '-', (149, 156))	('MWCNT-L', 'Chemical', '-', (52, 59))	('RANTES', 'Gene', '81780', (13, 19))	('PF68', 'Chemical', 'MESH:D020442', (143, 147))	('MWCNT-S', 'Chemical', '-', (162, 169))	('higher', 'PosReg', (38, 44))	('MWCNT-L', 'Var', (52, 59))	('MWCNT-S', 'Chemical', '-', (75, 82))
47329	24815191	Multiwalled carbon nanotubes, when injected into the peritoneal cavity or the scrotum, results in the development of mesothelioma.	('results in', 'Reg', (87, 97))	('mesothelioma', 'Disease', (117, 129))	('carbon', 'Chemical', 'MESH:D002244', (12, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('Multiwalled', 'Var', (0, 11))
47339	24815191	The results of this study show that MWCNT-L applied to the lung was found in the pleural cavity and deposited in the parietal pleura, and induced higher inflammatory reactions in the pleural cavity, fibrotic thickening of both the parietal and visceral pleura, and mesothelial proliferation, whereas MWCNT-S caused higher inflammatory reactions and 8-OHdG formation in the lung.	('higher', 'PosReg', (146, 152))	('parietal pleura', 'Disease', 'MESH:D054363', (117, 132))	('parietal pleura', 'Disease', (117, 132))	('visceral pleura', 'Disease', 'MESH:D054363', (244, 259))	('formation', 'biological_process', 'GO:0009058', ('356', '365'))	('rat', 'Species', '10116', (284, 287))	('inflammatory reactions', 'CPA', (153, 175))	('8-OHdG formation', 'CPA', (349, 365))	('8-OHdG', 'Chemical', 'MESH:C067134', (349, 355))	('MWCNT-S', 'Chemical', '-', (300, 307))	('MWCNT-L', 'Chemical', '-', (36, 43))	('visceral pleura', 'Disease', (244, 259))	('inflammatory reactions', 'CPA', (322, 344))	('mesothelial proliferation', 'CPA', (265, 290))	('induced', 'Reg', (138, 145))	('fibrotic thickening', 'CPA', (199, 218))	('MWCNT-L', 'Var', (36, 43))
47341	24815191	Due to its length and needle-like shape, MWCNT-L deposited in the pleura, especially in the parietal side, is difficult to clear and results in chronic inflammation in the deposited site.	('MWCNT-L', 'Chemical', '-', (41, 48))	('inflammation', 'Disease', 'MESH:D007249', (152, 164))	('MWCNT-L', 'Var', (41, 48))	('inflammation', 'Disease', (152, 164))	('results in', 'Reg', (133, 143))	('inflammation', 'biological_process', 'GO:0006954', ('152', '164'))
47342	24815191	Thus, MWCNT-L has more potential to cause pleural mesothelioma.	('cause', 'Reg', (36, 41))	('MWCNT-L', 'Var', (6, 13))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (42, 62))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (42, 62))	('pleural mesothelioma', 'Disease', (42, 62))	('MWCNT-L', 'Chemical', '-', (6, 13))
47482	24503412	The incidence in 3.0 mg/kg males was significantly greater than the vehicle control incidence and exceeded the historical control ranges for dermal studies and for all routes of administration by only one tumor (Table 1).	('3.0 mg/kg', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('greater', 'PosReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))
47489	24503412	The combined incidence of basal cell adenoma and carcinoma was statistically significant in the 0.3 mg/kg group and exceeded the historical control range for all routes of study (0-8%), but only by a single neoplasm.	('carcinoma', 'Disease', 'MESH:D002277', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('0.3 mg/kg', 'Var', (96, 105))	('neoplasm', 'Disease', (207, 215))	('basal cell adenoma', 'Disease', 'MESH:D000236', (26, 44))	('carcinoma', 'Disease', (49, 58))	('neoplasm', 'Disease', 'MESH:D009369', (207, 215))	('basal cell adenoma', 'Phenotype', 'HP:0002671', (26, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('basal cell adenoma', 'Disease', (26, 44))
47490	24503412	The increased incidence of basal cell adenoma or basal cell carcinoma (combined) was statistically significant in the 0.3 mg/kg group, the lowest dose group.	('basal cell adenoma', 'Phenotype', 'HP:0002671', (27, 45))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (49, 69))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (49, 69))	('basal cell carcinoma', 'Disease', (49, 69))	('basal cell adenoma', 'Disease', (27, 45))	('0.3 mg/kg', 'Var', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('basal cell adenoma', 'Disease', 'MESH:D000236', (27, 45))
47559	24503412	There was a positive trend in the incidences of mesothelioma; the incidence in 3.0 mg/kg males was significantly greater than in the concurrent vehicle controls receiving acetone.	('acetone', 'Chemical', 'MESH:D000096', (171, 178))	('3.0 mg/kg', 'Var', (79, 88))	('mesothelioma', 'Disease', (48, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('greater', 'PosReg', (113, 120))
47616	19744744	The increase in serum CA-125 produced by treatment with MORAb-009 is most likely due to MORAb-009 inhibiting the binding of tumor shed CA-125 to mesothelin present on mesothelial cells lining the pleural and peritoneal cavities.	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('pleural', 'Disease', 'MESH:D010995', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('pleural', 'Disease', (196, 203))	('MORAb-009', 'Chemical', 'MESH:C526187', (56, 65))	('increase in serum CA', 'Phenotype', 'HP:0003072', (4, 24))	('tumor', 'Disease', (124, 129))	('MORAb-009', 'Chemical', 'MESH:C526187', (88, 97))	('CA-125', 'Protein', (135, 141))	('MORAb-009', 'Var', (88, 97))	('increase', 'PosReg', (4, 12))	('serum CA-125', 'MPA', (16, 28))	('binding', 'Interaction', (113, 120))	('inhibiting', 'NegReg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
47617	19744744	Inhibiting the mesothelin-CA-125 interaction could be a useful strategy to prevent tumor metastasis in mesotheliomas and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mesothelin-CA-125', 'Protein', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Inhibiting', 'Var', (0, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('tumor metastasis in mesotheliomas and ovarian cancer', 'Disease', 'MESH:D009362', (83, 135))	('interaction', 'Interaction', (33, 44))	('prevent', 'NegReg', (75, 82))
47622	19744744	Mutant mice in which both copies of the mesothelin gene were inactivated showed no detectable abnormalities as compared to wild-type littermates.	('Mutant', 'Var', (0, 6))	('mesothelin', 'Gene', (40, 50))	('mice', 'Species', '10090', (7, 11))
47632	19744744	Laboratory studies show that MORAb-009 kills mesothelin-expressing cell lines via antibody dependent cellular cytotoxicity and, in addition, it inhibits the binding of mesothelin to CA-125.	('binding', 'Interaction', (157, 164))	('cytotoxicity', 'Disease', 'MESH:D064420', (110, 122))	('inhibits', 'NegReg', (144, 152))	('antibody', 'cellular_component', 'GO:0019814', ('82', '90'))	('antibody', 'molecular_function', 'GO:0003823', ('82', '90'))	('antibody', 'cellular_component', 'GO:0019815', ('82', '90'))	('CA-125', 'Protein', (182, 188))	('MORAb-009', 'Chemical', 'MESH:C526187', (29, 38))	('antibody', 'cellular_component', 'GO:0042571', ('82', '90'))	('binding', 'molecular_function', 'GO:0005488', ('157', '164'))	('MORAb-009', 'Var', (29, 38))	('cytotoxicity', 'Disease', (110, 122))	('mesothelin', 'Protein', (168, 178))	('antibody dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('82', '122'))
47633	19744744	Based on these studies a three-institution phase I clinical trial of MORAb-009 was conducted and recently completed in patients with mesothelin expressing cancers.1 This report describes the effect of MORAb-009 on raising the serum CA-125 level in all eight patients with mesothelioma treated at our site.	('serum CA-125 level', 'MPA', (226, 244))	('MORAb-009', 'Chemical', 'MESH:C526187', (69, 78))	('MORAb-009', 'Chemical', 'MESH:C526187', (201, 210))	('mesothelioma', 'Disease', (272, 284))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (119, 127))	('MORAb-009', 'Var', (201, 210))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (272, 284))	('patients', 'Species', '9606', (258, 266))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('raising', 'PosReg', (214, 221))	('cancers', 'Disease', (155, 162))
47685	19744744	Our results show that patients with mesothelioma treated with MORAb-009, a chimeric antibody reacting with mesothelin, have a very significant elevation in their CA-125 levels.	('MORAb-009', 'Chemical', 'MESH:C526187', (62, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('MORAb-009', 'Var', (62, 71))	('patients', 'Species', '9606', (22, 30))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('CA-125 levels', 'MPA', (162, 175))	('elevation', 'PosReg', (143, 152))	('mesothelioma', 'Disease', (36, 48))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))
47686	19744744	This finding suggests that MORAb-009 is causing an elevation of CA-125, possibly by preventing it from binding to mesothelin present on mesothelial cells lining the pleura and peritoneum.	('MORAb-009', 'Chemical', 'MESH:C526187', (27, 36))	('preventing', 'NegReg', (84, 94))	('MORAb-009', 'Var', (27, 36))	('CA-125', 'Gene', (64, 70))	('binding', 'Interaction', (103, 110))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('pleura', 'Disease', (165, 171))	('pleura', 'Disease', 'MESH:D054363', (165, 171))	('elevation', 'PosReg', (51, 60))
47691	19744744	Elevation of CA-125 levels was seen in patients treated at different doses of MORAb-009, ranging from 12.5 mg/m2 to 400 mg/m2, demonstrating that even low doses of MORAb-009 are sufficient to increase serum CA-125.	('MORAb-009', 'Var', (164, 173))	('patients', 'Species', '9606', (39, 47))	('CA-125 levels', 'MPA', (13, 26))	('MORAb-009', 'Chemical', 'MESH:C526187', (164, 173))	('Elevation of CA-125 levels', 'Phenotype', 'HP:0031030', (0, 26))	('MORAb-009', 'Chemical', 'MESH:C526187', (78, 87))	('increase serum CA', 'Phenotype', 'HP:0003072', (192, 209))	('increase', 'PosReg', (192, 200))	('serum CA-125', 'MPA', (201, 213))
47705	19744744	Based on the pre-clinical studies, showing inhibition of mesothelin-CA-125 interaction by MORAb-009, and results of this clinical trial, it is likely that the rise in serum CA-125 seen in patients while on MORAb-009 therapy is due to MORAb-009 inhibiting mesothelin-CA-125 binding.	('binding', 'Interaction', (273, 280))	('MORAb-009', 'Chemical', 'MESH:C526187', (234, 243))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))	('MORAb-009', 'Chemical', 'MESH:C526187', (206, 215))	('MORAb-009', 'Chemical', 'MESH:C526187', (90, 99))	('serum CA-125', 'MPA', (167, 179))	('rise', 'PosReg', (159, 163))	('patients', 'Species', '9606', (188, 196))	('MORAb-009', 'Gene', (206, 215))	('inhibiting', 'NegReg', (244, 254))	('interaction', 'Interaction', (75, 86))	('binding', 'molecular_function', 'GO:0005488', ('273', '280'))	('mesothelin-CA-125', 'Protein', (255, 272))	('MORAb-009', 'Var', (234, 243))
47729	33225621	28  They found that four PE microRNAs (miR-944, miR-139-5p, miR-210 and miR-320) were upregulated and seven (miR-200b, miR-200c, miR-143, miR-200a, miR-203, miR-31 and miR-874) were downregulated.	('miR-203', 'Gene', (148, 155))	('miR-210', 'Gene', '406992', (60, 67))	('miR-874', 'Gene', '100126343', (168, 175))	('miR-143', 'Gene', '406935', (129, 136))	('miR-200b', 'Gene', (109, 117))	('miR-203', 'Gene', '406986', (148, 155))	('miR-210', 'Gene', (60, 67))	('miR-143', 'Gene', (129, 136))	('miR-200a', 'Gene', (138, 146))	('PE', 'Phenotype', 'HP:0002202', (25, 27))	('miR-31', 'Gene', (157, 163))	('miR-200c', 'Gene', '406985', (119, 127))	('miR-944', 'Gene', (39, 46))	('miR-200b', 'Gene', '406984', (109, 117))	('miR-944', 'Gene', '100126340', (39, 46))	('miR-200c', 'Gene', (119, 127))	('miR-200a', 'Gene', '406983', (138, 146))	('miR-31', 'Gene', '407035', (157, 163))	('miR-139-5p', 'Var', (48, 58))	('upregulated', 'PosReg', (86, 97))	('miR-874', 'Gene', (168, 175))	('miR-320', 'Var', (72, 79))
47730	33225621	PCR further validated the levels of four microRNA (miR-210, miR-143, miR-139-5p, and miR-200c), and the ROC curve was used to evaluate their diagnostic accuracy.	('miR-143', 'Gene', '406935', (60, 67))	('miR-143', 'Gene', (60, 67))	('microRNA (miR-210', 'Gene', '406992', (41, 58))	('miR-139-5p', 'Var', (69, 79))	('miR-200c', 'Gene', (85, 93))	('miR-200c', 'Gene', '406985', (85, 93))
47732	33225621	To date, three studies have investigated the circulating microRNA profile of MPM patients with microRNA array and compared it with the circulating microRNA profile of healthy individuals, and workers ex-exposed to asbestos.29-31 Some differentially expressed microRNA were identified, including miR-197-3p, 29  miR-625-3p, 31  miR-29c, 31  miR-9231 and miR-132.	('miR-197-3p', 'Gene', (295, 305))	('miR-132', 'Gene', '406921', (353, 360))	('miR-625', 'Gene', '693210', (311, 318))	('patients', 'Species', '9606', (81, 89))	('miR-197-3p', 'Gene', '100302290', (295, 305))	('asbestos', 'Chemical', 'MESH:D001194', (214, 222))	('miR-625', 'Gene', (311, 318))	('miR-29c', 'Var', (327, 334))	('miR-132', 'Gene', (353, 360))	('miR-9231', 'Var', (340, 348))
47744	33225621	39  Among these microRNAs, miR-103, miR-98, miR-148b, miR-744, and miR-30e-3p had high diagnostic accuracy for MPM, with AUCs larger than 0.83.	('miR-98', 'Gene', '407054', (36, 42))	('miR-103', 'Var', (27, 34))	('miR-744', 'Gene', (54, 61))	('miR-98', 'Gene', (36, 42))	('miR-103', 'Chemical', '-', (27, 34))	('miR-30e-3p', 'Var', (67, 77))	('miR-148b', 'Gene', '442892', (44, 52))	('miR-148b', 'Gene', (44, 52))	('miR-744', 'Gene', '100126313', (54, 61))	('MPM', 'Disease', (111, 114))
47747	33225621	40  A further study with a relatively large sample size showed a similar AUC, and the AUC of miR-103 was lower than that of SMRP.	('lower', 'NegReg', (105, 110))	('miR-103', 'Var', (93, 100))	('SMRP', 'Gene', '10232', (124, 128))	('miR-103', 'Chemical', '-', (93, 100))	('SMRP', 'Gene', (124, 128))	('AUC', 'MPA', (86, 89))
47748	33225621	However, it has been previously reported that a logistic regression model contained miR-103 and SMRP had an AUC of 0.90, indicating that miR-103 can improve the diagnostic accuracy of SMRP.	('improve', 'PosReg', (149, 156))	('miR-103', 'Chemical', '-', (137, 144))	('SMRP', 'Gene', '10232', (96, 100))	('SMRP', 'Gene', (96, 100))	('SMRP', 'Gene', '10232', (184, 188))	('SMRP', 'Gene', (184, 188))	('miR-103', 'Var', (137, 144))	('diagnostic', 'MPA', (161, 171))	('miR-103', 'Chemical', '-', (84, 91))
47759	30759891	Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('epigenetic inhibitors', 'Var', (96, 117))	('delivery', 'MPA', (84, 92))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('improves', 'PosReg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
47762	30759891	These PTMs involve the methylation of carbon 5 on cytosine in DNA, and oxidized versions of this methylated form (CH2OH, CH=O, COOH), as well as modifications on protein histones, with the most important to date being the acetylation or (poly)methylation on lysine at the N-terminal tail and the (poly)methylation of arginine residues.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('cytosine', 'Chemical', 'MESH:D003596', (50, 58))	('COOH', 'Chemical', 'MESH:D002255', (127, 131))	('carbon', 'Chemical', 'MESH:D002244', (38, 44))	('methylation', 'biological_process', 'GO:0032259', ('243', '254'))	('methylation', 'biological_process', 'GO:0032259', ('302', '313'))	('CH2OH', 'Chemical', '-', (114, 119))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('arginine', 'Protein', (317, 325))	('modifications', 'Var', (145, 158))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('arginine', 'Chemical', 'MESH:D001120', (317, 325))	('protein histones', 'Protein', (162, 178))	('acetylation', 'Var', (222, 233))	('lysine', 'Chemical', 'MESH:D008239', (258, 264))
47763	30759891	This is the case with cancers, where malignant cells over-express some of these epigenetic modulators in order to reduce the expression of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor suppressor', 'biological_process', 'GO:0051726', ('139', '155'))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('139', '155'))	('cancers', 'Disease', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('expression', 'MPA', (125, 135))	('epigenetic modulators', 'Var', (80, 101))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('reduce', 'NegReg', (114, 120))	('over-express', 'PosReg', (53, 65))
47765	30759891	This includes the suberoyl anilide hydroxamic acid SAHA (vorinostat, Zolinza ) and FK228 (romidepsin, Istodax ) against cutaneous T-cell lymphoma (CTCL), belinostat (Beleodaq ) against the refractory or regressed peripheral T-cell lymphoma (PTCL), and panobinostat (Farydak ) against multiple myeloma.	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('multiple myeloma', 'Disease', 'MESH:D009101', (284, 300))	('Zolinza', 'Chemical', 'MESH:D000077337', (69, 76))	('FK228', 'Chemical', 'MESH:C087123', (83, 88))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (224, 239))	('vorinostat', 'Chemical', 'MESH:D000077337', (57, 67))	('T-cell lymphoma', 'Disease', (224, 239))	('cell lymphoma', 'Phenotype', 'HP:0012191', (226, 239))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (120, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (231, 239))	('cell lymphoma', 'Phenotype', 'HP:0012191', (132, 145))	('SAHA', 'Chemical', 'MESH:D000077337', (51, 55))	('multiple myeloma', 'Disease', (284, 300))	('cutaneous T-cell lymphoma', 'Disease', (120, 145))	('CTCL', 'Phenotype', 'HP:0012192', (147, 151))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (130, 145))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (120, 145))	('belinostat', 'Chemical', 'MESH:C487081', (154, 164))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (130, 145))	('FK228', 'Var', (83, 88))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (224, 239))	('multiple myeloma', 'Phenotype', 'HP:0006775', (284, 300))	('suberoyl anilide hydroxamic acid', 'Chemical', 'MESH:D000077337', (18, 50))
47788	30759891	In a xenograft orthotopic breast cancer model, the authors showed an interesting anti-tumor effect of the vectored HDACi compared to the free FK228.	('breast cancer', 'Disease', (26, 39))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('tumor', 'Disease', (86, 91))	('vectored', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('FK228', 'Chemical', 'MESH:C087123', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
47793	30759891	In this study, the authors obtained an interesting accumulation of the nanoparticles in the tumor tissues associated with a decrease of the tumor growth compared to bare nanoparticles.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('nanoparticles', 'Var', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('accumulation', 'PosReg', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('decrease', 'NegReg', (124, 132))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (140, 145))
47850	30759891	Treatment of mice with NPs 23 led to a decrease of 80% of the tumor weight (Figure 6A) associated with a decrease of the pancreas invasion (Figure 6B-D), compared to the control and with free NODH conditions.	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('decrease', 'NegReg', (39, 47))	('NODH', 'Chemical', '-', (192, 196))	('tumor', 'Disease', (62, 67))	('decrease of the pancreas invasion', 'Disease', 'MESH:D010190', (105, 138))	('NPs 23', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('decrease of the pancreas invasion', 'Disease', (105, 138))
47852	30759891	The anti-tumor effect obtained in the group treated with NPs 23 was associated with an increase of histone H3 acetylation in cancer cells (brown staining of cell nuclei) (Figure 7A) whereas no change in acetylation level was observed in the other analyzed organs including the liver and kidneys (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('increase', 'PosReg', (87, 95))	('histone H3', 'Protein', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('99', '121'))	('NPs 23', 'Var', (57, 63))	('tumor', 'Disease', (9, 14))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
47858	30759891	Whereas intra-tumoral acetylation of histone in vivo was improved with vectored vorinostat, compared to the free molecule, a poor anti-tumor effect was obtained.	('tumor', 'Disease', (14, 19))	('intra-tumoral', 'Disease', 'MESH:D009369', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('acetylation', 'MPA', (22, 33))	('histone', 'Protein', (37, 44))	('vectored', 'Var', (71, 79))	('tumor', 'Disease', (135, 140))	('vorinostat', 'Chemical', 'MESH:D000077337', (80, 90))	('intra-tumoral', 'Disease', (8, 21))	('improved', 'PosReg', (57, 65))	('vorinostat', 'Gene', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
47872	30687504	MPM caused 2542 deaths in the UK in 2015, and globally, mesothelioma is estimated to cause 38 400 deaths per year.	('mesothelioma', 'Disease', (56, 68))	('caused', 'Reg', (4, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))	('MPM', 'Var', (0, 3))
48177	26937070	The cells moved significantly faster under 5% (23.68 +- 12.84 mum h-1, p < 0.01), 10% (21.75 +- 15.38 mum h-1, p < 0.01), and 15% (21.81 +- 12.82 mum h-1, p < 0.01) FBS concentration gradients compared to the speed with no FBS (16.84 +- 10.77 mum h-1).	('mum', 'Gene', (146, 149))	('mum', 'Gene', '56925', (243, 246))	('mum', 'Gene', '56925', (102, 105))	('FBS', 'Var', (165, 168))	('mum', 'Gene', '56925', (62, 65))	('mum', 'Gene', (243, 246))	('mum', 'Gene', (102, 105))	('mum', 'Gene', (62, 65))	('faster', 'PosReg', (30, 36))	('mum', 'Gene', '56925', (146, 149))
48251	20049814	Unmodified graphene surfaces are hydrophobic, but many types of surface modifications commonly performed on CNTs and CNFs can increase hydrophilicity and improve their dispersion in medium or biological fluids As hydrophilic materials interact more readily with cell receptors, surface modifications that enhance hydrophilicity can modify target cell interactions and subsequent biological responses.	('dispersion in', 'MPA', (168, 181))	('graphene', 'Chemical', 'MESH:D006108', (11, 19))	('improve', 'PosReg', (154, 161))	('modifications', 'Var', (72, 85))	('CNF', 'Gene', '4868', (117, 120))	('target cell interactions', 'CPA', (339, 363))	('modify', 'Reg', (332, 338))	('interact', 'Interaction', (235, 243))	('increase', 'PosReg', (126, 134))	('biological responses', 'CPA', (379, 399))	('hydrophilicity', 'MPA', (135, 149))	('CNF', 'Gene', (117, 120))
48272	20049814	Nickel induces acute lung injury and tumorigenesis in rodent models, including mesotheliomas in rats when injected intrapleurally or intraperitoneally with metallic nickel powder.	('mesotheliomas', 'Disease', 'MESH:D008654', (79, 92))	('acute lung injury', 'Disease', (15, 32))	('nickel', 'Chemical', 'MESH:D009532', (165, 171))	('mesotheliomas', 'Disease', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('acute lung injury', 'Disease', 'MESH:D055371', (15, 32))	('rats', 'Species', '10116', (96, 100))	('Nickel', 'Chemical', 'MESH:D009532', (0, 6))	('Nickel', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('metal', 'Chemical', 'MESH:D008670', (156, 161))
48273	20049814	Carcinogenic nickel compounds, which are generally non-mutagenic, are hypothesized to transform target cells via epigenetic mechanisms.	('transform', 'Reg', (86, 95))	('epigenetic', 'Var', (113, 123))	('nickel', 'Chemical', 'MESH:D009532', (13, 19))
48274	20049814	Altered DNA methylation within regulatory regions of genes may result in transcriptional silencing of tumor suppressor genes.	('transcriptional', 'MPA', (73, 88))	('tumor', 'Disease', (102, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('silencing', 'NegReg', (89, 98))	('result', 'Reg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Altered DNA methylation', 'Var', (0, 23))	('DNA methylation', 'biological_process', 'GO:0006306', ('8', '23'))
48339	20049814	Importantly, peroxinitrite has been shown to activate numerous components of the extracellular-regulated kinase (ERK) signaling pathway, whose activity is associated with proliferation of asbestos-exposed mesothelial and lung epithelial cells.	('peroxinitrite', 'Chemical', '-', (13, 26))	('peroxinitrite', 'Var', (13, 26))	('associated', 'Reg', (155, 165))	('activate', 'PosReg', (45, 53))	('signaling pathway', 'biological_process', 'GO:0007165', ('118', '135'))	('ERK', 'Gene', (113, 116))	('ERK', 'Gene', '5595;5594;5595', (113, 116))	('rat', 'Species', '10116', (178, 181))	('extracellular', 'cellular_component', 'GO:0005576', ('81', '94'))	('asbestos', 'Chemical', 'MESH:D001194', (188, 196))	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))	('activity', 'MPA', (143, 151))
48346	20049814	Mice deficient in the p53 tumor suppressor gene, a critical regulator of DNA damage responses, have been used as an in vivo model to investigate the role of genotoxicity in fiber carcinogenesis.	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('toxicity', 'Disease', 'MESH:D064420', (161, 169))	('toxicity', 'Disease', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p53', 'Gene', (22, 25))	('carcinogenesis', 'Disease', (179, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('Mice', 'Species', '10090', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('p53', 'Gene', '22060', (22, 25))	('deficient', 'Var', (5, 14))
48347	20049814	The p53 deficiency increases susceptibility to asbestos-induced mesotheliomas, and the majority of mesotheliomas that form in p53 heterozygous mice exhibit loss of the remaining wild-type allele.	('mesotheliomas', 'Disease', (99, 112))	('asbestos-induced mesotheliomas', 'Disease', (47, 77))	('asbestos-induced mesotheliomas', 'Disease', 'MESH:D008654', (47, 77))	('p53', 'Gene', '22060', (126, 129))	('p53', 'Gene', '22060', (4, 7))	('mesotheliomas', 'Disease', 'MESH:D008654', (64, 77))	('mesotheliomas', 'Disease', (64, 77))	('deficiency', 'Var', (8, 18))	('p53', 'Gene', (126, 129))	('p53', 'Gene', (4, 7))	('mesotheliomas', 'Disease', 'MESH:D008654', (99, 112))	('mice', 'Species', '10090', (143, 147))
48349	20049814	It has been hypothesized that polymorphisms in genes related to xenobiotic metabolism, oxidative stress, or DNA repair could also influence susceptibility to asbestos-related diseases.	('asbestos', 'Chemical', 'MESH:D001194', (158, 166))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (64, 85))	('xenobiotic metabolism', 'Disease', (64, 85))	('influence', 'Reg', (130, 139))	('polymorphisms', 'Var', (30, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (87, 103))	('DNA repair', 'biological_process', 'GO:0006281', ('108', '118'))	('asbestos-related diseases', 'Disease', (158, 183))	('xenobiotic metabolism', 'biological_process', 'GO:0006805', ('64', '85'))
48350	20049814	Although no susceptibility gene has been conclusively identified, a recent study of genetic polymorphisms in DNA repair genes among individuals exposed to asbestos indicated an association between polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene and malignant mesothelioma.	('polymorphisms', 'Var', (197, 210))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (276, 298))	('XRCC1', 'Gene', (260, 265))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('asbestos', 'Chemical', 'MESH:D001194', (155, 163))	('malignant mesothelioma', 'Disease', (276, 298))	('DNA repair', 'biological_process', 'GO:0006281', ('109', '119'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (276, 298))	('X-ray repair cross-complementing group 1', 'Gene', '7515', (218, 258))	('XRCC1', 'Gene', '7515', (260, 265))	('X-ray repair cross-complementing group 1', 'Gene', (218, 258))
48361	20049814	Ground, purified MWCNTs containing less than 2% iron produced a dose-dependent increase in micronuclei in rat type II pneumocytes as well as in clastogenic and aneugenic micronuclei in a human lung epithelial cell line.	('increase', 'PosReg', (79, 87))	('micronuclei', 'CPA', (91, 102))	('iron', 'Chemical', 'MESH:D007501', (48, 52))	('human', 'Species', '9606', (187, 192))	('less than 2%', 'Var', (35, 47))	('rat', 'Species', '10116', (106, 109))
48364	20049814	Mesothelial cell proliferation is associated with fiber biopersistence, as crocidolite asbestos induces a more extended proliferative response than wollastonite, which is susceptible to dissolution and clearance in vivo.	('Mesothelial cell proliferation', 'CPA', (0, 30))	('crocidolite', 'Var', (75, 86))	('wollastonite', 'Chemical', 'MESH:C031293', (148, 160))	('rat', 'Species', '10116', (127, 130))	('cell proliferation', 'biological_process', 'GO:0008283', ('12', '30'))	('rat', 'Species', '10116', (24, 27))	('proliferative response', 'CPA', (120, 142))
48377	20049814	Cell proliferation in the context of chronic inflammation may result in accumulation of DNA damage and mutations that promote carcinogenesis.	('mutations', 'Var', (103, 112))	('inflammation', 'Disease', (45, 57))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('rat', 'Species', '10116', (12, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('DNA damage', 'Protein', (88, 98))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('carcinogenesis', 'Disease', (126, 140))	('accumulation', 'PosReg', (72, 84))	('inflammation', 'biological_process', 'GO:0006954', ('45', '57'))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('promote', 'PosReg', (118, 125))	('Cell proliferation', 'CPA', (0, 18))
48380	20049814	Chronic inflammation accompanied by oxidant generation has also been associated with epigenetic gene silencing by hypermethylation.	('Chronic inflammation', 'Disease', (0, 20))	('epigenetic', 'MPA', (85, 95))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('hypermethylation', 'Var', (114, 130))	('gene silencing', 'biological_process', 'GO:0016458', ('96', '110'))	('inflammation', 'biological_process', 'GO:0006954', ('8', '20'))	('rat', 'Species', '10116', (48, 51))
48416	31576173	NCT00513877 and NCT00458913 Malignant pleural mesothelioma (MPM) is a highly aggressive tumor arising from the mesothelium-lined surfaces.	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (28, 58))	('Malignant pleural mesothelioma', 'Disease', (28, 58))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MPM', 'Disease', 'MESH:C562839', (60, 63))	('MPM', 'Disease', (60, 63))	('NCT00458913', 'Var', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (38, 58))	('NCT00513877', 'Var', (0, 11))	('tumor', 'Disease', (88, 93))
48437	31576173	Subsequently, qPCR was carried out on a Step One Plus Real-Time PCR System using TaqMan Gene Expression Master Mix, MicroAmp Fast Optical 96-well plates, cDNA probes and Assays On Demand (TaqMan, all from Thermo Fisher Scientific: (PSMA1 (HS 01027362_g1), PSMA5 (HS 00932059_m1), PSMB1 (HS 00427357_m1), PSMB2 (HS 01002946_m1), PSMB4 (HS 01123843_g1), PSMB5 (HS 01002826_g1), PSMD1 (HS 00160631_m1) and as reference genes ACTB (HS 01060665_g1) and GAPDH (HS 02758991_g1)).	('PSMB1', 'Gene', '5689', (280, 285))	('HS 01060665_g1', 'Var', (428, 442))	('HS 00932059_m1', 'Var', (263, 277))	('HS 00160631_m1', 'Var', (383, 397))	('PSMB1', 'Gene', (280, 285))	('PSMA5', 'Gene', '5686', (256, 261))	('ACTB', 'Gene', '60', (422, 426))	('ACTB', 'Gene', (422, 426))	('PSMA1', 'Gene', (232, 237))	('Gene Expression', 'biological_process', 'GO:0010467', ('88', '103'))	('PSMB5', 'Gene', '5693', (352, 357))	('PSMA5', 'Gene', (256, 261))	('HS 00427357_m1', 'Var', (287, 301))	('PSMB4', 'Gene', (328, 333))	('PSMA', 'molecular_function', 'GO:0043275', ('232', '236'))	('PSMD1', 'Gene', '5707', (376, 381))	('PSMB5', 'Gene', (352, 357))	('HS 01123843_g1', 'Var', (335, 349))	('PSMA', 'molecular_function', 'GO:0043275', ('256', '260'))	('PSMD1', 'Gene', (376, 381))	('PSMB2', 'Gene', '5690', (304, 309))	('HS 01002826_g1', 'Var', (359, 373))	('HS 01027362_g1', 'Var', (239, 253))	('PSMB4', 'Gene', '5692', (328, 333))	('HS 01002946_m1', 'Var', (311, 325))	('PSMA1', 'Gene', '5682', (232, 237))	('PSMB2', 'Gene', (304, 309))
48463	31576173	MSTO-211H showed an elevated induction of apoptosis for cisplatin, but a negligible response to all other drugs and concentrations (Figure 4B).	('induction of apoptosis', 'biological_process', 'GO:0006915', ('29', '51'))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('apoptosis', 'CPA', (42, 51))	('cisplatin', 'Var', (56, 65))	('MSTO-211H', 'Chemical', 'MESH:C073773', (0, 9))
48469	31576173	This problem became visible in studies investigating the efficacy of bortezomib in MPM in two clinical trials (NCT00513877 and NCT00458913) and another clinical trial in non-small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (174, 196))	('NCT00513877', 'Var', (111, 122))	('non-small cell lung cancer', 'Disease', (170, 196))	('bortezomib', 'Chemical', 'MESH:C400082', (69, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (170, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('NSCLC', 'Disease', (198, 203))	('NCT00458913', 'Var', (127, 138))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (170, 196))	('MPM', 'Disease', 'MESH:C562839', (83, 86))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('MPM', 'Disease', (83, 86))
48497	31576173	Cells that have acquired a resistance against cisplatin, doxorubicin or MDM2 inhibitors are also more prone to acquire or present with a bortezomib resistance.	('bortezomib', 'Chemical', 'MESH:C400082', (137, 147))	('inhibitors', 'Var', (77, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('bortezomib resistance', 'MPA', (137, 158))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (72, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
48498	31576173	But on the other hand, a combination of bortezomib and MDM2 inhibitors showed synergistic effects on mantle cell lymphoma cell lines, which share a common feature with MPM namely being TP53 wild type.	('bortezomib', 'Gene', (40, 50))	('TP53', 'Gene', (185, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('inhibitors', 'Var', (60, 70))	('MPM', 'Disease', 'MESH:C562839', (168, 171))	('MPM', 'Disease', (168, 171))	('cell lymphoma', 'Phenotype', 'HP:0012191', (108, 121))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (101, 121))	('MDM2', 'Gene', '4193', (55, 59))	('mantle cell lymphoma', 'Disease', (101, 121))	('MDM2', 'Gene', (55, 59))	('bortezomib', 'Chemical', 'MESH:C400082', (40, 50))	('TP53', 'Gene', '7157', (185, 189))
48499	31576173	Most importantly, TP53 mutant mantle cell lymphoma, which is resistant against bortezomib, was successfully inhibited by activating the mitochondrial apoptosis pathway via combination of MDM2 inhibitor and bortezomib.	('bortezomib', 'Chemical', 'MESH:C400082', (79, 89))	('mantle cell lymphoma', 'Disease', (30, 50))	('bortezomib', 'Chemical', 'MESH:C400082', (206, 216))	('TP53', 'Gene', '7157', (18, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('activating', 'PosReg', (121, 131))	('TP53', 'Gene', (18, 22))	('mitochondrial apoptosis pathway', 'Pathway', (136, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))	('cell lymphoma', 'Phenotype', 'HP:0012191', (37, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('MDM2', 'Gene', '4193', (187, 191))	('MDM2', 'Gene', (187, 191))	('mutant', 'Var', (23, 29))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (30, 50))
48506	31576173	Combination therapy of MDM2 inhibitors and bortezomib showed synergistic effects and sensitized tumor cells to either of the cytostatics, although they showed insensitivity to either of the cytostatics alone.	('sensitized', 'Reg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MDM2', 'Gene', '4193', (23, 27))	('MDM2', 'Gene', (23, 27))	('tumor', 'Disease', (96, 101))	('inhibitors', 'Var', (28, 38))	('bortezomib', 'Chemical', 'MESH:C400082', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('bortezomib', 'Gene', (43, 53))
48554	26861734	The specified concentration corresponds to the previously determined IC50 value of the three MPM cell lines: H28 (15 muM), H2052 (13 muM), and Meso4 (12 muM).	('muM', 'Gene', (133, 136))	('muM', 'Gene', '56925', (133, 136))	('muM', 'Gene', (117, 120))	('muM', 'Gene', '56925', (117, 120))	('H2052', 'Chemical', '-', (123, 128))	('muM', 'Gene', '56925', (153, 156))	('H28', 'Chemical', '-', (109, 112))	('Meso4', 'Chemical', '-', (143, 148))	('H2052', 'Var', (123, 128))	('muM', 'Gene', (153, 156))
48558	26861734	The 48- and 72-hour treatments with hlMSC-CM elicited significant reductions in cell proliferation of H28 (48 hours -74 %; 72 hours -76 %), H2052 (48 hours -62 %; 72 hours -64 %) and Meso4 (48 hours -35 %; 72 hours -55 %) relative to the nontreated cells (Fig.	('Meso4', 'Chemical', '-', (183, 188))	('hlMSC-CM', 'Var', (36, 44))	('H2052', 'Chemical', '-', (140, 145))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('H2052', 'Var', (140, 145))	('H28', 'Chemical', '-', (102, 105))	('reductions', 'NegReg', (66, 76))
48559	26861734	hlMSC-CM evoked significant reductions in cell viability in all tested cell lines: H28 (48 hours -69 %; 72 hours -81 %), H2052 (48 hours -25 %; 72 hours -25.3 %), Meso4 (48 hours -26.3 %; 72 hours -31 %) compared with the nontreated cells (Fig.	('cell viability', 'CPA', (42, 56))	('H28', 'Chemical', '-', (83, 86))	('Meso4', 'Chemical', '-', (163, 168))	('reductions', 'NegReg', (28, 38))	('H2052', 'Chemical', '-', (121, 126))	('hlMSC-CM', 'Var', (0, 8))
48560	26861734	In our previous work, we found cisplatin-resistant tumor spheres in H28, H2052 and Meso4 indicating the presence of putative cancer stem cells (CSCs), which may, in part, be responsible for drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('drug resistance', 'Phenotype', 'HP:0020174', (190, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('H2052', 'Chemical', '-', (73, 78))	('drug resistance', 'biological_process', 'GO:0009315', ('190', '205'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (51, 56))	('drug resistance', 'biological_process', 'GO:0042493', ('190', '205'))	('cisplatin-resistant', 'Var', (31, 50))	('H28', 'Chemical', '-', (68, 71))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Meso4', 'Chemical', '-', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
48568	26861734	Our results showed that hlMSC-CM is capable of fully eliminating the sphere-forming phenotype in H28 cells, and that this effect has a higher efficacy compared with twice the IC50 of cisplatin.	('sphere-forming phenotype', 'CPA', (69, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('eliminating', 'NegReg', (53, 64))	('H28', 'Chemical', '-', (97, 100))	('hlMSC-CM', 'Var', (24, 32))
48654	24868221	There were poorer outcomes in patients with sarcomatoid subtype (hazard ratio [HR], 3.973; confidence interval [CI], 0.854 to 18.451) and patients with biphasic subtype (HR, 10.777; CI, 1.182 to 98.216) compared to those with epithelioid subtype.	('poorer', 'NegReg', (11, 17))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (44, 63))	('sarcomatoid subtype', 'Disease', (44, 63))	('patients', 'Species', '9606', (30, 38))	('biphasic', 'Var', (152, 160))	('patients', 'Species', '9606', (138, 146))
48793	19079719	Countries implementing bans recorded reductions in asbestos use about twice as fast as those not adopting bans, for which our study period was probably too early to observe their full effects.	('asbestos use', 'MPA', (51, 63))	('asbestos', 'Chemical', 'MESH:D001194', (51, 59))	('reductions', 'NegReg', (37, 47))	('bans', 'Var', (23, 27))	('men', 'Species', '9606', (15, 18))
48813	31612092	An electrocardiogram showed SR, HF 95 bpm, bifascicular block, R/S envelope in V2, and T-negativation in V1.	('bifascicular block', 'Phenotype', 'HP:0011715', (43, 61))	('envelope', 'cellular_component', 'GO:0009274', ('67', '75'))	('T-negativation', 'Var', (87, 101))	('bifascicular block', 'Disease', (43, 61))	('bifascicular block', 'Disease', 'MESH:D006327', (43, 61))	('envelope', 'cellular_component', 'GO:0031975', ('67', '75'))	('R/S envelope', 'Var', (63, 75))
48834	31612092	"Next-generation sequencing" with the OCAv3 panel was used to detect mutations in tumor tissue in genes coding for the mTOR/p21 signaling pathway (TSC2 and PIK3R1), the NOTCH signaling pathway (NOTCH2), and the "G1/S DANN damage checkpoints" (CDKN2A and CDKN2B).	('CDKN2A', 'Gene', (243, 249))	('NOTCH', 'Gene', '4853', (169, 174))	('PIK3R1', 'Gene', (156, 162))	('tumor', 'Disease', (82, 87))	('CDKN2B', 'Gene', '1030', (254, 260))	('TSC2', 'Gene', '7249', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('NOTCH2', 'Gene', (194, 200))	('CDKN2A', 'Gene', '1029', (243, 249))	('mTOR', 'Gene', (119, 123))	('mutations', 'Var', (69, 78))	('TSC2', 'Gene', (147, 151))	('NOTCH', 'Gene', (194, 199))	('p21', 'Gene', (124, 127))	('p21', 'Gene', '644914', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PIK3R1', 'Gene', '5295', (156, 162))	('mTOR', 'Gene', '2475', (119, 123))	('NOTCH', 'Gene', (169, 174))	('CDKN2B', 'Gene', (254, 260))	('NOTCH', 'Gene', '4853', (194, 199))	('NOTCH2', 'Gene', '4853', (194, 200))
48835	31612092	Alterations in these signaling pathways are statistically significantly associated with pleural mesotheliomas.	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (88, 109))	('pleural mesotheliomas', 'Disease', (88, 109))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (72, 82))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (88, 109))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))
48863	30744695	The circulating biomarkers miR-132-3p, miR-126-3p, and miR-103a-3p were analyzed in a nested case-control study using plasma samples from 17 prediagnostic mesothelioma cases and 34 matched asbestos-exposed controls without a malignant disease.	('asbestos', 'Chemical', 'MESH:D001194', (189, 197))	('mesothelioma', 'Disease', (155, 167))	('miR-132-3p', 'Gene', (27, 37))	('miR-126-3p', 'Gene', '100302148', (39, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('malignant disease', 'Disease', 'MESH:D009369', (225, 242))	('miR-132-3p', 'Gene', '100302255', (27, 37))	('miR-126-3p', 'Gene', (39, 49))	('miR-103a-3p', 'Var', (55, 66))	('malignant disease', 'Disease', (225, 242))
48864	30744695	Using prediagnostic plasma samples collected in median 8.9 months prior the clinical diagnosis miR-132-3p, miR-126-3p, and miR-103a-3p revealed 0% sensitivity on a defined specificity of 98%.	('miR-132-3p', 'Gene', (95, 105))	('miR-126-3p', 'Gene', '100302148', (107, 117))	('miR-132-3p', 'Gene', '100302255', (95, 105))	('miR-126-3p', 'Gene', (107, 117))	('miR-103a-3p', 'Var', (123, 134))
48874	30744695	For the detection of malignant mesothelioma miR-16, miR-17, miR-30e-3p, miR-103a-3p, miR-126, miR-625-3p, miR-132-3p, and miR-486 were introduced as blood-based biomarkers.	('miR-132-3p', 'Gene', '100302255', (106, 116))	('miR-126', 'Gene', '406913', (85, 92))	('miR-486', 'Gene', '619554', (122, 129))	('miR-17', 'Gene', (52, 58))	('miR-126', 'Gene', (85, 92))	('miR-16', 'Gene', '51573', (44, 50))	('miR-17', 'Gene', '406952', (52, 58))	('miR-132-3p', 'Gene', (106, 116))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (21, 43))	('miR-486', 'Gene', (122, 129))	('miR-30e-3p', 'Var', (60, 70))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (21, 43))	('miR-625-3p', 'Var', (94, 104))	('miR-103a-3p', 'Var', (72, 83))	('miR-16', 'Gene', (44, 50))	('malignant mesothelioma', 'Disease', (21, 43))
48888	30744695	Individual miRNAs were analyzed using commercial TaqMan microRNA assays (Life Technologies) for miR-103a-3p (ID 000439), miR-125a (ID 000448), miR-132-3p (ID 000457), miR-146b-5p (ID 001097), miR-126-3p (ID 002228), and U6 snRNA (ID 001973) as described previously.	('ID 000448', 'Var', (131, 140))	('miR-126-3p', 'Gene', '100302148', (192, 202))	('miR-126-3p', 'Gene', (192, 202))	('miR-103a-3p (ID 000439', 'Var', (96, 118))	('ID 001973', 'Var', (230, 239))	('miR-146b-5p', 'Var', (167, 178))	('ID 000457', 'Var', (155, 164))	('miR-132-3p', 'Gene', (143, 153))	('miR-125a', 'Gene', '406910', (121, 129))	('ID 002228', 'Var', (204, 213))	('ID 001097', 'Var', (180, 189))	('miR-125a', 'Gene', (121, 129))	('miR-132-3p', 'Gene', '100302255', (143, 153))
48889	30744695	Normalization was performed with the 2- Ct method using miR-146b-5p, U6 snRNA, and miR-125a, as references for miR-132-3p, miR-126-3p, and miR-103a-3p, respectively.	('miR-126-3p', 'Gene', '100302148', (123, 133))	('miR-132-3p', 'Gene', '100302255', (111, 121))	('miR-126-3p', 'Gene', (123, 133))	('miR-103a-3p', 'Var', (139, 150))	('miR-125a', 'Gene', '406910', (83, 91))	('miR-132-3p', 'Gene', (111, 121))	('miR-125a', 'Gene', (83, 91))	('miR-146b-5p', 'Var', (56, 67))
48892	30744695	The median level of miR-132-3p was 0.015 (IQR 0.012-0.020) for mesothelioma cases and 0.016 (IQR 0.012-0.024) in the control group (Fig.	('miR-132-3p', 'Gene', (20, 30))	('mesothelioma', 'Disease', (63, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('miR-132-3p', 'Gene', '100302255', (20, 30))	('0.016', 'Var', (86, 91))
48895	30744695	The median level of miR-103a-3p was 282 (IQR 221-523) in mesothelioma cases and 471 (IQR 228-707) in the control group (Fig.	('mesothelioma', 'Disease', (57, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('miR-103a-3p', 'Var', (20, 31))
48897	30744695	The ROC analyses showed an AUC of 0.542 (95% CI 0.370-0.713) for miR-132a-3p, 0.614 (95% CI 0.439-0.789) for miR-126-3p, and 0.603 (95% CI 0.440-0.765) for miR-103a-3p (Fig.	('miR-132a-3p', 'Var', (65, 76))	('miR-126-3p', 'Gene', (109, 119))	('miR-103a-3p', 'Var', (156, 167))	('miR-126-3p', 'Gene', '100302148', (109, 119))
48898	30744695	Using maximum YI resulted in 71%, 59%, and 82% sensitivity and 47%, 72%, and 42% specificity for miR-132-3p, miR-126-3p, and miR-103a-3p, respectively (Table 1).	('miR-126-3p', 'Gene', (109, 119))	('miR-103a-3p', 'Var', (125, 136))	('miR-132-3p', 'Gene', '100302255', (97, 107))	('miR-132-3p', 'Gene', (97, 107))	('miR-126-3p', 'Gene', '100302148', (109, 119))
48900	30744695	Using a defined specificity of 98% none of the mesothelioma cases were detected by miR-132-3p and miR-126-3p in plasma, as well as miR-103a-3p in the cellular fraction of blood.	('miR-126-3p', 'Gene', '100302148', (98, 108))	('miR-126-3p', 'Gene', (98, 108))	('miR-132-3p', 'Gene', '100302255', (83, 93))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('miR-103a-3p', 'Var', (131, 142))	('miR-132-3p', 'Gene', (83, 93))	('mesothelioma', 'Disease', (47, 59))
48902	30744695	Originally, for miR-132-3p, miR-126-3p, and miR-103a-3p promising sensitivities of 86%, 61%, and 83%, and specificities of 73%, 74%, and 71%, respectively, were revealed for the discrimination of mesothelioma patients and asbestos-exposed controls.	('asbestos', 'Chemical', 'MESH:D001194', (222, 230))	('mesothelioma', 'Disease', (196, 208))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('miR-132-3p', 'Gene', '100302255', (16, 26))	('miR-126-3p', 'Gene', (28, 38))	('miR-103a-3p', 'Var', (44, 55))	('miR-126-3p', 'Gene', '100302148', (28, 38))	('patients', 'Species', '9606', (209, 217))	('miR-132-3p', 'Gene', (16, 26))
48904	30744695	Globally, miRNAs are down-regulated in cancer patients and the same trend could be observed for miR-132-3p, miR-126-3p, and miR-103a-3p in manifest mesothelioma.	('miR-103a-3p', 'Var', (124, 135))	('patients', 'Species', '9606', (46, 54))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('miR-132-3p', 'Gene', (96, 106))	('down-regulated', 'NegReg', (21, 35))	('miR-126-3p', 'Gene', '100302148', (108, 118))	('mesothelioma', 'Disease', (148, 160))	('miR-126-3p', 'Gene', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('miRNAs', 'Protein', (10, 16))	('miR-132-3p', 'Gene', '100302255', (96, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
48911	30744695	However, circulating miRNAs are described as generally suitable to predict prognosis and response to therapy and this might be also true for miR-132-3p, miR-126-3p, and miR-103a-3p.	('miR-103a-3p', 'Var', (169, 180))	('miR-132-3p', 'Gene', '100302255', (141, 151))	('predict', 'Reg', (67, 74))	('miR-132-3p', 'Gene', (141, 151))	('miR-126-3p', 'Gene', '100302148', (153, 163))	('miR-126-3p', 'Gene', (153, 163))
48920	30744695	Only three miRNAs were analyzed in this study, although miR-16, miR-17, and miR-486, miR-30e-3p, and miR-625-3p were also suggested as blood-based biomarkers for mesothelioma.	('miR-486', 'Gene', (76, 83))	('miR-625-3p', 'Var', (101, 111))	('miR-486', 'Gene', '619554', (76, 83))	('miR-16', 'Gene', (56, 62))	('mesothelioma', 'Disease', (162, 174))	('miR-16', 'Gene', '51573', (56, 62))	('miR-17', 'Gene', (64, 70))	('miR-30e-3p', 'Var', (85, 95))	('miR-17', 'Gene', '406952', (64, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))
48923	22426987	Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('epidermal growth factor receptor', 'Gene', '1956', (167, 199))	('EGFR', 'Gene', (201, 205))	('tyrosine kinase', 'Gene', (76, 91))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('167', '190'))	('tyrosine kinase', 'Gene', '7294', (76, 91))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (14, 37))	('mesothelioma', 'Disease', (25, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('EGFR', 'Gene', '1956', (201, 205))	('EGFR', 'molecular_function', 'GO:0005006', ('201', '205'))	('tyrosine kinase', 'Gene', (136, 151))	('mutations', 'Var', (92, 101))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('43', '66'))	('tyrosine kinase', 'Gene', '7294', (136, 151))	('epidermal growth factor receptor', 'Gene', (43, 75))	('epidermal growth factor receptor', 'Gene', '1956', (43, 75))	('cancer', 'Disease', (233, 239))	('epidermal growth factor receptor', 'Gene', (167, 199))
48924	22426987	The presence of certain somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene is associated with clinical response to TK inhibitors (TKI) in patients with lung adenocarcinoma.	('TK', 'Gene', '7294', (149, 151))	('lung adenocarcinoma', 'Disease', (171, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('TK', 'Gene', '7294', (134, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('tyrosine kinase', 'Gene', '7294', (49, 64))	('patients', 'Species', '9606', (157, 165))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('associated with', 'Reg', (97, 112))	('mutations', 'Var', (32, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('TK', 'Gene', '7294', (66, 68))	('tyrosine kinase', 'Gene', (49, 64))	('presence', 'Var', (4, 12))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))
48925	22426987	In this study we evaluated the status of somatic mutations in the entire TK domain of the EGFR gene by direct sequencing using early passage peritoneal mesothelioma cells, established cell lines as well as 33 peritoneal mesothelioma tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (220, 238))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (209, 232))	('mutations', 'Var', (49, 58))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (141, 164))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('mesothelioma tumor', 'Disease', (220, 238))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (220, 238))	('peritoneal mesothelioma', 'Disease', (209, 232))	('EGFR', 'Gene', (90, 94))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (141, 164))	('TK', 'Gene', '7294', (73, 75))	('peritoneal mesothelioma', 'Disease', (141, 164))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (209, 232))
48926	22426987	Sequence analysis of the EGFR TK domain revealed the presence of a silent polymorphism (c.2607G A, Q787Q) at exon 20 of both peritoneal mesothelioma cell lines as well as tumor specimens.	('TK', 'Gene', '7294', (30, 32))	('EGFR', 'Gene', (25, 29))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (125, 148))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Q787Q', 'Mutation', 'rs1050171', (99, 104))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (125, 148))	('c.2607G A', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('EGFR', 'Gene', '1956', (25, 29))	('peritoneal mesothelioma', 'Disease', (125, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
48929	22426987	Of the 33 peritoneal mesothelioma tumor samples analyzed none had an EGFR TKI sensitizing mutation and only one specimen showed an earlier reported somatic mutation at codon 850 in exon 21 of the EGFR gene.	('EGFR', 'Gene', (196, 200))	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('196', '200'))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (10, 33))	('TK', 'Gene', '7294', (74, 76))	('EGFR', 'Gene', (69, 73))	('mesothelioma tumor', 'Disease', (21, 39))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (21, 39))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (10, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('EGFR', 'Gene', '1956', (196, 200))	('mutation', 'Var', (90, 98))	('peritoneal mesothelioma', 'Disease', (10, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (21, 39))
48930	22426987	Our data show that patients with peritoneal mesothelioma do not harbor somatic mutations in the EGFR TK domain that would make them sensitive to EGFR TKI.	('TK', 'Gene', '7294', (101, 103))	('peritoneal mesothelioma', 'Disease', (33, 56))	('TK', 'Gene', '7294', (150, 152))	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', (96, 100))	('EGFR', 'Gene', '1956', (145, 149))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (33, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))	('EGFR', 'Gene', (145, 149))	('sensitive', 'Reg', (132, 141))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (33, 56))	('mutations', 'Var', (79, 88))	('EGFR', 'Gene', '1956', (96, 100))
48942	22426987	Some patients with lung cancer have mutations in the EGFR that make them very sensitive to treatment with EGFR TK inhibitors (TKI), such as erlotinib and gefitinib.	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('patients', 'Species', '9606', (5, 13))	('sensitive', 'MPA', (78, 87))	('TK', 'Gene', '7294', (126, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('mutations', 'Var', (36, 45))	('lung cancer', 'Disease', (19, 30))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('erlotinib', 'Chemical', 'MESH:D000069347', (140, 149))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (53, 57))	('gefitinib', 'Chemical', 'MESH:D000077156', (154, 163))	('TK', 'Gene', '7294', (111, 113))	('EGFR', 'Gene', (106, 110))
48943	22426987	The presence of activating mutations (especially deletion in exon 19 and missense mutation in exon 21) in the TK domain enhances the kinase activity and maintains the EGFR in a constitutively active form with tumor growth dependent on EGFR signaling.	('kinase activity', 'MPA', (133, 148))	('TK', 'Gene', '7294', (110, 112))	('activating', 'PosReg', (16, 26))	('tumor', 'Disease', (209, 214))	('missense mutation', 'Var', (73, 90))	('enhances', 'PosReg', (120, 128))	('EGFR', 'Gene', '1956', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('EGFR', 'Gene', (167, 171))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('kinase activity', 'molecular_function', 'GO:0016301', ('133', '148'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('maintains', 'Reg', (153, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('constitutively', 'MPA', (177, 191))	('EGFR', 'Gene', (235, 239))	('EGFR', 'Gene', '1956', (167, 171))	('deletion', 'Var', (49, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('235', '239'))
48945	22426987	However, mutation in the TK domain of the EGFR gene are not present in malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', (71, 101))	('EGFR', 'Gene', '1956', (42, 46))	('mutation in', 'Var', (9, 20))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (81, 101))	('EGFR', 'Gene', (42, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('TK', 'Gene', '7294', (25, 27))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (71, 101))
48947	22426987	However, Foster et al described the presence of somatic EGFR TK mutations in 9 of 29 (31%) patients with peritoneal mesothelioma.	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (105, 128))	('patients', 'Species', '9606', (91, 99))	('TK', 'Gene', '7294', (61, 63))	('EGFR', 'Gene', '1956', (56, 60))	('peritoneal mesothelioma', 'Disease', (105, 128))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('mutations', 'Var', (64, 73))	('presence', 'Reg', (36, 44))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (105, 128))
48950	22426987	All of these novel mutations were shown to activate the TK activity in a transfected cell line and were sensitive to the EGFR inhibitor erlotinib in vitro.	('activate', 'PosReg', (43, 51))	('EGFR', 'Gene', '1956', (121, 125))	('mutations', 'Var', (19, 28))	('EGFR', 'Gene', (121, 125))	('erlotinib', 'Chemical', 'MESH:D000069347', (136, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('TK', 'Gene', '7294', (56, 58))
48951	22426987	Given the potential clinical implications of these findings, we conducted this study to evaluate EGFR mutations/polymorphisms in the TK domain of early passage peritoneal mesothelioma cell cultures, in established malignant peritoneal mesothelioma cell lines and in peritoneal mesothelioma tumor samples by completing direct sequencing.	('peritoneal mesothelioma', 'Disease', (266, 289))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (214, 247))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (277, 295))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (266, 289))	('TK', 'Gene', '7294', (133, 135))	('EGFR', 'Gene', (97, 101))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (266, 289))	('mutations/polymorphisms', 'Var', (102, 125))	('peritoneal mesothelioma', 'Disease', (160, 183))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (224, 247))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('mesothelioma tumor', 'Disease', (277, 295))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (160, 183))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (224, 247))	('EGFR', 'Gene', '1956', (97, 101))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (160, 183))	('malignant peritoneal mesothelioma', 'Disease', (214, 247))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (277, 295))
48958	22426987	In addition, established peritoneal mesothelioma cell lines were also evaluated for EGFR TK mutations.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (25, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('TK', 'Gene', '7294', (89, 91))	('mutations', 'Var', (92, 101))	('EGFR', 'Gene', '1956', (84, 88))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (25, 48))	('peritoneal mesothelioma', 'Disease', (25, 48))	('EGFR', 'Gene', (84, 88))
48959	22426987	The patients whose tumor samples were used to determine somatic EGFR mutations were obtained from the archival files of the NCI.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('tumor', 'Disease', (19, 24))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('patients', 'Species', '9606', (4, 12))
48969	22426987	However, we found the commonly known single nucleotide polymorphism (SNP) c.2607G A (rs1050171, Q787Q glutamine, CAG to CAA) in exon 20 of all cell lines either in the heterozygous (GA, 57.2%) or the homozygous form (AA, 42.8%) (Table II and Fig.	('GA', 'Chemical', 'MESH:D005708', (182, 184))	('CAG', 'Chemical', '-', (113, 116))	('Q787Q glutamine', 'Var', (96, 111))	('glutamine', 'Chemical', 'MESH:D005973', (102, 111))	('rs1050171', 'Var', (85, 94))	('rs1050171', 'Mutation', 'rs1050171', (85, 94))	('Q787Q', 'Mutation', 'rs1050171', (96, 101))
48970	22426987	The other SNPs that were found in these cells included earlier reported c.2709T C (rs1140475, T903T, threonine, ACT to ACC) in exon 23, c.2284-60T C (rs10241451) and c.2062104C A (rs17337100) in the intronic region of the EGFR gene (Fig.	('c.2284-60T C (rs10241451', 'Var', (136, 160))	('rs1140475', 'Mutation', 'rs1140475', (83, 92))	('threonine', 'Chemical', 'MESH:D013912', (101, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('rs10241451', 'Mutation', 'rs10241451', (150, 160))	('T903T', 'Var', (94, 99))	('rs17337100', 'Mutation', 'rs17337100', (180, 190))	('EGFR', 'Gene', '1956', (222, 226))	('c.2062104C A (rs17337100', 'Var', (166, 190))	('T903', 'CellLine', 'CVCL:1002', (94, 98))	('rs17337100', 'Var', (180, 190))	('EGFR', 'Gene', (222, 226))
48971	22426987	The c.2062-104C A and c.2709T C were present in 13.3% and the c.2284-60T C in 46.6% of the peritoneal mesothelioma cell lines, respectively, in the heterozygous form.	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (91, 114))	('c.2062-104C A', 'Var', (4, 17))	('peritoneal mesothelioma', 'Disease', (91, 114))	('c.2284-60T C', 'Var', (62, 74))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (91, 114))	('c.2709T C', 'Var', (22, 31))
48974	22426987	We found that peritoneal mesothelioma cell lines having homozygous AA genotype for c.2607G A were completely resistant (IC50 >50 muM) to erlotinib while 5 out of the 7 cell lines with heterozygous GA genotype showed moderate sensitivity (IC50 <50 muM) to treatment with erlotinib although this is not in the clinically relevant dose range (Table II).	('c.2607G A', 'Var', (83, 92))	('muM', 'Gene', (129, 132))	('muM', 'Gene', (247, 250))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (14, 37))	('erlotinib', 'Chemical', 'MESH:D000069347', (270, 279))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (14, 37))	('erlotinib', 'Chemical', 'MESH:D000069347', (137, 146))	('resistant', 'NegReg', (109, 118))	('GA', 'Chemical', 'MESH:D005708', (197, 199))	('muM', 'Gene', '56925', (129, 132))	('muM', 'Gene', '56925', (247, 250))	('peritoneal mesothelioma', 'Disease', (14, 37))
48977	22426987	Our results show that none of the cell lines is highly sensitive to erlotinib indicating that absence of sensitizing mutations in the EGFR gene contributes towards resistance to TKI therapy.	('mutations', 'Var', (117, 126))	('EGFR', 'Gene', (134, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('TK', 'Gene', '7294', (178, 180))	('resistance', 'MPA', (164, 174))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('EGFR', 'Gene', '1956', (134, 138))
48981	22426987	Of the 33 specimens we found only one case with a single mutation in exon 21 at codon 850 (H850Y, CAT to TAT, c.2548C T) of the EGFR gene (Table III and Fig.	('TAT', 'Disease', 'None', (105, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('TAT', 'Disease', (105, 108))	('c.2548C T', 'Var', (110, 119))	('H850Y', 'Mutation', 'p.H850Y', (91, 96))	('CAT', 'molecular_function', 'GO:0004096', ('98', '101'))
48982	22426987	No other previously reported or novel EGFR mutations were found.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))
48984	22426987	The SNP c.2607G A was present in 91% of malignant mesothelioma cases.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (40, 62))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (40, 62))	('c.2607G A', 'Var', (8, 17))	('malignant mesothelioma', 'Disease', (40, 62))
48987	22426987	However, no such mutations are found in patients with pleural mesothelioma and clinical trials of EGFR TKI have no activity in this disease.	('EGFR', 'Gene', (98, 102))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (54, 74))	('pleural mesothelioma', 'Disease', (54, 74))	('patients', 'Species', '9606', (40, 48))	('TK', 'Gene', '7294', (103, 105))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('mutations', 'Var', (17, 26))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (54, 74))
48988	22426987	However, a recent report suggested that EGFR somatic mutations are frequent in peritoneal mesothelioma patients.	('peritoneal mesothelioma', 'Disease', (79, 102))	('frequent', 'Reg', (67, 75))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (79, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('somatic mutations', 'Var', (45, 62))	('EGFR', 'Gene', '1956', (40, 44))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (79, 102))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (103, 111))
48989	22426987	Since these findings could have clinical implications we conducted a comprehensive analysis of EGFR TK mutation analysis by direct sequencing of the entire TK domain of the EGFR gene using early passage peritoneal mesothelioma cell cultures, established peritoneal mesothelioma cell lines and tumor samples from patients with peritoneal mesothelioma.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (254, 277))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (203, 226))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('EGFR', 'Gene', '1956', (95, 99))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (203, 226))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('EGFR', 'Gene', '1956', (173, 177))	('TK', 'Gene', '7294', (100, 102))	('TK', 'Gene', '7294', (156, 158))	('patients', 'Species', '9606', (312, 320))	('peritoneal mesothelioma', 'Disease', (326, 349))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('peritoneal mesothelioma', 'Disease', (254, 277))	('mutation', 'Var', (103, 111))	('EGFR', 'Gene', (95, 99))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (326, 349))	('tumor', 'Disease', (293, 298))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (254, 277))	('peritoneal mesothelioma', 'Disease', (203, 226))	('EGFR', 'Gene', (173, 177))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (326, 349))
48991	22426987	The most commonly found polymorphism in peritoneal mesothelioma cases was c.2607G A, present in exon 20 of the EGFR gene.	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (40, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('EGFR', 'Gene', '1956', (111, 115))	('peritoneal mesothelioma', 'Disease', (40, 63))	('EGFR', 'Gene', (111, 115))	('c.2607G A', 'Var', (74, 83))	('found', 'Reg', (18, 23))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (40, 63))
48993	22426987	Zhang et al have shown the association of the AA genotype of c.2607G A with an increased risk of lung cancer, although they did not show any correlation between this SNP and somatic EGFR mutations found in those samples.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('association', 'Interaction', (27, 38))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('c.2607G A', 'Var', (61, 70))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
48995	22426987	A study by Sasaki et al has shown a weak association between the SNP (GA/AA genotype) and a worse outcome with gefitinib treatment in Japanese lung cancer patients.	('SNP', 'Var', (65, 68))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gefitinib', 'Chemical', 'MESH:D000077156', (111, 120))	('GA', 'Chemical', 'MESH:D005708', (70, 72))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('patients', 'Species', '9606', (155, 163))
48996	22426987	All of these findings indicate that this SNP may affect either the stability of the EGFR protein, the rate of translation, or possibly gene transcription.	('affect', 'Reg', (49, 55))	('SNP', 'Var', (41, 44))	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('rate of translation', 'MPA', (102, 121))	('EGFR', 'Gene', '1956', (84, 88))	('gene transcription', 'MPA', (135, 153))	('stability', 'MPA', (67, 76))	('EGFR', 'Gene', (84, 88))	('translation', 'biological_process', 'GO:0006412', ('110', '121'))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
48999	22426987	Only once case showed the presence of a mutation in exon 21 (H850Y) of the EGFR gene.	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('H850Y', 'Mutation', 'p.H850Y', (61, 66))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('H850Y', 'Var', (61, 66))
49000	22426987	Mutation at codon 850 has been reported previously in other cancers although the change in amino acid was different from what we found in our study.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
49001	22426987	Jia and Chen reported the presence of H850D mutation in one patient with adenosquamous carcinoma of the lung.	('patient', 'Species', '9606', (60, 67))	('H850D', 'Mutation', 'p.H850D', (38, 43))	('adenosquamous carcinoma of the lung', 'Disease', (73, 108))	('H850D', 'Var', (38, 43))	('adenosquamous carcinoma of the lung', 'Disease', 'MESH:D018196', (73, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
49002	22426987	The mutation coexisted with the silent SNP c.2607G A. Yang et al showed the presence of the H850R mutation together with the EGFR sensitizing mutation L858R in two patients with lung cancer.	('lung cancer', 'Disease', (178, 189))	('EGFR', 'Gene', '1956', (125, 129))	('L858R', 'Mutation', 'rs121434568', (151, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('H850R', 'Var', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('EGFR', 'Gene', (125, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('patients', 'Species', '9606', (164, 172))	('H850R', 'Mutation', 'p.H850R', (92, 97))
49003	22426987	The results of our study are in contrast to the report by Foster et al who described the presence of somatic EGFR mutations in 9 out of 29 cases with peritoneal mesothelioma.	('mutations', 'Var', (114, 123))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (150, 173))	('peritoneal mesothelioma', 'Disease', (150, 173))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (109, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (150, 173))
49004	22426987	However, our results are in agreement with the study by Perrone et al who found no EGFR mutations in 20 patients with malignant peritoneal mesothelioma.	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (104, 112))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (128, 151))	('malignant peritoneal mesothelioma', 'Disease', (118, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (118, 151))
49005	22426987	Perrone et al performed the direct sequencing only for exons 18-21 where the activating mutations of the EGFR gene are present, whereas we performed the DNA sequencing of the entire TK domain (exons 18-24) to exclude the presence of any novel mutation.	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', '1956', (105, 109))	('TK', 'Gene', '7294', (182, 184))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('EGFR', 'Gene', (105, 109))
49023	28969080	Also, D2-40 is a marker for lymphatic endothelium and derived carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('carcinomas', 'Disease', 'MESH:D002277', (62, 72))	('carcinomas', 'Disease', (62, 72))	('D2-40', 'Chemical', '-', (6, 11))	('D2-40', 'Var', (6, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
49049	28969080	Our study further determined the diagnostic performance of D2-40 for these subtypes and found the performance of D2-40 for diagnosing epithelioid MM and biphasic MM is better than that for sarcomatoid MM.	('biphasic MM', 'Disease', (153, 164))	('epithelioid MM', 'Disease', (134, 148))	('D2-40', 'Chemical', '-', (113, 118))	('sarcomatoid MM', 'Disease', 'MESH:C538614', (189, 203))	('D2-40', 'Chemical', '-', (59, 64))	('sarcomatoid MM', 'Disease', (189, 203))	('D2-40', 'Var', (113, 118))
49118	26257929	Inactivation of the tumour suppressor genes the retinoblastoma-associated (RB1) and TP53 proteins which have an effect on cell growth and proliferation, has not yet been described in MPM.	('retinoblastoma', 'Disease', 'MESH:D012175', (48, 62))	('retinoblastoma', 'Disease', (48, 62))	('cell', 'CPA', (122, 126))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('RB1', 'Gene', (75, 78))	('tumour', 'Disease', (20, 26))	('TP53', 'Gene', '7157', (84, 88))	('cell growth', 'biological_process', 'GO:0016049', ('122', '133'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (48, 62))	('effect', 'Reg', (112, 118))	('TP53', 'Gene', (84, 88))	('RB1', 'Gene', '5925', (75, 78))	('Inactivation', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
49167	26257929	Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%).	('toxicities', 'Disease', (14, 24))	('hypotension', 'Disease', 'MESH:D007022', (99, 110))	('back pain', 'Disease', (78, 87))	('back pain', 'Phenotype', 'HP:0003418', (78, 87))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (55, 70))	('hypotension', 'Disease', (99, 110))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (55, 70))	('SS1P', 'Chemical', 'MESH:C474515', (41, 45))	('hypoalbuminemia', 'Disease', (55, 70))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('SS1P', 'Var', (41, 45))	('hypotension', 'Phenotype', 'HP:0002615', (99, 110))	('pain', 'Phenotype', 'HP:0012531', (83, 87))	('back pain', 'Disease', 'MESH:D001416', (78, 87))
49197	26257929	A randomised phase II study of axitinib in combination with cisplatin/pemetrexed showed more grade 3/4 toxicity (neutropenia) in the axitinib group versus the chemotherapy only group.	('neutropenia', 'Disease', 'MESH:D009503', (113, 124))	('axitinib', 'Chemical', 'MESH:D000077784', (133, 141))	('neutropenia', 'Phenotype', 'HP:0001875', (113, 124))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('axitinib', 'Chemical', 'MESH:D000077784', (31, 39))	('toxicity', 'Disease', (103, 111))	('pemetrexed', 'Chemical', 'MESH:D000068437', (70, 80))	('axitinib', 'Var', (133, 141))	('neutropenia', 'Disease', (113, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
49202	26257929	Dysregulation of TNF production has been implicated in cancer.	('Dysregulation', 'Var', (0, 13))	('TNF', 'Gene', '7124', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TNF', 'Gene', (17, 20))	('TNF production', 'biological_process', 'GO:0032640', ('17', '31'))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
49209	26257929	BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('disrupts tumour vasculature', 'Disease', 'MESH:D019958', (63, 90))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('suppresses', 'NegReg', (95, 105))	('disrupts tumour vasculature', 'Disease', (63, 90))	('BNC105P', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
49210	26257929	In a phase II study in patients with progressive MPM after first line chemotherapy BNC105P was given intravenously until progression or toxicity.	('patients', 'Species', '9606', (23, 31))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('BNC105P', 'Var', (83, 90))	('MPM', 'Disease', (49, 52))
49212	26257929	The recent discovery of activating driver genomic alterations has resulted in a significant breakthrough in solid cancer therapy and has changed the treatment paradigm in subsets of patients with advanced cancers, among them, gastrointestinal stromal tumour (GIST), melanoma, and non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (280, 306))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('activating', 'PosReg', (24, 34))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (182, 190))	('GIST', 'Phenotype', 'HP:0100723', (259, 263))	('alterations', 'Var', (50, 61))	('non-small cell lung cancer', 'Disease', (280, 306))	('changed', 'Reg', (137, 144))	('cancer', 'Disease', (300, 306))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('melanoma', 'Disease', (266, 274))	('cancers', 'Disease', (205, 212))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (280, 306))	('gastrointestinal stromal tumour', 'Disease', (226, 257))	('gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (226, 257))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (226, 257))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (284, 306))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (114, 120))
49218	26257929	A study to determine the prevalence of somatic and germline mutations in the BAP1 opened recently and is recruiting patients.	('BAP1', 'Gene', '8314', (77, 81))	('patients', 'Species', '9606', (116, 124))	('BAP1', 'Gene', (77, 81))	('germline mutations', 'Var', (51, 69))
49230	26257929	Inactivation of somatic NF2 occurs in around 40 per cent of the patients with mesothelioma, leading to inactive merlin.	('inactive', 'MPA', (103, 111))	('merlin', 'Gene', (112, 118))	('patients', 'Species', '9606', (64, 72))	('NF2', 'Gene', (24, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('NF2', 'Gene', '4771', (24, 27))	('merlin', 'Gene', '4771', (112, 118))	('Inactivation', 'Var', (0, 12))	('mesothelioma', 'Disease', (78, 90))
49236	26257929	Epigenetic regulation of tumour suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('leads to', 'Reg', (142, 150))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('Epigenetic regulation', 'Var', (0, 21))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('decondensation', 'MPA', (84, 98))	('tumour', 'Disease', (25, 31))	('chromatin', 'cellular_component', 'GO:0000785', ('57', '66'))
49268	26257929	Almost doubling of the PFS was observed, with a median PFS of 98 days for the experimental arm and 59 days for the control arm with a PFS HR 0.53 (95% CI 0.31-0.90), favouring ADI-PEG20.	('ADI-PEG20', 'Var', (176, 185))	('PFS HR', 'Disease', 'MESH:D001919', (134, 140))	('PFS HR', 'Disease', (134, 140))
49271	26257929	ASS1 negative patients will be randomised to cisplatin/pemetrexed and ADI-PEG20 or cisplatin/pemetrexed alone.	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('pemetrexed', 'Chemical', 'MESH:D000068437', (93, 103))	('pemetrexed', 'Chemical', 'MESH:D000068437', (55, 65))	('ADI-PEG20', 'Var', (70, 79))	('ASS1', 'Gene', '445', (0, 4))	('patients', 'Species', '9606', (14, 22))	('ASS1', 'Gene', (0, 4))
49314	25756664	Excretion of 111In-amatuximab was primarily through the hepatobiliary system.	('hepatobiliary system', 'Disease', 'MESH:D004066', (56, 76))	('111In-amatuximab', 'Chemical', '-', (13, 29))	('hepatobiliary system', 'Disease', (56, 76))	('Excretion', 'MPA', (0, 9))	('Excretion', 'biological_process', 'GO:0007588', ('0', '9'))	('111In-amatuximab', 'Var', (13, 29))
49316	25756664	111In-Amatuximab had the highest TBR at 96-168 hours post-infusion in four patients and at 24 hours in two patients.	('TBR', 'MPA', (33, 36))	('111In-Amatuximab', 'Chemical', '-', (0, 16))	('111In-Amatuximab', 'Var', (0, 16))	('patients', 'Species', '9606', (75, 83))	('TBR', 'Chemical', '-', (33, 36))	('patients', 'Species', '9606', (107, 115))
49351	25756664	This study shows that 111In amatuximab has the best TBR mainly at 96-168 hours post-infusion as would be expected for an antibody imaging agent, but at 24 hours also, TBR was visually distinct.	('antibody', 'cellular_component', 'GO:0019814', ('121', '129'))	('111In', 'Var', (22, 27))	('antibody', 'molecular_function', 'GO:0003823', ('121', '129'))	('amatuximab', 'Chemical', 'MESH:C526187', (28, 38))	('TBR', 'Chemical', '-', (167, 170))	('111In', 'Chemical', 'MESH:C000615551', (22, 27))	('TBR', 'MPA', (52, 55))	('antibody', 'cellular_component', 'GO:0042571', ('121', '129'))	('TBR', 'Chemical', '-', (52, 55))	('antibody', 'cellular_component', 'GO:0019815', ('121', '129'))
49368	25756664	The increase in serum CA125 after amatuximab (including the dose of cold amatuximab) is likely due to amatuximab inhibiting the binding of CA125 to mesothelin on mesothelial cells.	('CA125', 'Gene', '94025', (22, 27))	('mesothelin', 'Gene', (148, 158))	('inhibiting', 'NegReg', (113, 123))	('CA125', 'Gene', (22, 27))	('CA125', 'Gene', (139, 144))	('amatuximab', 'Chemical', 'MESH:C526187', (34, 44))	('amatuximab', 'Chemical', 'MESH:C526187', (102, 112))	('binding', 'molecular_function', 'GO:0005488', ('128', '135'))	('amatuximab', 'Var', (102, 112))	('binding', 'Interaction', (128, 135))	('mesothelin', 'Gene', '10232', (148, 158))	('increase', 'PosReg', (4, 12))	('CA125', 'Gene', '94025', (139, 144))	('amatuximab', 'Chemical', 'MESH:C526187', (73, 83))
49399	25756664	Serum mesothelin and CA-125 levels were measured using the Mesomark assay (Fujirebio Diagnostics, Inc., Malvern, PA) and an automated commercial assay respectively, prior to and 14 days after 111In-amatuximab.	('mesothelin', 'Gene', (6, 16))	('mesothelin', 'Gene', '10232', (6, 16))	('111In-amatuximab', 'Var', (192, 208))	('111In-amatuximab', 'Chemical', '-', (192, 208))
49461	22919425	The sensitivity, specificity, positive and negative predictive values of cases with PK-like cells for the diagnosis of mesothelioma were calculated as follows: Sensitivity = True positive / (True positive + False negative) Specificity = True negative / (True negative + False positive) Positive predictive value = True positive /(True positive + False positive) Negative predictive value = True negative /(True negative + False negative) The two key features of PK-like cells were: pyknotic nuclei and orange cytoplasm [Figure 1].	('pyknotic', 'Var', (482, 490))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('cytoplasm', 'cellular_component', 'GO:0005737', ('509', '518'))	('orange cytoplasm', 'CPA', (502, 518))	('mesothelioma', 'Disease', (119, 131))
49635	32248600	We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR-199/214 is a distinctive feature of iron saccharate-induced sarcomatoid mesothelioma (SM).	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (190, 214))	('SM', 'Chemical', '-', (216, 218))	('iron saccharate', 'Chemical', 'MESH:D000077605', (166, 181))	('miR-199/214', 'Var', (126, 137))	('sarcomatoid mesothelioma', 'Disease', (190, 214))
49641	32248600	The overexpression of miR-199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells.	('ERK', 'Gene', '5594', (107, 110))	('overexpression', 'PosReg', (4, 18))	('ERK', 'Gene', (107, 110))	('miR-199/214', 'Var', (22, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('cellular proliferation', 'CPA', (43, 65))	('ERK', 'molecular_function', 'GO:0004707', ('107', '110'))	('promoted', 'PosReg', (34, 42))	('phosphorylation', 'MPA', (80, 95))	('rat', 'Species', '10116', (59, 62))	('mobility', 'CPA', (67, 75))	('Akt', 'Pathway', (99, 102))
49642	32248600	These results indicate that miR-199/214 may affect the aggressive biological behavior of SM.	('aggressive biological behavior', 'CPA', (55, 85))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (55, 85))	('SM', 'Chemical', '-', (89, 91))	('affect', 'Reg', (44, 50))	('miR-199/214', 'Var', (28, 39))
49645	32248600	Sarcomatoid mesothelioma (SM), which is a worse prognostic factor, overexpressed miR-199/214 in iron saccharate-induced MM.	('Sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (0, 24))	('SM', 'Chemical', '-', (26, 28))	('miR-199/214', 'Var', (81, 92))	('iron saccharate', 'Chemical', 'MESH:D000077605', (96, 111))	('Sarcomatoid mesothelioma', 'Disease', (0, 24))	('overexpressed', 'PosReg', (67, 80))
49647	32248600	Overexpression of miR-199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK.	('miR-199/214', 'Var', (18, 29))	('ERK', 'Gene', (103, 106))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('mobility', 'CPA', (63, 71))	('cellular proliferation', 'CPA', (39, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('promoted', 'PosReg', (30, 38))	('phosphorylation', 'MPA', (76, 91))	('Akt', 'Pathway', (95, 98))	('rat', 'Species', '10116', (55, 58))	('ERK', 'Gene', '5594', (103, 106))
49658	32248600	8  The deletion of the Cdkn2a/2b genomic locus in iron saccharate-induced MM was reproduced in one out of five cases of EM in a different group.	('Cdkn2a/2b', 'Gene', (23, 32))	('EM', 'Chemical', '-', (120, 122))	('Cdkn2a/2b', 'Gene', '25163', (23, 32))	('deletion', 'Var', (7, 15))	('iron saccharate', 'Chemical', 'MESH:D000077605', (50, 65))
49669	32248600	24  When Twist1 was detected in EM (7/17), BM (6/10) and SM (6/6) by IHC, a worse prognostic trend (P = 0.061) was observed in Twist1-positive MM, 25  suggesting the tumor-promotional role of Twist1 in human MM.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('human', 'Species', '9606', (202, 207))	('tumor', 'Disease', (166, 171))	('EM', 'Chemical', '-', (32, 34))	('Twist1-positive', 'Var', (127, 142))	('SM', 'Chemical', '-', (57, 59))
49670	32248600	In this study, overexpression of miR-199/214, which are transcriptional products of Twist1, promoted cellular proliferation and migration in an immortalized mesothelial cell line (MeT5A), indicating a biological role of miR in the pathogenesis of MM.	('rat', 'Species', '10116', (131, 134))	('cellular proliferation', 'CPA', (101, 123))	('overexpression', 'PosReg', (15, 29))	('rat', 'Species', '10116', (117, 120))	('miR-199/214', 'Var', (33, 44))	('promoted', 'PosReg', (92, 100))	('migration', 'CPA', (128, 137))	('pathogenesis', 'biological_process', 'GO:0009405', ('231', '243'))
49678	32248600	TaqMan probes for hsa-miR-214, hsa-miR-199a, hsa-miR-199a-3p, rno-let-7b and U6 SNRNA, as well as the TaqMan Universal Master Mix II and TaqMan MicroRNA RT Kit were purchased from Applied Biosystems.	('hsa-miR-199a-3p', 'Var', (45, 60))	('hsa-miR-214', 'Gene', '406996', (18, 29))	('hsa-miR-214', 'Gene', (18, 29))
49691	32248600	The blotted membranes were incubated with antibodies as follows: anti-Twist1 (1:500), anti-alpha-tubulin (1:3000), anti-Akt (1:1000), anti-phospho-Akt(Ser473) (1:1500), anti-p44/42 MAPK(ERK1/2) (1:2000), anti-phospho-p44/42 MAPK (Thr202/Tyr204) (1:2000), anti-p38 MAPK (1:1000), anti-phospho-p38 MAPK (Thr180/Tyr182) (1:1000), anti-PTEN (1:1500) and anti-beta-actin (1:5000).	('p38 MAPK', 'Gene', (292, 300))	('Tyr182', 'Chemical', '-', (309, 315))	('alpha-tubulin', 'Gene', '10376', (91, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('296', '300'))	('MAPK', 'molecular_function', 'GO:0004707', ('264', '268'))	('Thr202', 'Chemical', '-', (230, 236))	('MAPK', 'molecular_function', 'GO:0004707', ('224', '228'))	('p38 MAPK', 'Gene', '26416', (260, 268))	('Tyr204', 'Chemical', '-', (237, 243))	('p38 MAPK', 'Gene', '26416', (292, 300))	('1:1500', 'Var', (338, 344))	('ERK1', 'molecular_function', 'GO:0004707', ('186', '190'))	('Ser', 'cellular_component', 'GO:0005790', ('151', '154'))	('p38 MAPK', 'Gene', (260, 268))	('alpha-tubulin', 'Gene', (91, 104))	('Thr180', 'Chemical', '-', (302, 308))	('Ser473', 'Chemical', '-', (151, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))
49697	32248600	After validation of mature miR-214, 199-3p or 199-5p expression by quantitative RT-PCR (qRT-PCR), a dual pre-miR expression vector was constructed according to the manufacturer's protocol.	('miR-214', 'Gene', (27, 34))	('5p', 'Chemical', '-', (50, 52))	('199-5p', 'Var', (46, 52))	('pre', 'molecular_function', 'GO:0003904', ('105', '108'))
49714	32248600	We investigated miR-199/214, which showed a greater increase in SM than in EM.	('miR-199/214', 'Var', (16, 27))	('increase', 'PosReg', (52, 60))	('SM', 'Chemical', '-', (64, 66))	('EM', 'Chemical', '-', (75, 77))
49715	32248600	A profile plot demonstrated the overexpression of miR-199a-3p, -5p and 214-3p, which was confirmed by qRT-PCR analysis (Figure 1B).	('rat', 'Species', '10116', (22, 25))	('5p', 'Chemical', '-', (64, 66))	('overexpression', 'PosReg', (32, 46))	('miR-199a-3p', 'Var', (50, 61))
49717	32248600	In situ hybridization for miR-214-3p revealed a stronger signal in SM than in EM (Figure 1C).	('stronger', 'PosReg', (48, 56))	('SM', 'Chemical', '-', (67, 69))	('EM', 'Chemical', '-', (78, 80))	('miR-214-3p', 'Var', (26, 36))
49718	32248600	This result confirmed that SM exhibited overexpression of miR-214-3p, as detected by microarray and qRT-PCR.	('miR-214-3p', 'Var', (58, 68))	('overexpression', 'PosReg', (40, 54))	('SM', 'Chemical', '-', (27, 29))
49724	32248600	The expression levels of miR-214 and 199-3p were also upregulated in SM (Figure 2E).	('expression levels', 'MPA', (4, 21))	('upregulated', 'PosReg', (54, 65))	('199-3p', 'Var', (37, 43))	('SM', 'Chemical', '-', (69, 71))	('miR-214', 'Var', (25, 32))
49727	32248600	The plasmid vector, which expressed either miR-214 or miR-199, also did not demonstrate morphological changes or cellular proliferation in MeT5A (data not shown).	('miR-214', 'Var', (43, 50))	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (129, 132))	('miR-199', 'Var', (54, 61))
49728	32248600	After transfection of plasmid and selection by blasticidin, the expression levels of mature miR-214-3p and miR-199-3p were quantified by qRT-PCR (Figure 3A).	('miR-199-3p', 'Chemical', '-', (107, 117))	('miR-199-3p', 'Var', (107, 117))	('miR-214-3p', 'Var', (92, 102))	('blasticidin', 'Chemical', 'MESH:C004500', (47, 58))
49730	32248600	Determination of intracellular GSH concentration revealed that GSH was significantly elevated after transfection of miR-199/214 at days 2 and 3 (Figure 3G).	('GSH', 'Chemical', 'MESH:D005978', (31, 34))	('GSH', 'Chemical', 'MESH:D005978', (63, 66))	('GSH', 'MPA', (63, 66))	('transfection', 'Var', (100, 112))	('elevated', 'PosReg', (85, 93))	('miR-199/214', 'Var', (116, 127))	('rat', 'Species', '10116', (42, 45))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))
49731	32248600	The results of a random migration assay showed that miR-199/214 promoted mobility in MeT5A cells (Figure 3H).	('mobility in MeT5A cells', 'CPA', (73, 96))	('miR-199/214', 'Var', (52, 63))	('rat', 'Species', '10116', (27, 30))	('promoted', 'PosReg', (64, 72))
49732	32248600	Overexpression of miR-199/214 significantly increased the expression level of phospho-Akt (Ser473) (Figure 4A), while the expression level of PTEN was unchanged by miR-199/214 in MeT5A cells (Figure 4B).	('miR-199/214', 'Var', (18, 29))	('expression level', 'MPA', (58, 74))	('Ser473', 'Chemical', '-', (91, 97))	('increased', 'PosReg', (44, 53))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))
49733	32248600	The expression level of phospho-ERK (Thr202/Tyr204) was elevated significantly by miR-199/214 in MeT5A cells (Figure 4C).	('expression level', 'MPA', (4, 20))	('ERK', 'Gene', '5594', (32, 35))	('elevated', 'PosReg', (56, 64))	('Tyr204', 'Chemical', '-', (44, 50))	('ERK', 'Gene', (32, 35))	('miR-199/214', 'Var', (82, 93))	('ERK', 'molecular_function', 'GO:0004707', ('32', '35'))	('Thr202', 'Chemical', '-', (37, 43))
49734	32248600	The expression level of phospho-p38 (Thr180/Tyr182) was not altered significantly by miR-199/214 in MeT5A cells (Figure 4D).	('Thr180', 'Chemical', '-', (37, 43))	('p38', 'Gene', (32, 35))	('miR-199/214', 'Var', (85, 96))	('Tyr182', 'Chemical', '-', (44, 50))	('p38', 'Gene', '1432', (32, 35))
49737	32248600	These results implied that miR have an essential role in inducing the sarcomatoid phenotype, which is characterized by highly aggressive biological behavior.	('sarcomatoid', 'Disease', (70, 81))	('miR', 'Var', (27, 30))	('sarcomatoid', 'Disease', 'MESH:C538614', (70, 81))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (126, 156))	('inducing', 'PosReg', (57, 65))
49742	32248600	Twist1 suppresses E-cadherin transcriptionally in several epithelial cells 19  and miR-199/214 also inhibit the expression of E-cadherin translationally in mesothelial cells.	('Twist1', 'Gene', (0, 6))	('E-cadherin', 'Gene', '999', (18, 28))	('E-cadherin', 'Gene', (126, 136))	('E-cadherin', 'Gene', '999', (126, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('suppresses', 'NegReg', (7, 17))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('miR-199/214', 'Var', (83, 94))	('inhibit', 'NegReg', (100, 107))	('E-cadherin', 'Gene', (18, 28))	('expression', 'MPA', (112, 122))
49744	32248600	Hence, we investigated the functional roles of miR-199/214 in a mesothelial cell line and discovered that miR-199/214 promoted cellular proliferation and mobility (Figure 3).	('miR-199/214', 'Var', (106, 117))	('rat', 'Species', '10116', (143, 146))	('cellular proliferation', 'CPA', (127, 149))	('promoted', 'PosReg', (118, 126))	('mobility', 'CPA', (154, 162))
49747	32248600	38  Indeed, the detection of miR-214 copy number gain 39  and the enhancement of miR-214-, miR-199-3p- or -5p-induced metastases were observed in malignant melanoma.	('malignant melanoma', 'Disease', 'MESH:D008545', (146, 164))	('gain', 'PosReg', (49, 53))	('miR-214', 'Gene', (29, 36))	('metastases', 'Disease', (118, 128))	('5p', 'Chemical', '-', (107, 109))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('malignant melanoma', 'Phenotype', 'HP:0002861', (146, 164))	('miR-214-', 'Var', (81, 89))	('miR-199-3p-', 'Var', (91, 102))	('enhancement', 'PosReg', (66, 77))	('miR-199-3p', 'Chemical', '-', (91, 101))	('malignant melanoma', 'Disease', (146, 164))
49756	32248600	As iron causes oxidative stress, which might activate signal transduction pathways, the ERK and p38 pathways were examined (Figure S3).	('signal transduction pathways', 'Pathway', (54, 82))	('ERK', 'Gene', '5594', (88, 91))	('iron', 'Chemical', 'MESH:D007501', (3, 7))	('iron', 'Var', (3, 7))	('activate', 'PosReg', (45, 53))	('oxidative stress', 'MPA', (15, 31))	('ERK', 'Gene', (88, 91))	('p38', 'Gene', '1432', (96, 99))	('signal transduction', 'biological_process', 'GO:0007165', ('54', '73'))	('ERK', 'molecular_function', 'GO:0004707', ('88', '91'))	('p38', 'Gene', (96, 99))	('oxidative stress', 'Phenotype', 'HP:0025464', (15, 31))
49759	32248600	To characterize the relationship between miR-199/214 and oxidative stress, we measured glutathione and phosphorylation levels of ERK and p38 after transfection of miR-199/214 in MeT5A.	('miR-199/214', 'Var', (163, 174))	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('oxidative stress', 'Phenotype', 'HP:0025464', (57, 73))	('p38', 'Gene', '1432', (137, 140))	('ERK', 'Gene', '5594', (129, 132))	('ERK', 'Gene', (129, 132))	('phosphorylation levels', 'MPA', (103, 125))	('glutathione', 'Chemical', 'MESH:D005978', (87, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('p38', 'Gene', (137, 140))
49760	32248600	The overexpression of miR-199/214 increased cellular glutathione levels (Figure 3G) and phosphorylation of ERK but not p38 in MeT5A (Figure 4C,D).	('phosphorylation', 'MPA', (88, 103))	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('p38', 'Gene', '1432', (119, 122))	('miR-199/214', 'Var', (22, 33))	('cellular glutathione levels', 'MPA', (44, 71))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))	('p38', 'Gene', (119, 122))	('ERK', 'molecular_function', 'GO:0004707', ('107', '110'))	('increased', 'PosReg', (34, 43))
49761	32248600	These results suggest that miR-199/214 maintained the cellular redox status and suppressed the activation of the p38 pathways.	('p38', 'Gene', '1432', (113, 116))	('cellular redox status', 'MPA', (54, 75))	('p38', 'Gene', (113, 116))	('suppressed', 'NegReg', (80, 90))	('miR-199/214', 'Var', (27, 38))
49763	32248600	52  Furthermore, the absence of p38alpha MAP kinase, which was phosphorylated by isoproterenol, in cardiac fibroblast suppressed the isoproterenol-induced elevation of miR-214.	('miR-214', 'MPA', (168, 175))	('MAP', 'molecular_function', 'GO:0004239', ('41', '44'))	('isoproterenol', 'Chemical', 'MESH:D007545', (133, 146))	('p38alpha', 'Gene', '1432', (32, 40))	('isoproterenol', 'Chemical', 'MESH:D007545', (81, 94))	('p38alpha', 'Gene', (32, 40))	('absence', 'Var', (21, 28))	('elevation', 'PosReg', (155, 164))	('isoproterenol-induced', 'MPA', (133, 154))	('suppressed', 'NegReg', (118, 128))
49765	32248600	Although MDA-MB231 was positive for Twist1, the expression level of miR-199/214 was lower than in Twist1-low MCF7 in this study, as previously described.	('expression level', 'MPA', (48, 64))	('MDA-MB231', 'CellLine', 'CVCL:0062', (9, 18))	('miR-199/214', 'Var', (68, 79))	('MCF7', 'CellLine', 'CVCL:0031', (109, 113))	('lower', 'NegReg', (84, 89))
49766	32248600	56  In miR-199/214-transfected HeLa cells, enhanced cellular proliferation without morphological changes was observed (Figure S4C), indicating a similar biological effect of miR-199/214 as that observed in MeT5A cells.	('cellular proliferation', 'CPA', (52, 74))	('HeLa', 'CellLine', 'CVCL:0030', (31, 35))	('enhanced', 'PosReg', (43, 51))	('miR-199/214-transfected', 'Var', (7, 30))	('rat', 'Species', '10116', (68, 71))
49773	32248600	In conclusion, we demonstrate the overexpression of miR-199/214 in iron saccharate-induced SM in rats.	('miR-199/214', 'Var', (52, 63))	('rat', 'Species', '10116', (97, 100))	('overexpression', 'PosReg', (34, 48))	('rat', 'Species', '10116', (78, 81))	('rats', 'Species', '10116', (97, 101))	('rat', 'Species', '10116', (25, 28))	('iron saccharate', 'Chemical', 'MESH:D000077605', (67, 82))	('SM', 'Chemical', '-', (91, 93))
49774	32248600	miR-199/214 is associated with Twist1 expression and promotes cellular proliferation and migration.	('promotes', 'PosReg', (53, 61))	('Twist1', 'Gene', (31, 37))	('rat', 'Species', '10116', (78, 81))	('rat', 'Species', '10116', (92, 95))	('cellular proliferation', 'CPA', (62, 84))	('miR-199/214', 'Var', (0, 11))	('migration', 'CPA', (89, 98))
49780	32477360	Clinical diagnosis of FMF was suspected at the age of 25, while genetic analysis, performed at the age of 50, confirmed homozygosity for the M694I mutation in the MEFV gene.	('M694I', 'Var', (141, 146))	('MEFV', 'Gene', '4210', (163, 167))	('M694I', 'Mutation', 'rs28940578', (141, 146))	('MEFV', 'Gene', (163, 167))	('FMF', 'Disease', 'MESH:D010505', (22, 25))	('FMF', 'Disease', (22, 25))
49787	32477360	In such cases, intolerance to colchicine or its erratic intake may lead to long-term recurrent inflammation, which usually precedes the development of the tumor, while pre-existing leukopenia, as in our patient, could also be a factor promoting or accelerating the tumor progression.	('promoting', 'PosReg', (235, 244))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('lead to', 'Reg', (67, 74))	('tumor', 'Disease', (265, 270))	('pre', 'molecular_function', 'GO:0003904', ('168', '171'))	('colchicine', 'Chemical', 'MESH:D003078', (30, 40))	('accelerating', 'PosReg', (248, 260))	('inflammation', 'biological_process', 'GO:0006954', ('95', '107'))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('leukopenia', 'Disease', 'MESH:D007970', (181, 191))	('intolerance', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('leukopenia', 'Phenotype', 'HP:0001882', (181, 191))	('leukopenia', 'Disease', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('patient', 'Species', '9606', (203, 210))	('inflammation', 'Disease', (95, 107))
49804	32477360	In 2003, at the age of 50 the genetic test was performed in our Center and revealed M694I homozygous mutations of the exon 10 of the MEFV gene (mutation c.2082G>A).	('MEFV', 'Gene', (133, 137))	('M694I', 'Var', (84, 89))	('M694I', 'Mutation', 'rs28940578', (84, 89))	('MEFV', 'Gene', '4210', (133, 137))	('c.2082G>A', 'Mutation', 'rs28940578', (153, 162))
49806	32477360	The subtype analysis showed marked reduction in CD3+ T lymphocytes with normal ratio CD4/CD8; CD3+ was 853 mm3 (72.4%), CD4+ was 542 mm3 (46%), CD8+ was 271 mm3 (23 %), CD4/CD8 ratio was 2, CD19+ was 47 mm3 (4%), and CD16+ was 2% of the total lymphocytes.	('CD4', 'Gene', (120, 123))	('CD3+', 'Var', (94, 98))	('CD8', 'Gene', '925', (144, 147))	('CD3+', 'MPA', (48, 52))	('CD4', 'Gene', (85, 88))	('CD8', 'Gene', '925', (173, 176))	('CD8', 'Gene', (89, 92))	('CD4', 'Gene', '920', (169, 172))	('reduction', 'NegReg', (35, 44))	('CD19', 'Gene', (190, 194))	('CD4', 'Gene', (169, 172))	('CD8', 'Gene', (144, 147))	('CD16', 'Gene', '2214', (217, 221))	('CD8', 'Gene', (173, 176))	('CD19', 'Gene', '930', (190, 194))	('CD4', 'Gene', '920', (120, 123))	('CD8', 'Gene', '925', (89, 92))	('CD16', 'Gene', (217, 221))	('CD4', 'Gene', '920', (85, 88))
49821	32477360	CT-guided biopsy was performed and a histological diagnosis of epithelioid MST (Figures 1, 2) (phenotype: CK-AE1AE3+, CK5/6+, Calretinin+, Vimentin+, WT1+, BerEp4-) was established.	('WT1', 'Gene', (150, 153))	('epithelioid MST', 'Disease', (63, 78))	('Vimentin', 'cellular_component', 'GO:0045098', ('139', '147'))	('Calretinin', 'Gene', '794', (126, 136))	('WT1', 'Gene', '7490', (150, 153))	('CK5/6+', 'Var', (118, 124))	('Vimentin', 'cellular_component', 'GO:0045099', ('139', '147'))	('Vimentin', 'Gene', (139, 147))	('Vimentin', 'Gene', '7431', (139, 147))	('Calretinin', 'Gene', (126, 136))	('CK-AE1AE3+', 'Var', (106, 116))
49826	32477360	The mutant FMF gene (MEFV gene) is located on the short arm of chromosome 16 and is known to have pleiotropic effects.	('short arm', 'Phenotype', 'HP:0009824', (50, 59))	('mutant', 'Var', (4, 10))	('FMF', 'Disease', (11, 14))	('MEFV', 'Gene', (21, 25))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('FMF', 'Disease', 'MESH:D010505', (11, 14))	('MEFV', 'Gene', '4210', (21, 25))
49827	32477360	The MEFV gene codifies for a protein known as Pyrin/Marenostrin, whose mutation has been associated with a gain-of-function that enhances inflammation in response to trigger factors (PAMPs/DAMPs etc.).	('Pyrin', 'Gene', (46, 51))	('inflammation', 'Disease', (138, 150))	('mutation', 'Var', (71, 79))	('MEFV', 'Gene', (4, 8))	('Marenostrin', 'Gene', (52, 63))	('Marenostrin', 'Gene', '4210', (52, 63))	('enhances', 'PosReg', (129, 137))	('inflammation', 'biological_process', 'GO:0006954', ('138', '150'))	('MEFV', 'Gene', '4210', (4, 8))	('Pyrin', 'Gene', '4210', (46, 51))	('inflammation', 'Disease', 'MESH:D007249', (138, 150))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
49828	32477360	An association of MEFV mutations with some neoplasms (as multiple myeloma) has been reported in the literature [it has been speculated that MEFV can act as an onco-suppressor gene ], but is not confirmed.	('MEFV', 'Gene', '4210', (140, 144))	('association', 'Interaction', (3, 14))	('MEFV', 'Gene', (140, 144))	('myeloma', 'Disease', 'MESH:D009101', (66, 73))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('MEFV', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('neoplasms', 'Disease', 'MESH:D009369', (43, 52))	('myeloma', 'Disease', (66, 73))	('neoplasms', 'Disease', (43, 52))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('MEFV', 'Gene', '4210', (18, 22))
49839	32477360	Although the exact mechanism by which inflammation leads to cancer development is not well-known, in chronic inflammatory conditions, a combination of DNA repair abnormalities and inappropriate immune response may lead to, and promote, oncogenesis.	('abnormalities', 'Var', (162, 175))	('lead to', 'Reg', (214, 221))	('DNA repair', 'Gene', (151, 161))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('immune response', 'biological_process', 'GO:0006955', ('194', '209'))	('inflammation', 'biological_process', 'GO:0006954', ('38', '50'))	('cancer', 'Disease', (60, 66))	('oncogenesis', 'biological_process', 'GO:0007048', ('236', '247'))	('promote', 'PosReg', (227, 234))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('DNA repair', 'biological_process', 'GO:0006281', ('151', '161'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('inflammation', 'Disease', (38, 50))	('oncogenesis', 'CPA', (236, 247))
49840	32477360	Such mutations arising in chronic inflammation may give origin to malignant proliferations.	('inflammation', 'Disease', (34, 46))	('give origin', 'Reg', (51, 62))	('mutations', 'Var', (5, 14))	('inflammation', 'biological_process', 'GO:0006954', ('34', '46'))	('malignant proliferations', 'CPA', (66, 90))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))
50052	27975069	As shown in Figures 6(b) and 6(c), the percentage of CFSE-positive (nonproliferating) and granzyme B-positive cells in CD8+ lymphocytes was 35.2% in asbestos-exposed cultures with exogenous IL-2, which tended to be higher than that observed in cultures without IL-2, being 19.3% (p = 0.057).	('IL-2', 'molecular_function', 'GO:0005134', ('261', '265'))	('CD8', 'Gene', (119, 122))	('exogenous', 'Var', (180, 189))	('CD8', 'Gene', '925', (119, 122))	('asbestos', 'Chemical', 'MESH:D001194', (149, 157))	('granzyme B', 'Gene', (90, 100))	('IL-2', 'molecular_function', 'GO:0005134', ('190', '194'))	('granzyme B', 'Gene', '3002', (90, 100))
50074	27975069	Our present investigation demonstrated that the suppressed induction of CTLs upon exposure to asbestos is not attributed to IL-2 insufficiency, whereas addition of IL-2 improved the cytotoxicity of asbestos-exposed CD8+ lymphocytes, even though in an incomplete manner.	('CD8', 'Gene', '925', (215, 218))	('IL-2', 'molecular_function', 'GO:0005134', ('124', '128'))	('IL-2', 'Gene', (164, 168))	('insufficiency', 'Disease', (129, 142))	('IL-2', 'molecular_function', 'GO:0005134', ('164', '168'))	('asbestos', 'Chemical', 'MESH:D001194', (94, 102))	('addition', 'Var', (152, 160))	('cytotoxicity', 'Disease', (182, 194))	('asbestos', 'Chemical', 'MESH:D001194', (198, 206))	('improved', 'PosReg', (169, 177))	('cytotoxicity', 'Disease', 'MESH:D064420', (182, 194))	('CD8', 'Gene', (215, 218))	('insufficiency', 'Disease', 'MESH:D000309', (129, 142))
50077	25889843	BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma Malignant mesothelioma (MM) arises from mesothelial cells that line the pleural, peritoneal and pericardial surfaces.	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (79, 101))	('pleural', 'Disease', 'MESH:D010995', (151, 158))	('mesothelioma', 'Disease', (89, 101))	('BAP1', 'Gene', (0, 4))	('peritoneal malignant mesothelioma', 'Phenotype', 'HP:0100003', (45, 78))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (79, 101))	('pleural', 'Disease', (151, 158))	('mesothelioma', 'Disease', (66, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('BAP1', 'Gene', '8314', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('Malignant mesothelioma', 'Disease', (79, 101))	('mutation', 'Var', (5, 13))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (56, 78))
50081	25889843	Peritoneal MM display few copy number alterations, with most samples having less than 10 Mbp total changes, mostly through deletions and no high copy number amplification.	('Mbp', 'Gene', '4155', (89, 92))	('deletions', 'Var', (123, 132))	('Mbp', 'Gene', (89, 92))
50084	25889843	In one additional case, loss of the entire chromosome 3 leaves a non-functional copy of BAP1 carrying a rare nonsense germline variant, thus suggesting a potential genetic predisposition in this patient.	('loss', 'Var', (24, 28))	('non-functional', 'NegReg', (65, 79))	('patient', 'Species', '9606', (195, 202))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('BAP1', 'Gene', (88, 92))
50085	25889843	Finally, with targeted sequencing of BAP1 in 3 additional cases, we conclude that BAP1 is frequently altered through copy number losses (N = 3/12), mutations (N = 3/12) or both (N = 2/12) sometimes at a sub-clonal level.	('BAP1', 'Gene', (82, 86))	('mutations', 'Var', (148, 157))	('altered', 'Reg', (101, 108))	('copy number loss', 'Disease', (117, 133))	('copy number loss', 'Disease', 'MESH:D016388', (117, 133))
50090	25889843	One of the largest studies to date screened 53 primary pleural MM for genome-wide copy-number-aberrations (CNAs) and performed targeted sequencing of selected potential driver genes from the recurrent CNAs.	('pleural MM', 'Disease', 'MESH:D010995', (55, 65))	('copy-number-aberrations', 'Var', (82, 105))	('pleural MM', 'Disease', (55, 65))
50092	25889843	BRCA1 associated protein-1 (BAP1) located at the epicenter of 3p21.1 was inactivated by somatic alterations in 42% of all tumors.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('alterations', 'Var', (96, 107))	('BRCA1 associated protein-1', 'Gene', (0, 26))	('p21', 'Gene', (63, 66))	('BAP1', 'Gene', (28, 32))	('p21', 'Gene', '644914', (63, 66))	('inactivated', 'NegReg', (73, 84))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('BRCA1 associated protein-1', 'Gene', '8314', (0, 26))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
50120	25889843	To analyze the large deletion in sample AA2476T we performed the PCR amplification using the following primers: BAP142delF: AGCCAGCATGGAGATAAAGG and BAP142delR TGCCTCAAGGAGGAGGTAGA.	('BAP142delF', 'Var', (112, 122))	('AA2476T', 'Mutation', 'c.2476AA>T', (40, 47))	('BAP142delR', 'Var', (149, 159))
50121	25889843	The results of the analysis of the BAP1 mutation in AA2476T are presented in Additional file 2: Figure S1.	('AA2476T', 'Mutation', 'c.2476AA>T', (52, 59))	('AA2476T', 'Var', (52, 59))	('BAP1', 'Gene', (35, 39))
50122	25889843	To date, most genome-wide analysis of MM have used copy number (or CGH) arrays to identify potentially recurrent chromosomal alterations in the tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('chromosomal alterations', 'Var', (113, 136))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
50123	25889843	We analyzed 9 tumors using the Illumina CoreExome arrays, identifying high confidence copy number segments.	('copy number segments', 'Var', (86, 106))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
50125	25889843	There were no detectable copy number gains recurring in more than 2 samples across the 9 tumors analyzed and none of them were high-level amplifications (max LogR = 0.55).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('copy number gains', 'Var', (25, 42))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
50126	25889843	We identified five cytobands where copy number losses or strong loss of heterozygosity are present in 3 or more samples (Additional file 1: Table S3): 12q24.13 (N = 4), 3p21 (N = 3) and 3p14 (N = 3), 15q15.3 (N = 3) and 15q21.1 (N = 3).	('loss of heterozygosity', 'NegReg', (64, 86))	('p21', 'Gene', '644914', (170, 173))	('15q15.3', 'Var', (200, 207))	('3p14', 'Var', (186, 190))	('copy number loss', 'Disease', (35, 51))	('15q21.1', 'Var', (220, 227))	('p21', 'Gene', (170, 173))	('copy number loss', 'Disease', 'MESH:D016388', (35, 51))	('12q24.13', 'Var', (151, 159))
50132	25889843	We were able to identify between 47 and 133 mutations per tumor, of which 2 to 33 are non-silent (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (44, 53))
50133	25889843	With a median of 1.3 mutations per million base pairs, peritoneal MM has a much lower mutation rate than other adult solid tumors, and comparable to pediatric cancers, leukemias or endocrine cancers.	('pediatric cancers', 'Disease', 'MESH:D009369', (149, 166))	('mutation rate', 'MPA', (86, 99))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('leukemias', 'Phenotype', 'HP:0001909', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('pediatric cancers', 'Disease', (149, 166))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('leukemias or endocrine cancers', 'Disease', 'MESH:D004701', (168, 198))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('lower', 'NegReg', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('peritoneal MM', 'Disease', (55, 68))	('leukemias or endocrine cancers', 'Disease', (168, 198))	('mutations', 'Var', (21, 30))
50134	25889843	BAP1 was the only recurrently mutated gene, affecting 3 tumors through 2 nonsense mutations and one 42 nt frameshift.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAP1', 'Gene', (0, 4))	('affecting', 'Reg', (44, 53))	('nonsense mutations', 'Var', (73, 91))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
50135	25889843	The BAP1-K453* mutation has an allelic fraction of 48% in a tumor without BAP1 loss (AA2273T), indicating that one WT copy remains.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('K453*', 'SUBSTITUTION', 'None', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('K453*', 'Var', (9, 14))	('tumor', 'Disease', (60, 65))	('AA2273T', 'Mutation', 'c.2273AA>T', (85, 92))
50136	25889843	Similarly, BAP1-Q393* is identified in 12% of the sequencing reads consistent with the genetic heterogeneity of this tumor where a subclonal loss of 3p21 was observed (AA1844T - Additional file 2: Figure S2).	('p21', 'Gene', '644914', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('AA1844T', 'Mutation', 'c.1844AA>T', (168, 175))	('p21', 'Gene', (150, 153))	('Q393*', 'SUBSTITUTION', 'None', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Q393*', 'Var', (16, 21))
50138	25889843	Alternatively, both loss and mutations in this tumor may occur at a sub-clonal level.	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
50139	25889843	Overall, our results suggest that BAP1 is affected by concurrent copy number loss and mutations (2/7), mutation only (1/7) or loss only (3/7).	('mutations', 'Var', (86, 95))	('BAP1', 'Gene', (34, 38))	('affected', 'Reg', (42, 50))	('copy number loss', 'Disease', (65, 81))	('copy number loss', 'Disease', 'MESH:D016388', (65, 81))	('mutation', 'Var', (103, 111))
50141	25889843	In particular, we identified a loss of function variant in BAP1 (BAP1-Y44*) in the germline DNA of one patient (AA2463T).	('Y44*', 'Var', (70, 74))	('BAP1', 'Gene', (59, 63))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('AA2463T', 'Mutation', 'c.2463AA>T', (112, 119))	('patient', 'Species', '9606', (103, 110))	('Y44*', 'SUBSTITUTION', 'None', (70, 74))
50144	25889843	Inherited loss of function variants in BAP1 are known to increase susceptibility to melanoma, renal cell carcinomas and malignant mesothelioma.	('variants', 'Var', (27, 35))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (120, 142))	('loss of function', 'NegReg', (10, 26))	('renal cell carcinomas', 'Disease', (94, 115))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (120, 142))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (94, 115))	('malignant mesothelioma', 'Disease', (120, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (94, 115))	('BAP1', 'Gene', (39, 43))
50147	25889843	We were able to confirm in three samples the presence of BAP1-Q393*, K453* and I71fs at an allelic fraction of 20%, 51% and 20% respectively, consistent with the whole exome sequencing findings (Additional file 1: Table S6).	('I71fs', 'Mutation', 'p.I71fsX', (79, 84))	('K453*', 'SUBSTITUTION', 'None', (69, 74))	('Q393*', 'SUBSTITUTION', 'None', (62, 67))	('Q393*', 'Var', (62, 67))	('I71fs', 'Var', (79, 84))	('K453*', 'Var', (69, 74))
50148	25889843	We find additional BAP1 somatic mutations in two samples: at Q684* (50% allelic fraction) and A95fs (39% allelic fraction).	('Q684*', 'SUBSTITUTION', 'None', (61, 66))	('A95fs', 'Mutation', 'p.A95fsX', (94, 99))	('BAP1', 'Gene', (19, 23))	('Q684*', 'Var', (61, 66))	('A95fs', 'Var', (94, 99))
50151	25889843	Early cytogenetic and loss of heterozygosity (LOH) analyses of pleural MMs described deletions as the most common cytogenetic aberration, suggesting that the inactivation of tumor suppressor genes residing in these deleted chromosomal regions may be responsible for neoplastic transformation.	('tumor', 'Disease', (174, 179))	('pleural MMs', 'Disease', (63, 74))	('pleural MMs', 'Disease', 'MESH:D010995', (63, 74))	('inactivation', 'Var', (158, 170))	('tumor suppressor', 'biological_process', 'GO:0051726', ('174', '190'))	('deletions', 'Var', (85, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('174', '190'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
50152	25889843	Losses of 3p21 were described as a common alteration (13/23, 57%) in pleural MM twenty years ago and in a recent study, the BAP1 tumor suppressor gene at 3p21 was frequently affected by loss, mutations or both (22/53; 42%).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('pleural MM', 'Disease', 'MESH:D010995', (69, 79))	('p21', 'Gene', (11, 14))	('pleural MM', 'Disease', (69, 79))	('affected', 'Reg', (174, 182))	('p21', 'Gene', (155, 158))	('loss', 'NegReg', (186, 190))	('p21', 'Gene', '644914', (11, 14))	('p21', 'Gene', '644914', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Losses', 'Var', (0, 6))	('tumor', 'Disease', (129, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('mutations', 'Var', (192, 201))
50154	25889843	Furthermore, germline mutations of BAP1 in two families have also been shown to predispose to pleural MM and heterozygous BAP1-/+ mice are more susceptible to mesothelioma than their wild type littermate thus strongly implicating BAP1 as a central player in MM tumorigenesis,.	('mice', 'Species', '10090', (130, 134))	('pleural MM', 'Disease', 'MESH:D010995', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('predispose', 'Reg', (80, 90))	('susceptible', 'Reg', (144, 155))	('mesothelioma', 'Disease', (159, 171))	('pleural MM', 'Disease', (94, 104))	('germline mutations', 'Var', (13, 31))	('BAP1', 'Gene', (35, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (159, 171))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
50156	25889843	Five samples revealed deletions at 3p21 resulting in loss of one or two cancer genes (BAP1 and/or PBRM1) per sample.	('PBRM1', 'Gene', (98, 103))	('deletions', 'Var', (22, 31))	('PBRM1', 'Gene', '55193', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('p21', 'Gene', (36, 39))	('BAP1', 'Gene', (86, 90))	('loss', 'NegReg', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('p21', 'Gene', '644914', (36, 39))	('cancer', 'Disease', (72, 78))
50157	25889843	Further investigation by whole exome and targeted sequencing suggests that BAP1 is the most significant gene in this region as it is recurrently altered by somatic loss of function mutations in 5 tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('BAP1', 'Gene', (75, 79))	('altered', 'Reg', (145, 152))	('tumors', 'Disease', (196, 202))	('loss of function', 'NegReg', (164, 180))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('mutations', 'Var', (181, 190))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
50158	25889843	While BAP1 is a natural candidate driver in 3p21 given its somatic alterations in pleural MM, PBRM1 is another potential tumor suppressor in the region.	('PBRM1', 'Gene', '55193', (94, 99))	('p21', 'Gene', (45, 48))	('BAP1', 'Gene', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('p21', 'Gene', '644914', (45, 48))	('alterations', 'Var', (67, 78))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('pleural MM', 'Disease', 'MESH:D010995', (82, 92))	('PBRM1', 'Gene', (94, 99))	('pleural MM', 'Disease', (82, 92))
50159	25889843	Frequent inactivation PBRM1 by somatic alterations have been described for kidney clear cell carcinoma (92/227, 42%) based on exome sequencing of 7 and targeted sequencing of 257 tumor samples.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PBRM1', 'Gene', '55193', (22, 27))	('inactivation', 'NegReg', (9, 21))	('kidney clear cell carcinoma', 'Disease', (75, 102))	('alterations', 'Var', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (75, 102))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PBRM1', 'Gene', (22, 27))	('tumor', 'Disease', (179, 184))
50161	25889843	Thus, PBRM1 is less likely to be the most relevant gene in 3p21, except perhaps in tumor AA1968T where the 3p21 deletion specifically affects PBRM1 and not BAP1.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('affects', 'Reg', (134, 141))	('p21', 'Gene', (108, 111))	('tumor', 'Disease', (83, 88))	('deletion', 'Var', (112, 120))	('PBRM1', 'Gene', (6, 11))	('p21', 'Gene', '644914', (108, 111))	('PBRM1', 'Gene', '55193', (6, 11))	('PBRM1', 'Gene', '55193', (142, 147))	('PBRM1', 'Gene', (142, 147))	('AA1968T', 'Mutation', 'c.1968AA>T', (89, 96))	('BAP1', 'Gene', (156, 160))	('p21', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('p21', 'Gene', '644914', (60, 63))
50164	25889843	A recent study demonstrated that, in contrast to wild-type animals, CDKN2A loss is not required for tumorigenesis in BAP1+/- mice, They further demonstrated that BAP1 mediates Rb1 expression loss via epigenetic down-regulation independent of CDKN2A status.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('epigenetic', 'Var', (200, 210))	('Rb1', 'Gene', (176, 179))	('tumor', 'Disease', (100, 105))	('loss', 'NegReg', (191, 195))	('expression', 'MPA', (180, 190))	('mice', 'Species', '10090', (125, 129))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
50166	25889843	Thus, while the mouse model may recapitulate a typical tumor suppressor loss pattern, with one inherited variant and one subsequent somatic loss, it appears that alteration or loss of the second allele may not be required in the majority of sporadic peritoneal MMs.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('loss', 'NegReg', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('variant', 'Var', (105, 112))	('tumor', 'Disease', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('mouse', 'Species', '10090', (16, 21))
50170	25889843	Inactivation of BAP1 was previously identified as a common event in pleural MM but had never been described in peritoneal MM before.	('BAP1', 'Gene', (16, 20))	('pleural MM', 'Disease', 'MESH:D010995', (68, 78))	('Inactivation', 'Var', (0, 12))	('pleural MM', 'Disease', (68, 78))
50203	31714372	This disease class comprised a combination of three select systemic autoimmune diseases (SAIDs henceforth): systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma (coded in ICD-10 as M32, M04/M06, and M34, respectively).	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (144, 164))	('SLE', 'Disease', 'MESH:D008180', (138, 141))	('SLE', 'Disease', (138, 141))	('SLE', 'Phenotype', 'HP:0002725', (138, 141))	('scleroderma', 'Disease', (174, 185))	('arthritis', 'Phenotype', 'HP:0001369', (155, 164))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (144, 164))	('M04/M06', 'Var', (211, 218))	('systemic lupus erythematosus', 'Disease', (108, 136))	('RA', 'Disease', 'MESH:D001172', (166, 168))	('scleroderma', 'Disease', 'MESH:C543759', (174, 185))	('scleroderma', 'Phenotype', 'HP:0100324', (174, 185))	('autoimmune diseases', 'Disease', 'MESH:D001327', (68, 87))	('rheumatoid arthritis', 'Disease', (144, 164))	('autoimmune diseases', 'Disease', (68, 87))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (108, 136))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (68, 87))	('autoimmune disease', 'Phenotype', 'HP:0002960', (68, 86))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (108, 136))	('RA', 'Phenotype', 'HP:0001370', (166, 168))
50262	31714372	The results from the present study show the presence of pleural abnormalities is associated with lung cancer and asbestosis mortality.	('mortality', 'Disease', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('asbestosis', 'Disease', 'MESH:D001195', (113, 123))	('pleural abnormalities', 'Phenotype', 'HP:0002103', (56, 77))	('pleural abnormalities', 'Disease', 'MESH:D010995', (56, 77))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('pleural abnormalities', 'Disease', (56, 77))	('presence', 'Var', (44, 52))	('mortality', 'Disease', 'MESH:D003643', (124, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('asbestosis', 'Disease', (113, 123))	('lung cancer', 'Disease', (97, 108))	('associated', 'Reg', (81, 91))
50313	33228230	Other compounds identified in the Oenothera paradoxa extracts like quercetin or epigallocatechin-3-gallate inhibit cancer cell growth via the downregulation of anti-apoptotic factors (e.g., Bcl-2) and the induction of pro-apoptotic Bax, thus forcing cancer cells' death.	('Bax', 'Gene', (232, 235))	('quercetin', 'Chemical', 'MESH:D011794', (67, 76))	('Oenothera', 'Species', '3942', (34, 43))	('w', 'Chemical', 'MESH:D014414', (130, 131))	('epigallocatechin-3-gallate', 'Var', (80, 106))	('Bcl-2', 'Gene', '596', (190, 195))	('Bax', 'Gene', '581', (232, 235))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('downregulation', 'NegReg', (142, 156))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('death', 'Disease', 'MESH:D003643', (264, 269))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (80, 106))	('w', 'Chemical', 'MESH:D014414', (144, 145))	('anti-apoptotic', 'CPA', (160, 174))	('Bcl-2', 'molecular_function', 'GO:0015283', ('190', '195'))	('inhibit', 'NegReg', (107, 114))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (250, 256))	('Bcl-2', 'Gene', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cell growth', 'biological_process', 'GO:0016049', ('122', '133'))	('death', 'Disease', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
50436	33228230	On the basis of the ELISA assay, we detected a substantial decrease of the MMP-7 secretion by the MSTO-H211 and JU77 as a result of EPE treatment (Figure 6B).	('EPE', 'Chemical', '-', (132, 135))	('MMP-7', 'Gene', (75, 80))	('men', 'Species', '9606', (141, 144))	('secretion', 'biological_process', 'GO:0046903', ('81', '90'))	('MMP-7', 'molecular_function', 'GO:0004235', ('75', '80'))	('w', 'Chemical', 'MESH:D014414', (33, 34))	('JU77', 'Var', (112, 116))	('JU77', 'CellLine', 'CVCL:2536', (112, 116))	('MMP-7', 'Gene', '4316', (75, 80))	('decrease', 'NegReg', (59, 67))	('MSTO-H211', 'Gene', (98, 107))
50469	33228230	We postulate that the presence of PGG in the composition of our extract, even in the minor concentration, enriches the value of all biologically active compounds.	('enriches', 'PosReg', (106, 114))	('value of', 'MPA', (119, 127))	('presence', 'Var', (22, 30))	('PGG', 'Chemical', '-', (34, 37))	('PGG', 'Gene', (34, 37))
50535	31467759	The tumor showed diffuse and strong positivity in all three components for calretinin, CK 5/6, AE1/AE3, D2-40, CD10, CK5D3, vimentin, and focally EMA, which was supportive of a mesothelial phenotype (Figures 4(a)-4(g)).	('calretinin', 'Gene', (75, 85))	('AE3', 'Gene', (99, 102))	('CD10', 'molecular_function', 'GO:0004245', ('111', '115'))	('CK 5/6', 'Gene', '3852', (87, 93))	('vimentin', 'cellular_component', 'GO:0045099', ('124', '132'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('AE1', 'Gene', '6521', (95, 98))	('D2-40', 'Chemical', '-', (104, 109))	('CK 5/6', 'Gene', (87, 93))	('calretinin', 'Gene', '794', (75, 85))	('D2-40', 'Var', (104, 109))	('CD10', 'Gene', '4311', (111, 115))	('AE3', 'Gene', '6508', (99, 102))	('AE1', 'Gene', (95, 98))	('vimentin', 'Gene', '7431', (124, 132))	('CD10', 'Gene', (111, 115))	('vimentin', 'Gene', (124, 132))	('vimentin', 'cellular_component', 'GO:0045098', ('124', '132'))	('CK5D3', 'Var', (117, 122))
50544	31467759	Germline mutations in the BAP1 gene predispose patients to malignant mesothelioma, uveal melanoma, and other tumors.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('malignant mesothelioma', 'Disease', (59, 81))	('uveal melanoma', 'Disease', (83, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('predispose', 'Reg', (36, 46))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (59, 81))
50681	30813957	High Ktrans values, in a setting where Ktrans predominantly reflects blood flow, is however believed to improved drug delivery and treatment response, as observed in other tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('High', 'Var', (0, 4))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('improved', 'PosReg', (104, 112))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('drug delivery', 'CPA', (113, 126))	('Ktrans', 'MPA', (5, 11))	('Ktrans', 'Chemical', '-', (39, 45))	('treatment response', 'CPA', (131, 149))	('men', 'Species', '9606', (136, 139))	('Ktrans', 'Chemical', '-', (5, 11))
50767	23694968	Depletion of MMP-7 or inhibition of p38 activity abolishes MSLN-mediated PC motility and invasion.	('abolishes', 'NegReg', (49, 58))	('p38', 'Gene', '5594', (36, 39))	('PC', 'Phenotype', 'HP:0002894', (73, 75))	('MMP-7', 'molecular_function', 'GO:0004235', ('13', '18'))	('inhibition', 'NegReg', (22, 32))	('MSLN', 'Gene', '10232', (59, 63))	('MMP-7', 'Gene', (13, 18))	('p38', 'Gene', (36, 39))	('Depletion', 'Var', (0, 9))	('MSLN', 'Gene', (59, 63))	('MMP-7', 'Gene', '4316', (13, 18))	('activity', 'MPA', (40, 48))
50777	23694968	Furthermore, the co-expression of MUC16 and MSLN is strongly correlated with a poor prognosis and unfavorable patient outcome.	('MSLN', 'Gene', '10232', (44, 48))	('MUC16', 'Gene', '94025', (34, 39))	('MSLN', 'Gene', (44, 48))	('co-expression', 'Var', (17, 30))	('correlated', 'Reg', (61, 71))	('patient', 'Species', '9606', (110, 117))	('MUC16', 'Gene', (34, 39))
50783	23694968	Recent work suggests that MSLN overexpression promotes ovarian cancer and mesothelioma cell invasion by inducing MMP-7 or MMP-9.	('ovarian cancer', 'Disease', (55, 69))	('inducing', 'PosReg', (104, 112))	('MMP-7', 'Gene', (113, 118))	('MSLN', 'Gene', '10232', (26, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('MSLN', 'Gene', (26, 30))	('overexpression', 'Var', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('MMP-7', 'molecular_function', 'GO:0004235', ('113', '118'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('MMP-7', 'Gene', '4316', (113, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('MMP-9', 'molecular_function', 'GO:0004229', ('122', '127'))	('MMP-9', 'Gene', '4318', (122, 127))	('promotes', 'PosReg', (46, 54))	('mesothelioma', 'Disease', (74, 86))	('MMP-9', 'Gene', (122, 127))
50816	23694968	Moreover, MUC16 silencing abrogated the enhanced MSLN-mediated pancreatic cancer invasion (Fig.	('pancreatic cancer', 'Disease', (63, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('MUC16', 'Gene', '94025', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MSLN', 'Gene', '10232', (49, 53))	('abrogated', 'NegReg', (26, 35))	('silencing', 'Var', (16, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('MSLN', 'Gene', (49, 53))	('enhanced', 'PosReg', (40, 48))	('MUC16', 'Gene', (10, 15))
50833	23694968	In addition, incubation with the ERK specific inhibitor PD98059 suppressed both the phosphorylation of MSLN-mediated ERK and MMP-7 protein expression (supplementary Fig.	('MMP-7', 'Gene', '4316', (125, 130))	('ERK', 'Gene', (117, 120))	('ERK', 'Gene', '5594', (117, 120))	('suppressed', 'NegReg', (64, 74))	('ERK', 'Gene', '5594', (33, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('protein', 'Protein', (131, 138))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('PD98059', 'Var', (56, 63))	('ERK', 'Gene', (33, 36))	('MSLN', 'Gene', (103, 107))	('MSLN', 'Gene', '10232', (103, 107))	('MMP-7', 'Gene', (125, 130))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))	('MMP-7', 'molecular_function', 'GO:0004235', ('125', '130'))	('PD98059', 'Chemical', 'MESH:C093973', (56, 63))	('phosphorylation', 'MPA', (84, 99))
50845	23694968	However, some studies suggest that this is attributed to hypomethylation of the MSLN promoter region and its upstream enhancer containing a transcription enhancer factor (TEF-1) dependent MCAT motif.	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('MCAT', 'Gene', '27349', (188, 192))	('MCAT', 'Gene', (188, 192))	('TEF-1', 'Gene', (171, 176))	('hypomethylation', 'Var', (57, 72))	('TEF-1', 'Gene', '7874', (171, 176))	('MSLN', 'Gene', '10232', (80, 84))	('MSLN', 'Gene', (80, 84))
50855	23694968	Importantly, MSLN expression correlates with MMP-7 production and increased cell invasive capability in ovarian cancer.	('increased', 'PosReg', (66, 75))	('ovarian cancer', 'Disease', (104, 118))	('MSLN', 'Gene', '10232', (13, 17))	('MSLN', 'Gene', (13, 17))	('MMP-7', 'molecular_function', 'GO:0004235', ('45', '50'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('MMP-7', 'Gene', (45, 50))	('cell invasive capability', 'CPA', (76, 100))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MMP-7', 'Gene', '4316', (45, 50))	('expression', 'Var', (18, 28))
50857	23694968	Additionally, MSLN silencing resulted in the reduction of mesothelioma, ovarian, and pancreatic tumor cell invasiveness.	('pancreatic tumor', 'Disease', 'MESH:D010190', (85, 101))	('reduction of mesothelioma', 'Disease', (45, 70))	('ovarian', 'Disease', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('silencing', 'Var', (19, 28))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (85, 101))	('MSLN', 'Gene', '10232', (14, 18))	('pancreatic tumor', 'Disease', (85, 101))	('MSLN', 'Gene', (14, 18))	('reduction of mesothelioma', 'Disease', 'MESH:D008654', (45, 70))
50876	23694968	Moreover, treatment with the p38 MAPK inhibitor SB203580 abrogates the p38 MAPK phosphorylation induced by the MSLN-MUC16 molecular interaction without altering total p38 MAPK levels.	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('MUC16', 'Gene', '94025', (116, 121))	('p38', 'Gene', '5594', (29, 32))	('p38', 'Gene', '5594', (167, 170))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('SB203580', 'Chemical', 'MESH:C093642', (48, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('p38', 'Gene', (29, 32))	('abrogates', 'NegReg', (57, 66))	('p38', 'Gene', (71, 74))	('SB203580', 'Var', (48, 56))	('MUC16', 'Gene', (116, 121))	('MSLN', 'Gene', '10232', (111, 115))	('MSLN', 'Gene', (111, 115))	('p38', 'Gene', (167, 170))	('p38', 'Gene', '5594', (71, 74))
50890	23694968	The forward (F) and reverse (R) primers were as follows: MMP-2, F-TCTCCTGACATTGACCTTGGC and R-CAAGGTGCTGGCTGAGTAGATC; MMP-7, F-TCCAACCTATGGAAATGGAGA and R-GGAGTGGAGGAACAGTGCTT; MMP-9, F-ACGTGACCTATGACATCCTGCAGT and R-TTGTATCCGGCAAACTGGCTCCTT; GAPDH, F-CCACCCATGGCAAATTCCATGGCA, R-TCTAGACGGCAGGTCAGGTCCACC.	('GAPDH', 'Gene', (243, 248))	('MMP-2', 'Gene', (57, 62))	('MMP-7', 'Gene', '4316', (118, 123))	('MMP-2', 'molecular_function', 'GO:0004228', ('57', '62'))	('MMP-7', 'molecular_function', 'GO:0004235', ('118', '123'))	('MMP-2', 'Gene', '4313', (57, 62))	('MMP-9', 'molecular_function', 'GO:0004229', ('177', '182'))	('MMP-9', 'Gene', (177, 182))	('F-CCACCCATGGCAAATTCCATGGCA', 'Var', (250, 276))	('MMP-9', 'Gene', '4318', (177, 182))	('GAPDH', 'Gene', '2597', (243, 248))	('MMP-7', 'Gene', (118, 123))
50895	23694968	Western blotting assays were performed as previously described and stained with antibodies for MUC16, MSLN, MMP-7, MMP-9, beta-actin, or signaling proteins including ERK1/2, p-ERK1/2 (Thr202/Tyr204), Akt, p-Akt (Ser473), p38 MAPK, and p-p38 MAPK (Thr180/Tyr182) (Cell Signaling Technology, Danvers, MA).	('Akt', 'Gene', '207', (207, 210))	('Akt', 'Gene', '207', (200, 203))	('ERK1', 'molecular_function', 'GO:0004707', ('176', '180'))	('p-ERK1/2', 'Var', (174, 182))	('MSLN', 'Gene', (102, 106))	('p38', 'Gene', '5594', (237, 240))	('Signaling', 'biological_process', 'GO:0023052', ('268', '277'))	('Thr180', 'Chemical', '-', (247, 253))	('p38', 'Gene', '5594', (221, 224))	('MMP-7', 'Gene', '4316', (108, 113))	('ERK1', 'molecular_function', 'GO:0004707', ('166', '170'))	('MMP-9', 'Gene', '4318', (115, 120))	('MSLN', 'Gene', '10232', (102, 106))	('MMP-9', 'Gene', (115, 120))	('beta-actin', 'Gene', (122, 132))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('MUC16', 'Gene', '94025', (95, 100))	('MMP-7', 'molecular_function', 'GO:0004235', ('108', '113'))	('Thr202', 'Chemical', '-', (184, 190))	('Tyr182', 'Chemical', '-', (254, 260))	('Ser', 'cellular_component', 'GO:0005790', ('212', '215'))	('p38', 'Gene', (237, 240))	('MAPK', 'molecular_function', 'GO:0004707', ('225', '229'))	('MAPK', 'molecular_function', 'GO:0004707', ('241', '245'))	('MMP-9', 'molecular_function', 'GO:0004229', ('115', '120'))	('p38', 'Gene', (221, 224))	('Akt', 'Gene', (207, 210))	('beta-actin', 'Gene', '728378', (122, 132))	('Akt', 'Gene', (200, 203))	('MUC16', 'Gene', (95, 100))	('MMP-7', 'Gene', (108, 113))	('Ser473', 'Chemical', '-', (212, 218))	('Tyr204', 'Chemical', '-', (191, 197))
50908	33381446	Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes.	('MPM', 'Chemical', '-', (103, 106))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('regulation', 'MPA', (71, 81))	('Epigenetic modifications', 'Var', (0, 24))
50911	33381446	In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.	('MPM', 'Disease', (176, 179))	('MPM', 'Chemical', '-', (176, 179))	('epigenetic alterations', 'Var', (48, 70))
50917	33381446	Common markers of carcinogenic processes include overexpression of growth factors such as VEGF, inactivating mutations of tumor suppressor genes (BAP1, CDKN2A, NF2, and TP53), extensive chromosomal deletions, and epigenetic alterations, which are essential for genetic abnormalities in malignant mesothelioma ( Table 1 ).	('tumor suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('TP53', 'Gene', '7157', (169, 173))	('NF2', 'Gene', (160, 163))	('tumor', 'Disease', (122, 127))	('malignant mesothelioma', 'Disease', (286, 308))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('genetic abnormalities', 'Disease', 'MESH:D030342', (261, 282))	('VEGF', 'Gene', '7422', (90, 94))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (286, 308))	('carcinogenic', 'Disease', (18, 30))	('genetic abnormalities', 'Disease', (261, 282))	('CDKN2A', 'Gene', (152, 158))	('VEGF', 'Gene', (90, 94))	('chromosomal deletions', 'Var', (186, 207))	('inactivating mutations', 'Var', (96, 118))	('carcinogenic', 'Disease', 'MESH:D063646', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('TP53', 'Gene', (169, 173))	('overexpression', 'PosReg', (49, 63))	('CDKN2A', 'Gene', '1029', (152, 158))	('BAP1', 'Gene', (146, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('epigenetic alterations', 'Var', (213, 235))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (286, 308))	('NF2', 'Gene', '4771', (160, 163))
50924	33381446	However, unlike other cancer types, active genetic mutation types such as epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are not well understood in MPM.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('74', '97'))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (114, 123))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('epidermal growth factor receptor', 'Gene', '1956', (74, 106))	('cancer', 'Disease', (22, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('MPM', 'Chemical', '-', (174, 177))	('lung adenocarcinoma', 'Disease', (127, 146))	('epidermal growth factor receptor', 'Gene', (74, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
50925	33381446	However, inactivating mutations of multiple tumor suppressor genes have been identified.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('inactivating mutations', 'Var', (9, 31))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))
50926	33381446	The most frequent tumor suppressor gene mutation in MPM is an inactivating mutation of CDKN2A (cyclin-dependent kinase inhibitor 2A gene), which occurs in approximately 70% or more MPM cases.	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('95', '128'))	('CDKN2A', 'Gene', '1029', (87, 93))	('tumor', 'Disease', (18, 23))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (95, 131))	('MPM', 'Chemical', '-', (52, 55))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (95, 131))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('112', '128'))	('inactivating mutation', 'Var', (62, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('MPM', 'Chemical', '-', (181, 184))	('CDKN2A', 'Gene', (87, 93))
50930	33381446	When inactivating CDKN2A mutations render the pl6 and pl4 proteins nonfunctional, pRB and p53 lose their ability to regulate the cell cycle, leading to constitutive cell growth.	('p53', 'Gene', (90, 93))	('cell growth', 'biological_process', 'GO:0016049', ('165', '176'))	('nonfunctional', 'MPA', (67, 80))	('cell cycle', 'CPA', (129, 139))	('mutations', 'Var', (25, 34))	('ability', 'MPA', (105, 112))	('pl6', 'Gene', (46, 49))	('CDKN2A', 'Gene', (18, 24))	('leading to', 'Reg', (141, 151))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))	('proteins', 'Protein', (58, 66))	('pl6', 'Gene', '11070', (46, 49))	('pRB', 'Gene', '5925', (82, 85))	('regulate', 'MPA', (116, 124))	('pRB', 'Gene', (82, 85))	('CDKN2A', 'Gene', '1029', (18, 24))	('lose', 'NegReg', (94, 98))	('p53', 'Gene', '7157', (90, 93))	('constitutive cell growth', 'CPA', (152, 176))
50933	33381446	Inactivating mutations in NF2 are reported in approximately 40-50% of MPMs.	('NF2', 'Gene', '4771', (26, 29))	('MPM', 'Chemical', '-', (70, 73))	('Inactivating mutations', 'Var', (0, 22))	('MPMs', 'Disease', (70, 74))	('NF2', 'Gene', (26, 29))
50934	33381446	NF2 encodes the Merlin protein, and deletion of the Merlin protein results in constant yes-associated protein (YAP) activation by Hippo pathway inactivation.	('inactivation', 'NegReg', (144, 156))	('NF2', 'Gene', (0, 3))	('Merlin', 'Gene', (16, 22))	('deletion', 'Var', (36, 44))	('Merlin', 'Gene', '4771', (16, 22))	('YAP', 'Gene', '10413', (111, 114))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('Hippo pathway', 'Pathway', (130, 143))	('yes-associated protein', 'Gene', (87, 109))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('NF2', 'Gene', '4771', (0, 3))	('YAP', 'Gene', (111, 114))	('activation', 'PosReg', (116, 126))	('yes-associated protein', 'Gene', '10413', (87, 109))	('Merlin', 'Gene', (52, 58))	('Merlin', 'Gene', '4771', (52, 58))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
50936	33381446	Merlin negatively regulates mTOR, and deletion of Merlin leads to mTOR signaling activation.	('mTOR', 'Gene', '2475', (28, 32))	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('mTOR', 'Gene', (66, 70))	('Merlin', 'Gene', (50, 56))	('mTOR', 'Gene', (28, 32))	('mTOR', 'Gene', '2475', (66, 70))	('Merlin', 'Gene', '4771', (50, 56))	('activation', 'PosReg', (81, 91))	('regulates', 'Reg', (18, 27))	('Merlin', 'Gene', '4771', (0, 6))	('deletion', 'Var', (38, 46))	('Merlin', 'Gene', (0, 6))
50937	33381446	BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on the short arm of chromosome 3, and the overall frequency of BAP1 alterations, including single-nucleotide variants, small indels, several exons to whole gene deletions, and structural variants, is reported to be approximately 57% in MPMs.	('small indels', 'Var', (188, 200))	('BRCA1-associated protein 1', 'Gene', (0, 26))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('single-nucleotide variants', 'Var', (160, 186))	('BAP1', 'Gene', (28, 32))	('MPM', 'Chemical', '-', (305, 308))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('tumor', 'Disease', (39, 44))	('alterations', 'Var', (137, 148))	('BRCA1-associated protein 1', 'Gene', '8314', (0, 26))	('short arm', 'Phenotype', 'HP:0009824', (76, 85))
50938	33381446	Germline mutations in BAP1 are reported in familial intraocular/cutaneous malignant melanoma.	('Germline mutations', 'Var', (0, 18))	('familial intraocular', 'Disease', (43, 63))	('reported', 'Reg', (31, 39))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (64, 92))	('familial intraocular', 'Disease', 'MESH:D009798', (43, 63))	('BAP1', 'Gene', (22, 26))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
50939	33381446	Similar mutations occur in familial MPM, drawing attention to the relationship between BAP1 and MPM.	('MPM', 'Chemical', '-', (96, 99))	('familial MPM', 'Disease', (27, 39))	('occur', 'Reg', (18, 23))	('mutations', 'Var', (8, 17))	('MPM', 'Chemical', '-', (36, 39))
50941	33381446	Multiple noncontiguous minute deletions in 3p21 carrying BAP1, SETD2, and PBRM1 and fusion transcripts caused by gene fusions including 3p21 region and NF2 have been reported.	('3p21 region', 'Gene', (136, 147))	('PBRM1', 'Gene', '55193', (74, 79))	('deletions', 'Var', (30, 39))	('NF2', 'Gene', (152, 155))	('SETD2', 'Gene', '29072', (63, 68))	('SETD2', 'Gene', (63, 68))	('NF2', 'Gene', '4771', (152, 155))	('BAP1', 'Gene', (57, 61))	('PBRM1', 'Gene', (74, 79))
50942	33381446	In a study, 2.4% of mesothelioma patients were diagnosed with microsatellite instability based on whole exome sequencing data, which revealed somatic mutations in the repair genes MSH2, MSH6, MLH1, PMS2, EXO1, POLD1, and POLE.	('POLD1', 'Gene', (210, 215))	('POLD1', 'Gene', '5424', (210, 215))	('mesothelioma', 'Disease', (20, 32))	('MLH1', 'Gene', '4292', (192, 196))	('patients', 'Species', '9606', (33, 41))	('MLH1', 'Gene', (192, 196))	('PMS2', 'Gene', '5395', (198, 202))	('MSH6', 'Gene', '2956', (186, 190))	('EXO1', 'Gene', '9156', (204, 208))	('MSH6', 'Gene', (186, 190))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('mutations', 'Var', (150, 159))	('PMS2', 'Gene', (198, 202))	('MSH2', 'Gene', (180, 184))	('MSH2', 'Gene', '4436', (180, 184))	('EXO1', 'Gene', (204, 208))
50944	33381446	These changes significantly affect gene regulation and expression as they occur in various cellular processes including differentiation, development, and tumorigenesis.	('affect', 'Reg', (28, 34))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('development', 'CPA', (137, 148))	('gene regulation', 'MPA', (35, 50))	('expression', 'MPA', (55, 65))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
50947	33381446	Indeed, transcriptionally silencing tumor suppressor genes causes tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('transcriptionally silencing', 'Var', (8, 35))	('tumor', 'Disease', (66, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('causes', 'Reg', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (36, 41))
50948	33381446	Studies analyzing DNA methylation indicate that silencing tumor suppressor genes through site-specific DNA hypermethylation and genome-wide hypomethylation are observed in MPM.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('103', '123'))	('hypermethylation', 'Var', (107, 123))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('MPM', 'Disease', (172, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('MPM', 'Chemical', '-', (172, 175))	('silencing', 'NegReg', (48, 57))
50950	33381446	Approximately 387 genes (6.3%) were hypermethylated in MPM in comparison with 544 genes (8.8%) in lung adenocarcinomas.	('MPM', 'Chemical', '-', (55, 58))	('hypermethylated', 'Var', (36, 51))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('lung adenocarcinomas', 'Disease', (98, 118))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (98, 118))	('MPM', 'Disease', (55, 58))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (98, 118))
50951	33381446	These results show that epithelial-type MPM with less methylation tends to have longer survival rates.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('epithelial-type MPM', 'Var', (24, 43))	('MPM', 'Chemical', '-', (40, 43))	('longer', 'PosReg', (80, 86))	('less', 'NegReg', (49, 53))	('survival rates', 'CPA', (87, 101))
50952	33381446	Hypermethylation of three genes (TMEM30B, KAZALD1, and MAPK13) distinguish MPM from adenocarcinoma.	('KAZALD1', 'Gene', '81621', (42, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('MPM', 'Disease', (75, 78))	('MAPK13', 'Gene', (55, 61))	('TMEM30B', 'Gene', '161291', (33, 40))	('Hypermethylation', 'Var', (0, 16))	('TMEM30B', 'Gene', (33, 40))	('MPM', 'Chemical', '-', (75, 78))	('KAZALD1', 'Gene', (42, 49))	('MAPK13', 'Gene', '5603', (55, 61))	('adenocarcinoma', 'Disease', (84, 98))	('distinguish', 'Reg', (63, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))
50955	33381446	This report showed that methylation status is significantly related with asbestos body burden and patient survival.	('patient', 'Species', '9606', (98, 105))	('related', 'Reg', (60, 67))	('asbestos', 'Chemical', 'MESH:D001194', (73, 81))	('asbestos body', 'Phenotype', 'HP:0011002', (73, 86))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('methylation status', 'Var', (24, 42))
50957	33381446	Differential methylation levels between MPMs and controls were observed mainly in the immune system-related genes.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('immune system-related genes', 'Gene', (86, 113))	('methylation levels', 'MPA', (13, 31))	('MPM', 'Chemical', '-', (40, 43))	('MPMs', 'Var', (40, 44))	('Differential', 'Reg', (0, 12))
50958	33381446	The gene showing the most hypomethylated single-CpG was FOXK1.	('FOXK1', 'Gene', '221937', (56, 61))	('single-CpG', 'Var', (41, 51))	('FOXK1', 'Gene', (56, 61))
50964	33381446	Gene expression is controlled by loosening and compacting DNA wrapped around core histones (H2A, H2B, H3, and H4) through histone modification, three major types of which are known.	('H2A', 'Protein', (92, 95))	('histone modification', 'biological_process', 'GO:0016570', ('122', '142'))	('histone', 'Var', (122, 129))	('H2B, H3', 'Gene', '8349', (97, 104))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('core', 'cellular_component', 'GO:0019013', ('77', '81'))	('Gene expression', 'MPA', (0, 15))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
50968	33381446	Histone H3K9 (histone H3 at lysine 9) and H3K27 methylation are associated with transcriptional repression, while H3K4, H3K36, or H3K79 methylations are linked with gene activation.	('associated', 'Reg', (64, 74))	('H3K4', 'Protein', (114, 118))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('methylation', 'Var', (48, 59))	('H3K36', 'Protein', (120, 125))	('Histone H3K9', 'Protein', (0, 12))	('H3K79', 'Var', (130, 135))	('H3K27', 'Protein', (42, 47))	('transcriptional repression', 'MPA', (80, 106))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
50984	33381446	This finding could provide a novel therapeutic approach against malignancies with BAP1 mutation.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('BAP1', 'Gene', (82, 86))	('mutation', 'Var', (87, 95))	('malignancies', 'Disease', (64, 76))
50988	33381446	observed somatic mutations of the histone methyltransferase family genes SETDB1, SETD5, ASH1L, PRDM2, and KMT2D, the histone demethylase gene KDM2B, and the histone acetyltransferase gene CREBBP in MPMs.	('SETDB1', 'Gene', '9869', (73, 79))	('ASH1L', 'Gene', (88, 93))	('ASH1L', 'Gene', '55870', (88, 93))	('KDM2B', 'Gene', (142, 147))	('PRDM2', 'Gene', (95, 100))	('SETD5', 'Gene', '55209', (81, 86))	('PRDM2', 'Gene', '7799', (95, 100))	('KMT2D', 'Gene', (106, 111))	('CREBBP', 'Gene', (188, 194))	('KDM2B', 'Gene', '84678', (142, 147))	('SETD5', 'Gene', (81, 86))	('KMT2D', 'Gene', '8085', (106, 111))	('MPM', 'Chemical', '-', (198, 201))	('SETDB1', 'Gene', (73, 79))	('CREBBP', 'Gene', '1387', (188, 194))	('mutations', 'Var', (17, 26))
50997	33381446	Mammalian SWI/SNF complexes are composed of 12-15 subunits, and mutations in subunit genes including ARID1A, SMARCA4, ARID1B, ARID2, and PBRM1 occur across a wide spectrum of human cancers.	('human', 'Species', '9606', (175, 180))	('ARID1A', 'Gene', (101, 107))	('Mammalian', 'Species', '9606', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('occur', 'Reg', (143, 148))	('ARID1B', 'Gene', '57492', (118, 124))	('PBRM1', 'Gene', (137, 142))	('ARID1B', 'Gene', (118, 124))	('PBRM1', 'Gene', '55193', (137, 142))	('ARID2', 'Gene', '196528', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('ARID1A', 'Gene', '8289', (101, 107))	('cancers', 'Disease', (181, 188))	('ARID2', 'Gene', (126, 131))	('SMARCA4', 'Gene', (109, 116))	('SMARCA4', 'Gene', '6597', (109, 116))
50998	33381446	In MPM, we found frequent multiple minute simultaneous biallelic deletions on chromosome 3p21.	('biallelic deletions', 'Var', (55, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('MPM', 'Disease', (3, 6))	('MPM', 'Chemical', '-', (3, 6))
50999	33381446	The top four frequently altered genes are associated with epigenetic modifications: BAP1, SETD2, PBRM1, and SMARCC1.	('BAP1', 'Gene', (84, 88))	('SETD2', 'Gene', (90, 95))	('altered', 'Reg', (24, 31))	('epigenetic modifications', 'Var', (58, 82))	('PBRM1', 'Gene', '55193', (97, 102))	('PBRM1', 'Gene', (97, 102))	('SMARCC1', 'Gene', (108, 115))	('SETD2', 'Gene', '29072', (90, 95))	('SMARCC1', 'Gene', '6599', (108, 115))
51004	33381446	Loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF complexes and impairs cancer and primary cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('impairs cancer', 'Disease', (82, 96))	('ARID1B', 'Gene', (8, 14))	('SWI/SNF complexes', 'Protein', (60, 77))	('destabilizes', 'NegReg', (47, 59))	('ARID1A', 'Gene', '8289', (18, 24))	('ARID1A', 'Gene', (18, 24))	('impairs cancer', 'Disease', 'MESH:D009369', (82, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('Loss', 'Var', (0, 4))	('ARID1B', 'Gene', '57492', (8, 14))
51010	33381446	It is reported that increased programmed death-ligand 1 (PD-L1) expression is associated with downregulated miRNAs, including miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c.	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (64, 74))	('miRNAs', 'MPA', (108, 114))	('miR-200c', 'Gene', '406985', (169, 177))	('miR-15b', 'Gene', '406949', (126, 133))	('ligand', 'molecular_function', 'GO:0005488', ('47', '53'))	('miR-200c', 'Gene', (169, 177))	('PD-L1', 'Gene', (57, 62))	('miR-193a-3p', 'Var', (143, 154))	('miR-16', 'Gene', (135, 141))	('miR-16', 'Gene', '51573', (135, 141))	('downregulated', 'NegReg', (94, 107))	('miR-195', 'Gene', (156, 163))	('miR-195', 'Gene', '406971', (156, 163))	('miR-15b', 'Gene', (126, 133))
51015	33381446	Recent insights about epigenetic mechanisms and dysregulated gene expression in MPM provide new opportunities with therapeutically challenging MPM.	('dysregulated gene', 'Var', (48, 65))	('MPM', 'Disease', (80, 83))	('MPM', 'Chemical', '-', (80, 83))	('MPM', 'Disease', (143, 146))	('MPM', 'Chemical', '-', (143, 146))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
51022	33381446	Further, PD-L1 is a spontaneously occurring factor that diminishes the anti-tumor immune response, and its expression is associated with poor prognosis in mesothelioma.	('mesothelioma', 'Disease', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('diminishes', 'NegReg', (56, 66))	('tumor', 'Disease', (76, 81))	('expression', 'MPA', (107, 117))	('immune response', 'biological_process', 'GO:0006955', ('82', '97'))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('PD-L1', 'Var', (9, 14))
51032	33381446	These studies have confirmed that combination therapy with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies results in an ORR of 26 ~ 29% and a DCR of 50 ~ 68% in patients with recurrent MPM.	('DCR', 'MPA', (138, 141))	('ORR', 'MPA', (116, 119))	('CTLA-4', 'Gene', '1493', (64, 70))	('patients', 'Species', '9606', (157, 165))	('combination', 'Interaction', (34, 45))	('MPM', 'Disease', (181, 184))	('anti-PD-1/PD-L1', 'Var', (75, 90))	('CTLA-4', 'Gene', (64, 70))	('MPM', 'Chemical', '-', (181, 184))
51041	32659970	Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model.	('NCI-H28', 'Chemical', '-', (214, 221))	('Mero-25', 'Chemical', '-', (191, 198))	('colony formation capabilities', 'CPA', (115, 144))	('formation', 'biological_process', 'GO:0009058', ('122', '131'))	('proliferation', 'CPA', (100, 113))	('IST-Mes2', 'Chemical', '-', (200, 208))	('Mero-14', 'Chemical', '-', (182, 189))	('caspase', 'CPA', (150, 157))	('migration', 'CPA', (89, 98))	('depletion', 'NegReg', (76, 85))	('gene', 'Var', (71, 75))	('activities', 'MPA', (158, 168))
51045	32659970	We showed that IPZ could have effects similar to those observed following RAN gene silencing.	('IPZ', 'Chemical', 'MESH:C568452', (15, 18))	('gene silencing', 'biological_process', 'GO:0016458', ('78', '92'))	('RAN', 'Gene', (74, 77))	('IPZ', 'Var', (15, 18))	('RAN', 'Gene', '5901', (74, 77))
51051	32659970	However, gene deregulation could also be an epiphenomenon, i.e., the consequence of phenotypic alterations not truly driving the process of tumorigenesis (these deregulated genes could be defined as "passenger genes" (PGs)).	('deregulation', 'Var', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('PGs', 'Chemical', '-', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
51065	32659970	Therefore, in the following paragraphs we will describe the main statistically significant results obtained with the phenotypic assays after gene silencing of the remaining candidate CDGs (ASS1, EIF4G1, IGF2BP3, GALNT7, RAN, and THBS2).	('THBS2', 'Gene', '7058', (229, 234))	('EIF4G1', 'Gene', '1981', (195, 201))	('GALNT7', 'Gene', (212, 218))	('EIF4G1', 'Gene', (195, 201))	('EIF4', 'cellular_component', 'GO:0008304', ('195', '199'))	('RAN', 'Gene', '5901', (220, 223))	('IGF2BP3', 'Gene', '10643', (203, 210))	('CDGs', 'Chemical', '-', (183, 187))	('gene silencing', 'biological_process', 'GO:0016458', ('141', '155'))	('GALNT7', 'Gene', '51809', (212, 218))	('IGF2BP3', 'Gene', (203, 210))	('THBS2', 'Gene', (229, 234))	('gene silencing', 'Var', (141, 155))	('ASS1', 'Gene', (189, 193))	('RAN', 'Gene', (220, 223))	('ASS1', 'Gene', '445', (189, 193))
51071	32659970	Thus, MeT-5A, Mero-14, and IST-Mes2 were further evaluated following EIF4G1 gene silencing.	('gene silencing', 'biological_process', 'GO:0016458', ('76', '90'))	('IST-Mes2', 'Chemical', '-', (27, 35))	('Mero-14', 'Chemical', '-', (14, 21))	('gene', 'Var', (76, 80))	('EIF4G1', 'Gene', '1981', (69, 75))	('EIF4G1', 'Gene', (69, 75))	('EIF4', 'cellular_component', 'GO:0008304', ('69', '73'))
51075	32659970	EIF4G1 depletion also caused a statistically significant increase of caspases 3 and 7 activity in all cell lines (ranging between 1.4- and 1.6-fold) with the exception of IST-Mes2 (Figure 4).	('IST-Mes2', 'Chemical', '-', (171, 179))	('activity', 'MPA', (86, 94))	('EIF4G1', 'Gene', '1981', (0, 6))	('EIF4G1', 'Gene', (0, 6))	('depletion', 'Var', (7, 16))	('increase', 'PosReg', (57, 65))	('EIF4', 'cellular_component', 'GO:0008304', ('0', '4'))
51081	32659970	Most of the assays were found not affected by gene silencing of IGF2BP3 (Supplementary A and Supplementary Materials Figures S13-S17).	('IGF2BP3', 'Gene', '10643', (64, 71))	('IGF2BP3', 'Gene', (64, 71))	('gene silencing', 'biological_process', 'GO:0016458', ('46', '60'))	('gene silencing', 'Var', (46, 60))
51090	32659970	As illustrated in Figure 7, RAN depletion also strongly impaired the capability of colony formation of all MPM cell lines, with Mero-14 being the most affected (-98%, p = 0.0065) (Figure 7).	('RAN', 'Gene', (28, 31))	('depletion', 'Var', (32, 41))	('RAN', 'Gene', '5901', (28, 31))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('Mero-14', 'Chemical', '-', (128, 135))	('colony formation', 'CPA', (83, 99))	('impaired', 'NegReg', (56, 64))
51099	32659970	Thus, we assayed IPZ in the same cell lines reported before with the expectation of eliciting an inhibition of proliferation to a similar extent to that observed following RAN gene-silencing.	('gene-silencing', 'biological_process', 'GO:0016458', ('176', '190'))	('gene-silencing', 'Var', (176, 190))	('RAN', 'Gene', '5901', (172, 175))	('IPZ', 'Chemical', 'MESH:C568452', (17, 20))	('RAN', 'Gene', (172, 175))
51106	32659970	In term of comparison, we employed cisplatin on the same cell lines, and we found that MMP1 cells were more sensitive to IPZ than cisplatin and that the combination of IPZ with cisplatin sensitized MMP1 cells to cisplatin (Figure 10).	('MMP1', 'molecular_function', 'GO:0004232', ('87', '91'))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('MMP1', 'Gene', (198, 202))	('MMP1', 'Gene', '4312', (87, 91))	('combination', 'Var', (153, 164))	('MMP1', 'molecular_function', 'GO:0004232', ('198', '202'))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('IPZ', 'Chemical', 'MESH:C568452', (168, 171))	('sensitized', 'Reg', (187, 197))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('MMP1', 'Gene', (87, 91))	('IPZ', 'Chemical', 'MESH:C568452', (121, 124))	('MMP1', 'Gene', '4312', (198, 202))	('sensitive', 'MPA', (108, 117))
51116	32659970	The rationale is that the silencing of a CDG is more likely to impact the phenotypes associated with the malignant behavior than the silencing of a PG.	('PG', 'Chemical', '-', (148, 150))	('malignant behavior', 'CPA', (105, 123))	('CDG', 'Gene', (41, 44))	('silencing', 'Var', (26, 35))	('impact', 'Reg', (63, 69))	('CDG', 'Chemical', '-', (41, 44))
51118	32659970	The in vitro silencing of ASS1, GALNT7, IGF2BP3, and THBS2 induced reductions in the proliferation, clonogenic ability, migration, or caspase activity of some, but not all, MPM cell lines.	('GALNT7', 'Gene', (32, 38))	('IGF2BP3', 'Gene', '10643', (40, 47))	('reductions', 'NegReg', (67, 77))	('THBS2', 'Gene', '7058', (53, 58))	('proliferation', 'CPA', (85, 98))	('GALNT7', 'Gene', '51809', (32, 38))	('caspase activity', 'molecular_function', 'GO:0097153', ('134', '150'))	('caspase activity', 'molecular_function', 'GO:0004197', ('134', '150'))	('ASS1', 'Gene', (26, 30))	('migration', 'CPA', (120, 129))	('IGF2BP3', 'Gene', (40, 47))	('ASS1', 'Gene', '445', (26, 30))	('caspase activity', 'molecular_function', 'GO:0030693', ('134', '150'))	('clonogenic ability', 'CPA', (100, 118))	('caspase activity', 'CPA', (134, 150))	('THBS2', 'Gene', (53, 58))	('silencing', 'Var', (13, 22))
51125	32659970	The silencing or the inhibition of EIF4G1 caused decreased cyclin D1 and Rb protein levels, cell cycle delay, reduced cell viability, proliferation, clonogenic activity, cancer spheroid formation, as well as increased sensitivity to chemotherapeutic drugs.	('cancer', 'Disease', (170, 176))	('EIF4G1', 'Gene', '1981', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('proliferation', 'CPA', (134, 147))	('sensitivity', 'MPA', (218, 229))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('decreased', 'NegReg', (49, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('EIF4', 'cellular_component', 'GO:0008304', ('35', '39'))	('inhibition', 'NegReg', (21, 31))	('silencing', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('clonogenic activity', 'CPA', (149, 168))	('reduced', 'NegReg', (110, 117))	('increased', 'PosReg', (208, 217))	('cell viability', 'CPA', (118, 132))	('cyclin', 'molecular_function', 'GO:0016538', ('59', '65'))	('cyclin D1', 'Gene', (59, 68))	('EIF4G1', 'Gene', (35, 41))	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('cyclin D1', 'Gene', '595', (59, 68))	('cell cycle delay', 'CPA', (92, 108))	('Rb protein levels', 'MPA', (73, 90))
51131	32659970	Their analysis revealed that patients with high EIF4G1 expression had lower median survival compared to the patients with low/medium expression (for mesothelioma, p  =  0.0043).	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (43, 47))	('EIF4', 'cellular_component', 'GO:0008304', ('48', '52'))	('expression', 'MPA', (55, 65))	('lower', 'NegReg', (70, 75))	('median survival', 'MPA', (76, 91))	('EIF4G1', 'Gene', (48, 54))	('EIF4G1', 'Gene', '1981', (48, 54))	('mesothelioma', 'Disease', (149, 161))	('patients', 'Species', '9606', (108, 116))
51132	32659970	Moreover, the marked overexpression of EIF4G1 mRNA across human cancers agreed with findings from immunohistochemistry of an increase in EIF4G1 protein levels in cancer tissues derived from different organs as a result of amplification and/or mRNA up-regulation.	('EIF4', 'cellular_component', 'GO:0008304', ('137', '141'))	('up-regulation', 'PosReg', (248, 261))	('EIF4G1', 'Gene', (39, 45))	('human', 'Species', '9606', (58, 63))	('cancer', 'Disease', (162, 168))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('overexpression', 'PosReg', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('EIF4G1', 'Gene', '1981', (137, 143))	('increase', 'PosReg', (125, 133))	('cancer', 'Disease', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('EIF4G1', 'Gene', '1981', (39, 45))	('EIF4G1', 'Gene', (137, 143))	('mRNA', 'MPA', (243, 247))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('amplification', 'Var', (222, 235))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('regulation', 'biological_process', 'GO:0065007', ('251', '261'))	('protein levels', 'MPA', (144, 158))	('EIF4', 'cellular_component', 'GO:0008304', ('39', '43'))
51133	32659970	The results from the phenotypic assays also showed that RAN depletion impacted on proliferation, clonogenicity, and caspase activities of MPM cells but not MeT-5A cells.	('RAN', 'Gene', (56, 59))	('depletion', 'Var', (60, 69))	('impacted', 'Reg', (70, 78))	('caspase activities', 'CPA', (116, 134))	('clonogenicity', 'CPA', (97, 110))	('RAN', 'Gene', '5901', (56, 59))	('proliferation', 'CPA', (82, 95))
51140	32659970	This hypothesis was reinforced by the observation that IPZ (an inhibitor of the nuclear transport by hampering the binding between RAN and importin-beta) inhibited the proliferation of MPM cell lines, and this finding was also confirmed in a primary culture from an MPM patient.	('proliferation', 'CPA', (168, 181))	('hampering', 'NegReg', (101, 110))	('importin-beta', 'Protein', (139, 152))	('nuclear transport', 'biological_process', 'GO:0051169', ('80', '97'))	('IPZ', 'Var', (55, 58))	('RAN', 'Gene', (131, 134))	('MPM', 'Disease', (266, 269))	('inhibited', 'NegReg', (154, 163))	('importin', 'cellular_component', 'GO:0005646', ('139', '147'))	('MPM cell lines', 'CPA', (185, 199))	('binding', 'Interaction', (115, 122))	('RAN', 'Gene', '5901', (131, 134))	('IPZ', 'Chemical', 'MESH:C568452', (55, 58))	('binding', 'molecular_function', 'GO:0005488', ('115', '122'))	('patient', 'Species', '9606', (270, 277))
51141	32659970	The data on primary cells suggested that the cells from MMP1 patient could be responsive to IPZ and that IPZ could also enhance the sensitivity of cancer cells to cisplatin administration.	('MMP1', 'molecular_function', 'GO:0004232', ('56', '60'))	('enhance', 'PosReg', (120, 127))	('patient', 'Species', '9606', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('IPZ', 'Chemical', 'MESH:C568452', (105, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('sensitivity', 'MPA', (132, 143))	('responsive to IPZ', 'MPA', (78, 95))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('MMP1', 'Gene', '4312', (56, 60))	('IPZ', 'Chemical', 'MESH:C568452', (92, 95))	('IPZ', 'Var', (105, 108))	('cancer', 'Disease', (147, 153))	('MMP1', 'Gene', (56, 60))
51147	32659970	Moreover, IPZ increased the sensitivity of MMP1 and MMP4 cells to cisplatin.	('increased', 'PosReg', (14, 23))	('MMP1', 'Gene', '4312', (43, 47))	('MMP', 'molecular_function', 'GO:0004235', ('52', '55'))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('IPZ', 'Var', (10, 13))	('MMP4', 'Gene', (52, 56))	('MMP4', 'Gene', '3609', (52, 56))	('sensitivity', 'MPA', (28, 39))	('MMP1', 'Gene', (43, 47))	('MMP1', 'molecular_function', 'GO:0004232', ('43', '47'))	('IPZ', 'Chemical', 'MESH:C568452', (10, 13))
51153	32659970	GLUT1, IGF2BP3, and THBS2 were evaluated using specific TaqMan assay probes (Life Technologies, Carlsbad, CA, USA): hs00892681_m1 (GLUT1), hs00559907_g1 (IGF2BP3), and 00170248_m1 (THBS2).	('00170248_m1', 'Var', (168, 179))	('IGF2BP3', 'Gene', '10643', (154, 161))	('THBS2', 'Gene', (20, 25))	('IGF2BP3', 'Gene', (154, 161))	('GLUT1', 'Gene', (0, 5))	('hs00892681_m1', 'Var', (116, 129))	('IGF2BP3', 'Gene', (7, 14))	('THBS2', 'Gene', (181, 186))	('THBS2', 'Gene', '7058', (20, 25))	('IGF2BP3', 'Gene', '10643', (7, 14))	('GLUT1', 'Gene', '6513', (0, 5))	('THBS2', 'Gene', '7058', (181, 186))	('GLUT1', 'Gene', (131, 136))	('hs00559907_g1', 'Var', (139, 152))	('GLUT1', 'Gene', '6513', (131, 136))
51156	32659970	Cells were collected 96 h after seeding, i.e., 72 h after siRNA transfection, washed twice with ice-cold PBS (Euroclone, Milan, Italy), and harvested by centrifugation at 9300x g for 1 min, at 4  C. Cell pellets were processed for Western blots as reported in Supplementary B.	('ice-cold PBS', 'Disease', (96, 108))	('transfection', 'Var', (64, 76))	('ice-cold PBS', 'Disease', 'MESH:D011535', (96, 108))
51163	32659970	Their specific siRNAs were tagged as siASS1-1 (SI04434255, Qiagen), siEIF4G1-1 (SI04189346, Qiagen), siGALNT7-1 (SI00424508, Qiagen), siIGF2BP3-1 (SI04344256, Qiagen), siRAN-1 (SI04950519, Qiagen), and siTHBS2-1 (HSS110726, Invitrogen).	('SI00424508', 'Var', (113, 123))	('IGF2BP3', 'Gene', (136, 143))	('IGF2BP3', 'Gene', '10643', (136, 143))	('SI04950519', 'Var', (177, 187))	('GALNT7', 'Gene', '51809', (103, 109))	('RAN', 'Gene', (170, 173))	('S11', 'Gene', '6267', (215, 218))	('ASS1', 'Gene', (39, 43))	('GALNT7', 'Gene', (103, 109))	('S11', 'Gene', (215, 218))	('ASS1', 'Gene', '445', (39, 43))	('EIF4G1', 'Gene', '1981', (70, 76))	('EIF4G1', 'Gene', (70, 76))	('SI04189346', 'Var', (80, 90))	('RAN', 'Gene', '5901', (170, 173))	('siTHBS2-1', 'Chemical', '-', (202, 211))	('SI04434255', 'Var', (47, 57))	('SI04344256', 'Var', (147, 157))
51210	29506546	According to previous publications and the actual situation, the factors were categorized as follows: NLR, < 3 versus >= 3; ALB, < 35 g/l versus >= 35 g/l; platelet count, >= 338 x 109/l versus < 338 x 109/l; WBC count, > 6.23 x 109/l versus < 6.23 x 109/l; age, < 63 years versus >= 63 years; gender, male versus female; and BMI, < 22.79 versus >= 22.79.	('< 35 g/l', 'Var', (129, 137))	('ALB', 'Gene', (124, 127))	('ALB', 'Gene', '213', (124, 127))
51226	29506546	The Kaplan-Meier method and log-rank test indicated that ALB >= 35 g/L and NLR < 3 were associated with longer OS (Fig.	('ALB', 'Gene', (57, 60))	('ALB', 'Gene', '213', (57, 60))	('OS', 'Chemical', '-', (111, 113))	('>= 35 g/L', 'Var', (61, 70))	('longer OS', 'Disease', (104, 113))	('NLR', 'Gene', (75, 78))
51229	29506546	The 1-year survival rate was 32.4% for patients with ALB < 35 g/L and 60.6% for patients with ALB >= 35 g/L (Fig.	('ALB', 'Gene', '213', (94, 97))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (39, 47))	('ALB', 'Gene', (94, 97))	('< 35 g/L', 'Var', (57, 65))	('ALB', 'Gene', '213', (53, 56))	('ALB', 'Gene', (53, 56))
51238	29506546	The result indicated that non-treatment was associated with shorter OS (P = 0.000; Fig.	('OS', 'Chemical', '-', (68, 70))	('shorter', 'Disease', (60, 67))	('non-treatment', 'Var', (26, 39))	('men', 'Species', '9606', (35, 38))
51260	29506546	Peripheral blood lymphocytes are decreased in patients with a high NLR, and the antitumor response is reduced.	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('lymphocytes are decreased', 'Phenotype', 'HP:0001888', (17, 42))	('tumor', 'Disease', (84, 89))	('decreased', 'NegReg', (33, 42))	('high', 'Var', (62, 66))	('reduced', 'NegReg', (102, 109))
51314	29345617	Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal.	('Malignant mesothelioma', 'Disease', (70, 92))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TRAIL', 'Gene', '8743', (48, 53))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (70, 92))	('cancer', 'Disease', (57, 63))	('BAP1', 'Gene', '8314', (19, 23))	('TRAIL', 'Gene', (48, 53))	('Loss of functional', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BAP1', 'Gene', (19, 23))	('augments', 'PosReg', (24, 32))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))
51319	29345617	We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (34, 43))	('loss-of-function', 'NegReg', (17, 33))	('BAP1', 'Gene', '8314', (12, 16))
51324	29345617	Cancer treatment has been at the forefront of personalised medicine because mutations in different genes underlie each different cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (76, 85))	('underlie', 'Reg', (105, 113))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
51329	29345617	set out to determine if any of the mutations commonly seen in mesothelioma affected how the cancer would respond to 94 anticancer drugs that are either in use or in development.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('affected', 'Reg', (75, 83))	('mesothelioma', 'Disease', (62, 74))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('respond', 'MPA', (105, 112))	('cancer', 'Disease', (123, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (35, 44))
51330	29345617	In the laboratory, mesothelioma cells that have mutations in the gene that codes for a protein known as BRCA associated protein-1 (or BAP1 for short) were killed much more effectively by a drug known as TNF-related apoptosis-inducing ligand (TRAIL).	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('BAP1', 'Gene', (134, 138))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (203, 240))	('mesothelioma', 'Disease', (19, 31))	('ligand', 'molecular_function', 'GO:0005488', ('234', '240'))	('TNF-related apoptosis-inducing ligand', 'Gene', (203, 240))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('BAP1', 'Gene', '8314', (134, 138))	('mutations', 'Var', (48, 57))
51332	29345617	studied why these tumours might be killed more effectively with TRAIL, they found that mutations in the gene for BAP1 result in a change in the levels of proteins that transmit the signal from the receptors targeted by the TRAIL drug.	('tumours', 'Disease', 'MESH:D009369', (18, 25))	('tumours', 'Disease', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('BAP1', 'Gene', '8314', (113, 117))	('levels of proteins', 'MPA', (144, 162))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('BAP1', 'Gene', (113, 117))	('mutations', 'Var', (87, 96))	('change', 'Reg', (130, 136))
51334	29345617	But first, the next step would be to conduct a clinical trial of TRAIL in patients with mesothelioma and assess if those with tumours that have mutations in the gene for BAP1 do indeed respond better.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('BAP1', 'Gene', '8314', (170, 174))	('patients', 'Species', '9606', (74, 82))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('BAP1', 'Gene', (170, 174))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('tumours', 'Disease', (126, 133))	('better', 'PosReg', (193, 199))	('mutations', 'Var', (144, 153))	('mesothelioma', 'Disease', (88, 100))
51337	29345617	Drugs such as the tyrosine kinase inhibitors (TKIs) developed against the BCR-ABL fusion product in chronic myeloid leukaemia (CML) and the receptor products of HER2 mutations in breast cancer have transformed the prognosis of these cancers .	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutations', 'Var', (166, 175))	('CML', 'Disease', 'MESH:D015464', (127, 130))	('BCR-ABL', 'Gene', (74, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (100, 125))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('HER2', 'Gene', (161, 165))	('CML', 'Disease', (127, 130))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (108, 125))	('breast cancer', 'Disease', (179, 192))	('chronic myeloid leukaemia', 'Disease', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('BCR-ABL', 'Gene', '25', (74, 81))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (100, 125))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('HER2', 'Gene', '2064', (161, 165))
51340	29345617	A plethora of genomic studies in MM has identified recurrent mutations in several genes considered to be tumour drivers.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('plethora', 'Phenotype', 'HP:0001050', (2, 10))	('tumour', 'Disease', (105, 111))	('mutations', 'Var', (61, 70))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
51341	29345617	CDKN2A, NF2, BAP1 and TP53 are the most frequently mutated  and there has been increased focus on these genes and their associated signaling pathways as potential therapeutic targets .	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('BAP1', 'Gene', (13, 17))	('NF2', 'Gene', (8, 11))	('TP53', 'Gene', '7157', (22, 26))	('CDKN2A', 'Gene', (0, 6))	('BAP1', 'Gene', '8314', (13, 17))	('NF2', 'Gene', '4771', (8, 11))	('TP53', 'Gene', (22, 26))	('CDKN2A', 'Gene', '1029', (0, 6))	('mutated', 'Var', (51, 58))
51342	29345617	We aimed to determine if the mutational status of these tumour driver genes could predict response to a range of existing anti-cancer compounds with a view to identifying genomic biomarkers for responsive subsets of MM.	('response', 'MPA', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutational', 'Var', (29, 39))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('predict', 'Reg', (82, 89))	('tumour', 'Disease', (56, 62))
51343	29345617	We have previously reported on the ability of such unbiased high-throughput chemical screens in cancer cell lines to identify drug-sensitising mutations in other cancer types .	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (143, 152))
51344	29345617	To this end, we conducted a high-throughput chemical screen of molecularly characterised MM cell lines seeking associations between MM driver gene mutations and compound response.	('mutations', 'Var', (147, 156))	('tween', 'Chemical', 'MESH:D011136', (126, 131))	('associations', 'Interaction', (111, 123))
51345	29345617	This strategy led to the discovery of a subset of MM cell lines defined by loss-of-function (LOF) mutations in BRCA associated protein-1 (BAP1) that demonstrated heightened sensitivity to the death receptor agonist recombinant tumour necrosis factor (TNF)-related apoptosis-inducing ligand (rTRAIL).	('necrosis', 'biological_process', 'GO:0008219', ('234', '242'))	('ligand', 'molecular_function', 'GO:0005488', ('283', '289'))	('TNF', 'Gene', '7124', (251, 254))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('loss-of-function', 'NegReg', (75, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('tumour necrosis', 'Disease', 'MESH:D009336', (227, 242))	('necrosis', 'biological_process', 'GO:0008220', ('234', '242'))	('tumour necrosis', 'Disease', (227, 242))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('rTRAIL', 'Gene', '246775', (291, 297))	('necrosis', 'biological_process', 'GO:0070265', ('234', '242'))	('BAP1', 'Gene', '8314', (138, 142))	('necrosis', 'biological_process', 'GO:0019835', ('234', '242'))	('rTRAIL', 'Gene', (291, 297))	('necrosis', 'biological_process', 'GO:0001906', ('234', '242'))	('sensitivity', 'MPA', (173, 184))	('TNF', 'Gene', (251, 254))	('BAP1', 'Gene', (138, 142))	('mutations', 'Var', (98, 107))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))
51349	29345617	Retrospective biomarker identification has led to the stratified use of other anti-cancer therapies that initially failed in unselected trials such as activating EGFR mutations and EGFR TKIs .	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', '1956', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('EGFR', 'Gene', (162, 166))	('activating', 'PosReg', (151, 161))	('mutations', 'Var', (167, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('EGFR', 'Gene', '1956', (181, 185))	('cancer', 'Disease', (83, 89))
51353	29345617	We further found that loss of BAP1 function modulates mRNA and protein expression of components of the extrinsic apoptotic pathway.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('modulates', 'Reg', (44, 53))	('BAP1', 'Gene', (30, 34))	('extrinsic apoptotic pathway', 'biological_process', 'GO:0097191', ('103', '130'))	('extrinsic apoptotic pathway', 'Pathway', (103, 130))	('BAP1', 'Gene', '8314', (30, 34))	('expression', 'Species', '29278', (71, 81))	('loss', 'Var', (22, 26))
51357	29345617	The most statistically significant sensitising association seen was between BAP1 LOF mutations (mt BAP1) and treatment with recombinant TRAIL (rTRAIL; FDR = 0.18, effect size -0.48) (Figure 1B,C and Supplementary file 4).	('BAP1', 'Gene', (99, 103))	('tween', 'Chemical', 'MESH:D011136', (70, 75))	('BAP1', 'Gene', '8314', (76, 80))	('LOF', 'NegReg', (81, 84))	('mutations', 'Var', (85, 94))	('BAP1', 'Gene', (76, 80))	('BAP1', 'Gene', '8314', (99, 103))	('rTRAIL', 'Gene', (143, 149))	('rTRAIL', 'Gene', '246775', (143, 149))
51359	29345617	Strikingly, 6 of the 8 cell lines (75%) harbouring a BAP1 LOF mutation were sensitive or partially sensitive to a dose range of rTRAIL while 7 of the 9 cell lines (78%) harbouring wild-type BAP1 were resistant.	('rTRAIL', 'Gene', (128, 134))	('BAP1', 'Gene', '8314', (190, 194))	('rTRAIL', 'Gene', '246775', (128, 134))	('LOF', 'NegReg', (58, 61))	('mutation', 'Var', (62, 70))	('BAP1', 'Gene', (190, 194))	('BAP1', 'Gene', '8314', (53, 57))	('sensitive', 'MPA', (76, 85))	('BAP1', 'Gene', (53, 57))
51360	29345617	BAP1 LOF mutations correlated with a loss of BAP1 protein expression in the majority of cell lines (Figure 1E).	('expression', 'Species', '29278', (58, 68))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (9, 18))	('LOF', 'NegReg', (5, 8))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('loss', 'NegReg', (37, 41))	('protein', 'Protein', (50, 57))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', '8314', (45, 49))
51362	29345617	A marginal trend towards increased sensitivity in BAP1 mutant MM lines in response to treatment with the agonistic FAS receptor antibody CH11 and a TNF-alpha/IAP inhibitor combination was observed.	('TNF-alpha', 'Gene', '7124', (148, 157))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('increased', 'PosReg', (25, 34))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('sensitivity', 'MPA', (35, 46))	('BAP1', 'Gene', '8314', (50, 54))	('mutant', 'Var', (55, 61))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('TNF-alpha', 'Gene', (148, 157))	('IAP', 'Gene', (158, 161))	('IAP', 'Gene', '961', (158, 161))	('BAP1', 'Gene', (50, 54))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))
51366	29345617	Knockdown of BAP1 resulted in increased cell death following rTRAIL treatment compared with empty vector (EV) control shRNA and the parental cell line in all four MM cell lines (Figure 2A and Figure 2:figure supplement 1B and C ).	('cell death', 'biological_process', 'GO:0008219', ('40', '50'))	('BAP1', 'Gene', (13, 17))	('Knockdown', 'Var', (0, 9))	('cell death', 'CPA', (40, 50))	('rTRAIL', 'Gene', (61, 67))	('rTRAIL', 'Gene', '246775', (61, 67))	('BAP1', 'Gene', '8314', (13, 17))
51368	29345617	Notably, knockdown of BAP1 in two CCRC lines resulted in increased sensitivity to rTRAIL in addition to the MDAMB-231 breast cancer line (Figure 2B and Figure 2:figure supplements 2 and 3).	('rTRAIL', 'Gene', '246775', (82, 88))	('knockdown', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('rTRAIL', 'Gene', (82, 88))	('MDAMB-231', 'CellLine', 'CVCL:0062', (108, 117))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('BAP1', 'Gene', '8314', (22, 26))	('increased', 'PosReg', (57, 66))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('BAP1', 'Gene', (22, 26))
51369	29345617	We also analysed a panel of 1001 cancer cell lines submitted for whole exome and copy number analysis as part of the COSMIC cell lines project  and identified nine additional non-mesothelioma cell lines harbouring truncating mutations in BAP1 (http://cancer.sanger.ac.uk/cancergenome/projects/cell_lines/).	('BAP1', 'Gene', (238, 242))	('cancer', 'Disease', (33, 39))	('truncating mutations', 'Var', (214, 234))	('mesothelioma', 'Disease', (179, 191))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('BAP1', 'Gene', '8314', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (179, 191))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (271, 277))
51371	29345617	Treatment of cancer cell lines harbouring nonsense mutations in BAP1 with rTRAIL resulted in markedly reduced cell viability compared with cancer cell lines harbouring missense mutations (Figure 2:figure supplement 4).	('BAP1', 'Gene', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('nonsense mutations', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rTRAIL', 'Gene', (74, 80))	('cell viability', 'CPA', (110, 124))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('BAP1', 'Gene', '8314', (64, 68))	('rTRAIL', 'Gene', '246775', (74, 80))	('reduced', 'NegReg', (102, 109))	('cancer', 'Disease', (139, 145))
51373	29345617	To elucidate the mechanism by which BAP1 modulates sensitivity to TRAIL we generated expression vectors containing wild-type or mutant forms of BAP1, each with an inactive functional site or protein-binding domain.	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('BAP1', 'Gene', (144, 148))	('BAP1', 'Gene', '8314', (36, 40))	('expression vectors', 'Species', '29278', (85, 103))	('mutant', 'Var', (128, 134))	('sensitivity', 'MPA', (51, 62))	('protein-binding', 'molecular_function', 'GO:0005515', ('191', '206'))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (144, 148))
51374	29345617	These included C91A (mutation in the deubiquitination catalytic site) , DeltaHBM (deletion of the HCF-1-binding site) , T493A (mutation in the FOXK2-binding site) , DeltaASXL (deletion of the ASXL1/2 protein-binding site)  and DeltaCTD (deletion of the C-terminal domain containing the nuclear localisation signal) .	('deletion', 'Var', (176, 184))	('T493A', 'Var', (120, 125))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('localisation', 'biological_process', 'GO:0051179', ('294', '306'))	('deubiquitination', 'biological_process', 'GO:0016579', ('37', '53'))	('T493A', 'Mutation', 'c.493T>A', (120, 125))	('protein-binding', 'molecular_function', 'GO:0005515', ('200', '215'))	('deletion', 'Var', (237, 245))	('FOXK2', 'Gene', (143, 148))	('binding', 'molecular_function', 'GO:0005488', ('149', '156'))	('DeltaASXL', 'Disease', (165, 174))	('DeltaHBM', 'Chemical', '-', (72, 80))	('C91A', 'Var', (15, 19))	('ASXL1', 'Gene', '171023', (192, 197))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('C91A', 'SUBSTITUTION', 'None', (15, 19))	('deletion', 'Var', (82, 90))	('FOXK2', 'Gene', '3607', (143, 148))	('ASXL1', 'Gene', (192, 197))	('HCF-1', 'Gene', '3054', (98, 103))	('HCF-1', 'Gene', (98, 103))
51375	29345617	H226 MM cells, which harbour a homozygous deletion of BAP1 and demonstrate complete loss of BAP1 expression, were transduced with a GFP (vector control), a wild-type BAP1 expression vector or one of these five mutant BAP1 expression vectors.	('BAP1', 'Gene', '8314', (217, 221))	('expression vectors', 'Species', '29278', (222, 240))	('BAP1', 'Gene', (217, 221))	('loss', 'NegReg', (84, 88))	('BAP1', 'Gene', '8314', (166, 170))	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', '8314', (92, 96))	('H226 MM', 'CellLine', 'CVCL:J621', (0, 7))	('BAP1', 'Gene', (166, 170))	('expression', 'Species', '29278', (97, 107))	('expression', 'Species', '29278', (222, 232))	('deletion', 'Var', (42, 50))	('expression', 'Species', '29278', (171, 181))	('BAP1', 'Gene', (54, 58))	('expression', 'MPA', (97, 107))	('BAP1', 'Gene', (92, 96))
51376	29345617	rTRAIL sensitivity of the parental BAP1-null H226 MM line was significantly diminished following expression of wild-type BAP1 and each of the mutant constructs except those with an inactive deubiquitinating or ASXL protein-binding site (Figure 2C), implicating the function of these sites in BAP1-induced TRAIL resistance.	('protein-binding', 'molecular_function', 'GO:0005515', ('215', '230'))	('BAP1', 'Gene', '8314', (121, 125))	('rTRAIL', 'Gene', '246775', (0, 6))	('BAP1', 'Gene', (292, 296))	('BAP1', 'Gene', '8314', (35, 39))	('BAP1', 'Gene', (121, 125))	('mutant', 'Var', (142, 148))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('expression', 'Species', '29278', (97, 107))	('BAP1', 'Gene', (35, 39))	('diminished', 'NegReg', (76, 86))	('rTRAIL', 'Gene', (0, 6))	('H226 MM', 'CellLine', 'CVCL:J621', (45, 52))	('BAP1', 'Gene', '8314', (292, 296))
51383	29345617	Furthermore, H2AK119Ub expression was unaltered in the rTRAIL-sensitive H226 cells transduced with mutant constructs that disrupt PR-DUB activity, while the rTRAIL-resistant H226 cells transduced with a wild-type BAP1 construct exhibited lower H2AK119Ub levels (Figure 2:figure supplement 7).	('rTRAIL', 'Gene', (55, 61))	('expression', 'Species', '29278', (23, 33))	('H2A', 'Gene', (13, 16))	('rTRAIL', 'Gene', '246775', (157, 163))	('BAP1', 'Gene', (213, 217))	('rTRAIL', 'Gene', '246775', (55, 61))	('H226', 'CellLine', 'CVCL:J621', (72, 76))	('H2A', 'Gene', '8337', (244, 247))	('PR-DUB', 'Protein', (130, 136))	('H2A', 'Gene', (244, 247))	('H226', 'CellLine', 'CVCL:J621', (174, 178))	('activity', 'MPA', (137, 145))	('rTRAIL', 'Gene', (157, 163))	('mutant', 'Var', (99, 105))	('H2A', 'Gene', '8337', (13, 16))	('BAP1', 'Gene', '8314', (213, 217))	('disrupt', 'NegReg', (122, 129))
51385	29345617	We therefore compared differential gene expression data from BAP1-null H226 cells transduced with the C91A BAP1 mutant or with wild-type BAP1 and carried out a signalling pathway impact analysis (SPIA) ((Figure 2:figure supplements 8 and 9 [SPIA_H226 C91A mutant vs WT]) (http://www.genome.jp/dbget-bin/www_bget?path:map04210).	('BAP1', 'Gene', (137, 141))	('BAP1', 'Gene', '8314', (107, 111))	('C91A', 'SUBSTITUTION', 'None', (102, 106))	('BAP1', 'Gene', (61, 65))	('expression', 'Species', '29278', (40, 50))	('C91A', 'SUBSTITUTION', 'None', (251, 255))	('mutant', 'Var', (112, 118))	('H226', 'CellLine', 'CVCL:J621', (246, 250))	('H226', 'CellLine', 'CVCL:J621', (71, 75))	('signalling pathway', 'biological_process', 'GO:0007165', ('160', '178'))	('BAP1', 'Gene', '8314', (61, 65))	('BAP1', 'Gene', (107, 111))	('BAP1', 'Gene', '8314', (137, 141))	('C91A', 'Var', (102, 106))	('C91A', 'Var', (251, 255))	('gene expression', 'biological_process', 'GO:0010467', ('35', '50'))
51386	29345617	Among those pathways significantly altered when comparing wild-type versus C91A BAP1 (FDR < 0.2) was that of apoptosis.	('altered', 'Reg', (35, 42))	('C91A', 'SUBSTITUTION', 'None', (75, 79))	('BAP1', 'Gene', '8314', (80, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('BAP1', 'Gene', (80, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('C91A', 'Var', (75, 79))
51388	29345617	This manifested as an imbalance in levels of pro- and anti-apoptotic mRNA expression with, for example, significantly decreased levels of the anti-apoptotic cIAP1/2 (p=2.32E-10) and increased levels of the pro-apoptotic death receptor 5 (p=7.79E-10) in the rTRAIL sensitive C91A BAP1-transduced cells relative to the rTRAIL resistant BAP1-wild-type transduced cells.	('increased', 'PosReg', (182, 191))	('levels', 'MPA', (128, 134))	('BAP1', 'Gene', (334, 338))	('BAP1', 'Gene', (279, 283))	('rTRAIL', 'Gene', '246775', (317, 323))	('cIAP1', 'Gene', (157, 162))	('death receptor 5', 'Gene', (220, 236))	('rTRAIL', 'Gene', (317, 323))	('imbalance', 'Phenotype', 'HP:0002172', (22, 31))	('death receptor 5', 'Gene', '8795', (220, 236))	('decreased', 'NegReg', (118, 127))	('expression', 'Species', '29278', (74, 84))	('cIAP1', 'Gene', '329', (157, 162))	('BAP1', 'Gene', '8314', (334, 338))	('BAP1', 'Gene', '8314', (279, 283))	('rTRAIL', 'Gene', '246775', (257, 263))	('C91A', 'Var', (274, 278))	('rTRAIL', 'Gene', (257, 263))	('levels', 'MPA', (192, 198))	('C91A', 'SUBSTITUTION', 'None', (274, 278))
51389	29345617	Immunoblot analysis confirmed reduced protein expression of cIAP1/2 and c-FLIP in both C91A and DeltaASXL BAP1-transduced cells relative to BAP1-wild-type transduced cells (Figure 2G).	('C91A', 'Var', (87, 91))	('protein expression', 'MPA', (38, 56))	('c-FLIP', 'Gene', '8837', (72, 78))	('c-FLIP', 'Gene', (72, 78))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', (140, 144))	('C91A', 'SUBSTITUTION', 'None', (87, 91))	('BAP1', 'Gene', '8314', (106, 110))	('reduced', 'NegReg', (30, 37))	('expression', 'Species', '29278', (46, 56))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('BAP1', 'Gene', '8314', (140, 144))	('cIAP1', 'Gene', (60, 65))	('cIAP1', 'Gene', '329', (60, 65))
51390	29345617	Flow cytometry analysis confirmed reduced DR4 and DR5 expression in C91A BAP1 transduced relative to BAP1-wild-type-transduced cells.	('BAP1', 'Gene', '8314', (73, 77))	('C91A', 'SUBSTITUTION', 'None', (68, 72))	('reduced', 'NegReg', (34, 41))	('BAP1', 'Gene', '8314', (101, 105))	('BAP1', 'Gene', (73, 77))	('DR5', 'Gene', (50, 53))	('BAP1', 'Gene', (101, 105))	('DR4', 'Protein', (42, 45))	('C91A', 'Var', (68, 72))	('expression', 'Species', '29278', (54, 64))
51393	29345617	25 human early passage MM lines from the UK Mesobank  were assessed for BAP1 expression by immunohistochemistry, a technique known to correlate strongly with BAP1 LOF mutations in the absence of strong nuclear staining .	('LOF', 'NegReg', (163, 166))	('BAP1', 'Gene', '8314', (72, 76))	('human', 'Species', '9606', (3, 8))	('BAP1', 'Gene', (158, 162))	('mutations', 'Var', (167, 176))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (158, 162))	('expression', 'Species', '29278', (77, 87))
51396	29345617	Remarkably, rTRAIL treatment of tumour explants derived from three patients with MM also revealed increased levels of apoptosis (as measured by poly (ADP-ribose) polymerase (PARP) cleavage) in explants with low BAP1 expression compared with those with high BAP1 expression (Figure 3B and C, Figure 3:figure supplement 2).	('poly (ADP-ribose) polymerase', 'Gene', (144, 172))	('poly (ADP-ribose) polymerase', 'Gene', '142', (144, 172))	('PARP', 'Gene', (174, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('BAP1', 'Gene', '8314', (211, 215))	('BAP1', 'Gene', '8314', (257, 261))	('low', 'Var', (207, 210))	('patients', 'Species', '9606', (67, 75))	('rTRAIL', 'Gene', '246775', (12, 18))	('expression', 'Var', (216, 226))	('BAP1', 'Gene', (211, 215))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('apoptosis', 'MPA', (118, 127))	('expression', 'Species', '29278', (262, 272))	('BAP1', 'Gene', (257, 261))	('expression', 'Species', '29278', (216, 226))	('tumour', 'Disease', (32, 38))	('rTRAIL', 'Gene', (12, 18))	('PARP', 'Gene', '142', (174, 178))
51397	29345617	To test the in vivo efficacy of TRAIL in inducing apoptosis in BAP1-mutant MM cells, we transduced the H226 BAP1-wild-type and the H226 C91A BAP1-mutant cell lines with luciferase and injected equal numbers of wild-type and mutant cells into the opposite flanks of mice (Figure 3:figure supplement 3A).	('H226', 'CellLine', 'CVCL:J621', (131, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('BAP1', 'Gene', '8314', (141, 145))	('C91A', 'SUBSTITUTION', 'None', (136, 140))	('BAP1', 'Gene', '8314', (108, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', (141, 145))	('BAP1', 'Gene', (108, 112))	('mice', 'Species', '10090', (265, 269))	('H226', 'CellLine', 'CVCL:J621', (103, 107))	('C91A', 'Var', (136, 140))	('H226', 'Var', (131, 135))	('BAP1', 'Gene', '8314', (63, 67))
51407	29345617	While next-generation sequencing reveals MM BAP1 mutation rates in the order of 20-30% , immunohistochemical analysis has identified loss of BAP1 function in up to 67% of MM tumours  opening our biomarker-driven approach to a significant proportion of MM patients.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('BAP1', 'Gene', '8314', (141, 145))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('MM tumours  opening', 'Disease', 'MESH:D005597', (171, 190))	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', (141, 145))	('loss', 'NegReg', (133, 137))	('patients', 'Species', '9606', (255, 263))	('BAP1', 'Gene', '8314', (44, 48))	('function', 'MPA', (146, 154))	('MM tumours  opening', 'Disease', (171, 190))	('BAP1', 'Gene', (44, 48))
51410	29345617	Chromosomal deletions and somatic inactivating mutations have been identified at high frequency in uveal melanoma , clear cell renal carcinoma  and cholangiocarcinoma , increasing the potential clinical impact of our discovery.	('Chromosomal deletions', 'Var', (0, 21))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (148, 166))	('clear cell renal carcinoma', 'Disease', (116, 142))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (116, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cholangiocarcinoma', 'Disease', (148, 166))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('identified', 'Reg', (67, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (116, 142))	('renal carcinoma', 'Phenotype', 'HP:0005584', (127, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 166))	('uveal melanoma', 'Disease', (99, 113))
51417	29345617	Notably there have been no trials of any death receptor agonists in MM or indeed any cancer with a high proportion of BAP1 mutations.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (123, 132))
51423	29345617	ASXL1 mutations have an important role in the pathogenesis of myeloid neoplasms primarily consisting of nonsense, missense and frameshift mutations resulting in a truncated ASXL1 protein that retains the BAP1-binding domain .	('myeloid neoplasms', 'Disease', 'MESH:D007951', (62, 79))	('consisting', 'Reg', (90, 100))	('myeloid neoplasms', 'Disease', (62, 79))	('ASXL1', 'Gene', (173, 178))	('ASXL1', 'Gene', '171023', (0, 5))	('neoplasms', 'Phenotype', 'HP:0002664', (70, 79))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (62, 79))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('missense', 'Var', (114, 122))	('BAP1', 'Gene', '8314', (204, 208))	('pathogenesis', 'biological_process', 'GO:0009405', ('46', '58'))	('ASXL1', 'Gene', (0, 5))	('binding', 'molecular_function', 'GO:0005488', ('209', '216'))	('BAP1', 'Gene', (204, 208))	('mutations', 'Var', (6, 15))	('ASXL1', 'Gene', '171023', (173, 178))	('frameshift mutations', 'Var', (127, 147))
51433	29345617	Differences from the reference genome were identified using the CaVEMan and Pindel algorithms identifying substitution and small insertions/deletions respectively (https://github.com/cancerit/CaVEMan; https://github.com/genome/pindel) .	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('substitution', 'Var', (106, 118))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
51439	29345617	We used 15 mesothelioma cell lines with molecular and drug response data: H2369, H2373, H2461, H2591, H2722, H2731, H2803, H2804, H2810, H2818, H2869, H513, MPP-89, NCI-H2452 and NCI-H28.	('MPP', 'molecular_function', 'GO:0004240', ('157', '160'))	('H2369', 'Var', (74, 79))	('H2818', 'Var', (137, 142))	('H2869', 'Var', (144, 149))	('H2722', 'CellLine', 'CVCL:U994', (102, 107))	('H513', 'Var', (151, 155))	('mesothelioma', 'Disease', (11, 23))	('H2591', 'CellLine', 'CVCL:A543', (95, 100))	('H2731', 'CellLine', 'CVCL:U995', (109, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('H2461', 'Var', (88, 93))	('H2810', 'Var', (130, 135))	('H2373', 'Var', (81, 86))	('H2722', 'Var', (102, 107))	('H2373', 'CellLine', 'CVCL:A533', (81, 86))	('H2803', 'Var', (116, 121))	('H2461', 'CellLine', 'CVCL:A536', (88, 93))	('H2731', 'Var', (109, 114))	('H2804', 'Var', (123, 128))	('H2803', 'CellLine', 'CVCL:U997', (116, 121))	('H2591', 'Var', (95, 100))	('NCI-H2452', 'CellLine', 'CVCL:1553', (165, 174))
51456	29345617	Vectors expressing mutant BAP1 constructs were generated by site-directed mutagenesis (New England Biolabs) of the pCCL-CMV-BAP1 vector.	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', '8314', (124, 128))	('mutagenesis', 'biological_process', 'GO:0006280', ('74', '85'))	('BAP1', 'Gene', (124, 128))	('mutant', 'Var', (19, 25))	('BAP1', 'Gene', '8314', (26, 30))	('mutagenesis', 'Var', (74, 85))
51457	29345617	BAP1-F CGTGGATCCGCCACCATGAATAAGGGCTGGCTGGA BAP1-R GTCGGTCGACTCACTGGCGCTTGGCCTTGTA C91A-F ATACCCAACTCTGCTGCAACTCATGCCTTGCTG C91A-R CAGCTGGTGGGCAAAGAACATGTTATTCACAATATCATC HBM-F CGCTGCTGCCAAGTCCCCCATGCAGGAGGA HBM-R GCAGCGTCTAGAAAGGCCGGCAGCCGCT CTD-F CGTGGATCCGCCACCATGAATAAGGGCTGGCTGGA CTD-R GTCGTTCGAATCAGTCAGGCTTCCGCTGCTTGTGG T493A-F GCAGACACGGCCTCTGAGATCGGCAGTGCT T493A-R ACTCTCATTGCTGGGGGTGGGTGA ASXL-F AACTACGATGAGTTCATCTGCACCT ASXL-R CTGGTCATCAATCTTGAACTTCTTCCTC The ZS-green luciferase plasmid, pHIV-Luc-ZsGreen (a gift from Bryan Welm, Addgene plasmid #39196) was used for generating ZS-Green luciferase-expressing lentivirus to transduce the H226 cells used in animal experiments.	('T493A', 'Mutation', 'c.493T>A', (365, 370))	('BAP1', 'Gene', (43, 47))	('C91A', 'SUBSTITUTION', 'None', (82, 86))	('C91A', 'SUBSTITUTION', 'None', (123, 127))	('BAP1', 'Gene', (0, 4))	('T493A', 'Mutation', 'c.493T>A', (326, 331))	('transduce', 'Reg', (635, 644))	('BAP1', 'Gene', '8314', (43, 47))	('C91A', 'Var', (123, 127))	('H226', 'CellLine', 'CVCL:J621', (649, 653))	('C91A', 'Var', (82, 86))	('BAP1', 'Gene', '8314', (0, 4))
51458	29345617	The clones used in this study include BAP1 (V2LHS_41473), ASXL1 (V2LHS_78829), ASXL2 (V3LHS_313940) and the empty GIPZ control vector.	('V3LHS_313940', 'Var', (86, 98))	('ASXL2', 'Gene', (79, 84))	('BAP1', 'Gene', (38, 42))	('V2LHS_78829', 'Var', (65, 76))	('ASXL1', 'Gene', '171023', (58, 63))	('V2LHS_41473', 'Var', (44, 55))	('ASXL1', 'Gene', (58, 63))	('ASXL2', 'Gene', '55252', (79, 84))	('BAP1', 'Gene', '8314', (38, 42))
51459	29345617	Lentiviral vectors were produced by co-transfection of 293 T cells with construct plasmids together with the packaging plasmids pCMV-dR8.74 and pMD2.G (kind gifts from Dr Adrian Thrasher, UCL, Addgene plasmid #22036 and #12259) in the presence of a DNA transfection reagent jetPEI (Source Bioscience UK Ltd).	('DNA', 'cellular_component', 'GO:0005574', ('249', '252'))	('PE', 'Chemical', '-', (277, 279))	('#12259', 'Var', (220, 226))	('dR8', 'Gene', (133, 136))	('dR8', 'Gene', '41889', (133, 136))	('293 T', 'CellLine', 'CVCL:0063', (55, 60))
51465	29345617	Gene expression was averaged across three biological replicates of H226 transduced cells with either a C91A mutant or a wild-type BAP1 construct.	('BAP1', 'Gene', (130, 134))	('H226', 'CellLine', 'CVCL:J621', (67, 71))	('C91A', 'SUBSTITUTION', 'None', (103, 107))	('BAP1', 'Gene', '8314', (130, 134))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('expression', 'Species', '29278', (5, 15))	('C91A', 'Var', (103, 107))
51472	29345617	Ubiquityl-histone H2A (Lys119) primary antibody (Cell Signaling, #8240) was incubated overnight at 4 C, before incubating for 1 hr at room temperature with Alexafluor 488-conjugated anti-rabbit secondary antibody.	('antibody', 'molecular_function', 'GO:0003823', ('39', '47'))	('antibody', 'cellular_component', 'GO:0042571', ('204', '212'))	('rabbit', 'Species', '9986', (187, 193))	('H2A', 'Gene', '8337', (18, 21))	('Signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('Ubiquityl-histone', 'Chemical', '-', (0, 17))	('antibody', 'cellular_component', 'GO:0042571', ('39', '47'))	('H2A', 'Gene', (18, 21))	('antibody', 'cellular_component', 'GO:0019814', ('204', '212'))	('antibody', 'cellular_component', 'GO:0019815', ('204', '212'))	('Lys119', 'Chemical', '-', (23, 29))	('Lys119', 'Var', (23, 29))	('antibody', 'molecular_function', 'GO:0003823', ('204', '212'))	('antibody', 'cellular_component', 'GO:0019815', ('39', '47'))	('Alexafluor 488', 'Chemical', '-', (156, 170))	('antibody', 'cellular_component', 'GO:0019814', ('39', '47'))
51489	29345617	12 8 week old NOD.CB17-Prkdcscid/NcrCrl (NOD SCID) mice (Charles River, UK; RRID:IMSR_CRL:394) were injected with 1 x 106 H226 cells transduced with a plasmid containing wild-type BAP1 and luciferase on the right flank and with a plasmid containing a catalytically inactive BAP1-mutant (C91A) and luciferase on the left flank in a 1:1 mixture of Matrigel (Corning, Corning, NY) and medium.	('C91A', 'SUBSTITUTION', 'None', (287, 291))	('NOD', 'Gene', (41, 44))	('mice', 'Species', '10090', (51, 55))	('BAP1', 'Gene', '8314', (180, 184))	('NOD', 'Gene', (14, 17))	('H226', 'CellLine', 'CVCL:J621', (122, 126))	('BAP1', 'Gene', '8314', (274, 278))	('SCID', 'Disease', 'MESH:D053632', (45, 49))	('SCID', 'Disease', (45, 49))	('C91A', 'Var', (287, 291))	('BAP1', 'Gene', (180, 184))	('NOD', 'Gene', '1822', (41, 44))	('NOD', 'Gene', '1822', (14, 17))	('BAP1', 'Gene', (274, 278))
51499	29345617	Reviewers found the data presented to be quite convincing and to support the authors' case that BAP1 can affect TRAIL sensitivity most likely through epigenetic regulation of gene expression by a mechanism involving the AXLS1 protein.	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('BAP1', 'Gene', (96, 100))	('expression', 'Species', '29278', (180, 190))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('161', '190'))	('AXLS1', 'Protein', (220, 225))	('affect', 'Reg', (105, 111))	('epigenetic', 'Var', (150, 160))	('TRAIL sensitivity', 'CPA', (112, 129))	('BAP1', 'Gene', '8314', (96, 100))
51502	29345617	Therefore, reviewers request a series of experiments addressing this issue, to define whether or not BAP1 mutation/loss is a general sensitizer to death ligands and/or general apoptotic stimuli.	('BAP1', 'Gene', '8314', (101, 105))	('mutation/loss', 'NegReg', (106, 119))	('BAP1', 'Gene', (101, 105))	('mutation/loss', 'Var', (106, 119))
51508	29345617	The report currently shows the effect of BAP1 knockdown in only two cell lines: H226 and MDA-MB-231.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (89, 99))	('knockdown', 'Var', (46, 55))	('BAP1', 'Gene', (41, 45))	('BAP1', 'Gene', '8314', (41, 45))	('H226', 'CellLine', 'CVCL:J621', (80, 84))
51509	29345617	All other cause-effect experiments involve artifact-prone overexpression experiments of BAP1 (wt or various mutants).	('expression', 'Species', '29278', (62, 72))	('mutants', 'Var', (108, 115))	('BAP1', 'Gene', '8314', (88, 92))	('overexpression', 'PosReg', (58, 72))	('BAP1', 'Gene', (88, 92))
51511	29345617	Additionally, BAP1 mutations are most frequent among kidney clear cell carcinomas (CRCC) estimated at 10% by tumorportal.org.	('BAP1', 'Gene', '8314', (14, 18))	('kidney clear cell carcinomas', 'Disease', (53, 81))	('kidney clear cell carcinomas', 'Disease', 'MESH:C538614', (53, 81))	('BAP1', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('frequent', 'Reg', (38, 46))	('tumor', 'Disease', (109, 114))
51516	29345617	Some data and discussion on the relationship between BAP1 mutation and gene expression of TRAIL-R1/2, FADD, FLIP, caspase-8, etc.	('FADD', 'Gene', (102, 106))	('FADD', 'Gene', '8772', (102, 106))	('TRAIL-R1/2', 'Gene', (90, 100))	('expression', 'Species', '29278', (76, 86))	('caspase-8', 'Gene', '12370', (114, 123))	('mutation', 'Var', (58, 66))	('caspase-8', 'Gene', (114, 123))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('BAP1', 'Gene', '8314', (53, 57))	('tween', 'Chemical', 'MESH:D011136', (47, 52))	('BAP1', 'Gene', (53, 57))
51520	29345617	Importantly the retrospective identification of drug sensitising mutations has re-directed the use of other anticancer therapies with initially disappointing results in unselected populations.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (65, 74))	('cancer', 'Disease', (112, 118))
51521	29345617	To demonstrate the specificity of BAP1 as a sensitising mutation to TRAIL, and other death receptor agonists, we have treated a panel of BAP1 mutant and wild-type MM lines with additional apoptotic stimuli as suggested.	('BAP1', 'Gene', (137, 141))	('BAP1', 'Gene', (34, 38))	('mutant', 'Var', (142, 148))	('BAP1', 'Gene', '8314', (137, 141))	('BAP1', 'Gene', '8314', (34, 38))
51528	29345617	This is not unusual, noting that TKI inhibition of EGFR activating mutant lung cancers show response rates of around 70%.	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('EGFR', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (74, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (74, 86))	('activating', 'PosReg', (56, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('mutant', 'Var', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('lung cancers', 'Disease', (74, 86))	('EGFR', 'Gene', '1956', (51, 55))
51531	29345617	[...] Notably, knockdown of BAP1 in two CCRC lines resulted in increased sensitivity to rTRAIL in addition to the MDAMB-231 breast cancer line (Figure 2B and Figure 2:figure supplements 2 and 3)."	('BAP1', 'Gene', '8314', (28, 32))	('increased', 'PosReg', (63, 72))	('knockdown', 'Var', (15, 24))	('rTRAIL', 'Gene', (88, 94))	('BAP1', 'Gene', (28, 32))	('rTRAIL', 'Gene', '246775', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('MDAMB-231', 'CellLine', 'CVCL:0062', (114, 123))	('breast cancer', 'Disease', (124, 137))
51534	29345617	We have compared gene expression data from a BAP1 null MM line with overexpression of BAP1 wild-type or the catalytically inactive BAP1 C91A.	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('C91A', 'SUBSTITUTION', 'None', (136, 140))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (86, 90))	('expression', 'Species', '29278', (72, 82))	('BAP1', 'Gene', '8314', (131, 135))	('BAP1', 'Gene', (86, 90))	('expression', 'Species', '29278', (22, 32))	('C91A', 'Var', (136, 140))	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (45, 49))
51535	29345617	Signaling pathway impact analysis highlighted apoptosis as being significantly altered by BAP1 function.	('apoptosis', 'CPA', (46, 55))	('altered', 'Reg', (79, 86))	('BAP1', 'Gene', '8314', (90, 94))	('BAP1', 'Gene', (90, 94))	('function', 'Var', (95, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('Signaling pathway', 'biological_process', 'GO:0007165', ('0', '17'))
51538	29345617	We have added the following text to the Results section: "We therefore compared differential gene expression data from BAP1-null H226 cells transduced with the C91A BAP1 mutant or with wild-type BAP1, and carried out a signalling pathway impact analysis SPIA ((Figure 2:figure supplement 7 and 8 [SPIA_H226 C91A mutant vs. WT]) (http://www.genome.jp/dbget-bin/www_bget?path:map04210).	('H226', 'CellLine', 'CVCL:J621', (129, 133))	('BAP1', 'Gene', (195, 199))	('BAP1', 'Gene', (165, 169))	('C91A', 'Var', (307, 311))	('C91A', 'Var', (160, 164))	('BAP1', 'Gene', '8314', (119, 123))	('C91A', 'SUBSTITUTION', 'None', (307, 311))	('mutant', 'Var', (170, 176))	('C91A', 'SUBSTITUTION', 'None', (160, 164))	('expression', 'Species', '29278', (98, 108))	('BAP1', 'Gene', '8314', (195, 199))	('BAP1', 'Gene', '8314', (165, 169))	('BAP1', 'Gene', (119, 123))	('H226', 'CellLine', 'CVCL:J621', (302, 306))
51539	29345617	[...] Flow cytometry analysis confirmed reduced DR4 and DR5 expression in C91A BAP1 transduced relative to wild-type BAP1 transduced cells.	('expression', 'MPA', (60, 70))	('expression', 'Species', '29278', (60, 70))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', '8314', (117, 121))	('DR5', 'Gene', (56, 59))	('BAP1', 'Gene', (79, 83))	('C91A', 'Var', (74, 78))	('reduced', 'NegReg', (40, 47))	('BAP1', 'Gene', (117, 121))	('transduced', 'Var', (84, 94))	('DR4', 'Gene', (48, 51))	('C91A', 'SUBSTITUTION', 'None', (74, 78))
51541	29345617	We have conducted immunoblot analysis of the death receptor pathway on BAP1 null MM cells transduced with the ASXL1/2 binding mutant DeltaASXL BAP1.	('BAP1', 'Gene', (143, 147))	('ASXL1', 'Gene', (110, 115))	('BAP1', 'Gene', '8314', (71, 75))	('DeltaASXL', 'Var', (133, 142))	('BAP1', 'Gene', '8314', (143, 147))	('ASXL1', 'Gene', '171023', (110, 115))	('BAP1', 'Gene', (71, 75))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
51542	29345617	The changes observed in this analysis are consistent with that of those cells transduced with the catalytically inactive C91A BAP1 mutant.	('C91A', 'Var', (121, 125))	('BAP1', 'Gene', '8314', (126, 130))	('C91A', 'SUBSTITUTION', 'None', (121, 125))	('BAP1', 'Gene', (126, 130))
51544	29345617	We have amended the title to: "Loss of functional BAP1 augments TRAIL sensitivity in cancer cells."	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('BAP1', 'Gene', '8314', (50, 54))	('cancer', 'Disease', (85, 91))	('Loss of', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BAP1', 'Gene', (50, 54))	('augments', 'PosReg', (55, 63))
51659	19893520	The size of mononuclear cell aggregates was significantly increased by high dose MWCNT (Fig.	('size of mononuclear cell aggregates', 'CPA', (4, 39))	('MWCNT', 'Var', (81, 86))	('increased', 'PosReg', (58, 67))	('MWCNT', 'Chemical', '-', (81, 86))
51671	19893520	We hypothesize that activated macrophages containing MWCNT traffic through the pleural lymphatic drainage and stimulate recruitment of mononuclear cells to enlarge these focal aggregates.	('enlarge', 'PosReg', (156, 163))	('pleural lymphatic drainage', 'Disease', (79, 105))	('MWCNT', 'Var', (53, 58))	('MWCNT', 'Chemical', '-', (53, 58))	('recruitment', 'MPA', (120, 131))	('pleural lymphatic drainage', 'Disease', 'MESH:D008206', (79, 105))	('stimulate', 'PosReg', (110, 119))
51677	19893520	However, the pathology we observed with MWCNT appears different from pleural pathology induced by asbestos fibers as MWCNT caused focal sub-pleural fibrosis and mononuclear cell aggregates, whereas asbestos causes pleural inflammation (granulomas) and diffuse pleural fibrosis.	('sub-pleural fibrosis', 'Disease', 'MESH:D005355', (136, 156))	('sub-pleural fibrosis', 'Disease', (136, 156))	('pleural pathology', 'Disease', 'MESH:D010995', (69, 86))	('MWCNT', 'Chemical', '-', (117, 122))	('asbestos fibers', 'Disease', (98, 113))	('pleural fibrosis', 'Disease', 'MESH:D005355', (140, 156))	('pleural fibrosis', 'Disease', 'MESH:D005355', (260, 276))	('granulomas', 'Disease', 'MESH:D006099', (236, 246))	('inflammation', 'biological_process', 'GO:0006954', ('222', '234'))	('pleural inflammation', 'Disease', (214, 234))	('MWCNT', 'Var', (117, 122))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('asbestos fibers', 'Disease', 'MESH:D001195', (98, 113))	('granulomas', 'Disease', (236, 246))	('pleural inflammation', 'Disease', 'MESH:D007249', (214, 234))	('pleural fibrosis', 'Disease', (260, 276))	('asbestos', 'Chemical', 'MESH:D001194', (198, 206))	('granulomas', 'Phenotype', 'HP:0032252', (236, 246))	('pleural pathology', 'Disease', (69, 86))	('MWCNT', 'Chemical', '-', (40, 45))
51795	33562413	Experimentally, LAA induces mesothelial cell autoantibodies (MCAAs), collagen deposition both in vitro and in vivo, and laminar pleural radiographic changes.	('collagen', 'molecular_function', 'GO:0005202', ('69', '77'))	('LAA', 'Chemical', '-', (16, 19))	('induces', 'Reg', (20, 27))	('LAA', 'Var', (16, 19))	('laminar pleural radiographic changes', 'CPA', (120, 156))	('collagen deposition', 'CPA', (69, 88))	('mesothelial cell', 'CPA', (28, 44))	('men', 'Species', '9606', (6, 9))
51913	33230247	High expression of fibulin-3 in tumor tissue could predict poor survival in patients with mesothelioma (P = 0.02).	('patients', 'Species', '9606', (76, 84))	('High', 'Var', (0, 4))	('fibulin-3', 'Gene', '2202', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mesothelioma', 'Disease', (90, 102))	('poor', 'NegReg', (59, 63))	('fibulin-3', 'Gene', (19, 28))	('tumor', 'Disease', (32, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
51926	33230247	Previous studies found that BAP1 mutation and Ki-67 index > 5% were associated with prolonged survival time of malignant mesothelioma, based on tissue microarray (TMA) method.	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('TMA', 'Disease', 'MESH:D000783', (163, 166))	('malignant mesothelioma', 'Disease', (111, 133))	('BAP1', 'Gene', (28, 32))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (111, 133))	('TMA', 'Disease', (163, 166))	('prolonged', 'PosReg', (84, 93))	('survival time', 'CPA', (94, 107))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (111, 133))
51969	33230247	High expression of fibulin-3 in tissue could independently predict worse overall survival of mesothelioma (HR = 1.91, P = 0.02; model 1 of Table 2).	('High', 'Var', (0, 4))	('fibulin-3', 'Gene', '2202', (19, 28))	('mesothelioma', 'Disease', (93, 105))	('fibulin-3', 'Gene', (19, 28))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('worse', 'NegReg', (67, 72))	('overall survival', 'MPA', (73, 89))
51974	33230247	In detail, mesothelioma patients with high expression of fibulin-3 had poor survival (median survival time: 8 vs. 19.5 months) than those with low expression among < 60 years patients.	('poor', 'NegReg', (71, 75))	('mesothelioma', 'Disease', (11, 23))	('high expression', 'Var', (38, 53))	('fibulin-3', 'Gene', '2202', (57, 66))	('patients', 'Species', '9606', (175, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('patients', 'Species', '9606', (24, 32))	('fibulin-3', 'Gene', (57, 66))
51976	33230247	High expression of fibulin-3 was also linked with poorer survival of mesothelioma among patients with epithelial type (median survival time = 10.5 months), peritoneal mesothelioma patients (median survival time = 8 months), and surgical patients (median survival time = 7.6 months).	('High', 'Var', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('patients', 'Species', '9606', (88, 96))	('fibulin-3', 'Gene', '2202', (19, 28))	('patients', 'Species', '9606', (180, 188))	('mesothelioma', 'Disease', (69, 81))	('survival', 'MPA', (57, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (156, 179))	('fibulin-3', 'Gene', (19, 28))	('patients', 'Species', '9606', (237, 245))	('mesothelioma', 'Disease', (167, 179))	('poorer', 'NegReg', (50, 56))
51977	33230247	High expression of HMGB1 was significantly associated with poor survival (median survival time = 9.6 months), while high expression of fibulin-3 and HMGB1 combination was associated with poor survival among patients of pleural mesothelioma (median survival time = 10.5 months).	('pleural mesothelioma', 'Disease', (219, 239))	('HMGB1', 'Gene', '3146', (19, 24))	('patients', 'Species', '9606', (207, 215))	('High expression', 'Var', (0, 15))	('fibulin-3', 'Gene', '2202', (135, 144))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (219, 239))	('poor', 'NegReg', (59, 63))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (219, 239))	('fibulin-3', 'Gene', (135, 144))	('HMGB1', 'Gene', (149, 154))	('HMGB1', 'Gene', (19, 24))	('HMGB1', 'Gene', '3146', (149, 154))
52041	29303405	Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines.	('PDAC', 'Phenotype', 'HP:0006725', (310, 314))	('PYK2', 'Gene', (164, 168))	('FAK', 'molecular_function', 'GO:0004717', ('124', '127'))	('invasion', 'CPA', (298, 306))	('PYK2', 'Gene', '2185', (263, 267))	('proline rich tyrosine kinase 2', 'Gene', '2185', (132, 162))	('PF-573228', 'Chemical', 'MESH:C521108', (57, 66))	('cell growth', 'biological_process', 'GO:0016049', ('272', '283'))	('motility', 'CPA', (285, 293))	('inhibits', 'NegReg', (242, 250))	('PF-431396', 'Var', (72, 81))	('PYK2', 'Gene', (263, 267))	('VS-6063', 'Var', (182, 189))	('VS-6063', 'Chemical', 'MESH:C584510', (182, 189))	('FAK', 'molecular_function', 'GO:0004717', ('251', '254'))	('FAK', 'Enzyme', (251, 254))	('PYK2', 'Gene', '2185', (164, 168))	('PF-573228', 'Var', (57, 66))	('PDAC', 'Chemical', '-', (310, 314))	('proline rich tyrosine kinase 2', 'Gene', (132, 162))	('PF-431396', 'Chemical', '-', (72, 81))
52042	29303405	Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines.	('PF-573228', 'Chemical', 'MESH:C521108', (15, 24))	('inhibition', 'NegReg', (83, 93))	('PF-431396', 'Var', (26, 35))	('inhibition of growth', 'biological_process', 'GO:0045926', ('83', '103'))	('PF-431396', 'Chemical', '-', (26, 35))	('PF-573228', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('VS-6063', 'Chemical', 'MESH:C584510', (40, 47))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
52043	29303405	Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines.	('phosphorylation', 'MPA', (44, 59))	('cell cycle arrest', 'CPA', (144, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('apoptosis', 'CPA', (130, 139))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('Y397', 'Chemical', '-', (87, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('144', '161'))	('induced', 'Reg', (110, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('Y397', 'Var', (87, 91))	('FAK', 'Protein', (63, 66))	('suppressed', 'NegReg', (29, 39))
52045	29303405	Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death.	('increase', 'PosReg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cell death', 'biological_process', 'GO:0008219', ('186', '196'))	('3D-tumor', 'Disease', (15, 23))	('tumor', 'Disease', (18, 23))	('decrease', 'NegReg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mice', 'Species', '10090', (78, 82))	('tumor', 'Disease', (141, 146))	('organoid cell death', 'CPA', (177, 196))	('Kras', 'Gene', (65, 69))	('PF-573228', 'Chemical', 'MESH:C521108', (96, 105))	('Kras', 'Gene', '16653', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('PF-573228', 'Var', (96, 105))	('3D-tumor', 'Disease', 'MESH:D009369', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
52055	29303405	Previously it has been shown that PDAC is a very complex genetic disease and could be due to successive accumulation of mutations in the KRAS, CDKN2A, TP53 and SMAD4 genes.	('SMAD4', 'Gene', '4089', (160, 165))	('PDAC', 'Chemical', '-', (34, 38))	('TP53', 'Gene', (151, 155))	('SMAD4', 'Gene', (160, 165))	('PDAC', 'Disease', (34, 38))	('CDKN2A', 'Gene', (143, 149))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('due', 'Reg', (86, 89))	('KRAS', 'Gene', (137, 141))	('mutations', 'Var', (120, 129))	('genetic disease', 'Disease', (57, 72))	('CDKN2A', 'Gene', '1029', (143, 149))	('KRAS', 'Gene', '3845', (137, 141))	('genetic disease', 'Disease', 'MESH:D030342', (57, 72))	('TP53', 'Gene', '7157', (151, 155))
52066	29303405	Src-mediated phosphorylation of tyrosine-397 (Y397) in FAK results in its activation.	('FAK', 'Disease', (55, 58))	('Y397', 'Var', (46, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('Y397', 'Chemical', '-', (46, 50))	('Src', 'Gene', (0, 3))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('Src', 'Gene', '6714', (0, 3))	('activation', 'PosReg', (74, 84))	('FAK', 'molecular_function', 'GO:0004717', ('55', '58'))
52068	29303405	FAK is over-expressed in various tumor types including colon, breast, prostate, thyroid, neuroblastoma, ovarian, cervical, brain, head and neck, liver, esophageal, pancreatic and acute myeloid leukemia; high expression of FAK invariably bodes poor prognosis.	('neck', 'cellular_component', 'GO:0044326', ('139', '143'))	('high expression', 'Var', (203, 218))	('neuroblastoma', 'Disease', (89, 102))	('poor', 'Disease', (243, 247))	('pancreatic', 'Disease', (164, 174))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('acute myeloid leukemia', 'Disease', (179, 201))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('tumor', 'Disease', (33, 38))	('thyroid', 'Disease', (80, 87))	('prostate', 'Disease', (70, 78))	('ovarian', 'Disease', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('FAK', 'Gene', (0, 3))	('ovarian', 'Disease', 'MESH:D010051', (104, 111))	('leukemia', 'Phenotype', 'HP:0001909', (193, 201))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (179, 201))	('bodes', 'Reg', (237, 242))	('FAK', 'molecular_function', 'GO:0004717', ('222', '225'))	('over-expressed', 'PosReg', (7, 21))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (179, 201))	('FAK', 'Gene', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (185, 201))	('pancreatic', 'Disease', 'MESH:D010195', (164, 174))	('esophageal', 'Disease', (152, 162))
52069	29303405	In the present study, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines and describe the effects of the three inhibitors of FAK on tumor growth using in vitro and ex vivo models of MPM and PDAC.	('FAK', 'molecular_function', 'GO:0004717', ('147', '150'))	('FAK', 'molecular_function', 'GO:0004717', ('42', '45'))	('MPM', 'Disease', (204, 207))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('inhibitors', 'Var', (133, 143))	('PDAC', 'Phenotype', 'HP:0006725', (212, 216))	('overexpressed', 'PosReg', (49, 62))	('FAK', 'Gene', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PDAC', 'Chemical', '-', (71, 75))	('effects', 'Reg', (112, 119))	('PDAC', 'Chemical', '-', (212, 216))	('tumor', 'Disease', (154, 159))
52070	29303405	PF-573228 (Pfizer, New York City) is a highly specific, ATP competitor that binds with the kinase domain of FAK.	('FAK', 'molecular_function', 'GO:0004717', ('108', '111'))	('binds', 'Interaction', (76, 81))	('PF-573228', 'Chemical', 'MESH:C521108', (0, 9))	('PF-573228', 'Var', (0, 9))	('ATP', 'Chemical', 'MESH:D000255', (56, 59))
52071	29303405	Treatment with PF-573228 blocks FAK phosphorylation on Tyr397 as well as the phosphorylation of its downstream target, paxillin.	('phosphorylation', 'MPA', (77, 92))	('PF-573228', 'Chemical', 'MESH:C521108', (15, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('FAK', 'molecular_function', 'GO:0004717', ('32', '35'))	('Tyr397', 'Var', (55, 61))	('PF-573228', 'Var', (15, 24))	('Tyr397', 'Chemical', '-', (55, 61))	('FAK phosphorylation', 'MPA', (32, 51))	('blocks', 'NegReg', (25, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))
52072	29303405	PF-431396 is an inhibitor of FAK and the proline-rich tyrosine kinase 2 (PYK2).	('PYK2', 'Gene', '2185', (73, 77))	('proline-rich tyrosine kinase 2', 'Gene', (41, 71))	('PYK2', 'Gene', (73, 77))	('PF-431396', 'Var', (0, 9))	('PF-431396', 'Chemical', '-', (0, 9))	('proline-rich tyrosine kinase 2', 'Gene', '2185', (41, 71))	('FAK', 'molecular_function', 'GO:0004717', ('29', '32'))
52075	29303405	Cleaved PARP (#5625), FAK (#130009), p-FAK (Y397) (#3283), and Cyclin D1 (#2922) were from Cell Signaling (Danvers, MA, USA).	('#3283', 'Var', (51, 56))	('Cyclin', 'molecular_function', 'GO:0016538', ('63', '69'))	('Y397', 'Chemical', '-', (44, 48))	('FAK', 'molecular_function', 'GO:0004717', ('22', '25'))	('PARP', 'Gene', '142', (8, 12))	('#5625', 'Var', (14, 19))	('#130009', 'Var', (27, 34))	('#2922', 'Var', (74, 79))	('Cyclin D1', 'Gene', '595', (63, 72))	('Signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('PARP', 'Gene', (8, 12))	('FAK', 'molecular_function', 'GO:0004717', ('39', '42'))	('Cyclin D1', 'Gene', (63, 72))
52077	29303405	Mesothelioma cell lines (H2596, H513, H2461, H2052, H2452, H28, H2373) and one benign transformed mesothelial control cell line Met-5A and also Pancreatic cancer cell lines (PANC-1, COLO-357, CD18, AsPC-1, MiaPaca 2, and Capan 1) were obtained from American Type Culture Collection (ATCC) (Manassas, VA, USA).	('H2052', 'Var', (45, 50))	('AsPC-1', 'CellLine', 'CVCL:0152', (198, 204))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('H2052', 'CellLine', 'CVCL:1518', (45, 50))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('H513', 'CellLine', 'CVCL:A570', (32, 36))	('H2596', 'Var', (25, 30))	('COLO', 'Species', '307630', (182, 186))	('MiaPaca 2', 'CellLine', 'CVCL:0428', (206, 215))	('H28', 'Var', (59, 62))	('Pancreatic cancer', 'Disease', (144, 161))	('CD18', 'Gene', (192, 196))	('PANC-1', 'CellLine', 'CVCL:0480', (174, 180))	('H2452', 'CellLine', 'CVCL:1553', (52, 57))	('CD18', 'Gene', '3689', (192, 196))	('H2461', 'Var', (38, 43))	('H2373', 'CellLine', 'CVCL:A533', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('H2452', 'Var', (52, 57))	('H2596', 'CellLine', 'CVCL:A546', (25, 30))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('H2461', 'CellLine', 'CVCL:A536', (38, 43))
52081	29303405	PF-573228, PF-431396, and VS-6063 were purchased from Selleck Chemicals (Houston, TX, USA) and the stock solutions were prepared in DMSO and stored at -20 C. Cells were treated with the indicated concentrations of inhibitors for the given time.	('PF-573228', 'Chemical', 'MESH:C521108', (0, 9))	('PF-573228', 'Var', (0, 9))	('PF-431396', 'Var', (11, 20))	('VS-6063', 'Var', (26, 33))	('DMSO', 'Chemical', 'MESH:D004121', (132, 136))	('PF-431396', 'Chemical', '-', (11, 20))	('VS-6063', 'Chemical', 'MESH:C584510', (26, 33))
52088	29303405	In brief, tumor organoids were established after tumor resection, mechanical and enzymatic digestion of pancreatic tumor from 50th week of KC autochthonous mouse model with 0.012% (w/v) collagenase XI (Sigma, St Louis, MO) and 0.012% (w/v) dispase (GIBCO, Waltham, MA) in DMEM media containing 1% FBS (GIBCO) and were embedded in (GFR) Matrigel (BD Biosciences, San Jose, CA) and seeded in 48 well plate as described previously.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('digestion', 'biological_process', 'GO:0007586', ('91', '100'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic tumor', 'Disease', 'MESH:D010190', (104, 120))	('FBS', 'Disease', 'MESH:D005198', (297, 300))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (115, 120))	('0.012%', 'Var', (227, 233))	('FBS', 'Disease', (297, 300))	('tumor', 'Disease', (49, 54))	('mouse', 'Species', '10090', (156, 161))	('0.012%', 'Var', (173, 179))	('pancreatic tumor', 'Disease', (104, 120))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (104, 120))
52104	29303405	However, both PF-573228 and VS-6063 at this concentration failed to demonstrate any discernable effect on apoptosis.	('VS-6063', 'Var', (28, 35))	('VS-6063', 'Chemical', 'MESH:C584510', (28, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('PF-573228', 'Chemical', 'MESH:C521108', (14, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('PF-573228', 'Var', (14, 23))
52105	29303405	The data clearly showed that, PF-431396 was more potent in inducing apoptosis (significant at all tested concentrations, P<= 0.001) in MPM cells as compared to PF-573228 (significant at 5 and 10 muM) and VS-6063 (only at 5 and 7.5 muM concentrations).	('inducing', 'Reg', (59, 67))	('muM', 'Gene', '56925', (195, 198))	('PF-431396', 'Var', (30, 39))	('muM', 'Gene', (195, 198))	('PF-431396', 'Chemical', '-', (30, 39))	('apoptosis', 'CPA', (68, 77))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('muM', 'Gene', '56925', (231, 234))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('VS-6063', 'Chemical', 'MESH:C584510', (204, 211))	('PF-573228', 'Chemical', 'MESH:C521108', (160, 169))	('muM', 'Gene', (231, 234))
52106	29303405	Similar results were observed with PDAC cells (Miapaca 2) (Fig 2C & D) (For PF-431396 P<0.001 at all the concentrations, PF-573228 P<0.001 at 10muM and VS-6068 P<0.001 at 5 and 7.5 muM concentrations).	('Miapaca', 'Chemical', '-', (47, 54))	('For PF-431396 P', 'Var', (72, 87))	('PDAC', 'Phenotype', 'HP:0006725', (35, 39))	('muM', 'Gene', '56925', (144, 147))	('muM', 'Gene', '56925', (181, 184))	('PDAC', 'Chemical', '-', (35, 39))	('muM', 'Gene', (144, 147))	('muM', 'Gene', (181, 184))	('and VS-6068', 'Var', (148, 159))	('PF-573228', 'Chemical', 'MESH:C521108', (121, 130))	('PF-431396', 'Chemical', '-', (76, 85))
52113	29303405	Treatment of H2596 cells with PF-431396 significantly arrested the MPM cells in G2/M phase at all the concentrations tested (1 to 10 muM) but maximum arrest was seen at 2.5 muM concentration (P <= 0.001 for all concentrations).	('arrested', 'NegReg', (54, 62))	('muM', 'Gene', (133, 136))	('PF-431396', 'Var', (30, 39))	('M phase', 'biological_process', 'GO:0000279', ('83', '90'))	('PF-431396', 'Chemical', '-', (30, 39))	('muM', 'Gene', '56925', (173, 176))	('H2596', 'CellLine', 'CVCL:A546', (13, 18))	('muM', 'Gene', '56925', (133, 136))	('muM', 'Gene', (173, 176))	('MPM cells in G2/M phase', 'CPA', (67, 90))
52114	29303405	In comparison, PF-573228 arrested the MPM cells in G2/M phase only at higher concentrations (5 and 10 muM, P <= 0.001) (Fig 3A).	('PF-573228', 'Chemical', 'MESH:C521108', (15, 24))	('muM', 'Gene', (102, 105))	('G2/M phase', 'CPA', (51, 61))	('PF-573228', 'Var', (15, 24))	('MPM cells', 'CPA', (38, 47))	('M phase', 'biological_process', 'GO:0000279', ('54', '61'))	('muM', 'Gene', '56925', (102, 105))
52116	29303405	Treatment with VS-6063 on the other hand, significantly arrested MPM cells in G2/M phase at all the concentrations tested (concentration-related P <= 0.05-0.001) (Fig 3B).	('M phase', 'biological_process', 'GO:0000279', ('81', '88'))	('MPM cells in G2/M phase', 'CPA', (65, 88))	('VS-6063', 'Var', (15, 22))	('arrested', 'NegReg', (56, 64))	('VS-6063', 'Chemical', 'MESH:C584510', (15, 22))
52117	29303405	MiaPaca 2 treated with VS-6063 succumbed to arrest at G2/M phase at higher concentrations (P <= 0.01 at 5 muM and P <= 0.001 at 7.5muM).	('muM', 'Gene', '56925', (106, 109))	('muM', 'Gene', (106, 109))	('M phase', 'biological_process', 'GO:0000279', ('57', '64'))	('MiaPaca 2', 'CellLine', 'CVCL:0428', (0, 9))	('muM', 'Gene', '56925', (131, 134))	('VS-6063', 'Var', (23, 30))	('VS-6063', 'Chemical', 'MESH:C584510', (23, 30))	('muM', 'Gene', (131, 134))
52122	29303405	Treatment with PF-431396 resulted in increased levels of cleaved PARP in both MPM cells as compared to PF-573228.	('PF-431396', 'Chemical', '-', (15, 24))	('cleaved', 'MPA', (57, 64))	('PARP', 'Gene', (65, 69))	('levels', 'MPA', (47, 53))	('PF-573228', 'Chemical', 'MESH:C521108', (103, 112))	('increased', 'PosReg', (37, 46))	('PARP', 'Gene', '142', (65, 69))	('PF-431396', 'Var', (15, 24))
52124	29303405	This clearly suggested that PF-431396 is relatively more potent in triggering apoptosis and inhibiting cell cycle progression as compared to PF-573228.	('triggering', 'Reg', (67, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('apoptosis', 'CPA', (78, 87))	('cell cycle progression', 'CPA', (103, 125))	('cell cycle', 'biological_process', 'GO:0007049', ('103', '113'))	('PF-431396', 'Var', (28, 37))	('PF-431396', 'Chemical', '-', (28, 37))	('PF-573228', 'Chemical', 'MESH:C521108', (141, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('inhibiting', 'NegReg', (92, 102))
52125	29303405	We next investigated the effect of PF-573228, PF-431396 and VS-6063 on FAK Y397 phosphorylation status, a reflection of its activity.	('PF-431396', 'Chemical', '-', (46, 55))	('PF-573228', 'Var', (35, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('Y397', 'Chemical', '-', (75, 79))	('VS-6063', 'Var', (60, 67))	('PF-573228', 'Chemical', 'MESH:C521108', (35, 44))	('PF-431396', 'Var', (46, 55))	('FAK', 'molecular_function', 'GO:0004717', ('71', '74'))	('VS-6063', 'Chemical', 'MESH:C584510', (60, 67))
52126	29303405	VS-6063 significantly inhibited phosphorylation of FAK at Y397 in both the MPM cell lines H2596 and H513, in a dose-dependent manner (Fig 5A).	('H2596', 'CellLine', 'CVCL:A546', (90, 95))	('VS-6063', 'Var', (0, 7))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('inhibited', 'NegReg', (22, 31))	('VS-6063', 'Chemical', 'MESH:C584510', (0, 7))	('H513', 'CellLine', 'CVCL:A570', (100, 104))	('FAK', 'molecular_function', 'GO:0004717', ('51', '54'))	('phosphorylation', 'MPA', (32, 47))	('FAK', 'Protein', (51, 54))	('Y397', 'Chemical', '-', (58, 62))
52128	29303405	Next, we detected the effect of both PF-573228 and PF-431396 on the levels of p-FAK protein in Miapaca 2 and Capan 1 cells in a dose-dependent manner.	('PF-573228', 'Chemical', 'MESH:C521108', (37, 46))	('FAK', 'molecular_function', 'GO:0004717', ('80', '83'))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('PF-573228', 'Var', (37, 46))	('PF-431396', 'Var', (51, 60))	('levels of p-FAK protein', 'MPA', (68, 91))	('Miapaca', 'Chemical', '-', (95, 102))	('PF-431396', 'Chemical', '-', (51, 60))
52129	29303405	PF-431396 decreased the levels of p-FAK in both Miapaca 2 and Capan 1 cells.	('decreased', 'NegReg', (10, 19))	('PF-431396', 'Var', (0, 9))	('FAK', 'molecular_function', 'GO:0004717', ('36', '39'))	('PF-431396', 'Chemical', '-', (0, 9))	('Miapaca', 'Chemical', '-', (48, 55))	('levels of p-FAK', 'MPA', (24, 39))
52130	29303405	However, PF-573228 had a dramatic suppressive effect only in Capan 1 cells, whereas in Miapaca 2 cells the same effect was observed only at a much higher concentration (Fig 5C).	('PF-573228', 'Var', (9, 18))	('suppressive', 'NegReg', (34, 45))	('PF-573228', 'Chemical', 'MESH:C521108', (9, 18))	('Miapaca', 'Chemical', '-', (87, 94))
52135	29303405	VS-6063 appeared to be the most effective at all the concentrations tested in inhibiting anchorage-independent growth of MPM cells followed by PF-431396.	('VS-6063', 'Var', (0, 7))	('anchorage-independent growth', 'CPA', (89, 117))	('VS-6063', 'Chemical', 'MESH:C584510', (0, 7))	('inhibiting', 'NegReg', (78, 88))	('PF-431396', 'Chemical', '-', (143, 152))
52138	29303405	Once again, VS-6063 exhibited the maximum effect followed by PF-431396, and PF-573228 had the least effect (P <= 0.001 for all the three FAK inhibitors) (Fig 6C, D).	('PF-431396', 'Var', (61, 70))	('PF-573228', 'Var', (76, 85))	('PF-431396', 'Chemical', '-', (61, 70))	('VS-6063', 'Var', (12, 19))	('FAK', 'molecular_function', 'GO:0004717', ('137', '140'))	('VS-6063', 'Chemical', 'MESH:C584510', (12, 19))	('PF-573228', 'Chemical', 'MESH:C521108', (76, 85))
52139	29303405	Similarly, MiaPaca 2 cells when treated individually with the three FAK inhibitors resulted in significant decrease in the number of colonies in a dose-dependent manner as compared to untreated control (P <= 0.001 for PF compounds and VS-6063 except at lowest concentration).	('FAK', 'molecular_function', 'GO:0004717', ('68', '71'))	('PF', 'Chemical', 'MESH:C002997', (218, 220))	('decrease', 'NegReg', (107, 115))	('VS-6063', 'Var', (235, 242))	('VS-6063', 'Chemical', 'MESH:C584510', (235, 242))	('MiaPaca 2', 'CellLine', 'CVCL:0428', (11, 20))
52140	29303405	PF-431396 and PF-573228 inhibitors were more effective than VS-6063 (Fig 6C, D).	('PF-573228 inhibitors', 'Var', (14, 34))	('PF-431396', 'Var', (0, 9))	('PF-431396', 'Chemical', '-', (0, 9))	('PF-573228', 'Chemical', 'MESH:C521108', (14, 23))	('VS-6063', 'Chemical', 'MESH:C584510', (60, 67))
52146	29303405	PDAC cells were treated with 1 muM of PF-431396 and 4 muM of PF-573228 for 24 h and inoculated to 96 well plate coated with fibronectin.	('muM', 'Gene', (54, 57))	('PDAC', 'Chemical', '-', (0, 4))	('PF-573228', 'Chemical', 'MESH:C521108', (61, 70))	('muM', 'Gene', '56925', (31, 34))	('fibronectin', 'Gene', (124, 135))	('PF-431396', 'Var', (38, 47))	('PF-573228', 'Var', (61, 70))	('PF-431396', 'Chemical', '-', (38, 47))	('muM', 'Gene', (31, 34))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('muM', 'Gene', '56925', (54, 57))	('fibronectin', 'Gene', '2335', (124, 135))
52153	29303405	4B & D, represent normalized resistance at indicated times for vehicle and PF-431396 and PF-573228 inhibitors for both the cell lines PF-573228 and PF-431396 significantly reduced maximum resistance of MiaPaca 2 (P <= 0.05) and Capan 1 (P <= 0.01) cells compared with vehicle (Supplementary Fig.	('PF-573228', 'Chemical', 'MESH:C521108', (134, 143))	('PF-573228', 'Chemical', 'MESH:C521108', (89, 98))	('PF-431396', 'Chemical', '-', (75, 84))	('and', 'Var', (144, 147))	('reduced maximum', 'MPA', (172, 187))	('lines', 'Var', (128, 133))	('PF-431396', 'Chemical', '-', (148, 157))	('significantly', 'NegReg', (158, 171))	('MiaPaca 2', 'CellLine', 'CVCL:0428', (202, 211))
52156	29303405	A statistically significant reduction in the growth of KC tumor organoids was observed at 10 microM concentration of PF-573228 (p = 0.03) as compared to untreated controls (Fig.	('PF-573228', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('growth', 'CPA', (45, 51))	('KC tumor', 'Disease', (55, 63))	('KC tumor', 'Disease', 'MESH:D009369', (55, 63))	('PF-573228', 'Chemical', 'MESH:C521108', (117, 126))	('reduction', 'NegReg', (28, 37))
52163	29303405	Here, we have shown that FAK is overexpressed in a variety of PDAC and MPM cell lines and when treated with FAK inhibitors (PF-573228, PF-431396, and VS-6063) suppressed cell proliferation and anchorage independent colony formation in a dose-dependent manner.	('FAK', 'molecular_function', 'GO:0004717', ('108', '111'))	('formation', 'biological_process', 'GO:0009058', ('222', '231'))	('PF-573228', 'Var', (124, 133))	('PF-431396', 'Chemical', '-', (135, 144))	('anchorage independent colony formation', 'CPA', (193, 231))	('PDAC', 'Chemical', '-', (62, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('cell proliferation', 'CPA', (170, 188))	('VS-6063', 'Var', (150, 157))	('suppressed', 'NegReg', (159, 169))	('PF-431396', 'Var', (135, 144))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))	('PF-573228', 'Chemical', 'MESH:C521108', (124, 133))	('VS-6063', 'Chemical', 'MESH:C584510', (150, 157))
52165	29303405	Ex-vivo experiments using tumor-organoids derived from autochthonous KC mice treated with FAK-specific inhibitor PF-573228 resulted in a significant decrease in size and promoted tumor organoid death suggesting drug effectiveness in a relatively complex 3D environment.	('tumor organoid death', 'Disease', (179, 199))	('PF-573228', 'Chemical', 'MESH:C521108', (113, 122))	('size', 'CPA', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PF-573228', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor organoid death', 'Disease', 'MESH:D003643', (179, 199))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('FAK', 'molecular_function', 'GO:0004717', ('90', '93'))	('decrease', 'NegReg', (149, 157))	('promoted', 'PosReg', (170, 178))	('tumor', 'Disease', (179, 184))
52166	29303405	Our results concur with several previous reports demonstrating FAK overexpression in a variety of cancers and a positive correlation between its overexpression and increased malignancy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('malignancy', 'Disease', (174, 184))	('overexpression', 'PosReg', (67, 81))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('FAK', 'Var', (63, 66))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('cancers', 'Disease', (98, 105))
52167	29303405	One of the underlying mechanisms could be amplification of the FAK gene or it's upregulation by tumor related transcription factors resulting in FAK overexpression and activation of FAK.	('FAK', 'molecular_function', 'GO:0004717', ('145', '148'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('upregulation', 'PosReg', (80, 92))	('tumor', 'Disease', (96, 101))	('FAK', 'molecular_function', 'GO:0004717', ('182', '185'))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('FAK', 'Gene', (63, 66))	('activation', 'PosReg', (168, 178))	('amplification', 'Var', (42, 55))	('FAK', 'Gene', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))	('overexpression', 'PosReg', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
52173	29303405	In contrast, H2373 and H2461 that expressed relatively low levels of FAK revealed much higher IC50 values to all the three FAK inhibitors suggesting that they were much less sensitive.	('H2373', 'Var', (13, 18))	('H2373', 'CellLine', 'CVCL:A533', (13, 18))	('H2461', 'CellLine', 'CVCL:A536', (23, 28))	('IC50 values', 'MPA', (94, 105))	('H2461', 'Var', (23, 28))	('FAK', 'molecular_function', 'GO:0004717', ('69', '72'))	('FAK', 'molecular_function', 'GO:0004717', ('123', '126'))	('higher', 'PosReg', (87, 93))
52176	29303405	Recently it was shown that hyperactivated FAK plays a key role in fibrosis and immunosuppression, which finally leads to progression of PDAC.	('FAK', 'Protein', (42, 45))	('PDAC', 'Phenotype', 'HP:0006725', (136, 140))	('PDAC', 'Disease', (136, 140))	('fibrosis', 'Disease', 'MESH:D005355', (66, 74))	('fibrosis', 'Disease', (66, 74))	('PDAC', 'Chemical', '-', (136, 140))	('hyperactivated', 'Var', (27, 41))	('leads to', 'Reg', (112, 120))	('FAK', 'molecular_function', 'GO:0004717', ('42', '45'))
52177	29303405	FAK inhibition, on the other hand using VS-4718 significantly suppressed tumor progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('VS-4718', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppressed', 'NegReg', (62, 72))	('tumor', 'Disease', (73, 78))
52178	29303405	In tumor cells, it has been reported that activated nuclear FAK enhances chemokine secretion and expansion of regulatory T cells, which in turn suppress cancer surveillance.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('activated nuclear', 'Var', (42, 59))	('chemokine secretion', 'MPA', (73, 92))	('cancer', 'Disease', (153, 159))	('regulatory T cells', 'CPA', (110, 128))	('expansion', 'CPA', (97, 106))	('tumor', 'Disease', (3, 8))	('enhances', 'PosReg', (64, 72))	('chemokine secretion', 'biological_process', 'GO:0090195', ('73', '92'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('FAK', 'molecular_function', 'GO:0004717', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('suppress', 'NegReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
52182	29303405	In case of esophageal cancer cells, TAE-226 inhibited cell migration and proliferation.	('esophageal cancer', 'Disease', (11, 28))	('inhibited', 'NegReg', (44, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (11, 28))	('TAE-226', 'Var', (36, 43))	('TAE-226', 'Chemical', 'MESH:C524632', (36, 43))	('cell migration', 'CPA', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cell migration', 'biological_process', 'GO:0016477', ('54', '68'))
52190	29303405	Interestingly, unlike our observations made here, PF-562271 does not affect growth or apoptosis of several human cancer cell lines; however, it strongly inhibits anchorage-independent growth in soft agar and tumor-xenografts in mice.	('PF-562271', 'Var', (50, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('agar', 'Chemical', 'MESH:D000362', (199, 203))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('PF', 'Chemical', 'MESH:C002997', (50, 52))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('anchorage-independent growth in soft agar', 'CPA', (162, 203))	('cancer', 'Disease', (113, 119))	('tumor', 'Disease', (208, 213))	('inhibits', 'NegReg', (153, 161))	('mice', 'Species', '10090', (228, 232))
52191	29303405	GSK2256098, another FAK inhibitor that suppresses Y397 phosphorylation also decreased cell viability, anchorage-independent growth, AKT/ERK phosphorylation and motility in a dose-dependent manner and increased apoptosis in PDAC.	('anchorage-independent growth', 'CPA', (102, 130))	('motility', 'CPA', (160, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('FAK', 'molecular_function', 'GO:0004717', ('20', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('phosphorylation', 'biological_process', 'GO:0016310', ('140', '155'))	('Y397', 'Chemical', '-', (50, 54))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('ERK', 'molecular_function', 'GO:0004707', ('136', '139'))	('ERK', 'Gene', '5594', (136, 139))	('AKT', 'Gene', (132, 135))	('GSK2256098', 'Var', (0, 10))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('cell viability', 'CPA', (86, 100))	('increased', 'PosReg', (200, 209))	('ERK', 'Gene', (136, 139))	('apoptosis', 'CPA', (210, 219))	('AKT', 'Gene', '207', (132, 135))	('GSK2256098', 'Chemical', 'MESH:C000600809', (0, 10))	('PDAC', 'Chemical', '-', (223, 227))	('decreased', 'NegReg', (76, 85))	('PDAC', 'Phenotype', 'HP:0006725', (223, 227))
52196	29303405	Our studies are in accordance; however low levels of CD1 should result in more of a G1/S arrest whereas our results show G2/M arrest.	('CD1', 'Gene', (53, 56))	('result in', 'Reg', (64, 73))	('G1/S arrest', 'Disease', (84, 95))	('low levels', 'Var', (39, 49))	('CD1', 'Gene', '911', (53, 56))
52201	29303405	In one such study, the effect of these inhibitors in neighboring endothelial cells residing in the tumor microenvironment was investigated using FAK inhibitors (PF-573228 and FAK Inhibitor 14).	('tumor', 'Disease', (99, 104))	('FAK', 'molecular_function', 'GO:0004717', ('145', '148'))	('PF-573228', 'Chemical', 'MESH:C521108', (161, 170))	('FAK', 'molecular_function', 'GO:0004717', ('175', '178'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PF-573228', 'Var', (161, 170))
52203	29303405	Also PF-573228 additionally induces apoptosis of endothelial cells within 36 h of post-drug administration.	('apoptosis', 'CPA', (36, 45))	('PF-573228', 'Var', (5, 14))	('apoptosis of endothelial cells', 'biological_process', 'GO:0072577', ('36', '66'))	('induces', 'Reg', (28, 35))	('PF-573228', 'Chemical', 'MESH:C521108', (5, 14))
52204	29303405	It is therefore very likely that inhibition of FAK adversely affects tumor growth via suppression of angiogenesis.	('inhibition', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('angiogenesis', 'CPA', (101, 113))	('suppression', 'NegReg', (86, 97))	('tumor', 'Disease', (69, 74))	('FAK', 'Gene', (47, 50))	('angiogenesis', 'biological_process', 'GO:0001525', ('101', '113'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('FAK', 'molecular_function', 'GO:0004717', ('47', '50'))
52251	26192180	The high asbestos exposure group also had a statistically significant increase in the risk of overall cancer (aHR= 1.71; 95% CI: 1.42-2.05), esophagus cancer (aHR= 2.31; 95% CI: 1.00-5.41), liver and intrahepatic bile duct cancer (aHR= 1.60; 95% CI: 1.08-2.36), and trachea, bronchus, and lung cancer (aHR= 3.08; 95% CI: 1.80-5.25).	('lung cancer', 'Disease', 'MESH:D008175', (289, 300))	('esophagus cancer', 'Disease', 'MESH:D004938', (141, 157))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (289, 300))	('cancer', 'Disease', (223, 229))	('bile duct cancer', 'Phenotype', 'HP:0030153', (213, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('trachea', 'Disease', (266, 273))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (102, 108))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('lung cancer', 'Disease', (289, 300))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('bronchus', 'Disease', (275, 283))	('esophagus cancer', 'Disease', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('high asbestos', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('liver and intrahepatic bile duct cancer', 'Disease', 'MESH:D002780', (190, 229))
52293	26192180	The real amount of asbestos within the eight job titles was: flame cutters (0.196 +- 0.202 f/cm3), odd-jobbers (0.208 +- 0.097 f/cm3), lifters (0.138 +- 0.156 f/cm3), supervisors (0.020 f/cm3), knockers (0.050 +- 0.014 f/cm3), sorters (0.060 f/cm3), drivers (0.020 f/cm3), and administrators (0.020 f/cm3).	('0.138 +- 0.156 f/cm3', 'Var', (144, 164))	('0.196', 'Var', (76, 81))	('0.050 +- 0.014 f/cm3', 'Var', (204, 224))	('0.060 f/cm3', 'Var', (236, 247))	('0.020', 'Var', (293, 298))	('0.020 f/cm3', 'Var', (180, 191))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('0.020 f/cm3', 'Var', (259, 270))	('0.208 +- 0.097 f/cm3', 'Var', (112, 132))
52322	26192180	The high asbestos exposure group also had a statistically significant increase in the risk of overall cancer (aHR = 1.71; 95% CI: 1.42-2.05), esophagus cancer (aHR = 2.31; 95% CI: 1.00-5.41), liver and intrahepatic bile duct cancer (aHR = 1.60; 95% CI: 1.08-2.36), trachea, bronchus, and lung cancer (aHR = 3.08; 95% CI: 1.80-5.25), and thymus, heart and mediastium cancer (aHR = 8.83; 95% CI: 1.19-65.7).	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Disease', (225, 231))	('lung cancer', 'Disease', 'MESH:D008175', (288, 299))	('cancer', 'Disease', (366, 372))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Disease', (152, 158))	('increase', 'PosReg', (70, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (288, 299))	('thymus', 'Disease', (337, 343))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('trachea', 'Disease', (265, 272))	('esophagus cancer', 'Disease', (142, 158))	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', (102, 108))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('lung cancer', 'Disease', (288, 299))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('liver and intrahepatic bile duct cancer', 'Disease', 'MESH:D002780', (192, 231))	('bile duct cancer', 'Phenotype', 'HP:0030153', (215, 231))	('bronchus', 'Disease', (274, 282))	('esophagus cancer', 'Disease', 'MESH:D004938', (142, 158))	('high asbestos', 'Var', (4, 17))
52326	26192180	Over the 24-year follow-up period, we found 61 cases of lung cancer (ICD-O3 code: C33 and C34) and two mesothelioma cases (ICD-O3 code: C35) in shipbreaking workers.	('C35', 'Gene', (136, 139))	('ICD', 'Disease', (69, 72))	('C35', 'Gene', '84299', (136, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('ship', 'Gene', '3635', (144, 148))	('C33', 'Gene', '3732', (82, 85))	('ship', 'Gene', (144, 148))	('mesothelioma', 'Disease', (103, 115))	('ICD', 'Disease', 'OMIM:252500', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))	('ICD', 'Disease', (123, 126))	('C33', 'Gene', (82, 85))	('lung cancer', 'Disease', (56, 67))	('ICD', 'Disease', 'OMIM:252500', (69, 72))	('C34', 'Var', (90, 93))
52337	26192180	Additionally, increased mortality with an increased risk for overall cancer (SMR = 1.44) and cancer of the liver (SMR = 1.86) were observed in Genoa shipyard workers.	('increased', 'PosReg', (14, 23))	('ship', 'Gene', (149, 153))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer of the liver', 'Phenotype', 'HP:0002896', (93, 112))	('Genoa', 'Var', (143, 148))	('ship', 'Gene', '3635', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
52455	25352940	The presence of necrosis, hemorrhages, infiltration of adjacent tissues, hypercellularity with oval cells, cell atypia, nuclear polymorphism and proliferative activity higher than 4 figures per 10 hpf also suggest a malignant form of solitary fibrous tumour (Table 3).	('necrosis', 'Disease', 'MESH:D009336', (16, 24))	('hemorrhages', 'Disease', 'MESH:D006470', (26, 37))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('necrosis', 'biological_process', 'GO:0008219', ('16', '24'))	('solitary fibrous tumour', 'Disease', 'MESH:D054364', (234, 257))	('nuclear polymorphism', 'Var', (120, 140))	('necrosis', 'biological_process', 'GO:0070265', ('16', '24'))	('hemorrhages', 'Disease', (26, 37))	('necrosis', 'biological_process', 'GO:0019835', ('16', '24'))	('necrosis', 'biological_process', 'GO:0008220', ('16', '24'))	('solitary fibrous tumour', 'Disease', (234, 257))	('necrosis', 'Disease', (16, 24))	('necrosis', 'biological_process', 'GO:0001906', ('16', '24'))	('proliferative activity', 'CPA', (145, 167))
52521	23055748	In addition, polyethylene glycol reduces endothelial cell interaction, and in turn the rate of extravasation is reduced.	('polyethylene glycol', 'Chemical', 'MESH:D011092', (13, 32))	('rate of extravasation', 'MPA', (87, 108))	('polyethylene glycol', 'Var', (13, 32))	('endothelial cell', 'CPA', (41, 57))	('reduced', 'NegReg', (112, 119))	('reduces', 'NegReg', (33, 40))
52522	23055748	Pegylated liposomal doxorubicin is extensively used for the treatment of cancer, especially breast cancer, ovarian cancer, and Kaposi's sarcoma, and has shown to be an active drug for MPM treatment in phase II studies.	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (127, 143))	("Kaposi's sarcoma", 'Disease', (127, 143))	('Pegylated', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ovarian cancer', 'Disease', (107, 121))	('cancer', 'Disease', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('especially breast cancer', 'Disease', 'MESH:D001943', (81, 105))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (99, 105))	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('especially breast cancer', 'Disease', (81, 105))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (127, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
52554	31967100	In particular, some polluting substances (asbestos, polycyclic aromatic hydrocarbons, carbon monoxide, heavy metals, gases) can cause respiratory and oncological diseases in the general population.	('polycyclic aromatic hydrocarbons', 'Var', (52, 84))	('cause', 'Reg', (128, 133))	('carbon monoxide', 'Chemical', 'MESH:D002248', (86, 101))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (52, 84))
52675	31967100	Cytogenetic studies have shown chromosomal and genetic alterations in patients with MM could play an important role in the initial development and subsequent progression of tumor .	('patients', 'Species', '9606', (70, 78))	('role', 'Reg', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('men', 'Species', '9606', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('genetic alterations', 'Var', (47, 66))	('chromosomal', 'Var', (31, 42))	('play', 'Reg', (93, 97))
52738	30888083	The ERC gene, originally discovered as the Erc (expressed in renal carcinoma) gene in the study of the Eker (Tsc2 mutant) rat model,6 is the name given to its human homolog gene, which was later identified as the MSLN gene.7 (The Eker rat is a rat model that is predisposed to develop hereditary renal carcinomas as a result of two hit mutations of the tumor suppressor gene, Tsc2.8 The Eker rat strain was originally developed by R. Eker, a Norwegian pathologist.	('renal carcinoma', 'Phenotype', 'HP:0005584', (61, 76))	('MSLN', 'Gene', (213, 217))	('tumor', 'Disease', (353, 358))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('Tsc2', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('hereditary renal carcinomas', 'Disease', 'MESH:D007680', (285, 312))	('MSLN', 'Gene', '10232', (213, 217))	('human', 'Species', '9606', (159, 164))	('Tsc2', 'Gene', '24855', (376, 380))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('hereditary renal carcinomas', 'Disease', (285, 312))	('renal carcinoma', 'Phenotype', 'HP:0005584', (296, 311))	('rat', 'Species', '10116', (244, 247))	('Erc', 'cellular_component', 'GO:0055037', ('43', '46'))	('renal carcinomas', 'Phenotype', 'HP:0005584', (296, 312))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('353', '369'))	('rat', 'Species', '10116', (235, 238))	('ERC', 'cellular_component', 'GO:0055037', ('4', '7'))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('Tsc2', 'Gene', (376, 380))	('rat', 'Species', '10116', (392, 395))	('tumor suppressor', 'biological_process', 'GO:0051726', ('353', '369'))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('mutations', 'Var', (336, 345))	('rat', 'Species', '10116', (122, 125))	('Tsc2', 'Gene', '24855', (109, 113))
52779	30888083	By using N-ERC 7-16 ELISA, we conducted a large-scale screening research study from February 2007 to March 2012; two subjects with abnormal N-ERC values did eventually develop mesothelioma, and one subject developed lung cancer and was surgically treated.	('N-ERC', 'Chemical', '-', (140, 145))	('abnormal N-ERC', 'Phenotype', 'HP:0000512', (131, 145))	('develop', 'PosReg', (168, 175))	('ERC', 'cellular_component', 'GO:0055037', ('142', '145'))	('N-ERC values', 'Gene', (140, 152))	('lung cancer', 'Disease', (216, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('abnormal', 'Var', (131, 139))	('mesothelioma', 'Disease', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('N-ERC', 'Chemical', '-', (9, 14))	('ERC', 'cellular_component', 'GO:0055037', ('11', '14'))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('mesothelioma', 'Disease', 'MESH:D008654', (176, 188))
52792	30888083	Other recent studies toward early diagnosis of mesothelioma include research regarding the antibodies YP218 and YP223 and histopathological marker development based on SKM9-2.	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('YP218', 'Var', (102, 107))	('YP223', 'Var', (112, 117))	('mesothelioma', 'Disease', (47, 59))
52804	29565815	Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (100, 109))	('BAP1', 'Gene', '8314', (138, 142))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('ARF', 'Disease', 'MESH:D058186', (124, 127))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('BAP1', 'Gene', (138, 142))	('CDKN2A', 'Gene', (117, 123))	('NF2', 'Gene', (129, 132))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('associated', 'Reg', (36, 46))	('CDKN2A', 'Gene', '1029', (117, 123))	('ARF', 'Disease', (124, 127))
52805	29565815	MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM.	('MMs', 'Chemical', 'MESH:D008741', (0, 3))	('Hippo pathway', 'Pathway', (33, 46))	('LATS1/2', 'Gene', (68, 75))	('dysregulation', 'Var', (123, 136))	('LATS1/2', 'Gene', '9113;26524', (68, 75))	('inactivation', 'NegReg', (17, 29))
52806	29565815	Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells.	('YAP1', 'Gene', (99, 103))	('YAP1', 'Gene', '10413', (99, 103))	('inactivation', 'Var', (27, 39))	('Hippo', 'Gene', (13, 18))	('malignant phenotypes to mesothelial cells', 'CPA', (157, 198))	('activation', 'PosReg', (81, 91))	('TAZ', 'Gene', '6901', (104, 107))	('TAZ', 'Gene', (104, 107))
52816	29565815	Recent investigations into the genetic factors that underlie MM pathogenesis have identified frequent mutations in CDKN2A/ARF, NF2, BRCA1-associated protein 1 (BAP1), and TP53, albeit only very rare mutations in other well-known oncogenes.	('TP53', 'Gene', (171, 175))	('CDKN2A', 'Gene', (115, 121))	('NF2', 'Gene', (127, 130))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('pathogenesis', 'biological_process', 'GO:0009405', ('64', '76'))	('CDKN2A', 'Gene', '1029', (115, 121))	('BAP1', 'Gene', '8314', (160, 164))	('ARF', 'Disease', 'MESH:D058186', (122, 125))	('BRCA1-associated protein 1', 'Gene', '8314', (132, 158))	('mutations', 'Var', (102, 111))	('BAP1', 'Gene', (160, 164))	('BRCA1-associated protein 1', 'Gene', (132, 158))	('ARF', 'Disease', (122, 125))	('TP53', 'Gene', '7157', (171, 175))
52817	29565815	A relatively small number of somatic mutations have also been observed in MM cases, whereas chromosome loss and/or mutations that affect genes involved in histone modification (SETDB1 and SETD2) and RNA processing (DDX3X, DDX51, and SF3B1), appear to be more common.	('DDX3X', 'Gene', '1654', (215, 220))	('DDX51', 'Gene', '317781', (222, 227))	('RNA', 'cellular_component', 'GO:0005562', ('199', '202'))	('RNA processing', 'biological_process', 'GO:0006396', ('199', '213'))	('mutations', 'Var', (115, 124))	('SETDB1', 'Gene', '9869', (177, 183))	('DDX3X', 'Gene', (215, 220))	('SF3B1', 'Gene', (233, 238))	('SETD2', 'Gene', '29072', (188, 193))	('histone modification', 'MPA', (155, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('histone modification', 'biological_process', 'GO:0016570', ('155', '175'))	('chromosome', 'CPA', (92, 102))	('SETD2', 'Gene', (188, 193))	('DDX51', 'Gene', (222, 227))	('SETDB1', 'Gene', (177, 183))	('SF3B1', 'Gene', '23451', (233, 238))	('loss', 'NegReg', (103, 107))
52819	29565815	Notably, however, it can also be caused by a familial cancer syndrome arising from germline BAP1 mutations.	('mutations', 'Var', (97, 106))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (45, 69))	('familial cancer syndrome', 'Disease', (45, 69))	('caused by', 'Reg', (33, 42))	('BAP1', 'Gene', '8314', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BAP1', 'Gene', (92, 96))
52828	29565815	Immune checkpoint inhibitors including anti-CTLA4 (tremelimumab and ipilimumab), anti-PD1 antibodies (nivolumab and pembrolizumab), and anti-PD-L1 antibodies (avelumab and durvalumab) are currently undergoing intensive investigation in relevant MM clinical trials.	('durvalumab', 'Chemical', 'MESH:C000613593', (172, 182))	('CTLA4', 'Gene', (44, 49))	('nivolumab', 'Chemical', 'MESH:D000077594', (102, 111))	('anti-PD1', 'Var', (81, 89))	('tremelimumab', 'Chemical', 'MESH:C520704', (51, 63))	('avelumab', 'Chemical', 'MESH:C000609138', (159, 167))	('anti-PD-L1', 'Var', (136, 146))	('pembrolizumab', 'Chemical', 'MESH:C582435', (116, 129))	('CTLA4', 'Gene', '1493', (44, 49))	('ipilimumab', 'Chemical', 'MESH:D000074324', (68, 78))
52834	29565815	The results of this study demonstrated that inhibiting EZH2 suppressed the proliferation of BAP1-mutant MM cell lines, suggesting that EZH2 inhibitors may represent promising candidate therapeutic agents for MM.	('suppressed', 'NegReg', (60, 70))	('EZH2', 'Gene', '2146', (55, 59))	('EZH2', 'Gene', (55, 59))	('BAP1', 'Gene', '8314', (92, 96))	('EZH2', 'Gene', '2146', (135, 139))	('proliferation', 'CPA', (75, 88))	('EZH2', 'Gene', (135, 139))	('inhibiting', 'Var', (44, 54))	('BAP1', 'Gene', (92, 96))
52836	29565815	MMs often exhibit reduced expression of arginosuccinate synthetase-1 (ASS1); thus, a synthetic lethal approach with pegylated-arginine deiminase ADI-PEG20, which depletes available arginine, showed a significant PFS improvement for patients with MM.	('expression', 'MPA', (26, 36))	('arginosuccinate synthetase-1', 'Gene', '445', (40, 68))	('MMs', 'Chemical', 'MESH:D008741', (0, 3))	('ASS1', 'Gene', (70, 74))	('ASS1', 'Gene', '445', (70, 74))	('arginosuccinate synthetase-1', 'Gene', (40, 68))	('patients', 'Species', '9606', (232, 240))	('arginine', 'Chemical', 'MESH:D001120', (126, 134))	('arginine', 'Chemical', 'MESH:D001120', (181, 189))	('ADI-PEG20', 'Var', (145, 154))
52837	29565815	Additional novel MM treatment strategies based on alterations of tumor suppressor genes, including BAP1, are currently under development.	('BAP1', 'Gene', (99, 103))	('tumor', 'Disease', (65, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('alterations', 'Var', (50, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('BAP1', 'Gene', '8314', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
52855	29565815	A previous study showed that a carboxyl-terminus NF2 (isoform 2) splicing variant does not exert any tumor suppressive activity, suggesting that functional merlin inactivation might also be caused by the expression of such variants; however, more recent studies conversely reported that both merlin isoforms 1 and 2 act as tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('merlin', 'Protein', (156, 162))	('tumor', 'Disease', (323, 328))	('variants', 'Var', (223, 231))	('tumor', 'Disease', (101, 106))	('variant', 'Var', (74, 81))	('inactivation', 'NegReg', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('splicing', 'biological_process', 'GO:0045292', ('65', '73'))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
52856	29565815	Merlin inactivation may also be caused via the upregulated expression of potential NF2-targeting microRNAs, such as hsa-miR-885-3p, although further research is required to elucidate how such mechanisms mediate MM pathogenesis.	('hsa-miR-885-3p', 'Var', (116, 130))	('inactivation', 'NegReg', (7, 19))	('upregulated', 'PosReg', (47, 58))	('NF2-targeting', 'Gene', (83, 96))	('pathogenesis', 'biological_process', 'GO:0009405', ('214', '226'))	('expression', 'MPA', (59, 69))	('Merlin', 'Gene', '4771', (0, 6))	('Merlin', 'Gene', (0, 6))
52858	29565815	Specifically, merlin expression attenuates the phosphorylation of focal adhesion kinase (FAK) at the critical Tyr397 phosphorylation site, and thereby disrupts the interaction between FAK and its binding partners, Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase (PI3K).	('p85', 'Gene', (222, 225))	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('focal adhesion kinase', 'Gene', '5747', (66, 87))	('disrupts', 'NegReg', (151, 159))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('merlin', 'Gene', (14, 20))	('expression', 'Var', (21, 31))	('Src', 'Gene', (214, 217))	('interaction', 'Interaction', (164, 175))	('phosphatidylinositol-3-kinase', 'Gene', '5293', (253, 282))	('FAK', 'molecular_function', 'GO:0004717', ('184', '187'))	('FAK', 'Gene', (89, 92))	('phosphatidylinositol-3-kinase', 'Gene', (253, 282))	('focal adhesion kinase', 'Gene', (66, 87))	('FAK', 'molecular_function', 'GO:0004717', ('89', '92'))	('FAK', 'Gene', (184, 187))	('Src', 'Gene', '6714', (214, 217))	('phosphorylation', 'MPA', (47, 62))	('FAK', 'Gene', '5747', (89, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('attenuates', 'NegReg', (32, 42))	('p85', 'Gene', '5296', (222, 225))	('FAK', 'Gene', '5747', (184, 187))	('Tyr397', 'Chemical', '-', (110, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('284', '288'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('66', '80'))
52859	29565815	These findings suggested that merlin inactivation is likely related, at least in part, to the upregulation of FAK activity.	('merlin', 'Protein', (30, 36))	('upregulation', 'PosReg', (94, 106))	('FAK', 'Gene', '5747', (110, 113))	('FAK', 'molecular_function', 'GO:0004717', ('110', '113'))	('FAK', 'Gene', (110, 113))	('inactivation', 'Var', (37, 49))
52860	29565815	As NF2 mutations are frequently detected in MM cases, genetically-engineered Nf2-knockout mouse models have been developed to evaluate the impact of NF2 inactivation on MM pathogenesis.	('mouse', 'Species', '10090', (90, 95))	('detected', 'Reg', (32, 40))	('pathogenesis', 'biological_process', 'GO:0009405', ('172', '184'))	('NF2', 'Gene', (3, 6))	('mutations', 'Var', (7, 16))
52862	29565815	Furthermore, loss of the wild-type Nf2 allele, leading to biallelic inactivation, was observed in all and 50% of asbestos-induced MMs from Nf2 (+/-) and wild-type mice, respectively.	('MMs', 'Chemical', 'MESH:D008741', (130, 133))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('Nf2', 'Gene', (35, 38))	('mice', 'Species', '10090', (163, 167))	('biallelic inactivation', 'MPA', (58, 80))	('Nf2', 'Var', (139, 142))	('asbestos-induced', 'Disease', (113, 129))
52863	29565815	Similar to human MMs, the tumors developed by the Nf2 (+/-) mice exhibited frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor-suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('149', '165'))	('MMs', 'Chemical', 'MESH:D008741', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('human', 'Species', '9606', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('mice', 'Species', '10090', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumors', 'Disease', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Cdkn2b', 'Gene', (142, 148))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (230, 235))	('Cdkn2a', 'Gene', '12578', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('Cdkn2b', 'Gene', '12579', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('deletions', 'Var', (95, 104))	('Tp53', 'Gene', (210, 214))	('Tp53', 'Gene', '22059', (210, 214))	('Cdkn2a', 'Gene', (112, 118))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('149', '165'))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumors', 'Disease', (26, 32))
52872	29565815	A previous study showed that four of five identified MM-associated TRAF7 mutations were mutually exclusive with NF2 mutations.	('MM-associated', 'Disease', (53, 66))	('TRAF7', 'Gene', (67, 72))	('mutations', 'Var', (73, 82))	('TRAF7', 'Gene', '84231', (67, 72))
52873	29565815	Notably, a similar pattern of exclusivity has been observed in TRAF7-mutated meningioma cases, which also frequently exhibit NF2 mutations.	('TRAF7', 'Gene', '84231', (63, 68))	('meningioma', 'Disease', (77, 87))	('meningioma', 'Phenotype', 'HP:0002858', (77, 87))	('mutations', 'Var', (129, 138))	('NF2', 'Gene', (125, 128))	('meningioma', 'Disease', 'MESH:D008577', (77, 87))	('TRAF7', 'Gene', (63, 68))
52875	29565815	Hippo pathway dysregulation has been indicated in a broad range of human carcinoma types including lung, colorectal, ovarian, and liver cancers.	('lung', 'Disease', (99, 103))	('colorectal', 'Disease', 'MESH:D015179', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('liver cancers', 'Disease', (130, 143))	('liver cancers', 'Disease', 'MESH:D006528', (130, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('carcinoma', 'Disease', (73, 82))	('ovarian', 'Disease', (117, 124))	('liver cancers', 'Phenotype', 'HP:0002896', (130, 143))	('dysregulation', 'Var', (14, 27))	('colorectal', 'Disease', (105, 115))	('ovarian', 'Disease', 'MESH:D010051', (117, 124))	('Hippo pathway', 'Pathway', (0, 13))	('human', 'Species', '9606', (67, 72))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
52877	29565815	In contrast, MM appears to be the only tumor type that is frequently associated with Hippo pathway mutations.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('associated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', (39, 44))	('Hippo pathway', 'Gene', (85, 98))
52878	29565815	In addition to NF2 mutations, genetic LATS2 inactivation is observed in MM cases, such that LATS2 inactivation, and its effects tumor suppression, were initially identified in seven of 20 MM cell lines analyzed in vitro.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('LATS2', 'Gene', (92, 97))	('LATS2', 'Gene', '26524', (92, 97))	('LATS2', 'Gene', (38, 43))	('mutations', 'Var', (19, 28))	('LATS2', 'Gene', '26524', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NF2', 'Gene', (15, 18))	('inactivation', 'NegReg', (44, 56))	('tumor', 'Disease', (128, 133))	('inactivation', 'NegReg', (98, 110))
52879	29565815	Similarly, 11% of 61 MPM primary cultures were found to harbor point mutations and/or large exon deletions that inactivated LATS2.	('LATS2', 'Gene', (124, 129))	('LATS2', 'Gene', '26524', (124, 129))	('inactivated', 'NegReg', (112, 123))	('point mutations', 'Var', (63, 78))
52880	29565815	Together, these findings indicate that NF2 and LATS2 mutations can be coincident in a given MM tumor.	('MM tumor', 'Disease', 'MESH:D009369', (92, 100))	('LATS2', 'Gene', (47, 52))	('LATS2', 'Gene', '26524', (47, 52))	('mutations', 'Var', (53, 62))	('NF2', 'Gene', (39, 42))	('MM tumor', 'Disease', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))
52881	29565815	A homozygous SAV1 deletion was also detected in an MM cell line, and one of 16 analyzed MM cell lines that were subjected to whole exome sequencing was previously shown to harbor a LATS1-inactivating LATS1-PSEN1 fusion gene.	('LATS1', 'Gene', '9113', (200, 205))	('PSEN1', 'Gene', (206, 211))	('PSEN1', 'Gene', '5663', (206, 211))	('SAV1', 'Gene', '60485', (13, 17))	('SAV1', 'Gene', (13, 17))	('LATS1', 'Gene', (181, 186))	('LATS1', 'Gene', '9113', (181, 186))	('deletion', 'Var', (18, 26))	('LATS1', 'Gene', (200, 205))
52882	29565815	Finally, a comprehensive genomic analysis of MM samples revealed frequent copy number loss among various Hippo pathway genes, including MST1 and LATS1.	('Hippo pathway genes', 'Gene', (105, 124))	('LATS1', 'Gene', '9113', (145, 150))	('copy number loss', 'Var', (74, 90))	('MST1', 'Gene', '4485', (136, 140))	('LATS1', 'Gene', (145, 150))	('MST1', 'Gene', (136, 140))
52884	29565815	Consistent with this finding, MM cell lines in which AJUBA is downregulated have been shown to exhibit higher levels of YAP1 dephosphorylation, whereas conversely, transducing MM cells with AJUBA has been demonstrated to significantly suppress YAP1 activity.	('YAP1', 'Gene', (120, 124))	('YAP1', 'Gene', '10413', (120, 124))	('YAP1', 'Gene', (244, 248))	('transducing', 'Var', (164, 175))	('YAP1', 'Gene', '10413', (244, 248))	('AJUBA', 'Gene', (190, 195))	('dephosphorylation', 'biological_process', 'GO:0016311', ('125', '142'))	('downregulated', 'NegReg', (62, 75))	('suppress', 'NegReg', (235, 243))	('AJUBA', 'Gene', (53, 58))	('AJUBA', 'Gene', '84962', (190, 195))	('higher', 'PosReg', (103, 109))	('AJUBA', 'Gene', '84962', (53, 58))
52887	29565815	As discussed, merlin-Hippo signaling inactivation leads to constitutive YAP1/TAZ activation.	('TAZ', 'Gene', '6901', (77, 80))	('TAZ', 'Gene', (77, 80))	('activation', 'PosReg', (81, 91))	('YAP1', 'Gene', (72, 76))	('YAP1', 'Gene', '10413', (72, 76))	('Hippo signaling', 'biological_process', 'GO:0035329', ('21', '36'))	('inactivation', 'Var', (37, 49))
52895	29565815	Notably, CTGF expression has been shown to be associated with abundant extracellular matrix formation in MM tissues.	('expression', 'Var', (14, 24))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('71', '91'))	('CTGF', 'Gene', '1490', (9, 13))	('CTGF', 'Gene', (9, 13))	('associated', 'Reg', (46, 56))
52896	29565815	Furthermore, CTGF expression was found to be significantly enhanced in MM cells in response to Hippo signaling inactivation, TGF-beta stimulation, and/or beta-catenin-TCF-LEF signaling (Figure 2).	('TGF-beta', 'Gene', '7040', (125, 133))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('TGF-beta', 'Gene', (125, 133))	('enhanced', 'PosReg', (59, 67))	('inactivation', 'Var', (111, 123))	('expression', 'MPA', (18, 28))	('Hippo signaling', 'biological_process', 'GO:0035329', ('95', '110'))	('CTGF', 'Gene', '1490', (13, 17))	('Hippo signaling', 'MPA', (95, 110))	('CTGF', 'Gene', (13, 17))
52900	29565815	PLCB4 (which encodes phospholipase-C beta4) was shown to be a YAP1-target gene, as inducing PLCB4 knockdown attenuated the growth of YAP1-transduced immortalized mesothelial cells, and YAP1-active (but not YAP1-non-active) MM cells.	('PLCB4', 'Gene', '5332', (0, 5))	('YAP1', 'Gene', (206, 210))	('YAP1', 'Gene', (62, 66))	('inducing', 'Reg', (83, 91))	('PLCB4', 'Gene', (92, 97))	('YAP1', 'Gene', (185, 189))	('knockdown', 'Var', (98, 107))	('YAP1', 'Gene', '10413', (185, 189))	('YAP1', 'Gene', '10413', (206, 210))	('YAP1', 'Gene', '10413', (62, 66))	('attenuated', 'NegReg', (108, 118))	('YAP1', 'Gene', (133, 137))	('PLCB4', 'Gene', (0, 5))	('phospholipase-C beta4', 'Gene', '5332', (21, 42))	('PLCB4', 'Gene', '5332', (92, 97))	('growth', 'CPA', (123, 129))	('phospholipase-C beta4', 'Gene', (21, 42))	('YAP1', 'Gene', '10413', (133, 137))
52901	29565815	Similarly, uveal melanoma has been reported to frequently harbor activating mutations in GNAQ and GNA11.	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('GNAQ', 'Gene', '2776', (89, 93))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('GNAQ', 'Gene', (89, 93))	('activating mutations', 'Var', (65, 85))
52904	29565815	Notably, uveal melanomas are also frequently associated with BAP1 mutations, in the same manner as MM.	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanomas', 'Disease', 'MESH:C536494', (9, 24))	('associated', 'Reg', (45, 55))	('BAP1', 'Gene', '8314', (61, 65))	('uveal melanomas', 'Disease', (9, 24))	('uveal melanomas', 'Phenotype', 'HP:0007716', (9, 24))
52906	29565815	Cancer develops via the accumulation of genetic and epigenetic alterations that promote malignant cell phenotypes.	('epigenetic alterations', 'Var', (52, 74))	('malignant cell phenotypes', 'CPA', (88, 113))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('promote', 'PosReg', (80, 87))
52907	29565815	Although the processes by which these occur during MM pathogenesis are not well understood, changes to critical MM-associated tumor suppressor genes are thought to confer one or more malignant phenotypes to normal mesothelial cells.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('changes', 'Var', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('pathogenesis', 'biological_process', 'GO:0009405', ('54', '66'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
52909	29565815	Treatment of the cells with exogenously transduced wild-type YAP1, and even more so, with an activated mutant YAP1 S127A, stimulated the mesothelial cells to form mesothelioma-like tumors.	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('YAP1', 'Gene', (110, 114))	('YAP1', 'Gene', '10413', (110, 114))	('YAP1', 'Gene', '10413', (61, 65))	('stimulated', 'PosReg', (122, 132))	('mesothelial cells', 'CPA', (137, 154))	('mesothelioma-like tumors', 'Disease', 'MESH:D008654', (163, 187))	('S127A', 'Mutation', 'rs762471803', (115, 120))	('S127A', 'Var', (115, 120))	('mesothelioma-like tumors', 'Disease', (163, 187))	('YAP1', 'Gene', (61, 65))
52912	29565815	Adding genetic NF2 screening to the standard methods of using fluorescence in situ hybridization (FISH) techniques to identify CDKN2A (p16Ink4a/p14Arf) deletions did not significantly improve the sensitivity or specificity of MM diagnosis.	('deletions', 'Var', (152, 161))	('CDKN2A', 'Gene', '1029', (127, 133))	('CDKN2A', 'Gene', (127, 133))	('p16Ink4a/p14Arf) deletions', 'Var', (135, 161))
52916	29565815	Likewise, a combination of homozygous CDKN2A deletions and hemizygous NF2 loss in peritoneal mesotheliomas has been shown to be an independent negative prognostic factor for both PFS and OS.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (82, 105))	('negative', 'NegReg', (143, 151))	('mesotheliomas', 'Disease', 'MESH:D008654', (93, 106))	('NF2', 'Gene', (70, 73))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (82, 106))	('mesotheliomas', 'Disease', (93, 106))	('loss', 'NegReg', (74, 78))	('deletions', 'Var', (45, 54))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (38, 44))	('PFS', 'Disease', (179, 182))
52918	29565815	This preferential effect of VS-4718 in merlin-deficient cells suggests that merlin may constitute a potential predictive biomarker for the enhanced response of MM cells to VS-4718 treatment.	('VS-4718', 'Var', (28, 35))	('VS-4718', 'Chemical', 'MESH:C559284', (172, 179))	('VS-4718', 'Chemical', 'MESH:C559284', (28, 35))	('merlin-deficient', 'Gene', (39, 55))
52923	29565815	The significant impact of Hippo pathway dysregulation and constitutive YAP1/TAZ activation on MM cells renders these events highly attractive as molecular targets for the development of novel therapeutic approaches to MM.	('Hippo pathway', 'Pathway', (26, 39))	('YAP1', 'Gene', '10413', (71, 75))	('dysregulation', 'Var', (40, 53))	('TAZ', 'Gene', '6901', (76, 79))	('YAP1', 'Gene', (71, 75))	('TAZ', 'Gene', (76, 79))	('activation', 'PosReg', (80, 90))
52926	29565815	For example, TEADs are thought to be the factors primarily expressed and involved in the prooncogenic functions of YAP1/TAZ in MM cells; thus, the disruption of YAP1/TAZ and TEAD interaction may represent a very promising approach.	('interaction', 'Interaction', (179, 190))	('YAP1', 'Gene', (161, 165))	('YAP1', 'Gene', '10413', (161, 165))	('TAZ', 'Gene', '6901', (120, 123))	('TAZ', 'Gene', (120, 123))	('disruption', 'Var', (147, 157))	('YAP1', 'Gene', (115, 119))	('YAP1', 'Gene', '10413', (115, 119))	('TAZ', 'Gene', '6901', (166, 169))	('TAZ', 'Gene', (166, 169))
52951	29565815	Conversely, they exert a weaker inhibitory effect in MM cells that also harbor BAP1 mutations; thus, the effectiveness of statin treatments in MM cells appears to vary dependent upon the cellular genetic/epigenetic background.	('mutations', 'Var', (84, 93))	('inhibitory effect', 'MPA', (32, 49))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))
52953	29565815	Although the mechanisms by which merlin suppresses mTOR signaling remain elusive, NF2 inactivation has been found to confer sensitivity to rapalogs in bladder cancer, suggesting that mTORC1 signaling likely sustains the expansion of merlin-deficient cancer cells.	('bladder cancer', 'Disease', (151, 165))	('mTORC1', 'Gene', (183, 189))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('mTOR signaling', 'MPA', (51, 65))	('mTORC1', 'cellular_component', 'GO:0031931', ('183', '189'))	('deficient cancer', 'Disease', 'MESH:D009369', (240, 256))	('suppresses', 'NegReg', (40, 50))	('deficient cancer', 'Disease', (240, 256))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('inactivation', 'Var', (86, 98))	('mTORC1', 'Gene', '382056', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('NF2', 'Gene', (82, 85))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
52958	29565815	MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, has been shown to suppress CRL4DCAF1 and attenuate YAP1 activation in NF2-mutant tumor cells.	('MLN4924', 'Var', (0, 7))	('DCAF1', 'Gene', '9730', (83, 88))	('suppress', 'NegReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('YAP1', 'Gene', (103, 107))	('NEDD8', 'Gene', (11, 16))	('DCAF1', 'Gene', (83, 88))	('YAP1', 'Gene', '10413', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('attenuate', 'NegReg', (93, 102))	('activation', 'MPA', (108, 118))	('NEDD8', 'Gene', '4738', (11, 16))	('tumor', 'Disease', (133, 138))	('NF2-mutant', 'Gene', (122, 132))
52959	29565815	Although MLN4924 alone did not exhibit significant preclinical activity, administering MLN4924 with the mTOR/PI3K inhibitor GCD-0980 suppressed the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts.	('patient', 'Species', '9606', (214, 221))	('suppressed', 'NegReg', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('MLN4924', 'Var', (87, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('109', '113'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('growth', 'CPA', (148, 154))	('GCD-0980', 'Chemical', '-', (124, 132))	('mouse', 'Species', '10090', (204, 209))	('tumor', 'Disease', (169, 174))	('NF2-mutant', 'Gene', (158, 168))
52961	29565815	Deregulated CTGF expression has been observed in many types of human malignancies including MM, and has been shown to be associated with increased cell proliferation, drug resistance, angiogenesis, adhesion/migration, and metastasis.	('cell proliferation', 'CPA', (147, 165))	('CTGF', 'Gene', '1490', (12, 16))	('metastasis', 'CPA', (222, 232))	('adhesion/migration', 'CPA', (198, 216))	('drug resistance', 'biological_process', 'GO:0009315', ('167', '182'))	('drug resistance', 'biological_process', 'GO:0042493', ('167', '182'))	('angiogenesis', 'CPA', (184, 196))	('drug resistance', 'CPA', (167, 182))	('Deregulated', 'Var', (0, 11))	('human', 'Species', '9606', (63, 68))	('CTGF', 'Gene', (12, 16))	('increased', 'PosReg', (137, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('observed', 'Reg', (37, 45))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('malignancies', 'Disease', (69, 81))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('associated', 'Reg', (121, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
52970	29565815	During detachment from the ECM, cells normally undergo anoikis (programmed cell death), which has been shown (in non-transformed cells) to be mediated by YAP1 inactivation.	('YAP1', 'Gene', (154, 158))	('YAP1', 'Gene', '10413', (154, 158))	('anoikis', 'Disease', (55, 62))	('ECM', 'Gene', '22915', (27, 30))	('anoikis', 'biological_process', 'GO:0043276', ('55', '62'))	('undergo', 'Reg', (47, 54))	('ECM', 'Gene', (27, 30))	('inactivation', 'Var', (159, 171))	('mediated', 'Reg', (142, 150))	('programmed cell death', 'biological_process', 'GO:0012501', ('64', '85'))
52971	29565815	Conversely, expression of constitutively active YAP1 has been found to promote the survival of detached cells.	('promote', 'PosReg', (71, 78))	('expression', 'Var', (12, 22))	('survival of detached cells', 'CPA', (83, 109))	('YAP1', 'Gene', '10413', (48, 52))	('YAP1', 'Gene', (48, 52))
52973	29565815	Although it is unclear how YAP1/TAZ is involved in these mesothelial repair processes, the anoikis-resistant phenotype characteristic of MM cells may be innate and/or enhanced by merlin-Hippo pathway inactivation.	('YAP1', 'Gene', (27, 31))	('enhanced', 'PosReg', (167, 175))	('YAP1', 'Gene', '10413', (27, 31))	('anoikis-resistant phenotype', 'CPA', (91, 118))	('TAZ', 'Gene', '6901', (32, 35))	('inactivation', 'Var', (200, 212))	('TAZ', 'Gene', (32, 35))	('anoikis', 'biological_process', 'GO:0043276', ('91', '98'))
52979	29565815	Although it remains unclear how these soluble factors influence MM cell growth and progression, and/or whether they influence YAP1/TAZ activity in MM cells, recurrent GRCR mutations (including GRM3, GPR149, and GPR98) have also been identified in MM cells.	('mutations', 'Var', (172, 181))	('YAP1', 'Gene', (126, 130))	('GPR149', 'Gene', (199, 205))	('GRCR', 'Gene', (167, 171))	('influence', 'Reg', (116, 125))	('YAP1', 'Gene', '10413', (126, 130))	('TAZ', 'Gene', '6901', (131, 134))	('GRM3', 'Gene', '2913', (193, 197))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))	('GPR149', 'Gene', '344758', (199, 205))	('GPR98', 'Gene', (211, 216))	('GRM3', 'Gene', (193, 197))	('soluble', 'cellular_component', 'GO:0005625', ('38', '45'))	('progression', 'CPA', (83, 94))	('TAZ', 'Gene', (131, 134))	('MM cell growth', 'CPA', (64, 78))	('GPR98', 'Gene', '84059', (211, 216))	('influence', 'Reg', (54, 63))
52983	29565815	For example, a small molecular compound termed C19 was recently shown to induce MST1/2 and LATS1/2 phosphorylation, and thereby stimulate TAZ degradation.	('C19', 'Var', (47, 50))	('stimulate', 'PosReg', (128, 137))	('LATS1/2', 'Gene', (91, 98))	('phosphorylation', 'MPA', (99, 114))	('degradation', 'biological_process', 'GO:0009056', ('142', '153'))	('induce', 'PosReg', (73, 79))	('MST1/2', 'Gene', '4485;6788', (80, 86))	('TAZ', 'Gene', '6901', (138, 141))	('LATS1/2', 'Gene', '9113;26524', (91, 98))	('TAZ', 'Gene', (138, 141))	('MST1/2', 'Gene', (80, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))
52990	29565815	For example, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib induces enhanced cytotoxicity in breast cancer cells that harbor BRCA1/2 mutations, as their endogenous DNA damage repair systems are suppressed by both BRCA1 inactivation and PARP inhibition.	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('BRCA1/2', 'Gene', (136, 143))	('mutations', 'Var', (144, 153))	('cytotoxicity', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('enhanced', 'PosReg', (79, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('PARP', 'Gene', '142', (247, 251))	('BRCA1', 'Gene', '672', (136, 141))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('BRCA1/2', 'Gene', '672;675', (136, 143))	('BRCA1', 'Gene', (136, 141))	('poly(ADP-ribose) polymerase', 'Gene', '142', (17, 44))	('PARP', 'Gene', (247, 251))	('BRCA1', 'Gene', '672', (224, 229))	('poly(ADP-ribose) polymerase', 'Gene', (17, 44))	('olaparib', 'Chemical', 'MESH:C531550', (62, 70))	('BRCA1', 'Gene', (224, 229))	('PARP', 'Gene', '142', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('PARP', 'Gene', (46, 50))
52994	29565815	To date, very few studies have investigated the effects of YAP1/TAZ-inhibition on MM either in vitro or in vivo; nevertheless, targeting YAP1/TAZ likely represents a very promising therapeutic strategy for patients with MM for several reasons.	('YAP1', 'Gene', '10413', (137, 141))	('TAZ', 'Gene', '6901', (64, 67))	('YAP1', 'Gene', (59, 63))	('TAZ', 'Gene', (64, 67))	('YAP1', 'Gene', '10413', (59, 63))	('targeting', 'Var', (127, 136))	('patients', 'Species', '9606', (206, 214))	('TAZ', 'Gene', (142, 145))	('TAZ', 'Gene', '6901', (142, 145))	('YAP1', 'Gene', (137, 141))
52995	29565815	Firstly, in contrast to other human malignancies, MMs are frequently and occasionally associated with mutations in NF2, and genes encoding other components of the Hippo pathway, respectively, strongly suggesting that disruption of merlin-Hippo signaling is a key event during MM development and progression.	('human', 'Species', '9606', (30, 35))	('MMs', 'Disease', (50, 53))	('malignancies', 'Disease', (36, 48))	('associated', 'Reg', (86, 96))	('Hippo signaling', 'biological_process', 'GO:0035329', ('238', '253'))	('NF2', 'Gene', (115, 118))	('mutations', 'Var', (102, 111))	('MMs', 'Chemical', 'MESH:D008741', (50, 53))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))
52998	29565815	Thirdly, MMs harbor a relatively small number of genetic changes, predominantly in tumor suppressor genes; however, as MM-associated mutations rarely affect targetable (e.g., kinase-encoding) oncogenes, new therapeutic targets and strategies are needed.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('MMs', 'Chemical', 'MESH:D008741', (9, 12))	('mutations', 'Var', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
53009	29075366	LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1beta by 89-96%, and TNFalpha by 67-78%, as well as activated NF-kappaB by 48-49% while decreasing levels of nitrates/nitrites by 85-93%.	('NF-kappaB', 'Protein', (125, 134))	('IL-1', 'molecular_function', 'GO:0005149', ('60', '64'))	(', and TNFalpha', 'Gene', '21926', (78, 92))	('LGM2605', 'Var', (0, 7))	('IL-1beta', 'MPA', (60, 68))	('NLRP3', 'Protein', (30, 35))	('decreasing', 'NegReg', (151, 161))	('reduced', 'NegReg', (22, 29))	('levels of nitrates/nitrites', 'MPA', (162, 189))	('activated', 'PosReg', (115, 124))
53018	29075366	Importantly, our recent study also found that LGM2605 possessed potent cell protective properties and, when tested on asbestos-activated elicited murine macrophages, it induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1, and reduced asbestos-induced ROS generation and markers of oxidative stress.	('cellular', 'Gene', (211, 219))	('markers of oxidative stress', 'MPA', (351, 378))	('Nqo1', 'Gene', '18104', (297, 301))	('ROS generation', 'biological_process', 'GO:1903409', ('332', '346'))	('Nrf2', 'Gene', '18024', (220, 224))	('cell protective', 'CPA', (177, 192))	('reduced', 'NegReg', (307, 314))	('induced', 'PosReg', (169, 176))	('activation', 'PosReg', (225, 235))	('Nqo1', 'molecular_function', 'GO:0003955', ('297', '301'))	('Nrf2', 'Gene', (220, 224))	('asbestos-induced ROS generation', 'MPA', (315, 346))	('cell protective properties', 'CPA', (71, 97))	('Nqo1', 'Gene', (297, 301))	('LGM2605', 'Var', (46, 53))	('HO-1', 'CellLine', 'CVCL:1E42', (288, 292))	('enzymes, HO-1 and Nqo1', 'Gene', '15368;18104', (279, 301))	('oxidative stress', 'Phenotype', 'HP:0025464', (362, 378))
53058	29075366	Inhibition of NADPH oxidase-derived ROS prevented ATP-induced caspase-1 activation and IL-1beta production in alveolar macrophages.	('activation', 'PosReg', (72, 82))	('IL-1', 'molecular_function', 'GO:0005149', ('87', '91'))	('IL-1beta production', 'biological_process', 'GO:0032611', ('87', '106'))	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('14', '27'))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('14', '27'))	('Inhibition', 'Var', (0, 10))	('IL-1beta production', 'MPA', (87, 106))	('caspase-1', 'Protein', (62, 71))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
53060	29075366	Indeed, monocyte THP-1 cells that produced caspase 1 (i.e., showed NLRP3 inflammasome activation) in response to asbestos or silica showed a blunted response in specific knockdown of NADPH oxidase subunit p22phox or when treated with ROS scavengers (N-acetylcysteine and ammonium pyrrolidine dithiocarbamate).	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('183', '196'))	('knockdown', 'Var', (170, 179))	('NLRP3', 'Gene', (67, 72))	('caspase 1', 'Gene', (43, 52))	('NLRP3 inflammasome activation', 'biological_process', 'GO:0044546', ('67', '96'))	('THP-1', 'CellLine', 'CVCL:0006', (17, 22))	('blunted', 'NegReg', (141, 148))	('ammonium pyrrolidine dithiocarbamate', 'Chemical', 'MESH:C020972', (271, 307))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (250, 266))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('183', '196'))
53135	28881848	A specific HMGB-1 isoform, namely hyper-acetylated HMGB-1, even outperforms previously described biomarkers.	('HMGB-1', 'Gene', (51, 57))	('HMGB-1', 'Gene', (11, 17))	('HMGB-1', 'Gene', '3146', (11, 17))	('hyper-acetylated', 'Var', (34, 50))	('HMGB-1', 'Gene', '3146', (51, 57))
53136	28881848	Hyperacetylation of HMGB-1 translocates this damage-associated molecular pattern to the cytosolic and subsequent extracellular space, promoting inflammation.	('Hyperacetylation', 'Var', (0, 16))	('HMGB-1', 'Gene', '3146', (20, 26))	('translocates', 'MPA', (27, 39))	('inflammation', 'Disease', 'MESH:D007249', (144, 156))	('inflammation', 'biological_process', 'GO:0006954', ('144', '156'))	('promoting', 'PosReg', (134, 143))	('HMGB-1', 'Gene', (20, 26))	('extracellular space', 'cellular_component', 'GO:0005615', ('113', '132'))	('inflammation', 'Disease', (144, 156))
53138	28881848	Combining fibulin-3 with either total or hyper-acetylated HMGB-1 improved both sensitivity and specificity for differentiating MPM patients from individuals with non-MPM pleural effusions.	('patients', 'Species', '9606', (131, 139))	('pleural effusions', 'Phenotype', 'HP:0002202', (170, 187))	('fibulin-3', 'Gene', (10, 19))	('improved', 'PosReg', (65, 73))	('MPM', 'Disease', (127, 130))	('HMGB-1', 'Gene', '3146', (58, 64))	('non-MPM pleural effusions', 'Disease', (162, 187))	('hyper-acetylated', 'Var', (41, 57))	('non-MPM pleural effusions', 'Disease', 'MESH:D010996', (162, 187))	('fibulin-3', 'Gene', '2202', (10, 19))	('HMGB-1', 'Gene', (58, 64))
53149	28881848	More specifically, the following microRNAs allowed differentiation between malignant and benign disease: hsa-miR-484, hsa-miR-320, hsa-let-7a and hsa-miR-125a-5p.	('hsa-miR-484', 'Gene', '619553', (105, 116))	('hsa-miR-320', 'Var', (118, 129))	('hsa-miR-125a-5p', 'Var', (146, 161))	('benign disease', 'Disease', (89, 103))	('benign disease', 'Disease', 'MESH:D009369', (89, 103))	('hsa-miR-484', 'Gene', (105, 116))	('hsa-let-7a', 'Var', (131, 141))
53153	28881848	They play an important role in regulating transcription and there is rising evidence that their aberrant expression plays a role in cancer biology, while being very specific for the tissue of origin.	('role', 'Reg', (124, 128))	('cancer', 'Disease', (132, 138))	('aberrant', 'Var', (96, 104))	('transcription', 'MPA', (42, 55))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('plays', 'Reg', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
53162	28881848	Furthermore, PTR-MS and SIFT-MS generate large fragmentation of the compounds in the entire sample at once, limiting their use for unsupervised biomarker detection.	('limiting', 'NegReg', (108, 116))	('men', 'Species', '9606', (51, 54))	('SIFT-MS', 'Disease', (24, 31))	('fragmentation', 'MPA', (47, 60))	('SIFT-MS', 'Disease', 'MESH:D009103', (24, 31))	('PTR', 'molecular_function', 'GO:0008975', ('13', '16'))	('PTR-MS', 'Var', (13, 19))
53443	23243350	in a genome-wide analysis of 11 affected individuals having congenital nail clubbing in a Pakistani consanguineous family reported a homozygous missense mutation in the human HPGD gene located at 4q33-q34.	('missense mutation', 'Var', (144, 161))	('HPGD', 'Gene', '3248', (175, 179))	('congenital nail', 'Phenotype', 'HP:0008394', (60, 75))	('clubbing', 'Phenotype', 'HP:0001217', (76, 84))	('human', 'Species', '9606', (169, 174))	('HPGD', 'Gene', (175, 179))
53446	23243350	also found mutation in 15-PGDH, the main enzyme of prostaglandin degradation.	('15-PGDH', 'Gene', (23, 30))	('15-PGDH', 'Gene', '3248', (23, 30))	('found', 'Reg', (5, 10))	('prostaglandin', 'Chemical', 'MESH:D011453', (51, 64))	('mutation', 'Var', (11, 19))	('prostaglandin degradation', 'biological_process', 'GO:1905344', ('51', '76'))
53452	23243350	Patients with unexplained clubbing, genetic testing for HPGD mutation, and measurements of PGE2 may become an important diagnostic tool.	('clubbing', 'Disease', (26, 34))	('PGE2', 'Chemical', 'MESH:D015232', (91, 95))	('mutation', 'Var', (61, 69))	('PGE2', 'Gene', (91, 95))	('HPGD', 'Gene', (56, 60))	('Patients', 'Species', '9606', (0, 8))	('HPGD', 'Gene', '3248', (56, 60))	('clubbing', 'Phenotype', 'HP:0001217', (26, 34))
53575	33498425	The diseases of interest and their respective ICD-10 codes were as follows: asbestos-related respiratory diseases including asbestosis (J61), pneumoconiosis except asbestosis (J60, J62-J65), pleural plaque (J92), pleural effusion (J90-J91), pleurisy (R09.1), and COPD (J40-J44).	('asbestosis', 'Disease', (124, 134))	('asbestos', 'Chemical', 'MESH:D001194', (124, 132))	('asbestos', 'Chemical', 'MESH:D001194', (164, 172))	('respiratory diseases', 'Disease', 'MESH:D012140', (93, 113))	('pleural effusion', 'Disease', (213, 229))	('asbestos', 'Chemical', 'MESH:D001194', (76, 84))	('pleurisy', 'Disease', (241, 249))	('pleural plaque', 'Disease', 'MESH:D010995', (191, 205))	('pneumoconiosis except asbestosis', 'Disease', 'MESH:D001195', (142, 174))	('J92', 'Var', (207, 210))	('J60', 'Var', (176, 179))	('J90-J91', 'CellLine', 'CVCL:M891', (231, 238))	('pleurisy', 'Phenotype', 'HP:0002102', (241, 249))	('asbestosis', 'Disease', 'MESH:D001195', (164, 174))	('pleural effusion', 'Disease', 'MESH:D010996', (213, 229))	('pleural plaque', 'Disease', (191, 205))	('asbestosis', 'Disease', 'MESH:D001195', (124, 134))	('COPD', 'Disease', 'MESH:D029424', (263, 267))	('pneumoconiosis except asbestosis', 'Disease', (142, 174))	('COPD', 'Disease', (263, 267))	('pleural effusion', 'Phenotype', 'HP:0002202', (213, 229))	('J40-J44', 'Var', (269, 276))	('respiratory diseases', 'Disease', (93, 113))	('asbestosis', 'Disease', (164, 174))	('J90-J91', 'Var', (231, 238))
53576	33498425	In the case of cancers, laryngeal cancer (C32), lung cancer (C33-C34), malignant mesothelioma (C45), and ovarian cancer (C56), for which there is sufficient evidence of their association with asbestos in the International Agency for Research on Cancer (IARC) classification, as well as pharyngeal cancer (C10-C13), stomach cancer (C16), colon cancer (C18), and rectal cancer (C19-C20), for which there is limited evidence of their association with asbestos in the IARC classification, were selected as asbestos-related cancers.	('cancer', 'Disease', (368, 374))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancers', 'Disease', (519, 526))	('Cancer', 'Disease', (245, 251))	('cancer', 'Disease', (519, 525))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (286, 303))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (71, 93))	('C33-C34', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', (113, 119))	('lung cancer', 'Disease', (48, 59))	('laryngeal', 'Disease', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('colon cancer', 'Disease', 'MESH:D015179', (337, 349))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('Cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('malignant mesothelioma', 'Disease', (71, 93))	('stomach cancer', 'Disease', 'MESH:D013274', (315, 329))	('asbestos', 'Chemical', 'MESH:D001194', (448, 456))	('stomach cancer', 'Phenotype', 'HP:0012126', (315, 329))	('cancer', 'Disease', 'MESH:D009369', (368, 374))	('cancer', 'Disease', 'MESH:D009369', (519, 525))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (71, 93))	('cancers', 'Disease', 'MESH:D009369', (519, 526))	('asbestos', 'Chemical', 'MESH:D001194', (192, 200))	('colon cancer', 'Disease', (337, 349))	('cancer', 'Disease', (53, 59))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('asbestos', 'Chemical', 'MESH:D001194', (502, 510))	('ovarian cancer', 'Disease', (105, 119))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('cancers', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('rectal cancer', 'Phenotype', 'HP:0100743', (361, 374))	('cancer', 'Disease', (297, 303))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (24, 40))	('Cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Disease', (323, 329))	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('colon cancer', 'Phenotype', 'HP:0003003', (337, 349))	('stomach cancer', 'Disease', (315, 329))	('cancers', 'Phenotype', 'HP:0002664', (519, 526))
53761	32770123	EWSR1/FUS-CREB Fusions Define a Distinctive Malignant Epithelioid Neoplasm with Predilection for Mesothelial-Lined Cavities Gene fusions constitute pivotal driver mutations often encoding aberrant chimeric transcription factors.	('Malignant Epithelioid Neoplasm', 'Disease', (44, 74))	('transcription', 'biological_process', 'GO:0006351', ('206', '219'))	('EWSR1', 'Gene', '2130', (0, 5))	('CREB', 'Gene', (10, 14))	('fusions', 'Var', (129, 136))	('FUS', 'Gene', (6, 9))	('CREB', 'Gene', '1385', (10, 14))	('EWSR1', 'Gene', (0, 5))	('Neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('FUS', 'Gene', '2521', (6, 9))	('Malignant Epithelioid Neoplasm', 'Disease', 'MESH:D009369', (44, 74))
53763	32770123	One such remarkable example of chromosomal translocation promiscuity is represented by fusions between EWSR1 or FUS with genes encoding for CREB-transcription factors family (ATF1, CREB1 and CREM), driving the pathogenesis of various tumor types spanning mesenchymal, neuroectodermal, and epithelial lineages.	('ATF1', 'Gene', (175, 179))	('pathogenesis', 'Reg', (210, 222))	('fusions', 'Var', (87, 94))	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('tumor', 'Disease', (234, 239))	('driving', 'Reg', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('CREB1', 'Gene', (181, 186))	('ATF1', 'Gene', '466', (175, 179))	('CREB', 'Gene', (181, 185))	('EWSR1', 'Gene', '2130', (103, 108))	('FUS', 'Gene', (112, 115))	('CREB1', 'Gene', '1385', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CREB', 'Gene', (140, 144))	('CREM', 'Gene', (191, 195))	('CREB', 'Gene', '1385', (181, 185))	('FUS', 'Gene', '2521', (112, 115))	('EWSR1', 'Gene', (103, 108))	('CREM', 'Gene', '1390', (191, 195))	('pathogenesis', 'biological_process', 'GO:0009405', ('210', '222'))	('CREB', 'Gene', '1385', (140, 144))
53810	32770123	Other pertinent negative stains included P40, P63, SF1, and S100.	('P40', 'Var', (41, 44))	('SF1', 'Gene', (51, 54))	('P40', 'cellular_component', 'GO:0043514', ('41', '44'))	('S100', 'Gene', '6271', (60, 64))	('P40', 'cellular_component', 'GO:0070743', ('41', '44'))	('SF1', 'Gene', '7536', (51, 54))	('P63', 'Var', (46, 49))	('S100', 'Gene', (60, 64))
53817	32770123	The rest of the cases were tested by FISH and showed gene rearrangements for EWSR1, FUS and CREM genes.	('FUS', 'Gene', (84, 87))	('FUS', 'Gene', '2521', (84, 87))	('gene rearrangements', 'Var', (53, 72))	('EWSR1', 'Gene', (77, 82))	('CREM', 'Gene', '1390', (92, 96))	('CREM', 'Gene', (92, 96))	('EWSR1', 'Gene', '2130', (77, 82))
53838	32770123	Most AFH show variable positivity for desmin, EMA, and CD99 in about half of the cases, but are consistently negative for cytokeratins.	('EMA', 'Gene', '4582', (46, 49))	('desmin', 'Gene', (38, 44))	('CD99', 'Gene', '4267', (55, 59))	('desmin', 'cellular_component', 'GO:0045098', ('38', '44'))	('CD99', 'Gene', (55, 59))	('desmin', 'Gene', '1674', (38, 44))	('EMA', 'Gene', (46, 49))	('desmin', 'cellular_component', 'GO:0045100', ('38', '44'))	('positivity', 'Var', (23, 33))
53839	32770123	AFH harbor mostly EWSR1-CREB1 fusions, though rare cases with EWSR1-ATF1 or FUS-ATF1 fusion have been reported.	('CREB1', 'Gene', (24, 29))	('EWSR1', 'Gene', (18, 23))	('FUS-ATF1', 'Gene', '466;2521', (76, 84))	('EWSR1', 'Gene', (62, 67))	('EWSR1', 'Gene', '2130', (18, 23))	('fusions', 'Var', (30, 37))	('ATF1', 'Gene', (80, 84))	('EWSR1', 'Gene', '2130', (62, 67))	('ATF1', 'Gene', '466', (80, 84))	('ATF1', 'Gene', (68, 72))	('CREB1', 'Gene', '1385', (24, 29))	('FUS-ATF1', 'Gene', (76, 84))	('ATF1', 'Gene', '466', (68, 72))
53842	32770123	Moreover, our group has reported recently on a small subset of epithelioid mesothelioma occurring in young adults harboring EWSR1/FUS-ATF1 fusions.	('FUS-ATF1', 'Gene', '466;2521', (130, 138))	('EWSR1', 'Gene', (124, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('FUS-ATF1', 'Gene', (130, 138))	('fusions', 'Var', (139, 146))	('EWSR1', 'Gene', '2130', (124, 129))	('mesothelioma', 'Disease', (75, 87))
53848	32770123	Only one case of myoepithelial tumor of soft tissue was so far reported with an EWSR1-ATF1 fusion; however, that case had a well-documented myoepithelial immunophenotype.	('fusion', 'Var', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (17, 36))	('EWSR1', 'Gene', (80, 85))	('ATF1', 'Gene', (86, 90))	('ATF1', 'Gene', '466', (86, 90))	('EWSR1', 'Gene', '2130', (80, 85))	('myoepithelial tumor', 'Disease', (17, 36))
53853	32770123	However, these tumors consistently show positivity for S100 protein, while none of the cases in the present cohort showed expression for this marker.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('S100', 'Gene', (55, 59))	('S100', 'Gene', '6271', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('positivity', 'Var', (40, 50))
53860	32770123	Similar to fusions encompassing other CREB family members, CREM-related fusions are evolving as promiscuous abnormalities, spanning the pathogenesis of a number of tumor entities, of different cell lineages.	('tumor', 'Disease', (164, 169))	('pathogenesis', 'biological_process', 'GO:0009405', ('136', '148'))	('CREM', 'Gene', '1390', (59, 63))	('CREM', 'Gene', (59, 63))	('CREB', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('CREB', 'Gene', '1385', (38, 42))	('fusions', 'Var', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
53862	32770123	However, a recent report has described 3 cases of myxoid AFH harboring EWSR1-CREM fusions.	('fusions', 'Var', (82, 89))	('myxoid', 'Disease', (50, 56))	('EWSR1', 'Gene', (71, 76))	('CREM', 'Gene', '1390', (77, 81))	('EWSR1', 'Gene', '2130', (71, 76))	('CREM', 'Gene', (77, 81))
54022	30567579	We have also found a positive and strong association between non-occupational asbestos exposure and the risk of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('non-occupational', 'Var', (61, 77))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('mesothelioma', 'Disease', (112, 124))
54060	25499640	In a prospective randomized controlled trial comparing PDT (n = 14) to Nd:YAG laser therapy (n = 17) in 31 patients with partial or complete tracheobronchial obstruction from NSCLC, Spanish investigators found that symptomatic relief was more durable among patients treated with PDT, with a significantly longer time until treatment failure (P = .03) and longer median survival (P = .007).	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('tracheobronchial obstruction', 'Disease', 'MESH:C566362', (141, 169))	('tracheobronchial obstruction', 'Disease', (141, 169))	('PDT', 'Var', (279, 282))	('patients', 'Species', '9606', (257, 265))	('NSCLC', 'Disease', (175, 180))	('patients', 'Species', '9606', (107, 115))
54066	25499640	In a small randomized trial by Vancouver investigators to determine if PDT improves outcomes when combined with external-beam radiation therapy for patients with inoperable NSCLC causing central airway obstructing, PDT before radiation therapy significantly improved responses and allowed for more durable local control.	('patients', 'Species', '9606', (148, 156))	('improved', 'PosReg', (258, 266))	('NSCLC', 'Disease', (173, 178))	('responses', 'MPA', (267, 276))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('PDT', 'Var', (215, 218))
54147	25499640	Additionally, as compared with nine patients not treated with PDT in their prospective nonrandomized trial, patients treated with PDT had an improved median survival (P = .0179) and were less likely to have tumor regrowth 6 months after surgery (29% v 73%, P <=.05).	('less', 'NegReg', (187, 191))	('PDT', 'Var', (130, 133))	('patients', 'Species', '9606', (36, 44))	('median survival', 'MPA', (150, 165))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('improved', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', (207, 212))
54244	32472073	The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events.	('cause', 'Reg', (77, 82))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
54245	32472073	Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism, or other perturbations that cause DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cellular metabolism', 'CPA', (89, 108))	('aberrant', 'Var', (80, 88))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('cellular metabolism', 'biological_process', 'GO:0044237', ('89', '108'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (55, 78))
54248	32472073	Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer, will allow the design of novel and effective preventive and therapeutic strategies.	('germline mutations', 'Var', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('promote', 'PosReg', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
54249	32472073	Whether two-thirds of all cancers are caused by the inevitable spontaneous accumulation of somatic (acquired) genetic mutations as a consequence of aging, or whether environmental carcinogens are responsible for most mutations and cause 70-90% of human cancers has been debated recently.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('human', 'Species', '9606', (247, 252))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (253, 260))	('mutations', 'Var', (118, 127))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('aging', 'biological_process', 'GO:0007568', ('148', '153'))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
54251	32472073	Similarly it is difficult to distinguish association from causation, and thus to define which of the thousands of mutations detected in a tumor biopsy or even in non-malignant or pre-malignant tissue are functioning as cancer 'driver' mutations.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (138, 143))	('mutations', 'Var', (114, 123))	('pre', 'molecular_function', 'GO:0003904', ('179', '182'))	("'driver", 'PosReg', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
54252	32472073	To overcome these challenges, we recommend the study of gene-environment interactions (GxE) in causing cancer in carriers of germline mutations that cause well defined tumor predisposition syndromes [G] (TPSs) and cancer syndromes [G].	('cancer', 'Disease', (214, 220))	('tumor', 'Disease', (168, 173))	('cancer syndrome', 'Disease', (214, 229))	('cancer syndrome', 'Disease', 'MESH:D009369', (214, 229))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	('TPSs', 'Disease', 'None', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mutations', 'Var', (134, 143))	('causing', 'Reg', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('TPSs', 'Disease', (204, 208))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cause', 'Reg', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
54257	32472073	The recent realization of the much more widespread impact of inherited pathogenic mutations in many cancers reflects the development of next-generation sequencing [G] (NGS), targeted NGS [G] (t-NGS), whole exome sequencing [G] (WES), whole genome sequencing [G] (WGS) and multiplex ligation-dependent probe amplification [G] (MLPA) assays that enable the simultaneous analyses of multiple genes in germline and tumor DNAs.	('tumor', 'Disease', (411, 416))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
54258	32472073	Several genes have been identified, that when mutated in the germline or in somatic cells confer a higher cancer risk.	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
54259	32472073	The current 'cancer gene census' of these genes (https://cancer.sanger.ac.uk/census) includes > 1% of all human genes, with ~90% implicated in cancer by somatic mutations, another 20% implicated by germline mutations, often in association with a TPS, and 10% displaying both cancer-associated somatic and germline mutations.	('implicated', 'Reg', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('TPS', 'Disease', (246, 249))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutations', 'Var', (161, 170))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (275, 281))
54276	32472073	In subsequent investigations in US families with a similarly high incidence of mesothelioma but no detectable exposure to asbestos, it was discovered that heterozygous pathogenic germline mutations in the BRCA1-associated protein 1 (BAP1) tumor suppressor gene caused the 'BAP1 cancer syndrome' (Table 1) characterized by familial clustering of mesothelioma and uveal melanoma (UVM), including bilateral UVM, and, although less frequently, by other malignancies.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('239', '255'))	('BAP1', 'Gene', (233, 237))	('mesothelioma', 'Disease', (345, 357))	('BRCA1-associated protein 1', 'Gene', (205, 231))	('mesothelioma', 'Disease', 'MESH:D008654', (345, 357))	('cancer syndrome', 'Disease', 'MESH:D009369', (278, 293))	('tumor suppressor', 'biological_process', 'GO:0051726', ('239', '255'))	('bilateral UVM', 'Disease', (394, 407))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (362, 376))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (345, 376))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('tumor', 'Disease', (239, 244))	('asbestos', 'Chemical', 'MESH:D001194', (122, 130))	('cancer syndrome', 'Disease', (278, 293))	('caused', 'Reg', (261, 267))	('mesothelioma', 'Disease', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('mutations', 'Var', (188, 197))	('malignancies', 'Disease', 'MESH:D009369', (449, 461))	('melanoma', 'Phenotype', 'HP:0002861', (368, 376))	('malignancies', 'Disease', (449, 461))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('BRCA1-associated protein 1', 'Gene', '8314', (205, 231))
54277	32472073	In vitro experiments revealed that primary fibroblasts derived from carriers of heterozygous BAP1 mutations and primary human mesothelial cells from BAP1 wild-type donors with down-regulated BAP1 expression were more susceptible than control BAP1 wild-type cells to the carcinogenic effects of ionizing radiation (IR), ultraviolet (UV) light and asbestos.	('human', 'Species', '9606', (120, 125))	('carcinogenic effects of ionizing radiation', 'Disease', 'MESH:D004194', (270, 312))	('mutations', 'Var', (98, 107))	('down-regulated', 'NegReg', (176, 190))	('susceptible', 'Reg', (217, 228))	('carcinogenic effects of ionizing radiation', 'Disease', (270, 312))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', (191, 195))	('asbestos', 'Chemical', 'MESH:D001194', (346, 354))
54282	32472073	Individuals with inherited, biallelic BLM and WRN mutations have Bloom (BS) and Werner syndrome (WS), respectively, which are autosomal recessive disorders that predispose to many cancer types.	('BLM', 'Gene', (38, 41))	('cancer', 'Disease', (180, 186))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (126, 155))	('mutations', 'Var', (50, 59))	('WRN', 'Gene', '7486', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('WRN', 'Gene', (46, 49))	('BLM', 'Gene', '641', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Werner syndrome', 'Disease', 'MESH:D014898', (80, 95))	('Werner syndrome', 'Disease', (80, 95))	('Bloom', 'Disease', (65, 70))	('autosomal recessive disorders', 'Disease', (126, 155))
54284	32472073	These mutations are associated with hypersensitivity to many different chemical classes of common DNA damaging agents, such as DNA topoisomerase I inhibitors, DNA cross-linking agents and radiation.	('associated', 'Reg', (20, 30))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('hypersensitivity', 'biological_process', 'GO:0002524', ('36', '52'))	('topoisomerase', 'molecular_function', 'GO:0003917', ('131', '144'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('131', '144'))	('hypersensitivity', 'Disease', (36, 52))	('hypersensitivity', 'Disease', 'MESH:D004342', (36, 52))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('mutations', 'Var', (6, 15))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
54289	32472073	Moreover, heterozygosity for BLMASH, a founder mutation present in 1 in 100 individuals with Ashkenazi Jewish ancestry, may mildly increase the risk of colorectal cancer.	('BLM', 'Gene', '641', (29, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('increase', 'PosReg', (131, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('BLM', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('heterozygosity', 'Var', (10, 24))	('colorectal cancer', 'Disease', (152, 169))
54294	32472073	Cancer incidence in carriers of pathogenic DDR mutations can be exacerbated by exposure to environmental carcinogens that induce genomic instability directly, for example, IR and UV light, or indirectly via chronic inflammation, for example, asbestos and chronic infections.	('DDR', 'Gene', (43, 46))	('asbestos and chronic infections', 'Disease', 'MESH:D007239', (242, 273))	('genomic instability', 'MPA', (129, 148))	('inflammation', 'Disease', 'MESH:D007249', (215, 227))	('pathogenic', 'Reg', (32, 42))	('mutations', 'Var', (47, 56))	('inflammation', 'Disease', (215, 227))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('inflammation', 'biological_process', 'GO:0006954', ('215', '227'))	('exacerbated', 'PosReg', (64, 75))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('induce', 'Reg', (122, 128))	('chronic infections', 'Phenotype', 'HP:0031035', (255, 273))
54298	32472073	Accordingly, mutations in genes that regulate either the DDR, cell death or cell metabolism account for most TPSs.	('TPSs', 'Disease', 'None', (109, 113))	('account', 'Reg', (92, 99))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))	('TPSs', 'Disease', (109, 113))	('mutations', 'Var', (13, 22))
54299	32472073	Mutations in the genes encoding p53 and BAP1 are powerful inducers of cancer in humans and mouse models largely because they simultaneously impair DNA repair by homologous recombination [G] (HR), cell death and mitochondrial respiration (Box 1).	('impair', 'NegReg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('homologous recombination', 'biological_process', 'GO:0035825', ('161', '185'))	('respiration', 'biological_process', 'GO:0007585', ('225', '236'))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('DNA repair', 'biological_process', 'GO:0006281', ('147', '157'))	('respiration', 'biological_process', 'GO:0045333', ('225', '236'))	('cell death', 'CPA', (196, 206))	('cell death', 'biological_process', 'GO:0008219', ('196', '206'))	('p53', 'Gene', (32, 35))	('DNA repair', 'MPA', (147, 157))	('Mutations', 'Var', (0, 9))	('mitochondrial respiration', 'MPA', (211, 236))	('cancer', 'Disease', (70, 76))	('BAP1', 'Gene', (40, 44))	('mouse', 'Species', '10090', (91, 96))	('humans', 'Species', '9606', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
54300	32472073	Heterozygous dominant mutations of TP53 and BAP1, cause the Li-Fraumeni syndrome (LFS) (Table 1), and the BAP1 cancer syndrome (Figure 2), respectively.	('cause', 'Reg', (50, 55))	('LFS', 'Disease', (82, 85))	('cancer syndrome', 'Disease', 'MESH:D009369', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('LFS', 'Disease', 'MESH:D016864', (82, 85))	('cancer syndrome', 'Disease', (111, 126))	('TP53', 'Gene', (35, 39))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (60, 80))	('mutations', 'Var', (22, 31))	('Li-Fraumeni syndrome', 'Disease', (60, 80))	('BAP1', 'Gene', (44, 48))
54302	32472073	Because TP53 and BAP1 heterozygous germline mutations cause cancer in close to 100% of mutation carriers, they are usually referred to as cancer syndromes.	('cancer', 'Disease', (138, 144))	('cause', 'Reg', (54, 59))	('cancer syndrome', 'Disease', (138, 153))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TP53', 'Gene', (8, 12))	('mutation', 'Var', (87, 95))	('cancer syndrome', 'Disease', 'MESH:D009369', (138, 153))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('BAP1', 'Gene', (17, 21))
54304	32472073	Breast cancer, brain tumors, sarcomas and adrenocortical carcinomas are the most common cancers in patients with LFS, whereas mesothelioma, UVM, cutaneous melanoma, and clear cell renal cell carcinoma (ccRCC) are most common in BAP1 mutation-carriers.	('clear cell renal cell carcinoma', 'Disease', (169, 200))	('UVM', 'Disease', (140, 143))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (180, 200))	('LFS', 'Disease', 'MESH:D016864', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('mutation-carriers', 'Var', (233, 250))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (42, 66))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (169, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cancers', 'Disease', (88, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('brain tumors', 'Disease', 'MESH:D001932', (15, 27))	('sarcomas and adrenocortical carcinomas', 'Disease', 'MESH:D018268', (29, 67))	('brain tumors', 'Phenotype', 'HP:0030692', (15, 27))	('patients', 'Species', '9606', (99, 107))	('BAP1', 'Gene', (228, 232))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 200))	('mesothelioma', 'Disease', (126, 138))	('brain tumors', 'Disease', (15, 27))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cutaneous melanoma', 'Disease', (145, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (145, 163))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 163))	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (42, 67))	('Breast cancer', 'Disease', (0, 13))	('LFS', 'Disease', (113, 116))
54307	32472073	Inactivating, somatic (acquired) TP53 mutations are common in most carcinomas, while biallelic somatic BAP1 mutations are frequent only in the same tumor types found in individuals affected by the BAP1 cancer syndrome, including ~90% of metastatic UVMs, >60 of mesotheliomas, and ~11% of ccRCCs.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mesotheliomas', 'Disease', 'MESH:D008654', (261, 274))	('tumor', 'Disease', (148, 153))	('carcinomas', 'Disease', 'MESH:D009369', (67, 77))	('mesotheliomas', 'Disease', (261, 274))	('metastatic UVMs', 'Disease', (237, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinomas', 'Disease', (67, 77))	('TP53', 'Gene', (33, 37))	('cancer syndrome', 'Disease', 'MESH:D009369', (202, 217))	('mutations', 'Var', (38, 47))	('ccRCCs', 'Disease', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer syndrome', 'Disease', (202, 217))	('common', 'Reg', (52, 58))
54308	32472073	The different tumor phenotypes caused by TP53 and BAP1 mutations underscore that the effects of many mutations are influenced by tissue type and species (e.g.	('TP53', 'Gene', (41, 45))	('tumor', 'Disease', (14, 19))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
54310	32472073	Moreover, intragenic polymorphisms, mutations, polymorphisms of genes in the p53 regulatory pathway, DNA methylation, altered expression of microRNAs, copy number variation, telomere attrition, and exposure to environmental carcinogens, can all modify the LFS phenotype.	('polymorphisms', 'Var', (47, 60))	('expression', 'MPA', (126, 136))	('telomere', 'cellular_component', 'GO:0005696', ('174', '182'))	('LFS', 'Disease', 'MESH:D016864', (256, 259))	('modify', 'Reg', (245, 251))	('copy', 'Var', (151, 155))	('p53 regulatory pathway', 'Pathway', (77, 99))	('mutations', 'Var', (36, 45))	('altered', 'Reg', (118, 125))	('DNA methylation', 'biological_process', 'GO:0006306', ('101', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('LFS', 'Disease', (256, 259))	('telomere', 'cellular_component', 'GO:0000781', ('174', '182'))
54312	32472073	Analysis of dermal-derived fibroblasts or lymphocytes from patients with LFS harboring TP53 heterozygous mutations revealed striking differences from normal cells in terms of chromosomal stability, apoptotic response to IR, G2 arrest after DNA damage, and gene expression profiles.	('chromosomal stability', 'CPA', (175, 196))	('arrest', 'Disease', 'MESH:D006323', (227, 233))	('differences', 'Reg', (133, 144))	('arrest', 'Disease', (227, 233))	('TP53', 'Gene', (87, 91))	('gene expression', 'biological_process', 'GO:0010467', ('256', '271'))	('LFS', 'Disease', (73, 76))	('mutations', 'Var', (105, 114))	('patients', 'Species', '9606', (59, 67))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('apoptotic', 'CPA', (198, 207))	('LFS', 'Disease', 'MESH:D016864', (73, 76))
54313	32472073	Similar to BAP1 mutations, analysis of TP53 mutations showed a connection between UV exposure, DNA damage, and skin carcinogenesis including melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('skin carcinogenesis', 'Disease', (111, 130))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (111, 130))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('mutations', 'Var', (44, 53))	('connection', 'Reg', (63, 73))	('TP53', 'Gene', (39, 43))
54316	32472073	When this response is reduced by a TP53 or BAP1 mutation, UV, IR and asbestos exposure can induce clonal expansion of the mutated cells with a higher risk of overt cancer formation.	('asbestos', 'Chemical', 'MESH:D001194', (69, 77))	('BAP1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('clonal expansion', 'CPA', (98, 114))	('TP53', 'Gene', (35, 39))	('cancer', 'Disease', (164, 170))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('mutated', 'Var', (122, 129))	('induce', 'Reg', (91, 97))
54317	32472073	Accordingly, Trp53-heterozygous mice and primary patient-derived LFS and BAP1-mutant cells exhibit reduced UV- and IR-induced cytotoxicity and apoptosis.	('cytotoxicity', 'Disease', 'MESH:D064420', (126, 138))	('BAP1-mutant', 'Gene', (73, 84))	('Trp53', 'Gene', '22059', (13, 18))	('cytotoxicity', 'Disease', (126, 138))	('LFS', 'Disease', (65, 68))	('patient', 'Species', '9606', (49, 56))	('apoptosis', 'CPA', (143, 152))	('mice', 'Species', '10090', (32, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('LFS', 'Disease', 'MESH:D016864', (65, 68))	('reduced', 'NegReg', (99, 106))	('BAP1-mutant', 'Var', (73, 84))	('Trp53', 'Gene', (13, 18))
54319	32472073	Smokers with germline TP53 mutations are at higher risk of lung cancer, and mice carrying a mutant Trp53 transgene become sensitive to cigarette smoke.	('mutations', 'Var', (27, 36))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('Trp53', 'Gene', '22059', (99, 104))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('mice', 'Species', '10090', (76, 80))	('mutant', 'Var', (92, 98))	('Trp53', 'Gene', (99, 104))	('TP53', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
54320	32472073	These mutant mice showed a significant age-related increase of unrepaired DNA adducts.	('increase', 'PosReg', (51, 59))	('mice', 'Species', '10090', (13, 17))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('mutant', 'Var', (6, 12))	('unrepaired DNA adducts', 'CPA', (63, 85))
54321	32472073	Moreover, whereas wild-type mice exhibit a significant increase in apoptotic cells in the bronchial epithelium, the mutant mice did not undergo extensive cigarette smoke-induced apoptosis, indicating that the loss of p53 contributes to genomic instability by permitting inappropriate survival of cells that would normally undergo apoptosis following DNA damage.	('permitting', 'PosReg', (259, 269))	('p53', 'Gene', (217, 220))	('mice', 'Species', '10090', (28, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('330', '339'))	('apoptosis', 'biological_process', 'GO:0006915', ('330', '339'))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('contributes', 'Reg', (221, 232))	('genomic instability', 'CPA', (236, 255))	('DNA', 'cellular_component', 'GO:0005574', ('350', '353'))	('loss', 'Var', (209, 213))	('mice', 'Species', '10090', (123, 127))
54328	32472073	The initial damage recognition proteins of global genome repair [G] (GGR), xeroderma pigmentosum complementation group C (XPC) and DNA damage binding protein 2 (DDB2 also named XPE) bind to damage that disrupts base pairing within DNA (part of the GGR pathway).	('bind', 'Reg', (182, 186))	('base pairing', 'molecular_function', 'GO:0003676', ('211', '223'))	('base pairing', 'MPA', (211, 223))	('DNA damage binding protein 2', 'Gene', '1643', (131, 159))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('xeroderma pigmentosum complementation group C', 'Gene', '7508', (75, 120))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('xeroderma pigmentosum complementation group C', 'Gene', (75, 120))	('XPC', 'Gene', '7508', (122, 125))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('DNA damage binding protein 2', 'Gene', (131, 159))	('disrupts', 'NegReg', (202, 210))	('damage', 'Var', (190, 196))	('GGR', 'biological_process', 'GO:0070911', ('248', '251'))	('XPC', 'Gene', (122, 125))	('DDB2', 'Gene', '1643', (161, 165))	('GGR', 'biological_process', 'GO:0070911', ('69', '72'))	('DDB2', 'Gene', (161, 165))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))
54330	32472073	Mutations in genes encoding the components of this common downstream pathway, XPB, XPD, XPA, XPF, and XPG, are associated with diseases such as trichothiodystrophy  (Figure 3).	('trichothiodystrophy', 'Disease', (144, 163))	('XPD', 'Gene', (83, 86))	('associated', 'Reg', (111, 121))	('XPF', 'Gene', '2072', (93, 96))	('XPA', 'Gene', '7507', (88, 91))	('Mutations', 'Var', (0, 9))	('XPA', 'Gene', (88, 91))	('XPD', 'Gene', '2068', (83, 86))	('XPG', 'Gene', '2073', (102, 105))	('XPB', 'Gene', (78, 81))	('XPF', 'Gene', (93, 96))	('trichothiodystrophy', 'Disease', 'MESH:D054463', (144, 163))	('XPG', 'Gene', (102, 105))
54331	32472073	Only biallelic mutations in XPC and other genes encoding proteins involved in NER have disease consequences.	('XPC', 'Gene', (28, 31))	('biallelic mutations', 'Var', (5, 24))	('XPC', 'Gene', '7508', (28, 31))	('NER', 'biological_process', 'GO:0006289', ('78', '81'))
54332	32472073	Patients with XP with mutations in the XPC or XPE genes retain active TCR but show elevated mutation frequencies that lead to SCC and melanomas following sun exposure.	('lead to', 'Reg', (118, 125))	('mutation', 'Var', (92, 100))	('melanomas', 'Disease', (134, 143))	('SCC', 'Disease', (126, 129))	('XPC', 'Gene', (39, 42))	('Patients', 'Species', '9606', (0, 8))	('TCR', 'MPA', (70, 73))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('mutations', 'Var', (22, 31))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('TCR', 'cellular_component', 'GO:0042101', ('70', '73'))	('XPE', 'Gene', (46, 49))	('XPC', 'Gene', '7508', (39, 42))	('TCR', 'biological_process', 'GO:0006283', ('70', '73'))
54333	32472073	However, SCCs from patients carrying mutations in XPC show no increased mutations in transcribed strands.	('patients', 'Species', '9606', (19, 27))	('XPC', 'Gene', (50, 53))	('mutations', 'Var', (37, 46))	('transcribed strands', 'MPA', (85, 104))	('XPC', 'Gene', '7508', (50, 53))
54335	32472073	Patients with CS with mutations in the Cockayne syndrome-type A (CSA; also known as ERCC8) or CSB (also known as ERCC6) genes have reduced TCR and display a wide range of developmental and neurological symptoms, though do not develop cancer despite severe photosensitivity.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('ERCC6', 'Gene', (113, 118))	('ERCC6', 'Gene', '2074', (113, 118))	('reduced', 'NegReg', (131, 138))	('ERCC8', 'Gene', (84, 89))	('TCR', 'cellular_component', 'GO:0042101', ('139', '142'))	('TCR', 'biological_process', 'GO:0006283', ('139', '142'))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('TCR', 'CPA', (139, 142))	('CS', 'Gene', '1431', (65, 67))	('neurological symptoms', 'Disease', 'MESH:D009422', (189, 210))	('Cockayne syndrome', 'Disease', (39, 56))	('Cockayne syndrome', 'Disease', 'MESH:D003057', (39, 56))	('mutations', 'Var', (22, 31))	('CS', 'Gene', '1431', (94, 96))	('neurological symptoms', 'Disease', (189, 210))	('severe photosensitivity', 'Phenotype', 'HP:0007537', (249, 272))	('ERCC8', 'Gene', '1161', (84, 89))	('photosensitivity', 'Phenotype', 'HP:0000992', (256, 272))	('cancer', 'Disease', (234, 240))	('CS', 'Gene', '1431', (14, 16))
54337	32472073	A related, mildly photosensitive disease, ultraviolet sensitive syndrome (UVS), also characterized by a deficiency in TCR, is associated with mutations in the gene UV-stimulated scaffold protein A (UVSSA) or occasionally CSA or CSB, but has no developmental or neurological symptoms.	('UV-stimulated scaffold protein A', 'Gene', (164, 196))	('mutations', 'Var', (142, 151))	('associated', 'Reg', (126, 136))	('deficiency', 'Disease', 'MESH:D007153', (104, 114))	('ultraviolet sensitive syndrome', 'Disease', (42, 72))	('photosensitive disease', 'Phenotype', 'HP:0000992', (18, 40))	('neurological symptoms', 'Disease', 'MESH:D009422', (261, 282))	('UVSSA', 'Gene', (198, 203))	('photosensitive disease', 'Disease', (18, 40))	('deficiency', 'Disease', (104, 114))	('TCR', 'Gene', (118, 121))	('UV-stimulated scaffold protein A', 'Gene', '57654', (164, 196))	('photosensitive disease', 'Disease', 'OMIM:132100', (18, 40))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('neurological symptoms', 'Disease', (261, 282))	('UVSSA', 'Gene', '57654', (198, 203))	('TCR', 'cellular_component', 'GO:0042101', ('118', '121'))	('TCR', 'biological_process', 'GO:0006283', ('118', '121'))	('developmental or neurological symptoms', 'Phenotype', 'HP:0000707', (244, 282))
54338	32472073	Patients homozygous for this mutation do not develop skin cancers.	('mutation', 'Var', (29, 37))	('develop', 'PosReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('skin cancers', 'Disease', (53, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('skin cancers', 'Disease', 'MESH:D012878', (53, 65))	('Patients', 'Species', '9606', (0, 8))	('skin cancer', 'Phenotype', 'HP:0008069', (53, 64))	('skin cancers', 'Phenotype', 'HP:0008069', (53, 65))
54339	32472073	In vitro analysis of primary cells with mutations in CSA, CSB or UVSSA revealed that they are essentially identical in sensitivity to most transcription-blocking DNA damage, but differ in their response to reactive oxygen species (ROS).	('transcription-blocking DNA damage', 'MPA', (139, 172))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('UVSSA', 'Gene', (65, 70))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('response to reactive oxygen species', 'biological_process', 'GO:0000302', ('194', '229'))	('mutations', 'Var', (40, 49))	('UVSSA', 'Gene', '57654', (65, 70))	('response to reactive oxygen species', 'MPA', (194, 229))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (206, 229))	('ROS', 'Chemical', 'MESH:D017382', (231, 234))	('differ', 'Reg', (178, 184))	('CSA', 'Gene', (53, 56))	('CSB', 'Gene', (58, 61))
54340	32472073	Whereas cells mutant in CSA or CSB are sensitive to ROS, cells with mutations in UVSSA are not, suggesting that the development and neurological pathologies have their origins in an altered response to ROS.	('response to ROS', 'MPA', (190, 205))	('UVSSA', 'Gene', (81, 86))	('UVSSA', 'Gene', '57654', (81, 86))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('response to ROS', 'biological_process', 'GO:0000302', ('190', '205'))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('mutations', 'Var', (68, 77))
54342	32472073	R-loops lead to S phase arrest with activation of ataxia telangiectasia mutated (ATM), the DNA damage transducing kinase that causes a delay in DNA replication until damage is removed from the template strand and transcription resumes; if the damage is not repaired, cell death is triggered.	('ataxia telangiectasia mutated', 'Gene', (50, 79))	('transcription', 'biological_process', 'GO:0006351', ('213', '226'))	('arrest', 'Disease', (24, 30))	('ATM', 'Gene', (81, 84))	('ataxia telangiectasia mutated', 'Gene', '472', (50, 79))	('delay', 'MPA', (135, 140))	('activation', 'PosReg', (36, 46))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('telangiectasia', 'Phenotype', 'HP:0001009', (57, 71))	('ATM', 'Gene', '472', (81, 84))	('S phase', 'biological_process', 'GO:0051320', ('16', '23'))	('DNA replication', 'biological_process', 'GO:0006260', ('144', '159'))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('R-loops', 'Var', (0, 7))	('cell death', 'biological_process', 'GO:0008219', ('267', '277'))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('ataxia', 'Phenotype', 'HP:0001251', (50, 56))
54346	32472073	In contrast, rodent cells and mice with CS-type mutations exhibit increased mutagenesis and increased cancer incidence.	('mice', 'Species', '10090', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('increased', 'PosReg', (66, 75))	('mutagenesis', 'biological_process', 'GO:0006280', ('76', '87'))	('CS', 'Gene', '1431', (40, 42))	('mutagenesis', 'MPA', (76, 87))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('increased', 'PosReg', (92, 101))	('mutations', 'Var', (48, 57))
54347	32472073	Since rodent cells naturally have much reduced GGR, mutation of the rodent Csa or Csb genes effectively creates rodents with defects in both GGR and TCR leading to greater mutagenesis and cancer incidence after UV irradiation.	('GGR', 'biological_process', 'GO:0070911', ('47', '50'))	('GGR', 'Protein', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('mutation', 'Var', (52, 60))	('Csa', 'Gene', (75, 78))	('greater', 'PosReg', (164, 171))	('GGR', 'Gene', (141, 144))	('Csb', 'Gene', '2074', (82, 85))	('defects', 'NegReg', (125, 132))	('TCR', 'Gene', (149, 152))	('mutagenesis', 'CPA', (172, 183))	('mutagenesis', 'biological_process', 'GO:0006280', ('172', '183'))	('TCR', 'cellular_component', 'GO:0042101', ('149', '152'))	('TCR', 'biological_process', 'GO:0006283', ('149', '152'))	('Csa', 'Gene', '1161', (75, 78))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('GGR', 'biological_process', 'GO:0070911', ('141', '144'))	('Csb', 'Gene', (82, 85))
54351	32472073	The mutS homolog 2 (MSH2)-MSH6 complex primarily recognizes base-base mispairs and small insertion or deletion mispairs, whereas the MSH2-MSH3 complex more broadly recognizes insertion or deletion mispairs as well as some single base mispairs.	('MSH2', 'Gene', (133, 137))	('base-base mispairs', 'MPA', (60, 78))	('MSH6', 'Gene', '2956', (26, 30))	('MSH3', 'Gene', '4437', (138, 142))	('MSH2', 'Gene', (20, 24))	('insertion', 'Var', (175, 184))	('MSH2', 'Gene', '4436', (133, 137))	('MSH2)-MSH6 complex', 'cellular_component', 'GO:0032301', ('20', '38'))	('MSH2-MSH3 complex', 'cellular_component', 'GO:0032302', ('133', '150'))	('mutS homolog 2', 'Gene', '4436', (4, 18))	('MSH2', 'Gene', '4436', (20, 24))	('MSH3', 'Gene', (138, 142))	('MSH6', 'Gene', (26, 30))	('mutS homolog 2', 'Gene', (4, 18))
54353	32472073	Mispair excision can then be initiated by exonuclease 1 (exo1), although exo1-independent mispair excision mechanisms exist.	('Mispair', 'Var', (0, 7))	('exo1', 'Gene', (73, 77))	('exonuclease 1', 'Gene', (42, 55))	('exonuclease 1', 'Gene', '9156', (42, 55))	('exo1', 'Gene', (57, 61))	('exo1', 'Gene', '9156', (57, 61))	('exo1', 'Gene', '9156', (73, 77))
54354	32472073	Mutations in the MMR genes (MLH1, MSH2, MSH6 and PMS2) impair the function of their encoded proteins, altering their recognition and repair of mismatched nucleotides and of insertion or deletion loops.	('altering', 'Reg', (102, 110))	('recognition', 'MPA', (117, 128))	('PMS2', 'Gene', (49, 53))	('insertion', 'MPA', (173, 182))	('MSH2', 'Gene', (34, 38))	('MMR', 'biological_process', 'GO:0006298', ('17', '20'))	('MSH6', 'Gene', (40, 44))	('MSH2', 'Gene', '4436', (34, 38))	('function', 'MPA', (66, 74))	('impair', 'NegReg', (55, 61))	('Mutations', 'Var', (0, 9))	('PMS2', 'Gene', '5395', (49, 53))	('repair', 'MPA', (133, 139))	('MLH1', 'Gene', '4292', (28, 32))	('MLH1', 'Gene', (28, 32))	('proteins', 'Protein', (92, 100))	('MMR', 'Gene', (17, 20))	('MSH6', 'Gene', '2956', (40, 44))
54356	32472073	In addition, LS carriers have a higher risk of developing many other different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('LS carriers', 'Var', (13, 24))
54371	32472073	Tumors in patients with tuberous sclerosis complex (TSC; an autosomal dominant disease) develop because of inactivation of both alleles of either TSC1 (also known as hamartin) or TSC2 (also known as tuberin), with the germline mutation inactivating one allele of TSC1 or TSC2 and a somatic event inactivating the remaining wild-type allele (Table 1).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('inactivation', 'NegReg', (107, 119))	('TSC', 'Gene', '7248;40201;7249;24855', (271, 274))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tuberous sclerosis complex', 'Disease', (24, 50))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (60, 86))	('TSC', 'Gene', '7248;40201;7249;24855', (263, 266))	('TSC', 'Gene', (179, 182))	('tuberin', 'Gene', '7249', (199, 206))	('Tumors', 'Disease', (0, 6))	('TSC', 'Gene', (52, 55))	('autosomal dominant disease', 'Disease', (60, 86))	('TSC', 'Gene', (146, 149))	('tuberin', 'Gene', (199, 206))	('TSC', 'Gene', (271, 274))	('inactivating', 'NegReg', (236, 248))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('24', '50'))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('patients', 'Species', '9606', (10, 18))	('TSC', 'Gene', (263, 266))	('germline mutation', 'Var', (218, 235))	('TSC', 'Gene', '7248;40201;7249;24855', (179, 182))	('hamartin', 'Gene', '7248', (166, 174))	('TSC', 'Gene', '7248;40201;7249;24855', (52, 55))	('hamartin', 'Gene', (166, 174))	('TSC', 'Gene', '7248;40201;7249;24855', (146, 149))	('tuberous sclerosis complex', 'Disease', 'MESH:D014402', (24, 50))
54376	32472073	These results implicate UV-induced DNA damage as a cause of second-hit mutations and the development of facial angiofibromas, and suggest that measures to limit UV exposure may reduce these often disfiguring tumors found in ~80% of patients.	('facial angiofibromas', 'Disease', 'MESH:D018322', (104, 124))	('facial angiofibromas', 'Phenotype', 'HP:0009720', (104, 124))	('patients', 'Species', '9606', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('angiofibromas', 'Phenotype', 'HP:0010615', (111, 124))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('cause', 'Reg', (51, 56))	('facial angiofibromas', 'Disease', (104, 124))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('reduce', 'NegReg', (177, 183))
54381	32472073	Eker rats were used to show that GxE during development can enhance the penetrance of a tumor suppressor gene defect in the adult.	('defect', 'Var', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('penetrance', 'MPA', (72, 82))	('rats', 'Species', '10116', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('enhance', 'PosReg', (60, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('tumor', 'Disease', (88, 93))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
54384	32472073	For example, patients with Birt-Hogg-Dube syndrome (BHD) (Table 1), an autosomal dominant inherited disorder caused by germline mutations in the folliculin (FLCN) gene, develop renal cancers subsequent to inactivation of the wild type allele in 12%-34% of affected patients at the early age of 46-52.	('patients', 'Species', '9606', (13, 21))	('FLCN', 'Gene', '201163', (157, 161))	('FLCN', 'Gene', (157, 161))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('patients', 'Species', '9606', (265, 273))	('renal cancers', 'Disease', (177, 190))	('Birt-Hogg-Dube syndrome', 'Disease', (27, 50))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (27, 50))	('autosomal dominant inherited disorder', 'Disease', 'MESH:D030342', (71, 108))	('caused', 'Reg', (109, 115))	('autosomal dominant inherited disorder', 'Disease', (71, 108))	('folliculin', 'Gene', (145, 155))	('BHD', 'Disease', 'MESH:C564185', (52, 55))	('renal cancer', 'Phenotype', 'HP:0009726', (177, 189))	('folliculin', 'Gene', '201163', (145, 155))	('develop', 'PosReg', (169, 176))	('renal cancers', 'Disease', 'MESH:D007680', (177, 190))	('BHD', 'Disease', (52, 55))	('inactivation', 'Var', (205, 217))
54385	32472073	Individuals within families who share the same FLCN alteration or between families who harbor the same FLCN mutation may or may not develop renal cancer, or the benign cutaneous and pulmonary manifestations associated with this syndrome.	('benign', 'Disease', (161, 167))	('FLCN', 'Gene', '201163', (47, 51))	('FLCN', 'Gene', (103, 107))	('renal cancer', 'Disease', 'MESH:D007680', (140, 152))	('renal cancer', 'Phenotype', 'HP:0009726', (140, 152))	('FLCN', 'Gene', '201163', (103, 107))	('develop', 'PosReg', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutation', 'Var', (108, 116))	('FLCN', 'Gene', (47, 51))	('renal cancer', 'Disease', (140, 152))
54388	32472073	However, most mutation carriers never develop cancer.	('cancer', 'Disease', (46, 52))	('mutation', 'Var', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
54391	32472073	For example, one study showed that macrophages from the lungs of smokers exhibited down-regulation of multiple miRNAs, which was mediated by SUMOylation [G] of DICER1.	('regulation', 'biological_process', 'GO:0065007', ('88', '98'))	('SUMOylation', 'biological_process', 'GO:0016925', ('141', '152'))	('DICER1', 'Gene', (160, 166))	('DICER1', 'Gene', '23405', (160, 166))	('SUMOylation [', 'Var', (141, 154))	('down-regulation', 'NegReg', (83, 98))
54392	32472073	The variable occurrence of cancer in TPS pedigrees provides the opportunity to use pathogenic TPS variants to anchor the search for additional genetic modifiers or environmental exposures that drive cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TPS', 'Gene', (94, 97))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('variants', 'Var', (98, 106))
54394	32472073	Specific mutational signatures (recurrent mutation types or patterns) have been strongly associated with germline variants in TPSs that modify DNA repair pathways and with the mutational consequences of exposure to DNA-damaging environmental agents such as UV light, tobacco carcinogens and environmental toxins.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('associated', 'Reg', (89, 99))	('tobacco', 'Species', '4097', (267, 274))	('TPSs', 'Disease', (126, 130))	('DNA repair', 'biological_process', 'GO:0006281', ('143', '153'))	('variants', 'Var', (114, 122))	('modify', 'Reg', (136, 142))	('TPSs', 'Disease', 'None', (126, 130))	('DNA repair pathways', 'Pathway', (143, 162))	('DNA', 'cellular_component', 'GO:0005574', ('215', '218'))
54396	32472073	By modulating gene expression, alterations in gene methylation may contribute to carcinogenesis, especially those that occur during the prenatal period and childhood, because they appear more stable than those occurring later in life.	('alterations', 'Var', (31, 42))	('modulating', 'Reg', (3, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('carcinogenesis', 'Disease', (81, 95))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('gene expression', 'MPA', (14, 29))	('contribute', 'Reg', (67, 77))
54402	32472073	One might imagine so, and conceivably, those genes might function not only in immunity but also in the development of tumor vasculature, the promotion of metastasis, and other known processes in the pathogenesis of cancer.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('promotion', 'PosReg', (141, 150))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('function', 'Reg', (57, 65))	('tumor', 'Disease', (118, 123))	('metastasis', 'CPA', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('pathogenesis', 'biological_process', 'GO:0009405', ('199', '211'))	('genes', 'Var', (45, 50))
54408	32472073	For example, the central role of interleukin-33 (IL-33) signaling in the pathogenesis of myeloproliferative neoplasms (MPNs) was discovered because the genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in mice lacking SH2 domain-containing inositol 5'-phosphatase (SHIP).	("SH2 domain-containing inositol 5'-phosphatase", 'Gene', '16331', (307, 352))	('IL-33', 'Gene', '77125', (176, 181))	('phosphatase', 'molecular_function', 'GO:0016791', ('341', '352'))	('lacking', 'NegReg', (299, 306))	('pathogenesis', 'biological_process', 'GO:0009405', ('73', '85'))	('IL-33', 'Gene', (176, 181))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (89, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))	('IL-33', 'Gene', '77125', (49, 54))	('myeloproliferative neoplasms', 'Disease', (89, 117))	('SHIP', 'Gene', '16331', (354, 358))	('IL-33', 'Gene', (49, 54))	('hematopoiesis', 'biological_process', 'GO:0030097', ('247', '260'))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (89, 117))	('MPN-like disease', 'Disease', (274, 290))	('ablation', 'Var', (160, 168))	('SHIP', 'Gene', (354, 358))	('hematopoiesis', 'Disease', 'MESH:C536227', (247, 260))	('restore', 'PosReg', (232, 239))	('mice', 'Species', '10090', (294, 298))	("SH2 domain-containing inositol 5'-phosphatase", 'Gene', (307, 352))	('IL-33', 'molecular_function', 'GO:0002112', ('49', '54'))	('abrogate', 'NegReg', (265, 273))	('IL-33 signaling pathway', 'biological_process', 'GO:0038172', ('176', '199'))	('interleukin-33', 'Gene', (33, 47))	('IL-33', 'molecular_function', 'GO:0002112', ('176', '181'))	('hematopoiesis', 'Disease', (247, 260))	('MPN-like disease', 'Disease', 'MESH:C566398', (274, 290))	('interleukin-33', 'Gene', '77125', (33, 47))	('genetic ablation', 'Var', (152, 168))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
54409	32472073	Additionally, in the transgenic Janus kinase 2 (JAK2)V617F (a mutation often found in BCR-ABL1-negative MPNs) mouse model, the onset of MPN was delayed in animals lacking IL-33 in radiation-resistant cells.	('IL-33', 'Gene', (171, 176))	('Janus kinase 2', 'Gene', '16452', (32, 46))	('IL-33', 'Gene', '77125', (171, 176))	('ABL1', 'Gene', '11350', (90, 94))	('IL-33', 'molecular_function', 'GO:0002112', ('171', '176'))	('Janus kinase 2', 'Gene', (32, 46))	('ABL1', 'Gene', (90, 94))	('mouse', 'Species', '10090', (110, 115))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('V617F', 'Var', (53, 58))	('JAK2', 'Gene', (48, 52))	('JAK2', 'Gene', '16452', (48, 52))
54416	32472073	The increased susceptibility of TP53+/-, BAP1+/- and XPC-/- mutation carriers to environmental carcinogens justifies measures to eliminate or reduce known, cancer-associated exposures in order to prevent or delay cancer onset.	('TP53+/-', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', (156, 162))	('BAP1+/-', 'Gene', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('XPC', 'Gene', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (213, 219))	('XPC', 'Gene', '7508', (53, 56))
54419	32472073	Moreover, enrollment in early detection cancer screening programs and the parallel implementation of preventive measures, such as screening with ultrasound and magnetic resonance imaging (MRI), rather than computed tomography (CT) imaging to diminish the risk of cancer caused by diagnostic IR, together with surgical removal of pre-malignant lesions and of early-stage tumors, has significantly increased survival in for example, patients with LS, BRCA1 or BRCA2 mutations, or LFS.	('diminish', 'NegReg', (242, 250))	('cancer', 'Disease', (263, 269))	('LFS', 'Disease', (478, 481))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('LFS', 'Disease', 'MESH:D016864', (478, 481))	('BRCA1', 'Gene', '672', (449, 454))	('tumors', 'Phenotype', 'HP:0002664', (370, 376))	('BRCA1', 'Gene', (449, 454))	('pre', 'molecular_function', 'GO:0003904', ('329', '332'))	('cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', (370, 376))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('patients', 'Species', '9606', (431, 439))	('BRCA2', 'Gene', (458, 463))	('mutations', 'Var', (464, 473))	('tumors', 'Disease', 'MESH:D009369', (370, 376))	('increased', 'PosReg', (396, 405))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('BRCA2', 'Gene', '675', (458, 463))
54420	32472073	Thus, patients with LS or LFS and BRCA1 or BRCA2 carriers, once identified, can begin these potentially life-saving procedures.	('carriers', 'Var', (49, 57))	('BRCA1', 'Gene', '672', (34, 39))	('BRCA1', 'Gene', (34, 39))	('LFS', 'Disease', 'MESH:D016864', (26, 29))	('BRCA2', 'Gene', (43, 48))	('patients', 'Species', '9606', (6, 14))	('BRCA2', 'Gene', '675', (43, 48))	('LFS', 'Disease', (26, 29))
54422	32472073	Although the prolonged survival - 5-10+ years for mesotheliomas occurring in carriers of germline BAP1 mutations, versus 1 year in sporadic mesothelioma - may be partly related to screening and early detection, better survival in patients carrying germline BAP1 mutations predates the discovery of the BAP1 cancer syndrome, pointing to differences in tumor biology and/or the microenvironment.	('BAP1', 'Gene', (98, 102))	('mesothelioma', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('mesotheliomas', 'Disease', 'MESH:D008654', (50, 63))	('mesothelioma', 'Disease', (50, 62))	('better', 'PosReg', (211, 217))	('mutations', 'Var', (262, 271))	('mutations', 'Var', (103, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('tumor', 'Disease', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('cancer syndrome', 'Disease', 'MESH:D009369', (307, 322))	('cancer syndrome', 'Disease', (307, 322))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('BAP1', 'Gene', (257, 261))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('mesotheliomas', 'Disease', (50, 63))	('patients', 'Species', '9606', (230, 238))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (131, 152))
54423	32472073	Amongst its various metabolic effects, metformin inhibits mitochondrial respiration [G].	('respiration', 'biological_process', 'GO:0045333', ('72', '83'))	('metformin', 'Chemical', 'MESH:D008687', (39, 48))	('inhibits', 'NegReg', (49, 57))	('mitochondrial respiration', 'MPA', (58, 83))	('respiration', 'biological_process', 'GO:0007585', ('72', '83'))	('metformin', 'Var', (39, 48))
54427	32472073	The TP53R337H mutation present in ~0.3% of the population of Southern Brazil, gives rise to a form of LFS frequently characterized by pediatric adrenocortical carcinoma.	('LFS', 'Disease', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (144, 168))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (144, 168))	('LFS', 'Disease', 'MESH:D016864', (102, 105))	('adrenocortical carcinoma', 'Disease', (144, 168))	('TP53R337H', 'Var', (4, 13))
54428	32472073	The R337H residue substitution is in the C-terminal oligomerization domain of p53 and is thought to decrease the stability of the active form of p53, a homotetramer, in a pH-dependent manner.	('stability', 'MPA', (113, 122))	('R337H', 'Var', (4, 9))	('R337H', 'SUBSTITUTION', 'None', (4, 9))	('decrease', 'NegReg', (100, 108))	('p53', 'Gene', (78, 81))	('active', 'MPA', (130, 136))
54430	32472073	The adrenal glands have a high tissue concentration of ascorbic acid (vitamin C) and, notably, TP53R337H carriers have decreased plasma ascorbate levels due to increased oxidative stress.	('decreased', 'NegReg', (119, 128))	('oxidative stress', 'MPA', (170, 186))	('increased', 'PosReg', (160, 169))	('vitamin C', 'Chemical', 'MESH:D001205', (70, 79))	('TP53R337H', 'Var', (95, 104))	('ascorbate', 'Chemical', 'MESH:D001205', (136, 145))	('ascorbic acid', 'Chemical', 'MESH:D001205', (55, 68))	('plasma ascorbate levels', 'MPA', (129, 152))	('oxidative stress', 'Phenotype', 'HP:0025464', (170, 186))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (160, 186))
54431	32472073	Thus, mutant p53 oligomerization in the adrenal glands of R337H mutation carriers might be further compromised by vitamin C deficiency.	('C deficiency', 'Disease', 'MESH:C537418', (122, 134))	('R337H', 'Var', (58, 63))	('C deficiency', 'Disease', (122, 134))	('vitamin C deficiency', 'Phenotype', 'HP:0100510', (114, 134))	('R337H', 'SUBSTITUTION', 'None', (58, 63))	('oligomerization', 'MPA', (17, 32))	('vitamin C', 'Chemical', 'MESH:D001205', (114, 123))	('compromised', 'Reg', (99, 110))	('p53', 'Gene', (13, 16))
54433	32472073	The presence of TP53 and BAP1 mutations may also help inform therapy: defective DNA repair leads to chromosomal instability and higher mutational load, which potentially provides a rationale for patient stratification with regard to immunotherapy.	('BAP1', 'Gene', (25, 29))	('TP53', 'Gene', (16, 20))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('patient', 'Species', '9606', (195, 202))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (100, 123))	('DNA repair', 'Gene', (80, 90))	('defective', 'Var', (70, 79))	('chromosomal instability', 'MPA', (100, 123))	('mutational load', 'MPA', (135, 150))	('higher', 'PosReg', (128, 134))
54445	32472073	Recognition of the causative role of germline mutations in cancer initiation and tumor progression identifies these genes and mutations as high-value therapeutic targets.	('germline mutations', 'Var', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', (81, 86))
54447	32472073	Many clinical trials targeting specific pathways in different cancer syndromes are ongoing (for example, NCT03207347, NCT01981525 and NCT03448718), and information from these trials will likely inform the use of similar therapies in sporadic malignancies carrying the equivalent acquired mutations.	('NCT03207347', 'Var', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('NCT03448718', 'Var', (134, 145))	('malignancies', 'Disease', 'MESH:D009369', (242, 254))	('cancer syndrome', 'Disease', 'MESH:D009369', (62, 77))	('cancer syndrome', 'Disease', (62, 77))	('NCT01981525', 'Var', (118, 129))	('malignancies', 'Disease', (242, 254))
54450	32472073	However, carcinogenesis is often a long process: spontaneous and environmentally-induced mutations can accumulate over the course of decades, with many cancers only becoming clinically overt 20 or more years after first carcinogen exposure.	('carcinogenesis', 'Disease', (9, 23))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (9, 23))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
54451	32472073	This long timespan for most cancers makes it difficult to clearly identify 'causative' mutations, and the timing of critical mutational events, or strongly promoting environmental exposures.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('mutations', 'Var', (87, 96))
54455	32472073	LOH occurs in most of these malignancies, further proof of the key oncogenic role of these mutations in driving tumor growth.	('malignancies', 'Disease', 'MESH:D009369', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('LOH', 'Disease', (0, 3))	('mutations', 'Var', (91, 100))	('malignancies', 'Disease', (28, 40))	('tumor', 'Disease', (112, 117))
54458	32472073	We need to identify the exposures and the mechanisms that make carriers of these mutations more susceptible to cancer and also to other diseases and develop and implement prevention strategies.	('more', 'PosReg', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('susceptible', 'Reg', (96, 107))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
54459	32472073	For example, recent discoveries linked specific mutations to increased individual susceptibility to various infectious agents: by avoiding travel in areas where these pathogens are prevalent, mutation carriers can reduce their risk of life-threatening infections.	('infections', 'Disease', 'MESH:D007239', (252, 262))	('mutation carriers', 'Var', (192, 209))	('infections', 'Disease', (252, 262))	('mutations', 'Var', (48, 57))	('reduce', 'NegReg', (214, 220))
54465	32472073	For example, the median age for colorectal cancer diagnosis for patients with LS and for breast cancer in BRCA1 or BRCA2 carriers is 45 years old, at or before the age at which colonoscopy and mammography screening, respectively are recommended.	('colorectal cancer', 'Disease', (32, 49))	('BRCA2', 'Gene', (115, 120))	('BRCA1', 'Gene', (106, 111))	('carriers', 'Var', (121, 129))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('BRCA2', 'Gene', '675', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('BRCA1', 'Gene', '672', (106, 111))
54467	32472073	It is anticipated that similar initiatives will soon be started elsewhere, and that genetic screening together with studies of GxE contributions to common adult cancers will help save lives, reduce health care costs and provide a major boost in our battle with cancer.	('save', 'NegReg', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancers', 'Disease', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('genetic screening', 'Var', (84, 101))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', (161, 167))	('reduce', 'NegReg', (191, 197))
54485	32472073	Depending on the gene that is mutated, a variable fraction of mutation-carriers develop one or more tumors during their lifetime.	('mutation-carriers', 'Var', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('develop', 'PosReg', (80, 87))
54490	32472073	The presence of BRCA1-associated protein 1 (BAP1) mutations in otherwise normal cells also induces aerobic glycolysis.	('glycolysis', 'biological_process', 'GO:0006096', ('107', '117'))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('mutations', 'Var', (50, 59))	('aerobic glycolysis', 'MPA', (99, 117))	('BRCA1-associated protein 1', 'Gene', '8314', (16, 42))	('BRCA1-associated protein 1', 'Gene', (16, 42))	('induces', 'Reg', (91, 98))	('BAP1', 'Gene', (44, 48))
54491	32472073	TP53 mutations cause an increase in OXPHOS in cells, confirmed in a mouse model (Trp53R172H) of the human TP53R175H mutation 'hotspot' in Li-Fraumeni syndrome and shown to be mediated by mutant p53 retention of mitochondrial regulatory activities.	('OXPHOS', 'biological_process', 'GO:0002082', ('36', '42'))	('mouse', 'Species', '10090', (68, 73))	('TP53', 'Gene', (0, 4))	('TP53R175H', 'Var', (106, 115))	('Trp53', 'Gene', '22059', (81, 86))	('retention', 'biological_process', 'GO:0051235', ('198', '207'))	('human', 'Species', '9606', (100, 105))	('mutations', 'Var', (5, 14))	('Li-Fraumeni syndrome', 'Disease', (138, 158))	('mutant', 'Var', (187, 193))	('p53', 'Gene', (194, 197))	('OXPHOS in cells', 'MPA', (36, 51))	('Trp53', 'Gene', (81, 86))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (138, 158))
54493	32472073	Crossing LFS mice with heterozygous polymerase gamma (POLG) mutant mice, which have a mild mitochondrial deficiency and a normal lifespan, resulted in a 40% increase in cancer-free survival associated with specific anti-proliferative cell signaling changes.	('LFS', 'Disease', (9, 12))	('mice', 'Species', '10090', (13, 17))	('POLG', 'Gene', (54, 58))	('cancer', 'Disease', (169, 175))	('mitochondrial deficiency', 'Disease', (91, 115))	('anti-proliferative cell signaling', 'MPA', (215, 248))	('LFS', 'Disease', 'MESH:D016864', (9, 12))	('POLG', 'Gene', '18975', (54, 58))	('mitochondrial deficiency', 'Disease', 'MESH:D028361', (91, 115))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('polymerase gamma', 'Gene', '18975', (36, 52))	('mutant', 'Var', (60, 66))	('increase', 'PosReg', (157, 165))	('polymerase gamma', 'Gene', (36, 52))	('mice', 'Species', '10090', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
54494	32472073	The abnormal accumulation of mitochondrial metabolites that can operate as oncometabolites, including fumarate, succinate, and D-2-hydroxyglutarate (D-2HG), can promote malignancy.	('accumulation', 'PosReg', (13, 25))	('succinate', 'MPA', (112, 121))	('fumarate', 'Chemical', 'MESH:D005650', (102, 110))	('D-2HG', 'Chemical', 'MESH:C019417', (149, 154))	('mitochondrial metabolites', 'MPA', (29, 54))	('malignancy', 'Disease', 'MESH:D009369', (169, 179))	('promote', 'PosReg', (161, 168))	('malignancy', 'Disease', (169, 179))	('succinate', 'Chemical', 'MESH:D019802', (112, 121))	('D-2-hydroxyglutarate', 'Var', (127, 147))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (127, 147))
54495	32472073	Succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase 2 (IDH2) can be affected by germline mutations.	('isocitrate dehydrogenase 2', 'Gene', (60, 86))	('IDH2', 'Gene', (88, 92))	('SDH', 'Gene', (25, 28))	('Succinate dehydrogenase', 'Gene', (0, 23))	('FH', 'Gene', '2271', (51, 53))	('germline mutations', 'Var', (113, 131))	('IDH2', 'Gene', '3418', (88, 92))	('fumarate hydratase', 'Gene', '2271', (31, 49))	('isocitrate dehydrogenase 2', 'Gene', '3418', (60, 86))	('fumarate hydratase', 'Gene', (31, 49))	('affected', 'Reg', (101, 109))	('Succinate dehydrogenase', 'Gene', '6390', (0, 23))	('SDH', 'Gene', '6390', (25, 28))
54498	32472073	While SDH and FH are prone to loss-of-function mutations, accompanied by the accumulation of fumarate and/or succinate, IDH1 and IDH2 frequently display gain-of-function mutations, leading to the synthesis of D-2HG.	('gain-of-function', 'PosReg', (153, 169))	('IDH2', 'Gene', (129, 133))	('accumulation', 'PosReg', (77, 89))	('loss-of-function', 'NegReg', (30, 46))	('synthesis', 'MPA', (196, 205))	('IDH1', 'Gene', '3417', (120, 124))	('FH', 'Gene', '2271', (14, 16))	('mutations', 'Var', (170, 179))	('SDH', 'Gene', (6, 9))	('mutations', 'Var', (47, 56))	('synthesis', 'biological_process', 'GO:0009058', ('196', '205'))	('IDH1', 'Gene', (120, 124))	('IDH2', 'Gene', '3418', (129, 133))	('succinate', 'Chemical', 'MESH:D019802', (109, 118))	('fumarate', 'Chemical', 'MESH:D005650', (93, 101))	('fumarate', 'MPA', (93, 101))	('D-2HG', 'Chemical', 'MESH:C019417', (209, 214))	('SDH', 'Gene', '6390', (6, 9))
54500	32472073	In summary, perturbations of mitochondrial metabolism may favor tumor development.	('tumor', 'Disease', (64, 69))	('perturbations', 'Var', (12, 25))	('mitochondrial metabolism', 'MPA', (29, 53))	('metabolism', 'biological_process', 'GO:0008152', ('43', '53'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('favor', 'PosReg', (58, 63))
54501	32472073	Reactive oxygen species (ROS) are genotoxins that favor the accumulation of DNA mutations and the activation of oncogenic signaling pathways.	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('mutations', 'Var', (80, 89))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('DNA', 'Gene', (76, 79))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('oncogenic signaling pathways', 'Pathway', (112, 140))	('accumulation', 'PosReg', (60, 72))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))
54504	32472073	Defects in autophagy or mitophagy promote oncogenesis, and indeed patients with FA are at a higher risk of developing different and often multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('autophagy', 'biological_process', 'GO:0006914', ('11', '20'))	('autophagy', 'CPA', (11, 20))	('mitophagy', 'CPA', (24, 33))	('Defects', 'Var', (0, 7))	('mitophagy', 'biological_process', 'GO:0000423', ('24', '33'))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('promote', 'PosReg', (34, 41))	('oncogenesis', 'CPA', (42, 53))	('cancer', 'Disease', (147, 153))	('oncogenesis', 'biological_process', 'GO:0007048', ('42', '53'))	('mitophagy', 'biological_process', 'GO:0000422', ('24', '33'))	('autophagy', 'biological_process', 'GO:0016236', ('11', '20'))	('patients', 'Species', '9606', (66, 74))
54507	32472073	Moreover, selectively disrupting respiration by knocking out p53-regulated SCO2, a gene essential for cytochrome c oxidase assembly, resulted in extreme oxidative stress and a DNA damage response that could be prevented by decreasing ambient oxygen levels.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('102', '114'))	('disrupting', 'NegReg', (22, 32))	('respiration', 'biological_process', 'GO:0007585', ('33', '44'))	('respiration', 'biological_process', 'GO:0045333', ('33', '44'))	('DNA damage response', 'biological_process', 'GO:0006974', ('176', '195'))	('resulted in', 'Reg', (133, 144))	('oxidative stress', 'MPA', (153, 169))	('respiration', 'MPA', (33, 44))	('oxygen', 'Chemical', 'MESH:D010100', (242, 248))	('cytochrome c', 'molecular_function', 'GO:0009461', ('102', '114'))	('decreasing ambient oxygen levels', 'Phenotype', 'HP:0012418', (223, 255))	('p53-regulated', 'Var', (61, 74))	('DNA damage response', 'MPA', (176, 195))	('SCO2', 'Gene', (75, 79))	('oxidative stress', 'Phenotype', 'HP:0025464', (153, 169))	('SCO2', 'Gene', '9997', (75, 79))	('knocking out p53-regulated', 'Var', (48, 74))
54512	32472073	Altering the 'E' component of ROS via antioxidants illustrates the intricacy of the balance between oxidative stress and redox functions in oncogenesis and underscores the controversy over the use of antioxidants in cancer prevention.	('Altering', 'Var', (0, 8))	('ROS', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('oncogenesis', 'biological_process', 'GO:0007048', ('140', '151'))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
54555	29701625	Deaths for all cancers were identified through ICD-9 codes 140 to 239; for malignant neoplasm of the pleura through code 163 and for lung cancer through code 162.	('malignant neoplasm of the pleura', 'Disease', (75, 107))	('Deaths', 'Disease', (0, 6))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('lung cancer', 'Disease', (133, 144))	('Deaths', 'Disease', 'MESH:D003643', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('codes 140', 'Var', (53, 62))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('code 163', 'Var', (116, 124))	('neoplasm of the pleura', 'Phenotype', 'HP:0100527', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('malignant neoplasm of the pleura', 'Disease', 'MESH:D009369', (75, 107))
54646	32887638	Moreover, MCT4 expression was significantly associated with reduced OS.	('MCT4', 'Gene', '9123', (10, 14))	('expression', 'Var', (15, 25))	('MCT', 'biological_process', 'GO:0120197', ('10', '13'))	('reduced', 'NegReg', (60, 67))	('MCT4', 'Gene', (10, 14))
54652	32887638	Low interstitial pH has been associated with increased levels of VEGF, IL8, and heparanase that could trigger cancer autocrine stimulation and enhance tumor aggressiveness.	('tumor aggressiveness', 'Disease', (151, 171))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('levels', 'MPA', (55, 61))	('enhance', 'PosReg', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('increased', 'PosReg', (45, 54))	('IL8', 'Gene', (71, 74))	('IL8', 'molecular_function', 'GO:0005153', ('71', '74'))	('VEGF', 'Gene', '7422', (65, 69))	('trigger', 'Reg', (102, 109))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (151, 171))	('IL8', 'Gene', '3576', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('aggressiveness', 'Phenotype', 'HP:0000718', (157, 171))	('heparanase', 'MPA', (80, 90))	('VEGF', 'Gene', (65, 69))	('Low', 'Var', (0, 3))
54671	32887638	Immunohistochemistry was performed as described in the study by Dalton et al.. We employed the following antibodies: basigin (dilution 1:250; AB49493 Abcam), MCT1 (dilution 1:400; AB3538P Merk Millipore), or MCT4 (dilution 1:200; 376101 (F-10), Santa Cruz).	('MCT1', 'Gene', (158, 162))	('basigin', 'Gene', '682', (117, 124))	('MCT', 'biological_process', 'GO:0120197', ('158', '161'))	('MCT4', 'Gene', (208, 212))	('MCT1', 'Gene', '6566', (158, 162))	('MCT4', 'Gene', '9123', (208, 212))	('dilution', 'Var', (214, 222))	('MCT', 'biological_process', 'GO:0120197', ('208', '211'))	('basigin', 'Gene', (117, 124))
54683	32887638	High expression of MCT4 was significantly associated with shortened OS (log-rank P = 0.019, HR = 1.70; 95% CI 1.09-2.70).	('MCT4', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('MCT4', 'Gene', '9123', (19, 23))	('MCT', 'biological_process', 'GO:0120197', ('19', '22'))	('shortened OS', 'Disease', (58, 70))
54702	32887638	On the other hand, a high expression of MTC4 was found to be significantly associated with a short OS of MPM patients and a similar trend (at mRNA level) was also confirmed by the data available within the TCGA data portal.	('associated with', 'Reg', (75, 90))	('MPM', 'Disease', (105, 108))	('patients', 'Species', '9606', (109, 117))	('high', 'Var', (21, 25))	('short OS', 'Disease', (93, 101))	('MTC4', 'Gene', (40, 44))
54712	32887638	Furthermore, the association between high expression of MCT4 and decreased survival has also been documented for colorectal cancer with peritoneal carcinomatosis.	('MCT', 'biological_process', 'GO:0120197', ('56', '59'))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (136, 161))	('colorectal cancer', 'Disease', (113, 130))	('high', 'Var', (37, 41))	('decreased', 'NegReg', (65, 74))	('MCT4', 'Gene', '9123', (56, 60))	('expression', 'MPA', (42, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('survival', 'MPA', (75, 83))	('peritoneal carcinomatosis', 'Disease', (136, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('MCT4', 'Gene', (56, 60))
54713	32887638	High MCT4 expression has been shown to correlate with enhanced metastatic processes, especially in oesophageal adenocarcinoma and in colorectal carcinoma, and with invasion in gastric cancer.	('MCT4', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('oesophageal adenocarcinoma', 'Disease', (99, 125))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (133, 153))	('MCT', 'biological_process', 'GO:0120197', ('5', '8'))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('expression', 'MPA', (10, 20))	('metastatic processes', 'CPA', (63, 83))	('colorectal carcinoma', 'Disease', (133, 153))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (99, 125))	('MCT4', 'Gene', '9123', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('enhanced', 'PosReg', (54, 62))	('gastric cancer', 'Disease', (176, 190))
54797	26600776	Therefore, a biopsy of the deep layer is necessary, including collecting a specimen by cutting the superficial layer of the parietal pleura, because only nonspecific findings were observed on pleural biopsy.	('pleural', 'Disease', 'MESH:D010995', (192, 199))	('pleural', 'Disease', (192, 199))	('parietal pleura', 'Disease', 'MESH:D054363', (124, 139))	('parietal pleura', 'Disease', (124, 139))	('cutting', 'Var', (87, 94))
54800	26600776	We also performed a tissue biopsy targeting the region with 18F-FDG accumulation on PET/CT in the patient, but the collected tumor tissue was insufficient and could not be definitively diagnosed.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('18F-FDG', 'Chemical', 'MESH:D019788', (60, 67))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('18F-FDG', 'Var', (60, 67))	('insufficient', 'Disease', 'MESH:D000309', (142, 154))	('insufficient', 'Disease', (142, 154))
54844	30497433	While QoL was still compromised 6 months following surgery, from the limited and low quality data available it would appear that P/D patients had better QoL than EPP patients across all measures.	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (166, 174))	('better', 'PosReg', (146, 152))	('P/D', 'Var', (129, 132))	('QoL', 'MPA', (153, 156))
54845	30497433	Physical function, social function and global health were better at follow-up for P/D than for EPP, while other indicators such as pain and cough were similar.	('P/D', 'Var', (82, 85))	('Physical function', 'CPA', (0, 17))	('better', 'PosReg', (58, 64))	('pain', 'Phenotype', 'HP:0012531', (131, 135))	('global health', 'CPA', (39, 52))	('social function', 'CPA', (19, 34))	('pain', 'Disease', 'MESH:D010146', (131, 135))	('cough', 'Phenotype', 'HP:0012735', (140, 145))	('pain', 'Disease', (131, 135))
54846	30497433	Although the existing evidence is limited and of low quality, it suggests that P/D patients have better QoL than EPP patients following surgery.	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (117, 125))	('QoL', 'MPA', (104, 107))	('P/D', 'Var', (79, 82))
54867	30497433	All EPP studies had less than 50 patients per sample, while only 4/8 P/D articles had more than 50 cases, while the EPP vs P/D studies had less than 25 patients or 40 patients in each group (Table 1).	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (167, 175))	('EPP', 'Disease', (4, 7))	('8 P/D', 'SUBSTITUTION', 'None', (67, 72))	('patients', 'Species', '9606', (152, 160))	('8 P/D', 'Var', (67, 72))
54919	30497433	With regard to extent of disease, critics of P/D may suggest that patients undergoing EPP have higher tumor burden and this might impact QoL.	('EPP', 'Var', (86, 89))	('impact', 'Reg', (130, 136))	('higher', 'PosReg', (95, 101))	('QoL', 'MPA', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('patients', 'Species', '9606', (66, 74))
55079	26421614	Pemetrexed (Alimta ) is a folate antimetabolite inhibiting thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, 3 enzymes of the purine and pyrimidine synthesis pathway.	('thymidylate synthase', 'Gene', '7298', (59, 79))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (0, 10))	('inhibiting', 'NegReg', (48, 58))	('Alimta', 'Chemical', 'MESH:D000068437', (12, 18))	('dihydrofolate reductase', 'Enzyme', (81, 104))	('folate antimetabolite', 'Chemical', '-', (26, 47))	('synthesis', 'biological_process', 'GO:0009058', ('194', '203'))	('Pemetrexed', 'Var', (0, 10))	('thymidylate synthase', 'Gene', (59, 79))	('purine', 'Chemical', 'MESH:C030985', (172, 178))	('pyrimidine', 'Chemical', 'MESH:C030986', (183, 193))	('glycinamide ribonucleotide formyltransferase', 'Enzyme', (109, 153))
55122	23840376	Selenite toxicity mainly depends on the level of selenium accumulated in the cell and it has been shown in cell lines that high expression of xc - cystine transporter (xCT) and MRP-1 causes an increased uptake of selenite.	('selenium', 'Chemical', 'MESH:D012643', (49, 57))	('selenite', 'Chemical', 'MESH:D020887', (213, 221))	('xCT', 'Gene', (168, 171))	('uptake', 'biological_process', 'GO:0098739', ('203', '209'))	('xc - cystine transporter', 'Gene', (142, 166))	('toxicity', 'Disease', 'MESH:D064420', (9, 17))	('high', 'Var', (123, 127))	('uptake', 'biological_process', 'GO:0098657', ('203', '209'))	('xCT', 'Gene', '23657', (168, 171))	('xc - cystine transporter', 'Gene', '23657', (142, 166))	('increased', 'PosReg', (193, 202))	('MRP-1', 'Gene', (177, 182))	('MRP-1', 'Gene', '4363', (177, 182))	('uptake of selenite', 'MPA', (203, 221))	('toxicity', 'Disease', (9, 17))	('Selenite', 'Chemical', 'MESH:D020887', (0, 8))
55219	23840376	Cysteine reduces selenite extracellularly which then results in a higher uptake of cystine by the cell, presumably leading to a tumor specific response.	('uptake', 'biological_process', 'GO:0098739', ('73', '79'))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('leading to', 'Reg', (115, 125))	('Cysteine', 'Var', (0, 8))	('cystine', 'Chemical', 'MESH:D003553', (83, 90))	('uptake', 'biological_process', 'GO:0098657', ('73', '79'))	('reduces', 'NegReg', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Cysteine', 'Chemical', 'MESH:D003545', (0, 8))	('higher', 'PosReg', (66, 72))	('uptake of cystine', 'MPA', (73, 90))	('tumor', 'Disease', (128, 133))	('selenite', 'Chemical', 'MESH:D020887', (17, 25))	('selenite extracellularly', 'MPA', (17, 41))
55230	23840376	Malignant cells often acquire mutations in proteins involved in these pathways during tumorigenesis and inhibition of the proteasome might overcome some of these effects, as reviewed in.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('proteasome', 'cellular_component', 'GO:0000502', ('122', '132'))	('proteins', 'Protein', (43, 51))	('mutations', 'Var', (30, 39))	('proteasome', 'molecular_function', 'GO:0004299', ('122', '132'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
55327	19874631	The greater is gammaP(D), the stronger the classification ability P is inclined to possess.	('in', 'Gene', '43565', (75, 77))	('stronger', 'PosReg', (30, 38))	('in', 'Gene', '43565', (71, 73))	('gammaP', 'Var', (15, 21))	('classification ability', 'CPA', (43, 65))
55385	19874631	The decision rules induced by gene #4847 in every leave-one-out training set are of the following form: if g(#4847) > t, then AML; if g(#4847) <= t, then ALL, where t is equal or close to 994.	('AML', 'Disease', (126, 129))	('in', 'Gene', '43565', (69, 71))	('in', 'Gene', '43565', (67, 69))	('in', 'Gene', '43565', (19, 21))	('AML', 'Disease', 'MESH:D015470', (126, 129))	('g(#4847) <= t', 'Var', (134, 147))	('g(#4847) > t', 'Var', (107, 119))	('in', 'Gene', '43565', (41, 43))	('gene #4847', 'Var', (30, 40))	('to 9', 'Species', '1214577', (185, 189))	('in', 'Gene', '43565', (94, 96))
55389	19874631	The two consistent decision rules generated by this gene were as follows: if g(#4847) > 994, then AML; if g(#4847) <= 994, then ALL.	('g(#4847) <= 994', 'Var', (106, 121))	('AML', 'Disease', (98, 101))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('g(#4847) > 994', 'Var', (77, 91))
55402	19874631	The decision rules produced by the gene pair were as follows:   if g(#3252) <= 156.5 and g(#6167) > 820.5, then ALL;   if g(#3252) <= 156.5 and g(#6167) <= 820.5, then ALL;   if g(#3252) > 156.5 and g(#6167) > 820.5, then ALL;   if g(#3252) > 156.5 and g(#6167) <= 820.5, then AML.	('g(#3252) > 156.5', 'Var', (232, 248))	('g(#3252) > 156.5', 'Var', (178, 194))	('AML', 'Disease', 'MESH:D015470', (277, 280))	('g(#3252) <= 156.5', 'Var', (67, 84))	('g(#6167) <= 820.5', 'Var', (253, 270))	('g(#6167) > 820.5', 'Var', (89, 105))	('g(#6167) > 820.5', 'Var', (199, 215))	('g(#3252) <=', 'Var', (122, 133))	('AML', 'Disease', (277, 280))
55403	19874631	The above rules were then simplified into three equivalent rules:   if g(#3252) <= 156.5, then ALL;   if g(#6167) > 820.5, then ALL;   if g(#3252) > 156.5 and g(#6167) <= 820.5, then AML.	('g(#6167) <= 820.5', 'Var', (159, 176))	('g(#6167) > 820.5', 'Var', (105, 121))	('g(#3252) <=', 'Var', (71, 82))	('AML', 'Disease', (183, 186))	('in', 'Gene', '43565', (37, 39))	('g(#3252) > 156.5', 'Var', (138, 154))	('AML', 'Disease', 'MESH:D015470', (183, 186))
55412	19874631	The rules induced by gene 37716_at were the following: if g(37716_at) > 197.75, then mesothelioma; if g(37716_at) <= 197.75, then ADCA.	('ADCA', 'Disease', 'MESH:D020754', (130, 134))	('mesothelioma', 'Disease', (85, 97))	('ADCA', 'Disease', (130, 134))	('in', 'Gene', '43565', (50, 52))	('g(37716_at) > 197.75', 'Var', (58, 78))	('g(37716_at) <= 197.75', 'Var', (102, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('in', 'Gene', '43565', (10, 12))
55415	19874631	From these rules, we suspected that 2047_s_at, 2266_s_at, 32046_at, 33245_at, 41286_at, 41402_at, 575_s_at, and 988_at have higher expression levels in ADCA, while the others have higher expression levels in mesothelioma.	('33245_at', 'Var', (68, 76))	('in', 'Gene', '43565', (205, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (208, 220))	('ADCA', 'Disease', 'MESH:D020754', (152, 156))	('expression levels', 'MPA', (131, 148))	('2047_s_at', 'Var', (36, 45))	('expression levels', 'MPA', (187, 204))	('ADCA', 'Disease', (152, 156))	('higher', 'PosReg', (124, 130))	('mesothelioma', 'Disease', (208, 220))	('in', 'Gene', '43565', (149, 151))
55455	19874631	When we examined the rules formed by gene 37639_at, we found the following: if g(37639_at) > -0.491443, then Tumor (100% confidence); if g(37639_at) <= -0.694377, then Normal (95% confidence).	('g(37639_at) <= -0.694377', 'Var', (137, 161))	('in', 'Gene', '43565', (12, 14))	('g(37639_at) > -0.491443', 'Var', (79, 102))	('in', 'Gene', '43565', (71, 73))	('Tumor', 'CPA', (109, 114))	('Tumor', 'Phenotype', 'HP:0002664', (109, 114))
55459	19874631	Gene 41755_at produced the following two rules: if g(41755_at) > 0.261438, then Tumor (100% confidence); if g(41755_at) <= -0.477124, then Normal (100% confidence).	('g(41755_at) <= -0.477124', 'Var', (108, 132))	('g(41755_at) > 0.261438', 'Var', (51, 73))	('Tumor', 'CPA', (80, 85))	('41755_at', 'Var', (5, 13))	('Tumor', 'Phenotype', 'HP:0002664', (80, 85))	('in', 'Gene', '43565', (33, 35))
55477	19874631	The classification rules induced by this gene were as follows: if g(36239_at) > 1796.5, then ALL; if g(36239_at) > 214 and g(36239_at) <= 1796.5, then MLL; if g(36239_at) <= 214, then AML; with 95.24%, 93.33%, and 90.48% confidence, respectively.	('AML', 'Disease', 'MESH:D015470', (184, 187))	('g(36239_at) <= 1796.5', 'Var', (123, 144))	('g(36239_at) > 1796.5', 'Var', (66, 86))	('MLL', 'Gene', (151, 154))	('AML', 'Disease', (184, 187))	('MLL', 'Gene', '4297', (151, 154))	('in', 'Gene', '43565', (25, 27))	('g(36239_at) > 214', 'Var', (101, 118))	('g(36239_at) <= 214', 'Var', (159, 177))
55534	19874631	7q monosomy or partial deletion of this chromosome arm is frequently found in myelodysplastic syndrome, acute myeloid, juvenile myelomonocytic, and acute lymphocytic leukemias, as well as in breast carcinoma.	('leukemias', 'Phenotype', 'HP:0001909', (166, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('in', 'Gene', '43565', (188, 190))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('juvenile myelomonocytic', 'Disease', (119, 142))	('breast carcinoma', 'Disease', 'MESH:D001943', (191, 207))	('acute myeloid', 'Disease', 'MESH:D015470', (104, 117))	('in', 'Gene', '43565', (75, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('in', 'Gene', '43565', (202, 204))	('acute lymphocytic leukemias', 'Disease', (148, 175))	('myelodysplastic syndrome', 'Disease', (78, 102))	('acute lymphocytic leukemias', 'Disease', 'MESH:D054198', (148, 175))	('breast carcinoma', 'Phenotype', 'HP:0003002', (191, 207))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (154, 175))	('breast carcinoma', 'Disease', (191, 207))	('partial deletion', 'Var', (15, 31))	('found', 'Reg', (69, 74))	('acute lymphocytic leukemias', 'Phenotype', 'HP:0006721', (148, 175))	('acute myeloid', 'Disease', (104, 117))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (78, 102))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (78, 102))
55548	19874631	CCND3 is also listed as one of the 50 genes selected by Huang et al.. KIAA0159 is an essential component of the human condensin complex required for mitotic chromosome condensation.	('KIAA0159', 'Var', (70, 78))	('CCND3', 'Gene', '896', (0, 5))	('mitotic chromosome', 'cellular_component', 'GO:0005708', ('149', '167'))	('KIAA0159', 'Chemical', '-', (70, 78))	('CCND3', 'Gene', (0, 5))	('mitotic chromosome condensation', 'biological_process', 'GO:0007076', ('149', '180'))	('in', 'Gene', '43565', (125, 127))	('condensin complex', 'cellular_component', 'GO:0000796', ('118', '135'))	('human', 'Species', '9606', (112, 117))	('mitotic chromosome', 'cellular_component', 'GO:0000793', ('149', '167'))
55550	19874631	However, past studies have indicated that nonrandom chromosomal translocations are characteristic of most human hematopoietic malignancies.	('human', 'Species', '9606', (106, 111))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (112, 138))	('hematopoietic malignancies', 'Disease', (112, 138))	('nonrandom chromosomal translocations', 'Var', (42, 78))	('in', 'Gene', '43565', (27, 29))
55551	19874631	Because KIAA0159 is correlated with the structural maintenance of chromosomes, it may be associated with the pathogenesis of leukemia.	('associated', 'Reg', (89, 99))	('KIAA0159', 'Var', (8, 16))	('in', 'Gene', '43565', (53, 55))	('KIAA0159', 'Chemical', '-', (8, 16))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('leukemia', 'Disease', 'MESH:D007938', (125, 133))	('leukemia', 'Disease', (125, 133))	('pathogenesis', 'biological_process', 'GO:0009405', ('109', '121'))
55586	19874631	These observations are supported by the following rules of the present study: if g(ANXA8) > 130.8, then MPM; if g(CALB2) > 490.5, then MPM; if g(PTGIS) > 193.25, then MPM.	('MPM', 'MPA', (135, 138))	('CALB2', 'Gene', (114, 119))	('in', 'Gene', '43565', (46, 48))	('ANXA8', 'Gene', (83, 88))	('PTGIS', 'Gene', (145, 150))	('ANXA8', 'Gene', '653145', (83, 88))	('PTGIS', 'Gene', '5740', (145, 150))	('CALB2', 'Gene', '794', (114, 119))	('MPM', 'MPA', (104, 107))	('> 130.8', 'Var', (90, 97))
55601	19874631	In the gene pairs, our rules indicate that KIAA0762 is downregulated, while TUBB and RGS10 are upregulated in tumor tissue; however, there exists insufficient evidence to directly link the three genes with prostate cancer.	('in', 'Gene', '43565', (29, 31))	('RGS10', 'Gene', '6001', (85, 90))	('In', 'Gene', '43565', (0, 2))	('KIAA0762', 'Var', (43, 51))	('TUBB', 'Gene', '203068', (76, 80))	('in', 'Gene', '43565', (181, 183))	('in', 'Gene', '43565', (107, 109))	('RGS10', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('RGS', 'molecular_function', 'GO:0016299', ('85', '88'))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('in', 'Gene', '43565', (146, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('downregulated', 'NegReg', (55, 68))	('prostate cancer', 'Disease', (206, 221))	('TUBB', 'Gene', (76, 80))	('upregulated', 'PosReg', (95, 106))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
55602	19874631	The three genes that we identified directly from the training set are hepsin (37639_at), KIAA0977 (41755_at), and S100A4 (38087_s_at).	('37639_at', 'Var', (78, 86))	('hepsin', 'Gene', '3249', (70, 76))	('41755_at', 'Var', (99, 107))	('38087_s_at', 'Var', (122, 132))	('S100A4', 'Gene', (114, 120))	('hepsin', 'Gene', (70, 76))	('S100A4', 'Gene', '6275', (114, 120))
55621	19874631	Our rules indicated that the overexpression of ATP5G3, TSPYL5, or NPC1 means an unfavorable prognosis, while the overexpression of HS1119D91, Contig38726_RC, PIB5PA, Contig51517_RC, or LOC63923 implies a favorable prognosis.	('overexpression', 'PosReg', (29, 43))	('Contig38726_RC', 'Var', (142, 156))	('TSPYL5', 'Gene', (55, 61))	('PIB5PA', 'Gene', (158, 164))	('LOC63923', 'Var', (185, 193))	('Contig51517_RC', 'Var', (166, 180))	('ATP5G3', 'Gene', '518', (47, 53))	('TSPYL5', 'Gene', '85453', (55, 61))	('NPC', 'cellular_component', 'GO:0005643', ('66', '69'))	('NPC1', 'Gene', '4864', (66, 70))	('PIB5PA', 'Gene', '27124', (158, 164))	('in', 'Gene', '43565', (10, 12))	('HS1119D91', 'Var', (131, 140))	('ATP5G3', 'Gene', (47, 53))	('NPC1', 'Gene', (66, 70))
55634	19874631	Of these genes, 36239_at (OBF-1) and 31886_at (human placental cDNA coding for 5' nucleotidase) are also contained in the best 26-gene prediction model proposed in.	('31886_at', 'Var', (37, 45))	('in', 'Gene', '43565', (115, 117))	('in', 'Gene', '43565', (71, 73))	('36239_at', 'Var', (16, 24))	('OBF-1', 'Gene', '5450', (26, 31))	('OBF-1', 'Gene', (26, 31))	('in', 'Gene', '43565', (161, 163))	('human', 'Species', '9606', (47, 52))	('in', 'Gene', '43565', (110, 112))
55699	19563663	Redox regulation is likely to influence cellular sensitivity to selenite, and we have reported that selenite decreases the activity of thioredoxin reductase (TrxR).	('TrxR', 'Gene', (158, 162))	('thioredoxin reductase', 'Gene', (135, 156))	('selenite', 'Chemical', 'MESH:D020887', (100, 108))	('thioredoxin', 'molecular_function', 'GO:0030508', ('135', '146'))	('thioredoxin reductase', 'Gene', '25824', (135, 156))	('influence', 'Reg', (30, 39))	('TrxR', 'Gene', '25824', (158, 162))	('thioredoxin', 'molecular_function', 'GO:0000008', ('135', '146'))	('selenite', 'Var', (100, 108))	('selenite', 'Chemical', 'MESH:D020887', (64, 72))	('activity', 'MPA', (123, 131))	('regulation', 'biological_process', 'GO:0065007', ('6', '16'))	('decreases', 'NegReg', (109, 118))
55731	19563663	The M-30 Apoptosense assay (Peviva, Stockholm) measures cytokeratin 18 fragments specifically produced by cleavage by caspases 3, 6, 7, and 9.	('cytokeratin 18', 'Gene', '3875', (56, 70))	('cytokeratin 18', 'Gene', (56, 70))	('cleavage', 'Var', (106, 114))
55748	19563663	Selenite is a strong prooxidant when used in cytotoxic doses, and may induce apoptosis.	('apoptosis', 'CPA', (77, 86))	('Selenite', 'Var', (0, 8))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('induce', 'PosReg', (70, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('Selenite', 'Chemical', 'MESH:D020887', (0, 8))
55760	19563663	None of the enzyme inhibitors affected the proportion of viable cells during Annexin-PI apoptosis assays, although the WST-1 viability assays indicated a modest growth inhibitory effect of CA 074-Me and SB 203580 (data not shown).	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('Annexin-PI', 'Chemical', '-', (77, 87))	('SB 203580', 'Chemical', 'MESH:C093642', (203, 212))	('CA 074-Me', 'Chemical', 'MESH:C400541', (189, 198))	('CA 074-Me', 'Var', (189, 198))	('growth', 'MPA', (161, 167))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))
55763	19563663	In the sarcomatoid cells, the p38 inhibitor SB203580 caused a small decrease in the apoptotic response to selenite (Figure 1D).	('sarcomatoid', 'Disease', (7, 18))	('SB203580', 'Var', (44, 52))	('p38', 'Gene', '1432', (30, 33))	('decrease', 'NegReg', (68, 76))	('sarcomatoid', 'Disease', 'MESH:C538614', (7, 18))	('SB203580', 'Chemical', 'MESH:C093642', (44, 52))	('apoptotic response to selenite', 'MPA', (84, 114))	('p38', 'Gene', (30, 33))	('selenite', 'Chemical', 'MESH:D020887', (106, 114))
55768	19563663	Inhibition of JNK increased the proportion of selenite-induced early apoptotic cells by more than two thirds in the epithelioid cells (Figure 1C).	('JNK', 'Gene', (14, 17))	('early apoptotic cells', 'CPA', (63, 84))	('JNK', 'molecular_function', 'GO:0004705', ('14', '17'))	('JNK', 'Gene', '5599', (14, 17))	('selenite', 'Chemical', 'MESH:D020887', (46, 54))	('Inhibition', 'Var', (0, 10))
55792	19563663	In a yeast experimental system, it has been shown that deletion of thioredoxin reductase (TrxR) downregulates p53 activity by keeping it in its oxidized form.	('keeping', 'Reg', (126, 133))	('yeast', 'Species', '4932', (5, 10))	('p53', 'Gene', (110, 113))	('thioredoxin reductase', 'Gene', (67, 88))	('activity', 'MPA', (114, 122))	('TrxR', 'Gene', (90, 94))	('p53', 'Gene', '7157', (110, 113))	('thioredoxin', 'molecular_function', 'GO:0030508', ('67', '78'))	('thioredoxin reductase', 'Gene', '25824', (67, 88))	('downregulates', 'NegReg', (96, 109))	('oxidized', 'MPA', (144, 152))	('TrxR', 'Gene', '25824', (90, 94))	('deletion', 'Var', (55, 63))	('thioredoxin', 'molecular_function', 'GO:0000008', ('67', '78'))
55793	19563663	Trx overexpression on the other hand has been shown to increase p53 transactivation of reporter genes in human cell lines.	('increase', 'PosReg', (55, 63))	('Trx', 'Gene', '7295', (0, 3))	('transactivation', 'biological_process', 'GO:2000144', ('68', '83'))	('Trx', 'Gene', (0, 3))	('overexpression', 'Var', (4, 18))	('human', 'Species', '9606', (105, 110))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
55816	19563663	Cells that were pretreated with cathepsin B inhibitor CA-074 Me showed slightly less apoptosis after selenite exposure (Figure 1).	('cathepsin B', 'Gene', '1508', (32, 43))	('less', 'NegReg', (80, 84))	('CA-074 Me', 'Var', (54, 63))	('selenite', 'Chemical', 'MESH:D020887', (101, 109))	('apoptosis', 'CPA', (85, 94))	('cathepsin B', 'Gene', (32, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('CA-074 Me', 'Chemical', 'MESH:C400541', (54, 63))
55820	19563663	Kim et al have shown that selenite induces autophagy in glioma cells.	('autophagy', 'biological_process', 'GO:0006914', ('43', '52'))	('glioma', 'Disease', (56, 62))	('selenite', 'Chemical', 'MESH:D020887', (26, 34))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('autophagy', 'CPA', (43, 52))	('autophagy', 'biological_process', 'GO:0016236', ('43', '52'))	('selenite', 'Var', (26, 34))
55852	33023656	Data included in the discovery dataset included the two micro-array releases of ImmGen (Gene Expression Omnibus (GEO) accession numbers GSE15907 and GSE37448), and parts of several datasets for: epithelial cells (GSE27456 and GSE74317), breast cancer (GSE25525, GSE54626, and GSE78698), hypothalamic cell line (GSE61402), melanoma B16F10 cells (GSE84155), pancreatic ductal adenocarcinoma (GSE48643), myoblasts (GSE26764), and hepatocytes (GSE18614).	('GSE84155', 'Var', (345, 353))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (356, 388))	('melanoma', 'Disease', 'MESH:D008545', (322, 330))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('GSE25525', 'Var', (252, 260))	('Gene Expression', 'biological_process', 'GO:0010467', ('88', '103'))	('GSE18614', 'Var', (440, 448))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('breast cancer', 'Disease', (237, 250))	('hypothalamic', 'Disease', 'MESH:D007027', (287, 299))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('melanoma', 'Disease', (322, 330))	('GSE61402', 'Var', (311, 319))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (356, 388))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('GSE26764', 'Var', (412, 420))	('B16F10', 'CellLine', 'CVCL:0159', (331, 337))	('GSE27456', 'Var', (213, 221))	('pancreatic ductal adenocarcinoma', 'Disease', (356, 388))	('hypothalamic', 'Disease', (287, 299))	('GSE48643', 'Var', (390, 398))
55960	27705545	Investigating palygorskite's role in the development of mesothelioma in southern Nevada: Insights into fiber-induced carcinogenicity Similar to asbestos fibers, nonregulated mineral fibers can cause malignant mesothelioma (MM).	('asbestos fibers', 'Disease', 'MESH:D001195', (144, 159))	('cause', 'Reg', (193, 198))	('mesothelioma', 'Disease', (209, 221))	('asbestos fibers', 'Disease', (144, 159))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (199, 221))	('mineral fiber', 'Chemical', 'MESH:D019016', (174, 187))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('mesothelioma', 'Disease', (56, 68))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (199, 221))	('malignant mesothelioma', 'Disease', (199, 221))	('nonregulated', 'Var', (161, 173))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
56041	27705545	As shown in Figure 2, all concentrations of palygorskite caused significantly more lactate dehydrogenase (LDH) to be released into culture supernatant than glass beads, demonstrating that palygorskite is capable of causing cellular damage to HM cells (Figure 2A).	('palygorskite', 'Chemical', 'MESH:C026325', (188, 200))	('palygorskite', 'Var', (188, 200))	('rat', 'Species', '10116', (176, 179))	('lactate dehydrogenase', 'MPA', (83, 104))	('rat', 'Species', '10116', (33, 36))	('HM', 'CellLine', 'CVCL:M679', (242, 244))	('cellular damage', 'CPA', (223, 238))	('palygorskite', 'Chemical', 'MESH:C026325', (44, 56))
56054	27705545	MexTAg transgenic mice express the SV40 large T antigen in mesothelial cells and are therefore much more susceptible to asbestos carcinogenesis (Robinson et al.).	('SV40 large', 'Var', (35, 45))	('MexTAg', 'Chemical', '-', (0, 6))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (120, 143))	('transgenic mice', 'Species', '10090', (7, 22))	('asbestos carcinogenesis', 'Disease', (120, 143))
56074	27705545	Crocidolite-injected animals also had significantly higher numbers of macrophages (Supplemental Figure 4B), neutrophils (Supplemental Figure 4C), and mast cells (Supplemental Figure 4D) in their peritoneal cavities than either glass or palygorskite-injected animals.	('mast cells', 'CPA', (150, 160))	('palygorskite', 'Chemical', 'MESH:C026325', (236, 248))	('macrophages', 'CPA', (70, 81))	('neutrophils', 'CPA', (108, 119))	('higher', 'PosReg', (52, 58))	('Crocidolite-injected', 'Var', (0, 20))	('Crocidolite', 'Chemical', 'MESH:D017638', (0, 11))
56075	27705545	However, only neutrophil numbers were elevated in palygorskite-injected mice compared to glass controls (p = .03), and this increase was still much lower than that observed in crocidolite-exposed mice (p = .004, Supplemental Figure 4C).	('mice', 'Species', '10090', (196, 200))	('palygorskite-injected', 'Var', (50, 71))	('crocidolite', 'Chemical', 'MESH:D017638', (176, 187))	('mice', 'Species', '10090', (72, 76))	('elevated', 'PosReg', (38, 46))	('neutrophil numbers', 'CPA', (14, 32))	('palygorskite', 'Chemical', 'MESH:C026325', (50, 62))
56079	27705545	These results indicate that palygorskite induced a weaker acute inflammatory response compared to crocidolite, as crocidolite elicited more HMGB1 and recruited an increased number of granulocytes and an increased number of macrophages.	('crocidolite', 'Var', (114, 125))	('HMGB1', 'Gene', (140, 145))	('crocidolite', 'Chemical', 'MESH:D017638', (98, 109))	('elicited', 'Reg', (126, 134))	('increased', 'PosReg', (163, 172))	('palygorskite', 'Chemical', 'MESH:C026325', (28, 40))	('recruited', 'PosReg', (150, 159))	('acute inflammatory response', 'biological_process', 'GO:0002526', ('58', '85'))	('HMGB1', 'Gene', '15289', (140, 145))	('crocidolite', 'Chemical', 'MESH:D017638', (114, 125))	('more', 'PosReg', (135, 139))	('increased', 'PosReg', (203, 212))
56097	27705545	Macrophages from mice that received palygorskite had only a slight increase in macrophage CD206 expression compared to macrophages from mice injected with glass (Figure 6B right panel, Figure 6C).	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (17, 21))	('CD206', 'Gene', (90, 95))	('CD206', 'Gene', '17533', (90, 95))	('macrophage', 'MPA', (79, 89))	('palygorskite', 'Chemical', 'MESH:C026325', (36, 48))	('palygorskite', 'Var', (36, 48))
56099	27705545	In summary, these data indicate that mice injected with crocidolite had a significantly increased amount of M2, or protumoral, macrophages compared to mice injected with glass or palygorskite.	('crocidolite', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('palygorskite', 'Chemical', 'MESH:C026325', (179, 191))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('increased', 'PosReg', (88, 97))	('tumor', 'Disease', (118, 123))	('crocidolite', 'Chemical', 'MESH:D017638', (56, 67))	('mice', 'Species', '10090', (37, 41))
56130	27705545	For example, the acute inflammatory response, based on neutrophil influx into the peritoneal cavity 3 d after fiber exposure, was 141% greater in crocidolite-injected mice compared to palygorskite-injected mice.	('mice', 'Species', '10090', (206, 210))	('neutrophil influx into the peritoneal cavity', 'MPA', (55, 99))	('acute inflammatory response', 'MPA', (17, 44))	('acute inflammatory response', 'biological_process', 'GO:0002526', ('17', '44'))	('crocidolite', 'Chemical', 'MESH:D017638', (146, 157))	('crocidolite-injected', 'Var', (146, 166))	('greater', 'PosReg', (135, 142))	('palygorskite', 'Chemical', 'MESH:C026325', (184, 196))	('mice', 'Species', '10090', (167, 171))
56179	27705545	For macrophage subtype analysis, a separate tube of cells was stained with CD11b (M1/70), F4/80 (CI:A3-1) AF488 (AbD Serotec), CD206 (CO68C2) APC (BD Biosciences), CD86 (GL1) PE (BD Biosciences).	('APC', 'cellular_component', 'GO:0005680', ('142', '145'))	('CD206', 'Gene', (127, 132))	('F4/80', 'Gene', (90, 95))	('M1/70', 'Gene', (82, 87))	('F4/80', 'Gene', '13733', (90, 95))	('rat', 'Species', '10116', (39, 42))	('CD86', 'Gene', (164, 168))	('CD86', 'Gene', '12524', (164, 168))	('CD206', 'Gene', '17533', (127, 132))	('CD11b', 'Var', (75, 80))	('M1/70', 'Gene', '22238', (82, 87))
56191	27705545	This work was supported by NCI-R01 CA160715, DOD CA120355, and The Riviera United 4-a Cure to HY and by NCI-R01 CA198138-01 to MC, and by the V Foundation to MC and HY, and by the University of Hawai'i Foundation, which received unrestricted donations to support mesothelioma research from Honeywell International, Inc., to MC.	('CA198138-01', 'Var', (112, 123))	('mesothelioma', 'Disease', (263, 275))	('CA120355', 'Var', (49, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (263, 275))
56221	25676622	A major accomplishment in the study of CNT toxicity over the past decade has been the recognition that CNT are capable of eliciting a wide range of biological effects in experimental systems, which exceed beyond what would be predicted from insoluble and "nuisance dust"-like materials, but are more similar to those of high toxicity dusts.	('toxicity', 'Disease', (43, 51))	('CNT toxicity', 'Disease', 'MESH:D064420', (39, 51))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))	('biological effects', 'MPA', (148, 166))	('CNT toxicity', 'Disease', (39, 51))	('toxicity', 'Disease', 'MESH:D064420', (325, 333))	('toxicity', 'Disease', (325, 333))	('CNT', 'Var', (103, 106))	('eliciting', 'Reg', (122, 131))
56243	25676622	Even with the same CNT product, minor variations among different batches of manufacturing may alter their behaviors and toxicological endpoints in biological systems considerably, underscoring the importance of identifying CNT properties critical for their toxicity in nanosafety evaluation.	('behaviors', 'MPA', (106, 115))	('toxicity', 'Disease', 'MESH:D064420', (257, 265))	('variations', 'Var', (38, 48))	('toxicological endpoints in biological systems', 'MPA', (120, 165))	('toxicity', 'Disease', (257, 265))	('alter', 'Reg', (94, 99))
56278	25676622	>15 microm in length) induced significant inflammatory and fibrotic responses and granuloma formation on the parietal mesothelium, as well as mesotheliomas in the case of peritoneal injection in p53+/- mice.	('mesotheliomas', 'Disease', 'MESH:D008654', (142, 155))	('mice', 'Species', '10090', (202, 206))	('granuloma', 'Disease', (82, 91))	('mesotheliomas', 'Disease', (142, 155))	('granuloma', 'Phenotype', 'HP:0032252', (82, 91))	('granuloma', 'Disease', 'MESH:D006099', (82, 91))	('granuloma formation', 'biological_process', 'GO:0002432', ('82', '101'))	('p53+/-', 'Var', (195, 201))
56286	25676622	First, long MWCNT (NM400, 0.7-3 microm and NM402, 0.7-4 microm) as well as crocidolite asbestos, but not short MWCNT (MWCNTg2400, 0.7 microm) and crushed NM400 (NM400c, 0.14-0.5 mm), were shown to stimulate fibroblast proliferation in vitro and induce fibrosis in the lungs.	('fibroblast proliferation', 'biological_process', 'GO:0048144', ('207', '231'))	('crocidolite asbestos', 'Disease', (75, 95))	('stimulate', 'PosReg', (197, 206))	('fibroblast proliferation in vitro', 'CPA', (207, 240))	('fibrosis', 'Disease', 'MESH:D005355', (252, 260))	('rat', 'Species', '10116', (225, 228))	('MWCNT', 'Chemical', '-', (111, 116))	('MWCNT', 'Chemical', '-', (118, 123))	('NM400', 'Var', (19, 24))	('MWCNT', 'Chemical', '-', (12, 17))	('crocidolite asbestos', 'Disease', 'MESH:D001195', (75, 95))	('induce', 'PosReg', (245, 251))	('fibrosis', 'Disease', (252, 260))
56287	25676622	Second, spontaneously hypertensive (SH) rats administered with long MWCNT (20-50 microm), but not short MWCNT (0.5-2 mm), were found to exhibit increased fibroblast proliferation, collagen deposition, granuloma formation in the lungs in a TGF-beta-depend-ent manner.	('collagen deposition', 'CPA', (180, 199))	('fibroblast proliferation', 'biological_process', 'GO:0048144', ('154', '178'))	('hypertensive', 'Disease', (22, 34))	('increased', 'PosReg', (144, 153))	('granuloma', 'Phenotype', 'HP:0032252', (201, 210))	('granuloma formation', 'biological_process', 'GO:0002432', ('201', '220'))	('MWCNT', 'Chemical', '-', (104, 109))	('fibroblast proliferation', 'CPA', (154, 178))	('granuloma', 'Disease', 'MESH:D006099', (201, 210))	('rat', 'Species', '10116', (40, 43))	('increased fibroblast', 'Phenotype', 'HP:0410157', (144, 164))	('collagen', 'molecular_function', 'GO:0005202', ('180', '188'))	('hypertensive', 'Disease', 'MESH:D006973', (22, 34))	('rat', 'Species', '10116', (172, 175))	('granuloma', 'Disease', (201, 210))	('rats', 'Species', '10116', (40, 44))	('20-50 microm', 'Var', (75, 87))	('MWCNT', 'Chemical', '-', (68, 73))
56297	25676622	Functionalization of CNT potentially affects their toxicity.	('CNT', 'Gene', (21, 24))	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('affects', 'Reg', (37, 44))	('toxicity', 'Disease', (51, 59))	('Functionalization', 'Var', (0, 17))
56301	25676622	MWCNT- COOH were found to have increased cytotoxicity in bronchial cells compared with pristine MWCNT, whereas the pristine MWCNT showed higher toxicity toward alveolar cells than MWCNT-COOH.	('MWCNT- COOH', 'Var', (0, 11))	('MWCNT', 'Chemical', '-', (96, 101))	('MWCNT', 'Chemical', '-', (180, 185))	('MWCNT', 'Chemical', '-', (124, 129))	('toxicity', 'Disease', (144, 152))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (45, 53))	('COOH', 'Chemical', 'MESH:D002255', (7, 11))	('cytotoxicity', 'Disease', (41, 53))	('COOH', 'Chemical', 'MESH:D002255', (186, 190))	('MWCNT', 'Chemical', '-', (0, 5))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
56304	25676622	These examples demonstrate that surface modification can both increase and decrease toxicity, depending on the particular modification taken, providing new ways of prevention-through-design for CNT and other nanomaterials.	('decrease', 'NegReg', (75, 83))	('rat', 'Species', '10116', (22, 25))	('surface modification', 'Var', (32, 52))	('increase', 'PosReg', (62, 70))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('toxicity', 'Disease', (84, 92))
56324	25676622	On one hand, deficiency of vitamin E in animal diet, which decreases the body's antioxidant capacity, caused oxidative stress and increased the sensitivity to SWCNT-induced lung lesions in mice.	('lung lesions', 'Disease', 'MESH:D008171', (173, 185))	('antioxidant capacity', 'MPA', (80, 100))	('oxidative stress', 'Phenotype', 'HP:0025464', (109, 125))	('decreases', 'NegReg', (59, 68))	('mice', 'Species', '10090', (189, 193))	('deficiency', 'Var', (13, 23))	('oxidative stress', 'MPA', (109, 125))	('vitamin E', 'Chemical', 'MESH:D014810', (27, 36))	('SWCNT', 'Chemical', '-', (159, 164))	('increased', 'PosReg', (130, 139))	('lung lesions', 'Disease', (173, 185))	('deficiency of vitamin E', 'Phenotype', 'HP:0100513', (13, 36))	('caused', 'Reg', (102, 108))
56326	25676622	In addition to directly damaging macromolecules and cellular structures to result in cytotoxicity and cell death, ROS can activate signaling pathways, such as the NF-kappaB (nuclear factor-kappaB) signaling pathway, to boost the production and secretion of proinflammatory and profibrotic cytokines and growth factors that promote inflammation and fibrosis.	('secretion', 'biological_process', 'GO:0046903', ('244', '253'))	('inflammation', 'Disease', 'MESH:D007249', (331, 343))	('ROS', 'Var', (114, 117))	('inflammation', 'biological_process', 'GO:0006954', ('331', '343'))	('nuclear factor-kappaB', 'Gene', '18033', (174, 195))	('nuclear factor-kappaB', 'Gene', (174, 195))	('inflammation', 'Disease', (331, 343))	('secretion', 'MPA', (244, 253))	('production', 'MPA', (229, 239))	('cell death', 'biological_process', 'GO:0008219', ('102', '112'))	('fibrosis', 'Disease', 'MESH:D005355', (348, 356))	('fibrosis', 'Disease', (348, 356))	('promote', 'PosReg', (323, 330))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('boost', 'PosReg', (219, 224))	('signaling pathway', 'biological_process', 'GO:0007165', ('197', '214'))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('cytotoxicity', 'Disease', (85, 97))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
56340	25676622	NOX2 was shown to play a role in the transition of CNT-induced acute inflammation to chronic fibrosis in mice, as the NOX2 knockout mice exposed to SWCNT exhibited significantly more proinflammatory, but not profibrotic, phenotypes compared with wild-type.	('inflammation', 'Disease', (69, 81))	('NOX2', 'Gene', (0, 4))	('NOX2', 'Gene', '13058', (0, 4))	('knockout', 'Var', (123, 131))	('fibrosis', 'Disease', 'MESH:D005355', (93, 101))	('fibrosis', 'Disease', (93, 101))	('proinflammatory', 'MPA', (183, 198))	('mice', 'Species', '10090', (132, 136))	('inflammation', 'biological_process', 'GO:0006954', ('69', '81'))	('NOX2', 'Gene', (118, 122))	('SWCNT', 'Chemical', '-', (148, 153))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))	('mice', 'Species', '10090', (105, 109))	('NOX2', 'Gene', '13058', (118, 122))
56344	25676622	Overproduction of NO , ONOO-, and their derivatives, which are collectively called reactive nitrogen species, causes nitrosative stress that contributes to toxicity and disease pathogenesis in the body.	('nitrosative stress', 'MPA', (117, 135))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (83, 108))	('contributes', 'Reg', (141, 152))	('Overproduction', 'Var', (0, 14))	('ONOO-', 'Chemical', '-', (23, 28))	('causes', 'Reg', (110, 116))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))	('toxicity', 'Disease', (156, 164))	('pathogenesis', 'biological_process', 'GO:0009405', ('177', '189'))
56381	25676622	Moreover, the mesothelioma induced by MWCNT had homozygous deletion of Cdkn2a/2b tumor suppressor genes similarly to asbestos-induced mesothelioma.	('Cdkn2a', 'Gene', '12578', (71, 77))	('MWCNT', 'Chemical', '-', (38, 43))	('mesothelioma', 'Disease', (134, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('Cdkn2a', 'Gene', (71, 77))	('mesothelioma', 'Disease', (14, 26))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (14, 26))	('deletion', 'Var', (59, 67))	('tumor', 'Disease', (81, 86))
56391	25676622	These findings would not support MWCNT as an initiator or a complete carcinogen, but demonstrate that MWCNT inhaled at a dose relevant to human exposures is a strong tumor promoter in mouse lungs.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('human', 'Species', '9606', (138, 143))	('tumor', 'Disease', (166, 171))	('MWCNT', 'Chemical', '-', (33, 38))	('rat', 'Species', '10116', (92, 95))	('mouse', 'Species', '10090', (184, 189))	('MWCNT', 'Var', (102, 107))	('MWCNT', 'Chemical', '-', (102, 107))
56399	25676622	The results demonstrate a role for COX-2 in the exacerbation of allergen-induced airway remodeling by MWCNT and suggest different pathways in the development of fibrotic and allergic responses, respectively.	('COX-2', 'Gene', (35, 40))	('COX-2', 'Gene', '19225', (35, 40))	('allergen-induced', 'Disease', (64, 80))	('rat', 'Species', '10116', (19, 22))	('MWCNT', 'Var', (102, 107))	('MWCNT', 'Chemical', '-', (102, 107))	('exacerbation', 'PosReg', (48, 60))
56406	25676622	NF-kappaB was activated by SWCNT in rat aortic endothelial cells (RAEC).	('rat', 'Species', '10116', (36, 39))	('SWCNT', 'Var', (27, 32))	('activated', 'PosReg', (14, 23))	('SWCNT', 'Chemical', '-', (27, 32))	('NF-kappaB', 'Protein', (0, 9))
56407	25676622	In a recent study, SWCNT were shown to activate the NF-kappaB signaling cascade and increase the secretion of a panel of NF-kappaB-regulated proinflammatory cytokines and chemokines, including TNF-alpha, IL-1beta, IL-6, IL-10, and MCP-1, in mouse RAW264.7 macrophages.	('MCP', 'molecular_function', 'GO:0004298', ('231', '234'))	('IL-10', 'molecular_function', 'GO:0005141', ('220', '225'))	('IL-6', 'Gene', (214, 218))	('IL-10', 'Gene', '16153', (220, 225))	('IL-1', 'molecular_function', 'GO:0005149', ('204', '208'))	('IL-6', 'molecular_function', 'GO:0005138', ('214', '218'))	('IL-6', 'Gene', '16193', (214, 218))	('RAW264.7', 'CellLine', 'CVCL:0493', (247, 255))	('MCP-1', 'Gene', '20296', (231, 236))	('increase', 'PosReg', (84, 92))	('signaling cascade', 'biological_process', 'GO:0007165', ('62', '79'))	('SWCNT', 'Chemical', '-', (19, 24))	('secretion', 'biological_process', 'GO:0046903', ('97', '106'))	('TNF-alpha', 'Gene', (193, 202))	('MCP-1', 'Gene', (231, 236))	('IL-10', 'Gene', (220, 225))	('NF-kappaB signaling cascade', 'Pathway', (52, 79))	('mouse', 'Species', '10090', (241, 246))	('TNF-alpha', 'Gene', '21926', (193, 202))	('secretion', 'MPA', (97, 106))	('SWCNT', 'Var', (19, 24))	('activate', 'PosReg', (39, 47))
56409	25676622	In a separate study, MWCNT were shown to activate the NF-kappaB signaling pathway and increase the secretion of a number of NF-kappaB-regulated proinflammatory cytokines and chemokines, including TNF-alpha, IL-1beta, IL-6, IL-10, and MCP-1, in mouse RAW264.7 macrophages; moreover, activation of NF-kappaB involved degradation of IkappaBalpha, nuclear translocation of NF-kappaB subunit p65, binding of NF-kappaB to specific kappaB-binding sites, and elevated NF-kappaB-controlled reporter gene expression.	('rat', 'Species', '10116', (9, 12))	('MCP', 'molecular_function', 'GO:0004298', ('234', '237'))	('degradation', 'MPA', (315, 326))	('IL-10', 'Gene', (223, 228))	('MWCNT', 'Chemical', '-', (21, 26))	('IL-6', 'molecular_function', 'GO:0005138', ('217', '221'))	('mouse', 'Species', '10090', (244, 249))	('increase', 'PosReg', (86, 94))	('RAW264.7', 'CellLine', 'CVCL:0493', (250, 258))	('IL-10', 'molecular_function', 'GO:0005141', ('223', '228'))	('gene expression', 'biological_process', 'GO:0010467', ('490', '505'))	('NF-kappaB', 'Protein', (369, 378))	('TNF-alpha', 'Gene', (196, 205))	('MCP-1', 'Gene', (234, 239))	('signaling pathway', 'biological_process', 'GO:0007165', ('64', '81'))	('NF-kappaB-controlled reporter gene expression', 'MPA', (460, 505))	('binding', 'Interaction', (392, 399))	('binding', 'molecular_function', 'GO:0005488', ('392', '399'))	('TNF-alpha', 'Gene', '21926', (196, 205))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('282', '305'))	('MWCNT', 'Var', (21, 26))	('degradation', 'biological_process', 'GO:0009056', ('315', '326'))	('IL-10', 'Gene', '16153', (223, 228))	('nuclear translocation', 'MPA', (344, 365))	('IL-6', 'Gene', (217, 221))	('IkappaBalpha', 'Protein', (330, 342))	('IL-1', 'molecular_function', 'GO:0005149', ('207', '211'))	('secretion', 'MPA', (99, 108))	('elevated', 'PosReg', (451, 459))	('binding', 'molecular_function', 'GO:0005488', ('432', '439'))	('IL-6', 'Gene', '16193', (217, 221))	('activation', 'PosReg', (282, 292))	('secretion', 'biological_process', 'GO:0046903', ('99', '108'))	('MCP-1', 'Gene', '20296', (234, 239))
56424	25676622	In the first report, long needlelike, but not tangled, MWCNT induced secretion of IL-1beta from LPS (lipopolysaccharides)-primed human primary macrophages, which involved NLRP3 inflammasome activation because knocking down of NLRP3 diminished MWCNT-induced IL-1beta secretion.	('LPS', 'Disease', (96, 99))	('diminished', 'NegReg', (232, 242))	('IL-1', 'molecular_function', 'GO:0005149', ('257', '261'))	('MWCNT', 'Chemical', '-', (55, 60))	('lipopolysaccharides', 'Chemical', 'MESH:D008070', (101, 120))	('LPS', 'Disease', 'MESH:C536528', (96, 99))	('NLRP3', 'Gene', (226, 231))	('secretion', 'biological_process', 'GO:0046903', ('69', '78'))	('secretion', 'MPA', (69, 78))	('human', 'Species', '9606', (129, 134))	('IL-1', 'molecular_function', 'GO:0005149', ('82', '86'))	('NLRP3 inflammasome activation', 'biological_process', 'GO:0044546', ('171', '200'))	('secretion', 'biological_process', 'GO:0046903', ('266', '275'))	('knocking down', 'Var', (209, 222))	('MWCNT', 'Chemical', '-', (243, 248))
56433	25676622	In addition to CNT, other particles and fibers, including silica, asbestos, alum, and nanoparticles, such as nano-TiO2 and nano-SiO2, have been shown to activate the NLRP3 inflammasome, but their underlying mechanisms and pathologic implications remain unaddressed to a large extent.	('nano-SiO2', 'Var', (123, 132))	('TiO2', 'Chemical', 'MESH:C009495', (114, 118))	('silica', 'Chemical', 'MESH:D012822', (58, 64))	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('nano-TiO2', 'Var', (109, 118))	('activate', 'PosReg', (153, 161))	('SiO2', 'Chemical', 'MESH:D012822', (128, 132))	('NLRP3 inflammasome', 'Pathway', (166, 184))
56442	25676622	In a separate study, long SWCNT increased the expression and secretion of TGF-beta1 in cultured normal human lung fibroblasts NHLF.	('secretion', 'MPA', (61, 70))	('rat', 'Species', '10116', (9, 12))	('long SWCNT', 'Var', (21, 31))	('SWCNT', 'Chemical', '-', (26, 31))	('human', 'Species', '9606', (103, 108))	('secretion', 'biological_process', 'GO:0046903', ('61', '70'))	('increased', 'PosReg', (32, 41))	('TGF-beta1', 'Gene', (74, 83))	('expression', 'MPA', (46, 56))
56451	25676622	For example, blockade of TGF-beta/Smad signaling was shown to enhance airway inflammation and reactivity, whereas over-expression of TGF-beta1 in regulatory T cells inhibited bleomycin-induced lung fibrosis.	('airway inflammation', 'Phenotype', 'HP:0002099', (70, 89))	('blockade', 'Var', (13, 21))	('enhance', 'PosReg', (62, 69))	('lung fibrosis', 'Disease', 'MESH:D005355', (193, 206))	('inflammation', 'biological_process', 'GO:0006954', ('77', '89'))	('inhibited', 'NegReg', (165, 174))	('over-expression', 'PosReg', (114, 129))	('Sma', 'Gene', (34, 37))	('Sma', 'Gene', '20589', (34, 37))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('TGF-beta1', 'Gene', (133, 142))	('inflammation', 'Disease', (77, 89))	('lung fibrosis', 'Disease', (193, 206))	('lung fibrosis', 'Phenotype', 'HP:0002206', (193, 206))	('reactivity', 'CPA', (94, 104))	('bleomycin', 'Chemical', 'MESH:D001761', (175, 184))
56458	25676622	In contrast, JNK and p38 MAPKs respond most robustly to inflammatory cytokines and cellular stresses, and are strongly associated with stress responses such as apoptosis and inflammation, although they can also be weakly activated by growth factors.	('JNK', 'Gene', '26419', (13, 16))	('associated with', 'Reg', (119, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('p38 MAPKs', 'Var', (21, 30))	('inflammation', 'Disease', 'MESH:D007249', (174, 186))	('JNK', 'Gene', (13, 16))	('JNK', 'molecular_function', 'GO:0004705', ('13', '16'))	('inflammation', 'Disease', (174, 186))	('inflammation', 'biological_process', 'GO:0006954', ('174', '186'))
56462	25676622	In human lung fibroblasts CRL-1490, SWCNT induced p38 phosphorylation in a dose-dependent manner, which in turn contributed to SWCNT-induced fibrogenesis and angiogenesis through the induction of TGF-b1 and vascular endothelial growth factor (VEGF).	('human', 'Species', '9606', (3, 8))	('vascular endothelial growth factor', 'Gene', '7422', (207, 241))	('SWCNT', 'Chemical', '-', (36, 41))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('207', '241'))	('SWCNT', 'Chemical', '-', (127, 132))	('SWCNT-induced', 'Var', (127, 140))	('VEGF', 'Gene', (243, 247))	('angiogenesis', 'biological_process', 'GO:0001525', ('158', '170'))	('fibrogenesis', 'CPA', (141, 153))	('angiogenesis', 'CPA', (158, 170))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('p38', 'Protein', (50, 53))	('contributed', 'Reg', (112, 123))	('TGF-b1', 'Gene', (196, 202))	('VEGF', 'Gene', '7422', (243, 247))	('vascular endothelial growth factor', 'Gene', (207, 241))
56471	25676622	In addition to stimulating the proliferation of lung cells such as fibroblasts and mesothelial cells for their fibrotic and mesothelioma-causing effects, CNT induce cell-cycle arrest, apoptosis, and autophagy.	('autophagy', 'CPA', (199, 208))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('165', '182'))	('autophagy', 'biological_process', 'GO:0006914', ('199', '208'))	('CNT', 'Var', (154, 157))	('mesothelioma', 'Disease', (124, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('cell-cycle arrest', 'CPA', (165, 182))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('autophagy', 'biological_process', 'GO:0016236', ('199', '208'))	('rat', 'Species', '10116', (38, 41))	('apoptosis', 'CPA', (184, 193))
56472	25676622	For instance, cell-cycle analyses revealed that SWCNT induced a G2 block in cell cycle, whereas exposure to MWCNT caused a G1/S block in cultured cells.	('MWCNT', 'Chemical', '-', (108, 113))	('G2 block', 'CPA', (64, 72))	('SWCNT', 'Var', (48, 53))	('cell cycle', 'CPA', (76, 86))	('SWCNT', 'Chemical', '-', (48, 53))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('cell-cycle', 'biological_process', 'GO:0007049', ('14', '24'))
56473	25676622	Recent studies showed that SWCNT induced apoptosis in rat pheochromocytoma PC12 cells and rat aorta endothelial cells, and MWCNT stimulated apoptosis in rat glioma cells and RAW 264.7 cell-derived osteoclasts.	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('rat', 'Species', '10116', (153, 156))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('PC12', 'CellLine', 'CVCL:0481', (75, 79))	('apoptosis', 'CPA', (140, 149))	('RAW 264.7', 'CellLine', 'CVCL:0493', (174, 183))	('rat', 'Species', '10116', (54, 57))	('MWCNT', 'Chemical', '-', (123, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('pheochromocytoma', 'Disease', 'MESH:D010673', (58, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('SWCNT', 'Chemical', '-', (27, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('pheochromocytoma', 'Disease', (58, 74))	('MWCNT', 'Var', (123, 128))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))	('rat', 'Species', '10116', (90, 93))	('glioma', 'Disease', (157, 163))
56481	25676622	A follow-up study confirmed that, in cells transformed by prolonged exposure to SWCNT, the total p53 protein level was dramatically decreased, which involved the plasma membrane-associated protein caveolin-1 (Cav-1), supporting a role of p53 and Cav-1 in CNT tumorigenesis.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('caveolin-1', 'Gene', '12389', (197, 207))	('Cav-1', 'Gene', '12389', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('Cav-1', 'Gene', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('Cav-1', 'Gene', '12389', (209, 214))	('caveolin-1', 'Gene', (197, 207))	('SWCNT', 'Var', (80, 85))	('plasma membrane', 'cellular_component', 'GO:0005886', ('162', '177'))	('p53 protein level', 'MPA', (97, 114))	('decreased', 'NegReg', (132, 141))	('tumor', 'Disease', (259, 264))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('SWCNT', 'Chemical', '-', (80, 85))	('Cav-1', 'Gene', (246, 251))
56487	25676622	The major findings conclude that CNT can induce a variety of adverse effects in experimental systems including cytotoxicity, inflammation, fibrosis, genotoxicity, tumorigenesis, and immune effects, which extend well beyond the predictions from "nuisance dust"-like fibers (Figure 2).	('fibrosis', 'Disease', 'MESH:D005355', (139, 147))	('inflammation', 'Disease', 'MESH:D007249', (125, 137))	('inflammation', 'Disease', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CNT', 'Var', (33, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('inflammation', 'biological_process', 'GO:0006954', ('125', '137'))	('toxicity', 'Disease', 'MESH:D064420', (153, 161))	('immune effects', 'CPA', (182, 196))	('tumor', 'Disease', (163, 168))	('cytotoxicity', 'Disease', (111, 123))	('toxicity', 'Disease', (115, 123))	('toxicity', 'Disease', 'MESH:D064420', (115, 123))	('fibrosis', 'Disease', (139, 147))	('toxicity', 'Disease', (153, 161))
56500	25676622	Further analyses of how modification of CNT surface alters CNT behavior and toxicity in vivo at cellular and molecular levels would yield valuable new insights into CNT biology and nanotoxicology.	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('alters', 'Reg', (52, 58))	('modification', 'Var', (24, 36))	('CNT behavior', 'MPA', (59, 71))	('toxicity', 'Disease', (76, 84))
56564	23285196	Our initial studies using MPeM parental cells have shown that injections of 3x106 Meso-CL1 cells were able to generate both subcutaneous and intraperitoneal tumors in immunocompromised mice whereas Meso-CL2 and Meso-CL3 were non-tumorigenic.	('tumor', 'Disease', (157, 162))	('CL1', 'Gene', '9201', (87, 90))	('-CL3', 'Chemical', '-', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('CL1', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mice', 'Species', '10090', (185, 189))	('subcutaneous', 'CPA', (124, 136))	('tumor', 'Disease', (229, 234))	('intraperitoneal tumors', 'Disease', 'MESH:D009369', (141, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('3x106', 'Var', (76, 81))	('intraperitoneal tumors', 'Disease', (141, 163))
56584	23285196	Clinical studies have shown that benefits from anti-angiogenic therapy for cancer are limited and in many cases anti-angiogenic therapies result in an initial response followed by tumor relapse.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Disease', (75, 81))	('anti-angiogenic', 'Var', (112, 127))	('tumor', 'Disease', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
56969	32021160	Kan and colleagues co-cultured SWNTs of different lengths with Hep G2 cells for 5 h. Confocal imaging and flow cytometry data disclosed that the internalization of L-SWNTs into cells mainly occurred through energy-dependent endocytosis.	('occurred', 'Reg', (190, 198))	('endocytosis', 'biological_process', 'GO:0006897', ('224', '235'))	('L-SWNTs', 'Var', (164, 171))	('internalization', 'MPA', (145, 160))	('Hep G2', 'CellLine', 'CVCL:0027', (63, 69))	('energy-dependent endocytosis', 'MPA', (207, 235))
56991	32021160	In the early stages of CNT-induced mesothelioma formation, M-MDSC rapidly and continuously accumulated in the peritoneal cavity of rats, preventing tumor cell monitoring by immune cells and thereby inducing mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('rats', 'Species', '10116', (131, 135))	('mesothelioma', 'Disease', (35, 47))	('tumor', 'Disease', (148, 153))	('M-MDSC', 'Var', (59, 65))	('mesothelioma', 'Disease', (207, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('inducing', 'Reg', (198, 206))	('preventing', 'NegReg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (207, 219))
57009	32021160	Moreover, activities of liver enzymes (ALT/GPT and AST/GOT) in various types of serum were enhanced with functionalized MWCNT concentration, leading to the conclusion that functionalized MWCNTs induce hepatotoxicity and oxidative stress as the main toxicological mechanisms.	('functionalized', 'Var', (172, 186))	('ALT', 'Gene', (39, 42))	('GPT', 'Gene', (43, 46))	('GPT', 'Gene', '76282', (43, 46))	('AST', 'Gene', '235504', (51, 54))	('AST', 'Gene', (51, 54))	('activities', 'MPA', (10, 20))	('hepatotoxicity', 'Disease', (201, 215))	('oxidative stress', 'Phenotype', 'HP:0025464', (220, 236))	('GPT', 'molecular_function', 'GO:0004021', ('43', '46'))	('ALT', 'Gene', '76282', (39, 42))	('liver enzymes', 'Enzyme', (24, 37))	('oxidative', 'CPA', (220, 229))	('hepatotoxicity', 'Disease', 'MESH:D056486', (201, 215))	('enhanced', 'PosReg', (91, 99))	('ALT', 'molecular_function', 'GO:0004021', ('39', '42'))
57014	32021160	The collective results clearly suggest that carboxylate MWCNTs cause damage to the liver by destroying the antioxidant defense system.	('carboxylate MWCNTs', 'Var', (44, 62))	('antioxidant defense system', 'MPA', (107, 133))	('destroying', 'NegReg', (92, 102))	('carboxylate', 'Chemical', 'MESH:C503382', (44, 55))
57057	32021160	In these experiments, the liver cancer cell line, HCC SMMC-7721, was treated with DOX and DOX/FA/CHI/SWNT (100 mug/mL), and cell viability recorded at 24, 48 and 72 h. The results showed lower cell viability of the DOX/FA/CHI/SWNT than the DOX group, indicative of time-dependent inhibition of liver cancer growth in nude mice.	('liver cancer', 'Disease', 'MESH:D006528', (294, 306))	('DOX', 'Chemical', 'MESH:D004317', (82, 85))	('mug', 'molecular_function', 'GO:0043739', ('111', '114'))	('liver cancer', 'Disease', (294, 306))	('liver cancer', 'Disease', (26, 38))	('cell viability', 'CPA', (193, 207))	('DOX', 'Chemical', 'MESH:D004317', (240, 243))	('DOX', 'Chemical', 'MESH:D004317', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('liver cancer', 'Phenotype', 'HP:0002896', (294, 306))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lower', 'NegReg', (187, 192))	('DOX', 'Chemical', 'MESH:D004317', (215, 218))	('DOX/FA/CHI/SWNT', 'Var', (215, 230))	('nude mice', 'Species', '10090', (317, 326))	('liver cancer', 'Phenotype', 'HP:0002896', (26, 38))	('liver cancer', 'Disease', 'MESH:D006528', (26, 38))	('HCC SMMC-7721', 'CellLine', 'CVCL:0534', (50, 63))
57098	32021160	Notably, the PCNA index of lung cells of the MWCNT-7 group was increased, compared with the DWCNT group.	('increased', 'PosReg', (63, 72))	('PCNA', 'Gene', (13, 17))	('PCNA', 'molecular_function', 'GO:0003892', ('13', '17'))	('MWCNT-7', 'Var', (45, 52))	('PCNA', 'Gene', '18538', (13, 17))
57136	31667333	High CA 19.9 serum concentration has been associated with the diagnosis of MCPM.	('MCPM', 'Disease', (75, 79))	('MCPM', 'Disease', 'MESH:D010534', (75, 79))	('associated', 'Reg', (42, 52))	('High', 'Var', (0, 4))
57146	31667333	However, hemorrhagic cysts may appear as hyperintense lesions on T1 and hypointense on T2.	('hyper', 'Disease', 'MESH:D053306', (41, 46))	('hyper', 'Disease', (41, 46))	('hypointense', 'Var', (72, 83))	('hemorrhagic cysts', 'Disease', (9, 26))	('hemorrhagic cysts', 'Disease', 'MESH:D006470', (9, 26))
57170	31667333	The use of the combined laparoscopy CRS - HIPEC may be a promising alternative approach to treat MCPM.	('MCPM', 'Disease', 'MESH:D010534', (97, 101))	('MCPM', 'Disease', (97, 101))	('CRS - HIPEC', 'Var', (36, 47))
57171	31667333	included in their study patients with low-grade PMP or MCPM, and compared 8 patients treated by laparoscopy with 8 patients treated by laparotomy.	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (115, 123))	('PMP', 'Disease', (48, 51))	('MCPM', 'Disease', (55, 59))	('PMP', 'Disease', 'MESH:D011553', (48, 51))	('patients', 'Species', '9606', (24, 32))	('MCPM', 'Disease', 'MESH:D010534', (55, 59))	('low-grade', 'Var', (38, 47))
57206	29538329	Collectively, it should be noted that a significant number of SqCCs or adenocarcinomas show a positivity for TTF-1 (clone SPT24) or TP63, respectively.	('TP63', 'Gene', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('SqCC', 'Phenotype', 'HP:0002860', (62, 66))	('SPT', 'molecular_function', 'GO:0004758', ('122', '125'))	('positivity', 'Var', (94, 104))	('SqCCs', 'Disease', (62, 67))	('SPT', 'molecular_function', 'GO:0004760', ('122', '125'))	('adenocarcinomas', 'Disease', 'MESH:D000230', (71, 86))	('TTF-1', 'Gene', (109, 114))	('adenocarcinomas', 'Disease', (71, 86))	('TP63', 'Gene', '8626', (132, 136))	('TTF-1', 'Gene', '7270', (109, 114))
57227	29538329	Immunohistochemistry for ALK represents a cost-effective and widely available method that is an effective screening tool to detect the presence of ALK rearrangement, in addition to conventional fluorescence in situ hybridization (FISH).	('ALK', 'Gene', (147, 150))	('rearrangement', 'Var', (151, 164))	('ALK', 'Gene', (25, 28))	('ALK', 'Gene', '238', (147, 150))	('ALK', 'Gene', '238', (25, 28))
57236	29538329	ROS1 rearrangement is an oncogenic driver in a subset (1-2%) of lung adenocarcinomas.	('ROS1', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('ROS1', 'Gene', '6098', (0, 4))	('lung adenocarcinomas', 'Disease', (64, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (64, 84))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (64, 84))	('rearrangement', 'Var', (5, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))
57238	29538329	Clinical trials have demonstrated the clinical efficacy of TKIs or ROS1 inhibitors in patients with NSCLC with ROS1 rearrangement confirmed by FISH assays.	('ROS1', 'Gene', (67, 71))	('rearrangement', 'Var', (116, 129))	('ROS1', 'Gene', '6098', (67, 71))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('ROS1', 'Gene', (111, 115))	('ROS1', 'Gene', '6098', (111, 115))	('patients', 'Species', '9606', (86, 94))
57239	29538329	As with ALK-rearranged NSCLCs, immunohistochemistry provides high sensitivity and specificity for the detection of ROS1 rearrangements.	('rearrangements', 'Var', (120, 134))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('ALK', 'Gene', '238', (8, 11))	('NSCLC', 'Disease', (23, 28))	('ROS1', 'Gene', (115, 119))	('ALK', 'Gene', (8, 11))	('ROS1', 'Gene', '6098', (115, 119))
57243	29538329	Therefore, tumors or cell lines with confirmed ROS1 rearrangement need to be used as an external positive control.	('ROS1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('ROS1', 'Gene', '6098', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('rearrangement', 'Var', (52, 65))	('tumors', 'Disease', (11, 17))
57245	29538329	Adenocarcinomas with CD74-ROS1 fusion, which is the most frequent fusion gene, usually shows globular cytoplasmic ROS1 immunoreactivity, whereas adenocarcinomas with EZR-ROS1 fusion usually show membranous immunostaining.	('ROS1', 'Gene', (26, 30))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (0, 15))	('ROS1', 'Gene', '6098', (170, 174))	('EZR', 'Gene', (166, 169))	('CD74', 'Gene', '972', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('adenocarcinomas', 'Disease', 'MESH:D000230', (145, 160))	('adenocarcinomas', 'Disease', (145, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('ROS1', 'Gene', '6098', (114, 118))	('ROS1', 'Gene', '6098', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('ROS1', 'Gene', (170, 174))	('EZR', 'Gene', '7430', (166, 169))	('CD74', 'Gene', (21, 25))	('Adenocarcinomas', 'Disease', (0, 15))	('fusion', 'Var', (31, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('ROS1', 'Gene', (114, 118))
57250	29538329	TKIs or ROS1 inhibitors should be applied only to cases that are positive for ROS1 rearrangement, as confirmed by both immunohistochemical and FISH analyses.	('ROS1', 'Gene', (78, 82))	('ROS1', 'Gene', '6098', (78, 82))	('rearrangement', 'Var', (83, 96))	('ROS1', 'Gene', (8, 12))	('ROS1', 'Gene', '6098', (8, 12))
57251	29538329	The EGFR mutation is one of the most common driver mutations in lung adenocarcinoma, and EGFR-mutated adenocarcinoma is characterized by East Asian ethnicity, female gender, and non-/light-smoking history.	('mutation', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (102, 116))	('EGFR', 'Gene', (89, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('EGFR', 'Gene', (4, 8))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('lung adenocarcinoma', 'Disease', (64, 83))	('adenocarcinoma', 'Disease', (69, 83))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (89, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))	('EGFR', 'Gene', '1956', (4, 8))
57253	29538329	In addition, adenocarcinoma with micropapillary morphology has a higher frequency of EGFR mutations than adenocarcinoma without this morphology.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('EGFR', 'Gene', (85, 89))	('adenocarcinoma', 'Disease', (105, 119))	('mutations', 'Var', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenocarcinoma', 'Disease', 'MESH:D000230', (105, 119))	('adenocarcinoma', 'Disease', (13, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (13, 27))	('EGFR', 'Gene', '1956', (85, 89))
57254	29538329	In the gene coding for the receptor, EGFR mutations are divided into four major types: point mutations in exon 18, deletions in exon 19, insertions in exon 20, and point mutations in exon 21.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('deletions in exon', 'Var', (115, 132))	('EGFR', 'Gene', '1956', (37, 41))	('point mutations', 'Var', (87, 102))	('EGFR', 'Gene', (37, 41))	('insertions in exon', 'Var', (137, 155))	('point mutations in', 'Var', (164, 182))
57255	29538329	Approximately 90% of EGFR mutations in NSCLCs involve in-frame deletions in exon 19 and the point mutation L858R in exon 21.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('L858R', 'Var', (107, 112))	('deletions', 'Var', (63, 72))	('mutations', 'Var', (26, 35))	('L858R', 'Mutation', 'rs121434568', (107, 112))	('NSCLC', 'Disease', (39, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
57256	29538329	These mutations, particularly exon 19 deletions, are associated with a superior and prolonged clinical response to EGFR TKIs.	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'Gene', (115, 119))	('deletions', 'Var', (38, 47))
57257	29538329	EGFR mutation-specific antibodies, recognizing a 15-bp deletion in exon 19 (clone: 6B6) and an L858R point mutation in exon 21 (clone: 43B2), have been developed.	('EGFR', 'Gene', (0, 4))	('L858R', 'Mutation', 'rs121434568', (95, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('deletion', 'Var', (55, 63))	('EGFR', 'Gene', '1956', (0, 4))	('L858R', 'Var', (95, 100))
57258	29538329	However, immunohistochemical analysis using these antibodies has not been recommended for screening EGFR mutations due to its low sensitivity.	('mutations', 'Var', (105, 114))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))
57261	29538329	Although various studies have reported the association of PD-L1 positivity in tumor cells with prognosis in lung cancer, the results are conflicting and inconclusive.	('association', 'Interaction', (43, 54))	('positivity', 'Var', (64, 74))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('PD-L1', 'Gene', (58, 63))	('tumor', 'Disease', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
57264	29538329	According to a clinical trial for PD-1 inhibitor, pembrolizumab, for the treatment of NSCLCs, NSCLCs with at least 50% positivity for PD-L1 were associated with a higher response rate and longer survival than NSCLCs with less than 50% positivity.	('positivity', 'Var', (119, 129))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('PD-1', 'Gene', (34, 38))	('NSCLC', 'Disease', (86, 91))	('PD-L1', 'Gene', (134, 139))	('PD-1', 'Gene', '5133', (34, 38))	('pembrolizumab', 'Chemical', 'MESH:C582435', (50, 63))	('NSCLC', 'Disease', (94, 99))	('longer', 'PosReg', (188, 194))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('higher', 'PosReg', (163, 169))	('NSCLC', 'Disease', (209, 214))	('response', 'CPA', (170, 178))
57272	29538329	According to these studies, the 22C3, 28-8, and SP263 assays showed a similar membranous staining on tumor cells; however, the SP142 assay consistently had fewer PD-L1 tumor cells expressing PD-L1.	('PD-L1 tumor', 'Disease', (162, 173))	('tumor', 'Disease', (168, 173))	('PD-L1', 'Var', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('fewer', 'NegReg', (156, 161))	('SP142', 'Chemical', '-', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
57285	29538329	The loss of BAP1, confirmed by immunohistochemistry, and homozygous CDKN2A (p16) deletions, identified by FISH, have recently emerged as potential indicators of MM.	('deletions', 'Var', (81, 90))	('p16', 'Gene', '1029', (76, 79))	('CDKN2A', 'Gene', (68, 74))	('BAP1', 'Gene', '8314', (12, 16))	('CDKN2A', 'Gene', '1029', (68, 74))	('p16', 'Gene', (76, 79))	('BAP1', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))
57289	29538329	In contrast to BAP1 loss, the CDKN2A deletion is observed more frequently in the sarcomatoid subtype than in the epithelioid/biphasic subtype.	('deletion', 'Var', (37, 45))	('sarcomatoid subtype', 'Disease', (81, 100))	('CDKN2A', 'Gene', (30, 36))	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (81, 100))	('BAP1', 'Gene', '8314', (15, 19))	('CDKN2A', 'Gene', '1029', (30, 36))	('observed', 'Reg', (49, 57))	('BAP1', 'Gene', (15, 19))
57299	29538329	NUT carcinoma is defined by a gene rearrangement between the NUT (NUTM1) gene on chromosome 15q14 and one of the other partner genes.	('NUT carcinoma', 'Disease', 'MESH:D002277', (0, 13))	('NUT carcinoma', 'Disease', (0, 13))	('gene rearrangement', 'Var', (30, 48))	('NUT', 'Gene', '256646', (61, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('NUTM1', 'Gene', '256646', (66, 71))	('NUT', 'Gene', (61, 64))	('NUT', 'Gene', (0, 3))	('NUT', 'Gene', '256646', (0, 3))	('NUT', 'Gene', '256646', (66, 69))	('NUT', 'Gene', (66, 69))	('NUTM1', 'Gene', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))
57302	29538329	Although NUT carcinoma occasionally exhibits abrupt foci of keratinization in morphology, NUT carcinomas show few cytogenetic alterations with the exception of chromosomal translocation involving NUT.	('keratinization', 'biological_process', 'GO:0031424', ('60', '74'))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('NUT', 'Gene', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('NUT carcinoma', 'Disease', 'MESH:D002277', (90, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('NUT carcinomas', 'Disease', (90, 104))	('NUT', 'Gene', '256646', (196, 199))	('NUT carcinoma', 'Disease', 'MESH:D002277', (9, 22))	('NUT', 'Gene', (196, 199))	('NUT', 'Gene', '256646', (90, 93))	('NUT carcinomas', 'Disease', 'MESH:D002277', (90, 104))	('NUT', 'Gene', (90, 93))	('chromosomal translocation', 'Var', (160, 185))	('NUT carcinoma', 'Disease', (9, 22))	('NUT', 'Gene', '256646', (9, 12))
57306	29538329	Although NUT carcinoma lacks benefit from chemotherapy or radiotherapy, molecular-targeted therapies against bromodomain may be beneficial as either a single agent or in combination with other agents.	('NUT carcinoma', 'Disease', (9, 22))	('NUT carcinoma', 'Disease', 'MESH:D002277', (9, 22))	('molecular-targeted', 'Var', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('bromodomain', 'Gene', (109, 120))
57328	26848772	It is also a prognostic marker since patients with tumors expressing high calretinin levels have better overall survival.	('overall survival', 'CPA', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('calretinin', 'Gene', '794', (74, 84))	('patients', 'Species', '9606', (37, 45))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('better', 'PosReg', (97, 103))	('high', 'Var', (69, 73))	('calretinin', 'Gene', (74, 84))
57329	26848772	Silencing of calretinin decreases viability of epithelioid mesothelioma cells.	('decreases', 'NegReg', (24, 33))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (47, 71))	('calretinin', 'Gene', '794', (13, 23))	('epithelioid mesothelioma', 'Disease', (47, 71))	('Silencing', 'Var', (0, 9))	('calretinin', 'Gene', (13, 23))
57336	26848772	EMSA and ChIP assays confirmed binding of NRF-1 and E2F2 to the CALB2 promoter and siRNA knockdown of NRF-1 led to decreased expression of calretinin.	('binding', 'Interaction', (31, 38))	('CALB2', 'Gene', '794', (64, 69))	('E2F2', 'Gene', '1870', (52, 56))	('calretinin', 'Gene', (139, 149))	('decreased', 'NegReg', (115, 124))	('NRF-1', 'Gene', (102, 107))	('expression', 'MPA', (125, 135))	('CALB2', 'Gene', (64, 69))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('knockdown', 'Var', (89, 98))	('calretinin', 'Gene', '794', (139, 149))	('E2F2', 'Gene', (52, 56))
57351	26848772	A mouse Calb2 promoter fragment (-115/+54bp) was shown to be active in neuronal and cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Calb2', 'Gene', (8, 13))	('mouse', 'Species', '10090', (2, 7))	('-115/+54bp', 'Var', (33, 43))	('active', 'MPA', (61, 67))	('Calb2', 'Gene', '12308', (8, 13))
57352	26848772	In human colon cancer cells, calretinin expression is downregulated by butyrate, a substance that induces cell differentiation.	('expression', 'MPA', (40, 50))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('human', 'Species', '9606', (3, 8))	('colon cancer', 'Disease', (9, 21))	('calretinin', 'Gene', (29, 39))	('cell differentiation', 'biological_process', 'GO:0030154', ('106', '126'))	('butyrate', 'Chemical', 'MESH:D002087', (71, 79))	('butyrate', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('downregulated', 'NegReg', (54, 67))	('calretinin', 'Gene', '794', (29, 39))
57359	26848772	Importantly, CALB2 mRNA expression was strongly positively (p = 0.0002) correlated with calretinin protein levels (Figure 1C), suggesting that calretinin expression could be regulated either through copy number variation or through control of mRNA levels.	('correlated', 'Reg', (72, 82))	('CALB2', 'Gene', '794', (13, 18))	('mRNA expression', 'MPA', (19, 34))	('copy number variation', 'Var', (199, 220))	('calretinin', 'Gene', (88, 98))	('calretinin', 'Gene', '794', (143, 153))	('CALB2', 'Gene', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('calretinin', 'Gene', (143, 153))	('calretinin', 'Gene', '794', (88, 98))	('expression', 'MPA', (154, 164))
57366	26848772	Although the expression of CTAG1B and MAGE-C1 mRNA was strongly enhanced by 5-Aza-CdR treatment in SPC111 and ZL55 cells (Figure 2A), the expression of calretinin mRNA and protein (Figure 2A and 2B) did not increase.	('MAGE-C1', 'Gene', '9947', (38, 45))	('calretinin', 'Gene', '794', (152, 162))	('SPC111', 'CellLine', 'CVCL:D311', (99, 105))	('expression', 'MPA', (13, 23))	('CTAG1B', 'Gene', '1485', (27, 33))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('CTAG1B', 'Gene', (27, 33))	('calretinin', 'Gene', (152, 162))	('ZL55', 'Chemical', '-', (110, 114))	('SPC', 'molecular_function', 'GO:0009004', ('99', '102'))	('MAGE-C1', 'Gene', (38, 45))	('5-Aza-CdR treatment', 'Var', (76, 95))	('enhanced', 'PosReg', (64, 72))
57367	26848772	On the contrary, treatment with 5-Aza-CdR resulted in a decrease in calretinin protein levels, especially in SPC111 cells.	('5-Aza-CdR', 'Var', (32, 41))	('SPC', 'molecular_function', 'GO:0009004', ('109', '112'))	('SPC111', 'CellLine', 'CVCL:D311', (109, 115))	('calretinin', 'Gene', '794', (68, 78))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('decrease', 'NegReg', (56, 64))	('calretinin', 'Gene', (68, 78))
57372	26848772	Importantly, several of the CpGs located at or near the transcriptional start site are significantly negatively correlated with gene expression (Supplementary Table 2) and the gene is lowly expressed in both biphasic and epithelioid tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CpGs', 'Var', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('epithelioid tumors', 'Disease', (221, 239))	('lowly', 'NegReg', (184, 189))	('negatively', 'NegReg', (101, 111))	('gene expression', 'MPA', (128, 143))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('epithelioid tumors', 'Disease', 'MESH:D012509', (221, 239))
57377	26848772	The shortest -161/+80bp CALB2 promoter construct appeared to be as active as the other longer sequences in all tested cell lines (Figure 3B) defining this fragment as the minimal CALB2 promoter.	('CALB2', 'Gene', '794', (179, 184))	('CALB2', 'Gene', '794', (24, 29))	('CALB2', 'Gene', (179, 184))	('active', 'MPA', (67, 73))	('CALB2', 'Gene', (24, 29))	('shortest -161/+80bp', 'Var', (4, 23))
57384	26848772	A strongly reduced activity of the E2F2/NRF-1 mutant construct was also observed in HEK293 cells (Supplementary Figure 5), indicating that this transcriptional control is not restricted to mesothelioma cells, but possibly to other cells of mesodermal origin.	('reduced', 'NegReg', (11, 18))	('mesothelioma', 'Disease', (189, 201))	('transcriptional control', 'biological_process', 'GO:0006355', ('144', '167'))	('activity', 'MPA', (19, 27))	('mutant', 'Var', (46, 52))	('E2F2', 'Gene', '1870', (35, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('HEK293', 'CellLine', 'CVCL:0045', (84, 90))	('E2F2', 'Gene', (35, 39))
57394	26848772	However, silencing of NRF-1 resulted in calretinin downregulation in SPC111 cells (Figure 5E and Supplementary Figure 7).	('SPC', 'molecular_function', 'GO:0009004', ('69', '72'))	('calretinin', 'Gene', '794', (40, 50))	('silencing', 'Var', (9, 18))	('NRF-1', 'Gene', (22, 27))	('calretinin', 'Gene', (40, 50))	('downregulation', 'NegReg', (51, 65))	('SPC111', 'CellLine', 'CVCL:D311', (69, 75))
57405	26848772	A 1.5 kb stretch of the mouse Calb2 promoter (-1485/+60bp) was demonstrated to drive reporter expression in cultured neuronal cell derived from primary embryonic mouse brain tissue.	('mouse', 'Species', '10090', (24, 29))	('rat', 'Species', '10116', (70, 73))	('drive', 'Reg', (79, 84))	('mouse', 'Species', '10090', (162, 167))	('-1485/+60bp', 'Var', (46, 57))	('Calb2', 'Gene', (30, 35))	('Calb2', 'Gene', '12308', (30, 35))
57415	26848772	This is consistent with the previously defined minimal mouse Calb2 promoter (-115/+54bp) shown to be active in rat cortical neuronal cells, rat cerebellar granule cells, colon adenocarcinoma (WiDr) and mesothelioma cells (SPC111).	('Calb2', 'Gene', '12308', (61, 66))	('rat', 'Species', '10116', (111, 114))	('mesothelioma', 'Disease', (202, 214))	('colon adenocarcinoma', 'Disease', (170, 190))	('SPC111', 'CellLine', 'CVCL:D311', (222, 228))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('mouse', 'Species', '10090', (55, 60))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (170, 190))	('SPC', 'molecular_function', 'GO:0009004', ('222', '225'))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('rat', 'Species', '10116', (140, 143))	('-115/+54bp', 'Var', (77, 87))	('Calb2', 'Gene', (61, 66))
57425	26848772	Mutation of E2F2 (-69), NRF-1 (-41), two NRF-1 (-41;-35) and CREB (-2) predicted binding sites significantly reduced CALB2 promoter activity in ZL55 and SPC111 cells.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('CREB', 'Gene', (61, 65))	('SPC111', 'CellLine', 'CVCL:D311', (153, 159))	('E2F2', 'Gene', (12, 16))	('CREB', 'Gene', '1385', (61, 65))	('Mutation', 'Var', (0, 8))	('ZL55', 'Chemical', '-', (144, 148))	('CALB2', 'Gene', '794', (117, 122))	('CALB2', 'Gene', (117, 122))	('reduced', 'NegReg', (109, 116))	('E2F2', 'Gene', '1870', (12, 16))	('SPC', 'molecular_function', 'GO:0009004', ('153', '156'))
57426	26848772	Mutations in the E2F2/NRF-1 (-64;-63;-61) putative binding sites (GAGCGCGCGCGCCCCCT; bold indicates NRF-1 consensus, underlined are the nucleotides mutated in the functional assay) led to a 70-80% decrease in the promoter activity revealing this sequence as the most important cis-acting site.	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('E2F2', 'Gene', (17, 21))	('promoter activity', 'MPA', (213, 230))	('Mutations', 'Var', (0, 9))	('E2F2', 'Gene', '1870', (17, 21))	('decrease', 'NegReg', (197, 205))
57428	26848772	Although trans-acting factors were not identified, functional inactivation in neuronal cells was obtained by mutating one nucleotide also present in the E2F2/NRF-1 putative binding site.	('E2F2', 'Gene', (153, 157))	('inactivation', 'NegReg', (62, 74))	('mutating', 'Var', (109, 117))	('binding', 'Interaction', (173, 180))	('E2F2', 'Gene', '1870', (153, 157))	('binding', 'molecular_function', 'GO:0005488', ('173', '180'))
57429	26848772	The same mutation did not abolish promoter activity in cancer cells.	('mutation', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('promoter activity', 'MPA', (34, 51))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
57430	26848772	This could be interpreted in two ways: either mutating a single base in the E2F2/NRF-1 binding site is not enough to abolish activity in cancer cells or different transcription factors are operational in neuronal and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('E2F2', 'Gene', (76, 80))	('abolish', 'NegReg', (117, 124))	('activity', 'MPA', (125, 133))	('mutating', 'Var', (46, 54))	('rat', 'Species', '10116', (192, 195))	('E2F2', 'Gene', '1870', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', (137, 143))	('transcription', 'biological_process', 'GO:0006351', ('163', '176'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
57439	26848772	Consistent with E2F regulating CALB2 promoter activity, calretinin expression was found to be cell cycle-dependent with a maximum level of expression at G1, and progressively decreased during cell cycle progression.	('cell cycle', 'biological_process', 'GO:0007049', ('192', '202'))	('calretinin', 'Gene', (56, 66))	('CALB2', 'Gene', (31, 36))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('activity', 'MPA', (46, 54))	('CALB2', 'Gene', '794', (31, 36))	('E2F', 'Var', (16, 19))	('expression', 'MPA', (67, 77))	('calretinin', 'Gene', '794', (56, 66))	('decreased', 'NegReg', (175, 184))
57441	26848772	Knowledge about mechanisms regulating NRF-1 and E2F would help for a better understanding of the complex biology of mesothelioma, where loss of calretinin expression during epithelioid tumor progression is associated with worst outcome (Vrugt et al., ms in preparation).	('tumor', 'Disease', (185, 190))	('mesothelioma', 'Disease', (116, 128))	('associated with', 'Reg', (206, 221))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('calretinin', 'Gene', '794', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('loss', 'Var', (136, 140))	('rat', 'Species', '10116', (262, 265))	('calretinin', 'Gene', (144, 154))
57446	26848772	In our study, we describe a CALB2 promoter fragment (-161/+80bp) with activity proportional to calretinin expression and identified NRF-1/E2F2 as specific trans-activating factors.	('calretinin', 'Gene', '794', (95, 105))	('activity', 'MPA', (70, 78))	('-161/+80bp', 'Var', (53, 63))	('E2F2', 'Gene', '1870', (138, 142))	('CALB2', 'Gene', '794', (28, 33))	('calretinin', 'Gene', (95, 105))	('CALB2', 'Gene', (28, 33))	('E2F2', 'Gene', (138, 142))
57478	26848772	For the supershift experiments, specific antibodies (NRF-1 ab34682 and E2F2 sc699 x) were added after 30 min incubation of the nuclear extracts and biotin-labeled probes and incubated another 20 min on ice.	('NRF-1', 'Gene', (53, 58))	('ab34682', 'Var', (59, 66))	('E2F2', 'Gene', (71, 75))	('E2F2', 'Gene', '1870', (71, 75))	('biotin', 'Chemical', 'MESH:D001710', (148, 154))
57494	25803691	We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations.	('p.E318K', 'SUBSTITUTION', 'None', (67, 74))	('CDKN2A', 'Gene', (33, 39))	('p.E318K', 'Var', (67, 74))	('CM', 'Phenotype', 'HP:0012056', (158, 160))	('CDKN2A', 'Gene', '1029', (33, 39))	('CDKN2A', 'Gene', (120, 126))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('CDKN2A', 'Gene', '1029', (120, 126))	('CDK4', 'Gene', (41, 45))	('BAP1', 'Gene', '8314', (47, 51))	('CDK', 'molecular_function', 'GO:0004693', ('41', '44'))	('CDK4', 'Gene', '1019', (41, 45))	('MC1R', 'Gene', '4157', (53, 57))	('BAP1', 'Gene', (47, 51))	('MC1R', 'Gene', (53, 57))
57496	25803691	The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls.	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('p.E318K', 'Var', (9, 16))
57503	25803691	Mutations are most frequently seen in CDKN2A, where pathogenic mutations are detected in 20-40% of families with three or more cases of CM.	('CM', 'Phenotype', 'HP:0012056', (136, 138))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (38, 44))	('seen', 'Reg', (30, 34))
57508	25803691	However, mutations in these other high-risk genes are rare and each account for a minority of melanoma-dense families.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('mutations', 'Var', (9, 18))	('melanoma', 'Disease', (94, 102))	('account', 'Reg', (68, 75))
57509	25803691	In CDK4 only two mutations (p.R24H, p.R24C), affecting binding to p16, have been identified.	('p.R24C', 'Var', (36, 42))	('p.R24C', 'Mutation', 'rs11547328', (36, 42))	('p16', 'Gene', (66, 69))	('affecting', 'Reg', (45, 54))	('binding', 'Interaction', (55, 62))	('p.R24H', 'Var', (28, 34))	('CDK4', 'Gene', (3, 7))	('CDK', 'molecular_function', 'GO:0004693', ('3', '6'))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('CDK4', 'Gene', '1019', (3, 7))	('p.R24H', 'Mutation', 'rs104894340', (28, 34))	('p16', 'Gene', '1029', (66, 69))
57510	25803691	Families with CDK4 and CDKN2A mutations have similar phenotypes regarding CM, with cases frequently having multiple primary melanoma (MPM), early onset CM, and high numbers of clinically atypical nevi.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('CDKN2A', 'Gene', (23, 29))	('atypical nevi', 'Phenotype', 'HP:0001062', (187, 200))	('CDKN2A', 'Gene', '1029', (23, 29))	('mutations', 'Var', (30, 39))	('CDK4', 'Gene', (14, 18))	('CM', 'Phenotype', 'HP:0012056', (152, 154))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('CDK4', 'Gene', '1019', (14, 18))	('nevi', 'Phenotype', 'HP:0003764', (196, 200))	('CM', 'Phenotype', 'HP:0012056', (74, 76))
57511	25803691	In a subset of families with CDKN2A mutations, an increased risk of pancreatic cancer has been reported.	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('mutations', 'Var', (36, 45))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 85))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
57512	25803691	The precise relationship between mutations in CDKN2A and pancreatic cancer is unknown, but pancreatic cancer has predominantly been reported in Swedish, Italian, Dutch and North American CM families, and mainly with mutations affecting ankyrin repeats 3 and 4.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN2A', 'Gene', (46, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('reported', 'Reg', (132, 140))	('mutations', 'Var', (33, 42))	('CDKN2A', 'Gene', '1029', (46, 52))	('CM', 'Phenotype', 'HP:0012056', (187, 189))	('ankyrin', 'Protein', (236, 243))	('mutations', 'Var', (216, 225))	('pancreatic cancer', 'Disease', (57, 74))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
57514	25803691	MC1R is highly polymorphic in the Caucasian population and the variants most strongly associated with red hair color (designated R alleles) confer a per-allele risk of ~2-fold for CM.	('MC1R', 'Gene', '4157', (0, 4))	('variants', 'Var', (63, 71))	('MC1R', 'Gene', (0, 4))	('associated', 'Reg', (86, 96))	('red hair color', 'Disease', (102, 116))	('red hair color', 'Disease', 'MESH:D003117', (102, 116))	('CM', 'Phenotype', 'HP:0012056', (180, 182))	('red hair', 'Phenotype', 'HP:0002297', (102, 110))
57518	25803691	One mutation in MITF (p.E318K) is linked to moderate (~2-fold) increased risk of CM and renal cell carcinoma (RCC).	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('CM', 'Phenotype', 'HP:0012056', (81, 83))	('p.E318K', 'Var', (22, 29))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('MITF', 'Gene', (16, 20))	('renal cell carcinoma', 'Disease', (88, 108))	('MITF', 'Gene', '4286', (16, 20))	('p.E318K', 'Mutation', 'rs149617956', (22, 29))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
57520	25803691	The p.E318K mutation is associated with non-blue eye color and increased nevus count.	('blue eye', 'Phenotype', 'HP:0000635', (44, 52))	('nevus count', 'CPA', (73, 84))	('nevus', 'Phenotype', 'HP:0003764', (73, 78))	('increased', 'PosReg', (63, 72))	('p.E318K', 'Mutation', 'rs149617956', (4, 11))	('non-blue eye color', 'Disease', (40, 58))	('p.E318K', 'Var', (4, 11))
57527	25803691	There have been isolated reports of UM in CDKN2A mutation carriers, and BRCA2 mutation carriers, but in light of the many families published with mutations in these two genes, and only single reports of UM, the risk of UM in carriers of CDKN2A or BRCA2 mutations is probably low.	('BRCA2', 'Gene', (72, 77))	('BRCA2', 'Gene', '675', (247, 252))	('mutation', 'Var', (78, 86))	('BRCA2', 'Gene', '675', (72, 77))	('mutations', 'Var', (253, 262))	('mutation', 'Var', (49, 57))	('CDKN2A', 'Gene', (42, 48))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('CDKN2A', 'Gene', '1029', (42, 48))	('CDKN2A', 'Gene', (237, 243))	('BRCA2', 'Gene', (247, 252))	('UM', 'Phenotype', 'HP:0007716', (219, 221))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('CDKN2A', 'Gene', '1029', (237, 243))
57528	25803691	To date there has been no large study of genetic alterations in Danish high-risk melanoma cases, and we were intrigued by a clinical observation of an apparently low frequency of CDKN2A mutations when testing was conducted in a clinical genetic setting.	('CDKN2A', 'Gene', '1029', (179, 185))	('mutations', 'Var', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('CDKN2A', 'Gene', (179, 185))
57529	25803691	A low frequency of CDKN2A mutations has previously been reported in German and Latvian studies.	('CDKN2A', 'Gene', '1029', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('mutations', 'Var', (26, 35))
57530	25803691	Here, we examined the frequency of CDKN2A, CDK4, BAP1, MC1R and MITF (p.E318K) mutations in a large sample of Danish high-risk CM and UM cases.	('CDKN2A', 'Gene', '1029', (35, 41))	('p.E318K) mutations', 'Var', (70, 88))	('p.E318K', 'Mutation', 'rs149617956', (70, 77))	('MC1R', 'Gene', '4157', (55, 59))	('MITF', 'Gene', '4286', (64, 68))	('MITF', 'Gene', (64, 68))	('BAP1', 'Gene', (49, 53))	('CM', 'Phenotype', 'HP:0012056', (127, 129))	('CDK4', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (49, 53))	('MC1R', 'Gene', (55, 59))	('CDK4', 'Gene', '1019', (43, 47))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('CDKN2A', 'Gene', (35, 41))	('mutations', 'Var', (79, 88))
57536	25803691	We did not contact all of the isolated MPM cases, because many of these patients were fair skinned and frequent users of indoor tanning facilities, and were judged less likely for finding mutations in high-risk melanoma genes, than patients with a family report of melanoma.	('patients', 'Species', '9606', (232, 240))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('fair skin', 'Phenotype', 'HP:0007513', (86, 95))	('fair skinned', 'Phenotype', 'HP:0007513', (86, 98))	('mutations', 'Var', (188, 197))	('melanoma', 'Disease', (265, 273))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('patients', 'Species', '9606', (72, 80))
57545	25803691	In families with a CDKN2A mutation, MC1R was examined in all mutation carriers.	('mutation', 'Var', (26, 34))	('CDKN2A', 'Gene', (19, 25))	('CDKN2A', 'Gene', '1029', (19, 25))	('MC1R', 'Gene', '4157', (36, 40))	('MC1R', 'Gene', (36, 40))
57547	25803691	Information of cancer occurrence in these families was included in the analysis of CDKN2A and CDK4 alterations.	('CDK4', 'Gene', (94, 98))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDK', 'molecular_function', 'GO:0004693', ('94', '97'))	('CDK4', 'Gene', '1019', (94, 98))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('alterations', 'Var', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CDKN2A', 'Gene', (83, 89))
57551	25803691	In families with a CDKN2A mutation, blood samples were also collected from healthy mutation carriers.	('CDKN2A', 'Gene', '1029', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('mutation', 'Var', (26, 34))
57552	25803691	164 families were screened for variants in BAP1 and CDKN2A in a targeted sequencing approach using Ion AmpliSeq library kits (Life Technologies, CA, USA).	('BAP1', 'Gene', (43, 47))	('variants', 'Var', (31, 39))	('BAP1', 'Gene', '8314', (43, 47))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', '1029', (52, 58))
57554	25803691	Variants occurring in the NHLBI Exome Sequencing Project (ESP6500) with minor allele frequency (MAF) >0.01, and synonymous variants were excluded.	('NHLBI', 'Gene', (26, 31))	('Variants', 'Var', (0, 8))	('ESP', 'Gene', (58, 61))	('ESP', 'Gene', '148713', (58, 61))
57555	25803691	130 blood samples were screened with high-resolution melting analysis for CDK4 mutations p.R24C or p.R24H.	('p.R24H', 'Var', (99, 105))	('p.R24C', 'Var', (89, 95))	('CDK4', 'Gene', (74, 78))	('p.R24C', 'Mutation', 'rs11547328', (89, 95))	('CDK4', 'Gene', '1019', (74, 78))	('p.R24H', 'Mutation', 'rs104894340', (99, 105))	('CDK', 'molecular_function', 'GO:0004693', ('74', '77'))
57556	25803691	Standard methods for Sanger sequencing were used to screen an additional 196 samples for mutations in CDKN2A and CDK4; 29 samples for mutations in BAP1; 280 samples for variants in MC1R, in which the following five variants: p.D84E, p.R151C, p.R160W, p.D294H, p.R142H; and null mutations, were classified as R variants and others were classified as r variants, except synonymous changes, which were counted as wild-type.	('p.R151C', 'Mutation', 'rs1805007', (233, 240))	('p.D84E', 'Mutation', 'rs1805006', (225, 231))	('mutations', 'Var', (89, 98))	('CDKN2A', 'Gene', '1029', (102, 108))	('MC1R', 'Gene', '4157', (181, 185))	('MC1R', 'Gene', (181, 185))	('p.R160W', 'Mutation', 'rs1805008', (242, 249))	('CDK4', 'Gene', (113, 117))	('p.D294H', 'Var', (251, 258))	('p.R160W', 'Var', (242, 249))	('BAP1', 'Gene', '8314', (147, 151))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('CDK4', 'Gene', '1019', (113, 117))	('p.D294H', 'Mutation', 'rs1805009', (251, 258))	('p.R142H', 'Var', (260, 267))	('p.R142H', 'Mutation', 'rs11547464', (260, 267))	('BAP1', 'Gene', (147, 151))	('p.D84E', 'Var', (225, 231))	('CDKN2A', 'Gene', (102, 108))	('p.R151C', 'Var', (233, 240))
57557	25803691	296 samples were assessed for MITF p.E318K by a standard TaqMan assay.	('p.E318K', 'Var', (35, 42))	('MITF', 'Gene', '4286', (30, 34))	('MITF', 'Gene', (30, 34))	('p.E318K', 'Mutation', 'rs149617956', (35, 42))
57558	25803691	Hazard ratios for CDKN2A mutation carriers were calculated using Cox regression.	('CDKN2A', 'Gene', '1029', (18, 24))	('Cox', 'Gene', '1351', (65, 68))	('mutation', 'Var', (25, 33))	('Cox', 'Gene', (65, 68))	('CDKN2A', 'Gene', (18, 24))
57559	25803691	A Cox proportional-hazards model was used to generate the survival curve showing age-specific probability of melanoma development for CDKN2A mutations carriers.	('mutations', 'Var', (141, 150))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('CDKN2A', 'Gene', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('CDKN2A', 'Gene', '1029', (134, 140))	('carriers', 'Reg', (151, 159))	('Cox', 'Gene', '1351', (2, 5))	('Cox', 'Gene', (2, 5))
57561	25803691	13 of 327 cases with early onset CM or MPM carried mutations in CDKN2A (Table 1).	('early onset CM', 'Disease', (21, 35))	('mutations', 'Var', (51, 60))	('CDKN2A', 'Gene', (64, 70))	('MPM', 'Disease', (39, 42))	('CDKN2A', 'Gene', '1029', (64, 70))	('CM', 'Phenotype', 'HP:0012056', (33, 35))
57562	25803691	Three mutations: c.47_50del p.(L16Pfs*9), c.62G>A p.(R21K), and c.94_99dup p.(L32_E33dup) mutations have not previously been described.	('c.62G>A', 'Var', (42, 49))	('c.47_50del', 'Mutation', 'c.47_50del', (17, 27))	('p.(L32_E33dup)', 'DUPLICATION', 'None', (75, 89))	('c.62G>A', 'Mutation', 'rs1057517601', (42, 49))	('p.(L16Pfs*9)', 'Mutation', 'rs587782206', (28, 40))	('c.47_50del', 'Var', (17, 27))	('p.(R21K)', 'Mutation', 'rs1057517601', (50, 58))	('p.(L32_E33dup', 'Var', (75, 88))	('c.94_99dup', 'DUPLICATION', 'None', (64, 74))	('c.94_99dup p.(L32_E33dup', 'Var', (64, 88))
57563	25803691	The novel frameshift mutation c.47_50del, p.(L16Pfs*9) is likely to be highly deleterious to the p16 protein function since it causes premature truncation of the protein.	('c.47_50del', 'Var', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('p16', 'Gene', '1029', (97, 100))	('p.(L16Pfs*9)', 'Mutation', 'rs587782206', (42, 54))	('causes', 'Reg', (127, 133))	('protein', 'Protein', (162, 169))	('p16', 'Gene', (97, 100))	('c.47_50del', 'Mutation', 'c.47_50del', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('premature truncation', 'MPA', (134, 154))
57565	25803691	In one family we found a duplication of 6 bp (c.94_99dup, p.(L32_E33dup)) causing a 2 amino acid duplication in the first ankyrin-repeat of p16.	('c.94_99dup', 'Mutation', 'c.94_99dup', (46, 56))	('c.94_99dup', 'Var', (46, 56))	('p16', 'Gene', (140, 143))	('p.(L32_E33dup)', 'DUPLICATION', 'None', (58, 72))	('causing', 'Reg', (74, 81))	('p16', 'Gene', '1029', (140, 143))
57566	25803691	A missense mutation in p14 (c.62G>A, p.(R21K), exon 1beta) was identified in an individual affected with CM aged 54 years and no family history of CM.	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('c.62G>A', 'Var', (28, 35))	('c.62G>A', 'Mutation', 'rs1057517601', (28, 35))	('p.(R21K)', 'Mutation', 'rs1057517601', (37, 45))	('CM', 'Phenotype', 'HP:0012056', (147, 149))	('p14', 'Gene', (23, 26))	('p14', 'Gene', '1029', (23, 26))
57567	25803691	To-date, no melanoma families have been identified that carry missense mutations in exon 1beta, however, very recent studies have shown that p14-specific alterations in CDKN2A exon 2 impair the ability of p14 to control superoxide levels and suppress growth of melanoma cells in vivo.	('CDKN2A', 'Gene', (169, 175))	('suppress', 'NegReg', (242, 250))	('ability', 'MPA', (194, 201))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('CDKN2A', 'Gene', '1029', (169, 175))	('control superoxide levels', 'MPA', (212, 237))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('p14', 'Gene', (141, 144))	('p14', 'Gene', (205, 208))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('alterations', 'Var', (154, 165))	('impair', 'NegReg', (183, 189))	('p14', 'Gene', '1029', (141, 144))	('superoxide', 'Chemical', 'MESH:D013481', (220, 230))	('p14', 'Gene', '1029', (205, 208))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))
57568	25803691	Previously, only whole gene deletions, insertions or splice-site mutations in p14, have been determined as pathogenetic.	('insertions', 'Var', (39, 49))	('splice-site mutations', 'Var', (53, 74))	('p14', 'Gene', '1029', (78, 81))	('p14', 'Gene', (78, 81))
57570	25803691	One family has previously been described with 9 persons affected with CM, many with MPM, and segregation of the mutation with melanoma resulting in a LOD-score of 3.6.	('mutation', 'Var', (112, 120))	('LOD', 'molecular_function', 'GO:0033736', ('150', '153'))	('CM', 'Phenotype', 'HP:0012056', (70, 72))	('persons', 'Species', '9606', (48, 55))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
57573	25803691	The missense mutation p.(G35R) in p16 has previously been found in melanoma cases (unpublished data) as well as in tumor tissue.	('p.(G35R)', 'Mutation', 'rs757066045', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('p16', 'Gene', (34, 37))	('tumor', 'Disease', (115, 120))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('p16', 'Gene', '1029', (34, 37))	('found', 'Reg', (58, 63))	('p.(G35R', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
57575	25803691	The other individual heterozygous for p.(G35R) mutation had MPM in young age, and no maternal history of cancer.	('MPM', 'Disease', (60, 63))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('p.(G35R)', 'Mutation', 'rs757066045', (38, 46))	('p.(G35R', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
57577	25803691	Several known mutations were also found in CDKN2A.	('CDKN2A', 'Gene', '1029', (43, 49))	('mutations', 'Var', (14, 23))	('found', 'Reg', (34, 39))	('CDKN2A', 'Gene', (43, 49))
57579	25803691	Additionally, we observed the p.(A4_P11dup), p.(A4_P11del), and p.G101W mutations.	('p.(A4_P11del', 'Var', (45, 57))	('p.(A4_P11dup', 'Var', (30, 42))	('p.G101W', 'Var', (64, 71))	('p.G101W', 'Mutation', 'rs104894094', (64, 71))	('p.(A4_P11del)', 'DELETION', 'None', (45, 58))	('p.(A4_P11dup)', 'DUPLICATION', 'None', (30, 43))
57580	25803691	In 18 cases we found the well-described CDKN2A p.A148T variant.	('p.A148T', 'Mutation', 'rs3731249', (47, 54))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))	('p.A148T', 'Var', (47, 54))
57582	25803691	The average age of first melanoma was 42.8 years in CDKN2A mutation carriers (excluding those carrying the missense variant in p14), which is significantly younger (48.3 years, p = 0.035) than non-CDKN2A mutation carriers (Table 2).	('p14', 'Gene', (127, 130))	('p14', 'Gene', '1029', (127, 130))	('CDKN2A', 'Gene', (197, 203))	('CDKN2A', 'Gene', '1029', (197, 203))	('mutation', 'Var', (59, 67))	('CDKN2A', 'Gene', (52, 58))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('CDKN2A', 'Gene', '1029', (52, 58))
57583	25803691	Overall, we analysed CDKN2A in 304 unrelated melanoma cases suspected of a hereditary predisposition to CM and found a pathogenetic mutation in 3.9% (Table 3).	('pathogenetic', 'Reg', (119, 131))	('CM', 'Phenotype', 'HP:0012056', (104, 106))	('CDKN2A', 'Gene', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('mutation', 'Var', (132, 140))	('CDKN2A', 'Gene', '1029', (21, 27))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
57584	25803691	In 107 individuals with MPM or melanoma before 40 years, we found 3 CDKN2A mutations, all in individuals with MPM, first diagnosed with CM aged 28, 33, and 40 years, respectively.	('CM', 'Phenotype', 'HP:0012056', (136, 138))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', '1029', (68, 74))	('mutations', 'Var', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))
57587	25803691	Similarly, no CDKN2A mutations were seen in 3 individuals with isolated pancreatic cancer, and 6 individuals with pancreatic cancer and a first-degree relative with pancreatic cancer.	('pancreatic cancer', 'Disease', (165, 182))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('CDKN2A', 'Gene', '1029', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))	('isolated pancreatic cancer', 'Disease', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('isolated pancreatic cancer', 'Disease', 'MESH:D010190', (63, 89))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
57588	25803691	Among 15 families with pancreatic cancer and CM, we found 1 family with a CDKN2A mutation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('mutation', 'Var', (81, 89))	('CDKN2A', 'Gene', '1029', (74, 80))	('CDKN2A', 'Gene', (74, 80))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('pancreatic cancer', 'Disease', (23, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))
57589	25803691	In the 13 families with CDKN2A mutations, only 1 had a case of pancreatic cancer, in a person with unknown carrier status (the same family as above) (Table 1).	('pancreatic cancer', 'Disease', (63, 80))	('mutations', 'Var', (31, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('person', 'Species', '9606', (87, 93))	('CDKN2A', 'Gene', (24, 30))	('carrier', 'molecular_function', 'GO:0005215', ('107', '114'))	('CDKN2A', 'Gene', '1029', (24, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
57590	25803691	The calculated age-specific penetrances for CM in CDKN2A mutation carriers are shown in Fig.	('mutation', 'Var', (57, 65))	('CDKN2A', 'Gene', '1029', (50, 56))	('CDKN2A', 'Gene', (50, 56))	('CM', 'Phenotype', 'HP:0012056', (44, 46))
57591	25803691	In the 12 CDKN2A mutation positive families we identified 34 cases with CM, of which 27 (79%) were known gene carriers.	('CDKN2A', 'Gene', '1029', (10, 16))	('CDKN2A', 'Gene', (10, 16))	('mutation', 'Var', (17, 25))	('CM', 'Phenotype', 'HP:0012056', (72, 74))
57593	25803691	Of the 327 families examined, a CDK4 mutation (p.R24H) was only found in one.	('CDK4', 'Gene', (32, 36))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('CDK4', 'Gene', '1019', (32, 36))	('p.R24H', 'Var', (47, 53))	('p.R24H', 'Mutation', 'rs104894340', (47, 53))
57594	25803691	This illustrates that CDK4 mutations are very rare in Denmark, which is in accordance with reports from other countries.	('mutations', 'Var', (27, 36))	('CDK4', 'Gene', (22, 26))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('CDK4', 'Gene', '1019', (22, 26))	('Denmark', 'Disease', (54, 61))
57597	25803691	In 12 individuals with UM and unknown family history of cancer, we found no BAP1 mutations.	('BAP1', 'Gene', '8314', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
57599	25803691	We analysed BAP1 in 6 families with 2 or more cases of UM and found truncating BAP1 mutations in 4 families (66.7%), all of which have been published.	('BAP1', 'Gene', '8314', (79, 83))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('BAP1', 'Gene', (79, 83))	('BAP1', 'Gene', '8314', (12, 16))	('mutations', 'Var', (84, 93))	('BAP1', 'Gene', (12, 16))
57600	25803691	We analysed 5 families with CM and mesothelioma, and found truncating BAP1 mutations in 2 of the families.	('mesothelioma', 'Disease', (35, 47))	('BAP1', 'Gene', '8314', (70, 74))	('CM', 'Phenotype', 'HP:0012056', (28, 30))	('BAP1', 'Gene', (70, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('mutations', 'Var', (75, 84))	('truncating', 'MPA', (59, 69))
57602	25803691	CDKN2A mutation carriers with MC1R variants had a hazard ratio of 3.39 for developing CM compared to CDKN2A mutation carriers with no MC1R variants.	('MC1R', 'Gene', '4157', (30, 34))	('MC1R', 'Gene', '4157', (134, 138))	('MC1R', 'Gene', (30, 34))	('MC1R', 'Gene', (134, 138))	('CDKN2A', 'Gene', (101, 107))	('variants', 'Var', (35, 43))	('CDKN2A', 'Gene', '1029', (101, 107))	('CM', 'Phenotype', 'HP:0012056', (86, 88))	('CDKN2A', 'Gene', (0, 6))	('developing CM', 'Disease', (75, 88))	('CDKN2A', 'Gene', '1029', (0, 6))
57603	25803691	CDKN2A mutation carriers with one or two R variants had a hazard ratio of 2.52, and CDKN2A mutation carriers with one or two r variants had a hazard ratio of 2.24 (Table 6).	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('CDKN2A', 'Gene', (0, 6))	('variants', 'Var', (43, 51))	('CDKN2A', 'Gene', '1029', (0, 6))
57604	25803691	CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes had a statistically significant (p = 0.038) increased OR (6.16) for developing CM compared to CDKN2A mutation carriers with [R/wt, r/r, r/wt, wt/wt] MC1R genotypes, and a statistically significant (p = 0.025) increased risk of developing melanoma 10 years earlier, with an OR of 2.25.	('increased', 'PosReg', (100, 109))	('MC1R', 'Gene', (41, 45))	('CDKN2A', 'Gene', (150, 156))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('developing', 'CPA', (124, 134))	('MC1R', 'Gene', '4157', (205, 209))	('CDKN2A', 'Gene', '1029', (150, 156))	('CM', 'Phenotype', 'HP:0012056', (135, 137))	('MC1R', 'Gene', (205, 209))	('[R/R', 'Var', (30, 34))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))	('MC1R', 'Gene', '4157', (41, 45))
57605	25803691	We also found that CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes, were 24 times more likely to have MPM compared to carriers with the [wt/wt] MC1R genotype (p = 0.033).	('CDKN2A', 'Gene', (19, 25))	('CDKN2A', 'Gene', '1029', (19, 25))	('MC1R', 'Gene', (60, 64))	('MC1R', 'Gene', '4157', (152, 156))	('MC1R', 'Gene', (152, 156))	('MC1R', 'Gene', '4157', (60, 64))	('[R/R', 'Var', (49, 53))	('MPM', 'Disease', (110, 113))
57606	25803691	The MITF p.E318K mutation was analysed in DNA from 276 participants with CM, and we found 4 carriers (Table 7).	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('participants', 'Species', '9606', (55, 67))	('CM', 'Phenotype', 'HP:0012056', (73, 75))	('p.E318K', 'Var', (9, 16))
57607	25803691	In the Danish population the MAF of MITF p.E318K was 9/3930 = 0.0023.	('MITF', 'Gene', '4286', (36, 40))	('MITF', 'Gene', (36, 40))	('p.E318K', 'Var', (41, 48))	('p.E318K', 'Mutation', 'rs149617956', (41, 48))
57609	25803691	We identified CDKN2A mutations in 3.9% of unrelated high-risk Danish CM cases.	('CDKN2A', 'Gene', '1029', (14, 20))	('CM', 'Phenotype', 'HP:0012056', (69, 71))	('Danish CM', 'Disease', (62, 71))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
57610	25803691	The frequency of CDKN2A mutations in population based CM cases is 2% in North America, Europe and Australia, so a frequency of 3.9% in high-risk CM cases is surprisingly low.	('CDKN2A', 'Gene', (17, 23))	('CM', 'Phenotype', 'HP:0012056', (145, 147))	('CDKN2A', 'Gene', '1029', (17, 23))	('mutations', 'Var', (24, 33))	('CM', 'Phenotype', 'HP:0012056', (54, 56))
57611	25803691	This is further illustrated by the fact that we only found CDKN2A mutations in 5.6% of 3-case CM families, where previous reports have found mutation in 30% and 40% of such families from North America and Europe, respectively.	('mutations', 'Var', (66, 75))	('CM', 'Phenotype', 'HP:0012056', (94, 96))	('CDKN2A', 'Gene', (59, 65))	('CDKN2A', 'Gene', '1029', (59, 65))
57612	25803691	However, in Australia, another high-risk country for CM like Denmark, only ~10% of 3-case CM families carried a CDKN2A mutation.	('mutation', 'Var', (119, 127))	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('CM', 'Phenotype', 'HP:0012056', (53, 55))
57614	25803691	As reported in other studies we found that carriers of CDKN2A mutations generally develop CM earlier, mean age 42.8 years, than other high-risk CM cases, mean age 48.3 years.	('CDKN2A', 'Gene', '1029', (55, 61))	('CM', 'Phenotype', 'HP:0012056', (144, 146))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('CDKN2A', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))	('develop', 'PosReg', (82, 89))
57615	25803691	The penetrance for CDKN2A mutation carriers was 50% at age 50 and 80% at age 70, which is in keeping with the previously observed penetrances in North America and Australia, but considerably higher than the penetrance observed in other European countries.	('CDKN2A', 'Gene', '1029', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('mutation', 'Var', (26, 34))
57616	25803691	Previously, it has been shown that the penetrance of CDKN2A mutations is greater in a high-risk cohort, compared to cases identified through screening of an unselected sample of melanoma cases.	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', '1029', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('mutations', 'Var', (60, 69))
57618	25803691	This is in contrast to other reports, where in North America and Europe CDKN2A mutations were observed in 70-80% of families with pancreatic caner and 3 cases of CM, and in Australia a CDKN2A mutation was only found in 30% of such families.	('CDKN2A', 'Gene', '1029', (185, 191))	('pancreatic caner', 'Disease', 'MESH:D010195', (130, 146))	('observed', 'Reg', (94, 102))	('CDKN2A', 'Gene', '1029', (72, 78))	('CM', 'Phenotype', 'HP:0012056', (162, 164))	('CDKN2A', 'Gene', (185, 191))	('pancreatic caner', 'Disease', (130, 146))	('CDKN2A', 'Gene', (72, 78))	('mutations', 'Var', (79, 88))
57620	25803691	It is unknown if pancreatic cancer among CDKN2A mutations carriers in different geographic regions is caused by life-style factors, environmental factors, or genetic modulators.	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (41, 47))	('mutations', 'Var', (48, 57))	('caused', 'Reg', (102, 108))
57621	25803691	Alternatively, there may be a genotype-phenotype correlation between the position of mutations in CDKN2A and risk of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('CDKN2A', 'Gene', (98, 104))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CDKN2A', 'Gene', '1029', (98, 104))
57622	25803691	In families with pancreatic cancer only we did not find CDKN2A mutations, which is in contrast to observations in Dutch and Italian pancreatic cancer families, but in accordance with reports from North America and Germany.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('CDKN2A', 'Gene', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('CDKN2A', 'Gene', '1029', (56, 62))
57624	25803691	In this study we examined BAP1 in 133 high-risk CM cases (Table 4) and found no mutations, but identified mutations in 4/16 (25%) UM-CM families, all of which had 2 or more cases of UM (Table 4).	('BAP1', 'Gene', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('CM', 'Phenotype', 'HP:0012056', (133, 135))	('CM', 'Phenotype', 'HP:0012056', (48, 50))	('UM-CM', 'Disease', (130, 135))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (106, 115))	('UM', 'Phenotype', 'HP:0007716', (130, 132))
57625	25803691	This is in line with previous reports by Njauw et al, where they found BAP1 mutations in 0.5% of CM families, and in 28.5% of UM-CM families.	('mutations', 'Var', (76, 85))	('CM', 'Phenotype', 'HP:0012056', (129, 131))	('BAP1', 'Gene', '8314', (71, 75))	('CM', 'Phenotype', 'HP:0012056', (97, 99))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('found', 'Reg', (65, 70))	('BAP1', 'Gene', (71, 75))
57626	25803691	One of the weaknesses of the study is that we did not recruit UM patients in a systematic manner, however, we are in the process of examining 100 UM patients for germline BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('BAP1', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (149, 157))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('patients', 'Species', '9606', (65, 73))	('BAP1', 'Gene', '8314', (171, 175))
57627	25803691	We found BAP1 mutations in 40% of families with CM and mesothelioma (Table 4).	('mesothelioma', 'Disease', (55, 67))	('CM', 'Phenotype', 'HP:0012056', (48, 50))	('BAP1', 'Gene', '8314', (9, 13))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
57630	25803691	Whether BAP1 screening should be conducted in Danish families with CM and RCC remains unclear and further studies are needed to examine the frequency of BAP1 mutations in families with RCC, with and without CM.	('RCC', 'Disease', (185, 188))	('CM', 'Phenotype', 'HP:0012056', (207, 209))	('BAP1', 'Gene', '8314', (8, 12))	('RCC', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (153, 157))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('CM', 'Phenotype', 'HP:0012056', (67, 69))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
57631	25803691	In Danish CM cases the frequency of MC1R R variants is high (39%, almost twice the frequency of controls, MAF 0.2).	('variants', 'Var', (43, 51))	('MC1R', 'Gene', '4157', (36, 40))	('CM', 'Phenotype', 'HP:0012056', (10, 12))	('MC1R', 'Gene', (36, 40))
57632	25803691	In cohorts of CM cases from Southern Europe the OR for association with CM of MC1R r variants has been reported to be highly variable (between 0.84-3).	('variants', 'Var', (85, 93))	('CM', 'Phenotype', 'HP:0012056', (72, 74))	('CM', 'Phenotype', 'HP:0012056', (14, 16))	('association', 'Interaction', (55, 66))	('MC1R', 'Gene', '4157', (78, 82))	('MC1R', 'Gene', (78, 82))
57633	25803691	As Denmark is a high incidence country for melanoma, there is a distinct possibility of phenocopies in families, and since only one person from each family was examined for CDKN2A and CDK4 mutations, it cannot be ruled out that mutations in some families have not been identified.	('phenocopies', 'Disease', 'MESH:C580174', (88, 99))	('CDK4', 'Gene', (184, 188))	('CDKN2A', 'Gene', (173, 179))	('CDK', 'molecular_function', 'GO:0004693', ('184', '187'))	('CDK4', 'Gene', '1019', (184, 188))	('person', 'Species', '9606', (132, 138))	('CDKN2A', 'Gene', '1029', (173, 179))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('phenocopies', 'Disease', (88, 99))	('mutations', 'Var', (189, 198))
57634	25803691	Alternatively, mutations in other yet unknown predisposition genes could explain the low rate of CDKN2A mutations identified.	('CDKN2A', 'Gene', '1029', (97, 103))	('CDKN2A', 'Gene', (97, 103))	('mutations', 'Var', (104, 113))
57637	25803691	Mutations in CDK4, and the MITF p.E318K mutation, are rare in the Danish population examined here, and only explain a minority of CM cases.	('CM', 'Phenotype', 'HP:0012056', (130, 132))	('p.E318K', 'Var', (32, 39))	('p.E318K', 'Mutation', 'rs149617956', (32, 39))	('Mutations', 'Var', (0, 9))	('MITF', 'Gene', (27, 31))	('CDK4', 'Gene', '1019', (13, 17))	('CDK4', 'Gene', (13, 17))	('MITF', 'Gene', '4286', (27, 31))	('CDK', 'molecular_function', 'GO:0004693', ('13', '16'))
57638	25803691	The MAF of MITF p.E318K in Danish CM cases (0.0072) is lower than previously observed in UK CM cases (0.0176), Australian CM cases (0.0165), and Italian and French CM cases (MAF 0.011 and 0.014), respectively.	('CM', 'Phenotype', 'HP:0012056', (122, 124))	('CM', 'Phenotype', 'HP:0012056', (92, 94))	('p.E318K', 'Var', (16, 23))	('CM', 'Phenotype', 'HP:0012056', (34, 36))	('CM', 'Phenotype', 'HP:0012056', (164, 166))	('p.E318K', 'Mutation', 'rs149617956', (16, 23))	('lower', 'NegReg', (55, 60))	('MITF', 'Gene', '4286', (11, 15))	('MITF', 'Gene', (11, 15))
57639	25803691	MC1R is a modulator of CDKN2A mutations and we found a trend of carrying any MC1R variant being associated with increased risk of CM in CDKN2A mutation carriers (Table 6).	('CM', 'Phenotype', 'HP:0012056', (130, 132))	('MC1R', 'Gene', '4157', (0, 4))	('MC1R', 'Gene', (77, 81))	('associated', 'Reg', (96, 106))	('MC1R', 'Gene', (0, 4))	('CDKN2A', 'Gene', (23, 29))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('variant', 'Var', (82, 89))	('CDKN2A', 'Gene', '1029', (23, 29))	('MC1R', 'Gene', '4157', (77, 81))
57640	25803691	CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes, had a significantly higher risk of developing melanoma compared to other carriers, and had an OR of 2.25 for developing CM 10 years earlier than carriers with [r/r, R/wt, r/wt, wt/wt] MC1R genotypes.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('MC1R', 'Gene', (41, 45))	('MC1R', 'Gene', '4157', (41, 45))	('MC1R', 'Gene', '4157', (241, 245))	('MC1R', 'Gene', (241, 245))	('developing CM', 'CPA', (166, 179))	('[R/R', 'Var', (30, 34))	('CDKN2A', 'Gene', (0, 6))	('CM', 'Phenotype', 'HP:0012056', (177, 179))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('CDKN2A', 'Gene', '1029', (0, 6))	('melanoma', 'Disease', (103, 111))
57641	25803691	It has previously been shown that MC1R variants increased the risk of melanoma in CDKN2A mutation carriers, however in Italian CDKN2A mutations carriers, who have few MC1R variants, other factors influence the risk of developing CM.	('melanoma', 'Disease', (70, 78))	('MC1R', 'Gene', '4157', (34, 38))	('MC1R', 'Gene', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutation', 'Var', (89, 97))	('MC1R', 'Gene', (34, 38))	('CDKN2A', 'Gene', (82, 88))	('CM', 'Phenotype', 'HP:0012056', (229, 231))	('increased', 'Reg', (48, 57))	('influence', 'Reg', (196, 205))	('CDKN2A', 'Gene', '1029', (82, 88))	('CDKN2A', 'Gene', (127, 133))	('MC1R', 'Gene', '4157', (167, 171))	('CDKN2A', 'Gene', '1029', (127, 133))	('variants', 'Var', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
57642	25803691	We found that CDKN2A mutation carriers with (R/R, R/r) MC1R genotypes had significantly higher risk of developing MPM compared to carriers with wt MC1R genotype.	('MPM', 'Disease', (114, 117))	('MC1R', 'Gene', '4157', (147, 151))	('MC1R', 'Gene', (147, 151))	('CDKN2A', 'Gene', '1029', (14, 20))	('MC1R', 'Gene', '4157', (55, 59))	('MC1R', 'Gene', (55, 59))	('R/R', 'Var', (45, 48))	('CDKN2A', 'Gene', (14, 20))
57644	25803691	The latter should be screened predominately when family history of CM or pancreatic cancer is unknown, since we identified three CDKN2A mutations in individuals with MPM and all had no or limited information about their family cancer history.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Disease', (84, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('CDKN2A', 'Gene', (129, 135))	('CDKN2A', 'Gene', '1029', (129, 135))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('CM', 'Phenotype', 'HP:0012056', (67, 69))
57645	25803691	The age-specific penetrance for CM in CDKN2A mutation carriers is high in Denmark, as in other high incidence melanoma countries, and MC1R variants modulate the penetrance of CM and the risk of MPM.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('modulate', 'Reg', (148, 156))	('MC1R', 'Gene', '4157', (134, 138))	('MPM', 'Disease', (194, 197))	('MC1R', 'Gene', (134, 138))	('melanoma countries', 'Disease', (110, 128))	('CM', 'Phenotype', 'HP:0012056', (175, 177))	('penetrance', 'MPA', (161, 171))	('melanoma countries', 'Disease', 'MESH:D008545', (110, 128))	('CDKN2A', 'Gene', (38, 44))	('variants', 'Var', (139, 147))	('CDKN2A', 'Gene', '1029', (38, 44))	('CM', 'Phenotype', 'HP:0012056', (32, 34))
57647	25803691	The MITF p.E318K mutation is a rare moderate risk CM allele in the Danish population.	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('CM', 'Phenotype', 'HP:0012056', (50, 52))	('p.E318K', 'Var', (9, 16))
57648	25803691	At present, routine clinical testing of MITF p.E318K in CM patients does not appear warranted.	('p.E318K', 'Mutation', 'rs149617956', (45, 52))	('MITF', 'Gene', '4286', (40, 44))	('MITF', 'Gene', (40, 44))	('CM', 'Phenotype', 'HP:0012056', (56, 58))	('patients', 'Species', '9606', (59, 67))	('p.E318K', 'Var', (45, 52))
57656	22510946	BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A.	('suppressed', 'NegReg', (16, 26))	('MESO-1', 'CellLine', 'CVCL:5759', (122, 128))	('proliferation', 'CPA', (27, 40))	('BMAL1', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('H290', 'CellLine', 'CVCL:A555', (133, 137))
57657	22510946	Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21WAF1/CIP1 and upregulation of cyclin E expression.	('depletion', 'Var', (15, 24))	('p21WAF1/CIP1', 'Gene', '1026', (188, 200))	('cyclin', 'molecular_function', 'GO:0016538', ('221', '227'))	('p21WAF1/CIP1', 'Gene', (188, 200))	('upregulation', 'PosReg', (205, 217))	('cell cycle disruption', 'CPA', (37, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('37', '47'))	('expression', 'MPA', (230, 240))	('increase', 'PosReg', (78, 86))	('Wee1', 'Gene', (169, 173))	('downregulation', 'NegReg', (151, 165))	('cyclin B', 'Protein', (175, 183))	('cyclin E', 'Protein', (221, 229))	('cyclin', 'molecular_function', 'GO:0016538', ('175', '181'))	('Wee1', 'Gene', '7465', (169, 173))	('BMAL1', 'Gene', (9, 14))
57658	22510946	BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1.	('induced', 'Reg', (16, 23))	('micronucleation', 'CPA', (151, 166))	('cell cycle', 'biological_process', 'GO:0007049', ('72', '82'))	('BMAL1', 'Gene', (0, 5))	('mitotic catastrophe', 'CPA', (24, 43))	('disruption', 'NegReg', (58, 68))	('knockdown', 'Var', (6, 15))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('24', '43'))	('MESO-1', 'CellLine', 'CVCL:5759', (194, 200))	('induction', 'Reg', (98, 107))
57668	22510946	Disruption of the circadian clock has been associated with a wide variety of human disorders including cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human disorders', 'Disease', 'MESH:D007251', (77, 92))	('clock', 'Gene', '9575', (28, 33))	('clock', 'Gene', (28, 33))	('associated', 'Reg', (43, 53))	('human disorders', 'Disease', (77, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('Disruption', 'Var', (0, 10))
57672	22510946	High BMAL1 expression was associated with poor patients' prognosis and distant metastasis in colorectal and breast cancer.	('High', 'Var', (0, 4))	('distant metastasis', 'CPA', (71, 89))	('expression', 'MPA', (11, 21))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (93, 121))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('BMAL1', 'Gene', (5, 10))
57674	22510946	showed that BMAL1 expression is inactivated by promoter methylation in hematologic malignancies but not in solid cancers and that exogenously overexpressed BMAL1 suppresses in vitro and in vivo growth of a lymphoma cell line, indicating a tumor suppressive role of BMAL1 that may be specific for hematologic malignancies.	('hematologic malignancies', 'Disease', 'MESH:D019337', (296, 320))	('hematologic malignancies', 'Disease', 'MESH:D019337', (71, 95))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('promoter methylation', 'Var', (47, 67))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('BMAL1', 'Gene', (12, 17))	('BMAL1', 'Gene', (156, 161))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('expression', 'MPA', (18, 28))	('tumor', 'Disease', (239, 244))	('inactivated', 'NegReg', (32, 43))	('solid cancers', 'Disease', 'MESH:D009369', (107, 120))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('solid cancers', 'Disease', (107, 120))	('lymphoma', 'Disease', (206, 214))	('hematologic malignancies', 'Disease', (296, 320))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('lymphoma', 'Disease', 'MESH:D008223', (206, 214))	('growth', 'CPA', (194, 200))	('hematologic malignancies', 'Disease', (71, 95))	('suppresses', 'NegReg', (162, 172))
57678	22510946	H290 and H2373 were gifts from Dr Adi F. Gazdar (University of Texas Southwestern Medical Center, Dallas, TX).	('H290', 'Var', (0, 4))	('H290', 'CellLine', 'CVCL:A555', (0, 4))	('H2373', 'Var', (9, 14))
57724	22510946	We found that in ACC-MESO-1 and H290 cells, BMAL1 knockdown significantly suppressed proliferation and dramatically suppressed colony formation in anchorage-dependent (liquid colony formation assay) and anchorage-independent conditions (soft agar assay) (Fig.	('BMAL1', 'Gene', (44, 49))	('suppressed', 'NegReg', (74, 84))	('suppressed', 'NegReg', (116, 126))	('knockdown', 'Var', (50, 59))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('colony formation', 'CPA', (127, 143))	('MESO-1', 'CellLine', 'CVCL:5759', (21, 27))	('H290', 'CellLine', 'CVCL:A555', (32, 36))	('formation', 'biological_process', 'GO:0009058', ('182', '191'))	('proliferation', 'CPA', (85, 98))
57725	22510946	BMAL1 knockdown resulted in massive apoptosis and necrosis in MPM cells (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('apoptosis', 'CPA', (36, 45))	('BMAL1', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('necrosis', 'biological_process', 'GO:0070265', ('50', '58'))	('necrosis', 'biological_process', 'GO:0008219', ('50', '58'))	('necrosis', 'Disease', (50, 58))	('necrosis', 'biological_process', 'GO:0019835', ('50', '58'))	('knockdown', 'Var', (6, 15))	('necrosis', 'Disease', 'MESH:D009336', (50, 58))	('necrosis', 'biological_process', 'GO:0001906', ('50', '58'))	('necrosis', 'biological_process', 'GO:0008220', ('50', '58'))
57727	22510946	Consistent with induction of apoptosis as measured by cleaved caspase-3 expression, there was an increase in subG1 DNA content in ACC-MESO-1 transfected with BMAL1-siRNA oligos compared to cells transfected with control oligos (Fig.	('increase', 'PosReg', (97, 105))	('MESO-1', 'CellLine', 'CVCL:5759', (134, 140))	('transfected', 'Var', (141, 152))	('subG1 DNA content', 'MPA', (109, 126))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('16', '38'))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))
57728	22510946	We noted that following BMAL1 knockdown, ACC-MESO-1 cells underwent drastic morphological changes; the cells enlarged and elongated by visual examination under phase contrast microscopy.	('BMAL1', 'Gene', (24, 29))	('MESO-1', 'CellLine', 'CVCL:5759', (45, 51))	('knockdown', 'Var', (30, 39))
57730	22510946	As shown in Figure 6a, dramatic morphological alterations were seen in ACC-MESO-1 cells after BMAL1 knockdown; cells exhibit much enlarged flattened shape, micronucleation, multiple nuclei and vacuolization occasionally were found.	('knockdown', 'Var', (100, 109))	('enlarged', 'PosReg', (130, 138))	('flattened shape', 'CPA', (139, 154))	('multiple nuclei', 'CPA', (173, 188))	('vacuolization', 'CPA', (193, 206))	('BMAL1', 'Gene', (94, 99))	('micronucleation', 'CPA', (156, 171))	('MESO-1', 'CellLine', 'CVCL:5759', (75, 81))
57734	22510946	To examine the possibility of mitotic catastrophe as a sequel of BMAL1 knockdown and to explain its role in BMAL1-induced cell death during the cell cycle, ACC-MESO-1 cells transfected with BMAL1-siRNA or control oligos synchronized using a double thymidine block (to induce pharmacological block of mitosis in these cells).	('mitosis', 'biological_process', 'GO:0000278', ('300', '307'))	('block of mitosis', 'Disease', 'MESH:D006327', (291, 307))	('thymidine', 'Chemical', 'MESH:D013936', (248, 257))	('cell cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('knockdown', 'Var', (71, 80))	('BMAL1', 'Gene', (65, 70))	('block of mitosis', 'Disease', (291, 307))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('30', '49'))	('MESO-1', 'CellLine', 'CVCL:5759', (160, 166))	('cell death', 'biological_process', 'GO:0008219', ('122', '132'))
57736	22510946	6d), suggesting aberrant mitosis as a cause of cell death after BMAL1 knockdown.	('aberrant', 'Var', (16, 24))	('knockdown', 'Var', (70, 79))	('BMAL1', 'Gene', (64, 69))	('mitosis', 'biological_process', 'GO:0000278', ('25', '32'))	('mitosis', 'Disease', (25, 32))	('mitosis', 'Disease', 'None', (25, 32))	('cell death', 'biological_process', 'GO:0008219', ('47', '57'))
57737	22510946	To confirm the occurrence of mitotic catastrophe following BMAL1 knockdown, we performed time lapse microscopic examination for ACC-MESO-1 cells transfected with BMAL1-siRNA or control oligos.	('knockdown', 'Var', (65, 74))	('MESO-1', 'CellLine', 'CVCL:5759', (132, 138))	('BMAL1', 'Gene', (59, 64))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('29', '48'))
57743	22510946	Notably, ACC-MESO-1 cells after BMAL1 knockdown showed profound alterations in cell cycle regulators, including significant decrease of Wee1, p21WAF1/CIP1, cyclin B proteins and accumulation of cyclin E protein (Fig.	('cyclin', 'molecular_function', 'GO:0016538', ('194', '200'))	('BMAL1', 'Gene', (32, 37))	('Wee1', 'Gene', '7465', (136, 140))	('cell cycle', 'biological_process', 'GO:0007049', ('79', '89'))	('cyclin B proteins', 'Protein', (156, 173))	('MESO-1', 'CellLine', 'CVCL:5759', (13, 19))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('p21WAF1/CIP1', 'Gene', (142, 154))	('cyclin', 'molecular_function', 'GO:0016538', ('156', '162'))	('p21WAF1/CIP1', 'Gene', '1026', (142, 154))	('cyclin E protein', 'Protein', (194, 210))	('alterations', 'Reg', (64, 75))	('decrease', 'NegReg', (124, 132))	('Wee1', 'Gene', (136, 140))	('knockdown', 'Var', (38, 47))	('cell cycle regulators', 'MPA', (79, 100))	('accumulation', 'PosReg', (178, 190))
57745	22510946	BMAL1 depletion from ACC-MESO-1 cells, which expressed the highest level of BMAL1, led to cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population as well as decreased levels of Wee1, cyclin B and p21WAF1/CIP1 expression and upregulation of cyclin E. BMAL1 knockdown in ACC-MESO-1 cells induced mitotic catastrophe denoted by marked disruption of cell cycle regulator proteins and drastic morphological changes including micronucleation, multiple nuclei and increased cellular volume of ACC-MESO-1 cells.	('MESO-1', 'CellLine', 'CVCL:5759', (311, 317))	('cellular volume', 'CPA', (505, 520))	('MESO-1', 'CellLine', 'CVCL:5759', (25, 31))	('cyclin', 'molecular_function', 'GO:0016538', ('278', '284'))	('p21WAF1/CIP1', 'Gene', '1026', (234, 246))	('mitotic catastrophe', 'CPA', (332, 351))	('p21WAF1/CIP1', 'Gene', (234, 246))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('384', '404'))	('Wee1', 'Gene', (215, 219))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('332', '351'))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('micronucleation', 'CPA', (458, 473))	('cyclin', 'molecular_function', 'GO:0016538', ('221', '227'))	('BMAL1', 'Gene', (288, 293))	('increased', 'PosReg', (495, 504))	('Wee1', 'Gene', '7465', (215, 219))	('multiple nuclei', 'CPA', (475, 490))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('384', '404'))	('MESO-1', 'CellLine', 'CVCL:5759', (528, 534))	('disruption', 'NegReg', (370, 380))	('knockdown', 'Var', (294, 303))	('cell', 'Protein', (384, 388))
57747	22510946	This suggests that BMAL1 expression may be associated with advanced stage-MPM, but the small patients' number makes it difficult to draw a firm conclusion on this possible association (Supporting Information, Fig.	('advanced stage-MPM', 'Disease', (59, 77))	('associated', 'Reg', (43, 53))	('expression', 'Var', (25, 35))	('patients', 'Species', '9606', (93, 101))	('BMAL1', 'Gene', (19, 24))
57756	22510946	Interestingly, we found that RNAi-mediated knockdown of BMAL1 resulted in cell cycle disruption of ACC-MESO-1 cells but not in MeT-5A cells.	('cell cycle disruption', 'CPA', (74, 95))	('knockdown', 'Var', (43, 52))	('MESO-1', 'CellLine', 'CVCL:5759', (103, 109))	('BMAL1', 'Gene', (56, 61))	('cell cycle', 'biological_process', 'GO:0007049', ('74', '84'))	('RNAi', 'biological_process', 'GO:0016246', ('29', '33'))
57757	22510946	Following BMAL1 transient knockdown, we observed multiple morphological abnormalities consistent with aberrant mitotic process.	('morphological abnormalities', 'Disease', 'MESH:D000013', (58, 85))	('BMAL1', 'Gene', (10, 15))	('knockdown', 'Var', (26, 35))	('morphological abnormalities', 'Disease', (58, 85))	('mitotic process', 'CPA', (111, 126))
57761	22510946	In this study, we observed downregulation of p21WAF1/CIP1 and cyclin E upregulation following BMAL1 knockdown, and the latter could also lead to increased number of polyploidy cells.	('knockdown', 'Var', (100, 109))	('cyclin E', 'Protein', (62, 70))	('increased', 'PosReg', (145, 154))	('p21WAF1/CIP1', 'Gene', '1026', (45, 57))	('p21WAF1/CIP1', 'Gene', (45, 57))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('upregulation', 'PosReg', (71, 83))	('downregulation', 'NegReg', (27, 41))	('BMAL1', 'Gene', (94, 99))
57762	22510946	Other investigators noted that BMAL1 modulate the transcriptional activity of p53 toward its target p21 and clearly showed that BMAL1 knockdown caused a decrease in p21 level.	('BMAL1', 'Gene', (128, 133))	('p21', 'Gene', (100, 103))	('p21', 'Gene', (165, 168))	('p21', 'Gene', '644914', (165, 168))	('p21', 'Gene', '644914', (100, 103))	('modulate', 'Reg', (37, 45))	('knockdown', 'Var', (134, 143))	('p53', 'Gene', (78, 81))	('transcriptional activity', 'MPA', (50, 74))	('p53', 'Gene', '7157', (78, 81))	('decrease', 'NegReg', (153, 161))
57764	22510946	We believe that accumulation of polyploidy, large multinucleated cells and micronucleation in ACC-MESO-1 after BMAL1 knockdown were consistent with cell death mechanism involving mitotic catastrophe.	('MESO-1', 'CellLine', 'CVCL:5759', (98, 104))	('cell death', 'biological_process', 'GO:0008219', ('148', '158'))	('polyploidy', 'Var', (32, 42))	('accumulation', 'PosReg', (16, 28))	('BMAL1', 'Gene', (111, 116))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('179', '198'))	('knockdown', 'Var', (117, 126))	('micronucleation', 'CPA', (75, 90))
57923	21534088	Plaques may be associated with decreases in lung function and symptoms of dyspnea, but most individuals with pleural plaques alone display no apparent symptoms and no obvious impaired lung function.	('impaired lung function', 'Disease', (175, 197))	('impaired lung function', 'Disease', 'MESH:D003072', (175, 197))	('dyspnea', 'Phenotype', 'HP:0002094', (74, 81))	('decreases', 'NegReg', (31, 40))	('lung', 'MPA', (44, 48))	('Plaques', 'Var', (0, 7))	('dyspnea', 'Disease', (74, 81))	('pleural plaques', 'Disease', 'MESH:D010995', (109, 124))	('pleural plaques', 'Disease', (109, 124))	('impaired lung function', 'Phenotype', 'HP:0005952', (175, 197))	('dyspnea', 'Disease', 'MESH:D004417', (74, 81))	('decreases in lung function', 'Phenotype', 'HP:0005952', (31, 57))
57970	21534088	Biopersistence in the lungs is a key physicochemical property of crystalline mineral fibers and is associated with induction of fibrosis, lung cancer, and malignant mesothelioma in rodent models.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('malignant mesothelioma', 'Disease', (155, 177))	('fibrosis', 'Disease', (128, 136))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (155, 177))	('Biopersistence', 'Var', (0, 14))	('fibrosis', 'Disease', 'MESH:D005355', (128, 136))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (155, 177))	('associated', 'Reg', (99, 109))
57986	21534088	Amphibole asbestos fibers contain surface redox-active iron (Fe) that generates ROS leading to lipid peroxidation, protein oxidation, and DNA damage in lung and pleural target cells.	('asbestos', 'Chemical', 'MESH:D001194', (10, 18))	('DNA damage', 'MPA', (138, 148))	('lipid', 'Chemical', 'MESH:D008055', (95, 100))	('iron', 'Chemical', 'MESH:D007501', (55, 59))	('pleural', 'Disease', 'MESH:D010995', (161, 168))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('pleural', 'Disease', (161, 168))	('Fe', 'Chemical', 'MESH:D007501', (61, 63))	('lipid peroxidation', 'MPA', (95, 113))	('protein oxidation', 'biological_process', 'GO:0018158', ('115', '132'))	('protein oxidation', 'MPA', (115, 132))	('ROS', 'Var', (80, 83))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))
57997	21534088	This chronic inflammatory environment may contribute to acquired, heritable genetic, or epigenetic alterations leading to inactivation of tumor suppressor genes, activation of oncogenes, and altered regulation of cell cycle and DNA repair pathways.	('oncogenes', 'Gene', (176, 185))	('DNA repair', 'biological_process', 'GO:0006281', ('228', '238'))	('epigenetic alterations', 'Var', (88, 110))	('DNA', 'cellular_component', 'GO:0005574', ('228', '231'))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('alterations', 'Var', (99, 110))	('altered', 'Reg', (191, 198))	('DNA repair pathways', 'Pathway', (228, 247))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('199', '223'))	('inactivation', 'MPA', (122, 134))	('regulation', 'MPA', (199, 209))	('iron', 'Chemical', 'MESH:D007501', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('activation', 'PosReg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
57998	21534088	Specific genetic, epigenetic, and chromosomal alterations are characteristic of diffuse malignant mesothelioma.	('epigenetic', 'Var', (18, 28))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (88, 110))	('malignant mesothelioma', 'Disease', (88, 110))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (88, 110))	('chromosomal alterations', 'Var', (34, 57))
58001	21534088	These genetic and epigenetic alterations may select for mesothelial cells that are able to survive and proliferate in a chronic inflammatory environment.	('iron', 'Chemical', 'MESH:D007501', (144, 148))	('select', 'Reg', (45, 51))	('proliferate', 'CPA', (103, 114))	('epigenetic alterations', 'Var', (18, 40))	('mesothelial cells', 'CPA', (56, 73))
58014	21534088	The ability of different fiber types to induce specific genetic and epigenetic alterations characteristic of diffuse malignant mesothelioma needs to be determined.	('malignant mesothelioma', 'Disease', (117, 139))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (117, 139))	('genetic', 'Var', (56, 63))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (117, 139))	('epigenetic alterations', 'Var', (68, 90))
58031	30459622	AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('autophagy', 'CPA', (95, 104))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('inhibited', 'NegReg', (7, 16))	('autophagy', 'biological_process', 'GO:0016236', ('95', '104'))	('AT-101', 'Var', (0, 6))	('triggered', 'Reg', (85, 94))	('autophagy', 'biological_process', 'GO:0006914', ('95', '104'))
58033	30459622	Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone.	('Z-VAD-FMK', 'Var', (0, 9))	('AT-101', 'Chemical', 'MESH:C028178', (113, 119))	('reduce', 'NegReg', (36, 42))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (0, 9))
58035	30459622	Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1.	('Bax/Bcl-2 ratio', 'MPA', (62, 77))	('Bcl-2', 'molecular_function', 'GO:0015283', ('66', '71'))	('modulates', 'Reg', (79, 88))	('cleavage', 'MPA', (133, 141))	('AT-101', 'Chemical', 'MESH:C028178', (45, 51))	('increases', 'PosReg', (52, 61))	('p53', 'Protein', (89, 92))	('activates', 'PosReg', (105, 114))	('expression', 'MPA', (93, 103))	('AT-101', 'Var', (45, 51))	('caspase', 'Enzyme', (115, 122))	('PARP-1', 'Protein', (145, 151))
58049	30459622	Polyphenols have demonstrated to inhibit several signaling pathways in cancer cells, and to induce their death.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('inhibit', 'NegReg', (33, 40))	('cancer', 'Disease', (71, 77))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('signaling pathways', 'Pathway', (49, 67))	('death', 'CPA', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('induce', 'Reg', (92, 98))	('Polyphenols', 'Var', (0, 11))
58068	30459622	Antibodies against AKT, phospho-AKT, Bax, Bcl-2, JNK/SAPK1, JNK/SAPK (pT183/pY185), p38a/SAPK2a, and p38 MAPK (pT180/pY182) were obtained from BD Pharmingen (BD Biosciences, San Jose, CA, United States).	('SAPK1', 'Gene', (53, 58))	('p38a', 'Gene', (84, 88))	('JNK/SAPK', 'Gene', (60, 68))	('JNK/SAPK', 'Gene', '26419', (49, 57))	('pT180/pY182', 'Var', (111, 122))	('JNK', 'molecular_function', 'GO:0004705', ('60', '63'))	('p38a', 'Gene', '26416', (84, 88))	('p38 MAPK', 'Gene', (101, 109))	('MAPK', 'molecular_function', 'GO:0004707', ('105', '109'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('42', '47'))	('SAPK1', 'molecular_function', 'GO:0004705', ('53', '58'))	('JNK/SAPK', 'Gene', '26419', (60, 68))	('JNK/SAPK', 'Gene', (49, 57))	('SAPK', 'molecular_function', 'GO:0004707', ('64', '68'))	('SAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('p38 MAPK', 'Gene', '26416', (101, 109))	('JNK', 'molecular_function', 'GO:0004705', ('49', '52'))	('SAPK1', 'Gene', '26419', (53, 58))
58110	30459622	One of the major detrimental effects of polyphenols on cancer cells is their ability to increase ROS production.	('polyphenols', 'Chemical', 'MESH:D059808', (40, 51))	('polyphenols', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('increase', 'PosReg', (88, 96))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('ROS production', 'MPA', (97, 111))	('cancer', 'Disease', (55, 61))	('increase ROS production', 'Phenotype', 'HP:0025464', (88, 111))
58114	30459622	However, AT-101 increased significantly the ROS production only at the higher dose in MM-F1 cells as compared to the vehicle (Table 2).	('MM-F1', 'CellLine', 'CVCL:5801', (86, 91))	('AT-101', 'Var', (9, 15))	('ROS production', 'MPA', (44, 58))	('increased', 'PosReg', (16, 25))	('AT-101', 'Chemical', 'MESH:C028178', (9, 15))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))
58127	30459622	Conversely, AT-101 increased the expression of Bcl-2 (p = 0.009), but not that of Bax, causing a decrease of the Bax/Bcl-2 ratio in MM-F1 cells (p = 0.030) (Figure 3A).	('Bcl-2', 'molecular_function', 'GO:0015283', ('117', '122'))	('AT-101', 'Var', (12, 18))	('MM-F1', 'CellLine', 'CVCL:5801', (132, 137))	('Bcl-2', 'Gene', (47, 52))	('increased', 'PosReg', (19, 28))	('Bcl-2', 'molecular_function', 'GO:0015283', ('47', '52'))	('Bax/Bcl-2 ratio', 'MPA', (113, 128))	('expression', 'MPA', (33, 43))	('decrease', 'NegReg', (97, 105))	('AT-101', 'Chemical', 'MESH:C028178', (12, 18))
58128	30459622	In addition, AT-101 increased p53 expression in MM-B1 (p = 0.0006), while decreased it in MM-F1 (p = 0.012) cells.	('increased', 'PosReg', (20, 29))	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('MM-F1', 'CellLine', 'CVCL:5801', (90, 95))	('expression', 'MPA', (34, 44))	('p53', 'Protein', (30, 33))	('AT-101', 'Var', (13, 19))	('decreased', 'NegReg', (74, 83))
58132	30459622	In addition, AT-101 was able to induce the activation of the extrinsic pathway of apoptosis, as demonstrated by the proteolytic cleavage of caspase 8 into the active fragments p43/41 and/or p18 in all human MM cell lines (Figure 3B).	('p43', 'Gene', '7284', (176, 179))	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('p43', 'Gene', (176, 179))	('activation', 'PosReg', (43, 53))	('caspase', 'Protein', (140, 147))	('p18', 'Gene', '100689229', (190, 193))	('AT-101', 'Var', (13, 19))	('p18', 'Gene', (190, 193))	('human', 'Species', '9606', (201, 206))	('extrinsic pathway of apoptosis', 'Pathway', (61, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('proteolytic cleavage', 'MPA', (116, 136))
58134	30459622	Our results showed that AT-101 induced the proteolytic cleavage of caspase 3 into the activated fragments p19 and p17 in MM-B1 cells.	('AT-101', 'Chemical', 'MESH:C028178', (24, 30))	('caspase 3', 'Gene', (67, 76))	('AT-101', 'Var', (24, 30))	('p17', 'Gene', '108900', (114, 117))	('p19', 'cellular_component', 'GO:0070743', ('106', '109'))	('p17', 'Gene', (114, 117))	('p19', 'Gene', '83430', (106, 109))	('caspase 3', 'Gene', '12367', (67, 76))	('proteolytic cleavage', 'MPA', (43, 63))	('p19', 'Gene', (106, 109))
58138	30459622	In this way, AT-101 activates Beclin-1-dependent autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('Beclin-1', 'Gene', (30, 38))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('Beclin-1', 'Gene', '56208', (30, 38))	('AT-101', 'Var', (13, 19))	('activates', 'PosReg', (20, 29))
58147	30459622	As shown in Figure 4B, AT-101 was able to induce autophagy in all AT-101-treated MM cell lines compared to control cells.	('AT-101', 'Chemical', 'MESH:C028178', (23, 29))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('autophagy', 'CPA', (49, 58))	('AT-101', 'Chemical', 'MESH:C028178', (66, 72))	('AT-101', 'Var', (23, 29))	('AT-101-treated', 'Gene', (66, 80))
58152	30459622	In addition, AT-101 decreased the level of phosphorylation of ERK1 in MM-B1 cells (p = 0.0002), while increased that of ERK1 in H-Meso-1 cells (p = 0.008) and that of ERK2 in MM-F1 cells (p = 0.03) (Figure 5).	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('phosphorylation', 'MPA', (43, 58))	('ERK2', 'Gene', (167, 171))	('decreased', 'NegReg', (20, 29))	('ERK1', 'molecular_function', 'GO:0004707', ('120', '124'))	('ERK1', 'Gene', '5595', (120, 124))	('ERK1', 'Gene', (120, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('AT-101', 'Var', (13, 19))	('ERK1', 'Gene', '5595', (62, 66))	('MM-F1', 'CellLine', 'CVCL:5801', (175, 180))	('ERK2', 'Gene', '5594', (167, 171))	('ERK2', 'molecular_function', 'GO:0004707', ('167', '171'))	('increased', 'PosReg', (102, 111))	('ERK1', 'Gene', (62, 66))	('ERK1', 'molecular_function', 'GO:0004707', ('62', '66'))
58153	30459622	p38 phosphorylation was increased after AT-101 treatment in MM-F1 (p = 0.014) and MM-B1 (p = 0.012) cells, while the effect was opposite in H-Meso-1 (p = 0.014) and #40a (p = 0.021) cells (Figure 5).	('AT-101', 'Var', (40, 46))	('MM-F1', 'CellLine', 'CVCL:5801', (60, 65))	('AT-101', 'Chemical', 'MESH:C028178', (40, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('increased', 'PosReg', (24, 33))	('p38 phosphorylation', 'MPA', (0, 19))
58154	30459622	All AT-101-treated cells showed the increased phosphorylation of p54 (MM-F1, p < 0.0001; MM-B1, p = 0.002; H-Meso-1, p < 0.0001; #40a, p = 0.0002) and p46 (MM-F1, p = 0.001; MM-B1, p = 0.0008; H-Meso-1, p = 0.02; #40a, p = 0.006) JNK compared to DMSO-treated cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('AT-101', 'Chemical', 'MESH:C028178', (4, 10))	('phosphorylation', 'MPA', (46, 61))	('p46', 'Var', (151, 154))	('DMSO', 'Chemical', 'MESH:D004121', (246, 250))	('MM-F1', 'CellLine', 'CVCL:5801', (156, 161))	('JNK', 'molecular_function', 'GO:0004705', ('230', '233'))	('p54', 'Gene', '15958', (65, 68))	('increased', 'PosReg', (36, 45))	('#40a', 'Var', (213, 217))	('p54', 'Gene', (65, 68))	('MM-F1', 'CellLine', 'CVCL:5801', (70, 75))
58155	30459622	Furthermore, AT-101 significantly increased the expression of c-Jun in MM-F1 (p = 0.002) and #40a (p < 0.0001) cells, and the c-Jun phosphorylation in all MM cells (MM-F1, p = 0.002; MM-B1, p = 0.007; H-Meso-1, p = 0.016; #40a, p = 0.001) (Figure 5).	('c-Jun', 'Gene', (62, 67))	('c-Jun', 'Gene', '16476', (126, 131))	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('Jun phosphorylation', 'biological_process', 'GO:0007258', ('128', '147'))	('MM-F1', 'CellLine', 'CVCL:5801', (71, 76))	('expression', 'MPA', (48, 58))	('c-Jun', 'Gene', '16476', (62, 67))	('AT-101', 'Var', (13, 19))	('MM-F1', 'CellLine', 'CVCL:5801', (165, 170))	('increased', 'PosReg', (34, 43))	('c-Jun', 'Gene', (126, 131))
58157	30459622	Our results showed that AT-101 decreased AKT phosphorylation in H-Meso-1 (p = 0.03) and #40a (p < 0.0001) cells, while increased it in MM-F1 (p < 0.0001) and MM-B1 (p = 0.002) cells (Figure 5).	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))	('AT-101', 'Chemical', 'MESH:C028178', (24, 30))	('MM-F1', 'CellLine', 'CVCL:5801', (135, 140))	('decreased', 'NegReg', (31, 40))	('AKT', 'Pathway', (41, 44))	('AT-101', 'Var', (24, 30))	('increased', 'PosReg', (119, 128))
58166	30459622	The increase in the median survival of AT-101-treated mice was significant compared to vehicle-treated mice (7 vs. 4.5 weeks; p = 0.0001) (Figure 6B).	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (54, 58))	('AT-101-treated', 'Var', (39, 53))	('AT-101', 'Chemical', 'MESH:C028178', (39, 45))	('increase', 'PosReg', (4, 12))	('median survival', 'CPA', (20, 35))
58180	30459622	In addition, AT-101 was shown to prevent the interaction between Bcl-2 and Beclin-1 at the endoplasmic reticulum, to decrease the levels of Bcl-2 and to increase Beclin-1 expression by inducing Beclin-1 Atg5-dependent autophagic pathway in cancer cells.	('prevent', 'NegReg', (33, 40))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('91', '112'))	('decrease', 'NegReg', (117, 125))	('cancer', 'Disease', (240, 246))	('inducing', 'PosReg', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('interaction', 'Interaction', (45, 56))	('Beclin-1', 'Gene', (162, 170))	('Beclin-1', 'Gene', '56208', (162, 170))	('Beclin-1', 'Gene', (194, 202))	('Beclin-1', 'Gene', '56208', (194, 202))	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('levels of Bcl-2', 'MPA', (130, 145))	('Beclin-1', 'Gene', (75, 83))	('Beclin-1', 'Gene', '56208', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('Bcl-2', 'molecular_function', 'GO:0015283', ('140', '145'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('65', '70'))	('expression', 'MPA', (171, 181))	('increase', 'PosReg', (153, 161))	('AT-101', 'Var', (13, 19))
58181	30459622	Here we demonstrated that AT-101 treatment was able to induce apoptosis and modulate cells cycle distribution in MM cells.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('modulate', 'Reg', (76, 84))	('cells cycle distribution in MM', 'CPA', (85, 115))	('AT-101', 'Var', (26, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('apoptosis', 'CPA', (62, 71))	('AT-101', 'Chemical', 'MESH:C028178', (26, 32))
58182	30459622	AT-101 induced an increase in the percentage of cells in subG1 phase, representing the apoptotic cell population in MM cell lines after 48 h of treatment.	('increase', 'PosReg', (18, 26))	('AT-101', 'Var', (0, 6))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('subG1 phase', 'CPA', (57, 68))
58183	30459622	The caspase inhibitor, Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase, thus corroborating the induction of cell death by apoptosis following treatment with AT-101.	('cell death', 'biological_process', 'GO:0008219', ('142', '152'))	('reduce', 'NegReg', (59, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('AT-101', 'Chemical', 'MESH:C028178', (191, 197))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (23, 32))	('Z-VAD-FMK', 'Var', (23, 32))
58186	30459622	In our study, AT-101 stimulated autophagy, but the process was then blocked, as indicated by the increase of the levels of p62/SQSMT1 and was coincident with the activation of apoptosis in MM-B1, H-Meso-1 and #40a cells.	('activation of apoptosis', 'biological_process', 'GO:0006915', ('162', '185'))	('increase', 'PosReg', (97, 105))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('162', '185'))	('AT-101', 'Chemical', 'MESH:C028178', (14, 20))	('autophagy', 'biological_process', 'GO:0016236', ('32', '41'))	('levels', 'MPA', (113, 119))	('autophagy', 'CPA', (32, 41))	('apoptosis', 'CPA', (176, 185))	('autophagy', 'biological_process', 'GO:0006914', ('32', '41'))	('AT-101', 'Var', (14, 20))	('p62/SQSMT1', 'MPA', (123, 133))
58188	30459622	Here, we provide evidence that AT-101 activates the extrinsic pathway of apoptosis, as indicated by the cleavage of caspase 8.	('extrinsic pathway of apoptosis', 'Pathway', (52, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('caspase', 'Protein', (116, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('AT-101', 'Chemical', 'MESH:C028178', (31, 37))	('cleavage', 'MPA', (104, 112))	('AT-101', 'Var', (31, 37))	('activates', 'PosReg', (38, 47))
58192	30459622	We demonstrated that AT-101 was also able to induce the intrinsic pathway of apoptosis, by increasing the Bax/Bcl-2 expression ratio, by activating caspase 9 and by inducing the proteolytic cleavage of PARP-1.	('proteolytic cleavage', 'MPA', (178, 198))	('inducing', 'PosReg', (165, 173))	('increasing', 'PosReg', (91, 101))	('activating', 'PosReg', (137, 147))	('AT-101', 'Chemical', 'MESH:C028178', (21, 27))	('induce', 'PosReg', (45, 51))	('intrinsic pathway of apoptosis', 'Pathway', (56, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('110', '115'))	('Bax/Bcl-2 expression ratio', 'MPA', (106, 132))	('AT-101', 'Var', (21, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('PARP-1', 'Gene', (202, 208))	('caspase', 'Enzyme', (148, 155))
58197	30459622	Thus, the effect of the compound might be histotype-specific and AT-101 promoted apoptosis through p53-dependent or -independent pathway.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('apoptosis', 'CPA', (81, 90))	('AT-101', 'Chemical', 'MESH:C028178', (65, 71))	('p53-dependent or -independent pathway', 'Pathway', (99, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('AT-101', 'Var', (65, 71))	('promoted', 'PosReg', (72, 80))
58204	30459622	In addition, AT-101 decreased the level of phosphorylation of ERK1 in MM-B1 cells while increased that of ERK1 in H-Meso-1 cells and that of ERK2 in MM-F1 cells.	('AT-101', 'Chemical', 'MESH:C028178', (13, 19))	('MM-F1', 'CellLine', 'CVCL:5801', (149, 154))	('ERK2', 'Gene', '5594', (141, 145))	('phosphorylation', 'MPA', (43, 58))	('decreased', 'NegReg', (20, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('ERK1', 'Gene', '5595', (106, 110))	('ERK1', 'Gene', (106, 110))	('increased', 'PosReg', (88, 97))	('AT-101', 'Var', (13, 19))	('ERK1', 'Gene', '5595', (62, 66))	('ERK1', 'molecular_function', 'GO:0004707', ('106', '110'))	('ERK2', 'molecular_function', 'GO:0004707', ('141', '145'))	('ERK2', 'Gene', (141, 145))	('ERK1', 'Gene', (62, 66))	('ERK1', 'molecular_function', 'GO:0004707', ('62', '66'))
58210	30459622	p38 phosphorylation was increased after AT-101 treatment in MM-F1 and MM-B1 cells, while the effect was opposite in cells with epithelial histotype H-Meso-1 and #40a.	('p38', 'Protein', (0, 3))	('AT-101', 'Var', (40, 46))	('phosphorylation', 'MPA', (4, 19))	('MM-F1', 'CellLine', 'CVCL:5801', (60, 65))	('AT-101', 'Chemical', 'MESH:C028178', (40, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('increased', 'PosReg', (24, 33))
58213	30459622	In addition, we previously demonstrated that gossypol-induced apoptosis was mediated by the activation of JNK and p38 in head and neck cancer cells.	('head and neck cancer', 'Disease', 'MESH:D006258', (121, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('gossypol', 'Chemical', 'MESH:D006072', (45, 53))	('activation', 'PosReg', (92, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('head and neck cancer', 'Phenotype', 'HP:0012288', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('apoptosis', 'CPA', (62, 71))	('JNK', 'Gene', (106, 109))	('JNK', 'molecular_function', 'GO:0004705', ('106', '109'))	('neck', 'cellular_component', 'GO:0044326', ('130', '134'))	('p38', 'Var', (114, 117))
58216	30459622	AT-101 significantly increased the expression of c-Jun in MM-F1 and #40a cells, and the c-Jun phosphorylation in all MM cells.	('increased', 'PosReg', (21, 30))	('c-Jun', 'Gene', (49, 54))	('Jun phosphorylation', 'biological_process', 'GO:0007258', ('90', '109'))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('expression', 'MPA', (35, 45))	('c-Jun', 'Gene', (88, 93))	('c-Jun', 'Gene', '16476', (49, 54))	('MM-F1', 'CellLine', 'CVCL:5801', (58, 63))	('AT-101', 'Var', (0, 6))	('c-Jun', 'Gene', '16476', (88, 93))
58217	30459622	Finally, we showed that AT-101 affected the expression and phosphorylation of the pro-survival kinase AKT, which promotes tumor growth, depending on the cell type.	('promotes', 'PosReg', (113, 121))	('expression', 'MPA', (44, 54))	('AT-101', 'Chemical', 'MESH:C028178', (24, 30))	('affected', 'Reg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('phosphorylation', 'MPA', (59, 74))	('AT-101', 'Var', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('pro-survival', 'biological_process', 'GO:0043066', ('82', '94'))
58218	30459622	AT-101 decreased AKT phosphorylation in H-Meso-1 and #40a cells, while increased it in MM-F1 and MM-B1 cells.	('decreased', 'NegReg', (7, 16))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('increased', 'PosReg', (71, 80))	('AT-101', 'Var', (0, 6))	('AKT', 'Protein', (17, 20))	('MM-F1', 'CellLine', 'CVCL:5801', (87, 92))
58228	30459622	AT-101 prolonged the median survival of mice.	('prolonged', 'PosReg', (7, 16))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('mice', 'Species', '10090', (40, 44))	('AT-101', 'Var', (0, 6))	('median survival', 'CPA', (21, 36))
58229	30459622	The increase in the median survival of mice administered with AT-101 was superior to that of mice receiving corn oil (7 vs. 4.5 weeks; p = 0.0001).	('corn', 'Species', '4577', (108, 112))	('AT-101', 'Chemical', 'MESH:C028178', (62, 68))	('mice', 'Species', '10090', (93, 97))	('AT-101', 'Var', (62, 68))	('increase', 'PosReg', (4, 12))	('mice', 'Species', '10090', (39, 43))
58231	30459622	Overall, our results provided evidence that the treatment with AT-101 is capable of inhibiting cell proliferation by targeting several signaling pathways, inducing apoptosis of human and murine MM cell lines and interfering with the in vivo tumor growth of MM #40a cells transplanted into the peritoneum of C57BL/6 mice.	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('inducing', 'NegReg', (155, 163))	('signaling pathways', 'Pathway', (135, 153))	('human', 'Species', '9606', (177, 182))	('interfering', 'NegReg', (212, 223))	('mice', 'Species', '10090', (315, 319))	('tumor', 'Disease', (241, 246))	('apoptosis', 'CPA', (164, 173))	('AT-101', 'Chemical', 'MESH:C028178', (63, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('cell proliferation', 'CPA', (95, 113))	('murine', 'Species', '10090', (187, 193))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('AT-101', 'Var', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('targeting', 'Reg', (117, 126))	('inhibiting', 'NegReg', (84, 94))
58241	27097020	We found that autophagic flux in 3D, but not in 2D, correlated with ATG13 positivity.	('autophagic flux', 'CPA', (14, 29))	('positivity', 'Var', (74, 84))	('correlated', 'Reg', (52, 62))	('ATG13', 'Gene', (68, 73))	('ATG13', 'Gene', '9776', (68, 73))
58263	27097020	We considered that some lysosomal inhibitors, including NH4+, may activate autophagy, especially at longer exposures.	('autophagy', 'biological_process', 'GO:0016236', ('75', '84'))	('activate', 'PosReg', (66, 74))	('autophagy', 'biological_process', 'GO:0006914', ('75', '84'))	('autophagy', 'CPA', (75, 84))	('NH4+', 'Chemical', '-', (56, 60))	('NH4+', 'Var', (56, 60))
58289	27097020	In addition, LC3 puncta analysis, performed in 2 cell lines representative of the MCS-low or MCS-high autophagy groups, confirmed that EBSS induced a high autophagic flux both in 2D and 3D (Fig.	('EBSS', 'Var', (135, 139))	('LC3', 'Gene', (13, 16))	('EBSS', 'Chemical', '-', (135, 139))	('MCS', 'cellular_component', 'GO:0044232', ('93', '96'))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('MCS', 'cellular_component', 'GO:0044232', ('82', '85'))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('autophagic flux', 'CPA', (155, 170))	('LC3', 'Gene', '84557', (13, 16))
58300	27097020	In TFS exposed to NH4+, the percentage of LC3-positive MPM cells in the TFS increased to different degrees identifying 2 groups: approximately half the TFS had a small increase, defining a TFS-low autophagy group, and the other half had a large increase, defining a TFS-high autophagy group (Fig.	('autophagy', 'biological_process', 'GO:0016236', ('275', '284'))	('LC3', 'Gene', '84557', (42, 45))	('LC3', 'Gene', (42, 45))	('autophagy', 'biological_process', 'GO:0016236', ('197', '206'))	('autophagy', 'CPA', (197, 206))	('autophagy', 'biological_process', 'GO:0006914', ('275', '284'))	('autophagy', 'biological_process', 'GO:0006914', ('197', '206'))	('NH4+', 'Chemical', '-', (18, 22))	('NH4+', 'Var', (18, 22))
58302	27097020	On average, the percentage of LC3-positive cells increased by less than 2-fold (from 1.7% to 2.9% of MPM cells) in the TFS-low autophagy and by 8-fold (from 2.5% to 20.8% of MPM cells) in the TFS-high autophagy (Table 1).	('autophagy', 'biological_process', 'GO:0016236', ('127', '136'))	('autophagy', 'biological_process', 'GO:0006914', ('201', '210'))	('increased', 'PosReg', (49, 58))	('LC3', 'Gene', '84557', (30, 33))	('autophagy', 'biological_process', 'GO:0006914', ('127', '136'))	('TFS-low', 'Var', (119, 126))	('LC3', 'Gene', (30, 33))	('autophagy', 'CPA', (127, 136))	('autophagy', 'biological_process', 'GO:0016236', ('201', '210'))
58314	27097020	After NH4+, the LC3 staining increased and, except for a few cells that stained for only one marker, LC3 staining was seen in the cells that also showed ATG13 puncta.	('ATG13', 'Gene', (153, 158))	('NH4+', 'Chemical', '-', (6, 10))	('increased', 'PosReg', (29, 38))	('LC3', 'Gene', '84557', (101, 104))	('NH4+', 'Var', (6, 10))	('LC3', 'Gene', '84557', (16, 19))	('ATG13', 'Gene', '9776', (153, 158))	('LC3', 'Gene', (16, 19))	('LC3', 'Gene', (101, 104))
58321	27097020	An increasing proportion of tumor cells with punctate ATG13 staining was associated with incrementally improved survival functions.	('tumor', 'Disease', (28, 33))	('men', 'Species', '9606', (94, 97))	('survival functions', 'CPA', (112, 130))	('punctate', 'Var', (45, 53))	('improved', 'PosReg', (103, 111))	('ATG13', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ATG13', 'Gene', '9776', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
58325	27097020	At the 6% cutpoint, median overall survival was significantly longer for patients with high ATG13 positivity (>=6% ATG13-positive tumor cells; 17.4 mo) than for those with low positivity (<6 % ATG13-positive tumor cells; 10.6 mo) (P = 0.0009; Bonferroni corrected P=0.0162).	('ATG13', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('>=6', 'Var', (110, 113))	('longer', 'PosReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('overall survival', 'MPA', (27, 43))	('ATG13', 'Gene', (92, 97))	('patients', 'Species', '9606', (73, 81))	('ATG13', 'Gene', (193, 198))	('high', 'Var', (87, 91))	('ATG13', 'Gene', '9776', (115, 120))	('ATG13', 'Gene', '9776', (92, 97))	('tumor', 'Disease', (208, 213))	('ATG13', 'Gene', '9776', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (130, 135))
58326	27097020	Time to recurrence was also significantly longer for patients with high ATG13 positivity (13.7 mo) than for low positivity (6.6 mo) (P < 0.0001; Bonferroni corrected P < 0.0018) (Fig.	('ATG13', 'Gene', (72, 77))	('positivity', 'Var', (78, 88))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('ATG13', 'Gene', '9776', (72, 77))
58327	27097020	ATG13 positivity was more commonly low among non-epithelioid tumors (P = 0.01), but was not correlated with other known prognostic factors including age, lymph node status, gender, tumor volume, anemia, resectability, surgical procedure, adjuvant therapy, or TNM stage (Fig.	('TNM', 'Gene', (259, 262))	('tumor', 'Disease', (181, 186))	('anemia', 'Phenotype', 'HP:0001903', (195, 201))	('positivity', 'Var', (6, 16))	('anemia', 'Disease', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('non-epithelioid tumors', 'Disease', 'MESH:D054973', (45, 67))	('anemia', 'Disease', 'MESH:D000740', (195, 201))	('non-epithelioid tumors', 'Disease', (45, 67))	('low', 'NegReg', (35, 38))	('ATG13', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('TNM', 'Gene', '10178', (259, 262))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (61, 66))	('ATG13', 'Gene', '9776', (0, 5))
58329	27097020	In this analysis, after adjusting for histology, ATG13 positivity remained significantly prognostic for overall survival and time to recurrence (Fig.	('overall survival', 'CPA', (104, 120))	('ATG13', 'Gene', '9776', (49, 54))	('positivity', 'Var', (55, 65))	('prognostic', 'Reg', (89, 99))	('ATG13', 'Gene', (49, 54))
58330	27097020	When applying a conservative correction for the multiple comparisons required to establish the cutpoint, ATG13 positivity level remained significantly prognostic for time to recurrence but not for overall survival (Fig.	('positivity level', 'Var', (111, 127))	('ATG13', 'Gene', (105, 110))	('prognostic', 'Reg', (151, 161))	('ATG13', 'Gene', '9776', (105, 110))
58385	27097020	NH4+ and HCQ are lysosomotropic compounds that act as weak bases increasing the lysosomal pH and, in turn, indirectly inhibiting the lysosomal proteases and the degradation of LC3-II in the autolysosomes.	('HCQ', 'Chemical', 'MESH:D006886', (9, 12))	('lysosomal pH', 'MPA', (80, 92))	('degradation', 'biological_process', 'GO:0009056', ('161', '172'))	('NH4+', 'Chemical', '-', (0, 4))	('LC3', 'Gene', '84557', (176, 179))	('LC3', 'Gene', (176, 179))	('NH4+', 'Var', (0, 4))	('increasing', 'PosReg', (65, 75))	('lysosomal', 'Enzyme', (133, 142))	('inhibiting', 'NegReg', (118, 128))	('degradation', 'MPA', (161, 172))
58386	27097020	Note: Prolonged exposure to lysosomal alkalyzers, including NH4+, may result in the simultaneous inhibition of the last phase of autophagy and upregulation of autophagy.	('NH4+', 'Chemical', '-', (60, 64))	('NH4+', 'Var', (60, 64))	('inhibition', 'NegReg', (97, 107))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('autophagy', 'CPA', (159, 168))	('autophagy', 'biological_process', 'GO:0016236', ('159', '168'))	('upregulation', 'PosReg', (143, 155))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('autophagy', 'biological_process', 'GO:0006914', ('159', '168'))	('last phase of autophagy', 'CPA', (115, 138))
58438	27097020	Kaplan Meier estimation and log rank comparison of survival functions, and Cox proportional hazards regression, with Bonferroni correction for multiple testing required to establish the cutpoint, were used to evaluate the association of ATG13 positivity level with time to tumor recurrence and all-causes of death following surgery, independently and with adjustment for tumor histology.	('association', 'Interaction', (222, 233))	('tumor', 'Disease', (371, 376))	('ATG13', 'Gene', '9776', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('men', 'Species', '9606', (362, 365))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('positivity level', 'Var', (243, 259))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('ATG13', 'Gene', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))
58513	24958746	Of the 31,099 probe sets on the array, 14,136 were differentially expressed in vinylidene chloride induced mesotheliomas compared to Fred-PE.	('vinylidene chloride', 'Chemical', 'MESH:C029297', (79, 98))	('vinylidene', 'Var', (79, 89))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', (107, 120))
58546	24958746	Previous studies have characterized gene expression profiles or molecular features of chemically-induced mesotheliomas in F344/N rats or F344 crosses; however, these studies did not consider the background gene expression of mesotheliomas when interpreting chemical effects.	('mesotheliomas', 'Disease', 'MESH:D008654', (105, 118))	('mesotheliomas', 'Disease', 'MESH:D008654', (225, 238))	('gene expression', 'biological_process', 'GO:0010467', ('206', '221'))	('mesotheliomas', 'Disease', (105, 118))	('mesotheliomas', 'Disease', (225, 238))	('F344', 'Var', (137, 141))	('rats', 'Species', '10116', (129, 133))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))
58548	24958746	Gene expression profiling and mutation analysis of human mesotheliomas has revealed a variety of genetic alterations including mutations in tumor suppressor genes (TP53, P16, BAP1, WT1, NF2, PTEN) and cell cycle genes (CDKN2A/2B and CDKN2C), and alterations in proteins associated with tumorigenesis (COL3, CCL2, LGALS).	('WT1', 'Gene', '7490', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('human', 'Species', '9606', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('CCL2', 'Gene', (307, 311))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('mesotheliomas', 'Disease', (57, 70))	('CDKN2C', 'Gene', '1031', (233, 239))	('TP53', 'Gene', (164, 168))	('BAP1', 'Gene', (175, 179))	('CDKN2A/2B', 'Gene', '1029', (219, 228))	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('rat', 'Species', '10116', (109, 112))	('mesotheliomas', 'Disease', 'MESH:D008654', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (127, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('201', '211'))	('CCL2', 'Gene', '6347', (307, 311))	('tumor', 'Disease', (286, 291))	('rat', 'Species', '10116', (250, 253))	('CCL', 'molecular_function', 'GO:0044101', ('307', '310'))	('PTEN', 'Gene', (191, 195))	('CDKN2A/2B', 'Gene', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('NF2', 'Gene', '4771', (186, 189))	('proteins', 'Protein', (261, 269))	('P16', 'Gene', '1029', (170, 173))	('alterations', 'Reg', (246, 257))	('CDKN2C', 'Gene', (233, 239))	('PTEN', 'Gene', '5728', (191, 195))	('WT1', 'Gene', (181, 184))	('NF2', 'Gene', (186, 189))	('BAP1', 'Gene', '8314', (175, 179))	('P16', 'Gene', (170, 173))	('tumor', 'Disease', (140, 145))
58557	24958746	Alterations in EpCAM protein interfere with cadherin-mediated cell-to-cell adhesion; cytoplasmic and nuclear translocation of this protein, as seen in rat mesotheliomas in this study, is associated with stimulation of cell proliferation.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('interfere', 'NegReg', (29, 38))	('cadherin-mediated cell-to-cell adhesion', 'CPA', (44, 83))	('Alterations', 'Var', (0, 11))	('EpCAM', 'Gene', (15, 20))	('mesotheliomas', 'Disease', 'MESH:D008654', (155, 168))	('mesotheliomas', 'Disease', (155, 168))	('stimulation', 'PosReg', (203, 214))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('EpCAM', 'Gene', '171577', (15, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('cell adhesion', 'biological_process', 'GO:0007155', ('70', '83'))	('rat', 'Species', '10116', (151, 154))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (230, 233))	('cell proliferation', 'CPA', (218, 236))	('protein', 'Protein', (21, 28))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('203', '236'))
58565	24958746	Direct mesothelial cell damage can lead to injury responses including cell proliferation and/or the activation of the mesothelial cell innate immune response.	('damage', 'Var', (24, 30))	('innate immune response', 'biological_process', 'GO:0045087', ('135', '157'))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('mesothelial cell innate immune response', 'CPA', (118, 157))	('rat', 'Species', '10116', (82, 85))	('lead to', 'Reg', (35, 42))	('activation', 'PosReg', (100, 110))	('injury responses', 'CPA', (43, 59))
58579	24958746	While the exact effects of vinylidene chloride on mesothelial cells are not known, it has been shown that exposure to vinylidene chloride results in the generation of reactive metabolites (1,1-diethylene oxide, chloroacetyl chloride), which have the potential to cause tissue damage and inflammation, which is an important contributor to tumorigenesis in a number of cancers, including mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (386, 398))	('reactive metabolites', 'MPA', (167, 187))	('tumor', 'Disease', (338, 343))	('cancers', 'Phenotype', 'HP:0002664', (367, 374))	('cancers', 'Disease', (367, 374))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('vinylidene chloride', 'Chemical', 'MESH:C029297', (118, 137))	('rat', 'Species', '10116', (157, 160))	('1,1-diethylene oxide', 'Chemical', '-', (189, 209))	('inflammation', 'biological_process', 'GO:0006954', ('287', '299'))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('inflammation', 'Disease', 'MESH:D007249', (287, 299))	('cancers', 'Disease', 'MESH:D009369', (367, 374))	('vinylidene chloride', 'Chemical', 'MESH:C029297', (27, 46))	('vinylidene chloride', 'Var', (118, 137))	('chloroacetyl chloride', 'Chemical', 'MESH:C045557', (211, 232))	('inflammation', 'Disease', (287, 299))	('mesothelioma', 'Disease', (386, 398))	('cause', 'Reg', (263, 268))
58581	24958746	Our data supports the possibility that VDC exposure increases mesothelioma incidence in F344/N rats through inducing a proinflammatory environment and exaggerated or dysfunctional immune response, resulting in direct or indirect damage to mesothelial cells.	('proinflammatory environment', 'MPA', (119, 146))	('exposure', 'Var', (43, 51))	('increases mesothelioma', 'Disease', 'MESH:D008654', (52, 74))	('VDC', 'Chemical', 'MESH:C029297', (39, 42))	('rats', 'Species', '10116', (95, 99))	('rat', 'Species', '10116', (95, 98))	('iron', 'Chemical', 'MESH:D007501', (138, 142))	('immune response', 'biological_process', 'GO:0006955', ('180', '195'))	('inducing', 'Reg', (108, 116))	('increases mesothelioma', 'Disease', (52, 74))	('dysfunctional', 'Disease', (166, 179))	('rat', 'Species', '10116', (157, 160))	('dysfunctional', 'Disease', 'MESH:D006331', (166, 179))	('exaggerated or dysfunctional immune response', 'Phenotype', 'HP:0002721', (151, 195))	('damage', 'Reg', (229, 235))
58594	24958746	Overall, the overrepresentation of genes associated with immune dysfunction, inflammation, and tissue injury in mesotheliomas associated with VDC-exposure suggests that exposure to VDC may lead to cytotoxicity and DNA damage resulting in regenerative hyperplasia and genomic instability, which are important risk factors for the development of neoplasia.	('exposure', 'Var', (169, 177))	('neoplasia', 'Disease', (344, 353))	('overrepresentation', 'PosReg', (13, 31))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('lead to', 'Reg', (189, 196))	('DNA damage', 'CPA', (214, 224))	('neoplasia', 'Phenotype', 'HP:0002664', (344, 353))	('VDC', 'Gene', (181, 184))	('inflammation', 'Disease', (77, 89))	('genomic instability', 'CPA', (267, 286))	('rat', 'Species', '10116', (244, 247))	('VDC', 'Chemical', 'MESH:C029297', (142, 145))	('hyperplasia', 'Disease', (251, 262))	('cytotoxicity', 'Disease', (197, 209))	('injury in mesotheliomas', 'Disease', (102, 125))	('hyperplasia', 'Disease', 'MESH:D006965', (251, 262))	('cytotoxicity', 'Disease', 'MESH:D064420', (197, 209))	('VDC', 'Chemical', 'MESH:C029297', (181, 184))	('inflammation', 'biological_process', 'GO:0006954', ('77', '89'))	('neoplasia', 'Disease', 'MESH:D009369', (344, 353))	('injury in mesotheliomas', 'Disease', 'MESH:D008654', (102, 125))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))
58627	21448170	Only three articles were identified that adequately selected a representative cohort of consecutive patients suspected for mesothelioma.r3,r22,r76 Of these, two articles were on the basis of one prospective French study.r3,r22 Other studies used a case-control design (n=70), or a cohort of patients with pleural effusions (n=9).	('pleural effusion', 'Phenotype', 'HP:0002202', (305, 321))	('pleural effusions', 'Disease', (305, 322))	('pleural effusions', 'Disease', 'MESH:D010996', (305, 322))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('pleural effusions', 'Phenotype', 'HP:0002202', (305, 322))	('patients', 'Species', '9606', (291, 299))	('study.r3', 'Var', (214, 222))	('patients', 'Species', '9606', (100, 108))	('mesothelioma', 'Disease', (123, 135))
58645	21448170	Four studiesr39,r42,r75,r82 made a distinction in staining pattern as well, showing that a membranous staining EMA pattern was mainly observed in mesothelioma patients (55-92%) and not in other malignant diseases (<20%) (Supplementary Appendix 4, Table 2.3).	('malignant diseases', 'Disease', (194, 212))	('membranous staining', 'MPA', (91, 110))	('observed', 'Reg', (134, 142))	('EMA', 'Gene', (111, 114))	('mesothelioma', 'Disease', (146, 158))	('r75', 'Var', (20, 23))	('mesothelioma', 'Disease', 'MESH:D008654', (146, 158))	('patients', 'Species', '9606', (159, 167))	('EMA', 'Gene', '4582', (111, 114))	('malignant diseases', 'Disease', 'MESH:D009369', (194, 212))
58653	21448170	Seven other studies directly compared the immunohistochemical markers CEA and Ber-EP4.r46,r48,r64,r67,r73,r82 Sensitivity values were highest for CEA, and in five of the seven studiesr42,r46,r64,r67,r73 Ber-Ep4 provided the highest specificity.	('CEA', 'Gene', (70, 73))	('CEA', 'Gene', '1048', (70, 73))	('CEA', 'Gene', (146, 149))	('CEA', 'Gene', '1048', (146, 149))	('studiesr42', 'Var', (176, 186))	('Ep4', 'Gene', (207, 210))	('EP4', 'Gene', '5734', (82, 85))	('EP4', 'Gene', (82, 85))	('r64', 'Var', (191, 194))	('Ber', 'biological_process', 'GO:0006284', ('78', '81'))	('r73', 'Var', (199, 202))	('r46', 'Var', (187, 190))	('Ber', 'biological_process', 'GO:0006284', ('203', '206'))	('r67', 'Var', (195, 198))	('Ep4', 'Gene', '5734', (207, 210))
58668	21448170	Several other studies used a prospective, consecutive patient inclusion, but selected patients on grounds of the presence of pleural effusion, rather than on the initial suspicion of mesothelioma.r2,r31,r34 Once pleural effusion is confirmed by imaging, only those patients that are still suspected of mesothelioma after imaging are warranted for further testing for mesothelioma.	('patient', 'Species', '9606', (54, 61))	('pleural effusion', 'Disease', (212, 228))	('mesothelioma', 'Disease', (367, 379))	('pleural effusion', 'Phenotype', 'HP:0002202', (212, 228))	('mesothelioma', 'Disease', 'MESH:D008654', (367, 379))	('mesothelioma', 'Disease', (302, 314))	('mesothelioma', 'Disease', (183, 195))	('patient', 'Species', '9606', (86, 93))	('pleural effusion', 'Disease', 'MESH:D010996', (125, 141))	('patient', 'Species', '9606', (265, 272))	('pleural effusion', 'Disease', (125, 141))	('r31', 'Var', (199, 202))	('patients', 'Species', '9606', (265, 273))	('pleural effusion', 'Phenotype', 'HP:0002202', (125, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (302, 314))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('pleural effusion', 'Disease', 'MESH:D010996', (212, 228))	('patients', 'Species', '9606', (86, 94))
58770	18218073	Leaching causes an increase in chemically active surface area, and facilitates penetration of solvent molecules.	('penetration of solvent molecules', 'MPA', (79, 111))	('rat', 'Species', '10116', (84, 87))	('Leaching', 'Var', (0, 8))	('increase', 'PosReg', (19, 27))	('facilitates', 'PosReg', (67, 78))	('chemically active surface area', 'MPA', (31, 61))
58985	31382483	OPN-a is considered the canonical transcript, OPN-b variant is lacking exon 5, and OPN-c variant is missing exon 4; translation of these variants leads to the expression of three different proteins called OPN-a (314 aa), OPN-b (300 aa), and OPN-c (287 aa).	('300 aa', 'Var', (228, 234))	('expression', 'Species', '29278', (159, 169))	('translation', 'biological_process', 'GO:0006412', ('116', '127'))	('leads to', 'Reg', (146, 154))	('expression', 'MPA', (159, 169))	('variants', 'Var', (137, 145))
58991	31382483	Other potential regulatory sequences in the SPP1 promoter have been identified, including a TATA-like sequence (nucleotides -27 to -22), vitamin-D-responsive (VDR)-like motifs (nucleotides -1892 to -1878 and -698 to -684), an AP-1 binding sequence (TGACACA, nucleotides -78 to -72), and an Ets-1 motif (nucleotides -47 to -39).	('vitamin-D', 'Chemical', 'MESH:D014807', (137, 146))	('SPP1', 'Gene', (44, 48))	('SPP', 'molecular_function', 'GO:0042499', ('44', '47'))	('AP-1', 'cellular_component', 'GO:0005907', ('226', '230'))	('binding', 'molecular_function', 'GO:0005488', ('231', '238'))	('SPP1', 'Gene', '6696', (44, 48))	('nucleotides', 'Var', (177, 188))
58993	31382483	For instance, in alveolar macrophages, the E3 ligase von Hippel-Lindau protein (VHL) promotes OPN expression by epigenetic modifications.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('VHL', 'Gene', (80, 83))	('epigenetic modifications', 'Var', (112, 136))	('VHL', 'Gene', '7428', (80, 83))	('OPN', 'Gene', (94, 97))	('von Hippel-Lindau', 'Disease', (53, 70))	('promotes', 'PosReg', (85, 93))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (53, 70))	('expression', 'Species', '29278', (98, 108))	('expression', 'MPA', (98, 108))
58999	31382483	OPN cleavage by matrix metalloprotease 3 (MMP3), MMP7, and thrombin renders the above motifs more accessible and enhances binding efficiency.	('cleavage', 'Var', (4, 12))	('accessible', 'MPA', (98, 108))	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('enhances', 'PosReg', (113, 121))	('matrix metalloprotease 3', 'Gene', '4314', (16, 40))	('MMP3', 'Gene', '4314', (42, 46))	('thrombin', 'Gene', '2147', (59, 67))	('MMP7', 'Gene', (49, 53))	('MMP3', 'Gene', (42, 46))	('MMP7', 'molecular_function', 'GO:0004235', ('49', '53'))	('MMP3', 'molecular_function', 'GO:0004248', ('42', '46'))	('MMP7', 'Gene', '4316', (49, 53))	('more', 'PosReg', (93, 97))	('matrix metalloprotease 3', 'Gene', (16, 40))	('thrombin', 'Gene', (59, 67))
59050	31382483	Interestingly, OPN splice variants seem to differentially participate in cancer progression.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('OPN', 'Gene', (15, 18))	('participate', 'Reg', (58, 69))	('splice variants', 'Var', (19, 34))
59051	31382483	For example, in thyroid cancer cells OPN-a overexpression stimulates higher matrix calcification and collagen synthesis when compared to overexpression of OPN-b or OPN-c.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('thyroid cancer', 'Disease', (16, 30))	('calcification', 'Disease', (83, 96))	('overexpression', 'Var', (43, 57))	('thyroid cancer', 'Phenotype', 'HP:0002890', (16, 30))	('expression', 'Species', '29278', (141, 151))	('OPN-a', 'Gene', (37, 42))	('collagen', 'molecular_function', 'GO:0005202', ('101', '109'))	('collagen synthesis', 'biological_process', 'GO:0032964', ('101', '119'))	('thyroid cancer', 'Disease', 'MESH:D013964', (16, 30))	('expression', 'Species', '29278', (47, 57))	('collagen synthesis', 'CPA', (101, 119))	('calcification', 'Disease', 'MESH:D002114', (83, 96))	('higher', 'PosReg', (69, 75))
59054	31382483	As previously described, in most types of cancer, high levels of OPN are correlated with a more aggressive cancer phenotype and worse prognosis.	('aggressive cancer', 'Disease', 'MESH:D009369', (96, 113))	('correlated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('OPN', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('aggressive cancer', 'Disease', (96, 113))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('high levels', 'Var', (50, 61))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
59059	31382483	While rs11730582 is the most studied SNP of OPN with the -443 CC genotype generally associated with higher expression of OPN and increased cancer risk, this SNP tends to have a better prognosis in NSCLC.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('better', 'Reg', (177, 183))	('expression', 'Species', '29278', (107, 117))	('OPN', 'Protein', (121, 124))	('rs11730582', 'Mutation', 'rs11730582', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (107, 117))	('rs11730582', 'Var', (6, 16))	('NSCLC', 'Disease', (197, 202))	('associated', 'Reg', (84, 94))	('higher', 'PosReg', (100, 106))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('cancer', 'Disease', (139, 145))
59060	31382483	On the other hand, the SNP rs17524488 (-156G/G) is associated with higher levels of OPN expression and is correlated to a more advanced stage disease.	('rs17524488', 'Mutation', 'rs17524488', (27, 37))	('higher', 'PosReg', (67, 73))	('OPN expression', 'MPA', (84, 98))	('rs17524488', 'Var', (27, 37))	('expression', 'Species', '29278', (88, 98))	('levels', 'MPA', (74, 80))	('correlated to', 'Reg', (106, 119))
59062	31382483	have reported that the combination of OPN and CD44v6 elevated expression of is a valuable independent predictor of tumor recurrence and survival in NSCLC patients.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD44', 'Gene', (46, 50))	('expression', 'Species', '29278', (62, 72))	('elevated', 'PosReg', (53, 61))	('OPN', 'Gene', (38, 41))	('NSCLC', 'Disease', (148, 153))	('expression', 'MPA', (62, 72))	('tumor', 'Disease', (115, 120))	('patients', 'Species', '9606', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('CD44', 'Gene', '960', (46, 50))	('combination', 'Var', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
59069	31382483	Interestingly, lung cancers presenting genomic alterations leading to KRAS activation are characterized by resistance to radiation and poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('lung cancers', 'Disease', 'MESH:D008175', (15, 27))	('KRAS', 'Gene', (70, 74))	('lung cancers', 'Phenotype', 'HP:0100526', (15, 27))	('KRAS', 'Gene', '3845', (70, 74))	('activation', 'PosReg', (75, 85))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('lung cancers', 'Disease', (15, 27))	('alterations', 'Var', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
59071	31382483	In another study, where the transmembrane 4 L6 family member 4 (TM4SF4) known to promote cancer was studied, authors demonstrated that OPN induced by upregulated beta-catenin via TM4SF4-driven phosphorylation of glycogen synthase kinase 3b (GSK3beta) activated the JAK2/STAT3 or FAK/STAT3 pathway in human lung cancer cells, which also upregulates OPN expression in an autocrine manner.	('cancer', 'Disease', (311, 317))	('STAT3', 'Gene', (270, 275))	('cancer', 'Disease', (89, 95))	('TM4SF4', 'Gene', (179, 185))	('upregulates', 'PosReg', (336, 347))	('TM4SF4', 'Gene', '7104', (64, 70))	('expression', 'MPA', (352, 362))	('activated', 'PosReg', (251, 260))	('GSK', 'molecular_function', 'GO:0050321', ('241', '244'))	('GSK3beta', 'Gene', (241, 249))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('JAK2', 'Gene', (265, 269))	('phosphorylation', 'Var', (193, 208))	('STAT3', 'Gene', '6774', (270, 275))	('JAK', 'molecular_function', 'GO:0004713', ('265', '268'))	('FAK', 'molecular_function', 'GO:0004717', ('279', '282'))	('transmembrane 4 L6 family member 4', 'Gene', '7104', (28, 62))	('STAT3', 'Gene', (283, 288))	('transmembrane', 'cellular_component', 'GO:0016021', ('28', '41'))	('lung cancer', 'Disease', (306, 317))	('FAK', 'Gene', (279, 282))	('transmembrane 4 L6 family member 4', 'Gene', (28, 62))	('STAT3', 'Gene', '6774', (283, 288))	('transmembrane', 'cellular_component', 'GO:0044214', ('28', '41'))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('TM4SF4', 'Gene', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (300, 305))	('FAK', 'Gene', '5747', (279, 282))	('expression', 'Species', '29278', (352, 362))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('upregulated', 'PosReg', (150, 161))	('GSK3beta', 'Gene', '2932', (241, 249))	('beta-catenin', 'Gene', (162, 174))	('TM4SF4', 'Gene', '7104', (179, 185))	('beta-catenin', 'Gene', '1499', (162, 174))	('OPN', 'Gene', (348, 351))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('JAK2', 'Gene', '3717', (265, 269))	('phosphorylation', 'biological_process', 'GO:0016310', ('193', '208'))
59073	31382483	Finally, in patients with lung adenocarcinoma, OPN was identified as a biomarker, and high expression of the protein has been associated with poor patient survival and identified as a predicting tool for disease stage prognosis.	('poor', 'NegReg', (142, 146))	('expression', 'MPA', (91, 101))	('associated', 'Reg', (126, 136))	('patients', 'Species', '9606', (12, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('patient', 'Species', '9606', (147, 154))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('patient', 'Species', '9606', (12, 19))	('expression', 'Species', '29278', (91, 101))	('high', 'Var', (86, 90))
59084	31382483	demonstrated in another study that lung cancer cell proliferation and migration were significantly reduced when OPN was silenced.	('OPN', 'Gene', (112, 115))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('silenced', 'Var', (120, 128))	('migration', 'CPA', (70, 79))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('reduced', 'NegReg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
59087	31382483	OPN can cause an increase in EMT-related transcription factors including Twist, Snail, and Slug.	('Slug', 'Gene', '6591', (91, 95))	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('Slug', 'Gene', (91, 95))	('EMT-related', 'CPA', (29, 40))	('OPN', 'Var', (0, 3))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('Snail', 'CPA', (80, 85))	('increase', 'PosReg', (17, 25))	('Twist', 'CPA', (73, 78))
59098	31382483	OPN may also activate ROCK signaling via the FAK/PI3K/AKT pathway, thereby facilitating the invasion of lung cancer cells through lamellipodia formation and the inactivation of cofilin.	('activate', 'PosReg', (13, 21))	('invasion', 'CPA', (92, 100))	('FAK', 'Gene', '5747', (45, 48))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('AKT', 'Gene', (54, 57))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('facilitating', 'PosReg', (75, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cofilin', 'Gene', '1072', (177, 184))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('inactivation', 'Var', (161, 173))	('AKT', 'Gene', '207', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lamellipodia formation', 'CPA', (130, 152))	('ROCK signaling', 'Pathway', (22, 36))	('cofilin', 'Gene', (177, 184))	('OPN', 'Gene', (0, 3))	('FAK', 'molecular_function', 'GO:0004717', ('45', '48'))	('lung cancer', 'Disease', (104, 115))	('FAK', 'Gene', (45, 48))
59113	31382483	Currently, two studies are recruiting and aim to assess the role of OPN as a biomarker of arteriovenous fistula (NCT03270358) without stenosis and as a risk factor for cerebrovascular stroke (NCT03561285).	('cerebrovascular stroke', 'Disease', 'MESH:D020521', (168, 190))	('OPN', 'Gene', (68, 71))	('NCT03270358', 'Var', (113, 124))	('cerebrovascular stroke', 'Disease', (168, 190))	('NCT03561285', 'Var', (192, 203))	('stroke', 'Phenotype', 'HP:0001297', (184, 190))	('stenosis', 'Disease', 'MESH:D003251', (134, 142))	('arteriovenous fistula', 'Disease', (90, 111))	('stenosis', 'Disease', (134, 142))	('arteriovenous fistula', 'Phenotype', 'HP:0004947', (90, 111))	('arteriovenous fistula', 'Disease', 'MESH:D001165', (90, 111))
59115	31382483	The expression vectors are useful for the overexpression of the protein or the introduction of mutations, while knockout mice models such as the B6.129S6(Cg)-Spp1tm1Blh/J strain are animals without functional OPN.	('Spp', 'molecular_function', 'GO:0042499', ('158', '161'))	('expression', 'Species', '29278', (4, 14))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('Spp1', 'Gene', (158, 162))	('expression vectors', 'Species', '29278', (4, 22))	('Spp1', 'Gene', '20750', (158, 162))	('expression', 'Species', '29278', (46, 56))	('mice', 'Species', '10090', (121, 125))	('mutations', 'Var', (95, 104))	('B6.129S6', 'CellLine', 'CVCL:C319', (145, 153))
59120	31382483	Taken together, OPN and its variants are highly involved in the regulation of tumor-associated inflammation as well as the aggressiveness of cancer cells and tumor growth enhancement.	('tumor', 'Disease', (158, 163))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('variants', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('involved', 'Reg', (48, 56))	('aggressiveness of cancer', 'Disease', (123, 147))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('inflammation', 'Disease', (95, 107))	('aggressiveness', 'Phenotype', 'HP:0000718', (123, 137))	('tumor', 'Disease', (78, 83))	('OPN', 'Gene', (16, 19))	('inflammation', 'biological_process', 'GO:0006954', ('95', '107'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (123, 147))
59121	31382483	Although there are still unknown mechanisms of action of each OPN isoform, it is obvious that OPN variants may be interesting therapeutic targets for chronic inflammatory diseases and cancer.	('cancer', 'Disease', (184, 190))	('inflammatory diseases', 'Disease', 'MESH:D007249', (158, 179))	('OPN', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inflammatory diseases', 'Disease', (158, 179))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('variants', 'Var', (98, 106))
59194	31026023	Known diagnostic markers for renal clear cell carcinoma, namely CA9 and CA12, were associated with renal clear cell carcinoma.	('renal clear cell carcinoma', 'Disease', (99, 125))	('CA9', 'Gene', '768', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (29, 55))	('associated', 'Reg', (83, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('renal clear cell carcinoma', 'Disease', (29, 55))	('CA9', 'Gene', (64, 67))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 125))	('CA12', 'Var', (72, 76))
59197	31026023	Unexpectedly, in the absence of a healthy tissue class corresponding to a primary tumor type, some important genes for the cancer reflect biological characteristics of the progenitor healthy tissue, such as DPPA3/5 for testicular germline cancers, and TYR and MLANA for uveal melanomas.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('DPPA3', 'Gene', '359787', (207, 212))	('tumor', 'Disease', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('TYR', 'Chemical', 'MESH:D014443', (252, 255))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('TYR', 'Var', (252, 255))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('DPPA3', 'Gene', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('testicular germline', 'Disease', (219, 238))	('MLANA', 'Var', (260, 265))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Disease', (123, 129))
59286	28599887	In vitro and xenograft mesothelioma studies have demonstrated that inhibition of the PDGF pathway leads to anti-tumor effects, and a phase I trial of imatinib mesylate, a PDGFR inhibitor, combined with cisplatin-pemetrexed showed potential clinical benefit but low tolerance to therapy.	('inhibition', 'Var', (67, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (150, 167))	('cisplatin-pemetrexed', 'Chemical', '-', (202, 222))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('PDGF', 'molecular_function', 'GO:0005161', ('85', '89'))	('PDGF pathway', 'Pathway', (85, 97))	('PDGFR', 'Gene', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDGFR', 'Gene', '5159', (171, 176))	('tumor', 'Disease', (112, 117))	('mesothelioma', 'Disease', (23, 35))
59383	28599887	Cediranib certainly caused gastrointestinal toxicity and dehydration that are not typically seen with cisplatin-pemetrexed alone.	('Cediranib', 'Chemical', 'MESH:C500926', (0, 9))	('cisplatin-pemetrexed', 'Chemical', '-', (102, 122))	('gastrointestinal toxicity', 'Disease', (27, 52))	('dehydration', 'Disease', (57, 68))	('Cediranib', 'Var', (0, 9))	('caused', 'Reg', (20, 26))	('dehydration', 'Phenotype', 'HP:0001944', (57, 68))	('dehydration', 'Disease', 'MESH:D003681', (57, 68))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (27, 52))
59393	28599887	Cediranib-cisplatin-pemetrexed did have higher rates of proteinuria and gastrointestinal events compared to the MAPS regimen.	('Cediranib', 'Chemical', 'MESH:C500926', (0, 9))	('Cediranib-cisplatin-pemetrexed', 'Var', (0, 30))	('gastrointestinal events', 'Phenotype', 'HP:0011024', (72, 95))	('higher', 'PosReg', (40, 46))	('gastrointestinal events', 'MPA', (72, 95))	('proteinuria', 'Disease', (56, 67))	('cisplatin-pemetrexed', 'Chemical', '-', (10, 30))	('proteinuria', 'Phenotype', 'HP:0000093', (56, 67))	('proteinuria', 'Disease', 'MESH:D011507', (56, 67))
59403	28599887	This finding is consistent with the IFCT MAPs trial in which cisplatin-pemetrexed-bevacizumab had a median PFS (9.2 months versus 7.3 months, HR 0.61, p<0.0001) and OS (18.8 months versus 16.1 months, HR 0.77, p=0.0167) benefit over platinum-pemetrexed alone.	('platinum-pemetrexed', 'Chemical', '-', (233, 252))	('cisplatin-pemetrexed', 'Chemical', '-', (61, 81))	('cisplatin-pemetrexed-bevacizumab', 'Var', (61, 93))	('benefit', 'PosReg', (220, 227))	('PFS', 'MPA', (107, 110))	('bevacizumab', 'Chemical', 'MESH:D000068258', (82, 93))
59406	28599887	Given that mesothelioma is known to be reliant on the PDGF/PDGFR pathway for proliferation and that prior studies with PDGFR inhibitors have shown a clinical benefit in mesothelioma, it is suspected that multi-angiokinase inhibition may ultimately provide additive benefit.	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('mesothelioma', 'Disease', (11, 23))	('PDGF', 'molecular_function', 'GO:0005161', ('54', '58'))	('PDGFR', 'Gene', (119, 124))	('PDGFR', 'Gene', (59, 64))	('mesothelioma', 'Disease', (169, 181))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('inhibitors', 'Var', (125, 135))	('PDGFR', 'Gene', '5159', (119, 124))	('PDGFR', 'Gene', '5159', (59, 64))	('benefit', 'PosReg', (158, 165))
59417	28291776	YS110 demonstrated preclinical anti-tumour effects without significant side effects.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('YS110', 'Chemical', '-', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('YS110', 'Var', (0, 5))
59419	28291776	YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.	('YS110', 'Chemical', '-', (0, 5))	('solid tumours', 'Disease', 'MESH:D009369', (187, 200))	('patients', 'Species', '9606', (157, 165))	('solid tumours', 'Disease', (187, 200))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('CD26-expressing', 'Var', (171, 186))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
59425	28291776	CD26 is a 110-kDa, type II transmembrane glycoprotein with known dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) activity in its extracellular domain and is capable of cleaving N-terminal dipeptides with either L-proline or L-alanine at the penultimate position.	('dipeptidyl peptidase IV', 'molecular_function', 'GO:0004274', ('65', '88'))	('cleaving N-terminal dipeptides', 'MPA', (165, 195))	('dipeptidyl peptidase IV', 'Gene', (65, 88))	('L-alanine', 'Chemical', 'MESH:D000409', (221, 230))	('dipeptides', 'Chemical', 'MESH:D004151', (185, 195))	('extracellular', 'cellular_component', 'GO:0005576', ('126', '139'))	('CD26', 'Gene', (0, 4))	('transmembrane', 'cellular_component', 'GO:0044214', ('27', '40'))	('L-proline', 'Chemical', 'MESH:D011392', (208, 217))	('L-alanine', 'Var', (221, 230))	('transmembrane', 'cellular_component', 'GO:0016021', ('27', '40'))	('dipeptidyl peptidase IV', 'Gene', '1803', (65, 88))
59429	28291776	We also reported robust in vivo data on the anti-tumour activity of anti-CD26 mAb in mouse xenograft models.	('mouse', 'Species', '10090', (85, 90))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('anti-CD26', 'Var', (68, 77))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (49, 55))
59439	28291776	Considering the lack of T-cell proliferation and cytokine production in vitro, YS110 was therefore considered not to have an agonistic nor activating effect on human CD26-positive lymphocytes.	('YS110', 'Var', (79, 84))	('cytokine production', 'biological_process', 'GO:0001816', ('49', '68'))	('T-cell', 'CPA', (24, 30))	('YS110', 'Chemical', '-', (79, 84))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('24', '44'))	('human', 'Species', '9606', (160, 165))
59440	28291776	This first-in-human phase 1 clinical trial aims to evaluate the safety, pharmacokinetic/pharmacodynamic profiles and preliminary anti-tumour effects of YS110 in patients with CD26-expressing solid tumours and, particularly, refractory malignant mesothelioma, a tumour type in which successful therapeutic advances are expected to be warranted for a long time.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (235, 257))	('tumour', 'Disease', (197, 203))	('solid tumours', 'Disease', (191, 204))	('YS110', 'Gene', (152, 157))	('CD26-expressing', 'Var', (175, 190))	('YS110', 'Chemical', '-', (152, 157))	('solid tumours', 'Disease', 'MESH:D009369', (191, 204))	('human', 'Species', '9606', (14, 19))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (235, 257))	('patients', 'Species', '9606', (161, 169))	('tumours', 'Phenotype', 'HP:0002664', (197, 204))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('refractory', 'Disease', (224, 234))	('tumour', 'Disease', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('malignant mesothelioma', 'Disease', (235, 257))	('tumour', 'Disease', (261, 267))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
59468	28291776	Assays for soluble CD26 and DPP4 were developed in the Morimoto's Laboratory (Juntendo University, Japan) using anti-human CD26 murine mAbs that exhibit no cross-reactivity with the therapeutic humanised anti-CD26 mAb YS110 as described previously.	('murine', 'Species', '10090', (128, 134))	('YS110', 'Chemical', '-', (218, 223))	('human', 'Species', '9606', (117, 122))	('CD26', 'Gene', (123, 127))	('human', 'Species', '9606', (194, 199))	('soluble', 'cellular_component', 'GO:0005625', ('11', '18'))	('anti-human', 'Var', (112, 122))
59473	28291776	Other tumour types screened included RCC (n=18, 71% CD26+ cases), hepatocellular carcinoma (n=7, 22% CD26+ cases) and various other tumour types (n=31, 13% CD26+ cases).	('tumour', 'Disease', (132, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('CD26+', 'Var', (52, 57))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('RCC', 'Disease', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('tumour', 'Disease', (6, 12))
59482	28291776	During the DLT observation period (i.e., 15 days following the first infusion), two DLTs were reported as serious unexpected adverse events (SUSARs) consisting of grade 3 infusion reactions (one patient at the Q2W 1 mg kg-1 dose level and another patient at the Q2W 2 mg kg-1 dose level) that completely resolved with supportive treatment, but led to permanent discontinuation of treatment.	('patient', 'Species', '9606', (247, 254))	('patient', 'Species', '9606', (195, 202))	('Q2W', 'Var', (210, 213))	('infusion', 'MPA', (171, 179))
59486	28291776	The most frequently reported AEs regardless of potential relationship to YS110 were asthenia (54.5%) and aggravation of prior conditions (30.3%).	('asthenia', 'Disease', 'MESH:D001247', (84, 92))	('asthenia', 'Disease', (84, 92))	('YS110', 'Var', (73, 78))	('AEs', 'Chemical', 'MESH:C045560', (29, 32))	('asthenia', 'Phenotype', 'HP:0025406', (84, 92))	('YS110', 'Chemical', '-', (73, 78))
59492	28291776	Except for the two DLTs, all other SAEs, most commonly general physical health deterioration, were considered to be unrelated to YS110 but rather related to consequences of disease progression as assessed by the investigator, including the six patient deaths during the study.	('related', 'Reg', (146, 153))	('YS110', 'Chemical', '-', (129, 134))	('physical health deterioration', 'Phenotype', 'HP:0001268', (63, 92))	('patient', 'Species', '9606', (244, 251))	('SAEs', 'Chemical', '-', (35, 39))	('YS110', 'Var', (129, 134))
59513	28291776	Indeed, in the first 12 patients tested using the M-A261 mAb (BD Pharmingen), we observed a dramatic decrease of CD26+ cells consequently to YS110 administration, suggesting the lack of detection of the CD26 epitope due to YS110 binding.	('CD26+ cells consequently', 'MPA', (113, 137))	('A261', 'CellLine', 'CVCL:2490', (52, 56))	('YS110', 'Chemical', '-', (223, 228))	('patients', 'Species', '9606', (24, 32))	('binding', 'molecular_function', 'GO:0005488', ('229', '236'))	('YS110', 'Chemical', '-', (141, 146))	('M-A261', 'Var', (50, 56))	('decrease', 'NegReg', (101, 109))
59517	28291776	(n=33) absolute values (x 106 per ml) of lymphocytes populations were 0.94 (65.7%)+-0.64 for CD3+CD4+, 0.33 (34.5%)+-0.26 for CD3+CD8+ T cells and 0.17 (8.2%)+-0.17 for CD3-CD16+/-CD56+ NK cells.	('CD16', 'Gene', '2214', (173, 177))	('CD8', 'Gene', (130, 133))	('0.33', 'Var', (103, 107))	('CD4', 'Gene', (97, 100))	('CD56', 'Gene', '4684', (180, 184))	('CD8', 'Gene', '925', (130, 133))	('CD16', 'Gene', (173, 177))	('CD4', 'Gene', '920', (97, 100))	('CD56', 'Gene', (180, 184))
59518	28291776	The mean percentage of CD26+ subpopulations in the T-CD4, T-CD8 and NK cells was 24.7%, 8.2% and 5.2%, respectively with a significant inter-patient variability.	('CD8', 'Gene', '925', (60, 63))	('patient', 'Species', '9606', (141, 148))	('CD26+', 'Var', (23, 28))	('CD4', 'Gene', (53, 56))	('CD4', 'Gene', '920', (53, 56))	('CD8', 'Gene', (60, 63))
59519	28291776	After YS110 infusions, the levels of the various PBL subpopulations decreased at day 1 and 2 (i.e., 24-48 h following YS110 infusions), with a subsequent recovery at day 15 and 29 pre-infusion samples in most patients (Supplementary Table S3).	('decreased', 'NegReg', (68, 77))	('YS110', 'Chemical', '-', (6, 11))	('YS110', 'Var', (118, 123))	('patients', 'Species', '9606', (209, 217))	('YS110 infusions', 'Var', (6, 21))	('pre', 'molecular_function', 'GO:0003904', ('180', '183'))	('infusions', 'Var', (12, 21))	('levels', 'MPA', (27, 33))	('YS110', 'Chemical', '-', (118, 123))
59523	28291776	Different kinetics of serum IL-6 and TNF-alpha production were observed in patients receiving 2 mg kg-1 of YS110, whereas low or undetectable levels were observed in patients receiving 4.0 and 6.0 mg kg-1 of YS110, likely due to the administration of systemic steroid prophylaxis.	('YS110', 'Chemical', '-', (208, 213))	('TNF-alpha production', 'biological_process', 'GO:0032640', ('37', '57'))	('IL-6', 'Gene', '3569', (28, 32))	('YS110', 'Var', (107, 112))	('IL-6', 'molecular_function', 'GO:0005138', ('28', '32'))	('patients', 'Species', '9606', (75, 83))	('TNF-alpha', 'Gene', '7124', (37, 46))	('TNF-alpha', 'Gene', (37, 46))	('YS110', 'Chemical', '-', (107, 112))	('IL-6', 'Gene', (28, 32))	('steroid', 'Chemical', 'MESH:D013256', (260, 267))	('patients', 'Species', '9606', (166, 174))
59527	28291776	This FIH study demonstrates that YS110 therapy exhibits a favourable safety profile and results in encouraging disease stabilisation in heavily pretreated CD26-positive MPM or RCC patients who had previously progressed on conventional standard therapies.	('YS110', 'Chemical', '-', (33, 38))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('YS110 therapy', 'Var', (33, 46))	('CD26-positive', 'Gene', (155, 168))	('patients', 'Species', '9606', (180, 188))	('MPM', 'Disease', (169, 172))	('disease stabilisation', 'CPA', (111, 132))
59535	28291776	These data indicate that YS110 administration resulted in a decrease in levels of peripheral lymphocytes including the CD26-positive lymphocyte subset soon after drug administration, and it is probable that YS110-mediated suppression of peripheral lymphocyte levels, including the CD26-positive subset, resolved by as early as Day 8.	('decrease', 'NegReg', (60, 68))	('YS110', 'Var', (25, 30))	('YS110', 'Chemical', '-', (207, 212))	('YS110-mediated', 'Var', (207, 221))	('peripheral lymphocyte levels', 'MPA', (237, 265))	('YS110', 'Chemical', '-', (25, 30))	('suppression', 'NegReg', (222, 233))
59537	28291776	Therefore, it is conceivable that YS110, but not premedication steroid, was responsible for the temporary effect on CD26-positive lymphocyte counts.	('YS110', 'Chemical', '-', (34, 39))	('CD26-positive', 'MPA', (116, 129))	('steroid', 'Chemical', 'MESH:D013256', (63, 70))	('YS110', 'Var', (34, 39))
59538	28291776	CD26 is also present in serum and other body fluids in a truncated form as sCD26/DPPIV, and our data also indicated that DPPIV enzyme activity decreased with increasing doses of YS110 (Figure 2B).	('decreased', 'NegReg', (143, 152))	('YS110', 'Chemical', '-', (178, 183))	('enzyme activity', 'molecular_function', 'GO:0003824', ('127', '142'))	('activity', 'MPA', (134, 142))	('YS110', 'Var', (178, 183))
59549	28291776	In view of these recent findings, data from our current trial showing that serum DPPIV activity was decreased following treatment with YS110 in a dose-dependent manner (Figure 2B).	('YS110', 'Chemical', '-', (135, 140))	('decreased', 'NegReg', (100, 109))	('serum DPPIV activity', 'MPA', (75, 95))	('YS110', 'Var', (135, 140))
59552	28291776	Preclinical models showed that antibody-mediated blocking of LAG3 as potential anti-cancer therapy led to enhanced activation of antigen-specific T cells at the tumour sites and disruption of tumour growth.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('enhanced activation', 'PosReg', (106, 125))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('disruption of tumour growth', 'Disease', (178, 205))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('LAG3', 'Gene', (61, 65))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('disruption of tumour growth', 'Disease', 'MESH:D019958', (178, 205))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (161, 167))	('tumour', 'Disease', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('blocking', 'Var', (49, 57))	('antigen-specific', 'Protein', (129, 145))
59555	28291776	In this scenario, CD26 blockade by YS110 may potentially function as an immune checkpoint blockade therapy, which can mediate anti-tumour activity in CD26-negative as well as CD26-positive cancers.	('tumour', 'Disease', (131, 137))	('YS110', 'Var', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('CD26', 'Protein', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('blockade', 'NegReg', (23, 31))	('YS110', 'Chemical', '-', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (189, 196))
59558	28291776	These preclinical results suggest that YS110 can function synergistically with other antineoplastic agents such as selected chemotherapeutic drugs to inhibit tumour growth.	('YS110', 'Chemical', '-', (39, 44))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('inhibit', 'NegReg', (150, 157))	('YS110', 'Var', (39, 44))	('tumour', 'Disease', (158, 164))
59561	28291776	Given the potential role of CD26 surface expression in cancer biology, YS110 therapy may also influence tumour growth through its potential effect on the cancer stem cells of selected tumours.	('effect', 'Reg', (140, 146))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('influence', 'Reg', (94, 103))	('cancer', 'Disease', (55, 61))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('YS110 therapy', 'Var', (71, 84))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))	('YS110', 'Chemical', '-', (71, 76))	('cancer', 'Disease', (154, 160))	('CD26', 'Protein', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
59562	28291776	In conclusion, our FIH study showed that YS110 therapy is generally well tolerated up to 6 mg kg-1 Q1W, which has been defined as the RP2D and results in encouraging disease stabilisation in a number of patients with advanced/refractory CD26-expressing cancers.	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('YS110', 'Var', (41, 46))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('patients', 'Species', '9606', (203, 211))	('YS110', 'Chemical', '-', (41, 46))	('disease stabilisation', 'CPA', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
59568	23936085	Furthermore, we demonstrate that known and novel small molecule inhibitors of the autotaxin signaling pathway dramatically blunt migratory and invasive behaviors of aggressive mesotheliomas.	('invasive behaviors of aggressive mesotheliomas', 'Disease', 'MESH:D001523', (143, 189))	('rat', 'Species', '10116', (132, 135))	('autotaxin', 'Gene', (82, 91))	('rat', 'Species', '10116', (23, 26))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('autotaxin', 'Gene', '5168', (82, 91))	('blunt', 'NegReg', (123, 128))	('invasive behaviors of aggressive mesotheliomas', 'Disease', (143, 189))	('small molecule', 'Var', (49, 63))
59604	23936085	As seen in Figure 6, this motile mesothelium was highly sensitive to inhibition of autotaxin signaling by S32826 as invasion dropped precipitously with inhibitor application (Figure 6 I, U).	('dropped', 'NegReg', (125, 132))	('autotaxin', 'Gene', '5168', (83, 92))	('S32826', 'Var', (106, 112))	('invasion', 'CPA', (116, 124))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('S32826', 'Chemical', 'MESH:C533861', (106, 112))	('autotaxin', 'Gene', (83, 92))
59605	23936085	Importantly, when cells were treated with the Lpar 1 inhibitors, 2440 or 8437, the same pattern of reduction in cell invasion was observed (Figure 6 M, Q, and U).	('cell invasion', 'CPA', (112, 125))	('Lpar 1', 'Gene', (46, 52))	('Lpar 1', 'Gene', '1902', (46, 52))	('reduction', 'NegReg', (99, 108))	('8437', 'Var', (73, 77))
59607	23936085	Linear migration was also sensitive to autotaxin inhibition as a dramatic decrease in motility was observed with S32826 (90% decrease in displacement; Figure 7A, Figure S1), with these cells moving at a rate seen with untreated parietal cells (Figure 5B).	('decrease', 'NegReg', (74, 82))	('autotaxin', 'Gene', (39, 48))	('S32826', 'Var', (113, 119))	('autotaxin', 'Gene', '5168', (39, 48))	('motility', 'CPA', (86, 94))	('S32826', 'Chemical', 'MESH:C533861', (113, 119))	('Linear migration', 'CPA', (0, 16))	('decrease', 'NegReg', (125, 133))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (203, 206))	('displacement', 'MPA', (137, 149))
59612	23936085	Taken together, these data demonstrate that autotaxin signaling is a key regulator of mesothelial phenotypes and that manipulation of this pathway can alter these key mesothelial behaviors through chemical genetic intervention.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('manipulation', 'Var', (118, 130))	('autotaxin', 'Gene', (44, 53))	('rat', 'Species', '10116', (34, 37))	('alter', 'Reg', (151, 156))	('autotaxin', 'Gene', '5168', (44, 53))
59618	23936085	Similarly, inhibition of Lpar 1 activity also significantly reduced mesothelioma cell migration (Figure 7 E-H; Figure S1).	('mesothelioma', 'Disease', (68, 80))	('cell migration', 'biological_process', 'GO:0016477', ('81', '95'))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('activity', 'MPA', (32, 40))	('rat', 'Species', '10116', (89, 92))	('reduced', 'NegReg', (60, 67))	('inhibition', 'Var', (11, 21))	('Lpar 1', 'Gene', '1902', (25, 31))	('Lpar 1', 'Gene', (25, 31))
59620	23936085	Importantly, this aggressive behavior in both mesotheliomas was also responsive to inhibition of autotaxin and Lpar 1 activity as S32826, 2440 and 8437 were highly effective reducing cellular invasion (Figure 6 K, L, O, P, S, T, U).	('S32826', 'Var', (130, 136))	('Lpar 1', 'Gene', (111, 117))	('aggressive behavior', 'biological_process', 'GO:0002118', ('18', '37'))	('reducing', 'NegReg', (174, 182))	('autotaxin', 'Gene', '5168', (97, 106))	('S32826', 'Chemical', 'MESH:C533861', (130, 136))	('8437', 'Var', (147, 151))	('mesotheliomas', 'Disease', 'MESH:D008654', (46, 59))	('mesotheliomas', 'Disease', (46, 59))	('Lpar 1', 'Gene', '1902', (111, 117))	('aggressive behavior', 'Phenotype', 'HP:0000718', (18, 37))	('autotaxin', 'Gene', (97, 106))	('cellular invasion', 'CPA', (183, 200))
59637	23936085	Our newly discovered Lpar1 inhibitors intervene at a novel point in the autotaxin signaling pathway presenting an opportunity for "combinatorial" intervention in combating this aggressive cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Lpar1', 'Gene', (21, 26))	('signaling pathway', 'biological_process', 'GO:0007165', ('82', '99'))	('intervene', 'Reg', (38, 47))	('autotaxin', 'Gene', '5168', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('inhibitors', 'Var', (27, 37))	('cancer', 'Disease', (188, 194))	('autotaxin', 'Gene', (72, 81))	('Lpar1', 'Gene', '1902', (21, 26))
59669	23626745	Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response.	('immune response', 'biological_process', 'GO:0006955', ('190', '205'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('blockade', 'Var', (133, 141))	('murine', 'Species', '10090', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (184, 189))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CTLA-4', 'Gene', (126, 132))	('tumor', 'Disease', (47, 52))
59673	23626745	These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients.	('patients', 'Species', '9606', (176, 184))	('cancer', 'Disease', (169, 175))	('anti-CTLA-4', 'Gene', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('anti-CTLA-4', 'Var', (67, 78))
59675	23626745	For example, treatment with anthracyclines and oxaliplatin results in immunogenic tumor cell death and platinum-based chemotherapeutics downregulate the inhibitory STAT6/PD-L2 pathway and sensitize tumor cells for T cell-mediated cytotoxicity.	('cell death', 'biological_process', 'GO:0008219', ('88', '98'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (47, 58))	('tumor', 'Disease', (82, 87))	('PD-L2', 'Gene', '58205', (170, 175))	('PD-L2', 'Gene', (170, 175))	('STAT6', 'Gene', '20852', (164, 169))	('oxaliplatin', 'Var', (47, 58))	('anthracyclines', 'Var', (28, 42))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('anthracyclines', 'Chemical', 'MESH:D018943', (28, 42))	('cytotoxicity', 'Disease', (230, 242))	('STAT6', 'Gene', (164, 169))	('cytotoxicity', 'Disease', 'MESH:D064420', (230, 242))	('immunogenic tumor cell death', 'Disease', (70, 98))	('platinum', 'Chemical', 'MESH:D010984', (103, 111))	('immunogenic tumor cell death', 'Disease', 'MESH:D003643', (70, 98))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (198, 203))	('T cell-mediated cytotoxicity', 'biological_process', 'GO:0001913', ('214', '242'))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('downregulate', 'NegReg', (136, 148))	('sensitize', 'Reg', (188, 197))
59685	23626745	In this study we show for the first time that CTLA-4 blockade and immunopotentiating chemotherapy in a therapeutic dose have a synergistic effect, resulting in the induction of a potent anti-tumor immune response and long-term protective immunity.	('immune response', 'biological_process', 'GO:0006955', ('197', '212'))	('blockade', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('protective immunity', 'CPA', (227, 246))	('CTLA-4', 'Gene', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))
59707	23626745	For depletion experiments, the following antibodies were used: anti-NK1.1 (clone PK136), anti-CD4 (clone GK1.5) and anti-CD8 (clone YTS169.4), all from the Monoclonal Antibody Facility, WAIMR (Perth, Australia).	('NK1.1', 'Gene', '17059', (68, 73))	('CD4', 'Gene', (94, 97))	('CD4', 'Gene', '12504', (94, 97))	('NK1.1', 'Gene', (68, 73))	('anti-CD8', 'Var', (116, 124))
59715	23626745	Lymph nodes from both flanks were harvested and pooled and stained for CD4, CD8, CD44 and CD62L, according to the same protocol as the flow cytometry analysis of peripheral blood (see above and Figure S5).	('CD44', 'Gene', (81, 85))	('CD62L', 'Gene', (90, 95))	('CD8', 'Var', (76, 79))	('CD4', 'Gene', (81, 84))	('CD44', 'Gene', '12505', (81, 85))	('CD62L', 'Gene', '20343', (90, 95))	('CD4', 'Gene', (71, 74))	('CD4', 'Gene', '12504', (71, 74))	('CD4', 'Gene', '12504', (81, 84))
59734	23626745	Interestingly, the relative loss of proliferating tumor-infiltrating CD8+ T cells in gemcitabine-treated mice was partly rescued by anti-CTLA-4 (Figure 2E).	('gemcitabine', 'Chemical', 'MESH:C056507', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('anti-CTLA-4', 'Var', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Disease', (50, 55))	('loss', 'NegReg', (28, 32))
59736	23626745	The percentage of tumor-infiltrating Foxp3+CD4+ T cells was significantly decreased in tumors treated with gemcitabine, anti-CTLA-4 or the combination treatment (Figure 2F), a finding consistent with previously published data.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('anti-CTLA-4', 'Var', (120, 131))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Foxp3', 'Gene', (37, 42))	('Foxp3', 'Gene', '20371', (37, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('decreased', 'NegReg', (74, 83))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('CD4', 'Gene', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('CD4', 'Gene', '12504', (43, 46))
59739	23626745	Taken together, these data demonstrate that anti-CTLA-4 and chemotherapy synergize in the induction of a potent anti-tumor immune response, with an important role for both CD4+ and CD8+ T cells for optimal therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('anti-CTLA-4', 'Var', (44, 55))	('CD4', 'Gene', (172, 175))	('CD4', 'Gene', '12504', (172, 175))	('tumor', 'Disease', (117, 122))	('immune response', 'biological_process', 'GO:0006955', ('123', '138'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
59766	23626745	Cisplatin has been shown to induce a non-immunogenic form of cell death, and although it does downregulate the inhibitory molecule PD-L2, the tumor model we use expresses only very low levels of PD-L2 (data not shown).	('downregulate', 'NegReg', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('PD-L2', 'Gene', (131, 136))	('cell death', 'CPA', (61, 71))	('tumor', 'Disease', (142, 147))	('non-immunogenic', 'CPA', (37, 52))	('cell death', 'biological_process', 'GO:0008219', ('61', '71'))	('PD-L2', 'Gene', '58205', (195, 200))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin', 'Var', (0, 9))	('PD-L2', 'Gene', (195, 200))	('PD-L2', 'Gene', '58205', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
59770	23626745	These findings accord with studies in a murine OVA-expressing Listeria monocytogenes model, in which CD8+ T cell memory was enhanced by a single dose of anti-CTLA-4.	('CD8+ T cell memory', 'CPA', (101, 119))	('Listeria monocytogenes', 'Species', '1639', (62, 84))	('murine', 'Species', '10090', (40, 46))	('enhanced', 'PosReg', (124, 132))	('anti-CTLA-4', 'Var', (153, 164))	('memory', 'biological_process', 'GO:0007613', ('113', '119'))
59773	23626745	In conclusion, our results demonstrate that anti-CTLA-4 therapy and cytotoxic chemotherapy can have a clear synergistic effect in the treatment of cancer.	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('anti-CTLA-4', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))
59818	18486741	Detailed dose modifications for each regimen were listed in the protocol, but generally, patients only received chemotherapy if they had an adequate blood count (total white blood cell count >3000 cells per muL, neutrophils >1500 cells per muL, and platelets >100 000 cells per muL) and if there was no clinical evidence of infection.	('>3000', 'Var', (191, 196))	('neutrophils', 'CPA', (212, 223))	('infection', 'Disease', (324, 333))	('patients', 'Species', '9606', (89, 97))	('infection', 'Disease', 'MESH:D007239', (324, 333))	('men', 'Species', '9606', (41, 44))	('received', 'Reg', (103, 111))
59930	33669318	The corresponding figures are 14.0% (95% CI: 12.5, 15.7) and 16.3% (95% CI: 16.2, 16.3) for PM2.5 exposure, and 3.9% (95% CI: 3.5, 4.2) and 1.6% (95% CI: 1.4, 1.7) for radon exposure.	('exp', 'Gene', (98, 101))	('exp', 'Gene', (174, 177))	('radon', 'Chemical', 'MESH:D011886', (168, 173))	('radon', 'MPA', (168, 173))	('exp', 'Gene', '4154', (174, 177))	('exp', 'Gene', '4154', (98, 101))	('PM2.5', 'Var', (92, 97))
59937	33669318	The most important occupational lung carcinogens are reported to be asbestos, silica, radon, heavy metals, and polycyclic aromatic hydrocarbons.	('occupational lung carcinogens', 'Disease', 'MESH:D009784', (19, 48))	('metal', 'Chemical', 'MESH:D008670', (99, 104))	('radon', 'Chemical', 'MESH:D011886', (86, 91))	('polycyclic', 'Var', (111, 121))	('silica', 'Chemical', 'MESH:D012822', (78, 84))	('asbestos', 'Chemical', 'MESH:D001194', (68, 76))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (111, 143))	('occupational lung carcinogens', 'Disease', (19, 48))
59948	33669318	The International Agency for Research on Cancer (IARC) classified Radon-222 and its decay products as a known cause of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cancer', 'Disease', (41, 47))	('Radon-222', 'Var', (66, 75))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('human', 'Species', '9606', (119, 124))
59958	33669318	In particular, exposure to PM2.5 is associated with an increase in the risk of lung cancer morbidity and mortality, while the association with PM10 has been analyzed less frequently and the results are not as solid as for PM2.5.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('mortality', 'Disease', 'MESH:D003643', (105, 114))	('PM2.5', 'Var', (27, 32))	('PM10', 'Chemical', '-', (143, 147))	('exp', 'Gene', '4154', (15, 18))	('lung cancer', 'Disease', (79, 90))	('mortality', 'Disease', (105, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('exp', 'Gene', (15, 18))
59973	33669318	As for LC mortality, we selected data with ICD-10 codes C33-C34 by municipality, year, gender, and age classes (0-34, 35-64, 65-74, 75-84, and 85+).	('mortality', 'Disease', 'MESH:D003643', (10, 19))	('C33-C34', 'Var', (56, 63))	('mortality', 'Disease', (10, 19))	('0-34', 'Var', (112, 116))	('LC', 'Phenotype', 'HP:0100526', (7, 9))
59986	33669318	To limit the impact of such heterogeneity, we categorized radon values in five different classes (0-50; 51-100; 101-150; 151-300; 300 + Bq/m3).	('radon', 'Chemical', 'MESH:D011886', (58, 63))	('151-300; 300 + Bq/m3', 'Var', (121, 141))	('101-150', 'Var', (112, 119))
60013	33669318	As far as environmental covariates are entailed, LC crude mortality rates are slightly increasing with PM2.5 and present an almost flat trend with increasing of radon concentrations, urbanization, and deprivation levels; nonetheless, we have to consider that these are just marginal associations that do not take into account the joint impact of multiple potential risk factors.	('radon', 'MPA', (161, 166))	('PM2.5', 'Var', (103, 108))	('LC', 'Phenotype', 'HP:0100526', (49, 51))	('mortality', 'Disease', 'MESH:D003643', (58, 67))	('radon', 'Chemical', 'MESH:D011886', (161, 166))	('increasing', 'PosReg', (87, 97))	('mortality', 'Disease', (58, 67))	('men', 'Species', '9606', (17, 20))
60039	33669318	COPD is the most common smoking-related disease and the presence of COPD increases the incidence of lung cancer.	('COPD', 'Disease', 'MESH:D029424', (68, 72))	('COPD', 'Disease', (68, 72))	('presence', 'Var', (56, 64))	('increases', 'PosReg', (73, 82))	('COPD', 'Phenotype', 'HP:0006510', (0, 4))	('COPD', 'Disease', 'MESH:D029424', (0, 4))	('COPD', 'Disease', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('COPD', 'Phenotype', 'HP:0006510', (68, 72))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
60045	33669318	In this study, the compensated cases of occupational respiratory diseases (ICD10: J40-J47 and J60-J67) have been included in the model as a measure of occupational exposure to lung carcinogen agents at municipal level.	('occupational respiratory diseases', 'Disease', 'MESH:D012140', (40, 73))	('exp', 'Gene', (164, 167))	('J60-J67', 'Var', (94, 101))	('respiratory disease', 'Phenotype', 'HP:0011947', (53, 72))	('J40-J47', 'Var', (82, 89))	('occupational respiratory diseases', 'Disease', (40, 73))	('exp', 'Gene', '4154', (164, 167))	('J40-J47', 'CellLine', 'CVCL:M891', (82, 89))
60144	31020037	moDCs have been shown to promote T cell differentiation and CD8+ T cell activation.	('moDCs', 'Var', (0, 5))	('CD8', 'Gene', '925', (60, 63))	('T cell differentiation', 'biological_process', 'GO:0030217', ('33', '55'))	('T cell differentiation', 'CPA', (33, 55))	('promote', 'PosReg', (25, 32))	('T cell activation', 'biological_process', 'GO:0042110', ('65', '82'))	('CD8', 'Gene', (60, 63))
60147	31020037	In second-generation DC therapy, moDCs were additionally matured after loading these immature moDCs, using maturation cocktails, including IL-6, TNF, IL-1beta, PGE2, and polyinosinic:polycytidylic acid (poly(I:C)).	('IL-1', 'molecular_function', 'GO:0005149', ('150', '154'))	('TNF', 'Gene', (145, 148))	('polyinosinic:polycytidylic acid', 'Chemical', 'MESH:D011070', (170, 201))	('IL-6', 'Gene', (139, 143))	('polyinosinic', 'Var', (170, 182))	('IL-6', 'Gene', '3569', (139, 143))	('IL-1beta', 'Gene', (150, 158))	('TNF', 'Gene', '7124', (145, 148))	('IL-1beta', 'Gene', '3553', (150, 158))	('PGE2', 'Chemical', 'MESH:D015232', (160, 164))	('IL-6', 'molecular_function', 'GO:0005138', ('139', '143'))
60152	31020037	cDC1s are superior in cross-presenting antigens and, thereby, inducing CD8+ T cell activation.	('CD8', 'Gene', '925', (71, 74))	('inducing', 'Reg', (62, 70))	('cDC1s', 'Var', (0, 5))	('cross-presenting antigens', 'MPA', (22, 47))	('T cell activation', 'biological_process', 'GO:0042110', ('76', '93'))	('CD8', 'Gene', (71, 74))
60166	31020037	Additionally, in pancreatic cancer patients treated with Wilms tumor protein 1 (WT1) I-II peptide-loaded DC therapy, positive DTH skin tests correlated with longer progression-free survival (PFS) and OS than negative DTH skin tests.	('Wilms tumor', 'Phenotype', 'HP:0002667', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('DTH', 'Gene', (126, 129))	('pancreatic cancer', 'Disease', (17, 34))	('progression-free survival', 'CPA', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Wilms tumor', 'Disease', (57, 68))	('Wilms tumor', 'Disease', 'MESH:D009396', (57, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('longer', 'PosReg', (157, 163))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('DTH', 'Phenotype', 'HP:0002972', (126, 129))	('positive', 'Var', (117, 125))	('DTH', 'Phenotype', 'HP:0002972', (217, 220))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('WT1', 'Gene', '7490', (80, 83))	('patients', 'Species', '9606', (35, 43))	('WT1', 'Gene', (80, 83))
60169	31020037	Blocking these inhibitory molecules has been shown to restore tumor-specific T cell activity.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Blocking', 'Var', (0, 8))	('tumor', 'Disease', (62, 67))	('restore', 'PosReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
60171	31020037	CTLA-4 blockage inhibits T cell activation in the lymph node, whereas blocking the PD-1 and PD-L1 axis mainly inhibits the effector function of activated T cells in the TME.	('blockage', 'Var', (7, 15))	('CTLA-4', 'Gene', (0, 6))	('T cell activation', 'biological_process', 'GO:0042110', ('25', '42'))	('inhibits', 'NegReg', (110, 118))	('CTLA-4', 'Gene', '1493', (0, 6))	('effector', 'MPA', (123, 131))	('inhibits', 'NegReg', (16, 24))	('T cell activation in the lymph node', 'CPA', (25, 60))
60173	31020037	The efficacy of these CIs, especially PD-(L)1 mAb, often depends on and correlates with PD-L1 expression in the TME, mutational burden, and the number of tumor-infiltrating lymphocytes (TILs).	('PD-L1', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutational burden', 'Var', (117, 134))	('PD-(L)1', 'Gene', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PD-(L)1', 'Gene', '29126', (38, 45))	('CI', 'Chemical', '-', (22, 24))	('tumor', 'Disease', (154, 159))
60179	31020037	Expression of PD-1 and its ligands likely limits the induction of tumor-specific immune responses, as high PD-L1 expression on DCs suppresses CD4+ and CD8+ T cell proliferation and promotes Treg proliferation in various diseases, including cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Treg', 'Chemical', '-', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (66, 71))	('high', 'Var', (102, 106))	('CD8', 'Gene', (151, 154))	('CD4', 'Gene', (142, 145))	('CD8', 'Gene', '925', (151, 154))	('CD4', 'Gene', '920', (142, 145))	('promotes', 'PosReg', (181, 189))	('T cell proliferation', 'biological_process', 'GO:0042098', ('156', '176'))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('suppresses', 'NegReg', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PD-L1', 'Gene', (107, 112))	('cancer', 'Disease', (240, 246))	('Treg proliferation', 'CPA', (190, 208))
60184	31020037	In addition, PD-1 blockage on DCs, administered in a breast tumor-bearing mouse model, that were subsequently systemically treated with anti-PD-1 mAb reduced tumor growth and increased survival compared to untreated mice.	('tumor', 'Disease', (158, 163))	('mice', 'Species', '10090', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('breast tumor', 'Disease', 'MESH:D001943', (53, 65))	('breast tumor', 'Phenotype', 'HP:0100013', (53, 65))	('survival', 'CPA', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast tumor', 'Disease', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('reduced', 'NegReg', (150, 157))	('mouse', 'Species', '10090', (74, 79))	('increased', 'PosReg', (175, 184))	('tumor', 'Disease', (60, 65))	('anti-PD-1', 'Var', (136, 145))
60219	31020037	In a phase I clinical trial, melanoma patients were treated with six biweekly injections of DCs electroporated with mRNA encoding p53, survivin, and hTER and concurrent low-dose cyclophosphamide (2 x 50 mg/day biweekly).	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('hTER', 'Gene', (149, 153))	('melanoma', 'Disease', (29, 37))	('patients', 'Species', '9606', (38, 46))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('mRNA', 'Var', (116, 120))	('survivin', 'Gene', (135, 143))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (178, 194))	('p53', 'Gene', (130, 133))	('hTER', 'Gene', '9524', (149, 153))	('p53', 'Gene', '7157', (130, 133))
60262	31020037	This suggests systemic effects of radiotherapy that can be explained by the upregulation of radiation-induced double-stranded DNA in the cytosol, which serves as a DAMP for the instigation of ICD.	('upregulation', 'PosReg', (76, 88))	('cytosol', 'cellular_component', 'GO:0005829', ('137', '144'))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('ICD', 'Disease', 'OMIM:252500', (192, 195))	('double-stranded', 'Var', (110, 125))	('ICD', 'Disease', (192, 195))
60278	31020037	CSF-1R blockade increased the efficacy of chemotherapy in pancreatic tumor-bearing mice.	('CSF-1', 'molecular_function', 'GO:0005011', ('0', '5'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('efficacy', 'CPA', (30, 38))	('pancreatic tumor', 'Disease', 'MESH:D010190', (58, 74))	('mice', 'Species', '10090', (83, 87))	('increased', 'PosReg', (16, 25))	('CSF-1R', 'Gene', (0, 6))	('blockade', 'Var', (7, 15))	('pancreatic tumor', 'Disease', (58, 74))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (58, 74))
60282	31020037	These studies indicate that TAM depletion can improve the immunosuppressive character of the TME and, thereby, act synergistically when combined with DC therapy.	('TAM', 'Gene', (28, 31))	('depletion', 'Var', (32, 41))	('immunosuppressive character', 'MPA', (58, 85))	('TAM', 'Gene', '8205', (28, 31))	('improve', 'PosReg', (46, 53))
60291	31020037	Apart from improving DC therapy itself, influencing the immunosuppressive character of the TME by targeting immune cells, such as Tregs, MDSCs, or TAMs, with already registered therapies could improve response rates upon DC therapy.	('TAMs', 'Chemical', '-', (147, 151))	('influencing', 'Var', (40, 51))	('Tregs', 'Chemical', '-', (130, 135))	('response rates', 'MPA', (201, 215))	('improve', 'PosReg', (193, 200))
60319	30555628	Additionally, signals for phospho-FAK modified at the major autophosphorylation site Tyr397 were stronger in CR-overexpressing cells.	('FAK', 'molecular_function', 'GO:0004717', ('34', '37'))	('phospho-FAK', 'MPA', (26, 37))	('Tyr397', 'Var', (85, 91))	('stronger', 'PosReg', (97, 105))	('Tyr397', 'Chemical', '-', (85, 91))
60322	30555628	Analyses of the ratios p-FAK (Tyr397)/FAK revealed a significant increase (1.314+-0.001 (normalized to wt); p <= 0.0001) in MSTO-CR cells compared to wt cells.	('increase', 'PosReg', (65, 73))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('FAK', 'molecular_function', 'GO:0004717', ('38', '41'))	('MSTO-CR cells', 'CPA', (124, 137))	('Tyr397', 'Chemical', '-', (30, 36))	('p-FAK', 'Var', (23, 28))
60325	30555628	However, in the latter two lines, signals for p-FAK (Tyr397) were strongly increased in the CR-overexpressing cells (Supplementary Figure 3A).	('FAK', 'molecular_function', 'GO:0004717', ('48', '51'))	('increased', 'PosReg', (75, 84))	('p-FAK (Tyr397', 'Var', (46, 59))	('Tyr397', 'Chemical', '-', (53, 59))
60343	30555628	Transcripts downregulated in SPC111-CR cells included CAV2 encoding the potent tumor suppressor caveolin-2, SPP1 (osteopontin) and cytokeratin 19 (KRT19), as well as DSP and F11R, genes implicated in the organization of desmosomes and tight junctions, respectively.	('downregulated', 'NegReg', (12, 25))	('caveolin-2', 'Gene', (96, 106))	('F11R', 'Var', (174, 178))	('SPP1', 'Gene', (108, 112))	('DSP', 'Gene', (166, 169))	('SPP1', 'Gene', '6696', (108, 112))	('SPP', 'molecular_function', 'GO:0042499', ('108', '111'))	('osteopontin', 'Gene', '6696', (114, 125))	('cytokeratin 19', 'Gene', (131, 145))	('F11R', 'SUBSTITUTION', 'None', (174, 178))	('caveolin-2', 'Gene', '858', (96, 106))	('tumor', 'Disease', (79, 84))	('osteopontin', 'Gene', (114, 125))	('KRT19', 'Gene', (147, 152))	('KRT19', 'Gene', '3880', (147, 152))	('CAV2', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cytokeratin 19', 'Gene', '3880', (131, 145))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('SPC', 'molecular_function', 'GO:0009004', ('29', '32'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('CAV2', 'Gene', '858', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
60354	30555628	Additionally, in mice injected with shCALB2-treated MSTO-211H cells, FAK staining of the tumor cells mostly confined to the thickened tunica serosa was weaker (Figure 5E, lower panel) than in mice injected with the shGFP-MSTO-211H cells (Figure 5E, upper panel).	('MSTO-211H', 'CellLine', 'CVCL:1430', (221, 230))	('weaker', 'NegReg', (152, 158))	('mice', 'Species', '10090', (17, 21))	('mice', 'Species', '10090', (192, 196))	('FAK', 'molecular_function', 'GO:0004717', ('69', '72'))	('MSTO-211H', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MSTO-211H', 'CellLine', 'CVCL:1430', (52, 61))	('tumor', 'Disease', (89, 94))
60357	30555628	Pathways dysregulated in MM are related to proliferation, differentiation, migration and invasion, survival, apoptosis, cell cycle control and metabolism, often accompanied by mutations in cell cycle control (CDKN2A) and tumor suppressor genes (BAP1 and NF2).	('mutations', 'Var', (176, 185))	('cell cycle control', 'biological_process', 'GO:1901987', ('120', '138'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('221', '237'))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('BAP1', 'Gene', '8314', (245, 249))	('CDKN2A', 'Gene', (209, 215))	('NF2', 'Gene', '4771', (254, 257))	('tumor suppressor', 'biological_process', 'GO:0051726', ('221', '237'))	('NF2', 'Gene', (254, 257))	('apoptosis', 'CPA', (109, 118))	('CDKN2A', 'Gene', '1029', (209, 215))	('BAP1', 'Gene', (245, 249))	('cell cycle control', 'biological_process', 'GO:1901987', ('189', '207'))	('tumor', 'Disease', (221, 226))	('invasion', 'CPA', (89, 97))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('migration', 'CPA', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('accompanied by', 'Reg', (161, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))
60363	30555628	In human MM cells, NRF-1 and E2F2 act as specific trans-activating factors binding to the CALB2 promoter (-161/+80bp).	('E2F2', 'Gene', (29, 33))	('human', 'Species', '9606', (3, 8))	('NRF-1', 'Gene', (19, 24))	('NRF-1', 'Gene', '4899', (19, 24))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('E2F2', 'Gene', '1870', (29, 33))	('binding', 'Interaction', (75, 82))	('-161/+80bp', 'Var', (106, 116))
60369	30555628	Here we show that CR overexpression in MM cells increased total FAK levels and more importantly, FAK tyrosine phosphorylation at the major FAK auto-phosphorylation site Tyr397.	('increased', 'PosReg', (48, 57))	('FAK', 'molecular_function', 'GO:0004717', ('64', '67'))	('FAK levels', 'MPA', (64, 74))	('Tyr397', 'Var', (169, 175))	('tyrosine', 'Chemical', 'MESH:D014443', (101, 109))	('Tyr397', 'Chemical', '-', (169, 175))	('overexpression', 'PosReg', (21, 35))	('FAK', 'molecular_function', 'GO:0004717', ('139', '142'))	('tyrosine phosphorylation', 'MPA', (101, 125))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('FAK', 'molecular_function', 'GO:0004717', ('97', '100'))
60370	30555628	Levels of p-FAK (Tyr397) are considered as proxy measure for augmented FAK signaling.	('FAK signaling', 'MPA', (71, 84))	('p-FAK', 'Var', (10, 15))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('FAK', 'molecular_function', 'GO:0004717', ('12', '15'))	('augmented', 'PosReg', (61, 70))	('FAK', 'molecular_function', 'GO:0004717', ('71', '74'))	('Tyr397', 'Chemical', '-', (17, 23))
60372	30555628	Moreover, FAK expression and key activation phosphorylation sites Tyr397 and Tyr576 are often elevated in invasive human cancers.	('Tyr397', 'Var', (66, 72))	('cancers', 'Disease', (121, 128))	('Tyr576', 'Var', (77, 83))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('Tyr397', 'Chemical', '-', (66, 72))	('activation', 'PosReg', (33, 43))	('elevated', 'PosReg', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('FAK', 'molecular_function', 'GO:0004717', ('10', '13'))	('Tyr576', 'Chemical', '-', (77, 83))	('human', 'Species', '9606', (115, 120))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('FAK', 'Protein', (10, 13))
60375	30555628	Besides CR's function as a Ca2+ buffer, direct binding partners including the pore forming unit of the P/Q type Ca2+ channel and a mutant form of huntingtin have also been identified; for more details about CR's sensor functions, see.	('Ca2+', 'Chemical', 'MESH:D000069285', (27, 31))	('mutant', 'Var', (131, 137))	('huntingtin', 'Gene', (146, 156))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('huntingtin', 'Gene', '3064', (146, 156))	('Ca2+', 'Chemical', 'MESH:D000069285', (112, 116))	('pore', 'cellular_component', 'GO:0046930', ('78', '82'))
60383	30555628	The increased resistance of CR-overexpressing MM cells to VS-6063 observed in this study is thus assumed to be the result of CR-mediated up-regulation of FAK signaling.	('VS-6063', 'Var', (58, 65))	('resistance', 'MPA', (14, 24))	('VS-6063', 'Chemical', 'MESH:C584510', (58, 65))	('FAK signaling', 'MPA', (154, 167))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('up-regulation', 'PosReg', (137, 150))	('regulation', 'biological_process', 'GO:0065007', ('140', '150'))	('FAK', 'molecular_function', 'GO:0004717', ('154', '157'))
60420	30555628	3,000 cells/well were seeded in 96-well plates (TPP) and grown for 48 h. The FAK inhibitor Defactinib (VS-6063, PF-04554878, Selleckchem, Houston, USA) was solubilized in dimethyl sulfoxide (DMSO) and added in a concentration range from 2.5 to 10 muM.	('Defactinib', 'Gene', (91, 101))	('DMSO', 'Chemical', 'MESH:D004121', (191, 195))	('TPP', 'Chemical', 'MESH:C016136', (48, 51))	('muM', 'Gene', (247, 250))	('VS-6063', 'Var', (103, 110))	('PF-04554878', 'Chemical', 'MESH:C584510', (112, 123))	('TPP', 'molecular_function', 'GO:0004294', ('48', '51'))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (171, 189))	('Defactinib', 'Chemical', 'MESH:C584510', (91, 101))	('VS-6063', 'Chemical', 'MESH:C584510', (103, 110))	('FAK', 'molecular_function', 'GO:0004717', ('77', '80'))	('PF-04554878', 'Var', (112, 123))	('muM', 'Gene', '56925', (247, 250))
60461	28603777	More recently, total and especially hyper-acetylated variant of HMGB1, a prototypical damage-associated protein, and mesothelioma-specific variants of the ENOX2 (ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2) protein have also been proposed.	('HMGB1', 'Gene', (64, 69))	('HMGB1', 'Gene', '3146', (64, 69))	('variant', 'Var', (53, 60))	('mesothelioma', 'Disease', (117, 129))	('exchanger', 'molecular_function', 'GO:0015297', ('225', '234'))	('hyper-acetylated', 'PosReg', (36, 52))	('ecto-nicotinamide adenine dinucleotide oxidase disulfide-thiol exchanger 2', 'Gene', '10495', (162, 236))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('variants', 'Var', (139, 147))	('ENOX2', 'Gene', (155, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))	('ENOX2', 'Gene', '10495', (155, 160))
60469	28603777	Independent animal models have supported the notion that BAP1 is a tumor suppressor gene whose mutations predispose to MM, as well as that low doses of asbestos might be sufficient to trigger MM in presence of a genetic predisposition.	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BAP1', 'Gene', '8314', (57, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('predispose', 'Reg', (105, 115))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', (67, 72))	('BAP1', 'Gene', (57, 61))
60470	28603777	However, germline BAP1 mutations are relatively rare events even among MM patients, as they are present in about 1-5% of unselected MM cases, and up to 18-20% of MM cases after careful clinical selection.	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (74, 82))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (18, 22))
60473	28603777	In fact, in recent years loss of BAP1 protein has been reported in more than 50% of human MMs, and somatic alterations in the gene encoding this deubiquitinating enzyme are among the most common events in MM - followed by alterations in NF2 (encoding merlin) and in CDKN2A (encoding p16INK4A and p14ARF).	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('145', '168'))	('CDKN2A', 'Gene', (266, 272))	('merlin', 'Gene', (251, 257))	('NF2', 'Gene', '4771', (237, 240))	('BAP1', 'Gene', (33, 37))	('NF2', 'Gene', (237, 240))	('p14ARF', 'Gene', '1029', (296, 302))	('alterations', 'Var', (107, 118))	('CDKN2A', 'Gene', '1029', (266, 272))	('loss', 'NegReg', (25, 29))	('merlin', 'Gene', '4771', (251, 257))	('protein', 'Protein', (38, 45))	('p14ARF', 'Gene', (296, 302))	('human', 'Species', '9606', (84, 89))	('MM -', 'Disease', (205, 209))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('p16INK4A', 'Gene', (283, 291))	('BAP1', 'Gene', '8314', (33, 37))	('p16INK4A', 'Gene', '1029', (283, 291))	('alterations', 'Var', (222, 233))
60475	28603777	These studies and others have collectively shed light on the most frequently altered pathways in MM, paving the way to potential targeted therapies of epigenetic control via post-translational modification of histones, mTOR signaling, Hippo pathway, or the p53 pathway (Figure 1).	('epigenetic', 'Var', (151, 161))	('Hippo pathway', 'Pathway', (235, 248))	('mTOR', 'Gene', (219, 223))	('p53', 'Gene', '7157', (257, 260))	('mTOR', 'Gene', '2475', (219, 223))	('histones', 'Protein', (209, 217))	('post-translational modification', 'biological_process', 'GO:0043687', ('174', '205'))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('p53', 'Gene', (257, 260))	('post-translational modification', 'Var', (174, 205))
60476	28603777	Notably, most of the genetic alterations found in MM are loss of function of tumor suppressor genes, rather than activating events of proto-oncogenes.	('loss of function', 'NegReg', (57, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('genetic alterations', 'Var', (21, 40))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
60477	28603777	overexpression of HER2 in breast cancer or expression of mutant ALK in lung cancer, the products of these mutations cannot therefore be directly inhibited, and surrogate targets whose activity is increased and necessary to cell survival have to be identified (Figure 1).	('breast cancer', 'Disease', (26, 39))	('HER2', 'Gene', '2064', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('ALK', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutant', 'Var', (57, 63))	('ALK', 'Gene', '238', (64, 67))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('overexpression', 'Reg', (0, 14))	('lung cancer', 'Disease', (71, 82))	('HER2', 'Gene', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
60489	28603777	Over-stimulation of the Hippo pathway in merlin-negative cells might be counteracted via inhibition of the transcriptional co-activator Yes-associated protein (YAP), which is constitutively activated in cells mutated for NF2.	('Yes-associated protein', 'Gene', (136, 158))	('Yes-associated protein', 'Gene', '10413', (136, 158))	('merlin', 'Gene', (41, 47))	('YAP', 'Gene', '10413', (160, 163))	('NF2', 'Gene', (221, 224))	('YAP', 'Gene', (160, 163))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('Hippo pathway', 'Pathway', (24, 37))	('mutated', 'Var', (209, 216))	('merlin', 'Gene', '4771', (41, 47))	('NF2', 'Gene', '4771', (221, 224))
60490	28603777	A note of caution about the potential role of NF2 mutations in MM comes from the observation of Lo Iacono et al.	('mutations', 'Var', (50, 59))	('NF2', 'Gene', (46, 49))	('NF2', 'Gene', '4771', (46, 49))
60491	28603777	that although 50% of the MMs tested contained NF2 mutations, 97% had normal NF2 expression by immunostaining.	('mutations', 'Var', (50, 59))	('NF2', 'Gene', (76, 79))	('NF2', 'Gene', (46, 49))	('expression', 'MPA', (80, 90))	('NF2', 'Gene', '4771', (76, 79))	('NF2', 'Gene', '4771', (46, 49))
60492	28603777	It is still unclear what percentage of the detected mutations is therefore of minor biological significance and what percentage represents mutations that might deregulate NF2 without affecting protein expression and stability.	('mutations', 'Var', (52, 61))	('NF2', 'Gene', '4771', (171, 174))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('NF2', 'Gene', (171, 174))
60493	28603777	Finally, mutations in the CDKN2A locus, found in about 27-50% of MMs result in alterations in the p53 and retinoblastoma pathways.	('alterations', 'Reg', (79, 90))	('retinoblastoma', 'Phenotype', 'HP:0009919', (106, 120))	('CDKN2A', 'Gene', (26, 32))	('mutations', 'Var', (9, 18))	('CDKN2A', 'Gene', '1029', (26, 32))	('p53', 'Gene', (98, 101))	('retinoblastoma', 'Disease', (106, 120))	('retinoblastoma', 'Disease', 'MESH:D012175', (106, 120))	('p53', 'Gene', '7157', (98, 101))
60495	28603777	Besides targeting intracellular molecules whose expression levels and activity are selectively increased in the presence of particular mutations, other potential therapeutic approaches in MM include1) targeting soluble factors that promote MM growth or their cellular receptors; and 2) targeting tumor-associated surface antigens and stimulating the immune system to autonomously eliminate MM cells.	('promote', 'PosReg', (232, 239))	('MM growth', 'CPA', (240, 249))	('soluble', 'cellular_component', 'GO:0005625', ('211', '218'))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('activity', 'MPA', (70, 78))	('mutations', 'Var', (135, 144))	('expression', 'MPA', (48, 58))	('tumor', 'Disease', (296, 301))	('targeting', 'Reg', (286, 295))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('intracellular', 'cellular_component', 'GO:0005622', ('18', '31'))
60497	28603777	Inhibition of the alarmin HMGB1 (High-mobility Group Box Protein 1) with salicylates or specific antagonists has also shown efficacy at a preclinical stage and is moving toward clinical testing.	('HMGB1', 'Gene', (26, 31))	('High-mobility Group Box Protein 1', 'Gene', (33, 66))	('HMGB1', 'Gene', '3146', (26, 31))	('Inhibition', 'Var', (0, 10))	('High-mobility Group Box Protein 1', 'Gene', '3146', (33, 66))
60533	27756323	Lastly, it is becoming apparent that detection of microRNAs or other molecules in circulation could be the first sign of early stage cancer, and could eventually become a blood test that saves thousands of lives.	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('microRNAs', 'Var', (50, 59))
60607	27756323	In 2002, his group reported that the PD-1 checkpoint also takes an important role in restraining endogenous anti-tumor immunity, and demonstrated that the blockade of the PD-1 checkpoint provides a potent therapeutic effect on tumors in animal models.	('tumor', 'Disease', (113, 118))	('PD-1', 'Gene', (171, 175))	('therapeutic', 'CPA', (205, 216))	('PD-1', 'Gene', '5133', (171, 175))	('tumor', 'Disease', (227, 232))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('blockade', 'Var', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('PD-1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('PD-1', 'Gene', '5133', (37, 41))
60611	27756323	A recent report has indicated that varying proportions of multiple human cancers show recurrent structural changes in PD-L1 gene locus at 3' UT region, which leads to a remarkable increase in PD-L1 expression.	('cancers', 'Disease', (73, 80))	('PD-L1', 'Gene', (118, 123))	('increase', 'PosReg', (180, 188))	('structural changes', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PD-L1 expression', 'MPA', (192, 208))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
60648	27756323	The first two microRNAs (miRNAs) discovered:lin-4 in 1993 and let-7 in 2000:have critical roles in worm development, as loss of either results in retarded worm development due to lack of cell differentiation.	('lack', 'NegReg', (179, 183))	('cell differentiation', 'CPA', (187, 207))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('retarded', 'Disease', (146, 154))	('cell differentiation', 'biological_process', 'GO:0030154', ('187', '207'))	('retarded', 'Disease', 'MESH:D008607', (146, 154))	('loss', 'Var', (120, 124))	('worm development', 'CPA', (155, 171))
60676	27756323	Score-positive patients showed increased median overall survival of 23 and 9 months for EPP and P/D, respectively.	('EPP', 'Disease', (88, 91))	('patients', 'Species', '9606', (15, 23))	('P/D', 'Var', (96, 99))	('increased', 'PosReg', (31, 40))
60684	27756323	It has been known since 1968 that DNA excision repair deficiency causes sensitivity to UV-light and skin cancer in Xeroderma pigmentosum.	('deficiency', 'Var', (54, 64))	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (115, 136))	('DNA excision repair', 'Gene', (34, 53))	('skin cancer', 'Phenotype', 'HP:0008069', (100, 111))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('skin cancer', 'Disease', (100, 111))	('sensitivity to UV-light', 'MPA', (72, 95))	('causes', 'Reg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DNA excision', 'biological_process', 'GO:0044349', ('34', '46'))	('skin cancer', 'Disease', 'MESH:D012878', (100, 111))	('Xeroderma pigmentosum', 'Disease', (115, 136))
60685	27756323	It is now known that more common cancers can be caused by unrepaired DNA damage and repair deficiencies.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('deficiencies', 'Var', (91, 103))	('caused by', 'Reg', (48, 57))
60686	27756323	Thus, inactivation of double strand break repair (DSBR) due to BRCA1 or 2 gene mutations results in defective DSBR and strongly increased risk of early onset breast cancer and ovarian cancer.	('BRCA1', 'Gene', '672', (63, 68))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('BRCA1', 'Gene', (63, 68))	('inactivation', 'Var', (6, 18))	('breast cancer', 'Disease', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('double strand break repair', 'biological_process', 'GO:0006302', ('22', '48'))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('defective', 'NegReg', (100, 109))	('ovarian cancer', 'Disease', (176, 190))	('double strand break repair', 'MPA', (22, 48))	('mutations', 'Var', (79, 88))	('DSBR', 'MPA', (110, 114))
60688	27756323	DNA mismatch-repair deficiency similarly causes hereditary non-polyposis colorectal cancer and several less common other cancers, the diagnosis of which is important to initiate preventive measures.	('cancers', 'Disease', (121, 128))	('non-polyposis colorectal cancer', 'Disease', (59, 90))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('deficiency', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('mismatch-repair', 'biological_process', 'GO:0006298', ('4', '19'))	('causes', 'Reg', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (59, 90))
60691	27756323	Furthermore, untargeted DNA-cytosine deamination by AID/APOBECs causes increased genomic uracil and AID/APOBEC mutational signatures in B-cell malignancies and several other types of cancer.	('uracil', 'Chemical', 'MESH:D014498', (89, 95))	('AID', 'Gene', '57379', (100, 103))	('AID', 'Gene', (100, 103))	('cancer', 'Disease', (183, 189))	('malignancies', 'Disease', 'MESH:D009369', (143, 155))	('mutational', 'Var', (111, 121))	('AID', 'Gene', '57379', (52, 55))	('AID', 'Gene', (52, 55))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('malignancies', 'Disease', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('increased', 'PosReg', (71, 80))	('DNA-cytosine deamination', 'biological_process', 'GO:0070383', ('24', '48'))	('APOBEC', 'cellular_component', 'GO:0030895', ('104', '110'))	('genomic uracil', 'MPA', (81, 95))
60692	27756323	In line with this, it was observed that clustered mutations (kataegis) in B-cell malignancies predominantly carry AID-hotspot mutational signatures.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('AID', 'Gene', (114, 117))	('AID', 'Gene', '57379', (114, 117))	('malignancies', 'Disease', (81, 93))	('clustered mutations', 'Var', (40, 59))
60693	27756323	Thus, AID/APOBEC-induced mutagenic U: G mismatches in DNA left unrepaired may be one fundamental and relatively common cause of several malignancies.	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('malignancies', 'Disease', (136, 148))	('cause', 'Reg', (119, 124))	('mutagenic', 'Var', (25, 34))	('mismatches', 'Var', (40, 50))	('APOBEC', 'cellular_component', 'GO:0030895', ('10', '16'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('AID', 'Gene', '57379', (6, 9))	('AID', 'Gene', (6, 9))
60696	27756323	The Cancer Genome Atlas Project (TCGA) extensively profiled 178 SCC tumor specimens for genomic alterations and identified that TP53 was almost universally mutated in the tumor samples, but other genes such as CDKN2A/RB1, NFE2L2/KEAP1/CUL3, PI3 K/AKT, and SOX2/TP63/NOTCH1 signaling pathways were also commonly altered.	('CUL3', 'Gene', (235, 239))	('NFE2L2', 'Gene', (222, 228))	('TP53', 'Gene', '7157', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('RB1', 'Gene', '5925', (217, 220))	('AKT', 'Gene', '207', (247, 250))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('CDKN2A', 'Gene', (210, 216))	('signaling', 'biological_process', 'GO:0023052', ('273', '282'))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))	('tumor', 'Disease', (68, 73))	('SCC tumor', 'Disease', (64, 73))	('mutated', 'Var', (156, 163))	('KEAP1', 'Gene', '9817', (229, 234))	('Cancer', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SOX2', 'Gene', (256, 260))	('SCC tumor', 'Disease', 'MESH:D009369', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('SOX2', 'Gene', '6657', (256, 260))	('PI3 K', 'molecular_function', 'GO:0016303', ('241', '246'))	('KEAP1', 'Gene', (229, 234))	('TP63', 'Gene', (261, 265))	('CDKN2A', 'Gene', '1029', (210, 216))	('CUL3', 'Gene', '8452', (235, 239))	('NOTCH1', 'Gene', (266, 272))	('TP53', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('NFE2L2', 'Gene', '4780', (222, 228))	('AKT', 'Gene', (247, 250))	('RB1', 'Gene', (217, 220))	('TP63', 'Gene', '8626', (261, 265))	('NOTCH1', 'Gene', '4851', (266, 272))	('altered', 'Reg', (311, 318))	('tumor', 'Disease', (171, 176))
60830	31191742	Among investigated polymorphisms, only rs17576 was associated with serum MMP9 levels before treatment (P = 0.041).	('rs17576', 'Mutation', 'rs17576', (39, 46))	('associated', 'Reg', (51, 61))	('MMP9', 'molecular_function', 'GO:0004229', ('73', '77'))	('serum MMP9 levels', 'MPA', (67, 84))	('rs17576', 'Var', (39, 46))
60834	31191742	For example, single nucleotide polymorphisms (SNPs) in the mesothelin gene (MSLN) could improve the prognostic value of mesothelin.	('improve', 'PosReg', (88, 95))	('prognostic value', 'MPA', (100, 116))	('MSLN', 'Gene', '10232', (76, 80))	('MSLN', 'Gene', (76, 80))	('single nucleotide polymorphisms', 'Var', (13, 44))
60840	31191742	We have shown that MMP9 rs2250889 CG genotype carriers had significantly shorter overall survival (OS) and time to progression (TTP), while MMP9 rs20544 CT allele carriers had longer OS.	('MMP9', 'molecular_function', 'GO:0004229', ('19', '23'))	('MMP9', 'molecular_function', 'GO:0004229', ('140', '144'))	('time', 'MPA', (107, 111))	('rs2250889 CG', 'Var', (24, 36))	('shorter', 'NegReg', (73, 80))	('MMP9', 'Gene', (19, 23))	('rs20544', 'Mutation', 'rs20544', (145, 152))	('overall survival', 'MPA', (81, 97))	('rs2250889', 'Mutation', 'rs2250889', (24, 33))	('rs20544 CT', 'Var', (145, 155))
60844	31191742	The remaining blood peripheral lymphocytes were used for DNA isolation, and all the patients have been genotyped for common MMP2, MMP9, and MMP14 polymorphisms.	('MMP', 'molecular_function', 'GO:0004235', ('140', '143'))	('MMP2', 'molecular_function', 'GO:0004228', ('124', '128'))	('MMP9', 'molecular_function', 'GO:0004229', ('130', '134'))	('MMP14', 'Gene', '4323', (140, 145))	('MMP2', 'Gene', (124, 128))	('MMP14', 'Gene', (140, 145))	('MMP9', 'Gene', (130, 134))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('polymorphisms', 'Var', (146, 159))
60848	31191742	Among the investigated SNPs, only rs17576 was associated with serum MMP9 levels before treatment (P = 0.041, Table 3).	('serum MMP9 levels', 'MPA', (62, 79))	('associated', 'Reg', (46, 56))	('rs17576', 'Var', (34, 41))	('MMP9', 'molecular_function', 'GO:0004229', ('68', '72'))	('rs17576', 'DBSNP_MENTION', 'None', (34, 41))
60849	31191742	We have observed two interesting associations: an association between MMP9 serum levels and ECOG performance status and between MMP9 expression and MMP9 rs17576 polymorphism.	('MMP9', 'molecular_function', 'GO:0004229', ('128', '132'))	('expression', 'MPA', (133, 143))	('rs17576', 'DBSNP_MENTION', 'None', (153, 160))	('MMP9', 'molecular_function', 'GO:0004229', ('148', '152'))	('MMP9', 'Gene', (128, 132))	('MMP9', 'Gene', (148, 152))	('MMP9', 'molecular_function', 'GO:0004229', ('70', '74'))	('rs17576', 'Var', (153, 160))	('MMP9 serum levels', 'MPA', (70, 87))
60853	31191742	The investigators suggested that the concentrations of MMP7 and MMP9 and the circulating tumor cell count could be used together as an effective, clinically predictive panel for lung adenocarcinoma metastasis and prognosis.	('lung adenocarcinoma metastasis', 'Disease', 'MESH:D009362', (178, 208))	('lung adenocarcinoma metastasis', 'Disease', (178, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('MMP9', 'molecular_function', 'GO:0004229', ('64', '68'))	('MMP7', 'molecular_function', 'GO:0004235', ('55', '59'))	('MMP9', 'Var', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
60855	31191742	In our previous study, we established the influence of MMP9 rs2250889 and rs20544 on TTP and OS.	('MMP9', 'Gene', (55, 59))	('rs2250889', 'DBSNP_MENTION', 'None', (60, 69))	('rs20544', 'Var', (74, 81))	('rs20544', 'DBSNP_MENTION', 'None', (74, 81))	('MMP9', 'molecular_function', 'GO:0004229', ('55', '59'))	('rs2250889', 'Var', (60, 69))
60856	31191742	In this study, statistically significant association was found between MMP9 rs17576 A>G GG genotype and higher MMP9 serum levels before treatment in comparison to the wild-type MMP9 rs17576 A>G AA genotype.	('MMP9 serum levels before treatment', 'MPA', (111, 145))	('rs17576', 'Var', (182, 189))	('rs17576', 'DBSNP_MENTION', 'None', (182, 189))	('rs17576', 'DBSNP_MENTION', 'None', (76, 83))	('MMP9', 'molecular_function', 'GO:0004229', ('71', '75'))	('rs17576', 'Var', (76, 83))	('MMP9', 'Gene', (71, 75))	('higher', 'PosReg', (104, 110))	('MMP9', 'molecular_function', 'GO:0004229', ('111', '115'))	('MMP9', 'molecular_function', 'GO:0004229', ('177', '181'))
60857	31191742	Our data suggests that, rather than as standalone biomarkers, MMP9 serum expression as well as MMP9 rs17576 A>G genotype may perform better in combination with other potential biomarkers.	('MMP9', 'Gene', (62, 66))	('rs17576', 'Var', (100, 107))	('MMP9', 'molecular_function', 'GO:0004229', ('95', '99'))	('MMP9', 'Gene', (95, 99))	('MMP9', 'molecular_function', 'GO:0004229', ('62', '66'))	('rs17576', 'DBSNP_MENTION', 'None', (100, 107))
60861	31191742	Our future perspective would therefore be to investigate if addition of miRNAs or other protein biomarkers to MMP9 plasma levels and MMP9 rs17576 A>G polymorphism may improve prognostic value of MMP9 in MM.	('rs17576', 'DBSNP_MENTION', 'None', (138, 145))	('prognostic', 'MPA', (175, 185))	('MMP9', 'molecular_function', 'GO:0004229', ('133', '137'))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('improve', 'PosReg', (167, 174))	('rs17576', 'Var', (138, 145))	('MMP9', 'molecular_function', 'GO:0004229', ('110', '114'))	('MMP9', 'molecular_function', 'GO:0004229', ('195', '199'))	('MMP9', 'Gene', (133, 137))
60862	31191742	In conclusion, we have shown that MMP9 concentration correlates with ECOG performance status and that MMP9 rs17576 influences MMP9 serum concentration in MM patients.	('MMP9', 'molecular_function', 'GO:0004229', ('34', '38'))	('MMP9 concentration', 'MPA', (34, 52))	('rs17576', 'DBSNP_MENTION', 'None', (107, 114))	('MMP9', 'molecular_function', 'GO:0004229', ('102', '106'))	('MMP9 serum concentration', 'MPA', (126, 150))	('influences', 'Reg', (115, 125))	('rs17576', 'Var', (107, 114))	('MMP9', 'Gene', (102, 106))	('MMP9', 'molecular_function', 'GO:0004229', ('126', '130'))
60874	30700254	Defects in HR compiled under the term BRCAness are a common event in MPM.	('BRCA', 'Gene', (38, 42))	('BRCA', 'Gene', '672', (38, 42))	('Defects', 'Var', (0, 7))
60881	30700254	Alterations in various genes, associated to BRCAness phenotype, were assessed in several tumours.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('Alterations', 'Var', (0, 11))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))
60882	30700254	Interestingly, BAP1 loss-of-function mutation has been found in 26-64% of MPMs.	('mutation', 'Var', (37, 45))	('loss-of-function', 'NegReg', (20, 36))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('MPMs', 'Disease', (74, 78))
60886	30700254	PARP-inhibitors are already FDA approved drugs for treatment of several cancers with Breast Cancer 1 (BRCA1) or BRCA2 mutations.	('BRCA1', 'Gene', (102, 107))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PARP', 'Gene', (0, 4))	('Breast Cancer 1', 'Gene', '672', (85, 100))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BRCA2', 'Gene', (112, 117))	('Breast Cancer 1', 'Gene', (85, 100))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('BRCA1', 'Gene', '672', (102, 107))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('BRCA2', 'Gene', '675', (112, 117))	('PARP', 'Gene', '142', (0, 4))	('Breast Cancer', 'Phenotype', 'HP:0003002', (85, 98))
60888	30700254	We hypothesize, that PARP-inhibitors might also be effective in cancers with alterations in related genes of the whole homologous recombination repair pathway.	('PARP', 'Gene', (21, 25))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('alterations', 'Var', (77, 88))	('cancers', 'Disease', (64, 71))	('homologous recombination', 'biological_process', 'GO:0035825', ('119', '143'))	('PARP', 'Gene', '142', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
60891	30700254	Analyse different human MPM cell lines for the presence of defects in HRR pathway.	('HRR pathway', 'Pathway', (70, 81))	('human', 'Species', '9606', (18, 23))	('defects', 'Var', (59, 66))	('HRR', 'biological_process', 'GO:0000724', ('70', '73'))
60904	30700254	We aimed to find associations between defects in HRR and response to cisplatin using survival prognosis with the help of the results of the digital gene expression analysis (Table 1).	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('response', 'MPA', (57, 65))	('gene expression', 'biological_process', 'GO:0010467', ('148', '163'))	('HRR', 'Protein', (49, 52))	('HRR', 'biological_process', 'GO:0000724', ('49', '52'))	('associations', 'Interaction', (17, 29))	('response to cisplatin', 'biological_process', 'GO:0072718', ('57', '78'))	('defects', 'Var', (38, 45))
60942	30700254	BRCA2 and checkpoint kinase2 (CHEK2) were expressed in NCI-H2452, while other cell lines showed no expression with counts < 100 (Fig.	('BRCA2', 'Gene', '675', (0, 5))	('NCI-H2452', 'CellLine', 'CVCL:1553', (55, 64))	('NCI-H2452', 'Var', (55, 64))	('checkpoint kinase2', 'Gene', (10, 28))	('BRCA2', 'Gene', (0, 5))	('checkpoint kinase2', 'Gene', '11200', (10, 28))	('CHEK2', 'Gene', '11200', (30, 35))	('CHEK2', 'Gene', (30, 35))
60950	30700254	High expression of DDB2 in patients showed a 4.373-fold chance of prolonged survival.	('DDB2', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('prolonged', 'PosReg', (66, 75))	('patients', 'Species', '9606', (27, 35))	('DDB2', 'Gene', '1643', (19, 23))
60953	30700254	Defects in individual genes that modulate HRR, compiled under the term "BRCAness", has been found in various tumours.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('BRCA', 'Gene', '672', (72, 76))	('Defects', 'Var', (0, 7))	('HRR', 'biological_process', 'GO:0000724', ('42', '45'))	('tumours', 'Disease', (109, 116))	('BRCA', 'Gene', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
60956	30700254	Additionally, to this lack of expression, a loss-of-function of three of those genes could already be determined by Betti et al., who also found deleterious mutations in BRCA1, BRCA2 and PALB2 gene loci.	('PALB2', 'Gene', '79728', (187, 192))	('PALB2', 'Gene', (187, 192))	('BRCA2', 'Gene', (177, 182))	('BRCA1', 'Gene', '672', (170, 175))	('mutations', 'Var', (157, 166))	('BRCA1', 'Gene', (170, 175))	('BRCA2', 'Gene', '675', (177, 182))	('loss-of-function', 'NegReg', (44, 60))
60966	30700254	In association with clinicopathological data, high expression of AURKA was associated with shortened overall survival and poor prognosis.	('AURKA', 'Gene', (65, 70))	('shortened', 'NegReg', (91, 100))	('overall', 'MPA', (101, 108))	('AURKA', 'Gene', '6790', (65, 70))	('high expression', 'Var', (46, 61))
60968	30700254	In contrast, high expression of DDB2 and RAD50 is significantly associated with prolonged survival.	('associated', 'Reg', (64, 74))	('RAD', 'biological_process', 'GO:1990116', ('41', '44'))	('high', 'Var', (13, 17))	('RAD50', 'Gene', (41, 46))	('RAD50', 'Gene', '10111', (41, 46))	('prolonged', 'PosReg', (80, 89))	('DDB2', 'Gene', '1643', (32, 36))	('DDB2', 'Gene', (32, 36))
60973	30700254	demonstrated likewise, that loss of RAD50 is a key marker of BRCAness in ovarian cancers (OvCa).	('BRCAness in ovarian cancers', 'Disease', (61, 88))	('ovarian cancers', 'Phenotype', 'HP:0100615', (73, 88))	('RAD', 'biological_process', 'GO:1990116', ('36', '39'))	('loss', 'Var', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('RAD50', 'Gene', (36, 41))	('RAD50', 'Gene', '10111', (36, 41))	('OvCa', 'CellLine', 'CVCL:0200', (90, 94))	('BRCAness in ovarian cancers', 'Disease', 'MESH:D010051', (61, 88))
60974	30700254	Cell culture analysis demonstrated, that loss of RAD50 augmented OvCa cell's response to cisplatin and PARP-inhibitors.	('RAD', 'biological_process', 'GO:1990116', ('49', '52'))	('loss', 'Var', (41, 45))	('PARP', 'Gene', '142', (103, 107))	('response to cisplatin', 'biological_process', 'GO:0072718', ('77', '98'))	('RAD50', 'Gene', (49, 54))	('RAD50', 'Gene', '10111', (49, 54))	('PARP', 'Gene', (103, 107))	('augmented', 'PosReg', (55, 64))	('response to cisplatin', 'MPA', (77, 98))	('OvCa', 'CellLine', 'CVCL:0200', (65, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))
60976	30700254	It is shown that BAP1 is commonly mutated in MPM and thereby might cause defects in HRR as well as a BRCAness phenotype of affected cells.	('cause', 'Reg', (67, 72))	('HRR', 'CPA', (84, 87))	('BRCA', 'Gene', '672', (101, 105))	('HRR', 'biological_process', 'GO:0000724', ('84', '87'))	('BAP1', 'Gene', '8314', (17, 21))	('BRCA', 'Gene', (101, 105))	('BAP1', 'Gene', (17, 21))	('mutated', 'Var', (34, 41))	('defects', 'NegReg', (73, 80))
60988	30700254	The BAP1 mutational status in combination with certain gene expression patterns seem to contribute significantly to cellular response to olaparib.	('olaparib', 'Chemical', 'MESH:C531550', (137, 145))	('contribute', 'Reg', (88, 98))	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('BAP1', 'Gene', (4, 8))	('mutational status', 'Var', (9, 26))	('cellular response to olaparib', 'MPA', (116, 145))	('BAP1', 'Gene', '8314', (4, 8))
61013	29165150	Moreover, asbestos exposure is known to cause malignant diseases such as lung cancer and malignant mesothelioma (MM), as well as other cancers such as those of the ovary, pharynx, and larynx.	('asbestos', 'Chemical', 'MESH:D001194', (10, 18))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cause', 'Reg', (40, 45))	('malignant diseases', 'Disease', 'MESH:D009369', (46, 64))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('malignant diseases', 'Disease', (46, 64))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (89, 111))	('cancers', 'Disease', (135, 142))	('exposure', 'Var', (19, 27))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (89, 111))	('asbestos exposure', 'Var', (10, 27))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('malignant mesothelioma', 'Disease', (89, 111))
61023	29165150	Although the physiological effects caused by silica and asbestos differ, including those produced by fibers and particles, asbestos fibers may influence the various circulating immune cells in a manner similar to silica particles.	('silica', 'Chemical', 'MESH:D012822', (45, 51))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('influence', 'Reg', (143, 152))	('man', 'Species', '9606', (195, 198))	('asbestos', 'Var', (123, 131))	('asbestos', 'Chemical', 'MESH:D001194', (123, 131))	('silica', 'Chemical', 'MESH:D012822', (213, 219))
61043	29165150	In addition, knockdown of IL-10 or TGF-beta using the siRNA method resulted in reduction of the inhibitory function of the sublines.	('inhibitory function of the sublines', 'MPA', (96, 131))	('TGF-beta', 'Gene', (35, 43))	('IL-10', 'Gene', '3586', (26, 31))	('IL-10', 'Gene', (26, 31))	('IL-10', 'molecular_function', 'GO:0005141', ('26', '31'))	('TGF-beta', 'Gene', '7040', (35, 43))	('knockdown', 'Var', (13, 22))	('reduction', 'NegReg', (79, 88))
61047	29165150	In addition, knockdown of FoxO1 in MT-2 original cells resulted in enhancement of cyclin D1 expression.	('MT-2', 'Gene', (35, 39))	('cyclin D1', 'Gene', '595', (82, 91))	('enhancement', 'PosReg', (67, 78))	('cyclin D1', 'Gene', (82, 91))	('FoxO1', 'Gene', (26, 31))	('FoxO1', 'Gene', '2308', (26, 31))	('cyclin', 'molecular_function', 'GO:0016538', ('82', '88'))	('MT-2', 'molecular_function', 'GO:0043851', ('35', '39'))	('MT-2', 'Gene', '4502', (35, 39))	('knockdown', 'Var', (13, 22))	('expression', 'MPA', (92, 102))
61049	29165150	All of these findings indicated the asbestos-exposed Treg exhibited enhanced function and increased numbers.	('function', 'CPA', (77, 85))	('enhanced', 'PosReg', (68, 76))	('asbestos-exposed', 'Var', (36, 52))	('increased', 'PosReg', (90, 99))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('numbers', 'CPA', (100, 107))
61072	29165150	In addition, IFN-gamma+ and CD107a+ (as the marker of degranulation and the secretion of cell attacking molecules such as granzymes and perforin) cells in phorbol 12-myristate 13-acetate (PMA) and ionomycin-stimulated CD8+ cells did not differ between these three groups.	('IFN-gamma', 'Gene', (13, 22))	('CD8', 'Gene', (218, 221))	('CD8', 'Gene', '925', (218, 221))	('CD107a+', 'Var', (28, 35))	('ionomycin', 'Chemical', 'MESH:D015759', (197, 206))	('PMA', 'Chemical', 'MESH:D013755', (188, 191))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (155, 186))	('secretion', 'biological_process', 'GO:0046903', ('76', '85'))	('IFN-gamma', 'Gene', '3458', (13, 22))
61185	27544053	In this case the effusion samples contained 54.8% CD3+PD-L1+ T cells whereas only 2.9% CD3+PD-L1+ T cells were present in PBMC.	('effusion', 'Disease', 'MESH:D010996', (17, 25))	('CD3+PD-L1+ T cells', 'Var', (50, 68))	('effusion', 'Disease', (17, 25))
61193	27544053	The paired PBMC sample on the other hand had 11.9, 4.23, 1.1% CD4+PD1+, CD8+PD-1+ and CD14+PD-1+ cells, respectively.	('PD-1', 'Gene', (91, 95))	('PD-1', 'Gene', '5133', (91, 95))	('CD4+PD1+', 'Var', (62, 70))	('CD8', 'Gene', (72, 75))	('PD-1', 'Gene', (76, 80))	('PD-1', 'Gene', '5133', (76, 80))	('CD8', 'Gene', '925', (72, 75))
61218	27544053	Our results show that two-thirds of pleural and peritoneal mesotheliomas express PD-L1 and PD-L1 expression is associated with a trend towards decreased overall survival.	('pleural and peritoneal mesotheliomas', 'Disease', 'MESH:D010997', (36, 72))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (48, 71))	('decreased', 'NegReg', (143, 152))	('overall survival', 'MPA', (153, 169))	('PD-L1', 'Gene', (81, 86))	('PD-L1', 'Var', (91, 96))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (48, 72))
61257	27544053	Whereas initial studies indicated that expression of PD-L1 on primary tumors or on tumor infiltrating lymphocytes is a predictor for worse prognosis, subsequent studies have yielded conflicting results.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PD-L1', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'Var', (39, 49))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
61261	27544053	At the same time, however, the presence of these immune checkpoints could make mesothelioma tumors susceptible to treatment with agents targeting PD-L1 or PD-1.	('make', 'Reg', (74, 78))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PD-1', 'Gene', (155, 159))	('PD-1', 'Gene', '5133', (155, 159))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (79, 98))	('mesothelioma tumors', 'Disease', (79, 98))	('PD-L1', 'Gene', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (79, 97))	('presence', 'Var', (31, 39))
61281	27034865	Examination of respiratory system revealed diminished movement of chest wall on right side, tracheal shifting to left, apical impulse in left fifth intercostal space, 1.5 cm lateral to the left midclavicular line, stony dull percussion note over right chest wall, absent vesicular breath sound, and diminished vocal resonance on right side, suggestive of right-sided pleural effusion.	('stony', 'Var', (214, 219))	('apical impulse', 'Phenotype', 'HP:0032176', (119, 133))	('vocal resonance', 'MPA', (310, 325))	('diminished movement', 'Phenotype', 'HP:0002374', (43, 62))	('pleural effusion', 'Phenotype', 'HP:0002202', (367, 383))	('absent vesicular breath', 'Disease', (264, 287))	('movement', 'MPA', (54, 62))	('diminished', 'NegReg', (299, 309))	('pleural effusion', 'Disease', 'MESH:D010996', (367, 383))	('absent vesicular breath', 'Disease', 'MESH:D012872', (264, 287))	('diminished', 'NegReg', (43, 53))	('pleural effusion', 'Disease', (367, 383))
61331	22427958	We detected tunneling nanotubes in mesothelioma cell lines and primary human mesothelioma cells.	('mesothelioma', 'Disease', (77, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('mesothelioma', 'Disease', (35, 47))	('tunneling', 'Var', (12, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('human', 'Species', '9606', (71, 76))	('detected', 'Reg', (3, 11))
61374	22427958	Furthermore, acidic pH has been reported to enhance the invasive potential of cancer cells.	('acidic pH', 'Var', (13, 22))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('enhance', 'PosReg', (44, 51))
61389	22427958	In many cases, staining was unipolar, and may indicate that fascin organizes and cross-links actin bundles at the origin of the TnTs which then extend to neighboring cells.	('actin bundles', 'Protein', (93, 106))	('fascin', 'Gene', '6624', (60, 66))	('cross-links', 'Var', (81, 92))	('fascin', 'Gene', (60, 66))	('TnTs', 'Chemical', '-', (128, 132))
61438	22427958	Also, the demonstration that normal and tumor cells harbor heteroplasmic and homoplasmic mitochondrial DNA mutations - even in a single individual patient with cancer - may implicate TnTs as a method of transfer of genetic change leading to tumor heterogeneity.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (107, 116))	('mitochondrial DNA', 'Gene', (89, 106))	('tumor', 'Disease', (241, 246))	('cancer', 'Disease', (160, 166))	('TnTs', 'Chemical', '-', (183, 187))	('patient', 'Species', '9606', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('89', '106'))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rat', 'Species', '10116', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
61458	22427958	Metformin significantly suppressed TnT formation at all concentrations tested: 9.7 nM, 97 nM, 970 nM, and 9.7 mM ( Figure 5B ).	('970 nM', 'Var', (94, 100))	('TnT', 'Chemical', '-', (35, 38))	('suppressed', 'NegReg', (24, 34))	('TnT formation', 'MPA', (35, 48))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('rat', 'Species', '10116', (63, 66))
61576	33289348	In several studies, patients with the epithelial type have been reported to have a significantly improved prognosis compared to those with the sarcomatous variant.	('improved', 'PosReg', (97, 105))	('sarcomatous', 'Disease', 'MESH:D018316', (143, 154))	('epithelial type', 'Var', (38, 53))	('patients', 'Species', '9606', (20, 28))	('prognosis', 'MPA', (106, 115))	('sarcomatous', 'Disease', (143, 154))
61604	31265162	MWCNT-7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT-7 developed lung tumors.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (33, 55))	('rat', 'Species', '10116', (179, 182))	('rats', 'Species', '10116', (122, 126))	('lung tumors', 'Disease', 'MESH:D008175', (224, 235))	('rats', 'Species', '10116', (179, 183))	('MWCNT-7', 'Chemical', '-', (0, 7))	('MWCNT-7', 'Chemical', '-', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('malignant mesothelioma', 'Disease', (33, 55))	('MWCNT-7', 'Var', (0, 7))	('rat', 'Species', '10116', (168, 171))	('rat', 'Species', '10116', (122, 125))	('mice', 'Species', '10090', (131, 135))	('lung tumors', 'Disease', (224, 235))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (33, 55))	('lung tumors', 'Phenotype', 'HP:0100526', (224, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))
61609	31265162	Overall, the incidence of malignant mesothelioma in the MWCNT-7 group was significantly higher than in the vehicle or crocidolite groups.	('higher', 'PosReg', (88, 94))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (26, 48))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (26, 48))	('MWCNT-7', 'Chemical', '-', (56, 63))	('crocidolite', 'Chemical', 'MESH:D017638', (118, 129))	('malignant mesothelioma', 'Disease', (26, 48))	('MWCNT-7', 'Var', (56, 63))
61614	31265162	We found that administration of MWCNT-7 via the airway using TIPS resulted in induction of malignant pleural mesothelioma in rats.	('malignant pleural mesothelioma', 'Disease', (91, 121))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (91, 121))	('rat', 'Species', '10116', (125, 128))	('MWCNT-7', 'Var', (32, 39))	('rat', 'Species', '10116', (22, 25))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (101, 121))	('rats', 'Species', '10116', (125, 129))	('MWCNT-7', 'Chemical', '-', (32, 39))	('induction', 'Reg', (78, 87))	('TIPS', 'Chemical', '-', (61, 65))
61615	31265162	This is the first study to demonstrate that administration of MWCNT-7 via the airway can result in the development of mesothelioma in rats.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('rat', 'Species', '10116', (52, 55))	('rats', 'Species', '10116', (134, 138))	('MWCNT-7', 'Chemical', '-', (62, 69))	('result in', 'Reg', (89, 98))	('mesothelioma', 'Disease', (118, 130))	('rat', 'Species', '10116', (134, 137))	('MWCNT-7', 'Var', (62, 69))	('rat', 'Species', '10116', (34, 37))
61638	31265162	A significant decrease in the average survival time was observed in the MWCNT-7 group compared to the vehicle group.	('MWCNT-7', 'Chemical', '-', (72, 79))	('decrease', 'NegReg', (14, 22))	('MWCNT-7', 'Var', (72, 79))
61667	31265162	The average length of MWCNT-7 fibers in the mediastinal lymph node was significantly shorter than that of MWCNT-7 fibers in the lung tissue (Figure 5, Table 3).	('shorter', 'NegReg', (85, 92))	('MWCNT-7', 'Var', (22, 29))	('MWCNT-7', 'Chemical', '-', (22, 29))	('MWCNT-7', 'Chemical', '-', (106, 113))
61669	31265162	We found that MWCNT-7 induced the development of malignant pleural mesothelioma.	('MWCNT-7', 'Chemical', '-', (14, 21))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (59, 79))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (49, 79))	('malignant pleural mesothelioma', 'Disease', (49, 79))	('MWCNT-7', 'Var', (14, 21))
61670	31265162	Thus, MWCNT-7 in the lung causes development of malignant tumors in both the lung6 and pleural cavity (this study) of rats.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('pleural', 'Disease', 'MESH:D010995', (87, 94))	('MWCNT-7', 'Chemical', '-', (6, 13))	('pleural', 'Disease', (87, 94))	('malignant tumors', 'Disease', (48, 64))	('MWCNT-7', 'Var', (6, 13))	('rats', 'Species', '10116', (118, 122))	('malignant tumors', 'Disease', 'MESH:D018198', (48, 64))
61671	31265162	It is also notable that under the conditions of the present study, MWCNT-7 was a much more potent carcinogen than crocidolite asbestos.	('MWCNT-7', 'Var', (67, 74))	('carcinogen', 'CPA', (98, 108))	('crocidolite asbestos', 'Disease', 'MESH:D001195', (114, 134))	('crocidolite asbestos', 'Disease', (114, 134))	('MWCNT-7', 'Chemical', '-', (67, 74))
61682	31265162	Notably, in the whole-body inhalation study reported by Kasai et al6, MWCNT-7 fibers did accumulate in the pleural cavity and rats did develop mesothelial hyperplastic lesions.	('rats', 'Species', '10116', (126, 130))	('MWCNT-7', 'Chemical', '-', (70, 77))	('mesothelial hyperplastic lesions', 'CPA', (143, 175))	('pleural', 'Disease', 'MESH:D010995', (107, 114))	('develop', 'PosReg', (135, 142))	('pleural', 'Disease', (107, 114))	('MWCNT-7', 'Var', (70, 77))	('accumulate', 'PosReg', (89, 99))
61693	31265162	Therefore, it is reasonable that carcinogenic levels of MWCNT-7 would be lower for the pleural cavity than for the lung, and once these levels are reached, carcinogenic processes in the pleural cavity would proceed more rapidly than in the lung.	('carcinogenic', 'Disease', 'MESH:D063646', (33, 45))	('MWCNT-7', 'Var', (56, 63))	('carcinogenic', 'Disease', (33, 45))	('pleural', 'Disease', 'MESH:D010995', (87, 94))	('MWCNT-7', 'Chemical', '-', (56, 63))	('pleural', 'Disease', (87, 94))	('pleural', 'Disease', 'MESH:D010995', (186, 193))	('lower', 'NegReg', (73, 78))	('carcinogenic', 'Disease', 'MESH:D063646', (156, 168))	('pleural', 'Disease', (186, 193))	('carcinogenic', 'Disease', (156, 168))
61696	31265162	Because we found that administration of 1.5 mg MWCNT-7 to the rat lung did induce the development of malignant pleural mesothelioma, our results strongly suggest that the MWCNT-7 that accumulated in the lungs of the rats exposed to MWCNT-7 by whole-body inhalation would have ultimately induced the development of mesotheliomas in these rats.	('MWCNT-7', 'Chemical', '-', (47, 54))	('rat', 'Species', '10116', (337, 340))	('rats', 'Species', '10116', (216, 220))	('MWCNT-7', 'Chemical', '-', (171, 178))	('induced', 'Reg', (287, 294))	('rat', 'Species', '10116', (30, 33))	('MWCNT-7', 'Chemical', '-', (232, 239))	('malignant pleural mesothelioma', 'Disease', (101, 131))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (101, 131))	('MWCNT-7', 'Var', (171, 178))	('mesotheliomas', 'Disease', (314, 327))	('rats', 'Species', '10116', (337, 341))	('mesotheliomas', 'Disease', 'MESH:D008654', (314, 327))	('rat', 'Species', '10116', (62, 65))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (111, 131))	('rat', 'Species', '10116', (216, 219))
61698	31265162	As can be seen in Figure S1, until the rats administered MWCNT-7 began dying from mesothelioma at week 47, the body weights of the MWCNT-7 group were only slightly decreased compared to the body weights of the control group.	('rats', 'Species', '10116', (39, 43))	('mesothelioma', 'Disease', (82, 94))	('decreased', 'NegReg', (164, 173))	('MWCNT-7', 'Var', (131, 138))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('MWCNT-7', 'Chemical', '-', (131, 138))	('MWCNT-7', 'Chemical', '-', (57, 64))
61702	31265162	While the 2-year inhalation study reported by Kasai et al6 found that exposure to MWCNT-7 caused lung tumors but not pleural mesotheliomas, the results of our study strongly suggest that the MWCNT-7 fibers that had accumulated in the lungs of the exposed male rats after 2 years would have induced malignant pleural mesotheliomas if the study could have been extended for approximately 12 to 18 months.	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (308, 329))	('rats', 'Species', '10116', (260, 264))	('lung tumors', 'Disease', 'MESH:D008175', (97, 108))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (117, 138))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('pleural mesotheliomas', 'Disease', (117, 138))	('MWCNT-7', 'Chemical', '-', (82, 89))	('lung tumors', 'Phenotype', 'HP:0100526', (97, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (308, 328))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (117, 137))	('MWCNT-7', 'Chemical', '-', (191, 198))	('lung tumors', 'Disease', (97, 108))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (308, 329))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (298, 329))	('MWCNT-7', 'Var', (191, 198))	('induced', 'Reg', (290, 297))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (117, 138))	('malignant pleural mesotheliomas', 'Disease', (298, 329))
61704	31265162	In conclusion, using TIPS administration, this study demonstrated that MWCNT-7 administered via the airway induces malignant pleural mesothelioma in rats.	('rat', 'Species', '10116', (149, 152))	('TIPS', 'Chemical', '-', (21, 25))	('MWCNT-7', 'Var', (71, 78))	('rat', 'Species', '10116', (60, 63))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (115, 145))	('MWCNT-7', 'Chemical', '-', (71, 78))	('induces', 'Reg', (107, 114))	('rats', 'Species', '10116', (149, 153))	('rat', 'Species', '10116', (34, 37))	('malignant pleural mesothelioma', 'Disease', (115, 145))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (125, 145))
61705	31265162	Our results also suggest that the MWCNT-7 that accumulated in the lungs of the male rats in the 2-year study reported by Kasai et al6 would probably have caused development of mesothelioma in exposed rats if it would have been possible to extend the study for approximately 12 to 18 months.	('MWCNT-7', 'Chemical', '-', (34, 41))	('mesothelioma', 'Disease', (176, 188))	('rats', 'Species', '10116', (200, 204))	('MWCNT-7', 'Var', (34, 41))	('rats', 'Species', '10116', (84, 88))	('caused', 'Reg', (154, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (176, 188))
61765	30697290	Prominent nucleoli with HMB45 positivity differentiate melanoma from SS.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('positivity', 'Var', (30, 40))	('HMB45', 'Protein', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
61771	30697290	Immunoreactivity to calretinin and negativity to HMB45 and other epithelial markers ruled out the possibility of metastatic melanoma, carcinoma.	('carcinoma', 'Disease', (134, 143))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('HMB45', 'Gene', (49, 54))	('calretinin', 'Gene', '794', (20, 30))	('carcinoma', 'Disease', 'MESH:D002277', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('negativity', 'Var', (35, 45))	('calretinin', 'Gene', (20, 30))
61785	30697290	Positivity for CD34, bcl2 with Vimentin characterises the tumor as seen in the present study.	('Vimentin', 'Gene', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Vimentin', 'Gene', '7431', (31, 39))	('CD34', 'Gene', (15, 19))	('CD34', 'Gene', '947', (15, 19))	('Vimentin', 'cellular_component', 'GO:0045098', ('31', '39'))	('bcl2', 'Gene', (21, 25))	('bcl2', 'molecular_function', 'GO:0015283', ('21', '25'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Vimentin', 'cellular_component', 'GO:0045099', ('31', '39'))	('Positivity', 'Var', (0, 10))	('bcl2', 'Gene', '596', (21, 25))
61822	26891694	This is particularly important as MM is associated with chromosomal loss, deletions in CDKN2A, CDKN2B, and NF2 genes and mutations in BAP1 and CUL1.	('deletions', 'Var', (74, 83))	('CUL1', 'Gene', '8454', (143, 147))	('mutations', 'Var', (121, 130))	('BAP1', 'Gene', (134, 138))	('CDKN2A', 'Gene', '1029', (87, 93))	('NF2', 'Gene', (107, 110))	('CDKN2B', 'Gene', (95, 101))	('CDKN2B', 'Gene', '1030', (95, 101))	('chromosomal loss', 'Var', (56, 72))	('NF2', 'Gene', '4771', (107, 110))	('CUL1', 'Gene', (143, 147))	('BAP1', 'Gene', '8314', (134, 138))	('CDKN2A', 'Gene', (87, 93))
61849	26891694	Relative quantification of gene copy number confirmed homozygous deletion of p16INK4A and p14ARF in seven out of eight patient-derived cell lines (with the exception of MESO-27T).	('patient', 'Species', '9606', (119, 126))	('p14ARF', 'Gene', '1029', (90, 96))	('p16INK4A', 'Gene', (77, 85))	('p14ARF', 'Gene', (90, 96))	('p16INK4A', 'Gene', '1029', (77, 85))	('deletion', 'Var', (65, 73))
61855	26891694	Patchy staining for p16 protein may be due to deletion of p16INK4A in some tumor cells and/or transcriptional silencing of the p16INK4A locus.	('p16INK4A', 'Gene', '1029', (58, 66))	('deletion', 'Var', (46, 54))	('p16', 'Gene', (127, 130))	('p16', 'Gene', (58, 61))	('due', 'Reg', (39, 42))	('p16', 'Gene', (20, 23))	('p16INK4A', 'Gene', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('p16INK4A', 'Gene', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('p16', 'Gene', '1029', (127, 130))	('p16', 'Gene', '1029', (58, 61))	('p16INK4A', 'Gene', '1029', (127, 135))	('p16', 'Gene', '1029', (20, 23))	('tumor', 'Disease', (75, 80))
61865	26891694	The similarity of the aberrantly expressed genes in primary MM cell lines with the gene sets associated with survival in other cancers is summarized in Supplementary Table 4 and Figure 5d.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('aberrantly', 'Var', (22, 32))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Disease', (127, 134))
61871	26891694	Although established primary cell lines were authenticated by short tandem repeat (STR) DNA profiling, their profiles were also matched to the original patient tumor genomic DNA (gDNA).	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('short tandem repeat', 'Var', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('tumor', 'Disease', (160, 165))	('patient', 'Species', '9606', (152, 159))
61895	26891694	This suggests an additional mechanism, transcriptional silencing, and exemplifies the possibility of two independent mechanisms simultaneously inactivating key tumor suppressor genes in MM.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('160', '176'))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('inactivating', 'NegReg', (143, 155))	('tumor', 'Disease', (160, 165))	('tumor suppressor', 'biological_process', 'GO:0051726', ('160', '176'))	('transcriptional', 'Var', (39, 54))
61898	26891694	MESO-27T was positioned close to the other primary cell lines, but was not included in the same cluster; this is perhaps not surprising, considering that MESO-27T, unlike the other primary cell lines, expresses p16 and Merlin.	('MESO-27T', 'Var', (154, 162))	('Merlin', 'Protein', (219, 225))	('p16', 'Gene', '1029', (211, 214))	('p16', 'Gene', (211, 214))
62027	26889212	The marked induction of mesothelioma by MWCNT registered in that study, compared to the absence of pathological signs produced by the same dose of fullerene (a compound very similar in chemical composition, but lacking the 'asbestiform' needle shape), highlights once again the importance of physical structure and biopersistence in tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('tumour', 'Disease', 'MESH:D009369', (333, 339))	('mesothelioma', 'Disease', (24, 36))	('fullerene', 'Chemical', 'MESH:D037741', (147, 156))	('tumour', 'Disease', (333, 339))	('mesothelioma', 'Disease', 'MESH:D008654', (24, 36))	('MWCNT', 'Var', (40, 45))	('MWCNT', 'Chemical', '-', (40, 45))
62055	26889212	This study produced an interesting model of 'real' occupational exposure, and highlighted at least two important factors: MWCNT, via inhalation and via the bloodstream, can rapidly be deposited in many organs and can generate amyloid tissue aggregation in a short period of time; hence, MWCNT-induced amyloid deposition may be a potential risk factor for the development of neurodegenerative diseases, hepatic cirrhosis and several other amyloid-related syndromes, particularly in predisposed individuals.	('amyloid tissue aggregation', 'MPA', (226, 252))	('MWCNT-induced', 'Var', (287, 300))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (374, 400))	('hepatic cirrhosis', 'Phenotype', 'HP:0001394', (402, 419))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (374, 400))	('hepatic cirrhosis', 'Disease', (402, 419))	('hepatic cirrhosis', 'Disease', 'MESH:D008103', (402, 419))	('MWCNT', 'Chemical', '-', (287, 292))	('neurodegenerative diseases', 'Disease', (374, 400))	('amyloid deposition', 'Phenotype', 'HP:0011034', (301, 319))	('generate', 'Reg', (217, 225))	('risk factor', 'Reg', (339, 350))	('man', 'Species', '9606', (197, 200))	('MWCNT', 'Chemical', '-', (122, 127))
62137	25422081	In addition, stable knockdown CK2alpha has recently been shown to inhibit cell migration and invasion of hepatocellular carcinoma.	('cell migration', 'CPA', (74, 88))	('cell migration', 'biological_process', 'GO:0016477', ('74', '88'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (105, 129))	('knockdown', 'Var', (20, 29))	('hepatocellular carcinoma', 'Disease', (105, 129))	('CK2alpha', 'Gene', '1459', (30, 38))	('CK2alpha', 'Gene', (30, 38))	('inhibit', 'NegReg', (66, 73))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('invasion', 'CPA', (93, 101))
62142	25422081	Deregulation of Hh/Gli signaling is implicated as an initiating or maintaining factor in the progression of various cancers, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (135, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('leukemia', 'Disease', (176, 184))	('leukemia', 'Disease', 'MESH:D007938', (176, 184))	('Gli', 'Gene', (19, 22))	('medulloblastomas', 'Disease', 'MESH:D008527', (158, 174))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('gastrointestinal, lung, ovarian, breast and prostate cancers', 'Disease', 'MESH:D061325', (186, 246))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (135, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (230, 245))	('prostate cancers', 'Phenotype', 'HP:0012125', (230, 246))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('basal cell carcinomas', 'Disease', (135, 156))	('Deregulation', 'Var', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('medulloblastomas', 'Disease', (158, 174))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('leukemia', 'Phenotype', 'HP:0001909', (176, 184))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (135, 156))	('cancers', 'Disease', (116, 123))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))	('Gli', 'Gene', '2735', (19, 22))
62155	25422081	Nine human mesothelioma cell lines (H28, H290, H2052, 211H, H2452, MS-1, H226, REN and H513) and a normal pleura cell line (LP9) were obtained from American Type Culture Collections (Manassas, VA).	('REN', 'Gene', (79, 82))	('H2452', 'Var', (60, 65))	('H2452', 'CellLine', 'CVCL:1553', (60, 65))	('H290', 'CellLine', 'CVCL:A555', (41, 45))	('mesothelioma', 'Disease', (11, 23))	('REN', 'Gene', '5972', (79, 82))	('H2052', 'Var', (47, 52))	('LP9', 'CellLine', 'CVCL:E109', (124, 127))	('H226', 'CellLine', 'CVCL:J621', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('human', 'Species', '9606', (5, 10))
62172	25422081	To measure Gli-mediated Hh transcriptional activity, the luciferase reporter constructs, 8x wild-type Gli binding site (8x Gli wt Luc) or 8x mutant Gli binding site (8x Gli mut Luc) plasmids and a human Gli1 expression vector (pcDNA3.1-Gli1) were co-transfected into H28 cells in 24-well plates.	('Gli', 'Gene', '2735', (102, 105))	('Gli', 'Gene', (203, 206))	('mutant', 'Var', (141, 147))	('Gli', 'Gene', '2735', (123, 126))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('Gli', 'Gene', (169, 172))	('Gli', 'Gene', '2735', (203, 206))	('Gli', 'Gene', '2735', (11, 14))	('Gli', 'Gene', (148, 151))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('Gli', 'Gene', (236, 239))	('Gli', 'Gene', '2735', (148, 151))	('Gli', 'Gene', '2735', (169, 172))	('Gli', 'Gene', '2735', (236, 239))	('human', 'Species', '9606', (197, 202))	('Gli', 'Gene', (123, 126))	('Gli', 'Gene', (102, 105))	('Gli', 'Gene', (11, 14))
62177	25422081	Quantitative RT-PCR was used to examine the mRNA level of CK2alpha and Gli1 in 44 primary mesothelioma samples and 8 mesothelioma cell lines (H28, H290, H2052, 211H, H2452, MS-1, H226 and H513).	('H290', 'CellLine', 'CVCL:A555', (147, 151))	('mesothelioma', 'Disease', (117, 129))	('H2052', 'Var', (153, 158))	('H226', 'CellLine', 'CVCL:J621', (179, 183))	('mesothelioma', 'Disease', (90, 102))	('H2452', 'CellLine', 'CVCL:1553', (166, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('CK2alpha', 'Gene', '1459', (58, 66))	('H2452', 'Var', (166, 171))	('CK2alpha', 'Gene', (58, 66))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (82, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
62191	25422081	For CK2alpha staining, H290, H2452 and MS-1 were strong positive (+++), while REN and H226 were weaker (+).	('H290', 'CellLine', 'CVCL:A555', (23, 27))	('H2452', 'CellLine', 'CVCL:1553', (29, 34))	('H290', 'Var', (23, 27))	('REN', 'Gene', '5972', (78, 81))	('positive', 'PosReg', (56, 64))	('REN', 'Gene', (78, 81))	('MS-1', 'Gene', (39, 43))	('CK2alpha', 'Gene', '1459', (4, 12))	('CK2alpha', 'Gene', (4, 12))	('H226', 'CellLine', 'CVCL:J621', (86, 90))	('H2452', 'Var', (29, 34))
62192	25422081	For Gli1 staining, H290, H2452 and MS-1 were strong positive (+++), while H28 was weaker (+).	('MS-1', 'Gene', (35, 39))	('H2452', 'CellLine', 'CVCL:1553', (25, 30))	('H290', 'Var', (19, 23))	('H2452', 'Var', (25, 30))	('H290', 'CellLine', 'CVCL:A555', (19, 23))	('positive', 'PosReg', (52, 60))
62197	25422081	It has been previously shown that 48 h of CK2alpha siRNA treatment is efficient to knockdown CK2alpha protein expression in the treated cells.	('CK2alpha', 'Gene', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('CK2alpha', 'Gene', '1459', (42, 50))	('CK2alpha', 'Gene', '1459', (93, 101))	('knockdown', 'Var', (83, 92))	('CK2alpha', 'Gene', (93, 101))
62199	25422081	Expression of Gli11 was inhibited after CK2alpha knockdown in the two cell lines (Figure 3A and B, middle lane).	('knockdown', 'Var', (49, 58))	('Gli11', 'Gene', (14, 19))	('Expression', 'MPA', (0, 10))	('CK2alpha', 'Gene', '1459', (40, 48))	('CK2alpha', 'Gene', (40, 48))	('inhibited', 'NegReg', (24, 33))
62201	25422081	Silencing of CK2alpha in H28 cells resulted in a significant decrease (48% at 50 muM, P < 0.01, Figure 3C) in the Gli reporter activity, compared with the non-targeting siRNA (control).	('decrease', 'NegReg', (61, 69))	('Gli', 'Gene', (114, 117))	('CK2alpha', 'Gene', '1459', (13, 21))	('Gli', 'Gene', '2735', (114, 117))	('CK2alpha', 'Gene', (13, 21))	('muM', 'Gene', '56925', (81, 84))	('Silencing', 'Var', (0, 9))	('muM', 'Gene', (81, 84))
62203	25422081	The mRNA level of the two Hh target genes decreased significantly (P < 0.01, Figure 3D) after CK2alpha knockdown.	('CK2alpha', 'Gene', '1459', (94, 102))	('decreased', 'NegReg', (42, 51))	('CK2alpha', 'Gene', (94, 102))	('mRNA level of', 'MPA', (4, 17))	('knockdown', 'Var', (103, 112))
62205	25422081	These results suggest a depressed transcriptional activity of Hh/Gli1 signaling after CK2alpha knockdown.	('depressed', 'NegReg', (24, 33))	('CK2alpha', 'Gene', (86, 94))	('transcriptional activity', 'MPA', (34, 58))	('knockdown', 'Var', (95, 104))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('Hh/Gli1 signaling', 'MPA', (62, 79))	('CK2alpha', 'Gene', '1459', (86, 94))
62207	25422081	Cells were treated with multiple concentrations of CX-4945 (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 muM), or with the vehicle DMSO for 72 hours.	('0.1', 'Var', (72, 75))	('0.01', 'Var', (60, 64))	('muM', 'Gene', (98, 101))	('CX-4945', 'Chemical', 'MESH:C555142', (51, 58))	('muM', 'Gene', '56925', (98, 101))	('0.03', 'Var', (66, 70))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))
62208	25422081	The cell proliferation assay demonstrated that treatments with CX-4945 led to cell growth inhibition in a dose-dependent manner, both in H28 and H2052 cell lines (IC50 values were 7.2 muM in H28 and 2.0 muM in H2052, respectively, Figure 4A).	('muM', 'Gene', '56925', (203, 206))	('CX-4945', 'Var', (63, 70))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('cell growth', 'CPA', (78, 89))	('muM', 'Gene', (203, 206))	('CX-4945', 'Chemical', 'MESH:C555142', (63, 70))	('muM', 'Gene', '56925', (184, 187))	('cell proliferation', 'biological_process', 'GO:0008283', ('4', '22'))	('muM', 'Gene', (184, 187))
62210	25422081	After treatment with CX-4945, Gli1 expression decreased noticeably at the dosage level of 3 muM in H2052 or 10 muM in H28, and decreased to minimal at 10 muM in H2052 (Figure 4C).	('muM', 'Gene', (92, 95))	('CX-4945', 'Chemical', 'MESH:C555142', (21, 28))	('expression', 'MPA', (35, 45))	('muM', 'Gene', '56925', (111, 114))	('H2052', 'Var', (99, 104))	('decreased', 'NegReg', (46, 55))	('muM', 'Gene', '56925', (92, 95))	('muM', 'Gene', '56925', (154, 157))	('muM', 'Gene', (111, 114))	('Gli1', 'Gene', (30, 34))	('muM', 'Gene', (154, 157))
62211	25422081	We further demonstrated that treatment with CX-4945 led to a dose-dependent decrease in Gli reporter activity in the H28 cells.	('Gli', 'Gene', '2735', (88, 91))	('CX-4945', 'Var', (44, 51))	('Gli', 'Gene', (88, 91))	('CX-4945', 'Chemical', 'MESH:C555142', (44, 51))	('decrease', 'NegReg', (76, 84))
62212	25422081	The decrease was 47% (P < 0.05) in the presence of 3 muM CX-4945 or 70% (P < 0.01) in the presence of 10 muM CX-4945 (Figure 4B).	('muM', 'Gene', (53, 56))	('CX-4945', 'Chemical', 'MESH:C555142', (57, 64))	('muM', 'Gene', (105, 108))	('decrease', 'NegReg', (4, 12))	('muM', 'Gene', '56925', (105, 108))	('CX-4945', 'Var', (57, 64))	('muM', 'Gene', '56925', (53, 56))	('CX-4945', 'Chemical', 'MESH:C555142', (109, 116))
62233	25422081	This is consistent with findings from the recent study that first reported the role of aberrant Hh/Gli1 signaling in human mesothelioma.	('human', 'Species', '9606', (117, 122))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('aberrant', 'Var', (87, 95))	('mesothelioma', 'Disease', (123, 135))
62237	25422081	The Hh pathway plays key roles in maintaining cancer stem cells, and an antagonist of hedgehog inhibits tumor growth, indicating a new therapeutic approach on mesothelioma.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mesothelioma', 'Disease', 'MESH:D008654', (159, 171))	('cancer', 'Disease', (46, 52))	('mesothelioma', 'Disease', (159, 171))	('tumor', 'Disease', (104, 109))	('Hh pathway', 'Pathway', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('hedgehog', 'Gene', (86, 94))	('inhibits', 'NegReg', (95, 103))	('antagonist', 'Var', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
62239	25422081	Recently, we have shown that CK2alpha regulates Hh/Gli1 signaling in human lung cancer, and silencing of CK2alpha promotes Gli1 degradation in a time-course experiment.	('lung cancer', 'Disease', (75, 86))	('CK2alpha', 'Gene', '1459', (29, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('CK2alpha', 'Gene', '1459', (105, 113))	('CK2alpha', 'Gene', (29, 37))	('CK2alpha', 'Gene', (105, 113))	('Gli1 degradation', 'MPA', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('regulates', 'Reg', (38, 47))	('silencing', 'Var', (92, 101))	('human', 'Species', '9606', (69, 74))	('degradation', 'biological_process', 'GO:0009056', ('128', '139'))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('promotes', 'PosReg', (114, 122))	('Hh/Gli1 signaling', 'MPA', (48, 65))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
62241	25422081	Another study showed that silencing CK2alpha inhibited the expressions of Gli1 and Patched homolog 1 (PTCH1) in hepatocellular carcinoma, resulting in the inactivation of Hh signaling pathway.	('Patched homolog 1', 'Gene', '5727', (83, 100))	('Hh signaling pathway', 'Pathway', (171, 191))	('PTCH1', 'Gene', (102, 107))	('Patched homolog 1', 'Gene', (83, 100))	('inactivation', 'NegReg', (155, 167))	('CK2alpha', 'Gene', (36, 44))	('CK2alpha', 'Gene', '1459', (36, 44))	('Hh signaling pathway', 'biological_process', 'GO:0007224', ('171', '191'))	('expressions', 'MPA', (59, 70))	('PTCH1', 'Gene', '5727', (102, 107))	('silencing', 'Var', (26, 35))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('Gli1', 'Protein', (74, 78))	('inhibited', 'NegReg', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
62244	25422081	For example, 32 of 38 (84.2%) of moderate and strong positive (++/+++) staining of Gli1 existed in the 52 samples with moderate and strong positive (++/+++) staining of CK2alpha.	('CK2alpha', 'Gene', '1459', (169, 177))	('Gli1', 'Gene', (83, 87))	('CK2alpha', 'Gene', (169, 177))	('++/+++', 'Var', (149, 155))
62261	23187004	While transient overexpression of Nrf2 conferred protection against the cytotoxicity caused by their combination, knockdown of Nrf2 expression using siRNA enhanced their cytotoxic effect.	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('overexpression', 'PosReg', (16, 30))	('Nrf2', 'Gene', '4780', (34, 38))	('Nrf2', 'Gene', (127, 131))	('knockdown', 'Var', (114, 123))	('enhanced', 'PosReg', (155, 163))	('Nrf2', 'Gene', (34, 38))	('expression', 'Species', '29278', (132, 142))	('cytotoxicity', 'Disease', (72, 84))	('cytotoxic effect', 'CPA', (170, 186))	('Nrf2', 'Gene', '4780', (127, 131))	('expression', 'Species', '29278', (20, 30))
62262	23187004	Pretreatment with Ly294002, a PI3K inhibitor, augmented the decrease in HO-1 level by their combination, whereas no obvious changes were observed in Nrf2 levels.	('Nrf2', 'Gene', (149, 153))	('Ly294002', 'Chemical', 'MESH:C085911', (18, 26))	('decrease', 'NegReg', (60, 68))	('HO-1', 'Gene', (72, 76))	('Ly294002', 'Var', (18, 26))	('HO-1', 'Gene', '3162', (72, 76))	('Nrf2', 'Gene', '4780', (149, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))
62267	23187004	Although the precise molecular mechanism(s) underlying chemoresistance in MPM remains controversial, dysregulation of cell death signaling has been implicated as a significant contributor to the chemoresistance.	('cell death', 'biological_process', 'GO:0008219', ('118', '128'))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('MPM', 'Chemical', '-', (74, 77))	('dysregulation', 'Var', (101, 114))	('cell', 'MPA', (118, 122))
62274	23187004	In several types of human cancers, recent studies have demonstrated that high Nrf2 expression results in enhanced resistance to toxic effects of chemotherapeutic drugs and that suppression of endogenous Nrf2, either by transfecting Nrf2-specific siRNA or overexpressing Keap1, renders these cells more susceptible to therapy.	('more', 'PosReg', (297, 301))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', (26, 33))	('Nrf2', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (83, 93))	('Nrf2', 'Gene', '4780', (232, 236))	('Keap1', 'Gene', (270, 275))	('Nrf2', 'Gene', '4780', (78, 82))	('Nrf2', 'Gene', (232, 236))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('expression', 'Species', '29278', (83, 93))	('human', 'Species', '9606', (20, 25))	('Nrf2', 'Gene', (78, 82))	('Nrf2', 'Gene', '4780', (203, 207))	('suppression', 'NegReg', (177, 188))	('high', 'Var', (73, 77))	('enhanced', 'PosReg', (105, 113))	('Keap1', 'Gene', '9817', (270, 275))
62277	23187004	Therefore, if Nrf2 inhibitors as adjuvant to chemotherapeutic drugs can be identified to maximize cancer cells death, this could have significant therapeutic potential.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Nrf2', 'Gene', '4780', (14, 18))	('inhibitors', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Nrf2', 'Gene', (14, 18))	('cancer', 'Disease', (98, 104))
62291	23187004	2B clearly demonstrates that nuclear localization of Nrf2 was potently inhibited by their combination, whereas it was increased slightly in cells treated with clofarabine or resveratrol alone.	('localization', 'biological_process', 'GO:0051179', ('37', '49'))	('Nrf2', 'Gene', (53, 57))	('clofarabine', 'Chemical', 'MESH:D000077866', (159, 170))	('inhibited', 'NegReg', (71, 80))	('combination', 'Var', (90, 101))	('nuclear localization', 'MPA', (29, 49))	('Nrf2', 'Gene', '4780', (53, 57))	('resveratrol', 'Chemical', 'MESH:D000077185', (174, 185))
62294	23187004	To investigate the biologic relevance between Nrf2 and drug resistance, we examined whether Nrf2 overexpression or knockdown affected sensitivity to combined treatment.	('Nrf2', 'Gene', (46, 50))	('Nrf2', 'Gene', (92, 96))	('drug resistance', 'biological_process', 'GO:0042493', ('55', '70'))	('drug resistance', 'Phenotype', 'HP:0020174', (55, 70))	('expression', 'Species', '29278', (101, 111))	('Nrf2', 'Gene', '4780', (46, 50))	('drug resistance', 'biological_process', 'GO:0009315', ('55', '70'))	('Nrf2', 'Gene', '4780', (92, 96))	('affected', 'Reg', (125, 133))	('knockdown', 'Var', (115, 124))
62295	23187004	When flag-Nrf2-transfected cells were treated with clofarabine and resveratrol in combination, the cell viability was significantly increased compared with that of cells transfected with the empty vector (Fig.	('Nrf2', 'Gene', '4780', (10, 14))	('clofarabine', 'Chemical', 'MESH:D000077866', (51, 62))	('increased', 'PosReg', (132, 141))	('clofarabine', 'Var', (51, 62))	('resveratrol', 'Chemical', 'MESH:D000077185', (67, 78))	('Nrf2', 'Gene', (10, 14))	('cell viability', 'CPA', (99, 113))
62296	23187004	Transfection of flag-Nrf2 markedly increased flag-Nrf2 level, which was accompanied by up-regulation of HO-1 protein expression (Fig.	('Nrf2', 'Gene', '4780', (21, 25))	('increased', 'PosReg', (35, 44))	('expression', 'Species', '29278', (117, 127))	('up-regulation', 'PosReg', (87, 100))	('HO-1', 'Gene', '3162', (104, 108))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('Nrf2', 'Gene', (21, 25))	('Transfection', 'Var', (0, 12))	('Nrf2', 'Gene', '4780', (50, 54))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('Nrf2', 'Gene', (50, 54))	('HO-1', 'Gene', (104, 108))
62297	23187004	These results clearly showed that ectopically expressed flag-Nrf2 has significant biological activity as a transcriptional factor and increases the resistance of MSTO-211H cells to the combination treatment.	('ectopically expressed', 'Var', (34, 55))	('resistance', 'CPA', (148, 158))	('Nrf2', 'Gene', (61, 65))	('increases', 'PosReg', (134, 143))	('MSTO-211H', 'CellLine', 'CVCL:1430', (162, 171))	('biological activity', 'MPA', (82, 101))	('Nrf2', 'Gene', '4780', (61, 65))
62298	23187004	Next, to knockdown the endogenous Nrf2 level, cells were transiently transfected with control siRNA and an Nrf2-specific siRNA.	('knockdown', 'Var', (9, 18))	('Nrf2', 'Gene', '4780', (34, 38))	('Nrf2', 'Gene', '4780', (107, 111))	('Nrf2', 'Gene', (34, 38))	('Nrf2', 'Gene', (107, 111))
62302	23187004	However, PD98059, a MEK inhibitor, slightly increased the Nrf2 level (Fig.	('PD98059', 'Chemical', 'MESH:C093973', (9, 16))	('MEK', 'Gene', (20, 23))	('Nrf2', 'Gene', '4780', (58, 62))	('MEK', 'Gene', '5609', (20, 23))	('increased', 'PosReg', (44, 53))	('Nrf2', 'Gene', (58, 62))	('PD98059', 'Var', (9, 16))
62312	23187004	Accumulating data in cancer studies indicate that Nrf2 is directly involved in the resistance against various drugs, such as cisplatin in lung cancer cells, cisplatin and paclitaxel in endometrial cancer, and 5-fluorouracil (5-FU) in esophageal squamous cancer.	('involved', 'Reg', (67, 75))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (254, 260))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (209, 223))	('5-FU', 'Chemical', 'MESH:D005472', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('esophageal squamous cancer', 'Disease', (234, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('Nrf2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('squamous cancer', 'Phenotype', 'HP:0002860', (245, 260))	('cisplatin', 'Var', (157, 166))	('cancer', 'Disease', (143, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('endometrial cancer', 'Phenotype', 'HP:0012114', (185, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (234, 260))	('cancer', 'Disease', (21, 27))	('lung cancer', 'Disease', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('endometrial cancer', 'Disease', (185, 203))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('endometrial cancer', 'Disease', 'MESH:D016889', (185, 203))	('Nrf2', 'Gene', '4780', (50, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (171, 181))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
62323	23187004	Transient overexpression of Nrf2 protected cells against the cytotoxicity caused by the combination of two agents and its knockdown led to the opposite effects.	('cytotoxicity', 'Disease', (61, 73))	('expression', 'Species', '29278', (14, 24))	('Nrf2', 'Gene', '4780', (28, 32))	('knockdown', 'Var', (122, 131))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('overexpression', 'PosReg', (10, 24))	('Nrf2', 'Gene', (28, 32))
62325	23187004	We also found that Nrf2 overexpression or knockdown potently elicited up-regulation or down-regulation of HO-1 expression, respectively.	('down-regulation', 'NegReg', (87, 102))	('HO-1', 'Gene', '3162', (106, 110))	('Nrf2', 'Gene', (19, 23))	('up-regulation', 'PosReg', (70, 83))	('expression', 'Species', '29278', (28, 38))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('expression', 'Species', '29278', (111, 121))	('expression', 'MPA', (111, 121))	('overexpression', 'PosReg', (24, 38))	('HO-1', 'Gene', (106, 110))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))	('knockdown', 'Var', (42, 51))	('Nrf2', 'Gene', '4780', (19, 23))
62334	23187004	Chemical blockage of PI3K/Akt signaling with Ly294002 augmented a decrease in HO-1 level caused by their combination, whereas no obvious changes were observed in Nrf2 levels.	('Ly294002', 'Chemical', 'MESH:C085911', (45, 53))	('Akt', 'Gene', '207', (26, 29))	('Ly294002', 'Var', (45, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('21', '25'))	('Nrf2', 'Gene', '4780', (162, 166))	('HO-1', 'Gene', (78, 82))	('Akt', 'Gene', (26, 29))	('decrease', 'NegReg', (66, 74))	('Nrf2', 'Gene', (162, 166))	('HO-1', 'Gene', '3162', (78, 82))	('Akt signaling', 'biological_process', 'GO:0043491', ('26', '39'))
62345	23187004	Although additional studies are necessary to elucidate the mechanism of their synergism, our data suggest the potential importance of Nrf2 targeting on enhancing chemotherapeutic potentials in mesothelioma.	('Nrf2', 'Gene', '4780', (134, 138))	('Nrf2', 'Gene', (134, 138))	('enhancing', 'PosReg', (152, 161))	('mesothelioma', 'Disease', (193, 205))	('targeting', 'Var', (139, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (193, 205))
62361	33020398	We have recently shown that the oncolytic adenovirus dl922-947 had antitumor effects in MM cell lines and murine xenografts.	('dl922-947', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('dl922-947', 'Chemical', '-', (53, 62))	('murine', 'Species', '10090', (106, 112))	('adenovirus', 'Species', '10508', (42, 52))	('tumor', 'Disease', (71, 76))
62362	33020398	Previous studies demonstrated that dl922-947-induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy.	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('58', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('dl922-947', 'Chemical', '-', (35, 44))	('host cell', 'cellular_component', 'GO:0043657', ('53', '62'))	('DNA lesions', 'MPA', (108, 119))	('dl922-947-induced', 'Var', (35, 52))	('host cell cycle checkpoint deregulation', 'CPA', (53, 92))
62364	33020398	Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to dl922-947.	('WEE1', 'Gene', '7465', (94, 98))	('enhance', 'PosReg', (106, 113))	('MM cell', 'CPA', (114, 121))	('AZD1775', 'Var', (31, 38))	('WEE1', 'Gene', (94, 98))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('dl922-947', 'Chemical', '-', (137, 146))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('65', '86'))
62365	33020398	Through cell viability assays, we found that AZD1775 synergized with dl922-947 selectively in MM cell lines and increased dl922-947-induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation).	('dl922-947-induced', 'Var', (122, 139))	('cell death', 'CPA', (140, 150))	('AZD1775', 'Var', (45, 52))	('chromatin', 'cellular_component', 'GO:0000785', ('247', '256'))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('AZD1775', 'Chemical', 'MESH:C549567', (45, 52))	('BCL-XL', 'Gene', (230, 236))	('apoptosis', 'CPA', (178, 187))	('decrease', 'NegReg', (237, 245))	('increased', 'PosReg', (112, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('dl922-947', 'Chemical', '-', (122, 131))	('BCL-XL', 'Gene', '598', (230, 236))	('dl922-947', 'Chemical', '-', (69, 78))
62366	33020398	Predictably, dl922-947 and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (gamma-H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1).	('AZD1775', 'Var', (30, 37))	('replication protein A (RPA)32', 'Gene', (167, 196))	('dl922-947', 'Chemical', '-', (13, 22))	('CHK1', 'Gene', '1111', (227, 231))	('DDR', 'CPA', (52, 55))	('increased', 'PosReg', (73, 82))	('RPA', 'cellular_component', 'GO:0005662', ('190', '193'))	('histone H2AX', 'Gene', '3014', (132, 144))	('phospho-checkpoint kinase 1', 'Gene', (198, 225))	('phospho-checkpoint kinase 1', 'Gene', '1111', (198, 225))	('DDR', 'Chemical', '-', (52, 55))	('replication protein A', 'cellular_component', 'GO:0005662', ('167', '188'))	('levels', 'MPA', (83, 89))	('histone H2AX', 'Gene', (132, 144))	('CHK1', 'Gene', (227, 231))	('DDR', 'Chemical', '-', (104, 107))	('dl922-947', 'Var', (13, 22))	('activated', 'PosReg', (38, 47))	('replication protein A (RPA)32', 'Gene', '6118', (167, 196))	('AZD1775', 'Chemical', 'MESH:C549567', (30, 37))
62367	33020398	Dl922-947 also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation.	('WEE1', 'Gene', (96, 100))	('Tyr', 'Chemical', 'MESH:D014443', (34, 37))	('cyclin-dependent kinase 1', 'Gene', '983', (56, 81))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('135', '150'))	('Dl922-947', 'Var', (0, 9))	('cyclin-dependent kinase 1', 'Gene', (56, 81))	('increased', 'PosReg', (15, 24))	('inactive Tyr-15-phosphorylated', 'MPA', (25, 55))	('CDK', 'molecular_function', 'GO:0004693', ('83', '86'))	('CDK1', 'Gene', (83, 87))	('CDK1', 'Gene', '983', (83, 87))	('WEE1', 'Gene', '7465', (96, 100))
62376	33020398	We used, in particular, the adenovirus dl922-947, the efficacy of which has previously been shown by our group and others in cells from different tumors.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('dl922-947', 'Var', (39, 48))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('dl922-947', 'Chemical', '-', (39, 48))	('adenovirus', 'Species', '10508', (28, 38))	('tumors', 'Disease', (146, 152))
62377	33020398	This OV carries a 24-bp deletion in the E1A-Conserved Region 2, which renders viral replication dependent on the inactivation of the retinoblastoma (RB1) pathway.	('RB1', 'Gene', (149, 152))	('retinoblastoma', 'Phenotype', 'HP:0009919', (133, 147))	('viral replication', 'biological_process', 'GO:0008166', ('78', '95'))	('RB1', 'Gene', '5925', (149, 152))	('viral replication', 'biological_process', 'GO:0019079', ('78', '95'))	('deletion', 'Var', (24, 32))	('retinoblastoma', 'Disease', 'MESH:D012175', (133, 147))	('retinoblastoma', 'Disease', (133, 147))	('inactivation', 'NegReg', (113, 125))	('viral replication', 'biological_process', 'GO:0019058', ('78', '95'))
62378	33020398	Since disruption of the oncosuppressive RB1 pathway is an almost universal hallmark of human cancers, including MM, dl922-947 can kill tumor cells, while sparing normal cells in which the RB1 pathway is functional.	('cancers', 'Disease', (93, 100))	('RB1', 'Gene', '5925', (188, 191))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('dl922-947', 'Var', (116, 125))	('oncosuppressive', 'Pathway', (24, 39))	('RB1', 'Gene', (40, 43))	('disruption', 'Var', (6, 16))	('RB1', 'Gene', (188, 191))	('dl922-947', 'Chemical', '-', (116, 125))	('RB1', 'Gene', '5925', (40, 43))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
62379	33020398	We showed that dl922-947 had antitumor effects in both MM cell lines and xenografts.	('dl922-947', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('dl922-947', 'Chemical', '-', (15, 24))	('tumor', 'Disease', (33, 38))
62380	33020398	In particular, dl922-947 affected cell cycle progression, triggered immunogenic cell death, and reduced the production of pro-angiogenic factors, consistent with the ability of OVs to induce an antitumor immune response and a re-shaping of the tumor microenvironment.	('cell cycle progression', 'CPA', (34, 56))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cell death', 'biological_process', 'GO:0008219', ('80', '90'))	('production of pro-angiogenic factors', 'MPA', (108, 144))	('dl922-947', 'Var', (15, 24))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('triggered', 'Reg', (58, 67))	('affected', 'Reg', (25, 33))	('immune response', 'biological_process', 'GO:0006955', ('204', '219'))	('cell cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('dl922-947', 'Chemical', '-', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('immunogenic cell death', 'CPA', (68, 90))	('reduced', 'NegReg', (96, 103))
62381	33020398	Beyond the above-mentioned mechanisms of dl922-947 action, the deregulation of multiple cell cycle checkpoints, which accelerates the host cell progression through the cycle, plays an important role for the activity of this OV.	('dl922-947', 'Chemical', '-', (41, 50))	('host cell', 'cellular_component', 'GO:0043657', ('134', '143'))	('host cell progression through the cycle', 'CPA', (134, 173))	('deregulation', 'MPA', (63, 75))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))	('dl922-947', 'Var', (41, 50))	('accelerates', 'PosReg', (118, 129))
62382	33020398	Abrogation of these checkpoints results in genomic DNA over-replication and, consequently, in the accumulation of DNA lesions, which have been found to associate with higher sensitivity to dl922-947.	('accumulation', 'PosReg', (98, 110))	('dl922-947', 'Chemical', '-', (189, 198))	('over-replication', 'PosReg', (55, 71))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('DNA', 'Gene', (114, 117))	('lesions', 'Var', (118, 125))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
62384	33020398	Consistently, we and others showed that inhibitors of crucial factors of the DNA damage signaling and repair, such as ataxia telangiectasia mutated (ATM), checkpoint kinase 1 (CHK1), and poly(ADP-ribose) polymerase (PARP), enhanced the effects of dl922-947.	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('ataxia telangiectasia mutated', 'Gene', '472', (118, 147))	('ATM', 'Gene', '472', (149, 152))	('CHK1', 'Gene', (176, 180))	('poly(ADP-ribose) polymerase', 'Gene', '142', (187, 214))	('poly(ADP-ribose) polymerase', 'Gene', (187, 214))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('enhanced', 'PosReg', (223, 231))	('dl922-947', 'Var', (247, 256))	('PARP', 'Gene', '142', (216, 220))	('ATM', 'Gene', (149, 152))	('telangiectasia', 'Phenotype', 'HP:0001009', (125, 139))	('CHK1', 'Gene', '1111', (176, 180))	('PARP', 'Gene', (216, 220))	('ataxia telangiectasia mutated', 'Gene', (118, 147))	('checkpoint kinase 1', 'Gene', '1111', (155, 174))	('dl922-947', 'Chemical', '-', (247, 256))	('ataxia', 'Phenotype', 'HP:0001251', (118, 124))	('checkpoint kinase 1', 'Gene', (155, 174))	('effects', 'MPA', (236, 243))
62385	33020398	Among the drugs targeting the DDR pathway, AZD1775 (MK-1775, adavosertib), an inhibitor of the tyrosine kinase WEE1, has shown efficacy in sensitizing many cancer types to DNA damaging agents in both preclinical studies and phase I/II clinical trials.	('WEE1', 'Gene', (111, 115))	('WEE1', 'Gene', '7465', (111, 115))	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('cancer', 'Disease', (156, 162))	('adavosertib', 'Chemical', 'MESH:C549567', (61, 72))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('sensitizing', 'Reg', (139, 150))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('DDR', 'Chemical', '-', (30, 33))	('AZD1775', 'Var', (43, 50))	('MK-1775', 'Chemical', 'MESH:C549567', (52, 59))
62390	33020398	Therefore, tumor cells treated with a WEE1 inhibitor are forced to enter aberrant and lethal mitosis in the presence of DNA damage; conversely, non-neoplastic cells, which retain G1/S checkpoint activity, are unaffected by this treatment.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mitosis', 'biological_process', 'GO:0000278', ('93', '100'))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('179', '194'))	('tumor', 'Disease', (11, 16))	('WEE1', 'Gene', '7465', (38, 42))	('enter', 'PosReg', (67, 72))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('WEE1', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('inhibitor', 'Var', (43, 52))
62391	33020398	Based on this rationale, many studies focused on the effects of WEE1 inhibition in combination with DNA damaging agents in tumors bearing TP53 mutations.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('TP53', 'Gene', '7157', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('TP53', 'Gene', (138, 142))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('WEE1', 'Gene', (64, 68))	('WEE1', 'Gene', '7465', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('inhibition', 'NegReg', (69, 79))	('mutations', 'Var', (143, 152))
62392	33020398	However, other mechanisms, such as DDR aberrations, nucleotide starvation, replicative stress, and, as more recently found, loss of the ATRX chromatin remodeler gene and low phosphatase and tensin homolog (PTEN) expression, contribute to sensitize cancer cells to WEE1 inhibition, which, thus, proved monotherapy activity even in TP53-wild-type cancer cells.	('WEE1', 'Gene', '7465', (264, 268))	('low', 'NegReg', (170, 173))	('TP53', 'Gene', (330, 334))	('stress', 'Disease', (87, 93))	('phosphatase', 'molecular_function', 'GO:0016791', ('174', '185'))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('inhibition', 'NegReg', (269, 279))	('cancer', 'Disease', (248, 254))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('174', '204'))	('loss', 'Var', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('TP53', 'Gene', '7157', (330, 334))	('WEE1', 'Gene', (264, 268))	('phosphatase and tensin homolog', 'Gene', '5728', (174, 204))	('DDR', 'Chemical', '-', (35, 38))	('sensitize', 'Reg', (238, 247))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('PTEN', 'Gene', (206, 210))	('cancer', 'Disease', (345, 351))	('low phosphatase', 'Phenotype', 'HP:0003282', (170, 185))	('ATRX', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('ATRX', 'Gene', '546', (136, 140))	('stress', 'Disease', 'MESH:D000079225', (87, 93))	('PTEN', 'Gene', '5728', (206, 210))	('chromatin', 'cellular_component', 'GO:0000785', ('141', '150'))
62395	33020398	We have also previously observed that dl922-947 induces DNA over-replication in MM cells, which could be indicative of possible DNA damage generation.	('DNA over-replication', 'MPA', (56, 76))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('induces', 'Reg', (48, 55))	('dl922-947', 'Var', (38, 47))	('dl922-947', 'Chemical', '-', (38, 47))
62396	33020398	In the present study, we found that dl922-947 induces, indeed, a DDR in MM cells and that WEE1 inhibition through AZD1775 synergizes with dl922-947 by abrogating the DNA damage checkpoint and increasing cell death.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('dl922-947', 'Chemical', '-', (138, 147))	('WEE1', 'Gene', (90, 94))	('DDR', 'MPA', (65, 68))	('WEE1', 'Gene', '7465', (90, 94))	('DDR', 'Chemical', '-', (65, 68))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('166', '187'))	('dl922-947', 'Var', (36, 45))	('DNA damage checkpoint', 'Pathway', (166, 187))	('increasing', 'PosReg', (192, 202))	('inhibition', 'NegReg', (95, 105))	('AZD1775', 'Gene', (114, 121))	('cell death', 'biological_process', 'GO:0008219', ('203', '213'))	('cell death', 'CPA', (203, 213))	('AZD1775', 'Chemical', 'MESH:C549567', (114, 121))	('dl922-947', 'Chemical', '-', (36, 45))	('abrogating', 'NegReg', (151, 161))	('induces', 'Reg', (46, 53))
62397	33020398	To evaluate whether WEE1 inhibition by AZD1775 enhances dl922-947 efficacy in MM cells, we challenged NCI-H28 and MSTO-211H cell lines for 5 days with the two agents, both alone and in combination at different concentrations in a constant ratio.	('AZD1775', 'Chemical', 'MESH:C549567', (39, 46))	('dl922-947 efficacy', 'MPA', (56, 74))	('MSTO-211H', 'CellLine', 'CVCL:1430', (114, 123))	('NCI-H28', 'Chemical', '-', (102, 109))	('inhibition', 'NegReg', (25, 35))	('dl922-947', 'Chemical', '-', (56, 65))	('enhances', 'PosReg', (47, 55))	('WEE1', 'Gene', '7465', (20, 24))	('AZD1775', 'Var', (39, 46))	('WEE1', 'Gene', (20, 24))
62399	33020398	Cell viability data were obtained through sulforhodamine B (SRB) assay (Figure 1A) and evaluated by isobologram analysis, which showed synergism between AZD1775 and dl922-947 in both cell lines (Figure 1B).	('sulforhodamine B', 'Gene', (42, 58))	('AZD1775', 'Var', (153, 160))	('dl922-947', 'Var', (165, 174))	('AZD1775', 'Chemical', 'MESH:C549567', (153, 160))	('sulforhodamine B', 'Gene', '10575', (42, 58))	('SRB', 'Gene', '10575', (60, 63))	('dl922-947', 'Chemical', '-', (165, 174))	('SRB', 'Gene', (60, 63))
62402	33020398	To assess cell death induction by dl922-947 and/or AZD1775 in NCI-H28 and MSTO-211H cell lines, we analyzed, through FACS, double staining with annexinV-FITC, which detects an early apoptosis marker, and propidium iodide (PI), which indicates membrane permeabilization in necrotic/late apoptotic cells.	('necrotic', 'Disease', (272, 280))	('propidium iodide', 'Chemical', 'MESH:D011419', (204, 220))	('AZD1775', 'Var', (51, 58))	('NCI-H28', 'Chemical', '-', (62, 69))	('MSTO-211H', 'CellLine', 'CVCL:1430', (74, 83))	('membrane', 'cellular_component', 'GO:0016020', ('243', '251'))	('necrotic', 'Disease', 'MESH:D009336', (272, 280))	('AZD1775', 'Chemical', 'MESH:C549567', (51, 58))	('annexinV-FITC', 'Chemical', '-', (144, 157))	('dl922-947', 'Var', (34, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('dl922-947', 'Chemical', '-', (34, 43))	('cell death', 'biological_process', 'GO:0008219', ('10', '20'))
62403	33020398	Ninety-six hours after treatment with the two agents at their IC50 values, we observed an increase in the percentage of both annexinV-positive-PI-negative cells (indicative of early apoptosis) and annexinV-positive-PI-positive cells (indicative of late apoptosis/necrosis), which was higher after dl922-947 and AZD1775 co-treatment than after dl922-947 infection alone (Figure 2A).	('dl922-947', 'Var', (297, 306))	('annexinV-positive-PI-negative', 'Protein', (125, 154))	('infection', 'Disease', (353, 362))	('infection', 'Disease', 'MESH:D007239', (353, 362))	('necrosis', 'biological_process', 'GO:0008220', ('263', '271'))	('necrosis', 'Disease', (263, 271))	('AZD1775 co-treatment', 'Var', (311, 331))	('necrosis', 'biological_process', 'GO:0070265', ('263', '271'))	('annexinV-positive-PI-positive', 'Var', (197, 226))	('necrosis', 'biological_process', 'GO:0019835', ('263', '271'))	('dl922-947', 'Chemical', '-', (297, 306))	('necrosis', 'biological_process', 'GO:0001906', ('263', '271'))	('apoptosis', 'biological_process', 'GO:0097194', ('253', '262'))	('AZD1775', 'Chemical', 'MESH:C549567', (311, 318))	('apoptosis', 'biological_process', 'GO:0006915', ('253', '262'))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('dl922-947', 'Chemical', '-', (343, 352))	('increase', 'PosReg', (90, 98))	('necrosis', 'biological_process', 'GO:0008219', ('263', '271'))	('co-treatment', 'Var', (319, 331))	('necrosis', 'Disease', 'MESH:D009336', (263, 271))
62404	33020398	Conversely, treatment with AZD1775 alone did not induce a significant increase in annexinV positivity.	('annexinV', 'Protein', (82, 90))	('AZD1775', 'Chemical', 'MESH:C549567', (27, 34))	('AZD1775', 'Var', (27, 34))
62405	33020398	We also evaluated the activation of the apoptosis marker caspase-3 in NCI-H28 and MSTO-211H cells treated as above, by Western blotting analysis; we observed that dl922-947, both alone and in combination with AZD1775, induced an increase in the active cleaved caspase-3 levels and a concurrent slight decrease in the full-length protein (Figure 2B).	('AZD1775', 'Chemical', 'MESH:C549567', (209, 216))	('dl922-947', 'Var', (163, 172))	('protein', 'cellular_component', 'GO:0003675', ('329', '336'))	('decrease', 'NegReg', (301, 309))	('MSTO-211H', 'CellLine', 'CVCL:1430', (82, 91))	('NCI-H28', 'Chemical', '-', (70, 77))	('dl922-947', 'Chemical', '-', (163, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('increase', 'PosReg', (229, 237))	('caspase-3', 'Gene', (57, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('full-length protein', 'MPA', (317, 336))	('caspase-3', 'Gene', (260, 269))	('caspase-3', 'Gene', '836', (57, 66))	('caspase-3', 'Gene', '836', (260, 269))
62408	33020398	Considering that, among BCL-2 family members, the anti-apoptotic protein BCL-XL was previously found to be particularly important for survival of MM cells, including NCI-H28 and MSTO-211H, we analyzed by Western blotting its expression in these cell lines treated with dl922-947 and/or AZD1775, as described above.	('dl922-947', 'Var', (269, 278))	('BCL-XL', 'Gene', '598', (73, 79))	('BCL-2', 'Gene', '596', (24, 29))	('dl922-947', 'Chemical', '-', (269, 278))	('BCL-2', 'Gene', (24, 29))	('BCL-2', 'molecular_function', 'GO:0015283', ('24', '29'))	('AZD1775', 'Var', (286, 293))	('AZD1775', 'Chemical', 'MESH:C549567', (286, 293))	('MSTO-211H', 'CellLine', 'CVCL:1430', (178, 187))	('BCL-XL', 'Gene', (73, 79))	('NCI-H28', 'Chemical', '-', (166, 173))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))
62409	33020398	We observed decreased BCL-XL levels in both cell lines upon treatment with dl922-947 and dl922-947-AZD1775 combination (Figure 2B).	('dl922-947', 'Chemical', '-', (75, 84))	('BCL-XL', 'Gene', '598', (22, 28))	('dl922-947-AZD1775', 'Var', (89, 106))	('dl922-947', 'Var', (75, 84))	('decreased', 'NegReg', (12, 21))	('dl922-947', 'Chemical', '-', (89, 98))	('AZD1775', 'Chemical', 'MESH:C549567', (99, 106))	('BCL-XL', 'Gene', (22, 28))
62410	33020398	Moreover, DAPI staining showed that NCI-H28 and MSTO-211H cells, treated with dl922-947 and its combination with AZD1775, had clumped or condensed chromatin, which is compatible with the apoptotic cell death.	('DAPI', 'Chemical', 'MESH:C007293', (10, 14))	('dl922-947', 'Var', (78, 87))	('chromatin', 'cellular_component', 'GO:0000785', ('147', '156'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('187', '207'))	('dl922-947', 'Chemical', '-', (78, 87))	('clumped', 'CPA', (126, 133))	('MSTO-211H', 'CellLine', 'CVCL:1430', (48, 57))	('NCI-H28', 'Chemical', '-', (36, 43))	('AZD1775', 'Chemical', 'MESH:C549567', (113, 120))
62411	33020398	Conversely, cells treated with AZD1775 alone had uncondensed and homogeneously distributed chromatin, similar to untreated control cells.	('uncondensed', 'MPA', (49, 60))	('chromatin', 'cellular_component', 'GO:0000785', ('91', '100'))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('AZD1775', 'Var', (31, 38))
62412	33020398	This is consistent with the lack of a significant increase in apoptotic markers that we observed in AZD1775-treated cells.	('apoptotic', 'MPA', (62, 71))	('AZD1775', 'Chemical', 'MESH:C549567', (100, 107))	('AZD1775-treated', 'Var', (100, 115))
62413	33020398	To study the molecular mechanism whereby WEE1 inhibition by AZD1775 sensitizes MM cells to dl922-947, we analyzed the effects of these agents on the WEE1 direct substrate, CDK1, and also on crucial factors of the DDR signaling.	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('WEE1', 'Gene', '7465', (149, 153))	('inhibition', 'NegReg', (46, 56))	('WEE1', 'Gene', (149, 153))	('CDK1', 'Gene', '983', (172, 176))	('CDK', 'molecular_function', 'GO:0004693', ('172', '175'))	('WEE1', 'Gene', '7465', (41, 45))	('CDK1', 'Gene', (172, 176))	('AZD1775', 'Var', (60, 67))	('dl922-947', 'Chemical', '-', (91, 100))	('WEE1', 'Gene', (41, 45))	('DDR', 'Chemical', '-', (213, 216))	('AZD1775', 'Chemical', 'MESH:C549567', (60, 67))
62418	33020398	Through Western blotting, we observed that dl922-947 and AZD1775, both alone and in combination at their respective IC50 values, induced the expression of gamma-H2AX, phospho-RPA32 Ser 4/Ser 8, and phospho-CHK1 Ser 345 in both MM cell lines, which is indicative of DDR activation (Figure 3).	('dl922-947', 'Var', (43, 52))	('Ser', 'Chemical', 'MESH:D012694', (181, 184))	('Ser', 'Chemical', 'MESH:D012694', (187, 190))	('Ser', 'Chemical', 'MESH:D012694', (211, 214))	('RPA', 'cellular_component', 'GO:0005662', ('175', '178'))	('CHK1', 'Gene', (206, 210))	('Ser', 'cellular_component', 'GO:0005790', ('181', '184'))	('dl922-947', 'Chemical', '-', (43, 52))	('Ser', 'cellular_component', 'GO:0005790', ('187', '190'))	('gamma-H2AX', 'Protein', (155, 165))	('Ser', 'cellular_component', 'GO:0005790', ('211', '214'))	('DDR', 'Chemical', '-', (265, 268))	('expression', 'MPA', (141, 151))	('CHK1', 'Gene', '1111', (206, 210))	('RPA32', 'Gene', (175, 180))	('AZD1775', 'Chemical', 'MESH:C549567', (57, 64))	('RPA32', 'Gene', '6118', (175, 180))	('AZD1775', 'Var', (57, 64))	('induced', 'PosReg', (129, 136))
62419	33020398	Consistently, we observed that dl922-947 increased the levels of the inactive Tyr-15-phosphorylated form of CDK1, denoting G2/M checkpoint activation (Figure 3).	('increased', 'PosReg', (41, 50))	('CDK', 'molecular_function', 'GO:0004693', ('108', '111'))	('dl922-947', 'Chemical', '-', (31, 40))	('levels of the', 'MPA', (55, 68))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('123', '138'))	('CDK1', 'Gene', '983', (108, 112))	('Tyr', 'Chemical', 'MESH:D014443', (78, 81))	('CDK1', 'Gene', (108, 112))	('G2/M checkpoint activation', 'CPA', (123, 149))	('dl922-947', 'Var', (31, 40))
62425	33020398	The replication of this OV, bearing a deletion in the RB1 binding site of the E1A region, is dependent on RB1 inactivation, which occurs very frequently in MM.	('RB1', 'Gene', '5925', (106, 109))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('RB1', 'Gene', (54, 57))	('deletion', 'Var', (38, 46))	('RB1', 'Gene', (106, 109))	('RB1', 'Gene', '5925', (54, 57))
62426	33020398	Indeed, although RB1 mutations are extremely rare in this cancer type (COSMIC, the Catalogue of Somatic Mutations in Cancer, ), the homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus, which results in RB1 functional inactivation, is one of the most common mutations in MM cells, including the NCI-H28 and MSTO-211H cell lines under study (COSMIC).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('159', '192'))	('RB1', 'Gene', '5925', (17, 20))	('functional', 'MPA', (233, 243))	('deletion', 'Var', (143, 151))	('RB1', 'Gene', (229, 232))	('CDKN2A', 'Gene', '1029', (197, 203))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cat', 'Gene', (83, 86))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (159, 195))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('176', '192'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('MSTO-211H', 'CellLine', 'CVCL:1430', (333, 342))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (159, 195))	('RB1', 'Gene', '5925', (229, 232))	('NCI-H28', 'Chemical', '-', (321, 328))	('Cat', 'Gene', '847', (83, 86))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('RB1', 'Gene', (17, 20))	('CDKN2A', 'Gene', (197, 203))	('Cancer', 'Disease', (117, 123))	('cancer', 'Disease', (58, 64))
62427	33020398	We have found that dl922-947 has antitumor effects in both MM cell lines and xenografts by affecting cell cycle progression, triggering immunogenic cell death, and reducing the production of pro-angiogenic factors.	('dl922-947', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('affecting', 'Reg', (91, 100))	('production of pro-angiogenic factors', 'MPA', (177, 213))	('dl922-947', 'Chemical', '-', (19, 28))	('reducing', 'NegReg', (164, 172))	('cell cycle progression', 'CPA', (101, 123))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('immunogenic cell death', 'CPA', (136, 158))	('triggering', 'Reg', (125, 135))
62428	33020398	In particular, we have observed that dl922-947 induces DNA over-replication in MM cells, which can generate DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('induces', 'Reg', (47, 54))	('dl922-947', 'Var', (37, 46))	('DNA over-replication', 'MPA', (55, 75))	('dl922-947', 'Chemical', '-', (37, 46))	('DNA', 'MPA', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
62429	33020398	Since the ability of dl922-947 to induce DNA lesion accumulation associates with its efficacy and given that DDR inhibitors can favor this mechanism of action, in the present study, we analyzed whether the abrogation of the G2/M DNA damage checkpoint through the WEE1 inhibitor AZD1775 enhanced MM cell sensitivity to dl922-947.	('WEE1', 'Gene', '7465', (263, 267))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('229', '250'))	('dl922-947', 'Chemical', '-', (318, 327))	('DNA', 'MPA', (41, 44))	('enhanced', 'PosReg', (286, 294))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('AZD1775', 'Chemical', 'MESH:C549567', (278, 285))	('WEE1', 'Gene', (263, 267))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('MM cell', 'CPA', (295, 302))	('abrogation', 'Var', (206, 216))	('DDR', 'Chemical', '-', (109, 112))	('dl922-947', 'Chemical', '-', (21, 30))
62431	33020398	We previously reported that both dl922-947 and AZD1775 sensitized MM cells to cisplatin, the drug currently used in MM chemotherapy.	('dl922-947', 'Var', (33, 42))	('AZD1775', 'Chemical', 'MESH:C549567', (47, 54))	('dl922-947', 'Chemical', '-', (33, 42))	('sensitized', 'Reg', (55, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('AZD1775', 'Var', (47, 54))
62432	33020398	The comparison of the present data with our previous findings shows that, at the same treatment time and doses, dl922-947 affects cell viability similarly or even more efficaciously when combined with AZD1775 than when combined with cisplatin in MSTO-211H and NCI-H28 cells, respectively.	('MSTO-211H', 'CellLine', 'CVCL:1430', (246, 255))	('combined', 'Interaction', (187, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))	('dl922-947', 'Var', (112, 121))	('affects', 'Reg', (122, 129))	('AZD1775', 'Chemical', 'MESH:C549567', (201, 208))	('dl922-947', 'Chemical', '-', (112, 121))	('cell viability', 'CPA', (130, 144))	('NCI-H28', 'Chemical', '-', (260, 267))
62435	33020398	We observed an increase in the percentage of annexinV-positive cells, which was higher after the combination treatment with dl922-947 and AZD1775 than after the treatment with dl922-947 alone.	('dl922-947', 'Var', (124, 133))	('combination', 'Interaction', (97, 108))	('AZD1775', 'Var', (138, 145))	('dl922-947', 'Chemical', '-', (176, 185))	('dl922-947', 'Chemical', '-', (124, 133))	('increase', 'PosReg', (15, 23))	('annexinV-positive', 'Protein', (45, 62))	('AZD1775', 'Chemical', 'MESH:C549567', (138, 145))	('higher', 'PosReg', (80, 86))
62436	33020398	Moreover, upon treatment with dl922-947, both alone and in combination with AZD1775, we also observed the activation of the apoptotic marker caspase-3.	('caspase-3', 'Gene', (141, 150))	('apoptotic marker', 'MPA', (124, 140))	('caspase-3', 'Gene', '836', (141, 150))	('dl922-947', 'Var', (30, 39))	('AZD1775', 'Chemical', 'MESH:C549567', (76, 83))	('dl922-947', 'Chemical', '-', (30, 39))	('activation', 'PosReg', (106, 116))
62437	33020398	We confirmed the caspase-dependency of the dl922-947-induced cell death by using the pan-caspase inhibitor Z-VAD-FMK, which significantly increased cell viability.	('increased', 'PosReg', (138, 147))	('dl922-947-induced', 'Var', (43, 60))	('cell death', 'CPA', (61, 71))	('cell death', 'biological_process', 'GO:0008219', ('61', '71'))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (107, 116))	('dl922-947', 'Chemical', '-', (43, 52))
62438	33020398	We also observed a decreased expression of the anti-apoptotic protein BCL-XL in NCI-H28 and MSTO-211 cells following treatment with dl922-947 and dl922-947-AZD1775 combination.	('dl922-947', 'Chemical', '-', (146, 155))	('dl922-947', 'Var', (132, 141))	('AZD1775', 'Chemical', 'MESH:C549567', (156, 163))	('dl922-947', 'Chemical', '-', (132, 141))	('BCL-XL', 'Gene', (70, 76))	('dl922-947-AZD1775', 'Var', (146, 163))	('decreased', 'NegReg', (19, 28))	('NCI-H28', 'Chemical', '-', (80, 87))	('expression', 'MPA', (29, 39))	('BCL-XL', 'Gene', '598', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
62440	33020398	Furthermore, we observed a nuclear morphology compatible with the apoptotic cell death upon treatment with dl922-947 and its combination with AZD1775.	('combination', 'Interaction', (125, 136))	('dl922-947', 'Chemical', '-', (107, 116))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('66', '86'))	('AZD1775', 'Chemical', 'MESH:C549567', (142, 149))	('nuclear morphology', 'biological_process', 'GO:0006997', ('27', '45'))	('dl922-947', 'Var', (107, 116))	('apoptotic cell death', 'CPA', (66, 86))
62441	33020398	Conversely, in previous studies on ovarian cancer cells, classical hallmarks of apoptosis were not detected after treatment with dl922-947 or other oncolytic adenoviral mutants, which have been suggested to induce a different type of programmed cell death.	('dl922-947', 'Var', (129, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('dl922-947', 'Chemical', '-', (129, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('programmed cell death', 'biological_process', 'GO:0012501', ('234', '255'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ovarian cancer', 'Disease', (35, 49))
62442	33020398	However, it seems plausible that dl922-947 could trigger different cell death processes in diverse cancer cell types, although further studies are necessary to understand the exact mode of cell death induced by this OV in MM.	('dl922-947', 'Var', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('dl922-947', 'Chemical', '-', (33, 42))	('cancer', 'Disease', (99, 105))	('cell death', 'biological_process', 'GO:0008219', ('67', '77'))	('trigger', 'Reg', (49, 56))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
62443	33020398	We observed that AZD1775 and dl922-947, both alone and in combination, activated the DDR pathway, as indicated by the increase in expression of gamma-H2AX, phospho-RPA32 Ser 4/Ser 8, and phospho-CHK1 Ser 345, and in line with what was previously found in other cancer cell types.	('expression', 'MPA', (130, 140))	('increase', 'PosReg', (118, 126))	('DDR pathway', 'Pathway', (85, 96))	('dl922-947', 'Chemical', '-', (29, 38))	('CHK1', 'Gene', '1111', (195, 199))	('DDR', 'Chemical', '-', (85, 88))	('RPA32', 'Gene', (164, 169))	('Ser', 'cellular_component', 'GO:0005790', ('200', '203'))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('Ser', 'Chemical', 'MESH:D012694', (170, 173))	('RPA32', 'Gene', '6118', (164, 169))	('cancer', 'Disease', (261, 267))	('AZD1775', 'Chemical', 'MESH:C549567', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('Ser', 'Chemical', 'MESH:D012694', (176, 179))	('Ser', 'Chemical', 'MESH:D012694', (200, 203))	('AZD1775', 'Var', (17, 24))	('CHK1', 'Gene', (195, 199))	('dl922-947', 'Var', (29, 38))	('activated', 'PosReg', (71, 80))	('Ser', 'cellular_component', 'GO:0005790', ('170', '173'))	('RPA', 'cellular_component', 'GO:0005662', ('164', '167'))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('gamma-H2AX', 'Protein', (144, 154))
62444	33020398	Moreover, we observed that dl922-947 increased the levels of the inactive Tyr-15-phosphorylated form of CDK1, which is a surrogate marker of G2/M checkpoint activation.	('dl922-947', 'Chemical', '-', (27, 36))	('levels of the inactive Tyr-15-phosphorylated', 'MPA', (51, 95))	('Tyr', 'Chemical', 'MESH:D014443', (74, 77))	('CDK1', 'Gene', (104, 108))	('increased', 'PosReg', (37, 46))	('CDK1', 'Gene', '983', (104, 108))	('CDK', 'molecular_function', 'GO:0004693', ('104', '107'))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('141', '156'))	('dl922-947', 'Var', (27, 36))
62445	33020398	This increase in phospho-CDK1 was suppressed by AZD1775.	('suppressed', 'NegReg', (34, 44))	('AZD1775', 'Var', (48, 55))	('CDK1', 'Gene', (25, 29))	('CDK1', 'Gene', '983', (25, 29))	('AZD1775', 'Chemical', 'MESH:C549567', (48, 55))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))
62446	33020398	Thus, this molecule seems indeed to abrogate the dl922-947-induced DNA damage checkpoint in MM cell lines by effectively preventing the WEE1-mediated phosphorylation and inactivation of CDK1.	('preventing', 'NegReg', (121, 131))	('CDK1', 'Gene', (186, 190))	('abrogate', 'NegReg', (36, 44))	('inactivation', 'MPA', (170, 182))	('dl922-947-induced', 'Var', (49, 66))	('DNA damage checkpoint', 'MPA', (67, 88))	('dl922-947', 'Chemical', '-', (49, 58))	('WEE1', 'Gene', (136, 140))	('WEE1', 'Gene', '7465', (136, 140))	('CDK1', 'Gene', '983', (186, 190))
62447	33020398	G2/M checkpoint abrogation through WEE1 inhibition in combination with DNA-damaging agents has initially been suggested to be mainly effective on cancer cells bearing mutations in the key G1/S checkpoint regulator TP53 since these cells rely on the G2/M checkpoint to detect and repair damaged DNA.	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('249', '264'))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('WEE1', 'Gene', (35, 39))	('WEE1', 'Gene', '7465', (35, 39))	('mutations', 'Var', (167, 176))	('inhibition', 'NegReg', (40, 50))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('294', '297'))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('188', '203'))	('TP53', 'Gene', '7157', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TP53', 'Gene', (214, 218))
62449	33020398	In particular, the homozygous deletion of the CDKN2A locus, which, as stated above, is very common in MM cells, results in the functional inactivation of both the key tumor suppressors controlling the G1/S checkpoint, p53 and RB1.	('inactivation', 'NegReg', (138, 150))	('CDKN2A', 'Gene', (46, 52))	('RB1', 'Gene', '5925', (226, 229))	('CDKN2A', 'Gene', '1029', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('deletion', 'Var', (30, 38))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('201', '216'))	('p53', 'Gene', (218, 221))	('p53', 'Gene', '7157', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RB1', 'Gene', (226, 229))	('tumor', 'Disease', (167, 172))
62450	33020398	Consistent with these observations, in this study, we found that the dl922-947-AZD1775 combination was effective in NCI-H28 and MSTO-211H cell lines, which, while expressing wild-type TP53, both carry a homozygous deletion of the tumor suppressor locus CDKN2A (COSMIC, ).	('tumor', 'Disease', (230, 235))	('tumor suppressor', 'biological_process', 'GO:0051726', ('230', '246'))	('deletion', 'Var', (214, 222))	('NCI-H28', 'Chemical', '-', (116, 123))	('MSTO-211H', 'CellLine', 'CVCL:1430', (128, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('230', '246'))	('CDKN2A', 'Gene', (253, 259))	('TP53', 'Gene', '7157', (184, 188))	('CDKN2A', 'Gene', '1029', (253, 259))	('TP53', 'Gene', (184, 188))	('AZD1775', 'Chemical', 'MESH:C549567', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('dl922-947', 'Chemical', '-', (69, 78))
62451	33020398	Thus, disruption of crucial tumor-suppressive pathways, which largely underlies MM development, seems to offer therapeutic opportunities for this cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', (28, 33))	('disruption', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
62453	33020398	Accordingly, in our previous preclinical studies on MM, we have shown the potential anticancer efficacy of strategies based on the reactivation of the oncosuppressive functions of p53, RBL2/p130, which is another crucial member of the RB family, and p27, which is a cell cycle inhibitor co-regulated with RBL2/p130; conversely, in the present study, we used agents that exploit tumor suppressor inactivation for their selective anticancer action: the oncolytic adenovirus dl922-947, which depends on RB1 inactivation for its replication, and AZD1775, which is considered to be mainly effective in cancer cells defective in G1/S checkpoint regulators.	('tumor', 'Disease', (378, 383))	('cancer', 'Disease', (88, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('378', '394'))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('cancer', 'Disease', (597, 603))	('p130', 'Gene', (190, 194))	('p130', 'Gene', (310, 314))	('tumor', 'Disease', 'MESH:D009369', (378, 383))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('p27', 'Gene', '10671', (250, 253))	('RB1', 'Gene', '5925', (500, 503))	('adenovirus', 'Species', '10508', (461, 471))	('tumor suppressor', 'biological_process', 'GO:0051726', ('378', '394'))	('cancer', 'Phenotype', 'HP:0002664', (597, 603))	('dl922-947', 'Chemical', '-', (472, 481))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('p27', 'Gene', (250, 253))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('AZD1775', 'Chemical', 'MESH:C549567', (542, 549))	('p53', 'Gene', '7157', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (597, 603))	('cell cycle', 'biological_process', 'GO:0007049', ('266', '276'))	('RBL2', 'Gene', (305, 309))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('623', '638'))	('p130', 'Gene', '5934', (190, 194))	('p130', 'Gene', '5934', (310, 314))	('AZD1775', 'Var', (542, 549))	('RBL2', 'Gene', (185, 189))	('RBL2', 'Gene', '5934', (305, 309))	('RBL2', 'Gene', '5934', (185, 189))	('p53', 'Gene', (180, 183))	('RB1', 'Gene', (500, 503))	('cancer', 'Disease', (432, 438))
62454	33020398	Similar combinations between dl922-947 and other DDR inhibitors were analyzed in previous studies on different cancer types by both our group and others.	('dl922-947', 'Var', (29, 38))	('DDR', 'Chemical', '-', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('dl922-947', 'Chemical', '-', (29, 38))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
62455	33020398	Here, we combined dl922-947 with AZD1775 based on our previous observation of the efficacy of WEE1 inhibition in sensitizing MM cells to the DNA-damaging agent cisplatin.	('WEE1', 'Gene', '7465', (94, 98))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('dl922-947', 'Chemical', '-', (18, 27))	('WEE1', 'Gene', (94, 98))	('inhibition', 'NegReg', (99, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('AZD1775', 'Var', (33, 40))	('dl922-947', 'Var', (18, 27))	('sensitizing', 'MPA', (113, 124))	('AZD1775', 'Chemical', 'MESH:C549567', (33, 40))
62456	33020398	Moreover, in a recent kinome-wide CRISPR/Cas9 knockout screening, which has identified several kinases whose deficiency improves chemotherapy efficacy in MM, WEE1 knockout has proved to induce the most significant effect.	('deficiency', 'Var', (109, 119))	('Cas', 'cellular_component', 'GO:0005650', ('41', '44'))	('chemotherapy efficacy', 'CPA', (129, 150))	('improves', 'PosReg', (120, 128))	('WEE1', 'Gene', '7465', (158, 162))	('WEE1', 'Gene', (158, 162))	('knockout', 'Var', (163, 171))
62458	33020398	Recent studies have shown that triplet regimens consisting of chemotherapy plus WEE1 and CHK1 inhibitors could be particularly efficacious.	('WEE1', 'Gene', (80, 84))	('WEE1', 'Gene', '7465', (80, 84))	('CHK1', 'Gene', (89, 93))	('CHK1', 'Gene', '1111', (89, 93))	('inhibitors', 'Var', (94, 104))
62460	33020398	In conclusion, we found that WEE1 inhibition through AZD1775 sensitizes MM cells to dl922-947 by abrogating the DNA damage checkpoint induced by the virus.	('abrogating', 'NegReg', (97, 107))	('sensitizes', 'Reg', (61, 71))	('WEE1', 'Gene', (29, 33))	('dl922-947', 'Chemical', '-', (84, 93))	('DNA damage checkpoint induced', 'MPA', (112, 141))	('WEE1', 'Gene', '7465', (29, 33))	('AZD1775', 'Var', (53, 60))	('inhibition', 'NegReg', (34, 44))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('112', '133'))	('AZD1775', 'Chemical', 'MESH:C549567', (53, 60))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
62468	33020398	MM cells were seeded in 96-well plates 24 h before treatment with dl922-947 and AZD1775 (MK1775, purchased from Axon Medchem), both alone and in combination at various concentrations in a constant ratio.	('dl922-947', 'Chemical', '-', (66, 75))	('Axon', 'cellular_component', 'GO:0030424', ('112', '116'))	('AZD1775', 'Var', (80, 87))	('AZD1775', 'Chemical', 'MESH:C549567', (80, 87))	('MK1775', 'Chemical', 'MESH:C549567', (89, 95))	('dl922-947', 'Var', (66, 75))
62470	33020398	Apoptosis was assessed through flow cytometric analysis (BD FACSCalibur, Becton Dickinson BD Biosciences, Franklin Lakes, NJ, USA) of MM cells treated for 96 h with dl922-947 and/or AZD1775 at their IC50 values and stained with annexinV-FITC and propidium iodide (AnnexinV-FITC Kit, Biolegend, San Diego, CA, USA) according to the manufacturer's instructions.	('AZD1775', 'Var', (182, 189))	('annexinV-FITC', 'Chemical', '-', (228, 241))	('propidium iodide', 'Chemical', 'MESH:D011419', (246, 262))	('AZD1775', 'Chemical', 'MESH:C549567', (182, 189))	('Kit', 'Gene', '3815', (278, 281))	('dl922-947', 'Var', (165, 174))	('AnnexinV-FITC', 'Chemical', '-', (264, 277))	('dl922-947', 'Chemical', '-', (165, 174))	('Kit', 'Gene', (278, 281))
62472	33020398	NCI-H28 and MSTO-211H cells were grown on coverslips and treated with dl922-947 and AZD1775, both alone and in combination.	('MSTO-211H', 'CellLine', 'CVCL:1430', (12, 21))	('NCI-H28', 'Chemical', '-', (0, 7))	('dl922-947', 'Chemical', '-', (70, 79))	('AZD1775', 'Var', (84, 91))	('AZD1775', 'Chemical', 'MESH:C549567', (84, 91))	('dl922-947', 'Var', (70, 79))
62488	33020398	ATM Ataxia telangiectasia mutated  ATR Ataxia telangiectasia and Rad3 related  CDK Cyclin-dependent kinase  CDKN2A Cyclin-dependent kinase inhibitor 2A  CHK1 Checkpoint kinase 1  CI Combination index  COSMIC  Catalogue of Somatic Mutations in Cancer  DDR DNA damage response  Fa Fraction affected  FBS Fetal bovine serum  IC50 Half maximal inhibitory concentration  MM Malignant mesothelioma  OV Oncolytic virus  PARP Poly(ADP-ribose) polymerase  PI Propidium iodide  RB Retinoblastoma  RPA Replication protein A  SRB Sulforhodamine B  gamma-H2AX Phosphorylated histone H2AX	('telangiectasia', 'Phenotype', 'HP:0001009', (11, 25))	('Cat', 'Gene', (209, 212))	('RPA', 'cellular_component', 'GO:0005662', ('487', '490'))	('Cancer', 'Phenotype', 'HP:0002664', (243, 249))	('Replication protein A', 'cellular_component', 'GO:0005662', ('491', '512'))	('iodide  RB Retinoblastoma', 'Disease', 'MESH:D012175', (460, 485))	('CHK1', 'Gene', (153, 157))	('SRB', 'Gene', '10575', (514, 517))	('DDR', 'Chemical', '-', (251, 254))	('CDKN2A', 'Gene', '1029', (108, 114))	('Ataxia', 'Phenotype', 'HP:0001251', (39, 45))	('Cancer', 'Disease', (243, 249))	('Cat', 'Gene', '847', (209, 212))	('DNA damage response', 'biological_process', 'GO:0006974', ('255', '274'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('132', '148'))	('Mutations', 'Var', (230, 239))	('ATM', 'Gene', (0, 3))	('Ataxia telangiectasia', 'Disease', (39, 60))	('RPA', 'Gene', (487, 490))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (39, 60))	('MM Malignant mesothelioma', 'Disease', 'MESH:C562839', (366, 391))	('SRB', 'Gene', (514, 517))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (418, 445))	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('Cyclin', 'molecular_function', 'GO:0016538', ('83', '89'))	('CHK1', 'Gene', '1111', (153, 157))	('MM Malignant mesothelioma', 'Disease', (366, 391))	('PARP', 'Gene', '142', (413, 417))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (369, 391))	('Cancer', 'Disease', 'MESH:D009369', (243, 249))	('Rad', 'biological_process', 'GO:1990116', ('65', '68'))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (471, 485))	('telangiectasia', 'Phenotype', 'HP:0001009', (46, 60))	('iodide  RB Retinoblastoma', 'Disease', (460, 485))	('histone H2AX', 'Gene', (562, 574))	('PARP', 'Gene', (413, 417))	('Ataxia telangiectasia', 'Disease', (4, 25))	('Poly(ADP-ribose) polymerase', 'Gene', (418, 445))	('Replication protein A', 'Gene', '6117', (491, 512))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (4, 25))	('RPA', 'Gene', '6117', (487, 490))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('115', '148'))	('histone H2AX', 'Gene', '3014', (562, 574))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('Ataxia', 'Phenotype', 'HP:0001251', (4, 10))	('CDKN2A', 'Gene', (108, 114))	('ATM', 'Gene', '472', (0, 3))	('Replication protein A', 'Gene', (491, 512))
62489	28468780	Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis Inactivation of NF2/Merlin causes the autosomal dominant cancer predisposition syndrome Familial Neurofibromatosis Type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM).	('mTOR', 'Gene', (51, 55))	('malignant pleural mesothelioma', 'Disease', (263, 293))	('NEDD8', 'Gene', '4738', (23, 28))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (194, 211))	('Familial Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (185, 218))	('Merlin', 'Gene', (117, 123))	('mTOR', 'Gene', '2475', (51, 55))	('NEDD8', 'Gene', (23, 28))	('Loss-Driven', 'NegReg', (71, 82))	('NF2', 'Gene', '4771', (220, 223))	('Inactivation', 'Var', (97, 109))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (263, 293))	('NF2', 'Gene', '4771', (67, 70))	('NF2', 'Gene', (220, 223))	('NF2', 'Gene', (67, 70))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (135, 160))	('autosomal dominant cancer', 'Disease', (135, 160))	('causes', 'Reg', (124, 130))	('contributes', 'Reg', (229, 240))	('Merlin', 'Gene', '4771', (117, 123))	('Familial Neurofibromatosis Type 2', 'Disease', (185, 218))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (273, 293))	('NF2', 'Gene', '4771', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('NF2', 'Gene', (113, 116))
62491	28468780	Here, we show that MLN4924 - a NEDD8 activating enzyme (NAE) inhibitor - suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('activation', 'MPA', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('CRL', 'Gene', '133396', (84, 87))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('YAP', 'Gene', (123, 126))	('tumor', 'Disease', (141, 146))	('YAP', 'Gene', '10413', (123, 126))	('MLN4924 -', 'Var', (19, 28))	('DCAF1', 'Gene', '9730', (88, 93))	('NEDD8', 'Gene', '4738', (31, 36))	('NEDD8', 'Gene', (31, 36))	('DCAF1', 'Gene', (88, 93))	('NF2-mutant', 'Gene', (130, 140))	('attenuates', 'NegReg', (98, 108))	('NAE', 'Chemical', '-', (56, 59))	('CRL', 'Gene', (84, 87))	('suppresses', 'NegReg', (73, 83))
62492	28468780	Additionally, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRLs) involved in DNA repair.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('CRL', 'Gene', '133396', (148, 151))	('DNA repair', 'biological_process', 'GO:0006281', ('166', '176'))	('MLN4924', 'Var', (14, 21))	('sensitizes', 'Reg', (22, 32))	('MPM', 'Disease', (33, 36))	('ubiquitin', 'molecular_function', 'GO:0031386', ('129', '138'))	('CRL', 'Gene', (148, 151))	('cullin', 'Gene', (117, 123))	('cullin', 'Gene', '143384', (117, 123))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))	('inhibition', 'NegReg', (103, 113))
62494	28468780	Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1.	('DCAF1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('activates', 'PosReg', (171, 180))	('CRL', 'Gene', '133396', (203, 206))	('mTOR', 'MPA', (181, 185))	('CRL', 'Gene', (203, 206))	('tumor', 'Disease', (127, 132))	('MLN4924', 'Chemical', 'MESH:C539933', (68, 75))	('loss', 'Var', (156, 160))	('Merlin', 'Gene', (164, 170))	('DCAF1', 'Gene', '9730', (207, 212))	('DCAF1', 'Gene', '9730', (44, 49))	('Merlin', 'Gene', '4771', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('MLN4924', 'Var', (68, 75))	('NF2-mutant', 'Gene', (116, 126))	('NF2-mutant', 'Var', (116, 126))	('DCAF1', 'Gene', (207, 212))
62495	28468780	Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts.	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('MLN4924', 'Var', (24, 31))	('growth', 'MPA', (85, 91))	('patient', 'Species', '9606', (151, 158))	('mouse', 'Species', '10090', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('GDC-0980', 'Chemical', 'MESH:C569670', (61, 69))	('NF2-mutant', 'Gene', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('suppresses', 'NegReg', (70, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))	('tumor', 'Disease', (106, 111))
62497	28468780	Loss-of-function NF2/Merlin mutations are among the most frequent events driving malignant pleural mesothelioma (MPM), a rare cancer associated with asbestos exposure.	('Loss-of-function', 'NegReg', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (91, 111))	('malignant pleural mesothelioma', 'Disease', (81, 111))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (81, 111))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Merlin', 'Gene', (21, 27))	('Merlin', 'Gene', '4771', (21, 27))	('mutations', 'Var', (28, 37))
62498	28468780	Biallelic NF2 mutations underlie Familial Neurofibromatosis Type 2 (NF2), characterized by debilitating nervous system tumors where treatment relies predominantly on surgeries or radiosurgery.	('NF2', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('nervous system tumors', 'Disease', (104, 125))	('nervous system tumors', 'Phenotype', 'HP:0004375', (104, 125))	('Familial Neurofibromatosis Type 2', 'Disease', (33, 66))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (42, 59))	('nervous system tumors', 'Disease', 'MESH:D009423', (104, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Familial Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (33, 66))	('mutations', 'Var', (14, 23))	('underlie', 'Reg', (24, 32))
62500	28468780	In contrast to some other cancers that can be effectively treated - although not cured - by targeted therapies, NF2-mutant tumors remain a therapeutic challenge owing to the lack of consensus on the molecular mechanisms that underlie their development and the absence of validated targets.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('NF2-mutant', 'Gene', (112, 122))	('NF2-mutant', 'Var', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
62504	28468780	Although the mechanism by which Merlin suppresses mTOR signaling remains elusive, inactivation of NF2 confers sensitivity to rapalogs in bladder cancer and cetuximab-resistant lung cancer, suggesting that mTORC1 signaling broadly sustains the expansion of Merlin-deficient cancer cells.	('mTORC1', 'cellular_component', 'GO:0031931', ('205', '211'))	('Merlin', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('bladder cancer', 'Disease', (137, 151))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('Merlin', 'Gene', '4771', (256, 262))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('cetuximab', 'Chemical', 'MESH:D000068818', (156, 165))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('inactivation', 'Var', (82, 94))	('Merlin-deficient cancer', 'Disease', (256, 279))	('suppresses', 'NegReg', (39, 49))	('Merlin', 'Gene', '4771', (32, 38))	('Merlin-deficient cancer', 'Disease', 'MESH:D009369', (256, 279))	('Merlin', 'Gene', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('signaling', 'biological_process', 'GO:0023052', ('212', '221'))	('mTORC1', 'Gene', (205, 211))	('mTOR signaling', 'MPA', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('mTORC1', 'Gene', '382056', (205, 211))	('lung cancer', 'Disease', (176, 187))	('NF2', 'Gene', (98, 101))
62508	28468780	Following up on this hypothesis, we found that de-repressed CRL4DCAF1 targets Lats1 and 2 for ubiquitylation and inhibition in the nucleus and thus activates YAP-driven transcription and oncogenesis.	('DCAF1', 'Gene', (64, 69))	('activates', 'PosReg', (148, 157))	('oncogenesis', 'CPA', (187, 198))	('DCAF1', 'Gene', '9730', (64, 69))	('de-repressed', 'Var', (47, 59))	('CRL', 'Gene', '133396', (60, 63))	('Lats1 and 2', 'Gene', '8140;7462', (78, 89))	('YAP', 'Gene', '10413', (158, 161))	('oncogenesis', 'biological_process', 'GO:0007048', ('187', '198'))	('nucleus', 'cellular_component', 'GO:0005634', ('131', '138'))	('ubiquitylation', 'MPA', (94, 108))	('CRL', 'Gene', (60, 63))	('YAP', 'Gene', (158, 161))	('inhibition', 'MPA', (113, 123))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))
62513	28468780	It was recently reported that NF2-mutant MPM is preferentially sensitive to a FAK inhibitor in pre-clinical models; however, clinical trials using a more selective FAK inhibitor were unable to demonstrate efficacy in NF2-mutant MPM (NCT01870609).	('clinical', 'Species', '191496', (125, 133))	('FAK', 'Gene', '5747', (164, 167))	('FAK', 'Gene', (78, 81))	('FAK', 'Gene', '5747', (78, 81))	('pre', 'molecular_function', 'GO:0003904', ('95', '98'))	('NCT01870609', 'Var', (233, 244))	('FAK', 'molecular_function', 'GO:0004717', ('164', '167'))	('FAK', 'Gene', (164, 167))	('FAK', 'molecular_function', 'GO:0004717', ('78', '81'))	('clinical', 'Species', '191496', (99, 107))
62517	28468780	Neddylation of the cullin subunit at a conserved lysine residue promotes a conformational shift that fully activates ubiquitin ligase-conjugating activity by bringing target substrates into closer proximity with the ubiquitin-charged E2 enzyme.	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('activates', 'PosReg', (107, 116))	('cullin', 'Gene', (19, 25))	('Neddylation', 'Var', (0, 11))	('cullin', 'Gene', '143384', (19, 25))	('conformational shift', 'MPA', (75, 95))	('ubiquitin', 'molecular_function', 'GO:0031386', ('216', '225'))	('ubiquitin ligase-conjugating', 'Enzyme', (117, 145))	('ubiquitin', 'molecular_function', 'GO:0031386', ('117', '126'))
62519	28468780	MLN4924 is a first-in-class inhibitor of the NEDD8 activating enzyme (NAE), blocking activation of NEDD8 and thereby depleting the pool of active NEDD8, which can be conjugated to target proteins.	('depleting', 'NegReg', (117, 126))	('MLN4924', 'Var', (0, 7))	('activation', 'MPA', (85, 95))	('NEDD8', 'Gene', (99, 104))	('NEDD8', 'Gene', '4738', (99, 104))	('blocking', 'NegReg', (76, 84))	('pool of active', 'MPA', (131, 145))	('NEDD8', 'Gene', '4738', (45, 50))	('NEDD8', 'Gene', (45, 50))	('NEDD8', 'Gene', '4738', (146, 151))	('NEDD8', 'Gene', (146, 151))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('NAE', 'Chemical', '-', (70, 73))
62520	28468780	Importantly, a recent Phase I study of MLN4924 in patients with advanced solid tumors established efficient on-target inhibition of NAE, acceptable dose-limiting toxicities, and anti-tumorigenic activity in some patients.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('toxicities', 'Disease', (162, 172))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('inhibition', 'NegReg', (118, 128))	('patients', 'Species', '9606', (50, 58))	('MLN4924', 'Chemical', 'MESH:C539933', (39, 46))	('patients', 'Species', '9606', (212, 220))	('solid tumors', 'Disease', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('NAE', 'Chemical', '-', (132, 135))	('MLN4924', 'Var', (39, 46))	('tumor', 'Disease', (183, 188))	('toxicities', 'Disease', 'MESH:D064420', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))	('NAE', 'Protein', (132, 135))
62521	28468780	Here we show that inhibition of CRL4DCAF1 using MLN4924 sensitizes cells to traditional chemotherapy but displays limited pre-clinical activity even in combination with chemotherapy.	('DCAF1', 'Gene', (36, 41))	('sensitizes', 'Reg', (56, 66))	('inhibition', 'NegReg', (18, 28))	('CRL', 'Gene', '133396', (32, 35))	('MLN4924', 'Var', (48, 55))	('clinical', 'Species', '191496', (126, 134))	('DCAF1', 'Gene', '9730', (36, 41))	('pre', 'molecular_function', 'GO:0003904', ('122', '125'))	('CRL', 'Gene', (32, 35))	('MLN4924', 'Chemical', 'MESH:C539933', (48, 55))
62527	28468780	Meso-33 and VAMT treated with cisplatin and MLN4924 were subjected to a Annexin-V/PI apoptosis assay using the Annexin V:FITC Apoptosis Detection Kit II (BD #556570) according to manufacturer's instructions.	('Annexin-V', 'Gene', '308', (72, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (44, 51))	('Annexin V', 'Gene', '308', (111, 120))	('Annexin V', 'Gene', (111, 120))	('VAMT', 'Chemical', '-', (12, 16))	('Meso-33', 'Chemical', '-', (0, 7))	('MLN4924', 'Var', (44, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('Annexin-V', 'Gene', (72, 81))	('FITC', 'Chemical', 'MESH:D016650', (121, 125))
62529	28468780	Mesothelial or mesothelioma cell lines Meso-9, Meso-10, Meso-33, H-Meso, 211H, H28, H2052, H2452, JMN, and VAMT were obtained from the same stocks as published previously and were obtained between 2003 and 2004.	('H2452', 'CellLine', 'CVCL:1553', (91, 96))	('H2452', 'Var', (91, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('VAMT', 'Chemical', '-', (107, 111))	('H2052', 'Var', (84, 89))	('Meso-10', 'Chemical', '-', (47, 54))	('stocks', 'Species', '3724', (140, 146))	('H2052', 'CellLine', 'CVCL:1518', (84, 89))	('Meso-33', 'Chemical', '-', (56, 63))	('mesothelioma', 'Disease', (15, 27))
62560	28468780	Since CRLs are differentially sensitive to the effects of NAE inhibition, we set out to determine whether NAE inhibition abrogates the ubiquitin conjugating activity of CRL4DCAF1.	('ubiquitin', 'molecular_function', 'GO:0031386', ('135', '144'))	('DCAF1', 'Gene', '9730', (173, 178))	('CRL', 'Gene', (6, 9))	('NAE', 'Chemical', '-', (58, 61))	('ubiquitin conjugating activity', 'MPA', (135, 165))	('NAE', 'Chemical', '-', (106, 109))	('CRL', 'Gene', (169, 172))	('DCAF1', 'Gene', (173, 178))	('inhibition', 'Var', (110, 120))	('CRL', 'Gene', '133396', (6, 9))	('abrogates', 'NegReg', (121, 130))	('CRL', 'Gene', '133396', (169, 172))
62561	28468780	Preliminary experiments indicated that the fraction of CUL4 associated with DCAF1 is effectively de-neddylated by MLN4924 (Fig.	('de-neddylated', 'NegReg', (97, 110))	('MLN4924', 'Chemical', 'MESH:C539933', (114, 121))	('DCAF1', 'Gene', '9730', (76, 81))	('MLN4924', 'Var', (114, 121))	('DCAF1', 'Gene', (76, 81))
62564	28468780	Following precipitation of DCAF1, we observed an MLN4924-induced dose-dependent decrease in the precipitation of lower molecular weight Myc-ubiquitylated species, consistent with inhibition of CRL4DCAF1 by MLN4924 (Fig.	('DCAF1', 'Gene', '9730', (27, 32))	('MLN4924', 'Var', (206, 213))	('CRL', 'Gene', '133396', (193, 196))	('MLN4924-induced', 'Var', (49, 64))	('Myc', 'Gene', '4609', (136, 139))	('Myc', 'Gene', (136, 139))	('DCAF1', 'Gene', (27, 32))	('CRL', 'Gene', (193, 196))	('DCAF1', 'Gene', '9730', (197, 202))	('MLN4924', 'Chemical', 'MESH:C539933', (206, 213))	('DCAF1', 'Gene', (197, 202))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('decrease', 'NegReg', (80, 88))
62566	28468780	CRL4DCAF1-mediated ubiquitylation and inhibition of the Lats tumor suppressor proteins promotes tumorigenesis across multiple NF2-mutant tissues.	('ubiquitylation', 'MPA', (19, 33))	('Lats', 'Gene', (56, 60))	('DCAF1', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('CRL', 'Gene', (0, 3))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('CRL', 'Gene', '133396', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NF2-mutant', 'Gene', (126, 136))	('inhibition', 'NegReg', (38, 48))	('promotes', 'PosReg', (87, 95))	('DCAF1', 'Gene', '9730', (4, 9))	('tumor', 'Disease', (61, 66))	('NF2-mutant', 'Var', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
62568	28468780	To examine the effect of MLN4924 on the ubiquitylation of pathogenically relevant substrates of CRL4DCAF1, we conducted ubiquitylation assays with recombinant forms of Lats1 and 2.	('MLN4924', 'Var', (25, 32))	('DCAF1', 'Gene', '9730', (100, 105))	('DCAF1', 'Gene', (100, 105))	('CRL', 'Gene', (96, 99))	('Lats1 and 2', 'Gene', '8140;7462', (168, 179))	('CRL', 'Gene', '133396', (96, 99))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))
62569	28468780	Importantly, MLN4924 administration inhibited Lats1 ubiquitylation as effectively as overexpression of Merlin (Fig.	('inhibited', 'NegReg', (36, 45))	('Lats1', 'Gene', (46, 51))	('MLN4924', 'Chemical', 'MESH:C539933', (13, 20))	('MLN4924 administration', 'Var', (13, 35))	('Merlin', 'Gene', (103, 109))	('Merlin', 'Gene', '4771', (103, 109))	('Lats1', 'Gene', '9113', (46, 51))
62571	28468780	In addition, MLN4924 treatment reduced the oligo-ubiquitylation of Lats2, although to a lesser extent than Merlin expression (Supplemental Fig.	('MLN4924 treatment', 'Var', (13, 30))	('reduced', 'NegReg', (31, 38))	('Lats2', 'Gene', '26524', (67, 72))	('oligo-ubiquitylation', 'MPA', (43, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (13, 20))	('Merlin', 'Gene', '4771', (107, 113))	('Lats2', 'Gene', (67, 72))	('Merlin', 'Gene', (107, 113))
62572	28468780	Combined, these data suggest that MLN4924 blocks the inhibitory ubiquitylation of Lats1 and 2, potentially restoring inhibition of YAP.	('MLN4924', 'Var', (34, 41))	('restoring', 'PosReg', (107, 116))	('inhibition', 'MPA', (117, 127))	('YAP', 'Gene', '10413', (131, 134))	('blocks', 'NegReg', (42, 48))	('YAP', 'Gene', (131, 134))	('Lats1 and 2', 'Gene', '8140;7462', (82, 93))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('inhibitory ubiquitylation', 'MPA', (53, 78))
62573	28468780	Based on these in vitro findings, we sought to assess the preclinical efficacy of NAE inhibition in NF2-mutant tumors as a method to inhibit oncogenic CRL4DCAF1 and its ensuing activation of YAP.	('CRL', 'Gene', (151, 154))	('DCAF1', 'Gene', '9730', (155, 160))	('NF2-mutant', 'Gene', (100, 110))	('NF2-mutant', 'Var', (100, 110))	('YAP', 'Gene', '10413', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('activation', 'PosReg', (177, 187))	('NAE', 'Chemical', '-', (82, 85))	('tumors', 'Disease', (111, 117))	('inhibit', 'NegReg', (133, 140))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('DCAF1', 'Gene', (155, 160))	('YAP', 'Gene', (191, 194))	('clinical', 'Species', '191496', (61, 69))	('CRL', 'Gene', '133396', (151, 154))	('oncogenic', 'MPA', (141, 150))
62574	28468780	We elected to first examine the effects of MLN4924 in the Nf2-null mouse schwannoma cells FC-1801, which were derived by infecting primary Nf2Flox/Flox Schwann cells with adenoviral Cre.	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))	('schwannoma', 'Disease', 'MESH:D009442', (73, 83))	('schwannoma', 'Disease', (73, 83))	('schwannoma', 'Phenotype', 'HP:0100008', (73, 83))	('mouse', 'Species', '10090', (67, 72))	('MLN4924', 'Var', (43, 50))
62575	28468780	FC-1801 undergo proliferation arrest and lose their tumorigenic potential upon knock-down of DCAF1 as they do upon re-expression of Merlin, consistent with the model that NF2-mutant cells are dependent on CRL4DCAF1 signaling.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Merlin', 'Gene', (132, 138))	('DCAF1', 'Gene', (209, 214))	('proliferation arrest', 'Disease', (16, 36))	('CRL', 'Gene', '133396', (205, 208))	('proliferation arrest', 'Disease', 'MESH:D006323', (16, 36))	('DCAF1', 'Gene', '9730', (93, 98))	('tumor', 'Disease', (52, 57))	('knock-down', 'Var', (79, 89))	('signaling', 'biological_process', 'GO:0023052', ('215', '224'))	('FC-1801', 'Gene', (0, 7))	('DCAF1', 'Gene', (93, 98))	('undergo', 'Reg', (8, 15))	('lose', 'NegReg', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CRL', 'Gene', (205, 208))	('DCAF1', 'Gene', '9730', (209, 214))	('Merlin', 'Gene', '4771', (132, 138))
62576	28468780	Notably, MLN4924 induced phosphorylation of YAP at Serine 127 - a negative regulatory site - in a dose-dependent fashion in FC-1801 cells (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('phosphorylation', 'MPA', (25, 40))	('YAP', 'Gene', '10413', (44, 47))	('MLN4924', 'Var', (9, 16))	('YAP', 'Gene', (44, 47))	('Serine', 'Chemical', 'MESH:D012694', (51, 57))
62578	28468780	This finding is consistent with the ability of MLN4924 to reduce CRL4DCAF1-mediated inhibition of Lats (Fig.	('DCAF1', 'Gene', '9730', (69, 74))	('inhibition', 'NegReg', (84, 94))	('CRL', 'Gene', (65, 68))	('DCAF1', 'Gene', (69, 74))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('reduce', 'NegReg', (58, 64))	('CRL', 'Gene', '133396', (65, 68))	('Lats', 'MPA', (98, 102))	('MLN4924', 'Var', (47, 54))
62580	28468780	To determine whether MLN4924 preferentially inhibits the proliferation of cells in which Merlin loss is the driving oncogenic lesion, we compared the anti-proliferative properties of MLN4924 in FC-1801 and the Nf2-WT Schwann cells FH-912, which provide for a genetically matched control for the FC-1801 cells.	('MLN4924', 'Chemical', 'MESH:C539933', (183, 190))	('MLN4924', 'Var', (183, 190))	('anti-proliferative', 'MPA', (150, 168))	('Merlin', 'Gene', '4771', (89, 95))	('Merlin', 'Gene', (89, 95))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('proliferation', 'CPA', (57, 70))	('inhibits', 'NegReg', (44, 52))	('loss', 'NegReg', (96, 100))	('MLN4924', 'Var', (21, 28))
62581	28468780	MLN4924 elicited a half-maximal growth inhibitory concentration (GI50) of 0.28 muM in FC-1801 cells and 2.7 muM in the Nf2-WT FH-912 cells, indicating that Nf2-mutant schwannoma cells are approximately ten-fold more sensitive to MLN4924 than their wild type counterparts (Fig.	('schwannoma', 'Disease', (167, 177))	('MLN4924', 'Var', (0, 7))	('schwannoma', 'Phenotype', 'HP:0100008', (167, 177))	('Nf2-mutant', 'Var', (156, 166))	('MLN4924', 'Chemical', 'MESH:C539933', (229, 236))	('growth inhibitory', 'MPA', (32, 49))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('schwannoma', 'Disease', 'MESH:D009442', (167, 177))
62582	28468780	Treatment of FC-1801 with MLN4924 for more than 24 hours revealed no change in Lats1 levels, suggesting that inhibition of kinase activity - as opposed to proteasomal degradation - is the predominant route of Lats1 inhibition by CRL4DCAF1 in FC-1801 (Supplemental Fig.	('DCAF1', 'Gene', '9730', (233, 238))	('CRL', 'Gene', '133396', (229, 232))	('kinase activity', 'molecular_function', 'GO:0016301', ('123', '138'))	('inhibition of kinase activity', 'biological_process', 'GO:0033673', ('109', '138'))	('degradation', 'biological_process', 'GO:0009056', ('167', '178'))	('DCAF1', 'Gene', (233, 238))	('inhibition', 'NegReg', (215, 225))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('Lats1', 'Gene', '9113', (209, 214))	('Lats1', 'Gene', '9113', (79, 84))	('kinase activity', 'MPA', (123, 138))	('MLN4924', 'Var', (26, 33))	('CRL', 'Gene', (229, 232))	('Lats1', 'Gene', (209, 214))	('Lats1', 'Gene', (79, 84))
62583	28468780	To examine the effects of MLN4924 on YAP downstream target genes, we treated Nf2-mutant FC-1801 and Nf2-WT FH-912 cells with MLN4924 for more than 24 hours.	('MLN4924', 'Chemical', 'MESH:C539933', (125, 132))	('FC-1801', 'Gene', (88, 95))	('YAP', 'Gene', '10413', (37, 40))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('MLN4924', 'Var', (125, 132))	('YAP', 'Gene', (37, 40))	('Nf2-mutant FC-1801', 'Gene', (77, 95))
62585	28468780	We compared transcript levels in both lines and found that FC-1801 expresses nearly identical or reduced levels of these canonical YAP targets as compared to FH-912, suggesting that these genes may not be most relevant to oncogenic CRL4DCAF1 signaling in Schwann cells.	('DCAF1', 'Gene', (236, 241))	('CRL', 'Gene', '133396', (232, 235))	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('YAP', 'Gene', '10413', (131, 134))	('reduced', 'NegReg', (97, 104))	('levels', 'MPA', (105, 111))	('FC-1801', 'Var', (59, 66))	('YAP', 'Gene', (131, 134))	('DCAF1', 'Gene', '9730', (236, 241))	('CRL', 'Gene', (232, 235))
62586	28468780	Moreover, MLN4924 treatment led to a dose-dependent increase in all transcripts, again suggesting that these specific YAP targets are not relevant to the oncogenic output of dysregulated CRL4DCAF1 in this tissue.	('CRL', 'Gene', '133396', (187, 190))	('YAP', 'Gene', '10413', (118, 121))	('MLN4924', 'Var', (10, 17))	('increase', 'PosReg', (52, 60))	('CRL', 'Gene', (187, 190))	('YAP', 'Gene', (118, 121))	('DCAF1', 'Gene', '9730', (191, 196))	('DCAF1', 'Gene', (191, 196))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))	('transcripts', 'MPA', (68, 79))
62587	28468780	Combined, these findings reveal that MLN4924 blocks CRL4DCAF1-mediated ubiquitylation of Lats and activation of YAP and exerts a selective anti-proliferative effect in Merlin-deficient schwannoma cells.	('anti-proliferative effect', 'CPA', (139, 164))	('DCAF1', 'Gene', '9730', (56, 61))	('ubiquitylation', 'MPA', (71, 85))	('Merlin-deficient schwannoma', 'Disease', (168, 195))	('activation', 'PosReg', (98, 108))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('Lats', 'Protein', (89, 93))	('DCAF1', 'Gene', (56, 61))	('YAP', 'Gene', '10413', (112, 115))	('Merlin-deficient schwannoma', 'Disease', 'MESH:D009442', (168, 195))	('blocks', 'NegReg', (45, 51))	('schwannoma', 'Phenotype', 'HP:0100008', (185, 195))	('CRL', 'Gene', (52, 55))	('MLN4924', 'Var', (37, 44))	('YAP', 'Gene', (112, 115))	('CRL', 'Gene', '133396', (52, 55))
62588	28468780	To confirm the identification of CRL4DCAF1 as a therapeutic target in NF2-mutant MPM, we tested the effect of iRNA-mediated depletion of DCAF1 in NF2-mutant Meso-33 and VAMT cells (Supplemental Fig.	('NF2-mutant', 'Gene', (70, 80))	('NF2-mutant', 'Var', (70, 80))	('DCAF1', 'Gene', (137, 142))	('CRL', 'Gene', '133396', (33, 36))	('tested', 'Reg', (89, 95))	('VAMT', 'Chemical', '-', (169, 173))	('Meso-33', 'Chemical', '-', (157, 164))	('DCAF1', 'Gene', '9730', (37, 42))	('DCAF1', 'Gene', (37, 42))	('CRL', 'Gene', (33, 36))	('DCAF1', 'Gene', '9730', (137, 142))
62589	28468780	Acute depletion of DCAF1 with a SMART pool reduced the proliferation of both MPM lines by 50-70% as compared to their control counterparts within 4 days.	('proliferation', 'CPA', (55, 68))	('DCAF1', 'Gene', '9730', (19, 24))	('depletion', 'Var', (6, 15))	('reduced', 'NegReg', (43, 50))	('DCAF1', 'Gene', (19, 24))
62592	28468780	As predicted, MLN4924 treatment caused a dose-dependent inhibition of cullin neddylation in NF2-mutant Meso-33 cells.	('inhibition', 'NegReg', (56, 66))	('MLN4924 treatment', 'Var', (14, 31))	('NF2-mutant', 'Gene', (92, 102))	('Meso-33', 'Chemical', '-', (103, 110))	('cullin', 'Gene', (70, 76))	('cullin', 'Gene', '143384', (70, 76))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))
62594	28468780	Notably, 0.5 muM MLN4924 induced phosphorylation of YAP at its inhibitory phosphorylation site Serine 127 to a similar extent - if not more efficiently - as compared to DCAF1 depletion (Fig.	('phosphorylation', 'MPA', (33, 48))	('inhibitory phosphorylation site Serine 127', 'MPA', (63, 105))	('Serine', 'Chemical', 'MESH:D012694', (95, 101))	('DCAF1', 'Gene', '9730', (169, 174))	('YAP', 'Gene', (52, 55))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('DCAF1', 'Gene', (169, 174))	('MLN4924', 'Var', (17, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('YAP', 'Gene', '10413', (52, 55))
62595	28468780	To examine MLN4924 effects on downstream YAP signaling, we assessed canonical YAP targets after 36 hours of MLN4924 exposure.	('YAP', 'Gene', (41, 44))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('MLN4924', 'Var', (108, 115))	('YAP', 'Gene', '10413', (78, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('YAP', 'Gene', '10413', (41, 44))	('MLN4924', 'Chemical', 'MESH:C539933', (108, 115))	('YAP', 'Gene', (78, 81))
62597	28468780	2C, left), extended MLN4924 reduced expression of canonical YAP target genes CTGF, BIRC5, and CYR61 (Fig.	('BIRC5', 'Gene', (83, 88))	('reduced', 'NegReg', (28, 35))	('CYR61', 'Gene', '3491', (94, 99))	('YAP', 'Gene', '10413', (60, 63))	('extended MLN4924', 'Var', (11, 27))	('CTGF', 'Gene', '1490', (77, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('YAP', 'Gene', (60, 63))	('CTGF', 'Gene', (77, 81))	('BIRC5', 'Gene', '332', (83, 88))	('expression', 'MPA', (36, 46))	('CYR61', 'Gene', (94, 99))
62599	28468780	Intriguingly, neither DCAF1 depletion nor MLN4924 administration reduced flux through the mTORC1 pathway as assessed by phosphorylation of S6 ribosomal protein, a key downstream effector of mTORC1, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1 (Fig.	('activates', 'PosReg', (229, 238))	('Merlin', 'Gene', (222, 228))	('DCAF1', 'Gene', (265, 270))	('loss', 'Var', (214, 218))	('CRL', 'Gene', '133396', (261, 264))	('mTOR', 'MPA', (239, 243))	('mTORC1', 'Gene', (90, 96))	('DCAF1', 'Gene', '9730', (265, 270))	('mTORC1', 'Gene', '382056', (90, 96))	('mTORC1', 'Gene', (190, 196))	('Merlin', 'Gene', '4771', (222, 228))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('142', '159'))	('mTORC1', 'Gene', '382056', (190, 196))	('DCAF1', 'Gene', (22, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('120', '135'))	('MLN4924', 'Chemical', 'MESH:C539933', (42, 49))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('DCAF1', 'Gene', '9730', (22, 27))	('CRL', 'Gene', (261, 264))	('mTORC1', 'cellular_component', 'GO:0031931', ('190', '196'))	('mTORC1', 'cellular_component', 'GO:0031931', ('90', '96'))
62600	28468780	Consistent with previous findings, DCAF1 inhibition and MLN4924 treatment induced p27 expression (Fig.	('p27', 'Gene', (82, 85))	('DCAF1', 'Gene', '9730', (35, 40))	('MLN4924 treatment', 'Var', (56, 73))	('induced', 'Reg', (74, 81))	('expression', 'MPA', (86, 96))	('inhibition', 'Var', (41, 51))	('DCAF1', 'Gene', (35, 40))	('p27', 'Gene', '10534', (82, 85))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
62601	28468780	Indeed, at a concentration that almost completely blocks cullin neddylation, MLN4924 strongly induced cell cycle progression as demonstrated by suppression of the phosphorylation of Rb and Histone H3 (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (77, 84))	('cullin', 'Gene', (57, 63))	('cullin', 'Gene', '143384', (57, 63))	('MLN4924', 'Var', (77, 84))	('Histone H3', 'Protein', (189, 199))	('cell cycle progression', 'CPA', (102, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('102', '112'))	('suppression', 'NegReg', (144, 155))	('phosphorylation', 'MPA', (163, 178))	('induced', 'Reg', (94, 101))	('phosphorylation', 'biological_process', 'GO:0016310', ('163', '178'))
62602	28468780	These findings suggest that NAE inhibition in Merlin-deficient cells inhibits oncogenic YAP signaling and suppresses cell cycle progression.	('oncogenic', 'MPA', (78, 87))	('cell cycle progression', 'CPA', (117, 139))	('inhibition', 'Var', (32, 42))	('Merlin', 'Gene', '4771', (46, 52))	('Merlin', 'Gene', (46, 52))	('cell cycle', 'biological_process', 'GO:0007049', ('117', '127'))	('inhibits', 'NegReg', (69, 77))	('YAP', 'Gene', '10413', (88, 91))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('YAP', 'Gene', (88, 91))	('NAE', 'Gene', (28, 31))	('NAE', 'Chemical', '-', (28, 31))	('suppresses', 'NegReg', (106, 116))
62603	28468780	To test the hypothesis that MLN4924 preferentially suppresses the proliferation of NF2-mutant mesothelioma cells, we determined the concentration of MLN4924 required to inhibit cell proliferation by 50% (GI50) in a large panel of MPM lines as well as in untransformed Met5a and LP9 mesothelial cells.	('MLN4924', 'Chemical', 'MESH:C539933', (149, 156))	('inhibit', 'NegReg', (169, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('177', '195'))	('MLN4924', 'Var', (28, 35))	('proliferation', 'CPA', (66, 79))	('MLN4924', 'Var', (149, 156))	('NF2-mutant', 'Gene', (83, 93))	('NF2-mutant', 'Var', (83, 93))	('mesothelioma', 'Disease', (94, 106))	('suppresses', 'NegReg', (51, 61))	('cell proliferation', 'CPA', (177, 195))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))
62605	28468780	2E), it was equal or lower than 0.55 muM in 5 out of 7 NF2-mutant MPM lines, providing evidence that the large majority of NF2-mutant MPM lines are highly sensitive to MLN4924 (Fig.	('sensitive', 'Reg', (155, 164))	('MLN4924', 'Chemical', 'MESH:C539933', (168, 175))	('NF2-mutant MPM', 'Gene', (123, 137))	('MPM', 'Gene', (134, 137))	('MLN4924', 'Var', (168, 175))
62606	28468780	MPM tumors and cell lines often have complex genotypes and a large fraction of them exhibit mutations not only in NF2 but also in CDKN2A, CDKN2B, and BAP1.	('BAP1', 'Gene', (150, 154))	('CDKN2A', 'Gene', (130, 136))	('NF2', 'Gene', (114, 117))	('CDKN2B', 'Gene', '1030', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MPM tumors', 'Disease', (0, 10))	('mutations', 'Var', (92, 101))	('CDKN2A', 'Gene', '1029', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('exhibit', 'Reg', (84, 91))	('MPM tumors', 'Disease', 'MESH:D009369', (0, 10))	('BAP1', 'Gene', '8314', (150, 154))	('CDKN2B', 'Gene', (138, 144))
62608	28468780	However, the NF2-mutant Meso-9 and Meso-10 lines have not been fully sequenced and it is therefore possible that their relative insensitivity to MLN4924 is due to an unidentified co-occurring genetic alteration.	('MLN4924', 'Var', (145, 152))	('insensitivity', 'NegReg', (128, 141))	('NF2-mutant', 'Gene', (13, 23))	('Meso-10', 'Chemical', '-', (35, 42))	('MLN4924', 'Chemical', 'MESH:C539933', (145, 152))
62609	28468780	These findings are consistent with the model that NF2-mutant MPM cells are sensitive to MLN4924 because of its ability to inhibit oncogenic signaling through CRL4DCAF1.	('CRL', 'Gene', (158, 161))	('DCAF1', 'Gene', '9730', (162, 167))	('CRL', 'Gene', '133396', (158, 161))	('MLN4924', 'Chemical', 'MESH:C539933', (88, 95))	('DCAF1', 'Gene', (162, 167))	('oncogenic signaling', 'MPA', (130, 149))	('NF2-mutant', 'Gene', (50, 60))	('inhibit', 'NegReg', (122, 129))	('MLN4924', 'Var', (88, 95))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))
62610	28468780	MLN4924 inhibits CRL ligases involved in the DNA damage response (DDR) including CRL4DDB2 and CRL4CSA, which function in global genome Nucleotide Excision Repair (NER) and transcription-coupled NER, as well as CRL4CDT2, which suppresses DNA re-replication and apoptosis.	('DNA', 'cellular_component', 'GO:0005574', ('237', '240'))	('suppresses', 'NegReg', (226, 236))	('CRL', 'Gene', '133396', (94, 97))	('apoptosis', 'CPA', (260, 269))	('CRL', 'Gene', (210, 213))	('DNA re-replication', 'CPA', (237, 255))	('CRL', 'Gene', (81, 84))	('MLN4924', 'Var', (0, 7))	('CRL', 'Gene', (17, 20))	('DNA damage response', 'biological_process', 'GO:0006974', ('45', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('global genome Nucleotide Excision Repair', 'biological_process', 'GO:0070911', ('121', '161'))	('CRL', 'Gene', '133396', (210, 213))	('apoptosis', 'biological_process', 'GO:0097194', ('260', '269'))	('apoptosis', 'biological_process', 'GO:0006915', ('260', '269'))	('NER', 'biological_process', 'GO:0006289', ('163', '166'))	('CRL', 'Gene', '133396', (81, 84))	('inhibits', 'NegReg', (8, 16))	('CRL', 'Gene', (94, 97))	('transcription-coupled NER', 'biological_process', 'GO:0006283', ('172', '197'))	('CRL', 'Gene', '133396', (17, 20))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
62611	28468780	We therefore set out to determine if MLN4924, in addition to inhibiting CRL4DCAF1 and YAP signaling, would also sensitize NF2-mutant tumor cells to DNA-damaging agents.	('CRL', 'Gene', '133396', (72, 75))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('inhibiting', 'NegReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('YAP', 'Gene', (86, 89))	('DCAF1', 'Gene', '9730', (76, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DCAF1', 'Gene', (76, 81))	('sensitize', 'Reg', (112, 121))	('YAP', 'Gene', '10413', (86, 89))	('tumor', 'Disease', (133, 138))	('MLN4924', 'Var', (37, 44))	('CRL', 'Gene', (72, 75))	('NF2-mutant', 'Gene', (122, 132))
62612	28468780	We first examined whether MLN4924 cooperates with cisplatin, a platinum-containing DNA cross-linking drug, because it is used in combination with the folate antimetabolite pemetrexed as first-line chemotherapy for MPM.	('folate', 'Chemical', 'MESH:D005492', (150, 156))	('MPM', 'Disease', (214, 217))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('pemetrexed', 'Chemical', 'MESH:D000068437', (172, 182))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('MLN4924', 'Var', (26, 33))	('platinum', 'Chemical', 'MESH:D010984', (63, 71))
62613	28468780	Treatment of NF2-mutant MPM with MLN4924, cisplatin, or both resulted in DNA damage as shown by Chk1 and Histone H2A.X phosphorylation (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('DNA damage', 'MPA', (73, 83))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('Chk1', 'Gene', '1111', (96, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('Chk1', 'Gene', (96, 100))	('MLN4924', 'Var', (33, 40))	('NF2-mutant', 'Gene', (13, 23))
62615	28468780	MLN4924 stabilized CDT1 even in the presence of cisplatin - an effect of MLN4924 that has been shown to induce DNA re-replication and to contribute to further DNA damage and apoptosis.	('MLN4924', 'Var', (0, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('MLN4924', 'Var', (73, 80))	('CDT1', 'Gene', '81620', (19, 23))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('apoptosis', 'CPA', (174, 183))	('induce', 'PosReg', (104, 110))	('contribute', 'Reg', (137, 147))	('CDT1', 'Gene', (19, 23))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('DNA', 'MPA', (159, 162))	('DNA re-replication', 'CPA', (111, 129))	('MLN4924', 'Chemical', 'MESH:C539933', (73, 80))
62616	28468780	MLN4924 and cisplatin monotherapy caused comparable levels of apoptosis in Merlin-deficient MPM, however, combining the compounds dramatically increased apoptosis, indicating that MLN4924 sensitizes NF2-mutant MPM cells to chemotherapy (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('increased', 'PosReg', (143, 152))	('Merlin', 'Gene', '4771', (75, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (180, 187))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('Merlin', 'Gene', (75, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('MLN4924', 'Var', (180, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('sensitizes', 'Reg', (188, 198))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('NF2-mutant', 'Gene', (199, 209))	('apoptosis', 'MPA', (153, 162))
62617	28468780	To examine the ability of MLN4924 to sensitize NF2-mutant MPM cells to chemotherapy in vivo, we treated NOD-scid IL2Rgammanull (NSG) mice bearing VAMT or Meso-10 xenografts of approximately 100 mm3 size with MLN4924, cisplatin + pemetrexed, or both.	('mice', 'Species', '10090', (133, 137))	('pemetrexed', 'Chemical', 'MESH:D000068437', (229, 239))	('VAMT', 'Chemical', '-', (146, 150))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('Meso-10', 'Chemical', '-', (154, 161))	('MLN4924', 'Chemical', 'MESH:C539933', (208, 215))	('NF2-mutant', 'Gene', (47, 57))	('NF2-mutant', 'Var', (47, 57))	('MLN4924', 'Var', (208, 215))	('IL2', 'molecular_function', 'GO:0005134', ('113', '116'))	('cisplatin', 'Chemical', 'MESH:D002945', (217, 226))
62618	28468780	Both MLN4924 monotherapy and combination chemotherapy induced a statistically significant reduction in tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduction', 'NegReg', (90, 99))	('MLN4924', 'Chemical', 'MESH:C539933', (5, 12))	('tumor', 'Disease', (103, 108))	('MLN4924', 'Var', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
62619	28468780	However, combination therapy with MLN4924 and pemetrexed + cisplatin displayed significantly improved inhibition of tumor growth as compared to either individual treatment modality in both types of tumors (Fig.	('pemetrexed', 'Chemical', 'MESH:D000068437', (46, 56))	('MLN4924', 'Var', (34, 41))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('improved', 'PosReg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibition', 'NegReg', (102, 112))	('tumors', 'Disease', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('tumor', 'Disease', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
62620	28468780	These preclinical data indicate that combining MLN4924 with first-line chemotherapy may improve the treatment NF2-mutant MPM.	('improve', 'PosReg', (88, 95))	('NF2-mutant', 'Gene', (110, 120))	('clinical', 'Species', '191496', (9, 17))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('MLN4924', 'Var', (47, 54))	('MPM', 'Disease', (121, 124))	('treatment', 'MPA', (100, 109))
62621	28468780	Although MLN4924 inhibited tumor growth, especially in combination with chemotherapy, it did not completely suppress this event or cause tumor regression, suggesting that NF2 loss-driven tumorigenesis does not depend solely on CRL4DCAF1.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (137, 142))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('tumor', 'Disease', (27, 32))	('DCAF1', 'Gene', '9730', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CRL', 'Gene', (227, 230))	('MLN4924', 'Var', (9, 16))	('tumor', 'Disease', (187, 192))	('inhibited', 'NegReg', (17, 26))	('DCAF1', 'Gene', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('loss-driven', 'NegReg', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('CRL', 'Gene', '133396', (227, 230))	('NF2', 'Gene', (171, 174))
62622	28468780	Intriguingly, we had observed that treatment with MLN4924 or depletion of DCAF1 does not diminish mTORC1 signaling in NF2-mutant Meso-33 cells (Fig.	('depletion', 'Var', (61, 70))	('mTORC1', 'Gene', '382056', (98, 104))	('Meso-33', 'Chemical', '-', (129, 136))	('MLN4924', 'Chemical', 'MESH:C539933', (50, 57))	('DCAF1', 'Gene', '9730', (74, 79))	('mTORC1', 'cellular_component', 'GO:0031931', ('98', '104'))	('NF2-mutant', 'Gene', (118, 128))	('NF2-mutant', 'Var', (118, 128))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('mTORC1', 'Gene', (98, 104))	('MLN4924', 'Var', (50, 57))	('DCAF1', 'Gene', (74, 79))	('diminish', 'NegReg', (89, 97))
62625	28468780	Consistently, we found that DCAF1 depletion dramatically reduces expression of the YAP target gene CTGF but does not affect the phosphorylation of S6 in two NF2-mutant MPM lines (Fig.	('YAP', 'Gene', '10413', (83, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('YAP', 'Gene', (83, 86))	('DCAF1', 'Gene', (28, 33))	('depletion', 'Var', (34, 43))	('expression', 'MPA', (65, 75))	('CTGF', 'Gene', '1490', (99, 103))	('CTGF', 'Gene', (99, 103))	('DCAF1', 'Gene', '9730', (28, 33))	('NF2-mutant', 'Var', (157, 167))	('reduces', 'NegReg', (57, 64))
62627	28468780	Even in this genetically-defined Nf2-null cell line, DCAF1 depletion and MLN4924 administration did not affect mTORC1 signaling (Fig.	('MLN4924', 'Var', (73, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('111', '117'))	('DCAF1', 'Gene', '9730', (53, 58))	('mTORC1', 'Gene', '382056', (111, 117))	('depletion', 'Var', (59, 68))	('MLN4924', 'Chemical', 'MESH:C539933', (73, 80))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('DCAF1', 'Gene', (53, 58))	('mTORC1', 'Gene', (111, 117))
62634	28468780	Notably, GDC-0980 blocked mTORC1 signaling without activating Akt or ERK in VAMT and Meso-33 (Fig.	('blocked', 'NegReg', (18, 25))	('GDC-0980', 'Chemical', 'MESH:C569670', (9, 17))	('mTORC1', 'Gene', (26, 32))	('Meso-33', 'Chemical', '-', (85, 92))	('VAMT', 'Chemical', '-', (76, 80))	('Akt', 'Gene', '207', (62, 65))	('ERK', 'Gene', '2048', (69, 72))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('ERK', 'molecular_function', 'GO:0004707', ('69', '72'))	('mTORC1', 'cellular_component', 'GO:0031931', ('26', '32'))	('mTORC1', 'Gene', '382056', (26, 32))	('GDC-0980', 'Var', (9, 17))	('Akt', 'Gene', (62, 65))	('ERK', 'Gene', (69, 72))
62636	28468780	Intriguingly, single agent therapy with GDC-0980 yielded marginally higher - albeit statistically insignificant - efficacy relative to MLN4924 alone (Fig.	('GDC-0980', 'Var', (40, 48))	('higher', 'PosReg', (68, 74))	('GDC-0980', 'Chemical', 'MESH:C569670', (40, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (135, 142))
62637	28468780	However, combination therapy with MLN4924 and GDC-0980 completely suppressed tumor growth (Fig.	('MLN4924', 'Var', (34, 41))	('GDC-0980', 'Chemical', 'MESH:C569670', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('suppressed', 'NegReg', (66, 76))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('tumor', 'Disease', (77, 82))	('GDC-0980', 'Gene', (46, 54))
62638	28468780	4E) and exceeded the efficacy of either single agent alone, standard first-line chemotherapy, and chemotherapy combined with MLN4924 with minimal toxicity (Fig.	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('MLN4924', 'Chemical', 'MESH:C539933', (125, 132))	('toxicity', 'Disease', (146, 154))	('MLN4924', 'Var', (125, 132))
62640	28468780	To determine whether combined inhibition of NAE and mTORC1 could be broadly exploited as a rational therapy in NF2 loss-driven tumorigenesis, we evaluated the efficacy of MLN4924 and GDC-0980 in human schwannoma - the hallmark tumor of NF2 patients.	('tumor', 'Disease', (227, 232))	('mTORC1', 'Gene', '382056', (52, 58))	('NAE', 'Chemical', '-', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('schwannoma', 'Phenotype', 'HP:0100008', (201, 211))	('schwannoma - the hallmark tumor', 'Disease', 'MESH:D009442', (201, 232))	('mTORC1', 'cellular_component', 'GO:0031931', ('52', '58'))	('NF2', 'Gene', (111, 114))	('MLN4924', 'Chemical', 'MESH:C539933', (171, 178))	('GDC-0980', 'Var', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('GDC-0980', 'Chemical', 'MESH:C569670', (183, 191))	('patients', 'Species', '9606', (240, 248))	('schwannoma - the hallmark tumor', 'Disease', (201, 232))	('human', 'Species', '9606', (195, 200))	('tumor', 'Disease', (127, 132))	('mTORC1', 'Gene', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('MLN4924', 'Var', (171, 178))
62641	28468780	Notably, MLN4924 suppressed the proliferation of primary human NF2-mutant schwannoma cells but did not affect that of NF2-WT Schwann cells (Fig.	('schwannoma', 'Disease', 'MESH:D009442', (74, 84))	('NF2-mutant', 'Gene', (63, 73))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('schwannoma', 'Phenotype', 'HP:0100008', (74, 84))	('MLN4924', 'Var', (9, 16))	('suppressed', 'NegReg', (17, 27))	('proliferation', 'CPA', (32, 45))	('schwannoma', 'Disease', (74, 84))	('human', 'Species', '9606', (57, 62))
62642	28468780	4F), providing genetic evidence that NF2-mutant tumor cells are selectively sensitive to MLN4924.	('tumor', 'Disease', (48, 53))	('NF2-mutant', 'Gene', (37, 47))	('NF2-mutant', 'Var', (37, 47))	('MLN4924', 'Chemical', 'MESH:C539933', (89, 96))	('sensitive', 'Reg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('MLN4924', 'Var', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
62643	28468780	Importantly, while GDC-0980 monotherapy inhibited NF2-mutant schwannoma to a similar extent as MLN4924, combination therapy significantly reduced the proliferation of these cells in vitro (Fig.	('schwannoma', 'Disease', (61, 71))	('reduced', 'NegReg', (138, 145))	('inhibited', 'NegReg', (40, 49))	('schwannoma', 'Phenotype', 'HP:0100008', (61, 71))	('GDC-0980', 'Chemical', 'MESH:C569670', (19, 27))	('MLN4924', 'Chemical', 'MESH:C539933', (95, 102))	('schwannoma', 'Disease', 'MESH:D009442', (61, 71))	('NF2-mutant', 'Gene', (50, 60))	('MLN4924', 'Var', (95, 102))	('proliferation', 'CPA', (150, 163))
62645	28468780	Finally, we examined the efficacy of mTOR and NAE inhibition in an NF2-mutant epithelioid MPM patient-derived xenograft (PDX), MSK-LX19, in which we had identified a total loss of expression of Merlin by immunoblotting (Supplemental Fig.	('Merlin', 'Gene', (194, 200))	('loss', 'NegReg', (172, 176))	('expression', 'MPA', (180, 190))	('NF2-mutant', 'Gene', (67, 77))	('NF2-mutant', 'Var', (67, 77))	('patient', 'Species', '9606', (94, 101))	('NAE', 'Chemical', '-', (46, 49))	('Merlin', 'Gene', '4771', (194, 200))
62646	28468780	Immunostaining and immunoblotting of small (<=200 mm3) MSK-LX19 tumors grown in NSG mice and treated once with each drug singly and in combination confirmed that MLN4924 inhibits neddylation of cullins but does not appreciably affect mTORC1 signaling (Fig.	('neddylation', 'MPA', (179, 190))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cullin', 'Gene', (194, 200))	('cullin', 'Gene', '143384', (194, 200))	('MSK-LX19 tumors', 'Disease', (55, 70))	('MLN4924', 'Chemical', 'MESH:C539933', (162, 169))	('mTORC1', 'cellular_component', 'GO:0031931', ('234', '240'))	('mTORC1', 'Gene', '382056', (234, 240))	('MLN4924', 'Var', (162, 169))	('inhibits', 'NegReg', (170, 178))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('mTORC1', 'Gene', (234, 240))	('MSK-LX19 tumors', 'Disease', 'MESH:D009369', (55, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mice', 'Species', '10090', (84, 88))
62647	28468780	Conversely, GDC-0980 efficiently blocks mTORC1 signaling in vivo but does not affect neddylation of cullins.	('cullin', 'Gene', '143384', (100, 106))	('GDC-0980', 'Chemical', 'MESH:C569670', (12, 20))	('mTORC1', 'Gene', (40, 46))	('mTORC1', 'cellular_component', 'GO:0031931', ('40', '46'))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('cullin', 'Gene', (100, 106))	('GDC-0980', 'Var', (12, 20))	('blocks', 'NegReg', (33, 39))	('mTORC1', 'Gene', '382056', (40, 46))
62648	28468780	Similarly, MLN4924 induced stabilization of p27 while combination therapy significantly increased p27 expression (Supplemental Fig.	('p27', 'Gene', (44, 47))	('MLN4924', 'Var', (11, 18))	('p27', 'Gene', (98, 101))	('expression', 'MPA', (102, 112))	('increased', 'PosReg', (88, 97))	('stabilization', 'MPA', (27, 40))	('p27', 'Gene', '10534', (44, 47))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('p27', 'Gene', '10534', (98, 101))
62649	28468780	S4D), suggesting that MLN4924 and GDC-0980 cooperatively induce cell cycle arrest.	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('GDC-0980', 'Gene', (34, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('MLN4924', 'Var', (22, 29))	('induce', 'Reg', (57, 63))	('GDC-0980', 'Chemical', 'MESH:C569670', (34, 42))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))	('cell cycle arrest', 'CPA', (64, 81))
62650	28468780	Whereas MLN4924 or GDC-0980 monotherapy significantly reduced tumor growth (P<0.01 and P<0.001, respectively), MLN4924 and GDC-0980 combination therapy completely suppressed tumor growth (P<0.001) (Fig.	('tumor', 'Disease', (174, 179))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('GDC-0980', 'Gene', (123, 131))	('GDC-0980', 'Chemical', 'MESH:C569670', (19, 27))	('tumor', 'Disease', (62, 67))	('MLN4924', 'Var', (111, 118))	('MLN4924', 'Var', (8, 15))	('reduced', 'NegReg', (54, 61))	('GDC-0980', 'Chemical', 'MESH:C569670', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('suppressed', 'NegReg', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
62652	28468780	Incomplete understanding of the signaling circuits dysregulated by inactivation of Merlin has so far prevented the development of rational and effective therapies for NF2 and MPM.	('inactivation', 'Var', (67, 79))	('NF2', 'Disease', (167, 170))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('MPM', 'Disease', (175, 178))	('prevented', 'NegReg', (101, 110))	('Merlin', 'Gene', '4771', (83, 89))	('Merlin', 'Gene', (83, 89))
62654	28468780	Intriguingly, loss of Merlin's inhibition of the nuclear E3 ligase CRL4DCAF1 stabilizes the Hippo pathway component Lats1/2 and hence activates YAP and TAZ, which play redundant roles in sustaining NF2-mutant tumorigenesis.	('Lats1/2', 'Gene', '8140;7462', (116, 123))	('YAP', 'Gene', (144, 147))	('Hippo pathway', 'Pathway', (92, 105))	('activates', 'PosReg', (134, 143))	('CRL', 'Gene', (67, 70))	('loss', 'Var', (14, 18))	('Merlin', 'Gene', (22, 28))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('YAP', 'Gene', '10413', (144, 147))	('DCAF1', 'Gene', (71, 76))	('CRL', 'Gene', '133396', (67, 70))	('stabilizes', 'PosReg', (77, 87))	('NF2-mutant', 'Gene', (198, 208))	('NF2-mutant', 'Var', (198, 208))	('DCAF1', 'Gene', '9730', (71, 76))	('TAZ', 'Gene', '6901', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('TAZ', 'Gene', (152, 155))	('Merlin', 'Gene', '4771', (22, 28))	('Lats1/2', 'Gene', (116, 123))
62655	28468780	Furthermore, loss of Merlin dysregulates additional signaling pathways - including mTORC1 - that may contribute to tumorigenesis.	('contribute', 'Reg', (101, 111))	('dysregulates', 'Reg', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('tumor', 'Disease', (115, 120))	('mTORC1', 'Gene', '382056', (83, 89))	('signaling pathways', 'Pathway', (52, 70))	('Merlin', 'Gene', (21, 27))	('mTORC1', 'cellular_component', 'GO:0031931', ('83', '89'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Merlin', 'Gene', '4771', (21, 27))	('loss', 'Var', (13, 17))	('mTORC1', 'Gene', (83, 89))
62657	28468780	In this study, we found that inactivation of NAE using MLN4924 inhibits CRL4DCAF1-mediated ubiquitylation of Lats1 and 2, and hence induces phosphorylation and inactivation of YAP.	('CRL', 'Gene', '133396', (72, 75))	('YAP', 'Gene', '10413', (176, 179))	('ubiquitylation', 'MPA', (91, 105))	('phosphorylation', 'MPA', (140, 155))	('MLN4924', 'Var', (55, 62))	('Lats1 and 2', 'Gene', '8140;7462', (109, 120))	('inhibits', 'NegReg', (63, 71))	('DCAF1', 'Gene', '9730', (76, 81))	('inactivation', 'MPA', (160, 172))	('DCAF1', 'Gene', (76, 81))	('YAP', 'Gene', (176, 179))	('induces', 'Reg', (132, 139))	('CRL', 'Gene', (72, 75))	('NAE', 'Chemical', '-', (45, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('140', '155'))	('MLN4924', 'Chemical', 'MESH:C539933', (55, 62))	('inactivation', 'Var', (29, 41))
62658	28468780	In addition, we found that MLN4924 preferentially inhibits the proliferation of NF2-mutant tumor cells, presumably as a consequence of their reliance on YAP/TAZ signaling for growth.	('proliferation', 'CPA', (63, 76))	('MLN4924', 'Var', (27, 34))	('YAP', 'Gene', '10413', (153, 156))	('TAZ', 'Gene', (157, 160))	('TAZ', 'Gene', '6901', (157, 160))	('NF2-mutant', 'Gene', (80, 90))	('NF2-mutant', 'Var', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('YAP', 'Gene', (153, 156))	('inhibits', 'NegReg', (50, 58))	('tumor', 'Disease', (91, 96))	('MLN4924', 'Chemical', 'MESH:C539933', (27, 34))
62659	28468780	In spite of its ability to curb YAP/TAZ and downstream target genes, MLN4924 did not inhibit the growth of NF2-mutant MPM xenografts as effectively as standard chemotherapy.	('TAZ', 'Gene', (36, 39))	('YAP', 'Gene', '10413', (32, 35))	('MLN4924', 'Var', (69, 76))	('NF2-mutant MPM', 'Gene', (107, 121))	('MPM', 'Gene', (118, 121))	('inhibit', 'NegReg', (85, 92))	('YAP', 'Gene', (32, 35))	('TAZ', 'Gene', '6901', (36, 39))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
62661	28468780	Our results clearly indicate that MLN4924 preferentially sensitizes NF2-mutant tumor cells to chemotherapy, inducing tumor cells exposed to both drugs to undergo apoptosis.	('MLN4924', 'Var', (34, 41))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('inducing', 'PosReg', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (117, 122))	('sensitizes', 'Reg', (57, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('NF2-mutant', 'Gene', (68, 78))
62662	28468780	Moreover, MLN4924 in combination with pemetrexed + cisplatin suppresses MPM xenograft growth to a much greater extent than either single treatment modality alone.	('MLN4924', 'Var', (10, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('suppresses', 'NegReg', (61, 71))	('pemetrexed', 'Chemical', 'MESH:D000068437', (38, 48))	('MPM xenograft growth', 'CPA', (72, 92))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))
62663	28468780	Therefore, MLN4924 inhibits oncogenic signaling through CRL4DCAF1 but also enhances the effect of chemotherapy as a result of collateral inhibition of CRLs involved in DNA repair.	('MLN4924', 'Var', (11, 18))	('oncogenic signaling', 'MPA', (28, 47))	('CRL', 'Gene', '133396', (56, 59))	('CRL', 'Gene', (151, 154))	('effect', 'MPA', (88, 94))	('DNA repair', 'biological_process', 'GO:0006281', ('168', '178'))	('enhances', 'PosReg', (75, 83))	('CRL', 'Gene', (56, 59))	('DCAF1', 'Gene', '9730', (60, 65))	('inhibition', 'NegReg', (137, 147))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('CRL', 'Gene', '133396', (151, 154))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('inhibits', 'NegReg', (19, 27))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('DCAF1', 'Gene', (60, 65))
62665	28468780	Prior studies have shown that activation of mTORC1 contributes to the hyperproliferation of NF2-mutant MPMs as well as canonical NF2 tumors including meningiomas and schwannomas.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mTORC1', 'Gene', '382056', (44, 50))	('hyperproliferation', 'MPA', (70, 88))	('meningiomas', 'Phenotype', 'HP:0002858', (150, 161))	('schwannomas', 'Phenotype', 'HP:0100008', (166, 177))	('mTORC1', 'cellular_component', 'GO:0031931', ('44', '50'))	('schwannoma', 'Phenotype', 'HP:0100008', (166, 176))	('mTORC1', 'Gene', (44, 50))	('activation', 'PosReg', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('meningioma', 'Phenotype', 'HP:0002858', (150, 160))	('meningiomas and schwannomas', 'Disease', 'MESH:D009442', (150, 177))	('NF2-mutant', 'Gene', (92, 102))	('NF2-mutant', 'Var', (92, 102))	('NF2 tumors', 'Disease', 'MESH:C537392', (129, 139))	('NF2 tumors', 'Disease', (129, 139))
62666	28468780	Based on the observation that loss of Merlin activates mTORC1 independently of CRL4DCAF1, we set out to test the effect of combined inhibition of CRL4DCAF1 and mTORC1.	('DCAF1', 'Gene', (150, 155))	('DCAF1', 'Gene', '9730', (83, 88))	('activates', 'PosReg', (45, 54))	('mTORC1', 'cellular_component', 'GO:0031931', ('160', '166'))	('CRL', 'Gene', '133396', (146, 149))	('mTORC1', 'Gene', (160, 166))	('CRL', 'Gene', (79, 82))	('DCAF1', 'Gene', (83, 88))	('mTORC1', 'Gene', '382056', (55, 61))	('mTORC1', 'cellular_component', 'GO:0031931', ('55', '61'))	('Merlin', 'Gene', '4771', (38, 44))	('CRL', 'Gene', (146, 149))	('DCAF1', 'Gene', '9730', (150, 155))	('Merlin', 'Gene', (38, 44))	('CRL', 'Gene', '133396', (79, 82))	('mTORC1', 'Gene', '382056', (160, 166))	('loss', 'Var', (30, 34))	('mTORC1', 'Gene', (55, 61))
62671	28468780	To block the two key oncogenic pathways underlying NF2-mutant tumorigenesis, we combined GDC-0980 and MLN4924.	('NF2-mutant', 'Gene', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('MLN4924', 'Chemical', 'MESH:C539933', (102, 109))	('GDC-0980', 'Chemical', 'MESH:C569670', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('MLN4924', 'Var', (102, 109))
62672	28468780	The combination almost completely suppressed the growth of NF2-mutant MPM cells in vivo and selectively inhibited the proliferation of NF2-mutant primary human schwannoma cells in vitro.	('NF2-mutant', 'Gene', (59, 69))	('schwannoma', 'Disease', 'MESH:D009442', (160, 170))	('human', 'Species', '9606', (154, 159))	('NF2-mutant', 'Var', (59, 69))	('suppressed', 'NegReg', (34, 44))	('NF2-mutant', 'Var', (135, 145))	('NF2-mutant', 'Gene', (135, 145))	('schwannoma', 'Phenotype', 'HP:0100008', (160, 170))	('proliferation', 'CPA', (118, 131))	('growth', 'MPA', (49, 55))	('inhibited', 'NegReg', (104, 113))	('schwannoma', 'Disease', (160, 170))
62673	28468780	Intriguingly, examination of the MSK-LX19 MPM PDX model revealed that these NF2-mutant tumor cells are highly sensitive to MLN4924 or GDC-0980 monotherapy, suggesting that activation of both pathways is required for their outgrowth.	('NF2-mutant', 'Gene', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MLN4924', 'MPA', (123, 130))	('NF2-mutant', 'Var', (76, 86))	('tumor', 'Disease', (87, 92))	('GDC-0980', 'Chemical', 'MESH:C569670', (134, 142))	('MLN4924', 'Chemical', 'MESH:C539933', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('sensitive', 'MPA', (110, 119))
62675	28468780	S4D) and thereby cell cycle arrest due to GDC-0980-mediated inhibition of AKT coupled with MLN4924-mediated accumulation of p27.	('p27', 'Gene', '10534', (124, 127))	('MLN4924', 'Chemical', 'MESH:C539933', (91, 98))	('MLN4924-mediated', 'Var', (91, 107))	('GDC-0980-mediated', 'Var', (42, 59))	('accumulation', 'PosReg', (108, 120))	('cell cycle arrest', 'CPA', (17, 34))	('AKT', 'Gene', '207', (74, 77))	('inhibition', 'NegReg', (60, 70))	('p27', 'Gene', (124, 127))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('17', '34'))	('AKT', 'Gene', (74, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (17, 34))	('GDC-0980', 'Chemical', 'MESH:C569670', (42, 50))
62676	28468780	MLN4924 likely induces p27 accumulation via inhibition of both CRL4DCAF1 and the p27 cullin E3 ligase SCFSkp2.	('induces', 'Reg', (15, 22))	('p27', 'Gene', (81, 84))	('accumulation', 'PosReg', (27, 39))	('p27', 'Gene', (23, 26))	('MLN4924', 'Var', (0, 7))	('CRL', 'Gene', (63, 66))	('DCAF1', 'Gene', '9730', (67, 72))	('cullin', 'Gene', (85, 91))	('inhibition', 'NegReg', (44, 54))	('p27', 'Gene', '10534', (81, 84))	('p27', 'Gene', '10534', (23, 26))	('cullin', 'Gene', '143384', (85, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('CRL', 'Gene', '133396', (63, 66))	('DCAF1', 'Gene', (67, 72))
62677	28468780	Simultaneously, inhibition of mTORC and PI3K may block AKT-mediated phosphorylation of p27, thereby promoting p27 nuclear import and proliferation arrest.	('nuclear import', 'MPA', (114, 128))	('AKT', 'Gene', (55, 58))	('proliferation arrest', 'Disease', (133, 153))	('p27', 'Gene', '10534', (87, 90))	('p27', 'Gene', '10534', (110, 113))	('promoting', 'PosReg', (100, 109))	('block', 'NegReg', (49, 54))	('proliferation arrest', 'Disease', 'MESH:D006323', (133, 153))	('p27', 'Gene', (110, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('p27', 'Gene', (87, 90))	('AKT', 'Gene', '207', (55, 58))	('mTORC', 'Gene', (30, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))	('nuclear import', 'biological_process', 'GO:0051170', ('114', '128'))	('inhibition', 'Var', (16, 26))
62680	28468780	Non-surgical therapies for NF2 tumors and NF2-mutant MPM are relatively ineffective in reducing morbidity and mortality.	('NF2 tumors', 'Disease', 'MESH:C537392', (27, 37))	('NF2-mutant', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('MPM', 'Gene', (53, 56))	('NF2 tumors', 'Disease', (27, 37))
62681	28468780	Our findings provide proof of principle that targeting oncogenic signaling pathways shared amongst NF2-mutant tumors, such as YAP and mTORC1, can radically alter disease progression.	('oncogenic signaling pathways', 'Pathway', (55, 83))	('alter', 'Reg', (156, 161))	('YAP', 'Gene', (126, 129))	('disease progression', 'CPA', (162, 181))	('mTORC1', 'Gene', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('YAP', 'Gene', '10413', (126, 129))	('NF2-mutant', 'Gene', (99, 109))	('NF2-mutant', 'Var', (99, 109))	('mTORC1', 'Gene', '382056', (134, 140))	('mTORC1', 'cellular_component', 'GO:0031931', ('134', '140'))
62684	21955238	These same tumor types have been found to contain SV40 DNA and proteins in humans.	('proteins', 'Protein', (63, 71))	('SV40', 'Species', '1891767', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('humans', 'Species', '9606', (75, 81))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('SV40 DNA', 'Var', (50, 58))
62708	21955238	Most of the differences of SV40 variants were detected in the sequence encoding the carboxyl-terminal variable region of Tag, within the amino acid residues 622 and 708; in addition, some sequence variability was detected in the early transcript intron and the sequences encoding tag, VP1 and Agnoprotein, were affected.	('SV40', 'Gene', (27, 31))	('variants', 'Var', (32, 40))	('SV40 variant', 'Species', '1891767', (27, 39))	('VP1 and Agnoprotein', 'Gene', '29031015', (285, 304))
62713	21955238	The efficiency of virus production in vitro by archetypal SV40 776 was improved by the duplication of the naturally occurring 72-bp enhancer element.	('duplication', 'Var', (87, 98))	('SV40', 'Species', '1891767', (58, 62))	('improved', 'PosReg', (71, 79))	('virus production', 'MPA', (18, 34))
62717	21955238	SV40 bypasses the Golgi complex en route to the endoplasmic reticulum, where calcium ions, bridging VP1 capsid proteins, are removed by endoplasmic reticulum absorption, resulting in capsid disassembly, which requires low cytosolic calcium concentrations.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('48', '69'))	('endoplasmic reticulum absorption', 'Disease', (136, 168))	('disassembly', 'NegReg', (190, 201))	('calcium', 'Chemical', 'MESH:D002118', (232, 239))	('calcium', 'Chemical', 'MESH:D002118', (77, 84))	('capsid', 'MPA', (183, 189))	('Golgi complex', 'cellular_component', 'GO:0005794', ('18', '31'))	('SV40', 'Species', '1891767', (0, 4))	('SV40', 'Var', (0, 4))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('136', '157'))	('endoplasmic reticulum absorption', 'Disease', 'MESH:C564600', (136, 168))
62718	21955238	Afterwards, SV40 genome is translocated to the nuclear compartment via mechanism mediated by the importin alpha2/beta heterodimer and by VP3.	('SV40', 'Species', '1891767', (12, 16))	('importin', 'cellular_component', 'GO:0005646', ('97', '105'))	('VP3', 'Gene', (137, 140))	('VP3', 'Gene', '29031016', (137, 140))	('SV40', 'Var', (12, 16))	('importin alpha2/beta heterodimer', 'Protein', (97, 129))
62723	21955238	In addition, Tag modulates intracellular signaling by recruiting several cellular proteins involved in cell progression and apoptosis pathways, and Tag transactivates several cellular genes including IGF-1, cdc2, hepatocyte growth factor receptor (Met) and Notch-1, thus promoting G2 phase progression (see SV40-mediated human primary mesothelial cells [HM] and astrocyte transformation).	('recruiting', 'PosReg', (54, 64))	('modulates', 'Reg', (17, 26))	('cdc2', 'Gene', (207, 211))	('intracellular signaling', 'MPA', (27, 50))	('SV40', 'Species', '1891767', (307, 311))	('G2 phase progression', 'CPA', (281, 301))	('intracellular', 'cellular_component', 'GO:0005622', ('27', '40'))	('cellular genes', 'Gene', (175, 189))	('G2 phase', 'biological_process', 'GO:0051319', ('281', '289'))	('IGF-1', 'Gene', (200, 205))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('213', '237'))	('transactivates', 'PosReg', (152, 166))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('Notch-1', 'Gene', (257, 264))	('Tag', 'Var', (148, 151))	('cdc2', 'Gene', '983', (207, 211))	('promoting', 'PosReg', (271, 280))	('human', 'Species', '9606', (321, 326))
62726	21955238	Only the SV40 genome, but not the host's genome, contains six tandem GC boxes, which represent the viral packaging signal for capsid assembly and viral DNA packaging.	('DNA packaging', 'biological_process', 'GO:0006323', ('152', '165'))	('SV40', 'Species', '1891767', (9, 13))	('SV40', 'Var', (9, 13))	('GC boxes', 'Protein', (69, 77))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))
62731	21955238	In human cells, SV40 Tag increases NFATs activity and NFATs provide a positive feedback loop, transactivating the SV40 promoters.	('SV40', 'Species', '1891767', (114, 118))	('human', 'Species', '9606', (3, 8))	('increases', 'PosReg', (25, 34))	('SV40 promoters', 'MPA', (114, 128))	('transactivating', 'MPA', (94, 109))	('SV40', 'Species', '1891767', (16, 20))	('SV40 Tag', 'Var', (16, 24))	('NFATs activity', 'MPA', (35, 49))
62743	21955238	Some of these HM and astrocytic cell lines release variable amounts of infectious SV40: in a few, the amount of virus released significantly decreased during cell culture, an effect we linked to the production of an antisense mRNA originating in the early region of the SV40 genome that leads to the degradation of late genes mRNAs [Carbone M, Unpublished Observations].	('Carbone', 'Chemical', 'MESH:D002244', (333, 340))	('SV40', 'Species', '1891767', (270, 274))	('SV40', 'Species', '1891767', (82, 86))	('decreased', 'NegReg', (141, 150))	('mRNAs', 'Gene', (326, 331))	('antisense', 'Var', (216, 225))	('degradation', 'biological_process', 'GO:0009056', ('300', '311'))	('amount', 'MPA', (102, 108))	('degradation', 'MPA', (300, 311))
62745	21955238	For this purpose, DNA replication-defective SV40 mutants and SV40 oncogene constructs under the control of an heterologous promoter are often used.	('mutants', 'Var', (49, 56))	('SV40', 'Species', '1891767', (44, 48))	('DNA replication', 'biological_process', 'GO:0006260', ('18', '33'))	('SV40', 'Gene', (44, 48))	('SV40', 'Species', '1891767', (61, 65))	('SV40', 'Gene', (61, 65))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))
62751	21955238	In HM and brain cells, Tag binds and inactivates the tumor suppressor activities of cellular p53, pRb, p130, p300 and p400.	('p53', 'Protein', (93, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('binds', 'Interaction', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('p130', 'Var', (103, 107))	('inactivates', 'NegReg', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('pRb', 'Gene', (98, 101))	('p400', 'Var', (118, 122))	('pRb', 'Gene', '5925', (98, 101))	('tumor', 'Disease', (53, 58))	('p300', 'Var', (109, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
62752	21955238	At the same time the Tag-p53-multiprotein complex acquires its own oncogenic activity and binds and activates the promoter, which in turn causes IGF-1 secretion and tumor cell growth.	('activates', 'PosReg', (100, 109))	('IGF-1', 'Protein', (145, 150))	('secretion', 'biological_process', 'GO:0046903', ('151', '160'))	('oncogenic activity', 'CPA', (67, 85))	('acquires', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('secretion', 'MPA', (151, 160))	('cell growth', 'biological_process', 'GO:0016049', ('171', '182'))	('causes', 'Reg', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Tag-p53-multiprotein', 'Var', (21, 41))	('tumor', 'Disease', (165, 170))
62756	21955238	Hamsters injected with SV40 developed osteosarcomas, sarcomas, ependymomas, mesotheliomas, choroid plexus tumors and true histiocytic lymphomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (76, 89))	('osteosarcomas', 'Phenotype', 'HP:0002669', (38, 51))	('SV40', 'Species', '1891767', (23, 27))	('SV40', 'Var', (23, 27))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (91, 112))	('ependymomas', 'Disease', 'MESH:D004806', (63, 74))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('lymphomas', 'Disease', (134, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (91, 112))	('sarcomas', 'Disease', (53, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (38, 50))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('ependymomas', 'Disease', (63, 74))	('osteosarcomas', 'Disease', 'MESH:D012516', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcomas', 'Disease', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('osteosarcomas', 'Disease', (38, 51))	('mesotheliomas', 'Disease', (76, 89))	('lymphomas', 'Disease', 'MESH:D008223', (134, 143))	('choroid plexus tumors', 'Disease', (91, 112))	('lymphomas', 'Phenotype', 'HP:0002665', (134, 143))
62758	21955238	Over 50% of hamsters injected with SV40 intracardiacally or intraperitoneally, and 100% of those injected intrapleurally, developed mesothelioma.	('SV40', 'Species', '1891767', (35, 39))	('developed', 'Reg', (122, 131))	('hamster', 'Species', '10034', (12, 19))	('SV40', 'Var', (35, 39))	('pleural', 'Disease', 'MESH:D010995', (111, 118))	('mesothelioma', 'Disease', (132, 144))	('pleural', 'Disease', (111, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (132, 144))
62768	21955238	These transgenic models indicate that the expression of SV40 Tag can cause cancer in any organ, making SV40 Tag the most potent oncogene known to date.	('SV40', 'Var', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('SV40 Tag', 'Var', (56, 64))	('cancer', 'Disease', (75, 81))	('cause', 'Reg', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('transgenic', 'Species', '10090', (6, 16))	('SV40', 'Species', '1891767', (103, 107))	('SV40', 'Species', '1891767', (56, 60))
62777	21955238	Thus, SV40 and asbestos are cocarcinogens, and act synergistically in causing malignant transformation of HM in vitro.	('causing', 'Reg', (70, 77))	('asbestos', 'Chemical', 'MESH:D001194', (15, 23))	('malignant transformation', 'CPA', (78, 102))	('SV40', 'Species', '1891767', (6, 10))	('SV40', 'Var', (6, 10))
62780	21955238	How could episomal SV40 persist in human cells when, as discussed previously, episomal SV40 should replicate, produce VP4 and cause cell lysis?	('produce', 'Reg', (110, 117))	('cause', 'Reg', (126, 131))	('SV40', 'Species', '1891767', (19, 23))	('human', 'Species', '9606', (35, 40))	('VP4', 'MPA', (118, 121))	('replicate', 'Var', (99, 108))	('episomal SV40', 'Var', (78, 91))	('cell lysis', 'CPA', (132, 142))	('SV40', 'Species', '1891767', (87, 91))	('lysis', 'biological_process', 'GO:0019835', ('137', '142'))
62781	21955238	We discovered that in HM and in human astrocytes, during SV40 late phase infection, late gene expression is suppressed by antisense RNAs that are produced as a result of extension of the early transcripts beyond the early polyadenylation signal into the late region (Figure 2).	('late gene expression', 'MPA', (84, 104))	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('infection', 'Disease', (73, 82))	('SV40', 'Species', '1891767', (57, 61))	('antisense', 'Var', (122, 131))	('infection', 'Disease', 'MESH:D007239', (73, 82))	('SV40', 'Var', (57, 61))	('suppressed', 'NegReg', (108, 118))	('human', 'Species', '9606', (32, 37))	('extension', 'PosReg', (170, 179))
62785	21955238	Figure 3 summarizes the molecular events driven by the expression of SV40 Tag in HM that leads to HM transformation and malignant growth.	('HM transformation', 'CPA', (98, 115))	('leads to', 'Reg', (89, 97))	('malignant growth', 'CPA', (120, 136))	('SV40', 'Species', '1891767', (69, 73))	('SV40 Tag', 'Var', (69, 77))
62788	21955238	Interestingly, Notch-1 and Met are highly expressed in HM and astrocytes transformed by nonarchetypal SV40, while the archetypal SV40 variant can only transform astrocytes.	('Notch-1', 'Gene', (15, 22))	('SV40', 'Species', '1891767', (129, 133))	('SV40', 'Species', '1891767', (102, 106))	('nonarchetypal SV40', 'Var', (88, 106))	('SV40 variant', 'Species', '1891767', (129, 141))	('Met', 'Gene', (27, 30))
62789	21955238	SV40 tag binds and inactivates the PP2A leading to an increase of ERK pathway activity and tumorigenesis.	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('SV40 tag', 'Var', (0, 8))	('inactivates', 'NegReg', (19, 30))	('increase', 'PosReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('binds', 'Interaction', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SV40', 'Species', '1891767', (0, 4))	('PP2A', 'Protein', (35, 39))	('activity', 'MPA', (78, 86))	('ERK pathway', 'Pathway', (66, 77))	('tumor', 'Disease', (91, 96))
62791	21955238	When HM in tissue culture are exposed to both SV40 and asbestos, the rate of malignant transformation increases synergistically.	('SV40', 'Species', '1891767', (46, 50))	('asbestos', 'Chemical', 'MESH:D001194', (55, 63))	('SV40', 'Var', (46, 50))	('malignant transformation', 'CPA', (77, 101))	('increases', 'PosReg', (102, 111))
62792	21955238	By using the tag-defective SV40 (strain dl883), which does not induce MM in vivo, we demonstrated that pleural and peritoneal injection of crocidolite asbestos, combined with intraventricle administration of dl883 SV40, induced mesothelioma in approximately 90% of hamsters with a shorter tumor latency compared with 20% mesothelioma induction in animals injected with asbestos alone.	('mesothelioma', 'Disease', 'MESH:D008654', (321, 333))	('SV40', 'Species', '1891767', (214, 218))	('mesothelioma', 'Disease', 'MESH:D008654', (228, 240))	('dl883', 'Var', (208, 213))	('crocidolite asbestos', 'Disease', (139, 159))	('tumor', 'Disease', (289, 294))	('crocidolite asbestos', 'Disease', 'MESH:D001195', (139, 159))	('asbestos', 'Chemical', 'MESH:D001194', (369, 377))	('SV40', 'Species', '1891767', (27, 31))	('hamster', 'Species', '10034', (265, 272))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('induced', 'PosReg', (220, 227))	('asbestos', 'Chemical', 'MESH:D001194', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('pleural', 'Disease', 'MESH:D010995', (103, 110))	('pleural', 'Disease', (103, 110))	('mesothelioma', 'Disease', (321, 333))	('SV40 (strain', 'Species', '1891767', (27, 39))	('mesothelioma', 'Disease', (228, 240))
62793	21955238	Therefore, two very different carcinogens, SV40 and asbestos, are cocarcinogens in causing malignant transformation of HM in vitro and in causing MM in animals.	('causing', 'Reg', (138, 145))	('asbestos', 'Chemical', 'MESH:D001194', (52, 60))	('SV40', 'Species', '1891767', (43, 47))	('SV40', 'Var', (43, 47))	('malignant transformation', 'CPA', (91, 115))
62799	21955238	It appears possible that this inflammatory environment may favor the growth of HM that have accumulated DNA damage owing to the reactive oxygen/nitrogen species released by cells exposed to asbestos, or owing to SV40 Tag expression, or both.	('SV40 Tag expression', 'Var', (212, 231))	('asbestos', 'Chemical', 'MESH:D001194', (190, 198))	('SV40', 'Species', '1891767', (212, 216))	('reactive oxygen/nitrogen species', 'MPA', (128, 160))	('growth', 'MPA', (69, 75))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('favor', 'PosReg', (59, 64))	('reactive oxygen/nitrogen species', 'Chemical', '-', (128, 160))
62800	21955238	Moreover, Tag expression protects HM from asbestos cytotoxicity by activating the PI3K/Akt pathway, thus increasing the percentage of cells that survive asbestos exposure and can therefore undergo malignant transformation.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('increasing', 'PosReg', (105, 115))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('PI3K/Akt pathway', 'Pathway', (82, 98))	('undergo', 'Reg', (189, 196))	('asbestos', 'Chemical', 'MESH:D001194', (153, 161))	('malignant transformation', 'CPA', (197, 221))	('activating', 'Reg', (67, 77))	('cytotoxicity', 'Disease', (51, 63))	('Tag expression', 'Var', (10, 24))
62803	21955238	In this town, 16% of blood specimens from healthy individuals tested positive for SV40 Tag DNA sequences.	('SV40 Tag DNA sequences', 'Var', (82, 104))	('positive', 'Reg', (69, 77))	('SV40', 'Species', '1891767', (82, 86))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))
62824	21955238	Microdissection experiments confirmed IHC findings, indicating that SV40 was present in tumor cells but not in the surrounding stroma.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SV40', 'Species', '1891767', (68, 72))	('SV40', 'Var', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
62827	21955238	Between 1975 and 2002, 13 studies reported an overall prevalence of about 18% of brain tumors containing SV40 sequences (reviewed in).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SV40', 'Species', '1891767', (105, 109))	('brain tumors', 'Disease', 'MESH:D001932', (81, 93))	('brain tumors', 'Phenotype', 'HP:0030692', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('brain tumors', 'Disease', (81, 93))	('SV40 sequences', 'Var', (105, 119))
62828	21955238	High frequencies of SV40 DNA sequence were found in choroid plexus tumors, ependymomas, low-grade astrocytomas, anaplastic astrocytomas and secondary glioblastomas, and lower frequencies were detected in gemistocytic astrocytomas, oligodendrogliomas, glioma and medulloblastoma (Table 3).	('ependymomas', 'Disease', (75, 86))	('astrocytomas', 'Disease', 'MESH:D001254', (123, 135))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('glioma', 'Disease', (242, 248))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (52, 73))	('medulloblastoma', 'Disease', 'MESH:D008527', (262, 277))	('glioblastomas', 'Disease', (150, 163))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('medulloblastoma', 'Phenotype', 'HP:0002885', (262, 277))	('medulloblastoma', 'Disease', (262, 277))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (231, 249))	('astrocytomas', 'Disease', 'MESH:D001254', (98, 110))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (52, 73))	('astrocytomas', 'Disease', 'MESH:D001254', (217, 229))	('glioblastomas', 'Disease', 'MESH:D005909', (150, 163))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('SV40', 'Species', '1891767', (20, 24))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('SV40 DNA sequence', 'Var', (20, 37))	('oligodendrogliomas', 'Disease', (231, 249))	('astrocytomas', 'Disease', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ependymomas', 'Disease', 'MESH:D004806', (75, 86))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('glioblastomas', 'Phenotype', 'HP:0012174', (150, 163))	('astrocytomas', 'Disease', (98, 110))	('choroid plexus tumors', 'Disease', (52, 73))	('astrocytomas', 'Disease', (217, 229))	('glioma', 'Disease', (251, 257))
62832	21955238	SV40 DNA sequences and Tag protein were detected in the choroid plexus carcinoma (CPC) sample from one LFS patient.	('CPC', 'Phenotype', 'HP:0030392', (82, 85))	('choroid plexus carcinoma', 'Disease', (56, 80))	('CPC', 'cellular_component', 'GO:0032133', ('82', '85'))	('SV40 DNA', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (56, 80))	('LFS', 'Disease', (103, 106))	('SV40', 'Species', '1891767', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('5', '8'))	('patient', 'Species', '9606', (107, 114))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (56, 80))	('LFS', 'Disease', 'MESH:D016864', (103, 106))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
62834	21955238	In a second LFS patient that had developed CPC, osteosarcoma and renal cell carcinoma, SV40 DNA and Tag were detected in both CPC and renal cell carcinoma specimens.	('CPC', 'Phenotype', 'HP:0030392', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('LFS', 'Disease', 'MESH:D016864', (12, 15))	('CPC', 'Phenotype', 'HP:0030392', (126, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('CPC', 'cellular_component', 'GO:0032133', ('126', '129'))	('CPC', 'Disease', (43, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 85))	('CPC', 'cellular_component', 'GO:0032133', ('43', '46'))	('SV40 DNA', 'Var', (87, 95))	('LFS', 'Disease', (12, 15))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('SV40', 'Species', '1891767', (87, 91))	('CPC and renal cell carcinoma', 'Disease', 'MESH:D020288', (126, 154))	('patient', 'Species', '9606', (16, 23))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))
62853	21955238	Unfortunately, the controversy over the percent of tumor specimens containing SV40 DNA and proteins has paralyzed this research field.	('paralyzed', 'Disease', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('paralyzed', 'Disease', 'MESH:D010243', (104, 113))	('SV40', 'Species', '1891767', (78, 82))	('tumor', 'Disease', (51, 56))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SV40 DNA', 'Var', (78, 86))
62856	21955238	Regardless of its pathogenic role, the presence of SV40 in some tumors provides a potential target for therapy.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('presence', 'Var', (39, 47))	('SV40', 'Species', '1891767', (51, 55))	('SV40', 'Gene', (51, 55))
62857	21955238	However, until the existing controversy over the presence of SV40 in human tumors is addressed and funding becomes available, it appears unlikely that progress will be made to develop therapies aimed at tumor cells carrying SV40 and or expressing SV40 antigens.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('human', 'Species', '9606', (69, 74))	('SV40', 'Species', '1891767', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SV40', 'Species', '1891767', (61, 65))	('SV40', 'Species', '1891767', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))	('SV40', 'Var', (224, 228))
62865	21955238	In addition, some authors detected SV40 DNA but did not detect SV40 proteins, raising the question of whether finding SV40 DNA was of any pathogenic significance (Table 2).	('SV40', 'Species', '1891767', (35, 39))	('SV40', 'Species', '1891767', (118, 122))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('SV40 DNA', 'Var', (35, 43))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('SV40', 'Species', '1891767', (63, 67))	('detected', 'Reg', (26, 34))
62879	21955238	In summary, the data suggest that at least 5% of human mesotheliomas and brain tumors - according to the so-called negative papers, or more according to the 'positive papers' - contain SV40 DNA, the possible pathogenic role of SV40 in these tumors should be further investigated to address causality issues.	('brain tumors', 'Phenotype', 'HP:0030692', (73, 85))	('brain tumors', 'Disease', (73, 85))	('human', 'Species', '9606', (49, 54))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('mesotheliomas', 'Disease', (55, 68))	('SV40 DNA', 'Var', (185, 193))	('mesotheliomas', 'Disease', 'MESH:D008654', (55, 68))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('brain tumors', 'Disease', 'MESH:D001932', (73, 85))	('SV40', 'Species', '1891767', (227, 231))	('SV40', 'Species', '1891767', (185, 189))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
62885	21955238	Recent work has indicated that an antisense mechanism that appears unique to HM and brain cells suppresses late viral gene expression, allowing these cell types to survive infection, maintain SV40 as episomal with expression of Tag and tag but not of the VP1-4 proteins and become transformed.	('Tag', 'Var', (228, 231))	('infection', 'Disease', (172, 181))	('infection', 'Disease', 'MESH:D007239', (172, 181))	('SV40', 'Species', '1891767', (192, 196))	('SV40', 'Gene', (192, 196))	('viral gene expression', 'biological_process', 'GO:0019080', ('112', '133'))	('suppresses', 'NegReg', (96, 106))	('late viral', 'MPA', (107, 117))	('expression', 'MPA', (214, 224))
62887	21955238	Researchers are starting to address the puzzle of why archetypal SV40 DNA sequences are detectable in human brain tumors, while the SV40 DNA sequence in MM samples are most often nonarchetypal.	('SV40', 'Species', '1891767', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('detectable', 'Reg', (88, 98))	('brain tumors', 'Disease', 'MESH:D001932', (108, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('SV40', 'Species', '1891767', (65, 69))	('brain tumors', 'Disease', (108, 120))	('SV40 DNA sequences', 'Var', (65, 83))	('human', 'Species', '9606', (102, 107))
62892	21955238	SV40 Tag interacts with and transactivates multiple intracellular signaling proteins.	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('interacts', 'Interaction', (9, 18))	('SV40', 'Species', '1891767', (0, 4))	('SV40 Tag', 'Var', (0, 8))	('intracellular', 'cellular_component', 'GO:0005622', ('52', '65'))	('transactivates', 'MPA', (28, 42))
62893	21955238	Tag-p53 complex recruits retinoblastoma protein, p300, p400 and CREB-binding protein to induce specific gene transcription, resulting in the activation of IGF-1, Met and Notch-1 pathways.	('retinoblastoma', 'Disease', 'MESH:D012175', (25, 39))	('retinoblastoma', 'Disease', (25, 39))	('IGF-1', 'Pathway', (155, 160))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('p400', 'Var', (55, 59))	('transcription', 'biological_process', 'GO:0006351', ('109', '122'))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('p300', 'Var', (49, 53))	('CREB-binding', 'molecular_function', 'GO:0008140', ('64', '76'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (25, 39))	('specific gene transcription', 'MPA', (95, 122))	('induce', 'PosReg', (88, 94))	('activation', 'PosReg', (141, 151))
62896	21955238	Many laboratories reported the presence of SV40 DNA, RNA or proteins in human tumor biopsies, other laboratories reported negative results, or more often reported a low incidence of SV40 in these specimens (6%).	('SV40 DNA', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('SV40', 'Species', '1891767', (43, 47))	('tumor', 'Disease', (78, 83))	('human', 'Species', '9606', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('proteins', 'Protein', (60, 68))	('RNA', 'MPA', (53, 56))	('SV40', 'Species', '1891767', (182, 186))
62913	33028834	Studies using several cancer cell lines have strongly suggested the involvement of aberrant epigenetic regulations of MMP-2 in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('MMP-2', 'Gene', '4313', (118, 123))	('cancer', 'Disease', (22, 28))	('involvement', 'Reg', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('MMP-2', 'molecular_function', 'GO:0004228', ('118', '123'))	('aberrant epigenetic regulations', 'Var', (83, 114))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('MMP-2', 'Gene', (118, 123))
62926	33028834	Small interference RNA (siRNA)-mediated knockdown of MT1-MMP responsible for activation of pro-MMP-2 resulted in the failure of pro-MMP-2 activation in invasive cells (Fig.	('MT1', 'molecular_function', 'GO:0043791', ('53', '56'))	('MT1', 'molecular_function', 'GO:0047152', ('53', '56'))	('MMP-2', 'Gene', '4313', (132, 137))	('MMP-2', 'Gene', (95, 100))	('MT1', 'molecular_function', 'GO:0043834', ('53', '56'))	('MMP', 'molecular_function', 'GO:0004235', ('57', '60'))	('MMP-2', 'molecular_function', 'GO:0004228', ('132', '137'))	('knockdown', 'Var', (40, 49))	('MMP-2', 'Gene', '4313', (95, 100))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('MMP-2', 'molecular_function', 'GO:0004228', ('95', '100'))	('MT1-MMP', 'Gene', (53, 60))	('MMP-2', 'Gene', (132, 137))	('MT1-MMP', 'Gene', '4323', (53, 60))
62928	33028834	Furthermore, siRNA-mediated knockdown of MMP-2 in invasive cells (Fig.	('MMP-2', 'Gene', '4313', (41, 46))	('MMP-2', 'molecular_function', 'GO:0004228', ('41', '46'))	('MMP-2', 'Gene', (41, 46))	('knockdown', 'Var', (28, 37))
62933	33028834	These results suggest epigenetic silencing of MMP-2 promoter in non-invasive mesothelioma cells.	('non-invasive mesothelioma', 'Disease', 'MESH:D008654', (64, 89))	('MMP-2', 'Gene', '4313', (46, 51))	('non-invasive mesothelioma', 'Disease', (64, 89))	('MMP-2', 'Gene', (46, 51))	('epigenetic silencing', 'Var', (22, 42))	('MMP-2', 'molecular_function', 'GO:0004228', ('46', '51'))
62938	33028834	Thus MMP-2 gene expression was epigenetically silenced in non-invasive mesothelioma cells.	('MMP-2', 'Gene', '4313', (5, 10))	('MMP-2', 'molecular_function', 'GO:0004228', ('5', '10'))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('non-invasive mesothelioma', 'Disease', 'MESH:D008654', (58, 83))	('epigenetically silenced', 'Var', (31, 54))	('non-invasive mesothelioma', 'Disease', (58, 83))	('expression', 'MPA', (16, 26))	('MMP-2', 'Gene', (5, 10))
62944	33028834	We next analyzed The Cancer Genome Atlas (TCGA) database for CpG methylation at 12 probes localized between BS3 to BS6 (p1 to p12 in Fig.	('p12', 'Gene', '57804', (126, 129))	('p12', 'Gene', (126, 129))	('BS3', 'Var', (108, 111))	('Cancer', 'Disease', (21, 27))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))
62950	33028834	To further characterize histone modifications at MMP-2 promoter, we performed the chromatin immunoprecipitation (ChIP) assay for Histone H3 tri-methylated Lys9 (H3K9me3) and H3K27me3 (Fig.	('MMP-2', 'molecular_function', 'GO:0004228', ('49', '54'))	('MMP-2', 'Gene', (49, 54))	('H3K27me3', 'Var', (174, 182))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))	('Lys9', 'Chemical', '-', (155, 159))	('MMP-2', 'Gene', '4313', (49, 54))
62954	33028834	The mRNA expression of MMP-2 was increased in these non-invasive cells (H28, Meso-4, H2052) by the knockdown of EZH2, CBX4, CBX6, and G9a alone (Fig.	('CBX6', 'Gene', '23466', (124, 128))	('EZH2', 'Gene', (112, 116))	('MMP-2', 'molecular_function', 'GO:0004228', ('23', '28'))	('MMP-2', 'Gene', '4313', (23, 28))	('H28', 'Chemical', '-', (72, 75))	('CBX4', 'Gene', '8535', (118, 122))	('increased', 'PosReg', (33, 42))	('mRNA expression', 'MPA', (4, 19))	('CBX4', 'Gene', (118, 122))	('knockdown', 'Var', (99, 108))	('G9a', 'Gene', (134, 137))	('G9a', 'Gene', '10919', (134, 137))	('MMP-2', 'Gene', (23, 28))	('CBX6', 'Gene', (124, 128))	('EZH2', 'Gene', '2146', (112, 116))
62955	33028834	The combined knockdown of CBX6 with EZH2 or G9a further increased MMP-2 mRNA levels compared to the levels caused by the individual knockdown of EZH2, CBX6, and G9a (Fig.	('MMP-2', 'Gene', '4313', (66, 71))	('increased', 'PosReg', (56, 65))	('MMP-2', 'molecular_function', 'GO:0004228', ('66', '71'))	('G9a', 'Gene', (44, 47))	('MMP-2', 'Gene', (66, 71))	('CBX6', 'Gene', (26, 30))	('EZH2', 'Gene', '2146', (145, 149))	('G9a', 'Gene', '10919', (44, 47))	('CBX6', 'Gene', '23466', (26, 30))	('G9a', 'Gene', (161, 164))	('G9a', 'Gene', '10919', (161, 164))	('CBX6', 'Gene', (151, 155))	('EZH2', 'Gene', (145, 149))	('CBX6', 'Gene', '23466', (151, 155))	('EZH2', 'Gene', '2146', (36, 40))	('knockdown', 'Var', (13, 22))	('EZH2', 'Gene', (36, 40))
62959	33028834	We next established H2052 cells stably knockdown the CBX6 by shRNA targeting CBX6, and recovered CBX6 expression by overexpression of Flag-CBX6 (Fig.	('CBX6', 'Gene', (97, 101))	('CBX6', 'Gene', '23466', (97, 101))	('CBX6', 'Gene', (139, 143))	('expression', 'MPA', (102, 112))	('knockdown', 'Var', (39, 48))	('CBX6', 'Gene', (77, 81))	('CBX6', 'Gene', '23466', (139, 143))	('CBX6', 'Gene', (53, 57))	('CBX6', 'Gene', '23466', (77, 81))	('CBX6', 'Gene', '23466', (53, 57))	('recovered', 'PosReg', (87, 96))
62960	33028834	The knockdown of CBX6 in H2052 cells changed the cells into flat and adhesive morphology (Fig.	('adhesive morphology', 'CPA', (69, 88))	('CBX6', 'Gene', (17, 21))	('CBX6', 'Gene', '23466', (17, 21))	('changed', 'Reg', (37, 44))	('knockdown', 'Var', (4, 13))
62964	33028834	Thus, the knockdown of CBX6 upregulated MMP-2 expression and mesothelioma invasion.	('MMP-2', 'Gene', (40, 45))	('mesothelioma invasion', 'Disease', 'MESH:D008654', (61, 82))	('MMP-2', 'molecular_function', 'GO:0004228', ('40', '45'))	('mesothelioma invasion', 'Disease', (61, 82))	('CBX6', 'Gene', '23466', (23, 27))	('CBX6', 'Gene', (23, 27))	('MMP-2', 'Gene', '4313', (40, 45))	('upregulated', 'PosReg', (28, 39))	('expression', 'MPA', (46, 56))	('knockdown', 'Var', (10, 19))
62966	33028834	We found 28 upregulated genes and 58 downregulated genes in the CBX6 knockdown condition (Fig.	('CBX6', 'Gene', '23466', (64, 68))	('knockdown', 'Var', (69, 78))	('upregulated', 'PosReg', (12, 23))	('CBX6', 'Gene', (64, 68))
62975	33028834	7c), and Flag-CBX6 level marginally increased by the treatment of MG132 for 5 h in non-invasive cells (Fig.	('MG132', 'Var', (66, 71))	('MG132', 'Chemical', 'MESH:C072553', (66, 71))	('increased', 'PosReg', (36, 45))	('CBX6', 'Gene', '23466', (14, 18))	('CBX6', 'Gene', (14, 18))
62980	33028834	To clarify the domains required for CBX6 degradation, we expressed the deletion forms of CBX6 in invasive JMN-1B cells and examined their stability and subcellular localization (Fig.	('CBX6', 'Gene', (36, 40))	('CBX6', 'Gene', '23466', (36, 40))	('degradation', 'biological_process', 'GO:0009056', ('41', '52'))	('deletion', 'Var', (71, 79))	('CBX6', 'Gene', (89, 93))	('CBX6', 'Gene', '23466', (89, 93))	('localization', 'biological_process', 'GO:0051179', ('164', '176'))
62982	33028834	Deletion of chromodomain or C-box domain did not restore CBX6 in the absence of MG132 (Fig.	('CBX6', 'Gene', (57, 61))	('MG132', 'Chemical', 'MESH:C072553', (80, 85))	('CBX6', 'Gene', '23466', (57, 61))	('Deletion', 'Var', (0, 8))
62984	33028834	Deletion of amino acids 201 to 300, 231 to 270, and 272 to 299 restored CBX6 even in the absence of MG132 (Fig.	('CBX6', 'Gene', (72, 76))	('CBX6', 'Gene', '23466', (72, 76))	('MG132', 'Chemical', 'MESH:C072553', (100, 105))	('restored', 'PosReg', (63, 71))	('Deletion', 'Var', (0, 8))
62985	33028834	8a, Delta201-300, Delta231-270, Delta272-299, respectively), suggesting that the degradation of CBX6 is dependent on amino acids 201-300 in CBX6.	('Delta231', 'Mutation', 'c.del231', (18, 26))	('Delta272-299', 'Var', (32, 44))	('degradation', 'biological_process', 'GO:0009056', ('81', '92'))	('Delta272-299', 'CellLine', 'CVCL:K058', (32, 44))	('CBX6', 'Gene', (96, 100))	('degradation', 'MPA', (81, 92))	('CBX6', 'Gene', (140, 144))	('Delta201-300', 'Var', (4, 16))	('CBX6', 'Gene', '23466', (140, 144))	('CBX6', 'Gene', '23466', (96, 100))	('dependent', 'Reg', (104, 113))	('Delta231-270', 'Var', (18, 30))
62996	33028834	TCGA analysis of human mesothelioma samples further supported the correlation between CpG methylation status in this specified region and MMP-2 expression levels.	('expression levels', 'MPA', (144, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('human', 'Species', '9606', (17, 22))	('MMP-2', 'molecular_function', 'GO:0004228', ('138', '143'))	('MMP-2', 'Gene', (138, 143))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('methylation', 'Var', (90, 101))	('MMP-2', 'Gene', '4313', (138, 143))	('mesothelioma', 'Disease', (23, 35))
62997	33028834	Collectively, these results suggest that the dysregulation of epigenetic silencing of MMP-2 is involved in mesothelioma progression to invasive tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('MMP-2', 'Gene', '4313', (86, 91))	('invasive tumors', 'Disease', (135, 150))	('epigenetic silencing', 'Var', (62, 82))	('mesothelioma', 'Disease', (107, 119))	('invasive tumors', 'Disease', 'MESH:D009361', (135, 150))	('MMP-2', 'Gene', (86, 91))	('dysregulation', 'Var', (45, 58))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('involved', 'Reg', (95, 103))	('MMP-2', 'molecular_function', 'GO:0004228', ('86', '91'))
63006	33028834	CBX6 mRNA was downregulated as the astrocytoma grade increased and ectopic expression of CBX6 in glioblastoma cells decreased cell proliferation.	('CBX6', 'Gene', '23466', (89, 93))	('astrocytoma', 'Disease', 'MESH:D001254', (35, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('ectopic expression', 'Var', (67, 85))	('cell proliferation', 'CPA', (126, 144))	('mRNA', 'MPA', (5, 9))	('downregulated', 'NegReg', (14, 27))	('astrocytoma', 'Disease', (35, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('astrocytoma', 'Phenotype', 'HP:0009592', (35, 46))	('increased', 'PosReg', (53, 62))	('CBX6', 'Gene', (89, 93))	('CBX6', 'Gene', (0, 4))	('CBX6', 'Gene', '23466', (0, 4))	('glioblastoma', 'Disease', (97, 109))	('decreased', 'NegReg', (116, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
63007	33028834	CBX6 mRNA was frequently downregulated in human breast cancer and ectopic expression of CBX6 reduced proliferation, migration, and invasion of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('human', 'Species', '9606', (42, 47))	('CBX6', 'Gene', (88, 92))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('CBX6', 'Gene', '23466', (88, 92))	('breast cancer', 'Disease', (48, 61))	('CBX6', 'Gene', (0, 4))	('CBX6', 'Gene', '23466', (0, 4))	('invasion', 'CPA', (131, 139))	('proliferation', 'CPA', (101, 114))	('downregulated', 'NegReg', (25, 38))	('migration', 'CPA', (116, 125))	('ectopic expression', 'Var', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mRNA', 'MPA', (5, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('reduced', 'NegReg', (93, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))
63011	33028834	Recently, it was shown that T437 phosphorylation in CBX4 by casein kinase 1alpha (CK1alpha) facilitated CBX4 ubiquitination at both K178 and K280 and subsequent degradation of CBX4 in osteosarcoma.	('ubiquitination', 'MPA', (109, 123))	('CBX4', 'Gene', '8535', (52, 56))	('CBX4', 'Gene', '8535', (176, 180))	('CBX4', 'Gene', (104, 108))	('CBX4', 'Gene', '8535', (104, 108))	('CBX4', 'Gene', (52, 56))	('CBX4', 'Gene', (176, 180))	('K280', 'Var', (141, 145))	('K178', 'Var', (132, 136))	('facilitated', 'PosReg', (92, 103))	('degradation', 'biological_process', 'GO:0009056', ('161', '172'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (184, 196))	('osteosarcoma', 'Disease', (184, 196))	('osteosarcoma', 'Disease', 'MESH:D012516', (184, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('T437 phosphorylation', 'Var', (28, 48))	('degradation', 'MPA', (161, 172))
63015	33028834	It is noteworthy that the phosphorylation at Ser301 and Ser303 of CBX6, which is adjacent to the region required for ubiquitination, has been detected in mass spectrometry analysis without functional validation.	('Ser303', 'Chemical', '-', (56, 62))	('Ser301', 'Chemical', '-', (45, 51))	('Ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('CBX6', 'Gene', (66, 70))	('Ser', 'cellular_component', 'GO:0005790', ('45', '48'))	('Ser303', 'Var', (56, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('CBX6', 'Gene', '23466', (66, 70))	('phosphorylation', 'MPA', (26, 41))
63047	33028834	MMP-2 genomic sequence, including promoter region (- 2049 to + 1, translation initiation site as + 1), was amplified by PCR using primers of 5'-ACGCGTGCTAGCCAAGGTTTGTCACTGGGTC-3' (containing NheI site) and 5'-AATGCCAAGCTTATCGTAGCGCTCCCTGGC-3' (containing HindIII site).	('MMP-2', 'Gene', (0, 5))	('- 2049', 'Var', (51, 57))	('MMP-2', 'Gene', '4313', (0, 5))	('translation initiation', 'biological_process', 'GO:0006413', ('66', '88'))	('MMP-2', 'molecular_function', 'GO:0004228', ('0', '5'))
63066	33028834	Briefly, the cross-linked chromatins were immunoprecipitated with anti-H3K9me3 (provided by Dr. Kimura), anti-H3K27me3 (Millipore), or normal mouse immunoglobulin G (IgG) (Jackson ImmunoResearch) bound to Dynabeads M-280 sheep anti-mouse IgG (Invitrogen).	('bound', 'Interaction', (196, 201))	('anti-H3K9me3', 'Var', (66, 78))	('anti-H3K27me3', 'Var', (105, 118))	('mouse', 'Species', '10090', (142, 147))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('148', '162'))	('mouse', 'Species', '10090', (232, 237))
63077	33028834	Full length and deletion mutants of CBX6 cDNA were prepared by the standard PCR procedure and cloned into the pLVSIN-CMV Pur vector (Takara) or pcDNA3.1(-) Neo vector (Thermo Fisher Scientific).	('CBX6', 'Gene', '23466', (36, 40))	('deletion', 'Var', (16, 24))	('CBX6', 'Gene', (36, 40))
63093	31824199	Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of c-MET exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors.	('c-MET', 'Gene', '4233', (329, 334))	('tyrosine', 'Chemical', 'None', (208, 216))	('skipping mutation', 'Var', (343, 360))	('PSC', 'Disease', (15, 18))	('c-MET', 'Gene', (329, 334))	('PD-L1', 'Gene', (258, 263))	('men', 'Species', '9606', (154, 157))	('men', 'Species', '9606', (283, 286))	('crizotinib', 'Chemical', 'MESH:C551994', (397, 407))	('PD-L1', 'Gene', '29126', (258, 263))	('PSC', 'Disease', 'MESH:D002292', (15, 18))
63102	31824199	Indeed, previous works have consistently evidenced the clonal origin of PSC demonstrating identical mutations of KRAS and p53 in either carcinoma and sarcoma/sarcomatous component, as also disclosed in sarcomatoid carcinoma arising in other sites.	('mutations', 'Var', (100, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (202, 223))	('carcinoma and sarcoma/sarcomatous component', 'Disease', 'MESH:D018316', (136, 179))	('PSC', 'Disease', (72, 75))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (202, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('p53', 'Gene', '7157', (122, 125))	('sarcomatoid carcinoma', 'Disease', (202, 223))	('KRAS', 'Gene', (113, 117))	('PSC', 'Disease', 'MESH:D002292', (72, 75))	('KRAS', 'Gene', '3845', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('p53', 'Gene', (122, 125))
63103	31824199	Basically, the appearance of an additional sarcomatoid/sarcomatous component in an otherwise conventional NSCLC is due to up-regulation of the epithelial-to-mesenchymal transition (EMT) secondary to activation of genetic mechanisms generally associated with resistance to chemotherapy and tyrosine kinase inhibitors, such as KRAS mutations, c-MET gene alterations, overexpression of vimentin, ZEB1, Snail, MiR-34 coupled to down-regulation of E-cadherin and expression of epithelial markers, miR-200, mutations of EGFR (Figure 1).	('ZEB1', 'Gene', '6935', (393, 397))	('cadherin', 'molecular_function', 'GO:0008014', ('445', '453'))	('regulation', 'biological_process', 'GO:0065007', ('429', '439'))	('sarcomatoid/sarcomatous component', 'Disease', 'MESH:D018316', (43, 76))	('miR-200', 'Gene', (492, 499))	('EGFR', 'Gene', '1956', (514, 518))	('c-MET', 'Gene', '4233', (341, 346))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('143', '179'))	('vimentin', 'cellular_component', 'GO:0045098', ('383', '391'))	('tyrosine', 'Chemical', 'None', (289, 297))	('mutations', 'Var', (501, 510))	('c-MET', 'Gene', (341, 346))	('vimentin', 'Gene', '7431', (383, 391))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('MiR-34', 'Gene', '407040', (406, 412))	('vimentin', 'Gene', (383, 391))	('Snail', 'Gene', (399, 404))	('ZEB1', 'Gene', (393, 397))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'molecular_function', 'GO:0005006', ('514', '518'))	('vimentin', 'cellular_component', 'GO:0045099', ('383', '391'))	('EGFR', 'Gene', (514, 518))	('regulation', 'biological_process', 'GO:0065007', ('125', '135'))	('epithelial-to-mesenchymal transition', 'CPA', (143, 179))	('expression', 'MPA', (458, 468))	('MiR-34', 'Gene', (406, 412))	('NSCLC', 'Disease', (106, 111))	('KRAS', 'Gene', '3845', (325, 329))	('overexpression', 'PosReg', (365, 379))	('EMT', 'biological_process', 'GO:0001837', ('181', '184'))	('E-cadherin', 'Gene', (443, 453))	('down-regulation', 'NegReg', (424, 439))	('sarcomatoid/sarcomatous component', 'Disease', (43, 76))	('up-regulation', 'PosReg', (122, 135))	('E-cadherin', 'Gene', '999', (443, 453))	('KRAS', 'Gene', (325, 329))	('Snail', 'Gene', '6615', (399, 404))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
63153	31824199	34betaE12 and 5/6) are found in squamous and adenosquamous carcinoma and low-weight cytokeratins (i.e.	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (45, 68))	('squamous', 'Disease', (32, 40))	('low-weight', 'Phenotype', 'HP:0004325', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('adenosquamous carcinoma', 'Disease', (45, 68))	('low-weight', 'Var', (73, 83))
63191	31824199	Of note, BAP-1 negativity at immunohistochemistry may be very helpful in ruling out PSC and favouring mesothelioma.	('mesothelioma', 'Disease', (102, 114))	('BAP-1', 'Gene', (9, 14))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('PSC', 'Disease', (84, 87))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('negativity', 'Var', (15, 25))	('BAP-1', 'Gene', '8314', (9, 14))
63198	31824199	They reported mutations in TP53 (22.6%) KRAS (27.2%), EGFR (22.2%) and STK1 (7.4%) as the most common genetic alterations in these lesions.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('STK1', 'Gene', (71, 75))	('KRAS', 'Gene', (40, 44))	('STK1', 'molecular_function', 'GO:0004740', ('71', '75'))	('EGFR', 'Gene', '1956', (54, 58))	('STK1', 'Gene', '2322', (71, 75))	('KRAS', 'Gene', '3845', (40, 44))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (14, 23))
63200	31824199	In 2016, Schrock et al used a deep sequencing approach to map whole-exome mutations in a cohort of 125 PSCs.	('PSC', 'Disease', (103, 106))	('mutations', 'Var', (74, 83))	('PSC', 'Disease', 'MESH:D002292', (103, 106))
63201	31824199	While confirming that mutations in KRAS (34.4%) and TP53 (73.6%) are the most common mutations in PSCs, the results of these study refined the frequency of mutations and called into questions other relevant oncogenes that were not present in the Sequenom panel.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('KRAS', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (52, 56))	('PSC', 'Disease', (98, 101))	('TP53', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (35, 39))	('mutations', 'Var', (22, 31))
63202	31824199	In particular, these authors showed that PSCs are characterized by a quite high tumor mutational burden (TMB, average of 8.1 mutations/Mb) and that both TP53 mutated tumors and KRAS mutated tumors were characterized by a higher TMB than WT samples.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TP53', 'Gene', '7157', (153, 157))	('tumors', 'Disease', (190, 196))	('PSC', 'Disease', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('higher', 'PosReg', (221, 227))	('KRAS', 'Gene', '3845', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (166, 172))	('TMB', 'MPA', (228, 231))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (80, 85))	('PSC', 'Disease', 'MESH:D002292', (41, 44))	('tumor', 'Disease', (190, 195))	('KRAS', 'Gene', (177, 181))	('TP53', 'Gene', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutated', 'Var', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
63203	31824199	TP53 mutations were found in a consistent part of PSCs analyzed in this study and were reported to be widely heterogeneous as subsequentially confirmed by other reports.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PSC', 'Disease', (50, 53))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('PSC', 'Disease', 'MESH:D002292', (50, 53))
63204	31824199	Furthermore, the occurrence of TP53 mutations in PSCs seemed to underpin a specific genetic subtype.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('PSC', 'Disease', 'MESH:D002292', (49, 52))	('mutations', 'Var', (36, 45))	('PSC', 'Disease', (49, 52))
63205	31824199	For instance, mutation in NF1 and RB1 were reported to preferentially occur in TP53 mutated vs wild-type samples while NF2 mutations were more frequent in TP53 wild-type samples, thus hypothesizing distinct evolution pathways for PSCs with different genetic assets.	('RB1', 'Gene', (34, 37))	('TP53', 'Gene', '7157', (79, 83))	('preferentially', 'PosReg', (55, 69))	('TP53', 'Gene', (79, 83))	('NF2', 'Gene', '4771', (119, 122))	('TP53', 'Gene', '7157', (155, 159))	('RB1', 'Gene', '5925', (34, 37))	('NF1', 'Gene', (26, 29))	('PSC', 'Disease', 'MESH:D002292', (230, 233))	('TP53', 'Gene', (155, 159))	('occur', 'Reg', (70, 75))	('mutated', 'Var', (84, 91))	('mutation', 'Var', (14, 22))	('NF1', 'Gene', '4763', (26, 29))	('PSC', 'Disease', (230, 233))	('NF2', 'Gene', (119, 122))
63206	31824199	Besides TP53 and KRAS mutations, additional frequent alterations were found, including those in CDKN2B (23.2%), CDKN2A (37.6%), MET (13.6%) and NF1 (17.6%).	('CDKN2B', 'Gene', '1030', (96, 102))	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('MET', 'Gene', (128, 131))	('TP53', 'Gene', '7157', (8, 12))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (8, 12))	('NF1', 'Gene', '4763', (144, 147))	('KRAS', 'Gene', '3845', (17, 21))	('NF1', 'Gene', (144, 147))	('CDKN2B', 'Gene', (96, 102))
63207	31824199	Noticeably, mutations in EGFR (8.8%) were detected at a lower frequency than previously reported and BRAF alterations (7.3%) were limited to a reduced number of PSC samples.	('BRAF', 'Gene', (101, 105))	('EGFR', 'Gene', (25, 29))	('PSC', 'Disease', 'MESH:D002292', (161, 164))	('mutations', 'Var', (12, 21))	('PSC', 'Disease', (161, 164))	('BRAF', 'Gene', '673', (101, 105))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
63209	31824199	By means of whole-exome sequencing, the Authors identified mutations in the exon 14 of MET as preferentially associated with PSC.	('associated', 'Reg', (109, 119))	('PSC', 'Disease', (125, 128))	('mutations in the', 'Var', (59, 75))	('MET', 'Gene', (87, 90))	('PSC', 'Disease', 'MESH:D002292', (125, 128))
63210	31824199	MET exon 14 skipping mutations already described in other tumors including NSCLC affect either donor or acceptor splice site between exon 13 and exon 14, causing a 47 amino acid deletion in the juxta-membrane domain of the MET proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (21, 30))	('membrane', 'cellular_component', 'GO:0016020', ('200', '208'))	('tumors', 'Disease', (58, 64))	('acceptor splice site', 'MPA', (104, 124))	('proteins', 'Protein', (227, 235))	('MET exon 14', 'Gene', (0, 11))	('donor', 'MPA', (95, 100))	('MET proteins', 'Protein', (223, 235))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('donor', 'Species', '9606', (95, 100))	('deletion', 'Var', (178, 186))	('affect', 'Reg', (81, 87))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('causing', 'Reg', (154, 161))
63212	31824199	Loss of c-CBL binding either by point mutations in the accepting site or by exon 14 skipping, leads to MET stabilization and constitutive activation of MET-dependent signaling.	('c-CBL', 'Gene', (8, 13))	('MET stabilization', 'MPA', (103, 120))	('binding', 'Interaction', (14, 21))	('Loss', 'NegReg', (0, 4))	('constitutive', 'MPA', (125, 137))	('MET-dependent signaling', 'MPA', (152, 175))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('c-CBL', 'Gene', '867', (8, 13))	('activation', 'PosReg', (138, 148))	('point mutations', 'Var', (32, 47))
63213	31824199	As in NSCLC, in PSC MET exon 14 mutations were mutually exclusive with other oncogene mutations like KRAS, BRAF, EGFR or ALK rearrangement, but co-occurrence with PI3K mutations has been reported.	('BRAF', 'Gene', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('PI3K', 'molecular_function', 'GO:0016303', ('163', '167'))	('PSC', 'Disease', (16, 19))	('PI3', 'Gene', (163, 166))	('ALK', 'Gene', '238', (121, 124))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('PI3', 'Gene', '5266', (163, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('BRAF', 'Gene', '673', (107, 111))	('ALK', 'Gene', (121, 124))	('NSCLC', 'Disease', (6, 11))	('PSC', 'Disease', 'MESH:D002292', (16, 19))	('men', 'Species', '9606', (134, 137))
63214	31824199	Furthermore, at least in the original report, MET exon 14 mutations were exclusively found in pure PSCs or PSCs with an ADK component.	('mutations', 'Var', (58, 67))	('PSC', 'Disease', (107, 110))	('PSC', 'Disease', 'MESH:D002292', (99, 102))	('MET', 'Var', (46, 49))	('ADK', 'Gene', '132', (120, 123))	('PSC', 'Disease', (99, 102))	('found', 'Reg', (85, 90))	('pure', 'molecular_function', 'GO:0034023', ('94', '98'))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('ADK', 'Gene', (120, 123))
63215	31824199	Noticeably, while MET exon 14 mutations occur in about 3% of NSCLCs (according to TCGA data), up to 32% of PSCs are reported to carry this alteration.	('PSC', 'Disease', (107, 110))	('MET exon 14', 'Gene', (18, 29))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (61, 66))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
63216	31824199	Indeed, according to a recent systematic meta-analysis, the incidence of MET exon 14 mutations in PSC is variable.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('MET exon 14', 'Var', (73, 84))	('PSC', 'Disease', (98, 101))
63218	31824199	Despite the different characteristics of analyzed case series, MET exon 14 mutations seem to occur particularly in PSC, ranging from 3% to 31.8%.	('PSC', 'Disease', (115, 118))	('occur', 'Reg', (93, 98))	('mutations', 'Var', (75, 84))	('PSC', 'Disease', 'MESH:D002292', (115, 118))	('MET exon', 'Var', (63, 71))
63219	31824199	The particular attention focused on MET exon 14 skipping mutations is then related to the relatively high frequency of this genetic alteration in PSC histology when compared with other conventional NSCLC, also predicting a good clinical response to MET inhibitors.	('predicting', 'Reg', (210, 220))	('PSC', 'Disease', (146, 149))	('MET inhibitors', 'MPA', (249, 263))	('skipping mutations', 'Var', (48, 66))	('NSCLC', 'Disease', (198, 203))	('MET', 'Gene', (36, 39))	('PSC', 'Disease', 'MESH:D002292', (146, 149))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
63220	31824199	The rate of MET exon 14 mutations is significantly higher in case series including PSC without common targetable mutations in EGFR, KRAS, ALK, ROS1, and RET.	('RET', 'Gene', (153, 156))	('ROS1', 'Gene', (143, 147))	('KRAS', 'Gene', (132, 136))	('EGFR', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (143, 147))	('MET exon', 'Var', (12, 20))	('ALK', 'Gene', '238', (138, 141))	('KRAS', 'Gene', '3845', (132, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('mutations', 'Var', (24, 33))	('RET', 'Gene', '5979', (153, 156))	('ALK', 'Gene', (138, 141))	('PSC', 'Disease', 'MESH:D002292', (83, 86))	('higher', 'PosReg', (51, 57))	('EGFR', 'Gene', '1956', (126, 130))	('PSC', 'Disease', (83, 86))
63235	31824199	The recent identification of MET exon 14 mutations shed new lights on the unique biology of PSCs and opened the first prospective on PSC-oriented therapy.	('mutations', 'Var', (41, 50))	('PSC', 'Disease', 'MESH:D002292', (133, 136))	('PSC', 'Disease', 'MESH:D002292', (92, 95))	('PSC', 'Disease', (92, 95))	('PSC', 'Disease', (133, 136))	('MET exon 14', 'Gene', (29, 40))
63238	31824199	For instance, EGFR actionable mutations are quite frequent in NSCLC and treatment with TKI is a first-line therapy for EGFR mutated patients.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('EGFR', 'Gene', '1956', (14, 18))	('NSCLC', 'Disease', (62, 67))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('actionable', 'Reg', (19, 29))	('men', 'Species', '9606', (77, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (119, 123))	('patients', 'Species', '9606', (132, 140))	('EGFR', 'Gene', (119, 123))
63240	31824199	EGFR mutations in PSC is controversial (0-28% depending on series) but surely inferior to NSCLC.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('PSC', 'Disease', 'MESH:D002292', (18, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('PSC', 'Disease', (18, 21))
63241	31824199	Furthermore, according to the available information, the number of actionable EGFR mutations (p.L858R) is even lower further reducing the rationale for the employment of these drugs in this setting.	('mutations', 'Var', (83, 92))	('men', 'Species', '9606', (162, 165))	('p.L858R', 'Mutation', 'rs121434568', (94, 101))	('reducing', 'NegReg', (125, 133))	('lower', 'NegReg', (111, 116))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))
63242	31824199	Besides, the absence of evident response to EGFR inhibitors even in EGFR mutated PSCs, seems to indicate that EGFR mutations in these tumors may not be an essential driver but rather a secondary event.	('tumors', 'Disease', (134, 140))	('mutations', 'Var', (115, 124))	('mutated', 'Var', (73, 80))	('EGFR', 'Gene', '1956', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('EGFR', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('PSC', 'Disease', (81, 84))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', '1956', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('EGFR', 'Gene', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('EGFR', 'Gene', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('PSC', 'Disease', 'MESH:D002292', (81, 84))
63243	31824199	KRAS mutations are among the most common alterations detected in non-squamous NSCLC.	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (78, 83))	('KRAS', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('KRAS', 'Gene', '3845', (0, 4))
63245	31824199	KRAS mutations have been found significantly associated with pure sarcomatoid or with PSC with an adenocarcinoma component.	('pure sarcomatoid', 'Disease', (61, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('pure', 'molecular_function', 'GO:0034023', ('61', '65'))	('pure sarcomatoid', 'Disease', 'MESH:D002292', (61, 77))	('adenocarcinoma component', 'Disease', (98, 122))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (45, 55))	('PSC', 'Disease', 'MESH:D002292', (86, 89))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (98, 122))	('PSC', 'Disease', (86, 89))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('KRAS', 'Gene', '3845', (0, 4))
63246	31824199	KRAS mutations are predominantly found in PSCs from smokers, and the majority of the alteration detected are transversions, the typical DNA alterations found in smokers' adenocarcinomas.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('transversions', 'Var', (109, 122))	('mutations', 'Var', (5, 14))	('PSC', 'Disease', 'MESH:D002292', (42, 45))	('adenocarcinomas', 'Disease', 'MESH:D000230', (170, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('adenocarcinomas', 'Disease', (170, 185))	('PSC', 'Disease', (42, 45))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
63247	31824199	Prognostic significance of KRAS mutations in PSC has been a matter of debate, in particular due to the limited number of cases in the analyzed series that precluded conclusive results.	('KRAS', 'Gene', '3845', (27, 31))	('PSC', 'Disease', 'MESH:D002292', (45, 48))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))	('PSC', 'Disease', (45, 48))
63248	31824199	However, we recently showed that KRAS mutations alone or in combination with TP53 mutations were associated with local metastases at recurrence and with a significantly decreased survival probability in a cohort of surgically resected PSCs.	('survival probability', 'CPA', (179, 199))	('KRAS', 'Gene', (33, 37))	('metastases', 'Disease', 'MESH:D009362', (119, 129))	('PSC', 'Disease', (235, 238))	('KRAS', 'Gene', '3845', (33, 37))	('metastases', 'Disease', (119, 129))	('decreased', 'NegReg', (169, 178))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))	('PSC', 'Disease', 'MESH:D002292', (235, 238))
63249	31824199	Similarly, Mehrad and colleagues reported a significant correlation of KRAS mutations with worse patients' outcome.	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', (71, 75))	('correlation', 'Interaction', (56, 67))	('KRAS', 'Gene', '3845', (71, 75))	('patients', 'Species', '9606', (97, 105))
63250	31824199	We also showed that the presence of KRAS mutations significantly correlates with increased PD-L1 expression suggesting a possible correlation, to be further investigated, between these mutations and response to immunotherapy.	('mutations', 'Var', (41, 50))	('increased PD', 'Phenotype', 'HP:0008151', (81, 93))	('PD-L1', 'Gene', (91, 96))	('KRAS', 'Gene', (36, 40))	('PD-L1', 'Gene', '29126', (91, 96))	('KRAS', 'Gene', '3845', (36, 40))	('increased', 'PosReg', (81, 90))	('expression', 'MPA', (97, 107))
63251	31824199	These results together with the recent emerging MEK inhibitors may imply a potential value of KRAS mutations as relevant predictive markers in orienting PSC tailored treatment.	('KRAS', 'Gene', (94, 98))	('PSC', 'Disease', (153, 156))	('MEK', 'Gene', (48, 51))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('MEK', 'Gene', '5609', (48, 51))	('men', 'Species', '9606', (171, 174))	('PSC', 'Disease', 'MESH:D002292', (153, 156))
63253	31824199	NSCLCs with activating alterations of MET (including MET locus amplification) have shown remarkable response to small molecules like crizotinib, cabozantinib or capmatinib that target MET activity.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('response', 'MPA', (100, 108))	('crizotinib', 'Chemical', 'MESH:C551994', (133, 143))	('capmatinib', 'Chemical', 'None', (161, 171))	('MET', 'MPA', (53, 56))	('cabozantinib', 'Chemical', 'MESH:C558660', (145, 157))	('MET', 'Gene', (38, 41))	('alterations', 'Var', (23, 34))	('activating', 'PosReg', (12, 22))	('NSCLC', 'Disease', (0, 5))
63254	31824199	For the same reason, the presence of MET activating mutations in PSCs would qualify a good portion of patients (about 30%) based on the reported mutations incidence for treatment with these drugs.	('patients', 'Species', '9606', (102, 110))	('PSC', 'Disease', 'MESH:D002292', (65, 68))	('men', 'Species', '9606', (174, 177))	('PSC', 'Disease', (65, 68))	('presence', 'Var', (25, 33))
63255	31824199	Preclinical evidence shows that tumor cells harboring MET ex14 mutations are responsive to MET inhibition, even if co-occurrence of PI3KCA concomitant gain of function alterations may partially reduce effectiveness of MET inhibition.	('MET ex14 mutations', 'Var', (54, 72))	('responsive to MET inhibition', 'MPA', (77, 105))	('MET inhibition', 'MPA', (218, 232))	('PI3', 'Gene', (132, 135))	('PI3', 'Gene', '5266', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('effectiveness', 'MPA', (201, 214))	('tumor', 'Disease', (32, 37))	('alterations', 'Var', (168, 179))	('reduce', 'NegReg', (194, 200))
63256	31824199	Preliminary clinical data on small series or single case confirmed that in vivo, PSC harboring MET exon 14 mutations show effective response to MET targeting drugs.	('MET targeting drugs', 'MPA', (144, 163))	('response', 'MPA', (132, 140))	('mutations', 'Var', (107, 116))	('PSC', 'Disease', (81, 84))	('PSC', 'Disease', 'MESH:D002292', (81, 84))	('MET exon 14', 'Gene', (95, 106))
63257	31824199	Even if revolutionary in the desolated PSC treatments landscape, the discovery of MET exon 14 mutations and the consequential possibility of directing patients to MET inhibitors is limited to a reduced number of patients.	('MET exon 14', 'Gene', (82, 93))	('PSC', 'Disease', 'MESH:D002292', (39, 42))	('men', 'Species', '9606', (48, 51))	('mutations', 'Var', (94, 103))	('PSC', 'Disease', (39, 42))	('patients', 'Species', '9606', (212, 220))	('patients', 'Species', '9606', (151, 159))
63267	31824199	Targetable mutations in PSC are less frequent than in NSCLC with adenocarcinoma histology.	('mutations', 'Var', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('PSC', 'Disease', (24, 27))	('PSC', 'Disease', 'MESH:D002292', (24, 27))	('adenocarcinoma', 'Disease', (65, 79))	('NSCLC', 'Disease', (54, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
63268	31824199	However, Fallet et al reported uncommon/rare EGFR mutations in 22%, NRAS and PI3KCA in 5%.	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('NRAS', 'Gene', (68, 72))	('PI3', 'Gene', (77, 80))	('NRAS', 'Gene', '4893', (68, 72))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('PI3', 'Gene', '5266', (77, 80))
63269	31824199	Li et al performed an NGS study evidencing hot spot druggable gene alterations involving EGFR (exon 19 deletion) and EML4-ALK fusion in sporadic cases.	('EGFR', 'Gene', (89, 93))	('alterations', 'Var', (67, 78))	('ALK', 'Gene', (122, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('EML4', 'Gene', (117, 121))	('EML4', 'Gene', '27436', (117, 121))	('EGFR', 'Gene', '1956', (89, 93))	('ALK', 'Gene', '238', (122, 125))
63270	31824199	Mehrad et al evidenced actionable genetic mutations in EGFR in 2 out of 23 PSCs (8.7%) and Schrock et al observed targetable genomic alteration in EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%).	('BRAF', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (55, 59))	('BRAF', 'Gene', '673', (160, 164))	('EGFR', 'Gene', (147, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('erb-b2 receptor tyrosine kinase 2', 'Gene', '2064', (173, 206))	('PSC', 'Disease', 'MESH:D002292', (75, 78))	('erb-b2 receptor tyrosine kinase 2', 'Gene', (173, 206))	('RET', 'Gene', '5979', (251, 254))	('EGFR', 'Gene', '1956', (147, 151))	('HER2', 'Gene', '2064', (213, 217))	('EGFR', 'Gene', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('ret', 'Gene', (231, 234))	('ret', 'Gene', '5979', (231, 234))	('PSC', 'Disease', (75, 78))	('RET', 'Gene', (251, 254))	('HER2', 'Gene', (213, 217))	('mutations', 'Var', (42, 51))
63272	31824199	Finally, Ali et al disclosed sporadic mutations in EGFR (1 case), MET (2 cases) and BRAF (1 case), KRAS (2 cases), PI3KCA (2 cases) and 1 ALK-rearranged case among 14 PSC using a combined approach with Sequenom Mass-Array and Sanger sequencing and NanoString technology.	('BRAF', 'Gene', '673', (84, 88))	('EGFR', 'Gene', (51, 55))	('PSC', 'Disease', 'MESH:D002292', (167, 170))	('ALK', 'Gene', '238', (138, 141))	('PI3', 'Gene', (115, 118))	('BRAF', 'Gene', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('PSC', 'Disease', (167, 170))	('ALK', 'Gene', (138, 141))	('KRAS', 'Gene', (99, 103))	('mutations', 'Var', (38, 47))	('PI3', 'Gene', '5266', (115, 118))	('KRAS', 'Gene', '3845', (99, 103))	('EGFR', 'Gene', '1956', (51, 55))
63273	31824199	By contrast, Nakagomi et al evidenced prevalent mutations in TP53 and KRAS coupled to Microsatellite instability/Mismatch repair system alteration in one case among four PSCs deeply investigated by NGS.	('PSC', 'Disease', (170, 173))	('KRAS', 'Gene', (70, 74))	('Mismatch repair', 'biological_process', 'GO:0006298', ('113', '128'))	('KRAS', 'Gene', '3845', (70, 74))	('Microsatellite instability', 'Disease', 'MESH:D053842', (86, 112))	('PSC', 'Disease', 'MESH:D002292', (170, 173))	('alteration', 'Reg', (136, 146))	('Microsatellite instability', 'Disease', (86, 112))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (48, 57))
63274	31824199	Several reasons may explain the wide range of incidence of druggable gene alterations in PSC, as follows: a) a selection bias related to the accuracy in diagnosing this unusual histology (i.e., application of morphologic criteria in biopsy versus resections, lack of specific diagnostic primary antibodies at immunohistochemistry); b) various methodologies in detecting gene alterations, including techniques with a significantly large range of sensitivity; and c) different ethnicities of the reported case series.	('PSC', 'Disease', 'MESH:D002292', (89, 92))	('PSC', 'Disease', (89, 92))	('alterations', 'Var', (74, 85))
63276	31824199	Interestingly, among acquired resistance mechanisms during treatments with tyrosine kinase inhibitors (i.e., EGFR and ALK inhibitors) or chemotherapy, histologic "change" from adenocarcinoma to small cell or squamous cell carcinomas have been well demonstrated in EGFR mutated (about 10% of cases) and ALK rearranged adenocarcinomas.	('mutated', 'Var', (269, 276))	('EGFR', 'Gene', '1956', (109, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (317, 331))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('squamous cell carcinomas', 'Disease', (208, 232))	('EGFR', 'Gene', (264, 268))	('tyrosine', 'Chemical', 'None', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('men', 'Species', '9606', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('adenocarcinoma', 'Disease', (176, 190))	('EGFR', 'Gene', (109, 113))	('ALK', 'Gene', (302, 305))	('EGFR', 'molecular_function', 'GO:0005006', ('262', '266'))	('ALK', 'Gene', '238', (302, 305))	('EGFR', 'Gene', '1956', (264, 268))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (208, 232))	('adenocarcinoma', 'Disease', (317, 331))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('adenocarcinomas', 'Disease', 'MESH:D000230', (317, 332))	('ALK', 'Gene', '238', (118, 121))	('adenocarcinomas', 'Disease', (317, 332))	('adenocarcinoma', 'Disease', 'MESH:D000230', (176, 190))	('ALK', 'Gene', (118, 121))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (208, 232))
63281	31824199	Xu et al reported a case of lung adenocarcinoma resistant to EGFR TKI with concurrent acquired T790M secondary EGFR mutation and sarcomatoid spindle cell occurrence.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('lung adenocarcinoma', 'Disease', (28, 47))	('sarcomatoid', 'Disease', 'MESH:D002292', (129, 140))	('EGFR', 'Gene', '1956', (111, 115))	('spindle', 'cellular_component', 'GO:0005819', ('141', '148'))	('T790M', 'Mutation', 'rs121434569', (95, 100))	('EGFR', 'Gene', (111, 115))	('T790M', 'Var', (95, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('sarcomatoid', 'Disease', (129, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (28, 47))
63282	31824199	Finally, a case of exon 21 L858R EGFR-mutated sarcomatoid carcinoma of the lung resistant to icotinib was recently reported.	('L858R', 'Var', (27, 32))	('sarcomatoid carcinoma of the lung', 'Disease', 'MESH:D002292', (46, 79))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('sarcomatoid carcinoma of the lung', 'Disease', (46, 79))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('icotinib', 'Chemical', 'MESH:C531470', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('EGFR', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (46, 67))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (58, 79))
63283	31824199	Coexistence of Nkx2-4 mutation was considered responsible of its intrinsic resistance to EGFR TKI.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (89, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('Nkx2-4', 'Gene', (15, 21))	('EGFR', 'Gene', '1956', (89, 93))	('Nkx2-4', 'Gene', '644524;4824', (15, 21))
63297	31824199	Chan et al assessed the PD-L1 expression in 713 consecutive NSCLC by four commercially available PD-L1 immunohistochemical assays (22C3, 28-8, SP142 and SP263) evidencing a high PD-L1 expression >=50% significantly associated with PSC (p < 0.001) and mutant KRAS (p = 0.005) also reporting good agreement between 22C2, 28-8 and SP263 primary antibodies.	('mutant', 'Var', (251, 257))	('PSC', 'Disease', (231, 234))	('PD-L1', 'Gene', '29126', (97, 102))	('men', 'Species', '9606', (300, 303))	('KRAS', 'Gene', '3845', (258, 262))	('PD-L1', 'Gene', '29126', (24, 29))	('PD-L1', 'Gene', (24, 29))	('associated', 'Reg', (215, 225))	('PD-L1', 'Gene', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('NSCLC', 'Disease', (60, 65))	('PD-L1', 'Gene', '29126', (178, 183))	('PSC', 'Disease', 'MESH:D002292', (231, 234))	('PD-L1', 'Gene', (97, 102))	('KRAS', 'Gene', (258, 262))
63301	31824199	Vieira et al reported high PD-L1 (clone 5H1) immunoreactivity in 40 out of 75 (53%) PSC, also confirming a significant association with the presence of KRAS mutations.	('KRAS', 'Gene', (152, 156))	('PSC', 'Disease', (84, 87))	('KRAS', 'Gene', '3845', (152, 156))	('mutations', 'Var', (157, 166))	('PD-L1', 'Gene', (27, 32))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('PD-L1', 'Gene', '29126', (27, 32))
63313	31824199	PD-L1 over-expression and MET exon 14 skipping mutation are the most important predictive biomarkers for effective targeted therapies in PSC.	('over-expression', 'PosReg', (6, 21))	('PSC', 'Disease', 'MESH:D002292', (137, 140))	('PD-L1', 'Gene', (0, 5))	('PSC', 'Disease', (137, 140))	('MET exon 14 skipping mutation', 'Var', (26, 55))	('PD-L1', 'Gene', '29126', (0, 5))
63320	30581150	SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range.	('SF3b', 'Gene', (0, 4))	('E7107', 'Var', (33, 38))	('Meayamycin-B', 'Chemical', 'MESH:C585895', (40, 52))	('cytotoxic activity', 'CPA', (68, 86))	('Pladienolide-B', 'Chemical', 'MESH:C522342', (17, 31))
63322	30581150	E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.	('tumor', 'Disease', (42, 47))	('survival rates', 'CPA', (90, 104))	('E7107', 'Var', (0, 5))	('improvement', 'PosReg', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
63324	30581150	Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo.	('Splicing modulators', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('impair', 'NegReg', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (88, 93))
63332	30581150	These studies reported that genetic alterations commonly found in pleural mesothelioma (BAP1, NF2, TP53 and CDKN2A mutations and/or copy number alterations) were also present in DMPM, although their frequencies vary according to the anatomical localization.	('TP53', 'Gene', (99, 103))	('CDKN2A', 'Gene', '1029', (108, 114))	('mutations', 'Var', (115, 124))	('NF2', 'Gene', (94, 97))	('CDKN2A', 'Gene', (108, 114))	('BAP1', 'Gene', '8314', (88, 92))	('NF2', 'Gene', '4771', (94, 97))	('copy number alterations', 'Var', (132, 155))	('DMPM', 'Chemical', '-', (178, 182))	('localization', 'biological_process', 'GO:0051179', ('244', '256'))	('TP53', 'Gene', '7157', (99, 103))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (66, 86))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (66, 86))	('BAP1', 'Gene', (88, 92))	('pleural mesothelioma', 'Disease', (66, 86))
63334	30581150	Besides the aforementioned MM-specific alterations, this study reported mutations affecting splicing factor 3b subunit 1 (SF3B1), which encodes an essential component of the spliceosome, as well as the histone methyltransferase SETD2 and the DEAD-box RNA helicases DDX51 and DDX3X, which are also involved in RNA processing and splicing.	('mutations', 'Var', (72, 81))	('RNA', 'cellular_component', 'GO:0005562', ('309', '312'))	('SF3B1', 'Gene', (122, 127))	('SETD2', 'Gene', '29072', (228, 233))	('spliceosome', 'cellular_component', 'GO:0005681', ('174', '185'))	('DDX3X', 'Gene', '1654', (275, 280))	('DDX51', 'Gene', (265, 270))	('SETD2', 'Gene', (228, 233))	('RNA', 'cellular_component', 'GO:0005562', ('251', '254'))	('splicing factor 3b subunit 1', 'Gene', (92, 120))	('SF3B1', 'Gene', '23451', (122, 127))	('splicing factor 3b subunit 1', 'Gene', '23451', (92, 120))	('splicing', 'biological_process', 'GO:0045292', ('92', '100'))	('splicing', 'biological_process', 'GO:0045292', ('328', '336'))	('RNA processing', 'biological_process', 'GO:0006396', ('309', '323'))	('DDX51', 'Gene', '317781', (265, 270))	('DDX3X', 'Gene', (275, 280))
63335	30581150	Collectively, these data highlight epigenetic and splicing deregulations as important features of MM pathogenesis and suggest their exploitation as novel antitumor strategy.	('splicing', 'MPA', (50, 58))	('tumor', 'Disease', (158, 163))	('splicing', 'biological_process', 'GO:0045292', ('50', '58'))	('pathogenesis', 'biological_process', 'GO:0009405', ('101', '113'))	('epigenetic and', 'Var', (35, 49))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
63337	30581150	Interestingly, these alterations have also prognostic significance and contribute significantly to all hallmarks of tumorigenesis.	('contribute', 'Reg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('alterations', 'Var', (21, 32))
63338	30581150	Therefore, splicing deregulation could represent a novel susceptibility to be explored for cancer therapy.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('splicing', 'biological_process', 'GO:0045292', ('11', '19'))	('splicing deregulation', 'Var', (11, 32))
63339	30581150	FR901464, GEX1A and pladienolides are natural antitumor molecules targeting the SF3b complex.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('pladienolides', 'Chemical', '-', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('FR901464', 'Var', (0, 8))	('tumor', 'Disease', (50, 55))
63341	30581150	The administration of E7107, a pladienolide derivative, in a Phase 1 trial stabilized the disease in 8 out of 40 cancer patients and reached partial response in one subject affected by metastatic pancreatic cancer.	('pancreatic cancer', 'Disease', (196, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (196, 213))	('E7107', 'Var', (22, 27))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (196, 213))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('pladienolide', 'Chemical', '-', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
63348	30581150	MesoII cells bear a SF3B1 heterozygous mutation (A1279S) which appears to be conserved and benign, according to several pathogenicity scores from the dbNSFP database (Supplementary Table 1).	('SF3B1', 'Gene', '23451', (20, 25))	('A1279S', 'Var', (49, 55))	('SF3B1', 'Gene', (20, 25))	('A1279S', 'Mutation', 'p.A1279S', (49, 55))
63352	30581150	Sequence D-020061-07-0002: CGAGUUUGCUUGGUCAGAA Sequence D-020061-05-0002: AGGCGGACCAUGAUAAUUU RNAi experiments were performed by using siRNA duplexes from the Dharmacon (Lafayette, CO, USA) SMARTpool siGENOME controls targeting UBB (M-013382-01) and NTp2 (D-001206-14) or two siGENOME siRNAs targeting SF3B1 (D-020061-07-0002 and D-020061-05-0002).	('SF3B1', 'Gene', '23451', (302, 307))	('D-001206-14', 'Var', (256, 267))	('RNAi', 'biological_process', 'GO:0016246', ('94', '98'))	('M-013382-01', 'Var', (233, 244))	('SF3B1', 'Gene', (302, 307))	('D-020061-07-0002', 'Var', (309, 325))
63356	30581150	For cell cycle analysis, ethanol-permeabilized cells were incubated with RNAse A (100 mug/ml, QIAgen, Venlo, the Netherlands) and stained with propidium iodide (Sigma-Aldrich).	('RNAse A', 'Gene', '6035', (73, 80))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('100', 'Var', (82, 85))	('mug', 'molecular_function', 'GO:0043739', ('86', '89'))	('propidium iodide', 'Chemical', 'MESH:D011419', (143, 159))	('RNAse A', 'Gene', (73, 80))	('ethanol', 'Chemical', 'MESH:D000431', (25, 32))
63369	30581150	At day 0, tumors were induced by injection of 2*106 fm/GC cells in the peritoneal cavity of the mice.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('2*106 fm/GC', 'Var', (46, 57))	('mice', 'Species', '10090', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))
63391	30581150	The univariate Cox regression analysis revealed a significant correlation between high SF3B1 level and shorter overall and progression-free survival (Fig.	('high', 'Var', (82, 86))	('SF3B1', 'Gene', (87, 92))	('shorter', 'NegReg', (103, 110))	('Cox', 'Gene', '1351', (15, 18))	('SF3B1', 'Gene', '23451', (87, 92))	('overall', 'CPA', (111, 118))	('Cox', 'Gene', (15, 18))
63395	30581150	To address this hypothesis, we tested the effects of three modulators of SF3b complex activity (Pladienolide-B, E7107 and Meayamycin-B, depicted in Fig.	('E7107', 'Var', (112, 117))	('SF3b', 'Gene', (73, 77))	('tested', 'Reg', (31, 37))	('Meayamycin-B', 'Chemical', 'MESH:C585895', (122, 134))	('Pladienolide-B', 'Chemical', 'MESH:C522342', (96, 110))
63396	30581150	Of note, siRNA-mediated knockdown of SF3B1 drastically decreased cell viability compared to non-targeting control, thus underlining the key role of SF3B1 in cell viability (Fig.	('SF3B1', 'Gene', '23451', (37, 42))	('cell viability', 'CPA', (65, 79))	('decreased', 'NegReg', (55, 64))	('SF3B1', 'Gene', (148, 153))	('SF3B1', 'Gene', (37, 42))	('knockdown', 'Var', (24, 33))	('SF3B1', 'Gene', '23451', (148, 153))
63403	30581150	One of the best documented effects of spliceosome modulation is the skipping of exon 2 of the apoptotic gene MCL-1 which is translated into a truncated protein isoform exhibiting pro-apoptotic functions.	('spliceosome', 'cellular_component', 'GO:0005681', ('38', '49'))	('skipping of', 'Var', (68, 79))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('MCL-1', 'Gene', '4170', (109, 114))	('MCL-1', 'Gene', (109, 114))
63407	30581150	In particular, we found that MesoII and STO cells express the truncated variant of the proto-oncogene RON (Fig.	('truncated', 'Var', (62, 71))	('RON', 'Gene', (102, 105))	('RON', 'Gene', '4486', (102, 105))
63412	30581150	This effect was more pronounced in STO cells, which express higher levels of the  RON variant compared to its wild type transcript.	('RON', 'Gene', (82, 85))	('variant', 'Var', (86, 93))	('RON', 'Gene', '4486', (82, 85))	('higher', 'PosReg', (60, 66))
63424	30581150	These lesions interfered with digestive processes, thus causing gallbladder enlargement and cachexia.	('digestive processes', 'CPA', (30, 49))	('cachexia', 'Phenotype', 'HP:0004326', (92, 100))	('causing', 'Reg', (56, 63))	('interfered', 'NegReg', (14, 24))	('cachexia', 'Disease', 'MESH:D002100', (92, 100))	('lesions', 'Var', (6, 13))	('gallbladder enlargement', 'Disease', (64, 87))	('cachexia', 'Disease', (92, 100))	('gallbladder enlargement', 'Disease', 'MESH:D005705', (64, 87))
63428	30581150	Starting already from Day 8, mean F-luc intensity was significantly decreased (P = 0.0011) in mice receiving E7107 as compared to untreated control mice (Fig.	('F-luc intensity', 'MPA', (34, 49))	('decreased', 'NegReg', (68, 77))	('E7107', 'Var', (109, 114))	('mice', 'Species', '10090', (148, 152))	('mice', 'Species', '10090', (94, 98))
63429	30581150	In addition, RT-PCR of tumor samples from mice showed that E7107 treatment altered the splicing profiles of the same genes affected by PB and E7107 exposure in vitro (Supplementary Fig.	('PB', 'Chemical', 'MESH:C522342', (135, 137))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('splicing profiles', 'MPA', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('splicing', 'biological_process', 'GO:0045292', ('87', '95'))	('altered', 'Reg', (75, 82))	('E7107', 'Var', (59, 64))	('E7107 exposure', 'Var', (142, 156))	('tumor', 'Disease', (23, 28))
63438	30581150	In particular, SF3B1 mutations are associated with a favorable prognosis in patients affected by myelodysplastic syndromes, in contrast to chronic lymphocytic leukemia where mutated SF3B1 dictated a poor prognosis and was associated with fludarabine resistance.	('mutations', 'Var', (21, 30))	('fludarabine', 'Chemical', 'MESH:C024352', (238, 249))	('patients', 'Species', '9606', (76, 84))	('associated with', 'Reg', (222, 237))	('SF3B1', 'Gene', '23451', (15, 20))	('SF3B1', 'Gene', (182, 187))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (139, 167))	('fludarabine resistance', 'MPA', (238, 260))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (139, 167))	('mutated', 'Var', (174, 181))	('SF3B1', 'Gene', '23451', (182, 187))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (97, 122))	('SF3B1', 'Gene', (15, 20))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (97, 122))	('myelodysplastic syndromes', 'Disease', (97, 122))	('chronic lymphocytic leukemia', 'Disease', (139, 167))
63440	30581150	SF3B1 is the most commonly mutated spliceosomal gene, both in hematological and solid cancers; mutations occur in 20% of myelodysplastic syndromes and above 22% of uveal melanoma cases.	('occur', 'Reg', (105, 110))	('SF3B1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (121, 146))	('hematological and solid cancers', 'Disease', 'MESH:D009369', (62, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SF3B1', 'Gene', '23451', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (164, 178))	('mutations', 'Var', (95, 104))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (121, 146))	('myelodysplastic syndromes', 'Disease', (121, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (164, 178))	('uveal melanoma', 'Disease', (164, 178))
63441	30581150	Darman and collaborators showed that SF3B1 hotspot mutations induce aberrant 3` splice site selection.	('mutations', 'Var', (51, 60))	('SF3B1', 'Gene', '23451', (37, 42))	('SF3B1', 'Gene', (37, 42))	('3` splice site selection', 'MPA', (77, 101))	('induce', 'Reg', (61, 67))
63443	30581150	Based on current data, we now speculate that not only mutations, but also the overexpression of SF3B1 perturbs splicing catalysis and results in the synthesis of pro-tumorigenic splice variants, which may constitute a vulnerability of cancer cells.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('perturbs', 'NegReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('synthesis', 'biological_process', 'GO:0009058', ('149', '158'))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('mutations', 'Var', (54, 63))	('SF3B1', 'Gene', (96, 101))	('tumor', 'Disease', (166, 171))	('overexpression', 'PosReg', (78, 92))	('results in', 'Reg', (134, 144))	('splicing catalysis', 'MPA', (111, 129))	('synthesis', 'MPA', (149, 158))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('SF3B1', 'Gene', '23451', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
63446	30581150	Two recent studies interrogating the molecular structure of U2 snRNP bound with PB and E7107 revealed that the conformation of the SF3B1 catalytic pocket, in association with PHF5A, is critical for BPS recognition and these compounds compete for the pre-mRNA substrate in a dose-dependent fashion.	('PHF5A', 'Gene', '84844', (175, 180))	('BPS', 'Disease', (198, 201))	('SF3B1', 'Gene', '23451', (131, 136))	('PHF5A', 'Gene', (175, 180))	('BPS', 'Disease', 'MESH:C564874', (198, 201))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('60', '68'))	('snRNP', 'molecular_function', 'GO:0003734', ('63', '68'))	('E7107', 'Var', (87, 92))	('SF3B1', 'Gene', (131, 136))	('PB', 'Chemical', 'MESH:C522342', (80, 82))	('pre', 'molecular_function', 'GO:0003904', ('250', '253'))
63447	30581150	Next to the potent in vitro antitumor activity of PB, E7107 and MAMB in two primary DMPM cultures, we also provide the first AS landscape of DMPM, as result of the perturbation by SF3b modulation.	('modulation', 'Var', (185, 195))	('DMPM', 'Chemical', '-', (141, 145))	('PB', 'Chemical', 'MESH:C522342', (50, 52))	('E7107', 'Var', (54, 59))	('DMPM', 'Chemical', '-', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('SF3b', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('perturbation', 'NegReg', (164, 176))	('tumor', 'Disease', (32, 37))	('DMPM', 'Disease', (141, 145))	('MAMB', 'Chemical', 'MESH:C585895', (64, 68))
63449	30581150	In particular, dysregulation of apoptosis has been demonstrated to play a crucial role in DMPM chemoresistance.	('DMPM', 'Disease', (90, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('dysregulation', 'Var', (15, 28))	('DMPM', 'Chemical', '-', (90, 94))
63450	30581150	For instance, we found that DDX3X was one of the genes affected upon splicing modulation within the apoptotic pathway.	('DDX3X', 'Gene', '1654', (28, 33))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('apoptotic', 'Pathway', (100, 109))	('affected', 'Reg', (55, 63))	('DDX3X', 'Gene', (28, 33))	('splicing modulation', 'Var', (69, 88))
63451	30581150	This gene encodes a RNA helicase involved in pre-mRNA splicing and apoptotic signaling and is mutated in a subset of DMPM patients.	('mutated', 'Var', (94, 101))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('pre', 'molecular_function', 'GO:0003904', ('45', '48'))	('patients', 'Species', '9606', (122, 130))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('45', '62'))	('RNA helicase', 'Protein', (20, 32))	('DMPM', 'Disease', (117, 121))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('DMPM', 'Chemical', '-', (117, 121))
63454	30581150	Our analysis showed exon 3 skipping of the HSPH1 member, thus adding additional evidence to the pro-apoptotic effect of SF3b modulation.	('skipping', 'Var', (27, 35))	('exon', 'Var', (20, 24))	('modulation', 'Var', (125, 135))	('pro-apoptotic', 'MPA', (96, 109))	('HSPH1', 'Gene', '10808', (43, 48))	('HSPH1', 'Gene', (43, 48))	('SF3b', 'Gene', (120, 124))
63463	30581150	Furthermore, several studies suggest that specific subtypes of cancers could be particularly sensitive to splicing modulation, most prominently those characterized by high MYC expression.	('MYC', 'Gene', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('high', 'Var', (167, 171))	('sensitive', 'Reg', (93, 102))	('splicing', 'biological_process', 'GO:0045292', ('106', '114'))	('MYC', 'Gene', '4609', (172, 175))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
63465	30581150	FISH analyses showed that mesotheliomas carry an amplification of the 8q24 chromosomal region, which includes the c-MYC locus (frequencies vary between 15% and 48%, of which 64% occur in DMPM cases).	('amplification', 'Var', (49, 62))	('MYC', 'Gene', '4609', (116, 119))	('chromosomal region', 'cellular_component', 'GO:0098687', ('75', '93'))	('mesotheliomas', 'Disease', 'MESH:D008654', (26, 39))	('mesotheliomas', 'Disease', (26, 39))	('DMPM', 'Chemical', '-', (187, 191))	('MYC', 'Gene', (116, 119))
63470	30581150	Therefore, splicing modulation could constitute a promising option for chemotherapy-resistant cases of DMPM and it may synergize with current standard treatments.	('DMPM', 'Disease', (103, 107))	('splicing modulation', 'Var', (11, 30))	('DMPM', 'Chemical', '-', (103, 107))	('splicing', 'biological_process', 'GO:0045292', ('11', '19'))
63471	30581150	Ultimately, our data support the implementation of splicing modulators into the clinic, since we showed that in vivo administration of E7107 with four consecutive intraperitoneal injections leads to complete eradication of the tumor masses in 50% of tested animals throughout the study.	('tumor', 'Disease', (227, 232))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('eradication', 'NegReg', (208, 219))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('E7107', 'Var', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
63606	22421191	Preclinical data in rats showed that administration of IP pemetrexed led to a significantly higher (up to 40.8-fold) IP:IV area under the concentration time curve (AUC) ratio, than did an equivalent dose of IV pemetrexed.	('IP pemetrexed', 'Var', (55, 68))	('higher', 'PosReg', (92, 98))	('rats', 'Species', '10116', (20, 24))	('pemetrexed', 'Chemical', 'MESH:D000068437', (58, 68))	('IP:IV area under the concentration time curve', 'MPA', (117, 162))	('pemetrexed', 'Chemical', 'MESH:D000068437', (210, 220))
63663	22421191	The selected reaction monitoring transition was: m/z 428.1   281.1 for pemetrexed and m/z 455.2   308.1 for the internal standard.	('m/z 428.1   281.1', 'Var', (49, 66))	('pemetrexed', 'Chemical', 'MESH:D000068437', (71, 81))	('m/z 455.2   308.1', 'Var', (86, 103))
63673	22421191	One patient was in cycle 5 at dose level 2 (120 mg/m2) when she experienced a seizure of unclear etiology.	('seizure', 'Disease', 'MESH:D012640', (78, 85))	('seizure', 'Phenotype', 'HP:0001250', (78, 85))	('patient', 'Species', '9606', (4, 11))	('120 mg/m2', 'Var', (44, 53))	('seizure', 'Disease', (78, 85))
63675	22421191	The remaining 2 patients who were at cycle 1or 2 of dose level 5 (1000 mg/m2), experienced significant >= grade 3 toxicities, as described below, and did not complete the regimen on that basis.	('toxicities', 'Disease', 'MESH:D064420', (114, 124))	('toxicities', 'Disease', (114, 124))	('patients', 'Species', '9606', (16, 24))	('1000 mg/m2', 'Var', (66, 76))
63783	28388291	Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia.	('ASS1', 'Gene', (278, 282))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('arginine', 'Chemical', 'MESH:D001120', (315, 323))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('ammonia', 'Chemical', 'MESH:D000641', (342, 349))	('tumors', 'Disease', (294, 300))	('ADI-PEG 20', 'Chemical', '-', (194, 204))	('Argininosuccinate Synthetase 1-Deficient Thoracic Cancers', 'Disease', 'MESH:D020159', (106, 163))	('depletes', 'NegReg', (206, 214))	('Cancers', 'Phenotype', 'HP:0002664', (156, 163))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('argininosuccinate synthetase 1', 'Gene', '445', (246, 276))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))	('essential amino acid', 'Chemical', 'MESH:D000601', (215, 235))	('arginine', 'Chemical', 'MESH:D001120', (174, 182))	('ASS1', 'Gene', '445', (278, 282))	('Pegylated', 'Var', (164, 173))	('Patients', 'Species', '9606', (92, 100))	('argininosuccinate synthetase 1', 'Gene', (246, 276))	('citrulline', 'Chemical', 'MESH:D002956', (327, 337))	('Cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (78, 88))	('essential amino acid levels', 'MPA', (215, 242))
63788	28388291	No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20.	('ADI-PEG', 'Var', (113, 120))	('ADI-PEG 20', 'Chemical', '-', (113, 123))	('toxicities', 'Disease', 'MESH:D064420', (17, 27))	('toxicities', 'Disease', (17, 27))
63798	28388291	However, it has been found that a number of tumor types (eg, melanoma and prostate and ovarian cancers) have abnormalities in arginine synthesis pathways so that tumor cells are not able to synthesize arginine de novo and are dependent on an exogenous supply for growth (termed arginine auxotrophy).	('tumor', 'Disease', (162, 167))	('abnormalities', 'Var', (109, 122))	('arginine', 'Chemical', 'MESH:D001120', (201, 209))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('abnormalities in arginine synthesis', 'Phenotype', 'HP:0010909', (109, 144))	('arginine synthesis', 'biological_process', 'GO:0006526', ('126', '144'))	('synthesize arginine', 'MPA', (190, 209))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('arginine', 'Chemical', 'MESH:D001120', (278, 286))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ovarian cancers', 'Phenotype', 'HP:0100615', (87, 102))	('melanoma and prostate and ovarian cancers', 'Disease', 'MESH:D010051', (61, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('arginine', 'Chemical', 'MESH:D001120', (126, 134))	('arginine', 'Enzyme', (126, 134))
63799	28388291	Arginine promotes tumor growth, and the observation that arginine-depleted feed is associated with reduced xenograft tumor growth was made in 1930.	('arginine', 'Chemical', 'MESH:D001120', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (117, 122))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('reduced', 'NegReg', (99, 106))	('arginine-depleted', 'Var', (57, 74))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
63802	28388291	Intratumoral deficiency of ASS1 has been detected in significant numbers of patients with cancers including mesothelioma and NSCLC.	('cancers', 'Disease', (90, 97))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('NSCLC', 'Disease', (125, 130))	('mesothelioma', 'Disease', (108, 120))	('deficiency', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('tumor', 'Disease', (5, 10))	('ASS1', 'Gene', '445', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('ASS1', 'Gene', (27, 31))	('detected', 'Reg', (41, 49))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
63803	28388291	Epigenetic modification via aberrant methylation of the ASS1 promoter is proposed as underlying this deficiency, especially in mesothelioma.	('mesothelioma', 'Disease', (127, 139))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('ASS1', 'Gene', (56, 60))	('ASS1', 'Gene', '445', (56, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('aberrant methylation', 'Var', (28, 48))	('Epigenetic modification', 'Var', (0, 23))
63804	28388291	Importantly, low ASS1 expression is associated with a more aggressive clinical phenotype and a worse clinical outcome in several different cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('low', 'Var', (13, 16))	('ASS1', 'Gene', '445', (17, 21))	('ASS1', 'Gene', (17, 21))	('expression', 'MPA', (22, 32))	('cancer', 'Disease', (139, 145))
63806	28388291	Indeed, recent work indicates that low ASS1 promotes the diversion of aspartate for pyrimidine synthesis and enhanced tumor-cell proliferation.	('synthesis', 'biological_process', 'GO:0009058', ('95', '104'))	('promotes', 'PosReg', (44, 52))	('diversion of aspartate for pyrimidine synthesis', 'MPA', (57, 104))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('ASS1', 'Gene', (39, 43))	('tumor', 'Disease', (118, 123))	('ASS1', 'Gene', '445', (39, 43))	('low', 'Var', (35, 38))	('enhanced', 'PosReg', (109, 117))	('aspartate', 'Chemical', 'MESH:D001224', (70, 79))	('pyrimidine', 'Chemical', 'MESH:C030986', (84, 94))
63807	28388291	Thus, it is noteworthy that patients selected on the basis of low ASS1 expression are likely to be a cohort with worse prognosis and a poor response to currently used chemotherapy regimens.	('ASS1', 'Gene', (66, 70))	('expression', 'MPA', (71, 81))	('ASS1', 'Gene', '445', (66, 70))	('low', 'Var', (62, 65))	('patients', 'Species', '9606', (28, 36))
63810	28388291	ADI-PEG 20 was well tolerated in early clinical trials as a single agent with promising biologic activity including for patients with hepatocellular carcinoma, metastatic melanoma, and mesothelioma.	('hepatocellular carcinoma', 'Disease', (134, 158))	('ADI-PEG 20', 'Var', (0, 10))	('mesothelioma', 'Disease', (185, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('ADI-PEG 20', 'Chemical', '-', (0, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('patients', 'Species', '9606', (120, 128))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
63816	28388291	We undertook a phase 1 dose-escalation study of ADI-PEG 20 combined with pemetrexed and cisplatin (ADIPemCis) in the first-line treatment of patients with nonsquamous NSCLC or mesothelioma tumors that were ASS1 deficient.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (176, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (176, 195))	('patients', 'Species', '9606', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ADI', 'Chemical', '-', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('ADI-PEG 20', 'Chemical', '-', (48, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('ADI-PEG', 'Var', (48, 55))	('mesothelioma tumors', 'Disease', (176, 195))	('pemetrexed', 'Chemical', 'MESH:D000068437', (73, 83))	('ASS1', 'Gene', '445', (206, 210))	('ADI', 'Chemical', '-', (99, 102))	('NSCLC', 'Disease', (167, 172))	('ASS1', 'Gene', (206, 210))
63840	28388291	Dose-limiting toxicities (DLTs) were assessed during cycle one (21 days) as AEs that were possibly, probably, or definitely related to study treatment, including grade 4 neutropenia (> 7 days duration); febrile neutropenia; grade 4 anemia (requiring transfusion therapy); grade 4 thrombocytopenia; or grade 3 or 4 nonhematologic toxicity with the exception of grade 3 nausea, vomiting, or diarrhea that resolved to a lower grade with supportive treatment within 7 days, grade 3 AST/ALT elevation without accompanying increase in bilirubin, alopecia, electrolyte abnormalities, or other grade 3 or 4 asymptomatic laboratory evaluations only deemed as DLTs if assessed clinically significant by the investigator; and a delay in cycle 2 for > 3 weeks.	('toxicities', 'Disease', (14, 24))	('thrombocytopenia', 'Disease', 'MESH:D013921', (280, 296))	('anemia', 'Disease', (232, 238))	('toxicity', 'Disease', (329, 337))	('neutropenia', 'Disease', (211, 222))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (280, 296))	('nausea', 'Disease', (368, 374))	('alopecia', 'Phenotype', 'HP:0001596', (540, 548))	('increase in bilirubin', 'Phenotype', 'HP:0003573', (517, 538))	('electrolyte abnormalities', 'Phenotype', 'HP:0003111', (550, 575))	('AST', 'Gene', (478, 481))	('febrile neutropenia', 'Disease', (203, 222))	('diarrhea', 'Phenotype', 'HP:0002014', (389, 397))	('neutropenia', 'Disease', (170, 181))	('nausea', 'Disease', 'MESH:D009325', (368, 374))	('neutropenia', 'Disease', 'MESH:D009503', (211, 222))	('vomiting', 'Disease', 'MESH:D014839', (376, 384))	('neutropenia', 'Phenotype', 'HP:0001875', (211, 222))	('elevation', 'PosReg', (486, 495))	('anemia', 'Disease', 'MESH:D000740', (232, 238))	('diarrhea', 'Disease', (389, 397))	('alopecia', 'MPA', (540, 548))	('vomiting', 'Phenotype', 'HP:0002013', (376, 384))	('neutropenia', 'Disease', 'MESH:D009503', (170, 181))	('thrombocytopenia', 'Disease', (280, 296))	('neutropenia', 'Phenotype', 'HP:0001875', (170, 181))	('vomiting', 'Disease', (376, 384))	('toxicity', 'Disease', 'MESH:D064420', (329, 337))	('ALT', 'molecular_function', 'GO:0004021', ('482', '485'))	('ALT elevation', 'Phenotype', 'HP:0031964', (482, 495))	('febrile neutropenia', 'Disease', 'MESH:D009503', (203, 222))	('diarrhea', 'Disease', 'MESH:D003967', (389, 397))	('anemia', 'Phenotype', 'HP:0001903', (232, 238))	('AST', 'Gene', '26503', (478, 481))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('nausea', 'Phenotype', 'HP:0002018', (368, 374))	('grade', 'Var', (470, 475))
63871	28388291	Arginine suppression was also detected for the first 8 weeks only, before reaching baseline levels by week 12, in a recent phase 1 combination study of ADI-PEG20 combined with docetaxel in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('Arginine', 'MPA', (0, 8))	('docetaxel', 'Chemical', 'MESH:D000077143', (176, 185))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (152, 161))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('solid tumors', 'Disease', (189, 201))	('ADI-PEG20', 'Var', (152, 161))	('solid tumors', 'Disease', 'MESH:D009369', (189, 201))
63874	28388291	Interestingly, this was in contrast to samples taken from patients treated in the monotherapy and docetaxel combination study, in which anti-ADI-PEG 20 antibodies increased rapidly and reached 10-3 by 9 weeks, followed by a continued increase in titers (10-5 to 10-6) before reaching a plateau by 16 weeks.	('titers', 'MPA', (246, 252))	('anti-ADI-PEG', 'Var', (136, 148))	('docetaxel', 'Chemical', 'MESH:D000077143', (98, 107))	('ADI-PEG 20', 'Chemical', '-', (141, 151))	('patients', 'Species', '9606', (58, 66))
63881	28388291	Recently, Bueno et al reported that the prognosis of patients with the non-epithelioid subtypes (sarcomatoid, biphasic-sarcomatoid, biphasic-epithelioid) was worse than that of patients with the pure epithelioid subtype of mesothelioma (P = .0001).	('sarcomatoid', 'Disease', 'MESH:C538614', (97, 108))	('biphasic-sarcomatoid', 'Disease', (110, 130))	('sarcomatoid', 'Disease', 'MESH:C538614', (119, 130))	('biphasic-epithelioid', 'Var', (132, 152))	('patients', 'Species', '9606', (53, 61))	('sarcomatoid', 'Disease', (97, 108))	('mesothelioma', 'Disease', (223, 235))	('patients', 'Species', '9606', (177, 185))	('pure', 'molecular_function', 'GO:0034023', ('195', '199'))	('sarcomatoid', 'Disease', (119, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (223, 235))	('biphasic-sarcomatoid', 'Disease', 'MESH:C538614', (110, 130))
63888	28388291	The key rationale is similar in that significant proportions of these tumors are auxotrophic for arginine and in that the disruption of arginine supply with ADI-PEG 20 suppresses, in particular, nucleotide metabolism.	('auxotrophic for arginine', 'MPA', (81, 105))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('arginine', 'Chemical', 'MESH:D001120', (136, 144))	('nucleotide metabolism', 'MPA', (195, 216))	('ADI-PEG 20', 'Chemical', '-', (157, 167))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('195', '216'))	('disruption', 'Var', (122, 132))	('ADI-PEG 20', 'Gene', (157, 167))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('arginine supply', 'MPA', (136, 151))	('suppresses', 'NegReg', (168, 178))	('arginine', 'Chemical', 'MESH:D001120', (97, 105))
63890	28388291	Importantly, the effects of combination chemotherapy are likely to be tumor cell type specific, as evidenced by the differential modulation of enzymes involved in nucleotide synthesis after treatment with ADI-PEG20 in mesothelioma compared with melanoma.	('ADI-PEG20', 'Var', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (218, 230))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('tumor', 'Disease', (70, 75))	('modulation', 'Reg', (129, 139))	('melanoma', 'Disease', (245, 253))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (205, 214))	('enzymes involved', 'MPA', (143, 159))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('163', '183'))	('mesothelioma', 'Disease', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
63891	28388291	In the case of platinum agents, resistance has been observed in ovarian cancer and NSCLC cell lines displaying loss of ASS1, whereas ADI-PEG 20 has been shown to induce cisplatin sensitivity in the latter.	('ADI-PEG', 'Var', (133, 140))	('ADI-PEG 20', 'Chemical', '-', (133, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('loss', 'Var', (111, 115))	('NSCLC', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('platinum', 'Chemical', 'MESH:D010984', (15, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('ASS1', 'Gene', '445', (119, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('ovarian cancer', 'Disease', (64, 78))	('ASS1', 'Gene', (119, 123))	('induce', 'PosReg', (162, 168))	('cisplatin sensitivity', 'MPA', (169, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
63924	29970876	Given his deconditioned state, low response rate, and the side effect profile of second-line therapy with combination gemcitabine and vinorelbine, the decision was made to pursue immunotherapy based on the results of immunohistochemical and tumor molecular profiling, which demonstrated 1% tumor cell staining for PD-1 receptor at a 2+ intensity score, 10% elevated PDL-1 staining on tumor infiltrating T-cells, and a high tumor mutational burden with 13 mutations per megabase.	('PDL-1', 'Gene', (366, 371))	('staining', 'MPA', (372, 380))	('PD-1', 'Gene', (314, 318))	('PD-1', 'Gene', '5133', (314, 318))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', (384, 389))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (423, 428))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (384, 389))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('PDL-1', 'Gene', '29126', (366, 371))	('elevated', 'PosReg', (357, 365))	('gemcitabine', 'Chemical', 'MESH:C056507', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('mutations', 'Var', (455, 464))	('vinorelbine', 'Chemical', 'MESH:D000077235', (134, 145))
63952	29970876	CTLA-4 blockade also resulted in long-term immunologic memory with 90% of mice that achieved complete tumor rejection remaining completely resistant to relapse following re-inoculation with tumor cells.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('CTLA-4', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('resulted in', 'Reg', (21, 32))	('tumor', 'Disease', (190, 195))	('blockade', 'Var', (7, 15))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', (102, 107))	('memory', 'biological_process', 'GO:0007613', ('55', '61'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
63961	29970876	These uncertainties notwithstanding, blockade of either PD-1 or PD-L1 receptor has already shown promising results in inducing lasting clinical response and prolonged stability of disease in advanced malignancies, such as renal cancer, melanoma, non-small cell lung cancer, and ovarian cancer even after failure of their respective frontline systemic therapies.	('renal cancer', 'Phenotype', 'HP:0009726', (222, 234))	('blockade', 'Var', (37, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (250, 272))	('malignancies', 'Disease', 'MESH:D009369', (200, 212))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('malignancies', 'Disease', (200, 212))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (246, 272))	('renal cancer', 'Disease', 'MESH:D007680', (222, 234))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('ovarian cancer', 'Disease', 'MESH:D010051', (278, 292))	('inducing', 'PosReg', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('non-small cell lung cancer', 'Disease', (246, 272))	('melanoma', 'Disease', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('PD-1', 'Gene', (56, 60))	('PD-1', 'Gene', '5133', (56, 60))	('ovarian cancer', 'Disease', (278, 292))	('PD-L1 receptor', 'Gene', (64, 78))	('ovarian cancer', 'Phenotype', 'HP:0100615', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('renal cancer', 'Disease', (222, 234))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (246, 272))
63965	29970876	Defective mismatch repair results in increased micro-mutations which give rise to neo-antigens that, although leading to increased T-cell recruitment, result in increased tumor PD-L1 expression.	('T-cell recruitment', 'MPA', (131, 149))	('mismatch repair', 'biological_process', 'GO:0006298', ('10', '25'))	('mismatch repair', 'Protein', (10, 25))	('increased', 'PosReg', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('increased T-cell', 'Phenotype', 'HP:0100828', (121, 137))	('micro-mutations', 'Var', (47, 62))	('increased', 'PosReg', (37, 46))	('Defective', 'Var', (0, 9))	('expression', 'MPA', (183, 193))	('increased', 'PosReg', (161, 170))	('tumor', 'Disease', (171, 176))
63968	29970876	Positive responses to checkpoint blockade were observed with defective mismatch repair, increased MSI, and elevated TMB, resulting in longer progression-free survival compared to tumors with intact mismatch repair mechanisms without an elevated MSI or TMB (78% vs. 40%, respectively).	('mismatch', 'Var', (71, 79))	('mismatch repair', 'biological_process', 'GO:0006298', ('198', '213'))	('longer', 'PosReg', (134, 140))	('TMB', 'Chemical', '-', (116, 119))	('mismatch repair', 'biological_process', 'GO:0006298', ('71', '86'))	('tumors', 'Disease', (179, 185))	('MSI', 'Disease', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('progression-free survival', 'CPA', (141, 166))	('increased', 'PosReg', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('MSI', 'Disease', 'None', (245, 248))	('TMB', 'MPA', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TMB', 'Chemical', '-', (252, 255))	('defective mismatch', 'Var', (61, 79))	('MSI', 'Disease', 'None', (98, 101))	('MSI', 'Disease', (245, 248))
63993	29899847	Heat shock protein 90 inhibitors augment endogenous wild-type p53 expression but down-regulate the adenovirally-induced expression by inhibiting a proteasome activity Heat shock protein 90 (HSP90) inhibitors suppressed MDM4 functions which mediated p53 ubiquitination, and blocked a chaperon function which influenced expression of the client proteins.	('adenovirally-induced expression', 'MPA', (99, 130))	('expression', 'MPA', (66, 76))	('p53', 'Gene', (249, 252))	('augment', 'PosReg', (33, 40))	('HSP90', 'Gene', (190, 195))	('p53', 'Gene', '7157', (62, 65))	('Heat shock protein 90', 'Gene', '3320', (167, 188))	('expression', 'MPA', (318, 328))	('Heat shock protein 90', 'Gene', '3320', (0, 21))	('Heat shock protein 90', 'Gene', (167, 188))	('Heat shock protein 90', 'Gene', (0, 21))	('chaperon function', 'MPA', (283, 300))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('ubiquitination', 'MPA', (253, 267))	('p53', 'Gene', (62, 65))	('HSP90', 'Gene', '3320', (190, 195))	('inhibitors', 'Var', (197, 207))	('inhibitors', 'Var', (22, 32))	('shock', 'Phenotype', 'HP:0031273', (5, 10))	('proteasome', 'molecular_function', 'GO:0004299', ('147', '157'))	('blocked', 'NegReg', (273, 280))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))	('shock', 'Phenotype', 'HP:0031273', (172, 177))	('proteasome activity', 'MPA', (147, 166))	('inhibiting', 'NegReg', (134, 144))	('influenced', 'Reg', (307, 317))	('MDM4', 'Gene', '4194', (219, 223))	('endogenous', 'MPA', (41, 51))	('down-regulate', 'NegReg', (81, 94))	('proteasome', 'cellular_component', 'GO:0000502', ('147', '157'))	('MDM4', 'Gene', (219, 223))	('p53', 'Gene', '7157', (249, 252))	('suppressed', 'NegReg', (208, 218))
63997	29899847	Furthermore, the inhibitors increased the endogenous p53 levels that were induced by cisplatin.	('increased', 'PosReg', (28, 37))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (53, 56))	('inhibitors', 'Var', (17, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
64006	29899847	Deletion of p16 expression increases cyclin-dependent kinase 4/6 activities and subsequently phosphorylates pRb, which induces uninhibited cell cycle progression.	('cyclin', 'molecular_function', 'GO:0016538', ('37', '43'))	('pRb', 'Gene', (108, 111))	('induces', 'Reg', (119, 126))	('cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (37, 64))	('p16', 'Gene', '1029', (12, 15))	('activities', 'MPA', (65, 75))	('increases', 'PosReg', (27, 36))	('pRb', 'Gene', '5925', (108, 111))	('p16', 'Gene', (12, 15))	('uninhibited', 'MPA', (127, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('139', '149'))	('cyclin-dependent kinase 4/6', 'Gene', (37, 64))	('Deletion', 'Var', (0, 8))
64010	29899847	Induction of p53 expression is therefore a direct way to reconstitute the tumor suppressor functions and can be a therapeutic strategy for mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('p53', 'Gene', (13, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('mesothelioma', 'Disease', (139, 151))	('p53', 'Gene', '7157', (13, 16))	('Induction', 'Var', (0, 9))
64014	29899847	An inhibitor for HSP90 disrupts actions of the oncoproteins and produces cytotoxic effects on tumor cells which are frequently addicted to oncogenic processes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cytotoxic effects', 'CPA', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('inhibitor', 'Var', (3, 12))	('HSP90', 'Gene', (17, 22))	('actions', 'MPA', (32, 39))	('tumor', 'Disease', (94, 99))	('HSP90', 'Gene', '3320', (17, 22))	('disrupts', 'NegReg', (23, 31))	('oncoproteins', 'Protein', (47, 59))
64016	29899847	Moreover, HSP90 inhibitors can augment p53 expression through inhibiting functions of MDM4 which constitutes a heterodimeric structure with MDM2.	('inhibitors', 'Var', (16, 26))	('augment', 'PosReg', (31, 38))	('functions', 'MPA', (73, 82))	('HSP90', 'Gene', (10, 15))	('MDM4', 'Gene', '4194', (86, 90))	('MDM2', 'Gene', '4193', (140, 144))	('MDM2', 'Gene', (140, 144))	('inhibiting', 'NegReg', (62, 72))	('p53', 'Gene', (39, 42))	('MDM4', 'Gene', (86, 90))	('HSP90', 'Gene', '3320', (10, 15))	('p53', 'Gene', '7157', (39, 42))	('expression', 'MPA', (43, 53))
64018	29899847	HSP90 inhibitors therefore increase p53 expression by suppressing the MDM2-mediated p53 degradation through MDM4.	('expression', 'MPA', (40, 50))	('MDM2', 'Gene', (70, 74))	('suppressing', 'NegReg', (54, 65))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('MDM4', 'Gene', '4194', (108, 112))	('p53', 'Gene', (36, 39))	('MDM4', 'Gene', (108, 112))	('p53', 'Gene', '7157', (36, 39))	('degradation', 'MPA', (88, 99))	('inhibitors', 'Var', (6, 16))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('degradation', 'biological_process', 'GO:0009056', ('88', '99'))	('MDM2', 'Gene', '4193', (70, 74))	('increase', 'PosReg', (27, 35))
64021	29899847	In this study we examined whether HSP90 inhibitors produced anti-tumor effects on mesothelioma and achieved combinatory effects with Ad-p53 by inhibiting a degradation process of transduced p53.	('mesothelioma', 'Disease', (82, 94))	('Ad-p', 'Gene', (133, 137))	('tumor', 'Disease', (65, 70))	('HSP90', 'Gene', (34, 39))	('p53', 'Gene', '7157', (136, 139))	('inhibitors', 'Var', (40, 50))	('Ad-p', 'Gene', '23038', (133, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('inhibiting', 'NegReg', (143, 153))	('p53', 'Gene', (190, 193))	('HSP90', 'Gene', '3320', (34, 39))	('p53', 'Gene', '7157', (190, 193))	('degradation', 'biological_process', 'GO:0009056', ('156', '167'))	('degradation process', 'MPA', (156, 175))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p53', 'Gene', (136, 139))
64025	29899847	The HSP90 inhibitors suppressed viability of these cells and 17-DMAG was more cytotoxic than 17-AAG.	('17-DMAG', 'Var', (61, 68))	('viability of these cells', 'CPA', (32, 56))	('17-AAG', 'Chemical', '-', (93, 99))	('HSP90', 'Gene', (4, 9))	('HSP90', 'Gene', '3320', (4, 9))	('suppressed', 'NegReg', (21, 31))	('17-DMAG', 'Chemical', 'MESH:C448659', (61, 68))	('cytotoxic', 'CPA', (78, 87))
64028	29899847	Comparison of a half maximal inhibitory concentration (IC50) values showed that the HSP90 inhibitors was in more effective to cells of the p53 non-functional type (IC50 values, 17-AAG average: 98.6 nM, 17-DMAG: 10.3 nM) than those of the p53 functional type (17-AAG: 319.8 nM, 17-DMAG: 39.0 nM) without statistical significance (17-AAG: P = 0.089, 17-DMAG: P = 0.086).	('17-DMAG', 'Chemical', 'MESH:C448659', (348, 355))	('17-AAG', 'Chemical', '-', (259, 265))	('17-AAG', 'Chemical', '-', (177, 183))	('p53', 'Gene', (238, 241))	('p53', 'Gene', '7157', (238, 241))	('17-DMAG', 'Chemical', 'MESH:C448659', (277, 284))	('17-DMAG', 'Chemical', 'MESH:C448659', (202, 209))	('17-AAG', 'Chemical', '-', (329, 335))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('effective', 'MPA', (113, 122))	('HSP90', 'Gene', (84, 89))	('HSP90', 'Gene', '3320', (84, 89))	('non-functional type', 'Var', (143, 162))
64030	29899847	We examined whether HSP90 inhibitors increased p53 expression in the p53 wild-type mesothelioma, MSTO-211H, NCI-H28 and EHMES-10 cells, which showed differential susceptibility to the HSP90 inhibitors.	('MSTO-211H', 'Chemical', '-', (97, 106))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('HSP90', 'Gene', (20, 25))	('HSP90', 'Gene', '3320', (20, 25))	('inhibitors', 'Var', (26, 36))	('p53', 'Gene', '7157', (47, 50))	('mesothelioma', 'Disease', (83, 95))	('expression', 'MPA', (51, 61))	('increased', 'PosReg', (37, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('NCI-H28', 'CellLine', 'CVCL:1555', (108, 115))	('p53', 'Gene', (47, 50))	('HSP90', 'Gene', (184, 189))	('HSP90', 'Gene', '3320', (184, 189))	('EHMES-10', 'CellLine', 'CVCL:M208', (120, 128))
64031	29899847	All the cells treated with HSP90 inhibitors up-regulated p53 expression and the phosphorylation at Ser 15 residue, a marker for p53 stabilization, and then showed cleavage of PARP (Figure 1B) (Summarized signal intensity of key molecules in each Western blot analysis in Supplementary Table 1).	('p53', 'Gene', '7157', (57, 60))	('Ser', 'Chemical', 'MESH:D012694', (99, 102))	('p53', 'Gene', (128, 131))	('PARP', 'Gene', (175, 179))	('p53', 'Gene', '7157', (128, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('Ser', 'cellular_component', 'GO:0005790', ('99', '102'))	('HSP90', 'Gene', (27, 32))	('HSP90', 'Gene', '3320', (27, 32))	('up-regulated', 'PosReg', (44, 56))	('PARP', 'Gene', '142', (175, 179))	('p53', 'Gene', (57, 60))	('cleavage', 'MPA', (163, 171))	('phosphorylation at', 'MPA', (80, 98))	('expression', 'MPA', (61, 71))	('inhibitors', 'Var', (33, 43))
64034	29899847	NCI-H28 cells with the wild-type p53 genotype increased p53 expression with cisplatin, and HSP90 inhibitors augmented p53 phosphorylation not only in cisplatin-unstimulated but also -treated cells.	('expression', 'MPA', (60, 70))	('HSP90', 'Gene', '3320', (91, 96))	('p53', 'Gene', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('p53', 'Gene', (118, 121))	('increased', 'PosReg', (46, 55))	('NCI-H28', 'CellLine', 'CVCL:1555', (0, 7))	('p53', 'Gene', '7157', (56, 59))	('phosphorylation', 'MPA', (122, 137))	('augmented', 'PosReg', (108, 117))	('p53', 'Gene', '7157', (118, 121))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('HSP90', 'Gene', (91, 96))	('inhibitors', 'Var', (97, 107))
64035	29899847	These data collectively indicated that HSP90 inhibitors increased endogenous wild-type p53 levels and the up-regulation can be associated with cell death of mesothelioma with the wild-type p53 genotype.	('HSP90', 'Gene', '3320', (39, 44))	('cell death', 'biological_process', 'GO:0008219', ('143', '153'))	('p53', 'Gene', '7157', (189, 192))	('increased', 'PosReg', (56, 65))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('endogenous wild-type', 'MPA', (66, 86))	('inhibitors', 'Var', (45, 55))	('death of mesothelioma', 'Disease', (148, 169))	('up-regulation', 'PosReg', (106, 119))	('HSP90', 'Gene', (39, 44))	('death of mesothelioma', 'Disease', 'MESH:D008654', (148, 169))	('p53', 'Gene', (189, 192))
64036	29899847	We then examined influence of HSP90 inhibitors on p53 expression in JMN-1B cells with mutated p53 genotype (Figure 2A).	('mutated', 'Var', (86, 93))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('HSP90', 'Gene', (30, 35))	('HSP90', 'Gene', '3320', (30, 35))	('JMN-1B', 'CellLine', 'CVCL:M006', (68, 74))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))
64048	29899847	Expression levels of autophagy-related molecules in cells treated with both Ad-p53 and HSP90 inhibitors were similar to those in cells treated with HSP90 inhibitors or Ad-LacZ alone.	('Ad-p', 'Gene', '23038', (76, 80))	('p53', 'Gene', (79, 82))	('Ad-p', 'Gene', (76, 80))	('p53', 'Gene', '7157', (79, 82))	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('HSP90', 'Gene', (87, 92))	('HSP90', 'Gene', '3320', (87, 92))	('HSP90', 'Gene', (148, 153))	('HSP90', 'Gene', '3320', (148, 153))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('inhibitors', 'Var', (93, 103))
64050	29899847	JMN-1B cells infected with Ad-p53 expressed both p53 types, endogenous mutated p53 and exogenous wild-type p53.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('mutated', 'Var', (71, 78))	('p53', 'Gene', (30, 33))	('Ad-p', 'Gene', (27, 31))	('p53', 'Gene', '7157', (30, 33))	('JMN-1B', 'CellLine', 'CVCL:M006', (0, 6))	('Ad-p', 'Gene', '23038', (27, 31))
64051	29899847	We discriminated the both type with 2 kinds of antibody (Ab), Pab1620 specifically reacting to wild-type p53 and DO-1 recognizing all the p53 types including mutated sequences.	('antibody', 'cellular_component', 'GO:0042571', ('47', '55'))	('p53', 'Gene', (138, 141))	('Pab1620', 'Chemical', '-', (62, 69))	('p53', 'Gene', '7157', (138, 141))	('antibody', 'cellular_component', 'GO:0019814', ('47', '55'))	('antibody', 'cellular_component', 'GO:0019815', ('47', '55'))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('antibody', 'molecular_function', 'GO:0003823', ('47', '55'))	('mutated', 'Var', (158, 165))
64055	29899847	These data indicated that HSP90 inhibitors suppressed expression of exogenously overexpressed wild-type p53 and had little effect on endogenous mutated p53.	('expression', 'MPA', (54, 64))	('p53', 'Gene', (104, 107))	('HSP90', 'Gene', (26, 31))	('inhibitors', 'Var', (32, 42))	('HSP90', 'Gene', '3320', (26, 31))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('suppressed', 'NegReg', (43, 53))
64060	29899847	These data collectively indicated that endogenous mutated p53 did not influence on Ad-p53- and HSP90 inhibitors-mediated effects.	('endogenous', 'Var', (39, 49))	('p53', 'Gene', '7157', (86, 89))	('HSP90', 'Gene', (95, 100))	('HSP90', 'Gene', '3320', (95, 100))	('p53', 'Gene', '7157', (58, 61))	('Ad-p', 'Gene', (83, 87))	('Ad-p', 'Gene', '23038', (83, 87))	('p53', 'Gene', (58, 61))	('p53', 'Gene', (86, 89))
64068	29899847	Cells treated with combination of Ad-p53 and HSP90 inhibitors showed increased sub-G1 fractions but the sub-G1 increase was less than that in cells treated with Ad-p53 alone.	('sub-G1 fractions', 'CPA', (79, 95))	('increased', 'PosReg', (69, 78))	('Ad-p', 'Gene', (161, 165))	('Ad-p', 'Gene', (34, 38))	('Ad-p', 'Gene', '23038', (161, 165))	('Ad-p', 'Gene', '23038', (34, 38))	('HSP90', 'Gene', (45, 50))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('HSP90', 'Gene', '3320', (45, 50))	('p53', 'Gene', (164, 167))	('inhibitors', 'Var', (51, 61))	('p53', 'Gene', '7157', (164, 167))
64070	29899847	The flow cytometry thus indicated that HSP90 inhibitors suppressed Ad-p53-mediated effects on cell cycle progression.	('HSP90', 'Gene', '3320', (39, 44))	('Ad-p', 'Gene', (67, 71))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('cell cycle progression', 'CPA', (94, 116))	('Ad-p', 'Gene', '23038', (67, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('suppressed', 'NegReg', (56, 66))	('inhibitors', 'Var', (45, 55))	('HSP90', 'Gene', (39, 44))
64074	29899847	We also examined NCI-H2452 cells expressing truncated p53 showed that Ad-p53 produced cytotoxic effects but additional 17-AAG was rather inhibitory to the Ad-p53-mediated effects (Supplementary Figure 3C).	('truncated', 'Var', (44, 53))	('Ad-p', 'Gene', '23038', (70, 74))	('cytotoxic effects', 'CPA', (86, 103))	('p53', 'Gene', '7157', (158, 161))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('p53', 'Gene', (54, 57))	('p53', 'Gene', '7157', (54, 57))	('Ad-p', 'Gene', (155, 159))	('p53', 'Gene', (158, 161))	('17-AAG', 'Chemical', '-', (119, 125))	('Ad-p', 'Gene', (70, 74))	('Ad-p', 'Gene', '23038', (155, 159))	('NCI-H2452', 'CellLine', 'CVCL:1553', (17, 26))
64076	29899847	These data indicated that HSP90 inhibitors decreased the Ad-p53-mediated effects through down-regulating p53 expression levels.	('HSP90', 'Gene', (26, 31))	('Ad-p', 'Gene', (57, 61))	('inhibitors', 'Var', (32, 42))	('HSP90', 'Gene', '3320', (26, 31))	('Ad-p', 'Gene', '23038', (57, 61))	('p53', 'Gene', (60, 63))	('p53', 'Gene', (105, 108))	('down-regulating', 'NegReg', (89, 104))	('p53', 'Gene', '7157', (105, 108))	('p53', 'Gene', '7157', (60, 63))	('decreased', 'NegReg', (43, 52))
64081	29899847	Expression of Ad-p53-mediated phosphorylated p53 and MDM2 was not influenced by PFT-mu although expression of truncated MDM2 at 50 kDa was slightly augmented in uninfected cells.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('MDM2', 'Gene', '4193', (53, 57))	('MDM2', 'Gene', (53, 57))	('augmented', 'PosReg', (148, 157))	('expression', 'MPA', (96, 106))	('MDM2', 'Gene', '4193', (120, 124))	('MDM2', 'Gene', (120, 124))	('truncated', 'Var', (110, 119))	('Ad-p', 'Gene', (14, 18))	('Ad-p', 'Gene', '23038', (14, 18))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
64082	29899847	PFT-mu scarcely influenced HSP70 and HSP90 expression, but produced cytotoxicity to JMN-1B cells (Supplementary Figure 4).	('JMN-1B', 'CellLine', 'CVCL:M006', (84, 90))	('HSP70', 'Gene', (27, 32))	('PFT-mu', 'Var', (0, 6))	('cytotoxicity', 'Disease', (68, 80))	('HSP70', 'Gene', '3308', (27, 32))	('cytotoxicity', 'Disease', 'MESH:D064420', (68, 80))	('HSP90', 'Gene', (37, 42))	('HSP90', 'Gene', '3320', (37, 42))
64084	29899847	These data collectively indicated that HSP70 was not involved in the down-regulated p53 expression induced by HSP90 inhibitors.	('HSP70', 'Gene', '3308', (39, 44))	('inhibitors', 'Var', (116, 126))	('HSP90', 'Gene', '3320', (110, 115))	('p53', 'Gene', (84, 87))	('down-regulated', 'NegReg', (69, 83))	('HSP90', 'Gene', (110, 115))	('HSP70', 'Gene', (39, 44))	('p53', 'Gene', '7157', (84, 87))	('expression', 'MPA', (88, 98))
64089	29899847	JMN-1B cells infected with Ad-EGFP showed increased GFP intensity and GFP-positive cell numbers depending on Ad doses used, and HSP90 inhibitors augmented the intensity and increased the positive cell numbers.	('increased', 'PosReg', (42, 51))	('inhibitors', 'Var', (134, 144))	('augmented', 'PosReg', (145, 154))	('increased', 'PosReg', (173, 182))	('GFP intensity', 'MPA', (52, 65))	('JMN-1B', 'CellLine', 'CVCL:M006', (0, 6))	('increased GFP', 'Phenotype', 'HP:0012214', (42, 55))	('HSP90', 'Gene', (128, 133))	('HSP90', 'Gene', '3320', (128, 133))
64090	29899847	These data indicated that HSP90 inhibitors increased expression of the transduced gene.	('HSP90', 'Gene', (26, 31))	('HSP90', 'Gene', '3320', (26, 31))	('inhibitors', 'Var', (32, 42))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))
64095	29899847	The p53 expression levels were lower in the inhibitor-treated cells than in untreated cells thereafter.	('lower', 'NegReg', (31, 36))	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (4, 7))	('inhibitor-treated', 'Var', (44, 61))
64097	29899847	These data showed that HSP90 inhibitors suppressed the p53 protein expression at a transcriptional and more significantly at a posttranscriptional level.	('inhibitors', 'Var', (29, 39))	('p53', 'Gene', (55, 58))	('suppressed', 'NegReg', (40, 50))	('p53', 'Gene', '7157', (55, 58))	('HSP90', 'Gene', (23, 28))	('HSP90', 'Gene', '3320', (23, 28))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
64102	29899847	NCI-H226 cells treated with MG-132 likewise increased endogenous wild-type p53 expression together with ubiquitinated proteins, and the increased p53 was also detected in cells treated with lactacystin, a proteasome inhibitor (Figure 7B).	('MG-132', 'Var', (28, 34))	('ubiquitinated proteins', 'MPA', (104, 126))	('expression', 'MPA', (79, 89))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('MG-132', 'Chemical', 'MESH:C072553', (28, 34))	('p53', 'Gene', (75, 78))	('lactacystin', 'Chemical', 'MESH:C067713', (190, 201))	('p53', 'Gene', '7157', (75, 78))	('NCI-H226', 'CellLine', 'CVCL:1544', (0, 8))	('increased', 'PosReg', (44, 53))	('proteasome', 'cellular_component', 'GO:0000502', ('205', '215'))	('proteasome', 'molecular_function', 'GO:0004299', ('205', '215'))
64103	29899847	These data suggested that wild-type and to a less extent mutated p53 were subjected to proteasome-mediated degradation.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('subjected', 'Reg', (74, 83))	('proteasome-mediated degradation', 'MPA', (87, 118))	('proteasome', 'molecular_function', 'GO:0004299', ('87', '97'))	('proteasome', 'cellular_component', 'GO:0000502', ('87', '97'))	('degradation', 'biological_process', 'GO:0009056', ('107', '118'))	('mutated', 'Var', (57, 64))
64105	29899847	HSP90 inhibitors decreased ubiquitinated proteins in MG-132-untreated cells and also suppressed MG-132-enhanced ubiquitination, suggesting that HSP90 inhibitors stimulated protein degradation through ubiquitination-proteasome processes.	('MG-132', 'Chemical', 'MESH:C072553', (96, 102))	('protein degradation', 'biological_process', 'GO:0030163', ('172', '191'))	('decreased', 'NegReg', (17, 26))	('HSP90', 'Gene', (0, 5))	('protein degradation', 'MPA', (172, 191))	('suppressed', 'NegReg', (85, 95))	('HSP90', 'Gene', '3320', (0, 5))	('HSP90', 'Gene', (144, 149))	('inhibitors', 'Var', (150, 160))	('HSP90', 'Gene', '3320', (144, 149))	('MG-132', 'Chemical', 'MESH:C072553', (53, 59))	('proteasome', 'molecular_function', 'GO:0004299', ('215', '225'))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('proteasome', 'cellular_component', 'GO:0000502', ('215', '225'))	('inhibitors', 'Var', (6, 16))	('stimulated', 'PosReg', (161, 171))	('ubiquitinated proteins', 'MPA', (27, 49))	('ubiquitination', 'MPA', (112, 126))
64109	29899847	Down-regulated expression of mutated p53 by HSP90 inhibitors suggested that mutated p53 was also degraded through proteasome-mediated degradation.	('HSP90', 'Gene', (44, 49))	('HSP90', 'Gene', '3320', (44, 49))	('mutated', 'Var', (76, 83))	('degraded', 'NegReg', (97, 105))	('proteasome', 'molecular_function', 'GO:0004299', ('114', '124'))	('proteasome', 'cellular_component', 'GO:0000502', ('114', '124'))	('expression', 'MPA', (15, 25))	('p53', 'Gene', (84, 87))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', '7157', (37, 40))	('degradation', 'biological_process', 'GO:0009056', ('134', '145'))	('Down-regulated', 'NegReg', (0, 14))
64112	29899847	The HSP90 inhibitors augmented endogenous wild-type p53 expression but decreased the exogenously expressed p53 levels.	('augmented', 'PosReg', (21, 30))	('HSP90', 'Gene', (4, 9))	('endogenous wild-type', 'MPA', (31, 51))	('p53', 'Gene', (107, 110))	('p53', 'Gene', (52, 55))	('HSP90', 'Gene', '3320', (4, 9))	('p53', 'Gene', '7157', (52, 55))	('p53', 'Gene', '7157', (107, 110))	('inhibitors', 'Var', (10, 20))	('decreased', 'NegReg', (71, 80))
64113	29899847	The present study therefore demonstrated a divalent function of HSP90 inhibitors regarding p53 expression.	('HSP90', 'Gene', (64, 69))	('HSP90', 'Gene', '3320', (64, 69))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('inhibitors', 'Var', (70, 80))	('expression', 'MPA', (95, 105))
64119	29899847	Inhibition of MDM4 functions can thus increase p53 levels and activate the p53 pathway.	('MDM4', 'Gene', '4194', (14, 18))	('increase', 'PosReg', (38, 46))	('MDM4', 'Gene', (14, 18))	('activate', 'PosReg', (62, 70))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('Inhibition', 'Var', (0, 10))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
64120	29899847	The current study showed that HSP90 inhibitors minimally suppressed p53 mRNA after 12 hours, while previous studies reported that the inhibitors did not influence the p53 transcript.	('HSP90', 'Gene', (30, 35))	('inhibitors', 'Var', (36, 46))	('HSP90', 'Gene', '3320', (30, 35))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (167, 170))	('suppressed', 'NegReg', (57, 67))
64123	29899847	Nevertheless, HSP90 inhibitors increased sub-G1 fractions and cleaved PARP levels.	('PARP', 'Gene', '142', (70, 74))	('increased', 'PosReg', (31, 40))	('HSP90', 'Gene', (14, 19))	('inhibitors', 'Var', (20, 30))	('HSP90', 'Gene', '3320', (14, 19))	('sub-G1 fractions', 'MPA', (41, 57))	('PARP', 'Gene', (70, 74))
64125	29899847	On the other hand, the inhibitors down-regulated expression of molecules associated with growth signals such as AKT (Supplementary Figure 5), which may contribute to the cytotoxicity irrelevant to p53.	('cytotoxicity', 'Disease', (170, 182))	('inhibitors', 'Var', (23, 33))	('down-regulated', 'NegReg', (34, 48))	('expression of molecules', 'MPA', (49, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('AKT', 'Gene', '207', (112, 115))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('AKT', 'Gene', (112, 115))
64126	29899847	Augmentation of wild-type p53 increases sensitivity of tumor cells to DNA damaging anti-cancer agents, and the present study in fact showed that HSP90 inhibitors further increased p53 expression induced by cisplatin.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Disease', (88, 94))	('p53', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Augmentation', 'Var', (0, 12))	('expression', 'MPA', (184, 194))	('HSP90', 'Gene', '3320', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('increased', 'PosReg', (170, 179))	('inhibitors', 'Var', (151, 161))	('sensitivity', 'MPA', (40, 51))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('p53', 'Gene', '7157', (180, 183))	('p53', 'Gene', (180, 183))	('tumor', 'Disease', (55, 60))	('HSP90', 'Gene', (145, 150))	('p53', 'Gene', '7157', (26, 29))	('increases', 'PosReg', (30, 39))
64129	29899847	MDM4 was therefore not involved in degradation of mutated p53 in mesothelioma.	('MDM4', 'Gene', '4194', (0, 4))	('mesothelioma', 'Disease', (65, 77))	('MDM4', 'Gene', (0, 4))	('mutated', 'Var', (50, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('p53', 'Gene', (58, 61))	('degradation', 'biological_process', 'GO:0009056', ('35', '46'))	('p53', 'Gene', '7157', (58, 61))
64130	29899847	The other mechanism of HSP90 inhibitors on p53 expression clarified in the present study was facilitation of proteasome-mediated p53 degradation, which subsequently down-regulated adenovirally-transduced p53 expression.	('degradation', 'biological_process', 'GO:0009056', ('133', '144'))	('inhibitors', 'Var', (29, 39))	('down-regulated', 'NegReg', (165, 179))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '7157', (204, 207))	('proteasome', 'molecular_function', 'GO:0004299', ('109', '119'))	('p53', 'Gene', (129, 132))	('p53', 'Gene', (43, 46))	('expression', 'MPA', (208, 218))	('degradation', 'MPA', (133, 144))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', '7157', (129, 132))	('HSP90', 'Gene', (23, 28))	('HSP90', 'Gene', '3320', (23, 28))	('proteasome', 'cellular_component', 'GO:0000502', ('109', '119'))
64132	29899847	We also showed that the proteasome inhibitor augmented expression of endogenous wild-type and less significantly mutated p53, and indicated that p53 molecules irrespective of the genotype were degraded through the proteasome pathway.	('proteasome pathway', 'Pathway', (214, 232))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('proteasome', 'cellular_component', 'GO:0000502', ('214', '224'))	('augmented', 'PosReg', (45, 54))	('proteasome', 'molecular_function', 'GO:0004299', ('214', '224'))	('expression', 'MPA', (55, 65))	('degraded', 'NegReg', (193, 201))	('proteasome', 'cellular_component', 'GO:0000502', ('24', '34'))	('mutated', 'Var', (113, 120))	('proteasome', 'molecular_function', 'GO:0004299', ('24', '34'))	('proteasome pathway', 'biological_process', 'GO:0043161', ('214', '232'))
64133	29899847	HSP90 inhibitors facilitated the proteasome functions since the inhibitors decreased ubiquitinated protein levels even under MG-132 treatment.	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('proteasome functions', 'MPA', (33, 53))	('inhibitors', 'Var', (64, 74))	('ubiquitinated protein levels', 'MPA', (85, 113))	('proteasome', 'cellular_component', 'GO:0000502', ('33', '43'))	('proteasome', 'molecular_function', 'GO:0004299', ('33', '43'))	('facilitated', 'PosReg', (17, 28))	('inhibitors', 'Var', (6, 16))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('MG-132', 'Chemical', 'MESH:C072553', (125, 131))	('decreased', 'NegReg', (75, 84))
64134	29899847	The present study showed that HSP90 inhibitors marginally decreased expression of mutated p53 and suppressed significantly Ad-p53-induced p53 levels, indicating that HSP90 inhibitors promoted ubiquitination-mediated p53 degradation regardless of the genotype.	('p53', 'Gene', (90, 93))	('p53', 'Gene', (138, 141))	('expression', 'MPA', (68, 78))	('decreased', 'NegReg', (58, 67))	('Ad-p', 'Gene', '23038', (123, 127))	('HSP90', 'Gene', (166, 171))	('p53', 'Gene', (216, 219))	('degradation', 'MPA', (220, 231))	('HSP90', 'Gene', '3320', (166, 171))	('p53', 'Gene', '7157', (126, 129))	('HSP90', 'Gene', (30, 35))	('Ad-p', 'Gene', (123, 127))	('inhibitors', 'Var', (172, 182))	('mutated', 'Var', (82, 89))	('degradation', 'biological_process', 'GO:0009056', ('220', '231'))	('p53', 'Gene', (126, 129))	('suppressed', 'NegReg', (98, 108))	('HSP90', 'Gene', '3320', (30, 35))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', '7157', (138, 141))	('promoted', 'PosReg', (183, 191))	('p53', 'Gene', '7157', (216, 219))
64137	29899847	Expression of endogenous wild-type p53 was augmented and that of overproduced wild-type p53 with Ad-p53 was suppressed by HSP90 inhibitors, whereas the inhibitors rather down-regulated endogenous mutated p53 through proteasome.	('p53', 'Gene', (35, 38))	('HSP90', 'Gene', '3320', (122, 127))	('p53', 'Gene', '7157', (88, 91))	('inhibitors', 'Var', (128, 138))	('p53', 'Gene', (88, 91))	('Ad-p', 'Gene', '23038', (97, 101))	('p53', 'Gene', '7157', (100, 103))	('proteasome', 'molecular_function', 'GO:0004299', ('216', '226'))	('Expression', 'MPA', (0, 10))	('p53', 'Gene', '7157', (204, 207))	('suppressed', 'NegReg', (108, 118))	('down-regulated', 'NegReg', (170, 184))	('p53', 'Gene', (100, 103))	('p53', 'Gene', '7157', (35, 38))	('HSP90', 'Gene', (122, 127))	('proteasome', 'cellular_component', 'GO:0000502', ('216', '226'))	('p53', 'Gene', (204, 207))	('Ad-p', 'Gene', (97, 101))	('augmented', 'PosReg', (43, 52))
64138	29899847	Previous studies showed that HSP90 inhibitors disrupted a stable complex of mutated p53 and MDM2, and mutated p53 released from the complex was subjected to degradation through ubiquitination.	('disrupted', 'NegReg', (46, 55))	('p53', 'Gene', (110, 113))	('MDM2', 'Gene', '4193', (92, 96))	('MDM2', 'Gene', (92, 96))	('degradation', 'biological_process', 'GO:0009056', ('157', '168'))	('p53', 'Gene', '7157', (110, 113))	('mutated', 'Var', (76, 83))	('complex', 'Interaction', (65, 72))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('ubiquitination', 'MPA', (177, 191))	('HSP90', 'Gene', (29, 34))	('HSP90', 'Gene', '3320', (29, 34))
64140	29899847	even proposed that HSP90 inhibitors induced a conformational shift of wild-type p53 to a mutated form and decreased wild-type p53 levels through MDM2-depedent degradation of the mutated form.	('decreased', 'NegReg', (106, 115))	('HSP90', 'Gene', '3320', (19, 24))	('MDM2', 'Gene', (145, 149))	('p53', 'Gene', '7157', (126, 129))	('MDM2', 'Gene', '4193', (145, 149))	('p53', 'Gene', (80, 83))	('conformational shift', 'MPA', (46, 66))	('degradation', 'biological_process', 'GO:0009056', ('159', '170'))	('p53', 'Gene', '7157', (80, 83))	('inhibitors', 'Var', (25, 35))	('p53', 'Gene', (126, 129))	('HSP90', 'Gene', (19, 24))
64142	29899847	A dual effect of HSP90 inhibitors on p53 expression, augmentation wild-type p53 and down-regulation of mutated p53, was previously reported, but the present study firstly to our knowledge demonstrated the divalent effect on the same wild-type p53.	('inhibitors', 'Var', (23, 33))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', (111, 114))	('down-regulation', 'NegReg', (84, 99))	('HSP90', 'Gene', (17, 22))	('HSP90', 'Gene', '3320', (17, 22))	('p53', 'Gene', '7157', (111, 114))	('regulation', 'biological_process', 'GO:0065007', ('89', '99'))	('p53', 'Gene', (37, 40))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('p53', 'Gene', '7157', (37, 40))	('augmentation', 'PosReg', (53, 65))
64145	29899847	On the other hand, HSP90 directly functioned as a p53 chaperon in the p53-overproduced cells and the inhibitors suppressed the chaperon effects, which influenced the p53 levels greater than the inhibitory effect on MDM4.	('HSP90', 'Gene', '3320', (19, 24))	('inhibitors', 'Var', (101, 111))	('suppressed', 'NegReg', (112, 122))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('MDM4', 'Gene', '4194', (215, 219))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('MDM4', 'Gene', (215, 219))	('influenced', 'Reg', (151, 161))	('chaperon effects', 'MPA', (127, 143))	('HSP90', 'Gene', (19, 24))
64146	29899847	HPS90 inhibitors facilitated proteasome-mediated p53 degradation which exceeded the p53 augmentation effect when cells were under a p53-excess condition.	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('HPS90', 'Gene', (0, 5))	('p53', 'Gene', (84, 87))	('facilitated', 'PosReg', (17, 28))	('inhibitors', 'Var', (6, 16))	('p53', 'Gene', '7157', (84, 87))	('proteasome', 'molecular_function', 'GO:0004299', ('29', '39'))	('proteasome', 'cellular_component', 'GO:0000502', ('29', '39'))	('degradation', 'biological_process', 'GO:0009056', ('53', '64'))
64155	29899847	Moreover, p53 levels modulated by HSP90 inhibitors can be influenced by expression of co-chaperone molecules which form a complex with HSP90.	('p53', 'Gene', '7157', (10, 13))	('HSP90', 'Gene', (34, 39))	('inhibitors', 'Var', (40, 50))	('HSP90', 'Gene', '3320', (34, 39))	('influenced', 'Reg', (58, 68))	('HSP90', 'Gene', (135, 140))	('HSP90', 'Gene', '3320', (135, 140))	('p53', 'Gene', (10, 13))
64156	29899847	HSP90 inhibitors augmented Ad vector-mediated EGFP gene expression which can be partly due to enhanced expression of Ad cellular receptors.	('Ad cellular receptors', 'Protein', (117, 138))	('augmented', 'PosReg', (17, 26))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('expression', 'MPA', (103, 113))	('Ad vector-mediated EGFP gene', 'Gene', (27, 55))	('expression', 'MPA', (56, 66))	('inhibitors', 'Var', (6, 16))	('enhanced', 'PosReg', (94, 102))
64159	29899847	HSP90 inhibitors rather induced up-regulated HSP70 expression since decrease chaperon functions by the inhibitors were compensated by augmented HSP70.	('HSP70', 'Gene', (144, 149))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('decrease', 'NegReg', (68, 76))	('HSP70', 'Gene', (45, 50))	('up-regulated', 'PosReg', (32, 44))	('inhibitors', 'Var', (103, 113))	('inhibitors', 'Var', (6, 16))	('expression', 'MPA', (51, 61))	('chaperon functions', 'MPA', (77, 95))	('HSP70', 'Gene', '3308', (144, 149))	('HSP70', 'Gene', '3308', (45, 50))	('augmented', 'PosReg', (134, 143))
64172	29899847	Mutated p53 can bind to wild-type p53 to form the hetero-tetrameric structure, which were generated in JMN-1B cells infected with Ad-p53.	('p53', 'Gene', (34, 37))	('form', 'Reg', (41, 45))	('p53', 'Gene', '7157', (34, 37))	('hetero-tetrameric structure', 'MPA', (50, 77))	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (133, 136))	('Ad-p', 'Gene', (130, 134))	('p53', 'Gene', '7157', (8, 11))	('Ad-p', 'Gene', '23038', (130, 134))	('bind', 'Interaction', (16, 20))	('JMN-1B', 'CellLine', 'CVCL:M006', (103, 109))	('p53', 'Gene', (133, 136))	('Mutated', 'Var', (0, 7))
64182	29899847	In contrast, EHMES-1 (R273S) and JMN-1B (G245S) cells had mutated p53.	('JMN-1B', 'CellLine', 'CVCL:M006', (33, 39))	('p53', 'Gene', '7157', (66, 69))	('R273S', 'Mutation', 'rs121913343', (22, 27))	('R273S', 'Var', (22, 27))	('G245S', 'Mutation', 'rs28934575', (41, 46))	('mutated', 'Var', (58, 65))	('p53', 'Gene', (66, 69))
64183	29899847	All the p53 wild-type mesothelioma cells have deficient expressions of p14ARF and p16INK4A resulting from either loss of the transcription or deletion of the genomic DNA.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('mesothelioma', 'Disease', (22, 34))	('p53', 'Gene', (8, 11))	('mesothelioma', 'Disease', 'MESH:D008654', (22, 34))	('p16INK4A', 'Gene', (82, 90))	('p53', 'Gene', '7157', (8, 11))	('p14ARF', 'Gene', '1029', (71, 77))	('loss', 'NegReg', (113, 117))	('transcription', 'MPA', (125, 138))	('expressions', 'MPA', (56, 67))	('p16INK4A', 'Gene', '1029', (82, 90))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('deletion', 'Var', (142, 150))	('deficient', 'NegReg', (46, 55))	('p14ARF', 'Gene', (71, 77))
64184	29899847	Met-5A cells, bearing the p14ARF, p16INK4A and wild-type p53 genes, expressed SV40 T antigen and consequently p53 functions were inactivated.	('p14ARF', 'Gene', (26, 32))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (110, 113))	('SV40 T', 'Var', (78, 84))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('78', '92'))	('p53', 'Gene', '7157', (110, 113))	('functions', 'MPA', (114, 123))	('p16INK4A', 'Gene', (34, 42))	('p14ARF', 'Gene', '1029', (26, 32))	('p53', 'Gene', (57, 60))	('p16INK4A', 'Gene', '1029', (34, 42))	('inactivated', 'NegReg', (129, 140))
64192	29899847	Cell lysate was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to a nitrocellulose membrane, and reacted with Ab against p53 (Ab-6, DO-1, Thermo Fisher, Cheshire, UK), phosphorylated p53 at Ser15 (#9284) or at Ser46 (#2521), caspase-8 (#9746), caspase-9 (#9502), poly (ADP-ribose) polymerase (PARP) (which also detects cleaved PARP) (#9542), LC3A/B (#4108), Beclin-1 (#3495), Atg5 (#2630), HSP90 (#4874), HSP70 (#4872), phosphorylated p70S6 kinase at Thr389 (#9205), IkappaBalpha (#9242), AKT (#9272), phosphorylated AKT at Ser 473 (#9271), p21 (#2947) (Cell Signaling, Danvers, MA, USA), MDM2 (sc-965, Santa Cruz Biotechnology, Santa Cruz, CA, USA), ubiquitin (ab7780, Abcam, Cambridge, MA, USA), MDM4 (A300-287A, Bethy Laboratories, Montogomery, TX, USA), actin (#4970) (Cell Signaling) and tubulin-alpha (MS-581-P1, Thermo Fisher) as a control.	('poly (ADP-ribose) polymerase', 'Gene', (300, 328))	('AKT', 'Gene', (554, 557))	('PARP', 'Gene', (330, 334))	('#4970', 'Var', (802, 807))	('PARP', 'Gene', (364, 368))	('Beclin-1', 'Gene', (395, 403))	('PARP', 'Gene', '142', (364, 368))	('caspase-8', 'Gene', '841', (262, 271))	('Ser', 'Chemical', 'MESH:D012694', (561, 564))	('Signaling', 'biological_process', 'GO:0023052', ('596', '605'))	('p53', 'Gene', '7157', (158, 161))	('Ser', 'cellular_component', 'GO:0005790', ('561', '564'))	('caspase-9', 'Gene', '842', (281, 290))	('Ab-6', 'Gene', '100132406', (163, 167))	('HSP70', 'Gene', '3308', (442, 447))	('Ab-6', 'Gene', (163, 167))	('Ser', 'Chemical', 'MESH:D012694', (227, 230))	('p21', 'Gene', (578, 581))	('p21', 'Gene', '644914', (578, 581))	('p53', 'Gene', (158, 161))	('MS', 'Disease', 'MESH:D009103', (845, 847))	('IkappaBalpha', 'Gene', (504, 516))	('AKT', 'Gene', '207', (554, 557))	('ubiquitin', 'molecular_function', 'GO:0031386', ('688', '697'))	('Ser', 'cellular_component', 'GO:0005790', ('227', '230'))	('MDM4', 'Gene', '4194', (735, 739))	('p53', 'Gene', '7157', (220, 223))	('Ser', 'Chemical', 'MESH:D012694', (247, 250))	('HSP90', 'Gene', (427, 432))	('caspase-8', 'Gene', (262, 271))	('membrane', 'cellular_component', 'GO:0016020', ('120', '128'))	('AKT', 'Gene', (526, 529))	('Atg5', 'Gene', '9474', (413, 417))	('IkappaBalpha', 'Gene', '4792', (504, 516))	('MDM4', 'Gene', (735, 739))	('caspase-9', 'Gene', (281, 290))	('Atg5', 'Gene', (413, 417))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (29, 51))	('MDM2', 'Gene', (626, 630))	('p53', 'Gene', (220, 223))	('HSP90', 'Gene', '3320', (427, 432))	('Signaling', 'biological_process', 'GO:0023052', ('815', '824'))	('Ser', 'cellular_component', 'GO:0005790', ('247', '250'))	('Beclin-1', 'Gene', '8678', (395, 403))	('HSP70', 'Gene', (442, 447))	('poly (ADP-ribose) polymerase', 'Gene', '142', (300, 328))	('AKT', 'Gene', '207', (526, 529))	('MDM2', 'Gene', '4193', (626, 630))	('PARP', 'Gene', '142', (330, 334))
64314	26281863	In six cases, there was positive labelling of dysplastic/malignant squamous epithelium for TTF-1 with the SP141 MAb (figures 1 and 2; table 1), whereas all of the cases were negative with the 8G7G3 MAb.	('labelling', 'MPA', (33, 42))	('SP141', 'Chemical', 'MESH:C000593082', (106, 111))	('positive', 'Reg', (24, 32))	('SP141', 'Var', (106, 111))	('TTF-1', 'Gene', (91, 96))	('dysplastic', 'Disease', (46, 56))	('dysplastic', 'Disease', 'MESH:D004416', (46, 56))
64316	26281863	Two of the 12 cases showed positive labelling of nuclei with the 8G7G3/1 MAb, whereas 4/12 cases labelled with the SP141 MAb (table 1, where these results relate only to labelling of sarcomatoid tissue).	('sarcomatoid', 'Disease', (183, 194))	('labelling', 'MPA', (36, 45))	('8G7G3/1', 'Var', (65, 72))	('SP141', 'Chemical', 'MESH:C000593082', (115, 120))	('sarcomatoid tissue', 'Phenotype', 'HP:0100242', (183, 201))	('sarcomatoid', 'Disease', 'MESH:C538614', (183, 194))
64320	26281863	In mice, genetic ablation of the NKX2 gene on chromosome 14q13:which encodes TTF-1 protein :results in agenesis of the thyroid gland and lung hypoplasia, as well as forebrain defects.	('lung hypoplasia', 'Phenotype', 'HP:0002089', (137, 152))	('agenesis of the thyroid gland', 'CPA', (103, 132))	('forebrain defects', 'Disease', 'MESH:C566067', (165, 182))	('results in', 'Reg', (92, 102))	('mice', 'Species', '10090', (3, 7))	('NKX2', 'Gene', (33, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('lung hypoplasia', 'Disease', (137, 152))	('lung hypoplasia', 'Disease', 'MESH:D008171', (137, 152))	('agenesis of the thyroid', 'Phenotype', 'HP:0008191', (103, 126))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('forebrain defects', 'Disease', (165, 182))	('genetic ablation', 'Var', (9, 25))
64336	26281863	Current approaches to the differential diagnosis of poorly differentiated non-small cell carcinoma (for the distinction between SCC vs adenocarcinoma) in limited bronchopulmonary biopsy samples (or cytology specimens) include restricted use of antibodies for this assessment, to optimise the amount of tissue remaining for molecular studies (eg, for epidermal growth factor receptor (EGFR) receptor mutation or naplastic lymphoma kinase (ALK) mutation status).	('epidermal growth factor receptor', 'Gene', (350, 382))	('cell carcinoma', 'Disease', 'MESH:C538614', (84, 98))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('naplastic lymphoma', 'Disease', (411, 429))	('lymphoma', 'Phenotype', 'HP:0002665', (421, 429))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('EGFR', 'Gene', (384, 388))	('EGFR', 'Gene', '13649', (384, 388))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (78, 98))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('350', '373'))	('naplastic lymphoma', 'Disease', 'MESH:D008223', (411, 429))	('mutation', 'Var', (399, 407))	('epidermal growth factor receptor', 'Gene', '13649', (350, 382))	('EGFR', 'molecular_function', 'GO:0005006', ('384', '388'))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cell carcinoma', 'Disease', (84, 98))	('ALK', 'Gene', (438, 441))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (74, 98))	('mutation', 'Var', (443, 451))	('adenocarcinoma', 'Disease', (135, 149))	('ALK', 'Gene', '11682', (438, 441))
64391	23563849	Binding to plasminogen active sites, lysine blocks plasminogen activation into plasmin by tissue plasminogen activator (t-PA).	('tissue plasminogen activator (t-PA', 'Gene', '5327', (90, 124))	('t-PA', 'molecular_function', 'GO:0008243', ('120', '124'))	('blocks', 'NegReg', (44, 50))	('plasmin', 'Gene', '5340', (11, 18))	('plasmin', 'Gene', '5340', (51, 58))	('plasmin', 'Gene', '5340', (79, 86))	('plasminogen activation', 'biological_process', 'GO:0031639', ('51', '73'))	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('plasmin', 'Gene', '5340', (97, 104))	('plasmin', 'Gene', (51, 58))	('lysine', 'Var', (37, 43))	('plasmin', 'Gene', (11, 18))	('plasmin', 'Gene', (79, 86))	('plasmin', 'Gene', (97, 104))
64436	23563849	Overexpression of u-PA in lung cancer has been correlated with cancer progression, metastasis and poor prognosis.	('u-PA', 'Gene', '5328', (18, 22))	('metastasis', 'CPA', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('u-PA', 'Gene', (18, 22))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('Overexpression', 'Var', (0, 14))	('u-PA', 'molecular_function', 'GO:0008243', ('18', '22'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (31, 37))	('lung cancer', 'Disease', (26, 37))	('cancer', 'Disease', (63, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
64455	23563849	In addition, lysine contributes to ECM stability as a natural inhibitor of plasmin-induced proteolysis.	('plasmin', 'Gene', (75, 82))	('lysine', 'Var', (13, 19))	('plasmin', 'Gene', '5340', (75, 82))	('proteolysis', 'biological_process', 'GO:0006508', ('91', '102'))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))
64470	21610146	CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T cell killing ability.	('transduction', 'Var', (6, 18))	('increased', 'PosReg', (56, 65))	('transmigration', 'CPA', (66, 80))	('CCR', 'molecular_function', 'GO:0043880', ('0', '3'))	('calcium', 'Chemical', 'MESH:D002118', (39, 46))	('in vitro T cell killing ability', 'CPA', (109, 140))	('augmentation', 'PosReg', (93, 105))	('transduction', 'biological_process', 'GO:0009293', ('6', '18'))	('CCR2b', 'Gene', (0, 5))	('CCL', 'molecular_function', 'GO:0044101', ('26', '29'))	('cell killing', 'biological_process', 'GO:0001906', ('120', '132'))	('CCL2-induced calcium flux', 'MPA', (26, 51))
64478	21610146	One reason for this may be that the immunosuppressive environment of many tumors induces tolerance by the deletion or functional inactivation of TIL T cell receptors (TCRs).	('TCR', 'Gene', '6962', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tolerance', 'CPA', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('deletion', 'Var', (106, 114))	('TCR', 'Gene', (167, 170))	('induces', 'PosReg', (81, 88))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
64485	21610146	Our group has focused on introducing CARs using lentiviral vectors and has initiated a clinical trial using this technology.	('CAR', 'Gene', '9970', (37, 40))	('lentiviral', 'Var', (48, 58))	('CAR', 'Gene', (37, 40))
64549	21610146	Whereas CCL2 only increased the migration rate of mesoCAR T cells by 0.7 +- 2.7% compared to media alone, CCL2 induced a 45 +- 4.4% increase in migration of mesoCAR + CCR2b T cells compared to media alone (p<0.001), indicating a robust functional enhancement of the CCR2b modified T cells.	('CAR', 'Gene', '9970', (54, 57))	('CCL2', 'Var', (106, 110))	('increase', 'PosReg', (132, 140))	('CAR', 'Gene', (161, 164))	('CCR', 'molecular_function', 'GO:0043880', ('266', '269'))	('CCL', 'molecular_function', 'GO:0044101', ('8', '11'))	('CAR', 'Gene', '9970', (161, 164))	('CCR', 'molecular_function', 'GO:0043880', ('167', '170'))	('enhancement', 'PosReg', (247, 258))	('migration', 'CPA', (32, 41))	('CCL', 'molecular_function', 'GO:0044101', ('106', '109'))	('migration', 'CPA', (144, 153))	('CAR', 'Gene', (54, 57))
64550	21610146	We next explored the susceptibility of M108 to mesoCAR and mesoCAR + CCR2b T cell-mediated lysis using in vitro killing assays.	('M108', 'Var', (39, 43))	('CAR', 'Gene', (63, 66))	('CAR', 'Gene', '9970', (63, 66))	('CAR', 'Gene', (51, 54))	('CCR', 'molecular_function', 'GO:0043880', ('69', '72'))	('CAR', 'Gene', '9970', (51, 54))	('lysis', 'biological_process', 'GO:0019835', ('91', '96'))
64571	21610146	Thus, the presence of CCR2b in the mesoCAR T cells significantly increased the number of intratumoral T cells and significantly enhanced anti-tumor efficacy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('increased', 'PosReg', (65, 74))	('CAR', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CCR', 'molecular_function', 'GO:0043880', ('22', '25'))	('CAR', 'Gene', '9970', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (94, 99))	('CCR2b', 'Gene', (22, 27))	('enhanced', 'PosReg', (128, 136))	('presence', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
64575	21610146	After transduction with CCR2b, T cell infiltration increased more than 12.5-fold, to represent ~5% of the tumor.	('transduction', 'Var', (6, 18))	('increased', 'PosReg', (51, 60))	('T cell infiltration', 'CPA', (31, 50))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('transduction', 'biological_process', 'GO:0009293', ('6', '18'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CCR', 'molecular_function', 'GO:0043880', ('24', '27'))	('CCR2b', 'Gene', (24, 29))	('tumor', 'Disease', (106, 111))
64600	21610146	In these studies, expression and function of the transduced CCRs were confirmed in vitro, followed by demonstration of increased in vivo migration and a resultant slowing in tumor growth.	('tumor', 'Disease', (174, 179))	('slowing', 'NegReg', (163, 170))	('transduced', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('CCRs', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('increased', 'PosReg', (119, 128))
64642	23364080	In the Mafefe villages, to the north of Penge, much lower asbestos concentrations were measured in the 1990s: 0.020 f/ml in school buildings, 0.012 f/ml along village pathways, and 0.016 f/ml during building and gardening activities.	('0.012 f/ml', 'Var', (142, 152))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('0.016 f/ml', 'Var', (181, 191))	('0.020 f/ml', 'Var', (110, 120))
64655	23364080	Fibrotic diseases are divided into those with mild to moderate lung function impairment (FEV1: 79-52% of predicted; FVC: 79-52% of predicted; FEV1/FVC: 75-55%) (ARD1) and those with severe lung function impairment (FEV1: <51%; FVC: <51%; FEV1/FVC: <55%) (ARD2).	('lung function impairment', 'Phenotype', 'HP:0005952', (189, 213))	('ARD1', 'Gene', (161, 165))	('ARD1', 'Gene', '8260', (161, 165))	('lung function impairment', 'Phenotype', 'HP:0005952', (63, 87))	('men', 'Species', '9606', (83, 86))	('ARD2', 'Gene', '84779', (255, 259))	('men', 'Species', '9606', (209, 212))	('Fibrotic diseases', 'Disease', (0, 17))	('Fibrotic diseases', 'Disease', 'MESH:D004194', (0, 17))	('ARD', 'molecular_function', 'GO:0010309', ('255', '258'))	('ARD1', 'molecular_function', 'GO:0010309', ('161', '165'))	('FEV1/FVC', 'Var', (142, 150))	('ARD2', 'Gene', (255, 259))
64690	23364080	In South Africa, crocidolite has been shown to be the most frequent cause of mesothelioma even after brief or slight exposures.	('mesothelioma', 'Disease', (77, 89))	('crocidolite', 'Chemical', 'MESH:D017638', (17, 28))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('cause', 'Reg', (68, 73))	('crocidolite', 'Var', (17, 28))
64795	21643459	Segawa et al reported that the major form of mesothelin in patients with mesothelioma is variant 1 and not the molecule (variant 3) with an 82 pb insert.	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('mesothelioma', 'Disease', (73, 85))	('patients', 'Species', '9606', (59, 67))	('variant 1', 'Var', (89, 98))
64822	21643459	Two Mabs, 2H5 and 3D8, which recognize the C-WFDC domain of HE4 (Fig.	('HE4', 'Gene', (60, 63))	('HE4', 'Gene', '10406', (60, 63))	('2H5', 'Chemical', '-', (10, 13))	('C-WFDC domain', 'Var', (43, 56))
64833	21643459	Moore et al obtained preoperative serum samples from 259 women undergoing surgery for an adnexal mass and analyzed them for CA125, mesothelin (using MESOMARK), HE4, CA72-4, activin, inhibin, osteopontin, EGFR and Her2.	('CA72-4', 'Var', (165, 171))	('activin', 'Gene', '83729', (173, 180))	('women', 'Species', '9606', (57, 62))	('Her2', 'Gene', '2064', (213, 217))	('CA125', 'Gene', (124, 129))	('EGFR', 'Gene', '1956', (204, 208))	('Her2', 'Gene', (213, 217))	('inhibin', 'Protein', (182, 189))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))	('HE4', 'Gene', '10406', (160, 163))	('activin', 'molecular_function', 'GO:0005160', ('173', '180'))	('CA125', 'Gene', '94025', (124, 129))	('inhibin', 'molecular_function', 'GO:0005160', ('182', '189'))	('activin', 'Gene', (173, 180))	('inhibin', 'molecular_function', 'GO:0016916', ('182', '189'))	('osteopontin', 'Gene', '6696', (191, 202))	('HE4', 'Gene', (160, 163))	('osteopontin', 'Gene', (191, 202))	('activin', 'molecular_function', 'GO:0016915', ('173', '180'))	('EGFR', 'Gene', (204, 208))
64855	21643459	As a single marker, HE4 had the highest sensitivity for detecting ovarian carcinoma (82.9%) including early disease (76.9%), and a combination of CA125 with HE4 was a better predictor of ovarian malignancy than either alone.	('CA125', 'Gene', (146, 151))	('ovarian malignancy', 'Disease', 'MESH:D010051', (187, 205))	('ovarian carcinoma', 'Disease', (66, 83))	('early disease', 'Disease', (102, 115))	('ovarian malignancy', 'Disease', (187, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HE4', 'Gene', '10406', (157, 160))	('CA125', 'Gene', '94025', (146, 151))	('combination', 'Var', (131, 142))	('HE4', 'Gene', (157, 160))	('HE4', 'Gene', '10406', (20, 23))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (66, 83))	('HE4', 'Gene', (20, 23))	('ovarian malignancy', 'Phenotype', 'HP:0100615', (187, 205))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (66, 83))
64889	21643459	For example, antibodies to HER-2/neu and p53 have been detected by capture ELISA in some patients with early stage breast cancer, and anti-MUC1 antibodies have been reported to be more frequent in healthy women with characteristics associated with a decreased risk for ovarian carcinoma.	('p53', 'Gene', '7157', (41, 44))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (269, 286))	('MUC1', 'Gene', (139, 143))	('detected', 'Reg', (55, 63))	('ovarian carcinoma', 'Disease', (269, 286))	('women', 'Species', '9606', (205, 210))	('antibodies', 'Var', (13, 23))	('MUC1', 'Gene', '4582', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('HER-2/neu', 'Gene', (27, 36))	('patients', 'Species', '9606', (89, 97))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HER-2/neu', 'Gene', '2064', (27, 36))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('p53', 'Gene', (41, 44))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (269, 286))
64893	21643459	Anti-mesothelin antibodies, determined as OD450 nm, was seen more frequently in ovarian cancer patients with advanced disease who were free of clinically detectable tumor after therapy (10 of 14) than in similar patients who had clinical evidence of disease (9 of 21) or in healthy women (6 of 23) or women with benign gynecologic diseases (5 of 24).	('ovarian cancer', 'Disease', (80, 94))	('patients', 'Species', '9606', (95, 103))	('women', 'Species', '9606', (301, 306))	('patients', 'Species', '9606', (212, 220))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Anti-mesothelin', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('women', 'Species', '9606', (282, 287))	('tumor', 'Disease', (165, 170))
64896	21643459	Subsequent studies, using recombinant mesothelin as antigen, have confirmed that anti-mesothelin antibodies in patients who have been treated for advanced ovarian carcinoma are most frequently seen when the patients are (temporarily) without clinical evidence of tumor than in patients with detectable disease.	('patients', 'Species', '9606', (207, 215))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (155, 172))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('ovarian carcinoma', 'Disease', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('seen', 'Reg', (193, 197))	('patients', 'Species', '9606', (277, 285))	('tumor', 'Disease', (263, 268))	('anti-mesothelin antibodies', 'Var', (81, 107))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (155, 172))	('antibodies', 'Var', (97, 107))	('patients', 'Species', '9606', (111, 119))
64899	21643459	There are several reasons why antibodies to mesothelin, HE4 and certain other tumor antigen can have an impact on the development and progression of ovarian cancer.	('HE4', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HE4', 'Gene', '10406', (56, 59))	('ovarian cancer', 'Disease', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('antibodies', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor antigen', 'molecular_function', 'GO:0008222', ('78', '91'))	('mesothelin', 'Protein', (44, 54))	('impact', 'Reg', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('tumor', 'Disease', (78, 83))	('have', 'Reg', (96, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))
64900	21643459	Anti-mesothelin antibodies can prevent binding of mesothelin to CA125 and thereby impact cellular adhesion, and antibodies can be cytotoxic in the presence of complement, mediate antibody-dependent cellular cytotoxicity in the presence of NK cells or macrophages.	('cellular adhesion', 'CPA', (89, 106))	('antibodies', 'Var', (16, 26))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('179', '219'))	('binding', 'molecular_function', 'GO:0005488', ('39', '46'))	('antibodies', 'Var', (112, 122))	('mediate', 'Reg', (171, 178))	('cytotoxicity', 'Disease', 'MESH:D064420', (207, 219))	('CA125', 'Gene', '94025', (64, 69))	('Anti-mesothelin', 'Protein', (0, 15))	('antibody', 'cellular_component', 'GO:0019815', ('179', '187'))	('impact', 'Reg', (82, 88))	('prevent', 'NegReg', (31, 38))	('antibody', 'molecular_function', 'GO:0003823', ('179', '187'))	('antibody', 'cellular_component', 'GO:0019814', ('179', '187'))	('CA125', 'Gene', (64, 69))	('binding', 'Interaction', (39, 46))	('cytotoxicity', 'Disease', (207, 219))	('antibody', 'cellular_component', 'GO:0042571', ('179', '187'))
64904	21643459	A recent collaborative study (Luborsky et al, manuscript in preparation) indicates that women with unexplained infertility more frequently than controls have antibodies also to mesothelin and HE4 and that the same subject often has antibodies to both those antigens.	('women', 'Species', '9606', (88, 93))	('antibodies', 'Var', (158, 168))	('unexplained infertility', 'Disease', 'MESH:D007247', (99, 122))	('infertility', 'Phenotype', 'HP:0000789', (111, 122))	('mesothelin', 'Protein', (177, 187))	('HE4', 'Gene', (192, 195))	('unexplained infertility', 'Disease', (99, 122))	('HE4', 'Gene', '10406', (192, 195))
64907	21643459	If women with antibodies to mesothelin, HE4 or other ovarian cancer antigens have a higher risk of developing ovarian cancer, they should be monitored accordingly.	('mesothelin', 'Protein', (28, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('ovarian cancer', 'Disease', (110, 124))	('ovarian cancer', 'Disease', (53, 67))	('HE4', 'Gene', '10406', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HE4', 'Gene', (40, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('women', 'Species', '9606', (3, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('antibodies', 'Var', (14, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))
64931	21643459	Antibodies to mesothelin and HE4 have been demonstrated in many patients and particularly in those who have been treated for ovarian carcinoma and are temporarily clinically tumor free.	('tumor', 'Disease', (174, 179))	('Antibodies', 'Var', (0, 10))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (125, 142))	('patients', 'Species', '9606', (64, 72))	('mesothelin', 'Protein', (14, 24))	('ovarian carcinoma', 'Disease', (125, 142))	('HE4', 'Gene', '10406', (29, 32))	('HE4', 'Gene', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('demonstrated', 'Reg', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (125, 142))
64933	21643459	Rather, we need to learn whether asymptomatic women who have the antibodies have an increased risk for ovarian cancer, as may be suggested by the finding that infertile women more frequently have antibodies to mesothelin and HE4 and that women with infertility have an increased risk of developing ovarian cancer.	('mesothelin', 'Protein', (210, 220))	('women', 'Species', '9606', (238, 243))	('HE4', 'Gene', '10406', (225, 228))	('ovarian cancer', 'Disease', 'MESH:D010051', (298, 312))	('women', 'Species', '9606', (169, 174))	('HE4', 'Gene', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('infertility', 'Disease', 'MESH:D007247', (249, 260))	('antibodies', 'Var', (196, 206))	('ovarian cancer', 'Disease', (298, 312))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('infertility', 'Phenotype', 'HP:0000789', (249, 260))	('ovarian cancer', 'Disease', (103, 117))	('infertility', 'Disease', (249, 260))	('ovarian cancer', 'Phenotype', 'HP:0100615', (298, 312))	('women', 'Species', '9606', (46, 51))
64936	21643459	Based on examination of ovaries and Fallopian tubes removed from healthy women with BRCA1/BRCA2 mutations, there is evidence that serous ovarian carcinoma needs to be detected when it is only about 4 mm in diameter to dramatically improve prognosis.	('improve', 'PosReg', (231, 238))	('BRCA2', 'Gene', (90, 95))	('serous ovarian carcinoma', 'Disease', (130, 154))	('ovaries', 'Disease', 'MESH:D010051', (24, 31))	('women', 'Species', '9606', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (130, 154))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA2', 'Gene', '675', (90, 95))	('ovaries', 'Disease', (24, 31))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (137, 154))	('BRCA1', 'Gene', (84, 89))	('mutations', 'Var', (96, 105))
64940	21643459	We also expect to learn within the next 5 years whether women who have antibodies to mesothelin, HE4, CA125 and/or other ovarian cancer antigens have an increased risk for ovarian carcinoma and should be monitored accordingly, and whether a combined testing for antigen and antibodies aids the monitoring of patients treated for ovarian cancer, including those receiving various forms of immunotherapy.	('ovarian carcinoma', 'Disease', (172, 189))	('ovarian cancer', 'Disease', 'MESH:D010051', (329, 343))	('patients', 'Species', '9606', (308, 316))	('mesothelin', 'Gene', (85, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (121, 135))	('women', 'Species', '9606', (56, 61))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CA125', 'Gene', '94025', (102, 107))	('ovarian cancer', 'Disease', (329, 343))	('ovarian cancer', 'Disease', (121, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (329, 343))	('antibodies', 'Var', (71, 81))	('HE4', 'Gene', '10406', (97, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('HE4', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('CA125', 'Gene', (102, 107))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (172, 189))
64956	32277165	Unlike mesothelioma cells harboring a mutation of negative regulators of YAP, the survival of multiple UM cell lines was not significantly reduced by YAP/TAZ depletion.	('YAP', 'Gene', '10413', (73, 76))	('survival', 'CPA', (82, 90))	('YAP', 'Gene', (73, 76))	('YAP', 'Gene', '10413', (150, 153))	('mesothelioma', 'Disease', (7, 19))	('depletion', 'Var', (158, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (7, 19))	('YAP', 'Gene', (150, 153))	('reduced', 'NegReg', (139, 146))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
64961	32277165	Most UM tumors harbor the GNAQ or GNA11 mutations; these mutants have been shown to activate oncogenic pathways, including the mitogen-activated protein kinase (MAPK) and Hippo-Yes-associated protein (YAP) pathways.	('YAP', 'Gene', '10413', (201, 204))	('GNAQ', 'Gene', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('mutations', 'Var', (40, 49))	('YAP', 'Gene', (201, 204))	('GNA11', 'Gene', (34, 39))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('oncogenic pathways', 'Pathway', (93, 111))	('activate', 'PosReg', (84, 92))	('GNA11', 'Gene', '2767', (34, 39))	('GNAQ', 'Gene', '2776', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('mitogen-activated protein kinase', 'Pathway', (127, 159))
64973	32277165	The mean RNA-seq by Expectation Maximization (RSEM)-normalized YAP mRNA levels were 1430.5 +- 362.4 and 2719.4 +- 700.8 for the low expression and high expression groups, respectively (P < 0.001).	('YAP', 'Gene', (63, 66))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('YAP', 'Gene', '10413', (63, 66))	('2719.4', 'Var', (104, 110))
64974	32277165	The mean Gene Set Variant Analysis (GSVA) scores for the YAP signature were 0.162 +- 0.115 and 0.168 +- 0.124 in the low YAP signature and high YAP signature groups, respectively (P < 0.001; Fig.	('GSVA', 'Chemical', '-', (36, 40))	('YAP', 'Gene', (144, 147))	('YAP', 'Gene', (121, 124))	('0.168', 'Var', (95, 100))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (57, 60))	('YAP', 'Gene', '10413', (144, 147))	('YAP', 'Gene', '10413', (121, 124))
64975	32277165	When compared with the YAP-downregulated group, the YAP signature gene sets were significantly upregulated in the high YAP signature group (normalized enrichment score: 2.30; P < 0.001; Fig.	('upregulated', 'PosReg', (95, 106))	('high', 'Var', (114, 118))	('YAP', 'Gene', '10413', (23, 26))	('YAP', 'Gene', '10413', (119, 122))	('YAP', 'Gene', (52, 55))	('YAP', 'Gene', (23, 26))	('YAP', 'Gene', (119, 122))	('YAP', 'Gene', '10413', (52, 55))
64989	32277165	UM-specific survival also did not differ between the low YAP signature and high YAP signature groups (HR: 1.272; 95% CI: 0.523-3.093; P = 0.62; Fig.	('YAP', 'Gene', '10413', (80, 83))	('low', 'Var', (53, 56))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (80, 83))	('YAP', 'Gene', (57, 60))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
64996	32277165	The siRNA-mediated knockdown of YAP and its paralog, TAZ, significantly suppressed expression of YAP mRNA (Supplementary Fig.	('YAP', 'Gene', '10413', (97, 100))	('YAP', 'Gene', '10413', (32, 35))	('knockdown', 'Var', (19, 28))	('YAP', 'Gene', (97, 100))	('YAP', 'Gene', (32, 35))	('suppressed', 'NegReg', (72, 82))	('expression', 'MPA', (83, 93))
64999	32277165	YAP/TAZ knockdown exhibited smaller effects on survival in multiple UM cell lines (92.1, MP41, MP46, and MP65).	('YAP', 'Gene', (0, 3))	('MP41', 'Var', (89, 93))	('MP46', 'Var', (95, 99))	('MP65', 'Var', (105, 109))	('YAP', 'Gene', '10413', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (68, 70))
65003	32277165	Remarkably, GNAQ and GNA11 are mutated in most UM tumors (~93%) with hotspot mutations (Q209P/L).	('GNAQ', 'Gene', (12, 16))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('Q209P', 'Var', (88, 93))	('GNA11', 'Gene', '2767', (21, 26))	('Q209P', 'SUBSTITUTION', 'None', (88, 93))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))
65004	32277165	Recent studies have highlighted the roles of GNAQ and GNA11 mutations in UM development.	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('GNA11', 'Gene', (54, 59))	('GNA11', 'Gene', '2767', (54, 59))	('GNAQ', 'Gene', (45, 49))	('UM development', 'CPA', (73, 87))	('mutations', 'Var', (60, 69))	('GNAQ', 'Gene', '2776', (45, 49))
65005	32277165	GNAQ and GNA11 mutations result in constitutive activation of oncogenic Gq/G11 subunits, leading to UM tumorigenesis by sequential activation of YAP.	('GNA11', 'Gene', (9, 14))	('activation', 'PosReg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('GNAQ', 'Gene', '2776', (0, 4))	('YAP', 'Gene', (145, 148))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (103, 108))	('GNAQ', 'Gene', (0, 4))	('Gq/G11', 'Protein', (72, 78))	('activation', 'PosReg', (48, 58))	('leading to', 'Reg', (89, 99))	('YAP', 'Gene', '10413', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('GNA11', 'Gene', '2767', (9, 14))
65023	32277165	To confirm this possibility, we investigated whether siRNA-mediated YAP knockdown affected the survival of UM cell lines.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('affected', 'Reg', (82, 90))	('YAP', 'Gene', '10413', (68, 71))	('YAP', 'Gene', (68, 71))	('knockdown', 'Var', (72, 81))
65024	32277165	YAP knockdown slightly reduced the survival of 92.1, MP41, MP46, and MP65 UM cell lines.	('YAP', 'Gene', (0, 3))	('survival', 'CPA', (35, 43))	('MP46', 'Var', (59, 63))	('YAP', 'Gene', '10413', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('MP65', 'Var', (69, 73))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (4, 13))	('MP41', 'Var', (53, 57))
65025	32277165	However, these effects were much smaller than the effects observed for the two mesothelioma cell types, MSTO-211H (LATS2 mutation) and H2373 (NF2 mutation), which harbor mutations in negative regulators of YAP.	('YAP', 'Gene', (206, 209))	('mesothelioma', 'Disease', (79, 91))	('mutations', 'Var', (170, 179))	('NF2', 'Gene', (142, 145))	('H2373', 'CellLine', 'CVCL:A533', (135, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('NF2', 'Gene', '4771', (142, 145))	('YAP', 'Gene', '10413', (206, 209))	('LATS2', 'Gene', (115, 120))	('LATS2', 'Gene', '26524', (115, 120))
65026	32277165	In the TCGA mesothelioma cohort, 35 (42%) of 83 patients had mutations in MST1/2, LAST1/2, or NF (negative upstream regulators of YAP).	('YAP', 'Gene', (130, 133))	('LAST1/2', 'Gene', (82, 89))	('MST1/2', 'Gene', (74, 80))	('mutations', 'Var', (61, 70))	('YAP', 'Gene', '10413', (130, 133))	('mesothelioma', 'Disease', (12, 24))	('patients', 'Species', '9606', (48, 56))	('MST1/2', 'Gene', '4485;6788', (74, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))
65027	32277165	In another analysis, a high YAP signature was associated with poor prognoses in the TCGA mesothelioma cohort (HR: 2.675; 95% CI: 1.63-4.389; P < 0.001).	('mesothelioma', 'Disease', (89, 101))	('high', 'Var', (23, 27))	('YAP', 'Gene', (28, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('YAP', 'Gene', '10413', (28, 31))
65030	32277165	It has been shown that YAP is important for acquisition of resistance to targeted therapy in tumors with KRAS and BRAF mutations, and that YAP can induce immune evasion by increasing the expression of PD-L1.	('PD-L1', 'Gene', (201, 206))	('induce', 'Reg', (147, 153))	('BRAF', 'Gene', (114, 118))	('immune evasion', 'MPA', (154, 168))	('YAP', 'Gene', '10413', (139, 142))	('BRAF', 'Gene', '673', (114, 118))	('PD-L1', 'Gene', '29126', (201, 206))	('KRAS', 'Gene', '3845', (105, 109))	('YAP', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('KRAS', 'Gene', (105, 109))	('increasing', 'PosReg', (172, 182))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (119, 128))	('immune evasion', 'biological_process', 'GO:0042783', ('154', '168'))	('YAP', 'Gene', '10413', (23, 26))	('immune evasion', 'biological_process', 'GO:0051842', ('154', '168'))	('YAP', 'Gene', (139, 142))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('expression', 'MPA', (187, 197))
65031	32277165	YAP activation by the GNAQ and GNA11 mutations may explain the failure of MEK1/2 inhibitors or immunotherapy in patients with UM.	('YAP', 'Gene', (0, 3))	('GNAQ', 'Gene', (22, 26))	('MEK1', 'molecular_function', 'GO:0004708', ('74', '78'))	('patients', 'Species', '9606', (112, 120))	('mutations', 'Var', (37, 46))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('YAP', 'Gene', '10413', (0, 3))	('MEK1/2', 'Gene', '5604;5605', (74, 80))	('GNAQ', 'Gene', '2776', (22, 26))	('MEK1/2', 'Gene', (74, 80))	('GNA11', 'Gene', (31, 36))	('activation', 'PosReg', (4, 14))	('GNA11', 'Gene', '2767', (31, 36))
65043	32277165	The normalized count data calculated by expectation maximization analysis were incorporated as a matrix in R. The enrichment score was then calculated by GSVA for each tumor sample in the matrix data using the following arguments: kcdf = "Poisson", min.sz = 5, max_sz = 500, mx.diff = TRUE.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('GSVA', 'Chemical', '-', (154, 158))	('kcdf = "Poisson', 'Var', (231, 246))	('max_sz = 500', 'Var', (261, 273))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
65044	32277165	GSEA was performed using the C6 MSigDB gene set database to test whether the YAP signature was enriched in the high YAP signature group, compared with the low YAP signature group.	('YAP', 'Gene', (116, 119))	('YAP', 'Gene', (159, 162))	('YAP', 'Gene', '10413', (77, 80))	('YAP', 'Gene', '10413', (116, 119))	('YAP', 'Gene', (77, 80))	('YAP', 'Gene', '10413', (159, 162))	('GSEA', 'Chemical', '-', (0, 4))	('high', 'Var', (111, 115))
65055	32277165	UM cells (MP41 MP46, and MP65) and RPE1 cells were acquired from the American Type Culture Collection (ATCC, Manassas, VA, USA).	('MP65', 'Var', (25, 29))	('MP41 MP46', 'Var', (10, 19))	('RPE1', 'CellLine', 'CVCL:4388', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
65062	32277165	performed the cell viability tests using multiple cancer cells; Y.J.K., S.C.L., S.K.K.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Y.J.K.', 'Var', (64, 70))	('S.C.L.', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
65295	28979837	Furthermore, we investigated the influence of the overexpression of miR-30d in pleural MM cells.	('pleural MM', 'Disease', 'MESH:D010995', (79, 89))	('miR-30d', 'Var', (68, 75))	('pleural MM', 'Disease', (79, 89))
65298	28979837	We therefore conclude that miR-30d is related to asbestos exposure and inhibits cell migration and invasion by regulating the epithelial-mesenchymal transition in NCI-H2452 cells.	('miR-30d', 'Var', (27, 34))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('epithelial-mesenchymal transition', 'CPA', (126, 159))	('NCI-H2452 cells', 'CellLine', 'CVCL:1553', (163, 178))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('126', '159'))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))	('regulating', 'Reg', (111, 121))	('inhibits', 'NegReg', (71, 79))
65310	28979837	However, more data on the role of dysregulated miRNA that are involved in the carcinogenesis of asbestos exposure with pleural MM are highly warranted.	('dysregulated', 'Var', (34, 46))	('carcinogenesis of asbestos', 'Disease', 'MESH:D063646', (78, 104))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('nt', 'Chemical', '-', (146, 148))	('carcinogenesis of asbestos', 'Disease', (78, 104))	('pleural MM', 'Disease', 'MESH:D010995', (119, 129))	('pleural MM', 'Disease', (119, 129))
65352	28979837	Cell cycle profiles were analyzed by flow cytometry after transfection with miR-30d mimics and NC for 48 h. Cell apoptosis was detected by flow cytometry coupled with the FITC-Annexin V Apoptosis Detection Kit (BD Biosciences Pharmingen, San Diego, CA, USA) after transfection with miR-30d mimics and NC for 72 h following the manufacturer's instructions.	('miR-30d', 'Var', (282, 289))	('Annexin V', 'Gene', '308', (176, 185))	('FITC', 'Chemical', 'MESH:D016650', (171, 175))	('Annexin V', 'Gene', (176, 185))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
65369	28979837	The relative expression level of miR-30d in pleural MM cells was 0.671 compared to MeT-5A cells (Fig.	('miR-30d', 'Var', (33, 40))	('expression', 'MPA', (13, 23))	('pleural MM', 'Disease', (44, 54))	('pleural MM', 'Disease', 'MESH:D010995', (44, 54))
65377	28979837	To better understand the mechanistic role of miR-30d in mesothelial progression, the pleural MM cell line NCI-H2452 was transfected with either miR-30d mimics or a nontargeting mimic control.	('nt', 'Chemical', '-', (185, 187))	('miR-30d', 'Gene', (144, 151))	('nt', 'Chemical', '-', (166, 168))	('pleural MM', 'Disease', 'MESH:D010995', (85, 95))	('NCI-H2452', 'CellLine', 'CVCL:1553', (106, 115))	('pleural MM', 'Disease', (85, 95))	('mimics', 'Var', (152, 158))
65383	28979837	After the upregulation of miR-30d, there was no significant difference in the percentage of NCI-H2452 cells that were in G1/S/G2 (Fig.	('S/G2', 'Var', (124, 128))	('S/G2', 'SUBSTITUTION', 'None', (124, 128))	('nt', 'Chemical', '-', (83, 85))	('nt', 'Chemical', '-', (57, 59))	('miR-30d', 'Var', (26, 33))	('NCI-H2452 cells', 'CellLine', 'CVCL:1553', (92, 107))	('upregulation', 'PosReg', (10, 22))
65387	28979837	Immunofluorescent staining results showed that mimics miR-30d led to a low expression of VIM and TWIST1 (Fig.	('low', 'NegReg', (71, 74))	('VIM', 'Gene', '7431', (89, 92))	('TWIST1', 'Gene', (97, 103))	('TWIST1', 'Gene', '7291', (97, 103))	('VIM', 'Gene', (89, 92))	('miR-30d', 'Var', (54, 61))	('nt', 'Chemical', '-', (15, 17))	('mimics miR-30d', 'Var', (47, 61))	('expression', 'MPA', (75, 85))
65389	28979837	VIM expression was found in the cytoplasm of NCI-H2452, while TWIST1 was expressed in the cytoplasm and nuclei.	('NCI-H2452', 'CellLine', 'CVCL:1553', (45, 54))	('cytoplasm', 'cellular_component', 'GO:0005737', ('32', '41'))	('TWIST1', 'Gene', (62, 68))	('TWIST1', 'Gene', '7291', (62, 68))	('VIM', 'Gene', '7431', (0, 3))	('NCI-H2452', 'Var', (45, 54))	('cytoplasm', 'cellular_component', 'GO:0005737', ('90', '99'))	('VIM', 'Gene', (0, 3))
65396	28979837	In this study, we found that miR-30d was downregulated in pleural MM cells, in line with previous studies that reported decreased miR-31 expression in mesothelioma cells 20, overexpressed 193-3p in pleural MM 21, and dysregulated miR-17-5p, miR-21, miR-29a, miR-30c, miR-30e-5p, miR-106a, and miR-143 in different histopathological subtypes.	('miR-31', 'Gene', '407035', (130, 136))	('downregulated', 'NegReg', (41, 54))	('miR-30c', 'Gene', (258, 265))	('nt', 'Chemical', '-', (311, 313))	('miR-30e', 'Gene', (267, 274))	('miR-21', 'Gene', '406991', (241, 247))	('miR-29a', 'Gene', (249, 256))	('miR-29a', 'Gene', '407021', (249, 256))	('decreased', 'NegReg', (120, 129))	('expression', 'MPA', (137, 147))	('pleural MM', 'Disease', 'MESH:D010995', (198, 208))	('miR-30e', 'Gene', '407034', (267, 274))	('miR-106a', 'Gene', (279, 287))	('miR-17-5p', 'Gene', '406952', (230, 239))	('pleural MM', 'Disease', (58, 68))	('dysregulated', 'Var', (217, 229))	('mesothelioma', 'Disease', (151, 163))	('miR-17-5p', 'Gene', (230, 239))	('miR-21', 'Gene', (241, 247))	('mesothelioma', 'Disease', 'MESH:D008654', (151, 163))	('miR-31', 'Gene', (130, 136))	('miR-143', 'Gene', '406935', (293, 300))	('miR-30c', 'Gene', '407031', (258, 265))	('miR-143', 'Gene', (293, 300))	('overexpressed', 'PosReg', (174, 187))	('miR-106a', 'Gene', '406899', (279, 287))	('pleural MM', 'Disease', (198, 208))	('miR-30d', 'Gene', (29, 36))	('pleural MM', 'Disease', 'MESH:D010995', (58, 68))
65400	28979837	The cumulative experimental data indicate that similar effects are caused by a variety of environmental carcinogens, including polycyclic aromatic hydrocarbons, nitropyrenes, endocrine disruptors, airborne mixtures, carcinogens in food and water, and carcinogenic drugs 28, 29.	('polycyclic', 'Var', (127, 137))	('carcinogenic', 'Disease', 'MESH:D063646', (251, 263))	('carcinogenic', 'Disease', (251, 263))	('nitropyrenes', 'Chemical', '-', (161, 173))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (127, 159))	('water', 'Chemical', 'MESH:D014867', (240, 245))	('nt', 'Chemical', '-', (99, 101))	('caused', 'Reg', (67, 73))	('nt', 'Chemical', '-', (23, 25))
65409	28979837	The downregulated expression of miR-30d in MeT-5A cells induced by acute and chronical asbestos exposure and in pleural MM cells indicated that miR-30d was involved in asbestos exposure and might be associated with asbestos carcinogenesis.	('miR-30d', 'Var', (144, 151))	('associated', 'Reg', (199, 209))	('asbestos', 'Chemical', 'MESH:D001194', (168, 176))	('downregulated', 'NegReg', (4, 17))	('asbestos', 'Chemical', 'MESH:D001194', (87, 95))	('pleural MM', 'Disease', 'MESH:D010995', (112, 122))	('miR-30d', 'Gene', (32, 39))	('asbestos', 'Chemical', 'MESH:D001194', (215, 223))	('expression', 'MPA', (18, 28))	('involved', 'Reg', (156, 164))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (215, 238))	('pleural MM', 'Disease', (112, 122))	('asbestos carcinogenesis', 'Disease', (215, 238))
65413	28979837	miR-30d could induce G1/S cell cycle arrest in NSCLC 31 but did not influence cell cycle in pleural MM cells in our study.	('G1/S cell cycle arrest', 'CPA', (21, 43))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('26', '43'))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('pleural MM', 'Disease', 'MESH:D010995', (92, 102))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('induce', 'Reg', (14, 20))	('NSCLC', 'Disease', (47, 52))	('pleural MM', 'Disease', (92, 102))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('miR-30d', 'Var', (0, 7))
65415	28979837	Taken together, miR-30d significantly reduced cell proliferation, migration, and invasion in vitro, which indicated that miR-30d might have a tumor suppressor function.	('invasion in vitro', 'CPA', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('142', '158'))	('migration', 'CPA', (66, 75))	('reduced', 'NegReg', (38, 45))	('nt', 'Chemical', '-', (33, 35))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('miR-30d', 'Var', (121, 128))	('miR-30d', 'Var', (16, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('142', '158'))	('cell proliferation', 'CPA', (46, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
65423	28979837	miR-30d reversed EMT gene expression, probably by targeting EMT-related genes such as VIM, which has been identified as a target gene of miR-30d by the target predicted databases, TargetScan (Fig.	('VIM', 'Gene', (86, 89))	('EMT', 'biological_process', 'GO:0001837', ('17', '20'))	('EMT gene expression', 'Gene', (17, 36))	('reversed', 'PosReg', (8, 16))	('VIM', 'Gene', '7431', (86, 89))	('EMT-related genes', 'Gene', (60, 77))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('nt', 'Chemical', '-', (109, 111))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('miR-30d', 'Var', (137, 144))	('miR-30d', 'Var', (0, 7))
65445	27445546	Further, BAP1 germline mutations have recently been found to be associated with mesothelioma.	('associated', 'Reg', (64, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('BAP1', 'Gene', '8314', (9, 13))	('mesothelioma', 'Disease', (80, 92))	('BAP1', 'Gene', (9, 13))	('germline mutations', 'Var', (14, 32))
65474	27445546	In animal experimental studies, using a very specific panel of different length classes, otherwise identical in composition, diameter, and solubility, a clear threshold effect was found demonstrating that fibers 5 microns and greater were pathogenic to the pleura while shorter fibers were not.	('pleura', 'Disease', (257, 263))	('men', 'Species', '9606', (16, 19))	('pathogenic', 'Reg', (239, 249))	('pleura', 'Disease', 'MESH:D054363', (257, 263))	('fibers', 'Var', (205, 211))
65560	25814815	The lung biopsies for alanine lymphoma kinase (ALK) by the fluorescence in situ hybridization (FISH) method, and the epidermal growth factor receptor (EGFR) mutation by polymerase chain reaction (PCR) were negative.	('alanine lymphoma', 'Disease', (22, 38))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('117', '140'))	('EGFR', 'Gene', (151, 155))	('ALK', 'Gene', (47, 50))	('alanine lymphoma', 'Disease', 'MESH:C536414', (22, 38))	('mutation', 'Var', (157, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (30, 38))	('ALK', 'Gene', '238', (47, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('EGFR', 'Gene', '1956', (151, 155))
65628	24523818	Because IgG4-LP might show obliterative phlebitis and arteritis, disease of vasculitis should be considered as differential diagnosis.	('vasculitis', 'Phenotype', 'HP:0002633', (76, 86))	('vasculitis', 'Disease', 'MESH:D014657', (76, 86))	('arteritis', 'Disease', 'MESH:D001167', (54, 63))	('arteritis', 'Disease', (54, 63))	('phlebitis', 'Disease', (40, 49))	('IgG4', 'cellular_component', 'GO:0071735', ('8', '12'))	('vasculitis', 'Disease', (76, 86))	('IgG4-LP', 'Var', (8, 15))	('arteritis', 'Phenotype', 'HP:0012089', (54, 63))	('phlebitis', 'Disease', 'MESH:D010689', (40, 49))
65798	31212858	Aberrant inflammation that could occur during wound healing has been linked to the pathogenesis of a variety of malignancies.	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', (112, 124))	('inflammation', 'Disease', (9, 21))	('linked', 'Reg', (69, 75))	('inflammation', 'Disease', 'MESH:D007249', (9, 21))	('inflammation', 'biological_process', 'GO:0006954', ('9', '21'))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('wound healing', 'biological_process', 'GO:0042060', ('46', '59'))
65800	31212858	In the case of MPM, asbestos-induced chronic inflammation:mainly due to the production of reactive oxygen/nitrogen species:results in decreased tumor immunity.	('chronic inflammation', 'Disease', 'MESH:D007249', (37, 57))	('chronic inflammation', 'Disease', (37, 57))	('decreased tumor', 'Disease', 'MESH:D009369', (134, 149))	('inflammation', 'biological_process', 'GO:0006954', ('45', '57'))	('reactive oxygen/nitrogen species', 'Chemical', '-', (90, 122))	('decreased tumor', 'Disease', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('asbestos', 'Chemical', 'MESH:D001194', (20, 28))	('MPM', 'Var', (15, 18))
65821	31212858	In the GDS1220 study, MPM patients with low ITGAV expression had a median overall survival of 15.7 months versus 12 months of those that had high expression (p = 0.0263) (Figure 1B).	('GDS', 'molecular_function', 'GO:0005085', ('7', '10'))	('low', 'Var', (40, 43))	('patients', 'Species', '9606', (26, 34))	('ITGAV', 'Gene', (44, 49))	('ITGAV', 'Gene', '3685', (44, 49))
65822	31212858	Analysis from the TCGA patient data derived from the PROGgeneV2 database corroborates that low ITGAV gene expression favors survival in MPM patients (p = 0.001) (Figure 2).	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	('low', 'Var', (91, 94))	('expression', 'MPA', (106, 116))	('patient', 'Species', '9606', (140, 147))	('MPM', 'Disease', (136, 139))	('survival', 'CPA', (124, 132))	('patients', 'Species', '9606', (140, 148))	('ITGAV', 'Gene', (95, 100))	('favors', 'PosReg', (117, 123))	('ITGAV', 'Gene', '3685', (95, 100))	('patient', 'Species', '9606', (23, 30))
65827	31212858	A recent study has suggested that asbestos induces mesothelial-to-fibroblastic transition in an inflammasome-dependent manner and this seems to apply for other pathogenic particles as well.	('induces', 'Reg', (43, 50))	('asbestos', 'Var', (34, 42))	('asbestos', 'Chemical', 'MESH:D001194', (34, 42))	('mesothelial-to-fibroblastic transition', 'CPA', (51, 89))
65848	30311833	Furthermore, inhibiting MET pharmacologically or knocking down its expression using siRNA, decreases DRP1 activity alluding to possible crosstalk between them in these two cancers.	('knocking', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('inhibiting', 'NegReg', (13, 23))	('DRP1', 'Protein', (101, 105))	('MET', 'Protein', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('expression', 'MPA', (67, 77))	('cancers', 'Disease', (172, 179))	('activity', 'MPA', (106, 114))	('decreases', 'NegReg', (91, 100))
65849	30311833	Consistently, a combination of MGCD516 and mdivi-1, a quinazolinone reported to inhibit mitochondrial fission, is more effective in attenuating proliferation of NSCLC and MPM cell lines than either drug alone.	('MGCD516', 'Var', (31, 38))	('mitochondrial fission', 'MPA', (88, 109))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('MGCD516', 'Chemical', 'MESH:C000611865', (31, 38))	('attenuating', 'NegReg', (132, 143))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('88', '109'))	('inhibit', 'NegReg', (80, 87))	('mdivi-1', 'Gene', (43, 50))	('quinazolinone', 'Chemical', 'MESH:D052999', (54, 67))	('NSCLC', 'Disease', (161, 166))	('proliferation', 'CPA', (144, 157))
65855	30311833	However, MET (and other RTKs) often activates signaling pathways in cancer cells that converge on common downstream effectors resulting in resistance to RTK-based treatment and hence, limiting their continued use.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('resistance', 'MPA', (139, 149))	('RTK', 'Gene', '5979', (24, 27))	('RTK', 'Gene', (153, 156))	('MET', 'Var', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('activates', 'PosReg', (36, 45))	('cancer', 'Disease', (68, 74))	('RTK', 'Gene', '5979', (153, 156))	('signaling pathways', 'Pathway', (46, 64))	('RTK', 'Gene', (24, 27))
65859	30311833	Further, MET amplification in NSCLC is implicated in acquired resistance to EGFR inhibitors and has been reported in approximately 20% of cases with EGFR inhibitor resistance.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('acquired resistance', 'MPA', (53, 72))	('implicated in', 'Reg', (39, 52))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('MET amplification', 'Var', (9, 26))	('EGFR', 'Gene', (149, 153))	('EGFR', 'Gene', (76, 80))	('reported', 'Reg', (105, 113))	('NSCLC', 'Disease', (30, 35))
65864	30311833	Alterations in mitochondrial structures and functions have been linked to a wide variety of cancers.	('mitochondrial', 'MPA', (15, 28))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('linked', 'Reg', (64, 70))	('functions', 'MPA', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
65867	30311833	Changes in DRP1 expression or activation are linked to various cancers suggesting that DRP1 can be a promising target for cancer therapy.	('linked', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (122, 128))	('cancers', 'Disease', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('Changes', 'Var', (0, 7))	('DRP1', 'Gene', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('expression', 'MPA', (16, 26))	('cancer', 'Disease', (63, 69))	('activation', 'MPA', (30, 40))
65871	30311833	Therefore, in this manuscript we explored the effect of combining MET and DRP1 inhibitors on NSCLC and MPM.	('MPM', 'Disease', (103, 106))	('NSCLC', 'Disease', (93, 98))	('DRP1', 'Gene', (74, 78))	('MET', 'Gene', (66, 69))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('inhibitors', 'Var', (79, 89))
65885	30311833	To assess the effect of MGCD516 on cell invasion, cells were treated with 2muM MGCD516 for 24 h and assayed using BioCoat  Matrigel  Invasion Chambers and quantitated by counting the invasive cells as described in Material and Methods.	('MGCD516', 'Var', (79, 86))	('muM', 'Gene', '56925', (75, 78))	('MGCD516', 'Chemical', 'MESH:C000611865', (79, 86))	('muM', 'Gene', (75, 78))	('MGCD516', 'Chemical', 'MESH:C000611865', (24, 31))
65886	30311833	Again, as can be seen from Figure 2(c-f), MGCD516 dramatically attenuated the invasiveness of the H1993 (17.6%, p = 0.0002) and the H2373 (35.0%, p = 0.0088) cells compared to pretreatment with the DMSO vehicle control.	('DMSO', 'Chemical', 'MESH:D004121', (198, 202))	('attenuated', 'NegReg', (63, 73))	('invasiveness', 'CPA', (78, 90))	('H2373', 'CellLine', 'CVCL:A533', (132, 137))	('H1993', 'CellLine', 'CVCL:1512', (98, 103))	('MGCD516', 'Chemical', 'MESH:C000611865', (42, 49))	('H2373', 'Var', (132, 137))	('MGCD516', 'Var', (42, 49))
65887	30311833	To investigate whether MGCD516 targets the MET-Erk1/2 signaling pathway and affects mitochondrial dynamics, we treated H1993 and H2373 cells with MGCD516 for 24 h and assayed changes in levels and/or activation of MET, Erk1/2, DRP1, and Fis1 by immunoblotting.	('H1993', 'CellLine', 'CVCL:1512', (119, 124))	('MGCD516', 'Var', (146, 153))	('mitochondrial dynamics', 'MPA', (84, 106))	('changes', 'Reg', (175, 182))	('MGCD516', 'Chemical', 'MESH:C000611865', (23, 30))	('Erk1', 'molecular_function', 'GO:0004707', ('219', '223'))	('H2373', 'CellLine', 'CVCL:A533', (129, 134))	('activation', 'PosReg', (200, 210))	('MET-Erk1/2 signaling pathway', 'Pathway', (43, 71))	('MET', 'Gene', (214, 217))	('affects', 'Reg', (76, 83))	('Fis1', 'Gene', '51024', (237, 241))	('MGCD516', 'Chemical', 'MESH:C000611865', (146, 153))	('Erk1/2', 'Gene', (219, 225))	('MGCD516', 'Var', (23, 30))	('Erk1', 'molecular_function', 'GO:0004707', ('47', '51'))	('Fis1', 'Gene', (237, 241))	('DRP1', 'Gene', (227, 231))	('signaling pathway', 'biological_process', 'GO:0007165', ('54', '71'))
65888	30311833	In both cell lines, MGCD516 significantly lowered the steady state levels of phosphorylated MET, Erk1/2 and DRP1, and also reduced the level of total Fis1 (Figure 3(a,d)) confirming crosstalk between MET and DRP1 that we suspected in these two cancers.	('MGCD516', 'Var', (20, 27))	('cancers', 'Disease', (244, 251))	('Fis1', 'Gene', '51024', (150, 154))	('Erk1', 'molecular_function', 'GO:0004707', ('97', '101'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('levels', 'MPA', (67, 73))	('phosphorylated MET', 'MPA', (77, 95))	('lowered', 'NegReg', (42, 49))	('Fis1', 'Gene', (150, 154))	('Erk1/2', 'Protein', (97, 103))	('level', 'MPA', (135, 140))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('MGCD516', 'Chemical', 'MESH:C000611865', (20, 27))	('DRP1', 'Gene', (108, 112))	('reduced', 'NegReg', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
65893	30311833	However, in MGCD516-treated cells the mitochondria appeared more elongated and showed a scattered cytoplasmic distribution (Figure 3(b,e)).	('more', 'PosReg', (60, 64))	('mitochondria', 'CPA', (38, 50))	('MGCD516', 'Chemical', 'MESH:C000611865', (12, 19))	('mitochondria', 'cellular_component', 'GO:0005739', ('38', '50'))	('MGCD516-treated', 'Var', (12, 27))
65894	30311833	The relative average length of the mitochondria in MGCD516-treated cells was significantly longer in both cancer cells than in DMSO-treated controls (Figure 3(c,f)).	('longer', 'PosReg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('DMSO', 'Chemical', 'MESH:D004121', (127, 131))	('MGCD516-treated', 'Var', (51, 66))	('cancer', 'Disease', (106, 112))	('mitochondria', 'cellular_component', 'GO:0005739', ('35', '47'))	('MGCD516', 'Chemical', 'MESH:C000611865', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
65895	30311833	Since MGCD516 can also inhibit other RTKs that interact with MET, it is quite possible that the effect of this drug that we observed on mitochondrial dynamics and morphology may have been indirect.	('inhibit', 'NegReg', (23, 30))	('RTK', 'Gene', (37, 40))	('mitochondrial dynamics', 'MPA', (136, 158))	('MGCD516', 'Var', (6, 13))	('MGCD516', 'Chemical', 'MESH:C000611865', (6, 13))	('RTK', 'Gene', '5979', (37, 40))
65897	30311833	As shown in Figure 4(a,d), knocking down MET downregulated DRP1 protein in H1993 and H2373 cells compared to the control siRNA.	('DRP1 protein', 'Protein', (59, 71))	('H2373', 'CellLine', 'CVCL:A533', (85, 90))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('knocking down', 'Var', (27, 40))	('downregulated', 'NegReg', (45, 58))	('H1993', 'CellLine', 'CVCL:1512', (75, 80))	('protein', 'Protein', (64, 71))
65898	30311833	Furthermore, the steady state levels of phospho-DRP1 and phospho-ERK1/2 proteins in the case of the MET-specific siRNA were also significantly decreased compared to the control siRNA.	('ERK1', 'molecular_function', 'GO:0004707', ('65', '69'))	('ERK1/2', 'Gene', (65, 71))	('decreased', 'NegReg', (143, 152))	('ERK1/2', 'Gene', '5594', (65, 71))	('MET-specific', 'Var', (100, 112))
65902	30311833	The maps within the "Lung Cancer" folder were ordered by the fraction of affected proteins for H1993 and H2373.	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('H1993', 'Var', (95, 100))	('Cancer', 'Disease', (26, 32))	('Lung Cancer', 'Phenotype', 'HP:0100526', (21, 32))	('H1993', 'CellLine', 'CVCL:1512', (95, 100))	('H2373', 'Var', (105, 110))	('H2373', 'CellLine', 'CVCL:A533', (105, 110))
65907	30311833	As can be seen from Figure 5(a), drug-treatment dramatically inhibited tumor growth compared vehicle-treated controls.	('inhibited', 'NegReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('drug-treatment', 'Var', (33, 47))	('tumor', 'Disease', (71, 76))
65908	30311833	Furthermore, immunohistochemistry of the xenograft tumor tissue revealed that the levels of both phospho-Met and phospho-DRP1 were significantly reduced in the drug-treated samples compared to the vehicle-treated controls (Figure 5(b)).	('reduced', 'NegReg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('phospho-Met', 'MPA', (97, 108))	('tumor', 'Disease', (51, 56))	('phospho-DRP1', 'Var', (113, 125))	('levels', 'MPA', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
65911	30311833	As shown in Figure 6, while both NSCLC and MPM cell lines were sensitive to the highest dose of MGCD516, mdivi-1 by itself was relatively ineffective.	('MGCD516', 'Var', (96, 103))	('sensitive', 'Reg', (63, 72))	('NSCLC', 'Disease', (33, 38))	('MGCD516', 'Chemical', 'MESH:C000611865', (96, 103))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
65924	30311833	Although the exact role of DRP1 phosphorylated by MET in cancer remains unknown, inhibiting DRP1 in conjunction with MET appears promising.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('inhibiting', 'NegReg', (81, 91))	('cancer', 'Disease', (57, 63))	('MET', 'Var', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('DRP1', 'Protein', (92, 96))
65931	30311833	Antibodies: Phospho-MET (Tyr1234/1235), phospho-DRP1 (Ser616), phospho-Erk1/2 (Thr202/Tyr204), and Erk1/2 antibodies were purchased from Cell Signaling (Danvers, MA, USA).	('Tyr1234', 'Chemical', '-', (25, 32))	('Tyr1234/1235', 'Var', (25, 37))	('Thr202', 'Chemical', '-', (79, 85))	('Ser616', 'Chemical', '-', (54, 60))	('Ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('Ser616', 'Var', (54, 60))	('Tyr204', 'Chemical', '-', (86, 92))	('Signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('Thr202/Tyr204', 'Var', (79, 92))	('Erk1', 'molecular_function', 'GO:0004707', ('71', '75'))	('Erk1', 'molecular_function', 'GO:0004707', ('99', '103'))
65997	27236396	Metastatic mesothelioma stains positively for Wilms tumor 1, calretinin, and podoplanin (D2-40) and negatively for carcinoembryonic antigen, Leu-M1, Ber-EP4, and periodic acid-Schiff.	('periodic acid', 'Chemical', 'MESH:D010504', (162, 175))	('Wilms tumor', 'Phenotype', 'HP:0002667', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('podoplanin', 'Gene', '10630', (77, 87))	('negatively', 'NegReg', (100, 110))	('Wilms tumor', 'Disease', (46, 57))	('Metastatic mesothelioma', 'Disease', (0, 23))	('Leu-M1', 'Var', (141, 147))	('Wilms tumor', 'Disease', 'MESH:D009396', (46, 57))	('calretinin', 'Gene', '794', (61, 71))	('podoplanin', 'Gene', (77, 87))	('carcinoembryonic', 'Disease', (115, 131))	('calretinin', 'Gene', (61, 71))	('Ber', 'biological_process', 'GO:0006284', ('149', '152'))	('carcinoembryonic', 'Disease', 'None', (115, 131))	('Metastatic mesothelioma', 'Disease', 'MESH:D008654', (0, 23))
66006	25462069	As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates.	('expression', 'Species', '29278', (48, 58))	('acidification', 'biological_process', 'GO:0045851', ('162', '175'))	('mitochondrial membrane potential', 'MPA', (69, 101))	('oxygen', 'Chemical', 'MESH:D010100', (125, 131))	('extracellular', 'cellular_component', 'GO:0005576', ('148', '161'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('69', '91'))	('increased', 'PosReg', (59, 68))	('knockdown', 'Var', (30, 39))	('mito', 'Species', '262676', (69, 73))	('PRX3', 'Gene', (43, 47))	('oxygen consumption', 'MPA', (125, 143))	('basal ATP production', 'MPA', (103, 123))	('extracellular acidification rates', 'MPA', (148, 181))	('ATP', 'Chemical', 'MESH:D000255', (109, 112))
66009	25462069	Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism.	('cell cycle-dependent dynamics', 'MPA', (227, 256))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('mito', 'Species', '262676', (265, 269))	('energy metabolism', 'MPA', (294, 311))	('cell cycle', 'biological_process', 'GO:0007049', ('227', '237'))	('proliferation', 'CPA', (201, 214))	('metabolism', 'biological_process', 'GO:0008152', ('301', '311'))	('perturbing', 'Var', (148, 158))	('PRX3', 'Gene', (188, 192))	('mitochondrial networking', 'MPA', (265, 289))	('impairs', 'NegReg', (193, 200))	('altering', 'Reg', (218, 226))
66011	25462069	Knockdown of PRX3 induces mitochondrial fusion and an increase in G2/M cells.	('PRX3', 'Gene', (13, 17))	('G2/M cells', 'CPA', (66, 76))	('Knockdown', 'Var', (0, 9))	('mitochondrial fusion', 'biological_process', 'GO:0008053', ('26', '46'))	('increase', 'PosReg', (54, 62))	('mitochondrial fusion', 'CPA', (26, 46))	('induces', 'Reg', (18, 25))	('mito', 'Species', '262676', (26, 30))
66012	25462069	Overexpression of catalase or mito-catalase rescues G2/M cell cycle block and mitochondrial defects.	('expression', 'Species', '29278', (4, 14))	('G2/M cell cycle block', 'CPA', (52, 73))	('mito', 'Species', '262676', (78, 82))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('mitochondrial defects', 'CPA', (78, 99))	('mito', 'Species', '262676', (30, 34))	('rescues', 'PosReg', (44, 51))	('mito-catalase', 'Var', (30, 43))
66021	25462069	Under basal conditions resident cytosolic and mitochondrial antioxidant enzymes maintain proper redox status while changes in the rate of oxidant production and metabolism activate redox-dependent signaling pathways.	('redox status', 'MPA', (96, 108))	('mito', 'Species', '262676', (46, 50))	('rate of oxidant production', 'MPA', (130, 156))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('redox-dependent signaling pathways', 'Pathway', (181, 215))	('metabolism', 'MPA', (161, 171))	('metabolism', 'biological_process', 'GO:0008152', ('161', '171'))	('changes', 'Var', (115, 122))
66035	25462069	Furthermore, loss of DRP1 leads to hyperfusion of mitochondrial networks and increased ATP levels.	('mito', 'Species', '262676', (50, 54))	('DRP1', 'Gene', (21, 25))	('hyperfusion', 'PosReg', (35, 46))	('ATP', 'Chemical', 'MESH:D000255', (87, 90))	('ATP levels', 'MPA', (87, 97))	('increased', 'PosReg', (77, 86))	('loss', 'Var', (13, 17))	('mitochondrial networks', 'MPA', (50, 72))
66039	25462069	Changes in the basal redox status of mitochondria through stable knockdown of PRX3 led to alterations in energy production and changes to the mitochondrial network through inactivation of DRP1 by dephosphorylation at Serine 616.	('alterations', 'Reg', (90, 101))	('mito', 'Species', '262676', (142, 146))	('DRP1', 'Gene', (188, 192))	('inactivation', 'NegReg', (172, 184))	('basal redox status', 'MPA', (15, 33))	('changes', 'Reg', (127, 134))	('dephosphorylation at Serine 616', 'MPA', (196, 227))	('mito', 'Species', '262676', (37, 41))	('Serine', 'Chemical', 'MESH:D012694', (217, 223))	('Changes', 'Reg', (0, 7))	('PRX3', 'Gene', (78, 82))	('energy production', 'MPA', (105, 122))	('mitochondria', 'cellular_component', 'GO:0005739', ('37', '49'))	('knockdown', 'Var', (65, 74))	('dephosphorylation', 'biological_process', 'GO:0016311', ('196', '213'))	('mitochondrial network', 'MPA', (142, 163))
66044	25462069	PRX3 is estimated to metabolize approximately 90% of mitochondrial H2O2  and therefore it would be expected that reduced expression of PRX3 would alter the redox status of the mitochondria.	('expression', 'Species', '29278', (121, 131))	('mito', 'Species', '262676', (176, 180))	('redox status of the mitochondria', 'MPA', (156, 188))	('H2O2', 'Chemical', 'MESH:D006861', (67, 71))	('PRX3', 'Gene', (135, 139))	('mito', 'Species', '262676', (53, 57))	('mitochondria', 'cellular_component', 'GO:0005739', ('176', '188'))	('alter', 'Reg', (146, 151))	('reduced', 'Var', (113, 120))
66053	25462069	Basal oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) were increased in HMshPRX3 cells compared to HM cells (Fig.	('increased', 'PosReg', (87, 96))	('HMshPRX3', 'Var', (100, 108))	('extracellular', 'cellular_component', 'GO:0005576', ('41', '54'))	('oxygen', 'Chemical', 'MESH:D010100', (6, 12))	('Basal oxygen consumption rates', 'MPA', (0, 30))	('extracellular acidification rates', 'MPA', (41, 74))	('acidification', 'biological_process', 'GO:0045851', ('55', '68'))	('OCR', 'Chemical', '-', (32, 35))
66064	25462069	Phosphorylation at serine 616 of DRP1 leads to increased activity and mitochondrial fission.	('DRP1', 'Gene', (33, 37))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('70', '91'))	('mitochondrial fission', 'CPA', (70, 91))	('mito', 'Species', '262676', (70, 74))	('increased', 'PosReg', (47, 56))	('Phosphorylation at serine 616', 'Var', (0, 29))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('activity', 'MPA', (57, 65))	('serine', 'Chemical', 'MESH:D012694', (19, 25))
66069	25462069	A representative cell cycle histogram as analyzed by flow cytometry after propidium iodide staining indicated HMshPRX3 cells have an increased proportion of cells in the G2/M cell cycle phase compared to HM cells (Fig.	('cell cycle phase', 'biological_process', 'GO:0022403', ('175', '191'))	('HMshPRX3', 'Var', (110, 118))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('cells in the G2/M cell cycle phase', 'CPA', (157, 191))	('propidium iodide', 'Chemical', 'MESH:D011419', (74, 90))	('increased', 'PosReg', (133, 142))
66081	25462069	Changes in the redox landscape of tumor cells activates stress response programs that would typically lead to senescence unless excessive oxidants are counterbalanced through metabolic reorganization, as for example by up-regulation of antioxidant enzymes.	('senescence', 'biological_process', 'GO:0010149', ('110', '120'))	('tumor', 'Disease', (34, 39))	('stress response', 'MPA', (56, 71))	('lead to', 'Reg', (102, 109))	('senescence', 'Disease', (110, 120))	('Changes', 'Var', (0, 7))	('antioxidant', 'Enzyme', (236, 247))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('up-regulation', 'PosReg', (219, 232))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('regulation', 'biological_process', 'GO:0065007', ('222', '232'))
66089	25462069	H2O2-dependent cell cycle arrest leads to the hyperoxidation of PRX2, inducing the formation of higher molecular weight oligomers, which must be reduced prior to cell cycle reentry.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (15, 32))	('formation', 'MPA', (83, 92))	('H2O2-dependent', 'Var', (0, 14))	('hyperoxidation', 'MPA', (46, 60))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('inducing', 'Reg', (70, 78))	('PRX2', 'Gene', (64, 68))	('cell cycle arrest', 'CPA', (15, 32))	('higher molecular weight oligomers', 'MPA', (96, 129))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('15', '32'))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('cell cycle', 'biological_process', 'GO:0007049', ('162', '172'))
66091	25462069	Inactivation of PRX1 through phosphorylation by CDK1 (Cdc2) stimulates transient, localized H2O2 levels hypothesized to be required for inactivation of the protein tyrosine phosphatase Cdc25C and the complete activation of CDK1 at mitosis.	('CDK', 'molecular_function', 'GO:0004693', ('48', '51'))	('phosphatase', 'molecular_function', 'GO:0016791', ('173', '184'))	('PRX1', 'Gene', (16, 20))	('mitosis', 'Disease', (231, 238))	('H2O2', 'Chemical', 'MESH:D006861', (92, 96))	('mitosis', 'Disease', 'None', (231, 238))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('mitosis', 'biological_process', 'GO:0000278', ('231', '238'))	('CDK', 'molecular_function', 'GO:0004693', ('223', '226'))	('CDK1', 'Gene', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('Inactivation', 'Var', (0, 12))	('phosphorylation', 'MPA', (29, 44))
66096	25462069	This is in agreement with other studies that show reversible cysteine modifications to mitochondrial ETC proteins regulate their activity and overall metabolic state.	('mito', 'Species', '262676', (87, 91))	('metabolic state', 'MPA', (150, 165))	('cysteine', 'Var', (61, 69))	('activity', 'MPA', (129, 137))	('regulate', 'Reg', (114, 122))	('cysteine', 'Chemical', 'MESH:D003545', (61, 69))
66108	25462069	Phosphorylation of DRP1 at serine 616 promotes mitochondrial fission, and we observed a significant reduction in phosphorylation levels of serine 616 of DRP1 in HMshPRX3 cells (Fig.	('mitochondrial', 'CPA', (47, 60))	('reduction', 'NegReg', (100, 109))	('DRP1', 'Gene', (153, 157))	('Phosphorylation', 'Var', (0, 15))	('serine', 'Chemical', 'MESH:D012694', (27, 33))	('promotes', 'PosReg', (38, 46))	('phosphorylation levels of serine 616', 'MPA', (113, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('mito', 'Species', '262676', (47, 51))	('serine', 'Chemical', 'MESH:D012694', (139, 145))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('47', '68'))	('DRP1', 'Protein', (19, 23))
66110	25462069	have recently reported that endoplasmic reticulum stress in Akita beta cells with mutations to the B insulin chain (Akita +/Ins2) have increased mitochondrial oxidative stress and concomitant mitochondrial network fragmentation.	('endoplasmic reticulum stress', 'MPA', (28, 56))	('insulin', 'Disease', (101, 108))	('insulin', 'Disease', 'MESH:D007333', (101, 108))	('mitochondrial oxidative stress', 'MPA', (145, 175))	('insulin', 'molecular_function', 'GO:0016088', ('101', '108'))	('mito', 'Species', '262676', (145, 149))	('increased', 'PosReg', (135, 144))	('mutations', 'Var', (82, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (159, 175))	('mito', 'Species', '262676', (192, 196))	('mitochondrial network fragmentation', 'CPA', (192, 227))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('28', '49'))
66116	25462069	Based on our results we propose a model in which increased mitochondrial oxidative stress caused by knockdown of PRX3 induces mitochondrial hyperfusion through the inactivation of DRP1.	('inactivation', 'NegReg', (164, 176))	('knockdown', 'Var', (100, 109))	('DRP1', 'Gene', (180, 184))	('mito', 'Species', '262676', (126, 130))	('increased', 'PosReg', (49, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('induces', 'Reg', (118, 125))	('PRX3', 'Gene', (113, 117))	('mitochondrial hyperfusion', 'MPA', (126, 151))	('mito', 'Species', '262676', (59, 63))	('mitochondrial oxidative stress', 'MPA', (59, 89))
66118	25462069	Ectopic expression of catalase or mito-catalase rescued the phenotypic effects caused by diminished expression of PRX3, implying that increased levels of H2O2 were responsible for the phenotypic effects of knocking down PRX3.	('knocking', 'Var', (206, 214))	('diminished', 'NegReg', (89, 99))	('expression', 'Species', '29278', (100, 110))	('expression', 'MPA', (100, 110))	('expression', 'Species', '29278', (8, 18))	('PRX3', 'Gene', (114, 118))	('mito', 'Species', '262676', (34, 38))	('H2O2', 'Chemical', 'MESH:D006861', (154, 158))
66189	25043725	Currently, only WHO fibers (L >= 5 mum, D < 3 mum and L/D > 3) are counted in the French legislation to assess both exposure of workers and general population.	('mum', 'Gene', (35, 38))	('mum', 'Gene', '56925', (46, 49))	('mum', 'Gene', (46, 49))	('mum', 'Gene', '56925', (35, 38))	('L/D >', 'Var', (54, 59))
66192	25043725	In both direct and indirect methods, only fibers greater than 5 mum in length are currently counted (L >= 5 mum, L/D > 3, 0.2 mum < D < 3 mum with PCM or D < 3 mum with TEM).	('mum', 'Gene', (108, 111))	('mum', 'Gene', '56925', (160, 163))	('mum', 'Gene', (126, 129))	('D < 3', 'Var', (154, 159))	('TEM', 'cellular_component', 'GO:0097197', ('169', '172'))	('mum', 'Gene', (160, 163))	('mum', 'Gene', '56925', (64, 67))	('mum', 'Gene', '56925', (126, 129))	('mum', 'Gene', (64, 67))	('L/D > 3', 'Var', (113, 120))	('mum', 'Gene', '56925', (138, 141))	('mum', 'Gene', '56925', (108, 111))	('mum', 'Gene', (138, 141))
66316	25043725	Rats treated by inhalation developed six times more pulmonary fibrosis and three times more lung tumors with LAF than with SAF.	('SAF', 'Chemical', '-', (123, 126))	('pulmonary fibrosis', 'Disease', (52, 70))	('Rats', 'Species', '10116', (0, 4))	('lung tumors', 'Disease', (92, 103))	('LAF', 'Var', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('lung tumors', 'Phenotype', 'HP:0100526', (92, 103))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (52, 70))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (52, 70))	('LAF', 'Chemical', '-', (109, 112))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('lung tumors', 'Disease', 'MESH:D008175', (92, 103))
66329	25043725	A small and transient increase in the percentage of lung cells incorporating 3HdThd was observed in mice treated with the sample of short fibers compared to control mice.	('rat', 'Species', '10116', (70, 73))	('mice', 'Species', '10090', (165, 169))	('mice', 'Species', '10090', (100, 104))	('short fibers', 'Var', (132, 144))	('increase', 'PosReg', (22, 30))
66395	25043725	The results showed that percentage of cells with abnormal anaphase/metaphase depended on the number of fibers corresponding to Stanton's criteria (L > 8 mum; d <= 0.25 mum) present in the sample.	('L >', 'Var', (147, 150))	('mum', 'Gene', '56925', (153, 156))	('metaphase', 'biological_process', 'GO:0051323', ('67', '76'))	('mum', 'Gene', '56925', (168, 171))	('mum', 'Gene', (153, 156))	('anaphase', 'biological_process', 'GO:0051322', ('58', '66'))	('mum', 'Gene', (168, 171))
66407	25043725	Different types of chromosomal damage caused by asbestos fibers may be observed in asbestos-exposed cells, including chromosomal breaks and fragments (micronuclei), lagging chromosomes, exchange of chromosomal segments between two chromosomes and chromosomal missegregation.	('exchange', 'Var', (186, 194))	('asbestos', 'Chemical', 'MESH:D001194', (83, 91))	('asbestos', 'Chemical', 'MESH:D001194', (48, 56))	('lagging chromosomes', 'CPA', (165, 184))	('chromosomal missegregation', 'CPA', (247, 273))	('chromosomal breaks', 'CPA', (117, 135))	('chromosomal damage', 'Disease', 'MESH:D004194', (19, 37))	('chromosomal damage', 'Disease', (19, 37))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (117, 135))
66510	20051956	Inhibition of TS leads to depleted levels of thymidine, which are crucial to DNA synthesis.	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('depleted', 'NegReg', (26, 34))	('thymidine', 'Chemical', 'MESH:D013936', (45, 54))	('TS', 'Gene', '7298', (14, 16))	('levels of thymidine', 'MPA', (35, 54))	('Inhibition', 'Var', (0, 10))	('DNA synthesis', 'biological_process', 'GO:0071897', ('77', '90'))
66530	20051956	Five cell lines were of epithelioid type: NCI-H28 (H28), NCI-H2052 (2052), NCI-H2452 (2452) (ATCC, Manassas, VA, USA), NCI-H226 (H226) (Cancer Research, London, UK) and JL1 (DSMZ, Braunschweig, Germany); MSTO-211H (MSTO) (ATCC) was of biphasic origin; two cell lines, DM3 and RS5 (DSMZ) were of sarcomatoid type.	('H226', 'CellLine', 'CVCL:J621', (129, 133))	('NCI-H2052', 'CellLine', 'CVCL:1518', (57, 66))	('H226', 'CellLine', 'CVCL:J621', (123, 127))	('Cancer', 'Disease', (136, 142))	('sarcomatoid type', 'Disease', 'MESH:C538614', (295, 311))	('MSTO-211H', 'Var', (204, 213))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('sarcomatoid type', 'Disease', (295, 311))	('Cancer', 'Disease', 'MESH:D009369', (136, 142))	('NCI-H2452', 'CellLine', 'CVCL:1553', (75, 84))	('NCI-H226', 'CellLine', 'CVCL:1544', (119, 127))
66545	20051956	A volume of 2.5 mul cDNA was used for quantitative real-time PCR in a total volume of 10 mul, repeated in triplicate, using the TaqMan gene expression assay Hs00357143_g1 for FRalpha, Hs00953344_m1 for RFC, Hs00611082_m1 for PCFT and Hs99999901_s1 for 18S (all from Applied Biosystems), as well as universal mastermix.	('PCFT', 'Gene', (225, 229))	('Hs00611082_m1', 'Var', (207, 220))	('RFC', 'Gene', (202, 205))	('RFC', 'Phenotype', 'HP:0100507', (202, 205))	('Hs00357143_g1', 'Var', (157, 170))	('FRalpha', 'Gene', (175, 182))	('Hs00953344_m1', 'Var', (184, 197))	('PCFT', 'Gene', '113235', (225, 229))	('FRalpha', 'Gene', '8061', (175, 182))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('RFC', 'Gene', '6573', (202, 205))	('Hs99999901_s1', 'Var', (234, 247))
66607	20051956	Other studies found that the sensitivity of mesothelioma cell lines after 8 h exposure to 30 muM pemetrexed was in the order H2052>H28>MSTO-211H, and that caffeine enhanced pemetrexed activity in the mesothelioma cell lines tested (Min et al, 2008).	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('caffeine', 'Chemical', 'MESH:D002110', (155, 163))	('H2052', 'Var', (125, 130))	('enhanced', 'PosReg', (164, 172))	('activity', 'MPA', (184, 192))	('H2052', 'CellLine', 'CVCL:1518', (125, 130))	('pemetrexed', 'Enzyme', (173, 183))	('muM', 'Gene', '56925', (93, 96))	('muM', 'Gene', (93, 96))	('mesothelioma', 'Disease', (200, 212))	('pemetrexed', 'Chemical', 'MESH:D000068437', (97, 107))	('mesothelioma', 'Disease', (44, 56))	('pemetrexed', 'Chemical', 'MESH:D000068437', (173, 183))
66625	20051956	There was no significant difference in FRalpha staining between the three histological subtypes of mesothelioma, and no difference was observed in the overall survival or time to treatment failure for patients with positive FRalpha tumours compared with those with negative FRalpha tumours.	('tumour', 'Phenotype', 'HP:0002664', (282, 288))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('FRalpha', 'Gene', '8061', (39, 46))	('FRalpha', 'Gene', (224, 231))	('FRalpha tumours', 'Disease', (274, 289))	('tumours', 'Phenotype', 'HP:0002664', (282, 289))	('positive', 'Var', (215, 223))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))	('FRalpha', 'Gene', '8061', (274, 281))	('men', 'Species', '9606', (184, 187))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('FRalpha', 'Gene', (39, 46))	('patients', 'Species', '9606', (201, 209))	('FRalpha tumours', 'Disease', 'MESH:D009369', (274, 289))	('FRalpha tumours', 'Disease', (224, 239))	('FRalpha', 'Gene', '8061', (224, 231))	('FRalpha', 'Gene', (274, 281))	('FRalpha tumours', 'Disease', 'MESH:D009369', (224, 239))	('mesothelioma', 'Disease', (99, 111))
66632	18096084	Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas Silencing of Fra-1, a component of the dimeric transcription factor, activator protein-1 (AP-1), inhibits mRNA expression of c-met and cd44 in rat mesothelioma cells and is causally linked to maintenance of the transformed phenotype.	('activator protein-1', 'Gene', '24516', (155, 174))	('human', 'Species', '9606', (66, 71))	('Fra-1', 'Gene', (0, 5))	('Fra-1', 'Gene', '8061', (0, 5))	('cell migration', 'biological_process', 'GO:0016477', ('14', '28'))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('mesothelioma', 'Disease', (233, 245))	('rat', 'Species', '10116', (22, 25))	('transcription factor', 'molecular_function', 'GO:0000981', ('133', '153'))	('rat', 'Species', '10116', (229, 232))	('mesotheliomas', 'Disease', (72, 85))	('mRNA expression', 'MPA', (192, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (233, 245))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('CD44', 'Gene', '960', (47, 51))	('Silencing', 'Var', (86, 95))	('c-met', 'Gene', '24553', (211, 216))	('mesotheliomas', 'Disease', 'MESH:D008654', (72, 85))	('CD44', 'Gene', (47, 51))	('mesothelioma', 'Disease', (72, 84))	('c-met', 'Gene', (211, 216))	('AP-1', 'cellular_component', 'GO:0005907', ('176', '180'))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('cd44', 'Gene', (221, 225))	('cd44', 'Gene', '25406', (221, 225))	('inhibits', 'NegReg', (183, 191))	('Fra-1', 'Gene', '8061', (99, 104))	('activator protein-1', 'Gene', (155, 174))	('Fra-1', 'Gene', (99, 104))
66635	18096084	Cell lines with PI3K-dependent Fra-1 expression were SV40 positive and expressed the lowest basal Fra-1 levels.	('expression', 'Var', (37, 47))	('Fra-1', 'Gene', (31, 36))	('lowest', 'NegReg', (85, 91))	('PI3K-dependent', 'Var', (16, 30))	('SV40', 'Species', '1891767', (53, 57))	('basal Fra-1 levels', 'MPA', (92, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))
66639	18096084	Lastly, in contrast to normal lung tissue, tissue microarrays revealed that Fra-1 was expressed in 33 of 34 human MMs, and that all CD44+ tumors were SV40-.	('SV40-', 'Var', (150, 155))	('SV40', 'Species', '1891767', (150, 154))	('Fra-1', 'Gene', (76, 81))	('tumors', 'Disease', (138, 144))	('human', 'Species', '9606', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('CD44', 'Gene', '960', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('CD44', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
66640	18096084	These results suggest that Fra-1 is associated with cell migration in human MMs and that Fra-1 modulation of CD44 may govern migration of selected MMs.	('CD44', 'Gene', '960', (109, 113))	('migration', 'CPA', (125, 134))	('cell migration', 'CPA', (52, 66))	('CD44', 'Gene', (109, 113))	('associated', 'Reg', (36, 46))	('rat', 'Species', '10116', (60, 63))	('human', 'Species', '9606', (70, 75))	('cell migration', 'biological_process', 'GO:0016477', ('52', '66'))	('modulation', 'Var', (95, 105))	('govern', 'Reg', (118, 124))	('rat', 'Species', '10116', (128, 131))
66653	18096084	The distribution of the CD44 variants is usually restricted, and some variants are only expressed in certain tumor cells where their expression can confer metastatic properties.	('CD44', 'Gene', '960', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('variants', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD44', 'Gene', (24, 28))	('tumor', 'Disease', (109, 114))
66659	18096084	Levels of Fra-1 correlated with CD44 protein levels that were higher in SV40- MMs.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('SV40', 'Species', '1891767', (72, 76))	('CD44', 'Gene', (32, 36))	('higher', 'PosReg', (62, 68))	('SV40- MMs', 'Var', (72, 81))	('CD44', 'Gene', '960', (32, 36))
66661	18096084	These experiments showed that inhibition of Fra-1 or CD44 significantly curtailed MM cell migration.	('Fra-1', 'Protein', (44, 49))	('MM cell migration', 'CPA', (82, 99))	('inhibition', 'Var', (30, 40))	('CD44', 'Gene', '960', (53, 57))	('CD44', 'Gene', (53, 57))	('rat', 'Species', '10116', (93, 96))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('curtailed', 'NegReg', (72, 81))
66664	18096084	In Figure 1A, we observed that the PI3K inhibitor, LY294002 (LY 20 muM), caused significant reduction of Fra-1 mRNA levels in 3 of the 4 MM lines initially examined, whereas addition of AG1478 (AG 10 muM), an inhibitor of EGFR phosphorylation, had no effects on Fra-1 expression.	('LY294002', 'Var', (51, 59))	('LY', 'Chemical', 'MESH:D008239', (51, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('Fra-1 mRNA levels', 'MPA', (105, 122))	('reduction', 'NegReg', (92, 101))	('LY', 'Chemical', 'MESH:D008239', (61, 63))	('AG1478', 'Chemical', 'MESH:C101044', (186, 192))	('phosphorylation', 'biological_process', 'GO:0016310', ('227', '242'))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
66665	18096084	Two of the 4 MM lines showed inhibition of Fra-1 expression after pretreatment with PP2 (10 muM) or PD98059 (PD, 30 muM), respectively, suggesting additional pathways of Fra-1 modulation in some MMs.	('inhibition', 'NegReg', (29, 39))	('PP2', 'Chemical', '-', (84, 87))	('expression', 'MPA', (49, 59))	('PD98059', 'Var', (100, 107))	('Fra-1', 'Gene', (43, 48))	('PD98059', 'Chemical', 'MESH:C093973', (100, 107))
66666	18096084	In MM3 cells in which Fra-1 mRNA levels were diminished significantly only after inhibition of the PI3K pathway, transactivation of Fra-1 dependent gene expression (Figure 1B) and protein levels (Figure 1C) were also inhibited selectively by LY294002 (20 muM).	('LY294002', 'Chemical', 'MESH:C085911', (242, 250))	('protein levels', 'MPA', (180, 194))	('Fra-1 dependent gene', 'Gene', (132, 152))	('mRNA levels', 'MPA', (28, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('transactivation', 'biological_process', 'GO:2000144', ('113', '128'))	('LY294002', 'Var', (242, 250))	('gene expression', 'biological_process', 'GO:0010467', ('148', '163'))	('inhibited', 'NegReg', (217, 226))	('PI3K pathway', 'Pathway', (99, 111))	('diminished', 'NegReg', (45, 55))	('transactivation', 'MPA', (113, 128))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
66668	18096084	In Figure 1D, we also show using an EMSA super-shift assay that inhibition of the PI3K pathway by LY294002 (10 and 20 muM) causes reduced expression of Fra-1 in the AP-1 complexes of these cells in a dose-related fashion.	('LY294002', 'Chemical', 'MESH:C085911', (98, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('AP-1', 'cellular_component', 'GO:0005907', ('165', '169'))	('inhibition', 'NegReg', (64, 74))	('PI3K pathway', 'Pathway', (82, 94))	('reduced', 'NegReg', (130, 137))	('expression', 'MPA', (138, 148))	('Fra-1', 'Protein', (152, 157))	('LY294002', 'Var', (98, 106))
66670	18096084	Here we examined levels of endogenous CD44 in SV40+ and SV40- MM lines after addition of LY294002 (Figure 3).	('LY294002', 'Var', (89, 97))	('SV40', 'Species', '1891767', (46, 50))	('levels', 'MPA', (17, 23))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('CD44', 'Gene', '960', (38, 42))	('CD44', 'Gene', (38, 42))	('SV40', 'Species', '1891767', (56, 60))
66671	18096084	These studies revealed that the PI3K inhibitor LY294002 diminished CD44 protein in a dose-related fashion in the SV40+ line, but not in the SV40- MM lines.	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('CD44', 'Gene', '960', (67, 71))	('SV40', 'Species', '1891767', (113, 117))	('CD44', 'Gene', (67, 71))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('LY294002', 'Chemical', 'MESH:C085911', (47, 55))	('SV40', 'Species', '1891767', (140, 144))	('diminished', 'NegReg', (56, 66))	('LY294002', 'Var', (47, 55))
66673	18096084	CD44 protein was decreased after addition of the PD98059 MEK1 inhibitor and in a SV40- cell line transformed with a dn-Fra-1 construct (Figure 3B).	('MEK1', 'molecular_function', 'GO:0004708', ('57', '61'))	('decreased', 'NegReg', (17, 26))	('CD44', 'Gene', '960', (0, 4))	('PD98059', 'Var', (49, 56))	('SV40', 'Species', '1891767', (81, 85))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('CD44', 'Gene', (0, 4))	('PD98059', 'Chemical', 'MESH:C093973', (49, 56))
66674	18096084	However, CD44 depletion was not increased synergistically after PD98059 or LY294002 was added to the dnFra-1 stable cell line (Figure 3B).	('CD44', 'Gene', (9, 13))	('PD98059', 'Var', (64, 71))	('PD98059', 'Chemical', 'MESH:C093973', (64, 71))	('LY294002', 'Chemical', 'MESH:C085911', (75, 83))	('LY294002', 'Var', (75, 83))	('CD44', 'Gene', '960', (9, 13))
66686	18096084	In Figure 6 we show that the uptake of BODIPY FL hyaluronic acid (green) is decreased in SV40- MM cells transfected with shFra-1 (Fra-1 expression is shown in red) compared to MM cells transfected with empty vector (EV).	('uptake', 'biological_process', 'GO:0098657', ('29', '35'))	('uptake', 'biological_process', 'GO:0098739', ('29', '35'))	('shFra-1', 'Gene', (121, 128))	('uptake of BODIPY FL hyaluronic acid', 'MPA', (29, 64))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (49, 64))	('decreased', 'NegReg', (76, 85))	('SV40- MM', 'Var', (89, 97))	('SV40', 'Species', '1891767', (89, 93))
66691	18096084	Using a similar tissue microarray set as used for Fra-1 expression above, we performed dual fluorescence studies on MMs using antibodies for SV40 T-antigen (blue/nuclear) and CD44 (red) (Figure 8).	('SV40', 'Species', '1891767', (141, 145))	('SV40', 'Var', (141, 145))	('CD44', 'Gene', '960', (175, 179))	('CD44', 'Gene', (175, 179))	('SV40 T-antigen', 'molecular_function', 'GO:0016887', ('141', '155'))
66692	18096084	Of the 34 MMs, 17 (50%) were SV40+ and 8 (24%) were CD44+.	('CD44', 'Gene', (52, 56))	('SV40+', 'Var', (29, 34))	('SV40', 'Species', '1891767', (29, 33))	('CD44', 'Gene', '960', (52, 56))
66693	18096084	Moreover, all SV40+ tumors were CD44-.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('CD44', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('SV40+', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('SV40', 'Species', '1891767', (14, 18))	('CD44', 'Gene', '960', (32, 36))
66702	18096084	In contrast, levels of Fra-1 in MMs were not modified by pre-addition of an inhibitor of EGFR phosphorylation (AG1478) although it is known that EGFR phosphorylation leads to ERK1/2 activation in rodent mesothelial and alveolar epithelial cells.	('ERK1', 'molecular_function', 'GO:0004707', ('175', '179'))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('phosphorylation', 'Var', (150, 165))	('EGFR phosphorylation', 'Var', (145, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))	('AG1478', 'Chemical', 'MESH:C101044', (111, 117))	('ERK1/2', 'Protein', (175, 181))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('activation', 'PosReg', (182, 192))
66707	18096084	Here we present evidence that Fra-1 activation is through multiple survival pathways and that its expression governs human mesothelioma cell migration partially via indirect modulation of CD44 expression.	('governs', 'Reg', (109, 116))	('CD44', 'Gene', '960', (188, 192))	('human', 'Species', '9606', (117, 122))	('expression', 'Var', (98, 108))	('CD44', 'Gene', (188, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('activation', 'PosReg', (36, 46))	('cell migration', 'biological_process', 'GO:0016477', ('136', '150'))	('modulation', 'Reg', (174, 184))	('expression', 'MPA', (193, 203))	('Fra-1', 'Gene', (30, 35))	('rat', 'Species', '10116', (144, 147))	('mesothelioma', 'Disease', (123, 135))
66711	18096084	We show here that low basal Fra-1 and CD44 levels correlated with SV40 positivity in MM cell lines and could be upregulated upon stimulation with serum.	('upregulated', 'PosReg', (112, 123))	('positivity', 'Var', (71, 81))	('CD44', 'Gene', '960', (38, 42))	('CD44', 'Gene', (38, 42))	('Fra-1', 'MPA', (28, 33))	('SV40', 'Species', '1891767', (66, 70))	('SV40', 'Gene', (66, 70))
66712	18096084	Previous studies have demonstrated that SV40 large T antigen can activate the PI3K pathway in different cell types, and, in line with these observations, we have shown that SV40+ MM cells have higher AKT activity.	('AKT', 'Pathway', (200, 203))	('SV40+ MM', 'Var', (173, 181))	('SV40', 'Species', '1891767', (40, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))	('SV40', 'Species', '1891767', (173, 177))	('rat', 'Species', '10116', (29, 32))	('activate', 'PosReg', (65, 73))	('PI3K pathway', 'Pathway', (78, 90))	('SV40 large T antigen', 'Var', (40, 60))	('higher', 'PosReg', (193, 199))
66713	18096084	Moreover, SV40+ MMs were more susceptible to killing when the PI3K pathway was inhibited.	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('PI3K pathway', 'Pathway', (62, 74))	('SV40+ MMs', 'Var', (10, 19))	('SV40', 'Species', '1891767', (10, 14))
66714	18096084	These studies suggest that SV40 positivity of MMs may render a survival advantage.	('SV40 positivity', 'Var', (27, 42))	('SV40', 'Species', '1891767', (27, 31))	('survival advantage', 'CPA', (63, 81))
66716	18096084	The presence and role of SV40 in human tumors is still very controversial, but SV40 T-antigen or DNA has been found in human MMs.	('tumors', 'Disease', (39, 45))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('human', 'Species', '9606', (33, 38))	('SV40', 'Species', '1891767', (25, 29))	('SV40 T-antigen', 'molecular_function', 'GO:0016887', ('79', '93'))	('SV40', 'Species', '1891767', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('SV40', 'Var', (79, 83))	('human', 'Species', '9606', (119, 124))
66718	18096084	The role of other Fra-1-dependent genes and signaling pathways should be explored in prevention and therapy of MMs of both SV40+ and SV40- MMs.	('MMs', 'Disease', (111, 114))	('SV40+', 'Var', (123, 128))	('SV40', 'Species', '1891767', (123, 127))	('SV40- MMs', 'Var', (133, 142))	('SV40', 'Species', '1891767', (133, 137))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))
66720	18096084	The MM1, MM2, MM5, and MM6 lines were negative for SV40 large T-antigen (SV40-), whereas MM3, MM4 and MM7 were SV40+.	('negative', 'NegReg', (38, 46))	('SV40+', 'Var', (111, 116))	('SV40', 'Species', '1891767', (73, 77))	('SV40', 'Species', '1891767', (51, 55))	('SV40', 'Species', '1891767', (111, 115))
66722	18096084	Stock solutions of all inhibitors were diluted in dimethyl sulfoxide (DMSO) and used at effective nontoxic concentrations as reported previously: The MEK1/2 inhibitor, PD98059, at 30 muM; the EGFR inhibitor, AG1478, at 10 muM; the PI3K inhibitor, LY294002, at 10 and 20 muM; and the Src inhibitor, PP2, at 10 muM.	('rat', 'Species', '10116', (114, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('192', '196'))	('Src', 'Gene', (283, 286))	('PD98059', 'Var', (168, 175))	('AG1478', 'Var', (208, 214))	('Src', 'Gene', '6714', (283, 286))	('MEK1', 'molecular_function', 'GO:0004708', ('150', '154'))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (50, 68))	('DMSO', 'Chemical', 'MESH:D004121', (70, 74))	('LY294002', 'Chemical', 'MESH:C085911', (247, 255))	('PD98059', 'Chemical', 'MESH:C093973', (168, 175))	('PP2', 'Chemical', '-', (298, 301))	('AG1478', 'Chemical', 'MESH:C101044', (208, 214))	('PI3K', 'molecular_function', 'GO:0016303', ('231', '235'))	('LY294002', 'Var', (247, 255))
66731	18096084	After exposure to LY294002 (20 muM) or DMSO as a control diluent (with samples N = 3), total cell extracts were prepared and assayed for luciferase and renilla activity (Luciferase Assay System; Promega Corp., Madison, WI) using a luminometer (Berthold Technologies, Lumat, Germany).	('LY294002', 'Var', (18, 26))	('DMSO', 'Chemical', 'MESH:D004121', (39, 43))	('renilla', 'Enzyme', (152, 159))	('activity', 'MPA', (160, 168))	('luciferase', 'Enzyme', (137, 147))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))
66733	18096084	For supershift assays, nuclear extracts were incubated with antibodies to Fra-1 (Santa Cruz, CA) for 15 min at room temperature prior to addition of labeled oligonucleotide.	('antibodies', 'Var', (60, 70))	('Fra-1', 'Gene', (74, 79))	('oligonucleotide', 'Chemical', 'MESH:D009841', (157, 172))	('rat', 'Species', '10116', (121, 124))
66737	18096084	RK7-Fra-1Deltazip, a dominant negative Fra-1 (dnFra-1) construct with deletion of the leucine zipper responsible for the dimerization function of Fra-1, was obtained from Dr. M. Busslinger (Research Institute of Molecular Pathology, Vienna, Austria) and cloned into pcDNA3 (InVitrogen, San Diego, CA) before transfection using electroporation.	('deletion', 'Var', (70, 78))	('Fra-1', 'Gene', (146, 151))	('rat', 'Species', '10116', (336, 339))
66740	18096084	Following an overnight recovery, cells were selected for neomycin resistance using 200 mug/ml G418 (Sigma).	('G418', 'Var', (94, 98))	('neomycin resistance', 'MPA', (57, 76))	('G418', 'Chemical', 'MESH:C010680', (94, 98))	('neomycin', 'Chemical', 'MESH:D009355', (57, 65))	('mug', 'molecular_function', 'GO:0043739', ('87', '90'))
66747	18096084	Following an overnight recovery, cells were selected for neomycin resistance using 200 mug/ml G418 (Sigma St. Louis, MO).	('G418', 'Var', (94, 98))	('neomycin resistance', 'MPA', (57, 76))	('G418', 'Chemical', 'MESH:C010680', (94, 98))	('neomycin', 'Chemical', 'MESH:D009355', (57, 65))	('mug', 'molecular_function', 'GO:0043739', ('87', '90'))
66765	31065954	A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma Fibroblast growth factors (FGFs) have a fundamental role in cancer.	('pemetrexed', 'Chemical', 'MESH:D000068437', (71, 81))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (123, 143))	('malignant pleural mesothelioma', 'Disease', (113, 143))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (113, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('patients', 'Species', '9606', (99, 107))	('GSK3052230', 'Var', (20, 30))	('GSK', 'molecular_function', 'GO:0050321', ('20', '23'))	('ligand', 'molecular_function', 'GO:0005488', ('39', '45'))
66766	31065954	Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities.	('toxicities', 'Disease', (216, 226))	('toxicities', 'Disease', 'MESH:D064420', (98, 108))	('blocks', 'NegReg', (44, 50))	('skin toxicities', 'Disease', 'MESH:D012871', (211, 226))	('FGFR', 'Gene', (154, 158))	('ability', 'MPA', (57, 64))	('GSK3052230', 'Var', (23, 33))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (170, 187))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (170, 187))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('FGFRs', 'Protein', (77, 82))	('toxicities', 'Disease', 'MESH:D064420', (216, 226))	('toxicities', 'Disease', (98, 108))	('hyperphosphatemia', 'Disease', (170, 187))	('Sequestering', 'biological_process', 'GO:0051235', ('0', '12'))	('avoiding', 'NegReg', (89, 97))	('GSK', 'molecular_function', 'GO:0050321', ('23', '26'))	('skin toxicities', 'Disease', (211, 226))
66767	31065954	A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma.	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (147, 177))	('pemetrexed', 'Chemical', 'MESH:D000068437', (79, 89))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (157, 177))	('malignant pleural mesothelioma', 'Disease', (147, 177))	('GSK3052230', 'Var', (59, 69))	('patients', 'Species', '9606', (103, 111))	('GSK', 'molecular_function', 'GO:0050321', ('59', '62'))
66780	31065954	GSK3052230 is a soluble fusion protein consisting of the extracellular domains of human FGFR1 alpha-IIIc linked to the modified hinge and native Fc regions of human immunoglobulin G1 (IgG1).	('soluble', 'cellular_component', 'GO:0005625', ('16', '23'))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (88, 93))	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('IgG1', 'cellular_component', 'GO:0071735', ('184', '188'))	('human', 'Species', '9606', (159, 164))	('human', 'Species', '9606', (82, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('GSK3052230', 'Var', (0, 10))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('165', '179'))	('alpha-IIIc', 'Protein', (94, 104))
66787	31065954	Arms A and B investigated GSK3052230 in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) in combination with first- and second-line standard therapies, respectively, and Arm C investigated GSK3052230 with first-line therapy in mesothelioma.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('GSK', 'molecular_function', 'GO:0050321', ('26', '29'))	('GSK', 'molecular_function', 'GO:0050321', ('202', '205'))	('sqNSCLC', 'Disease', (93, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('sqNSCLC', 'Disease', 'None', (93, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('mesothelioma', 'Disease', (240, 252))	('GSK3052230', 'Var', (26, 36))	('squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (56, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('squamous non-small cell lung cancer', 'Disease', (56, 91))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
66788	31065954	Doses of GSK3052230 were escalated according to a 3 + 3 design up to the maximum tolerated dose (MTD) at <=1 out of 6 patients experiencing a dose-limiting toxicities (DLT) (pre-specified as in Online Resource 2).	('toxicities', 'Disease', 'MESH:D064420', (156, 166))	('GSK', 'molecular_function', 'GO:0050321', ('9', '12'))	('toxicities', 'Disease', (156, 166))	('pre', 'molecular_function', 'GO:0003904', ('174', '177'))	('patients', 'Species', '9606', (118, 126))	('GSK3052230', 'Var', (9, 19))
66794	31065954	Dose-escalation was planned to 20 mg/kg, and an intermediate dose-level of 15 mg/kg was introduced after emerging safety data from Arms A and B of this study, investigating GSK3052230 in sqNSCLC patients.	('GSK3052230', 'Var', (173, 183))	('sqNSCLC', 'Disease', (187, 194))	('sqNSCLC', 'Disease', 'None', (187, 194))	('GSK', 'molecular_function', 'GO:0050321', ('173', '176'))	('patients', 'Species', '9606', (195, 203))
66796	31065954	Plasma concentrations of GSK3052230 were determined using a validated FGF2 ligand-binding enzyme-linked immunosorbent assay in accordance with FDA's published recommendations.	('FGF2', 'Gene', '2247', (70, 74))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('GSK', 'molecular_function', 'GO:0050321', ('25', '28'))	('GSK3052230', 'Var', (25, 35))	('FGF2', 'Gene', (70, 74))	('ligand', 'molecular_function', 'GO:0005488', ('75', '81'))
66813	31065954	Of the 35 patients tested for anti-GSK3052230 antibodies, 14 (39%) tested positive after two administrations of GSK3052230, at cycle 1 day 15, decreasing to 14% at cycle 6 which suggests transient immunogenicity (not shown).	('GSK', 'molecular_function', 'GO:0050321', ('35', '38'))	('GSK3052230', 'Var', (112, 122))	('anti-GSK3052230', 'Gene', (30, 45))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('patients', 'Species', '9606', (10, 18))	('positive', 'Reg', (74, 82))
66818	31065954	At the highest dose-level of GSK3052230 (20 mg/kg), three grade 4 events, being neutropenia, respiratory failure, and thrombocytopenia (n = 1 each) occurred, of which only thrombocytopenia was related to GSK3052230, and one grade 5 event occurred, namely intestinal ischemia/intestinal perforation with bowel involvement.	('GSK', 'molecular_function', 'GO:0050321', ('204', '207'))	('thrombocytopenia', 'Disease', 'MESH:D013921', (172, 188))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (172, 188))	('respiratory failure', 'Disease', 'MESH:D012131', (93, 112))	('thrombocytopenia', 'Disease', (118, 134))	('intestinal ischemia', 'Phenotype', 'HP:0002637', (255, 274))	('GSK', 'molecular_function', 'GO:0050321', ('29', '32'))	('intestinal ischemia', 'Disease', (255, 274))	('intestinal ischemia', 'Disease', 'MESH:D007511', (255, 274))	('respiratory failure', 'Disease', (93, 112))	('neutropenia', 'Disease', (80, 91))	('thrombocytopenia', 'Disease', 'MESH:D013921', (118, 134))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (118, 134))	('GSK3052230', 'Gene', (29, 39))	('intestinal perforation', 'Phenotype', 'HP:0031368', (275, 297))	('thrombocytopenia', 'Disease', (172, 188))	('respiratory failure', 'Phenotype', 'HP:0002878', (93, 112))	('20 mg/kg', 'Var', (41, 49))	('GSK3052230', 'Var', (204, 214))	('neutropenia', 'Disease', 'MESH:D009503', (80, 91))	('neutropenia', 'Phenotype', 'HP:0001875', (80, 91))	('bowel involvement', 'Disease', (303, 320))
66835	31065954	However, despite the small sample size (n = 15), a statistically significant correlation between PFS and cytoplasmic FGF2 H-score was observed for the 15 mg/kg GSK3052230 group, p = 0.0157 (Online Resource 4b).	('FGF2', 'Gene', '2247', (117, 121))	('GSK3052230', 'Var', (160, 170))	('GSK', 'molecular_function', 'GO:0050321', ('160', '163'))	('significant correlation', 'Reg', (65, 88))	('FGF2', 'Gene', (117, 121))
66839	31065954	Since GSK3052230 had not been previously associated with these toxicities from prior preclinical and clinical studies, a contribution of pemetrexed and cisplatin seems likely.	('toxicities', 'Disease', (63, 73))	('GSK', 'molecular_function', 'GO:0050321', ('6', '9'))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('pemetrexed', 'Chemical', 'MESH:D000068437', (137, 147))	('toxicities', 'Disease', 'MESH:D064420', (63, 73))	('GSK3052230', 'Var', (6, 16))
66840	31065954	In this study, we observed relevant and durable clinical activity in treatment-naive MPM patients when GSK3052230 was combined with standard first-line therapy.	('MPM', 'Disease', (85, 88))	('patients', 'Species', '9606', (89, 97))	('GSK', 'molecular_function', 'GO:0050321', ('103', '106'))	('GSK3052230', 'Var', (103, 113))
66847	31065954	While this study is the first to explore the potential of targeting the FGF/FGFR signaling pathway in patients with MPM, inhibition of FGF/FGFR signaling has been shown to be effective in several other tumor types using small molecules.	('tumor', 'Disease', (202, 207))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('FGFR signaling pathway', 'biological_process', 'GO:0008543', ('76', '98'))	('patients', 'Species', '9606', (102, 110))	('FGF/FGFR', 'Gene', (72, 80))	('inhibition', 'Var', (121, 131))	('MPM', 'Disease', (116, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
66849	31065954	Similarly, partial responses have been reported using the pan-FGFR inhibitor, erdafitinib, in urothelial cancer, glioblastoma, and endometrial cancer with FGFR1-4 or FGF3/4 alterations (amplifications/translocations/mutations), including FGFR3-TACC3 gene fusions.	('FGFR3', 'Gene', (238, 243))	('urothelial cancer', 'Disease', 'MESH:D014523', (94, 111))	('FGFR1-4', 'Gene', (155, 162))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGFR', 'molecular_function', 'GO:0005007', ('238', '242'))	('FGFR3', 'Gene', '2261', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('urothelial cancer', 'Disease', (94, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('FGF3/4', 'Gene', (166, 172))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('erdafitinib', 'Chemical', 'MESH:C000604580', (78, 89))	('glioblastoma', 'Disease', (113, 125))	('FGF3/4', 'Gene', '2248;2249', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('endometrial cancer', 'Disease', (131, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))	('TACC3', 'Gene', '10460', (244, 249))	('TACC3', 'Gene', (244, 249))	('alterations', 'Var', (173, 184))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (155, 162))
66851	31065954	This setting was the first to identify a genetic mechanism of resistance to FGFR kinase inhibition, as several patients acquired secondary FGFR2 mutations that rendered them resistant to BGJ398 treatment.	('mutations', 'Var', (145, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('FGFR2', 'Gene', (139, 144))	('BGJ398', 'Chemical', 'MESH:C568950', (187, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('FGFR2', 'Gene', '2263', (139, 144))	('resistant', 'MPA', (174, 183))	('patients', 'Species', '9606', (111, 119))
66852	31065954	Alternatively, GSK3052230 targets ligand-dependent signaling in tumors where overexpression of FGFs or co-expression of FGFs and FGFRs occur.	('tumors', 'Disease', (64, 70))	('FGFs', 'Protein', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('overexpression', 'PosReg', (77, 91))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('GSK', 'molecular_function', 'GO:0050321', ('15', '18'))	('co-expression', 'Interaction', (103, 116))	('ligand', 'molecular_function', 'GO:0005488', ('34', '40'))	('ligand-dependent signaling', 'MPA', (34, 60))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('GSK3052230', 'Var', (15, 25))
66858	31065954	A consequence of the selectivity of GSK3052230 for targeting FGFs that bind to the extracellular domain of FGFR1 alpha-IIIc could be that other FGFs that are not, or weakly, inhibited by GSK3052230 could still induce tumor growth.	('extracellular', 'cellular_component', 'GO:0005576', ('83', '96'))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('GSK3052230', 'Var', (187, 197))	('GSK', 'molecular_function', 'GO:0050321', ('187', '190'))	('GSK', 'molecular_function', 'GO:0050321', ('36', '39'))	('induce', 'PosReg', (210, 216))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('FGFR1', 'Gene', (107, 112))	('FGFR1', 'Gene', '2260', (107, 112))
66866	30992546	The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high).	('GSK2256098', 'Chemical', 'MESH:C000600809', (4, 14))	('GSK2256098/trametinib', 'Var', (4, 25))	('BID', 'Gene', (108, 111))	('BID', 'Gene', (56, 59))	('GSK', 'molecular_function', 'GO:0050321', ('4', '7'))	('trametinib', 'Chemical', 'MESH:C560077', (15, 25))	('BID', 'Gene', '637', (108, 111))	('BID', 'Gene', '637', (56, 59))
66868	30992546	Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib.	('GSK', 'molecular_function', 'GO:0050321', ('111', '114'))	('GSK', 'molecular_function', 'GO:0050321', ('68', '71'))	('trametinib', 'Chemical', 'MESH:C560077', (170, 180))	('GSK2256098', 'Chemical', 'MESH:C000600809', (111, 121))	('trametinib', 'Chemical', 'MESH:C560077', (21, 31))	('increased', 'PosReg', (32, 41))	('trametinib', 'Chemical', 'MESH:C560077', (87, 97))	('GSK2256098', 'Var', (68, 78))	('GSK2256098', 'Chemical', 'MESH:C000600809', (68, 78))	('Systemic exposure', 'MPA', (0, 17))
66870	30992546	Trametinib exposure increased when co-administered with GSK2256098, but not vice versa.	('increased', 'PosReg', (20, 29))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('Trametinib exposure', 'MPA', (0, 19))	('GSK2256098', 'Var', (56, 66))	('GSK2256098', 'Chemical', 'MESH:C000600809', (56, 66))	('GSK', 'molecular_function', 'GO:0050321', ('56', '59'))
66871	30992546	Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited.	('longer', 'PosReg', (46, 52))	('loss', 'Var', (27, 31))	('PFS', 'MPA', (53, 56))	('patients', 'Species', '9606', (13, 21))	('Merlin', 'Gene', (35, 41))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('Merlin', 'Gene', '4771', (35, 41))
66875	30992546	GSK2256098 is a potent, oral, reversible inhibitor of the tyrosine kinase activity measured by the autophosphorylation site (Tyr 397) of FAK.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (0, 10))	('FAK', 'Gene', (137, 140))	('FAK', 'Gene', '5747', (137, 140))	('Tyr', 'Chemical', 'MESH:D014443', (125, 128))	('kinase activity', 'molecular_function', 'GO:0016301', ('67', '82'))	('FAK', 'molecular_function', 'GO:0004717', ('137', '140'))	('tyrosine kinase activity', 'MPA', (58, 82))	('GSK2256098', 'Var', (0, 10))
66876	30992546	In preclinical studies, GSK2256098 was demonstrated to be at least 20 times more active in vitro in Merlin-negative (encoded by NF-2) mesothelioma cells than in Merlin-positive cells.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (24, 34))	('mesothelioma', 'Disease', (134, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('Merlin', 'Gene', '4771', (100, 106))	('Merlin', 'Gene', (161, 167))	('Merlin', 'Gene', '4771', (161, 167))	('Merlin', 'Gene', (100, 106))	('active', 'MPA', (81, 87))	('more', 'PosReg', (76, 80))	('GSK2256098', 'Var', (24, 34))
66881	30992546	We hypothesised that a combination of FAK and MEK inhibition may provide greater anticancer effect than FAK monotherapy, supported by preclinical evidence of synergistic growth inhibition and cell death between GSK2256098 and trametinib across a range of mesothelioma cell lines (GSK Internal data; manuscript in preparation).	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('FAK', 'Gene', '5747', (38, 41))	('GSK2256098', 'Chemical', 'MESH:C000600809', (211, 221))	('MEK', 'Gene', (46, 49))	('cell death', 'CPA', (192, 202))	('FAK', 'molecular_function', 'GO:0004717', ('104', '107'))	('FAK', 'molecular_function', 'GO:0004717', ('38', '41'))	('FAK', 'Gene', (104, 107))	('growth inhibition', 'CPA', (170, 187))	('GSK', 'molecular_function', 'GO:0050321', ('211', '214'))	('mesothelioma cell lines', 'Disease', (255, 278))	('GSK', 'molecular_function', 'GO:0050321', ('280', '283'))	('mesothelioma cell lines', 'Disease', 'MESH:D008654', (255, 278))	('cancer', 'Disease', (85, 91))	('trametinib', 'Chemical', 'MESH:C560077', (226, 236))	('cell death', 'biological_process', 'GO:0008219', ('192', '202'))	('FAK', 'Gene', '5747', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('greater', 'PosReg', (73, 80))	('inhibition', 'NegReg', (50, 60))	('GSK2256098', 'Var', (211, 221))	('FAK', 'Gene', (38, 41))	('MEK', 'Gene', '5609', (46, 49))
66882	30992546	This study aimed to identify the maximum tolerated doses (MTD) of GSK2256098 and trametinib when administered in combination and to examine the safety, pharmacokinetics, pharmacodynamics, and clinical activity of this combination in patients with mesothelioma or other solid tumours.	('GSK2256098', 'Var', (66, 76))	('mesothelioma', 'Disease', (247, 259))	('GSK2256098', 'Chemical', 'MESH:C000600809', (66, 76))	('trametinib', 'Chemical', 'MESH:C560077', (81, 91))	('solid tumours', 'Disease', (269, 282))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('tumours', 'Phenotype', 'HP:0002664', (275, 282))	('mesothelioma', 'Disease', 'MESH:D008654', (247, 259))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('patients', 'Species', '9606', (233, 241))	('solid tumours', 'Disease', 'MESH:D009369', (269, 282))
66883	30992546	Part 1 aimed to identify a low GSK2256098/high trametinib and a high GSK2256098/low trametinib MTD, using a standard adaptive 3 + 3 design.	('trametinib', 'Chemical', 'MESH:C560077', (47, 57))	('GSK2256098', 'Chemical', 'MESH:C000600809', (31, 41))	('GSK2256098', 'Chemical', 'MESH:C000600809', (69, 79))	('low GSK2256098/high', 'Var', (27, 46))	('GSK', 'molecular_function', 'GO:0050321', ('31', '34'))	('GSK', 'molecular_function', 'GO:0050321', ('69', '72'))	('trametinib', 'Chemical', 'MESH:C560077', (84, 94))	('GSK2256098/high', 'Var', (31, 46))
66884	30992546	Starting doses were GSK2256098 500 mg orally twice daily (BID), 50% of the single-agent MTD, and trametinib 1 mg orally once daily (QD), 50% of the recommended monotherapy dose.	('BID', 'Gene', '637', (58, 61))	('trametinib', 'Chemical', 'MESH:C560077', (97, 107))	('GSK', 'molecular_function', 'GO:0050321', ('20', '23'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (20, 30))	('GSK2256098 500', 'Var', (20, 34))	('BID', 'Gene', (58, 61))
66885	30992546	GSK2256098 was administered with a light meal to limit nausea while trametinib was administered >=2 h after a meal as per the prescription information.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('trametinib', 'Chemical', 'MESH:C560077', (68, 78))	('GSK2256098', 'Chemical', 'MESH:C000600809', (0, 10))	('nausea', 'Phenotype', 'HP:0002018', (55, 61))	('nausea', 'Disease', (55, 61))	('nausea', 'Disease', 'MESH:D009325', (55, 61))	('GSK2256098', 'Var', (0, 10))
66933	30992546	Seventeen percent of subjects in the group receiving high GSK2256098/low trametinib (500 mg BID/0.375 mg QD) had an AE causing dose interruption compared with 60% in the low GSK2256098/high trametinib (250 mg BID/0.5 mg QD) group.	('trametinib', 'Chemical', 'MESH:C560077', (190, 200))	('high GSK2256098/low', 'Var', (53, 72))	('GSK2256098', 'Chemical', 'MESH:C000600809', (58, 68))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('500', 'Var', (85, 88))	('BID', 'Gene', '637', (209, 212))	('BID', 'Gene', '637', (92, 95))	('GSK', 'molecular_function', 'GO:0050321', ('174', '177'))	('BID', 'Gene', (92, 95))	('trametinib', 'Chemical', 'MESH:C560077', (73, 83))	('GSK2256098', 'Chemical', 'MESH:C000600809', (174, 184))	('BID', 'Gene', (209, 212))
66935	30992546	The trametinib dose was reduced in three subjects, the GSK2256098 dose in one, and the dose of both agents in another.	('GSK2256098', 'Var', (55, 65))	('reduced', 'NegReg', (24, 31))	('GSK2256098', 'Chemical', 'MESH:C000600809', (55, 65))	('trametinib', 'Chemical', 'MESH:C560077', (4, 14))	('trametinib', 'Gene', (4, 14))	('GSK', 'molecular_function', 'GO:0050321', ('55', '58'))
66936	30992546	Trametinib exposure (Cmax and AUC) was 2- to 4-fold higher when administered with GSK2256098 versus trametinib monotherapy data (Table 3).	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('Trametinib exposure', 'MPA', (0, 19))	('GSK', 'molecular_function', 'GO:0050321', ('82', '85'))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('higher', 'PosReg', (52, 58))	('GSK2256098', 'Var', (82, 92))	('GSK2256098', 'Chemical', 'MESH:C000600809', (82, 92))
66938	30992546	The median time to Cmax (tmax) for GSK2256098 was generally 2 h post-dose for GSK2256098 and 1.5 to 2.5 h post-dose for trametinib.	('GSK2256098', 'Var', (35, 45))	('GSK2256098', 'Chemical', 'MESH:C000600809', (78, 88))	('trametinib', 'Chemical', 'MESH:C560077', (120, 130))	('GSK', 'molecular_function', 'GO:0050321', ('35', '38'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (35, 45))	('GSK', 'molecular_function', 'GO:0050321', ('78', '81'))	('GSK2256098', 'Var', (78, 88))
66939	30992546	The tmax of trametinib was slightly delayed with GSK2256098 co-administration.	('GSK2256098', 'Var', (49, 59))	('GSK', 'molecular_function', 'GO:0050321', ('49', '52'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (49, 59))	('tmax', 'MPA', (4, 8))	('delayed', 'NegReg', (36, 43))	('trametinib', 'Chemical', 'MESH:C560077', (12, 22))
66959	30992546	The mechanism of the pharmacokinetic interaction between GSK2256098 and trametinib is not fully understood, but in vitro investigation found that GSK2256098 inhibits deacetylation of trametinib by inhibiting human carboxylesterases (eg, hCES1b, hCES1c, and hCES2) and potentially other esterases (GSK data on file).	('inhibiting', 'NegReg', (197, 207))	('esterases', 'Enzyme', (286, 295))	('GSK', 'molecular_function', 'GO:0050321', ('146', '149'))	('deacetylation', 'MPA', (166, 179))	('GSK2256098', 'Var', (146, 156))	('hCES2', 'Gene', '8824', (257, 262))	('GSK', 'molecular_function', 'GO:0050321', ('57', '60'))	('human', 'Species', '9606', (208, 213))	('hCES1c', 'Enzyme', (245, 251))	('inhibits', 'NegReg', (157, 165))	('hCES1b', 'Enzyme', (237, 243))	('carboxylesterases', 'Gene', '8824', (214, 231))	('GSK2256098', 'Chemical', 'MESH:C000600809', (146, 156))	('GSK2256098', 'Chemical', 'MESH:C000600809', (57, 67))	('carboxylesterases', 'Gene', (214, 231))	('hCES2', 'Gene', (257, 262))	('trametinib', 'Chemical', 'MESH:C560077', (72, 82))	('trametinib', 'Chemical', 'MESH:C560077', (183, 193))	('GSK', 'molecular_function', 'GO:0050321', ('297', '300'))
66961	30992546	GSK2256098 also appears to impact trametinib's absorption, based on the delayed tmax in this study relative to historical trametinib monotherapy data.	('tmax', 'MPA', (80, 84))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (0, 10))	('trametinib', 'Chemical', 'MESH:C560077', (122, 132))	('trametinib', 'Chemical', 'MESH:C560077', (34, 44))	('trametinib', 'Gene', (34, 44))	('absorption', 'MPA', (47, 57))	('impact', 'Reg', (27, 33))	('GSK2256098', 'Var', (0, 10))
66965	30992546	Of note was the better tolerability of the high GSK2256098/low trametinib MTD versus the low GSK2256098/high trametinib dose level.	('GSK2256098', 'Chemical', 'MESH:C000600809', (48, 58))	('trametinib', 'Chemical', 'MESH:C560077', (109, 119))	('GSK', 'molecular_function', 'GO:0050321', ('48', '51'))	('GSK2256098/low', 'Var', (48, 62))	('GSK2256098', 'Chemical', 'MESH:C000600809', (93, 103))	('high GSK2256098/low', 'Var', (43, 62))	('tolerability', 'MPA', (23, 35))	('trametinib', 'Chemical', 'MESH:C560077', (63, 73))	('better', 'PosReg', (16, 22))	('GSK', 'molecular_function', 'GO:0050321', ('93', '96'))
66966	30992546	The results of the present study showed almost equivalent effect between GSK2256098 + trametinib combination and those from an earlier GSK2256098 monotherapy study in terms of reduction of FAK levels.	('reduction', 'NegReg', (176, 185))	('GSK2256098', 'Var', (73, 83))	('FAK', 'Gene', '5747', (189, 192))	('GSK2256098', 'Chemical', 'MESH:C000600809', (135, 145))	('FAK', 'molecular_function', 'GO:0004717', ('189', '192'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (73, 83))	('trametinib', 'Chemical', 'MESH:C560077', (86, 96))	('GSK', 'molecular_function', 'GO:0050321', ('73', '76'))	('FAK', 'Gene', (189, 192))	('GSK', 'molecular_function', 'GO:0050321', ('135', '138'))
66968	30992546	Pharmacodynamic studies demonstrated that GSK2256098 inhibited pFAK at the doses evaluated.	('GSK2256098', 'Chemical', 'MESH:C000600809', (42, 52))	('inhibited', 'NegReg', (53, 62))	('FAK', 'Gene', (64, 67))	('FAK', 'Gene', '5747', (64, 67))	('GSK2256098', 'Var', (42, 52))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))
66992	29602801	Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma.	('patients', 'Species', '9606', (215, 223))	('GM-CSF', 'Gene', (144, 150))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (63, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (229, 241))	('mesothelioma', 'Disease', (63, 75))	('targeting', 'Var', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mesothelioma', 'Disease', (229, 241))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (63, 82))	('mesothelioma tumors', 'Disease', (63, 82))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (63, 81))
67019	29602801	Tissue samples were digested using type II collagenase (Worthington) for 3 hours at 37 C. Immune populations were identified by staining with anti-CD11b, anti-HLA-DR, anti-CD13, anti-CD14, anti-CD15, anti-CD66b, and anti CD45 antibodies (BD Biosciences) on ice or at room temperature for 30 minutes.	('anti-HLA-DR', 'Var', (154, 165))	('CD11b', 'Gene', '3684', (147, 152))	('CD15', 'Gene', '2526', (194, 198))	('CD15', 'Gene', (194, 198))	('CD66b', 'Gene', '1088', (205, 210))	('CD45', 'Gene', (221, 225))	('CD11b', 'Gene', (147, 152))	('CD45', 'Gene', '5788', (221, 225))	('CD14', 'Gene', (183, 187))	('CD66b', 'Gene', (205, 210))	('CD13', 'Gene', '290', (172, 176))	('CD13', 'Gene', (172, 176))	('CD14', 'Gene', '929', (183, 187))	('CD13', 'molecular_function', 'GO:0004179', ('172', '176'))
67055	29602801	Flow cytometric analysis of 18 digested human mesothelioma tumors confirmed this data at the cellular level within the tumor microenvironment (mean: CD15 = 8.6%, CD14 = 4.8%, CD3 = 6.7%; Fig.	('tumor', 'Disease', (119, 124))	('human', 'Species', '9606', (40, 45))	('CD15', 'Gene', '2526', (149, 153))	('tumor', 'Disease', (59, 64))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (46, 65))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (46, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CD14', 'Gene', (162, 166))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (46, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CD14', 'Gene', '929', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CD3', 'Var', (175, 178))	('CD15', 'Gene', (149, 153))	('mesothelioma tumors', 'Disease', (46, 65))
67084	29602801	In a mesothelioma murine model, ROS have been demonstrated to suppress T-cell responses.	('suppress', 'NegReg', (62, 70))	('murine', 'Species', '10090', (18, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (5, 17))	('ROS', 'Var', (32, 35))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('T-cell responses', 'CPA', (71, 87))	('mesothelioma', 'Disease', (5, 17))
67094	29602801	The findings suggest that in the tumor, granulocyte PDL1 may be a secondary mechanism of modulating T-cell numbers inside the tumor microenvironment, but not peripherally.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (126, 131))	('PDL1', 'Gene', '29126', (52, 56))	('T-cell numbers', 'CPA', (100, 114))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('granulocyte', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PDL1', 'Gene', (52, 56))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('modulating', 'Reg', (89, 99))
67114	29602801	Culture of healthy-donor granulocytes with individual recombinant cytokines identified above showed that GM-CSF led to the highest upregulation of ROS production (Fig.	('upregulation', 'PosReg', (131, 143))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('GM-CSF', 'Var', (105, 111))	('ROS production', 'MPA', (147, 161))	('donor', 'Species', '9606', (19, 24))
67143	29602801	In a murine model of mesothelioma, prostaglandin inhibition reduced the number of granulocytic MDSCs.	('mesothelioma', 'Disease', (21, 33))	('murine', 'Species', '10090', (5, 11))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('prostaglandin', 'Protein', (35, 48))	('reduced', 'NegReg', (60, 67))	('prostaglandin', 'Chemical', 'MESH:D011453', (35, 48))	('inhibition', 'Var', (49, 59))	('number', 'CPA', (72, 78))
67225	30689265	The viability of HMM cells cultured with 5 and 10 mmol/L glucose was significantly decreased by metformin treatment, but this feature was minimally affected in HMM cells precultured under glucose-deficient conditions (Figure 1B,C).	('viability', 'CPA', (4, 13))	('decreased', 'NegReg', (83, 92))	('metformin', 'Var', (96, 105))	('glucose-deficient conditions', 'Disease', (188, 216))	('glucose', 'Chemical', 'MESH:D005947', (188, 195))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('metformin', 'Chemical', 'MESH:D008687', (96, 105))	('glucose-deficient conditions', 'Disease', 'MESH:D044882', (188, 216))
67231	30689265	Furthermore, either metformin treatment or glucose starvation increased the expression of cleaved Parp-1 (Figure 2B).	('increased', 'PosReg', (62, 71))	('cleaved', 'Var', (90, 97))	('Parp-1', 'Gene', '142', (98, 104))	('metformin', 'Chemical', 'MESH:D008687', (20, 29))	('Parp-1', 'Gene', (98, 104))	('expression', 'MPA', (76, 86))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))
67239	30689265	In particular, MDR1 mRNA expression in glucose-starved cells with metformin treatment was approximately 10-fold higher than those cells cultured in complete medium.	('higher', 'PosReg', (112, 118))	('MDR1', 'Gene', '5243', (15, 19))	('MDR', 'molecular_function', 'GO:0004745', ('15', '18'))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('mRNA expression', 'MPA', (20, 35))	('metformin treatment', 'Var', (66, 85))	('metformin', 'Chemical', 'MESH:D008687', (66, 75))	('MDR1', 'Gene', (15, 19))
67258	30689265	In the mPTP assay, the FITC intensity was significantly increased in HMM cells cultured under glucose-starved conditions or metformin treatment, but not in glucose-starved HMM cells with metformin treatment (Figure 4D).	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('metformin', 'Chemical', 'MESH:D008687', (187, 196))	('increased', 'PosReg', (56, 65))	('glucose', 'Chemical', 'MESH:D005947', (156, 163))	('FITC', 'Chemical', 'MESH:D016650', (23, 27))	('metformin', 'Var', (124, 133))	('mPTP', 'Chemical', 'MESH:D015632', (7, 11))	('FITC intensity', 'MPA', (23, 37))	('metformin', 'Chemical', 'MESH:D008687', (124, 133))
67263	30689265	To evaluate whether MDR1 is directly mediated metformin resistance in glucose-starved HMM cells, MDR1 was knocked out using the CRISPR/CAS9 system.	('MDR', 'molecular_function', 'GO:0004745', ('97', '100'))	('MDR', 'molecular_function', 'GO:0004745', ('20', '23'))	('MDR1', 'Gene', (20, 24))	('knocked', 'Var', (106, 113))	('CAS', 'cellular_component', 'GO:0005650', ('135', '138'))	('MDR1', 'Gene', '5243', (20, 24))	('glucose', 'Chemical', 'MESH:D005947', (70, 77))	('MDR1', 'Gene', (97, 101))	('metformin', 'Chemical', 'MESH:D008687', (46, 55))	('MDR1', 'Gene', '5243', (97, 101))
67264	30689265	The MDR1 gene was significantly decreased close to zero in MDR1 knockout (KO) HMM cells compared with control cells (Figure 5A).	('knockout', 'Var', (64, 72))	('MDR1', 'Gene', (4, 8))	('MDR1', 'Gene', (59, 63))	('MDR1', 'Gene', '5243', (59, 63))	('MDR1', 'Gene', '5243', (4, 8))	('MDR', 'molecular_function', 'GO:0004745', ('4', '7'))	('decreased', 'NegReg', (32, 41))	('MDR', 'molecular_function', 'GO:0004745', ('59', '62'))
67276	30689265	Therefore, during glucose starvation, metabolism-altered HMM cells survived for 3 days and exhibited enhanced resistance to metformin.	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('metabolism-altered', 'Var', (38, 56))	('resistance to metformin', 'MPA', (110, 133))	('enhanced', 'PosReg', (101, 109))	('metabolism', 'biological_process', 'GO:0008152', ('38', '48'))	('metformin', 'Chemical', 'MESH:D008687', (124, 133))
67287	30689265	Therefore, MMP hyperpolarization in the treatment of glucose-starved HMM cells with metformin promotes Mdr1 overexpression in compromised mitochondria.	('metformin', 'Chemical', 'MESH:D008687', (84, 93))	('Mdr', 'molecular_function', 'GO:0004745', ('103', '106'))	('MMP', 'Var', (11, 14))	('Mdr1', 'Gene', (103, 107))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('Mdr1', 'Gene', '5243', (103, 107))	('mitochondria', 'cellular_component', 'GO:0005739', ('138', '150'))	('overexpression', 'PosReg', (108, 122))	('MMP', 'molecular_function', 'GO:0004235', ('11', '14'))
67299	30689265	The present study demonstrated that overexpressed Mdr1 in defected mitochondria rescued glucose-starved HMM cells from metformin treatment.	('Mdr1', 'Gene', (50, 54))	('overexpressed', 'Var', (36, 49))	('metformin', 'Chemical', 'MESH:D008687', (119, 128))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('Mdr', 'molecular_function', 'GO:0004745', ('50', '53'))	('mitochondria', 'cellular_component', 'GO:0005739', ('67', '79'))	('Mdr1', 'Gene', '5243', (50, 54))
67329	29618661	Also increased in TiME-II tumors were neutrophils, conventional DCs (cDC), cancer-associated fibroblasts (CAF), and tumor-associated macrophages (TAM) with high PD-L1, which were associated with greater IL-10 production and phosphorylation of Akt and NF-kappabeta (Figure 2D and Supplemental Figure 5).	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('increased', 'PosReg', (5, 14))	('phosphorylation', 'MPA', (224, 239))	('NF-kappabeta', 'Gene', (251, 263))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('conventional DCs', 'Disease', (51, 67))	('Akt', 'Gene', (243, 246))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (26, 31))	('NF-kappabeta', 'Gene', '4790', (251, 263))	('TiME-II tumors', 'Disease', (18, 32))	('high', 'Var', (156, 160))	('IL-10', 'Gene', '3586', (203, 208))	('Akt', 'Gene', '207', (243, 246))	('greater', 'PosReg', (195, 202))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('IL-10', 'Gene', (203, 208))	('IL-10 production', 'biological_process', 'GO:0032613', ('203', '219'))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PD-L1', 'Gene', (161, 166))	('IL-10', 'molecular_function', 'GO:0005141', ('203', '208'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PD-L1', 'Gene', '29126', (161, 166))	('tumor', 'Disease', (116, 121))	('TiME-II tumors', 'Disease', 'MESH:D000377', (18, 32))
67330	29618661	Neoantigens have recently been shown to influence the clinical behavior and response to immunotherapy in a number of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('influence', 'Reg', (40, 49))	('human', 'Species', '9606', (117, 122))	('Neoantigens', 'Var', (0, 11))	('malignancies', 'Disease', (123, 135))	('clinical behavior', 'CPA', (54, 71))
67335	29618661	From next-generation sequencing data from a total of 640 tumors in the Brigham Women's Hospital (BWH) and Memorial Sloan Kettering Cancer Center (MSKCC) cohorts and the COSMIC database (http://cancer.sanger.ac.uk/cosmic), we generated a reference database containing 2,299 missense mutation sites in 1,885 genes where a detected mutation alters the amino acid sequence (Supplemental Figure 7 and Supplemental Table 3) in order to create a list of potential mutated peptides.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('Women', 'Species', '9606', (79, 84))	('cancer', 'Disease', (193, 199))	('mutation', 'Var', (329, 337))	('Memorial Sloan Kettering Cancer', 'Disease', (106, 137))	('amino acid sequence', 'MPA', (349, 368))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (106, 137))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('alters', 'Reg', (338, 344))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
67339	29618661	As an example, the RBP3V282M (GESDFFFTVPMS) neopeptide that is predicted to have high affinity to HLA-B*18:01 in patient MPM.003 (TiME-I) demonstrated high abundance in this tumor (Figure 3A).	('tumor', 'Disease', (174, 179))	('patient', 'Species', '9606', (113, 120))	('MPM', 'Chemical', '-', (121, 124))	('RBP3V282M', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('HLA-B', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('HLA-B', 'Gene', '3106', (98, 103))
67346	29618661	For example, in a patient with a TiME-I tumor (MPM.003; HLA-A*01:01, HLA-A*30:02, and HLA-B*18:01), the BAP1N645K neoantigen (LKCVEAEIAKY) (derived from the most common gene mutation in MPM; ref.)	('HLA-B', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('HLA-B', 'Gene', '3106', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HLA-A', 'Gene', '3105', (69, 74))	('MPM', 'Chemical', '-', (186, 189))	('BAP1N645K', 'Var', (104, 113))	('HLA-A', 'Gene', '3105', (56, 61))	('patient', 'Species', '9606', (18, 25))	('MPM', 'Chemical', '-', (47, 50))	('HLA-A', 'Gene', (69, 74))	('tumor', 'Disease', (40, 45))	('HLA-A', 'Gene', (56, 61))
67348	29618661	In contrast, in a patient with a TiME-II tumor (MPM.004; HLA-A*26:01, HLA-DRB1*08:01, and HLA-DRB1*13:01), the NF2E166V neoantigens (QVELLPKRVINLY and RGFLAQVELLPKRVI) with high predicted affinity to HLA-A and HLA-DRB1, respectively, were demonstrated at low abundance, along with low expression of its corresponding HLA proteins (Figure 3D).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TiME-II tumor', 'Disease', 'MESH:D000377', (33, 46))	('MPM', 'Chemical', '-', (48, 51))	('HLA', 'Gene', (200, 203))	('TiME-II tumor', 'Disease', (33, 46))	('HLA', 'Gene', (57, 60))	('patient', 'Species', '9606', (18, 25))	('HLA-DRB1', 'Gene', (90, 98))	('HLA', 'Gene', '3113', (70, 73))	('HLA', 'Gene', (317, 320))	('NF2E166V', 'Var', (111, 119))	('HLA', 'Gene', '3113', (210, 213))	('HLA-DRB1', 'Gene', '3123', (70, 78))	('HLA-A', 'Gene', (200, 205))	('HLA', 'Gene', '3113', (90, 93))	('HLA', 'Gene', (70, 73))	('HLA-A', 'Gene', (57, 62))	('HLA-DRB1', 'Gene', '3123', (210, 218))	('expression', 'MPA', (285, 295))	('HLA', 'Gene', (210, 213))	('HLA-DRB1', 'Gene', (70, 78))	('HLA', 'Gene', (90, 93))	('HLA', 'Gene', '3113', (200, 203))	('HLA', 'Gene', '3113', (57, 60))	('HLA-DRB1', 'Gene', (210, 218))	('HLA-A', 'Gene', '3105', (200, 205))	('HLA', 'Gene', '3113', (317, 320))	('HLA-DRB1', 'Gene', '3123', (90, 98))	('HLA-A', 'Gene', '3105', (57, 62))
67363	29618661	Notably, mutational load, neoantigen burden, copy number alteration, and diversity of T cell clonality did not correlate with patients likely to respond to PD-1 blockade (i.e., good-TiME tumors) (Supplemental Figure 14).	('good-TiME tumors', 'Disease', 'MESH:D000377', (177, 193))	('mutational', 'Var', (9, 19))	('PD-1 blockade', 'Disease', (156, 169))	('good-TiME tumors', 'Disease', (177, 193))	('PD-1 blockade', 'Disease', 'MESH:D010300', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('patients', 'Species', '9606', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
67395	29618661	Next-generation sequencing data from the BWH cohort, the MSKCC cohort, and the COSMIC database (http://cancer.sanger.ac.uk/cosmic) were used to generate a reference database containing 2,299 missense mutation sites in 1,885 proteins from 640 MPM tumors where a detected mutation alters the amino acid sequence (Supplemental Figure 7 and Supplemental Table 3).	('MPM tumors', 'Disease', 'MESH:D009369', (242, 252))	('mutation', 'Var', (270, 278))	('amino acid sequence', 'MPA', (290, 309))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('alters', 'Reg', (279, 285))	('missense mutation', 'Var', (191, 208))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', (103, 109))	('MPM tumors', 'Disease', (242, 252))
67402	29618661	We then applied standard prediction algorithms of the IEDB (http://www.iedb.org/) for identification of HLA class I and class II predicted neopeptides on all missense mutations and measured the AUC in MS, representing the amount of measured peptide ligands, termed neoantigen abundance.	('HLA', 'Gene', (104, 107))	('missense mutations', 'Var', (158, 176))	('HLA', 'Gene', '3113', (104, 107))	('AUC in MS', 'MPA', (194, 203))
67412	29618661	To consider HLA binding strength relative to its nonmutant (WT) counterpart, peptides with IEDB percentile rank <=2% affinity to mutant peptide sequence and rank >2% affinity to WT peptide sequence were regarded as potential binders to MHC-I.	('HLA', 'Gene', (12, 15))	('HLA', 'Gene', '3113', (12, 15))	('MHC', 'Gene', (236, 239))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('binders', 'Interaction', (225, 232))	('MHC', 'Gene', '3107', (236, 239))	('affinity', 'MPA', (117, 125))	('mutant', 'Var', (129, 135))
67413	29618661	Among them, peptides with IEDB percentile rank <=1% affinity to mutant peptide sequence and rank >1% affinity to WT peptide sequence were regarded as those with high affinity to MHC-I, and the others were regarded as those with intermediate affinity to MHC-I (Supplemental Table 6).	('MHC', 'Gene', (253, 256))	('MHC', 'Gene', (178, 181))	('MHC', 'Gene', '3107', (253, 256))	('affinity', 'MPA', (52, 60))	('MHC', 'Gene', '3107', (178, 181))	('mutant', 'Var', (64, 70))
67414	29618661	Peptides with IEDB percentile rank <=10% affinity to mutant peptide sequence and rank >10% affinity to WT peptide sequence were regarded as potential binders to MHC-II.	('MHC', 'Gene', '3107', (161, 164))	('affinity', 'MPA', (41, 49))	('binders', 'Interaction', (150, 157))	('mutant', 'Var', (53, 59))	('MHC', 'Gene', (161, 164))
67415	29618661	Among them, peptides with IEDB percentile rank <=5% affinity to mutant peptide sequence and rank >5% affinity to WT peptide sequence were regarded as those with high affinity to MHC-II, and the others were regarded as those with intermediate affinity to MHC-II (Supplemental Table 7).	('MHC', 'Gene', '3107', (254, 257))	('MHC', 'Gene', (178, 181))	('affinity', 'MPA', (52, 60))	('MHC', 'Gene', '3107', (178, 181))	('mutant', 'Var', (64, 70))	('MHC', 'Gene', (254, 257))
67440	29127457	In 2006, a previously uncharacterized facilitative transporter (SLC46A1), the proton-coupled folate transporter (PCFT), was reported to mediate uptake of dietary folates in the duodenum, with mutations in PCFT resulting in a rare autosomal recessive disorder, hereditary folate malabsorption.	('SLC46A1', 'Gene', '113235', (64, 71))	('folates', 'Chemical', 'MESH:D005492', (162, 169))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (230, 258))	('autosomal recessive disorder', 'Disease', (230, 258))	('proton-coupled folate transporter', 'Gene', (78, 111))	('mutations', 'Var', (192, 201))	('uptake', 'biological_process', 'GO:0098657', ('144', '150'))	('PCFT', 'Gene', (113, 117))	('uptake', 'MPA', (144, 150))	('PCFT', 'Gene', '113235', (113, 117))	('hereditary folate malabsorption', 'Disease', 'MESH:C562799', (260, 291))	('uptake', 'biological_process', 'GO:0098739', ('144', '150'))	('malabsorption', 'Phenotype', 'HP:0002024', (278, 291))	('hereditary folate malabsorption', 'Disease', (260, 291))	('PCFT', 'Gene', (205, 209))	('proton-coupled folate transporter', 'Gene', '113235', (78, 111))	('resulting in', 'Reg', (210, 222))	('PCFT', 'Gene', '113235', (205, 209))	('SLC46A1', 'Gene', (64, 71))
67457	29127457	For 2nd generation GARFTase inhibitors (i.e., LY309887, AG2034) (Figure 1), replacement of the 1,4-phenyl by a 2,5-thienyl ring increased drug potency over LMX.	('LMX', 'Chemical', 'MESH:C045894', (156, 159))	('replacement', 'Var', (76, 87))	('increased', 'PosReg', (128, 137))	('LY309887', 'Chemical', 'MESH:C105065', (46, 54))	('drug potency', 'MPA', (138, 150))
67458	29127457	Unfortunately, in phase I clinical trials, LY309887 and AG2034 showed similar toxicities to those encountered with LMX.	('toxicities', 'Disease', 'MESH:D064420', (78, 88))	('LMX', 'Chemical', 'MESH:C045894', (115, 118))	('LY309887', 'Var', (43, 51))	('AG2034', 'Var', (56, 62))	('toxicities', 'Disease', (78, 88))	('LY309887', 'Chemical', 'MESH:C105065', (43, 51))
67460	29127457	GARFTase inhibitors kill tumors independent of wild-type/mutant p53 status, and selectively target tumors secondary to 5'-deoxy-5'-methylthioadenosine (MTA) phosphorylase (MTAP) deletions in many cancers (e.g., non-small cell lung cancer), as MTAP-expressing normal tissues are protected by MTA.	('MTAP', 'Gene', '4507', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('non-small cell lung cancer', 'Disease', (211, 237))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('p53', 'Gene', '7157', (64, 67))	('deletions', 'Var', (178, 187))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (211, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('p53', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	("5'-deoxy-5'-methylthioadenosine", 'Chemical', 'MESH:C008500', (119, 150))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('MTAP', 'Gene', (172, 176))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (215, 237))	('cancers', 'Disease', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (211, 237))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('MTAP', 'Gene', (243, 247))	('MTAP', 'Gene', '4507', (243, 247))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
67464	29127457	Differences in the extent of MTX polyglutamylation between normal tissues and tumors likely contribute to drug selectivity and antitumor efficacy, and to the selectivity of leucovorin rescue from MTX toxicity.	('polyglutamylation', 'Var', (33, 50))	('tumors', 'Disease', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('contribute', 'Reg', (92, 102))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('MTX', 'Chemical', 'MESH:D008727', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (131, 136))	('MTX', 'Chemical', 'MESH:D008727', (196, 199))	('leucovorin', 'Chemical', 'MESH:D002955', (173, 183))	('tumor', 'Disease', (78, 83))	('toxicity', 'Disease', 'MESH:D064420', (200, 208))	('toxicity', 'Disease', (200, 208))
67467	29127457	In cancer cell lines, antifolate resistance due to loss of RFC function results from decreased RFC expression, or from synthesis of mutant RFC with impaired transport function.	('expression', 'MPA', (99, 109))	('synthesis', 'biological_process', 'GO:0009058', ('119', '128'))	('loss', 'NegReg', (51, 55))	('synthesis', 'MPA', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('RFC', 'Gene', '6573', (59, 62))	('function', 'MPA', (63, 71))	('folate', 'Chemical', 'MESH:D005492', (26, 32))	('RFC', 'Gene', '6573', (139, 142))	('RFC', 'Gene', (59, 62))	('antifolate resistance', 'MPA', (22, 43))	('transport', 'biological_process', 'GO:0006810', ('157', '166'))	('RFC', 'Gene', (139, 142))	('RFC', 'Gene', '6573', (95, 98))	('transport function', 'MPA', (157, 175))	('decreased', 'NegReg', (85, 94))	('mutant', 'Var', (132, 138))	('cancer', 'Disease', (3, 9))	('RFC', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
67513	29127457	Conversely, excellent RFC substrates such as the antifolates PT523 and GW1843U89 are poor PCFT substrates.	('RFC', 'Gene', '6573', (22, 25))	('PT523', 'Chemical', 'MESH:C085590', (61, 66))	('GW1843U89', 'Chemical', '-', (71, 80))	('PCFT', 'Gene', '113235', (90, 94))	('folates', 'Chemical', 'MESH:D005492', (53, 60))	('RFC', 'Gene', (22, 25))	('GW1843U89', 'Var', (71, 80))	('PCFT', 'Gene', (90, 94))
67527	29127457	Both shortening (1 carbon; AGF124) and lengthening (3-6 carbons; AGF126, AGF127, AGF128, AGF129) (Figure 3) the bridge region profoundly decreased anti-proliferative activity and PCFT transport, whereas RFC transport was modestly affected up to 5 bridge carbons.	('carbon', 'Chemical', 'MESH:D002244', (254, 260))	('transport', 'biological_process', 'GO:0006810', ('184', '193'))	('RFC', 'Gene', (203, 206))	('carbons', 'Chemical', 'MESH:D002244', (254, 261))	('lengthening', 'Var', (39, 50))	('carbons', 'Chemical', 'MESH:D002244', (56, 63))	('carbon', 'Chemical', 'MESH:D002244', (56, 62))	('PCFT', 'Gene', (179, 183))	('RFC', 'Gene', '6573', (203, 206))	('transport', 'biological_process', 'GO:0006810', ('207', '216'))	('anti-proliferative activity', 'CPA', (147, 174))	('shortening', 'Var', (5, 15))	('carbon', 'Chemical', 'MESH:D002244', (19, 25))	('decreased', 'NegReg', (137, 146))	('PCFT', 'Gene', '113235', (179, 183))
67532	29127457	Hence, isosteric heteroatom substitutions at C10 in AGF17, including N, O, and S (AGF183, AGF182, and AGF140, respectively), (Figure 3) preserved PCFT transport, albeit with slightly decreased (~4-fold) antiproliferative activities toward PCFT-expressing cells.	('PCFT', 'Gene', (146, 150))	('PCFT', 'Gene', '113235', (146, 150))	('antiproliferative activities', 'MPA', (203, 231))	('PCFT', 'Gene', (239, 243))	('preserved', 'PosReg', (136, 145))	('decreased', 'NegReg', (183, 192))	('PCFT', 'Gene', '113235', (239, 243))	('transport', 'biological_process', 'GO:0006810', ('151', '160'))	('AGF17', 'Gene', (52, 57))	('substitutions', 'Var', (28, 41))
67536	29127457	AGF94 (3-carbon bridge) was approximately 10-fold more potent toward PCFT-expressing cells than AGF71 (4-carbon bridge), although this was unrelated to differences in PCFT transport.	('PCFT', 'Gene', '113235', (69, 73))	('AGF94', 'Var', (0, 5))	('transport', 'biological_process', 'GO:0006810', ('172', '181'))	('AGF94', 'Chemical', '-', (0, 5))	('carbon', 'Chemical', 'MESH:D002244', (9, 15))	('PCFT', 'Gene', (167, 171))	('potent', 'MPA', (55, 61))	('PCFT', 'Gene', '113235', (167, 171))	('carbon', 'Chemical', 'MESH:D002244', (105, 111))	('PCFT', 'Gene', (69, 73))
67538	29127457	For AGF94, but not AGF71, modest uptake activity only partly attributed to RFC was also reported.	('RFC', 'Gene', '6573', (75, 78))	('uptake', 'biological_process', 'GO:0098739', ('33', '39'))	('AGF94', 'Var', (4, 9))	('uptake', 'biological_process', 'GO:0098657', ('33', '39'))	('AGF94', 'Chemical', '-', (4, 9))	('uptake activity', 'MPA', (33, 48))	('RFC', 'Gene', (75, 78))
67539	29127457	Replacement of L-glutamate in AGF94 with L-aspartate or with unnatural amino acids (alpha-amino adipate, 4-amino butanoate, alpha-amino pentanoate) abolished PCFT transport.	('AGF94', 'Gene', (30, 35))	('L-glutamate', 'Chemical', 'MESH:D018698', (15, 26))	('AGF94', 'Chemical', '-', (30, 35))	('alpha-amino adipate', 'Chemical', 'MESH:D015074', (84, 103))	('L-aspartate', 'Chemical', 'MESH:D001224', (41, 52))	('abolished', 'NegReg', (148, 157))	('4-amino butanoate', 'Chemical', 'MESH:D005680', (105, 122))	('alpha-amino pentanoate', 'Chemical', '-', (124, 146))	('transport', 'biological_process', 'GO:0006810', ('163', '172'))	('PCFT', 'Gene', (158, 162))	('Replacement', 'Var', (0, 11))	('PCFT', 'Gene', '113235', (158, 162))
67540	29127457	Based on the antitumor activity profiles for the 2',5' thienoyl analogs AGF71 and AGF94, 2',4' (AGF117 and AGF150, respectively) and 3',5' (AGF118 and AGF154, respectively) thienoyl regioisomers (Figure 3) were synthesized; all were potent inhibitors of cell proliferation, directly attributable to their selective transport by PCFT over RFC.	('AGF94', 'Var', (82, 87))	('analogs', 'Chemical', '-', (64, 71))	('tumor', 'Disease', (17, 22))	('transport', 'biological_process', 'GO:0006810', ('315', '324'))	('cell proliferation', 'CPA', (254, 272))	('RFC', 'Gene', (338, 341))	('thienoyl', 'Chemical', '-', (55, 63))	('AGF94', 'Chemical', '-', (82, 87))	('inhibitors', 'NegReg', (240, 250))	('PCFT', 'Gene', (328, 332))	('PCFT', 'Gene', '113235', (328, 332))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('RFC', 'Gene', '6573', (338, 341))	('thienoyl', 'Chemical', '-', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('254', '272'))
67542	29127457	When HeLa cells were incubated with AGF71 and AGF94 (16 h, pH 6.8), AGF94 polyglutamates accumulated to an ~8-fold greater extent than for AGF71, paralleling differences (~10-fold) in antiproliferative activities.	('antiproliferative activities', 'CPA', (184, 212))	('AGF94', 'Var', (68, 73))	('pH', 'Gene', '2821', (59, 61))	('HeLa', 'CellLine', 'CVCL:0030', (5, 9))	('AGF94', 'Chemical', '-', (68, 73))	('greater', 'PosReg', (115, 122))	('polyglutamates', 'Protein', (74, 88))	('polyglutamates', 'Chemical', 'MESH:D011099', (74, 88))	('accumulated', 'PosReg', (89, 100))	('AGF94', 'Chemical', '-', (46, 51))
67543	29127457	Following cellular uptake by PCFT, the 6-substituted pyrrolo[2,3-d]pyrimidine compounds [AGF17, AGF23, AGF71, AGF94, AGF140, AGF150, AGF154, AGF174, AGF182, AGF183, AGF209, and AGF219] all targeted GARFTase, the first folate-dependent step in the 10 step sequence from phosphoribosyl pyrophosphate (PRPP) to inosine monophosphate (IMP) (Figure 4), resulting in inhibition of de novo purine nucleotide biosynthesis and ATP depletion.	('ATP', 'Chemical', 'MESH:D000255', (418, 421))	('PCFT', 'Gene', (29, 33))	('AGF219]', 'Var', (177, 184))	('ATP depletion', 'MPA', (418, 431))	('PCFT', 'Gene', '113235', (29, 33))	('uptake', 'biological_process', 'GO:0098739', ('19', '25'))	('folate', 'Chemical', 'MESH:D005492', (218, 224))	('purine nucleotide biosynthesis', 'biological_process', 'GO:0006164', ('383', '413'))	('purine nucleotide', 'Chemical', 'MESH:D011685', (383, 400))	('de novo purine nucleotide biosynthesis', 'MPA', (375, 413))	('6-substituted pyrrolo[2,3-d]pyrimidine', 'Chemical', '-', (39, 77))	('inhibition', 'NegReg', (361, 371))	('AGF140', 'Var', (117, 123))	('AGF183', 'Var', (157, 163))	('AGF94', 'Chemical', '-', (110, 115))	('IMP', 'cellular_component', 'GO:0042720', ('331', '334'))	('targeted', 'Reg', (189, 197))	('IMP', 'molecular_function', 'GO:0004244', ('331', '334'))	('AGF209', 'Var', (165, 171))	('uptake', 'biological_process', 'GO:0098657', ('19', '25'))
67544	29127457	By in vitro assays with purified human GARFTase (formyltransferase domain), inhibition by 6-substituted pyrrolo[2,3-d]pyrimidine analogs including AGF23, AGF71, AGF94, AGF117, AGF118, AGF150, AGF154 and AGF183 was confirmed with IC50 values in the low-to-mid nanomolar concentration range.	('AGF94', 'Var', (161, 166))	('AGF94', 'Chemical', '-', (161, 166))	('AGF117', 'Var', (168, 174))	('AGF71', 'Var', (154, 159))	('AGF23', 'Var', (147, 152))	('human', 'Species', '9606', (33, 38))	('6-substituted pyrrolo[2,3-d]pyrimidine', 'Chemical', '-', (90, 128))	('analogs', 'Chemical', '-', (129, 136))
67548	29127457	Thus, dual FR- and PCFT-targeted analogs such as AGF94 and AGF154 would offer significant advantages over current iterations of exclusively FRalpha-targeted agents in clinical development for epithelial ovarian cancer, which would be expected to be less efficacious toward tumors expressing modest levels of FRalpha, along with high FRalpha-expressing tumors.	('advantages', 'PosReg', (90, 100))	('FRalpha', 'Gene', '8061', (308, 315))	('AGF154', 'Var', (59, 65))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (192, 217))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('FRalpha', 'Gene', (333, 340))	('ovarian cancer', 'Phenotype', 'HP:0100615', (203, 217))	('PCFT', 'Gene', (19, 23))	('AGF94', 'Gene', (49, 54))	('PCFT', 'Gene', '113235', (19, 23))	('FRalpha', 'Gene', '8061', (140, 147))	('AGF94', 'Chemical', '-', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('FRalpha', 'Gene', (308, 315))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (192, 217))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('analogs', 'Chemical', '-', (33, 40))	('tumors', 'Disease', (273, 279))	('FRalpha', 'Gene', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('FRalpha', 'Gene', '8061', (333, 340))	('epithelial ovarian cancer', 'Disease', (192, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', (352, 358))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
67550	29127457	By colony-forming assays with H460 and IGROV1 cells treated with AGF94 under conditions that favor PCFT transport (24 h, pH 6.8), AGF94 was cytotoxic to a far greater extent than PMX (Figure 5 shows results with IGROV1 cells).	('AGF94', 'Var', (130, 135))	('PMX', 'Chemical', 'MESH:D000068437', (179, 182))	('AGF94', 'Gene', (65, 70))	('cytotoxic', 'CPA', (140, 149))	('AGF94', 'Chemical', '-', (130, 135))	('pH', 'Gene', '2821', (121, 123))	('PCFT', 'Gene', (99, 103))	('transport', 'biological_process', 'GO:0006810', ('104', '113'))	('AGF94', 'Chemical', '-', (65, 70))	('PCFT', 'Gene', '113235', (99, 103))
67551	29127457	In vivo antitumor efficacies were confirmed for AGF94 and/or AGF154 with early and late-stage H2452 malignant pleural mesothelioma (Figure 6), early-stage H460 non-small cell lung cancer, and IGROV1 epithelial ovary cancer (subcutaneous) xenografts in severe-combined immunodeficient (SCID) mice.	('ovary cancer', 'Phenotype', 'HP:0100615', (210, 222))	('epithelial ovary cancer', 'Phenotype', 'HP:0025318', (199, 222))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (100, 130))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (110, 130))	('tumor', 'Disease', (12, 17))	('mice', 'Species', '10090', (291, 295))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (160, 186))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('AGF94', 'Var', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('AGF94', 'Chemical', '-', (48, 53))	('epithelial ovary cancer', 'Disease', 'MESH:D000077216', (199, 222))	('immunodeficient', 'Disease', 'MESH:D007153', (268, 283))	('immunodeficient', 'Disease', (268, 283))	('epithelial ovary cancer', 'Disease', (199, 222))	('AGF154', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('IGROV1', 'Gene', (192, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('non-small cell lung cancer', 'Disease', (160, 186))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('malignant pleural mesothelioma', 'Disease', (100, 130))	('SCID', 'Disease', 'MESH:D053632', (285, 289))	('SCID', 'Disease', (285, 289))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
67561	29127457	Cancers with mutant BCRA would also likely show increased sensitivities to inhibitors of de novo purine biosynthesis.	('mutant', 'Var', (13, 19))	('purine', 'Chemical', 'MESH:C030985', (97, 103))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('BCRA', 'Gene', (20, 24))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('sensitivities', 'MPA', (58, 71))	('de novo purine biosynthesis', 'biological_process', 'GO:0006189', ('89', '116'))
67640	29298350	The RNase activity was also determined to be critical for apoptosis induction in MDA-MB231 human breast cancer cells, as an amino acid-replaced mutant of cSBL that lacked RNase activity did not exhibit the apoptosis-inducing effect, even when internalized into the cells like native cSBL.	('cSBL', 'Gene', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('RNase activity', 'molecular_function', 'GO:0004522', ('171', '185'))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('MDA-MB231', 'CellLine', 'CVCL:0062', (81, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('RNase activity', 'molecular_function', 'GO:0004522', ('4', '18'))	('breast cancer', 'Disease', (97, 110))	('mutant', 'Var', (144, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('human', 'Species', '9606', (91, 96))
67677	29298350	The percentage of Annexin V-positive cells was significantly increased in both H2452 (16.13%, 72 h) and MSTO (40.05%, 72 h) cells (Fig 2A and 2B).	('MSTO', 'Gene', (104, 108))	('H2452', 'CellLine', 'CVCL:1553', (79, 84))	('Annexin V', 'Gene', '308', (18, 27))	('Annexin V', 'Gene', (18, 27))	('H2452', 'Var', (79, 84))	('increased', 'PosReg', (61, 70))
67692	29298350	In H2452 cells, all combinations decreased cell viability to a greater extent than each single treatment over the whole concentration range.	('decreased', 'NegReg', (33, 42))	('combinations', 'Var', (20, 32))	('cell viability', 'CPA', (43, 57))	('H2452', 'CellLine', 'CVCL:1553', (3, 8))
67708	29298350	In H2452 xenografted groups, cSBL showed a tumor-suppressive effect earlier than that of the pemetrexed-treated group, and the antitumor effect of pemetrexed was not observed in the MSTO xenografts (Fig 4C and 4D).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('H2452', 'Var', (3, 8))	('pemetrexed', 'Chemical', 'MESH:D000068437', (147, 157))	('tumor', 'Disease', (131, 136))	('H2452', 'CellLine', 'CVCL:1553', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('pemetrexed', 'Chemical', 'MESH:D000068437', (93, 103))	('tumor', 'Disease', (43, 48))
67710	29298350	We were unable to compare the effects of cSBL and pemetrexed directly due to the differences in the dosing conditions; however, our observations indicate that cSBL could potentially inhibit the tumor growth of mesothelioma without any toxicity, even if previously established pemetrexed administration had little or no effect.	('toxicity', 'Disease', (235, 243))	('pemetrexed', 'Chemical', 'MESH:D000068437', (50, 60))	('mesothelioma', 'Disease', (210, 222))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cSBL', 'Var', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('inhibit', 'NegReg', (182, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (210, 222))	('tumor', 'Disease', (194, 199))	('pemetrexed', 'Chemical', 'MESH:D000068437', (276, 286))	('toxicity', 'Disease', 'MESH:D064420', (235, 243))
67743	24824231	More importantly our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers.	('mesothelioma', 'Disease', (171, 183))	('SS1P', 'Var', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('patients', 'Species', '9606', (148, 156))	('pentostatin', 'Chemical', 'MESH:D015649', (73, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('patients', 'Species', '9606', (247, 255))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancers', 'Disease', (273, 280))	('tumor', 'Disease', (128, 133))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (89, 105))	('SS1P', 'Chemical', 'MESH:C474515', (48, 52))
67763	24824231	To determine if the antibody could be used to kill tumor cells, a fragment of Pseudomonas exotoxin A (PE) was attached to the antibody and the resulting immunotoxin (K1-LysPE38QQR) was shown to kill mesothelin expressing cell lines and to cause regressions of a mesothelin-expressing tumor in mice.	('cause', 'Reg', (239, 244))	('antibody', 'cellular_component', 'GO:0019814', ('20', '28'))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('mesothelin-expressing', 'Gene', (262, 283))	('tumor', 'Disease', (51, 56))	('antibody', 'molecular_function', 'GO:0003823', ('20', '28'))	('regressions', 'CPA', (245, 256))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('antibody', 'cellular_component', 'GO:0042571', ('20', '28'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('K1-LysPE38QQR', 'Var', (166, 179))	('antibody', 'cellular_component', 'GO:0019815', ('20', '28'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (293, 297))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('kill mesothelin expressing cell lines', 'CPA', (194, 231))	('tumor', 'Disease', (284, 289))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))
67766	24824231	The affinity of SS was low, but was improved to a Kd of about 1nM by mutagenizing residues in the CDR3 of the heavy chain of the Fv using a new technique called hot spot mutagenesis.	('CDR3', 'Gene', (98, 102))	('mutagenizing', 'Var', (69, 81))	('mutagenesis', 'biological_process', 'GO:0006280', ('170', '181'))	('improved', 'PosReg', (36, 44))	('affinity', 'Interaction', (4, 12))	('CDR3', 'Gene', '8163', (98, 102))
67767	24824231	The new Fv (SS1) was used to make a recombinant immunotoxin, termed SS1P, by fusing the Fv to a 38-kDa fragment of PE.	('SS1', 'Gene', '3123', (68, 71))	('SS1', 'Gene', (68, 71))	('SS1P', 'Chemical', 'MESH:C474515', (68, 72))	('SS1', 'Gene', '3123', (12, 15))	('fusing', 'Var', (77, 83))	('SS1', 'Gene', (12, 15))
67790	24824231	Recently it was shown that in patients with early-stage lung adenocarcinoma overexpression of mesothelin is associated with decreased overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('overexpression', 'Var', (76, 90))	('lung adenocarcinoma', 'Disease', (56, 75))	('mesothelin', 'Protein', (94, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('decreased', 'NegReg', (124, 133))	('patients', 'Species', '9606', (30, 38))	('overall survival', 'MPA', (134, 150))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))
67792	24824231	Results of several ongoing clinical trials of immunotherapy agents directed against mesothelin have shown that targeting mesothelin is safe and does not result in toxicity to essential normal tissues.	('mesothelin', 'Gene', (121, 131))	('toxicity', 'Disease', (163, 171))	('targeting', 'Var', (111, 120))	('toxicity', 'Disease', 'MESH:D064420', (163, 171))
67803	24824231	Results of this clinical trial showed that SS1P can be safely combined with pemetrexed and cisplatin and both chemotherapy and SS1P could be administered at their MTDs without overlapping toxicity.	('toxicity', 'Disease', (188, 196))	('SS1P', 'Chemical', 'MESH:C474515', (43, 47))	('SS1P', 'Chemical', 'MESH:C474515', (127, 131))	('SS1P', 'Var', (43, 47))	('pemetrexed', 'Chemical', 'MESH:D000068437', (76, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('toxicity', 'Disease', 'MESH:D064420', (188, 196))
67823	24824231	BAY94-9343 is an ADC in which a humanized IgG1 anti-mesothelin mAb is linked to the maytansine derivative DM4; it is currently undergoing phase I evaluation in patients with advanced solid tumors.	('DM4', 'Chemical', 'MESH:D008453', (106, 109))	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('patients', 'Species', '9606', (160, 168))	('IgG1', 'Gene', (42, 46))	('BAY94-9343', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('solid tumors', 'Disease', (183, 195))	('IgG1', 'cellular_component', 'GO:0071735', ('42', '46'))	('maytansine', 'Chemical', 'MESH:D008453', (84, 94))	('human', 'Species', '9606', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
67838	24824231	Our studies have shown that combining SS1P with pentostatin and cyclophosphamide can delay antibody formation to SS1P and lead to durable anti-tumor activity in some patients.	('delay', 'NegReg', (85, 90))	('tumor', 'Disease', (143, 148))	('antibody formation', 'MPA', (91, 109))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('SS1P', 'Chemical', 'MESH:C474515', (113, 117))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (64, 80))	('pentostatin', 'Chemical', 'MESH:D015649', (48, 59))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('SS1P', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('SS1P', 'Chemical', 'MESH:C474515', (38, 42))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))	('patients', 'Species', '9606', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
67841	24824231	Preclinical studies with RG7787 have shown that large doses can be safely given to mice, that it has a decreased capacity to cause capillary leak syndrome in rats and that it has significant anti-tumor activity in mice bearing several types of mesothelin expressing tumors.	('capillary leak syndrome', 'Disease', (131, 154))	('tumor', 'Disease', (196, 201))	('rats', 'Species', '10116', (158, 162))	('decreased', 'NegReg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('mice', 'Species', '10090', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cause', 'Reg', (125, 130))	('capillary leak', 'Phenotype', 'HP:0030005', (131, 145))	('RG7787', 'Var', (25, 31))	('capillary leak syndrome', 'Disease', 'MESH:D019559', (131, 154))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (266, 271))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('mice', 'Species', '10090', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', (266, 272))
67926	21984916	It is also upregulated in the adipose of Mif knockout mice.	('Mif', 'Gene', '17319', (41, 44))	('Mif', 'Gene', (41, 44))	('upregulated', 'PosReg', (11, 22))	('knockout', 'Var', (45, 53))	('mice', 'Species', '10090', (54, 58))
68187	22773919	In Table 4, gamma0, gamma1, and gamma2 measure the association between the random features b0i, b1i, and b2i of the LCSS trajectory and TTPD.	('gamma0, gamma1, and gamma2', 'Gene', '7453', (12, 38))	('association', 'Interaction', (51, 62))	('b2i', 'Var', (105, 108))	('b0i', 'Var', (91, 94))	('b1i', 'Var', (96, 99))
68188	22773919	For cough, dyspnea, pain, ASBI5, and ASBI8, all three features were significantly associated with TTPD (P-values for gamma0, gamma1 and gamma2 were less than 0.01).	('pain', 'Disease', (20, 24))	('dyspnea', 'Disease', 'MESH:D004417', (11, 18))	('pain', 'Phenotype', 'HP:0012531', (20, 24))	('ASBI8', 'Gene', (37, 42))	('associated', 'Reg', (82, 92))	('ASBI5', 'Var', (26, 31))	('cough', 'Disease', 'MESH:D003371', (4, 9))	('TTPD', 'Disease', (98, 102))	('ASBI8', 'Chemical', '-', (37, 42))	('dyspnea', 'Phenotype', 'HP:0002094', (11, 18))	('cough', 'Phenotype', 'HP:0012735', (4, 9))	('ASBI5', 'Chemical', '-', (26, 31))	('dyspnea', 'Disease', (11, 18))	('cough', 'Disease', (4, 9))	('gamma0, gamma1 and gamma2', 'Gene', '7453', (117, 142))	('pain', 'Disease', 'MESH:D010146', (20, 24))
68199	22773919	By looking at the same plots for other items, several common findings are found: (1) patients with better performance status at baseline had significantly smaller intercepts of the item; (2) At least one random effect showed a significant positive association with the hazard; and (3) Pemetrexed/cisplatin and stage III or less were significantly associated with improved TTPD.	('cisplatin', 'Chemical', 'MESH:D002945', (296, 305))	('Pemetrexed/cisplatin', 'Var', (285, 305))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (285, 295))	('smaller', 'NegReg', (155, 162))	('patients', 'Species', '9606', (85, 93))	('TTPD', 'MPA', (372, 376))	('intercepts', 'MPA', (163, 173))	('improved', 'PosReg', (363, 371))
68222	22773919	Several modifications may lead to improvement in the performance of the joint models.	('modifications', 'Var', (8, 21))	('performance', 'MPA', (53, 64))	('men', 'Species', '9606', (41, 44))	('improvement', 'PosReg', (34, 45))
68374	29601534	performed immunohistochemical staining on fifteen cases of epithelioid MPM, scoring CD45, CD3, CD20 and CD56 with 0 (no significant infiltrate), 1 (non-brisk) or 2 (brisk infiltrate).	('CD20', 'Gene', '54474', (95, 99))	('CD3', 'Var', (90, 93))	('CD20', 'Gene', (95, 99))	('CD56', 'Gene', '4684', (104, 108))	('CD45', 'Gene', (84, 88))	('CD56', 'Gene', (104, 108))	('CD45', 'Gene', '5788', (84, 88))
68379	29601534	The distribution of T cells varies, with only CD3+ and CD45RO+ TILs showing normal distribution.	('CD45', 'Gene', (55, 59))	('CD3+', 'Var', (46, 50))	('CD45', 'Gene', '5788', (55, 59))
68382	29601534	Presence of CD4+ and CD8+ T cells was strongly correlated (R = 0.74, and p = 0.001).	('CD4+', 'Var', (12, 16))	('CD8', 'Gene', (21, 24))	('CD8', 'Gene', '925', (21, 24))
68562	28757678	miRNA-16, miRNA-17, miRNA-126, and miRNA-486 were quantified in plasma and formalin-fixed paraffin-embedded samples to evaluate their diagnostic and prognostic roles compared to patients with other noncancerous pulmonary diseases (controls).	('miRNA-17', 'Gene', '406952', (10, 18))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('noncancerous pulmonary diseases', 'Disease', 'MESH:D008171', (198, 229))	('miRNA-16', 'Chemical', '-', (0, 8))	('paraffin', 'Chemical', 'MESH:D010232', (90, 98))	('noncancerous pulmonary diseases', 'Disease', (198, 229))	('miRNA-486', 'Var', (35, 44))	('miRNA-17', 'Gene', (10, 18))	('formalin', 'Chemical', 'MESH:D005557', (75, 83))	('miRNA-126', 'Gene', (20, 29))	('miRNA-126', 'Gene', '406913', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('pulmonary diseases', 'Disease', 'MESH:D008171', (211, 229))	('miRNA-486', 'Chemical', '-', (35, 44))
68570	28757678	A number of miRNA genes are located near sites of translocation breakpoints or deletions in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('deletions', 'Var', (79, 88))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('miRNA genes', 'Gene', (12, 23))
68579	28757678	In addition, decreased expression of miR-486 was observed in tumor tissues from patients with lung, colon, melanoma, and gastric cancer.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('miR-486', 'Var', (37, 44))	('melanoma', 'Disease', (107, 115))	('decreased', 'NegReg', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('lung', 'Disease', (94, 98))	('colon', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gastric cancer', 'Disease', (121, 135))	('expression', 'MPA', (23, 33))
68600	28757678	In the study of Ji et al., the overexpression of miRNA-486-attenuated pulmonary fibrosis in mice and repressed TGF-beta1-induced fibrogenesis in NIH/3T3 cells, thus demonstrating that miR-486 has a strong antifibrotic activity in lung tissues and may be a novel target in the treatment of pulmonary diseases.	('pulmonary fibrosis', 'CPA', (70, 88))	('TGF-beta1', 'Gene', '21803', (111, 120))	('miRNA-486-attenuated', 'NegReg', (49, 69))	('TGF-beta1', 'Gene', (111, 120))	('miRNA-486-attenuated', 'Gene', (49, 69))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (70, 88))	('antifibrotic activity', 'CPA', (205, 226))	('NIH/3T3', 'CellLine', 'CVCL:0594', (145, 152))	('miR-486', 'Var', (184, 191))	('overexpression', 'PosReg', (31, 45))	('fibrogenesis', 'CPA', (129, 141))
68601	28757678	miRNA-126 is an endothelial-specific miRNA that is located within intron 7 of epidermal growth factor-like domain 7 (EGFL7).	('miRNA-126', 'Var', (0, 9))	('EGFL7', 'Gene', (117, 122))	('EGFL7', 'Gene', '51162', (117, 122))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('78', '101'))	('epidermal growth factor-like domain 7', 'Gene', '51162', (78, 115))	('epidermal growth factor-like domain 7', 'Gene', (78, 115))
68605	28757678	miRNA-16 is located at chromosome 13q14, which is deleted in 68% of chronic lymphocytic leukemia cases and is downregulated in most solid tumors.	('lymphocytic leukemia', 'Disease', (76, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (76, 96))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('miRNA-16', 'Gene', (0, 8))	('deleted', 'Var', (50, 57))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (68, 96))	('downregulated', 'NegReg', (110, 123))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
68608	28757678	found that miRNA-16 induced an accumulation of A549 cells in G0/G1, and a similar cell cycle phenotype in MCF7 (breast cancer) and TOV21G (ovarian cancer) cells.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cell cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('ovarian cancer', 'Disease', (139, 153))	('accumulation', 'PosReg', (31, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))	('miRNA-16', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('A549', 'CellLine', 'CVCL:0023', (47, 51))	('A549', 'Var', (47, 51))
68638	28464918	Among those MPM with deficient ASS1 expression by immunohistochemistry, treatment with ADI-PEG20 achieved good metabolic response with significant improvement in progression-free survival (hazard ratio 0.53, 95% CI: 0.31 to 0.90, p = 0.02) compared with best supportive care alone.	('ASS1', 'Gene', (31, 35))	('metabolic response', 'MPA', (111, 129))	('progression-free survival', 'CPA', (162, 187))	('deficient', 'Var', (21, 30))	('ADI-PEG20', 'Var', (87, 96))	('PEG', 'Chemical', 'MESH:D011092', (91, 94))	('improvement', 'PosReg', (147, 158))
68678	28464918	More importantly, liver cirrhosis was observed in all mice in BCT-100/cisplatin arms.	('liver cirrhosis', 'Phenotype', 'HP:0001394', (18, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('mice', 'Species', '10090', (54, 58))	('liver cirrhosis', 'Disease', 'MESH:D008103', (18, 33))	('BCT-100/cisplatin', 'Var', (62, 79))	('observed', 'Reg', (38, 46))	('liver cirrhosis', 'Disease', (18, 33))
68709	28464918	Furthermore, ADI-PEG20 has been shown to have interesting anti-cancer effect on ASS-deficient cancers including lymphoma, head and neck cancer, small cell lung cancer, pancreatic cancer and breast cancer through apoptosis and cell cycle arrest.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('pancreatic cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('small cell lung cancer', 'Disease', (144, 166))	('apoptosis', 'CPA', (212, 221))	('ADI-PEG20', 'Var', (13, 22))	('cancer', 'Disease', (136, 142))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('neck', 'cellular_component', 'GO:0044326', ('131', '135'))	('cancer', 'Disease', (160, 166))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ASS-deficient cancers', 'Disease', (80, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('cancer', 'Disease', (63, 69))	('cell cycle arrest', 'CPA', (226, 243))	('cancer', 'Disease', (94, 100))	('head and neck cancer', 'Phenotype', 'HP:0012288', (122, 142))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (197, 203))	('neck cancer', 'Disease', 'MESH:D006258', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('neck cancer', 'Disease', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('lymphoma', 'Disease', (112, 120))	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('lymphoma', 'Disease', 'MESH:D008223', (112, 120))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('226', '243'))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (226, 243))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ASS-deficient cancers', 'Disease', 'MESH:D020159', (80, 101))	('PEG', 'Chemical', 'MESH:D011092', (17, 20))	('small cell lung cancer', 'Disease', 'MESH:D055752', (144, 166))	('cancer', 'Disease', (179, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
68780	31069554	This further uses scores >= 16, >= 23, and >= 28 to screen for possible, probable, and case depression, respectively.	('>= 28', 'Var', (43, 48))	('depression', 'Phenotype', 'HP:0000716', (92, 102))	('depression', 'Disease', 'MESH:D000275', (92, 102))	('screen', 'Reg', (52, 58))	('depression', 'Disease', (92, 102))
68797	31069554	An improved CES-D score was also noted in those who were perfused with mitomycin C compared with those who were perfused with cisplatin (p = 0.0051).	('CES-D', 'Disease', (12, 17))	('improved', 'PosReg', (3, 11))	('CES', 'Chemical', 'MESH:D002563', (12, 15))	('mitomycin C', 'Var', (71, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('mitomycin C', 'Chemical', 'MESH:D016685', (71, 82))
68798	31069554	BPI (p = 0.025), least pain (p = 0.045), and worst pain (p < 0.0001) improved following HIPEC, and continued to improve at each time point.	('BPI', 'MPA', (0, 3))	('pain', 'Disease', (51, 55))	('pain', 'Phenotype', 'HP:0012531', (51, 55))	('improved', 'PosReg', (69, 77))	('pain', 'Phenotype', 'HP:0012531', (23, 27))	('HIPEC', 'Var', (88, 93))	('pain', 'Disease', 'MESH:D010146', (23, 27))	('pain', 'Disease', (23, 27))	('pain', 'Disease', 'MESH:D010146', (51, 55))
68801	31069554	CRS/HIPEC is an effective means of reducing the disease burden, however it is not without complications or significant morbidity.	('CRS', 'Chemical', 'MESH:D002857', (0, 3))	('CRS/HIPEC', 'Var', (0, 9))	('disease burden', 'MPA', (48, 62))
68810	31069554	In this study, we found that patients who were perfused with mitomycin C had improved CES-D scores compared with those who were perfused with cisplatin (10.2 vs. 12.6; p = 0.0051).	('patients', 'Species', '9606', (29, 37))	('CES', 'Chemical', 'MESH:D002563', (86, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('CES-D scores', 'Disease', (86, 98))	('mitomycin C', 'Var', (61, 72))	('improved', 'PosReg', (77, 85))	('mitomycin C', 'Chemical', 'MESH:D016685', (61, 72))
68811	31069554	Some studies have shown that cisplatin may have greater adverse effects, specifically neutropenia, thrombocytopenia, gastrointestinal disturbances, metabolic disturbances, and nephrotoxicity.	('neutropenia', 'Disease', (86, 97))	('nephrotoxicity', 'Disease', (176, 190))	('cisplatin', 'Var', (29, 38))	('nephrotoxicity', 'Disease', 'MESH:D007674', (176, 190))	('neutropenia', 'Disease', 'MESH:D009503', (86, 97))	('metabolic disturbances', 'CPA', (148, 170))	('thrombocytopenia', 'Disease', 'MESH:D013921', (99, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('neutropenia', 'Phenotype', 'HP:0001875', (86, 97))	('gastrointestinal disturbances', 'Disease', 'MESH:D005767', (117, 146))	('gastrointestinal disturbances', 'Disease', (117, 146))	('thrombocytopenia', 'Disease', (99, 115))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (99, 115))
68857	30828567	This procedure selected a prognostic model containing three genes: LSM6 (ENSG00000164167), GZMB (ENSG00000164167), and HJURP (ENSG00000123485) (Tables 2, 3).	('HJURP', 'Gene', '55355', (119, 124))	('LSM6', 'Gene', '11157', (67, 71))	('GZMB', 'Gene', '3002', (91, 95))	('ENSG00000164167', 'Var', (97, 112))	('LSM6', 'Gene', (67, 71))	('ENSG00000164167', 'Var', (73, 88))	('GZMB', 'Gene', (91, 95))	('ENSG00000123485', 'Var', (126, 141))	('HJURP', 'Gene', (119, 124))
68858	30828567	Risk score = (0.0133323 x expression value of LSM6) + (0.01643 x expression value of GZMB) + (0.020926 x expression value of HJURP).	('LSM6', 'Gene', (46, 50))	('0.0133323', 'Var', (14, 23))	('HJURP', 'Gene', '55355', (125, 130))	('GZMB', 'Gene', '3002', (85, 89))	('HJURP', 'Gene', (125, 130))	('0.01643', 'Var', (55, 62))	('GZMB', 'Gene', (85, 89))	('LSM6', 'Gene', '11157', (46, 50))
68863	30828567	According to the protocol, this procedure selected a prognostic model containing nine genes: WT1 (ENSG00000184937), PTEN (ENSG00000171862), PGF (ENSG00000119630), PDPN (ENSG00000162493), HTRA1 (ENSG00000166033), EMX2 (ENSG00000170370), EGFR (ENSG00000146648), DPP4 (ENSG00000197635), and CALB2 (ENSG00000172137).	('ENSG00000171862', 'Var', (122, 137))	('ENSG00000119630', 'Var', (145, 160))	('ENSG00000166033', 'Var', (194, 209))	('CALB2', 'Gene', '794', (288, 293))	('WT1', 'Gene', '7490', (93, 96))	('CALB2', 'Gene', (288, 293))	('EGFR', 'molecular_function', 'GO:0005006', ('236', '240'))	('PTEN', 'Gene', (116, 120))	('PGF', 'Gene', (140, 143))	('DPP4', 'Gene', '1803', (260, 264))	('EMX2', 'Gene', '2018', (212, 216))	('PDPN', 'Gene', (163, 167))	('EGFR', 'Gene', '1956', (236, 240))	('ENSG00000162493', 'Var', (169, 184))	('PTEN', 'Gene', '5728', (116, 120))	('ENSG00000146648', 'Var', (242, 257))	('HTRA1', 'Gene', '5654', (187, 192))	('DPP4', 'Gene', (260, 264))	('HTRA1', 'Gene', (187, 192))	('EMX2', 'Gene', (212, 216))	('ENSG00000197635', 'Var', (266, 281))	('ENSG00000172137', 'Var', (295, 310))	('ENSG00000184937', 'Var', (98, 113))	('PGF', 'Gene', '5228', (140, 143))	('ENSG00000170370', 'Var', (218, 233))	('PDPN', 'Gene', '10630', (163, 167))	('WT1', 'Gene', (93, 96))	('EGFR', 'Gene', (236, 240))
68875	30828567	Adhesion and cadherin are classical cell-to-cell adhesion molecules with a homeostatic function in several normal tissues; however, dysregulation of these molecules might be associated with a more aggressive cancer cell phenotype, leading to epithelial-mesenchymal transition (EMT), invasion and metastasis and thus influencing the OS.	('cadherin', 'molecular_function', 'GO:0008014', ('13', '21'))	('metastasis', 'CPA', (296, 306))	('associated', 'Reg', (174, 184))	('EMT', 'biological_process', 'GO:0001837', ('277', '280'))	('invasion', 'CPA', (283, 291))	('influencing', 'Reg', (316, 327))	('cell adhesion', 'biological_process', 'GO:0007155', ('44', '57'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('242', '275'))	('leading to', 'Reg', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('epithelial-mesenchymal transition', 'CPA', (242, 275))	('aggressive cancer', 'Disease', 'MESH:D009369', (197, 214))	('aggressive cancer', 'Disease', (197, 214))	('dysregulation', 'Var', (132, 145))	('OS', 'Chemical', '-', (332, 334))
69030	28474658	Spontaneous massive hemopneumothorax: Double trouble with a twist Spontaneous hemopneumothorax (SHP) is observed in 3%-7% cases of spontaneous pneumothorax where the tear of an adhesion can lead to bleeding with associated hemothorax.	('pneumothorax', 'Phenotype', 'HP:0002107', (24, 36))	('Spontaneous hemopneumothorax', 'Phenotype', 'HP:0002108', (66, 94))	('bleeding', 'Disease', 'MESH:D006470', (198, 206))	('bleeding', 'Disease', (198, 206))	('spontaneous pneumothorax', 'Phenotype', 'HP:0002108', (131, 155))	('spontaneous pneumothorax', 'Disease', (131, 155))	('SHP', 'Phenotype', 'HP:0002108', (96, 99))	('pneumothorax', 'Phenotype', 'HP:0002107', (82, 94))	('hemothorax', 'Phenotype', 'HP:0012151', (223, 233))	('tear', 'Phenotype', 'HP:0009926', (166, 170))	('Spontaneous massive hemopneumothorax', 'Phenotype', 'HP:0002108', (0, 36))	('hemothorax', 'Disease', (223, 233))	('tear', 'Var', (166, 170))	('lead to', 'Reg', (190, 197))	('pneumothorax', 'Phenotype', 'HP:0002107', (143, 155))
69095	28239496	Other characteristics, including genomic factors such as BAP1 mutations, have been suggested as related to survival but are beyond the scope of the SEER national database used here.	('BAP1', 'Gene', '8314', (57, 61))	('related', 'Reg', (96, 103))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
69098	28239496	All but 3 of the cases were histologic codes 9051 (fibrous mesothelioma), 9052 (epithelioid mesothelioma), 9053 (biphasic mesothelioma), or 9050 (mesothelioma not otherwise specified [NOS]).	('9050', 'Var', (140, 144))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (113, 134))	('9052', 'Var', (74, 78))	('biphasic mesothelioma', 'Disease', (113, 134))	('epithelioid mesothelioma', 'Disease', (80, 104))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (80, 104))	('fibrous mesothelioma', 'Disease', (51, 71))	('9053', 'Var', (107, 111))	('fibrous mesothelioma', 'Disease', 'MESH:D054363', (51, 71))
69128	32671956	5  VPI is associated with more frequent locoregional recurrence and distant metastases.	('locoregional recurrence', 'CPA', (40, 63))	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('5  VPI', 'Var', (0, 6))	('VPI', 'Chemical', '-', (3, 6))	('metastases', 'Disease', (76, 86))
69142	32671956	found that small nucleoli or absent nucleoli were associated with better survival in epithelioid pleural malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (105, 127))	('pleural malignant mesothelioma', 'Phenotype', 'HP:0100002', (97, 127))	('better', 'PosReg', (66, 72))	('small nucleoli', 'Var', (11, 25))	('pleural malignant mesothelioma', 'Disease', (97, 127))	('pleural malignant mesothelioma', 'Disease', 'MESH:C562839', (97, 127))
69198	32671956	has shown that high nucleophosmin expression correlates with lymph node metastases of colon cancer.	('high', 'Var', (15, 19))	('metastases of colon cancer', 'Disease', (72, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('metastases of colon cancer', 'Disease', 'MESH:D009362', (72, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('nucleophosmin', 'Gene', '4869', (20, 33))	('nucleophosmin', 'Gene', (20, 33))
69226	32226777	Individuals with germline BRCA1 associated protein-1 (BAP1) mutations may be predisposed to MPM, since they may develop it without any apparent asbestos exposure.	('BRCA1 associated protein-1', 'Gene', (26, 52))	('asbestos', 'Chemical', 'MESH:D001194', (144, 152))	('MPM', 'Disease', (92, 95))	('BAP1', 'Gene', '8314', (54, 58))	('BRCA1 associated protein-1', 'Gene', '8314', (26, 52))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('predisposed', 'Reg', (77, 88))	('mutations', 'Var', (60, 69))	('BAP1', 'Gene', (54, 58))	('develop', 'PosReg', (112, 119))
69227	32226777	Recent biological and preclinical studies provided further insights into MPM carcinogenesis, revealing the importance of tumor suppressor gene inactivation, through several mechanisms (single nucleotide variants (SNVs), copy number losses, gene fusions, and splicing alterations).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('gene fusions', 'Var', (240, 252))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('MPM carcinogenesis', 'Disease', 'MESH:D063646', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('splicing alterations', 'Var', (258, 278))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))	('MPM carcinogenesis', 'Disease', (73, 91))	('single nucleotide variants', 'Var', (185, 211))	('copy number losses', 'Var', (220, 238))	('inactivation', 'NegReg', (143, 155))
69243	32226777	Two on-going trials, MARS 2 (NCT02040272) and EORTC1205-LCG (NCT02436733), are currently evaluating the usefulness, the feasibility and the best timing for the combined approach of surgery and chemotherapy.	('MARS 2', 'Gene', (21, 27))	('NCT02040272', 'Var', (29, 40))	('MARS 2', 'Gene', '92935', (21, 27))	('NCT02436733', 'Var', (61, 72))
69250	32226777	There are several ongoing neoadjuvant trials which aim to assess the immunomodulatory and pharmacodynamics effect of CIs, as monotherapy (NCT02707666), as combination of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and anti-programmed cell death protein (PD-1) agents (NCT02592551, NCT03918252) and as combination of anti-programmed death-ligand 1 (PD-L1) with standard chemotherapy (NCT03228537).	('anti-cytotoxic T-lymphocyte-associated protein 4', 'Gene', (170, 218))	('ligand', 'molecular_function', 'GO:0005488', ('351', '357'))	('NCT02592551', 'Var', (281, 292))	('anti-cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (170, 218))	('programmed cell death', 'biological_process', 'GO:0012501', ('236', '257'))	('CTLA4', 'Gene', '1493', (220, 225))	('NCT03918252', 'Var', (294, 305))	('CI', 'Chemical', '-', (117, 119))	('CTLA4', 'Gene', (220, 225))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))
69254	32226777	Increased tumor size correlates with major immune suppression and surgically shrinking tumor size may potentially reduce immune inhibition and T-cell exhaustion.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('immune inhibition', 'CPA', (121, 138))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (87, 92))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (143, 160))	('immune suppression', 'CPA', (43, 61))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('surgically shrinking', 'Var', (66, 86))	('reduce', 'NegReg', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('T-cell exhaustion', 'CPA', (143, 160))
69271	32226777	In human mesothelioma cell cultures, combining TTFields with cisplatin or pemetrexed led to reduction in cell count, induction of apoptosis and reduced clonogenic potential.	('TTFields', 'Var', (47, 55))	('reduced', 'NegReg', (144, 151))	('pemetrexed', 'Chemical', 'MESH:D000068437', (74, 84))	('apoptosis', 'CPA', (130, 139))	('human', 'Species', '9606', (3, 8))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('117', '139'))	('reduction', 'NegReg', (92, 101))	('induction', 'Reg', (117, 126))	('mesothelioma', 'Disease', (9, 21))	('cell count', 'CPA', (105, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('clonogenic potential', 'CPA', (152, 172))	('mesothelioma', 'Disease', 'MESH:D008654', (9, 21))
69300	32226777	Carriers of inherited loss-of-function mutations in BAP1 are predisposed to mesothelioma.	('BAP1', 'Gene', '8314', (52, 56))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', (52, 56))	('mesothelioma', 'Disease', (76, 88))	('loss-of-function', 'NegReg', (22, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
69303	32226777	Besides germline mutations, recent analysis of the BAP1 locus by targeted next-generation sequencing identified homozygous inactivating mutations in approximately 60% of patients.	('patients', 'Species', '9606', (170, 178))	('homozygous inactivating mutations', 'Var', (112, 145))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))
69305	32226777	In a recent paper, among 385 patients treated with platinum chemotherapy, median OS was increased for MPM patients who had inherited mutations in DNA repair and/or other tumor suppressor genes.	('platinum', 'Chemical', 'MESH:D010984', (51, 59))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('median OS', 'MPA', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('increased', 'PosReg', (88, 97))	('MPM', 'Disease', (102, 105))	('DNA repair', 'Gene', (146, 156))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (81, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))	('DNA repair', 'biological_process', 'GO:0006281', ('146', '156'))
69306	32226777	This is consistent with what already observed in ovarian and breast cancer patients with inherited mutations in BRCA1 and BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('patients', 'Species', '9606', (75, 83))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (49, 74))	('mutations', 'Var', (99, 108))	('BRCA2', 'Gene', (122, 127))	('BRCA1', 'Gene', '672', (112, 117))	('BRCA1', 'Gene', (112, 117))	('BRCA2', 'Gene', '675', (122, 127))
69307	32226777	Conversely, BAP1 mutant mesothelioma cell lines resulted significantly less sensitive than BAP1 wild type cells to gemcitabine.	('BAP1', 'Gene', (91, 95))	('mesothelioma', 'Disease', (24, 36))	('less', 'NegReg', (71, 75))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', '8314', (91, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (24, 36))	('gemcitabine', 'Chemical', 'MESH:C056507', (115, 126))	('mutant', 'Var', (17, 23))	('BAP1', 'Gene', (12, 16))	('sensitive', 'MPA', (76, 85))
69309	32226777	By inducing synthetic lethality of alternate DNA repair pathways, poly-ADP ribose polymerase (PARP) inhibitors have proved to be able to cause cell death in cell lines with loss of function of BAP1.	('cell death', 'biological_process', 'GO:0008219', ('143', '153'))	('alternate', 'Pathway', (35, 44))	('poly-ADP ribose polymerase', 'Gene', (66, 92))	('PARP', 'Gene', '142', (94, 98))	('BAP1', 'Gene', '8314', (193, 197))	('synthetic lethality', 'MPA', (12, 31))	('cell death', 'CPA', (143, 153))	('cause', 'Reg', (137, 142))	('poly-ADP ribose polymerase', 'Gene', '142', (66, 92))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('DNA repair', 'biological_process', 'GO:0006281', ('45', '55'))	('BAP1', 'Gene', (193, 197))	('inhibitors', 'Var', (100, 110))	('PARP', 'Gene', (94, 98))	('inducing', 'PosReg', (3, 11))
69310	32226777	This observation suggests that patients with mutations in BAP1 and in DNA repair genes might also benefit from treatment with PARP inhibitors.	('mutations', 'Var', (45, 54))	('DNA repair', 'biological_process', 'GO:0006281', ('70', '80'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('DNA repair', 'Gene', (70, 80))	('PARP', 'Gene', (126, 130))	('BAP1', 'Gene', (58, 62))	('patients', 'Species', '9606', (31, 39))	('PARP', 'Gene', '142', (126, 130))	('benefit', 'PosReg', (98, 105))	('BAP1', 'Gene', '8314', (58, 62))
69311	32226777	An enrolling clinical trial in MPM patients is examining the relationship between patient genotype and response to the PARP inhibitor olaparib (NCT03531840).	('PARP', 'Gene', (119, 123))	('olaparib', 'Chemical', 'MESH:C531550', (134, 142))	('patient', 'Species', '9606', (82, 89))	('patient', 'Species', '9606', (35, 42))	('NCT03531840', 'Var', (144, 155))	('PARP', 'Gene', '142', (119, 123))	('patients', 'Species', '9606', (35, 43))
69313	32226777	BAP1 inactivation also works as a putative epigenetic regulator involved in the polycomb repressive complex 2 (PRC2) and enhancer of zeste-homolog 2 (EZH2) pathway.	('EZH2', 'Gene', '2146', (150, 154))	('BAP1', 'Gene', (0, 4))	('enhancer of zeste-homolog 2', 'Gene', '2146', (121, 148))	('EZH2', 'Gene', (150, 154))	('enhancer of zeste-homolog 2', 'Gene', (121, 148))	('inactivation', 'Var', (5, 17))	('BAP1', 'Gene', '8314', (0, 4))
69325	32226777	Loss of ASS1 renders mesothelioma cells addicted to exogenous arginine, and this defect may be therapeutically exploited by pegylated arginine deiminase (ADI-PEG20), which works by clearing circulating arginine.	('mesothelioma', 'Disease', (21, 33))	('arginine', 'Chemical', 'MESH:D001120', (134, 142))	('ASS1', 'Gene', '445', (8, 12))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('arginine', 'Chemical', 'MESH:D001120', (202, 210))	('ASS1', 'Gene', (8, 12))	('arginine', 'Chemical', 'MESH:D001120', (62, 70))	('addicted to exogenous arginine', 'MPA', (40, 70))	('Loss', 'Var', (0, 4))
69327	32226777	In conclusion, despite our improved understanding of the biology of MPM, response to targeted therapies is hampered by intra-tumor heterogeneity and it is still unclear whether most of the actionable mutations constitute clonal or sub-clonal driver events.	('intra-tumor', 'Disease', 'MESH:D009369', (119, 130))	('intra-tumor', 'Disease', (119, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutations', 'Var', (200, 209))
69338	32226777	These results suggested that combining CRS-207 with traditional chemotherapy might potentially result in increased anti-tumor activity.	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('increased', 'PosReg', (105, 114))	('CRS-207', 'Var', (39, 46))	('tumor', 'Disease', (120, 125))
69373	32226777	Inhibiting FAK together with PD-1, may enhance immune cell-associated antitumor cytotoxicity in vivo, which is hampered by expression of PD-L1 and this represented the rationale for a phase I/IIa currently ongoing (NCT02758587).	('cell-associated', 'cellular_component', 'GO:0009986', ('54', '69'))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('FAK', 'molecular_function', 'GO:0004717', ('11', '14'))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('FAK', 'Protein', (11, 14))	('enhance', 'PosReg', (39, 46))	('cytotoxicity', 'Disease', (80, 92))
69374	32226777	Similarly, in addition to the direct anti-tumor effects, pegylated arginine deiminase (ADI-PEG 20) may boost tumor immune surveillance and might be a good primer for an additional anti-tumor immune therapy, raising the question whether combining ADI-PEG 20 with PD-1/PD-L1 blockers may further enhance these drugs' anti-tumor efficacy.	('boost', 'PosReg', (103, 108))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', (42, 47))	('arginine', 'Chemical', 'MESH:D001120', (67, 75))	('pegylated', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (109, 114))	('enhance', 'PosReg', (294, 301))
69379	32226777	Several trials are aiming to address whether the combination of CIs and antiangiogenic agents (either mAbs as bevacizumab and ramcirumab or TKIs as nintedanib) is able to improve outcomes in MPM patients (NCT03762018, NCT02856425, NCT03502746).	('bevacizumab', 'Chemical', 'MESH:D000068258', (110, 121))	('MPM', 'Disease', (191, 194))	('NCT02856425', 'Var', (218, 229))	('improve', 'PosReg', (171, 178))	('NCT03762018', 'Var', (205, 216))	('nintedanib', 'Chemical', 'MESH:C530716', (148, 158))	('NCT03502746', 'Var', (231, 242))	('patients', 'Species', '9606', (195, 203))	('ramcirumab', 'Chemical', '-', (126, 136))	('CI', 'Chemical', '-', (64, 66))
69380	32226777	Finally, similarly to certain types of chemotherapy, radiotherapy can be exploited for its ability to cause immunogenic cell death (ICD), thus priming the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) and inducing a systemic anti-tumor immune response, that may be further enhanced by PD-1 (pembrolizumab) or PD-L1 (avelumab) blockade (NCT02959463, NCT03399552).	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('enhanced', 'PosReg', (320, 328))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('release', 'MPA', (155, 162))	('damage-associated molecular patterns', 'MPA', (166, 202))	('ICD', 'Disease', (132, 135))	('immunogenic cell death', 'Disease', 'MESH:D003643', (108, 130))	('PD-L1', 'Gene', (356, 361))	('NCT03399552', 'Var', (396, 407))	('ICD', 'Disease', 'OMIM:252500', (132, 135))	('cell death', 'biological_process', 'GO:0008219', ('120', '130'))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (277, 282))	('immune response', 'biological_process', 'GO:0006955', ('283', '298'))	('NCT02959463', 'Var', (383, 394))	('immunogenic cell death', 'Disease', (108, 130))	('pembrolizumab', 'Chemical', 'MESH:C582435', (338, 351))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('inducing', 'PosReg', (252, 260))
69405	32226777	Combinations of virotherapy with CIs, chemotherapy, and radiation are expected to further boost the effects on antitumor immunity and represent the object of ongoing trials, such as the phase III INFINITE trial (NCT03710876), in which about 300 patients will receive gemcitabine and celecoxib with or without the ADV-delivered IFNalpha-2b (rAd-IFN).	('celecoxib', 'Chemical', 'MESH:D000068579', (283, 292))	('IFN', 'Gene', (327, 330))	('IFNalpha-2b', 'Gene', (327, 338))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (245, 253))	('rAd', 'biological_process', 'GO:1990116', ('340', '343'))	('boost', 'PosReg', (90, 95))	('tumor', 'Disease', (115, 120))	('Combinations', 'Var', (0, 12))	('IFN', 'Gene', '3439', (344, 347))	('CI', 'Chemical', '-', (33, 35))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('IFN', 'Gene', '3439', (327, 330))	('gemcitabine', 'Chemical', 'MESH:C056507', (267, 278))	('IFN', 'Gene', (344, 347))	('IFNalpha-2b', 'Gene', '3440', (327, 338))
69686	25791825	Cancer-directed surgery was used more often in patients with epithelioid (37%, 299/811) and biphasic (44%, 65/148) histologies as compared with patients with sarcomatoid histology (26%, 58/224; P < 0.01).	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (158, 179))	('sarcomatoid', 'Disease', 'MESH:C538614', (158, 169))	('patients', 'Species', '9606', (47, 55))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (144, 152))	('epithelioid', 'Disease', (61, 72))	('sarcomatoid', 'Disease', (158, 169))	('biphasic', 'Var', (92, 100))
69698	25791825	A randomized feasibility study did not find that EPP improved outcomes compared with chemotherapy alone for patients with mesothelioma.	('patients', 'Species', '9606', (108, 116))	('EPP', 'Var', (49, 52))	('mesothelioma', 'Disease', (122, 134))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))
69702	25791825	We reviewed the SEER database from 2004-2010 for patients with stage I-III MPM by ICD-O-3 morphology codes 9050-9053 and 9055.	('9050-9053', 'Var', (107, 116))	('9055', 'Var', (121, 125))	('stage I-III MPM', 'Disease', (63, 78))	('patients', 'Species', '9606', (49, 57))
69724	25791825	When stratified by histologic subtype, cancer-directed surgery was used more often in patients with epithelioid (37%, n = 299) and biphasic MPM (44%, n = 65) than sarcomatoid MPM (26%, n = 58; P < 0.01).	('epithelioid', 'Disease', (100, 111))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('sarcomatoid MPM', 'Disease', 'MESH:C538614', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('biphasic MPM', 'Var', (131, 143))	('sarcomatoid MPM', 'Disease', (163, 178))	('patients', 'Species', '9606', (86, 94))
69729	25791825	Kaplan-Meier survival curves for each histologic subtype stratified by surgery or no surgery are shown in Figure 4A-C. By univariate analysis, surgery was associated with increased survival for epithelioid (P < 0.01), sarcomatoid (P = 0.03), and biphasic MPM (P = 0.03).	('sarcomatoid', 'Disease', 'MESH:C538614', (218, 229))	('biphasic MPM', 'Disease', (246, 258))	('epithelioid', 'Disease', (194, 205))	('sarcomatoid', 'Disease', (218, 229))	('increased', 'PosReg', (171, 180))	('surgery', 'Var', (143, 150))
69773	25791825	A retrospective analysis of 663 patients reported enhanced survival after P/D compared with EPP; however, this finding may have been confounded by selection bias.	('enhanced', 'PosReg', (50, 58))	('survival', 'MPA', (59, 67))	('P/D', 'Var', (74, 77))	('patients', 'Species', '9606', (32, 40))
69785	20035240	Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('chromatin', 'cellular_component', 'GO:0000785', ('56', '65'))	('Epigenetic regulation', 'Var', (0, 21))	('decondensation', 'MPA', (83, 97))	('leads to', 'Reg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('tumor', 'Disease', (150, 155))
69795	20035240	Epigenetic modification has emerged as an important mechanism leading to tumorogenesis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('leading', 'Reg', (62, 69))	('Epigenetic modification', 'Var', (0, 23))
69998	20858727	Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H>MSTO-211H*>H-2452>VAMT>JMN.	('VAMT', 'Chemical', '-', (144, 148))	('susceptibility', 'MPA', (49, 63))	('H-2452', 'Var', (137, 143))	('H-2452', 'Chemical', '-', (137, 143))	('lysis', 'biological_process', 'GO:0019835', ('71', '76'))	('JMN', 'Chemical', '-', (149, 152))	('NDV', 'Species', '11176', (67, 70))	('MSTO-211H', 'Chemical', '-', (116, 125))	('MSTO-211H*>H-2452', 'Var', (126, 143))	('MSTO-211H', 'Chemical', '-', (126, 135))	('MSTO-211H', 'Var', (116, 125))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
70021	20858727	We studied 7 human malignant mesothelioma cancer cell lines of various histologic subtypes, including epithelioid (H-2452, HMESO), sarcomatoid (H-2052, H-2373, and VAMT), and biphasic (MSTO-211H and JMN).	('H-2052', 'Var', (144, 150))	('HMESO', 'CellLine', 'CVCL:5759', (123, 128))	('VAMT', 'Chemical', '-', (164, 168))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (19, 41))	('human', 'Species', '9606', (13, 18))	('JMN', 'Chemical', '-', (199, 202))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('H-2052', 'CellLine', 'CVCL:1518', (144, 150))	('malignant mesothelioma', 'Disease', (19, 41))	('sarcomatoid', 'Disease', (131, 142))	('mesothelioma cancer', 'Disease', 'MESH:D008654', (29, 48))	('MSTO-211H', 'Chemical', '-', (185, 194))	('H-2452', 'Chemical', '-', (115, 121))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (19, 41))	('H-2373', 'CellLine', 'CVCL:A533', (152, 158))	('mesothelioma cancer', 'Disease', (29, 48))	('sarcomatoid', 'Disease', 'MESH:C538614', (131, 142))
70028	20858727	The fusogenic NDV mutant viruses with modified F cleavage site (NDV(F3aa)) were previously described.	('NDV', 'Gene', (14, 17))	('NDV', 'Species', '11176', (64, 67))	('mutant', 'Var', (18, 24))	('NDV', 'Species', '11176', (14, 17))	('fusogenic', 'PosReg', (4, 13))
70030	20858727	After incubation for 6 hours, cells were infected with NDV(F3aa)-GFP at multiplicities of infection (MOI) of 1.00, 0.10, 0.01, and 0 (control wells).	('0.01', 'Var', (121, 125))	('NDV', 'Species', '11176', (55, 58))	('NDV(F3aa)-GFP', 'Var', (55, 68))	('0.10', 'Var', (115, 119))
70072	20858727	Even in the late treatment groups (T10S, T10M) 40% of animals survived longer than 80 days after tumor instillation.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('T10S', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('T10M', 'Mutation', 'p.T10M', (41, 45))	('tumor', 'Disease', (97, 102))	('T10S', 'Mutation', 'p.T10S', (35, 39))	('T10M', 'Var', (41, 45))
70091	20858727	Absolute log-difference decrease of tumor signal within the first 10 days after viral treatment initiation was 0.3 for single versus multiple treated animals in the early treatment groups (T1S vs. T1M) and 0.32 for the late treatment groups (T10S vs T10M).	('T1S', 'Var', (189, 192))	('T10S', 'Mutation', 'p.T10S', (242, 246))	('T10M', 'Mutation', 'p.T10M', (250, 254))	('T10S', 'Var', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('decrease', 'NegReg', (24, 32))	('T10M', 'Var', (250, 254))	('T1M', 'Var', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
70092	20858727	Overall, multiple-dose treatment with NDV(F3aa)-GFP demonstrated significant survival benefit when compared with single treatment (p = 0.005).	('survival benefit', 'CPA', (77, 93))	('NDV', 'Species', '11176', (38, 41))	('NDV(F3aa)-GFP', 'Var', (38, 51))
70105	20858727	Thirdly, application of NDV may stimulate the host to produce cytokines such as interferons (IFNs) or tumor necrosis factor (TNF), which in turn leads to the activation of natural killer (NK) cells, monocytes, macrophages, and sensitized T cells, which are supportive in tumor clearance.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('necrosis', 'biological_process', 'GO:0008220', ('108', '116'))	('stimulate', 'PosReg', (32, 41))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('102', '123'))	('natural killer', 'CPA', (172, 186))	('necrosis', 'Disease', 'MESH:D009336', (108, 116))	('necrosis', 'biological_process', 'GO:0070265', ('108', '116'))	('necrosis', 'biological_process', 'GO:0019835', ('108', '116'))	('necrosis', 'biological_process', 'GO:0001906', ('108', '116'))	('necrosis', 'Disease', (108, 116))	('tumor', 'Disease', (271, 276))	('activation', 'PosReg', (158, 168))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NDV', 'Species', '11176', (24, 27))	('necrosis', 'biological_process', 'GO:0008219', ('108', '116'))	('NDV', 'Var', (24, 27))
70150	31239765	Epidemiological studies have established that exposure to asbestos fibers causes pleural abnormalities (effusions and plaques), pulmonary fibrosis (asbestosis), and malignancies (bronchogenic carcinoma and mesothelioma).	('exposure', 'Var', (46, 54))	('causes', 'Reg', (74, 80))	('effusions', 'Disease', (104, 113))	('asbestosis', 'Disease', (148, 158))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('asbestos', 'Chemical', 'MESH:D001194', (148, 156))	('pleural abnormalities', 'Disease', (81, 102))	('pulmonary fibrosis', 'Disease', (128, 146))	('bronchogenic carcinoma and mesothelioma', 'Disease', 'MESH:D002283', (179, 218))	('effusions', 'Disease', 'MESH:D010996', (104, 113))	('malignancies', 'Disease', (165, 177))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (128, 146))	('pleural abnormalities', 'Phenotype', 'HP:0002103', (81, 102))	('pleural abnormalities', 'Disease', 'MESH:D010995', (81, 102))	('asbestosis', 'Disease', 'MESH:D001195', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (128, 146))
70174	31239765	Additionally, it has been reported that fibers <5 mum in length can also promote pulmonary fibrosis and malignancy, especially when administered as a pulmonary overload condition, as can occur in dust clouds.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (81, 99))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (81, 99))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('malignancy', 'Disease', (104, 114))	('pulmonary fibrosis', 'Disease', (81, 99))	('promote', 'PosReg', (73, 80))	('fibers', 'Var', (40, 46))
70217	31239765	The activation or deactivation of certain genes by amplification or structural rearrangements (deletions or inversions) has been associated with the progressive development and treatment of pleuro-pulmonary diseases.	('associated', 'Reg', (129, 139))	('pleuro-pulmonary diseases', 'Disease', 'MESH:D008171', (190, 215))	('pleuro-pulmonary diseases', 'Disease', (190, 215))	('genes', 'Gene', (42, 47))	('amplification', 'Var', (51, 64))	('structural rearrangements', 'Var', (68, 93))	('activation', 'PosReg', (4, 14))	('deactivation', 'NegReg', (18, 30))
70220	31239765	This gene is located on the short arm of chromosome 3 (3p21.1), a region that harbors germline mutations associated with an inherited multicancer syndrome with an autosomal dominant transmission (Table 1).	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('p21', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('inherited multicancer syndrome', 'Disease', (124, 154))	('p21', 'Gene', '644914', (56, 59))	('mutations', 'Var', (95, 104))	('associated', 'Reg', (105, 115))	('short arm', 'Phenotype', 'HP:0009824', (28, 37))	('inherited multicancer syndrome', 'Disease', 'None', (124, 154))
70221	31239765	BAP1 is the first and only gene that has been proposed to influence environmental carcinogenesis, such that a germinal mutation in the BAP1 gene leads to a greater susceptibility to asbestos, which favors the clinical onset of Malignant Mesothelioma (MM).	('susceptibility', 'MPA', (164, 178))	('mutation', 'Var', (119, 127))	('Malignant Mesothelioma', 'Disease', (227, 249))	('BAP1', 'Gene', (0, 4))	('asbestos', 'Chemical', 'MESH:D001194', (182, 190))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('BAP1', 'Gene', '8314', (135, 139))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (227, 249))	('carcinogenesis', 'Disease', (82, 96))	('BAP1', 'Gene', (135, 139))	('iron', 'Chemical', 'MESH:D007501', (71, 75))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (227, 249))	('BAP1', 'Gene', '8314', (0, 4))
70223	31239765	The loss of BAP1, independent of the mechanism that leads to such loss, including deletion or point mutation (detected with a high incidence in MM), translates into nuclear negativity for the expression of BAP1 assessed by immunohistochemistry.	('BAP1', 'Gene', '8314', (206, 210))	('negativity', 'NegReg', (173, 183))	('expression', 'MPA', (192, 202))	('BAP1', 'Gene', (206, 210))	('point mutation', 'Var', (94, 108))	('deletion', 'Var', (82, 90))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))
70227	31239765	Within the rearrangements that involve the ALK gene, the most frequently observed in lung cancer is the fusion of the ALK gene with the echinoderm gene associated with microtubules 4 (EML4) (Figure 3).	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ALK', 'Gene', (43, 46))	('ALK', 'Gene', '238', (118, 121))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('fusion', 'Var', (104, 110))	('ALK', 'Gene', '238', (43, 46))	('EML4', 'Gene', (184, 188))	('ALK', 'Gene', (118, 121))	('observed', 'Reg', (73, 81))	('EML4', 'Gene', '27436', (184, 188))
70228	31239765	The EML4-ALK fusion results in a paracentric inversion within the 2p chromosomal region that fuses different parts of the EML4 gene with a portion of the ALK gene (Table 1 and Figure 4).	('ALK', 'Gene', (9, 12))	('chromosomal region', 'cellular_component', 'GO:0098687', ('69', '87'))	('ALK', 'Gene', (154, 157))	('fusion', 'Var', (13, 19))	('EML4', 'Gene', (122, 126))	('EML4', 'Gene', (4, 8))	('ALK', 'Gene', '238', (9, 12))	('results in', 'Reg', (20, 30))	('EML4', 'Gene', '27436', (122, 126))	('ALK', 'Gene', '238', (154, 157))	('EML4', 'Gene', '27436', (4, 8))
70229	31239765	Such rearrangement leads to fusion of the 5' end of EML4 with the intracellular tyrosine kinase domain of ALK, leading to the constitutive activation of the ALK kinase and its downstream signaling pathways, and hence to uncontrolled cell proliferation and survival.	('ALK', 'Gene', '238', (106, 109))	('activation', 'PosReg', (139, 149))	('survival', 'CPA', (256, 264))	('rat', 'Species', '10116', (245, 248))	('fusion', 'Var', (28, 34))	('ALK', 'Gene', (106, 109))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('ALK', 'Gene', (157, 160))	('intracellular', 'cellular_component', 'GO:0005622', ('66', '79'))	('EML4', 'Gene', (52, 56))	('rearrangement', 'Var', (5, 18))	('leads to', 'Reg', (19, 27))	('ALK', 'Gene', '238', (157, 160))	('EML4', 'Gene', '27436', (52, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('233', '251'))
70232	31239765	Thus, the presence of EML4-ALK gene fusion (ALK positive) (Figure 5) has not only been associated with several distinctive clinicopathological features in lung diseases, including the absence of a history of smoking, but is considered an important therapeutic target, sensitive to treatment with small-molecule ALK kinase inhibitors, such as crizotinib.	('EML4', 'Gene', (22, 26))	('ALK', 'Gene', (311, 314))	('ALK', 'Gene', (44, 47))	('crizotinib', 'Chemical', 'MESH:D000077547', (342, 352))	('EML4', 'Gene', '27436', (22, 26))	('associated', 'Reg', (87, 97))	('ALK', 'Gene', (27, 30))	('lung diseases', 'Disease', (155, 168))	('ALK', 'Gene', '238', (311, 314))	('ALK', 'Gene', '238', (44, 47))	('lung diseases', 'Phenotype', 'HP:0002088', (155, 168))	('lung diseases', 'Disease', 'MESH:D008171', (155, 168))	('lung disease', 'Phenotype', 'HP:0002088', (155, 167))	('presence', 'Var', (10, 18))	('ALK', 'Gene', '238', (27, 30))
70235	31239765	The deregulation of MET and HGF has been implicated in tumor development, invasion, and angiogenesis for a variety of malignancies (Figure 3).	('deregulation', 'Var', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('invasion', 'CPA', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MET', 'Gene', (20, 23))	('angiogenesis', 'CPA', (88, 100))	('HGF', 'Gene', (28, 31))	('tumor', 'Disease', (55, 60))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('HGF', 'Gene', '3082', (28, 31))	('implicated', 'Reg', (41, 51))	('malignancies', 'Disease', (118, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('88', '100'))
70236	31239765	Amplification of the MET gene has been associated with poor prognosis, tumor development, invasion, and angiogenesis in a variety of malignancies including ovarian, breast, lung, thyroid, stomach, and colon cancer.	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ovarian', 'Disease', (156, 163))	('associated', 'Reg', (39, 49))	('angiogenesis', 'CPA', (104, 116))	('colon cancer', 'Disease', 'MESH:D015179', (201, 213))	('breast', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('invasion', 'CPA', (90, 98))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))	('poor prognosis', 'CPA', (55, 69))	('colon cancer', 'Disease', (201, 213))	('MET', 'Gene', (21, 24))	('malignancies', 'Disease', (133, 145))	('lung', 'Disease', (173, 177))	('tumor', 'Disease', (71, 76))	('Amplification', 'Var', (0, 13))	('thyroid', 'Disease', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('stomach', 'Disease', (188, 195))	('colon cancer', 'Phenotype', 'HP:0003003', (201, 213))
70237	31239765	Also, amplification of this gene has been associated with secondary resistance to the tyrosine kinase inhibitor and with aggressive anatomopathological features in lung adenocarcinoma, such as increased tumor size, pleural invasion, and invasion of lymphatic vessels.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('associated', 'Reg', (42, 52))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('95', '111'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (164, 183))	('pleural invasion', 'Disease', 'MESH:D010995', (215, 231))	('pleural invasion', 'Disease', (215, 231))	('amplification', 'Var', (6, 19))	('lung adenocarcinoma', 'Disease', (164, 183))	('increased tumor', 'Disease', 'MESH:D009369', (193, 208))	('invasion of lymphatic vessels', 'CPA', (237, 266))	('increased tumor', 'Disease', (193, 208))
70238	31239765	Additionally, studies in lung cancer cell lines with MET gene amplification have shown a significantly higher sensitivity to MET inhibitors, suggesting that patients with tumors harboring amplified MET may present clinical responses to MET inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', (25, 36))	('responses', 'PosReg', (223, 232))	('patients', 'Species', '9606', (157, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('sensitivity', 'MPA', (110, 121))	('higher', 'PosReg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('MET', 'Var', (198, 201))	('tumors', 'Disease', (171, 177))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
70255	31239765	Specifically, in Malignant Pleural Mesothelioma (MPM), losses of chromosome arms 1p, 3p, 4q, 6q, 9p, 13q, 14q, and 22q and gains of chromosome arms 1q, 5p, 7p, 8q, and 17q, deletions in CDKN2A, cyclin-dependent kinase inhibitor 2B (CDKN2B), and NF2 genes and mutations in BAP1 and Cullin 1 (CUL1) genes have been reported (Table 1 and Figure 3).	('Cullin 1', 'Gene', '8454', (281, 289))	('CDKN2B', 'Gene', '1030', (232, 238))	('BAP1', 'Gene', (272, 276))	('Cullin 1', 'Gene', (281, 289))	('CUL1', 'Gene', (291, 295))	('Malignant Pleural Mesothelioma', 'Disease', (17, 47))	('NF2', 'Gene', '4771', (245, 248))	('CDKN2A', 'Gene', '1029', (186, 192))	('NF2', 'Gene', (245, 248))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (27, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('cyclin-dependent kinase inhibitor 2B', 'Gene', (194, 230))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('194', '227'))	('gains', 'PosReg', (123, 128))	('BAP1', 'Gene', '8314', (272, 276))	('losses', 'NegReg', (55, 61))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (17, 47))	('CUL1', 'Gene', '8454', (291, 295))	('CDKN2B', 'Gene', (232, 238))	('cyclin-dependent kinase inhibitor 2B', 'Gene', '1030', (194, 230))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('211', '227'))	('CDKN2A', 'Gene', (186, 192))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))	('deletions', 'Var', (173, 182))
70256	31239765	Additional studies have demonstrated losses in chromosomal regions 3p14-p21, 8p12-pter, and 17p12-pter or gain in 7q.	('p14', 'Gene', '1029', (68, 71))	('gain', 'PosReg', (106, 110))	('losses', 'NegReg', (37, 43))	('p21', 'Gene', (72, 75))	('17p12-pter', 'Var', (92, 102))	('p21', 'Gene', '644914', (72, 75))	('rat', 'Species', '10116', (31, 34))	('p14', 'Gene', (68, 71))
70257	31239765	Losses of the short arm of chromosome 3 (3p) have been reported as an early common aberration in lung cancer, observed more frequently in tumors of patients exposed to asbestos than in unexposed patients.	('patients', 'Species', '9606', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('asbestos', 'Chemical', 'MESH:D001194', (168, 176))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('tumors', 'Disease', (138, 144))	('patients', 'Species', '9606', (195, 203))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('short arm', 'Phenotype', 'HP:0009824', (14, 23))	('aberration in lung', 'Phenotype', 'HP:0002088', (83, 101))	('Losses', 'Var', (0, 6))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('rat', 'Species', '10116', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
70284	31239765	Even if mesothelioma is commonly known as the primary type of cancer related to asbestos, it has been estimated that asbestos results in an equal or greater number of lung cancer cases compared to mesothelioma.	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('asbestos', 'Var', (117, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('asbestos', 'Chemical', 'MESH:D001194', (80, 88))	('mesothelioma', 'Disease', (8, 20))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mesothelioma', 'Disease', (197, 209))	('cancer', 'Disease', (172, 178))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))
70316	31239765	The high pathogenicity of this mineral fiber is currently known and has been shown that exposure to it causes oxidative stress, fibrosis, chronic inflammation, direct damage to DNA, and mutagenesis, all of the above associated with the development of lung diseases.	('damage', 'MPA', (167, 173))	('oxidative stress', 'MPA', (110, 126))	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('exposure', 'Var', (88, 96))	('associated with', 'Reg', (216, 231))	('inflammation', 'Disease', (146, 158))	('lung diseases', 'Disease', 'MESH:D008171', (251, 264))	('lung diseases', 'Phenotype', 'HP:0002088', (251, 264))	('lung diseases', 'Disease', (251, 264))	('fibrosis', 'Disease', (128, 136))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('causes', 'Reg', (103, 109))	('fibrosis', 'Disease', 'MESH:D005355', (128, 136))	('inflammation', 'biological_process', 'GO:0006954', ('146', '158'))	('mutagenesis', 'CPA', (186, 197))	('lung disease', 'Phenotype', 'HP:0002088', (251, 263))	('mutagenesis', 'biological_process', 'GO:0006280', ('186', '197'))
70447	26664161	CD34 positivity and S100 negativity favored the final verdict of SFT.	('positivity', 'Var', (5, 15))	('CD34', 'Gene', '947', (0, 4))	('S100', 'Gene', (20, 24))	('CD34', 'Gene', (0, 4))	('S100', 'Gene', '6271', (20, 24))
70453	26664161	IHC done on the original tumor demonstrated positivity for S100 and HMB45.	('original tumor', 'Disease', 'MESH:D009369', (16, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HMB45', 'Protein', (68, 73))	('S100', 'Gene', (59, 63))	('S100', 'Gene', '6271', (59, 63))	('positivity', 'Var', (44, 54))	('original tumor', 'Disease', (16, 30))
70488	26664161	The immunophenotype of SFT consists of diffuse CD34 and CD99 positivity and CD34 positivity was seen in the present case.	('CD34', 'Gene', '947', (47, 51))	('CD99', 'Gene', '4267', (56, 60))	('CD34', 'Gene', (47, 51))	('SFT', 'Disease', (23, 26))	('CD34', 'Gene', '947', (76, 80))	('CD99', 'Gene', (56, 60))	('positivity', 'Var', (61, 71))	('CD34', 'Gene', (76, 80))
70505	26664161	The close congener of this tumor, the atypical fibroxanthoma found in the skin may be positive for CD10, CD68 with focal smooth muscle actin (SMA), and CD34 positivity though they are not definitive but are supportive in the diagnosis.	('CD34', 'Gene', (152, 156))	('CD34', 'Gene', '947', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CD10', 'molecular_function', 'GO:0004245', ('99', '103'))	('positivity', 'Var', (157, 167))	('tumor', 'Disease', (27, 32))	('CD68', 'Gene', (105, 109))	('positive', 'Reg', (86, 94))	('CD68', 'Gene', '968', (105, 109))	('CD10', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CD10', 'Gene', '4311', (99, 103))
70510	25888633	Here, we explore the importance of MDM2 amplification and p53 mutation in LPS independently, to determine whether HDACi are therapeutically useful in LPS.	('HDAC', 'Gene', (114, 118))	('LPS', 'Disease', 'MESH:C536528', (150, 153))	('HDAC', 'Gene', '9734', (114, 118))	('LPS', 'Phenotype', 'HP:0012034', (74, 77))	('mutation', 'Var', (62, 70))	('LPS', 'Disease', (74, 77))	('amplification', 'Var', (40, 53))	('LPS', 'Disease', (150, 153))	('LPS', 'Phenotype', 'HP:0012034', (150, 153))	('p53', 'Gene', (58, 61))	('MDM2', 'Gene', '4193', (35, 39))	('LPS', 'Disease', 'MESH:C536528', (74, 77))	('MDM2', 'Gene', (35, 39))
70513	25888633	In control mesothelioma cell lines, HDACi treatment resulted in down-regulation of p53 in the p53 mutant cell line JMN1B, but resulted in no changes of MDM2 and p53 in two mesothelioma lines with normal MDM2 and wild-type p53.	('p53', 'Gene', (94, 97))	('p53', 'Gene', (83, 86))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('mesothelioma', 'Disease', (11, 23))	('down-regulation', 'NegReg', (64, 79))	('HDAC', 'Gene', (36, 40))	('mesothelioma', 'Disease', (172, 184))	('HDAC', 'Gene', '9734', (36, 40))	('MDM2', 'Gene', '4193', (203, 207))	('MDM2', 'Gene', (203, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (172, 184))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('MDM2', 'Gene', '4193', (152, 156))	('mutant', 'Var', (98, 104))	('MDM2', 'Gene', (152, 156))
70516	25888633	These findings underscore the importance of targeting both MDM2 and p53 in LPS and other cancers harboring p53 mutations.	('mutations', 'Var', (111, 120))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('p53', 'Gene', (107, 110))	('MDM2', 'Gene', '4193', (59, 63))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('MDM2', 'Gene', (59, 63))	('LPS', 'Disease', (75, 78))	('LPS', 'Phenotype', 'HP:0012034', (75, 78))	('cancers', 'Disease', (89, 96))	('p53', 'Gene', (68, 71))	('LPS', 'Disease', 'MESH:C536528', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
70523	25888633	Additionally, JUN maybe amplified in WDLPS cases with a dedifferentiated component, and down-regulation or complete loss of PTEN or an alternative mechanism of PIK3CA mutation results in AKT activation in a subset of LPS, implicating the PI3K/AKT/mTOR pathway as a therapeutic target.	('LPS', 'Phenotype', 'HP:0012034', (217, 220))	('PTEN', 'Gene', (124, 128))	('down-regulation', 'NegReg', (88, 103))	('mTOR', 'Gene', (247, 251))	('loss', 'NegReg', (116, 120))	('LPS', 'Disease', 'MESH:C536528', (39, 42))	('PIK3CA', 'Gene', '5290', (160, 166))	('PTEN', 'Gene', '5728', (124, 128))	('AKT', 'Gene', (187, 190))	('LPS', 'Phenotype', 'HP:0012034', (39, 42))	('mTOR', 'Gene', '2475', (247, 251))	('AKT', 'Gene', (243, 246))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('LPS', 'Disease', (217, 220))	('activation', 'PosReg', (191, 201))	('mutation', 'Var', (167, 175))	('PIK3CA', 'Gene', (160, 166))	('AKT', 'Gene', '207', (187, 190))	('AKT', 'Gene', '207', (243, 246))	('LPS', 'Disease', 'MESH:C536528', (217, 220))	('PI3K', 'molecular_function', 'GO:0016303', ('238', '242'))	('LPS', 'Disease', (39, 42))
70524	25888633	Dysregulation of the MDM2-p53 regulatory feedback loop is crucial in WDLPS pathogenesis, with most LPS harboring either MDM2 amplification or p53 mutation and individuals with germ-line p53 mutations are at an increased risk of WDLPS development at an earlier age.	('amplification', 'Var', (125, 138))	('LPS', 'Disease', 'MESH:C536528', (230, 233))	('LPS', 'Phenotype', 'HP:0012034', (71, 74))	('MDM2', 'Gene', '4193', (21, 25))	('p53', 'Gene', (186, 189))	('LPS', 'Disease', (99, 102))	('LPS', 'Phenotype', 'HP:0012034', (230, 233))	('mutation', 'Var', (146, 154))	('mutations', 'Var', (190, 199))	('pathogenesis', 'biological_process', 'GO:0009405', ('75', '87'))	('LPS', 'Disease', 'MESH:C536528', (99, 102))	('p53', 'Gene', (142, 145))	('LPS', 'Disease', (71, 74))	('MDM2', 'Gene', (120, 124))	('LPS', 'Phenotype', 'HP:0012034', (99, 102))	('LPS', 'Disease', (230, 233))	('MDM2', 'Gene', '4193', (120, 124))	('MDM2', 'Gene', (21, 25))	('LPS', 'Disease', 'MESH:C536528', (71, 74))
70532	25888633	However, Blagosklonny and colleagues found that HDACi (FR901228 and trichostatin A) were cytotoxic to cancer cells via depletion of mutant p53, and restored expression and function of pseudo-null p53.	('HDAC', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HDAC', 'Gene', '9734', (48, 52))	('expression', 'MPA', (157, 167))	('cytotoxic to cancer', 'Disease', 'MESH:D064420', (89, 108))	('mutant', 'Var', (132, 138))	('trichostatin A', 'Chemical', 'MESH:C012589', (68, 82))	('function', 'MPA', (172, 180))	('p53', 'Gene', (139, 142))	('cytotoxic to cancer', 'Disease', (89, 108))	('FR901228', 'Var', (55, 63))	('restored', 'PosReg', (148, 156))	('depletion', 'MPA', (119, 128))
70533	25888633	An additional study showed preferential cytotoxicity of an HDACi, SAHA, in mutant p53 cancer cell lines by destabilizing mutant p53 through inhibition of the HDAC6-HSP90 chaperone axis.	('mutant', 'Var', (121, 127))	('p53', 'Gene', (82, 85))	('cytotoxicity', 'Disease', (40, 52))	('p53', 'Gene', (128, 131))	('HDAC6', 'Gene', (158, 163))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('inhibition', 'NegReg', (140, 150))	('cancer', 'Disease', (86, 92))	('HDAC', 'Gene', '9734', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HSP90', 'Gene', (164, 169))	('SAHA', 'Chemical', 'MESH:D000077337', (66, 70))	('HDAC', 'Gene', '9734', (59, 63))	('HDAC', 'Gene', (158, 162))	('HDAC6', 'Gene', '10013', (158, 163))	('HSP90', 'Gene', '3320', (164, 169))	('mutant', 'Var', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('HDAC', 'Gene', (59, 63))	('destabilizing', 'NegReg', (107, 120))
70534	25888633	Functional inactivation of MDM2 and CHIP (carboxy-terminus of HSP70-interacting Protein) by HSP90 results in aberrant stabilization of mutant p53.	('HSP90', 'Gene', (92, 97))	('stabilization', 'MPA', (118, 131))	('HSP90', 'Gene', '3320', (92, 97))	('p53', 'Gene', (142, 145))	('inactivation', 'NegReg', (11, 23))	('mutant', 'Var', (135, 141))	('CHIP', 'Gene', '10273', (36, 40))	('carboxy-terminus of HSP70-interacting Protein', 'Gene', '10273', (42, 87))	('CHIP', 'Gene', (36, 40))	('MDM2', 'Gene', '4193', (27, 31))	('MDM2', 'Gene', (27, 31))	('carboxy-terminus of HSP70-interacting Protein', 'Gene', (42, 87))
70537	25888633	We examine the effects of HDACi on amplified MDM2, wild-type and mutant p53, PTEN and AKT.	('AKT', 'Gene', (86, 89))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('MDM2', 'Gene', '4193', (45, 49))	('MDM2', 'Gene', (45, 49))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('HDAC', 'Gene', (26, 30))	('HDAC', 'Gene', '9734', (26, 30))	('AKT', 'Gene', '207', (86, 89))
70538	25888633	We also demonstrate that dual targeting of amplified MDM2 and mutant p53 shows additive anti-proliferative effects, as compared to either intervention alone.	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('MDM2', 'Gene', '4193', (53, 57))	('MDM2', 'Gene', (53, 57))	('anti-proliferative effects', 'CPA', (88, 114))	('amplified', 'Var', (43, 52))
70539	25888633	These studies suggest that HDACi warrant clinical evaluation as a therapeutic strategy in LPS harboring mutant p53.	('HDAC', 'Gene', '9734', (27, 31))	('LPS', 'Phenotype', 'HP:0012034', (90, 93))	('LPS', 'Disease', (90, 93))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('LPS', 'Disease', 'MESH:C536528', (90, 93))	('HDAC', 'Gene', (27, 31))
70541	25888633	TP53 transcript was low in LPS510, which contains a TP53 point mutation, and normal in TP53 wild-type LPS141 and MESO257.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (52, 56))	('LPS510', 'Chemical', '-', (27, 33))	('TP53', 'Gene', (87, 91))	('MESO257', 'Chemical', '-', (113, 120))	('TP53', 'Gene', (52, 56))	('LPS141', 'Chemical', '-', (102, 108))	('low', 'NegReg', (20, 23))	('LPS', 'Phenotype', 'HP:0012034', (102, 105))	('LPS', 'Phenotype', 'HP:0012034', (27, 30))	('point mutation', 'Var', (57, 71))	('LPS510', 'Var', (27, 33))
70543	25888633	MDM2 protein expression was strong in LPS449, LPS778, LPS853, and LPS141, medium in LPS141/239 and LPS141/266, and weak in LPS510 (Figure 1B).	('LPS141/239', 'Var', (84, 94))	('weak', 'NegReg', (115, 119))	('LPS853', 'Var', (54, 60))	('LPS510', 'Chemical', '-', (123, 129))	('LPS141', 'Var', (66, 72))	('LPS853', 'Chemical', '-', (54, 60))	('LPS', 'Phenotype', 'HP:0012034', (46, 49))	('strong', 'PosReg', (28, 34))	('LPS778', 'Var', (46, 52))	('LPS449', 'Var', (38, 44))	('LPS', 'Phenotype', 'HP:0012034', (54, 57))	('LPS', 'Phenotype', 'HP:0012034', (38, 41))	('LPS141', 'Chemical', '-', (84, 90))	('LPS141/266', 'Var', (99, 109))	('LPS', 'Phenotype', 'HP:0012034', (84, 87))	('LPS778', 'Chemical', '-', (46, 52))	('MDM2', 'Gene', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (66, 69))	('expression', 'MPA', (13, 23))	('LPS141', 'Chemical', '-', (99, 105))	('LPS449', 'Chemical', '-', (38, 44))	('MDM2', 'Gene', '4193', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('LPS141', 'Chemical', '-', (66, 72))
70544	25888633	p53 protein expression was strong in p53 mutant LPS141/239 and LPS141/266 and weak in p53 wild-type LPS449 and LPS510.	('LPS', 'Phenotype', 'HP:0012034', (100, 103))	('LPS141', 'Chemical', '-', (63, 69))	('protein', 'Protein', (4, 11))	('LPS', 'Phenotype', 'HP:0012034', (48, 51))	('LPS', 'Phenotype', 'HP:0012034', (111, 114))	('strong', 'PosReg', (27, 33))	('mutant LPS141/239', 'Var', (41, 58))	('p53 protein', 'Protein', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('LPS141/266', 'Var', (63, 73))	('LPS141', 'Chemical', '-', (48, 54))	('p53', 'Gene', (37, 40))	('LPS449', 'Chemical', '-', (100, 106))	('LPS', 'Phenotype', 'HP:0012034', (63, 66))	('LPS141/239', 'Var', (48, 58))	('LPS510', 'Chemical', '-', (111, 117))
70546	25888633	MDM2 expression in LPS141/239 and LSP141/266, and p53 expression in the liposarcoma lines with wild-type p53 (LPS778, LPS853, and LPS141) were comparable to that in MESO924 cells (Figure 1B).	('expression', 'MPA', (54, 64))	('liposarcoma', 'Disease', 'MESH:D008080', (72, 83))	('liposarcoma', 'Phenotype', 'HP:0012034', (72, 83))	('LPS', 'Phenotype', 'HP:0012034', (110, 113))	('LPS141', 'Chemical', '-', (130, 136))	('LPS141', 'Chemical', '-', (19, 25))	('LPS', 'Phenotype', 'HP:0012034', (118, 121))	('LPS778', 'Chemical', '-', (110, 116))	('LPS141', 'Var', (130, 136))	('MDM2', 'Gene', '4193', (0, 4))	('p53', 'Gene', (50, 53))	('liposarcoma', 'Disease', (72, 83))	('MDM2', 'Gene', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (19, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('LPS', 'Phenotype', 'HP:0012034', (130, 133))	('MESO924', 'Chemical', '-', (165, 172))	('LPS853', 'Chemical', '-', (118, 124))
70548	25888633	Nutlin-3 dramatically inhibited cell proliferation in p53 wild-type LPS778 and LPS141 in a concentration-dependent manner.	('LPS778', 'Chemical', '-', (68, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('inhibited', 'NegReg', (22, 31))	('LPS778', 'Var', (68, 74))	('LPS141', 'Var', (79, 85))	('p53', 'Var', (54, 57))	('Nutlin-3', 'Chemical', 'MESH:C482205', (0, 8))	('LPS', 'Phenotype', 'HP:0012034', (68, 71))	('LPS141', 'Chemical', '-', (79, 85))	('cell proliferation', 'CPA', (32, 50))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))
70549	25888633	By contrast, Nutlin-3 had only minor effects (5-15% reduction in proliferation) in p53 mutant LPS141/239, LPS141/266, and LPS510, indicating that p53 mutation is a major Nutlin-3 resistant mechanism.	('Nutlin-3', 'Chemical', 'MESH:C482205', (170, 178))	('p53', 'Gene', (83, 86))	('LPS141/239', 'Var', (94, 104))	('LPS141/266', 'Var', (106, 116))	('LPS', 'Phenotype', 'HP:0012034', (94, 97))	('Nutlin-3', 'Chemical', 'MESH:C482205', (13, 21))	('LPS510', 'Var', (122, 128))	('LPS510', 'Chemical', '-', (122, 128))	('LPS141', 'Chemical', '-', (106, 112))	('mutant LPS141/239', 'Var', (87, 104))	('LPS', 'Phenotype', 'HP:0012034', (122, 125))	('LPS', 'Phenotype', 'HP:0012034', (106, 109))	('LPS141', 'Chemical', '-', (94, 100))
70553	25888633	HDAC inhibition induced acetyl tubulin in LPS778 and LPS510, but showed little effect in LPS141 and isogenic LPS141/239 and LPS141/266 (Figure 2).	('HDAC', 'Gene', (0, 4))	('induced', 'Reg', (16, 23))	('LPS', 'Phenotype', 'HP:0012034', (42, 45))	('HDAC', 'Gene', '9734', (0, 4))	('LPS778', 'Chemical', '-', (42, 48))	('LPS', 'Phenotype', 'HP:0012034', (124, 127))	('LPS778', 'Var', (42, 48))	('LPS510', 'Var', (53, 59))	('LPS510', 'Chemical', '-', (53, 59))	('LPS141', 'Chemical', '-', (109, 115))	('LPS141/266', 'Var', (124, 134))	('acetyl tubulin', 'MPA', (24, 38))	('LPS', 'Phenotype', 'HP:0012034', (109, 112))	('LPS141', 'Chemical', '-', (89, 95))	('LPS', 'Phenotype', 'HP:0012034', (53, 56))	('LPS', 'Phenotype', 'HP:0012034', (89, 92))	('LPS141', 'Chemical', '-', (124, 130))
70556	25888633	Treatment with HDACi resulted in degradation of mutant p53, and induction of p21, PTEN, and acetyl-H3, but had little effect on phosphorylation and expression of MDM2 in JMN1B.	('acetyl-H3', 'MPA', (92, 101))	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('MDM2', 'Gene', '4193', (162, 166))	('mutant', 'Var', (48, 54))	('degradation', 'NegReg', (33, 44))	('induction', 'PosReg', (64, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', '9734', (15, 19))	('p21', 'Gene', (77, 80))	('PTEN', 'Gene', (82, 86))	('p21', 'Gene', '644914', (77, 80))	('PTEN', 'Gene', '5728', (82, 86))	('MDM2', 'Gene', (162, 166))	('p53', 'Protein', (55, 58))
70558	25888633	Cell proliferation was strongly inhibited in all LPS and mesothelioma cell lines in a dose-dependent manner after HDAC inhibition (Figure 3C): LBH589 and SAHA IC50 values in p53-mutant lines were 66 nM and 6.5 muM (LPS141/239), 110 nM and 7.1 muM (LPS141/266), 34 nM and 4.2 muM (LPS510), and 52 nM and 3.7 muM (JMN1B), respectively, and in wild-type p53 lines were 59 nM and 5.8 muM (LPS141), 41 nM and 4.2 muM (LPS778), 520 nM and 3.8 muM (MESO924), and 540 nM and 4.7 muM (MESO296), respectively.	('muM', 'Gene', '56925', (471, 474))	('muM', 'Gene', '56925', (210, 213))	('LPS', 'Phenotype', 'HP:0012034', (248, 251))	('muM', 'Gene', (243, 246))	('muM', 'Gene', (408, 411))	('muM', 'Gene', (471, 474))	('muM', 'Gene', (210, 213))	('HDAC', 'Gene', '9734', (114, 118))	('LPS', 'Phenotype', 'HP:0012034', (215, 218))	('LPS141', 'Chemical', '-', (385, 391))	('Cell proliferation', 'CPA', (0, 18))	('LPS', 'Disease', (385, 388))	('LPS141', 'Chemical', '-', (248, 254))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('p53-mutant', 'Var', (174, 184))	('LPS141', 'Chemical', '-', (215, 221))	('MESO296', 'Chemical', '-', (476, 483))	('LPS510', 'Chemical', '-', (280, 286))	('HDAC', 'Gene', (114, 118))	('LPS', 'Disease', (280, 283))	('muM', 'Gene', '56925', (437, 440))	('LPS778', 'Chemical', '-', (413, 419))	('muM', 'Gene', '56925', (380, 383))	('muM', 'Gene', (437, 440))	('muM', 'Gene', (380, 383))	('LPS', 'Disease', (49, 52))	('mesothelioma', 'Disease', (57, 69))	('LPS', 'Disease', (248, 251))	('LPS', 'Disease', (413, 416))	('LPS', 'Disease', 'MESH:C536528', (385, 388))	('LPS', 'Disease', (215, 218))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('SAHA', 'Chemical', 'MESH:D000077337', (154, 158))	('LPS', 'Disease', 'MESH:C536528', (280, 283))	('LPS', 'Phenotype', 'HP:0012034', (385, 388))	('muM', 'Gene', '56925', (243, 246))	('muM', 'Gene', '56925', (275, 278))	('LBH589', 'Chemical', 'MESH:D000077767', (143, 149))	('inhibited', 'NegReg', (32, 41))	('LPS', 'Disease', 'MESH:C536528', (49, 52))	('LPS', 'Disease', 'MESH:C536528', (248, 251))	('muM', 'Gene', '56925', (307, 310))	('muM', 'Gene', (275, 278))	('MESO924', 'Chemical', '-', (442, 449))	('LPS', 'Phenotype', 'HP:0012034', (280, 283))	('LPS', 'Disease', 'MESH:C536528', (413, 416))	('muM', 'Gene', (307, 310))	('LPS', 'Disease', 'MESH:C536528', (215, 218))	('muM', 'Gene', '56925', (408, 411))	('LPS', 'Phenotype', 'HP:0012034', (49, 52))
70559	25888633	The anti-proliferative effect of LBH589 was stronger in all LPS cell lines and p53 mutant JMN1B than in p53 wild-type MESO924 and MESO296, whereas the anti-proliferative effect was greater in MESO924 and MESO296 than JMN1B and all LPS cell lines after treatment with SAHA (Figure 3C).	('stronger', 'PosReg', (44, 52))	('p53', 'Gene', (79, 82))	('mutant', 'Var', (83, 89))	('SAHA', 'Chemical', 'MESH:D000077337', (267, 271))	('MESO924', 'Chemical', '-', (118, 125))	('MESO296', 'Chemical', '-', (204, 211))	('MESO296', 'Chemical', '-', (130, 137))	('MESO924', 'Chemical', '-', (192, 199))	('LPS', 'Disease', (231, 234))	('anti-proliferative effect', 'CPA', (4, 29))	('LPS', 'Phenotype', 'HP:0012034', (60, 63))	('LPS', 'Phenotype', 'HP:0012034', (231, 234))	('LPS', 'Disease', (60, 63))	('LBH589', 'Chemical', 'MESH:D000077767', (33, 39))	('LPS', 'Disease', 'MESH:C536528', (231, 234))	('LPS', 'Disease', 'MESH:C536528', (60, 63))	('LBH589', 'Gene', (33, 39))
70560	25888633	HDAC inhibition also dramatically suppressed the expression of cyclin A in all five LPS lines and JMN1B, but moderately inhibited cyclin A expression in MESO924 and MESO296 (Figure 3D).	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('cyclin A', 'Gene', (130, 138))	('inhibition', 'Var', (5, 15))	('MESO924', 'Chemical', '-', (153, 160))	('MESO296', 'Chemical', '-', (165, 172))	('cyclin', 'molecular_function', 'GO:0016538', ('63', '69'))	('suppressed', 'NegReg', (34, 44))	('inhibited', 'NegReg', (120, 129))	('expression', 'MPA', (49, 59))	('LPS', 'Phenotype', 'HP:0012034', (84, 87))	('LPS', 'Disease', (84, 87))	('cyclin A', 'Gene', (63, 71))	('cyclin A', 'Gene', '890', (130, 138))	('expression', 'MPA', (139, 149))	('cyclin A', 'Gene', '890', (63, 71))	('LPS', 'Disease', 'MESH:C536528', (84, 87))	('cyclin', 'molecular_function', 'GO:0016538', ('130', '136'))
70563	25888633	Caspase 3/7 activity was more dramatic in LPS and mesothelioma cell lines with MDM2 amplification and/or p53 mutation than in cell lines with wild-type p53 (Figure 3E).	('LPS', 'Phenotype', 'HP:0012034', (42, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('LPS', 'Disease', (42, 45))	('amplification', 'Var', (84, 97))	('LPS', 'Disease', 'MESH:C536528', (42, 45))	('activity', 'MPA', (12, 20))	('Caspase 3', 'Gene', (0, 9))	('p53', 'Gene', (105, 108))	('MDM2', 'Gene', (79, 83))	('Caspase 3', 'Gene', '836', (0, 9))	('MDM2', 'Gene', '4193', (79, 83))	('mesothelioma', 'Disease', (50, 62))	('mutation', 'Var', (109, 117))
70564	25888633	LPS cell lines analyzed 48 hours after LBH589 and SAHA treatments showed a dramatic increase in apoptotic cells compared to vehicle-treated cells, particularly in lines harboring mutant p53 (Figure 3F and Supplementary Table 1).	('SAHA', 'Chemical', 'MESH:D000077337', (50, 54))	('mutant', 'Var', (179, 185))	('apoptotic cells', 'CPA', (96, 111))	('LPS', 'Disease', 'MESH:C536528', (0, 3))	('increase', 'PosReg', (84, 92))	('p53', 'Gene', (186, 189))	('LBH589', 'Chemical', 'MESH:D000077767', (39, 45))	('LPS', 'Phenotype', 'HP:0012034', (0, 3))	('LPS', 'Disease', (0, 3))
70565	25888633	Apoptosis was most prominent in LPS141 and LPS510, with nuclear fragmentation increasing from 0% (LPS141), 16% (LPS510), and 1% (LPS778) in cells treated with DMSO, to 10% (LPS141), 22% (LPS510), and 7% (LPS778) in cells treated with 250 nM LBH589 (Figure 3F and Supplementary Table 1).	('LPS510', 'Chemical', '-', (187, 193))	('LPS510', 'Chemical', '-', (43, 49))	('LPS', 'Phenotype', 'HP:0012034', (32, 35))	('LPS141', 'Chemical', '-', (98, 104))	('LPS', 'Phenotype', 'HP:0012034', (112, 115))	('DMSO', 'Chemical', 'MESH:D004121', (159, 163))	('LPS778', 'Chemical', '-', (129, 135))	('LBH589', 'Chemical', 'MESH:D000077767', (241, 247))	('LPS510', 'Var', (43, 49))	('LPS141', 'Chemical', '-', (32, 38))	('increasing', 'PosReg', (78, 88))	('LPS510', 'Chemical', '-', (112, 118))	('LPS141', 'Chemical', '-', (173, 179))	('LPS141', 'Var', (32, 38))	('LPS778', 'Chemical', '-', (204, 210))	('Apoptosis', 'CPA', (0, 9))	('LPS', 'Phenotype', 'HP:0012034', (129, 132))	('LPS', 'Phenotype', 'HP:0012034', (43, 46))	('LPS', 'Phenotype', 'HP:0012034', (98, 101))	('nuclear fragmentation', 'CPA', (56, 77))
70566	25888633	Cell-cycle analysis in LPS141, LPS141/266, LPS141/239, and LPS778 showed a G2 block after HDAC inhibition with an increase in the G2 peak from 27%, 28%, 33% and 20% in DMSO control cells to 41%, 65%, 64%, and 27% after LBH589 treatment, respectively (Figure 3G and Supplementary Table 2).	('LBH589', 'Chemical', 'MESH:D000077767', (219, 225))	('LPS', 'Phenotype', 'HP:0012034', (31, 34))	('increase', 'PosReg', (114, 122))	('Cell-cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('HDAC', 'Gene', (90, 94))	('LPS141', 'Chemical', '-', (43, 49))	('LPS141/239', 'Var', (43, 53))	('HDAC', 'Gene', '9734', (90, 94))	('LPS778', 'Chemical', '-', (59, 65))	('LPS141/266', 'Var', (31, 41))	('LPS778', 'Var', (59, 65))	('LPS141', 'Chemical', '-', (23, 29))	('LPS', 'Phenotype', 'HP:0012034', (43, 46))	('LPS', 'Phenotype', 'HP:0012034', (23, 26))	('block', 'NegReg', (78, 83))	('DMSO', 'Chemical', 'MESH:D004121', (168, 172))	('LPS141', 'Chemical', '-', (31, 37))	('LPS', 'Phenotype', 'HP:0012034', (59, 62))
70567	25888633	Treatment with 5 muM SAHA resulted in G1 arrest in LPS778 (DMSO: 66%; SAHA: 78%), and G2 arrest in LPS141 (DMSO: 27%; SAHA: 43%), LPS141/239 (DMSO: 33%; SAHA: 41%), and LPS510 (DMSO: 28%; SAHA: 31%) (Figure 3G and Supplementary Table 2).	('DMSO', 'Chemical', 'MESH:D004121', (177, 181))	('SAHA', 'Chemical', 'MESH:D000077337', (188, 192))	('LPS778', 'Chemical', '-', (51, 57))	('SAHA', 'Chemical', 'MESH:D000077337', (21, 25))	('LPS141', 'Var', (99, 105))	('SAHA', 'Chemical', 'MESH:D000077337', (70, 74))	('DMSO', 'Chemical', 'MESH:D004121', (142, 146))	('muM', 'Gene', '56925', (17, 20))	('SAHA', 'Chemical', 'MESH:D000077337', (118, 122))	('muM', 'Gene', (17, 20))	('LPS510', 'Chemical', '-', (169, 175))	('LPS778', 'Var', (51, 57))	('LPS141/239', 'Var', (130, 140))	('LPS510', 'Var', (169, 175))	('DMSO', 'Chemical', 'MESH:D004121', (59, 63))	('LPS', 'Phenotype', 'HP:0012034', (99, 102))	('DMSO', 'Chemical', 'MESH:D004121', (107, 111))	('G2 arrest', 'MPA', (86, 95))	('SAHA', 'Chemical', 'MESH:D000077337', (153, 157))	('LPS', 'Phenotype', 'HP:0012034', (51, 54))	('LPS', 'Phenotype', 'HP:0012034', (169, 172))	('LPS141', 'Chemical', '-', (99, 105))	('LPS141', 'Chemical', '-', (130, 136))	('G1 arrest', 'MPA', (38, 47))	('LPS', 'Phenotype', 'HP:0012034', (130, 133))
70568	25888633	MDM2 and TP53 gene expression was stably silenced by lentivirus-mediated shRNAs (Figure 4), and knockdown was evaluated by immunoblotting, in LPS141, LPS141/239, LPS141/266, and LPS510, and MESO924, at 10 days after transduction (Figure 4A).	('LPS141', 'Chemical', '-', (162, 168))	('TP53', 'Gene', '7157', (9, 13))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('LPS', 'Phenotype', 'HP:0012034', (150, 153))	('LPS510', 'Chemical', '-', (178, 184))	('transduction', 'biological_process', 'GO:0009293', ('216', '228'))	('LPS', 'Phenotype', 'HP:0012034', (142, 145))	('expression', 'MPA', (19, 29))	('LPS141', 'Chemical', '-', (150, 156))	('LPS141/266', 'Var', (162, 172))	('LPS510', 'Var', (178, 184))	('LPS141', 'Chemical', '-', (142, 148))	('MESO924', 'Chemical', '-', (190, 197))	('TP53', 'Gene', (9, 13))	('LPS', 'Phenotype', 'HP:0012034', (178, 181))	('MDM2', 'Gene', (0, 4))	('silenced', 'NegReg', (41, 49))	('LPS', 'Phenotype', 'HP:0012034', (162, 165))	('LPS141', 'Var', (142, 148))	('MDM2', 'Gene', '4193', (0, 4))	('LPS141/239', 'Var', (150, 160))
70570	25888633	MDM2 knockdown increased p53 and p21 expression, irrespective of p53 mutational status, in p53 wild-type LPS141 and MESO924.	('p21', 'Gene', '644914', (33, 36))	('p53', 'Gene', (65, 68))	('knockdown', 'Var', (5, 14))	('LPS141', 'Chemical', '-', (105, 111))	('LPS', 'Phenotype', 'HP:0012034', (105, 108))	('increased', 'PosReg', (15, 24))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('p21', 'Gene', (33, 36))	('MESO924', 'Chemical', '-', (116, 123))	('expression', 'MPA', (37, 47))	('p53', 'Protein', (25, 28))
70571	25888633	p53 knockdown had little effect on MDM2 and p21 in LPS cell lines but decreased MDM2 and p21 expression in MESO924 (Figure 4A).	('MDM2', 'Gene', (80, 84))	('p53', 'Gene', (0, 3))	('p21', 'Gene', '644914', (89, 92))	('LPS', 'Phenotype', 'HP:0012034', (51, 54))	('MDM2', 'Gene', (35, 39))	('p21', 'Gene', '644914', (44, 47))	('MESO924', 'Chemical', '-', (107, 114))	('decreased', 'NegReg', (70, 79))	('LPS', 'Disease', 'MESH:C536528', (51, 54))	('expression', 'MPA', (93, 103))	('p21', 'Gene', (44, 47))	('knockdown', 'Var', (4, 13))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', '4193', (80, 84))	('p21', 'Gene', (89, 92))	('LPS', 'Disease', (51, 54))
70573	25888633	The combination of MDM2 or p53 knockdown had an additive effect on cell growth, compared to either intervention alone (Figure 4B).	('MDM2', 'Gene', '4193', (19, 23))	('MDM2', 'Gene', (19, 23))	('cell growth', 'CPA', (67, 78))	('p53', 'Gene', (27, 30))	('knockdown', 'Var', (31, 40))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))
70574	25888633	MDM2 knockdown, in p53 wild-type LPS141, and p53-mutant LPS141/239 and LPS510, resulted in ~40% and ~60-70% inhibition of cell viability, respectively, at 10 days after MDM2 silencing, compared to the empty vector control.	('inhibition', 'NegReg', (108, 118))	('LPS141', 'Chemical', '-', (33, 39))	('LPS510', 'Var', (71, 77))	('LPS510', 'Chemical', '-', (71, 77))	('LPS', 'Phenotype', 'HP:0012034', (71, 74))	('p53', 'Var', (19, 22))	('LPS', 'Phenotype', 'HP:0012034', (56, 59))	('LPS141/239', 'Gene', (56, 66))	('MDM2', 'Gene', '4193', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (33, 36))	('MDM2', 'Gene', (0, 4))	('silencing', 'NegReg', (174, 183))	('LPS141', 'Chemical', '-', (56, 62))	('MDM2', 'Gene', '4193', (169, 173))	('cell viability', 'CPA', (122, 136))	('MDM2', 'Gene', (169, 173))
70575	25888633	MDM2 knockdown resulted in a mild reduction in viability for a p53 mutant LPS141/266 (Figure 4C).	('LPS141', 'Chemical', '-', (74, 80))	('viability', 'MPA', (47, 56))	('MDM2', 'Gene', '4193', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (74, 77))	('reduction', 'NegReg', (34, 43))	('MDM2', 'Gene', (0, 4))	('mutant', 'Var', (67, 73))	('LPS141/266', 'Gene', (74, 84))
70578	25888633	MDM2 knockdown resulted in a dramatic G1 block in p53-wild-type LPS141, or G2 block in p53-mutant LPS141/266 and LPS141/239.	('G1 block', 'MPA', (38, 46))	('LPS141', 'Chemical', '-', (64, 70))	('LPS141', 'Chemical', '-', (113, 119))	('p53-mutant', 'Var', (87, 97))	('MDM2', 'Gene', '4193', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (113, 116))	('LPS141', 'Chemical', '-', (98, 104))	('MDM2', 'Gene', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (64, 67))	('LPS', 'Phenotype', 'HP:0012034', (98, 101))	('LPS141/239', 'Var', (113, 123))	('LPS141/266', 'Gene', (98, 108))
70580	25888633	Cell cycle analyses also demonstrated a G2 block after p53 knockdown in LPS141/266, LPS141/239, and LPS510 (Figure 4D).	('LPS141', 'Chemical', '-', (84, 90))	('LPS', 'Phenotype', 'HP:0012034', (100, 103))	('p53', 'Gene', (55, 58))	('G2 block', 'CPA', (40, 48))	('LPS', 'Phenotype', 'HP:0012034', (72, 75))	('LPS141/239', 'Var', (84, 94))	('LPS141', 'Chemical', '-', (72, 78))	('LPS', 'Phenotype', 'HP:0012034', (84, 87))	('LPS510', 'Chemical', '-', (100, 106))	('knockdown', 'Var', (59, 68))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('LPS510', 'Var', (100, 106))
70581	25888633	The G2 peaks were 25-28% (LPS141/266), 34-35% (LPS141/239), and 12-13% (LPS510) in cells with p53 knockdown (Figure 4D and Supplementary Table 3).	('p53', 'Gene', (94, 97))	('LPS', 'Phenotype', 'HP:0012034', (72, 75))	('LPS141', 'Chemical', '-', (26, 32))	('knockdown', 'Var', (98, 107))	('LPS141', 'Chemical', '-', (47, 53))	('LPS', 'Phenotype', 'HP:0012034', (26, 29))	('LPS', 'Phenotype', 'HP:0012034', (47, 50))	('LPS141/239', 'Var', (47, 57))	('LPS510', 'Chemical', '-', (72, 78))
70582	25888633	Combination of MDM2 and p53 knockdown resulted in a G2 block for LPS141/239, LPS141/266, and LPS510 (Figure 4D).	('MDM2', 'Gene', '4193', (15, 19))	('p53', 'Gene', (24, 27))	('LPS141/239', 'Var', (65, 75))	('MDM2', 'Gene', (15, 19))	('LPS', 'Phenotype', 'HP:0012034', (93, 96))	('LPS510', 'Var', (93, 99))	('LPS141', 'Chemical', '-', (77, 83))	('LPS510', 'Chemical', '-', (93, 99))	('LPS', 'Phenotype', 'HP:0012034', (77, 80))	('knockdown', 'Var', (28, 37))	('G2 block', 'MPA', (52, 60))	('LPS141', 'Chemical', '-', (65, 71))	('LPS', 'Phenotype', 'HP:0012034', (65, 68))	('LPS141/266', 'Var', (77, 87))
70586	25888633	Almost all cases of WDLPS harbor MDM2 amplification or TP53 mutations.	('WDLPS harbor MDM2 amplification', 'Disease', (20, 51))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('LPS', 'Phenotype', 'HP:0012034', (22, 25))	('WDLPS harbor MDM2 amplification', 'Disease', 'MESH:C537062', (20, 51))	('mutations', 'Var', (60, 69))
70587	25888633	Amplification of MDM2 and CDK4 has been found in WD and DDLPS.	('Amplification', 'Var', (0, 13))	('LPS', 'Disease', 'MESH:C536528', (58, 61))	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))	('CDK4', 'Gene', '1019', (26, 30))	('found', 'Reg', (40, 45))	('CDK4', 'Gene', (26, 30))	('WD', 'Disease', 'MESH:D006527', (49, 51))	('LPS', 'Phenotype', 'HP:0012034', (58, 61))	('LPS', 'Disease', (58, 61))
70588	25888633	Our findings confirm amplification of MDM2 and CDK4 in LPS cell lines, as compared to unamplified mesothelioma cell lines (MESO257 or MESO924) (Figure 1A and 1B, and SNP data (not shown)).	('LPS', 'Phenotype', 'HP:0012034', (55, 58))	('LPS', 'Disease', (55, 58))	('CDK', 'molecular_function', 'GO:0004693', ('47', '50'))	('LPS', 'Disease', 'MESH:C536528', (55, 58))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('CDK4', 'Gene', (47, 51))	('MDM2', 'Gene', '4193', (38, 42))	('MESO257', 'Chemical', '-', (123, 130))	('MDM2', 'Gene', (38, 42))	('MESO924', 'Chemical', '-', (134, 141))	('CDK4', 'Gene', '1019', (47, 51))	('amplification', 'Var', (21, 34))	('mesothelioma', 'Disease', (98, 110))
70591	25888633	This result indicates that p53 mutation is a Nutlin-3 resistance mechanism in LPS.	('LPS', 'Disease', 'MESH:C536528', (78, 81))	('mutation', 'Var', (31, 39))	('LPS', 'Phenotype', 'HP:0012034', (78, 81))	('Nutlin-3', 'Chemical', 'MESH:C482205', (45, 53))	('LPS', 'Disease', (78, 81))	('p53', 'Gene', (27, 30))
70592	25888633	Control of p53 expression by MDM2 is lost in tumors harboring mutant p53, resulting in p53 hyperstabilization and accumulation.	('MDM2', 'Gene', '4193', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('MDM2', 'Gene', (29, 33))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('p53', 'MPA', (87, 90))	('accumulation', 'PosReg', (114, 126))	('hyperstabilization', 'PosReg', (91, 109))	('lost', 'NegReg', (37, 41))
70593	25888633	We hypothesized that HDAC inhibition might induce pro-apoptotic and anti-proliferative effects in liposarcoma cell lines harboring p53 mutations.	('HDAC', 'Gene', '9734', (21, 25))	('liposarcoma', 'Disease', (98, 109))	('mutations', 'Var', (135, 144))	('p53', 'Gene', (131, 134))	('anti-proliferative effects', 'CPA', (68, 94))	('pro-apoptotic', 'CPA', (50, 63))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('liposarcoma', 'Disease', 'MESH:D008080', (98, 109))	('induce', 'PosReg', (43, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('HDAC', 'Gene', (21, 25))
70594	25888633	Recent studies have demonstrated functional inactivation of MDM2 and CHIP E3 ligase activity by HSP90 inhibition, resulting in aberrant stabilization of mutant p53, and SAHA inhibited cell growth in mutant p53 human cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-HSP90 chaperone axis.	('MDM2', 'Gene', (60, 64))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('HSP90', 'Gene', (96, 101))	('stabilization', 'MPA', (136, 149))	('mutant', 'Var', (153, 159))	('human', 'Species', '9606', (210, 215))	('ligase activity', 'molecular_function', 'GO:0016874', ('77', '92'))	('cancer', 'Disease', (216, 222))	('HSP90', 'Gene', '3320', (289, 294))	('mutant', 'Var', (199, 205))	('MDM2', 'Gene', '4193', (60, 64))	('CHIP', 'Gene', '10273', (69, 73))	('cell growth', 'CPA', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('destabilizing', 'NegReg', (232, 245))	('p53', 'Gene', (160, 163))	('mutant', 'Var', (246, 252))	('HSP90', 'Gene', '3320', (96, 101))	('inhibition', 'NegReg', (102, 112))	('HDAC6', 'Gene', (283, 288))	('p53', 'Gene', (206, 209))	('p53', 'Gene', (253, 256))	('activity', 'MPA', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('inhibition', 'NegReg', (265, 275))	('SAHA', 'Chemical', 'MESH:D000077337', (169, 173))	('CHIP', 'Gene', (69, 73))	('inhibited', 'NegReg', (174, 183))	('inactivation', 'NegReg', (44, 56))	('HSP90', 'Gene', (289, 294))	('HDAC6', 'Gene', '10013', (283, 288))
70595	25888633	HDACi showed a strong impact on cell viability and apoptosis in LPS and mesothelioma cell lines containing mutant or wild-type p53 (Figure 3C-3G).	('HDAC', 'Gene', (0, 4))	('LPS', 'Disease', 'MESH:C536528', (64, 67))	('HDAC', 'Gene', '9734', (0, 4))	('mutant', 'Var', (107, 113))	('impact', 'Reg', (22, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('mesothelioma', 'Disease', (72, 84))	('cell viability', 'CPA', (32, 46))	('LPS', 'Phenotype', 'HP:0012034', (64, 67))	('LPS', 'Disease', (64, 67))	('apoptosis', 'CPA', (51, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('p53', 'Gene', (127, 130))
70596	25888633	Treatment with LBH589, in MDM2-amplified and/or p53-mutant cell lines (LPS141, LPS141/239, LPS141/266, LPS510, LPS778, and JMN1B), had greater inhibitory effects on viability than in normal MDM2 and p53-wild-type cell lines MESO924 and MESO296, whereas the anti-proliferative effects of HDAC inhibition by SAHA in p53-wild-type mesothelioma cell lines were greater (MESO924 and MESO296) than LPS cell lines (Figure 3C).	('MDM2', 'Gene', '4193', (190, 194))	('LPS', 'Disease', 'MESH:C536528', (79, 82))	('LPS', 'Phenotype', 'HP:0012034', (71, 74))	('LPS', 'Disease', (91, 94))	('MESO924', 'Chemical', '-', (366, 373))	('LPS', 'Disease', 'MESH:C536528', (111, 114))	('LPS', 'Disease', 'MESH:C536528', (103, 106))	('HDAC', 'Gene', '9734', (287, 291))	('mesothelioma', 'Disease', (328, 340))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))	('LPS141', 'Chemical', '-', (71, 77))	('MESO924', 'Chemical', '-', (224, 231))	('viability', 'CPA', (165, 174))	('LPS', 'Phenotype', 'HP:0012034', (111, 114))	('LPS', 'Disease', (392, 395))	('mesothelioma', 'Disease', 'MESH:D008654', (328, 340))	('LPS778', 'Chemical', '-', (111, 117))	('LPS', 'Phenotype', 'HP:0012034', (103, 106))	('inhibitory', 'NegReg', (143, 153))	('HDAC', 'Gene', (287, 291))	('LPS', 'Disease', 'MESH:C536528', (91, 94))	('LPS141', 'Chemical', '-', (79, 85))	('LPS510', 'Chemical', '-', (103, 109))	('SAHA', 'Chemical', 'MESH:D000077337', (306, 310))	('MDM2', 'Gene', (26, 30))	('LPS', 'Phenotype', 'HP:0012034', (91, 94))	('LPS', 'Disease', (71, 74))	('MESO296', 'Chemical', '-', (236, 243))	('LPS', 'Disease', 'MESH:C536528', (392, 395))	('LPS', 'Disease', (79, 82))	('MDM2', 'Gene', (190, 194))	('LPS', 'Disease', (103, 106))	('MDM2', 'Gene', '4193', (26, 30))	('LPS', 'Disease', (111, 114))	('LPS141', 'Chemical', '-', (91, 97))	('p53-mutant', 'Gene', (48, 58))	('JMN1B', 'Var', (123, 128))	('LPS', 'Disease', 'MESH:C536528', (71, 74))	('LBH589', 'Chemical', 'MESH:D000077767', (15, 21))	('MESO296', 'Chemical', '-', (378, 385))	('anti-proliferative effects', 'MPA', (257, 283))
70597	25888633	These data suggest that HDAC regulation of LPS cell viability can be targeted effectively in MDM2-amplified and/or p53-mutant cancer cells by LBH589, and that SAHA treatment can show dramatic anti-proliferative effects in-p53 wild type cancer cells.	('regulation', 'biological_process', 'GO:0065007', ('29', '39'))	('SAHA', 'Chemical', 'MESH:D000077337', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('MDM2', 'Gene', '4193', (93, 97))	('HDAC', 'Gene', '9734', (24, 28))	('cancer', 'Disease', (126, 132))	('LPS', 'Disease', (43, 46))	('p53-mutant', 'Gene', (115, 125))	('HDAC', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (236, 242))	('p53-mutant', 'Var', (115, 125))	('anti-proliferative', 'CPA', (192, 210))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('LPS', 'Disease', 'MESH:C536528', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('LBH589', 'Chemical', 'MESH:D000077767', (142, 148))	('LPS', 'Phenotype', 'HP:0012034', (43, 46))	('MDM2', 'Gene', (93, 97))
70599	25888633	Immunoblotting showed that treatment with HDACi LBH589 and SAHA for 48 hours induced the degradation of mutant p53 in three LPS cell lines (LPS141/239, LPS141/266, and LPS510) and a mesothelioma cell line (JMN1B) (Figures 2 and 3A).	('HDAC', 'Gene', '9734', (42, 46))	('LPS', 'Disease', (124, 127))	('LPS', 'Phenotype', 'HP:0012034', (152, 155))	('LPS', 'Disease', (140, 143))	('LPS', 'Phenotype', 'HP:0012034', (168, 171))	('HDAC', 'Gene', (42, 46))	('LPS141', 'Chemical', '-', (152, 158))	('degradation', 'biological_process', 'GO:0009056', ('89', '100'))	('mutant', 'Var', (104, 110))	('LPS', 'Disease', 'MESH:C536528', (124, 127))	('SAHA', 'Chemical', 'MESH:D000077337', (59, 63))	('LPS', 'Disease', (168, 171))	('LPS510', 'Chemical', '-', (168, 174))	('LPS', 'Phenotype', 'HP:0012034', (124, 127))	('LBH589', 'Chemical', 'MESH:D000077767', (48, 54))	('LPS', 'Disease', (152, 155))	('mesothelioma', 'Disease', (182, 194))	('LPS', 'Disease', 'MESH:C536528', (140, 143))	('p53', 'Gene', (111, 114))	('LPS141', 'Chemical', '-', (140, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('degradation', 'MPA', (89, 100))	('LPS', 'Phenotype', 'HP:0012034', (140, 143))	('LPS', 'Disease', 'MESH:C536528', (168, 171))	('LPS', 'Disease', 'MESH:C536528', (152, 155))
70600	25888633	This finding is in line with published data showing that SAHA treatment led to degradation of mutant p53.	('degradation', 'MPA', (79, 90))	('SAHA', 'Chemical', 'MESH:D000077337', (57, 61))	('mutant', 'Var', (94, 100))	('p53', 'Gene', (101, 104))	('degradation', 'biological_process', 'GO:0009056', ('79', '90'))
70601	25888633	Unexpectedly, HDAC inhibition by SAHA and LBH589 resulted in down-regulation of wild-type p53 in two LPS cell lines (LPS141 and LPS778), and a decrease in MDM2 and phospho-MDM2 in all LPS cell lines, irrespective of p53 status (Figures 2 and 3A).	('LPS', 'Phenotype', 'HP:0012034', (128, 131))	('LPS', 'Disease', (117, 120))	('LPS', 'Disease', (101, 104))	('LPS', 'Phenotype', 'HP:0012034', (184, 187))	('MDM2', 'Gene', (155, 159))	('MDM2', 'Gene', (172, 176))	('LBH589', 'Chemical', 'MESH:D000077767', (42, 48))	('down-regulation', 'NegReg', (61, 76))	('LPS778', 'Chemical', '-', (128, 134))	('LPS', 'Disease', 'MESH:C536528', (117, 120))	('LBH589', 'Var', (42, 48))	('LPS', 'Disease', 'MESH:C536528', (101, 104))	('MDM2', 'Gene', '4193', (155, 159))	('MDM2', 'Gene', '4193', (172, 176))	('LPS141', 'Chemical', '-', (117, 123))	('LPS', 'Phenotype', 'HP:0012034', (117, 120))	('LPS', 'Disease', (128, 131))	('HDAC', 'Gene', '9734', (14, 18))	('LPS', 'Disease', (184, 187))	('LPS', 'Phenotype', 'HP:0012034', (101, 104))	('HDAC', 'Gene', (14, 18))	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('SAHA', 'Chemical', 'MESH:D000077337', (33, 37))	('decrease', 'NegReg', (143, 151))	('LPS', 'Disease', 'MESH:C536528', (128, 131))	('LPS', 'Disease', 'MESH:C536528', (184, 187))
70603	25888633	Unexpectedly, HDAC inhibition resulted in p53 (wild-type and mutant) degradation in a dose-dependent manner in LPS cell lines, whereas treatment with HDACi induced p21 expression, a direct p53 downstream responder (Figure 3A), indicating that regulation of p21 is p53-independent after HDAC inhibition.	('p53', 'MPA', (42, 45))	('regulation', 'biological_process', 'GO:0065007', ('243', '253'))	('LPS', 'Disease', 'MESH:C536528', (111, 114))	('degradation', 'NegReg', (69, 80))	('inhibition', 'Var', (19, 29))	('LPS', 'Phenotype', 'HP:0012034', (111, 114))	('HDAC', 'Gene', '9734', (286, 290))	('HDAC', 'Gene', '9734', (150, 154))	('p21', 'Gene', (164, 167))	('HDAC', 'Gene', '9734', (14, 18))	('p21', 'Gene', '644914', (164, 167))	('HDAC', 'Gene', (286, 290))	('degradation', 'biological_process', 'GO:0009056', ('69', '80'))	('mutant', 'Var', (61, 67))	('HDAC', 'Gene', (150, 154))	('p21', 'Gene', (257, 260))	('HDAC', 'Gene', (14, 18))	('LPS', 'Disease', (111, 114))	('p21', 'Gene', '644914', (257, 260))
70606	25888633	Recent studies have demonstrated that the selective cyclin-dependent kinase 4/6 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in LPS cell lines and xenografts.	('growth', 'CPA', (121, 127))	('LPS', 'Disease', (154, 157))	('cyclin-dependent kinase 4/6', 'Gene', (52, 79))	('CDK6', 'Gene', '1021', (87, 91))	('cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (52, 79))	('induces', 'Reg', (132, 139))	('CDK6', 'Gene', (87, 91))	('LPS', 'Disease', 'MESH:C536528', (154, 157))	('CDK', 'molecular_function', 'GO:0004693', ('87', '90'))	('CDK4', 'Gene', (81, 85))	('LPS', 'Phenotype', 'HP:0012034', (154, 157))	('PD0332991', 'Chemical', 'MESH:C500026', (102, 111))	('senescence', 'MPA', (140, 150))	('senescence', 'biological_process', 'GO:0010149', ('140', '150'))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('CDK4', 'Gene', '1019', (81, 85))	('inhibits', 'NegReg', (112, 120))	('PD0332991', 'Var', (102, 111))	('cyclin', 'molecular_function', 'GO:0016538', ('52', '58'))
70607	25888633	Furthermore, treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free survival in patients with CDK4-amplified and RB-expressing WDLPS/DDLPS who had progressive disease despite systemic therapy.	('CDK4', 'Gene', '1019', (132, 136))	('CDK4', 'Gene', (32, 36))	('LPS', 'Disease', 'MESH:C536528', (167, 170))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('LPS', 'Phenotype', 'HP:0012034', (173, 176))	('LPS', 'Disease', (173, 176))	('CDK4', 'Gene', '1019', (32, 36))	('CDK', 'molecular_function', 'GO:0004693', ('132', '135'))	('PD0332991', 'Chemical', 'MESH:C500026', (47, 56))	('LPS', 'Disease', 'MESH:C536528', (173, 176))	('PD0332991', 'Var', (47, 56))	('LPS', 'Disease', (167, 170))	('LPS', 'Phenotype', 'HP:0012034', (167, 170))	('patients', 'Species', '9606', (118, 126))	('CDK4', 'Gene', (132, 136))
70608	25888633	In addition, JUN knockdown by shRNAs reduced cell viability in vitro and inhibited tumor formation in vivo without an observable effect on the differentiation state of the LPS cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LPS', 'Disease', 'MESH:C536528', (172, 175))	('tumor', 'Disease', (83, 88))	('cell viability', 'CPA', (45, 59))	('JUN', 'Gene', (13, 16))	('inhibited', 'NegReg', (73, 82))	('knockdown', 'Var', (17, 26))	('reduced', 'NegReg', (37, 44))	('LPS', 'Phenotype', 'HP:0012034', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('LPS', 'Disease', (172, 175))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
70610	25888633	Therefore, these data indicate that MDM2 amplification and/or p53 mutation play the crucial oncogenic role in LPS and mesothelioma cell proliferation and survival.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('MDM2', 'Gene', (36, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('LPS', 'Phenotype', 'HP:0012034', (110, 113))	('LPS', 'Disease', (110, 113))	('survival', 'CPA', (154, 162))	('LPS', 'Disease', 'MESH:C536528', (110, 113))	('mesothelioma', 'Disease', (118, 130))	('amplification', 'Var', (41, 54))	('mutation', 'Var', (66, 74))	('p53', 'Gene', (62, 65))	('MDM2', 'Gene', '4193', (36, 40))
70611	25888633	Previous studies have suggested that aberrant activation of PI3-K/AKT/mTOR signaling due to down-regulation or complete loss of PTEN or an alternative mechanism of PIK3CA mutation, is a potential therapeutic target in LPS and mesothelioma.	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('mesothelioma', 'Disease', (226, 238))	('mutation', 'Var', (171, 179))	('PIK3CA', 'Gene', (164, 170))	('mTOR', 'Gene', '2475', (70, 74))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('mesothelioma', 'Disease', 'MESH:D008654', (226, 238))	('PI3-K', 'molecular_function', 'GO:0016303', ('60', '65'))	('LPS', 'Disease', (218, 221))	('AKT', 'Gene', (66, 69))	('PTEN', 'Gene', (128, 132))	('down-regulation', 'NegReg', (92, 107))	('PIK3CA', 'Gene', '5290', (164, 170))	('loss', 'NegReg', (120, 124))	('LPS', 'Disease', 'MESH:C536528', (218, 221))	('mTOR', 'Gene', (70, 74))	('activation', 'PosReg', (46, 56))	('PTEN', 'Gene', '5728', (128, 132))	('LPS', 'Phenotype', 'HP:0012034', (218, 221))	('AKT', 'Gene', '207', (66, 69))
70612	25888633	Although the mechanism is unclear, we show here that HDACi LBH589 and SAHA induce PTEN expression in all LPS and mesothelioma cell lines tested (Figure 2 and Figure 3A) accompanied by AKT inhibition (Figure 3B), consistent with published data that NBM-HD-3, a potent HDAC inhibitor, increases PTEN expression.	('expression', 'MPA', (298, 308))	('PTEN', 'Gene', '5728', (293, 297))	('mesothelioma', 'Disease', (113, 125))	('SAHA', 'Chemical', 'MESH:D000077337', (70, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('AKT', 'Gene', '207', (184, 187))	('LBH589', 'Chemical', 'MESH:D000077767', (59, 65))	('LPS', 'Disease', (105, 108))	('LBH589', 'Var', (59, 65))	('inhibition', 'NegReg', (188, 198))	('PTEN', 'Gene', (82, 86))	('expression', 'MPA', (87, 97))	('HDAC', 'Gene', '9734', (267, 271))	('LPS', 'Disease', 'MESH:C536528', (105, 108))	('HDAC', 'Gene', '9734', (53, 57))	('PTEN', 'Gene', '5728', (82, 86))	('HD', 'Disease', 'MESH:D006816', (53, 55))	('PTEN', 'Gene', (293, 297))	('HD', 'Disease', 'MESH:D006816', (252, 254))	('LPS', 'Phenotype', 'HP:0012034', (105, 108))	('HD', 'Disease', 'MESH:D006816', (267, 269))	('HDAC', 'Gene', (267, 271))	('HDAC', 'Gene', (53, 57))	('AKT', 'Gene', (184, 187))	('increases', 'PosReg', (283, 292))
70615	25888633	In the present work, treatment with HDACi LBH589 and SAHA induced apoptosis and reduced cell viability in two p53 wild-type mesothelioma cell lines (MESO924 and MESO296) and one p53 mutant mesothelioma cell line (JMN1B), associated with an up-regulation of PTEN and p21, inactivation of AKT, and degradation of mutant p53 (Figure 3A-3F).	('regulation', 'biological_process', 'GO:0065007', ('243', '253'))	('degradation', 'biological_process', 'GO:0009056', ('296', '307'))	('cell viability', 'CPA', (88, 102))	('mutant', 'Var', (311, 317))	('PTEN', 'Gene', (257, 261))	('MESO296', 'Chemical', '-', (161, 168))	('inactivation', 'NegReg', (271, 283))	('LBH589', 'Chemical', 'MESH:D000077767', (42, 48))	('SAHA', 'Chemical', 'MESH:D000077337', (53, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('AKT', 'Gene', '207', (287, 290))	('p53', 'Gene', (318, 321))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('PTEN', 'Gene', '5728', (257, 261))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('degradation', 'MPA', (296, 307))	('MESO924', 'Chemical', '-', (149, 156))	('reduced', 'NegReg', (80, 87))	('HDAC', 'Gene', '9734', (36, 40))	('p21', 'Gene', (266, 269))	('apoptosis', 'CPA', (66, 75))	('p21', 'Gene', '644914', (266, 269))	('mesothelioma', 'Disease', (189, 201))	('HDAC', 'Gene', (36, 40))	('mesothelioma', 'Disease', (124, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('AKT', 'Gene', (287, 290))	('up-regulation', 'PosReg', (240, 253))
70617	25888633	Our data add to the already substantial evidence that targeting the crucial HDACi pathway might be an effective strategy in mesothelioma, especially in p53-mutant sublines.	('HDAC', 'Gene', (76, 80))	('HDAC', 'Gene', '9734', (76, 80))	('mesothelioma', 'Disease', (124, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('p53-mutant', 'Var', (152, 162))
70618	25888633	HDAC inhibition resulted in downregulation of amplified MDM2 and mutant p53, and significantly reduced LPS cell viability (Figures 2, 3A-3G).	('HDAC', 'Gene', (0, 4))	('LPS', 'Disease', (103, 106))	('HDAC', 'Gene', '9734', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (103, 106))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('amplified', 'Var', (46, 55))	('downregulation', 'NegReg', (28, 42))	('LPS', 'Disease', 'MESH:C536528', (103, 106))	('reduced', 'NegReg', (95, 102))	('MDM2', 'Gene', '4193', (56, 60))	('MDM2', 'Gene', (56, 60))
70619	25888633	On the basis of these findings, we hypothesized that additive effects would be obtained through attacking both amplified MDM2 and mutant p53 together.	('mutant', 'Var', (130, 136))	('p53', 'Gene', (137, 140))	('MDM2', 'Gene', (121, 125))	('MDM2', 'Gene', '4193', (121, 125))
70620	25888633	Therefore, we further evaluated the function of the amplified MDM2, mutant p53 alone, or both together, by shRNA knockdown.	('p53', 'Gene', (75, 78))	('MDM2', 'Gene', '4193', (62, 66))	('MDM2', 'Gene', (62, 66))	('mutant', 'Var', (68, 74))
70621	25888633	MDM2 or p53 shRNA knockdown in the MDM2-amplified and/or p53-mutant LPS cell lines had profound anti-proliferative consequences (Figure 4B-4D).	('LPS', 'Disease', 'MESH:C536528', (68, 71))	('p53-mutant', 'Gene', (57, 67))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('anti-proliferative', 'CPA', (96, 114))	('LPS', 'Phenotype', 'HP:0012034', (68, 71))	('p53-mutant', 'Var', (57, 67))	('LPS', 'Disease', (68, 71))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', (35, 39))
70622	25888633	By contrast, p53 silencing did not affect proliferation in wild-type p53 LPS cell line LPS141 (Figure 4C and 4D).	('LPS141', 'Chemical', '-', (87, 93))	('LPS', 'Phenotype', 'HP:0012034', (73, 76))	('LPS', 'Phenotype', 'HP:0012034', (87, 90))	('LPS', 'Disease', (73, 76))	('LPS', 'Disease', (87, 90))	('LPS', 'Disease', 'MESH:C536528', (73, 76))	('LPS', 'Disease', 'MESH:C536528', (87, 90))	('p53', 'Gene', (13, 16))	('silencing', 'Var', (17, 26))
70623	25888633	These findings suggest that MDM2 amplification or p53 mutation play essential oncogenic roles in LPS.	('mutation', 'Var', (54, 62))	('LPS', 'Phenotype', 'HP:0012034', (97, 100))	('LPS', 'Disease', (97, 100))	('amplification', 'Var', (33, 46))	('LPS', 'Disease', 'MESH:C536528', (97, 100))	('p53', 'Gene', (50, 53))	('MDM2', 'Gene', '4193', (28, 32))	('MDM2', 'Gene', (28, 32))
70624	25888633	Notably, additive effects were obtained through simultaneous MDM2 and p53 knockdowns, with this combination approach inhibiting cell growth more than either intervention alone (Figure 4B and 4C).	('cell growth', 'CPA', (128, 139))	('cell growth', 'biological_process', 'GO:0016049', ('128', '139'))	('p53', 'Gene', (70, 73))	('knockdowns', 'Var', (74, 84))	('MDM2', 'Gene', '4193', (61, 65))	('MDM2', 'Gene', (61, 65))	('inhibiting', 'NegReg', (117, 127))
70625	25888633	In addition, p53 mutations, including N239D (LPS141/239), H179R (LPS510) or G266R (LPS141/266) did not affect the interaction of MDM2 and p53 (Supplementary Figure 1), and MDM2 knockdown resulted in accumulation of mutant p53, indicating that MDM2 remains a major regulator of mutant p53.	('MDM2', 'Gene', (243, 247))	('G266R', 'Mutation', 'rs1057519990', (76, 81))	('N239D', 'Mutation', 'rs876660807', (38, 43))	('MDM2', 'Gene', (172, 176))	('mutations', 'Var', (17, 26))	('MDM2', 'Gene', (129, 133))	('MDM2', 'Gene', '4193', (243, 247))	('LPS', 'Phenotype', 'HP:0012034', (65, 68))	('mutant', 'Var', (215, 221))	('MDM2', 'Gene', '4193', (172, 176))	('LPS', 'Phenotype', 'HP:0012034', (45, 48))	('MDM2', 'Gene', '4193', (129, 133))	('LPS510', 'Chemical', '-', (65, 71))	('accumulation', 'PosReg', (199, 211))	('interaction', 'Interaction', (114, 125))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (222, 225))	('LPS141', 'Chemical', '-', (45, 51))	('LPS510', 'Var', (65, 71))	('N239D', 'Var', (38, 43))	('LPS', 'Phenotype', 'HP:0012034', (83, 86))	('G266R', 'Var', (76, 81))	('H179R', 'Mutation', 'rs1057519991', (58, 63))	('LPS141', 'Chemical', '-', (83, 89))
70626	25888633	Based on the evidence presented in this report, we propose MDM2 amplification and p53 mutation as essential proliferation mediators in LPS, and suggest that targeting HDAC or MDM2 amplification and mutant p53 inhibition is a therapeutic strategy in this challenging subset of LPS.	('LPS', 'Phenotype', 'HP:0012034', (276, 279))	('p53', 'Gene', (205, 208))	('LPS', 'Disease', (276, 279))	('MDM2', 'Gene', '4193', (175, 179))	('MDM2', 'Gene', (175, 179))	('LPS', 'Disease', (135, 138))	('MDM2', 'Gene', (59, 63))	('mutant', 'Var', (198, 204))	('MDM2', 'Gene', '4193', (59, 63))	('HDAC', 'Gene', (167, 171))	('LPS', 'Disease', 'MESH:C536528', (276, 279))	('LPS', 'Phenotype', 'HP:0012034', (135, 138))	('p53', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))	('LPS', 'Disease', 'MESH:C536528', (135, 138))	('HDAC', 'Gene', '9734', (167, 171))
70628	25888633	Monoclonal antibody to acetyl-tubulin, and polyclonal antibodies to phospho-MDM2 (Ser166), PTEN, phospho-AKT (Ser473), AKT, JUN, acetyl-histone H3, and cleaved caspase 3 were from Cell Signaling Technology (Beverly, MA).	('acetyl-histone', 'Chemical', '-', (129, 143))	('AKT', 'Gene', '207', (105, 108))	('antibody', 'cellular_component', 'GO:0042571', ('11', '19'))	('caspase 3', 'Gene', (160, 169))	('caspase 3', 'Gene', '836', (160, 169))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('MDM2', 'Gene', (76, 80))	('AKT', 'Gene', '207', (119, 122))	('antibody', 'cellular_component', 'GO:0019815', ('11', '19'))	('PTEN', 'Gene', (91, 95))	('Ser166', 'Var', (82, 88))	('MDM2', 'Gene', '4193', (76, 80))	('Signaling', 'biological_process', 'GO:0023052', ('185', '194'))	('Ser166', 'Chemical', '-', (82, 88))	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('AKT', 'Gene', (105, 108))	('antibody', 'cellular_component', 'GO:0019814', ('11', '19'))	('PTEN', 'Gene', '5728', (91, 95))	('Ser473', 'Var', (110, 116))	('Ser473', 'Chemical', '-', (110, 116))	('AKT', 'Gene', (119, 122))	('antibody', 'molecular_function', 'GO:0003823', ('11', '19'))
70630	25888633	Polybrene, puromycin, and antibody to beta-actin were from Sigma-Aldrich (St, Louis, MO).	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('puromycin', 'Chemical', 'MESH:D011691', (11, 20))	('Sigma-Aldrich', 'Disease', (59, 72))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('Polybrene', 'Chemical', 'MESH:D006583', (0, 9))	('beta-actin', 'Gene', '728378', (38, 48))	('antibody', 'Var', (26, 34))	('beta-actin', 'Gene', (38, 48))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))
70634	25888633	LPS141, LPS141/266, LPS141/239, and LPS510 were developed in the Department of Pathology at Brigham and Women's Hospital.	('LPS141', 'Chemical', '-', (0, 6))	('LPS', 'Phenotype', 'HP:0012034', (8, 11))	('LPS510', 'Var', (36, 42))	('LPS510', 'Chemical', '-', (36, 42))	('LPS141', 'Chemical', '-', (20, 26))	('LPS', 'Phenotype', 'HP:0012034', (36, 39))	('Women', 'Species', '9606', (104, 109))	('LPS141/239', 'Var', (20, 30))	('LPS141/266', 'Var', (8, 18))	('LPS', 'Phenotype', 'HP:0012034', (0, 3))	('LPS', 'Phenotype', 'HP:0012034', (20, 23))	('LPS141', 'Chemical', '-', (8, 14))
70636	25888633	LPS141/266 and LPS141/239 are isogenic sublines of LPS141 which retain the parental MDM2 and CDK4 genomic amplification but have p53 point mutations (G266R and N239D, respectively).	('LPS', 'Phenotype', 'HP:0012034', (0, 3))	('MDM2', 'Gene', (84, 88))	('G266R', 'Mutation', 'rs1057519990', (150, 155))	('CDK4', 'Gene', '1019', (93, 97))	('LPS', 'Phenotype', 'HP:0012034', (51, 54))	('CDK', 'molecular_function', 'GO:0004693', ('93', '96'))	('LPS141', 'Chemical', '-', (15, 21))	('N239D', 'Mutation', 'rs876660807', (160, 165))	('LPS', 'Phenotype', 'HP:0012034', (15, 18))	('N239D', 'Var', (160, 165))	('LPS141', 'Chemical', '-', (0, 6))	('G266R', 'Var', (150, 155))	('LPS141', 'Chemical', '-', (51, 57))	('CDK4', 'Gene', (93, 97))	('MDM2', 'Gene', '4193', (84, 88))
70638	25888633	T778 (LPS778) and LPS449 were a gift from Dr. Florence Pedeutour, were established from a patient with recurrent WDLPS, and are p53 wild-type.	('T778', 'Var', (0, 4))	('LPS449', 'Chemical', '-', (18, 24))	('LPS', 'Phenotype', 'HP:0012034', (18, 21))	('LPS', 'Phenotype', 'HP:0012034', (115, 118))	('LPS778', 'Chemical', '-', (6, 12))	('WDLPS', 'Disease', (113, 118))	('patient', 'Species', '9606', (90, 97))	('LPS', 'Phenotype', 'HP:0012034', (6, 9))	('LPS449', 'Var', (18, 24))
70645	25888633	Immunoblotting was performed after 48 hours of treatment with LBH589 or SAHA, and after 10 days post-infection with MDM2/p53 shRNAs.	('SAHA', 'Chemical', 'MESH:D000077337', (72, 76))	('LBH589', 'Chemical', 'MESH:D000077767', (62, 68))	('MDM2', 'Gene', '4193', (116, 120))	('MDM2', 'Gene', (116, 120))	('LBH589', 'Var', (62, 68))
70654	25888633	Following transduction, LPS141, LPS141/239, LPS141/266, LPS510, and MESO924 cells were selected for stable expression of the MDM2 or p53 shRNAs using 2 mug/ml puromycin.	('LPS510', 'Chemical', '-', (56, 62))	('LPS141', 'Chemical', '-', (32, 38))	('puromycin', 'Chemical', 'MESH:D011691', (159, 168))	('p53', 'Var', (133, 136))	('LPS141', 'Chemical', '-', (44, 50))	('LPS', 'Phenotype', 'HP:0012034', (32, 35))	('LPS', 'Phenotype', 'HP:0012034', (56, 59))	('transduction', 'biological_process', 'GO:0009293', ('10', '22'))	('LPS141', 'Chemical', '-', (24, 30))	('mug', 'molecular_function', 'GO:0043739', ('152', '155'))	('LPS', 'Phenotype', 'HP:0012034', (44, 47))	('MESO924', 'Chemical', '-', (68, 75))	('MDM2', 'Gene', '4193', (125, 129))	('MDM2', 'Gene', (125, 129))	('LPS', 'Phenotype', 'HP:0012034', (24, 27))
70655	25888633	Cell lines were plated at 3,000 cells/well in a 96-well flat-bottomed plate (Falcon, Lincoln NJ) and cultured for 24 hours before treatment with different inhibitors, which included Nutlin-3 (2.5, 5, 10 and 20 muM), LBH589 (0.05, 0.1, 0.25, 0.5 and 1 muM), SAHA (0.5, 1, 2, 5 and 10 muM), MDM2 shRNAs or p53 shRNAs.	('muM', 'Gene', '56925', (251, 254))	('muM', 'Gene', (283, 286))	('muM', 'Gene', '56925', (210, 213))	('Nutlin-3', 'Chemical', 'MESH:C482205', (182, 190))	('LBH589', 'Chemical', 'MESH:D000077767', (216, 222))	('muM', 'Gene', (251, 254))	('muM', 'Gene', (210, 213))	('MDM2', 'Gene', '4193', (289, 293))	('SAHA', 'Chemical', 'MESH:D000077337', (257, 261))	('p53 shRNAs', 'Var', (304, 314))	('0.5', 'Var', (263, 266))	('0.05', 'Var', (224, 228))	('muM', 'Gene', '56925', (283, 286))	('MDM2', 'Gene', (289, 293))
70658	25888633	Briefly, LPS141, LPS141/239, LPS141/266, LPS510, and LPS778 cells in 6-well plates were treated with LBH589 (250 nM) or SAHA (5 muM) for 48 hours, trypsinized and washed twice with cold Hanks Balanced Salt Solution and treated with 5 mul of PE Annexin V and 5 mul 7-AAD in 1X Binding Buffer for 15 minutes at RT (25 C) in the dark.	('LPS141', 'Chemical', '-', (9, 15))	('LPS', 'Phenotype', 'HP:0012034', (9, 12))	('LPS141', 'Chemical', '-', (17, 23))	('LBH589', 'Chemical', 'MESH:D000077767', (101, 107))	('LPS141/266', 'Var', (29, 39))	('LPS141', 'Var', (9, 15))	('muM', 'Gene', '56925', (128, 131))	('muM', 'Gene', (128, 131))	('LPS510', 'Chemical', '-', (41, 47))	('LPS141', 'Chemical', '-', (29, 35))	('LPS', 'Phenotype', 'HP:0012034', (29, 32))	('LPS', 'Phenotype', 'HP:0012034', (53, 56))	('LPS778', 'Chemical', '-', (53, 59))	('LPS141/239', 'Var', (17, 27))	('LPS510', 'Var', (41, 47))	('Annexin V and 5', 'Gene', '308', (244, 259))	('PE', 'Chemical', '-', (241, 243))	('SAHA', 'Chemical', 'MESH:D000077337', (120, 124))	('LPS', 'Phenotype', 'HP:0012034', (41, 44))	('LPS778', 'Var', (53, 59))	('LPS', 'Phenotype', 'HP:0012034', (17, 20))
70659	25888633	LPS141, LPS141/239, LPS141/266, LPS510, and LPS778 cells in 6-well plates were treated with inhibitors for 48 hours or MDM2 and p53 shRNAs for 10 days with selection, then trypsinized and washed once with ice-cold PBS.	('LPS778', 'Var', (44, 50))	('LPS141/266', 'Var', (20, 30))	('PBS', 'Chemical', 'MESH:D007854', (214, 217))	('LPS141/239', 'Var', (8, 18))	('LPS', 'Phenotype', 'HP:0012034', (8, 11))	('LPS510', 'Chemical', '-', (32, 38))	('MDM2', 'Gene', '4193', (119, 123))	('LPS', 'Phenotype', 'HP:0012034', (32, 35))	('MDM2', 'Gene', (119, 123))	('LPS141', 'Chemical', '-', (20, 26))	('LPS510', 'Var', (32, 38))	('LPS', 'Phenotype', 'HP:0012034', (44, 47))	('LPS141', 'Chemical', '-', (0, 6))	('LPS', 'Phenotype', 'HP:0012034', (0, 3))	('LPS', 'Phenotype', 'HP:0012034', (20, 23))	('LPS778', 'Chemical', '-', (44, 50))	('LPS141', 'Chemical', '-', (8, 14))
70662	25888633	Student's t-tests were performed on data from cells treated with control DMSO or inhibitors, as well as cells treated with empty vector, MDM2, or p53 shRNAs.	('DMSO', 'Chemical', 'MESH:D004121', (73, 77))	('MDM2', 'Gene', (137, 141))	('p53', 'Var', (146, 149))	('MDM2', 'Gene', '4193', (137, 141))
70873	25400582	When interpreting our findings of both cell proliferation rate and changes in TnT lengths, we take into account likely differences in natural biology and aggressiveness of the variable cell histologies (i.e., VAMT = sarcomatoid; H2052 = epithelioid, likely less aggressive; MSTO-211H = biphasic, encompassing features of both of VAMT and H2052).	('aggressiveness', 'Disease', (154, 168))	('sarcomatoid', 'Disease', 'MESH:C538614', (216, 227))	('MSTO-211H', 'CellLine', 'CVCL:1430', (274, 283))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('H2052', 'CellLine', 'CVCL:1518', (338, 343))	('aggressiveness', 'Disease', 'MESH:D001523', (154, 168))	('TnT', 'Chemical', '-', (78, 81))	('aggressiveness', 'Phenotype', 'HP:0000718', (154, 168))	('rat', 'Species', '10116', (58, 61))	('H2052', 'CellLine', 'CVCL:1518', (229, 234))	('H2052 =', 'Var', (229, 236))	('sarcomatoid', 'Disease', (216, 227))	('VAMT', 'Chemical', '-', (209, 213))	('VAMT', 'Chemical', '-', (329, 333))	('rat', 'Species', '10116', (51, 54))
70877	25400582	Knowing the clinical outcomes are worse with sarcomatoid variants than with other forms of mesothelioma, we postulate that this may hold true in the clinical setting.	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('sarcomatoid', 'Disease', 'MESH:C538614', (45, 56))	('mesothelioma', 'Disease', (91, 103))	('variants', 'Var', (57, 65))	('sarcomatoid', 'Disease', (45, 56))
70898	25400582	We attribute this decreased cell proliferation to both elements, i.e., low serum concentration (2.5% FBS) as well as high glucose, which induces reductions in cell proliferation as well as increased cell apoptosis of pericytes in vitro (Beltramo et al.,).	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('cell proliferation', 'biological_process', 'GO:0008283', ('159', '177'))	('high glucose', 'Phenotype', 'HP:0003074', (117, 129))	('decreased', 'NegReg', (18, 27))	('rat', 'Species', '10116', (40, 43))	('cell proliferation', 'CPA', (28, 46))	('cell apoptosis', 'CPA', (199, 213))	('rat', 'Species', '10116', (88, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('rat', 'Species', '10116', (171, 174))	('cell proliferation', 'CPA', (159, 177))	('glucose', 'Chemical', 'MESH:D005947', (122, 129))	('high glucose', 'Var', (117, 129))	('reductions', 'NegReg', (145, 155))	('increased', 'PosReg', (189, 198))
70903	25400582	In vitro 3-D spheroid models of mesothelioma demonstrate increased resistance to drugs and apoptosis compared to 2-dimensional cultures, and this is at least in part mediated by mTOR; however, inhibitors of mTOR can overcome this acquired resistance (Barbone et al.,; Wilson et al.,).	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('rat', 'Species', '10116', (52, 55))	('inhibitors', 'Var', (193, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('mTOR', 'Gene', (207, 211))	('mTOR', 'Gene', '2475', (207, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('mesothelioma', 'Disease', (32, 44))	('resistance to drugs', 'MPA', (67, 86))	('mTOR', 'Gene', (178, 182))	('mTOR', 'Gene', '2475', (178, 182))
70925	25400582	The Supplementary Material for this article can be found online at: http://www.frontiersin.org/journal/10.3389/fphys.2014.00400/abstract MPM malignant pleural mesothelioma TnTs tunneling nanotubes nm nanometers EMT epithelial-to-mesenchymal transition IF immunofluorescence FBS fetal bovine serum HA hyaluronic acid GFP green fluorescent protein EM electron microscopy TNFaip2 tumor necrosis factor-alpha-induced protein 2 (also called M-Sec), MSKCC, Memorial Sloan-Kettering Cancer Center.	('tumor necrosis factor-alpha-induced protein 2', 'Gene', '7127', (377, 422))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (151, 171))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (151, 171))	('EMT', 'Reg', (211, 214))	('necrosis', 'biological_process', 'GO:0008220', ('383', '391'))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (451, 482))	('TnTs', 'Chemical', '-', (172, 176))	('tunneling', 'Var', (177, 186))	('TNFaip2', 'Gene', '7127', (369, 376))	('necrosis', 'biological_process', 'GO:0070265', ('383', '391'))	('necrosis', 'biological_process', 'GO:0019835', ('383', '391'))	('HA', 'Chemical', 'MESH:D006820', (297, 299))	('protein', 'cellular_component', 'GO:0003675', ('413', '420'))	('necrosis', 'biological_process', 'GO:0001906', ('383', '391'))	('Cancer', 'Phenotype', 'HP:0002664', (476, 482))	('protein', 'cellular_component', 'GO:0003675', ('338', '345'))	('TNFaip2', 'Gene', (369, 376))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('215', '251'))	('epithelial-to-mesenchymal transition', 'CPA', (215, 251))	('pleural mesothelioma', 'Disease', (151, 171))	('bovine', 'Species', '9913', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (300, 315))	('EMT', 'biological_process', 'GO:0001837', ('211', '214'))	('necrosis', 'biological_process', 'GO:0008219', ('383', '391'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('377', '398'))	('Memorial Sloan-Kettering Cancer', 'Disease', (451, 482))	('tumor necrosis factor-alpha-induced protein 2', 'Gene', (377, 422))
70929	23468465	While DNA methylation is a normal and essential process for human development, aberrant methylation patterns have been linked to pathogenesis and progression of various human diseases, as well as a wide variety of exposures.	('DNA methylation', 'biological_process', 'GO:0006306', ('6', '21'))	('pathogenesis', 'biological_process', 'GO:0009405', ('129', '141'))	('aberrant', 'Var', (79, 87))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('human', 'Species', '9606', (169, 174))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('methylation', 'MPA', (88, 99))	('linked', 'Reg', (119, 125))	('human', 'Species', '9606', (60, 65))
70938	23468465	Given the prominent role of unsupervised clustering in revealing underlying structure in large-scale genomic data and the promise of such techniques for identifying clinically/biologically important profiles of DNA methylation, we aimed to understand whether incorporating correlation between pairs related probes within the framework of RPMM improves clustering performance (as measured by accurate estimation of the true number of clusters, model goodness-of-fit, and clustering consistency) and the ability to detect biologically meaningful clusters.	('incorporating', 'Var', (259, 272))	('improves', 'PosReg', (343, 351))	('RPMM', 'Chemical', '-', (338, 342))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('clustering consistency', 'CPA', (470, 492))	('DNA methylation', 'biological_process', 'GO:0006306', ('211', '226'))	('clustering performance', 'CPA', (352, 374))
70992	23468465	To put the results on goodness-of-fit between the CorrGaussian and StanGaussian methods into a possibly more meaningful context, we note that across the various analyses considered in our data application, the CorrGaussian had a lower BIC compared to StanGaussian on average, 94% of the time.	('BIC', 'Chemical', 'MESH:C100119', (235, 238))	('CorrGaussian', 'Var', (210, 222))	('BIC', 'MPA', (235, 238))	('lower', 'NegReg', (229, 234))
71003	23468465	We evaluated the clustering performance of our proposed modified within-gene correlated RPMMs relative to the standard RPMMs using both simulations and four array-based methylation data sets.	('RPMM', 'Chemical', '-', (88, 92))	('RPMMs', 'Disease', (88, 93))	('methylation', 'biological_process', 'GO:0032259', ('169', '180'))	('RPMM', 'Chemical', '-', (119, 123))	('modified', 'Var', (56, 64))
71005	23468465	Briefly, our simulation study suggested improved clustering performance of the modified within-gene correlated RPMMs relative to the RPMMs that assume class-conditional independence of features.	('RPMM', 'Chemical', '-', (111, 115))	('RPMMs', 'Disease', (111, 116))	('clustering', 'MPA', (49, 59))	('modified', 'Var', (79, 87))	('improved', 'PosReg', (40, 48))	('RPMM', 'Chemical', '-', (133, 137))
71066	23335100	A recombinant FP expressing survivin (FP-surv) was then generated by a swapping event between the gene encoding a red fluorescent protein gene in the control acceptor FP (FP-ctrl) and the TPG plasmid cassette coding for both the eGFP and survivin as previously described .	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('FP', 'Species', '10261', (167, 169))	('swapping', 'Var', (71, 79))	('FP', 'Species', '10261', (231, 233))	('FP', 'Species', '10261', (38, 40))	('survivin', 'Gene', (28, 36))	('rat', 'Species', '10116', (60, 63))	('survivin', 'Gene', (238, 246))	('FP', 'Species', '10261', (171, 173))	('FP', 'Species', '10261', (14, 16))	('survivin', 'Gene', '11799', (28, 36))	('survivin', 'Gene', '11799', (238, 246))
71082	23335100	Primary antibodies included anti-survivin clone 60.11 and anti-MHC-I clone EP1395Y (Abcam, Cambridge, MA, USA).	('MHC', 'Gene', (63, 66))	('MHC', 'Gene', '3107', (63, 66))	('survivin', 'Gene', '11799', (33, 41))	('EP1395Y', 'Var', (75, 82))	('survivin', 'Gene', (33, 41))
71159	23335100	As shown in Table 1, FP-surv induced higher mRNA levels of several inflammatory cytokines, with statistically significant increases found for IFN-gamma and IL-12 in AB12 tumors, and for IFN-gamma in CRH5 tumors.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('higher', 'PosReg', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mRNA levels of several inflammatory cytokines', 'MPA', (44, 89))	('IL-12', 'molecular_function', 'GO:0005143', ('156', '161'))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('FP', 'Species', '10261', (21, 23))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('FP-surv', 'Var', (21, 28))	('tumors', 'Disease', (170, 176))	('increases', 'PosReg', (122, 131))	('CRH5', 'Chemical', '-', (199, 203))
71188	23335100	In our experiments, FP-surv induced an increased number of tumor-infiltrating CD8+ T cells that correlated with improved animal survival and slower tumor growth in 3 different subcutaneous MM mouse models.	('CD8', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mouse', 'Species', '10090', (192, 197))	('tumor', 'Disease', (59, 64))	('rat', 'Species', '10116', (71, 74))	('tumor', 'Disease', (148, 153))	('CD8', 'Gene', '925', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('FP', 'Species', '10261', (20, 22))	('increased', 'PosReg', (39, 48))	('slower', 'NegReg', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('improved', 'PosReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('FP-surv', 'Var', (20, 27))
71200	23335100	with EKKH5 MM cells, the majority of vaccinated mice died because of the tumor mass growth.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('EKKH5 MM', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', (73, 78))
71212	23335100	Although these data did not perfectly match those obtained by RT-PCR and several concerns have been raised on the usefulness of intra-tumor cytokine protein measurements , our cytokine profiles suggest that FP-surv is capable of inducing immunologic changes in the tumor microenvironment that may favor for the killing of MM cells.	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('FP', 'Species', '10261', (207, 209))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', (265, 270))	('killing', 'CPA', (311, 318))	('FP-surv', 'Var', (207, 214))	('intra-tumor', 'Disease', (128, 139))	('intra-tumor', 'Disease', 'MESH:D009369', (128, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('inducing', 'Reg', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', (134, 139))
71221	20942962	Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma There is a paucity of information about the molecular perturbations involved in MPM tumor formation.	('EGFR', 'Gene', '1956', (42, 46))	('MPM tumor', 'Disease', 'MESH:D009369', (174, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (70, 93))	('EGFR', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('MPM tumor', 'Disease', (174, 183))	('activating', 'PosReg', (31, 41))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mesothelioma', 'Disease', (81, 93))
71222	20942962	Here we present the mutant EGFR activating potential and the matured survival data of the EGFR mutant(mut+) relative to wild type EGFR(mut-) mesothelioma.	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('EGFR', 'Gene', (90, 94))	('mesothelioma', 'Disease', (141, 153))	('mutant', 'Var', (95, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
71223	20942962	Twenty-nine patients were evaluated and their tumors were probed for mutations in the catalytic TK-domain.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('TK-domain', 'Gene', (96, 105))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
71227	20942962	All missense mutations were found to be activating mutations and responsive to erlotinib.	('activating', 'PosReg', (40, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (79, 88))	('missense mutations', 'Var', (4, 22))
71229	20942962	The novel EGFR mutations identified are activating mutations responsive to erlotinib.	('EGFR', 'Gene', (10, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))	('mutations', 'Var', (15, 24))	('erlotinib', 'Chemical', 'MESH:D000069347', (75, 84))
71232	20942962	Perturbations and mutations in the epidermal growth factor receptor gene family have been identified in many cancer subtypes with gain of function alterations occurring at all levels of gene and protein expression.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('epidermal growth factor receptor', 'Gene', (35, 67))	('gain of function', 'PosReg', (130, 146))	('alterations', 'Var', (147, 158))	('cancer', 'Disease', (109, 115))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('35', '58'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('mutations', 'Var', (18, 27))
71233	20942962	Recent studies in non small cell lung cancer (NSCLC) have revealed that mutations in epidermal growth factor receptor (EGFR) occur in 15% of Caucasians and 30% of Asians with NSCLC, and the presence of specific EGFR mutations is predictive of response to therapy and cancer outcome.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('epidermal growth factor receptor', 'Gene', (85, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (18, 44))	('mutations', 'Var', (72, 81))	('epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('cancer', 'Disease', (38, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('EGFR', 'Gene', (119, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (267, 273))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (18, 44))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('85', '108'))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (22, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('EGFR', 'Gene', (211, 215))	('mutations', 'Var', (216, 225))	('NSCLC', 'Disease', (175, 180))	('non small cell lung cancer', 'Disease', (18, 44))
71234	20942962	The reported mutations in NSCLC are deletion or missense mutations that occur between exons 18-24 in the tyrosine kinase domain of the receptor.	('missense', 'Var', (48, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (105, 113))	('NSCLC', 'Disease', (26, 31))	('mutations', 'Var', (13, 22))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
71235	20942962	Investigation of EGFR mutations in lung cancers has become a pivotal research paradigm that has begun to unlock the utility of mutations in predicting clinical outcomes, selection of patients for therapies (EGFR-TKIs), and predicting response/resistance to these therapies.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('lung cancers', 'Disease', (35, 47))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('mutations', 'Var', (22, 31))	('lung cancers', 'Disease', 'MESH:D008175', (35, 47))	('lung cancers', 'Phenotype', 'HP:0100526', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (183, 191))	('EGFR', 'Gene', (17, 21))
71236	20942962	Recapitulation of EGFR mutations in lung cancer cells in vitro have demonstrated that it is an example of an 'oncogenic addiction' mutation which provides a biologic explanation for the improved outcome seen in this EGFR mutant NSCLC group relative to the wild type group.	('lung cancer', 'Disease', (36, 47))	('EGFR', 'Gene', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (228, 233))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'molecular_function', 'GO:0005006', ('216', '220'))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('EGFR', 'Gene', (18, 22))	('mutant', 'Var', (221, 227))	('improved', 'PosReg', (186, 194))	('mutations', 'Var', (23, 32))	('NSCLC', 'Disease', (228, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))
71237	20942962	EGFR mutations are likely not limited to lung cancer and pervasive in other cancer.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('EGFR', 'Gene', (0, 4))	('cancer', 'Disease', (46, 52))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
71238	20942962	A potential cancer type similar to NSCLC that might harbor functional EGFR mutations is malignant mesothelioma.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('NSCLC', 'Disease', (35, 40))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (88, 110))	('cancer', 'Disease', (12, 18))	('malignant mesothelioma', 'Disease', (88, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (88, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))
71246	20942962	Therefore, identification of surrogate markers that can predict response to CRS/IPHC and lead to novel therapeutic targets in mesothelioma prompted the pursuit of EGFR mutations.	('IPHC', 'Chemical', '-', (80, 84))	('mesothelioma', 'Disease', (126, 138))	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('mutations', 'Var', (168, 177))
71247	20942962	We have previously reported that EGFR mutations occur in 31% of MPM, a rate similar to that reported in NSCLC.	('NSCLC', 'Disease', (104, 109))	('MPM', 'Disease', (64, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('EGFR', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
71250	20942962	Here we report the first identification of EGFR activating mutations in mesothelioma, as well as, the updated clinical outcome.	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('activating', 'PosReg', (48, 58))	('mesothelioma', 'Disease', (72, 84))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', (43, 47))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
71262	20942962	Mutations (W731L, E734Q, T785A, C797Y, Y801H, L831H, L858R and E868G) were introduced into full-length EGFR coding sequence by using a QuikChange II XL Site-Directed Mutagenesis kit (Stratagene).	('W731L', 'Var', (11, 16))	('T785A', 'Mutation', 'rs762950988', (25, 30))	('L858R', 'Mutation', 'rs121434568', (53, 58))	('L831H', 'Var', (46, 51))	('E734Q', 'Mutation', 'p.E734Q', (18, 23))	('C797Y', 'Var', (32, 37))	('L831H', 'Mutation', 'p.L831H', (46, 51))	('L858R', 'Var', (53, 58))	('Mutagenesis', 'biological_process', 'GO:0006280', ('166', '177'))	('EGFR', 'Gene', (103, 107))	('Y801H', 'Mutation', 'rs757642107', (39, 44))	('T785A', 'Var', (25, 30))	('E868G', 'Mutation', 'p.E868G', (63, 68))	('C797Y', 'Mutation', 'p.C797Y', (32, 37))	('E734Q', 'Var', (18, 23))	('E868G', 'Var', (63, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('Y801H', 'Var', (39, 44))	('W731L', 'Mutation', 'rs397517089', (11, 16))
71269	20942962	To evaluate the in vitro responsiveness of mutant receptors to EGFR inhibitor, cells were treated with various concentrations of Erlotinib (Tarceva  LC laboratories, Woburn, MA) three hours before the addition of 10 ng of EGF per milliliter.	('EGF', 'molecular_function', 'GO:0005154', ('222', '225'))	('EGF', 'Gene', (222, 225))	('EGF', 'Gene', '1950', (222, 225))	('mutant', 'Var', (43, 49))	('EGF', 'Gene', (63, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('Erlotinib', 'Chemical', 'MESH:D000069347', (129, 138))	('EGF', 'Gene', '1950', (63, 66))
71276	20942962	The level of cytoreduction was scored as R1 -- no visible disease, R2a -- residual tumor nodules <= 5 mm, R2b -- residual tumor nodules > 5 mm <= 2 cm, R2c > 2 cm, and R3-unresectable.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('R2b', 'Var', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (122, 127))
71277	20942962	We analyzed a cohort of MPM samples (n = 29) by DHPLC and sequencing analysis, and identified eight mutations in the tyrosine kinase domain (TKD) of EGFR.	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('mutations in', 'Var', (100, 112))	('tyrosine', 'Chemical', 'MESH:D014443', (117, 125))	('EGFR', 'Gene', (149, 153))
71278	20942962	Of the 8 mutations in the TK domain, 7 were novel (W731L, E734Q, T785A, C797Y, Y801H, L831H and E868G) (Figure 1A, B).	('W731L', 'Mutation', 'rs397517089', (51, 56))	('Y801H', 'Var', (79, 84))	('Y801H', 'Mutation', 'rs757642107', (79, 84))	('E868G', 'Mutation', 'p.E868G', (96, 101))	('W731L', 'Var', (51, 56))	('T785A', 'Var', (65, 70))	('E734Q', 'Var', (58, 63))	('C797Y', 'Var', (72, 77))	('L831H', 'Var', (86, 91))	('L831H', 'Mutation', 'p.L831H', (86, 91))	('T785A', 'Mutation', 'rs762950988', (65, 70))	('E868G', 'Var', (96, 101))	('C797Y', 'Mutation', 'p.C797Y', (72, 77))	('E734Q', 'Mutation', 'p.E734Q', (58, 63))
71279	20942962	One of the mutations (L858R) was previously identified in non-small cell lung cancer (NSCLC) patients and this mutation was found to increase sensitivity to EGFR inhibitor, Erlotinib.	('L858R', 'Mutation', 'rs121434568', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('patients', 'Species', '9606', (93, 101))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (58, 84))	('increase', 'PosReg', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('Erlotinib', 'Chemical', 'MESH:D000069347', (173, 182))	('non-small cell lung cancer', 'Disease', (58, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('sensitivity to EGFR inhibitor', 'MPA', (142, 171))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))	('L858R', 'Var', (22, 27))
71281	20942962	Each mutation was only observed once in this cohort, except L831H which was detected in two independent tumors.	('L831H', 'Mutation', 'p.L831H', (60, 65))	('L831H', 'Var', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
71284	20942962	Sequence alignment of the human wild- type EGFR with the Pfam model of protein kinase domain indicates W731, E734, T785, C797, Y801, R831, L858 and E868 that the mutations were in highly conserved residues (Figure 3).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('R831', 'Var', (133, 137))	('E868', 'Var', (148, 152))	('Y801', 'Var', (127, 131))	('C797', 'Var', (121, 125))	('T785', 'Var', (115, 119))	('L858', 'Var', (139, 143))	('E734', 'Var', (109, 113))	('W731', 'Var', (103, 107))	('human', 'Species', '9606', (26, 31))
71286	20942962	The mutant EGFRs were then transfected into COS-7 cells and exposed to EGF.	('COS-7', 'CellLine', 'CVCL:0224', (44, 49))	('EGF', 'Gene', (71, 74))	('mutant', 'Var', (4, 10))	('EGF', 'Gene', '1950', (71, 74))	('EGF', 'Gene', (11, 14))	('EGF', 'molecular_function', 'GO:0005154', ('71', '74'))	('EGF', 'Gene', '1950', (11, 14))
71289	20942962	In order to investigate whether the EGFR mutations are sensitive to the EGFR inhibitor Erlotinib, COS-7 cells transfected with mutant EGFR and treated with various concentrations (0.002 to 2.0 muM) of Erlotinib and exposed to EGF.	('mutant', 'Var', (127, 133))	('mutations', 'Var', (41, 50))	('EGF', 'Gene', '1950', (72, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGF', 'Gene', '1950', (36, 39))	('EGF', 'Gene', (226, 229))	('EGF', 'Gene', (134, 137))	('EGF', 'Gene', '1950', (226, 229))	('Erlotinib', 'Chemical', 'MESH:D000069347', (87, 96))	('EGF', 'molecular_function', 'GO:0005154', ('226', '229'))	('Erlotinib', 'Chemical', 'MESH:D000069347', (201, 210))	('EGF', 'Gene', (36, 39))	('EGF', 'Gene', '1950', (134, 137))	('COS-7', 'CellLine', 'CVCL:0224', (98, 103))	('EGF', 'Gene', (72, 75))
71291	20942962	Eight patients had tumors with mutant EGFR while the other 17 patients had wild type EGFR.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutant', 'Var', (31, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('patients', 'Species', '9606', (62, 70))
71292	20942962	In the EGFR mutant patients, median survival has not been reached but 29% (2/7) of patients have died due to disease progression with a median follow-up time of 22 months; while 56% (10/18) of wild type patients have died due to disease progression with a median survival of 14 months.	('patients', 'Species', '9606', (19, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('7', '11'))	('EGFR', 'Gene', (7, 11))	('mutant', 'Var', (12, 18))	('patients', 'Species', '9606', (203, 211))	('patients', 'Species', '9606', (83, 91))
71294	20942962	However, only 29% (2/7) of EGFR mutant patients have developed progressive disease and median TTP has not been reached.	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (39, 47))	('progressive disease', 'CPA', (63, 82))	('mutant', 'Var', (32, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))
71297	20942962	These mutation add to the list of previously identified mutations within the kinase domain of the EGFR gene, and also extends the spectrum of malignancies that harbor functional EGFR mutations.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (183, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('178', '182'))	('EGFR', 'Gene', (178, 182))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('malignancies', 'Disease', (142, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
71298	20942962	To our knowledge, this is the first report identifying functional EGFR mutations in malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (84, 106))	('malignant mesothelioma', 'Disease', (84, 106))	('EGFR', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (84, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
71299	20942962	Functional analyses of these mutant EGFRs in the cultured cells demonstrated that all EGFR mutants have enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to EGFR inhibitor Erlotinib.	('response to epidermal growth factor', 'biological_process', 'GO:0070849', ('141', '176'))	('EGFR', 'molecular_function', 'GO:0005006', ('206', '210'))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('enhanced tyrosine kinase activity', 'Phenotype', 'HP:0003231', (104, 137))	('enhanced', 'PosReg', (104, 112))	('response to epidermal growth factor', 'MPA', (141, 176))	('tyrosine kinase activity', 'MPA', (113, 137))	('EGFR', 'Gene', (86, 90))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('153', '176'))	('Erlotinib', 'Chemical', 'MESH:D000069347', (221, 230))	('mutants', 'Var', (91, 98))	('tyrosine', 'Chemical', 'MESH:D014443', (113, 121))	('sensitivity', 'MPA', (191, 202))	('increased', 'PosReg', (181, 190))	('kinase activity', 'molecular_function', 'GO:0016301', ('122', '137'))
71300	20942962	Like other mutants reported in the literature, all eight EGFR mutants were ligand dependent and in the absence of EGF stimulation there was little or no activation of any mutant EGFR.	('mutants', 'Var', (62, 69))	('EGF', 'Gene', '1950', (114, 117))	('EGF', 'Gene', (57, 60))	('EGF', 'Gene', '1950', (178, 181))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGF', 'Gene', (178, 181))	('EGFR', 'molecular_function', 'GO:0005006', ('178', '182'))	('EGF', 'molecular_function', 'GO:0005154', ('114', '117'))	('EGF', 'Gene', '1950', (57, 60))	('EGF', 'Gene', (114, 117))	('ligand', 'molecular_function', 'GO:0005488', ('75', '81'))
71301	20942962	These results confirm previous observations showing activation of TKD mutant EGFR as being ligand dependent in similar transient expression systems (NIH3T3 and HeLa cells), while there was no evidence of significant ligand independent EGFR activation.	('HeLa', 'CellLine', 'CVCL:0030', (160, 164))	('ligand', 'molecular_function', 'GO:0005488', ('91', '97'))	('ligand', 'molecular_function', 'GO:0005488', ('216', '222'))	('NIH3T3', 'CellLine', 'CVCL:0594', (149, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('TKD mutant', 'Var', (66, 76))	('EGFR', 'Gene', (77, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('235', '239'))	('activation', 'PosReg', (52, 62))
71302	20942962	Clinically, the presence of EGFR mutations in MPM appears to predict response to therapy (CRS/IPHC) and represents a potential predictor of improved outcome compared to the wild type MPM.	('improved', 'PosReg', (140, 148))	('IPHC', 'Chemical', '-', (94, 98))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('MPM', 'Gene', (46, 49))	('predict', 'Reg', (61, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('response', 'Disease', (69, 77))
71304	20942962	In figure 9A the optimal resected patients have a statistically significant survival benefit relative to sub-optimal group and a similar outcome was observed in the mutant EGFR patients relative to wild type EGFR group (Figure 9B).	('mutant', 'Var', (165, 171))	('EGFR', 'Gene', (172, 176))	('patients', 'Species', '9606', (177, 185))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('patients', 'Species', '9606', (34, 42))	('benefit', 'PosReg', (85, 92))	('survival', 'CPA', (76, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))
71306	20942962	The impact of EGFR mutations in MPM strikingly parallels the observation reported in NSCLC.	('NSCLC', 'Disease', (85, 90))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('mutations', 'Var', (19, 28))	('MPM', 'Gene', (32, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))
71309	20942962	This residual disease subsequently is treated with high dose intra-peritoneal chemotherapy and hyperthermia given intra-operatively, and the intrinsic susceptibility of EGFR MPM mutant tumors makes these cells more likely to undergo more extensive apoptosis which manifests as a prolonged progression free survival (Figure 9B).	('mutant', 'Var', (178, 184))	('hyperthermia', 'Disease', 'MESH:D005334', (95, 107))	('EGFR MPM', 'Gene', (169, 177))	('progression free survival', 'CPA', (289, 314))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('169', '173'))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('hyperthermia', 'Phenotype', 'HP:0001945', (95, 107))	('hyperthermia', 'Disease', (95, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('248', '257'))	('apoptosis', 'CPA', (248, 257))	('apoptosis', 'biological_process', 'GO:0006915', ('248', '257'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
71310	20942962	Although the mutant EGFR group experienced a prolonged survival, two patients in this group have succumbed to their disease, and likely with longer follow-up, more mutant EGFR patients will develop progressive disease.	('mutant', 'Var', (13, 19))	('EGFR', 'Gene', (171, 175))	('mutant', 'Var', (164, 170))	('patients', 'Species', '9606', (176, 184))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('develop', 'PosReg', (190, 197))	('patients', 'Species', '9606', (69, 77))	('progressive disease', 'Disease', (198, 217))
71311	20942962	This 'relative' outcome improvement in mutant MPM patients also parallels the observations in metastatic lung cancer which report prolonged median survival but ultimately most patients, including EGFR mutants succumb to progressive diseases.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('EGFR', 'Gene', (196, 200))	('patients', 'Species', '9606', (176, 184))	('succumb', 'Reg', (209, 216))	('patients', 'Species', '9606', (50, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('196', '200'))	('progressive diseases', 'Disease', (220, 240))	('MPM', 'Gene', (46, 49))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('mutants', 'Var', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutant', 'Var', (39, 45))	('lung cancer', 'Disease', (105, 116))
71312	20942962	Since NSCLC clinically are responsive to TKI therapy and given the in vitro response of the MPM mutations to Erlotinib, there may be a role for EGFR-TKI therapy in MPM EGFR mutant patients who develop disease recurrence or present with bulky unresectable tumor.	('EGFR', 'molecular_function', 'GO:0005006', ('168', '172'))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('EGFR', 'Gene', (168, 172))	('disease', 'Disease', (201, 208))	('patients', 'Species', '9606', (180, 188))	('MPM EGFR', 'Gene', (164, 172))	('mutant', 'Var', (173, 179))	('develop', 'PosReg', (193, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('NSCLC', 'Disease', (6, 11))	('Erlotinib', 'Chemical', 'MESH:D000069347', (109, 118))
71314	20942962	Interestingly in this erlotinib trial, the high EGFR expressing tumor group experienced a 2-fold longer survival, but study did not interrogate tumors for EGFR mutations.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('tumor', 'Disease', (64, 69))	('high', 'Var', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('erlotinib', 'Chemical', 'MESH:D000069347', (22, 31))	('survival', 'CPA', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('longer', 'PosReg', (97, 103))
71315	20942962	Therefore it is unknown if EGFR mutations occur in pleural mesothelioma or if a subset of mesothelioma patients might benefit from EGFR-TKI therapy and further investigation for perturbations in the EGFR pathway in pleural mesothelioma is warranted.	('EGFR', 'Gene', (27, 31))	('mesothelioma', 'Disease', (59, 71))	('occur', 'Reg', (42, 47))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('pleural mesothelioma', 'Disease', (51, 71))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (90, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('pleural mesothelioma', 'Disease', (215, 235))	('mesothelioma', 'Disease', (223, 235))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (51, 71))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (51, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (223, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('patients', 'Species', '9606', (103, 111))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (215, 235))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (215, 235))
71316	20942962	Clinically these mutations may ultimately have utility in patient selection for surgery, systemic therapy, and selection for EGFR-TKI.	('patient', 'Species', '9606', (58, 65))	('mutations', 'Var', (17, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('EGFR-TKI', 'Gene', (125, 133))
71317	20942962	The identification of EGFR mutations in peritoneal mesothelioma expands the spectrum of cancers with EGFR pathway perturbations and provides the first evidence of function EGFR mutations in mesothelioma.	('mutations', 'Var', (27, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('mesothelioma', 'Disease', 'MESH:D008654', (190, 202))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('mesothelioma', 'Disease', (51, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('cancers', 'Disease', (88, 95))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (40, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mesothelioma', 'Disease', (190, 202))	('EGFR', 'Gene', (22, 26))
71318	20942962	Not only does the 'in vitro' biological behavior of these mutations parallel those identified in NSCLC, but the clinical course of MPM patients with EGFR mutant tumors appear to share same 'relative' improved clinical outcome like mutant EGFR-NSCLC.	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('tumors', 'Disease', (161, 167))	('NSCLC', 'Disease', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('mutant', 'Var', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (243, 248))	('improved', 'PosReg', (200, 208))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('EGFR', 'Gene', (149, 153))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))	('NSCLC', 'Disease', (243, 248))
71364	32213537	These studies, with 979 participants, demonstrated a clear statistically significant benefit in LBM favouring anamorelin as well as a consistent improvement in appetite and QoL but failed the coprimary endpoint on hand grip strength.	('hand grip', 'Phenotype', 'HP:0001188', (214, 223))	('anamorelin', 'Var', (110, 120))	('improvement', 'PosReg', (145, 156))	('appetite', 'MPA', (160, 168))	('participants', 'Species', '9606', (24, 36))	('QoL', 'MPA', (173, 176))	('anamorelin', 'Chemical', 'MESH:C000593861', (110, 120))
71429	30459812	Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('Mice', 'Species', '10090', (32, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('Reduces', 'NegReg', (120, 127))	('Increases', 'PosReg', (79, 88))	('Cachexia', 'Disease', 'MESH:D002100', (146, 154))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('Cachexia', 'Phenotype', 'HP:0004326', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancers', 'Disease', (160, 167))	('cancer', 'Disease', (160, 166))	('mesothelioma', 'Disease', (217, 229))	('cancer', 'Disease', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mesothelioma', 'Disease', 'MESH:D008654', (217, 229))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('pre', 'molecular_function', 'GO:0003904', ('288', '291'))	('Improves', 'PosReg', (37, 45))	('lung cancer', 'Disease', (201, 212))	('Response', 'MPA', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('Tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (94, 99))	('Cachexia', 'Disease', (146, 154))	('Depletion', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
71451	30459812	Disturbance of the balance between pro- and anti-inflammatory factors may impact on physiological function of the host and account for the increasing cancer rates in the elderly population.	('physiological function', 'CPA', (84, 106))	('impact', 'Reg', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('Disturbance', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
71484	30459812	In this study we analyzed 20-24 months as the lifespan of C57BL/6J mice significantly declines after 24 months due to the development of comorbidities and age-related pathologies (less than 50% survival post 24 months,).	('less', 'NegReg', (180, 184))	('mice', 'Species', '10090', (67, 71))	('declines', 'NegReg', (86, 94))	('C57BL/6J', 'Var', (58, 66))
71494	30459812	Mice were inoculated s.c. with 5 x 105 AE17 or AE17-sOVA cells in 100 mul PBS and body weight, body condition score and tumors monitored daily.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('PBS', 'Chemical', '-', (74, 77))	('AE17-sOVA', 'Var', (47, 56))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
71604	30459812	Similarly, in a previous study where IL-2/anti-CD40 was given systemically, macrophages from elderly (16-22 months) female C57BL/6J but not young mice increased production of TNF-alpha and IL-6.	('TNF-alpha', 'Gene', (175, 184))	('increased', 'PosReg', (151, 160))	('C57BL/6J', 'Var', (123, 131))	('IL-6', 'molecular_function', 'GO:0005138', ('189', '193'))	('production', 'MPA', (161, 171))	('TNF-alpha', 'Gene', '21926', (175, 184))	('mice', 'Species', '10090', (146, 150))	('IL-2', 'molecular_function', 'GO:0005134', ('37', '41'))	('IL-6', 'Gene', (189, 193))	('IL-6', 'Gene', '16193', (189, 193))
71641	28860886	More recently, the expression of B7H1 (PDL1) has been related to nonepithelioid histology and worse overall survival (OS) in several series of MPM; however, its potential role as a surrogate marker of response to immunotherapy with immune-checkpoint inhibitors is still debated.	('PDL1', 'Gene', (39, 43))	('B7H1', 'Gene', '29126', (33, 37))	('B7H1', 'Gene', (33, 37))	('expression', 'Var', (19, 29))	('nonepithelioid histology', 'Disease', (65, 89))	('OS', 'Chemical', '-', (118, 120))	('MPM', 'Disease', (143, 146))	('related to', 'Reg', (54, 64))	('PDL1', 'Gene', '29126', (39, 43))
71642	28860886	The gene-ratio test, combined with other prognostic factors (histology, lymph-node status) stratified MPM patients undergoing surgery into four distinct groups with OS of 6.9-31.9 months.	('gene-ratio', 'Var', (4, 14))	('MPM', 'Disease', (102, 105))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (165, 167))
71644	28860886	Kirschner et al proposed a six-miRNA signature (miR21-5p, miR23a-3p, miR30e-5p, miR221-3p, miR222-3p, miR31-5p) able to predict survival outcomes in surgical patients treated with either extrapleural pneumonectomy or pleurectomy/decortication.	('pleural', 'Disease', 'MESH:D010995', (192, 199))	('miR31', 'Gene', '407035', (102, 107))	('miR221', 'Gene', '407006', (80, 86))	('pleural', 'Disease', (192, 199))	('pleurectomy/decortication', 'Disease', (217, 242))	('miR221', 'Gene', (80, 86))	('miR21-5p', 'Gene', (48, 56))	('miR31', 'Gene', (102, 107))	('miR21-5p', 'Gene', '406997', (48, 56))	('miR23a-3p', 'Var', (58, 67))	('patients', 'Species', '9606', (158, 166))	('miR30e-5p', 'Var', (69, 78))	('predict', 'Reg', (120, 127))	('miR222-3p', 'Var', (91, 100))
71666	28860886	Based on the results of the revision of the database, the main changes proposed in the eighth edition of the TNM classification for MPM were: T1a and T1b grouped in T1; N1 and former N2 grouped in "new" N1, including all homolateral nodes; former N3 nodes classified as N2; and T3 and T4 classified as IIIB, irrespective of N status (Table 1).	('T1a', 'Var', (142, 145))	('TNM', 'Gene', (109, 112))	('TNM', 'Gene', '10178', (109, 112))
71834	21305058	Mesothelioma cells grown as monolayers or as spheroids expressed comparable levels of mesothelin; however, spheroids were at least 100 times less affected by SS1P.	('SS1P', 'Chemical', 'MESH:C474515', (158, 162))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('SS1P', 'Var', (158, 162))
71918	21305058	#71-0600; Invitrogen), polyclonal anti-Mcl-1 (cat.	('Mcl-1', 'Gene', (39, 44))	('polyclonal', 'Var', (23, 33))	('Mcl-1', 'Gene', '4170', (39, 44))	('cat', 'molecular_function', 'GO:0004096', ('46', '49'))
71920	21305058	#2764; Cell Signaling), polyclonal anti-BAX (cat.	('BAX', 'Gene', '581', (40, 43))	('cat', 'molecular_function', 'GO:0004096', ('45', '48'))	('Signaling', 'biological_process', 'GO:0023052', ('12', '21'))	('polyclonal', 'Var', (24, 34))	('BAX', 'Gene', (40, 43))
71937	21305058	The NCI-H226 cells cultured as monolayers and spheroids were treated with SS1P and the anti-CD22 immunotoxin (BL22) was included as a negative control.	('CD22', 'Gene', (92, 96))	('CD22', 'Gene', '933', (92, 96))	('spheroids', 'Chemical', '-', (46, 55))	('SS1P', 'Var', (74, 78))	('SS1P', 'Chemical', 'MESH:C474515', (74, 78))	('NCI-H226', 'CellLine', 'CVCL:1544', (4, 12))
71977	21305058	Furthermore, we added an inhibitory mAb (SHE78-7) against E-Cadherin and found that it significantly enhanced the anti-tumor activity of SS1P if the mAb was added before the formation of spheroids (Fig.	('tumor', 'Disease', (119, 124))	('SHE78-7', 'Var', (41, 48))	('spheroids', 'Chemical', '-', (187, 196))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('SS1P', 'Chemical', 'MESH:C474515', (137, 141))	('E-Cadherin', 'Gene', (58, 68))	('enhanced', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('E-Cadherin', 'Gene', '999', (58, 68))
71978	21305058	However, when SHE78-7 was added after the formation of spheroids, it did not improve SS1P immunotoxin therapy (Fig.	('spheroids', 'Chemical', '-', (55, 64))	('SHE78-7', 'Var', (14, 21))	('SS1P immunotoxin therapy', 'MPA', (85, 109))	('SS1P', 'Chemical', 'MESH:C474515', (85, 89))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))
71980	21305058	We found that SS1P was not able to kill greater than 50% of mesothelioma cells cultured as a spheroid, but killed all of the cells cultured as a monolayer.	('SS1P', 'Var', (14, 18))	('mesothelioma', 'Disease', (60, 72))	('SS1P', 'Chemical', 'MESH:C474515', (14, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))
71990	21305058	In the first approach, we used siRNA to reduce greater than 80% of the protein expression of E-Cadherin and found that the anti-tumor activity of SS1P was significantly enhanced.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('SS1P', 'Var', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('E-Cadherin', 'Gene', '999', (93, 103))	('reduce', 'NegReg', (40, 46))	('Cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('protein expression', 'MPA', (71, 89))	('tumor', 'Disease', (128, 133))	('enhanced', 'PosReg', (169, 177))	('E-Cadherin', 'Gene', (93, 103))	('SS1P', 'Chemical', 'MESH:C474515', (146, 150))
71993	21305058	In the present study, we showed how silencing E-Cadherin expression or blocking its adhesive function does not completely disrupt spheroids, indicating that E-Cadherin is not essential for the formation of mesothelioma spheroids.	('expression', 'MPA', (57, 67))	('spheroids', 'Chemical', '-', (219, 228))	('E-Cadherin', 'Gene', (46, 56))	('adhesive function', 'CPA', (84, 101))	('mesothelioma spheroids', 'Disease', 'MESH:D008654', (206, 228))	('spheroids', 'Chemical', '-', (130, 139))	('E-Cadherin', 'Gene', '999', (46, 56))	('E-Cadherin', 'Gene', (157, 167))	('Cadherin', 'molecular_function', 'GO:0008014', ('159', '167'))	('formation', 'biological_process', 'GO:0009058', ('193', '202'))	('silencing', 'Var', (36, 45))	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (206, 228))	('mesothelioma spheroid', 'Phenotype', 'HP:0025014', (206, 227))	('Cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('E-Cadherin', 'Gene', '999', (157, 167))	('blocking', 'NegReg', (71, 79))	('mesothelioma spheroids', 'Disease', (206, 228))
71995	21305058	In fact, inhibition of integrins has been shown to enhance breast cancer therapy.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('enhance', 'PosReg', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('integrins', 'Protein', (23, 32))	('inhibition', 'Var', (9, 19))
72013	19551156	Inhibition of Erk1/2 MAPK by PD98059 or by Erk1 siRNA down-regulated heat stress-induced Hsp40 and Hsp70 expression and reduced mesothelioma cell survival.	('Hsp40', 'Gene', (89, 94))	('PD98059', 'Chemical', 'MESH:C093973', (29, 36))	('Hsp40', 'Gene', '171221', (89, 94))	('Erk1', 'Gene', '5595', (14, 18))	('PD98059', 'Var', (29, 36))	('expression', 'MPA', (105, 115))	('Erk1', 'Gene', (14, 18))	('mesothelioma', 'Disease', (128, 140))	('Erk1', 'molecular_function', 'GO:0004707', ('14', '18'))	('mesothelioma', 'Disease', 'MESH:D008654', (128, 140))	('reduced', 'NegReg', (120, 127))	('down-regulated', 'NegReg', (54, 68))	('Erk1', 'molecular_function', 'GO:0004707', ('43', '47'))	('Erk1', 'Gene', '5595', (43, 47))	('heat stress-induced', 'MPA', (69, 88))	('Erk1', 'Gene', (43, 47))	('Hsp70', 'Gene', (99, 104))	('Hsp70', 'Gene', '3308', (99, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('21', '25'))
72014	19551156	Inhibition of p38MAPK by SB203580 or siRNA reduced Hsp40, but not Hsp70, expression and also increased mesothelioma cell death.	('p38MAPK', 'Protein', (14, 21))	('cell death', 'biological_process', 'GO:0008219', ('116', '126'))	('Hsp70', 'Gene', (66, 71))	('Hsp40', 'Gene', (51, 56))	('mesothelioma cell death', 'Disease', (103, 126))	('SB203580', 'Var', (25, 33))	('increased', 'PosReg', (93, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('SB203580', 'Chemical', 'MESH:C093642', (25, 33))	('mesothelioma cell death', 'Disease', 'MESH:D008654', (103, 126))	('expression', 'MPA', (73, 83))	('Hsp40', 'Gene', '171221', (51, 56))	('reduced', 'NegReg', (43, 50))	('Hsp70', 'Gene', '3308', (66, 71))
72033	19551156	For MAP kinase experiments, cells were pretreated for 1 hour with Erk1/2 MAP kinase inhibitor PD98059 (10 muM), or p38 MAP kinase inhibitor SB203580 (10 muM) (Calbiochem-Novabiochem Corp., Kilsyth, Vic., Australia).	('muM', 'Gene', '56925', (106, 109))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('123', '139'))	('MAP', 'molecular_function', 'GO:0004239', ('73', '76'))	('p38', 'Gene', '5594', (115, 118))	('SB203580', 'Chemical', 'MESH:C093642', (140, 148))	('p38', 'Gene', (115, 118))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('77', '93'))	('muM', 'Gene', (106, 109))	('MAP', 'molecular_function', 'GO:0004239', ('4', '7'))	('Erk1', 'molecular_function', 'GO:0004707', ('66', '70'))	('PD98059', 'Var', (94, 101))	('muM', 'Gene', '56925', (153, 156))	('MAP', 'molecular_function', 'GO:0004239', ('119', '122'))	('PD98059', 'Chemical', 'MESH:C093973', (94, 101))	('muM', 'Gene', (153, 156))
72047	19551156	When PDMM cells were pre-treated for 1 hour with either a chemical inhibitor for Erk1/2 (PD98059, 10 muM) or for 24 hours with Erk1 MAPK siRNA, we observed an incomplete reduction of Hsp70 and a total decrease of Hsp40 (Figure 3(c)).	('Hsp70', 'Gene', '3308', (183, 188))	('reduction', 'NegReg', (170, 179))	('PD98059', 'Chemical', 'MESH:C093973', (89, 96))	('Hsp40', 'Gene', '171221', (213, 218))	('pre', 'molecular_function', 'GO:0003904', ('21', '24'))	('Erk1', 'molecular_function', 'GO:0004707', ('81', '85'))	('Erk1', 'molecular_function', 'GO:0004707', ('127', '131'))	('Hsp70', 'Gene', (183, 188))	('Erk1', 'Gene', '5595', (127, 131))	('muM', 'Gene', '56925', (101, 104))	('Erk1', 'Gene', '5595', (81, 85))	('decrease', 'NegReg', (201, 209))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('Erk1', 'Gene', (81, 85))	('muM', 'Gene', (101, 104))	('Erk1', 'Gene', (127, 131))	('Hsp40', 'Gene', (213, 218))	('PD98059', 'Var', (89, 96))
72048	19551156	The suppression of p38 MAPK by either a chemical inhibitor (SB203580, 10 muM) or by p38 MAPK siRNA downregulated the heat-induced (40 C, 20 minutes) expression of Hsp70 and reduced that of Hsp40 to a lesser degree in PDMM cells (Figure 3(d)).	('p38', 'Gene', '5594', (19, 22))	('SB203580', 'Var', (60, 68))	('p38', 'Gene', '5594', (84, 87))	('suppression', 'NegReg', (4, 15))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('downregulated', 'NegReg', (99, 112))	('reduced', 'NegReg', (173, 180))	('Hsp70', 'Gene', (163, 168))	('Hsp40', 'Gene', '171221', (189, 194))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('p38', 'Gene', (84, 87))	('muM', 'Gene', '56925', (73, 76))	('muM', 'Gene', (73, 76))	('p38', 'Gene', (19, 22))	('expression', 'MPA', (149, 159))	('SB203580', 'Chemical', 'MESH:C093642', (60, 68))	('Hsp70', 'Gene', '3308', (163, 168))	('Hsp40', 'Gene', (189, 194))
72056	19551156	For mesothelial cells the inhibition of Hsp40 also increased their sensitivity to heat (Figure 5(a)), but inhibition of Hsp70 had no effect at all (Figure 5(b)).	('Hsp40', 'Gene', '171221', (40, 45))	('increased', 'PosReg', (51, 60))	('Hsp70', 'Gene', '3308', (120, 125))	('inhibition', 'Var', (26, 36))	('sensitivity to heat', 'MPA', (67, 86))	('Hsp70', 'Gene', (120, 125))	('Hsp40', 'Gene', (40, 45))
72057	19551156	We also assessed the synthesis of caspase-3 as an indicator for apoptosis in heat stressed cells but observed only a relative small increase of caspase-3 levels by PDMM cells which did not correlate with the increase of the temperature (Figure 5(c)).	('caspase-3', 'Gene', '836', (34, 43))	('synthesis', 'biological_process', 'GO:0009058', ('21', '30'))	('caspase-3', 'Gene', '836', (144, 153))	('PDMM', 'Var', (164, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('caspase-3', 'Gene', (144, 153))	('caspase-3', 'Gene', (34, 43))
72061	19551156	Importantly, the down-regulation of either Hsp40 or Hsp70 or p38MAPK increased the heat sensitivity of PDMM cells.	('Hsp40', 'Gene', '171221', (43, 48))	('p38MAPK', 'Var', (61, 68))	('increased', 'PosReg', (69, 78))	('Hsp70', 'Gene', (52, 57))	('heat sensitivity of PDMM cells', 'CPA', (83, 113))	('MAPK', 'molecular_function', 'GO:0004707', ('64', '68'))	('regulation', 'biological_process', 'GO:0065007', ('22', '32'))	('Hsp40', 'Gene', (43, 48))	('down-regulation', 'NegReg', (17, 32))	('Hsp70', 'Gene', '3308', (52, 57))
72062	19551156	Several studies indicated that the malignant transformation of mesothelial cells is linked to a modification of p38 MAPK activity and its interaction with Erk1/2 MAPK on a yet to be defined level, which is essential for the malignant transformation.	('MAPK', 'molecular_function', 'GO:0004707', ('162', '166'))	('activity', 'MPA', (121, 129))	('p38', 'Gene', '5594', (112, 115))	('Erk1', 'molecular_function', 'GO:0004707', ('155', '159'))	('interaction', 'Interaction', (138, 149))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('modification', 'Var', (96, 108))	('linked', 'Reg', (84, 90))	('p38', 'Gene', (112, 115))	('malignant transformation of mesothelial cells', 'CPA', (35, 80))
72075	19551156	Therefore, we suggest that the inhibition of Hsp40 would be the best option to increase heat sensitivity of PDMM cells.	('increase', 'PosReg', (79, 87))	('heat sensitivity', 'MPA', (88, 104))	('Hsp40', 'Gene', (45, 50))	('increase heat sensitivity', 'Phenotype', 'HP:0002046', (79, 104))	('Hsp40', 'Gene', '171221', (45, 50))	('inhibition', 'Var', (31, 41))
72107	32677949	To test this hypothesis, we examined the effects of ERC/mesothelin overexpression or knockdown on cell morphology, as well as growth kinetics, adhesion, and migration/invasion of mesothelial cells in vitro.	('ERC/mesothelin', 'Chemical', '-', (52, 66))	('rat', 'Species', '10116', (160, 163))	('knockdown', 'Var', (85, 94))	('ERC', 'cellular_component', 'GO:0055037', ('52', '55'))	('migration/invasion', 'CPA', (157, 175))
72126	32677949	HEK293T, which was used as the packaging cell line, was cotransfected with Precision LentiORF for MSLN and trans-lentiviral packaging vectors (Thermo Scientific Open Biosystems, Waltham, MA, USA).	('HEK293T', 'Var', (0, 7))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('MSLN', 'Gene', '10232', (98, 102))	('MSLN', 'Gene', (98, 102))
72130	32677949	To establish stable ERC/mesothelin- or RFP-expressing cells, we infected H2452 cells with the titrated supernatant at a multiplicity of infection of 2.0, and selected cells that were resistant to 2.0 mug/mL blasticidin S. ON-TARGET plus Human MSLN siRNAs, including (5'-CAUUGGACCUGCUGCUAUU-3'), (5'-ACAUGAACGGGUCCGAAUA-3'), and (5'-GAUGAGCUCUACCCACAAG-3'), and ON-TARGET plus Non-targeting Pool siRNA (negative control) were purchased from Dharmacon/GE Healthcare (Lafayette, CO, USA).	('rat', 'Species', '10116', (97, 100))	('infection', 'Disease', (136, 145))	("5'-GAUGAGCUCUACCCACAAG-3", 'Var', (329, 353))	('infected', 'Disease', (64, 72))	('infection', 'Disease', 'MESH:D007239', (136, 145))	('H2452', 'Chemical', '-', (73, 78))	('MSLN', 'Gene', (243, 247))	('Human', 'Species', '9606', (237, 242))	('MSLN', 'Gene', '10232', (243, 247))	('ERC', 'cellular_component', 'GO:0055037', ('20', '23'))	("5'-ACAUGAACGGGUCCGAAUA-3", 'Var', (296, 320))	('mug', 'molecular_function', 'GO:0043739', ('200', '203'))	('infected', 'Disease', 'MESH:D007239', (64, 72))	('ERC/mesothelin', 'Chemical', '-', (20, 34))	('blasticidin S', 'Chemical', 'MESH:C004500', (207, 220))
72168	32677949	Figure 5 and Figure S2 (Additional file 1) showed that, irrespective of ERC/mesothelin expression and histological subtypes, the E-cadherin stain was negative, while those for AE1/AE3, vimentin, ZEB1 and Twist were weakly positive in tumors derived from H2452.	('AE3', 'Gene', '6508', (180, 183))	('ERC/mesothelin', 'Chemical', '-', (72, 86))	('vimentin', 'cellular_component', 'GO:0045099', ('185', '193'))	('negative', 'NegReg', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('cadherin', 'molecular_function', 'GO:0008014', ('131', '139'))	('tumors', 'Disease', (234, 240))	('H2452', 'Var', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('AE1', 'Gene', '6521', (176, 179))	('AE3', 'Gene', (180, 183))	('ERC', 'cellular_component', 'GO:0055037', ('72', '75'))	('AE1', 'Gene', (176, 179))	('vimentin', 'cellular_component', 'GO:0045098', ('185', '193'))	('H2452', 'Chemical', '-', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('positive', 'Reg', (222, 230))
72180	32677949	In this study, control cells expressing RFP formed tumors in 62.5% (5/8) of mice, and a frequency was almost identical to that of unmanipulated cells.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RFP', 'Var', (40, 43))	('tumors', 'Disease', (51, 57))	('mice', 'Species', '10090', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
72188	32677949	Our study showed that H2452 demonstrating a monophasic spindle-like shape in vitro developed into biphasic mesothelioma with both epithelioid (polygonal) and sarcomatoid (spindle) components in transplanted mice.	('H2452', 'Var', (22, 27))	('spindle', 'cellular_component', 'GO:0005819', ('55', '62'))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (98, 119))	('sarcomatoid', 'Disease', 'MESH:C538614', (158, 169))	('biphasic mesothelioma', 'Disease', (98, 119))	('H2452', 'Chemical', '-', (22, 27))	('spindle', 'cellular_component', 'GO:0005819', ('171', '178'))	('mice', 'Species', '10090', (207, 211))	('sarcomatoid', 'Disease', (158, 169))	('rat', 'Species', '10116', (35, 38))
72198	32677949	H2452 has multiple mutations in tumor suppressor genes, including a missense mutation in BAP1, a truncation of p53, and a homozygous deletion of CDKN2A and NF2.	('BAP1', 'Gene', (89, 93))	('CDKN2A', 'Gene', '1029', (145, 151))	('H2452', 'Var', (0, 5))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('BAP1', 'Gene', '8314', (89, 93))	('p53', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('p53', 'Gene', '7157', (111, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('NF2', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('H2452', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (32, 37))	('NF2', 'Gene', '4771', (156, 159))	('missense mutation', 'Var', (68, 85))	('truncation', 'MPA', (97, 107))	('CDKN2A', 'Gene', (145, 151))
72201	32677949	In our study, the histological differentiation of H2452 to polygonal and spindle-shaped components occurred without changes in expression of EMT markers such as E-cadherin, AE1/AE3, vimentin (Fig.	('AE3', 'Gene', '6508', (177, 180))	('vimentin', 'cellular_component', 'GO:0045098', ('182', '190'))	('EMT', 'biological_process', 'GO:0001837', ('141', '144'))	('H2452', 'Var', (50, 55))	('spindle', 'cellular_component', 'GO:0005819', ('73', '80'))	('AE1', 'Gene', '6521', (173, 176))	('AE3', 'Gene', (177, 180))	('H2452', 'Chemical', '-', (50, 55))	('AE1', 'Gene', (173, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('vimentin', 'cellular_component', 'GO:0045099', ('182', '190'))	('E-cadherin', 'Protein', (161, 171))
72214	32677949	The transplanted H2452 took a polygonal, epithelioid pattern at the invasion front where it contacted with the host hepatocytes, and in the distant area from the front the cell took a spindle-like, sarcomatoid pattern.	('sarcomatoid', 'Disease', 'MESH:C538614', (198, 209))	('H2452', 'Var', (17, 22))	('spindle', 'cellular_component', 'GO:0005819', ('184', '191'))	('sarcomatoid', 'Disease', (198, 209))	('H2452', 'Chemical', '-', (17, 22))
72223	32677949	MK established the ERC/mesothelin-overexpressing cells and those with knocked down ERC/mesothelin and studied effects on mesothelioma cells.	('ERC', 'cellular_component', 'GO:0055037', ('19', '22'))	('ERC/mesothelin', 'Gene', (83, 97))	('ERC/mesothelin', 'Chemical', '-', (19, 33))	('ERC', 'cellular_component', 'GO:0055037', ('83', '86'))	('knocked down', 'Var', (70, 82))	('mesothelioma', 'Disease', (121, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('ERC/mesothelin', 'Chemical', '-', (83, 97))
72225	32677949	This study was supported in part by a Grant-in-Aid (221S0001) for Scientific Research on Innovative Areas from the Japan Society for the Promotion of Science, Grants-in-Aid (S1311011 and S1511008L) from the Foundation of Strategic Research Projects in Private Universities of the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and grants from Shizuoka Medical Research Center for Disaster of Juntendo University Shizuoka Hospital, and from the Institute for Environmental and Gender-Specific Medicine of Juntendo University Urayasu Hospital.	('Aid', 'Gene', '57379', (47, 50))	('S1311011', 'Var', (174, 182))	('S1511008L', 'Mutation', 'p.S1511008L', (187, 196))	('Aid', 'Gene', (47, 50))	('rat', 'Species', '10116', (223, 226))	('Aid', 'Gene', '57379', (169, 172))	('Aid', 'Gene', (169, 172))	('S1511008L', 'Var', (187, 196))
72272	29666782	The inactivation and/or loss of their function is one of the fundamental events in the tumor development.	('inactivation', 'Var', (4, 16))	('men', 'Species', '9606', (100, 103))	('men', 'Species', '9606', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('loss', 'NegReg', (24, 28))
72273	29666782	Loss of heterozygosity, which commonly leads to unmasking a somatically mutated tumor suppressor gene through loss of the wild-type allele, seems to be a consistent feature in MPMs.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('loss', 'NegReg', (110, 114))	('Loss of heterozygosity', 'Var', (0, 22))	('unmasking', 'MPA', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MPM', 'Chemical', '-', (176, 179))	('tumor', 'Disease', (80, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('MPMs', 'Disease', (176, 180))
72274	29666782	Recent breakthrough studies have discovered a germline mutation/inactivation in BAP1 (BRCA1-associated protein 1), a tumor suppressor gene located on chromosome 3p21.3 in families with a genetic predisposition to develop MPM.	('MPM', 'Disease', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('BRCA1-associated protein 1', 'Gene', '8314', (86, 112))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('tumor', 'Disease', (117, 122))	('MPM', 'Chemical', '-', (221, 224))	('germline mutation/inactivation', 'Var', (46, 76))	('BRCA1-associated protein 1', 'Gene', (86, 112))	('BAP1', 'Gene', '8314', (80, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('BAP1', 'Gene', (80, 84))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
72275	29666782	BAP1 is a deubiquitinating hydrolase that binds the RING finger domain of the BRCA1 protein, thought to be a regulator of many pathways germane to cancer.	('binds', 'Interaction', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('RING finger domain', 'Var', (52, 70))	('BAP1', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('BRCA1', 'Gene', '672', (78, 83))	('protein', 'Protein', (84, 91))	('cancer', 'Disease', (147, 153))	('BAP1', 'Gene', '8314', (0, 4))	('BRCA1', 'Gene', (78, 83))
72278	29666782	A recently published study has shown that the heterozygous germline BAP1 mutations (BAP1+/-) induce cell metabolic changes linked to the increase aerobic glycolysis, leading to reprogramming of the activities that create a favorable environment to carcinogenesis and tumor growth.	('carcinogenesis', 'Disease', (248, 262))	('reprogramming of the', 'CPA', (177, 197))	('cell metabolic changes', 'CPA', (100, 122))	('men', 'Species', '9606', (240, 243))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('aerobic glycolysis', 'MPA', (146, 164))	('BAP1', 'Gene', '8314', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('BAP1', 'Gene', '8314', (68, 72))	('increase', 'PosReg', (137, 145))	('glycolysis', 'biological_process', 'GO:0006096', ('154', '164'))	('tumor', 'Disease', (267, 272))	('BAP1', 'Gene', (84, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (248, 262))	('BAP1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
72279	29666782	The germline BAP1 gene mutations lead to an abnormally short BAP1 protein that is likely broken down prematurely.	('lead to', 'Reg', (33, 40))	('BAP1', 'Gene', (13, 17))	('BAP1', 'Gene', (61, 65))	('broken down', 'Phenotype', 'HP:0001061', (89, 100))	('mutations', 'Var', (23, 32))	('short', 'NegReg', (55, 60))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', '8314', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
72280	29666782	These mutations have been associated with various malignancies other than malignant mesothelioma such as, uveal melanoma and melanocytic BAP1-associated intradermal tumors.	('BAP1', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignancies', 'Disease', (50, 62))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (74, 96))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('malignant mesothelioma', 'Disease', (74, 96))	('intradermal tumors', 'Disease', 'MESH:D018330', (153, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('BAP1', 'Gene', '8314', (137, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('intradermal tumors', 'Disease', (153, 171))	('associated', 'Reg', (26, 36))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (74, 96))	('mutations', 'Var', (6, 15))
72281	29666782	Somatic truncated BAP1 mutations and aberrant BAP1 expression are more common in sporadic MPM, with a frequency that varies widely among different histologic tumor types.	('sporadic MPM', 'Disease', (81, 93))	('tumor', 'Disease', (158, 163))	('BAP1', 'Gene', '8314', (18, 22))	('MPM', 'Chemical', '-', (90, 93))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (18, 22))	('common', 'Reg', (71, 77))	('mutations', 'Var', (23, 32))	('expression', 'MPA', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('BAP1', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('aberrant', 'Var', (37, 45))
72283	29666782	Besides single-point mutations in the BAP1 gene, copy number loss, rearrangements, and multiple alterations have also been found.	('single-point mutations', 'Var', (8, 30))	('BAP1', 'Gene', (38, 42))	('men', 'Species', '9606', (76, 79))	('rearrangements', 'Var', (67, 81))	('copy number loss', 'Var', (49, 65))	('rat', 'Species', '10116', (100, 103))	('BAP1', 'Gene', '8314', (38, 42))
72284	29666782	Interestingly, the analysis of chromosome 3p21, using a high-density microarray-based comparative genomic hybridization (aCGH) combined with targeted next-generation DNA sequencing (NGS), detected a much higher percentage of genetic alteration in BAP1 than reported in previous studies conducted with the NGS sequencing approach or aCGH alone, respectively.	('genetic alteration', 'Var', (225, 243))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('BAP1', 'Gene', (247, 251))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (237, 240))	('BAP1', 'Gene', '8314', (247, 251))	('rat', 'Species', '10116', (159, 162))
72286	29666782	To date, none of mesothelioma patients with germline BAP1 mutation was an ex-exposed asbestos worker, demonstrating that the development of MPM is not always directly associated with the amounts of asbestos exposure, signifying a decisive role of genetic factors among risk factors of this neoplasia.	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('neoplasia', 'Phenotype', 'HP:0002664', (290, 299))	('mesothelioma', 'Disease', (17, 29))	('neoplasia', 'Disease', 'MESH:D009369', (290, 299))	('men', 'Species', '9606', (132, 135))	('mutation', 'Var', (58, 66))	('asbestos', 'Chemical', 'MESH:D001194', (198, 206))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))	('rat', 'Species', '10116', (109, 112))	('neoplasia', 'Disease', (290, 299))	('MPM', 'Disease', (140, 143))	('BAP1', 'Gene', '8314', (53, 57))	('MPM', 'Chemical', '-', (140, 143))	('patients', 'Species', '9606', (30, 38))	('BAP1', 'Gene', (53, 57))
72287	29666782	The high incidence (around 25-60%) of the somatic BAP1 mutations reported in MPM is also associated with frequent alterations in other major tumor suppressor genes, such as p16/Cdkn2a, p19/Arf, and p19/Cdkn2b.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('p19', 'Gene', (185, 188))	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('MPM', 'Chemical', '-', (77, 80))	('Cdkn2b', 'Gene', '1030', (202, 208))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('p19', 'Gene', '1029', (185, 188))	('p19', 'cellular_component', 'GO:0070743', ('198', '201'))	('p19', 'Gene', (198, 201))	('mutations', 'Var', (55, 64))	('alterations', 'Reg', (114, 125))	('BAP1', 'Gene', '8314', (50, 54))	('p16', 'Gene', (173, 176))	('p19', 'Gene', '1029', (198, 201))	('Cdkn2a', 'Gene', (177, 183))	('p16', 'Gene', '1029', (173, 176))	('Cdkn2b', 'Gene', (202, 208))	('p19', 'cellular_component', 'GO:0070743', ('185', '188'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('Cdkn2a', 'Gene', '1029', (177, 183))	('tumor', 'Disease', (141, 146))	('BAP1', 'Gene', (50, 54))
72288	29666782	Independently of BAP1 mutations, p16/Cdkn2A, p19/Arf, and p19/Cdkn2b have been found frequently inactivated by point mutations, aberrant expression and epigenetic silencing, suggesting their role, together with asbestos exposure, in the induction of mesothelial transformation in vitro and in vivo.	('p19', 'Gene', '1029', (58, 61))	('asbestos', 'Chemical', 'MESH:D001194', (211, 219))	('Cdkn2A', 'Gene', '1029', (37, 43))	('aberrant expression', 'Var', (128, 147))	('mesothelial transformation', 'CPA', (250, 276))	('Cdkn2b', 'Gene', (62, 68))	('inactivated', 'NegReg', (96, 107))	('p19', 'cellular_component', 'GO:0070743', ('45', '48'))	('p16', 'Gene', (33, 36))	('p19', 'Gene', (45, 48))	('p16', 'Gene', '1029', (33, 36))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('p19', 'Gene', (58, 61))	('Cdkn2b', 'Gene', '1030', (62, 68))	('Cdkn2A', 'Gene', (37, 43))	('p19', 'Gene', '1029', (45, 48))	('epigenetic silencing', 'Var', (152, 172))	('p19', 'cellular_component', 'GO:0070743', ('58', '61'))	('point mutations', 'Var', (111, 126))	('BAP1', 'Gene', (17, 21))
72289	29666782	Moreover, in vivo studies have shown that the inactivation of both p16 and p19/Arf expression accelerated the initiation of asbestos-induced MPM and decreased percent survival, as compared with the inactivation of either gene alone.	('MPM', 'Chemical', '-', (141, 144))	('initiation', 'MPA', (110, 120))	('asbestos', 'Chemical', 'MESH:D001194', (124, 132))	('p16', 'Gene', '1029', (67, 70))	('p19', 'Gene', '1029', (75, 78))	('p19', 'Gene', (75, 78))	('p19', 'cellular_component', 'GO:0070743', ('75', '78'))	('p16', 'Gene', (67, 70))	('decreased', 'NegReg', (149, 158))	('inactivation', 'Var', (46, 58))	('rat', 'Species', '10116', (100, 103))	('accelerated', 'PosReg', (94, 105))	('percent survival', 'CPA', (159, 175))
72292	29666782	A study has found that 38% of MPM samples displayed NF2 gene mutations, and 29.4% displayed deletions, while no NF2 mutations were found in non-small cell lung cancer patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('NF2', 'Gene', '4771', (112, 115))	('MPM', 'Disease', (30, 33))	('patients', 'Species', '9606', (167, 175))	('mutations', 'Var', (61, 70))	('NF2', 'Gene', (52, 55))	('non-small cell lung cancer', 'Disease', (140, 166))	('MPM', 'Chemical', '-', (30, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('NF2', 'Gene', (112, 115))	('NF2', 'Gene', '4771', (52, 55))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('deletions', 'Var', (92, 101))
72333	29666782	Genetic and chemical modulation of the Notch pathway indicated that MPM cells are dependent on Notch signaling.	('modulation', 'Var', (21, 31))	('MPM', 'Chemical', '-', (68, 71))	('Notch pathway', 'Pathway', (39, 52))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
72336	29666782	Previous studies conducted by the same group have shown that SV40 activates Notch1 leading to immortalization and transformation of primary HMC.	('primary HMC', 'Disease', (132, 143))	('immortalization', 'CPA', (94, 109))	('Notch1', 'Gene', (76, 82))	('transformation', 'CPA', (114, 128))	('SV40', 'Species', '1891767', (61, 65))	('Notch1', 'Gene', '4851', (76, 82))	('SV40', 'Var', (61, 65))	('activates', 'PosReg', (66, 75))
72338	29666782	The effect of SV40 on Notch1 in mesothelial cells is similar to what reported in uterine cervical cancer, in which the infection of human papilloma virus has been linked to the activation of Notch1.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('activation', 'PosReg', (177, 187))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Notch1', 'Gene', (191, 197))	('cancer', 'Disease', (98, 104))	('Notch1', 'Gene', (22, 28))	('infection of human papilloma virus', 'Disease', (119, 153))	('Notch1', 'Gene', '4851', (22, 28))	('SV40', 'Species', '1891767', (14, 18))	('papilloma', 'Phenotype', 'HP:0012740', (138, 147))	('Notch1', 'Gene', '4851', (191, 197))	('SV40', 'Var', (14, 18))	('infection of human papilloma virus', 'Disease', 'MESH:D015658', (119, 153))
72347	29666782	have shown that operative mortality following EPP is higher compared with P/D (7 vs 4%, respectively); however, P/D has better survival, compared with EPP (16 vs 12 months, respectively).	('survival', 'MPA', (127, 135))	('P/D', 'Var', (112, 115))	('rat', 'Species', '10116', (19, 22))
72385	29666782	In a large clinical study, treatment with tremelimumab, a monoclonal antibody against cytotoxic-T-lymphocyte-associated antigen 4, expressed on the surface of activated T lymphocytes and interfering with their ability to kill cancer cells did not significantly prolong overall survival, compared with placebo (median survival of 7.3 months) in patients with previously treated MPM (median survival of 7.7 months).	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('overall survival', 'CPA', (269, 285))	('tremelimumab', 'Var', (42, 54))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('men', 'Species', '9606', (32, 35))	('MPM', 'Disease', (377, 380))	('cytotoxic-', 'Disease', (86, 96))	('MPM', 'Chemical', '-', (377, 380))	('cancer', 'Disease', (226, 232))	('tremelimumab', 'Chemical', 'MESH:C520704', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('cytotoxic-', 'Disease', 'MESH:D064420', (86, 96))	('patients', 'Species', '9606', (344, 352))	('prolong', 'PosReg', (261, 268))
72393	29666782	In preclinical setting, the dysregulation in MPM of ErbB, a protein structurally similar and a ligand to EGFR, is being exploited for immunotherapy.	('ErbB', 'Gene', '1956', (52, 56))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('ligand', 'molecular_function', 'GO:0005488', ('95', '101'))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('dysregulation', 'Var', (28, 41))	('ErbB', 'Gene', (52, 56))	('MPM', 'Chemical', '-', (45, 48))
72400	29666782	Inactivation of plasminogen activators inhibitor PAI-1, implicated in tumor progression by increasing angiogenesis, could constitute a strategy for inhibiting angiogenesis and growth of MPM.	('increasing', 'PosReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('growth', 'CPA', (176, 182))	('tumor', 'Disease', (70, 75))	('angiogenesis', 'biological_process', 'GO:0001525', ('102', '114'))	('MPM', 'Chemical', '-', (186, 189))	('rat', 'Species', '10116', (137, 140))	('angiogenesis', 'CPA', (102, 114))	('angiogenesis', 'CPA', (159, 171))	('PAI-1', 'Gene', (49, 54))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('Inactivation', 'Var', (0, 12))	('inhibiting', 'NegReg', (148, 158))
72421	29666782	Analyses carried out on serum samples from MPM patients have detected the presence of antibodies against SV40 viral capsid protein.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('viral capsid', 'cellular_component', 'GO:0019028', ('110', '122'))	('SV40', 'Species', '1891767', (105, 109))	('SV40', 'Gene', (105, 109))	('patients', 'Species', '9606', (47, 55))	('MPM', 'Chemical', '-', (43, 46))	('antibodies', 'Var', (86, 96))
72422	29666782	Since SV40 could synergize with asbestos in causing MPM, these antibodies in the serum could help to predict the risk of developing MPM in a population of asbestos-exposed worker.	('MPM', 'Chemical', '-', (132, 135))	('asbestos', 'Chemical', 'MESH:D001194', (155, 163))	('MPM', 'Chemical', '-', (52, 55))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('SV40', 'Species', '1891767', (6, 10))	('SV40', 'Var', (6, 10))	('MPM', 'Disease', (52, 55))
72431	29666782	A large body of evidence shows that inhibition of Notch signaling causes a reduction of tumor cell proliferation in vitro and arrests tumor growth in vivo, thus the targeting of Notch offers an attractive potential therapeutic strategy in oncology.	('oncology', 'Phenotype', 'HP:0002664', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibition', 'Var', (36, 46))	('arrests tumor', 'Disease', 'MESH:D006323', (126, 139))	('rat', 'Species', '10116', (229, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('arrests tumor', 'Disease', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduction', 'NegReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Disease', (88, 93))	('Notch', 'Gene', (50, 55))	('tumor', 'Disease', (134, 139))
72432	29666782	Notch inhibition is able to shrink the tumor not only by increasing the apoptotic rate in the bulk of tumor but also by inhibiting the growth of cancer stem cells, one main culprit for tumor recurrence, and by interfering with angiogenesis.	('cancer', 'Disease', (145, 151))	('angiogenesis', 'biological_process', 'GO:0001525', ('227', '239'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('apoptotic rate', 'MPA', (72, 86))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('inhibiting', 'NegReg', (120, 130))	('interfering', 'NegReg', (210, 221))	('Notch inhibition', 'Var', (0, 16))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (102, 107))	('increasing', 'PosReg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('rat', 'Species', '10116', (82, 85))	('inhibition', 'Var', (6, 16))	('angiogenesis', 'CPA', (227, 239))
72445	29666782	Furthermore, oncogene-targeted depth sequencing on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum revealed a mutation leading to 13-amino acids neo-peptide of the truncated BAP1 protein, which is predicted to be present on this examined patient's HLA-B protein.	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('HLA-B', 'Gene', (308, 313))	('protein', 'Protein', (239, 246))	('mutation', 'Var', (170, 178))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('BAP1', 'Gene', '8314', (234, 238))	('malignant mesothelioma', 'Disease', (118, 140))	('neo-peptide', 'MPA', (205, 216))	('leading to', 'Reg', (179, 189))	('HLA-B', 'Gene', '3106', (308, 313))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (118, 140))	('patient', 'Species', '9606', (298, 305))	('BAP1', 'Gene', (234, 238))	('tumor', 'Disease', (53, 58))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
72447	29666782	Comprehensive genomic analysis, followed by integrated analyses of 216 MPM biopsies, has identified recurrent mutations, gene fusions and splicing alterations leading to inactivation of NF2, BAP1, and SETD2 and alterations in Hippo, mTOR, histone methylation, RNA helicase, and p53 signaling pathways.	('rat', 'Species', '10116', (215, 218))	('inactivation', 'NegReg', (170, 182))	('BAP1', 'Gene', (191, 195))	('rat', 'Species', '10116', (151, 154))	('mTOR', 'Gene', (233, 237))	('p53', 'Gene', '7157', (278, 281))	('SETD2', 'Gene', (201, 206))	('alterations', 'Reg', (211, 222))	('signaling', 'biological_process', 'GO:0023052', ('282', '291'))	('RNA', 'cellular_component', 'GO:0005562', ('260', '263'))	('mTOR', 'Gene', '2475', (233, 237))	('SETD2', 'Gene', '29072', (201, 206))	('mutations', 'Var', (110, 119))	('p53', 'Gene', (278, 281))	('Hippo', 'Pathway', (226, 231))	('histone methylation', 'Pathway', (239, 258))	('splicing alterations', 'Var', (138, 158))	('NF2', 'Gene', '4771', (186, 189))	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('RNA helicase', 'Pathway', (260, 272))	('histone methylation', 'biological_process', 'GO:0016571', ('239', '258'))	('BAP1', 'Gene', '8314', (191, 195))	('MPM', 'Chemical', '-', (71, 74))	('gene fusions', 'Var', (121, 133))	('NF2', 'Gene', (186, 189))	('rat', 'Species', '10116', (49, 52))
72450	29666782	In conclusion, with the aim to achieve early detection of MPM and increased survival of these patients, with minimal side effects: (1) the comprehensive genomic profiling of MPM; (2) the targeting of pathways already known to be dysregulated in MPMs, such as the Notch pathway; (3) the characterization of dysregulated circulating miRNAs, and (4) the assessment of risks, such as exposure to asbestos and the presence of germline BAP1 mutations, should all be taken under consideration.	('patients', 'Species', '9606', (94, 102))	('BAP1', 'Gene', (430, 434))	('rat', 'Species', '10116', (479, 482))	('asbestos', 'Chemical', 'MESH:D001194', (392, 400))	('mutations', 'Var', (435, 444))	('MPM', 'Chemical', '-', (245, 248))	('men', 'Species', '9606', (357, 360))	('MPM', 'Chemical', '-', (174, 177))	('MPM', 'Chemical', '-', (58, 61))	('BAP1', 'Gene', '8314', (430, 434))
72467	27391433	In pancreatic carcinoma cells the inhibition of SRC, a Src Family Kinase (SFK) member strongly activated in many solid tumors and controlling key processes in tumor development, was shown to revert the 5-FU resistance of cancer cells through indirect TS regulation.	('revert', 'NegReg', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('inhibition', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('b', 'Chemical', 'MESH:D001895', (38, 39))	('regulation', 'biological_process', 'GO:0065007', ('254', '264'))	('Src', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('5-FU resistance', 'MPA', (202, 217))	('Src', 'Gene', '6714', (55, 58))	('b', 'Chemical', 'MESH:D001895', (82, 83))	('SRC', 'Gene', (48, 51))	('solid tumors', 'Disease', (113, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancer', 'Disease', (221, 227))	('tumor', 'Disease', (159, 164))	('TS', 'Gene', '7298', (251, 253))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (3, 23))	('tumor', 'Disease', (119, 124))	('activated', 'PosReg', (95, 104))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('pancreatic carcinoma', 'Disease', (3, 23))	('tumor', 'Disease', 'MESH:D009369', (119, 124))
72504	27391433	Unexpectedly, in REN cells dasatinib at IC50 reduced TS expression (Figure 2C, left panel) and we investigated if this effect was SRC-inhibition related.	('TS', 'Gene', '7298', (53, 55))	('reduced', 'NegReg', (45, 52))	('b', 'Chemical', 'MESH:D001895', (138, 139))	('REN', 'Gene', '5972', (17, 20))	('IC50', 'Var', (40, 44))	('b', 'Chemical', 'MESH:D001895', (35, 36))	('dasatinib', 'Chemical', 'MESH:D000069439', (27, 36))	('REN', 'Gene', (17, 20))
72509	27391433	The experiments on two independent REN TS-Prom-1191+176 clones, D7 and D9, showed that dasatinib impaired luciferase activity both at 24 and at 48 h (Figure 3A, middle panel), mirroring the endogenous TS protein expression pattern (Figure 3A, bottom panel).	('TS', 'Gene', '7298', (39, 41))	('b', 'Chemical', 'MESH:D001895', (243, 244))	('REN', 'Gene', (35, 38))	('b', 'Chemical', 'MESH:D001895', (126, 127))	('impaired', 'NegReg', (97, 105))	('activity', 'MPA', (117, 125))	('TS', 'Gene', '7298', (201, 203))	('b', 'Chemical', 'MESH:D001895', (95, 96))	('luciferase activity', 'molecular_function', 'GO:0047077', ('106', '125'))	('REN', 'Gene', '5972', (35, 38))	('dasatinib', 'Chemical', 'MESH:D000069439', (87, 96))	('luciferase activity', 'molecular_function', 'GO:0045289', ('106', '125'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('106', '125'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('106', '125'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('106', '125'))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('luciferase', 'Enzyme', (106, 116))	('dasatinib', 'Var', (87, 96))
72520	27391433	To better understand the specific involvement of SRC in this scenario, we transfected TS-promoter reporter gene, in the presence or absence of SRC dominant negative (K295M, kinase dead), as well as in presence of dasatinib.	('transfected', 'Reg', (74, 85))	('b', 'Chemical', 'MESH:D001895', (133, 134))	('b', 'Chemical', 'MESH:D001895', (3, 4))	('dasatinib', 'Chemical', 'MESH:D000069439', (213, 222))	('K295M', 'Var', (166, 171))	('SRC', 'Gene', (143, 146))	('b', 'Chemical', 'MESH:D001895', (221, 222))	('K295M', 'Mutation', 'p.K295M', (166, 171))	('TS', 'Gene', '7298', (86, 88))
72530	27391433	In REN cells treated with IC50 dasatinib, apoptosis was not affected, while treatment with PEM at IC50 increased the apoptotic rate by 11.8% when compared to untreated cells.	('REN', 'Gene', '5972', (3, 6))	('apoptotic', 'CPA', (117, 126))	('PEM', 'Chemical', 'MESH:D000068437', (91, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('dasatinib', 'Chemical', 'MESH:D000069439', (31, 40))	('b', 'Chemical', 'MESH:D001895', (132, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('REN', 'Gene', (3, 6))	('b', 'Chemical', 'MESH:D001895', (39, 40))	('IC50 dasatinib', 'Var', (26, 40))
72568	27391433	In our study, REN cells had the most aggressive behavior with high SRC expression: dasatinib inhibited cell migration after wound healing stress, as also demonstrated by others, even in the presence of PEM, which did not modify the impairment of dasatinib-mediated cell migration.	('dasatinib', 'Chemical', 'MESH:D000069439', (246, 255))	('wound healing', 'biological_process', 'GO:0042060', ('124', '137'))	('cell migration', 'biological_process', 'GO:0016477', ('265', '279'))	('aggressive behavior', 'biological_process', 'GO:0002118', ('37', '56'))	('b', 'Chemical', 'MESH:D001895', (254, 255))	('b', 'Chemical', 'MESH:D001895', (48, 49))	('dasatinib', 'Chemical', 'MESH:D000069439', (83, 92))	('b', 'Chemical', 'MESH:D001895', (97, 98))	('cell migration', 'biological_process', 'GO:0016477', ('103', '117'))	('REN', 'Gene', '5972', (14, 17))	('aggressive behavior', 'Phenotype', 'HP:0000718', (37, 56))	('dasatinib', 'Var', (83, 92))	('cell migration after wound healing stress', 'CPA', (103, 144))	('inhibited', 'NegReg', (93, 102))	('PEM', 'Chemical', 'MESH:D000068437', (202, 205))	('b', 'Chemical', 'MESH:D001895', (91, 92))	('REN', 'Gene', (14, 17))	('b', 'Chemical', 'MESH:D001895', (167, 168))
72580	27391433	This suggests that the loss of LKB1, reducing AMPK activation, makes cells more sensitive to dasatinib which, in turn, induces cellular stress and downregulates both p70S6K and Akt phosphorylation.	('induces', 'Reg', (119, 126))	('AMP', 'Chemical', 'MESH:D000249', (46, 49))	('downregulates', 'NegReg', (147, 160))	('AMPK', 'molecular_function', 'GO:0050405', ('46', '50'))	('LKB1', 'Gene', (31, 35))	('b', 'Chemical', 'MESH:D001895', (101, 102))	('loss', 'Var', (23, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('dasatinib', 'Chemical', 'MESH:D000069439', (93, 102))	('AMPK', 'molecular_function', 'GO:0004691', ('46', '50'))	('b', 'Chemical', 'MESH:D001895', (161, 162))	('p70S6K', 'Gene', (166, 172))	('Akt', 'Gene', (177, 180))	('LKB1', 'Gene', '6794', (31, 35))	('AMPK', 'molecular_function', 'GO:0047322', ('46', '50'))	('Akt', 'Gene', '207', (177, 180))	('cellular stress', 'MPA', (127, 142))	('AMPK activation', 'MPA', (46, 61))	('p70S6K', 'Gene', '6198', (166, 172))
72704	27933314	As gap junctions and TNTs are not mutually exclusive, but rather play complementary roles spatially for cells in close proximity or located at a distance away from each other, with communication most efficiently facilitated by gap junctions and TNTs, respectively.	('communication', 'MPA', (181, 194))	('TNTs', 'Chemical', '-', (245, 249))	('facilitated', 'Reg', (212, 223))	('TNTs', 'Chemical', '-', (21, 25))	('gap junctions', 'Var', (227, 240))
72709	27933314	Apoptosis was measured using terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay in the bottom chamber to assess whether TNT-mediated transfer of NV1066 and GCV affected the bystander effect (Figure 2b).	('terminal deoxynucleotidyl transferase', 'Gene', (29, 66))	('affected', 'Reg', (179, 187))	('NV1066', 'Var', (164, 170))	('terminal deoxynucleotidyl transferase', 'Gene', '1791', (29, 66))	('Apoptosis', 'CPA', (0, 9))	('GCV', 'Chemical', 'MESH:D015774', (175, 178))	('TNT', 'Chemical', '-', (139, 142))
72711	27933314	Additionally, adding GCV with NV1066 (positive control) to the bottom well significantly increased apoptosis further to 95%; notably, while the percentage cell death increased by 10-15%, it still did not induce 100% cell death.	('NV1066', 'Var', (30, 36))	('cell death', 'biological_process', 'GO:0008219', ('155', '165'))	('cell death', 'biological_process', 'GO:0008219', ('216', '226'))	('increased', 'PosReg', (89, 98))	('apoptosis', 'CPA', (99, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('GCV', 'Chemical', 'MESH:D015774', (21, 24))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))
72713	27933314	Together, these data strongly suggest that NV1066-infected donor cells in the top chamber caused viral TK-induced activation of GCV, which then was transferred to recipient cells in the bottom well via TNTs.	('activation', 'PosReg', (114, 124))	('GCV', 'Chemical', 'MESH:D015774', (128, 131))	('donor', 'Species', '9606', (59, 64))	('TNTs', 'Chemical', '-', (202, 206))	('NV1066-infected', 'Var', (43, 58))	('GCV', 'Protein', (128, 131))
72721	27933314	In our assay, CytoB was added at the same time as NV1066 virus; as compared with no drug, the addition of CytoB led to >50% reduction in cell death; the increase in amount of cell death when GCV was also added was minimal, indicating that the role of potential non-TNT transfer of viral TK-activated GCV through the membrane filter was minimal.	('GCV', 'Chemical', 'MESH:D015774', (300, 303))	('reduction', 'NegReg', (124, 133))	('cell death', 'CPA', (175, 185))	('GCV', 'Chemical', 'MESH:D015774', (191, 194))	('cell death', 'biological_process', 'GO:0008219', ('137', '147'))	('CytoB', 'Var', (106, 111))	('TNT', 'Chemical', '-', (265, 268))	('cell death', 'CPA', (137, 147))	('addition', 'Var', (94, 102))	('cell death', 'biological_process', 'GO:0008219', ('175', '185'))	('membrane', 'cellular_component', 'GO:0016020', ('316', '324'))
72722	27933314	Cell killing at 48 hours was significantly decreased when CytoB was added to the top chamber containing NV1066 alone (30 versus 11%; P = 0.0016) or both NV1066 and GCV (18 versus 71%; P = 0.002; Figure 3).	('Cell killing at 48 hours', 'CPA', (0, 24))	('NV1066', 'Var', (104, 110))	('GCV', 'Chemical', 'MESH:D015774', (164, 167))	('decreased', 'NegReg', (43, 52))	('NV1066', 'Var', (153, 159))
72723	27933314	These findings indicate that abrogation of TNTs reduced transfer of activated GCV to noninfected mesothelioma cells.	('abrogation', 'Var', (29, 39))	('TNTs', 'Gene', (43, 47))	('reduced', 'NegReg', (48, 55))	('GCV', 'Chemical', 'MESH:D015774', (78, 81))	('TNTs', 'Chemical', '-', (43, 47))	('infected mesothelioma', 'Disease', (88, 109))	('infected mesothelioma', 'Disease', 'MESH:D008654', (88, 109))	('transfer', 'MPA', (56, 64))
72724	27933314	The difference between NV1066 to the top chamber (30% cell death) and addition of NV1066 + GCV (~75%) was striking and statistically significant (P = 0.0007).	('NV1066 +', 'Var', (82, 90))	('cell death', 'biological_process', 'GO:0008219', ('54', '64'))	('NV1066', 'Var', (23, 29))	('GCV', 'Chemical', 'MESH:D015774', (91, 94))
72726	27933314	Our study demonstrates for the first time that TNTs provide an effective and previously undemonstrated alternate route for long-range cellular therapeutic drug delivery through amplification of the bystander effect following oncolytic viral treatment and activation through phosphorylation of a viral TK-activated drug (the nucleoside analog GCV).	('phosphorylation', 'biological_process', 'GO:0016310', ('274', '289'))	('TNTs', 'Chemical', '-', (47, 51))	('phosphorylation', 'Var', (274, 289))	('GCV', 'Chemical', 'MESH:D015774', (342, 345))	('nucleoside', 'Chemical', 'MESH:D009705', (324, 334))	('amplification', 'PosReg', (177, 190))	('activation', 'PosReg', (255, 265))
72732	27933314	The "bystander effect" results not only in the death of cancer cells transduced by HSV-1 upon activation of the prodrug, but also in the death of surrounding uninfected cells.	('death of cancer', 'Disease', (47, 62))	('death of cancer', 'Disease', 'MESH:D003643', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('transduced', 'Var', (69, 79))	('HSV-1', 'Gene', (83, 88))	('HSV-1', 'Species', '10298', (83, 88))	('activation', 'PosReg', (94, 104))
72735	27933314	This triphosphorylated nucleoside can then be incorporated into DNA during nucleic acid synthesis to induce chain termination, resulting in apoptosis.	('nucleoside', 'Chemical', 'MESH:D009705', (23, 33))	('resulting in', 'Reg', (127, 139))	('apoptosis', 'CPA', (140, 149))	('nucleic acid', 'cellular_component', 'GO:0005561', ('75', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('synthesis', 'biological_process', 'GO:0009058', ('88', '97'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('chain', 'Var', (108, 113))
72739	27933314	Our group has previously demonstrated that the NV1066 viral vector can induce apoptosis in neighboring, uninfected cancer cells; in light of the results reported here, it is very plausible that the mechanism for this effect was through direct cell-to-cell communication via TNT connections, and that inhibiting apoptosis may further improve the efficacy of the TNT-mediated bystander effect.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('TNT', 'Chemical', '-', (274, 277))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('NV1066', 'Var', (47, 53))	('apoptosis', 'CPA', (78, 87))	('cell communication', 'biological_process', 'GO:0007154', ('251', '269'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('311', '320'))	('TNT', 'Chemical', '-', (361, 364))	('uninfected cancer', 'Disease', (104, 121))	('uninfected cancer', 'Disease', 'MESH:D009369', (104, 121))	('apoptosis', 'biological_process', 'GO:0006915', ('311', '320'))
72755	27933314	Briefly, this virus is derived from the wild-type HSV-1 F-strain backbone, with single copy deletions of ICP-4, ICP-0, and gamma1-34.5 that increase tumor selectivity and decrease virulence.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('virulence', 'MPA', (180, 189))	('decrease', 'NegReg', (171, 179))	('ICP-4', 'Gene', (105, 110))	('virulence', 'biological_process', 'GO:0016032', ('180', '189'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('virulence', 'biological_process', 'GO:0009406', ('180', '189'))	('HSV-1', 'Species', '10298', (50, 55))	('tumor', 'Disease', (149, 154))	('virulence', 'biological_process', 'GO:0009405', ('180', '189'))	('increase', 'PosReg', (140, 148))	('deletions', 'Var', (92, 101))
72842	26845118	The greatest hazard ratio (HR) was seen for sarcomatoid mesothelioma (3.00 times higher risk of death than epithelioid mesothelioma), for platelet count > 450.000 mm3 (2.02 times greater than lower platelet count) and for patients with ECOG PS of >= 2 (1.88 times greater than good PS).	('patients', 'Species', '9606', (222, 230))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (44, 68))	('death than epithelioid mesothelioma', 'Disease', (96, 131))	('> 450.000 mm3', 'Var', (153, 166))	('death than epithelioid mesothelioma', 'Disease', 'MESH:D008654', (96, 131))	('sarcomatoid mesothelioma', 'Disease', (44, 68))	('lower platelet count', 'Phenotype', 'HP:0001873', (192, 212))
72847	26845118	Increased number of lymphocytes (> 1.4 K/mcL) was associated with clinical benefit from chemotherapy (p=0.010): 67% of patients with lymphocytes > 1.4 K/mcL vs 46% of patients with lymphocytes < 1.4 K/mcL demonstrated clinical benefit and received more than 2 cycles of chemotherapy.	('mcL', 'Gene', (153, 156))	('lymphocytes', 'Var', (133, 144))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (167, 175))	('mcL', 'Gene', '338339', (41, 44))	('mcL', 'Gene', (41, 44))	('Increased number of lymphocytes', 'Phenotype', 'HP:0100827', (0, 31))	('mcL', 'Gene', '338339', (201, 204))	('clinical benefit', 'CPA', (218, 234))	('mcL', 'Gene', (201, 204))	('mcL', 'Gene', '338339', (153, 156))
72881	26090445	The number of micronuclei in lung epithelial cells increases upon exposure to MWCNTs, which is indicative of genotoxicity such as chromosomal damage or mitotic spindle disruption.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('increases', 'PosReg', (51, 60))	('MWCNTs', 'Var', (78, 84))	('micronuclei', 'CPA', (14, 25))	('MWCNT', 'Chemical', '-', (78, 83))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('152', '167'))	('chromosomal damage', 'Disease', 'MESH:D004194', (130, 148))	('chromosomal damage', 'Disease', (130, 148))
72913	26090445	Human normal bronchial epithelial and mesothelial cells also showed MWNT-7 internalization and cytotoxicity dependent on MWNT-7, which accumulated in the lysosome in excessive concentrations.	('Human', 'Species', '9606', (0, 5))	('lysosome', 'cellular_component', 'GO:0005764', ('154', '162'))	('MWNT-7', 'Var', (121, 127))	('cytotoxicity', 'Disease', (95, 107))	('MWNT-7', 'Gene', (68, 74))	('cytotoxicity', 'Disease', 'MESH:D064420', (95, 107))	('internalization', 'MPA', (75, 90))
72922	26090445	The SSC ratios of the control, which was not pretreated by inhibitors in BEAS-2B and MESO-1 cells, were 1.355-1.426 and 1.137-1.258 in 2 h, respectively.	('MESO-1', 'CellLine', 'CVCL:5759', (85, 91))	('SSC ratios', 'MPA', (4, 14))	('inhibitors', 'Var', (59, 69))	('BEAS-2B', 'CellLine', 'CVCL:0168', (73, 80))	('BEAS-2B', 'Gene', (73, 80))
72965	17411443	Our major aim was to identify biological mechanisms, common to different kinds of cancer that involve genes and gene expression changes inducing poor outcomes, e.g.	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('changes', 'Var', (128, 135))
73011	17411443	Dysregulation of ANXA2 has been reported in human bone cancer metastases and is correlated with the clinical prognosis of prostate cancer.	('human', 'Species', '9606', (44, 49))	('correlated', 'Reg', (80, 90))	('bone cancer metastases', 'Disease', (50, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('Dysregulation', 'Var', (0, 13))	('ANXA2', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bone cancer metastases', 'Disease', 'MESH:D009362', (50, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('prostate cancer', 'Disease', (122, 137))	('reported', 'Reg', (32, 40))	('ANXA2', 'Gene', '302', (17, 22))
73023	17411443	Our results support the anti-angiogenic hypothesis concerning polymeric FN1 and ANXA2 and suggest more candidate markers.	('ANXA2', 'Gene', '302', (80, 85))	('polymeric', 'Var', (62, 71))	('FN1', 'Gene', '2335', (72, 75))	('ANXA2', 'Gene', (80, 85))	('FN1', 'Gene', (72, 75))	('anti-angiogenic', 'CPA', (24, 39))
73094	30560130	For tumor inoculation, mice were injected subcutaneously in the right flank with 5 x 105 AE17 or AE17sOVA tumor cells per mouse, in 100 mul of PBS.	('tumor', 'Disease', (4, 9))	('mouse', 'Species', '10090', (122, 127))	('tumor inoculation', 'Disease', (4, 21))	('PBS', 'Chemical', 'MESH:D007854', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('AE17', 'Var', (89, 93))	('AE17sOVA', 'Var', (97, 105))	('mice', 'Species', '10090', (23, 27))	('tumor', 'Disease', (106, 111))	('tumor inoculation', 'Disease', 'MESH:D002372', (4, 21))
73109	30560130	Samples stained with TGF-beta-biotin were incubated with streptavidin-V500 (diluted in FACS buffer + 0.1% saponin) for 30 min at 4 C in the dark, followed by two washes using FACS buffer, and resuspended in 200 mul of FACS buffer per well.	('FACS', 'Gene', '14081', (175, 179))	('FACS', 'Gene', (87, 91))	('FACS', 'Gene', '14081', (87, 91))	('saponin', 'Chemical', 'MESH:D012503', (106, 113))	('beta-biotin', 'Chemical', 'MESH:D001710', (25, 36))	('FACS', 'Gene', (218, 222))	('FACS', 'Gene', '14081', (218, 222))	('TGF-beta-biotin', 'Var', (21, 36))	('FACS', 'Gene', (175, 179))
73130	30560130	In contrast, mesothelioma increased MHC-II+ and CD80+CD11c+ cells in TDLNs, relative to age-matched healthy LNs (Supplementary Figure S2A).	('MHC-II', 'Gene', (36, 42))	('CD80+CD11c+', 'Var', (48, 59))	('mesothelioma', 'Disease', (13, 25))	('increased MHC', 'Phenotype', 'HP:0025548', (26, 39))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('MHC-II', 'Gene', '111364', (36, 42))	('increased', 'PosReg', (26, 35))
73145	30560130	Examination of regulatory markers showed that IL-10+CD11c+ cells increased (Supplementary Figure S4C), whilst CD39+, PD-L1+, and TGF-beta+ CD11c+ cells decreased in elderly tumors (Supplementary Figure S4C).	('increased', 'PosReg', (65, 74))	('decreased', 'NegReg', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('CD39+', 'Var', (110, 115))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('IL-10', 'molecular_function', 'GO:0005141', ('46', '51'))
73148	30560130	Reduced IFN-gamma was seen in CD8+ (Figures 4C,D) and CD4+ T cells (Figure 4C) in elderly tumors compared to young tumors implying reduced anti-tumor effector T cell activity with age.	('tumor', 'Disease', (115, 120))	('reduced', 'NegReg', (131, 138))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('CD8', 'Gene', '925', (30, 33))	('tumor', 'Disease', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('CD4+', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (144, 149))	('reduced anti-tumor effector T cell activity', 'Phenotype', 'HP:0031402', (131, 174))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Reduced', 'NegReg', (0, 7))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CD8', 'Gene', (30, 33))	('IFN-gamma', 'MPA', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
73159	30560130	Importantly, IL-2/CD40 reduced expression of a number of regulatory markers on young and elderly TDLN CD11c+ cells including: CD73 (Figure 6A), TGF-beta (Figure 6A), CD39 (Supplementary Figure S6C) and IL-10 (Supplementary Figure S6C), relative to age-matched untreated tumor-bearing mice.	('IL-10', 'molecular_function', 'GO:0005141', ('202', '207'))	('IL-2/CD40', 'Var', (13, 22))	('CD73', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('expression', 'MPA', (31, 41))	('TGF-beta', 'Gene', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('reduced', 'NegReg', (23, 30))	('mice', 'Species', '10090', (284, 288))	('IL-10', 'Gene', (202, 207))	('CD39', 'Gene', (166, 170))	('tumor', 'Disease', (270, 275))	('IL-2', 'molecular_function', 'GO:0005134', ('13', '17'))
73163	30560130	In contrast, CD40 on TDLN CD11c+ cells reduced (Figure 6B) in elderly, compared to young, IL-2/CD40-treated mice.	('IL-2', 'molecular_function', 'GO:0005134', ('90', '94'))	('CD40', 'Var', (13, 17))	('reduced', 'NegReg', (39, 46))	('mice', 'Species', '10090', (108, 112))
73179	30560130	Taken together, elderly TDLN CD4+ T cells also demonstrate an enhanced regulatory status during IL-2/CD40 treatment, which may contribute to the reduced efficacy of IL-2/CD40 in elderly mice.	('IL-2', 'molecular_function', 'GO:0005134', ('165', '169'))	('regulatory status', 'MPA', (71, 88))	('IL-2/CD40', 'Var', (96, 105))	('enhanced', 'PosReg', (62, 70))	('mice', 'Species', '10090', (186, 190))	('IL-2', 'molecular_function', 'GO:0005134', ('96', '100'))
73184	30560130	Concurrently, IL-2/CD40 reduced expression of several regulatory markers on young CD11c+ cells including: CD39 (Supplementary Figure S7C), A2AR (Supplementary Figure S7D), A2BR (Figure 9A) and PD-L1 (Supplementary Figure S7D), yet expression of CD73 increased (Supplementary Figure S7D), relative to PBS controls.	('CD73', 'Gene', (245, 249))	('PD-L1', 'Gene', (193, 198))	('CD39', 'Gene', (106, 110))	('reduced', 'NegReg', (24, 31))	('IL-2/CD40', 'Var', (14, 23))	('A2BR', 'Gene', (172, 176))	('A2BR', 'Gene', '11541', (172, 176))	('PBS', 'Chemical', 'MESH:D007854', (300, 303))	('increased', 'PosReg', (250, 259))	('expression', 'MPA', (32, 42))	('IL-2', 'molecular_function', 'GO:0005134', ('14', '18'))	('A2AR', 'Gene', (139, 143))	('expression', 'MPA', (231, 241))
73187	30560130	Examination of tumor-associated T cells showed that IL-2/CD40 reduced young, but not elderly, CD4+ T cell (Supplementary Figure S8A) and Treg proportions (Supplementary Figure S8A), leaving elevated Treg proportions in elderly IL-2/CD40-treated tumors (Supplementary Figure S8A), implying increased suppressive activity in elderly tumors.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('Treg', 'Chemical', '-', (137, 141))	('IL-2', 'molecular_function', 'GO:0005134', ('52', '56'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Treg proportions', 'CPA', (137, 153))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('Treg proportions', 'CPA', (199, 215))	('Treg', 'Chemical', '-', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('tumors', 'Disease', (245, 251))	('reduced', 'NegReg', (62, 69))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (245, 250))	('IL-2', 'molecular_function', 'GO:0005134', ('227', '231'))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumors', 'Disease', (331, 337))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('elevated', 'PosReg', (190, 198))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', (331, 336))	('tumors', 'Disease', 'MESH:D009369', (331, 337))	('IL-2/CD40-treated', 'Var', (227, 244))
73192	30560130	Unexpectedly, IL-2/CD40 promoted a more regulatory phenotype in young tumor-associated CD8+ T cells, on account of increases in several regulatory markers, relative to PBS controls, specifically: CD39, A2AR, A2BR, ICOS, LAG-3, and PD-1 (Supplementary Figures S8B,C).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('A2BR', 'Gene', '11541', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CD39', 'Var', (196, 200))	('IL-2/CD40', 'Var', (14, 23))	('PBS', 'Chemical', 'MESH:D007854', (168, 171))	('tumor', 'Disease', (70, 75))	('increases', 'PosReg', (115, 124))	('A2BR', 'Gene', (208, 212))	('promoted', 'PosReg', (24, 32))	('CD8', 'Gene', (87, 90))	('CD8', 'Gene', '925', (87, 90))	('IL-2', 'molecular_function', 'GO:0005134', ('14', '18'))	('regulatory phenotype', 'MPA', (40, 60))	('more', 'PosReg', (35, 39))	('A2AR', 'MPA', (202, 206))
73203	30560130	Significantly reduced SIINFEKL-specific lytic activity was observed in TDLNs (Figure 11A) and tumors (Figure 11B) of elderly IL-2/CD40-treated and PBS control mice, relative to their younger counterparts.	('reduced', 'NegReg', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TDLNs', 'CPA', (71, 76))	('mice', 'Species', '10090', (159, 163))	('PBS', 'Chemical', 'MESH:D007854', (147, 150))	('IL-2', 'molecular_function', 'GO:0005134', ('125', '129'))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('SIINFEKL-specific', 'CPA', (22, 39))	('IL-2/CD40-treated', 'Var', (125, 142))
73204	30560130	IL-2/CD40 induced increased trends for CTL activity in young TDLNs (p = 0.08; Figure 11A) and tumors (p = 0.1; Figure 11B) whilst no increase in CTL activity was observed in elderly IL-2/CD40-treated mice, relative to PBS controls (Figures 11A,B).	('IL-2', 'molecular_function', 'GO:0005134', ('0', '4'))	('IL-2/CD40', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PBS', 'Chemical', 'MESH:D007854', (218, 221))	('IL-2', 'molecular_function', 'GO:0005134', ('182', '186'))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('mice', 'Species', '10090', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('CTL activity', 'MPA', (39, 51))
73211	30560130	There are several mechanisms by which pDCs induce immune suppression, including: (i) inducing Th1 cell anergy and apoptosis via indoleamine 2,3-dioxygenase (IDO), (ii) inhibiting Th1 cell proliferation via granzyme B, and (iii) promoting suppressive Treg expansion via IDO and/or expression of ICOS ligand (ICOS-L), which binds ICOS expressed on Tregs, leading to Treg activation and IL-10 secretion.	('activation', 'PosReg', (369, 379))	('ICOS ligand', 'Gene', '50723', (294, 305))	('ligand', 'molecular_function', 'GO:0005488', ('299', '305'))	('Th1', 'Gene', (94, 97))	('Treg', 'Chemical', '-', (250, 254))	('promoting', 'PosReg', (228, 237))	('IDO', 'molecular_function', 'GO:0033754', ('269', '272'))	('IDO', 'molecular_function', 'GO:0033754', ('157', '160'))	('cell proliferation', 'biological_process', 'GO:0008283', ('183', '201'))	('IDO', 'Gene', (269, 272))	('IL-10', 'molecular_function', 'GO:0005141', ('384', '389'))	('IDO', 'Gene', '15930', (269, 272))	('ICOS ligand', 'Gene', (294, 305))	('granzyme B', 'Gene', (206, 216))	('inhibiting', 'NegReg', (168, 178))	('IL-10 secretion', 'biological_process', 'GO:0072608', ('384', '399'))	('suppressive Treg expansion', 'CPA', (238, 264))	('IDO', 'Gene', (157, 160))	('Treg', 'Chemical', '-', (364, 368))	('IDO', 'molecular_function', 'GO:0047719', ('157', '160'))	('IDO', 'molecular_function', 'GO:0047719', ('269', '272'))	('IDO', 'Gene', '15930', (157, 160))	('granzyme B', 'Gene', '14939', (206, 216))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('Treg', 'CPA', (364, 368))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('apoptosis', 'CPA', (114, 123))	('pDCs', 'Var', (38, 42))	('ICOS-L', 'Gene', '50723', (307, 313))	('ICOS-L', 'Gene', (307, 313))	('Treg', 'Chemical', '-', (346, 350))	('indoleamine 2,3-dioxygenase', 'Gene', '15930', (128, 155))	('inducing', 'PosReg', (85, 93))	('Th1 cell proliferation', 'CPA', (179, 201))	('IL-10 secretion', 'CPA', (384, 399))
73217	30560130	Increased CD73 on elderly CD11c+ cells represents another mechanism of T cell suppression as it indicates increased capacity to produce immunosuppressive adenosine, particularly if neighboring cells express CD39, such as the concomitant increase in CD39 expression we observed on elderly TDLN T cells.	('CD39', 'Gene', (249, 253))	('produce immunosuppressive adenosine', 'MPA', (128, 163))	('expression', 'MPA', (254, 264))	('CD73', 'Gene', (10, 14))	('adenosine', 'Chemical', 'MESH:D000241', (154, 163))	('LN T', 'CellLine', 'CVCL:F127', (290, 294))	('increased', 'PosReg', (106, 115))	('CD39', 'Var', (207, 211))
73232	30560130	Generation of anti-tumor Th1 responses within elderly tumors may be further compromised due to reduced CD4+ T cells and CD11b+CD8alpha-CD4+ cDCs whose main role is activation of Th1 responses.	('CD8alpha', 'Gene', '12525', (126, 134))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('CD8alpha', 'Gene', (126, 134))	('CD4+', 'Var', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('reduced CD4+ T', 'Phenotype', 'HP:0005407', (95, 109))	('tumor', 'Disease', (19, 24))	('reduced', 'NegReg', (95, 102))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('CD11b', 'Gene', (120, 125))	('tumors', 'Disease', (54, 60))	('CD11b', 'Gene', '16409', (120, 125))
73237	30560130	This is supported by this study showing that elderly tumor-associated CD8+ and CD4+ T cells had reduced IFN-gamma, implying reduced effector activity.	('reduced', 'NegReg', (124, 131))	('effector activity', 'CPA', (132, 149))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CD4+', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CD8', 'Gene', (70, 73))	('tumor', 'Disease', (53, 58))	('CD8', 'Gene', '925', (70, 73))	('IFN-gamma', 'MPA', (104, 113))	('reduced', 'NegReg', (96, 103))
73253	30560130	Moreover, elderly TDLN CD8+ and CD4+ T cells may be more suppressive/exhausted and more responsive to negative signals from antigen-presenting cells, as age-related increases in CTLA-4, ICOS, TGF-beta, A2AR, CD39, LAG-3, and/or PD-1 were further enhanced during IL-2/CD40 treatment.	('PD-1', 'Gene', (228, 232))	('increases', 'PosReg', (165, 174))	('enhanced', 'PosReg', (246, 254))	('CD8', 'Gene', (23, 26))	('A2AR', 'Gene', (202, 206))	('CD8', 'Gene', '925', (23, 26))	('IL-2/CD40', 'Var', (262, 271))	('suppressive/exhausted', 'MPA', (57, 78))	('LAG-3', 'Gene', (214, 219))	('IL-2', 'molecular_function', 'GO:0005134', ('262', '266'))	('TGF-beta', 'Gene', (192, 200))	('CD39', 'Gene', (208, 212))	('CTLA-4', 'Gene', (178, 184))	('ICOS', 'Gene', (186, 190))
73255	30560130	As previous studies from our laboratory have shown that CD8+ T cells and perforin-associated effector function are important for IL-2/CD40-mediated tumor regression in young mice, this likely contributes to poorer tumor responses by elderly mice to IL-2/CD40.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (148, 153))	('mice', 'Species', '10090', (241, 245))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('IL-2', 'molecular_function', 'GO:0005134', ('129', '133'))	('IL-2', 'molecular_function', 'GO:0005134', ('249', '253'))	('tumor', 'Disease', (214, 219))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('IL-2/CD40-mediated', 'Var', (129, 147))
73257	30560130	Specifically, IL-2/CD40 reduced expression of several regulatory molecules (CD39, A2AR, A2BR, PD-L1, ICOS, and/or IL-10) on young tumor-infiltrating CD11c+ cells and CD4+ T cells, suggesting reduced suppressive activity.	('tumor', 'Disease', (130, 135))	('IL-10', 'Gene', (114, 119))	('PD-L1', 'Gene', (94, 99))	('expression', 'MPA', (32, 42))	('A2AR', 'Gene', (82, 86))	('reduced', 'NegReg', (24, 31))	('IL-2/CD40', 'Var', (14, 23))	('reduced', 'NegReg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('IL-2', 'molecular_function', 'GO:0005134', ('14', '18'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('suppressive activity', 'CPA', (199, 219))	('A2BR', 'Gene', '11541', (88, 92))	('IL-10', 'molecular_function', 'GO:0005141', ('114', '119'))	('CD39', 'Gene', (76, 80))	('A2BR', 'Gene', (88, 92))	('ICOS', 'Gene', (101, 105))
73267	30560130	Furthermore, the age-related suppressive status of elderly TDLN CD11c+ cells and T cells was exacerbated during IL-2/CD40 immunotherapy, which may have contributed to its reduced efficacy in elderly mice with mesothelioma.	('mesothelioma', 'Disease', (209, 221))	('mice', 'Species', '10090', (199, 203))	('exacerbated', 'PosReg', (93, 104))	('IL-2', 'molecular_function', 'GO:0005134', ('112', '116'))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('suppressive status', 'MPA', (29, 47))	('IL-2/CD40', 'Var', (112, 121))
73352	23550303	Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome, characterized, at least in the affected families studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (274, 286))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('mutated', 'Var', (219, 226))	('cancers', 'Disease', 'MESH:D009369', (347, 354))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('uveal melanoma', 'Disease', (288, 302))	('benign melanocytic skin tumours', 'Disease', (182, 213))	('BAP1', 'Gene', (39, 43))	('cause', 'Reg', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('early age of benign melanocytic skin', 'Phenotype', 'HP:0007396', (169, 205))	('cancers', 'Phenotype', 'HP:0002664', (347, 354))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('cancers', 'Disease', (347, 354))	('germline', 'Var', (30, 38))	('benign melanocytic skin tumours', 'Disease', 'MESH:D012878', (182, 213))	('melanoma', 'Phenotype', 'HP:0002861', (314, 322))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (227, 231))	('mutations', 'Var', (44, 53))	('cancer syndrome', 'Disease', (68, 83))	('cutaneous melanoma', 'Disease', (304, 322))	('mesothelioma', 'Disease', (274, 286))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (304, 322))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (304, 322))
73359	23550303	Chromosome microarray and genetic linkage analyses on the L and W families implicated chromosome region 3p21, a locus frequently altered in both UVM and mesotheliomas.	('UVM', 'Disease', (145, 148))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('chromosome region 3p21', 'Var', (86, 108))	('mesotheliomas', 'Disease', 'MESH:D008654', (153, 166))	('chromosome region', 'cellular_component', 'GO:0098687', ('86', '103'))	('mesotheliomas', 'Disease', (153, 166))
73360	23550303	Sequencing this region of chromosome 3 led to the identification of BAP1 as the gene mutated and associated with high rates of mesothelioma in the L and W families (experiments are in progress to address whether BAP1 also causes the high incidence of mesothelioma in Cappadocia).	('mesothelioma in Cappadocia', 'Disease', (251, 277))	('mesothelioma', 'Disease', (127, 139))	('mesothelioma', 'Disease', (251, 263))	('BAP1', 'Var', (212, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('mesothelioma in Cappadocia', 'Disease', 'MESH:D008654', (251, 277))	('mesothelioma', 'Disease', 'MESH:D008654', (251, 263))	('associated', 'Reg', (97, 107))	('BAP1', 'Gene', (68, 72))	('causes', 'Reg', (222, 228))
73361	23550303	BAP1 is a member of the ubiquitin C-terminal hydrolases (UCH) subfamily of deubiquitylating enzymes (DUBs) and was mutated in each family member who had developed mesothelioma, UVM and other cancers.	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('mutated', 'Var', (115, 122))	('mesothelioma', 'Disease', (163, 175))	('UVM', 'Disease', (177, 180))	('developed', 'PosReg', (153, 162))	('ubiquitin C', 'Gene', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('ubiquitin', 'molecular_function', 'GO:0031386', ('24', '33'))	('ubiquitin C', 'Gene', '7316', (24, 35))
73362	23550303	None of these tumour types was detected in family members who did not carry BAP1 mutations.	('tumour', 'Disease', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('tumour', 'Disease', 'MESH:D009369', (14, 20))
73363	23550303	Moreover, among several cases of sporadic mesotheliomas, we found that 2/26 patients had germline BAP1 mutations and importantly we found that both of these patients had been previously diagnosed with UVM.	('BAP1', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (76, 84))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (33, 55))	('sporadic mesotheliomas', 'Disease', (33, 55))	('patients', 'Species', '9606', (157, 165))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (33, 55))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (33, 54))
73365	23550303	On the basis of these findings, we have proposed that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma and UVM.	('cause', 'Reg', (78, 83))	('cancer syndrome', 'Disease', (90, 105))	('UVM', 'Disease', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('mutations', 'Var', (68, 77))	('cancer syndrome', 'Disease', 'MESH:D009369', (90, 105))	('germline', 'Var', (54, 62))	('mesothelioma', 'Disease', (123, 135))
73366	23550303	In this Progress article, we discuss this potential inherited cancer syndrome, the possible mechanisms through which mutations in BAP1 might lead to tumour development and the clinical implications raised by detection of germline BAP1 mutations.	('mutations', 'Var', (117, 126))	('BAP1', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('lead to', 'Reg', (141, 148))	('cancer syndrome', 'Disease', 'MESH:D009369', (62, 77))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('cancer syndrome', 'Disease', (62, 77))	('tumour', 'Disease', (149, 155))
73367	23550303	reported that germline BAP1 mutations caused benign atypical melanocytic tumours.	('BAP1', 'Gene', (23, 27))	('melanocytic tumours', 'Disease', 'MESH:D009508', (61, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('melanocytic tumours', 'Disease', (61, 80))	('mutations', 'Var', (28, 37))	('caused', 'Reg', (38, 44))
73370	23550303	They studied 32 sporadic ASTs and found that 9 had loss of BAP1 expression and 8 of these had concomitant BRAF mutations.	('mutations', 'Var', (111, 120))	('expression', 'MPA', (64, 74))	('BAP1', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('loss', 'NegReg', (51, 55))
73371	23550303	Only 1 of 23 ASTs that expressed BAP1 had a BRAF mutation (P< 0.0001) .	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))	('BAP1', 'Gene', (33, 37))	('mutation', 'Var', (49, 57))
73372	23550303	BRAF mutations are common in melanocytic nevi (80%) and in cutaneous melanoma (65%) but are rare in ASTs.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (29, 45))	('common', 'Reg', (19, 25))	('BRAF', 'Gene', (0, 4))	('melanocytic', 'Disease', (29, 40))	('melanocytic', 'Disease', 'MESH:D009508', (29, 40))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))
73373	23550303	noted the same type of skin tumours arising in families with germline BAP1 mutations and referred to them as nevoid melanoma-like melanocytic proliferations (NEMMPs).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('skin tumours', 'Disease', 'MESH:D012878', (23, 35))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('skin tumours', 'Disease', (23, 35))	('melanoma-like melanocytic proliferations', 'Disease', (116, 156))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('melanoma-like melanocytic proliferations', 'Disease', 'MESH:D059545', (116, 156))
73377	23550303	We found that all the melanocytic tumors in these BAP1 mutant patients had the same histological and molecular characteristics.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('melanocytic tumors', 'Disease', 'MESH:D009508', (22, 40))	('mutant', 'Var', (55, 61))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', (50, 54))	('melanocytic tumors', 'Disease', (22, 40))
73378	23550303	In our review of the skin tumours in patients with mutant BAP1 we found that these are nevus-like lesions usually formed by a conventional junctional, compound or dermal nevus composed of small melanocytes expressing BAP1.	('patients', 'Species', '9606', (37, 45))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('BAP1', 'Gene', (58, 62))	('mutant', 'Var', (51, 57))	('skin tumours', 'Disease', 'MESH:D012878', (21, 33))	('skin tumours', 'Disease', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('nevus', 'Phenotype', 'HP:0003764', (87, 92))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
73379	23550303	Next to these conventional nevus cells there is a dermal lesion formed by large epithelioid BAP1 negative and most frequently BRAF mutated melanocytes with virtually no mitotic activity.	('mutated', 'Var', (131, 138))	('dermal lesion', 'Disease', (50, 63))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('nevus', 'Phenotype', 'HP:0003764', (27, 32))	('dermal lesion', 'Disease', 'MESH:D016136', (50, 63))
73381	23550303	Acknowledging that these lesions are characteristic of, although possibly not unique to, BAP1 mutation carriers, we proposed naming them melanocytic BAP1-mutated atypical intradermal tumours (MBAITs).	('melanocytic', 'Disease', 'MESH:D009508', (137, 148))	('melanocytic', 'Disease', (137, 148))	('BAP1', 'Gene', (89, 93))	('intradermal tumours', 'Disease', 'MESH:D018330', (171, 190))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('intradermal tumours', 'Disease', (171, 190))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('mutation', 'Var', (94, 102))
73385	23550303	reported inactivating mutations of BAP1 in 26 of 31 aggressive (class 2) UVMs, among which a germline mutation was found in 1 of 26 patients.	('inactivating mutations', 'Var', (9, 31))	('patients', 'Species', '9606', (132, 140))	('BAP1', 'Gene', (35, 39))
73388	23550303	In this family, there were 7 BAP1 mutation carriers (5 tested and two inferred) and only one was cancer free at age 55; the other six had developed UVM (2 cases), cutaneous melanoma, mesothelioma, meningioma, lung and other types of carcinoma.	('lung', 'Disease', (209, 213))	('carcinoma', 'Disease', (233, 242))	('meningioma', 'Disease', 'MESH:D008577', (197, 207))	('cancer', 'Disease', (97, 103))	('mutation', 'Var', (34, 42))	('mesothelioma', 'Disease', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('cutaneous melanoma', 'Disease', (163, 181))	('developed', 'PosReg', (138, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (163, 181))	('BAP1', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('meningioma', 'Disease', (197, 207))	('meningioma', 'Phenotype', 'HP:0002858', (197, 207))	('UVM', 'Disease', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
73392	23550303	Also, they found that 2 of 7 probands from families with UVM-cutaneous melanoma carried germline BAP1 mutations, compared to 1 of 193 probands from families with a history of cutaneous melanoma and no UVMs (p=0.003).	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('UVM-cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('UVM-cutaneous melanoma', 'Disease', (57, 79))	('cutaneous melanoma', 'Disease', (175, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))
73393	23550303	reported that 2 of 66 (3%) patients with UVM unselected for family history carried germline BAP1 mutations.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (27, 35))	('BAP1', 'Gene', (92, 96))
73394	23550303	Additional tumour types, including renal, breast and lung carcinomas were also found among BAP1 mutation carriers.	('BAP1', 'Gene', (91, 95))	('carriers', 'Reg', (105, 113))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('mutation', 'Var', (96, 104))	('renal', 'Disease', (35, 40))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('found', 'Reg', (79, 84))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (42, 68))	('tumour', 'Disease', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
73395	23550303	Very recently, BAP1 mutations have been reported in sporadic renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (61, 76))	('sporadic renal carcinoma', 'Disease', (52, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('sporadic renal carcinoma', 'Disease', 'MESH:C538614', (52, 76))	('reported', 'Reg', (40, 48))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
73396	23550303	Moreover, a novel inactivating germline splice mutation was reported in a family with UVM and cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cutaneous melanoma', 'Disease', (94, 112))	('UVM', 'Disease', (86, 89))	('inactivating germline splice mutation', 'Var', (18, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))
73398	23550303	To date, 53 of 76 BAP1 germline mutation carriers have developed malignancies; 13 of these 53 developed two or more cancers.	('germline mutation', 'Var', (23, 40))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('BAP1', 'Gene', (18, 22))	('developed', 'PosReg', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('malignancies', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
73401	23550303	In the BAP1 mutation families, there is an exceptionally high incidence of malignancy overall (69.74% cancer incidence among 76 mutation carriers).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', (7, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('mutation', 'Var', (12, 20))	('malignancy', 'Disease', (75, 85))
73403	23550303	All of the mutation carriers unaffected by cancer are younger than 55 years old and may develop malignancies later in life.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('cancer', 'Disease', (43, 49))	('malignancies', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (11, 19))	('develop', 'PosReg', (88, 95))
73404	23550303	However, the relatively high frequency in the general population of the carcinomas that develop in BAP1 mutation carriers does not allow us yet to distinguish with certainty if the association with carcinomas is causal.	('BAP1', 'Gene', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinomas', 'Disease', (72, 82))	('mutation', 'Var', (104, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('carcinomas', 'Disease', (198, 208))	('carcinomas', 'Disease', 'MESH:D002277', (198, 208))
73405	23550303	It should also be noted that population-based studies have shown that mutation carriers in the general population may have a lower risk than suggested by estimates obtained from families with multiple tumours, as for example observed for CDKN2A mutations.	('CDKN2A', 'Gene', (238, 244))	('multiple tumours', 'Disease', (192, 208))	('CDKN2A', 'Gene', '1029', (238, 244))	('mutations', 'Var', (245, 254))	('multiple tumours', 'Disease', 'MESH:D009369', (192, 208))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (70, 78))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
73406	23550303	Therefore, large population based studies will be required to validate the association of germline BAP1 mutations with the exceptionally high incidence of malignancies detected in the BAP1 mutant families.	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('mutant', 'Var', (189, 195))	('malignancies', 'Disease', 'MESH:D009369', (155, 167))	('BAP1', 'Gene', (184, 188))	('malignancies', 'Disease', (155, 167))	('association', 'Interaction', (75, 86))
73408	23550303	However, the Li-Fraumeni syndrome, caused by inherited mutations of the TP53 tumour suppressor gene, is an autosomal dominant cancer syndrome characteristically associated with the development of multiple tumour types .	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('caused by', 'Reg', (35, 44))	('Li-Fraumeni syndrome', 'Disease', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('multiple tumour', 'Disease', (196, 211))	('tumour', 'Disease', (205, 211))	('mutations', 'Var', (55, 64))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (107, 141))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('TP53', 'Gene', '7157', (72, 76))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('TP53', 'Gene', (72, 76))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (13, 33))	('autosomal dominant cancer syndrome', 'Disease', (107, 141))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('multiple tumour', 'Disease', 'MESH:D009369', (196, 211))
73413	23550303	Protein ubiquitylation was initially seen as a mechanism to label proteins for degradation; however, this notion has evolved as we have come to understand that ubiquitylation and DUBs regulate various cellular processes, including DNA repair, gene transcription, cell membrane trafficking, cell cycle progression, stress response, cell communication, differentiation and apoptosis, and that they have a role in cancer development.	('transcription', 'biological_process', 'GO:0006351', ('248', '261'))	('apoptosis', 'CPA', (371, 380))	('stress response', 'CPA', (314, 329))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cell membrane trafficking', 'CPA', (263, 288))	('cell communication', 'biological_process', 'GO:0007154', ('331', '349'))	('differentiation', 'CPA', (351, 366))	('role', 'Reg', (403, 407))	('cell cycle progression', 'CPA', (290, 312))	('DNA repair', 'MPA', (231, 241))	('cell cycle', 'biological_process', 'GO:0007049', ('290', '300'))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('cell membrane', 'cellular_component', 'GO:0005886', ('263', '276'))	('apoptosis', 'biological_process', 'GO:0097194', ('371', '380'))	('Protein ubiquitylation', 'biological_process', 'GO:0016567', ('0', '22'))	('cancer', 'Disease', (411, 417))	('apoptosis', 'biological_process', 'GO:0006915', ('371', '380'))	('degradation', 'biological_process', 'GO:0009056', ('79', '90'))	('regulate', 'Reg', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('ubiquitylation', 'Var', (160, 174))	('cell communication', 'CPA', (331, 349))	('cellular processes', 'CPA', (201, 219))	('DNA repair', 'biological_process', 'GO:0006281', ('231', '241'))	('gene transcription', 'CPA', (243, 261))
73420	23550303	Indeed, inhibition of BAP1 by short hairpin RNAs (shRNAs) impaired the DDR and caused HeLa cells to become hypersensitive to ionizing radiation resulting in S-phase retardation, a phenotype similar to BRCA1 deficiency.	('hypersensitive', 'Disease', (107, 121))	('HeLa', 'CellLine', 'CVCL:0030', (86, 90))	('hypersensitive to ionizing radiation', 'Phenotype', 'HP:0011133', (107, 143))	('hypersensitive', 'Disease', 'MESH:D004342', (107, 121))	('DDR', 'MPA', (71, 74))	('BRCA1 deficiency', 'Disease', 'OMIM:604370', (201, 217))	('S-phase', 'biological_process', 'GO:0051320', ('157', '164'))	('inhibition', 'Var', (8, 18))	('retardation', 'Disease', (165, 176))	('retardation', 'Disease', 'MESH:D008607', (165, 176))	('impaired', 'NegReg', (58, 66))	('BAP1', 'Gene', (22, 26))	('BRCA1 deficiency', 'Disease', (201, 217))
73424	23550303	Accordingly, NCI-H226 cells expressing exogenous wild-type BAP1 grew poorly in cell culture and when injected into athymic nude mice, they formed tumours that were about 10-15-fold smaller than those obtained with cells infected with vector alone or expressing BAP1 mutants lacking deubiquitylating activity (C91A substitution) or the second nuclear localization signal, NLS2, that is required for the nuclear compartmentalization of BAP1.	('lacking', 'NegReg', (274, 281))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('deubiquitylating activity', 'MPA', (282, 307))	('C91A', 'SUBSTITUTION', 'None', (309, 313))	('localization', 'biological_process', 'GO:0051179', ('350', '362'))	('BAP1', 'Gene', (261, 265))	('mutants', 'Var', (266, 273))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('NCI-H226', 'CellLine', 'CVCL:1544', (13, 21))	('nude mice', 'Species', '10090', (123, 132))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('C91A', 'Var', (309, 313))
73428	23550303	HCF1 is ubiquitylated on lysine residues, preferentially through K48-linked and K63-linked chains.	('HCF1', 'Gene', (0, 4))	('K63-linked chains', 'Var', (80, 97))	('preferentially', 'PosReg', (42, 56))	('K48-linked', 'Var', (65, 75))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
73439	23550303	PRC2 might also be important in tumours that have mutant BAP1.	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutant', 'Var', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('BAP1', 'Gene', (57, 61))
73441	23550303	proposed inhibiting PRC2 as a possible therapeutic strategy for treating mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('mesothelioma', 'Disease', (73, 85))	('inhibiting', 'Var', (9, 19))	('PRC2', 'Gene', (20, 24))
73451	23550303	In the tumours that develop in BAP1 mutant carriers, BAP1 expression is either absent because of loss of heterozygosity (LOH), resulting in biallelic inactivation, or the BAP1 protein is localized in the cytoplasm where it may retain DUB activity, with as yet unknown possible effects on the cellular 'ubiquitinome'.	('biallelic', 'MPA', (140, 149))	('absent', 'NegReg', (79, 85))	('expression', 'MPA', (58, 68))	('activity', 'MPA', (238, 246))	('tumours', 'Disease', (7, 14))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('BAP1', 'Gene', (31, 35))	('cytoplasm', 'cellular_component', 'GO:0005737', ('204', '213'))	('mutant', 'Var', (36, 42))	('heterozygosity', 'MPA', (105, 119))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('BAP1', 'Gene', (53, 57))
73452	23550303	Because germline BAP1 mutations are associated with mesotheliomas, UVMs and cutaneous melanomas, there should be some common pathways controlled by BAP1 that are of particular importance to the development of these malignancies.	('UVMs', 'Disease', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mesotheliomas', 'Disease', 'MESH:D008654', (52, 65))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('mesotheliomas', 'Disease', (52, 65))	('malignancies', 'Disease', (215, 227))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('cutaneous melanomas', 'Disease', (76, 95))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (36, 46))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))	('BAP1', 'Gene', (17, 21))
73453	23550303	The finding that somatic BAP1 mutations are common in these cancers supports this interpretation.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('BAP1', 'Gene', (25, 29))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('common', 'Reg', (44, 50))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
73454	23550303	Somatic BAP1 mutations were found in 84% of metastasizing UVM biopsies and in 22% and 23% of sporadic US mesothelioma biopsies.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('mesothelioma', 'Disease', (105, 117))	('found', 'Reg', (28, 33))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('metastasizing UVM', 'Disease', (44, 61))
73455	23550303	found somatic inactivating BAP1 mutations in 61% of Japanese mesothelioma biopsies.	('mesothelioma', 'Disease', 'MESH:D008654', (61, 73))	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (61, 73))
73456	23550303	Studies in mice revealed that Bap1 deletion is lethal during embryogenesis.	('embryogenesis', 'biological_process', 'GO:0009790', ('61', '74'))	('Bap1', 'Gene', (30, 34))	('embryogenesis', 'biological_process', 'GO:0009793', ('61', '74'))	('mice', 'Species', '10090', (11, 15))	('deletion', 'Var', (35, 43))	('embryogenesis', 'biological_process', 'GO:0009792', ('61', '74'))	('Bap1', 'Gene', '104416', (30, 34))
73460	23550303	We are presently testing the hypothesis that germline Bap1 mutations increase the susceptibility to mineral fibre-induced and UV light-induced carcinogenesis; this may explain the absence of mesothelioma and melanoma in mice that were not exposed to these carcinogens.	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('mice', 'Species', '10090', (220, 224))	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (191, 216))	('Bap1', 'Gene', '104416', (54, 58))	('mutations', 'Var', (59, 68))	('carcinogenesis', 'Disease', (143, 157))	('Bap1', 'Gene', (54, 58))	('susceptibility', 'MPA', (82, 96))
73464	23550303	In such an environment, an impaired DDR caused by BAP1 deletion, might be expected to favour the accumulation of genetic damage that eventually gives rise to a malignant clone.	('favour', 'PosReg', (86, 92))	('genetic damage', 'Disease', 'MESH:D030342', (113, 127))	('gives rise to', 'Reg', (144, 157))	('genetic damage', 'Disease', (113, 127))	('DDR', 'MPA', (36, 39))	('malignant clone', 'CPA', (160, 175))	('deletion', 'Var', (55, 63))	('BAP1', 'Gene', (50, 54))	('accumulation', 'MPA', (97, 109))
73466	23550303	Moreover, we found very minimal and Wiesner et al, found no evidence of exposure to asbestos or erionite among the patients who developed mesothelioma in the families with BAP1 mutations, findings that do not support gene-environment interaction in causing mesothelioma, at least in these families.	('patients', 'Species', '9606', (115, 123))	('mesothelioma', 'Disease', (257, 269))	('asbestos', 'Disease', (84, 92))	('BAP1', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('mesothelioma', 'Disease', (138, 150))	('asbestos', 'Disease', 'MESH:D001195', (84, 92))	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('erionite', 'Chemical', 'MESH:C083174', (96, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))
73470	23550303	Because BAP1 mutation carriers represent only a fraction of patients who develop UVM (3-4%), the overall association of UVM with UV light exposure should be re-evaluated in BAP1 mutations positive versus BAP1 mutation negative patients.	('mutation', 'Var', (13, 21))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (173, 177))	('patients', 'Species', '9606', (227, 235))
73473	23550303	We anticipate that as more studies uncover the precise mechanisms by which BAP1 mutations cause mesothelioma and melanomas, specific preventive and therapeutic approaches for these malignancies will be developed (Box 1).	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (96, 121))	('melanomas', 'Disease', (113, 122))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('malignancies', 'Disease', (181, 193))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('cause', 'Reg', (90, 95))
73474	23550303	It is worth noting that a recent paper showed that histone deacetylase inhibitors (HDACIs) impair the in vitro and in vivo growth of UVM metastatic tumours with BAP1 inactivating mutations.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('BAP1', 'Gene', (161, 165))	('inactivating mutations', 'Var', (166, 188))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('growth', 'CPA', (123, 129))	('impair', 'NegReg', (91, 97))	('UVM', 'Disease', (133, 136))
73475	23550303	The apparent ability of BAP1 mutations to cause multiple tumour types and the high tumour phenotype penetrance (Table 1) suggests that this gene has a major role in influencing cancer cell growth.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('BAP1', 'Gene', (24, 28))	('multiple tumour', 'Disease', 'MESH:D009369', (48, 63))	('mutations', 'Var', (29, 38))	('cause', 'Reg', (42, 47))	('high tumour', 'Disease', (78, 89))	('high tumour', 'Disease', 'MESH:D009369', (78, 89))	('multiple tumour', 'Disease', (48, 63))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
73483	23550303	Wiesner et al noted that in BAP1 mutation carriers benign melanocytic tumors develop during the second decade of life and their number increases with age, a finding confirmed in the BAP1 mutant families we are studying.	('mutation', 'Var', (33, 41))	('melanocytic tumors', 'Disease', 'MESH:D009508', (58, 76))	('BAP1', 'Gene', (28, 32))	('increases', 'PosReg', (135, 144))	('melanocytic tumors', 'Disease', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
73484	23550303	The occurrence of cutaneous melanoma in some BAP1 mutation carriers, including one that appeared to originate from these melanoctytic tumors, suggests that occasionally these benign tumors may undergo malignant transformation.	('melanoctytic tumors', 'Disease', (121, 140))	('melanoctytic tumors', 'Disease', 'MESH:D009369', (121, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('mutation', 'Var', (50, 58))
73485	23550303	This finding may account, at least in part, for the overall high risk of cutaneous melanoma detected among BAP1 germline mutation carriers (Table 1).	('cutaneous melanoma', 'Disease', (73, 91))	('germline mutation', 'Var', (112, 129))	('BAP1', 'Gene', (107, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
73488	23550303	Suspected MBAITs could be removed and tested to identify patients with BAP1 mutations.	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))
73492	23550303	Thus, the detection of families with inherited mutations of BAP1 offers opportunities for early cancer detection and more effective therapeutic approaches.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('BAP1', 'Gene', (60, 64))
73543	31316876	Pathogenic variants and mutations in genes including BRCA1, BRCA2, HOXB13 and mismatch repair genes confer modest to high life time risk of prostate cancer .	('HOXB13', 'Gene', (67, 73))	('variants', 'Var', (11, 19))	('mismatch repair', 'biological_process', 'GO:0006298', ('78', '93'))	('prostate cancer', 'Phenotype', 'HP:0012125', (140, 155))	('prostate cancer', 'Disease', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BRCA2', 'Gene', (60, 65))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA2', 'Gene', '675', (60, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (140, 155))	('BRCA1', 'Gene', (53, 58))	('HOXB13', 'Gene', '10481', (67, 73))
73544	31316876	Prostate cancer in carriers of BRCA pathogenic variants is associated with aggressive disease such as higher Gleason score, higher tumor stage and/or grade at diagnosis .	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('variants', 'Var', (47, 55))	('aggressive disease', 'Disease', 'MESH:D001523', (75, 93))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BRCA', 'Gene', '672', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Prostate cancer', 'Disease', (0, 15))	('aggressive disease', 'Disease', (75, 93))	('BRCA', 'Gene', (31, 35))	('higher', 'PosReg', (102, 108))	('associated', 'Reg', (59, 69))	('Gleason score', 'MPA', (109, 122))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))
73545	31316876	Studies have suggested that genetic susceptibility including germline BAP1 mutations is associated with increased risk of mesothelioma probably through modulating asbestos exposure or via gene-asbestos exposure interaction .	('mesothelioma', 'Disease', (122, 134))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (70, 74))	('asbestos', 'Chemical', 'MESH:D001194', (193, 201))	('asbestos', 'Chemical', 'MESH:D001194', (163, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('modulating', 'Reg', (152, 162))	('interaction', 'Interaction', (211, 222))
73547	31316876	They found that gene-asbestos interaction has significant association with risk of mesothelioma susceptibility.	('asbestos', 'Chemical', 'MESH:D001194', (21, 29))	('mesothelioma', 'Disease', (83, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('interaction', 'Var', (30, 41))	('association', 'Reg', (58, 69))
73548	31316876	Recurrent somatic mutations in a number of tumor suppressor genes (i.e., cyclin-dependent kinase inhibitor 2A gene [CDKN2A], neurofibromin 2 (merlin) gene [NF2], and BRCA1 associated protein 1 gene [BAP1]) have been associated with mesothelioma .	('associated', 'Reg', (216, 226))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('90', '106'))	('tumor', 'Disease', (43, 48))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (73, 109))	('CDKN2A]', 'Gene', (116, 123))	('merlin', 'Gene', '4771', (142, 148))	('CDKN2A]', 'Gene', '1029', (116, 123))	('BAP1', 'Gene', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('BRCA1 associated protein 1', 'Gene', (166, 192))	('mesothelioma', 'Disease', (232, 244))	('NF2', 'Gene', '4771', (156, 159))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (73, 109))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('73', '106'))	('mesothelioma', 'Disease', 'MESH:D008654', (232, 244))	('NF2', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('neurofibromin 2', 'Gene', '4771', (125, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('neurofibromin 2', 'Gene', (125, 140))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('BRCA1 associated protein 1', 'Gene', '8314', (166, 192))	('merlin', 'Gene', (142, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('BAP1', 'Gene', '8314', (199, 203))	('mutations', 'Var', (18, 27))
73552	31316876	Inhaled or ingested microscopic asbestos fibers, over the span of many years, cause genetic changes that can lead to asbestosis, lung cancer, mesothelioma and a number of other cancers like leukemia, esophageal, breast and prostate cancer .	('lead to', 'Reg', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('cancers', 'Disease', (177, 184))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (223, 238))	('asbestosis', 'Disease', 'MESH:D001195', (117, 127))	('genetic changes', 'Var', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('leukemia', 'Disease', (190, 198))	('leukemia', 'Disease', 'MESH:D007938', (190, 198))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('mesothelioma', 'Disease', (142, 154))	('esophageal', 'Disease', (200, 210))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('asbestosis', 'Disease', (117, 127))	('lung cancer', 'Disease', (129, 140))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (212, 238))
73726	30629589	Several research studies (for example,) confirm that low platelet count strongly relates to mesothelioma and it can also happen as a consequence of chemotherapy.	('platelet count', 'MPA', (57, 71))	('low platelet count', 'Phenotype', 'HP:0001873', (53, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('low', 'Var', (53, 56))	('relates', 'Reg', (81, 88))	('mesothelioma', 'Disease', (92, 104))
73751	30424481	In this context, it is worth noting that besides the two pathways widely mutated in cancer, namely, cell cycle control (cyclin-dependent kinase Inhibitor 2A, CDKN2A) and genome integrity (TP53), there are also two specific pathways frequently mutated in MPM, namely, the neurofibromatosis type 2 (NF2)/Hippo and the Breast-Repair-associated-Cancer 1(BRCA)-associated protein 1 (BAP1) pathways.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Breast-Repair-associated-Cancer 1', 'Pathway', (316, 349))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', '1029', (120, 156))	('Cancer', 'Phenotype', 'HP:0002664', (341, 347))	('NF2', 'Gene', '4771', (297, 300))	('TP53', 'Gene', '7157', (188, 192))	('mutated', 'Var', (243, 250))	('cyclin-dependent kinase Inhibitor', 'molecular_function', 'GO:0004861', ('120', '153'))	('kinase Inhibitor', 'biological_process', 'GO:0033673', ('137', '153'))	('cancer', 'Disease', (84, 90))	('neurofibromatosis type 2', 'Gene', (271, 295))	('NF2', 'Gene', (297, 300))	('CDKN2A', 'Gene', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('protein', 'cellular_component', 'GO:0003675', ('367', '374'))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (271, 288))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', (120, 156))	('cell cycle control', 'biological_process', 'GO:1901987', ('100', '118'))	('CDKN2A', 'Gene', '1029', (158, 164))	('neurofibromatosis type 2', 'Gene', '4771', (271, 295))	('TP53', 'Gene', (188, 192))
73752	30424481	With regard to NF2/Hippo, as pointed out by Sato and Sekido, it is intriguing that if their downstream targets are activated yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ domain-binding motif (TAZ), no mutations that result in their activation have been observed in mesothelioma.	('YAP1', 'Gene', (151, 155))	('YAP1', 'Gene', '10413', (151, 155))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('mesothelioma', 'Disease', 'MESH:D008654', (294, 306))	('PDZ domain-binding', 'molecular_function', 'GO:0030165', ('195', '213'))	('yes-associated protein 1', 'Gene', '10413', (125, 149))	('yes-associated protein 1', 'Gene', (125, 149))	('NF2', 'Gene', (15, 18))	('mutations', 'Var', (230, 239))	('NF2', 'Gene', '4771', (15, 18))	('mesothelioma', 'Disease', (294, 306))	('TAZ', 'Gene', (221, 224))	('TAZ', 'Gene', '6901', (221, 224))
73753	30424481	Mutations that result in their constitutive activation would involve mutations of individual or multiple phosphorylation sites, allowing YAP and TAZ retention in the cytosol preventing activation of YAP/TAZ-dependent transcription.	('mutations', 'Var', (69, 78))	('retention', 'biological_process', 'GO:0051235', ('149', '158'))	('YAP', 'Gene', (199, 202))	('YAP', 'Gene', '10413', (199, 202))	('activation', 'PosReg', (44, 54))	('transcription', 'biological_process', 'GO:0006351', ('217', '230'))	('TAZ', 'Gene', '6901', (203, 206))	('YAP', 'Gene', '10413', (137, 140))	('TAZ', 'Gene', '6901', (145, 148))	('Mutations', 'Var', (0, 9))	('TAZ', 'Gene', (203, 206))	('TAZ', 'Gene', (145, 148))	('activation', 'PosReg', (185, 195))	('cytosol', 'cellular_component', 'GO:0005829', ('166', '173'))	('YAP', 'Gene', (137, 140))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
73760	30424481	While the understanding of the mechanisms behind the contribution of the NF2/Hippo pathway to mesothelioma has progressed greatly since the seminal observation of the high frequency of NF2 mutations in mesothelioma, understanding of the mechanisms underlying BAP1 are less advanced.	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('NF2', 'Gene', (185, 188))	('mesothelioma', 'Disease', (202, 214))	('NF2', 'Gene', (73, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('NF2', 'Gene', '4771', (185, 188))	('mesothelioma', 'Disease', (94, 106))	('NF2', 'Gene', '4771', (73, 76))	('mutations', 'Var', (189, 198))
73766	30424481	Even though peritoneal mesothelioma is less frequent compared to pleural mesothelioma, the mutational landscape is similar, with BAP1 frequently being mutated.	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('mesothelioma', 'Disease', (73, 85))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (65, 85))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (12, 35))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (65, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('mesothelioma', 'Disease', (23, 35))	('BAP1', 'Gene', (129, 133))	('pleural mesothelioma', 'Disease', (65, 85))	('mutated', 'Var', (151, 158))
73775	30424481	However, both cancer-associated fibroblasts and the matrix, which are likely to be major contributors of stiffness-dependent effects such as modulation of YAP/TAZ transcriptional regulators, remain to be explored.	('cancer', 'Disease', (14, 20))	('YAP', 'Gene', (155, 158))	('modulation', 'Var', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TAZ', 'Gene', '6901', (159, 162))	('TAZ', 'Gene', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('YAP', 'Gene', '10413', (155, 158))
73778	30424481	Genetic alteration signatures observed in mice exposed to asbestos resemble what is observed in human clinical samples and is mostly associated with copy number variations.	('copy number variations', 'Var', (149, 171))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('human', 'Species', '9606', (96, 101))	('mice', 'Species', '10090', (42, 46))	('clinical samples', 'Species', '191496', (102, 118))	('associated', 'Reg', (133, 143))
73818	26961782	In addition, individuals carrying mutations in the BAP1 gene are at higher risk of developing MM.	('mutations', 'Var', (34, 43))	('developing MM', 'Disease', (83, 96))	('BAP1', 'Gene', '104416', (51, 55))	('BAP1', 'Gene', (51, 55))
73841	26961782	AB1-B/c and AB22-B/c cells are hyper-triploid (61-76 chromosomes and 64-75 chromosomes, respectively, with two nuclei of AB1-B/c cells containing 131 and 133 chromosomes), while AB12-B/c cells are nearly tetraploid (73-80 chromosomes).	('AB22-B/c', 'Var', (12, 20))	('hyper-triploid', 'Disease', 'MESH:D057885', (31, 45))	('hyper-triploid', 'Disease', (31, 45))
73932	21464917	The blood clearance T1/2alpha of 86Y-cetuximab (0.9-1.1 h) was faster than 86Y-panitumumab (2.6-3.1 h).	('86Y-cetuximab', 'Var', (33, 46))	('faster', 'PosReg', (63, 69))	('blood clearance', 'MPA', (4, 19))	('T1/2alpha', 'Gene', (20, 29))	('T1/2alpha', 'Gene', '17082', (20, 29))	('cetuximab', 'Chemical', 'MESH:D000068818', (37, 46))	('86Y-panitumumab', 'Chemical', '-', (75, 90))
73933	21464917	Also, the tumor area under the curve (AUC) to liver AUC ratios of 86Y-panitumumab were 1.5 to 2.5 times greater than 86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('cetuximab', 'Chemical', 'MESH:D000068818', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (10, 15))	('PET', 'Gene', '22095', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('greater', 'PosReg', (104, 111))	('86Y-panitumumab', 'Chemical', '-', (66, 81))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('86Y-panitumumab', 'Var', (66, 81))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (245, 250))	('PET', 'Gene', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumors', 'Disease', (245, 251))
73934	21464917	This study demonstrates the more favorable HER1-targeting characteristics of 86Y-panitumumab than 86Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging.	('HER1', 'Gene', '1956', (147, 151))	('86Y-panitumumab', 'Var', (77, 92))	('PET', 'Gene', '22095', (168, 171))	('HER1', 'Gene', (43, 47))	('PET', 'Gene', (168, 171))	('HER1', 'Gene', (147, 151))	('cetuximab', 'Chemical', 'MESH:D000068818', (102, 111))	('HER1', 'Gene', '1956', (43, 47))	('86Y-panitumumab', 'Chemical', '-', (77, 92))
73969	21464917	For 86Y-CHX-A''-DTPA-panitumumab, the blood % ID/g decreased from 12.06+-1.28 at 1 d to 6.94+-1.09% ID/g at 4 d, a 43% decrease.	('panitumumab', 'Chemical', 'MESH:D000077544', (21, 32))	("86Y-CHX-A''-DTPA-panitumumab", 'Var', (4, 32))	('decreased', 'NegReg', (51, 60))
73978	21464917	Similarly, for 86Y-CHX-A''-DTPA-cetuximab, the tumor % ID/g at 3 d was 29.4+-2.5, 22.8+-6.2 and 19.1+-1.9, respectively, and the corresponding tumor % ID/g in mice co-injected with 0.1 mg of cetuximab was 8.2+-0.7, 10.0+-2.3 and 9.2+-0.3, respectively, at the same time point.	('tumor', 'Disease', (143, 148))	('cetuximab', 'Chemical', 'MESH:D000068818', (191, 200))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	("86Y-CHX-A''-DTPA-cetuximab", 'Var', (15, 41))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
73981	21464917	At 1 and 2 d after injection, the liver uptake of 86Y-CHX-A''-DTPA-cetuximab was significantly greater (p = 0.007 and 0.040 at 1 and 2 d, respectively) than the liver uptake of 86Y-CHX-A''-DTPA-panitumumab in the same tumor model (Table 1).	('panitumumab', 'Chemical', 'MESH:D000077544', (194, 205))	('liver uptake', 'MPA', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('uptake', 'biological_process', 'GO:0098657', ('167', '173'))	('cetuximab', 'Chemical', 'MESH:D000068818', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('uptake', 'biological_process', 'GO:0098739', ('167', '173'))	('uptake', 'biological_process', 'GO:0098657', ('40', '46'))	('uptake', 'biological_process', 'GO:0098739', ('40', '46'))	('tumor', 'Disease', (218, 223))	("86Y-CHX-A''-DTPA-cetuximab", 'Var', (50, 76))	('greater', 'PosReg', (95, 102))
73982	21464917	However, at 4 d after injection, the blood, spleen, kidney, lung and heart uptake of 86Y-CHX-A''-DTPA-panitumumab was significantly greater than the uptake of 86Y-CHX-A''-DTPA-cetuximab in those organs in the same tumor model (Table 1).	('cetuximab', 'Chemical', 'MESH:D000068818', (176, 185))	('86Y-CHX-A', 'Var', (85, 94))	('spleen', 'MPA', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('lung', 'MPA', (60, 64))	('panitumumab', 'Chemical', 'MESH:D000077544', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('kidney', 'MPA', (52, 58))	('uptake', 'biological_process', 'GO:0098739', ('75', '81'))	('uptake', 'biological_process', 'GO:0098657', ('149', '155'))	('greater', 'PosReg', (132, 139))	('uptake', 'biological_process', 'GO:0098739', ('149', '155'))	('uptake', 'biological_process', 'GO:0098657', ('75', '81'))	('heart uptake', 'MPA', (69, 81))	('tumor', 'Disease', (214, 219))	('blood', 'MPA', (37, 42))
73989	21464917	Significant differences were found between the liver uptake of mice injected with 86Y-CHX-A''-DTPA-panitumumab and mice injected with 86Y-CHX-A''-DTPA-cetuximab, particularly in the NCI-H226 and MSTO-211H tumor models.	('liver uptake', 'MPA', (47, 59))	('NCI-H226', 'CellLine', 'CVCL:1544', (182, 190))	('cetuximab', 'Chemical', 'MESH:D000068818', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('panitumumab', 'Chemical', 'MESH:D000077544', (99, 110))	('NCI-H226', 'CPA', (182, 190))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('uptake', 'biological_process', 'GO:0098657', ('53', '59'))	("86Y-CHX-A''-DTPA-panitumumab", 'Var', (82, 110))	('uptake', 'biological_process', 'GO:0098739', ('53', '59'))	('mice', 'Species', '10090', (115, 119))
73990	21464917	The liver clearance of the 86Y-CHX-A''-DTPA-cetuximab was slower than that of 86Y-CHX-A''-DTPA-panitumumab therefore resulting in lower tumor-liver ratios than 86Y-CHX-A''-DTPA-panitumumab.	('lower', 'NegReg', (130, 135))	('liver clearance', 'MPA', (4, 19))	('panitumumab', 'Chemical', 'MESH:D000077544', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('slower', 'NegReg', (58, 64))	('86Y-CHX-A', 'Var', (27, 36))	('cetuximab', 'Chemical', 'MESH:D000068818', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('panitumumab', 'Chemical', 'MESH:D000077544', (177, 188))
73991	21464917	Pharmacokinetic analyses performed on biodistribution and PET derived values, and from values obtained from serial blood sampling revealed further differences between 86Y-CHX-A''-DTPA-panitumumab and 86Y-CHX-A''-DTPA-cetuximab (Table 2).	('panitumumab', 'Chemical', 'MESH:D000077544', (184, 195))	('PET', 'Gene', '22095', (58, 61))	('PET', 'Gene', (58, 61))	('differences', 'Reg', (147, 158))	("86Y-CHX-A''-DTPA-panitumumab", 'Var', (167, 195))	('cetuximab', 'Chemical', 'MESH:D000068818', (217, 226))
73992	21464917	The blood T1/2alpha for 86Y-CHX-A''-DTPA-panitumumab was significantly slower than that of 86Y-CHX-A''-DTPA-cetuximab; however, no significant difference was observed between the two RICs in the T1/2beta phase.	('slower', 'NegReg', (71, 77))	("86Y-CHX-A''-DTPA-panitumumab", 'Var', (24, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('T1/2alpha', 'Gene', '17082', (10, 19))	('T1/2alpha', 'Gene', (10, 19))	('panitumumab', 'Chemical', 'MESH:D000077544', (41, 52))
73993	21464917	The 86Y-CHX-A''-DTPA-panitumumab blood AUC[0 4] values were slightly greater than 86Y-CHX-A''-DTPA-cetuximab values, however the difference was not statistically significant.	("86Y-CHX-A''-DTPA-panitumumab", 'Var', (4, 32))	('greater', 'PosReg', (69, 76))	('panitumumab', 'Chemical', 'MESH:D000077544', (21, 32))	('blood AUC[0 4]', 'MPA', (33, 47))	('cetuximab', 'Chemical', 'MESH:D000068818', (99, 108))
73995	21464917	For each tumor model, the 86Y-CHX-A''-DTPA-cetuximab liver AUC[0 4] values were significantly greater than that of 86Y-CHX-A''-DTPA-panitumumab.	("86Y-CHX-A''-DTPA-cetuximab", 'Var', (26, 52))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('greater', 'PosReg', (94, 101))	('liver AUC[0 4] values', 'MPA', (53, 74))	('tumor', 'Disease', (9, 14))	('cetuximab', 'Chemical', 'MESH:D000068818', (43, 52))	('panitumumab', 'Chemical', 'MESH:D000077544', (132, 143))
74016	21464917	The slower first-phase blood clearance of 86Y-CHX-A''-DTPA-panitumumab may be attributed to the fact that panitumumab is an IgG2 whereas cetuximab is an IgG1.	('IgG1', 'Gene', '16017', (153, 157))	('IgG1', 'cellular_component', 'GO:0071735', ('153', '157'))	('panitumumab', 'Chemical', 'MESH:D000077544', (106, 117))	('IgG1', 'Gene', (153, 157))	('IgG2', 'cellular_component', 'GO:0071735', ('124', '128'))	('panitumumab', 'Chemical', 'MESH:D000077544', (59, 70))	('cetuximab', 'Chemical', 'MESH:D000068818', (137, 146))	('panitumumab', 'Var', (106, 117))	('first-phase blood clearance', 'MPA', (11, 38))
74019	21464917	2 and Table 2), the liver uptake and accumulation of 86Y- CHX-A''-DTPA-cetuximab was significantly greater than that of 86Y- CHX-A''-DTPA-panitumumab in all three xenograft tumor models, and as a result, tumor to liver ratios were better for 86Y- CHX-A''-DTPA-panitumumab than 86Y- CHX-A''-DTPA-cetuximab (Table 2).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	("86Y- CHX-A''", 'Var', (53, 65))	('cetuximab', 'Chemical', 'MESH:D000068818', (71, 80))	('liver', 'MPA', (20, 25))	('panitumumab', 'Chemical', 'MESH:D000077544', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('greater', 'PosReg', (99, 106))	('uptake', 'biological_process', 'GO:0098657', ('26', '32'))	('xenograft tumor', 'Disease', (163, 178))	('accumulation', 'MPA', (37, 49))	('xenograft tumor', 'Disease', 'MESH:D009369', (163, 178))	("86Y- CHX-A''-DTPA-panitumumab", 'Var', (242, 271))	('uptake', 'biological_process', 'GO:0098739', ('26', '32'))	('better', 'PosReg', (231, 237))	('panitumumab', 'Chemical', 'MESH:D000077544', (260, 271))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (204, 209))	('cetuximab', 'Chemical', 'MESH:D000068818', (295, 304))
74026	21464917	These differences can also have a significant impact for targeting intrapleural and intraperitoneal MM with respect to signal to noise ratios as well as radiation doses delivered to the liver, particularly in the setting of radionuclide therapy.	('signal to noise ratios', 'MPA', (119, 141))	('impact', 'Reg', (46, 52))	('differences', 'Var', (6, 17))	('pleura', 'Disease', (72, 78))	('pleura', 'Disease', 'MESH:D054363', (72, 78))
74031	21464917	In this study, the more favorable HER1-targeting characteristics of 86Y- CHX-A''-DTPA-panitumumab than 86Y- CHX-A''-DTPA-cetuximab for non-invasive staging and assessment of the HER1 status of MM has been demonstrated.	('HER1', 'Gene', '1956', (34, 38))	('cetuximab', 'Chemical', 'MESH:D000068818', (121, 130))	('HER1', 'Gene', '1956', (178, 182))	("86Y- CHX-A''-DTPA-panitumumab", 'Var', (68, 97))	('HER1', 'Gene', (178, 182))	('HER1', 'Gene', (34, 38))	('panitumumab', 'Chemical', 'MESH:D000077544', (86, 97))
74044	21464917	HuM195, an anti-CD33 mAb kindly provided by Dr. Michael McDevitt at Memorial Sloan-Kettering Cancer Center, served as a control mAb.	('CD33', 'Gene', '12489', (16, 20))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cancer', 'Disease', (93, 99))	('HuM195', 'Var', (0, 6))	('CD33', 'Gene', (16, 20))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
74048	21464917	Groups of 5-8 week old female athymic nu/nu mice (Charles River Laboratory, Wilmington, DE) were injected subcutaneously with 2-4x106 MSTO-211H, 6-10x106 NCI-H226, or 6-10x106 NCI-H2052 cells in 200 microL medium containing 20% matrigel.	('L', 'Chemical', '-', (64, 65))	('6-10x106 NCI-H2052', 'Var', (167, 185))	('6-10x106 NCI-H226', 'Var', (145, 162))	('NCI-H2052', 'CellLine', 'CVCL:1518', (176, 185))	('L', 'Chemical', '-', (204, 205))	('NCI-H226', 'CellLine', 'CVCL:1544', (154, 162))	('mice', 'Species', '10090', (44, 48))
74050	21464917	injected with 0.4-0.6 MBq (<5 microg) of 86Y-CHX-A''-DTPA-cetuximab or 86Y-CHX-A''-DTPA-panitumumab.	('cetuximab', 'Chemical', 'MESH:D000068818', (58, 67))	("86Y-CHX-A''", 'Var', (71, 82))	('panitumumab', 'Chemical', 'MESH:D000077544', (88, 99))	("86Y-CHX-A''-DTPA-cetuximab", 'Var', (41, 67))
74056	21464917	with 1.7-1.9 MBq (<5 microg) of 86Y-CHX-A''-DTPA-cetuximab or 86Y-CHX-A''-DTPA-panitumumab.	('cetuximab', 'Chemical', 'MESH:D000068818', (49, 58))	("86Y-CHX-A''-DTPA-cetuximab", 'Var', (32, 58))	("86Y-CHX-A''", 'Var', (62, 73))	('panitumumab', 'Chemical', 'MESH:D000077544', (79, 90))
74102	26959120	Cysmethynil also promoted M1 anti-tumor macrophage homing in the pleural space in vivo, and inhibited tumor-induced polarization of macrophages towards a M2 phenotype in vitro.	('inhibited', 'NegReg', (92, 101))	('Cysmethynil', 'Var', (0, 11))	('tumor', 'Disease', (34, 39))	('pleural', 'Disease', 'MESH:D010995', (65, 72))	('promoted', 'PosReg', (17, 25))	('pleural', 'Disease', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Cysmethynil', 'Chemical', 'MESH:C530692', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
74110	26959120	We hypothesized that cysmethynil would block MPE accumulation by inhibiting angiogenesis and pleural vascular permeability and by modulating tumor-initiated host immune response.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('angiogenesis', 'CPA', (76, 88))	('cysmethynil', 'Chemical', 'MESH:C530692', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('immune response', 'biological_process', 'GO:0006955', ('162', '177'))	('pleural vascular permeability', 'Disease', 'MESH:D010995', (93, 122))	('inhibiting', 'NegReg', (65, 75))	('cysmethynil', 'Var', (21, 32))	('block', 'NegReg', (39, 44))	('modulating', 'Reg', (130, 140))	('pleural vascular permeability', 'Disease', (93, 122))	('MPE', 'Protein', (45, 48))
74113	26959120	Even though cysmethynil reduced pleural fluid accumulation in both models, it impacted pleural tumor burden differently.	('cysmethynil', 'Var', (12, 23))	('pleural tumor', 'Disease', 'MESH:D010997', (87, 100))	('pleural fluid', 'Phenotype', 'HP:0002202', (32, 45))	('reduced', 'NegReg', (24, 31))	('pleural tumor', 'Disease', (87, 100))	('pleural fluid accumulation', 'Disease', 'MESH:D010995', (32, 58))	('cysmethynil', 'Chemical', 'MESH:C530692', (12, 23))	('fluid accumulation', 'Phenotype', 'HP:0000969', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('pleural fluid accumulation', 'Disease', (32, 58))	('impacted', 'Reg', (78, 86))
74119	26959120	We found that cysmethynil significantly inhibited endothelial cell viability (Figure 3A) and suppressed their migration by almost 50% (Figure 3B).	('inhibited', 'NegReg', (40, 49))	('migration', 'CPA', (110, 119))	('cysmethynil', 'Chemical', 'MESH:C530692', (14, 25))	('endothelial cell viability', 'CPA', (50, 76))	('cysmethynil', 'Var', (14, 25))	('suppressed', 'NegReg', (93, 103))
74120	26959120	Cysmethynil-treated endothelial cells formed shorter and less complicated vessel networks than the vehicle-treated ones (Figure 3C).	('shorter', 'NegReg', (45, 52))	('Cysmethynil-treated', 'Var', (0, 19))	('Cysmethynil', 'Chemical', 'MESH:C530692', (0, 11))	('less', 'NegReg', (57, 61))
74122	26959120	No significant difference in VEGF levels was measured in tumors, fluid or cells exposed to the inhibitor compared to the control ones (data not shown) implying that the anti-angiogenic effects of cysmethynil should be more likely ascribed to its direct effects on endothelial cells.	('VEGF', 'Gene', '22339', (29, 33))	('anti-angiogenic effects', 'CPA', (169, 192))	('VEGF', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cysmethynil', 'Var', (196, 207))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('cysmethynil', 'Chemical', 'MESH:C530692', (196, 207))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
74124	26959120	Although no significant difference was observed in total cellularity of pleural effusions among groups (data not shown), cysmethynil treated animals exhibited increased numbers of pleural space macrophages (Figure 4A).	('cysmethynil', 'Chemical', 'MESH:C530692', (121, 132))	('pleural', 'Disease', 'MESH:D010995', (72, 79))	('pleural', 'Disease', (72, 79))	('increased', 'PosReg', (159, 168))	('pleural effusions', 'Phenotype', 'HP:0002202', (72, 89))	('pleural effusion', 'Phenotype', 'HP:0002202', (72, 88))	('pleural', 'Disease', 'MESH:D010995', (180, 187))	('pleural effusions', 'Disease', (72, 89))	('pleural effusions', 'Disease', 'MESH:D010996', (72, 89))	('cysmethynil', 'Var', (121, 132))	('pleural', 'Disease', (180, 187))
74125	26959120	Moreover, analysis of the IL-12/IL-10 expression profile of the pleural macrophages demonstrated a significant shift towards an M1 anti-tumor phenotype in cysmethynil treated animals (Figure 4C).	('IL-10', 'Gene', '16153', (32, 37))	('IL-10', 'Gene', (32, 37))	('pleural', 'Disease', (64, 71))	('cysmethynil', 'Chemical', 'MESH:C530692', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IL-10', 'molecular_function', 'GO:0005141', ('32', '37'))	('pleural', 'Disease', 'MESH:D010995', (64, 71))	('tumor', 'Disease', (136, 141))	('cysmethynil', 'Var', (155, 166))	('IL-12', 'molecular_function', 'GO:0005143', ('26', '31'))
74129	26959120	In addition, cysmethynil promoted macrophage migration towards tumor cells (Figure 5B).	('cysmethynil', 'Chemical', 'MESH:C530692', (13, 24))	('tumor', 'Disease', (63, 68))	('macrophage migration', 'biological_process', 'GO:1905517', ('34', '54'))	('cysmethynil', 'Var', (13, 24))	('promoted', 'PosReg', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
74132	26959120	Cysmethynil was also found to reduce tumor cell viability in vitro (Figure 6C).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Cysmethynil', 'Var', (0, 11))	('reduce', 'NegReg', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cysmethynil', 'Chemical', 'MESH:C530692', (0, 11))
74136	26959120	Notably, while cysmethynil reduced the size of MPEs in both models, it differentially affected tumor progression: it stimulated apoptosis in vivo and reduced the number of pleural tumor foci in the adenocarcinoma model, but did not affect mesothelioma cell survival in vivo or the size of mesothelioma tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reduced', 'NegReg', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('mesothelioma', 'Disease', (289, 301))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (289, 301))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cysmethynil', 'Var', (15, 26))	('pleural tumor foci in the adenocarcinoma', 'Disease', 'MESH:D010997', (172, 212))	('reduced', 'NegReg', (150, 157))	('affected', 'Reg', (86, 94))	('mesothelioma', 'Disease', (239, 251))	('mesothelioma', 'Disease', 'MESH:D008654', (239, 251))	('tumor', 'Disease', (302, 307))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (289, 308))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('pleural tumor foci in the adenocarcinoma', 'Disease', (172, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (289, 308))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (289, 307))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cysmethynil', 'Chemical', 'MESH:C530692', (15, 26))	('mesothelioma tumors', 'Disease', (289, 308))	('stimulated', 'PosReg', (117, 127))	('apoptosis', 'CPA', (128, 137))
74141	26959120	We here demonstrate for the first time, that Icmt, besides inhibiting tumor cell growth, may impact certain host-related hallmarks of cancer, i.e.	('Icmt', 'Var', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (121, 140))	('inhibiting', 'NegReg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('impact', 'Reg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('hallmarks of cancer', 'Disease', (121, 140))
74150	26959120	Surprisingly, while cysmethynil uniformly increased MPE macrophage numbers in both models, only mesothelioma tumors were found to be affected in this fashion.	('increased', 'PosReg', (42, 51))	('cysmethynil', 'Chemical', 'MESH:C530692', (20, 31))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (96, 115))	('MPE macrophage numbers', 'CPA', (52, 74))	('mesothelioma tumors', 'Disease', (96, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (96, 115))	('cysmethynil', 'Var', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (96, 114))
74158	26959120	In conclusion, we here demonstrated that cysmethynil curtails experiential MPE formation, irrespective of its in vivo activity on the growth of the pleural tumors.	('cysmethynil', 'Chemical', 'MESH:C530692', (41, 52))	('curtails', 'NegReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('cysmethynil', 'Var', (41, 52))	('pleural tumors', 'Disease', (148, 162))	('experiential MPE formation', 'MPA', (62, 88))	('pleural tumors', 'Disease', 'MESH:D010997', (148, 162))
74172	26959120	For flow cytometry analysis, pleural fluid and tumor cells were fixed, permeabilised and stained with anti-CD45-APC-Cy-7 (pan-leucocyte marker), anti-CD11b-FITC (mature myeloid cell marker), anti-F4/80-PerCP (tumor-associated macrophages), anti-IL10-PE (prototype cytokine of pro-tumor M2 phenotype) and anti-IL12-APC (prototype cytokine of anti-tumor M1 phenotype).	('F4/80', 'Gene', '13733', (196, 201))	('CD45', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('IL10', 'molecular_function', 'GO:0005141', ('245', '249'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CD11b', 'Gene', '16409', (150, 155))	('F4/80', 'Gene', (196, 201))	('tumor', 'Disease', (209, 214))	('IL12', 'molecular_function', 'GO:0005143', ('309', '313'))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Disease', (280, 285))	('CD11b', 'Gene', (150, 155))	('pleural fluid', 'Disease', (29, 42))	('anti-IL10-PE', 'Var', (240, 252))	('pleural fluid', 'Phenotype', 'HP:0002202', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('APC', 'cellular_component', 'GO:0005680', ('314', '317'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', (47, 52))	('CD45', 'Gene', '19264', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('pleural fluid', 'Disease', 'MESH:D010995', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('anti-IL12-APC', 'Var', (304, 317))	('APC', 'cellular_component', 'GO:0005680', ('112', '115'))	('tumor', 'Disease', (346, 351))
74341	27147861	Light's criteria used for diagnosis of empyema are: exudate/pus with polymorphonuclear predominance; Gram stain showing organisms; low glucose; elevated lactate dehydrogenase >1000; and pH < 7.2.	('elevated lactate dehydrogenase', 'Phenotype', 'HP:0025435', (144, 174))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('empyema', 'Disease', 'MESH:D004653', (39, 46))	('empyema', 'Disease', (39, 46))	('elevated', 'PosReg', (144, 152))	('pH <', 'Var', (186, 190))	('lactate dehydrogenase', 'MPA', (153, 174))	('low', 'NegReg', (131, 134))	('glucose', 'MPA', (135, 142))
74366	27147861	It is defined by the presence of malignant cells in the pleural space; for which fluid needs to be sent for cytology (200 units of heparin in 20 mL of fluid).	('pleural', 'Disease', (56, 63))	('pleural', 'Disease', 'MESH:D010995', (56, 63))	('200', 'Var', (118, 121))	('heparin', 'Chemical', 'MESH:D006493', (131, 138))
74398	27147861	Diagnosis of lupus is likely if the fluid is positive for lupus erythematosus cells, antinuclear antibody is >1:160, and the pleural fluid/serum antinuclear antibody ratio is more than 1.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('pleural', 'Disease', 'MESH:D010995', (125, 132))	('lupus', 'Disease', 'MESH:D008180', (13, 18))	('pleural', 'Disease', (125, 132))	('lupus', 'Disease', (58, 63))	('antibody', 'cellular_component', 'GO:0019815', ('157', '165'))	('antinuclear', 'Var', (85, 96))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('lupus', 'Disease', 'MESH:D008180', (58, 63))	('antinuclear antibody', 'Phenotype', 'HP:0003493', (85, 105))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('pleural fluid', 'Phenotype', 'HP:0002202', (125, 138))	('antibody', 'cellular_component', 'GO:0019814', ('157', '165'))	('lupus erythematosus', 'Disease', (58, 77))	('serum antinuclear antibody', 'Phenotype', 'HP:0003493', (139, 165))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))	('lupus erythematosus', 'Disease', 'MESH:D008180', (58, 77))	('lupus erythematosus', 'Phenotype', 'HP:0002725', (58, 77))	('antinuclear antibody', 'Phenotype', 'HP:0003493', (145, 165))	('antibody', 'molecular_function', 'GO:0003823', ('157', '165'))	('antibody', 'cellular_component', 'GO:0042571', ('157', '165'))	('lupus', 'Disease', (13, 18))
74446	27147861	Radiation therapy can cause pleural effusion by two mechanisms, ie, radiation pleuritis and systemic venous hypertension or lymphatic obstruction from mediastinal fibrosis.	('cause', 'Reg', (22, 27))	('systemic venous hypertension', 'Phenotype', 'HP:0030950', (92, 120))	('pleuritis', 'Disease', 'MESH:D010998', (78, 87))	('pleural effusion', 'Disease', 'MESH:D010996', (28, 44))	('pleural effusion', 'Disease', (28, 44))	('Radiation therapy', 'Var', (0, 17))	('pleural effusion', 'Phenotype', 'HP:0002202', (28, 44))	('lymphatic obstruction', 'Phenotype', 'HP:0001004', (124, 145))	('pleuritis', 'Phenotype', 'HP:0002102', (78, 87))	('venous hypertension', 'Disease', (101, 120))	('venous hypertension', 'Disease', 'MESH:D006973', (101, 120))	('lymphatic obstruction', 'Disease', (124, 145))	('pleuritis', 'Disease', (78, 87))	('fibrosis', 'Disease', (163, 171))	('lymphatic obstruction', 'Disease', 'MESH:D008206', (124, 145))	('hypertension', 'Phenotype', 'HP:0000822', (108, 120))	('fibrosis', 'Disease', 'MESH:D005355', (163, 171))
74590	25868979	For example, expression of the ALDH1A3 has been experimentally shown to modulate survival of melanoma and glioma cell subpopulations exhibiting properties of cancer stem cells and to promote pro-tumorigenic features in breast cancer cells.	('survival', 'CPA', (81, 89))	('tumor', 'Disease', (195, 200))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('expression', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('promote', 'PosReg', (183, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('glioma', 'Disease', (106, 112))	('ALDH1A3', 'Gene', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Disease', (219, 232))	('modulate', 'Reg', (72, 80))	('ALDH', 'molecular_function', 'GO:0004030', ('31', '35'))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
74613	25868979	1F), suggesting that modulation of ALDH1A3 levels is the main mechanism mediating the effect of butein on the viability of the ALDHbright cells.	('modulation', 'Var', (21, 31))	('ALDH1A3', 'Gene', (35, 42))	('ALDH', 'molecular_function', 'GO:0004030', ('35', '39'))	('butein', 'Chemical', 'MESH:C040918', (96, 102))
74633	25868979	Thus, the MPM ALDHbright cells exhibited higher activation of the STAT3 pathway and responsivity to butein treatment.	('STAT3 pathway', 'Pathway', (66, 79))	('higher activation', 'PosReg', (41, 58))	('MPM', 'Var', (10, 13))	('responsivity', 'MPA', (84, 96))	('butein', 'Chemical', 'MESH:C040918', (100, 106))
74635	25868979	Since upregulation of DDIT3 by butein may result from increased promoter activity, we transfected HP-1 and MSTO-211H cells with a mCHERRY reporter driven by the minimal promoter of DDIT3 (-649/+136) (Fig.	('HP-1', 'CellLine', 'CVCL:C309', (98, 102))	('-649/+136', 'Var', (188, 197))	('promoter activity', 'MPA', (64, 81))	('upregulation', 'PosReg', (6, 18))	('MSTO-211H', 'CellLine', 'CVCL:1430', (107, 116))	('butein', 'Chemical', 'MESH:C040918', (31, 37))
74639	25868979	Staining with a phospho-STAT3 antibody (Tyr705) showed a strong reduction of the STAT3 phosphorylation in the butein-treated samples (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('30', '38'))	('antibody', 'cellular_component', 'GO:0019815', ('30', '38'))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('antibody', 'cellular_component', 'GO:0019814', ('30', '38'))	('Tyr705', 'Var', (40, 46))	('reduction', 'NegReg', (64, 73))	('antibody', 'molecular_function', 'GO:0003823', ('30', '38'))	('Tyr705', 'Chemical', '-', (40, 46))	('butein', 'Chemical', 'MESH:C040918', (110, 116))	('STAT3 phosphorylation', 'MPA', (81, 102))
74642	25868979	First, we immunoprecipitated the chromatin from vehicle and butein treated MSTO-211H cells (18 muM for 20hrs) with antibodies specific for STAT3, phosphoSTAT3 (tyr705) and NFkB (p65) (Fig.	('p65', 'Gene', '5970', (178, 181))	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (75, 84))	('tyr705', 'Var', (160, 166))	('butein', 'Chemical', 'MESH:C040918', (60, 66))	('p65', 'Gene', (178, 181))	('muM', 'Gene', '56925', (95, 98))	('tyr705', 'Chemical', '-', (160, 166))	('NFkB', 'Gene', (172, 176))	('muM', 'Gene', (95, 98))
74645	25868979	Additionally, the data suggested that the complex contained STAT3 in both its un-phosphorylated and phosphorylated (Tyr705) form (Fig.	('Tyr705', 'Var', (116, 122))	('STAT3', 'Gene', (60, 65))	('Tyr705', 'Chemical', '-', (116, 122))
74646	25868979	In order to assess the relevance of the single factors within the complex, we knocked-down STAT3 and NFkB (p65) in MSTO-211H and HP-1 cells by using RNAi.	('MSTO-211H', 'CellLine', 'CVCL:1430', (115, 124))	('p65', 'Gene', '5970', (107, 110))	('knocked-down', 'Var', (78, 90))	('RNAi', 'biological_process', 'GO:0016246', ('149', '153'))	('STAT3', 'Gene', (91, 96))	('HP-1', 'CellLine', 'CVCL:C309', (129, 133))	('p65', 'Gene', (107, 110))
74661	25868979	No statistically significant reduction in weight of the P+C treated tumors as compared to the vehicle-treated tumors was observed (Fig.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('reduction', 'NegReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('weight', 'MPA', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('P+C treated', 'Var', (56, 67))
74664	25868979	FACS analysis of tumors disaggregated within one hour from harvesting revealed that the percentage of ALDHbright cells was significantly reduced in the butein treated tumors (p < 0.05) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('butein', 'Chemical', 'MESH:C040918', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('butein', 'Var', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors disaggregated', 'Disease', (17, 37))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors disaggregated', 'Disease', 'MESH:D009369', (17, 37))	('tumors', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('ALDHbright cells', 'CPA', (102, 118))	('reduced', 'NegReg', (137, 144))
74665	25868979	Within the same experimental setting, we observed no statistically significant change in the number of ALDHbright cells within the pemetrexed + cisplatin treated tumors, while butein cotreatment caused the ALDHbright cell number to drop significantly and dramatically upon P+C treatment (as compared to the P+C treated mice, p < 0.05, Fig.	('P+C', 'Var', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mice', 'Species', '10090', (319, 323))	('tumors', 'Disease', (162, 168))	('pemetrexed', 'Chemical', 'MESH:D000068437', (131, 141))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('drop', 'NegReg', (232, 236))	('butein', 'Chemical', 'MESH:C040918', (176, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
74668	25868979	To verify this possibility, we performed 3D clonogenic assays (a surrogate of tumor relapse) on the same cells and this revealed that the B+P+C treated tumors exhibited a large loss of sphere forming potential as compared to those derived from the P+C treated mice which were mostly unaffected (as compared to the vehicle treated tumor masses, p < 0.05) (Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('sphere forming potential', 'CPA', (185, 209))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('mice', 'Species', '10090', (260, 264))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('B+P+C', 'Chemical', '-', (138, 143))	('tumor', 'Disease', (330, 335))	('B+P+C', 'Var', (138, 143))	('loss', 'NegReg', (177, 181))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
74678	25868979	In line with this, the fact that knocking down of ALDH1A3 did not increase the effect of butein strongly suggests that modulation of ALDH1A3 activity is a main target mechanism of this compound.	('ALDH1A3', 'Gene', (50, 57))	('butein', 'Chemical', 'MESH:C040918', (89, 95))	('ALDH', 'molecular_function', 'GO:0004030', ('50', '54'))	('knocking down', 'Var', (33, 46))	('ALDH', 'molecular_function', 'GO:0004030', ('133', '137'))
74684	25868979	Relevant to this, Marcato and Lee's groups have demonstrated that ALDH1A3-mediated modulation of RA-target genes contributes in vivo protumorigenic properties including the transcription of the MUC4 oncogene, to MDA-MB-231 breast cancer cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (212, 222))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ALDH1A3-mediated', 'Gene', (66, 82))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('modulation', 'Var', (83, 93))	('MUC4', 'Gene', '4585', (194, 198))	('breast cancer', 'Disease', (223, 236))	('ALDH', 'molecular_function', 'GO:0004030', ('66', '70'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('transcription', 'MPA', (173, 186))	('MUC4', 'Gene', (194, 198))	('transcription', 'biological_process', 'GO:0006351', ('173', '186'))	('tumor', 'Disease', (136, 141))
74687	25868979	On a wider perspective, low DDIT3 levels in the ALDHbright cells may promote unperturbed CEBPbeta activity during stress.	('CEBPbeta', 'Gene', '1051', (89, 97))	('low', 'Var', (24, 27))	('CEBPbeta', 'Gene', (89, 97))	('promote', 'PosReg', (69, 76))	('DDIT3 levels', 'MPA', (28, 40))
74697	25868979	H-2591, H-2818, H-2595, H-2373, H-2461, HP-1, H-2596 were obtained as described elsewhere.	('H-2373', 'CellLine', 'CVCL:A533', (24, 30))	('H-2595', 'CellLine', 'CVCL:A545', (16, 22))	('H-2461', 'CellLine', 'CVCL:A536', (32, 38))	('H-2596', 'Var', (46, 52))	('H-2595', 'Var', (16, 22))	('HP-1', 'CellLine', 'CVCL:C309', (40, 44))	('H-2818', 'CellLine', 'CVCL:V000', (8, 14))
74707	25868979	CHOP promoter/pmCherry-1(#36035, Addgene, Cambridge, MA) was transfected into MPM cells using Lipofectamine 2000 (Life Technologies) according to the manufacturer's instructions.	('#36035', 'Var', (25, 31))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (94, 112))	('CHOP', 'Gene', (0, 4))	('CHOP', 'Gene', '1649', (0, 4))
74728	25868979	The specific primers for the CEBPbeta binding site in the ALDH1A3 promoter (chr15: 101419959-101419973) and for the STAT3 binding site in the DDIT3 promoter (chr12: 57911053-57911074) and the "off target" controls (Epitect CHIP primers) were commercially available (Qiagen, Valencia, CA).	('CEBPbeta', 'Gene', (29, 37))	('chr12', 'Var', (158, 163))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('chr15: 101419959-101419973', 'Var', (76, 102))	('ALDH', 'molecular_function', 'GO:0004030', ('58', '62'))	('ALDH1A3', 'Gene', (58, 65))	('CEBPbeta', 'Gene', '1051', (29, 37))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))
74730	25868979	in PBS1X into 5-weeks-old male NOD/SCID mice (Charles River, Italy).	('PBS1X', 'Var', (3, 8))	('SCID', 'Disease', 'MESH:D053632', (35, 39))	('NOD', 'Gene', (31, 34))	('PBS1X', 'Chemical', '-', (3, 8))	('mice', 'Species', '10090', (40, 44))	('NOD', 'Gene', '1822', (31, 34))	('SCID', 'Disease', (35, 39))
74734	25952750	Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (212, 234))	('mutations', 'Var', (64, 73))	('BAP1', 'Gene', '8314', (59, 63))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (124, 146))	('patient', 'Species', '9606', (13, 20))	('human', 'Species', '9606', (118, 123))	('malignant mesothelioma', 'Disease', (212, 234))	('mesothelioma', 'Disease', (222, 234))	('malignant mesothelioma', 'Disease', (124, 146))	('mesothelioma', 'Disease', (134, 146))	('BAP1', 'Gene', (59, 63))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (212, 234))	('mesothelioma', 'Disease', 'MESH:D008654', (222, 234))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', (29, 34))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (124, 146))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
74739	25952750	Mutations of BAP1 and CDKN2A were each detected in four tumors.	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CDKN2A', 'Gene', (22, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
74740	25952750	Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (72, 78))	('mutant', 'Var', (57, 63))	('tumors', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('BAP1', 'Gene', (167, 171))	('loss', 'NegReg', (172, 176))	('enhance', 'PosReg', (181, 188))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('primary tumors', 'Disease', (64, 78))	('exhibited', 'Reg', (80, 89))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (135, 140))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Disease', (189, 194))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('anchorage independent growth', 'CPA', (90, 118))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
74741	25952750	Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors.	('CDKN2A', 'Gene', (88, 94))	('deletions', 'Var', (95, 104))	('xenograft tumors', 'Disease', (43, 59))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('BAP1', 'Gene', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mouse', 'Species', '10090', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('xenograft tumors', 'Disease', 'MESH:D009369', (43, 59))	('patient', 'Species', '9606', (159, 166))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
74742	25952750	The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mesothelioma', 'Disease', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('patient', 'Species', '9606', (17, 24))	('mesothelioma', 'Disease', (265, 277))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (115, 121))	('mutational alterations', 'Var', (55, 77))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('mesothelioma', 'Disease', 'MESH:D008654', (265, 277))	('tumor', 'Disease', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('patient', 'Species', '9606', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
74748	25952750	Primary tumor-derived cell lines have adapted to growth outside a natural tumor microenvironment and due to selective processes associated with long term culturing will develop genetic changes that are distinct from the genetic stress imposed on tumors in patients.	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('patients', 'Species', '9606', (256, 264))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('genetic changes', 'Var', (177, 192))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
74754	25952750	The most common genetic alterations associated with mesothelioma, including CDKN2A deletions and NF2 mutations, have been known for about two decades.	('mutations', 'Var', (101, 110))	('NF2', 'Gene', (97, 100))	('deletions', 'Var', (83, 92))	('mesothelioma', 'Disease', (52, 64))	('CDKN2A', 'Gene', (76, 82))	('NF2', 'Gene', '4771', (97, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
74755	25952750	More recently, mutations in the BAP1 tumor suppressor gene have been observed in 20-25% of mesothelioma tumor samples.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (91, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (91, 109))	('observed', 'Reg', (69, 77))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mesothelioma tumor', 'Disease', (91, 109))
74775	25952750	In addition, a panel of hotspot mutations in 7 genes (AKT1, BRAF, EBRR2, EGFR, KRAS, NRAS, and PIK3CA) was analyzed with pyrosequencing for single-nucleotide variants (SNVs) or with fragment analysis for insertions/deletions (indels).	('PIK3CA', 'Gene', (95, 101))	('EGFR', 'Gene', '1956', (73, 77))	('PIK3CA', 'Gene', '5290', (95, 101))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('KRAS', 'Gene', '3845', (79, 83))	('single-nucleotide', 'Var', (140, 157))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (32, 41))	('NRAS', 'Gene', (85, 89))	('EBRR2', 'Gene', (66, 71))	('AKT1', 'Gene', '207', (54, 58))	('NRAS', 'Gene', '4893', (85, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('AKT1', 'Gene', (54, 58))	('KRAS', 'Gene', (79, 83))
74803	25952750	The karyotype analysis showed a very high number of structural abnormalities in NCI-Meso19, a cell culture derived from a mesothelioma of a young patient harboring a somatic TP53 mutation.	('mesothelioma', 'Disease', (122, 134))	('TP53', 'Gene', (174, 178))	('structural abnormalities in NCI-Meso19', 'Disease', (52, 90))	('mutation', 'Var', (179, 187))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('patient', 'Species', '9606', (146, 153))	('structural abnormalities in NCI-Meso19', 'Disease', 'MESH:C566527', (52, 90))	('TP53', 'Gene', '7157', (174, 178))
74808	25952750	For western blot analysis, we used the mesothelioma cell lines NCI-H28 (harboring a BAP1 nonsense mutation) and NCI-H2052 (wild type for BAP1) as positive and negative controls, respectively, for the presence of a BAP1 protein (Figure 2C).	('mesothelioma cell lines NCI-H28', 'Disease', 'MESH:D008654', (39, 70))	('mutation', 'Var', (98, 106))	('NCI-H2052', 'CellLine', 'CVCL:1518', (112, 121))	('BAP1', 'Gene', (84, 88))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('mesothelioma cell lines NCI-H28', 'Disease', (39, 70))
74810	25952750	We also performed sequence analysis of NF2 and TP53, and hot spot mutation screening for several oncogenes, as summarized in Table 2.	('NF2', 'Gene', '4771', (39, 42))	('TP53', 'Gene', '7157', (47, 51))	('NF2', 'Gene', (39, 42))	('mutation', 'Var', (66, 74))	('TP53', 'Gene', (47, 51))
74811	25952750	A large deletion in NF2 and a missense mutation in exon 8 (P322S) of the TP53 gene were found in one of the primary cultures (Table 2).	('TP53', 'Gene', '7157', (73, 77))	('NF2', 'Gene', (20, 23))	('TP53', 'Gene', (73, 77))	('NF2', 'Gene', '4771', (20, 23))	('P322S', 'Var', (59, 64))	('P322S', 'Mutation', 'rs863224687', (59, 64))
74815	25952750	This finding was further supported by detection of the identical BAP1 mutations in tumor xenografts, and the corresponding primary tumor samples and primary cell cultures (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('BAP1', 'Gene', (65, 69))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
74816	25952750	In addition, xenograft tumors exhibited the same CDKN2A deletion status as in primary cell cultures, except in one case where most but not all cells had a homozygous deletion of CDKN2A, whereas the reverse was true in the corresponding primary cell culture.	('deletion', 'Var', (166, 174))	('xenograft tumors', 'Disease', (13, 29))	('CDKN2A', 'Gene', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('xenograft tumors', 'Disease', 'MESH:D009369', (13, 29))	('CDKN2A', 'Gene', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
74817	25952750	This suggests that the tumor cells with loss of CDKN2A had a selective growth advantage in vivo.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CDKN2A', 'Gene', (48, 54))	('loss', 'Var', (40, 44))	('tumor', 'Disease', (23, 28))
74818	25952750	The two remaining tumor samples completely matched with their primary cultures for their CDKN2A deletion status, further confirming that primary cells obtained from patient's malignant effusions have the same genetic alterations as in the corresponding primary human tumor.	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('patient', 'Species', '9606', (165, 172))	('human', 'Species', '9606', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('CDKN2A', 'Gene', (89, 95))	('deletion', 'Var', (96, 104))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
74823	25952750	In this report, we describe the establishment of primary mesothelioma cultures and patient derived tumor xenografts with mutational alterations that recapitulate those in the original patient tumors.	('tumor', 'Disease', (99, 104))	('mesothelioma', 'Disease', (57, 69))	('tumor', 'Disease', (192, 197))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (49, 69))	('tumors', 'Disease', (192, 198))	('mutational alterations', 'Var', (121, 143))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patient', 'Species', '9606', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('patient', 'Species', '9606', (184, 191))
74826	25952750	Three out of five cells, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in vivo, suggesting that BAP1 loss may enhance tumor growth in vivo.	('primary tumors', 'Disease', (68, 82))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('primary tumors', 'Disease', 'MESH:D009369', (68, 82))	('anchorage independent growth', 'CPA', (94, 122))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BAP1', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (193, 198))	('loss', 'NegReg', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (76, 82))	('mutant', 'Var', (61, 67))	('tumors', 'Disease', (139, 145))	('BAP1', 'Gene', (171, 175))	('enhance', 'PosReg', (185, 192))	('exhibited', 'Reg', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (139, 145))
74827	25952750	Both early passage cell cultures and mouse xenograft tumors harbored the BAP1 mutations and CDKN2A deletions identical to those observed in the corresponding primary tumor.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CDKN2A', 'Gene', (92, 98))	('xenograft tumors', 'Disease', 'MESH:D009369', (43, 59))	('xenograft tumors', 'Disease', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('deletions', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('BAP1', 'Gene', (73, 77))	('tumor', 'Disease', (166, 171))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mouse', 'Species', '10090', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))
74831	25952750	It is noteworthy that the cell cultures that formed colonies in vitro and tumors in nude mice were cell lines that had BAP1 mutations.	('mutations', 'Var', (124, 133))	('nude mice', 'Species', '10090', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('BAP1', 'Gene', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
74832	25952750	Previous studies of BAP1 have shown that BAP1 loss promotes colony-forming ability of mesothelioma cells, and that re-expression of BAP1 in BAP1-deficient markedly decreases colony-formation.	('re-expression', 'Var', (115, 128))	('decreases', 'NegReg', (164, 173))	('colony-formation', 'CPA', (174, 190))	('loss', 'NegReg', (46, 50))	('BAP1', 'Gene', (41, 45))	('formation', 'biological_process', 'GO:0009058', ('181', '190'))	('BAP1', 'Gene', (132, 136))	('mesothelioma', 'Disease', (86, 98))	('promotes', 'PosReg', (51, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
74834	25952750	A recent study has suggested that BAP1 inactivation is more closely associated with the epithelioid subtype of malignant pleural mesothelioma.	('associated', 'Reg', (68, 78))	('epithelioid subtype', 'Disease', (88, 107))	('BAP1', 'Gene', (34, 38))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (111, 141))	('malignant pleural mesothelioma', 'Disease', (111, 141))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (121, 141))	('inactivation', 'Var', (39, 51))
74837	25952750	These studies have shown that mice deficient for either p16Ink4a or p19Arf, the murine homolog of human p14ARF, have increased susceptibility to asbestos-induced mesothelioma and that inactivation of both p16Ink4a or p19Arf cooperate to accelerate asbestos-induced tumorigenesis.	('p19', 'cellular_component', 'GO:0070743', ('217', '220'))	('mesothelioma', 'Disease', (162, 174))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', (265, 270))	('accelerate', 'PosReg', (237, 247))	('asbestos-induced', 'Disease', (248, 264))	('p16Ink4a', 'Var', (56, 64))	('p16Ink4a', 'Var', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('asbestos', 'Chemical', 'MESH:D001194', (248, 256))	('p14ARF', 'Gene', '1029', (104, 110))	('asbestos', 'Chemical', 'MESH:D001194', (145, 153))	('p19', 'cellular_component', 'GO:0070743', ('68', '71'))	('inactivation', 'Var', (184, 196))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('susceptibility', 'Reg', (127, 141))	('p19Arf', 'Var', (68, 74))	('p19Arf', 'Var', (217, 223))	('p14ARF', 'Gene', (104, 110))	('human', 'Species', '9606', (98, 103))	('murine', 'Species', '10090', (80, 86))
74838	25952750	Karyotypic analysis revealed recurrent abnormalities in the short arm of chromosome 1, consistent with a deletion hotspot previously implicated in mesothelioma.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('mesothelioma', 'Disease', (147, 159))	('short arm', 'Phenotype', 'HP:0009824', (60, 69))	('abnormalities', 'Var', (39, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))
74839	25952750	Deletions of chromosome arms 3p, 9p and 22q, which include the tumor suppressor genes BAP1, CDKN2A, and NF2, respectively, have all been linked to mesothelioma.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('tumor', 'Disease', (63, 68))	('mesothelioma', 'Disease', (147, 159))	('CDKN2A', 'Gene', (92, 98))	('NF2', 'Gene', (104, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('BAP1', 'Gene', (86, 90))	('linked to', 'Reg', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('NF2', 'Gene', '4771', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('Deletions', 'Var', (0, 9))
74840	25952750	We also identified variable rearrangements of chromosome 10 in all our primary cultures, a finding that to our knowledge has not been reported earlier for malignant mesothelioma.	('malignant mesothelioma', 'Disease', (155, 177))	('rearrangements', 'Var', (28, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (155, 177))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (155, 177))
75111	26740245	Intracellular accumulation of green-Pax was nearly 5X greater in cells pre-treated with eNPs than in cells pre-treated with media or PLGA-NPs (Fig.	('green-Pax', 'Protein', (30, 39))	('Intracellular accumulation', 'MPA', (0, 26))	('Intracellular', 'cellular_component', 'GO:0005622', ('0', '13'))	('green-Pax', 'Chemical', '-', (30, 39))	('pre', 'molecular_function', 'GO:0003904', ('107', '110'))	('greater', 'PosReg', (54, 61))	('eNPs', 'Var', (88, 92))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
75134	26740245	The average Pax concentration within tumors in eNP pre-treated animals (2,341 +- 335 ng/g; n = 21) was significantly higher than the concentration in saline (439 +- 125 ng/g; n = 14) and PLGA-NP (487 +- 45 ng/g; n = 13) pretreated animals (P < 0.05 for eNP vs. PLGA-NP and eNP vs. saline; P = NS for PLGA-NP vs. saline).	('higher', 'PosReg', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('eNP', 'Var', (47, 50))	('Pax', 'Gene', (12, 15))	('pre', 'molecular_function', 'GO:0003904', ('51', '54'))	('saline', 'Chemical', 'MESH:D012965', (150, 156))	('saline', 'Chemical', 'MESH:D012965', (312, 318))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Pax', 'Chemical', 'MESH:D017239', (12, 15))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('saline', 'Chemical', 'MESH:D012965', (281, 287))
75195	25589494	There was no significant correlation of CD30 positivity with either tumor grade, stage or survival.	('tumor', 'Disease', (68, 73))	('positivity', 'Var', (45, 55))	('CD30', 'Gene', '943', (40, 44))	('CD30', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
75203	25589494	In addition, there is also growing concern that the widespread use of nano-sized particles for medical and industrial purposes may create new risks for developing mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('nano-sized', 'Var', (70, 80))	('mesothelioma', 'Disease', (163, 175))
75246	25589494	The incidence of CD30 positivity was 4.6% in the biphasic and sarcomatoid group vs. 19.7% for the epithelioid group, approaching significance (p < 0.094).	('sarcomatoid', 'Disease', (62, 73))	('sarcomatoid', 'Disease', 'MESH:C538614', (62, 73))	('CD30', 'Gene', (17, 21))	('biphasic', 'Disease', (49, 57))	('CD30', 'Gene', '943', (17, 21))	('positivity', 'Var', (22, 32))
75248	25589494	Representative results of CD30 positivity are shown in Figure 2 at three different magnifications.	('CD30', 'Gene', '943', (26, 30))	('positivity', 'Var', (31, 41))	('CD30', 'Gene', (26, 30))
75253	25589494	The mesothelioma cohort contained survival data on 63 patients, however univariate analyses using both Kaplan-Meier (p<0.935) and continuous measurement Cox regression models (p<0.82) predicted no statistical significance of CD30 positivity on overall survival.	('positivity', 'Var', (230, 240))	('mesothelioma', 'Disease', (4, 16))	('patients', 'Species', '9606', (54, 62))	('CD30', 'Gene', (225, 229))	('CD30', 'Gene', '943', (225, 229))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))
75264	25589494	We hypothesize that the expression of CD30 on the cell surface should sensitize mesothelioma cells to brentuximab vedotin.	('cell surface', 'cellular_component', 'GO:0009986', ('50', '62'))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('sensitize', 'Reg', (70, 79))	('brentuximab', 'Chemical', 'MESH:C504717', (102, 113))	('mesothelioma', 'Disease', (80, 92))	('expression', 'Var', (24, 34))	('CD30', 'Gene', '943', (38, 42))	('CD30', 'Gene', (38, 42))
75268	25589494	The two mesothelioma cell lines tested, H2052 and H2452, were both sensitive to the antibody-drug conjugate, with H2052 cells demonstrating more sensitivity than H2452 cells, although both were less sensitive than Karpas cells.	('H2052', 'Var', (114, 119))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('mesothelioma', 'Disease', (8, 20))	('H2052', 'CellLine', 'CVCL:1518', (114, 119))	('H2052', 'CellLine', 'CVCL:1518', (40, 45))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))
75270	25589494	Treatment of H2052 and H2452 cells for 48 h induced a dose-dependent decrease in cell viability compared to untreated control cells (Figure 4B).	('H2052', 'CellLine', 'CVCL:1518', (13, 18))	('H2452', 'Var', (23, 28))	('decrease', 'NegReg', (69, 77))	('H2052', 'Var', (13, 18))	('cell viability', 'CPA', (81, 95))
75319	25217189	Furthermore, some genetic abnormalities, such as inactivation of the BRCA1 associated protein-1 (BAP1) tumor suppressor gene vary based on the histological subtype.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('BAP1', 'Gene', '8314', (97, 101))	('BRCA1 associated protein-1', 'Gene', '8314', (69, 95))	('tumor', 'Disease', (103, 108))	('inactivation', 'Var', (49, 61))	('genetic abnormalities', 'Disease', 'MESH:D030342', (18, 39))	('BAP1', 'Gene', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('BRCA1 associated protein-1', 'Gene', (69, 95))	('genetic abnormalities', 'Disease', (18, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
75320	25217189	BAP-1 mutation appears to be more common among epithelioid tumors.	('epithelioid tumors', 'Disease', 'MESH:D012509', (47, 65))	('BAP-1', 'Gene', '8314', (0, 5))	('mutation', 'Var', (6, 14))	('epithelioid tumors', 'Disease', (47, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('BAP-1', 'Gene', (0, 5))	('common', 'Reg', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
75344	25217189	In other words, four out of 30 (13%) subjects treated with pemetrexed-based regimens responded to treatment in comparison to the 15 responders of 107 (14%) subjects treated with non-pemetrexed-based regimens.	('pemetrexed', 'Chemical', 'MESH:D000068437', (59, 69))	('pemetrexed-based regimens', 'Var', (59, 84))	('pemetrexed', 'Chemical', 'MESH:D000068437', (182, 192))	('responded to treatment', 'MPA', (85, 107))
75410	24027648	There are some similar features of these both patients including long history of dyspnea symptom, enhanced nodular pericardial lesion, positive calretinin and CK5/6, and short survival after pemetrexed and cisplatin treatment (Table 1).	('enhanced', 'PosReg', (98, 106))	('pemetrexed', 'Chemical', 'MESH:D000068437', (191, 201))	('patients', 'Species', '9606', (46, 54))	('dyspnea', 'Phenotype', 'HP:0002094', (81, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('CK5/6', 'Gene', (159, 164))	('dyspnea', 'Disease', (81, 88))	('calretinin', 'Gene', '794', (144, 154))	('nodular pericardial lesion', 'Disease', 'MESH:D020518', (107, 133))	('dyspnea', 'Disease', 'MESH:D004417', (81, 88))	('CK5/6', 'Gene', '3852', (159, 164))	('nodular pericardial lesion', 'Disease', (107, 133))	('positive', 'Var', (135, 143))	('calretinin', 'Gene', (144, 154))
75428	22552293	HMGB1 inhibition in vivo reduced the growth of MM xenografts in SCID mice and extended host survival.	('reduced', 'NegReg', (25, 32))	('SCID', 'Disease', (64, 68))	('HMGB1', 'Gene', (0, 5))	('SCID', 'Disease', 'MESH:D053632', (64, 68))	('extended', 'PosReg', (78, 86))	('mice', 'Species', '10090', (69, 73))	('inhibition', 'Var', (6, 16))	('host survival', 'CPA', (87, 100))	('growth of MM xenografts', 'CPA', (37, 60))
75438	22552293	Moreover, recently we discovered a novel cancer syndrome caused by BAP1 germline mutations, characterized by the development of uveal melanoma and mesothelioma and possibly other cancers.	('mesothelioma', 'Disease', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('uveal melanoma', 'Disease', (128, 142))	('caused', 'Reg', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('BAP1', 'Gene', '8314', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancer syndrome', 'Disease', 'MESH:D009369', (41, 56))	('cancer syndrome', 'Disease', (41, 56))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('germline', 'Var', (72, 80))	('BAP1', 'Gene', (67, 71))
75439	22552293	When individuals with BAP1 mutations are exposed to asbestos or erionite, mesothelioma predominates.	('mutations', 'Var', (27, 36))	('erionite', 'Chemical', 'MESH:C083174', (64, 72))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('asbestos', 'Chemical', 'MESH:D001194', (52, 60))	('BAP1', 'Gene', '8314', (22, 26))	('mesothelioma', 'Disease', (74, 86))	('BAP1', 'Gene', (22, 26))
75462	22552293	The following primers from Qiagen were used: Hs_AGER_1_SG (QT00000119), Hs_HMGB1_1_SG (QT01002190), Hs_TLR4_2_SG (QT01670123), and Hs_TLR2_1_SG (200) (QT00236131) to amplify the respective cDNAs as previously described.	('QT00000119', 'Disease', (59, 69))	('TLR4', 'Gene', '7099', (103, 107))	('TLR4', 'Gene', (103, 107))	('TLR2', 'Gene', '7097', (134, 138))	('TLR2', 'Gene', (134, 138))	('QT01670123', 'Var', (114, 124))	('QT00000119', 'Disease', 'None', (59, 69))	('QT01002190', 'Var', (87, 97))
75489	22552293	These results showed that these HMGB1 inhibitors interfere with asbestos-induced HM transformation.	('inhibitors', 'Var', (38, 48))	('asbestos', 'Chemical', 'MESH:D001194', (64, 72))	('asbestos-induced', 'Disease', (64, 80))	('HMGB1', 'Gene', (32, 37))	('interfere', 'NegReg', (49, 58))
75511	22552293	BoxA, anti-HMGB1 and anti-RAGE antibodies significantly reduced the viability of REN and PPM-Phi cells (Fig.	('RAGE', 'Gene', (26, 30))	('viability', 'CPA', (68, 77))	('RAGE', 'Gene', '101669765', (26, 30))	('reduced', 'NegReg', (56, 63))	('anti-HMGB1', 'Var', (6, 16))	('Phi', 'Gene', '2821', (93, 96))	('Phi', 'Gene', (93, 96))
75512	22552293	Both anti-HMGB1 and anti-RAGE antibodies induced marked cytotoxicity in REN and PPM-Phi cells (Fig.	('anti-HMGB1', 'Var', (5, 15))	('Phi', 'Gene', (84, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('anti-HMGB1', 'Gene', (5, 15))	('RAGE', 'Gene', (25, 29))	('RAGE', 'Gene', '101669765', (25, 29))	('cytotoxicity', 'Disease', (56, 68))	('Phi', 'Gene', '2821', (84, 87))
75513	22552293	4B), while a mild cytotoxic effect was observed in PPM-Mill cells only when treated with anti-RAGE antibody (Supplementary Fig.	('antibody', 'cellular_component', 'GO:0019814', ('99', '107'))	('antibody', 'molecular_function', 'GO:0003823', ('99', '107'))	('PPM-Mill', 'Var', (51, 59))	('antibody', 'cellular_component', 'GO:0042571', ('99', '107'))	('RAGE', 'Gene', (94, 98))	('antibody', 'cellular_component', 'GO:0019815', ('99', '107'))	('RAGE', 'Gene', '101669765', (94, 98))
75515	22552293	Flow cytometry revealed that BoxA, anti-HMGB1 and anti-RAGE antibodies significantly induced apoptosis in REN cells (Supplementary Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('anti-HMGB1', 'Var', (35, 45))	('induced', 'Reg', (85, 92))	('RAGE', 'Gene', (55, 59))	('RAGE', 'Gene', '101669765', (55, 59))	('apoptosis', 'CPA', (93, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
75519	22552293	All HMGB1 inhibitors (BoxA, anti-HMGB1, and anti-RAGE) caused a significant decrease in REN anchorage-independent growth, as indicated by a marked reduction in the number (Fig.	('HMGB1', 'Gene', (4, 9))	('anti-HMGB1', 'Var', (28, 38))	('RAGE', 'Gene', (49, 53))	('RAGE', 'Gene', '101669765', (49, 53))	('reduction', 'NegReg', (147, 156))	('decrease', 'NegReg', (76, 84))	('REN anchorage-independent growth', 'CPA', (88, 120))
75525	22552293	S10A and B); however, anti-HMGB1 mAb significantly reduced tumor growth (P < 0.05; Fig.	('anti-HMGB1', 'Gene', (22, 32))	('reduced', 'NegReg', (51, 58))	('S10A', 'Var', (0, 4))	('tumor', 'Disease', (59, 64))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
75529	22552293	Here we show that: 1) HMGB1 is secreted by MM cells in the serum of MM patients, making HMGB1 a potential MM biomarker; 2) HMGB1 supports MM cell viability and hallmarks of malignant phenotype, such as tumor invasion and tumor cell proliferation; and 3) treatment with HMGB1 inhibitors extended the survival of mice xenografted with MM cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('227', '245'))	('HMGB1', 'Gene', (269, 274))	('mice', 'Species', '10090', (311, 315))	('tumor', 'Disease', (202, 207))	('HMGB1', 'Gene', (123, 128))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('survival', 'CPA', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('inhibitors', 'Var', (275, 285))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('extended', 'PosReg', (286, 294))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('MM cell viability', 'CPA', (138, 155))
75540	22552293	To test whether the withdrawal of HMGB1 would affect MM cells, we used different HMGB1 inhibitors: 1) BoxA; 2) anti-HMGB1 mAb and 3) anti-RAGE mAb.	('RAGE', 'Gene', (138, 142))	('RAGE', 'Gene', '101669765', (138, 142))	('anti-HMGB1', 'Var', (111, 121))
75542	22552293	Next, we tested whether HMGB1 inhibition could reduce the growth of tumors in MM xenografted mice.	('tumors', 'Disease', (68, 74))	('reduce', 'NegReg', (47, 53))	('inhibition', 'Var', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('HMGB1', 'Gene', (24, 29))	('mice', 'Species', '10090', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tested', 'Reg', (9, 15))
75552	22485139	Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase.	('increase', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Mesothelin', 'Gene', '10232', (13, 23))	('S-phase', 'biological_process', 'GO:0051320', ('95', '102'))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('Mesothelin', 'Gene', (13, 23))	('silencing', 'Var', (24, 33))
75554	22485139	Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.	('malignancies', 'Disease', (101, 113))	('human', 'Species', '9606', (95, 100))	('inhibition', 'Var', (26, 36))	('rat', 'Species', '10116', (74, 77))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('Mesothelin', 'Gene', '10232', (40, 50))	('Mesothelin', 'Gene', (40, 50))
75560	22485139	Mutant mice with inactivation of both copies of MSLN gene were generated with the purpose of studying the function of this protein although no detectable abnormalities were reported for this phenotype  http://clincancerres.aacrjournals.org/cgi/content/full/10/12/3937 - B8#B8.	('inactivation', 'Var', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('rat', 'Species', '10116', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('mice', 'Species', '10090', (7, 11))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('MSLN', 'Gene', (48, 52))	('cancer', 'Disease', (213, 219))
75565	22485139	In models such as ovarian cancer, analyses of correlation between MSLN expression, pathological variability and clinical outcomes indicated that high MSLN expression was positively associated with chemo-resistance in epithelial ovarian carcinoma patients and short patient survival time.	('patient', 'Species', '9606', (246, 253))	('ovarian cancer', 'Disease', (18, 32))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (217, 245))	('patients', 'Species', '9606', (246, 254))	('chemo-resistance', 'Disease', (197, 213))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (228, 245))	('MSLN', 'Gene', (150, 154))	('associated with', 'Reg', (181, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('patient', 'Species', '9606', (265, 272))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('epithelial ovarian carcinoma', 'Disease', (217, 245))	('high', 'Var', (145, 149))
75570	22485139	For example, MSLN was found to induce expression of matrix metalloproteinases 7 (MMP-7) or to enhance expression levels of interleukin 6 (IL-6).	('IL-6', 'Gene', '3569', (138, 142))	('MMP-7', 'molecular_function', 'GO:0004235', ('81', '86'))	('MMP-7', 'Gene', (81, 86))	('matrix metalloproteinases 7', 'Gene', (52, 79))	('expression', 'MPA', (38, 48))	('interleukin 6', 'Gene', (123, 136))	('induce', 'PosReg', (31, 37))	('MSLN', 'Var', (13, 17))	('enhance', 'PosReg', (94, 101))	('MMP-7', 'Gene', '4316', (81, 86))	('matrix metalloproteinases 7', 'Gene', '4316', (52, 79))	('interleukin 6', 'Gene', '3569', (123, 136))	('enhance expression levels of interleukin 6', 'Phenotype', 'HP:0030783', (94, 136))	('expression levels', 'MPA', (102, 119))	('IL-6', 'Gene', (138, 142))	('IL-6', 'molecular_function', 'GO:0005138', ('138', '142'))
75579	22485139	In this work, we studied the effects of silencing MSLN on viability, invasiveness and cell signaling pathways in cancer cells derived from mesothelioma, pancreatic and ovarian cancer.	('MSLN', 'Gene', (50, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (168, 182))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (113, 119))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('silencing', 'Var', (40, 49))	('mesothelioma', 'Disease', (139, 151))	('pancreatic and ovarian cancer', 'Disease', 'MESH:D010190', (153, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
75580	22485139	Furthermore, silencing MSLN by a lentivirus expressing anti-mesothelin microRNA (miRNA) was also found to significantly reduce the viability and invasiveness of ovarian cancer cells.	('invasiveness of ovarian cancer', 'Disease', 'MESH:D010051', (145, 175))	('reduce', 'NegReg', (120, 126))	('MSLN', 'Gene', (23, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('viability', 'CPA', (131, 140))	('invasiveness of ovarian cancer', 'Disease', (145, 175))	('silencing', 'Var', (13, 22))
75581	22485139	We have also investigated the outcome of silencing MSLN on cell signaling characteristics of cancer cells and cell cycle progression in order to further understand the pathways involved in the biological role of this antigen.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('silencing', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MSLN', 'Gene', (51, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
75618	22485139	As shown in figure 1B, once electroporated with the anti-MSLN siRNA, the expression of MSLN was notably reduced as early as 24-48 hours post-electroporation as compared with the negative control treated cells.	('reduced', 'NegReg', (104, 111))	('anti-MSLN', 'Var', (52, 61))	('rat', 'Species', '10116', (37, 40))	('rat', 'Species', '10116', (150, 153))	('expression', 'MPA', (73, 83))	('MSLN', 'Gene', (87, 91))
75629	22485139	In next step, we decided to test the effects of silencing MSLN in other MSLN-expressing cells including ovarian and pancreatic cancer cell lines and compare such effects with our data about mesothelioma cells.	('silencing', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (190, 202))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010190', (104, 133))	('test', 'Reg', (28, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('MSLN', 'Gene', (58, 62))	('mesothelioma', 'Disease', (190, 202))
75632	22485139	Electroporation of all above mentioned cancer cell lines resulted in a significant reduction in their viability (figure 2B-2D, results shown for Skov3, BxPC3 and MiapaCa2).	('rat', 'Species', '10116', (9, 12))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('BxPC3', 'CellLine', 'CVCL:0186', (152, 157))	('MiapaCa2', 'CellLine', 'CVCL:0428', (162, 170))	('Electroporation', 'Var', (0, 15))	('viability', 'MPA', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('reduction', 'NegReg', (83, 92))
75635	22485139	While all cancer cells showed significant loss of viability upon electroporation with anti-MSLN siRNA, cells with no expression of MSLN such as NIH3T3 did not exhibit significant changes in their proliferation rates once electroporated with anti-MSLN siRNA (targeting mouse MSLN).	('NIH3T3', 'CellLine', 'CVCL:0594', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mouse', 'Species', '10090', (268, 273))	('rat', 'Species', '10116', (74, 77))	('anti-MSLN', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('rat', 'Species', '10116', (210, 213))	('rat', 'Species', '10116', (230, 233))	('rat', 'Species', '10116', (203, 206))	('cancer', 'Disease', (10, 16))	('loss', 'NegReg', (42, 46))
75637	22485139	Therefore inhibition of MSLN can be considered as a potential strategy for targeting tumors such as mesothelioma, ovarian and pancreatic cancer in a cell specific manner.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('mesothelioma', 'Disease', (100, 112))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010190', (114, 143))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('rat', 'Species', '10116', (64, 67))	('MSLN', 'Gene', (24, 28))	('inhibition', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
75640	22485139	We were also interested in investigating the corollary of silencing MSLN on the invasiveness of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MSLN', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('silencing', 'Var', (58, 67))
75642	22485139	Therefore, it is a logical step to study the outcome of silencing mesothelin on the capabilities of cancer cells to invade.	('silencing', 'Var', (56, 65))	('mesothelin', 'Protein', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
75646	22485139	To this end, we had observed the loss of viability and invasiveness in a range of cancer cells upon silencing of MSLN.	('invasiveness', 'CPA', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MSLN', 'Gene', (113, 117))	('silencing', 'Var', (100, 109))	('loss', 'NegReg', (33, 37))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
75649	22485139	We observed that upon MSLN silencing, phospho-ERK1 and phospho-AKT activation levels were profoundly decreased while the levels of phospho-p38 remained unchanged (figure 3D).	('ERK1', 'Gene', (46, 50))	('p38', 'Gene', '5594', (139, 142))	('AKT', 'Gene', (63, 66))	('silencing', 'Var', (27, 36))	('MSLN', 'Gene', (22, 26))	('p38', 'Gene', (139, 142))	('decreased', 'NegReg', (101, 110))	('AKT', 'Gene', '207', (63, 66))	('ERK1', 'Gene', '5595', (46, 50))	('ERK1', 'molecular_function', 'GO:0004707', ('46', '50'))
75650	22485139	With involvement of ERK in proliferation and metastasis and also involvement of PI3K/AKT pathway in protection against apoptosis, a decrease in the activation of these signaling pathways can explain the anti-proliferative effects of silencing MSLN.	('involvement', 'Reg', (5, 16))	('rat', 'Species', '10116', (215, 218))	('ERK', 'molecular_function', 'GO:0004707', ('20', '23'))	('anti-proliferative', 'CPA', (203, 221))	('AKT', 'Gene', (85, 88))	('ERK', 'Gene', (20, 23))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('decrease', 'NegReg', (132, 140))	('MSLN', 'Gene', (243, 247))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('activation', 'MPA', (148, 158))	('involvement', 'Reg', (65, 76))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('metastasis', 'CPA', (45, 55))	('AKT', 'Gene', '207', (85, 88))	('silencing', 'Var', (233, 242))	('rat', 'Species', '10116', (34, 37))	('ERK', 'Gene', '5594', (20, 23))
75651	22485139	However, p38-pathway (involved in stress signaling, apoptosis and senescence) seemed to remain unaltered upon inhibition of MSLN.	('inhibition', 'Var', (110, 120))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('p38', 'Gene', (9, 12))	('senescence', 'biological_process', 'GO:0010149', ('66', '76'))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('MSLN', 'Gene', (124, 128))	('p38', 'Gene', '5594', (9, 12))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
75652	22485139	Since p38-kinase acts as a growth inhibitory pathway, it is conceivable that the capacity of cells to undergo growth inhibition and/or apoptosis (dictated by p38-kinase pathway) remains unaffected by silencing MSLN.	('apoptosis', 'CPA', (135, 144))	('growth inhibition', 'CPA', (110, 127))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('p38', 'Gene', '5594', (158, 161))	('silencing', 'Var', (200, 209))	('p38', 'Gene', '5594', (6, 9))	('MSLN', 'Gene', (210, 214))	('p38', 'Gene', (158, 161))	('p38', 'Gene', (6, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
75654	22485139	Beta-Catenin, one of Wnt down-stream signaling molecules and also an important player in EMT, was found to be significantly reduced upon silencing MSLN (figure 3D, the middle panel).	('Beta-Catenin', 'Gene', '1499', (0, 12))	('reduced', 'NegReg', (124, 131))	('Beta-Catenin', 'Gene', (0, 12))	('Wnt', 'Gene', '22408;22418', (21, 24))	('MSLN', 'Gene', (147, 151))	('Wnt', 'Gene', (21, 24))	('silencing', 'Var', (137, 146))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))
75655	22485139	Slug, another transcriptional repressor involved in EMT was found to be somewhat increased upon MSLN silencing.	('Slug', 'Gene', '6591', (0, 4))	('silencing', 'Var', (101, 110))	('Slug', 'Gene', (0, 4))	('MSLN', 'Gene', (96, 100))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('increased', 'PosReg', (81, 90))
75656	22485139	With considerations to the role of Slug in repression of E-Cadherin it would be a logical next step to evaluate the expression levels of E-Cadherin upon mesothelin silencing.	('Cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('E-Cadherin', 'Gene', (57, 67))	('rat', 'Species', '10116', (12, 15))	('E-Cadherin', 'Gene', '999', (57, 67))	('E-Cadherin', 'Gene', (137, 147))	('Slug', 'Gene', '6591', (35, 39))	('Slug', 'Gene', (35, 39))	('E-Cadherin', 'Gene', '999', (137, 147))	('silencing', 'Var', (164, 173))	('Cadherin', 'molecular_function', 'GO:0008014', ('139', '147'))
75664	22485139	The significant decrease observed in Ero1 upon MSLN silencing might result in a decreased capacity of cancer cells to fold and clear proteins leading to their eventual death (Figure 3D, lower panel).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('decrease', 'NegReg', (16, 24))	('clear proteins', 'MPA', (127, 141))	('capacity', 'MPA', (90, 98))	('death', 'Disease', 'MESH:D003643', (168, 173))	('cancer', 'Disease', (102, 108))	('death', 'Disease', (168, 173))	('decreased', 'NegReg', (80, 89))	('MSLN silencing', 'Var', (47, 61))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Ero1', 'Gene', (37, 41))	('fold', 'MPA', (118, 122))
75666	22485139	Such observation might be indicative of elevated levels of protein unfolding upon MSLN silencing as Bip levels are usually raised in the cell to combat aggregation of unfolded proteins.	('aggregation', 'MPA', (152, 163))	('silencing', 'Var', (87, 96))	('MSLN', 'Gene', (82, 86))	('protein unfolding', 'biological_process', 'GO:0043335', ('59', '76'))	('Bip', 'Gene', (100, 103))	('Bip', 'Gene', '3309', (100, 103))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
75671	22485139	Ovarian cancer cell line Ovca429 cells, with high levels of MSLN expression, were infected by MSLNmiR3 and its negative control counterpart (encoding scrambled sequence) at MOI~30.	('MSLN', 'Gene', (60, 64))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('MSLNmiR3', 'Var', (94, 102))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('Ovca429', 'CellLine', 'CVCL:5401', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian cancer', 'Disease', (0, 14))
75675	22485139	Also, the rate of loss of viability upon targeting cancer cells with anti-mesothelin lentivirus is notably slower as compared to silencing mesothelin by siRNA electroporation.	('loss', 'NegReg', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('rat', 'Species', '10116', (168, 171))	('slower', 'NegReg', (107, 113))	('rat', 'Species', '10116', (10, 13))	('anti-mesothelin', 'Var', (69, 84))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
75729	33542313	Several published studies show the synergistic effect of CLD in worsening the severity of COVID-19.	('CLD', 'Var', (57, 60))	('worsening', 'NegReg', (64, 73))	('COVID-19', 'Disease', (90, 98))	('COVID-19', 'Disease', 'MESH:C000657245', (90, 98))	('severity', 'MPA', (78, 86))
75764	33542313	Air pollution is also linked to cellular damage, inflammation, CVD, and CLD, which are potential comorbidities associated with COVID-19 severity.	('inflammation', 'biological_process', 'GO:0006954', ('49', '61'))	('age', 'Gene', (44, 47))	('CVD', 'Disease', 'MESH:D002318', (63, 66))	('CLD', 'Disease', (72, 75))	('COVID-19', 'Disease', 'MESH:C000657245', (127, 135))	('Air pollution', 'Var', (0, 13))	('CVD', 'Disease', (63, 66))	('age', 'Gene', '5973', (44, 47))	('COVID-19', 'Disease', (127, 135))	('linked', 'Reg', (22, 28))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('inflammation', 'Disease', (49, 61))
75787	33542313	Both linear and non-linear LGMs were applied to 1736 U.S. counties with MIR > 0, i.e., counties with at least one confirmed death between Mar 25 to Nov 12, 2020.	('death', 'Disease', (124, 129))	('MIR', 'Var', (72, 75))	('death', 'Disease', 'MESH:D003643', (124, 129))
75920	33542313	Among the demographic and environmental factors, male-WA% (OR 1.8) and PM (OR 1.1) are significantly associated with an 80% and 10% increase in the relative log-odds of being in cluster 7 vs. cluster 0.	('male-WA%', 'Var', (49, 57))	('increase', 'PosReg', (132, 140))	('OR 1.1', 'Gene', '81399', (75, 81))	('men', 'Species', '9606', (33, 36))	('OR 1.1', 'Gene', (75, 81))	('OR 1.8', 'Gene', '343406', (59, 65))	('OR 1.8', 'Gene', (59, 65))
75964	33542313	Besides heart diseases, we found significant positive associations between COVID-19 MIR and cancer, including mesothelioma (0.58% MIR  in the 1st wave) and pancreatic (0.51% MIR  in the 1st wave) in the United States.	('heart diseases', 'Disease', 'MESH:D006331', (8, 22))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('heart diseases', 'Disease', (8, 22))	('pancreatic', 'Disease', (156, 166))	('COVID-19', 'Disease', 'MESH:C000657245', (75, 83))	('MIR', 'Var', (84, 87))	('mesothelioma', 'Disease', (110, 122))	('COVID-19', 'Disease', (75, 83))	('positive', 'PosReg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))
75970	33542313	Our findings also indicated that demographics and social factors at the county level, such as mean age, drug use disorders, smokers%, uninsured%, and population density, significantly increased COVID-19 MIR by 0.12%, 0.08%, 0.11%, 0.08%, and 0.0003%, respectively.	('COVID-19', 'Disease', 'MESH:C000657245', (194, 202))	('age', 'Gene', (99, 102))	('drug use disorder', 'Disease', 'MESH:D019966', (104, 121))	('increased', 'PosReg', (184, 193))	('age', 'Gene', '5973', (99, 102))	('COVID-19', 'Disease', (194, 202))	('drug use disorder', 'Disease', (104, 121))	('uninsured%', 'Var', (134, 144))
76022	29928505	ZL55-SOhigh cells show an increased tumor-initiating capacity in vivo compared to the parental ZL55 cells.	('ZL55-SOhigh', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('increased', 'PosReg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
76032	29928505	Primary antibodies (CR7696, CR7697 or CR7699/4; SWANT, Marly, Switzerland) were used at a 1:500 dilution with overnight incubation at 4  C. The expression of murine Calb2 mRNA was detected by semi-quantitative RT-PCR.	('Calb2', 'Gene', (165, 170))	('murine', 'Species', '10090', (158, 164))	('CR7696', 'Var', (20, 26))	('CR7697', 'Var', (28, 34))
76055	29928505	in mice heterozygous for the tumor suppressor NF2 either wild-type (C57-NF2+/-) or null-mutant (C57-NF2+/-CR-/-) for the Calb2 gene.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('C57-NF2+/-', 'Var', (68, 78))	('Calb2', 'Gene', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('tumor', 'Disease', (29, 34))	('C57-NF2+/-CR-/-', 'Var', (96, 111))
76079	29928505	Moreover, primary mesothelial cells from CR-/- mice are characterized by a lower proliferation rate and are slower to close a scratch evidenced in a 2D-wound assay compared to primary mesothelial cells from wild-type mice.	('lower', 'NegReg', (75, 80))	('mice', 'Species', '10090', (217, 221))	('slower', 'NegReg', (108, 114))	('mice', 'Species', '10090', (47, 51))	('CR-/- mice', 'Var', (41, 51))
76089	29928505	However, frequency of gene loci deletions containing genes likely involved in MM formation were reported to be similar in samples from human MM and asbestos-exposed NF2+/- mice including CDKN2A, CDKN2B, CHD5, TP53, and NF2.	('CHD5', 'Gene', (203, 207))	('deletions', 'Var', (32, 41))	('CDKN2A', 'Gene', '12578', (187, 193))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('TP53', 'Gene', (209, 213))	('CDKN2A', 'Gene', (187, 193))	('CHD5', 'Gene', '269610', (203, 207))	('CDKN2B', 'Gene', '12579', (195, 201))	('asbestos', 'Chemical', 'MESH:D001194', (148, 156))	('CDKN2B', 'Gene', (195, 201))	('mice', 'Species', '10090', (172, 176))	('human', 'Species', '9606', (135, 140))	('TP53', 'Gene', '22059', (209, 213))
76090	29928505	In contrast, 14/15 cell lines derived from asbestos-injected mice of several mouse strains showed homologous deletions of the CDKN2A locus, but no chromosomal losses in either the BAP1 and NF2 regions and moreover no mutations in these 2 genes as well as in LATS2, commonly mutated in human MM; this might again hint towards species differences in the pathways leading to MM II).	('mice', 'Species', '10090', (61, 65))	('deletions', 'Var', (109, 118))	('BAP1', 'Gene', '104416', (180, 184))	('CDKN2A', 'Gene', '12578', (126, 132))	('CDKN2A', 'Gene', (126, 132))	('human', 'Species', '9606', (285, 290))	('LATS2', 'Gene', (258, 263))	('BAP1', 'Gene', (180, 184))	('asbestos', 'Chemical', 'MESH:D001194', (43, 51))	('mouse', 'Species', '10090', (77, 82))	('LATS2', 'Gene', '50523', (258, 263))
76176	28435296	The importance of VEGF-A in angiogenesis is underscored by the fact that even one mutant allele for this protein is embryonically lethal in mice.	('angiogenesis', 'biological_process', 'GO:0001525', ('28', '40'))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('mice', 'Species', '10090', (140, 144))	('VEGF-A', 'Gene', (18, 24))	('mutant', 'Var', (82, 88))
76211	28435296	A 2011 pooled analysis of Phase II and III trials of patients receiving chemotherapy and bevacizumab reported rates of VTE of 10.9% with bevacizumab versus 9.8% in controls (odds ratio, 1.14; 95% confidence interval: 0.96-1.35; P=0.13), suggesting that there is no increased risk of VTE in patients receiving bevacizumab.	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (290, 298))	('VTE', 'Disease', (283, 286))	('bevacizumab', 'Chemical', 'MESH:D000068258', (89, 100))	('bevacizumab', 'Chemical', 'MESH:D000068258', (137, 148))	('VTE', 'Disease', 'MESH:D054556', (119, 122))	('VTE', 'Disease', 'MESH:D054556', (283, 286))	('bevacizumab', 'Chemical', 'MESH:D000068258', (309, 320))	('bevacizumab', 'Var', (137, 148))	('VTE', 'Disease', (119, 122))
76214	28435296	Therefore, inhibition of VEGF-mediated signaling causes a decrease in NO-mediated signaling, resulting in arterial vasoconstriction and resultant hypertension.	('hypertension', 'Phenotype', 'HP:0000822', (146, 158))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('vasoconstriction', 'biological_process', 'GO:0042310', ('115', '131'))	('NO-mediated signaling', 'MPA', (70, 91))	('VEGF-mediated', 'Protein', (25, 38))	('decrease', 'NegReg', (58, 66))	('inhibition', 'Var', (11, 21))	('hypertension', 'Disease', 'MESH:D006973', (146, 158))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('hypertension', 'Disease', (146, 158))	('arterial vasoconstriction', 'MPA', (106, 131))
76245	28435296	In an unplanned post hoc analysis restricted to 44 patients with MPM, the PFS rate at 6 months was 52%, and an objective tumor RR of 35% and a median OS of 14.1 months were observed.	('PFS', 'CPA', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('MPM', 'Var', (65, 68))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
76363	27698933	Nucleotide excision repair (NER) is capable of removing numerous types of DNA helix-distorting lesions, which are induced by platinum.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('platinum', 'Chemical', 'MESH:D010984', (125, 133))	('Nucleotide', 'Var', (0, 10))	('DNA helix-distorting', 'Disease', (74, 94))	('Nucleotide excision repair', 'biological_process', 'GO:0006289', ('0', '26'))	('NER', 'biological_process', 'GO:0006289', ('28', '31'))
76364	27698933	The endonuclease excision repair cross-complementing 1 (ERCC1) performs an essential late step in the NER process, where it nicks the damaged DNA strand at the 5' site of the helix-distorting lesion, and is the rate-limiting member of the NER pathway.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('NER', 'biological_process', 'GO:0006289', ('102', '105'))	('NER', 'biological_process', 'GO:0006289', ('239', '242'))	('nicks', 'NegReg', (124, 129))	('ERCC1', 'Gene', '2067', (56, 61))	('ERCC1', 'Gene', (56, 61))	('damaged', 'Var', (134, 141))
76367	27698933	Defects in DNA MMR have been shown to be a mechanism of resistance to cisplatin both in vivo and in vitro.	('resistance to cisplatin', 'MPA', (56, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('Defects', 'Var', (0, 7))	('mechanism', 'Reg', (43, 52))	('DNA MMR', 'Gene', (11, 18))	('MMR', 'biological_process', 'GO:0006298', ('15', '18'))
76371	27698933	As DNA lesions occurring in mesothelioma are in majority single strand breaks, the BER pathway plays a crucial role in survival of these cells.	('mesothelioma', 'Disease', (28, 40))	('single strand breaks', 'Var', (57, 77))	('BER', 'biological_process', 'GO:0006284', ('83', '86'))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))	('DNA', 'cellular_component', 'GO:0005574', ('3', '6'))
76393	27698933	In contrast, high PARP1 expression levels were significantly associated with lymph node spread (p=0.0078).	('associated with', 'Reg', (61, 76))	('PARP1', 'Gene', '142', (18, 23))	('high', 'Var', (13, 17))	('expression levels', 'MPA', (24, 41))	('lymph node spread', 'CPA', (77, 94))	('PARP1', 'Gene', (18, 23))
76408	27698933	DNA double-strand breaks (DSBs) and DNA replication stress activate the ATM signalling pathways, which transduce the signal to downstream ATR/CHEK1 pathway.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('double-strand breaks', 'Var', (4, 24))	('ATM', 'Gene', '472', (72, 75))	('CHEK1', 'Gene', '1111', (142, 147))	('activate', 'PosReg', (59, 67))	('DNA replication', 'biological_process', 'GO:0006260', ('36', '51'))	('CHEK1', 'Gene', (142, 147))	('DSBs', 'Chemical', '-', (26, 30))	('signalling', 'biological_process', 'GO:0023052', ('76', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('ATR', 'Gene', '545', (138, 141))	('ATR', 'Gene', (138, 141))	('ATM', 'Gene', (72, 75))
76415	27698933	Of note, a direct inhibition of CHEK1 by small molecules already showed to promising results in vitro in breast cancer, in vivo in hepatic carcinoma as well as in mesothelioma.	('CHEK1', 'Gene', (32, 37))	('inhibition', 'NegReg', (18, 28))	('small molecules', 'Var', (41, 56))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (131, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mesothelioma', 'Disease', (163, 175))	('CHEK1', 'Gene', '1111', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('breast cancer', 'Disease', (105, 118))	('hepatic carcinoma', 'Disease', (131, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
76416	27698933	In contrast to other solid tumours, mutations of the TP53 gene are extremely rare in MPM, so other mechanisms such as deletion of the locus or methylation contribute to inactivation of TP53.	('solid tumours', 'Disease', (21, 34))	('TP53', 'Gene', (185, 189))	('methylation', 'Var', (143, 154))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('MPM', 'Disease', (85, 88))	('TP53', 'Gene', '7157', (185, 189))	('mutations', 'Var', (36, 45))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('methylation', 'biological_process', 'GO:0032259', ('143', '154'))	('TP53', 'Gene', '7157', (53, 57))	('solid tumours', 'Disease', 'MESH:D009369', (21, 34))	('deletion', 'Var', (118, 126))	('TP53', 'Gene', (53, 57))
76418	27698933	Gene amplification can lead to increased MDM2 protein expression.	('increased', 'PosReg', (31, 40))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('MDM2', 'Gene', '4193', (41, 45))	('Gene amplification', 'Var', (0, 18))	('MDM2', 'Gene', (41, 45))
76442	27698933	Interestingly, high PARP1 expression associated with lymph node invasion.	('expression', 'MPA', (26, 36))	('high', 'Var', (15, 19))	('associated with', 'Reg', (37, 52))	('PARP1', 'Gene', '142', (20, 25))	('PARP1', 'Gene', (20, 25))	('lymph node invasion', 'CPA', (53, 72))
76443	27698933	Homologue recombination (HR) and non-homologous end-joining (NHEJ) are of great importance, since DNA DSBs induce chromosomal deletions and translocations which are common in MPM.	('translocations', 'CPA', (140, 154))	('induce', 'Reg', (107, 113))	('chromosomal deletions', 'CPA', (114, 135))	('NHEJ', 'biological_process', 'GO:0006303', ('61', '65'))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('DSBs', 'Chemical', '-', (102, 106))	('DNA DSBs', 'Var', (98, 106))
76450	27698933	Deregulation of H2AFX expression and modification has been reported to be associated with a variety of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('Deregulation', 'Var', (0, 12))	('malignancies', 'Disease', (109, 121))	('human', 'Species', '9606', (103, 108))	('H2AFX', 'Gene', '3014', (16, 21))	('H2AFX', 'Gene', (16, 21))	('modification', 'MPA', (37, 49))	('expression', 'MPA', (22, 32))	('associated', 'Reg', (74, 84))
76462	20920304	To acquire a fully transformed phenotype, cancer cells must bypass senescence induced by such stimuli and continue to proliferate, commonly by inactivation of core sentinels of cellular stress such as p53 and pRb.	('inactivation', 'Var', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('p53', 'Gene', (201, 204))	('senescence', 'biological_process', 'GO:0010149', ('67', '77'))	('core', 'cellular_component', 'GO:0019013', ('159', '163'))	('p53', 'Gene', '7157', (201, 204))	('cancer', 'Disease', (42, 48))	('pRb', 'Gene', '5925', (209, 212))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('pRb', 'Gene', (209, 212))
76528	20920304	Although we found somewhat lower scores overall, the trend toward higher expression of DAS than mSS is preserved in our hands in both lines (GSE5846 DAS scores: 75%, both cell lines; GSE5846 mSS scores: 56.3%, both cell lines; our cells DAS scores: 45.5% and 40.9%; our cells mSS scores: 33.3%, both lines).	('mSS', 'Gene', '23956', (96, 99))	('DAS', 'Chemical', '-', (237, 240))	('mSS', 'Gene', (191, 194))	('mSS', 'Gene', (276, 279))	('DAS', 'Chemical', '-', (87, 90))	('DAS', 'Chemical', '-', (149, 152))	('GSE5846', 'Chemical', '-', (141, 148))	('mSS', 'Gene', '23956', (191, 194))	('mSS', 'Gene', '23956', (276, 279))	('GSE5846', 'Chemical', '-', (183, 190))	('mSS', 'Gene', (96, 99))	('GSE5846', 'Var', (183, 190))
76537	20920304	Examples of significant regressions using the DAS and mSS signatures are shown in figures 4A and 4B, respectively, for compounds NSC300288 (p = 0.0015, slope = -3.34) and NSC638279 (p = 0.0002, slope = -4.04).	('NSC638279', 'Var', (171, 180))	('mSS', 'Gene', (54, 57))	('NSC300288', 'Var', (129, 138))	('DAS', 'Chemical', '-', (46, 49))	('mSS', 'Gene', '23956', (54, 57))
76540	20920304	This analysis revealed that cell lines with high DAS and high mSS are generally more sensitive to compound induced growth inhibition, as shown by the overall negative regression slopes (average DAS slope = -2.41; average mSS slope = -1.93).	('high', 'Var', (44, 48))	('mSS', 'Gene', (62, 65))	('mSS', 'Gene', '23956', (62, 65))	('high', 'Var', (57, 61))	('DAS', 'Chemical', '-', (49, 52))	('negative', 'NegReg', (158, 166))	('mSS', 'Gene', (221, 224))	('DAS', 'Chemical', '-', (194, 197))	('mSS', 'Gene', '23956', (221, 224))	('growth', 'MPA', (115, 121))
76551	20920304	For example differences in extant/latent senescence signalling could affect factors such as patient prognosis and response to therapy.	('extant/latent senescence signalling', 'MPA', (27, 62))	('senescence', 'biological_process', 'GO:0010149', ('41', '51'))	('affect', 'Reg', (69, 75))	('patient', 'Species', '9606', (92, 99))	('signalling', 'biological_process', 'GO:0023052', ('52', '62'))	('differences', 'Var', (12, 23))
76593	20920304	By regression analysis we found a subset of compounds for which GI50 across the cell panel significantly correlated with DAS or mSS score.	('DAS', 'MPA', (121, 124))	('mSS', 'Gene', (128, 131))	('correlated', 'Reg', (105, 115))	('mSS', 'Gene', '23956', (128, 131))	('DAS', 'Chemical', '-', (121, 124))	('GI50', 'Var', (64, 68))
76624	12610498	Irradiation for MPM assists in repelling tumour growth and temporarily relieving pain, but not attaining appreciably lengthened overall survival time (Kutcher et al, 1987; Soubra et al, 1990; Bissett et al, 1991).	('pain', 'Disease', (81, 85))	('tumour growth', 'Disease', (41, 54))	('repelling', 'NegReg', (31, 40))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour growth', 'Disease', 'MESH:D006130', (41, 54))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('relieving', 'NegReg', (71, 80))	('MPM', 'Var', (16, 19))	('pain', 'Disease', 'MESH:D010146', (81, 85))
76677	12610498	ZD0473 A phase II trial (Giaccone et al, 2001) assessed the efficacy of the new generation platinum compound ZD0473 at 120 mg m-2 on day 1 of a 21-day cycle in mesothelioma patients that had relapsed after previous platinum-based chemotherapy.	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('patients', 'Species', '9606', (173, 181))	('platinum', 'Chemical', 'MESH:D010984', (91, 99))	('platinum', 'Chemical', 'MESH:D010984', (215, 223))	('ZD0473', 'Var', (109, 115))	('mesothelioma', 'Disease', (160, 172))
76720	12610498	A phase I study conducted in 1999 first investigated the activity of the multitargeted antifolate pemetrexed (LY231514, ALIMTA ) combined with cisplatin in patients presenting with solid tumours (Thodtmann et al, 1999).	('patients', 'Species', '9606', (156, 164))	('LY231514', 'Chemical', 'MESH:D000068437', (110, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('pemetrexed', 'Chemical', 'MESH:D000068437', (98, 108))	('solid tumours', 'Disease', 'MESH:D009369', (181, 194))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('activity', 'MPA', (57, 65))	('solid tumours', 'Disease', (181, 194))	('LY231514', 'Var', (110, 118))	('folate', 'Chemical', 'MESH:D005492', (91, 97))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
76724	12610498	The combination of pemetrexed-cisplatin resulted in superior median overall survival, response rate, lung function and subjective quality-of-life measures (Vogelzang N http://www.asco.org/asco/ascoMainConstructor/1,47468,_12 002351,00.asp?cat=General+Oncology).	('lung', 'MPA', (101, 105))	('superior', 'PosReg', (52, 60))	('pemetrexed-cisplatin', 'Chemical', '-', (19, 39))	('pemetrexed-cisplatin', 'Var', (19, 39))	('Oncology', 'Phenotype', 'HP:0002664', (251, 259))	('overall survival', 'MPA', (68, 84))	('cat', 'molecular_function', 'GO:0004096', ('239', '242'))	('response', 'MPA', (86, 94))
76751	12610498	In particular, pemetrexed with cisplatin has demonstrated superior median overall survival, response rate, lung function and quality-of-life measures in the largest randomised trial in MPM.	('lung function', 'CPA', (107, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('response', 'CPA', (92, 100))	('pemetrexed', 'Chemical', 'MESH:D000068437', (15, 25))	('pemetrexed', 'Var', (15, 25))
76881	29723687	BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively.	('p16', 'Gene', (33, 36))	('BAP1', 'Gene', (0, 4))	('CDKN2A', 'Gene', (26, 32))	('CDKN2A', 'Gene', '1029', (26, 32))	('p16', 'Gene', '1029', (33, 36))	('deletion', 'Var', (49, 57))	('loss', 'NegReg', (17, 21))	('BAP1', 'Gene', '8314', (0, 4))	('HD', 'Disease', 'MESH:D006816', (59, 61))
76930	29723687	p16 loss of expression was not considered as a definitive argument of malignancy in the absence of homozygous CDKN2A (p16) deletion by FISH analysis.	('CDKN2A', 'Gene', (110, 116))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('CDKN2A', 'Gene', '1029', (110, 116))	('p16', 'Gene', '1029', (118, 121))	('malignancy', 'Disease', (70, 80))	('p16', 'Gene', (0, 3))	('deletion', 'Var', (123, 131))	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', (118, 121))	('loss of expression', 'NegReg', (4, 22))
76931	29723687	CDKN2A (p16) FISH for detection of homozygous deletion of CDKN2A (p16) was performed using the dual-color FISH analysis for the CDKN2A locus (9p21) and the centromere of the chromosome 9 (CEP-9), using the ZytoVision (Bremerhaven, Germany) probe (ZytoLight SPEC CDKN2A/CEN 9 Dual Color Probe, # Z-2063-200) and was used from fresh serial recuts of 3 mu to 5 mu in thickness from the FFPE block stored in the correct conditions.	('CDKN2A', 'Gene', '1029', (262, 268))	('p16', 'Gene', (66, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('centromere', 'cellular_component', 'GO:0000775', ('156', '166'))	('CDKN2A', 'Gene', (58, 64))	('p16', 'Gene', '1029', (66, 69))	('p21', 'Gene', (143, 146))	('centromere', 'cellular_component', 'GO:0005698', ('156', '166'))	('deletion', 'Var', (46, 54))	('SPEC', 'molecular_function', 'GO:0004586', ('257', '261'))	('p21', 'Gene', '644914', (143, 146))	('p16', 'Gene', (8, 11))	('CDKN2A', 'Gene', '1029', (58, 64))	('CDKN2A', 'Gene', (128, 134))	('p16', 'Gene', '1029', (8, 11))	('CDKN2A', 'Gene', (0, 6))	('CEP', 'molecular_function', 'GO:0047849', ('188', '191'))	('CDKN2A', 'Gene', (262, 268))	('CDKN2A', 'Gene', '1029', (128, 134))	('CDKN2A', 'Gene', '1029', (0, 6))
76934	29723687	A cutoff value of 20% of nuclei with no CDKN2A copy was considered as positive results for the presence of a homozygous deletion in both components.	('deletion', 'Var', (120, 128))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))
76936	29723687	The presence of homozygous CDKN2A(p16) deletion by FISH analysis on the spindle cells component was also regarded as a criterion for malignancy.	('malignancy', 'Disease', (133, 143))	('malignancy', 'Disease', 'MESH:D009369', (133, 143))	('p16', 'Gene', (34, 37))	('deletion', 'Var', (39, 47))	('CDKN2A', 'Gene', (27, 33))	('p16', 'Gene', '1029', (34, 37))	('CDKN2A', 'Gene', '1029', (27, 33))	('spindle', 'cellular_component', 'GO:0005819', ('72', '79'))
76954	29723687	Additionally, we observed that there was a trend for patients with a high-grade spindle cell component to have shorter survival than the low-grade group (p = 0.08) (Table 1) (Figs 1D-1E and 4).	('high-grade', 'Var', (69, 79))	('patients', 'Species', '9606', (53, 61))	('survival', 'MPA', (119, 127))	('shorter', 'NegReg', (111, 118))	('spindle', 'cellular_component', 'GO:0005819', ('80', '87'))
76962	29723687	We then considered the contribution of BAP1 IHC and loss of CDKN2A (p16 HD) by FISH analysis for the evaluation of the spindle cells component (Table 2).	('p16', 'Gene', (68, 71))	('loss', 'Var', (52, 56))	('spindle', 'cellular_component', 'GO:0005819', ('119', '126'))	('CDKN2A', 'Gene', (60, 66))	('BAP1', 'Gene', '8314', (39, 43))	('CDKN2A', 'Gene', '1029', (60, 66))	('p16', 'Gene', '1029', (68, 71))	('HD', 'Disease', 'MESH:D006816', (72, 74))	('BAP1', 'Gene', (39, 43))
76965	29723687	The presence of homozygous CDKN2A (P16) deletion by FISH analysis on the spindle cell component was also regarded as a criterion for malignancy (Figs.	('malignancy', 'Disease', (133, 143))	('malignancy', 'Disease', 'MESH:D009369', (133, 143))	('deletion', 'Var', (40, 48))	('spindle', 'cellular_component', 'GO:0005819', ('73', '80'))	('P16', 'Gene', (35, 38))	('CDKN2A', 'Gene', (27, 33))	('P16', 'Gene', '1029', (35, 38))	('CDKN2A', 'Gene', '1029', (27, 33))
76987	29723687	also reported that nuclear atypia, mitotic count, atypical mitoses, nuclear atypia, prominent nucleoli, and necrosis were predictive of OS.	('atypical', 'Var', (50, 58))	('necrosis', 'biological_process', 'GO:0001906', ('108', '116'))	('necrosis', 'Disease', (108, 116))	('mitotic count', 'CPA', (35, 48))	('necrosis', 'biological_process', 'GO:0070265', ('108', '116'))	('necrosis', 'Disease', 'MESH:D009336', (108, 116))	('nuclear', 'CPA', (19, 26))	('necrosis', 'biological_process', 'GO:0008219', ('108', '116'))	('nuclear', 'CPA', (68, 75))	('necrosis', 'biological_process', 'GO:0019835', ('108', '116'))	('necrosis', 'biological_process', 'GO:0008220', ('108', '116'))
76996	29723687	They observed that BAP1 loss was seen in 3 of 20 (15%) and deletion of p16 by FISH was seen in 16 of 20 (80%) of such difficult lesion cases.	('p16', 'Gene', (71, 74))	('BAP1', 'Gene', '8314', (19, 23))	('p16', 'Gene', '1029', (71, 74))	('BAP1', 'Gene', (19, 23))	('deletion', 'Var', (59, 67))	('loss', 'NegReg', (24, 28))
76997	29723687	Moreover, the presence of HD (p16) was a stronger and more sensitive indicator of poor prognosis when observed on both component (E and S) by multivariate analysis (p = 0.02) compared when present only in the epithelioid component showing a better outcome.	('HD', 'Disease', 'MESH:D006816', (26, 28))	('p16', 'Gene', '1029', (30, 33))	('p16', 'Gene', (30, 33))	('presence', 'Var', (14, 22))
77004	29723687	Additionally, high metabolic activity at 18-fluorodesoxyglucose positron-emission tomography in the primary tumor has been considered to be associated with a shorter OS.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('high', 'Var', (14, 18))	('shorter OS', 'Disease', (158, 168))	('18-fluorodesoxyglucose', 'Chemical', '-', (41, 63))
77026	31602579	In patients with colorectal cancer, macroscopically complete cytoreduction is associated with improved survival compared with limited cytoreduction.	('survival', 'MPA', (103, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('macroscopically', 'Var', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Disease', (17, 34))	('improved', 'PosReg', (94, 102))	('patients', 'Species', '9606', (3, 11))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
77055	31602579	Serum albumin concentration >= 3.85 g/dL was associated with decreased odds of undergoing CCR2/3 resection on univariate analysis.	('CCR2/3', 'Gene', '729230;1232', (90, 96))	('Serum albumin concentration', 'MPA', (0, 27))	('decreased', 'NegReg', (61, 70))	('CCR', 'molecular_function', 'GO:0043880', ('90', '93'))	('CCR2/3', 'Gene', (90, 96))	('>= 3.85', 'Var', (28, 35))
77058	31602579	male gender, presence of ascites, CA-125 >= 40 U/mL, and CEA >= 4.2 ng/mL.	('CA-125 >=', 'Var', (34, 43))	('ascites', 'Disease', (25, 32))	('ascites', 'Phenotype', 'HP:0001541', (25, 32))	('CEA', 'Gene', (57, 60))	('ascites', 'Disease', 'MESH:D001201', (25, 32))	('mL', 'Gene', '21832', (49, 51))	('CEA', 'Gene', '1084', (57, 60))	('mL', 'Gene', '21832', (71, 73))
77124	31314677	Ovarian cancer cases were classified by histologic type: serous (ICD-O-3 histology codes 8441, 8460, 8461, 9014), mucinous (8243, 8470, 8471, 8480-8482, 9015), endometrioid (8380-8383, 8560, 8570, 8930, 8933, 8950-8951, 8980), clear cell (8310, 8313), other epithelial (8010-8015, 8020-22, 8030-8033, 8035, 8041-8042, 8045,8050,8052,8070-8074, 8120, 8130, 8140-8141, 8144, 8160, 8201, 8230-8231, 8244, 8249-8250, 8255, 8260, 8262-8263, 8320, 8323, 8330, 8340, 8401, 8430, 8440, 8450, 8490, 8503-8504, 8562, 8572, 8574-8575, 9000), stromal tumors (8590, 8600, 8620-8621, 8623, 8630-8631, 8632, 8634, 8640, 8670, 8810), and germ cell tumors (8240, 8245-8246, 9060, 9064-9065, 9070-9072, 9080-9085, 9090-9091, 9100-9101, 9105, 9364, 9392, 9473).	('germ cell tumors', 'Phenotype', 'HP:0100728', (622, 638))	('9080-9085', 'Var', (685, 694))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('9064-9065', 'Var', (663, 672))	('tumors', 'Disease', (539, 545))	('cancer', 'Disease', (8, 14))	('8240, 8245-8246, 9060, 9064-9065, 9070-9072, 9080-9085, 9090-9091, 9100-9101, 9105, 9364, 9392', 'Mutation', 'c.8240,8245-8246dup', (640, 734))	('tumors', 'Phenotype', 'HP:0002664', (632, 638))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('stromal tumors', 'Disease', (531, 545))	('tumors', 'Disease', 'MESH:D009369', (539, 545))	('tumors', 'Disease', (632, 638))	('9070-9072', 'Var', (674, 683))	('8590', 'Var', (547, 551))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('germ cell', 'CPA', (622, 631))	('tumors', 'Disease', 'MESH:D009369', (632, 638))	('8240', 'Var', (640, 644))	('stromal tumors', 'Disease', 'MESH:D036821', (531, 545))	('9100-9101', 'Var', (707, 716))	('tumors', 'Phenotype', 'HP:0002664', (539, 545))
77226	27886124	Blockade of these inhibitory receptors may partially restore T cell function improving their ability to eradicate cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Blockade', 'Var', (0, 8))	('T cell function', 'CPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
77227	27886124	The clinical success of PD-1 inhibitors and anti CTLA-4 antibodies has validated this concept.	('CTLA-4', 'Gene', (49, 55))	('inhibitors', 'Var', (29, 39))	('PD-1', 'Gene', (24, 28))	('CTLA-4', 'Gene', '1493', (49, 55))
77228	27886124	The two major classes of checkpoint inhibitors currently used in the clinic are anti CTLA-4 antibodies (e.g., Ipilimumab) and anti PD-1 (Nivolumab, and Pembrolizumab) antibodies.	('Nivolumab', 'Chemical', 'MESH:D000077594', (137, 146))	('CTLA-4', 'Gene', '1493', (85, 91))	('anti', 'Var', (80, 84))	('CTLA-4', 'Gene', (85, 91))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (110, 120))	('PD-1', 'Gene', (131, 135))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (152, 165))
77238	27886124	In addition, there is some evidence that PD-1/PD-L1 interaction is key to the maintenance of Treg cells and thus blockade of this pathway may boost anti-tumor immunity in the tumor micro environment by affecting different cell types.	('boost', 'PosReg', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (175, 180))	('blockade', 'Var', (113, 121))	('affecting', 'Reg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
77241	27886124	CTLA-4 inhibition may affect broader T cell function and this may explain why anti CTLA-4 antibodies are associated with higher grade 3 immune side effects when compared to PD-1 inhibitors.	('CTLA-4', 'Gene', (0, 6))	('CTLA-4', 'Gene', (83, 89))	('broader T cell', 'CPA', (29, 43))	('affect', 'Reg', (22, 28))	('CTLA-4', 'Gene', '1493', (0, 6))	('CTLA-4', 'Gene', '1493', (83, 89))	('anti', 'Var', (78, 82))	('antibodies', 'Var', (90, 100))
77243	27886124	Ipilimumab, the anti-CTLA-4 antibody, was the first to be studied but with the advent of the PD-1 inhibitors which have a better toxicity and response profile, its use as a single agent has decreased in the clinic.	('toxicity', 'Disease', (129, 137))	('antibody', 'molecular_function', 'GO:0003823', ('28', '36'))	('CTLA-4', 'Gene', (21, 27))	('antibody', 'cellular_component', 'GO:0019814', ('28', '36'))	('inhibitors', 'Var', (98, 108))	('antibody', 'cellular_component', 'GO:0019815', ('28', '36'))	('antibody', 'cellular_component', 'GO:0042571', ('28', '36'))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('PD-1', 'Gene', (93, 97))	('CTLA-4', 'Gene', '1493', (21, 27))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))
77266	27886124	PD-1 inhibitors namely nivolumab and pembrolizumab are also being studied as adjuvant therapy in phase III studies (NCT02388906, NCT02362594, S1404) and results are awaited.	('NCT02388906', 'Var', (116, 127))	('NCT02362594', 'Var', (129, 140))	('PD-1', 'Gene', (0, 4))	('nivolumab', 'Chemical', 'MESH:D000077594', (23, 32))	('pembrolizumab', 'Chemical', 'MESH:C582435', (37, 50))	('S1404', 'Var', (142, 147))
77275	27886124	However, in contrast to the squamous lung cancer patients in Checkmate 017, PD-L1 positive status seemed to predict for response and improved survival in non squamous patients.	('survival', 'MPA', (142, 150))	('positive status', 'Var', (82, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('predict', 'Reg', (108, 115))	('squamous lung cancer', 'Disease', (28, 48))	('patients', 'Species', '9606', (167, 175))	('squamous lung cancer', 'Disease', 'MESH:D008175', (28, 48))	('response', 'Disease', (120, 128))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (28, 48))	('patients', 'Species', '9606', (49, 57))	('improved', 'PosReg', (133, 141))	('non', 'Disease', (154, 157))	('PD-L1', 'Gene', (76, 81))
77285	27886124	Current efforts are focused on establishing these agents as first line therapy in various phase 3 studies, either as monotherapy in PD-L1 positive NSCLC (CheckMate 026 NCT02041533, KEYNOTE-024 NCT02142738, MYSTIC NCT02453282) or in combination with ipilimumab or chemotherapy (CheckMate 227 NCT02477826, KEYNOTE-189 NCT02578680, KEYNOTE-407 NCT02775435, NEPTUNE NCT02542293, Impower 132 NCT02657434, Impower 150 NCT02366143).	('ipilimumab', 'Chemical', 'MESH:D000074324', (249, 259))	('NSCLC', 'Disease', (147, 152))	('Impower 132 NCT02657434', 'Var', (375, 398))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))
77288	27886124	At six months, 80.2% of patients in the pembrolizumab group were alive compared to 72.4% in the chemotherapy group (HR for death, 0.60; 95% CI, 0.41 to 0.89; p = 0.005) Pembrolizumab was associated with higher response rates (44.8% vs. 27.8%) and the responses were very durable with median duration not reached in the immunotherapy group (range 1.9+ to 14.5+ months) vs. 6.3 months in the chemotherapy group.	('Pembrolizumab', 'Chemical', 'MESH:C582435', (169, 182))	('death', 'Disease', 'MESH:D003643', (123, 128))	('patients', 'Species', '9606', (24, 32))	('death', 'Disease', (123, 128))	('higher', 'PosReg', (203, 209))	('response', 'MPA', (210, 218))	('pembrolizumab', 'Chemical', 'MESH:C582435', (40, 53))	('Pembrolizumab', 'Var', (169, 182))
77291	27886124	Beyond first line-therapy for metastatic disease, various clinical trials currently are also exploring its use in other settings, such as consolidation therapy after concurrent chemoradiation in locally advanced NSCLC (PACIFIC NCT02125461) or as adjuvant therapy in resected NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('NSCLC', 'Disease', (275, 280))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('PACIFIC NCT02125461', 'Var', (219, 238))	('NSCLC', 'Disease', (212, 217))
77303	27886124	When compared to the mTOR inhibitor everolimus, blockade of PD-1 signaling with nivolumab in the phase 3 CheckMate 025 increased median OS (25.0 months vs. 19.6 months), decreased hazard ratio (0.73; p = 0.002), and increased ORR (25% vs. 5%; p < 0.001) in patients who had received prior anti-angiogenic therapy.	('ORR', 'MPA', (226, 229))	('median OS', 'MPA', (129, 138))	('nivolumab', 'Chemical', 'MESH:D000077594', (80, 89))	('everolimus', 'Chemical', 'MESH:D000068338', (36, 46))	('blockade', 'Var', (48, 56))	('decreased', 'NegReg', (170, 179))	('PD-1 signaling', 'Gene', (60, 74))	('OS', 'Chemical', '-', (136, 138))	('patients', 'Species', '9606', (257, 265))	('hazard ratio', 'MPA', (180, 192))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))	('increased', 'PosReg', (216, 225))	('increased', 'PosReg', (119, 128))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
77311	27886124	Additional data from recently completed or ongoing phase 3 trials with either anti-PD-1 monotherapy or in combination regimens (IMvigor 2011 NCT02302807, JAVELIN Bladder 100 NCT02603432, NCT02516241), which may help further elucidate the utility of these therapeutic agents in urothelial cancers.	('urothelial cancers', 'Disease', 'MESH:D014523', (277, 295))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('urothelial cancers', 'Disease', (277, 295))	('anti-PD-1', 'Gene', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('NCT02516241', 'Var', (187, 198))
77327	27886124	A Phase II trial characterizing the role of anti-PD1 immunotherapy in patients with colorectal cancers with high microsatellite instability (MSI) found that patients with colorectal cancers that have deficient mismatch repair mechanism had significantly improved responses (40%) and immune-related progression-free survival rates (78%) than those who had cancers with an intact mismatch repair (0% and 11% respectively).	('patients', 'Species', '9606', (157, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('colorectal cancers', 'Disease', (84, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('patients', 'Species', '9606', (70, 78))	('cancers', 'Disease', 'MESH:D009369', (355, 362))	('improved', 'PosReg', (254, 262))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('colorectal cancers', 'Disease', (171, 189))	('cancers', 'Disease', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mismatch repair', 'biological_process', 'GO:0006298', ('378', '393'))	('cancers', 'Disease', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('colorectal cancers', 'Disease', 'MESH:D015179', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (355, 362))	('colorectal cancers', 'Disease', 'MESH:D015179', (171, 189))	('deficient', 'Var', (200, 209))	('cancers', 'Disease', (355, 362))	('mismatch repair', 'biological_process', 'GO:0006298', ('210', '225'))	('MSI', 'Disease', 'None', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('immune-related progression-free survival rates', 'CPA', (283, 329))	('MSI', 'Disease', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('responses', 'CPA', (263, 272))
77328	27886124	These results demonstrated a hazard ratio of 0.10 for disease progression or death with p < 0.001 for PD-1 blockade in mismatch repair deficient colorectal cancer.	('death', 'Disease', 'MESH:D003643', (77, 82))	('PD-1', 'Gene', (102, 106))	('death', 'Disease', (77, 82))	('deficient colorectal cancer', 'Disease', 'MESH:D015179', (135, 162))	('deficient colorectal cancer', 'Disease', (135, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('mismatch repair', 'biological_process', 'GO:0006298', ('119', '134'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mismatch', 'Var', (119, 127))
77330	27886124	The study also found that genomic analysis of tumors without mismatch repair demonstrated a mean of 1782 somatic mutations, while the proficient tumors only averaged 73 mutations Importantly, membranous PD-L1 expression was only observed in patients with mismatch repair deficient cancers.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('deficient cancers', 'Disease', 'MESH:D009369', (271, 288))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('deficient cancers', 'Disease', (271, 288))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('mismatch repair', 'biological_process', 'GO:0006298', ('255', '270'))	('mutations', 'Var', (113, 122))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('mismatch repair', 'biological_process', 'GO:0006298', ('61', '76'))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', (46, 52))	('patients', 'Species', '9606', (241, 249))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
77331	27886124	These findings reveal the importance of anti-PD1 immunotherapy not only for disruption of the PD1 signaling cascade, but also the ability of this inhibition to prime the immune system to response robustly to highly mutagenic cancers that may be expressing neoantigens.	('anti-PD1', 'Var', (40, 48))	('response', 'MPA', (187, 195))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancers', 'Disease', (225, 232))	('signaling cascade', 'biological_process', 'GO:0007165', ('98', '115'))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
77354	27886124	The amplification of chromosome 9p24.1 increases the expression of JAK2, which increases PD-1 ligand expression.	('PD-1', 'Protein', (89, 93))	('JAK', 'molecular_function', 'GO:0004713', ('67', '70'))	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('increases', 'PosReg', (79, 88))	('JAK2', 'Gene', (67, 71))	('increases PD', 'Phenotype', 'HP:0008151', (79, 91))	('amplification', 'Var', (4, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('expression', 'MPA', (53, 63))	('increases', 'PosReg', (39, 48))	('expression', 'MPA', (101, 111))	('JAK2', 'Gene', '3717', (67, 71))
77360	27886124	Importantly, FISH analysis of the tumor cells in a subgroup of patients with available tumor specimen demonstrated that Reed-Sternberg cells showed 3-15 copies of the PDL1 and PDL2 genes, correlating response to amplification, copy number gain or polysomy of the immunotherapy target.	('polysomy', 'Var', (247, 255))	('copy number gain', 'Disease', 'MESH:D015430', (227, 243))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PDL1', 'Gene', (167, 171))	('tumor', 'Disease', (87, 92))	('PDL2', 'Gene', '80380', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (63, 71))	('copy number gain', 'Disease', (227, 243))	('PDL2', 'Gene', (176, 180))
77372	27886124	studied mutational burden in two cohorts of lung cancer patients receiving pembrolizumab and found that the increased burden of nonsynonymous mutations seem to correlate with durable clinical benefit (DCB) defined as partial response or stable response lasting >6 months.	('patients', 'Species', '9606', (56, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('nonsynonymous mutations', 'Var', (128, 151))	('DCB', 'Chemical', '-', (201, 204))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('partial response', 'Disease', (217, 233))	('lung cancer', 'Disease', (44, 55))
77373	27886124	In the group with the high burden of mutations, DCB was noted in 73% compared to 13% with low burden.	('DCB', 'Disease', (48, 51))	('mutations', 'Var', (37, 46))	('DCB', 'Chemical', '-', (48, 51))
77375	27886124	Similarly, it has been shown that efficacy of anti CTLA4 antibodies in melanoma is linked to the mutational burden and the presence of neoantigens.	('CTLA4', 'Gene', '1493', (51, 56))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('anti', 'Var', (46, 50))	('CTLA4', 'Gene', (51, 56))
77380	27886124	More recently, structural variants in the 3'untranslated region of the PD-L1 were described as a potential genetic marker of response to anti-PD1 checkpoint inhibitor therapy These structural variants affected multiple cancer types, including adult T-cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), gastric adenocarcinoma (2%).	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('variants', 'Var', (192, 200))	('T-cell leukemia/lymphoma', 'Disease', (249, 273))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (265, 273))	('leukemia', 'Phenotype', 'HP:0001909', (256, 264))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (317, 339))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('gastric adenocarcinoma', 'Disease', (317, 339))	('B-cell lymphoma', 'Disease', (295, 310))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (295, 310))	('cancer', 'Disease', (219, 225))	('T-cell leukemia/lymphoma', 'Disease', 'MESH:D016399', (249, 273))	('affected', 'Reg', (201, 209))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (295, 310))	('lymphoma', 'Phenotype', 'HP:0002665', (302, 310))	('cell lymphoma', 'Phenotype', 'HP:0012191', (297, 310))	('T-cell leukemia/lymphoma', 'Phenotype', 'HP:0005517', (249, 273))
77382	27886124	These seem more prevalent with anti CTLA4 antibodies compared to anti PD-1/PDL1 agents as the former act in the antigen priming phase.	('CTLA4', 'Gene', (36, 41))	('anti', 'Var', (31, 35))	('prevalent', 'Reg', (16, 25))	('antibodies', 'Var', (42, 52))	('CTLA4', 'Gene', '1493', (36, 41))
77401	27886124	Radiation can lead to tumor shrinkage outside the radiation field, the so-called "abscopal effect" which is thought to be from the activation of the immune system by tumor specific antigens released by malignant cells killed by radiation.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Radiation', 'Var', (0, 9))	('tumor', 'Disease', (22, 27))
77409	27886124	Blockade of KIR boosts NK-mediated killing of tumor cells and thus provide rationale for further clinical evaluation.	('KIR', 'Gene', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (46, 51))	('boosts', 'PosReg', (16, 22))	('KIR', 'Gene', '3805', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
77476	27245839	We then applied this GSEA strategy to the three remaining MPM gene expression datasets [GSE2549, GSE12345, GSE51024] (outlined in Fig.	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('GSE51024]', 'Var', (107, 116))	('GSE12345', 'Var', (97, 105))	('GSEA', 'Chemical', '-', (21, 25))	('GSE2549', 'CellLine', 'CVCL:6F81', (88, 95))
77480	27245839	The miR-17 ~ 92 cluster has been characterized as oncogenic in various solid and hematological malignancies (reviewed in), but intriguingly there is frequent copy number loss or deletion of the genetic locus at 13q31 in various cancers and downregulation of this cluster is also implicated in aging.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Disease', (228, 235))	('aging', 'biological_process', 'GO:0007568', ('293', '298'))	('hematological malignancies', 'Disease', (81, 107))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('hematological malignancies', 'Disease', 'MESH:D019337', (81, 107))	('miR-17 ~ 92', 'Gene', '407975', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('deletion', 'Var', (178, 186))	('hematological malignancies', 'Phenotype', 'HP:0004377', (81, 107))	('miR-17 ~ 92', 'Gene', (4, 15))	('copy number loss', 'Var', (158, 174))
77489	27245839	While miR-17 expression is frequently reported to be upregulated as part of the miR-17 ~ 92 cluster, miR-17-5p downregulation and/or loss of heterozygosity/gene deletion at 13q31 has been reported in various tumors.	('miR-17', 'Gene', (6, 12))	('upregulated', 'PosReg', (53, 64))	('miR-17', 'Gene', (80, 86))	('expression', 'MPA', (13, 23))	('loss of heterozygosity/gene deletion', 'Var', (133, 169))	('miR-17', 'Gene', '406952', (6, 12))	('miR-17-5p', 'Gene', '406952', (101, 110))	('miR-17 ~ 92', 'Gene', '407975', (80, 91))	('miR-17', 'Gene', (101, 107))	('miR-17', 'Gene', '406952', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('miR-17-5p', 'Gene', (101, 110))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('downregulation', 'NegReg', (111, 125))	('miR-17', 'Gene', '406952', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('miR-17 ~ 92', 'Gene', (80, 91))
77520	27245839	Silencing KCNMA1 expression with siRNAs or miR-17-5p mimics had limited effects on the proliferation of a panel of MPM cell lines (Additional file 1: Figure S2), and did not lead to changes in the cell cycle (Additional file 1: Figure S3) or induction of apoptosis (Additional file 1: Figure S4) in transfected cells.	('miR-17-5p', 'Gene', (43, 52))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('242', '264'))	('Silencing', 'Var', (0, 9))	('KCNMA1', 'Gene', '3778', (10, 16))	('cell cycle', 'biological_process', 'GO:0007049', ('197', '207'))	('changes', 'Reg', (182, 189))	('induction', 'Reg', (242, 251))	('apoptosis', 'CPA', (255, 264))	('cell cycle', 'CPA', (197, 207))	('KCNMA1', 'Gene', (10, 16))	('miR-17-5p', 'Gene', '406952', (43, 52))
77524	27245839	Similarly, modulation of KCa1.1 activity with the inhibitor paxilline suppressed migration of MPM cell lines.	('paxilline', 'Chemical', 'MESH:C048220', (60, 69))	('KCa1.1', 'Gene', '3778', (25, 31))	('migration of MPM cell lines', 'CPA', (81, 108))	('modulation', 'Var', (11, 21))	('activity', 'MPA', (32, 40))	('suppressed', 'NegReg', (70, 80))	('KCa1.1', 'Gene', (25, 31))
77531	27245839	In MPM cells, KCNMA1 knockdown led to an increase in the basal intracellular calcium concentration (Fig.	('calcium', 'Chemical', 'MESH:D002118', (77, 84))	('KCNMA1', 'Gene', '3778', (14, 20))	('basal intracellular calcium concentration', 'MPA', (57, 98))	('knockdown', 'Var', (21, 30))	('increase', 'PosReg', (41, 49))	('KCNMA1', 'Gene', (14, 20))	('intracellular', 'cellular_component', 'GO:0005622', ('63', '76'))
77533	27245839	Furthermore, KCNMA1 silencing resulted in a more prolonged elevation in submembrane Ca2+ levels in response to high K+ containing buffer (Fig.	('KCNMA1', 'Gene', '3778', (13, 19))	('KCNMA1', 'Gene', (13, 19))	('response to high K+ containing buffer', 'MPA', (99, 136))	('elevation', 'PosReg', (59, 68))	('Ca2+', 'Chemical', 'MESH:D000069285', (84, 88))	('silencing', 'Var', (20, 29))	('submembrane Ca2+ levels', 'MPA', (72, 95))
77535	27245839	In light of these observations it is interesting that changes in basal Ca2+ levels following KCNMA1 knockdown had negligible effects on cell growth, despite altered Ca2+ handling being linked to apoptosis resistance in MPM cells.	('Ca2+', 'Chemical', 'MESH:D000069285', (165, 169))	('knockdown', 'Var', (100, 109))	('changes', 'Reg', (54, 61))	('linked', 'Reg', (185, 191))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('KCNMA1', 'Gene', '3778', (93, 99))	('Ca2+ handling', 'MPA', (165, 178))	('altered', 'Reg', (157, 164))	('Ca2+', 'Chemical', 'MESH:D000069285', (71, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))	('KCNMA1', 'Gene', (93, 99))
77536	27245839	Further research is required to understand exactly how the loss of KCNMA1 activity and resultant changes in Ca2+ flux reduces migration and invasion without impacting apoptosis, and is beyond the scope of the current study.	('Ca2+ flux', 'MPA', (108, 117))	('KCNMA1', 'Gene', (67, 73))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('activity', 'MPA', (74, 82))	('reduces', 'NegReg', (118, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('KCNMA1', 'Gene', '3778', (67, 73))	('changes', 'Reg', (97, 104))	('loss', 'Var', (59, 63))
77547	27245839	The Kv10.1 (EAG1, product of the KCNH1 gene) channel is normally only expressed in the brain, but is upregulated in multiple cancer types, and its inhibition or knockdown reduces cell migration and viability.	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cell migration', 'biological_process', 'GO:0016477', ('179', '193'))	('Kv10.1', 'Gene', '3756', (4, 10))	('Kv10.1', 'Gene', (4, 10))	('EAG1', 'Gene', (12, 16))	('inhibition', 'Var', (147, 157))	('KCNH1', 'Gene', '3756', (33, 38))	('knockdown', 'Var', (161, 170))	('EAG1', 'Gene', '3756', (12, 16))	('KCNH1', 'Gene', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('reduces', 'NegReg', (171, 178))	('upregulated', 'PosReg', (101, 112))
77551	27245839	For example, inhibition of KCa2.3 reduced bone metastases in a model of breast cancer, and blocking KCa1.1, which was induced by ionizing radiation, inhibited the increase in glioma cell migration.	('KCa1.1', 'Gene', (100, 106))	('reduced', 'NegReg', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('bone metastases', 'Disease', (42, 57))	('bone metastases', 'Disease', 'MESH:D009362', (42, 57))	('inhibition', 'Var', (13, 23))	('cell migration', 'biological_process', 'GO:0016477', ('182', '196'))	('blocking', 'NegReg', (91, 99))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('glioma', 'Disease', (175, 181))	('KCa2.3', 'Gene', '3782', (27, 33))	('breast cancer', 'Disease', (72, 85))	('KCa2.3', 'Gene', (27, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('inhibited', 'NegReg', (149, 158))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('KCa1.1', 'Gene', '3778', (100, 106))
77556	27245839	We have demonstrated that KCa1.1 is a direct target of miR-17-5p and inhibition of this combination modulates cell migration in MPM.	('inhibition', 'Var', (69, 79))	('KCa1.1', 'Gene', (26, 32))	('cell migration', 'CPA', (110, 124))	('KCa1.1', 'Gene', '3778', (26, 32))	('modulates', 'Reg', (100, 109))	('miR-17-5p', 'Gene', '406952', (55, 64))	('cell migration', 'biological_process', 'GO:0016477', ('110', '124'))	('miR-17-5p', 'Gene', (55, 64))	('MPM', 'Disease', (128, 131))
77590	26719535	Germline BAP1 mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('BAP1', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (55, 77))	('mesothelioma', 'Disease', (65, 77))	('BAP1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('mutations', 'Var', (127, 136))	('cancer', 'Disease', (110, 116))	('malignant mesothelioma', 'Disease', (55, 77))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (55, 77))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('mesothelioma', 'Disease', (197, 209))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('149', '165'))	('cancer', 'Disease', (220, 226))	('cancers', 'Disease', (220, 227))	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('BAP1', 'Gene', '8314', (9, 13))	('tumor suppressor', 'biological_process', 'GO:0051726', ('149', '165'))	('predispose', 'Reg', (171, 181))	('tumor', 'Disease', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('BAP1', 'Gene', '8314', (144, 148))
77594	26719535	Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared to wild-type BAP1.	('decreased', 'NegReg', (144, 153))	('frameshift mutations', 'Var', (70, 90))	('enzymatic activity', 'MPA', (96, 114))	('BAP1', 'Gene', '8314', (176, 180))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (176, 180))	('missense mutants', 'Var', (123, 139))	('missense', 'Var', (57, 65))	('BAP1', 'Gene', (118, 122))
77595	26719535	Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (5 of 9), and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('pleural', 'Disease', (113, 120))	('BAP1', 'Gene', (13, 17))	('mesothelioma', 'Disease', (185, 197))	('patients', 'Species', '9606', (198, 206))	('BAP1', 'Gene', '8314', (215, 219))	('BAP1', 'Gene', '8314', (13, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('improved', 'PosReg', (145, 153))	('mutation', 'Var', (18, 26))	('mesothelioma', 'Disease', (46, 58))	('pleural', 'Disease', 'MESH:D010995', (113, 120))	('developed', 'PosReg', (36, 45))	('BAP1', 'Gene', (215, 219))
77596	26719535	Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas.	('gastric', 'Disease', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('BAP1', 'Gene', (32, 36))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (192, 213))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (126, 144))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('breast', 'Disease', (165, 171))	('germline mutations', 'Var', (37, 55))	('BAP1', 'Gene', '8314', (77, 81))	('basal cell carcinomas', 'Disease', (192, 213))	('associated', 'Reg', (61, 71))	('tumors', 'Disease', (15, 21))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (126, 145))	('renal', 'Disease', (158, 163))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (192, 213))	('lung', 'Disease', (173, 177))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (192, 212))	('BAP1', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))	('BAP1', 'Gene', '8314', (32, 36))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('mesothelioma and ocular/cutaneous melanomas', 'Disease', 'MESH:C562393', (102, 145))
77597	26719535	Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.	('BAP1', 'Gene', '8314', (132, 136))	('genetic', 'Var', (137, 144))	('mesothelioma', 'Disease', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (132, 136))	('patients', 'Species', '9606', (55, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
77604	26719535	In 2011, germline mutations of the BAP1 tumor suppressor gene were reported in two families with multiple MMs and/or uveal melanomas (UMs) as well as other tumors such as kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('kidney cancer', 'Disease', (171, 184))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('BAP1', 'Gene', (35, 39))	('tumor', 'Disease', (156, 161))	('reported', 'Reg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('tumor', 'Disease', (40, 45))	('kidney cancer', 'Disease', 'MESH:D007680', (171, 184))	('tumors', 'Disease', (156, 162))	('germline mutations', 'Var', (9, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('BAP1', 'Gene', '8314', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('kidney cancer', 'Phenotype', 'HP:0009726', (171, 184))
77605	26719535	In addition, germline BAP1 mutations were identified in 2 of 26 sporadic MMs, and both individuals with mutant BAP1 were previously diagnosed with UM.	('MMs', 'Disease', (73, 76))	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', '8314', (111, 115))	('mutant', 'Var', (104, 110))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))
77606	26719535	described germline BAP1 mutations in two families with atypical melanocytic tumors as well as cutaneous melanoma (CM) and UM.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanocytic tumors', 'Disease', (64, 82))	('melanocytic tumors', 'Disease', 'MESH:D009508', (64, 82))	('cutaneous melanoma', 'Disease', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BAP1', 'Gene', '8314', (19, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CM', 'Disease', 'MESH:D009202', (114, 116))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
77607	26719535	To investigate the potential contribution of germline BAP1 mutations in UM patients with possible predisposition to hereditary cancer, Abdel-Rahman et al.	('hereditary cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (75, 83))	('BAP1', 'Gene', '8314', (54, 58))	('hereditary cancer', 'Disease', 'MESH:D009369', (116, 133))	('mutations', 'Var', (59, 68))	('BAP1', 'Gene', (54, 58))
77608	26719535	identified a patient with a germline truncating mutation of BAP1, which segregated in several family members with UM, lung adenocarcinoma, and meningioma.	('patient', 'Species', '9606', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinoma', 'Disease', (118, 137))	('germline truncating mutation', 'Var', (28, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('BAP1', 'Gene', '8314', (60, 64))	('meningioma', 'Disease', 'MESH:D008577', (143, 153))	('meningioma', 'Disease', (143, 153))	('meningioma', 'Phenotype', 'HP:0002858', (143, 153))	('BAP1', 'Gene', (60, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('segregated', 'Reg', (72, 82))
77610	26719535	Collectively, these findings have led to the identification of a BAP1 tumor predisposition syndrome characterized by MM, CM, UM, RCC and potentially other tumors due to heterozygous germline mutations of BAP1.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('BAP1', 'Gene', '8314', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CM', 'Disease', 'MESH:D009202', (121, 123))	('tumor', 'Disease', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', (65, 69))	('tumor', 'Disease', (155, 160))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('BAP1', 'Gene', '8314', (204, 208))	('RCC', 'Disease', (129, 132))	('tumors', 'Disease', (155, 161))	('germline mutations', 'Var', (182, 200))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('BAP1', 'Gene', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
77611	26719535	Based on these studies, we hypothesized that germline mutations in BAP1 may contribute to susceptibility to MM in asbestos-exposed individuals through a mechanism that involves a gene-environment interaction.	('asbestos', 'Chemical', 'MESH:D001194', (114, 122))	('BAP1', 'Gene', '8314', (67, 71))	('susceptibility', 'Reg', (90, 104))	('germline mutations', 'Var', (45, 63))	('contribute', 'Reg', (76, 86))	('BAP1', 'Gene', (67, 71))
77612	26719535	We further postulated that germline BAP1 mutations would more likely occur if an MM index case had a family history of various cancers, consistent with a genetic predisposition to cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('germline', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (36, 40))	('occur', 'Reg', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Disease', (127, 133))	('BAP1', 'Gene', (36, 40))	('cancer', 'Disease', (180, 186))
77613	26719535	We recently reported in vivo genetic evidence that germline heterozygous mutation of Bap1 accelerates development of asbestos-induced MM.	('Bap1', 'Gene', (85, 89))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('germline heterozygous mutation', 'Var', (51, 81))	('accelerates', 'PosReg', (90, 101))
77615	26719535	To further investigate its role in asbestos-induced MM, we determined the prevalence of germline BAP1 mutations in a population of asbestos-exposed MM cases and controls.	('BAP1', 'Gene', '8314', (97, 101))	('asbestos', 'Chemical', 'MESH:D001194', (35, 43))	('asbestos', 'Chemical', 'MESH:D001194', (131, 139))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))
77617	26719535	While no alterations of BAP1 were found in controls, BAP1 mutations were identified in a 9 of 150 MM cases with a personal or family history of cancer.	('mutations', 'Var', (58, 67))	('BAP1', 'Gene', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('identified', 'Reg', (73, 83))	('cancer', 'Disease', (144, 150))	('BAP1', 'Gene', '8314', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', '8314', (24, 28))	('BAP1', 'Gene', (53, 57))
77637	26719535	BAP1 mutations were described using cDNA and protein mutation nomenclature standardized by the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen) and cDNA accession # NM_004656 and protein accession # NP_004647 as references.	('Human', 'Species', '9606', (95, 100))	('BAP1', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('BAP1', 'Gene', '8314', (0, 4))
77638	26719535	293T cells were transfected with Myc-tagged wild-type (WT) or mutant BAP constructs.	('BAP', 'Gene', (69, 72))	('Myc', 'Gene', (33, 36))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('mutant', 'Var', (62, 68))	('BAP', 'Chemical', '-', (69, 72))	('Myc', 'Gene', '4609', (33, 36))
77651	26719535	Among the 150 MM cases with a family history of cancer, germline mutations of BAP1 were identified in 9 index cases, of which 8 tumors (88.9%) were of the epithelioid subtype, and 1 was sarcomatous.	('sarcomatous', 'Disease', 'MESH:D018316', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('identified', 'Reg', (88, 98))	('sarcomatous', 'Disease', (186, 197))	('cancer', 'Disease', (48, 54))	('tumors', 'Disease', (128, 134))	('BAP1', 'Gene', '8314', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('germline mutations', 'Var', (56, 74))	('BAP1', 'Gene', (78, 82))
77652	26719535	Of the 141 MM cases without BAP1 mutations, the histopathological subtype was available in 126 cases, of which 94 (74.6%) were epithelioid, 13 (10.3%) were biphasic, and 19 (15.1%) were sarcomatous.	('BAP1', 'Gene', '8314', (28, 32))	('sarcomatous', 'Disease', 'MESH:D018316', (186, 197))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('sarcomatous', 'Disease', (186, 197))	('epithelioid', 'Disease', (127, 138))
77653	26719535	Of the 9 index cases with a germline BAP1 mutation, 5 MMs (55.6%) were peritoneal and the 4 (44.4%) were thoracic.	('BAP1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('BAP1', 'Gene', '8314', (37, 41))	('MMs', 'Disease', (54, 57))
77656	26719535	Of the 9 cases found to harbor germline mutations affecting the coding sequence of the BAP1 protein, 3 were missense mutations, 2 were splice site mutations, and 4 were insertions/deletions (in/dels) (Table 2).	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('insertions/deletions', 'Var', (169, 189))	('affecting', 'Reg', (50, 59))
77657	26719535	Analysis of the missense mutations was done using three tools: Protein Variation Effect Analyzer (PROVEAN), Sorting Intolerant from Tolerant (SIFT), and PolyPhen-2 (Fig.	('SIFT', 'Disease', 'None', (142, 146))	('SIFT', 'Disease', (142, 146))	('missense mutations', 'Var', (16, 34))
77659	26719535	In addition, the Arg383Cys mutation is not a conservative change, as a basic, positively-charged arginine is changed to a non-basic, uncharged cysteine and, thus, could potentially affect BAP1 protein structure or function.	('BAP1', 'Gene', (188, 192))	('Arg383Cys', 'Var', (17, 26))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('Arg383Cys', 'SUBSTITUTION', 'None', (17, 26))	('protein', 'Protein', (193, 200))	('changed', 'Reg', (109, 116))	('BAP1', 'Gene', '8314', (188, 192))	('structure', 'MPA', (201, 210))	('arginine', 'Chemical', 'MESH:D001120', (97, 105))	('cysteine', 'Chemical', 'MESH:D003545', (143, 151))	('function', 'MPA', (214, 222))	('affect', 'Reg', (181, 187))
77660	26719535	In addition, the introduction of a cysteine residue could alter disulfide bonds within the protein.	('cysteine', 'Chemical', 'MESH:D003545', (35, 43))	('disulfide bonds within the protein', 'MPA', (64, 98))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('alter', 'Reg', (58, 63))	('introduction', 'Var', (17, 29))	('disulfide', 'Chemical', 'MESH:D004220', (64, 73))
77662	26719535	However, several studies have shown that BAP1 Ser583 is phosphorylated in human cells after UV light exposure, providing functional significance of the serine at position 583.	('BAP1', 'Gene', (41, 45))	('Ser583', 'Chemical', '-', (46, 52))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('Ser583', 'Var', (46, 52))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('human', 'Species', '9606', (74, 79))	('BAP1', 'Gene', '8314', (41, 45))
77663	26719535	The Ub-AMC assay revealed that the enzymatic activity of each of the three BAP1 missense mutants was reproducibly decreased compared to that of WT BAP1 protein (Fig.	('AMC', 'Chemical', '-', (7, 10))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', (75, 79))	('enzymatic activity', 'MPA', (35, 53))	('missense mutants', 'Var', (80, 96))	('Ub', 'Chemical', '-', (4, 6))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('decreased', 'NegReg', (114, 123))	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', '8314', (75, 79))
77664	26719535	However, as expected, these BAP1 mutant proteins could still bind ASXL2 substrate, which was expected given that the missense mutations do not affect the carboxy-terminal ASXL1/2 binding domain of BAP1.	('BAP1', 'Gene', '8314', (28, 32))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('ASXL2', 'Gene', '55252', (66, 71))	('BAP1', 'Gene', (28, 32))	('ASXL2', 'Gene', (66, 71))	('missense mutations', 'Var', (117, 135))	('BAP1', 'Gene', '8314', (197, 201))	('proteins', 'Protein', (40, 48))	('mutant', 'Var', (33, 39))	('bind', 'Interaction', (61, 65))	('BAP1', 'Gene', (197, 201))
77665	26719535	As a control, we used a BAP1 mutant construct corresponding to the S628fs*8 mutation seen in family ABS3428.	('BAP1', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (24, 28))	('S628fs', 'Mutation', 'p.S628fsX', (67, 73))	('S628fs*8', 'Var', (67, 75))
77668	26719535	Location of missense mutations and the S628fs*8 mutation are shown in Fig.	('missense mutations', 'Var', (12, 30))	('S628fs*8', 'Var', (39, 47))	('S628fs', 'Mutation', 'p.S628fsX', (39, 45))
77669	26719535	2A, and representative Ub-AMC experiment of exogenously expressed wild-type and mutant BAP1 proteins are depicted in Fig.	('BAP1', 'Gene', '8314', (87, 91))	('mutant', 'Var', (80, 86))	('BAP1', 'Gene', (87, 91))	('AMC', 'Chemical', '-', (26, 29))	('proteins', 'Protein', (92, 100))	('Ub', 'Chemical', '-', (23, 25))
77670	26719535	Two cases had germline BAP1 mutations at consensus splice sites: cases MC7039 and MC7058.	('BAP1', 'Gene', (23, 27))	('MC7039', 'Var', (71, 77))	('MC7058', 'Var', (82, 88))	('BAP1', 'Gene', '8314', (23, 27))
77671	26719535	In both of these MM cases, the loss of an exon and the retention of part of an intron were each predicted to lead to a frameshift and premature truncation of the translated BAP1 protein.	('protein', 'Protein', (178, 185))	('lead to', 'Reg', (109, 116))	('loss', 'NegReg', (31, 35))	('exon', 'MPA', (42, 46))	('BAP1', 'Gene', '8314', (173, 177))	('frameshift', 'Var', (119, 129))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('retention', 'biological_process', 'GO:0051235', ('55', '64'))	('BAP1', 'Gene', (173, 177))	('premature truncation', 'MPA', (134, 154))
77672	26719535	Interestingly, two cases (ABS2778 and ABS3554) had the same germline mutation, c.1717delC, and the pedigrees of these two cases did not indicate any known relationship, although they may have a common ancestor.	('c.1717delC', 'Mutation', 'rs869025212', (79, 89))	('ABS3554', 'Var', (38, 45))	('ABS2778', 'Var', (26, 33))	('c.1717delC', 'Var', (79, 89))
77674	26719535	Four intronic SNPs in BAP1 (rs116234404, rs141765555, rs187797012 and rs190356708), were found in <= 4 cases and in <= 1 control.	('rs190356708', 'Mutation', 'rs190356708', (70, 81))	('rs141765555', 'Mutation', 'rs141765555', (41, 52))	('rs116234404', 'Var', (28, 39))	('rs190356708', 'Var', (70, 81))	('rs187797012', 'Mutation', 'rs187797012', (54, 65))	('BAP1', 'Gene', '8314', (22, 26))	('rs116234404', 'Mutation', 'rs116234404', (28, 39))	('rs141765555', 'Var', (41, 52))	('BAP1', 'Gene', (22, 26))	('rs187797012', 'Var', (54, 65))
77676	26719535	Compared with MM cases without a BAP1 mutation, the cases harboring germline mutations that could affect BAP1 protein coding sequence were diagnosed at an earlier age and were more likely to have peritoneal rather than pleural MM (Table 1).	('pleural MM', 'Disease', (219, 229))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', '8314', (33, 37))	('peritoneal', 'Disease', (196, 206))	('mutations', 'Var', (77, 86))	('pleural MM', 'Disease', 'MESH:D010995', (219, 229))	('BAP1', 'Gene', (33, 37))	('affect', 'Reg', (98, 104))	('BAP1', 'Gene', (105, 109))
77677	26719535	There was no significant difference in cancer signal score, gender or latency between cases with and without a BAP1 mutation.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (39, 45))	('mutation', 'Var', (116, 124))	('BAP1', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
77678	26719535	Both families with and without mutations of BAP1 exhibited a significant number of malignancies that have been repeatedly associated with the BAP1 syndrome, i.e., MM, CM, UM and RCC, although the relative proportion of these neoplasms appeared to be greater in families of MM cases with a BAP1 mutation.	('associated', 'Reg', (122, 132))	('mutation', 'Var', (294, 302))	('mutations', 'Var', (31, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (225, 234))	('BAP1', 'Gene', '8314', (142, 146))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('BAP1', 'Gene', (289, 293))	('BAP1', 'Gene', (142, 146))	('neoplasms', 'Disease', (225, 234))	('BAP1', 'Gene', '8314', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('neoplasms', 'Disease', 'MESH:D009369', (225, 234))	('malignancies', 'Disease', (83, 95))	('BAP1', 'Gene', (44, 48))	('BAP1', 'Gene', '8314', (289, 293))
77679	26719535	A total of 11 such tumors (4 RCC, 3 MMs, 2 CMS, and 2 UMs) were identified in the 9 families in which the MM proband has a germline BAP1 mutation.	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('BAP1', 'Gene', '8314', (132, 136))	('mutation', 'Var', (137, 145))	('RCC', 'Disease', (29, 32))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('CM', 'Disease', 'MESH:D009202', (43, 45))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
77680	26719535	Among the 141 MM cases without a BAP1 mutation, 27 such tumors (7 RCCs, 9 MMs, 10 CMs, and 1 ocular tumor) were documented.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CM', 'Disease', 'MESH:D009202', (82, 84))	('ocular tumor', 'Disease', 'MESH:D009369', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ocular tumor', 'Disease', (93, 105))	('MMs', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (33, 37))	('ocular tumor', 'Phenotype', 'HP:0100012', (93, 105))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('RCC', 'Disease', (66, 69))
77681	26719535	Atypical cutaneous melanocytic tumors are also associated with the BAP1 syndrome, and we cannot rule out the existence of such lesions in some members of the 9 families with a germline BAP1 mutation, but detailed dermatological assessments of these families were not available.	('mutation', 'Var', (190, 198))	('Atypical cutaneous melanocytic tumors', 'Disease', (0, 37))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('BAP1', 'Gene', '8314', (67, 71))	('Atypical cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (0, 37))	('associated', 'Reg', (47, 57))	('BAP1', 'Gene', '8314', (185, 189))	('BAP1', 'Gene', (67, 71))
77682	26719535	Among the families of cases with BAP1 mutations, 4 MM index cases had a second primary tumor, including 3 with RCC and 1 with UM.	('primary tumor', 'Disease', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('primary tumor', 'Disease', 'MESH:D009369', (79, 92))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))
77683	26719535	Of the cases without a BAP1 mutation, 5 MM index cases had a second primary tumor (2 with RCC and 3 with CM).	('BAP1', 'Gene', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('primary tumor', 'Disease', 'MESH:D009369', (68, 81))	('BAP1', 'Gene', '8314', (23, 27))	('mutation', 'Var', (28, 36))	('CM', 'Disease', 'MESH:D009202', (105, 107))	('primary tumor', 'Disease', (68, 81))	('RCC', 'Disease', (90, 93))
77684	26719535	One MM case with a BAP1 mutation (ABS3554) had two siblings who also developed MM; similarly, two MM cases without a BAP1 mutation each had two siblings who developed MM.	('BAP1', 'Gene', '8314', (117, 121))	('mutation (ABS3554', 'Var', (24, 41))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (117, 121))	('MM', 'Disease', (79, 81))	('ABS3554', 'Var', (34, 41))	('BAP1', 'Gene', (19, 23))
77685	26719535	Thus, the existence of multiple MMs in a given family need not be due to inheritance of a BAP1 mutation.	('BAP1', 'Gene', '8314', (90, 94))	('BAP1', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
77686	26719535	Among the three cases (ABS2570, ABS3023, ABS3313) with missense mutations, multiple malignancies were observed in their past personal and family histories.	('malignancies', 'Disease', (84, 96))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('ABS2570', 'Var', (23, 30))	('missense mutations', 'Var', (55, 73))	('ABS3313', 'Var', (41, 48))	('ABS3023', 'Var', (32, 39))
77687	26719535	The cancers observed in families of these cases were similar to those identified in the six families with frameshift or splice site mutations, suggesting that families with missense BAP1 mutations also belong to the BAP1 syndrome.	('BAP1', 'Gene', (216, 220))	('BAP1', 'Gene', '8314', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BAP1', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('belong', 'Reg', (202, 208))	('missense', 'Var', (173, 181))	('BAP1', 'Gene', '8314', (216, 220))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
77688	26719535	For example, case ABS3023 had a daughter with breast cancer, and case ABS3313 had a daughter with cutaneous melanoma (Fig.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cutaneous melanoma', 'Disease', (98, 116))	('ABS3023', 'Var', (18, 25))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('breast cancer', 'Disease', (46, 59))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
77690	26719535	Of the two splice site mutations, the father of MM case MC7058 had a non-Hodgkin's lymphoma and his sister had thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (111, 125))	('thyroid cancer', 'Disease', (111, 125))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (73, 91))	('thyroid cancer', 'Disease', 'MESH:D013964', (111, 125))	("non-Hodgkin's lymphoma", 'Disease', (69, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (69, 91))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('MC7058', 'Var', (56, 62))
77692	26719535	The family history of case MC7039 is replete with malignancy (Fig.	('MC7039', 'Var', (27, 33))	('malignancy', 'Disease', (50, 60))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))
77695	26719535	As noted above, both ABS2778 and ABS3554 exhibited the same mutation c.1717delC, which is identical to that described in a sporadic MM (SP-002) we reported earlier.	('ABS2778', 'Var', (21, 28))	('c.1717delC', 'Var', (69, 79))	('ABS3554', 'Var', (33, 40))	('SP', 'Chemical', 'MESH:C000604007', (136, 138))	('c.1717delC', 'Mutation', 'rs869025212', (69, 79))
77696	26719535	Notably, both ABS2778 and ABS3554 had MM simultaneously affecting both the pleura and peritoneum.	('pleura', 'Disease', (75, 81))	('ABS3554', 'Var', (26, 33))	('pleura', 'Disease', 'MESH:D054363', (75, 81))	('ABS2778', 'Var', (14, 21))	('affecting', 'Reg', (56, 65))
77697	26719535	Case ABS3554 had two sisters with MM, one with peritoneal and the other with pleural disease.	('pleural disease', 'Phenotype', 'HP:0002103', (77, 92))	('pleural disease', 'Disease', (77, 92))	('pleural disease', 'Disease', 'MESH:D010995', (77, 92))	('ABS3554', 'Var', (5, 12))
77701	26719535	No family history of melanoma was evoked from either case ABS2778 or ABS3554.	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('ABS2778', 'Var', (58, 65))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('ABS3554', 'Var', (69, 76))
77702	26719535	The c.1882_1885delTCAC germline mutation observed in case ABS3428 was also previously described by us in a sporadic case (SP-008).	('SP-008', 'Chemical', 'MESH:C505413', (122, 128))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (4, 22))	('c.1882_1885delTCAC', 'Var', (4, 22))	('ABS3428', 'Gene', (58, 65))
77704	26719535	The fourth MM case with an in/del, ABS2573, had a past medical history of breast cancer and kidney cancer; thus, ABS2573 had three separate primary tumors.	('primary tumors', 'Disease', (140, 154))	('breast cancer', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('kidney cancer', 'Disease', (92, 105))	('primary tumors', 'Disease', 'MESH:D009369', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('kidney cancer', 'Disease', 'MESH:D007680', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('ABS2573', 'Var', (113, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
77708	26719535	Altogether, we found germline mutations of BAP1 in 9 of 150 (6%) cases with a personal or family history of cancer based on a high cancer signal, as defined above.	('cancer', 'Disease', (131, 137))	('BAP1', 'Gene', (43, 47))	('found', 'Reg', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('high cancer', 'Disease', 'MESH:D009369', (126, 137))	('high cancer', 'Disease', (126, 137))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('germline mutations', 'Var', (21, 39))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
77709	26719535	Among the 9 families with BAP1 mutations, a total of 11 MMs were identified.	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('BAP1', 'Gene', '8314', (26, 30))
77711	26719535	Among the 141 cases without a BAP1 mutation, the mean age of MM diagnosis was 68.2 years (Table 1).	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
77712	26719535	Since MM is generally regarded as a disease of the 60s and 70s, the age of onset in our BAP1 mutation carriers is younger than among the general population of sporadic MM cases.	('BAP1', 'Gene', '8314', (88, 92))	('mutation', 'Var', (93, 101))	('BAP1', 'Gene', (88, 92))
77714	26719535	However, it is noteworthy that while BAP1 mutation carriers tend to develop MM prior to the age of 60, two probands were diagnosed at 67 and 81 years of age (ABS3313 and ABS3023, respectively), and another (a sister of ABS3554) developed peritoneal MM at age 68.	('BAP1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('BAP1', 'Gene', '8314', (37, 41))	('develop', 'PosReg', (68, 75))
77715	26719535	Thus, not all MM cases with BAP1 mutations develop the disease at an early age.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
77716	26719535	Among the 11 MM cases identified from the 9 families with germline BAP1 mutations, the 7 deceased patients had a median survival of 60 months after the initial diagnosis.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (98, 106))	('germline', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (67, 71))	('BAP1', 'Gene', (67, 71))
77718	26719535	This 3.5-fold increased median survival rate among mutation carriers is similar to the improved long-term survival reported in a recent study in which a 60-month median survival was observed in MM patients with germline BAP1 mutations compared to a 9-month median survival among all MM cases recorded in the U.S. Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2010.	('patients', 'Species', '9606', (197, 205))	('mutations', 'Var', (225, 234))	('BAP1', 'Gene', (220, 224))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', '8314', (220, 224))
77719	26719535	In contrast, somatic BAP1 mutations in uveal melanomas are strongly associated with a more metastatic phenotype.	('uveal melanomas', 'Disease', (39, 54))	('uveal melanomas', 'Phenotype', 'HP:0007716', (39, 54))	('associated with', 'Reg', (68, 83))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('uveal melanomas', 'Disease', 'MESH:C536494', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('BAP1', 'Gene', '8314', (21, 25))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
77720	26719535	Some factors that may contribute to the prolonged survival observed in BAP1 mutation carriers include the high proportion of peritoneal and epithelioid tumors in this subgroup as well as the younger age of diagnosis compared to non-carriers.	('prolonged', 'PosReg', (40, 49))	('epithelioid tumors', 'Disease', 'MESH:D012509', (140, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('BAP1', 'Gene', '8314', (71, 75))	('epithelioid tumors', 'Disease', (140, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))
77722	26719535	Among the nine families corresponding to cases with germline BAP1 mutations, two had a single case of cutaneous melanoma (father of MC7039; daughter of ABS3313), and one family had two UMs (case ABS3428 and his mother).	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('germline', 'Var', (52, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('BAP1', 'Gene', '8314', (61, 65))
77723	26719535	Three of the families with germline BAP1 mutations exhibited RCCs: ABS2573 and her daughter, ABS2570 (who also had MM), and ABS2778 (who also had MM).	('mutations', 'Var', (41, 50))	('ABS2570', 'Var', (93, 100))	('BAP1', 'Gene', '8314', (36, 40))	('ABS2778', 'Var', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('BAP1', 'Gene', (36, 40))
77726	26719535	In our series, breast cancer was observed in three individuals (ABS2573 and her sister; daughter of MM case ABS3023).	('ABS2573', 'Var', (64, 71))	('observed', 'Reg', (33, 41))	('ABS3023', 'Var', (108, 115))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
77732	26719535	To date, at least one stomach cancer has been previously reported in a BAP1 mutation carrier.	('BAP1', 'Gene', (71, 75))	('carrier', 'molecular_function', 'GO:0005215', ('85', '92'))	('BAP1', 'Gene', '8314', (71, 75))	('stomach cancer', 'Disease', 'MESH:D013274', (22, 36))	('stomach cancer', 'Phenotype', 'HP:0012126', (22, 36))	('mutation', 'Var', (76, 84))	('stomach cancer', 'Disease', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
77736	26719535	Our finding of two basal cell carcinomas in MM index cases is of interest in relation to recent work showing that germline BAP1 mutations can predispose to multiple basal cell carcinomas.	('BAP1', 'Gene', (123, 127))	('multiple basal cell carcinomas', 'Disease', (156, 186))	('basal cell carcinomas', 'Disease', (19, 40))	('mutations', 'Var', (128, 137))	('multiple basal cell carcinomas', 'Disease', 'MESH:C537656', (156, 186))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (19, 40))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (165, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (19, 39))	('predispose to', 'Reg', (142, 155))	('BAP1', 'Gene', '8314', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (165, 186))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (19, 40))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
77741	26719535	In fact, even among the families of the 141 MM cases without BAP1 mutations, 11 family members were diagnosed with basal cell carcinoma, including 10 that were found in MM index cases, i.e., non-BAP1 associated individuals who developed two primary cancers.	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', '8314', (195, 199))	('BAP1', 'Gene', (61, 65))	('BAP1', 'Gene', (195, 199))	('primary cancer', 'Disease', (241, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('primary cancer', 'Disease', 'MESH:D009369', (241, 255))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (115, 135))	('cancers', 'Disease', (249, 256))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (115, 135))	('basal cell carcinoma', 'Disease', (115, 135))	('diagnosed', 'Reg', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('BAP1', 'Gene', '8314', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
77742	26719535	The BAP1 mutation sites observed in this study were spread widely within the gene, although most mutations occurred in the 3' end of the BAP1 coding region, with 7 of 9 mutations distributed between c.1695 and c.1891 (exons 13-14), corresponding to the ASXL1/2 binding domain of BAP1).	('BAP1', 'Gene', (137, 141))	('mutations', 'Var', (97, 106))	('BAP1', 'Gene', '8314', (279, 283))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', (279, 283))	('c.1695', 'Var', (199, 205))	('c.1891', 'Var', (210, 216))	('BAP1', 'Gene', '8314', (137, 141))	('binding', 'molecular_function', 'GO:0005488', ('261', '268'))	('BAP1', 'Gene', '8314', (4, 8))
77743	26719535	Although no BAP1 mutation hotspot has been identified to date, it was remarkable that two unrelated families (ABS2778 and ABS3554) had an identical mutation: c.1717delC, p.Leu573fs*3.	('p.Leu573fs*3', 'FRAMESHIFT', 'None', (170, 182))	('p.Leu573fs*3', 'Var', (170, 182))	('BAP1', 'Gene', '8314', (12, 16))	('c.1717delC', 'Mutation', 'rs869025212', (158, 168))	('BAP1', 'Gene', (12, 16))	('c.1717delC', 'Var', (158, 168))
77744	26719535	Upon review of reported germline hereditary and sporadic cases, we found the very same in/del mutation in a previously reported sporadic case of MM (SP-002) that was obtained through MARF.	('MARF', 'Gene', (183, 187))	('in/del mutation', 'Var', (87, 102))	('SP', 'Chemical', 'MESH:C000604007', (149, 151))	('MARF', 'Gene', '9927', (183, 187))
77745	26719535	In addition, the germline BAP1 mutation found in family ABS3428, i.e., c.1882_1885delTCAC, is identical to that seen in a previously reported "sporadic" MM case, SP-008, obtained through MARF.	('BAP1', 'Gene', (26, 30))	('MARF', 'Gene', '9927', (187, 191))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (71, 89))	('SP-008', 'Chemical', 'MESH:C505413', (162, 168))	('BAP1', 'Gene', '8314', (26, 30))	('MARF', 'Gene', (187, 191))	('c.1882_1885delTCAC', 'Var', (71, 89))
77747	26719535	The six BAP1 changes that involve frameshift or splice site mutations are predicted to result in loss of the carboxy-terminal region of the protein, which contains the nuclear localization signal.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('loss', 'NegReg', (97, 101))	('frameshift', 'Var', (34, 44))	('changes', 'Var', (13, 20))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))	('carboxy-terminal region of the protein', 'MPA', (109, 147))	('localization', 'biological_process', 'GO:0051179', ('176', '188'))
77748	26719535	In contrast, the carboxy terminus is retained in the three BAP1 missense mutants, although they appeared to have decreased activity (Fig.	('BAP1', 'Gene', (59, 63))	('missense mutants', 'Var', (64, 80))	('activity', 'MPA', (123, 131))	('BAP1', 'Gene', '8314', (59, 63))	('decreased', 'NegReg', (113, 122))
77749	26719535	The Ub-AMC assay demonstrated that the missense mutations still permit the BAP1 enzyme to be activated, but to a lesser extent than the WT protein.	('AMC', 'Chemical', '-', (7, 10))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('BAP1', 'Gene', (75, 79))	('Ub', 'Chemical', '-', (4, 6))	('activated', 'MPA', (93, 102))	('BAP1', 'Gene', '8314', (75, 79))	('missense mutations', 'Var', (39, 57))
77750	26719535	We had hypothesized that germline mutations of BAP1 contribute to susceptibility to MM in asbestos-exposed individuals through a mechanism that involves gene x environment interaction.	('asbestos', 'Chemical', 'MESH:D001194', (90, 98))	('susceptibility', 'Reg', (66, 80))	('BAP1', 'Gene', '8314', (47, 51))	('germline mutations', 'Var', (25, 43))	('BAP1', 'Gene', (47, 51))
77751	26719535	Our finding of an increased prevalence of inherited BAP1 mutations in asbestos-exposed MM cases versus asbestos-exposed controls appears to be consistent with this notion.	('BAP1', 'Gene', '8314', (52, 56))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
77752	26719535	The results from the cohort of 153 individuals with a significant exposure to asbestos but without MM or a familial cancer history did not, as expected, show any germline BAP1 mutations.	('BAP1', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('familial cancer', 'Disease', (107, 122))	('BAP1', 'Gene', '8314', (171, 175))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('familial cancer', 'Disease', 'MESH:D009369', (107, 122))
77753	26719535	The other control cohort, consisting of 50 asbestos-exposed individuals from non-MM families with a high cancer signal similar to that of the 150 MM case cohort, also did not show any germline BAP1 mutations.	('BAP1', 'Gene', '8314', (193, 197))	('mutations', 'Var', (198, 207))	('high cancer', 'Disease', 'MESH:D009369', (100, 111))	('high cancer', 'Disease', (100, 111))	('BAP1', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('asbestos', 'Chemical', 'MESH:D001194', (43, 51))
77756	26719535	In their single family with a germline BAP1 mutation, three individuals who had potential exposure to asbestos developed MM, whereas another family member who was not exposed developed a different tumor type, i.e., a mucoepidermoid carcinoma.	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (217, 241))	('mutation', 'Var', (44, 52))	('germline', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mucoepidermoid carcinoma', 'Disease', (217, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('BAP1', 'Gene', '8314', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('asbestos', 'Chemical', 'MESH:D001194', (102, 110))	('tumor', 'Disease', (197, 202))	('BAP1', 'Gene', (39, 43))
77758	26719535	Instead, the significantly higher incidence of BAP1 mutations observed in MM cases versus controls suggests that asbestos and genetic factors cooperate to enhance the onset of MM.	('mutations', 'Var', (52, 61))	('enhance', 'PosReg', (155, 162))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (47, 51))
77760	26719535	Taken together, the findings presented here indicate that patients presenting with MM and a personal or family history of other cancers should be considered for genetic testing, with the goal of identifying those families that might benefit from BAP1 mutation screening and regular clinical monitoring of family members for the purpose of early detection of cancers and clinical intervention.	('BAP1', 'Gene', (246, 250))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', (358, 365))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (358, 365))	('mutation', 'Var', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BAP1', 'Gene', '8314', (246, 250))	('patients', 'Species', '9606', (58, 66))	('cancers', 'Disease', 'MESH:D009369', (358, 365))
77828	23667371	It is known that malignant mesothelioma (MM) is associated with SV40, and that the virus works as a cofactor to the carcinogenetic effects of asbestos.	('asbestos', 'Chemical', 'MESH:D001194', (142, 150))	('associated', 'Reg', (48, 58))	('SV40', 'Species', '1891767', (64, 68))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (17, 39))	('SV40', 'Var', (64, 68))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (17, 39))	('malignant mesothelioma', 'Disease', (17, 39))
77831	23667371	We analyzed 62 cases of available paraffin-blocks enrolled through the Korean Malignant Mesothelioma Surveillance System and performed immunohistochemistry for SV40 protein and real-time polymerase chain reaction (PCR) for SV40 DNA.	('SV40', 'Species', '1891767', (160, 164))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (78, 100))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('paraffin', 'Chemical', 'MESH:D010232', (34, 42))	('DNA', 'cellular_component', 'GO:0005574', ('228', '231'))	('Malignant Mesothelioma Surveillance', 'Disease', (78, 113))	('SV40', 'Species', '1891767', (223, 227))	('SV40', 'Var', (223, 227))	('Malignant Mesothelioma Surveillance', 'Disease', 'MESH:C562839', (78, 113))
77841	23667371	T-Ag induces DNA synthesis in host cells and prolongs the onset of the S-phase through the inhibition of tumor suppressor proteins p53 and Rb.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('onset of the S-phase', 'MPA', (58, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('S-phase', 'biological_process', 'GO:0051320', ('71', '78'))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibition', 'NegReg', (91, 101))	('DNA synthesis', 'biological_process', 'GO:0071897', ('13', '26'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('T-Ag', 'Var', (0, 4))	('DNA synthesis', 'MPA', (13, 26))	('prolongs', 'PosReg', (45, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('induces', 'Reg', (5, 12))
77845	23667371	This suggests that SV40 may act as an independent carcinogenic agent or as a cofactor of asbestos to augment the risk of MM.	('asbestos', 'Chemical', 'MESH:D001194', (89, 97))	('SV40', 'Species', '1891767', (19, 23))	('SV40', 'Var', (19, 23))	('carcinogenic', 'Disease', 'MESH:D063646', (50, 62))	('carcinogenic', 'Disease', (50, 62))
77886	23667371	In a case-control study, PCR analysis revealed the presence of SV40 DNA in eight of 19 cases of MM among individuals exposed to asbestos, suggesting that SV40 may increase the risk of MM among patients exposed to asbestos.	('patients', 'Species', '9606', (193, 201))	('increase', 'PosReg', (163, 171))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('asbestos', 'Chemical', 'MESH:D001194', (128, 136))	('SV40 DNA', 'Var', (63, 71))	('SV40', 'Species', '1891767', (154, 158))	('SV40', 'Var', (154, 158))	('SV40', 'Species', '1891767', (63, 67))	('asbestos', 'Chemical', 'MESH:D001194', (213, 221))
77887	23667371	In hamsters, intrapleural injection of SV40 virus resulted in the development of MM in 100% of cases within two to six months.	('SV40', 'Species', '1891767', (39, 43))	('pleural', 'Disease', 'MESH:D010995', (18, 25))	('development', 'CPA', (66, 77))	('pleural', 'Disease', (18, 25))	('SV40 virus', 'Var', (39, 49))
77889	23667371	To understand the roles of both T-Ag and t-Ag in the development of MM in hamsters, t-Ag mutant SV40 virus was injected intracardially into newborn hamsters, after which only one animal developed MM, while the majority developed histiocytic lymphomas.	('lymphomas', 'Disease', 'MESH:D008223', (241, 250))	('lymphomas', 'Phenotype', 'HP:0002665', (241, 250))	('t-Ag mutant', 'Var', (84, 95))	('SV40', 'Species', '1891767', (96, 100))	('SV40', 'Gene', (96, 100))	('lymphomas', 'Disease', (241, 250))
78036	16202137	The ventilation was designed to simulate the upwards flow of air produced by thermal convection from a hot glass float bath and the results show that the presence of hot work equipment would probably have reduced the workers exposure.	('presence', 'Var', (154, 162))	('reduced', 'NegReg', (205, 212))	('men', 'Species', '9606', (180, 183))
78287	33159147	The two groups of mice (CA-SF and CA-SF + IRR groups) received three doses of CA-SF (37.5 mg/kg of boron), namely at day 0, when tumours reached 50 +- 10 mm3, at day 2 and at day 6.	('IRR', 'Gene', '23920', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('CA-SF', 'Chemical', '-', (78, 83))	('CA-SF', 'Var', (78, 83))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('mice', 'Species', '10090', (18, 22))	('CA-SF', 'Chemical', '-', (34, 39))	('tumours', 'Disease', (129, 136))	('CA-SF', 'Chemical', '-', (24, 29))	('boron', 'Chemical', 'MESH:D001895', (99, 104))	('IRR', 'Gene', (42, 45))
78399	29247244	Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein.	('bortezomib', 'Chemical', 'MESH:D000069286', (250, 260))	('proteasome', 'molecular_function', 'GO:0004299', ('148', '158'))	('cellular apoptotic threshold', 'CPA', (184, 212))	('ubiquitin', 'molecular_function', 'GO:0031386', ('116', '125'))	('polyubiquitinated', 'Var', (65, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (228, 240))	('lowers', 'NegReg', (173, 179))	('toxicity', 'Disease', 'MESH:D064420', (269, 277))	('toxicity', 'Disease', (269, 277))	('sensitizes', 'Reg', (217, 227))	('proteasome', 'cellular_component', 'GO:0000502', ('148', '158'))	('mesothelioma', 'Disease', (228, 240))
78444	29247244	In fact, several recent evidences indicate that not only the canonical lysine-48 linked polyubiquitin chains but also other alternative ubiquitin linked chains support degradation by the 26S proteasome.	('degradation', 'biological_process', 'GO:0009056', ('168', '179'))	('proteasome', 'molecular_function', 'GO:0004299', ('191', '201'))	('26S', 'Enzyme', (187, 190))	('lysine', 'Chemical', 'MESH:D008239', (71, 77))	('polyubiquitin', 'biological_process', 'GO:0000209', ('88', '101'))	('polyubiquitin', 'molecular_function', 'GO:0005552', ('88', '101'))	('26S proteasome', 'cellular_component', 'GO:0000504', ('187', '201'))	('26S proteasome', 'cellular_component', 'GO:0000502', ('187', '201'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('136', '145'))	('lysine-48 linked', 'Var', (71, 87))	('degradation', 'MPA', (168, 179))	('26S proteasome', 'cellular_component', 'GO:0005837', ('187', '201'))
78465	29247244	Importantly, saturation of the proteasomal proteolytic route may stabilize pro-apoptotic effectors, such as the Bcl-2 homology domain 3 (BH3)-only proteins Bim and Noxa and the mitochondrial outer membrane permeabilizers BAX/BAK, or abrogate activity of survival factors like NF-kB, which are all known to play a pivotal role in modulating the sensitivity of MPM cells to bortezomib.	('NF-kB', 'Protein', (276, 281))	('mitochondrial outer membrane', 'cellular_component', 'GO:0005741', ('177', '205'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('Noxa', 'Gene', '5366', (164, 168))	('activity', 'MPA', (242, 250))	('BAX', 'Gene', '581', (221, 224))	('BAK', 'Gene', (225, 228))	('bortezomib', 'Chemical', 'MESH:D000069286', (372, 382))	('BAK', 'Gene', '578', (225, 228))	('Noxa', 'Gene', (164, 168))	('Bcl-2', 'Gene', (112, 117))	('Bcl-2', 'Gene', '596', (112, 117))	('BAX', 'Gene', (221, 224))	('pro-apoptotic', 'MPA', (75, 88))	('abrogate', 'NegReg', (233, 241))	('Bim', 'Gene', (156, 159))	('saturation', 'Var', (13, 23))	('Bim', 'Gene', '10018', (156, 159))
78521	27783867	To evaluate the inhibition of tumor formation by the replication-competent Ad, intact NCI-H226 cells (9 x 106) mixed with NCI-H226 cells (1 x 106) infected with Ad5VEGFE1 or Ad5VEGFLuc were injected into the left pleural space of nude mice.	('Ad5VEGFE1', 'Var', (161, 170))	('NCI-H226', 'CellLine', 'CVCL:1544', (86, 94))	('pleural', 'Disease', (213, 220))	('formation', 'biological_process', 'GO:0009058', ('36', '45'))	('Ad5VEGFLuc', 'Var', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('nude mice', 'Species', '10090', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NCI-H226', 'CellLine', 'CVCL:1544', (122, 130))	('tumor', 'Disease', (30, 35))	('pleural', 'Disease', 'MESH:D010995', (213, 220))
78531	27783867	In these five mesothelioma cell lines infected by Ad5VEGFLuc, H226 showed 10-100 times higher luciferase expression than the other cell lines (Fig.	('mesothelioma cell lines infected', 'Disease', (14, 46))	('Ad5VEGFLuc', 'Var', (50, 60))	('expression', 'Species', '29278', (105, 115))	('H226', 'CellLine', 'CVCL:J621', (62, 66))	('mesothelioma cell lines infected', 'Disease', 'MESH:D008654', (14, 46))	('expression', 'MPA', (105, 115))	('luciferase', 'Enzyme', (94, 104))	('higher', 'PosReg', (87, 93))
78576	27783867	In previous studies, neutralizing antibodies in the serum and the pleural space developed following both intranasal33 and intrabronchial34 administration, but these immune responses induced no adverse clinical sequence.35 However, neutralizing antibodies in the pleural space might bind to the viral vector, limit gene-transfer efficiency, and potentially negate the effects of viral therapy.	('neutralizing', 'Var', (231, 243))	('limit', 'NegReg', (308, 313))	('bind', 'Interaction', (282, 286))	('pleural', 'Disease', 'MESH:D010995', (66, 73))	('pleural', 'Disease', (66, 73))	('pleural', 'Disease', 'MESH:D010995', (262, 269))	('pleural', 'Disease', (262, 269))	('gene-transfer efficiency', 'CPA', (314, 338))	('negate', 'NegReg', (356, 362))
78586	27080907	Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition.	('mesothelioma', 'Disease', (108, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('mitochondrial', 'Var', (25, 38))
78592	27080907	Recently, a number of genetic alterations in BAP1 and NF2 have been identified, that may be prognostic and potentially predictive of therapeutic response.	('NF2', 'Gene', '4771', (54, 57))	('BAP1', 'Gene', (45, 49))	('genetic alterations', 'Var', (22, 41))	('NF2', 'Gene', (54, 57))	('BAP1', 'Gene', '8314', (45, 49))
78593	27080907	As an example, loss or mutation of merlin (NF2) may be a predictor of effective targeting by anti-focal adhesion kinase (FAK) therapy.	('focal adhesion', 'cellular_component', 'GO:0005925', ('98', '112'))	('merlin', 'Gene', '4771', (35, 41))	('NF2', 'Gene', '4771', (43, 46))	('mutation', 'Var', (23, 31))	('anti-focal adhesion kinase', 'Gene', (93, 119))	('FAK', 'Gene', '5747', (121, 124))	('anti-focal adhesion kinase', 'Gene', '5747', (93, 119))	('merlin', 'Gene', (35, 41))	('loss', 'Disease', 'MESH:D015431', (15, 19))	('loss', 'Disease', (15, 19))	('NF2', 'Gene', (43, 46))	('FAK', 'Gene', (121, 124))	('FAK', 'molecular_function', 'GO:0004717', ('121', '124'))
78619	27080907	H2052 and H2596 cells had a high level of reticulated mitochondria but with a restricted distribution around the nucleus.	('H2052', 'CellLine', 'CVCL:1518', (0, 5))	('nucleus', 'cellular_component', 'GO:0005634', ('113', '120'))	('reticulated mitochondria', 'MPA', (42, 66))	('mitochondria', 'cellular_component', 'GO:0005739', ('54', '66'))	('H2052', 'Var', (0, 5))
78638	27080907	Basal OCR was significantly lower in multiple mesothelioma cell lines (p < 0.001 for H28, H2052, H2452, and H2596) compared to control MeT-5A cells (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('H2052', 'Var', (90, 95))	('Basal OCR', 'MPA', (0, 9))	('lower', 'NegReg', (28, 33))	('H2452', 'Var', (97, 102))	('OCR', 'Chemical', '-', (6, 9))	('H2052', 'CellLine', 'CVCL:1518', (90, 95))	('mesothelioma', 'Disease', (46, 58))	('H28', 'Var', (85, 88))	('H2596', 'Var', (108, 113))
78640	27080907	The majority of mesothelioma cells, with the exception of H513 and H2452, also had significantly reduced levels of reserve oxidative respiratory capacity (calculated as the difference between max OCR stimulated by FCCP treatment and basal OCR levels) (Fig.	('H2452', 'Var', (67, 72))	('mesothelioma', 'Disease', 'MESH:D008654', (16, 28))	('OCR', 'Chemical', '-', (239, 242))	('FCCP', 'Chemical', 'MESH:D002259', (214, 218))	('reduced', 'NegReg', (97, 104))	('OCR', 'Chemical', '-', (196, 199))	('levels of reserve oxidative respiratory capacity', 'MPA', (105, 153))	('mesothelioma', 'Disease', (16, 28))
78642	27080907	H513 and H2052 exhibited slightly higher ECAR but these did not reach statistical significance.	('H2052', 'Var', (9, 14))	('H513', 'Var', (0, 4))	('higher', 'PosReg', (34, 40))	('H2052', 'CellLine', 'CVCL:1518', (9, 14))	('ECAR', 'MPA', (41, 45))
78643	27080907	Similarly, the lower ECAR observed in H2372, H2452 and H2461 did not reach significance.	('H2461', 'CellLine', 'CVCL:A536', (55, 60))	('H2372', 'CellLine', 'CVCL:T041', (38, 43))	('H2372', 'Var', (38, 43))	('H2461', 'Var', (55, 60))	('H2452', 'Var', (45, 50))	('lower', 'NegReg', (15, 20))	('ECAR', 'MPA', (21, 25))
78645	27080907	The majority of the mesothelioma cell lines tested show a decrease in this ratio indicating an increased dependence on glycolysis compared to Met-5A cells (H28, H513, H2052, H2452, H2596).	('H2052', 'CellLine', 'CVCL:1518', (167, 172))	('mesothelioma', 'Disease', (20, 32))	('H513', 'Var', (161, 165))	('dependence', 'MPA', (105, 115))	('H2452', 'Var', (174, 179))	('H2596', 'Var', (181, 186))	('decrease', 'NegReg', (58, 66))	('H2052', 'Var', (167, 172))	('glycolysis', 'MPA', (119, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('119', '129'))
78646	27080907	Two of the cell lines tested (H2373 and H2461) had a higher OCR/ECAR ratio compared to control MeT-5A cells.	('H2373', 'CellLine', 'CVCL:A533', (30, 35))	('OCR', 'Chemical', '-', (60, 63))	('higher', 'PosReg', (53, 59))	('H2373', 'Var', (30, 35))	('H2461', 'CellLine', 'CVCL:A536', (40, 45))	('H2461', 'Var', (40, 45))	('OCR/ECAR ratio', 'MPA', (60, 74))
78653	27080907	H513 and H2596 were the most sensitive (EC50 5.5 muM and 6.769 muM).	('muM', 'Gene', '56925', (63, 66))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', (63, 66))	('muM', 'Gene', (49, 52))	('H2596', 'Var', (9, 14))
78667	27080907	The panel of MM cell lines examined displayed a spectrum of bioenergetic profiles, ranging from more oxidative (H2461), to more glycolytic (H28) and with decreased oxidative reserve capacities.	('decreased', 'NegReg', (154, 163))	('more', 'PosReg', (123, 127))	('glycolytic', 'MPA', (128, 138))	('oxidative reserve capacities', 'MPA', (164, 192))	('oxidative', 'MPA', (101, 110))	('more', 'PosReg', (96, 100))	('H2461', 'CellLine', 'CVCL:A536', (112, 117))	('H2461', 'Var', (112, 117))	('bioenergetic profiles', 'MPA', (60, 81))
78679	27080907	H2373 and H2461 both have relatively high levels of OCR and high fractal dimension/low lacunarity, while H28, H2452 exhibit low metabolic activity and relatively low fractal dimension and lacunarity.	('H2373', 'CellLine', 'CVCL:A533', (0, 5))	('lacunarity', 'MPA', (87, 97))	('H2373', 'Var', (0, 5))	('H2461', 'Var', (10, 15))	('metabolic activity', 'MPA', (128, 146))	('OCR', 'Chemical', '-', (52, 55))	('H2452', 'Var', (110, 115))	('OCR', 'MPA', (52, 55))	('H2461', 'CellLine', 'CVCL:A536', (10, 15))
78683	27080907	For example, when the mutant A127T paxillin protein, which stimulates focal adhesion formation, is introduced into cells the mitochondrial network appears swollen and more reticulated.	('A127T', 'Var', (29, 34))	('more', 'PosReg', (167, 171))	('paxillin', 'Gene', (35, 43))	('A127T', 'Mutation', 'rs78768932', (29, 34))	('mitochondrial network', 'CPA', (125, 146))	('focal adhesion formation', 'CPA', (70, 94))	('focal adhesion', 'cellular_component', 'GO:0005925', ('70', '84'))	('focal adhesion formation', 'biological_process', 'GO:0048041', ('70', '94'))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('paxillin', 'Gene', '5829', (35, 43))
78688	27080907	It is also possible that differential gene alterations (such as loss or mutation of NF2 or BAP1) can also contribute to metabolic changes and altered mitochondrial morphologies in mesothelioma and should be more thoroughly investigated.	('loss', 'Disease', (64, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('BAP1', 'Gene', (91, 95))	('metabolic changes', 'CPA', (120, 137))	('NF2', 'Gene', '4771', (84, 87))	('altered', 'Reg', (142, 149))	('mitochondrial morphologies', 'CPA', (150, 176))	('contribute', 'Reg', (106, 116))	('BAP1', 'Gene', '8314', (91, 95))	('mesothelioma', 'Disease', (180, 192))	('NF2', 'Gene', (84, 87))	('loss', 'Disease', 'MESH:D015431', (64, 68))	('mutation', 'Var', (72, 80))
78693	27080907	Inhibition or silencing of peroxirodoxin-3, a mitochondrial oxidoreductase, led to disrupted mitochondrial bioenergetics, cell cycle arrest and reduced MM tumor volumes in vivo.	('reduced', 'NegReg', (144, 151))	('silencing', 'Var', (14, 23))	('cell cycle arrest', 'CPA', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('MM tumor', 'Disease', (152, 160))	('peroxirodoxin-3', 'Chemical', '-', (27, 42))	('MM tumor', 'Disease', 'MESH:D009369', (152, 160))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('peroxirodoxin-3', 'Gene', (27, 42))	('disrupted', 'NegReg', (83, 92))	('mitochondrial bioenergetics', 'MPA', (93, 120))
78699	27080907	Mesothelioma cell lines H28, H513, H2052, H2461 (Epithelioid) and H2373, H2596 (Sarcomatoid) and H2452 (Biphasic) (ATCC) were maintained in RPMI-1640 (Corning), 10% fetal bovine serum (Sigma) as described previously.	('H2461', 'CellLine', 'CVCL:A536', (42, 47))	('H2373', 'CellLine', 'CVCL:A533', (66, 71))	('Sarcomatoid', 'Disease', (80, 91))	('RPMI-1640', 'Chemical', '-', (140, 149))	('Sarcomatoid', 'Disease', 'MESH:C538614', (80, 91))	('H2373', 'Var', (66, 71))	('H2052', 'CellLine', 'CVCL:1518', (35, 40))	('H2452', 'Var', (97, 102))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('H2596', 'Var', (73, 78))	('bovine', 'Species', '9913', (171, 177))
78735	19960346	Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines.	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('MDA MB-468', 'CellLine', 'CVCL:0419', (243, 253))	('H2461', 'CellLine', 'CVCL:A536', (202, 207))	('H2373', 'CellLine', 'CVCL:A533', (188, 193))	('H2373', 'Var', (188, 193))	('H2461', 'Var', (202, 207))	('H2595', 'Var', (181, 186))	('suppression', 'NegReg', (156, 167))	('H2452', 'CellLine', 'CVCL:1553', (195, 200))	('H2452', 'Var', (195, 200))	('H2595', 'CellLine', 'CVCL:A545', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('SKBR-3', 'CellLine', 'CVCL:0033', (255, 261))	('growth', 'MPA', (149, 155))	('breast cancer', 'Disease', (228, 241))	('H2714', 'Var', (213, 218))	('Velcade', 'Chemical', 'MESH:D000069286', (131, 138))
78748	19960346	Five MPM patient derived cell lines [H2373, H2452, H2595, H2461 and H2714] established in our laboratory and characterized in detail were cultured in RPMI 1640 (Mediatech Inc., Herndon, VA) supplemented with 100 units/ml of penicillin, 100 microg/ml streptomycin, 4 mM L-glutamine, and 10% fetal calf serum.	('H2452', 'CellLine', 'CVCL:1553', (44, 49))	('H2461', 'Var', (58, 63))	('H2373', 'CellLine', 'CVCL:A533', (37, 42))	('H2714]', 'Var', (68, 74))	('patient', 'Species', '9606', (9, 16))	('H2595', 'CellLine', 'CVCL:A545', (51, 56))	('calf', 'Species', '9913', (296, 300))	('H2461', 'CellLine', 'CVCL:A536', (58, 63))
78776	19960346	As a first step towards this goal, we determined the effects of Velcade on the growth of human MPM (H2373, H2452, H2595, H2461 and H2714) as well as HBC (MDA-MB-468 and SKBR-3) cell lines.	('human', 'Species', '9606', (89, 94))	('H2461', 'CellLine', 'CVCL:A536', (121, 126))	('Velcade', 'Chemical', 'MESH:D000069286', (64, 71))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (154, 164))	('SKBR-3', 'CellLine', 'CVCL:0033', (169, 175))	('H2373', 'CellLine', 'CVCL:A533', (100, 105))	('H2714', 'Var', (131, 136))	('H2461', 'Var', (121, 126))	('H2452', 'Var', (107, 112))	('H2373', 'Var', (100, 105))	('H2452', 'CellLine', 'CVCL:1553', (107, 112))	('H2595', 'Var', (114, 119))	('H2595', 'CellLine', 'CVCL:A545', (114, 119))
78781	19960346	Consistent with our earlier studies and observations from other laboratories, our current analyses revealed a G2-M arrest in a concentration-dependent manner in H2373 and H2595 MPM cells (Fig.	('H2373', 'CellLine', 'CVCL:A533', (161, 166))	('H2373', 'Var', (161, 166))	('H2595 MPM', 'Var', (171, 180))	('G2-M arrest', 'CPA', (110, 121))	('H2595 MPM', 'CellLine', 'CVCL:A545', (171, 180))
78798	19960346	Since ~50% inhibition of H2373, H2461, H2714, and H2595 MPM cell growth was noted in the presence of 40,40, 20, and 80 nM doses, respectively, of Velcade (Fig.	('H2595', 'Var', (50, 55))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('H2373', 'CellLine', 'CVCL:A533', (25, 30))	('H2461', 'CellLine', 'CVCL:A536', (32, 37))	('H2373', 'Var', (25, 30))	('H2714', 'Var', (39, 44))	('H2595 MPM', 'CellLine', 'CVCL:A545', (50, 59))	('inhibition', 'NegReg', (11, 21))	('Velcade', 'Chemical', 'MESH:D000069286', (146, 153))	('H2461', 'Var', (32, 37))
78800	19960346	MPM cells, with the exception of H2595, were pretreated with either 10 or 20 nM of Velcade for 24 h followed by treatments with 20, 40, or 80 microM cisplatin for additional 24 h. Since H2595 cells elicited higher IC50 for Velcade (~80 nM, Fig.	('H2595', 'CellLine', 'CVCL:A545', (186, 191))	('H2595', 'CellLine', 'CVCL:A545', (33, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('IC50', 'MPA', (214, 218))	('Velcade', 'Chemical', 'MESH:D000069286', (223, 230))	('H2595', 'Var', (186, 191))	('Velcade', 'Chemical', 'MESH:D000069286', (83, 90))	('higher', 'PosReg', (207, 213))
78808	19960346	Velcade alone or in combination with cisplatin also resulted in a significant increase in expression of pro-apoptotic protein Bax, cleaved caspase-3 and PARP proteins in H2373 cells, while a modest increase in levels of Bax and cleavage of caspase-3 and PARP proteins was noted in similarly treated H2595 cells (Fig.	('increase', 'PosReg', (78, 86))	('expression', 'MPA', (90, 100))	('H2373', 'CellLine', 'CVCL:A533', (170, 175))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('cisplatin', 'Var', (37, 46))	('PARP', 'Gene', '142', (153, 157))	('Velcade', 'Chemical', 'MESH:D000069286', (0, 7))	('Bax', 'Gene', (220, 223))	('Bax', 'Gene', (126, 129))	('caspase-3', 'Gene', '836', (139, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('H2595', 'CellLine', 'CVCL:A545', (299, 304))	('PARP', 'Gene', (153, 157))	('PARP', 'Gene', '142', (254, 258))	('Bax', 'Gene', '581', (126, 129))	('cleaved', 'MPA', (131, 138))	('caspase-3', 'Gene', '836', (240, 249))	('Bax', 'Gene', '581', (220, 223))	('PARP', 'Gene', (254, 258))	('caspase-3', 'Gene', (139, 148))	('caspase-3', 'Gene', (240, 249))
78812	19960346	5 strongly suggest that inhibition of proteasome causes MPM cell growth inhibition in part by inducing cell cycle arrest and apoptosis, and thus provide a mechanistic basis of MPM chemosensitization by Velcade pretreatment.	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('cell cycle arrest', 'CPA', (103, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('Velcade', 'Chemical', 'MESH:D000069286', (202, 209))	('inhibition', 'Var', (24, 34))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('103', '120'))	('inducing', 'Reg', (94, 102))	('apoptosis', 'CPA', (125, 134))	('proteasome', 'Protein', (38, 48))	('proteasome', 'molecular_function', 'GO:0004299', ('38', '48'))	('proteasome', 'cellular_component', 'GO:0000502', ('38', '48'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))
78833	19960346	The fact that alterations in apoptosis signaling pathways often contribute to MPM growth and survival, and data from several studies including our current investigation suggest that Velcade suppresses MPM growth in part by stimulating apoptosis, we undertook an in vitro and gene-array-based profiling to identify novel transducers of apoptosis signaling that may be targeted by Velcade.	('apoptosis', 'CPA', (235, 244))	('alterations', 'Var', (14, 25))	('contribute', 'Reg', (64, 74))	('stimulating', 'PosReg', (223, 234))	('Velcade', 'Chemical', 'MESH:D000069286', (182, 189))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('335', '354'))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))	('MPM growth', 'CPA', (201, 211))	('Velcade', 'Chemical', 'MESH:D000069286', (379, 386))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('29', '48'))	('suppresses', 'NegReg', (190, 200))
78865	23961330	The World Health Organization now asserts that asbestos causes cancer of the larynx and ovary, with sufficient evidence; and cancer of the stomach, colorectum and pharynx, with limited evidence.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer of the stomach', 'Phenotype', 'HP:0006753', (125, 146))	('causes', 'Reg', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (125, 131))	('asbestos', 'Var', (47, 55))	('cancer of the larynx', 'Phenotype', 'HP:0012118', (63, 83))	('ovary', 'Disease', (88, 93))	('asbestos', 'Chemical', 'MESH:D001194', (47, 55))	('cancer', 'Disease', (63, 69))	('ovary', 'Disease', 'MESH:D010051', (88, 93))
78902	23446998	ERK5 silencing increased DOX-induced cell death and DOX retention in MM cells.	('retention', 'biological_process', 'GO:0051235', ('56', '65'))	('DOX', 'Chemical', 'MESH:D004317', (25, 28))	('silencing', 'Var', (5, 14))	('DOX', 'Chemical', 'MESH:D004317', (52, 55))	('increased', 'PosReg', (15, 24))	('DOX retention', 'MPA', (52, 65))	('ERK5', 'Gene', (0, 4))	('cell death', 'biological_process', 'GO:0008219', ('37', '47'))	('DOX-induced cell death', 'CPA', (25, 47))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))
78903	23446998	In addition, shERK5 MM lines exhibited both attenuated colony formation on soft agar and invasion of MM cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion and drug resistance as shown by microarray analysis.	('modulation', 'Var', (144, 154))	('formation', 'biological_process', 'GO:0009058', ('62', '71'))	('migration/invasion', 'CPA', (215, 233))	('drug resistance', 'Phenotype', 'HP:0020174', (238, 253))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('colony formation on soft agar', 'CPA', (55, 84))	('shERK5', 'Chemical', '-', (13, 19))	('invasion of MM cells', 'CPA', (89, 109))	('drug resistance', 'biological_process', 'GO:0042493', ('238', '253'))	('drug resistance', 'biological_process', 'GO:0009315', ('238', '253'))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))	('attenuated', 'NegReg', (44, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('184', '202'))
78915	23446998	The MEK5/ERK5 pathway is essential for blood vessel and cardiac development, and removal of MEK5 or ERK5 is embryonically lethal with defects in these tissues.	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('ERK', 'molecular_function', 'GO:0004707', ('9', '12'))	('MEK5', 'Gene', '5607', (92, 96))	('cardiac development', 'biological_process', 'GO:0007507', ('56', '75'))	('MEK5', 'Gene', (92, 96))	('MEK5', 'Gene', '5607', (4, 8))	('MEK5', 'Gene', (4, 8))	('ERK5', 'Gene', (100, 104))	('removal', 'Var', (81, 88))
78919	23446998	A link between overexpression of ERK5 and decreased disease-free survival in breast cancer patients has recently been reported, and inhibition of ERK5 decreased both proliferation and sensitization of cells to anti-HER2 therapies.	('ERK', 'molecular_function', 'GO:0004707', ('146', '149'))	('sensitization', 'CPA', (184, 197))	('decreased', 'NegReg', (42, 51))	('proliferation', 'CPA', (166, 179))	('ERK5', 'Protein', (33, 37))	('HER2', 'Gene', '2064', (215, 219))	('ERK5', 'Gene', (146, 150))	('patients', 'Species', '9606', (91, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('breast cancer', 'Disease', (77, 90))	('HER2', 'Gene', (215, 219))	('decreased', 'NegReg', (151, 160))	('disease-free survival', 'CPA', (52, 73))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('overexpression', 'PosReg', (15, 29))	('sensitization', 'biological_process', 'GO:0046960', ('184', '197'))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))	('inhibition', 'Var', (132, 142))
78920	23446998	In addition, ERK5 is a target for gene amplification at 17p11 in hepatocellular carcinoma (HCC) and is detected in approximately 50% of primary HCC tumors.	('amplification at 17p11', 'Var', (39, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hepatocellular carcinoma', 'Disease', (65, 89))	('HCC tumors', 'Disease', (144, 154))	('detected', 'Reg', (103, 111))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('HCC tumors', 'Disease', 'MESH:D006528', (144, 154))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('ERK5', 'Gene', (13, 17))	('ERK', 'molecular_function', 'GO:0004707', ('13', '16'))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('HCC', 'Phenotype', 'HP:0001402', (144, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))
78924	23446998	In this preclinical study we show mechanistically that ERK5 plays a critical role in parameters of MM tumor development and demonstrate that inhibition of ERK5 alone or in combination with DOX or cisplatin is a potential therapeutic strategy for MMs.	('MM tumor', 'Disease', (99, 107))	('MMs', 'Disease', (246, 249))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('MM tumor', 'Disease', 'MESH:D009369', (99, 107))	('DOX', 'Chemical', 'MESH:D004317', (189, 192))	('ERK', 'molecular_function', 'GO:0004707', ('55', '58'))	('inhibition', 'Var', (141, 151))	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('ERK5', 'Gene', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
78989	23446998	For example, ERK5 inhibition resulted in decreased proliferation/survival related genes and transcription factors like p21 activated kinase 7 (PAK7), chemokine ligand 5 (CCL5/RANTES), and AKT 3 as well as decreased invasion/migration related genes such as matrix metalloproteinases 1 and 9 (MMP1 and 9) and ATP binding Cassettes (ABC) (ABCC2, ABCA8, ABCC5, ABCB) involved in drug resistance.	('ABCC2', 'Gene', '1244', (336, 341))	('ABC', 'Gene', '10058', (350, 353))	('ABC', 'Gene', '10058', (357, 360))	('ligand', 'molecular_function', 'GO:0005488', ('160', '166'))	('ABC', 'Gene', (350, 353))	('PAK7', 'Gene', '57144', (143, 147))	('ABC', 'Gene', (357, 360))	('ABCC5', 'Gene', '10057', (350, 355))	('proliferation/survival', 'CPA', (51, 73))	('ABCC2', 'Gene', (336, 341))	('decreased', 'NegReg', (41, 50))	('ABC', 'Gene', '10058', (330, 333))	('ABCA8', 'Gene', '10351', (343, 348))	('ATP binding', 'molecular_function', 'GO:0005524', ('307', '318'))	('ERK', 'molecular_function', 'GO:0004707', ('13', '16'))	('drug resistance', 'Phenotype', 'HP:0020174', (375, 390))	('CCL', 'molecular_function', 'GO:0044101', ('170', '173'))	('ABCC5', 'Gene', (350, 355))	('inhibition', 'Var', (18, 28))	('p21 activated kinase 7', 'Gene', (119, 141))	('ABC', 'Gene', (330, 333))	('p21 activated kinase 7', 'Gene', '57144', (119, 141))	('AKT 3', 'Gene', '10000', (188, 193))	('MMP1 and 9', 'Gene', '4312;4318', (291, 301))	('MMP1', 'molecular_function', 'GO:0004232', ('291', '295'))	('decreased', 'NegReg', (205, 214))	('AKT 3', 'Gene', (188, 193))	('invasion/migration', 'CPA', (215, 233))	('ABC', 'Gene', '10058', (343, 346))	('ABCA8', 'Gene', (343, 348))	('ABC', 'Gene', '10058', (336, 339))	('ERK5', 'Gene', (13, 17))	('PAK7', 'Gene', (143, 147))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('drug resistance', 'biological_process', 'GO:0009315', ('375', '390'))	('ABC', 'Gene', (343, 346))	('drug resistance', 'biological_process', 'GO:0042493', ('375', '390'))	('ABC', 'Gene', (336, 339))
78990	23446998	These gene expression results show that ERK5 inhibition can attenuate tumor growth by regulating expression of many critical genes related to tumorigenesis.	('ERK', 'molecular_function', 'GO:0004707', ('40', '43'))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('ERK5', 'Gene', (40, 44))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (70, 75))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('regulating', 'Reg', (86, 96))	('inhibition', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('expression', 'MPA', (97, 107))	('attenuate', 'NegReg', (60, 69))
78996	23446998	In contrast ERK5 inhibition significantly decreased tumor burden and further reduced tumor burden when combined with DOX (Fig 5A).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (85, 90))	('decreased', 'NegReg', (42, 51))	('tumor', 'Disease', (52, 57))	('DOX', 'Chemical', 'MESH:D004317', (117, 120))	('ERK', 'molecular_function', 'GO:0004707', ('12', '15'))	('inhibition', 'Var', (17, 27))	('ERK5', 'Protein', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('reduced', 'NegReg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
79018	23446998	These findings and our results in two MM SCID mice models show that inhibition of ERK5 in combination with chemotherapeutic drugs is a better approach to suppress tumorigenesis.	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('inhibition', 'Var', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('ERK5', 'Gene', (82, 86))	('MM SCID', 'Disease', 'MESH:D053632', (38, 45))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', (163, 168))	('suppress', 'NegReg', (154, 162))	('MM SCID', 'Disease', (38, 45))
79027	23446998	In these experiments, ERK5 silenced MM cells showed a significant decrease in MM tumor growth rate (SC model) and tumor volume (IP and SC models) as compared to tumors from transfected control MM cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('silenced', 'Var', (27, 35))	('MM tumor', 'Disease', 'MESH:D009369', (78, 86))	('ERK', 'molecular_function', 'GO:0004707', ('22', '25'))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('ERK5', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MM tumor', 'Disease', (78, 86))	('decrease', 'NegReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (81, 86))
79029	23446998	As listed in Table 1, ATP-binding cassette (ABC) transporters [ABCB (MDR/TAP), ABCC2, ABCA8, ABCC5] which are known transporters of various molecules, including chemotherapeutic drugs, across extra- and intracellular membranes were down regulated 2-4 fold by ERK5 attenuation.	('attenuation', 'Var', (264, 275))	('ERK5', 'Gene', (259, 263))	('ATP-binding', 'molecular_function', 'GO:0005524', ('22', '33'))	('ABC', 'Gene', '10058', (63, 66))	('ABC', 'Gene', '10058', (86, 89))	('ABC', 'Gene', '10058', (79, 82))	('intracellular', 'cellular_component', 'GO:0005622', ('203', '216'))	('ATP-binding cassette', 'Gene', '10058', (22, 42))	('ABCA8', 'Gene', (86, 91))	('ABC', 'Gene', (63, 66))	('ABC', 'Gene', (86, 89))	('ABC', 'Gene', (79, 82))	('ABCC2', 'Gene', '1244', (79, 84))	('ABC', 'Gene', '10058', (93, 96))	('ABC', 'Gene', '10058', (44, 47))	('MDR', 'molecular_function', 'GO:0004745', ('69', '72'))	('ABC', 'Gene', (93, 96))	('ABCC2', 'Gene', (79, 84))	('ABCC5', 'Gene', '10057', (93, 98))	('ATP-binding cassette', 'Gene', (22, 42))	('ABC', 'Gene', (44, 47))	('ABCA8', 'Gene', '10351', (86, 91))	('down regulated', 'NegReg', (232, 246))	('ERK', 'molecular_function', 'GO:0004707', ('259', '262'))	('ABCC5', 'Gene', (93, 98))
79032	23446998	To further understand the mechanisms of reduced MM tumorigenesis by ERK5 silencing, we assessed inflammatory profiles in PLF samples from tumor-bearing SCID mice.	('SCID', 'Disease', 'MESH:D053632', (152, 156))	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))	('silencing', 'Var', (73, 82))	('MM tumor', 'Disease', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ERK5', 'Gene', (68, 72))	('tumor', 'Disease', (138, 143))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', (51, 56))	('MM tumor', 'Disease', 'MESH:D009369', (48, 56))	('reduced', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('SCID', 'Disease', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
79034	23446998	In addition to affecting infiltration of inflammatory cells, ERK5 inhibition also significantly decreased levels of various human cytokines (IL-8, VEGF, MCP-1, CCL5/RANTES) in PLF.	('affecting', 'Reg', (15, 24))	('CCL', 'molecular_function', 'GO:0044101', ('160', '163'))	('decreased', 'NegReg', (96, 105))	('MCP', 'molecular_function', 'GO:0004298', ('153', '156'))	('human', 'Species', '9606', (124, 129))	('ERK5', 'Protein', (61, 65))	('inhibition', 'Var', (66, 76))	('IL-8', 'molecular_function', 'GO:0005153', ('141', '145'))	('infiltration of inflammatory cells', 'MPA', (25, 59))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
79037	23446998	As VEGF and IL-6 (as shown in Table 1) are prototypical STAT3-indicible factors and STAT3 activation was inhibited in ERK5-attenuated MM cells (data not shown), the ERK5-mediated effects could in part be STAT3-dependent.	('STAT3', 'Gene', '6774', (84, 89))	('STAT3', 'Gene', '6774', (204, 209))	('STAT3', 'Gene', (56, 61))	('ERK5-attenuated', 'Var', (118, 133))	('inhibited', 'NegReg', (105, 114))	('IL-6', 'Gene', (12, 16))	('IL-6', 'Gene', '3569', (12, 16))	('STAT3', 'Gene', (84, 89))	('STAT3', 'Gene', (204, 209))	('ERK', 'molecular_function', 'GO:0004707', ('165', '168'))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('IL-6', 'molecular_function', 'GO:0005138', ('12', '16'))	('STAT3', 'Gene', '6774', (56, 61))
79039	23446998	We report for the first time that ERK5 silencing plays an important role in reducing the expression of this gene in MM cells in vitro as well as secretion of this protein in PLF of MM tumor bearing mice.	('MM tumor', 'Disease', (181, 189))	('expression', 'MPA', (89, 99))	('mice', 'Species', '10090', (198, 202))	('ERK', 'molecular_function', 'GO:0004707', ('34', '37'))	('MM tumor', 'Disease', 'MESH:D009369', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('ERK5', 'Gene', (34, 38))	('silencing', 'Var', (39, 48))	('reducing', 'NegReg', (76, 84))	('secretion', 'MPA', (145, 154))	('secretion', 'biological_process', 'GO:0046903', ('145', '154'))
79040	23446998	Another multifunctional cytokine, IL-6, which is linked to the promotion of tumorigenesis in various malignancies including MM, is known to be regulated by ERK5 and was also downregulated by ERK5 silencing in MM cells.	('ERK5', 'Gene', (191, 195))	('malignancies', 'Disease', (101, 113))	('downregulated', 'NegReg', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('IL-6', 'Gene', '3569', (34, 38))	('IL-6', 'Gene', (34, 38))	('ERK', 'molecular_function', 'GO:0004707', ('191', '194'))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('IL-6', 'molecular_function', 'GO:0005138', ('34', '38'))	('silencing', 'Var', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('ERK', 'molecular_function', 'GO:0004707', ('156', '159'))
79044	23446998	As per this knowledge, ours is the first report showing that ERK5 inhibition can attenuate MM tumor growth primarily by inhibiting inflammation.	('attenuate', 'NegReg', (81, 90))	('inhibiting', 'NegReg', (120, 130))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ERK5', 'Protein', (61, 65))	('inhibition', 'Var', (66, 76))	('MM tumor', 'Disease', (91, 99))	('inflammation', 'biological_process', 'GO:0006954', ('131', '143'))	('MM tumor', 'Disease', 'MESH:D009369', (91, 99))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
79049	23446998	In addition, silencing of ERK5 decreased invasion of MM cells which may correlate with significantly diminished levels of MMPs 1, 9 and BMP5 genes actively involved in migration and invasion.	('diminished', 'NegReg', (101, 111))	('MMPs', 'Gene', (122, 126))	('ERK5', 'Gene', (26, 30))	('decreased', 'NegReg', (31, 40))	('invasion of MM cells', 'CPA', (41, 61))	('BMP5', 'Gene', (136, 140))	('BMP5', 'Gene', '653', (136, 140))	('MMPs', 'Gene', '4312;17386;4318;17381;17386', (122, 126))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('silencing', 'Var', (13, 22))
79053	23446998	Our findings also demonstrate that ERK5 inhibition may inhibit MM tumor development by elevating the expression of apoptosis-related genes and thereby apoptosis.	('elevating', 'PosReg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ERK', 'molecular_function', 'GO:0004707', ('35', '38'))	('ERK5', 'Protein', (35, 39))	('inhibition', 'Var', (40, 50))	('MM tumor', 'Disease', (63, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('MM tumor', 'Disease', 'MESH:D009369', (63, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('expression', 'MPA', (101, 111))	('apoptosis', 'CPA', (151, 160))	('inhibit', 'NegReg', (55, 62))	('apoptosis-related genes', 'Gene', (115, 138))
79054	23446998	As shown in Table 1, MEKK5/ASK1/MAPKKK5 (activator of proapoptotic pathways, JNK), MKK6/MAPKK6 (activator of proapoptotic pathway p38 MAPK) and MAPK10 (JNK activator) were upregulated by ERK5 inhibition.	('MEKK', 'molecular_function', 'GO:0004709', ('21', '25'))	('JNK', 'Gene', (152, 155))	('ASK1', 'Gene', (27, 31))	('JNK', 'molecular_function', 'GO:0004705', ('77', '80'))	('JNK', 'Gene', '5599', (152, 155))	('upregulated', 'PosReg', (172, 183))	('MKK6', 'Gene', '5608', (83, 87))	('MAPK10', 'Gene', (144, 150))	('MKK6', 'Gene', (83, 87))	('MEKK5', 'Gene', '4217', (21, 26))	('MEKK5', 'Gene', (21, 26))	('JNK', 'molecular_function', 'GO:0004705', ('152', '155'))	('MAPKK', 'molecular_function', 'GO:0004708', ('88', '93'))	('MAPK', 'molecular_function', 'GO:0004707', ('134', '138'))	('MKK6', 'molecular_function', 'GO:0004708', ('83', '87'))	('JNK', 'Gene', (77, 80))	('inhibition', 'Var', (192, 202))	('JNK', 'Gene', '5599', (77, 80))	('MAPK', 'Gene', (32, 36))	('MAPK', 'Gene', (88, 92))	('MAPKK6', 'Gene', (88, 94))	('ERK', 'molecular_function', 'GO:0004707', ('187', '190'))	('MAPKKK5', 'Gene', (32, 39))	('MAPK', 'Gene', (144, 148))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (32, 36))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (88, 92))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (144, 148))	('MAPKK6', 'Gene', '5608', (88, 94))	('MAPK10', 'Gene', '5602', (144, 150))	('ASK1', 'Gene', '4217', (27, 31))	('MAPK', 'Gene', (134, 138))	('MAPKKK5', 'Gene', '4217', (32, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (134, 138))	('ERK5', 'Gene', (187, 191))
79057	23446998	Furthermore, ERK5 inhibition can significantly reduce tumor growth, and when used in combination with chemotherapeutic drugs, can have a far better effect on MM tumor reduction when compared to either drug alone.	('MM tumor', 'Disease', (158, 166))	('reduce', 'NegReg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('MM tumor', 'Disease', 'MESH:D009369', (158, 166))	('ERK5', 'Protein', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ERK', 'molecular_function', 'GO:0004707', ('13', '16'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inhibition', 'Var', (18, 28))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (161, 166))
79063	23446998	Here we are the first to show that inhibition of ERK5 in MM tumors in vivo resulted in significantly decreased tumor burden and produced a synergistic effect with chemotherapeutic drugs.	('ERK', 'molecular_function', 'GO:0004707', ('49', '52'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('synergistic effect', 'MPA', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MM tumors', 'Disease', (57, 66))	('MM tumors', 'Disease', 'MESH:D009369', (57, 66))	('decreased', 'NegReg', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ERK5', 'Gene', (49, 53))	('inhibition', 'Var', (35, 45))	('tumor', 'Disease', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
79135	21145765	Mortality and morbidity rates are substantially lower for P/D than EPP and the less extensive nature of P/D means that it is available to more MPM patients (some of which are not suitable candidates for EPP).	('morbidity', 'CPA', (14, 23))	('P/D', 'Var', (58, 61))	('lower', 'NegReg', (48, 53))	('MPM', 'Disease', (143, 146))	('patients', 'Species', '9606', (147, 155))
79137	21145765	P/D is often applied for palliative effect to debulk the gross tumor and relieve symptoms such as shortness of breath and chest pains.	('tumor', 'Disease', (63, 68))	('pains', 'Phenotype', 'HP:0012531', (128, 133))	('P/D', 'Var', (0, 3))	('chest pains', 'Disease', (122, 133))	('shortness of breath', 'Phenotype', 'HP:0002098', (98, 117))	('shortness of breath', 'Disease', 'MESH:D004417', (98, 117))	('chest pains', 'Disease', 'MESH:D002637', (122, 133))	('shortness of breath', 'Disease', (98, 117))	('relieve', 'NegReg', (73, 80))	('debulk', 'NegReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('chest pains', 'Phenotype', 'HP:0100749', (122, 133))
79155	21145765	P/D is often applied to MPM patients as a palliative treatment to free trapped lung and improve respiratory mechanics; however, previous studies have neither confirmed nor quantified lung volume improvement in this population.	('P/D', 'Var', (0, 3))	('improve', 'PosReg', (88, 95))	('free trapped lung', 'MPA', (66, 83))	('free trapped lung', 'Phenotype', 'HP:0002108', (66, 83))	('patients', 'Species', '9606', (28, 36))	('respiratory mechanics', 'MPA', (96, 117))
79159	21145765	Normalization brings measurements from patients of different sizes to a common scale and thus mitigates inter-patient lung volume variability.	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (39, 47))	('mitigates', 'NegReg', (94, 103))	('Normalization', 'Var', (0, 13))	('lung volume variability', 'MPA', (118, 141))	('patient', 'Species', '9606', (110, 117))
79170	21145765	Although the majority of patients demonstrated improvement due to P/D, two patients were observed to have decreased normalized lung volume.	('decreased', 'NegReg', (106, 115))	('P/D', 'Var', (66, 69))	('normalized lung volume', 'MPA', (116, 138))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (25, 33))	('improvement', 'PosReg', (47, 58))
79243	33473097	Microscopically, the HE results showed that the tumors from s.c. model were epithelioid mesothelioma (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('HE', 'Chemical', '-', (21, 23))	('s.c.', 'Var', (60, 64))	('mesothelioma', 'Disease', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
79271	33473097	Both BAP1 and NF2 were frameshift mutations, with mutation abundances of 99.9% and 90.0%, respectively.	('NF2', 'Gene', (14, 17))	('BAP1', 'Gene', '8314', (5, 9))	('frameshift', 'Var', (23, 33))	('NF2', 'Gene', '4771', (14, 17))	('BAP1', 'Gene', (5, 9))
79272	33473097	Evidence previously reported that mutations or deletions of BAP1 and NF2 were found in malignant mesothelioma, with the mutation abundances of 57% and 35%, respectively, NF2 mutations or deletions were associated with poor prognosis, and provided a new target for MPM, while the relationship between the mutation of BAP1 and the prognosis in MPM patients was still controversial.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (87, 109))	('NF2', 'Gene', '4771', (170, 173))	('malignant mesothelioma', 'Disease', (87, 109))	('deletions', 'Var', (47, 56))	('NF2', 'Gene', (69, 72))	('found', 'Reg', (78, 83))	('BAP1', 'Gene', '8314', (316, 320))	('associated', 'Reg', (202, 212))	('patients', 'Species', '9606', (346, 354))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (87, 109))	('NF2', 'Gene', (170, 173))	('BAP1', 'Gene', '8314', (60, 64))	('NF2', 'Gene', '4771', (69, 72))	('BAP1', 'Gene', (316, 320))	('mutations', 'Var', (174, 183))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (34, 43))	('deletions', 'Var', (187, 196))
79276	33473097	However, the function of NECTIN2 mutation in MPM are unclear.	('NECTIN2', 'Gene', '5819', (25, 32))	('mutation', 'Var', (33, 41))	('NECTIN2', 'Gene', (25, 32))	('MPM', 'Disease', (45, 48))
79278	33473097	The causes could be the following: (1) Tumor heterogeneity led to the different mutant genes between the two groups, (2) The tumor tissues sequenced in the patient were paraffin section, while the models were fresh frozen tissues, which may led to the different results, and (3) The genes of the models may have changed due to the environment factors during the passaging process.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutant', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('paraffin', 'Chemical', 'MESH:D010232', (169, 177))	('Tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patient', 'Species', '9606', (156, 163))
79283	33473097	Compared with the existing MPM models, our established models have the following characteristics: (1) Using MPM surgical specimens to directly grafted nude mice to establish the MPM PDX models, this method not only saved time and cost, but also simulated maximally the tumor biological behavior of the clinical patients; (2) The established PDX models exhibited the pathological features highly consistent with the clinicopathological characteristics of MPM in terms of gross pathology and histopathology; and (3) The PDX models own the key mutant genes for the development of MPM, which may become a research tool for exploring the mechanism and new therapeutic targets for MPM.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('mutant genes', 'Var', (541, 553))	('tumor', 'Disease', (269, 274))	('patients', 'Species', '9606', (311, 319))	('nude mice', 'Species', '10090', (151, 160))
79365	31179006	For example, when there was a delay in processing and communicating diagnostic test results, participant's anxiety understandably increased.	('anxiety', 'Disease', 'MESH:D001008', (107, 114))	('anxiety', 'Disease', (107, 114))	('participant', 'Species', '9606', (93, 104))	('anxiety', 'Phenotype', 'HP:0000739', (107, 114))	('increased', 'PosReg', (130, 139))	('delay', 'Var', (30, 35))
79546	31037036	High cervical cordotomy involves the creation of a permanent lesion in the ascending pain pathways of the spinothalamic tract (often with heat created by radiofrequency) in the antero-lateral spinal cord.	('High cervical cordotomy', 'Disease', (0, 23))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('pain', 'Disease', 'MESH:D010146', (85, 89))	('pain', 'Disease', (85, 89))	('lesion', 'Var', (61, 67))
79573	31037036	Flores et al determined that patients who underwent P/D in fact had a decrease postoperative morbidity and mortality when compared to EPP.	('postoperative morbidity', 'CPA', (79, 102))	('patients', 'Species', '9606', (29, 37))	('P/D', 'Var', (52, 55))	('decrease', 'NegReg', (70, 78))	('mortality', 'CPA', (107, 116))
79579	31037036	Results assessing patients quality of life demonstrated worse function at 1 month improving at 3, 6, and 12 months with VATS compared to tacl pleurodesis; but no significant difference between the groups was identified.	('function', 'MPA', (62, 70))	('VATS', 'Var', (120, 124))	('patients', 'Species', '9606', (18, 26))	('pleurodesis', 'Disease', 'None', (142, 153))	('pleurodesis', 'Disease', (142, 153))
79651	30479777	Family history of ovarian cancer or breast cancer, mutation and abnormality of BRCA1 or BRCA2 gene, increasing number of ovulation, hormone replacement therapy, and old age increase the risk of ovarian cancer, whereas pregnancy, breast-feeding, use of an oral contraceptive reduce the risk.	('abnormality', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('BRCA2', 'Gene', (88, 93))	('mutation', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('old age increase', 'Phenotype', 'HP:0007495', (165, 181))	('ovarian cancer', 'Disease', (194, 208))	('ovulation', 'biological_process', 'GO:0030728', ('121', '130'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('BRCA2', 'Gene', '675', (88, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (18, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('BRCA1', 'Gene', '672', (79, 84))	('BRCA1', 'Gene', (79, 84))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('breast cancer', 'Disease', (36, 49))	('ovarian cancer', 'Disease', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (18, 32))	('ovarian cancer', 'Disease', 'MESH:D010051', (194, 208))
79749	28680533	Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted.	('cyclin', 'molecular_function', 'GO:0016538', ('91', '97'))	('aberrations', 'Var', (110, 121))	('cyclin D1/3', 'Gene', (91, 102))	('p16', 'Gene', (106, 109))	('CDK4/6', 'Gene', '1019;1021', (41, 47))	('CDK', 'molecular_function', 'GO:0004693', ('83', '86'))	('CDK4/6', 'Gene', '1019;1021', (83, 89))	('CDK', 'molecular_function', 'GO:0004693', ('41', '44'))	('cyclin D1/3', 'Gene', '595', (91, 102))	('CDK4/6', 'Gene', (41, 47))	('p16', 'Gene', '1029', (106, 109))	('CDK4/6', 'Gene', (83, 89))
79754	28680533	In accordance with previous reports, two recent studies found that 52.2% and 45% of pleural MMs showed deletions in the 9p21 area containing CDKN2A and CDKN2B genes.	('CDKN2A', 'Gene', '1029', (141, 147))	('CDKN2B', 'Gene', (152, 158))	('CDKN2B', 'Gene', '1030', (152, 158))	('deletions', 'Var', (103, 112))	('pleural', 'Disease', 'MESH:D010995', (84, 91))	('CDKN2A', 'Gene', (141, 147))	('MMs', 'Chemical', 'MESH:D008741', (92, 95))	('pleural', 'Disease', (84, 91))
79760	28680533	When CDKN2A is mutated or hypermetylated, inhibition of CDK4/6 by p16 is lost and pro-mitotic signals prevail.	('CDK', 'molecular_function', 'GO:0004693', ('56', '59'))	('inhibition', 'MPA', (42, 52))	('CDKN2A', 'Gene', (5, 11))	('p16', 'Gene', (66, 69))	('CDK4/6', 'Gene', '1019;1021', (56, 62))	('lost', 'NegReg', (73, 77))	('CDKN2A', 'Gene', '1029', (5, 11))	('mutated', 'Var', (15, 22))	('hypermetylated', 'Var', (26, 40))	('pro-mitotic signals', 'CPA', (82, 101))	('CDK4/6', 'Gene', (56, 62))	('p16', 'Gene', '1029', (66, 69))
79761	28680533	In the same fashion, when RB1 is mutated, cyclin E1 and CDK2 are constitutively activated, with the initiation of transcription of pro-mitotic genes.	('CDK2', 'Gene', '1017', (56, 60))	('cyclin E1', 'Gene', (42, 51))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('CDK', 'molecular_function', 'GO:0004693', ('56', '59'))	('cyclin E1', 'Gene', '898', (42, 51))	('mutated', 'Var', (33, 40))	('RB1', 'Gene', (26, 29))	('CDK2', 'Gene', (56, 60))	('cyclin', 'molecular_function', 'GO:0016538', ('42', '48'))	('RB1', 'Gene', '5925', (26, 29))	('activated', 'PosReg', (80, 89))
79768	28680533	The p16 peptide (TAT-p16) expression over three MM cell lines (H2452, H2052 and H2461) induced RB1 phosphorylation and consequent cell cycle arrest at G1, followed by cell death.	('cell death', 'biological_process', 'GO:0008219', ('167', '177'))	('p16', 'Gene', (4, 7))	('H2052', 'CellLine', 'CVCL:1518', (70, 75))	('H2452', 'CellLine', 'CVCL:1553', (63, 68))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('RB1', 'Gene', '5925', (95, 98))	('p16', 'Gene', '1029', (4, 7))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('130', '147'))	('cell cycle arrest at G1', 'CPA', (130, 153))	('cell death', 'CPA', (167, 177))	('induced', 'Reg', (87, 94))	('H2461', 'Var', (80, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))	('H2052', 'Var', (70, 75))	('phosphorylation', 'MPA', (99, 114))	('H2461', 'CellLine', 'CVCL:A536', (80, 85))	('RB1', 'Gene', (95, 98))	('p16', 'Gene', (21, 24))	('p16', 'Gene', '1029', (21, 24))
79771	28680533	Another proof-of-concept supporting the anti-tumour activity of p16-mimicking molecules comes from a patent filed for novel CDK4/6 inhibitors for the treatment of malignant mesothelioma, where the authors showed that the new inhibitors are able to stop proliferation of three MM cell lines (namely MSTO-211, NCI-H2052, NCI-H28) in vitro with cytostatic activity in the micromolar range.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (163, 185))	('CDK4/6', 'Gene', (124, 130))	('p16', 'Gene', (64, 67))	('inhibitors', 'Var', (225, 235))	('NCI-H2052', 'CellLine', 'CVCL:1518', (308, 317))	('CDK', 'molecular_function', 'GO:0004693', ('124', '127'))	('malignant mesothelioma', 'Disease', (163, 185))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('CDK4/6', 'Gene', '1019;1021', (124, 130))	('p16', 'Gene', '1029', (64, 67))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (163, 185))	('tumour', 'Disease', (45, 51))	('stop', 'NegReg', (248, 252))
79773	28680533	Our report would support the need for randomized phase III clinical studies specifically designed to test the anti-tumour activity of CDK4/6 inhibitors as single agents or in combination in MM on the basis of the molecular characteristics of this tumour.	('CDK4/6', 'Gene', '1019;1021', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('CDK4/6', 'Gene', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour', 'Disease', (247, 253))	('inhibitors', 'Var', (141, 151))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('tumour', 'Disease', (115, 121))
79795	28105159	Previously, gemcitabine in combination with nab-paclitaxel demonstrated efficient clinical activity in a phase III trial, with statistically significant improvement in median overall survival compared with gemcitabine alone.	('nab', 'Chemical', '-', (44, 47))	('improvement', 'PosReg', (153, 164))	('gemcitabine', 'Chemical', 'MESH:C056507', (206, 217))	('nab-paclitaxel', 'Var', (44, 58))	('gemcitabine', 'Chemical', 'MESH:C056507', (12, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
79836	28105159	Based on this immunohistochemical profile (negativity for CK20 and positivity for CK7 and CDX2), pathologists excluded an intestinal origin.	('CK20', 'Gene', (58, 62))	('CK20', 'Gene', '54474', (58, 62))	('CDX2', 'Gene', '1045', (90, 94))	('CK7', 'Gene', (82, 85))	('positivity', 'Var', (67, 77))	('CK7', 'Gene', '3855', (82, 85))	('CDX2', 'Gene', (90, 94))
79854	28105159	Therefore, to determine the origin of the bowel metastases, the pathologist performed a revision of the small intestine sample, and further immunohistochemical analysis demonstrated negativity for CK5, CK6, EpCAM and calretinin.	('calretinin', 'Gene', (217, 227))	('CK6', 'Protein', (202, 205))	('calretinin', 'Gene', '794', (217, 227))	('EpCAM', 'Gene', (207, 212))	('negativity', 'Var', (182, 192))	('CK5', 'Gene', '3852', (197, 200))	('bowel metastases', 'Disease', 'MESH:D009362', (42, 58))	('EpCAM', 'Gene', '4072', (207, 212))	('bowel metastases', 'Disease', (42, 58))	('CK5', 'Gene', (197, 200))
79859	28105159	Immunohistochemical analysis reported positivity for CK7 and vimentin, and negativity for cluster of differentiation (CD)34, CD117 and calretinin.	('CD', 'Disease', 'MESH:D006223', (118, 120))	('positivity', 'Var', (38, 48))	('vimentin', 'cellular_component', 'GO:0045099', ('61', '69'))	('calretinin', 'Gene', (135, 145))	('CD117', 'Gene', '3815', (125, 130))	('CK7', 'Gene', (53, 56))	('CD117', 'Gene', (125, 130))	('vimentin', 'Gene', '7431', (61, 69))	('CK7', 'Gene', '3855', (53, 56))	('CD', 'Disease', 'MESH:D006223', (125, 127))	('vimentin', 'cellular_component', 'GO:0045098', ('61', '69'))	('calretinin', 'Gene', '794', (135, 145))	('vimentin', 'Gene', (61, 69))
79861	28105159	Immunohistochemical examination on the intestinal sample reported vimentin and cytokeratin positivity and calretinin, CK20 and thyroid transcription factor-1 negativity.	('calretinin', 'Gene', (106, 116))	('transcription factor', 'molecular_function', 'GO:0000981', ('135', '155'))	('thyroid transcription factor-1', 'Gene', '7080', (127, 157))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('vimentin', 'Gene', '7431', (66, 74))	('vimentin', 'cellular_component', 'GO:0045099', ('66', '74'))	('vimentin', 'Gene', (66, 74))	('CK20', 'Gene', (118, 122))	('calretinin', 'Gene', '794', (106, 116))	('thyroid transcription factor-1', 'Gene', (127, 157))	('vimentin', 'cellular_component', 'GO:0045098', ('66', '74'))	('CK20', 'Gene', '54474', (118, 122))	('negativity', 'NegReg', (158, 168))	('positivity', 'Var', (91, 101))	('cytokeratin', 'Protein', (79, 90))
80278	29112861	Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf) Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure.	('Asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('Disruption', 'Var', (73, 83))	('Ink4a/Arf', 'Gene', '12578', (121, 130))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('Mesothelioma', 'Disease', (55, 67))	('Mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('tumor of the pleura', 'Disease', (156, 175))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('91', '107'))	('tumor of the pleura', 'Phenotype', 'HP:0100527', (156, 175))	('Mesothelioma', 'Disease', 'MESH:D008654', (132, 144))	('Mesothelioma', 'Disease', (132, 144))	('Cdkn2a', 'Gene', '12578', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('asbestos', 'Chemical', 'MESH:D001194', (208, 216))	('tumor of the pleura', 'Disease', 'MESH:D054363', (156, 175))	('Tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Carbon', 'Chemical', 'MESH:D002244', (11, 17))	('Ink4a/Arf', 'Gene', (121, 130))	('Cdkn2a', 'Gene', (113, 119))
80281	29112861	Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('mesothelioma', 'Disease', 'MESH:D008654', (192, 204))	('pleural lesions', 'Disease', 'MESH:D010995', (166, 181))	('tumor', 'Disease', (141, 146))	('pleural lesions', 'Disease', (166, 181))	('CDKN2A', 'Gene', (27, 33))	('pleural lesions', 'Phenotype', 'HP:0002102', (166, 181))	('INK4A/ARF', 'Gene', (35, 44))	('disruption', 'Var', (9, 19))	('mesothelioma', 'Disease', (192, 204))	('INK4A/ARF', 'Gene', '12578', (35, 44))
80285	29112861	We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer.	('loss', 'NegReg', (180, 184))	('mesothelioma', 'Disease', (114, 126))	('protein', 'Protein', (200, 207))	('gatekeeper', 'Species', '111938', (258, 268))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))	('Arf', 'Gene', '12578', (171, 174))	('Arf', 'Gene', '12578', (51, 54))	('p19', 'cellular_component', 'GO:0070743', ('196', '199'))	('cancer', 'Disease', (277, 283))	('p19', 'cellular_component', 'GO:0070743', ('47', '50'))	('Arf', 'Gene', (171, 174))	('asbestos', 'Chemical', 'MESH:D001194', (67, 75))	('Arf', 'Gene', (51, 54))	('Cdkn2a', 'Gene', (157, 163))	('hypermethylation', 'Var', (13, 29))	('p19 protein', 'Protein', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('silencing', 'NegReg', (144, 153))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('cancer', 'Disease', 'MESH:D009369', (277, 283))
80286	29112861	In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease.	('Arf', 'Gene', '12578', (83, 86))	('mesothelioma', 'Disease', (13, 25))	('p16/Ink4a', 'Gene', (40, 49))	('silencing', 'Var', (27, 36))	('p19', 'cellular_component', 'GO:0070743', ('79', '82'))	('deletion', 'Var', (67, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('human', 'Species', '9606', (115, 120))	('Arf', 'Gene', (83, 86))
80293	29112861	Genetic analyses identified several key genetic alterations in end-stage disease, with most common deletions or mutations in CDKN2A, NF2, and BAP1 genes, and suggested that two main pathways, p53/DNA repair and PI3K-AKT, were associated with mesothelioma progression.	('BAP1', 'Gene', '104416', (142, 146))	('DNA repair', 'biological_process', 'GO:0006281', ('196', '206'))	('AKT', 'Gene', (216, 219))	('NF2', 'Gene', '18016', (133, 136))	('p53', 'Gene', '22060', (192, 195))	('deletions', 'Var', (99, 108))	('associated', 'Reg', (226, 236))	('mutations', 'Var', (112, 121))	('mesothelioma', 'Disease', (242, 254))	('BAP1', 'Gene', (142, 146))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('AKT', 'Gene', '11651', (216, 219))	('CDKN2A', 'Gene', (125, 131))	('p53', 'Gene', (192, 195))	('NF2', 'Gene', (133, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (242, 254))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))
80294	29112861	Epigenetic alterations play a gatekeeper role in cancer as they are the earliest observable genetic change.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gatekeeper', 'Species', '111938', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
80297	29112861	Although disruption of the CDKN2A locus, including p16/INK4A silencing, has been reported in end-stage disease, the key molecular events that occur during the long latency period of mesothelioma are unknown.	('mesothelioma', 'Disease', (182, 194))	('INK4A', 'Gene', (55, 60))	('silencing', 'NegReg', (61, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('end-stage disease', 'Disease', (93, 110))	('CDKN2A', 'Gene', (27, 33))	('INK4A', 'Gene', '12578', (55, 60))	('disruption', 'Var', (9, 19))
80299	29112861	In vivo studies have indicated that CNTs can cause sustained inflammation and fibrosis of the pleura and can also induce tumor development; however, this has only been shown in genetically susceptible or peritoneally exposed rodent models.	('fibrosis of the pleura', 'Disease', (78, 100))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CNTs', 'Var', (36, 40))	('tumor', 'Disease', (121, 126))	('fibrosis of the pleura', 'Disease', 'MESH:D005355', (78, 100))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('induce', 'Reg', (114, 120))	('cause', 'Reg', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
80302	29112861	We show that long CNTs and long asbestos induce mesothelioma with deletion of p19/Arf and silencing of p16/Ink4a, highlighting that epigenetic alterations play a gatekeeper role in mesothelioma.	('mesothelioma', 'Disease', (181, 193))	('p19', 'cellular_component', 'GO:0070743', ('78', '81'))	('silencing', 'Var', (90, 99))	('Arf', 'Gene', (82, 85))	('mesothelioma', 'Disease', (48, 60))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('induce', 'PosReg', (41, 47))	('mesothelioma', 'Disease', 'MESH:D008654', (181, 193))	('Arf', 'Gene', '12578', (82, 85))	('p16/Ink4a', 'Gene', (103, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('deletion', 'Var', (66, 74))	('gatekeeper', 'Species', '111938', (162, 172))
80314	29112861	Immunostaining of mesothelioma patient tissue demonstrated positive staining for the mesothelial marker HBME-1 and phosphorylated mTOR, 4EBP1, and Src in mesothelioma cells, as well as phospho-ERK1/2 in mesothelioma cells and fibroblasts, while phospho-STAT3 was predominant in lymphocytes and fibroblasts (Figure 1G).	('HBME-1', 'Gene', (104, 110))	('mesothelioma', 'Disease', (154, 166))	('HBME-1', 'CellLine', 'CVCL:U718', (104, 110))	('mesothelioma', 'Disease', (203, 215))	('mesothelioma', 'Disease', (18, 30))	('patient', 'Species', '9606', (31, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (203, 215))	('4EBP1', 'Gene', '1978', (136, 141))	('ERK1', 'molecular_function', 'GO:0004707', ('193', '197'))	('4EBP1', 'Gene', (136, 141))	('phospho-ERK1/2', 'Var', (185, 199))
80328	29112861	In 10%-25% of animals across three independent studies, LNT-induced lesions progressed to pleural mesothelioma (1/4 wild-type animals exposed to 2.5 mug LNTs for 1 year; 1/4 animals exposed to 1 mug LNTs for 18 months, 1/5 animals exposed to 0.5 mug LNTs, and 1/12 animals exposed to 0.2 mug LNTs for 20 months) (Figures 4A, S5, and S7).	('LNT', 'Chemical', '-', (199, 202))	('mug', 'molecular_function', 'GO:0043739', ('246', '249'))	('lesions', 'Var', (68, 75))	('LNTs', 'Chemical', '-', (153, 157))	('LNT', 'Chemical', '-', (56, 59))	('LNT-induced', 'Gene', (56, 67))	('LNTs', 'Chemical', '-', (250, 254))	('LNT', 'Chemical', '-', (250, 253))	('LNT', 'Chemical', '-', (292, 295))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (90, 110))	('LNT', 'Chemical', '-', (153, 156))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (90, 110))	('mug', 'molecular_function', 'GO:0043739', ('195', '198'))	('mug', 'molecular_function', 'GO:0043739', ('149', '152'))	('LNTs', 'Chemical', '-', (199, 203))	('LNTs', 'Chemical', '-', (292, 296))	('pleural mesothelioma', 'Disease', (90, 110))	('mug', 'molecular_function', 'GO:0043739', ('288', '291'))
80329	29112861	Out of 32 animals exposed to asbestos (25 mug or 50 mug) for 18-20 months, three mice developed mesothelioma (Figure S6).	('mug', 'molecular_function', 'GO:0043739', ('52', '55'))	('mice', 'Species', '10090', (81, 85))	('25 mug', 'Var', (39, 45))	('mesothelioma', 'Disease', (96, 108))	('asbestos', 'Chemical', 'MESH:D001194', (29, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('mug', 'molecular_function', 'GO:0043739', ('42', '45'))
80335	29112861	In LNT-induced tumors, relative quantification of gene copy number confirmed loss of the p19Arf locus in the p19-negative areas, as evidenced by ~60% reduction in p19Arf genomic DNA (gDNA) compared to controls (Figure 4D).	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('LNT', 'Chemical', '-', (3, 6))	('p19', 'cellular_component', 'GO:0070743', ('89', '92'))	('p19', 'cellular_component', 'GO:0070743', ('163', '166'))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('p19', 'cellular_component', 'GO:0070743', ('109', '112'))	('reduction', 'NegReg', (150, 159))	('loss', 'NegReg', (77, 81))	('p19Arf', 'Gene', (89, 95))	('p19Arf', 'Var', (163, 169))	('tumors', 'Disease', (15, 21))
80337	29112861	Similarly, LNT tumor (#461) induced by a lower fiber dose (1 mug versus 2.5 mug) displayed loss of p16 and p19 protein expression, a reduction in Cdkn2a mRNA, and allelic loss of p19Arf (Figure S7).	('Cdkn2a', 'Enzyme', (146, 152))	('mug', 'molecular_function', 'GO:0043739', ('61', '64'))	('mRNA', 'MPA', (153, 157))	('p19 protein', 'Protein', (107, 118))	('p19', 'cellular_component', 'GO:0070743', ('107', '110'))	('p19', 'cellular_component', 'GO:0070743', ('179', '182'))	('LNT tumor', 'Disease', 'MESH:D009369', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('reduction', 'NegReg', (133, 142))	('mug', 'molecular_function', 'GO:0043739', ('76', '79'))	('p19Arf', 'Var', (179, 185))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('loss', 'NegReg', (91, 95))	('loss', 'NegReg', (171, 175))	('p16', 'Protein', (99, 102))	('LNT tumor', 'Disease', (11, 20))
80341	29112861	LNT-induced chronic inflammatory lesions from animals that did not develop tumors at the 1 year study end point (Figure 5A) displayed no reduction in p16Ink4a or p19Arf gene copy number (Figure 5D); however, mRNA levels were reduced (data not shown), and both p16 and p19 protein expression was absent in the majority of mesothelial cells in LNT-induced lesions (Figures 5B and 5C).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('p19', 'cellular_component', 'GO:0070743', ('268', '271'))	('p16Ink4a', 'Gene', '12578', (150, 158))	('reduced', 'NegReg', (225, 232))	('reduction', 'NegReg', (137, 146))	('mRNA levels', 'MPA', (208, 219))	('LNT', 'Chemical', '-', (342, 345))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p16Ink4a', 'Gene', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('protein', 'cellular_component', 'GO:0003675', ('272', '279'))	('p19', 'cellular_component', 'GO:0070743', ('162', '165'))	('tumors', 'Disease', (75, 81))	('LNT', 'Chemical', '-', (0, 3))	('p19Arf', 'Var', (162, 168))
80342	29112861	Consistent with loss of the CDKN2A-encoded proteins p16/p14 in human mesothelioma, loss of p16 and p19 protein expression was also evident in advanced LFA-induced lesions from animals that did not develop mesothelioma at the 1 year study end point (Figures 5B and 5C).	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('p19', 'cellular_component', 'GO:0070743', ('99', '102'))	('human', 'Species', '9606', (63, 68))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('p19', 'Var', (99, 102))	('mesothelioma', 'Disease', (69, 81))	('p14', 'Gene', (56, 59))	('mesothelioma', 'Disease', (205, 217))	('p16', 'Var', (91, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('p14', 'Gene', '1029', (56, 59))	('LFA', 'Chemical', '-', (151, 154))	('loss', 'NegReg', (83, 87))	('LFA-induced', 'Disease', (151, 162))
80347	29112861	To explore possible epigenetic mechanisms of fiber-induced carcinogenesis, we examined gDNA from animals with advanced LNT-induced inflammatory lesions and inflammatory lesions and/or tumors from animals with LNT-induced mesothelioma (#610 and #461), as well as inflammatory lesions and/or tumors from animals with LFA-induced mesothelioma (#398), for p16Ink4a or p19Arf methylation status.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('p16Ink4a', 'Gene', (352, 360))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('p16Ink4a', 'Gene', '12578', (352, 360))	('p19Arf', 'Var', (364, 370))	('mesothelioma', 'Disease', (327, 339))	('methylation', 'biological_process', 'GO:0032259', ('371', '382'))	('LNT', 'Chemical', '-', (209, 212))	('carcinogenesis', 'Disease', (59, 73))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('mesothelioma', 'Disease', 'MESH:D008654', (327, 339))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('mesothelioma', 'Disease', (221, 233))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))	('tumors', 'Disease', (290, 296))	('p19', 'cellular_component', 'GO:0070743', ('364', '367'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('LFA', 'Chemical', '-', (315, 318))	('LNT', 'Chemical', '-', (119, 122))
80348	29112861	Bisulphite sequencing confirmed hypermethylation of CpG islands in p16Ink4a and p19Arf (located in exon 1alpha and the 5' region flanking exon 1beta, respectively) in mesothelial cells in advanced LNT- and LFA-induced lesions, as well as in LFA- and LNT-induced tumors, compared with VC (Figures 6 and S7E).	('p16Ink4a', 'Gene', '12578', (67, 75))	('LFA', 'Chemical', '-', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('LFA-', 'Disease', (241, 245))	('p16Ink4a', 'Gene', (67, 75))	('S7E', 'Mutation', 'p.S7E', (302, 305))	('tumors', 'Disease', (262, 268))	('LNT', 'Chemical', '-', (197, 200))	('LNT', 'Chemical', '-', (250, 253))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('hypermethylation', 'Var', (32, 48))	('p19', 'cellular_component', 'GO:0070743', ('80', '83'))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('Bisulphite', 'Chemical', 'MESH:C042345', (0, 10))	('p19Arf', 'Var', (80, 86))	('LFA', 'Chemical', '-', (241, 244))
80353	29112861	The presence of oxidative DNA damage could also contribute to pro-oncogenic events within the microenvironment, favoring aberrant DNA methylation in target cells, with hypermethylation of Cdkn2a (Ink4a/Arf) in LNT- and LFA-induced lesions prior to tumor development leading to allelic loss of p19Arf, as has been suggested in other cancers.	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('DNA methylation', 'biological_process', 'GO:0006306', ('130', '145'))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('favoring', 'PosReg', (112, 120))	('LFA', 'Chemical', '-', (219, 222))	('tumor', 'Disease', (248, 253))	('hypermethylation', 'Var', (168, 184))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('p19Arf', 'Gene', (293, 299))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Cdkn2a', 'Gene', (188, 194))	('LNT', 'Chemical', '-', (210, 213))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('cancers', 'Disease', (332, 339))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('loss', 'NegReg', (285, 289))	('p19', 'cellular_component', 'GO:0070743', ('293', '296'))	('DNA methylation', 'MPA', (130, 145))
80355	29112861	Alteration of the CDKN2A locus in human malignant mesothelioma has been reported with inactivation of p16 in more than a half of mesothelioma patients and, in more recent studies, with hypermethylation and silencing of p19 in 44% of patients.	('human', 'Species', '9606', (34, 39))	('silencing', 'NegReg', (206, 215))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (40, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('p16', 'Gene', (102, 105))	('Alteration', 'Var', (0, 10))	('p19', 'cellular_component', 'GO:0070743', ('219', '222'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (40, 62))	('inactivation', 'NegReg', (86, 98))	('mesothelioma', 'Disease', (50, 62))	('mesothelioma', 'Disease', (129, 141))	('CDKN2A', 'Gene', (18, 24))	('patients', 'Species', '9606', (142, 150))	('malignant mesothelioma', 'Disease', (40, 62))	('patients', 'Species', '9606', (233, 241))	('hypermethylation', 'Var', (185, 201))
80356	29112861	Significantly, we discovered that epigenetic silencing of Cdkn2a (Ink4a/Arf) and deletion of p19Arf observed in LNT-induced tumors recapitulates common features of human asbestos-induced mesothelioma (Figure 7).	('asbestos-induced mesothelioma', 'Disease', (170, 199))	('epigenetic silencing', 'Var', (34, 54))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('p19Arf', 'Gene', (93, 99))	('human', 'Species', '9606', (164, 169))	('p19', 'cellular_component', 'GO:0070743', ('93', '96'))	('deletion', 'Var', (81, 89))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('LNT', 'Chemical', '-', (112, 115))	('Cdkn2a', 'Gene', (58, 64))	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (170, 199))
80357	29112861	Overall, these findings provide important new insights into the early molecular changes that occur during the long latency period between fiber exposure and mesothelioma development and identifies epigenetic and/or genetic disruption of Cdkn2a as a key event in long-fiber-induced malignant transformation (Figure 7).	('mesothelioma', 'Disease', (157, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (157, 169))	('epigenetic', 'Var', (197, 207))	('genetic disruption', 'Var', (215, 233))	('Cdkn2a', 'Gene', (237, 243))
80362	29112861	Overall, the common signature of LFA- and LNT-induced pathology demonstrates that there is a conserved molecular mechanism through which long fibers induce pleural disease, including mesothelioma, and crucially our data place long CNT fibers on the same adverse outcome pathway as asbestos.	('LNT', 'Chemical', '-', (42, 45))	('long fibers', 'Var', (137, 148))	('pleural disease', 'Disease', (156, 171))	('induce pleural disease', 'Phenotype', 'HP:0002102', (149, 171))	('mesothelioma', 'Disease', (183, 195))	('induce', 'Reg', (149, 155))	('LFA', 'Chemical', '-', (33, 36))	('pleural disease', 'Disease', 'MESH:D010995', (156, 171))	('pleural disease', 'Phenotype', 'HP:0002103', (156, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('asbestos', 'Chemical', 'MESH:D001194', (281, 289))
80412	29112861	Genomic DNA (gDNA) was extracted using PureLink Genomic DNA Mini Kit (Fisher Scientific, Loughborough, UK) accordingly to the manufacturer's instruction, from tumor areas positively and negatively stained for p16 and p19, and control tissues including unaffected tissue (heart) from fiber-exposed mice, diaphragm tissue from VC group, and liver tissue from a C57/Bl6 mouse.	('mouse', 'Species', '10090', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('negatively', 'NegReg', (186, 196))	('p19', 'cellular_component', 'GO:0070743', ('217', '220'))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', (159, 164))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('mice', 'Species', '10090', (297, 301))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('p16', 'Var', (209, 212))
80414	29112861	The first gene in each pair was from a region of a frequent loss or deletion (p16 or p19), whereas the second gene was the "housekeeping" gene, Supervillin, from a different chromosome.	('p19', 'cellular_component', 'GO:0070743', ('85', '88'))	('loss', 'NegReg', (60, 64))	('Supervillin', 'Gene', '225115', (144, 155))	('p19', 'Var', (85, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('Supervillin', 'Gene', (144, 155))	('p16', 'Var', (78, 81))
80637	27066377	In conclusion, the current study identify the best stratified level of baseline serum CA125 associated with OS was 280 U/ml.	('OS', 'Chemical', '-', (108, 110))	('CA125', 'Gene', '94025', (86, 91))	('CA125', 'Gene', (86, 91))	('280 U/ml', 'Var', (115, 123))
80730	25203873	Generally, P/D is preferred for tumors apparently confined to the pleura, as it affords an MCR while sparing the lung.	('P/D', 'Var', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
80750	23555949	Approximately 70-80% of mesothelioma cells have the wild-type p53 gene but show a homologous deletion at the INK4A/ARF locus containing the p14ARF and the p16INK4A genes, which consequently leads to decreased p53 functions despite the wild-type genotype.	('INK4A/ARF', 'Gene', '1029', (109, 118))	('p14ARF', 'Gene', (140, 146))	('mesothelioma', 'Disease', (24, 36))	('decreased', 'NegReg', (199, 208))	('p53', 'Gene', (62, 65))	('p16INK4A', 'Gene', (155, 163))	('INK4A/ARF', 'Gene', (109, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (24, 36))	('p14ARF', 'Gene', '1029', (140, 146))	('p53', 'Gene', (209, 212))	('deletion', 'Var', (93, 101))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', '7157', (209, 212))	('p16INK4A', 'Gene', '1029', (155, 163))
80757	23555949	BPs inhibit bone absorption through interfering osteoclasts' actions, and are currently used as a therapeutic agent for osteoporosis, malignancy-linked hypercalcemia and similar bone diseases.	('osteoporosis', 'Disease', 'MESH:D010024', (120, 132))	('osteoporosis', 'Disease', (120, 132))	('hypercalcemia', 'Phenotype', 'HP:0003072', (152, 165))	('BPs', 'Var', (0, 3))	('malignancy-linked hypercalcemia', 'Disease', (134, 165))	('osteoporosis', 'Phenotype', 'HP:0000939', (120, 132))	('BPs', 'Chemical', 'MESH:D004164', (0, 3))	('bone diseases', 'Disease', (178, 191))	('malignancy-linked hypercalcemia', 'Disease', 'MESH:D006934', (134, 165))	('bone absorption', 'CPA', (12, 27))	('interfering', 'NegReg', (36, 47))	('inhibit', 'NegReg', (4, 11))	('bone diseases', 'Disease', 'MESH:D001847', (178, 191))	('actions', 'MPA', (61, 68))
80758	23555949	Recent reports demonstrated that BPs also achieved cytotoxicity on tumor cells through apoptosis induction and produced anti-tumor effects in vitro .	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('BPs', 'Chemical', 'MESH:D004164', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (125, 130))	('apoptosis', 'CPA', (87, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('cytotoxicity', 'Disease', (51, 63))	('tumor', 'Disease', (67, 72))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('BPs', 'Var', (33, 36))
80793	23555949	Cell cycle analyses indicated that sub-G1 phase populations in ZOL- plus CDDP-treated MSTO-211H cells were greater than those in ZOL- or CDDP- treated cells (Fig.	('ZOL', 'Chemical', 'MESH:D000077211', (129, 132))	('CDDP', 'Chemical', 'MESH:D002945', (73, 77))	('CDDP-treated', 'Var', (73, 85))	('greater', 'PosReg', (107, 114))	('G1 phase', 'biological_process', 'GO:0051318', ('39', '47'))	('ZOL', 'Chemical', 'MESH:D000077211', (63, 66))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('CDDP', 'Chemical', 'MESH:D002945', (137, 141))	('MSTO-211H', 'CellLine', 'CVCL:1430', (86, 95))	('sub-G1 phase populations', 'CPA', (35, 59))
80816	23555949	In contract, the p53-siRNA treatment increased S and G2/M phase and decreased G0/G1 phase fractions, showing that down-regulated p53 promoted cell cycle progression.	('decreased', 'NegReg', (68, 77))	('cell cycle progression', 'CPA', (142, 164))	('promoted', 'PosReg', (133, 141))	('G1 phase', 'biological_process', 'GO:0051318', ('81', '89'))	('p53', 'Gene', (17, 20))	('M phase', 'biological_process', 'GO:0000279', ('56', '63'))	('G0/G1 phase fractions', 'CPA', (78, 99))	('cell cycle', 'biological_process', 'GO:0007049', ('142', '152'))	('p53', 'Gene', (129, 132))	('increased', 'PosReg', (37, 46))	('p53', 'Gene', '7157', (129, 132))	('down-regulated', 'Var', (114, 128))	('p53', 'Gene', '7157', (17, 20))
80826	23555949	5B), demonstrating that induction of p53 produced cytotoxic effects in MSTO-211H cells.	('induction', 'Var', (24, 33))	('MSTO-211H', 'CellLine', 'CVCL:1430', (71, 80))	('cytotoxic effects', 'CPA', (50, 67))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))
80833	23555949	Augmentation of p53 is therefore a possible therapeutic strategy for mesothelioma by restoring p53 functions.	('Augmentation', 'Var', (0, 12))	('p53', 'Gene', (16, 19))	('mesothelioma', 'Disease', (69, 81))	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('restoring', 'PosReg', (85, 94))	('functions', 'MPA', (99, 108))
80855	23555949	For example, CDDP-treated cells can activate non-p53-mediated pathways and Ad-mediated transduction activates type I interferons-mediated pathways.	('activates', 'PosReg', (100, 109))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('transduction', 'biological_process', 'GO:0009293', ('87', '99'))	('activate', 'PosReg', (36, 44))	('Ad-mediated', 'Var', (75, 86))	('type I interferons-mediated pathways', 'Pathway', (110, 146))	('CDDP', 'Chemical', 'MESH:D002945', (13, 17))
80869	23555949	Inhibited protein prenylation can cause downstream activation of p53, and ZOL thereby is a candidate to analyze a possible cross-talk between small G proteins and the p53 pathways.	('ZOL', 'Chemical', 'MESH:D000077211', (74, 77))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('protein prenylation', 'biological_process', 'GO:0018342', ('10', '29'))	('p53', 'Gene', '7157', (167, 170))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('Inhibited', 'Var', (0, 9))	('p53', 'Gene', (167, 170))	('activation', 'PosReg', (51, 61))	('protein prenylation', 'Protein', (10, 29))
80870	23555949	Previous studies also showed that combinatory cytotoxicity of ZOL and an anti-cancer agent was linked with ZOL-mediated inhibition of P-glycoprotein functions and that a combinatory use of doxorubicin and ZOL inhibited angiogenesis.	('ZOL', 'Chemical', 'MESH:D000077211', (205, 208))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('P-glycoprotein functions', 'MPA', (134, 158))	('inhibited', 'NegReg', (209, 218))	('cancer', 'Disease', (78, 84))	('ZOL', 'Chemical', 'MESH:D000077211', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('P-glycoprotein', 'molecular_function', 'GO:0008559', ('134', '148'))	('angiogenesis', 'biological_process', 'GO:0001525', ('219', '231'))	('ZOL', 'Chemical', 'MESH:D000077211', (107, 110))	('inhibition', 'NegReg', (120, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('ZOL-mediated', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('angiogenesis', 'CPA', (219, 231))	('cytotoxicity', 'Disease', (46, 58))
80875	19118007	Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome Mechanisms of action of non-mutagenic carcinogens such as asbestos remain poorly characterized.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (32, 52))	('asbestos', 'Chemical', 'MESH:D001194', (89, 97))	('pleural mesothelioma', 'Disease', (32, 52))	('asbestos', 'Chemical', 'MESH:D001194', (184, 192))	('lung asbestos burden', 'Disease', 'MESH:D001195', (84, 104))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (32, 52))	('Epigenetic profiles', 'Var', (0, 19))	('distinguish', 'Reg', (20, 31))	('lung asbestos burden', 'Disease', (84, 104))
80880	19118007	Among tumors, methylation class membership was significantly associated with lung tissue asbestos body burden (P < 0.03), and significantly predicted survival (likelihood ratio P < 0.01).	('asbestos', 'Chemical', 'MESH:D001194', (89, 97))	('lung tissue asbestos body burden', 'MPA', (77, 109))	('predicted', 'Reg', (140, 149))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('asbestos body', 'Phenotype', 'HP:0011002', (89, 102))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('methylation', 'Var', (14, 25))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('survival', 'MPA', (150, 158))	('associated', 'Reg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
80883	19118007	We have added to the growing body of evidence that cellular epigenetic dysregulation is a critical mode of action for asbestos in the induction of pleural mesothelioma.	('cellular epigenetic dysregulation', 'Var', (51, 84))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (147, 167))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (147, 167))	('pleural mesothelioma', 'Disease', (147, 167))
80884	19118007	Importantly, these findings hold great promise for using epigenetic profiling in the diagnosis and prognosis of human cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('epigenetic', 'Var', (57, 67))	('human', 'Species', '9606', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
80891	19118007	Aberrant epigenetic events, including DNA hypermethylation-induced gene silencing, are well recognized as important contributors to carcinogenesis.	('carcinogenesis', 'Disease', (132, 146))	('gene silencing', 'biological_process', 'GO:0016458', ('67', '81'))	('gene', 'MPA', (67, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('38', '58'))	('DNA', 'Var', (38, 41))
80892	19118007	Methylation associated gene silencing occurs when certain cytosines in specific clustered regions primarily located in gene promoters are hypermethylated.	('cytosines', 'Chemical', 'MESH:D003596', (58, 67))	('Methylation', 'Var', (0, 11))	('gene silencing', 'biological_process', 'GO:0016458', ('23', '37'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('gene silencing', 'NegReg', (23, 37))	('hypermethylated', 'Var', (138, 153))
80894	19118007	Approximately half of all human genes contain CpG islands and are, therefore, potentially subject to this type of aberrant silencing.	('CpG islands', 'Var', (46, 57))	('human genes', 'Gene', (26, 37))	('human', 'Species', '9606', (26, 31))
80904	19118007	Additionally, methylation-induced tumor suppressor gene silencing has been observed in recent studies of mesothelioma leading to the hypothesis that asbestos fibers contribute to epigenetic silencing of tumor suppressor genes in this disease.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('epigenetic silencing', 'Var', (179, 199))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('203', '219'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('203', '219'))	('gene silencing', 'biological_process', 'GO:0016458', ('51', '65'))	('asbestos', 'Chemical', 'MESH:D001194', (149, 157))	('methylation-induced', 'Var', (14, 33))	('mesothelioma', 'Disease', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('silencing', 'NegReg', (56, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
80905	19118007	observed a significant association between self-reported asbestos exposure and methylation at the MT1A, and MT2A gene loci in mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (126, 139))	('MT1A', 'Gene', (98, 102))	('MT1', 'molecular_function', 'GO:0043834', ('98', '101'))	('mesotheliomas', 'Disease', (126, 139))	('MT2A', 'Gene', '4502', (108, 112))	('MT2A', 'Gene', (108, 112))	('methylation', 'Var', (79, 90))	('MT1', 'molecular_function', 'GO:0043791', ('98', '101'))	('MT1', 'molecular_function', 'GO:0047152', ('98', '101'))	('asbestos', 'Chemical', 'MESH:D001194', (57, 65))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('MT2', 'molecular_function', 'GO:0043851', ('108', '111'))	('MT1A', 'Gene', '4489', (98, 102))
80906	19118007	Concomitantly, work in our laboratory, using quantitative asbestos body counts as a measure of asbestos exposure burden, revealed an association between cell cycle control tumor suppressor gene methylation and increased asbestos burden in mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('172', '188'))	('methylation', 'Var', (194, 205))	('asbestos burden', 'MPA', (220, 235))	('asbestos', 'Chemical', 'MESH:D001194', (220, 228))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('increased', 'PosReg', (210, 219))	('tumor', 'Disease', (172, 177))	('mesothelioma', 'Disease', 'MESH:D008654', (239, 251))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('cell cycle control', 'biological_process', 'GO:1901987', ('153', '171'))	('asbestos', 'Chemical', 'MESH:D001194', (95, 103))	('asbestos body', 'Phenotype', 'HP:0011002', (58, 71))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('172', '188'))	('mesothelioma', 'Disease', (239, 251))
80907	19118007	To comprehensively investigate aberrant tumor-specific, phenotypically relevant methylation events in pleural mesothelioma, we profiled 158 tumors and 18 non-tumorigenic parietal pleura samples for methylation at 1505 CpG dinucleotides associated with 803 cancer-related genes using the Illumina GoldenGate  methylation bead array.	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (102, 122))	('methylation', 'Var', (198, 209))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (102, 122))	('parietal pleura', 'Disease', (170, 185))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('tumors', 'Disease', (140, 146))	('methylation', 'biological_process', 'GO:0032259', ('308', '319'))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Disease', (40, 45))	('non-tumor', 'Disease', (154, 163))	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('non-tumor', 'Disease', 'MESH:D009369', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('methylation', 'biological_process', 'GO:0032259', ('198', '209'))	('pleural mesothelioma', 'Disease', (102, 122))	('parietal pleura', 'Disease', 'MESH:D054363', (170, 185))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (140, 145))
80928	19118007	In this study GoldenGate  arrays were used to assess methylation in 158 incident cases of mesothelioma and 18 non-tumorigenic parietal pleura specimens.	('parietal pleura', 'Disease', 'MESH:D054363', (126, 141))	('parietal pleura', 'Disease', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('non-tumor', 'Disease', (110, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))	('mesothelioma', 'Disease', (90, 102))	('non-tumor', 'Disease', 'MESH:D009369', (110, 119))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('men', 'Species', '9606', (147, 150))	('methylation', 'Var', (53, 64))
80947	19118007	was significantly positively associated with asbestos burden; promoter associated CpG49 (P < 0.04), and exonic CpG13 (P < 0.02).	('associated', 'Interaction', (29, 39))	('positively', 'PosReg', (18, 28))	('asbestos', 'Chemical', 'MESH:D001194', (45, 53))	('CpG49', 'Var', (82, 87))	('exonic CpG13', 'Var', (104, 116))	('asbestos burden', 'Disease', (45, 60))
80951	19118007	In a proportional hazards model including all cases (n = 158), women had half the risk of death of men (HR = 0.5, 95% CI, 0.3 - 0.96), and patients with mixed histology tumors were at greater risk of death compared to those with epithelial tumors (HR = 2.7, 95% CI, 1.7 - 4.4).	('epithelial tumors', 'Disease', (229, 246))	('epithelial tumors', 'Disease', 'MESH:D002277', (229, 246))	('tumors', 'Disease', (240, 246))	('women', 'Species', '9606', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('men', 'Species', '9606', (65, 68))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', 'MESH:D003643', (200, 205))	('tumors', 'Disease', (169, 175))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('men', 'Species', '9606', (99, 102))	('death', 'Disease', (90, 95))	('death', 'Disease', (200, 205))	('mixed', 'Var', (153, 158))
80953	19118007	In particular, membership in methylation classes four and seven were both independently associated with a significant 3-fold increased risk of death compared to the class with the lowest median asbestos count (95% CIs, class four: 1.4 - 7.0, class seven: 1.3 - 7.4) (Table 2).	('methylation', 'Var', (29, 40))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('death', 'Disease', 'MESH:D003643', (143, 148))	('death', 'Disease', (143, 148))	('asbestos', 'Chemical', 'MESH:D001194', (194, 202))	('associated', 'Reg', (88, 98))
80957	19118007	Exposure to asbestos is the single most important risk factor for pleural mesothelioma and prior research has established that somatic mutations and alterations in gene expression are a feature of this disease.	('alterations', 'Var', (149, 160))	('asbestos', 'Chemical', 'MESH:D001194', (12, 20))	('mutations', 'Var', (135, 144))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (66, 86))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (66, 86))	('pleural mesothelioma', 'Disease', (66, 86))
80962	19118007	Our findings indicate that an extremely large number of loci are epigenetically altered in mesothelioma, asbestos exposure is associated with the degree of epigenetic alteration, and that profiles of gene silencing are associated with clinical outcome.	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('associated', 'Reg', (219, 229))	('altered', 'Reg', (80, 87))	('profiles', 'Var', (188, 196))	('mesothelioma', 'Disease', (91, 103))	('asbestos', 'Chemical', 'MESH:D001194', (105, 113))	('gene silencing', 'biological_process', 'GO:0016458', ('200', '214'))
80964	19118007	Precisely why epigenetic alterations are a prominent feature of pleural mesothelioma is not clear.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (64, 84))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (64, 84))	('epigenetic alterations', 'Var', (14, 36))	('pleural mesothelioma', 'Disease', (64, 84))
80966	19118007	Epigenetic alterations have been associated with inflammation in colon cancer, and it has been suggested that inflammation-related epigenetic alterations are common in human cancers.	('Epigenetic alterations', 'Var', (0, 22))	('colon cancer', 'Disease', (65, 77))	('inflammation', 'biological_process', 'GO:0006954', ('49', '61'))	('human', 'Species', '9606', (168, 173))	('inflammation', 'Disease', (110, 122))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('associated', 'Reg', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('inflammation', 'biological_process', 'GO:0006954', ('110', '122'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))	('inflammation', 'Disease', (49, 61))
80970	19118007	Both 5-methylcytosine adjacent to 8- oxoguanine, and 5-hydroxymethylcytosine have been shown to inhibit binding of methyl-CpG binding protein 2, a critical epigenetic regulator that recruits cytosine methyltransferases and histone deacetylases.	('5-hydroxymethylcytosine', 'Var', (53, 76))	('5-methylcytosine', 'Var', (5, 21))	('binding', 'Interaction', (104, 111))	('methyl-CpG binding', 'molecular_function', 'GO:0008327', ('115', '133'))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (5, 21))	('methyl-CpG binding protein 2', 'Gene', (115, 143))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (53, 76))	('8- oxoguanine', 'Chemical', 'MESH:C024829', (34, 47))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('inhibit', 'NegReg', (96, 103))	('methyl-CpG binding protein 2', 'Gene', '4204', (115, 143))
80974	19118007	This is consistent with our data suggesting that asbestos burden (and the resultant inflammatory response) is associated with epigenetic alterations.	('epigenetic alterations', 'Var', (126, 148))	('associated', 'Reg', (110, 120))	('inflammatory response', 'biological_process', 'GO:0006954', ('84', '105'))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))
80975	19118007	Furthermore, the decades-long latency of MPM would allow ample time for cellular turnover and selection of cells with altered epigenetic programs that favor survival and deregulated proliferation We also found that epigenetic profiles differentiate tumor from non-tumor pleura (P < 0.0001).	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('epigenetic profiles', 'Var', (215, 234))	('tumor', 'Disease', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('differentiate', 'Reg', (235, 248))	('non-tumor pleura', 'Disease', (260, 276))	('tumor', 'Disease', (249, 254))	('non-tumor pleura', 'Disease', 'MESH:D054363', (260, 276))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
80977	19118007	Epigenetic gene inactivation is inherently more stable and less prone to variability than measures of mRNA, making our approach for differentiating tumors from non-tumor pleura likely more reproducible.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('non-tumor pleura', 'Disease', 'MESH:D054363', (160, 176))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Epigenetic gene inactivation', 'Var', (0, 28))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('non-tumor pleura', 'Disease', (160, 176))
80980	19118007	Consequently, it may be that the relative epigenetic similarity between certain tumors and non-tumor pleura is explained by a difference in the prevalence of somatic genetic aberrations (such as gene deletions) among these tumors.	('non-tumor pleura', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (223, 229))	('non-tumor pleura', 'Disease', 'MESH:D054363', (91, 107))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('gene deletions', 'Var', (195, 209))
80984	19118007	Some of the pathways and processes whose genes are differentially methylated include epigenetic regulation, cell cycle control, and inflammation, among others.	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('inflammation', 'Disease', (132, 144))	('inflammation', 'biological_process', 'GO:0006954', ('132', '144'))	('cell cycle control', 'biological_process', 'GO:1901987', ('108', '126'))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('epigenetic regulation', 'Var', (85, 106))	('cell cycle control', 'CPA', (108, 126))	('pathways', 'Pathway', (12, 20))
80985	19118007	For instance, HIC1 was hypermethylated in tumors, which may prevent its transcriptional repression of the histone deacetylase SIRT1, and DNMT3B had significantly lower methylation in tumors, suggesting epigenetic dysregulation.	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('lower', 'NegReg', (162, 167))	('DNMT3B', 'Gene', (137, 143))	('DNMT3B', 'Gene', '1789', (137, 143))	('tumors', 'Disease', (183, 189))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('prevent', 'NegReg', (60, 67))	('methylation', 'MPA', (168, 179))	('HIC1', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('SIRT1', 'Gene', '23411', (126, 131))	('transcriptional repression', 'MPA', (72, 98))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('hypermethylated', 'Var', (23, 38))	('HIC1', 'Gene', '3090', (14, 18))	('SIRT1', 'Gene', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
80992	19118007	Alternatively, a 'hit' at a locus essential for epigenetic regulation, the chronic inflammatory process, or altered tumor metabolism, for example, may induce a change in overall epigenetic regulation that results in the targeting and aberrant methylation of many genes in a wholesale fashion.	('genes', 'Gene', (263, 268))	('results in', 'Reg', (205, 215))	('targeting', 'MPA', (220, 229))	('induce', 'Reg', (151, 157))	('aberrant', 'Var', (234, 242))	('methylation', 'biological_process', 'GO:0032259', ('243', '254'))	('epigenetic regulation', 'MPA', (178, 199))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('metabolism', 'biological_process', 'GO:0008152', ('122', '132'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('regulation', 'biological_process', 'GO:0065007', ('59', '69'))	('regulation', 'biological_process', 'GO:0065007', ('189', '199'))	('change', 'Reg', (160, 166))	('tumor', 'Disease', (116, 121))	('methylation', 'MPA', (243, 254))
80999	19118007	Furthermore, specific genes, or gene pathways, may be more likely to be selected for, or more susceptible to asbestos-related epigenetic alterations; consistent with this, associations between CpG methylation of specific genes and asbestos previously reported by our group and others were confirmed in this study.	('associations', 'Interaction', (172, 184))	('methylation', 'biological_process', 'GO:0032259', ('197', '208'))	('asbestos', 'Chemical', 'MESH:D001194', (231, 239))	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('methylation', 'Var', (197, 208))	('asbestos', 'Disease', (231, 239))
81001	19118007	Finally, overall methylation profile class membership was a significant, independent predictor of patient survival (P < 0.01), suggesting that epigenetic dysregulation is strongly associated with disease progression.	('patient', 'Species', '9606', (98, 105))	('epigenetic dysregulation', 'Var', (143, 167))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('associated with', 'Reg', (180, 195))	('disease', 'Disease', (196, 203))
81004	19118007	In summary, our data show that epigenetic alterations are extraordinarily common in mesothelioma and discriminate the malignant phenotype from normal pleura.	('mesothelioma', 'Disease', (84, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('epigenetic alterations', 'Var', (31, 53))	('common', 'Reg', (74, 80))
81005	19118007	Epigenetic changes are also significantly associated with asbestos burden and significantly predict clinical outcome.	('associated', 'Reg', (42, 52))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('predict', 'Reg', (92, 99))	('asbestos burden', 'Disease', (58, 73))	('Epigenetic changes', 'Var', (0, 18))
81103	29701689	However, more recently, expression of EGFR on MPM has been used for the targeted delivery of microRNA mimics delivered by targeted bacterial minicells (TargomiRs) in a recent clinical trial in MPM, while most recently a patient harbouring mutations in EGFR (G719C and S768I) was successfully treated with Afatinib an EGFR TKI; an lncRNA associated with EGFR called EGFR-AS1 has been identified.	('G719C and S768I', 'Var', (258, 273))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', '1956', (317, 321))	('miR', 'Gene', (157, 160))	('mutations', 'Var', (239, 248))	('Afatinib', 'Chemical', 'MESH:D000077716', (305, 313))	('EGFR', 'Gene', '1956', (365, 369))	('EGFR', 'molecular_function', 'GO:0005006', ('317', '321'))	('S768I', 'Var', (268, 273))	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('353', '357'))	('EGFR-AS1', 'Gene', (365, 373))	('EGFR', 'Gene', '1956', (353, 357))	('EGFR', 'Gene', '1956', (252, 256))	('G719C', 'Mutation', 'rs28929495', (258, 263))	('S768I', 'Mutation', 'rs121913465', (268, 273))	('EGFR', 'molecular_function', 'GO:0005006', ('365', '369'))	('EGFR-AS1', 'Gene', '100507500', (365, 373))	('EGFR', 'Gene', (317, 321))	('EGFR', 'Gene', (365, 369))	('patient', 'Species', '9606', (220, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('252', '256'))	('EGFR', 'Gene', (38, 42))	('miR', 'Gene', '220972', (157, 160))	('EGFR', 'Gene', (252, 256))	('EGFR', 'Gene', (353, 357))
81105	29701689	Strikingly, knockdown of EGFR-AS1 in vitro and in vivo lead to increased sensitivity, whereas overexpression is sufficient to induce resistance to EGFR TKIs.	('EGFR', 'Gene', (147, 151))	('increased', 'PosReg', (63, 72))	('EGFR', 'Gene', (25, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('knockdown', 'Var', (12, 21))	('sensitivity', 'MPA', (73, 84))	('resistance', 'MPA', (133, 143))	('EGFR-AS1', 'Gene', '100507500', (25, 33))	('EGFR', 'Gene', '1956', (147, 151))	('EGFR-AS1', 'Gene', (25, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('EGFR', 'Gene', '1956', (25, 29))
81115	29701689	Across the TCGA dataset, KDM5B appears to have significant alterations in about 14% of MPM cases, including amplification of its genomic region, overexpression, or indeed downregulation of its mRNA (Figure 2D), all of which are found in either the epithelioid or biphasic subtypes (Figure 2E).	('amplification', 'Var', (108, 121))	('mRNA', 'MPA', (193, 197))	('downregulation', 'NegReg', (171, 185))	('alterations', 'Reg', (59, 70))	('overexpression', 'PosReg', (145, 159))	('KDM5B', 'Gene', '10765', (25, 30))	('MPM', 'Disease', (87, 90))	('KDM5B', 'Gene', (25, 30))
81118	29701689	(Figure 2I).The functional role of this lncRNA in EMT is as yet unknown, but knockdown of this lncRNA in lung cancer is associated with inhibited cellular proliferation and metastasis.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('inhibited', 'NegReg', (136, 145))	('knockdown', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('lung cancer', 'Disease', (105, 116))
81126	29701689	A significant body of research has shown that many short non-coding RNAs, such as microRNAs (miRNAs), have extensive alterations and diverse roles in MPM, and have been discussed by us in depth in a previous review.	('miR', 'Gene', (93, 96))	('short non-coding RNAs', 'Var', (51, 72))	('MPM', 'Disease', (150, 153))	('miR', 'Gene', '220972', (93, 96))
81131	29701689	The other ways PVT1 has been shown to elicit responses include by acting as a competitive endogenous RNA (ceRNA) for various miRNAs, or by interactions with EZH2 to epigenetically regulate genes associated with EMT.	('EZH2', 'Gene', '2146', (157, 161))	('EZH2', 'Gene', (157, 161))	('responses', 'MPA', (45, 54))	('PVT1', 'Gene', '5820', (15, 19))	('EMT', 'biological_process', 'GO:0001837', ('211', '214'))	('epigenetically', 'Var', (165, 179))	('genes', 'Gene', (189, 194))	('RNA', 'cellular_component', 'GO:0005562', ('101', '104'))	('interactions', 'Interaction', (139, 151))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))	('PVT1', 'Gene', (15, 19))
81133	29701689	In this regard, frequent coamplification and cooperation between c-MYC and PVT1 oncogenes have been observed to promote malignant pleural mesothelioma.	('c-MYC', 'Gene', (65, 70))	('malignant pleural mesothelioma', 'Disease', (120, 150))	('promote', 'PosReg', (112, 119))	('coamplification', 'Var', (25, 40))	('PVT1', 'Gene', (75, 79))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (130, 150))	('cooperation', 'Var', (45, 56))	('c-MYC', 'Gene', '4609', (65, 70))	('PVT1', 'Gene', '5820', (75, 79))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (120, 150))
81135	29701689	In silico analysis of the TCGA provisional dataset demonstrated that amplification occurred only in epithelioid samples (Figure 4A,B), which is somewhat in agreement with the observations made by Riquelme et al., where copy number gains were seen in the biphasic (6 of 26, 23%) and epithelioid (5 of 37, 13%) histotypes but not in the sarcomatoid cases.	('epithelioid', 'Disease', (282, 293))	('gains', 'PosReg', (231, 236))	('sarcomatoid', 'Disease', 'MESH:C538614', (335, 346))	('copy number', 'Var', (219, 230))	('biphasic', 'Disease', (254, 262))	('TCGA', 'Gene', (26, 30))	('sarcomatoid', 'Disease', (335, 346))
81140	29701689	Given that it is estimated that approximately 65% of mesotheliomas harbour mutations inactivating BAP1, this may have implications with respect to the role of this lncRNA in MPM pathogenesis.	('BAP1', 'Gene', (98, 102))	('pathogenesis', 'biological_process', 'GO:0009405', ('178', '190'))	('mesotheliomas', 'Disease', 'MESH:D008654', (53, 66))	('BAP1', 'Gene', '8314', (98, 102))	('mesotheliomas', 'Disease', (53, 66))	('mutations inactivating', 'Var', (75, 97))
81147	29701689	Moreover, restoration of GAS5 expression could greatly sensitise these cells to gefitinib treatment in xenograft mouse models.	('expression', 'MPA', (30, 40))	('restoration', 'Var', (10, 21))	('GAS5', 'Protein', (25, 29))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('GAS', 'molecular_function', 'GO:0034005', ('25', '28'))	('sensitise', 'Reg', (55, 64))	('mouse', 'Species', '10090', (113, 118))
81169	29701689	MALAT-1 knockdown significantly reduced MAPK/ERK signalling in gallbladder cancer cells, and in glioma, MALAT-1 acts as a tumour suppressor by attenuating ERK/MAPK mediated signalling.	('ERK', 'Gene', (45, 48))	('ERK', 'Gene', (155, 158))	('MAPK', 'molecular_function', 'GO:0004707', ('159', '163'))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('MALAT-1', 'Gene', '378938', (104, 111))	('attenuating', 'NegReg', (143, 154))	('ERK', 'Gene', '2048', (45, 48))	('ERK', 'Gene', '2048', (155, 158))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('MALAT-1', 'Gene', (104, 111))	('gallbladder cancer', 'Disease', 'MESH:D005706', (63, 81))	('signalling', 'biological_process', 'GO:0023052', ('173', '183'))	('reduced', 'NegReg', (32, 39))	('tumour', 'Disease', (122, 128))	('MALAT-1', 'Gene', '378938', (0, 7))	('MALAT-1', 'Gene', (0, 7))	('glioma', 'Disease', (96, 102))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('signalling', 'biological_process', 'GO:0023052', ('49', '59'))	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('gallbladder cancer', 'Disease', (63, 81))	('knockdown', 'Var', (8, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
81170	29701689	In osteosarcoma cells, downregulation of MALAT-1 inhibits PI3K/Akt signalling, whereas in breast and ovarian cancer cells, knockdown of MALAT-1 knockdown results in increased PI3K/Akt signalling and induction of EMT.	('downregulation', 'NegReg', (23, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('EMT', 'biological_process', 'GO:0001837', ('212', '215'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (90, 115))	('MALAT-1', 'Gene', '378938', (136, 143))	('signalling', 'biological_process', 'GO:0023052', ('67', '77'))	('MALAT-1', 'Gene', (136, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('MALAT-1', 'Gene', '378938', (41, 48))	('Akt', 'Gene', '207', (63, 66))	('signalling', 'biological_process', 'GO:0023052', ('184', '194'))	('MALAT-1', 'Gene', (41, 48))	('EMT', 'CPA', (212, 215))	('induction', 'Reg', (199, 208))	('Akt', 'Gene', (180, 183))	('knockdown', 'Var', (123, 132))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('Akt', 'Gene', '207', (180, 183))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('175', '179'))	('inhibits', 'NegReg', (49, 57))	('increased', 'PosReg', (165, 174))	('Akt', 'Gene', (63, 66))
81175	29701689	For example, MALAT-1 induces EMT in various cancers via the Wnt/beta-catenin signalling pathway, while loss of WIF1 enhances the migratory potential of glioblastoma cells through WNT5A activation mediated by MALAT1.	('MALAT1', 'Gene', '378938', (208, 214))	('WIF1', 'Gene', (111, 115))	('loss', 'Var', (103, 107))	('WNT5A', 'Gene', '7474', (179, 184))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))	('signalling pathway', 'biological_process', 'GO:0007165', ('77', '95'))	('induces', 'Reg', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('EMT', 'CPA', (29, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('MALAT-1', 'Gene', '378938', (13, 20))	('MALAT-1', 'Gene', (13, 20))	('glioblastoma', 'Disease', (152, 164))	('WNT5A', 'Gene', (179, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('enhances', 'PosReg', (116, 124))	('WIF1', 'Gene', '11197', (111, 115))	('MALAT1', 'Gene', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
81178	29701689	N-Myc (MYCN) belongs to the MYC family and was originally identified as being amplified in 20-30% of neuroblastoma tumours, but it is now well established that dysregulation of this transcription factor is common in many non-neuronal tumours.	('transcription factor', 'molecular_function', 'GO:0000981', ('182', '202'))	('MYC', 'Gene', (28, 31))	('MYCN', 'Gene', (7, 11))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('non-neuronal tumours', 'Disease', 'MESH:D009410', (221, 241))	('N-Myc', 'Gene', (0, 5))	('N-Myc', 'Gene', '4613', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('MYC', 'Gene', '4609', (28, 31))	('MYC', 'Gene', (7, 10))	('dysregulation', 'Var', (160, 173))	('neuroblastoma tumours', 'Disease', 'MESH:D009447', (101, 122))	('MYCN', 'Gene', '4613', (7, 11))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('neuroblastoma tumours', 'Disease', (101, 122))	('non-neuronal tumours', 'Disease', (221, 241))	('MYC', 'Gene', '4609', (7, 10))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))
81181	29701689	While a role for this lncRNA has not yet been identified in MPM, MYCNOS is upregulated in a proportion of MPM (5%:Figure 8A), and is mostly upregulated in the biphasic subset:Figure 8B.	('MPM', 'Var', (106, 109))	('upregulated', 'PosReg', (75, 86))	('MYCNOS', 'Gene', (65, 71))	('MYCNOS', 'Gene', '10408', (65, 71))
81194	29701689	cBioPortal analysis of the current TCGA mesothelioma dataset finds that 7% of samples have either amplifications or deletions in HULC, or overexpress this lncRNA (Figure 10A).	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('HULC', 'Gene', (129, 133))	('deletions', 'Var', (116, 125))	('overexpress', 'PosReg', (138, 149))	('HULC', 'Gene', '728655', (129, 133))	('mesothelioma', 'Disease', (40, 52))	('amplifications', 'Var', (98, 112))
81199	29701689	As CASC2 is downregulated in human HCC samples, it may therefore be of interest to examine the levels of this lncRNA in MPM to see if loss of CASC is associated with a more aggressive histological phenotype as observed in Table 1.	('associated', 'Reg', (150, 160))	('downregulated', 'NegReg', (12, 25))	('human', 'Species', '9606', (29, 34))	('CASC2', 'Gene', '255082', (3, 8))	('CASC2', 'Gene', (3, 8))	('CASC', 'Gene', (142, 146))	('loss', 'Var', (134, 138))
81451	24061575	We observed that ESR2 modulation did not influence SDHB gene transcription (Figure 1c), even though there was a negative correlation between ERbeta and SDHB-expressed proteins (Figures 1d and e).	('negative', 'NegReg', (112, 120))	('transcription', 'biological_process', 'GO:0006351', ('61', '74'))	('SDHB', 'Gene', (152, 156))	('SDHB', 'Gene', '6390', (152, 156))	('correlation', 'Interaction', (121, 132))	('ESR2', 'Gene', (17, 21))	('SDHB', 'Gene', '6390', (51, 55))	('modulation', 'Var', (22, 32))	('SDHB', 'Gene', (51, 55))	('ESR2', 'Gene', '2100', (17, 21))	('transcription', 'MPA', (61, 74))
81454	24061575	To study the impact of SDHB subunit loss on mitochondrial function in vitro, SDHB was silenced by transient small interfering RNA (siRNAs) transfection of REN cells.	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('silenced', 'NegReg', (86, 94))	('SDHB', 'Gene', '6390', (23, 27))	('SDHB', 'Gene', '6390', (77, 81))	('SDHB', 'Gene', (23, 27))	('SDHB', 'Gene', (77, 81))	('transfection', 'Var', (139, 151))
81461	24061575	Activation of ERbeta by KB9520 and diarylpropionitrile (DPN), two different selective ligands, resulted in strong impairment of complex II and IV activity both in control and SDHB-silenced cells (Figure 3b).	('ERbeta', 'Protein', (14, 20))	('impairment', 'NegReg', (114, 124))	('impairment of complex II', 'Phenotype', 'HP:0008314', (114, 138))	('KB9520', 'Chemical', '-', (24, 30))	('KB9520', 'Var', (24, 30))	('SDHB', 'Gene', '6390', (175, 179))	('complex II', 'molecular_function', 'GO:0008177', ('128', '138'))	('SDHB', 'Gene', (175, 179))	('IV activity', 'MPA', (143, 154))	('complex', 'MPA', (128, 135))	('diarylpropionitrile', 'Chemical', 'MESH:C492519', (35, 54))	('DPN', 'Chemical', 'MESH:C492519', (56, 59))
81463	24061575	Furthermore, ERbeta activation by KB9520 impaired proliferation of SDHB-silenced cells (Supplementary Figure 2A).	('SDHB', 'Gene', '6390', (67, 71))	('KB9520', 'Chemical', '-', (34, 40))	('proliferation', 'CPA', (50, 63))	('KB9520', 'Var', (34, 40))	('SDHB', 'Gene', (67, 71))	('ERbeta', 'Protein', (13, 19))	('activation', 'PosReg', (20, 30))	('impaired', 'NegReg', (41, 49))
81464	24061575	Importantly, KB9520 and DPN did not severely impair MRC complex II and IV activities, COX7AR expression or cell proliferation of normal ERbeta-positive mesothelial MET5A cells (Supplementary Figures 3A-C) and human mesothelial cells (HMC; data not shown), suggesting that selective agonist activation of ERbeta is not cytotoxic to normal cells.	('MRC', 'CellLine', 'CVCL:0440', (52, 55))	('COX7AR', 'Enzyme', (86, 92))	('human', 'Species', '9606', (209, 214))	('MRC complex II', 'Enzyme', (52, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('impair', 'NegReg', (45, 51))	('KB9520', 'Chemical', '-', (13, 19))	('cell proliferation', 'CPA', (107, 125))	('KB9520', 'Var', (13, 19))	('IV activities', 'MPA', (71, 84))	('DPN', 'Var', (24, 27))	('complex II', 'molecular_function', 'GO:0008177', ('56', '66'))	('DPN', 'Chemical', 'MESH:C492519', (24, 27))
81472	24061575	In contrast, KB9520 treatment of mice injected with REN cells, which express endogenous ERbeta, resulted in a decrease in tumor dimensions as compared with vehicle controls within 10 days of treatment (Figures 4a and b).	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('KB9520', 'Chemical', '-', (13, 19))	('KB9520', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mice', 'Species', '10090', (33, 37))	('decrease', 'NegReg', (110, 118))	('tumor', 'Disease', (122, 127))
81473	24061575	In 2 out of 7 KB9520-treated mice, a reduction in initial tumor mass was observed after 20 days of treatment, whereas 5 out of 7 mice KB9520 inhibited the rate of tumor growth as compared with vehicle control mice.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mice', 'Species', '10090', (209, 213))	('KB9520', 'Chemical', '-', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('KB9520', 'Var', (134, 140))	('reduction', 'NegReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('KB9520', 'Chemical', '-', (14, 20))	('mice', 'Species', '10090', (129, 133))	('mice', 'Species', '10090', (29, 33))	('inhibited', 'NegReg', (141, 150))
81475	24061575	In vivo treatment of REN cell tumors with daily doses of KB9520 resulted in upregulation of ERbeta at both mRNA and protein levels (Supplementary Figures 4A and B).	('KB9520', 'Chemical', '-', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('KB9520', 'Var', (57, 63))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('upregulation', 'PosReg', (76, 88))	('ERbeta', 'Protein', (92, 98))	('REN cell tumors', 'Disease', 'MESH:D005935', (21, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('REN cell tumors', 'Disease', (21, 36))
81479	24061575	To confirm that alterations in MRC complexes activities had consequences on mitochondrial ATP production, we performed a spectrophotometric measurement of the mitochondrial ATP production in ERbeta-silenced and over-expressing cells.	('consequences', 'Reg', (60, 72))	('activities', 'MPA', (45, 55))	('alterations', 'Var', (16, 27))	('mitochondrial ATP production', 'MPA', (159, 187))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('mitochondrial ATP production', 'MPA', (76, 104))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('MRC', 'CellLine', 'CVCL:0440', (31, 34))
81481	24061575	In contrast, silencing of ERbeta led to a marked increase in mitochondrial ATP production both under basal conditions and after stimuli (Figure 5b).	('mitochondrial ATP production', 'MPA', (61, 89))	('increase', 'PosReg', (49, 57))	('silencing', 'Var', (13, 22))	('ERbeta', 'Gene', (26, 32))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))
81486	24061575	In all experimental conditions, glycolysis inhibitors potentiated the effects of over-expressed or KB9520-activated ERbeta (Figures 6b and c).	('KB9520-activated', 'Var', (99, 115))	('KB9520', 'Chemical', '-', (99, 105))	('potentiated', 'PosReg', (54, 65))	('glycolysis', 'biological_process', 'GO:0006096', ('32', '42'))	('over-expressed', 'PosReg', (81, 95))
81492	24061575	The MRC complex II is composed of four nuclear-encoded subunits whose alterations have been related to many different diseases: SDHA mutations have been associated to Leigh syndrome, mitochondrial encephalopathy, and optic atrophy and SDHB, SDHC and SDHD alterations have been correlated to hereditary pheochromocytoma and paraganglioma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (302, 318))	('paraganglioma', 'Disease', 'MESH:D010235', (323, 336))	('SDHA', 'Gene', (128, 132))	('optic atrophy', 'Disease', (217, 230))	('SDHD', 'Gene', (250, 254))	('SDHC', 'Gene', '6391', (241, 245))	('complex II', 'molecular_function', 'GO:0008177', ('8', '18'))	('optic atrophy', 'Phenotype', 'HP:0000648', (217, 230))	('SDHA', 'Gene', '6389', (128, 132))	('SDHB', 'Gene', '6390', (235, 239))	('glioma', 'Phenotype', 'HP:0009733', (330, 336))	('paraganglioma', 'Phenotype', 'HP:0002668', (323, 336))	('encephalopathy', 'Phenotype', 'HP:0001298', (197, 211))	('mutations', 'Var', (133, 142))	('MRC', 'CellLine', 'CVCL:0440', (4, 7))	('mitochondrial encephalopathy', 'Disease', (183, 211))	('mitochondrial encephalopathy', 'Disease', 'MESH:C538525', (183, 211))	('alterations', 'Var', (255, 266))	('hereditary pheochromocytoma', 'Disease', 'MESH:D010673', (291, 318))	('Leigh syndrome', 'Disease', 'MESH:D007888', (167, 181))	('hereditary pheochromocytoma', 'Disease', (291, 318))	('SDHC', 'Gene', (241, 245))	('SDHB', 'Gene', (235, 239))	('correlated', 'Reg', (277, 287))	('Leigh syndrome', 'Disease', (167, 181))	('optic atrophy', 'Disease', 'MESH:D009896', (217, 230))	('mitochondrial encephalopathy', 'Phenotype', 'HP:0006789', (183, 211))	('SDHD', 'Gene', '6392', (250, 254))	('associated', 'Reg', (153, 163))	('paraganglioma', 'Disease', (323, 336))
81494	24061575	In paraganglioma and pheochromocytoma, sporadic and familial mutations in the SDHB gene support a link between mitochondrial dysfunction and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (111, 136))	('SDHB', 'Gene', '6390', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (111, 136))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('link', 'Reg', (98, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (3, 16))	('tumor', 'Disease', (141, 146))	('mutations', 'Var', (61, 70))	('SDHB', 'Gene', (78, 82))	('paraganglioma', 'Disease', (3, 16))	('mitochondrial dysfunction', 'Disease', (111, 136))	('pheochromocytoma', 'Disease', (21, 37))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (21, 37))	('paraganglioma', 'Disease', 'MESH:D010235', (3, 16))	('pheochromocytoma', 'Disease', 'MESH:D010673', (21, 37))
81502	24061575	These data further strengthen the role of ERbeta as a tumor suppressor, and that the antitumor effect of KB9520 is target specific.	('KB9520', 'Chemical', '-', (105, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('KB9520', 'Var', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ERbeta', 'Protein', (42, 48))	('tumor', 'Disease', (54, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
81504	24061575	Interestingly, in tumor tissues recovered from REN-injected mice, treatment with KB9520 resulted in increased ERbeta expression at both the levels of transcription and protein, compared with vehicle-treated controls.	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('KB9520', 'Chemical', '-', (81, 87))	('increased', 'PosReg', (100, 109))	('tumor', 'Disease', (18, 23))	('KB9520', 'Var', (81, 87))	('expression', 'MPA', (117, 127))	('increased ERbeta', 'Phenotype', 'HP:0003141', (100, 116))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mice', 'Species', '10090', (60, 64))	('ERbeta', 'Protein', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
81509	24061575	Consistent with the inhibition of OXPHOS, KB9520 in combination with the hexokinase inhibitor 2-Deoxy-D-glucose or the PFKFB3 kinase inhibitor 3PO, two drugs that target important rate-limiting enzymes in the glycolysis pathway resulted in synergistic inhibition of MMe cell growth.	('glycolysis', 'biological_process', 'GO:0006096', ('209', '219'))	('PFKFB3', 'Gene', (119, 125))	('cell growth', 'biological_process', 'GO:0016049', ('270', '281'))	('synergistic', 'MPA', (240, 251))	('inhibition', 'NegReg', (252, 262))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('126', '142'))	('2-Deoxy-D-glucose', 'Chemical', 'MESH:D003847', (94, 111))	('KB9520', 'Chemical', '-', (42, 48))	('OXPHOS', 'biological_process', 'GO:0002082', ('34', '40'))	('PFKFB3', 'Gene', '5209', (119, 125))	('KB9520', 'Var', (42, 48))	('MMe cell growth', 'CPA', (266, 281))	('3PO', 'Chemical', 'MESH:C527590', (143, 146))
81520	24061575	The plasmid expressing human ERbeta mutated in the DBD was kindly provided by Dr Strom A (University of Houston, Houston, TX, USA).	('mutated', 'Var', (36, 43))	('ERbeta', 'Gene', (29, 35))	('human', 'Species', '9606', (23, 28))
81533	24061575	The primers sequences for ESR2 were: Fw 5'-GTCAGGCATGCGAGT-3' and Rev 5'-GGGAGCCCTCTTTGC-3' SDHB and COX7AR primers were QT00066507 and QT01012368 from Qiagen (Hilden, Germany).	('SDHB', 'Gene', '6390', (92, 96))	('ESR2', 'Gene', (26, 30))	('SDHB', 'Gene', (92, 96))	('QT01012368', 'Var', (136, 146))	('QT00066507', 'Var', (121, 131))	('ESR2', 'Gene', '2100', (26, 30))
81562	18728672	Spending more than 40 h per week stripping rather than less than 10, increased mortality risk from all causes (RR 1.4, 95% CI 1.2-1.7), circulatory disease and ischaemic heart disease.	('ischaemic heart disease', 'Disease', 'MESH:D003324', (160, 183))	('increased', 'PosReg', (69, 78))	('stripping', 'Var', (33, 42))	('ischaemic heart disease', 'Disease', (160, 183))	('circulatory disease', 'Disease', (136, 155))
81640	18498639	NSAIDs inhibit cyclooxygenases (COX-1 and COX-2), key enzymes in arachidonic acid metabolism, which catalyze an intermediate step in the production of prostaglandins, prostacyclins and thromboxanes.	('COX-2', 'Gene', '5743', (42, 47))	('arachidonic acid metabolism', 'biological_process', 'GO:0019369', ('65', '92'))	('cyclooxygenases', 'Enzyme', (15, 30))	('thromboxanes', 'Chemical', 'MESH:D013931', (185, 197))	('prostaglandins', 'Chemical', 'MESH:D011453', (151, 165))	('inhibit', 'NegReg', (7, 14))	('COX-1', 'Gene', (32, 37))	('prostacyclins', 'Chemical', 'MESH:D044062', (167, 180))	('COX-2', 'Gene', (42, 47))	('COX-1', 'Gene', '4512', (32, 37))	('NSAIDs', 'Var', (0, 6))	('arachidonic acid', 'Chemical', 'MESH:D016718', (65, 81))
81652	18498639	In particular, NS398 has produced a significant reduction of proliferation level in MM cell lines established and derived from previously untreated patients and celecoxib has proved to be efficient in inhibiting mesothelioma cell growth In a previous work we have demonstrated a significant anti-proliferative effect of piroxicam in two mesothelioma cell lines (MSTO-211H and NCI-H2452), not expressing COX-2, treated with piroxicam alone or in combination with CDDP.	('piroxicam', 'Chemical', 'MESH:D010894', (423, 432))	('anti-proliferative effect', 'MPA', (291, 316))	('mesothelioma', 'Disease', (337, 349))	('CDDP', 'Chemical', '-', (462, 466))	('NS398', 'Var', (15, 20))	('piroxicam', 'Chemical', 'MESH:D010894', (320, 329))	('cell growth', 'biological_process', 'GO:0016049', ('225', '236'))	('mesothelioma', 'Disease', 'MESH:D008654', (337, 349))	('patients', 'Species', '9606', (148, 156))	('NCI-H2452', 'CellLine', 'CVCL:1553', (376, 385))	('COX-2', 'Gene', (403, 408))	('celecoxib', 'Chemical', 'MESH:D000068579', (161, 170))	('proliferation level', 'MPA', (61, 80))	('inhibiting', 'NegReg', (201, 211))	('COX-2', 'Gene', '5743', (403, 408))	('reduction', 'NegReg', (48, 57))	('MSTO-211H', 'CellLine', 'CVCL:1430', (362, 371))	('mesothelioma', 'Disease', (212, 224))	('mesothelioma', 'Disease', 'MESH:D008654', (212, 224))
81665	18498639	The fluorescent substrates for caspase 3, 8 and 9 were respectively FAM-DEVD-FMK, FAM-LETD-FMK, FAM-LEHD-FMK.	('FAM-LEHD-FMK', 'Var', (96, 108))	('FAM-DEVD-FMK', 'Chemical', '-', (68, 80))	('FAM-LETD-FMK', 'Chemical', '-', (82, 94))	('FAM-LETD-FMK', 'Var', (82, 94))	('caspase 3, 8 and 9', 'Gene', '836;841;842', (31, 49))	('FAM-LEHD-FMK', 'Chemical', '-', (96, 108))	('FAM-DEVD-FMK', 'Var', (68, 80))
81707	18498639	For example, in colon carcinoma the regulation by NSAIDs of the molecular pathways of cellular proliferation includes modulation of Ras and MAP Kinase signal transduction pathways, nuclear factor kB protein activation and cyclin expression.	('cellular proliferation', 'CPA', (86, 108))	('MAP Kinase signal transduction pathways', 'Pathway', (140, 179))	('cyclin', 'Gene', '5111', (222, 228))	('cyclin', 'molecular_function', 'GO:0016538', ('222', '228'))	('MAP', 'molecular_function', 'GO:0004239', ('140', '143'))	('molecular pathways', 'Pathway', (64, 82))	('activation', 'PosReg', (207, 217))	('NSAIDs', 'Var', (50, 56))	('cyclin', 'Gene', (222, 228))	('signal transduction', 'biological_process', 'GO:0007165', ('151', '170'))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('nuclear', 'Protein', (181, 188))	('colon carcinoma', 'Disease', 'MESH:D015179', (16, 31))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('colon carcinoma', 'Disease', (16, 31))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
81715	18498639	Nevertheless, the greater sensitivity of the MSTO cell line to apoptosis induced by the single CDDP is in line with the higher caspase 8 and 9 activation.	('CDDP', 'Var', (95, 99))	('single CDDP', 'Var', (88, 99))	('CDDP', 'Chemical', '-', (95, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('caspase 8', 'Gene', '841', (127, 136))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('caspase 8', 'Gene', (127, 136))
81738	18454162	These malignancy-associated variations suggest that MUC1 may be an attractive target for anticancer therapies.	('malignancy', 'Disease', 'MESH:D009369', (6, 16))	('variations', 'Var', (28, 38))	('malignancy', 'Disease', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MUC1', 'Gene', (52, 56))	('MUC1', 'Gene', '4582', (52, 56))
81774	18454162	The sensitivity of the different antibody clones for mesothelioma effusion samples ranged from 25% for the VU2G7 and VU4H5 clones to 100% for the Mc5 clone.	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('mesothelioma effusion', 'Disease', 'MESH:D008654', (53, 74))	('mesothelioma effusion', 'Disease', (53, 74))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('VU4H5', 'Var', (117, 122))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('VU2G7', 'Var', (107, 112))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))
81804	18454162	Alteration in MUC1 glycosylation has been reported in many malignancies (Baldus et al, 2004).	('glycosylation', 'biological_process', 'GO:0070085', ('19', '32'))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('Alteration', 'Var', (0, 10))	('reported', 'Reg', (42, 50))	('malignancies', 'Disease', (59, 71))	('MUC1', 'Gene', (14, 18))	('MUC1', 'Gene', '4582', (14, 18))
81815	18454162	Interestingly, the lack of MUC-SEC expression has been associated with ovarian cancer (Obermair et al, 2002).	('lack', 'Var', (19, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MUC-SEC expression', 'Protein', (27, 45))	('ovarian cancer', 'Disease', (71, 85))	('associated', 'Reg', (55, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))
81971	33668103	Research reported in this publication was supported by the National Institute Environmental Health Sciences of the National Institutes of Health under award number P42 ES023720, the Penn Superfund Research Program Center Grant, the Center of Excellence in Environmental Toxicology (P30 ES013508) and by a Science Education Partnership Award (SEPA) from the National Institutes of Health.	('P30 ES013508', 'Var', (282, 294))	('men', 'Species', '9606', (263, 266))	('P42 ES023720', 'Var', (164, 176))	('men', 'Species', '9606', (85, 88))
81992	26463707	Native PE has three functional domains: Domain I, which enables PE to bind to the surface of most cells, Domain II, which enables the toxin to be processed by furin separating the Fv from the toxin, and Domain III, which catalyzes the inactivation of elongation factor 2 leading to inhibition of protein synthesis and cell death.	('cell death', 'CPA', (318, 328))	('protein synthesis', 'biological_process', 'GO:0006412', ('296', '313'))	('furin', 'Gene', '5045', (159, 164))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('cell death', 'biological_process', 'GO:0008219', ('318', '328'))	('elongation factor 2', 'Gene', '1938', (251, 270))	('elongation factor 2', 'Gene', (251, 270))	('furin', 'Gene', (159, 164))	('inhibition', 'NegReg', (282, 292))	('protein synthesis', 'MPA', (296, 313))	('inactivation', 'Var', (235, 247))
82003	26463707	SS1P consists of an anti-mesothelin Fv linked to PE38.	('SS1', 'Gene', '3123', (0, 3))	('mesothelin', 'Gene', '10232', (25, 35))	('PE38', 'Var', (49, 53))	('SS1', 'Gene', (0, 3))	('mesothelin', 'Gene', (25, 35))
82017	26463707	RG7787 is very active against a variety of mesothelin expressing cell lines and is more active than SS1P against cells directly isolated from mesothelioma patients (R.H. unpublished data).	('mesothelin', 'Gene', (43, 53))	('SS1', 'Gene', '3123', (100, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('active', 'MPA', (88, 94))	('mesothelioma', 'Disease', (142, 154))	('SS1', 'Gene', (100, 103))	('patients', 'Species', '9606', (155, 163))	('mesothelin', 'Gene', '10232', (43, 53))	('RG7787', 'Var', (0, 6))
82019	26463707	Also, when RG7787 was combined with paclitaxel, it produced complete or near-complete remissions in a pancreatic cancer model in mice.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('RG7787', 'Var', (11, 17))	('paclitaxel', 'Chemical', 'MESH:D017239', (36, 46))	('mice', 'Species', '10090', (129, 133))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
82023	26463707	Most anti-cancer monoclonal antibodies have little cytotoxic activity but conjugation to tubulin inhibiting drugs to produce antibody-drug conjugates has proven beneficial in some tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('conjugation', 'biological_process', 'GO:0000746', ('74', '85'))	('antibody', 'cellular_component', 'GO:0042571', ('125', '133'))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (180, 185))	('antibody', 'cellular_component', 'GO:0019815', ('125', '133'))	('antibody', 'cellular_component', 'GO:0019814', ('125', '133'))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('antibody', 'molecular_function', 'GO:0003823', ('125', '133'))	('cancer', 'Disease', (10, 16))	('conjugation', 'Var', (74, 85))
82028	26463707	RG7787 is a de-immunized immunotoxin targeting mesothelin has just entered clinical trials for treatment of mesothelin expressing cancers.	('mesothelin', 'Gene', (108, 118))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('mesothelin', 'Gene', (47, 57))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('mesothelin', 'Gene', '10232', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mesothelin', 'Gene', '10232', (47, 57))	('RG7787', 'Var', (0, 6))
82033	24510578	D-type cyclins were effectively suppressed in mixed tissue type MSTO-211H, leading to cell cycle arrest at sub G1/G1 phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('G1 phase', 'biological_process', 'GO:0051318', ('114', '122'))	('cell cycle arrest at sub G1/G1 phase', 'CPA', (86, 122))	('MSTO-211H', 'CellLine', 'CVCL:1430', (64, 73))	('cyclin', 'Gene', '5111', (7, 13))	('cyclin', 'Gene', (7, 13))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('86', '103'))	('MSTO-211H', 'Var', (64, 73))	('suppressed', 'NegReg', (32, 42))
82151	24510578	In the subcutaneous implanted model, the pretreatment of cells with an NF-kappaB inhibitor delayed tumor growth.	('tumor', 'Disease', (99, 104))	('inhibitor', 'Var', (81, 90))	('NF-kappaB', 'Gene', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('delayed', 'NegReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('71', '90'))
82184	23951555	Several earlier studies have highlighted rearrangements on chromosome 3 in malignant mesothelioma, and we have previously shown that the frequency of rearrangements at specific break-points on chromosome 3 correlates to the degree of genomic instability in cancer cells.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (75, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (75, 97))	('rearrangements', 'Var', (41, 55))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('malignant mesothelioma', 'Disease', (75, 97))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('genomic instability', 'MPA', (234, 253))	('cancer', 'Disease', (257, 263))	('rearrangements', 'Var', (150, 164))
82219	23951555	Tumor take after 15 weeks was 3/10; two of five mice inoculated with STAV-FCS and one of five with STAV-AB cells.	('STAV-FCS', 'Var', (69, 77))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('STAV-AB', 'Chemical', '-', (99, 106))	('STAV', 'Chemical', '-', (99, 103))	('mice', 'Species', '10090', (48, 52))	('STAV', 'Chemical', '-', (69, 73))	('Tumor take', 'CPA', (0, 10))
82237	23951555	Irrespective of their original cell sub-line, xenografts derived from both cell sub-lines showed a similar pattern of chromosome 3 aberrations rather resembling the sarcomatoid STAV-FCS cells (Figure 7; Table 2).	('sarcomatoid STAV-FCS', 'Disease', (165, 185))	('chromosome', 'Var', (118, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('aberrations', 'Var', (131, 142))	('sarcomatoid STAV-FCS', 'Disease', 'MESH:D056685', (165, 185))
82239	23951555	Copy number gains were seen in the sarcomatoid STAV-FCS cell sub-line and in both xenografts.	('Copy number', 'Var', (0, 11))	('sarcomatoid STAV-FCS', 'Disease', (35, 55))	('gains', 'PosReg', (12, 17))	('sarcomatoid STAV-FCS', 'Disease', 'MESH:D056685', (35, 55))
82254	23951555	The original heterogeneity seen by cytogenetics was maintained in the xenografts, as evidenced by an increased proportion of heterogeneous subpopulation in the STAV-FCS-derived xenografts compared to the STAV-AB-derived ones.	('STAV', 'Chemical', '-', (204, 208))	('STAV-AB', 'Chemical', '-', (204, 211))	('increased', 'PosReg', (101, 110))	('STAV-FCS-derived', 'Var', (160, 176))	('heterogeneous subpopulation', 'MPA', (125, 152))	('STAV', 'Chemical', '-', (160, 164))
82265	23951555	Rearrangement at this region was shown to be characteristic for tumors with high plasticity/rearrangement rate and more aggressive genotype.	('Rearrangement', 'Var', (0, 13))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
82269	23951555	There were three common regions suggestive of increased copy number in sarcomatoid cells and both xenografts, in which some genes are of particular interest.	('sarcomatoid', 'Disease', 'MESH:C538614', (71, 82))	('increased', 'PosReg', (46, 55))	('sarcomatoid', 'Disease', (71, 82))	('copy number', 'Var', (56, 67))
82283	22329991	Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP).	('NF2', 'Gene', (58, 61))	('inactivating mutations', 'Var', (28, 50))	('transcription factor', 'molecular_function', 'GO:0000981', ('202', '222'))	('regulates', 'Reg', (188, 197))	('neurofibromatosis type 2', 'Gene', (63, 87))	('Yes-associated protein', 'Gene', (223, 245))	('NF2', 'Gene', '4771', (58, 61))	('Merlin', 'Gene', '4771', (89, 95))	('Yes-associated protein', 'Gene', '10413', (223, 245))	('transcription', 'biological_process', 'GO:0006351', ('202', '215'))	('Hippo signaling cascade', 'biological_process', 'GO:0035329', ('146', '169'))	('Merlin', 'Gene', (89, 95))	('negatively', 'NegReg', (177, 187))	('neurofibromatosis type 2', 'Gene', '4771', (63, 87))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (63, 80))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))
82286	22329991	Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens.	('patient', 'Species', '9606', (209, 216))	('Knocking down', 'Var', (0, 13))	('prolonged', 'PosReg', (42, 51))	('extracellular matrix deposition', 'CPA', (153, 184))	('CTGF expression', 'Gene', (14, 29))	('expression', 'Species', '29278', (138, 148))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('153', '173'))	('mice', 'Species', '10090', (80, 84))	('survival', 'CPA', (56, 64))	('CTGF', 'Gene', (133, 137))	('expression', 'Species', '29278', (19, 29))
82293	22329991	The NF2 gene, known to be responsible for NF2 syndrome, encodes Merlin, and deletions or mutations of this gene were found in 40-50% of MMs.	('NF2', 'Gene', (42, 45))	('NF2 syndrome', 'Disease', (42, 54))	('Merlin', 'Gene', (64, 70))	('Merlin', 'Gene', '4771', (64, 70))	('MMs', 'Disease', (136, 139))	('NF2', 'Gene', '4771', (4, 7))	('NF2 syndrome', 'Disease', 'MESH:C537392', (42, 54))	('mutations', 'Var', (89, 98))	('NF2', 'Gene', '4771', (42, 45))	('deletions', 'Var', (76, 85))	('found', 'Reg', (117, 122))	('NF2', 'Gene', (4, 7))
82296	22329991	In the conditional transgenic mouse model, the dysregulation of the pathway leads to tumorigenesis.	('tumor', 'Disease', (85, 90))	('dysregulation', 'Var', (47, 60))	('leads to', 'Reg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mouse', 'Species', '10090', (30, 35))
82297	22329991	Considering Merlin and downstream components of the Hippo cascade, SAV1 (Salvador 1) and LATS2 (large tumor suppressor 2), 75% of MM cell lines had genetic inactivation of at least one of these three proteins.	('Salvador 1', 'Gene', (73, 83))	('Merlin', 'Gene', '4771', (12, 18))	('Salvador 1', 'Gene', '60485', (73, 83))	('Merlin', 'Gene', (12, 18))	('SAV1', 'Gene', '60485', (67, 71))	('LATS2', 'Gene', (89, 94))	('LATS2', 'Gene', '26524', (89, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('SAV1', 'Gene', (67, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('large tumor suppressor 2', 'Gene', (96, 120))	('large tumor suppressor 2', 'Gene', '26524', (96, 120))	('genetic inactivation', 'Var', (148, 168))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
82299	22329991	YAP accumulation in the nucleus is also observed in MMs accompanied by mutation or deletion of LATS2.	('YAP', 'MPA', (0, 3))	('mutation', 'Var', (71, 79))	('LATS2', 'Gene', (95, 100))	('LATS2', 'Gene', '26524', (95, 100))	('deletion', 'Var', (83, 91))	('nucleus', 'cellular_component', 'GO:0005634', ('24', '31'))	('MMs', 'Disease', (52, 55))
82309	22329991	Given the involvement of genetic inactivation of components of the Hippo pathway in 75% of mesotheliomas and previous evidence for a protumorigenic role for the TGF-beta pathway, we examined the relationship between these two pathways to further understand the molecular mechanisms underlying mesothelioma genesis.	('genetic inactivation', 'Var', (25, 45))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mesothelioma genesis', 'Disease', 'MESH:D008654', (293, 313))	('mesotheliomas', 'Disease', 'MESH:D008654', (91, 104))	('mesotheliomas', 'Disease', (91, 104))	('mesothelioma genesis', 'Disease', (293, 313))	('tumor', 'Disease', (136, 141))	('involvement', 'Reg', (10, 21))
82317	22329991	We further show that antagonism of the TGF-beta pathway and CTGF expression can prolong the survival of mice with MM tumor xenografts, suggesting new approaches for the treatment of MM.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('survival', 'CPA', (92, 100))	('TGF-beta pathway', 'Pathway', (39, 55))	('MM tumor', 'Disease', (114, 122))	('prolong', 'PosReg', (80, 87))	('mice', 'Species', '10090', (104, 108))	('expression', 'Species', '29278', (65, 75))	('MM tumor', 'Disease', 'MESH:D009369', (114, 122))	('antagonism', 'Var', (21, 31))	('CTGF', 'Gene', (60, 64))
82334	22329991	Genetic alteration of the tumor suppressor gene NF2 and downstream components of the Hippo pathway, SAV1 and LATS2, were observed in 75% of MM tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Hippo pathway', 'Pathway', (85, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('MM tumors', 'Disease', (140, 149))	('NF2', 'Gene', '4771', (48, 51))	('SAV1', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('NF2', 'Gene', (48, 51))	('MM tumors', 'Disease', 'MESH:D009369', (140, 149))	('tumor', 'Disease', (26, 31))	('rat', 'Species', '10116', (12, 15))	('LATS2', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('LATS2', 'Gene', '26524', (109, 114))	('Genetic alteration', 'Var', (0, 18))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('SAV1', 'Gene', '60485', (100, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('observed', 'Reg', (121, 129))
82335	22329991	This suggests that the disturbance of the Hippo pathway is strongly associated with the development of mesothelioma.	('associated', 'Reg', (68, 78))	('mesothelioma', 'Disease', (103, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))	('Hippo pathway', 'Pathway', (42, 55))	('disturbance', 'Var', (23, 34))
82339	22329991	Thus, many genetic alterations in the Hippo pathway that have been seen in mesothelioma converge to increase YAP activity.	('YAP', 'Disease', (109, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('rat', 'Species', '10116', (23, 26))	('increase', 'PosReg', (100, 108))	('Hippo pathway', 'Pathway', (38, 51))	('mesothelioma', 'Disease', (75, 87))	('genetic alterations', 'Var', (11, 30))
82340	22329991	To analyze the possible alteration in TGF-beta response in mesothelioma cells caused by defects in the Hippo pathway, we suppressed endogenous YAP expression using short hairpin RNA (shRNA) vectors in NCI-H290 cells, which have a genetic deletion of NF2.	('NF2', 'Gene', '4771', (250, 253))	('expression', 'Species', '29278', (147, 157))	('mesothelioma', 'Disease', (59, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('suppressed', 'NegReg', (121, 131))	('endogenous', 'MPA', (132, 142))	('NF2', 'Gene', (250, 253))	('RNA', 'cellular_component', 'GO:0005562', ('178', '181'))	('deletion', 'Var', (238, 246))	('NCI-H290', 'CellLine', 'CVCL:A555', (201, 209))	('rat', 'Species', '10116', (28, 31))
82365	22329991	An immunoprecipitation assay using HEK293T cells with ectopic expression of Smad3 and p300 showed that the binding between ectopic p300 and endogenous YAP was enhanced in the presence of ectopic Smad3 (Fig.	('ectopic', 'Var', (187, 194))	('p300', 'Gene', '2033', (131, 135))	('expression', 'Species', '29278', (62, 72))	('YAP', 'Protein', (151, 154))	('enhanced', 'PosReg', (159, 167))	('p300', 'Gene', (86, 90))	('p300', 'Gene', (131, 135))	('binding', 'Interaction', (107, 114))	('HEK293T', 'CellLine', 'CVCL:0063', (35, 42))	('p300', 'Gene', '2033', (86, 90))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
82368	22329991	Furthermore, endogenous TEAD4 bound to ectopic p300 in the presence of ectopic Smad3 and with ectopic Smad3 in the presence of ectopic p300 (Fig.	('p300', 'Gene', (47, 51))	('ectopic', 'Var', (71, 78))	('p300', 'Gene', '2033', (135, 139))	('p300', 'Gene', '2033', (47, 51))	('p300', 'Gene', (135, 139))	('TEAD4', 'Gene', '7004', (24, 29))	('bound', 'Interaction', (30, 35))	('TEAD4', 'Gene', (24, 29))
82370	22329991	TGF-beta treatment further increased the amount of p-Smad3 that was immunoprecipitated with TEAD4 (Fig.	('TEAD4', 'Gene', '7004', (92, 97))	('p-Smad3', 'Var', (51, 58))	('increased', 'PosReg', (27, 36))	('TEAD4', 'Gene', (92, 97))
82381	22329991	Interestingly, CTGF expression showed the same response as the constitutive activation of the TGF-beta type I receptor, which showed aggressive formation of foci, whereas the knockdown of CTGF reduced the number of foci (Fig.	('TGF-beta type I receptor', 'Gene', '7046', (94, 118))	('formation', 'biological_process', 'GO:0009058', ('144', '153'))	('reduced', 'NegReg', (193, 200))	('knockdown', 'Var', (175, 184))	('TGF-beta type I receptor', 'Gene', (94, 118))	('CTGF', 'Gene', (188, 192))	('expression', 'Species', '29278', (20, 30))
82387	22329991	The knockdown of CTGF expression abolished the aggressive formation of foci induced by the constitutively activated TGF-beta type I receptor (Fig.	('expression', 'Species', '29278', (22, 32))	('aggressive formation of foci', 'CPA', (47, 75))	('TGF-beta type I receptor', 'Gene', (116, 140))	('TGF-beta type I receptor', 'Gene', '7046', (116, 140))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('abolished', 'NegReg', (33, 42))	('knockdown', 'Var', (4, 13))	('CTGF', 'Gene', (17, 21))
82390	22329991	Of note, the amount of stroma, which plays an important role in the cancer microenvironment, also appeared to strongly correlate with CTGF expression in MMs, suggesting that CTGF regulates the growth of MMs and also leads to a tumor environment suitable for their growth.	('growth', 'MPA', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('leads to', 'Reg', (216, 224))	('tumor', 'Disease', (227, 232))	('regulates', 'Reg', (179, 188))	('MMs', 'CPA', (203, 206))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('expression', 'Species', '29278', (139, 149))	('CTGF', 'Var', (174, 178))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
82391	22329991	Based on the aforementioned findings implicating TGF-beta signaling and CTGF in MM cell and tumor growth, we determined whether inhibition of TGF-beta type I receptor signaling and CTGF expression induces growth suppression of MM tumors in a mouse model.	('MM tumors', 'Disease', (227, 236))	('tumor', 'Disease', (230, 235))	('TGF-beta type I receptor', 'Gene', (142, 166))	('TGF-beta type I receptor', 'Gene', '7046', (142, 166))	('MM tumors', 'Disease', 'MESH:D009369', (227, 236))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('mouse', 'Species', '10090', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('expression', 'Species', '29278', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('inhibition', 'Var', (128, 138))	('growth suppression', 'CPA', (205, 223))	('CTGF', 'Gene', (181, 185))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
82416	22329991	Because at least 75% of MM tumors have a disturbance in the Hippo signaling pathway, this type of tumor mostly relies on this pathway for oncogenesis, whereas only 20-25% of MM tumors have a p53 mutation, which is the most frequently inactivated tumor suppressor gene in human malignancies.	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('60', '83'))	('p53', 'Gene', '7157', (191, 194))	('mutation', 'Var', (195, 203))	('MM tumors', 'Disease', 'MESH:D009369', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (27, 32))	('disturbance', 'Reg', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('human', 'Species', '9606', (271, 276))	('p53', 'Gene', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MM tumors', 'Disease', (24, 33))	('tumor', 'Disease', (177, 182))	('malignancies', 'Disease', 'MESH:D009369', (277, 289))	('malignancies', 'Disease', (277, 289))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('246', '262'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Hippo signaling pathway', 'Pathway', (60, 83))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MM tumors', 'Disease', (174, 183))	('tumor', 'Disease', (246, 251))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('246', '262'))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('oncogenesis', 'biological_process', 'GO:0007048', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('MM tumors', 'Disease', 'MESH:D009369', (24, 33))
82425	22329991	Consistent with previous data showing that inactivation of the NF2 and Hippo pathway is the most frequent defect in mesothelioma, immunohistochemical analysis of MM specimens revealed overexpression and nuclear accumulation of YAP, whereas no signals were observed in normal pleural mesothelial cells.	('expression', 'Species', '29278', (188, 198))	('mesothelioma', 'Disease', (116, 128))	('pleural mesothelial', 'Disease', 'MESH:D018301', (275, 294))	('NF2', 'Gene', (63, 66))	('Hippo pathway', 'Pathway', (71, 84))	('nuclear', 'MPA', (203, 210))	('pleural mesothelial', 'Disease', (275, 294))	('YAP', 'Gene', (227, 230))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('NF2', 'Gene', '4771', (63, 66))	('overexpression', 'PosReg', (184, 198))	('inactivation', 'Var', (43, 55))
82426	22329991	In looking for synergy between the inactivation of the Hippo pathway and TGF-beta signaling, we found that knocking down YAP, which predominantly resides in the nucleus of NCI-H290 cells, affected only a small portion of TGF-beta-responsive genes, suggesting that functional association between YAP and Smad2/3 only occurs under a specific situation.	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('nucleus', 'cellular_component', 'GO:0005634', ('161', '168'))	('TGF-beta-responsive', 'Gene', (221, 240))	('Smad2/3', 'Gene', '4087;4088', (303, 310))	('knocking down', 'Var', (107, 120))	('affected', 'Reg', (188, 196))	('YAP', 'Gene', (121, 124))	('NCI-H290', 'CellLine', 'CVCL:A555', (172, 180))	('Smad2/3', 'Gene', (303, 310))
82433	22329991	In addition to recent studies that indicate that tumor cell-derived CTGF plays an important role in the proliferation of breast cancer cells and growth of pancreatic tumors, CTGF also affects vascularization, migration, and epithelial-mesenchymal transition in the context of oncogenic properties.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pancreatic tumors', 'Disease', 'MESH:D010190', (155, 172))	('pancreatic tumors', 'Disease', (155, 172))	('CTGF', 'Var', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('vascularization', 'CPA', (192, 207))	('rat', 'Species', '10116', (111, 114))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('224', '257'))	('epithelial-mesenchymal transition', 'CPA', (224, 257))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('rat', 'Species', '10116', (212, 215))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (49, 54))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (155, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('migration', 'CPA', (209, 218))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('affects', 'Reg', (184, 191))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('breast cancer', 'Disease', (121, 134))
82450	22329991	Our findings propose Smad3 and YAP to be the factors influencing expression of CTGF, and we show for the first time that CTGF might be a strong candidate for molecularly targeted therapy, affecting both mesothelioma cell growth and the tumor microenvironment.	('CTGF', 'Var', (121, 125))	('mesothelioma cell growth', 'Disease', (203, 227))	('CTGF', 'Gene', (79, 83))	('cell growth', 'biological_process', 'GO:0016049', ('216', '227'))	('affecting', 'Reg', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('expression', 'Species', '29278', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))	('mesothelioma cell growth', 'Disease', 'MESH:D008654', (203, 227))
82466	22329991	Extracted mRNA was subjected to generate cRNA, which was labeled with Cy3 or Cy5 (GE Healthcare) using a low RNA Fluorescent Linear Amplification kit (Agilent Technologies) according to the manufacturer's protocol.	('Cy5', 'Var', (77, 80))	('Cy3', 'Chemical', '-', (70, 73))	('Cy5', 'Chemical', 'MESH:C085321', (77, 80))	('rat', 'Species', '10116', (36, 39))	('Cy3', 'Var', (70, 73))	('RNA', 'cellular_component', 'GO:0005562', ('109', '112'))
82474	22329991	The antibodies used for immunohistochemical staining were anti-p-Smad2, p-specific (Ser 463/467; Millipore), YAP (H-125; Santa Cruz Biotechnology, Inc.), and CTGF (L-20; Santa Cruz Biotechnology, Inc.).	('L-20', 'Gene', '28876', (164, 168))	('anti-p-Smad2', 'Var', (58, 70))	('Ser', 'Chemical', 'MESH:D012694', (84, 87))	('L-20', 'Gene', (164, 168))	('Ser', 'cellular_component', 'GO:0005790', ('84', '87'))
82566	18770046	This may be explained, in part, by the rarity of EGFR mutations in mesothelioma.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('mutations', 'Var', (54, 63))	('mesothelioma', 'Disease', (67, 79))
82569	18770046	High serum VEGF, a negative prognostic factor in this disease, is inversely correlated with survival.	('VEGF', 'Gene', (11, 15))	('inversely', 'NegReg', (66, 75))	('High serum', 'Var', (0, 10))	('VEGF', 'Gene', '7422', (11, 15))
82697	22905093	Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed.	('mesothelioma', 'Disease', (25, 37))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (80, 90))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('NT5C', 'Gene', '30833', (13, 17))	('NT5C', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))
82704	22905093	Thymidylate synthase is considered the main target of pemetrexed and current studies indicate that low expression levels of this protein is predictive for good pemetrexed response, longer time to progression and overall survival, but the mechanisms and pathways involved in pemetrexed resistance are inadequately elucidated.	('pemetrexed', 'Chemical', 'MESH:D000068437', (160, 170))	('pemetrexed', 'Chemical', 'MESH:D000068437', (54, 64))	('pemetrexed', 'Chemical', 'MESH:D000068437', (274, 284))	('expression levels', 'MPA', (103, 120))	('low', 'Var', (99, 102))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('Thymidylate synthase', 'Gene', '7298', (0, 20))	('Thymidylate synthase', 'Gene', (0, 20))
82788	22905093	Low TS expression increases the pemetrexed response in vitro.	('pemetrexed', 'Chemical', 'MESH:D000068437', (32, 42))	('pemetrexed response', 'CPA', (32, 51))	('increases', 'PosReg', (18, 27))	('TS', 'Gene', '7298', (4, 6))	('Low', 'Var', (0, 3))
82790	22905093	After resistance, TS staining increased from below 1% to 25% of the cells (Table 1, Fig 4) while TYMS mRNA did not change.	('TYMS', 'Gene', '7298', (97, 101))	('resistance', 'Var', (6, 16))	('TYMS', 'Gene', (97, 101))	('increased', 'PosReg', (30, 39))	('TS', 'Gene', '7298', (18, 20))
82807	22905093	Silencing of this gene in prostate cancer sensitizes the tumour cells to both irradiation and doxorubicin as well as reversal of acquired resistance to gemcitabine, which also showed cross-resistance to pemetrexed in cell lines with acquired resistance.	('tumour', 'Disease', (57, 63))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Silencing', 'Var', (0, 9))	('pemetrexed', 'Chemical', 'MESH:D000068437', (203, 213))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('acquired resistance', 'MPA', (129, 148))	('gemcitabine', 'Chemical', 'MESH:C056507', (152, 163))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))	('sensitizes', 'Reg', (42, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
82821	22905093	DNA is the main cytotoxic target of cisplatin and carboplatin by the induction of single and double-strand DNA breaks through adducts and cross-linking, leading to cell death through apoptosis.	('single', 'Var', (82, 88))	('cell death', 'biological_process', 'GO:0008219', ('164', '174'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cell death', 'CPA', (164, 174))	('adducts', 'Var', (126, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('DNA', 'Gene', (107, 110))	('cross-linking', 'Var', (138, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('carboplatin', 'Chemical', 'MESH:D016190', (50, 61))	('apoptosis', 'CPA', (183, 192))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))
82830	22905093	Homozygous mutation of LIG3 confers a high risk for pancreatic and other forms of cancer.	('pancreatic', 'Disease', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Homozygous mutation', 'Var', (0, 19))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('LIG3', 'Gene', '3980', (23, 27))	('pancreatic', 'Disease', 'MESH:D010195', (52, 62))	('LIG3', 'Gene', (23, 27))
82846	22905093	Here, CDH5 or vascular endothelial cadherin is a key protein controlling the endothelial barrier and its disruption by specific antibody both amplifies metastasis in normal mice and overcomes the genetic resistance in mice.	('vascular endothelial cadherin', 'Gene', (14, 43))	('disruption', 'Var', (105, 115))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('metastasis', 'CPA', (152, 162))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('amplifies', 'PosReg', (142, 151))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('overcomes', 'NegReg', (182, 191))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('CDH5', 'Gene', (6, 10))	('mice', 'Species', '10090', (218, 222))	('vascular endothelial cadherin', 'Gene', '12562', (14, 43))	('genetic resistance', 'CPA', (196, 214))	('mice', 'Species', '10090', (173, 177))
82851	22905093	Importantly, another tight junction gene, OCLN, occludin, was shown to be closely involved in resistance to apoptogenes as cisplatin and gamma irradiation, and re-expression of OCLN sensitized cancer cells to these agents.	('OCLN', 'Gene', '100506658', (42, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('re-expression', 'Var', (160, 173))	('OCLN', 'Gene', (42, 46))	('involved', 'Reg', (82, 90))	('occludin', 'Gene', (48, 56))	('sensitized', 'Reg', (182, 192))	('cancer', 'Disease', (193, 199))	('OCLN', 'Gene', '100506658', (177, 181))	('OCLN', 'Gene', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('occludin', 'Gene', '100506658', (48, 56))	('tight junction', 'cellular_component', 'GO:0070160', ('21', '35'))
82856	22905093	JAM2/JAMB inhibition decreases leukocyte infiltration.	('decreases', 'NegReg', (21, 30))	('JAM2', 'Gene', (0, 4))	('JAMB', 'Gene', (5, 9))	('JAMB', 'Gene', '58494', (5, 9))	('JAM2', 'Gene', '58494', (0, 4))	('decreases leukocyte', 'Phenotype', 'HP:0001882', (21, 40))	('leukocyte infiltration', 'MPA', (31, 53))	('inhibition', 'Var', (10, 20))
82863	22905093	Positivity for CK7 in more then 75% of cells is regularly observed in several types of carcinoma (www.proteinatlas.org), as well as mesotheliomas, but to our knowledge there has not been reported such a degree of augmentation of immunoreactivity for cytokeratins in the course of therapy resistance in carcinomas, nor in mesothelioma.	('augmentation', 'PosReg', (213, 225))	('mesothelioma', 'Disease', 'MESH:D008654', (321, 333))	('mesotheliomas', 'Disease', 'MESH:D008654', (132, 145))	('mesothelioma', 'Disease', (321, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('carcinomas', 'Disease', 'MESH:D002277', (302, 312))	('carcinoma', 'Disease', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('carcinoma', 'Disease', (302, 311))	('CK7', 'Gene', (15, 18))	('immunoreactivity', 'MPA', (229, 245))	('carcinoma', 'Disease', 'MESH:D002277', (87, 96))	('carcinoma', 'Disease', 'MESH:D002277', (302, 311))	('carcinomas', 'Disease', (302, 312))	('CK7', 'Gene', '3855', (15, 18))	('mesotheliomas', 'Disease', (132, 145))	('mesothelioma', 'Disease', (132, 144))	('Positivity', 'Var', (0, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (132, 144))
82878	22905093	Low p27 also was predictive to survival of breast cancer after fluorouracil, cyclophosphamide, and methotrexate treatment.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('p27', 'Gene', '3429', (4, 7))	('p27', 'Gene', (4, 7))	('predictive to', 'Reg', (17, 30))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (77, 93))	('methotrexate', 'Chemical', 'MESH:D008727', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('fluorouracil', 'Chemical', 'MESH:D005472', (63, 75))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('Low', 'Var', (0, 3))
82886	22905093	NQO1 is a detoxifying reductase, where lack of function in somatic cells is related to increased benzene oncogenesis and inactivating polymorphism has been related to dismal prognosis and predictive of treatment failure in breast cancer.	('increased', 'PosReg', (87, 96))	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('inactivating polymorphism', 'Var', (121, 146))	('breast cancer', 'Disease', (223, 236))	('NQO1', 'Gene', (0, 4))	('oncogenesis', 'biological_process', 'GO:0007048', ('105', '116'))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('benzene oncogenesis', 'MPA', (97, 116))	('NQO1', 'Gene', '1728', (0, 4))	('benzene', 'Chemical', 'MESH:D001554', (97, 104))
82895	22905093	Silencing of RAD21 gene expression decreased cell growth and enhanced cytotoxicity of etoposide and bleomycin in human breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('enhanced', 'PosReg', (61, 69))	('etoposide', 'Chemical', 'MESH:D005047', (86, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('breast cancer', 'Disease', (119, 132))	('Silencing', 'Var', (0, 9))	('bleomycin', 'Chemical', 'MESH:D001761', (100, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('RAD', 'biological_process', 'GO:1990116', ('13', '16'))	('decreased', 'NegReg', (35, 44))	('RAD21', 'Gene', (13, 18))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))	('RAD21', 'Gene', '5885', (13, 18))	('cytotoxicity', 'Disease', (70, 82))	('cell growth', 'CPA', (45, 56))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))	('human', 'Species', '9606', (113, 118))
82921	22905093	Gene silencing of RAN induces aberrant mitotic spindle formation, mitochondrial dysfunction, and apoptosis.	('RAN', 'Gene', (18, 21))	('spindle formation', 'biological_process', 'GO:0051225', ('47', '64'))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (66, 91))	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('39', '54'))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (66, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('RAN', 'Gene', '5901', (18, 21))	('Gene silencing', 'Var', (0, 14))	('mitochondrial dysfunction', 'Disease', (66, 91))	('apoptosis', 'CPA', (97, 106))	('induces', 'Reg', (22, 29))
82956	33020246	It is an antibody-mediated autoimmune glomerular disease, where approximately 70% of patients will produce autoantibodies to the M-type phospholipase A2 receptor (PLA2R) on glomerular podocytes.	('phospholipase A2 receptor', 'Gene', (136, 161))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('PLA2R', 'Gene', (163, 168))	('phospholipase A2 receptor', 'Gene', '22925', (136, 161))	('autoantibodies', 'Var', (107, 121))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('phospholipase A', 'molecular_function', 'GO:0004623', ('136', '151'))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('patients', 'Species', '9606', (85, 93))	('autoimmune glomerular disease', 'Disease', 'MESH:D007674', (27, 56))	('glomerular disease', 'Phenotype', 'HP:0100820', (38, 56))	('autoimmune glomerular disease', 'Disease', (27, 56))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('PLA2R', 'Gene', '22925', (163, 168))
83014	33020246	Those with the sarcomatoid and biphasic histologic subtypes have more aggressive disease.	('aggressive disease', 'Disease', (70, 88))	('biphasic', 'Var', (31, 39))	('sarcomatoid', 'Disease', (15, 26))	('aggressive disease', 'Disease', 'MESH:D001523', (70, 88))	('sarcomatoid', 'Disease', 'MESH:C538614', (15, 26))
83020	33020246	Cyclophosphamide, an alkylating agent, non-discriminatorily crosslinks DNA resulting in absolute lymphopenia in both T and B cells and is associated with increase cancer risk.	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('lymphopenia', 'Disease', (97, 108))	('increase cancer', 'Disease', (154, 169))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('increase cancer', 'Disease', 'MESH:D009369', (154, 169))	('lymphopenia', 'Phenotype', 'HP:0001888', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lymphopenia', 'Disease', 'MESH:D008231', (97, 108))	('Cyclophosphamide', 'Var', (0, 16))	('non-discriminatorily', 'Var', (39, 59))
83029	33020246	This could suggest that while CPIs may trigger the irAE(s), the underlying B cell pathophysiology of the disease remains unchanged.	('CPIs', 'Var', (30, 34))	('trigger', 'Reg', (39, 46))	('CPIs', 'Chemical', '-', (30, 34))
83154	29354180	In turn, labeling estrogen receptors enables the detection of breast cancer metastases.	('breast cancer metastases', 'Disease', (62, 86))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer metastases', 'Disease', 'MESH:D009362', (62, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('labeling', 'Var', (9, 17))	('estrogen receptors', 'Protein', (18, 36))
83179	29354180	The very aggressive surgical treatment in the form of extrapleural pneumonectomy can be performed in patients with: Karnofsky Performance Score > 70 pts, normal renal and liver function, thrombocytosis (> 400 000/mm3), leukocytosis (> 8300/mm3).	('> 8300/mm3', 'Var', (233, 243))	('patients', 'Species', '9606', (101, 109))	('> 400 000/mm3', 'Var', (203, 216))	('thrombocytosis', 'Disease', 'MESH:D013922', (187, 201))	('leukocytosis', 'Disease', (219, 231))	('thrombocytosis', 'Disease', (187, 201))	('leukocytosis', 'Disease', 'MESH:D007964', (219, 231))	('leukocytosis', 'Phenotype', 'HP:0001974', (219, 231))	('thrombocytosis', 'Phenotype', 'HP:0001894', (187, 201))	('men', 'Species', '9606', (34, 37))
83315	33660947	For CK20, 15 (11.0%) patients were evaluated, eight (5.9%) were positive +++, six (4.4%) were ++ and one (0.7%) was +.	('CK20', 'Gene', (4, 8))	('+++', 'Var', (73, 76))	('CK20', 'Gene', '54474', (4, 8))
83701	25026285	Indeed, high CD157 was a negative prognostic factor and an independent predictor of poor survival for patients with biphasic MPM by multivariate survival analysis (HR = 2.433, 95% CI 1.120-5.284; p = 0.025).	('high', 'Var', (8, 12))	('poor', 'NegReg', (84, 88))	('negative', 'NegReg', (25, 33))	('patients', 'Species', '9606', (102, 110))	('CD157', 'Gene', (13, 18))
83702	25026285	In mesothelioma cell lines, CD157 gain (in CD157-negative cells) or knockdown (in CD157-positive cells) affected cell growth, migration, invasion and tumorigenicity, most notably in biphasic MPM cell lines.	('gain', 'PosReg', (34, 38))	('invasion', 'CPA', (137, 145))	('mesothelioma', 'Disease', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CD157', 'Gene', (28, 33))	('cell growth', 'CPA', (113, 124))	('knockdown', 'Var', (68, 77))	('affected', 'Reg', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('cell growth', 'biological_process', 'GO:0016049', ('113', '124'))	('migration', 'CPA', (126, 135))	('tumor', 'Disease', (150, 155))
83703	25026285	In these cells, CD157 expression was associated with increased activation of the mTOR signaling pathway, resulting in decreased platinum sensitivity.	('CD157', 'Var', (16, 21))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('platinum sensitivity', 'CPA', (128, 148))	('signaling pathway', 'biological_process', 'GO:0007165', ('86', '103'))	('decreased', 'NegReg', (118, 127))	('mTOR signaling pathway', 'Pathway', (81, 103))	('expression', 'MPA', (22, 32))	('increased activation', 'PosReg', (53, 73))
83714	25026285	In the last decade, we established that CD157 (BST1), a glycosylphosphatidylinositol (GPI)-anchored member of the NADase/ADP-ribosyl cyclase gene family, regulates cytoskeleton reorganization and diapedesis in human leukocytes by a non-enzymatic receptor activity.	('diapedesis', 'MPA', (196, 206))	('diapedesis', 'biological_process', 'GO:0050904', ('196', '206'))	('CD157', 'Var', (40, 45))	('GPI', 'Chemical', 'MESH:D017261', (86, 89))	('regulates', 'Reg', (154, 163))	('BST1', 'Gene', '683', (47, 51))	('receptor activity', 'molecular_function', 'GO:0038023', ('246', '263'))	('human', 'Species', '9606', (210, 215))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('164', '176'))	('receptor activity', 'molecular_function', 'GO:0038024', ('246', '263'))	('BST1', 'Gene', (47, 51))	('glycosylphosphatidylinositol', 'Chemical', 'MESH:D017261', (56, 84))	('cytoskeleton reorganization', 'CPA', (164, 191))
83732	25026285	By Kaplan-Meier analysis, median survival was 13.067 months in patients with biphasic MPM and CD157 H-score >50 (95% CI = 4.771 to 21.362); with CD157 H-score <=50, the median survival was 20.433 months (95% CI = 16.546 to 24.321; log-rank test p = 0.037) (Fig.	('CD157', 'Var', (145, 150))	('CD157', 'Var', (94, 99))	('patients', 'Species', '9606', (63, 71))
83733	25026285	Kaplan-Meier analysis stratified by CD157 subcellular localization demonstrated that median OS was 13.067 months (95% CI = 7.509 to 18.624) for biphasic MPM patients with membrane CD157 and 18.633 months (95% CI = 13.301 to 23.966; log-rank test p = 0.039) for patients with cytoplasmic CD157 (Supplementary Fig.	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('MPM', 'Disease', (153, 156))	('biphasic', 'Disease', (144, 152))	('patients', 'Species', '9606', (157, 165))	('membrane', 'cellular_component', 'GO:0016020', ('171', '179'))	('patients', 'Species', '9606', (261, 269))	('membrane CD157', 'Var', (171, 185))
83742	25026285	Contrasting with the impact of CD157 in biphasic MPM cell lines, epithelioid cell line morphology and fibronectin expression remained essentially unchanged by modulation of CD157 (Fig.	('fibronectin', 'Gene', '2335', (102, 113))	('modulation', 'Var', (159, 169))	('epithelioid cell line morphology', 'CPA', (65, 97))	('CD157', 'Gene', (173, 178))	('fibronectin', 'Gene', (102, 113))
83743	25026285	In cell proliferation assays, CD157 expression affected the biphasic, but not epithelioid, MPM cell lines: loss of CD157 significantly reduced the growth of CG98 but not of MPP89 cells compared to their CD157-positive controls, whereas forced expression of CD157 enhanced the growth of MSTO but not those of REN cells (Fig.	('growth', 'MPA', (276, 282))	('MPP', 'molecular_function', 'GO:0004240', ('173', '176'))	('loss', 'Var', (107, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('3', '21'))	('growth', 'MPA', (147, 153))	('reduced', 'NegReg', (135, 142))	('REN', 'Gene', (308, 311))	('CG98', 'Chemical', '-', (157, 161))	('CD157', 'Gene', (115, 120))	('enhanced', 'PosReg', (263, 271))	('REN', 'Gene', '5972', (308, 311))
83744	25026285	As a further marker of cell growth, plating efficiency was examined: CD157 knockdown reduced the number and size of colonies in CG98 cells whereas CD157 expression significantly increased plating efficiency in MSTO cells.	('cell growth', 'biological_process', 'GO:0016049', ('23', '34'))	('plating efficiency', 'CPA', (188, 206))	('CG98', 'Chemical', '-', (128, 132))	('CD157', 'Gene', (147, 152))	('knockdown', 'Var', (75, 84))	('CD157', 'Gene', (69, 74))	('reduced', 'NegReg', (85, 92))	('increased', 'PosReg', (178, 187))
83750	25026285	First, in wound healing scratch assays, CD157 knockdown in CG98 cells led to a marked reduction (~25%) in wound closure at 24 hours compared to CD157-positive CG98 cells.	('reduction', 'NegReg', (86, 95))	('CG98', 'Chemical', '-', (59, 63))	('CD157', 'Gene', (40, 45))	('wound healing', 'biological_process', 'GO:0042060', ('10', '23'))	('knockdown', 'Var', (46, 55))	('CG98', 'Chemical', '-', (159, 163))	('wound closure at 24 hours', 'CPA', (106, 131))
83751	25026285	Gain or loss of CD157 did not affect motility in the epithelioid MPP89 and REN cells (Fig.	('CD157', 'Gene', (16, 21))	('REN', 'Gene', (75, 78))	('MPP', 'molecular_function', 'GO:0004240', ('65', '68'))	('loss', 'Var', (8, 12))	('REN', 'Gene', '5972', (75, 78))
83753	25026285	CD157 knockdown in biphasic CG98 decreased cell invasion compared to the CD157-positive counterpart.	('knockdown', 'Var', (6, 15))	('cell invasion', 'CPA', (43, 56))	('decreased', 'NegReg', (33, 42))	('CG98', 'Chemical', '-', (28, 32))
83757	25026285	By western blot, mTOR phosphorylation was evident in all the MPM cell lines analysed; however, phospho-mTOR (p-mTOR) and phospho-p70S6K (p-p70S6K) were more elevated in CG98 and MSTO biphasic cell lines expressing CD157 (endogenous or exogenous) than in their CD157-negative counterparts.	('CD157', 'Var', (214, 219))	('elevated', 'PosReg', (157, 165))	('phospho-mTOR', 'MPA', (95, 107))	('CG98', 'Chemical', '-', (169, 173))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('phospho-p70S6K', 'MPA', (121, 135))
83758	25026285	Gain or loss of CD157 expression in MPP89 and REN epithelioid cell lines did not significantly perturb the phosphorylation status of mTOR and p70S6K (Fig.	('CD157', 'Gene', (16, 21))	('perturb', 'Reg', (95, 102))	('REN', 'Gene', (46, 49))	('MPP', 'molecular_function', 'GO:0004240', ('36', '39'))	('phosphorylation status', 'MPA', (107, 129))	('Gain', 'PosReg', (0, 4))	('mTOR', 'Protein', (133, 137))	('loss', 'NegReg', (8, 12))	('p70S6K', 'Var', (142, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('REN', 'Gene', '5972', (46, 49))
83761	25026285	Biphasic cell lines expressing CD157 were significantly more resistant to both CDDP and CPT than their CD157-negative counterparts.	('CDDP', 'Chemical', '-', (79, 83))	('CPT', 'Chemical', 'MESH:D016190', (88, 91))	('resistant', 'CPA', (61, 70))	('CPT', 'molecular_function', 'GO:0004142', ('88', '91'))	('CD157', 'Var', (31, 36))	('CPT', 'molecular_function', 'GO:0004095', ('88', '91'))
83764	25026285	MSTO CD157-positive cells were significantly more resistant to both CDDP and CPT treatment, and showed a markedly increased IC50 value compared to MSTO CD157-negative cells (Fig.	('CPT', 'Chemical', 'MESH:D016190', (77, 80))	('CD157-positive', 'Var', (5, 19))	('CPT', 'molecular_function', 'GO:0004142', ('77', '80'))	('increased', 'PosReg', (114, 123))	('CDDP', 'Chemical', '-', (68, 72))	('CPT', 'molecular_function', 'GO:0004095', ('77', '80'))	('IC50 value', 'MPA', (124, 134))
83773	25026285	However, when chemotherapy-treated or untreated biphasic MPM patients were grouped according to CD157 H-score, the group with chemotherapy and CD157 H-score >50 showed a clear trend towards shorter survival than the group with chemotherapy and CD157 H-score <=50, although the difference was not statistically significant (log-rank test p = 0.062) (Fig.	('CD157 H-score >50', 'Var', (143, 160))	('patients', 'Species', '9606', (61, 69))	('survival', 'MPA', (198, 206))	('shorter', 'NegReg', (190, 197))
83776	25026285	These data suggest that CD157 could be a promising candidate as a predictive marker of response to platinum-based therapy in biphasic MPM patients.	('platinum', 'Chemical', 'MESH:D010984', (99, 107))	('CD157', 'Var', (24, 29))	('biphasic', 'Disease', (125, 133))	('patients', 'Species', '9606', (138, 146))	('response to platinum', 'biological_process', 'GO:0070541', ('87', '107'))
83778	25026285	High CD157 expression was found consistently associated with exacerbated tumor aggressiveness in the biphasic histotype both in vitro and in vivo.	('CD157', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor aggressiveness', 'Disease', (73, 93))	('exacerbated', 'PosReg', (61, 72))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (73, 93))
83783	25026285	This is supported by the observation that the expression of CD157 emphasized some distinctive mesenchymal properties of biphasic CG98 and MSTO MPM cell lines, such as spindle-shape morphology, motility, invasiveness and resistance to chemotherapy.	('invasiveness', 'CPA', (203, 215))	('resistance to chemotherapy', 'CPA', (220, 246))	('expression', 'Var', (46, 56))	('CD157', 'Gene', (60, 65))	('mesenchymal properties', 'CPA', (94, 116))	('spindle-shape morphology', 'CPA', (167, 191))	('motility', 'CPA', (193, 201))	('CG98', 'Chemical', '-', (129, 133))	('emphasized', 'PosReg', (66, 76))	('spindle', 'cellular_component', 'GO:0005819', ('167', '174'))
83785	25026285	However, when cultured in the presence of a surrogate ECM (such as Matrigel) that generates a more permissive environment, CD157-positive epithelioid REN cells showed enhanced invasiveness with respect to CD157-negative cells.	('REN', 'Gene', '5972', (150, 153))	('enhanced', 'PosReg', (167, 175))	('invasiveness', 'CPA', (176, 188))	('REN', 'Gene', (150, 153))	('CD157-positive', 'Var', (123, 137))
83792	25026285	However, patients with high and membrane-localized CD157 expression had a worse prognosis than patients with cytoplasmic localization, further corroborating the notion that the interaction with currently unidentified components in the tumor microenvironment is critical for CD157 to exert its functions.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('high', 'Var', (23, 27))	('patients', 'Species', '9606', (95, 103))	('localization', 'biological_process', 'GO:0051179', ('121', '133'))	('expression', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('interaction', 'Interaction', (177, 188))	('tumor', 'Disease', (235, 240))	('CD157', 'Gene', (51, 56))	('membrane', 'cellular_component', 'GO:0016020', ('32', '40'))
83799	25026285	Although further studies are required before drawing definitive conclusions, clinical data indicated that patients with biphasic MPM and high CD157 H-score receiving platinum-based therapy had shorter survival than patients with low CD157 H-score.	('patients', 'Species', '9606', (215, 223))	('survival', 'MPA', (201, 209))	('platinum', 'Chemical', 'MESH:D010984', (166, 174))	('patients', 'Species', '9606', (106, 114))	('high CD157 H-score', 'Var', (137, 155))	('shorter', 'NegReg', (193, 200))
83808	25026285	Anti-mTOR (L24D4, #4517), anti-phospho-mTOR (Ser2448/49F9, #2976), anti-p70S6K (49D7, #2708) and anti-phospho-p70S6K (Thr389/1A5, #9206) antibodies were from Cell Signalling Technology.	('Ser', 'cellular_component', 'GO:0005790', ('45', '48'))	('L24D4', 'Var', (11, 16))	('Signalling', 'biological_process', 'GO:0023052', ('163', '173'))	('Ser2448/49F9', 'Var', (45, 57))	('anti-p70S6K', 'Var', (67, 78))	('Ser2448', 'Chemical', '-', (45, 52))	('Thr389', 'Chemical', '-', (118, 124))
83823	25026285	Each cycle consisted of denaturation at 95 C for 10 s, annealing for 10 s and extension at 72 C for 1 s. The primers used were as follow: CD157, 5'-CCAAAGTTCCCCGATGGCGGCC-3' (forward) and 5'-GGTTAGAGCAACACAGTTTCC-3' (reverse), GAPDH, 5'-GAGTCAACGGATTTGGTCGT-3' (forward) and 5'-TTGATTTTGGAGGGATCTCG-3' (reverse).	('GAPDH', 'Gene', (227, 232))	('CD157', 'Var', (138, 143))	('GAPDH', 'Gene', '2597', (227, 232))
83948	24491244	For appendiceal tumors, patients with low grade mucinous carcinoma peritonei (which is also described as disseminated peritoneal adenomucinosis or pseudomyxoma peritonei (PMP)) experience better clinical outcomes than those with higher grade non-mucinous appendiceal malignancies.	('appendiceal malignancies', 'Disease', 'MESH:D001063', (255, 279))	('low grade', 'Var', (38, 47))	('better', 'PosReg', (188, 194))	('adenomucinosis or pseudomyxoma peritonei', 'Disease', (129, 169))	('adenomucinosis or pseudomyxoma peritonei', 'Disease', 'MESH:D011553', (129, 169))	('appendiceal tumors', 'Disease', 'MESH:D001063', (4, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('patients', 'Species', '9606', (24, 32))	('appendiceal tumors', 'Disease', (4, 22))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (48, 66))	('appendiceal malignancies', 'Disease', (255, 279))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (48, 66))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mucinous carcinoma', 'Disease', (48, 66))
83961	24491244	This finding confirms data from our institution, and others, that demonstrate a significant survival advantage for patients undergoing R0/R1 resection compared to those with R2 resections.	('patients', 'Species', '9606', (115, 123))	('R0/R1 resection', 'Var', (135, 150))	('survival', 'CPA', (92, 100))
84022	20651364	Stem cell migration in vitro was enhanced by exogenous SDF1 and abrogated by CXCR4 inhibition and.	('SDF1', 'Gene', '20315', (55, 59))	('cell migration', 'biological_process', 'GO:0016477', ('5', '19'))	('CXCR4', 'molecular_function', 'GO:0038147', ('77', '82'))	('SDF1', 'Gene', (55, 59))	('abrogated', 'NegReg', (64, 73))	('enhanced', 'PosReg', (33, 41))	('exogenous', 'Var', (45, 54))
84043	20651364	In epithelial ovarian carcinoma and gastric cancer, CXCR4 expression enhances peritoneal metastasis, a pathogenic feature similar to diffuse malignant mesothelioma.	('CXCR4 expression', 'Var', (52, 68))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (3, 31))	('malignant mesothelioma', 'Disease', (141, 163))	('peritoneal metastasis', 'CPA', (78, 99))	('gastric cancer', 'Disease', (36, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (141, 163))	('epithelial ovarian carcinoma', 'Disease', (3, 31))	('enhances', 'PosReg', (69, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('CXCR4', 'molecular_function', 'GO:0038147', ('52', '57'))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (14, 31))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (141, 163))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
84047	20651364	In cancer therapy, AMD3100 synergizes with cytotoxic chemotherapy in gliomas by decreasing activation of the Akt survival pathway.	('AMD3100', 'Var', (19, 26))	('decreasing', 'NegReg', (80, 90))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Disease', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('Akt', 'Gene', '11651', (109, 112))	('activation', 'PosReg', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('Akt', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
84048	20651364	We therefore hypothesize that mesenchymal stem cells home to transplanted malignant mesothelioma spheroids along a SDF1/CXCL12 chemotactic axis and that targeting this chemotactic axis can abrogate tumor growth and progression.	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (84, 106))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (74, 96))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('SDF1', 'Gene', '20315', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('malignant mesothelioma spheroids', 'Disease', 'MESH:C562839', (74, 106))	('CXCL12', 'Gene', (120, 126))	('malignant mesothelioma spheroids', 'Disease', (74, 106))	('tumor', 'Disease', (198, 203))	('CXCL12', 'Gene', '20315', (120, 126))	('abrogate', 'NegReg', (189, 197))	('targeting', 'Var', (153, 162))	('SDF1', 'Gene', (115, 119))
84061	20651364	Total RNA was reverse transcribed and PCR was performed using the following forward and reverse primers: CXCR4 (345bp product, 5'-TCTTCCTGCCCACCATCTAC, 3'-TCAGCAGCAGTTTCCTTGG); 18S (106bp product, 5'-AAACGGCTACCACATCCAAG, 3'-GGCCTCGAAAGAGTCCTGTA); beta-actin (250bp product, 5'-GTGGGCCGCTCTAGGCACCA, 3'-TCACGGTTGGCCTTAGGGTTCAGGG).	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('beta-actin', 'Gene', '11461', (248, 258))	('250bp', 'Var', (260, 265))	('CXCR4', 'molecular_function', 'GO:0038147', ('105', '110'))	('beta-actin', 'Gene', (248, 258))
84095	20651364	The total number of tumors in AMD3100-treated mice also increases up to 14 days, but then the number significantly decreases in the treatment group.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('AMD3100-treated', 'Var', (30, 45))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
84100	20651364	At 14 days after injection of malignant mesothelioma cells, AMD3100-treated mice had a significantly higher percentage of tumor spheroids than PBS-injected control mice.	('higher', 'PosReg', (101, 107))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (30, 52))	('mice', 'Species', '10090', (164, 168))	('AMD3100-treated', 'Var', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('PBS', 'Chemical', 'MESH:D007854', (143, 146))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (30, 52))	('mice', 'Species', '10090', (76, 80))	('malignant mesothelioma', 'Disease', (30, 52))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
84131	20651364	By 21 days after tumor cell injection, the percentage of tumor spheroids significantly decreased in AMD3100-injected mice but not in PBS-injected mice.	('tumor', 'Disease', (17, 22))	('PBS', 'Chemical', 'MESH:D007854', (133, 136))	('decreased', 'NegReg', (87, 96))	('AMD3100-injected', 'Var', (100, 116))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mice', 'Species', '10090', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
84133	20651364	When total tumor area is divided into solid tumor area versus tumor spheroid area, it is clear that AMD3100-injected mice have less tumor area than PBS-injected mice, and that tumor area in AMD3100-injected mice is comprised mostly of tumor spheroids and not solid tumor.	('solid tumor area versus tumor', 'Disease', 'MESH:D009369', (38, 67))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('AMD3100-injected', 'Var', (100, 116))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('less', 'NegReg', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('solid tumor area versus tumor', 'Disease', (38, 67))	('mice', 'Species', '10090', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mice', 'Species', '10090', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (235, 240))	('PBS', 'Chemical', 'MESH:D007854', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
84134	20651364	Taken together, there is a trend towards decreased tumor burden in mice treated with AMD3100.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('decreased', 'NegReg', (41, 50))	('tumor', 'Disease', (51, 56))	('AMD3100', 'Var', (85, 92))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
84218	18775081	One such study showed that after installation of intra-pleural asbestos, the presence of large numbers of pleural macrophages led to pleural plaque formation while their paucity resulted in DPT.	('intra-pleural asbestos', 'Disease', 'MESH:D010995', (49, 71))	('intra-pleural asbestos', 'Disease', (49, 71))	('pleural macrophages', 'Disease', 'MESH:D055501', (106, 125))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('DPT', 'Chemical', '-', (190, 193))	('presence', 'Var', (77, 85))	('pleural macrophages', 'Disease', (106, 125))	('led to', 'Reg', (126, 132))	('pleural plaque', 'Disease', (133, 147))	('pleural plaque', 'Disease', 'MESH:D010995', (133, 147))
84249	18775081	Their presence is associated with a higher risk of malignant mesothelioma and lung cancer compared with workers with a similar exposure history but no plaques, but there is no evidence to suggest that they are in themselves pre-malignant.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('malignant mesothelioma', 'Disease', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pre', 'molecular_function', 'GO:0003904', ('224', '227'))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (51, 73))	('presence', 'Var', (6, 14))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (51, 73))
84444	31620941	In addition to environmental agents, other risk factors are germline BAP1 mutations and other deleterious mutations of tumor suppressor genes.	('tumor', 'Disease', (119, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('BAP1', 'Gene', (69, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('men', 'Species', '9606', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('germline', 'Var', (60, 68))	('BAP1', 'Gene', '8314', (69, 73))
84456	31620941	Because CRS-HIPEC can significantly improve survival for selected candidates, this procedure should be available for as many patients as possible.	('improve', 'PosReg', (36, 43))	('survival', 'MPA', (44, 52))	('CRS-HIPEC', 'Var', (8, 17))	('patients', 'Species', '9606', (125, 133))
84579	28861460	Incidental fallopian tube mesothelioma diagnosed at time of elective bilateral salpingectomy for sterilisation: A case report Incidental finding of a fallopian tube lesion at the time of bilateral salpingectomy Histopathological appearance not consistent with mucinous or serous carcinoma, appearance of mesothelioma Very rare known primary neoplasm of tubal mesothelium, favours an indolent course Recommendation for prophylactic hysterectomy and bilateral oophorectomy If nil further spread, generally nil further treatment is required  Mesothelioma is a well-known malignancy arising from mutations in mesothelium, a simple squamous epithelium arising from the embryonic mesoderm.	('fallopian tube mesothelioma', 'Disease', 'MESH:D005184', (11, 38))	('fallopian tube mesothelioma', 'Phenotype', 'HP:0030394', (11, 38))	('mesothelioma', 'Disease', (304, 316))	('serous carcinoma', 'Disease', (272, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('malignancy', 'Disease', 'MESH:D009369', (568, 578))	('mesothelioma', 'Disease', 'MESH:D008654', (304, 316))	('neoplasm', 'Disease', 'MESH:D009369', (341, 349))	('Mesothelioma', 'Disease', (539, 551))	('Mesothelioma', 'Disease', 'MESH:D008654', (539, 551))	('finding of a fallopian tube', 'Phenotype', 'HP:0011027', (137, 164))	('tubal mesothelium', 'Chemical', '-', (353, 370))	('mesothelioma', 'Disease', (26, 38))	('fallopian tube lesion', 'Disease', 'MESH:D005184', (150, 171))	('serous carcinoma', 'Disease', 'MESH:D018284', (272, 288))	('mesothelium', 'Gene', (605, 616))	('neoplasm', 'Disease', (341, 349))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('malignancy', 'Disease', (568, 578))	('fallopian tube mesothelioma', 'Disease', (11, 38))	('mutations', 'Var', (592, 601))	('neoplasm', 'Phenotype', 'HP:0002664', (341, 349))	('fallopian tube lesion', 'Disease', (150, 171))
84589	28861460	It has also been noted that a tumour suppressor gene previously identified in pleural mesothelioma, BRCA-associated protein (BAP) 1, is frequently mutated in extra-pleural mesothelioma.	('extra-pleural mesothelioma', 'Disease', 'MESH:D008654', (158, 184))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (78, 98))	('BRCA-associated protein (BAP) 1', 'Gene', '8314', (100, 131))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (78, 98))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('pleural mesothelioma', 'Disease', (78, 98))	('tumour', 'Disease', (30, 36))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (164, 184))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (164, 184))	('extra-pleural mesothelioma', 'Disease', (158, 184))	('mutated', 'Var', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
84630	28611824	Targeted mutagenesis was used to generate variants harboring mutated miR-30 family and ARE binding sites.	('ARE', 'Chemical', '-', (87, 90))	('mutagenesis', 'biological_process', 'GO:0006280', ('9', '20'))	('variants', 'Var', (42, 50))	('rat', 'Species', '10116', (37, 40))	('miR', 'Gene', '220972', (69, 72))	('ARE binding', 'molecular_function', 'GO:0017091', ('87', '98'))	('miR', 'Gene', (69, 72))	('mutated', 'Var', (61, 68))	('binding', 'Interaction', (91, 98))
84633	28611824	Analysis of mutation in the ARE site revealed a further destabilization of the reporter and human antigen R (HuR) binding to the ARE sequence was detected.	('ARE', 'Chemical', '-', (28, 31))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('ARE', 'Chemical', '-', (129, 132))	('HuR', 'Gene', '1994', (109, 112))	('destabilization', 'NegReg', (56, 71))	('binding', 'Interaction', (114, 121))	('reporter', 'MPA', (79, 87))	('HuR', 'Gene', (109, 112))	('mutation', 'Var', (12, 20))	('human', 'Species', '9606', (92, 97))
84634	28611824	The mutation of two miR-30 binding sites abolished CALB2-3'UTR destabilization effect; a transient delivery of miR-30e-5p mimics or anti-miR into MPM cells resulted in a significant decrease/increase of the luciferase reporter expression and calretinin protein, respectively.	('miR-30e', 'Gene', '407034', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('binding', 'molecular_function', 'GO:0005488', ('27', '34'))	('luciferase', 'Enzyme', (207, 217))	('miR-30e', 'Gene', (111, 118))	('calretinin protein', 'Protein', (242, 260))	('miR', 'Gene', (137, 140))	('miR', 'Gene', '220972', (137, 140))	('P', 'Chemical', 'MESH:D010758', (147, 148))	('mutation', 'Var', (4, 12))	('decrease/increase', 'PosReg', (182, 199))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('5p', 'Chemical', '-', (119, 121))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))
84635	28611824	Moreover, overexpression of CALB2-3'UTR quenched the effect of miR-30e-5p mimics on calretinin protein levels, possibly by sequestering the mimics, thereby suggesting a competitive endogenous RNA network.	('quenched', 'NegReg', (40, 48))	('miR-30e', 'Gene', (63, 70))	('effect', 'MPA', (53, 59))	('sequestering', 'biological_process', 'GO:0051235', ('123', '135'))	('mimics', 'Var', (74, 80))	('5p', 'Chemical', '-', (71, 73))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('sequestering', 'NegReg', (123, 135))	('RNA', 'cellular_component', 'GO:0005562', ('192', '195'))	('calretinin protein levels', 'MPA', (84, 109))	('mimics', 'MPA', (140, 146))	('miR-30e', 'Gene', '407034', (63, 70))
84661	28611824	All in all, this data may explain the highest efficiency of targeting 3' sequence for silencing calretinin which has been suggested as a potential therapeutic strategy for epithelioid MPM.	('calretinin', 'Gene', (96, 106))	('silencing', 'Var', (86, 95))	('P', 'Chemical', 'MESH:D010758', (185, 186))	('epithelioid MPM', 'Disease', (172, 187))	('rat', 'Species', '10116', (161, 164))
84696	28611824	Four additional luciferase reporter constructs carrying mutations in either ARE and/or miR-30 binding sites were generated and their activity was tested in ONE58 cells.	('ONE58', 'CellLine', 'CVCL:2671', (156, 161))	('luciferase', 'Enzyme', (16, 26))	('mutations', 'Var', (56, 65))	('rat', 'Species', '10116', (117, 120))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('ARE', 'Chemical', '-', (76, 79))	('binding', 'Interaction', (94, 101))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))
84697	28611824	(D) Insertion of CALB2-3'UTR significantly downregulated luciferase expression when compared to the vector pmiRGLO alone.	('Insertion', 'Var', (4, 13))	('downregulated', 'NegReg', (43, 56))	('expression', 'MPA', (68, 78))	('luciferase', 'Enzyme', (57, 67))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))
84698	28611824	Mutation of the ARE-motif further downregulated reporter expression, whereas the double mutation of miR-30 binding sites abolished the downregulatory effect of the calretinin 3'UTR.	('downregulated', 'NegReg', (34, 47))	('reporter expression', 'MPA', (48, 67))	('ARE', 'Chemical', '-', (16, 19))	('Mutation', 'Var', (0, 8))	('miR', 'Gene', '220972', (100, 103))	('abolished', 'NegReg', (121, 130))	('miR', 'Gene', (100, 103))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))	('downregulatory effect', 'MPA', (135, 156))
84699	28611824	The empty vector pmiRGLO plasmid expression was arbitrarily set to 100% and the reporter activity of the mutants was expressed as a percentage of the wild-type construct.	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('mutants', 'Var', (105, 112))
84702	28611824	To detect the presence of calretinin variants CALB2, CALB2b, and CALB2c, real-time quantitative PCR (RT-qPCR) was performed with cDNA from ZL55, ACC-MESO-4 and ONE58 cells using boundary-spanning primers approach (Figure 1A and Supplementary Figure 1).	('CALB2', 'Gene', (46, 51))	('MESO-4', 'CellLine', 'CVCL:H668', (149, 155))	('CALB2b', 'Gene', (53, 59))	('ZL55', 'Chemical', '-', (139, 143))	('P', 'Chemical', 'MESH:D010758', (96, 97))	('S', 'Chemical', 'MESH:D013455', (228, 229))	('CALB2c', 'Gene', (65, 71))	('variants', 'Var', (37, 45))	('ONE58', 'CellLine', 'CVCL:2671', (160, 165))	('P', 'Chemical', 'MESH:D010758', (105, 106))	('S', 'Chemical', 'MESH:D013455', (151, 152))
84710	28611824	Insertion of the CALB2-3'UTR led to 40% (p = 0.0012) decreased expression of Firefly luciferase when compared to the empty vector (pmiRGLO), indicating that the calretinin 3'UTR conveys a downregulatory effect (Figure 2D).	('Firefly luciferase', 'Enzyme', (77, 95))	('downregulatory', 'NegReg', (188, 202))	('expression', 'MPA', (63, 73))	('miR', 'Gene', (132, 135))	('miR', 'Gene', '220972', (132, 135))	('Insertion', 'Var', (0, 9))	('decreased', 'NegReg', (53, 62))
84711	28611824	We then generated an additional four constructs harboring mutations of the consensus sequence for the predicted ARE motif and miR-30 binding sites and transiently transfected all variants into ONE58 cells to test for their effects on luciferase expression (Figures 2C,D).	('mutations', 'Var', (58, 67))	('variants', 'Var', (179, 187))	('rat', 'Species', '10116', (12, 15))	('effects', 'Reg', (223, 230))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('ARE', 'Chemical', '-', (112, 115))	('test', 'Reg', (208, 212))	('expression', 'MPA', (245, 255))	('luciferase', 'Enzyme', (234, 244))	('ONE58', 'CellLine', 'CVCL:2671', (193, 198))
84712	28611824	Mutation of the predicted ARE motif induced an even further significant decrease of 20% (p = 0.0055), indicating that the ARE site binds to a stabilizing factor.	('decrease', 'NegReg', (72, 80))	('ARE', 'Chemical', '-', (122, 125))	('Mutation', 'Var', (0, 8))	('ARE', 'Chemical', '-', (26, 29))
84713	28611824	In contrast, mutation of both miR-30 binding sites restored the expression of the luciferase reporter to the level of the empty vector.	('miR', 'Gene', '220972', (30, 33))	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('miR', 'Gene', (30, 33))	('expression', 'MPA', (64, 74))	('mutation', 'Var', (13, 21))	('restored', 'PosReg', (51, 59))	('luciferase', 'Enzyme', (82, 92))
84718	28611824	Replacing the AUUUA with GUCUG results in a mutated ARE motif paired in a newly formed secondary structure predicted to be less likely to be accessible for putative interacting protein (Supplementary Figure 3).	('ARE', 'Chemical', '-', (52, 55))	('S', 'Chemical', 'MESH:D013455', (186, 187))	('AU', 'Chemical', '-', (14, 16))	('ARE motif', 'MPA', (52, 61))	('mutated', 'Var', (44, 51))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))
84723	28611824	Since the mutational reporter analysis had identified the ARE motif as a stabilizing element, we quantified the expression of HuR (stabilizer) along with TTP (destabilizer) across 10 mesothelioma cell lines and observed that HuR is abundantly expressed in all tested cells lines and 5- to 50-fold enriched compared to TTP (Figure 3B).	('HuR', 'Gene', (126, 129))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('HuR', 'Gene', '1994', (126, 129))	('mutational', 'Var', (10, 20))	('mesothelioma', 'Disease', (183, 195))	('HuR', 'Gene', (225, 228))	('HuR', 'Gene', '1994', (225, 228))	('TTP', 'Gene', (154, 157))	('ARE', 'Chemical', '-', (58, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('TTP', 'Gene', (318, 321))	('TTP', 'Gene', '7538', (318, 321))	('TTP', 'Gene', '7538', (154, 157))
84727	28611824	The observation that the double miR-30 mutant construct (pmiRGLO-CALB2-3'UTR-mir30-dmt) abolished the downregulatory effect mediated by CALB2-3'UTR, led us to identify the critical miR-30 member conveying this effect.	('miR', 'Gene', (32, 35))	('downregulatory effect', 'MPA', (102, 123))	('miR', 'Gene', '220972', (181, 184))	('miR', 'Gene', (58, 61))	('miR', 'Gene', (181, 184))	('miR', 'Gene', '220972', (58, 61))	('abolished', 'NegReg', (88, 97))	('mutant', 'Var', (39, 45))	('miR', 'Gene', '220972', (32, 35))
84745	28611824	In contrast, when anti-miR-30e-5p was transiently delivered, increase of calretinin protein levels was observed only in ONE58-CALB2-3'UTR and not in ONE58-EV-pmiRGLO cells (Figure 5B).	('ONE58', 'CellLine', 'CVCL:2671', (120, 125))	('calretinin protein levels', 'MPA', (73, 98))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('miR-30e', 'Gene', '407034', (23, 30))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('miR-30e', 'Gene', (23, 30))	("ONE58-CALB2-3'UTR", 'Var', (120, 137))	('miR', 'Gene', '220972', (159, 162))	('ONE58', 'CellLine', 'CVCL:2671', (149, 154))	('miR', 'Gene', (159, 162))	('5p', 'Chemical', '-', (31, 33))	('increase', 'PosReg', (61, 69))
84754	28611824	Employing a reporter plasmid assay, where the 573-nt stretch of the CALB2-3'UTR was inserted downstream of the Firefly luciferase reporter, we observed that CALB2-3'UTR affected the reporter mRNA stability, as it downregulated the reporter expression in mesothelioma cells.	("CALB2-3'UTR", 'Var', (157, 168))	('affected', 'Reg', (169, 177))	('downregulated', 'NegReg', (213, 226))	('reporter mRNA stability', 'MPA', (182, 205))	('mesothelioma', 'Disease', (254, 266))	('mesothelioma', 'Disease', 'MESH:D008654', (254, 266))	('reporter expression', 'MPA', (231, 250))
84758	28611824	Since the mutational approach revealed a stabilization element in the ARE site and we detected HuR, an mRNA stabilizing protein, in the ARE-sequence pull-down we propose that HuR is a potential CALB2 regulator.	('ARE', 'Chemical', '-', (70, 73))	('mutational', 'Var', (10, 20))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('stabilization', 'MPA', (41, 54))	('HuR', 'Gene', (95, 98))	('HuR', 'Gene', '1994', (95, 98))	('ARE', 'Chemical', '-', (136, 139))	('HuR', 'Gene', (175, 178))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('HuR', 'Gene', '1994', (175, 178))
84761	28611824	It would be interesting to test whether silencing HuR in cells expressing CALB2-3'UTR would increase the effects of miR-30e on reporter expression.	('effects', 'MPA', (105, 112))	('reporter expression', 'MPA', (127, 146))	('increase', 'PosReg', (92, 100))	('miR-30e', 'Gene', '407034', (116, 123))	('HuR', 'Gene', '1994', (50, 53))	('silencing', 'Var', (40, 49))	('HuR', 'Gene', (50, 53))	('miR-30e', 'Gene', (116, 123))	("CALB2-3'UTR", 'Var', (74, 85))
84785	28611824	Indeed, our data show the role of (1) AUBPs in calretinin stabilization and (2) miR-30e-5p in the posttranscriptional negative regulation of calretinin expression via interaction with its 3'UTR.	('AUBPs', 'Var', (38, 43))	('interaction', 'Interaction', (167, 178))	('calretinin', 'Gene', (141, 151))	('AU', 'Chemical', '-', (38, 40))	('miR-30e', 'Gene', '407034', (80, 87))	('regulation', 'biological_process', 'GO:0065007', ('127', '137'))	('miR-30e', 'Gene', (80, 87))	('5p', 'Chemical', '-', (88, 90))	('expression', 'MPA', (152, 162))	('negative', 'NegReg', (118, 126))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('calretinin stabilization', 'MPA', (47, 71))	('posttranscriptional', 'MPA', (98, 117))
84786	28611824	These results may provide a rationale why targeting 3'UTR sequence for silencing calretinin, a suggested therapeutic approach for epithelioid MPM, is more efficient compared to targeting translated regions.	('silencing', 'Var', (71, 80))	('calretinin', 'Gene', (81, 91))	('rat', 'Species', '10116', (28, 31))	('P', 'Chemical', 'MESH:D010758', (143, 144))
84834	26024351	Pedra et al described 2,414 mesothelioma deaths in the period 1996 to 2003 in Brazil, using a combination of International Classification of Diseases 9 (ICD-9) codes 163 (malignant neoplasm of pleura) for 1980-1995 and ICD-I0 codes C45 (mesothelioma) and C38.4 (malignant neoplasm of pleura) for 1996-2003.	('C45', 'Var', (232, 235))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('malignant neoplasm of pleura', 'Disease', (171, 199))	('neoplasm of pleura', 'Phenotype', 'HP:0100527', (181, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('malignant neoplasm of pleura', 'Disease', 'MESH:D009369', (262, 290))	('mesothelioma deaths', 'Disease', 'MESH:D008654', (28, 47))	('neoplasm', 'Phenotype', 'HP:0002664', (272, 280))	('mesothelioma', 'Disease', (237, 249))	('mesothelioma', 'Disease', (28, 40))	('neoplasm of pleura', 'Phenotype', 'HP:0100527', (272, 290))	('mesothelioma deaths', 'Disease', (28, 47))	('malignant neoplasm of pleura', 'Disease', (262, 290))	('C38.4', 'Var', (255, 260))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))	('malignant neoplasm of pleura', 'Disease', 'MESH:D009369', (171, 199))
84905	22695319	In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('ectopic', 'Var', (15, 22))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('TGFBI', 'Gene', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('mesothelioma', 'Disease', (141, 153))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
84910	22695319	In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('cellular growth', 'CPA', (185, 200))	('mesothelioma', 'Disease', (83, 95))	('cellular growth', 'biological_process', 'GO:0016049', ('185', '200'))	('plating efficiency', 'CPA', (202, 220))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('anchorage-independent growth', 'CPA', (226, 254))	('TGFBI', 'Gene', (40, 45))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('reduced', 'NegReg', (173, 180))	('ectopic expression', 'Var', (18, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('NCI-H28', 'CellLine', 'CVCL:1555', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
84911	22695319	The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression.	('tumor', 'Disease', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TGFBI', 'Gene', (129, 134))	('nude mice', 'Species', '10090', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('suppressed', 'NegReg', (115, 125))	('cancer', 'Disease', (28, 34))	('expression', 'Var', (135, 145))
84916	22695319	Mutations of the TGFBI gene have been shown to be involved in several corneal dystrophies.	('corneal dystrophies', 'Disease', 'MESH:D003317', (70, 89))	('corneal dystrophies', 'Phenotype', 'HP:0001131', (70, 89))	('Mutations', 'Var', (0, 9))	('TGFBI', 'Gene', (17, 22))	('corneal dystrophies', 'Disease', (70, 89))	('involved', 'Reg', (50, 58))
84922	22695319	Recent findings have suggested that TGFBI also sensitizes ovarian cancer cells to paclitaxel by inducing microtubule stabilization and that the loss of TGFBI induces drug resistance and mitotic spindle abnormalities in ovarian cancer cells.	('loss', 'Var', (144, 148))	('induces', 'Reg', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('186', '201'))	('mitotic spindle abnormalities in ovarian cancer', 'Disease', (186, 233))	('inducing', 'PosReg', (96, 104))	('microtubule', 'cellular_component', 'GO:0005874', ('105', '116'))	('mitotic spindle abnormalities in ovarian cancer', 'Disease', 'MESH:D010051', (186, 233))	('drug resistance', 'biological_process', 'GO:0009315', ('166', '181'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (219, 233))	('microtubule stabilization', 'biological_process', 'GO:0007026', ('105', '130'))	('abnormalities in ovarian', 'Phenotype', 'HP:0000137', (202, 226))	('sensitizes', 'Reg', (47, 57))	('drug resistance', 'biological_process', 'GO:0042493', ('166', '181'))	('drug resistance', 'CPA', (166, 181))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('ovarian cancer', 'Disease', (58, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('microtubule stabilization', 'MPA', (105, 130))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('ovarian cancer', 'Disease', 'MESH:D010051', (219, 233))	('TGFBI', 'Gene', (36, 41))	('drug resistance', 'Phenotype', 'HP:0020174', (166, 181))	('TGFBI', 'Gene', (152, 157))
84929	22695319	Although the mechanism of how these two types of malignancy undergo malignant transformation remains largely unknown, evidence indicate a multistep process involving both activation of oncogenes and inactivation of tumor suppressor genes exists The observation that many late-stage tumors are highly resistant to traditional chemotherapy and radiation therapy, highlights the need for innovative therapies based on mechanistic insight of the cancer process.	('cancer', 'Disease', 'MESH:D009369', (442, 448))	('radiation', 'Disease', 'MESH:D004194', (342, 351))	('tumor', 'Disease', (282, 287))	('malignancy', 'Disease', (49, 59))	('radiation', 'Disease', (342, 351))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Disease', (442, 448))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (442, 448))	('tumor', 'Disease', (215, 220))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('215', '231'))	('malignancy', 'Disease', 'MESH:D009369', (49, 59))	('inactivation', 'Var', (199, 211))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor suppressor', 'biological_process', 'GO:0051726', ('215', '231'))
84931	22695319	Engineered mesothelioma cell clones (T2804, T2806, and T2807) and breast cancer cell clones (T23108, T23109, and T23113) ectopically expressing TGFBI were generated from their respective parental tumor cell lines, which only contained trace amounts of TGFBI.	('Engineered mesothelioma', 'Disease', 'MESH:D008654', (0, 23))	('T23113', 'Var', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('parental tumor', 'Disease', 'MESH:D063129', (187, 201))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('parental tumor', 'Disease', (187, 201))	('T23109', 'Var', (101, 107))	('breast cancer', 'Disease', (66, 79))	('T2806', 'CellLine', 'CVCL:9L17', (44, 49))	('Engineered mesothelioma', 'Disease', (0, 23))	('TGFBI', 'Gene', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
84933	22695319	The results demonstrated that the reintroduction of TGFBI into NCI-H28 and MDA-MB-231 cells dramatically slowed cell growth and prolonged population doubling time 4.38 and 1.16 times (Figures 2A and 2B), respectively.	('slowed', 'NegReg', (105, 111))	('population doubling time', 'CPA', (138, 162))	('cell growth', 'biological_process', 'GO:0016049', ('112', '123'))	('slowed cell growth', 'Phenotype', 'HP:0001510', (105, 123))	('cell growth', 'CPA', (112, 123))	('NCI-H28', 'CellLine', 'CVCL:1555', (63, 70))	('prolonged', 'PosReg', (128, 137))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))	('reintroduction', 'Var', (34, 48))	('TGFBI', 'Gene', (52, 57))
84935	22695319	TGFBI expression inhibited anchorage-independent growth in these two cancer cell lines, exhibiting a drop of 48.54% in mesothelioma cells and 90.89% in breast cancer cells relative to control cells of both types (Figures 2D).	('cancer', 'Disease', (159, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('drop', 'NegReg', (101, 105))	('anchorage-independent growth', 'CPA', (27, 55))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('inhibited', 'NegReg', (17, 26))	('TGFBI', 'Gene', (0, 5))	('breast cancer', 'Disease', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('expression', 'Var', (6, 16))	('mesothelioma', 'Disease', (119, 131))	('cancer', 'Disease', (69, 75))
84939	22695319	In contrast, mice injected with TGFBI-expressing cells (T23108, T23109, and T23113) showed signs of tumor growth at 6 weeks post inoculation, 2 weeks later than control groups.	('T23109', 'Var', (64, 70))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('T23108', 'Var', (56, 62))	('T23113', 'Var', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
84947	22695319	When TGFBI was expressed, the cell proliferation rate (T2807 and T2313) was lower than that of control cells at 12-24 h after serum stimulation (#, P < 0.05; Figures 4C and 4D).	('TGFBI', 'Gene', (5, 10))	('lower', 'NegReg', (76, 81))	('T2807', 'Var', (55, 60))	('T2313', 'Var', (65, 70))	('T2313', 'CellLine', 'CVCL:9J59', (65, 70))	('cell proliferation rate', 'CPA', (30, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
84949	22695319	TGFBI-expressing cells T2807 and T23113 exhibited elevated p21 and p53 levels at 12 h and up to 24 h upon serum stimulation.	('p21', 'Gene', (59, 62))	('elevated', 'PosReg', (50, 58))	('p21', 'Gene', '644914', (59, 62))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('T23113', 'Var', (33, 39))
84956	22695319	However, two well-known senescence regulators, p16 and p14, were found to be unaffected by TGFBI re-expression (Figures 6E).	('p16', 'Gene', (47, 50))	('TGFBI', 'Gene', (91, 96))	('p14', 'Gene', (55, 58))	('p14', 'Gene', '1029', (55, 58))	('senescence', 'biological_process', 'GO:0010149', ('24', '34'))	('p16', 'Gene', '1029', (47, 50))	('re-expression', 'Var', (97, 110))
84957	22695319	This indicated that TGFBI could not recovery expression of p16 and p14 in mesothelioma cells with biallelic deletion.	('p16', 'Gene', '1029', (59, 62))	('biallelic', 'Var', (98, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('p16', 'Gene', (59, 62))	('p14', 'Gene', (67, 70))	('p14', 'Gene', '1029', (67, 70))	('mesothelioma', 'Disease', (74, 86))
84964	22695319	Recent evidence has shown that TGFBI expression causes significantly higher sensitivity to apoptotic induction by upregulation of IGFBP3.	('TGFBI', 'Gene', (31, 36))	('expression', 'Var', (37, 47))	('upregulation', 'PosReg', (114, 126))	('IGFBP3', 'Gene', '3486', (130, 136))	('sensitivity to apoptotic induction', 'MPA', (76, 110))	('IGFBP3', 'Gene', (130, 136))	('higher', 'PosReg', (69, 75))
84969	22695319	Dysregulation of the G1/S transition may arrest the cells in quiescence or drive them into nonstop proliferation, depending on the specific scenario.	('drive', 'Reg', (75, 80))	('nonstop proliferation', 'CPA', (91, 112))	('Dysregulation', 'Var', (0, 13))	('cells', 'CPA', (52, 57))	('arrest', 'Disease', (41, 47))	('quiescence', 'biological_process', 'GO:0044838', ('61', '71'))	('arrest', 'Disease', 'MESH:D006323', (41, 47))
84973	22695319	Similarly, ablation of TGFBI increases the frequency of chromosomal aberration and micronuclear formation, as observed in fibroblast cells isolated from TGFBI knock-out mice.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('micronuclear formation', 'CPA', (83, 105))	('TGFBI', 'Gene', (23, 28))	('increases the frequency of chromosomal aberration', 'Phenotype', 'HP:0040012', (29, 78))	('increases', 'PosReg', (29, 38))	('mice', 'Species', '10090', (169, 173))	('chromosomal aberration', 'CPA', (56, 78))	('ablation', 'Var', (11, 19))
84977	22695319	It can be triggered by a number of sensing mechanisms, such as telomere shortening, epigenetic derepression of the INK4a/ARF locus that encodes two physically linked tumor suppressor proteins p16/p14, and DNA damage.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ARF', 'Disease', (121, 124))	('p14', 'Gene', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('telomere', 'cellular_component', 'GO:0000781', ('63', '71'))	('p16', 'Gene', (192, 195))	('p14', 'Gene', '1029', (196, 199))	('tumor', 'Disease', (166, 171))	('telomere', 'cellular_component', 'GO:0005696', ('63', '71'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('INK4a', 'Gene', (115, 120))	('INK4a', 'Gene', '1029', (115, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('telomere shortening', 'Phenotype', 'HP:0031413', (63, 82))	('epigenetic derepression', 'Var', (84, 107))	('p16', 'Gene', '1029', (192, 195))	('ARF', 'Disease', 'MESH:D058186', (121, 124))
84980	22695319	To our surprise, an enhanced senescence accompanied by the expression of TGFBI was evidenced by the increased levels of SA-beta-gal, a classic marker of cellular senescence.	('TGFBI', 'Gene', (73, 78))	('increased', 'PosReg', (100, 109))	('enhanced', 'PosReg', (20, 28))	('levels of SA-beta-gal', 'MPA', (110, 131))	('senescence', 'CPA', (29, 39))	('cellular senescence', 'biological_process', 'GO:0090398', ('153', '172'))	('senescence', 'biological_process', 'GO:0010149', ('29', '39'))	('SA-beta-gal', 'Chemical', '-', (120, 131))	('expression', 'Var', (59, 69))
84982	22695319	In NCI-H28 cells, telomerase activity increased significantly with the expression of TGFBI, which directs cells into senescence.	('telomerase activity', 'molecular_function', 'GO:0003720', ('18', '37'))	('expression', 'Var', (71, 81))	('NCI-H28', 'CellLine', 'CVCL:1555', (3, 10))	('senescence', 'biological_process', 'GO:0010149', ('117', '127'))	('TGFBI', 'Gene', (85, 90))	('increased', 'PosReg', (38, 47))	('telomerase activity', 'MPA', (18, 37))
84988	22695319	In both types of cells, p21 and p53 were both up-regulated upon TGFBI expression.	('p21', 'Gene', (24, 27))	('up-regulated', 'PosReg', (46, 58))	('p21', 'Gene', '644914', (24, 27))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('TGFBI', 'Gene', (64, 69))	('expression', 'Var', (70, 80))
84989	22695319	Our results clearly showed that SA-beta-gal and telomerase activity were both up-regulated by TGFBI re-expression.	('activity', 'MPA', (59, 67))	('TGFBI', 'Gene', (94, 99))	('SA-beta-gal', 'Chemical', '-', (32, 43))	('telomerase activity', 'molecular_function', 'GO:0003720', ('48', '67'))	('SA-beta-gal', 'Protein', (32, 43))	('up-regulated', 'PosReg', (78, 90))	('telomerase', 'Enzyme', (48, 58))	('re-expression', 'Var', (100, 113))
84992	22695319	After implanting cells with TGFBI and leaving others without, we analyzed the onset, incidence, and volume of the resulting tumors in mice, in order to assess the tumor suppressive effect of TGFBI.	('mice', 'Species', '10090', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('TGFBI', 'Var', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
84999	22695319	The number of ki67-positive cells inversely correlated with the level of TGFBI expression; the more ki67-positive cells observed in the vector control groups, the stronger the evidence that TGFBI diminishes the ability of cells to proliferate and therefore inhibits tumorigenicity in vivo.	('inhibits', 'NegReg', (257, 265))	('diminishes', 'NegReg', (196, 206))	('TGFBI', 'Var', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('ki67', 'Gene', (100, 104))	('ki67', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('ki67', 'Gene', '17345', (100, 104))	('ki67', 'Gene', '17345', (14, 18))
85023	22695319	The relative plating efficiencies (PE) were determined using the following formula: Relative PE = number of colonies of TGFBI expression or vector control cells / number of colonies of parental cells.	('colon', 'Disease', 'MESH:D015179', (108, 113))	('colon', 'Disease', 'MESH:D015179', (173, 178))	('TGFBI', 'Gene', (120, 125))	('expression', 'Var', (126, 136))	('colon', 'Disease', (108, 113))	('colon', 'Disease', (173, 178))
85045	22695319	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/12/239/prepub The work was supported in part by funding from National Institutes of Health grants ES05786, CA49062, Superfund grant P42 ES10349, Environmental Center grant P30 ES 09089, National Natural Science Foundation grants 81072286 and 81020108028 and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).	('P42', 'Gene', (236, 239))	('CA49062', 'Var', (211, 218))	('P30', 'Gene', (276, 279))	('P42', 'Gene', '2038', (236, 239))	('ES05786', 'Var', (202, 209))	('81072286', 'Var', (333, 341))	('81020108028', 'Var', (346, 357))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))	('P30', 'Gene', '201161', (276, 279))
85176	22737246	Our results showed that protein expression of MMP2, TNFAIP6/TSG-6, RANTES/CCL5 and BAFF/BLyS/TNFSF13B was higher in NCI-H226 spheroids compared to monolayers (Fig.	('TNFSF13B', 'Gene', '10673', (93, 101))	('RANTES', 'Gene', '6352', (67, 73))	('CCL5', 'Gene', '6352', (74, 78))	('MMP2', 'Gene', '4313', (46, 50))	('TNFAIP6', 'Gene', '7130', (52, 59))	('BAFF', 'Gene', (83, 87))	('MMP2', 'molecular_function', 'GO:0004228', ('46', '50'))	('BLyS', 'Gene', '10673', (88, 92))	('NCI-H226', 'CellLine', 'CVCL:1544', (116, 124))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('CCL5', 'Gene', (74, 78))	('NCI-H226', 'Var', (116, 124))	('protein expression', 'MPA', (24, 42))	('BAFF', 'Gene', '10673', (83, 87))	('TNFSF13B', 'Gene', (93, 101))	('MMP2', 'Gene', (46, 50))	('TNFAIP6', 'Gene', (52, 59))	('TSG-6', 'Gene', (60, 65))	('TSG-6', 'Gene', '7130', (60, 65))	('BLyS', 'Gene', (88, 92))	('CCL', 'molecular_function', 'GO:0044101', ('74', '77'))	('higher', 'PosReg', (106, 112))	('RANTES', 'Gene', (67, 73))
85214	22737246	They also showed that inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids.	('mammalian target of rapamycin', 'Gene', '2475', (74, 103))	('mammalian target of rapamycin', 'Gene', (74, 103))	('inhibitors', 'Var', (22, 32))	('acquired resistance of the spheroids', 'CPA', (164, 200))	('Akt', 'Gene', (70, 73))	('rapamycin', 'Chemical', 'MESH:D020123', (133, 142))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('blocked', 'NegReg', (144, 151))	('Akt', 'Gene', '207', (70, 73))	('rapamycin', 'Chemical', 'MESH:D020123', (94, 103))
85250	32899932	Due to the labile nature of mRNA, IVT- mRNA CAR T reduces the side effects associated with on-target off-tumor toxicity.	('side effects', 'MPA', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('reduces', 'NegReg', (50, 57))	('tumor toxicity', 'Disease', (105, 119))	('IVT- mRNA CAR', 'Var', (34, 47))	('tumor toxicity', 'Disease', 'MESH:D064420', (105, 119))	('CAR', 'cellular_component', 'GO:0005826', ('44', '47'))
85264	32899932	Accordingly, insertion of CXCR4 or CCR7 mRNA contributes to the homing of CAR T cells towards bone marrow and lymphnodes, respectively, and binding with CD19 surface antigen.	('homing', 'CPA', (64, 70))	('CXCR4', 'Gene', '7852', (26, 31))	('CAR', 'cellular_component', 'GO:0005826', ('74', '77'))	('binding', 'Interaction', (140, 147))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('CD19', 'Protein', (153, 157))	('insertion', 'Var', (13, 22))	('CCR7', 'Gene', (35, 39))	('CXCR4', 'Gene', (26, 31))	('CCR7', 'Gene', '1236', (35, 39))	('CXCR4', 'molecular_function', 'GO:0038147', ('26', '31'))	('CCR', 'molecular_function', 'GO:0043880', ('35', '38'))
85275	32899932	Interestingly, the authors found CD19-independent severe toxicity in ALL mice.	('toxicity', 'Disease', (57, 65))	('mice', 'Species', '10090', (73, 77))	('CD19-independent', 'Var', (33, 49))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
85295	32899932	documented the evidence that human peripheral blood lymphocytes (PBLs) transfected with mRNA against receptor tyrosine protein kinase Her-2/neu killed human ovarian cancer cell line SKOV3 in vitro.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('mRNA', 'Var', (88, 92))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('human', 'Species', '9606', (151, 156))	('Her-2/neu', 'Gene', '2064', (134, 143))	('Her-2/neu', 'Gene', (134, 143))	('ovarian cancer', 'Disease', (157, 171))	('SKOV3', 'CellLine', 'CVCL:0532', (182, 187))	('human', 'Species', '9606', (29, 34))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
85300	32899932	In addition, FRalpha-targeted mRNA significantly inhibited the cancer cell growth in localized and disseminated murine models of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('cell growth', 'biological_process', 'GO:0016049', ('70', '81'))	('murine', 'Species', '10090', (112, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('ovarian cancer', 'Disease', (129, 143))	('mRNA', 'Var', (30, 34))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('inhibited', 'NegReg', (49, 58))	('cancer', 'Disease', (63, 69))
85306	32899932	In a recent study, it was reported that c-Met IVT mRNA-expressing T cells suppressed tumor growth in a murine ovarian cancer model and elicited a marked cytotoxic effect in human breast cancer cell lines BT20 and TB129.	('tumor', 'Disease', (85, 90))	('ovarian cancer', 'Disease', (110, 124))	('suppressed', 'NegReg', (74, 84))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (179, 192))	('c-Met', 'Var', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('elicited', 'Reg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('human', 'Species', '9606', (173, 178))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('cytotoxic effect', 'CPA', (153, 169))	('murine', 'Species', '10090', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
85308	32899932	TAAs identified in neuroblastoma include disialoganglioside GD2 and L1 cell adhesion molecule (L1-CAM).	('disialoganglioside', 'Chemical', 'MESH:C025447', (41, 59))	('neuroblastoma', 'Disease', 'MESH:D009447', (19, 32))	('neuroblastoma', 'Disease', (19, 32))	('L1-CAM', 'Gene', (95, 101))	('neuroblastoma', 'Phenotype', 'HP:0003006', (19, 32))	('disialoganglioside', 'Var', (41, 59))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('71', '93'))	('L1 cell adhesion molecule', 'Gene', (68, 93))	('L1-CAM', 'Gene', '3897', (95, 101))	('cell adhesion', 'biological_process', 'GO:0007155', ('71', '84'))	('L1 cell adhesion molecule', 'Gene', '3897', (68, 93))
85309	32899932	TAAs identified in glioblastoma multiforme include variant III of the epidermal growth factor receptor, HER2, CD133 and B7-H3.	('variant III', 'Var', (51, 62))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('70', '93'))	('glioblastoma multiforme', 'Disease', (19, 42))	('CD133', 'Gene', (110, 115))	('B7-H3', 'Gene', (120, 125))	('CD133', 'Gene', '8842', (110, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('epidermal growth factor receptor', 'Gene', (70, 102))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (19, 42))	('epidermal growth factor receptor', 'Gene', '1956', (70, 102))	('HER2', 'Gene', (104, 108))	('B7-H3', 'Gene', '80381', (120, 125))	('HER2', 'Gene', '2064', (104, 108))
85333	32899932	Antigen-specific cytokine release was noticed in anti-VEGFR2 mRNA CAR T cells, which triggered cytotoxic events in cancer cells and suppressed tumor growth.	('cancer', 'Disease', (115, 121))	('cytotoxic events', 'MPA', (95, 111))	('tumor', 'Disease', (143, 148))	('anti-VEGFR2', 'Var', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('CAR', 'cellular_component', 'GO:0005826', ('66', '69'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('triggered', 'Reg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('suppressed', 'NegReg', (132, 142))
85336	32899932	Trials with anti-mesothelin CARs and anti-cMet CARs against malignant pleural mesothelioma (NCT01355965), metastatic pancreatic ductal adenocarcinoma (NCT01897415) and metastatic triple-negative breast cancer (NCT01837602) have been completed.	('NCT01897415', 'Var', (151, 162))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (60, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('NCT01355965', 'Var', (92, 103))	('malignant pleural mesothelioma', 'Disease', (60, 90))	('breast cancer', 'Disease', (195, 208))	('NCT01837602', 'Var', (210, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (117, 149))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (70, 90))	('pancreatic ductal adenocarcinoma', 'Disease', (117, 149))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (117, 149))
85337	32899932	A few of the ongoing clinical trials are studying the therapeutic effect of anti-cMet CARs, anti-CD19 CARs and anti-CD20 CARs against malignant melanoma breast cancer (NCT03060356), Hodgkin's lymphoma (NCT02624258), B cell leukemia B cell lymphoma (NCT03166878) and non-Hodgkin's lymphoma B cell chronic lymphocyticeukemia (NCT02315118).	('lymphoma', 'Phenotype', 'HP:0002665', (280, 288))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (270, 288))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('anti-CD20', 'Var', (111, 120))	('leukemia', 'Phenotype', 'HP:0001909', (223, 231))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (182, 200))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (232, 247))	('cell lymphoma', 'Phenotype', 'HP:0012191', (234, 247))	("Hodgkin's lymphoma", 'Disease', (270, 288))	('lymphoma', 'Phenotype', 'HP:0002665', (239, 247))	('NCT03166878', 'Var', (249, 260))	("Hodgkin's lymphoma", 'Disease', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('anti-CD19', 'Var', (92, 101))	('malignant melanoma', 'Phenotype', 'HP:0002861', (134, 152))	("non-Hodgkin's lymphoma B cell chronic lymphocyticeukemia", 'Disease', 'MESH:D008228', (266, 322))	('B cell leukemia B cell lymphoma', 'Disease', 'MESH:D016393', (216, 247))	('B cell leukemia B cell lymphoma', 'Disease', (216, 247))	('malignant melanoma breast cancer', 'Disease', (134, 166))	('NCT03060356', 'Var', (168, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('NCT02624258', 'Var', (202, 213))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (270, 288))	('malignant melanoma breast cancer', 'Disease', 'MESH:D001943', (134, 166))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (182, 200))
85353	32899932	reported that no side effect was noticed in metastatic breast cancer patients who intratumorally received c-Met IVT mRNA CAR T cells in a phase 0 clinical trial.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CAR', 'cellular_component', 'GO:0005826', ('121', '124'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('c-Met', 'Var', (106, 111))	('breast cancer', 'Disease', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
85354	32899932	Interestingly, immunohistochemical analysis from excised tumors displayed a high degree of necrosis, suggesting the anti-cancer effect of c-Met IVT mRNA CAR T cells in breast cancer patients.	('CAR', 'cellular_component', 'GO:0005826', ('153', '156'))	('necrosis', 'biological_process', 'GO:0008219', ('91', '99'))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (175, 181))	('breast cancer', 'Disease', (168, 181))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('necrosis', 'biological_process', 'GO:0008220', ('91', '99'))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('c-Met', 'Var', (138, 143))	('necrosis', 'Disease', 'MESH:D009336', (91, 99))	('necrosis', 'biological_process', 'GO:0070265', ('91', '99'))	('necrosis', 'biological_process', 'GO:0019835', ('91', '99'))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('necrosis', 'Disease', (91, 99))	('necrosis', 'biological_process', 'GO:0001906', ('91', '99'))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('cancer', 'Disease', (121, 127))
85371	32600123	Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored.	('malignant pleural mesothelioma', 'Disease', (177, 207))	('EML4', 'Gene', (157, 161))	('L1196M', 'Var', (40, 46))	('EML4', 'Gene', '27436', (157, 161))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (243, 262))	('malignant pleural mesothelioma', 'Disease', (111, 141))	('G1202R', 'Var', (51, 57))	('lorlatinib', 'Chemical', 'MESH:C000590786', (312, 322))	('anaplastic lymphoma kinase', 'Gene', '238', (243, 269))	('ALK', 'Gene', '238', (28, 31))	('L1196M', 'Mutation', 'rs1057519784', (40, 46))	('ALK', 'Gene', '238', (162, 165))	('anaplastic lymphoma kinase', 'Gene', (243, 269))	('ALK', 'Gene', (28, 31))	('MPM', 'Chemical', '-', (209, 212))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (187, 207))	('ALK', 'Gene', (162, 165))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (177, 207))	('lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('ALK', 'Gene', '238', (271, 274))	('ALK', 'Gene', '238', (96, 99))	('I1171N', 'Mutation', 'rs1057519698', (32, 38))	('EML4', 'Gene', (91, 95))	('mediate', 'Reg', (58, 65))	('ALK', 'Gene', (271, 274))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (111, 141))	('EML4', 'Gene', '27436', (91, 95))	('ALK', 'Gene', (96, 99))	('I1171N', 'Var', (32, 38))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (121, 141))	('G1202R', 'Mutation', 'rs1057519783', (51, 57))	('alectinib', 'Chemical', 'MESH:C582670', (298, 307))	('lorlatinib', 'Chemical', 'MESH:C000590786', (66, 76))
85373	32600123	Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression.	('L1196M', 'Mutation', 'rs1057519784', (61, 67))	('alectinib', 'Gene', (71, 80))	('L1196M', 'Var', (61, 67))	('I1171N', 'Mutation', 'rs1057519698', (50, 56))	('ALK', 'Gene', '238', (46, 49))	('alectinib', 'Chemical', 'MESH:C582670', (71, 80))	('ALK', 'Gene', (46, 49))
85374	32600123	Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R.	('G1202R', 'Mutation', 'rs1057519783', (35, 41))	('L1196M', 'Mutation', 'rs1057519784', (23, 29))	('L1196M', 'Var', (23, 29))	('I1171N', 'Mutation', 'rs1057519698', (15, 21))	('lorlatinib progression', 'MPA', (71, 93))	('L1196M', 'Mutation', 'rs1057519784', (103, 109))	('L1196M', 'Var', (103, 109))	('ALK', 'Gene', (11, 14))	('G1202R', 'Mutation', 'rs1057519783', (139, 145))	('lorlatinib', 'Chemical', 'MESH:C000590786', (71, 81))	('G1202R', 'Var', (35, 41))	('G1202R', 'Var', (139, 145))	('ALK', 'Gene', '238', (11, 14))
85375	32600123	We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib.	('resistance to', 'MPA', (72, 85))	('mutations', 'Var', (33, 42))	('mediated', 'Reg', (59, 67))	('lorlatinib', 'Chemical', 'MESH:C000590786', (105, 115))	('alectinib', 'Chemical', 'MESH:C582670', (91, 100))
85377	32600123	Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy.	('lorlatinib', 'Chemical', 'MESH:C000590786', (56, 66))	('ALK', 'Gene', '238', (261, 264))	('ALK', 'Gene', (109, 112))	('mediated', 'Reg', (78, 86))	('I1171N', 'Var', (113, 119))	('ALK', 'Gene', (261, 264))	('G1202R', 'Var', (133, 139))	('I1171N', 'Mutation', 'rs1057519698', (113, 119))	('L1196M', 'Mutation', 'rs1057519784', (121, 127))	('L1196M', 'Var', (121, 127))	('ALK', 'Gene', '238', (109, 112))	('G1202R', 'Mutation', 'rs1057519783', (133, 139))	('lorlatinib resistance', 'MPA', (56, 77))
85384	32600123	Conversely, ALK rearrangements have been identified only in peritoneal mesothelioma, but not in MPM.	('MPM', 'Chemical', '-', (96, 99))	('ALK', 'Gene', (12, 15))	('mesothelioma', 'Disease', (71, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('ALK', 'Gene', '238', (12, 15))	('rearrangements', 'Var', (16, 30))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (60, 83))
85406	32600123	Plasma NGS at PD revealed the emergence of two acquired missense mutations in the ALK kinase domain, I1171N and L1196M.	('L1196M', 'Var', (112, 118))	('I1171N', 'Var', (101, 107))	('ALK', 'Gene', (82, 85))	('I1171N', 'Mutation', 'rs1057519698', (101, 107))	('PD', 'Disease', 'MESH:D010300', (14, 16))	('ALK', 'Gene', '238', (82, 85))	('L1196M', 'Mutation', 'rs1057519784', (112, 118))
85411	32600123	In addition to the concurrent mutations detected previously, plasma NGS revealed the emergence of ALK G1202R.	('G1202R', 'Mutation', 'rs1057519783', (102, 108))	('ALK', 'Gene', '238', (98, 101))	('ALK', 'Gene', (98, 101))	('G1202R', 'Var', (102, 108))
85413	32600123	To the best of our knowledge, our study is the first to identify EML4-ALK rearrangements in a patient with MPM and describes his clinical response and molecular mechanisms of resistance to alectinib and lorlatinib.	('lorlatinib', 'Chemical', 'MESH:C000590786', (203, 213))	('alectinib', 'Chemical', 'MESH:C582670', (189, 198))	('MPM', 'Chemical', '-', (107, 110))	('MPM', 'Disease', (107, 110))	('ALK', 'Gene', '238', (70, 73))	('EML4', 'Gene', (65, 69))	('EML4', 'Gene', '27436', (65, 69))	('patient', 'Species', '9606', (94, 101))	('ALK', 'Gene', (70, 73))	('rearrangements', 'Var', (74, 88))
85414	32600123	Furthermore, our report is also the first to provide clinical evidence of the mechanism of lorlatinib resistance mediated by acquired multiple mutations ALK I1171N, L1196M, and G1202R.	('G1202R', 'Mutation', 'rs1057519783', (177, 183))	('G1202R', 'Var', (177, 183))	('ALK', 'Gene', (153, 156))	('mediated', 'Reg', (113, 121))	('L1196M', 'Mutation', 'rs1057519784', (165, 171))	('lorlatinib', 'Chemical', 'MESH:C000590786', (91, 101))	('ALK', 'Gene', '238', (153, 156))	('L1196M', 'Var', (165, 171))	('I1171N', 'Mutation', 'rs1057519698', (157, 163))
85416	32600123	Instead of genetic alterations in classic NSCLC oncogenic drivers, comprehensive genomic studies in MPM have revealed mutations in four pathways including the TP53/DNA repair, cell cycle, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways.	('cell cycle', 'CPA', (176, 186))	('DNA repair', 'biological_process', 'GO:0006281', ('164', '174'))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('MPM', 'Chemical', '-', (100, 103))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('phosphoinositide 3-kinase', 'Gene', '5293', (233, 258))	('TP53', 'Gene', '7157', (159, 163))	('AKT', 'Gene', (266, 269))	('MAPK', 'molecular_function', 'GO:0004707', ('222', '226'))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('mutations', 'Var', (118, 127))	('phosphoinositide 3-kinase', 'Gene', (233, 258))	('cell cycle', 'biological_process', 'GO:0007049', ('176', '186'))	('MPM', 'Gene', (100, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('260', '264'))	('NSCLC', 'Disease', (42, 47))	('AKT', 'Gene', '207', (266, 269))	('TP53', 'Gene', (159, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))
85418	32600123	Despite the remarkable clinical responses he achieved with alectinib and lorlatinib, resistance to these inhibitors developed within 3.5 months through the emergence of multiple secondary missense mutations in the kinase domain of ALK.	('lorlatinib', 'Chemical', 'MESH:C000590786', (73, 83))	('ALK', 'Gene', '238', (231, 234))	('missense mutations in', 'Var', (188, 209))	('alectinib', 'Chemical', 'MESH:C582670', (59, 68))	('ALK', 'Gene', (231, 234))
85419	32600123	His resistance to alectinib was potentially mediated by the acquisition of ALK I1171N and L1196M (Figure 1).	('I1171N', 'Var', (79, 85))	('mediated', 'Reg', (44, 52))	('ALK', 'Gene', (75, 78))	('alectinib', 'Chemical', 'MESH:C582670', (18, 27))	('ALK', 'Gene', '238', (75, 78))	('L1196M', 'Var', (90, 96))	('L1196M', 'Mutation', 'rs1057519784', (90, 96))	('I1171N', 'Mutation', 'rs1057519698', (79, 85))
85420	32600123	He responded to lorlatinib until the emergence of ALK G1202R confirmed to be in cis to L1196M (Figure 2) and concurrent to I1171N.	('ALK', 'Gene', (50, 53))	('G1202R', 'Var', (54, 60))	('G1202R', 'Mutation', 'rs1057519783', (54, 60))	('lorlatinib', 'Chemical', 'MESH:C000590786', (16, 26))	('I1171N', 'Mutation', 'rs1057519698', (123, 129))	('ALK', 'Gene', '238', (50, 53))	('responded to lorlatinib', 'MPA', (3, 26))	('L1196M', 'Mutation', 'rs1057519784', (87, 93))
85421	32600123	These three missense mutations are commonly acquired, albeit as single or double mutation(s), during ALK-TKI therapy, and mediate drug resistance.	('missense mutations', 'Var', (12, 30))	('ALK', 'Gene', (101, 104))	('mediate', 'Reg', (122, 129))	('ALK', 'Gene', '238', (101, 104))	('drug resistance', 'biological_process', 'GO:0009315', ('130', '145'))	('drug resistance', 'biological_process', 'GO:0042493', ('130', '145'))	('double mutation', 'Var', (74, 89))	('drug resistance', 'Phenotype', 'HP:0020174', (130, 145))
85422	32600123	ALK I1171N has been shown to be resistant to crizotinib and alectinib, but sensitive to ceritinib and lorlatinib, whereas L1196M is resistant to crizotinib and sensitive to alectinib, ceritinib, and lorlatinib; G1202R is resistant to crizotinib, alectinib, and ceritinib, and is sensitive to lorlatinib.	('G1202R', 'Var', (211, 217))	('I1171N', 'Mutation', 'rs1057519698', (4, 10))	('lorlatinib', 'Chemical', 'MESH:C000590786', (199, 209))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))	('ceritinib', 'Chemical', 'MESH:C586847', (184, 193))	('ceritinib', 'Chemical', 'MESH:C586847', (88, 97))	('crizotinib', 'Chemical', 'MESH:D000077547', (234, 244))	('alectinib', 'Chemical', 'MESH:C582670', (246, 255))	('I1171N', 'Var', (4, 10))	('crizotinib', 'Chemical', 'MESH:D000077547', (145, 155))	('lorlatinib', 'Chemical', 'MESH:C000590786', (292, 302))	('L1196M', 'Var', (122, 128))	('alectinib', 'Chemical', 'MESH:C582670', (173, 182))	('lorlatinib', 'Chemical', 'MESH:C000590786', (102, 112))	('ALK', 'Gene', '238', (0, 3))	('L1196M', 'Mutation', 'rs1057519784', (122, 128))	('ceritinib', 'Chemical', 'MESH:C586847', (261, 270))	('G1202R', 'Mutation', 'rs1057519783', (211, 217))	('ALK', 'Gene', (0, 3))	('alectinib', 'Chemical', 'MESH:C582670', (60, 69))
85423	32600123	Whereas single mutations of I1171N, L1196M, and G1202R are sensitive to lorlatinib, preclinical evidence had demonstrated lorlatinib resistance in compound mutations between G1202R and either L1196M or I1171N.	('L1196M', 'Var', (36, 42))	('L1196M', 'Mutation', 'rs1057519784', (192, 198))	('L1196M', 'Var', (192, 198))	('demonstrated', 'Reg', (109, 121))	('G1202R', 'Var', (174, 180))	('I1171N', 'Mutation', 'rs1057519698', (202, 208))	('G1202R', 'Mutation', 'rs1057519783', (174, 180))	('lorlatinib', 'Chemical', 'MESH:C000590786', (122, 132))	('G1202R', 'Var', (48, 54))	('lorlatinib resistance', 'MPA', (122, 143))	('I1171N', 'Var', (202, 208))	('I1171N', 'Mutation', 'rs1057519698', (28, 34))	('G1202R', 'Mutation', 'rs1057519783', (48, 54))	('I1171N', 'Var', (28, 34))	('L1196M', 'Mutation', 'rs1057519784', (36, 42))	('lorlatinib', 'Chemical', 'MESH:C000590786', (72, 82))
85424	32600123	Ceritinib is potentially effective in targeting ALK I1171N/L1196M double mutations, whereas ALK G1202R/L1196M is resistant to all available ALK-TKI.	('ALK', 'Gene', (92, 95))	('ALK', 'Gene', '238', (48, 51))	('ALK', 'Gene', (140, 143))	('L1196M', 'Mutation', 'rs1057519784', (103, 109))	('L1196M', 'Mutation', 'rs1057519784', (59, 65))	('ALK', 'Gene', (48, 51))	('I1171N', 'Mutation', 'rs1057519698', (52, 58))	('ALK', 'Gene', '238', (92, 95))	('ALK', 'Gene', '238', (140, 143))	('G1202R', 'Mutation', 'rs1057519783', (96, 102))	('Ceritinib', 'Chemical', 'MESH:C586847', (0, 9))	('G1202R/L1196M', 'Var', (96, 109))
85425	32600123	The resistance to alectinib and lorlatinib therapy in our patient was potentially mediated by multiple mutations ALK I1171N/L1196M and ALK I1171N/L1196M/G1202R, respectively.	('ALK', 'Gene', (135, 138))	('G1202R', 'Mutation', 'rs1057519783', (153, 159))	('alectinib', 'Chemical', 'MESH:C582670', (18, 27))	('I1171N/L1196M/G1202R', 'Var', (139, 159))	('ALK', 'Gene', (113, 116))	('patient', 'Species', '9606', (58, 65))	('ALK', 'Gene', '238', (135, 138))	('lorlatinib', 'Chemical', 'MESH:C000590786', (32, 42))	('L1196M', 'Mutation', 'rs1057519784', (146, 152))	('L1196M', 'Mutation', 'rs1057519784', (124, 130))	('mediated by', 'Reg', (82, 93))	('ALK', 'Gene', '238', (113, 116))	('I1171N', 'Mutation', 'rs1057519698', (117, 123))	('I1171N', 'Mutation', 'rs1057519698', (139, 145))
85428	32600123	Our report provides clinical evidence of the identification of EML4-ALK rearrangement in a patient with MPM, which is very rare, as well as his therapeutic response to ALK-TKIs.	('ALK', 'Gene', '238', (168, 171))	('MPM', 'Chemical', '-', (104, 107))	('ALK', 'Gene', (68, 71))	('EML4', 'Gene', (63, 67))	('ALK', 'Gene', (168, 171))	('rearrangement', 'Var', (72, 85))	('ALK', 'Gene', '238', (68, 71))	('EML4', 'Gene', '27436', (63, 67))	('patient', 'Species', '9606', (91, 98))	('MPM', 'Disease', (104, 107))
85429	32600123	Moreover, our case also identified the acquired mechanisms of lorlatinib resistance mediated by multiple missense mutations in ALK kinase domain, I1171N, L1196M, and G1202R.	('G1202R', 'Var', (166, 172))	('lorlatinib', 'Chemical', 'MESH:C000590786', (62, 72))	('G1202R', 'Mutation', 'rs1057519783', (166, 172))	('L1196M', 'Mutation', 'rs1057519784', (154, 160))	('L1196M', 'Var', (154, 160))	('I1171N', 'Mutation', 'rs1057519698', (146, 152))	('I1171N', 'Var', (146, 152))	('mediated by', 'Reg', (84, 95))	('ALK', 'Gene', (127, 130))	('ALK', 'Gene', '238', (127, 130))
85499	31341276	Antagonizing this signalling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through upregulation of multiple ferroptosis modulators, including acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor.	('ACSL4', 'Gene', (251, 256))	('acyl-CoA synthetase long chain family member 4', 'Gene', '2182', (203, 249))	('ferroptosis', 'biological_process', 'GO:0097707', ('169', '180'))	('transferrin receptor', 'Gene', (262, 282))	('activity', 'MPA', (48, 56))	('acyl-CoA synthetase long chain family member 4', 'Gene', (203, 249))	('ferroptosis', 'biological_process', 'GO:0097707', ('124', '135'))	('transferrin receptor', 'Gene', '7037', (262, 282))	('promote', 'PosReg', (116, 123))	('Antagonizing', 'Var', (0, 12))	('upregulation', 'PosReg', (144, 156))	('ferroptosis', 'Disease', (124, 135))	('signalling', 'biological_process', 'GO:0023052', ('18', '28'))
85501	31341276	Finally, we found that genetic inactivation of the tumour suppressor Merlin, a frequent tumourigenic event in mesothelioma, renders cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma.	('mouse', 'Species', '10090', (192, 197))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (207, 229))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('more', 'PosReg', (145, 149))	('genetic inactivation', 'Var', (23, 43))	('mesothelioma', 'Disease', (217, 229))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('malignant mesothelioma', 'Disease', (207, 229))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (217, 229))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('ferroptosis', 'biological_process', 'GO:0097707', ('163', '174'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (207, 229))	('Merlin', 'Gene', (69, 75))	('tumour', 'Disease', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('mesothelioma', 'Disease', (110, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('sensitive to ferroptosis', 'MPA', (150, 174))
85502	31341276	Together, this study unveils the role of intercellular interaction and intracellular Merlin-YAP signalling in dictating ferroptotic death; it also suggests that malignant mutations in Merlin-YAP signalling can serve as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies.	('intracellular', 'cellular_component', 'GO:0005622', ('71', '84'))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('mutations', 'Var', (171, 180))	('ferroptosis', 'biological_process', 'GO:0097707', ('278', '289'))	('signalling', 'biological_process', 'GO:0023052', ('195', '205'))	('Merlin-YAP signalling', 'Gene', (184, 205))	('signalling', 'biological_process', 'GO:0023052', ('96', '106'))
85512	31341276	Strong expression of Ecad was detected in spheroids generated from HCT116 cells, but not those generated from MDA231 cells (Extended Data Fig.	('MDA231', 'CellLine', 'CVCL:0062', (110, 116))	('HCT116', 'Var', (67, 73))	('HCT116', 'CellLine', 'CVCL:0291', (67, 73))	('Ecad', 'Gene', (21, 25))
85521	31341276	Importantly, knockdown of Ecad, Merlin, and Lats1/2 did not decrease cell proliferation within the time frame of the experiment, ruling out the possibility that increased ferroptosis was due to reduced cell confluence (Extended Data Fig.	('Lats1/2', 'Gene', (44, 51))	('ferroptosis', 'biological_process', 'GO:0097707', ('171', '182'))	('ferroptosis', 'Disease', (171, 182))	('cell confluence', 'CPA', (202, 217))	('reduced', 'NegReg', (194, 201))	('Ecad', 'Gene', (26, 30))	('Lats1/2', 'Gene', '8140;7462', (44, 51))	('increased', 'PosReg', (161, 170))	('knockdown', 'Var', (13, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
85522	31341276	Heterozygous deletion and loss-of-function mutations of the Merlin-encoding gene NF2 are detected with high frequency in malignant mesothelioma (MM), and inactivation of either Merlin or Lats1/2 is observed in ~50% of MM patients.	('NF2', 'Gene', '4771', (81, 84))	('patients', 'Species', '9606', (221, 229))	('malignant mesothelioma', 'Disease', (121, 143))	('Lats1/2', 'Gene', (187, 194))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (121, 143))	('mutations', 'Var', (43, 52))	('Lats1/2', 'Gene', '8140;7462', (187, 194))	('NF2', 'Gene', (81, 84))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (121, 143))	('loss-of-function', 'NegReg', (26, 42))
85533	31341276	The YAPS127A mutant cannot be phosphorylated by Lats1/2 at the S127 residue, thus enhancing nuclear retention and transcriptional co-regulatory activity even at high density (Extended Data Fig.	('Lats1/2', 'Gene', (48, 55))	('retention', 'biological_process', 'GO:0051235', ('100', '109'))	('transcriptional co-regulatory activity', 'MPA', (114, 152))	('YAPS127A', 'Mutation', 'rs762471803', (4, 12))	('Lats1/2', 'Gene', '8140;7462', (48, 55))	('enhancing', 'PosReg', (82, 91))	('nuclear retention', 'MPA', (92, 109))	('S127', 'Chemical', 'MESH:C000670', (7, 11))	('S127', 'Chemical', 'MESH:C000670', (63, 67))	('YAPS127A', 'Var', (4, 12))
85534	31341276	HCT116 or 211H cells expressing YAPS127A were markedly more sensitive to ferroptosis at high density or in spheroids (Fig.	('sensitive', 'Reg', (60, 69))	('YAPS127A', 'Var', (32, 40))	('ferroptosis', 'MPA', (73, 84))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('ferroptosis', 'biological_process', 'GO:0097707', ('73', '84'))	('more', 'PosReg', (55, 59))	('YAPS127A', 'Mutation', 'rs762471803', (32, 40))
85536	31341276	Putative YAP-TEAD gene targets were selected from TEAD4 ENCODE ChIP-seq datasets GSM1010875 and GSM1010868.	('GSM1010875', 'Chemical', 'MESH:C581775', (81, 91))	('GSM1010875', 'Var', (81, 91))	('GSM1010868', 'Chemical', 'MESH:C581775', (96, 106))	('GSM1010868', 'Var', (96, 106))	('TEAD4', 'Gene', '7004', (50, 55))	('TEAD4', 'Gene', (50, 55))
85538	31341276	Expression of TFRC and ACSL4 decreased with increasing cell density, and TFRC and ACSL4 were upregulated by Ecad depletion, Merlin knockdown, or YAPS127A overexpression (Fig.	('knockdown', 'Var', (131, 140))	('Expression', 'MPA', (0, 10))	('TFRC', 'Gene', (14, 18))	('TFRC', 'Gene', (73, 77))	('YAPS127A', 'Var', (145, 153))	('depletion', 'Var', (113, 122))	('ACSL4', 'Gene', (23, 28))	('overexpression', 'PosReg', (154, 168))	('ACSL4', 'Gene', (82, 87))	('decreased', 'NegReg', (29, 38))	('upregulated', 'PosReg', (93, 104))	('YAPS127A', 'Mutation', 'rs762471803', (145, 153))
85539	31341276	TEAD4 binds to the promoter regions of TFRC and ACSL4 genes, and binding was enhanced by YAPS127A overexpression (Fig.	('YAPS127A', 'Var', (89, 97))	('ACSL4', 'Gene', (48, 53))	('enhanced', 'PosReg', (77, 85))	('binding', 'Interaction', (65, 72))	('overexpression', 'PosReg', (98, 112))	('YAPS127A', 'Mutation', 'rs762471803', (89, 97))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('TEAD4', 'Gene', '7004', (0, 5))	('TEAD4', 'Gene', (0, 5))	('binds', 'Interaction', (6, 11))	('TFRC', 'Gene', (39, 43))
85541	31341276	As loss of Merlin frequently drives mesothelioma, we examined whether Merlin status could predict mesothelioma sensitivity to ferroptosis.	('loss', 'Var', (3, 7))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('drives', 'Reg', (29, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('ferroptosis', 'biological_process', 'GO:0097707', ('126', '137'))	('Merlin', 'Protein', (11, 17))	('mesothelioma', 'Disease', (36, 48))	('mesothelioma', 'Disease', (98, 110))
85544	31341276	In tumours, Merlin knockdown increased TFRC and ACSL4 expression, and nuclear YAP (Extended Data Fig.	('expression', 'MPA', (54, 64))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('TFRC', 'MPA', (39, 43))	('Merlin', 'Gene', (12, 18))	('knockdown', 'Var', (19, 28))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('ACSL4', 'Protein', (48, 53))	('increased', 'PosReg', (29, 38))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))
85547	31341276	Similarly, Lats1/2 knockdown rendered xenograft tumours generated by HCT116 cells significantly more sensitive to imidazole ketone erastin (IKE), an erastin derivative amenable for use in vivo (Fig.	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('knockdown', 'Var', (19, 28))	('Lats1/2', 'Gene', '8140;7462', (11, 18))	('more', 'PosReg', (96, 100))	('imidazole ketone', 'Chemical', 'MESH:D007659', (114, 130))	('sensitive to imidazole', 'MPA', (101, 123))	('HCT116', 'CellLine', 'CVCL:0291', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('Lats1/2', 'Gene', (11, 18))
85552	31341276	Importantly, the metastatic capability of shMerlin tumours was reduced by Dox-induced GPX4 knockout (Fig.	('shMerlin tumours', 'Disease', (42, 58))	('Dox', 'Chemical', 'MESH:C561093', (74, 77))	('knockout', 'Var', (91, 99))	('reduced', 'NegReg', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('shMerlin tumours', 'Disease', 'MESH:D009369', (42, 58))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('GPX4', 'Gene', (86, 90))	('metastatic capability', 'CPA', (17, 38))
85562	31341276	Further, unlike YAPS127A, overexpression of the oncogenic PIK3CAH1047R mutant failed to sensitise confluent 211H cells to ferroptosis, although both increased proliferation (Extended Data Fig.	('YAPS127A', 'Mutation', 'rs762471803', (16, 24))	('PIK3', 'Gene', (58, 62))	('increased', 'PosReg', (149, 158))	('ferroptosis', 'biological_process', 'GO:0097707', ('122', '133'))	('proliferation', 'CPA', (159, 172))	('PIK3', 'Gene', '5294', (58, 62))	('mutant', 'Var', (71, 77))
85563	31341276	As the cadherin-Merlin-Hippo-YAP signalling axis is frequently mutated in cancer, this study has clear cancer therapeutic implications - malignant alterations of multiple components in this signalling axis all sensitise cancer cells to ferroptosis.	('axis all sensitise cancer', 'Disease', (201, 226))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (103, 109))	('ferroptosis', 'biological_process', 'GO:0097707', ('236', '247'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('alterations', 'Var', (147, 158))	('cadherin', 'Gene', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('signalling', 'biological_process', 'GO:0023052', ('33', '43'))	('cadherin', 'molecular_function', 'GO:0008014', ('7', '15'))	('ferroptosis', 'CPA', (236, 247))	('signalling', 'biological_process', 'GO:0023052', ('190', '200'))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('axis all sensitise cancer', 'Disease', 'MESH:D009369', (201, 226))	('cadherin', 'Gene', '999;12550;1000', (7, 15))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))
85735	25175943	The redox-directed mechanism of action of Taurolidine is apparent from the finding that reducing agents e.g., N-acetylcysteine or glutathione impair its cytotoxicity, while its effectiveness is enhanced by agents which inhibit the cellular anti-oxidant capacity.	('glutathione impair', 'Phenotype', 'HP:0003343', (130, 148))	('effectiveness', 'MPA', (177, 190))	('Taurolidine', 'Chemical', 'MESH:C012566', (42, 53))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (110, 126))	('cytotoxicity', 'Disease', 'MESH:D064420', (153, 165))	('glutathione', 'MPA', (130, 141))	('impair', 'NegReg', (142, 148))	('N-acetylcysteine', 'Var', (110, 126))	('enhanced', 'PosReg', (194, 202))	('glutathione', 'Chemical', 'MESH:D005978', (130, 141))	('cytotoxicity', 'Disease', (153, 165))
85750	25175943	In keeping with this hypothesis, small molecular weight pro-oxidant drugs, which enhance the oxidative stress in tumor cells, are considered as potential antineoplastic agents.	('tumor', 'Disease', (113, 118))	('oxidative stress', 'MPA', (93, 109))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('enhance', 'PosReg', (81, 88))	('small molecular', 'Var', (33, 48))
85804	25175943	In keeping with the ROS-dependent mechanism of action, Taurolidine was effective independent of whether p53 was mutated or not.	('p53', 'Gene', (104, 107))	('Taurolidine', 'Chemical', 'MESH:C012566', (55, 66))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('p53', 'Gene', '7157', (104, 107))	('mutated', 'Var', (112, 119))
85904	33472486	Immunohistochemical staining showed that the lesions were positive for AE1/AE3, vimentin, cytokeratin 5/6 (CK5/6), calretinin, podoplanin (D2-40), Wilms' tumor protein (WT-1), p53 (>50%), and Ki-67 (<15%); partially positive for Pax-8; and negative for desmin, estrogen receptor (ER), progesterone receptor (PR), and carcinoembryonic antigen (CEA) (Figure 2).	('CK5/6', 'Gene', (107, 112))	('carcinoembryonic antigen', 'Gene', (317, 341))	('calretinin', 'Gene', (115, 125))	('estrogen receptor', 'Gene', (261, 278))	("Wilms' tumor protein", 'Gene', '7490', (147, 167))	('p53', 'Gene', '7157', (176, 179))	('podoplanin', 'Gene', '10630', (127, 137))	('desmin', 'cellular_component', 'GO:0045098', ('253', '259'))	('Pax-8', 'Gene', '7849', (229, 234))	('AE3', 'Gene', (75, 78))	('cytokeratin 5/6', 'Gene', '3852', (90, 105))	('desmin', 'Gene', (253, 259))	('Ki-67', 'Var', (192, 197))	('vimentin', 'cellular_component', 'GO:0045099', ('80', '88'))	('WT-1', 'Gene', '7490', (169, 173))	('p53', 'Gene', (176, 179))	("Wilms' tumor protein", 'Gene', (147, 167))	('CEA', 'Gene', (343, 346))	('AE1', 'Gene', '6521', (71, 74))	('podoplanin', 'Gene', (127, 137))	('calretinin', 'Gene', '794', (115, 125))	('PR', 'Gene', '5241', (308, 310))	('carcinoembryonic antigen', 'Gene', '1084', (317, 341))	('progesterone receptor', 'Gene', (285, 306))	('progesterone receptor', 'Gene', '5241', (285, 306))	('AE3', 'Gene', '6508', (75, 78))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('desmin', 'Gene', '1674', (253, 259))	('vimentin', 'Gene', '7431', (80, 88))	('estrogen receptor', 'Gene', '2099', (261, 278))	('vimentin', 'Gene', (80, 88))	('CEA', 'Gene', '1084', (343, 346))	('AE1', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CK5/6', 'Gene', '3852', (107, 112))	('WT-1', 'Gene', (169, 173))	('desmin', 'cellular_component', 'GO:0045100', ('253', '259'))	('Pax-8', 'Gene', (229, 234))	('vimentin', 'cellular_component', 'GO:0045098', ('80', '88'))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (147, 159))	('ER', 'Gene', '2099', (280, 282))	('cytokeratin 5/6', 'Gene', (90, 105))
85947	30423827	Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells.	('Pyruvate', 'Chemical', 'MESH:D019289', (0, 8))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (107, 127))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('resistant phenotype', 'CPA', (224, 243))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('metabolism', 'biological_process', 'GO:0008152', ('197', '207'))	('dysfunction', 'Var', (177, 188))	('Effectiveness', 'MPA', (32, 45))	('Human', 'Species', '9606', (76, 81))	('Colon Adenocarcinoma and Pleural Mesothelioma', 'Disease', 'MESH:D008654', (82, 127))	('sustain', 'Reg', (214, 221))
85950	30423827	For the first time, we have shown that human colon adenocarcinoma cells (HT29) and its chemoresistant counterpart (HT29-dx) displayed different carbon metabolism: HT29-dx cells had a higher glucose consumption compared to HT29 cells, whereas human malignant mesothelioma (HMM) cells showed a lower glucose consumption compared to HT29 cells, accompanied by a lower pyruvate production and, consequently, a higher production of lactate.	('HT29-', 'CellLine', 'CVCL:0320', (115, 120))	('higher', 'PosReg', (183, 189))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (45, 65))	('HT29-dx', 'Var', (163, 170))	('HT29-', 'CellLine', 'CVCL:0320', (163, 168))	('higher', 'PosReg', (406, 412))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (248, 270))	('production of lactate', 'MPA', (413, 434))	('glucose consumption', 'Disease', 'MESH:D014397', (298, 317))	('MM', 'Disease', 'MESH:D009101', (273, 275))	('pyruvate production', 'MPA', (365, 384))	('lactate', 'Chemical', 'MESH:D019344', (427, 434))	('HT29 cells', 'CellLine', 'CVCL:0320', (222, 232))	('lower', 'NegReg', (359, 364))	('human', 'Species', '9606', (39, 44))	('colon adenocarcinoma', 'Disease', (45, 65))	('metabolism', 'biological_process', 'GO:0008152', ('151', '161'))	('HT29)', 'CellLine', 'CVCL:0320', (73, 78))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (248, 270))	('glucose consumption', 'Disease', (190, 209))	('pyruvate', 'Chemical', 'MESH:D019289', (365, 373))	('carbon', 'Chemical', 'MESH:D002244', (144, 150))	('HT29 cells', 'CellLine', 'CVCL:0320', (330, 340))	('glucose consumption', 'Disease', 'MESH:D014397', (190, 209))	('human', 'Species', '9606', (242, 247))	('malignant mesothelioma', 'Disease', (248, 270))	('glucose consumption', 'Disease', (298, 317))
85951	30423827	When treated with pyruvate, both HT29-dx and HMM cells exhibited a re-established accumulation of doxorubicin and a lower survival ability, a decreased activity of multidrug resistance protein 1 (MRP1) and a restored mitochondrial respiratory chain function, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells.	('lower', 'NegReg', (116, 121))	('improving', 'PosReg', (259, 268))	('activity', 'MPA', (152, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('multidrug resistance protein 1', 'Gene', '5243', (164, 194))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('mitochondrial respiratory chain function', 'MPA', (217, 257))	('accumulation', 'PosReg', (82, 94))	('mitochondrial respiratory chain', 'cellular_component', 'GO:0005746', ('217', '248'))	('MRP1', 'Gene', (196, 200))	('restored', 'Reg', (208, 216))	('HT29-', 'CellLine', 'CVCL:0320', (33, 38))	('decreased', 'NegReg', (142, 151))	('pyruvate', 'Chemical', 'MESH:D019289', (18, 26))	('drug resistance', 'Phenotype', 'HP:0020174', (169, 184))	('MRP1', 'Gene', '5243', (196, 200))	('HT29-dx', 'Var', (33, 40))	('cancer', 'Disease', (337, 343))	('doxorubicin', 'MPA', (98, 109))	('multidrug resistance protein 1', 'Gene', (164, 194))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('164', '192'))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('survival ability', 'CPA', (122, 138))	('MM', 'Disease', 'MESH:D009101', (46, 48))
85964	30423827	Consequently, the pyruvate level increased in all the cell lines during the incubation time (as described in Section 4), and we observed that the production of pyruvate was significantly lower in HT29-dx and HMM cells compared to HT29 cells (Figure 1A).	('HT29-dx', 'Var', (196, 203))	('MM', 'Disease', 'MESH:D009101', (209, 211))	('HT29 cells', 'CellLine', 'CVCL:0320', (230, 240))	('pyruvate level', 'MPA', (18, 32))	('pyruvate level increased', 'Phenotype', 'HP:0003542', (18, 42))	('pyruvate', 'Chemical', 'MESH:D019289', (18, 26))	('increased', 'PosReg', (33, 42))	('lower', 'NegReg', (187, 192))	('HT29-', 'CellLine', 'CVCL:0320', (196, 201))	('production of pyruvate', 'MPA', (146, 168))	('pyruvate', 'Chemical', 'MESH:D019289', (160, 168))
85965	30423827	Moreover, as shown by both techniques, HT29-dx and HMM cells produced a higher amount of lactate compared to HT29 cells (Figure 1B).	('lactate', 'Chemical', 'MESH:D019344', (89, 96))	('HT29-', 'CellLine', 'CVCL:0320', (39, 44))	('MM', 'Disease', 'MESH:D009101', (52, 54))	('HT29 cells', 'CellLine', 'CVCL:0320', (109, 119))	('lactate', 'MPA', (89, 96))	('higher', 'PosReg', (72, 78))	('HT29-dx', 'Var', (39, 46))
85977	30423827	The lack of the increase in 13CO2 production in HT29-dx compared to HT29 cells suggests a limitation of the functioning of the Krebs cycle, which did not respond to an increase in pyruvate levels and afterwards acetyl-CoA production.	('acetyl-CoA', 'Chemical', 'MESH:D000105', (211, 221))	('increase in pyruvate levels', 'Phenotype', 'HP:0003542', (168, 195))	('Krebs', 'Chemical', '-', (127, 132))	('acetyl-CoA production', 'MPA', (211, 232))	('Krebs cycle', 'biological_process', 'GO:0006099', ('127', '138'))	('HT29-dx', 'Var', (48, 55))	('13CO2', 'Chemical', '-', (28, 33))	('13CO2 production', 'MPA', (28, 44))	('HT29 cells', 'CellLine', 'CVCL:0320', (68, 78))	('pyruvate', 'Chemical', 'MESH:D019289', (180, 188))	('HT29-', 'CellLine', 'CVCL:0320', (48, 53))	('pyruvate levels', 'MPA', (180, 195))
85988	30423827	The LDH-A mRNA expression and the LDH intracellular activity were significantly increased in HT29-dx cells compared to HT29 cells (Figure 4).	('LDH-A', 'Gene', (4, 9))	('HT29-dx', 'Var', (93, 100))	('increased', 'PosReg', (80, 89))	('intracellular', 'cellular_component', 'GO:0005622', ('38', '51'))	('mRNA expression', 'MPA', (10, 25))	('HT29 cells', 'CellLine', 'CVCL:0320', (119, 129))	('LDH-A', 'Gene', '3939', (4, 9))	('HT29-', 'CellLine', 'CVCL:0320', (93, 98))	('LDH intracellular activity', 'MPA', (34, 60))
85994	30423827	The intracellular fluorescence of rhodamine 123, used as index of Pgp plus MRP1 activity, was significantly lower in HT29-dx and HMM cells compared to HT29 cells, whereas it was significantly higher in HT29-dx and HMM cells treated with pyruvate compared to the untreated ones (Figure 7).	('MM', 'Disease', 'MESH:D009101', (215, 217))	('HT29 cells', 'CellLine', 'CVCL:0320', (151, 161))	('MM', 'Disease', 'MESH:D009101', (130, 132))	('MRP1', 'Gene', (75, 79))	('intracellular', 'cellular_component', 'GO:0005622', ('4', '17'))	('HT29-dx', 'Var', (117, 124))	('pyruvate', 'Chemical', 'MESH:D019289', (237, 245))	('higher', 'PosReg', (192, 198))	('rhodamine 123', 'Chemical', 'MESH:D020112', (34, 47))	('intracellular fluorescence of', 'MPA', (4, 33))	('lower', 'NegReg', (108, 113))	('Pgp', 'Gene', (66, 69))	('Pgp', 'Gene', '5243', (66, 69))	('MRP1', 'Gene', '5243', (75, 79))	('HT29-', 'CellLine', 'CVCL:0320', (202, 207))	('HT29-', 'CellLine', 'CVCL:0320', (117, 122))
86004	30423827	As shown in Figure 10, 20 muM UK5099 for 48 h promoted a significant reduction in doxorubicin accumulation induced by pyruvate in HT29-dx and HMM cells.	('doxorubicin accumulation induced by pyruvate', 'MPA', (82, 126))	('MM', 'Disease', 'MESH:D009101', (143, 145))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('UK5099', 'Var', (30, 36))	('HT29-', 'CellLine', 'CVCL:0320', (130, 135))	('UK5099', 'Chemical', 'MESH:C043654', (30, 36))	('pyruvate', 'Chemical', 'MESH:D019289', (118, 126))	('reduction', 'NegReg', (69, 78))
86005	30423827	Despite the reversion of sensitive phenotype after pyruvate treatment, demonstrating that intramitochondrial pyruvate is required for this phenomenon, the lack of complete effect of UK5099 in doxorubicin accumulation is probably due to a significantly, but not total, reduced pyruvate concentration in mitochondria, as reported by Zhong Y. et al.	('mitochondria', 'cellular_component', 'GO:0005739', ('302', '314'))	('UK5099', 'Chemical', 'MESH:C043654', (182, 188))	('reduced', 'NegReg', (268, 275))	('pyruvate', 'Chemical', 'MESH:D019289', (51, 59))	('doxorubicin', 'Chemical', 'MESH:D004317', (192, 203))	('UK5099', 'Var', (182, 188))	('pyruvate', 'Chemical', 'MESH:D019289', (109, 117))	('pyruvate', 'Chemical', 'MESH:D019289', (276, 284))	('pyruvate concentration', 'MPA', (276, 298))	('doxorubicin accumulation', 'MPA', (192, 216))
86006	30423827	Indeed, there was significantly reduced intramitochondrial pyruvate levels after UK5099 incubation for 48 h in HT29-dx and HMM cells (Figure 11).	('reduced', 'NegReg', (32, 39))	('pyruvate', 'Chemical', 'MESH:D019289', (59, 67))	('UK5099', 'Var', (81, 87))	('UK5099', 'Chemical', 'MESH:C043654', (81, 87))	('intramitochondrial pyruvate levels', 'MPA', (40, 74))	('MM', 'Disease', 'MESH:D009101', (124, 126))	('HT29-', 'CellLine', 'CVCL:0320', (111, 116))
86010	30423827	As shown in Figure 12, doxorubicin (doxo), 5-fluorouracil (5-FU) and oxaliplatin (OPT) had a maximal cytotoxic effect in HT29 cells after 48 h of treatment, whereas the three drugs alone had no effect in HT29-dx and HMM cells.	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('HT29-', 'CellLine', 'CVCL:0320', (204, 209))	('5-fluorouracil', 'Var', (43, 57))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (69, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (23, 34))	('MM', 'Disease', 'MESH:D009101', (217, 219))	('doxo', 'Chemical', 'MESH:D004317', (36, 40))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (43, 57))	('cytotoxic effect', 'CPA', (101, 117))	('doxo', 'Chemical', 'MESH:D004317', (23, 27))	('doxorubicin', 'Var', (23, 34))	('HT29 cells', 'CellLine', 'CVCL:0320', (121, 131))
86013	30423827	As expected, doxorubicin, 5-fluorouracil and oxaliplatin increased the reactive oxygen species (ROS) production in HT29 cells, but not in HT29-dx and HMM cells (Figure 13).	('HT29 cells', 'CellLine', 'CVCL:0320', (115, 125))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (71, 94))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (26, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('MM', 'Disease', 'MESH:D009101', (151, 153))	('5-fluorouracil', 'Var', (26, 40))	('increased', 'PosReg', (57, 66))	('HT29-', 'CellLine', 'CVCL:0320', (138, 143))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (45, 56))
86017	30423827	We observed that HT29-dx and HMM cells had a significant lower activity of the respiratory chain and a significant reduced ATP level compared to HT29 cells (Figure 14A, B).	('activity', 'MPA', (63, 71))	('MM', 'Disease', 'MESH:D009101', (30, 32))	('HT29 cells', 'CellLine', 'CVCL:0320', (145, 155))	('ATP', 'Chemical', 'MESH:D000255', (123, 126))	('reduced', 'NegReg', (115, 122))	('lower activity of the respiratory chain', 'Phenotype', 'HP:0008972', (57, 96))	('respiratory chain', 'cellular_component', 'GO:0070469', ('79', '96'))	('respiratory chain', 'Enzyme', (79, 96))	('HT29-', 'CellLine', 'CVCL:0320', (17, 22))	('ATP level', 'MPA', (123, 132))	('HT29-dx', 'Var', (17, 24))	('lower', 'NegReg', (57, 62))
86019	30423827	As shown in Figure 14, pyruvate was able to restore both respiratory activity and ATP synthesis in HT29-dx and HMM cells, at the same level of HT29 cells.	('restore', 'PosReg', (44, 51))	('MM', 'Disease', 'MESH:D009101', (112, 114))	('pyruvate', 'Chemical', 'MESH:D019289', (23, 31))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))	('pyruvate', 'Var', (23, 31))	('ATP synthesis', 'biological_process', 'GO:0006754', ('82', '95'))	('ATP synthesis', 'MPA', (82, 95))	('HT29-', 'CellLine', 'CVCL:0320', (99, 104))	('respiratory activity', 'MPA', (57, 77))	('HT29 cells', 'CellLine', 'CVCL:0320', (143, 153))
86020	30423827	In presence of pyruvate treatment, the intracellular NAD+/NADH ratio was lower in HT29-dx and HMM cells (Figure 14C).	('NAD+', 'Chemical', 'MESH:D009243', (53, 57))	('pyruvate', 'Var', (15, 23))	('MM', 'Disease', 'MESH:D009101', (95, 97))	('NADH', 'Chemical', 'MESH:D009243', (58, 62))	('HT29-', 'CellLine', 'CVCL:0320', (82, 87))	('intracellular', 'cellular_component', 'GO:0005622', ('39', '52'))	('lower', 'NegReg', (73, 78))	('pyruvate', 'Chemical', 'MESH:D019289', (15, 23))	('intracellular NAD+/NADH ratio', 'MPA', (39, 68))	('HT29-dx', 'Disease', (82, 89))
86026	30423827	As shown in Figure 6, pyruvate was able to significantly revert the doxorubicin accumulation in both HT29-dx and HMM cells.	('HT29-', 'CellLine', 'CVCL:0320', (101, 106))	('doxorubicin accumulation', 'MPA', (68, 92))	('revert', 'NegReg', (57, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (68, 79))	('pyruvate', 'Var', (22, 30))	('MM', 'Disease', 'MESH:D009101', (114, 116))	('pyruvate', 'Chemical', 'MESH:D019289', (22, 30))
86029	30423827	In the present work, we demonstrated that pyruvate treatment re-establishes the sensibility to different chemotherapeutic drugs in HT29-dx and HMM cells through the restoration of respiratory chain functionality.	('restoration', 'PosReg', (165, 176))	('respiratory chain functionality', 'MPA', (180, 211))	('MM', 'Disease', 'MESH:D009101', (144, 146))	('pyruvate', 'Chemical', 'MESH:D019289', (42, 50))	('respiratory chain', 'cellular_component', 'GO:0070469', ('180', '197'))	('sensibility', 'MPA', (80, 91))	('pyruvate', 'Var', (42, 50))	('HT29-', 'CellLine', 'CVCL:0320', (131, 136))
86031	30423827	Firstly, we demonstrated that HT29, HT29-dx and HMM cells had a different carbon metabolism.	('carbon metabolism', 'MPA', (74, 91))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('HT29-dx', 'Var', (36, 43))	('HT29-', 'CellLine', 'CVCL:0320', (36, 41))	('MM', 'Disease', 'MESH:D009101', (49, 51))	('carbon', 'Chemical', 'MESH:D002244', (74, 80))
86049	30423827	The evidence that UK5099 compound promotes a significant reduction in doxorubicin accumulation induced by pyruvate in HT29-dx and HMM cells, is also supported by Li et al.	('pyruvate', 'Chemical', 'MESH:D019289', (106, 114))	('UK5099', 'Chemical', 'MESH:C043654', (18, 24))	('HT29-', 'CellLine', 'CVCL:0320', (118, 123))	('reduction', 'NegReg', (57, 66))	('doxorubicin accumulation induced by pyruvate', 'MPA', (70, 114))	('MM', 'Disease', 'MESH:D009101', (131, 133))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('UK5099 compound', 'Var', (18, 33))
86050	30423827	Indeed, the authors demonstrated that MPC-1 gene knockout cells or blocking MPC activity revealed a metabolic reprogramming to aerobic glycolysis with reduced pyruvate transport into mitochondria and ATP production, and, as a consequence, the cells became more migratory and resistant to both chemotherapy and radiotherapy.	('resistant', 'CPA', (275, 284))	('cells', 'Var', (58, 63))	('reduced', 'NegReg', (151, 158))	('ATP production', 'MPA', (200, 214))	('more', 'PosReg', (256, 260))	('pyruvate', 'Chemical', 'MESH:D019289', (159, 167))	('mitochondria', 'cellular_component', 'GO:0005739', ('183', '195'))	('pyruvate transport', 'biological_process', 'GO:0006848', ('159', '177'))	('PC', 'Gene', '5091', (39, 41))	('metabolic reprogramming', 'CPA', (100, 123))	('gene knockout cells', 'Var', (44, 63))	('PC', 'Gene', '5091', (77, 79))	('ATP', 'Chemical', 'MESH:D000255', (200, 203))	('glycolysis', 'biological_process', 'GO:0006096', ('135', '145'))	('pyruvate transport into mitochondria', 'MPA', (159, 195))
86058	30423827	Furthermore, our results strongly suggest that intramitochondrial pyruvate can restore both respiratory activity and ATP synthesis of HT29-dx and HMM cells at the same level to the one of HT29 cells.	('ATP synthesis', 'MPA', (117, 130))	('ATP synthesis', 'biological_process', 'GO:0006754', ('117', '130'))	('MM', 'Disease', 'MESH:D009101', (147, 149))	('restore', 'PosReg', (79, 86))	('ATP', 'Chemical', 'MESH:D000255', (117, 120))	('intramitochondrial', 'Var', (47, 65))	('HT29-', 'CellLine', 'CVCL:0320', (134, 139))	('respiratory activity', 'MPA', (92, 112))	('HT29 cells', 'CellLine', 'CVCL:0320', (188, 198))	('pyruvate', 'Chemical', 'MESH:D019289', (66, 74))
86060	30423827	Indeed, we demonstrated that ETC inhibitors and FCCP, when added to both HT29 and HT29-dx cells, decreased intracellular doxorubicin accumulation, whereas they had no effect on HMM cells where the respiratory chain was impaired.	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('MM', 'Disease', 'MESH:D009101', (178, 180))	('HT29-', 'CellLine', 'CVCL:0320', (82, 87))	('respiratory chain', 'cellular_component', 'GO:0070469', ('197', '214'))	('decreased', 'NegReg', (97, 106))	('doxorubicin', 'Chemical', 'MESH:D004317', (121, 132))	('intracellular doxorubicin accumulation', 'MPA', (107, 145))	('FCCP', 'Chemical', 'MESH:D002259', (48, 52))	('HT29-dx', 'Var', (82, 89))
86061	30423827	Moreover, in both HT29-dx and HMM cells, pyruvate is sufficient to restore the doxorubicin accumulation, when treatment with any of the inhibitors is used to block the respiratory chain activities, reinforcing the role of electron transport chain in the reversion of MDR phenotype.	('MDR', 'molecular_function', 'GO:0004745', ('267', '270'))	('doxorubicin accumulation', 'MPA', (79, 103))	('electron transport chain', 'biological_process', 'GO:0022900', ('222', '246'))	('pyruvate', 'Chemical', 'MESH:D019289', (41, 49))	('respiratory chain', 'cellular_component', 'GO:0070469', ('168', '185'))	('pyruvate', 'Var', (41, 49))	('MM', 'Disease', 'MESH:D009101', (31, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('HT29-', 'CellLine', 'CVCL:0320', (18, 23))
86062	30423827	In conclusion, we demonstrated that pyruvate treatment restores the respiratory chain functionality and diminishes MRP1 activity, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells.	('pyruvate', 'Var', (36, 44))	('cancer', 'Disease', (208, 214))	('MRP1', 'Gene', '5243', (115, 119))	('diminishes', 'NegReg', (104, 114))	('improving', 'PosReg', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('respiratory chain', 'cellular_component', 'GO:0070469', ('68', '85'))	('restores', 'PosReg', (55, 63))	('pyruvate', 'Chemical', 'MESH:D019289', (36, 44))	('activity', 'MPA', (120, 128))	('MRP1', 'Gene', (115, 119))	('respiratory chain functionality', 'MPA', (68, 99))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
86065	30423827	HT29-dx cells have higher Pgp, MRP1 and breast cancer resistance protein (BCRP) than HT29 cells; moreover, compared to HT29 cells, HT29-dx cells have a higher IC50 for doxorubicin, irinotecan, oxaliplatin and 5-fluorouracil representing a reliable model of MDR cells.	('higher', 'PosReg', (152, 158))	('IC50 for doxorubicin', 'MPA', (159, 179))	('Pgp', 'Gene', '5243', (26, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('doxorubicin', 'Chemical', 'MESH:D004317', (168, 179))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (209, 223))	('HT29-dx', 'Var', (131, 138))	('HT29-', 'CellLine', 'CVCL:0320', (0, 5))	('MRP1', 'Gene', (31, 35))	('HT29 cells', 'CellLine', 'CVCL:0320', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancer resistance protein', 'Gene', '9429', (40, 72))	('Pgp', 'Gene', (26, 29))	('MRP1', 'Gene', '5243', (31, 35))	('irinotecan', 'Chemical', 'MESH:D000077146', (181, 191))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (193, 204))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('HT29 cells', 'CellLine', 'CVCL:0320', (85, 95))	('BCRP', 'Gene', (74, 78))	('breast cancer resistance protein', 'Gene', (40, 72))	('BCRP', 'Gene', '9429', (74, 78))	('MDR', 'molecular_function', 'GO:0004745', ('257', '260'))	('HT29-', 'CellLine', 'CVCL:0320', (131, 136))
86150	30294454	Chromosomal abnormalities commonly associated with mesothelioma are the deletion of chromosomal regions 1p, 3p, 9p, 6q and deletion of chromosome 22.	('Chromosomal abnormalities', 'Disease', 'MESH:D002869', (0, 25))	('associated', 'Reg', (35, 45))	('deletion', 'Var', (123, 131))	('mesothelioma', 'Disease', (51, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('Chromosomal abnormalities', 'Disease', (0, 25))	('deletion', 'Var', (72, 80))
86180	30123503	Many solid tumours and hematologic malignancies lack expression of the MTAP enzyme, due to either deletion of the MTAP gene or methylation of the MTAP promoter.	('solid tumours', 'Disease', 'MESH:D009369', (5, 18))	('MTAP', 'Gene', (114, 118))	('hematologic malignancies', 'Disease', 'MESH:D019337', (23, 47))	('methylation', 'Var', (127, 138))	('lack', 'NegReg', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('deletion', 'Var', (98, 106))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('solid tumours', 'Disease', (5, 18))	('hematologic malignancies', 'Disease', (23, 47))	('expression', 'MPA', (53, 63))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))
86182	30123503	The hypermethylation of MTAP promoter is also involved in hepatocellular carcinoma as well as gastric adenocarcinoma onset.	('hepatocellular carcinoma', 'Disease', (58, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('MTAP promoter', 'Gene', (24, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (94, 116))	('involved', 'Reg', (46, 54))	('gastric adenocarcinoma', 'Disease', (94, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('hypermethylation', 'Var', (4, 20))
86184	30123503	Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases.	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (85, 106))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (85, 106))	('CDKN2A', 'Gene', (23, 29))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (85, 105))	('pleural mesotheliomas', 'Disease', (85, 106))	('Homozygous', 'Var', (0, 10))
86200	30123503	They hypothesized that some tumours may only harbour a hemizygous deletion rather than the homozygous deletion leading to complete protein loss.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('protein loss', 'Disease', (131, 143))	('protein loss', 'Disease', 'MESH:D011488', (131, 143))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('deletion', 'Var', (66, 74))
86202	30123503	Overall, we could conclude that MTAP hypermethylation might not behave as a good biomarker for malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (95, 117))	('MTAP', 'Gene', (32, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (95, 117))	('malignant mesothelioma', 'Disease', (95, 117))	('hypermethylation', 'Var', (37, 53))
86204	30123503	The global epigenetic profile determined by high-throughput methylation analysis differs between MPM and normal pleura, indicating that MPM, like other cancers, has aberrant CpG island methylation.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('MPM', 'Var', (136, 139))	('methylation', 'biological_process', 'GO:0032259', ('185', '196'))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CpG island methylation', 'MPA', (174, 196))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('MPM', 'Disease', (97, 100))
86211	30123503	Overall, a prevalence of sarcomatoid mesotheliomas showed a methylation profile recalling what has been called 'epigenetic cancer stem cell signature', characterized by a permanent gene silencing, which favors the stay of the cell in one self-renewal state, predisposing it to malignant transformation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('stay', 'CPA', (214, 218))	('recalling', 'Disease', 'MESH:D008569', (80, 89))	('gene silencing', 'biological_process', 'GO:0016458', ('181', '195'))	('methylation', 'Var', (60, 71))	('sarcomatoid mesotheliomas', 'Disease', 'MESH:C538614', (25, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('favors', 'PosReg', (203, 209))	('cancer', 'Disease', (123, 129))	('recalling', 'Disease', (80, 89))	('sarcomatoid mesotheliomas', 'Disease', (25, 50))	('malignant transformation', 'CPA', (277, 301))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))
86226	28283772	About 45% of these familial melanomas have been attributed to inheritance of a mutation in a highly penetrant predisposition gene.	('familial melanomas', 'Disease', (19, 37))	('familial melanomas', 'Disease', 'OMIM:155600', (19, 37))	('mutation', 'Var', (79, 87))	('attributed', 'Reg', (48, 58))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
86231	28283772	Within the melanoma-dominant syndromes caused by cyclin-dependent kinase inhibitor 2A (CDKN2A), and BRCA1-associated protein 1 (BAP1), pathogenic mutations in these genes cause increased incidence of other cancer types (e.g., pancreatic cancer, neurological tumors, renal cell carcinoma, mesothelioma) but with lower penetrance than melanoma.	('neurological tumors', 'Disease', (245, 264))	('melanoma-dominant syndromes', 'Disease', 'MESH:D008545', (11, 38))	('renal cell carcinoma', 'Disease', (266, 286))	('CDKN2A', 'Gene', '1029', (87, 93))	('BRCA1-associated protein 1', 'Gene', '8314', (100, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (266, 286))	('BAP1', 'Gene', (128, 132))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('49', '82'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (49, 85))	('mesothelioma', 'Disease', (288, 300))	('neurological tumors', 'Disease', 'MESH:D009423', (245, 264))	('pancreatic cancer', 'Disease', 'MESH:D010190', (226, 243))	('mesothelioma', 'Disease', 'MESH:D008654', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('BRCA1-associated protein 1', 'Gene', (100, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('melanoma-dominant syndromes', 'Disease', (11, 38))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('66', '82'))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('melanoma', 'Disease', (333, 341))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (49, 85))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (237, 243))	('pancreatic cancer', 'Disease', (226, 243))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 286))	('CDKN2A', 'Gene', (87, 93))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', '8314', (128, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (226, 243))	('melanoma', 'Disease', 'MESH:D008545', (333, 341))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
86238	28283772	Genetic testing of appropriate individuals and the tailored follow-up recommendations that ensue can improve early detection, reduce mortality, and enhance compliance with prevention recommendations.	('early detection', 'MPA', (109, 124))	('reduce', 'NegReg', (126, 132))	('Genetic testing', 'Var', (0, 15))	('compliance', 'MPA', (156, 166))	('mortality', 'CPA', (133, 142))	('men', 'Species', '9606', (75, 78))	('enhance', 'PosReg', (148, 155))	('improve', 'PosReg', (101, 108))	('men', 'Species', '9606', (188, 191))
86255	28283772	Families that carry a pathogenic mutation in CDKN2A have an increased risk for melanoma, pancreatic cancer, and perhaps neurological tumors like astrocytoma.	('CDKN2A', 'Gene', '1029', (45, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('neurological tumors', 'Disease', 'MESH:D009423', (120, 139))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mutation', 'Var', (33, 41))	('astrocytoma', 'Disease', 'MESH:D001254', (145, 156))	('neurological tumors', 'Disease', (120, 139))	('astrocytoma', 'Disease', (145, 156))	('pathogenic', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('CDKN2A', 'Gene', (45, 51))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('pancreatic cancer', 'Disease', (89, 106))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
86256	28283772	A substantially increased number of atypical moles in the setting of a CDKN2A mutation has been termed familial atypical mole and malignant melanoma syndrome (FAMMM), although it is also called the familial melanoma and pancreatic cancer syndrome (FMPC) or the familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMPC), because of the increased risk of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('mole', 'Phenotype', 'HP:0003764', (288, 292))	('FAMMM', 'Gene', '1243', (159, 164))	('atypical mole', 'Phenotype', 'HP:0001062', (36, 49))	('melanoma-pancreatic carcinoma syndrome', 'Disease', (293, 331))	('mole', 'Phenotype', 'HP:0003764', (121, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (375, 392))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))	('FMPC', 'Disease', (248, 252))	('familial melanoma', 'Disease', (198, 215))	('familial melanoma', 'Disease', 'OMIM:155600', (198, 215))	('melanoma and pancreatic cancer', 'Disease', 'MESH:C563985', (207, 237))	('pancreatic cancer syndrome', 'Disease', 'MESH:D010190', (220, 246))	('FAMMM', 'Gene', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('moles', 'Phenotype', 'HP:0003764', (45, 50))	('atypical multiple mole', 'Phenotype', 'HP:0001062', (270, 292))	('atypical mole', 'Phenotype', 'HP:0001062', (112, 125))	('malignant melanoma syndrome', 'Disease', 'MESH:D008545', (130, 157))	('CDKN2A', 'Gene', (71, 77))	('atypical moles', 'Phenotype', 'HP:0001062', (36, 50))	('melanoma-pancreatic carcinoma syndrome', 'Disease', 'MESH:C563985', (293, 331))	('pancreatic cancer', 'Disease', 'MESH:D010190', (375, 392))	('malignant melanoma syndrome', 'Disease', (130, 157))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('mole', 'Phenotype', 'HP:0003764', (45, 49))	('FMPC', 'Disease', 'None', (248, 252))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (357, 392))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('mutation', 'Var', (78, 86))	('multiple mole', 'Phenotype', 'HP:0001054', (279, 292))	('pancreatic cancer', 'Disease', (375, 392))	('pancreatic cancer syndrome', 'Disease', (220, 246))	('CDKN2A', 'Gene', '1029', (71, 77))	('familial', 'Disease', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('malignant melanoma', 'Phenotype', 'HP:0002861', (130, 148))
86257	28283772	Clinical genetic testing for CDKN2A mutations has been widely available since the mid-2000s, and guidelines for use of this test were published in 2009 and are detailed below.	('CDKN2A', 'Gene', (29, 35))	('mutations', 'Var', (36, 45))	('CDKN2A', 'Gene', '1029', (29, 35))
86260	28283772	Deleterious mutations in these genes lead to a disproportionately high risk of melanoma development relative to other cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('Deleterious mutations', 'Var', (0, 21))	('lead to', 'Reg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('men', 'Species', '9606', (95, 98))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
86263	28283772	Families shown to be mutation negative at the CDKN2A locus are sometimes tested reflexively for the most common CDK4 mutation site, Arg24.	('tested', 'Reg', (73, 79))	('CDKN2A', 'Gene', (46, 52))	('CDKN2A', 'Gene', '1029', (46, 52))	('CDK4', 'Gene', (112, 116))	('Arg24', 'Chemical', '-', (132, 137))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('CDK4', 'Gene', '1019', (112, 116))	('Arg24', 'Var', (132, 137))
86264	28283772	This CDKN2A/p16 binding site (Arg24) is required for CDK4 inhibition by CDKN2A/p16 and mutation transforms the protein into an unregulated oncoprotein, making single site testing of this codon a reasonable consideration.	('p16', 'Gene', '1029', (79, 82))	('Arg24', 'Var', (30, 35))	('p16', 'Gene', '1029', (12, 15))	('CDKN2A', 'Gene', (5, 11))	('CDKN2A', 'Gene', '1029', (72, 78))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('CDK4', 'Gene', '1019', (53, 57))	('CDK4', 'Gene', (53, 57))	('CDKN2A', 'Gene', '1029', (5, 11))	('p16', 'Gene', (79, 82))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('p16', 'Gene', (12, 15))	('mutation', 'Var', (87, 95))	('CDKN2A', 'Gene', (72, 78))	('Arg24', 'Chemical', '-', (30, 35))
86265	28283772	Melanoma is also observed at higher-than-expected rates in other hereditary cancer syndromes arising from germline mutations in tumor susceptibility genes (melanoma-subordinate syndromes).	('melanoma-subordinate syndromes', 'Disease', 'MESH:D008545', (156, 186))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('germline mutations', 'Var', (106, 124))	('Melanoma', 'Disease', (0, 8))	('melanoma-subordinate syndromes', 'Disease', (156, 186))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('arising', 'Reg', (93, 100))	('hereditary cancer syndromes', 'Disease', (65, 92))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (65, 92))	('tumor', 'Disease', (128, 133))
86269	28283772	Furthermore, use of genetic panel testing for a variety of syndromes, including those with a predominance of melanoma, will begin to refine the constellation of cancers seen in association with various mutations.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('constellation of cancers', 'Disease', 'MESH:D009369', (144, 168))	('constellation of cancers', 'Disease', (144, 168))	('mutations', 'Var', (202, 211))
86270	28283772	In 2009, international guidelines were published suggesting that individuals with an estimated 10% or greater pre-test probability of carrying a mutation in CDKN2A should be referred for genetic counseling.	('pre', 'molecular_function', 'GO:0003904', ('110', '113'))	('CDKN2A', 'Gene', '1029', (157, 163))	('CDKN2A', 'Gene', (157, 163))	('mutation', 'Var', (145, 153))
86271	28283772	However, accurate estimates of pre-test probabilities of mutation carriage were complicated by the interdependence upon ethnicity and geography that underlie a general population's risk for melanoma.	('mutation', 'Var', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))
86277	28283772	Use of this "rule of twos or threes" criteria for melanoma genetic testing leads to approximately 10% positive results for CDKN2A mutation.	('mutation', 'Var', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', '1029', (123, 129))
86279	28283772	For instance, it is unclear how environment, other prognostic risk factors such as the hair, eye, and skin color, and/or ethnicity contribute to the overall risk in individuals with CDKN2A (or other melanoma gene) mutations.	('mutations', 'Var', (214, 223))	('CDKN2A', 'Gene', (182, 188))	('men', 'Species', '9606', (39, 42))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('CDKN2A', 'Gene', '1029', (182, 188))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
86283	28283772	To accomplish this task, we have created a simplified scoring system that identifies individuals or families that have a pattern of cancer development suspicious for germline inheritance of a pathogenic mutation.	('cancer', 'Disease', (132, 138))	('men', 'Species', '9606', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutation', 'Var', (203, 211))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
86288	28283772	Third, we account for clinical findings consistent with the melanoma-dominant tumor syndrome caused by a BAP1 mutation.	('caused by', 'Reg', (93, 102))	('melanoma-dominant tumor syndrome', 'Disease', 'MESH:D008545', (60, 92))	('BAP1', 'Gene', '8314', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('melanoma-dominant tumor syndrome', 'Disease', (60, 92))	('mutation', 'Var', (110, 118))	('BAP1', 'Gene', (105, 109))
86290	28283772	The original "rule of twos and threes" was based on finding criteria that would provide at least a 10% pre-test probability of finding an actionable CDKN2A mutation.	('CDKN2A', 'Gene', '1029', (149, 155))	('CDKN2A', 'Gene', (149, 155))	('mutation', 'Var', (156, 164))
86301	28283772	Once an individual or family has met criteria for genetic testing and has received genetic counseling with informed consent, our centers create a tailored panel test that includes the genes that are most likely to be mutated, based on the other cancer types observed in the pedigree.	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Disease', (245, 251))	('mutated', 'Var', (217, 224))	('cancer', 'Disease', 'MESH:D009369', (245, 251))
86310	28283772	Co-occurrence of pancreatic cancer and melanoma usually occurs in the setting of a CDKN2A mutation.	('CDKN2A', 'Gene', '1029', (83, 89))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('mutation', 'Var', (90, 98))	('CDKN2A', 'Gene', (83, 89))
86348	28283772	Analysis of a Lynch syndrome registry has observed melanoma in patients with pathogenic mutations in these mismatch repair enzymes; however, the increased incidence was not found to be statistically significant.	('mismatch repair', 'biological_process', 'GO:0006298', ('107', '122'))	('Lynch syndrome', 'Disease', (14, 28))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
86349	28283772	Cowden Syndrome (CS) arises from a pathogenic mutation in the PTEN gene.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('Cowden Syndrome', 'Disease', (0, 15))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (0, 15))	('mutation', 'Var', (46, 54))
86355	28283772	Germline mutation carriers of TP53 have a substantial lifetime risk for a variety of cancers including childhood cancers and multiple primary cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('Germline mutation carriers', 'Var', (0, 26))	('childhood cancers', 'Disease', 'MESH:C536928', (103, 120))	('childhood cancers', 'Disease', (103, 120))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('TP53', 'Gene', (30, 34))	('multiple primary cancers', 'Disease', 'MESH:D009369', (125, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Disease', (142, 149))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', (85, 92))	('TP53', 'Gene', '7157', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('multiple primary cancers', 'Disease', (125, 149))
86371	28283772	In melanoma-dominant or melanoma-subordinate pedigrees or in individuals carrying a BAP1, CDK4, CDKN2A, MITF, or POT1 mutation, individuals should be educated on the importance of melanoma prevention and early detection.	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('melanoma-dominant or melanoma-subordinate', 'Disease', (3, 44))	('MITF', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('BAP1', 'Gene', '8314', (84, 88))	('CDKN2A', 'Gene', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('CDK4', 'Gene', (90, 94))	('melanoma-dominant or melanoma-subordinate', 'Disease', 'MESH:D008545', (3, 44))	('POT1', 'Gene', '25913', (113, 117))	('mutation', 'Var', (118, 126))	('BAP1', 'Gene', (84, 88))	('CDKN2A', 'Gene', '1029', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('CDK4', 'Gene', '1019', (90, 94))	('POT1', 'Gene', (113, 117))	('MITF', 'Gene', '4286', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
86377	28283772	Annual screening for uveal melanoma, mesothelioma, and renal cancer should be considered for carriers of BAP1 germline mutations.	('carriers', 'Reg', (93, 101))	('uveal melanoma', 'Disease', (21, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('renal cancer', 'Disease', (55, 67))	('BAP1', 'Gene', '8314', (105, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (55, 67))	('germline', 'Var', (110, 118))	('renal cancer', 'Disease', 'MESH:D007680', (55, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mesothelioma', 'Disease', (37, 49))	('BAP1', 'Gene', (105, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
86383	28283772	For women who have high-risk breast cancer genetic mutations, breast awareness with self-breast exams and clinical breast exams is recommended starting at age 18.	('genetic mutations', 'Var', (43, 60))	('women', 'Species', '9606', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('men', 'Species', '9606', (136, 139))	('men', 'Species', '9606', (6, 9))
86384	28283772	Imaging may begin as early as age 20 for TP53 mutation carriers or age 25 for BRCA1 and BRCA2 mutation carriers.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('BRCA2', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (78, 83))	('BRCA2', 'Gene', '675', (88, 93))	('mutation', 'Var', (46, 54))	('BRCA1', 'Gene', (78, 83))
86386	28283772	Consideration of risk-reducing mastectomy (RRM) is an option for women who have mutations in risk genes conferring a 50% or greater lifetime risk for breast cancer or have a mutation in a moderate risk gene with significant family history.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('mutations', 'Var', (80, 89))	('mutation', 'Var', (174, 182))	('breast cancer', 'Disease', (150, 163))	('women', 'Species', '9606', (65, 70))
86387	28283772	If a woman has a mutation in a gene associated with an increased risk for ovarian cancer, the option of a salpingo-oophorectomy (RRSO) should be discussed between 35 and 40 years of age and upon completion of child bearing.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('woman', 'Species', '9606', (5, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('mutation', 'Var', (17, 25))	('ovarian cancer', 'Disease', (74, 88))	('child', 'Species', '9606', (209, 214))
86389	28283772	Guidelines for patients with a high-risk prostate cancer mutations have not been established by the NCCN; however, recent results from the IMPACT study have shown that the positive predictive values of prostate serum antigen (PSA) of 3.0 ng/mL are higher in patients with a high-risk genetic mutation compared to controls and that the former is more likely to have an intermediate or high-risk for disease.	('patients', 'Species', '9606', (15, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('genetic mutation', 'Var', (284, 300))	('prostate cancer', 'Disease', (41, 56))	('patients', 'Species', '9606', (258, 266))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('higher', 'PosReg', (248, 254))
86390	28283772	Generally, patients who have a high-risk colon cancer mutation should have a colonoscopy at age 20-25 years or 2 to 5 years prior to the earliest colon cancer if it is diagnosed before age 25 years.	('mutation', 'Var', (54, 62))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('colon cancer', 'Disease', (146, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('colon cancer', 'Disease', 'MESH:D015179', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (11, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('colon cancer', 'Disease', (41, 53))
86392	28283772	Lynch syndrome is caused by autosomal dominantly inherited mutations in the mismatch repair genes MLH1, MSH2, EPCAM, MSH6, and PMS2.	('PMS2', 'Gene', (127, 131))	('EPCAM', 'Gene', '4072', (110, 115))	('PMS2', 'Gene', '5395', (127, 131))	('mismatch repair', 'biological_process', 'GO:0006298', ('76', '91'))	('MLH1', 'Gene', '4292', (98, 102))	('MSH6', 'Gene', (117, 121))	('MLH1', 'Gene', (98, 102))	('MSH2', 'Gene', (104, 108))	('MSH6', 'Gene', '2956', (117, 121))	('Lynch syndrome', 'Disease', (0, 14))	('MSH2', 'Gene', '4436', (104, 108))	('mutations', 'Var', (59, 68))	('caused by', 'Reg', (18, 27))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('EPCAM', 'Gene', (110, 115))
86393	28283772	Individuals who carry mutations tend to form colon polyps at an earlier age and are at a high lifetime risk for colon cancer (up to 80%) unless frequent surveillance is done.	('colon polyps', 'Disease', (45, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('form', 'Reg', (40, 44))	('mutations', 'Var', (22, 31))	('colon polyps', 'Disease', 'MESH:D003111', (45, 57))
86401	28283772	FAP is caused by autosomal dominantly inherited mutations in the APC gene, although 20-25% of probands have a de novo mutation.	('APC', 'Gene', (65, 68))	('APC', 'cellular_component', 'GO:0005680', ('65', '68'))	('APC', 'Gene', '324', (65, 68))	('caused by', 'Reg', (7, 16))	('FAP', 'Disease', (0, 3))	('mutations', 'Var', (48, 57))
86405	28283772	Attenuated FAP is characterized by an increased risk for colon cancer but fewer colon polyps, more proximally located polyps, and diagnosis of colon cancer at a later age.	('colon polyps', 'Disease', 'MESH:D003111', (80, 92))	('polyps', 'Disease', 'MESH:D011127', (118, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('fewer', 'NegReg', (74, 79))	('Attenuated', 'Var', (0, 10))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('polyps', 'Disease', (86, 92))	('colon cancer', 'Disease', (143, 155))	('colon cancer', 'Disease', (57, 69))	('polyps', 'Disease', (118, 124))	('colon polyps', 'Disease', (80, 92))	('FAP', 'Disease', (11, 14))	('polyps', 'Disease', 'MESH:D011127', (86, 92))
86411	28283772	MUTYH-associated polyposis is caused by biallelic mutations in the MUTYH gene and tends to have a similar number of polyps as patients who have AFAP.	('MUTYH', 'Gene', (67, 72))	('MUTYH', 'Gene', '4595', (67, 72))	('biallelic mutations', 'Var', (40, 59))	('polyposis', 'Disease', (17, 26))	('MUTYH', 'Gene', (0, 5))	('MUTYH', 'Gene', '4595', (0, 5))	('polyps', 'Disease', 'MESH:D011127', (116, 122))	('caused by', 'Reg', (30, 39))	('patients', 'Species', '9606', (126, 134))	('polyposis', 'Disease', 'MESH:D011125', (17, 26))	('AFAP', 'Disease', 'MESH:D011125', (144, 148))	('polyps', 'Disease', (116, 122))	('AFAP', 'Disease', (144, 148))
86418	28283772	Screening is recommended for high-risk individuals, including patients with a family history of pancreatic cancer or patients with an STK11, CDKN2A/p16, or a BRCA2 mutation with >=1 affected first-degree relative.	('CDKN2A', 'Gene', '1029', (141, 147))	('STK11', 'molecular_function', 'GO:0033868', ('134', '139'))	('STK11', 'Gene', (134, 139))	('pancreatic cancer', 'Disease', (96, 113))	('p16', 'Gene', '1029', (148, 151))	('men', 'Species', '9606', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('STK11', 'Gene', '6794', (134, 139))	('patients', 'Species', '9606', (62, 70))	('mutation', 'Var', (164, 172))	('p16', 'Gene', (148, 151))	('patients', 'Species', '9606', (117, 125))	('BRCA2', 'Gene', (158, 163))	('CDKN2A', 'Gene', (141, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('BRCA2', 'Gene', '675', (158, 163))
86422	28283772	Any pedigree that carries a mutation that overlaps with cancer predisposition genes for these syndromes or that has these types of cancers in the pedigree needs to be monitored carefully for signs and symptoms of these cancers.	('cancer', 'Disease', (131, 137))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutation', 'Var', (28, 36))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancer', 'Disease', (219, 225))	('cancers', 'Disease', (219, 226))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
86423	28283772	For example, ophthalmologic examinations should be performed every 6-12 months in BAP1 mutation carriers.	('BAP1', 'Gene', (82, 86))	('mutation', 'Var', (87, 95))	('BAP1', 'Gene', '8314', (82, 86))	('carriers', 'Reg', (96, 104))
86424	28283772	BAP1 mutation carriers should also be explicitly warned about asbestos exposures, given their predisposition toward mesothelioma.	('mesothelioma', 'Disease', (116, 128))	('asbestos', 'Chemical', 'MESH:D001194', (62, 70))	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
86429	28283772	The field of cancer genetics is quickly moving from a descriptive era, in which predisposition is defined primarily by disease phenotypes, into a whole-genome era, in which the relative contributions of high- and low-penetrance mutations, polymorphisms of modifier genes, and environmentally-induced somatic mutations are understood.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (228, 237))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('low-penetrance', 'NegReg', (213, 227))	('men', 'Species', '9606', (283, 286))
86478	28188257	The effects of risk factors on PFS and OS were estimated as logarithms of the hazard ratio (log HR), respectively: log HROS and log HRPFS log, through Cox proportional hazards model with the risk factor of interest as a single predictor.	('Cox', 'Gene', '1351', (151, 154))	('OS', 'Chemical', '-', (121, 123))	('Cox', 'Gene', (151, 154))	('log', 'Var', (128, 131))	('OS', 'Chemical', '-', (39, 41))
86514	28188257	As seen in Table 1, two studies (C8435 and C9131) are randomized phase II trials and the cohort consists of 138 patients.	('C8435', 'Var', (33, 38))	('patients', 'Species', '9606', (112, 120))	('C9131', 'Var', (43, 48))
86519	28188257	Our analysis suggests that PFS is associated with OS, but the measures on both individual-level and summary-level surrogacy are not strong enough to allow the use of PFS as a surrogate endpoint for OS, regardless of which risk factor was considered.	('PFS', 'Var', (27, 30))	('associated', 'Reg', (34, 44))	('OS', 'Chemical', '-', (50, 52))	('OS', 'Chemical', '-', (198, 200))
86607	21624382	Indeed, several studies reported that MWCNT induce inflammation, granuloma formation, and biopersistence in the rodent lung after 60 days post-exposure.	('biopersistence', 'CPA', (90, 104))	('MWCNT', 'Chemical', '-', (38, 43))	('inflammation', 'Disease', (51, 63))	('granuloma', 'Disease', 'MESH:D006099', (65, 74))	('granuloma', 'Disease', (65, 74))	('granuloma formation', 'biological_process', 'GO:0002432', ('65', '84'))	('granuloma', 'Phenotype', 'HP:0032252', (65, 74))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))	('inflammation', 'biological_process', 'GO:0006954', ('51', '63'))	('MWCNT', 'Var', (38, 43))	('induce', 'Reg', (44, 50))
86624	21624382	Alterations in the TGF-beta have been associated with human cancers, including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('associated', 'Reg', (38, 48))	('cancers', 'Disease', (60, 67))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TGF-beta', 'Gene', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))
86680	21624382	Taken together, these results indicate that exposure to MWCNT may be potentially carcinogenic in humans, which could be enhanced over a prolonged post-exposure period.	('MWCNT', 'Var', (56, 61))	('MWCNT', 'Chemical', '-', (56, 61))	('humans', 'Species', '9606', (97, 103))	('carcinogenic', 'Disease', 'MESH:D063646', (81, 93))	('carcinogenic', 'Disease', (81, 93))
86682	21624382	Furthermore, it has been proposed that CNT exposure can induce an asbestos-like pathogenicity and may pose a similar carcinogenic risk as exposure to asbestos fiber does.	('exposure', 'Var', (43, 51))	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('induce', 'Reg', (56, 62))	('asbestos-like', 'Disease', (66, 79))	('carcinogenic', 'Disease', 'MESH:D063646', (117, 129))	('carcinogenic', 'Disease', (117, 129))	('asbestos', 'Chemical', 'MESH:D001194', (150, 158))
86684	21624382	The concern of their potential health hazards has been raised due to their unique physical properties, such as high aspect ratio (length/diameter), nanoscale diameters, micrometer length fiber like-shape and durability, which are analogous to asbestos fibers.	('nanoscale', 'Var', (148, 157))	('asbestos fibers', 'Disease', (243, 258))	('durability', 'CPA', (208, 218))	('micrometer', 'Var', (169, 179))	('asbestos fibers', 'Disease', 'MESH:D001195', (243, 258))
86693	21624382	Particularly, the characteristics of MWCNT-induced mesotheliomas were hobnail appearance to large tumors along with high mitotic rate cells and central necrosis due to high grade of malignant mesothelioma.	('necrosis', 'biological_process', 'GO:0070265', ('152', '160'))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('necrosis', 'biological_process', 'GO:0008219', ('152', '160'))	('necrosis', 'biological_process', 'GO:0019835', ('152', '160'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (182, 204))	('necrosis', 'Disease', (152, 160))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('necrosis', 'biological_process', 'GO:0008220', ('152', '160'))	('mesotheliomas', 'Disease', 'MESH:D008654', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('necrosis', 'biological_process', 'GO:0001906', ('152', '160'))	('mesotheliomas', 'Disease', (51, 64))	('MWCNT', 'Chemical', '-', (37, 42))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (182, 204))	('necrosis', 'Disease', 'MESH:D009336', (152, 160))	('MWCNT-induced', 'Var', (37, 50))	('malignant mesothelioma', 'Disease', (182, 204))
86702	21624382	found that MWCNT induce mitotic abnormality with one mitotic spindle pole, showing the evidence of the mechanism responsible for the disruption of cell division by MWCNT.	('induce', 'Reg', (17, 23))	('mitotic abnormality', 'Disease', (24, 43))	('MWCNT', 'Var', (11, 16))	('MWCNT', 'Chemical', '-', (11, 16))	('mitotic abnormality', 'Disease', 'MESH:C536987', (24, 43))	('mitotic spindle pole', 'cellular_component', 'GO:0097431', ('53', '73'))	('cell division', 'biological_process', 'GO:0051301', ('147', '160'))	('MWCNT', 'Chemical', '-', (164, 169))
86726	21624382	Interestingly, our previous in vivo studies have shown that MWCNT-induced pulmonary inflammation and damage peaked at 7 days post-exposure of MWCNT; while interstitial fibrosis was significantly elevated at 28 days post-exposure and peaked at 56 days.	('MWCNT', 'Var', (142, 147))	('pulmonary inflammation', 'Disease', (74, 96))	('MWCNT', 'Chemical', '-', (142, 147))	('MWCNT', 'Chemical', '-', (60, 65))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (155, 176))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (74, 96))	('elevated', 'PosReg', (195, 203))	('interstitial fibrosis', 'Disease', (155, 176))	('damage', 'CPA', (101, 107))	('interstitial fibrosis', 'Disease', 'MESH:D005355', (155, 176))
86735	21624382	An in vivo animal study demonstrated that asbestos exposure induces malignant mesothelioma in mouse lungs at 60 weeks post-exposure.	('induces', 'Reg', (60, 67))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (68, 90))	('mouse', 'Species', '10090', (94, 99))	('exposure', 'Var', (51, 59))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (68, 90))	('malignant mesothelioma', 'Disease', (68, 90))
86739	21624382	The combined results from the gene expression profiling in this study and the histopathological changes observed in the previous study indicate that exposure to MWCNT may potentially enhance the risk of pulmonary diseases, including lung carcinogenesis, in humans.	('pulmonary diseases', 'Disease', (203, 221))	('pulmonary diseases', 'Disease', 'MESH:D008171', (203, 221))	('lung carcinogenesis', 'Disease', (233, 252))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (233, 252))	('MWCNT', 'Var', (161, 166))	('enhance', 'PosReg', (183, 190))	('MWCNT', 'Chemical', '-', (161, 166))	('humans', 'Species', '9606', (257, 263))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
86753	21624382	Pathological disorders, such as organismal disorders and injuries (including fibrosis), were also retrieved from the IPA database as significant functions, indicating that the genes identified in this study were associated with the observed MWCNT-induced lung pathology.	('MWCNT', 'Chemical', '-', (241, 246))	('MWCNT-induced lung pathology', 'Disease', (241, 269))	('fibrosis', 'Disease', (77, 85))	('associated', 'Reg', (212, 222))	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('injuries', 'Disease', (57, 65))	('injuries', 'Disease', 'MESH:D058186', (57, 65))	('genes', 'Var', (176, 181))
86755	21624382	The results of the IPA also indicate that MWCNT exposure may induce alterations in several disease-related signaling transduction pathways.	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('transduction', 'biological_process', 'GO:0009293', ('117', '129'))	('alterations', 'Reg', (68, 79))	('disease-related signaling transduction pathways', 'Pathway', (91, 138))	('MWCNT', 'Var', (42, 47))	('MWCNT', 'Chemical', '-', (42, 47))
86767	18709470	An exciting new development comes from the discovery that genetic susceptibility to mineral fiber carcinogenesis plays a critical role in the incidence of this cancer in certain families.	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('genetic susceptibility', 'Var', (58, 80))
86814	18709470	In addition, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), asbestos fibers can indirectly induce genotoxicity including base substitutions, deletions, rearrangements, insertions, sister chromatid exchanges, and chromosomal aberrations which may lead to a broad spectrum of mutations in mammalian cells.	('base substitutions', 'Var', (167, 185))	('rearrangements', 'Var', (198, 212))	('lead', 'Reg', (292, 296))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (258, 281))	('mammalian', 'Species', '9606', (333, 342))	('deletions', 'Var', (187, 196))	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('induce', 'Reg', (137, 143))	('chromosomal aberrations', 'CPA', (258, 281))	('sister chromatid exchanges', 'CPA', (226, 252))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (39, 62))	('chromatid', 'cellular_component', 'GO:0005694', ('233', '242'))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))	('release', 'MPA', (28, 35))	('asbestos', 'Chemical', 'MESH:D001194', (106, 114))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (73, 98))	('chromatid', 'cellular_component', 'GO:0005695', ('233', '242'))	('rat', 'Species', '10116', (274, 277))	('toxicity', 'Disease', (148, 156))	('insertions', 'Var', (214, 224))	('causing', 'Reg', (16, 23))	('RNS', 'Chemical', 'MESH:D026361', (100, 103))	('reactive oxygen species', 'MPA', (39, 62))
86823	18709470	Mutations of the p53 gene (TP53) are occasionally observed in MMs.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
86824	18709470	Loss and/or inactivation of these tumor suppressor genes may play a role in the development and progression of MM.	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('Loss', 'NegReg', (0, 4))	('play', 'Reg', (61, 65))	('inactivation', 'Var', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
86826	18709470	The NF2 product, Merlin, represses cyclin D1 expression, and loss/inactivation of NF2 in MM leads to cell cycle progression in connection with up regulation of cyclin D1.	('cyclin D1', 'Gene', (35, 44))	('cyclin D1', 'Gene', (160, 169))	('cell cycle progression', 'CPA', (101, 123))	('up regulation', 'PosReg', (143, 156))	('cyclin D1', 'Gene', '595', (35, 44))	('cyclin D1', 'Gene', '595', (160, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('101', '111'))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('cyclin', 'molecular_function', 'GO:0016538', ('160', '166'))	('Merlin', 'Gene', '4771', (17, 23))	('NF2', 'Gene', '4771', (4, 7))	('leads to', 'Reg', (92, 100))	('NF2', 'Gene', (4, 7))	('NF2', 'Gene', '4771', (82, 85))	('represses', 'NegReg', (25, 34))	('loss/inactivation', 'Var', (61, 78))	('expression', 'MPA', (45, 55))	('Merlin', 'Gene', (17, 23))	('NF2', 'Gene', (82, 85))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))
86827	18709470	Merlin also inhibits Rac/Pak and focal adhesion kinase (FAK) signaling, which play a role in cell migration and spreading, and inactivation of NF2 in MM promotes cell invasiveness annd spreading.	('FAK', 'molecular_function', 'GO:0004717', ('56', '59'))	('inactivation', 'Var', (127, 139))	('rat', 'Species', '10116', (101, 104))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('33', '47'))	('NF2', 'Gene', '4771', (143, 146))	('FAK', 'Gene', '5747', (56, 59))	('focal adhesion kinase', 'Gene', '5747', (33, 54))	('FAK', 'Gene', (56, 59))	('Merlin', 'Gene', '4771', (0, 6))	('inhibits', 'NegReg', (12, 20))	('Merlin', 'Gene', (0, 6))	('cell migration', 'biological_process', 'GO:0016477', ('93', '107'))	('promotes', 'PosReg', (153, 161))	('cell invasiveness annd spreading', 'CPA', (162, 194))	('focal adhesion kinase', 'Gene', (33, 54))	('NF2', 'Gene', (143, 146))
86831	18709470	reported that initially they detected SV40 in about 60% of MM specimens, and then they determined that most of the positive results were caused by plasmid PCR contamination, and that only 6% of the initially positive samples were confirmed to contain SV40 DNA.	('SV40', 'Var', (38, 42))	('SV40 DNA', 'Var', (251, 259))	('caused by', 'Reg', (137, 146))	('detected', 'Reg', (29, 37))	('DNA', 'cellular_component', 'GO:0005574', ('256', '259'))	('SV40', 'Species', '1891767', (251, 255))	('SV40', 'Species', '1891767', (38, 42))
86833	18709470	Analysis of human MMs revealed that SV40 sequences are present in tumor cells but not in the normal adjacent tissue.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SV40', 'Species', '1891767', (36, 40))	('tumor', 'Disease', (66, 71))	('SV40', 'Var', (36, 40))	('human', 'Species', '9606', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
86835	18709470	For instance, 100% of hamsters injected intrapleurally with SV40 and 60% of those injected intracardially developed MM within 6 months.	('pleural', 'Disease', 'MESH:D010995', (45, 52))	('SV40', 'Var', (60, 64))	('pleural', 'Disease', (45, 52))	('SV40', 'Species', '1891767', (60, 64))
86840	18709470	In other words, the binding of Tag to p53, p300, pRb, on one hand, inactivates the tumor suppressor activities of these proteins, on the other, the Tag-p53-pRb-p300 multi-protein complex acquire its own oncogenic activity by activating the IGF-1/IGF1R pathway.	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('pRb', 'Gene', (156, 159))	('p53', 'Gene', '7157', (152, 155))	('Rb', 'Phenotype', 'HP:0009919', (157, 159))	('p300', 'Gene', '2033', (43, 47))	('protein complex', 'cellular_component', 'GO:0032991', ('171', '186'))	('p300', 'Gene', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('p300', 'Gene', '2033', (160, 164))	('inactivates', 'NegReg', (67, 78))	('binding', 'Interaction', (20, 27))	('pRb', 'Gene', '5925', (156, 159))	('p53', 'Gene', (152, 155))	('IGF1R', 'Gene', '3480', (246, 251))	('Tag', 'Var', (31, 34))	('IGF-1', 'Gene', (240, 245))	('pRb', 'Gene', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Rb', 'Phenotype', 'HP:0009919', (50, 52))	('IGF1R', 'Gene', (246, 251))	('p53', 'Gene', '7157', (38, 41))	('IGF-1', 'Gene', '3479', (240, 245))	('oncogenic activity', 'CPA', (203, 221))	('pRb', 'Gene', '5925', (49, 52))	('p53', 'Gene', (38, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('activating', 'PosReg', (225, 235))	('p300', 'Gene', (43, 47))
86843	18709470	In addition, SV40 induces HGF/Met receptor activation, telomerase activity, and Notch-1 activation in human mesothelial cells and MM biopsies.	('telomerase', 'CPA', (55, 65))	('activation', 'PosReg', (88, 98))	('HGF', 'Gene', '3082', (26, 29))	('telomerase activity', 'molecular_function', 'GO:0003720', ('55', '74'))	('activation', 'PosReg', (43, 53))	('activity', 'MPA', (66, 74))	('SV40', 'Species', '1891767', (13, 17))	('SV40', 'Var', (13, 17))	('Notch-1', 'Gene', (80, 87))	('HGF', 'Gene', (26, 29))	('human', 'Species', '9606', (102, 107))
86847	18709470	Asbestos and SV40 dl883 (SV40 dl883 does not express tag and it does not cause MM in animals) together caused MM in 90% of hamsters, whereas SV40 dl883 alone did not cause MM in any animal, and asbestos alone caused MM in only 20% of hamsters.	('SV40', 'Species', '1891767', (141, 145))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('caused', 'Reg', (103, 109))	('SV40', 'Species', '1891767', (13, 17))	('asbestos', 'Chemical', 'MESH:D001194', (194, 202))	('SV40', 'Species', '1891767', (25, 29))	('SV40 dl883', 'Var', (13, 23))
86848	18709470	Importantly, significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40.	('SV40', 'Species', '1891767', (106, 110))	('cause', 'Reg', (72, 77))	('asbestos', 'Chemical', 'MESH:D001194', (44, 52))	('SV40', 'Var', (106, 110))
86874	33614918	More importantly, intratumoral injection of rAAV-sPD1-TWIST1 significantly enhanced immune surveillance by inducing TWIST1-specific CTL responses against vaccine-encoded TWIST1 and bystander gp70-AH1 epitopes, increasing CTL infiltration into the TME and decreasing tumor-associated immunosuppression, leading to complete elimination of established mesothelioma in 5 of 8 tumor-bearing mice.	('enhanced', 'PosReg', (75, 83))	('infiltration', 'CPA', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('inducing', 'PosReg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mice', 'Species', '10090', (386, 390))	('gp70', 'Gene', '13723', (191, 195))	('tumor', 'Disease', (266, 271))	('immune surveillance', 'MPA', (84, 103))	('gp70', 'Gene', (191, 195))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('CTL responses', 'MPA', (132, 145))	('rAAV-sPD1-TWIST1', 'Var', (44, 60))	('CTL', 'MPA', (221, 224))	('mesothelioma', 'Disease', (349, 361))	('mesothelioma', 'Disease', 'MESH:D008654', (349, 361))	('TWIST1-specific', 'Gene', (116, 131))	('rAAV', 'Chemical', '-', (44, 48))	('tumor', 'Disease', (372, 377))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('increasing', 'PosReg', (210, 220))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('TWIST1', 'Gene', (170, 176))
86895	33614918	Furthermore, the sPD1-TWIST1 vaccine generated by genetic fusion of sPD1 to TWIST1, a widely expressed tumor antigen, enables tumor growth control by breaking immune tolerance to the endogenous self-antigen.	('breaking', 'NegReg', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('immune tolerance', 'MPA', (159, 175))	('tumor', 'Disease', (103, 108))	('sPD1', 'Gene', (68, 72))	('TWIST1', 'Gene', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('genetic fusion', 'Var', (50, 64))	('tumor antigen', 'molecular_function', 'GO:0008222', ('103', '116'))	('enables', 'PosReg', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (126, 131))
86902	33614918	Furthermore, localized rAAV-sPD1-TWIST1 administration into human mesothelioma effectively combined AAV-mediated tumor growth inhibition and enhanced immune infiltration in a humanized mouse model.	('human', 'Species', '9606', (175, 180))	('tumor', 'Disease', (113, 118))	('mouse', 'Species', '10090', (185, 190))	('immune infiltration', 'CPA', (150, 169))	('mesothelioma', 'Disease', (66, 78))	('rAAV', 'Chemical', '-', (23, 27))	('AAV', 'Chemical', '-', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('rAAV-sPD1-TWIST1', 'Var', (23, 39))	('enhanced', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('AAV', 'Chemical', '-', (24, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('human', 'Species', '9606', (60, 65))
86903	33614918	We conclude that tumor-localized delivery of sPD1-TWIST1 by rAAV improves antitumor efficacy and is a feasible approach for cancer immunotherapy.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (17, 22))	('sPD1-TWIST1', 'Var', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('rAAV', 'Chemical', '-', (60, 64))	('tumor', 'Disease', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('improves', 'PosReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
86907	33614918	Although the sPD1-p24 and p24 proteins could be secreted as soluble forms, only sPD1-p24 interacted with PD-L1/L2-expressing cells (Figure S1A).	('soluble', 'cellular_component', 'GO:0005625', ('60', '67'))	('PD-L1', 'Gene', (105, 110))	('sPD1-p24', 'Var', (80, 88))	('PD-L1', 'Gene', '60533', (105, 110))	('interacted', 'Interaction', (89, 99))
86913	33614918	We found that both vectors elicited antibody responses to p24, but only rAAV-sPD1-p24 enhanced Th1 (immunoglobulin G2a [IgG2a]) and Th2 (IgG1) responses, which persisted until animal sacrifice on day 93 (Figure S1C).	('antibody', 'cellular_component', 'GO:0042571', ('36', '44'))	('rAAV-sPD1-p24', 'Var', (72, 85))	('elicited', 'Reg', (27, 35))	('IgG1', 'Gene', '16017', (137, 141))	('antibody', 'cellular_component', 'GO:0019815', ('36', '44'))	('antibody', 'cellular_component', 'GO:0019814', ('36', '44'))	('enhanced', 'PosReg', (86, 94))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('100', '114'))	('IgG2a', 'Gene', '668478', (120, 125))	('IgG2a', 'cellular_component', 'GO:0071735', ('120', '125'))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))	('IgG1', 'Gene', (137, 141))	('IgG1', 'cellular_component', 'GO:0071735', ('137', '141'))	('IgG2a', 'Gene', (120, 125))	('rAAV', 'Chemical', '-', (72, 76))
86914	33614918	In contrast, p24-specific CD8+ T cell responses reached peak levels on day 21 and decreased thereafter (Figure 1D).	('CD8', 'Gene', '925', (26, 29))	('p24-specific', 'Var', (13, 25))	('decreased', 'NegReg', (82, 91))	('CD8', 'Gene', (26, 29))
86915	33614918	Critically, rAAV-sPD1-p24 induced a significantly higher frequency of tetramer+CD8+ T cells, reaching up to 6.84% of total splenic CD8+ T cells on day 21, compared with 2% by rAAV-p24 (Figures 1D and 1E).	('Critically', 'Disease', (0, 10))	('higher', 'PosReg', (50, 56))	('rAAV', 'Chemical', '-', (12, 16))	('CD8', 'Gene', (79, 82))	('rAAV', 'Chemical', '-', (175, 179))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('CD8', 'Gene', '925', (79, 82))	('rAAV-sPD1-p24', 'Var', (12, 25))	('CD8', 'Gene', (131, 134))	('CD8', 'Gene', '925', (131, 134))
86916	33614918	At the endpoint, mice vaccinated with rAAV-sPD1-p24 also showed substantially higher frequencies of p24-specific CD4+ and CD8+ T cells (Figures S1D and S1E).	('p24-specific', 'Var', (100, 112))	('mice', 'Species', '10090', (17, 21))	('higher', 'PosReg', (78, 84))	('CD8', 'Gene', (122, 125))	('CD8', 'Gene', '925', (122, 125))	('rAAV', 'Chemical', '-', (38, 42))	('rAAV-sPD1-p24', 'Var', (38, 51))
86918	33614918	We next sought to study the antitumor efficacy of rAAV-sPD1-p24 in the AB1-GAG mesothelioma challenge model.	('mesothelioma', 'Disease', (79, 91))	('rAAV', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rAAV-sPD1-p24', 'Var', (50, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
86919	33614918	Groups of mice were vaccinated with rAAV-sPD1-p24, rAAV-p24, and AAV vector, respectively, followed by subcutaneous (s.c.) inoculation of AB1-GAG cells on day 21 (Figure 1F).	('AAV', 'Chemical', '-', (52, 55))	('rAAV-p24', 'Var', (51, 59))	('rAAV', 'Chemical', '-', (36, 40))	('mice', 'Species', '10090', (10, 14))	('AAV', 'Chemical', '-', (37, 40))	('rAAV-sPD1-p24', 'Var', (36, 49))	('rAAV', 'Chemical', '-', (51, 55))	('AAV', 'Chemical', '-', (65, 68))
86924	33614918	These results demonstrate that one-time vaccination with rAAV-sPD1-p24, but not with rAAV-p24, has potent prophylactic effects against AB1-GAG mesothelioma.	('mesothelioma', 'Disease', (143, 155))	('rAAV', 'Chemical', '-', (57, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('rAAV-sPD1-p24', 'Var', (57, 70))	('rAAV', 'Chemical', '-', (85, 89))
86925	33614918	Considering that AAV-encoded sPD1-p24 was readily detected in the plasma (Figure S1B), we sought to determine whether the sPD1 portion of sPD1-p24 would exhibit antitumor activity through blockade of the PD-1/PD-L1 immune checkpoint.	('sPD1', 'Var', (122, 126))	('PD-L1', 'Gene', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('sPD1-p24', 'Gene', (138, 146))	('AAV', 'Chemical', '-', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PD-L1', 'Gene', '60533', (209, 214))	('tumor', 'Disease', (165, 170))
86927	33614918	vaccination with rAAV-sPD1-p24 or rAAV-p24 (Figure 1F).	('rAAV', 'Chemical', '-', (34, 38))	('rAAV-sPD1-p24', 'Var', (17, 30))	('rAAV-p24', 'Var', (34, 42))	('rAAV', 'Chemical', '-', (17, 21))
86928	33614918	As expected, rAAV-p24 did not show any antitumor activity against wild-type AB1 mesothelioma, and all mice died within 31 days (Figures 1J and 1K).	('mice', 'Species', '10090', (102, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('rAAV', 'Chemical', '-', (13, 17))	('rAAV-p24', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mesothelioma', 'Disease', (80, 92))	('tumor', 'Disease', (43, 48))
86929	33614918	In contrast, rAAV-sPD1-p24 slowed tumor growth and eventually eliminated implanted tumors in 2 of 4 mice, leading to 50% tumor-free survival at the endpoint.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (83, 88))	('mice', 'Species', '10090', (100, 104))	('tumors', 'Disease', (83, 89))	('tumor', 'Disease', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('slowed', 'NegReg', (27, 33))	('rAAV', 'Chemical', '-', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('eliminated', 'NegReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('rAAV-sPD1-p24', 'Var', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
86930	33614918	Interestingly, although rAAV-sPD1-p24 and rAAV-p24 elicited p24-specific T cell responses, interferon gamma (IFN-gamma) T cell responses against two well-defined AB1 tumor antigens, gp70-AH1 and TWIST1, were only detected in rAAV-sPD1-p24-vaccinated mice with tumor elimination (Figure 1L).	('tumor', 'Disease', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('rAAV', 'Chemical', '-', (24, 28))	('interferon gamma', 'molecular_function', 'GO:0005133', ('91', '107'))	('rAAV-sPD1-p24', 'Var', (24, 37))	('IFN-gamma', 'Gene', '15978', (109, 118))	('IFN-gamma', 'Gene', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('mice', 'Species', '10090', (250, 254))	('rAAV-p24', 'Var', (42, 50))	('tumor', 'Disease', (166, 171))	('gp70', 'Gene', '13723', (182, 186))	('interferon', 'MPA', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('gp70', 'Gene', (182, 186))	('rAAV', 'Chemical', '-', (225, 229))	('AB1', 'Gene', (162, 165))	('rAAV', 'Chemical', '-', (42, 46))
86931	33614918	Notably, among rAAV-sPD1-p24-vaccinated mice, tumor-free animals also had stronger cytotoxic CD8+ T cells than tumor-bearing ones (Figure 1M).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('rAAV', 'Chemical', '-', (15, 19))	('rAAV-sPD1-p24-vaccinated', 'Var', (15, 39))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (111, 116))	('CD8', 'Gene', (93, 96))	('mice', 'Species', '10090', (40, 44))	('CD8', 'Gene', '925', (93, 96))	('stronger', 'PosReg', (74, 82))
86932	33614918	Therefore, sPD1-p24, but not p24, likely blocked the PD-1 immune checkpoint, leading to reactivation of specific anti-mesothelioma CTLs.	('sPD1-p24', 'Var', (11, 19))	('reactivation', 'MPA', (88, 100))	('mesothelioma CTLs', 'Disease', 'MESH:D008654', (118, 135))	('PD-1 immune checkpoint', 'Pathway', (53, 75))	('blocked', 'NegReg', (41, 48))	('mesothelioma CTLs', 'Disease', (118, 135))
86935	33614918	Similar to sPD1-p24, the interaction of sPD1-TWIST1 with PD-L1/L2-expressing cells was confirmed by flow cytometry analysis (Figure S2A).	('interaction', 'Interaction', (25, 36))	('PD-L1', 'Gene', (57, 62))	('sPD1-TWIST1', 'Var', (40, 51))	('PD-L1', 'Gene', '60533', (57, 62))
86939	33614918	rAAV-sPD1-TWIST1 elicited comparably higher frequencies of peripheral TWIST1-specific CD8+ T cells at the peak level, although this difference was not statistically significant.	('higher', 'PosReg', (37, 43))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('rAAV', 'Chemical', '-', (0, 4))	('TWIST1-specific', 'Gene', (70, 85))	('rAAV-sPD1-TWIST1', 'Var', (0, 16))
86941	33614918	We consistently found that animals vaccinated with rAAV-sPD1-TWIST1 had substantially higher frequencies of TNF-alpha-expressing splenic CD4+ T cells, IFN-gamma-, and IL-2-expressing splenic CD8+ T cells.	('CD8', 'Gene', '925', (191, 194))	('IFN-gamma', 'Gene', (151, 160))	('IL-2', 'molecular_function', 'GO:0005134', ('167', '171'))	('TNF-alpha', 'Gene', (108, 117))	('IL-2', 'Gene', '16183', (167, 171))	('higher', 'PosReg', (86, 92))	('IFN-gamma', 'Gene', '15978', (151, 160))	('rAAV', 'Chemical', '-', (51, 55))	('CD8', 'Gene', (191, 194))	('rAAV-sPD1-TWIST1', 'Var', (51, 67))	('IL-2', 'Gene', (167, 171))	('TNF-alpha', 'Gene', '21926', (108, 117))
86947	33614918	We found that vaccination with rAAV-sPD1-TWIST1 or rAAV-TWIST1 significantly inhibited AB1 mesothelioma growth compared with vector and mock treatment (Figure 3A).	('rAAV', 'Chemical', '-', (31, 35))	('mesothelioma growth', 'Disease', (91, 110))	('AB1', 'Gene', (87, 90))	('mesothelioma growth', 'Disease', 'MESH:D008654', (91, 110))	('rAAV-TWIST1', 'Var', (51, 62))	('inhibited', 'NegReg', (77, 86))	('rAAV', 'Chemical', '-', (51, 55))	('rAAV-sPD1-TWIST1', 'Var', (31, 47))
86948	33614918	Furthermore, although both vaccines prolonged the survival of wild-type AB1-challenged mice, rAAV-sPD1-TWIST1 also improved animal survival slightly more, with 3 of 7 tumor-free mice compared with 2 of 7 in the rAAV-TWIST1 group at the endpoint (Figure 3B).	('rAAV', 'Chemical', '-', (93, 97))	('rAAV', 'Chemical', '-', (211, 215))	('rAAV-sPD1-TWIST1', 'Var', (93, 109))	('mice', 'Species', '10090', (178, 182))	('mice', 'Species', '10090', (87, 91))	('animal survival', 'CPA', (124, 139))	('improved', 'PosReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('survival', 'CPA', (50, 58))	('tumor', 'Disease', (167, 172))	('prolonged', 'PosReg', (36, 45))
86955	33614918	To investigate the therapeutic potential of rAAV-sPD1-TWIST1 for treating established mesothelioma, we sought to determine its antitumor activity through conventional i.m.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('rAAV', 'Chemical', '-', (44, 48))	('mesothelioma', 'Disease', (86, 98))	('tumor', 'Disease', (131, 136))	('rAAV-sPD1-TWIST1', 'Var', (44, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
86960	33614918	rAAV-sPD1-TWIST1 injection might be an alternative means to modulate the TME because purified sPD1-TWIST1, but not TWIST1, was able to bind to PD-L2-expressing AB1 cells and compete with the anti-PD-L2/L1 antibodies in vitro (Figures 4B and 4C; Figure S3B).	('S3B', 'Gene', (252, 255))	('sPD1-TWIST1', 'Var', (94, 105))	('bind', 'Interaction', (135, 139))	('PD-L2', 'Gene', '58205', (196, 201))	('PD-L2', 'Gene', '58205', (143, 148))	('rAAV', 'Chemical', '-', (0, 4))	('PD-L2', 'Gene', (196, 201))	('S3B', 'Gene', '11778', (252, 255))	('PD-L2', 'Gene', (143, 148))
86962	33614918	AAV vector treatment did not suppress tumor growth or prolong animal survival, administration of rAAV-TWIST1 and rAAV-sPD1-p24 induced antitumor efficacies with survival of 1 of 5 and 1 of 6 animals, respectively, and rAAV-sPD1-TWIST1 showed the highest efficacy, with tumor-free survival of 5 of 8 mice during the experimental period (Figures 4D and 4E; Figure S3C).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('mice', 'Species', '10090', (299, 303))	('tumor', 'Disease', (139, 144))	('AAV', 'Chemical', '-', (219, 222))	('rAAV-sPD1-p24', 'Var', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('AAV', 'Chemical', '-', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('AAV', 'Chemical', '-', (98, 101))	('rAAV-sPD1-TWIST1', 'Var', (218, 234))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AAV', 'Chemical', '-', (0, 3))	('tumor', 'Disease', (38, 43))	('rAAV', 'Chemical', '-', (218, 222))	('rAAV', 'Chemical', '-', (113, 117))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('rAAV', 'Chemical', '-', (97, 101))
86969	33614918	In addition, sPD1-TWIST1 and sPD1-p24 proteins were detected in rAAV-sPD1-TWIST1- or rAAV-sPD1-p24-treated tumors, respectively, and may interact with PD-L1/L2+ cells in the TME and compete with anti-PD-L1/L2 antibodies (Figure 4H; Figure S3F).	('PD-L1', 'Gene', '60533', (151, 156))	('PD-L1', 'Gene', (200, 205))	('proteins', 'Protein', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rAAV-sPD1-TWIST1-', 'Var', (64, 81))	('tumors', 'Disease', (107, 113))	('PD-L1', 'Gene', '60533', (200, 205))	('rAAV', 'Chemical', '-', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('rAAV', 'Chemical', '-', (85, 89))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('sPD1-p24', 'Var', (29, 37))	('interact', 'Interaction', (137, 145))	('PD-L1', 'Gene', (151, 156))	('sPD1-TWIST1', 'Var', (13, 24))
86971	33614918	Only rAAV-sPD1-TWIST1 induced tumor-specific T cell responses against TWIST1 in spleens and tumor-draining lymph nodes (TDLNs) but induced hardly any in the contralateral non-draining lymph nodes (NdLNs) (Figure 4I).	('rAAV', 'Chemical', '-', (5, 9))	('induced', 'Reg', (22, 29))	('T cell responses', 'MPA', (45, 61))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TWIST1', 'Gene', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('rAAV-sPD1-TWIST1', 'Var', (5, 21))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (30, 35))
86973	33614918	Interestingly, rAAV-sPD1-TWIST1 also induced hrGFP-specific T cell responses (Figure S3G).	('rAAV-sPD1-TWIST1', 'Var', (15, 31))	('rAAV', 'Chemical', '-', (15, 19))	('induced', 'Reg', (37, 44))	('hrGFP-specific', 'Disease', (45, 59))
86975	33614918	We found that rAAV-sPD1-TWIST1 significantly elevated CD3+ T cell infiltration and reduced tumor-associated immunosuppressive cells, including tumor-associated macrophage (TAM; CD11b+Ly6Clow/-F4/80+), CD4+ regulatory T cells (Treg), and myeloid-derived suppressor cell (MDSC) subsets (CD11b+Ly6G+Ly6Clow/int, polymorphonuclear [PMN-] MDSCs; CD11b+Ly6G-Ly6Chi, monocytic [M-] MDSCs), in the TME (Figure 4J).	('reduced', 'NegReg', (83, 90))	('Ly6G', 'Gene', '546644', (347, 351))	('CD11b', 'Gene', '16409', (341, 346))	('CD11b', 'Gene', (177, 182))	('tumor', 'Disease', (91, 96))	('Ly6G', 'Gene', '546644', (291, 295))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('rAAV-sPD1-TWIST1', 'Var', (14, 30))	('Ly6G', 'Gene', (347, 351))	('Ly6C', 'Gene', '17067', (296, 300))	('Ly6C', 'Gene', '17067', (183, 187))	('CD11b', 'Gene', (341, 346))	('CD11b', 'Gene', '16409', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Ly6G', 'Gene', (291, 295))	('rAAV', 'Chemical', '-', (14, 18))	('Ly6C', 'Gene', '17067', (352, 356))	('CD3', 'Gene', '12503', (54, 57))	('Ly6C', 'Gene', (296, 300))	('Ly6C', 'Gene', (183, 187))	('PMN', 'biological_process', 'GO:0034727', ('328', '331'))	('CD11b', 'Gene', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Ly6C', 'Gene', (352, 356))	('CD3', 'Gene', (54, 57))	('tumor', 'Disease', (143, 148))	('elevated', 'PosReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('CD11b', 'Gene', '16409', (177, 182))
86976	33614918	In accordance with their immunoactivating status, we also observed elevated expression of effector cytokines, including IFN-gamma and IL-2, in the rAAV-sPD1-TWIST1-treated TME (Figure S3I).	('IL-2', 'Gene', (134, 138))	('elevated', 'PosReg', (67, 75))	('IFN-gamma', 'Gene', '15978', (120, 129))	('rAAV', 'Chemical', '-', (147, 151))	('expression', 'MPA', (76, 86))	('IL-2', 'molecular_function', 'GO:0005134', ('134', '138'))	('IFN-gamma', 'Gene', (120, 129))	('rAAV-sPD1-TWIST1-treated', 'Var', (147, 171))	('IL-2', 'Gene', '16183', (134, 138))
86977	33614918	injection of rAAV-sPD1-TWIST1 elicits systemic anti-mesothelioma effects through activation of tumor-specific T cells, increasing T cell infiltration and reducing tumor-associated immunosuppression.	('T cell infiltration', 'CPA', (130, 149))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('reducing', 'NegReg', (154, 162))	('increasing', 'PosReg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('activation', 'PosReg', (81, 91))	('mesothelioma', 'Disease', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('rAAV', 'Chemical', '-', (13, 17))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('rAAV-sPD1-TWIST1', 'Var', (13, 29))	('elicits', 'Reg', (30, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('tumor', 'Disease', (95, 100))
86979	33614918	We found that human mesothelioma REN cells were susceptible to infection, displaying green fluorescence and expressing vector-encoded proteins in culture supernatants after cells were infected with rAAV-TWIST1 and rAAV-hsPD1-TWIST1 but not heat-inactivated vector (Figures 5A and 5B).	('infected', 'Disease', (184, 192))	('mesothelioma', 'Disease', (20, 32))	('rAAV', 'Chemical', '-', (198, 202))	('infection', 'Disease', (63, 72))	('human', 'Species', '9606', (14, 19))	('infection', 'Disease', 'MESH:D007239', (63, 72))	('rAAV', 'Chemical', '-', (214, 218))	('rAAV-hsPD1-TWIST1', 'Var', (214, 231))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('infected', 'Disease', 'MESH:D007239', (184, 192))	('rAAV-TWIST1', 'Var', (198, 209))
86985	33614918	administration of rAAV-TWIST1, rAAV-hsPD1-TWIST1, heat-inactivated rAAV-hsPD1-TWIST1, or PBS when solid tumors were palpable (>5 mm) (Figure 5E).	('rAAV', 'Chemical', '-', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('rAAV-hsPD1-TWIST1', 'Var', (31, 48))	('PBS', 'Chemical', 'MESH:D007854', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('rAAV', 'Chemical', '-', (67, 71))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('rAAV', 'Chemical', '-', (18, 22))
86987	33614918	This effect was maintained through 4 weeks after treatment; expression of vector-encoded hrGFP was readily detected in tumors treated with rAAV-TWIST1 or rAAV-hsPD1-TWIST1 (Figure 5E).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('rAAV', 'Chemical', '-', (139, 143))	('tumors', 'Disease', (119, 125))	('detected', 'Reg', (107, 115))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('hrGFP', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('rAAV', 'Chemical', '-', (154, 158))	('rAAV-hsPD1-TWIST1', 'Var', (154, 171))	('rAAV-TWIST1', 'Var', (139, 150))
86992	33614918	Although live vector-treated mice showed retarded tumor growth and had significantly smaller tumor volumes compared with PBS or heat-inactivated vector treatment, rAAV-hsPD1-TWIST1 had the most potent effect on tumor regression (Figure 5F; Figure S4F).	('smaller', 'NegReg', (85, 92))	('rAAV', 'Chemical', '-', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('retarded tumor growth', 'Disease', (41, 62))	('tumor', 'Disease', (93, 98))	('rAAV-hsPD1-TWIST1', 'Var', (163, 180))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('retarded tumor growth', 'Disease', 'MESH:D006130', (41, 62))	('tumor', 'Disease', (211, 216))	('PBS', 'Chemical', 'MESH:D007854', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mice', 'Species', '10090', (29, 33))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
86994	33614918	Although the frequencies of PD-1+ T cells remained unchanged after rAAV-hsPD1-TWIST1 treatment, T cell infiltration in the TME was increased significantly increased (Figure 5G).	('PD-1+ T', 'Disease', 'MESH:D010300', (28, 35))	('increased', 'PosReg', (131, 140))	('T cell infiltration in the', 'CPA', (96, 122))	('increased', 'PosReg', (155, 164))	('rAAV', 'Chemical', '-', (67, 71))	('rAAV-hsPD1-TWIST1', 'Var', (67, 84))	('PD-1+ T', 'Disease', (28, 35))
86995	33614918	Collectively, these results demonstrated that rAAV-hsPD1-TWIST1 induced a direct oncosuppressive effect on tumor cells and mediated recruitment of T cells, which may work synergistically to establish an antitumor TME to arrest REN human mesothelioma.	('arrest REN human mesothelioma', 'Disease', (220, 249))	('rAAV', 'Chemical', '-', (46, 50))	('recruitment', 'MPA', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('rAAV-hsPD1-TWIST1', 'Var', (46, 63))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('arrest REN human mesothelioma', 'Disease', 'MESH:D006323', (220, 249))	('oncosuppressive effect', 'MPA', (81, 103))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (207, 212))
87004	33614918	Rational employment of this approach using the AAV-DJ system demonstrated similar enhancement of antibody and CD8+ T cell responses in delivery of p24 xenoantigen or TWIST1 self-antigen, highlighting the uniqueness of the PD1-based vaccine in promoting antigen-specific immunity across different vector systems.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('antibody', 'CPA', (97, 105))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('AAV', 'Chemical', '-', (47, 50))	('CD8', 'Gene', (110, 113))	('enhancement', 'PosReg', (82, 93))	('p24', 'Var', (147, 150))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))	('CD8', 'Gene', '925', (110, 113))
87011	33614918	administration of rAAV-sPD1-p24 provokes tumor-specific T cell responses against novel AB1 epitopes of gp70 and TWIST1.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('AB1', 'Gene', (87, 90))	('rAAV-sPD1-p24', 'Var', (18, 31))	('gp70', 'Gene', (103, 107))	('tumor', 'Disease', (41, 46))	('gp70', 'Gene', '13723', (103, 107))	('provokes', 'PosReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('TWIST1', 'Gene', (112, 118))	('rAAV', 'Chemical', '-', (18, 22))
87013	33614918	Immunotherapy for established AB1 mesothelioma requires localized delivery of sPD1-TWIST1 by rAAVs.	('AAVs', 'Chemical', '-', (94, 98))	('rAAV', 'Chemical', '-', (93, 97))	('mesothelioma', 'Disease', (34, 46))	('AB1', 'Gene', (30, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('sPD1-TWIST1', 'Var', (78, 89))
87017	33614918	Our results demonstrate that localized rAAV administration can deliver sPD1 directly into the TME to foster immune activation, immune cell infiltration, and tumor eradication.	('tumor', 'Disease', (157, 162))	('foster', 'PosReg', (101, 107))	('immune activation', 'CPA', (108, 125))	('sPD1', 'Var', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('rAAV', 'Chemical', '-', (39, 43))	('immune cell infiltration', 'CPA', (127, 151))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
87018	33614918	In this system, vector-encoded TWIST1 could be processed by local DCs for priming tumor-reactive T cells, as evidenced by the fact that rAAV-sPD1-TWIST1 treatment elicited significant proportions of tumor antigen-specific T cells in TDLNs but not the contralateral NdLNs.	('tumor', 'Disease', (199, 204))	('TDLNs', 'Disease', (233, 238))	('tumor antigen', 'molecular_function', 'GO:0008222', ('199', '212'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('elicited', 'Reg', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('rAAV', 'Chemical', '-', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('rAAV-sPD1-TWIST1', 'Var', (136, 152))	('tumor', 'Disease', (82, 87))
87019	33614918	In addition, persistent localized release of sPD1 could maintain the functionality of infiltrated antitumor T cells by blocking PD-L1/L2 on tumor/stromal cells and could potentially reduce PD-1/PD-L blockade toxicity associated with systemic immune checkpoint antibody administration.	('reduce PD', 'Phenotype', 'HP:0032198', (182, 191))	('reduce', 'NegReg', (182, 188))	('sPD1', 'Var', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('antibody', 'cellular_component', 'GO:0019815', ('260', '268'))	('PD-L1', 'Gene', (128, 133))	('PD-1/PD-L blockade toxicity', 'Disease', 'MESH:D010300', (189, 216))	('blocking', 'NegReg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('functionality', 'MPA', (69, 82))	('antibody', 'cellular_component', 'GO:0019814', ('260', '268'))	('PD-1/PD-L blockade toxicity', 'Disease', (189, 216))	('tumor', 'Disease', (102, 107))	('antibody', 'molecular_function', 'GO:0003823', ('260', '268'))	('PD-L1', 'Gene', '60533', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('antibody', 'cellular_component', 'GO:0042571', ('260', '268'))	('tumor', 'Disease', (140, 145))
87023	33614918	rAAV-sPD1-TWIST1 offers an in situ vaccination approach to activate TWIST1-specific T cell responses.	('TWIST1-specific', 'Gene', (68, 83))	('activate', 'PosReg', (59, 67))	('rAAV', 'Chemical', '-', (0, 4))	('rAAV-sPD1-TWIST1', 'Var', (0, 16))	('T cell responses', 'CPA', (84, 100))
87025	33614918	Therefore, rAAV-sPD1-TWIST1 likely converts the immunosuppressive TME into an immunostimulatory one, resulting in effective rejection of established AB1 mesothelioma.	('rAAV', 'Chemical', '-', (11, 15))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('rAAV-sPD1-TWIST1', 'Var', (11, 27))	('mesothelioma', 'Disease', (153, 165))
87026	33614918	Our findings support the hypothesis that localized delivery of rAAV-sPD1-TWIST1 has the ability to alter the TME by enriching tumor infiltration of immune cells, reducing immune suppressive cells in tumors, and activating tumor-infiltrating effector T cells.	('tumors', 'Disease', (199, 205))	('immune', 'MPA', (171, 177))	('alter', 'Reg', (99, 104))	('TME', 'MPA', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('rAAV', 'Chemical', '-', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (222, 227))	('enriching', 'PosReg', (116, 125))	('activating', 'PosReg', (211, 221))	('tumor', 'Disease', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('reducing', 'NegReg', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('rAAV-sPD1-TWIST1', 'Var', (63, 79))
87032	33614918	Our incorporation of sPD1-TWIST1 into the rAAV enhanced antitumor efficacy in a humanized mouse model compared with the rAAV-TWIST1 or AAV vector.	('incorporation', 'Var', (4, 17))	('sPD1-TWIST1', 'Var', (21, 32))	('enhanced', 'PosReg', (47, 55))	('AAV', 'Chemical', '-', (135, 138))	('AAV', 'Chemical', '-', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mouse', 'Species', '10090', (90, 95))	('rAAV', 'Chemical', '-', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('human', 'Species', '9606', (80, 85))	('rAAV', 'Chemical', '-', (42, 46))	('tumor', 'Disease', (60, 65))	('AAV', 'Chemical', '-', (121, 124))
87066	33614918	The following antibodies were used for western blotting: anti-TWIST1 (clone Twist2C1a, Abcam), anti-beta-actin (clone AC-15, Abcam), and anti-GAPDH (clone EPR16891, Abcam).	('anti-beta-actin', 'Var', (95, 110))	('GAPDH', 'Gene', (142, 147))	('GAPDH', 'Gene', '14433', (142, 147))
87067	33614918	The following antibodies were purchased from eBioscience and used for flow cytometry: anti-CD11b (clone M1/70), anti-Ly6C (clone HK1.4), anti-Ly6G (clone 1A8-Ly6g), anti-CD3 (clone 17A2), anti-CD4 (clone GK1.5), anti-CD8 (clone 53-6.7), and anti-PD-1 (clone J43).	('HK1', 'molecular_function', 'GO:0004673', ('129', '132'))	('Ly6g', 'Gene', '546644', (158, 162))	('Ly6C', 'Gene', (117, 121))	('anti-CD4', 'Var', (188, 196))	('Ly6C', 'Gene', '17067', (117, 121))	('Ly6G', 'Gene', '546644', (142, 146))	('Ly6g', 'Gene', (158, 162))	('CD3', 'Gene', '12503', (170, 173))	('CD8', 'Gene', (217, 220))	('CD3', 'Gene', (170, 173))	('CD8', 'Gene', '925', (217, 220))	('CD11b', 'Gene', (91, 96))	('CD11b', 'Gene', '16409', (91, 96))	('Ly6G', 'Gene', (142, 146))
87068	33614918	The following antibodies were purchased from BioLegend and used for flow cytometry: anti-FLAG (clone L5), anti-CD45 (clone S18009F), anti-CD25 (clone 3C7), anti-Foxp3 (clone 150D), anti-PD-L1 (clone 10F.9G2, MIH6), anti-PD-L2 (clone TY25), anti-IFN-gamma (clone XMG1.2), anti-TNF-alpha (clone MP6-XT22), and anti-IL-2 (clone JES6-5H4).	('TNF-alpha', 'Gene', '21926', (276, 285))	('PD-L1', 'Gene', (186, 191))	('IL-2', 'Gene', '16183', (313, 317))	('Foxp3', 'Gene', (161, 166))	('IL-2', 'molecular_function', 'GO:0005134', ('313', '317'))	('PD-L1', 'Gene', '60533', (186, 191))	('S18009F', 'SUBSTITUTION', 'None', (123, 130))	('IL-2', 'Gene', (313, 317))	('IFN-gamma', 'Gene', (245, 254))	('PD-L2', 'Gene', '58205', (220, 225))	('TNF-alpha', 'Gene', (276, 285))	('IFN-gamma', 'Gene', '15978', (245, 254))	('PD-L2', 'Gene', (220, 225))	('Foxp3', 'Gene', '20371', (161, 166))	('S18009F', 'Var', (123, 130))
87069	33614918	The following human-reactive antibodies were purchased from BioLegend and used for flow cytometry: anti-Ki67 (clone Ki-67), anti-CD3 (clone HIT3a), anti-CD4 (clone A161A1), anti-CD8a (clone HIT8a), anti-CD45 (clone 2D1), and anti-PD-1 (clone EH12.2H7).	('CD3', 'Gene', '12503', (129, 132))	('Ki67', 'Gene', '17345', (104, 108))	('human', 'Species', '9606', (14, 19))	('anti-CD45', 'Var', (198, 207))	('CD8a', 'Gene', (178, 182))	('CD8a', 'Gene', '925', (178, 182))	('Ki67', 'Gene', (104, 108))	('anti-CD4', 'Var', (148, 156))	('CD3', 'Gene', (129, 132))
87102	33513730	ROS and RNS are produced by mitochondria and by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, usually present in phagocytes; for this reason, the first DNA affected by mutation is indeed mtDNA (mitochondrial DNA).	('RNS', 'Gene', (8, 11))	('NADPH', 'Chemical', 'MESH:D009249', (48, 53))	('RNS', 'Gene', '56975', (8, 11))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('nicotinamide adenine dinucleotide phosphate) oxidase', 'Gene', '50506', (55, 107))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('209', '226'))	('mutation', 'Var', (183, 191))	('mtDNA', 'cellular_component', 'GO:0000262', ('202', '207'))	('mitochondria', 'cellular_component', 'GO:0005739', ('28', '40'))
87103	33513730	mtDNA mutation is involved in cancer-related inflammation of several tumors, such as malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (85, 115))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inflammation', 'Disease', (45, 57))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (95, 115))	('mtDNA', 'cellular_component', 'GO:0000262', ('0', '5'))	('malignant pleural mesothelioma', 'Disease', (85, 115))	('cancer', 'Disease', (30, 36))	('mutation', 'Var', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('inflammation', 'biological_process', 'GO:0006954', ('45', '57'))	('involved', 'Reg', (18, 26))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mtDNA', 'Gene', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
87107	33513730	However, oxidation can also inactivate DNA in a non-specific way, and this modulation causes accumulation of DNA lesions, genomic instability and cancer.	('cancer', 'Disease', (146, 152))	('DNA', 'Gene', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('genomic', 'MPA', (122, 129))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('accumulation', 'PosReg', (93, 105))	('DNA', 'Protein', (39, 42))	('inactivate', 'NegReg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('oxidation', 'Var', (9, 18))
87108	33513730	The presence of several viral agents, such as DNA tumor viruses, can lead to tumorigenesis by direct transformation of the cells through the insertion of active oncogenes into the host genome.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('lead to', 'Reg', (69, 76))	('insertion', 'Var', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (50, 55))
87110	33513730	The intrinsic pathway is triggered by tumor-promoting genetic events, such as mutations that activate oncogenes, chromosomal rearrangement and inactivation of onco-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('inactivation', 'Var', (143, 155))	('chromosomal rearrangement', 'Var', (113, 138))	('mutations', 'Var', (78, 87))	('oncogenes', 'Gene', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('activate', 'PosReg', (93, 101))	('onco-suppressor genes', 'Gene', (159, 180))
87111	33513730	The resulting mutated cells release inflammatory mediators and generate an inflammatory tumor microenvironment, although there is not underlying inflammation.	('mutated', 'Var', (14, 21))	('release', 'PosReg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inflammation', 'Disease', (145, 157))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inflammation', 'biological_process', 'GO:0006954', ('145', '157'))	('generate', 'Reg', (63, 71))	('tumor', 'Disease', (88, 93))
87138	33513730	However, their aerosol can also induce a considerable oxidative and inflammatory response in the lungs; in bronchial epithelial cells, e-cigarettes can induce acute toxicity and reduce the antiviral response.	('toxicity', 'Disease', 'MESH:D064420', (165, 173))	('reduce', 'NegReg', (178, 184))	('toxicity', 'Disease', (165, 173))	('induce', 'Reg', (152, 158))	('antiviral response', 'MPA', (189, 207))	('inflammatory response', 'biological_process', 'GO:0006954', ('68', '89'))	('induce', 'Reg', (32, 38))	('oxidative', 'MPA', (54, 63))	('e-cigarettes', 'Var', (135, 147))	('antiviral response', 'biological_process', 'GO:0051607', ('189', '207'))
87141	33513730	These results suggest that e-cigarettes, considered the safe alternative to tobacco cigarettes, can also induce lung inflammation and could therefore cause lung cancer.	('tobacco', 'Species', '4097', (76, 83))	('induce', 'PosReg', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cause', 'Reg', (150, 155))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('lung inflammation', 'Disease', 'MESH:D011014', (112, 129))	('e-cigarettes', 'Var', (27, 39))	('inflammation', 'biological_process', 'GO:0006954', ('117', '129'))	('lung inflammation', 'Disease', (112, 129))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
87142	33513730	Although moderate levels of UV exposure for a limited time are favorable for humans, since it stimulates the production of Vitamin D in our skin, an overexposure can cause skin inflammation (i.e., sunburn) and/or skin damage and skin cancer.	('skin cancer', 'Disease', (229, 240))	('skin inflammation', 'Disease', (172, 189))	('Vitamin D', 'Chemical', 'MESH:D014807', (123, 132))	('skin damage', 'Disease', 'MESH:D012871', (213, 224))	('production', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('overexposure', 'Var', (149, 161))	('humans', 'Species', '9606', (77, 83))	('skin cancer', 'Disease', 'MESH:D012878', (229, 240))	('skin inflammation', 'Phenotype', 'HP:0011123', (172, 189))	('skin inflammation', 'Disease', 'MESH:D007249', (172, 189))	('skin cancer', 'Phenotype', 'HP:0008069', (229, 240))	('inflammation', 'biological_process', 'GO:0006954', ('177', '189'))	('cause', 'Reg', (166, 171))	('stimulates', 'PosReg', (94, 104))	('skin damage', 'Disease', (213, 224))
87149	33513730	demonstrated that skin cells, upon UV exposure, increase the production of prostaglandin and the release of histamine: mice deficient in prostaglandin E2 receptors are less susceptible to chemically-induced tumor formation.	('mice', 'Species', '10090', (119, 123))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (137, 153))	('prostaglandin', 'Chemical', 'MESH:D011453', (75, 88))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('histamine', 'Chemical', 'MESH:D006632', (108, 117))	('deficient in prostaglandin E2', 'Phenotype', 'HP:0003566', (124, 153))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('formation', 'biological_process', 'GO:0009058', ('213', '222'))	('tumor', 'Disease', (207, 212))	('less', 'NegReg', (168, 172))	('deficient', 'Var', (124, 133))	('prostaglandin', 'Chemical', 'MESH:D011453', (137, 150))
87157	33513730	Over several years, this unleashed inflammation causes DNA damage, accumulation of DNA mutations and, ultimately, neoplastic transformation.	('DNA damage', 'MPA', (55, 65))	('inflammation', 'biological_process', 'GO:0006954', ('35', '47'))	('neoplastic transformation', 'CPA', (114, 139))	('DNA', 'Gene', (83, 86))	('causes', 'Reg', (48, 54))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('mutations', 'Var', (87, 96))	('inflammation', 'Disease', (35, 47))	('accumulation', 'PosReg', (67, 79))
87158	33513730	Overall, a comprehensive range of several mutations have been found in different genes, such as BAP1 (BRCA1 associated protein 1), CDKN2A (cyclin-dependent kinase inhibitor 2A), Ras (rat sarcoma protein), Wnt (wingless-related integration site), TP53 (tumor protein P53), SMARCB1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1), NF2 (neurofibromin 2) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha).	('Wnt', 'Gene', (205, 208))	('neurofibromin 2', 'Gene', (386, 401))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', '306257', (96, 100))	('P53', 'Gene', '24842', (266, 269))	('PIK3CA', 'Gene', '170911', (407, 413))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '170911', (415, 485))	('NF2', 'Gene', (381, 384))	('neurofibromin 2', 'Gene', '25744', (386, 401))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (139, 175))	('BRCA1 associated protein 1', 'Gene', '306257', (102, 128))	('P53', 'Gene', '24842', (247, 250))	('sarcoma', 'Disease', (187, 194))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('CDKN2A', 'Gene', '25163', (131, 137))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('156', '172'))	('PIK3CA', 'Gene', (407, 413))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('SMARCB1', 'Gene', (272, 279))	('P53', 'Gene', (266, 269))	('Ras', 'Gene', (178, 181))	('SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1', 'Gene', '361825', (281, 378))	('chromatin', 'cellular_component', 'GO:0000785', ('346', '355'))	('NF2', 'Gene', '25744', (381, 384))	('BRCA1 associated protein 1', 'Gene', (102, 128))	('TP53', 'Gene', '24842', (246, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('SMARCB1', 'Gene', '361825', (272, 279))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '25163', (139, 175))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('139', '172'))	('P53', 'Gene', (247, 250))	('TP53', 'Gene', (246, 250))	('tumor', 'Disease', (252, 257))	('mutations', 'Var', (42, 51))	('CDKN2A', 'Gene', (131, 137))
87159	33513730	This variety of gene mutations in mesothelioma indicates that there are no specific driver mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('mesothelioma', 'Disease', (34, 46))	('mutations', 'Var', (21, 30))
87175	33513730	These microbiota changes are able to deeply influence the immune system through different ways, such as modification of signaling via the NLRP6 (NLR Family Pyrin Domain Containing 6) inflammasome and TLRs, the decrease of AMP (Adenosine Monophosphate) and mucus release in the lumen, the degradation of secretory IgAs (immunoglobulin A) and the selective loss of Treg lymphocytes producing IL-10.	('NLRP6', 'Gene', '171389', (138, 143))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('319', '333'))	('loss', 'NegReg', (355, 359))	('AMP', 'Chemical', 'MESH:D000249', (222, 225))	('IL-10', 'Gene', '3586', (390, 395))	('Pyrin', 'Gene', '4210', (156, 161))	('signaling', 'MPA', (120, 129))	('mucus', 'cellular_component', 'GO:0070701', ('256', '261'))	('IL-10', 'Gene', (390, 395))	('NLRP6', 'Gene', (138, 143))	('Treg lymphocytes producing', 'CPA', (363, 389))	('decrease', 'NegReg', (210, 218))	('IL-10', 'molecular_function', 'GO:0005141', ('390', '395'))	('Adenosine', 'Chemical', 'MESH:D000241', (227, 236))	('changes', 'Var', (17, 24))	('modification', 'Reg', (104, 116))	('TLRs', 'MPA', (200, 204))	('degradation', 'MPA', (288, 299))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('degradation', 'biological_process', 'GO:0009056', ('288', '299'))	('Pyrin', 'Gene', (156, 161))	('influence', 'Reg', (44, 53))	('secretory IgAs', 'MPA', (303, 317))
87197	33513730	Some infections are able to directly induce oncogenic events, such as Epstein-Barr virus (EBV) and human Papillomavirus (HPV): it has been shown that they are able to transform cells by inserting active oncogenes into the host genome.	('infections', 'Disease', (5, 15))	('inserting', 'Var', (186, 195))	('EBV', 'Species', '10376', (90, 93))	('transform', 'Reg', (167, 176))	('infections', 'Disease', 'MESH:D007239', (5, 15))	('oncogenes', 'Gene', (203, 212))	('human Papillomavirus', 'Species', '10566', (99, 119))	('human Papillomavirus', 'Disease', (99, 119))	('HPV', 'Species', '10566', (121, 124))	('Epstein-Barr virus', 'Disease', (70, 88))	('cells', 'CPA', (177, 182))
87210	33513730	As described above, the process of tissue repair in the presence of ROS and RNS, produced by inflammatory cells, mutates DNA.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('RNS', 'Gene', (76, 79))	('mutates', 'Var', (113, 120))	('ROS', 'Chemical', 'MESH:D017382', (68, 71))	('RNS', 'Gene', '56975', (76, 79))	('DNA', 'MPA', (121, 124))
87211	33513730	One of the observed mutated gene is p53, which has been shown to be mutated both in tumors and in chronic inflammatory diseases, such as inflammatory bowel disease, a predisposing condition for colon carcinogenesis.	('colon carcinogenesis', 'Disease', (194, 214))	('inflammatory diseases', 'Disease', 'MESH:D007249', (106, 127))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (137, 163))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inflammatory bowel disease', 'Disease', (137, 163))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (137, 163))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('inflammatory diseases', 'Disease', (106, 127))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutated', 'Var', (68, 75))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (194, 214))
87266	30316012	Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones.	('MHC', 'Gene', (155, 158))	('rearrangement-related', 'Var', (17, 38))	('tumor', 'Disease', (188, 193))	('Transcription', 'Var', (0, 13))	('MHC', 'Gene', '3107', (155, 158))	('neoantigens', 'MPA', (91, 102))	('expand', 'PosReg', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('bind', 'Interaction', (133, 137))	('patient', 'Species', '9606', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('result in', 'Reg', (66, 75))
87270	30316012	Malignant pleural mesothelioma (MPM) is characterized by exposure to the carcinogen asbestos, although some cases develop after therapeutic radiation or are inherited due to loss of function mutations in BRCA1 Associated Protein 1 (BAP1).	('MPM', 'Disease', 'MESH:C562839', (32, 35))	('BAP1', 'Gene', (232, 236))	('MPM', 'Disease', (32, 35))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (0, 30))	('Malignant pleural mesothelioma', 'Disease', (0, 30))	('mutations', 'Var', (191, 200))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (10, 30))	('BRCA1 Associated Protein 1', 'Gene', (204, 230))	('BRCA1 Associated Protein 1', 'Gene', '8314', (204, 230))	('BAP1', 'Gene', '8314', (232, 236))
87272	30316012	More recent studies that used next-generation sequencing (NGS) to evaluate single nucleotide variation mutations in MPM reported a very low mutation burden overall.	('single nucleotide variation mutations', 'Var', (75, 112))	('MPM', 'Disease', (116, 119))	('MPM', 'Disease', 'MESH:C562839', (116, 119))
87275	30316012	We previously used MPseq to determine the lineage relationships of multifocal lung cancer, to identify a chromoplectic ALK rearrangement in an inflammatory myofibroblastic tumor, to discover recurrent t(6:7)(p25.3;q32.3) translocations in "ALK-negative" anaplastic large cell lymphomas and for other purposes.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('anaplastic large cell lymphomas', 'Phenotype', 'HP:0012193', (254, 285))	('ALK', 'Gene', '238', (119, 122))	('ALK', 'Gene', '238', (240, 243))	('lymphomas', 'Phenotype', 'HP:0002665', (276, 285))	('lymphomas', 'Disease', (276, 285))	('ALK', 'Gene', (119, 122))	('lymphomas', 'Disease', 'MESH:D008223', (276, 285))	('t(6:7)(p25.3;q32.3)', 'STRUCTURAL_ABNORMALITY', 'None', (201, 220))	('translocations', 'Var', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ALK', 'Gene', (240, 243))	('myofibroblastic tumor', 'Disease', (156, 177))	('multifocal lung cancer', 'Disease', 'None', (67, 89))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (156, 177))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (156, 177))	('multifocal lung cancer', 'Disease', (67, 89))
87278	30316012	We hypothesized that this method would identify expression of rearrangement-related peptides with neoantigenic potential and define a novel mechanism of tumor immunogenicity that may not be detected with standard sequencing approaches.	('rearrangement-related', 'Var', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('expression', 'MPA', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))
87297	30316012	This was developed based on observations that larger and more aromatic residues tended to increase the likelihood of TCR interaction in a consistent manner, namely that particular features at different residue positions favored T cell interaction.	('TCR', 'Gene', (117, 120))	('favored', 'PosReg', (220, 227))	('aromatic residues', 'Var', (62, 79))	('increase', 'PosReg', (90, 98))	('TCR', 'cellular_component', 'GO:0042101', ('117', '120'))	('TCR', 'Gene', '6962', (117, 120))	('TCR', 'biological_process', 'GO:0006283', ('117', '120'))
87324	30316012	These chromosomal rearrangements were associated with amplifications and deletions of many chromosomal segments, affecting genes such as CDKN2A and NF2 at similar rates as reported by others (Supplemental Table 2 and Figure 24).	('affecting', 'Reg', (113, 122))	('NF2', 'Gene', (148, 151))	('CDKN2A', 'Gene', (137, 143))	('deletions', 'Var', (73, 82))	('CDKN2A', 'Gene', '1029', (137, 143))	('NF2', 'Gene', '4771', (148, 151))	('amplifications', 'Var', (54, 68))
87332	30316012	These candidate peptides resulted from the rearrangement of non-coding DNA with CADPS2 or non-coding DNA with NOD1 (Supplemental Tables 5-9).	('resulted from', 'Reg', (25, 38))	('CADPS2', 'Gene', '93664', (80, 86))	('NOD1', 'Gene', '10392', (110, 114))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('NOD1', 'Gene', (110, 114))	('CADPS2', 'Gene', (80, 86))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('rearrangement', 'Var', (43, 56))
87335	30316012	In other words, an increase in predicted neoantigens resulting from chromosomal rearrangements was correlated with clonal expansion of tumor infiltrating T cells.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('increase', 'PosReg', (19, 27))	('chromosomal rearrangements', 'Var', (68, 94))	('neoantigens', 'MPA', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
87342	30316012	We used MPseq to identify that chromosomal rearrangements are common in MPM and frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis.	('chromothripsis', 'Disease', (147, 161))	('chromosomal rearrangements', 'Var', (31, 57))	('chromoplexy', 'Disease', (132, 143))	('MPM', 'Disease', 'MESH:C562839', (72, 75))	('MPM', 'Disease', (72, 75))
87351	30316012	Our data also build upon recent findings that gene fusions may result in loss of copy or function of tumor suppressor genes such as BAP1, NF2 and others.	('BAP1', 'Gene', '8314', (132, 136))	('loss of', 'NegReg', (73, 80))	('NF2', 'Gene', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('BAP1', 'Gene', (132, 136))	('gene fusions', 'Var', (46, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('101', '117'))	('NF2', 'Gene', '4771', (138, 141))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('101', '117'))	('copy or', 'MPA', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
87352	30316012	We most frequently identified involvement of RBFOX1 with chromosomal rearrangements.	('RBFOX1', 'Gene', (45, 51))	('involvement', 'Reg', (30, 41))	('chromosomal rearrangements', 'Var', (57, 83))	('RBFOX1', 'Gene', '54715', (45, 51))
87353	30316012	The significance of RBFOX1 remains uncertain in MPM, but it belongs to a family of proteins that regulate alternative mRNA splicing and its absence in the brain may increase susceptibility to seizures.	('RBFOX1', 'Gene', '54715', (20, 26))	('seizures', 'Disease', 'MESH:D012640', (192, 200))	('mRNA splicing', 'biological_process', 'GO:0000394', ('118', '131'))	('RBFOX1', 'Gene', (20, 26))	('mRNA splicing', 'biological_process', 'GO:0000374', ('118', '131'))	('seizures', 'Disease', (192, 200))	('seizures', 'Phenotype', 'HP:0001250', (192, 200))	('increase', 'Reg', (165, 173))	('absence', 'Var', (140, 147))	('mRNA splicing', 'biological_process', 'GO:0000373', ('118', '131'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('118', '131'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('118', '131'))	('MPM', 'Disease', 'MESH:C562839', (48, 51))	('mRNA splicing', 'biological_process', 'GO:0000372', ('118', '131'))	('MPM', 'Disease', (48, 51))	('susceptibility', 'MPA', (174, 188))
87357	30316012	Over the last few decades there have been many attempts to target non-mutant cancer-germline or cancer testis antigens such as NY-ESO-1 and MAGE-A3 in a variety of tumors; however, the availability of affordable sequencing technologies has facilitated more recent efforts to identify and target tumor-specific neoantigens resulting from point mutations.	('tumor', 'Disease', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer testis', 'Phenotype', 'HP:0010788', (96, 109))	('NY-ESO-1', 'Gene', (127, 135))	('cancer', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('point mutations', 'Var', (337, 352))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('NY-ESO-1', 'Gene', '246100', (127, 135))	('tumor', 'Disease', (295, 300))	('tumors', 'Disease', (164, 170))	('cancer', 'Disease', (77, 83))	('MAGE-A3', 'Gene', '4102', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('MAGE-A3', 'Gene', (140, 147))
87360	30316012	These frameshifts were predictive of response to PD-1 inhibition in separate cohorts of patients with melanoma.	('frameshifts', 'Var', (6, 17))	('predictive', 'Reg', (23, 33))	('patients', 'Species', '9606', (88, 96))	('PD-1', 'Gene', (49, 53))	('PD-1', 'Gene', '5133', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))
87361	30316012	Although MPM has a relatively low nonsynonymous tumor mutation burden, our finding of rearrangement-related peptides with neoantigenic potential may promote the immunogenicity of MPM in a similar fashion as frameshift indel high-affinity neoantigens.	('MPM', 'Disease', (9, 12))	('tumor', 'Disease', (48, 53))	('MPM', 'Disease', 'MESH:C562839', (9, 12))	('frameshift indel', 'Var', (207, 223))	('MPM', 'Disease', 'MESH:C562839', (179, 182))	('immunogenicity', 'MPA', (161, 175))	('MPM', 'Disease', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('promote', 'PosReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
87365	30018519	Matrix Metalloproteinases Polymorphisms as Baseline Risk Predictors in Malignant Pleural Mesothelioma Malignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases.	('Polymorphisms', 'Var', (26, 39))	('asbestos', 'Chemical', 'MESH:D001194', (159, 167))	('Malignant Pleural Mesothelioma', 'Disease', (71, 101))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (102, 124))	('Malignant mesothelioma', 'Disease', (102, 124))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (81, 101))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (102, 124))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (71, 101))
87367	30018519	Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM.	('MMPs', 'Gene', '4312;4313;4314;4316;4318;4320;4323', (26, 30))	('Polymorphisms', 'Var', (0, 13))	('MMPs', 'Gene', (26, 30))
87370	30018519	Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257.	('MMP2', 'Gene', '4313', (133, 137))	('MMP9', 'molecular_function', 'GO:0004229', ('169', '173'))	('MMP', 'molecular_function', 'GO:0004235', ('219', '222'))	('rs743257', 'Mutation', 'rs743257', (250, 258))	('rs1042703', 'Var', (225, 234))	('rs243849', 'Mutation', 'rs243849', (148, 156))	('MMP14', 'Gene', '4323', (219, 224))	('rs20544', 'Mutation', 'rs20544', (206, 213))	('rs243865', 'Var', (138, 146))	('rs7201', 'Mutation', 'rs7201', (161, 167))	('rs17577', 'Mutation', 'rs17577', (183, 190))	('MMP14', 'Gene', (219, 224))	('rs2250889', 'Mutation', 'rs2250889', (192, 201))	('rs743257', 'Var', (250, 258))	('rs1042704', 'Var', (236, 245))	('MMP2', 'molecular_function', 'GO:0004228', ('133', '137'))	('MMP', 'molecular_function', 'GO:0004235', ('37', '40'))	('rs7201', 'Var', (161, 167))	('rs243849', 'Var', (148, 156))	('MMP2', 'Gene', (133, 137))	('rs243865', 'Mutation', 'rs243865', (138, 146))	('rs17576', 'Var', (174, 181))	('rs17576', 'Mutation', 'rs17576', (174, 181))	('MMP9', 'Gene', '4318', (169, 173))	('MMP9', 'Gene', (169, 173))	('rs1042704', 'Mutation', 'rs1042704', (236, 245))	('rs17577', 'Var', (183, 190))	('rs20544', 'Var', (206, 213))	('rs1042703', 'Mutation', 'rs1042703', (225, 234))	('rs2250889', 'Var', (192, 201))
87371	30018519	Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44-1.00; P = 0.050).	('MMP2', 'molecular_function', 'GO:0004228', ('37', '41'))	('MMP2', 'Gene', '4313', (37, 41))	('rs243865', 'Var', (42, 50))	('MMP2', 'Gene', (37, 41))	('rs243865', 'Mutation', 'rs243865', (42, 50))	('decreased', 'NegReg', (75, 84))
87374	30018519	The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (71, 91))	('malignant pleural mesothelioma', 'Disease', (61, 91))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (61, 91))	('MMP2', 'Gene', (4, 8))	('rs243865', 'Mutation', 'rs243865', (9, 17))	('rs243865', 'Var', (9, 17))	('MMP2', 'Gene', '4313', (4, 8))	('MMP2', 'molecular_function', 'GO:0004228', ('4', '8'))
87384	30018519	We identified MMP9 rs2250889, MMP9 rs20544, MMP14 rs1042703 as statistically significantly associated with overall survival (OS) in MM.	('MMP9', 'Gene', (30, 34))	('MMP9', 'Gene', (14, 18))	('MMP9', 'molecular_function', 'GO:0004229', ('14', '18'))	('overall survival', 'MPA', (107, 123))	('MMP9', 'Gene', '4318', (14, 18))	('MMP14', 'Gene', '4323', (44, 49))	('MMP9', 'molecular_function', 'GO:0004229', ('30', '34'))	('MMP', 'molecular_function', 'GO:0004235', ('44', '47'))	('MMP14', 'Gene', (44, 49))	('rs2250889', 'Mutation', 'rs2250889', (19, 28))	('rs2250889', 'Var', (19, 28))	('rs20544', 'Mutation', 'rs20544', (35, 42))	('rs1042703', 'Var', (50, 59))	('rs1042703', 'Mutation', 'rs1042703', (50, 59))	('rs20544', 'Var', (35, 42))	('associated with', 'Reg', (91, 106))	('MMP9', 'Gene', '4318', (30, 34))
87385	30018519	Carriers of the polymorphic MMP9 rs2250889 and MMP14 rs1042703 alleles had shorter OS, compared to non-carriers, while carriers of polymorphic MMP9 rs20544 allele had longer OS.	('rs1042703', 'Var', (53, 62))	('MMP14', 'Gene', '4323', (47, 52))	('rs1042703', 'Mutation', 'rs1042703', (53, 62))	('rs2250889', 'Mutation', 'rs2250889', (33, 42))	('MMP9', 'Gene', '4318', (28, 32))	('MMP9', 'Gene', (28, 32))	('MMP14', 'Gene', (47, 52))	('MMP', 'molecular_function', 'GO:0004235', ('47', '50'))	('rs2250889', 'Var', (33, 42))	('MMP9', 'molecular_function', 'GO:0004229', ('28', '32'))	('shorter', 'NegReg', (75, 82))	('MMP9', 'Gene', '4318', (143, 147))	('rs20544', 'Mutation', 'rs20544', (148, 155))	('MMP9', 'Gene', (143, 147))	('MMP9', 'molecular_function', 'GO:0004229', ('143', '147'))
87386	30018519	Many studies investigated the role of MMP polymorphisms in the baseline genetic risk for common diseases and tumours, however, the role of MMP polymorphisms was found to be conflicting in different diseases.	('investigated', 'Reg', (13, 25))	('diseases and tumours', 'Disease', 'MESH:D009369', (96, 116))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('MMP', 'molecular_function', 'GO:0004235', ('139', '142'))	('MMP', 'molecular_function', 'GO:0004235', ('38', '41'))	('MMP', 'Gene', (38, 41))	('polymorphisms', 'Var', (42, 55))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
87387	30018519	In a large nested case-control study investigating skin cancer risk, MMP9 Arg668Gln polymorphism has been associated with a decreased risk of squamous cell skin cancer (SCC).	('Arg668Gln', 'Var', (74, 83))	('skin cancer', 'Disease', 'MESH:D012878', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MMP9', 'Gene', '4318', (69, 73))	('MMP9', 'Gene', (69, 73))	('Arg668Gln', 'SUBSTITUTION', 'None', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('decreased', 'NegReg', (124, 133))	('squamous cell skin cancer', 'Phenotype', 'HP:0006739', (142, 167))	('squamous cell skin cancer', 'Disease', 'MESH:D002294', (142, 167))	('MMP9', 'molecular_function', 'GO:0004229', ('69', '73'))	('skin cancer', 'Disease', (51, 62))	('squamous cell skin cancer', 'Disease', (142, 167))	('SCC', 'Phenotype', 'HP:0008069', (169, 172))	('skin cancer', 'Phenotype', 'HP:0008069', (156, 167))	('skin cancer', 'Disease', 'MESH:D012878', (51, 62))
87388	30018519	The opposite effect was observed in T-cell acute lymphoblastic leukaemia (T-ALL), where MMP2 rs243865 and MMP9 rs3918242 polymorphisms were associated with an increased risk of T-ALL.	('rs243865', 'Mutation', 'rs243865', (93, 101))	('MMP9', 'Gene', '4318', (106, 110))	('MMP9', 'molecular_function', 'GO:0004229', ('106', '110'))	('associated', 'Reg', (140, 150))	('MMP2', 'Gene', '4313', (88, 92))	('T-cell acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006727', (36, 72))	('MMP2', 'molecular_function', 'GO:0004228', ('88', '92'))	('rs3918242', 'Mutation', 'rs3918242', (111, 120))	('T-ALL', 'Disease', (177, 182))	('rs243865', 'Var', (93, 101))	('rs3918242', 'Var', (111, 120))	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (43, 72))	('T-cell acute lymphoblastic leukaemia (T-ALL)', 'Disease', 'MESH:D054218', (36, 80))	('T-ALL', 'Phenotype', 'HP:0006727', (74, 79))	('MMP2', 'Gene', (88, 92))	('MMP9', 'Gene', (106, 110))	('T-ALL', 'Phenotype', 'HP:0006727', (177, 182))
87399	30018519	Ten different polymorphisms in three MMP genes were genotyped: MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257.	('rs20544', 'Mutation', 'rs20544', (136, 143))	('rs7201', 'Mutation', 'rs7201', (91, 97))	('rs1042703', 'Var', (155, 164))	('rs743257', 'Var', (180, 188))	('rs2250889', 'Mutation', 'rs2250889', (122, 131))	('rs243849', 'Mutation', 'rs243849', (78, 86))	('rs1042704', 'Var', (166, 175))	('MMP14', 'Gene', '4323', (149, 154))	('rs243865', 'Var', (68, 76))	('rs17577', 'Mutation', 'rs17577', (113, 120))	('MMP14', 'Gene', (149, 154))	('MMP', 'molecular_function', 'GO:0004235', ('149', '152'))	('rs7201', 'Var', (91, 97))	('MMP9', 'molecular_function', 'GO:0004229', ('99', '103'))	('rs243849', 'Var', (78, 86))	('MMP2', 'Gene', (63, 67))	('rs1042704', 'Mutation', 'rs1042704', (166, 175))	('rs17576', 'Var', (104, 111))	('MMP', 'molecular_function', 'GO:0004235', ('37', '40'))	('rs20544', 'Var', (136, 143))	('rs243865', 'Mutation', 'rs243865', (68, 76))	('rs2250889', 'Var', (122, 131))	('rs17576', 'Mutation', 'rs17576', (104, 111))	('MMP9', 'Gene', '4318', (99, 103))	('MMP2', 'molecular_function', 'GO:0004228', ('63', '67'))	('MMP9', 'Gene', (99, 103))	('rs743257', 'Mutation', 'rs743257', (180, 188))	('rs17577', 'Var', (113, 120))	('rs1042703', 'Mutation', 'rs1042703', (155, 164))	('MMP2', 'Gene', '4313', (63, 67))
87404	30018519	Nevertheless, haplotypes that included the polymorphic MMP2 rs243865 allele had slightly lower risk, consistent with single SNP analysis, but the association did not reach statistical significance.	('lower', 'NegReg', (89, 94))	('MMP2', 'molecular_function', 'GO:0004228', ('55', '59'))	('MMP2', 'Gene', (55, 59))	('rs243865', 'Mutation', 'rs243865', (60, 68))	('MMP2', 'Gene', '4313', (55, 59))	('rs243865', 'Var', (60, 68))
87406	30018519	Carriers of MMP2 rs243865 CT or CT/TT genotypes had significantly decreased risk for developing MM in comparison with CC homozygous genotype, especially in patients with known asbestos exposure.	('patients', 'Species', '9606', (156, 164))	('MMP2', 'Gene', '4313', (12, 16))	('asbestos', 'Chemical', 'MESH:D001194', (176, 184))	('decreased', 'NegReg', (66, 75))	('rs243865 CT', 'Var', (17, 28))	('MMP2', 'molecular_function', 'GO:0004228', ('12', '16'))	('MMP2', 'Gene', (12, 16))	('rs243865', 'Mutation', 'rs243865', (17, 25))
87407	30018519	MMP2 rs243865 (c.-1306C>T) is a promoter polymorphism and our prior in silico analysis has shown that it may influence binding of transcription factors and may alter chromatin states.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('MMP2', 'Gene', (0, 4))	('chromatin', 'cellular_component', 'GO:0000785', ('166', '175'))	('alter', 'Reg', (160, 165))	('rs243865', 'Mutation', 'rs243865', (5, 13))	('rs243865 (c.-1306C>T', 'Var', (5, 25))	('influence', 'Reg', (109, 118))	('transcription', 'biological_process', 'GO:0006351', ('130', '143'))	('chromatin states', 'MPA', (166, 182))	('transcription', 'Protein', (130, 143))	('MMP2', 'Gene', '4313', (0, 4))	('c.-1306C>T', 'Mutation', 'rs243865', (15, 25))	('MMP2', 'molecular_function', 'GO:0004228', ('0', '4'))	('binding', 'Interaction', (119, 126))
87408	30018519	The data on whether the MMP2 rs243865 T allele has a protective function or if it contributes to higher risk for cancer, is somewhat conflicting for different malignancies.	('rs243865 T', 'Var', (29, 39))	('MMP2', 'Gene', (24, 28))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('MMP2', 'molecular_function', 'GO:0004228', ('24', '28'))	('rs243865', 'Mutation', 'rs243865', (29, 37))	('cancer', 'Disease', (113, 119))	('malignancies', 'Disease', (159, 171))	('MMP2', 'Gene', '4313', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
87410	30018519	The most attractive and most significant MMPs in risk assessment studies were MMP2, MMP9 and MMP3 polymorphisms.	('MMP3', 'molecular_function', 'GO:0004248', ('93', '97'))	('MMP9', 'molecular_function', 'GO:0004229', ('84', '88'))	('polymorphisms', 'Var', (98, 111))	('MMP2', 'Gene', '4313', (78, 82))	('MMP3', 'Gene', '4314', (93, 97))	('MMPs', 'Gene', '4312;4313;4314;4316;4318;4320;4323', (41, 45))	('MMPs', 'Gene', (41, 45))	('MMP3', 'Gene', (93, 97))	('MMP9', 'Gene', '4318', (84, 88))	('MMP9', 'Gene', (84, 88))	('MMP2', 'molecular_function', 'GO:0004228', ('78', '82'))	('MMP2', 'Gene', (78, 82))
87411	30018519	MMP2 rs243865, that was associated with modified cancer risk in our study, had the greatest influence on cancer risk in general.	('MMP2', 'Gene', (0, 4))	('rs243865', 'Mutation', 'rs243865', (5, 13))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('MMP2', 'Gene', '4313', (0, 4))	('MMP2', 'molecular_function', 'GO:0004228', ('0', '4'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('rs243865', 'Var', (5, 13))	('cancer', 'Disease', (49, 55))
87412	30018519	In accordance with our study, two meta-analysis presented the results showing that MMP2 rs243865 polymorphism had a protective role in lung cancer susceptibility in both dominant and recessive models, which is consistent with our results.	('MMP2', 'Gene', (83, 87))	('rs243865', 'Mutation', 'rs243865', (88, 96))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('rs243865', 'Var', (88, 96))	('MMP2', 'molecular_function', 'GO:0004228', ('83', '87'))	('MMP2', 'Gene', '4313', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
87413	30018519	Seventeen studies were included in the meta-analysis and reported that the MMP2 rs2438651 polymorphism had a protective role only in the Asian population.	('MMP2', 'Gene', (75, 79))	('rs2438651', 'Var', (80, 89))	('MMP2', 'Gene', '4313', (75, 79))	('MMP2', 'molecular_function', 'GO:0004228', ('75', '79'))	('rs2438651', 'DBSNP_MENTION', 'None', (80, 89))
87416	30018519	A meta-analysis of 12 publications studying urinary (renal and bladder) cancers showed a lower risk for bladder cancer with the T allele of MMP2 rs243865 in Asian patients but not in the Caucasian population.	('bladder cancer', 'Disease', (104, 118))	('patients', 'Species', '9606', (163, 171))	('MMP2', 'Gene', (140, 144))	('rs243865', 'Mutation', 'rs243865', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MMP2', 'Gene', '4313', (140, 144))	('MMP2', 'molecular_function', 'GO:0004228', ('140', '144'))	('rs243865', 'Var', (145, 153))	('(renal and bladder) cancers', 'Disease', 'MESH:D001749', (52, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
87417	30018519	All of the above discussed publications present the MMP2 rs243865 T allele as having a somewhat protective role in cancer.	('cancer', 'Disease', (115, 121))	('rs243865 T', 'Var', (57, 67))	('MMP2', 'Gene', (52, 56))	('rs243865', 'Mutation', 'rs243865', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MMP2', 'Gene', '4313', (52, 56))	('MMP2', 'molecular_function', 'GO:0004228', ('52', '56'))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
87418	30018519	There are publications that suggest the opposite effect of the T allele in MMP2 rs243865.	('MMP2', 'Gene', (75, 79))	('rs243865', 'Mutation', 'rs243865', (80, 88))	('MMP2', 'Gene', '4313', (75, 79))	('MMP2', 'molecular_function', 'GO:0004228', ('75', '79'))	('rs243865', 'Var', (80, 88))
87420	30018519	They concluded that the combined genotype carrying MMP2 rs243865 allele T with MMP9 rs3918242 allele T was found to increase bladder cancer risk.	('MMP2', 'Gene', (51, 55))	('MMP9', 'Gene', (79, 83))	('rs3918242', 'Mutation', 'rs3918242', (84, 93))	('rs243865', 'Mutation', 'rs243865', (56, 64))	('MMP9', 'Gene', '4318', (79, 83))	('MMP9', 'molecular_function', 'GO:0004229', ('79', '83'))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('rs243865', 'Var', (56, 64))	('increase', 'PosReg', (116, 124))	('MMP2', 'Gene', '4313', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MMP2', 'molecular_function', 'GO:0004228', ('51', '55'))	('rs3918242', 'Var', (84, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
87423	30018519	With regard to the MMP2 rs243865, T allele containing genotypes seem to have a protective role in predominantly thoracic malignancies, such as lung cancer and MM.	('MMP2', 'Gene', '4313', (19, 23))	('MMP2', 'molecular_function', 'GO:0004228', ('19', '23'))	('lung cancer', 'Disease', (143, 154))	('rs243865', 'Var', (24, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('MMP2', 'Gene', (19, 23))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('rs243865', 'Mutation', 'rs243865', (24, 32))	('malignancies', 'Disease', (121, 133))
87424	30018519	Genome Wide Associated Study (GWAS) of 759 subjects in the Northern Italian population investigated 15 different SNPs in several genes, and one of them was MMP14 rs2236304.	('rs2236304', 'Var', (162, 171))	('MMP14', 'Gene', '4323', (156, 161))	('MMP14', 'Gene', (156, 161))	('rs2236304', 'Mutation', 'rs2236304', (162, 171))	('MMP', 'molecular_function', 'GO:0004235', ('156', '159'))
87426	30018519	The MMP2 rs243865, T allele genotypes seem to have a protective role in predominantly thoracic malignancies, such as lung cancer and MM.	('MMP2', 'molecular_function', 'GO:0004228', ('4', '8'))	('MMP2', 'Gene', (4, 8))	('malignancies', 'Disease', (95, 107))	('rs243865', 'Mutation', 'rs243865', (9, 17))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('rs243865', 'Var', (9, 17))	('MMP2', 'Gene', '4313', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
87430	30018519	Our results suggest a combined effect of asbestos exposure and MMP2 rs243865.	('asbestos', 'Chemical', 'MESH:D001194', (41, 49))	('MMP2', 'Gene', (63, 67))	('rs243865', 'Mutation', 'rs243865', (68, 76))	('MMP2', 'Gene', '4313', (63, 67))	('combined', 'Interaction', (22, 30))	('rs243865', 'Var', (68, 76))	('MMP2', 'molecular_function', 'GO:0004228', ('63', '67'))
87432	30018519	Besides gene-gene interactions between MnSOD Ala -9Val and CAT-262 C>T polymorphisms as well as iNOS and CAT -262 C>T polymorphisms and the risk of asbestosis, gene-environment interactions were also reported.	('polymorphisms', 'Var', (71, 84))	('CAT', 'molecular_function', 'GO:0004096', ('59', '62'))	('Ala', 'Chemical', 'MESH:D000409', (45, 48))	('iNOS', 'Gene', '4843', (96, 100))	('asbestosis', 'Disease', (148, 158))	('iNOS', 'Gene', (96, 100))	('C>T polymorphisms', 'Var', (67, 84))	('-262 C>T', 'Mutation', 'rs1393539936', (109, 117))	('MnSOD', 'Gene', '6648', (39, 44))	('CAT', 'molecular_function', 'GO:0004096', ('105', '108'))	('CAT-262', 'Gene', (59, 66))	('MnSOD', 'Gene', (39, 44))	('-262 C>T', 'Mutation', 'rs1393539936', (62, 70))	('asbestosis', 'Disease', 'MESH:D001195', (148, 158))	('CAT', 'Var', (105, 108))
87433	30018519	A strong interaction was reported between GSTM1 - null polymorphism and smoking, iNOS (CCTTT)n polymorphism and smoking, and between iNOS (CCTTT)n polymorphism and cumulative asbestos exposure, suggesting that interactions between different genotypes, genotypes and smoking, and between genotypes and asbestos exposure have an important influence on the development of asbestosis.	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))	('polymorphism', 'Var', (55, 67))	('asbestosis', 'Disease', (369, 379))	('asbestos', 'Chemical', 'MESH:D001194', (369, 377))	('iNOS', 'Gene', '4843', (81, 85))	('influence', 'Reg', (337, 346))	('asbestos', 'Chemical', 'MESH:D001194', (301, 309))	('asbestosis', 'Disease', 'MESH:D001195', (369, 379))	('iNOS', 'Gene', '4843', (133, 137))	('GSTM1', 'Gene', (42, 47))	('iNOS', 'Gene', (133, 137))	('GSTM1', 'Gene', '2944', (42, 47))	('iNOS', 'Gene', (81, 85))
87436	30018519	In conclusion, our data suggests that MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (105, 125))	('malignant pleural mesothelioma', 'Disease', (95, 125))	('MMP2', 'Gene', (38, 42))	('MMP2', 'molecular_function', 'GO:0004228', ('38', '42'))	('rs243865', 'Mutation', 'rs243865', (43, 51))	('MMP2', 'Gene', '4313', (38, 42))	('rs243865', 'Var', (43, 51))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (95, 125))
87508	26903362	In univariable analyses, some of the variables that were significantly associated with reduced survival across all cohorts have been previously reported to be similarly prognostic, including poor performance status, weight loss, low hemoglobin, high white count, increased NLR, a high platelet count and the inability to cytoreduce.	('high', 'Var', (245, 249))	('weight loss', 'Disease', (216, 227))	('NLR', 'MPA', (273, 276))	('reduced', 'NegReg', (87, 94))	('high platelet count', 'Phenotype', 'HP:0001894', (280, 299))	('weight loss', 'Phenotype', 'HP:0001824', (216, 227))	('survival', 'MPA', (95, 103))	('increased', 'PosReg', (263, 272))	('low hemoglobin', 'Phenotype', 'HP:0001903', (229, 243))	('high white count', 'Phenotype', 'HP:0001974', (245, 261))	('weight loss', 'Disease', 'MESH:D015431', (216, 227))	('low', 'NegReg', (229, 232))
87530	28198461	Germline mutations in BAP1 also predispose to cutaneous melanoma, but the mutations are relatively more important in rare cancers (uveal melanoma and mesothelioma) constituting a novel cancer syndrome.	('Germline mutations', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('cancer syndrome', 'Disease', (185, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('BAP1', 'Gene', '8314', (22, 26))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('predispose', 'Reg', (32, 42))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('BAP1', 'Gene', (22, 26))	('mutations', 'Var', (74, 83))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (131, 162))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer syndrome', 'Disease', 'MESH:D009369', (185, 200))
87532	28198461	In the case of melanoma, it would be pertinent to assess familial clusters, with sites which are manifested in CDKN2A and BAP1 mutation carriers, or whether the risks could be extended to as yet unknown cancer sites.	('BAP1', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('mutation', 'Var', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('CDKN2A', 'Gene', (111, 117))	('BAP1', 'Gene', '8314', (122, 126))	('CDKN2A', 'Gene', '1029', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
87569	28198461	As to the genetic architecture of melanoma, high-risk CDKN2A mutations contribute to about 30% of melanomas in families of three or more affected individuals.	('melanomas', 'Disease', (98, 107))	('contribute', 'Reg', (71, 81))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('CDKN2A', 'Gene', (54, 60))	('mutations', 'Var', (61, 70))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('CDKN2A', 'Gene', '1029', (54, 60))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
87570	28198461	According to a recent Swedish study, CDKN2A positive families accounted for 11.5% (31/269) of all families, and these presented with a median of 6 melanomas compared to 2 in mutation negative families.	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('melanomas', 'Disease', (147, 156))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanomas', 'Disease', 'MESH:D008545', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('positive', 'Var', (44, 52))
87571	28198461	We show here that families of 3 or more diagnosed melanomas accounted for less than 8% of familial melanoma, which together with the above data suggest that CDKN2A mutations are likely to be, at most, a minor contributor to the present findings on discordant cancers.	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('familial melanoma', 'Disease', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('cancers', 'Disease', (259, 266))	('familial melanoma', 'Disease', 'OMIM:155600', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('CDKN2A', 'Gene', (157, 163))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Disease', (50, 59))	('CDKN2A', 'Gene', '1029', (157, 163))	('mutations', 'Var', (164, 173))
87585	28198461	Nervous system and thyroid cancers also showed independent support for being true associations, both may also manifest CDKN2A mutations or deletions.	('thyroid cancers', 'Disease', 'MESH:D013964', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Nervous system', 'Disease', (0, 14))	('CDKN2A', 'Gene', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('CDKN2A', 'Gene', '1029', (119, 125))	('mutations', 'Var', (126, 135))	('thyroid cancers', 'Disease', (19, 34))	('deletions', 'Var', (139, 148))
87589	28198461	It is known that ocular and cutaneous melanomas share familial risks and BAP1 and possibly also BRCA2 mutations may be involved.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('BAP1', 'Gene', '8314', (73, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('BRCA2', 'Gene', '675', (96, 101))	('BAP1', 'Gene', (73, 77))	('cutaneous melanomas', 'Disease', (28, 47))	('mutations', 'Var', (102, 111))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('ocular', 'Disease', (17, 23))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRCA2', 'Gene', (96, 101))
87627	25702974	It was also found in Drosophila that phosphorylated Yorkie (the Drosophila ortholog of YAP/TAZ) is actively excluded from the nucleus in an Exportin 1 (XPO1)-dependent manner.	('nucleus', 'cellular_component', 'GO:0005634', ('126', '133'))	('Yorkie', 'Gene', '37851', (52, 58))	('XPO1', 'Gene', '34167', (152, 156))	('Exportin 1', 'Gene', '34167', (140, 150))	('Exportin 1', 'Gene', (140, 150))	('Drosophila', 'Species', '7227', (64, 74))	('Drosophila', 'Species', '7227', (21, 31))	('XPO1', 'Gene', (152, 156))	('Exportin', 'cellular_component', 'GO:0005651', ('140', '148'))	('Yorkie', 'Gene', (52, 58))	('phosphorylated', 'Var', (37, 51))
87640	25702974	Hepatocyte-specific MST1/2 knockout is sufficient to dramatically increase hepatocyte proliferation, resulting in massive liver overgrowth due to aberrant YAP activity.	('increase', 'PosReg', (66, 74))	('liver overgrowth', 'Disease', (122, 138))	('MST1/2', 'Gene', (20, 26))	('knockout', 'Var', (27, 35))	('overgrowth', 'Phenotype', 'HP:0001548', (128, 138))	('hepatocyte proliferation', 'biological_process', 'GO:0072574', ('75', '99'))	('YAP activity', 'CPA', (155, 167))	('hepatocyte', 'MPA', (75, 85))	('liver overgrowth', 'Disease', 'MESH:D008107', (122, 138))	('massive liver', 'Phenotype', 'HP:0002240', (114, 127))
87644	25702974	Deleting MST1/2 to activate YAP also protects the liver from acetaminophen-induced liver injury.	('liver injury', 'Disease', 'MESH:D056486', (83, 95))	('liver injury', 'Disease', (83, 95))	('acetaminophen', 'Chemical', 'MESH:D000082', (61, 74))	('protects', 'Reg', (37, 45))	('Deleting', 'Var', (0, 8))
87647	25702974	Liver-specific knockdown of alpha-catenin also results in increased YAP activity and liver overgrowth following partial hepatectomy, indicating that alpha-catenin may play a role in inactivating YAP following regeneration.	('overgrowth', 'Phenotype', 'HP:0001548', (91, 101))	('increased', 'PosReg', (58, 67))	('knockdown', 'Var', (15, 24))	('liver overgrowth', 'Disease', (85, 101))	('YAP activity', 'CPA', (68, 80))	('regeneration', 'biological_process', 'GO:0031099', ('209', '221'))	('liver overgrowth', 'Disease', 'MESH:D008107', (85, 101))	('alpha-catenin', 'Protein', (28, 41))
87649	25702974	Knocking down YAP is sufficient to block pancreatic progenitor cell proliferation.	('block pancreatic', 'Disease', 'MESH:D010195', (35, 51))	('Knocking down', 'Var', (0, 13))	('block pancreatic', 'Disease', (35, 51))	('YAP', 'Gene', (14, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
87651	25702974	Pancreas-specific MST1/2 knockout and ectopic YAP overexpression both result in decreased pancreas size.	('MST1/2', 'Gene', (18, 24))	('decreased pancreas size', 'Phenotype', 'HP:0002594', (80, 103))	('decreased pancreas', 'Disease', (80, 98))	('knockout', 'Var', (25, 33))	('decreased pancreas', 'Disease', 'MESH:D010190', (80, 98))
87652	25702974	Dysregulation of the Hippo pathway does not appear to play a significant role for the endocrine compartment, and MST1/2 knockout mice have normal fed blood glucose levels.	('glucose', 'Chemical', 'MESH:D005947', (156, 163))	('MST1/2', 'Gene', (113, 119))	('normal fed blood glucose levels', 'MPA', (139, 170))	('knockout', 'Var', (120, 128))	('Hippo pathway', 'Pathway', (21, 34))	('mice', 'Species', '10090', (129, 133))
87653	25702974	However, the exocrine compartment of MST1/2 knockout mice shows a dramatic increase in cell proliferation, accompanied by a similar increase in cell death.	('MST1/2', 'Gene', (37, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('knockout', 'Var', (44, 52))	('cell proliferation', 'CPA', (87, 105))	('increase', 'PosReg', (75, 83))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('mice', 'Species', '10090', (53, 57))
87654	25702974	This appears to be YAP-dependent because deleting a single allele of YAP in the MST1/2 knockout mice results in improved pancreatic growth and structure.	('mice', 'Species', '10090', (96, 100))	('YAP', 'Gene', (69, 72))	('deleting', 'Var', (41, 49))	('pancreatic growth', 'Disease', 'MESH:D006130', (121, 138))	('pancreatic growth', 'Disease', (121, 138))	('improved', 'PosReg', (112, 120))
87655	25702974	For instance, Sveinsson's Chorioretinal Atrophy (SCRA), a rare genetic disease resulting in degeneration of the choroid and retina, is caused by a mutation in TEAD1.	('caused by', 'Reg', (135, 144))	('TEAD1', 'Gene', '21676', (159, 164))	('mutation', 'Var', (147, 155))	('genetic disease', 'Disease', (63, 78))	('Chorioretinal Atrophy', 'Phenotype', 'HP:0000533', (26, 47))	('genetic disease', 'Disease', 'MESH:D030342', (63, 78))	('TEAD1', 'Gene', (159, 164))	('degeneration of the choroid', 'Disease', (92, 119))	("Sveinsson's Chorioretinal Atrophy", 'Disease', 'MESH:C566236', (14, 47))	('degeneration of the choroid', 'Disease', 'MESH:D002833', (92, 119))	("Sveinsson's Chorioretinal Atrophy", 'Disease', (14, 47))
87656	25702974	This mutant TEAD1 is defective in YAP/TAZ binding and has no transcriptional activity.	('YAP/TAZ', 'Protein', (34, 41))	('transcriptional activity', 'MPA', (61, 85))	('TEAD1', 'Gene', '21676', (12, 17))	('mutant', 'Var', (5, 11))	('defective', 'NegReg', (21, 30))	('TEAD1', 'Gene', (12, 17))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))
87664	25702974	found that YAP is silenced in a subset of human CRC, and YAP blocks regeneration by inhibiting Wnt signaling and preventing Dishevelled (DVL) nuclear translocation.	('Wnt signaling', 'MPA', (95, 108))	('regeneration', 'biological_process', 'GO:0031099', ('68', '80'))	('blocks', 'NegReg', (61, 67))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('human', 'Species', '9606', (42, 47))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('YAP', 'Var', (57, 60))	('regeneration', 'CPA', (68, 80))	('preventing', 'NegReg', (113, 123))	('inhibiting', 'NegReg', (84, 94))
87668	25702974	Conversely, overexpressing dominant-negative MST1 or LATS2 showed improved cardiac function following either myocardial infarction or ischemia and reperfusion.	('MST1', 'Gene', '15235', (45, 49))	('improved cardiac function', 'Phenotype', 'HP:0001635', (66, 91))	('MST1', 'Gene', (45, 49))	('LATS2', 'Gene', (53, 58))	('myocardial infarction', 'Phenotype', 'HP:0001658', (109, 130))	('overexpressing', 'PosReg', (12, 26))	('improved', 'PosReg', (66, 74))	('dominant-negative', 'Var', (27, 44))	('ischemia', 'Disease', (134, 142))	('cardiac', 'MPA', (75, 82))	('ischemia', 'Disease', 'MESH:D007511', (134, 142))	('myocardial infarction', 'Disease', (109, 130))	('myocardial infarction', 'Disease', 'MESH:D009203', (109, 130))
87669	25702974	In addition, SAV1 deficient cardiomyocytes can re-enter the cell cycle and undergo cell division, and SAV1 heart-specific knockout mice show improved recovery following ischemia with ejection fraction and fractional shortening values comparable to control, non-ischemic mice.	('ischemia', 'Disease', (169, 177))	('ejection', 'MPA', (183, 191))	('ischemia', 'Disease', 'MESH:D007511', (169, 177))	('SAV1', 'Gene', (102, 106))	('SAV1', 'Gene', (13, 17))	('recovery', 'MPA', (150, 158))	('improved', 'PosReg', (141, 149))	('knockout', 'Var', (122, 130))	('mice', 'Species', '10090', (131, 135))	('mice', 'Species', '10090', (270, 274))	('deficient', 'Var', (18, 27))	('cell division', 'biological_process', 'GO:0051301', ('83', '96'))	('cell division', 'CPA', (83, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('60', '70'))
87672	25702974	Thus, manipulating the Hippo pathway following injury could be key to improving heart regeneration, decreasing fibrosis, and increasing survival.	('improving', 'PosReg', (70, 79))	('Hippo pathway', 'Pathway', (23, 36))	('survival', 'CPA', (136, 144))	('regeneration', 'biological_process', 'GO:0031099', ('86', '98'))	('manipulating', 'Var', (6, 18))	('fibrosis', 'Disease', 'MESH:D005355', (111, 119))	('fibrosis', 'Disease', (111, 119))	('heart regeneration', 'CPA', (80, 98))	('increasing', 'PosReg', (125, 135))	('decreasing', 'NegReg', (100, 110))
87673	25702974	Not surprisingly, dysregulation of the Hippo pathway can lead to uncontrolled proliferation, resulting in a wide range of diseases (Boxes 1-3) and cancers.	('uncontrolled', 'MPA', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Hippo pathway', 'Pathway', (39, 52))	('lead to', 'Reg', (57, 64))	('resulting in', 'Reg', (93, 105))	('dysregulation', 'Var', (18, 31))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('diseases', 'Disease', (122, 130))	('cancers', 'Disease', (147, 154))
87674	25702974	The Hippo pathway can become dysregulated by a variety of mechanisms, including YAP gene amplification, methylation or deletion of upstream Hippo pathway components, mutations in upstream GPCRs, or by crosstalk with other signaling pathways including Wnt signaling.	('dysregulated', 'Reg', (29, 41))	('Hippo', 'Gene', (140, 145))	('mutations', 'Var', (166, 175))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('GPCR', 'Gene', (188, 192))	('deletion', 'Var', (119, 127))	('signaling', 'biological_process', 'GO:0023052', ('255', '264'))	('crosstalk', 'Reg', (201, 210))	('methylation', 'Var', (104, 115))	('Wnt signaling', 'Pathway', (251, 264))	('Hippo pathway', 'Pathway', (4, 17))	('amplification', 'Var', (89, 102))	('YAP gene', 'Gene', (80, 88))	('GPCR', 'Gene', '23890', (188, 192))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
87675	25702974	Polycystic kidney disease (PKD) is a life-threatening disease caused by cyst formation throughout the kidneys, and is frequently caused by inactivating mutations in either the PKD1 or PKD2.	('PKD1', 'Gene', '18763', (176, 180))	('Polycystic kidney', 'Phenotype', 'HP:0000113', (0, 17))	('PKD2', 'Gene', '18764', (184, 188))	('PKD', 'Disease', (27, 30))	('caused by', 'Reg', (129, 138))	('PKD', 'Disease', 'MESH:C537180', (27, 30))	('inactivating mutations', 'Var', (139, 161))	('kidney disease', 'Phenotype', 'HP:0000112', (11, 25))	('PKD2', 'Gene', (184, 188))	('PKD1', 'Gene', (176, 180))	('Polycystic kidney disease', 'Disease', (0, 25))	('PKD', 'Disease', (176, 179))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('PKD', 'Disease', 'MESH:C537180', (184, 187))	('PKD', 'Disease', 'MESH:C537180', (176, 179))	('PKD', 'Disease', (184, 187))	('Polycystic kidney disease', 'Disease', 'MESH:D007690', (0, 25))
87684	25702974	TAZ knockout results in PC2 accumulation, leading to PKD, and also results in the down-regulation of other genes necessary for proper cilia development and function.	('PC2', 'Gene', (24, 27))	('PKD', 'Disease', 'MESH:C537180', (53, 56))	('PKD', 'Disease', (53, 56))	('PC2', 'Gene', '18764', (24, 27))	('accumulation', 'PosReg', (28, 40))	('TAZ', 'Gene', (0, 3))	('down-regulation', 'NegReg', (82, 97))	('knockout', 'Var', (4, 12))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('leading', 'Reg', (42, 49))
87691	25702974	TBX5, which is essential for cardiac and limb development, is often mutated in Holt-Oram patients.	('limb development', 'biological_process', 'GO:0060173', ('41', '57'))	('patients', 'Species', '9606', (89, 97))	('Holt-Oram', 'Disease', (79, 88))	('TBX5', 'Gene', (0, 4))	('mutated', 'Var', (68, 75))
87692	25702974	TBX5 normally interacts with YAP/TAZ, but mutations in TBX5 prevent its binding to TAZ and results in a congenital heart defect called Tetralogy of Fallot (TOF).	('prevent', 'NegReg', (60, 67))	('heart defect', 'Phenotype', 'HP:0030680', (115, 127))	('Tetralogy of Fallot', 'Disease', (135, 154))	('congenital heart defect', 'Disease', 'MESH:D006330', (104, 127))	('binding', 'Interaction', (72, 79))	('results in', 'Reg', (91, 101))	('TAZ', 'Protein', (83, 86))	('congenital heart defect', 'Disease', (104, 127))	('congenital heart defect', 'Phenotype', 'HP:0001627', (104, 127))	('Tetralogy of Fallot', 'Phenotype', 'HP:0001636', (135, 154))	('TOF', 'Phenotype', 'HP:0001636', (156, 159))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('mutations', 'Var', (42, 51))	('TBX5', 'Gene', (55, 59))
87698	25702974	When MST1 is knocked out in these mice, they show increased motor neuron viability, delayed symptom onset, and extended survival, although it is not clear whether YAP or TAZ are involved in this phenotype.	('increased motor neuron', 'Phenotype', 'HP:0002450', (50, 72))	('motor neuron viability', 'CPA', (60, 82))	('mice', 'Species', '10090', (34, 38))	('increased', 'PosReg', (50, 59))	('MST1', 'Gene', '15235', (5, 9))	('MST1', 'Gene', (5, 9))	('knocked out', 'Var', (13, 24))
87706	25702974	One study deleted MOB1A, with a heterozygous mutation for MOB1B, and found that these mice have an increased lifetime chance of developing HCC.	('HCC', 'Disease', (139, 142))	('deleted', 'Var', (10, 17))	('MOB1A', 'Gene', (18, 23))	('MOB1B', 'Gene', (58, 63))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('mice', 'Species', '10090', (86, 90))	('MOB1B', 'Gene', '68473', (58, 63))	('mutation', 'Var', (45, 53))	('MOB1A', 'Gene', '232157', (18, 23))
87707	25702974	Increased liver growth and HCC have also been reported in liver-specific SAV1 knockout, NF2 knockout, and MST1/2 knockout mice.	('mice', 'Species', '10090', (122, 126))	('knockout', 'Var', (92, 100))	('knockout', 'Var', (78, 86))	('Increased', 'PosReg', (0, 9))	('NF2', 'Gene', (88, 91))	('HCC', 'Phenotype', 'HP:0001402', (27, 30))	('SAV1', 'Gene', (73, 77))	('HCC', 'CPA', (27, 30))	('liver growth', 'CPA', (10, 22))	('Increased liver', 'Phenotype', 'HP:0002240', (0, 15))
87710	25702974	However, much of the current understanding of the Hippo pathway in HCC has been derived from genetic models, and few mutations or deletions in Hippo pathway components have been observed in human HCC.	('HCC', 'Disease', (67, 70))	('deletions', 'Var', (130, 139))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('human', 'Species', '9606', (190, 195))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))
87714	25702974	Although research on the role of YAP/TAZ in EHE is at its infancy, the observation that YAP/TAZ chromosome translocations occur in virtually all cases of EHE strongly suggest that dysregulated YAP/TAZ fusion proteins may act as cancer drivers.	('cancer', 'Disease', (228, 234))	('EHE', 'Phenotype', 'HP:0032060', (44, 47))	('EHE', 'Phenotype', 'HP:0032060', (154, 157))	('YAP/TAZ', 'Protein', (193, 200))	('dysregulated', 'Var', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('EHE', 'Disease', (154, 157))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
87718	25702974	Similarly, overexpressing YAP in breast cancer cell lines induces tumor formation and growth in xenograft experiments, and deleting YAP prevents tumor growth in an oncogene-induced breast cancer model.	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('tumor', 'Disease', (66, 71))	('breast cancer', 'Disease', (181, 194))	('YAP', 'Gene', (132, 135))	('tumor', 'Disease', (145, 150))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('growth', 'CPA', (86, 92))	('deleting', 'Var', (123, 131))	('induces', 'PosReg', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('prevents', 'NegReg', (136, 144))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
87721	25702974	YAP protein expression is decreased in luminal breast cancer tissues, and YAP knockdown in breast cancer cell lines actually enhances tumor migration, invasion, and tumor growth in nude mice.	('YAP', 'Gene', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('nude mice', 'Species', '10090', (181, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('invasion', 'CPA', (151, 159))	('luminal breast cancer', 'Disease', (39, 60))	('YAP', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (165, 170))	('breast cancer', 'Disease', (91, 104))	('enhances', 'PosReg', (125, 133))	('protein', 'Protein', (4, 11))	('luminal breast cancer', 'Disease', 'MESH:D001943', (39, 60))	('knockdown', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
87722	25702974	A recent study reported that hyperactivation of YAP alone is not sufficient to drive mammary tumorigenesis in vivo, and YAP-induced oncogenic growth may be dependent on the presence of additional mutations or amplifications.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('YAP', 'Gene', (48, 51))	('hyperactivation', 'Var', (29, 44))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
87723	25702974	YAP/TAZ are both highly expressed in non-small cell lung cancer (NSCLC) in humans, and knockdown of either YAP or TAZ in NSCLC cells is sufficient to suppress proliferation, invasion, and tumor growth in mice.	('tumor', 'Disease', (188, 193))	('proliferation', 'CPA', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mice', 'Species', '10090', (204, 208))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('TAZ', 'Gene', (114, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('invasion', 'CPA', (174, 182))	('YAP', 'Gene', (107, 110))	('humans', 'Species', '9606', (75, 81))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('suppress', 'NegReg', (150, 158))	('NSCLC', 'Disease', (65, 70))	('knockdown', 'Var', (87, 96))	('NSCLC', 'Disease', (121, 126))	('non-small cell lung cancer', 'Disease', (37, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
87724	25702974	In fact, it has been shown that knockdown of either YAP or TAZ is sufficient to decrease cell migration in vitro and metastasis in vivo, and expression of constitutively active YAP is sufficient to drive lung cancer progression in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('YAP', 'Gene', (177, 180))	('YAP', 'Gene', (52, 55))	('knockdown', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cell migration', 'biological_process', 'GO:0016477', ('89', '103'))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('cell migration', 'CPA', (89, 103))	('decrease', 'NegReg', (80, 88))	('drive', 'PosReg', (198, 203))
87726	25702974	Overexpression of MST1 is sufficient to inhibit cell proliferation and apoptosis in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('MST1', 'Gene', (18, 22))	('inhibit', 'NegReg', (40, 47))	('apoptosis', 'CPA', (71, 80))	('MST1', 'Gene', '15235', (18, 22))	('cell proliferation', 'CPA', (48, 66))	('NSCLC', 'Disease', (84, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
87729	25702974	Vestigial-like family member 4 (VGLL4) is frequently down-regulated in lung cancer, and expressing VGLL4 in lung cancer cells suppresses cell proliferation and tumor growth in mice by competitively inhibiting YAP-TEAD binding and transcriptional activity.	('VGLL4', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('VGLL4', 'Gene', '232334', (32, 37))	('transcriptional activity', 'CPA', (230, 254))	('cell proliferation', 'CPA', (137, 155))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Disease', (108, 119))	('Vestigial-like family member 4', 'Gene', (0, 30))	('expressing', 'Var', (88, 98))	('down-regulated', 'NegReg', (53, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('suppresses', 'NegReg', (126, 136))	('mice', 'Species', '10090', (176, 180))	('VGLL4', 'Gene', (99, 104))	('tumor', 'Disease', (160, 165))	('Vestigial-like family member 4', 'Gene', '232334', (0, 30))	('inhibiting', 'NegReg', (198, 208))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('VGLL4', 'Gene', '232334', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('YAP-TEAD', 'Protein', (209, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('lung cancer', 'Disease', (71, 82))
87730	25702974	Another study found that high YAP expression was correlated with increased AXL receptor tyrosine kinase (Axl) expression in lung adenocarcinomas, and that knocking down YAP also resulted in loss of Axl, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase-9 (MMP-9).	('expression', 'MPA', (34, 44))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('203', '237'))	('YAP', 'Gene', (30, 33))	('PCNA', 'Gene', (239, 243))	('Axl', 'Gene', '26362', (105, 108))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (124, 144))	('Axl', 'Gene', (198, 201))	('AXL', 'Gene', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('increased', 'PosReg', (65, 74))	('proliferating cell nuclear antigen', 'Gene', '18538', (203, 237))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (124, 144))	('YAP', 'Gene', (169, 172))	('AXL', 'Gene', '26362', (75, 78))	('expression', 'MPA', (110, 120))	('MMP-9', 'molecular_function', 'GO:0004229', ('278', '283'))	('PCNA', 'molecular_function', 'GO:0003892', ('239', '243'))	('matrix metalloproteinase-9', 'Gene', (250, 276))	('lung adenocarcinomas', 'Disease', (124, 144))	('MMP-9', 'Gene', '17395', (278, 283))	('proliferating cell nuclear antigen', 'Gene', (203, 237))	('Axl', 'Gene', (105, 108))	('MMP-9', 'Gene', (278, 283))	('loss', 'NegReg', (190, 194))	('knocking down', 'Var', (155, 168))	('Axl', 'Gene', '26362', (198, 201))	('PCNA', 'Gene', '18538', (239, 243))	('matrix metalloproteinase-9', 'Gene', '17395', (250, 276))
87731	25702974	This study further confirmed that knocking down YAP inhibits proliferation and invasion of lung cancer cells, an effect which is potentially mediated through Axl.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('YAP', 'Gene', (48, 51))	('Axl', 'Gene', (158, 161))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('inhibits', 'NegReg', (52, 60))	('Axl', 'Gene', '26362', (158, 161))	('invasion', 'CPA', (79, 87))	('proliferation', 'CPA', (61, 74))	('lung cancer', 'Disease', (91, 102))	('knocking down', 'Var', (34, 47))
87732	25702974	Finally, miR-135b expression increases lung cancer metastasis by targeting LATS2, and inhibiting miR-135b suppresses tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('miR-135b', 'Gene', (9, 17))	('miR-135b', 'Gene', '723818', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('increases lung cancer', 'Disease', 'MESH:D008175', (29, 50))	('LATS2', 'Gene', (75, 80))	('tumor', 'Disease', (117, 122))	('inhibiting', 'Var', (86, 96))	('miR-135b', 'Gene', '723818', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('targeting', 'Reg', (65, 74))	('suppresses', 'NegReg', (106, 116))	('miR-135b', 'Gene', (97, 105))	('increases lung cancer', 'Disease', (29, 50))
87733	25702974	Expression of miR-135b is regulated by DNA demethylation and nuclear factor-kappa B (NFKb) signaling, raising the possibility that inflammatory and epigenetic modifications may regulate expression of miR-135b, thereby resulting in LATS2 inhibition, YAP/TAZ nuclear translocation, and cancer.	('miR-135b', 'Gene', '723818', (14, 22))	('miR-135b', 'Gene', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('regulate', 'Reg', (177, 185))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('39', '56'))	('cancer', 'Disease', (284, 290))	('modifications', 'Var', (159, 172))	('miR-135b', 'Gene', '723818', (200, 208))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('LATS2', 'Protein', (231, 236))	('miR-135b', 'Gene', (14, 22))	('expression', 'MPA', (186, 196))	('inhibition', 'NegReg', (237, 247))	('resulting in', 'Reg', (218, 230))	('YAP/TAZ', 'MPA', (249, 256))
87735	25702974	Recent work has found that homozygous deletion or inactivating mutations in NF2, SAV1, or LATS2 are frequently observed in human malignant mesothelioma tissues and cell lines.	('observed', 'Reg', (111, 119))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (129, 151))	('human', 'Species', '9606', (123, 128))	('NF2', 'Gene', (76, 79))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (129, 151))	('SAV1', 'Gene', (81, 85))	('inactivating mutations', 'Var', (50, 72))	('malignant mesothelioma', 'Disease', (129, 151))	('LATS2', 'Gene', (90, 95))
87737	25702974	These deletions or mutations contribute to increased YAP protein levels and aberrant YAP-TEAD transcriptional activity, which drive increased cell proliferation and anchorage-independent growth by up-regulating the cell cycle-promoting Cyclin D1 and Forkhead box M1.	('Cyclin', 'molecular_function', 'GO:0016538', ('236', '242'))	('cell cycle', 'biological_process', 'GO:0007049', ('215', '225'))	('YAP protein', 'Protein', (53, 64))	('cell cycle-promoting', 'CPA', (215, 235))	('up-regulating', 'PosReg', (197, 210))	('mutations', 'Var', (19, 28))	('deletions', 'Var', (6, 15))	('aberrant', 'Var', (76, 84))	('Cyclin D1', 'Gene', (236, 245))	('cell proliferation', 'CPA', (142, 160))	('anchorage-independent growth', 'CPA', (165, 193))	('increased', 'PosReg', (132, 141))	('YAP-TEAD', 'Gene', (85, 93))	('increased', 'PosReg', (43, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('Cyclin D1', 'Gene', '12443', (236, 245))	('Forkhead', 'Protein', (250, 258))
87738	25702974	Knocking down YAP in malignant mesothelioma cells is sufficient to inhibit cell proliferation and anchorage-independent growth.	('inhibit', 'NegReg', (67, 74))	('anchorage-independent growth', 'CPA', (98, 126))	('Knocking down', 'Var', (0, 13))	('YAP', 'Gene', (14, 17))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (21, 43))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (21, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('malignant mesothelioma', 'Disease', (21, 43))	('cell proliferation', 'CPA', (75, 93))
87739	25702974	Together, these findings strongly implicate dysregulation of the Hippo pathway in malignant mesothelioma and YAP as a potential therapeutic target.	('YAP', 'Disease', (109, 112))	('dysregulation', 'Var', (44, 57))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (82, 104))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (82, 104))	('Hippo pathway', 'Pathway', (65, 78))	('malignant mesothelioma', 'Disease', (82, 104))
87740	25702974	As cases of malignant mesothelioma are primarily associated with asbestos exposure, it may be informative to determine whether there is something about asbestos that is pre-inclined to inducing mutations in Hippo pathway components.	('asbestos', 'Chemical', 'MESH:D001194', (65, 73))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (12, 34))	('associated', 'Reg', (49, 59))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('mutations', 'Var', (194, 203))	('malignant mesothelioma', 'Disease', (12, 34))	('pre', 'molecular_function', 'GO:0003904', ('169', '172'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (12, 34))
87742	25702974	Moreover, in pancreatic cancer cells, YAP knockdown results in reduced proliferation and reduced anchorage-independent growth, suggesting YAP may play an important role in PDAC progression.	('pancreatic cancer', 'Disease', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('YAP', 'Gene', (38, 41))	('reduced', 'NegReg', (63, 70))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('PDAC', 'Disease', (172, 176))	('proliferation', 'CPA', (71, 84))	('reduced', 'NegReg', (89, 96))	('anchorage-independent growth', 'CPA', (97, 125))	('knockdown', 'Var', (42, 51))
87744	25702974	KRAS is frequently mutated in PDAC, but in a mouse model expressing mutated KRAS, deleting YAP is sufficient to prevent PDAC.	('KRAS', 'Gene', '16653', (76, 80))	('deleting', 'Var', (82, 90))	('KRAS', 'Gene', (76, 80))	('PDAC', 'Disease', (120, 124))	('mouse', 'Species', '10090', (45, 50))	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('YAP', 'Gene', (91, 94))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '16653', (0, 4))
87745	25702974	In addition, deleting YAP in pancreatic cancer cells harboring the mutant KRAS is sufficient to prevent proliferation and growth in mice.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('proliferation', 'CPA', (104, 117))	('deleting', 'Var', (13, 21))	('prevent', 'NegReg', (96, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('KRAS', 'Gene', '16653', (74, 78))	('KRAS', 'Gene', (74, 78))	('pancreatic cancer', 'Disease', (29, 46))	('mice', 'Species', '10090', (132, 136))	('mutant', 'Var', (67, 73))	('YAP', 'Gene', (22, 25))	('growth', 'CPA', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
87746	25702974	A similar study found that in an inducible KRAS-driven PDAC mouse model where removal of KRAS resulted in complete tumor regression, some mice later developed spontaneous tumors due to YAP amplification and increased YAP-TEAD2 transcriptional activity.	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('transcriptional activity', 'MPA', (227, 251))	('mice', 'Species', '10090', (138, 142))	('developed', 'PosReg', (149, 158))	('KRAS', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('KRAS', 'Gene', '16653', (43, 47))	('mouse', 'Species', '10090', (60, 65))	('KRAS', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('YAP', 'Gene', (185, 188))	('increased', 'PosReg', (207, 216))	('amplification', 'Var', (189, 202))	('TEAD2', 'Gene', '21677', (221, 226))	('tumor', 'Disease', (171, 176))	('TEAD2', 'Gene', (221, 226))	('KRAS', 'Gene', '16653', (89, 93))
87754	25702974	Although overexpression of mutant Gq/11 is sufficient to transform melanocytes, the signaling events downstream of Gq/11 were unknown.	('Gq/11', 'Gene', (34, 39))	('transform', 'Reg', (57, 66))	('overexpression', 'PosReg', (9, 23))	('mutant', 'Var', (27, 33))	('melanocytes', 'CPA', (67, 78))	('Gq/11', 'Chemical', '-', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('Gq/11', 'Chemical', '-', (34, 39))
87760	25702974	Indeed, RCC tissues show elevated levels of YAP, and knocking down YAP in RCC cell lines blocks cell proliferation and increases apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('RCC', 'Disease', (8, 11))	('increases', 'PosReg', (119, 128))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('blocks', 'NegReg', (89, 95))	('apoptosis', 'CPA', (129, 138))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('cell proliferation', 'CPA', (96, 114))	('YAP', 'Gene', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('knocking down', 'Var', (53, 66))
87762	25702974	Although the most common mutations in CRC involve adenomatous polyposis coli (APC) and dysregulated beta-catenin signaling, YAP/TAZ may be required downstream mediators of these mutations.	('APC', 'Phenotype', 'HP:0005227', (78, 81))	('beta-catenin', 'Gene', (100, 112))	('mutations', 'Var', (25, 34))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('CRC', 'Gene', (38, 41))	('APC', 'Disease', (78, 81))	('beta-catenin', 'Gene', '12387', (100, 112))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (50, 76))	('adenomatous polyposis coli', 'Gene', '11789', (50, 76))	('adenomatous polyposis coli', 'Gene', (50, 76))	('APC', 'cellular_component', 'GO:0005680', ('78', '81'))
87769	25702974	LATS1 promoter methylation has also been reported in CRC, which may lead to increased YAP activity.	('methylation', 'Var', (15, 26))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('increased', 'PosReg', (76, 85))	('CRC', 'Disease', (53, 56))	('LATS1', 'Gene', (0, 5))	('LATS1', 'Gene', '16798', (0, 5))	('YAP activity', 'CPA', (86, 98))	('CRC', 'Phenotype', 'HP:0003003', (53, 56))
87775	25702974	These cancers are typically characterized by genetic instability and inactivating mutations in tumor protein p53 (TP53).	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('inactivating mutations', 'Var', (69, 91))	('TP53', 'Gene', '22059', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p53', 'Gene', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('p53', 'Gene', '22059', (109, 112))	('TP53', 'Gene', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancers', 'Disease', (6, 13))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('tumor', 'Disease', (95, 100))
87781	25702974	Loss of function mutations in NF2 causes Neurofibromatosis Type 2, a genetic disorder characterized by the development of schwannomas and meningiomas with increased YAP expression and nuclear localization.	('genetic disorder', 'Disease', 'MESH:D030342', (69, 85))	('schwannomas and meningiomas', 'Disease', 'MESH:D009442', (122, 149))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (41, 58))	('Loss of function', 'NegReg', (0, 16))	('schwannomas', 'Phenotype', 'HP:0100008', (122, 133))	('Neurofibromatosis Type 2', 'Disease', (41, 65))	('NF2', 'Gene', (30, 33))	('meningiomas', 'Phenotype', 'HP:0002858', (138, 149))	('genetic disorder', 'Disease', (69, 85))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (41, 65))	('mutations', 'Var', (17, 26))	('localization', 'biological_process', 'GO:0051179', ('192', '204'))
87782	25702974	Loss of function mutations in NF2 results in increased LATS degradation and YAP accumulation, so loss of NF2 and subsequent tumor growth could be due to aberrant YAP activity.	('loss', 'NegReg', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('increased', 'PosReg', (45, 54))	('LATS degradation', 'MPA', (55, 71))	('tumor', 'Disease', (124, 129))	('YAP accumulation', 'MPA', (76, 92))	('Loss of function', 'NegReg', (0, 16))	('NF2', 'Gene', (105, 108))	('NF2', 'Gene', (30, 33))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
87783	25702974	In the central nervous system, NF2 expression is also significantly reduced in human malignant gliomas, and expression of NF2 has been shown to inhibit human glioma growth both in vitro and in vivo.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('NF2', 'Gene', (122, 125))	('malignant gliomas', 'Disease', (85, 102))	('NF2', 'Gene', (31, 34))	('malignant gliomas', 'Disease', 'MESH:D005910', (85, 102))	('human', 'Species', '9606', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('expression', 'MPA', (35, 45))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('human', 'Species', '9606', (152, 157))	('glioma', 'Disease', (158, 164))	('inhibit', 'NegReg', (144, 151))	('reduced', 'NegReg', (68, 75))	('expression', 'Var', (108, 118))
87796	25702974	APC is frequently mutated in colorectal cancer Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) a genetic disease caused by mutations in desmosome components.	('Arrhythmogenic Right Ventricular Cardiomyopathy', 'Disease', 'MESH:D019571', (47, 94))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('Cardiomyopathy', 'Phenotype', 'HP:0001638', (80, 94))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('Arrhythmogenic Right Ventricular Cardiomyopathy', 'Disease', (47, 94))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('genetic disease', 'Disease', (104, 119))	('caused by', 'Reg', (120, 129))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (130, 139))	('genetic disease', 'Disease', 'MESH:D030342', (104, 119))	('Right Ventricular Cardiomyopathy', 'Phenotype', 'HP:0011663', (62, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))	('desmosome', 'cellular_component', 'GO:0030057', ('143', '152'))
87798	25702974	YAP may block intestinal regeneration by preventing DVL nuclear translocation FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB) a transcription factor that is frequently fused with TAZ due to a chromosomal translocation in epithelioid hemangioendothelioma Gq/11 GNAQ and GNA11 encode the GPCR subunits Gq and G11.	('Osteosarcoma Viral', 'Disease', 'MESH:D012516', (89, 107))	('regeneration', 'biological_process', 'GO:0031099', ('25', '37'))	('Osteosarcoma Viral', 'Disease', (89, 107))	('FOSB', 'Gene', '14282', (128, 132))	('GNA11', 'Gene', (277, 282))	('epithelioid hemangioendothelioma', 'Disease', (229, 261))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('transcription factor', 'molecular_function', 'GO:0000981', ('136', '156'))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (229, 261))	('GNAQ', 'Gene', (268, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('GNA11', 'Gene', '14672', (277, 282))	('chromosomal translocation', 'Var', (200, 225))	('GNAQ', 'Gene', '14682', (268, 272))	('Murine', 'Species', '10090', (82, 88))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (229, 261))	('intestinal regeneration', 'CPA', (14, 37))	('GPCR', 'Gene', '23890', (294, 298))	('G11', 'Gene', '319922', (315, 318))	('G11', 'Gene', (315, 318))	('FOSB', 'Gene', (128, 132))	('Gq/11', 'Chemical', '-', (262, 267))	('Gq/11', 'Gene', (262, 267))	('GPCR', 'Gene', (294, 298))	('DVL', 'MPA', (52, 55))	('block', 'NegReg', (8, 13))
87799	25702974	Mutations in GNAQ and GNA11 are frequently observed in uveal melanoma G-Protein Coupled Receptors (GPCR) GPCRs make up the largest class of receptors in the cell, and are responsible for regulating a variety of important cellular responses including cell proliferation and survival Plakoglobin (JUP) Plakoglobin is a required component for intact desmosome assembly.	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('GNAQ', 'Gene', (13, 17))	('G-Protein Coupled Receptors', 'Gene', (70, 97))	('G-Protein Coupled Receptors', 'Gene', '23890', (70, 97))	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', '14682', (13, 17))	('Mutations', 'Var', (0, 9))	('responsible', 'Reg', (171, 182))	('GPCR', 'Gene', '23890', (105, 109))	('regulating', 'Reg', (187, 197))	('GPCR', 'Gene', '23890', (99, 103))	('GPCR', 'Gene', (105, 109))	('GNA11', 'Gene', '14672', (22, 27))	('GPCR', 'Gene', (99, 103))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('desmosome assembly', 'biological_process', 'GO:0002159', ('347', '365'))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('desmosome', 'cellular_component', 'GO:0030057', ('347', '356'))	('cell proliferation', 'biological_process', 'GO:0008283', ('250', '268'))	('JUP', 'Gene', '16480', (295, 298))	('JUP', 'Gene', (295, 298))	('cell proliferation', 'CPA', (250, 268))
87801	25702974	Mutations in JUP are associated with ARVC Large Tumor Suppressor 1/2 (LATS1/2) LATS1 and 2 are serine/threonine kinases that are phosphorylated and activated by MST1/2 and MOB1.	('JUP', 'Gene', (13, 16))	('Tumor', 'Phenotype', 'HP:0002664', (48, 53))	('JUP', 'Gene', '16480', (13, 16))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('LATS1 and 2', 'Gene', '16798;50523', (79, 90))	('Mutations', 'Var', (0, 9))	('Large Tumor Suppressor 1/2', 'Gene', (42, 68))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('Large Tumor Suppressor 1/2', 'Gene', '50523', (42, 68))
87802	25702974	Once activated, LATS1/2 phosphorylate and inactivate YAP Lysophosphatidic Acid (LPA) a potent inducer of YAP activity via signaling through GPCRs Mob1 Homolog (MOB1) MOB1 is phosphorylated by MST1/2.	('GPCR', 'Gene', '23890', (140, 144))	('Mob1', 'Gene', '232157', (146, 150))	('Mob1', 'Gene', (146, 150))	('inactivate', 'Var', (42, 52))	('Lysophosphatidic Acid', 'Chemical', 'MESH:C032881', (57, 78))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('LPA', 'Chemical', 'MESH:C032881', (80, 83))	('GPCR', 'Gene', (140, 144))
87807	25702974	Mutations in TBX5 are associated with Holt-Oram Syndrome TEA Domain Family Members 1-4 (TEAD1-4) the main transcription factors that interact with YAP/TAZ to drive transcription.	('TEAD1-4', 'Gene', (88, 95))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (88, 95))	('Holt-Oram Syndrome', 'Disease', (38, 56))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('TBX5', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('associated', 'Reg', (22, 32))
87809	25702974	When dephosphorylated, YAP translocates to the nucleus and interacts with a variety of transcription factors, including TEAD1-4, to induce gene expression Dysregulation of the Hippo pathway is implicated in a variety of cancers and diseases Hippo pathway may be a therapeutic target in a number of cancers Manipulating the Hippo pathway may improve regeneration following injury	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TEAD1-4', 'Gene', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('Dysregulation', 'Var', (155, 168))	('cancers', 'Disease', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('nucleus', 'cellular_component', 'GO:0005634', ('47', '54'))	('improve', 'PosReg', (341, 348))	('cancers', 'Disease', (220, 227))	('regeneration following', 'CPA', (349, 371))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('gene expression', 'biological_process', 'GO:0010467', ('139', '154'))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('regeneration', 'biological_process', 'GO:0031099', ('349', '361'))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
87930	26998120	The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000).	('SV40 Tag expression', 'Var', (45, 64))	('patients', 'Species', '9606', (18, 26))	('epithelioid', 'Disease', (109, 120))	('SV40', 'Species', '1891767', (45, 49))	('patients', 'Species', '9606', (189, 197))
87933	26998120	SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies.	('cause', 'Reg', (24, 29))	('SV40', 'Var', (0, 4))	('MPM', 'Disease', (33, 36))	('SV40', 'Species', '1891767', (0, 4))
87939	26998120	SV40 may infect human mesothelial cells, and may transform the cells using a mechanism whereby the tumor antigens, large T antigen (Tag) and small t antigen (tag), bind and inactivate the cellular tumor suppressors tumor protein p53 and retinoblastoma 1.	('inactivate', 'NegReg', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('retinoblastoma', 'Phenotype', 'HP:0009919', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('transform', 'Reg', (49, 58))	('tumor', 'Disease', (99, 104))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('retinoblastoma 1', 'Gene', '5925', (237, 253))	('p53', 'Gene', '7157', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('retinoblastoma 1', 'Gene', (237, 253))	('human', 'Species', '9606', (16, 21))	('infect', 'Reg', (9, 15))	('p53', 'Gene', (229, 232))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('small t', 'Var', (141, 148))	('SV40', 'Species', '1891767', (0, 4))	('bind', 'Interaction', (164, 168))	('SV40', 'Var', (0, 4))
87942	26998120	Certain studies have detected SV40 DNA sequences or SV40 Tag in mesothelioma cells, but others have not.	('SV40 Tag', 'Var', (52, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('SV40 DNA sequences', 'Var', (30, 48))	('SV40', 'Species', '1891767', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('SV40', 'Species', '1891767', (52, 56))	('detected', 'Reg', (21, 29))	('mesothelioma', 'Disease', (64, 76))
87961	26998120	Specimens with nuclear immunoreactive tumor cells were considered to express SV40 Tag (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SV40', 'Species', '1891767', (77, 81))	('SV40 Tag', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('men', 'Species', '9606', (5, 8))
87962	26998120	The positive results were scored according to the Allred score system as follows: 1-25% of tumor cells demonstrate SV40 Tag expression, 1+; 26-50%, 2+; and >50%, 3+.	('SV40', 'Species', '1891767', (115, 119))	('SV40 Tag', 'Var', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
87986	26998120	By contrast, the median survival time was significantly increased in the patients receiving chemotherapy compared with the patients not receiving chemotherapy (435 vs. 196 days; P=0.0397) (Fig.	('patients', 'Species', '9606', (123, 131))	('increased', 'PosReg', (56, 65))	('patients', 'Species', '9606', (73, 81))	('chemotherapy', 'Var', (92, 104))
87993	26998120	To the best of our knowledge, the present study is the first to propose the association between SV40 and MPM in Vietnamese patients and to register Vietnam as one of the countries in which SV40 may potentially affect the pathogenesis of MPM.	('SV40', 'Var', (189, 193))	('affect', 'Reg', (210, 216))	('MPM', 'Disease', (105, 108))	('association', 'Interaction', (76, 87))	('patients', 'Species', '9606', (123, 131))	('pathogenesis', 'biological_process', 'GO:0009405', ('221', '233'))	('MPM', 'Disease', (237, 240))	('SV40', 'Species', '1891767', (189, 193))	('SV40', 'Species', '1891767', (96, 100))	('SV40', 'Gene', (96, 100))
87994	26998120	However, the proportion of patients with SV40 in the present study is decreased compared with previously published studies.	('SV40', 'Species', '1891767', (41, 45))	('patients', 'Species', '9606', (27, 35))	('SV40', 'Var', (41, 45))	('decreased', 'NegReg', (70, 79))
88006	26998120	The finding also supports the speculation that SV40 may be an independent carcinogen or a co-carcinogen, and interact with other environmental or genetic factors in the pathogenesis of malignant mesothelioma.	('interact', 'Reg', (109, 117))	('SV40', 'Species', '1891767', (47, 51))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (185, 207))	('pathogenesis', 'biological_process', 'GO:0009405', ('169', '181'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (185, 207))	('SV40', 'Var', (47, 51))	('malignant mesothelioma', 'Disease', (185, 207))	('men', 'Species', '9606', (136, 139))
88021	26998120	SV40 may be another potential cause of MPM in Vietnam and this potential association requires thorough investigation with a larger sample size and more reliable methods of SV40 detection.	('cause', 'Reg', (30, 35))	('SV40', 'Var', (0, 4))	('MPM', 'Disease', (39, 42))	('SV40', 'Species', '1891767', (0, 4))	('SV40', 'Species', '1891767', (172, 176))
88124	21432714	Male and female rats exposed to high-level GMVC had significantly reduced body weights at final sacrifice (Table 4); weights were 91.5% and 91.8% of control, respectively.	('reduced', 'NegReg', (66, 73))	('GMVC', 'Chemical', '-', (43, 47))	('body weights at final sacrifice', 'CPA', (74, 105))	('GMVC', 'Var', (43, 47))	('reduced body weights', 'Phenotype', 'HP:0004325', (66, 86))	('rats', 'Species', '10116', (16, 20))
88125	21432714	The absolute kidney weights for mid- and high-level GVC female rats were significantly greater than mean control values; however, weight did not correlate with kidney pathology findings.	('GVC', 'Chemical', '-', (52, 55))	('GVC', 'Var', (52, 55))	('kidney weights', 'MPA', (13, 27))	('rats', 'Species', '10116', (63, 67))	('greater', 'PosReg', (87, 94))
88132	21432714	Fibroadenoma of the mammary gland was significantly increased among females exposed to GMVC.	('Fibroadenoma', 'Disease', 'MESH:D018226', (0, 12))	('increased', 'PosReg', (52, 61))	('Fibroadenoma', 'Disease', (0, 12))	('Fibroadenoma of the mammary gland', 'Phenotype', 'HP:0010619', (0, 33))	('GMVC', 'Chemical', '-', (87, 91))	('GMVC', 'Var', (87, 91))
88137	21432714	Similarly, male rats exposed to the mid-dose level of GMVC demonstrated significant increases in the incidence of renal-tubule adenomas (6/50; 12%) compared to controls (0/50).	('GMVC', 'Chemical', '-', (54, 58))	('renal-tubule adenomas', 'Disease', (114, 135))	('GMVC', 'Var', (54, 58))	('rat', 'Species', '10116', (16, 19))	('renal-tubule adenomas', 'Disease', 'MESH:D007673', (114, 135))	('increases', 'PosReg', (84, 93))	('rat', 'Species', '10116', (66, 69))	('rats', 'Species', '10116', (16, 20))
88154	21432714	Thyroid adenomas and carcinomas occurred in males exposed to GVC or GMVC, but only the incidence of follicular-cell carcinoma among GVC-exposed rats showed a significant trend with increasing exposure concentration.	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (8, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('GVC', 'Chemical', '-', (132, 135))	('Thyroid adenomas', 'Phenotype', 'HP:0000854', (0, 16))	('rat', 'Species', '10116', (208, 211))	('follicular-cell carcinoma', 'Disease', (100, 125))	('Thyroid', 'Disease', (0, 7))	('GMVC', 'Chemical', '-', (68, 72))	('rats', 'Species', '10116', (144, 148))	('follicular-cell carcinoma', 'Phenotype', 'HP:0031548', (100, 125))	('GMVC', 'Var', (68, 72))	('GVC', 'Var', (61, 64))	('GVC', 'Chemical', '-', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('follicular-cell carcinoma', 'Disease', 'MESH:D018263', (100, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('rat', 'Species', '10116', (144, 147))
88161	21432714	The incidence of mammary-gland fibroadenoma showed a trend for increased incidence with GMVC exposure, but there were no group differences.	('gland fibroadenoma', 'Phenotype', 'HP:0010619', (25, 43))	('GMVC', 'Chemical', '-', (88, 92))	('fibroadenoma', 'Disease', 'MESH:D018226', (31, 43))	('GMVC', 'Var', (88, 92))	('fibroadenoma', 'Disease', (31, 43))
88219	21432714	However, the incidences among rats inhaling GMVC and GVC at any level are comparable, suggesting the trend for increased incidence among GMVC males may have been driven by the lower incidence seen in concurrent controls in that study.	('rats', 'Species', '10116', (30, 34))	('increased', 'PosReg', (111, 120))	('GMVC', 'Chemical', '-', (137, 141))	('GMVC', 'Chemical', '-', (44, 48))	('GMVC', 'Var', (137, 141))	('GVC', 'Chemical', '-', (53, 56))
88236	21432714	Mutation of thyroid follicular cell DNA may lead directly to cancer and is the only mechanism verified to be carcinogenic in humans, but rodents are believed to be more susceptible to carcinogenic processes involving stimulation of thyroid follicular cell growth through disruption of pituitary-thyroid hormonal physiology.	('carcinogenic', 'Disease', 'MESH:D063646', (109, 121))	('cell growth', 'biological_process', 'GO:0016049', ('251', '262'))	('carcinogenic', 'Disease', (109, 121))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('lead', 'Reg', (44, 48))	('stimulation', 'PosReg', (217, 228))	('cancer', 'Disease', (61, 67))	('Mutation', 'Var', (0, 8))	('humans', 'Species', '9606', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('carcinogenic', 'Disease', 'MESH:D063646', (184, 196))	('carcinogenic', 'Disease', (184, 196))
88243	21432714	The background incidences of respiratory and olfactory epithelial degeneration are notably higher in the GVC compared to the GMVC study.	('rat', 'Species', '10116', (72, 75))	('higher', 'PosReg', (91, 97))	('GVC', 'Var', (105, 108))	('olfactory epithelial degeneration', 'Disease', (45, 78))	('GVC', 'Chemical', '-', (105, 108))	('olfactory epithelial degeneration', 'Disease', 'MESH:D002277', (45, 78))	('rat', 'Species', '10116', (34, 37))	('GMVC', 'Chemical', '-', (125, 129))
88255	25197555	CARs were successfully constructed from multiple murine antibodies (225.28S, TP41.2, 149.53) using second generation (CD28.CD3zeta) signaling domains.	('225.28S', 'Var', (68, 75))	('CAR', 'Gene', (0, 3))	('CAR', 'Gene', '9970', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('TP41', 'Gene', (77, 81))	('TP41', 'Gene', '924', (77, 81))	('murine', 'Species', '10090', (49, 55))
88261	25197555	Furthermore, we report for the first time that CSPG4 is expressed on glioblastoma cancer stem cells (GSC) and demonstrate that anti-CSPG4 CAR-transduced T cells recognize and kill these GSC.	('glioblastoma cancer', 'Disease', 'MESH:D005909', (69, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('anti-CSPG4', 'Var', (127, 137))	('GSC', 'cellular_component', 'GO:0032593', ('186', '189'))	('CAR', 'cellular_component', 'GO:0005826', ('138', '141'))	('glioblastoma cancer', 'Disease', (69, 88))	('CAR', 'Gene', (138, 141))	('CAR', 'Gene', '9970', (138, 141))	('GSC', 'cellular_component', 'GO:0032593', ('101', '104'))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
88267	25197555	T cell receptor (TCR) genes that target specific tumor antigens have been inserted into peripheral blood lymphocytes (PBL) and, when transfused back into patients in conjunction with administration of high-dose interleukin-2 after non-myeloablative chemotherapy, have been shown to effect tumor regression in patients with melanoma and synovial cell sarcoma.	('melanoma', 'Disease', 'MESH:D008545', (323, 331))	('TCR', 'cellular_component', 'GO:0042101', ('17', '20'))	('genes', 'Var', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TCR', 'biological_process', 'GO:0006283', ('17', '20'))	('TCR', 'Gene', (17, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (350, 357))	('interleukin-2', 'Gene', '3558', (211, 224))	('tumor', 'Disease', (289, 294))	('synovial cell sarcoma', 'Disease', (336, 357))	('interleukin-2', 'Gene', (211, 224))	('melanoma', 'Phenotype', 'HP:0002861', (323, 331))	('melanoma', 'Disease', (323, 331))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('synovial cell sarcoma', 'Disease', 'MESH:D013584', (336, 357))	('synovial cell sarcoma', 'Phenotype', 'HP:0012570', (336, 357))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('patients', 'Species', '9606', (309, 317))
88275	25197555	PBL transduced with the 225.28S CAR demonstrated cytokine secretion and cytolytic function when co-cultured with melanoma cell lines in vitro and were reactive against explanted human melanomas.	('melanomas', 'Disease', 'MESH:D008545', (184, 193))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('cytolytic function', 'CPA', (72, 90))	('human', 'Species', '9606', (178, 183))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('cytokine secretion', 'biological_process', 'GO:0050663', ('49', '67'))	('225.28S', 'Var', (24, 31))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('CAR', 'cellular_component', 'GO:0005826', ('32', '35'))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('cytokine secretion', 'MPA', (49, 67))	('CAR', 'Gene', (32, 35))	('melanomas', 'Disease', (184, 193))	('CAR', 'Gene', '9970', (32, 35))
88285	25197555	CARs were constructed from four different murine scFv fragments: 225.28S, TP41.2, 149.53 and G71.1 all of which have demonstrated reactivity with CSPG4.	('scFv', 'Gene', '652070', (49, 53))	('CAR', 'Gene', (0, 3))	('scFv', 'Gene', (49, 53))	('TP41', 'Gene', (74, 78))	('CAR', 'Gene', '9970', (0, 3))	('225.28S', 'Var', (65, 72))	('murine', 'Species', '10090', (42, 48))	('G71.1', 'Var', (93, 98))	('TP41', 'Gene', '924', (74, 78))	('reactivity', 'MPA', (130, 140))	('CSPG4', 'Protein', (146, 151))
88291	25197555	Each of the CSPG4 CAR transduced PBL cultures yielded IFN-gamma effector cytokine release with considerably lower levels observed with the CSPG4-negative non-small cell lung cancer line H1299 (Figure 5).	('transduced', 'Var', (22, 32))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (154, 180))	('H1299', 'CellLine', 'CVCL:0060', (186, 191))	('IFN-gamma', 'Gene', '3458', (54, 63))	('IFN-gamma', 'Gene', (54, 63))	('CSPG4', 'Gene', (12, 17))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CAR', 'Gene', (18, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('CAR', 'Gene', '9970', (18, 21))	('CAR', 'cellular_component', 'GO:0005826', ('18', '21'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (158, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
88292	25197555	Again the CAR constructed from the TP41.2 antibody was the most reactive overall.We next determined the ability of the CSPG4 CAR transduced T cells to produce multiple cytokines (Figure 6).	('CAR', 'Gene', '9970', (125, 128))	('CAR', 'cellular_component', 'GO:0005826', ('125', '128'))	('transduced', 'Var', (129, 139))	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('TP41', 'Gene', (35, 39))	('produce', 'MPA', (151, 158))	('TP41', 'Gene', '924', (35, 39))	('CAR', 'Gene', (10, 13))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('CAR', 'Gene', '9970', (10, 13))	('CAR', 'cellular_component', 'GO:0005826', ('10', '13'))	('CSPG4', 'Gene', (119, 124))	('CAR', 'Gene', (125, 128))
88302	25197555	Although it was difficult to disaggregate and then label gliospheres with 51Cr, we also determined that three of three GSC lines tested could be specifically lysed by CSPG4 CAR transduced T cells (Figure 8B).	('GSC', 'cellular_component', 'GO:0032593', ('119', '122'))	('CSPG4', 'Var', (167, 172))	('CAR', 'Gene', (173, 176))	('CAR', 'cellular_component', 'GO:0005826', ('173', '176'))	('CAR', 'Gene', '9970', (173, 176))
88318	25197555	CSCs have been shown to effect tumor recurrence and development of metastatic disease, exhibit characteristics of self-renewal and resistance to chemotherapy and radiotherapy, and can induce tumor formation in immunodeficient mice.	('development of metastatic disease', 'CPA', (52, 85))	('CSCs', 'Var', (0, 4))	('mice', 'Species', '10090', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('tumor', 'Disease', (31, 36))	('induce', 'Reg', (184, 190))	('immunodeficient', 'Disease', 'MESH:D007153', (210, 225))	('immunodeficient', 'Disease', (210, 225))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('self-renewal', 'CPA', (114, 126))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('effect', 'Reg', (24, 30))
88319	25197555	In this study, an anti-CSPG4 CAR demonstrated recognition and cytolysis of multiple GSC lines, a finding with potential therapeutic implications.	('recognition', 'CPA', (46, 57))	('CAR', 'Gene', '9970', (29, 32))	('CAR', 'cellular_component', 'GO:0005826', ('29', '32'))	('anti-CSPG4', 'Gene', (18, 28))	('anti-CSPG4', 'Var', (18, 28))	('cytolysis', 'CPA', (62, 71))	('cytolysis', 'biological_process', 'GO:0019835', ('62', '71'))	('GSC', 'cellular_component', 'GO:0032593', ('84', '87'))	('CAR', 'Gene', (29, 32))
88329	25197555	Tumor cell lines were grown under standard conditions in Roswell Park Memorial Institute (RPMI) 1640 or Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, CA) with 10% fetal bovine serum (FBS) medium (Sigma Aldrich, St. Louis, MO), 25 mM Hepes (Invitrogen) and 100U/mug per mL of penicillin/streptomycin (Invitrogen) at 37 C in a 5% CO2 atmosphere.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('streptomycin', 'Chemical', 'MESH:D013307', (303, 315))	('Hepes', 'Chemical', 'MESH:D006531', (250, 255))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (104, 136))	('CO2', 'Chemical', '-', (345, 348))	('mug', 'molecular_function', 'GO:0043739', ('278', '281'))	('DMEM', 'Chemical', '-', (138, 142))	('bovine', 'Species', '9913', (186, 192))	('FBS', 'Disease', (200, 203))	('100U/mug', 'Var', (273, 281))	('penicillin', 'Chemical', 'MESH:D010406', (292, 302))	('FBS', 'Disease', 'MESH:D005198', (200, 203))
88330	25197555	Lymphocytes were maintained in AIM-V medium (Invitrogen) supplemented with 5% human antibody serum (Valley Biomedical, Winchester, VA), 25 mM Hepes (Invitrogen), 100U/mug per mL of penicillin/streptomycin (Invitrogen), and 300 IU/mL interleukin-2 (Aldesleukin, Prometheus, San Diego, CA).	('mug', 'molecular_function', 'GO:0043739', ('167', '170'))	('Aldesleukin', 'Gene', '3558', (248, 259))	('100U/mug', 'Var', (162, 170))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('interleukin-2', 'Gene', (233, 246))	('penicillin', 'Chemical', 'MESH:D010406', (181, 191))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('Aldesleukin', 'Gene', (248, 259))	('Hepes', 'Chemical', 'MESH:D006531', (142, 147))	('streptomycin', 'Chemical', 'MESH:D013307', (192, 204))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('human', 'Species', '9606', (78, 83))	('interleukin-2', 'Gene', '3558', (233, 246))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))
88438	20587528	Our findings define a strong association between global genetic and global epigenetic dysregulation in mesothelioma, rather than a discrete, local coordination of gene inactivation.	('mesothelioma', 'Disease', (103, 115))	('epigenetic dysregulation', 'Var', (75, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))
88441	20587528	Although the number of phenotypically important point mutations in pleural mesotheliomas has been shown to be relatively low, reports of extensive gene copy number (CN) alterations in this disease are numerous, and common regions of allele loss include 1p, 3p21, 6q, 9p21, 15q11-15, and 22q.	('alterations', 'Var', (169, 180))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (67, 88))	('pleural mesotheliomas', 'Disease', (67, 88))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (67, 87))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (67, 88))
88442	20587528	There have also been several reports of promoter hypermethylation at tumor suppressor gene loci in mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumor', 'Disease', (69, 74))	('promoter hypermethylation', 'Var', (40, 65))	('mesothelioma', 'Disease', (99, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
88445	20587528	Other recent work from our group confirmed the relationship between asbestos exposure and DNA methylation in an investigation of over 750 cancer-related genes, and defined the distinct profiles of coordinated DNA methylation in mesotheliomas relative to non-tumorigenic pleural tissues.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('DNA methylation', 'biological_process', 'GO:0006306', ('90', '105'))	('cancer', 'Disease', (138, 144))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('tumor', 'Disease', (258, 263))	('methylation', 'Var', (213, 224))	('DNA methylation', 'biological_process', 'GO:0006306', ('209', '224'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mesotheliomas', 'Disease', 'MESH:D008654', (228, 241))	('mesotheliomas', 'Disease', (228, 241))	('asbestos', 'Chemical', 'MESH:D001194', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
88446	20587528	The spectrum of somatic alterations in mesothelioma and all human cancers includes both genetic and epigenetic events that act in concert to drive tumorigenesis and promote progression to a malignant phenotype.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('alterations', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('promote', 'PosReg', (165, 172))	('drive', 'PosReg', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))	('progression', 'CPA', (173, 184))	('mesothelioma', 'Disease', (39, 51))
88447	20587528	The Cancer Genome Atlas Research Network examined mutations, CN alterations, and DNA methylation in an integrative manner and highlighted alterations of core pathways in glioblastoma.	('core pathways', 'Pathway', (153, 166))	('alterations', 'Reg', (138, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('mutations', 'Var', (50, 59))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'biological_process', 'GO:0006306', ('81', '96'))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('core', 'cellular_component', 'GO:0019013', ('153', '157'))	('CN alterations', 'Var', (61, 75))	('glioblastoma', 'Disease', (170, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (170, 182))
88450	20587528	In pleural mesotheliomas, we investigated both genetic and epigenetic alterations using high-throughput, array based approaches and established and robust analytical strategies with the objective of gaining a more complete understanding of how genetic and epigenetic alterations may interact to drive tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (3, 23))	('drive', 'PosReg', (295, 300))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (3, 24))	('epigenetic alterations', 'Var', (256, 278))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('interact', 'Interaction', (283, 291))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (3, 24))	('pleural mesotheliomas', 'Disease', (3, 24))	('tumor', 'Disease', (301, 306))
88457	20587528	All 23 tumors analyzed for copy number alteration passed quality control.	('copy number alteration', 'Var', (27, 49))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
88466	20587528	Tumors in methylation class two were previously shown to be from patients with significantly lower asbestos burden than other classes, and relative to these class two cases, classes four and seven had significantly poorer prognosis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('asbestos burden', 'Disease', (99, 114))	('Tumors', 'Disease', (0, 6))	('lower', 'NegReg', (93, 98))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (65, 73))	('methylation', 'Var', (10, 21))	('asbestos burden', 'Disease', 'MESH:D001195', (99, 114))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
88470	20587528	Only two genes - TGFB2 and GDF10 - had any visually detectable coordinate methylation and CN loss and in each case only one tumor had both alterations (Figure 2).	('methylation', 'Var', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('loss', 'NegReg', (93, 97))	('TGFB2', 'Gene', '7042', (17, 22))	('tumor', 'Disease', (124, 129))	('GDF10', 'Gene', (27, 32))	('TGFB2', 'Gene', (17, 22))	('GDF10', 'Gene', '2662', (27, 32))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
88471	20587528	Though not among the genes in Supplementary Table 4, RASSF1A is commonly inactivated in mesothelioma and in our samples 7 tumors (30%) had allele loss, 2 (22%) were hypermethylated (Figure 2), and consistent with results above, only one tumor had coordinate methylation and CN loss.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('inactivated', 'NegReg', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('mesothelioma', 'Disease', (88, 100))	('allele', 'Var', (139, 145))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('methylation', 'Var', (258, 269))	('RASSF1A', 'Gene', '11186', (53, 60))	('tumors', 'Disease', (122, 128))	('tumor', 'Disease', (237, 242))	('loss', 'NegReg', (277, 281))	('RASSF1A', 'Gene', (53, 60))	('hypermethylated', 'Var', (165, 180))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('methylation', 'biological_process', 'GO:0032259', ('258', '269'))
88473	20587528	Similarly, the volcano plot of methylation alterations was also skewed to the left, indicating a genome-wide trend for loss of methylation relative to non-tumor pleural samples (663 genes).	('methylation', 'MPA', (127, 138))	('non-tumor pleural', 'Disease', 'MESH:D010997', (151, 168))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('alterations', 'Var', (43, 54))	('loss', 'NegReg', (119, 123))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('non-tumor pleural', 'Disease', (151, 168))
88475	20587528	Tumors in the left branch had a wider range of methylation alteration compared to tumors in the right branch, indicating that the trend toward an overall increase or decrease in the degree of methylation was associated with allele copy number loss.	('methylation', 'MPA', (192, 203))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('allele copy number loss', 'Var', (224, 247))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('increase', 'PosReg', (154, 162))	('methylation', 'MPA', (47, 58))	('decrease', 'NegReg', (166, 174))	('alteration', 'Reg', (59, 69))
88476	20587528	The evidence for a global relationship between CN alterations and methylation alterations could suggest that CN alterations of master epigenetic regulatory genes influence overall tumor methylation.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('tumor', 'Disease', (180, 185))	('methylation', 'biological_process', 'GO:0032259', ('186', '197'))	('influence', 'Reg', (162, 171))	('alterations', 'Var', (112, 123))
88478	20587528	Plotting the average CpG methylation for tumors with DNMT1 allele loss versus tumors without loss, we observed a significant trend for increased methylation among tumors with no allele loss at DNMT1 compared to tumors with allele loss (Figure 4, P = 0.05).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('loss versus tumors', 'Disease', (66, 84))	('tumors', 'Disease', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('loss versus tumors', 'Disease', 'MESH:D006086', (66, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('DNMT1', 'Gene', (53, 58))	('methylation', 'MPA', (145, 156))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('DNMT1', 'Gene', '1786', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('allele', 'Var', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('DNMT1', 'Gene', (193, 198))	('increased', 'PosReg', (135, 144))	('DNMT1', 'Gene', '1786', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (163, 169))
88479	20587528	Further, DNMT1 allele loss was associated with significantly reduced patient survival in a Cox proportional hazards model controlling for age, gender and tumor histology (HR, 5.07; 95% C.I.	('DNMT1', 'Gene', (9, 14))	('allele', 'Var', (15, 21))	('DNMT1', 'Gene', '1786', (9, 14))	('patient survival', 'CPA', (69, 85))	('loss', 'NegReg', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patient', 'Species', '9606', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('reduced', 'NegReg', (61, 68))	('tumor', 'Disease', (154, 159))
88484	20587528	In an effort to further our understanding of the relationship between two forms of somatic alterations known to be important in the genesis of mesothelioma, we profiled CN alterations in a subset of tumors for which we had available DNA methylation profiling data.	('mesothelioma', 'Disease', (143, 155))	('DNA methylation', 'biological_process', 'GO:0006306', ('233', '248'))	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('alterations', 'Var', (172, 183))
88485	20587528	Investigating single loci and specific genes, we found no significant correlations between CN and methylation, indicating that two-hit gene inactivation is not commonly achieved by coordinate hypermethylation and allele loss in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (228, 240))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('allele', 'Var', (213, 219))	('hypermethylation', 'Var', (192, 208))	('mesothelioma', 'Disease', (228, 240))
88491	20587528	Despite generally extensive CN and methylation alterations, we observed very few instances of locally coordinate allele loss and methylation in these tumors.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('alterations', 'Var', (47, 58))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))	('methylation alterations', 'Var', (35, 58))
88492	20587528	On the other hand, among other genes with highly-ranked correlation between methylation and CN alteration there were two single instances of coordinate CN loss and hypermethylation, one at TGFB2 and one tumor at GDF10.	('loss', 'NegReg', (155, 159))	('hypermethylation', 'Var', (164, 180))	('tumor', 'Disease', (203, 208))	('GDF10', 'Gene', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('TGFB2', 'Gene', '7042', (189, 194))	('GDF10', 'Gene', '2662', (212, 217))	('TGFB2', 'Gene', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))
88494	20587528	Interestingly, the other target of coordinate methylation and CN loss was GDF10, which encodes bone morphogenic protein 3b (BMP3b); the BMPs are part of the transforming growth factor-beta superfamily, and a low prevalence of GDF10 methylation has previously been shown in mesotheliomas.	('methylation', 'Var', (232, 243))	('GDF10', 'Gene', '2662', (74, 79))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('GDF10', 'Gene', (226, 231))	('transforming growth factor-beta', 'Gene', '7040', (157, 188))	('GDF10', 'Gene', '2662', (226, 231))	('methylation', 'biological_process', 'GO:0032259', ('232', '243'))	('mesotheliomas', 'Disease', 'MESH:D008654', (273, 286))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('mesotheliomas', 'Disease', (273, 286))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('157', '188'))	('transforming growth factor-beta', 'Gene', (157, 188))	('GDF10', 'Gene', (74, 79))	('BMP3b', 'Gene', (124, 129))	('BMP3b', 'Gene', '2662', (124, 129))
88498	20587528	It is reasonable to suggest that loss of DNMT1 may also result in hypomethylation of repeat elements and thereby further contribute to genomic instability and increased CN alterations, though additional investigations are necessary.	('DNMT1', 'Gene', (41, 46))	('DNMT1', 'Gene', '1786', (41, 46))	('genomic instability', 'CPA', (135, 154))	('increased', 'PosReg', (159, 168))	('hypomethylation', 'MPA', (66, 81))	('repeat elements', 'Protein', (85, 100))	('contribute', 'Reg', (121, 131))	('loss', 'Var', (33, 37))	('CN alterations', 'CPA', (169, 183))	('result in', 'Reg', (56, 65))
88499	20587528	Furthermore, we found that loss of DNMT1 was associated with a significantly increased risk of death.	('loss', 'Var', (27, 31))	('DNMT1', 'Gene', '1786', (35, 40))	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('associated', 'Reg', (45, 55))	('DNMT1', 'Gene', (35, 40))
88503	20587528	We have shown that fulfillment of the two-hit paradigm is generally not achieved by coordinate methylation and CN alteration mechanisms in mesothelioma, but that there is a strong association between CN alteration and methylation state in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('methylation', 'biological_process', 'GO:0032259', ('218', '229'))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('alteration', 'Var', (203, 213))	('mesothelioma', 'Disease', (139, 151))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumors', 'Disease', (245, 251))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))
88523	30693974	Thus, in the presence of GTP/GDP TG2 flips closed and in the presence of calcium it flips open.	('calcium', 'Chemical', 'MESH:D002118', (73, 80))	('GTP', 'Chemical', 'MESH:D006160', (25, 28))	('flips', 'Reg', (84, 89))	('TG2', 'Gene', (33, 36))	('GTP/GDP', 'Var', (25, 32))	('flips', 'MPA', (37, 42))	('GDP', 'Chemical', 'MESH:D006153', (29, 32))
88544	30693974	2A) TG2 TGase activity appears to be important for this death response, as TG2 knockdown or treatment with BAPTA-AM (to chelate intracellular calcium) reduces apoptosis and cell death in response to photodynamic therapy.	('cell death', 'CPA', (173, 183))	('calcium', 'Chemical', 'MESH:D002118', (142, 149))	('reduces', 'NegReg', (151, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('TG2', 'Gene', (75, 78))	('TGase activity', 'molecular_function', 'GO:0003810', ('8', '22'))	('intracellular', 'cellular_component', 'GO:0005622', ('128', '141'))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('cell death', 'biological_process', 'GO:0008219', ('173', '183'))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (107, 115))	('knockdown', 'Var', (79, 88))	('apoptosis', 'CPA', (159, 168))
88550	30693974	This suggests that TG2 inhibitors, which suppress GTP binding by indirectly disordering the TG2 GTP binding site, may be a useful treatment for gastric cancer.	('GTP binding', 'molecular_function', 'GO:0005525', ('50', '61'))	('GTP binding site', 'MPA', (96, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('disordering', 'NegReg', (76, 87))	('inhibitors', 'Var', (23, 33))	('GTP', 'Protein', (50, 53))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('TG2', 'Gene', (19, 22))	('TG2', 'Gene', (92, 95))	('GTP binding', 'molecular_function', 'GO:0005525', ('96', '107'))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('gastric cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('suppress', 'NegReg', (41, 49))	('GTP', 'Chemical', 'MESH:D006160', (50, 53))
88552	30693974	TG1 expression is increased in patient tumors and in cultured gastric cancer cells, and TG1 knockdown inhibits cell proliferation, enhances apoptosis and increases gastric cancer cell susceptibility to chemotherapeutic agents.	('TG1', 'Gene', (0, 3))	('enhances', 'PosReg', (131, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('knockdown', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gastric cancer', 'Disease', (62, 76))	('tumors', 'Disease', (39, 45))	('inhibits', 'NegReg', (102, 110))	('increases gastric cancer', 'Disease', 'MESH:D013274', (154, 178))	('apoptosis', 'CPA', (140, 149))	('cell proliferation', 'CPA', (111, 129))	('patient', 'Species', '9606', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('increased', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('rat', 'Species', '10116', (123, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (154, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('increases gastric cancer', 'Disease', (154, 178))	('TG1', 'Gene', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
88557	30693974	TG3 may have a tumor suppressor role in oral cancer, as proteomic analysis reveals a marked reduction in TG3 levels in oral cancer samples due to hypermethylation of the TG3 gene locus.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('hypermethylation', 'Var', (146, 162))	('reduction', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('TG3', 'Gene', (170, 173))	('tumor', 'Disease', (15, 20))	('TG3 levels', 'MPA', (105, 115))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
88558	30693974	TG3 TGase activity is involved in crosslinking precursor structural proteins to facilitate terminal cell differentiation in stratified epithelia, and so loss of TG3 would be consistent with reduced cell differentiation during cancer progression.	('terminal cell differentiation', 'CPA', (91, 120))	('TG3', 'Gene', (0, 3))	('cell differentiation', 'biological_process', 'GO:0030154', ('100', '120'))	('cell differentiation', 'biological_process', 'GO:0030154', ('198', '218'))	('facilitate', 'PosReg', (80, 90))	('loss', 'Var', (153, 157))	('reduced', 'NegReg', (190, 197))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('TGase activity', 'molecular_function', 'GO:0003810', ('4', '18'))	('cell differentiation', 'CPA', (198, 218))	('rat', 'Species', '10116', (126, 129))	('TG3', 'Gene', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
88569	30693974	The authors propose that TG2 forms a complex with keratin 19 and src and that TGase activity modifies keratin 19 to activate src signaling and enhance cancer cell survival (Fig.	('modifies', 'Var', (93, 101))	('activate', 'PosReg', (116, 124))	('enhance', 'PosReg', (143, 150))	('src', 'Gene', (125, 128))	('TGase activity', 'molecular_function', 'GO:0003810', ('78', '92'))	('keratin 19', 'Gene', (50, 60))	('src', 'Gene', '6714', (65, 68))	('keratin 19', 'Gene', '3880', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('complex', 'Interaction', (37, 44))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('keratin 19', 'Gene', (102, 112))	('src', 'Gene', '6714', (125, 128))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('src', 'Gene', (65, 68))	('keratin 19', 'Gene', '3880', (50, 60))
88570	30693974	2B) Thus, it appears that TG2 TGase modification of K19 is necessary to form a scaffold that activates Src signaling.	('modification', 'Var', (36, 48))	('activates', 'PosReg', (93, 102))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('Src', 'Gene', (103, 106))	('Src', 'Gene', '6714', (103, 106))	('K19', 'Gene', '3880', (52, 55))	('K19', 'Gene', (52, 55))
88573	30693974	TG2 knockdown sensitizes cells to docetaxel.	('sensitizes', 'Reg', (14, 24))	('knockdown', 'Var', (4, 13))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))	('TG2', 'Gene', (0, 3))
88574	30693974	TG2 level is increased in breast cancer cells following treatment with rapamycin, an mTOR (mechanistic target of rapamycin complex 1) inhibitor and TG2 knockdown renders these cells hypersensitive to rapamycin.	('breast cancer', 'Disease', (26, 39))	('knockdown', 'Var', (152, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('TG2', 'Gene', (148, 151))	('rapamycin', 'Chemical', 'MESH:D020123', (200, 209))	('target of rapamycin complex', 'cellular_component', 'GO:0038201', ('103', '130'))	('rapamycin', 'Chemical', 'MESH:D020123', (71, 80))	('TG2 level', 'MPA', (0, 9))	('rapamycin', 'Chemical', 'MESH:D020123', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mTOR', 'Gene', '2475', (85, 89))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('mTOR', 'Gene', (85, 89))	('increased', 'PosReg', (13, 22))	('hypersensitive', 'PosReg', (182, 196))
88576	30693974	TG2 knockdown also restores breast cancer cell sensitivity to doxorubicin.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('restores', 'PosReg', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('sensitivity to doxorubicin', 'MPA', (47, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('breast cancer', 'Disease', (28, 41))	('TG2', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))
88583	30693974	Both wild-type TG2 and TGase activity-inactive TG2 mutants stimulate NFkappaB leading to HIF-1alpha induction, suggesting that the regulation requires the TG2 GTP-binding domain.	('GTP-binding', 'molecular_function', 'GO:0005525', ('159', '170'))	('mutants', 'Var', (51, 58))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('stimulate', 'PosReg', (59, 68))	('TG2', 'Gene', (47, 50))	('NFkappaB', 'Gene', (69, 77))	('GTP', 'Chemical', 'MESH:D006160', (159, 162))	('TGase activity', 'molecular_function', 'GO:0003810', ('23', '37'))	('induction', 'MPA', (100, 109))	('NFkappaB', 'Gene', '4790', (69, 77))	('HIF-1alpha', 'Gene', (89, 99))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))
88587	30693974	Covalent modification of TG2 can also influence TG2 regulation of NFkappaB.	('TG2 regulation', 'MPA', (48, 62))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('influence', 'Reg', (38, 47))	('TG2', 'Gene', (25, 28))	('NFkappaB', 'Gene', (66, 74))	('NFkappaB', 'Gene', '4790', (66, 74))	('Covalent modification', 'Var', (0, 21))
88588	30693974	For example, protein kinase A phosphorylation of TG2 at serine-216 precedes NFkappaB activation and PTEN downregulation in MCF-7 and T47D cells (Fig.	('PTEN', 'Gene', (100, 104))	('NFkappaB', 'Gene', '4790', (76, 84))	('phosphorylation', 'MPA', (30, 45))	('PTEN', 'Gene', '5728', (100, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('downregulation', 'NegReg', (105, 119))	('TG2', 'Gene', (49, 52))	('serine', 'Chemical', 'MESH:D012694', (56, 62))	('activation', 'PosReg', (85, 95))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('serine-216', 'Var', (56, 66))	('protein kinase A', 'Enzyme', (13, 29))	('NFkappaB', 'Gene', (76, 84))	('T47D', 'CellLine', 'CVCL:0553', (133, 137))
88590	30693974	Moreover, IL-1beta induces IL-6 production in TG2 overexpressing MCF-7 cells via a mechanism that requires NFkappaB, PI3K and JNK, and leads to enhanced stemness, invasion, survival, and tumor growth, while suppressing IL-6 or IL-1beta production attenuates these events.	('TG2', 'Gene', (46, 49))	('IL-6', 'molecular_function', 'GO:0005138', ('27', '31'))	('IL-6 production', 'biological_process', 'GO:0032635', ('27', '42'))	('IL-1beta', 'Gene', '3552', (10, 18))	('tumor', 'Disease', (187, 192))	('IL-1beta production', 'biological_process', 'GO:0032611', ('227', '246'))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('IL-1', 'molecular_function', 'GO:0005149', ('10', '14'))	('NFkappaB', 'Gene', '4790', (107, 115))	('IL-6', 'molecular_function', 'GO:0005138', ('219', '223'))	('invasion', 'CPA', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('enhanced', 'PosReg', (144, 152))	('JNK', 'Gene', (126, 129))	('NFkappaB', 'Gene', (107, 115))	('IL-1beta', 'Gene', (227, 235))	('IL-6', 'Gene', (27, 31))	('survival', 'CPA', (173, 181))	('JNK', 'Gene', '5599', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IL-1beta', 'Gene', (10, 18))	('MCF-7', 'CellLine', 'CVCL:0031', (65, 70))	('IL-1beta', 'Gene', '3552', (227, 235))	('PI3K', 'Var', (117, 121))	('stemness', 'CPA', (153, 161))	('JNK', 'molecular_function', 'GO:0004705', ('126', '129'))	('IL-1', 'molecular_function', 'GO:0005149', ('227', '231'))
88600	30693974	Treatment of cells with recombinant wild-type TG2 induced non-canonical NFkappaB signaling, but this was not observed with recombinant TG2(C277A), a TGase activity-inactive TG2 mutant, suggesting that TG2 TGase activity is required for malignant spread.	('C277A', 'Var', (139, 144))	('C277A', 'Mutation', 'c.277C>A', (139, 144))	('TGase activity', 'molecular_function', 'GO:0003810', ('149', '163'))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('TGase activity', 'molecular_function', 'GO:0003810', ('205', '219'))	('NFkappaB', 'Gene', (72, 80))	('NFkappaB', 'Gene', '4790', (72, 80))
88603	30693974	These events require interaction of TG2 with fibronectin, as inhibiting the TG2/fibronectin interaction reduces stability of the TGFbeta/fibronectin/TG2 complex to reduce adhesion and biological response.	('stability', 'MPA', (112, 121))	('fibronectin', 'Gene', (45, 56))	('fibronectin', 'Gene', (80, 91))	('TGFbeta', 'Gene', (129, 136))	('reduces', 'NegReg', (104, 111))	('reduce', 'NegReg', (164, 170))	('biological response', 'CPA', (184, 203))	('fibronectin', 'Gene', '2335', (137, 148))	('fibronectin', 'Gene', '2335', (45, 56))	('TGFbeta', 'Gene', '7039', (129, 136))	('fibronectin', 'Gene', '2335', (80, 91))	('inhibiting', 'Var', (61, 71))	('fibronectin', 'Gene', (137, 148))	('interaction', 'Interaction', (92, 103))	('adhesion', 'CPA', (171, 179))
88612	30693974	In A549 lung cancer cells, TG2 knockdown or pharmacologic suppression of JNK activity, reduces TGFbeta1-induced EMT, and additional studies suggest that TG2 activates JNK, via suppression of PP2A activity (Fig.	('JNK', 'Gene', (73, 76))	('TG2', 'Var', (153, 156))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('JNK', 'Gene', '5599', (73, 76))	('PP2A', 'Gene', '5524', (191, 195))	('suppression', 'NegReg', (176, 187))	('activates', 'PosReg', (157, 166))	('JNK', 'Gene', (167, 170))	('JNK', 'Gene', '5599', (167, 170))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('activity', 'MPA', (196, 204))	('TGFbeta1', 'Gene', '7040', (95, 103))	('PP2A', 'Gene', (191, 195))	('JNK', 'molecular_function', 'GO:0004705', ('167', '170'))	('reduces', 'NegReg', (87, 94))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('suppression', 'NegReg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TGFbeta1', 'Gene', (95, 103))	('JNK', 'molecular_function', 'GO:0004705', ('73', '76'))	('lung cancer', 'Disease', (8, 19))	('knockdown', 'Var', (31, 40))
88613	30693974	TG2 also appears to influence drug sensitivity in these tumors, as treatment with TG2 inhibitor or TG2 knockdown restores TRAIL-induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TRAIL', 'Gene', (122, 127))	('restores', 'PosReg', (113, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('TG2', 'Gene', (99, 102))	('tumors', 'Disease', (56, 62))	('influence', 'Reg', (20, 29))	('TRAIL', 'Gene', '8743', (122, 127))	('TG2', 'Gene', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('drug sensitivity', 'Phenotype', 'HP:0020174', (30, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('drug sensitivity', 'MPA', (30, 46))	('knockdown', 'Var', (103, 112))
88615	30693974	Screening of the cancer genome atlas indicates a correlation between high TG2 expression and reduced overall patient survival.	('expression', 'MPA', (78, 88))	('patient', 'Species', '9606', (109, 116))	('reduced', 'NegReg', (93, 100))	('TG2', 'Gene', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('high', 'Var', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
88616	30693974	TG2 knockdown in pancreatic ductal adenocarcinoma cells reduces xenograft growth and enhances sensitivity to gemcitabine, and it has been suggested that TG2 released from pancreatic tumor cells activates fibroblasts in the tumor microenvironment to produce laminin which protects the cancer cells by constructing a dense desmoplastic stroma.	('desmoplastic stroma', 'Disease', 'MESH:D018220', (321, 340))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (17, 49))	('knockdown', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('sensitivity to gemcitabine', 'MPA', (94, 120))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (171, 187))	('pancreatic ductal adenocarcinoma', 'Disease', (17, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('xenograft growth', 'CPA', (64, 80))	('tumor', 'Disease', (223, 228))	('cancer', 'Disease', (284, 290))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (17, 49))	('reduces', 'NegReg', (56, 63))	('pancreatic tumor', 'Disease', (171, 187))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gemcitabine', 'Chemical', 'MESH:C056507', (109, 120))	('pancreatic tumor', 'Disease', 'MESH:D010190', (171, 187))	('tumor', 'Disease', (182, 187))	('desmoplastic stroma', 'Disease', (321, 340))	('TG2', 'Gene', (153, 156))	('enhances', 'PosReg', (85, 93))	('TG2', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
88621	30693974	Moreover, knockdown of eEF2K reduces cell invasion and migration, and reduces TG2 mRNA and protein level.	('eEF2K', 'Gene', (23, 28))	('reduces', 'NegReg', (70, 77))	('eEF2K', 'molecular_function', 'GO:0004686', ('23', '28'))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('eEF2K', 'Gene', '29904', (23, 28))	('rat', 'Species', '10116', (58, 61))	('reduces', 'NegReg', (29, 36))	('cell invasion', 'CPA', (37, 50))	('knockdown', 'Var', (10, 19))	('TG2', 'Protein', (78, 81))
88622	30693974	TG2 appears to have a role in regulating downstream signaling events, as knockdown of either eEF2K, or TG2, reduces Snail and ZEB1 level leading to reduced EMT (Fig.	('TG2', 'Gene', (103, 106))	('Snail', 'Gene', (116, 121))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('eEF2K', 'Gene', '29904', (93, 98))	('reduced', 'NegReg', (148, 155))	('Snail', 'Gene', '6615', (116, 121))	('EMT', 'CPA', (156, 159))	('reduces', 'NegReg', (108, 115))	('EMT', 'biological_process', 'GO:0001837', ('156', '159'))	('ZEB1', 'Gene', (126, 130))	('reduced EMT', 'Phenotype', 'HP:0032198', (148, 159))	('ZEB1', 'Gene', '6935', (126, 130))	('eEF2K', 'Gene', (93, 98))	('eEF2K', 'molecular_function', 'GO:0004686', ('93', '98'))	('knockdown', 'Var', (73, 82))
88624	30693974	TG2 also regulates pancreatic cell morphology, since TG2 silencing reduces the 2-O-tetradecanoylphorbol-13-acetate dependent phosphorylation of keratin 8, and suppresses 2-O-tetradecanoylphorbol-13-acetate dependent keratin filament reorganization in PANC-1 cells.	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (79, 114))	('rat', 'Species', '10116', (146, 149))	('pancreatic', 'Disease', 'MESH:D010195', (19, 29))	('keratin 8', 'Gene', (144, 153))	('keratin 8', 'Gene', '3856', (144, 153))	('TG2', 'Gene', (53, 56))	('silencing', 'Var', (57, 66))	('rat', 'Species', '10116', (218, 221))	('PANC-1', 'CellLine', 'CVCL:0480', (251, 257))	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (170, 205))	('pancreatic', 'Disease', (19, 29))	('reduces', 'NegReg', (67, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('keratin filament', 'cellular_component', 'GO:0045095', ('216', '232'))	('regulates', 'Reg', (9, 18))	('suppresses', 'NegReg', (159, 169))
88626	30693974	TG2 is highly elevated in epidermal cancer stem cells (ECS cells) and TG2 knockdown or suppression of TG2 function with TG2 inhibitor (NC9) reduces ECS cell survival, spheroid formation, matrigel invasion, migration and EMT (Fig.	('NC9', 'Chemical', '-', (135, 138))	('formation', 'biological_process', 'GO:0009058', ('176', '185'))	('reduces', 'NegReg', (140, 147))	('TG2', 'Gene', (70, 73))	('function', 'MPA', (106, 114))	('migration', 'CPA', (206, 215))	('suppression', 'NegReg', (87, 98))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('matrigel invasion', 'CPA', (187, 204))	('EMT', 'biological_process', 'GO:0001837', ('220', '223'))	('cancer', 'Disease', (36, 42))	('knockdown', 'Var', (74, 83))	('spheroid formation', 'CPA', (167, 185))	('rat', 'Species', '10116', (209, 212))	('TG2', 'Gene', (102, 105))	('TG2', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('elevated', 'PosReg', (14, 22))
88627	30693974	This reduction in stem cell phenotype is associated with activation of apoptosis, and TG2 mutant studies reveal that TG2 GTP-binding activity, but not TGase activity, is required to maintain the ECS cell phenotype (Fig.	('TGase activity', 'molecular_function', 'GO:0003810', ('151', '165'))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('57', '80'))	('GTP-binding', 'Protein', (121, 132))	('TG2', 'Gene', (117, 120))	('mutant', 'Var', (90, 96))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('57', '80'))	('activity', 'MPA', (133, 141))	('stem cell phenotype', 'CPA', (18, 37))	('GTP-binding', 'molecular_function', 'GO:0005525', ('121', '132'))	('TG2', 'Gene', (86, 89))	('ECS', 'Disease', (195, 198))
88629	30693974	In this cascade TG2 interacts with alpha6/beta4-integrin to stimulate FAK/Src signaling leading to PI3K activation of PDK1.	('PI3K', 'Var', (99, 103))	('alpha6/beta4', 'Gene', '28898', (35, 47))	('PDK1', 'Gene', (118, 122))	('activation', 'PosReg', (104, 114))	('Src', 'Gene', '6714', (74, 77))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))	('TG2', 'Gene', (16, 19))	('alpha6/beta4', 'Gene', (35, 47))	('stimulate', 'PosReg', (60, 69))	('FAK', 'Gene', '5747', (70, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('interacts', 'Interaction', (20, 29))	('PDK1', 'molecular_function', 'GO:0004740', ('118', '122'))	('PDK1', 'Gene', '5163', (118, 122))	('Src', 'Gene', (74, 77))	('FAK', 'Gene', (70, 73))
88636	30693974	Studies using ECS cells establish the intracellular mechanism of action of several transglutaminase 2 inhibitors, including NC9, VA4, VA5 and CP4d (Fig.	('transglutaminase 2', 'Gene', '7052', (83, 101))	('intracellular', 'cellular_component', 'GO:0005622', ('38', '51'))	('CP4d', 'Var', (142, 146))	('transglutaminase 2', 'Gene', (83, 101))	('NC9', 'Chemical', '-', (124, 127))
88645	30693974	Treatment with TG2 inhibitors, KC009 or ERW1227B, sensitives cultured glioblastoma cells to chemotherapeutic agents, and enhances apoptosis in glioblastoma xenografts, and the GK921 TG2 inhibitor suppresses tumor cell transition to the mesenchymal phenotype.	('GK921', 'Var', (176, 181))	('ERW1227B', 'Var', (40, 48))	('TG2', 'Gene', (15, 18))	('GK921', 'Chemical', 'MESH:C000588709', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('glioblastoma', 'Disease', (70, 82))	('enhances', 'PosReg', (121, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('KC009', 'Var', (31, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('KC009', 'Chemical', '-', (31, 36))	('apoptosis', 'CPA', (130, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('tumor', 'Disease', (207, 212))	('glioblastoma', 'Disease', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('TG2', 'Gene', (182, 185))	('suppresses', 'NegReg', (196, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('ERW1227B', 'Chemical', 'MESH:C561342', (40, 48))
88652	30693974	Moreover, TG2 expression is dependent upon retinoic acid which is produced by aldehyde dehydrogenase 1A3 (ALDH1A3), suggesting that ALDH1A3, in glioblastoma stem cells, maintains TG2 level.	('retinoic acid', 'Chemical', 'MESH:D014212', (43, 56))	('ALDH', 'molecular_function', 'GO:0004030', ('132', '136'))	('TG2 level', 'MPA', (179, 188))	('glioblastoma', 'Disease', (144, 156))	('maintains', 'PosReg', (169, 178))	('ALDH1A3', 'Var', (132, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('aldehyde dehydrogenase 1A3', 'Gene', '56847', (78, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('ALDH', 'molecular_function', 'GO:0004030', ('106', '110'))	('aldehyde dehydrogenase 1A3', 'Gene', (78, 104))
88660	30693974	Another study reports a substantial increase in TG2 in hepatocellular carcinoma and shows that inhibition of TG2 in HepG2.2.15 or Hep3B cell suppresses cell proliferation, invasion and migration.	('Hep3B', 'CellLine', 'CVCL:0326', (130, 135))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('inhibition', 'Var', (95, 105))	('increase', 'PosReg', (36, 44))	('TG2', 'Protein', (48, 51))	('TG2', 'Gene', (109, 112))	('rat', 'Species', '10116', (188, 191))	('rat', 'Species', '10116', (164, 167))	('suppresses', 'NegReg', (141, 151))	('cell proliferation', 'biological_process', 'GO:0008283', ('152', '170'))	('cell proliferation', 'CPA', (152, 170))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (116, 126))
88662	30693974	Acrylic retinoids inhibit post-surgery hepatocellular carcinoma recurrence via mechanisms that involve TG2 crosslinking of Sp1 transcription factor in the cell nucleus leading to loss of EGF receptor expression and cell apoptosis.	('EGF receptor', 'Gene', (187, 199))	('inhibit', 'NegReg', (18, 25))	('EGF', 'molecular_function', 'GO:0005154', ('187', '190'))	('transcription factor', 'molecular_function', 'GO:0000981', ('127', '147'))	('crosslinking', 'Var', (107, 119))	('cell apoptosis', 'CPA', (215, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('Acrylic retinoids', 'Chemical', '-', (0, 17))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('expression', 'MPA', (200, 210))	('EGF receptor', 'Gene', '1956', (187, 199))	('cell nucleus', 'cellular_component', 'GO:0005634', ('155', '167'))	('loss', 'NegReg', (179, 183))	('hepatocellular carcinoma', 'Disease', (39, 63))
88665	30693974	It is interesting that the miR-1285 microRNA regulates TG2 in renal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('miR-1285', 'Var', (27, 35))	('miR-1285', 'Chemical', '-', (27, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('regulates', 'Reg', (45, 54))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('TG2', 'Gene', (55, 58))
88667	30693974	Moreover, silencing of TG2 or forced overexpression of miR-1285, reduce TG2 level and cell proliferation.	('miR-1285', 'Gene', (55, 63))	('TG2', 'Gene', (23, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('rat', 'Species', '10116', (98, 101))	('cell proliferation', 'CPA', (86, 104))	('reduce', 'NegReg', (65, 71))	('TG2 level', 'MPA', (72, 81))	('miR-1285', 'Chemical', '-', (55, 63))	('silencing', 'Var', (10, 19))
88668	30693974	TG2 also regulates renal carcinoma cell survival, as TG2 knockdown leads to increased p53 level and enhanced apoptosis in 786-O, A498, CAKI-1 and ACHN cells.	('renal carcinoma', 'Disease', 'MESH:C538614', (19, 34))	('p53', 'Gene', '7157', (86, 89))	('increased', 'PosReg', (76, 85))	('renal carcinoma', 'Disease', (19, 34))	('enhanced', 'PosReg', (100, 108))	('apoptosis', 'CPA', (109, 118))	('knockdown', 'Var', (57, 66))	('TG2', 'Gene', (53, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (19, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('regulates', 'Reg', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('p53', 'Gene', (86, 89))
88671	30693974	Moreover, treatment with GK921, a TG2 inhibitor, reduces ACHN and CAKI-1 renal carcinoma cell tumor growth in xenograft models.	('reduces', 'NegReg', (49, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GK921', 'Chemical', 'MESH:C000588709', (25, 30))	('ACHN', 'Protein', (57, 61))	('CAKI-1 renal carcinoma cell tumor', 'Disease', (66, 99))	('GK921', 'Var', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('CAKI-1 renal carcinoma cell tumor', 'Disease', 'MESH:C538557', (66, 99))
88672	30693974	Glycolysis is enhanced in renal carcinoma cells and high TG2 level increases glucose consumption and lactate production, while decreasing mitochondrial aconitase level.	('mitochondrial aconitase', 'Gene', (138, 161))	('mitochondrial aconitase', 'Gene', '50', (138, 161))	('lactate', 'Chemical', 'MESH:D019344', (101, 108))	('renal carcinoma', 'Disease', (26, 41))	('enhanced', 'PosReg', (14, 22))	('renal carcinoma', 'Phenotype', 'HP:0005584', (26, 41))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('lactate production', 'MPA', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('Glycolysis', 'biological_process', 'GO:0006096', ('0', '10'))	('decreasing', 'NegReg', (127, 137))	('TG2', 'Gene', (57, 60))	('Glycolysis', 'MPA', (0, 10))	('high', 'Var', (52, 56))	('increases', 'PosReg', (67, 76))	('glucose consumption', 'MPA', (77, 96))	('renal carcinoma', 'Disease', 'MESH:C538614', (26, 41))
88673	30693974	The ubiquitination system also influences TG2 function, as TG2 level is reduced following modification by CHIP (carboxyl-terminus of hsp70-interacting protein), an E3 ubiquitin ligase, and CHIP knockdown is associated with elevated TG2 and aggressive cancer (Fig.	('reduced', 'NegReg', (72, 79))	('aggressive cancer', 'Disease', (240, 257))	('TG2', 'Gene', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('influences', 'Reg', (31, 41))	('TG2 level', 'MPA', (59, 68))	('ubiquitination', 'MPA', (4, 18))	('ubiquitin', 'molecular_function', 'GO:0031386', ('167', '176'))	('function', 'MPA', (46, 54))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('CHIP knockdown', 'Var', (189, 203))	('aggressive cancer', 'Disease', 'MESH:D009369', (240, 257))	('elevated', 'PosReg', (223, 231))	('modification', 'Var', (90, 102))
88676	30693974	Silencing of TG2 in renal carcinoma cells reduces actin stress fiber formation and adhesion to fibronectin, collagen type I and laminin, leading to impaired invasion and migration, and reduced cancer stem cell marker expression.	('actin', 'MPA', (50, 55))	('impaired', 'NegReg', (148, 156))	('cancer', 'Disease', (193, 199))	('fibronectin', 'Gene', (95, 106))	('TG2', 'Gene', (13, 16))	('laminin', 'Protein', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (185, 192))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('rat', 'Species', '10116', (173, 176))	('collagen', 'molecular_function', 'GO:0005202', ('108', '116'))	('reduces', 'NegReg', (42, 49))	('renal carcinoma', 'Disease', 'MESH:C538614', (20, 35))	('renal carcinoma', 'Phenotype', 'HP:0005584', (20, 35))	('renal carcinoma', 'Disease', (20, 35))	('stress fiber', 'cellular_component', 'GO:0001725', ('56', '68'))	('adhesion', 'CPA', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('fibronectin', 'Gene', '2335', (95, 106))	('invasion', 'CPA', (157, 165))
88682	30693974	TG4 has a role in prostate cancer cell survival, as it stimulates cell motility and N-cadherin expression, changes which are reversed by TG4 knockdown.	('N-cadherin', 'Gene', '1000', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TG4', 'Chemical', '-', (137, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (18, 33))	('TG4', 'Chemical', '-', (0, 3))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('TG4', 'Var', (0, 3))	('cell motility', 'CPA', (66, 79))	('cell motility', 'biological_process', 'GO:0048870', ('66', '79'))	('N-cadherin', 'Gene', (84, 94))	('stimulates', 'PosReg', (55, 65))	('prostate cancer', 'Disease', (18, 33))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))	('expression', 'MPA', (95, 105))
88684	30693974	In addition, prostate cancer cells are more motile following forced TG4 expression and this involves TG2 co-localization and interaction with RON, the hepatocyte growth factor-like/macrophage-stimulating protein receptor.	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('151', '175'))	('RON', 'Gene', (142, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('more', 'PosReg', (39, 43))	('TG2', 'Gene', (101, 104))	('TG4', 'Chemical', '-', (68, 71))	('interaction', 'Interaction', (125, 136))	('RON', 'Gene', '4486', (142, 145))	('prostate cancer', 'Disease', (13, 28))	('TG4', 'Gene', (68, 71))	('forced', 'Var', (61, 67))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('expression', 'Var', (72, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('localization', 'biological_process', 'GO:0051179', ('108', '120'))	('co-localization', 'MPA', (105, 120))
88691	30693974	Consistent with a role of TG2 in meningioma cell survival, TG2 knockdown, or treatment with cystamine, induces meningioma cell death which is associated with reduced Akt signaling.	('Akt signaling', 'biological_process', 'GO:0043491', ('166', '179'))	('meningioma', 'Disease', (33, 43))	('meningioma', 'Phenotype', 'HP:0002858', (33, 43))	('cystamine', 'Chemical', 'MESH:D003538', (92, 101))	('meningioma', 'Disease', 'MESH:D008577', (111, 121))	('Akt', 'Gene', '207', (166, 169))	('meningioma cell death', 'Disease', 'MESH:D003643', (111, 132))	('Akt', 'Gene', (166, 169))	('meningioma', 'Disease', 'MESH:D008577', (33, 43))	('meningioma cell death', 'Disease', (111, 132))	('induces', 'Reg', (103, 110))	('meningioma', 'Disease', (111, 121))	('TG2', 'Gene', (59, 62))	('knockdown', 'Var', (63, 72))	('meningioma', 'Phenotype', 'HP:0002858', (111, 121))	('cell death', 'biological_process', 'GO:0008219', ('122', '132'))
88698	30693974	It is interesting that inhibition of TG2 TGase activity, using calcium blockers, increases interaction of p65 with IkappaBalpha to reduce NFkappaB signaling and enhance mantle cell lymphoma cell sensitivity to bortezomib.	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (169, 189))	('mantle cell lymphoma', 'Disease', (169, 189))	('NFkappaB', 'Gene', '4790', (138, 146))	('TGase activity', 'molecular_function', 'GO:0003810', ('41', '55'))	('TG2', 'Gene', (37, 40))	('p65', 'Gene', (106, 109))	('NFkappaB', 'Gene', (138, 146))	('interaction', 'Interaction', (91, 102))	('reduce', 'NegReg', (131, 137))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('increases', 'PosReg', (81, 90))	('cell lymphoma', 'Phenotype', 'HP:0012191', (176, 189))	('IkappaBalpha', 'Gene', (115, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('p65', 'Gene', '5970', (106, 109))	('calcium', 'Chemical', 'MESH:D002118', (63, 70))	('IkappaBalpha', 'Gene', '4792', (115, 127))	('enhance', 'PosReg', (161, 168))	('inhibition', 'Var', (23, 33))	('bortezomib', 'Chemical', 'MESH:D000069286', (210, 220))
88706	30693974	The pro-cancer action of TG2 appears to require TG2 TGase activity, as expression of wild-type TG2, but not TGase inactive TG2, restores tumor formation in TG2 knockdown MC-1 cells.	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', (137, 142))	('TGase activity', 'molecular_function', 'GO:0003810', ('52', '66'))	('MC-1', 'CellLine', 'CVCL:H810', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('restores', 'PosReg', (128, 136))	('TG2', 'Var', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
88714	30693974	This increase is linked to increased TG2 gene copy number, and TG2 levels are further increased in chemotherapy and radiation-resistant cancer cells.	('copy number', 'Var', (46, 57))	('radiation-resistant cancer', 'Disease', (116, 142))	('TG2', 'MPA', (63, 66))	('increased', 'PosReg', (86, 95))	('increased', 'PosReg', (27, 36))	('TG2', 'Gene', (37, 40))	('radiation-resistant cancer', 'Disease', 'MESH:D009369', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
88722	30693974	In this context, TG2 protects cells from apoptosis by suppressing Bax level and reducing cytochrome c release, and these protective actions are attenuated by TG2 knockdown; however, it is not known if the TG2 TGase activity mediates the change in intracellular distribution of Bax and cytochrome c. Elevated TG2 expression is also associated with osteosarcoma cell cisplatin resistance and TG2 knockdown restores chemosensitivity.	('Bax', 'Gene', '581', (66, 69))	('suppressing', 'NegReg', (54, 65))	('osteosarcoma', 'Disease', (347, 359))	('TG2', 'Gene', (308, 311))	('intracellular', 'cellular_component', 'GO:0005622', ('247', '260'))	('osteosarcoma', 'Disease', 'MESH:D012516', (347, 359))	('knockdown', 'Var', (394, 403))	('chemosensitivity', 'MPA', (413, 429))	('cytochrome c', 'Gene', '54205', (89, 101))	('expression', 'MPA', (312, 322))	('cytochrome c', 'molecular_function', 'GO:0009461', ('285', '297'))	('cytochrome c', 'Gene', '54205', (285, 297))	('cisplatin', 'Chemical', 'MESH:D002945', (365, 374))	('Elevated', 'PosReg', (299, 307))	('cytochrome c', 'molecular_function', 'GO:0045155', ('89', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('Bax', 'Gene', (277, 280))	('osteosarcoma', 'Phenotype', 'HP:0002669', (347, 359))	('TGase activity', 'molecular_function', 'GO:0003810', ('209', '223'))	('associated', 'Reg', (331, 341))	('cytochrome c', 'Gene', (89, 101))	('Bax', 'Gene', '581', (277, 280))	('cytochrome c', 'Gene', (285, 297))	('restores', 'PosReg', (404, 412))	('TG2', 'Gene', (390, 393))	('cytochrome c', 'molecular_function', 'GO:0009461', ('89', '101'))	('sarcoma', 'Phenotype', 'HP:0100242', (352, 359))	('cytochrome c', 'molecular_function', 'GO:0045155', ('285', '297'))	('Bax', 'Gene', (66, 69))
88727	30693974	TG2 appears to act with oncostatin M receptor to drive tumor cell invasion and migration, and TG2 knockdown attenuates these actions (Fig.	('oncostatin M', 'Gene', '5008', (24, 36))	('oncostatin M', 'Gene', (24, 36))	('TG2', 'Gene', (94, 97))	('migration', 'CPA', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('knockdown', 'Var', (98, 107))	('tumor', 'Disease', (55, 60))	('oncostatin M', 'molecular_function', 'GO:0005147', ('24', '36'))	('attenuates', 'NegReg', (108, 118))	('rat', 'Species', '10116', (82, 85))	('drive', 'PosReg', (49, 54))
88732	30693974	TG6 may also have a role in leukemia, as whole exome sequencing revealed a missense mutation in the TG6 gene which co-segregated with the cancer phenotype in a family, but was absent in healthy control patients.	('TG6', 'Gene', (100, 103))	('cancer', 'Disease', (138, 144))	('leukemia', 'Disease', (28, 36))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('leukemia', 'Disease', 'MESH:D007938', (28, 36))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('missense mutation', 'Var', (75, 92))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
88735	30693974	Moreover, TG2 knockdown in HT-1080 cells suppresses invasion and migration, and this is associated with reduced NFkappaB, MMP-2 and MMP-9 level and activity.	('MMP-9', 'molecular_function', 'GO:0004229', ('132', '137'))	('MMP-2', 'Gene', (122, 127))	('reduced', 'NegReg', (104, 111))	('NFkappaB', 'Gene', (112, 120))	('HT-1080', 'CellLine', 'CVCL:0317', (27, 34))	('NFkappaB', 'Gene', '4790', (112, 120))	('activity', 'MPA', (148, 156))	('MMP-9', 'Gene', '4318', (132, 137))	('rat', 'Species', '10116', (68, 71))	('MMP-2', 'Gene', '4313', (122, 127))	('suppresses', 'NegReg', (41, 51))	('MMP-9', 'Gene', (132, 137))	('knockdown', 'Var', (14, 23))	('TG2', 'Gene', (10, 13))	('MMP-2', 'molecular_function', 'GO:0004228', ('122', '127'))
88738	30693974	Interestingly, knockdown of TG2 is associated with reduced beta1-integrin interaction with fibronectin and reduced secretion of MMP-9 and MMP-1 (Fig.	('beta1-integrin', 'Gene', '3688', (59, 73))	('fibronectin', 'Gene', '2335', (91, 102))	('MMP-1', 'molecular_function', 'GO:0004232', ('138', '143'))	('reduced', 'NegReg', (51, 58))	('knockdown', 'Var', (15, 24))	('beta1-integrin', 'Gene', (59, 73))	('MMP-1', 'Gene', '4312', (138, 143))	('MMP-9', 'Gene', '4318', (128, 133))	('reduced', 'NegReg', (107, 114))	('secretion', 'biological_process', 'GO:0046903', ('115', '124'))	('MMP-9', 'Gene', (128, 133))	('MMP-1', 'Gene', (138, 143))	('interaction with', 'Interaction', (74, 90))	('fibronectin', 'Gene', (91, 102))	('MMP-9', 'molecular_function', 'GO:0004229', ('128', '133'))	('TG2', 'Gene', (28, 31))
88742	30693974	Analysis of laryngeal squamous cell carcinoma tumors isolated from 148 patients showed that high TG2 expression is associated with reduced survival in patients receiving postoperative radiotherapy, suggesting that TG2 has a role in cancer survival.	('TG2', 'Gene', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('high', 'Var', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rat', 'Species', '10116', (177, 180))	('cancer', 'Disease', (232, 238))	('patients', 'Species', '9606', (71, 79))	('survival', 'MPA', (139, 147))	('patients', 'Species', '9606', (151, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('reduced', 'NegReg', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (22, 52))	('expression', 'MPA', (101, 111))	('squamous cell carcinoma tumors', 'Disease', (22, 52))
88748	30693974	TG2 knockdown or treatment with a TG2 inhibitor, in hypoxia-challenged cells, reduces cancer stem cell viability.	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TG2', 'Gene', (0, 3))	('TG2', 'Gene', (34, 37))	('hypoxia', 'Disease', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('knockdown', 'Var', (4, 13))	('reduces', 'NegReg', (78, 85))	('cancer', 'Disease', (86, 92))
88749	30693974	Moreover, TG2 is highly expressed in mesothelioma cancer stem cells and knockdown results in reduced spheroid formation, matrigel invasion, migration and tumor formation (Fig.	('tumor', 'Disease', (154, 159))	('mesothelioma cancer', 'Disease', (37, 56))	('formation', 'biological_process', 'GO:0009058', ('160', '169'))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('spheroid formation', 'CPA', (101, 119))	('reduced', 'NegReg', (93, 100))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (37, 56))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rat', 'Species', '10116', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mesothelioma cancer', 'Disease', 'MESH:D009369', (37, 56))	('TG2', 'Gene', (10, 13))	('migration', 'CPA', (140, 149))	('knockdown', 'Var', (72, 81))	('matrigel invasion', 'CPA', (121, 138))
88750	30693974	In xenograft mesothelioma tumor models, time to tumor first appearance is doubled from nine weeks for wild-type cells, to eighteen weeks for TG2 knockout cells.	('knockout', 'Var', (145, 153))	('mesothelioma tumor', 'Disease', (13, 31))	('tumor', 'Disease', (48, 53))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (13, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('time', 'MPA', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (13, 31))	('tumor', 'Disease', (26, 31))	('TG2', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
88754	30693974	Moreover, TG2 level is markedly elevated in cultured human colon cancer stem cells, and knockdown reduces cell proliferation, invasion, EMT, and stem cell marker (CD133, SOX2, and beta-catenin) expression.	('cell proliferation', 'CPA', (106, 124))	('SOX2', 'Gene', (170, 174))	('SOX2', 'Gene', '6657', (170, 174))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('reduces', 'NegReg', (98, 105))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('stem cell', 'CPA', (145, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))	('colon cancer', 'Disease', (59, 71))	('elevated', 'PosReg', (32, 40))	('beta-catenin', 'Gene', (180, 192))	('knockdown', 'Var', (88, 97))	('TG2 level', 'MPA', (10, 19))	('beta-catenin', 'Gene', '1499', (180, 192))	('human', 'Species', '9606', (53, 58))	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('CD133', 'Gene', (163, 168))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('invasion', 'CPA', (126, 134))	('CD133', 'Gene', '8842', (163, 168))	('expression', 'MPA', (194, 204))	('EMT', 'CPA', (136, 139))
88759	30693974	TG2 knockdown in SW480 cells, a modestly aggressive colon cancer cell type, increases invasive behavior in a matrigel invasion assay.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('SW480', 'CellLine', 'CVCL:0546', (17, 22))	('increases', 'PosReg', (76, 85))	('aggressive colon cancer', 'Disease', 'MESH:D015179', (41, 64))	('aggressive colon cancer', 'Disease', (41, 64))	('TG2', 'Gene', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('knockdown', 'Var', (4, 13))	('invasive behavior in a matrigel invasion assay', 'CPA', (86, 132))
88769	30693974	In renal cell carcinoma, cancer cell survival is increased due to TGase modification and inactivation of p53.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inactivation', 'Var', (89, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('increased', 'PosReg', (49, 58))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('renal cell carcinoma', 'Disease', (3, 23))	('TGase', 'Protein', (66, 71))	('cancer', 'Disease', (25, 31))	('modification', 'Var', (72, 84))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))
88770	30693974	Thus, both GTP-bound/signaling-active and calcium-bound/transamidase-active TG2 conformations have been reported to enhance cancer cell survival.	('cancer', 'Disease', (124, 130))	('TG2', 'Gene', (76, 79))	('enhance', 'PosReg', (116, 123))	('GTP', 'Chemical', 'MESH:D006160', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('conformations', 'Var', (80, 93))	('calcium', 'Chemical', 'MESH:D002118', (42, 49))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
88776	30693974	The first involves expression of TG2 GTP binding-deficient or TGase activity-deficient mutants in cells and assessing the impact on the cancer cell phenotype.	('TGase', 'Gene', (62, 67))	('GTP', 'Protein', (37, 40))	('mutants', 'Var', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('TG2', 'Gene', (33, 36))	('cancer', 'Disease', (136, 142))	('TGase activity', 'molecular_function', 'GO:0003810', ('62', '76'))	('GTP binding', 'molecular_function', 'GO:0005525', ('37', '48'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
88787	30693974	In addition, high level expression of TG2 or treating cells with stress agents, that compromise plasma and endoplasmic reticulum membranes to increase intracellular calcium, cause massive activation of the open/extended transamidase-active form leading to crosslinking activation and cell death.	('increase', 'PosReg', (142, 150))	('crosslinking', 'MPA', (256, 268))	('intracellular calcium', 'MPA', (151, 172))	('cell death', 'CPA', (284, 294))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('107', '128'))	('open/extended transamidase-active form', 'Enzyme', (206, 244))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (142, 172))	('cell death', 'biological_process', 'GO:0008219', ('284', '294'))	('activation', 'PosReg', (188, 198))	('expression', 'Var', (24, 34))	('TG2', 'Gene', (38, 41))	('calcium', 'Chemical', 'MESH:D002118', (165, 172))	('intracellular', 'cellular_component', 'GO:0005622', ('151', '164'))	('activation', 'PosReg', (269, 279))
88801	32269966	Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('GEM', 'Chemical', '-', (130, 133))	('mutations', 'Var', (146, 155))	('tumoroids', 'Chemical', '-', (24, 33))	('MM tumor', 'Disease', (176, 184))	('human', 'Species', '9606', (83, 88))	('mice', 'Species', '10090', (124, 128))	('patient', 'Species', '9606', (35, 42))	('mice', 'Species', '10090', (93, 97))	('human', 'Species', '9606', (170, 175))	('MM tumor', 'Disease', 'MESH:D009369', (176, 184))
88816	32269966	Malignant mesothelioma are heterogeneous tumors that show a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations, all of which should be considered to model this pathology.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('chromosomic', 'Var', (117, 128))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('epigenetic alterations', 'Var', (134, 156))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))
88824	32269966	The only recurrent oncogenic mutation was identified in the promoter of TERT, which encodes telomerase, the essential enzyme that maintains the length of the telomeres.	('mutation', 'Var', (29, 37))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
88827	32269966	Up to 7% of MPM patients may have germline mutations, but experimental validations are needed to confirm that some of these genes are MPM susceptibility genes (like BAP1).	('MPM', 'Disease', (12, 15))	('BAP1', 'Gene', (165, 169))	('to 7', 'Species', '1214577', (3, 7))	('patients', 'Species', '9606', (16, 24))	('germline mutations', 'Var', (34, 52))	('BAP1', 'Gene', '8314', (165, 169))
88832	32269966	Altogether, these molecular alterations lead to changes in gene expression and deregulation of several biomolecular pathways, including signaling pathways such as Hippo or the PI3K/AKT/mTOR pathways, the cell cycle and apoptosis, among others.	('deregulation', 'Reg', (79, 91))	('changes', 'Reg', (48, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('204', '214'))	('mTOR', 'Gene', (185, 189))	('AKT', 'Gene', (181, 184))	('alterations', 'Var', (28, 39))	('Hippo', 'Gene', (163, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('apoptosis', 'CPA', (219, 228))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('mTOR', 'Gene', '2475', (185, 189))	('gene expression', 'MPA', (59, 74))	('cell cycle', 'CPA', (204, 214))	('AKT', 'Gene', '207', (181, 184))	('biomolecular pathways', 'Pathway', (103, 124))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('signaling pathways', 'Pathway', (136, 154))
88837	32269966	A new subtype with a poor prognosis and characterized by a double mutation in the TSG NF2 and LATS2, both of which are involved in the Hippo signaling pathway, was identified by coupling genetic and transcriptomic analysis.	('NF2', 'Gene', (86, 89))	('double mutation', 'Var', (59, 74))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('135', '158'))	('NF2', 'Gene', '4771', (86, 89))	('LATS2', 'Gene', (94, 99))	('LATS2', 'Gene', '26524', (94, 99))
88875	32269966	These in vivo imaging methods require specific equipment and facilities and, for bioluminescence detection, the genetic modification of tumor cells with the luc gene.	('bioluminescence', 'biological_process', 'GO:0008218', ('81', '96'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('luc', 'Gene', (157, 160))	('genetic modification', 'Var', (112, 132))
88887	32269966	GEM have been generated to obtain "spontaneous" MM, without exposure to asbestos fibers, by heterozygous (htz) or homozygous (hom) conditional mutation of Ink4a and/or Nf2 and/or Trp53, or by IPl/IPe injection of AdCre to mimic the human condition.	('IPe', 'Chemical', '-', (196, 199))	('Trp53', 'Gene', (179, 184))	('GEM', 'Chemical', '-', (0, 3))	('Nf2', 'Gene', '4771', (168, 171))	('asbestos', 'Chemical', 'MESH:D001194', (72, 80))	('Trp53', 'Gene', '7157', (179, 184))	('Nf2', 'Gene', (168, 171))	('Ink4a', 'Gene', '1029', (155, 160))	('conditional mutation', 'Var', (131, 151))	('IPl', 'molecular_function', 'GO:0043904', ('190', '193'))	('human', 'Species', '9606', (232, 237))	('AdCre', 'Chemical', '-', (213, 218))	('Ink4a', 'Gene', (155, 160))
88889	32269966	Similar results were recently reported by inactivating Ink4a, Nf2, and Bap1.	('Bap1', 'Gene', (71, 75))	('Nf2', 'Gene', (62, 65))	('Ink4a', 'Gene', '1029', (55, 60))	('Nf2', 'Gene', '4771', (62, 65))	('Bap1', 'Gene', '8314', (71, 75))	('inactivating', 'Var', (42, 54))	('Ink4a', 'Gene', (55, 60))
88899	32269966	Although these models are physiologically different from humans, GEM mice form tumors that carry relevant gene changes, show histological similarities, and should allow one to perform tests in an immunocompetent environment.	('changes', 'Var', (111, 118))	('GEM', 'Chemical', '-', (65, 68))	('humans', 'Species', '9606', (57, 63))	('mice', 'Species', '10090', (69, 73))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('gene', 'MPA', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
88946	32269966	Among recent developments are PDX models and the generation of GEM that carry mutations identified in human MM tumor cells.	('MM tumor', 'Disease', (108, 116))	('GEM', 'Chemical', '-', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MM tumor', 'Disease', 'MESH:D009369', (108, 116))	('mutations', 'Var', (78, 87))	('human', 'Species', '9606', (102, 107))
89019	28817839	On multivariate analysis low FOXP3+ remained independently associated with survival in both groups.	('FOXP3', 'Gene', '50943', (29, 34))	('FOXP3', 'Gene', (29, 34))	('low', 'Var', (25, 28))	('associated with', 'Reg', (59, 74))
89020	28817839	In the epithelioid group additionally high CD4+, high CD20+, and low NP57+ counts were prognostic.	('high', 'Var', (38, 42))	('high', 'Var', (49, 53))	('CD20', 'Gene', '54474', (54, 58))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))	('CD20', 'Gene', (54, 58))
89025	28817839	There is also a genetic component, with family clusters of patients who possess BAP1 mutations having an increased likelihood of developing mesothelioma and uveal melanoma.	('mesothelioma', 'Disease', (140, 152))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('BAP1', 'Gene', '8314', (80, 84))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (59, 67))	('BAP1', 'Gene', (80, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('uveal melanoma', 'Disease', (157, 171))
89036	28817839	A meta-analysis of 23 studies of solid tumours demonstrated the presence of CD8+ TILs conferred a prognostic advantage and a similar analysis of six studies of CD4+ TILs showed a significant effect on overall survival.	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('solid tumours', 'Disease', 'MESH:D009369', (33, 46))	('TIL', 'Gene', (81, 84))	('TIL', 'Gene', '7096', (165, 168))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('prognostic advantage', 'CPA', (98, 118))	('overall', 'MPA', (201, 208))	('solid tumours', 'Disease', (33, 46))	('presence', 'Var', (64, 72))	('TIL', 'Gene', (165, 168))	('CD4', 'Gene', (160, 163))	('CD8', 'Gene', (76, 79))	('CD4', 'Gene', '920', (160, 163))	('TIL', 'Gene', '7096', (81, 84))	('CD8', 'Gene', '925', (76, 79))
89078	28817839	In the epithelioid group, we found that high CD4+ (P=0.005), low FOXP3+ (P=0.024) and high CD20+ counts (P=0.008) were associated with a better outcome.	('CD20', 'Gene', '54474', (91, 95))	('CD20', 'Gene', (91, 95))	('FOXP3', 'Gene', (65, 70))	('CD4', 'Gene', (45, 48))	('low', 'NegReg', (61, 64))	('CD4', 'Gene', '920', (45, 48))	('FOXP3', 'Gene', '50943', (65, 70))	('high', 'Var', (86, 90))
89096	28817839	Chemotherapy administration but also high CD4+, high CD20+, low FOXP3+ counts were independent prognostic factors (P=0.001, P=0.005, P=0.015, P=0.046) in multivariate analysis.	('CD20', 'Gene', (53, 57))	('high', 'Var', (37, 41))	('CD4', 'Gene', (42, 45))	('low', 'NegReg', (60, 63))	('FOXP3', 'Gene', '50943', (64, 69))	('CD4', 'Gene', '920', (42, 45))	('high', 'Var', (48, 52))	('FOXP3', 'Gene', (64, 69))	('CD20', 'Gene', '54474', (53, 57))
89137	28817839	To our knowledge, our group is the first to detect the prognostic value of a low neutrophil count on survival in epithelioid mesothelioma.	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (113, 137))	('low neutrophil count', 'Phenotype', 'HP:0001875', (77, 97))	('low', 'Var', (77, 80))	('epithelioid mesothelioma', 'Disease', (113, 137))
89144	28817839	In summary, our data demonstrate for the first time an association of survival with high CD4+, low FOXP3+, high CD20+, low NP57+ and low CD68+ counts in epithelioid mesothelioma, treated with palliative intent.	('FOXP3', 'Gene', (99, 104))	('CD20', 'Gene', (112, 116))	('CD4', 'Gene', '920', (89, 92))	('high', 'Var', (84, 88))	('low', 'Var', (95, 98))	('low', 'Var', (119, 122))	('low', 'Var', (133, 136))	('FOXP3', 'Gene', '50943', (99, 104))	('epithelioid mesothelioma', 'Disease', (153, 177))	('CD20', 'Gene', '54474', (112, 116))	('CD68', 'Gene', (137, 141))	('CD68', 'Gene', '968', (137, 141))	('CD4', 'Gene', (89, 92))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (153, 177))
89156	28577549	One tumour retained the first exon of both of the p16INK4a and p19ARF isoforms though this tumour also contained genetic amplification of Myc resulting in increased expression of the c-Myc proto-oncogene in the mRNA.	('Myc', 'Gene', '17869', (185, 188))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('p19', 'cellular_component', 'GO:0070743', ('63', '66'))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('increased', 'PosReg', (155, 164))	('tumour', 'Disease', (91, 97))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('p16INK4a', 'Gene', '12578', (50, 58))	('tumour', 'Disease', (4, 10))	('p19ARF', 'Gene', '12578', (63, 69))	('c-Myc proto-oncogene', 'Gene', '17869', (183, 203))	('p16INK4a', 'Gene', (50, 58))	('genetic amplification', 'Var', (113, 134))	('Myc', 'Gene', (138, 141))	('p19ARF', 'Gene', (63, 69))	('Myc', 'Gene', (185, 188))	('expression', 'MPA', (165, 175))	('Myc', 'Gene', '17869', (138, 141))	('c-Myc proto-oncogene', 'Gene', (183, 203))
89166	28577549	Importantly, asbestos induces mesotheliomas in mice which are almost identical to their human counterpart in terms of pathology, immunology and clinical behavior, which is rare in mouse modeling of cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mesotheliomas', 'Disease', (30, 43))	('cancer', 'Disease', (198, 204))	('mouse', 'Species', '10090', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('asbestos', 'Var', (13, 21))	('human', 'Species', '9606', (88, 93))	('asbestos', 'Chemical', 'MESH:D001194', (13, 21))	('mice', 'Species', '10090', (47, 51))	('induces', 'Reg', (22, 29))	('mesotheliomas', 'Disease', 'MESH:D008654', (30, 43))
89170	28577549	Recent large scale genomic analyses have also found recurrent, low frequency mutations in a number of additional genes including LATS2 (22%), CUL1 (9%), TP53 (8%) and SETD2 (8%).	('LATS2', 'Gene', (129, 134))	('CUL1', 'Gene', (142, 146))	('SETD2', 'Gene', (167, 172))	('TP53', 'Gene', '22059', (153, 157))	('SETD2', 'Gene', '235626', (167, 172))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', (153, 157))	('CUL1', 'Gene', '26965', (142, 146))
89190	28577549	Fifteen murine MM cell lines previously established from ascites generated following intra-peritoneal crocidolite asbestos injection into BALB/c (n = 4), CBA (n = 5) and C57BL/6 (n = 6) mice were assessed for somatic mutations and copy number variation (CNV) aberrations (Table 1).	('ascites', 'Disease', (57, 64))	('copy number', 'Var', (231, 242))	('ascites', 'Disease', 'MESH:D001201', (57, 64))	('ascites', 'Phenotype', 'HP:0001541', (57, 64))	('mice', 'Species', '10090', (186, 190))	('intra-peritoneal crocidolite asbestos', 'Disease', 'MESH:D010534', (85, 122))	('intra-peritoneal crocidolite asbestos', 'Disease', (85, 122))	('murine', 'Species', '10090', (8, 14))
89194	28577549	Copy number aberrations in candidate loci previously implicated in MM were identified in the region of Setd2 in 2 out 15 cell lines and in Lats2 in 3 out of 15 (20%) cell lines.	('Setd2', 'Gene', '235626', (103, 108))	('Setd2', 'Gene', (103, 108))	('Copy number aberrations', 'Var', (0, 23))
89197	28577549	A homozygous deletion of Trp53 was found in AC29 which was confirmed in the messenger RNA by the absence of product using RT-PCR.	('deletion', 'Var', (13, 21))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('Trp53', 'Gene', (25, 30))	('Trp53', 'Gene', '22059', (25, 30))
89202	28577549	However, a single missense SNV in Trp53 occurred in one BALB/c sample (Fig.	('Trp53', 'Gene', (34, 39))	('missense SNV', 'Var', (18, 30))	('Trp53', 'Gene', '22059', (34, 39))
89205	28577549	Six pathways known to be dysregulated in human MM were affected by missense mutations in the murine MM tumour cell lines: 5/15 samples harbored missense mutations in genes in the Wnt signaling pathway; 3/15 in the Hedgehog signaling pathway; 3/15 in the Notch signaling pathway; 2/15 in the mTOR signaling pathway and 2/15 in the p53 signaling pathway (Fig.	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('330', '351'))	('murine', 'Species', '10090', (93, 99))	('signaling pathway', 'biological_process', 'GO:0007165', ('296', '313'))	('Hedgehog signaling pathway', 'Pathway', (214, 240))	('Wnt signaling pathway', 'Pathway', (179, 200))	('MM tumour', 'Disease', (100, 109))	('missense mutations', 'Var', (144, 162))	('MM tumour', 'Disease', 'MESH:D009369', (100, 109))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (41, 46))	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('214', '240'))	('affected', 'Reg', (55, 63))	('p53 signaling pathway', 'Pathway', (330, 351))	('Notch signaling pathway', 'Pathway', (254, 277))	('mTOR signaling pathway', 'Pathway', (291, 313))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('254', '277'))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('179', '200'))	('missense mutations', 'Var', (67, 85))
89209	28577549	Previously, in a genetically engineered MM mouse model, heterozygous for Nf2 +/-, a high rate of homozygous deletion of Cdkn2a was observed in MM tumours induced by asbestos exposure.	('observed', 'Reg', (131, 139))	('asbestos', 'Chemical', 'MESH:D001194', (165, 173))	('MM tumours', 'Disease', (143, 153))	('Nf2', 'Var', (73, 76))	('Cdkn2a', 'Gene', (120, 126))	('MM tumours', 'Disease', 'MESH:D009369', (143, 153))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('mouse', 'Species', '10090', (43, 48))	('deletion', 'Var', (108, 116))
89210	28577549	In the human context CDKN2A loss, deletion of NF2 and/or mutation of BAP1 has been reported in up to 80% of clinical cases.	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', (69, 73))	('human', 'Species', '9606', (7, 12))	('deletion', 'Var', (34, 42))	('CDKN2A', 'Gene', (21, 27))	('NF2', 'Gene', (46, 49))	('loss', 'NegReg', (28, 32))
89211	28577549	Dysregulation of the Hippo pathway is often reported in human MM, typically through mutations or copy number aberrations of NF2, YAP and/or LATS2.	('NF2', 'Gene', (124, 127))	('Dysregulation', 'Var', (0, 13))	('copy number aberrations', 'Var', (97, 120))	('LATS2', 'Gene', (140, 145))	('human', 'Species', '9606', (56, 61))	('mutations', 'Var', (84, 93))	('YAP', 'Gene', '10413', (129, 132))	('Hippo pathway', 'Pathway', (21, 34))	('YAP', 'Gene', (129, 132))
89212	28577549	With post-transcriptional modification potentially accounting for loss of these tumour suppressors in the mouse asbestos induced MM model it is not possible to conclusively say that Cdkn2a deletion is an independent driver of MM.	('tumour', 'Disease', (80, 86))	('Cdkn2a', 'Gene', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('asbestos', 'Chemical', 'MESH:D001194', (112, 120))	('deletion', 'Var', (189, 197))	('mouse', 'Species', '10090', (106, 111))
89220	28577549	Human MM tumours display recurrent losses in 1p21-p22, 9p21-p22, 3p21, 6q15-q21, 17p13.1 and 22q12.2.	('Human', 'Species', '9606', (0, 5))	('MM tumours', 'Disease', (6, 16))	('22q12.2', 'Gene', (93, 100))	('p22', 'Gene', (60, 63))	('p22', 'Gene', '11331', (50, 53))	('MM tumours', 'Disease', 'MESH:D009369', (6, 16))	('p22', 'Gene', (50, 53))	('p22', 'Gene', '11331', (60, 63))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('6q15-q21', 'Var', (71, 79))	('3p21', 'Var', (65, 69))	('17p13.1', 'Gene', (81, 88))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('losses', 'NegReg', (35, 41))
89223	28577549	To date no common oncogenic driver has been identified in MM, although amplification of the C-MYC locus in MM has been reported to occur in MM human tumour cell lines and may contribute to a malignant phenotype.	('human', 'Species', '9606', (143, 148))	('tumour', 'Disease', (149, 155))	('amplification', 'Var', (71, 84))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('C-MYC', 'Gene', '4609', (92, 97))	('contribute to', 'Reg', (175, 188))	('malignant', 'MPA', (191, 200))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('C-MYC', 'Gene', (92, 97))
89226	28577549	Carcinogen-induced cancers such as melanoma and lung cancer typically show a high rate of mutation when compared to spontaneous cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('mutation', 'Var', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
89231	28577549	Patterns of mutations can be used to identify mutational signatures which represent the underlying process of DNA damage, (for example tobacco smoking induces a mutational pattern that exhibits transcriptional strand bias for C > A mutations and CC > AA dinucleotide substitutions).	('tobacco', 'Species', '4097', (135, 142))	('C > A mutations', 'Var', (226, 241))	('CC > AA dinucleotide substitutions', 'Var', (246, 280))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('transcriptional strand bias', 'MPA', (194, 221))
89233	28577549	The current exome sequencing study was underpowered to perform a full mutational signature analysis but did show a high rate of C > T and G > A mutations, consistent with previous studies in humans.	('C > T', 'Var', (128, 133))	('humans', 'Species', '9606', (191, 197))	('G > A mutations', 'Var', (138, 153))
89235	28577549	Given the genetically independent nature of MM tumours and the low likelihood of the same gene being mutated at different positions in more than one sample, the presence of different mutations in Nkd1 in two BALB/c samples and Cacna2d2 in samples from two different strains is informative.	('mutations', 'Var', (183, 192))	('MM tumours', 'Disease', 'MESH:D009369', (44, 54))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('Cacna2d2', 'Gene', '56808', (227, 235))	('Nkd1', 'Gene', (196, 200))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('Nkd1', 'Gene', '93960', (196, 200))	('MM tumours', 'Disease', (44, 54))	('Cacna2d2', 'Gene', (227, 235))
89236	28577549	The mutation of Nkd1 may implicate the role of Wnt signaling pathway regulation in the BALB/c strain.	('Wnt signaling pathway', 'Pathway', (47, 68))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('47', '68'))	('mutation', 'Var', (4, 12))	('Nkd1', 'Gene', (16, 20))	('implicate', 'Reg', (25, 34))	('Nkd1', 'Gene', '93960', (16, 20))
89248	28577549	aCGH Array comparative genomic hybridisation Bap1 BRCA1 associated protein 1 Cdkn2a Cyclin dependent kinase inhibitor 2A CIGAR Concise idiosyncratic gapped alignment report CNV Copy number variation DNA Deoxyribonucleic acid GATK Genome Analysis Toolkit GISTIC Genetic identification of significant targets in cancer IGV Integrative Genomics Viewer Indel Short insertion or deletion KEGG Kyoto Encyclopedia of Genes and Genomes Mb Million bases MD Match/mismatch MM Mesothelioma mRNA Messenger RNA Nf2 Neurofibromin 2 RNA Ribonucleic acid RT-PCR Reverse transcription polymerase chain reaction SNV Single nucleotide variation Trp53 Tumour protein 53 UV Ultraviolet -x -fold coverage	('BRCA1 associated protein', 'Gene', (50, 74))	('Single nucleotide variation', 'Var', (598, 625))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('Trp53', 'Gene', (626, 631))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('deletion', 'Var', (374, 382))	('cancer', 'Disease', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('Tumour', 'Phenotype', 'HP:0002664', (632, 638))	('Reverse transcription', 'biological_process', 'GO:0001171', ('546', '567'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('101', '117'))	('Neurofibromin', 'Gene', '18015', (502, 515))	('Cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('84', '117'))	('RNA', 'cellular_component', 'GO:0005562', ('494', '497'))	('Mesothelioma', 'Disease', (466, 478))	('Mesothelioma', 'Disease', 'MESH:D008654', (466, 478))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('protein', 'cellular_component', 'GO:0003675', ('639', '646'))	('RNA', 'cellular_component', 'GO:0005562', ('518', '521'))	('Trp53', 'Gene', '22059', (626, 631))	('Neurofibromin', 'Gene', (502, 515))	('BRCA1 associated protein', 'Gene', '72399', (50, 74))
89249	26119930	Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (228, 240))	('deregulated inflammatory response', 'MPA', (80, 113))	('particular malignant mesothelioma', 'Disease', (207, 240))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('particular malignant mesothelioma', 'Disease', 'MESH:C562839', (207, 240))	('cancers', 'Disease', (195, 202))	('predispose to', 'Reg', (173, 186))	('mesothelioma', 'Disease', (136, 148))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (218, 240))	('asbestos', 'Chemical', 'MESH:D001194', (8, 16))	('BAP1', 'Gene', (38, 42))	('BAP1', 'Gene', (158, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (136, 148))	('inflammatory response', 'biological_process', 'GO:0006954', ('92', '113'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (163, 172))	('mice', 'Species', '10090', (56, 60))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('BAP1', 'Gene', '104416', (38, 42))	('BAP1', 'Gene', '104416', (158, 162))	('mesothelioma', 'Disease', (228, 240))
89251	26119930	However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos.	('mesothelioma', 'Disease', (43, 55))	('patients', 'Species', '9606', (56, 64))	('BAP1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))
89252	26119930	We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure.	('BAP1', 'Gene', (30, 34))	('asbestos', 'Chemical', 'MESH:D001194', (65, 73))	('asbestos-induced inflammatory response', 'CPA', (65, 103))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (122, 145))	('mesothelioma', 'Disease', (189, 201))	('inflammatory response', 'biological_process', 'GO:0006954', ('82', '103'))	('increasing', 'PosReg', (155, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('influence', 'Reg', (51, 60))	('asbestos carcinogenesis', 'Disease', (122, 145))	('asbestos', 'Chemical', 'MESH:D001194', (122, 130))	('mutations', 'Var', (35, 44))
89253	26119930	Using a BAP1+/- mouse model, we found that, compared to their wild type littermates, BAP1+/- mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines.	('peritoneal', 'CPA', (172, 182))	('tumor', 'Disease', (251, 256))	('alterations', 'Reg', (153, 164))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('inflammatory response', 'biological_process', 'GO:0006954', ('183', '204'))	('mice', 'Species', '10090', (93, 97))	('higher', 'PosReg', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lower', 'NegReg', (307, 312))	('mouse', 'Species', '10090', (16, 21))	('BAP1+/-', 'Var', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
89254	26119930	Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild type mice.	('mice', 'Species', '10090', (192, 196))	('asbestos', 'Chemical', 'MESH:D001194', (130, 138))	('higher', 'PosReg', (61, 67))	('BAP1+/-', 'Var', (28, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('mesothelioma', 'Disease', (166, 178))	('mice', 'Species', '10090', (36, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('mesothelioma', 'Disease', (81, 93))
89255	26119930	Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (105, 127))	('BAP1', 'Gene', (185, 189))	('mutations', 'Var', (190, 199))	('increase', 'PosReg', (84, 92))	('malignant mesothelioma', 'Disease', (105, 127))	('inflammatory response', 'biological_process', 'GO:0006954', ('233', '254'))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (46, 65))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (105, 127))	('carcinogenic fibers', 'Disease', (46, 65))
89267	26119930	Recently, we identified germline mutations in the tumor suppressor gene BRCA1 associated protein-1 (BAP1) as causative of a novel hereditary cancer syndrome characterized by a very high risk of MM, uveal and cutaneous melanoma, several other malignancies, and characteristic benign melanocytic tumors we named MBAITs.	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('hereditary cancer syndrome', 'Disease', (130, 156))	('causative', 'Reg', (109, 118))	('BRCA1 associated protein-1', 'Gene', (72, 98))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanocytic tumors', 'Disease', (282, 300))	('BAP1', 'Gene', (100, 104))	('melanocytic tumors', 'Disease', 'MESH:D009508', (282, 300))	('BRCA1 associated protein-1', 'Gene', '104416', (72, 98))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('malignancies', 'Disease', 'MESH:D009369', (242, 254))	('malignancies', 'Disease', (242, 254))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('tumor', 'Disease', (294, 299))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (130, 156))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('cutaneous melanoma', 'Disease', (208, 226))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (208, 226))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (208, 226))	('germline mutations', 'Var', (24, 42))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
89268	26119930	The penetrance of the BAP1 cancer syndrome is ~100%, and several patients carrying germline BAP1 mutations develop multiple cancers.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer syndrome', 'Disease', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('patients', 'Species', '9606', (65, 73))	('develop', 'Reg', (107, 114))	('cancer syndrome', 'Disease', 'MESH:D009369', (27, 42))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('BAP1', 'Gene', (92, 96))
89269	26119930	Notably, none of the germline BAP1 heterozygous patients who developed MM reported professional exposure to asbestos fibers, suggesting that either these MMs were not caused by asbestos, or that minimal amounts of asbestos - as in the case of some indoor exposure or naturally occurring outdoor environmental exposure - may be sufficient to cause MM in germline BAP1 mutation carriers.	('asbestos', 'Chemical', 'MESH:D001194', (108, 116))	('mutation', 'Var', (367, 375))	('BAP1', 'Gene', (362, 366))	('asbestos', 'Chemical', 'MESH:D001194', (177, 185))	('asbestos', 'Chemical', 'MESH:D001194', (214, 222))	('cause', 'Reg', (341, 346))	('MMs', 'Chemical', 'MESH:D008741', (154, 157))	('patients', 'Species', '9606', (48, 56))
89270	26119930	Here, we experimentally tested in a BAP1+/- murine model whether germline BAP1 heterozygosity would result in alterations of the asbestos-induced inflammatory response, and whether low doses of asbestos might be sufficient to cause MM.	('alterations', 'Reg', (110, 121))	('murine', 'Species', '10090', (44, 50))	('result', 'Reg', (100, 106))	('heterozygosity', 'Var', (79, 93))	('tested', 'Reg', (24, 30))	('asbestos', 'Chemical', 'MESH:D001194', (194, 202))	('inflammatory response', 'biological_process', 'GO:0006954', ('146', '167'))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('asbestos-induced inflammatory response', 'MPA', (129, 167))	('BAP1', 'Gene', (74, 78))
89280	26119930	Accordingly, the percentage of M1 macrophages (CD206-CD86+ cells) was significantly lower in BAP1+/- mice (43.2% [28.9-44.9] vs 67.3% [46.7-78.2] of total macrophages, P < 0.05).	('CD86', 'Gene', (53, 57))	('CD86', 'Gene', '12524', (53, 57))	('BAP1+/-', 'Var', (93, 100))	('mice', 'Species', '10090', (101, 105))	('lower', 'NegReg', (84, 89))	('M1 macrophages', 'CPA', (31, 45))	('CD206', 'Gene', (47, 52))	('CD206', 'Gene', '17533', (47, 52))
89281	26119930	On the other hand, the percentage of M2 macrophages (defined as CD206+ CD86-cells) was significantly higher in BAP1+/- mice compared to wild type littermates (3.8% [2.1-6.8] vs 1.2% [0.5-3.6%] of total macrophages, P < 0.05).	('CD206', 'Gene', (64, 69))	('CD86', 'Gene', (71, 75))	('mice', 'Species', '10090', (119, 123))	('higher', 'PosReg', (101, 107))	('CD86', 'Gene', '12524', (71, 75))	('BAP1+/-', 'Var', (111, 118))	('M2 macrophages', 'CPA', (37, 51))	('CD206', 'Gene', '17533', (64, 69))
89282	26119930	Double positive (CD206+ CD86+) macrophages, which represent a transition state from M1 to M2, were also more represented in BAP1+/- mice compared to wild type littermates (40.0% [30.7-47.0] vs 26.0% [13.3-37.6] of total macrophages, P < 0.05) (Fig.	('CD206', 'Gene', (17, 22))	('CD206', 'Gene', '17533', (17, 22))	('BAP1+/-', 'Var', (124, 131))	('CD86', 'Gene', (24, 28))	('CD86', 'Gene', '12524', (24, 28))	('mice', 'Species', '10090', (132, 136))	('more', 'PosReg', (104, 108))
89285	26119930	Compared to wild type littermates, the levels of monocyte chemoattractant protein-1 (MCP-1) were significantly lower in BAP1+/- mice exposed to glass (2.5 pg/mL [2.3-5.2] vs 33.6 pg/mL [6.5-51.7], P < 0.01) and in BAP1+/- mice exposed to asbestos (52.4 pg/mL [4.7-113.4] vs 178.5 pg/mL [102.9-373.2], P < 0.05) (Fig.	('mice', 'Species', '10090', (222, 226))	('BAP1+/-', 'Var', (120, 127))	('monocyte chemoattractant protein-1', 'Gene', '20296', (49, 83))	('MCP-1', 'Gene', (85, 90))	('levels', 'MPA', (39, 45))	('monocyte chemoattractant protein-1', 'Gene', (49, 83))	('asbestos', 'Chemical', 'MESH:D001194', (238, 246))	('mice', 'Species', '10090', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('lower', 'NegReg', (111, 116))	('MCP-1', 'Gene', '20296', (85, 90))	('MCP', 'molecular_function', 'GO:0004298', ('85', '88'))
89286	26119930	Analogously, compared to wild type littermates, the levels of leukemia inhibitory factor (LIF) were significantly lower in the BAP1+/- mice exposed to glass (0.9 pg/mL [0.9-1.0] vs 6.9 pg/mL [1.1-13.5], P < 0.01), and in the BAP1+/- mice exposed to asbestos (78.2 pg/mL [41.0-134.4] vs 201.9 pg/mL [116.9-274.8], P < 0.05) (Fig.	('BAP1+/-', 'Var', (127, 134))	('leukemia inhibitory factor', 'Gene', (62, 88))	('mice', 'Species', '10090', (233, 237))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('LIF', 'Gene', (90, 93))	('mice', 'Species', '10090', (135, 139))	('asbestos', 'Chemical', 'MESH:D001194', (249, 257))	('lower', 'NegReg', (114, 119))	('leukemia inhibitory factor', 'molecular_function', 'GO:0005146', ('62', '88'))	('leukemia inhibitory factor', 'Gene', '16878', (62, 88))	('LIF', 'Gene', '16878', (90, 93))	('levels', 'MPA', (52, 58))
89288	26119930	We also observed that eotaxin levels were significantly lower in BAP1+/- mice compared to wild type littermates in the glass exposed control group (1.73 ng/mL [1.11-2.06] vs 3.27 ng/mL [1.94-3.92], P < 0.05); the same trend, although non-significant, was retained following asbestos exposure (3.33 ng/mL [2.56-4.33] vs 4.70 ng/mL [3.13-6.30], P = 0.28) (Fig.	('BAP1+/-', 'Var', (65, 72))	('eotaxin', 'Gene', (22, 29))	('mice', 'Species', '10090', (73, 77))	('lower', 'NegReg', (56, 61))	('eotaxin', 'Gene', '20292', (22, 29))	('asbestos', 'Chemical', 'MESH:D001194', (274, 282))
89292	26119930	Together, these results indicated that germline BAP1 heterozygosity significantly influenced the peritoneal inflammatory response upon asbestos exposure.	('heterozygosity', 'Var', (53, 67))	('inflammatory response', 'biological_process', 'GO:0006954', ('108', '129'))	('peritoneal inflammatory response', 'CPA', (97, 129))	('BAP1', 'Gene', (48, 52))	('asbestos', 'Chemical', 'MESH:D001194', (135, 143))	('influenced', 'Reg', (82, 92))	('germline', 'Var', (39, 47))
89301	26119930	In sporadic human MM, somatic BAP1 inactivation is one of the most frequent events, and it has been reported in about 40-60% of the cases.	('inactivation', 'Var', (35, 47))	('BAP1', 'Gene', (30, 34))	('human', 'Species', '9606', (12, 17))
89302	26119930	Consistent with these human data, BAP1 nuclear staining was absent in all MM analyzed arising from BAP1+/- mice and in 66.7% from BAP1+/+ mice (Fig.	('BAP1', 'Gene', (34, 38))	('mice', 'Species', '10090', (138, 142))	('BAP1+/-', 'Var', (99, 106))	('mice', 'Species', '10090', (107, 111))	('human', 'Species', '9606', (22, 27))	('absent', 'NegReg', (60, 66))
89303	26119930	With regard to histology, all the MMs we observed in human germline BAP1 mutation carriers were epithelioid.	('MMs', 'Chemical', 'MESH:D008741', (34, 37))	('epithelioid', 'Disease', (96, 107))	('human', 'Species', '9606', (53, 58))	('mutation', 'Var', (73, 81))	('BAP1', 'Gene', (68, 72))
89304	26119930	In sporadic human MMs, several groups have reported that mutations of BAP1 occur primarily in epithelioid MM, although this is not unequivocal.	('MMs', 'Chemical', 'MESH:D008741', (18, 21))	('mutations', 'Var', (57, 66))	('BAP1', 'Gene', (70, 74))	('human', 'Species', '9606', (12, 17))	('occur', 'Reg', (75, 80))	('epithelioid MM', 'Disease', (94, 108))
89307	26119930	BAP1+/- mice had also a significantly shorter survival, i.e.	('survival', 'CPA', (46, 54))	('BAP1+/-', 'Var', (0, 7))	('mice', 'Species', '10090', (8, 12))	('shorter', 'NegReg', (38, 45))
89309	26119930	Taken together, our results showed that germline BAP1 heterozygosity is associated with a significantly altered peritoneal inflammatory response upon exposure to asbestos fibers and to an increased risk of MM following exposure to minimal amounts of asbestos that rarely cause MM in wild type animals.	('heterozygosity', 'Var', (54, 68))	('altered', 'Reg', (104, 111))	('BAP1', 'Gene', (49, 53))	('asbestos', 'Chemical', 'MESH:D001194', (162, 170))	('asbestos', 'Chemical', 'MESH:D001194', (250, 258))	('inflammatory response', 'biological_process', 'GO:0006954', ('123', '144'))	('germline', 'Var', (40, 48))	('peritoneal inflammatory response', 'MPA', (112, 144))
89311	26119930	BAP1 knockdown in MM cell lines has been paradoxically associated to a decreased proliferation, with an accumulation of cells in the S phase of the cell cycle, suggesting that BAP1 loss might promote tumorigenesis inducing a delayed, but more permissive, G1/S checkpoint.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('knockdown', 'Var', (5, 14))	('promote', 'PosReg', (192, 199))	('cell cycle', 'biological_process', 'GO:0007049', ('148', '158'))	('tumor', 'Disease', (200, 205))	('BAP1', 'Gene', (176, 180))	('loss', 'NegReg', (181, 185))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('255', '270'))	('decreased', 'NegReg', (71, 80))	('S phase', 'biological_process', 'GO:0051320', ('133', '140'))
89312	26119930	Heterozygous germline mutations of other important tumor suppressor genes, such as BRCA1, CDKN2A, and RB1, increase risk of cancer specifically to one or very few anatomical sites.	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('BRCA1', 'Gene', '12189', (83, 88))	('RB1', 'Gene', '19645', (102, 105))	('Heterozygous', 'Var', (0, 12))	('tumor', 'Disease', (51, 56))	('BRCA1', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('germline mutations', 'Var', (13, 31))	('increase', 'Reg', (107, 115))	('CDKN2A', 'Gene', '12578', (90, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('RB1', 'Gene', (102, 105))	('CDKN2A', 'Gene', (90, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
89313	26119930	One of the few tumor suppressor genes whose germline heterozygosity, similar to BAP1, is associated to increased risk of cancer to several sites is TP53, which encodes p53.	('p53', 'Gene', '22059', (168, 171))	('germline heterozygosity', 'Var', (44, 67))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', '22059', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('tumor', 'Disease', (15, 20))	('cancer', 'Disease', (121, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('p53', 'Gene', (168, 171))
89315	26119930	Our results suggest that germline BAP1 heterozygosity, similarly to TP53, influences in vivo macrophage polarization and cytokine release.	('influences', 'Reg', (74, 84))	('BAP1', 'Gene', (34, 38))	('cytokine release', 'MPA', (121, 137))	('macrophage polarization', 'biological_process', 'GO:0042116', ('93', '116'))	('TP53', 'Gene', '22059', (68, 72))	('TP53', 'Gene', (68, 72))	('heterozygosity', 'Var', (39, 53))
89317	26119930	Also, the chemokines MCP-1 and KC, and two cytokines of the IL-6 family (IL-6 itself and LIF) are soluble mediators significantly reduced in BAP1+/- mice exposed to asbestos.	('MCP-1', 'Gene', '20296', (21, 26))	('LIF', 'Gene', (89, 92))	('BAP1+/-', 'Var', (141, 148))	('IL-6', 'Gene', (60, 64))	('IL-6', 'Gene', '16193', (60, 64))	('LIF', 'Gene', '16878', (89, 92))	('IL-6', 'molecular_function', 'GO:0005138', ('73', '77'))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('soluble', 'cellular_component', 'GO:0005625', ('98', '105'))	('MCP', 'molecular_function', 'GO:0004298', ('21', '24'))	('MCP-1', 'Gene', (21, 26))	('mice', 'Species', '10090', (149, 153))	('reduced', 'NegReg', (130, 137))	('IL-6', 'Gene', (73, 77))	('IL-6', 'Gene', '16193', (73, 77))	('asbestos', 'Chemical', 'MESH:D001194', (165, 173))
89322	26119930	To explain the observed intra- and inter-familial variability of cancer types in germline BAP1 mutated carriers, we hypothesized that MM might be more prevalent in individuals/families exposed to low levels of asbestos, levels that are not, or only marginally, carcinogenic for the population at large.	('prevalent', 'Reg', (151, 160))	('carcinogenic', 'Disease', 'MESH:D063646', (261, 273))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('carcinogenic', 'Disease', (261, 273))	('mutated', 'Var', (95, 102))	('BAP1', 'Gene', (90, 94))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('asbestos', 'Chemical', 'MESH:D001194', (210, 218))
89327	26119930	Accordingly, although MMs in carriers of germline BAP1 mutations are less aggressive and are associated with survivals from diagnosis of 5-10 years, compared to an average of 1 year in sporadic MM patients, the former die at an earlier age compared to the latter.	('patients', 'Species', '9606', (197, 205))	('mutations', 'Var', (55, 64))	('germline', 'Var', (41, 49))	('aggressive', 'CPA', (74, 84))	('MMs', 'Chemical', 'MESH:D008741', (22, 25))	('BAP1', 'Gene', (50, 54))	('less', 'NegReg', (69, 73))
89332	26119930	Therefore, although it is not possible to directly compare the low-dose exposure in mice to indoor and/or outdoor environmental exposure in humans, our findings support our hypothesis that germline BAP1 heterozygosity increases susceptibility to the carcinogenic effects of low doses of asbestos.	('carcinogenic', 'Disease', 'MESH:D063646', (250, 262))	('carcinogenic', 'Disease', (250, 262))	('humans', 'Species', '9606', (140, 146))	('heterozygosity', 'Var', (203, 217))	('increases', 'PosReg', (218, 227))	('susceptibility', 'MPA', (228, 242))	('asbestos', 'Chemical', 'MESH:D001194', (287, 295))	('BAP1', 'Gene', (198, 202))	('mice', 'Species', '10090', (84, 88))
89333	26119930	Based on our results, we suggest that prevention programs of MM in individuals carrying germline BAP1 mutations should focus on reducing exposure to even minimal sources of carcinogenic fibers, levels that are within the acceptable "safe" limits for the population at large (0.1 fibers/cc of air as an eight-hour time-weighted average, as per US Occupational Safety & Health Administration standards).	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('carcinogenic fibers', 'Disease', (173, 192))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (173, 192))
89445	33993055	This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217, JSPS), FOREST-Souhatsu, CREST (JST).	('CREST', 'Gene', (176, 181))	('18K15923', 'Var', (132, 140))	('CREST', 'Gene', '269397', (176, 181))
89455	33993055	In vitro NIR-PIT targeting GPR87 only injured GPR87-expressing cells and did not affect non-targeted cells.	('GPR87', 'Var', (27, 32))	('GPR87-expressing', 'Gene', (46, 62))	('injured', 'NegReg', (38, 45))	('NIR-PIT', 'Chemical', '-', (9, 16))
89464	33993055	High GPR87 expression in lung and pancreatic cancer is associated with a worse prognosis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('lung', 'Disease', (25, 29))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('GPR87', 'Gene', (5, 10))	('pancreatic cancer', 'Disease', (34, 51))
89467	33993055	Near-infrared photoimmunotherapy (NIR-PIT) is an emerging cancer modality, where IRDye700DX (IR700), a photosensitiser, is bound to an antibody, and near-infrared-light irradiation specifically destroys the targeting cell.	('IRDye700DX', 'Var', (81, 91))	('IR700', 'Chemical', '-', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bound', 'Interaction', (123, 128))	('NIR-PIT', 'Chemical', '-', (34, 41))	('antibody', 'cellular_component', 'GO:0019815', ('135', '143'))	('antibody', 'cellular_component', 'GO:0019814', ('135', '143'))	('antibody', 'molecular_function', 'GO:0003823', ('135', '143'))	('destroys', 'NegReg', (194, 202))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('antibody', 'cellular_component', 'GO:0042571', ('135', '143'))	('cancer', 'Disease', (58, 64))
89473	33993055	The HAMA response is significantly reduced or abolished by chimerisation and humanisation.	('reduced', 'NegReg', (35, 42))	('HAMA response', 'MPA', (4, 17))	('abolished', 'NegReg', (46, 55))	('chimerisation', 'Var', (59, 72))	('human', 'Species', '9606', (77, 82))
89476	33993055	The aim of this study was to develop NIR-PIT targeting GPR87, and the therapeutic targets were MPM and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('MPM', 'Disease', (95, 98))	('GPR87', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('NIR-PIT', 'Chemical', '-', (37, 44))
89505	33993055	Cells (1 x 105) were seeded onto 12-well plates and incubated with moGPR87ab-IR700 or huGPR87ab-IR700 at 10 mug/mL for 12 h at 37  C. The medium was replaced with PBS after washing twice.	('IR700', 'Chemical', '-', (96, 101))	('IR700', 'Chemical', '-', (77, 82))	('huGPR87ab-IR700', 'Var', (86, 101))	('moGPR87ab-IR700', 'Var', (67, 82))	('PBS', 'Chemical', 'MESH:D007854', (163, 166))	('huGPR87ab', 'Chemical', '-', (86, 95))	('mug', 'molecular_function', 'GO:0043739', ('108', '111'))
89538	33993055	The mice were injected with 200 mug of huGPR87-IR700 on day -1 (9 days after tumour cell injection into mice) and irradiated with NIR-light laser at 50 J/cm2 on day 0 and again at 100 J/cm2 on day 1 at 100 mW/cm2.	('mice', 'Species', '10090', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('huGPR87-IR700', 'Var', (39, 52))	('mice', 'Species', '10090', (104, 108))	('tumour', 'Disease', (77, 83))	('mug', 'molecular_function', 'GO:0043739', ('32', '35'))	('IR700', 'Chemical', '-', (47, 52))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
89539	33993055	Tumour volume and luciferase activity were measured immediately before administration of huGPR87-IR700 (day-1), and on day 0 and 1 before NIR-irradiation, and on day 2, 3, 4 and 7.	('luciferase activity', 'molecular_function', 'GO:0045289', ('18', '37'))	('Tumour volume', 'CPA', (0, 13))	('luciferase activity', 'molecular_function', 'GO:0047712', ('18', '37'))	('IR700', 'Chemical', '-', (97, 102))	('luciferase activity', 'molecular_function', 'GO:0050397', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('18', '37'))	('activity', 'MPA', (29, 37))	('huGPR87-IR700', 'Var', (89, 102))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('luciferase', 'Enzyme', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0047077', ('18', '37'))
89540	33993055	Mice seeded with pleura were injected with 200 mug of huGPR87ab-IR700 on day 0 (5 days after tumour cell injection into the mice), and therefore the larger tumour was irradiated with NIR-light laser at 45 J/cm2 at 60 mW/cm2 on day 1.	('huGPR87ab', 'Chemical', '-', (54, 63))	('huGPR87ab-IR700', 'Var', (54, 69))	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', (156, 162))	('mice', 'Species', '10090', (124, 128))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('IR700', 'Chemical', '-', (64, 69))	('Mice', 'Species', '10090', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('mug', 'molecular_function', 'GO:0043739', ('47', '50'))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
89541	33993055	Luciferase activity was measured immediately before administration of huGPR87-IR700 (day 0) and on day 1 (before NIR-irradiation), 2, 3 and 4.	('Luciferase activity', 'molecular_function', 'GO:0050397', ('0', '19'))	('activity', 'MPA', (11, 19))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('0', '19'))	('IR700', 'Chemical', '-', (78, 83))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('0', '19'))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('0', '19'))	('Luciferase', 'Enzyme', (0, 10))	('huGPR87-IR700', 'Var', (70, 83))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('0', '19'))
89545	33993055	The integrity of the huGPR87ab-IR700 conjugate was confirmed by observing strong IR700-fluorescence, which was detected in the band of huGPR87ab, while huGPR87ab alone had no detectable fluorescent signals on SDS-PAGE (Fig.	('IR700-fluorescence', 'MPA', (81, 99))	('huGPR87ab', 'Chemical', '-', (135, 144))	('IR700', 'Chemical', '-', (31, 36))	('SDS', 'Chemical', 'MESH:D012967', (209, 212))	('huGPR87ab', 'Var', (135, 144))	('huGPR87ab', 'Chemical', '-', (21, 30))	('IR700', 'Chemical', '-', (81, 86))	('huGPR87ab', 'Chemical', '-', (152, 161))
89547	33993055	On binding with GPR87-CHO cells, which were stably GPR87-overexpressing strains, both moGPR87ab-IR700 and huGPR87ab-IR700 showed similar reactions; almost no signals were observed in either 3T3 mouse fibroblasts or human normal bronchial epithelial cell line HBEC3.	('mouse fibroblasts', 'CellLine', 'CVCL:0594', (194, 211))	('moGPR87ab-IR700', 'Var', (86, 101))	('binding', 'Interaction', (3, 10))	('IR700', 'Chemical', '-', (96, 101))	('HBEC3', 'CellLine', 'CVCL:X491', (259, 264))	('huGPR87ab', 'Chemical', '-', (106, 115))	('huGPR87ab-IR700', 'Var', (106, 121))	('GPR87-CHO', 'CellLine', 'CVCL:U007', (16, 25))	('IR700', 'Chemical', '-', (116, 121))	('binding', 'molecular_function', 'GO:0005488', ('3', '10'))	('CHO', 'molecular_function', 'GO:0043848', ('22', '25'))	('human', 'Species', '9606', (215, 220))
89550	33993055	3c), confirming that huGPR87ab-IR700 bound to GPR87 proteins.	('huGPR87ab-IR700', 'Var', (21, 36))	('IR700', 'Chemical', '-', (31, 36))	('bound', 'Interaction', (37, 42))	('huGPR87ab', 'Chemical', '-', (21, 30))
89551	33993055	These results indicated that huGPR87ab and IR700 were conjugated properly, and the binding was stronger with huGPR87ab than with moGPR87ab-IR700.	('huGPR87ab', 'Chemical', '-', (29, 38))	('stronger', 'PosReg', (95, 103))	('binding', 'Interaction', (83, 90))	('huGPR87ab', 'Chemical', '-', (109, 118))	('IR700', 'Chemical', '-', (139, 144))	('IR700', 'Chemical', '-', (43, 48))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('huGPR87ab', 'Var', (109, 118))
89552	33993055	The fluorescent signals obtained with huGPR87ab-IR700 from H1975 (NSLAC), H661 (large cell lung carcinoma), H226 (NSLSCC), SBC3, SBC5 (SCLC), MSTO-211H, and H2373 (MPM) were evaluated using flow cytometry.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('H2373', 'CellLine', 'CVCL:A533', (157, 162))	('H661', 'CellLine', 'CVCL:1577', (74, 78))	('SCLC', 'Disease', (135, 139))	('SCLC', 'Disease', 'MESH:D018288', (135, 139))	('lung carcinoma', 'Disease', (91, 105))	('H661', 'Var', (74, 78))	('huGPR87ab-IR700', 'Var', (38, 53))	('lung carcinoma', 'Disease', 'MESH:D008175', (91, 105))	('large cell lung carcinoma', 'Phenotype', 'HP:0030360', (80, 105))	('huGPR87ab', 'Chemical', '-', (38, 47))	('H226', 'CellLine', 'CVCL:J621', (108, 112))	('H1975', 'CellLine', 'CVCL:1511', (59, 64))	('IR700', 'Chemical', '-', (48, 53))
89553	33993055	Fluorescent signals from lung carcinoma and malignant mesothelioma cells were higher for huGPR87ab-IR700 than for moGPR87ab-IR700 (Fig.	('lung carcinoma', 'Disease', (25, 39))	('IR700', 'Chemical', '-', (124, 129))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (44, 66))	('huGPR87ab-IR700', 'Var', (89, 104))	('higher', 'PosReg', (78, 84))	('huGPR87ab', 'Chemical', '-', (89, 98))	('lung carcinoma', 'Disease', 'MESH:D008175', (25, 39))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (44, 66))	('malignant mesothelioma', 'Disease', (44, 66))	('Fluorescent signals', 'MPA', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('IR700', 'Chemical', '-', (99, 104))
89554	33993055	These data indicated that GPR87 is widely expressed, and huGPR87ab-IR700 had sufficient binding affinity to lung carcinoma and malignant mesothelioma cell lines.	('lung carcinoma', 'Disease', (108, 122))	('huGPR87ab', 'Chemical', '-', (57, 66))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (127, 149))	('binding affinity', 'Interaction', (88, 104))	('IR700', 'Chemical', '-', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (127, 149))	('huGPR87ab-IR700', 'Var', (57, 72))	('lung carcinoma', 'Disease', 'MESH:D008175', (108, 122))	('malignant mesothelioma', 'Disease', (127, 149))
89555	33993055	Moreover, huGPR87ab-IR700 had a higher affinity to the protein in vitro than moGPR87ab-IR700.	('IR700', 'Chemical', '-', (87, 92))	('higher', 'PosReg', (32, 38))	('protein', 'Protein', (55, 62))	('affinity', 'Interaction', (39, 47))	('huGPR87ab', 'Chemical', '-', (10, 19))	('huGPR87ab-IR700', 'Var', (10, 25))	('IR700', 'Chemical', '-', (20, 25))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))
89561	33993055	In vitro NIR-PIT with huGPR87-IR700 was also performed with SBC5-luc (SCLC) and H2373-luc (MPM), and similar results were obtained (Fig.	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('huGPR87-IR700', 'Var', (22, 35))	('H2373', 'CellLine', 'CVCL:A533', (80, 85))	('IR700', 'Chemical', '-', (30, 35))	('NIR-PIT', 'Chemical', '-', (9, 16))	('H2373-luc', 'Var', (80, 89))	('SCLC', 'Disease', (70, 74))
89563	33993055	These cellular changes were observed within 30 min after NIR-light irradiation, suggesting that necrotic cell death was rapidly induced by NIR-PIT.	('NIR-PIT', 'Var', (139, 146))	('necrotic cell death', 'Disease', 'MESH:D003643', (96, 115))	('necrotic cell death', 'biological_process', 'GO:0070265', ('96', '115'))	('necrotic cell death', 'Disease', (96, 115))	('NIR-PIT', 'Chemical', '-', (139, 146))
89564	33993055	Next, to quantify the effect of NIR-PIT in vitro, we performed a cytotoxicity assay after 24 h using luciferase activity quantitation with PC9-luc, SBC5, and H2373-luc.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('H2373', 'CellLine', 'CVCL:A533', (158, 163))	('luciferase', 'Enzyme', (101, 111))	('luciferase activity', 'molecular_function', 'GO:0047077', ('101', '120'))	('PC9', 'CellLine', 'CVCL:B260', (139, 142))	('H2373-luc', 'Var', (158, 167))	('NIR-PIT', 'Chemical', '-', (32, 39))	('luciferase activity', 'molecular_function', 'GO:0045289', ('101', '120'))	('cytotoxicity', 'Disease', (65, 77))	('luciferase activity', 'molecular_function', 'GO:0047712', ('101', '120'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('101', '120'))	('activity', 'MPA', (112, 120))	('luciferase activity', 'molecular_function', 'GO:0050248', ('101', '120'))
89568	33993055	After 200 microg of GPR87hu-IR700 injection, high fluorescence was observed across the whole mouse body; the tumour was then gradually visualised over the subsequent 1 h (Fig.	('GPR87hu-IR700', 'Var', (20, 33))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('mouse', 'Species', '10090', (93, 98))	('tumour', 'Disease', (109, 115))	('fluorescence', 'MPA', (50, 62))	('IR700', 'Chemical', '-', (28, 33))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
89573	33993055	These results indicated that huGPR87ab-IR700 is distributed specifically in GPR87-expressing tumours.	('huGPR87ab', 'Chemical', '-', (29, 38))	('tumours', 'Disease', (93, 100))	('IR700', 'Chemical', '-', (39, 44))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('huGPR87ab-IR700', 'Var', (29, 44))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
89580	33993055	In summary, GPR87-targeted NIR-PIT with huGPR87ab-IR700 was effective against the flank tumour and successfully achieved site-specific tumour ablation.	('huGPR87ab-IR700', 'Var', (40, 55))	('tumour ablation', 'Disease', 'MESH:D009369', (135, 150))	('NIR-PIT', 'Chemical', '-', (27, 34))	('huGPR87ab', 'Chemical', '-', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour ablation', 'Disease', (135, 150))	('flank tumour', 'Disease', 'MESH:D021501', (82, 94))	('IR700', 'Chemical', '-', (50, 55))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('flank tumour', 'Disease', (82, 94))
89588	33993055	The rate of EGFR mutation, the most common mutation in lung cancer, is 10-40%, and it is rare in NSLSCC.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('mutation', 'Var', (17, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('lung cancer', 'Disease', (55, 66))	('EGFR', 'Gene', '13649', (12, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('EGFR', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
89593	33993055	Clinical experience shows that the murine variable region of the chimeric mAb induces HAMA and produces humanised antibodies.	('HAMA', 'MPA', (86, 90))	('induces', 'Reg', (78, 85))	('human', 'Species', '9606', (104, 109))	('humanised antibodies', 'MPA', (104, 124))	('chimeric', 'Var', (65, 73))	('murine', 'Species', '10090', (35, 41))
89610	33993055	This indicates that NIR-PIT may cause damage to organs.	('NIR-PIT', 'Chemical', '-', (20, 27))	('NIR-PIT', 'Var', (20, 27))	('damage', 'CPA', (38, 44))	('cause', 'Reg', (32, 37))
89616	33993055	Patients with high GPR87 expression are expected to be treated with GPR87ab-IR700 followed by NIR irradiation from the body surface or transendoscopically or transdrainally using a fiber light source.	('GPR87ab-IR700', 'Var', (68, 81))	('high GPR87 expression', 'Var', (14, 35))	('IR700', 'Chemical', '-', (76, 81))	('Patients', 'Species', '9606', (0, 8))
89618	33993055	In conclusion, the present study demonstrated the frequently expressed high levels of GPR87 in lung cancer and MPM.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('GPR87', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('MPM', 'Disease', (111, 114))
89684	22826778	To our knowledge, liver metastasis from PMPM has never been reported in literature previously.	('liver metastasis', 'Disease', 'MESH:D009362', (18, 34))	('PMPM', 'Var', (40, 44))	('liver metastasis', 'Disease', (18, 34))
89758	26719804	In a chest X-ray study on lung cancer in the Wittenoom cohort, Klerk et al demonstrated an increase in the relative risk (RR) with increasing cumulative exposure to asbestos, in the absence of radiographic asbestosis; the presence of asbestosis conferred an additional risk, but with a less steep slope for the dose-response line.	('asbestos', 'Chemical', 'MESH:D001194', (206, 214))	('asbestos', 'Chemical', 'MESH:D001194', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('asbestosis', 'Disease', 'MESH:D001195', (206, 216))	('asbestosis', 'Disease', 'MESH:D001195', (234, 244))	('asbestosis', 'Disease', (206, 216))	('presence', 'Var', (222, 230))	('lung cancer', 'Disease', (26, 37))	('asbestos', 'Chemical', 'MESH:D001194', (165, 173))	('asbestosis', 'Disease', (234, 244))
89873	33643607	A 72-year-old man was diagnosed with stage IV (cT4N0M0) epithelioid MPM with diffuse invasion of soft tissues of the right chest wall, according to the criteria of International Mesothelioma Interest Group, by computed tomography (CT), positron emission tomography (PET)-CT, and pleural biopsy 18 months ago.	('cT4N0M0', 'Var', (47, 54))	('MPM', 'Chemical', '-', (68, 71))	('Mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('epithelioid MPM', 'Disease', (56, 71))	('Mesothelioma', 'Disease', (178, 190))
90023	28558669	Regarding the detection in prediagnostic serum samples, transcript variants of the protein ENOX2 give hope that a detection of MM before onset of clinical symptoms may be feasible.	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('ENOX2', 'Gene', (91, 96))	('ENOX2', 'Gene', '10495', (91, 96))	('transcript variants', 'Var', (56, 75))
90025	28558669	For mesothelin it has been shown that single nucleotide polymorphisms (SNPs) can affect biomarker levels.	('single nucleotide polymorphisms', 'Var', (38, 69))	('mesothelin', 'Gene', '10232', (4, 14))	('affect', 'Reg', (81, 87))	('mesothelin', 'Gene', (4, 14))	('biomarker levels', 'MPA', (88, 104))
90043	28558669	AUC Area Under the Curve CI Confidence Interval FPR False Positive Rate IQR Interquartile Range LOD Limit Of Detection MM Malignant Mesothelioma; OD Optical Density OR Odds Ratio ROC Receiver Operating Characteristic SNPs Single Nucleotide Polymorphisms	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (122, 144))	('LOD', 'molecular_function', 'GO:0033736', ('96', '99'))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (122, 144))	('Single Nucleotide Polymorphisms', 'Var', (222, 253))	('Malignant Mesothelioma', 'Disease', (122, 144))
90046	21294125	Forty-one mesothelioma tumor tissues, 10 normal human pleural tissues and 2 mesothelioma cell lines were stained with anti-CXCR4, anti-CXCL12, anti-CXCR7 and anti-p-Akt antibodies.	('CXCR4', 'molecular_function', 'GO:0038147', ('123', '128'))	('mesothelioma tumor', 'Disease', (10, 28))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (10, 28))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (10, 28))	('mesothelioma', 'Disease', (10, 22))	('human', 'Species', '9606', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mesothelioma', 'Disease', (76, 88))	('Akt', 'Gene', '207', (165, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (10, 22))	('CXCR7', 'molecular_function', 'GO:0038147', ('148', '153'))	('anti-CXCR4', 'Var', (118, 128))	('Akt', 'Gene', (165, 168))	('anti-CXCL12', 'Var', (130, 141))
90047	21294125	RT-PCR was performed to determine the expression of CXCR4, CXCL12 and CXCR7 in 6 human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, and H513) and 1 human normal mesothelial cell line LP9.	('H290', 'CellLine', 'CVCL:A555', (136, 140))	('CXCR4', 'molecular_function', 'GO:0038147', ('52', '57'))	('human', 'Species', '9606', (158, 163))	('mesothelioma', 'Disease', (87, 99))	('H513', 'CellLine', 'CVCL:A570', (146, 150))	('CXCR7', 'molecular_function', 'GO:0038147', ('70', '75'))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('H2052', 'Var', (123, 128))	('human', 'Species', '9606', (81, 86))
90050	21294125	Furthermore, RT-PCR showed that CXCR4 and CXCL12 were over-expressed in 5/6 mesothelioma cell lines (211H, H2052, ms-1, H290, and H513), whereas CXCR7 was over-expressed in only 2/6 (H513 and H2052).	('H2052', 'Var', (107, 112))	('H513', 'CellLine', 'CVCL:A570', (130, 134))	('CXCR4', 'molecular_function', 'GO:0038147', ('32', '37'))	('CXCR4', 'MPA', (32, 37))	('H513', 'CellLine', 'CVCL:A570', (183, 187))	('mesothelioma', 'Disease', (76, 88))	('CXCL12', 'MPA', (42, 48))	('over-expressed', 'PosReg', (54, 68))	('CXCR7', 'molecular_function', 'GO:0038147', ('145', '150'))	('H290', 'CellLine', 'CVCL:A555', (120, 124))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
90064	21294125	In colorectal cancer, CXCR4 is significantly associated with advanced tumors and with lymphatic or distant metastasis, and high expression of CXCR4 is reportedly a strong and independent predictor of early distant relapse.	('CXCR4', 'MPA', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('lymphatic or distant metastasis', 'CPA', (86, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('high', 'Var', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('associated', 'Reg', (45, 55))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', (3, 20))	('CXCR4', 'molecular_function', 'GO:0038147', ('22', '27'))	('CXCR4', 'molecular_function', 'GO:0038147', ('142', '147'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
90069	21294125	In addition, recent data suggest that CXCR7 has key functions in promoting tumor development and progression.	('promoting', 'PosReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CXCR7', 'Var', (38, 43))	('progression', 'CPA', (97, 108))	('CXCR7', 'molecular_function', 'GO:0038147', ('38', '43'))	('tumor', 'Disease', (75, 80))
90078	21294125	The mesothelioma cell lines were maintained in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated FBS, penicillin (100IU/ml) and streptomycin (100microg/ml).	('FBS', 'Disease', 'MESH:D005198', (109, 112))	('mesothelioma', 'Disease', (4, 16))	('RPMI 1640 medium', 'Chemical', '-', (47, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('100IU/ml', 'Var', (126, 134))	('FBS', 'Disease', (109, 112))	('streptomycin', 'Chemical', 'MESH:D013307', (140, 152))	('penicillin', 'Chemical', 'MESH:D010406', (114, 124))
90127	21294125	CXCL12 was over-expressed in H2052, ms-1, 211H, H513 and H290, but was weakly expressed in LP9 and was not detectable in H28.	('H2052', 'Var', (29, 34))	('over-expressed', 'PosReg', (11, 25))	('H290', 'CellLine', 'CVCL:A555', (57, 61))	('H513', 'CellLine', 'CVCL:A570', (48, 52))
90128	21294125	CXCR7 was expressed in H2052 and H513, but only minimally expressed in H28, 211H, H290 and LP9, and was not detectable in ms-1.	('H290', 'CellLine', 'CVCL:A555', (82, 86))	('CXCR7', 'molecular_function', 'GO:0038147', ('0', '5'))	('H2052', 'Var', (23, 28))	('H513', 'CellLine', 'CVCL:A570', (33, 37))	('H513', 'Var', (33, 37))
90132	21294125	The dose response curve indicated that the higher dose of AMD3100, the lower the viability of mesothelioma, and the IC50 values show that the inhibiting effects differed among the mesothelioma cell lines (Table 4).	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('AMD3100', 'Var', (58, 65))	('mesothelioma', 'Disease', (180, 192))	('mesothelioma', 'Disease', (94, 106))	('lower', 'NegReg', (71, 76))
90139	21294125	We found that CXCR4 is over-expressed in most of the human mesothelioma samples tested, and that it is expressed at low levels in most normal pleural tissue.	('mesothelioma', 'Disease', (59, 71))	('CXCR4', 'Var', (14, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('human', 'Species', '9606', (53, 58))	('over-expressed', 'PosReg', (23, 37))	('CXCR4', 'molecular_function', 'GO:0038147', ('14', '19'))
90145	21294125	In these patients, inactivation of the VHL tumor suppressor gene in incipient tumor cells results in over-expression of CXCR4, which confers a selective survival advantage and the tendency to home to selected organs.	('patients', 'Species', '9606', (9, 17))	('VHL tumor', 'Disease', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('CXCR4', 'MPA', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CXCR4', 'molecular_function', 'GO:0038147', ('120', '125'))	('tumor', 'Disease', (78, 83))	('VHL tumor', 'Disease', 'MESH:D006623', (39, 48))	('survival advantage', 'CPA', (153, 171))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('over-expression', 'PosReg', (101, 116))	('inactivation', 'Var', (19, 31))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))
90149	21294125	In breast cancer cells, CXCR7 activation fails to cause Ca2+ mobilization or cell migration, but provides a growth advantage, whereas in prostate cancer cells, CXCR7 expression is associated with enhanced adhesive and invasive activities in addition to increased survival.	('enhanced', 'PosReg', (196, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('CXCR7', 'molecular_function', 'GO:0038147', ('160', '165'))	('CXCR7 expression', 'Var', (160, 176))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('invasive activities', 'CPA', (218, 237))	('breast cancer', 'Disease', (3, 16))	('Ca2+', 'Chemical', 'MESH:D000069285', (56, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('increased', 'PosReg', (253, 262))	('prostate cancer', 'Disease', (137, 152))	('cell migration', 'biological_process', 'GO:0016477', ('77', '91'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CXCR7', 'molecular_function', 'GO:0038147', ('24', '29'))	('growth', 'MPA', (108, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))
90152	21294125	Our finding that CXCR4 and CXCL12 were both highly expressed in five (H2052, ms -1, 211H, H513 and H290) of the six mesothelioma cell lines studied, whereas CXCR7 was expressed in only two (H2052 and H513) and minimally expressed in another three (H28, 211H and H290), suggests that the expression of chemokines and their receptors varies in mesothelioma cells.	('H2052', 'Var', (70, 75))	('H290', 'CellLine', 'CVCL:A555', (99, 103))	('mesothelioma', 'Disease', (116, 128))	('CXCR4', 'molecular_function', 'GO:0038147', ('17', '22'))	('CXCR4', 'Var', (17, 22))	('mesothelioma', 'Disease', 'MESH:D008654', (342, 354))	('CXCR7', 'molecular_function', 'GO:0038147', ('157', '162'))	('H290', 'CellLine', 'CVCL:A555', (262, 266))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('H513', 'CellLine', 'CVCL:A570', (90, 94))	('H513', 'CellLine', 'CVCL:A570', (200, 204))	('mesothelioma', 'Disease', (342, 354))
90153	21294125	Interestingly, the two mesothelioma cell lines that express CXCR7 also showed the highest expression level of CXCR4 among all mesothelioma cell lines tested.	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('mesothelioma', 'Disease', (126, 138))	('CXCR7', 'Var', (60, 65))	('CXCR4', 'molecular_function', 'GO:0038147', ('110', '115'))	('expression level of CXCR4', 'MPA', (90, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('mesothelioma', 'Disease', (23, 35))	('CXCR7', 'molecular_function', 'GO:0038147', ('60', '65'))
90159	21294125	Our results suggest that CXCL12 can induce proliferation in most mesothelioma cell lines.	('CXCL12', 'Var', (25, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('proliferation', 'CPA', (43, 56))	('mesothelioma', 'Disease', (65, 77))
90161	21294125	These results suggest that the CXCL12/CXCR4 axis is important for most mesothelioma cells and that blocking it impairs their viability.	('mesothelioma', 'Disease', (71, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('blocking', 'Var', (99, 107))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('viability', 'CPA', (125, 134))	('impairs', 'NegReg', (111, 118))
90172	21294125	Phosphorylation of 4E-BP1 regulates cap-dependent translation by enabling the formation of an active eIF4E complex.	('translation', 'biological_process', 'GO:0006412', ('50', '61'))	('4E-BP1', 'Gene', '1978', (19, 25))	('regulates', 'Reg', (26, 35))	('eIF4E', 'Gene', (101, 106))	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('enabling', 'PosReg', (65, 73))	('Phosphorylation', 'Var', (0, 15))	('cap-dependent translation', 'MPA', (36, 61))	('4E-BP1', 'Gene', (19, 25))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('eIF4', 'cellular_component', 'GO:0008304', ('101', '105'))	('eIF4E', 'Gene', '1977', (101, 106))	('formation', 'MPA', (78, 87))
90277	21255833	It can be seen from the image taken 24 h post injection that the 111In-IL-M1(50) showed marked uptake into both M28 and VAMT-1 mesothelioma tumors.	('uptake', 'biological_process', 'GO:0098739', ('95', '101'))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('111In', 'Chemical', 'MESH:C000615551', (65, 70))	('111In-IL-M1', 'Var', (65, 76))	('uptake', 'MPA', (95, 101))	('VAMT-1 mesothelioma tumors', 'Disease', (120, 146))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (127, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (127, 145))	('VAMT-1 mesothelioma tumors', 'Disease', 'MESH:D008654', (120, 146))	('uptake', 'biological_process', 'GO:0098657', ('95', '101'))
90279	21255833	It can seen from the Table 3 and Figure 6 and 7 that 111In-IL-M1(50) was cleared from most normal organs (except the liver and the spleen), giving M28 and VAMT-1 tumors to blood ratios of 31:1 and 36:1 and tumor to muscle ratios of 47:1, 55:1 respectively at 48 h after injection.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (162, 167))	('VAMT-1 tumors', 'Disease', 'MESH:D009369', (155, 168))	('VAMT-1 tumors', 'Disease', (155, 168))	('M28', 'Var', (147, 150))	('111In', 'Chemical', 'MESH:C000615551', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
90280	21255833	More importantly, at 48 h after injection there was markedly high and almost comparable tumor uptake of 4.01+-0.39 and 4.69+-0.72 % ID/g of tissue for M28 and VAMT-1 tumors respectively, which were much higher than all organs/tissues studied (except the liver 7.97+-0.34) (Table 3 and Figure 6).	('VAMT-1 tumors', 'Disease', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('VAMT-1 tumors', 'Disease', 'MESH:D009369', (159, 172))	('higher', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('uptake', 'biological_process', 'GO:0098657', ('94', '100'))	('uptake', 'biological_process', 'GO:0098739', ('94', '100'))	('M28', 'Var', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (88, 93))
90287	21255833	For the IL preparation, we used a method of first conjugating the scFv at the distal end of PEG2000 chains (before insertion onto the surface of liposomes) instead of direct labeling of the scFv onto the liposomes (Figure 1), based on favorable results reported earlier.	('scFv', 'Gene', (66, 70))	('scFv', 'Gene', '652070', (66, 70))	('PEG2000', 'Chemical', '-', (92, 99))	('scFv', 'Gene', '652070', (190, 194))	('scFv', 'Gene', (190, 194))	('PEG2000 chains', 'Var', (92, 106))
90297	21255833	Although the findings from the in vitro cell studies using 111In-IL-M1(50) are very encouraging, it is essential to test the ILs in vivo on animal tumor models for successful translation into clinics.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('translation', 'biological_process', 'GO:0006412', ('175', '186'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('111In', 'Chemical', 'MESH:C000615551', (59, 64))	('111In-IL-M1', 'Var', (59, 70))
90300	21255833	From the Figures 6 and 7, it can be noted that for the time frame from 24 h to 48 h the clearance of the 111In-IL-M1(50) from most of the non-target organs and tissues occurred rapidly whereas the tumor uptake remained high, even at 48 h time point.	('clearance', 'MPA', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('uptake', 'biological_process', 'GO:0098739', ('203', '209'))	('uptake', 'biological_process', 'GO:0098657', ('203', '209'))	('111In-IL-M1', 'Var', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('111In', 'Chemical', 'MESH:C000615551', (105, 110))	('tumor', 'Disease', (197, 202))
90301	21255833	This result may be attributed to the efficient binding and rapid internalization of the 111In-IL-M1(50) into the tumor cells.	('tumor', 'Disease', (113, 118))	('internalization', 'MPA', (65, 80))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('111In', 'Chemical', 'MESH:C000615551', (88, 93))	('111In-IL-M1', 'Var', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('binding', 'Interaction', (47, 54))
90302	21255833	It should be noted that we intentionally used a low % of PEG in our liposome formulations in order distinguish the internalizing property and the 'active tumor targeting' ability of the 111In-IL-M150 in comparison to the 111In-CL.	('111In-CL', 'Chemical', '-', (221, 229))	('internalizing property', 'MPA', (115, 137))	('111In', 'Chemical', 'MESH:C000615551', (221, 226))	('111In', 'Chemical', 'MESH:C000615551', (186, 191))	('111In-IL-M150', 'Var', (186, 199))	('PEG', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PEG', 'Gene', '5047', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
90303	21255833	From our results it is clear that the 111In-IL-M1(50) showed much higher tumor targeted uptake in comparison to 111In-CL (Figure 5, 6 and 7, Table 3).	('111In', 'Chemical', 'MESH:C000615551', (38, 43))	('uptake', 'biological_process', 'GO:0098739', ('88', '94'))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('111In-CL', 'Chemical', '-', (112, 120))	('tumor', 'Disease', (73, 78))	('higher', 'PosReg', (66, 72))	('111In', 'Chemical', 'MESH:C000615551', (112, 117))	('111In-IL-M1', 'Var', (38, 49))	('uptake', 'biological_process', 'GO:0098657', ('88', '94'))
90304	21255833	It can also be observed that the lower % PEGylation of 111In-IL-M1(50) may have attributed at least in part for their faster clearance from the blood as early as 24 h (Figure 6), thus providing a good contrast for early tumor imaging by SPECT/CT (Figure 5).	('111In-IL-M1', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('111In', 'Chemical', 'MESH:C000615551', (55, 60))	('faster', 'PosReg', (118, 124))	('PEG', 'Gene', (41, 44))	('clearance', 'MPA', (125, 134))	('PEG', 'Gene', '5047', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
90311	33543019	However, in murine models, the depletion of fibroblasts, the main ExtraCellular Matrix (ECM)-producing cells, led to more aggressive tumors even though they were more susceptible to anti-angiogenic and immuno-modulators.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('murine', 'Species', '10090', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ExtraCellular Matrix', 'cellular_component', 'GO:0031012', ('66', '86'))	('aggressive tumors', 'Disease', 'MESH:D001523', (122, 139))	('depletion', 'Var', (31, 40))	('aggressive tumors', 'Disease', (122, 139))	('more', 'PosReg', (117, 121))
90317	33543019	We thus demonstrated that, in most cancers, TNX expression is significantly downregulated during cancer progression and we also highlighted, when data were available, that high TNXB mRNA expression in cancer is correlated with a good survival prognosis.	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (97, 103))	('expression', 'MPA', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('TNX', 'Gene', '7148', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('TNXB', 'Gene', '7148', (177, 181))	('TNX', 'Gene', (44, 47))	('mRNA expression', 'MPA', (182, 197))	('TNX', 'Gene', '7148', (177, 180))	('high', 'Var', (172, 176))	('TNXB', 'Gene', (177, 181))	('TNX', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('downregulated', 'NegReg', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
90318	33543019	Tumor development is a multi-step process initially involving (1) chronic inflammation and viral and bacterial infections and/or (2) the genetic alteration of critical genes thus allowing the selection of the malignant cells with the highest proliferative potential.	('bacterial infections', 'Disease', 'MESH:D001424', (101, 121))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('genetic alteration', 'Var', (137, 155))	('bacterial infections', 'Disease', (101, 121))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('bacterial infections', 'Phenotype', 'HP:0002718', (101, 121))	('allowing', 'Reg', (179, 187))	('inflammation', 'biological_process', 'GO:0006954', ('74', '86'))
90352	33543019	Collectively, our results demonstrated (1) TNX is downregulated in most cancers, except gliomas, and (2) high TNXB mRNA expression in tumoral samples is correlated with a good survival prognosis in the 2 cancers with the highest incidence and mortality worldwide, i.e.	('tumoral', 'Disease', (134, 141))	('tumoral', 'Disease', 'MESH:D009369', (134, 141))	('mortality', 'Disease', (243, 252))	('TNX', 'Gene', '7148', (110, 113))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TNX', 'Gene', (110, 113))	('cancers', 'Disease', (72, 79))	('mRNA expression', 'MPA', (115, 130))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mortality', 'Disease', 'MESH:D003643', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('gliomas', 'Disease', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('TNXB', 'Gene', '7148', (110, 114))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('TNX', 'Gene', '7148', (43, 46))	('high', 'Var', (105, 109))	('TNX', 'Gene', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('TNXB', 'Gene', (110, 114))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('downregulated', 'NegReg', (50, 63))
90404	33543019	Altogether, these data clearly demonstrated that TNXB expression is correlated with tumor progression and that high level of TNXB mRNA is a good survival marker in carcinomas and could thus be used as a novel survival prognosis marker.	('carcinomas', 'Disease', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('high level', 'Var', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TNXB', 'Gene', '7148', (125, 129))	('mRNA', 'MPA', (130, 134))	('TNXB', 'Gene', (49, 53))	('tumor', 'Disease', (84, 89))	('TNXB', 'Gene', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Disease', 'MESH:D009369', (164, 174))	('TNXB', 'Gene', '7148', (49, 53))	('correlated', 'Reg', (68, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
90411	33543019	Our results are reinforced by the data recently published by Chakravarthy et al., in which they examined TCGA database and analyzed the pan-cancer landscape of ECM gene dysregulation in 8043 malignant tissues from 15 different tumor types and 704 corresponding normal tissues.	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('ECM gene', 'Gene', (160, 168))	('dysregulation', 'Var', (169, 182))
90454	33543019	This promoter was shown to be activated by hypoxia and subsequent histone deacetylase 1 (HDAC1) dissociation from Sp1/HDAC1 complex resulting in a transcript encoding an N-terminally truncated and shorter TNXB (TNXB-S) protein with cytoplasmic localization.	('HDAC1', 'Gene', (118, 123))	('TNXB', 'Gene', '7148', (211, 215))	('dissociation', 'Var', (96, 108))	('histone deacetylase 1', 'Gene', (66, 87))	('HDAC1', 'Gene', (89, 94))	('hypoxia', 'Disease', (43, 50))	('TNXB-S', 'Gene', '7148', (211, 217))	('HDAC1', 'Gene', '3065', (118, 123))	('hypoxia', 'Disease', 'MESH:D000860', (43, 50))	('histone deacetylase 1', 'Gene', '3065', (66, 87))	('localization', 'biological_process', 'GO:0051179', ('244', '256'))	('TNXB', 'Gene', (205, 209))	('TNXB', 'Gene', (211, 215))	('TNXB-S', 'Gene', (211, 217))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('HDAC1', 'Gene', '3065', (89, 94))	('TNXB', 'Gene', '7148', (205, 209))
90458	33543019	By analyzing the GEO datasets used for TNXB mRNA expression (GSE31210 for lung cancer and GSE37751 for breast cancer), we demonstrated that HDAC1 mRNA expression was significantly upregulated in lung (Fc = 0.401; p = 1.30 10-4) and breast (Fc = 0.457; p = 4.90 10-6) carcinomas compared to non-tumoral tissues.	('tumoral', 'Disease', (294, 301))	('tumoral', 'Disease', 'MESH:D009369', (294, 301))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('breast cancer', 'Disease', (103, 116))	('carcinomas', 'Disease', (267, 277))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('mRNA expression', 'MPA', (146, 161))	('upregulated', 'PosReg', (180, 191))	('GSE31210', 'Var', (61, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('HDAC1', 'Gene', (140, 145))	('GSE37751', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carcinomas', 'Disease', 'MESH:D009369', (267, 277))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('breast', 'Disease', (232, 238))	('HDAC1', 'Gene', '3065', (140, 145))	('lung', 'Disease', (195, 199))	('lung cancer', 'Disease', (74, 85))	('TNXB', 'Gene', '7148', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('TNXB', 'Gene', (39, 43))
90467	33543019	These results thus suggest that high TNXB expression could limit metastasis formation and thus could be a good prognosis factor during cancer progression.	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('high', 'Var', (32, 36))	('TNXB', 'Gene', (37, 41))	('cancer', 'Disease', (135, 141))	('TNXB', 'Gene', '7148', (37, 41))	('expression', 'MPA', (42, 52))	('limit', 'NegReg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('metastasis formation', 'CPA', (65, 85))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
90468	33543019	Indeed, in our study, we observed that high TNXB expression is correlated with a good survival rate in breast and lung carcinomas.	('high', 'Var', (39, 43))	('TNXB', 'Gene', (44, 48))	('TNXB', 'Gene', '7148', (44, 48))	('expression', 'MPA', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (103, 129))
90480	33543019	Briefly, after deparaffinization and rehydration, epitopes retrieval step was performed in sodium citrate buffer pH 6 for 20 min at 98  C. Endogenous peroxidases were then quenched by 3% H2O2 (v/v) in phosphate Buffered Saline (PBS) and non-specific sites were blocked with 2.5% (v/v) normal horse serum in Tris-buffered saline (TBS).	('sodium citrate', 'Chemical', 'MESH:D000077559', (91, 105))	('PBS', 'Chemical', '-', (228, 231))	('H2O2', 'Chemical', 'MESH:D006861', (187, 191))	('H2O2', 'Var', (187, 191))	('TBS', 'Chemical', '-', (329, 332))	('Tris-buffered saline', 'Chemical', '-', (307, 327))	('quenched', 'NegReg', (172, 180))	('phosphate Buffered Saline', 'Chemical', '-', (201, 226))
90484	33543019	TNX labelling was first assessed on human skin sections with different antibodies (sc-271594 (1/100) from Santa Cruz, AF6999 (1/100) from R&D Systems and two home-made antibodies provided by Joost SCHALKWIJK (1/100) and Manuel KOCH (1/1000)) (Supplementary Fig.	('TNX', 'Gene', '7148', (0, 3))	('sc-271594', 'Var', (83, 92))	('TNX', 'Gene', (0, 3))	('ALK', 'Gene', '238', (200, 203))	('human', 'Species', '9606', (36, 41))	('ALK', 'Gene', (200, 203))
90535	32849853	From the univariate analysis of GSE2549 dataset in Table 1, we observed that patients with mixed histological subtype, lymph node positive or high risk score were more likely to have shorter survival time and worse prognosis compared to patients with epithelial subtype, lymph node negative or low-risk score.	('high risk score', 'Var', (142, 157))	('shorter', 'NegReg', (183, 190))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (237, 245))	('lymph node positive', 'Var', (119, 138))	('survival time', 'CPA', (191, 204))
90558	32849853	reported a proliferation inhibitory effect in MPM cell lines with GSK269962A, a selective inhibitor of Rho-Kinase.	('proliferation', 'CPA', (11, 24))	('inhibitory', 'NegReg', (25, 35))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('GSK269962A', 'Var', (66, 76))	('GSK269962A', 'Chemical', 'MESH:C516969', (66, 76))
90560	32849853	Dysfunction of this checkpoint contributes to tumorigenesis.	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Dysfunction', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
90565	32849853	The inhibitory effect on cell proliferation following treatment with the PLK1 small inhibitors BI6727, and BI2539 or the PLK1-specific siRNA and artificial microRNA, have been validated in multiple MPM cell lines.	('PLK1', 'Gene', (121, 125))	('BI2539', 'Chemical', '-', (107, 113))	('BI2539', 'Var', (107, 113))	('PLK1', 'Gene', '5347', (73, 77))	('PLK1', 'Gene', '5347', (121, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('cell proliferation', 'CPA', (25, 43))	('BI6727', 'Var', (95, 101))	('PLK1', 'Gene', (73, 77))
90583	32849853	High levels of KIF18B were associated with poor prognosis in lung adenocarcinoma patients.	('KIF18B', 'Gene', (15, 21))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('High levels', 'Var', (0, 11))	('patients', 'Species', '9606', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung adenocarcinoma', 'Disease', (61, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('KIF18B', 'Gene', '146909', (15, 21))
90584	32849853	Our analysis showed the high expression of KIF18B was significantly associated with poor prognosis of MPM patients (Supplementary Figures 4D, 5D).	('associated', 'Reg', (68, 78))	('MPM', 'Disease', (102, 105))	('patients', 'Species', '9606', (106, 114))	('high', 'Var', (24, 28))	('KIF18B', 'Gene', '146909', (43, 49))	('KIF18B', 'Gene', (43, 49))
90598	32234848	We separately profiled PD1+ and PD1-CD4+ and CD8+ T cells, as well as Tregs and analyzed 70 000 TCRbeta sequences per patient.	('PD1-CD4+', 'Var', (32, 40))	('patient', 'Species', '9606', (118, 125))	('CD8', 'Gene', '925', (45, 48))	('CD8', 'Gene', (45, 48))
90621	32234848	Furthermore, the frequency of HLA-DR, PD1 and inducible T-cell costimulator (ICOS)-expressing CD4+ T cells and LAG3-expressing CD8+ T cells increased after DC vaccination.	('CD8', 'Gene', (127, 130))	('CD8', 'Gene', '925', (127, 130))	('inducible T-cell costimulator', 'Gene', (46, 75))	('inducible T-cell costimulator', 'Gene', '733597', (46, 75))	('PD1', 'Var', (38, 41))	('LAG3', 'Gene', '100125962', (111, 115))	('LAG3', 'Gene', (111, 115))	('increased', 'PosReg', (140, 149))
90630	32234848	The PD1- and PD1+CD8+ T cell fractions showed the largest degree of clonal expansion, given their highest average clone size, both pre-therapy and post-therapy (figure 1A).	('PD1-', 'Var', (4, 8))	('CD8', 'Gene', (17, 20))	('pre', 'molecular_function', 'GO:0003904', ('131', '134'))	('CD8', 'Gene', '925', (17, 20))
90632	32234848	The HECs accounted for 46.2% (+-12.8%) and 49.7% (+-9.2%) of the total repertoire in PD1- and PD1+CD8+ T cells, respectively, and was in the range of 2.7%-16.2% for the CD4+ T cell and Treg fractions (figure 1C).	('PD1-', 'Var', (85, 89))	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', '925', (98, 101))
90640	32234848	Decreasing TCRbeta clones were mainly retrieved in the PD1+CD4+ and PD1+CD8+ T cell fractions (figure 3D).	('PD1+CD4+', 'Var', (55, 63))	('CD8', 'Gene', (72, 75))	('CD8', 'Gene', '925', (72, 75))
90649	32234848	Numbers of expanding PD1+CD8+ T cells clones correlate with clinical response to DC-therapy Because DC-therapy mainly affected the TCRbeta repertoires of PD1+CD4+, PD1+CD8+ and Treg cell fractions, we investigated the characteristics of these subpopulations in more detail.	('CD8', 'Gene', (25, 28))	('CD8', 'Gene', (168, 171))	('CD8', 'Gene', '925', (168, 171))	('TCRbeta', 'Gene', (131, 138))	('CD8', 'Gene', '925', (25, 28))	('affected', 'Reg', (118, 126))	('PD1+CD4+', 'Var', (154, 162))
90652	32234848	The numbers of expanding clones did not differ significantly between PD1+CD4+ T cells, PD1+CD8+ T cells and Tregs (see online supplementary figure S6A).	('CD8', 'Gene', (91, 94))	('CD8', 'Gene', '925', (91, 94))	('PD1+CD4+ T', 'Var', (69, 79))
90662	32234848	We analyzed total CD3+ T cells and five fluorescence-activated cell sorting (FACS)-sorted subpopulations: PD1- and PD1+CD4+ and CD8+ T cells and CD25+CD127low Tregs.	('PD1-', 'Var', (106, 110))	('PD1+CD4+', 'Var', (115, 123))	('CD8', 'Gene', (128, 131))	('CD8', 'Gene', '925', (128, 131))	('CD25', 'Gene', '396814', (145, 149))	('CD25', 'Gene', (145, 149))
90759	29599911	Interestingly, the proportion of CD44+/CD26+ cells was significantly increased by X-ray combined with cisplatin when compared to the combination of carbon ion beams and cisplatin combination or cisplatin alone.	('increased', 'PosReg', (69, 78))	('CD26', 'Gene', '1803', (39, 43))	('CD44', 'Gene', (33, 37))	('cisplatin', 'Var', (102, 111))	('CD26', 'Gene', (39, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('carbon', 'Chemical', 'MESH:D002244', (148, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('X-ray', 'Var', (82, 87))	('CD44', 'Gene', '960', (33, 37))
90766	29599911	Cisplatin, a typical DNA damaging drug has been reported to work as a radiosensitizer by inducing apoptosis and autophagy in MM cells.	('apoptosis', 'CPA', (98, 107))	('autophagy', 'biological_process', 'GO:0016236', ('112', '121'))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('Cisplatin', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('autophagy', 'biological_process', 'GO:0006914', ('112', '121'))	('autophagy', 'CPA', (112, 121))	('inducing', 'PosReg', (89, 97))
90768	29599911	This finding indicates that cisplatin enhances CSC killing effect of carbon ion irradiation when used together.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('carbon', 'Chemical', 'MESH:D002244', (69, 75))	('cisplatin', 'Var', (28, 37))	('CSC killing effect', 'CPA', (47, 65))	('enhances', 'PosReg', (38, 46))
90827	27000958	Both persistence and expansion of CAR T cells are often used to compare second-generation CARs containing a CD28 signalling domain and 4-1BB signalling domain.	('signalling', 'biological_process', 'GO:0023052', ('113', '123'))	('CD28 signalling domain', 'Var', (108, 130))	('4-1BB', 'Gene', '3604', (135, 140))	('signalling', 'biological_process', 'GO:0023052', ('141', '151'))	('CAR', 'cellular_component', 'GO:0005826', ('34', '37'))	('4-1BB', 'Gene', (135, 140))
90831	27000958	The co-stimulatory signalling moieties used in third-generation CARs include CD28, 4-1BB, or OX40 (CD134).	('CD134', 'Gene', (99, 104))	('OX40', 'Gene', '7293', (93, 97))	('4-1BB', 'Gene', (83, 88))	('CD134', 'Gene', '7293', (99, 104))	('OX40', 'Gene', (93, 97))	('signalling', 'biological_process', 'GO:0023052', ('19', '29'))	('4-1BB', 'Gene', '3604', (83, 88))	('CD28', 'Var', (77, 81))
90868	27000958	An ongoing trial at UPenn will investigate CD19-specific CAR T cells for the treatment of multiple myeloma (MM), using the rationale that CD19 is expressed in a minor subclonal population of MM cells (NCT02135406).	('CD19', 'Gene', '930', (138, 142))	('multiple myeloma', 'Phenotype', 'HP:0006775', (90, 106))	('multiple myeloma', 'Disease', 'MESH:D009101', (90, 106))	('multiple myeloma', 'Disease', (90, 106))	('CD19', 'Gene', (43, 47))	('NCT02135406', 'Var', (201, 212))	('CD19', 'Gene', '930', (43, 47))	('CD19', 'Gene', (138, 142))	('CAR', 'cellular_component', 'GO:0005826', ('57', '60'))
90899	27000958	Preclinical studies investigating T cells modified to express an Igkappa-specific CAR demonstrated that this strategy enables the efficient lysis of tumour cells expressing Igkappa.	('lysis', 'biological_process', 'GO:0019835', ('140', '145'))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('Igkappa', 'Var', (173, 180))	('CAR', 'cellular_component', 'GO:0005826', ('82', '85'))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))	('lysis', 'CPA', (140, 145))
90950	27000958	CARs specific for EGFR and EGFR variant receptors are undergoing clinical evaluation in patients with glioma.	('EGFR', 'Gene', '1956', (27, 31))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('EGFR', 'Gene', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('variant', 'Var', (32, 39))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', (18, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('glioma', 'Disease', (102, 108))
90952	27000958	The mutated form of EGFR, EGFRvIII (EGFR variant III), is also frequently overexpressed in cancer, and is commonly associated with glioblastoma.	('mutated', 'Var', (4, 11))	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', (20, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('EGFR', 'Gene', '1956', (20, 24))	('associated', 'Reg', (115, 125))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', '1956', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EGFR', 'Gene', (36, 40))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
90953	27000958	EGFRvIII might be a suitable target for CAR-T-cell therapy, as indicated by the results of clinical studies in which monoclonal antibodies targeting EGFR variants were well tolerated.	('CAR-T', 'Gene', (40, 45))	('variants', 'Var', (154, 162))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('EGFR', 'Gene', (149, 153))	('CAR-T', 'Gene', '9607', (40, 45))	('CAR', 'cellular_component', 'GO:0005826', ('40', '43'))	('EGFR', 'Gene', '1956', (0, 4))
90959	27000958	Nonmutated EGFR, which is ubiquitously expressed, is the target of the CAR being used in this study, and, therefore, the safety of this approach is a concern.	('Nonmutated', 'Var', (0, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('CAR', 'cellular_component', 'GO:0005826', ('71', '74'))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))
91028	27000958	The results of preclinical studies indicate that targeting VEGFR-2 with a CAR can redirect T-cell efficacy to target tumour stromal cells while sparing nontransformed tissues.	('VEGFR-2', 'Gene', '3791', (59, 66))	('CAR', 'cellular_component', 'GO:0005826', ('74', '77'))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('redirect', 'Reg', (82, 90))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('VEGFR-2', 'Gene', (59, 66))	('T-cell efficacy', 'CPA', (91, 106))	('targeting', 'Var', (49, 58))	('tumour', 'Disease', (117, 123))
91310	27274438	We found a significant association between high and low TS and DPD expression and survival time (P = 0.029, P = 0.0067 respectively).	('survival time', 'CPA', (82, 95))	('high', 'Var', (43, 47))	('DPD', 'Gene', '1806', (63, 66))	('TS', 'Gene', '7298', (56, 58))	('DPD', 'Gene', (63, 66))	('low', 'NegReg', (52, 55))	('DPD', 'molecular_function', 'GO:0017113', ('63', '66'))
91333	27274438	We previously reported successful S-1 treatment for refractory thymic carcinoma with high OPRT expression.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('S-1', 'Gene', '5707', (34, 37))	('high', 'Var', (85, 89))	('S-1', 'Gene', (34, 37))	('OPRT', 'Gene', '7372', (90, 94))	('thymic carcinoma', 'Disease', (63, 79))	('OPRT', 'Gene', (90, 94))	('thymic carcinoma', 'Disease', 'MESH:D013945', (63, 79))
91340	27274438	However, the mechanism of its anti-tumor effect also occurs through dysfunction of RNA synthesis.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('RNA synthesis', 'biological_process', 'GO:0032774', ('83', '96'))	('RNA synthesis', 'MPA', (83, 96))	('dysfunction', 'Var', (68, 79))
91374	27274438	Theoretically, high OPRT expression could be expected to be more effective for S-1 treatment.	('high', 'Var', (15, 19))	('S-1', 'Gene', '5707', (79, 82))	('OPRT', 'Gene', '7372', (20, 24))	('OPRT', 'Gene', (20, 24))	('S-1', 'Gene', (79, 82))
91393	25877069	Mutations in the NF2 gene have been found in about 40% of human mesothelioma (Bianchi et al.	('human', 'Species', '9606', (58, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('found', 'Reg', (36, 41))	('Mutations', 'Var', (0, 9))	('NF2', 'Gene', (17, 20))	('mesothelioma', 'Disease', (64, 76))
91394	25877069	), and the influence of Nf2 heterozygosity has been investigated in mice; Nf2 heterozygosity was shown to result in MM at high frequency (85%) within 1 yr after repetitive asbestos exposure (Altomare).	('Nf2', 'Gene', (74, 77))	('asbestos', 'Chemical', 'MESH:D001194', (172, 180))	('mice', 'Species', '10090', (68, 72))	('heterozygosity', 'Var', (78, 92))	('result in', 'Reg', (106, 115))
91395	25877069	In another transgenic mouse model, SV40 TAg expression driven by the mesothelin promoter leads to asbestos-induced MM in <1 yr (Robinson et al.	('mouse', 'Species', '10090', (22, 27))	('mesothelin', 'Gene', '56047', (69, 79))	('leads to', 'Reg', (89, 97))	('SV40 TAg expression', 'Var', (35, 54))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('transgenic', 'Species', '10090', (11, 21))	('mesothelin', 'Gene', (69, 79))	('asbestos-induced MM', 'Disease', (98, 117))
91407	25877069	), the different immortalized mesothelial cell lines also provide a model to investigate the effect of inactivating p53 in different genotypes (WT, Nf2+/-).	('inactivating', 'Var', (103, 115))	('p53', 'Gene', '22060', (116, 119))	('p53', 'Gene', (116, 119))
91442	25877069	Of note, primary mesothelial cells (initial density, 1500 cells/cm2) from Nf2+/- mice showed slightly enhanced proliferation compared to the cell lines generated from WT mice (Fig.	('enhanced', 'PosReg', (102, 110))	('mice', 'Species', '10090', (81, 85))	('Nf2+/-', 'Var', (74, 80))	('proliferation', 'CPA', (111, 124))	('mice', 'Species', '10090', (170, 174))
91517	24108494	Using ICD-10 codes for causes of death listed in the NCHS multiple-cause-of-death data files, we identified two non-overlapping groups of decedents with diseases attributable to asbestos exposure as follows: (1) Asbestosis [J61]: pneumoconiosis due to asbestos and other mineral fibers as underlying cause of death and death with underlying cause coded as J65 (pneumoconiosis associate with tuberculosis) or J92.0 (pleural plaques with presence of asbestos) with asbestosis as a contributing cause of death and (2) Malignant Mesothelioma: mesothelioma [C45] as underlying cause of death.	('death', 'Disease', (33, 38))	('pneumoconiosis', 'Disease', 'MESH:D011009', (361, 375))	('death', 'Disease', (319, 324))	('death', 'Disease', (309, 314))	('death', 'Disease', (501, 506))	('death', 'Disease', 'MESH:D003643', (76, 81))	('asbestos', 'Chemical', 'MESH:D001194', (252, 260))	('asbestosis', 'Disease', (463, 473))	('asbestos', 'Chemical', 'MESH:D001194', (178, 186))	('pneumoconiosis', 'Disease', 'MESH:D011009', (230, 244))	('asbestos', 'Chemical', 'MESH:D001194', (448, 456))	('death', 'Disease', 'MESH:D003643', (581, 586))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (515, 537))	('death', 'Disease', 'MESH:D003643', (33, 38))	('tuberculosis', 'Disease', 'MESH:D014376', (391, 403))	('Malignant Mesothelioma', 'Disease', (515, 537))	('asbestos', 'Chemical', 'MESH:D001194', (463, 471))	('death and death', 'Disease', 'MESH:D003643', (309, 324))	('pleural plaques', 'Disease', 'MESH:D010995', (415, 430))	('pneumoconiosis', 'Disease', (361, 375))	('death', 'Disease', 'MESH:D003643', (319, 324))	('death', 'Disease', 'MESH:D003643', (309, 314))	('tuberculosis', 'Disease', (391, 403))	('death', 'Disease', 'MESH:D003643', (501, 506))	('Asbestosis', 'Disease', 'MESH:D001195', (212, 222))	('Asbestosis', 'Disease', (212, 222))	('J92.0', 'Var', (408, 413))	('death', 'Disease', (76, 81))	('pleural plaques', 'Disease', (415, 430))	('mesothelioma', 'Disease', (539, 551))	('asbestosis', 'Disease', 'MESH:D001195', (463, 473))	('mesothelioma', 'Disease', 'MESH:D008654', (539, 551))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (515, 537))	('death', 'Disease', (581, 586))	('pneumoconiosis', 'Disease', (230, 244))
91550	24108494	No significant temporal trend in malignant mesothelioma attributable YPLL or YPLL65 was observed over the years for which data were available.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (33, 55))	('malignant mesothelioma', 'Disease', (33, 55))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (33, 55))	('YPLL65', 'Var', (77, 83))	('YPLL', 'Var', (69, 73))
91587	24145282	Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P.	('killing', 'MPA', (116, 123))	('SS1P', 'Chemical', 'MESH:C474515', (40, 44))	('Knocking down', 'Var', (0, 13))	('A431/H9', 'CellLine', 'CVCL:0037', (56, 63))	('SS1P', 'Chemical', 'MESH:C474515', (127, 131))	('enhanced', 'PosReg', (107, 115))	('SRC', 'Gene', '6714', (17, 20))	('SRC', 'Gene', (17, 20))	('knocking down', 'Var', (75, 88))	('increased', 'PosReg', (30, 39))	('HCK', 'Gene', (89, 92))	('HCK', 'Gene', '3055', (89, 92))
91588	24145282	We investigated the mechanism of enhancement and found that HCK knock down enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax.	('Bax', 'Gene', (146, 149))	('Mcl-1', 'Gene', (129, 134))	('SS1P cleavage', 'MPA', (84, 97))	('raised', 'PosReg', (139, 145))	('enhanced', 'PosReg', (75, 83))	('lowered levels of Mcl', 'Phenotype', 'HP:0025066', (111, 132))	('furin', 'Gene', '5045', (101, 106))	('SS1P', 'Chemical', 'MESH:C474515', (84, 88))	('lowered', 'NegReg', (111, 118))	('Bax', 'Gene', '581', (146, 149))	('furin', 'Gene', (101, 106))	('Mcl-1', 'Gene', '4170', (129, 134))	('HCK', 'Gene', (60, 63))	('knock down', 'Var', (64, 74))	('HCK', 'Gene', '3055', (60, 63))
91589	24145282	We then found that Src inhibitors mimic the stimulatory effect of HCK knock down, both SU6656 and SKI-606 (Bosutinib) enhanced immunotoxin killing of mesothelin expressing cells by SS1P and CD22 expressing cells by HA22 (Moxetumomab pasudotox).	('knock down', 'Var', (70, 80))	('HCK', 'Gene', (66, 69))	('HCK', 'Gene', '3055', (66, 69))	('SKI-606', 'CellLine', 'CVCL:E053', (98, 105))	('enhanced', 'PosReg', (118, 126))	('Bosutinib', 'Chemical', 'MESH:C471992', (107, 116))	('immunotoxin killing', 'MPA', (127, 146))	('SU6656', 'Chemical', 'MESH:C416927', (87, 93))	('SKI-606', 'Var', (98, 105))	('SS1P', 'Chemical', 'MESH:C474515', (181, 185))	('SU6656', 'Var', (87, 93))
91590	24145282	SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models.	('mouse', 'Species', '10090', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (79, 84))	('SS1P', 'Chemical', 'MESH:C474515', (46, 50))	('SU6656', 'Chemical', 'MESH:C416927', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SS1P', 'Gene', (46, 50))	('SU6656', 'Var', (0, 6))	('tumor', 'Disease', (29, 34))	('enhanced', 'PosReg', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
91603	24145282	In the cytosol it catalyzes the ADP-ribosylation and inactivation of elongation factor 2 (EF2) leading to the arrest of protein synthesis.	('arrest of protein synthesis', 'MPA', (110, 137))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('ADP-ribosylation', 'Var', (32, 48))	('EF2', 'Gene', '1938', (90, 93))	('ADP', 'Chemical', 'MESH:D000244', (32, 35))	('EF2', 'Gene', (90, 93))	('elongation factor 2', 'Gene', '1938', (69, 88))	('protein synthesis', 'biological_process', 'GO:0006412', ('120', '137'))	('inactivation', 'NegReg', (53, 65))	('cytosol', 'cellular_component', 'GO:0005829', ('7', '14'))	('elongation factor 2', 'Gene', (69, 88))
91609	24145282	We report here that knock down of HCK, and to a lesser extent, SRC, enhance immunotoxin action by a different mechanism than that regulated by the INSR.	('HCK', 'Gene', (34, 37))	('INSR', 'Gene', '3643', (147, 151))	('HCK', 'Gene', '3055', (34, 37))	('INSR', 'Gene', (147, 151))	('immunotoxin action', 'MPA', (76, 94))	('SRC', 'Gene', '6714', (63, 66))	('SRC', 'Gene', (63, 66))	('knock down', 'Var', (20, 30))	('enhance', 'PosReg', (68, 75))
91610	24145282	We also report that two Src family inhibitors, SU6656 and Bosutininb, enhanced immunotoxin killing of cultured cells and that SU6656 synergized with immunotoxins HA22 or SS1P to cause tumor regression in tumor bearing mice.	('SU6656', 'Chemical', 'MESH:C416927', (126, 132))	('SU6656', 'Var', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('SU6656', 'Var', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('SS1P', 'Chemical', 'MESH:C474515', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Bosutininb', 'Chemical', '-', (58, 68))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', (204, 209))	('enhanced', 'PosReg', (70, 78))	('mice', 'Species', '10090', (218, 222))	('immunotoxin killing', 'MPA', (79, 98))	('SU6656', 'Chemical', 'MESH:C416927', (47, 53))
91618	24145282	Cell viability is expressed as the percentage of luminescence with SS1P compared to control without SS1P treatment.	('SS1P', 'Chemical', 'MESH:C474515', (67, 71))	('luminescence', 'MPA', (49, 61))	('SS1P', 'Chemical', 'MESH:C474515', (100, 104))	('SS1P', 'Var', (67, 71))
91646	24145282	We found that knock down of 5 genes, SRC, HCK, PDGFRbeta, BMX and INSR, reproducibly enhanced killing of cells by SS1P.	('SRC', 'Gene', '6714', (37, 40))	('knock down', 'Var', (14, 24))	('killing of cells', 'CPA', (94, 110))	('SRC', 'Gene', (37, 40))	('enhanced', 'PosReg', (85, 93))	('HCK', 'Gene', (42, 45))	('PDGFRbeta', 'Gene', '5159', (47, 56))	('BMX', 'Gene', (58, 61))	('INSR', 'Gene', '3643', (66, 70))	('HCK', 'Gene', '3055', (42, 45))	('SS1P', 'Chemical', 'MESH:C474515', (114, 118))	('PDGFRbeta', 'Gene', (47, 56))	('BMX', 'Gene', '660', (58, 61))	('INSR', 'Gene', (66, 70))
91649	24145282	Knock down of Src slightly enhanced SS1P killing in both A431/H9 and KB cells (IC50 value decreased 25% in both cell lines, Supplemental Fig.	('Knock down', 'Var', (0, 10))	('SS1P', 'Chemical', 'MESH:C474515', (36, 40))	('enhanced', 'PosReg', (27, 35))	('Src', 'Gene', (14, 17))	('SS1P killing', 'MPA', (36, 48))	('A431/H9', 'CellLine', 'CVCL:0037', (57, 64))
91650	24145282	However, knock down of HCK gene greatly enhanced SS1P toxicity, with the IC50 decreasing 3-fold as described below.	('toxicity', 'Disease', (54, 62))	('IC50', 'MPA', (73, 77))	('knock down', 'Var', (9, 19))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('SS1P', 'Chemical', 'MESH:C474515', (49, 53))	('HCK', 'Gene', '3055', (23, 26))	('enhanced', 'PosReg', (40, 48))	('HCK', 'Gene', (23, 26))
91655	24145282	To determine if the HCK knock down effect would enhance killing of A431/H9 cells by an immunotoxin targeting another receptor on A431/H9 cells, we treated the cells with immunotoxin HB21-PE40 (anti-TFR-PE40) that targets the human transferrin receptor and found that its cytotoxic activity was greatly increased upon knock down of HCK (Fig.	('knock down', 'Var', (317, 327))	('HCK', 'Gene', '3055', (20, 23))	('HCK', 'Gene', (20, 23))	('increased', 'PosReg', (302, 311))	('TFR', 'Gene', '7037', (198, 201))	('PE', 'Chemical', '-', (202, 204))	('enhance', 'PosReg', (48, 55))	('A431/H9', 'CellLine', 'CVCL:0037', (67, 74))	('A431/H9', 'CellLine', 'CVCL:0037', (129, 136))	('HCK', 'Gene', (331, 334))	('PE', 'Chemical', '-', (187, 189))	('HCK', 'Gene', '3055', (331, 334))	('transferrin', 'Gene', '7018', (231, 242))	('human', 'Species', '9606', (225, 230))	('cytotoxic activity', 'CPA', (271, 289))	('transferrin', 'Gene', (231, 242))	('TFR', 'Gene', (198, 201))
91658	24145282	As shown in Figure 1F, knock down of HCK did not stimulate CHX-induced cell killing.	('cell killing', 'biological_process', 'GO:0001906', ('71', '83'))	('knock down', 'Var', (23, 33))	('CHX-induced cell killing', 'CPA', (59, 83))	('CHX', 'Chemical', 'MESH:D003513', (59, 62))	('HCK', 'Gene', '3055', (37, 40))	('HCK', 'Gene', (37, 40))
91659	24145282	These results demonstrate that knock down of HCK enhances the activity of immunotoxins that have specific receptors on target cells and does not provoke nonspecific internalization or cell killing of a non-targeted immunotoxin.	('knock down', 'Var', (31, 41))	('HCK', 'Gene', '3055', (45, 48))	('activity', 'MPA', (62, 70))	('HCK', 'Gene', (45, 48))	('immunotoxins', 'Protein', (74, 86))	('cell killing', 'biological_process', 'GO:0001906', ('184', '196'))	('enhances', 'PosReg', (49, 57))
91660	24145282	To determine if siHCK knock down would enhance killing of a lymphoma cell line, we used CA46 cells, which express CD22 and the immunotoxin HA22 that targets CD22 expressing cells.	('lymphoma', 'Disease', 'MESH:D008223', (60, 68))	('HCK', 'Gene', '3055', (18, 21))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('HCK', 'Gene', (18, 21))	('knock down', 'Var', (22, 32))	('CD22', 'Gene', (114, 118))	('enhance', 'PosReg', (39, 46))	('lymphoma', 'Disease', (60, 68))
91663	24145282	Nevertheless it was sufficient to allow cytotoxicity studies and as shown in Figure 1I, the cytotoxic activity of HA22 was significantly stimulated by HCK knock down; the IC50 value shifted from above 5 ng/ml to 2.4 ng/ml.	('HCK', 'Gene', '3055', (151, 154))	('cytotoxicity', 'Disease', (40, 52))	('cytotoxic activity', 'CPA', (92, 110))	('knock down', 'Var', (155, 165))	('HCK', 'Gene', (151, 154))	('HA22', 'Gene', (114, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('stimulated', 'PosReg', (137, 147))
91664	24145282	We conclude that HCK knock down can enhance immunotoxin action on several different cell types.	('HCK', 'Gene', (17, 20))	('immunotoxin action', 'MPA', (44, 62))	('HCK', 'Gene', '3055', (17, 20))	('enhance', 'PosReg', (36, 43))	('knock down', 'Var', (21, 31))
91665	24145282	To investigate where in the intoxication pathway the stimulatory effect of HCK knock down was occurring, we examined several different steps in the intoxication pathway.	('HCK', 'Gene', '3055', (75, 78))	('HCK', 'Gene', (75, 78))	('knock down', 'Var', (79, 89))
91670	24145282	While furin protein levels did not increase after knock down of HCK, the amount of the 35-kDa fragment increased about 2-3 fold at the 5, 20 and 60 minute time points when HCK is knocked down (Fig.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('HCK', 'Gene', '3055', (172, 175))	('increased', 'PosReg', (103, 112))	('knock', 'Var', (50, 55))	('HCK', 'Gene', (172, 175))	('furin', 'Gene', (6, 11))	('amount', 'MPA', (73, 79))	('knocked down', 'Var', (179, 191))	('HCK', 'Gene', (64, 67))	('furin', 'Gene', '5045', (6, 11))	('HCK', 'Gene', '3055', (64, 67))
91673	24145282	Figure 2F shows that in cells treated with increasing amounts of SS1P, there is a greater decrease in leucine incorporation in cells treated with siRNAs for HCK compared to a control siRNA.	('HCK', 'Gene', '3055', (157, 160))	('HCK', 'Gene', (157, 160))	('decrease', 'NegReg', (90, 98))	('leucine', 'Chemical', 'MESH:D007930', (102, 109))	('SS1P', 'Chemical', 'MESH:C474515', (65, 69))	('SS1P', 'Var', (65, 69))	('leucine incorporation', 'MPA', (102, 123))
91675	24145282	To investigate if knock down of HCK also affected the levels of proteins involved in apoptosis and previously shown to control immunotoxin killing, we examined the levels of Bak, Bax, Mcl-1, Bcl2 and BclxL in A431/H9 cells by western blot.	('knock down', 'Var', (18, 28))	('Bax', 'Gene', '581', (179, 182))	('HCK', 'Gene', (32, 35))	('Bak', 'Gene', (174, 177))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('levels', 'MPA', (54, 60))	('BclxL', 'Gene', (200, 205))	('Mcl-1', 'Gene', '4170', (184, 189))	('Bcl2', 'Gene', (191, 195))	('Bak', 'Gene', '578', (174, 177))	('HCK', 'Gene', '3055', (32, 35))	('BclxL', 'Gene', '598', (200, 205))	('A431/H9', 'CellLine', 'CVCL:0037', (209, 216))	('Bcl2', 'molecular_function', 'GO:0015283', ('191', '195'))	('Bcl2', 'Gene', '596', (191, 195))	('affected', 'Reg', (41, 49))	('Bax', 'Gene', (179, 182))	('Mcl-1', 'Gene', (184, 189))
91678	24145282	We examined the markers of apoptosis PARP and cleaved caspase-3 (Fig.	('PARP', 'Gene', (37, 41))	('PARP', 'Gene', '142', (37, 41))	('cleaved', 'Var', (46, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))
91679	24145282	3B) and found that HCK knock down by itself substantially decreased full-length PARP levels.	('PARP', 'Gene', '142', (80, 84))	('decreased', 'NegReg', (58, 67))	('knock down', 'Var', (23, 33))	('HCK', 'Gene', '3055', (19, 22))	('HCK', 'Gene', (19, 22))	('PARP', 'Gene', (80, 84))
91680	24145282	When knock down was combined with SS1P treatment, PARP levels were further decreased and cleaved caspase-3 levels increased, as would be expected in cells undergoing apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('PARP', 'Gene', '142', (50, 54))	('increased', 'PosReg', (114, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('cleaved caspase-3 levels', 'MPA', (89, 113))	('knock down', 'Var', (5, 15))	('SS1P', 'Chemical', 'MESH:C474515', (34, 38))	('PARP', 'Gene', (50, 54))	('decreased', 'NegReg', (75, 84))
91681	24145282	To investigate if we could enhance SS1P or HA22 activity with a TK inhibitor, we tested SU6656 and SKI-606 (Bosutinib), known to inhibit members of the Src family.	('SKI-606', 'CellLine', 'CVCL:E053', (99, 106))	('enhance', 'PosReg', (27, 34))	('HA22 activity', 'MPA', (43, 56))	('Bosutinib', 'Chemical', 'MESH:C471992', (108, 117))	('SU6656', 'Chemical', 'MESH:C416927', (88, 94))	('SU6656', 'Var', (88, 94))	('SS1P', 'MPA', (35, 39))	('SS1P', 'Chemical', 'MESH:C474515', (35, 39))
91682	24145282	We found that combining the Src kinase inhibitor (SU6656) with SS1P gave a synergistic inhibition of cell growth compared with the addition of either agent alone, on three different epithelial cancer lines A431/H9, A1847 and KLM-1, a pancreatic cancer line (Fig.	('epithelial cancer', 'Disease', (182, 199))	('pancreatic cancer', 'Disease', 'MESH:D010190', (234, 251))	('SS1P', 'Gene', (63, 67))	('epithelial cancer', 'Disease', 'MESH:D000077216', (182, 199))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('87', '112'))	('cell growth', 'CPA', (101, 112))	('epithelial cancer', 'Phenotype', 'HP:0031492', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (234, 251))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('32', '48'))	('SU6656', 'Chemical', 'MESH:C416927', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('SS1P', 'Chemical', 'MESH:C474515', (63, 67))	('SU6656', 'Var', (50, 56))	('pancreatic cancer', 'Disease', (234, 251))	('A431/H9', 'CellLine', 'CVCL:0037', (206, 213))
91683	24145282	SU6656 also enhanced the cytotoxic activity of HA22 on the CA46 lymphoma cell line (Fig.	('lymphoma', 'Disease', (64, 72))	('lymphoma', 'Disease', 'MESH:D008223', (64, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('SU6656', 'Chemical', 'MESH:C416927', (0, 6))	('SU6656', 'Var', (0, 6))	('enhanced', 'PosReg', (12, 20))	('cytotoxic activity', 'CPA', (25, 43))
91684	24145282	Bosutinib/SKI606 synergistically enhanced killing of A431/H9 cells by SS1P and CA46 cells by HA22 (Fig.	('SS1P', 'Var', (70, 74))	('Bosutinib', 'Chemical', 'MESH:C471992', (0, 9))	('HA22', 'Var', (93, 97))	('SS1P', 'Chemical', 'MESH:C474515', (70, 74))	('A431/H9', 'CellLine', 'CVCL:0037', (53, 60))	('killing', 'CPA', (42, 49))	('enhanced', 'PosReg', (33, 41))
91685	24145282	To determine if SU6656 could enhance the antitumor activity of SS1P, mice were implanted with A431/H9 cells and treatment was initiated on day 6.	('SU6656', 'Var', (16, 22))	('A431/H9', 'CellLine', 'CVCL:0037', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mice', 'Species', '10090', (69, 73))	('SU6656', 'Chemical', 'MESH:C416927', (16, 22))	('enhance', 'PosReg', (29, 36))	('SS1P', 'Chemical', 'MESH:C474515', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
91686	24145282	Mice received either SS1P or SU6656 or SS1P and Su6656 in combination.	('SS1P', 'Var', (39, 43))	('Su6656', 'Chemical', 'MESH:C416927', (48, 54))	('SS1P', 'Chemical', 'MESH:C474515', (39, 43))	('SS1P', 'Chemical', 'MESH:C474515', (21, 25))	('Su6656', 'Var', (48, 54))	('SU6656', 'Chemical', 'MESH:C416927', (29, 35))	('SS1P', 'Var', (21, 25))	('Mice', 'Species', '10090', (0, 4))	('SU6656', 'Var', (29, 35))
91687	24145282	As shown in Figure 5A, when mice were treated with SU6656, there was a minimal change in tumor growth compared with control.	('mice', 'Species', '10090', (28, 32))	('SU6656', 'Chemical', 'MESH:C416927', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('SU6656', 'Var', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
91689	24145282	We tested the effect of SU6656 in mice bearing CA46 lymphomas and found that SU6656 alone had very little effect on the growth of the tumors but greatly enhanced the antitumor activity of HA22 (Fig.	('SU6656', 'Var', (77, 83))	('lymphomas', 'Disease', (52, 61))	('SU6656', 'Chemical', 'MESH:C416927', (24, 30))	('tumors', 'Disease', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('mice', 'Species', '10090', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('lymphomas', 'Disease', 'MESH:D008223', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('lymphomas', 'Phenotype', 'HP:0002665', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('enhanced', 'PosReg', (153, 161))	('SU6656', 'Chemical', 'MESH:C416927', (77, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (52, 60))	('tumor', 'Disease', (134, 139))
91691	24145282	We have used siRNAs targeting members of the 88 TKs to identify genes that can regulate immunotoxin killing, and found that knock down of several TK genes enhanced killing of A431/H9 cells.	('enhanced', 'PosReg', (155, 163))	('knock down', 'Var', (124, 134))	('killing', 'CPA', (164, 171))	('A431/H9', 'CellLine', 'CVCL:0037', (175, 182))
91696	24145282	However, the finding that HCK knock down also enhances killing of A1847 ovarian cancer cells and CA46 lymphoma cells indicates that Hck has an important regulatory role in several types of cancer.	('lymphoma', 'Disease', (102, 110))	('lymphoma', 'Disease', 'MESH:D008223', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Hck', 'Gene', '3055', (132, 135))	('knock down', 'Var', (30, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('HCK', 'Gene', '3055', (26, 29))	('enhances', 'PosReg', (46, 54))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('ovarian cancer', 'Disease', (72, 86))	('Hck', 'Gene', (132, 135))	('cancer', 'Disease', (189, 195))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('HCK', 'Gene', (26, 29))	('killing', 'CPA', (55, 62))
91697	24145282	We have previously shown that knock down of the INSR can enhance immunotoxin action by increasing the processing of the immunotoxin by furin.	('furin', 'Gene', '5045', (135, 140))	('INSR', 'Gene', '3643', (48, 52))	('furin', 'Gene', (135, 140))	('knock down', 'Var', (30, 40))	('immunotoxin action', 'MPA', (65, 83))	('INSR', 'Gene', (48, 52))	('increasing', 'PosReg', (87, 97))	('enhance', 'PosReg', (57, 64))
91698	24145282	Knock down of HCK similarly increased the furin cleavage and increased the amount of 35-kDa PE fragment, indicating that Hck also modulates immunotoxin processing.	('increased', 'PosReg', (28, 37))	('furin', 'Gene', '5045', (42, 47))	('furin', 'Gene', (42, 47))	('Hck', 'Gene', '3055', (121, 124))	('HCK', 'Gene', (14, 17))	('amount of 35-kDa PE fragment', 'MPA', (75, 103))	('HCK', 'Gene', '3055', (14, 17))	('increased', 'PosReg', (61, 70))	('Hck', 'Gene', (121, 124))	('Knock down', 'Var', (0, 10))	('modulates', 'Reg', (130, 139))	('PE', 'Chemical', '-', (92, 94))
91700	24145282	It has major effects on the levels of two important proteins that regulate apoptosis: lowering HCK decreases the anti-apoptotic Mcl-1 protein and elevates the pro-apoptotic Bax protein.	('decreases', 'NegReg', (99, 108))	('Mcl-1', 'Gene', (128, 133))	('Bax', 'Gene', (173, 176))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('elevates', 'PosReg', (146, 154))	('Mcl-1', 'Gene', '4170', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('Bax', 'Gene', '581', (173, 176))	('HCK', 'Gene', (95, 98))	('lowering', 'Var', (86, 94))	('HCK', 'Gene', '3055', (95, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
91702	24145282	There are studies on other Src family kinases; for example, Src and Fyn play a role in the anti-apoptotic response in fibroblasts and knock down of Lyn induced caspase-8 activation in a mesothelioma cell line.	('Fyn', 'Gene', '2534', (68, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (186, 198))	('Fyn', 'Gene', (68, 71))	('Lyn', 'Gene', '4067', (148, 151))	('activation', 'PosReg', (170, 180))	('caspase-8', 'Gene', (160, 169))	('knock down', 'Var', (134, 144))	('mesothelioma', 'Disease', (186, 198))	('caspase-8', 'Gene', '841', (160, 169))	('Lyn', 'Gene', (148, 151))	('anti-apoptotic response', 'MPA', (91, 114))
91713	24145282	We found that both of these inhibitors would replicate the effect of HCK knock down and enhance immunotoxin killing of both epithelial and lymphoma cells.	('lymphoma', 'Disease', 'MESH:D008223', (139, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('knock down', 'Var', (73, 83))	('HCK', 'Gene', '3055', (69, 72))	('HCK', 'Gene', (69, 72))	('immunotoxin killing', 'CPA', (96, 115))	('lymphoma', 'Disease', (139, 147))	('enhance', 'PosReg', (88, 95))
91714	24145282	We performed antitumor experiments in mice with SU6656 and found that using a dose of SU6656, which by itself had no antitumor activity, produced synergistic antitumor effects when combined with an immunotoxin targeting mesothelin on an epithelial cancer or an immunotoxin that targets CD22 on B cell malignancies (Fig.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('combined', 'Interaction', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('epithelial cancer', 'Disease', (237, 254))	('epithelial cancer', 'Disease', 'MESH:D000077216', (237, 254))	('SU6656', 'Chemical', 'MESH:C416927', (48, 54))	('mice', 'Species', '10090', (38, 42))	('SU6656', 'Chemical', 'MESH:C416927', (86, 92))	('tumor', 'Disease', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Disease', (121, 126))	('SU6656', 'Var', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('epithelial cancer', 'Phenotype', 'HP:0031492', (237, 254))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
91734	19773437	Use of an oncolytic virus extends our previous work in which inclusion of the IFN-beta gene into a replication-defective adenoviral vector led to significant therapy following intratumoral injections.	('tumor', 'Disease', (181, 186))	('inclusion', 'Var', (61, 70))	('led to', 'Reg', (139, 145))	('therapy', 'MPA', (158, 165))	('IFN-beta', 'Gene', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
91737	19773437	Moreover, inclusion of IFN-beta within the VSV vector should also increase the safety of VSV in the event that it were to infect normal cells.	('increase', 'PosReg', (66, 74))	('VSV', 'Species', '11276', (89, 92))	('safety', 'MPA', (79, 85))	('VSV', 'Species', '11276', (43, 46))	('inclusion', 'Var', (10, 19))
91740	19773437	Here, we tested IFN-beta as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma, based upon the potential of VSV-IFN-beta to increase immunotherapeutic efficacy, enhance tumor cell transduction and increase the safety of previous approaches using VSV alone.	('tumor', 'Disease', (199, 204))	('increase', 'PosReg', (227, 235))	('transduction', 'biological_process', 'GO:0009293', ('210', '222'))	('VSV', 'Species', '11276', (67, 70))	('mesothelioma', 'Disease', (96, 108))	('VSV', 'Species', '11276', (276, 279))	('enhance', 'PosReg', (191, 198))	('immunotherapeutic efficacy', 'CPA', (163, 189))	('VSV-IFN-beta', 'Var', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('increase', 'PosReg', (154, 162))	('VSV', 'Species', '11276', (138, 141))
91741	19773437	We demonstrate VSV-IFN-beta efficiently lyses the murine mesothelioma AB12 cell line, and that added expression of IFN-beta does not significantly interfere with VSV replication.	('VSV', 'Species', '11276', (162, 165))	('mesothelioma', 'Disease', (57, 69))	('murine', 'Species', '10090', (50, 56))	('VSV', 'Species', '11276', (15, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('VSV-IFN-beta', 'Var', (15, 27))	('lyses', 'NegReg', (40, 45))
91742	19773437	Loco-regional delivery of VSV-IFN-beta generated tumor regressions, at least in part dependent upon virus-induced activation of CD8+ T-cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('VSV-IFN-beta', 'Var', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('VSV', 'Species', '11276', (26, 29))	('tumor', 'Disease', (49, 54))
91758	19773437	Once s.c. tumors reached approximately 200mm3 in size, intratumoral injections were performed with saline, 5x108 pfu (C57Bl/6) or 6.6x108 pfu in 100microL of each vector (VSV-mIFN-beta and VSV-hIFN-beta) once weekly for two (SCID, C57Bl/6) or three consecutive weeks (BALB/c).	('hIFN-beta', 'Gene', '3456', (193, 202))	('tumors', 'Disease', (10, 16))	('mIFN-beta', 'Gene', '15977', (175, 184))	('tumor', 'Disease', (60, 65))	('SCID', 'Disease', 'MESH:D053632', (225, 229))	('tumor', 'Disease', (10, 15))	('hIFN-beta', 'Gene', (193, 202))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SCID', 'Disease', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mIFN-beta', 'Gene', (175, 184))	('VSV', 'Species', '11276', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('saline', 'Chemical', 'MESH:D012965', (99, 105))	('C57Bl/6', 'Var', (231, 238))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('VSV', 'Species', '11276', (171, 174))
91769	19773437	Both VSV (Fig.1A) and VSV-mIFN-beta (Fig.1B) induced rapid, and extensive, cell killing following infection of AB12 cells at MOI ranging from 0.01 to 10, associated with ongoing replication of the viruses (Fig.1C&D).	('cell killing', 'CPA', (75, 87))	('infection', 'Disease', 'MESH:D007239', (98, 107))	('VSV', 'Species', '11276', (22, 25))	('cell killing', 'biological_process', 'GO:0001906', ('75', '87'))	('VSV', 'Var', (5, 8))	('VSV', 'Species', '11276', (5, 8))	('mIFN-beta', 'Gene', (26, 35))	('mIFN-beta', 'Gene', '15977', (26, 35))	('infection', 'Disease', (98, 107))
91777	19773437	However, survival of tumor-bearing mice treated with VSV-IFN-beta (median survival 54 days) was extended significantly over control-treated animals (median survival 26 days) (p<0.01).	('tumor', 'Disease', (21, 26))	('VSV', 'Species', '11276', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('extended', 'PosReg', (96, 104))	('mice', 'Species', '10090', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('survival', 'CPA', (9, 17))	('VSV-IFN-beta', 'Var', (53, 65))
91779	19773437	Based upon our previous studies using a replication-defective adenovirus expressing IFN-beta, our hypothesis was addition of the IFN-beta gene to the replication-competent VSV would further enhance the immunostimulatory activity of virus-mediated tumor cell killing.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', (247, 252))	('IFN-beta', 'Gene', (129, 137))	('addition', 'Var', (113, 121))	('enhance', 'PosReg', (190, 197))	('VSV', 'Species', '11276', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('cell killing', 'biological_process', 'GO:0001906', ('253', '265'))	('immunostimulatory activity', 'MPA', (202, 228))
91784	19773437	In contrast, intratumoral injection of VSV-hIFN-beta gave no significant therapy over PBS (Fig.2A) (p=0.27), suggesting a major component of the therapy in vivo associated with VSV-IFN-beta is contributed by immune reactivity of local IFN-beta expression as opposed to direct oncolysis by the virus.	('VSV', 'Species', '11276', (177, 180))	('tumor', 'Disease', (18, 23))	('hIFN-beta', 'Gene', (43, 52))	('hIFN-beta', 'Gene', '3456', (43, 52))	('VSV', 'Species', '11276', (39, 42))	('IFN-beta', 'Protein', (235, 243))	('PBS', 'Chemical', 'MESH:D007854', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('VSV-IFN-beta', 'Var', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
91793	19773437	Consistent with the results of Fig.3A&B, tumors grown in mice depleted of CD8+ T-cells, and treated with VSV-IFN-beta, were approximately 25% smaller than control-treated tumors at day 14 compared to a 60% GI of tumors treated identically in immune-competent mice (p<0.0001) (Fig.3C&D).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (212, 218))	('VSV', 'Species', '11276', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumors', 'Disease', (41, 47))	('with', 'Var', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mice', 'Species', '10090', (259, 263))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
91800	19773437	Intratumoral injection of VSV into B16ova tumors appeared to prime increased numbers of T-cells specific for the immunodominant epitope of the viral N protein, compared to mice in which tumors were injected with control heat-inactivated VSV (Fig.4B, column 2 vs 7), although there is no statistically significant increase in the N-specific T-cell response compared to the control in mice injected with VSV (Fig.4B, column 6 vs 7).	('VSV', 'Species', '11276', (26, 29))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (172, 176))	('increased', 'PosReg', (67, 76))	('VSV', 'Species', '11276', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mice', 'Species', '10090', (383, 387))	('tumors', 'Disease', (186, 192))	('VSV', 'Species', '11276', (402, 405))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('B16ova', 'Var', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('tumor', 'Disease', (5, 10))
91802	19773437	However, we also consistently observed splenocytes from mice treated with either VSV or VSV-mIFN-beta exhibited a generalised, non-antigen-specific activation, as evidenced by the elevated frequencies of IFN-beta-producing spots generated in response to stimulation with no added peptide (Fig.4B, column 11).	('IFN-beta-producing spots generated', 'MPA', (204, 238))	('VSV', 'Var', (81, 84))	('activation', 'PosReg', (148, 158))	('VSV', 'Species', '11276', (88, 91))	('VSV', 'Species', '11276', (81, 84))	('mIFN-beta', 'Gene', (92, 101))	('mIFN-beta', 'Gene', '15977', (92, 101))	('mice', 'Species', '10090', (56, 60))	('elevated', 'PosReg', (180, 188))
91807	19773437	Similarly, although we observed a trend towards increased number of tetramer-positive OVA-specific T-cells infiltrating tumors treated with VSV compared to control-treated animals, this was not significant (Fig.4D).	('increased', 'PosReg', (48, 57))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tetramer-positive', 'Protein', (68, 85))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('VSV', 'Var', (140, 143))	('VSV', 'Species', '11276', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
91812	19773437	A principal rationale for the inclusion of the IFN-beta gene within the VSV platform was to increase the safety of this virus should it become disseminated within a patient and infect normal cells - in which case the expression of IFN-beta would enhance the anti-viral response of normal cells and extinguish extraneous viral replication.	('viral replication', 'biological_process', 'GO:0019058', ('320', '337'))	('VSV', 'Species', '11276', (72, 75))	('IFN-beta', 'Gene', (231, 239))	('viral replication', 'biological_process', 'GO:0019079', ('320', '337'))	('IFN-beta', 'Gene', (47, 55))	('patient', 'Species', '9606', (165, 172))	('increase', 'PosReg', (92, 100))	('expression', 'Var', (217, 227))	('safety', 'MPA', (105, 111))	('extraneous viral replication', 'CPA', (309, 337))	('extinguish', 'NegReg', (298, 308))	('viral replication', 'biological_process', 'GO:0008166', ('320', '337'))	('enhance', 'PosReg', (246, 253))	('anti-viral response', 'CPA', (258, 277))
91825	19773437	We showed previously that inclusion of the IFN-beta gene into a replication-defective adenoviral vector led to significant therapy following intratumoral injections through priming of immune-mediated anti-tumor responses.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('therapy', 'MPA', (123, 130))	('IFN-beta', 'Gene', (43, 51))	('inclusion', 'Var', (26, 35))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
91828	19773437	To justify the similarities between the mesothelioma and melanoma models, we have shown VSV-mIFN-beta provides effective therapy against B16ova and that addition of IFN-beta to VSV has similar effects as seen in the AB12 model (Fig.4A).	('VSV', 'Species', '11276', (177, 180))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('VSV', 'Species', '11276', (88, 91))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mIFN-beta', 'Gene', (92, 101))	('melanoma', 'Disease', (57, 65))	('mIFN-beta', 'Gene', '15977', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('mesothelioma', 'Disease', (40, 52))	('B16ova', 'Var', (137, 143))	('therapy', 'MPA', (121, 128))
91847	19773437	Thus, inclusion of the biologically inactive human IFN-beta gene into VSV unmasked very significant neurotoxicity of intratumorally injected VSV in the context of SCID mice, in which toxicity of VSV is more readily apparent, compared to the immune-competent counterpart hosts.	('IFN-beta gene', 'Gene', (51, 64))	('toxicity', 'Disease', (183, 191))	('tumor', 'Disease', (122, 127))	('SCID', 'Disease', 'MESH:D053632', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('inclusion', 'Var', (6, 15))	('VSV', 'Species', '11276', (141, 144))	('unmasked', 'Reg', (74, 82))	('SCID', 'Disease', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('VSV', 'Species', '11276', (70, 73))	('neurotoxicity', 'Disease', (100, 113))	('mice', 'Species', '10090', (168, 172))	('human', 'Species', '9606', (45, 50))	('toxicity', 'Disease', 'MESH:D064420', (183, 191))	('neurotoxicity', 'Disease', 'MESH:D020258', (100, 113))	('VSV', 'Species', '11276', (195, 198))	('toxicity', 'Disease', (105, 113))
91850	19773437	In this respect, we have observed that incorporation of a biologically active IFN-beta gene into VSV significantly increases the maximum tolerated dose by in excess of two orders of magnitude when administered in rodent models.	('maximum tolerated dose', 'MPA', (129, 151))	('IFN-beta gene', 'Gene', (78, 91))	('increases', 'PosReg', (115, 124))	('incorporation', 'Var', (39, 52))	('VSV', 'Species', '11276', (97, 100))
91868	23412628	Our results demonstrate potent antitumor efficacy of compound 2 toward H2452 MPM in vitro and in vivo, reflecting its efficient membrane transport by PCFT over RFC, synthesis of polyglutamates, and inhibition of GARFTase.	('membrane transport', 'biological_process', 'GO:0055085', ('128', '146'))	('inhibition', 'NegReg', (198, 208))	('H2452 MPM', 'Var', (71, 80))	('synthesis', 'MPA', (165, 174))	('efficient', 'PosReg', (118, 127))	('tumor', 'Disease', (35, 40))	('polyglutamates', 'Chemical', 'MESH:D011099', (178, 192))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('GARFTase', 'Gene', '2618', (212, 220))	('membrane transport', 'MPA', (128, 146))	('polyglutamates', 'Protein', (178, 192))	('membrane', 'cellular_component', 'GO:0016020', ('128', '136'))	('synthesis', 'biological_process', 'GO:0009058', ('165', '174'))	('GARFTase', 'Gene', (212, 220))	('RFC', 'Gene', '6573', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PCFT', 'Gene', (150, 154))	('H2452 MPM', 'CellLine', 'CVCL:1553', (71, 80))	('RFC', 'Gene', (160, 163))	('PCFT', 'Gene', '113235', (150, 154))
91879	23412628	Hence, the antifolates PT523 and GW1843U89 are both excellent substrates for RFC but are poorly transported by PCFT.	('PT523', 'Chemical', 'MESH:C085590', (23, 28))	('GW1843U89', 'Chemical', '-', (33, 42))	('PCFT', 'Gene', '113235', (111, 115))	('folates', 'Chemical', 'MESH:D005492', (15, 22))	('RFC', 'Gene', (77, 80))	('GW1843U89', 'Var', (33, 42))	('PCFT', 'Gene', (111, 115))	('RFC', 'Gene', '6573', (77, 80))
91899	23412628	The H2452 subline is a patient-derived biphasic MPM cell line and was a gift from Dr. Anil Wali (National Cancer Institute).	('Cancer', 'Disease', (106, 112))	('H2452', 'Var', (4, 9))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patient', 'Species', '9606', (23, 30))
91904	23412628	Metabolically active cells (a measure of cell viability) were assayed with CellTiter-blue  cell viability assay (Promega; Madison, WI) and a fluorescent plate reader (590 nm emission, 560 nm excitation) for determining IC50s, corresponding to drug concentrations that result in 50% loss of cell growth.	('loss', 'NegReg', (282, 286))	('IC50s', 'Var', (219, 224))	('cell growth', 'CPA', (290, 301))	('50s', 'Species', '1214577', (221, 224))	('cell growth', 'biological_process', 'GO:0016049', ('290', '301'))
91947	23412628	Analogous results were reported by Nutt et al.. We selected the H2452 MPM (biphasic) cell line from our prior study to begin to explore the question of whether the modest level of hPCFT in these cells was sufficient to deliver PCFT-selective cytotoxic antifolates for therapy.	('PCFT', 'Gene', '113235', (227, 231))	('hPCFT', 'Gene', '113235', (180, 185))	('H2452', 'Var', (64, 69))	('folates', 'Chemical', 'MESH:D005492', (256, 263))	('PCFT', 'Gene', (181, 185))	('hPCFT', 'Gene', (180, 185))	('H2452 MPM', 'CellLine', 'CVCL:1553', (64, 73))	('PCFT', 'Gene', (227, 231))	('PCFT', 'Gene', '113235', (181, 185))
91948	23412628	For our study we correlated levels of hPCFT transcripts (Figure 2A) and [3H]Mtx transport (0.5 muM, 5 min) at pH 5.5 (Figure 2B) for H2452 MPM cells, compared to those in wild-type HeLa cells and in engineered HeLa cells ectopically expressing hPCFT (R1-11-PCFT4, derived from the hRFC- and hPCFT-null R1-11 HeLa subline).	('H2452 MPM', 'Var', (133, 142))	('[3H]Mtx transport', 'MPA', (72, 89))	('muM', 'Gene', '56925', (95, 98))	('hRFC', 'Gene', (281, 285))	('R1-11', 'Gene', (302, 307))	('muM', 'Gene', (95, 98))	('R1-11', 'Gene', '5514', (251, 256))	('hPCFT', 'Gene', '113235', (38, 43))	('hPCFT', 'Gene', '113235', (244, 249))	('transport', 'biological_process', 'GO:0006810', ('80', '89'))	('HeLa', 'CellLine', 'CVCL:0030', (308, 312))	('3H', 'Chemical', 'MESH:D014316', (73, 75))	('hPCFT', 'Gene', (38, 43))	('hPCFT', 'Gene', (244, 249))	('HeLa', 'CellLine', 'CVCL:0030', (181, 185))	('Mtx', 'Chemical', 'MESH:D008727', (76, 79))	('hPCFT', 'Gene', '113235', (291, 296))	('hPCFT', 'Gene', (291, 296))	('R1-11-PCFT4', 'Gene', '5514', (251, 262))	('R1-11-PCFT4', 'Gene', (251, 262))	('H2452 MPM', 'CellLine', 'CVCL:1553', (133, 142))	('R1-11', 'Gene', (251, 256))	('hRFC', 'Gene', '6573', (281, 285))	('HeLa', 'CellLine', 'CVCL:0030', (210, 214))	('R1-11', 'Gene', '5514', (302, 307))
91951	23412628	These results establish the presence of functional hPCFT in H2452 MPM cells.	('hPCFT', 'Gene', (51, 56))	('H2452 MPM', 'CellLine', 'CVCL:1553', (60, 69))	('hPCFT', 'Gene', '113235', (51, 56))	('H2452 MPM', 'Var', (60, 69))
91966	23412628	In H2452, this manifests as cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('cytotoxicity', 'Disease', (28, 40))	('H2452', 'Var', (3, 8))
92016	23412628	In this report, we studied the H2452 human malignant mesothelioma subline, a biphasic subtype composed of a mixture of epithelioid and sarcomatoid cells, representing the most aggressive form of this disease.	('mesothelioma subline', 'Disease', 'MESH:D008654', (53, 73))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (43, 65))	('sarcomatoid', 'Disease', (135, 146))	('human', 'Species', '9606', (37, 42))	('H2452', 'Var', (31, 36))	('mesothelioma subline', 'Disease', (53, 73))	('sarcomatoid', 'Disease', 'MESH:C538614', (135, 146))
92021	23412628	Further, H2452 like other MPM cell lines and primary patient specimens, express minimal amounts of FRalpha.	('FRalpha', 'Gene', (99, 106))	('FRalpha', 'Gene', '8061', (99, 106))	('H2452', 'Var', (9, 14))	('patient', 'Species', '9606', (53, 60))
92034	19929949	For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines.	('mesothelioma', 'Disease', (82, 94))	('Cul4A', 'Gene', (55, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('amplification', 'Var', (34, 47))	('Cul4A', 'Gene', '8451', (55, 60))
92041	19929949	Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line.	('faster', 'PosReg', (24, 30))	('degradation', 'MPA', (31, 42))	('Cul4A', 'Gene', '8451', (118, 123))	('p27', 'Var', (13, 16))	('Cul4A', 'Gene', (118, 123))	('degradation', 'MPA', (97, 108))	('p21', 'Var', (5, 8))	('degradation', 'biological_process', 'GO:0009056', ('31', '42'))	('degradation', 'biological_process', 'GO:0009056', ('97', '108'))	('Cul4A', 'Gene', (52, 57))	('Cul4A', 'Gene', '8451', (52, 57))
92042	19929949	Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma.	('mesothelioma', 'Disease', (110, 122))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('overexpression', 'PosReg', (49, 63))	('Cul4A', 'Gene', '8451', (25, 30))	('amplification', 'Var', (31, 44))	('Cul4A', 'Gene', (25, 30))
92051	19929949	Inactivation of Cul4A is associated with G1 cell-cycle arrest both in Drosophila and human cells, and overexpression of Cul4A increases cell growth in irradiated mammary epithelial cells.	('increases', 'PosReg', (126, 135))	('G1 cell-cycle arrest', 'CPA', (41, 61))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('Cul4A', 'Gene', '8451', (16, 21))	('Cul4A', 'Gene', (16, 21))	('overexpression', 'PosReg', (102, 116))	('cell growth', 'CPA', (136, 147))	('Cul4A', 'Gene', '8451', (120, 125))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('Cul4A', 'Gene', (120, 125))	('Drosophila', 'Species', '7227', (70, 80))	('Inactivation', 'Var', (0, 12))	('human', 'Species', '9606', (85, 90))
92054	19929949	In addition, Cul4A overexpression may contribute to tumorgenesis and cancer development in cancer cells, because Cul4A has been observed in the ubiquitination and proteolysis of tumour suppressors, such as p21, p27, DDB2 and p53.	('p53', 'Gene', (225, 228))	('Cul4A', 'Gene', '8451', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('ubiquitination', 'MPA', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', (178, 184))	('Cul4A', 'Gene', (13, 18))	('p21', 'Var', (206, 209))	('p27', 'Gene', (211, 214))	('proteolysis', 'MPA', (163, 174))	('proteolysis', 'biological_process', 'GO:0006508', ('163', '174'))	('Cul4A', 'Gene', '8451', (13, 18))	('cancer', 'Disease', (69, 75))	('DDB2', 'Gene', '1643', (216, 220))	('tumorgenesis and cancer', 'Disease', 'MESH:D009369', (52, 75))	('DDB2', 'Gene', (216, 220))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('contribute', 'Reg', (38, 48))	('p53', 'Gene', '7157', (225, 228))	('Cul4A', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('observed', 'Reg', (128, 136))
92080	19929949	The following primary antibodies were used: Cul4A (Abcam, Cambridge, MA, USA), p27, p21 (Santa Cruz, CA, USA), p53 and beta-actin (Sigma).	('p21', 'Var', (84, 87))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('Cul4A', 'Gene', '8451', (44, 49))	('beta-actin', 'Gene', (119, 129))	('beta-actin', 'Gene', '728378', (119, 129))	('Cul4A', 'Gene', (44, 49))	('p27', 'Var', (79, 82))
92101	19929949	The lysates from these stably transfected cells were analysed for expression of p53, p21 and p27 proteins, which are important regulators of the cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('proteins', 'Protein', (97, 105))	('p53', 'Gene', (80, 83))	('p53', 'Gene', '7157', (80, 83))	('p21', 'Protein', (85, 88))	('p27', 'Var', (93, 96))
92106	19929949	To confirm this, HCT116 p-53 null (-/-) colon cancer cells were transfected with Cul4A shRNA, and increased levels of p21 and p27 proteins were also noted after Cul4A shRNA knockdown (Fig.	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('levels', 'MPA', (108, 114))	('HCT116', 'CellLine', 'CVCL:0291', (17, 23))	('knockdown', 'Var', (173, 182))	('Cul4A', 'Gene', '8451', (161, 166))	('colon cancer', 'Disease', (40, 52))	('Cul4A', 'Gene', '8451', (81, 86))	('Cul4A', 'Gene', (161, 166))	('Cul4A', 'Gene', (81, 86))	('increased', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('p21', 'MPA', (118, 121))	('p27 proteins', 'MPA', (126, 138))
92109	19929949	A time-course study showed significantly more G0/G1 cells in Cul4A knockdown H290 and H28 cells at 0 hr, 2 hrs and 8 hrs and Cul4A knockdown MS-1 cells at 8 hrs (Fig.	('Cul4A', 'Gene', '8451', (125, 130))	('Cul4A', 'Gene', (125, 130))	('knockdown', 'Var', (67, 76))	('G0/G1 cells', 'CPA', (46, 57))	('Cul4A', 'Gene', '8451', (61, 66))	('more', 'PosReg', (41, 45))	('Cul4A', 'Gene', (61, 66))	('H290', 'CellLine', 'CVCL:A555', (77, 81))
92111	19929949	Significantly lower colony numbers were noted in Cul4A knockdown H290, H28 and MS-1 mesothelioma cells than in controls (Fig.	('knockdown', 'Var', (55, 64))	('Cul4A', 'Gene', (49, 54))	('lower', 'NegReg', (14, 19))	('colony numbers', 'CPA', (20, 34))	('H290', 'CellLine', 'CVCL:A555', (65, 69))	('MS-1 mesothelioma', 'Disease', 'MESH:D009103', (79, 96))	('MS-1 mesothelioma', 'Disease', (79, 96))	('Cul4A', 'Gene', '8451', (49, 54))
92112	19929949	To determine roles of p21 and p27 in G0/G1 cell cycle arrest after Cul4A down-regulation, cell cycle analysis was performed at 72 and 96 hrs after transient transfection of p21 and/or p27 siRNA in H290 cells transfected with Cul4A shRNA.	('down-regulation', 'NegReg', (73, 88))	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('Cul4A', 'Gene', (225, 230))	('p21', 'Var', (173, 176))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('43', '60'))	('Cul4A', 'Gene', '8451', (67, 72))	('Cul4A', 'Gene', (67, 72))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('p27 siRNA', 'Var', (184, 193))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('H290', 'CellLine', 'CVCL:A555', (197, 201))	('Cul4A', 'Gene', '8451', (225, 230))
92113	19929949	Notably, compared to the cell cycle of empty vector transfected H290 cells, H290 cells transfected with Cul4A shRNA showed partially reversed effects of G0/G1 arrest at 96 hrs after p21 and/or p27 siRNA transfection (Fig.	('Cul4A', 'Gene', (104, 109))	('Cul4A', 'Gene', '8451', (104, 109))	('G0/G1 arrest', 'CPA', (153, 165))	('p21', 'Var', (182, 185))	('H290', 'CellLine', 'CVCL:A555', (76, 80))	('cell cycle', 'biological_process', 'GO:0007049', ('25', '35'))	('p27 siRNA', 'Var', (193, 202))	('H290', 'CellLine', 'CVCL:A555', (64, 68))
92115	19929949	In the contrary to Cul4A knockdown, overexpression of ectopic Cul4A in H28 mesothelioma cells down-regulates p21 and p27 proteins (Fig.	('Cul4A', 'Gene', (62, 67))	('ectopic', 'Var', (54, 61))	('Cul4A', 'Gene', '8451', (19, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('Cul4A', 'Gene', (19, 24))	('p21', 'Protein', (109, 112))	('down-regulates', 'NegReg', (94, 108))	('p27 proteins', 'Protein', (117, 129))	('Cul4A', 'Gene', '8451', (62, 67))	('mesothelioma', 'Disease', (75, 87))
92123	19929949	Further knockdown of Cul4A by shRNA in mesothelioma cells also inhibited cells growth.	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('cells growth', 'CPA', (73, 85))	('knockdown', 'Var', (8, 17))	('inhibited', 'NegReg', (63, 72))	('Cul4A', 'Gene', '8451', (21, 26))	('Cul4A', 'Gene', (21, 26))	('mesothelioma', 'Disease', (39, 51))
92124	19929949	In the contrary, overexpression of ectopic Cul4A in mesothelioma cells promoted cells growth.	('promoted', 'PosReg', (71, 79))	('Cul4A', 'Gene', '8451', (43, 48))	('Cul4A', 'Gene', (43, 48))	('mesothelioma', 'Disease', (52, 64))	('cells growth', 'CPA', (80, 92))	('ectopic', 'Var', (35, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
92125	19929949	Thus, our results indicate that amplification of Cul4A gene may be an important oncogenic event in mesothelioma development.	('Cul4A', 'Gene', (49, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('amplification', 'Var', (32, 45))	('mesothelioma', 'Disease', (99, 111))	('Cul4A', 'Gene', '8451', (49, 54))
92129	19929949	Third, a very recent report provided the evidence of direct degradation of p21 through a Cul4-DDB1Cdt2 pathway, suggesting that up-regulation of p21 may be due to decreased proteolysis of p21 after Cul4A knockdown without participation of p53.	('knockdown', 'Var', (204, 213))	('Cul4A', 'Gene', '8451', (198, 203))	('proteolysis', 'MPA', (173, 184))	('up-regulation', 'PosReg', (128, 141))	('p21', 'Gene', (145, 148))	('proteolysis', 'biological_process', 'GO:0006508', ('173', '184'))	('Cul4A', 'Gene', (198, 203))	('DDB1', 'Gene', '1642', (94, 98))	('p53', 'Gene', (239, 242))	('DDB1', 'Gene', (94, 98))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('decreased', 'NegReg', (163, 172))	('p53', 'Gene', '7157', (239, 242))	('p21', 'Gene', (188, 191))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))
92137	19929949	In this study, up-regulation of p21 and p27 proteins after Cul4A knockdown and down-regulation of p21 and p27 proteins after expression of ectopic Cul4A were observed.	('p27 proteins', 'Protein', (40, 52))	('p27', 'Protein', (106, 109))	('knockdown', 'Var', (65, 74))	('Cul4A', 'Gene', '8451', (147, 152))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('up-regulation', 'PosReg', (15, 28))	('p21', 'Protein', (32, 35))	('regulation', 'biological_process', 'GO:0065007', ('18', '28'))	('Cul4A', 'Gene', '8451', (59, 64))	('p21', 'Protein', (98, 101))	('Cul4A', 'Gene', (59, 64))	('down-regulation', 'NegReg', (79, 94))	('Cul4A', 'Gene', (147, 152))
92140	19929949	Deficiency of p21 protein is associated with abrogation of cells that undergo G1 arrest after DNA damage in p21 knockout mice and colon cancer cells.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('abrogation', 'NegReg', (45, 55))	('cells', 'CPA', (59, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('protein', 'Protein', (18, 25))	('p21', 'Gene', (14, 17))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('mice', 'Species', '10090', (121, 125))	('colon cancer', 'Disease', (130, 142))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Deficiency', 'Var', (0, 10))
92141	19929949	Overexpression of p21 in hamster BHK21 cells causes cell cycle arrest in G1 phase, and reduces cell growth and DNA synthesis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('52', '69'))	('cell cycle arrest in G1 phase', 'CPA', (52, 81))	('reduces', 'NegReg', (87, 94))	('cell growth', 'biological_process', 'GO:0016049', ('95', '106'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('cell growth', 'CPA', (95, 106))	('DNA synthesis', 'biological_process', 'GO:0071897', ('111', '124'))	('Overexpression', 'Var', (0, 14))	('G1 phase', 'biological_process', 'GO:0051318', ('73', '81'))	('hamster', 'Species', '10034', (25, 32))	('BHK21', 'CellLine', 'CVCL:1914', (33, 38))
92142	19929949	In addition to p21 overexpression, we noted up-regulation of p27 after Cul4A knockdown.	('p27', 'Protein', (61, 64))	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('Cul4A', 'Gene', '8451', (71, 76))	('knockdown', 'Var', (77, 86))	('Cul4A', 'Gene', (71, 76))	('up-regulation', 'PosReg', (44, 57))
92143	19929949	p27 is also a cyclin-dependent kinase inhibitor, and its expression inversely correlates with poor patient prognosis in a large variety of cancers.	('patient', 'Species', '9606', (99, 106))	('expression', 'MPA', (57, 67))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('p27', 'Var', (0, 3))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('31', '47'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('14', '47'))
92144	19929949	In mouse models, p27 has been noted to be a haplo-insufficient tumour suppressor.	('mouse', 'Species', '10090', (3, 8))	('p27', 'Var', (17, 20))	('haplo-insufficient tumour', 'Disease', 'MESH:D000309', (44, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('haplo-insufficient tumour', 'Disease', (44, 69))
92145	19929949	Previous work has shown that inactivation of the Cul4A ubiquitin E3 ligases pathway by siRNA knockdown of Cul4A is associated with p27 stabilization and p27-dependent G1 cell cycle arrest in human cancer cells.	('knockdown', 'Var', (93, 102))	('stabilization', 'MPA', (135, 148))	('Cul4A', 'Gene', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (170, 187))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('170', '187'))	('cancer', 'Disease', (197, 203))	('Cul4A', 'Gene', '8451', (106, 111))	('ubiquitin', 'molecular_function', 'GO:0031386', ('55', '64'))	('inactivation', 'NegReg', (29, 41))	('Cul4A', 'Gene', (106, 111))	('p27', 'Protein', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('human', 'Species', '9606', (191, 196))	('p27-dependent G1 cell cycle arrest', 'CPA', (153, 187))	('Cul4A', 'Gene', '8451', (49, 54))
92146	19929949	However, the association of Cul4A knockdown and p21 up-regulation in human cancer cells has not been elucidated.	('up-regulation', 'PosReg', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('p21', 'Gene', (48, 51))	('cancer', 'Disease', (75, 81))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('Cul4A', 'Gene', '8451', (28, 33))	('knockdown', 'Var', (34, 43))	('Cul4A', 'Gene', (28, 33))
92148	19929949	Interestingly, knockdown of p21 and/or p27 at least partially reversed in Cul4A stably knockdown mesothelioma cells.	('p27', 'Var', (39, 42))	('Cul4A', 'Gene', '8451', (74, 79))	('knockdown', 'Var', (15, 24))	('Cul4A', 'Gene', (74, 79))	('mesothelioma', 'Disease', (97, 109))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('p21', 'Var', (28, 31))
92149	19929949	Importantly, up-regulation of p21 seems also to have effects on G0/G1 arrest in Cul4A knockdown mesothelioma cells, because restoration effects of G0/G1 arrest appear earlier and stronger after siRNA knockdown of p21 than after siRNA knockdown of p27.	('Cul4A', 'Gene', (80, 85))	('mesothelioma', 'Disease', (96, 108))	('effects', 'Reg', (53, 60))	('stronger', 'PosReg', (179, 187))	('regulation', 'biological_process', 'GO:0065007', ('16', '26'))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('p21', 'Var', (213, 216))	('up-regulation', 'PosReg', (13, 26))	('Cul4A', 'Gene', '8451', (80, 85))
92153	19929949	Our study demonstrates that the amplification of Cul4A may be an oncogenic event in mesothelioma development.	('Cul4A', 'Gene', (49, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('amplification', 'Var', (32, 45))	('mesothelioma', 'Disease', (84, 96))	('Cul4A', 'Gene', '8451', (49, 54))
92163	21904690	Lung carcinogenesis is a multistep process that arises from the accumulation of genetic and epigenetic modifications, which lead to the emergence of invasive cancer cells.	('epigenetic modifications', 'Var', (92, 116))	('Lung carcinogenesis', 'Disease', (0, 19))	('invasive cancer', 'Disease', (149, 164))	('Lung carcinogenesis', 'Disease', 'MESH:D063646', (0, 19))	('lead to', 'Reg', (124, 131))	('invasive cancer', 'Disease', 'MESH:D009362', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
92165	21904690	In addition, epigenetic modification of genes may also contribute to the development and progression of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('epigenetic modification', 'Var', (13, 36))	('genes', 'Gene', (40, 45))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('contribute', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
92174	21904690	Thus, the development and progression of cancer is due to both genetic mutations and epigenetic changes involving DNA methylation and histone modifications.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('histone', 'Protein', (134, 141))	('DNA', 'Var', (114, 117))	('DNA methylation', 'biological_process', 'GO:0006306', ('114', '129'))	('genetic mutations', 'Var', (63, 80))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
92200	21904690	The relatively greater expression of hK1, hKB1, and the B1 and B2 receptors, in H2126 compared with BEAS-2B cells, appeared to parallel the respective mRNA expression profiles in these two cell types.	('H2126', 'CellLine', 'CVCL:1532', (80, 85))	('hKB1', 'Gene', '390221', (42, 46))	('hK1', 'molecular_function', 'GO:0004673', ('37', '40'))	('hKB1', 'Gene', (42, 46))	('H2126', 'Var', (80, 85))	('hK1', 'Gene', '3848', (37, 40))	('BEAS-2B', 'CellLine', 'CVCL:0168', (100, 107))	('greater', 'PosReg', (15, 22))	('hK1', 'Gene', (37, 40))	('expression', 'MPA', (23, 33))
92208	21904690	KLK1 mRNA expression was greater in NO36 (>50-fold), LO68 (>30-fold), and JU77 cells (>2-fold) compared with Met-5A cells (Figure 3(a)).	('LO68', 'CellLine', 'CVCL:2581', (53, 57))	('JU77', 'Var', (74, 78))	('greater', 'PosReg', (25, 32))	('mRNA expression', 'MPA', (5, 20))	('KLK1', 'Gene', (0, 4))	('KLK1', 'Gene', '3816', (0, 4))	('LO68', 'Var', (53, 57))
92209	21904690	Similarly, basal KLKB1 mRNA expression was greater in JU77 (>45-fold), NO36 (>20-fold), and LO68 cells (10-fold) compared with Met-5A cells.	('KLKB1', 'Gene', (17, 22))	('JU77', 'Var', (54, 58))	('LO68', 'Var', (92, 96))	('mRNA expression', 'MPA', (23, 38))	('KLKB1', 'Gene', '3818', (17, 22))	('LO68', 'CellLine', 'CVCL:2581', (92, 96))	('greater', 'PosReg', (43, 50))
92220	21904690	The development of cancer is associated with gene mutations and epigenetic dysregulation of the nucleosome.	('epigenetic dysregulation', 'Var', (64, 88))	('gene mutations', 'Var', (45, 59))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('associated', 'Reg', (29, 39))	('nucleosome', 'cellular_component', 'GO:0000786', ('96', '106'))
92221	21904690	In tumours, about 60 to 70% of genes are methylated, resulting in silencing of these genes.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('methylated', 'Var', (41, 51))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('silencing', 'NegReg', (66, 75))
92235	21904690	Silencing of gene expression by methylation can be reversed by treatment with demethylating agents such as 5-azacytidine.	('methylation', 'Var', (32, 43))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('5-azacytidine', 'Chemical', 'MESH:D001374', (107, 120))	('Silencing', 'NegReg', (0, 9))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))
92239	21904690	These results therefore provide the first evidence that the KLKB1 gene is downregulated or silenced by aberrant methylation in carcinomas of the lung and pleura, and that KLKB1 may function as a tumour suppressor gene in these carcinomas.	('carcinomas', 'Disease', (127, 137))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('methylation', 'Var', (112, 123))	('tumour', 'Disease', (195, 201))	('KLKB1', 'Gene', (60, 65))	('carcinomas', 'Disease', (227, 237))	('KLKB1', 'Gene', '3818', (171, 176))	('silenced', 'NegReg', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('aberrant methylation', 'Var', (103, 123))	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('KLKB1', 'Gene', '3818', (60, 65))	('carcinomas of the lung and pleura', 'Disease', 'MESH:D054363', (127, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('carcinomas', 'Disease', 'MESH:D002277', (227, 237))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (127, 149))	('KLKB1', 'Gene', (171, 176))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('downregulated', 'NegReg', (74, 87))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
92244	21904690	Expression of kininogen mRNA was variable but tended to be upregulated after 5-AZA treatment in H520 cells and downregulated in NO36 and LO68 cells.	('H520', 'CellLine', 'CVCL:1566', (96, 100))	('LO68', 'CellLine', 'CVCL:2581', (137, 141))	('Expression', 'MPA', (0, 10))	('upregulated', 'PosReg', (59, 70))	('5-AZA treatment', 'Var', (77, 92))	('downregulated', 'NegReg', (111, 124))	('5-AZA', 'Chemical', 'MESH:D001374', (77, 82))
92250	21904690	The reason why expression of some kallikrein-kinin genes is downregulated after treatment with 5-AZA is not known, but possible explanations are that hypomethylation of CpG islands allows repressor proteins to access the gene, that there may be indirect epigenetic regulation through demethylation and reactivation of the genes for silencing proteins or repressor proteins, and that 5-AZA treatment may have unknown toxic effects on the expression of some genes.	('demethylation', 'Var', (284, 297))	('silencing proteins', 'Protein', (332, 350))	('regulation', 'biological_process', 'GO:0065007', ('265', '275'))	('kallikrein', 'Gene', '9622', (34, 44))	('kallikrein', 'Gene', (34, 44))	('demethylation', 'biological_process', 'GO:0070988', ('284', '297'))	('5-AZA', 'Chemical', 'MESH:D001374', (383, 388))	('proteins', 'Protein', (342, 350))	('kallikrein', 'molecular_function', 'GO:0003807', ('34', '44'))	('hypomethylation', 'Var', (150, 165))	('kallikrein', 'molecular_function', 'GO:0004293', ('34', '44'))	('5-AZA', 'Chemical', 'MESH:D001374', (95, 100))
92253	21904690	Although DNA methylation at CpG islands in the promoter region is known to cause gene silencing, the specific details of the demethylating effects of 5-AZA on particular genes are not clear.	('silencing', 'NegReg', (86, 95))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA', 'Var', (9, 12))	('gene', 'MPA', (81, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('gene silencing', 'biological_process', 'GO:0016458', ('81', '95'))	('5-AZA', 'Chemical', 'MESH:D001374', (150, 155))
92257	21904690	Furthermore, gene regulatory elements may not necessarily be located on the same chromosome or in close proximity to the genes that they regulate; thus methylation of CpG islands in regulatory elements at distal loci may affect expression of the kallikrein-kinin genes.	('kallikrein', 'Gene', (246, 256))	('kallikrein', 'Gene', '9622', (246, 256))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('affect', 'Reg', (221, 227))	('kallikrein', 'molecular_function', 'GO:0003807', ('246', '256'))	('kallikrein', 'molecular_function', 'GO:0004293', ('246', '256'))	('methylation', 'Var', (152, 163))	('expression', 'MPA', (228, 238))
92262	21904690	Advances in the characterization of epigenetic modifications in cancer cells have improved our understanding of the mechanisms of gene regulation.	('regulation', 'biological_process', 'GO:0065007', ('135', '145'))	('epigenetic modifications', 'Var', (36, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('improved', 'PosReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
92264	21904690	In addition, detection of methylated DNA in plasma of cancer patients may provide a noninvasive means of diagnosis or monitoring responses to treatment.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('methylated', 'Var', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
92265	21904690	Knowledge of the epigenetic changes that occur in specific genes should provide us with biomarkers for following cancer progression, as well as new tools for cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('epigenetic changes', 'Var', (17, 35))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
92266	21904690	This paper describes for the first time important new findings on epigenetic regulation of the kallikrein-kinin genes by DNA methylation in lung cancer and mesothelioma cells.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('lung cancer', 'Disease', (140, 151))	('mesothelioma', 'Disease', 'MESH:D008654', (156, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('kallikrein', 'Gene', (95, 105))	('kallikrein', 'Gene', '9622', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('kallikrein', 'molecular_function', 'GO:0004293', ('95', '105'))	('epigenetic regulation', 'MPA', (66, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('121', '136'))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('mesothelioma', 'Disease', (156, 168))	('kallikrein', 'molecular_function', 'GO:0003807', ('95', '105'))	('DNA methylation', 'Var', (121, 136))	('regulation', 'biological_process', 'GO:0065007', ('77', '87'))
92267	21904690	Our results show that following treatment with the demethylating agent, 5-azacytidine, expression of plasma kallikrein mRNA was consistently increased in both lung carcinoma and mesothelioma cells, whereas expression of tissue kallikrein, kininogen, and kinin B1 and B2 receptor mRNA was either decreased or unchanged.	('lung carcinoma', 'Disease', 'MESH:D008175', (159, 173))	('lung carcinoma', 'Disease', (159, 173))	('mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('increased', 'PosReg', (141, 150))	('kallikrein', 'molecular_function', 'GO:0004293', ('108', '118'))	('kallikrein', 'molecular_function', 'GO:0003807', ('108', '118'))	('plasma kallikrein', 'Gene', '3818', (101, 118))	('5-azacytidine', 'Chemical', 'MESH:D001374', (72, 85))	('tissue kallikrein', 'Gene', '3816', (220, 237))	('expression', 'MPA', (87, 97))	('plasma kallikrein', 'Gene', (101, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('B1 and B2 receptor', 'Gene', '623;624', (260, 278))	('5-azacytidine', 'Var', (72, 85))	('kallikrein', 'molecular_function', 'GO:0003807', ('227', '237'))	('kallikrein', 'molecular_function', 'GO:0004293', ('227', '237'))	('mesothelioma', 'Disease', (178, 190))	('tissue kallikrein', 'Gene', (220, 237))
92268	21904690	Increased expression of plasma kallikrein after 5-azacytidine treatment suggests that it may function as a tumour suppressor gene with an important and novel role in regulating the vasculature of cancers of the lung and pleura.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers of the lung', 'Disease', (196, 215))	('plasma kallikrein', 'Gene', '3818', (24, 41))	('plasma kallikrein', 'Gene', (24, 41))	('5-azacytidine', 'Chemical', 'MESH:D001374', (48, 61))	('expression', 'MPA', (10, 20))	('vasculature', 'MPA', (181, 192))	('cancers of the lung', 'Disease', 'MESH:D008175', (196, 215))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('Increased', 'PosReg', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('5-azacytidine', 'Var', (48, 61))	('kallikrein', 'molecular_function', 'GO:0003807', ('31', '41'))	('kallikrein', 'molecular_function', 'GO:0004293', ('31', '41'))	('tumour', 'Disease', (107, 113))
92290	33153245	Various immunohistochemical markers (epithelial membrane antigen, p53, p100, p-glycoprotein, desmin, etc.)	('p-glycoprotein', 'molecular_function', 'GO:0008559', ('77', '91'))	('p53', 'Gene', '7157', (66, 69))	('p-glycoprotein', 'Gene', (77, 91))	('membrane', 'cellular_component', 'GO:0016020', ('48', '56'))	('desmin', 'cellular_component', 'GO:0045098', ('93', '99'))	('desmin', 'Gene', (93, 99))	('p-glycoprotein', 'Gene', '5243', (77, 91))	('desmin', 'cellular_component', 'GO:0045100', ('93', '99'))	('p100', 'Var', (71, 75))	('desmin', 'Gene', '1674', (93, 99))	('p53', 'Gene', (66, 69))
92436	31857849	The presence of septin 7 is indispensable for cytokinesis in fibroblasts; deficiency causes incomplete cytokinesis and constitutive multinucleation.	('deficiency', 'Var', (74, 84))	('cytokinesis', 'biological_process', 'GO:0000910', ('46', '57'))	('incomplete cytokinesis', 'Disease', 'MESH:C536298', (92, 114))	('cytokinesis', 'biological_process', 'GO:0000910', ('103', '114'))	('incomplete cytokinesis', 'Disease', (92, 114))
92437	31857849	Constitutive deletion of septin 7 leads to early embryonic lethality in mice.	('leads to', 'Reg', (34, 42))	('embryonic lethality', 'Disease', 'MESH:D020964', (49, 68))	('septin 7', 'Gene', (25, 33))	('embryonic lethality', 'Disease', (49, 68))	('deletion', 'Var', (13, 21))	('mice', 'Species', '10090', (72, 76))
92445	31857849	Moreover, FCF induces septin polymerization and stabilizes extended septin polymers reversibly.	('stabilizes', 'MPA', (48, 58))	('induces', 'Reg', (14, 21))	('septin polymerization', 'MPA', (22, 43))	('FCF', 'Var', (10, 13))	('septin polymers', 'Chemical', '-', (68, 83))
92446	31857849	This process is inhibited by FCF in breast, lung, prostate and pancreas cancer cells in vitro indicating that septins play an essential role in the metastatic behavior of tumor cells.	('pancreas cancer', 'Disease', 'MESH:D010190', (63, 78))	('pancreas cancer', 'Phenotype', 'HP:0002894', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('FCF', 'Var', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('pancreas cancer', 'Disease', (63, 78))
92475	31857849	Likewise, disruption of filamentous septin structures by FCF reduces the tumorigenic properties like proliferation, migration and transformation in prostate cancer cells via ubiquitination and degradation of HIF-1alpha protein, a process normally prevented by filamentous septin structures.	('tumorigenic properties', 'CPA', (73, 95))	('FCF', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ubiquitination', 'MPA', (174, 188))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('degradation', 'MPA', (193, 204))	('HIF-1alpha', 'Gene', '15251', (208, 218))	('HIF-1alpha', 'Gene', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('degradation', 'biological_process', 'GO:0009056', ('193', '204'))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('migration', 'CPA', (116, 125))	('disruption', 'Var', (10, 20))	('transformation', 'CPA', (130, 144))	('reduces', 'NegReg', (61, 68))	('prostate cancer', 'Disease', (148, 163))
92508	23851502	Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome, due to mutations in either TSC1 encoding the protein harmartin, or TSC2 encoding the protein tuberin.	('tuberin', 'Gene', (175, 182))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('Tuberous sclerosis', 'Disease', (0, 18))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('TSC1', 'Gene', (109, 113))	('due', 'Reg', (82, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('TSC2', 'Gene', (149, 153))	('autosomal dominant tumor', 'Disease', (31, 55))	('autosomal dominant tumor', 'Disease', 'MESH:D030342', (31, 55))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('tuberin', 'Gene', '22084', (175, 182))
92510	23851502	In addition, TSC1 or TSC2 mutations have recently been identified at significant frequency in pancreatic neuroendocrine tumors, bladder cancer, PEComa, and are seen rarely in a variety of malignancies analyzed in the TCGA, e.g.	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('TSC2', 'Gene', (21, 25))	('malignancies', 'Disease', (188, 200))	('PEComa', 'Disease', (144, 150))	('identified', 'Reg', (55, 65))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (94, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('pancreatic neuroendocrine tumors', 'Disease', (94, 126))	('mutations', 'Var', (26, 35))	('TSC1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PEComa', 'Disease', 'MESH:D054973', (144, 150))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (105, 126))	('malignancies', 'Disease', 'MESH:D009369', (188, 200))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
92512	23851502	Both TSC-associated and TSC-independent cancers with mutation in TSC1 or TSC2 have shown dramatic responses to everolimus treatment in some cases.	('everolimus', 'Chemical', 'MESH:D000068338', (111, 121))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('mutation', 'Var', (53, 61))	('TSC-associated', 'Disease', (5, 19))	('TSC2', 'Gene', (73, 77))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('responses', 'MPA', (98, 107))	('TSC1', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('men', 'Species', '9606', (127, 130))
92516	23851502	In our initial experiments, we sought to induce a Tsc1-mutant bladder cancer model in mice, since TSC1 is known to be mutated in about 10% of bladder cancers, by injection of Adenovirus Cre into the bladders of mice that had various combinations of homozygous conditional alleles of each of Tsc1 and Tp53: wild type, Tsc1cc, Tp53cc, Tsc1ccTp53cc.	('mutated', 'Var', (118, 125))	('Tsc1', 'Gene', '64930', (291, 295))	('Tsc1', 'Gene', (333, 337))	('mice', 'Species', '10090', (86, 90))	('mice', 'Species', '10090', (211, 215))	('Tsc1ccTp53', 'Gene', '64930;22059', (333, 343))	('Tsc1', 'Gene', '64930', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Tsc1', 'Gene', (291, 295))	('TSC1', 'Gene', (98, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('Tp53', 'Gene', (325, 329))	('Tsc1', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('Tsc1ccTp53', 'Gene', (333, 343))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Tp53', 'Gene', '22059', (325, 329))	('bladder cancers', 'Phenotype', 'HP:0009725', (142, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('Tp53', 'Gene', (300, 304))	('Tp53', 'Gene', '22059', (300, 304))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('men', 'Species', '9606', (21, 24))	('Tsc1', 'Gene', '64930', (317, 321))	('Tp53', 'Gene', (339, 343))	('Tp53', 'Gene', '22059', (339, 343))	('bladder cancers', 'Disease', 'MESH:D001749', (142, 157))	('Tsc1', 'Gene', '64930', (333, 337))	('Tsc1', 'Gene', (317, 321))	('bladder cancers', 'Disease', (142, 157))
92567	23851502	We also examined the prevalence of TP53 mutation in these 9 lines, and found that two of them, H2452 and H2461, had mutations in TP53, c.817delCGTGTTTG and c.C817T, p.R273C, respectively.	('c.817delCGTGTTTG', 'Var', (135, 151))	('c.817delCGTGTTTG', 'Mutation', 'c.817delCGTGTTTG', (135, 151))	('p.R273C', 'Var', (165, 172))	('TP53', 'Gene', '22059', (35, 39))	('TP53', 'Gene', (35, 39))	('TP53', 'Gene', '22059', (129, 133))	('c.C817T', 'Var', (156, 163))	('p.R273C', 'Mutation', 'rs121913343', (165, 172))	('c.C817T', 'Mutation', 'rs121913343', (156, 163))	('TP53', 'Gene', (129, 133))
92572	23851502	There was a trend toward an association of high pS6(S235/S236) staining with reduced TSC2 staining (p = 0.0867) suggesting that there was the predicted relationship between those two phenomena in vivo in these tumors prior to resection.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('high', 'Var', (43, 47))	('pS6', 'Gene', (48, 51))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('TSC2 staining', 'MPA', (85, 98))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('reduced', 'NegReg', (77, 84))	('pS6', 'Gene', '338413', (48, 51))	('men', 'Species', '9606', (188, 191))
92573	23851502	Furthermore, the reduced expression of TSC2 that was seen suggests that genetic, epigenetic, or other mechanisms may lead to reduced TSC1/TSC2 expression in vivo in mesothelioma and contribute to its pathogenesis.	('expression', 'MPA', (143, 153))	('mesothelioma', 'Disease', (165, 177))	('pathogenesis', 'biological_process', 'GO:0009405', ('200', '212'))	('expression', 'MPA', (25, 35))	('reduced', 'NegReg', (125, 132))	('epigenetic', 'Var', (81, 91))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('TSC1/TSC2', 'Gene', (133, 142))	('reduced', 'NegReg', (17, 24))
92577	23851502	Further, pAKT(S473) levels were also shown to be increased in both murine and human mesothelioma cell lines under standard culture conditions, but were sharply reduced with overnight serum withdrawal, suggesting that growth factor stimulation was required for AKT activation and that it was not due to some intrinsic or genetic defect in AKT regulation or in upstream regulation, such as PIK3CA mutation or PTEN loss.	('AKT', 'Protein', (338, 341))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('murine', 'Species', '10090', (67, 73))	('regulation', 'biological_process', 'GO:0065007', ('368', '378'))	('PIK3CA', 'Gene', (388, 394))	('PTEN loss', 'Disease', 'MESH:D006223', (407, 416))	('PIK3CA', 'Gene', '5290', (388, 394))	('mutation', 'Var', (395, 403))	('regulation', 'biological_process', 'GO:0065007', ('342', '352'))	('reduced', 'NegReg', (160, 167))	('genetic defect', 'Disease', 'MESH:D030342', (320, 334))	('mesothelioma', 'Disease', (84, 96))	('PTEN loss', 'Disease', (407, 416))	('human', 'Species', '9606', (78, 83))	('genetic defect', 'Disease', (320, 334))
92586	23851502	Although our initial experiments were done with bladder injection of Adenovirus Cre in an attempt to generate a Tsc1 mutant model of bladder cancer, we then showed that similar and somewhat more consistent pathology and clinical phenotype were seen when AdenoCre was delivered directly to the peritoneum by IP injection.	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('Tsc1', 'Gene', (112, 116))	('mutant', 'Var', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Tsc1', 'Gene', '64930', (112, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('men', 'Species', '9606', (27, 30))
92587	23851502	Notably, loss of either Tp53 or Tsc1 alone by similar means led to a much lower rate of early mortality, and none of the mice with single gene loss developed malignant ascites, suggesting that mortality may have been due to another cause, possibly a different type of malignancy.	('malignant ascites', 'Disease', 'MESH:D001201', (158, 175))	('Tsc1', 'Gene', '64930', (32, 36))	('Tsc1', 'Gene', (32, 36))	('malignancy', 'Disease', 'MESH:D009369', (268, 278))	('Tp53', 'Gene', (24, 28))	('malignancy', 'Disease', (268, 278))	('Tp53', 'Gene', '22059', (24, 28))	('ascites', 'Phenotype', 'HP:0001541', (168, 175))	('loss', 'Var', (9, 13))	('early mortality', 'CPA', (88, 103))	('mice', 'Species', '10090', (121, 125))	('lower', 'NegReg', (74, 79))	('malignant ascites', 'Disease', (158, 175))
92590	23851502	This dramatic response is consistent with the response to rapamycin seen in multiple other tumor models involving loss of either Tsc1 or Tsc2, in which a similar near 99% reduction in tumor volume is seen.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('Tsc2', 'Gene', '22084', (137, 141))	('Tsc1', 'Gene', '64930', (129, 133))	('Tsc1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Tsc2', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'Var', (114, 118))	('reduction', 'NegReg', (171, 180))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('rapamycin', 'Chemical', 'MESH:D020123', (58, 67))	('tumor', 'Disease', (91, 96))	('response to rapamycin', 'biological_process', 'GO:1901355', ('46', '67'))
92592	23851502	Similarly, dramatic responses to rapamycin or everolimus have been reported in a small number of human PEComas, in which TSC2 mutations are very common, and in a single case of a bladder cancer with a TSC1 mutation.	('bladder cancer', 'Phenotype', 'HP:0009725', (179, 193))	('rapamycin', 'Chemical', 'MESH:D020123', (33, 42))	('TSC2', 'Gene', (121, 125))	('everolimus', 'Chemical', 'MESH:D000068338', (46, 56))	('human', 'Species', '9606', (97, 102))	('PEComas', 'Disease', (103, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (179, 193))	('bladder cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (126, 135))	('PEComas', 'Disease', 'MESH:D054973', (103, 110))
92600	23851502	Overall our studies suggest that loss of Tp53 and Tsc1 are critical gatekeeper mutations that enable mesothelial proliferation and mesothelioma development in the mouse.	('mesothelial proliferation', 'CPA', (101, 126))	('men', 'Species', '9606', (151, 154))	('Tp53', 'Gene', (41, 45))	('Tsc1', 'Gene', '64930', (50, 54))	('enable', 'PosReg', (94, 100))	('Tp53', 'Gene', '22059', (41, 45))	('mesothelioma', 'Disease', (131, 143))	('gatekeeper', 'Species', '111938', (68, 78))	('loss', 'Var', (33, 37))	('mouse', 'Species', '10090', (163, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))	('Tsc1', 'Gene', (50, 54))
92617	23851502	Nine human mesothelioma cell lines (H2373, H2452, H2461, H2591, H2595, H2596, HP-1, HP-3 and Met5A) were described previously, and were grown in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin-amphotericin B (PSA), in an incubator at 37 C in 5% CO2.	('H2452', 'Var', (43, 48))	('H2596', 'CellLine', 'CVCL:A546', (71, 76))	('penicillin-streptomycin-amphotericin B', 'Gene', '354', (183, 221))	('H2591', 'CellLine', 'CVCL:A543', (57, 62))	('CO2', 'Chemical', '-', (259, 262))	('H2373', 'Var', (36, 41))	('H2373', 'CellLine', 'CVCL:A533', (36, 41))	('penicillin-streptomycin-amphotericin B', 'Gene', (183, 221))	('mesothelioma', 'Disease', (11, 23))	('DMEM', 'Chemical', '-', (145, 149))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('H2461', 'Var', (50, 55))	('H2595', 'Var', (64, 69))	('H2596', 'Var', (71, 76))	('H2591', 'Var', (57, 62))	('H2595', 'CellLine', 'CVCL:A545', (64, 69))	('human', 'Species', '9606', (5, 10))	('FBS', 'Disease', (172, 175))	('men', 'Species', '9606', (156, 159))	('FBS', 'Disease', 'MESH:D005198', (172, 175))	('HP-1, HP-3', 'Gene', '23468;144124', (78, 88))
92652	29440675	The roots of resistance are most often ascribed to tumor heterogeneity, genetic mutation, oncogenic amplification, and changes in protein expression that influence the uptake, metabolism, and removal of drugs from the cell.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('metabolism', 'MPA', (176, 186))	('genetic mutation', 'Var', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('uptake', 'biological_process', 'GO:0098739', ('168', '174'))	('influence', 'Reg', (154, 163))	('tumor', 'Disease', (51, 56))	('uptake', 'biological_process', 'GO:0098657', ('168', '174'))	('changes', 'Var', (119, 126))	('uptake', 'MPA', (168, 174))	('removal of drugs from the', 'MPA', (192, 217))	('metabolism', 'biological_process', 'GO:0008152', ('176', '186'))	('protein', 'Protein', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
92655	29440675	Here, a tumor biopsy is profiled genetically to identify mutations that may indicate drugable targets.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))
92673	29440675	Precision medicine analysis of the tumor revealed two genomic alterations (BAP1 splice site 1729 + 1 G > A and PBRM1 N258fs*6) for which no targeted drugs or clinical trials were available.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('BAP1', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('N258fs', 'Mutation', 'p.N258fsX', (117, 123))	('tumor', 'Disease', (35, 40))	('PBRM1', 'Gene', '55193', (111, 116))	('1729 + 1 G > A', 'Mutation', 'c.1729+1G>A', (92, 106))	('PBRM1', 'Gene', (111, 116))	('BAP1', 'Gene', '8314', (75, 79))	('1729 + 1 G > A', 'Var', (92, 106))
92714	29440675	Results identified two known mutations in the tumor biospecimen: BAP1 splice site 1729 + 1 G > A and PBRM1 N258fs*6.	('1729 + 1 G > A', 'Mutation', 'c.1729+1G>A', (82, 96))	('N258fs*6', 'Var', (107, 115))	('BAP1', 'Gene', '8314', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('BAP1', 'Gene', (65, 69))	('N258fs', 'Mutation', 'p.N258fsX', (107, 113))	('PBRM1', 'Gene', (101, 106))	('PBRM1', 'Gene', '55193', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
92716	29440675	At the time of testing, neither mutation was associated with a therapy approved by the FDA for either mesothelioma or any other tumor type.	('mesothelioma', 'Disease', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('mutation', 'Var', (32, 40))
92717	29440675	However, the positive identification of the BAP1 gene mutation provided an opportunity to test an experimental targeted therapy: inhibition of enhancer of zeste homolog 2 (EZH2), a DNA methyltransferase and transcriptional repressor.	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('mutation', 'Var', (54, 62))	('EZH2', 'Gene', '2146', (172, 176))	('enhancer of zeste homolog 2', 'Gene', (143, 170))	('EZH2', 'Gene', (172, 176))	('BAP1', 'Gene', '8314', (44, 48))	('inhibition', 'NegReg', (129, 139))	('enhancer of zeste homolog 2', 'Gene', '2146', (143, 170))	('BAP1', 'Gene', (44, 48))
92718	29440675	Importantly, mutations of BAP1 have been targeted with success in animal models and in vitro studies by inhibition of EZH2.	('BAP1', 'Gene', (26, 30))	('inhibition', 'NegReg', (104, 114))	('EZH2', 'Gene', (118, 122))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (13, 22))	('EZH2', 'Gene', '2146', (118, 122))
92723	29440675	Importantly, HCT116 cells have been shown to undergo cell cycle arrest under DZNep exposure, but insignificant cell death, and so they were viewed as an appropriate control for this study.	('HCT116', 'Gene', (13, 19))	('HCT116', 'CellLine', 'CVCL:0291', (13, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('cell death', 'biological_process', 'GO:0008219', ('111', '121'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('53', '70'))	('DZNep', 'Var', (77, 82))	('cell cycle arrest', 'CPA', (53, 70))	('DZNep', 'Chemical', 'MESH:C048460', (77, 82))
92725	29440675	Although viability was similar for both HCT116 and mesothelioma without drug, the DZNep treated mesothelioma showed a concentration dependent decrease in metabolism and in relative live cell percentages (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('mesothelioma', 'Disease', (96, 108))	('mesothelioma', 'Disease', (51, 63))	('metabolism', 'biological_process', 'GO:0008152', ('154', '164'))	('decrease', 'NegReg', (142, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('DZNep', 'Var', (82, 87))	('metabolism', 'MPA', (154, 164))	('DZNep', 'Chemical', 'MESH:C048460', (82, 87))
92728	29440675	This response further indicated that DZNep reduced proliferation of the patient-derived sample specifically.	('patient', 'Species', '9606', (72, 79))	('DZNep', 'Var', (37, 42))	('reduced', 'NegReg', (43, 50))	('DZNep', 'Chemical', 'MESH:C048460', (37, 42))	('proliferation of the patient-derived', 'CPA', (51, 87))
92729	29440675	Additionally, immunohistochemistry indicated that Annexin V levels increased in mesothelioma with DZNep concentration, representing an increase in apoptotic cells (Fig.	('DZNep', 'Chemical', 'MESH:C048460', (98, 103))	('apoptotic cells', 'CPA', (147, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('increase', 'PosReg', (135, 143))	('increased', 'PosReg', (67, 76))	('Annexin V', 'Gene', '308', (50, 59))	('mesothelioma', 'Disease', (80, 92))	('Annexin V', 'Gene', (50, 59))	('DZNep concentration', 'Var', (98, 117))	('V levels increased', 'Phenotype', 'HP:0011996', (58, 76))
92736	29440675	5e) Precision oncology, whereby tumor DNA is sequenced to identify actionable gene mutations, is poised to become a standard clinical practice for therapeutic decision making of cancer treatment.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('oncology', 'Phenotype', 'HP:0002664', (14, 22))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('tumor', 'Disease', (32, 37))
92741	29440675	Patient cells also adapt to their new environment and exhibit genetic drift, adding variability.	('exhibit', 'Reg', (54, 61))	('genetic', 'Var', (62, 69))	('Patient', 'Species', '9606', (0, 7))
92751	29440675	Exposure to each drug for 7 days through infusion into circulating media via the microfluidic system yielded a distinctly higher efficacy for cisplatin/pemetrexed as compared to carboplatin/pemetrexed at the same concentrations in organoids derived from subject 1.	('pemetrexed', 'Chemical', 'MESH:D000068437', (152, 162))	('cisplatin/pemetrexed', 'Var', (142, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('carboplatin', 'Chemical', 'MESH:D016190', (178, 189))	('efficacy', 'MPA', (129, 137))	('higher', 'PosReg', (122, 128))	('pemetrexed', 'Chemical', 'MESH:D000068437', (190, 200))
92758	29440675	Second, genetic testing of the tumor cells from subject 1 identified two mutations specific to the studied tumor: BAP1 splice site 1729 + 1 G > A and PBRM1 N258fs*6.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PBRM1', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('N258fs*6', 'Var', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (31, 36))	('PBRM1', 'Gene', '55193', (150, 155))	('1729 + 1 G > A', 'Var', (131, 145))	('BAP1', 'Gene', '8314', (114, 118))	('1729 + 1 G > A', 'Mutation', 'c.1729+1G>A', (131, 145))	('N258fs', 'Mutation', 'p.N258fsX', (156, 162))	('BAP1', 'Gene', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
92760	29440675	At the time of these studies, neither mutation was associated with a FDA-approved therapy, either in mesothelioma or in any other tumor type, nor were any pertinent clinical trials under way.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mesothelioma', 'Disease', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutation', 'Var', (38, 46))	('tumor', 'Disease', (130, 135))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
92761	29440675	However, mutations of BAP1 have been targeted in animal models and in vitro studies by EZH2 inhibition, and so we queried organoid drug response to the EZH2 inhibitor DZNep as a demonstration vehicle for whether the identified mutation could be used as an actionable target (Figs 4 and 5).	('mutations', 'Var', (9, 18))	('EZH2', 'Gene', '2146', (87, 91))	('EZH2', 'Gene', (87, 91))	('BAP1', 'Gene', '8314', (22, 26))	('EZH2', 'Gene', (152, 156))	('EZH2', 'Gene', '2146', (152, 156))	('DZNep', 'Chemical', 'MESH:C048460', (167, 172))	('BAP1', 'Gene', (22, 26))
92782	29440675	Lastly, as precision oncology currently seeks to personalize therapies based on tumor genetic mutations, when such mutations are identified in the tumor, organoids from that tumor should respond when subjected to drugs that exploit those mutations.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutations', 'Var', (115, 124))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('oncology', 'Phenotype', 'HP:0002664', (21, 29))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
92817	29440675	For Annexin V and Ki67 staining (Abcam, Cambridge, MA, ab14196 and ab16667, respectively) in subsequent biomarker-driven experiments, an identical protocol was employed.	('Ki67', 'Chemical', '-', (18, 22))	('Annexin V', 'Gene', (4, 13))	('Annexin V', 'Gene', '308', (4, 13))	('ab16667', 'Var', (67, 74))
92870	29180928	The mean VEGF level in pleural effusion was detected as 3359 +-700 pg/ml in group 1, 2175 +-435 pg/ml in group 2, and 1092 +-435 pg/ml in group 3 (p = 0.041) in the sub-group analysis, while the difference between group 1 and group 2 (p = 0.233) and between group 2 and group 3 (p = 0.086) was not statistically significant.	('pleural effusion', 'Phenotype', 'HP:0002202', (23, 39))	('VEGF', 'Gene', (9, 13))	('VEGF', 'Gene', '7422', (9, 13))	('pleural effusion', 'Disease', 'MESH:D010996', (23, 39))	('pleural effusion', 'Disease', (23, 39))	('3359 +-700 pg/ml', 'Var', (56, 72))
92949	27801976	Thus, it is reasonable to postulate that disrupting or preventing TNT-mediated communication by targeted drugs or other means will present a novel therapeutic strategy.	('preventing', 'NegReg', (55, 65))	('disrupting', 'Var', (41, 51))	('TNT', 'Chemical', '-', (66, 69))	('rat', 'Species', '10116', (161, 164))	('TNT-mediated communication', 'MPA', (66, 92))
92967	27801976	Furthermore, they also provided clear evidence linking the finding of tumor microtubes to clinical prognosis, as they correlated microtubes to established prognostic factors in gliomas such as the presence or absence of deletions of chromosomes 1p and 19q.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor microtubes', 'Disease', (70, 86))	('gliomas', 'Disease', (177, 184))	('deletions', 'Var', (220, 229))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('tumor microtubes', 'Disease', 'MESH:D009369', (70, 86))
93025	27801976	Our group has demonstrated TNT-mediated intercellular transfer of miRNAs implicated in chemoresistance, including transfer between malignant and stromal cells as well as between malignant cells.	('chemoresistance', 'Disease', (87, 102))	('TNT', 'Chemical', '-', (27, 30))	('transfer', 'CPA', (114, 122))	('rat', 'Species', '10116', (21, 24))	('miRNAs', 'Var', (66, 72))
93028	25518732	The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40 Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies.	('malignancies', 'Disease', (221, 233))	('anti-CD40', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('Tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))
93041	25518732	Adjuvant immunotherapy is gaining renewed interest due to the recent success of checkpoint blockade with drugs such as anti-CTLA-4 and anti-PD-1.	('CTLA-4', 'Gene', (124, 130))	('CTLA-4', 'Gene', '12477', (124, 130))	('anti-PD-1', 'Var', (135, 144))
93045	25518732	Agonistic anti-CD40 (CP-870,893) further promotes DC-driven cytotoxic T lymphocyte (CTL) responses through its ability to substitute for CD4 T help and has shown some success in clinical trials due to its synergism with chemotherapy.	('CD4', 'Gene', (137, 140))	('CD4', 'Gene', '12504', (137, 140))	('DC-driven', 'MPA', (50, 59))	('CD40', 'Gene', '21939', (15, 19))	('promotes', 'PosReg', (41, 49))	('CD40', 'Gene', (15, 19))	('CD4', 'Gene', (15, 18))	('CD4', 'Gene', '12504', (15, 18))	('CP-870,893', 'Var', (21, 31))	('CP-870', 'Chemical', '-', (21, 27))
93062	25518732	For cell depletion studies, anti-CD4 (GK1.5) or anti-CD8 (YTS.169) (Ab Solutions, Perth, Australia) was administered from day 17 (1 day pre-surgery), given every second day for a total of three doses.	('CD4', 'Gene', (33, 36))	('CD4', 'Gene', '12504', (33, 36))	('pre', 'molecular_function', 'GO:0003904', ('136', '139'))	('anti-CD8', 'Var', (48, 56))
93082	25518732	There were no changes in the proportion of activated (ICOS+) CD4 or CD8 T cells in the different surgical debulking groups either in the tumor itself or in the peripheral lymphoid organs (data not shown).	('CD4', 'Gene', '12504', (61, 64))	('tumor', 'Disease', (137, 142))	('ICOS', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ICOS', 'Gene', '54167', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CD4', 'Gene', (61, 64))	('CD8', 'Var', (68, 71))
93091	25518732	In contrast to CD4 T cell depletion, which did not result in any long-term survivors, depletion of CD8 T cells resulted in a significantly decreased survival and increased residual tumour outgrowth compared to debulk plus IMQ ( and Figure 2).	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('increased', 'PosReg', (162, 171))	('survival', 'CPA', (149, 157))	('tumour outgrowth', 'Phenotype', 'HP:0001548', (181, 197))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('decreased', 'NegReg', (139, 148))	('tumour', 'Disease', (181, 187))	('CD4', 'Gene', (15, 18))	('CD4', 'Gene', '12504', (15, 18))	('CD8', 'Var', (99, 102))	('depletion', 'Var', (86, 95))	('IMQ', 'Chemical', 'MESH:D000077271', (222, 225))
93102	25518732	Combination treatment of debulking surgery with IMQ and anti-CD40 resulted in significant increases in CTL killing to over 45% in the dLN (p < 0.001), 15% in the ndLN (p < 0.05) and 15% in the spleen (p < 0.01) (Figure 4).	('CTL killing', 'CPA', (103, 114))	('IMQ', 'Var', (48, 51))	('increases', 'PosReg', (90, 99))	('IMQ', 'Chemical', 'MESH:D000077271', (48, 51))	('CD40', 'Gene', '21939', (61, 65))	('CD40', 'Gene', (61, 65))
93104	25518732	Overall, there was no significant difference between CD4 and CD8 T cell proportions and activation following debulking surgery compared to untreated mice, in all tissues analysed (Figure 6).	('mice', 'Species', '10090', (149, 153))	('CD4', 'Gene', (53, 56))	('CD8', 'Var', (61, 64))	('CD4', 'Gene', '12504', (53, 56))
93105	25518732	In the dLN, we found that mice receiving debulk + IMQ exhibited a slight increase in the percentage of both CD4 and CD8 T cells compared to debulk alone, while the activation status (ICOS expression) of CD4 T and CD8 T cells remained unchanged compared to both debulk alone and untreated mice (Figure 6).	('CD4', 'Gene', (203, 206))	('increase', 'PosReg', (73, 81))	('debulk + IMQ', 'Var', (41, 53))	('CD4', 'Gene', '12504', (203, 206))	('CD8 T cells', 'CPA', (116, 127))	('CD4', 'Gene', (108, 111))	('ICOS', 'Gene', '54167', (183, 187))	('CD4', 'Gene', '12504', (108, 111))	('ICOS', 'Gene', (183, 187))	('mice', 'Species', '10090', (288, 292))	('IMQ', 'Chemical', 'MESH:D000077271', (50, 53))	('mice', 'Species', '10090', (26, 30))
93109	25518732	There was also a trend towards increasing CD8 T cell activation, with >10% increase following debulk + anti-CD40 and >20% increase following debulk + IMQ + anti-CD40 (Figure 7).	('CD8 T cell', 'CPA', (42, 52))	('CD40', 'Gene', (161, 165))	('CD40', 'Gene', '21939', (108, 112))	('IMQ', 'Chemical', 'MESH:D000077271', (150, 153))	('CD40', 'Gene', (108, 112))	('activation', 'PosReg', (53, 63))	('T cell activation', 'biological_process', 'GO:0042110', ('46', '63'))	('debulk', 'Var', (94, 100))	('CD40', 'Gene', '21939', (161, 165))	('increase', 'PosReg', (75, 83))
93138	25518732	For future studies it would be interesting to incorporate a combination of immunotherapies that 'accelerate' the immune response (i.e., anti-CD40) and release the 'brakes' on existing responses (i.e., anti-CTLA-4, anti-PD-1) to produce an even stronger immune response after surgery.	('CTLA-4', 'Gene', (206, 212))	('CD40', 'Gene', '21939', (141, 145))	('immune response', 'CPA', (113, 128))	('immune response', 'biological_process', 'GO:0006955', ('113', '128'))	('CD40', 'Gene', (141, 145))	('immune response', 'MPA', (253, 268))	("'accelerate'", 'PosReg', (96, 108))	('immune response', 'biological_process', 'GO:0006955', ('253', '268'))	('CTLA-4', 'Gene', '12477', (206, 212))	('anti-PD-1', 'Var', (214, 223))
93146	32002299	Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (99, 108))	('cancers', 'Disease', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
93150	32002299	We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2.	('mutant', 'Var', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('UQCRC2', 'Gene', '67003', (136, 142))	('UQCRC2', 'Gene', (136, 142))	('tumor', 'Disease', (106, 111))
93155	32002299	Immunotherapies such as anti-cytotoxic T lymphocyte associated antigen (CTLA)-4 and anti-programmed death (PD)-1 antibodies can cause long term, durable tumor regression in some cancers.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cytotoxic T lymphocyte associated antigen (CTLA)-4', 'Gene', '12477', (29, 79))	('antibodies', 'Var', (113, 123))	('PD)-1', 'Gene', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancers', 'Disease', (178, 185))
93161	32002299	It has been observed that ICPB increases the magnitude of T cell responses against tumor neo-antigens, enabling detection of neo-antigen specific immune responses not detectable prior to treatment.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('enabling', 'PosReg', (103, 111))	('increases', 'PosReg', (31, 40))	('T cell responses', 'MPA', (58, 74))	('ICPB', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('detection', 'MPA', (112, 121))
93178	32002299	Mice bearing AB1/AB1-HA were administered intraperitoneally (ip) with 100 microg anti-CTLA-4 (clone 9H10; Bioceros; Netherlands) and 50 microg anti-GITR (clone DTA-1; BioXcell, NH, USA) antibodies in a total volume of 200 microL PBS at indicated time points.	('PBS', 'Chemical', 'MESH:C104682', (229, 232))	('CTLA-4', 'Gene', (86, 92))	('AB1/AB1-HA', 'Var', (13, 23))	('CTLA-4', 'Gene', '12477', (86, 92))	('NH', 'Chemical', 'MESH:D000641', (177, 179))	('GITR', 'Gene', '21936', (148, 152))	('Mice', 'Species', '10090', (0, 4))	('GITR', 'Gene', (148, 152))
93187	32002299	High-confidence SNVs as defined by Varscan (at least 10% mutant reads in tumor, < 5% in normal and a one-tailed Fisher's exact test P-value < 0.07) and Somatic sniper (variant supporting reads with an average mapping quality of >= 40 and a somatic score of >= 40) were pooled.	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutant reads', 'Var', (57, 69))
93194	32002299	IFNgamma SFU made in response to mutant peptides were compared to those made in responses to corresponding wild type peptides.	('IFNgamma', 'Gene', (0, 8))	('IFNgamma', 'Gene', '15978', (0, 8))	('mutant', 'Var', (33, 39))
93196	32002299	Target splenocytes were pulsed with either 1 mug/mL HA518-526 (IYSTVASSL), UNC45a730-738 mutant (IYEVVRSLV), UQCRC2405-413 wildtype (SYMPPSTVL) or UQCRC2405-413 mutant (SYMAPSTVL) peptides for 1 h at 37 C. After washing, cells pulsed with two different peptides were labeled with 2.5 muM of either CFSE (Invitrogen, VIC, Australia) (CFSEhi) or Violet-Tag (Biolegend, CA, USA) (Violethi) for 10 min at 37 C .	('VIC', 'Gene', '13615', (316, 319))	('mutant', 'Var', (161, 167))	('UNC45a', 'Gene', (75, 81))	('UNC45a', 'Gene', '101869', (75, 81))	('mug', 'molecular_function', 'GO:0043739', ('45', '48'))	('Violet', 'Chemical', 'MESH:C006394', (377, 383))	('UQCRC2', 'Gene', '67003', (109, 115))	('UQCRC2', 'Gene', (109, 115))	('Violet', 'Chemical', 'MESH:C006394', (344, 350))	('Violethi', 'Chemical', 'None', (377, 385))	('VIC', 'Gene', (316, 319))	('mutant', 'Var', (89, 95))	('UQCRC2', 'Gene', '67003', (147, 153))	('UQCRC2', 'Gene', (147, 153))
93200	32002299	UNC45a mutant synthetic long peptide (MTFPGERIYEVVRSLVSLLHLSCSGLQ) was emulsified in MontanideTM ISA 51 VG (Seppic, Paris, France).	('Montanide', 'Chemical', 'MESH:C477385', (85, 94))	('UNC45a', 'Gene', (0, 6))	('UNC45a', 'Gene', '101869', (0, 6))	('mutant', 'Var', (7, 13))
93202	32002299	Paired student's T-test was used to compare IFNgamma responses of individual mice to mutant peptide or controls.	('mutant', 'Var', (85, 91))	('mice', 'Species', '10090', (77, 81))	('IFNgamma', 'Gene', (44, 52))	('IFNgamma', 'Gene', '15978', (44, 52))
93208	32002299	There was no significant response against any of the 33 mutant peptides in the dLN of AB1-HA bearing animals (Figure 1a and b) yet strong, spontaneous responses to mutated UQCRC2 and HA peptides were again detected (Figure 1b).	('responses', 'MPA', (151, 160))	('UQCRC2', 'Gene', '67003', (172, 178))	('UQCRC2', 'Gene', (172, 178))	('mutated', 'Var', (164, 171))
93213	32002299	Substantial variability in immune responses against HA and mutant UQCRC2 peptides were observed between AB1-HA bearing animals (median response to HA: 17 SFU/105 cells, IQR 7-52; Mutant UQCRC2: 22 SFU/105 cells, IQR 11-43) (Figure 2a).	('UQCRC2', 'Gene', '67003', (66, 72))	('UQCRC2', 'Gene', (66, 72))	('UQCRC2', 'Gene', (186, 192))	('UQCRC2', 'Gene', '67003', (186, 192))	('mutant', 'Var', (59, 65))	('Mutant', 'Var', (179, 185))
93215	32002299	The number of IFNgamma SFU in response to HA and UQCRC2 mutant peptide correlated with each other (r2 = 0.7308, p < 0.0001) (Figure 2b).	('UQCRC2', 'Gene', (49, 55))	('UQCRC2', 'Gene', '67003', (49, 55))	('mutant', 'Var', (56, 62))	('IFNgamma', 'Gene', (14, 22))	('IFNgamma', 'Gene', '15978', (14, 22))
93216	32002299	There was no association between increasing tumor size and the magnitude of the neo-antigen responses (HA r2 = 0.03294, p = 0.1192; Mutant UQCRC2 r2 = 0.01283, p = 0.3365).	('Mutant', 'Var', (132, 138))	('UQCRC2', 'Gene', (139, 145))	('UQCRC2', 'Gene', '67003', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('neo-antigen', 'MPA', (80, 91))	('tumor', 'Disease', (44, 49))
93218	32002299	As there were minimal detectable immune responses against our panel of candidate neo-antigens, we hypothesised that ICPB would increase the magnitude and substantially broaden the range of neo-antigen responses, as suggested by some studies, albeit in outbred humans.	('ICPB', 'Var', (116, 120))	('increase', 'PosReg', (127, 135))	('neo-antigen responses', 'MPA', (189, 210))	('humans', 'Species', '9606', (260, 266))
93219	32002299	AB1-HA bearing animals were treated with a combination of anti-CT LA-4 and anti-GITR, which results in reliable immune-mediated tumor regression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('GITR', 'Gene', '21936', (80, 84))	('tumor', 'Disease', (128, 133))	('anti-CT', 'Var', (58, 65))	('GITR', 'Gene', (80, 84))
93220	32002299	We first tested for dLN responses against short peptides of the 33 neo-antigen panel and found significant responses against HA and mutant UQCRC2 peptides in both treated and untreated mice.	('UQCRC2', 'Gene', (139, 145))	('UQCRC2', 'Gene', '67003', (139, 145))	('mutant', 'Var', (132, 138))	('mice', 'Species', '10090', (185, 189))	('tested', 'Reg', (9, 15))
93222	32002299	Responses to mutant UQCRC2 long peptide were again detected and seen in both untreated and treated mice (Figure 3d, e).	('mutant', 'Var', (13, 19))	('UQCRC2', 'Gene', '67003', (20, 26))	('UQCRC2', 'Gene', (20, 26))	('mice', 'Species', '10090', (99, 103))
93226	32002299	We tested two more predicted minimal epitopes within the mutant UNC45a sequence, and observed reactivity to the 9mer IYEVVRSLV (H2-Kd, 364nM), but not RSLVSLLHL (H2-Dd, 7139nM)(Figure 3g).	('H2-Kd', 'Chemical', 'MESH:C542777', (128, 133))	('UNC45a', 'Gene', '101869', (64, 70))	('H2-Dd', 'Chemical', 'MESH:C062226', (162, 167))	('UNC45a', 'Gene', (64, 70))	('reactivity', 'MPA', (94, 104))	('mutant', 'Var', (57, 63))
93233	32002299	Responses to HA, mutant UQCRC2 and UNC45a in the dLN of treated mice were significantly higher compared to untreated mice (Figure 4a-c) (HA, 96 +- 101 vs 10 +- 35 SFU/105, p = 0.03; UQCRC2, 73 +- 71 vs 19 +- 22 SFU/105 p = 0.021; UNC45a, 83 +- 88 vs 15 +- 28 SFU/105, p = 0.03) and this increase in magnitude was also observed in the tumor (Figure 4d-f) (HA, 107 +- 68 vs 34 +- 32 SFU/104 CD8+ TILs, p = 0.002; UQCRC2, 172 +- 97 vs 53 +- 44 SFU/104 CD8+ TILs, p = 0.014; UNC45a, 159 +- 86 vs 18 +- 18 SFU/104 CD8+ TILs, p < 0.001).	('UQCRC2', 'Gene', '67003', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('mice', 'Species', '10090', (117, 121))	('UQCRC2', 'Gene', (182, 188))	('mutant', 'Var', (17, 23))	('UQCRC2', 'Gene', '67003', (411, 417))	('UNC45a', 'Gene', '101869', (230, 236))	('UNC45a', 'Gene', (230, 236))	('UQCRC2', 'Gene', (411, 417))	('tumor', 'Disease', (334, 339))	('UQCRC2', 'Gene', '67003', (24, 30))	('mice', 'Species', '10090', (64, 68))	('higher', 'PosReg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('UNC45a', 'Gene', (471, 477))	('UNC45a', 'Gene', '101869', (471, 477))	('UQCRC2', 'Gene', (24, 30))	('UNC45a', 'Gene', '101869', (35, 41))	('UNC45a', 'Gene', (35, 41))
93234	32002299	ICPB increased the proportion of individual mice that made a significant response to UNC45a in both the dLN (15% to 73%) and tumor (20% to 90%) (Table 1).	('ICPB', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('UNC45a', 'Gene', '101869', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('UNC45a', 'Gene', (85, 91))	('tumor', 'Disease', (125, 130))	('response', 'MPA', (73, 81))	('mice', 'Species', '10090', (44, 48))
93237	32002299	As the endogenous neo-antigen response varied between identical animals, we hypothesized that those with stronger mutant UQCRC2 and UNC45a ELISPOT responses would successfully respond to ICPB therapy.	('UQCRC2', 'Gene', '67003', (121, 127))	('UQCRC2', 'Gene', (121, 127))	('mutant', 'Var', (114, 120))	('respond', 'Reg', (176, 183))	('UNC45a', 'Gene', (132, 138))	('UNC45a', 'Gene', '101869', (132, 138))
93242	32002299	Similarly, the UNC45a response was significantly higher in the responders (24 +- 14 SFU/105 vs 5 +- 2 SFU/105, p = 0.0004) (Figure 5d).	('UNC45a', 'Gene', (15, 21))	('responders', 'Var', (63, 73))	('higher', 'PosReg', (49, 55))	('UNC45a', 'Gene', '101869', (15, 21))
93253	32002299	Again, mice that responded to ICPB had a higher UNC45a response pre-treatment compared to non-responders (37 +- 20 SFU/105 vs 11 +- 12 SFU/105 , p = 0.0016) (Figure 6g).	('ICPB', 'Var', (30, 34))	('pre', 'molecular_function', 'GO:0003904', ('64', '67'))	('mice', 'Species', '10090', (7, 11))	('UNC45a', 'Gene', '101869', (48, 54))	('higher', 'PosReg', (41, 47))	('UNC45a', 'Gene', (48, 54))
93255	32002299	Tumor mutations can be targets of anti-tumor immunity, and mutational load has been associated with response to ICPB in the clinic.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutational load', 'Var', (59, 74))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', (39, 44))
93261	32002299	Relaxing the immune suppressive environment in our model by ICPB increased the magnitude of immune responses against the endogenously recognized neo-antigen UQCRC2 by 3.5-fold and enabled immune responses to a previously undescribed neo-antigen, mutant UNC45a, to be detected.	('immune responses', 'MPA', (92, 108))	('UQCRC2', 'Gene', '67003', (157, 163))	('increased', 'PosReg', (65, 74))	('UNC45a', 'Gene', '101869', (253, 259))	('UNC45a', 'Gene', (253, 259))	('ICPB', 'Gene', (60, 64))	('mutant', 'Var', (246, 252))	('UQCRC2', 'Gene', (157, 163))	('immune responses', 'MPA', (188, 204))
93352	31068670	Studies on lung cancer tissue have shown that adenocarcinomas tend to exhibit less allelic loss than squamous cell carcinomas and that asbestos exposure correlates with a greater frequency of p53 mutation, which again implies a tumour promoting effect through loss of suppression.	('tumour', 'Disease', (228, 234))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('adenocarcinomas', 'Disease', 'MESH:D000230', (46, 61))	('p53', 'Gene', (192, 195))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (101, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('allelic loss', 'MPA', (83, 95))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('less', 'NegReg', (78, 82))	('lung cancer', 'Disease', (11, 22))	('squamous cell carcinomas', 'Disease', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('mutation', 'Var', (196, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('asbestos', 'Chemical', 'MESH:D001194', (135, 143))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('p53', 'Gene', '7157', (192, 195))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('adenocarcinomas', 'Disease', (46, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
93353	31068670	In mesotheliomas, increased mutation frequency has consistently been reported in tumour suppressors such as neurofibromatosis type 2 (NF2) and the nuclear deubiquitinase Bap1.	('mesotheliomas', 'Disease', 'MESH:D008654', (3, 16))	('mesotheliomas', 'Disease', (3, 16))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (108, 125))	('Bap1', 'Gene', '8314', (170, 174))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('155', '169'))	('tumour', 'Disease', (81, 87))	('NF2', 'Gene', '4771', (134, 137))	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (108, 132))	('mutation', 'Var', (28, 36))	('Bap1', 'Gene', (170, 174))	('neurofibromatosis type 2', 'Disease', (108, 132))	('NF2', 'Gene', (134, 137))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
93354	31068670	Monosomy of chromosome 22 or deletions in 22q that include NF2 as well as homozygous deletions in 9p21, which encompass the cyclin-dependent kinase inhibitor 2A (CDKN2A locus), are reported in up to 72% cases of mesothelioma, but there are also frequent deletions at other sites, including 1p, 3p, 4p, 6q, 13q, 14q, and 15q.	('Monosomy', 'Var', (0, 8))	('reported', 'Reg', (181, 189))	('CDKN2A', 'Gene', (162, 168))	('NF2', 'Gene', (59, 62))	('mesothelioma', 'Disease', (212, 224))	('deletions', 'Var', (85, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('CDKN2A', 'Gene', '1029', (162, 168))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('124', '157'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('141', '157'))	('NF2', 'Gene', '4771', (59, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (212, 224))	('deletions', 'Var', (29, 38))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (124, 160))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (124, 160))
93358	31068670	Notably, gene copy number changes are very common in oesophageal adenocarcinoma with a large number of chromosomal rearrangements reported.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('men', 'Species', '9606', (124, 127))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (53, 79))	('common', 'Reg', (43, 49))	('gene copy number changes', 'Var', (9, 33))	('oesophageal adenocarcinoma', 'Disease', (53, 79))
93359	31068670	It is perhaps not surprising that there is some overlap with the typical chromosomal alterations found in mesothelioma such as 9p21 deletions, which have long been known to occur early in disease pathogenesis, including in premalignant Barrett's oesophagus.	('mesothelioma', 'Disease', (106, 118))	('pathogenesis', 'biological_process', 'GO:0009405', ('196', '208'))	("premalignant Barrett's oesophagus", 'Disease', (223, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('9p21', 'Gene', (127, 131))	('deletions', 'Var', (132, 141))	("Barrett's oesophagus", 'Phenotype', 'HP:0100580', (236, 256))
93361	31068670	A complementary approach that has been facilitated by the advent of whole genome sequencing is to identify and classify mutational processes through the statistical analysis of the frequency of base changes (A > C, T > G, etc.)	('men', 'Species', '9606', (8, 11))	('A > C', 'Var', (208, 213))	('T > G', 'Var', (215, 220))
93364	31068670	The most frequent and specific signatures observed in oesophageal adenocarcinoma are T>G substitutions in a CTT context, called the 'S17 signature'.	('oesophageal adenocarcinoma', 'Disease', (54, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (54, 80))	('T>G substitutions', 'Var', (85, 102))	('substitutions', 'Var', (89, 102))
93365	31068670	Other signatures reflect ageing (S1); a complex pattern caused by defects in the BRCA1/2-led homologous recombination pathway (S3); C>T mutations in a TCA/TCT context, which is due to mutations in the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins (S2); and C>A/T dominant in a GCA/TCT context (S18), which is also found in gastric carcinoma as well as neuroblastoma.	('APOBEC', 'cellular_component', 'GO:0030895', ('267', '273'))	('homologous recombination', 'biological_process', 'GO:0035825', ('93', '117'))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('201', '215'))	('neuroblastoma', 'Disease', (389, 402))	('neuroblastoma', 'Phenotype', 'HP:0003006', (389, 402))	('BRCA1', 'Gene', '672', (81, 86))	('C>T mutations', 'Var', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (389, 402))	('BRCA1', 'Gene', (81, 86))	('C>A/T', 'Var', (294, 299))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('201', '215'))	('defects', 'NegReg', (66, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('gastric carcinoma', 'Disease', 'MESH:D013274', (360, 377))	('ageing', 'biological_process', 'GO:0007568', ('25', '31'))	('gastric carcinoma', 'Disease', (360, 377))	('apolipoprotein B', 'Protein', (201, 217))	('mRNA editing', 'biological_process', 'GO:0016556', ('218', '230'))	('GCA', 'molecular_function', 'GO:0033968', ('314', '317'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (360, 377))
93501	30533436	Furthermore, the ECBDT classifier consistently improves classification performance compared to other individual classifiers: SVM, ANN, NB, KNN, LR, LDA, and DT.	('ECBDT', 'Chemical', '-', (17, 22))	('classification performance', 'MPA', (56, 82))	('ECBDT', 'Var', (17, 22))	('improves', 'PosReg', (47, 55))
93614	25045139	The epitope of mAb 20A2 was searched against a series of deletion mutants of recombinant N-ERC/mesothelin protein expressed in an in vitro translation system using wheat germ extract, as described previously.	('N-ERC/mesothelin', 'Gene', '10232', (89, 105))	('deletion mutants', 'Var', (57, 73))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('translation', 'biological_process', 'GO:0006412', ('139', '150'))	('N-ERC/mesothelin', 'Gene', (89, 105))	('ERC', 'cellular_component', 'GO:0055037', ('91', '94'))	('wheat', 'Species', '4565', (164, 169))
93615	25045139	A series of recombinant proteins produced using the deletion mutant N-ERC/mesothelin construct was analyzed using western blotting analysis with mAb 20A2 to identify epitopes as described.	('N-ERC/mesothelin', 'Gene', '10232', (68, 84))	('N-ERC/mesothelin', 'Gene', (68, 84))	('ERC', 'cellular_component', 'GO:0055037', ('70', '73'))	('deletion mutant', 'Var', (52, 67))
93709	25526639	More importantly, humanized anti-CD26 antibody inhibited the growth of malignant mesothelioma cells and induced long-term survival of tumor-transplanted SCID mice.	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (71, 93))	('mice', 'Species', '10090', (158, 162))	('induced', 'PosReg', (104, 111))	('human', 'Species', '9606', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('malignant mesothelioma', 'Disease', (71, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (71, 93))	('SCID', 'Disease', 'MESH:D053632', (153, 157))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('anti-CD26', 'Gene', (28, 37))	('long-term survival', 'CPA', (112, 130))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))	('SCID', 'Disease', (153, 157))	('tumor', 'Disease', (134, 139))	('inhibited', 'NegReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('anti-CD26', 'Var', (28, 37))
93736	25526639	1A, serum sCD26 levels in patients with MPM were significantly decreased compared with the SPE group (P = 0.000).	('serum sCD26 levels', 'MPA', (4, 22))	('decreased', 'NegReg', (63, 72))	('patients', 'Species', '9606', (26, 34))	('MPM', 'Chemical', '-', (40, 43))	('MPM', 'Var', (40, 43))
93746	25526639	3C, the median OS of patients with MPM who had higher DPPIV enzyme activity (>=17.0 microM/min) was 15.0 months (95% CI, 8.1-21.9 months), which was significantly longer than that of those with lower DPPIV enzyme activity (<17.0 microM/min) who had a median OS of 11.4 months (95% CI, 7.8-15.0 months) (P = 0.032, log-rank test).	('MPM', 'Chemical', '-', (35, 38))	('DPPIV', 'Gene', '1803', (54, 59))	('enzyme activity', 'molecular_function', 'GO:0003824', ('206', '221'))	('enzyme activity', 'molecular_function', 'GO:0003824', ('60', '75'))	('higher', 'PosReg', (47, 53))	('patients', 'Species', '9606', (21, 29))	('activity', 'MPA', (67, 75))	('MPM', 'Var', (35, 38))	('DPPIV', 'Gene', (200, 205))	('DPPIV', 'Gene', '1803', (200, 205))	('DPPIV', 'Gene', (54, 59))
93794	25526639	On the other hand, inhibition of CD26 in renal cell carcinoma decreased tumor growth and reduced the ability of cancer cells to bind to fibronectin and collagen.	('renal cell carcinoma decreased tumor', 'Disease', (41, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('fibronectin', 'Gene', '2335', (136, 147))	('inhibition', 'Var', (19, 29))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('collagen', 'molecular_function', 'GO:0005202', ('152', '160'))	('reduced', 'NegReg', (89, 96))	('fibronectin', 'Gene', (136, 147))	('collagen', 'Protein', (152, 160))	('renal cell carcinoma decreased tumor', 'Disease', 'MESH:C538614', (41, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))	('ability', 'MPA', (101, 108))	('CD26', 'Protein', (33, 37))
93813	25526639	Although we cannot exclude the possibility that any genetic mutations or epigenetic modifications in CD26 appear to occur and potentiate DPPIV enzyme activity in the sarcomatous subtype of MPM, the discrepancy of specific DPPIV enzyme activity in the serum of patients with a sarcomatous subtype of MPM will be investigated in future studies.	('DPPIV', 'Gene', (222, 227))	('CD26', 'Gene', (101, 105))	('DPPIV', 'Gene', '1803', (222, 227))	('MPM', 'Chemical', '-', (189, 192))	('sarcomatous subtype', 'Disease', (166, 185))	('potentiate', 'PosReg', (126, 136))	('enzyme activity', 'molecular_function', 'GO:0003824', ('143', '158'))	('DPPIV', 'Gene', (137, 142))	('sarcomatous subtype', 'Disease', 'MESH:D018316', (166, 185))	('DPPIV', 'Gene', '1803', (137, 142))	('sarcomatous subtype', 'Disease', 'MESH:D018316', (276, 295))	('patients', 'Species', '9606', (260, 268))	('sarcomatous subtype', 'Disease', (276, 295))	('epigenetic modifications', 'Var', (73, 97))	('enzyme activity', 'molecular_function', 'GO:0003824', ('228', '243'))	('genetic mutations', 'Var', (52, 69))	('activity', 'MPA', (150, 158))	('MPM', 'Chemical', '-', (299, 302))
93831	25162674	Cooperation of epigenetic events including host genetic factors and carcinogens including virus infection, mainly SV40, has been also suggested for the onset of asbestos related malignancy.	('asbestos', 'Chemical', 'MESH:D001194', (161, 169))	('epigenetic', 'Var', (15, 25))	('malignancy', 'Disease', (178, 188))	('virus infection', 'Disease', 'MESH:D015658', (90, 105))	('virus infection', 'Disease', (90, 105))	('malignancy', 'Disease', 'MESH:D009369', (178, 188))
93832	25162674	Particularly, the direct involvement of the oncogenic virus SV40 in the growth and tumorigenicity of mesothelial cells, subordinate to insulin-like growth factor-1 release, has been documented and associated with a shorter survival of MM patients.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('growth', 'CPA', (72, 78))	('tumor', 'Disease', (83, 88))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('135', '161'))	('SV40', 'Var', (60, 64))	('shorter', 'NegReg', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('patients', 'Species', '9606', (238, 246))
93865	25162674	Of note, among the above cited cytokines, the C-C chemokine RANTES showed the highest level of expression documented by an increased concentration gradient from the healthy subjects (0.52 pg/ml) to the Asb-workers (23004 pg/ml) and MM patients (34539 pg/ml) (p<0.001) suggesting a strong association of this growth factor with the exposure to asbestos fibres.	('increased', 'PosReg', (123, 132))	('RANTES', 'Gene', (60, 66))	('34539', 'Var', (245, 250))	('23004 pg/ml', 'Var', (215, 226))	('patients', 'Species', '9606', (235, 243))	('RANTES', 'Gene', '6352', (60, 66))	('concentration', 'MPA', (133, 146))	('asbestos', 'Chemical', 'MESH:D001194', (343, 351))	('expression', 'MPA', (95, 105))
93868	25162674	The cytokines profile in SV40-positive MM patients compared to that of SV40-negative MM patients showed that six cytokines, IL-15, EOTAXIN, MIP-1beta, IL-18, IFN-alpha2, and HGF were up-regulated (p<0.01) whereas 2 cytokines, MCP-3 and MIF (p<0.01) were found at lower levels (Figure 4).	('MIF', 'Gene', '4282', (236, 239))	('MIP', 'molecular_function', 'GO:0004243', ('140', '143'))	('MCP', 'molecular_function', 'GO:0004298', ('226', '229'))	('SV40-positive', 'Var', (25, 38))	('IFN-alpha2', 'Gene', (158, 168))	('EOTAXIN', 'Gene', '6356', (131, 138))	('IL-15', 'Gene', '3600', (124, 129))	('MCP-3', 'Gene', (226, 231))	('IL-18', 'Gene', (151, 156))	('MIF', 'Gene', (236, 239))	('HGF', 'Gene', '3082', (174, 177))	('IL-15', 'molecular_function', 'GO:0016170', ('124', '129'))	('cytokines', 'MPA', (113, 122))	('IL-18', 'molecular_function', 'GO:0045515', ('151', '156'))	('HGF', 'Gene', (174, 177))	('MIP-1beta', 'Gene', '6351', (140, 149))	('patients', 'Species', '9606', (42, 50))	('IFN-alpha2', 'Gene', '3440', (158, 168))	('IL-18', 'Gene', '3606', (151, 156))	('MIP-1beta', 'Gene', (140, 149))	('up-regulated', 'PosReg', (183, 195))	('patients', 'Species', '9606', (88, 96))	('IL-15', 'Gene', (124, 129))	('MCP-3', 'Gene', '6354', (226, 231))	('EOTAXIN', 'Gene', (131, 138))	('cytokines', 'MPA', (4, 13))
93886	25162674	A synergistic action between SV40 and asbestos fibers has been recently suggested showing human mesothelioma cells to be highly sensitive to SV40-mediated transformation, acting on the expression of cellular growth factors.	('SV40-mediated', 'Var', (141, 154))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('mesothelioma', 'Disease', (96, 108))	('human', 'Species', '9606', (90, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('cellular growth', 'biological_process', 'GO:0016049', ('199', '214'))
93898	18973227	Deletions in chromosomes 22q12.2, 19q13.32, and 17p13.1 appeared to be the most frequent events (55-74%) shared between MM patients followed by deletions in 1p, 9p, 9q, 4p, 3p and gains in 5p, 18q, 8q, and 17q (23-55%).	('deletions', 'Var', (144, 153))	('Deletions', 'Var', (0, 9))	('patients', 'Species', '9606', (123, 131))
93899	18973227	Deletions in 9p21.3 encompassing CDKN2A/ARF and CDKN2B were characterized as specific for the short-term recurrence group.	('CDKN2B', 'Gene', '1030', (48, 54))	('CDKN2A', 'Gene', (33, 39))	('ARF', 'Disease', 'MESH:D058186', (40, 43))	('CDKN2A', 'Gene', '1029', (33, 39))	('ARF', 'Disease', (40, 43))	('CDKN2B', 'Gene', (48, 54))	('Deletions', 'Var', (0, 9))
93903	18973227	CGH analysis of cell lines and tumor specimens derived from MM patients has confirmed previous karyotypic abnormalities and has revealed other genomic alterations, such as losses of 15q11.1-15, 14q24.2-qter, and 13q12-14, as well as gains on 5p.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('14q24.2-qter', 'Var', (194, 206))	('13q12-14', 'Var', (212, 220))	('tumor', 'Disease', (31, 36))	('gains', 'Var', (233, 238))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('losses', 'Var', (172, 178))
93911	18973227	BglII genomic representations, and Cy3-dCTP (reference DNA) or Cy5-dCTP (DNA of interest) incorporation, hybridization, and washing conditions were done as described recently.	('Cy3-dCTP', 'Var', (35, 43))	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (63, 71))	('Cy5-dCTP', 'Var', (63, 71))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('Cy3-dCTP', 'Chemical', '-', (35, 43))
93931	18973227	However, in the model where stage is not incorporated, the CNA >5000 and platelet count > 350 were independent predictors of survival (p=0.01 and p=0.003, respectively) with a relative risk of death 3.7 fold and 6.9 fold higher than for lower CNAs and platelet counts.	('death', 'Disease', 'MESH:D003643', (193, 198))	('> 350', 'Var', (88, 93))	('death', 'Disease', (193, 198))	('CNA >5000', 'Var', (59, 68))	('higher', 'PosReg', (221, 227))
93932	18973227	The capability of ROMA to detect copy number alterations in individual tumor specimens was validated using Affymetrix 250K NspI arrays.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('copy number alterations', 'Var', (33, 56))
93935	18973227	Losses in chromosomes 22q12.2, 19, and 1p36 appeared to be the most frequent events (55-74%) in pleural MM followed by gains in 5p14-p15 and deletions in 17p and 9q (41-46%).	('p15', 'Gene', (133, 136))	('Losses', 'NegReg', (0, 6))	('p15', 'Gene', '1030', (133, 136))	('pleural MM', 'Disease', (96, 106))	('p14', 'Gene', '1029', (129, 132))	('gains', 'PosReg', (119, 124))	('deletions', 'Var', (141, 150))	('pleural MM', 'Disease', 'MESH:D010995', (96, 106))	('p14', 'Gene', (129, 132))
93936	18973227	Deletions in 1p13-21, 9p21, 3p14-21, and 17q21 as well as gains in 8q and 18q were observed in 27-36% of cases.	('p14', 'Gene', '1029', (29, 32))	('18q', 'Protein', (74, 77))	('p14', 'Gene', (29, 32))	('gains', 'PosReg', (58, 63))	('Deletions', 'Var', (0, 9))
93940	18973227	No discrimination between biphasic and epithelial types of MM was observed, and R125, the only sarcomatoid tumor in the study, clustered loosely with the rest of the group (Fig.	('R125', 'Var', (80, 84))	('sarcomatoid tumor', 'Disease', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('sarcomatoid tumor', 'Disease', 'MESH:C538614', (95, 112))	('sarcomatoid tumor', 'Phenotype', 'HP:0100242', (95, 112))
93954	18973227	Using RNA samples isolated from tumor specimens used for ROMA we found that DNAJA1 showed reduced expression in the STR cohort, which correlated with its allelic loss (4 out of 5 specimens with the deletions also showed down-regulation or lack of gene expression) pointing at the possible link between gene silencing and adverse clinical outcome (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('reduced', 'NegReg', (90, 97))	('gene silencing', 'biological_process', 'GO:0016458', ('302', '316'))	('expression', 'MPA', (98, 108))	('DNAJA1', 'Gene', '3301', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('regulation', 'biological_process', 'GO:0065007', ('225', '235'))	('gene expression', 'biological_process', 'GO:0010467', ('247', '262'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('down-regulation', 'NegReg', (220, 235))	('tumor', 'Disease', (32, 37))	('DNAJA1', 'Gene', (76, 82))	('lack', 'NegReg', (239, 243))	('deletions', 'Var', (198, 207))
93960	18973227	Loss of 9p21.3, observed by us in 32% of MM cases (Table 2), is one of the most thoroughly studied abnormalities in cancer and is linked to the tumor suppressors p16INK4aand p14ARF (encoded by alternative reading frames of CDKN2A), and p15INK4b (encoded by CDKN2B).	('CDKN2B', 'Gene', '1030', (257, 263))	('tumor', 'Disease', (144, 149))	('p14ARF', 'Gene', (174, 180))	('cancer', 'Disease', (116, 122))	('p15INK4b', 'Gene', (236, 244))	('p16INK4', 'Gene', '1029', (162, 169))	('p15INK4b', 'Gene', '1030', (236, 244))	('p16INK4', 'Gene', (162, 169))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('9p21.3', 'Gene', (8, 14))	('CDKN2B', 'Gene', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CDKN2A', 'Gene', (223, 229))	('p14ARF', 'Gene', '1029', (174, 180))	('Loss', 'Var', (0, 4))	('CDKN2A', 'Gene', '1029', (223, 229))
93961	18973227	About 85% of MM cell lines and more than 20% of MM tumor specimens show homozygous deletions in this chromosomal region.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MM tumor', 'Disease', (48, 56))	('deletions', 'Var', (83, 92))	('MM tumor', 'Disease', 'MESH:D009369', (48, 56))	('chromosomal region', 'cellular_component', 'GO:0098687', ('101', '119'))
93962	18973227	Mice deficient for all three 9p21.3 tumor suppressor genes are more tumor-prone and develop a wider spectrum of tumors than Cdkn2a mutant mice, with a preponderance of skin tumors and soft tissue sarcomas frequently composed of mixed cell types and often showing biphasic differentiation.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('skin tumors', 'Disease', 'MESH:D012878', (168, 179))	('sarcomas', 'Disease', 'MESH:D012509', (196, 204))	('Mice', 'Species', '10090', (0, 4))	('skin tumors', 'Phenotype', 'HP:0008069', (168, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))	('Cdkn2a', 'Gene', '12578', (124, 130))	('tumor', 'Disease', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('deficient', 'Var', (5, 14))	('tumor', 'Disease', (68, 73))	('sarcomas', 'Disease', (196, 204))	('mice', 'Species', '10090', (138, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (184, 204))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Disease', (173, 179))	('tumor', 'Disease', (112, 117))	('develop', 'Reg', (84, 91))	('Cdkn2a', 'Gene', (124, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('skin tumors', 'Disease', (168, 179))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (173, 178))	('tumors', 'Disease', (112, 118))
93963	18973227	Allelic loss and mutations in NF2, located at 22q12.2, have been observed in ~50% of MMs.	('NF2', 'Gene', '4771', (30, 33))	('MMs', 'Disease', (85, 88))	('loss', 'NegReg', (8, 12))	('NF2', 'Gene', (30, 33))	('MMs', 'Chemical', 'MESH:D008741', (85, 88))	('mutations', 'Var', (17, 26))
93967	18973227	We hypothesize that co-deletion of OSM with NF2 may be advantageous for tumor progression.	('NF2', 'Gene', '4771', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('co-deletion', 'Var', (20, 31))	('OSM', 'Gene', (35, 38))	('tumor', 'Disease', (72, 77))	('NF2', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
93970	18973227	The 3p21.3 deletion is involved in many malignancies including asbestos-associated lung cancers suggesting its significance for common tumorigenesis.	('asbestos', 'Chemical', 'MESH:D001194', (63, 71))	('lung cancers', 'Phenotype', 'HP:0100526', (83, 95))	('malignancies', 'Disease', (40, 52))	('3p21.3', 'Gene', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung cancers', 'Disease', (83, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Disease', (135, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('malignancies', 'Disease', 'MESH:D009369', (40, 52))	('lung cancers', 'Disease', 'MESH:D008175', (83, 95))	('deletion', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('involved', 'Reg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
93974	18973227	Forced expression of FUS1 resulted in tumor growth suppression, and its disruption in a mouse model produced a compromised immune response and increased susceptibility to spontaneous cancers.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('cancers', 'Disease', (183, 190))	('immune response', 'CPA', (123, 138))	('compromised immune response', 'Phenotype', 'HP:0002721', (111, 138))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('immune response', 'biological_process', 'GO:0006955', ('123', '138'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mouse', 'Species', '10090', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('susceptibility', 'Reg', (153, 167))	('disruption', 'Var', (72, 82))	('FUS1', 'Gene', (21, 25))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
93976	18973227	Silencing of PL6 observed in all clinical specimens of renal clear cell carcinoma (n=57) and other VHL-dependent malignancies suggests its involvement in early stages of VHL-deficient cancers.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('VHL-dependent malignancies', 'Disease', 'MESH:C563918', (99, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('involvement', 'Reg', (139, 150))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 81))	('VHL-dependent malignancies', 'Disease', (99, 125))	('VHL-deficient cancers', 'Disease', 'MESH:D006623', (170, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('PL6', 'Gene', (13, 16))	('PL6', 'Gene', '11070', (13, 16))	('VHL-deficient cancers', 'Disease', (170, 191))	('renal clear cell carcinoma', 'Disease', (55, 81))	('Silencing', 'Var', (0, 9))
93979	18973227	Remarkably, deletions that coincide with our MCA area (19p13) were recently found in asbestos-induced lung cancer and associated with the genotoxic effect of asbestos.	('deletions', 'Var', (12, 21))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('asbestos', 'Chemical', 'MESH:D001194', (158, 166))	('found', 'Reg', (76, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('asbestos-induced lung cancer', 'Disease', 'MESH:D008175', (85, 113))	('associated', 'Reg', (118, 128))	('asbestos-induced lung cancer', 'Disease', (85, 113))
93993	32723695	Role of non-coding-RNAs in response to environmental stressors and consequences on human health Environmental risk factors, including physicochemical agents, noise and mental stress, have a considerable impact on human health.	('human', 'Species', '9606', (213, 218))	('mental stress', 'Disease', (168, 181))	('human', 'Species', '9606', (83, 88))	('mental stress', 'Disease', 'MESH:D000079225', (168, 181))	('non-coding-RNAs', 'Var', (8, 23))	('impact', 'Reg', (203, 209))	('mental stress', 'Disease', (46, 59))	('mental stress', 'Disease', 'MESH:D000079225', (46, 59))
93996	32723695	We focus on well-studied miRNAs and analyze the novel roles of long-non-coding-RNAs (lncRNAs).	('As', 'Chemical', 'MESH:D001151', (81, 83))	('ncRNA', 'Gene', '220202', (86, 91))	('long-non-coding-RNAs', 'Var', (63, 83))	('miR', 'Gene', '220972', (25, 28))	('As', 'Chemical', 'MESH:D001151', (90, 92))	('miR', 'Gene', (25, 28))	('As', 'Chemical', 'MESH:D001151', (29, 31))	('ncRNA', 'Gene', (86, 91))
94000	32723695	Cellular dysregulation of ncRNAs can accelerate mechanisms of disease and malignancy like cancer, vascular disease or neurogenerative disease.	('malignancy', 'Disease', (74, 84))	('Cellular dysregulation', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ncRNA', 'Gene', (26, 31))	('neurogenerative disease', 'Phenotype', 'HP:0002180', (118, 141))	('rat', 'Species', '10116', (43, 46))	('neurogenerative disease', 'Disease', 'MESH:D020078', (118, 141))	('neurogenerative disease', 'Disease', (118, 141))	('vascular disease', 'Disease', 'MESH:D000783', (98, 114))	('rat', 'Species', '10116', (127, 130))	('ncRNA', 'Gene', '220202', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('cancer', 'Disease', (90, 96))	('accelerate', 'PosReg', (37, 47))	('vascular disease', 'Disease', (98, 114))	('As', 'Chemical', 'MESH:D001151', (30, 32))
94012	32723695	Those shorter than 200 nucleotides (nt) are considered short non-coding RNAs and include microRNAs (miRNAs), short interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), whereas those longer than 200 nt are termed long non-coding RNAs (lncRNAs).	('As', 'Chemical', 'MESH:D001151', (129, 131))	('As', 'Chemical', 'MESH:D001151', (74, 76))	('As', 'Chemical', 'MESH:D001151', (164, 166))	('As', 'Chemical', 'MESH:D001151', (137, 139))	('As', 'Chemical', 'MESH:D001151', (96, 98))	('As', 'Chemical', 'MESH:D001151', (172, 174))	('miR', 'Gene', '220972', (100, 103))	('As', 'Chemical', 'MESH:D001151', (104, 106))	('miR', 'Gene', (100, 103))	('ncRNA', 'Gene', (244, 249))	('As', 'Chemical', 'MESH:D001151', (248, 250))	('short interfering', 'Var', (109, 126))	('ncRNA', 'Gene', '220202', (244, 249))	('As', 'Chemical', 'MESH:D001151', (239, 241))
94037	32723695	They can be classified into five groups regarding genomic location: 1) stand-alone lncRNAs, 2) natural antisense transcripts, 3) pseudogenes, 4) long-intronic RNAs, and 5) promoter-associated RNAs or enhancers.	('ncRNA', 'Gene', (84, 89))	('As', 'Chemical', 'MESH:D001151', (88, 90))	('As', 'Chemical', 'MESH:D001151', (161, 163))	('ncRNA', 'Gene', '220202', (84, 89))	('long-intronic RNAs', 'Var', (145, 163))	('As', 'Chemical', 'MESH:D001151', (194, 196))
94039	32723695	These lncRNAs are transcribed by Pol II, polyadenylated and have multiple splicing isoforms.	('splicing', 'biological_process', 'GO:0045292', ('74', '82'))	('polyadenylated', 'Var', (41, 55))	('As', 'Chemical', 'MESH:D001151', (11, 13))	('ncRNA', 'Gene', (7, 12))	('ncRNA', 'Gene', '220202', (7, 12))
94046	32723695	A clear case is the antisense Igfr2 non-coding RNA (AIRN) that generates transcriptional interference with the imprinted Igfr2 gene, silencing the paternal allele.	('AIRN', 'Gene', '100271873', (52, 56))	('rat', 'Species', '10116', (67, 70))	('Igfr2', 'Gene', '9103', (30, 35))	('Igfr2', 'Gene', (121, 126))	('silencing', 'NegReg', (133, 142))	('Igfr2', 'Gene', '9103', (121, 126))	('AIRN', 'Gene', (52, 56))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('antisense', 'Var', (20, 29))	('Igfr2', 'Gene', (30, 35))	('gene, silencing', 'biological_process', 'GO:0016458', ('127', '142'))	('transcriptional interference', 'MPA', (73, 101))
94052	32723695	Abnormal expression of ncRNAs can induce developmental changes or lead to disease progression.	('induce', 'Reg', (34, 40))	('ncRNA', 'Gene', (23, 28))	('Abnormal expression', 'Var', (0, 19))	('men', 'Species', '9606', (48, 51))	('As', 'Chemical', 'MESH:D001151', (27, 29))	('developmental changes', 'CPA', (41, 62))	('ncRNA', 'Gene', '220202', (23, 28))	('lead to', 'Reg', (66, 73))	('disease progression', 'CPA', (74, 93))
94059	32723695	MALAT1 also dampens endogenous microRNAs and promotes changes in the redox state.	('As', 'Chemical', 'MESH:D001151', (38, 40))	('changes', 'Reg', (54, 61))	('endogenous microRNAs', 'MPA', (20, 40))	('dampens', 'NegReg', (12, 19))	('MALAT1', 'Var', (0, 6))	('promotes', 'PosReg', (45, 53))	('redox state', 'MPA', (69, 80))
94065	32723695	This mechanism has shown benefit in cancer cells, as inhibition of H19 increases oxidative stress on hepatocellular carcinoma and counteracts chemotherapy resistance.	('inhibition', 'Var', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('cancer', 'Disease', (36, 42))	('H19', 'Gene', (67, 70))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('increases', 'PosReg', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('oxidative stress', 'MPA', (81, 97))
94072	32723695	The lncRNAs hepatocyte nuclear factors 1A antisense-RNA-1 (HNF1A-AS1) and 4A antisense-RNA-1 (HNF4A-AS1) are important regulators of CYP gene expression as well, interfering with the xenobiotic-dependent CYP2E1 bioactivation.	('ncRNA', 'Gene', (5, 10))	('CYP', 'Gene', (133, 136))	('ncRNA', 'Gene', '220202', (5, 10))	('CYP2E1', 'Gene', (204, 210))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('As', 'Chemical', 'MESH:D001151', (9, 11))	('CYP', 'Gene', (204, 207))	('antisense-RNA-1', 'Var', (77, 92))	('HNF4A-AS1', 'Gene', (94, 103))	('xenobiotic-', 'Phenotype', 'HP:0031838', (183, 194))	('antisense-RNA', 'molecular_function', 'GO:0009388', ('77', '90'))	('gene expression', 'biological_process', 'GO:0010467', ('137', '152'))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))	('interfering', 'NegReg', (162, 173))	('CYP2E1', 'Gene', '1571', (204, 210))	('CYP', 'Gene', '9360', (133, 136))	('HNF4A-AS1', 'Gene', '101927219', (94, 103))	('hepatocyte nuclear factors 1A antisense-RNA-1 (HNF1A-AS1', 'Gene', '283460', (12, 68))	('antisense-RNA', 'molecular_function', 'GO:0009388', ('42', '55'))	('CYP', 'Gene', '9360', (204, 207))
94082	32723695	Inhibition of this specific lncRNA leads to senescence through a p16/pRB-dependent mechanism.	('p16', 'Gene', '1029', (65, 68))	('ncRNA', 'Gene', (29, 34))	('senescence', 'biological_process', 'GO:0010149', ('44', '54'))	('ncRNA', 'Gene', '220202', (29, 34))	('pRB', 'Gene', (69, 72))	('p16', 'Gene', (65, 68))	('Inhibition', 'Var', (0, 10))	('senescence', 'MPA', (44, 54))	('pRB', 'Gene', '5925', (69, 72))
94089	32723695	PCBs are associated with several vascular alterations such as endothelial cell dysfunction and atherosclerosis, by producing oxidative stress and induction of proinflammatory cytokines and cell adhesion proteins.	('atherosclerosis', 'Disease', 'MESH:D050197', (95, 110))	('atherosclerosis', 'Phenotype', 'HP:0002621', (95, 110))	('oxidative stress', 'MPA', (125, 141))	('rat', 'Species', '10116', (46, 49))	('endothelial cell dysfunction', 'Disease', (62, 90))	('vascular alterations', 'Phenotype', 'HP:0002597', (33, 53))	('induction', 'Reg', (146, 155))	('associated', 'Reg', (9, 19))	('cell adhesion', 'biological_process', 'GO:0007155', ('189', '202'))	('atherosclerosis', 'Disease', (95, 110))	('oxidative stress', 'Phenotype', 'HP:0025464', (125, 141))	('producing', 'Reg', (115, 124))	('PCBs', 'Var', (0, 4))	('PCBs', 'Chemical', 'MESH:D011078', (0, 4))	('proinflammatory cytokines', 'MPA', (159, 184))
94093	32723695	The polybrominated diphenyl ether BDE-209 reduces pluripotent gene expression via epigenetic regulation, including the modulation of miR-145 and miR-335 and the triggering of apoptosis through ROS generation.	('miR-145', 'Gene', '406937', (133, 140))	('miR-335', 'Gene', (145, 152))	('epigenetic regulation', 'MPA', (82, 103))	('diphenyl ether BDE-209', 'Chemical', '-', (19, 41))	('polybrominated', 'Var', (4, 18))	('reduces', 'NegReg', (42, 49))	('miR-145', 'Gene', (133, 140))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('modulation', 'MPA', (119, 129))	('ROS generation', 'biological_process', 'GO:1903409', ('193', '207'))	('pluripotent gene expression', 'MPA', (50, 77))	('polybrominated', 'Chemical', '-', (4, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('rat', 'Species', '10116', (201, 204))	('apoptosis', 'CPA', (175, 184))	('triggering', 'Reg', (161, 171))	('miR-335', 'Gene', '442904', (145, 152))	('ROS', 'Chemical', 'MESH:D017382', (193, 196))
94099	32723695	The perfluorocarboxylic acid PFNA generates hepatomegaly, increases hepatic triglycerides and total cholesterol, and enhances serum transaminases at least partially through the modulation of miR-34a, miR-362-3p, and miR-338-3p.	('miR-33', 'Gene', '777924', (216, 222))	('perfluorocarboxylic acid PFNA', 'Chemical', '-', (4, 33))	('increases', 'PosReg', (58, 67))	('enhances serum transaminases', 'Phenotype', 'HP:0002910', (117, 145))	('serum transaminases', 'MPA', (126, 145))	('miR', 'Gene', '220972', (216, 219))	('total cholesterol', 'MPA', (94, 111))	('rat', 'Species', '10116', (38, 41))	('miR', 'Gene', '220972', (191, 194))	('miR', 'Gene', '220972', (200, 203))	('hepatic triglycerides', 'MPA', (68, 89))	('triglycerides', 'Chemical', 'MESH:D014280', (76, 89))	('miR', 'Gene', (216, 219))	('miR-34a', 'Gene', (191, 198))	('hepatomegaly', 'Disease', (44, 56))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('enhances', 'PosReg', (117, 125))	('miR', 'Gene', (191, 194))	('miR', 'Gene', (200, 203))	('generates', 'PosReg', (34, 43))	('miR-33', 'Gene', (216, 222))	('perfluorocarboxylic acid', 'Var', (4, 28))	('modulation', 'Reg', (177, 187))	('miR-34a', 'Gene', '407040', (191, 198))	('hepatomegaly', 'Disease', 'MESH:D006529', (44, 56))	('hepatomegaly', 'Phenotype', 'HP:0002240', (44, 56))
94100	32723695	PFOS induces adipogenesis and glucose uptake in preadipocytes.	('adipogenesis', 'biological_process', 'GO:0045444', ('13', '25'))	('adipogenesis', 'biological_process', 'GO:0060612', ('13', '25'))	('PFOS', 'Chemical', 'MESH:C076994', (0, 4))	('glucose uptake', 'MPA', (30, 44))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('PFOS', 'Var', (0, 4))	('glucose uptake', 'biological_process', 'GO:0046323', ('30', '44'))	('adipogenesis', 'MPA', (13, 25))	('induces', 'Reg', (5, 12))
94111	32723695	Although the studies are limited, BPA affects gene imprinting in the placenta and global and CpG methylation.	('global', 'CPA', (82, 88))	('BPA', 'Chemical', 'MESH:C006780', (34, 37))	('affects', 'Reg', (38, 45))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('BPA', 'Gene', (34, 37))	('CpG', 'CPA', (93, 96))	('methylation', 'Var', (97, 108))
94118	32723695	miR-21a-5p promoted BPA-induced obesity in vivo while BPA-induced preadipocyte differentiation is repressed by miR-21a-5p by targeting map2k3 in the MKK3/p38/mitogen-activated protein kinase (MAPK) pathway.	('MKK', 'molecular_function', 'GO:0004708', ('149', '152'))	('obesity', 'Phenotype', 'HP:0001513', (32, 39))	('p38', 'Gene', (154, 157))	('miR-21a-5p', 'Var', (0, 10))	('map2k3', 'Gene', (135, 141))	('BPA', 'Chemical', 'MESH:C006780', (54, 57))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('MKK3', 'Gene', '5606', (149, 153))	('MKK3', 'Gene', (149, 153))	('miR-21a-5p', 'Chemical', '-', (111, 121))	('obesity', 'Disease', (32, 39))	('p38', 'Gene', '1432', (154, 157))	('map2k', 'molecular_function', 'GO:0004708', ('135', '140'))	('MAPK', 'molecular_function', 'GO:0004707', ('192', '196'))	('BPA', 'Chemical', 'MESH:C006780', (20, 23))	('miR-21a-5p', 'Chemical', '-', (0, 10))	('obesity', 'Disease', 'MESH:D009765', (32, 39))	('targeting', 'Reg', (125, 134))	('promoted', 'PosReg', (11, 19))	('map2k3', 'Gene', '5606', (135, 141))	('miR-21a-5p', 'Var', (111, 121))
94120	32723695	H19 is a lncRNA expressed from the maternal strand and hypermethylation of this ncRNA has been previously connected to changes in fetal growth.	('hypermethylation', 'Var', (55, 71))	('ncRNA', 'Gene', '220202', (80, 85))	('connected', 'Reg', (106, 115))	('ncRNA', 'Gene', (10, 15))	('ncRNA', 'Gene', '220202', (10, 15))	('ncRNA', 'Gene', (80, 85))
94123	32723695	Therefore, changes in the levels of H19 due to BPA can trigger severe complications in development.	('BPA', 'Chemical', 'MESH:C006780', (47, 50))	('men', 'Species', '9606', (94, 97))	('levels', 'MPA', (26, 32))	('changes', 'Var', (11, 18))	('trigger', 'Reg', (55, 62))	('H19', 'Protein', (36, 39))
94134	32723695	Li D et al., found a strong correlation between the lncRNAs AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 in human placenta and a number of maternal urinary phthalate metabolites.	('ncRNA', 'Gene', (53, 58))	('AS1', 'Gene', (72, 75))	('ncRNA', 'Gene', '220202', (53, 58))	('DACT3', 'Gene', '147906', (66, 71))	('LOC91450', 'Var', (113, 121))	('DLX6', 'Gene', '1750', (77, 81))	('AIRN', 'Gene', (60, 64))	('DACT3', 'Gene', (66, 71))	('AIRN', 'Gene', '100271873', (60, 64))	('phthalate', 'Chemical', 'MESH:C032279', (173, 182))	('AS1', 'Gene', '5729', (72, 75))	('human', 'Species', '9606', (125, 130))	('LOC143666', 'Var', (98, 107))	('DPP10', 'Gene', (83, 88))	('HOTTIP', 'Gene', (90, 96))	('DPP10', 'Gene', '57628', (83, 88))	('DLX6', 'Gene', (77, 81))	('As', 'Chemical', 'MESH:D001151', (57, 59))	('HOTTIP', 'Gene', '100316868', (90, 96))
94181	32723695	MiR-122-5p and miR-326-3p may serve as novel biomarkers for Cd-induced nephrotoxicity.	('miR-326-3p', 'Chemical', '-', (15, 25))	('nephrotoxicity', 'Disease', (71, 85))	('MiR-122-5p', 'Gene', '100188847', (0, 10))	('MiR-122-5p', 'Gene', (0, 10))	('Cd-induced', 'Disease', (60, 70))	('nephrotoxicity', 'Disease', 'MESH:D007674', (71, 85))	('miR-326-3p', 'Var', (15, 25))	('Cd', 'Chemical', 'MESH:D002104', (60, 62))
94194	32723695	Interestingly, the silencing of this ENST00000414355 decreased Cd-induced DNA damage through increased expression of essential DNA repair genes such as DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1.	('BARD1', 'Gene', (200, 205))	('increased', 'PosReg', (93, 102))	('ERCC1', 'Gene', (170, 175))	('OGG1', 'Gene', '4968', (164, 168))	('OGG1', 'Gene', (164, 168))	('BARD1', 'Gene', '580', (200, 205))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('DDB2', 'Gene', '1643', (158, 162))	('expression', 'MPA', (103, 113))	('XRCC1', 'Gene', '7515', (190, 195))	('DNA repair', 'biological_process', 'GO:0006281', ('127', '137'))	('Cd-induced DNA', 'Disease', (63, 77))	('RAD50', 'Gene', (183, 188))	('DDB2', 'Gene', (158, 162))	('DDB1', 'Gene', '1642', (152, 156))	('S', 'Chemical', 'MESH:D013455', (178, 179))	('MSH2', 'Chemical', '-', (177, 181))	('silencing', 'Var', (19, 28))	('ENST00000414355', 'Gene', (37, 52))	('RAD50', 'Gene', '10111', (183, 188))	('decreased', 'NegReg', (53, 62))	('DDB1', 'Gene', (152, 156))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('RAD', 'biological_process', 'GO:1990116', ('183', '186'))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('ERCC1', 'Gene', '2067', (170, 175))	('Cd', 'Chemical', 'MESH:D002104', (63, 65))	('XRCC1', 'Gene', (190, 195))	('MSH2', 'Gene', (177, 181))
94203	32723695	They found a negative correlation between H19 methylation and mercury levels in urine.	('negative', 'NegReg', (13, 21))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('mercury levels', 'MPA', (62, 76))	('H19', 'Protein', (42, 45))	('mercury', 'Chemical', 'MESH:D008628', (62, 69))
94204	32723695	As previously mentioned, changes in H19 methylation and imprinting can have severe consequences in fetal growth.	('consequences', 'Reg', (83, 95))	('fetal growth', 'CPA', (99, 111))	('men', 'Species', '9606', (14, 17))	('As', 'Chemical', 'MESH:D001151', (0, 2))	('changes', 'Var', (25, 32))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('methylation', 'MPA', (40, 51))	('imprinting', 'CPA', (56, 66))	('H19', 'Protein', (36, 39))
94207	32723695	These included miR-126-3p, miR-19b-3p, miR-93-5p, miR-223-3p, and miR-142-3p with 6 months of exposure, and miR-23a-3p, miR-150-5p, miR-15a-5p, miR-191-5p, and let-7a-5p with 1 year of PM2.5 exposure.	('miR', 'Gene', (39, 42))	('miR-1', 'Gene', (15, 20))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', (108, 111))	('miR', 'Gene', (132, 135))	('miR-93', 'Gene', (39, 45))	('miR', 'Gene', '220972', (50, 53))	('miR-223', 'Gene', '407008', (50, 57))	('miR', 'Gene', (66, 69))	('miR', 'Gene', (27, 30))	('miR-1', 'Gene', '83856', (132, 137))	('miR', 'Gene', '220972', (132, 135))	('miR-93', 'Gene', '407051', (39, 45))	('miR', 'Gene', (50, 53))	('miR-1', 'Gene', '83856', (27, 32))	('miR', 'Gene', '220972', (120, 123))	('miR-1', 'Gene', (132, 137))	('miR-1', 'Gene', '83856', (66, 71))	('miR', 'Gene', '220972', (144, 147))	('miR-126-3p', 'Gene', (15, 25))	('miR-1', 'Gene', '83856', (120, 125))	('let-7a-5p', 'Var', (160, 169))	('miR', 'Gene', '220972', (15, 18))	('miR-1', 'Gene', '83856', (144, 149))	('miR-1', 'Gene', (66, 71))	('miR-1', 'Gene', (27, 32))	('miR', 'Gene', '220972', (39, 42))	('miR-191', 'Gene', '406966', (144, 151))	('miR', 'Gene', (120, 123))	('miR-191', 'Gene', (144, 151))	('miR', 'Gene', '220972', (108, 111))	('miR-126-3p', 'Gene', '100302148', (15, 25))	('miR', 'Gene', (144, 147))	('miR-1', 'Gene', (120, 125))	('miR-223', 'Gene', (50, 57))	('miR-1', 'Gene', '83856', (15, 20))	('miR-1', 'Gene', (144, 149))	('miR', 'Gene', (15, 18))
94213	32723695	The relationships between the expression of these miRNAs and PM exposures were influenced by polymorphisms in the RNA processing genes GEMIN4 and DGCR8.	('miR', 'Gene', '220972', (50, 53))	('GEMIN4', 'Gene', (135, 141))	('expression', 'MPA', (30, 40))	('miR', 'Gene', (50, 53))	('DGCR8', 'Gene', '54487', (146, 151))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('RNA processing', 'biological_process', 'GO:0006396', ('114', '128'))	('influenced', 'Reg', (79, 89))	('GEMIN4', 'Gene', '50628', (135, 141))	('polymorphisms', 'Var', (93, 106))	('relationships', 'Interaction', (4, 17))	('As', 'Chemical', 'MESH:D001151', (54, 56))	('DGCR8', 'Gene', (146, 151))
94214	32723695	found that miRNAs provide a likely regulatory mechanism underlying the BP-related effects of air pollution exposure, showing that changes in miR-101 expression provide an important epigenetic basis for this action.	('changes', 'Var', (130, 137))	('miR-101', 'Gene', '387143', (141, 148))	('miR-101', 'Gene', (141, 148))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('miR', 'Gene', '220972', (141, 144))	('expression', 'MPA', (149, 159))	('miR', 'Gene', (141, 144))	('BP', 'Chemical', 'MESH:C038809', (71, 73))	('As', 'Chemical', 'MESH:D001151', (15, 17))
94230	32723695	studied that silencing this specific lncRNA would be beneficial for the treatment of COPD.	('COPD', 'Disease', 'MESH:D029424', (85, 89))	('COPD', 'Disease', (85, 89))	('men', 'Species', '9606', (77, 80))	('ncRNA', 'Gene', (38, 43))	('ncRNA', 'Gene', '220202', (38, 43))	('silencing', 'Var', (13, 22))
94231	32723695	Disruption of MEG3 expression in human bronchial cells prevented apoptosis and autophagy, potentially through a p53 dependent mechanism, while it regulates cigarette smoke extract (CSE)-induced apoptosis and inflammation via miR-218 in 16HBE cells.	('autophagy', 'CPA', (79, 88))	('16HBE', 'CellLine', 'CVCL:0112', (236, 241))	('CSE', 'Gene', (181, 184))	('human', 'Species', '9606', (33, 38))	('regulates', 'Reg', (146, 155))	('inflammation', 'biological_process', 'GO:0006954', ('208', '220'))	('p53', 'Gene', '7157', (112, 115))	('Disruption', 'Var', (0, 10))	('miR-21', 'Gene', '406991', (225, 231))	('MEG3', 'Chemical', '-', (14, 18))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('p53', 'Gene', (112, 115))	('prevented', 'NegReg', (55, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('MEG3', 'Gene', (14, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('194', '203'))	('apoptosis', 'CPA', (194, 203))	('apoptosis', 'biological_process', 'GO:0006915', ('194', '203'))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('apoptosis', 'CPA', (65, 74))	('miR-21', 'Gene', (225, 231))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('inflammation', 'Disease', (208, 220))	('CSE', 'Gene', '1433', (181, 184))
94233	32723695	Aberrantly expressed long non-coding RNAs due to air pollution can also induce congenital defects.	('Aberrantly expressed', 'Var', (0, 20))	('congenital defects', 'Disease', 'MESH:D009358', (79, 97))	('induce', 'Reg', (72, 78))	('long non-coding RNAs', 'Protein', (21, 41))	('congenital defects', 'Disease', (79, 97))	('As', 'Chemical', 'MESH:D001151', (39, 41))
94234	32723695	He et al., showed the correlation between lncRNA H19 methylation and length and weight at birth.	('ncRNA', 'Gene', (43, 48))	('ncRNA', 'Gene', '220202', (43, 48))	('correlation', 'Interaction', (22, 33))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('methylation', 'Var', (53, 64))
94235	32723695	Their data showed that prenatal NO2 exposure correlated with increased H19 methylation, whereas PM10 exposure and SO2 exposure did so with reduced H19 methylation.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('H19 methylation', 'MPA', (147, 162))	('SO2', 'Chemical', 'MESH:D013458', (114, 117))	('increased', 'PosReg', (61, 70))	('PM10', 'Chemical', '-', (96, 100))	('methylation', 'MPA', (75, 86))	('PM10', 'Var', (96, 100))	('reduced', 'NegReg', (139, 146))	('NO2', 'Chemical', '-', (32, 35))	('H19', 'Protein', (71, 74))	('NO2', 'Var', (32, 35))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
94244	32723695	Several lncRNAs, AK130275, AK129685, EF177379, BX648695, NR_003584, and AF268386 were upregulated in mesothelioma tissue compared to healthy pleura.	('BX648695', 'Var', (47, 55))	('AK130275', 'Var', (17, 25))	('As', 'Chemical', 'MESH:D001151', (13, 15))	('ncRNA', 'Gene', '220202', (9, 14))	('AK129685', 'Var', (27, 35))	('NR_003584', 'Var', (57, 66))	('mesothelioma', 'Disease', (101, 113))	('upregulated', 'PosReg', (86, 97))	('EF177379', 'Var', (37, 45))	('ncRNA', 'Gene', (9, 14))	('AF268386', 'Var', (72, 80))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
94264	32723695	In a mouse model of paraquat-induced pulmonary fibrosis, two upregulated lncRNAs, uc.77 and 2700086A05Rik, were involved in modulation of EMT.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (37, 55))	('upregulated', 'PosReg', (61, 72))	('EMT', 'CPA', (138, 141))	('ncRNA', 'Gene', (74, 79))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (37, 55))	('EMT', 'biological_process', 'GO:0001837', ('138', '141'))	('pulmonary fibrosis', 'Disease', (37, 55))	('ncRNA', 'Gene', '220202', (74, 79))	('2700086A05Rik', 'Var', (92, 105))	('paraquat', 'Chemical', 'MESH:D010269', (20, 28))	('mouse', 'Species', '10090', (5, 10))	('As', 'Chemical', 'MESH:D001151', (78, 80))
94281	32723695	Mutation in this lncRNA can lead to incomplete X-chromosome inactivation favoring X-linked diseases such as Duchenne muscular dystrophy or hemophilia A.	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('47', '72'))	('Duchenne muscular dystrophy', 'Disease', (108, 135))	('Mutation', 'Var', (0, 8))	('hemophilia A', 'Disease', (139, 151))	('X-chromosome', 'cellular_component', 'GO:0000805', ('47', '59'))	('hemophilia A', 'Disease', 'MESH:D006467', (139, 151))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (117, 135))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (108, 135))	('ncRNA', 'Gene', (18, 23))	('X-linked diseases', 'Disease', 'MESH:D040181', (82, 99))	('ncRNA', 'Gene', '220202', (18, 23))	('X-linked diseases', 'Disease', (82, 99))
94282	32723695	Fluctuations of lncRNAs due to environmental toxins in utero or germ line can lead to dramatic developmental and growth defects in the fetus.	('men', 'Species', '9606', (38, 41))	('As', 'Chemical', 'MESH:D001151', (21, 23))	('lead to', 'Reg', (78, 85))	('ncRNA', 'Gene', (17, 22))	('Fluctuations', 'Var', (0, 12))	('men', 'Species', '9606', (102, 105))	('ncRNA', 'Gene', '220202', (17, 22))
94284	32723695	H19 has been linked to pathologies like diabetes.	('diabetes', 'Disease', 'MESH:D003920', (40, 48))	('H19', 'Var', (0, 3))	('linked', 'Reg', (13, 19))	('diabetes', 'Disease', (40, 48))
94536	29342862	The MPM genomic landscape is dominated by inactivating mutations in several tumor suppressor genes; such as CDKN2A; BAP1 and NF2.	('BAP1', 'Gene', (116, 120))	('tumor suppressor', 'Gene', (76, 92))	('inactivating mutations', 'Var', (42, 64))	('CDKN2A', 'Gene', '1029', (108, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor suppressor', 'Gene', '7248', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('NF2', 'Gene', (125, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('MPM', 'Disease', (4, 7))	('BAP1', 'Gene', '8314', (116, 120))	('NF2', 'Gene', '4771', (125, 128))	('CDKN2A', 'Gene', (108, 114))
94563	29342862	Inhibition of VEGF or its receptors can decrease proliferation in mesothelioma.	('decrease', 'NegReg', (40, 48))	('rat', 'Species', '10116', (56, 59))	('VEGF', 'Gene', '7422', (14, 18))	('proliferation', 'CPA', (49, 62))	('mesothelioma', 'Disease', (66, 78))	('Inhibition', 'Var', (0, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('VEGF', 'Gene', (14, 18))
94575	29342862	Programmed cell death, or apoptosis, is a carefully regulated process evaded by most cancers, partly because of inactivating mutations in the tumor suppressor gene, TP53, which is found to be mutated in about 50% of human tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('142', '158'))	('human', 'Species', '9606', (216, 221))	('TP53', 'Gene', (165, 169))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor suppressor', 'biological_process', 'GO:0051726', ('142', '158'))	('tumors', 'Disease', (222, 228))	('tumor suppressor', 'Gene', (142, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('inactivating mutations', 'Var', (112, 134))	('TP53', 'Gene', '7157', (165, 169))	('Programmed cell death', 'biological_process', 'GO:0012501', ('0', '21'))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor suppressor', 'Gene', '7248', (142, 158))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('Programmed', 'Disease', (0, 10))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
94576	29342862	Distinct from other cancers, mesothelioma typically expresses functional p53 and only 20-25% of cases harbor TP53 mutations; thus, both p53-dependent and independent mechanisms of apoptosis occur in MPM.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('mutations', 'Var', (114, 123))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (136, 139))	('p53', 'Gene', '7157', (73, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('TP53', 'Gene', '7157', (109, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('TP53', 'Gene', (109, 113))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('mesothelioma', 'Disease', (29, 41))	('p53', 'Gene', (136, 139))
94578	29342862	Survivin, a negative regulator of p53, is an anti-apoptotic protein associated with unfavorable patient outcomes and as a treatment strategy, introduction of inhibitory anti-sense Survivin oligonucleotides sensitized mesothelioma cells to chemotherapy and induced apoptosis.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('sensitized', 'Reg', (206, 216))	('induced', 'Reg', (256, 263))	('mesothelioma', 'Disease', (217, 229))	('patient', 'Species', '9606', (96, 103))	('inhibitory', 'Var', (158, 168))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('rat', 'Species', '10116', (134, 137))	('apoptosis', 'CPA', (264, 273))	('mesothelioma', 'Disease', 'MESH:D008654', (217, 229))	('oligonucleotides', 'Chemical', 'MESH:D009841', (189, 205))
94582	29342862	Small molecule HDAC inhibitors and antisense oligonucleotides directed at Bcl-xL were shown to induce tumor cell death via apoptosis and enhance chemo-sensitivity in MPM.	('enhance', 'PosReg', (137, 144))	('Bcl-xL', 'Gene', (74, 80))	('cell death', 'biological_process', 'GO:0008219', ('108', '118'))	('antisense oligonucleotides', 'Var', (35, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('HDAC', 'Gene', (15, 19))	('apoptosis', 'CPA', (123, 132))	('oligonucleotides', 'Chemical', 'MESH:D009841', (45, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Bcl-xL', 'Gene', '598', (74, 80))	('tumor', 'Disease', (102, 107))	('induce', 'PosReg', (95, 101))	('chemo-sensitivity', 'CPA', (145, 162))
94589	29342862	Dual pharmacological inhibition of FAK and MDM2 was synergistic and resulted in decreased cell viability and increased total phosphorylation of p53 and p21, along with a decrease in the proliferative marker, cyclin A.	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('cell viability', 'CPA', (90, 104))	('p21', 'Gene', (152, 155))	('FAK', 'Gene', (35, 38))	('p21', 'Gene', '644914', (152, 155))	('increased', 'PosReg', (109, 118))	('p53', 'Gene', '7157', (144, 147))	('MDM2', 'Gene', (43, 47))	('cyclin', 'molecular_function', 'GO:0016538', ('208', '214'))	('decreased', 'NegReg', (80, 89))	('FAK', 'Gene', '5747', (35, 38))	('phosphorylation', 'MPA', (125, 140))	('decrease', 'NegReg', (170, 178))	('p53', 'Gene', (144, 147))	('cyclin A', 'Gene', '890', (208, 216))	('MDM2', 'Gene', '4193', (43, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('proliferative marker', 'MPA', (186, 206))	('cyclin A', 'Gene', (208, 216))	('rat', 'Species', '10116', (193, 196))	('inhibition', 'Var', (21, 31))
94599	29342862	Uncontrolled cell growth results in cancer when mutations accumulate in several control mechanisms that cause cells to no longer respond to biological signals.	('accumulate', 'PosReg', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('results in', 'Reg', (25, 35))	('cell growth', 'biological_process', 'GO:0016049', ('13', '24'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (48, 57))
94601	29342862	demonstrated that several cell cycle genes:APC, CCND2, CDKN2A, CDKN2B, APPBP1, and RASSF1:are methylated in older mesothelioma patients, and those with methylation of RASSF1, a gene that encodes an activator of G1/S cell cycle arrest, through sequestering of CCND1, is significantly associated with elevated asbestos body counts and therefore longer asbestos exposure.	('APPBP1', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (55, 61))	('older mesothelioma', 'Disease', (108, 126))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (216, 233))	('rat', 'Species', '10116', (7, 10))	('APC', 'cellular_component', 'GO:0005680', ('43', '46'))	('asbestos body counts', 'Disease', (308, 328))	('CDKN2B', 'Gene', (63, 69))	('sequestering', 'biological_process', 'GO:0051235', ('243', '255'))	('cell cycle genes', 'Gene', (26, 42))	('associated', 'Reg', (283, 293))	('CCND2', 'Gene', (48, 53))	('APPBP1', 'Gene', '8883', (71, 77))	('CCND2', 'Gene', '894', (48, 53))	('CDKN2B', 'Gene', '1030', (63, 69))	('sequestering', 'Var', (243, 255))	('cell cycle', 'biological_process', 'GO:0007049', ('26', '36'))	('CCND1', 'Gene', '595', (259, 264))	('RASSF1', 'Gene', '11186', (83, 89))	('asbestos', 'Chemical', 'MESH:D001194', (350, 358))	('CDKN2A', 'Gene', (55, 61))	('APC', 'Disease', 'MESH:D011125', (43, 46))	('RASSF1', 'Gene', '11186', (167, 173))	('RASSF1', 'Gene', (83, 89))	('asbestos body', 'Phenotype', 'HP:0011002', (308, 321))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('216', '233'))	('CCND1', 'Gene', (259, 264))	('older mesothelioma', 'Disease', 'MESH:D008654', (108, 126))	('APC', 'Disease', (43, 46))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('RASSF1', 'Gene', (167, 173))	('patients', 'Species', '9606', (127, 135))	('elevated', 'PosReg', (299, 307))	('asbestos', 'Chemical', 'MESH:D001194', (308, 316))	('methylation', 'Var', (152, 163))
94603	29342862	Counterintuitively, an important regulator of DNA damage-mediated cell cycle arrest, checkpoint kinase 1 (CHEK1), is overexpressed in 50% of mesothelioma cases compared to normal pleural tissue, and CHEK1 knockdown leads to synergistic apoptosis in mesothelioma cell lines when combined with the chemotherapeutic drug, doxorubicin.	('CHEK1', 'Gene', '1111', (199, 204))	('apoptosis', 'biological_process', 'GO:0097194', ('236', '245'))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('236', '245'))	('CHEK1', 'Gene', (106, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (319, 330))	('knockdown', 'Var', (205, 214))	('mesothelioma', 'Disease', (249, 261))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (249, 261))	('CHEK1', 'Gene', (199, 204))	('synergistic apoptosis', 'CPA', (224, 245))	('mesothelioma cell lines', 'Disease', (249, 272))	('mesothelioma cell lines', 'Disease', 'MESH:D008654', (249, 272))	('checkpoint kinase 1', 'Gene', '1111', (85, 104))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('66', '83'))	('CHEK1', 'Gene', '1111', (106, 111))	('overexpressed', 'PosReg', (117, 130))	('checkpoint kinase 1', 'Gene', (85, 104))	('mesothelioma', 'Disease', (141, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
94605	29342862	Given that YAP promotes TEA domain family member 1 (TEAD)-mediated transcription of cell cycle genes, such as CCND1 and FOXM1, one study found that silencing YAP in mesothelioma resulted in suppression of these genes and inhibition of cell motility, invasion and anchorage-independent growth.	('TEAD', 'Disease', (52, 56))	('TEAD', 'Disease', 'None', (52, 56))	('cell cycle genes', 'Gene', (84, 100))	('FOXM1', 'Gene', '2305', (120, 125))	('cell motility', 'CPA', (235, 248))	('inhibition', 'NegReg', (221, 231))	('silencing', 'Var', (148, 157))	('suppression', 'NegReg', (190, 201))	('cell cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('YAP', 'Gene', '10413', (158, 161))	('YAP', 'Gene', (11, 14))	('CCND1', 'Gene', '595', (110, 115))	('FOXM1', 'Gene', (120, 125))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('transcription', 'MPA', (67, 80))	('CCND1', 'Gene', (110, 115))	('mesothelioma', 'Disease', (165, 177))	('cell motility', 'biological_process', 'GO:0048870', ('235', '248'))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('YAP', 'Gene', '10413', (11, 14))	('YAP', 'Gene', (158, 161))
94606	29342862	Concurrently, inhibition of YAP led to decreases in E2F1, AURKB, PLK1, NEK2, and anti-apoptotic BIRC5/Survivin, as well as an increase in pro-apoptotic BCL2L11/BIM, which ultimately resulted in broad decreases in anchorage properties, proliferation, migration, and invasion.	('NEK2', 'Gene', '4751', (71, 75))	('anchorage properties', 'CPA', (213, 233))	('pro-apoptotic', 'MPA', (138, 151))	('AURKB', 'Gene', (58, 63))	('BCL2', 'molecular_function', 'GO:0015283', ('152', '156'))	('invasion', 'CPA', (265, 273))	('increase', 'PosReg', (126, 134))	('PLK1', 'Gene', (65, 69))	('proliferation', 'CPA', (235, 248))	('rat', 'Species', '10116', (253, 256))	('AURKB', 'Gene', '9212', (58, 63))	('rat', 'Species', '10116', (242, 245))	('PLK1', 'Gene', '5347', (65, 69))	('BCL2L11', 'Gene', '10018', (152, 159))	('YAP', 'Gene', (28, 31))	('decreases', 'NegReg', (200, 209))	('E2F1', 'Gene', '1869', (52, 56))	('migration', 'CPA', (250, 259))	('BIRC5', 'Gene', '332', (96, 101))	('anti-apoptotic', 'MPA', (81, 95))	('YAP', 'Gene', '10413', (28, 31))	('BIRC5', 'Gene', (96, 101))	('NEK2', 'Gene', (71, 75))	('E2F1', 'Gene', (52, 56))	('BCL2L11', 'Gene', (152, 159))	('decreases', 'NegReg', (39, 48))	('inhibition', 'Var', (14, 24))
94611	29342862	While TERT can be mutated at its promoter region (>15% of cases present with C228T somatic mutations), the TERT locus (5p15.3) can also be amplified to induce higher TERT levels (around 50% of mesothelioma); however, the TERT promoter mutation is responsible for elevated TERT expression.	('TERT', 'Gene', '7015', (221, 225))	('expression', 'MPA', (277, 287))	('elevated', 'PosReg', (263, 271))	('TERT', 'Gene', '7015', (166, 170))	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (107, 111))	('TERT', 'Gene', '7015', (6, 10))	('mesothelioma', 'Disease', (193, 205))	('TERT', 'Gene', (272, 276))	('TERT', 'Gene', '7015', (272, 276))	('C228T', 'Var', (77, 82))	('TERT', 'Gene', (221, 225))	('TERT', 'Gene', (107, 111))	('TERT', 'Gene', (166, 170))	('induce', 'PosReg', (152, 158))	('C228T', 'Mutation', 'rs756564761', (77, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (193, 205))
94612	29342862	Mutations in the TERT promoter along with NF2 and CDKN2A alterations frequently occur concurrently and anti-telomerase drugs might therefore have clinical utility when combined with other targeted therapies.	('NF2', 'Gene', (42, 45))	('CDKN2A', 'Gene', (50, 56))	('clinical', 'Species', '191496', (146, 154))	('TERT', 'Gene', (17, 21))	('CDKN2A', 'Gene', '1029', (50, 56))	('TERT', 'Gene', '7015', (17, 21))	('rat', 'Species', '10116', (61, 64))	('Mutations', 'Var', (0, 9))	('NF2', 'Gene', '4771', (42, 45))
94614	29342862	Although mutations that lead to overexpression of EGFR have been associated with a wide range of malignancies, the role of elevated levels of EGFR in MPM appears limited.	('overexpression', 'PosReg', (32, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('mutations', 'Var', (9, 18))	('associated', 'Reg', (65, 75))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('EGFR', 'Gene', (50, 54))	('malignancies', 'Disease', (97, 109))
94615	29342862	Although another study reported higher rates of EGFR expression in MPM tumors using IHC (38/83 positive for EGFR), both studies confirmed by fluorescence in situ hybridization (FISH) analysis that there are only few occurrences of EGFR copy number gains, and thus EGFR overexpression did not appear to be due to gene amplification.	('copy number', 'Var', (236, 247))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('MPM tumors', 'Disease', 'MESH:D009369', (67, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('264', '268'))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('231', '235'))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('EGFR', 'Gene', (231, 235))	('MPM tumors', 'Disease', (67, 77))	('gains', 'PosReg', (248, 253))
94616	29342862	Whereas growth in EGFR-expressing mesothelioma cell lines is significantly deterred by EGFR small molecule inhibitors, clinical evaluations of gefitinib and erlotinib were dismal in MPM patients.	('mesothelioma cell lines', 'Disease', 'MESH:D008654', (34, 57))	('gefitinib', 'Chemical', 'MESH:D000077156', (143, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (87, 91))	('erlotinib', 'Chemical', 'MESH:D000069347', (157, 166))	('MPM', 'Disease', (182, 185))	('small', 'Var', (92, 97))	('deterred', 'NegReg', (75, 83))	('mesothelioma cell lines', 'Disease', (34, 57))	('clinical', 'Species', '191496', (119, 127))	('growth', 'MPA', (8, 14))	('patients', 'Species', '9606', (186, 194))
94623	29342862	Since non-malignant Met5A cells showed no noticeable adverse effects after PDGFRbeta silencing, it could be a potential target gene for therapeutic intervention.	('PDGFRbeta', 'Gene', (75, 84))	('PDGFRbeta', 'Gene', '5159', (75, 84))	('silencing', 'Var', (85, 94))
94627	29342862	Use of the FGFR1 inhibitor, PD-166866, was particularly promising as it not only hindered in vitro MPM cell proliferation and caused an increase in death via apoptosis, but also reduced in vivo MPM tumor growth in mouse models; this was accompanied by synergism when coupled with cisplatin or radiotherapy treatment.	('rat', 'Species', '10116', (115, 118))	('MPM tumor', 'Disease', (194, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('PD-166866', 'Var', (28, 37))	('hindered', 'NegReg', (81, 89))	('FGFR1', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('increase', 'PosReg', (136, 144))	('mouse', 'Species', '10090', (214, 219))	('MPM tumor', 'Disease', 'MESH:D009369', (194, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))	('reduced', 'NegReg', (178, 185))	('death via apoptosis', 'CPA', (148, 167))	('PD-166866', 'Chemical', 'MESH:C113399', (28, 37))
94631	29342862	The genomic landscape of mesothelioma is characterized by frequent alterations in tumor suppressor genes resulting from mutational events involving copy number losses, single nucleotide variants (SNVs), gene fusions and splicing events.	('splicing events', 'Var', (220, 235))	('copy number losses', 'Var', (148, 166))	('gene fusions', 'Var', (203, 215))	('rat', 'Species', '10116', (71, 74))	('splicing', 'biological_process', 'GO:0045292', ('220', '228'))	('mesothelioma', 'Disease', (25, 37))	('alterations', 'Reg', (67, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('tumor suppressor', 'Gene', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('tumor suppressor', 'Gene', '7248', (82, 98))	('single nucleotide variants', 'Var', (168, 194))
94632	29342862	MPM exhibits a distinct genomic signature, including inactivating mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), and more recently, ubiquitin carboxyl-terminal hydrolase (BAP1) and neurofibromin 2 (NF2), have been shown to be the most prevalent in this type of cancer (Figure 1A).	('NF2', 'Gene', '4771', (211, 214))	('prevalent', 'Reg', (248, 257))	('neurofibromin 2', 'Gene', '4771', (194, 209))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('96', '112'))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('79', '112'))	('neurofibromin 2', 'Gene', (194, 209))	('cancer', 'Disease', (274, 280))	('inactivating mutations', 'Var', (53, 75))	('MPM', 'Disease', (0, 3))	('NF2', 'Gene', (211, 214))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (79, 115))	('CDKN2A', 'Gene', (117, 123))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (79, 115))	('ubiquitin carboxyl-terminal hydrolase (BAP1', 'Gene', '8314', (145, 188))	('ubiquitin', 'molecular_function', 'GO:0031386', ('145', '154'))	('CDKN2A', 'Gene', '1029', (117, 123))
94633	29342862	Of particular interest, although the frequency of point mutations in cancer genes is low, several studies report global tumor suppressor inactivation, associated with CpG promoter methylation in MPM, which contrasts with the epigenetic landscape of normal pleura.	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor suppressor', 'Gene', (120, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CpG promoter methylation', 'Var', (167, 191))	('tumor suppressor', 'Gene', '7248', (120, 136))	('cancer', 'Disease', (69, 75))	('MPM', 'Gene', (195, 198))
94634	29342862	Occurring at a frequency of over 70%, the most common homozygous deletion or incidence of gene inactivation in MPM is found in the 9p21 region of CDKN2A.	('CDKN2A', 'Gene', (146, 152))	('CDKN2A', 'Gene', '1029', (146, 152))	('MPM', 'Gene', (111, 114))	('p21', 'Gene', (132, 135))	('p21', 'Gene', '644914', (132, 135))	('deletion', 'Var', (65, 73))
94637	29342862	Inactivating mutations can thus disrupt this cell growth control pathway and contribute to carcinogenesis.	('contribute', 'Reg', (77, 87))	('cell growth control pathway', 'Pathway', (45, 72))	('carcinogenesis', 'Disease', (91, 105))	('Inactivating mutations', 'Var', (0, 22))	('disrupt', 'NegReg', (32, 39))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))
94639	29342862	As part of the p53 pathway, P14 promotes ubiquitylation and degradation of MDM2, but loss of P14 increases MDM2 stability and activation, thereby repressing p53 and disrupting cell cycle control.	('activation', 'MPA', (126, 136))	('repressing', 'PosReg', (146, 156))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('P14 increases MDM2 stability', 'Disease', 'MESH:D043171', (93, 121))	('MDM2', 'Gene', (107, 111))	('MDM2', 'Gene', (75, 79))	('p53', 'Gene', '7157', (15, 18))	('P14', 'Gene', '1029', (93, 96))	('ubiquitylation', 'MPA', (41, 55))	('degradation', 'MPA', (60, 71))	('MDM2', 'Gene', '4193', (107, 111))	('p53', 'Gene', '7157', (157, 160))	('loss', 'Var', (85, 89))	('MDM2', 'Gene', '4193', (75, 79))	('P14', 'Gene', '1029', (28, 31))	('p53', 'Gene', (15, 18))	('P14', 'Gene', (93, 96))	('disrupting', 'NegReg', (165, 175))	('P14 increases MDM2 stability', 'Disease', (93, 121))	('p53', 'Gene', (157, 160))	('cell cycle control', 'biological_process', 'GO:1901987', ('176', '194'))	('P14', 'Gene', (28, 31))	('cell cycle control', 'CPA', (176, 194))
94641	29342862	established the importance of losses in both P16INK4a and P14ARF in the latency and development of mesothelioma tumorigenesis.	('P14ARF', 'Gene', (58, 64))	('P16INK4a', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (99, 117))	('P14ARF', 'Gene', '1029', (58, 64))	('losses', 'NegReg', (30, 36))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (99, 117))	('mesothelioma tumor', 'Disease', (99, 117))
94642	29342862	When exposed to asbestos, mice with mono-allelic deletions of P16INK4a or P19ARF (human: P14ARF) developed mesothelioma earlier and more often than their wild type littermates, and those with deletions of both P16INK4a and P19ARF showed even faster progression into malignancy relative to the mice bearing single deletions.	('malignancy', 'Disease', (266, 276))	('P19', 'cellular_component', 'GO:0070743', ('223', '226'))	('developed', 'PosReg', (97, 106))	('P16INK4a', 'Gene', (62, 70))	('mesothelioma', 'Disease', (107, 119))	('P14ARF', 'Gene', '1029', (89, 95))	('deletions', 'Var', (192, 201))	('mice', 'Species', '10090', (293, 297))	('asbestos', 'Chemical', 'MESH:D001194', (16, 24))	('malignancy', 'Disease', 'MESH:D009369', (266, 276))	('P14ARF', 'Gene', (89, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('P19', 'cellular_component', 'GO:0070743', ('74', '77'))	('P19ARF', 'Gene', (74, 80))	('human', 'Species', '9606', (82, 87))	('mice', 'Species', '10090', (26, 30))
94643	29342862	Furthermore, adenoviral-based reintroduction of P16INK4a or P14ARF showed reversal of mesothelioma growth by decreasing hyper-phosphorylation of RB, increasing p53 levels, and ultimately resulted in cell cycle arrest.	('resulted in', 'Reg', (187, 198))	('cell cycle arrest', 'CPA', (199, 216))	('decreasing', 'NegReg', (109, 119))	('hyper-phosphorylation', 'MPA', (120, 141))	('P14ARF', 'Gene', '1029', (60, 66))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('199', '216'))	('P16INK4a', 'Var', (48, 56))	('p53', 'Gene', (160, 163))	('mesothelioma', 'Disease', (86, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('p53', 'Gene', '7157', (160, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (199, 216))	('P14ARF', 'Gene', (60, 66))	('increasing', 'PosReg', (149, 159))
94644	29342862	Interestingly, over 75% of patients with mesothelioma have only P16INK4a deletions, and these patients generally have poor prognoses and shorter survival rates; almost 30% of primary tumors have been reported to have methylated P16INK4a.	('patients', 'Species', '9606', (94, 102))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('mesothelioma', 'Disease', (41, 53))	('rat', 'Species', '10116', (154, 157))	('methylated P16INK4a', 'Var', (217, 236))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('patients', 'Species', '9606', (27, 35))	('deletions', 'Var', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('P16INK4a', 'Gene', (64, 72))	('tumors', 'Disease', (183, 189))	('P16INK4a', 'Var', (228, 236))
94645	29342862	Moreover, sustained P16INK4a expression is associated with better survival in patients after chemotherapy, regardless of histological subtypes, and deletion of P16INK4a correlates with poor outcomes.	('deletion', 'Var', (148, 156))	('patients', 'Species', '9606', (78, 86))	('P16INK4a', 'Protein', (20, 28))	('better', 'PosReg', (59, 65))	('survival', 'CPA', (66, 74))	('P16INK4a', 'Gene', (160, 168))	('expression', 'MPA', (29, 39))
94647	29342862	Deleted in around 35-40% of MPM cases and often functionally inactive if present due to somatic mutations, the tumor suppressor, Neurofibromin 2 (NF2) gene, has been implicated as a "gatekeeper" in asbestos-induced mesothelioma tumorigenicity via several mechanisms.	('Neurofibromin 2', 'Gene', '4771', (129, 144))	('tumor suppressor', 'Gene', (111, 127))	('gatekeeper', 'Species', '111938', (183, 193))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('Neurofibromin 2', 'Gene', (129, 144))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NF2', 'Gene', (146, 149))	('tumor suppressor', 'Gene', '7248', (111, 127))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (215, 233))	('asbestos', 'Chemical', 'MESH:D001194', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (215, 233))	('NF2', 'Gene', '4771', (146, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('mesothelioma tumor', 'Disease', (215, 233))	('mutations', 'Var', (96, 105))
94650	29342862	Whereas the Hippo pathway typically halts cell growth and inhibits the transcriptional regulator, YAP, the lack of Merlin leads to overactive YAP and thus uncontrolled cell growth and cancer progression.	('cancer', 'Disease', (184, 190))	('cell growth', 'CPA', (42, 53))	('YAP', 'Gene', '10413', (142, 145))	('overactive', 'PosReg', (131, 141))	('leads to', 'Reg', (122, 130))	('halts', 'NegReg', (36, 41))	('YAP', 'Gene', (142, 145))	('inhibits', 'NegReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cell growth', 'biological_process', 'GO:0016049', ('42', '53'))	('YAP', 'Gene', '10413', (98, 101))	('cell growth', 'biological_process', 'GO:0016049', ('168', '179'))	('lack', 'Var', (107, 111))	('Merlin', 'Gene', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('Merlin', 'Gene', '4771', (115, 121))	('YAP', 'Gene', (98, 101))
94651	29342862	By transducing NF2 into MM cells that had NF2 mutations, YAP has been shown to be translocated from the nucleus to the cytoplasm, suggestive of NF2's role in YAP activity.	('NF2', 'Gene', (144, 147))	('NF2', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	('transducing', 'Reg', (3, 14))	('YAP', 'Gene', '10413', (57, 60))	('NF2', 'Gene', (15, 18))	('YAP', 'Gene', '10413', (158, 161))	('NF2', 'Gene', '4771', (144, 147))	('NF2', 'Gene', '4771', (42, 45))	('cytoplasm', 'cellular_component', 'GO:0005737', ('119', '128'))	('YAP', 'Gene', (57, 60))	('nucleus', 'cellular_component', 'GO:0005634', ('104', '111'))	('YAP', 'Gene', (158, 161))	('NF2', 'Gene', '4771', (15, 18))
94654	29342862	In tumors that lack Merlin, the use of mTOR inhibitors led to reduced proliferation, yet were ineffective in Merlin-expressing tumors, suggestive of the role of the NF2 deletion in MPM oncogenesis and its association with mTOR.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('deletion', 'Var', (169, 177))	('oncogenesis', 'biological_process', 'GO:0007048', ('185', '196'))	('association', 'Interaction', (205, 216))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('rat', 'Species', '10116', (77, 80))	('Merlin', 'Gene', (109, 115))	('Merlin', 'Gene', (20, 26))	('proliferation', 'CPA', (70, 83))	('NF2', 'Gene', '4771', (165, 168))	('reduced', 'NegReg', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mTOR', 'Disease', (222, 226))	('NF2', 'Gene', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('MPM', 'Gene', (181, 184))	('Merlin', 'Gene', '4771', (109, 115))	('tumors', 'Disease', (3, 9))	('Merlin', 'Gene', '4771', (20, 26))
94660	29342862	Rare germline mutations in BAP1 contribute to predispositions in malignant mesothelioma, among other cancers, despite lack of exposure to high levels of asbestos or other carcinogens, suggesting that BAP1 may serve as a predictive biomarker.	('malignant mesothelioma', 'Disease', (65, 87))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (65, 87))	('cancers', 'Disease', (101, 108))	('germline mutations', 'Var', (5, 23))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', '8314', (200, 204))	('asbestos', 'Chemical', 'MESH:D001194', (153, 161))	('predispositions', 'Reg', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (65, 87))	('BAP1', 'Gene', (200, 204))	('BAP1', 'Gene', '8314', (27, 31))
94661	29342862	reported that BAP1 also harbored nonsynonymous mutations in 12/53 samples, was located in the center of the 3p21.1 locus, and also had somatic mutations and copy number losses.	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', (14, 18))	('harbored', 'Reg', (24, 32))	('nonsynonymous mutations', 'Var', (33, 56))	('p21', 'Gene', (109, 112))	('p21', 'Gene', '644914', (109, 112))
94662	29342862	Although they found no significant correlation between BAP1 mutations and MPM subtype, Yoshikawa et al.	('mutations', 'Var', (60, 69))	('BAP1', 'Gene', (55, 59))	('BAP1', 'Gene', '8314', (55, 59))
94664	29342862	BAP1 plays a key role in chromatin biology by mediating deubiquitination of core histones and is recruited to double-strand breaks in DNA, given its role in DNA repair.	('recruited', 'PosReg', (97, 106))	('mediating', 'Reg', (46, 55))	('core histones', 'Protein', (76, 89))	('BAP1', 'Gene', (0, 4))	('deubiquitination', 'MPA', (56, 72))	('chromatin', 'cellular_component', 'GO:0000785', ('25', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('double-strand breaks', 'Var', (110, 130))	('core', 'cellular_component', 'GO:0019013', ('76', '80'))	('BAP1', 'Gene', '8314', (0, 4))	('deubiquitination', 'biological_process', 'GO:0016579', ('56', '72'))	('DNA repair', 'biological_process', 'GO:0006281', ('157', '167'))
94665	29342862	Accordingly, BAP1 inactivation results in impaired DNA repair functions, which can have dire consequences, consistent with its role as an epigenetic modulator and transcriptional regulator.	('BAP1', 'Gene', (13, 17))	('DNA repair functions', 'MPA', (51, 71))	('DNA repair', 'biological_process', 'GO:0006281', ('51', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('inactivation', 'Var', (18, 30))	('BAP1', 'Gene', '8314', (13, 17))	('impaired', 'NegReg', (42, 50))
94666	29342862	Thus, drugs designed to target the epigenome, and, in particular, enhancer of zeste homolog 2 (EZH2), may hold promise for MPM harboring BAP1 mutations, but these have not been evaluated clinically.	('BAP1', 'Gene', (137, 141))	('mutations', 'Var', (142, 151))	('EZH2', 'Gene', (95, 99))	('clinical', 'Species', '191496', (187, 195))	('enhancer of zeste homolog 2', 'Gene', (66, 93))	('BAP1', 'Gene', '8314', (137, 141))	('enhancer of zeste homolog 2', 'Gene', '2146', (66, 93))	('EZH2', 'Gene', '2146', (95, 99))
94679	29342862	Thus, targeting fibroblast activation protein (FAP) in stromal cells has led to a decrease in mesothelioma tumor growth in preclinical animal studies.	('FAP', 'Gene', '2191', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (94, 112))	('decrease', 'NegReg', (82, 90))	('fibroblast activation protein', 'Gene', '2191', (16, 45))	('FAP', 'Gene', (47, 50))	('targeting', 'Var', (6, 15))	('mesothelioma tumor', 'Disease', (94, 112))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (94, 112))	('fibroblast activation', 'biological_process', 'GO:0072537', ('16', '37'))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('fibroblast activation protein', 'Gene', (16, 45))	('clinical', 'Species', '191496', (126, 134))
94692	29342862	This is due to the presence of distinct somatic mutations in different areas of the tumors, leading to discrete clonotypes of T cell receptors, and ultimate results in pronounced region-specific TILs.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('T cell receptors', 'Protein', (126, 142))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('results in', 'Reg', (157, 167))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (48, 57))
94701	29342862	Cutting off the supply of one or more of the above-mentioned factors in the surrounding milieu is a therapeutic strategy being used to combat MPM tumors.	('rat', 'Species', '10116', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Cutting', 'Var', (0, 7))	('MPM tumors', 'Disease', (142, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('MPM tumors', 'Disease', 'MESH:D009369', (142, 152))
94707	29342862	Hedgehog-dependent Gli-mediated transactivation of target genes is negatively regulated by suppressor of fused homolog (Sufu); it is required for normal embryonic development and its loss leads to unfettered Hh activation and lethality.	('suppressor of fused homolog', 'Gene', '51684', (91, 118))	('Sufu', 'Gene', (120, 124))	('loss', 'Var', (183, 187))	('Hedgehog', 'Gene', (0, 8))	('unfettered Hh activation', 'CPA', (197, 221))	('suppressor of fused homolog', 'Gene', (91, 118))	('transactivation', 'biological_process', 'GO:2000144', ('32', '47'))	('Sufu', 'Gene', '51684', (120, 124))	('lethality', 'CPA', (226, 235))	('leads to', 'Reg', (188, 196))	('Hedgehog', 'Gene', '50846;3549', (0, 8))
94710	29342862	When aberrantly reactivated, this developmental pathway has been implicated in multiple human cancers, including MPM.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('MPM', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('aberrantly', 'Var', (5, 15))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('implicated', 'Reg', (65, 75))	('cancers', 'Disease', (94, 101))
94715	29342862	Their study provides evidence for targeting Hh signaling, as well as a number of MPM-specific pathway perturbations in the stromal compartment, as a treatment strategy for MPM.	('perturbations', 'Var', (102, 115))	('MPM', 'Disease', (172, 175))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('MPM-specific', 'Gene', (81, 93))	('rat', 'Species', '10116', (161, 164))
94718	29342862	Evidence suggests that crosstalk between Gli and other cell signaling pathways that are independent of Hh, such as Kirsten rat sarcoma (KRAS), EGFR and mTOR, are linked to worse clinical outcomes in MPM and crosstalk between Gli and mTOR actually causes increased Gli activation.	('increased', 'PosReg', (254, 263))	('mTOR', 'Gene', (233, 237))	('Gli', 'CPA', (264, 267))	('crosstalk', 'Var', (207, 216))	('rat', 'Species', '10116', (123, 126))	('linked', 'Reg', (162, 168))	('KRAS', 'Gene', (136, 140))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('MPM', 'Disease', (199, 202))	('clinical', 'Species', '191496', (178, 186))	('KRAS', 'Gene', '24525', (136, 140))	('sarcoma', 'Disease', (127, 134))	('activation', 'PosReg', (268, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
94727	29342862	In the absence of Wnt, beta-catenin is degraded in the cytoplasm via a destruction complex (Axin, APC, GSK3, PP2A, CK1alpha) and the pathway becomes inactive.	('APC', 'Disease', 'MESH:D011125', (98, 101))	('PP2A', 'Var', (109, 113))	('cytoplasm', 'cellular_component', 'GO:0005737', ('55', '64'))	('GSK', 'molecular_function', 'GO:0050321', ('103', '106'))	('APC', 'Disease', (98, 101))	('Axin', 'Gene', '8312', (92, 96))	('beta-catenin', 'Gene', (23, 35))	('APC', 'cellular_component', 'GO:0005680', ('98', '101'))	('CK1', 'Species', '2498238', (115, 118))	('degraded', 'NegReg', (39, 47))	('Axin', 'Gene', (92, 96))	('beta-catenin', 'Gene', '1499', (23, 35))
94729	29342862	Mutations in the Wnt pathway are frequently observed in cancer, including germline mutations in APC, responsible for familiar adenomatous polyposis and colorectal cancers.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Mutations', 'Var', (0, 9))	('adenomatous polyposis', 'Disease', (126, 147))	('APC', 'cellular_component', 'GO:0005680', ('96', '99'))	('colorectal cancers', 'Disease', 'MESH:D015179', (152, 170))	('observed', 'Reg', (44, 52))	('Wnt pathway', 'Pathway', (17, 28))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (126, 147))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (126, 147))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (163, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('germline mutations', 'Var', (74, 92))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('APC', 'Disease', (96, 99))	('colorectal cancers', 'Disease', (152, 170))
94730	29342862	Loss-of-function mutations in Axin lead to hepatocellular carcinomas, and mutations in beta-catenin lead to melanoma and several solid tumors; in addition, studies have reported the expression of beta-catenin, a Wnt stem cell pathway activation indicator, in the progression of mesothelioma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('solid tumor', 'Disease', (129, 140))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (43, 68))	('tumors', 'Disease', (135, 141))	('mutations', 'Var', (17, 26))	('hepatocellular carcinomas', 'Disease', (43, 68))	('beta-catenin', 'Gene', (87, 99))	('solid tumor', 'Disease', 'MESH:D009369', (129, 140))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('beta-catenin', 'Gene', (196, 208))	('beta-catenin', 'Gene', '1499', (196, 208))	('mesothelioma', 'Disease', (278, 290))	('Axin', 'Gene', '8312', (30, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (278, 290))	('Loss-of-function', 'NegReg', (0, 16))	('Axin', 'Gene', (30, 34))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (43, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
94734	29342862	We found that Wnt7A expression predicted sensitivity to chemotherapy; in particular, low Wnt7A expression was significantly correlated with negative overall survival in a univariate analysis, and patients with epithelioid tumors and low Wnt7A had significantly worse prognoses.	('Wnt7A', 'Gene', '7476', (14, 19))	('negative', 'NegReg', (140, 148))	('epithelioid tumors', 'Disease', (210, 228))	('Wnt7A', 'Gene', '7476', (89, 94))	('low', 'NegReg', (85, 88))	('Wnt7A', 'Gene', '7476', (237, 242))	('overall survival', 'MPA', (149, 165))	('patients', 'Species', '9606', (196, 204))	('Wnt7A', 'Gene', (89, 94))	('low', 'Var', (233, 236))	('epithelioid tumors', 'Disease', 'MESH:D012509', (210, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('Wnt7A', 'Gene', (237, 242))	('Wnt7A', 'Gene', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('expression', 'MPA', (95, 105))
94738	29342862	Of these inhibitors, LGK-974, a protein-serine O-palmitoleoyltransferase porcupine (PORCN)-specific inhibitor that is a key regulator of the Wnt signaling pathway, is currently being evaluated in phase I clinical studies for solid malignancies with documented genetic alterations upstream in the Wnt pathway, but no MPM patients were reported to have enrolled (NCT01351103).	('PORCN', 'Gene', '64840', (84, 89))	('rat', 'Species', '10116', (272, 275))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('141', '162'))	('solid malignancies', 'Disease', 'MESH:D009369', (225, 243))	('clinical', 'Species', '191496', (204, 212))	('Wnt pathway', 'Pathway', (296, 307))	('solid malignancies', 'Disease', (225, 243))	('genetic alterations', 'Var', (260, 279))	('LGK-974', 'Gene', (21, 28))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('PORCN', 'Gene', (84, 89))	('patients', 'Species', '9606', (320, 328))
94747	29342862	We have shown that CK2alpha inhibition down-regulates Notch1 signaling and reduces CSC-like populations in human lung cancer cells.	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('human', 'Species', '9606', (107, 112))	('CK2alpha', 'Gene', '1459', (19, 27))	('inhibition', 'Var', (28, 38))	('CSC-like populations', 'CPA', (83, 103))	('CK2alpha', 'Gene', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduces', 'NegReg', (75, 82))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('Notch1', 'Gene', (54, 60))	('down-regulates', 'NegReg', (39, 53))	('Notch1', 'Gene', '4851', (54, 60))
94750	29342862	Hippo signaling regulates organ size, cell contact inhibition, and stem cell self-renewal, but dysregulation can result in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('regulates', 'Reg', (16, 25))	('dysregulation', 'Var', (95, 108))	('organ size', 'CPA', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('stem cell self-renewal', 'CPA', (67, 89))	('cell contact inhibition', 'CPA', (38, 61))	('result in', 'Reg', (113, 122))	('cancer', 'Disease', (123, 129))	('contact inhibition', 'biological_process', 'GO:0060242', ('43', '61'))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))
94754	29342862	The Hippo pathway is regulated by several upstream factors, and two in particular, the NF2/Merlin and YAP oncogenes, are mutated or overactive in approximately 40% and 70% of MPM cases, respectively.	('Merlin', 'Gene', (91, 97))	('NF2', 'Gene', (87, 90))	('Merlin', 'Gene', '4771', (91, 97))	('mutated', 'Var', (121, 128))	('overactive', 'PosReg', (132, 142))	('MPM', 'Disease', (175, 178))	('YAP', 'Gene', '10413', (102, 105))	('Hippo pathway', 'Pathway', (4, 17))	('NF2', 'Gene', '4771', (87, 90))	('YAP', 'Gene', (102, 105))
94759	29342862	They identified a new subgroup, C2LN, in which mutations in the LATS2 and NF2 genes co-occur within the same MPM and these patients showed enhanced sensitivity to PF-04691502, a PI3K-AKT-mTOR inhibitor.	('NF2', 'Gene', '4771', (74, 77))	('LATS2', 'Gene', (64, 69))	('AKT', 'Gene', (183, 186))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (123, 131))	('LATS2', 'Gene', '26524', (64, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('178', '182'))	('NF2', 'Gene', (74, 77))	('sensitivity', 'MPA', (148, 159))	('enhanced', 'PosReg', (139, 147))	('AKT', 'Gene', '207', (183, 186))
94762	29342862	demonstrated that MLN4924, an NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 (E3 ubiquitin ligase) and interferes with YAP activation in NF2-mutant cancers alone, and in combination with, the PI3K-mTOR inhibitor, GDC-0980.	('NF2', 'Gene', (152, 155))	('GDC-0980', 'Chemical', 'MESH:C569670', (228, 236))	('interferes', 'NegReg', (118, 128))	('rat', 'Species', '10116', (7, 10))	('YAP', 'Gene', (134, 137))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('NEDD8', 'Gene', '4738', (30, 35))	('E3 ubiquitin ligase', 'Gene', (93, 112))	('MLN4924', 'Var', (18, 25))	('CRL4DCAF1', 'Gene', (82, 91))	('NEDD8', 'Gene', (30, 35))	('suppresses', 'NegReg', (71, 81))	('YAP', 'Gene', '10413', (134, 137))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('ubiquitin', 'molecular_function', 'GO:0031386', ('96', '105'))	('cancers', 'Disease', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('E3 ubiquitin ligase', 'Gene', '79594', (93, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('207', '211'))	('NF2', 'Gene', '4771', (152, 155))
94767	29342862	Therapeutic strategies, aimed at disrupting YAP activity, include (1) targeting the Hh pathway as it down-regulates the YAP protein, (2) a small molecule called verteporfin, which inhibits YAP-TEAD transcription factor assembly, and (3) obstructions of lysophosphatidic acid (LPA) and thrombin receptor signaling, because upon agonist binding, they activate YAP.	('TEAD', 'Disease', 'None', (193, 197))	('TEAD', 'Disease', (193, 197))	('verteporfin', 'Chemical', 'MESH:D000077362', (161, 172))	('Hh pathway', 'Pathway', (84, 94))	('YAP', 'Gene', '10413', (358, 361))	('YAP', 'Gene', (189, 192))	('transcription factor', 'molecular_function', 'GO:0000981', ('198', '218'))	('binding', 'molecular_function', 'GO:0005488', ('335', '342'))	('inhibits', 'NegReg', (180, 188))	('YAP', 'Gene', (44, 47))	('YAP', 'Gene', '10413', (120, 123))	('down-regulates', 'NegReg', (101, 115))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (253, 274))	('rat', 'Species', '10116', (14, 17))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('signaling', 'biological_process', 'GO:0023052', ('303', '312'))	('YAP', 'Gene', '10413', (189, 192))	('activate', 'PosReg', (349, 357))	('LPA', 'Chemical', 'MESH:C032881', (276, 279))	('YAP', 'Gene', (358, 361))	('YAP', 'Gene', '10413', (44, 47))	('transcription', 'biological_process', 'GO:0006351', ('198', '211'))	('obstructions', 'Var', (237, 249))	('YAP', 'Gene', (120, 123))
94805	29244982	Genetic predisposition is related to mutations of the BAP1 gene; however, the overall magnitude of risk remains undefined.	('BAP1', 'Gene', '8314', (54, 58))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (54, 58))
94949	25683976	It is estimated that close to 10-20% of all human tumors contain mutated versions of Ras proteins.	('human', 'Species', '9606', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('Ras proteins', 'Protein', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mutated', 'Var', (65, 72))
94955	25683976	These apoptotic pathways (Bcl-2/Bax and Fas/Fas L) were assessed by immunohistochemistry for expression patterns in tissue sections from patients who had E-MPM and A-MPM, with adenocarcinoma sections serving as control group samples (Table 3).	('Bax', 'Gene', (32, 35))	('Bcl-2', 'molecular_function', 'GO:0015283', ('26', '31'))	('Fas L', 'Gene', (44, 49))	('MPM', 'Chemical', '-', (166, 169))	('Fas', 'Chemical', 'MESH:C038178', (40, 43))	('A-MPM', 'Var', (164, 169))	('MPM', 'Chemical', '-', (156, 159))	('Fas', 'Chemical', 'MESH:C038178', (44, 47))	('patients', 'Species', '9606', (137, 145))	('E-MPM', 'Chemical', '-', (154, 159))	('E-MPM', 'Var', (154, 159))	('adenocarcinoma', 'Disease', (176, 190))	('Bcl-2', 'Gene', (26, 31))	('Bcl-2', 'Gene', '596', (26, 31))	('Fas L', 'Gene', '356', (44, 49))	('adenocarcinoma', 'Disease', 'MESH:D000230', (176, 190))	('Bax', 'Gene', '581', (32, 35))
94989	25683976	Four retrospective studies reported an E-MPM-related mortality of 2.30% to 20.6% among the inhabitants of three villages in the Cappadocia region of Central Anatolia followed by lung cancer in 2.30% to 12.1% and then malignant peritoneal mesotheliomas in 2.8% (4 of 141).	('lung cancer', 'Disease', (178, 189))	('E-MPM-related', 'Var', (39, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('E-MPM', 'Chemical', '-', (39, 44))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (227, 251))	('mesotheliomas', 'Disease', 'MESH:D008654', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mesotheliomas', 'Disease', (238, 251))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))
94992	25683976	(52 patients), who studied the impact of apoptotic pathways Bcl-2/Bax and Fas/Fas L on survival in tissue sections from patients with E-MPM and A-MPM, with adenocarcinoma sections serving as a control group.	('adenocarcinoma', 'Disease', (156, 170))	('Fas L', 'Gene', (78, 83))	('Bax', 'Gene', '581', (66, 69))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('MPM', 'Chemical', '-', (146, 149))	('A-MPM', 'Var', (144, 149))	('Fas', 'Chemical', 'MESH:C038178', (74, 77))	('Fas', 'Chemical', 'MESH:C038178', (78, 81))	('E-MPM', 'Chemical', '-', (134, 139))	('Bcl-2', 'molecular_function', 'GO:0015283', ('60', '65'))	('E-MPM', 'Var', (134, 139))	('Fas L', 'Gene', '356', (78, 83))	('patients', 'Species', '9606', (120, 128))	('Bcl-2', 'Gene', (60, 65))	('Bax', 'Gene', (66, 69))	('Bcl-2', 'Gene', '596', (60, 65))	('patients', 'Species', '9606', (4, 12))	('MPM', 'Chemical', '-', (136, 139))
95022	25683976	As expected, chest CT was more reliable in detecting various pleural changes in E-MPM than CxR (Table 4), and PE was the most common finding in E-MPM, by both CxR and chest CT, followed by PT and IC.	('E-MPM', 'Chemical', '-', (80, 85))	('pleural', 'Disease', (61, 68))	('PT', 'Chemical', '-', (189, 191))	('E-MPM', 'Chemical', '-', (144, 149))	('CxR', 'Var', (159, 162))	('pleural', 'Disease', 'MESH:D010995', (61, 68))
95026	25683976	In other instances, pleural sampling can be achieved through pleural biopsy, thoracoscopy, or thoracotomy, with a 29% to 95.7% yield for E-MPM by light microscopy.	('pleural', 'Disease', (61, 68))	('pleural', 'Disease', 'MESH:D010995', (20, 27))	('pleural', 'Disease', (20, 27))	('E-MPM', 'Chemical', '-', (137, 142))	('pleural', 'Disease', 'MESH:D010995', (61, 68))	('E-MPM', 'Var', (137, 142))
95034	25683976	Survival in patients with E-MPM remains low when compared to patients with A-MPM (Table 5).	('patients', 'Species', '9606', (12, 20))	('MPM', 'Chemical', '-', (28, 31))	('low', 'NegReg', (40, 43))	('E-MPM', 'Chemical', '-', (26, 31))	('patients', 'Species', '9606', (61, 69))	('MPM', 'Chemical', '-', (77, 80))	('E-MPM', 'Var', (26, 31))
95061	19458589	The pencil beam algorithm underestimated lung MLD, V20, and V5, compared with MC, by a mean (range) of 16% (11-22%), 9.0% (2.4 - 30.1%), and 11.8% (2 - 30%), respectively.	('lung MLD', 'Disease', 'MESH:D007966', (41, 49))	('underestimated lung', 'Phenotype', 'HP:0002089', (26, 45))	('lung MLD', 'Disease', (41, 49))	('underestimated', 'NegReg', (26, 40))	('V20', 'Var', (51, 54))
95079	19458589	The patients had been contoured to include the following structures:   The dose prescription was 54Gy to CTV54, 48Gy to CTV48, and 60Gy to GTV60, all treated simultaneously, with GTV60 receiving 2.	('CTV54', 'Gene', (105, 110))	('CTV48', 'Var', (120, 125))	('patients', 'Species', '9606', (4, 12))
95312	27162550	Overexpression or abnormal activities of these regulators have been linked to human disease like cancers for many years.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('linked', 'Reg', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('activities', 'MPA', (27, 37))	('abnormal', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (78, 83))
95319	27162550	Clinical data have shown that sustained delivery and low drug dosing of epigenetic target inhibitors can reduce off-target effects such as systemic toxicity.	('reduce', 'NegReg', (105, 111))	('systemic toxicity', 'Disease', 'MESH:D010523', (139, 156))	('low drug dosing', 'Phenotype', 'HP:0020171', (53, 68))	('epigenetic target inhibitors', 'Var', (72, 100))	('systemic toxicity', 'Disease', (139, 156))	('off-target effects', 'MPA', (112, 130))
95321	27162550	With epigenetic targeting drugs, side effects or systemic toxicity can be reduced with highly active compounds used alone or in combination, at low dosage, in association with the tumor targeting mediated by drug delivery systems (DDS).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('side effects', 'CPA', (33, 45))	('systemic toxicity', 'Disease', (49, 66))	('tumor', 'Disease', (180, 185))	('epigenetic targeting drugs', 'Var', (5, 31))	('systemic toxicity', 'Disease', 'MESH:D010523', (49, 66))	('reduced', 'NegReg', (74, 81))
95334	27162550	Epigenetic errors observed in mesothelioma contribute to ineffective chemotherapy treatment and characterize this cancer as a candidate for epigenetic therapeutic strategies.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mesothelioma', 'Disease', (30, 42))	('Epigenetic errors', 'Var', (0, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
95382	27162550	Acetone-d6) delta ppm: 9.80 (1H, s, NH), 7.74 (1H, s, Ha), 7.36 (1H, d, J = 12.1 Hz, Hc), 7.30 (4H, d, J = 8.3 Hz, Hd), 7.12 (4H, d, J = 8.1 Hz, He), 6.54 (1H, dd, J = 12.1, 4.2 Hz, Hf), 6.23 (1H, s, Hg), 5.95 (1H, d, J = 16.0 Hz, Hh), 5.88 (1H, s, Hi), 4.53 (2H, t, J = 4.0 Hz, Hj), 4.15 (2H, d, J = 0.8 Hz, Hk), 3.84 (2H, t, J = 8.0 Hz, Hl), 3.52 (12H, m, Hm), 3.13 (6H, s, Hn), 2.93 (1H, t, J = 0.8 Hz, Ho), 2.31 (6H, s, Hp), 1.82 (3H, s, Hq), 1.52 (3H, s, Hr); 13C NMR (400 MHz, Acetone-d6) delta ppm: 197.8, 173.7, 158.9 (2C), 128.9-126.03 (10C), 108.9, 108.2, 93.1, 89.6, 75.8, 71.1-69.8 (7C), 58.6, 50.1, 40.5 (2C), 24.5, 20.9 (2C), 13.6; HRMS ESI: found 786.3495; calculated 786.3473 for [M+Na]+.C45H53N5O8Na.	('2H', 'Chemical', 'MESH:D003903', (260, 262))	('1H', 'Chemical', '-', (65, 67))	('786.3473', 'Var', (683, 691))	('2H', 'Chemical', 'MESH:D003903', (290, 292))	('1H', 'Chemical', '-', (29, 31))	('2H', 'Chemical', 'MESH:D003903', (320, 322))	('2H', 'Chemical', 'MESH:D003903', (351, 353))	('3H', 'Chemical', 'MESH:D014316', (453, 455))	('Hk), 3', 'molecular_function', 'GO:0008257', ('309', '315'))	('1H', 'Chemical', '-', (47, 49))	('1H', 'Chemical', '-', (387, 389))	('HRMS ESI', 'Disease', 'None', (646, 654))	('6H', 'Chemical', '-', (369, 371))	('6H', 'Chemical', '-', (417, 419))	('13C', 'Chemical', '-', (465, 468))	('1H', 'Chemical', '-', (211, 213))	('1H', 'Chemical', '-', (242, 244))	('1H', 'Chemical', '-', (156, 158))	('HRMS ESI', 'Disease', (646, 654))	('3H', 'Chemical', 'MESH:D014316', (435, 437))	('1H', 'Chemical', '-', (193, 195))
95441	27162550	4) induced no toxicity for all tested polymer concentrations whereas NPs 8 led to a rapid cell viability decrease even at 0.05 mg/ml of polymer.	('polymer', 'Chemical', 'MESH:D011108', (136, 143))	('cell viability', 'CPA', (90, 104))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('toxicity', 'Disease', (14, 22))	('polymer', 'Chemical', 'MESH:D011108', (38, 45))	('NPs', 'Var', (69, 72))	('decrease', 'NegReg', (105, 113))
95443	27162550	The toxicity of NPs 8 compared to NPs 10 provided a wide safe window for in vivo experiments.	('NPs 8', 'Var', (16, 21))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('toxicity', 'Disease', (4, 12))
95480	24682649	They establish the selective cytotoxic effects of double-deleted vaccinia virus (vvDD) against two different mesothelioma cell lines and demonstrate improved survival in two different orthotopic murine models of malignant peritoneal mesothelioma after regional (intraperitoneal) treatment with vvDD.	('double-deleted', 'Var', (50, 64))	('malignant peritoneal mesothelioma', 'Disease', (212, 245))	('mesothelioma', 'Disease', 'MESH:D008654', (109, 121))	('mesothelioma', 'Disease', (233, 245))	('murine', 'Species', '10090', (195, 201))	('improved', 'PosReg', (149, 157))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (212, 245))	('mesothelioma', 'Disease', 'MESH:D008654', (233, 245))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (222, 245))	('mesothelioma', 'Disease', (109, 121))	('vaccinia virus', 'Species', '10245', (65, 79))
95482	24682649	In a model, believed by the authors to be a surrogate for cytoreductive surgery (removal of all macroscopic disease), mice with only microscopic disease achieved a significant survival benefit when treated with vvDD compared to controls.	('survival benefit', 'CPA', (176, 192))	('mice', 'Species', '10090', (118, 122))	('vvDD', 'Var', (211, 215))
95490	24682649	vvDD is an efficient, tumor selective virus due to its deletion of both the thymidine kinase and vaccinia growth factor genes, and it has been shown to be both tumor selective and a potent oncolytic agent.	('vaccinia growth factor', 'Gene', (97, 119))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('thymidine', 'Gene', (76, 85))	('vaccinia', 'Species', '10245', (97, 105))	('tumor', 'Disease', (22, 27))	('deletion', 'Var', (55, 63))	('tumor', 'Disease', (160, 165))
95544	20003222	Carbone, et al., report that at least 60% of mesotheliomas in the United States contain and express SV40, which results in suppression of tumor suppressors p53 and Rb, thereby leading to tumor development.	('Carbone', 'Chemical', 'MESH:D002244', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('suppression', 'NegReg', (123, 134))	('tumor', 'Disease', (138, 143))	('mesotheliomas', 'Disease', 'MESH:D008654', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mesotheliomas', 'Disease', (45, 58))	('SV40', 'Var', (100, 104))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('leading to', 'Reg', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
95639	29213079	Paradoxically, CD26high T cells persist in and regress multiple solid tumors following adoptive cell transfer.	('solid tumors', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('regress', 'CPA', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('CD26high', 'Var', (15, 23))
95641	29213079	These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors.	('traffic to', 'MPA', (69, 79))	('CD26high', 'Var', (25, 33))	('regress', 'CPA', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
95654	29213079	reported that human T cells with a high expression of CD26 on their cell surface:termed CD26high T cells:produce large amounts of the Th17 hallmark cytokine, IL-17.	('Th1', 'Gene', (134, 137))	('human', 'Species', '9606', (14, 19))	('cell surface', 'cellular_component', 'GO:0009986', ('68', '80'))	('IL-17', 'molecular_function', 'GO:0030367', ('158', '163'))	('Th1', 'Gene', '51497', (134, 137))	('CD26high', 'Var', (88, 96))	('IL-17', 'Gene', (158, 163))	('IL-17', 'Gene', '3605', (158, 163))
95659	29213079	CD26high T cells persist and regress/control tumors to a far greater extent than CD26neg T cells and surprisingly, slightly better than naive CD26int T cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CD26high', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('CD26neg', 'Chemical', '-', (81, 88))	('persist', 'CPA', (17, 24))
95660	29213079	Our data reveal that CD26high T cells have enhanced multi-functionality (IL-17A, IFNgamma, IL-2, TNFalpha, and IL-22), stemness properties (elevated beta-catenin and Lef1), memory (long-term persistence and Bcl2 expression), and a rich profile of chemokine receptors (including CCR2 and CCR5), thereby enabling them to traffic to, regress mesothelioma and inhibit the growth of pancreatic tumors.	('pancreatic tumors', 'Disease', (378, 395))	('enhanced', 'PosReg', (43, 51))	('IL-17A', 'Gene', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('CCR', 'molecular_function', 'GO:0043880', ('278', '281'))	('traffic to', 'CPA', (319, 329))	('mesothelioma', 'Disease', (339, 351))	('TNFalpha', 'Gene', (97, 105))	('mesothelioma', 'Disease', 'MESH:D008654', (339, 351))	('IL-22', 'Gene', '50616', (111, 116))	('IL-22', 'Gene', (111, 116))	('CCR5', 'Gene', (287, 291))	('chemokine receptor', 'Gene', (247, 265))	('inhibit', 'NegReg', (356, 363))	('IL-22', 'molecular_function', 'GO:0045518', ('111', '116'))	('IL-2', 'molecular_function', 'GO:0005134', ('91', '95'))	('memory', 'CPA', (173, 179))	('regress', 'CPA', (331, 338))	('stemness', 'Disease', 'MESH:D020295', (119, 127))	('stemness', 'Disease', (119, 127))	('beta-catenin', 'Gene', (149, 161))	('multi-functionality', 'CPA', (52, 71))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (378, 395))	('Bcl2', 'Gene', (207, 211))	('Lef1', 'Gene', '51176', (166, 170))	('CCR', 'molecular_function', 'GO:0043880', ('287', '290'))	('TNFalpha', 'Gene', '7124', (97, 105))	('beta-catenin', 'Gene', '1499', (149, 161))	('IL-17A', 'Gene', '3605', (73, 79))	('memory', 'biological_process', 'GO:0007613', ('173', '179'))	('CCR2', 'Gene', (278, 282))	('Bcl2', 'Gene', '596', (207, 211))	('CD26high', 'Var', (21, 29))	('chemokine receptor', 'Gene', '7852', (247, 265))	('CCR2', 'Gene', '729230', (278, 282))	('enabling', 'PosReg', (302, 310))	('IFNgamma', 'Gene', '3458', (81, 89))	('IFNgamma', 'Gene', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (389, 395))	('CCR5', 'Gene', '1234', (287, 291))	('IL-17', 'molecular_function', 'GO:0030367', ('73', '78'))	('Bcl2', 'molecular_function', 'GO:0015283', ('207', '211'))	('pancreatic tumors', 'Disease', 'MESH:D010190', (378, 395))	('Lef1', 'Gene', (166, 170))
95665	29213079	To address this question, we flow-sorted murine TRP-1 CD4+ T cells, which express a transgenic TCR specific for tyrosinase on melanoma, via CD26 expression.	('TCR', 'biological_process', 'GO:0006283', ('95', '98'))	('CD26', 'Var', (140, 144))	('TRP-1', 'Gene', '22178', (48, 53))	('murine', 'Species', '10090', (41, 47))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('TRP-1', 'molecular_function', 'GO:0004167', ('48', '53'))	('melanoma', 'Disease', (126, 134))	('TCR', 'cellular_component', 'GO:0042101', ('95', '98'))	('TRP-1', 'Gene', (48, 53))
95668	29213079	Moreover, half of the mice treated with CD26high T cells experienced a curative response (Supplementary Fig.	('CD26high T cells', 'Var', (40, 56))	('mice', 'Species', '10090', (22, 26))	('curative response', 'CPA', (71, 88))
95669	29213079	We next determined the antitumor activity of human CD26high T cells in a CAR-T model.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('CD26high T', 'Var', (51, 61))	('human', 'Species', '9606', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CAR', 'cellular_component', 'GO:0005826', ('73', '76'))
95674	29213079	Surprisingly, CD26high T cells express more FoxP3 than CD26neg T cells (Fig.	('FoxP3', 'Gene', '50943', (44, 49))	('CD26high', 'Var', (14, 22))	('CD26neg', 'Chemical', '-', (55, 62))	('FoxP3', 'Gene', (44, 49))
95678	29213079	As expected, CD26high T cells had a ten-fold higher expression of the activation markers CD25 and CD69 (~20%) than CD26neg T cells (~2%) (Supplementary Fig.	('CD25', 'Gene', '3559', (89, 93))	('CD69', 'Gene', (98, 102))	('CD26neg', 'Chemical', '-', (115, 122))	('expression', 'MPA', (52, 62))	('CD25', 'Gene', (89, 93))	('higher', 'PosReg', (45, 51))	('CD26high T', 'Var', (13, 23))	('CD69', 'Gene', '969', (98, 102))
95679	29213079	CD26neg T cells also displayed a higher frequency of CD25+CD127- cells (CD26neg ~12%; CD26high ~5%), an extracellular phenotype associated with Tregs (Fig.	('CD26neg', 'Chemical', '-', (72, 79))	('CD25', 'Gene', (53, 57))	('CD26neg', 'Var', (0, 7))	('Tregs', 'Chemical', '-', (144, 149))	('CD127', 'Gene', (58, 63))	('CD25', 'Gene', '3559', (53, 57))	('CD26neg', 'Chemical', '-', (0, 7))	('extracellular', 'cellular_component', 'GO:0005576', ('104', '117'))	('CD127', 'Gene', '3575', (58, 63))
95681	29213079	Conversely, <9% of CD26neg T cells were capable of cytokine production.	('CD26neg', 'Var', (19, 26))	('CD26neg', 'Chemical', '-', (19, 26))	('cytokine production', 'MPA', (51, 70))	('cytokine production', 'biological_process', 'GO:0001816', ('51', '70'))
95682	29213079	Collectively, our data reveal that a portion of CD26high T cells are activated post-enrichment and clear tumors when redirected with a CAR.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('CAR', 'Gene', '653108', (135, 138))	('CAR', 'cellular_component', 'GO:0005826', ('135', '138'))	('CD26high', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CAR', 'Gene', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
95684	29213079	As CD26int cells have briefly been described as naive (CCR7+CD45RA+), we hypothesized that they would elicit superior antitumor immunity compared to CD26neg or CD26high T cells.	('CD45', 'Gene', '5788', (60, 64))	('CD26neg', 'Chemical', '-', (149, 156))	('superior', 'PosReg', (109, 117))	('CCR7', 'Gene', (55, 59))	('elicit', 'Reg', (102, 108))	('CD45', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('CCR7', 'Gene', '1236', (55, 59))	('CCR', 'molecular_function', 'GO:0043880', ('55', '58'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CD26int', 'Var', (3, 10))	('tumor', 'Disease', (122, 127))
95685	29213079	CD4+ T cells were enriched from healthy donors and FACS-sorted into bulk CD4+, CD26neg, CD26int or CD26high subsets (sorting purity >80%:Fig.	('CD26high', 'Var', (99, 107))	('donor', 'Species', '9606', (40, 45))	('CD26neg', 'Chemical', '-', (79, 86))	('CD26int', 'Var', (88, 95))
95686	29213079	As expected, ~65% of CD26int cells were naive (CD45RA+CD62L+), whereas more than half of CD26neg and CD26high T cells possessed a more differentiated central or effector memory phenotype (Fig.	('CD45', 'Gene', '5788', (47, 51))	('CD26neg', 'Var', (89, 96))	('CD45', 'Gene', (47, 51))	('CD26neg', 'Chemical', '-', (89, 96))	('CD26high T', 'Var', (101, 111))	('memory', 'biological_process', 'GO:0007613', ('170', '176'))
95688	29213079	Gene array analysis corroborated our findings, showing both CD26neg and CD26high T cells expressed less CCR7, CD27 and CD62L than CD26int T cells (Fig.	('CCR7', 'Gene', (104, 108))	('CCR7', 'Gene', '1236', (104, 108))	('CCR', 'molecular_function', 'GO:0043880', ('104', '107'))	('less', 'NegReg', (99, 103))	('CD26neg', 'Chemical', '-', (60, 67))	('CD27', 'Gene', '939', (110, 114))	('CD26high', 'Var', (72, 80))	('CD27', 'Gene', (110, 114))	('CD62L', 'Var', (119, 124))	('CD26neg', 'Var', (60, 67))
95690	29213079	Importantly, the differentiated phenotype of CD26neg and CD26high T cells and naive characteristics of CD26int T cells were reproducibly observed in more than 25 healthy donors.	('CD26high', 'Var', (57, 65))	('CD26neg', 'Chemical', '-', (45, 52))	('donor', 'Species', '9606', (170, 175))	('CD26neg', 'Var', (45, 52))
95694	29213079	Despite the increased co-inhibitory markers on CD26high T cells, they also expressed many co-stimulatory markers, including CD40L (CD40LG), 41BB (TNFRSF9), and GITR (TNFRSF18) (Fig.	('41BB', 'Gene', '3604', (140, 144))	('TNFRSF9', 'Gene', (146, 153))	('GITR', 'Gene', (160, 164))	('CD40L', 'Gene', '959', (124, 129))	('CD40L', 'Gene', '959', (131, 136))	('co-inhibitory markers', 'MPA', (22, 43))	('CD40L', 'Gene', (124, 129))	('increased', 'PosReg', (12, 21))	('CD40L', 'Gene', (131, 136))	('expressed', 'MPA', (75, 84))	('TNFRSF9', 'Gene', '3604', (146, 153))	('GITR', 'Gene', '8784', (160, 164))	('CD40LG', 'Gene', '959', (131, 137))	('CD40LG', 'Gene', (131, 137))	('CD26high T', 'Var', (47, 57))	('TNFRSF18', 'Gene', '8784', (166, 174))	('41BB', 'Gene', (140, 144))	('TNFRSF18', 'Gene', (166, 174))
95695	29213079	Overall, these findings reveal that CD26int T cells possess a naive phenotype and express less co-stimulatory/inhibitory receptors compared to CD26neg and CD26high T cells.	('CD26int', 'Var', (36, 43))	('less', 'NegReg', (90, 94))	('CD26neg', 'Chemical', '-', (143, 150))	('co-stimulatory/inhibitory receptors', 'MPA', (95, 130))
95697	29213079	Given that CD26int T cells appear naive, we hypothesized that they would not express the chemokine receptors indicative of any particular subset, whereas CD26neg and CD26high T cells would exhibit their reported Treg and Th1/Th17 phenotypes.	('CD26neg', 'Var', (154, 161))	('Th1', 'Gene', '51497', (221, 224))	('Th1', 'Gene', '51497', (225, 228))	('exhibit', 'Reg', (189, 196))	('chemokine receptor', 'Gene', '7852', (89, 107))	('chemokine receptor', 'Gene', (89, 107))	('Th1', 'Gene', (225, 228))	('CD26high', 'Var', (166, 174))	('Th1', 'Gene', (221, 224))	('Treg', 'CPA', (212, 216))	('CD26neg', 'Chemical', '-', (154, 161))
95704	29213079	Using TCRbeta analysis, we found that many TCRs in CD26high T cells overlap with Th1, Th17, and Th1/Th17 cells, but not with Th2 cells (Fig.	('TCRbeta', 'Gene', '6957', (6, 13))	('Th1', 'Gene', (100, 103))	('Th1', 'Gene', (86, 89))	('Th1', 'Gene', '51497', (81, 84))	('Th1', 'Gene', (96, 99))	('CD26high', 'Var', (51, 59))	('Th1', 'Gene', '51497', (96, 99))	('Th1', 'Gene', '51497', (86, 89))	('Th1', 'Gene', (81, 84))	('TCRbeta', 'Gene', (6, 13))	('Th1', 'Gene', '51497', (100, 103))
95705	29213079	Although CD26high T cells had greater overlap with Th1 cells than CD26neg did, the overlapping TCRs between Th1 and CD26neg were more highly expressed (Supplementary Fig.	('Th1', 'Gene', (51, 54))	('CD26neg', 'Var', (116, 123))	('Th1', 'Gene', (108, 111))	('CD26neg', 'Chemical', '-', (116, 123))	('Th1', 'Gene', '51497', (108, 111))	('Th1', 'Gene', '51497', (51, 54))	('CD26neg', 'Chemical', '-', (66, 73))
95707	29213079	Although CD26high T cells exhibited significant overlap with Th1/Th17 cells, they shared little TCRbeta overlap with CD26neg or CD26int cells (Fig.	('TCRbeta', 'Gene', '6957', (96, 103))	('CD26neg', 'Chemical', '-', (117, 124))	('Th1', 'Gene', (65, 68))	('Th1', 'Gene', '51497', (61, 64))	('Th1', 'Gene', '51497', (65, 68))	('CD26high', 'Var', (9, 17))	('TCRbeta', 'Gene', (96, 103))	('Th1', 'Gene', (61, 64))
95708	29213079	Likewise, CD26int cells had minimal TCRbeta overlap with any of the Th subsets.	('CD26int', 'Var', (10, 17))	('TCRbeta', 'Gene', '6957', (36, 43))	('TCRbeta', 'Gene', (36, 43))
95709	29213079	Overall, these data confirm that CD26high and CD26neg T cells are differentiated cells containing multiple cell subsets while CD26int T cells are primarily uncommitted.	('CD26neg', 'Chemical', '-', (46, 53))	('CD26neg', 'Var', (46, 53))	('CD26high', 'Var', (33, 41))
95711	29213079	Interestingly, CD26high T cells had heightened production of multiple cytokines, including IL-2, IFNgamma, IL-17A, IL-22, and TNFalpha (Fig.	('IL-17A', 'Gene', (107, 113))	('TNFalpha', 'Gene', (126, 134))	('IFNgamma', 'Gene', '3458', (97, 105))	('IL-17', 'molecular_function', 'GO:0030367', ('107', '112'))	('TNFalpha', 'Gene', '7124', (126, 134))	('IL-17A', 'Gene', '3605', (107, 113))	('IL-22', 'Gene', '50616', (115, 120))	('production of multiple cytokines', 'MPA', (47, 79))	('IL-22', 'molecular_function', 'GO:0045518', ('115', '120'))	('CD26high', 'Var', (15, 23))	('IL-2', 'molecular_function', 'GO:0005134', ('91', '95'))	('heightened', 'PosReg', (36, 46))	('IL-22', 'Gene', (115, 120))	('IFNgamma', 'Gene', (97, 105))
95712	29213079	However, this heightened cytokine profile did not directly correlate with cell differentiation, as evidenced by similar cytokine production between bulk CD4+, CD26neg, and CD26int T cells.	('CD26neg', 'Chemical', '-', (159, 166))	('CD26int T', 'Var', (172, 181))	('cell differentiation', 'biological_process', 'GO:0030154', ('74', '94'))	('CD26neg', 'Var', (159, 166))	('cytokine production', 'biological_process', 'GO:0001816', ('120', '139'))
95713	29213079	When we took into account the percentage of these donors not producing any cytokines, we discovered that 60-80% of CD4+, CD26neg, and CD26int T cells were incapable of producing cytokines on day 0, whereas the majority of CD26high T cells produced 3-5 cytokines simultaneously (Supplementary Fig.	('producing cytokines', 'MPA', (168, 187))	('CD26neg', 'Chemical', '-', (121, 128))	('donor', 'Species', '9606', (50, 55))	('CD26int', 'Var', (134, 141))	('CD26neg', 'Var', (121, 128))	('CD4+', 'Var', (115, 119))	('incapable', 'NegReg', (155, 164))
95714	29213079	Furthermore, CD26high T cells produced more cytotoxic granules (Granzyme B, CD107A) and chemokines (MIP1beta, RANTES) compared to other subsets, a property normally used to define cytotoxic CD8+ T cells (Fig.	('CD8', 'Gene', '925', (190, 193))	('CD26high', 'Var', (13, 21))	('more', 'PosReg', (39, 43))	('CD107A', 'Gene', (76, 82))	('Granzyme B', 'Gene', '3002', (64, 74))	('MIP', 'molecular_function', 'GO:0004243', ('100', '103'))	('CD107A', 'Gene', '3916', (76, 82))	('MIP1beta', 'Gene', '6351', (100, 108))	('cytotoxic granules', 'MPA', (44, 62))	('RANTES', 'Gene', (110, 116))	('MIP1beta', 'Gene', (100, 108))	('Granzyme B', 'Gene', (64, 74))	('CD8', 'Gene', (190, 193))	('RANTES', 'Gene', '6352', (110, 116))
95719	29213079	Furthermore, the mean fluorescence intensity (MFI) of CD26 on all subsets was similar between cancer patients and healthy individuals, with CD26high T cells maintaining the greatest CD26 expression (Supplementary Fig.	('patients', 'Species', '9606', (101, 109))	('CD26high', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CD26', 'Gene', (182, 186))	('expression', 'MPA', (187, 197))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
95720	29213079	The phenotype of CD26neg, CD26int, and CD26high T cells in melanoma patients was similar to that seen in health donors.	('CD26neg', 'Var', (17, 24))	('donor', 'Species', '9606', (112, 117))	('CD26int', 'Var', (26, 33))	('patients', 'Species', '9606', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('CD26neg', 'Chemical', '-', (17, 24))	('CD26high', 'Var', (39, 47))
95726	29213079	Finally, CD26high T cells expressed more CCR2 and CCR8 than other subsets (Supplementary Fig.	('CCR8', 'Gene', '1237', (50, 54))	('CCR2', 'Gene', '729230', (41, 45))	('CCR', 'molecular_function', 'GO:0043880', ('41', '44'))	('CCR', 'molecular_function', 'GO:0043880', ('50', '53'))	('CCR8', 'Gene', (50, 54))	('CCR2', 'Gene', (41, 45))	('CD26high', 'Var', (9, 17))
95728	29213079	Collectively, we found that CD26neg, CD26int, and CD26high T cells from melanoma patients possess a similar biological profile as those identified in healthy donors.	('CD26neg', 'Chemical', '-', (28, 35))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('patients', 'Species', '9606', (81, 89))	('CD26int', 'Var', (37, 44))	('donor', 'Species', '9606', (158, 163))	('CD26high', 'Var', (50, 58))
95732	29213079	Surprisingly, despite the seemingly exhausted phenotype of CD26high T cells, they regressed tumor slightly, but not significantly, better than CD26int T cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CD26high T', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
95737	29213079	Collectively, we found that CAR+ T cells that express CD26 are more effective at clearing tumors.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CAR', 'Gene', (28, 31))	('clearing tumors', 'Disease', (81, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CAR', 'cellular_component', 'GO:0005826', ('28', '31'))	('clearing tumors', 'Disease', 'MESH:D054973', (81, 96))	('CD26', 'Var', (54, 58))	('CAR', 'Gene', '653108', (28, 31))
95739	29213079	Thus, we next sought to determine if CAR-T cells that express CD26 (CD26high and CD26int) could better control pancreatic cancer (PANC1) in mice to a greater extent than CD26neg T cells.	('PANC1', 'Gene', (130, 135))	('CAR', 'cellular_component', 'GO:0005826', ('37', '40'))	('mice', 'Species', '10090', (140, 144))	('CD26', 'Var', (62, 66))	('CD26neg', 'Chemical', '-', (170, 177))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('pancreatic cancer', 'Disease', (111, 128))	('CD26int', 'Var', (81, 88))	('control', 'PosReg', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PANC1', 'Gene', '104066', (130, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))
95741	29213079	6d), both CD26int and CD26high T cells significantly slowed the progression of pancreatic tumors, whereas bulk CD4+ and CD26neg T cells yielded little-to-no antitumor response (Fig.	('CD26int', 'Var', (10, 17))	('pancreatic tumors', 'Disease', 'MESH:D010190', (79, 96))	('CD26high', 'Var', (22, 30))	('pancreatic tumors', 'Disease', (79, 96))	('progression', 'CPA', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CD26neg', 'Chemical', '-', (120, 127))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('slowed', 'NegReg', (53, 59))
95742	29213079	These findings were confirmed by decreased tumor growth and weight in mice treated with CD26int or CD26high T cells compared to mice treated with CD4+ or CD26neg T cells (Fig.	('CD26high T cells', 'Var', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CD26int', 'Var', (88, 95))	('CD26neg', 'Chemical', '-', (154, 161))	('decreased', 'NegReg', (33, 42))	('tumor', 'Disease', (43, 48))
95744	29213079	Given that CD26int and CD26high T cells yielded the best antitumor response, we next posited that CD26 expression on T cells in the tumor itself might correlate with overall response.	('CD26high', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CD26', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CD26int', 'Var', (11, 18))	('tumor', 'Disease', (61, 66))
95747	29213079	On the contrary, we found that CD26 expression on TIL tightly correlated with response as smaller tumors exhibited heightened percentages of CD26+ TIL (Fig.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CD26+ TIL', 'Var', (141, 150))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('heightened', 'PosReg', (115, 125))	('CD26', 'Protein', (31, 35))	('correlated', 'Reg', (62, 72))
95751	29213079	These observations not only exhibit that distinct CD26-expressing CD4+ T cell subsets exist in both endogenous and adoptively transferred TIL, but also identify a direct correlation between CD26 and their subsequent ability to slow/regress tumors.	('regress tumors', 'Disease', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('CD26', 'Var', (190, 194))	('regress tumors', 'Disease', 'MESH:D009365', (232, 246))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
95752	29213079	Although we found that CD4+CD26high T cells exhibit greater antitumor activity than other CD4+ subsets, how they compare to the commonly used cytotoxic CD8+ T cells is unknown.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('CD4+CD26high', 'Var', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CD8', 'Gene', (152, 155))	('CD8', 'Gene', '925', (152, 155))
95754	29213079	An in vitro cytotoxic assay using mesothelin-expressing K562 cells revealed that CD4+CD26high T cells have a similar, if not enhanced, capacity to kill cancer compared to CD8+ cells (Supplementary Fig.	('cancer', 'Disease', (152, 158))	('CD4+CD26high T', 'Var', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CD8', 'Gene', (171, 174))	('CD8', 'Gene', '925', (171, 174))	('K562', 'CellLine', 'CVCL:0004', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
95755	29213079	Furthermore, adoptive transfer into mesothelioma-bearing mice showed that CD4+CD26high T cells clear tumors significantly better than traditionally used CD8+ T cells (Supplementary Fig.	('mice', 'Species', '10090', (57, 61))	('CD8', 'Gene', (153, 156))	('better', 'PosReg', (122, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('CD8', 'Gene', '925', (153, 156))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CD4+CD26high', 'Var', (74, 86))	('mesothelioma', 'Disease', (36, 48))	('tumors', 'Disease', (101, 107))
95756	29213079	This finding, in addition to our previously discussed NSG mouse models in which no inherent immune system exists, reveals that CD4+CD26high T cells are directly cytotoxic and capable of clearing tumors in the absence of other immune cells, including CD8+ T cells.	('CD8', 'Gene', (250, 253))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mouse', 'Species', '10090', (58, 63))	('CD8', 'Gene', '925', (250, 253))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('clearing tumors', 'Disease', (186, 201))	('clearing tumors', 'Disease', 'MESH:D054973', (186, 201))	('CD4+CD26high', 'Var', (127, 139))
95761	29213079	Collectively, these findings reveal that CD26int and CD26high T cells persist in the tumor to a greater extent than bulk CD4+ and CD26neg T cells.	('tumor', 'Disease', (85, 90))	('CD26neg', 'Chemical', '-', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CD26int', 'Var', (41, 48))	('CD26high', 'Var', (53, 61))
95762	29213079	Given the ample amount of donor T cells persisting in the tumors of mice treated with CD26int and CD26high T cells, we next sought to determine if they have an enhanced capacity to migrate.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('CD26high T cells', 'Var', (98, 114))	('donor', 'Species', '9606', (26, 31))	('enhanced', 'PosReg', (160, 168))	('CD26int', 'Var', (86, 93))
95767	29213079	Furthermore, we discovered that CD26high T cells migrated to M108 and PANC1 in vitro to a greater extent than bulk CD4+, CD26neg, or CD26int T cells (Fig.	('migrated', 'CPA', (49, 57))	('PANC1', 'Gene', '104066', (70, 75))	('M108', 'Var', (61, 65))	('CD26neg', 'Chemical', '-', (121, 128))	('PANC1', 'Gene', (70, 75))	('CD26high T', 'Var', (32, 42))
95771	29213079	We found that CD26neg T cells were more apoptotic than bulk CD4+, CD26int, and CD26high T cells (Supplementary Fig.	('CD26neg', 'Chemical', '-', (14, 21))	('CD26neg', 'Var', (14, 21))	('apoptotic', 'CPA', (40, 49))
95774	29213079	Compared to naive CD26int or regulatory CD26neg T cells, CD26high T cells had greater beta-catenin expression (Fig.	('CD26high', 'Var', (57, 65))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '1499', (86, 98))	('CD26neg', 'Chemical', '-', (40, 47))	('greater', 'PosReg', (78, 85))
95778	29213079	Collectively, our findings reveal that CD26high T cells have remarkable self-renewal potential and a profound ability to migrate, survive, and persist in the tumor long-term.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('self-renewal potential', 'CPA', (72, 94))	('CD26high', 'Var', (39, 47))
95780	29213079	First, CD26neg T cells exhibit poor persistence and antitumor activity due to increased Treg expression and lack of stemness properties.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('stemness', 'Disease', 'MESH:D020295', (116, 124))	('stemness', 'Disease', (116, 124))	('CD26neg', 'Var', (7, 14))	('tumor', 'Disease', (56, 61))	('persistence', 'CPA', (36, 47))	('increased', 'PosReg', (78, 87))	('Treg expression', 'CPA', (88, 103))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD26neg', 'Chemical', '-', (7, 14))
95781	29213079	CD26int T cells are mainly naive, persistent, and effectively slow/regress human tumors.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('slow/regress', 'NegReg', (62, 74))	('human', 'Species', '9606', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('CD26int', 'Var', (0, 7))
95782	29213079	Finally, CD26high T cells possess qualities of stemness and migration factors that support their persistence and antitumor activity in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('solid tumors', 'Disease', 'MESH:D009369', (135, 147))	('stemness', 'Disease', 'MESH:D020295', (47, 55))	('stemness', 'Disease', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (117, 122))	('persistence', 'CPA', (97, 108))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (141, 146))	('solid tumors', 'Disease', (135, 147))	('CD26high', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
95786	29213079	Moreover, exhausted and terminally differentiated T cells are epigenetically stable, regardless of PD-1 blockade therapy, and thus fail to become memory T cells.	('PD-1', 'Gene', '5133', (99, 103))	('memory', 'biological_process', 'GO:0007613', ('146', '152'))	('PD-1', 'Gene', (99, 103))	('epigenetically', 'Var', (62, 76))
95788	29213079	Several markers, such as CD45RA, CCR7, CD62L, and CD95, identify naive or stem memory T cells.	('CD95', 'Gene', (50, 54))	('naive', 'CPA', (65, 70))	('CD45', 'Gene', '5788', (25, 29))	('CD62L', 'Var', (39, 44))	('CCR', 'molecular_function', 'GO:0043880', ('33', '36'))	('CD95', 'Gene', '355', (50, 54))	('CCR7', 'Gene', '1236', (33, 37))	('CD45', 'Gene', (25, 29))	('CCR7', 'Gene', (33, 37))	('memory', 'biological_process', 'GO:0007613', ('79', '85'))
95790	29213079	We discovered that CD26int T cells were naive, CD26neg cultures contained Treg, Th1 and Th2 cells, and CD26high T cells displayed a Th1/Th17 profile and were highly multi-functional/cytotoxic.	('Th1', 'Gene', '51497', (132, 135))	('Th1', 'Gene', (136, 139))	('Th1', 'Gene', '51497', (80, 83))	('Th1', 'Gene', (132, 135))	('CD26high', 'Var', (103, 111))	('Th1', 'Gene', (80, 83))	('Th1', 'Gene', '51497', (136, 139))	('CD26neg', 'Chemical', '-', (47, 54))
95792	29213079	Surprisingly, CD26high T cells controlled pancreatic tumors and regressed mesothelioma slightly, but not significantly, better than CD26int.	('pancreatic tumors', 'Disease', (42, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (42, 59))	('CD26high', 'Var', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('controlled', 'PosReg', (31, 41))	('mesothelioma', 'Disease', (74, 86))	('pancreatic tumors', 'Disease', 'MESH:D010190', (42, 59))
95793	29213079	In addition to regressing tumors in multiple cancer models, CD26high T cells also exhibited long-term persistence.	('CD26high', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cancer', 'Disease', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
95794	29213079	Similar to Th17 cells that persist in vivo via the Wnt/beta-catenin signaling pathway despite their effector memory profile, we discovered that CD26high T cells display markers of stemness, such as increased beta-catenin, BCL2 and Lef1.	('Lef1', 'Gene', (231, 235))	('beta-catenin', 'Gene', (55, 67))	('signaling pathway', 'biological_process', 'GO:0007165', ('68', '85'))	('BCL2', 'Gene', (222, 226))	('memory', 'biological_process', 'GO:0007613', ('109', '115'))	('Th1', 'Gene', (11, 14))	('CD26high', 'Var', (144, 152))	('increased', 'PosReg', (198, 207))	('beta-catenin', 'Gene', '1499', (55, 67))	('beta-catenin', 'Gene', '1499', (208, 220))	('Th1', 'Gene', '51497', (11, 14))	('beta-catenin', 'Gene', (208, 220))	('Lef1', 'Gene', '51176', (231, 235))	('BCL2', 'Gene', '596', (222, 226))	('stemness', 'Disease', 'MESH:D020295', (180, 188))	('stemness', 'Disease', (180, 188))	('BCL2', 'molecular_function', 'GO:0015283', ('222', '226'))
95796	29213079	On the basis of our work herein, we posit that CD26+ T cells would persist and protect the host from malignancy, whereas CD26- T cells would be short-lived and unable to prevent tumor growth.	('tumor', 'Disease', (178, 183))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('CD26+ T', 'Var', (47, 54))	('malignancy', 'Disease', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
95797	29213079	Also, CD26high T cells naturally expressed the chemokine receptors CCR2 and CCR5, which likely helped CD26high T cells migrate to the tumor site; a notion supported by data showing that transduction of CCR2 into transferred T cells improved their trafficking to tumors.	('chemokine receptor', 'Gene', '7852', (47, 65))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('CCR2', 'Gene', (202, 206))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('improved', 'PosReg', (232, 240))	('CCR', 'molecular_function', 'GO:0043880', ('67', '70'))	('CCR2', 'Gene', '729230', (202, 206))	('CCR2', 'Gene', (67, 71))	('CCR', 'molecular_function', 'GO:0043880', ('76', '79'))	('tumors', 'Disease', (262, 268))	('CCR2', 'Gene', '729230', (67, 71))	('chemokine receptor', 'Gene', (47, 65))	('CCR5', 'Gene', '1234', (76, 80))	('tumor', 'Disease', (262, 267))	('migrate', 'CPA', (119, 126))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Disease', (134, 139))	('transduction', 'biological_process', 'GO:0009293', ('186', '198'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CCR', 'molecular_function', 'GO:0043880', ('202', '205'))	('transduction', 'Var', (186, 198))	('CCR5', 'Gene', (76, 80))	('helped', 'PosReg', (95, 101))
95798	29213079	Thus, CD26high T cells employ key mechanisms, including enhanced stemness and migration, to persist and lyse tumor.	('CD26high', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('stemness', 'Disease', (65, 73))	('stemness', 'Disease', 'MESH:D020295', (65, 73))	('migration', 'CPA', (78, 87))	('enhanced', 'PosReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
95803	29213079	Finally, we discovered that mice bearing melanoma, mesothelioma or pancreatic cancer experienced a better treatment outcome when a heightened percentage of CD26+ donor T cells infiltrated the tumor.	('tumor', 'Disease', (192, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('donor', 'Species', '9606', (162, 167))	('mice', 'Species', '10090', (28, 32))	('mesothelioma', 'Disease', (51, 63))	('melanoma', 'Disease', (41, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('CD26+', 'Var', (156, 161))
95805	29213079	First, our finding that human MesoCAR+ T cells and endogenous mouse TIL expressing CD26 correlate with reduced tumor size suggests that CD26 augments antitumor immunity in an MHC-independent manner.	('augments', 'PosReg', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CD26', 'Var', (136, 140))	('human', 'Species', '9606', (24, 29))	('mouse', 'Species', '10090', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('reduced', 'NegReg', (103, 110))	('MesoCAR+', 'Chemical', '-', (30, 38))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD26', 'Gene', (83, 87))	('tumor', 'Disease', (154, 159))
95807	29213079	It is also worth noting that human regulatory T cells express little-to-no CD26, a fact that could implicate that the enhanced regression seen in mice expressing a greater percentage of CD26+ TIL is simply due to a greater Teff to Treg ratio at the tumor site.	('regression', 'CPA', (127, 137))	('human', 'Species', '9606', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('Teff to', 'MPA', (223, 230))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('enhanced', 'PosReg', (118, 126))	('CD26+ TIL', 'Var', (186, 195))	('tumor', 'Disease', (249, 254))	('mice', 'Species', '10090', (146, 150))	('greater', 'PosReg', (215, 222))
95810	29213079	In addition, recent reports have shown that mutation-specific CD4+ T cells in a patient with metastatic cholangiocarcinoma have clinical benefit.	('cholangiocarcinoma', 'Disease', (104, 122))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('mutation-specific CD4+ T cells', 'Var', (44, 74))	('benefit', 'PosReg', (137, 144))	('patient', 'Species', '9606', (80, 87))
95811	29213079	Intriguingly, the phenotype described by Tran et al., specifically the functional nature and increased OX40 and 4-1BB on erbb2 mutation-specific T helper cells, is similar to our CD26high T cells described herein.	('erbb2', 'Gene', (121, 126))	('increased', 'PosReg', (93, 102))	('OX40 and 4-1BB', 'Gene', '7293;3604', (103, 117))	('erbb2', 'Gene', '2064', (121, 126))	('mutation-specific', 'Var', (127, 144))
95812	29213079	Therefore, our data might also imply that a small cohort of CD26-expressing CD4+ T cells recognize mutated tumor antigens displayed on MHC II-positive tumors, which has been shown to mediate antitumor efficacy in patients treated with cell therapy and checkpoint modulators.	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('MHC', 'Gene', (135, 138))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutated', 'Var', (99, 106))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
95814	29213079	Collectively, our findings indicate that CD4+CD26+ T cells could be used for TCR-based immunotherapy, as they may potentially mediate enhanced responses to mutated tumor antigen in an MHC II-restricted fashion.	('tumor', 'Disease', (164, 169))	('CD4+CD26+', 'Var', (41, 50))	('enhanced', 'PosReg', (134, 142))	('TCR', 'cellular_component', 'GO:0042101', ('77', '80'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor antigen', 'molecular_function', 'GO:0008222', ('164', '177'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('TCR', 'biological_process', 'GO:0006283', ('77', '80'))
95820	29213079	On the contrary, inhibiting CD26 has also been shown to accelerate tumor metastasis via NRF2 activation.	('activation', 'PosReg', (93, 103))	('inhibiting', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('accelerate', 'PosReg', (56, 66))	('NRF2', 'Gene', '4780', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NRF2', 'Gene', (88, 92))	('CD26', 'Protein', (28, 32))	('tumor', 'Disease', (67, 72))
95824	29213079	Data herein suggest that although CD26int and CD26high T cells are promising for cancer immunotherapy, CD26neg T cells are deleterious to this field but may have an important role in suppressing autoimmune diseases, such as GVHD or rheumatoid arthritis.	('autoimmune diseases', 'Disease', (195, 214))	('CD26neg', 'Chemical', '-', (103, 110))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (232, 252))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (195, 214))	('cancer', 'Disease', (81, 87))	('arthritis', 'Phenotype', 'HP:0001369', (243, 252))	('CD26neg', 'Var', (103, 110))	('GVHD', 'Disease', 'MESH:D006086', (224, 228))	('rheumatoid arthritis', 'Disease', (232, 252))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (232, 252))	('suppressing', 'NegReg', (183, 194))	('GVHD', 'Disease', (224, 228))	('autoimmune diseases', 'Disease', 'MESH:D001327', (195, 214))
95826	29213079	Second, our findings reveal that CD26high T cells are not terminally differentiated, but rather have durable memory, enabling them to persist and regress multiple solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (163, 175))	('regress', 'CPA', (146, 153))	('memory', 'biological_process', 'GO:0007613', ('109', '115'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('solid tumors', 'Disease', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('persist', 'CPA', (134, 141))	('CD26high', 'Var', (33, 41))
95828	29213079	Finally, our finding that mice with better responses had more CD26+ T cells in both mesothelioma and pancreatic tumors reveals a possible significance of this marker in cancer immunotherapy.	('mesothelioma and pancreatic tumors', 'Disease', 'MESH:D008654', (84, 118))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD26+ T cells', 'Var', (62, 75))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (101, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('mice', 'Species', '10090', (26, 30))
95848	29213079	CD4+ T cells were isolated from four individual healthy individuals and sorted into the following groups: bulk CD4+, CD26neg, CD26int, CD26high, Th1 (CXCR3+CCR6-), Th2 (CCR4+CCR6-), Th17 (CCR4+CCR6+), and Th1/Th17 (CCR6+CXCR3+).	('CCR4', 'Gene', '1233', (169, 173))	('Th1', 'Gene', (182, 185))	('CCR4', 'Gene', (188, 192))	('CCR6', 'Gene', '1235', (193, 197))	('CD26neg', 'Chemical', '-', (117, 124))	('CXCR3', 'Gene', (220, 225))	('Th1', 'Gene', '51497', (182, 185))	('Th1', 'Gene', (205, 208))	('CCR6', 'Gene', (174, 178))	('CCR', 'molecular_function', 'GO:0043880', ('188', '191'))	('CCR', 'molecular_function', 'GO:0043880', ('193', '196'))	('CCR', 'molecular_function', 'GO:0043880', ('156', '159'))	('CXCR3', 'Gene', '2833', (220, 225))	('Th1', 'Gene', '51497', (205, 208))	('CCR6', 'Gene', (156, 160))	('CCR4', 'Gene', '1233', (188, 192))	('CCR6', 'Gene', '1235', (215, 219))	('CCR', 'molecular_function', 'GO:0043880', ('215', '218'))	('CCR6', 'Gene', (193, 197))	('Th1', 'Gene', (209, 212))	('Th1', 'Gene', (145, 148))	('Th1', 'Gene', '51497', (209, 212))	('CCR6', 'Gene', '1235', (174, 178))	('CD26int', 'Var', (126, 133))	('Th1', 'Gene', '51497', (145, 148))	('CD26high', 'Var', (135, 143))	('CCR4', 'Gene', (169, 173))	('CCR6', 'Gene', '1235', (156, 160))	('CCR', 'molecular_function', 'GO:0043880', ('169', '172'))	('CXCR3', 'Gene', (150, 155))	('CCR6', 'Gene', (215, 219))	('CCR', 'molecular_function', 'GO:0043880', ('174', '177'))	('CD26neg', 'Var', (117, 124))	('CXCR3', 'Gene', '2833', (150, 155))
95857	29213079	B16F10: B6 mice were subcutaneously injected with 4e5 B16F10 melanoma 10 days prior to adoptive cell transfer of 5e4 CD4+Vbeta14+ CD26neg or CD26high T cells.	('5e4 CD4+Vbeta14+ CD26neg', 'Var', (113, 137))	('mice', 'Species', '10090', (11, 15))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('B16F10', 'Gene', (54, 60))	('CD26neg', 'Chemical', '-', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('CD26high T cells', 'Var', (141, 157))
95860	29213079	5: 1e6 MesoCAR+ CD4+, CD26neg, CD26int, or CD26high T cells were infused into NSG mice bearing M108 tumors that were established for 60 days (N = 7-9 mice per group).	('mice', 'Species', '10090', (82, 86))	('CD26high', 'Var', (43, 51))	('mice', 'Species', '10090', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('M108 tumors', 'Disease', (95, 106))	('CD26neg', 'Chemical', '-', (22, 29))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('M108 tumors', 'Disease', 'MESH:D009369', (95, 106))	('MesoCAR+', 'Chemical', '-', (7, 15))	('CD26neg', 'Var', (22, 29))
95862	29213079	PANC1: NSG mice were subcutaneously injected with 5e6 PANC1 cells (50% PANC1, 50% Matrigel) 7 days prior to intravenous ACT of 1.75e6 CD4+, CD26neg, CD26int, or CD26high T cells (N = 6-9 mice per group).	('PANC1', 'Gene', '104066', (0, 5))	('PANC1', 'Gene', (0, 5))	('CD4+', 'Var', (134, 138))	('CD26neg', 'Var', (140, 147))	('CD26int', 'Var', (149, 156))	('CD26high', 'Var', (161, 169))	('mice', 'Species', '10090', (11, 15))	('mice', 'Species', '10090', (187, 191))	('PANC1', 'Gene', '104066', (71, 76))	('PANC1', 'Gene', '104066', (54, 59))	('CD26neg', 'Chemical', '-', (140, 147))	('PANC1', 'Gene', (54, 59))	('PANC1', 'Gene', (71, 76))
95892	27835874	In addition, the deletion of CDKN2A and BAP1 are the most common genetic alterations in MPM and for this reason they have been suggested as diagnostic and prognostic markers.	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('MPM', 'Disease', (88, 91))	('BAP1', 'Gene', '8314', (40, 44))	('deletion', 'Var', (17, 25))	('BAP1', 'Gene', (40, 44))
95929	27835874	Likewise, the deregulated genes might be evaluated as immunohistochemical markers, thus potentially allowing the development of immunohistochemical panels for mesothelioma.	('deregulated', 'Var', (14, 25))	('mesothelioma', 'Disease', (159, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (159, 171))
95983	27605433	Human MM cells (JO38, JU77, OLD1612, LO68) displayed a fibroblast-like mesenchymal phenotype in culture (Fig.	('OLD1612', 'Var', (28, 35))	('fibroblast-like mesenchymal phenotype in', 'CPA', (55, 95))	('Human', 'Species', '9606', (0, 5))
95989	27605433	Nearly a quarter of the total number of exosomal proteins identified from JO38, JU77, OLD1612, and LO68 cells (506/2,178 (23%)) have not been previously reported in the EV database, Vesiclepedia (Supplementary Dataset).	('Vesiclepedia', 'Disease', 'None', (182, 194))	('Vesiclepedia', 'Disease', (182, 194))	('exosomal proteins', 'Protein', (40, 57))	('JO38', 'Var', (74, 78))
96006	27605433	3d) associated with "pathways in cancer" (ko05200), "cytokine receptor interaction" (ko04060), "regulation of actin cytoskeleton" (ko04810), "focal adhesion" (ko04510), "metabolic pathways" (ko01100), "antigen processing and presentation" (ko04612), "extracellular matrix-receptor interaction" (ko04512), "PI3K-Akt signalling pathway" (ko04151) and "Jak-STAT signalling pathway" (ko04630).	('Akt', 'Gene', '207', (311, 314))	('ko04512', 'Var', (295, 302))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('associated', 'Reg', (4, 14))	('extracellular matrix-receptor', 'Pathway', (251, 280))	('ko04060', 'Var', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Akt', 'Gene', (311, 314))	('ko04630', 'Var', (380, 387))	('ko01100', 'Var', (191, 198))	('ko04612', 'Var', (240, 247))	('Jak-STAT signalling pathway', 'Pathway', (350, 377))	('ko04151', 'Var', (336, 343))
96008	27605433	These protein expression cluster analyses align the cell models with the amount of exosomes released from malignant mesothelioma cells, with JU77 and JO38 (low yield producing) and LO68 and OLD1612 (high yield producing) (Figs 2b and 3a).	('JU77', 'Var', (141, 145))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('LO68', 'Var', (181, 185))	('OLD1612', 'Var', (190, 197))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (106, 128))	('JO38', 'Var', (150, 154))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (106, 128))	('malignant mesothelioma', 'Disease', (106, 128))
96013	27605433	We report 5 known tubulin isotypes in mEXOS, including proteins TUBB4A (470 SpC), Q8IWP6 (class IVb beta tubulin) (544 SpC), and B3KPS3 (455 SpC).	('TUBB4A', 'Gene', (64, 70))	('TUBB4A', 'Gene', '10382', (64, 70))	('SpC', 'molecular_function', 'GO:0009004', ('76', '79'))	('Q8IWP6', 'Var', (82, 88))	('SpC', 'molecular_function', 'GO:0009004', ('119', '122'))	('SpC', 'molecular_function', 'GO:0009004', ('141', '144'))
96026	27605433	High levels of G6PD are observed in some cancers and its expression can transform fibroblasts to induce tumour formation in vivo.	('G6PD', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('expression', 'Var', (57, 67))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('induce', 'PosReg', (97, 103))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('transform', 'Reg', (72, 81))	('G6PD', 'Gene', '2539', (15, 19))	('tumour', 'Disease', (104, 110))	('cancers', 'Disease', (41, 48))
96038	27605433	Importantly, high COX-2 expression is a marker of poor prognosis in MM.	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('COX-2', 'Gene', (18, 23))	('COX-2', 'Gene', '5743', (18, 23))
96046	27605433	The RUVBL1/2 proteins are involved in chromatin remodelling, DNA interaction and repair, and promote interaction of the modified histones with other proteins which positively regulate transcription.	('RUVBL1/2', 'Gene', '8607;10856', (4, 12))	('involved', 'Reg', (26, 34))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('38', '59'))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('RUVBL1/2', 'Gene', (4, 12))	('chromatin', 'cellular_component', 'GO:0000785', ('38', '47'))	('histones', 'Protein', (129, 137))	('interaction', 'Interaction', (101, 112))	('modified', 'Var', (120, 128))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('promote', 'PosReg', (93, 100))	('proteins', 'Protein', (13, 21))
96100	27605433	5a), and exosomes derived from JU77 and OLD1612 significantly increased neoHFF cell migration (Fig.	('increased', 'PosReg', (62, 71))	('OLD1612', 'Var', (40, 47))	('HFF', 'CellLine', 'CVCL:3285', (75, 78))	('cell migration', 'biological_process', 'GO:0016477', ('79', '93'))	('neoHFF cell migration', 'CPA', (72, 93))	('JU77', 'Var', (31, 35))
96111	27605433	In fact, in this study we observed FN1 in mEXOS and for MM models JU77, LO68, and OLD1612 (Table S4).	('OLD1612', 'Var', (82, 89))	('LO68', 'Var', (72, 76))	('observed', 'Reg', (26, 34))	('FN1', 'Gene', '2335', (35, 38))	('FN1', 'Gene', (35, 38))	('JU77', 'Var', (66, 70))
96132	27605433	To our knowledge, this is the first demonstration of selective enrichment in exosomes of immunomodulatory components (T- and B-cell immune responses and MHC I/II-peptide antigen processing and presentation), signal transduction molecules (ALCAM, HSP90AA1, LGALS1, TNIK), and metastatic factors (MET, MIF, S100A10, S100A11, TNC, MMP2, ADAM10, ADAMTS1) in different human mesothelioma models.	('S100A11', 'Gene', (314, 321))	('mesothelioma', 'Disease', (370, 382))	('HSP90AA1', 'Gene', (246, 254))	('mesothelioma', 'Disease', 'MESH:D008654', (370, 382))	('HSP90AA1', 'Gene', '3320', (246, 254))	('ADAM10', 'Gene', (334, 340))	('MIF', 'Gene', '4282', (300, 303))	('ADAMTS1', 'Gene', '9510', (342, 349))	('MMP2', 'Gene', (328, 332))	('MMP2', 'molecular_function', 'GO:0004228', ('328', '332'))	('LGALS1', 'Gene', (256, 262))	('ALCAM', 'Gene', '214', (239, 244))	('LGALS1', 'Gene', '3956', (256, 262))	('TNC', 'Gene', (323, 326))	('ADAM10', 'Gene', '102', (334, 340))	('S100A11', 'Gene', '6282', (314, 321))	('MET', 'Var', (295, 298))	('MIF', 'Gene', (300, 303))	('S100A10', 'Gene', (305, 312))	('human', 'Species', '9606', (364, 369))	('TNC', 'Gene', '3371', (323, 326))	('MMP2', 'Gene', '4313', (328, 332))	('ADAMTS1', 'Gene', (342, 349))	('ALCAM', 'Gene', (239, 244))	('S100A10', 'Gene', '6281', (305, 312))	('signal transduction', 'biological_process', 'GO:0007165', ('208', '227'))	('peptide antigen processing and presentation', 'biological_process', 'GO:0048002', ('162', '205'))	('TNIK', 'Gene', '23043', (264, 268))	('TNIK', 'Gene', (264, 268))
96235	27587956	Ultra-low dose CT compares favorably with standard CT in detecting pleural plaques and diffuse pleural thickening, however interstitial pulmonary abnormalities are less frequent in ultra-low dose CT than standard CT.	('ultra-low', 'Var', (181, 190))	('pleural plaques', 'Disease', 'MESH:D010995', (67, 82))	('interstitial pulmonary abnormalities', 'Disease', (123, 159))	('pleural plaques', 'Disease', (67, 82))	('interstitial pulmonary abnormalities', 'Phenotype', 'HP:0006530', (123, 159))	('pleural thickening', 'Phenotype', 'HP:0031944', (95, 113))	('pleural', 'Disease', 'MESH:D010995', (67, 74))	('interstitial pulmonary abnormalities', 'Disease', 'MESH:D008171', (123, 159))	('pleural', 'Disease', (67, 74))	('pleural', 'Disease', 'MESH:D010995', (95, 102))	('pleural', 'Disease', (95, 102))
96516	24860692	Studies have shown that several immunohistochemical (IHC) markers are highly expressed in CC including Annexin A1 (94.1%), CK19 (89%), MOC31 (88.2%), CK7 (83.4%), CD133 (79%), claudin4 (69.2%), high mobility group A1 (HMGA1) (31.5%) and S100P, while others has no or very low expression in CC such as glypican 3 (GPC3) (7%) and biglycan (7%).	('HMGA1', 'Gene', (218, 223))	('GPC3', 'Gene', '2719', (313, 317))	('high mobility group A1', 'Gene', (194, 216))	('S100P', 'Var', (237, 242))	('claudin4', 'Gene', '1364', (176, 184))	('glypican 3', 'Gene', (301, 311))	('CK7', 'Gene', (150, 153))	('CC', 'Phenotype', 'HP:0030153', (290, 292))	('CK19', 'Gene', (123, 127))	('CK19', 'Gene', '3880', (123, 127))	('CC', 'Phenotype', 'HP:0030153', (90, 92))	('Annexin A1', 'Gene', '301', (103, 113))	('MOC31', 'Var', (135, 140))	('CK7', 'Gene', '3855', (150, 153))	('Annexin A1', 'Gene', (103, 113))	('HMGA1', 'Gene', '3159', (218, 223))	('high mobility group A1', 'Gene', '3159', (194, 216))	('CD133', 'Gene', (163, 168))	('glypican', 'molecular_function', 'GO:0015017', ('301', '309'))	('GPC3', 'Gene', (313, 317))	('claudin4', 'Gene', (176, 184))	('CD133', 'Gene', '8842', (163, 168))	('S100P', 'SUBSTITUTION', 'None', (237, 242))	('glypican 3', 'Gene', '2719', (301, 311))
96548	24860692	In contrast, CK19 positivity does not discriminate CC and non-cancerous NBD, and should be used only for confirmation of a bile duct (biliary) lineage.	('CC', 'Phenotype', 'HP:0030153', (51, 53))	('non-cancerous NBD', 'Disease', (58, 75))	('non-cancerous NBD', 'Disease', 'MESH:D009369', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('positivity', 'Var', (18, 28))	('CK19', 'Gene', (13, 17))	('CK19', 'Gene', '3880', (13, 17))
96660	32382335	3A-D; Table III) and a lower Ki-67LI had significantly positive effects on OS in patients with MPeM (Fig.	('Ki-67', 'Chemical', '-', (29, 34))	('patients', 'Species', '9606', (81, 89))	('Ki-67LI', 'Var', (29, 36))	('MPeM', 'Chemical', '-', (95, 99))	('positive effects', 'PosReg', (55, 71))	('lower', 'NegReg', (23, 28))
96662	32382335	4C; Table III), while high CD146 expression was associated with poor MPeM prognosis (P=0.041; Fig.	('MPeM', 'Chemical', '-', (69, 73))	('CD146', 'Gene', '4162', (27, 32))	('CD146', 'Gene', (27, 32))	('high', 'Var', (22, 26))	('MPeM', 'Disease', (69, 73))	('expression', 'MPA', (33, 43))
96692	32382335	Ki-67 is an indicator of tumour replication.	('Ki-67', 'Var', (0, 5))	('Ki-67', 'Chemical', '-', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumour', 'Disease', (25, 31))
96735	29320538	These two consortia have been instrumental in increasing our knowledge of cancer genomics and have identified significantly mutated genes, candidate actionable mutations and mutational processes that occur during tumour development.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (74, 80))	('tumour', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
96754	29320538	Variants were annotated with Ensembl v75 gene feature information and transcript or protein consequences using SnpEff (version 4.2).	('v75', 'Gene', (37, 40))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('Variants', 'Var', (0, 8))	('v75', 'Gene', '7448', (37, 40))
96755	29320538	Variants were considered "called" and used in subsequent analysis if they passed the following filters: a minimum read depth of 8 reads in the normal control data and 12 in the tumour data; at least 4 reads containing the variant where the variant was identified on both strands and not within the first or last 5 bases.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('variant', 'Var', (222, 229))	('tumour', 'Disease', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))
96757	29320538	In this manuscript the term 'somatic variants' refers to mutations acquired by the tumour, or tumour specific variants which are not present in the germline (matched normal sample).	('tumour', 'Disease', (94, 100))	('tumour', 'Disease', (83, 89))	('variants', 'Var', (110, 118))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
96768	29320538	An average of 232,987 germline indels were called in each patient (representing 233,527; 232,260 and 233,174 germline indels in patients: 9869, 11202 and 11398 respectively) (Fig 2b).	('patient', 'Species', '9606', (58, 65))	('11398', 'Var', (154, 159))	('9869', 'Var', (138, 142))	('patient', 'Species', '9606', (128, 135))	('patients', 'Species', '9606', (128, 136))
96775	29320538	To determine why a small proportion of the total germline calls across all patients were unique to each platform (0.36 and 1.85% SNV and 0.19 to 3.23% indels in the BGISEQ-500 and HiSeq X Ten respectively), an analysis of the read depth at the position of each variant was performed.	('HiSeq', 'Chemical', '-', (180, 185))	('patients', 'Species', '9606', (75, 83))	('indels', 'Var', (151, 157))	('SNV', 'Var', (129, 132))
96780	29320538	However, these variants are a small fraction of the total germline calls (3.4 and 9.76% of SNVs and 2.8 and 15% of indels for BGISEQ-500 and HiSeq XTen, respectively).	('HiSeq', 'Chemical', '-', (141, 146))	('indels', 'Var', (115, 121))	('BGISEQ-500', 'Gene', (126, 136))	('HiSeq', 'Gene', (141, 146))
96786	29320538	An average of 424 somatic indels were called using the HiSeq X Ten and BGISEQ-500 platforms each patient (representing 434; 417 and 421 somatic indels in patients: 9869, 11202 and 11398 respectively) (Fig 4b).	('patient', 'Species', '9606', (154, 161))	('9869', 'Var', (164, 168))	('HiSeq', 'Chemical', '-', (55, 60))	('patients', 'Species', '9606', (154, 162))	('patient', 'Species', '9606', (97, 104))	('11202', 'Var', (170, 175))	('11398', 'Var', (180, 185))
96797	29320538	These differences will introduce a degree of bias that could particularly affect somatic variant calling where the tumour specific signal may be reduced as compared with the germline signal.	('reduced', 'NegReg', (145, 152))	('differences', 'Var', (6, 17))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))
96815	28561728	Additional genetic modifications have yielded third-generation CARs composed of two distinct costimulatory domains, such as CD28/4-1BB/CD3zeta or CD28/OX-40/CD3zeta, all with varying degrees of efficacy.	('CD3zeta', 'Gene', (157, 164))	('4-1BB', 'Gene', '3604', (129, 134))	('CD3zeta', 'Gene', '919', (135, 142))	('modifications', 'Var', (19, 32))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('al', 'Chemical', 'MESH:D000535', (166, 168))	('CD3zeta', 'Gene', '919', (157, 164))	('CD3zeta', 'Gene', (135, 142))	('OX-40', 'Gene', '7293', (151, 156))	('OX-40', 'Gene', (151, 156))	('4-1BB', 'Gene', (129, 134))
96820	28561728	Despite this, acceptable antigens, such as EGFR variant III (EGFRIII), GD2, mucin 1 (MUC-1), mucin 16 (MUC-16), carcinoem-bryonicantigen, mesothelin, CA-IX, and prostate-specific membrane antigen (PSMA) have been characterized and are in various stages of clinical development (Table 1).	('PSMA', 'Gene', (197, 201))	('CA-IX', 'Gene', (150, 155))	('EGFR', 'Gene', (43, 47))	('PSMA', 'molecular_function', 'GO:0043275', ('197', '201'))	('mucin 1', 'Gene', (76, 83))	('al', 'Chemical', 'MESH:D000535', (262, 264))	('MUC-16', 'Gene', (103, 109))	('MUC-1', 'Gene', (103, 108))	('MUC-16', 'Gene', '94025', (103, 109))	('EGFR', 'Gene', '1956', (61, 65))	('CA-IX', 'Gene', '768', (150, 155))	('variant', 'Var', (48, 55))	('mucin 16', 'Gene', '94025', (93, 101))	('MUC-1', 'Gene', '4582', (103, 108))	('mesothelin', 'Gene', (138, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('mucin 1', 'Gene', '4582', (93, 100))	('EGFR', 'Gene', '1956', (43, 47))	('MUC-1', 'Gene', (85, 90))	('PSMA', 'Gene', '2346', (197, 201))	('mucin 1', 'Gene', '4582', (76, 83))	('mesothelin', 'Gene', '10232', (138, 148))	('MUC-1', 'Gene', '4582', (85, 90))	('membrane', 'cellular_component', 'GO:0016020', ('179', '187'))	('prostate-specific membrane antigen', 'molecular_function', 'GO:0043275', ('161', '195'))	('mucin 16', 'Gene', (93, 101))	('EGFR', 'Gene', (61, 65))
96837	28561728	EGFRIII is a tumor-specific, mutated form of wild-type EGFR and is commonly expressed in glioblastoma.	('tumor', 'Disease', (13, 18))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Disease', (89, 101))	('EGFR', 'Gene', (55, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('mutated', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('EGFR', 'Gene', '1956', (0, 4))
96839	28561728	Multiple preclinical studies demonstrate that EGFRIII-specific CAR T cells recognize and eliminate antigen-positive glioblastoma tumors in vitro and in vivo without cross-reacting with wild-type receptors present on normal tissues.	('antigen-positive', 'Var', (99, 115))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('al', 'Chemical', 'MESH:D000535', (220, 222))	('EGFR', 'Gene', '1956', (46, 50))	('CAR', 'cellular_component', 'GO:0005826', ('63', '66'))	('al', 'Chemical', 'MESH:D000535', (18, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('EGFR', 'Gene', (46, 50))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (116, 135))	('eliminate', 'NegReg', (89, 98))	('glioblastoma tumors', 'Disease', (116, 135))
96843	28561728	In a preclinical study, GD2-specific CAR T cells exhibited potent cytotoxicity and cytokine production in response to antigen stimulation.	('GD2-specific', 'Var', (24, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('CAR', 'cellular_component', 'GO:0005826', ('37', '40'))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('cytokine production', 'biological_process', 'GO:0001816', ('83', '102'))	('cytokine production', 'MPA', (83, 102))	('cytotoxicity', 'Disease', (66, 78))
96856	28561728	Therefore, genetically modifying CAR T cells to secrete TNF-alpha is one potential approach to overcome this limitation and improve CAR T-cell efficacy.	('TNF-alpha', 'Gene', '7124', (56, 65))	('CAR T-cell efficacy', 'CPA', (132, 151))	('TNF-alpha', 'Gene', (56, 65))	('al', 'Chemical', 'MESH:D000535', (80, 82))	('CAR', 'cellular_component', 'GO:0005826', ('33', '36'))	('CAR', 'cellular_component', 'GO:0005826', ('132', '135'))	('al', 'Chemical', 'MESH:D000535', (18, 20))	('improve', 'PosReg', (124, 131))	('genetically', 'Var', (11, 22))	('al', 'Chemical', 'MESH:D000535', (60, 62))
96872	28561728	Therefore, strategies to optimize T-cell efficacy for head and neck squamous cell carcinoma could involve rational combinations of anti-PD-1/PD-L1 antibody with CAR T cells or armored CAR T cells modified to secrete blocking PD-1/PD-L1 scFvs.	('antibody', 'molecular_function', 'GO:0003823', ('147', '155'))	('antibody', 'cellular_component', 'GO:0019814', ('147', '155'))	('neck', 'cellular_component', 'GO:0044326', ('63', '67'))	('anti-PD-1/PD-L1', 'Var', (131, 146))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (54, 91))	('antibody', 'cellular_component', 'GO:0042571', ('147', '155'))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('neck squamous cell carcinoma', 'Disease', (63, 91))	('CAR', 'cellular_component', 'GO:0005826', ('184', '187'))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (63, 91))	('CAR', 'cellular_component', 'GO:0005826', ('161', '164'))	('combinations', 'Interaction', (115, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('antibody', 'cellular_component', 'GO:0019815', ('147', '155'))	('scFv', 'Gene', '652070', (236, 240))	('al', 'Chemical', 'MESH:D000535', (112, 114))	('scFv', 'Gene', (236, 240))
96874	28561728	Amplification of HER2 oncogene leads to uncontrolled cell proliferation and occurs in approximately 20% of breast cancers.	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('Amplification', 'Var', (0, 13))	('breast cancers', 'Phenotype', 'HP:0003002', (107, 121))	('leads to', 'Reg', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancers', 'Disease', 'MESH:D001943', (107, 121))	('breast cancers', 'Disease', (107, 121))	('occurs', 'Reg', (76, 82))	('uncontrolled', 'MPA', (40, 52))	('HER2 oncogene', 'Gene', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
96895	28561728	Despite equivalent cytotoxicity in vitro, third-generation CARs, which contained CD137 and CD28 costimulatory domains in tandem, showed marginally superior tumor rejection in a subcutaneous mesothelioma tumor model compared with second-generation CARs that had either costimulatory domain alone.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('al', 'Chemical', 'MESH:D000535', (13, 15))	('cytotoxicity', 'Disease', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (190, 208))	('al', 'Chemical', 'MESH:D000535', (289, 291))	('al', 'Chemical', 'MESH:D000535', (142, 144))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (19, 31))	('CD137', 'Gene', (81, 86))	('CD137', 'Gene', '3604', (81, 86))	('mesothelioma tumor', 'Disease', (190, 208))	('superior', 'PosReg', (147, 155))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (190, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('CD28', 'Var', (91, 95))
96915	28561728	Westwood et al designed a CD28zeta second-generation CAR directed against LeY+ tumors, one of which included ovarian cancer in an OVCAR-3 tumor model.	('CAR', 'cellular_component', 'GO:0005826', ('53', '56'))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (138, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (109, 123))	('CD28zeta', 'Var', (26, 34))	('ovarian cancer', 'Disease', (109, 123))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('al', 'Chemical', 'MESH:D000535', (12, 14))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
96917	28561728	Furthermore, treatment with LeY+-specific CARs inhibited growth of flank-implanted OVCAR-3 in immunodeficient NOD-SCID mice.	('growth', 'MPA', (57, 63))	('mice', 'Species', '10090', (119, 123))	('inhibited', 'NegReg', (47, 56))	('immunodeficient NOD-SCID', 'Disease', 'MESH:D020191', (94, 118))	('LeY+-specific CARs', 'Var', (28, 46))	('OVCAR-3', 'Gene', (83, 90))	('immunodeficient NOD-SCID', 'Disease', (94, 118))
96921	28561728	Chekmasova et al engineered a second-generation (CD28zeta MUC-16-CD-directed CAR that showed efficacy against OVCAR-3 and patient-derived tumor samples.	('tumor', 'Disease', (138, 143))	('CAR', 'cellular_component', 'GO:0005826', ('77', '80'))	('patient', 'Species', '9606', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('MUC-16', 'Gene', (58, 64))	('CD28zeta', 'Var', (49, 57))	('OVCAR-3', 'Disease', (110, 117))	('MUC-16', 'Gene', '94025', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
96938	28561728	Zhong et al generated a PSMA-directed third-generation CAR by engineering the 4-1BB receptor costimulatory molecule in tandem with CD28 and CD3zeta (named P28BBzeta) and tested its efficacy against a human prostate cancer cell line in an SCID/beige mouse model.	('SCID', 'Disease', (238, 242))	('human', 'Species', '9606', (200, 205))	('al', 'Chemical', 'MESH:D000535', (9, 11))	('CAR', 'cellular_component', 'GO:0005826', ('55', '58'))	('4-1BB', 'Gene', (78, 83))	('P28BBzeta', 'Chemical', '-', (155, 164))	('4-1BB', 'Gene', '3604', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('PSMA', 'Gene', '2346', (24, 28))	('P28', 'cellular_component', 'GO:0070744', ('155', '158'))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('PSMA', 'molecular_function', 'GO:0043275', ('24', '28'))	('CD3zeta', 'Gene', (140, 147))	('PSMA', 'Gene', (24, 28))	('mouse', 'Species', '10090', (249, 254))	('prostate cancer', 'Disease', (206, 221))	('CD3zeta', 'Gene', '919', (140, 147))	('tested', 'Reg', (170, 176))	('SCID', 'Disease', 'MESH:D053632', (238, 242))	('efficacy', 'MPA', (181, 189))	('engineering', 'Var', (62, 73))
96940	28561728	In tumor-bearing mice, treatment with P28BBzeta greatly enhanced survival compared with control mice.	('tumor', 'Disease', (3, 8))	('mice', 'Species', '10090', (17, 21))	('mice', 'Species', '10090', (96, 100))	('P28BBzeta', 'Chemical', '-', (38, 47))	('P28', 'cellular_component', 'GO:0070744', ('38', '41'))	('P28BBzeta', 'Var', (38, 47))	('survival', 'CPA', (65, 73))	('enhanced', 'PosReg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('al', 'Chemical', 'MESH:D000535', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
96972	28561728	Second-generation (CD28zeta NKG2D ligand-directed CAR T cells also have shown efficacy in preclinical in vitro models of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('NKG2D', 'Gene', (28, 33))	('al', 'Chemical', 'MESH:D000535', (62, 64))	('CD28zeta', 'Var', (19, 27))	('CAR', 'cellular_component', 'GO:0005826', ('50', '53'))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (121, 134))	('ligand', 'molecular_function', 'GO:0005488', ('34', '40'))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Disease', (127, 134))	('NKG2D', 'Gene', '22914', (28, 33))	('al', 'Chemical', 'MESH:D000535', (99, 101))
96976	28561728	IL-11Ralpha-specific CAR T cells were effective against both primary tumors and pulmonary metastasis in a nude mouse model of osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('pulmonary metastasis', 'CPA', (80, 100))	('osteosarcoma', 'Disease', (126, 138))	('mouse', 'Species', '10090', (111, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('CAR', 'cellular_component', 'GO:0005826', ('21', '24'))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('IL-11', 'molecular_function', 'GO:0005142', ('0', '5'))	('IL-11Ralpha-specific', 'Var', (0, 20))
97011	23702885	The IRR of mesothelioma was increased for subjects exposed to EBRT (1.28; 95 % CI 1.05, 1.55) compared to non-irradiated patients, and a population attributable fraction of 0.49 % (95 % CI 0.11, 0.81) was estimated.	('EBRT', 'Var', (62, 66))	('mesothelioma', 'Disease', (11, 23))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('EBRT', 'Chemical', '-', (62, 66))	('patients', 'Species', '9606', (121, 129))
97014	23702885	Our study provides evidence that EBRT for prostate cancer is a small but detectable risk factor for mesothelioma.	('EBRT', 'Chemical', '-', (33, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('mesothelioma', 'Disease', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('prostate cancer', 'Disease', (42, 57))	('EBRT', 'Var', (33, 37))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
97033	23702885	There have, however, been three studies linking EBRT for prostate cancer to increased risk of lung cancer.	('prostate cancer', 'Disease', (57, 72))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('EBRT', 'Var', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('EBRT', 'Chemical', '-', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
97035	23702885	The aim of this study was to investigate the possible association between EBRT for primary prostate cancer and the risk of malignant mesothelioma using data from the SEER registries.	('primary prostate cancer', 'Disease', 'MESH:D011471', (83, 106))	('EBRT', 'Chemical', '-', (74, 78))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (123, 145))	('SE', 'Disease', 'None', (166, 168))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (123, 145))	('primary prostate cancer', 'Disease', (83, 106))	('EBRT', 'Var', (74, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))	('malignant mesothelioma', 'Disease', (123, 145))
97081	23702885	An increased risk of mesothelioma was observed for patients exposed to EBRT compared to those who received no radiotherapy (adjusted IRR 1.28, 95 % CI 1.05, 1.55), while no increase in risk was seen from other radiotherapies (Table 2).	('mesothelioma', 'Disease', (21, 33))	('EBRT', 'Chemical', '-', (71, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('patients', 'Species', '9606', (51, 59))	('EBRT', 'Var', (71, 75))
97114	23702885	On the one hand, previous studies highlighted a possible association between EBRT for prostate cancer and risk of lung cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('EBRT', 'Chemical', '-', (77, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('prostate cancer', 'Disease', (86, 101))	('EBRT', 'Var', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
97165	23702885	Our study provides evidence that EBRT for prostate cancer is a risk factor for mesothelioma.	('EBRT', 'Chemical', '-', (33, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('mesothelioma', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('EBRT', 'Var', (33, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
97167	23702885	Our findings corroborate the hypothesis that EBRT could be a risk factor not only for cancer sites proximal to the primary treated tumor, but also for radiogenic cancers throughout the body.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('EBRT', 'Var', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancer', 'Disease', (162, 168))	('cancers', 'Disease', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('risk factor', 'Reg', (61, 72))	('tumor', 'Disease', (131, 136))	('EBRT', 'Chemical', '-', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('cancer', 'Disease', (86, 92))
97183	32605175	This modification inactivates EF-2, a critical and non-redundant enzyme required for protein translation, resulting in a typically fatal inhibition of new protein synthesis in the affected cell.	('modification', 'Var', (5, 17))	('EF-2', 'Gene', (30, 34))	('inactivates', 'NegReg', (18, 29))	('protein synthesis', 'biological_process', 'GO:0006412', ('155', '172'))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('new protein synthesis', 'MPA', (151, 172))	('inhibition', 'NegReg', (137, 147))	('EF-2', 'Gene', '1938', (30, 34))	('protein translation', 'biological_process', 'GO:0006412', ('85', '104'))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
97205	32605175	Recent evidence has shown that MSLN promotes peritoneal metastases via induction of angiogenesis in the local microenvironment, though the exact mechanism by which this occurs has yet to be elucidated.	('angiogenesis', 'CPA', (84, 96))	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('MSLN', 'Var', (31, 35))	('promotes', 'PosReg', (36, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))	('metastases', 'Disease', (56, 66))
97214	32605175	Strong anti-tumor activity of the MSLN-targeted iTox K1-LysPE38QQR was first reported in the pre-clinical models of MSLN-expressing human ovarian cancer and malignant mesothelioma in 2000.	('pre', 'molecular_function', 'GO:0003904', ('93', '96'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (157, 179))	('K1-LysPE38QQR', 'Var', (53, 66))	('human ovarian cancer', 'Disease', (132, 152))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('human ovarian cancer', 'Disease', 'MESH:D010051', (132, 152))	('PE', 'Chemical', '-', (59, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (157, 179))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('malignant mesothelioma', 'Disease', (157, 179))	('tumor', 'Disease', (12, 17))
97219	32605175	Tumor regressions were seen when SS1P was given as monotherapy to nude mice harboring human tumors expressing MSLN.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SS1', 'Gene', (33, 36))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('SS1', 'Gene', '3123', (33, 36))	('MSLN', 'Var', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('nude mice', 'Species', '10090', (66, 75))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
97224	32605175	For the T cell independent pathway, protein drug-derived epitopes can directly activate B-cells and produce ADA through the classical immune pathway.	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('activate', 'PosReg', (79, 87))	('B-cells', 'CPA', (88, 95))	('T cell independent pathway', 'Pathway', (8, 34))	('epitopes', 'Var', (57, 65))	('ADA', 'molecular_function', 'GO:0008774', ('108', '111'))	('classical immune pathway', 'Pathway', (124, 148))	('ADA', 'Chemical', '-', (108, 111))	('ADA', 'MPA', (108, 111))
97226	32605175	To identify B cell epitopes, regions within PE38 that were reactive with phage display libraries assembled from the Fv's of patients who had developed neutralizing ADAs to PE38 iTox were catalogued.	('ADAs', 'Gene', (164, 168))	('PE', 'Chemical', '-', (172, 174))	('PE38', 'Var', (172, 176))	('ADAs', 'Gene', '8540', (164, 168))	('patients', 'Species', '9606', (124, 132))	('PE', 'Chemical', '-', (44, 46))
97227	32605175	T cell epitopes were identified by incubating donor peripheral blood mononuclear cells with PE38 iTox, to simulate exposure to iTox, and then exposing the induced T cells from these samples to overlapping 15-mer peptides occurring in PE38.	('PE', 'Chemical', '-', (92, 94))	('PE38 iTox', 'Var', (92, 101))	('PE', 'Chemical', '-', (234, 236))	('PE38', 'Var', (234, 238))
97232	32605175	PE24 is 14 kD smaller than PE38, because it lacks the majority of domain II.	('lacks', 'NegReg', (44, 49))	('PE', 'Chemical', '-', (0, 2))	('PE', 'Chemical', '-', (27, 29))	('PE24', 'Var', (0, 4))	('PE24', 'Chemical', '-', (0, 4))
97238	32605175	It consists of a fully humanized Fab, to eliminate the possibility of ADA formation against the murine-derived SS1 Fv, attached to a modified version of PE24 (PE24LO10R).	('Fab', 'Gene', '2187', (33, 36))	('PE24', 'Chemical', '-', (153, 157))	('Fab', 'Gene', (33, 36))	('PE24', 'Chemical', '-', (159, 163))	('human', 'Species', '9606', (23, 28))	('SS1', 'Gene', '3123', (111, 114))	('ADA', 'molecular_function', 'GO:0008774', ('70', '73'))	('PE24LO10R', 'Var', (159, 168))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('ADA', 'Chemical', '-', (70, 73))	('murine', 'Species', '10090', (96, 102))	('SS1', 'Gene', (111, 114))
97239	32605175	PE24LO10R includes the large domain II deletion present in PE24 and point mutations at each of the six B-cell epitopes within the toxin catalytic domain (Figure 1).	('PE24', 'Chemical', '-', (0, 4))	('PE24', 'Chemical', '-', (59, 63))	('point mutations', 'Var', (68, 83))	('PE24LO10R', 'Var', (0, 9))
97240	32605175	These mutations include: R490A (B cell epitope), R427A (B and T cell shared epitope), R505A (B and T cell shared epitope), R467A (B cell epitope), D463A (B cell epitope), R538A (B cell epitope), and R456A (B cell epitope).	('R505A', 'Mutation', 'p.R505A', (86, 91))	('R467A', 'Mutation', 'p.R467A', (123, 128))	('R490A', 'Mutation', 'p.R490A', (25, 30))	('R505A', 'Var', (86, 91))	('R490A', 'Var', (25, 30))	('R427A', 'Mutation', 'p.R427A', (49, 54))	('R427A', 'Var', (49, 54))	('D463A', 'Var', (147, 152))	('R538A', 'Mutation', 'p.R538A', (171, 176))	('R456A', 'Mutation', 'p.R456A', (199, 204))	('D463A', 'Mutation', 'rs1287531915', (147, 152))	('R538A', 'Var', (171, 176))	('R467A', 'Var', (123, 128))	('R456A', 'Var', (199, 204))
97256	32605175	reported that PEGylated SS1P showed stronger cytotoxicity on cultured MSLN-overexpressing A431-K5 cells and exhibited higher anti-tumor activity in mouse A431-K5 xenografts.	('higher', 'PosReg', (118, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (45, 57))	('A431', 'CellLine', 'CVCL:0037', (154, 158))	('PEGylated', 'Var', (14, 23))	('mouse', 'Species', '10090', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('SS1', 'Gene', '3123', (24, 27))	('PE', 'Chemical', '-', (14, 16))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cytotoxicity', 'Disease', (45, 57))	('A431', 'CellLine', 'CVCL:0037', (90, 94))	('SS1', 'Gene', (24, 27))	('tumor', 'Disease', (130, 135))	('stronger', 'PosReg', (36, 44))
97257	32605175	reported a 10- to 30-fold increase in the half-life of MSLN-targeted iTox after site-specific PEGylation, and demonstrated the improved anti-tumor activity of these biomolecules in mouse tumor models.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('half-life', 'MPA', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (187, 192))	('PE', 'Chemical', '-', (94, 96))	('mouse', 'Species', '10090', (181, 186))	('MSLN-targeted', 'Var', (55, 68))	('iTox', 'Protein', (69, 73))	('increase', 'PosReg', (26, 34))	('improved', 'PosReg', (127, 135))
97260	32605175	This modification increased serum half-life in mice by more than 10-fold, and greatly enhanced anti-tumor efficacy against a mouse model of pancreas cancer when administered at equal mg dose as LMB-12, previously the most active iTox against this tumor cell type.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('modification', 'Var', (5, 17))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increased', 'PosReg', (18, 27))	('serum half-life', 'MPA', (28, 43))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (100, 105))	('mouse', 'Species', '10090', (125, 130))	('LMB-12', 'Chemical', '-', (194, 200))	('pancreas cancer', 'Disease', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('enhanced', 'PosReg', (86, 94))	('pancreas cancer', 'Disease', 'MESH:D010190', (140, 155))	('pancreas cancer', 'Phenotype', 'HP:0002894', (140, 155))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mice', 'Species', '10090', (47, 51))
97280	32605175	In the first cycle, patients were pre-treated with an induction regimen of P+C for 9 days, followed by SS1P given on the standard schedule.	('P+C', 'Var', (75, 78))	('SS1', 'Gene', '3123', (103, 106))	('pre', 'molecular_function', 'GO:0003904', ('34', '37'))	('patients', 'Species', '9606', (20, 28))	('SS1', 'Gene', (103, 106))
97281	32605175	The primary objectives were to determine if SS1P with P+C was safe and effective in delaying anti-SS1P neutralizing antibody formation.	('P+C', 'Var', (54, 57))	('SS1', 'Gene', (44, 47))	('SS1', 'Gene', (98, 101))	('antibody', 'cellular_component', 'GO:0019815', ('116', '124'))	('antibody', 'cellular_component', 'GO:0019814', ('116', '124'))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('antibody', 'molecular_function', 'GO:0003823', ('116', '124'))	('SS1', 'Gene', '3123', (44, 47))	('antibody', 'cellular_component', 'GO:0042571', ('116', '124'))	('SS1', 'Gene', '3123', (98, 101))	('delaying', 'NegReg', (84, 92))
97295	32605175	Following treatment with LMB-100 on NCT02798536, a total of nine patients received the anti-PD1 antibody pembrolizumab as their next therapy.	('pembrolizumab', 'Chemical', 'MESH:C582435', (105, 118))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('PD1', 'Gene', '5133', (92, 95))	('patients', 'Species', '9606', (65, 73))	('NCT02798536', 'Var', (36, 47))	('LMB', 'Chemical', '-', (25, 28))	('PD1', 'Gene', (92, 95))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))
97299	32605175	This anecdotal clinical data have formed the basis for a phase II trial evaluating whether LMB-100 (140 mcg/kg), for two cycles followed by pembrolizumab for up to two years, is effective in treating patients with epithelioid or biphasic (with at least >50% epithelioid component) mesothelioma (NCT03644550), or with non-squamous non-small cell lung cancer (NCT04027946).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (334, 356))	('non-squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (317, 356))	('NCT03644550', 'Var', (295, 306))	('non-squamous non-small cell lung cancer', 'Disease', (317, 356))	('patients', 'Species', '9606', (200, 208))	('NCT04027946', 'Var', (358, 369))	('mesothelioma', 'Disease', 'MESH:D008654', (281, 293))	('LMB', 'Chemical', '-', (91, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (330, 356))	('epithelioid', 'Disease', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('LMB-100', 'Gene', (91, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (345, 356))	('pembrolizumab', 'Chemical', 'MESH:C582435', (140, 153))	('mesothelioma', 'Disease', (281, 293))	('biphasic', 'Disease', (229, 237))
97303	32605175	The elevated expression of MSLN alone and co-expression with MSLN binding partner MUC-16/CA-125, has been associated with decreased progression-free and overall survival.	('CA-125', 'Gene', (89, 95))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('expression', 'MPA', (13, 23))	('co-expression', 'Var', (42, 55))	('MUC-16', 'Gene', (82, 88))	('overall survival', 'CPA', (153, 169))	('MUC-16', 'Gene', '94025', (82, 88))	('MSLN', 'Var', (27, 31))	('elevated', 'PosReg', (4, 12))	('progression-free', 'CPA', (132, 148))	('CA-125', 'Gene', '94025', (89, 95))	('decreased', 'NegReg', (122, 131))
97314	32605175	As mentioned above, the lymphodepleting regimen of P+C followed by SS1P delayed ADA formation and extended the number of cycles, where SS1P reached bioactive circulating blood levels in patients.	('SS1', 'Gene', (67, 70))	('extended', 'PosReg', (98, 106))	('delayed', 'NegReg', (72, 79))	('ADA formation', 'CPA', (80, 93))	('SS1', 'Gene', '3123', (67, 70))	('P+C', 'Var', (51, 54))	('SS1', 'Gene', '3123', (135, 138))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('SS1', 'Gene', (135, 138))	('ADA', 'molecular_function', 'GO:0008774', ('80', '83'))	('patients', 'Species', '9606', (186, 194))	('ADA', 'Chemical', '-', (80, 83))
97316	32605175	Specifically, the chemotherapy caused severe lymphocyte depletion that lasted three or more months post-therapy and precluded patient treatment with other types of immunotherapy.	('patient', 'Species', '9606', (126, 133))	('lymphocyte depletion', 'MPA', (45, 65))	('chemotherapy', 'Var', (18, 30))
97341	32605175	In addition, it has been observed that many cancer cell lines have differing sensitivities to PE38 versus PE24-based iTox, and it may be that mesothelial cells behave similarly.	('sensitivities', 'MPA', (77, 90))	('PE', 'Chemical', '-', (106, 108))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('PE', 'Chemical', '-', (94, 96))	('PE38', 'Var', (94, 98))	('PE24', 'Chemical', '-', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
97355	32605175	This study further demonstrated that co-administration of l-lysine for renal protection can reduce renal damage in mice.	('reduce', 'NegReg', (92, 98))	('l-lysine', 'Var', (58, 66))	('renal damage', 'Disease', 'MESH:D007674', (99, 111))	('renal damage', 'Disease', (99, 111))	('l-lysine', 'Chemical', 'MESH:D008239', (58, 66))	('mice', 'Species', '10090', (115, 119))
97374	32605175	In fact, pre-clinical data demonstrated that tumor cells expressing mutant MSLN constructs with impaired shedding are more sensitive to iTox.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('pre', 'molecular_function', 'GO:0003904', ('9', '12'))	('tumor', 'Disease', (45, 50))	('MSLN', 'Gene', (75, 79))	('shedding', 'MPA', (105, 113))	('sensitive to iTox', 'MPA', (123, 140))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('mutant', 'Var', (68, 74))
97523	31483564	In conclusion, CRS and HIPEC lead to long-term survival in patients with peritoneal mesothelioma of both borderline and DMPM subtypes with acceptable morbidity and postoperative mortality.	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (73, 96))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (73, 96))	('CRS', 'Var', (15, 18))	('patients', 'Species', '9606', (59, 67))	('peritoneal mesothelioma', 'Disease', (73, 96))
97535	30993587	Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study.	('CD30', 'Gene', '943', (66, 70))	('solid tumors', 'Disease', (112, 124))	('CD30', 'Gene', (66, 70))	('expression', 'Var', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patients', 'Species', '9606', (98, 106))	('solid tumors', 'Disease', 'MESH:D009369', (112, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (20, 28))	('solid tumors', 'Disease', (48, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('solid tumors', 'Disease', 'MESH:D009369', (48, 60))
97763	32429446	In fact, it is well documented that asbestos inhalation determines the production of cytokine and reactive oxygen species (ROS), therefore inducing lipid peroxidation of the mesothelial cell wall, mutagenic DNA lesions and thus, malignant pleural mesothelioma.	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('lipid peroxidation', 'MPA', (148, 166))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (239, 259))	('cell wall', 'cellular_component', 'GO:0005618', ('186', '195'))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (229, 259))	('lipid', 'Chemical', 'MESH:D008055', (148, 153))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (98, 121))	('malignant pleural mesothelioma', 'Disease', (229, 259))	('inducing', 'Reg', (139, 147))	('DNA', 'Gene', (207, 210))	('mutagenic', 'Var', (197, 206))
97795	32429446	The other four VOCs, such as p-benzoquinone, 2,2,4,6,6-pentamethyl-heptane, benzene and ethylbezene, have been, to date, reported as potentially diagnostic in previous studies focused on lung cancer.	('benzene', 'Chemical', 'MESH:D001554', (76, 83))	('2,2,4,6,6-pentamethyl-heptane', 'Chemical', 'MESH:C469781', (45, 74))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('ethylbezene', 'Disease', (88, 99))	('benzene', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ethylbezene', 'Chemical', '-', (88, 99))	('p-benzoquinone', 'Var', (29, 43))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('p-benzoquinone', 'Chemical', 'MESH:C004532', (29, 43))
97810	32429446	For example, in several studies, acethophenone has been found to be a marker of lung cancer and MPM.	('MPM', 'Chemical', '-', (96, 99))	('acethophenone', 'Chemical', '-', (33, 46))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Disease', (80, 91))	('acethophenone', 'Var', (33, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('MPM', 'Disease', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
97881	29616141	If the trial results indicate that PET-CT is superior to standard CT, it could alter the investigation pathway for patients with suspected pleural malignancy and help to expedite a diagnosis.	('patients', 'Species', '9606', (115, 123))	('PET-CT', 'Var', (35, 41))	('alter', 'Reg', (79, 84))	('investigation pathway', 'Pathway', (89, 110))	('expedite', 'Reg', (170, 178))	('pleural malignancy', 'Disease', 'MESH:D016066', (139, 157))	('pleural malignancy', 'Disease', (139, 157))
98035	30891101	In addition, fibulin-3 is useful for prognosis, and high values are statistically correlated with worse prognosis.	('fibulin-3', 'Gene', (13, 22))	('fibulin-3', 'Gene', '2202', (13, 22))	('high', 'Var', (52, 56))
98047	30891101	Most nonacetylated HMGB1 is normally localized in the nucleus, whereas acetylation of the lysine residues in the two nuclear localization signals (NLS1/2) redirects HMGB1 to the cytoplasm.	('lysine', 'Chemical', 'MESH:D008239', (90, 96))	('localization', 'biological_process', 'GO:0051179', ('125', '137'))	('HMGB1', 'Gene', (165, 170))	('nucleus', 'cellular_component', 'GO:0005634', ('54', '61'))	('acetylation', 'Var', (71, 82))	('redirects', 'Reg', (155, 164))	('NLS1/2', 'Gene', (147, 153))	('cytoplasm', 'cellular_component', 'GO:0005737', ('178', '187'))	('NLS1/2', 'Gene', '84879;29968', (147, 153))
98088	30891101	However, the levels of hyperacetylated HMGB1 were very low in both healthy controls (median level: 0.5 ng/ml) and asbestos-exposed individuals (median level: 0.4 ng/ml), and there was no significant difference between the two groups.	('asbestos', 'Chemical', 'MESH:D001194', (114, 122))	('low', 'NegReg', (55, 58))	('hyperacetylated', 'Var', (23, 38))	('levels', 'MPA', (13, 19))	('HMGB1', 'Gene', (39, 44))
98089	30891101	In addition, hyperacetylated HMGB1 comprised ~10% of the total HMGB1 in the serum of asbestos-exposed individuals.	('hyperacetylated', 'Var', (13, 28))	('HMGB1', 'Gene', (63, 68))	('HMGB1', 'Gene', (29, 34))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))
98096	30891101	AUCs of 0.674 (95% confidence interval (CI): 0.589-0.758) and 0.821 (95% CI: 0.706-0.935) were reported for MPM and DMPM patients, respectively.	('MPM', 'Chemical', '-', (108, 111))	('MPM', 'Chemical', '-', (117, 120))	('DMPM', 'Disease', (116, 120))	('DMPM', 'Chemical', '-', (116, 120))	('MPM', 'Disease', (108, 111))	('patients', 'Species', '9606', (121, 129))	('0.821', 'Var', (62, 67))
98099	30891101	reported that hyperacetylated HMGB1, a specific isoform, but not total HMGB1 reliably discriminated MM patients from asbestos-exposed individuals or healthy controls, with 100% specificity and sensitivity.	('discriminated', 'Reg', (86, 99))	('HMGB1', 'Gene', (30, 35))	('hyperacetylated', 'Var', (14, 29))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('patients', 'Species', '9606', (103, 111))
98114	30891101	It is noteworthy that TNF-alpha may activate NF-kappaB, a signaling pathway that allows HM cells that have undergone asbestos-induced DNA damage to survive rather than die, thereby creating a pool of aneuploid mesothelial cells with the potential to develop cancerization.	('signaling pathway', 'biological_process', 'GO:0007165', ('58', '75'))	('rat', 'Species', '10116', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('aneuploid', 'Var', (200, 209))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('NF-kappaB', 'Pathway', (45, 54))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('TNF-alpha', 'Gene', '7124', (22, 31))	('activate', 'PosReg', (36, 44))	('TNF-alpha', 'Gene', (22, 31))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
98115	30891101	Furthermore, Box-A suppresses the growth, migration, and viability of the REN mesothelioma cell line, though Box-A does not induce cytotoxicity in MM cell lines.	('REN mesothelioma', 'Disease', (74, 90))	('cytotoxicity', 'Disease', 'MESH:D064420', (131, 143))	('suppresses', 'NegReg', (19, 29))	('REN mesothelioma', 'Disease', 'MESH:D008654', (74, 90))	('Box-A', 'Var', (13, 18))	('cytotoxicity', 'Disease', (131, 143))	('growth', 'CPA', (34, 40))	('rat', 'Species', '10116', (45, 48))
98120	30891101	For instance, in rat models of hemorrhage-induced brain injury and Parkinson's disease, anti-HMGB1 mAbs protected blood-brain barrier integrity and suppressed HMGB1 release from neurons and astrocytes into the extracellular space, reducing the level of HMGB1 in the blood as well as the expression of inflammatory cytokines.	('HMGB1 release', 'MPA', (159, 172))	("Parkinson's disease", 'Disease', (67, 86))	('hemorrhage-induced brain injury', 'Disease', (31, 62))	('extracellular space', 'cellular_component', 'GO:0005615', ('210', '229'))	('blood-brain barrier integrity', 'CPA', (114, 143))	('level', 'MPA', (244, 249))	("Parkinson's disease", 'Disease', 'MESH:D010300', (67, 86))	('mAbs', 'Gene', (99, 103))	('anti-HMGB1', 'Var', (88, 98))	('rat', 'Species', '10116', (17, 20))	('hemorrhage-induced brain injury', 'Disease', 'MESH:D020300', (31, 62))	('reducing', 'NegReg', (231, 239))	('mAbs', 'Gene', '72935', (99, 103))	('suppressed', 'NegReg', (148, 158))	('expression', 'MPA', (287, 297))
98121	30891101	Interestingly, anti-HMGB1 mAbs had a long-term anti-seizure effect with minimal side effects in a mouse epilepsy model.	('epilepsy', 'Disease', 'MESH:D004827', (104, 112))	('epilepsy', 'Phenotype', 'HP:0001250', (104, 112))	('seizure', 'Disease', 'MESH:D012640', (52, 59))	('mAbs', 'Gene', (26, 30))	('anti-HMGB1', 'Var', (15, 25))	('seizure', 'Disease', (52, 59))	('epilepsy', 'Disease', (104, 112))	('mouse', 'Species', '10090', (98, 103))	('mAbs', 'Gene', '72935', (26, 30))	('seizure', 'Phenotype', 'HP:0001250', (52, 59))
98166	29641489	Nf2 heterozygote background was chosen based on the fact that NF2 mutations are often observed in mesothelioma, and a previous study showing its contribution to tumor development.	('mutations', 'Var', (66, 75))	('observed', 'Reg', (86, 94))	('NF2', 'Gene', '4771', (62, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('NF2', 'Gene', (62, 65))	('mesothelioma', 'Disease', (98, 110))
98178	29641489	Interestingly, FENDRR expression was increased in the tissue of the patient, which had maintained epithelioid histology (P236A_tum and P236B_tum), compared to the patient that had initially been diagnosed as epitheloid mesothelioma (P95A_tum) but where we have observed epithelial to mesenchymal transition (EMT) during tumor progression.	('FENDRR', 'Gene', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('P236B_tum', 'Var', (135, 144))	('P236A_tum', 'Var', (121, 130))	('patient', 'Species', '9606', (68, 75))	('epitheloid mesothelioma', 'Disease', 'MESH:D008654', (208, 231))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('epitheloid mesothelioma', 'Disease', (208, 231))	('tumor', 'Disease', (320, 325))	('P236A', 'Mutation', 'p.P236A', (121, 126))	('patient', 'Species', '9606', (163, 170))	('increased', 'PosReg', (37, 46))	('EMT', 'biological_process', 'GO:0001837', ('308', '311'))	('FENDRR', 'Gene', '400550', (15, 21))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('270', '306'))	('expression', 'MPA', (22, 32))	('P95A', 'Mutation', 'p.P95A', (233, 237))
98194	29641489	Silencing FENDRR increases FN1 expression in gastric cancer cells and increases their migration.	('increases', 'PosReg', (17, 26))	('migration', 'CPA', (86, 95))	('FENDRR', 'Gene', '400550', (10, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('FN1', 'Gene', '2335', (27, 30))	('increases', 'PosReg', (70, 79))	('FN1', 'Gene', (27, 30))	('expression', 'MPA', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FENDRR', 'Gene', (10, 16))	('gastric cancer', 'Disease', (45, 59))	('Silencing', 'Var', (0, 9))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))
98196	29641489	Not much is known about gm26902, except that its expression characterizes a subset of microglia CD11c+ population, which sustains brain development, while expression of gm17501 has been associated with cardiac hypertrophy.	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (202, 221))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (202, 221))	('brain development', 'biological_process', 'GO:0007420', ('130', '147'))	('gm26902', 'Var', (24, 31))	('CD11c', 'Gene', (96, 101))	('associated', 'Reg', (186, 196))	('CD11c', 'Gene', '3687', (96, 101))	('cardiac hypertrophy', 'Disease', (202, 221))	('brain development', 'CPA', (130, 147))	('expression', 'Var', (155, 165))	('gm17501', 'Var', (169, 176))
98207	29641489	Malat1 loss of function in mouse revealed that it is a nonessential gene in development or for adult normal tissue homeostasis, but depletion of MALAT1 in lung carcinoma cells impairs cellular motility in vitro and metastasis in mice.	('depletion', 'Var', (132, 141))	('cellular motility', 'CPA', (184, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('loss of function', 'NegReg', (7, 23))	('mouse', 'Species', '10090', (27, 32))	('lung carcinoma', 'Disease', 'MESH:D008175', (155, 169))	('metastasis', 'CPA', (215, 225))	('MALAT1', 'Gene', (145, 151))	('mice', 'Species', '10090', (229, 233))	('impairs', 'NegReg', (176, 183))	('lung carcinoma', 'Disease', (155, 169))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('108', '126'))
98224	29641489	Although for FENDRR the contribution to heterogeneity is based on the observation that it is enriched in epitheloid histotype and that one patient has a deletion in this gene, the fact that it is overexpressed in tumors and associates with epithelioid commitment in the patients analyzed indicate that further studies should explore the role of this lncRNA in mesothelioma.	('FENDRR', 'Gene', '400550', (13, 19))	('deletion', 'Var', (153, 161))	('tumors', 'Disease', (213, 219))	('mesothelioma', 'Disease', (360, 372))	('overexpressed', 'PosReg', (196, 209))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (270, 278))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('patient', 'Species', '9606', (139, 146))	('FENDRR', 'Gene', (13, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (360, 372))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('patient', 'Species', '9606', (270, 277))
98226	29641489	In an era where immunotherapy is also being intensively explored in mesothelioma treatment, it might be wise to consider the deletion of miRlet7b as a possible biomarker for response.	('mesothelioma', 'Disease', (68, 80))	('miRlet7b', 'Gene', (137, 145))	('miRlet7b', 'Gene', '406884', (137, 145))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('deletion', 'Var', (125, 133))
98236	27187383	A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure.	('asbestos', 'Chemical', 'MESH:D001194', (233, 241))	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('Frameshift Mutation', 'Var', (41, 60))	('Malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (144, 177))	('Peritoneal Mesothelioma', 'Phenotype', 'HP:0100003', (120, 143))	('malignancy', 'Disease', (206, 216))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (154, 177))	('Malignant peritoneal mesothelioma', 'Disease', (144, 177))	('Malignant Peritoneal Mesothelioma', 'Disease', (110, 143))	('BAP1', 'Gene', '8314', (64, 68))	('Mesothelioma Malignant', 'Phenotype', 'HP:0100001', (131, 153))	('Malignant Peritoneal Mesothelioma', 'Disease', 'MESH:C562839', (110, 143))	('Tumor', 'Phenotype', 'HP:0002664', (2, 7))	('BAP1', 'Gene', (64, 68))
98238	27187383	Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level.	('NOTCH2', 'Gene', (35, 41))	('BAP1', 'Gene', '8314', (105, 109))	('NSD1', 'Gene', '64324', (43, 47))	('ATP10B and 1', 'Gene', '23120;498', (62, 74))	('PDE', 'molecular_function', 'GO:0004114', ('49', '52'))	('NOTCH2', 'Gene', '4853', (35, 41))	('base-substitutions', 'Var', (13, 31))	('PDE4DIP', 'Gene', (49, 56))	('NSD1', 'Gene', (43, 47))	('BAP1', 'Gene', (105, 109))	('PDE4DIP', 'Gene', '9659', (49, 56))
98239	27187383	A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient's HLA-B protein.	('HLA-B', 'Gene', '3106', (174, 179))	('patient', 'Species', '9606', (164, 171))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('frameshift mutation', 'Var', (105, 124))	('Bap1', 'Gene', (46, 50))	('HLA-B', 'Gene', (174, 179))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
98241	27187383	A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation.	('mutations', 'Var', (103, 112))	('BAP1', 'Gene', (116, 120))	('frameshift indels', 'Var', (126, 143))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('neo-peptide formation', 'MPA', (149, 170))	('peptide formation', 'biological_process', 'GO:0043043', ('153', '170'))	('BAP1', 'Gene', '8314', (116, 120))
98250	27187383	Among mutations in known mesothelioma-related genes, such as NF2 and CDKN2A, somatic mutations in BAP1 are the most common recurrent events.	('BAP1', 'Gene', (98, 102))	('CDKN2A', 'Gene', '1029', (69, 75))	('NF2', 'Gene', '4771', (61, 64))	('mesothelioma', 'Disease', (25, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('mutations', 'Var', (85, 94))	('common', 'Reg', (116, 122))	('CDKN2A', 'Gene', (69, 75))	('BAP1', 'Gene', '8314', (98, 102))	('NF2', 'Gene', (61, 64))
98254	27187383	Compared to point mutations, the novel open reading frames (neoORFs) generated by small inserts or deletions could induce highly specific antitumor immunity and could be recognized by T cells.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('deletions', 'Var', (99, 108))	('tumor', 'Disease', (142, 147))	('induce', 'PosReg', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
98260	27187383	After bioinformatics analyses of somatic mutations and prediction of MHC presentation, we validated a novel somatic insert frameshift variation in BAP1.	('frameshift variation', 'Var', (123, 143))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', '8314', (147, 151))
98265	27187383	Second, the non-annotated variants in dbSNP and 1000Genome and their further functional prediction by Sorting Intolerant From Tolerant (SIFT) or Polymorphism phenotyping (Polyphen) showed that "damaged" segments were kept.	('dbSNP', 'Gene', (38, 43))	('SIFT', 'Disease', 'None', (136, 140))	('SIFT', 'Disease', (136, 140))	('variants', 'Var', (26, 34))
98266	27187383	Only 5 mutations were confirmed by the Sanger method to be somatic variants of MPM in this case: mutations in NOTCH2 (exon13, c.2108G > A, p.G703D), PDE4DIP (exon1, c.862C > A, p.L288M), BAP1 (exon13, c.1568_1569insTGTC, p.V523fs), ATP10B (exon7, c.628G > A, p.E210K), and NSD1 (exon23, c.7445A > C, p.K2482T).	('mutations', 'Var', (97, 106))	('ATP10B', 'Gene', '23120', (232, 238))	('c.628G > A', 'Mutation', 'rs781678212', (247, 257))	('p.K2482T', 'Mutation', 'p.K2482T', (300, 308))	('NOTCH2', 'Gene', (110, 116))	('p.E210K', 'Mutation', 'rs767430182', (259, 266))	('p.G703D', 'Mutation', 'p.G703D', (139, 146))	('exon13', 'Var', (193, 199))	('BAP1', 'Gene', '8314', (187, 191))	('c.862C > A', 'Var', (165, 175))	('p.K2482T', 'Var', (300, 308))	('c.1568_1569insTGTC', 'Mutation', 'c.1568_1569insTGTC', (201, 219))	('c.7445A > C', 'Mutation', 'c.7445A>C', (287, 298))	('NSD1', 'Gene', (273, 277))	('PDE4DIP', 'Gene', (149, 156))	('MPM', 'Gene', (79, 82))	('c.862C > A', 'Mutation', 'rs782022203', (165, 175))	('PDE', 'molecular_function', 'GO:0004114', ('149', '152'))	('c.2108G > A', 'Mutation', 'rs782114316', (126, 137))	('BAP1', 'Gene', (187, 191))	('p.V523fs', 'Var', (221, 229))	('exon7', 'Var', (240, 245))	('NOTCH2', 'Gene', '4853', (110, 116))	('p.V523fs', 'Mutation', 'p.V523fsX', (221, 229))	('p.E210K', 'Var', (259, 266))	('exon23', 'Var', (279, 285))	('exon13', 'Var', (118, 124))	('c.628G > A', 'Var', (247, 257))	('c.2108G > A', 'Var', (126, 137))	('p.L288M', 'Mutation', 'p.L288M', (177, 184))	('p.G703D', 'Var', (139, 146))	('NSD1', 'Gene', '64324', (273, 277))	('ATP10B', 'Gene', (232, 238))	('PDE4DIP', 'Gene', '9659', (149, 156))
98268	27187383	However, the number of mutant reads in MN1 and PRG4 was 3/total 14 reads and 6/total 33 reads, respectively, which suggested a poor coverage depth in these two positions.	('MN1', 'Gene', '4330', (39, 42))	('PRG4', 'Gene', '10216', (47, 51))	('PRG4', 'Gene', (47, 51))	('mutant', 'Var', (23, 29))	('MN1', 'Gene', (39, 42))
98269	27187383	Although the Sanger method has limited sensitivity due to the rare mutant allele copies in heterogeneous cancer DNA samples, MN1 and PRG4 remain potential candidates responsible for the development and progress of malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (214, 236))	('responsible', 'Reg', (166, 177))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (214, 236))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('malignant mesothelioma', 'Disease', (214, 236))	('PRG4', 'Gene', '10216', (133, 137))	('MN1', 'Gene', (125, 128))	('mutant', 'Var', (67, 73))	('MN1', 'Gene', '4330', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('PRG4', 'Gene', (133, 137))
98270	27187383	We also identified a second somatic mutation in filtered NSD1 (exon 7, c.3982A > G, p.K1328E) with a low percentage of mutant reads (5.08%).	('c.3982A > G', 'Var', (71, 82))	('c.3982A > G', 'Mutation', 'rs372655919', (71, 82))	('p.K1328E', 'Mutation', 'rs372655919', (84, 92))	('NSD1', 'Gene', '64324', (57, 61))	('NSD1', 'Gene', (57, 61))	('p.K1328E', 'Var', (84, 92))
98271	27187383	Among the 5 confirmed mutations, 4 missense mutations in NOTCH2, PDE4DIP, ATP10B and NSD1 caused only one amino acid substitution in protein sequence and did not change the length of the respective proteins.	('NOTCH2', 'Gene', '4853', (57, 63))	('PDE', 'molecular_function', 'GO:0004114', ('65', '68'))	('ATP10B', 'Gene', (74, 80))	('ATP10B', 'Gene', '23120', (74, 80))	('caused', 'Reg', (90, 96))	('NSD1', 'Gene', '64324', (85, 89))	('NOTCH2', 'Gene', (57, 63))	('mutations', 'Var', (22, 31))	('missense mutations', 'Var', (35, 53))	('PDE4DIP', 'Gene', '9659', (65, 72))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('PDE4DIP', 'Gene', (65, 72))	('NSD1', 'Gene', (85, 89))
98275	27187383	The MHC class-I binding affinity across all possible 8-mer to 11-mer peptides of wild-type and mutant proteins was predicted using NetMHCpan 2.8 Server.	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('NetMHCpan', 'Chemical', '-', (131, 140))	('mutant', 'Var', (95, 101))	('binding affinity', 'Interaction', (16, 32))
98278	27187383	Only 3 of 7 peptides with mutated sites were predicted to specifically bind to HLA molecules: neo 8-mer LPHLQGAF peptide of mutated Bap1 (IC50 = 17.46 nM), 11-mer KTNLKQRCVVK of mutated Atp10b (IC50 = 135.45 nM), and 8-mer TPQADETM of mutated Nsd1 (IC50 = 78.89 nM).	('Atp10b', 'Gene', (186, 192))	('mutated', 'Var', (124, 131))	('Nsd1', 'Gene', '64324', (243, 247))	('Bap1', 'Gene', (132, 136))	('mutated', 'Var', (178, 185))	('Nsd1', 'Gene', (243, 247))	('Atp10b', 'Gene', '23120', (186, 192))
98280	27187383	Only the 8-mer LPHLQGAF peptide of mutant Bap1 provoked a strong immune response in rabbits.	('rabbits', 'Species', '9986', (84, 91))	('immune response', 'biological_process', 'GO:0006955', ('65', '80'))	('Bap1', 'Gene', (42, 46))	('mutant', 'Var', (35, 41))	('immune response', 'CPA', (65, 80))
98282	27187383	The 725-oncogene depth targeted sequencing revealed four confirmed base-substitution somatic mutations in NOTCH2, NSD1, PDE4DIP, and ATP10B and one verified 4-base insert frameshift somatic mutation in BAP1.	('BAP1', 'Gene', (202, 206))	('ATP10B', 'Gene', '23120', (133, 139))	('PDE', 'molecular_function', 'GO:0004114', ('120', '123'))	('NSD1', 'Gene', '64324', (114, 118))	('base-substitution', 'Var', (67, 84))	('NOTCH2', 'Gene', '4853', (106, 112))	('PDE4DIP', 'Gene', '9659', (120, 127))	('PDE4DIP', 'Gene', (120, 127))	('NSD1', 'Gene', (114, 118))	('BAP1', 'Gene', '8314', (202, 206))	('ATP10B', 'Gene', (133, 139))	('NOTCH2', 'Gene', (106, 112))
98283	27187383	According to the results of the functional prediction, the mutations in BAP1, NOTCH2 and NSD1 were the most possible driver somatic mutations in the development of MM in our patient.	('NSD1', 'Gene', (89, 93))	('BAP1', 'Gene', '8314', (72, 76))	('patient', 'Species', '9606', (174, 181))	('NOTCH2', 'Gene', '4853', (78, 84))	('BAP1', 'Gene', (72, 76))	('mutations', 'Var', (59, 68))	('NOTCH2', 'Gene', (78, 84))	('NSD1', 'Gene', '64324', (89, 93))
98288	27187383	The germline abrogation in NSD1 results in a childhood overgrowth syndrome called Sotos syndrome (OMIM 117550).	('overgrowth syndrome', 'Disease', 'MESH:C537340', (55, 74))	('results in', 'Reg', (32, 42))	('NSD1', 'Gene', (27, 31))	('Sotos syndrome', 'Disease', 'MESH:D058495', (82, 96))	('germline abrogation', 'Var', (4, 23))	('Sotos syndrome', 'Disease', (82, 96))	('overgrowth', 'Phenotype', 'HP:0001548', (55, 65))	('overgrowth syndrome', 'Disease', (55, 74))	('NSD1', 'Gene', '64324', (27, 31))
98291	27187383	Considering the results of several studies that identified recurrent genetic alternations in MMs that could be "driver" mutations, this frameshift mutation in BAP1 seems to be the best candidate.	('BAP1', 'Gene', (159, 163))	('frameshift mutation', 'Var', (136, 155))	('BAP1', 'Gene', '8314', (159, 163))	('genetic alternations', 'Var', (69, 89))
98296	27187383	The excessive activation of the Notch signaling pathway and the resulting dysfunction in transcription could initiate primary carcinogenesis.	('dysfunction', 'Var', (74, 85))	('activation', 'PosReg', (14, 24))	('transcription', 'MPA', (89, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('initiate', 'Reg', (109, 117))	('carcinogenesis', 'Disease', (126, 140))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('32', '55'))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('Notch signaling pathway', 'Pathway', (32, 55))
98299	27187383	Compared to all variants in BAP1 regardless of tumor type, 134/532 (25.2%) variants are frameshift mutations.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('frameshift mutations', 'Var', (88, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('variants', 'Var', (75, 83))	('tumor', 'Disease', (47, 52))
98303	27187383	The mutations in BAP1 were the most common events not only in MM patients but also in other types of cancer, such as uveal melanoma and renal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('renal cancer', 'Disease', (136, 148))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('uveal melanoma', 'Disease', (117, 131))	('cancer', 'Disease', (142, 148))	('renal cancer', 'Phenotype', 'HP:0009726', (136, 148))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('renal cancer', 'Disease', 'MESH:D007680', (136, 148))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('common', 'Reg', (36, 42))	('patients', 'Species', '9606', (65, 73))	('BAP1', 'Gene', '8314', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (4, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('BAP1', 'Gene', (17, 21))
98305	27187383	The germline mutation in BAP1 was recommended for screening for hereditary case diagnosis.	('BAP1', 'Gene', '8314', (25, 29))	('germline mutation', 'Var', (4, 21))	('BAP1', 'Gene', (25, 29))
98306	27187383	For sporadic MM patients with no obvious clinical treatment, the tumor-specific neo-antigen caused by frameshift mutations of Bap1 could be identified based on patient's sequencing results and the prediction of its MHC-binding ability.	('binding', 'molecular_function', 'GO:0005488', ('219', '226'))	('Bap1', 'Gene', (126, 130))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('patients', 'Species', '9606', (16, 24))	('caused', 'Reg', (92, 98))	('frameshift mutations', 'Var', (102, 122))	('patient', 'Species', '9606', (160, 167))	('patient', 'Species', '9606', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
98311	27187383	She was diagnosed with an epithelial type peritoneal malignant mesothelioma characterized by the following clinical features: CK5/6 (+++), CK7 (+++), calretinin (++), D2-40 (+), Vim (++), CK (++), ER (-), PR (-), CEA (-), Ki67 (<10% +).	('epithelial type peritoneal malignant mesothelioma', 'Disease', 'MESH:C562839', (26, 75))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (53, 75))	('epithelial type peritoneal malignant mesothelioma', 'Disease', (26, 75))	('Vim', 'Gene', '7431', (178, 181))	('CK7', 'Gene', (139, 142))	('D2-40 (+', 'Var', (167, 175))	('CEA', 'Gene', (213, 216))	('CK5/6', 'Gene', '3852', (126, 131))	('Vim', 'Gene', (178, 181))	('CK7', 'Gene', '3855', (139, 142))	('CEA', 'Gene', '5670', (213, 216))	('peritoneal malignant mesothelioma', 'Phenotype', 'HP:0100003', (42, 75))	('CK5/6', 'Gene', (126, 131))
98326	27187383	This frameshift mutation was translated into a truncated protein with a 13-mer neo-peptide tail, which was predicted to be presented by the patient's HLA-B molecule as a tumor-specific neo-antigen.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('patient', 'Species', '9606', (140, 147))	('tumor', 'Disease', (170, 175))	('frameshift', 'Var', (5, 15))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('HLA-B', 'Gene', (150, 155))	('HLA-B', 'Gene', '3106', (150, 155))
98329	27187383	Frameshift mutations in BAP1 are common events in MM, and the neo-antigens could be ideal biomarkers for diagnosis.	('Frameshift mutations', 'Var', (0, 20))	('BAP1', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (24, 28))
98330	27187383	MPM Malignant peritoneal mesothelioma  NGS Next generation sequencing  MHC Major histocompatibility complex  HLA Human leukocyte antigen	('Major histocompatibility complex', 'biological_process', 'GO:0046776', ('75', '107'))	('Human', 'Species', '9606', (113, 118))	('Malignant peritoneal mesothelioma  NGS', 'Disease', 'MESH:C562839', (4, 42))	('Malignant peritoneal mesothelioma  NGS', 'Disease', (4, 42))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (14, 37))	('MPM', 'Var', (0, 3))
98339	26695618	The length of the S/G2/M phase is unchanged, however the G1 phase is clearly prolonged in CR-/- cells.	('S/G2', 'Var', (18, 22))	('S/G2', 'SUBSTITUTION', 'None', (18, 22))	('G1 phase', 'biological_process', 'GO:0051318', ('57', '65'))	('prolonged', 'PosReg', (77, 86))	('M phase', 'biological_process', 'GO:0000279', ('23', '30'))
98353	26695618	LP-9/TERT1) results in a G1 growth arrest without leading to apoptosis or necrosis.	('necrosis', 'Disease', 'MESH:D009336', (74, 82))	('growth arrest', 'Phenotype', 'HP:0001510', (28, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('LP-9/TERT1', 'Var', (0, 10))	('TERT1', 'CellLine', 'CVCL:C452', (5, 10))	('necrosis', 'biological_process', 'GO:0070265', ('74', '82'))	('necrosis', 'biological_process', 'GO:0008219', ('74', '82'))	('necrosis', 'biological_process', 'GO:0019835', ('74', '82'))	('necrosis', 'biological_process', 'GO:0008220', ('74', '82'))	('necrosis', 'biological_process', 'GO:0001906', ('74', '82'))	('growth arrest', 'Disease', (28, 41))	('necrosis', 'Disease', (74, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('growth arrest', 'Disease', 'MESH:D006323', (28, 41))
98354	26695618	Impairment of Ca2+ handling in MM cells reduces uptake of Ca2+ into mitochondria and this reduces apoptosis in these cells.	('uptake', 'biological_process', 'GO:0098739', ('48', '54'))	('apoptosis', 'CPA', (98, 107))	('Ca2', 'Gene', (14, 17))	('uptake', 'biological_process', 'GO:0098657', ('48', '54'))	('reduces', 'NegReg', (90, 97))	('mitochondria', 'cellular_component', 'GO:0005739', ('68', '80'))	('Ca2', 'Gene', '12349', (58, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('reduces', 'NegReg', (40, 47))	('Impairment', 'Var', (0, 10))	('Ca2', 'Gene', '12349', (14, 17))	('Ca2', 'Gene', (58, 61))
98403	26695618	The expression level of mCherry-hCdt1 is cell cycle-dependent showing an accumulation during the G0/G1 phase, followed by an ubiquitination-based protein degradation during S/G2/M phases.	('hCdt1', 'Gene', '81620', (32, 37))	('protein degradation', 'biological_process', 'GO:0030163', ('146', '165'))	('S/G2', 'Var', (173, 177))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('expression', 'MPA', (4, 14))	('accumulation', 'PosReg', (73, 85))	('S/G2', 'SUBSTITUTION', 'None', (173, 177))	('cell cycle', 'biological_process', 'GO:0007049', ('41', '51'))	('ubiquitination-based protein degradation', 'MPA', (125, 165))	('hCdt1', 'Gene', (32, 37))	('G1 phase', 'biological_process', 'GO:0051318', ('100', '108'))
98410	26695618	Endogenous peroxidases were quenched in 0.3 % H2O2 for 20 min followed by tissue permeabilization in 0.1 % PBS Tween 20 for 5 min and blocked at room temperature for 20 min in PBS containing 2 % BSA and 1 % horse serum.	('PBS', 'Chemical', 'MESH:D007854', (176, 179))	('0.3', 'Var', (40, 43))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('quenched', 'NegReg', (28, 36))	('Tween 20', 'Chemical', 'MESH:D011136', (111, 119))	('PBS', 'Chemical', 'MESH:D007854', (107, 110))	('horse', 'Species', '9796', (207, 212))	('Endogenous peroxidases', 'Enzyme', (0, 22))	('rat', 'Species', '10116', (155, 158))
98424	26695618	At confluence, the number of mesothelial cells per surface was smaller also evidenced by a more pronounced cell flattening in the CR-/- samples hinting towards a reduced rate of cell proliferation.	('CR-/-', 'Var', (130, 135))	('reduced', 'NegReg', (162, 169))	('rat', 'Species', '10116', (170, 173))	('cell proliferation', 'CPA', (178, 196))	('rat', 'Species', '10116', (190, 193))	('smaller', 'NegReg', (63, 70))	('cell flattening', 'CPA', (107, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('178', '196'))
98442	26695618	As a positive control, WT cells were transfected with the SV40 plasmid coding for the large T and small t antigen (TAg and tag, respectively); increased TAg and tag expression was previously shown to result in increased proliferation, telomerase activity and favor transformation of mesothelial cells.	('TAg', 'Var', (153, 156))	('rat', 'Species', '10116', (227, 230))	('increased', 'PosReg', (210, 219))	('favor transformation of mesothelial cells', 'CPA', (259, 300))	('telomerase', 'CPA', (235, 245))	('activity', 'MPA', (246, 254))	('telomerase activity', 'molecular_function', 'GO:0003720', ('235', '254'))	('tag', 'Var', (161, 164))
98445	26695618	The strongest effect on increasing proliferation was observed after SV40 transfection, but also CR overexpression significantly increased proliferation determined by the 2 assays (live cell-imaging, MTT assay; Fig.	('proliferation', 'CPA', (35, 48))	('overexpression', 'PosReg', (99, 113))	('SV40 transfection', 'Var', (68, 85))	('increased', 'PosReg', (128, 137))	('proliferation', 'CPA', (138, 151))	('increasing', 'PosReg', (24, 34))	('MTT', 'Chemical', 'MESH:C070243', (199, 202))	('rat', 'Species', '10116', (145, 148))	('transfection', 'Var', (73, 85))	('rat', 'Species', '10116', (42, 45))
98456	26695618	Expression of hCdt1-mCherry is highest at the end of the G1 phase and decreases/disappears during the S/G2 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('57', '65'))	('G2 phase', 'biological_process', 'GO:0051319', ('104', '112'))	('Expression', 'MPA', (0, 10))	('hCdt1', 'Gene', (14, 19))	('S/G2', 'Var', (102, 106))	('S/G2', 'SUBSTITUTION', 'None', (102, 106))	('hCdt1', 'Gene', '81620', (14, 19))	('decreases/disappears', 'NegReg', (70, 90))
98459	26695618	However cells entering S phase characterized by a decrease in hCdt1 fluorescence, generally entered mitosis within the observation period and thus allowed to determine the length of the S/G2/M phase, which was found to be approximately of 8 h, irrespective of genotype (Fig.	('entered mitosis', 'Disease', 'MESH:D004751', (92, 107))	('S/G2', 'Var', (186, 190))	('S/G2', 'SUBSTITUTION', 'None', (186, 190))	('hCdt1', 'Gene', (62, 67))	('entered mitosis', 'Disease', (92, 107))	('decrease', 'NegReg', (50, 58))	('mitosis', 'biological_process', 'GO:0000278', ('100', '107'))	('S phase', 'biological_process', 'GO:0051320', ('23', '30'))	('hCdt1', 'Gene', '81620', (62, 67))	('M phase', 'biological_process', 'GO:0000279', ('191', '198'))	('fluorescence', 'MPA', (68, 80))
98470	26695618	A significant increase in the closure rate was observed for both, CR and NLS-CR overexpressing cells in comparison to control prMC from either WT or CR-/-mice; the magnitude of the effect, i.e.	('overexpressing', 'Var', (80, 94))	('mice', 'Species', '10090', (154, 158))	('NLS-CR', 'Gene', (73, 79))	('rat', 'Species', '10116', (38, 41))	('closure rate', 'CPA', (30, 42))	('prMC', 'Chemical', '-', (126, 130))	('increase', 'PosReg', (14, 22))
98478	26695618	Overexpression of both CR and NLS-CR was accompanied by a morphological change resulting in cells with a rather cobblestone-like morphology, typical for reactive mesothelial cells in situ, as well as for epithelioid MM cells (Fig.	('resulting in', 'Reg', (79, 91))	('NLS-CR', 'Var', (30, 36))	('cobblestone', 'Chemical', '-', (112, 123))	('rat', 'Species', '10116', (105, 108))
98486	26695618	Expression of CR was observed in some dispersed cells in the lung mesenchyme of E14.5 and E16.5 mouse embryos (Fig.	('E14.5', 'Var', (80, 85))	('E16.5', 'Var', (90, 95))	('mouse', 'Species', '10090', (96, 101))
98490	26695618	In this study we provide evidence that CR and moreover nuclear-targeted CR is able to increase proliferation and mobility when expressed in prMC in vitro; the presence of either variant caused a morphological change towards a more epithelioid morphology.	('increase', 'PosReg', (86, 94))	('presence', 'Var', (159, 167))	('rat', 'Species', '10116', (102, 105))	('proliferation', 'CPA', (95, 108))	('mobility', 'CPA', (113, 121))	('prMC', 'Chemical', '-', (140, 144))
98507	26695618	Here we showed that mesothelial precursor cells with cuboid morphology transiently expressed high levels of CR in WT mice evidenced at E14.5 and E16.5.	('mice', 'Species', '10090', (117, 121))	('E16.5', 'Var', (145, 150))	('E14.5', 'Var', (135, 140))
98522	33266025	During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/beta-catenin signaling pathway during APC-driven intestinal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('regeneration', 'biological_process', 'GO:0031099', ('127', '139'))	('homeostasis', 'biological_process', 'GO:0042592', ('103', '114'))	('FAK', 'Var', (189, 192))	('FAK', 'molecular_function', 'GO:0004717', ('189', '192'))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('Wnt', 'Gene', (61, 64))	('Wnt', 'Gene', (140, 143))	('FAK', 'molecular_function', 'GO:0004717', ('174', '177'))	('Wnt', 'Gene', '34007', (61, 64))	('Wnt', 'Gene', '34007', (140, 143))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('tumor', 'Disease', (271, 276))	('APC', 'Phenotype', 'HP:0005227', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('Wnt', 'Gene', (207, 210))	('APC', 'cellular_component', 'GO:0005680', ('249', '252'))	('Wnt', 'Gene', '34007', (207, 210))	('activates', 'PosReg', (193, 202))	('signaling pathway', 'biological_process', 'GO:0007165', ('224', '241'))	('FAK', 'molecular_function', 'GO:0004717', ('33', '36'))
98523	33266025	In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt.	('lung', 'Disease', (11, 15))	('modulate', 'Reg', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (21, 39))	('prostate cancer', 'Disease', (105, 120))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('73', '94'))	('FAK', 'molecular_function', 'GO:0004717', ('122', '125'))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('pancreatic cancers', 'Disease', (21, 39))	('breast', 'Disease', (3, 9))	('FAK', 'Var', (41, 44))	('FAK', 'molecular_function', 'GO:0004717', ('41', '44'))	('pancreatic cancers', 'Disease', 'MESH:D010190', (21, 39))	('Wnt', 'Gene', (73, 76))	('Wnt', 'Gene', '34007', (73, 76))	('Wnt', 'Gene', (143, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('Wnt', 'Gene', '34007', (143, 146))
98524	33266025	In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (3, 25))	('Wnt', 'Gene', (113, 116))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('Wnt', 'Gene', '34007', (113, 116))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (3, 25))	('FAK', 'Protein', (85, 88))	('activates', 'PosReg', (99, 108))	('FAK', 'molecular_function', 'GO:0004717', ('27', '30'))	('Inhibiting', 'Var', (74, 84))	('Wnt', 'Gene', (35, 38))	('FAK', 'molecular_function', 'GO:0004717', ('85', '88'))	('malignant mesothelioma', 'Disease', (3, 25))	('Wnt', 'Gene', '34007', (35, 38))
98532	33266025	Dysregulation of this pathway is associated with a broad spectrum of human diseases, ranging from neurodegenerative disorders to fibrosis, osteoporosis, and cancer.	('neurodegenerative disorders', 'Disease', (98, 125))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('fibrosis', 'Disease', 'MESH:D005355', (129, 137))	('Dysregulation', 'Var', (0, 13))	('osteoporosis', 'Phenotype', 'HP:0000939', (139, 151))	('human', 'Species', '9606', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('associated', 'Reg', (33, 43))	('osteoporosis', 'Disease', 'MESH:D010024', (139, 151))	('cancer', 'Disease', (157, 163))	('osteoporosis', 'Disease', (139, 151))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (98, 125))	('fibrosis', 'Disease', (129, 137))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (98, 125))
98536	33266025	Feedback loops and crosstalk between signaling pathways can significantly impact the efficacy of cancer therapeutics and cause resistance to targeted agents, thereby representing a major barrier to effective treatments.	('cancer', 'Disease', (97, 103))	('efficacy', 'CPA', (85, 93))	('impact', 'Reg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('crosstalk', 'Reg', (19, 28))	('cause', 'Reg', (121, 126))	('Feedback', 'Var', (0, 8))	('resistance', 'MPA', (127, 137))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
98544	33266025	The kinase domain of FAK is localized in the middle of the molecule and contains the activation loop and important tyrosine (Y) residues, such as Y397, Y576, and Y577.	('Y576', 'Var', (152, 156))	('FAK', 'molecular_function', 'GO:0004717', ('21', '24'))	('tyrosine', 'Chemical', 'MESH:D014443', (115, 123))	('FAK', 'Gene', (21, 24))	('Y397', 'Var', (146, 150))	('Y577', 'Var', (162, 166))
98553	33266025	Given its importance it is not surprising that mutations in the Wnt pathway are frequently observed in cancer, most notably in tissues that normally depend on Wnt for high self-renewal or repair.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('observed', 'Reg', (91, 99))	('Wnt', 'Gene', (64, 67))	('mutations', 'Var', (47, 56))	('Wnt', 'Gene', '34007', (64, 67))	('Wnt', 'Gene', (159, 162))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('Wnt', 'Gene', '34007', (159, 162))
98564	33266025	Deletion of FAK during mouse development results in lethality at embryonic day 8.5 and a block in cell proliferation.	('FAK', 'Gene', (12, 15))	('cell proliferation', 'CPA', (98, 116))	('block', 'NegReg', (89, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('lethality', 'MPA', (52, 61))	('mouse', 'Species', '10090', (23, 28))	('FAK', 'molecular_function', 'GO:0004717', ('12', '15'))	('Deletion', 'Var', (0, 8))
98569	33266025	Both pathways have been also shown to be implicated in bone remodeling; FAK promotes osteoblast progenitor cell proliferation and differentiation by enhancing Wnt signaling.	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('osteoblast progenitor cell proliferation', 'CPA', (85, 125))	('Wnt', 'Gene', (159, 162))	('enhancing', 'PosReg', (149, 158))	('FAK', 'Var', (72, 75))	('promotes', 'PosReg', (76, 84))	('differentiation', 'CPA', (130, 145))	('bone remodeling', 'biological_process', 'GO:0046849', ('55', '70'))	('FAK', 'molecular_function', 'GO:0004717', ('72', '75'))	('Wnt', 'Gene', '34007', (159, 162))
98570	33266025	In addition, FAK was shown to play a pivotal role in promoting BMP9-induced osteogenesis of synovial mesenchymal stem cells via the activation of Wnt and MAPK pathways, while another study demonstrated that FAK and BMP-9 synergistically trigger osteogenic differentiation and bone formation of adipose tissue-derived stem cells by enhancing Wnt-beta-catenin signaling.	('Wnt', 'Gene', (341, 344))	('MAPK pathways', 'Pathway', (154, 167))	('Wnt', 'Gene', '34007', (341, 344))	('promoting', 'PosReg', (53, 62))	('BMP9', 'Gene', '2658', (63, 67))	('osteogenesis of synovial mesenchymal', 'Disease', (76, 112))	('enhancing', 'PosReg', (331, 340))	('bone formation', 'CPA', (276, 290))	('osteogenesis of synovial mesenchymal', 'Disease', 'MESH:D013581', (76, 112))	('FAK', 'molecular_function', 'GO:0004717', ('13', '16'))	('BMP9', 'Gene', (63, 67))	('osteogenic differentiation', 'CPA', (245, 271))	('signaling', 'biological_process', 'GO:0023052', ('358', '367'))	('Wnt', 'Gene', (146, 149))	('BMP-9', 'Gene', '2658', (215, 220))	('Wnt', 'Gene', '34007', (146, 149))	('BMP-9', 'Gene', (215, 220))	('FAK', 'Var', (207, 210))	('bone formation', 'biological_process', 'GO:0001503', ('276', '290'))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))	('trigger', 'PosReg', (237, 244))	('FAK', 'molecular_function', 'GO:0004717', ('207', '210'))	('osteogenesis', 'biological_process', 'GO:0001503', ('76', '88'))
98574	33266025	Given Wnt's essential role in embryonic development, tissue homoeostasis, and stem cell biology, this pathway must be tightly regulated; its dysregulation has been associated with many types of cancer.	('cancer', 'Disease', (194, 200))	('associated', 'Reg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Wnt', 'Gene', (6, 9))	('dysregulation', 'Var', (141, 154))	('Wnt', 'Gene', '34007', (6, 9))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
98577	33266025	Genetic alterations in Wnt signaling occur in over 90% of human sporadic CRC, among which inactivation of the tumor suppressor adenomatous polyposis coli (APC) occur in 85% of the cases, while activating mutations of the proto-oncogene beta-catenin (CTNNB1) occur only in 5% of the cases.	('Wnt', 'Gene', (23, 26))	('human', 'Species', '9606', (58, 63))	('Wnt', 'Gene', '34007', (23, 26))	('tumor suppressor', 'Gene', (110, 126))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (127, 153))	('CTNNB1', 'Gene', (250, 256))	('APC', 'cellular_component', 'GO:0005680', ('155', '158'))	('APC', 'Phenotype', 'HP:0005227', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('inactivation', 'MPA', (90, 102))	('adenomatous polyposis coli', 'Gene', (127, 153))	('CRC', 'Disease', (73, 76))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('tumor suppressor', 'Gene', '7248', (110, 126))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('alterations', 'Var', (8, 19))	('adenomatous polyposis coli', 'Gene', '324', (127, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('CTNNB1', 'Gene', '1499', (250, 256))
98578	33266025	Activating mutations of BRAF (mostly V600E mutation), a serine/threonine kinase downstream of KRAS and upstream of MEK (mitogen-activated protein kinase kinase) have been reported to occur in approximately 10% of all CRC patients.	('mitogen-activated protein kinase kinase', 'Gene', '5609', (120, 159))	('Activating', 'PosReg', (0, 10))	('patients', 'Species', '9606', (221, 229))	('mitogen-activated protein kinase kinase', 'Gene', (120, 159))	('KRAS', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('CRC', 'Phenotype', 'HP:0003003', (217, 220))	('serine', 'Chemical', 'MESH:D012694', (56, 62))	('KRAS', 'Gene', '3845', (94, 98))	('V600E', 'Var', (37, 42))	('BRAF', 'Gene', (24, 28))	('MEK', 'Gene', (115, 118))	('MEK', 'Gene', '5609', (115, 118))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('CRC', 'Disease', (217, 220))
98583	33266025	The tumorigenic consequences of dysregulated beta-catenin activity are the stimulation of cellular growth and proliferation, and the disruption of differentiation programs.	('tumor', 'Disease', (4, 9))	('stimulation', 'PosReg', (75, 86))	('activity', 'MPA', (58, 66))	('cellular growth', 'biological_process', 'GO:0016049', ('90', '105'))	('dysregulated', 'Var', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cellular growth', 'CPA', (90, 105))	('disruption', 'Reg', (133, 143))	('beta-catenin', 'Protein', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('differentiation programs', 'CPA', (147, 171))
98585	33266025	Pharmacological inhibition of FAK/PYK2 repressed adenoma formation in APCmin/+ mice and reduced intestinal levels of phospho-GSK3beta and beta-catenin, indicating that the FAK/PYK2/GSK3beta axis is critical in APC-driven intestinal tumorigenesis.	('adenoma', 'Disease', (49, 56))	('APC', 'cellular_component', 'GO:0005680', ('210', '213'))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('PYK2', 'Gene', (34, 38))	('PYK2', 'Gene', (176, 180))	('adenoma', 'Disease', 'MESH:D000236', (49, 56))	('APC', 'Phenotype', 'HP:0005227', (70, 73))	('GSK', 'molecular_function', 'GO:0050321', ('181', '184'))	('tumor', 'Disease', (232, 237))	('reduced', 'NegReg', (88, 95))	('inhibition', 'Var', (16, 26))	('PYK2', 'Gene', '19229', (34, 38))	('APC', 'Phenotype', 'HP:0005227', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('FAK', 'molecular_function', 'GO:0004717', ('172', '175'))	('beta-catenin', 'MPA', (138, 150))	('GSK', 'molecular_function', 'GO:0050321', ('125', '128'))	('PYK2', 'Gene', '19229', (176, 180))	('FAK', 'molecular_function', 'GO:0004717', ('30', '33'))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))
98588	33266025	Co-targeting of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture and mouse xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FAK', 'molecular_function', 'GO:0004717', ('42', '45'))	('tumor', 'Disease', (86, 91))	('Wnt', 'Gene', (21, 24))	('Co-targeting', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('BRAF/FAK pathways', 'Gene', (37, 54))	('Wnt', 'Gene', '34007', (21, 24))	('mouse', 'Species', '10090', (120, 125))
98589	33266025	Given that Wnt/beta-catenin pathway activation is one of the causes of CRC resistance to BRAF inhibition, co-targeting the Wnt/beta-catenin pathway using FAK inhibitors may represent a new feasible solution to overcome resistance to BRAF inhibitors with great potential to change the landscape for patients with BRAF mutations.	('mutations', 'Var', (317, 326))	('Wnt', 'Gene', (123, 126))	('patients', 'Species', '9606', (298, 306))	('Wnt', 'Gene', (11, 14))	('BRAF', 'Gene', (312, 316))	('Wnt', 'Gene', '34007', (123, 126))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('FAK', 'molecular_function', 'GO:0004717', ('154', '157'))	('Wnt', 'Gene', '34007', (11, 14))
98592	33266025	Another link between Wnt and FAK signaling is the finding that the expression of HEF1 (human enhancer of filamentation 1), implicated in progression of CRC, was also shown to modulate both pathways.	('enhancer of filamentation 1', 'Gene', (93, 120))	('CRC', 'Disease', (152, 155))	('enhancer of filamentation 1', 'Gene', '4739', (93, 120))	('expression', 'Var', (67, 77))	('human', 'Species', '9606', (87, 92))	('HEF1', 'Gene', '4739', (81, 85))	('Wnt', 'Gene', (21, 24))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('modulate', 'Reg', (175, 183))	('HEF1', 'Gene', (81, 85))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('FAK', 'molecular_function', 'GO:0004717', ('29', '32'))	('Wnt', 'Gene', '34007', (21, 24))
98601	33266025	Both pathways were already described to independently play a role in MM by promoting different tumorigenic properties; dysregulated Wnt signaling was implicated in invasion and resistance to apoptosis, while FAK signaling was shown to promote invasion and EMT.	('Wnt', 'Gene', (132, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('191', '200'))	('apoptosis', 'biological_process', 'GO:0006915', ('191', '200'))	('signaling', 'biological_process', 'GO:0023052', ('212', '221'))	('promote', 'PosReg', (235, 242))	('Wnt', 'Gene', '34007', (132, 135))	('invasion', 'CPA', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('EMT', 'biological_process', 'GO:0001837', ('256', '259'))	('EMT', 'CPA', (256, 259))	('FAK', 'molecular_function', 'GO:0004717', ('208', '211'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('dysregulated', 'Var', (119, 131))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('FAK', 'MPA', (208, 211))	('tumor', 'Disease', (95, 100))
98603	33266025	The inhibition of FAK decreased the activation of the Wnt and NF-kappaB signaling pathways, accompanied by a reduction in inflammatory activity.	('Wnt', 'Gene', (54, 57))	('inflammatory activity', 'CPA', (122, 143))	('activation', 'PosReg', (36, 46))	('reduction', 'NegReg', (109, 118))	('Wnt', 'Gene', '34007', (54, 57))	('inhibition', 'Var', (4, 14))	('FAK', 'molecular_function', 'GO:0004717', ('18', '21'))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('FAK', 'Gene', (18, 21))	('decreased', 'NegReg', (22, 31))
98604	33266025	In another study using the same cell line, FAK was shown to act upstream the Wnt/beta-catenin pathway.	('Wnt', 'Gene', '34007', (77, 80))	('FAK', 'Var', (43, 46))	('Wnt', 'Gene', (77, 80))	('FAK', 'molecular_function', 'GO:0004717', ('43', '46'))
98622	33266025	APC is silenced by hypermethylation or mutated in about 70% of human breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('human', 'Species', '9606', (63, 68))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutated', 'Var', (39, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast cancers', 'Disease', 'MESH:D001943', (69, 83))	('hypermethylation', 'Var', (19, 35))	('breast cancers', 'Disease', (69, 83))
98623	33266025	Recently it was reported that APC mutation promoted mammary tumor cell proliferation in a PyMT mouse model through the activation of Src and JNK signaling downstream of FAK.	('APC', 'Gene', (30, 33))	('promoted', 'PosReg', (43, 51))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('FAK', 'molecular_function', 'GO:0004717', ('169', '172'))	('activation', 'PosReg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('JNK', 'molecular_function', 'GO:0004705', ('141', '144'))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('APC', 'Phenotype', 'HP:0005227', (30, 33))	('tumor', 'Disease', (60, 65))	('APC', 'cellular_component', 'GO:0005680', ('30', '33'))	('mouse', 'Species', '10090', (95, 100))
98624	33266025	In addition, inhibiting Src or JNK diminished the APC-mediated cell proliferation, suggesting that targeted inhibition of these signaling pathways downstream FAK appears as a promising strategy in APC-mutated breast cancers.	('APC', 'cellular_component', 'GO:0005680', ('197', '200'))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('APC', 'Phenotype', 'HP:0005227', (197, 200))	('diminished', 'NegReg', (35, 45))	('JNK', 'Gene', (31, 34))	('breast cancers', 'Disease', 'MESH:D001943', (209, 223))	('breast cancers', 'Disease', (209, 223))	('APC', 'cellular_component', 'GO:0005680', ('50', '53'))	('FAK', 'molecular_function', 'GO:0004717', ('158', '161'))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('JNK', 'molecular_function', 'GO:0004705', ('31', '34'))	('inhibiting', 'Var', (13, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('breast cancers', 'Phenotype', 'HP:0003002', (209, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('APC-mediated cell proliferation', 'CPA', (50, 81))	('APC', 'Phenotype', 'HP:0005227', (50, 53))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('Src', 'Protein', (24, 27))
98631	33266025	Deletion of FAK in hepatocytes blocks tumor proliferation and prolongs the survival in a c-Met/beta-catenin-driven hepatocellular carcinoma (HCC) mouse model, suggesting that FAK is required for c-Met/beta-catenin-driven hepatocarcinogenesis.	('FAK', 'Gene', (12, 15))	('FAK', 'molecular_function', 'GO:0004717', ('12', '15'))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('c-Met', 'Gene', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('c-Met', 'Gene', '17295', (195, 200))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (115, 139))	('hepatocarcinogenesis', 'Disease', (221, 241))	('Deletion', 'Var', (0, 8))	('blocks tumor', 'Disease', 'MESH:D006327', (31, 43))	('mouse', 'Species', '10090', (146, 151))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (115, 139))	('FAK', 'molecular_function', 'GO:0004717', ('175', '178'))	('blocks tumor', 'Disease', (31, 43))	('c-Met', 'Gene', (89, 94))	('prolongs', 'PosReg', (62, 70))	('survival', 'CPA', (75, 83))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (221, 241))	('c-Met', 'Gene', '17295', (89, 94))	('hepatocellular carcinoma', 'Disease', (115, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))
98632	33266025	More recently it was demonstrated that overexpressed FAK and beta-catenin cooperate to induce HCC in mice and that FAK functionally stimulates Wnt/beta-catenin signaling, activates CSC traits, and drives tumorigenicity in HCC cells.	('drives', 'PosReg', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('FAK', 'molecular_function', 'GO:0004717', ('115', '118'))	('CSC traits', 'MPA', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Wnt', 'Gene', (143, 146))	('HCC', 'Phenotype', 'HP:0001402', (222, 225))	('tumor', 'Disease', (204, 209))	('mice', 'Species', '10090', (101, 105))	('FAK', 'molecular_function', 'GO:0004717', ('53', '56'))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('activates', 'PosReg', (171, 180))	('HCC', 'Disease', (94, 97))	('FAK', 'Var', (115, 118))	('Wnt', 'Gene', '34007', (143, 146))	('stimulates', 'PosReg', (132, 142))
98634	33266025	This elevated pVE-cadherin (Y658) allows for upregulation of Kaiso-dependent genes in the nucleus (WNT11 and CCDN1), accelerating the vasculogenic mimicry capacity in these cells, which is associated with a high tumor grade, invasion, metastasis, and a short survival.	('Kaiso-dependent genes', 'Gene', (61, 82))	('elevated', 'PosReg', (5, 13))	('E-cadherin', 'Gene', (16, 26))	('WNT11', 'Gene', (99, 104))	('CCDN1', 'Gene', (109, 114))	('E-cadherin', 'Gene', '999', (16, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('nucleus', 'cellular_component', 'GO:0005634', ('90', '97'))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('vasculogenic mimicry capacity', 'CPA', (134, 163))	('accelerating', 'PosReg', (117, 129))	('WNT11', 'Gene', '7481', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('upregulation', 'PosReg', (45, 57))	('Y658', 'Var', (28, 32))
98640	33266025	Another study demonstrated that silencing Cripto-1 (CR-1) expression in prostate cancer cells, suppressed proliferation, migration, and invasion of these cells through the inhibition of both FAK/Src/PI3K and Wnt/beta-catenin signaling pathways.	('Wnt', 'Gene', (208, 211))	('suppressed', 'NegReg', (95, 105))	('migration', 'CPA', (121, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (72, 87))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('invasion', 'CPA', (136, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('silencing', 'Var', (32, 41))	('Wnt', 'Gene', '34007', (208, 211))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))	('CR-1', 'Gene', (52, 56))	('prostate cancer', 'Disease', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('proliferation', 'CPA', (106, 119))	('FAK', 'molecular_function', 'GO:0004717', ('191', '194'))	('inhibition', 'NegReg', (172, 182))
98642	33266025	In addition to the roles of Wnt signaling in development, dysregulated Wnt also contributes to cell proliferation, chemoresistance and enhanced tumorigenic potential of CSC, all of which are factors involved in tumor recurrence after therapy, resistance to further anticancer therapies, and poor survival.	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('enhanced', 'PosReg', (135, 143))	('Wnt', 'Gene', (28, 31))	('cancer', 'Disease', (269, 275))	('Wnt', 'Gene', '34007', (28, 31))	('cell proliferation', 'CPA', (95, 113))	('tumor', 'Disease', (144, 149))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('dysregulated', 'Var', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('chemoresistance', 'CPA', (115, 130))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Wnt', 'Gene', (71, 74))	('Wnt', 'Gene', '34007', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
98646	33266025	In general, agents targeting Wnt signaling include compounds at the ligand/receptor level (Vantictumab, Ipafricept, Rosmantuzumab, Foxy-5, and OTSA101-DTPA), transcriptional level (CWP232291, PRI-724, and SM08502) and at the level of Wnt secretion (Porcupine inhibitors: WNT974 and ETC-159, RXC004, and CGX1321) (Table 1) (for more details see additional reviews).	('secretion', 'biological_process', 'GO:0046903', ('238', '247'))	('Wnt', 'Gene', (29, 32))	('ligand', 'molecular_function', 'GO:0005488', ('68', '74'))	('Wnt', 'Gene', '34007', (29, 32))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('Rosmantuzumab', 'Chemical', '-', (116, 129))	('Wnt', 'Gene', (234, 237))	('OTSA101-DTPA', 'Chemical', '-', (143, 155))	('PRI-724', 'Chemical', 'MESH:C492448', (192, 199))	('Wnt', 'Gene', '34007', (234, 237))	('CWP232291', 'Var', (181, 190))	('Vantictumab', 'Chemical', '-', (91, 102))	('Foxy-5', 'Chemical', '-', (131, 137))
98653	33266025	Inhibitors at the transcriptional level include PRI-724, CWP232291 and SM08502.	('CWP232291', 'Var', (57, 66))	('SM08502', 'Var', (71, 78))	('PRI-724', 'Var', (48, 55))	('PRI-724', 'Chemical', 'MESH:C492448', (48, 55))
98654	33266025	While the small molecule PRI-724 inhibits the recruiting of beta-catenin with its coactivator CBP, the small-molecule CWP232291 (CWP291) binds to Sam68, decreasing the expression of beta-catenin target genes.	('decreasing', 'NegReg', (153, 163))	('recruiting', 'MPA', (46, 56))	('binds', 'Interaction', (137, 142))	('expression', 'MPA', (168, 178))	('CBP', 'Gene', (94, 97))	('beta-catenin', 'Protein', (60, 72))	('CBP', 'Gene', '1387', (94, 97))	('CWP291', 'Var', (129, 135))	('Sam68', 'Gene', '10657', (146, 151))	('Sam68', 'Gene', (146, 151))	('inhibits', 'NegReg', (33, 41))	('PRI-724', 'Chemical', 'MESH:C492448', (25, 32))	('CBP', 'molecular_function', 'GO:0008140', ('94', '97'))
98655	33266025	In a phase I study, CWP291 was considered safe and demonstrated single-agent activity in acute myeloid leukemia patients, with plans for future combination studies.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (95, 111))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (89, 111))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('patients', 'Species', '9606', (112, 120))	('acute myeloid leukemia', 'Disease', (89, 111))	('CWP291', 'Var', (20, 26))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (89, 111))
98658	33266025	The small molecule SM08502 was shown to reduce Wnt pathway signaling and gene expression through the potent inhibition of CDC-like kinase (CLK) activity and is currently in "recruiting" state in a phase I clinical trial for patients with advanced solid tumors (NCT03355066).	('Wnt', 'Gene', '34007', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('solid tumors', 'Disease', (247, 259))	('inhibition', 'NegReg', (108, 118))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('reduce', 'NegReg', (40, 46))	('Wnt', 'Gene', (47, 50))	('SM08502', 'Var', (19, 26))	('CLK', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('solid tumors', 'Disease', 'MESH:D009369', (247, 259))	('CDC-like kinase', 'Gene', '1195', (122, 137))	('patients', 'Species', '9606', (224, 232))	('CLK', 'Gene', '1195', (139, 142))	('gene expression', 'MPA', (73, 88))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('activity', 'MPA', (144, 152))	('CDC-like kinase', 'Gene', (122, 137))
98662	33266025	Wnt974 (LGK974) and ETC-159 are under phase I studies in "recruiting" state (NCT01351103 and NCT02521844, respectively).	('Wnt', 'Gene', '34007', (0, 3))	('Wnt', 'Gene', (0, 3))	('NCT01351103', 'Var', (77, 88))	('NCT02521844', 'Var', (93, 104))
98664	33266025	RXC004 and CGX1321, other potent selective orally bioavailable inhibitors of Porcupine, are also in "recruiting" state in phase I studies in patients with advanced solid tumors (NCT03447470 and NCT02675946, respectively).	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('patients', 'Species', '9606', (141, 149))	('solid tumors', 'Disease', (164, 176))	('NCT02675946', 'Var', (194, 205))	('NCT03447470', 'Var', (178, 189))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('solid tumors', 'Disease', 'MESH:D009369', (164, 176))	('CGX1321', 'Gene', (11, 18))
98665	33266025	Several other small molecules antagonizing the interaction between beta-catenin and TCF/LEF1, such as PNU74654, 2,4 diamino-quinazoline, PKF115-584, or CGP 049090, have been identified.	('antagonizing', 'NegReg', (30, 42))	('CGP', 'Var', (152, 155))	('interaction', 'Interaction', (47, 58))	('TCF/LEF1', 'Gene', '3172;51176', (84, 92))	('2,4 diamino-quinazoline', 'Chemical', 'MESH:C013474', (112, 135))	('beta-catenin', 'Protein', (67, 79))	('PNU74654', 'Chemical', '-', (102, 110))	('PKF115-584', 'Var', (137, 147))	('TCF/LEF1', 'Gene', (84, 92))	('PNU74654', 'Var', (102, 110))
98671	33266025	Secondly, we do not know whether the inhibition of Wnt signaling will activate resistance response mechanisms by other signaling pathways.	('Wnt', 'Gene', '34007', (51, 54))	('inhibition', 'Var', (37, 47))	('resistance response mechanisms', 'Pathway', (79, 109))	('activate', 'PosReg', (70, 78))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('Wnt', 'Gene', (51, 54))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))
98674	33266025	In the case of FAK inhibitors, translation in the clinical setting is more advanced: four adenosine triphosphate (ATP)-competitive, small-molecule inhibitors of FAK (GSK2256098, BI 853520, PF-00562271, and VS-6063), have been proven effective in several preclinical studies and have advanced into phase I and II clinical trials (Table 2).	('VS-6063', 'Var', (206, 213))	('PF-00562271', 'Var', (189, 200))	('BI 853520', 'Chemical', '-', (178, 187))	('adenosine', 'Chemical', 'MESH:D000241', (90, 99))	('FAK', 'molecular_function', 'GO:0004717', ('161', '164'))	('translation', 'biological_process', 'GO:0006412', ('31', '42'))	('FAK', 'molecular_function', 'GO:0004717', ('15', '18'))	('BI 853520', 'Var', (178, 187))	('GSK2256098', 'Var', (166, 176))	('FAK', 'Gene', (161, 164))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('GSK2256098', 'Chemical', 'MESH:C000600809', (166, 176))	('GSK', 'molecular_function', 'GO:0050321', ('166', '169'))
98676	33266025	In a phase I study (NCT01138033), GSK2256098 showed clinical activity in patients with malignant mesothelioma, particularly those with merlin (encoded by NF2) loss.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (87, 109))	('malignant mesothelioma', 'Disease', (87, 109))	('NF2', 'Gene', '4771', (154, 157))	('merlin', 'Gene', '4771', (135, 141))	('loss', 'NegReg', (159, 163))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('patients', 'Species', '9606', (73, 81))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (87, 109))	('merlin', 'Gene', (135, 141))	('NF2', 'Gene', (154, 157))	('GSK2256098', 'Chemical', 'MESH:C000600809', (34, 44))	('GSK2256098', 'Var', (34, 44))
98678	33266025	Mesothelioma patients with loss of merlin had longer progression-free survival than subjects with wild-type NF2, although support for efficacy with this combination was limited.	('longer', 'PosReg', (46, 52))	('loss', 'Var', (27, 31))	('merlin', 'Gene', '4771', (35, 41))	('NF2', 'Gene', (108, 111))	('patients', 'Species', '9606', (13, 21))	('merlin', 'Gene', (35, 41))	('NF2', 'Gene', '4771', (108, 111))	('progression-free survival', 'CPA', (53, 78))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
98680	33266025	Two studies have evaluated the effect of BI 853520 monotherapy in advanced or metastatic tumors (NCT01335269 and NCT01905111).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('advanced', 'Disease', (66, 74))	('BI 853520', 'Chemical', '-', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('NCT01335269', 'Var', (97, 108))	('BI 853520', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('NCT01905111', 'Var', (113, 124))
98681	33266025	These studies have demonstrated that BI 853520 has a manageable and acceptable safety profile and preliminary antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('BI 853520', 'Chemical', '-', (37, 46))	('BI 853520', 'Var', (37, 46))
98685	33266025	Although several attempts have been made in testing the effect of Defactinib in patients with malignant mesothelioma, due in part to the fact that merlin deficiency has been shown to predict FAK-inhibitor sensitivity, several trials were discontinued due to insufficient efficacy (NCT02004028, NCT01870609, and NCT02372227).	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (94, 116))	('patients', 'Species', '9606', (80, 88))	('predict', 'Reg', (183, 190))	('NCT01870609', 'Var', (294, 305))	('deficiency', 'Var', (154, 164))	('NCT02372227', 'Var', (311, 322))	('malignant mesothelioma', 'Disease', (94, 116))	('Defactinib', 'Chemical', 'MESH:C584510', (66, 76))	('merlin', 'Gene', (147, 153))	('FAK-inhibitor sensitivity', 'MPA', (191, 216))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (94, 116))	('FAK', 'molecular_function', 'GO:0004717', ('191', '194'))	('NCT02004028', 'Var', (281, 292))	('merlin', 'Gene', '4771', (147, 153))
98686	33266025	Nevertheless, a phase I study evaluating Defactinib in combination with the immune checkpoint inhibitor Pembrolizumab is planned for patients with pleural malignant mesothelioma (NCT04201145), and another phase II study is currently evaluating the effects of this drug as single agents in patients with NF2 mutations (NCT04439331).	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (155, 177))	('pleural malignant mesothelioma', 'Phenotype', 'HP:0100002', (147, 177))	('NF2', 'Gene', (303, 306))	('patients', 'Species', '9606', (133, 141))	('NCT04439331', 'Var', (318, 329))	('mutations (NCT04439331', 'Var', (307, 329))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (104, 117))	('pleural malignant mesothelioma', 'Disease', 'MESH:C562839', (147, 177))	('pleural malignant mesothelioma', 'Disease', (147, 177))	('NF2', 'Gene', '4771', (303, 306))	('Defactinib', 'Chemical', 'MESH:C584510', (41, 51))	('patients', 'Species', '9606', (289, 297))
98688	33266025	At present time, other phase I/II studies that are in "active" or "recruiting" phases, are evaluating the effects of Defactinib in combination with Pembrolizumab (NCT03727880 and NCT02758587), Pembrolizumab, and Gemcitabine (NCT02546531), or RAF/MEK inhibitors (NCT03875820) in patients with different advanced solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('solid tumors', 'Disease', (311, 323))	('Gemcitabine', 'Chemical', 'MESH:C056507', (212, 223))	('NCT02546531', 'Var', (225, 236))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (193, 206))	('RAF', 'Gene', '22882', (242, 245))	('RAF', 'Gene', (242, 245))	('NCT03875820', 'Var', (262, 273))	('solid tumors', 'Disease', 'MESH:D009369', (311, 323))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('MEK', 'Gene', (246, 249))	('patients', 'Species', '9606', (278, 286))	('MEK', 'Gene', '5609', (246, 249))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (148, 161))	('NCT03727880', 'Var', (163, 174))	('Defactinib', 'Chemical', 'MESH:C584510', (117, 127))
98698	33266025	Loss of PTEN causes the activation of the pro-survival pathway PI3K/AKT/mTOR, but results obtained with specific inhibitors of PI3K/AKT/mTOR are not so encouraging.	('pro-survival', 'biological_process', 'GO:0043066', ('42', '54'))	('AKT', 'Gene', '207', (132, 135))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('PTEN', 'Gene', (8, 12))	('PI3K', 'molecular_function', 'GO:0016303', ('127', '131'))	('PTEN', 'Gene', '5728', (8, 12))	('AKT', 'Gene', (132, 135))	('AKT', 'Gene', '207', (68, 71))	('activation', 'PosReg', (24, 34))	('Loss', 'Var', (0, 4))	('AKT', 'Gene', (68, 71))
98703	33266025	Pharmacological inhibition of FAK/PYK2 repressed adenoma formation in APCmin/+ mice and reduced phospho-GSK3beta and beta-catenin intestinal levels, decreasing Wnt signaling.	('Wnt', 'Gene', (160, 163))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('PYK2', 'Gene', (34, 38))	('PYK2', 'Gene', '19229', (34, 38))	('adenoma', 'Disease', 'MESH:D000236', (49, 56))	('mice', 'Species', '10090', (79, 83))	('Wnt', 'Gene', '34007', (160, 163))	('GSK', 'molecular_function', 'GO:0050321', ('104', '107'))	('APC', 'Phenotype', 'HP:0005227', (70, 73))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('adenoma', 'Disease', (49, 56))	('reduced', 'NegReg', (88, 95))	('FAK', 'molecular_function', 'GO:0004717', ('30', '33'))	('decreasing', 'NegReg', (149, 159))	('inhibition', 'Var', (16, 26))
98706	33266025	The inhibition of FAK blocks tumor proliferation and prolongs the survival in a c-Met/beta-catenin-driven hepatocellular carcinoma (HCC) mouse model, suggesting that inhibition of FAK might be beneficial for treating HCC, especially in patients showing activated beta-catenin.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('hepatocellular carcinoma', 'Disease', (106, 130))	('mouse', 'Species', '10090', (137, 142))	('inhibition', 'Var', (4, 14))	('blocks tumor', 'Disease', (22, 34))	('patients', 'Species', '9606', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('FAK', 'molecular_function', 'GO:0004717', ('180', '183'))	('FAK', 'molecular_function', 'GO:0004717', ('18', '21'))	('FAK', 'Gene', (18, 21))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (106, 130))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (106, 130))	('inhibition', 'Var', (166, 176))	('c-Met', 'Gene', (80, 85))	('prolongs', 'PosReg', (53, 61))	('survival', 'CPA', (66, 74))	('HCC', 'Disease', (217, 220))	('blocks tumor', 'Disease', 'MESH:D006327', (22, 34))	('c-Met', 'Gene', '17295', (80, 85))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))
98707	33266025	In various malignant mesothelioma cell lines, the pharmacological inhibition of both pathways decreased dramatically cell proliferation and survival, indicating that the simultaneous targeting of Wnt and FAK might be considered as a prospective strategy for malignant mesothelioma treatment.	('malignant mesothelioma', 'Disease', (11, 33))	('FAK', 'molecular_function', 'GO:0004717', ('204', '207'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (258, 280))	('cell proliferation', 'CPA', (117, 135))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (11, 33))	('decreased', 'NegReg', (94, 103))	('inhibition', 'Var', (66, 76))	('Wnt', 'Gene', (196, 199))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (258, 280))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (11, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('Wnt', 'Gene', '34007', (196, 199))	('malignant mesothelioma', 'Disease', (258, 280))
98725	31371807	Genomic characterization identified several subgroups: (1) BAP1 mutations with deletions of CDKN2A and NF2 in two tumors; (2) TRAF7 mutations in two tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and (3) genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7.	('CDKN2A', 'Gene', '1029', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('TRAF7', 'Gene', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('NF2', 'Gene', '4771', (103, 106))	('near-haploidization', 'Var', (238, 257))	('NF2', 'Gene', (103, 106))	('haploidization', 'biological_process', 'GO:0090485', ('243', '257'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('mutations', 'Var', (64, 73))	('BAP1', 'Gene', '8314', (59, 63))	('deletions', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('CDKN2A', 'Gene', (92, 98))	('TRAF7', 'Gene', '84231', (126, 131))	('BAP1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (132, 141))	('tumors', 'Disease', (114, 120))
98728	31371807	Genomic near-haploidization, identified recently in a subset of diffuse malignant pleural mesotheliomas, suggests a novel mechanism in the pathogenesis of both localized pleural mesothelioma and diffuse malignant pleural mesothelioma.	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (82, 103))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (82, 102))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (72, 103))	('malignant pleural mesothelioma', 'Disease', (203, 233))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (203, 233))	('localized pleural mesothelioma', 'Disease', (160, 190))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (213, 233))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (72, 102))	('haploidization', 'biological_process', 'GO:0090485', ('13', '27'))	('localized pleural mesothelioma', 'Disease', 'MESH:D054363', (160, 190))	('pathogenesis', 'biological_process', 'GO:0009405', ('139', '151'))	('near-haploidization', 'Var', (8, 27))	('malignant pleural mesotheliomas', 'Disease', (72, 103))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (170, 190))
98734	31371807	Several studies have extensively profiled the genomic features of diffuse malignant pleural mesothelioma and uncovered recurrent mutations in BAP1, NF2, TP53, SETD2, and others, along with frequent deletions of CDKN2A and NF2.	('malignant pleural mesothelioma', 'Disease', (74, 104))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (84, 104))	('NF2', 'Gene', '4771', (222, 225))	('BAP1', 'Gene', '8314', (142, 146))	('CDKN2A', 'Gene', (211, 217))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', '7157', (153, 157))	('CDKN2A', 'Gene', '1029', (211, 217))	('NF2', 'Gene', (148, 151))	('BAP1', 'Gene', (142, 146))	('TP53', 'Gene', (153, 157))	('SETD2', 'Gene', '29072', (159, 164))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (74, 104))	('NF2', 'Gene', (222, 225))	('NF2', 'Gene', '4771', (148, 151))	('SETD2', 'Gene', (159, 164))
98746	31371807	The sequencing panel covered exonic sequences from 447 cancer-related genes for single-nucleotide and copy-number alterations, as well as 191 regions across 60 genes for rearrangement detection; the entire gene list has been published.	('men', 'Species', '9606', (179, 182))	('copy-number alterations', 'Var', (102, 125))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('single-nucleotide', 'Var', (80, 97))	('cancer', 'Disease', (55, 61))
98783	31371807	Localized pleural mesotheliomas comprised distinct and apparently mutually exclusive genetic subgroups: first, BAP1 mutations with deletions of CDKN2A and NF2 in two tumors (Cases 1 and 2, Fig.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('BAP1', 'Gene', '8314', (111, 115))	('NF2', 'Gene', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (10, 31))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (10, 30))	('CDKN2A', 'Gene', (144, 150))	('BAP1', 'Gene', (111, 115))	('NF2', 'Gene', '4771', (155, 158))	('mutations', 'Var', (116, 125))	('Localized pleural mesotheliomas', 'Disease', (0, 31))	('CDKN2A', 'Gene', '1029', (144, 150))	('deletions', 'Var', (131, 140))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('Localized pleural mesotheliomas', 'Disease', 'MESH:D054363', (0, 31))
98784	31371807	1); second, TRAF7 mutations in two tumors (Cases 3 and 4, Fig.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TRAF7', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('TRAF7', 'Gene', '84231', (12, 17))	('mutations', 'Var', (18, 27))
98785	31371807	1); and third, genomic near-haploidization in the remainder one tumor (Case 5, Fig.	('tumor', 'Disease', (64, 69))	('genomic near-haploidization', 'Var', (15, 42))	('haploidization', 'biological_process', 'GO:0090485', ('28', '42'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('near-haploidization', 'Var', (23, 42))
98787	31371807	BAP1 alterations detected included a focal two-copy deletion in one tumor and a nonsense mutation p.L137* in the other tumor.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (119, 124))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('p.L137*', 'Mutation', 'p.L137*', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p.L137*', 'Var', (98, 105))	('BAP1', 'Gene', '8314', (0, 4))
98790	31371807	Other concurrent mutations in the BAP1-mutated tumors included SETD2 nonsense mutation p.R2040* in Case 1 and PTEN nonsense mutation p.Q17* in Case 2 (Fig.	('PTEN', 'Gene', '5728', (110, 114))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('BAP1', 'Gene', (34, 38))	('p.R2040*', 'Mutation', 'p.R2040*', (87, 95))	('p.Q17*', 'Mutation', 'p.Q17*', (133, 139))	('p.Q17*', 'Var', (133, 139))	('SETD2', 'Gene', '29072', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('p.R2040*', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SETD2', 'Gene', (63, 68))	('BAP1', 'Gene', '8314', (34, 38))	('PTEN', 'Gene', (110, 114))
98791	31371807	1); the PTEN mutation was considered sub-clonal in view of its allelic fraction at 4%, as compared to that of the BAP1 mutation at 18%.	('mutation', 'Var', (13, 21))	('PTEN', 'Gene', (8, 12))	('BAP1', 'Gene', '8314', (114, 118))	('PTEN', 'Gene', '5728', (8, 12))	('BAP1', 'Gene', (114, 118))
98792	31371807	Furthermore, homozygous deletion of CDKN2A and deletion of NF2 was detected by single nucleotide polymorphism array (Fig.	('CDKN2A', 'Gene', (36, 42))	('NF2', 'Gene', (59, 62))	('CDKN2A', 'Gene', '1029', (36, 42))	('NF2', 'Gene', '4771', (59, 62))	('deletion', 'Var', (47, 55))	('deletion', 'Var', (24, 32))
98797	31371807	Notably, two BAP1-wild-type tumors harbored mutations in TRAF7, including the pathogenic mutation p.S561R in Case 3 and the mutation p.Q613E in Case 4.	('BAP1', 'Gene', (13, 17))	('p.S561R', 'Var', (98, 105))	('p.Q613E', 'Var', (133, 140))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('TRAF7', 'Gene', (57, 62))	('BAP1', 'Gene', '8314', (13, 17))	('p.S561R', 'Mutation', 'p.S561R', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('p.Q613E', 'Mutation', 'p.Q613E', (133, 140))	('TRAF7', 'Gene', '84231', (57, 62))
98798	31371807	For each of the two TRAF7 mutations, its allelic fraction was 15%, consistent with a somatic heterozygous mutation (given an estimated tumor cellularity of 30-40%).	('TRAF7', 'Gene', '84231', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('mutations', 'Var', (26, 35))	('TRAF7', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
98799	31371807	The localized pleural mesothelioma with TRAF7 p.Q613E also demonstrated a distinct karyotype with trisomies of chromosomes 3, 5, 7 and X, as detected by single nucleotide polymorphism array (Fig.	('p.Q613E', 'Var', (46, 53))	('TRAF7', 'Gene', (40, 45))	('localized pleural mesothelioma', 'Disease', 'MESH:D054363', (4, 34))	('p.Q613E', 'Mutation', 'p.Q613E', (46, 53))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (14, 34))	('localized pleural mesothelioma', 'Disease', (4, 34))	('TRAF7', 'Gene', '84231', (40, 45))
98800	31371807	No evidence of loss of heterozygosity or segmental chromosomal deletion (including BAP1, CDKN2A/CDKN2B, and NF2 loci) was noted by single nucleotide polymorphism array (Fig.	('CDKN2B', 'Gene', '1030', (96, 102))	('NF2', 'Gene', (108, 111))	('BAP1', 'Gene', (83, 87))	('CDKN2A', 'Gene', (89, 95))	('NF2', 'Gene', '4771', (108, 111))	('single nucleotide polymorphism', 'Var', (131, 161))	('men', 'Species', '9606', (44, 47))	('CDKN2A', 'Gene', '1029', (89, 95))	('CDKN2B', 'Gene', (96, 102))	('BAP1', 'Gene', '8314', (83, 87))
98803	31371807	This near-haploid tumor harbored an NF2 p.H116P mutation, considered to be a variant of unknown significance.	('NF2', 'Gene', '4771', (36, 39))	('p.H116P', 'Mutation', 'p.H116P', (40, 47))	('NF2', 'Gene', (36, 39))	('p.H116P', 'Var', (40, 47))	('haploid tumor', 'Disease', (10, 23))	('haploid tumor', 'Disease', 'MESH:D009369', (10, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
98805	31371807	The five tumors had a median tumor mutational burden of 3.0 (range 0.8-3.8) non-synonymous mutations per megabase sequenced.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('non-synonymous mutations', 'Var', (76, 100))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
98807	31371807	No structural rearrangements (including the NAB2-STAT6 fusion pathognomonic of solitary fibrous tumors or rearrangements in ALK or EWSR1/FUS present in some peritoneal/pleural mesotheliomas) were detected in the five tumors with available sequencing data.	('NAB2', 'Gene', '4665', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('STAT6', 'Gene', (49, 54))	('fibrous tumors', 'Disease', 'MESH:D054364', (88, 102))	('ALK', 'Gene', '238', (124, 127))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Disease', (96, 102))	('men', 'Species', '9606', (115, 118))	('fibrous tumors', 'Disease', (88, 102))	('FUS', 'Gene', (137, 140))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (168, 188))	('ALK', 'Gene', (124, 127))	('EWSR1', 'Gene', (131, 136))	('STAT6', 'Gene', '6778', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('FUS', 'Gene', '2521', (137, 140))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (168, 189))	('men', 'Species', '9606', (23, 26))	('rearrangements', 'Var', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('NAB2', 'Gene', (44, 48))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (168, 189))	('EWSR1', 'Gene', '2130', (131, 136))	('pleural mesotheliomas', 'Disease', (168, 189))
98811	31371807	Two BAP1-mutated localized pleural mesotheliomas harbor other alterations typical of diffuse malignant pleural mesotheliomas, such as mutation in SETD2 and copy-number loss of CDKN2A and NF2.	('malignant pleural mesotheliomas', 'Disease', (93, 124))	('BAP1', 'Gene', (4, 8))	('NF2', 'Gene', (187, 190))	('localized pleural mesotheliomas', 'Disease', (17, 48))	('mutation', 'Var', (134, 142))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (93, 124))	('copy-number loss', 'Var', (156, 172))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (27, 47))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (27, 48))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (103, 124))	('SETD2', 'Gene', '29072', (146, 151))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (103, 123))	('CDKN2A', 'Gene', (176, 182))	('localized pleural mesotheliomas', 'Disease', 'MESH:D054363', (17, 48))	('SETD2', 'Gene', (146, 151))	('NF2', 'Gene', '4771', (187, 190))	('BAP1', 'Gene', '8314', (4, 8))	('CDKN2A', 'Gene', '1029', (176, 182))
98829	31371807	Recurrent BAP1 mutations, often somatic and rarely germline in the setting of BAP1 tumor predisposition syndrome, are present in 40-70% of diffuse malignant mesotheliomas of the pleura and the peritoneum, as well as a subset of uveal melanoma, cutaneous spitzoid lesions, renal cell carcinoma, and cholangiocarcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (272, 292))	('BAP1', 'Gene', (10, 14))	('tumor', 'Disease', (83, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (298, 316))	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('BAP1', 'Gene', '8314', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('malignant mesotheliomas of the pleura', 'Disease', 'MESH:C562839', (147, 184))	('malignant mesotheliomas of the pleura', 'Disease', (147, 184))	('cholangiocarcinoma', 'Disease', (298, 316))	('cutaneous spitzoid lesions', 'Disease', (244, 270))	('diffuse', 'Disease', (139, 146))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (147, 170))	('mutations', 'Var', (15, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (298, 316))	('present', 'Reg', (118, 125))	('renal cell carcinoma', 'Disease', (272, 292))	('BAP1', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (272, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('BAP1', 'Gene', '8314', (10, 14))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('uveal melanoma', 'Disease', (228, 242))
98831	31371807	Recurrent mutations in TRAF7 are present in a subset of meningiomas, intraneural perineuriomas, well-differentiated papillary mesotheliomas, most adenomatoid tumors of the genital type, and rare cases of diffuse malignant pleural mesothelioma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('intraneural perineuriomas', 'Disease', (69, 94))	('intraneural perineuriomas', 'Disease', 'MESH:D010524', (69, 94))	('malignant pleural mesothelioma', 'Disease', (212, 242))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (212, 242))	('meningiomas', 'Disease', 'MESH:D008577', (56, 67))	('TRAF7', 'Gene', (23, 28))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (222, 242))	('meningiomas', 'Disease', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (146, 164))	('adenomatoid tumors', 'Disease', (146, 164))	('TRAF7', 'Gene', '84231', (23, 28))	('meningiomas', 'Phenotype', 'HP:0002858', (56, 67))	('mutations', 'Var', (10, 19))	('present', 'Reg', (33, 40))	('papillary mesotheliomas', 'Disease', (116, 139))	('papillary mesotheliomas', 'Disease', 'MESH:D008654', (116, 139))
98832	31371807	The two TRAF7 mutations p.S561R and p.Q613E in localized pleural mesotheliomas are located in one of the seven C-terminal WD40 domain repeats.	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (57, 78))	('p.Q613E', 'Var', (36, 43))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (57, 77))	('TRAF7', 'Gene', (8, 13))	('p.S561R', 'Mutation', 'p.S561R', (24, 31))	('localized pleural mesotheliomas', 'Disease', 'MESH:D054363', (47, 78))	('TRAF7', 'Gene', '84231', (8, 13))	('p.Q613E', 'Mutation', 'p.Q613E', (36, 43))	('p.S561R', 'Var', (24, 31))	('localized pleural mesotheliomas', 'Disease', (47, 78))
98833	31371807	In fact, the pathogenic p. S561R mutation is the most common TRAF7 alteration in adenomatoid tumors of the genital type and intraneural perineuriomas.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TRAF7', 'Gene', (61, 66))	('S561R', 'SUBSTITUTION', 'None', (27, 32))	('S561R', 'Var', (27, 32))	('adenomatoid tumors of the genital type and intraneural perineuriomas', 'Disease', 'MESH:D010524', (81, 149))	('common', 'Reg', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('pathogenic', 'Reg', (13, 23))	('TRAF7', 'Gene', '84231', (61, 66))
98834	31371807	While the functional role of the TRAF7 p.Q613E mutation has not been clearly established, similar mutations nearby, such as p.K615E, are pathogenic in a subset of meningiomas.	('p.K615E', 'Mutation', 'p.K615E', (124, 131))	('meningiomas', 'Disease', 'MESH:D008577', (163, 174))	('p.Q613E', 'Var', (39, 46))	('meningiomas', 'Disease', (163, 174))	('p.K615E', 'Var', (124, 131))	('TRAF7', 'Gene', (33, 38))	('TRAF7', 'Gene', '84231', (33, 38))	('meningiomas', 'Phenotype', 'HP:0002858', (163, 174))	('p.Q613E', 'Mutation', 'p.Q613E', (39, 46))	('pathogenic', 'Reg', (137, 147))
98835	31371807	Nonetheless, except for one TRAF7/NF2 co-mutant diffuse malignant pleural mesothelioma in Bueno et al., all TRAF7-mutant mesothelial tumors described to date lack mutations in BAP1, NF2, SETD2, and TP53, implicating TRAF7 as a novel driver in the pathogenesis of these mesothelial lesions.	('NF2', 'Gene', (34, 37))	('SETD2', 'Gene', (187, 192))	('TRAF7', 'Gene', '84231', (28, 33))	('NF2', 'Gene', '4771', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('malignant pleural mesothelioma', 'Disease', (56, 86))	('BAP1', 'Gene', (176, 180))	('TRAF7', 'Gene', '84231', (108, 113))	('SETD2', 'Gene', '29072', (187, 192))	('TRAF7', 'Gene', '84231', (216, 221))	('NF2', 'Gene', (182, 185))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', '7157', (198, 202))	('TRAF7', 'Gene', (28, 33))	('TRAF7', 'Gene', (108, 113))	('pathogenesis', 'biological_process', 'GO:0009405', ('247', '259'))	('tumors', 'Disease', (133, 139))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (56, 86))	('TRAF7', 'Gene', (216, 221))	('lack', 'NegReg', (158, 162))	('mutations', 'Var', (163, 172))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('BAP1', 'Gene', '8314', (176, 180))	('NF2', 'Gene', '4771', (34, 37))	('TP53', 'Gene', (198, 202))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (66, 86))
98836	31371807	In a subset of tumors, genome endo-reduplication ensues, leading to copy-number-neutral uniparental disomy.	('uniparental disomy', 'Disease', 'MESH:D024182', (88, 106))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('leading to', 'Reg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('copy-number-neutral', 'Var', (68, 87))	('uniparental disomy', 'Disease', (88, 106))	('tumors', 'Disease', (15, 21))
98838	31371807	Of 154 diffuse malignant pleural mesotheliomas in the combined The Cancer Genome Atlas (TCGA) and Japanese International Cancer Genome Consortium (ICGC) cohorts, genomic near-haploidization is identified in five (3.2%).	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('haploidization', 'biological_process', 'GO:0090485', ('175', '189'))	('malignant pleural mesotheliomas', 'Disease', (15, 46))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (25, 45))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Cancer', 'Disease', (121, 127))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (25, 46))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (15, 46))	('Cancer', 'Disease', 'MESH:D009369', (121, 127))	('Cancer', 'Disease', (67, 73))	('near-haploidization', 'Var', (170, 189))
98840	31371807	Similar to our case of near-haploid localized pleural mesothelioma, the near-haploid diffuse malignant pleural and peritoneal mesotheliomas almost always retain chromosomes 5 and 7.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (46, 66))	('mesotheliomas', 'Disease', 'MESH:D008654', (126, 139))	('mesotheliomas', 'Disease', (126, 139))	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (115, 139))	('localized pleural mesothelioma', 'Disease', (36, 66))	('chromosomes', 'Var', (161, 172))	('malignant pleural', 'Disease', 'MESH:D016066', (93, 110))	('localized pleural mesothelioma', 'Disease', 'MESH:D054363', (36, 66))	('malignant pleural', 'Disease', (93, 110))
98841	31371807	Notably, our case of TRAF7 p.Q613E-mutated localized pleural mesothelioma is trisomic for chromosomes 3, 5, 7 and X, with no evidence of genomic near-haploidization.	('haploidization', 'biological_process', 'GO:0090485', ('150', '164'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (53, 73))	('TRAF7', 'Gene', '84231', (21, 26))	('p.Q613E-mutated', 'Var', (27, 42))	('p.Q613E', 'Mutation', 'p.Q613E', (27, 34))	('localized pleural mesothelioma', 'Disease', 'MESH:D054363', (43, 73))	('localized pleural mesothelioma', 'Disease', (43, 73))	('TRAF7', 'Gene', (21, 26))
98851	32021524	It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('activity', 'MPA', (193, 201))	('reduce', 'NegReg', (182, 188))	('epigenetic alterations', 'Var', (154, 176))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('genetic', 'MPA', (142, 149))	('oxygen', 'Chemical', 'MESH:D010100', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))
98853	32021524	So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer.	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('epigenetic', 'Var', (77, 87))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))
98855	32021524	Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers.	('cancer', 'Disease', (87, 93))	('cancers', 'Disease', (87, 94))	('Epigenetic aberrations', 'Var', (0, 22))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
98856	32021524	It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancer', 'Disease', (117, 128))	('epigenetic changes', 'Var', (42, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
98857	32021524	Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum.	('epigenetic alterations', 'Var', (54, 76))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
98859	32021524	Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('epigenetic aberrations', 'Var', (19, 41))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
98878	32021524	The identification of genetic alterations in lung cancers allows clinicians to select optimal treatments tailored to an individual's pathology.	('lung cancers', 'Disease', (45, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('genetic alterations', 'Var', (22, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('lung cancers', 'Disease', 'MESH:D008175', (45, 57))	('lung cancers', 'Phenotype', 'HP:0100526', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
98880	32021524	Amongst these biomarkers, alterations in EGFR, ALK, ROS1 and BRAF genes are currently the most relevant in clinical practice with clinically effective specific targeted treatments available.	('EGFR', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (61, 65))	('ALK', 'Gene', (47, 50))	('alterations', 'Var', (26, 37))	('BRAF', 'Gene', (61, 65))	('ROS1', 'Gene', (52, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('ROS1', 'Gene', '6098', (52, 56))	('ALK', 'Gene', '238', (47, 50))	('EGFR', 'Gene', '1956', (41, 45))
98881	32021524	EGFR mutations for example, present in approximately 15% of patients with adenocarcinoma in Western countries and over 50% in some Asian populations, have been managed with first generation EGFR tyrosine kinase inhibitors (TKIs) (e.g.	('adenocarcinoma', 'Disease', (74, 88))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('mutations', 'Var', (5, 14))	('adenocarcinoma', 'Disease', 'MESH:D000230', (74, 88))	('EGFR', 'Gene', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('tyrosine', 'Chemical', 'None', (195, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EGFR', 'Gene', '1956', (0, 4))
98883	32021524	These agents traditionally proved ineffective in tumours with T790M EGFR mutations, though third generation agents (e.g.	('tumours', 'Disease', (49, 56))	('EGFR', 'Gene', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('EGFR', 'Gene', '1956', (68, 72))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('T790M', 'Mutation', 'rs121434569', (62, 67))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('T790M', 'Var', (62, 67))
98884	32021524	osimertinib) have proven capable of not only overcoming the development of this resistance mutation, but offer improved progression free survival over first generation agents in treatment naive EGFR mutation positive populations, with or without a T790M mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('194', '198'))	('progression free survival', 'CPA', (120, 145))	('overcoming', 'PosReg', (45, 55))	('improved', 'PosReg', (111, 119))	('mutation', 'Var', (199, 207))	('EGFR', 'Gene', '1956', (194, 198))	('T790M', 'Mutation', 'rs121434569', (248, 253))	('EGFR', 'Gene', (194, 198))	('T790M', 'Var', (248, 253))	('osimertinib', 'Chemical', 'None', (0, 11))
98885	32021524	Additional driver mutations are currently under investigation with preliminary evidence of treatment efficacy when targeted therapies are utilised, including HER2 mutations, MET14 mutation or amplification, and RET rearrangements, whilst RAS and PIK3CA mutations may confer worse prognosis and response to other therapies (e.g.	('RET', 'Gene', (211, 214))	('PIK3CA', 'Gene', '5290', (246, 252))	('mutations', 'Var', (163, 172))	('HER2', 'Gene', (158, 162))	('RET', 'Gene', '5979', (211, 214))	('amplification', 'Var', (192, 205))	('HER2', 'Gene', '2064', (158, 162))	('MET14', 'Gene', (174, 179))	('rearrangements', 'Var', (215, 229))	('PIK3CA', 'Gene', (246, 252))
98887	32021524	It is hoped that future characterisation of epigenetic alterations will increase the number of targetable individual cancers for which a potentially beneficial treatment can be identified.	('increase', 'PosReg', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('epigenetic alterations', 'Var', (44, 66))	('cancers', 'Disease', (117, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))
98892	32021524	The chronic inflammation caused by exposure of serosal surfaces to asbestos fibres is likely to represent a central factor in the carcinogenesis and is likely to be mediated through epigenetic changes.	('inflammation', 'Disease', 'MESH:D007249', (12, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('inflammation', 'Disease', (12, 24))	('carcinogenesis', 'Disease', (130, 144))	('inflammation', 'biological_process', 'GO:0006954', ('12', '24'))	('epigenetic', 'Var', (182, 192))
98893	32021524	Many studies have investigated microRNAs associated with asbestos induced epigenetic alteration in mesothelioma (a highly specific cancer induced by asbestos exposure).	('cancer', 'Disease', (131, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('epigenetic alteration', 'Var', (74, 95))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('mesothelioma', 'Disease', (99, 111))
98896	32021524	Dysregulation of epigenetic transcriptional control, particularly aberrant promoter DNA methylation and histone modifications, is a fundamental feature of human malignancies.	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('histone modifications', 'MPA', (104, 125))	('malignancies', 'Disease', (161, 173))	('human', 'Species', '9606', (155, 160))	('aberrant', 'Var', (66, 74))	('transcriptional control', 'biological_process', 'GO:0006355', ('28', '51'))	('promoter DNA', 'MPA', (75, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('84', '99'))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
98897	32021524	Many cancers present with a global DNA hypomethylation of non-coding regions, and site-specific hypermethylation of CpG islands (CGI) in tumour suppressor regions.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('tumour', 'Disease', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('35', '54'))	('hypermethylation', 'Var', (96, 112))
98898	32021524	To what extent epigenetic changes cause carcinogenesis is currently being investigated.	('carcinogenesis', 'Disease', (40, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('epigenetic changes', 'Var', (15, 33))
98903	32021524	Promoter hypermethylation has been linked to the silencing of tumour suppressor genes and oncogenesis.	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('linked', 'Reg', (35, 41))	('silencing', 'MPA', (49, 58))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('oncogenesis', 'CPA', (90, 101))	('oncogenesis', 'biological_process', 'GO:0007048', ('90', '101'))	('Promoter hypermethylation', 'Var', (0, 25))
98905	32021524	These differentially methylated CpGs (DMCs) are consistently methylated in a non-cancer group, and variably methylated in cancer groups, with the highly variable CpGs hypothesised to contribute to tumour heterogeneity.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('CpGs', 'Chemical', 'MESH:C024660', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (81, 87))	('tumour', 'Disease', (197, 203))	('CpGs', 'Chemical', 'MESH:C024660', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('differentially methylated', 'Var', (6, 31))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
98907	32021524	There are a number of epigenetic biomarkers that show potential for the early detection of cancers due to their involvement in the initiation of carcinogenic pathways.	('initiation of carcinogenic', 'Disease', (131, 157))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('epigenetic', 'Var', (22, 32))	('involvement', 'Reg', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('initiation of carcinogenic', 'Disease', 'MESH:D011230', (131, 157))
98908	32021524	Amongst all epigenetic alterations in cancer, aberrant DNA hypermethylation is more studied than aberrant hypomethylation, and diagnostic tests being developed also tend to look for hypermethylated regions rather than hypomethylated ones.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('55', '75'))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('aberrant', 'Var', (46, 54))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
98910	32021524	Studies have shown that epigenetic alterations (Figure 1), especially DNA methylation, can be used to identify patients at risk of developing lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('DNA methylation', 'biological_process', 'GO:0006306', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('DNA', 'MPA', (70, 73))	('epigenetic alterations', 'Var', (24, 46))	('patients', 'Species', '9606', (111, 119))
98914	32021524	Lung cancer cases with no documented occupational exposure to asbestos have been found to have larger methylation variability and a higher proportion of hypomethylated DVMCs than asbestos-exposed subjects.	('methylation variability', 'MPA', (102, 125))	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('hypomethylated', 'Var', (153, 167))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('larger', 'PosReg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
98923	32021524	Hypomethylation of TPO was observed in asbestos-associated lung tumours.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('Hypomethylation', 'Var', (0, 15))	('lung tumours', 'Disease', (59, 71))	('observed', 'Reg', (27, 35))	('TPO', 'Gene', '7173', (19, 22))	('TPO', 'Gene', (19, 22))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('lung tumours', 'Disease', 'MESH:D008175', (59, 71))
98929	32021524	Of all the known types of epigenetic alterations, DNA methylation is the most widely studied in cancer due to the stability of DNA and it being readily detectable in blood circulation.	('blood circulation', 'biological_process', 'GO:0008015', ('166', '183'))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('methylation', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('DNA', 'Var', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
98935	32021524	TMEFF2 is inactivated through hypermethylation in many cancers including NSCLC and is common in non-EGFR mutated patients who have never smoked.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('EGFR', 'Gene', '1956', (100, 104))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('patients', 'Species', '9606', (113, 121))	('EGFR', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('TMEFF2', 'Gene', '23671', (0, 6))	('NSCLC', 'Disease', (73, 78))	('TMEFF2', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('hypermethylation', 'Var', (30, 46))	('cancers', 'Disease', (55, 62))
98936	32021524	RASFF1A hypermethylation was detected in 33.8% of NSCLC patients and not in healthy control benign pulmonary disease.	('patients', 'Species', '9606', (56, 64))	('hypermethylation', 'Var', (8, 24))	('pulmonary disease', 'Disease', 'MESH:D008171', (99, 116))	('detected', 'Reg', (29, 37))	('NSCLC', 'Disease', (50, 55))	('pulmonary disease', 'Disease', (99, 116))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('RASFF1A', 'Gene', (0, 7))
98941	32021524	Studies suggest that epigenetic dysregulation may contribute to drug-resistance in subpopulations of cells within the heterogeneous tumour population.	('tumour', 'Disease', (132, 138))	('contribute', 'Reg', (50, 60))	('drug-resistance', 'biological_process', 'GO:0042493', ('64', '79'))	('epigenetic dysregulation', 'Var', (21, 45))	('drug-resistance', 'biological_process', 'GO:0009315', ('64', '79'))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('drug-resistance', 'Phenotype', 'HP:0020174', (64, 79))	('drug-resistance', 'MPA', (64, 79))
98946	32021524	The results of a phase I/II study of azacytidine and etinostat combination therapy in 45 heavily pre-treated advanced NSCLC patients indicate that combinations with low-dose epigenetic therapy may be beneficial for treating solid tumours.	('etinostat', 'Chemical', 'None', (53, 62))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('solid tumours', 'Disease', 'MESH:D009369', (224, 237))	('NSCLC', 'Disease', (118, 123))	('epigenetic', 'Var', (174, 184))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('solid tumours', 'Disease', (224, 237))	('azacytidine', 'Chemical', 'MESH:D001374', (37, 48))	('pre', 'molecular_function', 'GO:0003904', ('97', '100'))	('patients', 'Species', '9606', (124, 132))	('combinations', 'Interaction', (147, 159))
98947	32021524	In summary, DNA methylation and microRNA alterations are key epigenetic alteration features in asbestos-related lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancers', 'Disease', 'MESH:D008175', (112, 124))	('microRNA', 'MPA', (32, 40))	('DNA methylation', 'Var', (12, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancers', 'Phenotype', 'HP:0100526', (112, 124))	('DNA methylation', 'biological_process', 'GO:0006306', ('12', '27'))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('lung cancers', 'Disease', (112, 124))
98959	27753121	UF6 does react violently with water or moisture in the atmosphere, resulting in uranyl fluoride (UO2F2), a soluble uranium compound and the primary exposure of interest in this study.	('resulting in', 'Reg', (67, 79))	('uranium', 'Chemical', 'MESH:D014501', (115, 122))	('UF6', 'Var', (0, 3))	('UO2F2', 'Chemical', '-', (97, 102))	('water', 'Chemical', 'MESH:D014867', (30, 35))	('uranyl fluoride', 'Chemical', 'MESH:C036637', (80, 95))	('UF6', 'Chemical', 'MESH:C036638', (0, 3))	('soluble', 'cellular_component', 'GO:0005625', ('107', '114'))
99167	23346982	Suquet reported on the assessment of the structural damage produced by grinding or acid leaching of chrysotile.	('men', 'Species', '9606', (29, 32))	('grinding', 'Var', (71, 79))	('acid', 'MPA', (83, 87))	('structural', 'MPA', (41, 51))
99276	23346982	In addition, one-third of the animals treated with long fibers developed pulmonary tumors or mesothelioma while no pulmonary neoplasms were found in the animals treated with short fibers.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pulmonary tumors', 'Disease', 'MESH:D008175', (73, 89))	('pulmonary tumors', 'Disease', (73, 89))	('pulmonary neoplasms', 'Disease', (115, 134))	('pulmonary neoplasms', 'Phenotype', 'HP:0100526', (115, 134))	('pulmonary neoplasms', 'Disease', 'MESH:D008175', (115, 134))	('pulmonary tumors', 'Phenotype', 'HP:0100526', (73, 89))	('mesothelioma', 'Disease', (93, 105))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('long fibers', 'Var', (51, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('neoplasms', 'Phenotype', 'HP:0002664', (125, 134))
99297	23346982	By comparison, after chronic inhalation exposure of rats to another CMS fiber, X607 fiber, which had considerably fewer non-fibrous particles present (particles with an aspect ration of < 3:1), no lung tumors or fibrosis was detected (Hesterberg et al.,).	('lung tumors', 'Disease', (197, 208))	('rat', 'Species', '10116', (52, 55))	('fibrosis', 'Disease', (212, 220))	('rat', 'Species', '10116', (176, 179))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('lung tumors', 'Phenotype', 'HP:0100526', (197, 208))	('fibrosis', 'Disease', 'MESH:D005355', (212, 220))	('rats', 'Species', '10116', (52, 56))	('X607 fiber', 'Var', (79, 89))	('lung tumors', 'Disease', 'MESH:D008175', (197, 208))	('lung tumor', 'Phenotype', 'HP:0100526', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
99316	23346982	The long chrysotile fibers (L > 20 mum) cleared rapidly (T 1/2 of 4.5 d) and were not observed in the pleural cavity.	('L > 20 mum', 'Var', (28, 38))	('T 1/2 of 4.5 d', 'Gene', '921', (57, 71))	('T 1/2 of 4.5 d', 'Gene', (57, 71))
99711	32929059	However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines.	('migration ability', 'CPA', (77, 94))	('miR-320a', 'Gene', (104, 112))	('proliferation', 'CPA', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('miR-320a', 'Gene', '407037', (104, 112))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('miR-320a', 'Gene', (16, 24))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('miR-320a', 'Gene', '407037', (16, 24))	('higher', 'PosReg', (52, 58))	('ectopic expression', 'Var', (25, 43))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('173', '189'))
99721	32929059	It is estimated that at least 12% of MMs develop in carriers of genetic mutations: beyond BAP1, which is found inactivated by both germline and somatic mutations in MM, other tumor suppressor genes, such as TP53 and BRCA2, or genes that regulate DNA repair, bear germline mutations in MMs.	('DNA repair', 'biological_process', 'GO:0006281', ('246', '256'))	('mutations', 'Var', (152, 161))	('MMs', 'Disease', (37, 40))	('TP53', 'Gene', '7157', (207, 211))	('BAP1', 'Gene', (90, 94))	('BRCA2', 'Gene', '675', (216, 221))	('mutations', 'Var', (72, 81))	('tumor', 'Disease', (175, 180))	('TP53', 'Gene', (207, 211))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('175', '191'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('germline mutations', 'Var', (263, 281))	('BAP1', 'Gene', '8314', (90, 94))	('develop', 'Reg', (41, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('175', '191'))	('BRCA2', 'Gene', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MMs', 'Gene', (285, 288))
99742	32929059	The mutant 3'UTR (PDL1 Mut=G2767C; C2768G) was generated through the QuikChange Site-Directed Mutagenesis Kit (AgilentTechnologies).	('AgilentTechnologies', 'Disease', (111, 130))	('G2767C', 'Mutation', 'c.2767G>C', (27, 33))	('AgilentTechnologies', 'Disease', 'None', (111, 130))	('PDL1', 'Gene', '29126', (18, 22))	('Mut=G2767C; C2768G', 'Var', (23, 41))	('C2768G', 'Var', (35, 41))	('PDL1', 'Gene', (18, 22))	('Mutagenesis', 'biological_process', 'GO:0006280', ('94', '105'))	('C2768G', 'Mutation', 'c.2768C>G', (35, 41))
99744	32929059	For miR-320a silencing, a previously described sponge320a pSilencer5.1 expressing-vector was used.	('pSilencer', 'Disease', 'None', (58, 67))	('pSilencer', 'Disease', (58, 67))	('miR-320a', 'Gene', (4, 12))	('silencing', 'Var', (13, 22))	('miR-320a', 'Gene', '407037', (4, 12))
99751	32929059	HEK-293 were cotransfected with mimic-miR320a or mimic-miRscr (50 nM) together with pmirGLO-PDL1 3'UTR (2 mug) containing either the wt or the mut miR-320a-binding site.	('PDL1', 'Gene', (92, 96))	('miR320a', 'Gene', (38, 45))	('mimic-miRscr', 'Var', (49, 61))	('mug', 'molecular_function', 'GO:0043739', ('106', '109'))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('miR-320a', 'Gene', '407037', (147, 155))	('miR-320a', 'Gene', (147, 155))	('PDL1', 'Gene', '29126', (92, 96))	('HEK-293', 'CellLine', 'CVCL:0045', (0, 7))	('miR320a', 'Gene', '407037', (38, 45))
99774	32929059	We then specifically focused on miR-320a because its role in MPM has not been investigated yet and we were intrigued by the fact that other miRNAs of the miR-320 family (miR-320b, 320c, and 320d) were similarly downregulated in MPMs.	('miR-320', 'Chemical', '-', (154, 161))	('miR-320b', 'Var', (170, 178))	('320d', 'Var', (190, 194))	('miR-320a', 'Gene', (32, 40))	('miR-320a', 'Gene', '407037', (32, 40))	('320c', 'Var', (180, 184))	('miR-320', 'Chemical', '-', (170, 177))	('miR-320', 'Chemical', '-', (32, 39))	('downregulated', 'NegReg', (211, 224))	('MPMs', 'Disease', (228, 232))
99787	32929059	To minimize the effect of proliferation on wound closure, cells were kept confluent and migration was evaluated early, at 24 h. MiR-320a-over-expressing MSTO-211H cl7 and cl9 cells showed a higher migration ability, although statistical significance was reached only for cl9 compared with parental cells.	('migration ability', 'CPA', (197, 214))	('MSTO-211H', 'Chemical', '-', (153, 162))	('MiR-320a', 'Gene', (128, 136))	('MSTO-211H', 'Var', (153, 162))	('MiR-320a', 'Gene', '407037', (128, 136))	('higher', 'PosReg', (190, 196))
99795	32929059	To confirm miR-320a and PDL1 interaction, we cloned, downstream the luciferase reporter, the wt (or mutated) binding site within PDL1 3'-UTR, which was predicted with the highest score (Fig.	('mutated', 'Var', (100, 107))	('PDL1', 'Gene', '29126', (24, 28))	('miR-320a', 'Gene', (11, 19))	('PDL1', 'Gene', (129, 133))	('miR-320a', 'Gene', '407037', (11, 19))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('PDL1', 'Gene', (24, 28))	('PDL1', 'Gene', '29126', (129, 133))
99796	32929059	We then evaluated luciferase activity 48 h after HEK-293 transfection with the wt or mutated binding site, along with either miR-320a mimics or scramble control (Fig.	('luciferase activity', 'molecular_function', 'GO:0045289', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('18', '37'))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('miR-320a', 'Gene', (125, 133))	('luciferase activity', 'molecular_function', 'GO:0050248', ('18', '37'))	('activity', 'MPA', (29, 37))	('miR-320a', 'Gene', '407037', (125, 133))	('mutated', 'Var', (85, 92))	('evaluated', 'Reg', (8, 17))	('luciferase', 'Enzyme', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0047077', ('18', '37'))	('HEK-293', 'CellLine', 'CVCL:0045', (49, 56))
99798	32929059	Conversely, no repression of luciferase activity was observed when miR-320a mimics were co-transfected with the vector containing the mutated 3'UTR.	('luciferase activity', 'molecular_function', 'GO:0047077', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('29', '48'))	('mutated', 'Var', (134, 141))	('miR-320a', 'Gene', (67, 75))	('miR-320a', 'Gene', '407037', (67, 75))
99799	32929059	The slightly higher basal luciferase activity of the mutated-site-containing vector is likely due to the impaired binding of endogenous miR-320a.	('basal', 'MPA', (20, 25))	('impaired', 'NegReg', (105, 113))	('miR-320a', 'Gene', '407037', (136, 144))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('higher', 'PosReg', (13, 19))	('luciferase activity', 'molecular_function', 'GO:0047077', ('26', '45'))	('binding', 'Interaction', (114, 121))	('activity', 'MPA', (37, 45))	('luciferase activity', 'molecular_function', 'GO:0047712', ('26', '45'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('26', '45'))	('miR-320a', 'Gene', (136, 144))	('luciferase activity', 'molecular_function', 'GO:0050397', ('26', '45'))	('mutated-site-containing', 'Var', (53, 76))	('luciferase activity', 'molecular_function', 'GO:0050248', ('26', '45'))
99805	32929059	Consistently, silencing endogenous miR-320a levels in MSTO-211H cells, by transient transfection of the pSilencer-sponge320a, led to increased PDL1 mRNA and protein levels (Fig.	('silencing', 'Var', (14, 23))	('PDL1', 'Gene', '29126', (143, 147))	('miR-320a', 'Gene', (35, 43))	('MSTO-211H', 'Chemical', '-', (54, 63))	('miR-320a', 'Gene', '407037', (35, 43))	('PDL1', 'Gene', (143, 147))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('increased', 'PosReg', (133, 142))	('pSilencer', 'Disease', 'None', (104, 113))	('pSilencer', 'Disease', (104, 113))
99816	32929059	We transfected parental MSTO-211H and miR-320a-over-expressing cl9 with either TSBs or TSBK control and found that both TSB-320a and TSB-200a increased PDL1 mRNA and protein levels, whereas TSB-34a did not, probably because it acts through a different binding site within PDL1 mRNA (Supplementary Fig.	('miR-320a', 'Gene', (38, 46))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('PDL1', 'Gene', (152, 156))	('increased', 'PosReg', (142, 151))	('miR-320a', 'Gene', '407037', (38, 46))	('PDL1', 'Gene', '29126', (272, 276))	('PDL1', 'Gene', '29126', (152, 156))	('binding', 'molecular_function', 'GO:0005488', ('252', '259'))	('TSB-320a', 'Var', (120, 128))	('PDL1', 'Gene', (272, 276))	('MSTO-211H', 'Chemical', '-', (24, 33))	('TSB-200a', 'Var', (133, 141))	('TSBs', 'Chemical', '-', (79, 83))
99830	32929059	We then focused specifically on miRNA-320a, which was recently shown to act as a tumor suppressor in different cancer types in which it was found downregulated, such as colorectal, breast, bladder, lung, prostate and gastric cancer, multiple myeloma and gliomas.	('colorectal', 'Disease', (169, 179))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (111, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (233, 249))	('miRNA-320a', 'Var', (32, 42))	('bladder', 'Disease', (189, 196))	('gliomas', 'Phenotype', 'HP:0009733', (254, 261))	('breast', 'Disease', (181, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung', 'Disease', (198, 202))	('multiple myeloma', 'Disease', 'MESH:D009101', (233, 249))	('tumor', 'Disease', (81, 86))	('prostate', 'Disease', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('gastric cancer', 'Disease', (217, 231))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('multiple myeloma', 'Disease', (233, 249))	('gliomas', 'Disease', (254, 261))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('miRNA-320a', 'Chemical', '-', (32, 42))	('downregulated', 'NegReg', (146, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (217, 231))	('gliomas', 'Disease', 'MESH:D005910', (254, 261))
99832	32929059	Our microarray results revealed, among the top-ranking alterations, the simultaneous downregulation of multiple miR-320 family members, located at different chromosomes (miR-320a on Chr8, miR-320b on Chr1, miR-320c on Chr18, and miR-320d on Chr13, respectively), suggesting that decreased expression of miR-320 family is not a casual event in MPM tumorigenesis.	('miR-320', 'Chemical', '-', (112, 119))	('miR-320d', 'Var', (229, 237))	('tumor', 'Disease', (347, 352))	('downregulation', 'NegReg', (85, 99))	('miR-320', 'Chemical', '-', (206, 213))	('miR-320', 'Chemical', '-', (303, 310))	('miR-320a', 'Gene', (170, 178))	('MPM', 'Disease', (343, 346))	('miR-320a', 'Gene', '407037', (170, 178))	('miR-320', 'Chemical', '-', (170, 177))	('miR-320b', 'Var', (188, 196))	('miR-320 family', 'Gene', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('miR-320', 'Chemical', '-', (229, 236))	('miR-320', 'Chemical', '-', (188, 195))	('miR-320c', 'Var', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
99841	32929059	Interestingly, high expression of PDL1 in MPM predicts poorer survival and is associated to the non-epithelioid histotypes, which are those with the lower expression of miR-320a in our study.	('high', 'Var', (15, 19))	('associated', 'Reg', (78, 88))	('survival', 'MPA', (62, 70))	('PDL1', 'Gene', '29126', (34, 38))	('poorer', 'NegReg', (55, 61))	('non-epithelioid', 'Disease', (96, 111))	('miR-320a', 'Gene', (169, 177))	('PDL1', 'Gene', (34, 38))	('miR-320a', 'Gene', '407037', (169, 177))
99844	32929059	Consistently, we showed that miR-320a modulation in MPM cell lines of different histotypes regulates PDL1 expression.	('modulation', 'Var', (38, 48))	('regulates', 'Reg', (91, 100))	('expression', 'MPA', (106, 116))	('miR-320a', 'Gene', (29, 37))	('PDL1', 'Gene', '29126', (101, 105))	('miR-320a', 'Gene', '407037', (29, 37))	('PDL1', 'Gene', (101, 105))
99848	32929059	Recently, various miRNAs were found to regulate PDL1 in cancer, including miR-15a-miR-16, miR-34, miR-142-5p, miR-152, and miR-200a.	('miR-16', 'Gene', (82, 88))	('miR-200a', 'Gene', (123, 131))	('regulate', 'Reg', (39, 47))	('miR-200a', 'Gene', '406983', (123, 131))	('miR-34', 'Gene', '407040', (90, 96))	('miR-16', 'Gene', '51573', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PDL1', 'Gene', '29126', (48, 52))	('miR-152', 'Gene', '406943', (110, 117))	('miR-152', 'Gene', (110, 117))	('miR-15a', 'Gene', '406948', (74, 81))	('miR-142-5p', 'Var', (98, 108))	('miR-15a', 'Gene', (74, 81))	('PDL1', 'Gene', (48, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('miR-34', 'Gene', (90, 96))
99853	32929059	P53, likely the most frequently inactivated protein in cancer is reported as infrequently mutated in MPMs, however its function is inactivated by common defects in its pathway, such as the CDKN2A deletion occurring in most MPMs.	('function', 'MPA', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('deletion', 'Var', (196, 204))	('CDKN2A', 'Gene', '1029', (189, 195))	('P53', 'Gene', (0, 3))	('inactivated', 'NegReg', (131, 142))	('P53', 'Gene', '7157', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('CDKN2A', 'Gene', (189, 195))	('cancer', 'Disease', (55, 61))
99854	32929059	More recently p53 mutations have been associated with poorer overall survival.	('poorer', 'NegReg', (54, 60))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('overall', 'MPA', (61, 68))	('mutations', 'Var', (18, 27))
99857	32929059	Among the latter, although a study reported increased PDL1 levels upon p53 induction in MCF7 breast cancer cells, TP53 mutations increase PDL1 levels in lung adenocarcinomas.	('PDL1', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (114, 118))	('p53', 'Gene', '7157', (71, 74))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (153, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('PDL1', 'Gene', '29126', (54, 58))	('lung adenocarcinomas', 'Disease', (153, 173))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('p53', 'Gene', (71, 74))	('PDL1', 'Gene', (138, 142))	('breast cancer', 'Disease', (93, 106))	('increased', 'PosReg', (44, 53))	('mutations', 'Var', (119, 128))	('PDL1', 'Gene', '29126', (138, 142))	('MCF7', 'CellLine', 'CVCL:0031', (88, 92))	('increase', 'PosReg', (129, 137))	('TP53', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (153, 173))
99860	32929059	It remains to be established whether the miR-320a downregulation observed in our MPM cohorts could be a consequence of p53 pathway inactivation (being a passenger rather than a driver alteration) and whether p53 mysfunction might favor tumor escape from immune surveillance.	('miR-320a', 'Gene', '407037', (41, 49))	('downregulation', 'NegReg', (50, 64))	('p53', 'Gene', '7157', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('inactivation', 'NegReg', (131, 143))	('p53', 'Gene', (208, 211))	('p53', 'Gene', '7157', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('favor', 'PosReg', (230, 235))	('p53', 'Gene', (119, 122))	('mysfunction', 'Var', (212, 223))	('tumor', 'Disease', (236, 241))	('miR-320a', 'Gene', (41, 49))
99879	32787452	From the histology, MM is classified into epithelioid, sarcomatoid, or biphasic (mixed) with epithelioid MM remaining the most common with its polygonal cells resembling reactive mesothelial cells.	('sarcomatoid', 'Disease', (55, 66))	('sarcomatoid', 'Disease', 'MESH:C538614', (55, 66))	('epithelioid MM', 'Var', (93, 107))
99914	32787452	While not completed in our patient, other markers present in MM include the deletion of p16, occurring in 70% of epithelioid MM, and the presence of a BAP1 mutation.	('deletion', 'Var', (76, 84))	('presence', 'Reg', (137, 145))	('p16', 'Gene', (88, 91))	('BAP1', 'Gene', (151, 155))	('patient', 'Species', '9606', (27, 34))	('p16', 'Gene', '1029', (88, 91))	('BAP1', 'Gene', '8314', (151, 155))	('mutation', 'Var', (156, 164))
100012	31648983	The discovery of a two-dimensional summary of molecular variation uncovered important associations with the 10 currently accepted hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (130, 149))	('associations', 'Interaction', (86, 98))	('hallmarks of cancer', 'Disease', (130, 149))	('variation', 'Var', (56, 65))
100022	31648983	Despite its suggested immunosuppressive role, VISTA expression in tumour cells has been associated with increased tumour-infiltrating lymphocytes, PD-1, a favourable immune microenvironment, and with better overall survival in hepatocellular carcinoma and non-small cell lung cancer.	('PD-1', 'Gene', (147, 151))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (256, 282))	('PD-1', 'Gene', '5133', (147, 151))	('expression', 'Var', (52, 62))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (227, 251))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('non-small cell lung cancer', 'Disease', (256, 282))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('better', 'PosReg', (200, 206))	('tumour', 'Disease', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', (114, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (227, 251))	('VISTA', 'Gene', '64115', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('VISTA', 'Gene', (46, 51))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (256, 282))	('increased', 'PosReg', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('hepatocellular carcinoma', 'Disease', (227, 251))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (260, 282))
100090	28381756	studied 153 patients with ascites of unknown etiology and found that all of them showed abnormalities of the peritoneum or greater omentum on ultrasonography.	('ascites', 'Disease', 'MESH:D001201', (26, 33))	('patients', 'Species', '9606', (12, 20))	('ascites', 'Disease', (26, 33))	('ascites', 'Phenotype', 'HP:0001541', (26, 33))	('abnormalities', 'Var', (88, 101))	('abnormalities of the peritoneum', 'Phenotype', 'HP:0002585', (88, 119))
100106	28377727	Transcriptomic Analysis of the Claudin Interactome in Malignant Pleural Mesothelioma: Evaluation of the Effect of Disease Phenotype, Asbestos Exposure, and CDKN2A Deletion Status Malignant pleural mesothelioma (MPM) is a highly aggressive tumor primarily associated with asbestos exposure.	('Malignant pleural mesothelioma', 'Disease', (179, 209))	('CDKN2A', 'Gene', (156, 162))	('Deletion', 'Var', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('CDKN2A', 'Gene', '1029', (156, 162))	('asbestos', 'Chemical', 'MESH:D001194', (271, 279))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (189, 209))	('Malignant Pleural Mesothelioma', 'Disease', (54, 84))	('tumor', 'Disease', (239, 244))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (54, 84))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (179, 209))
100107	28377727	Subsequently, we evaluated the effect of tumor histology, asbestos exposure, CDKN2A deletion status, and gender on the gene expression level of the claudin interactome.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('CDKN2A', 'Gene', (77, 83))	('deletion status', 'Var', (84, 99))	('CDKN2A', 'Gene', '1029', (77, 83))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
100122	28377727	Furthermore, accumulating data suggest roles for claudins in tumor development and progression as well as in signal transduction while in several cancers expression of claudins is associated with prognosis (Osanai et al.,).	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('signal transduction', 'biological_process', 'GO:0007165', ('109', '128'))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('expression', 'Var', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('men', 'Species', '9606', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated with', 'Reg', (180, 195))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('claudins', 'Gene', (168, 176))	('tumor', 'Disease', (61, 66))
100127	28377727	Finally, we evaluated the effect of MPM histology, asbestos exposure, CDKN2A deletion status, and gender on the gene expression level of the claudin interactome.	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('asbestos', 'Chemical', 'MESH:D001194', (51, 59))	('deletion status', 'Var', (77, 92))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))
100139	28377727	Furthermore, the same genes were analyzed based asbestos exposure (exposed/unexposed), CDKN2A deletion status (deletion/no deletion), and gender (male/female).	('deletion', 'Var', (94, 102))	('asbestos', 'Chemical', 'MESH:D001194', (48, 56))	('CDKN2A', 'Gene', '1029', (87, 93))	('deletion/no', 'Var', (111, 122))	('CDKN2A', 'Gene', (87, 93))
100144	28377727	The levels of gene expression were subsequently arranged into strata with respect to asbestos exposure history (exposed/unexposed), CDKN2A deletion status (deletion/no deletion) and gender (male/female).	('CDKN2A', 'Gene', (132, 138))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('deletion', 'Var', (139, 147))	('CDKN2A', 'Gene', '1029', (132, 138))	('deletion/no', 'Var', (156, 167))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))
100146	28377727	Regarding CDKN2A deletion status, homozygous deletion was present in 59 patients, in 29 patients it was not present while in 19 patients the information was not available thus they were excluded from the subanalysis.	('CDKN2A', 'Gene', '1029', (10, 16))	('patients', 'Species', '9606', (88, 96))	('deletion', 'Var', (17, 25))	('patients', 'Species', '9606', (128, 136))	('CDKN2A', 'Gene', (10, 16))	('patients', 'Species', '9606', (72, 80))
100148	28377727	Analysis with respect to asbestos exposure history (exposed/unexposed), CDKN2A deletion status (deletion/no deletion) and gender (male/female) was performed with the un-paired t-test and the Mann-Whitney U-test for parametric and non-parametric data respectively.	('CDKN2A', 'Gene', '1029', (72, 78))	('deletion', 'Var', (79, 87))	('asbestos', 'Chemical', 'MESH:D001194', (25, 33))	('CDKN2A', 'Gene', (72, 78))
100158	28377727	In addition, CLDN-15 was found significantly under-expressed in the subgroup of patients with homozygous deletion of the CDKN2A gene as opposed to the patients with no deletion (p = 0.035; Figure 4).	('CDKN2A', 'Gene', '1029', (121, 127))	('deletion', 'Var', (105, 113))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (151, 159))	('under-expressed', 'NegReg', (45, 60))	('CLDN-15', 'Gene', (13, 20))	('CDKN2A', 'Gene', (121, 127))	('CLDN-15', 'Gene', '24146', (13, 20))
100170	28377727	An in vitro study using M14K (epithelioid MPM) and M38K (biphasic MPM) cell lines (Chaouche-Mazouni et al.,) has shown by means of immunohistochemistry and immunoblotting a high level of claudin 15 in both cell lines as opposed to claudins 3 and 4.	('claudin 15', 'Gene', '24146', (187, 197))	('M14K', 'Var', (24, 28))	('M38K', 'Var', (51, 55))	('M14K', 'SUBSTITUTION', 'None', (24, 28))	('claudin 15', 'Gene', (187, 197))	('M38K', 'SUBSTITUTION', 'None', (51, 55))
100187	28377727	The inactivation of both p16INK4a and Arf products of the CDKN2A gene has been suggested to act synergistically in accelerating asbestos-induced tumorigenesis in vivo (Sekido,).	('inactivation', 'Var', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('asbestos', 'Chemical', 'MESH:D001194', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('asbestos-induced', 'Disease', (128, 144))	('tumor', 'Disease', (145, 150))	('p16INK4a', 'Gene', (25, 33))	('CDKN2A', 'Gene', (58, 64))	('CDKN2A', 'Gene', '1029', (58, 64))	('p16INK4a', 'Gene', '1029', (25, 33))	('accelerating', 'PosReg', (115, 127))
100189	28377727	A significant association has been described between increasing number of methylated cell cycle control genes and asbestos burden.	('methylated', 'Var', (74, 84))	('asbestos', 'Chemical', 'MESH:D001194', (114, 122))	('cell cycle control genes', 'Gene', (85, 109))	('cell cycle control', 'biological_process', 'GO:1901987', ('85', '103'))	('asbestos burden', 'Disease', (114, 129))
100192	28377727	Likewise, the results of this study are indicative of the epigenetic effect of asbestos in the transcriptional level of the CLDN-15 gene suggesting its potential utility as a screening biomarker for populations at risk.	('CLDN-15', 'Gene', (124, 131))	('transcriptional level', 'MPA', (95, 116))	('asbestos', 'Chemical', 'MESH:D001194', (79, 87))	('CLDN-15', 'Gene', '24146', (124, 131))	('epigenetic effect', 'Var', (58, 75))
100207	28377727	Inhibition of IL-8 has been shown to reduce human MPM propagation in a nude mouse model (Galffy et al.,).	('human', 'Species', '9606', (44, 49))	('reduce', 'NegReg', (37, 43))	('mouse', 'Species', '10090', (76, 81))	('IL-8', 'Gene', '3576', (14, 18))	('IL-8', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('IL-8', 'molecular_function', 'GO:0005153', ('14', '18'))	('human MPM propagation', 'CPA', (44, 65))
100213	28377727	These results suggest that any changes in CDH5 will impact the endothelial barrier function at multiple levels and also explain why CDH5 inhibition may cause a marked increase in permeability (Gavard and Gutkind,; Taddei et al.,).	('CDH5', 'Gene', '1003', (132, 136))	('changes', 'Var', (31, 38))	('CDH5', 'Gene', '1003', (42, 46))	('permeability', 'MPA', (179, 191))	('impact', 'Reg', (52, 58))	('inhibition', 'NegReg', (137, 147))	('CDH5', 'Gene', (42, 46))	('increase', 'PosReg', (167, 175))	('CDH5', 'Gene', (132, 136))	('endothelial', 'MPA', (63, 74))
100215	28377727	On the other hand, it has been demonstrated that induction of CDH5 during EMT promotes breast cancer progression via TGFbeta signaling indicating that in certain tumor cells, CDH5 can induce cellular responses that are in contrast to its role in cell-cell contact growth inhibition in endothelial cells (Labelle et al.,).	('promotes', 'PosReg', (78, 86))	('cellular responses', 'MPA', (191, 209))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('tumor', 'Disease', (162, 167))	('induce', 'Reg', (184, 190))	('CDH5', 'Gene', (175, 179))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('TGFbeta signaling', 'MPA', (117, 134))	('CDH5', 'Gene', '1003', (175, 179))	('induction', 'Var', (49, 58))	('breast cancer', 'Disease', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('CDH5', 'Gene', (62, 66))	('CDH5', 'Gene', '1003', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
100353	24885398	Silencing of GAS5 increased the expression of glucocorticoid responsive genes glucocorticoid inducible leucine-zipper and serum/glucocorticoid-regulated kinase-1 and shortened the length of the cell cycle.	('serum/glucocorticoid-regulated kinase-1', 'Gene', (122, 161))	('increased', 'PosReg', (18, 27))	('expression', 'MPA', (32, 42))	('GAS5', 'Gene', (13, 17))	('cell cycle', 'biological_process', 'GO:0007049', ('194', '204'))	('length of the cell cycle', 'CPA', (180, 204))	('GAS', 'molecular_function', 'GO:0034005', ('13', '16'))	('shortened', 'NegReg', (166, 175))	('serum/glucocorticoid-regulated kinase-1', 'Gene', '6446', (122, 161))	('Silencing', 'Var', (0, 9))	('glucocorticoid', 'MPA', (78, 92))
100363	24885398	Interestingly, a minimal region of deletion was identified in asbestos induced murine malignant mesothelioma which includes gas5 locus.	('malignant mesothelioma', 'Disease', (86, 108))	('gas5', 'Gene', (124, 128))	('asbestos', 'Chemical', 'MESH:D001194', (62, 70))	('nt', 'Chemical', '-', (51, 53))	('nt', 'Chemical', '-', (93, 95))	('gas5', 'Gene', '14455', (124, 128))	('nt', 'Chemical', '-', (1, 3))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (86, 108))	('deletion', 'Var', (35, 43))	('murine', 'Species', '10090', (79, 85))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (86, 108))
100367	24885398	Recent studies have shown that GAS5 silencing in T cells increased the proportion of cells in S phase, reduced the rate of spontaneous apoptosis and protected cells from rapalogue (temsirolimus, everolimus) induced proliferation arrest.	('nt', 'Chemical', '-', (4, 6))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('S phase', 'biological_process', 'GO:0051320', ('94', '101'))	('reduced', 'NegReg', (103, 110))	('proliferation arrest', 'Disease', 'MESH:D006323', (215, 235))	('T cells increased', 'Phenotype', 'HP:0100828', (49, 66))	('spontaneous apoptosis', 'MPA', (123, 144))	('GAS5', 'Protein', (31, 35))	('GAS', 'molecular_function', 'GO:0034005', ('31', '34'))	('S phase', 'CPA', (94, 101))	('silencing', 'Var', (36, 45))	('increased', 'PosReg', (57, 66))	('rate', 'MPA', (115, 119))	('nt', 'Chemical', '-', (126, 128))	('proliferation arrest', 'Disease', (215, 235))
100382	24885398	While it is not possible to investigate the effect of HhAntag in cell grown in serum containing medium, a significant increase of GAS5 levels was observed after treatment of ZL55SPT and SDM103T2 to NVP-BEZ235 (Additional file 6: Figure S4), indicating that cells grown in dedifferentiating conditions remain sensitive to this drug.	('nt', 'Chemical', '-', (168, 170))	('SDM103T2 to NVP-BEZ235', 'Var', (186, 208))	('nt', 'Chemical', '-', (87, 89))	('increase', 'PosReg', (118, 126))	('SPT', 'molecular_function', 'GO:0004760', ('178', '181'))	('SPT', 'molecular_function', 'GO:0004758', ('178', '181'))	('GAS5 levels', 'MPA', (130, 141))	('BEZ235', 'Chemical', 'MESH:C531198', (202, 208))	('nt', 'Chemical', '-', (115, 117))	('SDM103T2', 'CellLine', 'CVCL:D313', (186, 194))	('ZL55SPT', 'Var', (174, 181))	('nt', 'Chemical', '-', (57, 59))	('nt', 'Chemical', '-', (281, 283))	('GAS', 'molecular_function', 'GO:0034005', ('130', '133'))
100383	24885398	To investigate whether increased GAS5 RNA levels observed after treatment with HhAntag and NVP-BEZ235 were associated with increased GAS5 promoter activity, we transfected ZL55SPT and ZL55 cells with a luciferase reporter gene under the control of GAS5 promoter sequences (pGL3-B-pGAS5).	('BEZ235', 'Chemical', 'MESH:C531198', (95, 101))	('SPT', 'molecular_function', 'GO:0004760', ('176', '179'))	('pGL', 'molecular_function', 'GO:0004598', ('273', '276'))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('GAS', 'molecular_function', 'GO:0034005', ('248', '251'))	('GAS', 'molecular_function', 'GO:0034005', ('33', '36'))	('GAS5 RNA levels', 'MPA', (33, 48))	('pGL3', 'Gene', (273, 277))	('nt', 'Chemical', '-', (71, 73))	('increased', 'PosReg', (23, 32))	('nt', 'Chemical', '-', (239, 241))	('NVP-BEZ235', 'Var', (91, 101))	('GAS', 'molecular_function', 'GO:0034005', ('133', '136'))	('nt', 'Chemical', '-', (82, 84))	('pGL3', 'Gene', '6391', (273, 277))	('SPT', 'molecular_function', 'GO:0004758', ('176', '179'))
100390	24885398	To determine whether the observed 35 and 25% (in shGAS-1 and shGAS5-2, respectively) decrease in GAS5 expression was functionally relevant, we determined the consequences on glucocorticoid regulated genes such as glucocorticoid inducible leucine-zipper (GILZ) and serum/glucocorticoid-regulated kinase-1 (SGK1).	('GAS', 'molecular_function', 'GO:0034005', ('97', '100'))	('SGK1', 'Gene', (305, 309))	('serum/glucocorticoid-regulated kinase-1', 'Gene', '6446', (264, 303))	('GILZ', 'Gene', '1831', (254, 258))	('serum/glucocorticoid-regulated kinase-1', 'Gene', (264, 303))	('decrease', 'NegReg', (85, 93))	('shGAS-1', 'Var', (49, 56))	('SGK1', 'Gene', '6446', (305, 309))	('GILZ', 'Gene', (254, 258))	('nt', 'Chemical', '-', (136, 138))	('shGAS5-2', 'Var', (61, 69))	('GAS5', 'Gene', (97, 101))
100392	24885398	As ZL55SPT cells are grown in a serum-free medium containing pharmacological concentrations of glucocorticoids, which are essential for optimal cell growth, we expected that modulation of GAS5 levels would modify the expression of glucocorticoid regulated genes.	('modulation', 'Var', (174, 184))	('nt', 'Chemical', '-', (52, 54))	('cell growth', 'biological_process', 'GO:0016049', ('144', '155'))	('expression', 'MPA', (217, 227))	('SPT', 'molecular_function', 'GO:0004758', ('7', '10'))	('SPT', 'molecular_function', 'GO:0004760', ('7', '10'))	('modify', 'Reg', (206, 212))	('nt', 'Chemical', '-', (126, 128))	('nt', 'Chemical', '-', (82, 84))	('glucocorticoid regulated genes', 'Gene', (231, 261))	('GAS', 'molecular_function', 'GO:0034005', ('188', '191'))
100405	24885398	This was unexpected considering the upregulation GAS5 during growth arrest and the shortening of cell-cycle observed upon GAS5 silencing.	('cell-cycle', 'CPA', (97, 107))	('GAS', 'molecular_function', 'GO:0034005', ('49', '52'))	('growth arrest', 'Disease', (61, 74))	('GAS5', 'Gene', (122, 126))	('upregulation', 'PosReg', (36, 48))	('growth arrest', 'Disease', 'MESH:D006323', (61, 74))	('GAS', 'molecular_function', 'GO:0034005', ('122', '125'))	('growth arrest', 'Phenotype', 'HP:0001510', (61, 74))	('cell-cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('silencing', 'Var', (127, 136))
100410	24885398	Furthermore, GAS5 expression was higher in samples with high podoplanin (D2-40) expression (Figure 5A and Additional file 8: Figure S6B).	('GAS5', 'Protein', (13, 17))	('higher', 'PosReg', (33, 39))	('podoplanin', 'Gene', '10630', (61, 71))	('D2-40', 'Gene', (73, 78))	('podoplanin', 'Gene', (61, 71))	('GAS', 'molecular_function', 'GO:0034005', ('13', '16'))	('expression', 'MPA', (80, 90))	('high', 'Var', (56, 60))
100422	24885398	Silencing of GAS5 resulted in shortening cell cycle in MPM cells demonstrating that also in these cells GAS5 controls cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('118', '129'))	('GAS5', 'Gene', (13, 17))	('cell cycle', 'CPA', (41, 51))	('GAS', 'molecular_function', 'GO:0034005', ('104', '107'))	('nt', 'Chemical', '-', (111, 113))	('GAS', 'molecular_function', 'GO:0034005', ('13', '16'))	('cell cycle', 'biological_process', 'GO:0007049', ('41', '51'))	('Silencing', 'Var', (0, 9))	('shortening', 'NegReg', (30, 40))
100423	24885398	The underlying mechanism can be linked to the fact that GAS5 is a glucocorticoid receptor-decoy and it inhibits transcription of glucocorticoid responsive genes.	('GAS', 'molecular_function', 'GO:0034005', ('56', '59'))	('inhibits', 'NegReg', (103, 111))	('glucocorticoid receptor', 'Gene', '2908', (66, 89))	('transcription', 'MPA', (112, 125))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))	('glucocorticoid receptor', 'Gene', (66, 89))	('GAS5', 'Var', (56, 60))
100432	24885398	Besides interference with glucocorticoids signalling, other mechanisms may involve chromatin remodelling, since GAS5 expression is increased after growth arrest induced by silencing of Brahma ATPase subunit of mammalian SWI/SNF complexes.	('mammalian', 'Species', '9606', (210, 219))	('signalling', 'biological_process', 'GO:0023052', ('42', '52'))	('chromatin', 'cellular_component', 'GO:0000785', ('83', '92'))	('ATP', 'Chemical', 'MESH:D000255', (192, 195))	('increased', 'PosReg', (131, 140))	('expression', 'MPA', (117, 127))	('GAS5', 'Gene', (112, 116))	('growth arrest', 'Disease', (147, 160))	('GAS', 'molecular_function', 'GO:0034005', ('112', '115'))	('growth arrest', 'Disease', 'MESH:D006323', (147, 160))	('nt', 'Chemical', '-', (9, 11))	('growth arrest', 'Phenotype', 'HP:0001510', (147, 160))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('83', '104'))	('silencing', 'Var', (172, 181))
100437	24885398	Control of cell cycle mediated by lncRNA has been demonstrated for MALAT1, whereby silencing MALAT1 resulted in decreased proliferation because MALAT1 is required for mitotic progression during which MALAT1 migrated from the nucleus to the cytoplasm shuttling heterogeneous ribonucleoprotein C, which is necessary to increase IRES-dependent translation of c-myc.	('cytoplasm', 'cellular_component', 'GO:0005737', ('240', '249'))	('MALAT1', 'Gene', (144, 150))	('nucleus', 'cellular_component', 'GO:0005634', ('225', '232'))	('MALAT1', 'Gene', '378938', (200, 206))	('nt', 'Chemical', '-', (2, 4))	('MALAT1', 'Gene', '378938', (144, 150))	('ribonucleoprotein', 'molecular_function', 'GO:0003733', ('274', '291'))	('decreased', 'NegReg', (112, 121))	('c-myc', 'Gene', (356, 361))	('translation', 'biological_process', 'GO:0006412', ('341', '352'))	('silencing', 'Var', (83, 92))	('cell cycle', 'biological_process', 'GO:0007049', ('11', '21'))	('MALAT1', 'Gene', (93, 99))	('proliferation', 'CPA', (122, 135))	('MALAT1', 'Gene', (67, 73))	('c-myc', 'Gene', '4609', (356, 361))	('MALAT1', 'Gene', '378938', (93, 99))	('nt', 'Chemical', '-', (338, 340))	('MALAT1', 'Gene', '378938', (67, 73))	('MALAT1', 'Gene', (200, 206))
100466	24885398	The sense and antisense strands of the 19-nucleotide (nt) which targets nucleotides 199 to 217 of the human GAS5 sequence (GenBank accession number NR_002578) are indicated in italics and are separated by a 9-nt loop sequence (TTCAAGAGA).	('nt', 'Chemical', '-', (54, 56))	('nucleotides', 'Var', (72, 83))	('GAS5', 'Gene', (108, 112))	('nt', 'Chemical', '-', (15, 17))	('nt', 'Chemical', '-', (209, 211))	('19-nucleotide', 'Chemical', '-', (39, 52))	('GAS', 'molecular_function', 'GO:0034005', ('108', '111'))	('human', 'Species', '9606', (102, 107))
100539	29587685	Additionally, MPM causes debilitating physical symptoms, such as pain, dyspnea, fatigue, and loss of appetite.	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('dyspnea', 'Phenotype', 'HP:0002094', (71, 78))	('MPM', 'Chemical', '-', (14, 17))	('pain', 'Disease', 'MESH:D010146', (65, 69))	('pain', 'Disease', (65, 69))	('dyspnea', 'Disease', (71, 78))	('fatigue', 'Disease', 'MESH:D005221', (80, 87))	('loss of appetite', 'Disease', 'MESH:D001068', (93, 109))	('MPM', 'Var', (14, 17))	('dyspnea', 'Disease', 'MESH:D004417', (71, 78))	('loss of appetite', 'Disease', (93, 109))	('fatigue', 'Disease', (80, 87))	('causes', 'Reg', (18, 24))	('fatigue', 'Phenotype', 'HP:0012378', (80, 87))	('loss of appetite', 'Phenotype', 'HP:0004396', (93, 109))
100544	29587685	There are previous reports that MPM impairs the QOL of patients and their care givers.	('QOL of patients', 'CPA', (48, 63))	('MPM', 'Chemical', '-', (32, 35))	('MPM', 'Var', (32, 35))	('patients', 'Species', '9606', (55, 63))	('impairs', 'NegReg', (36, 43))
100550	29587685	Nurses who care for patients with MPM also experienced difficulties, such as struggling with care, failure to introduce palliative care, limited support for patients with decision making, difficulty in dealing with families, unsuccessful communication, and emotional distress after being with patients with MPM.	('MPM', 'Chemical', '-', (307, 310))	('MPM', 'Var', (34, 37))	('emotional distress', 'Phenotype', 'HP:0000712', (257, 275))	('patients', 'Species', '9606', (157, 165))	('patients', 'Species', '9606', (20, 28))	('emotional distress', 'CPA', (257, 275))	('patients', 'Species', '9606', (293, 301))	('MPM', 'Chemical', '-', (34, 37))
100601	29587685	Several studies have been performed from a qualitative perspective, focusing on the MPM patient's perspective, suggesting that patients living with MPM undergo a traumatic shock and a "Damocles' syndrome" characterized by intense fears of death and anxiety along with the awareness of the absence of effective treatments.	('death', 'Disease', (239, 244))	('patient', 'Species', '9606', (88, 95))	('intense fears', 'Phenotype', 'HP:0000739', (222, 235))	('anxiety', 'Disease', 'MESH:D001008', (249, 256))	('patient', 'Species', '9606', (127, 134))	('traumatic shock', 'Disease', (162, 177))	('MPM', 'Chemical', '-', (148, 151))	('patients', 'Species', '9606', (127, 135))	('MPM', 'Chemical', '-', (84, 87))	('traumatic shock', 'Disease', 'MESH:D012774', (162, 177))	('anxiety', 'Disease', (249, 256))	('MPM', 'Var', (148, 151))	('anxiety', 'Phenotype', 'HP:0000739', (249, 256))	('a "Damocles', 'Species', '268636', (182, 193))	('shock', 'Phenotype', 'HP:0031273', (172, 177))	('death', 'Disease', 'MESH:D003643', (239, 244))
100635	28352271	The first study about the role of S1P was reported by Choi's group using rat mast-cell line (RBL-2H3) and showed that crosslinking and stimulation of FcepsilonRI (high-affinity IgE receptor) could activate SphK1 and subsequently lead to S1P production.	('S1P', 'Gene', (34, 37))	('lead to', 'Reg', (229, 236))	('crosslinking', 'Var', (118, 130))	('S1P', 'Gene', '13609', (34, 37))	('FcepsilonRI', 'Gene', (150, 161))	('S1P', 'Gene', '13609', (237, 240))	('FcepsilonRI', 'Gene', '14125', (150, 161))	('activate', 'PosReg', (197, 205))	('RBL-2H3', 'CellLine', 'CVCL:0591', (93, 100))	('S1P', 'Gene', (237, 240))	('rat', 'Species', '10116', (73, 76))	('SphK1', 'Enzyme', (206, 211))
100646	28352271	Interestingly, S1P-mediated effects were abrogated by JTE-013 (an S1PR2 antagonist) or Y-27632 (an inhibitor of Rho kinase) indicating the role of S1PR2.	('abrogated', 'NegReg', (41, 50))	('JTE-013', 'Chemical', 'MESH:C471998', (54, 61))	('S1P', 'Gene', (15, 18))	('Y-27632', 'Var', (87, 94))	('Y-27632', 'Chemical', 'MESH:C108830', (87, 94))	('S1P', 'Gene', '13609', (147, 150))	('S1P', 'Gene', '13609', (66, 69))	('S1P', 'Gene', (147, 150))	('S1P', 'Gene', (66, 69))	('S1P', 'Gene', '13609', (15, 18))
100647	28352271	This was further confirmed by silencing of S1PR2 using siRNA approach, which also showed the inhibition of S1P-driven Rho kinase activity.	('inhibition', 'NegReg', (93, 103))	('S1P', 'Gene', (107, 110))	('Rho kinase', 'Enzyme', (118, 128))	('S1P', 'Gene', '13609', (43, 46))	('S1P', 'Gene', (43, 46))	('activity', 'MPA', (129, 137))	('S1P', 'Gene', '13609', (107, 110))	('silencing', 'Var', (30, 39))	('kinase activity', 'molecular_function', 'GO:0016301', ('122', '137'))
100649	28352271	It was observed that the inhibitor augmented the hyperresponsiveness but had no effect on airway inflammation.	('airway inflammation', 'Disease', 'MESH:D007249', (90, 109))	('airway inflammation', 'Disease', (90, 109))	('airway inflammation', 'Phenotype', 'HP:0002099', (90, 109))	('inhibitor', 'Var', (25, 34))	('inflammation', 'biological_process', 'GO:0006954', ('97', '109'))	('hyperresponsiveness', 'MPA', (49, 68))
100651	28352271	SK1-I attenuated the antigen-dependent activation of both human and mouse mast cells and also reduced the circulating level of S1P in both lung and circulation.	('mouse', 'Species', '10090', (68, 73))	('SK1-I', 'Var', (0, 5))	('attenuated', 'NegReg', (6, 16))	('human', 'Species', '9606', (58, 63))	('antigen-dependent activation', 'MPA', (21, 49))	('reduced', 'NegReg', (94, 101))	('SK1', 'Species', '580239', (0, 3))	('S1P', 'Gene', '13609', (127, 130))	('S1P', 'Gene', (127, 130))
100654	28352271	FTY720, an approved drug for multiple sclerosis, binds to all S1PRs except S1PR2.	('S1P', 'Gene', '13609', (75, 78))	('multiple sclerosis', 'Disease', 'MESH:D009103', (29, 47))	('S1P', 'Gene', '13609', (62, 65))	('S1P', 'Gene', (75, 78))	('binds', 'Interaction', (49, 54))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('FTY720', 'Var', (0, 6))	('S1P', 'Gene', (62, 65))	('multiple sclerosis', 'Disease', (29, 47))
100655	28352271	Treatment with FTY720 suppressed both Th1- and Th2-driven lung inflammation.	('lung inflammation', 'Disease', 'MESH:D011014', (58, 75))	('FTY720', 'Chemical', 'MESH:D000068876', (15, 21))	('suppressed', 'NegReg', (22, 32))	('Th2', 'Gene', '15111', (47, 50))	('inflammation', 'biological_process', 'GO:0006954', ('63', '75'))	('lung inflammation', 'Disease', (58, 75))	('Th1', 'Gene', (38, 41))	('Th2', 'Gene', (47, 50))	('Th1', 'Gene', '57314', (38, 41))	('FTY720', 'Var', (15, 21))
100669	28352271	Interestingly, FTY720 reduced the ORMDL3 expression, AHR and associated inflammation, and mucus production and elevated the ceramide levels in house dust mite-induced lung inflammation model in mice, further confirming the potential beneficial role of FTY720 in the treatment of asthma.	('inflammation', 'Disease', (72, 84))	('mucus production', 'biological_process', 'GO:0070254', ('90', '106'))	('FTY720', 'Var', (15, 21))	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('lung inflammation', 'Disease', (167, 184))	('ceramide levels', 'MPA', (124, 139))	('expression', 'MPA', (41, 51))	('dust mite', 'Phenotype', 'HP:0410324', (149, 158))	('inflammation', 'biological_process', 'GO:0006954', ('172', '184'))	('lung inflammation', 'Disease', 'MESH:D011014', (167, 184))	('inflammation', 'biological_process', 'GO:0006954', ('72', '84'))	('mice', 'Species', '10090', (194, 198))	('FTY720', 'Chemical', 'MESH:D000068876', (15, 21))	('FTY720', 'Chemical', 'MESH:D000068876', (252, 258))	('inflammation', 'Disease', (172, 184))	('asthma', 'Disease', 'MESH:D001249', (279, 285))	('reduced', 'NegReg', (22, 29))	('asthma', 'Phenotype', 'HP:0002099', (279, 285))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))	('elevated', 'PosReg', (111, 119))	('ORMDL3', 'Gene', '66612', (34, 40))	('asthma', 'Disease', (279, 285))	('ceramide', 'Chemical', 'MESH:D002518', (124, 132))	('ORMDL3', 'Gene', (34, 40))	('mucus production', 'MPA', (90, 106))	('AHR', 'MPA', (53, 56))	('mucus', 'cellular_component', 'GO:0070701', ('90', '95'))
100670	28352271	Moreover, mice with increased expression of ORMDL were shown to have reduced levels of different types of sphingolipids.	('increased', 'PosReg', (20, 29))	('ORMDL', 'Gene', (44, 49))	('mice', 'Species', '10090', (10, 14))	('reduced', 'NegReg', (69, 76))	('sphingolipids', 'Chemical', 'MESH:D013107', (106, 119))	('expression', 'Var', (30, 40))	('levels of different types of sphingolipids', 'MPA', (77, 119))
100672	28352271	It was shown that DSCG inhibited asthma-like features induced by S1P in mice as seen from the reduced recruitment of mast cells and B cells to lungs, decrease in AHR, and inflammation.	('inhibited', 'NegReg', (23, 32))	('DSCG', 'Var', (18, 22))	('reduced', 'NegReg', (94, 101))	('inflammation', 'biological_process', 'GO:0006954', ('171', '183'))	('decrease', 'NegReg', (150, 158))	('AHR', 'MPA', (162, 165))	('inflammation', 'Disease', 'MESH:D007249', (171, 183))	('S1P', 'Gene', '13609', (65, 68))	('asthma', 'Disease', (33, 39))	('asthma', 'Phenotype', 'HP:0002099', (33, 39))	('asthma', 'Disease', 'MESH:D001249', (33, 39))	('inflammation', 'Disease', (171, 183))	('mice', 'Species', '10090', (72, 76))	('recruitment', 'MPA', (102, 113))	('S1P', 'Gene', (65, 68))	('DSCG', 'Chemical', 'MESH:D004205', (18, 22))
100675	28352271	Beneficial effects of FTY720 in reducing tumor burden in a murine model of urethane-induced lung cancer were also reported.	('lung cancer', 'Disease', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('urethane', 'Chemical', 'MESH:D014520', (75, 83))	('FTY720', 'Var', (22, 28))	('reducing', 'NegReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('murine', 'Species', '10090', (59, 65))	('FTY720', 'Chemical', 'MESH:D000068876', (22, 28))
100677	28352271	It was also noticed that signaling through S1PR3 increased the expression of EGFR and silencing of S1PR3 abolished the S1P-dependent EGFR activation.	('S1P', 'Gene', '13609', (43, 46))	('silencing', 'Var', (86, 95))	('S1P', 'Gene', '13609', (99, 102))	('S1P', 'Gene', '13609', (119, 122))	('EGFR', 'Gene', '13649', (77, 81))	('increased', 'PosReg', (49, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('S1P', 'Gene', (43, 46))	('expression', 'MPA', (63, 73))	('S1P', 'Gene', (99, 102))	('S1P', 'Gene', (119, 122))	('EGFR', 'Gene', (77, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('abolished', 'NegReg', (105, 114))	('EGFR', 'Gene', (133, 137))	('EGFR', 'Gene', '13649', (133, 137))
100679	28352271	A combination of ABC294640, an inhibitor of SphK2, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) increased the apoptosis in NSCLC cell lines in vitro.	('ABC294640', 'Chemical', 'MESH:C548780', (17, 26))	('apoptosis', 'CPA', (133, 142))	('necrosis', 'biological_process', 'GO:0008220', ('61', '69'))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('55', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('necrosis', 'biological_process', 'GO:0070265', ('61', '69'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ABC294640', 'Var', (17, 26))	('necrosis', 'biological_process', 'GO:0019835', ('61', '69'))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('necrosis', 'biological_process', 'GO:0001906', ('61', '69'))	('ligand', 'molecular_function', 'GO:0005488', ('104', '110'))	('TRAIL', 'Gene', (112, 117))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('TRAIL', 'Gene', '22035', (112, 117))	('necrosis', 'biological_process', 'GO:0008219', ('61', '69'))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '22035', (55, 110))	('increased', 'PosReg', (119, 128))
100680	28352271	Silencing of Sphk2 showed similar effects with TRAIL, as shown by ABC294640.	('TRAIL', 'Gene', (47, 52))	('Sphk2', 'Gene', '56632', (13, 18))	('ABC294640', 'Chemical', 'MESH:C548780', (66, 75))	('Sphk2', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('TRAIL', 'Gene', '22035', (47, 52))
100682	28352271	Silencing either SphK2 or S1P binding pockets leads to decreased stability of hTERT and loss of telomere integrity.	('telomere', 'cellular_component', 'GO:0000781', ('96', '104'))	('binding', 'Interaction', (30, 37))	('S1P', 'Gene', '13609', (26, 29))	('telomere', 'cellular_component', 'GO:0005696', ('96', '104'))	('S1P', 'Gene', (26, 29))	('loss', 'NegReg', (88, 92))	('decreased', 'NegReg', (55, 64))	('SphK2', 'Gene', (17, 22))	('hTERT', 'Gene', '7015', (78, 83))	('telomere', 'MPA', (96, 104))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('hTERT', 'Gene', (78, 83))	('Silencing', 'Var', (0, 9))
100683	28352271	Genetical or pharmacological inhibition of SphK2 decreased the growth of lung tumor in mice.	('lung tumor', 'Disease', 'MESH:D008175', (73, 83))	('SphK2', 'Gene', (43, 48))	('mice', 'Species', '10090', (87, 91))	('lung tumor', 'Phenotype', 'HP:0100526', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decreased', 'NegReg', (49, 58))	('inhibition', 'Var', (29, 39))	('lung tumor', 'Disease', (73, 83))
100686	28352271	Inhibition of this enzyme enhanced the anticancer potential of ABC294640 in lung cancer.	('enhanced', 'PosReg', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (43, 49))	('ABC294640', 'Var', (63, 72))	('cancer', 'Disease', (81, 87))	('ABC294640', 'Chemical', 'MESH:C548780', (63, 72))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
100687	28352271	This study advocates the possibility of a combination of SphK2 inhibitors and GCS inhibitors in lung cancer treatment.	('SphK2', 'Gene', (57, 62))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('inhibitors', 'Var', (63, 73))
100691	28352271	In a mouse model of this disease, the granulomatous inflammation (which was considered as a nearly mesothelioma like symptom) was greatly attenuated in SphK1-/- mice as compared to SphK1+/+ mice indicating the possibility of targeting SphK1 for the treatment of mesothelioma.	('mice', 'Species', '10090', (161, 165))	('granulomatous inflammation', 'Disease', 'MESH:D007249', (38, 64))	('granulomatous inflammation', 'Disease', (38, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('mouse', 'Species', '10090', (5, 10))	('mesothelioma', 'Disease', (262, 274))	('inflammation', 'biological_process', 'GO:0006954', ('52', '64'))	('attenuated', 'NegReg', (138, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (262, 274))	('mice', 'Species', '10090', (190, 194))	('granulomatous inflammation', 'Phenotype', 'HP:0002955', (38, 64))	('mesothelioma', 'Disease', (99, 111))	('SphK1-/-', 'Var', (152, 160))
100698	28352271	Interestingly, there was no protective effect in SphK2-/- against HPH indicating the beneficial role of SphK 1 inhibition in the treatment of PH.	('SphK2-/-', 'Var', (49, 57))	('SphK 1', 'Gene', (104, 110))	('SphK 1', 'Gene', '20698', (104, 110))	('beneficial', 'PosReg', (85, 95))	('HPH', 'Disease', (66, 69))
100702	28352271	The blocking of LTB4 production reversed fulminant PH through the restoration of the SphK1-eNOS pathway.	('LTB4 production', 'Gene', (16, 31))	('fulminant PH', 'Disease', (41, 53))	('rat', 'Species', '10116', (71, 74))	('blocking', 'Var', (4, 12))	('restoration', 'NegReg', (66, 77))	('LTB4', 'Chemical', 'MESH:D007975', (16, 20))	('SphK1-eNOS pathway', 'Pathway', (85, 103))
100705	28352271	It was observed that neutral sphingomyelinase and hypoxia-induced pulmonary vasoconstriction were inhibited by genetic or pharmacological silencing of SphK1 or through antagonism of S1PR 2 and 4.	('sphingomyelinase', 'Disease', (29, 45))	('silencing', 'Var', (138, 147))	('neutral sphingomyelinase', 'molecular_function', 'GO:0061751', ('21', '45'))	('inhibited', 'NegReg', (98, 107))	('S1PR 2 and 4', 'Gene', '14739;13611', (182, 194))	('pulmonary vasoconstriction', 'Phenotype', 'HP:0005308', (66, 92))	('antagonism', 'Var', (168, 178))	('SphK1', 'Gene', (151, 156))	('hypoxia-induced pulmonary vasoconstriction', 'Disease', (50, 92))	('sphingomyelinase', 'Disease', 'MESH:D052536', (29, 45))	('vasoconstriction', 'biological_process', 'GO:0042310', ('76', '92'))	('hypoxia-induced pulmonary vasoconstriction', 'Disease', 'MESH:D000860', (50, 92))
100710	28352271	The exogenous addition of S1P or FTY720 to the CF BALF could restore the expression of MHCII and CD40.	('MHCII', 'Gene', (87, 92))	('CD40', 'Gene', '21939', (97, 101))	('S1P', 'Gene', '13609', (26, 29))	('restore', 'PosReg', (61, 68))	('CD40', 'Gene', (97, 101))	('S1P', 'Gene', (26, 29))	('expression', 'MPA', (73, 83))	('FTY720', 'Chemical', 'MESH:D000068876', (33, 39))	('FTY720', 'Var', (33, 39))
100711	28352271	This effect seems to be mediated through S1PR as the addition of JTE-013 and VPC20319 (an S1PR1/3 agonist) brought down the expression of the activation markers.	('S1P', 'Gene', (90, 93))	('VPC20319', 'Var', (77, 85))	('S1PR1', 'Gene', (90, 95))	('S1P', 'Gene', '13609', (41, 44))	('S1PR1', 'Gene', '13609', (90, 95))	('expression', 'MPA', (124, 134))	('S1P', 'Gene', (41, 44))	('JTE-013', 'Chemical', 'MESH:C471998', (65, 72))	('S1P', 'Gene', '13609', (90, 93))	('activation markers', 'MPA', (142, 160))	('brought', 'Reg', (107, 114))
100712	28352271	The dysfunction of CFTR alters immune cell responses, and CFTR is involved in cellular uptake of S1P.	('immune cell responses', 'CPA', (31, 52))	('S1P', 'Gene', (97, 100))	('uptake', 'biological_process', 'GO:0098657', ('87', '93'))	('uptake', 'biological_process', 'GO:0098739', ('87', '93'))	('alters', 'Reg', (24, 30))	('dysfunction', 'Var', (4, 15))	('S1P', 'Gene', '13609', (97, 100))	('CFTR', 'Gene', (19, 23))
100716	28352271	The expression of a mutated form of CFTR (DeltaF508) is observed in a vast majority of CF patients and leads to an increased sphingolipid synthesis, which indicated that CFTR functions as a feedback system in sphingolipid biosynthesis.	('DeltaF508', 'Mutation', 'p.508delF', (42, 51))	('sphingolipid', 'Chemical', 'MESH:D013107', (209, 221))	('sphingolipid synthesis', 'MPA', (125, 147))	('increased', 'PosReg', (115, 124))	('sphingolipid', 'Chemical', 'MESH:D013107', (125, 137))	('sphingolipid synthesis', 'biological_process', 'GO:0030148', ('125', '147'))	('CFTR', 'Gene', (36, 40))	('sphingolipid biosynthesis', 'biological_process', 'GO:0030148', ('209', '234'))	('patients', 'Species', '9606', (90, 98))	('mutated', 'Var', (20, 27))
100717	28352271	The level of S1P was found to be reduced in a mutant form of CFTR mouse.	('S1P', 'Gene', '13609', (13, 16))	('level', 'MPA', (4, 9))	('mouse', 'Species', '10090', (66, 71))	('mutant', 'Var', (46, 52))	('reduced', 'NegReg', (33, 40))	('S1P', 'Gene', (13, 16))
100718	28352271	However, treatment with SPL inhibitor (LX2931) could restore the S1P levels.	('SPL', 'Gene', (24, 27))	('LX2931', 'Var', (39, 45))	('SPL', 'Gene', '8879', (24, 27))	('S1P', 'Gene', '13609', (65, 68))	('S1P', 'Gene', (65, 68))	('restore', 'PosReg', (53, 60))
100719	28352271	Moreover, the CF phenotype of CFTR mutant mice was partially corrected by LX2931 further confirming the possible therapeutic targeting of S1P signaling in CF.	('S1P', 'Gene', (138, 141))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('LX2931', 'Var', (74, 80))	('mice', 'Species', '10090', (42, 46))	('mutant', 'Var', (35, 41))	('S1P', 'Gene', '13609', (138, 141))
100723	28352271	The knockdown of SphK1 protected mice from lung fibrogenesis.	('lung fibrogenesis', 'CPA', (43, 60))	('SphK1', 'Gene', (17, 22))	('lung fibrogenesis', 'Phenotype', 'HP:0002206', (43, 60))	('mice', 'Species', '10090', (33, 37))	('knockdown', 'Var', (4, 13))
100731	28352271	Further, knockdown of FOXF1 leads to increased expression of S1PR1 and thereby maintain the endothelial barrier integrity.	('knockdown', 'Var', (9, 18))	('FOXF1', 'Gene', (22, 27))	('endothelial', 'MPA', (92, 103))	('FOXF1', 'Gene', '15227', (22, 27))	('maintain', 'PosReg', (79, 87))	('increased', 'PosReg', (37, 46))	('S1PR1', 'Gene', (61, 66))	('S1PR1', 'Gene', '13609', (61, 66))	('expression', 'MPA', (47, 57))
100732	28352271	Genetic screening of ALI subjects found a striking link between a single nucleotide polymorphism in cortactin gene and ALI.	('ALI', 'Disease', (119, 122))	('cortactin', 'Gene', '13043', (100, 109))	('single nucleotide polymorphism', 'Var', (66, 96))	('cortactin', 'Gene', (100, 109))
100734	28352271	Interestingly, this polymorphism in cortactin was responsible for diminishing the barrier protective effects of S1P in endothelial cells making them more susceptible to ALI.	('diminishing', 'NegReg', (66, 77))	('barrier protective effects', 'CPA', (82, 108))	('susceptible', 'MPA', (154, 165))	('polymorphism', 'Var', (20, 32))	('S1P', 'Gene', '13609', (112, 115))	('cortactin', 'Gene', (36, 45))	('cortactin', 'Gene', '13043', (36, 45))	('S1P', 'Gene', (112, 115))	('more', 'PosReg', (149, 153))
100736	28352271	SphK1-/- mice were highly susceptible to RILI and S1P receptor agonists like FTY720, p-FTY720, and SEW2871 attenuated RILI.	('S1P', 'Gene', '13609', (50, 53))	('susceptible', 'Reg', (26, 37))	('attenuated', 'NegReg', (107, 117))	('S1P', 'Gene', (50, 53))	('SEW2871', 'Var', (99, 106))	('RILI', 'CPA', (118, 122))	('FTY720', 'Chemical', 'MESH:D000068876', (87, 93))	('mice', 'Species', '10090', (9, 13))	('p-FTY720', 'Var', (85, 93))	('FTY720', 'Chemical', 'MESH:D000068876', (77, 83))	('RILI', 'CPA', (41, 45))	('FTY720', 'Var', (77, 83))
100743	28352271	reported another mechanism for S1PR2 where it inhibited the signaling through Akt, eNOS, and nitric oxide production and protected the animals from anaphylactic shock.	('eNOS', 'Pathway', (83, 87))	('nitric oxide', 'Chemical', 'MESH:D009569', (93, 105))	('S1PR2', 'Var', (31, 36))	('anaphylactic shock', 'Phenotype', 'HP:0100845', (148, 166))	('signaling', 'MPA', (60, 69))	('Akt', 'Gene', '11651', (78, 81))	('Akt', 'Gene', (78, 81))	('anaphylactic shock', 'MPA', (148, 166))	('nitric oxide production', 'MPA', (93, 116))	('protected', 'PosReg', (121, 130))	('shock', 'Phenotype', 'HP:0031273', (161, 166))	('inhibited', 'NegReg', (46, 55))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
100746	28352271	mRNA expression profiles of different SphKs, S1PRs, SPL, and phosphatase were analyzed in COPD patients and found significant upregulation of SphKs, S1PR2, and S1PR5.	('S1P', 'Gene', (45, 48))	('SPL', 'Gene', (52, 55))	('S1P', 'Gene', (149, 152))	('S1PR5', 'Gene', (160, 165))	('phosphatase', 'molecular_function', 'GO:0016791', ('61', '72'))	('patients', 'Species', '9606', (95, 103))	('S1P', 'Gene', (160, 163))	('SphKs', 'Var', (142, 147))	('SPL', 'Gene', '8879', (52, 55))	('S1P', 'Gene', '13609', (45, 48))	('S1P', 'Gene', '13609', (149, 152))	('S1PR5', 'Gene', '53637', (160, 165))	('COPD', 'Disease', 'MESH:D029424', (90, 94))	('upregulation', 'PosReg', (126, 138))	('COPD', 'Disease', (90, 94))	('S1P', 'Gene', '13609', (160, 163))
100748	28352271	Cigarette smoke-inhibited efferocytosis was significantly reversed by either S1P or FTY720.	('S1P', 'Gene', '13609', (77, 80))	('S1P', 'Gene', (77, 80))	('FTY720', 'Var', (84, 90))	('efferocytosis', 'biological_process', 'GO:0043277', ('26', '39'))	('FTY720', 'Chemical', 'MESH:D000068876', (84, 90))	('efferocytosis', 'MPA', (26, 39))
100755	28352271	S1PR1 located mainly in the pulmonary endothelial cells and agonists such as CYM-5442, RP-002, and AAL-R were effective in protecting the mice from lethal infection with influenza virus.	('influenza virus', 'Species', '11309', (170, 185))	('mice', 'Species', '10090', (138, 142))	('infection', 'Disease', (155, 164))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('S1PR1', 'Gene', '13609', (0, 5))	('CYM-5442', 'Var', (77, 85))	('S1PR1', 'Gene', (0, 5))
100756	28352271	Using a Ferret model of human 2009 pandemic influenza virus infection, it was observed that the S1PR1 agonist RP-002 was effective in alleviating clinical symptoms and lung pathology independent of virus replication.	('pandemic influenza virus infection', 'Disease', 'MESH:D007251', (35, 69))	('human', 'Species', '9606', (24, 29))	('clinical symptoms', 'CPA', (146, 163))	('lung pathology', 'CPA', (168, 182))	('S1PR1', 'Gene', (96, 101))	('S1PR1', 'Gene', '13609', (96, 101))	('pandemic influenza virus infection', 'Disease', (35, 69))	('alleviating', 'NegReg', (134, 145))	('Ferret', 'Species', '9669', (8, 14))	('RP-002', 'Var', (110, 116))
100757	28352271	Importantly, a combination of RP-002 and oseltamivir (an antiviral drug) was more effective in blunting immune response and suppressing viral replication.	('immune response', 'biological_process', 'GO:0006955', ('104', '119'))	('viral replication', 'biological_process', 'GO:0008166', ('136', '153'))	('RP-002', 'Var', (30, 36))	('blunting', 'NegReg', (95, 103))	('viral replication', 'biological_process', 'GO:0019058', ('136', '153'))	('viral replication', 'MPA', (136, 153))	('oseltamivir', 'Chemical', 'MESH:D053139', (41, 52))	('viral replication', 'biological_process', 'GO:0019079', ('136', '153'))	('suppressing', 'NegReg', (124, 135))	('immune response', 'MPA', (104, 119))	('blunting immune response', 'Phenotype', 'HP:0002721', (95, 119))
100820	24981653	In the same study, SWCNT was found to induce MAPK, AP-1 and NF-kappaB, all of which recapitulate the key molecular signaling involved in lung carcinogenesis.	('AP-1', 'Gene', '2353', (51, 55))	('SWCNT', 'Chemical', '-', (19, 24))	('NF-kappaB', 'Gene', '4790', (60, 69))	('lung carcinogenesis', 'Disease', (137, 156))	('induce', 'PosReg', (38, 44))	('MAPK', 'Gene', (45, 49))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (137, 156))	('NF-kappaB', 'Gene', (60, 69))	('AP-1', 'Gene', (51, 55))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('AP-1', 'cellular_component', 'GO:0005907', ('51', '55'))	('SWCNT', 'Var', (19, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))
100824	24981653	Cancer is generally accepted as a disease of the genome as significant genomic alterations (e.g., point mutations, large deletions and amplifications) are observed in almost all forms of human cancer.	('rat', 'Species', '10116', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('point mutations', 'Var', (98, 113))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('large deletions', 'Var', (115, 130))	('amplifications', 'Var', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('human', 'Species', '9606', (187, 192))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
100829	24981653	Alterations in the barrier function are therefore an important determinant of the interaction of xenobiotics with other compartments of the organisms.	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Var', (0, 11))	('interaction', 'Interaction', (82, 93))
100840	24981653	Knockout of IL-1 receptor (Il1r1) gene in C57Bl/6 mice (IL1R-/-) abrogated MWCNT-induced lung inflammation.	('Il1r1', 'Gene', (27, 32))	('lung inflammation', 'Disease', (89, 106))	('IL-1', 'molecular_function', 'GO:0005149', ('12', '16'))	('Il1r1', 'Gene', '16177', (27, 32))	('Il1r', 'molecular_function', 'GO:0004908', ('27', '31'))	('inflammation', 'biological_process', 'GO:0006954', ('94', '106'))	('Knockout', 'Var', (0, 8))	('MWCNT', 'Chemical', '-', (75, 80))	('mice', 'Species', '10090', (50, 54))	('MWCNT-induced', 'Disease', (75, 88))	('lung inflammation', 'Disease', 'MESH:D011014', (89, 106))	('IL1R', 'molecular_function', 'GO:0004908', ('56', '60'))	('abrogated', 'NegReg', (65, 74))
100849	24981653	In the same study, MWCNT was also shown to induce collagen production by lung fibroblasts in a dose-dependent manner.	('collagen', 'molecular_function', 'GO:0005202', ('50', '58'))	('MWCNT', 'Var', (19, 24))	('MWCNT', 'Chemical', '-', (19, 24))	('collagen production', 'MPA', (50, 69))	('induce', 'PosReg', (43, 49))
100873	24981653	Apoptosis plays an essential role in the removal of mutated or transformed cells, and its disruption contributes to abnormal cell growth and malignancy.	('cell growth', 'CPA', (125, 136))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('malignancy', 'Disease', (141, 151))	('contributes', 'Reg', (101, 112))	('Apoptosis', 'CPA', (0, 9))	('cell growth', 'biological_process', 'GO:0016049', ('125', '136'))	('disruption', 'Var', (90, 100))
100876	24981653	Aberrant p53 signaling was shown to be involved in CNT apoptosis resistance, consistent with the findings that most human cancers have mutated or inactivated p53.	('involved', 'Reg', (39, 47))	('p53 signaling', 'MPA', (9, 22))	('Aberrant', 'Var', (0, 8))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('mutated', 'Var', (135, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('inactivated', 'NegReg', (146, 157))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('human', 'Species', '9606', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('p53', 'Gene', (158, 161))	('CNT', 'MPA', (51, 54))
100896	24981653	investigated the topical effects of SWCNT in mice and showed an increase in skin bi-fold thickness, an indicator of edema and inflammation, after topical exposure to SWCNT (40-160 mug/mouse) for 5 days.	('40-160 mug/mouse', 'Var', (173, 189))	('edema', 'Disease', (116, 121))	('mice', 'Species', '10090', (45, 49))	('SWCNT', 'Chemical', '-', (36, 41))	('inflammation', 'biological_process', 'GO:0006954', ('126', '138'))	('mug', 'molecular_function', 'GO:0043739', ('180', '183'))	('increase', 'PosReg', (64, 72))	('mouse', 'Species', '10090', (184, 189))	('edema', 'Disease', 'MESH:D004487', (116, 121))	('inflammation', 'Disease', 'MESH:D007249', (126, 138))	('skin bi-fold thickness', 'CPA', (76, 98))	('edema', 'Phenotype', 'HP:0000969', (116, 121))	('topical', 'molecular_function', 'GO:0003809', ('146', '153'))	('topical', 'molecular_function', 'GO:0003809', ('17', '24'))	('SWCNT', 'Chemical', '-', (166, 171))	('inflammation', 'Disease', (126, 138))
100969	25670913	EGFR overexpression in mesothelioma samples was reported by several authors, and inhibition of EGFR-dependent signaling pathway in mesothelioma cell lines also leads to decreased cell survival.	('cell survival', 'CPA', (179, 192))	('EGFR', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('inhibition', 'Var', (81, 91))	('overexpression', 'PosReg', (5, 19))	('mesothelioma', 'Disease', (131, 143))	('signaling pathway', 'biological_process', 'GO:0007165', ('110', '127'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', '1956', (95, 99))	('decreased', 'NegReg', (169, 178))	('mesothelioma', 'Disease', (23, 35))	('EGFR', 'Gene', '1956', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))	('EGFR', 'Gene', (95, 99))
100971	25670913	Additional data showed that mutations found in patients with other cancers may not be the same in malignant mesothelioma tumors, or alternatively the frequency of mutation may be too low in mesothelioma patients, resulting in the lack of clinical response in non-selected patients.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (190, 202))	('cancers', 'Disease', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mesothelioma', 'Disease', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (47, 55))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (98, 120))	('patients', 'Species', '9606', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('patients', 'Species', '9606', (272, 280))	('mesothelioma', 'Disease', (190, 202))	('malignant mesothelioma tumors', 'Disease', 'MESH:C562839', (98, 127))	('malignant mesothelioma tumors', 'Disease', (98, 127))	('mutations', 'Var', (28, 37))
100997	25670913	Preclinical studies showed a dose-dependent and receptor-dependent 94% reduction of tumor growth with BAY 94-9343 compared to 70% with cisplatin and pemetrexed chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('reduction', 'NegReg', (71, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('tumor', 'Disease', (84, 89))	('BAY 94-9343', 'Var', (102, 113))	('pemetrexed', 'Chemical', 'MESH:D000068437', (149, 159))
100999	25670913	Mesothelin acts as an antigen and stimulates activation of T-cells upon exposure to CRS-207.	('Mesothelin', 'Gene', '10232', (0, 10))	('Mesothelin', 'Gene', (0, 10))	('stimulates activation', 'PosReg', (34, 55))	('CRS-207', 'Var', (84, 91))	('CRS', 'Chemical', 'MESH:D002857', (84, 87))	('T-cells', 'CPA', (59, 66))
101034	25670913	This approach utilizes engineered viruses that deliver transgenes encoding enzymes that metabolize prodrugs into toxic metabolites capable of killing tumor cells.	('metabolize', 'MPA', (88, 98))	('engineered viruses', 'Disease', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('transgenes', 'Var', (55, 65))	('engineered viruses', 'Disease', 'MESH:D006482', (23, 41))	('tumor', 'Disease', (150, 155))
101054	25670913	Cryotherapy also may enhance immune responses through enhanced natural killer cell activity, T-cell responses and systemic IFN production.	('Cryotherapy', 'Var', (0, 11))	('IFN', 'Gene', '3439', (123, 126))	('enhance', 'PosReg', (21, 28))	('systemic', 'CPA', (114, 122))	('IFN', 'Gene', (123, 126))	('T-cell responses', 'CPA', (93, 109))	('natural killer cell activity', 'CPA', (63, 91))	('immune responses', 'CPA', (29, 45))	('enhanced', 'PosReg', (54, 62))	('enhanced natural killer cell activity', 'Phenotype', 'HP:0012178', (54, 91))
101055	25670913	In an animal model of prostate cancer, tumor cryotherapy with simultaneous anti-CTLA-4 immunotherapy produced enhanced immune-mediated protection against tumor rechallenge at both primary and distant tumor sites.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('immune-mediated protection', 'CPA', (119, 145))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('anti-CTLA-4', 'Gene', (75, 86))	('enhanced', 'PosReg', (110, 118))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('tumor', 'Disease', (39, 44))	('anti-CTLA-4', 'Var', (75, 86))	('tumor', 'Disease', (154, 159))
101061	18827603	Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins.	('proteasomal degradation of', 'MPA', (38, 64))	('Hsp90', 'Gene', (14, 19))	('degradation', 'biological_process', 'GO:0009056', ('50', '61'))	('Hsp90', 'Gene', '3320', (14, 19))	('Inhibition', 'Var', (0, 10))	('leads to', 'Reg', (29, 37))
101067	18827603	These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.	('Hsp90', 'Gene', (27, 32))	('growth', 'CPA', (65, 71))	('Hsp90', 'Gene', '3320', (27, 32))	('associated', 'Reg', (45, 55))	('Hsp90', 'Gene', (114, 119))	('inhibition', 'Var', (100, 110))	('Hsp90', 'Gene', '3320', (114, 119))	('survival', 'CPA', (76, 84))
101075	18827603	Inhibition of Hsp90 function disrupts the complex and leads to degradation of client proteins in a proteasome-dependent manner.	('Hsp90', 'Gene', (14, 19))	('Hsp90', 'Gene', '3320', (14, 19))	('proteasome', 'cellular_component', 'GO:0000502', ('99', '109'))	('complex', 'MPA', (42, 49))	('proteasome', 'molecular_function', 'GO:0004299', ('99', '109'))	('degradation', 'biological_process', 'GO:0009056', ('63', '74'))	('Inhibition', 'Var', (0, 10))	('degradation of client proteins', 'MPA', (63, 93))	('leads to', 'Reg', (54, 62))	('disrupts', 'NegReg', (29, 37))
101081	18827603	It has been demonstrated that AKT is constitutively active in many types of human cancers and that aberrant activation of the PI3K/AKT survival pathway leads to an increase in antiapoptotic signals that inhibit the effectiveness of conventional chemotherapy.	('AKT', 'Gene', '207', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('aberrant', 'Var', (99, 107))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('AKT', 'Gene', (131, 134))	('AKT', 'Gene', '207', (30, 33))	('cancers', 'Disease', (82, 89))	('antiapoptotic signals', 'MPA', (176, 197))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('human', 'Species', '9606', (76, 81))	('effectiveness of conventional chemotherapy', 'CPA', (215, 257))	('inhibit', 'NegReg', (203, 210))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('AKT', 'Gene', (30, 33))	('increase', 'PosReg', (164, 172))	('activation', 'PosReg', (108, 118))
101110	18827603	Specifically, in H2052 cells significant accumulation of cells in G1 phase was observed in both the 1 microM and the 2 microM 17-AAG treated cells as opposed to in the DMSO treated ones (1 microM: p = 0.03, 2 microM: p < 0.01).	('H2052', 'Var', (17, 22))	('AAG', 'Gene', (129, 132))	('accumulation', 'PosReg', (41, 53))	('G1 phase', 'biological_process', 'GO:0051318', ('66', '74'))	('AAG', 'Gene', '4350', (129, 132))	('H2052', 'Chemical', '-', (17, 22))	('DMSO', 'Chemical', 'MESH:D004121', (168, 172))	('cells in G1 phase', 'CPA', (57, 74))
101118	18827603	Increased levels of Hsp90 and Hsp70 are an indication of cellular stress response, and inhibition of Hsp90 function has been previously reported to increase Hsp90 and Hsp70 levels in various cancer cell types.	('cancer', 'Disease', (191, 197))	('levels', 'MPA', (10, 16))	('increase', 'PosReg', (148, 156))	('Hsp90', 'Gene', '3320', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Hsp70', 'Gene', '3308', (30, 35))	('Hsp70', 'Gene', '3308', (167, 172))	('Hsp90', 'Gene', (101, 106))	('Hsp90', 'Gene', '3320', (101, 106))	('Hsp70', 'Gene', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Hsp90', 'Gene', (157, 162))	('Hsp70', 'Gene', (30, 35))	('inhibition', 'Var', (87, 97))	('Hsp90', 'Gene', (20, 25))	('Hsp90', 'Gene', '3320', (157, 162))
101127	18827603	In H2052 and 211H cells, significant apoptosis induction was observed after three days of treatment with 2 microM 17-AAG (H2052: p < 0.01; 211H: p = 0.02).	('H2052', 'Var', (3, 8))	('AAG', 'Gene', '4350', (117, 120))	('apoptosis', 'CPA', (37, 46))	('H2052', 'Chemical', '-', (122, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('H2052', 'Chemical', '-', (3, 8))	('AAG', 'Gene', (117, 120))
101129	18827603	In H2052 and 211H, the expression of cleaved PARP protein increased after three days of treatment with 2 microM 17-AAG.	('H2052', 'Var', (3, 8))	('AAG', 'Gene', '4350', (115, 118))	('increased', 'PosReg', (58, 67))	('PARP', 'Gene', (45, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('H2052', 'Chemical', '-', (3, 8))	('AAG', 'Gene', (115, 118))	('expression of cleaved', 'MPA', (23, 44))	('PARP', 'Gene', '142', (45, 49))
101145	18827603	There are extensive preclinical data both in vitro and in vivo suggesting that inhibition of Hsp90 is a rational therapeutic approach to cancer, either alone or in combination with standard chemotherapeutic drugs.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Hsp90', 'Gene', (93, 98))	('Hsp90', 'Gene', '3320', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('inhibition', 'Var', (79, 89))	('cancer', 'Disease', (137, 143))
101161	18827603	It has also been reported that inhibition of AKT leads to suppression of cell growth and apoptosis in MM.	('cell growth', 'CPA', (73, 84))	('AKT', 'Gene', (45, 48))	('apoptosis', 'CPA', (89, 98))	('inhibition', 'Var', (31, 41))	('cell growth', 'biological_process', 'GO:0016049', ('73', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('AKT', 'Gene', '207', (45, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('suppression', 'NegReg', (58, 69))
101164	18827603	Our findings suggest that inhibition of Hsp90 function is a promising therapeutic target for a highly aggressive and inexorably fatal cancer.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('inhibition', 'Var', (26, 36))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('Hsp90', 'Gene', (40, 45))	('Hsp90', 'Gene', '3320', (40, 45))
101218	32921755	Furthermore, the diagnostic performance of additional CT features (table 5) was evaluated: concomitant costal, mediastinal and diaphragmatic pleura lesions nodular/irregular thickening with mediastinal pleural involvement nodular/irregular thickening with diaphragmatic pleural involvement (Fig.	('pleural involvement', 'Disease', (270, 289))	('diaphragmatic pleura lesions', 'Disease', (127, 155))	('pleural involvement', 'Disease', 'MESH:D010995', (270, 289))	('pleural involvement', 'Disease', (202, 221))	('diaphragmatic pleura lesions', 'Disease', 'MESH:D054363', (127, 155))	('pleural involvement', 'Disease', 'MESH:D010995', (202, 221))	('nodular/irregular', 'Var', (156, 173))	('nodular/irregular', 'Var', (222, 239))
101243	32921755	The good sensibility such as detection of nodular pleural thickening, it may lead to reconsider the diagnostic pathway of diffuse pleural disease, avoiding the use of VATS in patients not eligible for surgery, in favor of US or CT guided core biopsy.	('pleural disease', 'Phenotype', 'HP:0002103', (130, 145))	('pleural thickening', 'Phenotype', 'HP:0031944', (50, 68))	('patients', 'Species', '9606', (175, 183))	('nodular', 'Var', (42, 49))	('pleural disease', 'Disease', (130, 145))	('core', 'cellular_component', 'GO:0019013', ('238', '242'))	('pleural disease', 'Disease', 'MESH:D010995', (130, 145))
101254	19470726	The feasibility of imaging virus-targeted tumor using the hNET reporter system with [123I]MIBG gamma-camera and [124I]MIBG PET was demonstrated in an orthotopic pleural mesothelioma tumor model.	('tumor', 'Disease', (42, 47))	('pleural mesothelioma tumor', 'Disease', (161, 187))	('tumor', 'Disease', (182, 187))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (169, 187))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (161, 181))	('hNET', 'Gene', (58, 62))	('hNET', 'Gene', '6530', (58, 62))	('[124I]MIBG', 'Chemical', '-', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (84, 94))	('[123I', 'Var', (84, 89))	('[124I]', 'Var', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pleural mesothelioma tumor', 'Disease', 'MESH:D008654', (161, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
101270	19470726	This is a recombinant vaccina virus expressing transgenes for the human norepinephrine transporter (hNET) and ss-galactosidase.	('norepinephrine transporter', 'Gene', '6530', (72, 98))	('transgenes', 'Var', (47, 57))	('hNET', 'Gene', (100, 104))	('human', 'Species', '9606', (66, 71))	('hNET', 'Gene', '6530', (100, 104))	('norepinephrine transporter', 'Gene', (72, 98))
101272	19470726	The use of hNET reporter gene imaging is particularly attractive from a clinical-investigative standpoint because (a) hNET is a human protein that should minimize immunogenicity and (b) MIBG can be radiolabeled with 123I or 131I for single-photon emission computed tomography (SPECT) and gamma-camera imaging and also with 124I for positron emission tomography (PET) imaging.	('123I', 'Chemical', 'MESH:C000614958', (216, 220))	('131I', 'Var', (224, 228))	('hNET', 'Gene', (11, 15))	('123I', 'Var', (216, 220))	('124I', 'Chemical', 'MESH:C000614959', (323, 327))	('hNET', 'Gene', '6530', (11, 15))	('MIBG', 'Chemical', 'MESH:D019797', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('human', 'Species', '9606', (128, 133))	('hNET', 'Gene', (118, 122))	('hNET', 'Gene', '6530', (118, 122))	('MIBG', 'Gene', (186, 190))
101273	19470726	Currently, [123I]MIBG is a clinically approved radiolabeled probe for imaging hNET expression.	('[123I]MIBG', 'Chemical', 'MESH:D019797', (11, 21))	('hNET', 'Gene', (78, 82))	('hNET', 'Gene', '6530', (78, 82))	('[123I]', 'Var', (11, 17))
101274	19470726	In this study we show that insertion of the hNET reporter gene into a recombinant vaccinia virus does not alter tumor killing; GLV-1h99 retains excellent tumor specificity and cytotoxic efficacy.	('GLV-1h99', 'Var', (127, 135))	('GLV-1h99', 'Chemical', '-', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('hNET', 'Gene', (44, 48))	('vaccinia virus', 'Species', '10245', (82, 96))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cytotoxic efficacy', 'CPA', (176, 194))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (112, 117))	('hNET', 'Gene', '6530', (44, 48))	('tumor', 'Disease', (154, 159))
101275	19470726	In addition, we demonstrate the feasibility of using the hNET reporter system for in vivo noninvasive imaging of oncolytic viral therapy in an orthotopic pleural mesothelioma tumor model by [123I]MIBG gamma-camera imaging and [124I]MIBG PET imaging.	('pleural mesothelioma tumor', 'Disease', 'MESH:D008654', (154, 180))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (154, 174))	('[123I]', 'Var', (190, 196))	('pleural mesothelioma tumor', 'Disease', (154, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (190, 200))	('[124I]MIBG', 'Chemical', '-', (226, 236))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (162, 180))	('hNET', 'Gene', (57, 61))	('hNET', 'Gene', '6530', (57, 61))
101283	19470726	After incubation for 6 hours, cells were infected with GLV-1h99 or GLV-1h68 at MOI's (multiplicity of infection) of 1.0, 0.10, and 0.01 and 0 (control wells).	('GLV-1h99', 'Var', (55, 63))	('GLV-1h99', 'Chemical', '-', (55, 63))	('GLV-1h68', 'Species', '502057', (67, 75))	('GLV-1h68', 'Var', (67, 75))
101288	19470726	[123I]MIBG radiotracer uptake studies were performed in MSTO-211h and PANC1 cells after infection with virus (GLV-1h99 or GLV-1h68) as well as in the neuroblastoma cell line, SK-N-SH, using previously described methods.	('SK-N-SH', 'CellLine', 'CVCL:0531', (175, 182))	('GLV-1h68', 'Species', '502057', (122, 130))	('1h', 'Chemical', '-', (126, 128))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (0, 10))	('uptake', 'biological_process', 'GO:0098657', ('23', '29'))	('uptake', 'biological_process', 'GO:0098739', ('23', '29'))	('GLV-1h99', 'Chemical', '-', (110, 118))	('neuroblastoma', 'Disease', 'MESH:D009447', (150, 163))	('PANC1', 'CellLine', 'CVCL:0480', (70, 75))	('1h', 'Chemical', '-', (63, 65))	('neuroblastoma', 'Disease', (150, 163))	('1h', 'Chemical', '-', (114, 116))	('GLV-1h68', 'Var', (122, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (150, 163))
101304	19470726	The maximum specific activities (no carrier-added synthesis) for the [123I]- and [124I]-labeled compounds were 8.9 and 1.2 TBq/mumol (241 and 33 Ci/mumol), respectively, due to the 7.4-fold difference in the decay rate of the two isotopes.	('decay', 'MPA', (208, 213))	('[123I]-', 'Var', (69, 76))	('TBq', 'Chemical', '-', (123, 126))	('synthesis', 'biological_process', 'GO:0009058', ('50', '59'))	('123I', 'Chemical', 'MESH:C000614958', (70, 74))	('carrier', 'molecular_function', 'GO:0005215', ('36', '43'))	('[124I]', 'Var', (81, 87))	('124I', 'Chemical', 'MESH:C000614959', (82, 86))
101305	19470726	Each animal was injected intravenously with ~18.5 MBq (500 muCi) of [123I]MIBG 48h after intrapleural GLV-1h99 injection and imaged on a X-SPECT  dedicated small-animal gamma camera SPECT-CT scanner (Gamma Medica, Northridge, CA).	('GLV-1h99', 'Chemical', '-', (102, 110))	('[123I]', 'Var', (68, 74))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (68, 78))	('MIBG', 'Gene', (74, 78))
101321	19470726	At all acquired scans (including [18F]FDG PET, serial [124I]MIBG PET and [123I]MIBG gamma-camera) ROI's were manually drawn over tumor, lung, liver and skeletal muscle.	('[123I]MIBG', 'Var', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('[124I]MIBG', 'Chemical', '-', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (73, 83))	('tumor', 'Disease', (129, 134))
101325	19470726	Four mesothelioma and four pancreatic cancer cell lines demonstrated lytic cytotoxicity following exposure to GLV-1h99 (hNET-expressing virus) and to GLV-1h68 (non-hNET containing virus).	('hNET', 'Gene', (120, 124))	('hNET', 'Gene', '6530', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cytotoxicity', 'Disease', (75, 87))	('hNET', 'Gene', (164, 168))	('GLV-1h68', 'Species', '502057', (150, 158))	('pancreatic cancer', 'Disease', (27, 44))	('mesothelioma', 'Disease', 'MESH:D008654', (5, 17))	('hNET', 'Gene', '6530', (164, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('GLV-1h99', 'Var', (110, 118))	('GLV-1h99', 'Chemical', '-', (110, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('GLV-1h68', 'Var', (150, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('mesothelioma', 'Disease', (5, 17))
101326	19470726	Similar cytotoxicity was observed with GLV-1h99 and GLV-1h68 at a MOI of 1.0 (Figure 1A) and a dose-dependent lytic effect was also demonstrated (Figure 1B).	('GLV-1h68', 'Var', (52, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (8, 20))	('GLV-1h68', 'Species', '502057', (52, 60))	('cytotoxicity', 'Disease', (8, 20))	('GLV-1h99', 'Chemical', '-', (39, 47))	('GLV-1h99', 'Var', (39, 47))
101348	19470726	The highest levels of radioactivity in the pleural tumors were found 48h after injection of GLV-1h99 (hNET-expressing virus), followed by tumors that were injected with GLV-1h99 72h prior to [124I]MIBG administration.	('hNET', 'Gene', '6530', (102, 106))	('pleural tumors', 'Disease', 'MESH:D010997', (43, 57))	('2h', 'Chemical', 'MESH:D003903', (179, 181))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GLV-1h99', 'Var', (92, 100))	('[124I]MIBG', 'Chemical', '-', (191, 201))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('radioactivity', 'MPA', (22, 35))	('pleural tumors', 'Disease', (43, 57))	('GLV-1h99', 'Chemical', '-', (169, 177))	('GLV-1h99', 'Chemical', '-', (92, 100))	('hNET', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
101349	19470726	Low levels of radioactivity were observed in tumors that were injected with GLV-1h68 (non-hNET containing virus) and in tumors that were not injected with virus (Figure 4B).	('GLV-1h68', 'Var', (76, 84))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('radioactivity', 'MPA', (14, 27))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('hNET', 'Gene', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('GLV-1h68', 'Species', '502057', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('hNET', 'Gene', '6530', (90, 94))
101351	19470726	The decrease in tumor activity was more rapid over the first 12 hours after [124I]MIBG administration in the two control groups; tumors injected with GLV-1h68 (non-hNET containing virus) or no virus.	('tumors', 'Disease', (129, 135))	('hNET', 'Gene', (164, 168))	('GLV-1h68', 'Species', '502057', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('hNET', 'Gene', '6530', (164, 168))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('decrease', 'NegReg', (4, 12))	('[124I]', 'Var', (76, 82))	('MIBG', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (129, 134))	('[124I]MIBG', 'Chemical', '-', (76, 86))
101352	19470726	Tumor-to-organ (lung, liver, muscle) ratios were calculated from the PET image data (as described in the Material and Methods section) and the highest values were obtained for the group of animals that were infected with GLV-1h99 (hNET-expressing virus) 48h before radiotracer administration (Figure 5).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('hNET', 'Gene', (231, 235))	('GLV-1h99', 'Var', (221, 229))	('GLV-1h99', 'Chemical', '-', (221, 229))	('hNET', 'Gene', '6530', (231, 235))
101357	19470726	The pleural tumors were visualized by [18F]FDG PET imaging, but image contrast at 48 and 72 hours after GLV-1h99 virus (hNET-expressing virus) injection was greater with [124I]MIBG PET compared to [18F]FDG PET.	('hNET', 'Gene', (120, 124))	('hNET', 'Gene', '6530', (120, 124))	('[124I]MIBG PET', 'Var', (170, 184))	('GLV-1h99', 'Chemical', '-', (104, 112))	('pleural tumors', 'Disease', (4, 18))	('[124I]MIBG', 'Chemical', '-', (170, 180))	('pleural tumors', 'Disease', 'MESH:D010997', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('image contrast', 'MPA', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('greater', 'PosReg', (157, 164))
101358	19470726	The [124I]MIBG and [18F]FDG tumor-to-lung, tumor-to-liver and tumor-to-muscle ratios in control animals were similar.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('[124I]MIBG', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (43, 48))	('[124I]MIBG', 'Chemical', '-', (4, 14))	('[18F]FDG', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
101361	19470726	The tumor-to-background ratios for the GLV-1h99 infected animals was with 2.4 +- 0.2, significantly (p < 0.01) higher compared to the group that received no virus, 1.5 +- 0.1.	('tumor', 'Disease', (4, 9))	('GLV-1h99', 'Gene', (39, 47))	('infected', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('higher', 'PosReg', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('GLV-1h99', 'Chemical', '-', (39, 47))
101364	19470726	In addition, all tumors infected with vaccinia virus stained positive for lacZ, confirming the presence of the virus in tumors and indicating that all tumors visualized by [124I]MIBG PET or [123I]MIBG scintigraphy reflect GLV-1h99 expression of a functional hNET transporter protein (Figure 7C and D).	('GLV-1h99', 'Chemical', '-', (222, 230))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors infected', 'Disease', 'MESH:D009369', (17, 32))	('[124I]MIBG', 'Chemical', '-', (172, 182))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (151, 157))	('hNET', 'Gene', '6530', (258, 262))	('[124I]MIBG', 'Var', (172, 182))	('vaccinia virus', 'Species', '10245', (38, 52))	('tumors infected', 'Disease', (17, 32))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (190, 200))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('hNET', 'Gene', (258, 262))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
101376	19470726	The oncolytic potency of GLV-1h99 was shown to be similar to the non-hNET-containing parent virus, GLV-1h68, in eight pancreatic and mesothelioma cancer cell lines.	('GLV-1h99', 'Var', (25, 33))	('GLV-1h68', 'Species', '502057', (99, 107))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('oncolytic', 'CPA', (4, 13))	('GLV-1h99', 'Chemical', '-', (25, 33))	('mesothelioma cancer', 'Disease', (133, 152))	('hNET', 'Gene', (69, 73))	('pancreatic', 'Disease', (118, 128))	('mesothelioma cancer', 'Disease', 'MESH:D008654', (133, 152))	('hNET', 'Gene', '6530', (69, 73))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (133, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
101377	19470726	GLV-1h68 has also been shown to successfully treat an orthotopic animal model of mesothelioma with pleural disease.	('pleural disease', 'Phenotype', 'HP:0002103', (99, 114))	('GLV-1h68', 'Species', '502057', (0, 8))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('pleural disease', 'Disease', (99, 114))	('GLV-1h68', 'Var', (0, 8))	('pleural disease', 'Disease', 'MESH:D010995', (99, 114))	('mesothelioma', 'Disease', (81, 93))
101384	19470726	Interestingly, the low-molecular weight bands were more intense early (12-24h) after GLV-1h99 infection, compared to later time points (48-72h) (Figure 2).	('GLV-1h99', 'Chemical', '-', (85, 93))	('low-molecular weight bands', 'MPA', (19, 45))	('GLV-1h99', 'Gene', (85, 93))	('intense', 'PosReg', (56, 63))	('2h', 'Chemical', 'MESH:D003903', (140, 142))	('infection', 'Var', (94, 103))
101388	19470726	The uptake levels were lower in the GLV-1h99 infected cells compared to the hNET-expressing neuroblastoma cells.	('uptake', 'biological_process', 'GO:0098657', ('4', '10'))	('neuroblastoma', 'Disease', 'MESH:D009447', (92, 105))	('uptake', 'biological_process', 'GO:0098739', ('4', '10'))	('hNET', 'Gene', (76, 80))	('neuroblastoma', 'Disease', (92, 105))	('GLV-1h99', 'Chemical', '-', (36, 44))	('GLV-1h99', 'Var', (36, 44))	('hNET', 'Gene', '6530', (76, 80))	('neuroblastoma', 'Phenotype', 'HP:0003006', (92, 105))	('lower', 'NegReg', (23, 28))	('uptake levels', 'MPA', (4, 17))
101414	19470726	The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [123I]MIBG gamma-camera and [124I]MIBG PET imaging in an orthotopic pleural mesothelioma animal model.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (266, 286))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (266, 286))	('norepinephrine transporter', 'Gene', '6530', (114, 140))	('vaccinia virus', 'Species', '10245', (69, 83))	('GLV-1h99', 'Chemical', '-', (85, 93))	('[124I]', 'Var', (226, 232))	('pleural mesothelioma', 'Disease', (266, 286))	('hNET', 'Gene', (142, 146))	('hNET', 'Gene', '6530', (142, 146))	('human', 'Species', '9606', (108, 113))	('[124I]MIBG', 'Chemical', '-', (226, 236))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (198, 208))	('norepinephrine transporter', 'Gene', (114, 140))
101442	24565018	The capabilities of MTBHsp70 as a potent immune adjuvant have been well characterized in cancer models including murine models of melanoma and lymphoma .	('MTBHsp70', 'Var', (20, 28))	('melanoma and lymphoma', 'Disease', 'MESH:D008545', (130, 151))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('murine', 'Species', '10090', (113, 119))	('cancer', 'Disease', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
101443	24565018	While in these studies, proteins or peptides fused with Hsp70 used for immunizations in mice were shown to generate humoral or cellular immune responses, we expect that fusion of anti-MSLN scFv and MTBHsp70 takes advantage of the immune-activating action of MTBHsp70 and the tumor-targeting activity of the scFv, which will yield anti-tumor responses against the broadest profile of tumor antigens.	('tumor', 'Disease', (275, 280))	('Hsp70', 'Gene', (56, 61))	('Hsp70', 'Gene', '15511', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('rat', 'Species', '10116', (111, 114))	('Hsp70', 'Gene', (261, 266))	('scFv', 'Gene', '652070', (189, 193))	('scFv', 'Gene', (189, 193))	('scFv', 'Gene', (307, 311))	('Hsp70', 'Gene', '15511', (261, 266))	('scFv', 'Gene', '652070', (307, 311))	('tumor', 'Disease', (383, 388))	('yield', 'Reg', (324, 329))	('fusion', 'Var', (169, 175))	('tumor', 'Disease', (335, 340))	('tumor', 'Disease', 'MESH:D009369', (383, 388))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('Hsp70', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('Hsp70', 'Gene', '15511', (201, 206))
101446	24565018	VH and VL from anti-MSLN P4 scFv  are linked using a (G4S)3 linker and fused to full length MTBHsp70 with a (G4S)3 linker in between.	('scFv', 'Gene', '652070', (28, 32))	('scFv', 'Gene', (28, 32))	('anti-MSLN P4', 'Var', (15, 27))
101449	24565018	Furthermore, the binding of MTBHsp70 to cancer cells cannot be blocked by recombinant MSLN.	('binding', 'Interaction', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('MTBHsp70', 'Var', (28, 36))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
101452	24565018	In order to determine if scFvMTBHsp70 also binds to normal tissue in addition to tumor cells, we incubated the fusion protein with peripheral blood leukocytes (PBLs), splenocytes, or peritoneal mesothelial cells from healthy FVB/NJ mice, and stained the cells using the same method as was used for staining tumor cells.	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('scFvMTBHsp70', 'Var', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PBLs', 'Chemical', '-', (160, 164))	('tumor', 'Disease', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('mice', 'Species', '10090', (232, 236))
101453	24565018	As shown in Figure  1E, scFvMTBHsp70 binds with peritoneal mesothelial cells at a low level compared to ovarian cancer and mesothelioma cells.	('ovarian cancer', 'Disease', (104, 118))	('scFvMTBHsp70', 'Var', (24, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('binds', 'Interaction', (37, 42))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mesothelioma', 'Disease', (123, 135))
101455	24565018	Since scFvMTBHsp70 may potentially target peritoneal mesothelial cells, we also explored whether it could induce inflammation in peritoneal mesothelial tissues.	('induce', 'Reg', (106, 112))	('inflammation in peritoneal', 'Phenotype', 'HP:0002586', (113, 139))	('scFvMTBHsp70', 'Var', (6, 18))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('inflammation', 'biological_process', 'GO:0006954', ('113', '125'))	('inflammation', 'Disease', (113, 125))
101456	24565018	We injected naive mice with saline, scFvMTBHsp70, or MTBHsp70 plus P4 scFv at the same doses as those used for tumor therapy described in Method, sacrificed the mice 7 days post final treatments, and examined haematoxylin and eosin (H&E) stained sections prepared from abdominal and intestinal peritoneum.	('MTBHsp70', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mice', 'Species', '10090', (161, 165))	('neu', 'Gene', (300, 303))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('H&E', 'Chemical', '-', (233, 236))	('mice', 'Species', '10090', (18, 22))	('saline', 'Chemical', 'MESH:D012965', (28, 34))	('haematoxylin', 'Chemical', 'MESH:D006416', (209, 221))	('tumor', 'Disease', (111, 116))	('scFv', 'Gene', '652070', (70, 74))	('scFv', 'Gene', (70, 74))	('scFv', 'Gene', '652070', (36, 40))	('eosin', 'Chemical', 'MESH:D004801', (226, 231))	('scFv', 'Gene', (36, 40))	('neu', 'Gene', '13866', (300, 303))
101458	24565018	To determine whether scFvMTBHsp70 can prolong survival in tumor-bearing mice, we first evaluated the protein in a syngeneic mouse model of papillary ovarian cancer using immune-competent FVB/NJ mice.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('scFvMTBHsp70', 'Var', (21, 33))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mouse', 'Species', '10090', (124, 129))	('papillary ovarian cancer', 'Disease', (139, 163))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('mice', 'Species', '10090', (72, 76))	('papillary ovarian cancer', 'Disease', 'MESH:D010051', (139, 163))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('mice', 'Species', '10090', (194, 198))
101462	24565018	To investigate whether the anti-tumor effects of scFvMTBHsp70 was associated with anti-tumor effector CD8+ T-cell responses, we re-stimulated splenocytes from ovarian tumor-bearing FVB mice that received different treatments with the CD8+ T-cell Her2/neu epitope or MSLN Ld1 as a negative control, ex vivo, and analyzed the cells for production of IFNgamma and Granzyme B using flow cytometry.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD8', 'Gene', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('neu epitope', 'Disease', 'MESH:C537366', (251, 262))	('CD8', 'Gene', '925', (102, 105))	('tumor', 'Disease', (167, 172))	('ovarian tumor', 'Disease', (159, 172))	('ovarian tumor', 'Disease', 'MESH:D010051', (159, 172))	('tumor', 'Disease', (87, 92))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CD8', 'Gene', '925', (234, 237))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (32, 37))	('CD8', 'Gene', (102, 105))	('scFvMTBHsp70', 'Var', (49, 61))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('neu epitope', 'Disease', (251, 262))	('ovarian tumor', 'Phenotype', 'HP:0100615', (159, 172))
101465	24565018	This indicates that scFvMTBHsp70 enhances anti-tumor specific CD8+ T-cell responses in ovarian tumor-bearing mice.	('ovarian tumor', 'Disease', 'MESH:D010051', (87, 100))	('enhances', 'PosReg', (33, 41))	('CD8', 'Gene', (62, 65))	('CD8', 'Gene', '925', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mice', 'Species', '10090', (109, 113))	('ovarian tumor', 'Disease', (87, 100))	('ovarian tumor', 'Phenotype', 'HP:0100615', (87, 100))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (95, 100))	('scFvMTBHsp70', 'Var', (20, 32))
101466	24565018	However, no significant difference was seen in the number of tumor-infiltrating CD8+ T cells and no tumor-infiltrating Foxp3+ T cells were seen in tumors from mice in different treatment groups, indicating that scFvMTBHsp70 may improve effector cell function rather than the number of intratumoral CD8+ T cells (Additional file 3: Figure S3A and B).	('tumor', 'Disease', (100, 105))	('CD8', 'Gene', (298, 301))	('S3A and B', 'Gene', '252903;11778', (338, 347))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('rat', 'Species', '10116', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('improve', 'PosReg', (228, 235))	('Foxp3', 'Gene', '20371', (119, 124))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', (147, 152))	('CD8', 'Gene', '925', (80, 83))	('scFvMTBHsp70', 'Var', (211, 223))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('rat', 'Species', '10116', (259, 262))	('CD8', 'Gene', '925', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('CD8', 'Gene', (80, 83))	('effector cell function', 'CPA', (236, 258))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Foxp3', 'Gene', (119, 124))	('tumors', 'Disease', (147, 153))	('rat', 'Species', '10116', (288, 291))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', (61, 66))	('rat', 'Species', '10116', (73, 76))
101467	24565018	To determine whether CD8+ T cells play a major role in the protective anti-tumor effects observed in mice treated with scFvMTBHsp70, we conducted in vivo CD8+ T-cell depletion experiments using monoclonal antibodies.	('CD8', 'Gene', (154, 157))	('CD8', 'Gene', '925', (154, 157))	('CD8', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CD8', 'Gene', '925', (21, 24))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('scFvMTBHsp70', 'Var', (119, 131))	('tumor', 'Disease', (75, 80))
101472	24565018	In order to investigate immunological mechanisms involved in the scFvMTBHsp70-enhanced anti-tumor immune response, we first examined if the scFvMTBHsp70 or MTBHsp70 proteins used in our study could stimulate maturation of bone marrow-derived dendritic cells (BMDCs) as shown in previous studies .	('scFvMTBHsp70', 'Var', (140, 152))	('stimulate', 'PosReg', (198, 207))	('MTBHsp70', 'Gene', (156, 164))	('immune response', 'biological_process', 'GO:0006955', ('98', '113'))	('scFvMTBHsp70-enhanced', 'Var', (65, 86))	('maturation', 'CPA', (208, 218))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('rat', 'Species', '10116', (212, 215))	('tumor', 'Disease', (92, 97))
101475	24565018	After a 24 h-incubation, both scFvMTBHsp70 and MTBHsp70 induced DC maturation indicated by an increase in the expression of CD40, CD80, CD86 and MHC class II molecules in comparison to the control cultures in medium.	('CD80', 'Gene', (130, 134))	('CD40', 'Gene', (124, 128))	('rat', 'Species', '10116', (71, 74))	('MTBHsp70', 'Var', (47, 55))	('increase', 'PosReg', (94, 102))	('CD86', 'Gene', (136, 140))	('CD86', 'Gene', '12524', (136, 140))	('CD80', 'Gene', '12519', (130, 134))	('MHC class', 'Gene', (145, 154))	('DC maturation', 'CPA', (64, 77))	('expression', 'MPA', (110, 120))	('scFvMTBHsp70', 'Var', (30, 42))	('CD40', 'Gene', '21939', (124, 128))
101477	24565018	The contamination control showed that addition of 0.1 ng/ml LPS did not replicate the effects of scFvMTBHsp70 or MTBHsp70, allowing us to discriminate the scFvMTBHsp70- or MTBHsp70-specific effects from effects of LPS (Figure  4A and B).	('scFvMTBHsp70-', 'Var', (155, 168))	('LPS', 'Gene', '21898', (60, 63))	('LPS', 'Gene', '21898', (214, 217))	('LPS', 'Gene', (60, 63))	('LPS', 'Gene', (214, 217))
101479	24565018	To determine whether scFvMTBHsp70 promotes tumor specific T-cell responses by enhancing antigen presentation and cross-presentation by antigen presenting cells, we co-cultured BR5FVB1 tumor cell-primed T cells with DCs that had been pulsed with BR5FVB1 tumor cells in the presence of scFv-MTBHsp70, MTBHsp70, or PBS.	('cross-presentation', 'MPA', (113, 131))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('scFv', 'Gene', '652070', (284, 288))	('PBS', 'Disease', (312, 315))	('scFv', 'Gene', (284, 288))	('tumor', 'Disease', (43, 48))	('cross-presentation', 'biological_process', 'GO:0042590', ('113', '131'))	('enhancing', 'PosReg', (78, 87))	('antigen presentation', 'MPA', (88, 108))	('scFv', 'Gene', (21, 25))	('scFv', 'Gene', '652070', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (184, 189))	('antigen presentation', 'biological_process', 'GO:0019882', ('88', '108'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cross-presentation', 'biological_process', 'GO:0002479', ('113', '131'))	('promotes', 'PosReg', (34, 42))	('MTBHsp70', 'Var', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cross-presentation', 'biological_process', 'GO:0002480', ('113', '131'))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PBS', 'Disease', 'MESH:D011535', (312, 315))
101480	24565018	The scFvMTBHsp70/tumor cell-pulsed DCs induced significantly higher production of IFN-gamma and Granzyme B from both CD4+ and CD8+ tumor cell-primed T cells as compared with MTBHsp70 or PBS, indicating that scFvMTBHsp70 enhances tumor antigen presentation and cross-presentation by DCs (Figure  4C and D).	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PBS', 'Disease', (186, 189))	('tumor', 'Disease', (131, 136))	('cross-presentation', 'biological_process', 'GO:0042590', ('260', '278'))	('tumor antigen', 'molecular_function', 'GO:0008222', ('229', '242'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('higher', 'PosReg', (61, 67))	('CD8', 'Gene', '925', (126, 129))	('cross-presentation', 'biological_process', 'GO:0002479', ('260', '278'))	('cross-presentation', 'MPA', (260, 278))	('tumor', 'Disease', (17, 22))	('IFN-gamma', 'Gene', '15978', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cross-presentation', 'biological_process', 'GO:0002480', ('260', '278'))	('tumor', 'Disease', (229, 234))	('IFN-gamma', 'Gene', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('enhances', 'PosReg', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('production', 'MPA', (68, 78))	('CD8', 'Gene', (126, 129))	('PBS', 'Disease', 'MESH:D011535', (186, 189))	('scFvMTBHsp70', 'Var', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('antigen presentation', 'biological_process', 'GO:0019882', ('235', '255'))
101481	24565018	Having demonstrated in vitro that scFvMTBHsp70 enhances tumor antigen presentation and cross-presentation by DCs, we next explored whether scFvMTBHsp70 enhances tumor antigen presentation and cross-presentation by DCs and consequently enhances tumor cell immunogenicity in vivo.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cross-presentation', 'MPA', (192, 210))	('tumor antigen', 'molecular_function', 'GO:0008222', ('56', '69'))	('cross-presentation', 'MPA', (87, 105))	('cross-presentation', 'biological_process', 'GO:0042590', ('192', '210'))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('enhances', 'PosReg', (152, 160))	('cross-presentation', 'biological_process', 'GO:0042590', ('87', '105'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('antigen presentation', 'biological_process', 'GO:0019882', ('167', '187'))	('rat', 'Species', '10116', (14, 17))	('cross-presentation', 'biological_process', 'GO:0002479', ('192', '210'))	('tumor', 'Disease', (56, 61))	('cross-presentation', 'biological_process', 'GO:0002479', ('87', '105'))	('cross-presentation', 'biological_process', 'GO:0002480', ('192', '210'))	('enhances', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor antigen', 'molecular_function', 'GO:0008222', ('161', '174'))	('scFvMTBHsp70', 'Var', (139, 151))	('cross-presentation', 'biological_process', 'GO:0002480', ('87', '105'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('enhances', 'PosReg', (235, 243))	('scFvMTBHsp70', 'Var', (34, 46))	('tumor', 'Disease', (244, 249))	('antigen presentation', 'biological_process', 'GO:0019882', ('62', '82'))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
101485	24565018	injection of BR5FVB1 tumor cells with or without scFvMTBHsp70 or MTBhsp70.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('MTB', 'Species', '1773', (65, 68))	('MTBhsp70', 'Var', (65, 73))	('MTB', 'Species', '1773', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
101494	24565018	Treatment using a mixture of MTBHsp70 plus P4 scFv for ovarian tumor or malignant mesothelioma-bearing mice did not increase survival or enhance tumor-specific immune responses, suggesting that only through fusion of the two elements is the immune system effectively activated.	('malignant mesothelioma', 'Disease', (72, 94))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ovarian tumor', 'Phenotype', 'HP:0100615', (55, 68))	('ovarian tumor', 'Disease', 'MESH:D010051', (55, 68))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('scFv', 'Gene', '652070', (46, 50))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (72, 94))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('scFv', 'Gene', (46, 50))	('MTBHsp70', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ovarian tumor', 'Disease', (55, 68))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (72, 94))
101498	24565018	Although several previous studies suggested that MTBHsp70 had pro-inflammatory properties only when contaminated with LPS , other studies have decisively demonstrated that MTBHsp70 alone while not LPS promotes DC maturation and innate immune responses .	('DC maturation', 'CPA', (210, 223))	('MTBHsp70', 'Var', (172, 180))	('LPS', 'Gene', '21898', (118, 121))	('innate immune responses', 'CPA', (228, 251))	('LPS', 'Gene', '21898', (197, 200))	('LPS', 'Gene', (118, 121))	('LPS', 'Gene', (197, 200))	('rat', 'Species', '10116', (161, 164))	('promotes', 'PosReg', (201, 209))	('rat', 'Species', '10116', (217, 220))
101501	24565018	Secondly, MTBHsp70 is capable of delivering epitopes for enhanced processing and MHC-I presentation by DCs to naive CD8+ T cells, a process known as cross-presentation .	('cross-presentation', 'biological_process', 'GO:0002480', ('149', '167'))	('cross-presentation', 'biological_process', 'GO:0042590', ('149', '167'))	('CD8', 'Gene', (116, 119))	('epitopes', 'MPA', (44, 52))	('MTBHsp70', 'Var', (10, 18))	('processing', 'MPA', (66, 76))	('CD8', 'Gene', '925', (116, 119))	('cross-presentation', 'biological_process', 'GO:0002479', ('149', '167'))	('MHC-I presentation', 'Gene', (81, 99))	('enhanced', 'PosReg', (57, 65))
101512	24565018	MTBHsp70 has also been shown to stimulate inflammation and DC maturation via an interaction with CD40 receptors on both DCs and monocytes, thus acting as an alternative ligand to CD40L .	('inflammation', 'Disease', (42, 54))	('DC maturation', 'CPA', (59, 72))	('stimulate', 'PosReg', (32, 41))	('CD40L', 'Gene', '21947', (179, 184))	('CD40', 'Gene', '21939', (97, 101))	('inflammation', 'biological_process', 'GO:0006954', ('42', '54'))	('MTBHsp70', 'Var', (0, 8))	('interaction', 'Interaction', (80, 91))	('CD40', 'Gene', (97, 101))	('ligand', 'molecular_function', 'GO:0005488', ('169', '175'))	('CD40', 'Gene', '21939', (179, 183))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('rat', 'Species', '10116', (66, 69))	('CD40', 'Gene', (179, 183))	('CD40L', 'Gene', (179, 184))
101533	24565018	After purification and hIgG-Fc tag removal, the integrity of scFv-MTBHsp70 and MTBHsp70 were determined by SDS-PAGE, followed by staining with RAPIDstain (G-Bioscience).	('SDS', 'Chemical', 'MESH:D012967', (107, 110))	('MTBHsp70', 'Var', (79, 87))	('scFv', 'Gene', '652070', (61, 65))	('scFv', 'Gene', (61, 65))
101538	24565018	To test whether scFvMTBHsp70 or MTBHsp70 binds to the MSLN-expressing tumor cells, or non-cancerous cells, we incubated BR5FVB1 ovarian tumor cells, 40L mesothelioma cells, or normal cells from FVB mice including PBLs, splenocytes, and peritoneal mesothelial cells with 40 mug/ml scFvMTBHsp70 or 26 mug/ml MTBHsp70, followed by anti-MTBHsp70 (IgG2a) (Biodesign International), biotinylated anti-IgG2a (BD Bioscience), and Streptavidin-APC (BioLegend), and then analyzed the tumor cells by flow cytometry.	('IgG2a', 'Gene', (343, 348))	('ovarian tumor', 'Phenotype', 'HP:0100615', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IgG2a', 'Gene', '668478', (395, 400))	('tumor', 'Disease', 'MESH:D009369', (474, 479))	('tumor', 'Phenotype', 'HP:0002664', (474, 479))	('IgG2a', 'Gene', (395, 400))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('IgG2a', 'cellular_component', 'GO:0071735', ('343', '348'))	('mug', 'molecular_function', 'GO:0043739', ('299', '302'))	('anti-MTBHsp70', 'Var', (328, 341))	('mesothelioma', 'Disease', (153, 165))	('APC', 'cellular_component', 'GO:0005680', ('435', '438'))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', (136, 141))	('ovarian tumor', 'Disease', (128, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('ovarian tumor', 'Disease', 'MESH:D010051', (128, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IgG2a', 'cellular_component', 'GO:0071735', ('395', '400'))	('scFvMTBHsp70', 'Var', (280, 292))	('PBLs', 'Chemical', '-', (213, 217))	('tumor', 'Disease', (474, 479))	('tumor', 'Disease', (70, 75))	('mug', 'molecular_function', 'GO:0043739', ('273', '276'))	('MTBHsp70', 'Var', (306, 314))	('IgG2a', 'Gene', '668478', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mice', 'Species', '10090', (198, 202))	('cancer', 'Disease', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
101548	24565018	injections of scFvMTBHsp70 (2 mug per mouse), normal saline, or an equimolar mixture of MTBHsp70 plus P4 scFv.	('mouse', 'Species', '10090', (38, 43))	('scFv', 'Gene', (14, 18))	('scFv', 'Gene', '652070', (14, 18))	('mug', 'molecular_function', 'GO:0043739', ('30', '33'))	('scFv', 'Gene', (105, 109))	('saline', 'Chemical', 'MESH:D012965', (53, 59))	('scFv', 'Gene', '652070', (105, 109))	('MTBHsp70', 'Var', (88, 96))
101550	24565018	with scFvMTBHsp70 (2 mug per mouse), normal saline, or an equimolar mixture of MTBHsp70 plus P4 scFv.	('scFv', 'Gene', '652070', (96, 100))	('mug', 'molecular_function', 'GO:0043739', ('21', '24'))	('scFv', 'Gene', (96, 100))	('MTBHsp70', 'Var', (79, 87))	('scFv', 'Gene', '652070', (5, 9))	('mouse', 'Species', '10090', (29, 34))	('scFv', 'Gene', (5, 9))	('saline', 'Chemical', 'MESH:D012965', (44, 50))
101556	24565018	Cells were plated in round-bottomed 96-well plates, pulsed with a validated CD8+ T-cell Her2/neu peptide (PDSLRDLSVF, 1 mug/ml; EZBiolab) , an in-house designed H2d-restricted MSLN Ld1 peptide (IPLSYLCDF, 1 mug/ml; EZBiolab) that did not induce ovarian cancer specific T-cell response in H-2q FVB mice, or medium alone for 72 hours when Golgi Plug (BD Bioscience) was added for the last 5 hours as previously described , and then stained with fluorophore-conjugated anti-CD3, anti-CD4, anti-CD8, anti-IFNgamma (BD Pharmingen), and anti-Granzyme B (eBioscience) antibodies.	('mice', 'Species', '10090', (297, 301))	('Golgi', 'cellular_component', 'GO:0005794', ('337', '342'))	('mug', 'molecular_function', 'GO:0043739', ('207', '210'))	('CD3', 'Gene', (471, 474))	('ovarian cancer', 'Disease', 'MESH:D010051', (245, 259))	('anti-CD4', 'Var', (476, 484))	('ovarian cancer', 'Disease', (245, 259))	('mug', 'molecular_function', 'GO:0043739', ('120', '123'))	('CD3', 'Gene', '12501', (471, 474))	('CD8', 'Gene', (491, 494))	('CD8', 'Gene', '925', (491, 494))	('CD8', 'Gene', (76, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (245, 259))	('CD8', 'Gene', '925', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
101566	24565018	Cells were then placed on ice, collected by vigorous pipetting, washed and stained with the following fluorophore-conjugated antibodies: anti-CD11c and anti-CD40 (eBioscience), anti-CD80 (BD Horizon), anti-CD86 and anti-MHC class II (I-Aq) (BD Pharmingen).	('anti-CD11c', 'Var', (137, 147))	('CD80', 'Gene', (182, 186))	('I-Aq', 'Chemical', '-', (234, 238))	('CD86', 'Gene', (206, 210))	('CD86', 'Gene', '12524', (206, 210))	('CD40', 'Gene', '21939', (157, 161))	('CD80', 'Gene', '12519', (182, 186))	('CD40', 'Gene', (157, 161))
101574	24565018	with 50 mul of PBS, or 1 x 106 tumor cells in 50 mul of PBS with or without a pre-incubation with scFvMTBHsp70 or MTBHsp70 at both flanks.	('PBS', 'Disease', 'MESH:D011535', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PBS', 'Disease', 'MESH:D011535', (15, 18))	('PBS', 'Disease', (56, 59))	('PBS', 'Disease', (15, 18))	('tumor', 'Disease', (31, 36))	('MTBHsp70', 'Var', (114, 122))	('pre', 'molecular_function', 'GO:0003904', ('78', '81'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
101655	21534087	It is likely that the carcinogenic effects of asbestos are linked to mutations in certain genes in addition to chromosomal aberrations (CA).	('mutations', 'Var', (69, 78))	('linked', 'Reg', (59, 65))	('carcinogenic', 'Disease', 'MESH:D063646', (22, 34))	('carcinogenic', 'Disease', (22, 34))	('asbestos', 'Chemical', 'MESH:D001194', (46, 54))	('rat', 'Species', '10116', (127, 130))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (111, 134))
101662	21534087	It is known that applying crocidolite or chrysotile to lavaged peritoneal macrophages results in protrusion of fibers from membrane-bound vacuoles, as well as free in the cytoplasm and penetrating the nucleus, as seen by both scanning electron microscopy (SEM) and TEM.	('cytoplasm', 'cellular_component', 'GO:0005737', ('171', '180'))	('crocidolite', 'Var', (26, 37))	('rat', 'Species', '10116', (190, 193))	('nucleus', 'cellular_component', 'GO:0005634', ('201', '208'))	('protrusion', 'CPA', (97, 107))	('membrane', 'cellular_component', 'GO:0016020', ('123', '131'))	('TEM', 'cellular_component', 'GO:0097197', ('265', '268'))	('fibers', 'Protein', (111, 117))	('crocidolite', 'Chemical', 'MESH:D017638', (26, 37))
101666	21534087	Furthermore, crocidolite-stimulated nitric oxide synthase (NOS) activity and expression in murine glial cells was inhibited by Fe supplementation and enhanced by Fe chelation.	('expression', 'MPA', (77, 87))	('enhanced', 'PosReg', (150, 158))	('crocidolite', 'Chemical', 'MESH:D017638', (13, 24))	('NOS) activity', 'molecular_function', 'GO:0047829', ('59', '72'))	('Fe', 'Chemical', 'MESH:D007501', (162, 164))	('nitric oxide synthase', 'Gene', '18125', (36, 57))	('murine', 'Species', '10090', (91, 97))	('supplementation', 'Var', (130, 145))	('activity', 'MPA', (64, 72))	('nitric oxide synthase', 'Gene', (36, 57))	('Fe', 'Chemical', 'MESH:D007501', (127, 129))	('men', 'Species', '9606', (136, 139))	('inhibited', 'NegReg', (114, 123))
101679	21534087	Studies suggest that changes in iron overload resulting in increased oxidative stress is an important mechanism attributable to the development of asbestos-induced peritoneal cancer.	('asbestos-induced peritoneal cancer', 'Disease', 'MESH:D010534', (147, 181))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('asbestos-induced peritoneal cancer', 'Disease', (147, 181))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('men', 'Species', '9606', (139, 142))	('changes', 'Var', (21, 28))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('iron', 'MPA', (32, 36))	('increased', 'PosReg', (59, 68))	('oxidative stress', 'MPA', (69, 85))
101758	21534087	Furthermore, presoaking asbestos fibers with the Fe chelator deferoxamine diminishes toxicity in vitro, and modifying the surface of asbestos with metal oxides reduces the hemolytic potential of chrysotile, amosite, and crocidolite in sheep erythrocytes.	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('asbestos', 'Chemical', 'MESH:D001194', (24, 32))	('toxicity', 'Disease', (85, 93))	('Fe', 'Chemical', 'MESH:D007501', (49, 51))	('sheep', 'Species', '9940', (235, 240))	('amosite', 'Chemical', 'MESH:D017639', (207, 214))	('crocidolite', 'Chemical', 'MESH:D017638', (220, 231))	('metal oxides', 'Chemical', '-', (147, 159))	('modifying', 'Var', (108, 117))	('asbestos', 'Chemical', 'MESH:D001194', (133, 141))	('reduces', 'NegReg', (160, 167))	('diminishes', 'NegReg', (74, 84))	('hemolytic potential', 'MPA', (172, 191))	('deferoxamine', 'Chemical', 'MESH:D003676', (61, 73))	('crocidolite', 'MPA', (220, 231))
101823	21534087	In studies on Chinese hamster ovary cells, UICC chrysotile fiber type B was shown to exert a greater toxicity than either UICC crocidolite or amosite, suggesting that chrysotile is more likely to produce adverse reproductive effects.	('UICC', 'Var', (43, 47))	('ovary', 'Disease', (30, 35))	('crocidolite', 'Chemical', 'MESH:D017638', (127, 138))	('ovary', 'Disease', 'MESH:D010051', (30, 35))	('amosite', 'Chemical', 'MESH:D017639', (142, 149))	('Chinese hamster', 'Species', '10029', (14, 29))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))	('toxicity', 'Disease', (101, 109))
101874	21534087	Moreover, phospholipase A(2) and phosphokinase C inhibitors prevented a chrysotile-induced increase in superoxide formation in murine peritoneal macrophages.	('prevented', 'NegReg', (60, 69))	('phospholipase A', 'molecular_function', 'GO:0004623', ('10', '25'))	('superoxide formation', 'MPA', (103, 123))	('increase', 'PosReg', (91, 99))	('phospholipase A(2', 'Gene', '18778;27281', (10, 27))	('inhibitors', 'Var', (49, 59))	('murine', 'Species', '10090', (127, 133))	('superoxide', 'Chemical', 'MESH:D013481', (103, 113))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))
101904	32083805	We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients.	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('genetic alterations', 'Var', (17, 36))	('tumor', 'Disease', (75, 80))
101907	32083805	The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM.	('mutations', 'Var', (198, 207))	('MPM', 'Gene', (211, 214))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))	('affected', 'Reg', (186, 194))
101908	32083805	Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score.	('TERT', 'Gene', (13, 17))	('nonepithelioid MPM', 'Disease', (65, 83))	('TERT', 'Gene', '7015', (13, 17))	('frequent', 'Reg', (53, 61))	('NF2', 'Gene', (28, 31))	('LATS2', 'Gene', (37, 42))	('Mutations', 'Var', (0, 9))	('S.score', 'Disease', (119, 126))	('associated', 'Reg', (99, 109))	('LATS2', 'Gene', '26524', (37, 42))
101909	32083805	BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes.	('TP53', 'Gene', (26, 30))	('NF2', 'Gene', (6, 9))	('BAP1', 'Gene', (0, 4))	('SETD2', 'Gene', '29072', (36, 41))	('TERT', 'Gene', '7015', (11, 15))	('SETD2', 'Gene', (36, 41))	('TERT', 'Gene', (11, 15))	('TP53', 'Gene', '7157', (26, 30))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (42, 51))
101910	32083805	NF2 mutation rate was higher in asbestos unexposed patient.	('NF2', 'Gene', (0, 3))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('mutation', 'Var', (4, 12))	('higher', 'Reg', (22, 28))	('patient', 'Species', '9606', (51, 58))
101911	32083805	TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival.	('overall', 'MPA', (69, 76))	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('poorer', 'NegReg', (62, 68))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('NF2', 'Gene', (15, 18))	('TP53', 'Gene', '7157', (24, 28))
101924	32083805	A further step requires the integration of somatic mutations in the histologic and molecular profiles of tumors will permit to take into account genetic alterations of key genes, extend our biological information on the tumors, and improve the transfer to clinical practices (Horlings et al., 2015; Huntsman and Ladanyi, 2018).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sma', 'Gene', (303, 306))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sma', 'Gene', '6606', (303, 306))
101925	32083805	The genetic landscape of MPM, recently specified by next-generation sequencing studies (NGS) (Bueno et al., 2016; Hmeljak et al., 2018), confirmed the complexity and the heterogeneity of MPM mutation profiles between patients already suggested by previous sequencing studies (Andujar et al., 2016).	('patients', 'Species', '9606', (217, 225))	('mutation', 'Var', (191, 199))	('MPM', 'Gene', (187, 190))
101927	32083805	Some associations between specific gene mutations and clinical data or histologic and molecular subtypes have been already described, such as the association of TP53 mutations with survival (Bueno et al., 2016), TERT promoter (TERT_prom) mutations with histology (Tallet et al., 2014), or BAP1 mutations with the C1 and the iCluster 1 subtypes, both enriched in MME tumor (de Reynies et al., 2014; Hmeljak et al., 2018).	('TP53', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('MME tumor', 'Disease', 'MESH:D009369', (362, 371))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('BAP1', 'Gene', (289, 293))	('mutations', 'Var', (40, 49))	('TERT', 'Gene', (227, 231))	('associations', 'Interaction', (5, 17))	('association', 'Interaction', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('mutations', 'Var', (294, 303))	('TP53', 'Gene', '7157', (161, 165))	('MME tumor', 'Disease', (362, 371))	('TERT', 'Gene', '7015', (227, 231))	('BAP1', 'Gene', '8314', (289, 293))
101949	32083805	To ensure only high-confidence mutation, the resulting vcf files were filtered according to the criteria in the following order: (a) Low quality: QUAL < 100, Allelic Depth of Alternative variant < 6, Genotype Quality < 99, Variant Frequency < 0.1; (b) Frequent polymorphism: referenced in databases (ExAC version 0.3, 1000 genomes phase 1, version 3 and gnomAD) over 0.1% (1000 Genomes Project Consortium et al.,  2012; Lek et al., 2016); (c) Rare polymorphism: referenced in databases under 0.1%; (d) Artefacts: detected in a series of 71 nontumoral frozen tissue samples from hepatocellular carcinoma (HCC) patients; (e) Variant silent: 'Variant_Classification' = Silent; (f) Variant in noncoding region: 'Variant_Classification' = intron, IGR, 3'UTR, 5'UTR, 5'Flank, 3'Flank; (g) Variant with structural consequence: 'Variant_Classification' = nonsense, missense, splice site, inframe deletion, inframe insertion, frameshift deletion, and frameshift insertion.	('inframe deletion', 'Var', (880, 896))	("'Variant_Classification", 'Reg', (820, 843))	('patients', 'Species', '9606', (609, 617))	('tumor', 'Phenotype', 'HP:0002664', (543, 548))	('nonsense', 'Var', (847, 855))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (578, 602))	('tumor', 'Disease', (543, 548))	('hepatocellular carcinoma', 'Disease', (578, 602))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (578, 602))	('inframe insertion', 'Var', (898, 915))	('carcinoma', 'Phenotype', 'HP:0030731', (593, 602))	('frameshift insertion', 'Var', (942, 962))	('splice site', 'Var', (867, 878))	('frameshift deletion', 'Var', (917, 936))	('missense', 'Var', (857, 865))	('tumor', 'Disease', 'MESH:D009369', (543, 548))	('HCC', 'Phenotype', 'HP:0001402', (604, 607))
101951	32083805	Finally, all the damaging variants and TERT_prom hotspot mutation sites were confirmed using the integrative genomics viewer (igv) software (Broad Institute, Cambridge, MA, USA).	('TERT', 'Gene', (39, 43))	('TERT', 'Gene', '7015', (39, 43))	('variants', 'Var', (26, 34))
101966	32083805	Mutations in 21 key altered genes in MPM and in the TERT_prom were determined by targeted sequencing (see Table S2 for gene selection based on literature data).	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', (52, 56))	('MPM', 'Gene', (37, 40))	('TERT', 'Gene', '7015', (52, 56))
101967	32083805	Damaging variants were found in 52.3% (139/266) of the MPM tumors (153/266, i.e., 57.5% taking into account mutations in TERT_prom), consistent with the percentage of mutated tumors in TCGA series (48.8%), when restricted to the same set of genes with putative driver mutation.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('TERT', 'Gene', (121, 125))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('variants', 'Var', (9, 17))	('TERT', 'Gene', '7015', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
101970	32083805	The distribution of mutations in MPM is shown in the heat map for the six most frequently mutated genes with more than 3% of mutation and TERT_prom (Fig.	('MPM', 'Gene', (33, 36))	('TERT', 'Gene', (138, 142))	('TERT', 'Gene', '7015', (138, 142))	('mutations', 'Var', (20, 29))
101972	32083805	A significant co-occurrence of mutations in TERT_prom and NF2 was found (P = 0.0004); that is, NF2 mutations were more frequent in TERT_prom mutant MPM than in wild-type MPM, 45.2% and 15.8%, respectively.	('TERT', 'Gene', (44, 48))	('MPM', 'Disease', (148, 151))	('TERT', 'Gene', '7015', (44, 48))	('mutant', 'Var', (141, 147))	('frequent', 'Reg', (119, 127))	('mutations', 'Var', (99, 108))	('NF2', 'Gene', (95, 98))	('TERT', 'Gene', (131, 135))	('TERT', 'Gene', '7015', (131, 135))
101974	32083805	Mutations in BAP1 and TP53 seem also to be mutually exclusive (not significant) with only one tumor case with both mutated genes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (22, 26))	('BAP1', 'Gene', '8314', (13, 17))	('TP53', 'Gene', (22, 26))
101975	32083805	Interestingly, mutations in genes of the SWI/SNF family (ARID1A, ARID2, and SMARCA4) and genes related to histone methylation (KMT2D, SETD2) were also mutually exclusive.	('SETD2', 'Gene', '29072', (134, 139))	('ARID2', 'Gene', '196528', (65, 70))	('mutations', 'Var', (15, 24))	('SETD2', 'Gene', (134, 139))	('KMT2D', 'Gene', '8085', (127, 132))	('histone methylation', 'biological_process', 'GO:0016571', ('106', '125'))	('SWI/SNF family', 'Gene', (41, 55))	('KMT2D', 'Gene', (127, 132))	('SMARCA4', 'Gene', (76, 83))	('SMARCA4', 'Gene', '6597', (76, 83))	('ARID1A', 'Gene', (57, 63))	('ARID2', 'Gene', (65, 70))	('ARID1A', 'Gene', '8289', (57, 63))
101976	32083805	This was not the case for genes belonging to Hippo signaling pathway (NF2 and LATS2), with two MPM showing mutations in both genes, in agreement with our previous observation in MPM primary cell lines (Tranchant et al., 2017).	('LATS2', 'Gene', (78, 83))	('LATS2', 'Gene', '26524', (78, 83))	('mutations', 'Var', (107, 116))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('45', '68'))
101978	32083805	BAP1 and SETD2 showed a high proportion of frameshift deletions.	('SETD2', 'Gene', (9, 14))	('BAP1', 'Gene', (0, 4))	('frameshift deletions', 'Var', (43, 63))	('SETD2', 'Gene', '29072', (9, 14))	('BAP1', 'Gene', '8314', (0, 4))
101979	32083805	NF2 showed a majority of nonsense mutations, but very few missense substitutions contrary to the other genes such as BAP1 or TP53 that show a substantial proportion of missense substitutions in their functional domains.	('nonsense mutations', 'Var', (25, 43))	('NF2', 'Gene', (0, 3))	('BAP1', 'Gene', '8314', (117, 121))	('TP53', 'Gene', '7157', (125, 129))	('TP53', 'Gene', (125, 129))	('BAP1', 'Gene', (117, 121))
101980	32083805	Our data were consistent with COSMIC in MPM, but were significantly different from COSMIC pan-cancer data for BAP1 and NF2 (P = 0.008 and P = 0.004, respectively), suggesting specific mutation types for both genes in MPM.	('BAP1', 'Gene', '8314', (110, 114))	('MPM', 'Gene', (217, 220))	('BAP1', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (184, 192))
101982	32083805	We verified that these mutations were associated with overexpression of TERT mRNA as previously described (Tallet et al., 2014).	('associated', 'Reg', (38, 48))	('overexpression', 'MPA', (54, 68))	('mutations', 'Var', (23, 32))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
101983	32083805	As expected, MPM with TERT_prom mutation including mutations in the TERT 5'UTR showed a higher expression of TERT mRNA than wild-type MPM (P = 0.0015) (Fig.	('higher', 'PosReg', (88, 94))	('TERT', 'Gene', (22, 26))	('mutations', 'Var', (51, 60))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (109, 113))	('TERT', 'Gene', '7015', (68, 72))	('TERT', 'Gene', '7015', (22, 26))	('TERT', 'Gene', (109, 113))	('expression', 'MPA', (95, 105))
101986	32083805	Mutations in TERT_prom, NF2, and LATS2 were significantly less frequent in MME than in non_MME samples (MMB and MMS) (Fig.	('MME', 'Gene', '4311', (91, 94))	('LATS2', 'Gene', (33, 38))	('MMS', 'Gene', (112, 115))	('LATS2', 'Gene', '26524', (33, 38))	('TERT', 'Gene', (13, 17))	('NF2', 'Gene', (24, 27))	('TERT', 'Gene', '7015', (13, 17))	('MMS', 'Gene', '338340', (112, 115))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (63, 71))	('MME', 'Gene', (91, 94))	('MME', 'Gene', '4311', (75, 78))	('MME', 'Gene', (75, 78))	('less', 'NegReg', (58, 62))
101990	32083805	Significant positive associations were found between the S.score and TERT_prom, NF2, and LATS2 mutations, the same mutations associated with the non_MME histologic subtypes (Fig.	('positive', 'PosReg', (12, 20))	('S.score', 'Gene', (57, 64))	('LATS2', 'Gene', (89, 94))	('LATS2', 'Gene', '26524', (89, 94))	('associated', 'Reg', (125, 135))	('MME', 'Gene', '4311', (149, 152))	('MME', 'Gene', (149, 152))	('NF2', 'Gene', (80, 83))	('mutations', 'Var', (95, 104))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))
101991	32083805	Analysis of NF2 and LATS2 mutation data showed also significant statistical associations in these series (Fig.	('LATS2', 'Gene', (20, 25))	('LATS2', 'Gene', '26524', (20, 25))	('NF2', 'Gene', (12, 15))	('mutation', 'Var', (26, 34))
101995	32083805	We showed a significant enrichment of BAP1 mutations in the C1 subtype, and of TERT_prom in the C2 subtype (Fig.	('BAP1', 'Gene', (38, 42))	('TERT', 'Gene', (79, 83))	('mutations', 'Var', (43, 52))	('TERT', 'Gene', '7015', (79, 83))	('BAP1', 'Gene', '8314', (38, 42))
101996	32083805	Distribution of mutations between intra-subtypes (C1A, C1B, C2A, and C2B) is shown in Fig.	('C2B', 'Gene', '100130342', (69, 72))	('C2B', 'Gene', (69, 72))	('C1A, C1B', 'Gene', '100862690', (50, 58))	('mutations', 'Var', (16, 25))
101997	32083805	Comparison of mutation profiles between C1A and C2B subtypes highlighted increase frequency of BAP1 and SETD2 mutations in C1A subtype and, TERT_prom, NF2, TP53, ARID2, and LATS2 mutations in C2B subtypes (Fig.	('C2B', 'Gene', '100130342', (192, 195))	('ARID2', 'Gene', (162, 167))	('C1A', 'Gene', (123, 126))	('C1A', 'Gene', '100862690', (40, 43))	('TP53', 'Gene', (156, 160))	('BAP1', 'Gene', '8314', (95, 99))	('C2B', 'Gene', '100130342', (48, 51))	('TERT', 'Gene', (140, 144))	('TERT', 'Gene', '7015', (140, 144))	('LATS2', 'Gene', (173, 178))	('LATS2', 'Gene', '26524', (173, 178))	('SETD2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('BAP1', 'Gene', (95, 99))	('C1A', 'Gene', (40, 43))	('TP53', 'Gene', '7157', (156, 160))	('C2B', 'Gene', (192, 195))	('C1A', 'Gene', '100862690', (123, 126))	('SETD2', 'Gene', '29072', (104, 109))	('ARID2', 'Gene', '196528', (162, 167))	('C2B', 'Gene', (48, 51))
102000	32083805	NF2 mutations were significantly associated with asbestos exposure status (P = 0.036) and were more frequent in nonexposed patients (31%) than in exposed patients (17%) (Fig.	('NF2', 'Gene', (0, 3))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('asbestos exposure', 'Disease', (49, 66))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (123, 131))	('associated', 'Reg', (33, 43))	('frequent', 'Reg', (100, 108))	('mutations', 'Var', (4, 13))
102001	32083805	TERT_prom and NF2 mutations were significantly associated with the tumor stage (P = 0.025 and P = 0.007, respectively) and showed significant higher mutation rate in patients with stage IV tumors (20% and 28%, respectively) than in patients with stage I/III tumors (9% and 13%, respectively) (Fig.	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (67, 72))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('higher', 'PosReg', (142, 148))	('III tumors', 'Disease', 'MESH:D009369', (254, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('NF2', 'Gene', (14, 17))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (189, 194))	('mutation', 'MPA', (149, 157))	('patients', 'Species', '9606', (232, 240))	('III tumors', 'Disease', (254, 264))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('TERT', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('TERT', 'Gene', '7015', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (166, 174))	('mutations', 'Var', (18, 27))
102002	32083805	Overall survival frequency was lower in patients with MPM mutated for TERT_prom, TP53, and NF2 compared to patients with MPM wild-type (Fig.	('MPM mutated', 'Var', (54, 65))	('patients', 'Species', '9606', (107, 115))	('patients', 'Species', '9606', (40, 48))	('lower', 'NegReg', (31, 36))	('NF2', 'Gene', (91, 94))	('TERT', 'Gene', (70, 74))	('Overall survival', 'CPA', (0, 16))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (70, 74))
102004	32083805	Multivariate analysis considering age at diagnostic, tumor stage, histology, S.score based on a threshold of 0.22, which was shown to be the more predictive for prognosis (Blum et al., 2019), and mutation status in these three genes showed that the mutation status is predictive of prognosis only for TP53 and not for TERT_prom and NF2 (Fig.	('mutation', 'Var', (249, 257))	('TERT', 'Gene', (318, 322))	('TERT', 'Gene', '7015', (318, 322))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', '7157', (301, 305))	('tumor', 'Disease', (53, 58))	('TP53', 'Gene', (301, 305))
102005	32083805	However, multivariate analysis considering MPM samples with at least one mutation in TP53, NF2, or TERT_prom highlighted the strong prognosis value of all three genes considered together (Fig.	('TP53', 'Gene', (85, 89))	('TERT', 'Gene', (99, 103))	('TERT', 'Gene', '7015', (99, 103))	('NF2', 'Gene', (91, 94))	('TP53', 'Gene', '7157', (85, 89))	('mutation', 'Var', (73, 81))
102009	32083805	Among six sample pairs with characterized mutations, mutations were identical between tumor samples and cell lines (Fig.	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
102012	32083805	(2016) used so far to screen mutations in key altered genes in MPM, and the largest for TERT_prom mutations that are not evaluated by exome sequencing.	('TERT', 'Gene', '7015', (88, 92))	('MPM', 'Gene', (63, 66))	('mutations', 'Var', (29, 38))	('TERT', 'Gene', (88, 92))
102013	32083805	In the Inserm series, TERT_prom is the third locus most affected by mutations in MPM and deserved to be considered in the genetic landscape of MPM given the importance of telomerase upregulation in cancer (Pestana et al., 2017).	('TERT', 'Gene', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('TERT', 'Gene', '7015', (22, 26))	('MPM', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (68, 77))	('affected', 'Reg', (56, 64))
102016	32083805	Even if the large majority of the mutations identified in this study are likely somatic mutations, we cannot exclude that some of the mutations correspond to germline mutations especially in BAP1 gene, the gene with the highest frequency of germline mutations in MPM (Panou et al., 2018; Pastorino et al., 2018).	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', '8314', (191, 195))	('MPM', 'Gene', (263, 266))	('BAP1', 'Gene', (191, 195))
102017	32083805	Among the 65 patients showing BAP1 mutation of Inserm series (Table S1), none had previous cutaneous or uveal melanoma, renal cell carcinoma, basal cell carcinoma, meningioma, or cholangiocarcinoma, which were recently described in a study on 181 families carrying BAP1 germline variants as the core tumor spectrum for the BAP1 tumor predisposition syndrome (Walpole et al., 2018).	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (142, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('BAP1', 'Gene', (265, 269))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', (328, 333))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 140))	('meningioma', 'Disease', 'MESH:D008577', (164, 174))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('melanoma', 'Disease', (110, 118))	('BAP1', 'Gene', '8314', (323, 327))	('basal cell carcinoma', 'Disease', (142, 162))	('variants', 'Var', (279, 287))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (323, 327))	('renal cell carcinoma', 'Disease', (120, 140))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('core', 'cellular_component', 'GO:0019013', ('295', '299'))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('BAP1', 'Gene', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (142, 162))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('tumor', 'Disease', (300, 305))	('BAP1', 'Gene', '8314', (265, 269))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('meningioma', 'Disease', (164, 174))	('meningioma', 'Phenotype', 'HP:0002858', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('cholangiocarcinoma', 'Disease', (179, 197))
102018	32083805	The only significant discrepancy was for TP53 mutation frequencies suggesting a variability between MPM series for this gene (Fig.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))
102020	32083805	Our detailed mutation analysis also gives a precise overview of the mutation types profile observed in the main TSG mutated in MPM and in the TERT_prom.	('mutated', 'Var', (116, 123))	('TERT', 'Gene', (142, 146))	('TERT', 'Gene', '7015', (142, 146))
102021	32083805	BAP1 and SETD2 are enriched in deletion consistent with their chromosome localizations in 3p21 region, which harbors multiple noncontiguous minute deletions in MPM (Yoshikawa et al., 2016).	('SETD2', 'Gene', (9, 14))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('MPM', 'Gene', (160, 163))	('deletion', 'Var', (31, 39))	('SETD2', 'Gene', '29072', (9, 14))	('BAP1', 'Gene', '8314', (0, 4))
102023	32083805	The three mutations in TERT_prom were previously described in other cancers and generate de novo ETS binding sites (Huang et al., 2015).	('ETS binding', 'Interaction', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('described', 'Reg', (49, 58))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('mutations', 'Var', (10, 19))
102024	32083805	However, while the C228T mutation is the most frequent in MPM as in other tumors, the C250T, the second most common mutation in tumors, is not found in MPM.	('C250T', 'SUBSTITUTION', 'None', (86, 91))	('C228T', 'SUBSTITUTION', 'None', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('C228T', 'Var', (19, 24))	('MPM', 'Disease', (58, 61))	('C250T', 'Var', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('frequent', 'Reg', (46, 54))
102025	32083805	The two others less frequent mutation sites A161C and C1581 in MPM are mostly found in the bladder transitional carcinoma in COSMIC database.	('C1581', 'Var', (54, 59))	('MPM', 'Gene', (63, 66))	('bladder transitional carcinoma', 'Disease', (91, 121))	('A161C', 'SUBSTITUTION', 'None', (44, 49))	('bladder transitional carcinoma', 'Disease', 'MESH:D001749', (91, 121))	('bladder transitional', 'Phenotype', 'HP:0100645', (91, 111))	('A161C', 'Var', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))
102026	32083805	We also validated the correlation between promoter mutation and TERT overexpression in MPM, observed previously (Tallet et al., 2014).	('TERT', 'Gene', '7015', (64, 68))	('TERT', 'Gene', (64, 68))	('promoter mutation', 'Var', (42, 59))	('MPM', 'Gene', (87, 90))
102028	32083805	As we found mutually exclusive mutations between both alterations, we compared TERT expression based on the BAP1 mutation status, but did not find any significant association in MPM (Fig.	('mutation', 'Var', (113, 121))	('BAP1', 'Gene', '8314', (108, 112))	('MPM', 'Disease', (178, 181))	('BAP1', 'Gene', (108, 112))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('mutations', 'Reg', (31, 40))
102029	32083805	For example, the mutation in the oncogene KRAS Q61H has been referenced in COSMIC database (COSM555) and is a hotspot known to be oncogenic and found in several other malignancies such as large intestine and lung carcinomas.	('Q61H', 'Var', (47, 51))	('malignancies', 'Disease', 'MESH:D009369', (167, 179))	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('Q61H', 'SUBSTITUTION', 'None', (47, 51))	('malignancies', 'Disease', (167, 179))	('lung carcinomas', 'Disease', (208, 223))	('large intestine', 'Disease', (188, 203))	('found', 'Reg', (144, 149))	('lung carcinomas', 'Disease', 'MESH:D008175', (208, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (213, 223))
102031	32083805	The NRAS Q61K mutation is also an oncogenic hotspot (COSM580), and there is promising clinical data in patients with oncogenic NRAS-mutant melanoma treated with the MEK1/2-inhibitor, binimetinib (Dummer et al., 2017).	('Q61K', 'SUBSTITUTION', 'None', (9, 13))	('Q61K', 'Var', (9, 13))	('MEK1/2', 'Gene', (165, 171))	('binimetinib', 'Chemical', 'MESH:C581313', (183, 194))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('MEK1', 'molecular_function', 'GO:0004708', ('165', '169'))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('NRAS', 'Gene', (127, 131))	('NRAS', 'Gene', '4893', (4, 8))	('NRAS', 'Gene', (4, 8))	('patients', 'Species', '9606', (103, 111))	('NRAS', 'Gene', '4893', (127, 131))	('MEK1/2', 'Gene', '5604;5605', (165, 171))
102033	32083805	For most patients, genes or pathways deregulated as a consequence of TSG inactivation should be targeted, as it was suggested for hippo signal pathway linked to NF2 and LATS2 inactivation (Felley-Bosco and Stahel, 2014; Sato and Sekido, 2018).	('LATS2', 'Gene', (169, 174))	('NF2', 'Gene', (161, 164))	('LATS2', 'Gene', '26524', (169, 174))	('patients', 'Species', '9606', (9, 17))	('inactivation', 'Var', (175, 187))	('inactivation', 'Var', (73, 85))	('hippo signal pathway', 'Pathway', (130, 150))
102034	32083805	We identified significant increase in the mutation rate for LATS2, NF2, and TERT_prom in non_MME allowing us to confirm in a larger MPM series the association with TERT_prom previously observed (Tallet et al., 2014) and to demonstrate at the statistical level the previously suggested association with NF2 (Sato and Sekido, 2018).	('TERT', 'Gene', '7015', (76, 80))	('LATS2', 'Gene', (60, 65))	('LATS2', 'Gene', '26524', (60, 65))	('TERT', 'Gene', (164, 168))	('NF2', 'Gene', (67, 70))	('TERT', 'Gene', '7015', (164, 168))	('mutation', 'Var', (42, 50))	('MME', 'Gene', (93, 96))	('TERT', 'Gene', (76, 80))	('MME', 'Gene', '4311', (93, 96))	('increase', 'PosReg', (26, 34))
102035	32083805	Mutations in LATS2, NF2, and TERT_prom were also positively associated with the S.score, bringing new insights on the intratumor heterogeneity and strengthening the link between these mutations and the sarcomatoid cell type.	('TERT', 'Gene', '7015', (29, 33))	('NF2', 'Gene', (20, 23))	('tumor', 'Disease', (123, 128))	('sarcomatoid', 'Disease', 'MESH:C538614', (202, 213))	('LATS2', 'Gene', (13, 18))	('LATS2', 'Gene', '26524', (13, 18))	('S.score', 'Disease', (80, 87))	('associated', 'Reg', (60, 70))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('sarcomatoid', 'Disease', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TERT', 'Gene', (29, 33))
102036	32083805	NF2 and TP53 mutations were previously found to be associated with the S.score, based on TCGA series data (Blum et al., 2019).	('NF2', 'Gene', (0, 3))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', '7157', (8, 12))	('S.score', 'Disease', (71, 78))	('TP53', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
102037	32083805	Here, we confirmed the association of NF2 mutations in this larger Inserm series, possibly due to the variability of TP53 mutations between MPM series mentioned above.	('NF2', 'Gene', (38, 41))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('association', 'Reg', (23, 34))	('mutations', 'Var', (42, 51))
102038	32083805	We confirmed the previously described association of BAP1 mutations to the C1 subtype (de Reynies et al., 2014) and identified a significant enrichment of TERT_prom mutations in the C2 subtype.	('mutations', 'Var', (58, 67))	('association', 'Interaction', (38, 49))	('BAP1', 'Gene', '8314', (53, 57))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))	('BAP1', 'Gene', (53, 57))
102040	32083805	(2018) reported a strong significant association of BAP1 mutation with iCluster 1 and an enrichment of LATS2 mutation in iCluster 4.	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))	('BAP1', 'Gene', (52, 56))	('iCluster 1', 'Disease', (71, 81))	('LATS2', 'Gene', (103, 108))	('LATS2', 'Gene', '26524', (103, 108))
102041	32083805	Moreover, we highlighted new significant associations between TERT_prom and TP53 mutations, and C2B subtype.	('C2B', 'Gene', '100130342', (96, 99))	('TP53', 'Gene', '7157', (76, 80))	('TERT', 'Gene', (62, 66))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('C2B', 'Gene', (96, 99))	('TERT', 'Gene', '7015', (62, 66))
102042	32083805	Pan-series analysis confirmed all these associations and revealed a significant association of NF2 mutations with C2B subtype.	('C2B', 'Gene', (114, 117))	('C2B', 'Gene', '100130342', (114, 117))	('association', 'Interaction', (80, 91))	('mutations', 'Var', (99, 108))	('NF2', 'Gene', (95, 98))
102043	32083805	Interestingly, TERT_prom and NF2 mutations are associated with histologic and molecular classifications, and molecular gradients, but not TP53 and BAP1 mutations (Fig.	('TERT', 'Gene', '7015', (15, 19))	('BAP1', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (138, 142))	('molecular gradients', 'CPA', (109, 128))	('mutations', 'Var', (33, 42))	('TP53', 'Gene', (138, 142))	('BAP1', 'Gene', '8314', (147, 151))	('NF2', 'Gene', (29, 32))	('associated', 'Reg', (47, 57))	('TERT', 'Gene', (15, 19))
102045	32083805	In a previous study, we demonstrate the impact of epigenetic mechanisms in the establishment of epithelioid and sarcomatoid-related cell entities (Blum et al., 2019).	('epigenetic', 'Var', (50, 60))	('sarcomatoid', 'Disease', 'MESH:C538614', (112, 123))	('sarcomatoid', 'Disease', (112, 123))	('epithelioid', 'Disease', (96, 107))
102047	32083805	However, to our knowledge, our study is the first to identify a link between gene mutations and asbestos status.	('gene mutations', 'Var', (77, 91))	('asbestos status', 'Disease', (96, 111))	('asbestos', 'Chemical', 'MESH:D001194', (96, 104))
102048	32083805	In our series, NF2 mutation was the most frequent alteration in asbestos nonexposed patients with a third of patients carrying NF2 mutation.	('NF2', 'Gene', (127, 130))	('mutation', 'Var', (19, 27))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (109, 117))	('NF2', 'Gene', (15, 18))	('asbestos', 'Chemical', 'MESH:D001194', (64, 72))
102049	32083805	Only one study reported a MPM patient with constitutional NF2 mutation missense mutation (Baser et al., 2005).	('MPM', 'Disease', (26, 29))	('NF2', 'Gene', (58, 61))	('patient', 'Species', '9606', (30, 37))	('mutation missense', 'Var', (62, 79))
102050	32083805	Furthermore, in two recent studies screening germline cancer susceptibility mutations in large cohort of MPM patients, NF2, was not identified as a cancer susceptibility gene (Panou et al., 2018; Pastorino et al., 2018), suggesting that NF2 mutations observed in our series in unexposed patient are likely somatic.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('patient', 'Species', '9606', (287, 294))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('NF2', 'Gene', (237, 240))	('mutations', 'Var', (241, 250))
102051	32083805	This high frequency of mutations supports NF2 as a key driver of asbestos independent mesothelial carcinogenesis that was previously suggested in mice models.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('NF2', 'Gene', (42, 45))	('asbestos', 'Chemical', 'MESH:D001194', (65, 73))	('carcinogenesis', 'Disease', (98, 112))	('mutations', 'Var', (23, 32))	('mice', 'Species', '10090', (146, 150))
102053	32083805	Conditional mouse model leading to both Ink4a/Arf and Nf2 inactivation was shown to develop malignant thoracic mesothelioma at a high incidence without asbestos exposure, mostly of sarcomatoid type (Jongsma et al., 2008).	('malignant thoracic mesothelioma', 'Disease', (92, 123))	('Ink4a/Arf', 'Gene', (40, 49))	('inactivation', 'Var', (58, 70))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('sarcomatoid type', 'Disease', 'MESH:C538614', (181, 197))	('Nf2', 'Gene', '18016', (54, 57))	('sma', 'Gene', (203, 206))	('sma', 'Gene', '6606', (203, 206))	('sarcomatoid type', 'Disease', (181, 197))	('develop', 'PosReg', (84, 91))	('mouse', 'Species', '10090', (12, 17))	('Ink4a/Arf', 'Gene', '12578', (40, 49))	('malignant thoracic mesothelioma', 'Disease', 'MESH:C562839', (92, 123))	('Nf2', 'Gene', (54, 57))
102054	32083805	Interestingly, LATS2 is the second gene showing the mutations more frequent in nonexposed patients (7%) than in exposed patients (2%).	('mutations', 'Var', (52, 61))	('LATS2', 'Gene', '26524', (15, 20))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (90, 98))	('LATS2', 'Gene', (15, 20))
102056	32083805	One of the major strengths of our study is to demonstrate the strong link between the mutation status of TERT_prom, NF2 and TP53, and overall survival.	('TERT', 'Gene', (105, 109))	('NF2', 'Gene', (116, 119))	('TERT', 'Gene', '7015', (105, 109))	('mutation status', 'Var', (86, 101))	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (124, 128))	('overall survival', 'CPA', (134, 150))
102057	32083805	Accordingly, TERT_prom and NF2 mutations were significantly more frequent in MPM with an advanced stage.	('NF2', 'Gene', (27, 30))	('mutations', 'Var', (31, 40))	('MPM', 'Disease', (77, 80))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('frequent', 'Reg', (65, 73))
102062	32083805	One tumor sample pair (T004LE and T288LE), corresponding to primary versus recurrence tumors, showed two BAP1 mutations (K337fs and N157fs) present in both samples.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('N157fs', 'Var', (132, 138))	('K337fs', 'Var', (121, 127))	('K337fs', 'FRAMESHIFT', 'None', (121, 127))	('tumor', 'Disease', (86, 91))	('BAP1', 'Gene', '8314', (105, 109))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('N157fs', 'FRAMESHIFT', 'None', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('BAP1', 'Gene', (105, 109))
102065	32083805	Our results show that mutations in primary cell lines are representative from the mutations present in the tumor of the patient.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('patient', 'Species', '9606', (120, 127))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
102149	31752449	In particular, these studies have shown that DMPM is characterized by mutations in BRCA1 associated protein 1 (BAP 1), Neurofibromin 2 (NF2), DEAD-Box Helicase 3 X-Linked (DDX3X), SET Domain Containing 2, Histone Lysine Methyltransferase (SETD2) genes, as well as by the loss of 3p21 locus, which includes chromatin modifiers and epigenetic regulatory genes such as BAP1, SETD2, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member (SMARCC1), and Polybromo 1 (PBRM1).	('DEAD-Box Helicase 3 X-Linked', 'Gene', '1654', (142, 170))	('Neurofibromin 2', 'Gene', '4771', (119, 134))	('Neurofibromin 2', 'Gene', (119, 134))	('NF2', 'Gene', '4771', (136, 139))	('Polybromo 1', 'Gene', (488, 499))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('SMARCC1', 'Gene', '6599', (474, 481))	('PBRM1', 'Gene', '55193', (501, 506))	('BAP1', 'Gene', (366, 370))	('NF2', 'Gene', (136, 139))	('SETD2', 'Gene', (239, 244))	('BRCA1 associated protein 1', 'Gene', '8314', (83, 109))	('Polybromo 1', 'Gene', '55193', (488, 499))	('PBRM1', 'Gene', (501, 506))	('SMARCC1', 'Gene', (474, 481))	('DDX3X', 'Gene', (172, 177))	('SETD2', 'Gene', (372, 377))	('SETD2', 'Gene', '29072', (239, 244))	('mutations', 'Var', (70, 79))	('SET Domain Containing 2', 'Gene', (180, 203))	('Lysine', 'Chemical', 'MESH:C114808', (213, 219))	('DMPM', 'Disease', (45, 49))	('SETD2', 'Gene', '29072', (372, 377))	('DEAD-Box Helicase 3 X-Linked', 'Gene', (142, 170))	('BAP 1', 'Gene', '8314', (111, 116))	('SET Domain Containing 2', 'Gene', '29072', (180, 203))	('chromatin', 'cellular_component', 'GO:0000785', ('444', '453'))	('DDX3X', 'Gene', '1654', (172, 177))	('BRCA1 associated protein 1', 'Gene', (83, 109))	('chromatin', 'cellular_component', 'GO:0000785', ('306', '315'))	('BAP 1', 'Gene', (111, 116))
102151	31752449	In addition, anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements have recently been described in a small subset of younger women affected by DMPM (3%), suggesting that these selected patients may benefit from ALK inhibitors.	('ALK', 'Gene', '238', (59, 62))	('anaplastic lymphoma receptor tyrosine kinase', 'Gene', (13, 57))	('patients', 'Species', '9606', (197, 205))	('ALK', 'Gene', '238', (223, 226))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (13, 32))	('described', 'Reg', (98, 107))	('ALK', 'Gene', (59, 62))	('anaplastic lymphoma receptor tyrosine kinase', 'Gene', '238', (13, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('women', 'Species', '9606', (137, 142))	('ALK', 'Gene', (223, 226))	('rearrangements', 'Var', (64, 78))
102159	31752449	The phosphorylation sites detected are as follows: HER2 at residues T686 and S1113 in 12 (100%) cases; HER3 at residue T1289 in 10 (83%) cases; and HER4 at residue T1284 in 9 (75%) cases (Figure 1A).	('S1113', 'Chemical', 'MESH:C456082', (77, 82))	('HER3', 'Gene', (103, 107))	('HER3', 'Gene', '2065', (103, 107))	('S1113', 'Var', (77, 82))	('HER4', 'Gene', (148, 152))	('HER2', 'Gene', (51, 55))	('HER4', 'Gene', '2066', (148, 152))	('HER2', 'Gene', '2064', (51, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
102160	31752449	Unexpectedly, EGFR activation (at residues T1173 and T845) was observed in only 3 (25%) cases.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('T845', 'Var', (53, 57))	('activation', 'PosReg', (19, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('T1173', 'Var', (43, 48))
102162	31752449	Moreover, it was possible to confirm the absence of EGFR mutation in 16 FFPE DMPMs by highly sensitive NGS, as we had previously confirmed by direct sequencing, similarly to Karla et al.. NGS revealed also BAP1 and NF2 mutations in 25% and 19% of cases, respectively.	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('revealed', 'Reg', (192, 200))	('BAP1', 'Gene', (206, 210))	('NF2', 'Gene', (215, 218))	('mutations', 'Var', (219, 228))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('NF2', 'Gene', '4771', (215, 218))
102173	31752449	The expression of the HER3 ligand heregulin was observed in 10 (45%) cases, and a new damaging p.P30L mutation in HER3 exon 2 (case #8) was found by NGS.	('p.P30L', 'Var', (95, 101))	('HER3', 'Gene', (114, 118))	('HER3', 'Gene', '2065', (114, 118))	('p.P30L', 'Mutation', 'rs56017157', (95, 101))	('HER3', 'Gene', (22, 26))	('ligand', 'molecular_function', 'GO:0005488', ('27', '33'))	('HER3', 'Gene', '2065', (22, 26))
102183	31752449	Interestingly, by NGS MET mutations were exclusively found in the two "progressed" DMPMs (p.R359Q case #16 and p.E168D case #17).	('p.E168D', 'Var', (111, 118))	('p.R359Q', 'Var', (90, 97))	('found', 'Reg', (53, 58))	('p.R359Q', 'Mutation', 'rs201274041', (90, 97))	('p.E168D', 'Mutation', 'rs55985569', (111, 118))
102184	31752449	Even if these MET mutations have conflicting interpretations of pathogenicity, they are located in the MET Sema domain that is necessary for HGF binding and receptor dimerization/activation, and mutations in this domain can promote an invasive malignant phenotype.	('invasive malignant phenotype', 'CPA', (235, 263))	('HGF binding', 'molecular_function', 'GO:0036458', ('141', '152'))	('HGF', 'Gene', (141, 144))	('mutations', 'Var', (195, 204))	('promote', 'PosReg', (224, 231))	('HGF', 'Gene', '3082', (141, 144))
102187	31752449	After 24 h, only few SSL1 cells treated with 2 microM and 5 microM BMS repopulated the scratch area, indicating a sensible reduction in cell migration capacity compared with NT- and DMSO-treated cells that completely filled the empty surface left by the scratch (Figure 3).	('cell migration capacity', 'CPA', (136, 159))	('cell migration', 'biological_process', 'GO:0016477', ('136', '150'))	('reduction', 'NegReg', (123, 132))	('DMSO', 'Chemical', 'MESH:D004121', (182, 186))	('BMS', 'Var', (67, 70))
102188	31752449	By contrast, cellular proliferation experiments on SSL1 treated with BMS-777607 showed a lower proliferation than NT only at high dosages (5 and 10 microM) (Figure 3C).	('cellular proliferation', 'CPA', (13, 35))	('BMS-777607', 'Var', (69, 79))	('lower', 'NegReg', (89, 94))	('BMS-777607', 'Chemical', 'MESH:C550356', (69, 79))
102203	31752449	Furthermore, we confirmed frequent MET expression/activation mediated by MET-EGFR heterodimerization, expression of the cognate ligand HGF in most of DMPM, as well as, exclusively in "progressed" DMPMs, MET mutations on the Sema domain.	('expression', 'MPA', (102, 112))	('MET mutations', 'Var', (203, 216))	('DMPM', 'Disease', (150, 154))	('MET expression/activation', 'MPA', (35, 60))	('heterodimerization', 'MPA', (82, 100))	('EGFR', 'Gene', '1956', (77, 81))	('HGF', 'Gene', (135, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('ligand', 'molecular_function', 'GO:0005488', ('128', '134'))	('HGF', 'Gene', '3082', (135, 138))
102211	31752449	Accordingly, Axl expression is responsible for resistance to chemotherapy, while anti-Axl monoclonal antibodies enhance the antitumor effect of chemotherapy, in addition to reversing resistance to EGFR-inhibitors.	('monoclonal antibodies', 'Var', (90, 111))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('anti-Axl', 'Protein', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EGFR', 'Gene', '1956', (197, 201))	('tumor', 'Disease', (128, 133))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('enhance', 'PosReg', (112, 119))	('EGFR', 'Gene', (197, 201))
102227	31752449	Axl anti-Rabbit monoclonal antibody (clone C44G1, Cell Signaling Technology, Danvers, MA, USA) was used for the WB, anti-phosphotyrosine mouse monoclonal antibody (clone 4G10, 1:3000, Merck Millipore, Burlington, MA, USA) was used to test Axl phosphorylation, and Axl anti-Rabbit monoclonal antibody (C44G1, 1:1000, Cell Signaling Technology, Danvers, MA, USA) was used to test Axl expression.	('mouse', 'Species', '10090', (137, 142))	('Rabbit', 'Species', '9986', (9, 15))	('C44G1', 'Var', (301, 306))	('Axl expression', 'MPA', (378, 392))	('antibody', 'molecular_function', 'GO:0003823', ('291', '299'))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('Signaling', 'biological_process', 'GO:0023052', ('321', '330'))	('phosphotyrosine', 'Chemical', 'MESH:C117571', (121, 136))	('antibody', 'cellular_component', 'GO:0042571', ('291', '299'))	('antibody', 'cellular_component', 'GO:0019815', ('154', '162'))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('antibody', 'cellular_component', 'GO:0019815', ('291', '299'))	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('antibody', 'cellular_component', 'GO:0019814', ('154', '162'))	('phosphorylation', 'biological_process', 'GO:0016310', ('243', '258'))	('Axl phosphorylation', 'MPA', (239, 258))	('antibody', 'cellular_component', 'GO:0019814', ('291', '299'))	('Signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('Rabbit', 'Species', '9986', (273, 279))	('antibody', 'molecular_function', 'GO:0003823', ('154', '162'))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('antibody', 'cellular_component', 'GO:0042571', ('154', '162'))
102243	31752449	The double AXL and MET inhibitor BMS-777607 (CAT: S1561, SELLEK) was prediluted to 5 mM in DMSO.	('BMS-777607', 'Var', (33, 43))	('BMS-777607', 'Chemical', 'MESH:C550356', (33, 43))	('DMSO', 'Chemical', 'MESH:D004121', (91, 95))	('AXL', 'Gene', '558', (11, 14))	('CAT', 'molecular_function', 'GO:0004096', ('45', '48'))	('AXL', 'Gene', (11, 14))
102304	25886502	Density-adjusted serum, 4 ml, was loaded into a 13.5 ml thin-walled polycarbonate tube (Beckman Coulter, Brea, USA) and overlaid with a discontinuous gradient constructed by sequentially layering 2 ml each of solutions of d = 1.063, 1.04, 1.02 g/ml, followed by 2 ml MilliQ water.	('1.04', 'Var', (233, 237))	('water', 'Chemical', 'MESH:D014867', (274, 279))	('1.02 g/ml', 'Var', (239, 248))
102310	25886502	At day 0, mice were injected subcutaneously in the right flank with 5 x 105 AE17 or AE17sOVA tumor cells per mouse in 100 mul of PBS and tumors measured regularly using microcallipers.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('AE17sOVA', 'Var', (84, 92))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mice', 'Species', '10090', (10, 14))	('AE17', 'Var', (76, 80))	('tumor', 'Disease', (93, 98))	('mouse', 'Species', '10090', (109, 114))	('PBS and tumors', 'Disease', 'MESH:D011535', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
102338	25886502	Exposure to JU77 cells also promoted a greater increase in iMoDC lipid content compared to Met5A cells (Fig 1F).	('DC lipid', 'Chemical', '-', (62, 70))	('iMoDC lipid content', 'MPA', (59, 78))	('JU77', 'Var', (12, 16))	('increase', 'PosReg', (47, 55))
102348	25886502	The changes to iMoDC surface phenotype are likely to be tumor-driven, as exposure to Met5A cells did not alter the percent of CD1a+, CD86+ or CD80+ iMoDCs (S2B:S2D Fig), nor did it alter surface expression levels (MFIs) of CD86 or CD80 on iMoDCs, relative to DCs only (S2E and S2F Fig).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('surface expression levels', 'MPA', (187, 212))	('CD86+', 'Var', (133, 138))	('tumor', 'Disease', (56, 61))	('alter', 'Reg', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
102360	25886502	Immature MoDCs exposed to JU77 TCM demonstrated significantly higher lipid levels relative to iMoDCs cultured without TCM (Fig 4B).	('higher', 'PosReg', (62, 68))	('JU77 TCM', 'Var', (26, 34))	('lipid', 'Chemical', 'MESH:D008055', (69, 74))	('lipid levels', 'MPA', (69, 81))
102361	25886502	These data suggest that tumor-derived factors present in JU77 TCM modulate iMoDC lipid accumulation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('iMoDC lipid accumulation', 'MPA', (75, 99))	('tumor', 'Disease', (24, 29))	('JU77', 'Var', (57, 61))	('DC lipid', 'Chemical', '-', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('modulate', 'Reg', (66, 74))
102367	25886502	To do this, MoDCs were differentiated in the presence of JU77 TCM and TG-rich lipoproteins or low-density lipoproteins (LDL; a cholesterol-rich lipoprotein).	('TG', 'Chemical', 'MESH:D014280', (70, 72))	('cholesterol', 'Chemical', 'MESH:D002784', (127, 138))	('LDL', 'molecular_function', 'GO:0005322', ('120', '123'))	('low-density lipoproteins', 'MPA', (94, 118))	('JU77 TCM', 'Var', (57, 65))
102369	25886502	Furthermore, iMoDCs exposed to TG-rich lipoproteins (either alone or in combination with TCM), but not LDL, had reduced antigen processing capacity (Fig 5C and 5D).	('antigen processing', 'biological_process', 'GO:0019882', ('120', '138'))	('LDL', 'molecular_function', 'GO:0005322', ('103', '106'))	('TG', 'Chemical', 'MESH:D014280', (31, 33))	('antigen processing capacity', 'MPA', (120, 147))	('TG-rich', 'Var', (31, 38))	('reduced', 'NegReg', (112, 119))
102377	25886502	Immature MoDCs co-exposed to LPS and JU77 TCM (S5A Fig) did not demonstrate significant changes in lipid content (S5B Fig).	('LPS', 'Disease', 'MESH:C536528', (29, 32))	('JU77 TCM', 'Var', (37, 45))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('LPS', 'Disease', (29, 32))	('S5B', 'Gene', '66998', (114, 117))	('S5B', 'Gene', (114, 117))	('lipid content', 'MPA', (99, 112))
102381	25886502	Skewing DCs away from the production of pro-inflammatory cytokines may impair the generation of anti-mesothelioma T cell responses.	('mesothelioma T', 'Disease', (101, 115))	('mesothelioma T', 'Disease', 'MESH:D008654', (101, 115))	('Skewing', 'Var', (0, 7))	('impair', 'NegReg', (71, 77))	('mesothelioma T', 'Phenotype', 'HP:0100001', (101, 115))
102383	25886502	Differentiating BMDCs exposed to AE17 TCM (Fig 6A) appeared to contain higher lipid levels than BMDCs cultured without TCM, but the differences did not reach statistical significance (Fig 6B).	('higher', 'PosReg', (71, 77))	('lipid', 'Chemical', 'MESH:D008055', (78, 83))	('AE17', 'Var', (33, 37))	('lipid levels', 'MPA', (78, 90))
102384	25886502	LPS-matured BMDCs exposed to AE17 TCM contained similar lipid levels relative to the controls (Fig 6C and 6D).	('AE17 TCM', 'Var', (29, 37))	('LPS', 'Disease', 'MESH:C536528', (0, 3))	('lipid', 'Chemical', 'MESH:D008055', (56, 61))	('lipid levels', 'MPA', (56, 68))	('LPS', 'Disease', (0, 3))
102386	25886502	CD11c+ DC numbers and lipid levels were examined in mice bearing small (< 40 mm2) or large (> 80 mm2) mesothelioma tumors (Fig 7A and 7B).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lipid', 'Chemical', 'MESH:D008055', (22, 27))	('mice', 'Species', '10090', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (102, 120))	('mesothelioma tumors', 'Disease', (102, 121))	('> 80', 'Var', (92, 96))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (102, 121))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (102, 121))
102387	25886502	The proportion of tumor-infiltrating CD11c+ DCs decreased in large tumors compared to small tumors (Fig 7C).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('CD11c+ DCs', 'Var', (37, 47))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('decreased', 'NegReg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Disease', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('small tumors', 'Disease', (86, 98))	('tumor', 'Disease', (92, 97))	('small tumors', 'Disease', 'MESH:D058405', (86, 98))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
102389	25886502	CD11c+ DCs in large tumors appeared to contain higher lipid levels than DCs from small tumors (Fig 7G).	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('tumors', 'Disease', (20, 26))	('small tumors', 'Disease', (81, 93))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('small tumors', 'Disease', 'MESH:D058405', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('higher', 'PosReg', (47, 53))	('CD11c+ DCs', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (87, 93))	('lipid levels', 'MPA', (54, 66))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
102411	25886502	The growth rate and tumor size of AE17sOVA is shown in Fig 10A.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('AE17sOVA', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
102423	25886502	From day 9 to day 13, both TOFA and DMSO appeared to slow tumor growth rate relative to untreated tumor-bearing controls (S9E Fig).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('DMSO', 'Chemical', 'MESH:D004121', (36, 40))	('slow', 'NegReg', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TOFA', 'Chemical', '-', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (98, 103))	('DMSO', 'Var', (36, 40))
102521	18442410	A right pleural biopsy done in mid August 2007 revealed sheets of pleura infiltrated by malignant epithelioid cells that on immune staining expressed CK7 (cytokeratin) with focal expression of CK5/6 whereas staining for carcino-embriogenic antigen, BerEP4, thyroid transcription factor-1 mesothelin, Wilms' tumour -1, CK20 or prostate specific antigen was negative, confirming a diagnosis of epithelioid mesothelioma.	('prostate specific antigen', 'Gene', '354', (326, 351))	("Wilms' tumour", 'Disease', 'MESH:D009396', (300, 313))	('transcription', 'biological_process', 'GO:0006351', ('265', '278'))	('epithelioid mesothelioma', 'Disease', (392, 416))	('CK7', 'Gene', (150, 153))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (392, 416))	('pleura infiltrated', 'Phenotype', 'HP:0002113', (66, 84))	('prostate specific antigen', 'Gene', (326, 351))	("Wilms' tumour", 'Disease', (300, 313))	('CK20', 'Gene', (318, 322))	('CK20', 'Gene', '54474', (318, 322))	('CK7', 'Gene', '3855', (150, 153))	('CK5/6', 'Var', (193, 198))	("Wilms' tumour", 'Phenotype', 'HP:0002667', (300, 313))	('tumour', 'Phenotype', 'HP:0002664', (307, 313))	('transcription factor', 'molecular_function', 'GO:0000981', ('265', '285'))
102528	18442410	Neither the FIP1L1-PDGFRA fusion transcript (deletion 4q12) nor other cytogenetic abnormalities were found on a cellular sample of peripheral blood.	('FIP1L1', 'Gene', '81608', (12, 18))	('FIP1L1', 'Gene', (12, 18))	('deletion 4q12', 'Var', (45, 58))	('PDGFRA', 'Gene', (19, 25))	('PDGFRA', 'Gene', '5156', (19, 25))
102578	30410726	Statistical analyses of the IASLC database of patients with T1a and T1b showed no significant difference in overall survival.	('patients', 'Species', '9606', (46, 54))	('T1b', 'Var', (68, 71))	('T1a', 'Var', (60, 63))
102587	30410726	It was hypothesized that EPP was less likely to leave residual tumor cells when compared with P/D; however, more recent studies have shown that in many cases neither EPP nor P/D results in complete R0 resections .	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('EPP', 'Var', (166, 169))
102664	27123108	The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos.	('contribute', 'Reg', (229, 239))	('alterations', 'Var', (166, 177))	('growth activity of mesothelial cells', 'CPA', (112, 148))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('asbestos', 'Chemical', 'MESH:D001194', (283, 291))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('increase', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
102677	27123108	Therefore, in the current study, peripheral blood mononuclear cells (PBMCs) from healthy donors were directly exposed to asbestos under stimulation with antibodies against CD3 and CD28, and the effects of the resulting culture supernatants on the cell growth of mesothelial cells were examined in vitro.	('CD28', 'Gene', '940', (180, 184))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('CD3', 'Gene', (172, 175))	('CD28', 'Gene', (180, 184))	('antibodies', 'Var', (153, 163))	('cell growth', 'biological_process', 'GO:0016049', ('247', '258'))
102709	27123108	These results indicate that IL-1alpha, IL-1beta, IL-3, Il-5, Il-13 and IL-17A have the potential to augment the growth activity of mesothelial cells, although these effects are not strong and are altered in the presence of other cytokines.	('IL-17', 'molecular_function', 'GO:0030367', ('71', '76'))	('IL-1beta', 'Gene', (39, 47))	('growth activity of mesothelial cells', 'CPA', (112, 148))	('IL-1alpha', 'Gene', '3552', (28, 37))	('Il-5', 'molecular_function', 'GO:0005137', ('55', '59'))	('Il-5', 'Gene', (55, 59))	('IL-17A', 'Var', (71, 77))	('IL-3', 'molecular_function', 'GO:0005135', ('49', '53'))	('IL-3', 'Gene', '3562', (49, 53))	('IL-1', 'molecular_function', 'GO:0005149', ('28', '32'))	('Il-13', 'Gene', (61, 66))	('IL-1alpha', 'Gene', (28, 37))	('Il-5', 'Gene', '3567', (55, 59))	('Il-13', 'molecular_function', 'GO:0005144', ('61', '66'))	('IL-3', 'Gene', (49, 53))	('Il-13', 'Gene', '3596', (61, 66))	('IL-1beta', 'Gene', '3553', (39, 47))	('IL-1', 'molecular_function', 'GO:0005149', ('39', '43'))	('augment', 'NegReg', (100, 107))
102726	27123108	Silencing of IL-13Ra2 has also been demonstrated to decrease migration and invasion in colorectal cancer cells, while IL-13 has increased these events.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('IL-13', 'Gene', '3596', (13, 18))	('invasion', 'CPA', (75, 83))	('IL-13', 'molecular_function', 'GO:0005144', ('13', '18'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('IL-13Ra2', 'Gene', '3598', (13, 21))	('IL-13', 'molecular_function', 'GO:0005144', ('118', '123'))	('IL-13', 'Gene', (118, 123))	('migration', 'CPA', (61, 70))	('IL-13Ra2', 'Gene', (13, 21))	('colorectal cancer', 'Disease', (87, 104))	('decrease', 'NegReg', (52, 60))	('IL-13', 'Gene', '3596', (118, 123))	('Silencing', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('IL-13', 'Gene', (13, 18))
102729	27123108	The suggested role of IL-17A in the development of cancer is controversial: Poor prognosis of colorectal cancer patients with high expression of Th17 has been suggested; however, a tumor suppressive effect has also been reported.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('IL-17', 'molecular_function', 'GO:0030367', ('22', '27'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Th1', 'Gene', (145, 148))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('high expression', 'Var', (126, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('colorectal cancer', 'Disease', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Th1', 'Gene', '51497', (145, 148))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
102800	26681974	Recommended antibodies for excluding a mesothelial origin include carcinoembryonic antigen (CEA), BerEp4 and MOC-31, thyroid transcription factor-1 (TTF-1), CD15 and Sialyl-TN.	('Sialyl-TN', 'Var', (166, 175))	('carcinoembryonic antigen', 'Gene', (66, 90))	('men', 'Species', '9606', (5, 8))	('BerEp4', 'Gene', (98, 104))	('TTF-1', 'Gene', '7080', (149, 154))	('transcription factor', 'molecular_function', 'GO:0000981', ('125', '145'))	('thyroid transcription factor-1', 'Gene', '7080', (117, 147))	('CD15', 'Gene', '2526', (157, 161))	('TTF-1', 'Gene', (149, 154))	('CD15', 'Gene', (157, 161))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('MOC-31', 'Gene', (109, 115))	('CEA', 'Gene', (92, 95))	('carcinoembryonic antigen', 'Gene', '1084', (66, 90))	('CEA', 'Gene', '1084', (92, 95))	('thyroid transcription factor-1', 'Gene', (117, 147))
102806	26681974	As well, additional MM negative antibodies such as CD15 and/or B72.3 can be considered.	('B72.3', 'Var', (63, 68))	('CD15', 'Gene', '2526', (51, 55))	('CD15', 'Gene', (51, 55))
102819	26681974	However, the serous carcinomas of ovary and uterus and peritoneal origin stain positive for BerEp4, PAX8, B72.3, BG8, CA 19-9, Leu-M1 (CD15), MUC4 and estrogen receptor, all of which are rarely or never expressed in MM [Figure 6].	('PAX8', 'Gene', '7849', (100, 104))	('Leu-M1', 'Var', (127, 133))	('B72.3', 'Var', (106, 111))	('BerEp4', 'Gene', (92, 98))	('estrogen receptor', 'Gene', '2099', (151, 168))	('BG8', 'CellLine', 'CVCL:M614', (113, 116))	('carcinomas of ovary', 'Phenotype', 'HP:0100615', (20, 39))	('serous carcinomas of ovary', 'Disease', 'MESH:D010051', (13, 39))	('CD15', 'Gene', (135, 139))	('serous carcinomas of ovary', 'Disease', (13, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (20, 30))	('estrogen receptor', 'Gene', (151, 168))	('CD15', 'Gene', '2526', (135, 139))	('MUC4', 'Gene', '4585', (142, 146))	('serous carcinomas of ovary', 'Phenotype', 'HP:0012887', (13, 39))	('MUC4', 'Gene', (142, 146))	('PAX8', 'Gene', (100, 104))	('BG8', 'Gene', (113, 116))
102845	26681974	Metastatic adenocarcinomas react with BerEp4, B72.3, CEA and/or CD15.	('Metastatic adenocarcinomas', 'Disease', 'MESH:C538445', (0, 26))	('CD15', 'Gene', '2526', (64, 68))	('CD15', 'Gene', (64, 68))	('B72.3', 'Var', (46, 51))	('CEA', 'Gene', (53, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('CEA', 'Gene', '1084', (53, 56))	('Metastatic adenocarcinomas', 'Disease', (0, 26))
102921	26211743	Briefly, test and reference genomic DNA samples (1500 ng per sample) were labeled fluorescently with Cy5 (test) and Cy3 (reference) using a ULS Labeling Kit (Agilent Technologies).	('Cy5', 'Chemical', 'MESH:C085321', (101, 104))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('Cy3', 'Chemical', '-', (116, 119))	('Cy5', 'Var', (101, 104))	('Cy3', 'Var', (116, 119))
102927	26211743	The copy number ratio of TBXAS1 to GAPDH was calculated using RT2 qPCR Primer Assays for rat Tbxas1 and Gapdh (catalog numbers PPR46265A and PPR06557B, respectively; Qiagen).	('PPR46265A', 'Var', (127, 136))	('GAPDH', 'Gene', '24383', (35, 40))	('rat', 'Species', '10116', (16, 19))	('Tbxas1', 'Gene', (93, 99))	('Gapdh', 'Gene', (104, 109))	('PPR06557B', 'Var', (141, 150))	('GAPDH', 'Gene', (35, 40))	('Gapdh', 'Gene', '24383', (104, 109))	('rat', 'Species', '10116', (89, 92))	('Tbxas1', 'Gene', '24886', (93, 99))
102944	26211743	There were numerous other genomic amplifications and deletions, but they were not consistent among tumors.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('deletions', 'Var', (53, 62))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
102955	26211743	Molecular studies have identified somatic genetic and epigenetic alterations, including those in NF2, BAP1 and CDKN2A, in malignant mesothelioma.	('BAP1', 'Gene', (102, 106))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (122, 144))	('NF2', 'Gene', '25744', (97, 100))	('NF2', 'Gene', (97, 100))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (122, 144))	('epigenetic alterations', 'Var', (54, 76))	('CDKN2A', 'Gene', '25163', (111, 117))	('CDKN2A', 'Gene', (111, 117))	('malignant mesothelioma', 'Disease', (122, 144))	('rat', 'Species', '10116', (69, 72))	('BAP1', 'Gene', '306257', (102, 106))
102958	26211743	Concerning histologic types, H2052 and H290 are epithelial, H28 is sarcomatoid and MSTO-211H is biphasic.	('H28', 'Gene', '310968', (60, 63))	('H2052', 'Var', (29, 34))	('sarcomatoid', 'Disease', (67, 78))	('H28', 'Gene', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('H290', 'Var', (39, 43))	('H2052', 'CellLine', 'CVCL:1518', (29, 34))	('sarcomatoid', 'Disease', 'MESH:C538614', (67, 78))	('H290', 'CellLine', 'CVCL:A555', (39, 43))
102961	26211743	Defects in TBXAS1 cause Ghosal hematodiaphyseal dysplasia (GHDD), a rare autosomal recessive disorder characterized by increased bone density with predominant diaphyseal involvement and aregenerative corticosteroid-sensitive anemia.	('GHDD', 'Disease', 'MESH:C565551', (59, 63))	('GHDD', 'Disease', (59, 63))	('rat', 'Species', '10116', (193, 196))	('increased bone density', 'Phenotype', 'HP:0011001', (119, 141))	('anemia', 'Disease', 'MESH:D000740', (225, 231))	('anemia', 'Disease', (225, 231))	('Defects', 'Var', (0, 7))	('men', 'Species', '9606', (177, 180))	('cause', 'Reg', (18, 23))	('Ghosal hematodiaphyseal dysplasia', 'Disease', 'MESH:C565551', (24, 57))	('Ghosal hematodiaphyseal dysplasia', 'Disease', (24, 57))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (73, 101))	('anemia', 'Phenotype', 'HP:0001903', (225, 231))	('TBXAS1', 'Gene', (11, 17))	('autosomal recessive disorder', 'Disease', (73, 101))
102967	26211743	Moreover, common single nucleotide polymorphisms or haplotypes in TBXAS1 genes were associated with breast cancer risk.	('single nucleotide polymorphisms', 'Var', (17, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('associated', 'Reg', (84, 94))	('breast cancer', 'Disease', (100, 113))	('haplotypes', 'Var', (52, 62))	('TBXAS1', 'Gene', (66, 72))
102979	26211743	found homozygous deletion of CDKN2A/2B in iron saccharate-induced mesothelioma rat model.	('CDKN2A/2B', 'Gene', (29, 38))	('iron saccharate', 'Chemical', 'MESH:D000077605', (42, 57))	('CDKN2A/2B', 'Gene', '25163', (29, 38))	('mesothelioma', 'Disease', (66, 78))	('rat', 'Species', '10116', (53, 56))	('deletion', 'Var', (17, 25))	('rat', 'Species', '10116', (79, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))
102981	26211743	The downregulation of TBXAS1 and the homozygous deletion of CDKN2A/2B might be exclusive in the rat models.	('CDKN2A/2B', 'Gene', '25163', (60, 69))	('TBXAS1', 'Gene', (22, 28))	('CDKN2A/2B', 'Gene', (60, 69))	('downregulation', 'NegReg', (4, 18))	('rat', 'Species', '10116', (96, 99))	('deletion', 'Var', (48, 56))
102985	26211743	Moreover, iron reduction could make lower risk of hepatic likely other cancers.	('lower', 'NegReg', (36, 41))	('iron', 'Chemical', 'MESH:D007501', (10, 14))	('hepatic likely other cancers', 'Disease', 'MESH:D008113', (50, 78))	('iron', 'Var', (10, 14))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('hepatic likely other cancers', 'Disease', (50, 78))	('reduction', 'NegReg', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
103052	33490271	Patients with high COL1A1 expression usually experienced shorten overall survival time than those with its low expression.	('expression', 'MPA', (26, 36))	('shorten', 'NegReg', (57, 64))	('COL1A1', 'Gene', (19, 25))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (65, 81))
103115	33207594	Five different S100 proteins were detected, S10A4 (encoded by S100a4), S10A6 encoded by S100a6), S10A8 (encoded by S100a8), S10AA (encoded by S100a10), and S10AB (encoded by S100a11).	('S100a11', 'Gene', (174, 181))	('S10A8', 'Gene', '116547', (97, 102))	('S100a4', 'Gene', (62, 68))	('S10A6', 'Var', (71, 76))	('S100a8', 'Gene', '116547', (115, 121))	('S100a11', 'Gene', '445415', (174, 181))	('S100a10', 'Gene', '81778', (142, 149))	('S100a10', 'Gene', (142, 149))	('S10AB', 'Chemical', '-', (156, 161))	('S10A4', 'Gene', (44, 49))	('S100a6', 'Gene', (88, 94))	('S10AA', 'Var', (124, 129))	('S100', 'Gene', (15, 19))	('S10A4', 'Gene', '24615', (44, 49))	('S100a6', 'Gene', '85247', (88, 94))	('S10AB', 'Var', (156, 161))	('S10A8', 'Gene', (97, 102))	('S100a4', 'Gene', '24615', (62, 68))	('S100a8', 'Gene', (115, 121))
103116	33207594	For three proteins, a return to normal levels (no significant differences relative to the liver from normal rats) was observed under curcumin treatment, the abundance being increased for S10A6 and S10AB and decreased for S10A8 (Figure 5).	('curcumin', 'Chemical', 'MESH:D003474', (133, 141))	('S10A8', 'Gene', '116547', (221, 226))	('S10AB', 'Chemical', '-', (197, 202))	('S10AB', 'Var', (197, 202))	('S10A6', 'Var', (187, 192))	('increased', 'PosReg', (173, 182))	('rats', 'Species', '10116', (108, 112))	('abundance', 'MPA', (157, 166))	('S10A8', 'Gene', (221, 226))	('decreased', 'NegReg', (207, 216))
103142	33207594	The characteristics of this enzyme have been extensively reviewed by Bzowska et al., emphasizing, in particular, the impact of its deficiency on impairment of T-cell function.	('impairment of T', 'Disease', (145, 160))	('deficiency', 'Var', (131, 141))	('impairment of T-cell function', 'Phenotype', 'HP:0005435', (145, 174))	('impairment of T', 'Disease', 'MESH:D060825', (145, 160))
103160	33207594	In this study, the combined increase in S10A6 and S10AB in untreated rats and return to normal values following curcumin treatment are consistent with previous findings that, among eight proteins belonging to this family, these two showed the most dramatic increase in tumor vs. normal tissues.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('curcumin', 'Chemical', 'MESH:D003474', (112, 120))	('rats', 'Species', '10116', (69, 73))	('tumor', 'Disease', (269, 274))	('S10AB', 'Chemical', '-', (50, 55))	('S10AB', 'Var', (50, 55))	('increase', 'PosReg', (257, 265))	('S10A6', 'Var', (40, 45))	('increase', 'PosReg', (28, 36))
103162	33207594	The absence of further difference in abundance of S10A6 in treated vs. normal rats also tends to confirm the impact of curcumin treatment on cancer cell motility given the involvement of S10A6 on cytoskeletal organization.	('rats', 'Species', '10116', (78, 82))	('cell motility', 'biological_process', 'GO:0048870', ('148', '161'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('curcumin', 'Chemical', 'MESH:D003474', (119, 127))	('S10A6', 'Var', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
103174	33207594	The involvement of alterations of the Prss1 gene has previously been associated with elevated gastric cancer risk and pediatric tumors including sarcomas.	('gastric cancer', 'Disease', (94, 108))	('pediatric tumors', 'Disease', (118, 134))	('elevated gastric cancer risk', 'Phenotype', 'HP:0006753', (85, 113))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Prss1', 'Gene', (38, 43))	('associated', 'Reg', (69, 79))	('rat', 'Species', '10116', (23, 26))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('alterations', 'Var', (19, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('sarcomas', 'Disease', (145, 153))	('pediatric tumors', 'Disease', 'MESH:D063766', (118, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
103184	33207594	The dysregulation of the SSR3 gene has also been found to be included in the transcriptomic profile of resting NK (Natural Killer) cells.	('dysregulation', 'Var', (4, 17))	('SSR3', 'Gene', '81784', (25, 29))	('SSR3', 'Gene', (25, 29))	('SSR', 'cellular_component', 'GO:0071212', ('25', '28'))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('N', 'Chemical', 'MESH:D009584', (115, 116))
103187	33207594	Elevated levels of HS71B (also named Hsp 70-2) in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HS71B', 'Var', (19, 24))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (86, 91))	('Hsp 70-2', 'Gene', '294254', (37, 45))	('tumor', 'Disease', (108, 113))	('Hsp 70-2', 'Gene', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('responsible', 'Reg', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
103246	31741710	Pleural effusions are not limited to malignancies and can occur when the regulation of pleural fluid volume is disrupted by pathologic changes affecting the mechanical movement of the thoracic cage, the pulmonary or systemic circulations or lymphatic drainage.	('changes', 'Var', (135, 142))	('Pleural effusions', 'Disease', (0, 17))	('malignancies', 'Disease', (37, 49))	('regulation of pleural', 'MPA', (73, 94))	('occur', 'Reg', (58, 63))	('affecting', 'Reg', (143, 152))	('Pleural effusions', 'Disease', 'MESH:D010996', (0, 17))	('mechanical movement', 'CPA', (157, 176))	('Pleural effusions', 'Phenotype', 'HP:0002202', (0, 17))	('pleural fluid', 'Phenotype', 'HP:0002202', (87, 100))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('disrupted', 'NegReg', (111, 120))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))
103292	31741710	Indeed, high plasma levels of TGFbeta1 is predictive of poor prognosis in NSCLC.	('high', 'Var', (8, 12))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('TGFbeta1', 'Gene', '7040', (30, 38))	('high plasma levels of TGFbeta1', 'Phenotype', 'HP:0030269', (8, 38))	('TGFbeta1', 'Gene', (30, 38))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
103336	30777124	Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('mesothelioma', 'Disease', (44, 56))	('positivity', 'Var', (68, 78))
103349	30777124	Previous studies in mesotheliomas have revealed that over 60% of mesotheliomas harbor BRCA1 associated protein 1 (BAP1) inactivating mutation or copy number loss, making BAP1 the most commonly altered gene in this malignancy.	('mesotheliomas', 'Disease', 'MESH:D008654', (20, 33))	('mesotheliomas', 'Disease', 'MESH:D008654', (65, 78))	('mesotheliomas', 'Disease', (20, 33))	('mesotheliomas', 'Disease', (65, 78))	('inactivating mutation', 'Var', (120, 141))	('BAP1', 'Gene', '8314', (170, 174))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('copy number loss', 'Var', (145, 161))	('BAP1', 'Gene', '8314', (114, 118))	('malignancy', 'Disease', 'MESH:D009369', (214, 224))	('BAP1', 'Gene', (170, 174))	('BRCA1 associated protein 1', 'Gene', '8314', (86, 112))	('BAP1', 'Gene', (114, 118))	('BRCA1 associated protein 1', 'Gene', (86, 112))	('malignancy', 'Disease', (214, 224))
103353	30777124	In addition, inactivating mutations of neurofibromin 2 (NF2) and cyclin-dependent kinase inhibitor 2A (CDKN2A) are also relatively common, while other mutations are rare.	('inactivating mutations', 'Var', (13, 35))	('neurofibromin 2', 'Gene', '4771', (39, 54))	('NF2', 'Gene', (56, 59))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('65', '98'))	('neurofibromin 2', 'Gene', (39, 54))	('CDKN2A', 'Gene', (103, 109))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (65, 101))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('82', '98'))	('NF2', 'Gene', '4771', (56, 59))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (65, 101))	('CDKN2A', 'Gene', '1029', (103, 109))
103356	30777124	However, the role of immunostaining for PD-L1, the usual approach to predicting a response to immunotherapy for other tumor types, is controversial in PM, since positive stating has generally been associated with a worse prognosis, and it is unclear what marker should be used to predict tumors that may respond to immunotherapy.	('tumor', 'Disease', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('positive', 'Var', (161, 169))	('PD-L1', 'Gene', (40, 45))	('PM', 'Phenotype', 'HP:0100002', (151, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Disease', (118, 123))	('PD-L1', 'Gene', '29126', (40, 45))	('associated with', 'Reg', (197, 212))	('tumors', 'Disease', (288, 294))
103396	30777124	Among the 5 BAP1-mutated cases, 2 cases (MESO-06 and MESO-09) were predicted to have inactivated BAP1, whereas despite BAP1 mutation in 3 cases (MESO-18A/E and MESO-19), their mRNA transcripts were expressed in high levels (Fig.	('mRNA transcripts', 'MPA', (176, 192))	('BAP1', 'Gene', '8314', (97, 101))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (97, 101))	('BAP1', 'Gene', '8314', (119, 123))	('mutation', 'Var', (124, 132))	('BAP1', 'Gene', (12, 16))	('BAP1', 'Gene', (119, 123))	('inactivated', 'NegReg', (85, 96))
103397	30777124	We identified that all variants of BAP1 (except a 42-bp deletion in MESO-09) were expressed at the RNA level (Additional file 2: Table S16).	('variants', 'Var', (23, 31))	('BAP1', 'Gene', '8314', (35, 39))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('BAP1', 'Gene', (35, 39))
103398	30777124	In addition, we identified mutations in genes such as TP53, SETD2, SETDB1, and LATS1 each present in just a single case (Fig.	('mutations', 'Var', (27, 36))	('SETD2', 'Gene', '29072', (60, 65))	('SETDB1', 'Gene', '9869', (67, 73))	('SETD2', 'Gene', (60, 65))	('TP53', 'Gene', '7157', (54, 58))	('LATS1', 'Gene', (79, 84))	('LATS1', 'Gene', '9113', (79, 84))	('TP53', 'Gene', (54, 58))	('SETDB1', 'Gene', (67, 73))
103404	30777124	Tumors with BAP1 heterozygous loss still displayed BAP1 nuclear staining (Additional file 1: Figure S10).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))	('displayed', 'Reg', (41, 50))	('BAP1', 'Gene', '8314', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BAP1', 'Gene', (12, 16))	('heterozygous loss', 'Var', (17, 34))
103414	30777124	Unlike in transcriptome profiles, the proteome profiles of tumor samples in BAP1intact and BAP1del subtypes did not group into distinct clusters (Additional file 1: Figure S16B).	('BAP1', 'Gene', (91, 95))	('tumor', 'Disease', (59, 64))	('BAP1', 'Gene', '8314', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('S16B', 'Var', (172, 176))	('BAP1', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('BAP1', 'Gene', '8314', (91, 95))	('S16B', 'SUBSTITUTION', 'None', (172, 176))
103441	30777124	Prior studies of mesotheliomas, performed using a single omic platform, have established BAP1 inactivation as a key driver event in mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (17, 30))	('mesotheliomas', 'Disease', (17, 30))	('BAP1', 'Gene', (89, 93))	('mesotheliomas', 'Disease', 'MESH:D008654', (132, 145))	('mesotheliomas', 'Disease', (132, 145))	('inactivation', 'Var', (94, 106))	('BAP1', 'Gene', '8314', (89, 93))
103447	30777124	Loss of BAP1 is known to alter chromatin architecture exposing the DNA to damage and also impairing the DNA repair machinery .	('impairing', 'NegReg', (90, 99))	('BAP1', 'Gene', '8314', (8, 12))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA repair', 'MPA', (104, 114))	('alter', 'Reg', (25, 30))	('BAP1', 'Gene', (8, 12))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('Loss', 'Var', (0, 4))	('chromatin architecture', 'MPA', (31, 53))	('DNA repair', 'biological_process', 'GO:0006281', ('104', '114'))
103448	30777124	The DNA repair defects thus drive genomic instability and dysregulate tumor microenvironment.	('DNA repair', 'biological_process', 'GO:0006281', ('4', '14'))	('dysregulate tumor', 'Disease', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('DNA repair', 'Gene', (4, 14))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('drive', 'Reg', (28, 33))	('defects', 'Var', (15, 22))	('genomic instability', 'CPA', (34, 53))	('dysregulate tumor', 'Disease', 'MESH:D021081', (58, 75))
103449	30777124	DNA repair deficiency leads to the increased secretion of cytokines, including interferons that promote tumor-antigen presentation and trigger recruitment of T lymphocytes to destroy tumor cells.	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('increased', 'PosReg', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA repair', 'Gene', (0, 10))	('tumor', 'Disease', (104, 109))	('deficiency', 'Var', (11, 21))	('promote', 'PosReg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('antigen presentation', 'biological_process', 'GO:0019882', ('110', '130'))	('tumor', 'Disease', (183, 188))	('tumor-antigen', 'molecular_function', 'GO:0008222', ('104', '117'))	('secretion', 'biological_process', 'GO:0046903', ('45', '54'))	('secretion of cytokines', 'MPA', (45, 67))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
103453	30777124	However, in a small subset of PM tumors in TCGA dataset, the loss of BAP1 did not elevate the expression of immune checkpoint marker genes.	('BAP1', 'Gene', '8314', (69, 73))	('PM tumors', 'Disease', (30, 39))	('BAP1', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('expression', 'MPA', (94, 104))	('loss', 'Var', (61, 65))	('PM', 'Phenotype', 'HP:0100002', (30, 32))	('PM tumors', 'Disease', 'MESH:D009369', (30, 39))
103460	30777124	We hypothesize based on this evidence presented that response rates for immune checkpoint blockade therapies in clinical trials for PeM will improve when patients are segregated by their BAP1 copy number status.	('BAP1', 'Gene', '8314', (187, 191))	('PeM', 'Phenotype', 'HP:0100003', (132, 135))	('response', 'MPA', (53, 61))	('patients', 'Species', '9606', (154, 162))	('copy number', 'Var', (192, 203))	('BAP1', 'Gene', (187, 191))	('improve', 'PosReg', (141, 148))
103465	30777124	BAM Binary alignment map BAP1 BRCA1-associated protein 1 CDKN2A Cyclin-dependent kinase inhibitor 2A CNA Copy number aberration CRS Cytoreductive surgery GESD Generalized extreme studentized deviate HIPEC Hyperthermic intraperitoneal chemotherapy IHC Immunohistochemical ILP Integer linear programming NF2 Neurofibromin 2 NIPEC Normothermic intraperitoneal chemotherapy PCR Polymerase chain reaction PeM Peritoneal mesothelioma PM Pleural mesothelioma PSM Peptide-spectrum match qPCR Quantitative PCR SETD2 SET domain containing 2 SNV Single nucleotide variation SPS Synchronous precursor selection TMA Tissue microarray VCF Variant call format RS, NN, SLB, YW, AC, and CCC conceived the study.	('BAP1', 'Gene', (25, 29))	('BRCA1-associated protein', 'Gene', (30, 54))	('SLB', 'Gene', (653, 656))	('CCC', 'cellular_component', 'GO:0030896', ('670', '673'))	('NF2', 'Gene', '4771', (302, 305))	('Pleural mesothelioma', 'Phenotype', 'HP:0100002', (431, 451))	('Neurofibromin', 'Gene', '4763', (306, 319))	('Variant', 'Var', (625, 632))	('SPS', 'Disease', (563, 566))	('mesothelioma', 'Disease', (415, 427))	('CDKN2A', 'Gene', (57, 63))	('mesothelioma', 'Disease', (439, 451))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('64', '97'))	('SLB', 'molecular_function', 'GO:0046560', ('653', '656'))	('Pleural mesothelioma', 'Disease', (431, 451))	('NF2', 'Gene', (302, 305))	('mesothelioma', 'Disease', 'MESH:D008654', (439, 451))	('SLB', 'Gene', '26160', (653, 656))	('mesothelioma', 'Disease', 'MESH:D008654', (415, 427))	('Pleural mesothelioma', 'Disease', 'MESH:D008654', (431, 451))	('SETD2', 'Gene', (501, 506))	('SPS', 'Disease', 'MESH:C535540', (563, 566))	('PM', 'Phenotype', 'HP:0100002', (428, 430))	('TMA', 'Disease', 'MESH:D000783', (599, 602))	('CDKN2A', 'Gene', '1029', (57, 63))	('SPS', 'molecular_function', 'GO:0046524', ('563', '566'))	('SETD2', 'Gene', '29072', (501, 506))	('BAP1', 'Gene', '8314', (25, 29))	('TMA', 'Disease', (599, 602))	('Neurofibromin', 'Gene', (306, 319))	('PeM', 'Phenotype', 'HP:0100003', (400, 403))	('Peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (404, 427))	('BRCA1-associated protein', 'Gene', '8315', (30, 54))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('81', '97'))
103473	30777124	H1500902 and V15-00902).	('V15', 'Gene', '28814', (13, 16))	('H1500902', 'Var', (0, 8))	('V15', 'Gene', (13, 16))
103516	30705816	In summary, we present a fourth case where PMPM contributed to SCD showing cytopathological, histopathologic and post-mortem autopsy findings.	('contributed', 'Reg', (48, 59))	('SCD', 'Phenotype', 'HP:0001645', (63, 66))	('PMPM', 'Var', (43, 47))	('SCD', 'Disease', 'MESH:C536778', (63, 66))	('SCD', 'Disease', (63, 66))
103567	27833109	Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer with a high mortality rate as it responds poorly to standard therapeutic interventions.	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (161, 191))	('Mouse', 'Species', '10090', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('aggressive thoracic cancer', 'Disease', 'MESH:D009369', (204, 230))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (171, 191))	('Endothelial Cell Protein C Receptor', 'Gene', (33, 68))	('aggressive thoracic cancer', 'Disease', (204, 230))	('Malignant Pleural Mesothelioma', 'Disease', (113, 143))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (123, 143))	('Endothelial Cell Protein C Receptor', 'Gene', '19124', (33, 68))	('Gene Transfer', 'Var', (69, 82))	('Malignant pleural mesothelioma', 'Disease', (161, 191))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (113, 143))	('Suppresses', 'NegReg', (83, 93))
103570	27833109	Measurement of cytokines from the pleural lavage showed that mice implanted with MPM cells expressing EPCR had elevated levels of IFNgamma and TNFalpha compared to mice implanted with MPM cells lacking EPCR.	('elevated', 'PosReg', (111, 119))	('levels of IFNgamma', 'MPA', (120, 138))	('mice', 'Species', '10090', (61, 65))	('mice', 'Species', '10090', (164, 168))	('pleural lavage', 'Disease', (34, 48))	('EPCR', 'Var', (102, 106))	('TNFalpha', 'MPA', (143, 151))	('pleural lavage', 'Disease', 'MESH:D010995', (34, 48))
103578	27833109	EPCR-APC-induced cell signaling was shown to inhibit apoptosis in endothelial cells, cancer cells, and other cell types.	('apoptosis', 'CPA', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('cancer', 'Disease', (85, 91))	('EPCR-APC-induced', 'Var', (0, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('inhibit', 'NegReg', (45, 52))	('APC', 'cellular_component', 'GO:0005680', ('5', '8'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
103584	27833109	Confirming the tumor suppressive effect of EPCR in MPM, the knock-down of EPCR in non-aggressive TF expressing MPM cells that constitutively express EPCR increased the tumorigenicity of the non-aggressive MPM cells.	('knock-down', 'Var', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (168, 173))	('TF', 'Gene', '14066', (97, 99))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('EPCR', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('increased', 'PosReg', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
103585	27833109	This study also revealed that EPCR in MPM cells promotes tumor cell apoptosis in vivo.	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('promotes', 'PosReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('EPCR', 'Var', (30, 34))	('tumor', 'Disease', (57, 62))
103596	27833109	Since our recent studies clearly showed that transduction of EPCR expression in highly aggressive MPM cells that lack EPCR promoted tumor cell apoptosis and suppressed the tumor growth, the present study was undertaken to investigate whether intrapleural EPCR gene transfer will have therapeutic value in halting the progression of MPM.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (172, 177))	('transduction', 'biological_process', 'GO:0009293', ('45', '57'))	('suppressed', 'NegReg', (157, 167))	('promoted', 'PosReg', (123, 131))	('transduction', 'Var', (45, 57))	('MPM', 'Disease', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('EPCR', 'Gene', (61, 65))
103598	27833109	This study revealed that tumors originating from MPM cells expressing EPCR were more apoptotic compared to tumors originating from MPM cells lacking EPCR.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('apoptotic', 'CPA', (85, 94))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('EPCR', 'Var', (70, 74))
103602	27833109	In contrast to the increased TNFalpha and IFNgamma levels, IL-6 levels were reduced in the pleural lavage of mice implanted with REN(+EPCR) MPM cells compared to mice implanted with REN(z) cells (Fig.	('pleural lavage', 'Disease', (91, 105))	('IL-6', 'molecular_function', 'GO:0005138', ('59', '63'))	('MPM cells', 'Var', (140, 149))	('mice', 'Species', '10090', (162, 166))	('reduced', 'NegReg', (76, 83))	('IL-6', 'Gene', (59, 63))	('IL-6', 'Gene', '16193', (59, 63))	('pleural lavage', 'Disease', 'MESH:D010995', (91, 105))	('mice', 'Species', '10090', (109, 113))
103606	27833109	Evaluation of apoptotic markers in REN and (REN + EPCR) cells by western blot analysis showed increased levels of cleaved caspase 3 and cleaved PARP, and reduced levels of p-BAD in REN(+EPCR) cells treated with TNFalpha + IFNgamma compared to REN cells treated TNFalpha + IFNgamma (Fig.	('p-BAD', 'MPA', (172, 177))	('levels', 'MPA', (104, 110))	('TNFalpha + IFNgamma', 'Var', (211, 230))	('cleaved', 'MPA', (136, 143))	('cleaved caspase 3', 'MPA', (114, 131))	('increased', 'PosReg', (94, 103))	('PARP', 'Gene', (144, 148))	('levels', 'MPA', (162, 168))	('PARP', 'Gene', '11545', (144, 148))	('reduced', 'NegReg', (154, 161))
103615	27833109	Analysis of the resultant data revealed that mice receiving EPCR adenovirus showed a significant decrease in tumor number, tumor volume, and tumor burden compared to the group of mice receiving PBS (p < 0.001 in both t-test and ANOVA) or the control adenovirus (p < 0.01 for tumor volume in both t-test and ANOVA; p < 0.05 for tumor number and burden in t-test) (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (123, 128))	('mice', 'Species', '10090', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('EPCR adenovirus', 'Var', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('PBS', 'Chemical', '-', (194, 197))	('decrease', 'NegReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (109, 114))
103616	27833109	Somewhat less pronounced differences in tumor statistics between Ad.EPCR virus and Ad.Control injected mice reflect a slight protective effect of the control adenovirus in comparison to PBS control.	('PBS', 'Chemical', '-', (186, 189))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('protective effect', 'CPA', (125, 142))	('Ad.EPCR virus', 'Var', (65, 78))	('Ad', 'Chemical', '-', (65, 67))	('Ad', 'Chemical', '-', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
103617	27833109	Immunohistochemical analysis of tumor tissue sections derived from tumors excised at the end of the 30-day experimental period showed EPCR expression in tumor cells in mice injected with EPCR adenovirus but not in the control adenovirus or PBS.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('EPCR', 'Var', (187, 191))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mice', 'Species', '10090', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('PBS', 'Chemical', '-', (240, 243))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', (67, 73))	('EPCR', 'Gene', (134, 138))
103619	27833109	TUNEL staining of tumor tissue sections to assess tumor cell apoptosis revealed that treatment of mice with EPCR adenovirus markedly increased tumor cell apoptosis (Fig.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'biological_process', 'GO:0097194', ('154', '163'))	('apoptosis', 'biological_process', 'GO:0006915', ('154', '163'))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('increased', 'PosReg', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('EPCR', 'Var', (108, 112))	('mice', 'Species', '10090', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
103621	27833109	Analysis of tumor tissue extracts by western blot analysis showed increased levels of proapoptotic protein, BAX, decreased p-BAD, and increased levels of cleaved caspase 3 and PARP in tumor tissues obtained from mice treated with Ad.EPCR compared to mice treated with PBS or Ad.Con (Fig.	('mice', 'Species', '10090', (212, 216))	('Ad', 'Chemical', '-', (275, 277))	('BAX', 'Gene', '12028', (108, 111))	('tumor', 'Disease', (12, 17))	('decreased', 'NegReg', (113, 122))	('PBS', 'Chemical', '-', (268, 271))	('Ad.EPCR', 'Var', (230, 237))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (184, 189))	('p-BAD', 'MPA', (123, 128))	('PARP', 'Gene', '11545', (176, 180))	('mice', 'Species', '10090', (250, 254))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('levels', 'MPA', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('increased', 'PosReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('BAX', 'Gene', (108, 111))	('PARP', 'Gene', (176, 180))	('cleaved caspase 3', 'MPA', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Ad', 'Chemical', '-', (230, 232))	('levels', 'MPA', (144, 150))	('increased', 'PosReg', (134, 143))
103622	27833109	These data suggest a greater extent of apoptosis in tumors of mice that were treated with Ad.EPCR compared to mice treated with a control vehicle or control vector.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('apoptosis', 'CPA', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('mice', 'Species', '10090', (62, 66))	('mice', 'Species', '10090', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('Ad.EPCR', 'Var', (90, 97))	('Ad', 'Chemical', '-', (90, 92))
103623	27833109	These data further strengthen our observation that EPCR adenovirus treatment promotes tumor apoptosis in MPM.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('MPM', 'Disease', (105, 108))	('promotes', 'PosReg', (77, 85))	('tumor', 'Disease', (86, 91))	('EPCR', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
103625	27833109	Analysis of tissue sections of tumors derived from mice treated with EPCR adenovirus showed a significant increase in the number of macrophages (greater than 15%) recruited into tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (51, 55))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('EPCR adenovirus', 'Var', (69, 84))	('increase', 'PosReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
103629	27833109	Measurement of TNFalpha and IFNgamma levels in the pleural lavage showed a significant increase in TNFalpha and IFNgamma levels in mice treated with EPCR adenovirus but not in mice treated with saline or control adenovirus (Fig.	('EPCR adenovirus', 'Var', (149, 164))	('increase', 'PosReg', (87, 95))	('pleural lavage', 'Disease', 'MESH:D010995', (51, 65))	('pleural lavage', 'Disease', (51, 65))	('mice', 'Species', '10090', (176, 180))	('saline', 'Chemical', 'MESH:D012965', (194, 200))	('mice', 'Species', '10090', (131, 135))	('TNFalpha', 'MPA', (99, 107))
103633	27833109	Treatment of mice with EPCR adenovirus and not the control adenovirus significantly decreased the levels of IL-3, IL-4, IL-6, IL-12 and RANTES.	('IL-3', 'Gene', (108, 112))	('IL-4', 'Gene', (114, 118))	('EPCR adenovirus', 'Var', (23, 38))	('mice', 'Species', '10090', (13, 17))	('RANTES', 'Gene', (136, 142))	('IL-3', 'molecular_function', 'GO:0005135', ('108', '112'))	('RANTES', 'Gene', '20304', (136, 142))	('IL-12', 'molecular_function', 'GO:0005143', ('126', '131'))	('IL-4', 'Gene', '16189', (114, 118))	('IL-6', 'Gene', (120, 124))	('IL-6', 'Gene', '16193', (120, 124))	('IL-6', 'molecular_function', 'GO:0005138', ('120', '124'))	('IL-12', 'MPA', (126, 131))	('IL-4', 'molecular_function', 'GO:0005136', ('114', '118'))	('IL-3', 'Gene', '16187', (108, 112))	('decreased', 'NegReg', (84, 93))
103636	27833109	This observation raised a possibility that EPCR gene therapy may curtail MPM tumor growth and progression.	('MPM tumor', 'Disease', 'MESH:D009369', (73, 82))	('curtail', 'NegReg', (65, 72))	('progression', 'CPA', (94, 105))	('EPCR gene therapy', 'Var', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MPM tumor', 'Disease', (73, 82))
103638	27833109	The data show that EPCR gene transfer to MPM cells induces tumor apoptosis, both in vitro and in vivo.	('tumor', 'Disease', (59, 64))	('EPCR gene transfer', 'Var', (19, 37))	('induces', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
103640	27833109	Many cancer cell types and cancer tissues were also shown to express EPCR.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('EPCR', 'Var', (69, 73))
103643	27833109	Supporting this notion, EPCR expression was shown to promote tumor metastasis in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('EPCR expression', 'Var', (24, 39))	('tumor metastasis in lung adenocarcinoma', 'Disease', (61, 100))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor metastasis in lung adenocarcinoma', 'Disease', 'MESH:D009362', (61, 100))	('promote', 'PosReg', (53, 60))
103647	27833109	In light of the above reports, it was totally surprising to find in our recent study that EPCR suppresses tumor growth in MPM.	('EPCR', 'Var', (90, 94))	('suppresses', 'NegReg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
103654	27833109	Consistent with our earlier report, the data presented here show that EPCR exerts an antitumor effect in vivo.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('EPCR', 'Var', (70, 74))
103656	27833109	It is interesting to note that administration of Ad.EPCR not only reduced tumor burden and volume, but it also decreased the total number of tumors in the thoracic cavity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('reduced', 'NegReg', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('volume', 'CPA', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decreased', 'NegReg', (111, 120))	('tumors', 'Disease', (141, 147))	('Ad.EPCR', 'Var', (49, 56))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (74, 79))	('Ad', 'Chemical', '-', (49, 51))
103658	27833109	Minor antitumor effects seen with a control adenoviral vector might have come from the known activation of innate immune response by adenoviruses and the associated anti-tumor effects.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('activation', 'PosReg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('innate immune', 'MPA', (107, 120))	('activation of innate immune response', 'biological_process', 'GO:0002218', ('93', '129'))	('adenoviruses', 'Var', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
103663	27833109	It is interesting to note that EPCR transduction in tumor cells significantly increased the infiltration of macrophages and NK cells into the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (52, 57))	('infiltration of macrophages', 'CPA', (92, 119))	('tumor', 'Disease', (142, 147))	('EPCR transduction', 'Var', (31, 48))	('increased', 'PosReg', (78, 87))	('transduction', 'biological_process', 'GO:0009293', ('36', '48'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
103664	27833109	At present, it is unknown how EPCR expression in MPM tumor cells attracts macrophages or NK cells into the tumor.	('MPM tumor', 'Disease', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MPM tumor', 'Disease', 'MESH:D009369', (49, 58))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('EPCR expression', 'Var', (30, 45))
103670	27833109	Interestingly, in contrast to the increased levels of TNFalpha and IFNgamma, the levels of other cytokines, both proinflammatory and anti-inflammatory, were significantly lower in the pleural lavage of mice treated with Ad.EPCR compared to mice treated with PBS vehicle or control adenovirus.	('mice', 'Species', '10090', (202, 206))	('levels of', 'MPA', (81, 90))	('pleural lavage', 'Disease', 'MESH:D010995', (184, 198))	('mice', 'Species', '10090', (240, 244))	('Ad.EPCR', 'Var', (220, 227))	('Ad', 'Chemical', '-', (220, 222))	('pleural lavage', 'Disease', (184, 198))	('PBS', 'Chemical', '-', (258, 261))	('lower', 'NegReg', (171, 176))
103671	27833109	Consistent with our earlier observation that EPCR acts as a tumor suppressor in mesothelioma, transduction of EPCR expression in MPM originating from MPM cells that are devoid of EPCR markedly increased apoptosis in tumors.	('tumors', 'Disease', (216, 222))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (216, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('transduction', 'biological_process', 'GO:0009293', ('94', '106'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increased', 'PosReg', (193, 202))	('mesothelioma', 'Disease', (80, 92))	('transduction', 'Var', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('EPCR', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))
103674	27833109	A marked increase in tumor cell apoptosis in mice administered with Ad.EPCR probably stems from the combined effect of EPCR-induced specific changes in the genome of MPM cells and increased levels of IFNgamma and TNFalpha in the pleural space.	('mice', 'Species', '10090', (45, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('levels', 'MPA', (190, 196))	('tumor', 'Disease', (21, 26))	('genome', 'MPA', (156, 162))	('MPM', 'Gene', (166, 169))	('increased', 'PosReg', (180, 189))	('increase', 'PosReg', (9, 17))	('Ad', 'Chemical', '-', (68, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('changes', 'Reg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Ad.EPCR', 'Var', (68, 75))
103676	27833109	Therefore, the antitumor effect of Ad.EPCR in the present study is attributable primarily to factors related to innate immunity and not to an acquired T-cell immunity.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Ad.EPCR', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Ad', 'Chemical', '-', (35, 37))	('tumor', 'Disease', (19, 24))	('innate immunity', 'biological_process', 'GO:0045087', ('112', '127'))
103685	27833109	Preclinical models showed that inhibition of cycloxygenase-2 to mitigate the immunosuppressive tumor microenvironment by reducing PGE2 and IL-10 production or concomitant chemotherapy improved the efficacy of IFN gene therapy.	('IL-10', 'Gene', (139, 144))	('gene therapy', 'Var', (213, 225))	('IFN', 'Gene', '3439', (209, 212))	('efficacy', 'MPA', (197, 205))	('PGE2', 'Chemical', 'MESH:D015232', (130, 134))	('cycloxygenase-2', 'Enzyme', (45, 60))	('PGE2', 'MPA', (130, 134))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (77, 100))	('IL-10', 'molecular_function', 'GO:0005141', ('139', '144'))	('IFN', 'Gene', (209, 212))	('reducing', 'NegReg', (121, 129))	('improved', 'PosReg', (184, 192))	('inhibition', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IL-10 production', 'biological_process', 'GO:0032613', ('139', '155'))	('IL-10', 'Gene', '16153', (139, 144))	('immunosuppressive tumor', 'Disease', (77, 100))
103697	27833109	Details of the sequences of oligonucleotides used for the knock-down of EPCR gene and experimental procedures to generate MS-1(-EPCR), and M9K(-EPCR) were described in detail in an earlier publication.	('M9K', 'Var', (139, 142))	('knock-down', 'Var', (58, 68))	('oligonucleotides', 'Chemical', 'MESH:D009841', (28, 44))	('EPCR gene', 'Gene', (72, 81))	('MS-1', 'Var', (122, 126))
103728	27833109	Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model.	('Mouse', 'Species', '10090', (149, 154))	('Progression', 'CPA', (98, 109))	('Ad', 'Chemical', '-', (13, 15))	('Endothelial Cell Protein C Receptor', 'Gene', (33, 68))	('Malignant Pleural Mesothelioma', 'Disease', (113, 143))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (123, 143))	('Endothelial Cell Protein C Receptor', 'Gene', '19124', (33, 68))	('Gene Transfer', 'Var', (69, 82))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (113, 143))	('Suppresses', 'NegReg', (83, 93))
103729	20717113	SV40 associated miRNAs are not detectable in mesotheliomas Simian virus-40 (SV40) is a DNA tumour virus that was introduced into the human population with contaminated poliovirus vaccine, and its role in mesothelioma is widely debated.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('SV40', 'Species', '1891767', (76, 80))	('mesothelioma', 'Disease', (45, 57))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('mesotheliomas', 'Disease', 'MESH:D008654', (45, 58))	('Simian virus-40', 'Species', '1891767', (59, 74))	('mesotheliomas', 'Disease', (45, 58))	('SV40', 'Var', (76, 80))	('tumour', 'Disease', (91, 97))	('human', 'Species', '9606', (133, 138))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('SV40', 'Species', '1891767', (0, 4))	('mesothelioma', 'Disease', (204, 216))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (204, 216))	('poliovirus', 'Species', '138950', (168, 178))
103732	20717113	Our work indicates that SV40 miRNAs are not likely to contribute to mesothelioma tumourogenesis, but highlights the value of this approach when compared with the relatively unspecific current testing methods.	('mesothelioma tumourogenesis', 'Disease', 'MESH:D008654', (68, 95))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (68, 87))	('SV40', 'Species', '1891767', (24, 28))	('SV40 miRNAs', 'Var', (24, 35))	('mesothelioma tumourogenesis', 'Disease', (68, 95))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
103734	20717113	SV40 has been shown to cause tumours in hamsters and sporadically produce small quantities of infectious virus.	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('cause', 'Reg', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('SV40', 'Species', '1891767', (0, 4))	('SV40', 'Var', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
103735	20717113	The fact that SV40 can have cytopathic effects and can transform human cells has led to the debate as to whether this virus can cause cancer in humans.	('transform', 'Reg', (55, 64))	('human', 'Species', '9606', (65, 70))	('human', 'Species', '9606', (144, 149))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('humans', 'Species', '9606', (144, 150))	('SV40', 'Species', '1891767', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('SV40', 'Var', (14, 18))
103761	20717113	Each assay discriminated the mismatched oligonucleotides, although the position of the mismatches influenced the sensitivity of the assays.	('oligonucleotides', 'Chemical', 'MESH:D009841', (40, 56))	('influenced', 'Reg', (98, 108))	('mismatched', 'Var', (29, 39))
103855	27031777	Interestingly, patients with BAP1 germline mutation mesotheliomas are reported to have dramatically better survival rates.	('patients', 'Species', '9606', (15, 23))	('mesotheliomas', 'Disease', 'MESH:D008654', (52, 65))	('mesotheliomas', 'Disease', (52, 65))	('better', 'PosReg', (100, 106))	('BAP1', 'Gene', '8314', (29, 33))	('survival', 'CPA', (107, 115))	('germline mutation', 'Var', (34, 51))	('BAP1', 'Gene', (29, 33))
103941	25501304	We further demonstrate that expression of NK4 suppresses beta-catenin nuclear localization and transcriptional activity.	('suppresses', 'NegReg', (46, 56))	('NK4', 'Gene', (42, 45))	('expression', 'Var', (28, 38))	('localization', 'biological_process', 'GO:0051179', ('78', '90'))	('beta-catenin', 'Gene', (57, 69))	('transcriptional activity', 'CPA', (95, 119))	('NK4', 'Gene', '9235', (42, 45))	('beta-catenin', 'Gene', '1499', (57, 69))
103966	25501304	We show that expression of NK4 via an adenoviral delivery system has pronounced anti-CSC activity on MM cells.	('expression', 'Var', (13, 23))	('anti-CSC activity', 'CPA', (80, 97))	('NK4', 'Gene', '9235', (27, 30))	('NK4', 'Gene', (27, 30))
103995	25501304	Briefly, single cells were plated in Ultra Low Attachment plates (Corning) in serum-free DMEM-F12 supplemented with 10 ng/mL bFGF, 10 ng/mL EGF, and B27 (all from Invitrogen).	('B27', 'Var', (149, 152))	('EGF', 'molecular_function', 'GO:0005154', ('140', '143'))	('bFGF', 'Gene', '2247', (125, 129))	('DMEM-F12', 'Chemical', '-', (89, 97))	('bFGF', 'Gene', (125, 129))
104026	25501304	However, infection with Ad-NK4 significantly inhibited the invasiveness of both Hmeso and Meso 10 cells (Fig.	('invasiveness of', 'CPA', (59, 74))	('Hmeso', 'Chemical', '-', (80, 85))	('NK4', 'Gene', (27, 30))	('Meso 10', 'Chemical', '-', (90, 97))	('inhibited', 'NegReg', (45, 54))	('NK4', 'Gene', '9235', (27, 30))	('infection', 'Var', (9, 18))
104058	25501304	TOP-Flash or FOP-Flash vector that contains wild-type or mutated TCF/LEF binding sites, respectively, was transfected into Hmeso and Meso 10 cells followed by infection with Ad-LacZ or Ad-NK4.	('TCF', 'Gene', (65, 68))	('NK4', 'Gene', (188, 191))	('TCF', 'Gene', '3172', (65, 68))	('Meso 10', 'Chemical', '-', (133, 140))	('Hmeso', 'Chemical', '-', (123, 128))	('NK4', 'Gene', '9235', (188, 191))	('Ad-LacZ', 'Chemical', '-', (174, 181))	('mutated', 'Var', (57, 64))	('FOP-', 'Phenotype', 'HP:0500062', (13, 17))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
104059	25501304	As expected, luciferase activity of the control vector FOP-Flash was unchanged in response to expression of either Ad-LacZ or Ad-NK4.	('luciferase activity', 'molecular_function', 'GO:0045289', ('13', '32'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('13', '32'))	('activity', 'MPA', (24, 32))	('NK4', 'Gene', (129, 132))	('Ad-LacZ', 'Var', (115, 122))	('Ad-LacZ', 'Chemical', '-', (115, 122))	('FOP-', 'Phenotype', 'HP:0500062', (55, 59))	('luciferase activity', 'molecular_function', 'GO:0050397', ('13', '32'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('13', '32'))	('luciferase', 'Enzyme', (13, 23))	('NK4', 'Gene', '9235', (129, 132))	('luciferase activity', 'molecular_function', 'GO:0047077', ('13', '32'))
104062	25501304	To further explore mechanism underlying NK4's anti-CSC activity, we compared effects of NK4 with PHA-665752, which is a selective small molecule inhibitor of Met kinase and exhibits potent antitumor activity in a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('PHA-665752', 'Var', (97, 107))	('NK4', 'Gene', '9235', (40, 43))	('NK4', 'Gene', '9235', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('tumor', 'Disease', (193, 198))	('cancers', 'Disease', (224, 231))	('NK4', 'Gene', (40, 43))	('NK4', 'Gene', (88, 91))
104063	25501304	We found that both PHA-665752 and NK4 inhibited phosphorylation of Met and suppressed active form of beta-catenin in mesothelioma cells.	('suppressed', 'NegReg', (75, 85))	('mesothelioma', 'Disease', (117, 129))	('beta-catenin', 'Gene', (101, 113))	('NK4', 'Gene', (34, 37))	('inhibited', 'NegReg', (38, 47))	('PHA-665752', 'Var', (19, 29))	('phosphorylation', 'MPA', (48, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('NK4', 'Gene', '9235', (34, 37))	('Met', 'MPA', (67, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('beta-catenin', 'Gene', '1499', (101, 113))
104077	25501304	Our results show that expression of NK4 substantially reduces Met and AKT activity and inhibits viability, invasiveness, and tumorigenicity of MM cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('invasiveness', 'CPA', (107, 119))	('expression', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('NK4', 'Gene', '9235', (36, 39))	('viability', 'CPA', (96, 105))	('Met and', 'CPA', (62, 69))	('inhibits', 'NegReg', (87, 95))	('tumor', 'Disease', (125, 130))	('reduces', 'NegReg', (54, 61))	('NK4', 'Gene', (36, 39))
104092	25501304	We further demonstrated that expression of NK4 markedly suppresses the nuclear localization and transcriptional activity of beta-catenin.	('expression', 'Var', (29, 39))	('NK4', 'Gene', (43, 46))	('transcriptional activity', 'MPA', (96, 120))	('beta-catenin', 'Gene', (124, 136))	('beta-catenin', 'Gene', '1499', (124, 136))	('nuclear localization', 'MPA', (71, 91))	('localization', 'biological_process', 'GO:0051179', ('79', '91'))	('NK4', 'Gene', '9235', (43, 46))	('suppresses', 'NegReg', (56, 66))
104113	24128712	Brief Report: Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations Genomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BAP1 gene.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (149, 169))	('BAP1', 'Gene', '8314', (227, 231))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (210, 219))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', (227, 231))	('malignant pleural mesothelioma', 'Disease', (56, 86))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (56, 86))	('malignant pleural mesothelioma', 'Disease', (139, 169))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (139, 169))	('patients', 'Species', '9606', (42, 50))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (66, 86))	('BAP1', 'Gene', (105, 109))
104114	24128712	In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (22, 53))	('BAP1', 'Gene', (55, 59))	('clear cell renal cell carcinoma', 'Disease', (22, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (33, 53))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (22, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('mutations', 'Var', (60, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('BAP1', 'Gene', '8314', (55, 59))
104115	24128712	We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (113, 121))	('MPM tumors', 'Disease', (82, 92))	('BAP1', 'Gene', '8314', (108, 112))	('harbor', 'Reg', (93, 99))	('BAP1', 'Gene', '8314', (162, 166))	('patients', 'Species', '9606', (67, 75))	('MPM tumors', 'Disease', 'MESH:D009369', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', (162, 166))
104116	24128712	We reviewed the charts of 121 patients with MPM tumors diagnosed between 1990 and 2009 tested for BAP1 mutation and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.	('MPM tumors', 'Disease', (44, 54))	('BAP1', 'Gene', (98, 102))	('MPM tumors', 'Disease', 'MESH:D009369', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('malignancy', 'Disease', 'MESH:D009369', (259, 269))	('patients', 'Species', '9606', (30, 38))	('BAP1', 'Gene', '8314', (98, 102))	('malignancy', 'Disease', (259, 269))	('men', 'Species', '9606', (280, 283))	('mutation', 'Var', (103, 111))	('tested', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('asbestos', 'Chemical', 'MESH:D001194', (210, 218))
104117	24128712	Twenty-four (20%) of the 121 tumors harbored somatic BAP1 mutations.	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('BAP1', 'Gene', '8314', (53, 57))	('tumors', 'Disease', (29, 35))	('BAP1', 'Gene', (53, 57))
104118	24128712	The percent of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% vs 42%; p=0.006).	('mutations', 'Var', (63, 72))	('BAP1', 'Gene', (106, 110))	('higher', 'PosReg', (91, 97))	('BAP1', 'Gene', (58, 62))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', '8314', (58, 62))
104119	24128712	However, the types of nucleotide substitutions in BAP1 did not suggest that this association was due to a causative role of smoking in BAP1 mutations.	('BAP1', 'Gene', '8314', (135, 139))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('BAP1', 'Gene', (50, 54))
104120	24128712	No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM.	('BAP1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('BAP1', 'Gene', '8314', (83, 87))
104121	24128712	There was also no difference in survival according to somatic BAP1 mutation status.	('BAP1', 'Gene', (62, 66))	('BAP1', 'Gene', '8314', (62, 66))	('mutation', 'Var', (67, 75))
104122	24128712	There is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation.	('BAP1', 'Gene', '8314', (70, 74))	('mutation', 'Var', (75, 83))	('BAP1', 'Gene', (70, 74))	('MPM', 'Disease', (53, 56))
104128	24128712	While it has been known for many years that inactivating mutations in neurofibromatosis 2 (NF2) and deletions of p16 are common in MPM, another commonly mutated gene, BRCA-associated protein 1 (BAP1), was only recently identified.	('p16', 'Gene', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('BRCA-associated protein 1', 'Gene', (167, 192))	('neurofibromatosis 2', 'Gene', (70, 89))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (70, 87))	('MPM', 'Gene', (131, 134))	('p16', 'Gene', '1029', (113, 116))	('BAP1', 'Gene', '8314', (194, 198))	('NF2', 'Gene', (91, 94))	('neurofibromatosis 2', 'Gene', '4771', (70, 89))	('deletions', 'Var', (100, 109))	('BRCA-associated protein 1', 'Gene', '8314', (167, 192))	('inactivating mutations', 'Var', (44, 66))	('BAP1', 'Gene', (194, 198))	('NF2', 'Gene', '4771', (91, 94))
104129	24128712	In the initial report, BAP1 mutations were identified in 23% of the MPM specimens.	('BAP1', 'Gene', (23, 27))	('men', 'Species', '9606', (77, 80))	('MPM', 'Disease', (68, 71))	('BAP1', 'Gene', '8314', (23, 27))	('mutations', 'Var', (28, 37))
104130	24128712	Loss of nuclear BAP1 protein expression was confirmed by immunohistochemistry in MPM with BAP1 mutation.	('MPM', 'Disease', (81, 84))	('BAP1', 'Gene', '8314', (90, 94))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (90, 94))	('BAP1', 'Gene', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('mutation', 'Var', (95, 103))
104131	24128712	No association was identified between BAP1 mutation and other commonly identified genetic alterations including p16 loss and NF2 mutation and/or loss.	('p16', 'Gene', (112, 115))	('mutation', 'Var', (129, 137))	('mutation', 'Var', (43, 51))	('BAP1', 'Gene', (38, 42))	('loss', 'NegReg', (145, 149))	('NF2', 'Gene', (125, 128))	('p16', 'Gene', '1029', (112, 115))	('loss', 'NegReg', (116, 120))	('NF2', 'Gene', '4771', (125, 128))	('BAP1', 'Gene', '8314', (38, 42))
104135	24128712	Mutations in BAP1 have also been described in other cancers.	('BAP1', 'Gene', (13, 17))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('described', 'Reg', (33, 42))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('BAP1', 'Gene', '8314', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
104136	24128712	In particular, BAP1 mutation is common in uveal melanoma (UM), the most frequent ocular tumor in Caucasian adults, where it is strongly associated with poor outcomes.	('associated', 'Reg', (136, 146))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (15, 19))	('common', 'Reg', (32, 38))	('ocular tumor', 'Disease', 'MESH:D009369', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ocular tumor', 'Disease', (81, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('BAP1', 'Gene', (15, 19))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('ocular tumor', 'Phenotype', 'HP:0100012', (81, 93))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
104138	24128712	A multi-gene expression profiling assay divides UMs into low and high metastatic risk with 84% of metastatic UM harboring BAP1 mutation compared to only 4% of low risk cases.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('BAP1', 'Gene', (122, 126))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('mutation', 'Var', (127, 135))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('BAP1', 'Gene', '8314', (122, 126))
104139	24128712	Likewise, in clear cell renal cell carcinoma, somatic BAP1 mutations associated with higher grade tumors shorter cancer-specific survival.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (13, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('higher grade', 'Disease', (85, 97))	('associated', 'Reg', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 44))	('clear cell renal cell carcinoma', 'Disease', (13, 44))	('BAP1', 'Gene', '8314', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (59, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('shorter', 'NegReg', (105, 112))	('BAP1', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
104140	24128712	Furthermore, recent reports have described germline BAP1 mutations in families predisposed to MPM and UM as well as atypical melanocytic tumors and renal cell carcinoma.	('renal cell carcinoma', 'Disease', (148, 168))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('BAP1', 'Gene', '8314', (52, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (148, 168))	('melanocytic tumors', 'Disease', (125, 143))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('MPM', 'Disease', (94, 97))
104141	24128712	These findings clearly suggest the existence of a new hereditary cancer predisposition syndrome but the phenotype and penetrance of germline BAP1 mutations remains unclear as does the role of gene-environment interactions in the development of these tumors.	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (146, 155))	('hereditary cancer', 'Disease', 'MESH:D009369', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BAP1', 'Gene', (141, 145))	('men', 'Species', '9606', (236, 239))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('men', 'Species', '9606', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('hereditary cancer', 'Disease', (54, 71))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))
104142	24128712	While BAP1 mutation is considered a crucial event in the progression of UM, the clinical impact of BAP1 mutation in MPM remains unknown.	('BAP1', 'Gene', (99, 103))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('BAP1', 'Gene', (6, 10))	('mutation', 'Var', (104, 112))	('BAP1', 'Gene', '8314', (99, 103))	('BAP1', 'Gene', '8314', (6, 10))
104143	24128712	Therefore, the purpose of this study was to characterize the clinical features of MPM patients whose tumors harbor BAP1 mutations.	('BAP1', 'Gene', '8314', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MPM', 'Disease', (82, 85))	('BAP1', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('patients', 'Species', '9606', (86, 94))
104144	24128712	Additionally, we examined the relationship between BAP1 mutation and survival.	('mutation', 'Var', (56, 64))	('BAP1', 'Gene', '8314', (51, 55))	('examined', 'Reg', (17, 25))	('BAP1', 'Gene', (51, 55))
104145	24128712	With the approval of the Memorial Sloan-Kettering Cancer Center Institutional Review Board, the clinical records of 121 patients whose MPM tumors had been tested for BAP1 mutation by conventional Sanger sequencing were reviewed.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (171, 179))	('BAP1', 'Gene', '8314', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MPM tumors', 'Disease', (135, 145))	('patients', 'Species', '9606', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('BAP1', 'Gene', (166, 170))	('MPM tumors', 'Disease', 'MESH:D009369', (135, 145))	('tested', 'Reg', (155, 161))
104148	24128712	The relationship between BAP1 mutation status and age, sex, histology, stage, smoking status, asbestos exposure, and family or personal history of malignancy was assessed using Fisher's exact tests.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('BAP1', 'Gene', (25, 29))	('malignancy', 'Disease', (147, 157))	('mutation', 'Var', (30, 38))	('asbestos', 'Chemical', 'MESH:D001194', (94, 102))	('BAP1', 'Gene', '8314', (25, 29))
104152	24128712	The BAP1 mutant and BAP1 wild-type groups were compared with respect to OS using the log-rank test.	('BAP1', 'Gene', (20, 24))	('BAP1', 'Gene', (4, 8))	('mutant', 'Var', (9, 15))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', '8314', (4, 8))
104153	24128712	Twenty-four of 121 MPM tumors harbored a somatic BAP1 mutation, giving a frequency of 20% (95% CI: 13-27%).	('MPM tumors', 'Disease', (19, 29))	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', (49, 53))	('harbored', 'Reg', (30, 38))	('MPM tumors', 'Disease', 'MESH:D009369', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('BAP1', 'Gene', '8314', (49, 53))
104162	24128712	As shown in Table 2, there was no significant difference in age, sex, asbestos exposure, surgery, chemotherapy, radiation, family history of mesothelioma, family history of cancer, and personal history of cancer among patients with BAP1 mutant and BAP1 wild-type MPM.	('BAP1', 'Gene', (232, 236))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('mutant', 'Var', (237, 243))	('BAP1', 'Gene', '8314', (248, 252))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (173, 179))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (205, 211))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('BAP1', 'Gene', (248, 252))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mesothelioma', 'Disease', (141, 153))	('BAP1', 'Gene', '8314', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
104163	24128712	However, a smoking history, either former or current, was more common among those with BAP1 mutant tumors, 75% versus 42% (p=0.006).	('BAP1', 'Gene', '8314', (87, 91))	('common', 'Reg', (63, 69))	('BAP1', 'Gene', (87, 91))	('mutant', 'Var', (92, 98))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
104164	24128712	Based on this association, we reviewed the spectrum of nucleotide substitutions in BAP1-mutated cases for evidence of a causal link to smoking.	('nucleotide substitutions', 'Var', (55, 79))	('BAP1', 'Gene', (83, 87))	('BAP1', 'Gene', '8314', (83, 87))
104165	24128712	Fourteen of the 24 mutations identified in BAP1 were point mutations.	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (43, 47))	('point mutations', 'Var', (53, 68))	('mutations', 'Var', (19, 28))
104167	24128712	There was no significant difference (p=0.43) in the stage at presentation for BAP1 mutant versus wild-type disease (Figure 1).	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', (78, 82))	('mutant', 'Var', (83, 89))
104168	24128712	Similarly, there was no difference (p=0.28) in the distribution of histologies among BAP1 mutant versus wild-type disease (Figure 2).	('BAP1', 'Gene', (85, 89))	('mutant', 'Var', (90, 96))	('BAP1', 'Gene', '8314', (85, 89))
104169	24128712	No difference in overall survival was associated with BAP1 mutation status (Figure 3).	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (54, 58))	('mutation status', 'Var', (59, 74))
104170	24128712	Those with BAP1 mutant tumors had a median overall survival of 14.3 months (95% CI: 12.4-19.4) while those with BAP1 wild-type tumors had a median overall survival of 14.8 months (95% CI: 10.6-37.3), p=0.81.	('BAP1', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (127, 133))	('BAP1', 'Gene', '8314', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BAP1', 'Gene', (11, 15))	('mutant', 'Var', (16, 22))	('BAP1', 'Gene', '8314', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
104171	24128712	Twenty percent of MPM tumors harbor mutations in BAP1.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('MPM tumors', 'Disease', (18, 28))	('MPM tumors', 'Disease', 'MESH:D009369', (18, 28))	('BAP1', 'Gene', '8314', (49, 53))
104172	24128712	We find that a smoking history is significantly more common in MPM patients whose tumors harbor a BAP1 mutation.	('BAP1', 'Gene', (98, 102))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('common', 'Reg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', '8314', (98, 102))	('MPM', 'Disease', (63, 66))	('mutation', 'Var', (103, 111))
104173	24128712	Perhaps, BAP1 mutation is a sequela of toxic exposure to smoking but the wide variety of mutations is not typical of tobacco smoke mutagenesis (only 2 of 24 mutations were G to T transversions consistent with classic smoking associated changes).	('BAP1', 'Gene', '8314', (9, 13))	('mutations', 'Var', (157, 166))	('tobacco', 'Species', '4097', (117, 124))	('BAP1', 'Gene', (9, 13))	('mutagenesis', 'biological_process', 'GO:0006280', ('131', '142'))	('G to T transversions', 'Var', (172, 192))
104175	24128712	Other clinical characteristics were similar among those with mutant and wild-type BAP1 MPM.	('BAP1', 'Gene', (82, 86))	('mutant', 'Var', (61, 67))	('BAP1', 'Gene', '8314', (82, 86))
104176	24128712	While another group reported that BAP1 mutated cases were more likely to be partly or entirely epithelioid, this difference was not statistically significant in our larger cohort.	('mutated', 'Var', (39, 46))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', (34, 38))
104177	24128712	Similarly, while the initial report of BAP1 mutations in MPM found an association between older age and BAP1 mutation, this is not confirmed in this larger series.	('BAP1', 'Gene', '8314', (104, 108))	('mutation', 'Var', (109, 117))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (44, 53))	('MPM', 'Gene', (57, 60))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
104179	24128712	Finally, as these specimens were obtained over an 18 year period, changes in therapy could have obscured differences in survival by BAP1 mutation status.	('mutation status', 'Var', (137, 152))	('BAP1', 'Gene', '8314', (132, 136))	('men', 'Species', '9606', (23, 26))	('BAP1', 'Gene', (132, 136))
104180	24128712	Since the initial reports of germline BAP1 mutations, numerous other neoplasms including meningiomas, renal cell carcinoma, lung cancer, breast cancer, ovarian cancer, pancreas cancer, and leukemia have been associated with BAP1 mutation.	('BAP1', 'Gene', (224, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreas cancer', 'Disease', 'MESH:D010190', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', '8314', (38, 42))	('pancreas cancer', 'Phenotype', 'HP:0002894', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('neoplasms', 'Disease', 'MESH:D009369', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('pancreas cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', (124, 135))	('meningiomas', 'Disease', 'MESH:D008577', (89, 100))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('meningiomas', 'Phenotype', 'HP:0002858', (89, 100))	('neoplasms', 'Disease', (69, 78))	('BAP1', 'Gene', (38, 42))	('leukemia', 'Disease', (189, 197))	('leukemia', 'Disease', 'MESH:D007938', (189, 197))	('meningiomas', 'Disease', (89, 100))	('BAP1', 'Gene', '8314', (224, 228))	('mutation', 'Var', (229, 237))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('ovarian cancer', 'Disease', (152, 166))	('breast cancer', 'Disease', (137, 150))	('renal cell carcinoma', 'Disease', (102, 122))	('associated', 'Reg', (208, 218))	('mutations', 'Var', (43, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
104181	24128712	While there is no apparent distinct phenotype for MPM with somatic BAP1 mutation, further study is needed to identify and characterize patients with germline BAP1 mutations.	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', (158, 162))	('BAP1', 'Gene', '8314', (67, 71))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (67, 71))
104182	24128712	To help describe the spectrum of disease associated with germline BAP1 mutation, we have initiated a prospective clinical protocol for patients with MPM, UM, and choroidal nevus (a premalignant eye tumor).	('premalignant eye tumor', 'Disease', 'MESH:D005134', (181, 203))	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', '8314', (66, 70))	('mutation', 'Var', (71, 79))	('premalignant eye tumor', 'Disease', (181, 203))	('BAP1', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('eye tumor', 'Phenotype', 'HP:0100012', (194, 203))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('choroidal nevus', 'Disease', (162, 177))	('nevus', 'Phenotype', 'HP:0003764', (172, 177))	('MPM', 'Disease', (149, 152))	('choroidal nevus', 'Phenotype', 'HP:0025314', (162, 177))
104183	24128712	First, patients will provide samples to participate in an anonymous estimate of the prevalence of germline BAP1 mutations.	('mutations', 'Var', (112, 121))	('BAP1', 'Gene', '8314', (107, 111))	('patients', 'Species', '9606', (7, 15))	('BAP1', 'Gene', (107, 111))
104184	24128712	Additionally, patients whose tumors harbor BAP1 mutation or meet pre-specified criteria will be offered identified germline BAP1 testing.	('BAP1', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BAP1', 'Gene', (124, 128))	('BAP1', 'Gene', '8314', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('mutation', 'Var', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('patients', 'Species', '9606', (14, 22))
104185	24128712	Those patients identified as carrying germline BAP1 mutations will be asked to invite both potentially affected and unaffected family members for testing through our Clinical Genetics Service.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (47, 51))	('patients', 'Species', '9606', (6, 14))	('BAP1', 'Gene', (47, 51))
104186	24128712	We will also continue to explore the interaction of BAP1 mutation with other somatic mutations, environmental exposures, and single nucleotide polymorphisms.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('men', 'Species', '9606', (103, 106))	('BAP1', 'Gene', '8314', (52, 56))
104188	30140191	Occupational Burden of Asbestos-Related Diseases in Korea, 1998-2013: Asbestosis, Mesothelioma, Lung Cancer, Laryngeal Cancer, and Ovarian Cancer Asbestos exposure causes asbestos-related diseases (ARDs) including asbestosis, malignant mesothelioma, lung cancer, laryngeal cancer, and ovarian cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('ovarian cancer', 'Disease', (285, 299))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (131, 145))	('Asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('ovarian cancer', 'Phenotype', 'HP:0100615', (285, 299))	('asbestosis', 'Disease', 'MESH:D001195', (214, 224))	('Laryngeal Cancer', 'Phenotype', 'HP:0012118', (109, 125))	('Laryngeal Cancer', 'Disease', (109, 125))	('asbestos', 'Chemical', 'MESH:D001194', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('Asbestos', 'Chemical', 'MESH:D001194', (146, 154))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (226, 248))	('Asbestosis, Mesothelioma, Lung Cancer', 'Disease', 'MESH:D001195', (70, 107))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (131, 145))	('lung cancer', 'Disease', (250, 261))	('laryngeal cancer', 'Disease', 'MESH:D007822', (263, 279))	('asbestosis', 'Disease', (214, 224))	('causes', 'Reg', (164, 170))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('laryngeal cancer', 'Disease', (263, 279))	('asbestos-related diseases', 'Disease', (171, 196))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('malignant mesothelioma', 'Disease', (226, 248))	('ovarian cancer', 'Disease', 'MESH:D010051', (285, 299))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (263, 279))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (226, 248))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('Ovarian Cancer', 'Disease', (131, 145))	('asbestos', 'Chemical', 'MESH:D001194', (214, 222))	('Asbestos', 'Chemical', 'MESH:D001194', (23, 31))	('Asbestos', 'Var', (146, 154))	('Laryngeal Cancer', 'Disease', 'MESH:D007822', (109, 125))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Lung Cancer', 'Phenotype', 'HP:0100526', (96, 107))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
104294	29462963	In healthy individuals, miRNAs are secreted by cells into body fluids with stable and constant concentrations; however, similar to tissue miRNAs, alterations in their expression levels have been associated with several cancers.	('associated', 'Reg', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('alterations', 'Var', (146, 157))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('expression levels', 'MPA', (167, 184))
104300	29462963	As shown in Figure 2, miRNAs are sorted into multivesicular bodies (MVBs) derived from early endosomes, which is a process that requires neutral sphingomyelinase 2 (nSMase2), endosomal sorting complex transport machinery (ESCRT) and sumoylated hnRNPA2B1 protein.	('hnRNPA2B1', 'Gene', (244, 253))	('hnRNPA2B1', 'Gene', '3181', (244, 253))	('transport', 'biological_process', 'GO:0006810', ('201', '210'))	('protein', 'Protein', (254, 261))	('neutral sphingomyelinase', 'molecular_function', 'GO:0061751', ('137', '161'))	('sumoylated', 'Var', (233, 243))	('neutral sphingomyelinase 2', 'Gene', '55512', (137, 163))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('neutral sphingomyelinase 2', 'Gene', (137, 163))	('nSMase2', 'Gene', (165, 172))	('nSMase2', 'Gene', '55512', (165, 172))
104314	29462963	They reported 12 over-expressed miRNAs (let-7b*, miR-1228*, miR-195*, miR-30b*, miR-32*, miR-345, miR-483-3p, miR-584, miR-595, miR-615-3p, and miR-885-3p) and nine sub-expressed (let-7e*, miR-144*, miR-203, miR-340*, miR-34a*, miR-423, miR-582, miR-7-1* and miR-9) in MPM tissue compared to the single control.	('miR-582', 'Gene', (237, 244))	('miR-423', 'Gene', (228, 235))	('miR-595', 'Gene', '693180', (119, 126))	('miR-144', 'Gene', (189, 196))	('miR-7-1', 'Gene', (246, 253))	('miR-345', 'Gene', '442910', (89, 96))	('miR-1228', 'Gene', (49, 57))	('miR-483', 'Gene', (98, 105))	('miR-195', 'Gene', (60, 67))	('miR-595', 'Gene', (119, 126))	('miR-483', 'Gene', '619552', (98, 105))	('miR-1228', 'Gene', '100302201', (49, 57))	('miR-340', 'Gene', '442908', (208, 215))	('miR-32', 'Gene', '407036', (80, 86))	('miR-34a', 'Gene', (218, 225))	('miR-340', 'Gene', (208, 215))	('over-expressed', 'PosReg', (17, 31))	('miR-423', 'Gene', '494335', (228, 235))	('miR-34a', 'Gene', '407040', (218, 225))	('let-7e', 'Gene', (180, 186))	('miR-584', 'Gene', '693169', (110, 117))	('miR-144', 'Gene', '406936', (189, 196))	('miR-345', 'Gene', (89, 96))	('miR-203', 'Gene', (199, 206))	('miR-32', 'Gene', (80, 86))	('miR-30b', 'Gene', '407030', (70, 77))	('let-7e', 'Gene', '406887', (180, 186))	('miR-30b', 'Gene', (70, 77))	('miR-582', 'Gene', '693167', (237, 244))	('miR-584', 'Gene', (110, 117))	('let-7b*', 'Var', (40, 47))	('miR-7-1', 'Gene', '407043', (246, 253))	('miR-203', 'Gene', '406986', (199, 206))	('miR-195', 'Gene', '406971', (60, 67))
104316	29462963	Bioinformatic analysis was used to identify three suppressor genes (CDKN2A, NF2 and RB1) as putative targets of over-expressed miR-30b*, miR-32*, miR-483-3p, miR-584, and miR-885-3p, whereas oncogenes hepatocyte growth factor (HGF), Platelet Derived Growth Factor Subunit (PDGFA), Epidermal Growth Factor (EGF) and Jun proto-oncogene (JUN) were identified as putative targets of sub-expressed miR-9, miR-7-1* and miR-203.	('Platelet Derived Growth Factor', 'molecular_function', 'GO:0005161', ('233', '263'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('201', '225'))	('miR-483', 'Gene', (146, 153))	('Epidermal Growth Factor', 'Gene', '1950', (281, 304))	('CDKN2A', 'Gene', (68, 74))	('HGF', 'Gene', (227, 230))	('EGF', 'molecular_function', 'GO:0005154', ('306', '309'))	('miR-483', 'Gene', '619552', (146, 153))	('hepatocyte growth factor', 'Gene', '3082', (201, 225))	('miR-32', 'Gene', '407036', (137, 143))	('PDGFA', 'Gene', (273, 278))	('RB1', 'Gene', (84, 87))	('hepatocyte growth factor', 'Gene', (201, 225))	('CDKN2A', 'Gene', '1029', (68, 74))	('over-expressed', 'PosReg', (112, 126))	('Platelet Derived Growth Factor Subunit', 'Gene', (233, 271))	('miR-203', 'Gene', (413, 420))	('miR-584', 'Gene', '693169', (158, 165))	('miR-32', 'Gene', (137, 143))	('miR-584', 'Gene', (158, 165))	('Platelet Derived Growth Factor Subunit', 'Gene', '5154', (233, 271))	('miR-7-1', 'Gene', '407043', (400, 407))	('miR-30b', 'Gene', '407030', (127, 134))	('RB1', 'Gene', '5925', (84, 87))	('miR-30b', 'Gene', (127, 134))	('miR-9', 'Var', (393, 398))	('NF2', 'Gene', '4771', (76, 79))	('miR-203', 'Gene', '406986', (413, 420))	('Epidermal Growth Factor', 'Gene', (281, 304))	('NF2', 'Gene', (76, 79))	('PDGFA', 'Gene', '5154', (273, 278))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('281', '304'))	('miR-7-1', 'Gene', (400, 407))	('HGF', 'Gene', '3082', (227, 230))
104337	29462963	Because this study aimed to identify biologically relevant miRNAs in the development of MPM instead of miRNAs with diagnostic value, under-expressed miR-1 was transfected into two MPM cell lines (H513, epithelioid type and H2052, sarcomatoid type), which caused cycle arrest and apoptosis.	('caused', 'Reg', (255, 261))	('H2052', 'CellLine', 'CVCL:1518', (223, 228))	('apoptosis', 'biological_process', 'GO:0097194', ('279', '288'))	('miR-1', 'Gene', (149, 154))	('sarcomatoid type', 'Disease', 'MESH:C538614', (230, 246))	('under-expressed', 'Var', (133, 148))	('cycle arrest', 'CPA', (262, 274))	('apoptosis', 'biological_process', 'GO:0006915', ('279', '288'))	('apoptosis', 'CPA', (279, 288))	('sarcomatoid type', 'Disease', (230, 246))	('miR-1', 'Gene', '79187', (149, 154))
104354	29462963	The authors reported 19 miRNAs that were differentially expressed in MPM samples compared to control samples, 11 that were sub-expressed (miR-517b-3p, miR-627, miR-766-3p, miR-101-3p, miR-501-3p, miR-212-3p, miR-596, miR-145-5p, miR-671-3p, miR-181a-5p and miR-18a-3p), and eight that were over-expressed (miR-30e-3p, miR-34a-3p, miR-622, let-7a-5p, miR-196b-5p, miR-135b-5p, miR-18a-5p and miR-302-3p).	('miR-1', 'Gene', (363, 368))	('miR-1', 'Gene', '79187', (217, 222))	('miR-766-3p', 'Var', (160, 170))	('miR-1', 'Gene', '79187', (257, 262))	('miR-1', 'Gene', '79187', (241, 246))	('miR-596', 'Gene', '693181', (208, 215))	('miR-302-3p', 'Var', (391, 401))	('miR-21', 'Gene', (196, 202))	('miR-30e', 'Gene', (306, 313))	('miR-1', 'Gene', '79187', (350, 355))	('let-7a-5p', 'Var', (339, 348))	('miR-622', 'Gene', (330, 337))	('miR-627', 'Gene', '693212', (151, 158))	('miR-596', 'Gene', (208, 215))	('miR-622', 'Gene', '693207', (330, 337))	('miR-1', 'Gene', (172, 177))	('miR-1', 'Gene', (376, 381))	('miR-196b', 'Gene', '442920', (350, 358))	('miR-1', 'Gene', '79187', (363, 368))	('miR-30e', 'Gene', '407034', (306, 313))	('miR-517b-3p', 'Var', (138, 149))	('miR-34a', 'Gene', (318, 325))	('miR-1', 'Gene', (257, 262))	('miR-101', 'Chemical', '-', (172, 179))	('miR-1', 'Gene', (241, 246))	('miR-1', 'Gene', (217, 222))	('miR-34a', 'Gene', '407040', (318, 325))	('miR-501-3p', 'Var', (184, 194))	('miR-627', 'Gene', (151, 158))	('miR-21', 'Gene', '406991', (196, 202))	('miR-1', 'Gene', '79187', (172, 177))	('miR-1', 'Gene', '79187', (376, 381))	('miR-1', 'Gene', (350, 355))	('miR-196b', 'Gene', (350, 358))
104357	29462963	The authors chose four sub-expressed (miR-126, miR-143, miR-145 and miR-653) and two over-expressed (miR-193a-3p, miR-193b) miRNAs found in either the DB or MPM samples compared to NNP samples for RT-qPCR validation using 40 MPM, 12 DB and 14 NNP samples.	('miR-193a', 'Gene', (101, 109))	('miR-193b', 'Gene', '574455', (114, 122))	('miR-193b', 'Gene', (114, 122))	('miR-143', 'Gene', '406935', (47, 54))	('miR-193a', 'Gene', '406968', (101, 109))	('miR-126', 'Gene', '406913', (38, 45))	('miR-653', 'Gene', (68, 75))	('miR-143', 'Gene', (47, 54))	('miR-126', 'Gene', (38, 45))	('miR-653', 'Gene', '724023', (68, 75))	('miR-145', 'Var', (56, 63))
104358	29462963	The results indicated statistically significant sub-expression of miR-126, miR-652, miR-145 and miR-143 in both DB and MMP compared to NNP.	('MMP', 'molecular_function', 'GO:0004235', ('119', '122'))	('miR-652', 'Gene', (75, 82))	('miR-652', 'Gene', '724022', (75, 82))	('miR-126', 'Gene', '406913', (66, 73))	('miR-145', 'Var', (84, 91))	('miR-126', 'Gene', (66, 73))	('sub-expression', 'MPA', (48, 62))	('miR-143', 'Gene', '406935', (96, 103))	('miR-143', 'Gene', (96, 103))	('MMP', 'Disease', (119, 122))
104359	29462963	It was reported that miR-145 and miR-652 had a sensitivity or specificity >80%, whereas miR-143 and miR-126 had a sensitivity or specificity <80% (Receiver operating characteristic curve or ROC curve).	('miR-143', 'Gene', '406935', (88, 95))	('miR-652', 'Gene', (33, 40))	('miR-126', 'Gene', '406913', (100, 107))	('miR-143', 'Gene', (88, 95))	('miR-145', 'Var', (21, 28))	('miR-126', 'Gene', (100, 107))	('miR-652', 'Gene', '724022', (33, 40))
104365	29462963	The authors performed PCRArray (384 miRNAs, Applied Biosystems) on 18 MPM (11 with chemotherapy treatment) and six BAPE samples and reported 11 over-expressed miRNAs in MPM samples compared to BAPE (miR-484, miR-320, let-7a, miR-744, miR-20a, miR-193b, let-7d, miR-125a-5p, miR-92a, miR-155, and miR-152).	('miR-20a', 'Gene', (234, 241))	('miR-20a', 'Gene', '406982', (234, 241))	('miR-744', 'Gene', '100126313', (225, 232))	('miR-32', 'Gene', '407036', (208, 214))	('miR-155', 'Gene', (283, 290))	('let-7d', 'Gene', '406886', (253, 259))	('miR-155', 'Gene', '406947', (283, 290))	('miR-193b', 'Gene', (243, 251))	('miR-92a', 'Var', (274, 281))	('miR-32', 'Gene', (208, 214))	('over-expressed', 'PosReg', (144, 158))	('miR-744', 'Gene', (225, 232))	('miR-125a', 'Gene', '406910', (261, 269))	('miR-152', 'Gene', (296, 303))	('let-7d', 'Gene', (253, 259))	('miR-125a', 'Gene', (261, 269))	('miR-484', 'Gene', '619553', (199, 206))	('miR-152', 'Gene', '406943', (296, 303))	('miR-193b', 'Gene', '574455', (243, 251))	('miR-484', 'Gene', (199, 206))
104366	29462963	The results showed that four miRNAs had AUC values >=0.90 (miR-484, miR-320, let-7a and miR-125a-5p).	('miR-484', 'Gene', '619553', (59, 66))	('miR-32', 'Gene', '407036', (68, 74))	('miR-125a', 'Gene', (88, 96))	('AUC', 'MPA', (40, 43))	('miR-32', 'Gene', (68, 74))	('let-7a', 'Var', (77, 83))	('miR-125a', 'Gene', '406910', (88, 96))	('miR-484', 'Gene', (59, 66))
104367	29462963	Meanwhile, miR-484 had a sensitivity and specificity of 100%, miR-320 had a sensitivity of 78% and a specificity of 100%, let-7a had a sensitivity of 94% and a specificity of 83% and miR-125a-5p had a sensitivity of 89% and a specificity of 100%.	('miR-484', 'Gene', '619553', (11, 18))	('miR-32', 'Gene', '407036', (62, 68))	('let-7a', 'Var', (122, 128))	('miR-125a', 'Gene', '406910', (183, 191))	('miR-32', 'Gene', (62, 68))	('miR-484', 'Gene', (11, 18))	('miR-125a', 'Gene', (183, 191))
104396	29462963	The analysis of 43 male MPM patients and 52 male controls formerly exposed to asbestos revealed that the combination of mesothelin and miR-103a-3p showed a sensitivity of 95% and a specificity of 81% for MPM diagnosis.	('miR-103', 'Chemical', '-', (135, 142))	('miR-103a-3p', 'Var', (135, 146))	('MPM', 'Disease', (204, 207))	('mesothelin', 'Gene', (120, 130))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('patients', 'Species', '9606', (28, 36))	('mesothelin', 'Gene', '10232', (120, 130))
104397	29462963	For individual determinations, mesothelin showed a sensitivity of 74% and specificity of 85%, whereas miR-103a-3p showed a sensitivity of 89% and a specificity of 63%.	('mesothelin', 'Gene', '10232', (31, 41))	('miR-103a-3p', 'Var', (102, 113))	('miR-103', 'Chemical', '-', (102, 109))	('mesothelin', 'Gene', (31, 41))
104415	29462963	Unlike previous results in plasma and serum, the data indicated an over-expression of miR-625-3p and an under-expression of miR-29c*, miR-16, miR-196b, miR-26a-2-3p and miR-1914-3p in MPM tumor samples compared to controls.	('miR-16', 'Var', (134, 140))	('tumor', 'Disease', (188, 193))	('miR-29c', 'Gene', (124, 131))	('miR-1914', 'Gene', (169, 177))	('miR-196b', 'Gene', (142, 150))	('MPM', 'Disease', (184, 187))	('miR-196b', 'Gene', '442920', (142, 150))	('miR-26a-2-3p', 'Var', (152, 164))	('miR-625', 'Gene', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('miR-625', 'Gene', '693210', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('over-expression', 'PosReg', (67, 82))	('miR-29c', 'Gene', '407026', (124, 131))	('under-expression', 'NegReg', (104, 120))	('miR-1914', 'Gene', '100302137', (169, 177))
104421	29462963	Among these miRNAs, four were common to both neoplasms (miR-4791, miR-185-5p, miR-96-5p and miR-1271-5p), whereas miR-1292, miR-409-5 and miR-92b -5p were over-expressed exclusively in MPM.	('over-expressed', 'PosReg', (155, 169))	('miR-1271', 'Gene', '100302203', (92, 100))	('miR-1', 'Gene', '79187', (66, 71))	('miR-409-5', 'Var', (124, 133))	('neoplasms', 'Phenotype', 'HP:0002664', (45, 54))	('miR-1', 'Gene', '79187', (114, 119))	('miR-1', 'Gene', (92, 97))	('miR-4791', 'Gene', (56, 64))	('miR-4791', 'Gene', '100616291', (56, 64))	('miR-92b', 'Gene', '693235', (138, 145))	('neoplasms', 'Disease', 'MESH:D009369', (45, 54))	('miR-96-5p', 'Var', (78, 87))	('miR-1292', 'Gene', (114, 122))	('miR-1271', 'Gene', (92, 100))	('miR-1', 'Gene', (66, 71))	('miR-1', 'Gene', '79187', (92, 97))	('miR-1', 'Gene', (114, 119))	('neoplasms', 'Disease', (45, 54))	('miR-92b', 'Gene', (138, 145))	('miR-1292', 'Gene', '100302138', (114, 122))
104425	29462963	The results indicated over-expression of miR-101, miR-25, miR-26b, miR-335 and miR-433 and sub-expression of miR-191 and miR-223 in MPM.	('miR-191', 'Gene', (109, 116))	('miR-101', 'Chemical', '-', (41, 48))	('miR-101', 'Var', (41, 48))	('miR-25', 'Gene', '407014', (50, 56))	('miR-223', 'Var', (121, 128))	('miR-25', 'Gene', (50, 56))	('miR-433', 'Gene', '574034', (79, 86))	('miR-335', 'Gene', (67, 74))	('miR-433', 'Gene', (79, 86))	('over-expression', 'PosReg', (22, 37))	('miR-26b', 'Gene', '407017', (58, 65))	('miR-26b', 'Gene', (58, 65))	('miR-335', 'Gene', '442904', (67, 74))	('miR-191', 'Gene', '406966', (109, 116))
104426	29462963	Additionally, miR-29a and miR-516 were detected exclusively in MPM patients.	('patients', 'Species', '9606', (67, 75))	('miR-29a', 'Gene', '407021', (14, 21))	('miR-29a', 'Gene', (14, 21))	('MPM', 'Disease', (63, 66))	('miR-516', 'Var', (26, 33))
104428	29462963	Patients were subdivided into two groups: group A, which was composed of patients with over-expression of >=3/9 miRNAs and miR-516 undetectable or unchanged, and group B, which contained patients with at least 3/9 miRNAs sub-expressed or without change and/or miR-29a sub-expressed.	('patients', 'Species', '9606', (187, 195))	('miR-516', 'Var', (123, 130))	('Patients', 'Species', '9606', (0, 8))	('miR-29a', 'Gene', '407021', (260, 267))	('patients', 'Species', '9606', (73, 81))	('miR-29a', 'Gene', (260, 267))
104441	29462963	The data indicated that the risk of MPM significantly increased at high SMRP levels with at least one or both altered epigenetic biomarkers (low miR-16 or high Met-TM), whereas the disease risk was maximum when all three biomarkers were altered.	('high', 'Var', (67, 71))	('MPM', 'Disease', (36, 39))	('increased', 'PosReg', (54, 63))	('SMRP', 'Gene', '10232', (72, 76))	('SMRP', 'Gene', (72, 76))	('low', 'Var', (141, 144))	('high', 'Var', (155, 159))	('epigenetic', 'MPA', (118, 128))
104443	29462963	The combination of SMRPs, miR-126 and Met-TM improves the differential diagnosis of MPM up to an AUC of 0.857 (95% CI, 0.767-0.927) compared to SMRP alone at 0.818 (95% CI, 0.723-0.914).	('SMRP', 'Gene', '10232', (144, 148))	('differential', 'MPA', (58, 70))	('miR-126', 'Gene', (26, 33))	('SMRP', 'Gene', (144, 148))	('MPM', 'Disease', (84, 87))	('Met-TM', 'Var', (38, 44))	('SMRP', 'Gene', '10232', (19, 23))	('improves', 'PosReg', (45, 53))	('SMRP', 'Gene', (19, 23))	('miR-126', 'Gene', '406913', (26, 33))
104451	29462963	The authors found a signature of the five best discriminating miRNAs of miR-103a-3p, miR-98, miR-148b, miR-744 and miR-30e-3p with an AUC of 0.864, 0.864, 0.852, 0.845 and 0.827, respectively.	('miR-30e', 'Gene', '407034', (115, 122))	('miR-98', 'Gene', '407054', (85, 91))	('miR-148b', 'Gene', '442892', (93, 101))	('miR-744', 'Gene', '100126313', (103, 110))	('miR-30e', 'Gene', (115, 122))	('miR-148b', 'Gene', (93, 101))	('miR-103', 'Chemical', '-', (72, 79))	('miR-98', 'Gene', (85, 91))	('miR-103a-3p', 'Var', (72, 83))	('miR-744', 'Gene', (103, 110))
104452	29462963	They further simplified the signature with miR-30e-3p and miR-103a-3p, which generated an AUC of 0.942 with a sensitivity of 95.5% and specificity of 80%.	('miR-103', 'Chemical', '-', (58, 65))	('miR-30e', 'Gene', '407034', (43, 50))	('miR-30e', 'Gene', (43, 50))	('miR-103a-3p', 'Var', (58, 69))
104454	29462963	In addition, the authors tested other miRNAs reported in the literature as potential biomarkers of MPM (miR-126, miR-625-3p, miR-25, miR-29 and miR-433) and did not find significant differences between the study groups.	('miR-433', 'Gene', (144, 151))	('miR-433', 'Gene', '574034', (144, 151))	('MPM', 'Disease', (99, 102))	('miR-625', 'Gene', '693210', (113, 120))	('miR-29', 'Var', (133, 139))	('miR-126', 'Gene', '406913', (104, 111))	('miR-25', 'Gene', '407014', (125, 131))	('miR-126', 'Gene', (104, 111))	('miR-25', 'Gene', (125, 131))	('miR-625', 'Gene', (113, 120))
104483	29462963	This method identified nine miRNAs as the most significant in tissue (miR-145-5p, miR-126-3p, miR-16-5p, miR-192-5p, miR-193a-3p, miR-200b-3p, miR-203-3p, miR-143-3p and miR-652-3p) and three circulating miRNAs (miR126-3p, miR-103a-3p and miR-625-3p).	('miR-16-5p', 'Var', (94, 103))	('miR-192', 'Gene', (105, 112))	('miR-625', 'Gene', (239, 246))	('miR-200b', 'Gene', '406984', (130, 138))	('miR-103', 'Chemical', '-', (223, 230))	('miR-103a-3p', 'Var', (223, 234))	('miR-193a', 'Gene', (117, 125))	('miR-625', 'Gene', '693210', (239, 246))	('miR-193a', 'Gene', '406968', (117, 125))	('miR-126-3p', 'Gene', (82, 92))	('miR-203', 'Gene', (143, 150))	('miR-192', 'Gene', '406967', (105, 112))	('miR-126-3p', 'Gene', '100302148', (82, 92))	('miR-652', 'Gene', (170, 177))	('miR-200b', 'Gene', (130, 138))	('miR-143', 'Gene', '406935', (155, 162))	('miR-203', 'Gene', '406986', (143, 150))	('miR-652', 'Gene', '724022', (170, 177))	('miR-145-5p', 'Var', (70, 80))	('miR-143', 'Gene', (155, 162))	('miR126-3p', 'Var', (212, 221))
104498	29462963	In addition, increasing evidence suggests that aberrant levels of miRNAs contribute to oncogenesis, progression and metastasis of several cancers, such as tumor suppressor or oncomiR.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('contribute', 'Reg', (73, 83))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('oncomiR', 'Disease', (175, 182))	('aberrant levels', 'Var', (47, 62))	('tumor', 'Disease', (155, 160))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('oncogenesis', 'biological_process', 'GO:0007048', ('87', '98'))	('progression', 'CPA', (100, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('miRNAs', 'Protein', (66, 72))	('metastasis', 'CPA', (116, 126))	('oncogenesis', 'CPA', (87, 98))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
104499	29462963	As previously mentioned, the potential association of altered miRNAs with MPM carcinogenic mechanisms increases the likelihood of having a diagnostic value for this disease.	('miRNAs', 'MPA', (62, 68))	('MPM carcinogenic', 'Disease', (74, 90))	('MPM carcinogenic', 'Disease', 'MESH:D063646', (74, 90))	('altered', 'Var', (54, 61))	('association', 'Interaction', (39, 50))
104501	29462963	Table 3 summarizes deregulated miRNAs associated with carcinogenesis mechanisms in MPM.	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('miRNAs', 'MPA', (31, 37))	('deregulated', 'Var', (19, 30))	('carcinogenesis', 'Disease', (54, 68))	('MPM', 'Disease', (83, 86))
104521	26867193	Inactivation of pro-apoptotic proteins or up-regulation of anti-apoptotic proteins can lead to unchecked growth of cells and eventually leads to cancer.	('cancer', 'Disease', (145, 151))	('unchecked', 'MPA', (95, 104))	('leads to', 'Reg', (136, 144))	('anti-apoptotic', 'Protein', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('lead to', 'Reg', (87, 94))	('up-regulation', 'PosReg', (42, 55))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Inactivation', 'Var', (0, 12))
104525	26867193	Hitherto, a growing number of publications show that some upregulated miRNAs, such as miRNA-21, miRNA-221, -222, and miRNA-272, -273 can be recognized as oncogenes while others that are down-regulated can be defined as tumor suppressor genes, such as miR-15a-miR-16-1 cluster, and miR-29.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('miRNA-272', 'Var', (117, 126))	('tumor suppressor', 'Gene', '7248', (219, 235))	('miRNA-21', 'Gene', (86, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('miRNA-221', 'Gene', '407006', (96, 105))	('upregulated', 'PosReg', (58, 69))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('miR-16', 'Gene', (259, 265))	('miR-16', 'Gene', '51573', (259, 265))	('tumor suppressor', 'Gene', (219, 235))	('miRNA-221', 'Gene', (96, 105))	('miRNA-21', 'Gene', '406991', (86, 94))
104526	26867193	Dysregulation of miRNAs was reported to associate with various types of cancer.	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associate', 'Reg', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
104563	26867193	Elucidation of the functional interaction between altered p53 and MAPK signaling transduction pathways is critical for understanding how cell proliferation and survival are deregulated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('transduction', 'biological_process', 'GO:0009293', ('81', '93'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('66', '80'))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('altered', 'Var', (50, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('cancer', 'Disease', (188, 194))	('p53', 'Gene', (58, 61))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))	('p53', 'Gene', '7157', (58, 61))
104568	26867193	Notably, miRNAs can act as either tumor suppressors or oncogenes; therefore, miRNAs could repress the expression of important cancer-related genes and have been already utilized for the diagnosis and treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumor suppressor', 'Gene', '7248', (34, 50))	('expression', 'MPA', (102, 112))	('cancer', 'Disease', (126, 132))	('repress', 'NegReg', (90, 97))	('miRNAs', 'Var', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('tumor suppressor', 'Gene', (34, 50))	('cancer', 'Disease', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
104571	26867193	There are five miRNAs, including (Homo sapiens) hsa-miR-124, hsa-miR-182, hsa-miR-504, hsa -miR-506 and hsa-miR-96, and these five miRNAs may negatively regulate caspase-9-mediated signaling pathways.	('hsa -miR-506', 'Gene', '574511', (87, 99))	('Homo sapiens', 'Species', '9606', (34, 46))	('hsa-miR-124', 'Var', (48, 59))	('hsa-miR-96', 'Gene', (104, 114))	('negatively', 'NegReg', (142, 152))	('hsa -miR-506', 'Gene', (87, 99))	('hsa-miR-504', 'Gene', (74, 85))	('caspase-9', 'Gene', '842', (162, 171))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('miR-182', 'Gene', (65, 72))	('hsa-miR-96', 'Gene', '407053', (104, 114))	('miR-182', 'Gene', '406958', (65, 72))	('hsa-miR-504', 'Gene', '574507', (74, 85))	('caspase-9', 'Gene', (162, 171))
104573	26867193	It is well known that cancer is a complex genetic disease resulting from mutations of tumor suppressor genes or oncogenes that would cause the alteration of signaling pathways.	('tumor suppressor', 'Gene', '7248', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('genetic disease', 'Disease', 'MESH:D030342', (42, 57))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('genetic disease', 'Disease', (42, 57))	('signaling pathways', 'Pathway', (157, 175))	('cancer', 'Disease', (22, 28))	('oncogenes', 'Gene', (112, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('86', '102'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('86', '102'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('alteration', 'Reg', (143, 153))	('tumor suppressor', 'Gene', (86, 102))	('mutations', 'Var', (73, 82))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('cause', 'Reg', (133, 138))
104624	26867567	The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival.	('overall', 'MPA', (217, 224))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (42, 61))	('expression', 'Var', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('HXR9', 'Gene', (150, 154))	('mesothelioma tumors', 'Disease', (42, 61))	('HOXB4', 'Gene', (183, 188))	('associated with', 'Reg', (201, 216))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (42, 61))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (34, 54))
104633	26867567	The dys-regulation of HOX genes has been demonstrated in a range of cancers, and in some it has been shown to be a potential therapeutic target through the use of a peptide, HXR9.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('regulation', 'biological_process', 'GO:0065007', ('8', '18'))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('HOX genes', 'Gene', (22, 31))	('cancers', 'Disease', (68, 75))	('dys-regulation', 'Var', (4, 18))	('cancers', 'Disease', 'MESH:D009369', (68, 75))
104638	26867567	Furthermore, antagonism of the HOX / PBX interaction in these cell lines triggers apoptosis, with malignant cells generally being considerably more sensitive to HXR9 than cells derived from non-malignant mesothelium cells.	('malignant mesothelium', 'Phenotype', 'HP:0100001', (194, 215))	('interaction', 'Interaction', (41, 52))	('more', 'PosReg', (143, 147))	('apoptosis', 'CPA', (82, 91))	('triggers', 'Reg', (73, 81))	('antagonism', 'Var', (13, 23))	('PBX', 'Chemical', '-', (37, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('sensitive', 'MPA', (148, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))
104672	26867567	Analysis of HOX genes that are known to have oncogenic or tumor suppressive functions (Table 1) likewise reveals considerable variation, although Met-5A showed higher expression of the potential tumor suppressor genes HOXA4 and HOXA5 compared to the malignant cell lines (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (195, 200))	('higher', 'PosReg', (160, 166))	('Met-5A', 'Var', (146, 152))	('HOXA4', 'Gene', '3201', (218, 223))	('tumor suppressor', 'biological_process', 'GO:0051726', ('195', '211'))	('HOXA5', 'Gene', '3202', (228, 233))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('195', '211'))	('HOXA4', 'Gene', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('HOXA5', 'Gene', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('expression', 'MPA', (167, 177))
104676	26867567	1c), and likewise a Kaplan-Meier analysis of overall survival (OS) showed that high HOXB4 tumor expression was associated with a significantly shorter OS (p = 0.041; Fig.	('shorter', 'NegReg', (143, 150))	('OS', 'Chemical', '-', (151, 153))	('OS', 'Chemical', '-', (63, 65))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('HOXB4', 'Gene', (84, 89))	('high', 'Var', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
104678	26867567	2a), and the MTS assay for cell viability revealed that HXR9 is cytotoxic in all five cell lines (Fig.	('HXR9', 'Var', (56, 60))	('cytotoxic', 'CPA', (64, 73))	('S', 'Chemical', 'MESH:D013455', (15, 16))
104694	26867567	HXR9 significantly retarded tumor growth compared to PBS alone (Fig.	('HXR9', 'Var', (0, 4))	('retarded tumor', 'Disease', 'MESH:D009369', (19, 33))	('PBS', 'Disease', 'MESH:D011535', (53, 56))	('PBS', 'Disease', (53, 56))	('retarded tumor', 'Disease', (19, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
104696	26867567	The dys-regulation of HOX genes in cancer is now well established, and in many cases a putative function for individual HOX genes has been established.	('regulation', 'biological_process', 'GO:0065007', ('8', '18'))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('HOX genes', 'Gene', (22, 31))	('dys-regulation', 'Var', (4, 18))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
104700	26867567	One of the most striking differences is the expression of HOXC12 and HOXD12 by Met-5a but not by any of the mesothelioma cell lines.	('expression', 'MPA', (44, 54))	('HOXD12', 'Gene', (69, 75))	('mesothelioma', 'Disease', (108, 120))	('HOXD12', 'Gene', '3238', (69, 75))	('HOXC12', 'Gene', (58, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('Met-5a', 'Var', (79, 85))	('HOXC12', 'Gene', '3228', (58, 64))
104701	26867567	HOXC12 is repressed in follicular lymphoma through hypermethylation of its promoter, and has also been implicated in the differentiation of follicle cells, both of which suggest a possible function in tumor suppression.	('HOXC12', 'Gene', '3228', (0, 6))	('follicular lymphoma', 'Disease', 'MESH:D008224', (23, 42))	('hypermethylation', 'Var', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('HOXC12', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('lymphoma', 'Phenotype', 'HP:0002665', (34, 42))	('tumor', 'Disease', (201, 206))	('implicated', 'Reg', (103, 113))	('follicular lymphoma', 'Disease', (23, 42))
104702	26867567	Likewise, the function of HOXD12 has not been defined, but it has been shown to be silenced in melanoma cells through the methylation of its promoter.	('methylation', 'Var', (122, 133))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('HOXD12', 'Gene', (26, 32))	('melanoma', 'Disease', (95, 103))	('HOXD12', 'Gene', '3238', (26, 32))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))
104714	26867567	Targeting the interaction between HOX proteins and their PBX cofactor causes apoptosis in mesothelioma cells in vitro and retards tumor growth in vivo, indicating that HOX proteins are a potential therapeutic target in this malignancy.	('PBX', 'Chemical', '-', (57, 60))	('malignancy', 'Disease', 'MESH:D009369', (224, 234))	('interaction', 'Interaction', (14, 25))	('apoptosis', 'CPA', (77, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('retards tumor', 'Disease', 'MESH:D009369', (122, 135))	('retards tumor', 'Disease', (122, 135))	('mesothelioma', 'Disease', (90, 102))	('malignancy', 'Disease', (224, 234))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('Targeting', 'Var', (0, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
104773	23526965	Lysates were adjusted to 1,000 microg/mL protein for use in an assay for 6 different phosphorylated proteins, including Akt (Ser473), Erk 1/2 (Thr202/Tyr204, Thr185/Tyr187), JNK (Thr183/Tyr185), p38 MAPK (Thr180/Tyr182), p70 S6 kinase (Thr421/Ser424), IkappaBalpha (Ser32/Ser36).	('IkappaBalpha', 'Gene', '18035', (252, 264))	('Tyr204', 'Chemical', '-', (150, 156))	('JNK', 'molecular_function', 'GO:0004705', ('174', '177'))	('Thr202', 'Chemical', '-', (143, 149))	('Ser32', 'Chemical', '-', (266, 271))	('Ser', 'cellular_component', 'GO:0005790', ('266', '269'))	('Akt', 'Gene', '11651', (120, 123))	('JNK', 'Gene', (174, 177))	('Erk 1/2', 'Gene', (134, 141))	('Erk 1/2', 'Gene', '26417;26413', (134, 141))	('Tyr182', 'Chemical', '-', (212, 218))	('Thr185/Tyr187', 'Var', (158, 171))	('JNK', 'Gene', '26419', (174, 177))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('Ser32/Ser36', 'Var', (266, 277))	('Erk 1', 'molecular_function', 'GO:0004707', ('134', '139'))	('p38 MAPK', 'Gene', '26416', (195, 203))	('Thr183/Tyr185', 'Var', (179, 192))	('p38 MAPK', 'Gene', (195, 203))	('IkappaBalpha', 'Gene', (252, 264))	('MAPK', 'molecular_function', 'GO:0004707', ('199', '203'))	('Tyr187', 'Chemical', '-', (165, 171))	('Thr180', 'Chemical', '-', (205, 211))	('Thr185', 'Chemical', '-', (158, 164))	('Ser', 'cellular_component', 'GO:0005790', ('125', '128'))	('Thr202/Tyr204', 'Var', (143, 156))	('Ser473', 'Var', (125, 131))	('Ser', 'cellular_component', 'GO:0005790', ('272', '275'))	('Thr183', 'Chemical', '-', (179, 185))	('Ser424', 'Chemical', '-', (243, 249))	('Ser473', 'Chemical', '-', (125, 131))	('Thr180/Tyr182', 'Var', (205, 218))	('Thr421/Ser424', 'Var', (236, 249))	('Thr421', 'Chemical', '-', (236, 242))	('Ser36', 'Chemical', '-', (272, 277))	('Ser', 'cellular_component', 'GO:0005790', ('243', '246'))	('Tyr185', 'Chemical', '-', (186, 192))	('Akt', 'Gene', (120, 123))
104824	23526965	At population level, Kaplan-Meier analysis showed significant survival increase for gemcitabine-treated mice, but an identical result was achieved with AND treatment, where gemcitabine dosage was about one third lower.	('gemcitabine-treated', 'Var', (84, 103))	('mice', 'Species', '10090', (104, 108))	('survival', 'CPA', (62, 70))	('increase', 'PosReg', (71, 79))	('gemcitabine', 'Chemical', 'MESH:C056507', (173, 184))	('gemcitabine', 'Chemical', 'MESH:C056507', (84, 95))
104851	19852844	Recurrent loss of heterozygosity in the 3p21.3 chromosomal region, as well as homozygous deletions and epigenetic inactivation of this area are observed in early stages of lung, breast, ovarian, liver, cervical, and other cancers suggesting a critical role for one or more genes that reside in 3p21.3.	('breast', 'Disease', (178, 184))	('cervical', 'Disease', (202, 210))	('lung', 'Disease', (172, 176))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('liver', 'Disease', (195, 200))	('homozygous deletions', 'Var', (78, 98))	('cancers', 'Disease', (222, 229))	('ovarian', 'Disease', (186, 193))	('epigenetic inactivation', 'Var', (103, 126))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('chromosomal region', 'cellular_component', 'GO:0098687', ('47', '65'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('loss', 'NegReg', (10, 14))
104875	19852844	Analysis of different tumor stages implied that the 3p21.3 deletion in MM is a frequent event in stages 2 and 3 but could also be detected as early as stage 1 (one out of five stage 1 patients studied showed the deletion).	('3p21.3', 'Gene', (52, 58))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('deletion', 'Var', (59, 67))
104885	19852844	The results of these experiments provide a link between asbestos exposure, asbestos-generated ROS, and modulation of TUSC2 expression in mesothelial cells.	('TUSC2', 'Gene', (117, 122))	('modulation', 'Var', (103, 113))	('expression', 'MPA', (123, 133))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('asbestos', 'Chemical', 'MESH:D001194', (75, 83))
104890	19852844	Consistent with the TUSC2 tumor suppressor role, 21 genes with anti-tumorigenic properties including BCL211, FOXN3, GAS1, and NME5 were up-regulated by TUSC2.	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('GAS1', 'Gene', '2619', (116, 120))	('GAS', 'molecular_function', 'GO:0034005', ('116', '119'))	('tumor', 'Disease', (68, 73))	('TUSC2', 'Var', (152, 157))	('TUSC2 tumor', 'Disease', (20, 31))	('NME5', 'Gene', '8382', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (26, 31))	('NME5', 'Gene', (126, 130))	('GAS1', 'Gene', (116, 120))	('FOXN3', 'Gene', '1112', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('TUSC2 tumor', 'Disease', 'MESH:D009369', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('BCL211', 'Gene', (101, 107))	('FOXN3', 'Gene', (109, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('up-regulated', 'PosReg', (136, 148))
104897	19852844	In agreement with the mouse KO data, one of the multiple targets modulated by TUSC2 in MPM cells was IL15 that was 2-fold up-regulated by FUS1 introduction.	('IL15', 'Gene', '16168', (101, 105))	('TUSC2', 'Gene', (78, 83))	('IL15', 'Gene', (101, 105))	('IL15', 'molecular_function', 'GO:0016170', ('101', '105'))	('mouse', 'Species', '10090', (22, 27))	('up-regulated', 'PosReg', (122, 134))	('FUS1', 'Var', (138, 142))
104908	19852844	While studies on lung cancer cell lines revealed a limited (~4%) frequency of mutations in the TUSC2 gene and infrequent methylation of its promoter, large-scale analysis of TUSC2 expression in lung cancers and in bronchial squamous metaplastic and dysplastic lesions have revealed significantly lower levels of TUSC2 as compared to normal hyperplastic epithelia.	('dysplastic lesions', 'Disease', (249, 267))	('levels', 'MPA', (302, 308))	('lung cancers', 'Disease', 'MESH:D008175', (194, 206))	('hyperplastic epithelia', 'Disease', (340, 362))	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('lung cancers', 'Disease', (194, 206))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('lung cancers', 'Phenotype', 'HP:0100526', (194, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('mutations', 'Var', (78, 87))	('lower', 'NegReg', (296, 301))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('hyperplastic epithelia', 'Disease', 'MESH:D054514', (340, 362))	('TUSC2', 'Gene', (95, 100))	('TUSC2', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', (17, 28))	('dysplastic lesions', 'Disease', 'MESH:D021782', (249, 267))	('TUSC2', 'MPA', (312, 317))
104910	19852844	Targeted disruption of the Tusc2 gene in mice that our group performed previously resulted in a complex immunological autoimmune phenotype with an inflammatory background and recurrent tumorigenesis at the sites of chronic inflammation.	('tumor', 'Disease', (185, 190))	('inflammation', 'Disease', (223, 235))	('Targeted disruption', 'Var', (0, 19))	('mice', 'Species', '10090', (41, 45))	('inflammation', 'biological_process', 'GO:0006954', ('223', '235'))	('resulted in', 'Reg', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Tusc2', 'Gene', '80385', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('inflammation', 'Disease', 'MESH:D007249', (223, 235))	('Tusc2', 'Gene', (27, 32))
104915	19852844	Indeed, mice hetero- or homozygous on the Tusc2 deletion shared similar immunological and tumorigenic phenotypes at comparable frequencies.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Tusc2', 'Gene', '80385', (42, 47))	('Tusc2', 'Gene', (42, 47))	('deletion', 'Var', (48, 56))	('mice', 'Species', '10090', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
104927	19852844	As a result, we found in the NCBI Gene Expression Omnibus several experimental assays performed on different cell types that consistently showed TUSC2 mRNA suppression by hypoxia (see records GDS2759, GDS2018, GDS2760, and GDS2951 for FUS1/TUSC2 at ).	('TUSC2', 'Gene', (145, 150))	('GDS', 'molecular_function', 'GO:0005085', ('223', '226'))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('suppression', 'NegReg', (156, 167))	('GDS2951', 'Var', (223, 230))	('GDS2760', 'Var', (210, 217))	('hypoxia', 'Disease', (171, 178))	('GDS', 'molecular_function', 'GO:0005085', ('210', '213'))	('GDS', 'molecular_function', 'GO:0005085', ('192', '195'))	('GDS', 'molecular_function', 'GO:0005085', ('201', '204'))	('GDS2018', 'Var', (201, 208))	('Gene Expression', 'biological_process', 'GO:0010467', ('34', '49'))
104936	19852844	Since blocking of CD274 is now actively pursued as a novel immunotherapy, we suggest that TUSC2 may also have important immunotherapeutic implications.	('CD274', 'Gene', '29126', (18, 23))	('CD274', 'Gene', (18, 23))	('blocking', 'Var', (6, 14))
104945	19852844	On the molecular level, we associated TUSC2 with activation of multiple tumor-suppressor genes, down-regulation of oncogenes, and modulation of numerous immune genes.	('oncogenes', 'Gene', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('modulation', 'Reg', (130, 140))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('tumor', 'Disease', (72, 77))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('TUSC2', 'Var', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('down-regulation', 'NegReg', (96, 111))	('activation', 'PosReg', (49, 59))
104962	19852844	Since FUS1 has been previously associated with the 3p21.3 deletion in lung and other cancers, we used our previously produced Representational Oligonucleotide Microarray Analysis (ROMA) data for assessment of this association in MPM specimens.	('FUS1', 'Gene', (6, 10))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('associated', 'Reg', (31, 41))	('cancers', 'Disease', (85, 92))	('lung', 'Disease', (70, 74))	('deletion', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
104974	19852844	MM: Malignant Pleural Mesothelioma; ROS: Reactive Oxygen Species; TMA: Tissue MicroArray; ROMA: Representational Oligonucleotide Microarray Analysis; CAN: Copy Number Alteration; ACE: Analysis of Copy Errors.	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (14, 34))	('Reactive Oxygen Species', 'Chemical', 'MESH:D017382', (41, 64))	('Copy Number', 'Var', (155, 166))	('TMA', 'Disease', (66, 69))	('Malignant Pleural Mesothelioma', 'Disease', (4, 34))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('TMA', 'Disease', 'MESH:D000783', (66, 69))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (4, 34))
105000	33602699	This high specificity is necessary in screening with tumour markers to reduce false-positive tests in cancer-free subjects to an acceptable minimum, because false-positive tests might result in psychological stress and needless invasive diagnostic work-up procedures for the individuals concerned.	('false', 'biological_process', 'GO:0071878', ('157', '162'))	('result in', 'Reg', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (53, 59))	('false-positive', 'Var', (157, 171))	('cancer', 'Disease', (102, 108))	('stress', 'Disease', (208, 214))	('stress', 'Disease', 'MESH:D000079225', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('false', 'biological_process', 'GO:0071877', ('157', '162'))	('false', 'biological_process', 'GO:0071878', ('78', '83'))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('false', 'biological_process', 'GO:0071877', ('78', '83'))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
105015	33602699	Mesothelin was determined between September 2019 and October 2019 (CLEIA) and October 2019 and November 2019 (ELISA), respectively.	('October 2019', 'Var', (78, 90))	('Mesothelin', 'Gene', '10232', (0, 10))	('Mesothelin', 'Gene', (0, 10))
105023	33602699	Marker results were marked as positive if mesothelin concentrations were >=1.5 nM (mesothelin CLEIA) and >=2.0 nM (mesothelin ELISA), respectively.	('mesothelin', 'Gene', (115, 125))	('mesothelin', 'Gene', '10232', (42, 52))	('mesothelin', 'Gene', (83, 93))	('>=2.0', 'Var', (105, 110))	('mesothelin', 'Gene', '10232', (83, 93))	('mesothelin', 'Gene', '10232', (115, 125))	('mesothelin', 'Gene', (42, 52))
105133	29792222	The incidence data for primary malignant pleural mesothelioma (International Classification of Diseases for Oncology, 3rd edition, histology codes 9050-9055, sites C38.4 and C38.8) was obtained from the US Surveillance, Epidemiology, and End Results (SEER) 9 population-based cancer registries from 1973 to 2013.	('C38.8', 'Var', (174, 179))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (31, 61))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (41, 61))	('malignant pleural mesothelioma', 'Disease', (31, 61))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('Oncology', 'Phenotype', 'HP:0002664', (108, 116))
105179	26577445	The dose-volume planning objectives defined for the organs at risk were as follows: contralateral lung, percentage of volume receiving 5 Gy (V5) <50 %, V20 <7 %; liver, V20 <50 %; heart, V45 <50 %; kidney, V15 <20 %; spinal cord, maximum dose <48 Gy.	('V45 <50 %', 'Var', (187, 196))	('V15', 'Gene', (206, 209))	('V15', 'Gene', '28814', (206, 209))	('V20 <50 %', 'Var', (169, 178))	('V20 <', 'Var', (152, 157))
105213	26577445	MST and the 2-year survival rate of patients who completed EPP (n = 30) were 22.7 months and 50.0 %, respectively, and those for non-EPP patients (n = 12) were 17.1 months and 25.0 %, respectively (Fig.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (137, 145))	('EPP', 'Var', (59, 62))	('MST', 'CPA', (0, 3))
105304	25378740	The early-ban group reported the highest burden of asbestos related disease, while the no-ban group recorded the lowest.	('asbestos related disease', 'Disease', (51, 75))	('asbestos', 'Chemical', 'MESH:D001194', (51, 59))	('early-ban', 'Var', (4, 13))
105385	24405760	In addition, enhanced darkfield analysis demonstrated MWCNT in the diaphragm (Figure 2C).	('MWCNT', 'Chemical', '-', (54, 59))	('diaphragm', 'MPA', (67, 76))	('rat', 'Species', '10116', (48, 51))	('MWCNT', 'Var', (54, 59))
105394	24405760	Incidences of macrophage infiltration were higher in the MWCNT or MCA + MWCNT groups relative to the air or MCA groups (Table 1).	('MCA', 'Gene', (108, 111))	('MWCNT', 'Chemical', '-', (72, 77))	('higher', 'PosReg', (43, 49))	('macrophage infiltration', 'CPA', (14, 37))	('MCA', 'Gene', '22092', (66, 69))	('MWCNT', 'Var', (57, 62))	('MWCNT', 'Chemical', '-', (57, 62))	('MCA', 'Gene', '22092', (108, 111))	('MCA', 'Gene', (66, 69))	('rat', 'Species', '10116', (31, 34))
105452	24405760	The data demonstrate that MWCNT may act as a carcinogen that promotes the growth of initiated lung cells, resulting in the development of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 157))	('lung adenocarcinoma', 'Disease', (138, 157))	('resulting in', 'Reg', (106, 118))	('promotes', 'PosReg', (61, 69))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (138, 157))	('rat', 'Species', '10116', (16, 19))	('MWCNT', 'Var', (26, 31))	('growth', 'CPA', (74, 80))	('MWCNT', 'Chemical', '-', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
105486	24405760	There are multiple mutagens in cigarette smoke that have the potential to initiate cancer.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutagens', 'Var', (19, 27))	('cancer', 'Disease', (83, 89))
105487	24405760	Humans are also potentially exposed to many other mutagens that could initiate cancer such as radon, polychlorinated biphenyls, hexavalent chromium, naphthalene and benzo-a-pyrene in diesel exhaust.	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (101, 126))	('Humans', 'Species', '9606', (0, 6))	('man', 'Species', '9606', (39, 42))	('hexavalent chromium', 'MPA', (128, 147))	('chromium', 'Chemical', 'MESH:D002857', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('naphthalene', 'Chemical', 'MESH:C031721', (149, 160))	('radon', 'Chemical', 'MESH:D011886', (94, 99))	('benzo-a-pyrene', 'Chemical', 'MESH:D001564', (165, 179))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('man', 'Species', '9606', (2, 5))	('initiate', 'PosReg', (70, 78))	('polychlorinated', 'Var', (101, 116))
105592	24405760	Primary antibodies were hamster anti-podoplanin (NB600-1015, Novus Biologicals, Littleton, CO), mouse anti-pancytokeratin (C2652, Sigma-Aldrich, St Louis, MO), rabbit anti-vimentin (GTX62264, GeneTex, Irvine, CA), and rabbit anti-wide spectrum cytokeratin (rabbit ab9377).	('hamster', 'Species', '10034', (24, 31))	('mouse', 'Species', '10090', (96, 101))	('rat', 'Species', '10116', (250, 253))	('rabbit', 'Species', '9986', (160, 166))	('vimentin', 'cellular_component', 'GO:0045098', ('172', '180'))	('C2652', 'Var', (123, 128))	('rabbit', 'Species', '9986', (218, 224))	('C2652', 'CellLine', 'CVCL:1W45', (123, 128))	('rat', 'Species', '10116', (116, 119))	('NB600-1015', 'Var', (49, 59))	('rabbit', 'Species', '9986', (257, 263))	('vimentin', 'cellular_component', 'GO:0045099', ('172', '180'))
105593	24405760	Secondary anti-bodies were DyLight 488, donkey anti-mouse (715-486-150, lot# 97733, Jackson ImmunoResearch Laboratories, West Grove, PA), DyLight 594 goat anti-hamster (107-515-142, lot 90054, Jackson ImmunoResearch Laboratories, West Grove, PA), Dylight 488 F(ab')2 donkey anti-rabbit and DyLight 594 donkey anti-rabbit (711-516-152, lot 97356, Jackson ImmunoResearch Laboratories, West Grove, PA).	('rabbit', 'Species', '9986', (279, 285))	('rat', 'Species', '10116', (111, 114))	('donkey', 'Species', '9793', (302, 308))	('rabbit', 'Species', '9986', (314, 320))	('107-515-142', 'Var', (169, 180))	('mouse', 'Species', '10090', (52, 57))	('donkey', 'Species', '9793', (267, 273))	('goat', 'Species', '9925', (150, 154))	('hamster', 'Species', '10034', (160, 167))	('donkey', 'Species', '9793', (40, 46))	('rat', 'Species', '10116', (373, 376))	('rat', 'Species', '10116', (220, 223))	('711-516-152', 'Var', (322, 333))	('715-486-150', 'Var', (59, 70))
105890	19727362	With regard to the primary end point, the fall in the isotope clearance half time was greater in the mixed-talc group as compared to the tetracycline group {-9.26 [SD 14.3] vs. 4.10 [SD 13.8] min (P = 0.05)}.	('mixed-talc', 'Var', (101, 111))	('isotope clearance half time', 'MPA', (54, 81))	('fall', 'NegReg', (42, 46))	('talc', 'Chemical', 'MESH:D013627', (107, 111))	('fall', 'Phenotype', 'HP:0002527', (42, 46))	('tetracycline', 'Chemical', 'MESH:D013752', (137, 149))
105953	19727362	The large majority of TPC insertion procedures lead to symptom improvement in these patients, which is the primary goal of treatment for patients in this condition.	('symptom improvement', 'MPA', (55, 74))	('patients', 'Species', '9606', (84, 92))	('men', 'Species', '9606', (128, 131))	('men', 'Species', '9606', (70, 73))	('patients', 'Species', '9606', (137, 145))	('TPC', 'Chemical', '-', (22, 25))	('procedures', 'Var', (36, 46))	('TPC', 'Gene', (22, 25))
105983	28435517	Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy.	('mesothelioma', 'Disease', (171, 183))	('imatinib', 'Chemical', 'MESH:D000068877', (118, 126))	('gene silencing', 'Var', (78, 92))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('hampers', 'NegReg', (136, 143))	('cancer of the pleural', 'Disease', (237, 258))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (205, 225))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (195, 225))	('malignant phenotype', 'CPA', (148, 167))	('gene silencing', 'biological_process', 'GO:0016458', ('78', '92'))	('crenolanib', 'Chemical', 'MESH:C577197', (94, 104))	('cancer of the pleural', 'Disease', 'MESH:D010995', (237, 258))	('cancer of the pleural cavity', 'Phenotype', 'HP:0100527', (237, 265))	('Malignant pleural mesothelioma', 'Disease', (195, 225))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('18', '48'))	('mesothelioma', 'Disease', (213, 225))	('platelet-derived growth factor receptor beta', 'Gene', '5159', (18, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (213, 225))	('PDGFRB', 'Gene', '5159', (64, 70))	('PDGFRB', 'Gene', (64, 70))	('platelet-derived growth factor receptor beta', 'Gene', (18, 62))
105986	28435517	The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25).	('PDGFR', 'Gene', (135, 140))	('crenolanib', 'Chemical', 'MESH:C577197', (110, 120))	('Mero-25', 'Chemical', '-', (190, 197))	('imatinib', 'Chemical', 'MESH:D000068877', (125, 133))	('PDGFR', 'Gene', '5159', (135, 140))	('gene silencing', 'Var', (44, 58))	('Mero-14', 'Chemical', '-', (181, 188))	('gene silencing', 'biological_process', 'GO:0016458', ('44', '58'))
106005	28435517	High PDGFRs expression correlates with advanced stage disease and poor prognosis in breast, liver, and pancreatic carcinomas.	('liver', 'Disease', (92, 97))	('High', 'Var', (0, 4))	('PDGFR', 'Gene', (5, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (103, 124))	('breast', 'Disease', (84, 90))	('PDGFR', 'Gene', '5159', (5, 10))	('pancreatic carcinomas', 'Disease', (103, 124))	('expression', 'MPA', (12, 22))	('advanced stage disease', 'Disease', (39, 61))
106009	28435517	The approaches included the use of gene silencing and PDGFRB inhibitors.	('PDGFRB', 'Gene', (54, 60))	('gene silencing', 'Var', (35, 49))	('gene silencing', 'biological_process', 'GO:0016458', ('35', '49'))	('PDGFRB', 'Gene', '5159', (54, 60))
106026	28435517	As shown in Figure 2B, PDGFRB silencing had a strong effect on abolishing clonogenicity in Mero-14 (-80.1%; P=2.9x10-3) and IstMes2 (-86.3%, P=5x10-4), when compared to control C-PDGFRB-transfected cells.	('PDGFRB', 'Gene', '5159', (179, 185))	('PDGFRB', 'Gene', (179, 185))	('abolishing', 'NegReg', (63, 73))	('PDGFRB', 'Gene', '5159', (23, 29))	('silencing', 'Var', (30, 39))	('Mero-14', 'Chemical', '-', (91, 98))	('clonogenicity', 'CPA', (74, 87))	('PDGFRB', 'Gene', (23, 29))
106027	28435517	A slight reduction of colony formation capacity was also observed in Mero-25 cells after PDGFRB silencing, but this decrease was not statistically significant (data not shown).	('formation', 'biological_process', 'GO:0009058', ('29', '38'))	('silencing', 'Var', (96, 105))	('PDGFRB', 'Gene', (89, 95))	('reduction', 'NegReg', (9, 18))	('colony formation capacity', 'CPA', (22, 47))	('Mero-25', 'Chemical', '-', (69, 76))	('PDGFRB', 'Gene', '5159', (89, 95))
106032	28435517	The activity of caspases 3 and 7 was measured for the evaluation of the apoptotic rate following PDGFRB silencing.	('apoptotic rate', 'CPA', (72, 86))	('silencing', 'Var', (104, 113))	('PDGFRB', 'Gene', (97, 103))	('PDGFRB', 'Gene', '5159', (97, 103))
106035	28435517	Wound-healing assay was employed to assess the effect of PDGFRB silencing on cellular migration of MPM cell lines.	('silencing', 'Var', (64, 73))	('Wound-healing', 'biological_process', 'GO:0042060', ('0', '13'))	('PDGFRB', 'Gene', '5159', (57, 63))	('PDGFRB', 'Gene', (57, 63))	('cellular migration', 'CPA', (77, 95))
106037	28435517	Nevertheless, Mero-14 cells showed a statistically significant reduced migration ability, as compared to C-PDGFRB, at 72 h after PDGFRB depletion (P=0,019) (Figure 3B).	('migration ability', 'CPA', (71, 88))	('PDGFRB', 'Gene', '5159', (107, 113))	('reduced', 'NegReg', (63, 70))	('depletion', 'Var', (136, 145))	('PDGFRB', 'Gene', (107, 113))	('Mero-14', 'Chemical', '-', (14, 21))	('PDGFRB', 'Gene', '5159', (129, 135))	('PDGFRB', 'Gene', (129, 135))
106041	28435517	Hence the results of the soft agar assay confirmed that PDGFRB depletion decreased in vitro tumorigenic potential of MPM cells.	('PDGFRB', 'Gene', '5159', (56, 62))	('agar', 'Chemical', 'MESH:D000362', (30, 34))	('decreased', 'NegReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('PDGFRB', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('depletion', 'Var', (63, 72))	('tumor', 'Disease', (92, 97))
106044	28435517	Similar to that found after PDGFRB gene-silencing, reductions of proliferative capabilities were observed, where the strongest activity of crenolanib was found on Mero-14 and IstMes2 cells, as reported in Figure 5A.	('proliferative capabilities', 'CPA', (65, 91))	('reductions', 'NegReg', (51, 61))	('PDGFRB', 'Gene', (28, 34))	('crenolanib', 'Chemical', 'MESH:C577197', (139, 149))	('gene-silencing', 'Var', (35, 49))	('PDGFRB', 'Gene', '5159', (28, 34))	('Mero-14', 'Chemical', '-', (163, 170))	('gene-silencing', 'biological_process', 'GO:0016458', ('35', '49'))	('activity', 'MPA', (127, 135))
106051	28435517	Similar to the observations made following treatment with siPDGFRB, the flow cytometry analysis showed that crenolanib induces an increase in the share of cells in sub-G1 for Mero-14 (P=2x10-3) and IstMes2 (P=0.04), a reduced share of cells in G0/G1 phase (P=1x10-3 for Mero-14 cells, and P=0.05 for IstMes2 cells), and an accumulation in G2/M phase for IstMes2 cells (P=0.04).	('G0/G1 phase', 'CPA', (244, 255))	('PDGFRB', 'Gene', '5159', (60, 66))	('M phase', 'biological_process', 'GO:0000279', ('342', '349'))	('Mero-14', 'Chemical', '-', (175, 182))	('accumulation', 'PosReg', (323, 335))	('increase', 'PosReg', (130, 138))	('cells', 'CPA', (235, 240))	('G2/M phase', 'CPA', (339, 349))	('reduced', 'NegReg', (218, 225))	('G1 phase', 'biological_process', 'GO:0051318', ('247', '255'))	('PDGFRB', 'Gene', (60, 66))	('crenolanib', 'Var', (108, 118))	('Mero-14', 'Chemical', '-', (270, 277))	('crenolanib', 'Chemical', 'MESH:C577197', (108, 118))
106055	28435517	With crenolanib at 1muM (Figure 7A), Mero-14 and IstMes2 showed a strong and statistically significant increase of apoptosis (+54%, P=3.8x10-3, and +100% P=0.017, respectively), in agreement with the share of sub-G1 cells observed with flow cytometry analysis.	('muM', 'Gene', '56925', (20, 23))	('increase', 'PosReg', (103, 111))	('Mero-14', 'Chemical', '-', (37, 44))	('crenolanib', 'Var', (5, 15))	('muM', 'Gene', (20, 23))	('crenolanib', 'Chemical', 'MESH:C577197', (5, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('apoptosis', 'CPA', (115, 124))
106079	28435517	Thus, we analyzed the impact of PDGFRB gene silencing on MPM cell proliferation, cell cycle, apoptosis induction, and invasive behavior on a panel of cell lines, in order to widen the cancer representativeness.	('cancer', 'Disease', (184, 190))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cell cycle', 'biological_process', 'GO:0007049', ('81', '91'))	('PDGFRB', 'Gene', '5159', (32, 38))	('silencing', 'NegReg', (44, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('PDGFRB', 'Gene', (32, 38))	('gene silencing', 'biological_process', 'GO:0016458', ('39', '53'))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('gene', 'Var', (39, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
106081	28435517	Moreover, PDGFRB depletion was associated with an increase in the share of cells in sub-G1 phase, as well as with an increased apoptotic rate of these cells.	('apoptotic rate', 'CPA', (127, 141))	('G1 phase', 'biological_process', 'GO:0051318', ('88', '96'))	('increased', 'PosReg', (117, 126))	('PDGFRB', 'Gene', (10, 16))	('PDGFRB', 'Gene', '5159', (10, 16))	('depletion', 'Var', (17, 26))	('increase', 'PosReg', (50, 58))
106083	28435517	In addition, Wang and co-workers showed that PDGFRB inhibition alone reduces spontaneous growth and metastasis in Ewing Sarcoma (EWS).	('PDGFRB', 'Gene', '5159', (45, 51))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('PDGFRB', 'Gene', (45, 51))	('metastasis in Ewing Sarcoma', 'Disease', 'MESH:C563168', (100, 127))	('reduces', 'NegReg', (69, 76))	('spontaneous growth', 'CPA', (77, 95))	('inhibition', 'Var', (52, 62))	('EWS', 'Gene', '2130', (129, 132))	('EWS', 'Gene', (129, 132))	('EWS', 'Phenotype', 'HP:0012254', (129, 132))	('metastasis in Ewing Sarcoma', 'Disease', (100, 127))	('Sarcoma', 'Phenotype', 'HP:0100242', (120, 127))
106084	28435517	In further work they demonstrated that PDGFRB depletion is fundamental in increasing the activity of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) for the significant reduction of growth of EWS, as well as decreasing the number of incidences of spontaneous EWS pulmonary metastasis.	('necrosis', 'biological_process', 'GO:0008220', ('114', '122'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('108', '129'))	('pulmonary metastasis', 'CPA', (279, 299))	('necrosis', 'biological_process', 'GO:0070265', ('114', '122'))	('ligand', 'molecular_function', 'GO:0005488', ('157', '163'))	('necrosis', 'biological_process', 'GO:0019835', ('114', '122'))	('activity', 'MPA', (89, 97))	('EWS', 'Gene', '2130', (275, 278))	('necrosis', 'biological_process', 'GO:0001906', ('114', '122'))	('growth', 'CPA', (198, 204))	('EWS', 'Gene', (208, 211))	('reduction', 'NegReg', (185, 194))	('EWS', 'Phenotype', 'HP:0012254', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TRAIL', 'Gene', '8743', (101, 106))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (108, 163))	('decreasing', 'NegReg', (224, 234))	('necrosis', 'biological_process', 'GO:0008219', ('114', '122'))	('EWS', 'Gene', (275, 278))	('depletion', 'Var', (46, 55))	('increasing', 'PosReg', (74, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('EWS', 'Gene', '2130', (208, 211))	('PDGFRB', 'Gene', '5159', (39, 45))	('TRAIL', 'Gene', (101, 106))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('PDGFRB', 'Gene', (39, 45))	('EWS', 'Phenotype', 'HP:0012254', (275, 278))
106085	28435517	In a previous work, Zhang and co-workers showed that altered phosphorylation at the tyrosine kinase domain may potentially induce impaired signaling via the PDGF-B/PDGFRbeta pathway, triggering a series of intracellular kinase cascades, such as those of Ras/Raf, MAPK, PI3K/AKT and FAK.	('induce', 'Reg', (123, 129))	('PDGFRbeta', 'Gene', '5159', (164, 173))	('MAPK', 'Pathway', (263, 267))	('altered', 'Var', (53, 60))	('PDGF', 'molecular_function', 'GO:0005161', ('157', '161'))	('FAK', 'Gene', (282, 285))	('Raf', 'Gene', '22882', (258, 261))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('MAPK', 'molecular_function', 'GO:0004707', ('263', '267'))	('AKT', 'Gene', (274, 277))	('PDGF-B', 'Gene', (157, 163))	('intracellular kinase cascades', 'Pathway', (206, 235))	('impaired', 'NegReg', (130, 138))	('FAK', 'Gene', '5747', (282, 285))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('PI3K', 'molecular_function', 'GO:0016303', ('269', '273'))	('PDGF-B', 'Gene', '5155', (157, 163))	('phosphorylation at the tyrosine kinase domain', 'MPA', (61, 106))	('AKT', 'Gene', '207', (274, 277))	('intracellular', 'cellular_component', 'GO:0005622', ('206', '219'))	('Raf', 'Gene', (258, 261))	('FAK', 'molecular_function', 'GO:0004717', ('282', '285'))	('signaling', 'MPA', (139, 148))	('triggering', 'Reg', (183, 193))	('PDGFRbeta', 'Gene', (164, 173))
106087	28435517	This data suggests that inhibition of PDGFRB could determine the G2 checkpoint recovery arrest.	('PDGFRB', 'Gene', '5159', (38, 44))	('PDGFRB', 'Gene', (38, 44))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('determine', 'Reg', (51, 60))	('inhibition', 'Var', (24, 34))	('arrest', 'Disease', (88, 94))
106089	28435517	More recently, in support of this hypothesis, it has been shown that imatinib delayed recovery from checkpoint arrest and inhibited the subsequent S-G2-M transition, through a persistent activation of ATR-Chk1 signaling, known to be fundamental for the maintenance of G2 checkpoint arrest.	('arrest', 'Disease', 'MESH:D006323', (282, 288))	('delayed', 'NegReg', (78, 85))	('recovery', 'MPA', (86, 94))	('arrest', 'Disease', 'MESH:D006323', (111, 117))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('activation', 'PosReg', (187, 197))	('arrest', 'Disease', (282, 288))	('inhibited', 'NegReg', (122, 131))	('arrest', 'Disease', (111, 117))	('imatinib', 'Chemical', 'MESH:D000068877', (69, 77))	('S-G2-M transition', 'MPA', (147, 164))	('Chk1', 'Gene', (205, 209))	('ATR', 'Gene', '545', (201, 204))	('ATR', 'Gene', (201, 204))	('imatinib', 'Var', (69, 77))	('Chk1', 'Gene', '1111', (205, 209))
106096	28435517	Interestingly, non-malignant cells (Met5A) did not seem to be affected by the PDGFRB silencing, suggesting that this gene might be an effective therapeutic target.	('PDGFRB', 'Gene', (78, 84))	('PDGFRB', 'Gene', '5159', (78, 84))	('silencing', 'Var', (85, 94))
106109	28435517	Moreover, preclinical evidences showed benefit for lung cancer patients with deregulated PDGFR signaling.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('deregulated', 'Var', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('PDGFR', 'Gene', (89, 94))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('PDGFR', 'Gene', '5159', (89, 94))	('patients', 'Species', '9606', (63, 71))	('benefit', 'PosReg', (39, 46))
106115	28435517	Ninety-six samples from formalin fixed and paraffin embedded tissues (FFPE) of MPM patients hospitalized and surgically resected for the tumor were enrolled for PDGFRB mutation screening.	('PDGFRB', 'Gene', '5159', (161, 167))	('tumor', 'Disease', (137, 142))	('PDGFRB', 'Gene', (161, 167))	('mutation', 'Var', (168, 176))	('MPM', 'Disease', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patients', 'Species', '9606', (83, 91))	('paraffin', 'Chemical', 'MESH:D010232', (43, 51))	('formalin', 'Chemical', 'MESH:D005557', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
106120	28435517	Copy number alterations data of 83 MPM patients were obtained from Cancer Genome Atlas (TCGA) consortium.	('Cancer Genome Atlas', 'Disease', (67, 86))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (67, 86))	('patients', 'Species', '9606', (39, 47))	('Copy', 'Var', (0, 4))
106125	28435517	Further experiments were performed by using a single specific siRNA for PDGFRB (SI00605738, the so-called "siPDGFRB" now-on) and the "AllStars Negative Control siRNA" (SI03650318, used as non-targeting control - the so-called "C-PDGFRB" now-on).	('PDGFRB', 'Gene', (72, 78))	('PDGFRB', 'Gene', '5159', (72, 78))	('SI00605738', 'Var', (80, 90))	('PDGFRB', 'Gene', '5159', (229, 235))	('PDGFRB', 'Gene', '5159', (109, 115))	('PDGFRB', 'Gene', (229, 235))	('PDGFRB', 'Gene', (109, 115))
106132	28435517	Normalised cytotoxicity percentages were obtained from the formula: (A570 mean values of extracts from treated samples/A570 mean values of extracts from untreated control samples) x 100.	('cytotoxicity', 'Disease', (11, 23))	('samples/A570', 'Var', (111, 123))	('cytotoxicity', 'Disease', 'MESH:D064420', (11, 23))
106151	27737701	Absolute and relative lung weights were significantly elevated in male rats exposed to 0.2 and 2 mg/m3 MWNT-7 and in all exposed female groups.	('0.2', 'Var', (87, 90))	('elevated', 'PosReg', (54, 62))	('MWNT-7', 'Gene', (103, 109))	('rats', 'Species', '10116', (71, 75))	('MWNT-7', 'Chemical', '-', (103, 109))
106153	27737701	There is clear evidence that MWNT-7 is carcinogenic to the lungs of male and female F344 rats, however no plural mesothelioma was observed.	('carcinogenic', 'Disease', 'MESH:D063646', (39, 51))	('carcinogenic', 'Disease', (39, 51))	('rats', 'Species', '10116', (89, 93))	('plural mesothelioma', 'Disease', 'MESH:D008654', (106, 125))	('MWNT-7', 'Chemical', '-', (29, 35))	('MWNT-7', 'Var', (29, 35))	('plural mesothelioma', 'Disease', (106, 125))
106167	27737701	Taken together, these results show that airborne long straight MWCNT fibers are potentially carcinogenic to mouse lung and pleural tissues.	('carcinogenic', 'Disease', 'MESH:D063646', (92, 104))	('MWCNT', 'Chemical', '-', (63, 68))	('carcinogenic', 'Disease', (92, 104))	('pleural', 'Disease', (123, 130))	('long straight MWCNT', 'Var', (49, 68))	('mouse', 'Species', '10090', (108, 113))	('pleural', 'Disease', 'MESH:D010995', (123, 130))
106173	27737701	These results indicate that inhaled MWNT-7 is deposited deep into the respiratory tract and can be translocated into the pleural cavity, and that exposure to MWNT-7 induces pathological changes in the lung and chest cavity.	('MWNT-7', 'Var', (158, 164))	('rat', 'Species', '10116', (75, 78))	('induces', 'Reg', (165, 172))	('MWNT-7', 'Chemical', '-', (36, 42))	('pathological changes', 'CPA', (173, 193))	('pleural', 'Disease', 'MESH:D010995', (121, 128))	('pleural', 'Disease', (121, 128))	('MWNT-7', 'Chemical', '-', (158, 164))
106178	27737701	MWNT-7 aerosols were freshly generated during each exposure period, and the MWNT-7 concentrations in the inhalation chambers were at the target doses throughout the 104-week experimental period: 0.020 +- 0.001 (mean +- SD) mg/m3 for the 0.02 mg/m3 group, 0.204 +- 0.014 mg/m3 for the 0.2 mg/m3 group, and 2.018 +- 0.069 mg/m3 for the 2 mg/m3 group.	('MWNT-7', 'Chemical', '-', (76, 82))	('0.204 +- 0.014 mg/m3', 'Var', (255, 275))	('0.020 +- 0.001', 'Var', (195, 209))	('rat', 'Species', '10116', (33, 36))	('MWNT-7', 'Chemical', '-', (0, 6))	('rat', 'Species', '10116', (90, 93))
106190	27737701	Absolute and relative lung weights were significantly elevated in male rats exposed to 0.2 and 2 mg/m3 MWNT-7, and they were significantly increased in all exposed female groups (Table 2).	('0.2', 'Var', (87, 90))	('elevated', 'PosReg', (54, 62))	('increased', 'PosReg', (139, 148))	('MWNT-7', 'Gene', (103, 109))	('rats', 'Species', '10116', (71, 75))	('MWNT-7', 'Chemical', '-', (103, 109))
106208	27737701	In female rats exposed to 2 mg/m3 MWNT-7, there was a non-significant increase in the incidences of simple mesothelial hyperplasia and focal fibrosis of the parietal pleura.	('mesothelial hyperplasia', 'Disease', (107, 130))	('increase', 'PosReg', (70, 78))	('rats', 'Species', '10116', (10, 14))	('mesothelial hyperplasia', 'Disease', 'MESH:D018301', (107, 130))	('fibrosis of the parietal pleura', 'Disease', 'MESH:D005355', (141, 172))	('MWNT-7', 'Chemical', '-', (34, 40))	('fibrosis of the parietal pleura', 'Disease', (141, 172))	('MWNT-7', 'Var', (34, 40))
106212	27737701	Incidences of eosinophilic globules, which appeared in the cytoplasm of the respiratory and olfactory epithelia in the nasal cavity, were increased in male and female rats exposed to 0.2 and 2 mg/m3 MWNT-7.	('increased', 'PosReg', (138, 147))	('eosin', 'Chemical', 'MESH:D004801', (14, 19))	('0.2', 'Var', (183, 186))	('olfactory epithelia', 'Disease', 'MESH:D012640', (92, 111))	('rat', 'Species', '10116', (81, 84))	('olfactory epithelia', 'Disease', (92, 111))	('rat', 'Species', '10116', (167, 170))	('MWNT-7', 'Chemical', '-', (199, 205))	('eosinophilic', 'MPA', (14, 26))	('cytoplasm', 'cellular_component', 'GO:0005737', ('59', '68'))	('rats', 'Species', '10116', (167, 171))
106230	27737701	The number of fibers that induced lung carcinoma was calculated to be 1.38 x 109 MWNT-7 fibers in 0.2 mg/m3 MWNT-7 exposed males and 10.4 x 109 MWNT-7 fibers in 2 mg/m3 MWNT-7 exposed females.	('induced', 'Reg', (26, 33))	('MWNT-7', 'Chemical', '-', (169, 175))	('MWNT-7', 'Chemical', '-', (108, 114))	('fibers', 'Var', (14, 20))	('MWNT-7', 'Chemical', '-', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('lung carcinoma', 'Disease', (34, 48))	('lung carcinoma', 'Disease', 'MESH:D008175', (34, 48))	('MWNT-7', 'Chemical', '-', (144, 150))
106276	27737701	Our results suggest that not only the length but also the quantity of MWNT-7 fibers is important in the pulmonary toxicity of MWNT-7.	('MWNT-7', 'Var', (126, 132))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (104, 122))	('MWNT-7', 'Chemical', '-', (70, 76))	('pulmonary toxicity', 'Disease', (104, 122))	('MWNT-7', 'Chemical', '-', (126, 132))
106288	27737701	These two results suggest that not only amounts of MWNT-7 but also exposure duration have important roles in lung carcinogenesis mediated by MWNT-7.	('MWNT-7', 'Chemical', '-', (141, 147))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (109, 128))	('MWNT-7', 'Chemical', '-', (51, 57))	('MWNT-7', 'Var', (141, 147))	('rat', 'Species', '10116', (78, 81))	('roles', 'Reg', (100, 105))	('lung carcinogenesis', 'Disease', (109, 128))
106314	27737701	In the present study, induction of lung carcinoma in male rats was observed at 0.2 mg/m3 MWNT-7 and the BMCL10 of adverse effect in exposed male rats was calculated to be 0.01 mg/m3.	('lung carcinoma', 'Disease', (35, 49))	('rats', 'Species', '10116', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('MWNT-7', 'Chemical', '-', (89, 95))	('rats', 'Species', '10116', (145, 149))	('lung carcinoma', 'Disease', 'MESH:D008175', (35, 49))	('MWNT-7', 'Var', (89, 95))
106315	27737701	MWNT-7 is classified as a genotoxicic substance but not directively DNA-reactive, and it has been accepted that there are thresholds for carcinogens that induce mutations via secondary genotoxic mechanisms.	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('carcinogens', 'Disease', 'MESH:D063646', (137, 148))	('mutations', 'Var', (161, 170))	('carcinogens', 'Disease', (137, 148))	('MWNT-7', 'Chemical', '-', (0, 6))
106318	27737701	The chronic toxicity of MWNT-7, the low-observed-adverse-effect level (LOAEL), was 0.02 mg/m3 since absolute and relative lung weights were significantly elevated in female rats exposed to 0.02 mg/m3 MWNT-7.	('rats', 'Species', '10116', (173, 177))	('MWNT-7', 'Chemical', '-', (200, 206))	('0.02 mg/m3', 'Var', (189, 199))	('elevated', 'PosReg', (154, 162))	('toxicity', 'Disease', 'MESH:D064420', (12, 20))	('toxicity', 'Disease', (12, 20))	('MWNT-7', 'Chemical', '-', (24, 30))
106467	27222787	Recent studies have identified germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) which can predispose to MPM.	('BAP1', 'Gene', (99, 103))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('predispose', 'Reg', (115, 125))	('MPM', 'Disease', (129, 132))	('BRCA1 associated protein-1', 'Gene', '8314', (71, 97))	('BAP1', 'Gene', '8314', (99, 103))	('germline mutations', 'Var', (31, 49))	('BRCA1 associated protein-1', 'Gene', (71, 97))
106468	27222787	Mesothelioma occurring in germline BAP1 mutation carriers have been reported to be less aggressive clinically and associated with prolonged survival compared with sporadic MPM.	('mutation', 'Var', (40, 48))	('germline', 'Var', (26, 34))	('BAP1', 'Gene', '8314', (35, 39))	('BAP1', 'Gene', (35, 39))	('less', 'NegReg', (83, 87))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
106469	27222787	In addition, germline BAP1 mutations confer increased susceptibility for the development of several other tumors including uveal melanoma, cutaneous melanoma, renal cell cancers and possibly other cancers.	('mutations', 'Var', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('susceptibility', 'Reg', (54, 68))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('tumors', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('uveal melanoma', 'Disease', (123, 137))	('renal cell cancers', 'Disease', (159, 177))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('BAP1', 'Gene', '8314', (22, 26))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancers', 'Disease', (197, 204))	('cutaneous melanoma', 'Disease', (139, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BAP1', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('men', 'Species', '9606', (84, 87))	('renal cell cancers', 'Disease', 'MESH:C538614', (159, 177))
106470	27222787	Because our patient does not have a report of familiar clustering of cancer, germline BAP1 mutations alone cannot explain the development of MPM.	('BAP1', 'Gene', '8314', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('men', 'Species', '9606', (133, 136))	('MPM', 'Disease', (141, 144))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('patient', 'Species', '9606', (12, 19))	('cancer', 'Disease', (69, 75))
106518	24518925	While erionite is known to cause mesothelioma and other diseases associated with asbestos, there is little known about its effects on the immune system.	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('cause', 'Reg', (27, 32))	('erionite', 'Chemical', 'MESH:C083174', (6, 14))	('erionite', 'Var', (6, 14))	('asbestos', 'Chemical', 'MESH:D001194', (81, 89))	('mesothelioma', 'Disease', (33, 45))
106531	24518925	They are both mixtures of long and straight mineral fibers composed of long chain silicon oxides (averaging Si14O36 and Si8O22, respectively) with various cations depending on the specific type of fiber.	('Si8O22', 'Chemical', '-', (120, 126))	('silicon oxides', 'Chemical', 'MESH:D012822', (82, 96))	('Si14O36', 'Var', (108, 115))	('Si8O22', 'Var', (120, 126))	('Si14O36', 'Chemical', '-', (108, 115))
106553	24518925	Autoantibodies against ubiquitous antigens are hallmarks of systemic autoimmune diseases.	('ubiquitous antigens', 'Protein', (23, 42))	('autoimmune disease', 'Phenotype', 'HP:0002960', (69, 87))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (69, 88))	('systemic autoimmune diseases', 'Disease', 'MESH:D020274', (60, 88))	('Autoantibodies', 'Var', (0, 14))	('systemic autoimmune diseases', 'Disease', (60, 88))
106706	24518925	Erionite is a fibrous mineral that is a current public health concern in the Northern Rocky Mountain states Erionite exposure induces antinuclear autoantibodies in mice exposed intratracheally Erionite induces a clear Th17 cytokine response in vitro (splenocyte culture) and in vivo (serum) These responses were distinct from responses caused by amphibole or chrysotile asbestos These data in mice raise the possibility that exposed humans may be at risk for autoimmune responses.	('Erionite', 'Chemical', 'MESH:C083174', (193, 201))	('Th17 cytokine response', 'MPA', (218, 240))	('chrysotile asbestos', 'Disease', (359, 378))	('mice', 'Species', '10090', (164, 168))	('chrysotile asbestos', 'Disease', 'MESH:D001195', (359, 378))	('Erionite', 'Chemical', 'MESH:C083174', (0, 8))	('mice', 'Species', '10090', (393, 397))	('humans', 'Species', '9606', (433, 439))	('antinuclear', 'MPA', (134, 145))	('Erionite', 'Var', (108, 116))	('Erionite', 'Chemical', 'MESH:C083174', (108, 116))	('antinuclear autoantibodies', 'Phenotype', 'HP:0003493', (134, 160))
106714	23936803	Biodistribution studies revealed that the accumulation of 18F-FPAMT in the heart, lungs, thyroid, spleen, and brain was significantly lower than that of 18F-FDG.	('18F-FDG', 'Chemical', '-', (153, 160))	('lower', 'NegReg', (134, 139))	('18F-FPAMT', 'Var', (58, 67))	('accumulation', 'MPA', (42, 54))	('18F-FPAMT', 'Chemical', '-', (58, 67))
106728	23936803	A number of 18F-labeled amino acid analogs in PET have been investigated, including L-2-18F-fluorotyrosine (18F-TYR), O-2-18F-fluoroethyl-L-tyrosine (18F-FET), and L-3-18F-fluoro-alpha-methyl tyrosine (18F-FAMT).	('18F', 'Chemical', 'MESH:C000615276', (108, 111))	('O-2-18F-fluoroethyl-L-tyrosine', 'Var', (118, 148))	('18F', 'Chemical', 'MESH:C000615276', (12, 15))	('18F', 'Chemical', 'MESH:C000615276', (88, 91))	('L-3-18F-fluoro-alpha-methyl tyrosine', 'Chemical', '-', (164, 200))	('L-2-18F-fluorotyrosine', 'Var', (84, 106))	('L-3-18F-fluoro-alpha-methyl', 'Var', (164, 191))	('18F', 'Chemical', 'MESH:C000615276', (150, 153))	('18F', 'Chemical', 'MESH:C000615276', (168, 171))	('18F', 'Chemical', 'MESH:C000615276', (202, 205))	('18F', 'Chemical', 'MESH:C000615276', (122, 125))	('O-2-18F-fluoroethyl-L-tyrosine', 'Chemical', 'MESH:C117289', (118, 148))	('L-2-18F-fluorotyrosine', 'Chemical', '-', (84, 106))
106729	23936803	found that, unlike 18F-TYR, 18F-FET, and other 18F-labeled amino acids, 18F-FAMT is transported into cells through L-type amino transporter 1, which contributes to its highly tumor-specific accumulation.	('18F-FAMT', 'Var', (72, 80))	('18F', 'Chemical', 'MESH:C000615276', (28, 31))	('tumor', 'Disease', (175, 180))	('18F', 'Chemical', 'MESH:C000615276', (72, 75))	('18F', 'Chemical', 'MESH:C000615276', (19, 22))	('18F', 'Chemical', 'MESH:C000615276', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
106807	23936803	The distributions of 18F-FPAMT and 18F-FDG in various tissues in mesothelioma-bearing rats are shown in Tables 1 and 2, respectively.	('mesothelioma', 'Disease', (65, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('rats', 'Species', '10116', (86, 90))	('18F-FPAMT', 'Chemical', '-', (21, 30))	('18F-FDG', 'Chemical', '-', (35, 42))	('18F-FDG', 'Var', (35, 42))
106813	23936803	Scintigraphic images of mesothelioma-bearing rats administrated 18F-FPAMT or 18F-FDG showed that tumors could be clearly detected, and bone uptake was low (Figure 4).	('18F-FDG', 'Chemical', '-', (77, 84))	('rats', 'Species', '10116', (45, 49))	('mesothelioma', 'Disease', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('low', 'NegReg', (151, 154))	('18F-FDG', 'Var', (77, 84))	('tumors', 'Disease', (97, 103))	('18F-FPAMT', 'Chemical', '-', (64, 73))	('rat', 'Species', '10116', (58, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (24, 36))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('18F-FPAMT', 'Var', (64, 73))	('bone uptake', 'CPA', (135, 146))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('uptake', 'biological_process', 'GO:0098657', ('140', '146'))	('uptake', 'biological_process', 'GO:0098739', ('140', '146'))	('rat', 'Species', '10116', (45, 48))
106841	23936803	For the in vitro studies, although the result showed that 18F-FPAMT had lower cellular uptake than that of 18F-FDG, the uptake mechanism of these two compounds is different.	('cellular uptake', 'CPA', (78, 93))	('18F-FDG', 'Chemical', '-', (107, 114))	('18F-FPAMT', 'Var', (58, 67))	('uptake', 'biological_process', 'GO:0098657', ('87', '93'))	('uptake', 'biological_process', 'GO:0098739', ('87', '93'))	('lower', 'NegReg', (72, 77))	('uptake', 'biological_process', 'GO:0098739', ('120', '126'))	('18F-FPAMT', 'Chemical', '-', (58, 67))	('uptake', 'biological_process', 'GO:0098657', ('120', '126'))
106845	23936803	Compared with 18F-FDG, the accumulation of 18F-FPAMT was significantly lower in heart, lungs, thyroid, spleen, and brain.	('accumulation', 'MPA', (27, 39))	('18F-FPAMT', 'Chemical', '-', (43, 52))	('18F-FPAMT', 'Var', (43, 52))	('18F-FDG', 'Chemical', '-', (14, 21))	('lower', 'NegReg', (71, 76))
107026	32195318	In particular, the first randomized phase III trial against mesothelioma using anti-CTLA-4 antibody failed to meet its primary end point of improved overall survival.	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('anti-CTLA-4', 'Var', (79, 90))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('anti-CTLA-4', 'Gene', (79, 90))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('mesothelioma', 'Disease', (60, 72))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))
107038	32195318	Previous studies have demonstrated that high EMT level is closely related to increased mesothelioma metastasis and poor prognosis.	('high', 'Var', (40, 44))	('increased mesothelioma metastasis', 'Disease', (77, 110))	('high EMT', 'Phenotype', 'HP:0008151', (40, 48))	('EMT', 'biological_process', 'GO:0001837', ('45', '48'))	('increased mesothelioma metastasis', 'Disease', 'MESH:D009362', (77, 110))
107047	32195318	Using this vaccination strategy, we subsequently found that antigen-specific CD8+ CTLs is capable of eliminating established mesothelioma expressing a xenoantigen.	('mesothelioma', 'Disease', (125, 137))	('CD8+', 'Var', (77, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (125, 137))	('eliminating', 'NegReg', (101, 112))
107062	32195318	Although TWIST1 overexpression or silencing did not alter the short-term proliferation of AB1 cells in vitro (Figure S1B), colony-formation efficiency of AB1 cells closely correlated with TWIST1 expression (Figure 1F).	('TWIST1', 'Gene', (188, 194))	('expression', 'MPA', (195, 205))	('colony-formation efficiency', 'CPA', (123, 150))	('silencing', 'Var', (34, 43))	('correlated', 'Reg', (172, 182))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('expression', 'Species', '29278', (195, 205))	('expression', 'Species', '29278', (20, 30))
107069	32195318	Using this model, we found that, compared to wild-type (WT) cells, TWIST1 overexpression enhanced metastatic activity of AB1 cells, while KO significantly suppressed their ability to metastasize to the lungs and prolonged tumor-free survival of animals.	('enhanced', 'PosReg', (89, 97))	('prolonged', 'PosReg', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('suppressed', 'NegReg', (155, 165))	('TWIST1', 'Gene', (67, 73))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('metastatic activity', 'CPA', (98, 117))	('expression', 'Species', '29278', (78, 88))	('overexpression', 'Var', (74, 88))
107077	32195318	We found that sPD1-TWIST1 vaccination significantly elevated TWIST1-specific T cell responses compared to sTWIST1 vaccination (Figure 2E).	('TWIST1-specific', 'Gene', (61, 76))	('sPD1', 'Gene', '3239', (14, 18))	('vaccination', 'Var', (26, 37))	('sPD1', 'Gene', (14, 18))	('elevated', 'PosReg', (52, 60))
107130	32195318	Consistent with IFN-gamma ELISpot responses described above, CD3+ T cells from mice receiving combined sPD1-TWIST1 and alpha-CTLA-4 showed enhanced in vitro cytotoxic activity in comparison to either the sTWIST1 combined therapy (Figure 6C) or monotherapies (Figure S6A).	('vitro cytotoxic activity', 'CPA', (151, 175))	('CD3', 'Gene', (61, 64))	('IFN-gamma', 'Gene', '15978', (16, 25))	('alpha-CTLA-4', 'Var', (119, 131))	('mice', 'Species', '10090', (79, 83))	('CD3', 'Gene', '12501', (61, 64))	('IFN-gamma', 'Gene', (16, 25))	('sPD1', 'Gene', '3239', (103, 107))	('enhanced', 'PosReg', (139, 147))	('sPD1', 'Gene', (103, 107))
107131	32195318	More importantly, the killing of target cells was performed by CD8+ T cells, but not CD4+ T cells (Figure 6C).	('CD8+ T cells', 'Var', (63, 75))	('CD4', 'Gene', (85, 88))	('CD4', 'Gene', '12504', (85, 88))
107132	32195318	In addition, adoptive transfer of these cytotoxic CD8+ T cells resulted in retarded tumor growth and prolonged survival in SCID mice bearing AB1-Luc tumors (Figure 6D), demonstrating the critical role of the combined therapy in inducing efficacious antimesothelioma CTLs.	('retarded tumor', 'Disease', (75, 89))	('AB1-Luc tumors', 'Disease', (141, 155))	('AB1-Luc tumors', 'Disease', 'MESH:D009369', (141, 155))	('mesothelioma', 'Disease', 'MESH:D008654', (253, 265))	('SCID', 'Disease', 'MESH:D053632', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SCID', 'Disease', (123, 127))	('CD8+ T', 'Var', (50, 56))	('mice', 'Species', '10090', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('retarded tumor', 'Disease', 'MESH:D009369', (75, 89))	('prolonged', 'PosReg', (101, 110))	('survival', 'CPA', (111, 119))	('mesothelioma', 'Disease', (253, 265))
107151	32195318	We found that silencing TWIST1 nearly abolished the metastatic ability of AB1 mesothelioma, while its overexpression did not further enhance metastasis significantly, implying that maintenance of extremely high TWIST1 expression may not be necessary for mesothelioma when invasion and intravasation are accomplished.	('silencing', 'Var', (14, 23))	('abolished', 'NegReg', (38, 47))	('TWIST1', 'Gene', (24, 30))	('expression', 'Species', '29278', (106, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('mesothelioma', 'Disease', (254, 266))	('mesothelioma', 'Disease', 'MESH:D008654', (254, 266))	('AB1', 'Gene', (74, 77))	('expression', 'Species', '29278', (218, 228))	('metastatic ability', 'CPA', (52, 70))	('mesothelioma', 'Disease', (78, 90))
107154	32195318	Overall, inhibiting TWIST1 arrests mesothelioma growth and metastasis.	('TWIST1', 'Gene', (20, 26))	('inhibiting', 'Var', (9, 19))	('arrests mesothelioma growth', 'Disease', 'MESH:D006323', (27, 54))	('arrests mesothelioma growth', 'Disease', (27, 54))
107165	32195318	In addition, sPD1-p24 vaccination as a monotherapy elicited potent effector CD8+ T cells to prevent and cure malignant mesothelioma expressing the p24 xenoantigen.	('sPD1', 'Gene', '3239', (13, 17))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (109, 131))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (109, 131))	('sPD1', 'Gene', (13, 17))	('malignant mesothelioma', 'Disease', (109, 131))	('p24', 'Var', (147, 150))
107180	32195318	Their combined immunotherapy, however, induces effective and durable CD8+ CTLs for the clearance of mesothelioma.	('CD8+', 'Var', (69, 73))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))
107183	32195318	Nevertheless, activation of CD8+ CTLs is critical to the success of the combined immunotherapy observed in both AB1 mesothelioma and 4T1 breast cancer models, although the detailed mechanisms by which they mediate antitumor activity have yet to be elucidated.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('mesothelioma', 'Disease', (116, 128))	('CD8+', 'Var', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
107188	32195318	Previously, the TWIST1 epitope LYQVLQSDEL was identified to specifically activate murine CTLs against the 4T1 breast cancer, which was published as an abstract form (B. Wang et al., 2006, Am.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('LYQVLQSDEL', 'Var', (31, 41))	('murine', 'Species', '10090', (82, 88))	('activate', 'PosReg', (73, 81))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
87066	32195318	The following antibodies were used for western blotting: anti-TWIST1 (clone Twist2C1a, Abcam), anti-beta-actin (clone AC-15, Abcam), and anti-GAPDH (clone EPR16891, Abcam).	('anti-beta-actin', 'Var', (95, 110))	('GAPDH', 'Gene', (142, 147))	('GAPDH', 'Gene', '14433', (142, 147))
107208	32195318	The following antibodies were purchased from eBioscience and used for flow cytometry: anti-CD11b (clone M1/70), anti-Ly6C (clone HK1.4), anti-Ly6G (clone 1A8-Ly6g), anti-CD3 (clone 17A2), anti-CD4 (clone GK1.5), anti-CD8 (clone 53-6.7), and anti-PD1 (clone J43).	('HK1', 'molecular_function', 'GO:0004673', ('129', '132'))	('CD3', 'Gene', '12501', (170, 173))	('M1/70', 'Gene', (104, 109))	('Ly6g', 'Gene', '546644', (158, 162))	('Ly6C', 'Gene', (117, 121))	('Ly6C', 'Gene', '17067', (117, 121))	('CD4', 'Gene', (193, 196))	('Ly6G', 'Gene', '546644', (142, 146))	('M1/70', 'Gene', '22238', (104, 109))	('Ly6g', 'Gene', (158, 162))	('anti-PD1', 'Var', (241, 249))	('CD3', 'Gene', (170, 173))	('CD4', 'Gene', '12504', (193, 196))	('CD11b', 'Gene', (91, 96))	('CD11b', 'Gene', '16409', (91, 96))	('Ly6G', 'Gene', (142, 146))
107239	29507420	How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development.	('YAP', 'Gene', '22601', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('RNA editing', 'biological_process', 'GO:0009451', ('113', '124'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('YAP', 'Gene', (47, 50))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('asbestos', 'Chemical', 'MESH:D001194', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('asbestos', 'Chemical', 'MESH:D001194', (4, 12))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (252, 257))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (138, 147))
107252	29507420	Nf2+/- mice on a C57Bl/6J genetic background were used for several reasons including the observation that tumor that develop in Nf2+/- mice exposed to asbestos show common genomic alterations with human mesothelioma and loss of NF2 function has a driver role in mesothelioma development, and C57Bl/6J mice being widely used in functional studies.	('mesothelioma', 'Disease', (203, 215))	('rat', 'Species', '10116', (184, 187))	('mice', 'Species', '10090', (7, 11))	('mesothelioma', 'Disease', 'MESH:D008654', (203, 215))	('NF2', 'Gene', '4771', (228, 231))	('tumor', 'Disease', (106, 111))	('loss', 'Var', (220, 224))	('alterations', 'Reg', (180, 191))	('NF2', 'Gene', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Nf2', 'Gene', (128, 131))	('mesothelioma', 'Disease', (262, 274))	('Nf2', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mesothelioma', 'Disease', 'MESH:D008654', (262, 274))	('human', 'Species', '9606', (197, 202))	('asbestos', 'Chemical', 'MESH:D001194', (151, 159))	('Nf2', 'Gene', '18016', (128, 131))	('mice', 'Species', '10090', (135, 139))	('Nf2', 'Gene', '18016', (0, 3))	('mice', 'Species', '10090', (301, 305))
107258	29507420	During embryonic development, a mesothelial precursor population has been identified as Msln+ CD105low, CD90high, CD44low, and CD34high.	('CD90high', 'Var', (104, 112))	('CD44', 'Gene', '12505', (114, 118))	('CD44', 'Gene', (114, 118))	('CD34', 'Gene', (127, 131))	('Msln', 'Gene', (88, 92))	('CD34', 'Gene', '12490', (127, 131))	('Msln', 'Gene', '56047', (88, 92))
107275	29507420	After tumorigenesis, the number of mutations was even further increased.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('mutations', 'Var', (35, 44))
107276	29507420	Figure 3d shows that there is one crocidolite non-tumor sample with a very high number of mutations.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (90, 99))	('crocidolite non-tumor', 'Disease', 'MESH:D009369', (34, 55))	('crocidolite non-tumor', 'Disease', (34, 55))
107281	29507420	3f shows that the fraction of A to G alterations that overlaps with known A to I sites also increases (p = 0.0012).	('increases', 'PosReg', (92, 101))	('rat', 'Species', '10116', (41, 44))	('alterations', 'Var', (37, 48))
107285	29507420	Analysis of TCGA mesothelioma data revealed that high expression of ADARB1 is associated with worst overall survival (Supplementary Figure 2) supporting the idea that RNA editing is relevant in mesothelioma as it is in other cancers.	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('mesothelioma', 'Disease', (17, 29))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancers', 'Disease', (225, 232))	('worst', 'NegReg', (94, 99))	('RNA editing', 'biological_process', 'GO:0009451', ('167', '178'))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))	('high expression', 'Var', (49, 64))	('ADARB1', 'Gene', (68, 74))	('mesothelioma', 'Disease', (194, 206))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('overall survival', 'MPA', (100, 116))	('RNA', 'cellular_component', 'GO:0005562', ('167', '170'))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
107287	29507420	Fisher's exact test indicated that AZIN1 editing is significantly (p = 0.010) enriched in samples from asbestos-exposed animals (Supplementary Figure 3A).	('AZIN1', 'Gene', (35, 40))	('enriched', 'Reg', (78, 86))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('AZIN1', 'Gene', '54375', (35, 40))	('editing', 'Var', (41, 48))
107291	29507420	We then used a recently developed sensitive RNA editing site-specific quantitative RT_PCR to document that silencing ADAR and ADARB1 (Supplementary Figure 3B) results in decreased AZIN1 RNA editing (Supplementary Figure 3C).	('silencing', 'Var', (107, 116))	('AZIN1', 'Gene', (180, 185))	('AZIN1', 'Gene', '54375', (180, 185))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('RNA', 'cellular_component', 'GO:0005562', ('186', '189'))	('ADAR', 'Gene', (117, 121))	('ADARB1', 'Gene', (126, 132))	('decreased', 'NegReg', (170, 179))	('RNA editing', 'biological_process', 'GO:0009451', ('186', '197'))	('RNA editing', 'biological_process', 'GO:0009451', ('44', '55'))
107297	29507420	We observed that loss of one allele in Bap1 gene was accompanied by decreased protein levels, while loss of the second Nf2 allele abolished Nf2 protein expression (Supplementary Figure 4A and B).	('loss', 'Var', (100, 104))	('decreased', 'NegReg', (68, 77))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('Nf2', 'Gene', (119, 122))	('Nf2', 'Gene', (140, 143))	('Nf2', 'Gene', '18016', (119, 122))	('protein levels', 'MPA', (78, 92))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('Nf2', 'Gene', '18016', (140, 143))	('Bap1', 'Gene', '104416', (39, 43))	('loss', 'NegReg', (17, 21))	('expression', 'MPA', (152, 162))	('abolished', 'NegReg', (130, 139))	('Bap1', 'Gene', (39, 43))
107329	29507420	Decreased expression of ADARB1 has been observed upon YAP silencing in mesothelioma cells, which resulted in decreased cell growth providing a possible mechanism behind the TCGA data associating high ADARB1 expression with worst overall survival.	('decreased', 'NegReg', (109, 118))	('ADARB1', 'Gene', (200, 206))	('mesothelioma', 'Disease', (71, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('Decreased', 'NegReg', (0, 9))	('YAP', 'Var', (54, 57))	('expression', 'MPA', (10, 20))	('cell growth', 'CPA', (119, 130))	('ADARB1', 'Gene', (24, 30))	('cell growth', 'biological_process', 'GO:0016049', ('119', '130'))	('expression', 'MPA', (207, 217))
107354	29507420	Indeed, in another mesothelioma model induced by asbestos in Nf2+/-; Cdkn2a+/- mice in a FVB genetic background, blockage of IL-1beta using IL1beta receptor antagonist anakinra delayed mesothelioma development, indicating a promoting role of IL1beta.	('IL1beta', 'Gene', '16176', (140, 147))	('Nf2', 'Gene', (61, 64))	('IL1', 'molecular_function', 'GO:0005149', ('140', '143'))	('IL-1beta', 'Gene', '16176', (125, 133))	('delayed', 'NegReg', (177, 184))	('Cdkn2a', 'Gene', '12578', (69, 75))	('mesothelioma', 'Disease', (19, 31))	('IL-1beta', 'Gene', (125, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('mesothelioma', 'Disease', (185, 197))	('Nf2', 'Gene', '18016', (61, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('Cdkn2a', 'Gene', (69, 75))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('blockage', 'Var', (113, 121))	('IL1beta', 'Gene', (242, 249))	('IL1', 'molecular_function', 'GO:0005149', ('242', '245'))	('IL1beta', 'Gene', (140, 147))	('mice', 'Species', '10090', (79, 83))	('IL1beta', 'Gene', '16176', (242, 249))	('IL-1', 'molecular_function', 'GO:0005149', ('125', '129'))
107355	29507420	Besides experimental models, tumor-associated macrophages are a major component of the immune cell infiltration of the tumor microenvironment in mesothelioma patients and the presence of "M2"-polarized macrophages is associated with the worst outcome.	('tumor', 'Disease', (119, 124))	('"M2', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('rat', 'Species', '10116', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mesothelioma', 'Disease', (145, 157))	('tumor', 'Disease', (29, 34))	('"M2', 'Gene', '110333', (187, 190))	('presence', 'Var', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))
107358	29507420	In conclusion, our comprehensive analysis of loss of homeostasis in the mesothelial environment in asbestos-exposed mice during tumor development suggest a progressive activation of YAP/TAZ-dependent gene transcription, RNA-editing accumulation of single nucleotide variations and a possible role for immunosuppressive macrophages and/or mesothelial precursor cells in tumor development.	('asbestos', 'Chemical', 'MESH:D001194', (99, 107))	('mice', 'Species', '10090', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('homeostasis', 'biological_process', 'GO:0042592', ('53', '64'))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('RNA', 'cellular_component', 'GO:0005562', ('220', '223'))	('tumor', 'Disease', (369, 374))	('transcription', 'MPA', (205, 218))	('activation', 'PosReg', (168, 178))	('tumor', 'Disease', (128, 133))	('single nucleotide variations', 'Var', (248, 276))	('RNA-editing', 'biological_process', 'GO:0009451', ('220', '231'))	('YAP/TAZ-dependent gene', 'Gene', (182, 204))	('RNA-editing', 'MPA', (220, 231))	('transcription', 'biological_process', 'GO:0006351', ('205', '218'))
107386	29507420	Expression of ADAR and ADARB1 was investigated by western blot analysis performed as previously described using anti-ADAR (HPA003890) and anti-ADARB1 (HPA018277) antibodies (Sigma Life Science) in NCI-H226 (from ATCC) and SPC111 mesothelioma cells (authenticated by STR profiling) grown as previously described.	('anti-ADARB1', 'Var', (138, 149))	('mesothelioma', 'Disease', 'MESH:D008654', (229, 241))	('SPC111', 'CellLine', 'CVCL:D311', (222, 228))	('NCI-H226', 'CellLine', 'CVCL:1544', (197, 205))	('SPC', 'molecular_function', 'GO:0009004', ('222', '225'))	('Lif', 'Gene', '3976', (180, 183))	('mesothelioma', 'Disease', (229, 241))	('Lif', 'Gene', (180, 183))
107390	29507420	Protein levels were evaluated by western blot using anti Nf2 (sc-332) and anti-Bap1 (Sc-28383) antibodies (Santa-Cruz).	('Bap1', 'Gene', '104416', (79, 83))	('Nf2', 'Gene', (57, 60))	('Bap1', 'Gene', (79, 83))	('Nf2', 'Gene', '18016', (57, 60))	('Sc-28383', 'Var', (85, 93))
107405	27167198	The antibodies involved in the immunogenicity response against SS1P mostly react with PE38, the toxin portion of the RIT.	('SS1', 'Gene', (63, 66))	('PE38', 'Var', (86, 90))	('react', 'Reg', (75, 80))	('SS1', 'Gene', '3123', (63, 66))
107407	27167198	Mouse models have shown that elimination of murine B-cell epitopes can significantly reduce the formation of anti-drug antibodies (ADA) against therapeutic foreign proteins and specifically against PE38.	('ADA', 'Chemical', '-', (131, 134))	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('ADA', 'molecular_function', 'GO:0008774', ('131', '134'))	('reduce', 'NegReg', (85, 91))	('murine', 'Species', '10090', (44, 50))	('formation', 'MPA', (96, 105))	('PE38', 'Var', (198, 202))	('Mouse', 'Species', '10090', (0, 5))	('anti-drug antibodies', 'MPA', (109, 129))
107410	27167198	These Fvs were used to identify the human B-cell epitopes in domain III and mutations identified that suppressed these epitopes.	('human', 'Species', '9606', (36, 41))	('mutations', 'Var', (76, 85))	('suppressed', 'NegReg', (102, 112))	('epitopes', 'MPA', (119, 127))
107411	27167198	Finally this information was used to make a new mutant RIT (SS1-LO10-R),which has a deletion of domain II and six mutations in domain III (Figure 1).	('SS1', 'Gene', '3123', (60, 63))	('domain II', 'Gene', (96, 105))	('SS1', 'Gene', (60, 63))	('deletion', 'Var', (84, 92))
107412	27167198	To increase half-life and further decrease immunogenicity, the mouse Fv was replaced with a larger humanized anti-mesothelin Fab, resulting in an immunotoxin (RG7787) with a molecular weight of 72-kDa (Figure 1).	('mouse', 'Species', '10090', (63, 68))	('immunogenicity', 'MPA', (43, 57))	('decrease', 'NegReg', (34, 42))	('human', 'Species', '9606', (99, 104))	('half-life', 'MPA', (12, 21))	('RG7787', 'Var', (159, 165))	('increase', 'PosReg', (3, 11))
107417	27167198	To construct the new de-immunized RIT(LMB-T14) we used the dsFv and toxin present in SS1P, deleted most of domain II and made mutations in domain III as shown Figure 1.	('SS1', 'Gene', '3123', (85, 88))	('SS1', 'Gene', (85, 88))	('LMB-T14', 'Chemical', '-', (38, 45))	('deleted', 'NegReg', (91, 98))	('mutations', 'Var', (126, 135))	('domain II', 'Protein', (107, 116))
107419	27167198	PE38 is made up of two domains; domain II (amino acids 253-364) contains a furin cleavage site necessary for toxin processing, and domain III (amino acids 395-613) contains the ADP ribosylation activity.	('ADP', 'Chemical', 'MESH:D000244', (177, 180))	('amino acids 395-613', 'Var', (143, 162))	('ADP ribosylation activity', 'MPA', (177, 202))	('furin cleavage site', 'MPA', (75, 94))
107420	27167198	Previous work showed that modifying SS1P by deletion of the majority of domain II and retaining the 11 amino acid furin cleavage site followed by a GGS spacer results in a RIT (SS1-LR-GGS) with high cytotoxic activity on many cell lines and decreased nonspecific toxicity in mice.	('toxicity', 'Disease', (263, 271))	('modifying', 'Var', (26, 35))	('mice', 'Species', '10090', (275, 279))	('decreased', 'NegReg', (241, 250))	('deletion', 'Var', (44, 52))	('amino acid furin', 'Chemical', '-', (103, 119))	('cytotoxic activity', 'CPA', (199, 217))	('SS1', 'Gene', '3123', (177, 180))	('SS1', 'Gene', '3123', (36, 39))	('toxicity', 'Disease', 'MESH:D064420', (263, 271))	('SS1', 'Gene', (177, 180))	('SS1', 'Gene', (36, 39))
107421	27167198	SS1-LO10R is derived from SS1-LR-GGS; it has six mutations in amino acids that suppress human B-cell epitopes (Figure 1B).	('SS1', 'Gene', (26, 29))	('SS1', 'Gene', '3123', (0, 3))	('mutations', 'Var', (49, 58))	('SS1', 'Gene', (0, 3))	('human B-cell epitopes', 'MPA', (88, 109))	('human', 'Species', '9606', (88, 93))	('SS1', 'Gene', '3123', (26, 29))	('suppress', 'NegReg', (79, 87))
107423	27167198	LMB-T20 (Figure 1C) contains the same deletion in domain II as SS1-LO10R and six mutations in domain III that suppress T-cell epitopes.	('suppress', 'NegReg', (110, 118))	('LMB-T20', 'Chemical', '-', (0, 7))	('SS1', 'Gene', '3123', (63, 66))	('SS1', 'Gene', (63, 66))	('T-cell epitopes', 'MPA', (119, 134))	('deletion', 'Var', (38, 46))
107425	27167198	To make a cytotoxic protein with mutations in both B- and T-cell epitopes, we started with SS1-LO10R and introduced amino acid mutations that eliminate T-cell epitopes, usually one at a time as shown in Table 1.	('T-cell epitopes', 'MPA', (152, 167))	('SS1', 'Gene', (91, 94))	('mutations', 'Var', (33, 42))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('mutations', 'Var', (127, 136))	('SS1', 'Gene', '3123', (91, 94))
107426	27167198	We previously observed that introduction of point mutation R494A in CD22 targeting RIT induces a 2-4-fold decrease in relative activity.	('relative activity', 'MPA', (118, 135))	('CD22', 'Gene', '933', (68, 72))	('CD22', 'Gene', (68, 72))	('decrease', 'NegReg', (106, 114))	('R494A', 'Mutation', 'p.R494A', (59, 64))	('R494A', 'Var', (59, 64))
107427	27167198	Here, similarly to the anti CD22 RIT, the mutation R494A (V3) resulted in a 4 fold decrease in activity (Table 1).	('R494A', 'Var', (51, 56))	('CD22', 'Gene', (28, 32))	('decrease', 'NegReg', (83, 91))	('CD22', 'Gene', '933', (28, 32))	('activity', 'MPA', (95, 103))	('R494A', 'Mutation', 'p.R494A', (51, 56))
107428	27167198	The activity of the intermediate construct was improved by the addition of F443A, which by itself induces a positive effect on the activity (V4), and when combined, it moderated the decrease in activity to 2.5-fold.LMB-T14 (Figure 1D) is the most de-immunized RIT.	('F443A', 'Var', (75, 80))	('activity', 'MPA', (4, 12))	('LMB-T14', 'Chemical', '-', (215, 222))	('F443A', 'Mutation', 'p.F443A', (75, 80))
107429	27167198	Despite all the changes, it maintained very high cytotoxic activity, although a little less than LMB-T20 and LO10R.	('changes', 'Var', (16, 23))	('cytotoxic activity', 'MPA', (49, 67))	('LMB-T20', 'Chemical', '-', (97, 104))
107432	27167198	We found that LMB-T14 and its parent molecules (LMB-T20 and LO10R) were all more cytotoxic than SS1P with IC50s that were less than 100 pM on NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29, (Figure 2A-2D).	('LMB-T14', 'Var', (14, 21))	('SS1', 'Gene', '3123', (96, 99))	('50s', 'Species', '1214577', (108, 111))	('LO10R', 'Var', (60, 65))	('LMB-T20', 'Chemical', '-', (48, 55))	('SS1', 'Gene', (96, 99))	('LMB-T20', 'Var', (48, 55))	('LMB-T14', 'Chemical', '-', (14, 21))	('cytotoxic', 'CPA', (81, 90))
107433	27167198	Figure 2E, which contains averaged data from four assays, shows that LMB-T14 had similar activity to LMB-T20 and LO10R and significantly better cytotoxic activity than SS1P (Figure 2E) (p < 0.05 in one way ANOVA in Dunn's multiple comparison test).	('LMB-T14', 'Var', (69, 76))	('better', 'PosReg', (137, 143))	('SS1', 'Gene', '3123', (168, 171))	('cytotoxic activity', 'CPA', (144, 162))	('SS1', 'Gene', (168, 171))	('LMB-T20', 'Chemical', '-', (101, 108))	('LMB-T14', 'Chemical', '-', (69, 76))
107436	27167198	In stomach cell lines, MKN45 and MKN74, LMB-T14 had a small change in activity compared to LMB-T20 with 1.5-1.8-fold loss in activity.	('LMB-T14', 'Chemical', '-', (40, 47))	('activity', 'MPA', (70, 78))	('activity', 'MPA', (125, 133))	('LMB-T14', 'Var', (40, 47))	('LMB-T20', 'Chemical', '-', (91, 98))
107443	27167198	LO10R also had excellent stability, whereas LMB-T20 was less stable and lost 2-fold activity in the time interval between 6 and 24 hr.	('2-fold activity', 'MPA', (77, 92))	('stability', 'MPA', (25, 34))	('LO10R', 'Var', (0, 5))	('lost', 'NegReg', (72, 76))	('LMB-T20', 'Chemical', '-', (44, 51))
107444	27167198	To simulate the stability of LMB-T14 in the circulation of humans, we diluted it and the other variants in 100% human AB serum to 15mug/ml, incubated at 37 C for various times and measured cytotoxic activity.	('LMB-T14', 'Chemical', '-', (29, 36))	('human', 'Species', '9606', (59, 64))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('measured', 'Reg', (180, 188))	('variants', 'Var', (95, 103))	('humans', 'Species', '9606', (59, 65))	('human', 'Species', '9606', (112, 117))
107446	27167198	To evaluate the non-specific toxicity of LMB-T14, we treated small groups of Swiss mice with single doses of LMB-T14 and LMB-T20 (Table S1).	('LMB-T20', 'Chemical', '-', (121, 128))	('mice', 'Species', '10090', (83, 87))	('LMB-T14', 'Var', (109, 116))	('LMB-T14', 'Chemical', '-', (41, 48))	('toxicity', 'Disease', 'MESH:D064420', (29, 37))	('toxicity', 'Disease', (29, 37))	('LMB-T14', 'Chemical', '-', (109, 116))
107448	27167198	There was no significant weight loss at a dose of 20 mg/kg, where as a similar dose of LMB-T20 was toxic in 4/4 mice.LMB-T14 was also well tolerated at a dose of 22 mg/kg, which is the highest tolerated dose reported for active immunotoxins in our lab.	('weight loss', 'Disease', 'MESH:D015431', (25, 36))	('weight loss', 'Disease', (25, 36))	('LMB-T20', 'Chemical', '-', (87, 94))	('weight loss', 'Phenotype', 'HP:0001824', (25, 36))	('LMB-T14', 'Chemical', '-', (117, 124))	('mice.LMB-T14', 'Var', (112, 124))	('mice', 'Species', '10090', (112, 116))
107458	27167198	Because LMB-T14 has mutations that are designed to diminish binding to B-cell receptors and to antibodies in human serum, we compared the reactivity of LMB-T14 and SS1-LO10R with SS1P using serum from 19 patients, who had developed neutralizing antibodies after treatment with SS1P.	('SS1', 'Gene', '3123', (277, 280))	('patients', 'Species', '9606', (204, 212))	('binding', 'Interaction', (60, 67))	('diminish', 'NegReg', (51, 59))	('human', 'Species', '9606', (109, 114))	('SS1', 'Gene', '3123', (164, 167))	('SS1', 'Gene', '3123', (179, 182))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('SS1', 'Gene', (277, 280))	('SS1', 'Gene', (164, 167))	('SS1', 'Gene', (179, 182))	('LMB-T14', 'Gene', (8, 15))	('LMB-T14', 'Chemical', '-', (8, 15))	('LMB-T14', 'Chemical', '-', (152, 159))	('mutations', 'Var', (20, 29))	('B-cell', 'Protein', (71, 77))
107459	27167198	Figure 4D shows that LMB-T14 had significantly reduced binding to human anti-sera, and the magnitude of the decrease ranged from very little to more than a 3-log decrease with a mean of 16% (p < 0.001 in Friedman's test and Dunn's multiple comparisons).LO10R also had significantly reduced binding compared to SS1P (p < 0.05 in Friedman's test and Dunn's multiple comparisons) (Figure 4D).	('binding', 'Interaction', (290, 297))	('SS1', 'Gene', (310, 313))	('binding', 'molecular_function', 'GO:0005488', ('290', '297'))	('sera', 'molecular_function', 'GO:0004617', ('77', '81'))	('LMB-T14', 'Chemical', '-', (21, 28))	('reduced', 'NegReg', (282, 289))	('human', 'Species', '9606', (66, 71))	('.LO10R', 'Var', (252, 258))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('SS1', 'Gene', '3123', (310, 313))
107462	27167198	To investigate the magnitude of the decrease in T-cell immunogenicity and to determine whether the four additional mutations (designed to remove B-cell epitopes) induced formation of new T-cell epitopes, we stimulated peripheral blood mononuclear cells (PBMC) from 10 normal donors with SS1P or the variants LMB-T20 and LMB-T14.	('LMB-T20', 'Var', (308, 315))	('mutations', 'Var', (115, 124))	('SS1', 'Gene', (287, 290))	('variants LMB-T20', 'Var', (299, 315))	('LMB-T14', 'Gene', (320, 327))	('LMB-T14', 'Chemical', '-', (320, 327))	('LMB-T20', 'Chemical', '-', (308, 315))	('SS1', 'Gene', '3123', (287, 290))	('formation', 'biological_process', 'GO:0009058', ('170', '179'))
107463	27167198	After 14 days of in vitro expansion, the cells that were stimulated with SS1P were re-stimulated with 111 peptides spanning the sequence of PE38 and the cells that were stimulated with LMB-T14 or LMB-T20 were re-stimulated with 76 peptides spanning the sequence of LMB-T14 or LMB-T20, respectively.	('PE38', 'Var', (140, 144))	('LMB-T20', 'Gene', (276, 283))	('peptides', 'Chemical', 'MESH:D010455', (106, 114))	('LMB-T14', 'Chemical', '-', (185, 192))	('SS1', 'Gene', '3123', (73, 76))	('LMB-T14', 'Chemical', '-', (265, 272))	('peptides', 'Chemical', 'MESH:D010455', (231, 239))	('LMB-T20', 'Chemical', '-', (276, 283))	('SS1', 'Gene', (73, 76))	('LMB-T20', 'Chemical', '-', (196, 203))
107465	27167198	As expected, both de-immunized RITs (LMB-T20 and LMB-T14) had a significant reduction in the number of IL-2 specific spots.	('LMB-T14', 'Var', (49, 56))	('IL-2', 'molecular_function', 'GO:0005134', ('103', '107'))	('reduction', 'NegReg', (76, 85))	('IL-2', 'Gene', '3558', (103, 107))	('LMB-T20', 'Var', (37, 44))	('IL-2', 'Gene', (103, 107))	('LMB-T14', 'Chemical', '-', (49, 56))	('RITs', 'Chemical', '-', (31, 35))	('LMB-T20', 'Chemical', '-', (37, 44))
107466	27167198	The decrease was 61% with LMB-T14 and 81% with LMB-T20 (p < 0.01 in Wilcoxon matched-pairs signed rank test) (Figure 5).	('LMB-T14', 'Chemical', '-', (26, 33))	('LMB-T20', 'Var', (47, 54))	('decrease', 'NegReg', (4, 12))	('LMB-T14', 'Var', (26, 33))	('LMB-T20', 'Chemical', '-', (47, 54))
107468	27167198	Peptides 63-65 from LMB-T14 differ from WT and LMB-T20 by two separate mutations, which are D463A and R467A (labeled with blue stars).	('D463A', 'Var', (92, 97))	('LMB-T14', 'Gene', (20, 27))	('D463A', 'Mutation', 'p.D463A', (92, 97))	('R467A', 'Mutation', 'p.R467A', (102, 107))	('LMB-T14', 'Chemical', '-', (20, 27))	('R467A', 'Var', (102, 107))	('LMB-T20', 'Chemical', '-', (47, 54))
107470	27167198	We describe here the properties of a new RIT, LMB-T14, that has greatly reduced immunogenicity because it contains mutations that suppress both T and B-cell epitopes.	('LMB-T14', 'Chemical', '-', (46, 53))	('mutations', 'Var', (115, 124))	('suppress', 'NegReg', (130, 138))
107471	27167198	The new protein, which contains a large deletion of domain II and 10 amino acid mutations in domain III, is very cytotoxic to mesothelioma cells as well as other cancer cell lines, is well tolerated by mice and produces complete remissions of mesothelin expressing cancers in mice.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('cancer', 'Disease', (162, 168))	('deletion', 'Var', (40, 48))	('mesothelioma cells', 'Disease', (126, 144))	('mice', 'Species', '10090', (202, 206))	('mesothelioma cells', 'Disease', 'MESH:D008654', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('mesothelin expressing', 'MPA', (243, 264))	('domain III', 'Gene', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('domain II', 'Protein', (52, 61))	('mice', 'Species', '10090', (276, 280))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('cancers', 'Disease', (265, 272))
107472	27167198	Furthermore, the six mutations that eliminated B-cell epitopes do not decrease the binding of all tested human anti-sera.	('binding', 'Interaction', (83, 90))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('sera', 'molecular_function', 'GO:0004617', ('116', '120'))	('human', 'Species', '9606', (105, 110))	('decrease', 'NegReg', (70, 78))	('mutations', 'Var', (21, 30))
107474	27167198	They found that B-cell depletion with Rituximab was not sufficient to prevent ADA formation against PE38.	('PE38', 'Var', (100, 104))	('ADA', 'Chemical', '-', (78, 81))	('ADA', 'molecular_function', 'GO:0008774', ('78', '81'))	('Rituximab', 'Chemical', 'MESH:D000069283', (38, 47))	('ADA formation', 'CPA', (78, 91))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))
107477	27167198	In the process of combining six mutations designed to eliminate B-cell epitopes and the six mutations designed to diminish T-cell epitopes, we found that two point mutations (R427A and R505A) diminished both B- and T-cell mediated immunity.	('R427A', 'Mutation', 'p.R427A', (175, 180))	('R427A', 'Var', (175, 180))	('diminish T-cell', 'Phenotype', 'HP:0005403', (114, 129))	('T-cell mediated immunity', 'biological_process', 'GO:0002456', ('215', '239'))	('diminished', 'NegReg', (192, 202))	('R505A', 'Mutation', 'p.R505A', (185, 190))	('R505A', 'Var', (185, 190))
107478	27167198	R505A and R427A have very large ASAs (150A and 142A) indicating that the arginines are located on the surface of the protein.	('R427A', 'Mutation', 'p.R427A', (10, 15))	('ASAs', 'Chemical', 'MESH:D001241', (32, 36))	('R427A', 'Var', (10, 15))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('arginines', 'Chemical', 'MESH:D001120', (73, 82))	('R505A', 'Mutation', 'p.R505A', (0, 5))	('R505A', 'Var', (0, 5))
107479	27167198	Since B-cell epitopes are known to contain bulky hydrophilic amino acid like arginine, it is not surprising that R505A and R427A, which we found to suppress T-cell epitopes, also diminished B-cell epitopes.	('R427A', 'Mutation', 'p.R427A', (123, 128))	('suppress', 'NegReg', (148, 156))	('R427A', 'Var', (123, 128))	('arginine', 'Chemical', 'MESH:D001120', (77, 85))	('diminished', 'NegReg', (179, 189))	('R505A', 'Mutation', 'p.R505A', (113, 118))	('T-cell epitopes', 'MPA', (157, 172))	('R505A', 'Var', (113, 118))	('B-cell epitopes', 'MPA', (190, 205))
107480	27167198	Our finding that the mutations (D463A and R467A) created a new T-cell epitope was unexpected, because alanine substitutions are frequently found to reduce the binding of a peptide to an HLA molecule due to loss of non-polar side chains and not to induce binding.	('D463A', 'Var', (32, 37))	('non-polar side chains', 'MPA', (214, 235))	('peptide', 'Protein', (172, 179))	('D463A', 'Mutation', 'p.D463A', (32, 37))	('binding', 'Interaction', (159, 166))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('R467A', 'Mutation', 'p.R467A', (42, 47))	('binding', 'molecular_function', 'GO:0005488', ('254', '261'))	('reduce', 'NegReg', (148, 154))	('R467A', 'Var', (42, 47))	('alanine substitutions', 'Var', (102, 123))	('alanine', 'Chemical', 'MESH:D000409', (102, 109))	('loss', 'NegReg', (206, 210))
107484	27167198	However reverting D463A and R467A back to WT also restores the B-cell epitope that those mutations eliminated.	('R467A', 'Var', (28, 33))	('B-cell epitope', 'MPA', (63, 77))	('restores', 'PosReg', (50, 58))	('D463A', 'Var', (18, 23))	('R467A', 'Mutation', 'p.R467A', (28, 33))	('D463A', 'Mutation', 'p.D463A', (18, 23))
107485	27167198	This tradeoff is demonstrated in Table 1 that shows that addition of some of the de-immunizing mutations reduced the cytotoxic activity on several cancer cell lines, but not on cells from patients with mesothelioma (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mesothelioma', 'Disease', (202, 214))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('reduced', 'NegReg', (105, 112))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (147, 153))	('cytotoxic activity', 'CPA', (117, 135))
107499	27167198	Briefly, PBMC from naive donors were stimulated with 5mug/ml of SS1P, LMB-T14 or LMB-T20 in separate plates.	('SS1', 'Gene', (64, 67))	('LMB-T20', 'Gene', (81, 88))	('LMB-T14', 'Chemical', '-', (70, 77))	('mug', 'molecular_function', 'GO:0043739', ('54', '57'))	('LMB-T20', 'Chemical', '-', (81, 88))	('SS1', 'Gene', '3123', (64, 67))	('LMB-T14', 'Var', (70, 77))
107519	27148420	Reduced expression of micro ribonucleic acid (miR)-591 in a range of cancer types has suggested it is a potent tumor suppressor, and overexpression has been shown to inhibit tumor cell growth.	('overexpression', 'Var', (133, 147))	('inhibit', 'NegReg', (166, 173))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('expression', 'MPA', (8, 18))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('micro ribonucleic acid (miR)-591', 'Gene', '693176', (22, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('cell growth', 'biological_process', 'GO:0016049', ('180', '191'))	('cancer', 'Disease', (69, 75))
107554	27148420	Total RNA was isolated from miR-591 transfected and control MPM cells.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('miR-591', 'Gene', '693176', (28, 35))	('miR-591', 'Gene', (28, 35))	('transfected', 'Var', (36, 47))
107556	27148420	We transfected three MPM cell lines (H513, H2052, and H2373) with miR-591 mimic and a scramble control and confirmed that miR-591 expression increased in all of the miR-591-transfected cells, compared with the scramble control: there was a 9.3-fold increase for H513, 8.2-fold for H2052 and 7.9-fold for H2373.	('H2052', 'CellLine', 'CVCL:1518', (281, 286))	('miR-591', 'Gene', (66, 73))	('expression', 'MPA', (130, 140))	('increased', 'PosReg', (141, 150))	('H513', 'CellLine', 'CVCL:A570', (262, 266))	('increase', 'PosReg', (249, 257))	('H513', 'Var', (262, 266))	('H2052', 'Var', (281, 286))	('miR-591', 'Gene', '693176', (122, 129))	('miR-591', 'Gene', '693176', (165, 172))	('miR-591', 'Gene', '693176', (66, 73))	('H513', 'CellLine', 'CVCL:A570', (37, 41))	('miR-591', 'Gene', (122, 129))	('H2052', 'CellLine', 'CVCL:1518', (43, 48))	('miR-591', 'Gene', (165, 172))
107559	27148420	We dissolved and quantitated the crystal violet dye and found a significant decrease in the crystal violet dye reading in all three miR-591 transfected MPM cell lines (P < 0.05; Fig 1b).	('crystal violet dye reading', 'MPA', (92, 118))	('crystal violet', 'Chemical', 'MESH:D005840', (33, 47))	('miR-591', 'Gene', '693176', (132, 139))	('crystal violet', 'Chemical', 'MESH:D005840', (92, 106))	('miR-591', 'Gene', (132, 139))	('decrease', 'NegReg', (76, 84))	('transfected', 'Var', (140, 151))
107561	27148420	In all 3 MPM cell lines, the number of invasive cells were significantly suppressed in miR-591 transfected cells, compared with the scrambled control (232 +- 18 vs. 658 +- 58 for H513, P < 0.01; 17 +- 7 vs. 180 +- 20 for H2052, P < 0.01; 165 +- 75 vs. 452 +- 112 for H2373, P < 0.01; Fig 3b).	('miR-591', 'Gene', '693176', (87, 94))	('miR-591', 'Gene', (87, 94))	('H513', 'CellLine', 'CVCL:A570', (179, 183))	('H2052', 'Var', (221, 226))	('H513', 'Var', (179, 183))	('H2052', 'CellLine', 'CVCL:1518', (221, 226))	('transfected', 'Var', (95, 106))	('suppressed', 'NegReg', (73, 83))	('H2373', 'Var', (267, 272))
107564	27148420	Gene expressions of Bax (2.5-fold increase for H513, P < 0.01; 3.6-fold increase for H2052, P < 0.01; 1.8-fold increase for H2373, P < 0.01) and p21 (4-fold increase for H513, P < 0.01; 5.8-fold increase for H2052, P < 0.01; 2.4-fold increase for H2373, P < 0.01) were both significantly increased in miR-591 overexpressed cells (Fig 4).	('H513', 'Var', (47, 51))	('H2052', 'CellLine', 'CVCL:1518', (85, 90))	('Bax', 'Gene', '581', (20, 23))	('miR-591', 'Gene', '693176', (301, 308))	('H2052', 'Var', (208, 213))	('H2373', 'Var', (247, 252))	('Gene expressions', 'MPA', (0, 16))	('p21', 'Gene', (145, 148))	('p21', 'Gene', '644914', (145, 148))	('miR-591', 'Gene', (301, 308))	('H2052', 'CellLine', 'CVCL:1518', (208, 213))	('H513', 'CellLine', 'CVCL:A570', (170, 174))	('Bax', 'Gene', (20, 23))	('H2052', 'Var', (85, 90))	('H2373', 'Var', (124, 129))	('increase', 'PosReg', (34, 42))	('increased', 'PosReg', (288, 297))	('H513', 'CellLine', 'CVCL:A570', (47, 51))
107573	27148420	Mutations and deletions of the TP53 gene are rare in MPM.21 The antiapoptotic potential of MPM has been considered to arise downstream of p53.22 Both p21 and Bax are the downstream targets of p53.	('p21', 'Gene', '644914', (150, 153))	('antiapoptotic potential', 'MPA', (64, 87))	('p53', 'Gene', (138, 141))	('TP53', 'Gene', '7157', (31, 35))	('p53', 'Gene', '7157', (138, 141))	('TP53', 'Gene', (31, 35))	('p53', 'Gene', '7157', (192, 195))	('Bax', 'Gene', (158, 161))	('deletions', 'Var', (14, 23))	('p21', 'Gene', (150, 153))	('p53', 'Gene', (192, 195))	('Bax', 'Gene', '581', (158, 161))
107579	27148420	PF-03446962 is an anti-TGF-beta type I receptor monoclonal antibody.	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('PF-03446962', 'Var', (0, 11))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('TGF-beta', 'Gene', '7040', (23, 31))	('TGF-beta', 'Gene', (23, 31))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))
107605	25205429	Five thousand H2052 pleural mesothelioma cells per well were plated in 96-well plates in RPMI 1640 media (Gibco) supplemented with 10 % dialyzed FBS (Invitrogen).	('H2052', 'Var', (14, 19))	('FBS', 'Disease', (145, 148))	('H2052', 'CellLine', 'CVCL:1518', (14, 19))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (20, 40))	('RPMI 1640 media', 'Chemical', '-', (89, 104))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (20, 40))	('FBS', 'Disease', 'MESH:D005198', (145, 148))	('pleural mesothelioma', 'Disease', (20, 40))
107615	25205429	H2052 cells were also more sensitive to PDX than pemetrexed (Fig.	('H2052', 'CellLine', 'CVCL:1518', (0, 5))	('pemetrexed', 'Chemical', 'MESH:D000068437', (49, 59))	('sensitive', 'MPA', (27, 36))	('H2052', 'Var', (0, 5))	('PDX', 'Chemical', 'MESH:C418863', (40, 43))
107652	21775520	Based on preclinical studies that show marked synergy between SS1P and chemotherapy a clinical trial of SS1P in combination with pemetrexed and cisplatin is currently ongoing in patients with pleural mesothelioma.	('pemetrexed', 'Chemical', 'MESH:D000068437', (129, 139))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (192, 212))	('clinical', 'Species', '191496', (86, 94))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (192, 212))	('patients', 'Species', '9606', (178, 186))	('clinical', 'Species', '191496', (12, 20))	('pleural mesothelioma', 'Disease', (192, 212))	('SS1P', 'Chemical', 'MESH:C474515', (104, 108))	('SS1P', 'Var', (104, 108))	('SS1P', 'Chemical', 'MESH:C474515', (62, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
107662	21775520	In addition, shed mesothelin accumulates in interstitial fluid of solid tumors, forming a barrier which prevents monoclonal antibodies from reaching the tumor cells and therefore reduces the targeting efficiency.	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('reduces', 'NegReg', (179, 186))	('tumor', 'Disease', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('solid tumors', 'Disease', (66, 78))	('monoclonal', 'Var', (113, 123))	('targeting', 'MPA', (191, 200))	('prevents', 'NegReg', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
107664	21775520	In addition we show that by modulating mesothelin shedding, we can significantly improve the cytotoxic effect of SS1P.	('improve', 'PosReg', (81, 88))	('modulating', 'Reg', (28, 38))	('SS1P', 'Var', (113, 117))	('SS1P', 'Chemical', 'MESH:C474515', (113, 117))	('mesothelin', 'Protein', (39, 49))	('cytotoxic effect', 'CPA', (93, 109))
107682	21775520	It is derived from non-cancerous mesothelial cells which expresses SV40 T antigen.	('SV40 T antigen', 'Var', (67, 81))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('67', '81'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
107718	21775520	The presence of two C-terminal peptides of mesothelin ending in Leu or Tyr most likely indicates simultaneous (not step-wise) cleavage of glycosylphosphatidylinositol (GPI)-anchored mesothelin.	('peptides', 'Chemical', 'MESH:D010455', (31, 39))	('Leu', 'Var', (64, 67))	('Tyr', 'Chemical', 'MESH:D014443', (71, 74))	('glycosylphosphatidylinositol', 'Chemical', 'MESH:D017261', (138, 166))	('Leu', 'Chemical', 'MESH:D007930', (64, 67))	('Tyr', 'Var', (71, 74))	('GPI', 'Chemical', 'MESH:D017261', (168, 171))
107727	21775520	But PLC inhibitors (U73122, ET18-OCH3 and neomycin) failed to inhibit mesothelin shedding (Fig.	('PLC', 'cellular_component', 'GO:0042824', ('4', '7'))	('ET18-OCH3', 'Chemical', 'MESH:C026659', (28, 37))	('mesothelin shedding', 'MPA', (70, 89))	('U73122', 'Var', (20, 26))	('neomycin', 'Chemical', 'MESH:D009355', (42, 50))	('U73122', 'Chemical', 'MESH:C060229', (20, 26))
107728	21775520	Instead, sPLA2-IIA inhibitor I and D609 (PLC/phospholipase D [PLD] inhibitor) significantly increased mesothelin shedding by an unknown mechanism.	('D609', 'Chemical', 'MESH:C046498', (35, 39))	('increased', 'PosReg', (92, 101))	('PLC', 'cellular_component', 'GO:0042824', ('41', '44'))	('D609', 'Var', (35, 39))	('mesothelin shedding', 'MPA', (102, 121))
107729	21775520	We then tried several broad-spectrum MMP/ADAM inhibitors (GM6001, batimastat and marimastat), and all of them showed an inhibitory effect on mesothelin shedding.	('batimastat', 'Chemical', 'MESH:C080985', (66, 76))	('inhibitory', 'NegReg', (120, 130))	('mesothelin shedding', 'MPA', (141, 160))	('GM6001', 'Chemical', 'MESH:C078131', (58, 64))	('MMP', 'molecular_function', 'GO:0004235', ('37', '40'))	('GM6001', 'Var', (58, 64))	('MMP', 'Gene', '4321', (37, 40))	('MMP', 'Gene', (37, 40))	('marimastat', 'Chemical', 'MESH:C100342', (81, 91))
107731	21775520	Consistent with our results, GM6001 was previously shown to inhibit mesothelin shedding of primary mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('inhibit', 'NegReg', (60, 67))	('GM6001', 'Chemical', 'MESH:C078131', (29, 35))	('mesothelin shedding', 'MPA', (68, 87))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (91, 111))	('mesothelioma', 'Disease', (99, 111))	('GM6001', 'Var', (29, 35))
107754	21775520	The transfection of TACE siRNA into A431/H9 cells caused more than a 90% decrease of TACE protein expression (Fig.	('TACE', 'Gene', (85, 89))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('TACE', 'Gene', (20, 24))	('transfection', 'Var', (4, 16))	('A431/H9', 'CellLine', 'CVCL:0037', (36, 43))	('decrease', 'NegReg', (73, 81))	('TACE', 'Gene', '6868', (85, 89))	('TACE', 'Gene', '6868', (20, 24))
107757	21775520	The cells were also two-fold more sensitive to SS1P's cytotoxic effect as compared to controls (Fig.	('SS1P', 'Var', (47, 51))	('cytotoxic effect', 'CPA', (54, 70))	('SS1P', 'Chemical', 'MESH:C474515', (47, 51))
107762	21775520	We tested GM6001, the pan-MMP/ADAM inhibitor, because it had been shown to inhibit mesothelin shedding.	('GM6001', 'Chemical', 'MESH:C078131', (10, 16))	('mesothelin shedding', 'MPA', (83, 102))	('inhibit', 'NegReg', (75, 82))	('MMP', 'molecular_function', 'GO:0004235', ('26', '29'))	('GM6001', 'Var', (10, 16))	('MMP', 'Gene', '4321', (26, 29))	('MMP', 'Gene', (26, 29))
107763	21775520	GM6001 treatment increased cell-surface mesothelin level by about 2.6 folds (Fig.	('increased', 'PosReg', (17, 26))	('cell-surface', 'cellular_component', 'GO:0009986', ('27', '39'))	('GM6001', 'Chemical', 'MESH:C078131', (0, 6))	('cell-surface mesothelin level', 'MPA', (27, 56))	('GM6001', 'Var', (0, 6))
107765	21775520	Even at a very early time point (5 min), there was increased SS1P internalization in the GM6001-treated group.	('GM6001', 'Chemical', 'MESH:C078131', (89, 95))	('GM6001-treated', 'Var', (89, 103))	('increased', 'PosReg', (51, 60))	('SS1P', 'Chemical', 'MESH:C474515', (61, 65))	('SS1P', 'Protein', (61, 65))
107766	21775520	At the plateau phase (from 1-6 hours), internalized SS1P was increased 6-fold by GM6001 treatment.	('GM6001', 'Var', (81, 87))	('internalized SS1P', 'MPA', (39, 56))	('increased', 'PosReg', (61, 70))	('SS1P', 'Chemical', 'MESH:C474515', (52, 56))	('GM6001', 'Chemical', 'MESH:C078131', (81, 87))
107768	21775520	As expected, GM6001 made cells 5-fold more sensitive to SS1P (Fig.	('SS1P', 'Chemical', 'MESH:C474515', (56, 60))	('sensitive', 'MPA', (43, 52))	('more', 'PosReg', (38, 42))	('GM6001', 'Var', (13, 19))	('GM6001', 'Chemical', 'MESH:C078131', (13, 19))
107770	21775520	Both Cycloheximide and SS1P kill cells by inhibiting protein synthesis but CHX diffuses through cell membrane instead of binding to mesothelin and being internalized by endocytosis.	('cell membrane', 'cellular_component', 'GO:0005886', ('96', '109'))	('CHX', 'Chemical', 'MESH:D003513', (75, 78))	('inhibiting', 'NegReg', (42, 52))	('SS1P', 'Chemical', 'MESH:C474515', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('SS1P', 'Var', (23, 27))	('protein synthesis', 'MPA', (53, 70))	('Cycloheximide', 'Chemical', 'MESH:D003513', (5, 18))	('protein synthesis', 'biological_process', 'GO:0006412', ('53', '70'))	('binding', 'Interaction', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('endocytosis', 'biological_process', 'GO:0006897', ('169', '180'))
107771	21775520	Therefore, the increased sensitivity to SS1P following pre-treatment with GM6001 is likely due to the modulation of the mesothelin shedding process.	('SS1P', 'Chemical', 'MESH:C474515', (40, 44))	('mesothelin', 'MPA', (120, 130))	('sensitivity', 'MPA', (25, 36))	('GM6001', 'Var', (74, 80))	('pre', 'molecular_function', 'GO:0003904', ('55', '58'))	('GM6001', 'Chemical', 'MESH:C078131', (74, 80))
107773	21775520	GM6001 inhibited mesothelin shedding by these cell lines.	('GM6001', 'Chemical', 'MESH:C078131', (0, 6))	('mesothelin shedding', 'MPA', (17, 36))	('GM6001', 'Var', (0, 6))	('inhibited', 'NegReg', (7, 16))
107774	21775520	When treated with GM6001, the sensitivity of cells to SS1P increased 1.2-5 fold.	('sensitivity', 'MPA', (30, 41))	('SS1P', 'Chemical', 'MESH:C474515', (54, 58))	('GM6001', 'Chemical', 'MESH:C078131', (18, 24))	('increased', 'PosReg', (59, 68))	('GM6001', 'Var', (18, 24))
107775	21775520	We then examined the effect of GM6001 on primary mesothelioma cells isolated from two mesothelioma patients and found it increased cytotxicity by 2-2.5 fold.	('primary mesothelioma', 'Phenotype', 'HP:0100001', (41, 61))	('mesothelioma', 'Disease', (49, 61))	('increased', 'PosReg', (121, 130))	('cytotxicity', 'MPA', (131, 142))	('GM6001', 'Chemical', 'MESH:C078131', (31, 37))	('mesothelioma', 'Disease', (86, 98))	('patients', 'Species', '9606', (99, 107))	('GM6001', 'Var', (31, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (49, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
107790	21775520	These inhibitors included synthetic reagents (GM6001, batimastat and marimastat) and an endogenous factor (TIMP-3).	('GM6001', 'Var', (46, 52))	('TIMP-3', 'Gene', '7078', (107, 113))	('TIMP-3', 'Gene', (107, 113))	('marimastat', 'Chemical', 'MESH:C100342', (69, 79))	('batimastat', 'Chemical', 'MESH:C080985', (54, 64))	('GM6001', 'Chemical', 'MESH:C078131', (46, 52))
107796	21775520	The specific knock-down of TACE expression by siRNA significantly decreased mesothelin shedding and increased membrane-bound mesothelin.	('mesothelin shedding', 'MPA', (76, 95))	('knock-down', 'Var', (13, 23))	('increased', 'PosReg', (100, 109))	('decreased', 'NegReg', (66, 75))	('TACE', 'Gene', (27, 31))	('membrane-bound mesothelin', 'MPA', (110, 135))	('membrane', 'cellular_component', 'GO:0016020', ('110', '118'))	('TACE', 'Gene', '6868', (27, 31))
107808	21775520	In this study TACE knock-down caused about a 50% reduction in mesothelin shedding, demonstrating the prominent role that TACE plays in mesothelin shedding.	('mesothelin shedding', 'MPA', (62, 81))	('reduction', 'NegReg', (49, 58))	('TACE', 'Gene', '6868', (121, 125))	('TACE', 'Gene', (14, 18))	('TACE', 'Gene', (121, 125))	('TACE', 'Gene', '6868', (14, 18))	('knock-down', 'Var', (19, 29))
107863	22531174	Keratin AE1/AE3 positivity (usually focal) was seen in 46% (6/13) of cases of proliferative fasciitis, mainly in the ganglion cell-like elements, some of which showed dendritic morphology in the keratin immunostaining (Fig.	('Keratin AE1/AE3', 'Gene', (0, 15))	('fasciitis', 'Disease', 'MESH:D005208', (92, 101))	('Keratin AE1/AE3', 'Gene', '6508', (0, 15))	('fasciitis', 'Disease', (92, 101))	('fasciitis', 'Phenotype', 'HP:0100537', (92, 101))	('positivity', 'Var', (16, 26))
107879	22531174	Focal keratin AE1/AE3 and keratin 18 positivity beyond endothelia and pericytes was detected in 3 cases, all of which were negative for calretinin.	('keratin 18', 'Gene', (26, 36))	('calretinin', 'Gene', '794', (136, 146))	('keratin 18', 'Gene', '3875', (26, 36))	('detected', 'Reg', (84, 92))	('AE1/AE3', 'Gene', (14, 21))	('AE1/AE3', 'Gene', '6521;6508', (14, 21))	('positivity', 'Var', (37, 47))	('calretinin', 'Gene', (136, 146))
107894	22531174	Other studies demonstrate calretinin positivity in thymoma and thymic carcinoma, schwannoma, and high-grade breast carcinomas among others.	('schwannoma', 'Disease', 'MESH:D009442', (81, 91))	('schwannoma', 'Disease', (81, 91))	('breast carcinomas', 'Phenotype', 'HP:0003002', (108, 125))	('calretinin', 'Gene', '794', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('thymoma and thymic carcinoma', 'Disease', 'MESH:D013953', (51, 79))	('schwannoma', 'Phenotype', 'HP:0100008', (81, 91))	('breast carcinomas', 'Disease', 'MESH:D001943', (108, 125))	('breast carcinomas', 'Disease', (108, 125))	('calretinin', 'Gene', (26, 36))	('positivity', 'Var', (37, 47))	('thymoma', 'Phenotype', 'HP:0100522', (51, 58))
107897	22531174	Calretinin positivity in desmoid and other myofibroblastic tumors, if interpreted out of context in a small sample (cytologic or needle biopsy specimen), may mislead one to suspect a mesothelioma.	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (43, 64))	('Calretinin', 'Gene', (0, 10))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (43, 65))	('desmoid', 'Disease', (25, 32))	('positivity', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('myofibroblastic tumors', 'Disease', (43, 65))	('mesothelioma', 'Disease', (183, 195))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Calretinin', 'Gene', '794', (0, 10))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (43, 65))	('mislead', 'Reg', (158, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))
107899	22531174	The same is true for other myofibroblastic neoplasms with calretinin positivity.	('myofibroblastic neoplasms', 'Disease', 'MESH:D009369', (27, 52))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('calretinin', 'Gene', '794', (58, 68))	('positivity', 'Var', (69, 79))	('myofibroblastic neoplasms', 'Disease', (27, 52))	('myofibroblastic neoplasms', 'Phenotype', 'HP:0020135', (27, 52))	('calretinin', 'Gene', (58, 68))
107919	22531174	Furthermore, focal keratin AE1/AE3 immunoreactivity also occurs in some benign and malignant myofibroblastic lesions, further increasing the risk of misinterpretation of these elements as evidence of a mesothelial proliferation.	('malignant myofibroblastic lesions', 'Disease', 'MESH:D009369', (83, 116))	('focal', 'Var', (13, 18))	('benign', 'Disease', (72, 78))	('malignant myofibroblastic lesions', 'Disease', (83, 116))	('myofibroblastic lesions', 'Phenotype', 'HP:0020135', (93, 116))	('AE1/AE3', 'Gene', (27, 34))	('AE1/AE3', 'Gene', '6521;6508', (27, 34))
108061	26999172	showed that lung cancer antigens, MAGE A2 and MAGE A11, covalently attached to SWCNT-chitosan composites detected anti-MAGE A2 and anti-MAGE A11, respectively.	('MAGE A2', 'Gene', '17138', (34, 41))	('anti-MAGE A11', 'Var', (131, 144))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('MAGE A2', 'Gene', (34, 41))	('MAGE A2', 'Gene', '17138', (119, 126))	('lung cancer', 'Disease', (12, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('MAGE A2', 'Gene', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
108068	26999172	For example, numerous studies have shown that the presence of transition metals (e.g., Fe, Ni, Cu) in CNTs induces the formation of molecular oxygen-dependent superoxide anion radicals (O2 -), hydrogen peroxide (H2O2) and hydroxyl radicals ( HO), all of which have high redox potentials and reactivities (Figure 1).	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('superoxide anion radicals', 'Chemical', 'MESH:D013481', (159, 184))	('Fe', 'Chemical', 'MESH:D007501', (87, 89))	('O2', 'Chemical', '-', (214, 216))	('hydrogen peroxide', 'MPA', (193, 210))	('formation', 'MPA', (119, 128))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (222, 239))	('Cu', 'Chemical', 'MESH:D003300', (95, 97))	('presence', 'Var', (50, 58))	('oxygen', 'Chemical', 'MESH:D010100', (142, 148))	('induces', 'Reg', (107, 114))	('H2O2', 'Chemical', 'MESH:D006861', (212, 216))	('metal', 'Chemical', 'MESH:D008670', (73, 78))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (193, 210))	('HO', 'Chemical', 'MESH:D017665', (242, 244))	('hydroxyl', 'MPA', (222, 230))	('O2', 'Chemical', '-', (186, 188))
108093	26999172	showed that MWCNT potentiated allergen-induced increase in Th2, Th1, Th17 cytokines, prostaglandin D2, thromboxane B2, inflammation, and mucus-cell metaplasia in the lungs of COX-2(-/-) mice compared to wild type mice.	('Th1', 'Gene', (64, 67))	('Th2', 'Gene', (59, 62))	('mice', 'Species', '10090', (213, 217))	('Th2', 'Gene', '15111', (59, 62))	('thromboxane B2', 'Chemical', 'MESH:D013929', (103, 117))	('increase', 'PosReg', (47, 55))	('Th1', 'Gene', '57314', (69, 72))	('inflammation', 'biological_process', 'GO:0006954', ('119', '131'))	('prostaglandin D2', 'MPA', (85, 101))	('Th1', 'Gene', (69, 72))	('MWCNT', 'Chemical', '-', (12, 17))	('metaplasia', 'biological_process', 'GO:0036074', ('148', '158'))	('mice', 'Species', '10090', (186, 190))	('COX-2', 'Gene', '19225', (175, 180))	('mucus-cell metaplasia', 'CPA', (137, 158))	('thromboxane B2', 'MPA', (103, 117))	('inflammation', 'Disease', 'MESH:D007249', (119, 131))	('MWCNT', 'Var', (12, 17))	('allergen-induced', 'Disease', (30, 46))	('Th1', 'Gene', '57314', (64, 67))	('inflammation', 'Disease', (119, 131))	('COX-2', 'Gene', (175, 180))	('mucus', 'cellular_component', 'GO:0070701', ('137', '142'))	('prostaglandin D2', 'Chemical', 'MESH:D015230', (85, 101))
108114	26999172	Aneuploidy is the result of imbalanced chromosome separation during cell division leading to the formation of daughter cells with an abnormal chromosome number.	('imbalanced', 'Var', (28, 38))	('abnormal chromosome number', 'Phenotype', 'HP:0031411', (133, 159))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('chromosome separation', 'biological_process', 'GO:0051304', ('39', '60'))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('cell division', 'biological_process', 'GO:0051301', ('68', '81'))	('Aneuploidy', 'Disease', (0, 10))
108125	26999172	Long-term post-exposure of mice (C57BL/6) to SWCNTs via inhalation or aspiration, and CNFs via aspiration demonstrated that SWCNTs induced K-ras mutations regardless of the mode of administration, whereas CNFs induced such mutations only at very high doses.	('induced', 'Reg', (131, 138))	('CNF', 'Gene', (205, 208))	('K-ras', 'Gene', '16653', (139, 144))	('mice', 'Species', '10090', (27, 31))	('mutations', 'Var', (145, 154))	('K-ras', 'Gene', (139, 144))	('CNF', 'Gene', '4868', (205, 208))	('SWCNTs', 'Chemical', '-', (45, 51))	('SWCNTs', 'Chemical', '-', (124, 130))	('aspiration', 'Phenotype', 'HP:0002835', (95, 105))	('CNF', 'Gene', (86, 89))	('aspiration', 'Phenotype', 'HP:0002835', (70, 80))	('CNF', 'Gene', '4868', (86, 89))
108126	26999172	However, despite oncogenic K-ras mutations, no tumors were found after one year in mice exposed to SWCNTs, CNFs, or asbestos, regardless of the mode of administration.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CNF', 'Gene', '4868', (107, 110))	('SWCNTs', 'Chemical', '-', (99, 105))	('CNF', 'Gene', (107, 110))	('mutations', 'Var', (33, 42))	('mice', 'Species', '10090', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('asbestos', 'Chemical', 'MESH:D001194', (116, 124))	('K-ras', 'Gene', (27, 32))	('K-ras', 'Gene', '16653', (27, 32))
108140	26999172	Of the four microRNAs signatures, miR-1275 negatively correlated with MtMP-dysfunction genes.	('miR-1275', 'Var', (34, 42))	('MtMP-dysfunction', 'Disease', (70, 86))	('correlated', 'Reg', (54, 64))	('negatively', 'NegReg', (43, 53))	('MtMP-dysfunction', 'Disease', 'MESH:D006331', (70, 86))
108144	26999172	MWCNT also aggravated allergic airway inflammation via infiltration of inflammatory cells and antigen presenting cells in the bronchial epithelium; increased Th cytokines/chemokines; and increased IgG1 and IgE levels.	('allergic airway inflammation', 'Disease', 'MESH:D004342', (22, 50))	('Th cytokines/chemokines', 'MPA', (158, 181))	('allergic airway inflammation', 'Disease', (22, 50))	('IgG1', 'Gene', '16017', (197, 201))	('increased', 'PosReg', (148, 157))	('airway inflammation', 'Phenotype', 'HP:0002099', (31, 50))	('allergic airway inflammation', 'Phenotype', 'HP:0002099', (22, 50))	('inflammation', 'biological_process', 'GO:0006954', ('38', '50'))	('IgE levels', 'MPA', (206, 216))	('increased', 'PosReg', (187, 196))	('infiltration', 'PosReg', (55, 67))	('IgG1', 'Gene', (197, 201))	('IgG1', 'cellular_component', 'GO:0071735', ('197', '201'))	('MWCNT', 'Var', (0, 5))	('aggravated', 'PosReg', (11, 21))	('MWCNT', 'Chemical', '-', (0, 5))
108148	26999172	In a mouse model of asthma, MWCNTs induced an influx of inflammatory cells, increased mucus and IgG1 production, and increased the activation of inflammatory genes IL-13, Il-25, IL-33 and GM-CSF.	('activation', 'PosReg', (131, 141))	('increased', 'PosReg', (117, 126))	('IL-33', 'Gene', (178, 183))	('asthma', 'Phenotype', 'HP:0002099', (20, 26))	('GM-CSF', 'Gene', '12981', (188, 194))	('IL-33', 'molecular_function', 'GO:0002112', ('178', '183'))	('IL-13', 'molecular_function', 'GO:0005144', ('164', '169'))	('IL-13', 'Gene', (164, 169))	('IgG1', 'Gene', (96, 100))	('asthma', 'Disease', (20, 26))	('IL-13', 'Gene', '16163', (164, 169))	('increased', 'PosReg', (76, 85))	('GM-CSF', 'Gene', (188, 194))	('increased mucus', 'Phenotype', 'HP:0032068', (76, 91))	('mouse', 'Species', '10090', (5, 10))	('MWCNTs', 'Chemical', '-', (28, 34))	('Il-25', 'Gene', '140806', (171, 176))	('MWCNTs', 'Var', (28, 34))	('Il-25', 'Gene', (171, 176))	('Il-25', 'molecular_function', 'GO:0045521', ('171', '176'))	('IgG1', 'cellular_component', 'GO:0071735', ('96', '100'))	('influx', 'PosReg', (46, 52))	('mucus', 'cellular_component', 'GO:0070701', ('86', '91'))	('IgG1', 'Gene', '16017', (96, 100))	('IL-33', 'Gene', '77125', (178, 183))	('asthma', 'Disease', 'MESH:D001249', (20, 26))
108154	26999172	MWCNTs increased goblet cells hyperplasia and airway fibrosis in mice bearing a deletion of STAT1 and OVA-sensitized mice.	('hyperplasia', 'Disease', 'MESH:D006965', (30, 41))	('increased', 'PosReg', (7, 16))	('deletion', 'Var', (80, 88))	('fibrosis', 'Disease', 'MESH:D005355', (53, 61))	('mice', 'Species', '10090', (65, 69))	('STAT1', 'Gene', '20846', (92, 97))	('mice', 'Species', '10090', (117, 121))	('hyperplasia', 'Disease', (30, 41))	('MWCNTs', 'Chemical', '-', (0, 6))	('STAT1', 'Gene', (92, 97))	('fibrosis', 'Disease', (53, 61))
108158	26999172	Regardless of the mode of administration (e.g., inhalation, instillation, intratracheal instillation), MWCNTs induced the recruitment of eosinophils, neutrophils, macrophages, and antigen-activated dendritic or goblet cells.	('recruitment', 'MPA', (122, 133))	('MWCNTs', 'Var', (103, 109))	('MWCNTs', 'Chemical', '-', (103, 109))
108208	26554828	Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (p<0.001).	('observed', 'Reg', (54, 62))	('sarcomatoid MPM', 'Disease', 'MESH:C538614', (118, 133))	('BAP1', 'Gene', '8314', (44, 48))	('single-nucleotide variants', 'Var', (14, 40))	('sarcomatoid MPM', 'Disease', (118, 133))	('BAP1', 'Gene', (44, 48))
108209	26554828	Chromosome 22q loss was more frequently associated with the epithelioid than that non-epitheliod histology (p=0.037), whereas CDKN2A deletions occurred more frequently in non-epithelioid subtypes among men (p=0.021) and were correlated with shorter overall survival for the entire cohort (p=0.002) and for men (p=0.012).	('Chromosome 22q', 'Gene', (0, 14))	('men', 'Species', '9606', (202, 205))	('deletions', 'Var', (133, 142))	('shorter', 'NegReg', (241, 248))	('men', 'Species', '9606', (306, 309))	('overall survival', 'MPA', (249, 265))	('CDKN2A', 'Gene', (126, 132))	('loss', 'NegReg', (15, 19))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('CDKN2A', 'Gene', '1029', (126, 132))	('epithelioid', 'Disease', (60, 71))	('associated', 'Reg', (40, 50))
108210	26554828	Furthermore, women were more likely to harbor TP53 mutations (p=0.004).	('women', 'Species', '9606', (13, 18))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))
108211	26554828	Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA.	('RHOA', 'Gene', '387', (107, 111))	('MYH9', 'Gene', (98, 102))	('integrin-linked kinase pathway', 'Pathway', (56, 86))	('RHOA', 'Gene', (107, 111))	('MYH9', 'Gene', '4627', (98, 102))	('associated', 'Reg', (36, 46))	('mutations', 'Var', (6, 15))
108218	26554828	High-throughput sequencing techniques have revealed that each cancer genome appears to have a unique genetic profile acquired through cumulative genetic alterations, including driver mutations, that may confer advantageous survival phenotypes on the cancerous cells and represent precise therapeutic targets.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('mutations', 'Var', (183, 192))	('alterations', 'Var', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (250, 256))	('cancerous', 'Disease', (250, 259))	('survival phenotypes', 'CPA', (223, 242))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancerous', 'Disease', 'MESH:D009369', (250, 259))	('advantageous', 'PosReg', (210, 222))
108221	26554828	Recently, two independent investigations have identified BAP1 as frequently mutated in the chromosomal region 3p21.1 in sporadic and familial MPM indicating the importance of genetic factors in MPM susceptibility.	('mutated', 'Var', (76, 83))	('BAP1', 'Gene', '8314', (57, 61))	('chromosomal region', 'cellular_component', 'GO:0098687', ('91', '109'))	('MPM', 'Disease', (142, 145))	('BAP1', 'Gene', (57, 61))	('familial MPM', 'Disease', (133, 145))
108222	26554828	Although BAP1 mutations have been associated with age and with the epithelioid subtype, no other significant correlation of these genes to demographic, clinical or pathological variables has so far been identified.	('associated', 'Reg', (34, 44))	('BAP1', 'Gene', (9, 13))	('BAP1', 'Gene', '8314', (9, 13))	('epithelioid subtype', 'Disease', (67, 86))	('mutations', 'Var', (14, 23))
108223	26554828	Whole-genome sequencing data of tumor specimens from 10 MPM patients and their matched normal tissue were analyzed to identify novel somatic point mutations.	('patients', 'Species', '9606', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('point mutations', 'Var', (141, 156))	('men', 'Species', '9606', (43, 46))	('tumor', 'Disease', (32, 37))
108236	26554828	The numbers of reads containing single nucleotide variants (SNVs) and indels in both tumor and germline samples were counted and the quality score of each base and the read direction information were collected.	('tumor', 'Disease', (85, 90))	('single nucleotide variants', 'Var', (32, 58))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
108238	26554828	Selected candidate SNVs were further characterized using PCR and conventional Sanger sequencing to confirm tumor-specific single nucleotide mutations.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('single nucleotide mutations', 'Var', (122, 149))	('tumor', 'Disease', (107, 112))
108244	26554828	Bacterial artificial chromosome (BAC) DNA probes (CHORI, BAC PAC Resource, Oakland, CA) containing most or all of the coding sequence for NF2 (RP11-155B12, 159 kb) and MYH9 (RP11-105I18, 161 kb) were selected and labeled by nick translation (Abbott), NF2 with Orange dUTP and MYH9 with Green dUTP.	('dUTP', 'Chemical', 'MESH:C027078', (292, 296))	('PAC', 'Phenotype', 'HP:0006699', (61, 64))	('translation', 'biological_process', 'GO:0006412', ('229', '240'))	('MYH9', 'Gene', (276, 280))	('NF2', 'Gene', (138, 141))	('MYH9', 'Gene', '4627', (168, 172))	('RP11-155B12', 'Var', (143, 154))	('RP11-105I18', 'Var', (174, 185))	('dUTP', 'Chemical', 'MESH:C027078', (267, 271))	('NF2', 'Gene', '4771', (251, 254))	('MYH9', 'Gene', '4627', (276, 280))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('MYH9', 'Gene', (168, 172))	('NF2', 'Gene', '4771', (138, 141))	('NF2', 'Gene', (251, 254))
108262	26554828	Point mutations, small (<30 bp) structural variations, and copy number alterations were discovered in 10 pairs of WGS MPM tumor and germline DNA samples using computational approaches.	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('WGS MPM tumor', 'Disease', 'MESH:D009369', (114, 127))	('WGS MPM tumor', 'Disease', (114, 127))	('copy number alterations', 'Var', (59, 82))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
108263	26554828	Single nucleotide variants (N=146; SNVs) mapping in the amino acid coding regions of annotated exons and generating non-synonymous amino acid changes were further re-sequenced in the tumor and normal DNA by Sanger methodology.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Single nucleotide variants', 'Var', (0, 26))	('tumor', 'Disease', (183, 188))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))
108265	26554828	Each patient's sample pair displayed a unique small number of point mutations ranging from three to 20 per tumor.	('patient', 'Species', '9606', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('point mutations', 'Var', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
108271	26554828	Mutations affecting genes involved in the integrin-linked kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched.	('ILK', 'Gene', '3611', (66, 69))	('Mutations', 'Var', (0, 9))	('ILK', 'Gene', (66, 69))
108272	26554828	Specifically, 5 of the 10 sequenced MPM samples showed point mutations in at least one of 6 identified genes associated with this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A) (Figure 1A).	('MYH9', 'Gene', (139, 143))	('PIK3C2A', 'Gene', '5286', (158, 165))	('TNFRSF1A', 'Gene', '7132', (177, 185))	('RHOA', 'Gene', '387', (167, 171))	('PIK3C2A', 'Gene', (158, 165))	('MYH6', 'Gene', '4624', (145, 149))	('MYH6', 'Gene', (145, 149))	('MYH9', 'Gene', '4627', (139, 143))	('MYH10', 'Gene', '4628', (151, 156))	('point mutations', 'Var', (55, 70))	('MYH10', 'Gene', (151, 156))	('RHOA', 'Gene', (167, 171))	('TNFRSF1A', 'Gene', (177, 185))
108276	26554828	Targeted re-sequencing revealed 116 non-synonymous SNVs and/or INDELs (Supplementary Table 5A, B, C).	('non-synonymous SNVs', 'Var', (36, 55))	('INDELs', 'Var', (63, 69))	('SNVs', 'Var', (51, 55))	('men', 'Species', '9606', (77, 80))
108278	26554828	BAP1 was mutated in 31 of 147 (21%) samples (Supplementary Table 5A).	('BAP1', 'Gene', '8314', (0, 4))	('mutated', 'Var', (9, 16))	('BAP1', 'Gene', (0, 4))	('men', 'Species', '9606', (51, 54))
108280	26554828	In six samples, multiple BAP1 mutations were identified.	('BAP1', 'Gene', '8314', (25, 29))	('mutations', 'Var', (30, 39))	('BAP1', 'Gene', (25, 29))
108281	26554828	The mutations occurred mostly in epithelioid (23%) and biphasic (24%) samples, whereas only two out of 24 sarcomatoid (8%) samples had tumor specific BAP1 mutations.	('occurred', 'Reg', (14, 22))	('BAP1', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('sarcomatoid', 'Disease', 'MESH:C538614', (106, 117))	('tumor', 'Disease', (135, 140))	('epithelioid', 'Disease', (33, 44))	('biphasic', 'Disease', (55, 63))	('sarcomatoid', 'Disease', (106, 117))	('BAP1', 'Gene', '8314', (150, 154))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
108282	26554828	No significant correlation was found between mutation in BAP1 and gender, exposure to asbestos, or survival.	('mutation', 'Var', (45, 53))	('asbestos', 'Chemical', 'MESH:D001194', (86, 94))	('BAP1', 'Gene', (57, 61))	('BAP1', 'Gene', '8314', (57, 61))
108283	26554828	BAP1 mutations were associated with marginally older age compared to wild-type tumors (median 67 versus 64 years; p = 0.050).	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
108284	26554828	BAP1 mutations were also observed in cell lines H2452 and H28.	('BAP1', 'Gene', '8314', (0, 4))	('H2452', 'CellLine', 'CVCL:1553', (48, 53))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
108285	26554828	Table 3 describes the cases carrying BAP1 germline mutations.	('BAP1', 'Gene', (37, 41))	('BAP1', 'Gene', '8314', (37, 41))	('germline mutations', 'Var', (42, 60))
108286	26554828	NF2 point mutations occurred in 21 (14%) of 147 analyzed samples (Supplementary Table 5A).	('NF2', 'Gene', (0, 3))	('men', 'Species', '9606', (72, 75))	('NF2', 'Gene', '4771', (0, 3))	('point mutations', 'Var', (4, 19))	('occurred', 'Reg', (20, 28))
108287	26554828	Eleven of 133 (8%) had both NF2 point mutation and 22q deletion.	('point mutation', 'Var', (32, 46))	('NF2', 'Gene', (28, 31))	('NF2', 'Gene', '4771', (28, 31))
108289	26554828	Mutations in NF2 were not correlated with any of the other clinical or pathologic variables examined.	('NF2', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF2', 'Gene', '4771', (13, 16))
108290	26554828	NF2 mutation was found in H2052.	('NF2', 'Gene', (0, 3))	('H2052', 'CellLine', 'CVCL:1518', (26, 31))	('H2052', 'Var', (26, 31))	('NF2', 'Gene', '4771', (0, 3))
108292	26554828	Eighty-two (62%) of 133 samples had deletion of the CDKN2A region on 9p (determined by karyotyping) and/or confirmed CDKN2A deletion (as determined by FISH with a CDKN2A probe).	('CDKN2A', 'Gene', '1029', (163, 169))	('deletion', 'Var', (36, 44))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', (117, 123))	('CDKN2A', 'Gene', (163, 169))	('deletion', 'Var', (124, 132))	('CDKN2A', 'Gene', '1029', (52, 58))	('CDKN2A', 'Gene', '1029', (117, 123))
108293	26554828	Forty-one of 74 (55%) epithelioid, 29 of 41 (71%) biphasic, 11 of 17 (65%) sarcomatoid, and one of one desmoplastic samples had CDKN2A deletion.	('deletion', 'Var', (135, 143))	('sarcomatoid', 'Disease', 'MESH:C538614', (75, 86))	('CDKN2A', 'Gene', '1029', (128, 134))	('desmoplastic', 'Disease', (103, 115))	('sarcomatoid', 'Disease', (75, 86))	('desmoplastic', 'Disease', 'MESH:D018220', (103, 115))	('CDKN2A', 'Gene', (128, 134))
108294	26554828	Compared to the cases with two copies of CDKN2A, cases with CDKN2A deletion appeared to be more frequently associated with the non-epithelioid histology (p=0.117).	('non-epithelioid histology', 'Disease', (127, 152))	('associated', 'Reg', (107, 117))	('deletion', 'Var', (67, 75))	('CDKN2A', 'Gene', (60, 66))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (60, 66))	('CDKN2A', 'Gene', '1029', (41, 47))
108296	26554828	Interestingly, deletions in CDKN2A were correlated with shorter overall survival in the whole cohort (p=0.002), but the difference was statistically significant only in the men (p=0.012).	('men', 'Species', '9606', (173, 176))	('shorter', 'NegReg', (56, 63))	('CDKN2A', 'Gene', (28, 34))	('overall survival', 'MPA', (64, 80))	('CDKN2A', 'Gene', '1029', (28, 34))	('deletions', 'Var', (15, 24))
108297	26554828	TP53 was mutated in 22 cases (15%) in this sample set (Supplementary Table 5B).	('TP53', 'Gene', '7157', (0, 4))	('mutated', 'Var', (9, 16))	('TP53', 'Gene', (0, 4))	('men', 'Species', '9606', (61, 64))
108298	26554828	Three mutations (D49N, C176F, A86T) were present in both the tumor and the normal DNA (Table 3).	('D49N', 'Mutation', 'rs587780728', (17, 21))	('C176F', 'Mutation', 'rs786202962', (23, 28))	('A86T', 'Var', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('C176F', 'Var', (23, 28))	('D49N', 'Var', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('A86T', 'Mutation', 'rs587782148', (30, 34))	('tumor', 'Disease', (61, 66))
108299	26554828	Notably, one sample showed only one germline TP53 mutation (D49N) and no mutation in any of the other genes investigated herein.	('D49N', 'Var', (60, 64))	('D49N', 'Mutation', 'rs587780728', (60, 64))	('TP53', 'Gene', '7157', (45, 49))	('TP53', 'Gene', (45, 49))
108300	26554828	None of the cell lines examined exhibited TP53 mutations.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
108301	26554828	No difference was observed in overall survival between the group of 62 patients with point mutation in at least one of the established MPM-related genes (BAP1, NF2, TP53) and the group wild type for these genes (p = 0.646).	('point mutation', 'Var', (85, 99))	('TP53', 'Gene', (165, 169))	('BAP1', 'Gene', (154, 158))	('patients', 'Species', '9606', (71, 79))	('MPM-related', 'Gene', (135, 146))	('NF2', 'Gene', (160, 163))	('BAP1', 'Gene', '8314', (154, 158))	('TP53', 'Gene', '7157', (165, 169))	('NF2', 'Gene', '4771', (160, 163))
108303	26554828	Fifteen patients (43 %) carrying a germline mutation in one or more of these genes had familial history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('familial', 'Disease', (87, 95))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('germline mutation', 'Var', (35, 52))	('cancer', 'Disease', (107, 113))	('patients', 'Species', '9606', (8, 16))
108307	26554828	Two samples displayed germline mutation of MYH10.	('germline mutation', 'Var', (22, 39))	('MYH10', 'Gene', (43, 48))	('MYH10', 'Gene', '4628', (43, 48))
108309	26554828	Nine germline mutations were detected in MYH6, two of which had a predicted "probably damaging" effect and one caused a reading frame shift.	('MYH6', 'Gene', (41, 45))	('germline mutations', 'Var', (5, 23))	('MYH6', 'Gene', '4624', (41, 45))	('caused', 'Reg', (111, 117))
108310	26554828	Twelve samples exhibited germline mutations in MYH9; seven had a predicted "possibly or probably damaging" effect.	('MYH9', 'Gene', (47, 51))	('germline mutations', 'Var', (25, 43))	('MYH9', 'Gene', '4627', (47, 51))
108311	26554828	Although many mutations of MYH9 have been identified in several other cancers, only R1576Q identified in our series has been previously described.	('identified', 'Reg', (42, 52))	('MYH9', 'Gene', '4627', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('R1576Q', 'Var', (84, 90))	('R1576Q', 'Mutation', 'rs143269195', (84, 90))	('MYH9', 'Gene', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('mutations', 'Var', (14, 23))
108312	26554828	In 4 patients, tumor specific mutations of ILK pathway-associated genes were identified: 3 in MYH9 (1.4%) (Q738*, K737N, A1197fs) and 2 in RHOA (1.4%) (Y66N, A161V).	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('MYH9', 'Gene', '4627', (94, 98))	('A161V', 'Var', (158, 163))	('MYH9', 'Gene', (94, 98))	('RHOA', 'Gene', '387', (139, 143))	('patients', 'Species', '9606', (5, 13))	('ILK', 'Gene', (43, 46))	('ILK', 'Gene', '3611', (43, 46))	('RHOA', 'Gene', (139, 143))	('A1197fs', 'Mutation', 'p.A1197fsX', (121, 128))	('Y66N', 'Mutation', 'p.Y66N', (152, 156))	('Q738*', 'SUBSTITUTION', 'None', (107, 112))	('A161V', 'Mutation', 'rs11552757', (158, 163))	('A1197fs', 'Var', (121, 128))	('K737N', 'Var', (114, 119))	('tumor', 'Disease', (15, 20))	('Y66N', 'Var', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('K737N', 'Mutation', 'p.K737N', (114, 119))	('Q738*', 'Var', (107, 112))
108314	26554828	No significant correlation was found between the mutations in the ILK pathway-associated genes and clinical or pathological variables.	('ILK', 'Gene', (66, 69))	('ILK', 'Gene', '3611', (66, 69))	('mutations', 'Var', (49, 58))
108315	26554828	Figure 1B depicts the mutations found in the myosin heavy chain genes and RHOA.	('RHOA', 'Gene', '387', (74, 78))	('RHOA', 'Gene', (74, 78))	('mutations', 'Var', (22, 31))	('myosin heavy chain', 'Protein', (45, 63))
108318	26554828	Dual-color FISH analysis using MYH9- and NF2-specific probes was undertaken for the 13 cases carrying MYH9 mutation.	('NF2', 'Gene', (41, 44))	('MYH9', 'Gene', '4627', (31, 35))	('MYH9', 'Gene', (102, 106))	('NF2', 'Gene', '4771', (41, 44))	('mutation', 'Var', (107, 115))	('MYH9', 'Gene', '4627', (102, 106))	('MYH9', 'Gene', (31, 35))
108319	26554828	Of the 13 primary tumors in which the two markers could be assessed, 2 (15%) exhibited no aberrations involving NF2 or MYH9; 1 (8%) was abnormal by losing NF2 only; 7 (54%) had loss of both markers; and 3 (23%) samples exhibited extra copies of both markers likely due to polyploidy (Supplementary Table 5D).	('losing', 'NegReg', (148, 154))	('NF2', 'Gene', (155, 158))	('NF2', 'Gene', '4771', (112, 115))	('polyploidy', 'Var', (272, 282))	('MYH9', 'Gene', (119, 123))	('tumors', 'Disease', (18, 24))	('men', 'Species', '9606', (290, 293))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('NF2', 'Gene', '4771', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('NF2', 'Gene', (112, 115))	('MYH9', 'Gene', '4627', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
108320	26554828	Two of the 7 cases displaying loss of both markers had tumor specific mutation in both MYH9 and NF2, whereas 5 had tumor-specific mutation of MYH9 only.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NF2', 'Gene', (96, 99))	('MYH9', 'Gene', '4627', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MYH9', 'Gene', '4627', (142, 146))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (55, 60))	('NF2', 'Gene', '4771', (96, 99))	('MYH9', 'Gene', (87, 91))	('mutation', 'Var', (70, 78))	('MYH9', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
108322	26554828	In MPM, tumor-specific mutations in RHOA, MYH9 and TP53 were mutually exclusive events that occurred more frequently in women (30%) than in men (12%) (p=0.023).	('men', 'Species', '9606', (140, 143))	('RHOA', 'Gene', '387', (36, 40))	('MYH9', 'Gene', '4627', (42, 46))	('TP53', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('RHOA', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('women', 'Species', '9606', (120, 125))	('mutations', 'Var', (23, 32))	('MPM', 'Disease', (3, 6))	('MYH9', 'Gene', (42, 46))	('tumor', 'Disease', (8, 13))	('TP53', 'Gene', '7157', (51, 55))	('men', 'Species', '9606', (122, 125))
108324	26554828	Notably, in 26 of 31 (84%) tumor types that had mutations in both genes, RHOA and MYH9 mutations had a strong tendency toward mutual exclusivity (Supplementary Table 6).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RHOA', 'Gene', (73, 77))	('tumor', 'Disease', (27, 32))	('MYH9', 'Gene', (82, 86))	('mutual exclusivity', 'MPA', (126, 144))	('mutations', 'Var', (87, 96))	('men', 'Species', '9606', (152, 155))	('RHOA', 'Gene', '387', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MYH9', 'Gene', '4627', (82, 86))	('mutations', 'Var', (48, 57))
108325	26554828	Given that mutations of TP53 were found more commonly in women, and that women with MPM generally have lower levels of asbestos exposure than men, we expanded our validation cohort to power exploration of these associations.	('mutations', 'Var', (11, 20))	('men', 'Species', '9606', (142, 145))	('women', 'Species', '9606', (73, 78))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (24, 28))	('women', 'Species', '9606', (57, 62))	('lower', 'NegReg', (103, 108))	('men', 'Species', '9606', (75, 78))	('men', 'Species', '9606', (59, 62))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('levels of asbestos exposure', 'MPA', (109, 136))
108329	26554828	Expanding the cohort added one case (total 4/283) with germline TP53 mutation (R248W; Table 3).	('R248W', 'Var', (79, 84))	('R248W', 'Mutation', 'rs121912651', (79, 84))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
108330	26554828	Although TP53 mutations were found more frequently in tumors with background versus higher asbestos exposure, the analysis did not have sufficient power to exclude exposure level as a risk factor in either the whole cohort (p = 0.068) or among women (p = 0.498).	('TP53', 'Gene', '7157', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TP53', 'Gene', (9, 13))	('asbestos', 'Chemical', 'MESH:D001194', (91, 99))	('tumors', 'Disease', (54, 60))	('women', 'Species', '9606', (244, 249))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
108331	26554828	No significant correlation of mutations in TP53 was found to either survival, or histological subtype.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))
108349	26554828	CDKN2A and NF2 are the tumor suppressor genes most commonly found mutated, and recently, evidence for a role for BAP1 was demonstrated.	('mutated', 'Var', (66, 73))	('NF2', 'Gene', (11, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('NF2', 'Gene', '4771', (11, 14))	('BAP1', 'Gene', '8314', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('CDKN2A', 'Gene', (0, 6))	('tumor', 'Disease', (23, 28))	('BAP1', 'Gene', (113, 117))	('CDKN2A', 'Gene', '1029', (0, 6))
108350	26554828	During the preparation of this work, a whole-exome sequencing study using DNA from 22 MPMs and matched blood samples found 517 somatic mutations across 490 mutated genes, confirmed frequent mutation in BAP1, NF2, and CDKN2A, and identified alterations of CUL1 in 2/22 cases.	('mutation', 'Var', (190, 198))	('CUL1', 'Gene', (255, 259))	('BAP1', 'Gene', (202, 206))	('alterations', 'Var', (240, 251))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('CUL1', 'Gene', '8454', (255, 259))	('mutations', 'Var', (135, 144))	('CDKN2A', 'Gene', (217, 223))	('CDKN2A', 'Gene', '1029', (217, 223))	('NF2', 'Gene', (208, 211))	('BAP1', 'Gene', '8314', (202, 206))	('NF2', 'Gene', '4771', (208, 211))
108354	26554828	Novel molecular alterations in MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A were documented, and bioinformatic analyses found these genes to be linked.	('PIK3C2A', 'Gene', '5286', (50, 57))	('MYH10', 'Gene', (43, 48))	('MYH10', 'Gene', '4628', (43, 48))	('men', 'Species', '9606', (87, 90))	('TNFRSF1A', 'Gene', (69, 77))	('alterations', 'Var', (16, 27))	('MYH9', 'Gene', '4627', (31, 35))	('RHOA', 'Gene', '387', (59, 63))	('MYH6', 'Gene', '4624', (37, 41))	('MYH6', 'Gene', (37, 41))	('TNFRSF1A', 'Gene', '7132', (69, 77))	('RHOA', 'Gene', (59, 63))	('MYH9', 'Gene', (31, 35))	('PIK3C2A', 'Gene', (50, 57))
108355	26554828	TP53 mutations occurred in 13% of MPM cases analyzed here.	('MPM', 'Disease', (34, 37))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
108357	26554828	In one prior study, TP53 genotype was predictive of survival in women following adjuvant therapy for colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('TP53', 'Gene', (20, 24))	('colon cancer', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('predictive of', 'Reg', (38, 51))	('women', 'Species', '9606', (64, 69))	('genotype', 'Var', (25, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('TP53', 'Gene', '7157', (20, 24))
108358	26554828	In another study of 152 TP53-germline mutation carriers, TP53 PIN3 polymorphism was found to have a sex-specific effect, conferring cancer risk in men (P = 0.0041) but not women.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('TP53', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', '7157', (57, 61))	('men', 'Species', '9606', (174, 177))	('TP53', 'Gene', (57, 61))	('women', 'Species', '9606', (172, 177))	('polymorphism', 'Var', (67, 79))	('men', 'Species', '9606', (147, 150))	('TP53', 'Gene', '7157', (24, 28))
108359	26554828	To our knowledge, this is the first report of TP53 mutation in tumor and germline DNA in sporadic MPM or in patients with familial history of cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Disease', (63, 68))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('MPM', 'Disease', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', (142, 148))
108360	26554828	Interestingly, only germline mutations in women had predicted deleterious functional impact on p53, whereas the mutations identified in men had predicted neutral impact on the protein.	('germline', 'Var', (20, 28))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', (95, 98))	('women', 'Species', '9606', (42, 47))	('men', 'Species', '9606', (44, 47))	('men', 'Species', '9606', (136, 139))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
108361	26554828	No evidence was found in the clinical profile of patients carrying these TP53 mutations to suggest Li-Fraumeni syndrome.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (99, 119))	('patients', 'Species', '9606', (49, 57))	('Li-Fraumeni syndrome', 'Disease', (99, 119))
108362	26554828	Although women with MPM have TP53 mutations at a higher rate compared to men, no significant correlation of TP53 status was found to survival in this cohort.	('women', 'Species', '9606', (9, 14))	('men', 'Species', '9606', (73, 76))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('MPM', 'Disease', (20, 23))	('mutations', 'Var', (34, 43))	('men', 'Species', '9606', (11, 14))
108363	26554828	A recent study reports BAP1 mutation in ~70% of MPM and suggests that large chromosomal deletions commonly inferred by immunohistochemistry are missed by Sanger sequencing.	('BAP1', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('MPM', 'Disease', (48, 51))	('BAP1', 'Gene', '8314', (23, 27))
108365	26554828	Five cases showed germline BAP1 mutations of which 4 had familial history of cancer.	('BAP1', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (77, 83))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BAP1', 'Gene', '8314', (27, 31))
108370	26554828	In the current study, deletion of the p16 gene, CDKN2A, was correlated with shorter survival.	('deletion', 'Var', (22, 30))	('p16', 'Gene', (38, 41))	('CDKN2A', 'Gene', (48, 54))	('shorter', 'NegReg', (76, 83))	('CDKN2A', 'Gene', '1029', (48, 54))	('p16', 'Gene', '1029', (38, 41))
108371	26554828	CDKN2A deletions were more frequent in the non-epitheliod subtype among men.	('men', 'Species', '9606', (72, 75))	('deletions', 'Var', (7, 16))	('frequent', 'Reg', (27, 35))	('CDKN2A', 'Gene', (0, 6))	('non-epitheliod subtype', 'Disease', (43, 65))	('CDKN2A', 'Gene', '1029', (0, 6))
108373	26554828	The heavy chain, type A, myosin MYH9 was the most commonly mutated in the current MPM cohort.	('myosin MYH9', 'Disease', (25, 36))	('myosin MYH9', 'Disease', 'MESH:C535507', (25, 36))	('mutated', 'Var', (59, 66))
108376	26554828	Fifteen mutations of this gene were identified in 13 (9%) MPM patients of which 6 had familial history of cancer.	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('mutations', 'Var', (8, 17))	('MPM', 'Disease', (58, 61))	('cancer', 'Disease', (106, 112))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
108377	26554828	Three of the 15 mutations were tumor specific and 12 were germline.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (31, 36))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))
108378	26554828	One patient carried two tumor specific and one germline mutation of MYH9.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('germline mutation', 'Var', (47, 64))	('MYH9', 'Gene', (68, 72))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MYH9', 'Gene', '4627', (68, 72))
108381	26554828	It has been suggested that cancer genes other than NF2 may be involved in some malignancies associated with chromosome 22 allelic losses in which NF2 mutations are not detected or found at very low frequencies.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('NF2', 'Gene', (51, 54))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('NF2', 'Gene', (146, 149))	('involved', 'Reg', (62, 70))	('NF2', 'Gene', '4771', (51, 54))	('NF2', 'Gene', '4771', (146, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('malignancies', 'Disease', (79, 91))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('allelic losses', 'Var', (122, 136))
108382	26554828	Because both NF2 and MYH9 are within this region, deletions encompassing both probes indicate loss of both genes.	('MYH9', 'Gene', '4627', (21, 25))	('NF2', 'Gene', '4771', (13, 16))	('loss', 'NegReg', (94, 98))	('MYH9', 'Gene', (21, 25))	('NF2', 'Gene', (13, 16))	('deletions', 'Var', (50, 59))
108383	26554828	However, rearrangements associated with deletion of only one of the probes do not necessarily indicate deletion of either of these genes, and, conversely, cases lacking deletion of these probes could still have NF2 and/or MYH9 deletions.	('NF2', 'Gene', '4771', (211, 214))	('deletion', 'Var', (40, 48))	('men', 'Species', '9606', (18, 21))	('MYH9', 'Gene', (222, 226))	('deletions', 'Var', (227, 236))	('NF2', 'Gene', (211, 214))	('MYH9', 'Gene', '4627', (222, 226))
108384	26554828	In the current study, dual-color FISH analysis using probe sets specific for each gene indicated that 45% of the samples with MYH9 mutation and wild-type NF2 had loss of one allele for both genes.	('MYH9', 'Gene', '4627', (126, 130))	('NF2', 'Gene', '4771', (154, 157))	('loss', 'NegReg', (162, 166))	('MYH9', 'Gene', (126, 130))	('NF2', 'Gene', (154, 157))	('mutation', 'Var', (131, 139))
108385	26554828	This finding suggests that mutated MYH9 may contribute to tumorigenesis in some 22q-deletion cases.	('MYH9', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutated', 'Var', (27, 34))	('contribute', 'Reg', (44, 54))	('MYH9', 'Gene', '4627', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('22q-deletion', 'Disease', (80, 92))
108396	23977234	A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma.	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('cutaneous melanoma', 'Disease', (302, 320))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (302, 320))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (302, 320))	('uveal melanoma', 'Phenotype', 'HP:0007716', (283, 297))	('BRCA-1 associated protein-1', 'Gene', '8314', (142, 169))	('Mutation', 'Var', (7, 15))	('BAP1', 'Gene', (2, 6))	('BRCA-1 associated protein-1', 'Gene', (142, 169))	('Truncating', 'Var', (83, 93))	('BAP1', 'Gene', '8314', (171, 175))	('Cancers', 'Phenotype', 'HP:0002664', (75, 82))	('tumor', 'Disease', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('Melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Disease', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('BAP1', 'Gene', (171, 175))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('uveal melanoma', 'Disease', 'MESH:C536494', (283, 297))	('Predisposes', 'Reg', (35, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('reported', 'Reg', (187, 195))	('BAP1', 'Gene', '8314', (2, 6))	('uveal melanoma', 'Disease', (283, 297))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Melanoma and Other Cancers', 'Disease', 'MESH:C563985', (56, 82))
108397	23977234	There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers.	('BAP1', 'Gene', (85, 89))	('BAP1', 'Gene', (150, 154))	('amelanotic tumor', 'Disease', (43, 59))	('amelanotic tumor', 'Disease', 'MESH:D018328', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('germline', 'Var', (76, 84))	('BAP1', 'Gene', '8314', (85, 89))	('BAP1', 'Gene', '8314', (150, 154))	('mutation', 'Var', (90, 98))
108398	23977234	Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('BAP1', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('germline', 'Var', (60, 68))	('BAP1', 'Gene', '8314', (69, 73))
108405	23977234	BAP1 was found to be the only gene that was mutated on chromosome 3 in each of these samples and both mutations led to truncation of the protein.	('BAP1', 'Gene', (0, 4))	('truncation', 'MPA', (119, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('led to', 'Reg', (112, 118))	('mutations', 'Var', (102, 111))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('BAP1', 'Gene', '8314', (0, 4))	('protein', 'Protein', (137, 144))
108406	23977234	They next interrogated 57 UMM tumors using Sanger sequencing and found that BAP1 mutations occurred predominantly in tumors that had metastasized.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('BAP1', 'Gene', '8314', (76, 80))	('UMM', 'Phenotype', 'HP:0007716', (26, 29))	('occurred', 'Reg', (91, 99))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('BAP1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (81, 90))
108407	23977234	Overall, 26/31 of the metastasizing (high risk) tumors had inactivating BAP1 somatic mutations compared to only 1/26 of the low risk (non-metastatic) group.	('BAP1', 'Gene', '8314', (72, 76))	('tumors', 'Disease', (48, 54))	('metastasizing', 'CPA', (22, 35))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BAP1', 'Gene', (72, 76))	('inactivating', 'Var', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
108408	23977234	For the 20 samples with a matched normal DNA sample, almost all BAP1 mutations were found to be acquired somatically, the exception being a single case with a matching germline frameshift mutation.	('mutations', 'Var', (69, 78))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('BAP1', 'Gene', '8314', (64, 68))	('BAP1', 'Gene', (64, 68))
108409	23977234	This mutation introduced the possibility that BAP1 defects could predispose to UMM.	('defects', 'Var', (51, 58))	('predispose', 'Reg', (65, 75))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (46, 50))	('UMM', 'Disease', (79, 82))	('UMM', 'Phenotype', 'HP:0007716', (79, 82))
108410	23977234	al., several groups have looked at the risk of disease conferred by germline BAP1 mutation.	('BAP1', 'Gene', '8314', (77, 81))	('germline', 'Var', (68, 76))	('BAP1', 'Gene', (77, 81))
108411	23977234	Testa and colleagues investigated BAP1 mutations in two American families presenting with mesothelioma and who had no contact with any of the known environmental risk factors for this disease.	('BAP1', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('mesothelioma', 'Disease', (90, 102))	('BAP1', 'Gene', '8314', (34, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
108412	23977234	They found two different frameshift mutations in BAP1 responsible for the elevated risk of mesothelioma in these individuals.	('frameshift mutations', 'Var', (25, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('BAP1', 'Gene', (49, 53))	('responsible', 'Reg', (54, 65))	('mesothelioma', 'Disease', (91, 103))	('BAP1', 'Gene', '8314', (49, 53))
108416	23977234	A report by Wiesner showed BAP1 mutations in two families that had an autosomal dominant syndrome characterized by UMM, CMM and atypical benign melanocytic nevi.	('melanocytic nevi', 'Phenotype', 'HP:0000995', (144, 160))	('UMM', 'Phenotype', 'HP:0007716', (115, 118))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (70, 97))	('UMM', 'Disease', (115, 118))	('CMM', 'Gene', (120, 123))	('BAP1', 'Gene', (27, 31))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('mutations', 'Var', (32, 41))	('CMM', 'Gene', '1243', (120, 123))	('CMM', 'Phenotype', 'HP:0012056', (120, 123))	('BAP1', 'Gene', '8314', (27, 31))	('atypical benign melanocytic nevi', 'Disease', (128, 160))	('autosomal dominant syndrome', 'Disease', (70, 97))
108417	23977234	In a follow up report, Wiesner and colleagues identified a third family with a BAP1 mutation that co-segregated with mesothelioma and also showed evidence of a melanocytic lesion in a mutation carrier.	('BAP1', 'Gene', '8314', (79, 83))	('mutation', 'Var', (84, 92))	('mesothelioma', 'Disease', (117, 129))	('BAP1', 'Gene', (79, 83))	('melanocytic lesion', 'Disease', 'MESH:D009508', (160, 178))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('carrier', 'molecular_function', 'GO:0005215', ('193', '200'))	('melanocytic lesion', 'Disease', (160, 178))
108418	23977234	Other groups have also described BAP1 mutations in individuals presenting with atypical intradermal tumors, proposing that these lesions may be a phenotypic characteristic of BAP1 mutation carriers.	('intradermal tumors', 'Disease', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BAP1', 'Gene', (175, 179))	('BAP1', 'Gene', '8314', (175, 179))	('BAP1', 'Gene', '8314', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('intradermal tumors', 'Disease', 'MESH:D018330', (88, 106))
108419	23977234	A recent study of Portuguese siblings with a rare subtype of epithelioid mesothelioma uncovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma.	('BAP1', 'Gene', '8314', (107, 111))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (61, 85))	('mutation', 'Var', (112, 120))	('papillary mesothelioma', 'Disease', (204, 226))	('BAP1', 'Gene', (107, 111))	('cause', 'Reg', (137, 142))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (204, 226))	('epithelioid mesothelioma', 'Disease', (61, 85))
108421	23977234	BAP1 mutation has also been implicated in the development of renal cell carcinoma and some of the relatives of these cases have had UMM or CMM also.	('UMM', 'Phenotype', 'HP:0007716', (132, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('BAP1', 'Gene', (0, 4))	('CMM', 'Gene', '1243', (139, 142))	('CMM', 'Phenotype', 'HP:0012056', (139, 142))	('BAP1', 'Gene', '8314', (0, 4))	('renal cell carcinoma', 'Disease', (61, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (61, 81))	('CMM', 'Gene', (139, 142))	('implicated', 'Reg', (28, 38))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 81))	('mutation', 'Var', (5, 13))	('UMM', 'Disease', (132, 135))
108422	23977234	As evidenced by the literature, there is a large tumor spectrum that appears to accompany BAP1 germline mutation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BAP1', 'Gene', '8314', (90, 94))	('germline mutation', 'Var', (95, 112))	('tumor', 'Disease', (49, 54))	('BAP1', 'Gene', (90, 94))
108429	23977234	Aside from the striking incidence of cancer, this family presents with other clinical features that have become indications of BAP1 mutation.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('BAP1', 'Gene', (127, 131))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', '8314', (127, 131))	('mutation', 'Var', (132, 140))
108435	23977234	In order to find disease-associated variants, whole-exome sequencing was carried out on key individuals representative of the tumor burden in this family.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('variants', 'Var', (36, 44))	('tumor', 'Disease', (126, 131))
108436	23977234	SAMTOOLS was then used to detect the SNPs and indels.	('indels', 'Var', (46, 52))	('SAMTOOLS', 'Chemical', '-', (0, 8))	('SNPs', 'Var', (37, 41))
108437	23977234	Exome-sequencing uncovered a BAP1 splice mutation, which results in the premature truncation of the protein, in one (III:17) of the two individuals and was seen as a likely candidate responsible for UMM susceptibility due to the supporting literature.	('premature truncation of the protein', 'MPA', (72, 107))	('results in', 'Reg', (57, 67))	('BAP1', 'Gene', '8314', (29, 33))	('splice mutation', 'Var', (34, 49))	('UMM', 'Phenotype', 'HP:0007716', (199, 202))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('UMM', 'Disease', (199, 202))	('BAP1', 'Gene', (29, 33))
108438	23977234	Following this, co-segregation analysis was carried out to determine how well the variant segregated with disease in the family and whether it was present in individuals with different cancer types.	('segregated', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('variant', 'Var', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
108440	23977234	Additionally, a new blood sample was obtained from individual III:14 since the initial sample did not show presence of a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (130, 134))	('mutation', 'Var', (135, 143))	('BAP1', 'Gene', (130, 134))
108442	23977234	RT-PCR was performed on cDNA from one carrier (III:6) to verify that the BAP1 mutation was indeed a splicing variant.	('BAP1', 'Gene', '8314', (73, 77))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('mutation', 'Var', (78, 86))	('carrier', 'molecular_function', 'GO:0005215', ('38', '45'))	('BAP1', 'Gene', (73, 77))
108449	23977234	Whole-exome-sequencing identified a BAP1 splice mutation (c.581-2A>G) in an individual with UMM from a Danish family predisposed to developing UMM as well as a host of other cancers.	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('UMM', 'Phenotype', 'HP:0007716', (92, 95))	('BAP1', 'Gene', '8314', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('UMM', 'Disease', (143, 146))	('UMM', 'Phenotype', 'HP:0007716', (143, 146))	('c.581-2A>G', 'Var', (58, 68))	('BAP1', 'Gene', (36, 40))	('c.581-2A>G', 'Mutation', 'rs1430317959', (58, 68))
108450	23977234	Co-segregation analysis showed that three out of the four UMM cases with DNA available for research purposes were carriers of this mutation, which causes premature truncation of BAP1.	('BAP1', 'Gene', '8314', (178, 182))	('BAP1', 'Gene', (178, 182))	('causes', 'Reg', (147, 153))	('UMM', 'Phenotype', 'HP:0007716', (58, 61))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('premature truncation', 'MPA', (154, 174))	('mutation', 'Var', (131, 139))
108451	23977234	Additionally, there were four other individuals with different cancer types that also carried the mutation.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (63, 69))	('mutation', 'Var', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
108453	23977234	To confirm that individual III:14 was wildtype for the BAP1 mutation a newly obtained blood sample was screened.	('BAP1', 'Gene', '8314', (55, 59))	('BAP1', 'Gene', (55, 59))	('mutation', 'Var', (60, 68))
108454	23977234	Indeed, the analysis confirmed the absence of BAP1 mutation suggesting that this case is a phenocopy.	('BAP1', 'Gene', '8314', (46, 50))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', (46, 50))
108455	23977234	Loss of heterozygosity (LOH) of the BAP1 mutation was also observed in DNA from tumor tissue from II:11.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('BAP1', 'Gene', '8314', (36, 40))	('tumor', 'Disease', (80, 85))	('mutation', 'Var', (41, 49))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', (36, 40))
108456	23977234	Consistent with data from the 1000 Genomes Project, genotyping results showed that this variant was only present in the current family, that is only 1/1655 melanoma probands carried the variant and 0/1596 controls.	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('variant', 'Var', (186, 193))
108457	23977234	Exome data from 200 healthy Danish controls was also examined for BAP1 mutation and no protein altering variant was seen.	('mutation', 'Var', (71, 79))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
108458	23977234	There have been several cancer types associated with BAP1 germline mutations but the full spectrum of tumor susceptibility is still to be ascertained.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('BAP1', 'Gene', '8314', (53, 57))	('germline mutations', 'Var', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('BAP1', 'Gene', (53, 57))
108460	23977234	Whole-exome sequencing of a UMM case identified a BAP1 splice mutation (c.581-2A>G), which leads to premature truncation of BAP1.	('c.581-2A>G', 'Mutation', 'rs1430317959', (72, 82))	('premature truncation', 'MPA', (100, 120))	('BAP1', 'Gene', '8314', (124, 128))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (124, 128))	('BAP1', 'Gene', (50, 54))	('UMM', 'Phenotype', 'HP:0007716', (28, 31))	('c.581-2A>G', 'Var', (72, 82))	('leads to', 'Reg', (91, 99))
108464	23977234	The exome sequence data of the person with UMM and wild type BAP1 did not reveal mutations in other known cancer predisposition genes.	('person', 'Species', '9606', (31, 37))	('BAP1', 'Gene', (61, 65))	('UMM', 'Phenotype', 'HP:0007716', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('UMM', 'Var', (43, 46))	('BAP1', 'Gene', '8314', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
108466	23977234	The family described here also had a variety of other cancer types, some of which have been implicated with BAP1 mutation (lung) and some that have not (stomach, neuroendocrine).	('mutation', 'Var', (113, 121))	('BAP1', 'Gene', '8314', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('BAP1', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
108469	20038816	We evaluate sorafenib efficacy and impact on the cellular pro-survival machinery in vitro, efficacy of sorafenib as monotherapy and in combination with the naturally occurring death receptor agonist, TRAIL using human MPM cell lines, MSTO-211H, M30, REN, H28, H2052 and H2452.	('human', 'Species', '9606', (212, 217))	('REN', 'Gene', '5972', (250, 253))	('H2452', 'CellLine', 'CVCL:1553', (270, 275))	('sorafenib', 'Chemical', 'MESH:D000077157', (103, 112))	('REN', 'Gene', (250, 253))	('TRAIL', 'Gene', '8743', (200, 205))	('sorafenib', 'Chemical', 'MESH:D000077157', (12, 21))	('H2052', 'Var', (260, 265))	('MSTO-211H', 'Chemical', '-', (234, 243))	('TRAIL', 'Gene', (200, 205))	('H2052', 'CellLine', 'CVCL:1518', (260, 265))	('pro-survival', 'biological_process', 'GO:0043066', ('58', '70'))
108471	20038816	H28 and H2452 demonstrated augmented apoptosis with the addition of TRAIL to sorafenib in vitro.	('H2452', 'Var', (8, 13))	('TRAIL', 'Gene', '8743', (68, 73))	('apoptosis', 'CPA', (37, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('augmented', 'PosReg', (27, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('TRAIL', 'Gene', (68, 73))	('sorafenib', 'Chemical', 'MESH:D000077157', (77, 86))	('H2452', 'CellLine', 'CVCL:1553', (8, 13))
108503	20038816	In H2452 and H28, pre-treatment with low concentrations of sorafenib demonstrated a synergistic cytotoxic effect when followed by the addition of TRAIL (Fig.	('sorafenib', 'Chemical', 'MESH:D000077157', (59, 68))	('TRAIL', 'Gene', '8743', (146, 151))	('sorafenib', 'Gene', (59, 68))	('H2452', 'Var', (3, 8))	('pre', 'molecular_function', 'GO:0003904', ('18', '21'))	('TRAIL', 'Gene', (146, 151))	('H2452', 'CellLine', 'CVCL:1553', (3, 8))
108506	20038816	Interestingly, basal phosphorylation levels of VEGFR2 (tyrosines 951 & 1175), PDGFRbeta were modest and revealed minimal changes after therapy with sorafenib in most cell lines (data not shown).	('VEGFR2', 'Gene', (47, 53))	('PDGFRbeta', 'Gene', '5159', (78, 87))	('sorafenib', 'Chemical', 'MESH:D000077157', (148, 157))	('tyrosines 951', 'Var', (55, 68))	('phosphorylation levels', 'MPA', (21, 43))	('PDGFRbeta', 'Gene', (78, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('tyrosines', 'Chemical', 'MESH:D014443', (55, 64))	('VEGFR2', 'Gene', '3791', (47, 53))	('phospho', 'Chemical', 'MESH:D004099', (21, 28))
108525	20038816	To further confirm that sorafenib cell killing in MPM cell lines is caspase independent, cells were treated for 2 h with Z-VAD-FMK (10 microM), a potent, cell permeable, irreversible, pan-caspase inhibitor, prior to treatment with TRAIL and/or sorafenib.	('sorafenib', 'Chemical', 'MESH:D000077157', (244, 253))	('Z-VAD-FMK', 'Var', (121, 130))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (121, 130))	('TRAIL', 'Gene', '8743', (231, 236))	('cell killing', 'biological_process', 'GO:0001906', ('34', '46'))	('TRAIL', 'Gene', (231, 236))	('sorafenib', 'Chemical', 'MESH:D000077157', (24, 33))
108529	20038816	In order to establish a tumor-bearing xenograft model for human malignant pleural mesothelioma, we tested the ability of H28, H2052, H2452 and MSTO-211H to form subcutaneous tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('H2052', 'CellLine', 'CVCL:1518', (126, 131))	('human', 'Species', '9606', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MSTO-211H', 'Chemical', '-', (143, 152))	('H2452', 'CellLine', 'CVCL:1553', (133, 138))	('malignant pleural mesothelioma', 'Disease', (64, 94))	('tumors', 'Disease', (174, 180))	('H2452', 'Var', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', (24, 29))	('tested', 'Reg', (99, 105))	('H2052', 'Var', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (174, 179))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (74, 94))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (64, 94))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (161, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('MSTO-211H', 'Var', (143, 152))
108559	20038816	One exception is the heterodimerization of BCL-2 family member Bad with BCL-XL which leads to apoptosis, the association of which is blocked by Bad phosphorylation and subsequent binding and sequestration by 14-3-3.	('BCL-XL', 'Gene', '598', (72, 78))	('heterodimerization', 'Var', (21, 39))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('leads to', 'Reg', (85, 93))	('BCL-2', 'Gene', (43, 48))	('binding', 'Interaction', (179, 186))	('phospho', 'Chemical', 'MESH:D004099', (148, 155))	('BCL-XL', 'Gene', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('phosphorylation', 'MPA', (148, 163))	('BCL-2', 'molecular_function', 'GO:0015283', ('43', '48'))	('BCL-2', 'Gene', '596', (43, 48))	('apoptosis', 'CPA', (94, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
108568	20038816	FLIPL expression levels were noted to be elevated in H2052, MSTO-211H, H2452 and M30 but not H28 and REN.	('H2452', 'CellLine', 'CVCL:1553', (71, 76))	('H2452', 'Var', (71, 76))	('REN', 'Gene', (101, 104))	('FLIPL expression levels', 'MPA', (0, 23))	('H2052', 'CellLine', 'CVCL:1518', (53, 58))	('H2052', 'Var', (53, 58))	('elevated', 'PosReg', (41, 49))	('MSTO-211H', 'Chemical', '-', (60, 69))	('M30', 'Var', (81, 84))	('REN', 'Gene', '5972', (101, 104))	('MSTO-211H', 'Var', (60, 69))
108578	20038816	Human cell lines utilized for in vitro include MSTO-211H, H2052, H2452, H28 (purchased from ATCC) and REN, M30 (provided by Dr. Steven Albelda, University of Pennsylvania).	('Human', 'Species', '9606', (0, 5))	('H2052', 'CellLine', 'CVCL:1518', (58, 63))	('H2452', 'CellLine', 'CVCL:1553', (65, 70))	('MSTO-211H', 'Chemical', '-', (47, 56))	('H2452', 'Var', (65, 70))	('REN', 'Gene', (102, 105))	('REN', 'Gene', '5972', (102, 105))
108607	20038816	This technique yielded poor xenograft tumor induction using H28 (one cage) and H2452 (one cage) with little tumor growth, and some tumor regression, over a 2 mon period.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('H2452', 'CellLine', 'CVCL:1553', (79, 84))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (131, 136))	('H2452', 'Var', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('H28', 'Var', (60, 63))
108692	20628387	There was no difference between the intelectin-1 mRNA of ACC-MESO-1 and that of ACC-MESO-4; both cell lines transcribed a similar amount of intelectin-1 mRNA (Figure 2B) and each intelectin-1 had the same single-nucleotide polymorphisms: A48G (silent mutation), T258C (silent mutation), and A326T (D109V).	('intelectin-1', 'Gene', '55600', (140, 152))	('intelectin-1', 'Gene', '55600', (179, 191))	('A48G', 'Mutation', 'rs35779394', (238, 242))	('intelectin-1', 'Gene', (140, 152))	('intelectin-1', 'Gene', (179, 191))	('A326T (D109V', 'Var', (291, 303))	('T258C', 'Var', (262, 267))	('D109V', 'Mutation', 'rs2274907', (298, 303))	('T258C', 'Mutation', 'rs2274908', (262, 267))	('intelectin-1', 'Gene', '55600', (36, 48))	('A326T', 'Mutation', 'rs2274907', (291, 296))	('intelectin-1', 'Gene', (36, 48))	('A48G', 'Var', (238, 242))	('ACC-MESO-4', 'Chemical', '-', (80, 90))
108709	20628387	Trimeric intelectin-1 (120 kDa) was detected in plasma (Figure 4A) and pleural effusion (Figure 4B) of all MPM patients on western blotting.	('120 kDa', 'Var', (23, 30))	('intelectin-1', 'Gene', '55600', (9, 21))	('pleural effusion', 'Phenotype', 'HP:0002202', (71, 87))	('intelectin-1', 'Gene', (9, 21))	('pleural effusion', 'Disease', 'MESH:D010996', (71, 87))	('MPM', 'Disease', (107, 110))	('pleural effusion', 'Disease', (71, 87))	('patients', 'Species', '9606', (111, 119))
108934	23617783	Over-expression of HMGB1 is associated with the hallmark of cancer such as unlimited potential for replication, angiogenesis, apoptosis, self-sufficiency in growth signals, insensitivity to antigrowth signals, inflammatory microenvironment, tissue invasion, and metastasis.	('insensitivity', 'MPA', (173, 186))	('apoptosis', 'CPA', (126, 135))	('self-sufficiency', 'Disease', 'MESH:D012652', (137, 153))	('self-sufficiency', 'Disease', (137, 153))	('Over-expression', 'Var', (0, 15))	('tissue invasion', 'biological_process', 'GO:0001404', ('241', '256'))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('unlimited potential for replication', 'CPA', (75, 110))	('angiogenesis', 'CPA', (112, 124))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('HMGB1', 'Gene', (19, 24))	('HMGB1', 'Gene', '3146', (19, 24))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (142, 163))	('associated', 'Reg', (28, 38))	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('tissue invasion', 'CPA', (241, 256))	('cancer', 'Disease', (60, 66))	('metastasis', 'CPA', (262, 272))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
108935	23617783	Taguchi and colleagues demonstrated that blockade of RAGE-HMGB1 signaling suppressed tumor growth and metastasis.	('tumor', 'Disease', (85, 90))	('RAGE', 'Gene', (53, 57))	('suppressed', 'NegReg', (74, 84))	('HMGB1', 'Gene', (58, 63))	('HMGB1', 'Gene', '3146', (58, 63))	('blockade', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RAGE', 'Gene', '177', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
108945	23617783	In this study, we first examined HMGB1 production in MPM cells and found that mesothelioma cells such as H28 (epithelioid) and H2052 (sarcomatoid) produced higher levels of HMGB1 protein than that of human mesothelial cell line MeT-5A.	('HMGB1', 'Gene', '3146', (33, 38))	('protein', 'Protein', (179, 186))	('higher', 'PosReg', (156, 162))	('sarcomatoid', 'Disease', 'MESH:C538614', (134, 145))	('H2052', 'CellLine', 'CVCL:1518', (127, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('HMGB1', 'Gene', '3146', (173, 178))	('sarcomatoid', 'Disease', (134, 145))	('human', 'Species', '9606', (200, 205))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('HMGB1', 'Gene', (33, 38))	('HMGB1', 'Gene', (173, 178))	('H2052', 'Var', (127, 132))	('mesothelioma', 'Disease', (78, 90))
108983	23350030	Concerning this issue, the recent reviews by D. Kell analyse the wide but dispersed literature via a systems biology approach, and indicate that iron that is weakly complexed boosts many biochemical processes leading to a large variety of apparently unrelated diseases.	('boosts', 'PosReg', (175, 181))	('iron', 'Chemical', 'MESH:D007501', (145, 149))	('biochemical processes', 'MPA', (187, 208))	('iron', 'Var', (145, 149))
109160	22007251	In addition, mesothelioma-specific epigenetic profiles were identified for differential diagnosis with lung adenomatous cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung adenomatous cancers', 'Disease', (103, 127))	('lung adenomatous cancers', 'Disease', 'MESH:D008175', (103, 127))	('mesothelioma-specific', 'Disease', (13, 34))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('epigenetic profiles', 'Var', (35, 54))
109165	22007251	Moreover, the importance of a homozygous deletion of CDKN2A/2B was found in rat mesothelioma with the suggestion that this deletion seems to be fundamental for the development of mesothelioma, since these genes are also known to be homozygously deleted in human mesothelioma.	('human', 'Species', '9606', (256, 261))	('CDKN2A/2B', 'Gene', (53, 62))	('mesothelioma', 'Disease', (179, 191))	('deletion', 'Var', (41, 49))	('CDKN2A/2B', 'Gene', '25163', (53, 62))
109179	22007251	As shown on the left side of Figure 2, transient and relatively high-dose exposure (25-50 mug/mL, not likely to comprise adhesive cells such as alveolar epithelial or mesothelial cells, since we are using suspended cells, and thus, mug/mL was used instead of mug/cm2) caused production of ROS as measured by production of O 2 - using flow cytometry, phosphorylation of proapoptotic molecules in the mitogen-activated protein kinase (MAPK) pathway such as p38 and c-Jun N-terminal kinase (JNK), release of cytochrome-c from mitochondria to the cytosol, BAX overexpression, cleavage of caspase-9 and -3, and thereafter the appearance of apoptosis.	('cleavage', 'CPA', (572, 580))	('cytochrome-c', 'Gene', '54205', (505, 517))	('apoptosis', 'biological_process', 'GO:0097194', ('635', '644'))	('apoptosis', 'biological_process', 'GO:0006915', ('635', '644'))	('MAPK', 'Gene', (433, 437))	('cytosol', 'cellular_component', 'GO:0005829', ('543', '550'))	('cytochrome-c', 'molecular_function', 'GO:0045155', ('505', '517'))	('MAPK', 'Gene', '5594', (433, 437))	('c-Jun N-terminal kinase', 'Gene', '5599', (463, 486))	('cytochrome-c', 'Gene', (505, 517))	('p38', 'Gene', (455, 458))	('release of cytochrome-c from mitochondria', 'biological_process', 'GO:0001836', ('494', '535'))	('c-Jun N-terminal kinase', 'Gene', (463, 486))	('mug', 'molecular_function', 'GO:0043739', ('232', '235'))	('mug', 'molecular_function', 'GO:0043739', ('90', '93'))	('JNK', 'molecular_function', 'GO:0004705', ('488', '491'))	('overexpression', 'PosReg', (556, 570))	('release', 'MPA', (494, 501))	('phosphorylation', 'biological_process', 'GO:0016310', ('350', '365'))	('JNK', 'Gene', (488, 491))	('p38', 'Gene', '1432', (455, 458))	('mitochondria', 'cellular_component', 'GO:0005739', ('523', '535'))	('mug/mL', 'Var', (232, 238))	('JNK', 'Gene', '5599', (488, 491))	('MAPK', 'molecular_function', 'GO:0004707', ('433', '437'))	('cytochrome-c', 'molecular_function', 'GO:0009461', ('505', '517'))	('BAX', 'Gene', (552, 555))	('apoptosis', 'CPA', (635, 644))	('BAX', 'Gene', '581', (552, 555))	('protein', 'cellular_component', 'GO:0003675', ('417', '424'))	('caspase-9 and -3', 'Gene', '842;836', (584, 600))	('mug', 'molecular_function', 'GO:0043739', ('259', '262'))
109194	22007251	Focusing on the NK cell-activating receptors, including NKG2D (also known as KLRK1 (killer cell lectin-like receptor subfamily K, member 1), klr and CD314, binding to a diverse family of ligands that include MHC class I chain-related A and B proteins and UL-16 binding proteins, where ligand-receptor interactions can result in the activation of NK and T cells), 2B4 (also known as NAIL; Nmrk; NKR2B4; SLAMF4 and CD244, mediate nonmajor histocompatibility complex (MHC) restricted killing), and NKp46 (also known as NCR1 (natural cytotoxicity triggering receptor 1), LY94 and CD335, constituting a natural cytotoxic receptor family with NKp44 and NKp30, and being important in killing tumor cells and dendritic cells), the YT-A1 human NK cell line exposed continuously to chrysotile asbestos revealed reduced expression of NKG2D and 2B4.	('NKp44', 'Gene', (637, 642))	('ligand', 'molecular_function', 'GO:0005488', ('285', '291'))	('LY94', 'Gene', (567, 571))	('NKG2D', 'Gene', (56, 61))	('NKp44', 'Gene', '9436', (637, 642))	('KLRK1', 'Gene', '22914', (77, 82))	('CD314', 'Gene', (149, 154))	('2B4', 'Gene', (833, 836))	('NCR1', 'Gene', (516, 520))	('NKG2D', 'Gene', (823, 828))	('2B4', 'Gene', (363, 366))	('NKG2D', 'Gene', '22914', (56, 61))	('CD244', 'Gene', '51744', (413, 418))	('NKp30', 'Gene', '259197', (647, 652))	('NAIL', 'Gene', (382, 386))	('natural cytotoxicity triggering receptor 1', 'Gene', '9437', (522, 564))	('NKR2B4', 'Gene', '51744', (394, 400))	('NKG2D', 'Gene', '22914', (823, 828))	('expression', 'MPA', (809, 819))	('Nmrk', 'Gene', (388, 392))	('CD314', 'Gene', '22914', (149, 154))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('binding', 'molecular_function', 'GO:0005488', ('261', '268'))	('NKR2B4', 'Gene', (394, 400))	('CD244', 'Gene', (413, 418))	('2B4', 'Gene', '51744', (397, 400))	('SLAMF4', 'Gene', (402, 408))	('tumor', 'Phenotype', 'HP:0002664', (685, 690))	('NKp46', 'Gene', '9437', (495, 500))	('NCR1', 'Gene', '9437', (516, 520))	('reduced', 'NegReg', (801, 808))	('LY94', 'Gene', '9437', (567, 571))	('SLAMF4', 'Gene', '51744', (402, 408))	('CD335', 'Gene', '9437', (576, 581))	('cytotoxicity', 'Disease', (530, 542))	('NKp46', 'Gene', (495, 500))	('interactions', 'Var', (301, 313))	('lectin', 'molecular_function', 'GO:0005530', ('96', '102'))	('cytotoxicity', 'Disease', 'MESH:D064420', (530, 542))	('NAIL', 'Gene', '51744', (382, 386))	('2B4', 'Gene', '51744', (833, 836))	('natural cytotoxicity triggering receptor 1', 'Gene', (522, 564))	('2B4', 'Gene', '51744', (363, 366))	('Nmrk', 'Gene', '51744', (388, 392))	('2B4', 'Gene', (397, 400))	('NKp30', 'Gene', (647, 652))	('KLRK1', 'Gene', (77, 82))	('CD335', 'Gene', (576, 581))
109246	20839315	We used previously prepared probe and primer sets for PIK3CA (Hs.00907966_m1) and RICTOR (Hs.00380903_m1).	('PIK3CA', 'Gene', '5290', (54, 60))	('Hs.00907966_m1', 'Var', (62, 76))	('Hs.00380903_m1', 'Var', (90, 104))	('PIK3CA', 'Gene', (54, 60))
109251	20839315	We reconstituted the dual PI3K-mTOR inhibitor NVP-BEZ235-AN (Novartis Institutes for Biomedical Research, East Hanover, NJ) in dimethyl sulfoxide (DMSO) for experimental studies to test the therapeutic significance of the PI3K and mTOR signaling pathways.	('test', 'Reg', (181, 185))	('men', 'Species', '9606', (163, 166))	('signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('DMSO', 'Chemical', 'MESH:D004121', (147, 151))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (127, 145))	('PI3K', 'molecular_function', 'GO:0016303', ('222', '226'))	('NVP-BEZ235-AN', 'Chemical', 'MESH:C531198', (46, 59))	('NVP-BEZ235-AN', 'Var', (46, 59))
109253	20839315	We identified the optimal concentration of BEZ235 to inhibit cell proliferation in our dose-escalation studies.	('inhibit', 'NegReg', (53, 60))	('cell proliferation', 'CPA', (61, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('BEZ235', 'Var', (43, 49))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
109273	20839315	The 2 significantly overexpressed pathways that were identified in patients who had a poor prognosis were associated with PI3K and mTOR signaling (P < .01) (Table 2).	('PI3K', 'Var', (122, 126))	('mTOR signaling', 'MPA', (131, 145))	('patients', 'Species', '9606', (67, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('overexpressed', 'PosReg', (20, 33))
109285	20839315	Our gene expression studies indicated that PI3K and mTOR signaling are associated significantly with aggressive MPM growth and shortened patient survival.	('PI3K', 'Var', (43, 47))	('MPM', 'Disease', 'MESH:D010534', (112, 115))	('patient', 'Species', '9606', (137, 144))	('shortened', 'NegReg', (127, 136))	('mTOR', 'MPA', (52, 56))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('MPM', 'Disease', (112, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('patient survival', 'CPA', (137, 153))	('associated', 'Reg', (71, 81))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
109286	20839315	We reasoned that inhibition of these pathways might have antitumor activity by suppressing tumor cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('inhibition', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('suppressing', 'NegReg', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (61, 66))
109289	20839315	Cells that were treated with 250 nm BEZ235 revealed the marked suppression of PI3K and mTOR signaling and resulted in significant inhibition of cell proliferation (Fig.	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))	('suppression', 'NegReg', (63, 74))	('cell proliferation', 'CPA', (144, 162))	('mTOR signaling', 'Pathway', (87, 101))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('130', '162'))	('PI3K', 'Pathway', (78, 82))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('inhibition', 'NegReg', (130, 140))	('BEZ235', 'Var', (36, 42))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))
109290	20839315	In both cell lines, BEZ235 inhibited PI3K-p110alpha, mTOR, and RICTOR protein expression and phosphorylation of PI3K-p85 and AKT (Fig.	('PI3K-p85', 'Pathway', (112, 120))	('BEZ235', 'Var', (20, 26))	('RICTOR protein', 'Protein', (63, 77))	('BEZ235', 'Chemical', 'MESH:C531198', (20, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('PI3K-p110alpha', 'Var', (37, 51))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('mTOR', 'Protein', (53, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('112', '116'))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('inhibited', 'NegReg', (27, 36))	('phosphorylation', 'MPA', (93, 108))	('AKT', 'Pathway', (125, 128))
109309	20839315	It is known that PIK3CA, the gene that encodes PI3K-P110alpha, regulates cell proliferation and angiogenesis and has a highly significant association with a poor prognosis in patients with MPM.	('association', 'Reg', (138, 149))	('PI3K-P110alpha', 'Var', (47, 61))	('regulates', 'PosReg', (63, 72))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('angiogenesis', 'biological_process', 'GO:0001525', ('96', '108'))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('MPM', 'Disease', 'MESH:D010534', (189, 192))	('angiogenesis', 'CPA', (96, 108))	('patients', 'Species', '9606', (175, 183))	('cell proliferation', 'CPA', (73, 91))	('MPM', 'Disease', (189, 192))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))
109315	20839315	Recent studies have demonstrated that RICTOR results in the phosphorylation of AKT and is relatively insensitive to rapamycin but sensitive to PI3K inhibitors.	('phosphorylation', 'MPA', (60, 75))	('RICTOR', 'Var', (38, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('rapamycin', 'Chemical', 'MESH:D020123', (116, 125))	('AKT', 'Pathway', (79, 82))
109324	20839315	It has been demonstrated that BEZ235, a dual-class PI3K and mTOR inhibitor, significantly reduces growth in human xenograft models of lung cancer and glioma.	('lung cancer', 'Disease', (134, 145))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('reduces', 'NegReg', (90, 97))	('growth', 'MPA', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('glioma', 'Disease', (150, 156))	('human', 'Species', '9606', (108, 113))	('BEZ235', 'Var', (30, 36))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
109325	20839315	In our study, treatment of the MPM cell lines Meso-1 and Meso-2 with BEZ235 significantly reduced cell proliferation, indicating that BEZ235 may be an effective inhibitor of MPM tumor progression.	('cell proliferation', 'CPA', (98, 116))	('tumor', 'Disease', (178, 183))	('BEZ235', 'Chemical', 'MESH:C531198', (134, 140))	('reduced', 'NegReg', (90, 97))	('MPM', 'Disease', 'MESH:D010534', (174, 177))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('MPM', 'Disease', 'MESH:D010534', (31, 34))	('BEZ235', 'Var', (69, 75))	('MPM', 'Disease', (174, 177))	('BEZ235', 'Chemical', 'MESH:C531198', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('men', 'Species', '9606', (19, 22))	('MPM', 'Disease', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
109326	20839315	Protein analyses have indicated that BEZ235 results in the global inhibition of downstream PI3K and mTOR signaling.	('mTOR signaling', 'Pathway', (100, 114))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('BEZ235', 'Var', (37, 43))	('inhibition', 'NegReg', (66, 76))	('BEZ235', 'Chemical', 'MESH:C531198', (37, 43))
109448	27806086	Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin.	('increases', 'PosReg', (7, 16))	('death', 'Disease', 'MESH:D003643', (26, 31))	('Ptac2S', 'Chemical', '-', (0, 6))	('cell death', 'biological_process', 'GO:0008219', ('21', '31'))	('Ptac2S', 'Var', (0, 6))	('death', 'Disease', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))
109449	27806086	Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9.	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('Bcl-2', 'Gene', '596', (214, 219))	('mitochondria', 'cellular_component', 'GO:0005739', ('171', '183'))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('bax', 'Gene', (137, 140))	('cytosol', 'cellular_component', 'GO:0005829', ('160', '167'))	('increase', 'PosReg', (125, 133))	('Ptac2S', 'Var', (0, 6))	('decrease', 'NegReg', (202, 210))	('cytosol-to-mitochondria translocation', 'MPA', (160, 197))	('mitochondria', 'cellular_component', 'GO:0005739', ('92', '104'))	('mitochondria depolarization', 'biological_process', 'GO:0051882', ('92', '119'))	('Ptac2S', 'Chemical', '-', (0, 6))	('caspase-7 and -9', 'Gene', '840;842', (250, 266))	('Bcl-2', 'molecular_function', 'GO:0015283', ('214', '219'))	('apoptosis', 'CPA', (60, 69))	('bax', 'Gene', '581', (137, 140))	('expression', 'MPA', (141, 151))	('expression', 'MPA', (220, 230))	('activation', 'PosReg', (236, 246))	('inducing', 'Reg', (51, 59))	('mitochondria depolarization', 'MPA', (92, 119))	('Bcl-2', 'Gene', (214, 219))
109454	27806086	Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (81, 103))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (81, 103))	('Ptac2S', 'Chemical', '-', (37, 43))	('malignant mesothelioma', 'Disease', (81, 103))	('Ptac2S', 'Var', (37, 43))
109462	27806086	Remarkably, in a preclinical model based on the subcutaneous injection of MCF-7 breast cancer, Ptac2S stands out for higher anticancer activity than CDDP toward both the murine tumor models examined, and also for an enhanced in vivo pharmacokinetics (PK), biodistribution and tolerability in Wistar rats.	('enhanced', 'PosReg', (216, 224))	('higher', 'PosReg', (117, 123))	('cancer', 'Disease', (128, 134))	('Ptac2S', 'Var', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Ptac2S', 'Chemical', '-', (95, 101))	('tumor', 'Disease', (177, 182))	('cancer', 'Disease', (87, 93))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (74, 93))	('CDDP', 'Chemical', '-', (149, 153))	('MCF-7 breast cancer', 'Disease', (74, 93))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Wistar rats', 'Species', '10116', (292, 303))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('murine', 'Species', '10090', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
109464	27806086	Theoretically, this compound could provide a broader spectrum of application since, alongside to the cytotoxic effects, Ptac2S also exerts specific anti-metastatic responses in vitro.	('anti-metastatic responses', 'CPA', (148, 173))	('Ptac2S', 'Chemical', '-', (120, 126))	('Ptac2S', 'Var', (120, 126))
109465	27806086	Keeping in mind these results it is important to understand whether or not Ptac2S is cytotoxic to malignant mesothelioma, which is resistant to conventional therapies.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (98, 120))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (98, 120))	('malignant mesothelioma', 'Disease', (98, 120))	('Ptac2S', 'Chemical', '-', (75, 81))	('Ptac2S', 'Var', (75, 81))
109467	27806086	Being epithelial type the most represented, here we used the human ZL55 cells, obtained from asbestos-exposed patients that represent a trustworthy model for evaluating the ability of Ptac2S to cause cell death and also to understand its mechanisms of toxicity.	('toxicity', 'Disease', (252, 260))	('ZL55', 'Chemical', '-', (67, 71))	('death', 'Disease', 'MESH:D003643', (205, 210))	('Ptac2S', 'Chemical', '-', (184, 190))	('asbestos', 'Chemical', 'MESH:D001194', (93, 101))	('toxicity', 'Disease', 'MESH:D064420', (252, 260))	('Ptac2S', 'Var', (184, 190))	('cause', 'Reg', (194, 199))	('human', 'Species', '9606', (61, 66))	('cell death', 'biological_process', 'GO:0008219', ('200', '210'))	('patients', 'Species', '9606', (110, 118))	('death', 'Disease', (205, 210))
109468	27806086	Previously we have shown CDDP was cytotoxic for ZL55 cells with an IC50 obtained after 48 h of 11 muM.	('muM', 'Gene', (98, 101))	('CDDP', 'Var', (25, 29))	('ZL55', 'Chemical', '-', (48, 52))	('CDDP', 'Chemical', '-', (25, 29))	('muM', 'Gene', '56925', (98, 101))
109470	27806086	In the current investigation, we aimed to assess the cytotoxicity of Ptac2S both in vitro and in vivo and to compare to that of CDDP, and also to understand what differences we may have in the cellular mechanisms that determine the ZL55 death/survival fate.	('ZL55', 'Chemical', '-', (232, 236))	('CDDP', 'Chemical', '-', (128, 132))	('cytotoxicity', 'Disease', (53, 65))	('Ptac2S', 'Chemical', '-', (69, 75))	('death', 'Disease', 'MESH:D003643', (237, 242))	('death', 'Disease', (237, 242))	('Ptac2S', 'Var', (69, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))
109508	27806086	Ptac2S was significantly more cytotoxic than CDDP also by using the clonogenic assay (Fig 1C).	('cytotoxic', 'CPA', (30, 39))	('Ptac2S', 'Chemical', '-', (0, 6))	('Ptac2S', 'Var', (0, 6))	('CDDP', 'Chemical', '-', (45, 49))	('clonogenic assay', 'CPA', (68, 84))
109513	27806086	The time course of the nuclear changes revealed that ZL55 cells reacted differently from platinum compounds, inasmuch as 50% of apoptotic cells were seen after 6 h of treatment with Ptac2S (Fig 2B) but after 12 h of treatment with CDDP (Fig 2C).	('ZL55', 'Chemical', '-', (53, 57))	('Ptac2S', 'Var', (182, 188))	('CDDP', 'Chemical', '-', (231, 235))	('apoptotic cells', 'CPA', (128, 143))	('platinum', 'Chemical', 'MESH:D010984', (89, 97))	('Ptac2S', 'Chemical', '-', (182, 188))
109517	27806086	As shown in Fig 2D, PARP-1 was cleaved both in cells treated with 5 muM Ptac2S that with 50 muM CDDP; however, proteolysis was faster with Ptac2S.	('muM', 'Gene', (92, 95))	('CDDP', 'Chemical', '-', (96, 100))	('proteolysis', 'MPA', (111, 122))	('muM', 'Gene', (68, 71))	('Ptac2S', 'Chemical', '-', (139, 145))	('PARP-1', 'Gene', '142', (20, 26))	('Ptac2S', 'Chemical', '-', (72, 78))	('proteolysis', 'biological_process', 'GO:0006508', ('111', '122'))	('Ptac2S', 'Var', (72, 78))	('muM', 'Gene', '56925', (92, 95))	('PARP-1', 'Gene', (20, 26))	('muM', 'Gene', '56925', (68, 71))
109520	27806086	Ptac2S increased Bax expression whilst decreased the levels of Bcl-2.	('Ptac2S', 'Chemical', '-', (0, 6))	('increased', 'PosReg', (7, 16))	('Bcl-2', 'molecular_function', 'GO:0015283', ('63', '68'))	('Ptac2S', 'Var', (0, 6))	('Bax', 'Gene', (17, 20))	('decreased', 'NegReg', (39, 48))	('Bcl-2', 'Gene', '596', (63, 68))	('Bcl-2', 'Gene', (63, 68))	('Bax', 'Gene', '581', (17, 20))
109522	27806086	Ptac2S also provoked the cytosol-to-mitochondria translocation of Bax, and the translocation of Bcl-2 from mitochondria to cytosol, phenomena that precede the decrease in the electric potential of the mitochondrial membrane (DeltaPsim) (Fig 3A and 3B).	('Ptac2S', 'Chemical', '-', (0, 6))	('Bcl-2', 'Gene', (96, 101))	('Bax', 'Gene', '581', (66, 69))	('Bcl-2', 'Gene', '596', (96, 101))	('electric potential of the mitochondrial membrane', 'MPA', (175, 223))	('cytosol-to-mitochondria translocation', 'MPA', (25, 62))	('mitochondria', 'cellular_component', 'GO:0005739', ('107', '119'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('201', '223'))	('translocation', 'MPA', (79, 92))	('Ptac2S', 'Var', (0, 6))	('mitochondria', 'cellular_component', 'GO:0005739', ('36', '48'))	('cytosol', 'cellular_component', 'GO:0005829', ('25', '32'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('96', '101'))	('Bax', 'Gene', (66, 69))	('provoked', 'Reg', (12, 20))	('cytosol', 'cellular_component', 'GO:0005829', ('123', '130'))
109540	27806086	Furthermore, PKC-delta-siRNA also inhibited the Ptac2S-provoked caspase-7 activation and PARP-1 cleavage (Fig 4F and 4G).	('PKC-delta', 'Gene', (13, 22))	('PKC-delta', 'Gene', '5580', (13, 22))	('Ptac2S', 'Chemical', '-', (48, 54))	('caspase-7', 'Gene', (64, 73))	('inhibited', 'NegReg', (34, 43))	('caspase-7', 'Gene', '840', (64, 73))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('activation', 'PosReg', (74, 84))	('Ptac2S-provoked', 'Var', (48, 63))	('cleavage', 'MPA', (96, 104))	('PARP-1', 'Gene', (89, 95))	('PARP-1', 'Gene', '142', (89, 95))
109542	27806086	We have previously demonstrated that Ptac2S activates the MAPK signaling pathway in several tumor cell lines.	('MAPK signaling pathway', 'Pathway', (58, 80))	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Ptac2S', 'Chemical', '-', (37, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('58', '62'))	('activates', 'PosReg', (44, 53))	('tumor', 'Disease', (92, 97))	('MAPK signaling', 'biological_process', 'GO:0000165', ('58', '72'))	('Ptac2S', 'Var', (37, 43))
109543	27806086	In the specific case of ZL-55, we have also shown that CDDP causes activation of the MAPK ERK1/2.	('CDDP', 'Chemical', '-', (55, 59))	('activation', 'PosReg', (67, 77))	('ERK1/2', 'Gene', (90, 96))	('ERK1/2', 'Gene', '5595;5594', (90, 96))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('CDDP', 'Var', (55, 59))	('ERK1', 'molecular_function', 'GO:0004707', ('90', '94'))
109564	27806086	First of all we report here the different dynamics of the effects of Ptac2S on cell apoptosis compared to CDDP: the cytotoxic effects of Ptac2S were faster than those elicited by CDDP.	('Ptac2S', 'Var', (137, 143))	('Ptac2S', 'Chemical', '-', (69, 75))	('faster', 'PosReg', (149, 155))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('CDDP', 'Chemical', '-', (106, 110))	('CDDP', 'Chemical', '-', (179, 183))	('Ptac2S', 'Chemical', '-', (137, 143))	('cytotoxic effects', 'CPA', (116, 133))
109571	27806086	Caspase-7 cleavage pattern was detected earlier in Ptac2S-treated cells compared to CDDP treatment, and matched the cleavage of PARP-1, thus supporting the study showing that caspase-7 is responsible for PARP-1 cleavage.	('Ptac2S', 'Chemical', '-', (51, 57))	('PARP-1', 'Gene', (128, 134))	('PARP-1', 'Gene', (204, 210))	('caspase-7', 'Gene', (175, 184))	('cleavage pattern', 'MPA', (10, 26))	('caspase-7', 'Gene', '840', (175, 184))	('CDDP', 'Chemical', '-', (84, 88))	('PARP-1', 'Gene', '142', (128, 134))	('PARP-1', 'Gene', '142', (204, 210))	('Caspase-7', 'Gene', (0, 9))	('Ptac2S-treated', 'Var', (51, 65))	('Caspase-7', 'Gene', '840', (0, 9))
109573	27806086	Ptac2S more rapidly than CDDP dissipated mitochondrial membrane potential (DeltaPsim).	('Ptac2S', 'Chemical', '-', (0, 6))	('Ptac2S', 'Var', (0, 6))	('dissipated mitochondrial membrane potential', 'MPA', (30, 73))	('CDDP', 'Chemical', '-', (25, 29))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('41', '63'))
109578	27806086	Albeit in some mesothelioma cell lines, low levels of Bcl-2 mRNA and protein were found, treatment with oligonucleotides Bcl-2 antisense lowered the apoptosis threshold in ZL34 mesothelioma cells.	('apoptosis threshold', 'CPA', (149, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (177, 189))	('Bcl-2', 'Gene', (121, 126))	('lowered', 'NegReg', (137, 144))	('Bcl-2', 'Gene', '596', (121, 126))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('121', '126'))	('antisense', 'Var', (127, 136))	('Bcl-2', 'molecular_function', 'GO:0015283', ('54', '59'))	('Bcl-2', 'Gene', (54, 59))	('oligonucleotides', 'Chemical', 'MESH:D009841', (104, 120))	('Bcl-2', 'Gene', '596', (54, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('mesothelioma', 'Disease', (15, 27))	('mesothelioma', 'Disease', (177, 189))
109588	27806086	Our in vitro findings suggest that Ptac2S might prove to be a more effective drug than CDDP in the treatment of MPM.	('CDDP', 'Chemical', '-', (87, 91))	('Ptac2S', 'Chemical', '-', (35, 41))	('MPM', 'Disease', (112, 115))	('Ptac2S', 'Var', (35, 41))
109590	27806086	Thus, we assessed the antitumor effects of Ptac2S in a xenograft model of mesothelioma developed by injection of ZL55, and compared with the effects obtained with CDDP.	('ZL55', 'Chemical', '-', (113, 117))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('CDDP', 'Chemical', '-', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Ptac2S', 'Chemical', '-', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mesothelioma', 'Disease', (74, 86))	('Ptac2S', 'Var', (43, 49))
109591	27806086	In vivo antitumor activity was consistent with the in vitro sensitivity, since mice inoculated with ZL55 cells showed a statistically significant reduction of tumor volume at every time point in the Ptac2S groups compared with both not treated and CDDP -treated mice.	('CDDP', 'Chemical', '-', (248, 252))	('Ptac2S', 'Var', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mice', 'Species', '10090', (262, 266))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mice', 'Species', '10090', (79, 83))	('ZL55', 'Chemical', '-', (100, 104))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('reduction', 'NegReg', (146, 155))	('Ptac2S', 'Chemical', '-', (199, 205))
109592	27806086	The difference of the effects in vivo between Ptac2S and CDDP was considerable inasmuch as Ptac2S induced up to 62% reduction of tumor mass compared to an average 10% inhibition obtained with CDDP.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('CDDP', 'Chemical', '-', (192, 196))	('Ptac2S', 'Chemical', '-', (46, 52))	('reduction', 'NegReg', (116, 125))	('Ptac2S', 'Chemical', '-', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CDDP', 'Chemical', '-', (57, 61))	('tumor', 'Disease', (129, 134))	('Ptac2S', 'Var', (91, 97))
109595	27806086	Concerning the intracellular events that Ptac2S causes in ZL55 cells, it is noteworthy the fact that, compared to CDDP, there is activation of PKCepsilon, while remains the fundamental pro apoptotic role of PKC-delta.	('PKC', 'molecular_function', 'GO:0004697', ('207', '210'))	('PKCepsilon', 'Gene', (143, 153))	('Ptac2S', 'Var', (41, 47))	('CDDP', 'Chemical', '-', (114, 118))	('ZL55', 'Chemical', '-', (58, 62))	('activation', 'PosReg', (129, 139))	('PKC-delta', 'Gene', (207, 216))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('143', '153'))	('intracellular', 'cellular_component', 'GO:0005622', ('15', '28'))	('PKC-delta', 'Gene', '5580', (207, 216))	('PKCepsilon', 'Gene', '5581', (143, 153))	('Ptac2S', 'Chemical', '-', (41, 47))
109598	25469901	Combination of MiR-103a-3p and Mesothelin Improves the Biomarker Performance of Malignant Mesothelioma Diagnosis For the detection of malignant mesothelioma no single biomarker with reasonable sensitivity and specificity has been described so far.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (134, 156))	('Biomarker Performance', 'MPA', (55, 76))	('Mesothelin', 'Gene', (31, 41))	('Mesothelin', 'Gene', '10232', (31, 41))	('MiR-103a-3p', 'Var', (15, 26))	('Malignant Mesothelioma', 'Disease', (80, 102))	('Improves', 'PosReg', (42, 50))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (134, 156))	('malignant mesothelioma', 'Disease', (134, 156))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (80, 102))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (80, 102))
109600	25469901	The aim of this study was to assess the performance of the combination of mesothelin and miR-103a-3p as blood-based biomarker for mesothelioma.	('mesothelioma', 'Disease', (130, 142))	('miR-103a-3p', 'Chemical', '-', (89, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('mesothelin', 'Gene', (74, 84))	('miR-103a-3p', 'Var', (89, 100))	('mesothelin', 'Gene', '10232', (74, 84))
109602	25469901	For the discrimination of epithelioid and biphasic mesothelioma from asbestos-exposed controls mesothelin and miR-103a-3p showed 74% and 89% sensitivity and 85% and 63% specificity, respectively.	('miR-103a-3p', 'Var', (110, 121))	('asbestos', 'Chemical', 'MESH:D001194', (69, 77))	('mesothelin', 'Gene', (95, 105))	('epithelioid', 'Disease', (26, 37))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (42, 63))	('miR-103a-3p', 'Chemical', '-', (110, 121))	('biphasic mesothelioma', 'Disease', (42, 63))	('mesothelin', 'Gene', '10232', (95, 105))
109603	25469901	For the combination of mesothelin and miR-103a-3p a sensitivity of 95% and a specificity of 81% were calculated.	('miR-103a-3p', 'Chemical', '-', (38, 49))	('mesothelin', 'Gene', '10232', (23, 33))	('miR-103a-3p', 'Var', (38, 49))	('mesothelin', 'Gene', (23, 33))
109604	25469901	The results of this study show that the combination of mesothelin and miR-103a-3p improves the diagnostic performance of individual blood-based biomarker to detect malignant mesothelioma.	('combination', 'Interaction', (40, 51))	('improves', 'PosReg', (82, 90))	('mesothelin', 'Gene', '10232', (55, 65))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (164, 186))	('individual blood-based biomarker', 'MPA', (121, 153))	('diagnostic performance', 'MPA', (95, 117))	('miR-103a-3p', 'Chemical', '-', (70, 81))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (164, 186))	('malignant mesothelioma', 'Disease', (164, 186))	('mesothelin', 'Gene', (55, 65))	('miR-103a-3p', 'Var', (70, 81))
109612	25469901	Several candidate biomarkers of both molecular classes were described, e.g., mesothelin, calretinin, fibulin-3, miR-126, miR-625-3p, and miR-103a-3p (previous miRBase ID: miR-103).	('miR-126', 'Gene', '406913', (112, 119))	('miR-126', 'Gene', (112, 119))	('miR-103', 'Chemical', '-', (137, 144))	('miR-103', 'Chemical', '-', (171, 178))	('miR-103a-3p', 'Chemical', '-', (137, 148))	('calretinin', 'Gene', '794', (89, 99))	('fibulin-3', 'Gene', '2202', (101, 110))	('3p', 'Chemical', '-', (146, 148))	('fibulin-3', 'Gene', (101, 110))	('mesothelin', 'Gene', (77, 87))	('miR-103a-3p', 'Var', (137, 148))	('3p', 'Chemical', '-', (129, 131))	('mesothelin', 'Gene', '10232', (77, 87))	('miR-625-3p', 'Var', (121, 131))	('calretinin', 'Gene', (89, 99))
109625	25469901	Twenty-three mesothelioma patients and 17 asbestos-exposed controls were part of a previous screening group identifying miR-103a-3p as a potential biomarker for mesothelioma.	('mesothelioma', 'Disease', (13, 25))	('mesothelioma', 'Disease', (161, 173))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('miR-103a-3p', 'Chemical', '-', (120, 131))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('miR-103a-3p', 'Var', (120, 131))	('patients', 'Species', '9606', (26, 34))
109629	25469901	TaqMan miRNA Assays (Life Technologies) were used for quantitative miRNA expression analysis of miR-103a-3p as biomarker and miR-125a as reference.	('miR-125a', 'Gene', '406910', (125, 133))	('miR-103a-3p', 'Var', (96, 107))	('miR-103a-3p', 'Chemical', '-', (96, 107))	('miR-125a', 'Gene', (125, 133))
109631	25469901	Box plots with median and inter-quartile range (IQR) were used to depict the distribution of mesothelin and miR-103a-3p.	('mesothelin', 'Gene', (93, 103))	('mesothelin', 'Gene', '10232', (93, 103))	('miR-103a-3p', 'Var', (108, 119))	('miR-103a-3p', 'Chemical', '-', (108, 119))
109646	25469901	Applying the calculated cut-off based on ROC analysis with maximum YI of the combination of mesothelin and miR-103a-3p (Table 3), sarcomatoid mesothelioma showed an increased OR of 72 (95% CI 5; 982) to be tested false-negative, whereas all other group characteristics showed no significant altered OR to be tested false-negative or false-positive (data not shown).	('sarcomatoid mesothelioma', 'Disease', (130, 154))	('false', 'biological_process', 'GO:0071877', ('333', '338'))	('false', 'biological_process', 'GO:0071878', ('333', '338'))	('mesothelin', 'Gene', (92, 102))	('false', 'biological_process', 'GO:0071878', ('213', '218'))	('false', 'biological_process', 'GO:0071877', ('213', '218'))	('false', 'biological_process', 'GO:0071877', ('315', '320'))	('mesothelin', 'Gene', '10232', (92, 102))	('miR-103a-3p', 'Chemical', '-', (107, 118))	('false', 'biological_process', 'GO:0071878', ('315', '320'))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (130, 154))	('miR-103a-3p', 'Var', (107, 118))
109649	25469901	Using ROC analyses including all subjects AUCs of 0.81 for mesothelin (Figure 3 A), 0.76 for miR-103a-3p (Figure 3 B), and 0.90 for the combination of mesothelin and miR-103a-3p (Figure 3 C) were calculated.	('miR-103a-3p', 'Var', (93, 104))	('mesothelin', 'Gene', '10232', (59, 69))	('mesothelin', 'Gene', '10232', (151, 161))	('miR-103a-3p', 'Chemical', '-', (93, 104))	('mesothelin', 'Gene', (151, 161))	('miR-103a-3p', 'Chemical', '-', (166, 177))	('mesothelin', 'Gene', (59, 69))
109650	25469901	Excluding the five sarcomatoid mesothelioma cases from the analysis revealed higher AUCs of 0.85 for mesothelin (Figure 3 D), 0.78 for miR-103a-3p (Figure 3 E), and 0.93 for the combination of mesothelin and miR-103a-3p (Figure 3 F).	('mesothelin', 'Gene', (101, 111))	('miR-103a-3p', 'Var', (135, 146))	('miR-103a-3p', 'Chemical', '-', (135, 146))	('mesothelin', 'Gene', (193, 203))	('miR-103a-3p', 'Var', (208, 219))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (19, 43))	('mesothelin', 'Gene', '10232', (193, 203))	('mesothelin', 'Gene', '10232', (101, 111))	('sarcomatoid mesothelioma', 'Disease', (19, 43))	('miR-103a-3p', 'Chemical', '-', (208, 219))	('AUCs', 'MPA', (84, 88))
109651	25469901	Sensitivities and specificities for mesothelin and miR-103a-3p are shown in Table 3.	('mesothelin', 'Gene', (36, 46))	('mesothelin', 'Gene', '10232', (36, 46))	('miR-103a-3p', 'Chemical', '-', (51, 62))	('miR-103a-3p', 'Var', (51, 62))
109652	25469901	Using maximum YI for cut-off selection resulted in 60% sensitivity and 92% specificity for mesothelin and 86% sensitivity and 63% specificity for miR-103a-3p.	('mesothelin', 'Gene', '10232', (91, 101))	('mesothelin', 'Gene', (91, 101))	('miR-103a-3p', 'Chemical', '-', (146, 157))	('miR-103a-3p', 'Var', (146, 157))
109653	25469901	Excluding the five sarcomatoid mesothelioma cases resulted in 74% sensitivity and 85% specificity for mesothelin and 89% sensitivity and 63% specificity for miR-103a-3p.	('miR-103a-3p', 'Chemical', '-', (157, 168))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (19, 43))	('mesothelin', 'Gene', (102, 112))	('miR-103a-3p', 'Var', (157, 168))	('sarcomatoid mesothelioma', 'Disease', (19, 43))	('mesothelin', 'Gene', '10232', (102, 112))
109655	25469901	Excluding the sarcomatoid mesothelioma cases resulted in sensitivities of 55% for mesothelin and 8% for miR-103a-3p.	('sensitivities', 'MPA', (57, 70))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (14, 38))	('sarcomatoid mesothelioma', 'Disease', (14, 38))	('mesothelin', 'Gene', (82, 92))	('miR-103a-3p', 'Chemical', '-', (104, 115))	('mesothelin', 'Gene', '10232', (82, 92))	('miR-103a-3p', 'Var', (104, 115))
109657	25469901	Combination of mesothelin and miR-103a-3p resulted in continuously higher sensitivities and consistently high specificities (Table 3).	('mesothelin', 'Gene', (15, 25))	('higher', 'PosReg', (67, 73))	('specificities', 'MPA', (110, 123))	('miR-103a-3p', 'Chemical', '-', (30, 41))	('miR-103a-3p', 'Var', (30, 41))	('mesothelin', 'Gene', '10232', (15, 25))	('sensitivities', 'MPA', (74, 87))
109661	25469901	ROC analyses of 1,000 bootstrap samples resulted in similar sensitivities and specificities for the combination of mesothelin and miR-103a-3p in comparison to the original analyses (Table 4).	('mesothelin', 'Gene', (115, 125))	('sensitivities', 'MPA', (60, 73))	('miR-103a-3p', 'Var', (130, 141))	('mesothelin', 'Gene', '10232', (115, 125))	('miR-103a-3p', 'Chemical', '-', (130, 141))
109665	25469901	In this study mesothelin was combined with miR-103a-3p, resulting in an improved AUC of 0.93.	('miR-103a-3p', 'Chemical', '-', (43, 54))	('improved', 'PosReg', (72, 80))	('mesothelin', 'Gene', '10232', (14, 24))	('AUC', 'MPA', (81, 84))	('miR-103a-3p', 'Var', (43, 54))	('mesothelin', 'Gene', (14, 24))
109669	25469901	The combination of mesothelin and miR-103a-3p appears to be more complementary than a combination of biomarkers within the same molecular class.	('mesothelin', 'Gene', (19, 29))	('miR-103a-3p', 'Var', (34, 45))	('mesothelin', 'Gene', '10232', (19, 29))	('miR-103a-3p', 'Chemical', '-', (34, 45))
109673	25469901	Thus, it has to be considered that changes in levels of miR-103a-3p may be the result of an indirect effect, i.e., a response of the immune system to the tumor.	('response', 'MPA', (117, 125))	('miR-103a-3p', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('miR-103a-3p', 'Chemical', '-', (56, 67))	('tumor', 'Disease', (154, 159))
109677	25469901	Thus, it might be reasonable to evaluate the potential roles of miR-103a-3p and GPRC5A in mesothelioma.	('miR-103a-3p', 'Chemical', '-', (64, 75))	('miR-103a-3p', 'Var', (64, 75))	('mesothelioma', 'Disease', (90, 102))	('GPRC5A', 'Gene', (80, 86))	('GPRC5A', 'Gene', '9052', (80, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
109682	25469901	This is also true for miR-103a-3p and mesothelin alone.	('miR-103a-3p', 'Chemical', '-', (22, 33))	('miR-103a-3p', 'Var', (22, 33))	('mesothelin', 'Gene', (38, 48))	('mesothelin', 'Gene', '10232', (38, 48))
109705	25469901	In conclusion, we showed that the combination of mesothelin and miR-103a-3p improved the diagnostic performance of a blood-based screening test, resulting in higher sensitivity and specificity to detect malignant mesothelioma.	('diagnostic performance', 'MPA', (89, 111))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (203, 225))	('miR-103a-3p', 'Chemical', '-', (64, 75))	('sensitivity', 'MPA', (165, 176))	('mesothelin', 'Gene', '10232', (49, 59))	('higher', 'PosReg', (158, 164))	('miR-103a-3p', 'Var', (64, 75))	('improved', 'PosReg', (76, 84))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (203, 225))	('malignant mesothelioma', 'Disease', (203, 225))	('mesothelin', 'Gene', (49, 59))
109712	32727552	Patients with epithelioid MPM or biphasic MPM had higher calretinin plasma levels than patients with sarcomatoid MPM.	('higher', 'PosReg', (50, 56))	('calretinin', 'Gene', '794', (57, 67))	('Patients', 'Species', '9606', (0, 8))	('epithelioid MPM', 'Disease', (14, 29))	('sarcomatoid MPM', 'Disease', 'MESH:C538614', (101, 116))	('calretinin', 'Gene', (57, 67))	('biphasic MPM', 'Var', (33, 45))	('patients', 'Species', '9606', (87, 95))	('sarcomatoid MPM', 'Disease', (101, 116))
109785	32727552	However, tissue manipulation could initially cause a short-term increase of tumor markers in plasma.	('tissue manipulation', 'Var', (9, 28))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('increase', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
109786	32727552	Patients with epithelioid or biphasic MPM showed higher calretinin concentrations than cancer-free controls with benign asbestos-related lung diseases.	('cancer', 'Disease', (87, 93))	('epithelioid', 'Disease', (14, 25))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('calretinin', 'Gene', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Patients', 'Species', '9606', (0, 8))	('calretinin', 'Gene', '794', (56, 66))	('lung diseases', 'Disease', (137, 150))	('lung diseases', 'Phenotype', 'HP:0002088', (137, 150))	('higher', 'PosReg', (49, 55))	('asbestos', 'Chemical', 'MESH:D001194', (120, 128))	('biphasic MPM', 'Var', (29, 41))	('lung diseases', 'Disease', 'MESH:D008171', (137, 150))
109827	32120810	This form of cell death results from the high tropism of OR141 for the endoplasmic reticulum (ER) that leads to the induction of a major ER stress response, further exacerbated by the inactivation of proteasomal deubiquitinases.	('ER stress response', 'biological_process', 'GO:0034976', ('137', '155'))	('ER stress response', 'MPA', (137, 155))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('71', '92'))	('OR141', 'Var', (57, 62))	('OR141', 'Chemical', '-', (57, 62))	('cell death', 'biological_process', 'GO:0008219', ('13', '23'))	('inactivation', 'NegReg', (184, 196))	('tropism', 'biological_process', 'GO:0009606', ('46', '53'))	('proteasomal', 'Enzyme', (200, 211))	('exacerbated', 'PosReg', (165, 176))
109830	32120810	In the current study, we tested OR141 as a single ICD inducer to boost the priming of naive DC with PDT-killed mesothelioma cells and, consecutively, to treat peritoneal MM in mice.	('OR141', 'Var', (32, 37))	('ICD', 'Disease', 'OMIM:252500', (50, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (111, 123))	('mesothelioma', 'Disease', (111, 123))	('ICD', 'Disease', (50, 53))	('mice', 'Species', '10090', (176, 180))	('priming', 'MPA', (75, 82))	('boost', 'PosReg', (65, 70))	('OR141', 'Chemical', '-', (32, 37))
109833	32120810	OR141 belongs to a new class of photosensitizers (PS) with a highly favorable light vs. dark efficacy ratio and a capacity to work under low pO2, as encountered in many tumors (Figure 1A).	('pO2', 'Chemical', 'MESH:C093415', (141, 144))	('OR141', 'Chemical', '-', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('OR141', 'Var', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
109837	32120810	We found that from the dose of 1 microM, OR141 induced cell death, as documented by the flow cytometry analysis using propidium iodide (PI) and Annexin V (Figure 1B).	('propidium iodide', 'Chemical', 'MESH:D011419', (118, 134))	('Annexin V', 'Gene', (144, 153))	('Annexin V', 'Gene', '11747', (144, 153))	('cell death', 'biological_process', 'GO:0008219', ('55', '65'))	('OR141', 'Chemical', '-', (41, 46))	('cell death', 'CPA', (55, 65))	('OR141', 'Var', (41, 46))
109839	32120810	A net increase in the amounts of extracellular HMGB1 and Hsp90 was observed upon exposure to photoactivated OR141 (Figure 1C).	('amounts', 'MPA', (22, 29))	('HMGB1', 'Gene', (47, 52))	('OR141', 'Chemical', '-', (108, 113))	('extracellular', 'cellular_component', 'GO:0005576', ('33', '46'))	('Hsp90', 'Gene', '111042', (57, 62))	('HMGB1', 'Gene', '15289', (47, 52))	('Hsp90', 'Gene', (57, 62))	('OR141', 'Var', (108, 113))	('increase', 'PosReg', (6, 14))
109840	32120810	Flow cytometry analysis also revealed the OR141 dose-dependent translocation of calreticulin at the plasma membrane (Figure 1D).	('translocation', 'MPA', (63, 76))	('OR141', 'Chemical', '-', (42, 47))	('calreticulin', 'Gene', '12317', (80, 92))	('OR141', 'Var', (42, 47))	('calreticulin', 'Gene', (80, 92))	('plasma membrane', 'cellular_component', 'GO:0005886', ('100', '115'))
109846	32120810	The generation of the PDT-based DC vaccine was obtained by exposing DC to mesothelioma cells treated with the highest OR141 dose tested (i.e., 10 microM) to achieve complete cancer cell avitalization.	('OR141', 'Var', (118, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('mesothelioma', 'Disease', (74, 86))	('OR141', 'Chemical', '-', (118, 123))
109854	32120810	The PDT-based DC vaccination also showed a strong increase in the IFN-gamma positive CD8+ population in comparison to the sham and anti-CTLA4 conditions (Figure 3C and Figure S2B).	('CD8', 'Gene', (85, 88))	('PDT-based', 'Var', (4, 13))	('CTLA4', 'Gene', (136, 141))	('IFN-gamma', 'Gene', (66, 75))	('CD8', 'Gene', '925', (85, 88))	('increase', 'PosReg', (50, 58))	('IFN-gamma', 'Gene', '15978', (66, 75))	('CTLA4', 'Gene', '12477', (136, 141))
109865	32120810	We found that CD8+ cells collected from the PDT-based DC vaccinated mice exhibited a larger increase in INF-gamma than T cells derived from control mice and mice treated with the DC vaccine (Figure 5F).	('mice', 'Species', '10090', (68, 72))	('PDT-based', 'Var', (44, 53))	('mice', 'Species', '10090', (157, 161))	('INF-gamma', 'MPA', (104, 113))	('CD8', 'Gene', (14, 17))	('increase', 'PosReg', (92, 100))	('mice', 'Species', '10090', (148, 152))	('CD8', 'Gene', '925', (14, 17))
109866	32120810	Notably, as further evidence of the strong immune response induced by PDT-based DC vaccination, a net decrease in tumor size was already observable six days after vaccination (Figure 5G).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('decrease', 'NegReg', (102, 110))	('tumor', 'Disease', (114, 119))	('PDT-based', 'Var', (70, 79))	('immune response', 'biological_process', 'GO:0006955', ('43', '58'))
109868	32120810	The fast chemotaxis of DCs primed with OR141-killed mesothelioma cells towards luciferase-positive tumor areas was detected only 15 min after injection, whereas LPS-treated DCs mainly remained located next to the injection point (Figure 6A, with the injection point marked with an arrow and Figure 6B for quantification).	('tumor', 'Disease', (99, 104))	('OR141', 'Chemical', '-', (39, 44))	('LPS', 'Disease', 'MESH:C536528', (161, 164))	('OR141-killed', 'Var', (39, 51))	('mesothelioma', 'Disease', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('chemotaxis', 'biological_process', 'GO:0006935', ('9', '19'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('LPS', 'Disease', (161, 164))
109873	32120810	Next, we collected mesothelioma six days post-DC vaccination to evaluate the presence of CD11c+ DCs within the tumor mass.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CD11c+ DCs', 'Var', (89, 99))	('tumor', 'Disease', (111, 116))	('mesothelioma', 'Disease', (19, 31))
109921	32120810	DC maturation was analyzed with antibodies against CD11c-BV421 (BD Biosciences, San Jose, CA, USA, 565452), MHCII (I-A/I-E)-APC (BD Pharm, San Jose, CA, USA, 565367), CD40-PE (BD Pharm, 553791), CD80-PE (eBioscience, San Diego, CA, USA, 12-0801), CD86-PE (eBioscience, 12-0862) or CCR7-PE (BioLegend, San Diego, CA, USA, 120105).	('CCR7', 'Gene', (281, 285))	('CD86', 'Gene', (247, 251))	('CD80', 'Gene', (195, 199))	('CD86', 'Gene', '12524', (247, 251))	('APC', 'cellular_component', 'GO:0005680', ('124', '127'))	('MHCII (I-A/I-E)-APC', 'Gene', (108, 127))	('CCR7', 'Gene', '12775', (281, 285))	('CD40', 'Gene', '21939', (167, 171))	('MHCII (I-A/I-E)-APC', 'Gene', '111364', (108, 127))	('CD80', 'Gene', '12519', (195, 199))	('CD40', 'Gene', (167, 171))	('CCR', 'molecular_function', 'GO:0043880', ('281', '284'))	('CD11c-BV421', 'Var', (51, 62))
109967	32002015	For example, the insertion of the herpes simplex virus thymidine kinase (HSV-TK) gene into tumour cells which are subsequently induced to "commit suicide" when in the presence of a non-toxic dosages of ganciclovir (GCV).	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('GCV', 'Chemical', 'MESH:D015774', (215, 218))	('tumour', 'Disease', (91, 97))	('thymidine', 'Chemical', 'MESH:D013936', (55, 64))	('insertion', 'Var', (17, 26))	('ganciclovir', 'Chemical', 'MESH:D015774', (202, 213))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('herpes simplex', 'Phenotype', 'HP:0012302', (34, 48))	('HSV-TK', 'Gene', (73, 79))
109977	32002015	In this study we have shown for the first time to our knowledge the effect of GCV preloading (pre-treatment) on the fate of the bystander killing of TK-modified tumour cells, both in vitro and in vivo as well as possible ways to improve its action.	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('GCV', 'Chemical', 'MESH:D015774', (78, 81))	('tumour', 'Disease', (161, 167))	('pre', 'molecular_function', 'GO:0003904', ('94', '97'))	('TK-modified', 'Var', (149, 160))
110019	32002015	The two different harvesting procedures were examined in order to find out whether trypsinisation inhibits the bystander killing by inhibiting the formation of gap junctions between PA-1 and PA-STK cells; this could be expected to affect the gap-junctional transfer of GCV-PPP.	('bystander killing', 'CPA', (111, 128))	('GCV', 'Chemical', 'MESH:D015774', (269, 272))	('STK', 'Gene', '19882', (194, 197))	('STK', 'Gene', (194, 197))	('gap-junctional transfer', 'MPA', (242, 265))	('formation', 'biological_process', 'GO:0009058', ('147', '156'))	('affect', 'Reg', (231, 237))	('trypsinisation', 'Var', (83, 97))	('inhibiting', 'NegReg', (132, 142))	('inhibits', 'NegReg', (98, 106))	('STK', 'molecular_function', 'GO:0050359', ('194', '197'))	('formation of gap junctions', 'MPA', (147, 173))
110020	32002015	Touraine and his colleagues have shown that the magnitude of the bystander effect appears to correlate with the cell to cell transfer of phosphorylated GCV from the TK+ve cells to the adjacent wild-type cells.	('GCV', 'Protein', (152, 155))	('phosphorylated', 'Var', (137, 151))	('cell to cell transfer', 'CPA', (112, 133))	('GCV', 'Chemical', 'MESH:D015774', (152, 155))
110022	32002015	the cells which provide GCV-PPP) inhibited the bystander effect whereas trypsinisation of the target cells, PA-1, did not affect the bystander killing effect.	('bystander effect', 'CPA', (47, 63))	('GCV', 'Chemical', 'MESH:D015774', (24, 27))	('GCV-PPP', 'Var', (24, 31))	('inhibited', 'NegReg', (33, 42))
110063	32002015	The data presented in this study has shown that the TK-expressing tumour cells need only a short incubation with GCV (16 h), to bring about almost 100% tumour cell death over the subsequent 3-days of culture without GCV.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('cell death', 'biological_process', 'GO:0008219', ('159', '169'))	('tumour', 'Disease', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('GCV', 'Chemical', 'MESH:D015774', (113, 116))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumour', 'Disease', (66, 72))	('GCV', 'Chemical', 'MESH:D015774', (216, 219))	('TK-expressing', 'Var', (52, 65))
110076	32002015	Preferential homing to the tumour site has been postulated by Freeman and his colleagues to explain anti-tumour activity seen after injection of TK+ve tumour cells in anatomical cavities which contain tumours.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('tumour', 'Disease', (201, 207))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('TK+ve', 'Var', (145, 150))	('tumours', 'Disease', (201, 208))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Disease', (105, 111))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (151, 157))	('tumour', 'Disease', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
110085	29949929	After intra-thoracic injection of H2052/484 cells, thoracic tumors developed in nearly all mice (86%) within 14 days, faster than from parental NCI-H2052 cells.	('mice', 'Species', '10090', (91, 95))	('thoracic tumors', 'Disease', 'MESH:D013899', (51, 66))	('thoracic tumors', 'Disease', (51, 66))	('H2052', 'Chemical', '-', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NCI-H2052', 'CellLine', 'CVCL:1518', (144, 153))	('H2052', 'Chemical', '-', (148, 153))	('H2052/484 cells', 'Var', (34, 49))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
110094	29949929	Previous results from our laboratory, mostly obtained from in vitro experiments, suggest that inhibition of the Macrophage migration inhibitory factor (MIF)/CD74 pathway decreases the development of MPM.	('Macrophage migration inhibitory factor', 'Gene', (112, 150))	('Macrophage migration', 'biological_process', 'GO:1905517', ('112', '132'))	('decreases', 'NegReg', (170, 179))	('Macrophage migration inhibitory factor', 'Gene', '17319', (112, 150))	('development of MPM', 'CPA', (184, 202))	('inhibition', 'Var', (94, 104))
110100	29949929	For example, there are two CD74 isoforms in mice (p31 and p41) and four in humans (p33, p35, p41, and p43).	('p41', 'Var', (58, 61))	('p43', 'Gene', '9255', (102, 105))	('CD74', 'Gene', (27, 31))	('p31', 'Gene', (50, 53))	('p33', 'Gene', '972', (83, 86))	('p33', 'Gene', (83, 86))	('p35', 'Gene', '3592', (88, 91))	('humans', 'Species', '9606', (75, 81))	('p31', 'Gene', '11973', (50, 53))	('p41', 'Var', (93, 96))	('p35', 'cellular_component', 'GO:0070745', ('88', '91'))	('p43', 'Gene', (102, 105))	('p35', 'Gene', (88, 91))	('p35', 'cellular_component', 'GO:0043514', ('88', '91'))	('mice', 'Species', '10090', (44, 48))
110115	29949929	In order to evaluate whether preliminary in vivo engraftment of H2052 cells increased their tumorigenicity, thoracic tumors were mechanically dissociated into cell suspensions.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('thoracic tumors', 'Disease', 'MESH:D013899', (108, 123))	('increased', 'PosReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (117, 122))	('H2052', 'Chemical', '-', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('H2052', 'Var', (64, 69))	('thoracic tumors', 'Disease', (108, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
110118	29949929	We observed similar vitality and multiplication rates for H2052/484 and the parental H2052 cells (Figure 1).	('H2052/484', 'Var', (58, 67))	('H2052', 'Chemical', '-', (85, 90))	('H2052', 'Chemical', '-', (58, 63))	('multiplication', 'CPA', (33, 47))
110120	29949929	After 48 h, the density of cells cultured with 10% FBS compared to cells cultured with 0% FBS, estimated by the absorbance level, was 2.81 +- 0.94 times higher for H28 (n = 3), 2.99 +- 0.80 times higher for H2052 (n = 7), and 6.53 +- 3.10 times higher for H2052/484 (n = 7).	('higher', 'PosReg', (153, 159))	('H2052/484', 'Var', (256, 265))	('H2052', 'Chemical', '-', (207, 212))	('H2052', 'Chemical', '-', (256, 261))	('H2052', 'Var', (207, 212))	('higher', 'PosReg', (196, 202))	('H28', 'Var', (164, 167))	('H28', 'Chemical', '-', (164, 167))
110122	29949929	Compared to parental H2052 cells, H2052/484 cells expressed 1.9 higher mRNA levels of the epithelial marker E-cadherin (CDH1) (Figure 2) and higher mRNA levels of the transcription factors SNAIL2 (3.3-fold change), ZEB1 (1.9-fold change), and ZEB2 (1.4-fold change), which are considered mesenchymal markers.	('mRNA levels', 'MPA', (148, 159))	('higher', 'PosReg', (64, 70))	('ZEB2', 'Gene', (243, 247))	('H2052/484', 'Var', (34, 43))	('mRNA levels', 'MPA', (71, 82))	('H2052', 'Chemical', '-', (34, 39))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('H2052', 'Chemical', '-', (21, 26))	('higher', 'PosReg', (141, 147))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))
110123	29949929	The mRNA expression levels of these three transcription factors were higher in H2052/484 cells compared to the three other MPM cell lines (H28, JL-1, and MSTO).	('H2052', 'Chemical', '-', (79, 84))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('mRNA expression levels', 'MPA', (4, 26))	('H28', 'Chemical', '-', (139, 142))	('H2052/484', 'Var', (79, 88))	('higher', 'PosReg', (69, 75))
110129	29949929	injection of H2052/484 cells into athymic nude mice yielded sizable tumor masses identifiable by ([18F]FDG)-PET/CT imaging within 2 weeks.	('tumor', 'Disease', (68, 73))	('H2052', 'Chemical', '-', (13, 18))	('H2052/484', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('nude mice', 'Species', '10090', (42, 51))
110130	29949929	H2052/484 tumors developed in nearly all injected mice (24/28).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('H2052', 'Chemical', '-', (0, 5))	('H2052/484', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mice', 'Species', '10090', (50, 54))
110152	29949929	Second, labelling of immune cells with specific antibodies was performed as follows: CD19+B220+ for B lymphocytes, CD19-CD11b+ for monocytes/macrophages, CD19-CD11b+ F4/80+ for macrophages, CD11b+F4/80+CD206+ for M2 macrophages, CD49b+ for NK cells, CD11b+Gr1+ for myeloid-derived suppressor cells (MDSC).	('F4/80', 'Gene', (196, 201))	('CD206', 'Gene', (202, 207))	('CD206', 'Gene', '17533', (202, 207))	('F4/80', 'Gene', '13733', (196, 201))	('F4/80', 'Gene', (166, 171))	('CD19', 'Gene', '12478', (115, 119))	('CD19', 'Gene', (85, 89))	('F4/80', 'Gene', '13733', (166, 171))	('CD49b', 'Gene', '16398', (229, 234))	('CD19', 'Gene', (154, 158))	('CD11b+Gr1+', 'Var', (250, 260))	('CD49b', 'Gene', (229, 234))	('CD19', 'Gene', '12478', (85, 89))	('CD19', 'Gene', '12478', (154, 158))	('CD19', 'Gene', (115, 119))
110164	29949929	In this model, the percentage of CD11b+Gr1+ MDSC was two-fold higher in mice with tumors compared to mice without tumors (Table 3).	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('higher', 'PosReg', (62, 68))	('CD11b+Gr1+ MDSC', 'Var', (33, 48))	('mice', 'Species', '10090', (101, 105))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('mice', 'Species', '10090', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
110167	29949929	In summary, a high score (4-6) of H2052/484 tumor development in athymic mice was associated with an increase of immune cells in the thoracic cavity.	('immune cells in the thoracic cavity', 'CPA', (113, 148))	('mice', 'Species', '10090', (73, 77))	('H2052/484', 'Var', (34, 43))	('increase', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('H2052', 'Chemical', '-', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
110169	29949929	In order to assess the effect of the MIF/CD74 pathway in the development of MPM, we derived a new human MPM cell line expressing MIF, CD74, and CD44 and able to generate orthotopic intra-thoracic tumors.	('intra-thoracic tumors', 'Disease', 'MESH:D013899', (181, 202))	('CD74', 'Var', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('intra-thoracic tumors', 'Disease', (181, 202))	('CD44', 'Var', (144, 148))	('MIF', 'Var', (129, 132))	('human', 'Species', '9606', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
110175	29949929	H2052/484 cells were modestly virulent in vivo, and the mice were found to tolerate a certain level of tumor burden (1 x 106 cells) over a two-week time course, without euthanasia requirements due to distress.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('H2052', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (103, 108))	('H2052/484', 'Var', (0, 9))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
110189	29949929	In this model, MIF secretion by H2052/484 tumor cells may attract immunosuppressive cells such as MDSC and polarized macrophages toward an immunosuppressive M2 phenotype, thus promoting tumor growth.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (42, 47))	('promoting', 'PosReg', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('H2052/484', 'Var', (32, 41))	('attract', 'PosReg', (58, 65))	('MIF', 'Protein', (15, 18))	('secretion', 'biological_process', 'GO:0046903', ('19', '28'))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('H2052', 'Chemical', '-', (32, 37))
110193	29949929	In these models, immunocompromised mice (generally non-obese diabetic (NOD) scid gamma and NOD Rag gamma mice characterized by a great immunodeficiency) are immunologically reconstituted with human immune cells.	('non-obese diabetic', 'Disease', (51, 69))	('non-obese diabetic', 'Disease', 'MESH:D009765', (51, 69))	('human', 'Species', '9606', (192, 197))	('NOD Rag', 'Var', (91, 98))	('immunodeficiency', 'Phenotype', 'HP:0002721', (135, 151))	('immunodeficiency', 'Disease', (135, 151))	('immunodeficiency', 'Disease', 'MESH:D007153', (135, 151))	('mice', 'Species', '10090', (35, 39))	('great immunodeficiency', 'Phenotype', 'HP:0004430', (129, 151))	('mice', 'Species', '10090', (105, 109))
110196	29949929	This model can be used to test the therapeutic effects of MIF inhibition on human MPM development and possibly to develop new therapies for this fatal disease.	('MPM', 'Disease', (82, 85))	('human', 'Species', '9606', (76, 81))	('inhibition', 'Var', (62, 72))	('MIF', 'Gene', (58, 61))
110242	29949929	The antibodies used to analyze monocytes, macrophages, and MDSC were PE anti-CD11b (M1/70), PE/Cy7 anti-F4-80 (BM8), APC anti-CD206 (C068C2), and FITC anti-Gr1 (RB6-8C5).	('anti-CD11b', 'Var', (72, 82))	('APC', 'Disease', 'MESH:D011125', (117, 120))	('APC', 'Disease', (117, 120))	('CD206', 'Gene', (126, 131))	('CD206', 'Gene', '17533', (126, 131))	('FITC', 'Chemical', 'MESH:D016650', (146, 150))	('APC', 'cellular_component', 'GO:0005680', ('117', '120'))
110252	28507279	Furthermore, high soluble mesothelin level may lead to a poor prognosis for malignant pleural mesothelioma patients.	('high', 'Var', (13, 17))	('mesothelin', 'Gene', (26, 36))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (86, 106))	('malignant pleural mesothelioma', 'Disease', (76, 106))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (76, 106))	('soluble', 'cellular_component', 'GO:0005625', ('18', '25'))	('patients', 'Species', '9606', (107, 115))	('mesothelin', 'Gene', '10232', (26, 36))
110272	28507279	The results of subgroup analysis indicated that patients with high soluble mesothelin level had poorer overall survival compared with patients with low soluble mesothelin level in the following subgroups: serum subgroup (HR = 2.016; 95% CI =1.571-2.588; p = 0.000), cut-off value <5 subgroup (HR = 1.980; 95% CI = 1.516-2.586; p = 0.000), sample size <50 subgroup (HR = 4.970; 95% CI = 1.633- 15.131; p = 0.005), sample size >=50 subgroup (HR = 1.866; 95% CI = 1.450- 2.402; p = 0.000), HR reported subgroup (HR = 2.016; 95% CI = 1.569-2.591; p = 0.000), multivariate analysis subgroup (HR = 1.925; 95% CI = 1.466-2.528; p = 0.000), non-multivariate analysis subgroup (HR = 2.111; 95% CI = 1.188-3.752; p = 0.011).	('soluble', 'cellular_component', 'GO:0005625', ('67', '74'))	('mesothelin', 'Gene', (75, 85))	('soluble', 'cellular_component', 'GO:0005625', ('152', '159'))	('poorer', 'NegReg', (96, 102))	('mesothelin', 'Gene', (160, 170))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (48, 56))	('mesothelin', 'Gene', '10232', (160, 170))	('high', 'Var', (62, 66))	('mesothelin', 'Gene', '10232', (75, 85))
110276	28507279	The pooled HR for age, gender, tumor histology and tumor stage were, respectively, 1.256(95% CI =0.907-1.739; p = 0.170), 0.932(95% CI =0.168-5.17; p = 0.936), 3.214(95% CI = 2.071-4.988; p = 0.000), 2.007(95% CI = 1.477-2.727; p = 0.000).	('0.932', 'Var', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
110302	28507279	Mesothelin gene silencing has an antitumor effect on cell lines overexpressing mesothelin deriving from MPM, which means mesothelin could be considered as a key molecular target for novel gene-based targeted therapies of MPM.	('Mesothelin', 'Gene', '10232', (0, 10))	('mesothelin', 'Gene', '10232', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Mesothelin', 'Gene', (0, 10))	('mesothelin', 'Gene', '10232', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mesothelin', 'Gene', (79, 89))	('gene silencing', 'Var', (11, 25))	('gene silencing', 'biological_process', 'GO:0016458', ('11', '25'))	('mesothelin', 'Gene', (121, 131))
110307	28507279	Furthermore, high soluble mesothelin level may lead to a poor prognosis for MPM patients.	('MPM', 'Disease', (76, 79))	('patients', 'Species', '9606', (80, 88))	('high', 'Var', (13, 17))	('mesothelin', 'Gene', (26, 36))	('soluble', 'cellular_component', 'GO:0005625', ('18', '25'))	('mesothelin', 'Gene', '10232', (26, 36))
110318	28507279	MPM malignant pleural mesothelioma CI confidence interval HR hazard ratio	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (14, 34))	('malignant pleural mesothelioma', 'Disease', (4, 34))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (4, 34))	('MPM', 'Var', (0, 3))
110392	28335760	The AUCs of serum mesothelin and midkine to distinguish patients with the early-staged mesothelioma from patients with benign asbestos pleurisy were 0.655 (0.490-0.796), with a sensitivity of 42.9% and a specificity of 85%, and 0.557 (0.394-0.712), with a sensitivity of 33.3% and a specificity of 95.0%, respectively.	('mesothelin', 'Gene', (18, 28))	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (105, 113))	('pleurisy', 'Phenotype', 'HP:0002102', (135, 143))	('midkine', 'Gene', '4192', (33, 40))	('mesothelioma', 'Disease', (87, 99))	('0.655', 'Var', (149, 154))	('mesothelin', 'Gene', '10232', (18, 28))	('midkine', 'Gene', (33, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('benign asbestos pleurisy', 'Disease', 'MESH:D010998', (119, 143))	('benign asbestos pleurisy', 'Disease', (119, 143))
110402	28335760	In contrast, high serum midkine levels were independently associated with poor prognosis in mesothelioma (HR = 1.84; 95% CI: 1.09-3.09) (p = 0.022).	('high', 'Var', (13, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('midkine', 'Gene', '4192', (24, 31))	('mesothelioma', 'Disease', (92, 104))	('midkine', 'Gene', (24, 31))
110460	28335760	In clinical settings, many factors can affect drug sensitivity in vivo, which include genetic alterations of tumors such as those influencing anti-apoptotic and pro-apoptotic pathways.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('anti-apoptotic', 'Pathway', (142, 156))	('drug sensitivity', 'Phenotype', 'HP:0020174', (46, 62))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('drug sensitivity', 'MPA', (46, 62))	('affect', 'Reg', (39, 45))	('pro-apoptotic pathways', 'Pathway', (161, 183))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('clinical', 'Species', '191496', (3, 11))	('genetic alterations', 'Var', (86, 105))
110625	25940505	Pathological examination of malignant mesothelioma included an immunohistochemical antibody panel; positive markers were calretinin, mesothelin, WT1 (Wilms tumor 1), D2-40 (mAb directed against M2A antigen), and CK5/6 (cytokeratin 5/6).	('antibody', 'molecular_function', 'GO:0003823', ('83', '91'))	('antibody', 'cellular_component', 'GO:0042571', ('83', '91'))	('mesothelin', 'Gene', (133, 143))	('WT1', 'Gene', (145, 148))	('calretinin', 'Gene', (121, 131))	('WT1', 'Gene', '7490', (145, 148))	('antibody', 'cellular_component', 'GO:0019815', ('83', '91'))	('CK5/6', 'Gene', '3852', (212, 217))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (28, 50))	('mesothelin', 'Gene', '10232', (133, 143))	('D2-40', 'Var', (166, 171))	('Wilms tumor', 'Phenotype', 'HP:0002667', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cytokeratin 5/6', 'Gene', (219, 234))	('calretinin', 'Gene', '794', (121, 131))	('antibody', 'cellular_component', 'GO:0019814', ('83', '91'))	('CK5/6', 'Gene', (212, 217))	('Wilms tumor 1', 'Gene', '7490', (150, 163))	('malignant mesothelioma', 'Disease', (28, 50))	('cytokeratin 5/6', 'Gene', '3852', (219, 234))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (28, 50))	('Wilms tumor 1', 'Gene', (150, 163))
110760	25378643	Collectively, these observations support targeting MSLN in MPM and other solid cancers.	('solid cancers', 'Disease', 'MESH:D009369', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MPM', 'Disease', (59, 62))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('MSLN', 'Var', (51, 55))	('solid cancers', 'Disease', (73, 86))
110769	25378643	We constructed two CARs incorporating a human MSLN-specific scFv and either CD3zeta or CD28/CD3zeta signaling domains (Mz and M28z, Fig.	('human', 'Species', '9606', (40, 45))	('scFv', 'Gene', (60, 64))	('M28z', 'Chemical', '-', (126, 130))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('scFv', 'Gene', '652070', (60, 64))	('M28z', 'Var', (126, 130))	('rat', 'Species', '10116', (31, 34))
110770	25378643	The P28z CAR, specific for prostate-specific membrane antigen (PSMA), served as a negative control for alloreactivity and xenoreactivity.	('PSMA', 'Gene', '2346', (63, 67))	('prostate-specific membrane antigen', 'molecular_function', 'GO:0043275', ('27', '61'))	('P28z', 'Var', (4, 8))	('membrane', 'cellular_component', 'GO:0016020', ('45', '53'))	('CAR', 'cellular_component', 'GO:0005826', ('9', '12'))	('PSMA', 'Gene', (63, 67))	('P28', 'cellular_component', 'GO:0070744', ('4', '7'))	('PSMA', 'molecular_function', 'GO:0043275', ('63', '67'))
110773	25378643	Mz- and M28z-transduced T cells demonstrated similar MSLN-specific lysis in vitro.	('rat', 'Species', '10116', (39, 42))	('lysis', 'biological_process', 'GO:0019835', ('67', '72'))	('M28z-transduced', 'Var', (8, 23))	('MSLN-specific', 'MPA', (53, 66))	('M28z', 'Chemical', '-', (8, 12))
110774	25378643	P28z CAR T cells did not lyse MSTO MSLN+ and mesothelin-targeted CARs did not lyse EL4 PSMA+.	('PSMA', 'molecular_function', 'GO:0043275', ('87', '91'))	('P28z', 'Var', (0, 4))	('EL4', 'Gene', '111979', (83, 86))	('EL4', 'Gene', (83, 86))	('PSMA', 'Gene', (87, 91))	('CAR', 'cellular_component', 'GO:0005826', ('5', '8'))	('P28', 'cellular_component', 'GO:0070744', ('0', '3'))	('PSMA', 'Gene', '2346', (87, 91))
110775	25378643	As expected for second generation CARs, M28z CAR T cells secreted a 2- to 5-fold greater amount of Th1 cytokines (Fig.	('Th1', 'Gene', '57314', (99, 102))	('M28z', 'Var', (40, 44))	('CAR', 'cellular_component', 'GO:0005826', ('45', '48'))	('rat', 'Species', '10116', (27, 30))	('secreted', 'MPA', (57, 65))	('M28z', 'Chemical', '-', (40, 44))	('greater', 'PosReg', (81, 88))	('Th1', 'Gene', (99, 102))
110777	25378643	Based on these findings, we proceeded to evaluate the therapeutic potential of M28z in mice bearing established pleural tumors.	('pleural tumors', 'Disease', 'MESH:D010997', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('M28z', 'Var', (79, 83))	('mice', 'Species', '10090', (87, 91))	('M28z', 'Chemical', '-', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('pleural tumors', 'Disease', (112, 126))
110779	25378643	Mice with established pleural tumor were treated 12 days after tumor inoculation with either a single intravenous or intra-pleural administration of 1x105 M28z CAR T cells (Effector to target [E:T] ratio of 1:3000, estimated from tumor burden quantification as previously described).	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('pleural tumor', 'Disease', 'MESH:D010997', (22, 35))	('Mice', 'Species', '10090', (0, 4))	('M28z', 'Chemical', '-', (155, 159))	('rat', 'Species', '10116', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CAR', 'cellular_component', 'GO:0005826', ('160', '163'))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (63, 68))	('pleural tumor', 'Disease', (22, 35))	('intra-pleural', 'Disease', (117, 130))	('intra-pleural', 'Disease', 'MESH:D010995', (117, 130))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('1x105 M28z', 'Var', (149, 159))	('rat', 'Species', '10116', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (30, 35))
110782	25378643	In contrast, intra-pleurally administered M28z T cells induced major responses.	('intra-pleural', 'Disease', 'MESH:D010995', (13, 26))	('M28z', 'Var', (42, 46))	('M28z', 'Chemical', '-', (42, 46))	('intra-pleural', 'Disease', (13, 26))
110784	25378643	In contrast, a 10-fold lower dose of M28z CAR T cells (3x105, E:T 1:1000) administered intra-pleurally rapidly decreased tumor burden within 10 days of administration (Fig.	('M28z', 'Chemical', '-', (37, 41))	('intra-pleurally rapidly decreased tumor burden', 'Disease', 'MESH:D010997', (87, 133))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rat', 'Species', '10116', (160, 163))	('CAR', 'cellular_component', 'GO:0005826', ('42', '45'))	('intra-pleurally rapidly decreased tumor burden', 'Disease', (87, 133))	('M28z', 'Var', (37, 41))
110788	25378643	All mice were treated with a single dose of T cells (1x106) co-expressing M28z and enhanced firefly luciferase (effLuc).	('M28z', 'Chemical', '-', (74, 78))	('mice', 'Species', '10090', (4, 8))	('enhanced', 'PosReg', (83, 91))	('M28z', 'Var', (74, 78))	('firefly', 'MPA', (92, 99))
110790	25378643	This rapid and sustained accumulation occurred with M28z (Fig.	('M28z', 'Chemical', '-', (52, 56))	('accumulation', 'PosReg', (25, 37))	('M28z', 'Var', (52, 56))
110791	25378643	Intravenously administered M28z T cells yielded signal comparable to intra-pleurally delivered T cells after 5 to 7 days.	('M28z', 'Var', (27, 31))	('intra-pleurally delivered T', 'Disease', (69, 96))	('M28z', 'Chemical', '-', (27, 31))	('intra-pleurally delivered T', 'Disease', 'MESH:D010995', (69, 96))	('to 7', 'Species', '1214577', (111, 115))
110797	25378643	Furthermore, most intravenously administered CD4+ T cells demonstrated a non-activated (CD62L+) T-cell phenotype 1 week after administration.	('CD62L', 'Gene', (88, 93))	('CD4+', 'Var', (45, 49))	('non-activated', 'MPA', (73, 86))	('rat', 'Species', '10116', (134, 137))	('CD62L', 'Gene', '20343', (88, 93))	('rat', 'Species', '10116', (65, 68))
110807	25378643	In this dual pleural/peritoneal disease model, intra-pleurally administered M28z T cells rapidly accumulated (days 1-2) and at a higher number than intravenously administered T cells (Fig.	('intra-pleural', 'Disease', (47, 60))	('intra-pleural', 'Disease', 'MESH:D010995', (47, 60))	('pleural', 'Disease', (13, 20))	('M28z', 'Var', (76, 80))	('higher', 'PosReg', (129, 135))	('pleural', 'Disease', 'MESH:D010995', (53, 60))	('pleural', 'Disease', (53, 60))	('M28z', 'Chemical', '-', (76, 80))	('pleural', 'Disease', 'MESH:D010995', (13, 20))
110808	25378643	Having demonstrated rapid activation of regionally dispensed M28z T cells and their efficient extra-thoracic redistribution, we further examined their persistence and function.	('activation', 'PosReg', (26, 36))	('M28z', 'Var', (61, 65))	('rat', 'Species', '10116', (14, 17))	('M28z', 'Chemical', '-', (61, 65))
110809	25378643	After establishing large pleural tumor burdens over 18 days, we administered Mz, M28z or P28z T cells into the pleural cavity at a low dose of 3x105 CAR+ T cells (E:T, 1:1000).	('pleural tumor', 'Disease', 'MESH:D010997', (25, 38))	('pleural tumor', 'Disease', (25, 38))	('pleural', 'Disease', 'MESH:D010995', (25, 32))	('M28z', 'Chemical', '-', (81, 85))	('pleural', 'Disease', (25, 32))	('P28z', 'Var', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('P28', 'cellular_component', 'GO:0070744', ('89', '92'))	('pleural', 'Disease', 'MESH:D010995', (111, 118))	('pleural', 'Disease', (111, 118))	('M28z', 'Var', (81, 85))	('CAR', 'cellular_component', 'GO:0005826', ('149', '152'))
110810	25378643	Treatment with M28z T cells induced a uniform reduction in tumor bioluminescence to background emission levels, as well as long-term tumor-free survival (median survival not reached vs. 63 days in Mz vs. 36 days in P28z, P=0.01, Fig 4).	('reduction', 'NegReg', (46, 55))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('P28', 'cellular_component', 'GO:0070744', ('215', '218'))	('M28z', 'Var', (15, 19))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('bioluminescence', 'biological_process', 'GO:0008218', ('65', '80'))	('M28z', 'Chemical', '-', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
110811	25378643	Serial assessment of CAR+ T cell counts in the peripheral blood of treated mice demonstrated increased T-cell persistence in M28z-treated mice when compared to Mz treated mice (50 days after T-cell infusion; Fig.	('mice', 'Species', '10090', (75, 79))	('mice', 'Species', '10090', (171, 175))	('increased', 'PosReg', (93, 102))	('T-cell persistence', 'CPA', (103, 121))	('mice', 'Species', '10090', (138, 142))	('CAR', 'cellular_component', 'GO:0005826', ('21', '24'))	('M28z-treated', 'Var', (125, 137))	('M28z', 'Chemical', '-', (125, 129))	('rat', 'Species', '10116', (87, 90))
110813	25378643	Phenotype assessment of persisting T cells demonstrated progressive and predominant enrichment in CD4+ T cells 30 days after T-cell infusion in both Mz- and M28z-treated mice (Fig.	('M28z-treated', 'Var', (157, 169))	('M28z', 'Chemical', '-', (157, 161))	('rat', 'Species', '10116', (50, 53))	('CD4+ T cells', 'CPA', (98, 110))	('mice', 'Species', '10090', (170, 174))
110815	25378643	Mice with established MSLN+ pleural tumors were intra-pleurally administered either 3x105 Mz or M28z T cells to eradicate pleural tumor and promote long term survival.	('pleural tumors', 'Disease', (28, 42))	('pleural tumor', 'Disease', 'MESH:D010997', (28, 41))	('M28z', 'Var', (96, 100))	('eradicate', 'NegReg', (112, 121))	('intra-pleural', 'Disease', (48, 61))	('pleural tumors', 'Disease', 'MESH:D010997', (28, 42))	('promote', 'PosReg', (140, 147))	('M28z', 'Chemical', '-', (96, 100))	('intra-pleural', 'Disease', 'MESH:D010995', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Mice', 'Species', '10090', (0, 4))	('pleural tumor', 'Disease', (122, 135))	('pleural tumor', 'Disease', 'MESH:D010997', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
110816	25378643	Eighty-seven days after initial T-cell injection, either MSLN+ or MSLN- tumor cells (1x106) were administered into the peritoneal cavity to long-term survivors and tumor burden was monitored using BLI.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (164, 169))	('MSLN- tumor', 'Disease', (66, 77))	('tumor', 'Disease', (72, 77))	('MSLN+', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MSLN- tumor', 'Disease', 'MESH:D009369', (66, 77))
110819	25378643	After an initial increase in tumor burden in all mice, antigen-specific control of tumor burden was seen in both the Mz and M28z T-cell-treated mice, most markedly in M28z-treated mice (Fig 5B).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('M28z', 'Var', (124, 128))	('M28z', 'Chemical', '-', (167, 171))	('M28z-treated', 'Var', (167, 179))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (83, 88))	('mice', 'Species', '10090', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Disease', (29, 34))	('mice', 'Species', '10090', (180, 184))	('M28z', 'Chemical', '-', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
110822	25378643	Mice initially treated with M28z T cells and rechallenged with MSLN+ tumor showed a 4-fold higher T cell expansion than those rechallenged with MSLN- tumor (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MSLN- tumor', 'Disease', (144, 155))	('higher', 'PosReg', (91, 97))	('tumor', 'Disease', (69, 74))	('M28z', 'Var', (28, 32))	('T cell expansion', 'CPA', (98, 114))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cell expansion', 'biological_process', 'GO:0016049', ('100', '114'))	('M28z', 'Chemical', '-', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Mice', 'Species', '10090', (0, 4))	('MSLN- tumor', 'Disease', 'MESH:D009369', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (150, 155))
110823	25378643	The greater T cell accumulation was predominantly attributable to the CD4+ subpopulation in the M28z group (Fig.	('T cell accumulation', 'CPA', (12, 31))	('M28z', 'Chemical', '-', (96, 100))	('CD4+', 'MPA', (70, 74))	('M28z', 'Var', (96, 100))
110824	25378643	To assess the relative contribution of CD28 costimulation to CD4+ and CD8+ cytokine and proliferative responses, we stimulated CD4+, CD8+, and bulk T cells transduced with either Mz or M28z with MSLN+ tumor cells and quantified the secretion of Th1 cytokines and proliferation.	('M28z', 'Var', (185, 189))	('CD8', 'Gene', (133, 136))	('Th1', 'Gene', '57314', (245, 248))	('rat', 'Species', '10116', (95, 98))	('CD8', 'Gene', '925', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('rat', 'Species', '10116', (270, 273))	('secretion of', 'MPA', (232, 244))	('M28z', 'Chemical', '-', (185, 189))	('Th1', 'Gene', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('secretion', 'biological_process', 'GO:0046903', ('232', '241'))	('CD8', 'Gene', (70, 73))	('tumor', 'Disease', (201, 206))	('CD8', 'Gene', '925', (70, 73))
110826	25378643	CD28-costimulated CD4+ T cells secreted 11- to 50-fold higher levels of cytokines than CD8+ T cells, showing that cytokine secretion is strongly enhanced in CD28-costimulated T cells, particularly in CD4+ T cells.	('cytokine secretion', 'biological_process', 'GO:0050663', ('114', '132'))	('CD28-costimulated', 'Var', (157, 174))	('CD8', 'Gene', (87, 90))	('enhanced', 'PosReg', (145, 153))	('CD8', 'Gene', '925', (87, 90))	('cytokine secretion', 'MPA', (114, 132))
110827	25378643	As expected, repeated stimulation with MSLN+ targets did not induce T-cell expansion in either the CD4+ or CD8+ Mz T-cell population and rather rapidly induced a decline in T cell number upon antigen stimulation in the absence of exogenous IL-2 (Fig.	('MSLN+', 'Var', (39, 44))	('antigen stimulation', 'MPA', (192, 211))	('IL-2', 'Gene', (240, 244))	('cell expansion', 'biological_process', 'GO:0016049', ('70', '84'))	('decline', 'NegReg', (162, 169))	('IL-2', 'molecular_function', 'GO:0005134', ('240', '244'))	('rat', 'Species', '10116', (137, 140))	('CD8', 'Gene', (107, 110))	('CD8', 'Gene', '925', (107, 110))	('IL-2', 'Gene', '16183', (240, 244))
110828	25378643	In contrast, CD4+ M28z T cells expanded >20-fold greater mean proliferation by the third stimulation, compared with a 2-fold increase in CD8+ M28z T cells (P<0.001).	('greater', 'PosReg', (49, 56))	('CD8', 'Gene', (137, 140))	('CD8', 'Gene', '925', (137, 140))	('M28z', 'Chemical', '-', (142, 146))	('M28z', 'Chemical', '-', (18, 22))	('rat', 'Species', '10116', (69, 72))	('CD4+ M28z', 'Var', (13, 22))
110829	25378643	The importance of CD4+ CAR T cells in supporting M28z CAR T-cell function was further demonstrated by the robust accumulation of CD8+ M28z T cells when cocultured with CD4+ M28z T cells and stimulated by MSLN+ targets (3-fold greater accumulation; P<0.001; Fig.	('M28z', 'Chemical', '-', (173, 177))	('CAR', 'cellular_component', 'GO:0005826', ('23', '26'))	('CD8', 'Gene', (129, 132))	('M28z', 'Var', (49, 53))	('CD8', 'Gene', '925', (129, 132))	('CD4+', 'Var', (168, 172))	('M28z', 'Chemical', '-', (134, 138))	('M28z', 'Chemical', '-', (49, 53))	('CAR', 'cellular_component', 'GO:0005826', ('54', '57'))	('rat', 'Species', '10116', (93, 96))
110831	25378643	CD8+ M28z CAR T cells had significantly enhanced in vivo accumulation when administered with CD4+ M28z T cells, as determined by tracking of T-cell signal emission by BLI (2.3- vs. 1.2-fold increase in T-cell bioluminescent signal at 72 h; Figs.	('CD4+ M28z', 'Var', (93, 102))	('accumulation', 'MPA', (57, 69))	('M28z', 'Chemical', '-', (98, 102))	('CD8', 'Gene', (0, 3))	('CAR', 'cellular_component', 'GO:0005826', ('10', '13'))	('CD8', 'Gene', '925', (0, 3))	('enhanced', 'PosReg', (40, 48))	('M28z', 'Chemical', '-', (5, 9))
110832	25378643	The enhanced anti-tumor efficacy of pleurally administered M28z T cells could be explained by an earlier antigen-activation of CD4+ M28z T cells which may lead to optimal cytokine secretion to sustain the expansion of both the CD4+ and CD8+ CAR T-cell subsets.	('M28z', 'Var', (59, 63))	('CD8', 'Gene', '925', (236, 239))	('cytokine secretion', 'MPA', (171, 189))	('enhanced', 'PosReg', (4, 12))	('tumor', 'Disease', (18, 23))	('CAR', 'cellular_component', 'GO:0005826', ('241', '244'))	('M28z', 'Var', (132, 136))	('M28z', 'Chemical', '-', (59, 63))	('cytokine secretion', 'biological_process', 'GO:0050663', ('171', '189'))	('pleural', 'Disease', 'MESH:D010995', (36, 43))	('M28z', 'Chemical', '-', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CD8', 'Gene', (236, 239))	('CD4+ M28z', 'Var', (127, 136))	('pleural', 'Disease', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
110834	25378643	CD4+ CAR T-cell pre-activation resulted in an enhancement in both CD4+ and CD8+ accumulation in vitro compared to the experimental condition where CD4+ T cells are antigen exposed simultaneously with CD8+ T cells (Fig.	('CD4+ CAR', 'Var', (0, 8))	('pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('CD8', 'Gene', '925', (200, 203))	('CD8', 'Gene', '925', (75, 78))	('enhancement', 'PosReg', (46, 57))	('CD4+', 'MPA', (66, 70))	('CD8', 'Gene', (200, 203))	('CD8', 'Gene', (75, 78))	('CAR', 'cellular_component', 'GO:0005826', ('5', '8'))
110837	25378643	CD4+ M28z+ T cells had lower rapid cytotoxic potential but reached equivalent levels to CD8+ M28z+ T cells by 18 hrs.	('CD8', 'Gene', '925', (88, 91))	('CD4+ M28z+ T', 'Var', (0, 12))	('rapid', 'MPA', (29, 34))	('M28z', 'Chemical', '-', (5, 9))	('M28z', 'Chemical', '-', (93, 97))	('lower', 'NegReg', (23, 28))	('CD8', 'Gene', (88, 91))
110838	25378643	CD28 costimulatory signaling enhanced lysis by CD4+ M28z CAR T cells by 13-16% at multiple E:T ratios (P<0.001; Fig.	('CD28', 'MPA', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('lysis', 'MPA', (38, 43))	('rat', 'Species', '10116', (95, 98))	('CD4+ M28z', 'Var', (47, 56))	('M28z', 'Chemical', '-', (52, 56))	('enhanced', 'PosReg', (29, 37))	('CAR', 'cellular_component', 'GO:0005826', ('57', '60'))	('lysis', 'biological_process', 'GO:0019835', ('38', '43'))
110840	25378643	Transfer of cytokine-rich supernatant obtained from stimulated CD4+ M28z T cells added at the time of 51Cr-release assay enhanced the cytotoxicity of both CD4+ M28z T cells (5%-23% enhancement; P<0.0001; Fig.	('CD4+ M28z', 'Var', (155, 164))	('M28z', 'Chemical', '-', (68, 72))	('cytotoxicity', 'Disease', (134, 146))	('enhanced', 'PosReg', (121, 129))	('cytotoxicity', 'Disease', 'MESH:D064420', (134, 146))	('M28z', 'Chemical', '-', (160, 164))	('enhancement', 'PosReg', (181, 192))
110842	25378643	We therefore conclude that the M28z CAR favors formation of cytotoxic CD4+ T cell effectors and helps CD8+ T cell cytoxicity in CD4-dependent manner.	('toxicity', 'Disease', 'MESH:D064420', (116, 124))	('toxicity', 'Disease', (116, 124))	('CD8', 'Gene', (102, 105))	('M28z', 'Var', (31, 35))	('CD8', 'Gene', '925', (102, 105))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('favors', 'PosReg', (40, 46))	('M28z', 'Chemical', '-', (31, 35))	('helps', 'PosReg', (96, 101))	('CAR', 'cellular_component', 'GO:0005826', ('36', '39'))	('formation of cytotoxic CD4+ T cell effectors', 'MPA', (47, 91))
110844	25378643	Antibody blockade of Fas ligand/Fas receptor (FasL/FasR) interaction did not reduce target cell lysis by either Mz or M28z CAR T cells (P>0.05; Fig.	('ligand', 'molecular_function', 'GO:0005488', ('25', '31'))	('target cell lysis', 'CPA', (84, 101))	('CAR', 'cellular_component', 'GO:0005826', ('123', '126'))	('M28z', 'Var', (118, 122))	('FasL', 'Gene', '14103', (46, 50))	('lysis', 'biological_process', 'GO:0019835', ('96', '101'))	('FasL', 'Gene', (46, 50))	('interaction', 'Interaction', (57, 68))	('M28z', 'Chemical', '-', (118, 122))
110851	25378643	The most prominent reduction in lysis was seen in the Mz (mean reduction, 27.6% vs. 17.6% for M28z) and CD8+ (29.4% for CD8+ Mz vs. 15.3% for CD4+ Mz; 24.2% for CD8+ M28z vs. 11.1% for CD4+ M28z) T cell groups.	('CD8', 'Gene', '925', (104, 107))	('reduction', 'NegReg', (19, 28))	('CD8', 'Gene', (161, 164))	('CD8', 'Gene', (120, 123))	('CD8', 'Gene', '925', (120, 123))	('lysis', 'biological_process', 'GO:0019835', ('32', '37'))	('CD8', 'Gene', (104, 107))	('CD8', 'Gene', '925', (161, 164))	('CD4+ M28z', 'Var', (185, 194))	('M28z', 'Chemical', '-', (94, 98))	('reduction', 'NegReg', (63, 72))	('M28z', 'Chemical', '-', (190, 194))	('lysis', 'MPA', (32, 37))	('M28z', 'Chemical', '-', (166, 170))
110854	25378643	Granzyme B was expressed in >95% of CD4+ and CD8+ M28z CAR T cells within 18 h after stimulation with MSLN-expressing tumor cells.	('M28z', 'Chemical', '-', (50, 54))	('CAR', 'cellular_component', 'GO:0005826', ('55', '58'))	('Granzyme B', 'Gene', '14939', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CD8', 'Gene', (45, 48))	('tumor', 'Disease', (118, 123))	('CD8', 'Gene', '925', (45, 48))	('CD4+', 'Var', (36, 40))	('Granzyme B', 'Gene', (0, 10))
110855	25378643	CD8+ M28z T cells had a 1.8-fold increase in MFI after 4-h coculture, and granzyme B expression was further upregulated to 2.6-fold during the final 12 h. With CD4+ M28z T cells, however, granzyme B expression was upregulated to a much greater degree during the final 12 h of culture (1.5-fold during the first 4 h, to 3.7-fold during the final 12 h).	('upregulated', 'PosReg', (214, 225))	('granzyme B', 'Gene', (188, 198))	('expression', 'MPA', (199, 209))	('CD4+ M28z', 'Var', (160, 169))	('granzyme B', 'Gene', '14939', (74, 84))	('CD8', 'Gene', (0, 3))	('M28z', 'Chemical', '-', (165, 169))	('granzyme B', 'Gene', '14939', (188, 198))	('CD8', 'Gene', '925', (0, 3))	('granzyme B', 'Gene', (74, 84))	('M28z', 'Chemical', '-', (5, 9))
110856	25378643	Furthermore, M28z enhanced granzyme B expression in both CD4+ and CD8+ T-cell subsets (Fig.	('granzyme B', 'Gene', (27, 37))	('M28z', 'Chemical', '-', (13, 17))	('CD8', 'Gene', (66, 69))	('enhanced', 'PosReg', (18, 26))	('CD8', 'Gene', '925', (66, 69))	('granzyme B', 'Gene', '14939', (27, 37))	('M28z', 'Var', (13, 17))
110857	25378643	7E, expression following 18 h of coculture), possibly explaining the enhanced cytotoxicity seen with CD4+ M28z T cells compared with CD4+ Mz T cells (Fig.	('CD4+ M28z', 'Var', (101, 110))	('cytotoxicity', 'Disease', (78, 90))	('M28z', 'Chemical', '-', (106, 110))	('enhanced', 'PosReg', (69, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))
110858	25378643	Our observations of a potent CD4+ M28z in vitro effector function and CD4+ predominant long-term immunity led us to hypothesize that CD4+ M28z T cells would demonstrate in vivo efficacy in the absence of CD8+ T cells.	('CD8', 'Gene', '925', (204, 207))	('M28z', 'Chemical', '-', (34, 38))	('CD4+ M28z', 'Var', (133, 142))	('rat', 'Species', '10116', (164, 167))	('M28z', 'Chemical', '-', (138, 142))	('absence of CD8+ T cells', 'Phenotype', 'HP:0005422', (193, 216))	('CD8', 'Gene', (204, 207))
110859	25378643	Tumor-bearing mice were treated with CD4+ M28z, CD8+ M28z, or bulk unsorted M28z T cells administered into the pleural cavity at 3 different doses following 18 days of tumor growth (Figs.	('M28z', 'Chemical', '-', (53, 57))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (168, 173))	('mice', 'Species', '10090', (14, 18))	('CD4+ M28z', 'Var', (37, 46))	('CD8', 'Gene', (48, 51))	('pleural', 'Disease', 'MESH:D010995', (111, 118))	('M28z', 'Chemical', '-', (42, 46))	('pleural', 'Disease', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CD8', 'Gene', '925', (48, 51))	('M28z', 'Chemical', '-', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
110860	25378643	In P28z treated mice, the tumor burden steadily progressed until mice had to be sacrificed (median survival, 28 days).	('P28', 'cellular_component', 'GO:0070744', ('3', '6'))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mice', 'Species', '10090', (65, 69))	('progressed', 'PosReg', (48, 58))	('P28z', 'Var', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mice', 'Species', '10090', (16, 20))
110861	25378643	Treatment with CD4+ M28z and bulk M28z CAR T cells (3x105; E:T, 1:1000) resulted in tumor eradication in 100% of mice, with mice remaining tumor free through 200 days of follow-up.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CD4+ M28z', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CAR', 'cellular_component', 'GO:0005826', ('39', '42'))	('mice', 'Species', '10090', (124, 128))	('M28z', 'Chemical', '-', (34, 38))	('M28z', 'Chemical', '-', (20, 24))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mice', 'Species', '10090', (113, 117))
110864	25378643	Even at the lower doses, CD4+ M28z CAR T cells had higher efficacy than CD8+ CAR T cells (1x105: E:T, 1:3000, 112 vs. 67 days [P=0.04]; 3x104: E:T, 1:10000, 160 vs. 37 days [P=0.001]).	('CAR', 'cellular_component', 'GO:0005826', ('77', '80'))	('efficacy', 'CPA', (58, 66))	('M28z', 'Chemical', '-', (30, 34))	('CD8', 'Gene', (72, 75))	('CAR', 'cellular_component', 'GO:0005826', ('35', '38'))	('higher', 'PosReg', (51, 57))	('CD4+ M28z', 'Var', (25, 34))	('CD8', 'Gene', '925', (72, 75))
110866	25378643	Finally, to address whether CD4+ T cells can establish long-term functional persistence when administered without CD8+ T cells, we performed peritoneal tumor re-challenge in mice 196 days after initial intra-pleural administration of CD4+ sorted or bulk M28z T cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CD4+', 'Var', (234, 238))	('intra-pleural', 'Disease', (202, 215))	('tumor', 'Disease', (152, 157))	('intra-pleural', 'Disease', 'MESH:D010995', (202, 215))	('M28z', 'Chemical', '-', (254, 258))	('CD8', 'Gene', (114, 117))	('CD8', 'Gene', '925', (114, 117))	('rat', 'Species', '10116', (224, 227))
110867	25378643	Although there was an initial increase in tumor burden with persisting CD4+ M28z T cells compared to the bulk population containing both CD4+ and CD8+, tumors then regressed, and subsequent tumor growth was controlled for >4 weeks (Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (152, 157))	('CD4+ M28z', 'Var', (71, 80))	('tumor', 'Disease', (190, 195))	('increase', 'PosReg', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CD8', 'Gene', (146, 149))	('tumors', 'Disease', (152, 158))	('CD8', 'Gene', '925', (146, 149))	('M28z', 'Chemical', '-', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
110869	25378643	We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, inducing long-term complete remissions with less than 30-fold fewer M28z CAR T cells.	('CAR', 'cellular_component', 'GO:0005826', ('179', '182'))	('intra-pleural', 'Disease', (14, 27))	('M28z', 'Chemical', '-', (174, 178))	('intra-pleural', 'Disease', 'MESH:D010995', (14, 27))	('CAR', 'cellular_component', 'GO:0005826', ('43', '46'))	('inducing', 'PosReg', (106, 114))	('M28z', 'Var', (174, 178))
110873	25378643	In our studies, we intra-pleurally administered MSLN-targeted CAR T cells to mice bearing established pleural tumors (12-18 days post-inoculation, control mice die by day 25-36).	('mice', 'Species', '10090', (77, 81))	('pleural tumors', 'Disease', 'MESH:D010997', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CAR', 'cellular_component', 'GO:0005826', ('62', '65'))	('MSLN-targeted', 'Var', (48, 61))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mice', 'Species', '10090', (155, 159))	('pleural tumors', 'Disease', (102, 116))	('intra-pleural', 'Disease', (19, 32))	('intra-pleural', 'Disease', 'MESH:D010995', (19, 32))
110888	25378643	M28z CAR T cells were multifunctional, displaying potent CD4+ T-cell cytotoxicity as well as helper function supporting T cell effector formation, survival and proliferation.	('M28z', 'Var', (0, 4))	('cytotoxicity', 'Disease', 'MESH:D064420', (69, 81))	('survival', 'CPA', (147, 155))	('M28z', 'Chemical', '-', (0, 4))	('proliferation', 'CPA', (160, 173))	('CAR', 'cellular_component', 'GO:0005826', ('5', '8'))	('rat', 'Species', '10116', (167, 170))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))	('cytotoxicity', 'Disease', (69, 81))	('T cell effector formation', 'CPA', (120, 145))
110891	25378643	The lesser ability of intravenously administered T cells to achieve potent accumulation of both CD4+ and CD8+ subsets, suggests that M28z CAR T cells are negatively impacted by their delayed arrival at the tumor site.	('CD8', 'Gene', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('CD8', 'Gene', '925', (105, 108))	('M28z', 'Chemical', '-', (133, 137))	('tumor', 'Disease', (206, 211))	('CAR', 'cellular_component', 'GO:0005826', ('138', '141'))	('CD4+', 'MPA', (96, 100))	('M28z', 'Var', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
110892	25378643	M28z T cells eliminated large pleural tumors even at low T-cell doses.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('M28z', 'Var', (0, 4))	('pleural tumors', 'Disease', 'MESH:D010997', (30, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('eliminated', 'NegReg', (13, 23))	('M28z', 'Chemical', '-', (0, 4))	('pleural tumors', 'Disease', (30, 44))
110894	25378643	Compared to Mz T cells, M28z T cells provided superior tumor control and robust proliferation upon tumor rechallenge >100 days after intrapleural administration.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('pleural', 'Disease', 'MESH:D010995', (138, 145))	('rat', 'Species', '10116', (154, 157))	('pleural', 'Disease', (138, 145))	('tumor', 'Disease', (55, 60))	('M28z', 'Chemical', '-', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('rat', 'Species', '10116', (87, 90))	('M28z', 'Var', (24, 28))
110895	25378643	The potentiating properties of CD28 signaling are particularly notable in the CD4+ subset, as demonstrated by their superior cytokine secretion and proliferation, relative to CD8+ T cells.	('cytokine secretion', 'biological_process', 'GO:0050663', ('125', '143'))	('rat', 'Species', '10116', (101, 104))	('proliferation', 'CPA', (148, 161))	('CD8', 'Gene', (175, 178))	('superior', 'PosReg', (116, 124))	('CD8', 'Gene', '925', (175, 178))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('cytokine secretion', 'MPA', (125, 143))	('rat', 'Species', '10116', (155, 158))	('CD4+', 'Var', (78, 82))
110897	25378643	It is well established that CD4+ T cells require a higher-avidity interaction to mediate effector functions compared to CD8+ T cells.	('CD8', 'Gene', (120, 123))	('CD4+', 'Var', (28, 32))	('CD8', 'Gene', '925', (120, 123))
110909	25378643	Another strategy to limit CAR T cell toxicity is to transiently express the CAR using mRNA electroporation, albeit at the expense of CAR T cell persistence and requiring multiple T-cell administrations to attain efficacy.	('toxicity', 'Disease', (37, 45))	('rat', 'Species', '10116', (194, 197))	('mRNA electroporation', 'Var', (86, 106))	('CAR', 'cellular_component', 'GO:0005826', ('26', '29'))	('rat', 'Species', '10116', (10, 13))	('CAR', 'cellular_component', 'GO:0005826', ('76', '79'))	('rat', 'Species', '10116', (100, 103))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))	('CAR', 'cellular_component', 'GO:0005826', ('133', '136'))
110913	25378643	Patients with primary pleural malignancy or secondary pleural malignancies from lung and breast cancers overexpressing MSLN, which we have shown to have more aggressive disease, will be enrolled on this trial.	('pleural malignancies', 'Disease', (54, 74))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('breast cancers', 'Disease', (89, 103))	('primary pleural malignancy', 'Disease', 'MESH:D016066', (14, 40))	('aggressive disease', 'Disease', 'MESH:D001523', (158, 176))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MSLN', 'Var', (119, 123))	('lung', 'Disease', (80, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('aggressive disease', 'Disease', (158, 176))	('primary pleural malignancy', 'Disease', (14, 40))	('Patients', 'Species', '9606', (0, 8))	('pleural malignancies', 'Disease', 'MESH:D016066', (54, 74))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
110916	25378643	Our studies strongly support that regional CAR T cell administration to subjects with MPM will result in greater T cell anti-tumor potency with reduced T cell doses, owing in part to early CD4+ T cell activation and the systemic benefits that ensue.	('activation', 'PosReg', (201, 211))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rat', 'Species', '10116', (62, 65))	('T cell activation', 'biological_process', 'GO:0042110', ('194', '211'))	('MPM', 'Var', (86, 89))	('tumor', 'Disease', (125, 130))	('CAR', 'cellular_component', 'GO:0005826', ('43', '46'))	('reduced T cell', 'Phenotype', 'HP:0005403', (144, 158))	('CD4+ T', 'MPA', (189, 195))	('greater', 'PosReg', (105, 112))
110928	25378643	To generate MSLN-specific CARs, we engineered a fusion protein encoding a fully human scFv, m912 (kindly provided by D. Dimitrov, NCI-Frederick) linked to the human CD8 leader peptide and the CD8/CD3zeta or CD28/CD3zeta sequences as previously described.	('CD8', 'Gene', (192, 195))	('CD8', 'Gene', '925', (192, 195))	('scFv', 'Gene', '652070', (86, 90))	('human', 'Species', '9606', (159, 164))	('CD8', 'Gene', (165, 168))	('scFv', 'Gene', (86, 90))	('rat', 'Species', '10116', (7, 10))	('CD8', 'Gene', '925', (165, 168))	('human', 'Species', '9606', (80, 85))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('m912', 'Var', (92, 96))
110930	25378643	The Mz, M28z, and P28z-encoding plasmids were then transfected into 293T H29 packaging cell lines as previously described.	('P28', 'cellular_component', 'GO:0070744', ('18', '21'))	('293T H29', 'CellLine', 'CVCL:0063', (68, 76))	('P28z-encoding', 'Var', (18, 31))	('M28z', 'Var', (8, 12))	('M28z', 'Chemical', '-', (8, 12))
110932	25378643	Two days after isolation, PBMCs were transduced with 293T RD114-produced supernatant containing Mz, M28z, or P28z vectors for 1 h on plates coated with 15 mug/mL retronectin daily for 2 days.	('M28z', 'Var', (100, 104))	('M28z', 'Chemical', '-', (100, 104))	('P28z vectors', 'Var', (109, 121))	('293T', 'CellLine', 'CVCL:0063', (53, 57))	('P28', 'cellular_component', 'GO:0070744', ('109', '112'))	('mug', 'molecular_function', 'GO:0043739', ('155', '158'))
110943	25378643	In total, 1x106 to 3x106 T cells transduced with M28z, Mz, or P28z were stimulated over irradiated MSTO-211H cells with or without MSLN expression and were plated in 6- or 24-well tissue culture plates at a density of 1x105 to 3x105 cells/well.	('P28', 'cellular_component', 'GO:0070744', ('62', '65'))	('M28z', 'Chemical', '-', (49, 53))	('P28z', 'Var', (62, 66))	('M28z', 'Var', (49, 53))
110949	25378643	T-cell phenotypes were determined with monoclonal antibodies for CD3, CD4, CD8, CD62L, CD25, CD27 and CD45RA.	('CD8', 'Gene', '925', (75, 78))	('CD3', 'Gene', (65, 68))	('CD3', 'Gene', '12503', (65, 68))	('CD4', 'Var', (70, 73))	('CD25', 'Gene', (87, 91))	('CD62L', 'Gene', '20343', (80, 85))	('CD27', 'Gene', '21940', (93, 97))	('CD62L', 'Gene', (80, 85))	('CD25', 'Gene', '16184', (87, 91))	('CD45RA', 'Var', (102, 108))	('CD8', 'Gene', (75, 78))	('CD27', 'Gene', (93, 97))
110997	21697949	Silencing successfully reduced bortezomib-induced Noxa upregulation, without alteration of other Bcl-2 molecules, Mcl-1 or Bim (Figure 3a).	('Bim', 'Gene', (123, 126))	('Noxa', 'Gene', (50, 54))	('Bcl-2', 'Gene', (97, 102))	('Bcl-2', 'Gene', '596', (97, 102))	('Bim', 'Gene', '10018', (123, 126))	('Silencing', 'Var', (0, 9))	('Mcl-1', 'Gene', '4170', (114, 119))	('bortezomib', 'Chemical', 'MESH:D000069286', (31, 41))	('Bcl-2', 'molecular_function', 'GO:0015283', ('97', '102'))	('reduced', 'NegReg', (23, 30))	('Mcl-1', 'Gene', (114, 119))	('Noxa', 'Gene', '5366', (50, 54))
111000	21697949	Although an R8 control peptide had no activity, R8-NoxaBH3 enhanced the apoptotic response of the spheroids, thereby significantly reducing the multicellular resistance of spheroids to bortezomib (Figure 3b).	('multicellular resistance', 'MPA', (144, 168))	('bortezomib', 'Chemical', 'MESH:D000069286', (185, 195))	('enhanced', 'PosReg', (59, 67))	('R8-NoxaBH3', 'Chemical', '-', (48, 58))	('reducing', 'NegReg', (131, 139))	('apoptotic response of the spheroids', 'CPA', (72, 107))	('R8-NoxaBH3', 'Var', (48, 58))
111001	21697949	In addition, R8-NoxaBH3 alone induced apoptosis in REN spheroids.	('REN', 'Gene', (51, 54))	('REN', 'Gene', '5972', (51, 54))	('R8-NoxaBH3', 'Chemical', '-', (13, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'CPA', (38, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('R8-NoxaBH3', 'Var', (13, 23))
111014	21697949	We ablated Mcl-1 using siRNA to determine its contribution to resistance in spheroids.	('Mcl-1', 'Gene', (11, 16))	('Mcl-1', 'Gene', '4170', (11, 16))	('ablated', 'Var', (3, 10))
111015	21697949	Ablation of Mcl-1 increased the apoptotic responses to ABT-737 and to bortezomib (Figure 5b).	('increased', 'PosReg', (18, 27))	('Mcl-1', 'Gene', (12, 17))	('ABT-737', 'Chemical', 'MESH:C501332', (55, 62))	('ABT-737', 'Gene', (55, 62))	('Ablation', 'Var', (0, 8))	('bortezomib', 'Chemical', 'MESH:D000069286', (70, 80))	('Mcl-1', 'Gene', '4170', (12, 17))	('apoptotic', 'CPA', (32, 41))
111029	21697949	Indeed, spheroids of both cell lines were sensitive to ABT-737- and R8-NoxaBH3-induced apoptosis, even in the absence of bortezomib (Figure 7a).	('ABT-737', 'Chemical', 'MESH:C501332', (55, 62))	('R8-NoxaBH3', 'Chemical', '-', (68, 78))	('sensitive', 'Reg', (42, 51))	('apoptosis', 'CPA', (87, 96))	('bortezomib', 'Chemical', 'MESH:D000069286', (121, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('R8-NoxaBH3-induced', 'Var', (68, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('ABT-737-', 'Var', (55, 63))
111030	21697949	When spheroids from all four cell lines were compared, the M28 spheroids appeared to have less sensitivity, with no response to R8-NoxaBH3 given alone (see also Figure 3b).	('R8-NoxaBH3', 'Chemical', '-', (128, 138))	('sensitivity', 'MPA', (95, 106))	('M28', 'Var', (59, 62))
111034	21697949	In tumor fragments from five of the tumors, ABT-737 did sensitize the mesothelioma cells to bortezomib-induced apoptosis (Figures 8a and b).	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ABT-737', 'Var', (44, 51))	('mesothelioma', 'Disease', (70, 82))	('bortezomib-induced apoptosis', 'MPA', (92, 120))	('ABT-737', 'Chemical', 'MESH:C501332', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Disease', (36, 42))	('sensitize', 'Reg', (56, 65))	('tumor', 'Disease', (36, 41))	('bortezomib', 'Chemical', 'MESH:D000069286', (92, 102))
111047	21697949	In the ex vivo human mesothelioma tumor model, we found that blockade of the Bcl-2 anti-apoptotic molecules enhanced the apoptotic response to bortezomib, at least in tumors with overexpression of the pro-apoptotic BH3-only molecule Bim.	('blockade', 'Var', (61, 69))	('mesothelioma tumor', 'Disease', (21, 39))	('Bcl-2', 'Gene', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('bortezomib', 'Chemical', 'MESH:D000069286', (143, 153))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (21, 39))	('apoptotic response to', 'MPA', (121, 142))	('Bim', 'Gene', '10018', (233, 236))	('BH3', 'Chemical', '-', (215, 218))	('human', 'Species', '9606', (15, 20))	('Bcl-2', 'Gene', '596', (77, 82))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (21, 39))	('Bim', 'Gene', (233, 236))	('enhanced', 'PosReg', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('Bcl-2', 'molecular_function', 'GO:0015283', ('77', '82'))
111052	21697949	Because Noxa acts indirectly by releasing Bim, we suspected that the effect of Noxa depended on Bim and, as expected, the ablation of Bim decreased the activity of Noxa.	('Bim', 'Gene', (134, 137))	('Noxa', 'Gene', (8, 12))	('decreased', 'NegReg', (138, 147))	('activity', 'MPA', (152, 160))	('Noxa', 'Gene', '5366', (164, 168))	('Noxa', 'Gene', '5366', (79, 83))	('Bim', 'Gene', (42, 45))	('Bim', 'Gene', (96, 99))	('Bim', 'Gene', '10018', (134, 137))	('Bim', 'Gene', '10018', (96, 99))	('Noxa', 'Gene', (164, 168))	('ablation', 'Var', (122, 130))	('Noxa', 'Gene', (79, 83))	('Bim', 'Gene', '10018', (42, 45))	('Noxa', 'Gene', '5366', (8, 12))
111056	21697949	In fact, when used as single agents in the resistant spheroids, ABT-737 was more effective than bortezomib.	('ABT-737', 'Var', (64, 71))	('bortezomib', 'Chemical', 'MESH:D000069286', (96, 106))	('ABT-737', 'Chemical', 'MESH:C501332', (64, 71))	('effective', 'MPA', (81, 90))
111063	21697949	For example, R8-NoxaBH3 was less effective than ABT-737 in the cell line with the lowest increase in Bim (M28).	('ABT-737', 'Chemical', 'MESH:C501332', (48, 55))	('R8-NoxaBH3', 'Chemical', '-', (13, 23))	('R8-NoxaBH3', 'Var', (13, 23))	('Bim', 'Gene', (101, 104))	('Bim', 'Gene', '10018', (101, 104))
111079	21697949	In sum, using 3D culture models, we have shown that multicellular resistance to bortezomib is mediated by alterations in the Bcl-2 repertoire, which provides a druggable target specific to the malignant cells.	('Bcl-2', 'molecular_function', 'GO:0015283', ('125', '130'))	('Bcl-2', 'Gene', (125, 130))	('Bcl-2', 'Gene', '596', (125, 130))	('multicellular resistance', 'MPA', (52, 76))	('bortezomib', 'Chemical', 'MESH:D000069286', (80, 90))	('alterations', 'Var', (106, 117))	('mediated by', 'Reg', (94, 105))
111080	21697949	Inhibition of the anti-apoptotic buffers in association with chemotherapy represents a promising strategy for the treatment of mesothelioma.	('mesothelioma', 'Disease', (127, 139))	('Inhibition', 'Var', (0, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))
111098	21697949	The antibodies against Bcl-2 (#2872) and Bcl-XL (#2764) were from Cell Signaling Technology (Beverly, MA, USA).	('Bcl-2', 'molecular_function', 'GO:0015283', ('23', '28'))	('#2764', 'Var', (49, 54))	('Signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('Bcl-2', 'Gene', (23, 28))	('Bcl-2', 'Gene', '596', (23, 28))	('Bcl-XL', 'Gene', '598', (41, 47))	('#2872', 'Var', (30, 35))	('Bcl-XL', 'Gene', (41, 47))
111099	21697949	The Mcl-1 (sc-819) antibody was from Santa Cruz Biotechnology (Santa Cruz, CA, USA), the Bim antibody (#559685) was from BD Pharmingen (San Jose, CA, USA), and the Noxa antibody was from Calbiochem (#OP180, San Diego, CA, USA).	('antibody', 'cellular_component', 'GO:0019815', ('19', '27'))	('antibody', 'cellular_component', 'GO:0019814', ('169', '177'))	('Mcl-1', 'Gene', '4170', (4, 9))	('antibody', 'cellular_component', 'GO:0019815', ('93', '101'))	('Noxa', 'Gene', '5366', (164, 168))	('antibody', 'cellular_component', 'GO:0019814', ('19', '27'))	('antibody', 'molecular_function', 'GO:0003823', ('169', '177'))	('antibody', 'cellular_component', 'GO:0042571', ('169', '177'))	('Bim', 'Gene', '10018', (89, 92))	('Mcl-1', 'Gene', (4, 9))	('antibody', 'cellular_component', 'GO:0019814', ('93', '101'))	('antibody', 'molecular_function', 'GO:0003823', ('19', '27'))	('Noxa', 'Gene', (164, 168))	('antibody', 'cellular_component', 'GO:0042571', ('19', '27'))	('#559685', 'Var', (103, 110))	('antibody', 'cellular_component', 'GO:0019815', ('169', '177'))	('Bim', 'Gene', (89, 92))	('antibody', 'molecular_function', 'GO:0003823', ('93', '101'))	('antibody', 'cellular_component', 'GO:0042571', ('93', '101'))
111239	29138529	Matrix Metalloproteinases Polymorphisms as Prognostic Biomarkers in Malignant Pleural Mesothelioma Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS).	('Polymorphisms', 'Var', (26, 39))	('rare disease', 'Disease', (141, 153))	('rare disease', 'Disease', 'MESH:D035583', (141, 153))	('mesothelioma', 'Disease', (117, 129))	('Pro', 'Chemical', 'MESH:D011392', (43, 46))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (78, 98))	('Mesothelioma Malignant', 'Phenotype', 'HP:0100001', (86, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('Malignant Pleural Mesothelioma', 'Disease', (68, 98))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (99, 129))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (109, 129))	('Malignant pleural mesothelioma', 'Disease', (99, 129))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (68, 98))
111241	29138529	We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9; and rs1042703, rs1042704, and rs743257 in MMP14.	('rs2250889', 'Mutation', 'rs2250889', (124, 133))	('rs20544', 'Var', (111, 118))	('rs17576', 'Var', (93, 100))	('rs1042703', 'Mutation', 'rs1042703', (147, 156))	('patients', 'Species', '9606', (21, 29))	('MMP', 'molecular_function', 'GO:0004235', ('185', '188'))	('rs743257', 'Var', (173, 181))	('rs243865', 'Var', (53, 61))	('rs17576', 'Mutation', 'rs17576', (93, 100))	('rs7201', 'Var', (76, 82))	('rs243849', 'Var', (63, 71))	('rs17577', 'Var', (102, 109))	('rs1042704', 'Var', (158, 167))	('rs1042703', 'Var', (147, 156))	('MMP9', 'molecular_function', 'GO:0004229', ('137', '141'))	('rs7201', 'Mutation', 'rs7201', (76, 82))	('rs20544', 'Mutation', 'rs20544', (111, 118))	('MMP2', 'molecular_function', 'GO:0004228', ('87', '91'))	('patient', 'Species', '9606', (21, 28))	('rs2250889', 'Var', (124, 133))	('MMP2', 'Gene', (87, 91))	('MMP14', 'Gene', '4323', (185, 190))	('rs243865', 'Mutation', 'rs243865', (53, 61))	('MMP14', 'Gene', (185, 190))	('MMP9', 'Gene', (137, 141))	('rs1042704', 'Mutation', 'rs1042704', (158, 167))	('MMP9', 'Gene', '4318', (137, 141))	('rs17577', 'Mutation', 'rs17577', (102, 109))	('rs743257', 'Mutation', 'rs743257', (173, 181))	('MMP2', 'Gene', '4313', (87, 91))	('rs243849', 'Mutation', 'rs243849', (63, 71))
111243	29138529	Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45-4.14, p = 0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37-4.18, p = 0.002).	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('time to progression', 'MPA', (58, 77))	('rs2250889', 'Var', (29, 38))	('shorter', 'NegReg', (50, 57))	('rs2250889', 'DBSNP_MENTION', 'None', (29, 38))	('MMP9', 'Gene', (24, 28))
111244	29138529	In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38-0.86 p = 0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37-0.85, p = 0.007).	('rs20544', 'Var', (55, 62))	('longer', 'PosReg', (74, 80))	('rs20544', 'DBSNP_MENTION', 'None', (55, 62))	('TTP', 'MPA', (81, 84))	('MMP9', 'Gene', (50, 54))	('MMP9', 'molecular_function', 'GO:0004229', ('50', '54'))
111245	29138529	MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06-4.12, p = 0.032).	('rs1042703', 'Var', (6, 15))	('TTP', 'MPA', (54, 57))	('rs1042703', 'DBSNP_MENTION', 'None', (6, 15))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('shorter', 'NegReg', (46, 53))
111256	29138529	Different MMPs (MMP2, MMP9, MMP11, and MMP14) and their expression were studied in the mesothelioma tissue, but only a few have been prognostically significant.	('MMP9', 'molecular_function', 'GO:0004229', ('22', '26'))	('MMP11', 'Gene', '4320', (28, 33))	('MMP11', 'molecular_function', 'GO:0004249', ('28', '33'))	('MMP2', 'molecular_function', 'GO:0004228', ('16', '20'))	('MMP', 'molecular_function', 'GO:0004235', ('39', '42'))	('MMP14', 'Var', (39, 44))	('MMP9', 'Var', (22, 26))	('MMP11', 'Gene', (28, 33))
111257	29138529	The calculated relative risk of death in MPM patients with low MMP14 expression was significantly lower than in patients with high MMP14 expression.	('death', 'Disease', (32, 37))	('MMP', 'molecular_function', 'GO:0004235', ('131', '134'))	('MMP', 'molecular_function', 'GO:0004235', ('63', '66'))	('MPM', 'Disease', (41, 44))	('low', 'Var', (59, 62))	('MMP14', 'Gene', (63, 68))	('death', 'Disease', 'MESH:D003643', (32, 37))	('lower', 'NegReg', (98, 103))
111261	29138529	Ten different polymorphisms in three MMP genes fulfilling these criteria were genotyped: MMP2 rs243865, rs243849, and rs7201; MMP9 rs17576, rs17577, rs2250889, and rs20544; and MMP14 rs1042703, rs1042704, and rs743257.	('rs1042704', 'DBSNP_MENTION', 'None', (194, 203))	('rs243849', 'Var', (104, 112))	('rs20544', 'Var', (164, 171))	('rs17577', 'DBSNP_MENTION', 'None', (140, 147))	('rs243865', 'Var', (94, 102))	('rs243849', 'DBSNP_MENTION', 'None', (104, 112))	('rs2250889', 'Var', (149, 158))	('rs17576', 'Var', (131, 138))	('MMP2', 'molecular_function', 'GO:0004228', ('89', '93'))	('rs7201', 'DBSNP_MENTION', 'None', (118, 124))	('MMP9', 'molecular_function', 'GO:0004229', ('126', '130'))	('MMP2', 'Gene', (89, 93))	('rs1042703', 'DBSNP_MENTION', 'None', (183, 192))	('rs17577', 'Var', (140, 147))	('rs743257', 'Var', (209, 217))	('MMP', 'molecular_function', 'GO:0004235', ('37', '40'))	('MMP', 'molecular_function', 'GO:0004235', ('177', '180'))	('rs1042703', 'Var', (183, 192))	('rs243865', 'DBSNP_MENTION', 'None', (94, 102))	('rs1042704', 'Var', (194, 203))	('rs743257', 'DBSNP_MENTION', 'None', (209, 217))	('rs17576', 'DBSNP_MENTION', 'None', (131, 138))	('rs20544', 'DBSNP_MENTION', 'None', (164, 171))	('rs2250889', 'DBSNP_MENTION', 'None', (149, 158))	('rs7201', 'Var', (118, 124))
111265	29138529	Carriers of polymorphic MMP9 rs2250889 allele had shorter TTP (6.07 versus 10.03 months, p = 0.001, HR = 2.45, 95% CI = 1.45-4.14) compared to noncarriers.	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('rs2250889', 'Var', (29, 38))	('shorter', 'NegReg', (50, 57))	('TTP', 'MPA', (58, 61))	('rs2250889', 'DBSNP_MENTION', 'None', (29, 38))	('MMP9', 'Gene', (24, 28))
111266	29138529	On the other hand, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP than noncarriers (10.13 versus 7.53 months, p = 0.015, HR = 0.63, 95% CI = 0.43-0.91).	('TTP', 'MPA', (87, 90))	('MMP9', 'Gene', (56, 60))	('MMP9', 'molecular_function', 'GO:0004229', ('56', '60'))	('rs20544', 'Var', (61, 68))	('rs20544', 'DBSNP_MENTION', 'None', (61, 68))	('longer', 'PosReg', (80, 86))
111267	29138529	A nominally significant association with shorter TTP was observed in carriers of polymorphic MMP14 rs1042703 allele when compared to noncarriers, but only after adjustment for histological type, weight loss, and performance status (HR = 1.44, 95% CI = 1.01-2.03, p = 0.042).	('rs1042703', 'Var', (99, 108))	('shorter', 'NegReg', (41, 48))	('rs1042703', 'DBSNP_MENTION', 'None', (99, 108))	('weight loss', 'Phenotype', 'HP:0001824', (195, 206))	('MMP', 'molecular_function', 'GO:0004235', ('93', '96'))	('MMP14', 'Gene', (93, 98))	('TTP', 'MPA', (49, 52))
111268	29138529	Additionally, carriers of two polymorphic MMP2 rs243849 alleles tended to have shorter TTP after adjustment for clinical parameters (HR = 2.16, 95% CI = 1.02-4.55, p = 0.043).	('TTP', 'MPA', (87, 90))	('MMP2', 'Gene', (42, 46))	('shorter', 'NegReg', (79, 86))	('MMP2', 'molecular_function', 'GO:0004228', ('42', '46'))	('rs243849', 'DBSNP_MENTION', 'None', (47, 55))	('rs243849', 'Var', (47, 55))
111269	29138529	Carriers of polymorphic MMP9 rs2250889 allele had shorter overall survival (OS) compared to noncarriers (OS 9.23 versus 19.10 months, p = 0.002, HR = 2.39, 95% CI = 1.37-4.18, Figure 1(a)).	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('overall survival', 'MPA', (58, 74))	('rs2250889', 'Var', (29, 38))	('shorter', 'NegReg', (50, 57))	('rs2250889', 'DBSNP_MENTION', 'None', (29, 38))	('MMP9', 'Gene', (24, 28))
111270	29138529	Again, carriers of at least one polymorphic MMP9 rs20544 had longer OS compared to noncarriers (OS 19.3 versus 13.5 months, p = 0.014, HR = 0.61, 95% CI = 0.41-0.90, Figure 1(b)).	('rs20544', 'DBSNP_MENTION', 'None', (49, 56))	('MMP9', 'Gene', (44, 48))	('rs20544', 'Var', (49, 56))	('MMP9', 'molecular_function', 'GO:0004229', ('44', '48'))
111271	29138529	Carriers of two polymorphic alleles MMP14 rs1042703 had shorter OS compared to the carriers of the wild-type alleles (OS 12.7 versus 17.5 months, p = 0.043, HR = 1.92, 95% CI = 1.02-3.06).	('MMP', 'molecular_function', 'GO:0004235', ('36', '39'))	('MMP14', 'Gene', (36, 41))	('rs1042703', 'Var', (42, 51))	('shorter', 'NegReg', (56, 63))	('rs1042703', 'DBSNP_MENTION', 'None', (42, 51))
111272	29138529	MMP14 rs1042703 remained nominally significantly associated with OS (HR = 2.14, 95% CI = 1.12-4.0, p = 0.020) after the adjustment for histological type and performance status.	('rs1042703', 'Var', (6, 15))	('associated with', 'Reg', (49, 64))	('rs1042703', 'DBSNP_MENTION', 'None', (6, 15))	('MMP14', 'Gene', (0, 5))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))
111273	29138529	Polymorphic MMP9 rs2250889 allele that was associated with survival in single SNP analysis was present on two rare MMP9 haplotypes, AGGC and AGAC, that were both associated with significantly shorter TTP and OS.	('rs2250889', 'Var', (17, 26))	('shorter', 'NegReg', (192, 199))	('MMP9', 'molecular_function', 'GO:0004229', ('12', '16'))	('MMP9', 'molecular_function', 'GO:0004229', ('115', '119'))	('rs2250889', 'DBSNP_MENTION', 'None', (17, 26))	('TTP', 'MPA', (200, 203))	('MMP9', 'Gene', (115, 119))	('MMP9', 'Gene', (12, 16))
111274	29138529	Two of the investigated MMP9 SNPs, rs2250889 and rs20544, had significant but opposite effects on TTP and OS in our patient population.	('rs20544', 'DBSNP_MENTION', 'None', (49, 56))	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('effects', 'Reg', (87, 94))	('rs2250889', 'Var', (35, 44))	('TTP', 'MPA', (98, 101))	('rs2250889', 'DBSNP_MENTION', 'None', (35, 44))	('rs20544', 'Var', (49, 56))
111275	29138529	Additionally, nonsynonymous MMP14 rs1042703 genotype was associated with shorter survival in MPM patients.	('rs1042703', 'Var', (34, 43))	('shorter', 'NegReg', (73, 80))	('MMP14', 'Gene', (28, 33))	('survival', 'MPA', (81, 89))	('rs1042703', 'DBSNP_MENTION', 'None', (34, 43))	('MPM', 'Disease', (93, 96))	('MMP', 'molecular_function', 'GO:0004235', ('28', '31'))
111276	29138529	MMP9 rs2250889 polymorphic genotype (c.1721C>G) was strongly and statistically significantly associated with both lower TTP and OS in our study.	('MMP9', 'Gene', (0, 4))	('MMP9', 'molecular_function', 'GO:0004229', ('0', '4'))	('rs2250889', 'Var', (5, 14))	('lower', 'NegReg', (114, 119))	('c.1721C>G', 'Var', (37, 46))	('c.1721C>G', 'Mutation', 'rs2250889', (37, 46))	('rs2250889', 'DBSNP_MENTION', 'None', (5, 14))
111277	29138529	This polymorphism is nonsynonymous, leading to the p.Arg574Pro substitution, although the function prediction also indicated a possibility that it may influence splicing.	('splicing', 'biological_process', 'GO:0045292', ('161', '169'))	('p.Arg574Pro', 'Mutation', 'rs2250889', (51, 62))	('splicing', 'MPA', (161, 169))	('leading to', 'Reg', (36, 46))	('p.Arg574Pro', 'Var', (51, 62))	('influence', 'Reg', (151, 160))
111279	29138529	One of the previous studies in MMP9 SNPs showed that the risk for developing metastatic lung cancer is higher in heterozygous (p.574 Pro/Arg) and homozygous (p.574 Pro/Pro) carriers of rs2250889 polymorphism compared to noncarriers.	('lung cancer', 'Disease', (88, 99))	('rs2250889', 'DBSNP_MENTION', 'None', (185, 194))	('p.574 Pro/Pro', 'Var', (158, 171))	('p.574 Pro/Arg', 'Mutation', 'rs2250889', (127, 140))	('MMP9', 'molecular_function', 'GO:0004229', ('31', '35'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('rs2250889', 'Var', (185, 194))	('p.574 Pro/Arg', 'Var', (127, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
111280	29138529	In the study that included 744 patients with lung cancer and 747 cancer-free controls from Southeastern Chinese population, subjects with the rs2250889 encoded heterozygous p.574 Pro/Arg and homozygous p.574 Pro/Pro genotypes had 1.46-fold (95% CI = 0.94-2.26) and 1.69-fold elevated risk (95% CI = 1.10-2.60), respectively, compared to subjects with p.574Arg/Arg genotype.	('rs2250889', 'Var', (142, 151))	('p.574 Pro/Pro', 'Var', (202, 215))	('p.574 Pro/Arg', 'Var', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('rs2250889', 'DBSNP_MENTION', 'None', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('elevated', 'PosReg', (275, 283))
111281	29138529	Subsequent studies that investigated the prognostic role of MMP9 rs2250889 in 200 nasopharyngeal carcinoma patients showed increased death risk (HR = 2.287, 95% CI = 1.400-3.735) in subjects with MMP9 rs2250889 encoded p.574Pro/Pro and p.574Pro/Arg genotypes compared to p.574Arg/Arg genotype.	('nasopharyngeal carcinoma', 'Disease', (82, 106))	('increased death', 'Disease', 'MESH:D003643', (123, 138))	('rs2250889', 'Var', (65, 74))	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('rs2250889', 'Var', (201, 210))	('p.574Pro/Arg', 'Var', (236, 248))	('rs2250889', 'DBSNP_MENTION', 'None', (65, 74))	('p.574Pro/Pro', 'Var', (219, 231))	('carcinoma', 'Disease', (97, 106))	('MMP9', 'molecular_function', 'GO:0004229', ('60', '64'))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (82, 106))	('rs2250889', 'DBSNP_MENTION', 'None', (201, 210))	('increased death', 'Disease', (123, 138))	('MMP9', 'molecular_function', 'GO:0004229', ('196', '200'))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (82, 106))
111282	29138529	This dual biological function could also partially explain the beneficial effect of MMP9 rs25044 on TTP and OS observed in our study.	('beneficial', 'PosReg', (63, 73))	('MMP9', 'molecular_function', 'GO:0004229', ('84', '88'))	('TTP', 'Disease', (100, 103))	('rs25044', 'Mutation', 'rs25044', (89, 96))	('MMP9', 'Gene', (84, 88))	('rs25044', 'Var', (89, 96))
111283	29138529	The function prediction analysis suggested a role of MMP9 rs25044 in differential miRNA binding.	('rs25044', 'Var', (58, 65))	('rs25044', 'DBSNP_MENTION', 'None', (58, 65))	('MMP9', 'molecular_function', 'GO:0004229', ('53', '57'))	('miRNA binding', 'molecular_function', 'GO:0035198', ('82', '95'))	('MMP9', 'Gene', (53, 57))
111284	29138529	The proposed rs25044-miRNA interaction could have a putative protective effect and thus influence survival in MPM patients.	('rs25044', 'Var', (13, 20))	('survival', 'CPA', (98, 106))	('rs25044', 'DBSNP_MENTION', 'None', (13, 20))	('influence', 'Reg', (88, 97))	('protective effect', 'CPA', (61, 78))	('MPM', 'Disease', (110, 113))
111286	29138529	MMP14 rs1042703 had nominally significant influence on TTP in our study, but only after adjustment for weight loss, histological type, and performance status.	('rs1042703', 'Var', (6, 15))	('rs1042703', 'DBSNP_MENTION', 'None', (6, 15))	('MMP14', 'Gene', (0, 5))	('influence', 'Reg', (42, 51))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('weight loss', 'Phenotype', 'HP:0001824', (103, 114))	('TTP', 'MPA', (55, 58))
111287	29138529	The MMP14 rs1042703 is a nonsynonymous SNP leading to amino acid substitution (p.Pro8Ser) and can thus influence an individual's phenotype.	('leading to', 'Reg', (43, 53))	('MMP', 'molecular_function', 'GO:0004235', ('4', '7'))	('phenotype', 'MPA', (129, 138))	('rs1042703', 'Var', (10, 19))	('MMP14', 'Gene', (4, 9))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('influence', 'Reg', (103, 112))	('amino acid substitution', 'MPA', (54, 77))	('rs1042703', 'DBSNP_MENTION', 'None', (10, 19))	('p.Pro8Ser', 'Mutation', 'rs1042703', (79, 88))
111288	29138529	A possible role of MMP14 rs1042703 as a biomarker in hepatocellular carcinoma (HCC) was investigated in a Taiwanese study with rs1042703 CC genotype resulting in lower MMP14 expression and lower risk of acquiring HCC.	('MMP', 'molecular_function', 'GO:0004235', ('168', '171'))	('expression', 'MPA', (174, 184))	('rs1042703', 'Var', (127, 136))	('rs1042703', 'Var', (25, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('MMP14', 'Protein', (168, 173))	('lower', 'NegReg', (162, 167))	('MMP', 'molecular_function', 'GO:0004235', ('19', '22'))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('rs1042703', 'DBSNP_MENTION', 'None', (127, 136))	('HCC', 'Phenotype', 'HP:0001402', (213, 216))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('rs1042703', 'DBSNP_MENTION', 'None', (25, 34))
111289	29138529	In our study, we have also investigated MMP2 SNPs (rs243865, rs243849, and rs7201) that failed to support any statistically significant association with the TTP and OS.	('rs243865', 'Var', (51, 59))	('rs7201', 'Var', (75, 81))	('TTP', 'Disease', (157, 160))	('MMP2', 'molecular_function', 'GO:0004228', ('40', '44'))	('rs243849', 'DBSNP_MENTION', 'None', (61, 69))	('rs243865', 'DBSNP_MENTION', 'None', (51, 59))	('rs7201', 'DBSNP_MENTION', 'None', (75, 81))	('rs243849', 'Var', (61, 69))
111290	29138529	The function prediction analysis showed that rs243865 may alter the transcription factors' binding site.	('binding site', 'Interaction', (91, 103))	('transcription', 'biological_process', 'GO:0006351', ('68', '81'))	('rs243865', 'Var', (45, 53))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('rs243865', 'DBSNP_MENTION', 'None', (45, 53))	('alter', 'Reg', (58, 63))	('transcription', 'Protein', (68, 81))
111292	29138529	Both heterozygous rs243865 CT and homozygous TT genotype were associated with significantly increased risk for osteosarcoma (OR = 1.86, 95% CI = 1.18-4.22, p = 0.014 and OR = 1.92, 95% CI = 1.21-3.52, p = 0.028, resp.).	('rs243865', 'Var', (18, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('osteosarcoma', 'Disease', (111, 123))	('rs243865', 'DBSNP_MENTION', 'None', (18, 26))
111293	29138529	On the other hand, rs243849 may influence splicing, but was, thus far, investigated in a prostate cancer population of 1817 African American men, where the results showed an increased risk of disease aggressiveness (OR = 1.44; p = 0.04) in Stage 3 for the T allele of rs243849.	('rs243849', 'DBSNP_MENTION', 'None', (268, 276))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('influence', 'Reg', (32, 41))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('aggressiveness', 'Disease', 'MESH:D001523', (200, 214))	('rs243849', 'Var', (268, 276))	('rs243849', 'DBSNP_MENTION', 'None', (19, 27))	('splicing', 'MPA', (42, 50))	('aggressiveness', 'Disease', (200, 214))	('aggressiveness', 'Phenotype', 'HP:0000718', (200, 214))	('rs243849', 'Var', (19, 27))
111294	29138529	Lastly, rs7201 may lead to differential miRNA binding, and its potential role was investigated in a nasopharyngeal (NC) carcinoma study.	('rs7201', 'Var', (8, 14))	('lead to', 'Reg', (19, 26))	('nasopharyngeal', 'Disease', (100, 114))	('miRNA binding', 'molecular_function', 'GO:0035198', ('40', '53'))	('rs7201', 'DBSNP_MENTION', 'None', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('miRNA binding', 'MPA', (40, 53))
111295	29138529	MiR-151 correlation to rs7201 was investigated but did not have any statistically significant influence on NC risk.	('MiR-151', 'Gene', (0, 7))	('rs7201', 'Var', (23, 29))	('MiR-151', 'Gene', '442893', (0, 7))	('rs7201', 'DBSNP_MENTION', 'None', (23, 29))
111317	26134238	So it appears we all agree that our findings identifying environmental exposure to asbestos in Southern Nevada are important and require follow up because asbestos causes mesothelioma.	('mesothelioma', 'Disease', (171, 183))	('asbestos', 'Chemical', 'MESH:D001194', (83, 91))	('asbestos', 'Var', (155, 163))	('asbestos', 'Chemical', 'MESH:D001194', (155, 163))	('causes', 'Reg', (164, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))
111459	22021531	Melanoma metastases are prone to hemorrhage; the presence of methemoglobin can also cause T1 shortening.	('presence', 'Var', (49, 57))	('Melanoma metastases', 'Disease', 'MESH:D009362', (0, 19))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma metastases', 'Disease', (0, 19))	('methemoglobin', 'Gene', '3048', (61, 74))	('hemorrhage', 'Disease', (33, 43))	('shortening', 'NegReg', (93, 103))	('methemoglobin', 'Gene', (61, 74))	('cause', 'Reg', (84, 89))	('hemorrhage', 'Disease', 'MESH:D006470', (33, 43))
111678	32727149	Actually, drug repurposing alleviates the pre-clinical steps of a classical drug development allowing significant time savings.	('pre', 'molecular_function', 'GO:0003904', ('42', '45'))	('repurposing', 'Var', (15, 26))	('alleviates', 'NegReg', (27, 37))	('men', 'Species', '9606', (88, 91))
111686	32727149	Actually, metformin seems to reduce cancer cells growth by activating the Adenosine Monophosphate-activated protein kinase (AMPK) and thereby modulating the activity of several metabolic pathways required for tumour growth.	('AMPK', 'molecular_function', 'GO:0047322', ('124', '128'))	('reduce', 'NegReg', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('metformin', 'Var', (10, 19))	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('tumour', 'Disease', (209, 215))	('activity', 'MPA', (157, 165))	('Adenosine Monophosphate-activated protein kinase', 'Gene', '5563', (74, 122))	('AMPK', 'Gene', '5563', (124, 128))	('AMPK', 'molecular_function', 'GO:0050405', ('124', '128'))	('modulating', 'Reg', (142, 152))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('activating', 'PosReg', (59, 69))	('cancer', 'Disease', (36, 42))	('AMPK', 'molecular_function', 'GO:0004691', ('124', '128'))	('Adenosine Monophosphate-activated protein kinase', 'Gene', (74, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('AMPK', 'Gene', (124, 128))
111691	32727149	Smooth muscles express the three alpha1-AR subtypes with a predominant alpha1A and alpha1D expression, which are also found in aorta and cerebral cortex tissues.	('alpha1A', 'Gene', '5265', (71, 78))	('alpha1D', 'Var', (83, 90))	('alpha1A', 'Gene', (71, 78))
111704	32727149	The widely held concept is that BPH leads to prostate enlargement that impinges upon the prostatic urethra and bladder outlet which is responsible of mechanical obstruction to urinary outflow and bladder detrusor muscle irritability.	('irritability', 'Phenotype', 'HP:0000737', (220, 232))	('bladder detrusor muscle irritability', 'Disease', (196, 232))	('bladder detrusor muscle irritability', 'Disease', 'MESH:D001745', (196, 232))	('men', 'Species', '9606', (61, 64))	('obstruction', 'Disease', 'MESH:D000402', (161, 172))	('obstruction to urinary outflow', 'Phenotype', 'HP:0041047', (161, 191))	('BPH', 'Var', (32, 35))	('bladder detrusor', 'Phenotype', 'HP:0100645', (196, 212))	('prostatic urethra', 'Disease', (89, 106))	('prostate', 'Disease', (45, 53))	('enlargement', 'PosReg', (54, 65))	('obstruction', 'Disease', (161, 172))	('prostatic urethra', 'Disease', 'MESH:D011472', (89, 106))	('BPH', 'Phenotype', 'HP:0008711', (32, 35))
111756	32727149	They showed that naftopidil had an anti-proliferative effect on both cell lines with IC50 around 20 and 30 microM respectively and induced a cell cycle arrest with a blockade in G0/G1 phase.	('naftopidil', 'Chemical', 'MESH:C064357', (17, 27))	('induced', 'Reg', (131, 138))	('naftopidil', 'Var', (17, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('rat', 'Species', '10116', (47, 50))	('arrest', 'Disease', (152, 158))	('G1 phase', 'biological_process', 'GO:0051318', ('181', '189'))	('G0/G1 phase', 'CPA', (178, 189))	('anti-proliferative effect', 'CPA', (35, 60))
111765	32727149	As well, naftopidil was proven to reduce proliferation of colon adenocarcinoma cells HT29 and that of ovarian cancer cell lines SKOV3 and IGROV1-R10 in a dose-dependent manner.	('colon adenocarcinoma', 'Disease', (58, 78))	('rat', 'Species', '10116', (48, 51))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('SKOV3', 'CellLine', 'CVCL:0532', (128, 133))	('naftopidil', 'Chemical', 'MESH:C064357', (9, 19))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (58, 78))	('naftopidil', 'Var', (9, 19))	('reduce', 'NegReg', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Disease', (102, 116))	('HT29', 'CellLine', 'CVCL:0320', (85, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('proliferation', 'CPA', (41, 54))
111768	32727149	For example, in Hori's study, naftopidil also reduced the growth of the fibroblasts cells PrSC derived from the prostate stroma as well as their secretion of IL-6, a growth factor for most prostate cancer cells, suggesting that naftopidil could interfere with tumour-stroma interactions.	('interfere', 'NegReg', (245, 254))	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('secretion', 'MPA', (145, 154))	('IL-6', 'Gene', (158, 162))	('naftopidil', 'Var', (30, 40))	('secretion', 'biological_process', 'GO:0046903', ('145', '154'))	('IL-6', 'molecular_function', 'GO:0005138', ('158', '162'))	('growth', 'MPA', (58, 64))	('tumour-stroma', 'Disease', (260, 273))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumour-stroma', 'Disease', 'MESH:D009369', (260, 273))	('reduced', 'NegReg', (46, 53))	('prostate stroma', 'Disease', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (189, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (189, 204))	('naftopidil', 'Chemical', 'MESH:C064357', (228, 238))	('prostate cancer', 'Disease', (189, 204))	('naftopidil', 'Chemical', 'MESH:C064357', (30, 40))	('IL-6', 'Gene', '3569', (158, 162))	('prostate stroma', 'Disease', 'MESH:D011472', (112, 127))
111789	32727149	Finally, naftopidil exerted anti-angiogenic properties through reduction of the microvessels density (MVD) in renal carcinoma cell line (ACHN) and prostate cancer cell (PC-3) xenograft models, but also, in-patient renal carcinoma xenografted into nude mice.	('renal carcinoma', 'Phenotype', 'HP:0005584', (110, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('prostate cancer', 'Disease', (147, 162))	('ACHN', 'Gene', (137, 141))	('nude mice', 'Species', '10090', (247, 256))	('naftopidil', 'Chemical', 'MESH:C064357', (9, 19))	('PC-3', 'CellLine', 'CVCL:0035', (169, 173))	('patient', 'Species', '9606', (206, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('microvessels density', 'CPA', (80, 100))	('ACHN', 'Gene', '55323', (137, 141))	('naftopidil', 'Var', (9, 19))	('anti-angiogenic', 'MPA', (28, 43))	('renal carcinoma', 'Disease', 'MESH:C538614', (214, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('reduction', 'NegReg', (63, 72))	('renal carcinoma', 'Disease', (214, 229))	('renal carcinoma', 'Phenotype', 'HP:0005584', (214, 229))	('renal carcinoma', 'Disease', 'MESH:C538614', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('renal carcinoma', 'Disease', (110, 125))
111798	32727149	Moreover, these authors also showed that prostate cancer cells from men treated with naftopidil over-expressed p21 and under-expressed Bcl-2 compared with men exposed to tamsulosin or no treatment, suggesting that naftopidil acted through inhibition of cell cycle progression and perturbation of apoptosis member expression in clinic.	('perturbation', 'NegReg', (280, 292))	('apoptosis', 'Protein', (296, 305))	('Bcl-2', 'Gene', '596', (135, 140))	('inhibition', 'NegReg', (239, 249))	('expression', 'MPA', (313, 323))	('men', 'Species', '9606', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('naftopidil', 'Var', (85, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('cell cycle', 'biological_process', 'GO:0007049', ('253', '263'))	('p21', 'Gene', (111, 114))	('prostate cancer', 'Disease', (41, 56))	('under-expressed', 'NegReg', (119, 134))	('tamsulosin', 'Chemical', 'MESH:D000077409', (170, 180))	('over-expressed', 'PosReg', (96, 110))	('naftopidil', 'Chemical', 'MESH:C064357', (214, 224))	('Bcl-2', 'molecular_function', 'GO:0015283', ('135', '140'))	('apoptosis', 'biological_process', 'GO:0097194', ('296', '305'))	('apoptosis', 'biological_process', 'GO:0006915', ('296', '305'))	('men', 'Species', '9606', (155, 158))	('p21', 'Gene', '1026', (111, 114))	('Bcl-2', 'Gene', (135, 140))	('cell cycle progression', 'CPA', (253, 275))	('men', 'Species', '9606', (68, 71))	('naftopidil', 'Chemical', 'MESH:C064357', (85, 95))
111817	32727149	In fact, naftopidil reduced mesothelioma cell viability, while the alpha1D-AR knock-down enhanced it.	('reduced', 'NegReg', (20, 27))	('enhanced', 'PosReg', (89, 97))	('knock-down', 'Var', (78, 88))	('naftopidil', 'Chemical', 'MESH:C064357', (9, 19))	('mesothelioma', 'Disease', (28, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))	('alpha1D-AR', 'Protein', (67, 77))
111819	32727149	However, the PKC inhibitor GF109203X attenuated naftopidil-induced apoptosis of mesothelioma cells.	('naftopidil', 'Chemical', 'MESH:C064357', (48, 58))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('GF109203X', 'Chemical', 'MESH:C070515', (27, 36))	('attenuated', 'NegReg', (37, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('mesothelioma', 'Disease', (80, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('GF109203X', 'Var', (27, 36))
111820	32727149	Moreover, neither the PKA inhibitor H89 nor the GF109203X increased naftopidil cytoxic effects on bladder cancer cells.	('increased', 'PosReg', (58, 67))	('PKA', 'molecular_function', 'GO:0004691', ('22', '25'))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('H89', 'Chemical', 'MESH:C063509', (36, 39))	('naftopidil', 'Chemical', 'MESH:C064357', (68, 78))	('PKA', 'cellular_component', 'GO:0005952', ('22', '25'))	('GF109203X', 'Chemical', 'MESH:C070515', (48, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('naftopidil cytoxic effects', 'MPA', (68, 94))	('GF109203X', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
111824	32727149	Lastly, naftopidil reduced proliferation of the prostate cancer cells AIDL (Androgen-Independent LNCaP), although this cell line does not express the alpha1D-AR subtype.	('reduced proliferation of the prostate', 'Phenotype', 'HP:0008687', (19, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('proliferation', 'CPA', (27, 40))	('naftopidil', 'Chemical', 'MESH:C064357', (8, 18))	('naftopidil', 'Var', (8, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('reduced', 'NegReg', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('rat', 'Species', '10116', (34, 37))	('prostate cancer', 'Disease', (48, 63))	('LNCaP', 'CellLine', 'CVCL:0395', (97, 102))
111835	32727149	Depending on cellular context in ovarian cancer cell lines, naftopidil induced either ER stress-activated ATF4 transcription factor or JNK/c-Jun phosphorylation; both pathways leading to BH3-only protein up-regulation.	('JNK', 'molecular_function', 'GO:0004705', ('135', '138'))	('naftopidil', 'Chemical', 'MESH:C064357', (60, 70))	('Jun phosphorylation', 'biological_process', 'GO:0007258', ('141', '160'))	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('JNK', 'Gene', (135, 138))	('ATF4', 'Gene', (106, 110))	('JNK', 'Gene', '5599', (135, 138))	('regulation', 'biological_process', 'GO:0065007', ('207', '217'))	('transcription factor', 'molecular_function', 'GO:0000981', ('111', '131'))	('ATF4', 'Gene', '468', (106, 110))	('naftopidil', 'Var', (60, 70))	('ovarian cancer', 'Disease', (33, 47))	('up-regulation', 'PosReg', (204, 217))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('c-Jun', 'Gene', '3725', (139, 144))	('BH3-only protein', 'Protein', (187, 203))	('c-Jun', 'Gene', (139, 144))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
111837	32727149	In fact, in this study, Ishii and colleagues showed that naftopidil, as well as other phenylpiperazine derivates RS100329, BMY-7378, and KN-62, were able to bind tubulin and to inhibit its polymerization.	('tubulin', 'Protein', (162, 169))	('phenylpiperazine', 'Chemical', 'MESH:C031503', (86, 102))	('inhibit', 'NegReg', (177, 184))	('RS100329', 'Var', (113, 121))	('KN-62', 'Chemical', 'MESH:C063302', (137, 142))	('BMY-7378', 'Chemical', 'MESH:C053428', (123, 131))	('naftopidil', 'Chemical', 'MESH:C064357', (57, 67))	('polymerization', 'MPA', (189, 203))	('bind', 'Interaction', (157, 161))	('naftopidil', 'Gene', (57, 67))
111840	32727149	This property was supported by the fact that AK301, a piperazine-based compound, was also known to inhibit tubulin polymerization and to induce a blockade of colon cancer cells in the G2/M phase of the cell cycle which restored their apoptosis in presence of TNF-alpha.	('cell cycle', 'biological_process', 'GO:0007049', ('202', '212'))	('AK301', 'Chemical', '-', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('blockade of colon cancer', 'Disease', (146, 170))	('inhibit', 'NegReg', (99, 106))	('G2/M phase of the cell cycle', 'CPA', (184, 212))	('TNF-alpha', 'Gene', '7124', (259, 268))	('apoptosis', 'CPA', (234, 243))	('blockade of colon cancer', 'Disease', 'MESH:D015179', (146, 170))	('tubulin polymerization', 'MPA', (107, 129))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('TNF-alpha', 'Gene', (259, 268))	('piperazine', 'Chemical', 'MESH:D000077489', (54, 64))	('M phase', 'biological_process', 'GO:0000279', ('187', '194'))	('apoptosis', 'biological_process', 'GO:0097194', ('234', '243'))	('apoptosis', 'biological_process', 'GO:0006915', ('234', '243'))	('AK301', 'Var', (45, 50))
111844	32727149	Moreover, an in-silico drug repositioning-approach carried out to predict drugs that can modulate transcription factor activity identified naftopidil among more than 6700 drugs as a potential activator of p53.	('transcription factor activity', 'molecular_function', 'GO:0003700', ('98', '127'))	('transcription factor activity', 'molecular_function', 'GO:0000988', ('98', '127'))	('p53', 'Gene', (205, 208))	('naftopidil', 'Chemical', 'MESH:C064357', (139, 149))	('naftopidil', 'Var', (139, 149))	('p53', 'Gene', '7157', (205, 208))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))
111847	32727149	Interestingly, the naftopidil major metabolite HUHS190, also reduced cell viability of prostate, bladder and renal cancer cell lines in dose-dependent manner.	('bladder and renal cancer', 'Disease', 'MESH:D001749', (97, 121))	('renal cancer', 'Phenotype', 'HP:0009726', (109, 121))	('HUHS190', 'CellLine', 'CVCL:0671', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cell viability', 'CPA', (69, 83))	('naftopidil', 'Chemical', 'MESH:C064357', (19, 29))	('HUHS190', 'Var', (47, 54))	('prostate', 'Disease', (87, 95))	('reduced', 'NegReg', (61, 68))
111849	32727149	Thus, naftopidil derivates containing methyl phenylacetate moiety exhibited alpha1-AR antagonist properties but their potential anti-cancerous activity has not been studied yet.	('alpha1-AR antagonist', 'Protein', (76, 96))	('naftopidil', 'Chemical', 'MESH:C064357', (6, 16))	('cancerous', 'Disease', (133, 142))	('methyl phenylacetate', 'Var', (38, 58))	('cancerous', 'Disease', 'MESH:D009369', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('methyl phenylacetate', 'Chemical', 'MESH:C024906', (38, 58))
111852	32727149	Nishizaki and colleagues synthesized 21 naftopidil analogues and among them HUHS1015 seemed to present interesting anti-cancerous properties.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HUHS1015', 'Var', (76, 84))	('cancerous', 'Disease', (120, 129))	('HUHS1015', 'Chemical', 'MESH:C586405', (76, 84))	('naftopidil', 'Chemical', 'MESH:C064357', (40, 50))	('cancerous', 'Disease', 'MESH:D009369', (120, 129))
111853	32727149	In vitro, HUHS1015 reduced mesothelioma cell lines proliferation by inducing an arrest in G0/G1 phase of the cell cycle at 10 microM and induced their necrosis and apoptosis at 15 microM after a 24 h treatment.	('G1 phase', 'biological_process', 'GO:0051318', ('93', '101'))	('mesothelioma', 'Disease', (27, 39))	('necrosis', 'Disease', 'MESH:D009336', (151, 159))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('induced', 'Reg', (137, 144))	('reduced', 'NegReg', (19, 26))	('necrosis', 'Disease', (151, 159))	('necrosis', 'biological_process', 'GO:0008220', ('151', '159'))	('arrest', 'Disease', 'MESH:D006323', (80, 86))	('HUHS1015', 'Chemical', 'MESH:C586405', (10, 18))	('apoptosis', 'CPA', (164, 173))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('necrosis', 'biological_process', 'GO:0070265', ('151', '159'))	('HUHS1015', 'Var', (10, 18))	('necrosis', 'biological_process', 'GO:0019835', ('151', '159'))	('necrosis', 'biological_process', 'GO:0001906', ('151', '159'))	('men', 'Species', '9606', (205, 208))	('rat', 'Species', '10116', (58, 61))	('inducing', 'Reg', (68, 76))	('arrest', 'Disease', (80, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('109', '119'))	('necrosis', 'biological_process', 'GO:0008219', ('151', '159'))
111854	32727149	Moreover, HUHS1015 was able to reduce cell viability in other several models, notably it induced cell death in lung, liver, gastric, bladder and renal cancer cells.	('cell viability', 'CPA', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('induced', 'Reg', (89, 96))	('HUHS1015', 'Chemical', 'MESH:C586405', (10, 18))	('gastric', 'Disease', (124, 131))	('HUHS1015', 'Var', (10, 18))	('lung', 'Disease', (111, 115))	('bladder and renal cancer', 'Disease', 'MESH:D001749', (133, 157))	('liver', 'Disease', (117, 122))	('reduce', 'NegReg', (31, 37))	('renal cancer', 'Phenotype', 'HP:0009726', (145, 157))	('cell death', 'biological_process', 'GO:0008219', ('97', '107'))	('cell death', 'CPA', (97, 107))
111855	32727149	Concerning mesothelioma cell lines, it is interesting to note that HUHS1015 is less cytotoxic for the non-malignant MeT-5A cell line than for malignant ones.	('mesothelioma', 'Disease', (11, 23))	('HUHS1015', 'Var', (67, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('cytotoxic', 'CPA', (84, 93))	('less', 'NegReg', (79, 83))	('HUHS1015', 'Chemical', 'MESH:C586405', (67, 75))
111856	32727149	Molecular pathways involved in mesothelioma cell lines showed that caspase 3 and 4 are activated, but not caspase 8 and 9, suggesting that HUHS1015 induced apoptosis not through canonical extrinsic and intrinsic pathways but perhaps through reticulum stress (known to activate apoptosis through caspase 4) or through independent-caspase pathway.	('caspase', 'Gene', (67, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('277', '286'))	('caspase', 'Gene', (329, 336))	('HUHS1015', 'Chemical', 'MESH:C586405', (139, 147))	('apoptosis', 'CPA', (156, 165))	('caspase', 'Gene', '837;841', (106, 113))	('HUHS1015', 'Var', (139, 147))	('caspase', 'Gene', (106, 113))	('caspase 8', 'Gene', (106, 115))	('caspase', 'Gene', '837;841', (295, 302))	('mesothelioma', 'Disease', (31, 43))	('caspase', 'Gene', (295, 302))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('caspase 4', 'Gene', '837', (295, 304))	('caspase 3 and 4', 'Gene', '836;837', (67, 82))	('caspase 4', 'Gene', (295, 304))	('caspase 8', 'Gene', '841', (106, 115))	('caspase', 'Gene', '837;841', (67, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('caspase', 'Gene', '837;841', (329, 336))	('apoptosis', 'biological_process', 'GO:0097194', ('277', '286'))
111858	32727149	Interestingly, HUHS1015 triggered MKN45 cells apoptosis by activating caspase 3, 4 and 8 while it acted by a caspase-independent way, probably through nuclear accumulation of AMID (Apoptosis-inducing factor-homologous Mitochondrion-associated Inducer of Death) in MKN28 cell line.	('apoptosis', 'CPA', (46, 55))	('caspase', 'Gene', '837;841', (70, 77))	('Death', 'Disease', 'MESH:D003643', (254, 259))	('caspase', 'Gene', (109, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('activating', 'Reg', (59, 69))	('caspase 3', 'Gene', (70, 79))	('caspase 3', 'Gene', '836', (70, 79))	('Death', 'Disease', (254, 259))	('HUHS1015', 'Var', (15, 23))	('caspase', 'Gene', (70, 77))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('Mitochondrion', 'cellular_component', 'GO:0005739', ('218', '231'))	('HUHS1015', 'Chemical', 'MESH:C586405', (15, 23))	('caspase', 'Gene', '837;841', (109, 116))
111859	32727149	HUHS1015 was also able to bring colorectal cancer cell lines Caco-2 and CW2 in apoptosis by inducing mitochondria damages.	('colorectal cancer', 'Disease', (32, 49))	('mitochondria damages', 'MPA', (101, 121))	('HUHS1015', 'Chemical', 'MESH:C586405', (0, 8))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('Caco-2', 'CellLine', 'CVCL:0025', (61, 67))	('apoptosis', 'CPA', (79, 88))	('mitochondria', 'cellular_component', 'GO:0005739', ('101', '113'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('HUHS1015', 'Var', (0, 8))	('inducing', 'Reg', (92, 100))
111860	32727149	Moreover, HUHS1015 modulated the expression of proteins implicated in apoptosis regulation, which could explain its ability to induce this type of cell death.	('expression of', 'MPA', (33, 46))	('modulated', 'Reg', (19, 28))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('HUHS1015', 'Chemical', 'MESH:C586405', (10, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('cell death', 'biological_process', 'GO:0008219', ('147', '157'))	('proteins', 'Protein', (47, 55))	('HUHS1015', 'Var', (10, 18))
111863	32727149	Like naftopidil in mesothelioma cells, HUHS1015 also increased expression of factors implicated in the extrinsic apoptosis pathway, such as the cytokine TNF-alpha in MKN45 gastric cells; however, this effect has been called into question due to the very high concentrations of HUHS1015 used.	('HUHS1015', 'Chemical', 'MESH:C586405', (277, 285))	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('extrinsic apoptosis', 'biological_process', 'GO:0097191', ('103', '122'))	('rat', 'Species', '10116', (266, 269))	('expression', 'MPA', (63, 73))	('TNF-alpha', 'Gene', '7124', (153, 162))	('increased', 'PosReg', (53, 62))	('HUHS1015', 'Var', (39, 47))	('TNF-alpha', 'Gene', (153, 162))	('naftopidil', 'Chemical', 'MESH:C064357', (5, 15))	('mesothelioma', 'Disease', (19, 31))	('HUHS1015', 'Chemical', 'MESH:C586405', (39, 47))
111864	32727149	In vivo, HUHS1015 was described to be well tolerated by mice, as it did not induce a loss of weight and it reduced the tumour volume in mesothelioma, gastric and colorectal cancer cells xenografted mice.	('HUHS1015', 'Chemical', 'MESH:C586405', (9, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('mesothelioma', 'Disease', (136, 148))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('reduced', 'NegReg', (107, 114))	('HUHS1015', 'Var', (9, 17))	('rat', 'Species', '10116', (47, 50))	('mice', 'Species', '10090', (56, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (136, 148))	('tumour', 'Disease', (119, 125))	('colorectal cancer', 'Disease', (162, 179))	('loss of weight', 'Phenotype', 'HP:0001824', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mice', 'Species', '10090', (198, 202))	('gastric', 'Disease', (150, 157))
111865	32727149	Moreover, HUHS1015 seemed to be more efficient than naftopidil on gastric and colorectal cancer models as it induced a stronger decrease of tumour for the same dose used.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('naftopidil', 'Chemical', 'MESH:C064357', (52, 62))	('gastric', 'Disease', (66, 73))	('decrease of tumour', 'Disease', 'MESH:D009369', (128, 146))	('HUHS1015', 'Chemical', 'MESH:C586405', (10, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('decrease of tumour', 'Disease', (128, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('HUHS1015', 'Var', (10, 18))	('colorectal cancer', 'Disease', (78, 95))
111874	32727149	Among them, HUHS1015 and compound 12 display anti-cancerous activities in several cancer types at lower concentrations than naftopidil, suggesting their better efficacy.	('rat', 'Species', '10116', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('HUHS1015', 'Var', (12, 20))	('cancerous', 'Disease', (50, 59))	('naftopidil', 'Chemical', 'MESH:C064357', (124, 134))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('HUHS1015', 'Chemical', 'MESH:C586405', (12, 20))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
111880	32727149	Naftopidil can also exert cytotoxic effects when used as a single agent, but in other models it was also able to induce apoptosis only when combined with other antineoplasic drugs in vitro, in vivo as well as ex vivo in high grade serous ovarian cancer PDO models.	('induce', 'PosReg', (113, 119))	('apoptosis', 'CPA', (120, 129))	('serous ovarian cancer', 'Disease', (231, 252))	('Naftopidil', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (231, 252))	('ovarian cancer', 'Phenotype', 'HP:0100615', (238, 252))	('Naftopidil', 'Chemical', 'MESH:C064357', (0, 10))
111884	32727149	Interestingly, anti-cancerous effects of naftopidil seem to be independent of its alpha1-AR antagonist property and, depending on cellular context, naftopidil is able to modulate activity of various signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('activity', 'MPA', (179, 187))	('cancerous', 'Disease', 'MESH:D009369', (20, 29))	('naftopidil', 'Chemical', 'MESH:C064357', (41, 51))	('modulate', 'Reg', (170, 178))	('naftopidil', 'Chemical', 'MESH:C064357', (148, 158))	('naftopidil', 'Var', (148, 158))	('cancerous', 'Disease', (20, 29))	('signaling', 'biological_process', 'GO:0023052', ('199', '208'))
111890	32727149	This is in agreement with Thebault's work showing that LNCaP cells expressed alpha1A-AR and that the inhibition of these receptors prevented cancer epithelial cell proliferation.	('inhibition', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('148', '177'))	('alpha1A-AR', 'Gene', (77, 87))	('men', 'Species', '9606', (16, 19))	('rat', 'Species', '10116', (171, 174))	('prevented', 'NegReg', (131, 140))	('alpha1A-AR', 'Gene', '148', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('LNCaP', 'CellLine', 'CVCL:0395', (55, 60))	('cancer', 'Disease', (141, 147))
111895	32727149	In addition, it would prevent the acquisition of mutations and the development of chemoresistance.	('prevent', 'NegReg', (22, 29))	('mutations', 'Var', (49, 58))	('chemoresistance', 'CPA', (82, 97))	('men', 'Species', '9606', (74, 77))	('acquisition', 'CPA', (34, 45))
112011	32244839	In consequence, Cx43 deficiency was observed to lead to a reduction in tumor size.	('Cx43', 'Gene', '2697', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Cx43', 'Gene', (16, 20))	('deficiency', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('reduction', 'NegReg', (58, 67))	('tumor', 'Disease', (71, 76))
112015	32244839	The chromosomal location of the ttyh1 gene to chromosome 19q is interesting, since codeletion of 1p and 19q is a characteristic in oligodendrogliomas, a brain tumor subtype with a better prognosis as compared to astrocytoma or glioma.	('brain tumor', 'Phenotype', 'HP:0030692', (153, 164))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('codeletion', 'Var', (83, 93))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('brain tumor', 'Disease', (153, 164))	('brain tumor', 'Disease', 'MESH:D001932', (153, 164))	('astrocytoma', 'Disease', 'MESH:D001254', (212, 223))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('astrocytoma', 'Disease', (212, 223))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('oligodendrogliomas', 'Disease', (131, 149))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (131, 149))	('ttyh1', 'Gene', (32, 37))	('glioma', 'Disease', (142, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (212, 223))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('ttyh1', 'Gene', '57776', (32, 37))	('glioma', 'Disease', (227, 233))
112021	32244839	Consistently, the structure and branching of TMs were affected in primary glioblastoma cell lines with a genetic knockdown of GAP-43.	('affected', 'Reg', (54, 62))	('GAP-43', 'Gene', (126, 132))	('structure', 'CPA', (18, 27))	('primary glioblastoma', 'Disease', 'MESH:D005909', (66, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('primary glioblastoma', 'Disease', (66, 86))	('knockdown', 'Var', (113, 122))	('branching', 'CPA', (32, 41))
112031	32244839	NGS were found to strongly contribute to the proliferation promoting effect of glutamate on glioblastoma cells and consequently stimulate tumor growth.	('stimulate', 'PosReg', (128, 137))	('proliferation promoting', 'CPA', (45, 68))	('rat', 'Species', '10116', (52, 55))	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('tumor', 'Disease', (138, 143))	('glutamate', 'Chemical', 'MESH:D018698', (79, 88))	('glutamate', 'Protein', (79, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('NGS', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
112032	32244839	Therefore, gliomas integrate into electrical networks and depolarizing current promotes tumor progression.	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('promotes', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('depolarizing', 'Var', (58, 70))	('rat', 'Species', '10116', (24, 27))	('tumor', 'Disease', (88, 93))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
112036	32244839	Upon ablation of a single TM-connected glioma cell, the dead cell was approached by new TMs that extended from surrounding live glioma cells.	('glioma', 'Disease', (39, 45))	('ablation', 'Var', (5, 13))	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
112053	32244839	demonstrated that MSC mitochondria were able to increase proliferative and invasive capacity in a breast cancer cell line.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('mitochondria', 'cellular_component', 'GO:0005739', ('22', '34'))	('MSC', 'Var', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('rat', 'Species', '10116', (64, 67))	('invasive capacity', 'CPA', (75, 92))	('rat', 'Species', '10116', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increase', 'PosReg', (48, 56))
112064	32244839	Such intercellular translocation of oncogenes results in a heterogeneous distribution of mutant KRAS in cells with endogenous wild-type KRAS.	('KRAS', 'Gene', '3845', (96, 100))	('KRAS', 'Gene', '3845', (136, 140))	('results in', 'Reg', (46, 56))	('heterogeneous distribution', 'MPA', (59, 85))	('KRAS', 'Gene', (136, 140))	('mutant', 'Var', (89, 95))	('KRAS', 'Gene', (96, 100))
112088	32244839	Moreover, genetic targeting of GAP-43 could suppress tumor growth after surgery by impairing formation and function of TMs and therefore could reduce tumor recurrence upon surgery by repopulation.	('impairing', 'NegReg', (83, 92))	('genetic targeting', 'Var', (10, 27))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('GAP-43', 'Gene', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('reduce', 'NegReg', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppress', 'NegReg', (44, 52))	('formation', 'CPA', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('function of TMs', 'CPA', (107, 122))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (150, 155))
112104	32244839	Such gap junctional communication between astrocytes and glioma cells may protect the tumor from chemotherapy, too.	('gap junctional communication', 'Var', (5, 33))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('glioma', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
112109	32244839	Consistently, knockdown of Cx43 impaired the radioprotective effect of the TM network.	('impaired', 'NegReg', (32, 40))	('Cx43', 'Gene', '2697', (27, 31))	('knockdown', 'Var', (14, 23))	('radioprotective effect of the TM network', 'CPA', (45, 85))	('Cx43', 'Gene', (27, 31))
112116	32244839	Pharmacological perturbation of TNTs/TMs consequentially reduced the metastatic potential of tumors in vivo in experimental metastasis models.	('perturbation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TNTs/TMs', 'Gene', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('reduced', 'NegReg', (57, 64))
112117	32244839	Therefore disruption of TNTs/TMs connections has the potential to decrease resistance and recurrence rates of cancer by pharmacologically disconnecting tumor networks.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('disconnecting', 'NegReg', (138, 151))	('rat', 'Species', '10116', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('recurrence rates', 'CPA', (90, 106))	('decrease', 'NegReg', (66, 74))	('disruption', 'Var', (10, 20))	('resistance', 'CPA', (75, 85))
112176	31497016	The following mAbs generated in the Laboratory of Molecular Immunology, DIMES, University of Genoa were used in this study: A6/136 (IgM, anti-HLA-1); L14 (IgG2A, anti-Nectin-2); 5A10 (IgG1, anti-PVR); 11PB6 (IgG1, anti- KIR2DL1/S1); GL183 (IgG1, anti-KIR2DL2/L3/S2); AZ158 (IGg2A, anti-KIR3DL1/S1/L2); C227 (IgG1, anti-CD69); BAB281 (IgG1, anti- NKp46); AZ20 (IgG1, anti-NKp30); QA79 (IgG1, anti-p75); F278 (IgG1 anti-LIR1); ECM217 (IgG2b, anti-NKG2D); GN18 (IgG3, anti-DNAM-1); PP97 (IgM, anti-CD45).	('KIR3DL1/S1', 'Gene', (286, 296))	('LIR1', 'Gene', '10859', (418, 422))	('KIR2DL2', 'Gene', '3803', (251, 258))	('QA79', 'Gene', '27036', (379, 383))	('IgG1', 'cellular_component', 'GO:0071735', ('184', '188'))	('IgG3', 'Gene', (459, 463))	('KIR2DL2', 'Gene', (251, 258))	('KIR2DL1', 'Gene', '3802', (220, 227))	('L14', 'Gene', (150, 153))	('A6/136', 'Gene', '28873', (124, 130))	('NKp30', 'Gene', '259197', (371, 376))	('NKp46', 'Gene', '9437', (346, 351))	('C227', 'Var', (302, 306))	('IgG1', 'cellular_component', 'GO:0071735', ('208', '212'))	('NKG2D', 'Gene', (445, 450))	('L14', 'Gene', '28900', (150, 153))	('IgG3', 'cellular_component', 'GO:0071735', ('459', '463'))	('CD45', 'Gene', (495, 499))	('NKG2D', 'Gene', '22914', (445, 450))	('CD45', 'Gene', '5788', (495, 499))	('IGg2A', 'cellular_component', 'GO:0071735', ('274', '279'))	('Nectin-2', 'Gene', '5819', (167, 175))	('IgG1', 'cellular_component', 'GO:0071735', ('334', '338'))	('KIR2DL1', 'Gene', (220, 227))	('IgG1', 'cellular_component', 'GO:0071735', ('385', '389'))	('CD69', 'Gene', '969', (319, 323))	('IgG1', 'cellular_component', 'GO:0071735', ('360', '364'))	('Nectin-2', 'Gene', (167, 175))	('NKp46', 'Gene', (346, 351))	('CD69', 'Gene', (319, 323))	('QA79', 'Gene', (379, 383))	('GL183', 'Gene', '3804', (233, 238))	('p75', 'Gene', '27036', (396, 399))	('IgG1', 'cellular_component', 'GO:0071735', ('308', '312'))	('IgG2A', 'cellular_component', 'GO:0071735', ('155', '160'))	('A6/136', 'Gene', (124, 130))	('IgG1', 'cellular_component', 'GO:0071735', ('240', '244'))	('p75', 'Gene', (396, 399))	('DNAM-1', 'Gene', '10666', (470, 476))	('PVR', 'Gene', '5817', (195, 198))	('IgG1', 'cellular_component', 'GO:0071735', ('408', '412'))	('IgG2b', 'cellular_component', 'GO:0071735', ('433', '438'))	('NKp30', 'Gene', (371, 376))	('PP97', 'Var', (479, 483))	('PVR', 'Gene', (195, 198))	('DL2', 'molecular_function', 'GO:0033904', ('255', '258'))	('DNAM-1', 'Gene', (470, 476))	('LIR1', 'Gene', (418, 422))	('KIR3DL1/S1', 'Gene', '3811;5707', (286, 296))	('IgG3', 'Gene', '3502', (459, 463))	('GL183', 'Gene', (233, 238))
112177	31497016	The following purchased mAbs were used in this study: anti-ULBP1 (clone M295), anti-ULBP2 (clone M310), anti-ULBP3 (clone M550) (Amgen, Seattle, WA); anti-CXCR4-APC (R&D Systems, MN, USA); anti-ESA, IgG1 (Novocastra Laboratories Ltd.); anti-CD90, IgG1 (BD Biosciences, Pharmingen, CA, USA); anti-CD16-PerCP5.5 (clone 3G8) (BD Biosciences, Pharmingen, CA, USA); anti-CD107-PE (clone H4A3) (BD Biosciences, Pharmingen, CA, USA); anti-NKG2A-APC (clone Z199) (Beckman Coulter/Immunotech, Marseille, France); anti-PD-1 PE (clone 1.3.1.3) (Miltenyi Biotec, Bergisch Gladbach, Germany); anti-CD57-Vioblue (Miltenyi Biotec, Bergisch Gladbach, Germany); anti-B7-H6 (clone MAB7144) (R&D Systems, MN, USA); anti-PD-L1 (clone 27A2) (MBL, Woburn, MA); anti-PD-L2 (clone 176611) (R&D Systems, MN, USA); anti-CK7 (clone OV-TL 12/30) (Abcam, Cambridge, Regno Unito); anti-MUC2 (clone Ccp58) (Abcam, Cambridge, Regno Unito); anti-CD56-PC7 (clone c218) (Beckman Coulter/Immunotech, Marseille, France); anti-CD3-Viogreen (BW264/56 clone), anti-CD19-VioGreen (LT20 clone), anti-CD14-Viogreen (TUK4 clone) (Miltenyi Biotec, Bergisch Gladbach, Germany).	('ULBP1', 'Gene', (59, 64))	('MN', 'CellLine', 'CVCL:U508', (779, 781))	('ULBP3', 'Gene', (109, 114))	('PD-L1', 'Gene', '29126', (701, 706))	('MBL', 'Gene', '50639', (721, 724))	('CD56', 'Gene', '4684', (913, 917))	('IgG1', 'cellular_component', 'GO:0071735', ('247', '251'))	('PD-L2', 'Gene', (744, 749))	('MUC2', 'Gene', '4583', (856, 860))	('CK7', 'Gene', (794, 797))	('NKG2A', 'Gene', '3821', (432, 437))	('ULBP2', 'Gene', '80328', (84, 89))	('CD19', 'Gene', (1025, 1029))	('APC', 'cellular_component', 'GO:0005680', ('161', '164'))	('MUC2', 'Gene', (856, 860))	('BW264/56', 'CellLine', 'CVCL:X356', (1003, 1011))	('ULBP1', 'Gene', '80329', (59, 64))	('CXCR4', 'Gene', '7852', (155, 160))	('B7-H6', 'Gene', '374383', (650, 655))	('CXCR4', 'Gene', (155, 160))	('clone', 'Var', (1012, 1017))	('CK7', 'Gene', '3855', (794, 797))	('CD90', 'Gene', (241, 245))	('IgG1', 'cellular_component', 'GO:0071735', ('199', '203'))	('NKG2A', 'Gene', (432, 437))	('CD19', 'Gene', '930', (1025, 1029))	('ULBP3', 'Gene', '79465', (109, 114))	('CD14', 'Gene', (1058, 1062))	('B7-H6', 'Gene', (650, 655))	('CD14', 'Gene', '929', (1058, 1062))	('CD57', 'Gene', '27087', (585, 589))	('MN', 'CellLine', 'CVCL:U508', (686, 688))	('MBL', 'Gene', (721, 724))	('CD16', 'Gene', '2214', (296, 300))	('CD90', 'Gene', '7070', (241, 245))	('MN', 'CellLine', 'CVCL:U508', (179, 181))	('APC', 'cellular_component', 'GO:0005680', ('438', '441'))	('CXCR4', 'molecular_function', 'GO:0038147', ('155', '160'))	('PD-L2', 'Gene', '80380', (744, 749))	('ULBP2', 'Gene', (84, 89))	('CD56', 'Gene', (913, 917))	('CD57', 'Gene', (585, 589))	('PD-L1', 'Gene', (701, 706))	('CD16', 'Gene', (296, 300))
112184	31497016	in the presence of sub-doses of IL15 (0.5 ng/ml) and then co-incubated with K562 target cells at an E/T ratio of 1:4 in a final volume of 200 mul in round-bottomed 96-well plates at 37 C and 5% CO2 for 3 h in culture medium supplemented with anti-CD107a-PE mAb.	('IL15', 'molecular_function', 'GO:0016170', ('32', '36'))	('0.5', 'Var', (38, 41))	('CD107a', 'Gene', (247, 253))	('CO2', 'Chemical', '-', (194, 197))	('CD107a', 'Gene', '3916', (247, 253))	('IL15', 'Gene', (32, 36))	('K562', 'CellLine', 'CVCL:0004', (76, 80))	('IL15', 'Gene', '3600', (32, 36))
112185	31497016	Surface staining was done by incubating the cells with anti-CD3, anti-CD56 anti-CD19, and anti-CD16 for 30 min at 4 C. The cells were washed and analyzed by flow cytometry (FACSVerse, Becton Dickinson).	('CD16', 'Gene', (95, 99))	('CD19', 'Gene', (80, 84))	('anti-CD3', 'Var', (55, 63))	('CD19', 'Gene', '930', (80, 84))	('CD56', 'Gene', '4684', (70, 74))	('CD16', 'Gene', '2214', (95, 99))	('CD56', 'Gene', (70, 74))
112214	31497016	In addition, PF microenvironment of low-grade PC patients contained a much higher concentration of TGF-beta1 (an increment over 80%) as compared to high-grade PC patients.	('patients', 'Species', '9606', (162, 170))	('TGF-beta1', 'Protein', (99, 108))	('higher', 'PosReg', (75, 81))	('PF', 'Phenotype', 'HP:0030995', (13, 15))	('patients', 'Species', '9606', (49, 57))	('low-grade', 'Var', (36, 45))	('concentration', 'MPA', (82, 95))
112230	31497016	As shown in Figure 5, PB-NK cells derived from a representative low-grade PC patient or a representative high-grade PC patient as well as HD-NK cells displayed ability to degranulate following exposure to K562.	('patient', 'Species', '9606', (119, 126))	('K562', 'Var', (205, 209))	('HD-NK', 'Disease', 'MESH:D006816', (138, 143))	('K562', 'CellLine', 'CVCL:0004', (205, 209))	('HD-NK', 'Disease', (138, 143))	('patient', 'Species', '9606', (77, 84))	('degranulate', 'MPA', (171, 182))
112272	31497016	A high amount of sB7-H6 is correlated with a greater downmodulation of NKp30.	('sB7-H6', 'Chemical', '-', (17, 23))	('downmodulation', 'NegReg', (53, 67))	('NKp30', 'Gene', '259197', (71, 76))	('sB7-H6', 'Var', (17, 23))	('NKp30', 'Gene', (71, 76))
112286	31497016	Remarkably, we show that in a low-grade PC patient, with no evidence of disease recurrence after 4 years after treatment, CRS/HIPEC treatment could restore the NK cells impaired phenotype, thus reverting tumor-induced NK cell suppression.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('patient', 'Species', '9606', (43, 50))	('reverting', 'NegReg', (194, 203))	('NK cells', 'CPA', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CRS/HIPEC', 'Var', (122, 131))	('tumor', 'Disease', (204, 209))	('restore', 'PosReg', (148, 155))
112298	29363016	We were able to demonstrate the feasibility, efficacy, and safety of CRS + HIPEC in patients suffering from PSM at our institution.	('PSM', 'Disease', (108, 111))	('CRS +', 'Var', (69, 74))	('patients', 'Species', '9606', (84, 92))
112307	29363016	CRS + HIPEC, by contrast, can increase median survival and achieve long-term survival in select patients.	('median survival', 'MPA', (39, 54))	('long-term', 'MPA', (67, 76))	('patients', 'Species', '9606', (96, 104))	('CRS + HIPEC', 'Var', (0, 11))	('increase', 'PosReg', (30, 38))
112308	29363016	A multicenter registry study comparing CRS + HIPEC with sole systemic chemotherapy showed a median survival of 32 months and a 5-year survival of 27% after CRS + HIPEC in patients with PSM of colorectal origin.	('PSM of colorectal origin', 'Disease', (185, 209))	('CRS + HIPEC', 'Var', (156, 167))	('patients', 'Species', '9606', (171, 179))
112309	29363016	In patients with limited (low volume of carcinomatosis, defined as only two out of five abdominal regions affected) disease, this effect could even be amplified with a median survival of 63 months in the CRS + HIPEC group vs. 23.9 months in the modern systemic chemotherapy group.	('patients', 'Species', '9606', (3, 11))	('carcinomatosis', 'Disease', (40, 54))	('carcinomatosis', 'Disease', 'MESH:D002277', (40, 54))	('CRS + HIPEC', 'Var', (204, 215))
112356	29363016	One patient died within 90 days after CRS + HIPEC due to an iatrogenic perforation during upper gastrointestinal endoscopy for duodenal ulcer at an outside institution, giving an overall 90-day mortality of 1.7% (1/60).	('CRS +', 'Var', (38, 43))	('duodenal', 'Disease', (127, 135))	('upper gastrointestinal', 'Disease', 'MESH:D005767', (90, 112))	('patient', 'Species', '9606', (4, 11))	('duodenal ulcer', 'Phenotype', 'HP:0002588', (127, 141))	('upper gastrointestinal', 'Disease', (90, 112))	('ulcer', 'Disease', 'MESH:D014456', (136, 141))	('ulcer', 'Disease', (136, 141))
112370	29363016	In colorectal cancer, median OS can be drastically increased with CRS + HIPEC to up to 60 months with a 5-year OS of up to 51%.	('increased', 'PosReg', (51, 60))	('OS', 'Chemical', 'MESH:D009992', (29, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('OS', 'Chemical', 'MESH:D009992', (111, 113))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('CRS + HIPEC', 'Var', (66, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
112372	29363016	Even for patients suffering from PSM arising from gastric cancer, which is generally associated with a very poor prognosis (median survival 1-3 months), CRS + HIPEC can increase median overall survival to up to 7-9 months, or even 15 months if a CC score of 0/1 is realized.	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('PSM', 'Disease', (33, 36))	('increase', 'PosReg', (169, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('overall survival', 'MPA', (185, 201))	('to 7', 'Species', '1214577', (208, 212))	('CRS + HIPEC', 'Var', (153, 164))
112406	29363016	In conclusion, since we started our program in 2006 at our surgical department, we have been able to confirm the feasibility of CRS + HIPEC for PSM of various tumor entities.	('CRS', 'Var', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('men', 'Species', '9606', (74, 77))	('PSM', 'Disease', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
112419	25227779	Median mesothelin level was 2.7 nM and this value was used to dichotomize categories: <=2.7 nM (low) and >2.7 nM (high).	('<=2.7 nM', 'Var', (86, 94))	('mesothelin', 'Gene', (7, 17))	('>2.7', 'Var', (105, 109))	('mesothelin', 'Gene', '10232', (7, 17))
112420	25227779	The progression free survival (PFS) for low vs high mesothelin was 8.0 vs 5.1 months (HR 1.8, p-0.058).	('low', 'Var', (40, 43))	('mesothelin', 'Gene', (52, 62))	('mesothelin', 'Gene', '10232', (52, 62))
112422	25227779	The overall survival (OS) for low vs high mesothelin was 17.2 vs 11.3 months (HR 1.9, p = 0.088).	('mesothelin', 'Gene', (42, 52))	('mesothelin', 'Gene', '10232', (42, 52))	('low', 'Var', (30, 33))	('OS', 'Chemical', '-', (22, 24))
112443	25227779	Additionally, several studies have provided some evidence for an association between high mesothelin level and poorer survival.	('mesothelin', 'Gene', (90, 100))	('mesothelin', 'Gene', '10232', (90, 100))	('poorer survival', 'CPA', (111, 126))	('high', 'Var', (85, 89))
112474	25227779	The median PFS was 7.0 months (95% CI: 4.7 - 9.2 months) and the median follow-up for censored patients was 18.1 months (Figure 2A).When mesothelin was analysed as a categorical variable (>2.7 nM vs <=2.7 nM) the HR was 1.8 (95% CI: 0.9 - 3.2); p = 0.059).	('>2.7', 'Var', (188, 192))	('mesothelin', 'Gene', (137, 147))	('mesothelin', 'Gene', '10232', (137, 147))	('patients', 'Species', '9606', (95, 103))
112479	25227779	The median survival was 15.4 months (95% CI: 9.2 - 21.6 months) and the median follow-up time for censored patients was 13.8 months (Figure 2C).When mesothelin was analysed as a categorical variable (>2.7 nM vs <=2.7 nM) the HR was 1.9 (95% CI: 0.9 - 4.1); p = 0.088).	('mesothelin', 'Gene', (149, 159))	('mesothelin', 'Gene', '10232', (149, 159))	('patients', 'Species', '9606', (107, 115))	('>2.7', 'Var', (200, 204))
112495	25227779	The improved survival in our study compared to historical controls, likely reflects a higher proportion of female patients (32% vs 20%) and epithelioid histology (87% compared to 67%), both of which are recognised to carry a better prognosis.	('survival', 'MPA', (13, 21))	('improved', 'PosReg', (4, 12))	('patients', 'Species', '9606', (114, 122))	('epithelioid histology', 'Var', (140, 161))
112510	21874000	Germline BAP1 mutations predispose to malignant mesothelioma Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors.	('malignant mesothelioma', 'Disease', (131, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (38, 60))	('mesothelioma', 'Disease', (48, 60))	('asbestos', 'Chemical', 'MESH:D001194', (94, 102))	('BAP1', 'Gene', '8314', (9, 13))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (131, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (131, 153))	('mesothelioma', 'Disease', (141, 153))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (38, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('BAP1', 'Gene', (9, 13))	('predispose', 'Reg', (24, 34))	('mutations', 'Var', (14, 23))	('mesothelioma', 'Disease', (167, 179))	('malignant mesothelioma', 'Disease', (38, 60))
112511	21874000	We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma.	('BRCA1-associated protein 1', 'Gene', '8314', (42, 68))	('BRCA1-associated protein 1', 'Gene', (42, 68))	('BAP1', 'Gene', '8314', (36, 40))	('mesothelioma', 'Disease', (111, 123))	('BAP1', 'Gene', (36, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (111, 123))	('germline mutations', 'Var', (14, 32))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
112513	21874000	Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('BAP1', 'Gene', (27, 31))	('mesothelioma', 'Disease', (8, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('developed', 'Reg', (50, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('mutation', 'Var', (32, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('BAP1', 'Gene', '8314', (27, 31))
112514	21874000	Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma.	('BAP1', 'Gene', '8314', (103, 107))	('sporadic mesotheliomas', 'Disease', (53, 75))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mutant', 'Var', (96, 102))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (53, 75))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (53, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('patients', 'Species', '9606', (82, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('BAP1', 'Gene', (103, 107))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanoma', 'Disease', (139, 153))	('BAP1', 'Gene', (9, 13))	('diagnosed', 'Reg', (124, 133))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (53, 75))
112515	21874000	Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations.	('Truncating mutations', 'Var', (0, 20))	('BAP1', 'Gene', (34, 38))	('common', 'Reg', (55, 61))	('aberrant', 'Var', (25, 33))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (65, 86))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (65, 87))	('expression', 'MPA', (39, 49))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (65, 87))	('BAP1', 'Gene', '8314', (34, 38))	('sporadic mesotheliomas', 'Disease', (65, 87))
112532	21874000	Array-CGH analysis of two tumors (one/family) uncovered alterations encompassing or adjacent to the BAP1 locus in 3p21.1.	('BAP1', 'Gene', '8314', (100, 104))	('alterations', 'Var', (56, 67))	('tumors', 'Disease', (26, 32))	('BAP1', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
112538	21874000	We sequenced BAP1 in germline DNA from family W and found that six affected members (four with mesothelioma; two with breast or renal cancer) had identical mutations, whereas unaffected family members did not (Fig.	('breast or renal cancer', 'Disease', 'MESH:D007680', (118, 140))	('BAP1', 'Gene', (13, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('breast or renal cancer', 'Disease', (118, 140))	('mutations', 'Var', (156, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('BAP1', 'Gene', '8314', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mesothelioma', 'Disease', (95, 107))
112540	21874000	Transfection of mammalian cells with a genomic construct containing exons 6-8, and with the intron 6 splice site mutation, resulted in an aberrant splice product lacking exon 7 (Supplementary Fig.	('mammalian', 'Species', '9606', (16, 25))	('mutation', 'Var', (113, 121))	('splice product', 'MPA', (147, 161))	('exon 7', 'MPA', (170, 176))
112541	21874000	Besides the somatic genetic alteration detected by array-CGH in sample W-III-06T, in tumor W-III-08T only mutant BAP1 could be detected, consistent with loss of wild-type BAP1 on the other homologue.	('tumor', 'Disease', (85, 90))	('BAP1', 'Gene', (171, 175))	('mutant', 'Var', (106, 112))	('BAP1', 'Gene', '8314', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('BAP1', 'Gene', '8314', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAP1', 'Gene', (113, 117))
112542	21874000	Additionally, W-III-04T had both the splice site mutation and a 25-bp exon 4 deletion resulting in a frameshift and premature termination of BAP1 (p.I72fsX7) (Supplementary Fig.	('p.I72fsX7', 'Mutation', 'p.I72fsX7', (147, 156))	('frameshift', 'Var', (101, 111))	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', (141, 145))
112543	21874000	Cloning of genomic PCR products encompassing exons 4-7 from tumor DNA suggested that the splice site mutation and deletion reside in different alleles, consistent with biallelic inactivation of BAP1.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('BAP1', 'Gene', '8314', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('BAP1', 'Gene', (194, 198))	('deletion', 'Var', (114, 122))
112544	21874000	In family L, germline DNA from three individuals with mesothelioma (one recently treated for uveal melanoma) and two with skin carcinomas exhibited a germline C/G to T/A transition in exon 16, creating a stop codon (p.Q684X) (Supplementary Fig.	('skin carcinomas', 'Disease', (122, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('p.Q684X', 'Var', (216, 223))	('uveal melanoma', 'Disease', (93, 107))	('skin carcinomas', 'Phenotype', 'HP:0008069', (122, 137))	('skin carcinomas', 'Disease', 'MESH:D012878', (122, 137))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('p.Q684X', 'Mutation', 'rs387906848', (216, 223))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('mesothelioma', 'Disease', (54, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))
112545	21874000	There was complete concordance between BAP1 mutation status and linkage analysis.	('BAP1', 'Gene', '8314', (39, 43))	('mutation', 'Var', (44, 52))	('BAP1', 'Gene', (39, 43))
112551	21874000	Having linked BAP1 mutations to familial mesothelioma, we next sequenced BAP1 (17 exons/introns/promoter) in 26 germline DNAs from sporadic mesothelioma patients.	('linked', 'Reg', (7, 13))	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', '8314', (73, 77))	('familial mesothelioma', 'Phenotype', 'HP:0100001', (32, 53))	('mesothelioma', 'Disease', (140, 152))	('patients', 'Species', '9606', (153, 161))	('mesothelioma', 'Disease', (41, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('BAP1', 'Gene', (14, 18))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (19, 28))	('familial mesothelioma', 'Disease', (32, 53))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (131, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('familial mesothelioma', 'Disease', 'MESH:D008654', (32, 53))
112553	21874000	Two of 26 had BAP1 deletions: c.1832delC in exon 13 (p.P572fsX3) and c.2008-2011delTACT in exon 14 (p.Y627fsX9) (Supplementary Table 1).	('c.1832delC', 'Mutation', 'c.1832delC', (30, 40))	('BAP1', 'Gene', '8314', (14, 18))	('c.2008-2011delTACT', 'Var', (69, 87))	('BAP1', 'Gene', (14, 18))	('p.P572fsX3', 'Mutation', 'p.P572fsX3', (53, 63))	('c.2008-2011delTACT', 'Mutation', 'c.2008_2011delTACT', (69, 87))	('c.1832delC', 'Var', (30, 40))	('p.Y627fsX9', 'Mutation', 'p.Y627fsX9', (100, 110))
112554	21874000	Both mutations result in a frameshift leading to a stop codon upstream of the region encoding the BAP1 nuclear localization signal (Fig.	('BAP1', 'Gene', (98, 102))	('result', 'Reg', (15, 21))	('stop codon', 'MPA', (51, 61))	('BAP1', 'Gene', '8314', (98, 102))	('localization', 'biological_process', 'GO:0051179', ('111', '123'))	('frameshift', 'Var', (27, 37))
112557	21874000	Tumor DNA was available from 18 of the 26 sporadic mesothelioma patients: DNA sequencing revealed truncating BAP1 mutations in 4/18 (22%) tumors (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (114, 123))	('truncating', 'MPA', (98, 108))	('mesothelioma', 'Disease', (51, 63))	('BAP1', 'Gene', '8314', (109, 113))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('tumors', 'Disease', (138, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (42, 63))	('BAP1', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
112565	21874000	A paper published while our manuscript was being reviewed reported somatic BAP1 mutations in 23% of sporadic mesotheliomas, which concurs with our findings in sporadic tumors.	('sporadic tumors', 'Disease', (159, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (100, 122))	('sporadic tumors', 'Disease', 'MESH:D009369', (159, 174))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (100, 121))	('BAP1', 'Gene', '8314', (75, 79))	('sporadic mesotheliomas', 'Disease', (100, 122))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (100, 122))
112566	21874000	In addition, and most importantly, we demonstrate the presence of germline BAP1 mutations in members of U.S. families that experience an extremely high incidence of mesothelioma, in spite of very modest exposure to asbestos; thus, our results point to BAP1 as the first reported gene that may modulate mineral fiber carcinogenesis.	('BAP1', 'Gene', (252, 256))	('modulate', 'Reg', (293, 301))	('BAP1', 'Gene', (75, 79))	('mesothelioma', 'Disease', (165, 177))	('mutations', 'Var', (80, 89))	('asbestos', 'Chemical', 'MESH:D001194', (215, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('carcinogenesis', 'Disease', 'MESH:D063646', (316, 330))	('BAP1', 'Gene', '8314', (252, 256))	('BAP1', 'Gene', '8314', (75, 79))	('carcinogenesis', 'Disease', (316, 330))
112567	21874000	Furthermore, we show that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma and potentially other cancers.	('BAP1', 'Gene', (26, 30))	('mesothelioma', 'Disease', (116, 128))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Disease', (167, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('uveal melanoma', 'Disease', (130, 144))	('hereditary cancer syndrome', 'Disease', (69, 95))	('BAP1', 'Gene', '8314', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (69, 95))
112572	21874000	Altogether, we observed BAP1 mutations in four uveal melanoma patients, three of whom subsequently developed mesothelioma; the fourth (L-II-18) died of metastatic uveal melanoma to the liver (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (109, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('BAP1', 'Gene', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma to the liver', 'Disease', (163, 190))	('uveal melanoma', 'Disease', (47, 61))	('mesothelioma', 'Disease', (109, 121))	('uveal melanoma to the liver', 'Disease', 'MESH:C536494', (163, 190))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', '8314', (24, 28))
112573	21874000	Thus, our findings suggest that uveal melanoma patients with germline BAP1 mutations are at high risk of developing mesothelioma and should be closely monitored.	('mesothelioma', 'Disease', (116, 128))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (70, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('patients', 'Species', '9606', (47, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('BAP1', 'Gene', (70, 74))	('uveal melanoma', 'Disease', (32, 46))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
112579	21874000	We hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates.	('mesothelioma', 'Disease', (82, 94))	('BAP1', 'Gene', '8314', (42, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('asbestos', 'Chemical', 'MESH:D001194', (72, 80))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
112580	21874000	Alternatively, BAP1 mutation alone may be sufficient to cause mesothelioma.	('mutation', 'Var', (20, 28))	('mesothelioma', 'Disease', (62, 74))	('BAP1', 'Gene', '8314', (15, 19))	('cause', 'Reg', (56, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('BAP1', 'Gene', (15, 19))
112588	29375377	AXL knockdown in these cells enhances sensitivity to cisplatin and pemetrexed.	('enhances', 'PosReg', (29, 37))	('knockdown', 'Var', (4, 13))	('sensitivity to cisplatin', 'MPA', (38, 62))	('AXL', 'Gene', '558', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('AXL', 'Gene', (0, 3))	('pemetrexed', 'Chemical', 'MESH:D000068437', (67, 77))
112591	29375377	These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed.	('enhances', 'PosReg', (109, 117))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('AXL', 'Gene', (94, 97))	('pemetrexed', 'Chemical', 'MESH:D000068437', (40, 50))	('ROS', 'Protein', (58, 61))	('blocking', 'Var', (85, 93))	('AXL', 'Gene', (76, 79))	('pemetrexed', 'Chemical', 'MESH:D000068437', (148, 158))	('AXL', 'Gene', '558', (76, 79))	('efficacy', 'MPA', (122, 130))	('AXL', 'Gene', '558', (94, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('activation', 'MPA', (98, 108))	('activate', 'PosReg', (67, 75))
112596	29375377	These alterations are associated with both cancer initiation and tumor progression (Storz,).	('alterations', 'Var', (6, 17))	('cancer initiation and tumor', 'Disease', 'MESH:D009369', (43, 70))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('associated', 'Reg', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
112609	29375377	DNA adducts caused by cisplatin correlate with cell death, but at higher concentrations cisplatin can generate ROS and cause acute apoptosis (Berndtsson et al.,).	('cisplatin', 'Var', (88, 97))	('ROS', 'MPA', (111, 114))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cause', 'Reg', (119, 124))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('cell death', 'biological_process', 'GO:0008219', ('47', '57'))
112620	29375377	We hypothesize ROS, generated by cisplatin and pemetrexed, induce the activation of AXL and cell survival pathway, which can be blocked by AXL inhibitors to enhance the efficacy of current MPM chemotherapy drugs.	('AXL', 'Gene', '558', (139, 142))	('pemetrexed', 'Chemical', 'MESH:D000068437', (47, 57))	('enhance', 'PosReg', (157, 164))	('cisplatin', 'Var', (33, 42))	('AXL', 'Gene', '558', (84, 87))	('AXL', 'Gene', (139, 142))	('AXL', 'Gene', (84, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('cell survival pathway', 'Pathway', (92, 113))	('activation', 'PosReg', (70, 80))	('ROS', 'Gene', (15, 18))
112622	29375377	Blocking AXL activation with the BGB324 inhibitor enhances sensitivity to cisplatin and pemetrexed in MPM cell lines.	('BGB324', 'Gene', (33, 39))	('enhances', 'PosReg', (50, 58))	('BGB324', 'Chemical', 'MESH:C548378', (33, 39))	('AXL', 'Gene', (9, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('activation', 'PosReg', (13, 23))	('AXL', 'Gene', '558', (9, 12))	('pemetrexed', 'Chemical', 'MESH:D000068437', (88, 98))	('inhibitor', 'Var', (40, 49))
112628	29375377	MPM cells lines used were SPC111, VMC14, VMC31, M38K, VMC40, Meso53, SPC212, and P31 (Marklund et al.,; Pelin-Enlund et al.,; Schmitter et al.,; Janson et al.,; Garay et al.,; Schelch et al.,; Hoda et al.,).	('SPC', 'molecular_function', 'GO:0009004', ('69', '72'))	('M38K', 'Var', (48, 52))	('M38K', 'SUBSTITUTION', 'None', (48, 52))	('SPC', 'molecular_function', 'GO:0009004', ('26', '29'))	('SPC212', 'CellLine', 'CVCL:D312', (69, 75))	('P31', 'Gene', (81, 84))	('P31', 'Gene', '529', (81, 84))
112664	29375377	Of these cell lines, AXL expression was highest in VMC40 cells (normalized log2 median-centered value of 1.35), and P31 cells had AXL expression near the median (-0.07).	('P31', 'Gene', (116, 119))	('highest', 'Reg', (40, 47))	('P31', 'Gene', '529', (116, 119))	('AXL', 'Gene', '558', (21, 24))	('AXL', 'Gene', '558', (130, 133))	('VMC40', 'Var', (51, 56))	('AXL', 'Gene', (130, 133))	('AXL', 'Gene', (21, 24))
112665	29375377	The immunoblot analysis confirmed that AXL expression and phosphorylation were higher in VMC40 than the nonmalignant mesothelial cell line Met-5a (Figure 1C).	('AXL', 'Gene', '558', (39, 42))	('phosphorylation', 'MPA', (58, 73))	('VMC40', 'Var', (89, 94))	('AXL', 'Gene', (39, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('higher', 'PosReg', (79, 85))
112666	29375377	In addition, GAS6 expression was also higher in VMC40 than in Met-5a cells.	('GAS6', 'Gene', '2621', (13, 17))	('VMC40', 'Var', (48, 53))	('GAS6', 'Gene', (13, 17))	('GAS', 'molecular_function', 'GO:0034005', ('13', '16'))	('expression', 'MPA', (18, 28))	('higher', 'PosReg', (38, 44))
112679	29375377	Again, consistent with prior studies indicating that pro-survival kinase Akt1 was activated downstream of AXL (Huang et al.,), both cisplatin and pemetrexed induce Akt phosphorylation of S473 at variable time points.	('pemetrexed', 'Chemical', 'MESH:D000068437', (146, 156))	('induce', 'Reg', (157, 163))	('Akt', 'Gene', (73, 76))	('pro-survival', 'biological_process', 'GO:0043066', ('53', '65'))	('Akt1', 'Gene', (73, 77))	('S473', 'Var', (187, 191))	('Akt', 'Gene', '207', (164, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('AXL', 'Gene', '558', (106, 109))	('Akt1', 'Gene', '207', (73, 77))	('Akt', 'Gene', '207', (73, 76))	('Akt', 'Gene', (164, 167))	('AXL', 'Gene', (106, 109))
112681	29375377	The pAkt levels did not change from adding BGB324 inhibitor alone compared to no treatment (Supplementary Figure 4B), suggesting that BGB324 does not inhibit Akt directly.	('BGB324', 'Chemical', 'MESH:C548378', (43, 49))	('Akt', 'Gene', '207', (5, 8))	('BGB324', 'Var', (134, 140))	('inhibit', 'NegReg', (150, 157))	('Akt', 'Gene', '207', (158, 161))	('BGB324', 'Chemical', 'MESH:C548378', (134, 140))	('Akt', 'Gene', (5, 8))	('Akt', 'Gene', (158, 161))
112687	29375377	The presence of BGB324 significantly increased the caspase-3 activity in cells treated with cisplatin and pemetrexed.	('BGB324', 'Chemical', 'MESH:C548378', (16, 22))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('51', '69'))	('BGB324', 'Gene', (16, 22))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('51', '69'))	('caspase-3', 'Gene', '836', (51, 60))	('pemetrexed', 'Chemical', 'MESH:D000068437', (106, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('increased', 'PosReg', (37, 46))	('activity', 'MPA', (61, 69))	('presence', 'Var', (4, 12))	('caspase-3', 'Gene', (51, 60))
112692	29375377	Detected AXL of VMC40 cells averaged 37.7% for shRNA#1 and 36.1% for shRNA#2 compared to NTC controls, and of P31 cells averaged 33.0% for shRNA#1 and 28.4% for shRNA#2.	('P31', 'Gene', (110, 113))	('AXL', 'Gene', (9, 12))	('P31', 'Gene', '529', (110, 113))	('NTC', 'cellular_component', 'GO:0000974', ('89', '92'))	('shRNA#1', 'Var', (47, 54))	('AXL', 'Gene', '558', (9, 12))
112695	29375377	To analyze the drug response following AXL knockdown, drug response was compared at each concentration respective to the absence of drug.	('AXL', 'Gene', '558', (39, 42))	('AXL', 'Gene', (39, 42))	('knockdown', 'Var', (43, 52))
112696	29375377	A significant decrease in cell survival was observed in AXL knockdown cells compared to NTC at 1.88 and 15 muM for cisplatin in VMC40 cells, and at 1 and 8 muM for pemetrexed in both VMC40 and P31 cells (Supplementary Figure 5).	('NTC', 'cellular_component', 'GO:0000974', ('88', '91'))	('AXL', 'Gene', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('muM', 'Gene', '56925', (107, 110))	('pemetrexed', 'Chemical', 'MESH:D000068437', (164, 174))	('muM', 'Gene', (107, 110))	('decrease', 'NegReg', (14, 22))	('knockdown', 'Var', (60, 69))	('P31', 'Gene', (193, 196))	('muM', 'Gene', (156, 159))	('AXL', 'Gene', '558', (56, 59))	('P31', 'Gene', '529', (193, 196))	('muM', 'Gene', '56925', (156, 159))	('cell survival', 'CPA', (26, 39))
112698	29375377	Building upon the observation that AXL knockdown enhances sensitivity to cisplatin and pemetrexed, we next evaluated if inhibiting AXL phosphorylation would result in enhanced sensitivity to cisplatin and pemetrexed.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('pemetrexed', 'Chemical', 'MESH:D000068437', (205, 215))	('inhibiting', 'NegReg', (120, 130))	('enhanced', 'PosReg', (167, 175))	('AXL', 'Gene', (35, 38))	('knockdown', 'Var', (39, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('AXL', 'Gene', (131, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('AXL', 'Gene', '558', (35, 38))	('pemetrexed', 'Chemical', 'MESH:D000068437', (87, 97))	('enhances', 'PosReg', (49, 57))	('AXL', 'Gene', '558', (131, 134))
112705	29375377	Moreover, mean CIs from the clonogenic assay were 0.95 for 1.4 muM cisplatin with BGB324 and 0.91 for 0.1 muM pemetrexed with BGB324 in VMC40 cells, which suggests marginal synergistic cytotoxicity.	('muM', 'Gene', '56925', (106, 109))	('muM', 'Gene', '56925', (63, 66))	('cisplatin', 'Var', (67, 76))	('muM', 'Gene', (106, 109))	('BGB324', 'Chemical', 'MESH:C548378', (126, 132))	('muM', 'Gene', (63, 66))	('cytotoxicity', 'Disease', (185, 197))	('BGB324', 'Chemical', 'MESH:C548378', (82, 88))	('BGB324', 'Gene', (82, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('pemetrexed', 'Chemical', 'MESH:D000068437', (110, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (185, 197))
112710	29375377	Calculated CI means for these combinations suggest more cell death synergy for both VMC40 and P31 cells (Figure 6B), compared to when agents were added to cells at the same time (Figure 5B).	('cell death', 'biological_process', 'GO:0008219', ('56', '66'))	('P31', 'Gene', (94, 97))	('P31', 'Gene', '529', (94, 97))	('cell death synergy', 'CPA', (56, 74))	('VMC40', 'Var', (84, 89))
112718	29375377	For VMC40 cells, the mean CIs were 0.91 for co-treatment with BGB324 and 0.74 for pretreated with BGB324, indicating synergistic cytotoxic effects.	('BGB324', 'Gene', (62, 68))	('co-treatment', 'Var', (44, 56))	('BGB324', 'Chemical', 'MESH:C548378', (98, 104))	('BGB324', 'Chemical', 'MESH:C548378', (62, 68))
112719	29375377	For P31 cells, the mean CIs were 1.04 for co-treatment with BGB324 and 0.92 for pretreatment with BGB324.	('co-treatment', 'Var', (42, 54))	('P31', 'Gene', (4, 7))	('BGB324', 'Chemical', 'MESH:C548378', (60, 66))	('P31', 'Gene', '529', (4, 7))	('BGB324', 'Chemical', 'MESH:C548378', (98, 104))	('BGB324', 'Gene', (60, 66))
112720	29375377	Prior evidence of elevated cellular ROS promoting cell survival (Clerkin et al.,; Niederst and Engelman,) led to the hypothesis that chemotherapy-induced ROS may also promote these signaling pathways, and inhibiting these pathways may enhance chemotherapy efficacy.	('cellular ROS', 'Protein', (27, 39))	('signaling pathways', 'Pathway', (181, 199))	('enhance', 'PosReg', (235, 242))	('elevated cellular ROS', 'Phenotype', 'HP:0025464', (18, 39))	('promote', 'PosReg', (167, 174))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('chemotherapy efficacy', 'CPA', (243, 264))	('cell survival', 'CPA', (50, 63))	('inhibiting', 'Var', (205, 215))	('ROS', 'Var', (154, 157))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('promoting', 'PosReg', (40, 49))	('elevated', 'PosReg', (18, 26))
112722	29375377	Moreover, knocking down AXL or blocking AXL activation with BGB324 enhances sensitivity to cisplatin and pemetrexed (Figures 4-7).	('pemetrexed', 'Chemical', 'MESH:D000068437', (105, 115))	('knocking', 'Var', (10, 18))	('AXL', 'Gene', (24, 27))	('AXL', 'Gene', '558', (40, 43))	('BGB324', 'Chemical', 'MESH:C548378', (60, 66))	('enhances', 'PosReg', (67, 75))	('activation', 'PosReg', (44, 54))	('BGB324', 'Gene', (60, 66))	('sensitivity to cisplatin', 'MPA', (76, 100))	('AXL', 'Gene', (40, 43))	('AXL', 'Gene', '558', (24, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('blocking', 'NegReg', (31, 39))
112729	29375377	We investigated AXL activation using 150 muM H2O2, which is a level of ROS consistent with moderate cellular oxidative stress (Ravid et al.,; Pal et al.,; Oien and Moskovitz,; Oien et al.,).	('AXL', 'Gene', '558', (16, 19))	('oxidative stress', 'Phenotype', 'HP:0025464', (109, 125))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (41, 44))	('AXL', 'Gene', (16, 19))	('Pal', 'molecular_function', 'GO:0004598', ('142', '145'))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))	('H2O2', 'Var', (45, 49))
112735	29375377	In support of this concept, we have shown that AXL knockdown enhances sensitivity cisplatin and pemetrexed (Figure 4), suggesting that chemotherapy-induced AXL activation is an adaptive response that may blunt the cytotoxic effect of chemotherapy.	('blunt', 'NegReg', (204, 209))	('AXL', 'Gene', '558', (47, 50))	('cytotoxic effect of chemotherapy', 'CPA', (214, 246))	('AXL', 'Gene', (156, 159))	('enhances', 'PosReg', (61, 69))	('pemetrexed', 'Chemical', 'MESH:D000068437', (96, 106))	('sensitivity cisplatin', 'MPA', (70, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('AXL', 'Gene', (47, 50))	('AXL', 'Gene', '558', (156, 159))	('knockdown', 'Var', (51, 60))
112749	29375377	Moreover, IGF1R is rapidly expressed and activated in the presence of hydrogen peroxide, and inhibition of this receptor has been shown to promote apoptosis (Azar et al.,; Baregamian et al.,).	('promote', 'PosReg', (139, 146))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (70, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('IGF1R', 'Gene', (10, 15))	('apoptosis', 'CPA', (147, 156))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('inhibition', 'Var', (93, 103))	('IGF1R', 'Gene', '3480', (10, 15))
112905	24479647	MWCNT induced a dose responsive increase in disrupted centrosomes, abnormal mitotic spindles and aneuploid chromosome number 24 hours after exposure to 0.024, 0.24, 2.4 and 24 mug/cm2 MWCNT.	('increase', 'PosReg', (32, 40))	('disrupted centrosomes', 'CPA', (44, 65))	('MWCNT', 'Chemical', '-', (184, 189))	('0.24', 'Var', (159, 163))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('mug', 'molecular_function', 'GO:0043739', ('176', '179'))	('aneuploid chromosome number', 'CPA', (97, 124))	('0.024', 'Var', (152, 157))	('abnormal mitotic spindles', 'CPA', (67, 92))	('MWCNT', 'Chemical', '-', (0, 5))
112907	24479647	Cell cycle analysis demonstrated a greater number of cells in S-phase and fewer cells in the G2 phase in MWCNT-treated compared to diluent control, indicating a G1/S block in the cell cycle.	('G1/S', 'CPA', (161, 165))	('S-phase', 'biological_process', 'GO:0051320', ('62', '69'))	('fewer', 'NegReg', (74, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('179', '189'))	('rat', 'Species', '10116', (27, 30))	('MWCNT', 'Chemical', '-', (105, 110))	('G2 phase', 'biological_process', 'GO:0051319', ('93', '101'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('S-phase', 'CPA', (62, 69))	('MWCNT-treated', 'Var', (105, 118))
112910	24479647	Our results demonstrate significant disruption of the mitotic spindle by MWCNT at occupationally relevant exposure levels.	('MWCNT', 'Var', (73, 78))	('MWCNT', 'Chemical', '-', (73, 78))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('54', '69'))	('rat', 'Species', '10116', (19, 22))	('disruption', 'NegReg', (36, 46))	('mitotic spindle', 'CPA', (54, 69))
112930	24479647	In a manner similar to asbestos, rodent pulmonary exposure to biopersistant carbon nanotubes has been shown to result in lung inflammation, epithelial cell proliferation, cellular atypia and mutations in the K-ras gene.	('rat', 'Species', '10116', (163, 166))	('cellular atypia', 'CPA', (171, 186))	('lung inflammation', 'Disease', 'MESH:D011014', (121, 138))	('epithelial cell proliferation', 'CPA', (140, 169))	('mutations', 'Var', (191, 200))	('lung inflammation', 'Disease', (121, 138))	('K-ras', 'Gene', (208, 213))	('carbon', 'Chemical', 'MESH:D002244', (76, 82))	('K-ras', 'Gene', '3845', (208, 213))	('result', 'Reg', (111, 117))	('inflammation', 'biological_process', 'GO:0006954', ('126', '138'))	('asbestos', 'Chemical', 'MESH:D001194', (23, 31))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('140', '169'))
112932	24479647	In vivo investigations have demonstrated that carbon nanotube exposure can cause macrophages without nuclei as well as dividing macrophages connected by nanotubes.	('cause', 'Reg', (75, 80))	('macrophages without', 'CPA', (81, 100))	('carbon', 'Chemical', 'MESH:D002244', (46, 52))	('rat', 'Species', '10116', (35, 38))	('carbon nanotube', 'Var', (46, 61))
112934	24479647	Inflammation, cellular proliferation, cellular atypia, mitotic spindle disruption, centrosome fragmentation and errors in chromosome number are linked with the development of cancer.	('centrosome', 'cellular_component', 'GO:0005813', ('83', '93'))	('Inflammation', 'biological_process', 'GO:0006954', ('0', '12'))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('Inflammation', 'Disease', (0, 12))	('rat', 'Species', '10116', (30, 33))	('centrosome fragmentation', 'CPA', (83, 107))	('errors', 'Var', (112, 118))	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('linked', 'Reg', (144, 150))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('55', '70'))	('mitotic spindle disruption', 'CPA', (55, 81))	('cellular proliferation', 'CPA', (14, 36))	('cellular atypia', 'CPA', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
112936	24479647	Although the lung is the key target organ for particle toxicity, high aspect ratio carbon nanotubes have been shown to translocate to the subpleural space indicating that the mesothelial cells are also a potential target.	('high aspect ratio', 'Var', (65, 82))	('translocate', 'MPA', (119, 130))	('rat', 'Species', '10116', (77, 80))	('carbon', 'Chemical', 'MESH:D002244', (83, 89))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))	('toxicity', 'Disease', (55, 63))
112961	24479647	Moreover, acid washing also increased nanotube solubility in DMEM + FBS by two-fold compared to pristine MWCNT as a result of the addition of the free carboxylic acid groups.	('increased', 'PosReg', (28, 37))	('DMEM + FBS', 'Var', (61, 71))	('carboxylic acid', 'Chemical', 'MESH:D002264', (151, 166))	('MWCNT', 'Chemical', '-', (105, 110))	('nanotube solubility', 'MPA', (38, 57))	('DMEM', 'Chemical', '-', (61, 65))	('carboxylic', 'Protein', (151, 161))
112969	24479647	By contrast, the MWCNT-treated SAEC cells had a level of aneuploidy that was comparable to the vanadium pentoxide-treated positive control cells (Figure 2D; Table 1).	('vanadium pentoxide', 'Chemical', 'MESH:C066075', (95, 113))	('MWCNT-treated', 'Var', (17, 30))	('aneuploidy', 'Disease', (57, 67))	('MWCNT', 'Chemical', '-', (17, 22))	('aneuploidy', 'Disease', 'MESH:D000782', (57, 67))
112970	24479647	Abnormal chromosome number was significantly elevated following MWCNT treatment as follows: 62 +- 7.0%, 24 mug/cm2; 59.0 +- 6.0%, 2.4 mug/cm2; 49 +- 6.0%, 0.24 mug/cm2 and 42 +- 10%, 0.024 mug/cm2 compared with control incidence of 2.25 +- 1.0%.	('Abnormal chromosome number', 'CPA', (0, 26))	('0.24', 'Var', (155, 159))	('mug', 'molecular_function', 'GO:0043739', ('189', '192'))	('Abnormal chromosome number', 'Phenotype', 'HP:0031411', (0, 26))	('mug', 'molecular_function', 'GO:0043739', ('160', '163'))	('chromosome', 'cellular_component', 'GO:0005694', ('9', '19'))	('mug', 'molecular_function', 'GO:0043739', ('134', '137'))	('mug', 'molecular_function', 'GO:0043739', ('107', '110'))	('0.024 mug/cm2', 'Var', (183, 196))	('elevated', 'PosReg', (45, 53))	('MWCNT', 'Chemical', '-', (64, 69))
112972	24479647	Chromosomal gains accounted for over 70% of the aneuploidy (Table 1).	('aneuploidy', 'Disease', (48, 58))	('Chromosomal gains', 'Var', (0, 17))	('aneuploidy', 'Disease', 'MESH:D000782', (48, 58))
112981	24479647	Seventy-two hours following exposure, the viability of the SAEC cells was significantly reduced in cells exposed to 0.024, 0.24, 2.4 or 24 mug/cm2 MWCNT (Figure 5B).	('MWCNT', 'Chemical', '-', (147, 152))	('0.024', 'Var', (116, 121))	('viability', 'CPA', (42, 51))	('mug', 'molecular_function', 'GO:0043739', ('139', '142'))	('0.24', 'Var', (123, 127))	('reduced', 'NegReg', (88, 95))
113000	24479647	observed polyploid cells in cancer cell lines following exposure to 0.25 to 50 mug MWCNT of 80 nm diameter.	('polyploid', 'Var', (9, 18))	('MWCNT', 'Chemical', '-', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mug', 'molecular_function', 'GO:0043739', ('79', '82'))	('cancer', 'Disease', (28, 34))
113001	24479647	Although detailed analysis of chromosome loss and gain was not possible in a cancer cell line, the study demonstrated a significant number of polyploid cells which they attributed to a failure of cytokinesis.	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cytokinesis', 'biological_process', 'GO:0000910', ('196', '207'))	('rat', 'Species', '10116', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cytokinesis', 'CPA', (196, 207))	('polyploid cells', 'Var', (142, 157))
113011	24479647	Aberrant cell signaling is a concern because it is important in the progression of carcinogenesis.	('carcinogenesis', 'Disease', (83, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('Aberrant', 'Var', (0, 8))
113143	22323052	The human mesothelioma cell lines MSTO211H, H28, H226, H2452, H2052 were obtained from American Type Culture Collection (Manassas, VA).	('H2052', 'Var', (62, 67))	('human', 'Species', '9606', (4, 9))	('mesothelioma', 'Disease', (10, 22))	('H2052', 'CellLine', 'CVCL:1518', (62, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (10, 22))	('H2452', 'CellLine', 'CVCL:1553', (55, 60))	('MSTO211H', 'CellLine', 'CVCL:1430', (34, 42))	('H226', 'CellLine', 'CVCL:J621', (49, 53))
113222	22323052	Cixutumumab treatment down-regulated the phosphorylated levels of IGF-IR and Akt induced by IGF-I in H28 and H226 cell lines with high total expression of IGF-IR (Fig.	('H226', 'CellLine', 'CVCL:J621', (109, 113))	('Akt', 'Gene', '207', (77, 80))	('IGF-I', 'Var', (92, 97))	('phosphorylated levels', 'MPA', (41, 62))	('down-regulated', 'NegReg', (22, 36))	('Cixutumumab', 'Chemical', 'MESH:C557414', (0, 11))	('Akt', 'Gene', (77, 80))	('IGF-IR', 'Gene', (155, 161))	('IGF-IR', 'Gene', (66, 72))	('IGF-IR', 'Gene', '3480', (66, 72))	('IGF-IR', 'Gene', '3480', (155, 161))
113227	22323052	Our results show that cixutumumab can inhibit signaling by blocking activation of Akt and up to some extent the activation of Erk pathway in MM cell lines.	('activation', 'MPA', (68, 78))	('cixutumumab', 'Var', (22, 33))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('Akt', 'Gene', '207', (82, 85))	('Erk', 'Gene', '5594', (126, 129))	('cixutumumab', 'Chemical', 'MESH:C557414', (22, 33))	('Erk', 'molecular_function', 'GO:0004707', ('126', '129'))	('Akt', 'Gene', (82, 85))	('signaling', 'MPA', (46, 55))	('inhibit', 'NegReg', (38, 45))	('Erk', 'Gene', (126, 129))	('blocking', 'NegReg', (59, 67))
113229	22323052	As shown in Figure 5A treatment with cixutumumab in presence of effector cells induced >30% specific lysis in H28 cells, whereas control IgG in presence of PBMC or cixutumumab alone resulted in no specific cell lysis.	('cixutumumab', 'Var', (37, 48))	('lysis', 'biological_process', 'GO:0019835', ('211', '216'))	('specific lysis', 'MPA', (92, 106))	('cixutumumab', 'Chemical', 'MESH:C557414', (37, 48))	('lysis', 'biological_process', 'GO:0019835', ('101', '106'))	('cixutumumab', 'Chemical', 'MESH:C557414', (164, 175))
113234	22323052	As early as day 14 of treatment with cixutumumab, the anti-tumorigenic effect was apparent in terms of decrease in total luminescence count in the cixutumumab treated group of mice in comparison to the saline treated control group (Fig.	('tumor', 'Disease', (59, 64))	('saline', 'Chemical', 'MESH:D012965', (202, 208))	('cixutumumab', 'Chemical', 'MESH:C557414', (147, 158))	('cixutumumab', 'Chemical', 'MESH:C557414', (37, 48))	('cixutumumab', 'Var', (147, 158))	('mice', 'Species', '10090', (176, 180))	('total luminescence count', 'MPA', (115, 139))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('decrease', 'NegReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
113237	22323052	The mice treated with cixutumumab showed enhanced survival in comparison to the saline treated control group, 90 versus 81 days respectively (p<0.004, Fig.	('mice', 'Species', '10090', (4, 8))	('enhanced', 'PosReg', (41, 49))	('cixutumumab', 'Chemical', 'MESH:C557414', (22, 33))	('saline', 'Chemical', 'MESH:D012965', (80, 86))	('cixutumumab', 'Var', (22, 33))
113249	22323052	Similarly, in non-small cell lung cancer cell lines the cell growth inhibition by the anti-IGF-IR mAb R1507 was dependent on the total IGF-IR protein expression.	('IGF-IR', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('cell growth', 'biological_process', 'GO:0016049', ('56', '67'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('cell growth', 'CPA', (56, 67))	('IGF-IR', 'Gene', '3480', (91, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('IGF-IR', 'Gene', (135, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('non-small cell lung cancer', 'Disease', (14, 40))	('R1507', 'Var', (102, 107))	('IGF-IR', 'Gene', '3480', (135, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))
113254	22323052	We also showed that cixutumumab decreased the phosphorylation of IGF-IR, Akt and Erk that was dependent on IGF-IR expression.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('Akt', 'Gene', (73, 76))	('cixutumumab', 'Chemical', 'MESH:C557414', (20, 31))	('Akt', 'Gene', '207', (73, 76))	('Erk', 'Gene', (81, 84))	('IGF-IR', 'Gene', (107, 113))	('cixutumumab', 'Var', (20, 31))	('IGF-IR', 'Gene', '3480', (107, 113))	('IGF-IR', 'Gene', (65, 71))	('phosphorylation', 'MPA', (46, 61))	('Erk', 'molecular_function', 'GO:0004707', ('81', '84'))	('Erk', 'Gene', '5594', (81, 84))	('decreased', 'NegReg', (32, 41))	('IGF-IR', 'Gene', '3480', (65, 71))
113256	22323052	In addition, to cixutumumab inhibiting the viability of mesothelioma cells by direct inhibition of the IGF-IR signal transduction pathway we show that it can also kill mesothelioma cells via ADCC.	('mesothelioma', 'Disease', (168, 180))	('inhibiting', 'NegReg', (28, 38))	('cixutumumab', 'Chemical', 'MESH:C557414', (16, 27))	('signal transduction', 'biological_process', 'GO:0007165', ('110', '129'))	('inhibition', 'NegReg', (85, 95))	('IGF-IR', 'Gene', (103, 109))	('mesothelioma', 'Disease', (56, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (168, 180))	('ADCC', 'biological_process', 'GO:0001788', ('191', '195'))	('IGF-IR', 'Gene', '3480', (103, 109))	('cixutumumab', 'Var', (16, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
113262	22323052	In addition to the in vitro activity of cixutumumab against mesothelioma cell lines, we also show that treatment with cixutumumab inhibits tumor growth of the human mesothelioma tumor xenograft H226 in nude mice.	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('mesothelioma tumor', 'Disease', (165, 183))	('tumor', 'Disease', (139, 144))	('cixutumumab', 'Var', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (178, 183))	('cixutumumab', 'Chemical', 'MESH:C557414', (40, 51))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (165, 183))	('human', 'Species', '9606', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (165, 183))	('cixutumumab', 'Chemical', 'MESH:C557414', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('inhibits', 'NegReg', (130, 138))	('H226', 'CellLine', 'CVCL:J621', (194, 198))	('mesothelioma', 'Disease', (165, 177))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('nude mice', 'Species', '10090', (202, 211))	('mesothelioma', 'Disease', (60, 72))
113446	21505561	Alteration to the tumor microenvironment by targeting key immunoregulatory factors and host immune cells has shown the potential to deactivate tumor immunosuppression.	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (18, 23))	('Alteration', 'Var', (0, 10))	('deactivate', 'NegReg', (132, 142))	('rat', 'Species', '10116', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
113553	21505561	4c) suggests that MDSCs accelerate tumor progression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MDSCs', 'Var', (18, 23))	('accelerate', 'PosReg', (24, 34))	('tumor', 'Disease', (35, 40))	('rat', 'Species', '10116', (30, 33))
113556	21505561	MDSCs have been shown to inhibit CD4+ and CD8+ T cell proliferation, block natural killer cell activation, limit dendritic cell maturation and polarize macrophage towards an M2 phenotype both with and without TGF-beta expression.	('MDSCs', 'Var', (0, 5))	('natural killer cell activation', 'biological_process', 'GO:0030101', ('75', '105'))	('rat', 'Species', '10116', (132, 135))	('block', 'NegReg', (69, 74))	('dendritic cell maturation', 'CPA', (113, 138))	('CD4', 'Gene', '12504', (33, 36))	('T cell proliferation', 'biological_process', 'GO:0042098', ('47', '67'))	('cell maturation', 'biological_process', 'GO:0048469', ('123', '138'))	('natural killer cell activation', 'CPA', (75, 105))	('CD8', 'Gene', (42, 45))	('rat', 'Species', '10116', (61, 64))	('limit', 'NegReg', (107, 112))	('TGF-beta', 'Gene', '21803', (209, 217))	('inhibit', 'NegReg', (25, 32))	('CD4', 'Gene', (33, 36))	('CD8', 'Gene', '925', (42, 45))	('polarize', 'Reg', (143, 151))	('TGF-beta', 'Gene', (209, 217))
113577	21505561	WT C57Bl/6 eGFP C57Bl/6 TgN (bACT-eGFP) 10sb FGF Fibroblast growth factor FACS Fluorescence-activated cell sorting FGF2 Fibroblast growth factor 2 H&E Hematoxylin and eosin IL Interleukin i.p.	('L', 'Chemical', '-', (174, 175))	('H&E', 'Chemical', '-', (147, 150))	('C57Bl/6', 'Var', (16, 23))	('FGF2', 'Gene', '2247', (115, 119))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('120', '144'))	('eosin', 'Chemical', 'MESH:D004801', (167, 172))	('Hematoxylin', 'Chemical', 'MESH:D006416', (151, 162))	('TgN', 'cellular_component', 'GO:0005802', ('24', '27'))	('FGF2', 'Gene', (115, 119))	('Fibroblast growth factor', 'molecular_function', 'GO:0005104', ('49', '73'))
113601	32530527	6  Loss of BAP1 detected by immunohistochemistry and homozygous deletion of p16 by fluorescence in situ hybridization are reliable markers for the diagnosis of MPM.	('MPM', 'Disease', (160, 163))	('BAP1', 'Gene', '8314', (11, 15))	('p16', 'Gene', '1029', (76, 79))	('deletion', 'Var', (64, 72))	('MPM', 'Chemical', '-', (160, 163))	('BAP1', 'Gene', (11, 15))	('Loss', 'NegReg', (3, 7))	('p16', 'Gene', (76, 79))
113602	32530527	7  However, it is difficult to consider these MPM-causal abnormal proteins as candidates for molecular targeted therapy because they are the products not of oncogenic driver mutations but of inactivating mutations of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('MPM', 'Chemical', '-', (46, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('217', '233'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('217', '233'))	('inactivating mutations', 'Var', (191, 213))	('tumor', 'Disease', 'MESH:D009369', (217, 222))
113640	32530527	For CD26 KD analysis, H2452 cells were grown in 12-well tissue culture-treated plates (Corning, New York, NY) and transfected with either 20 pmol/L of small interfering RNA (siRNA) targeted CD26 (Silencer  Select, s4254 as #1 and s4255 as #2, Ambion, Austin, TX), or control siRNA (Silencer  Select, Negative Control #1) using Lipofectamine RNAiMAX (Invitrogen).	('CD26', 'Gene', (190, 194))	('CD26', 'Gene', '1803', (190, 194))	('H2452', 'CellLine', 'CVCL:1553', (22, 27))	('Lipofectamine', 'Chemical', 'MESH:C086724', (327, 340))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('CD26', 'Gene', '1803', (4, 8))	('CD26', 'Gene', (4, 8))	('s4255', 'Var', (230, 235))
113673	32530527	28  As shown in Figure 2D, rhIL-1beta-induced CD26 upregulation was significantly inhibited by AP-1 inhibitor SR11302 but not by NF-kappaB inhibitor QNZ.	('upregulation', 'PosReg', (51, 63))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('129', '148'))	('IL-1beta', 'Gene', (29, 37))	('CD26', 'Gene', (46, 50))	('CD26', 'Gene', '1803', (46, 50))	('AP-1', 'Gene', '3726', (95, 99))	('IL-1beta', 'Gene', '3552', (29, 37))	('NF-kappaB', 'Gene', (129, 138))	('inhibited', 'NegReg', (82, 91))	('AP-1', 'Gene', (95, 99))	('SR11302', 'Chemical', 'MESH:C106195', (110, 117))	('AP-1', 'cellular_component', 'GO:0005907', ('95', '99'))	('SR11302', 'Var', (110, 117))	('NF-kappaB', 'Gene', '4790', (129, 138))
113689	32530527	To clarify the role of inflammasome in macrophages, we knocked down CASP1 in THP-1-derived macrophages (Figure S4).	('CASP1', 'Gene', '834', (68, 73))	('CASP1', 'Gene', (68, 73))	('knocked', 'Var', (55, 62))	('THP-1', 'Gene', '2736', (77, 82))	('THP-1', 'Gene', (77, 82))
113829	32316178	The recent oncological studies have shown, in the cases of PSFT, a fusion of NAB2-STAT6 gene, which is a result of intrachromosomal inversion 12q13.3., characteristic for this type of disease.	('NAB2', 'Gene', '4665', (77, 81))	('NAB2', 'Gene', (77, 81))	('PSFT', 'Disease', (59, 63))	('STAT6', 'Gene', (82, 87))	('STAT6', 'Gene', '6778', (82, 87))	('fusion', 'Var', (67, 73))
113831	32316178	Moreover, the mitotic number equal to higher than 4/10 HPF, TERD promoter, and mutation TP53 were correlated with the biological aggressiveness of the tumor.	('aggressiveness of the tumor', 'Disease', (129, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (129, 156))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('correlated', 'Reg', (98, 108))	('mitotic number', 'CPA', (14, 28))	('mutation', 'Var', (79, 87))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))
113925	29527515	Membranes were probed with the following primary antibodies: anti-calretinin (Sigma, HPA007306), mouse anti-actin (#69100) from MP Biomedicals, N-Cadherin (BD Biosciences, 610920), YAP (Cell Signaling 4912), Mesothelin (Rockland Inc. 200-301-A88), GATA4 (C-20) (Santa Cruz sc-1237), p62 (Progen GP62-C), LC3B (Cell Signaling 2775S), p53 (DO-1) (Santa Cruz sc-126), Thy1 (H-110) (Santa Cruz sc-9163), and gamma-H2AX (Millipore 05-636).	('H2AX', 'Gene', '3014', (410, 414))	('p53', 'Gene', '7157', (333, 336))	('LC3B', 'Gene', (304, 308))	('Signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('GATA4', 'Gene', (248, 253))	('YAP', 'Gene', (181, 184))	('calretinin', 'Gene', (66, 76))	('LC3B', 'Gene', '81631', (304, 308))	('N-Cadherin', 'Gene', (144, 154))	('Mesothelin', 'Gene', '10232', (208, 218))	('N-Cadherin', 'Gene', '1000', (144, 154))	('p53', 'Gene', (333, 336))	('p62', 'Gene', '23636', (283, 286))	('p62', 'Gene', (283, 286))	('Cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('Thy1', 'Gene', '7070', (365, 369))	('Santa Cruz', 'Var', (379, 389))	('Signaling', 'biological_process', 'GO:0023052', ('315', '324'))	('calretinin', 'Gene', '794', (66, 76))	('YAP', 'Gene', '10413', (181, 184))	('GATA4', 'Gene', '2626', (248, 253))	('Mesothelin', 'Gene', (208, 218))	('Thy1', 'Gene', (365, 369))	('H2AX', 'Gene', (410, 414))	('mouse', 'Species', '10090', (97, 102))
113935	29527515	The filtering chain included removal of all synonymous mutations, variants that are found in the UCSC Common SNPs database, variants with an allele ratio below 10% or a read count below 50.	('rat', 'Species', '10116', (148, 151))	('variants', 'Var', (124, 132))	('variants', 'Var', (66, 74))
113942	29527515	Primary cultures from two patients (P236 and P95) for whom samples were available at different stages of the disease (for nomenclature defining the different samples from these patients see Figure S2 in Supplementary Material) and where we had observed maintenance of epithelioid histology in one (P236) and epithelial to mesenchymal transition (EMT) in the second (P95), were selected for this proof of principle study.	('P95', 'Gene', '4683', (45, 48))	('P236', 'Var', (298, 302))	('EMT', 'biological_process', 'GO:0001837', ('346', '349'))	('P95', 'Gene', (366, 369))	('P95', 'Gene', (45, 48))	('patients', 'Species', '9606', (177, 185))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('308', '344'))	('epithelial to mesenchymal transition', 'CPA', (308, 344))	('patients', 'Species', '9606', (26, 34))	('P95', 'Gene', '4683', (366, 369))	('epithelioid histology', 'CPA', (268, 289))
113944	29527515	While few genetic alterations were present in P236, consistent with current knowledge on papillary mesothelioma, P95 was characterized by a widespread LOH including NF2, BAP1, and TP53 tumor suppressor genes, as well an additional truncating mutation in NF2 (c.553G > T/p.Glu185Ter, no Cosmic annotation) and a point mutation in TP53 (c.839G > C/p.p.Arg280Thr, cosm254987).	('c.553G > T', 'Mutation', 'c.553G>T', (259, 269))	('p.Arg280Thr', 'Mutation', 'rs121912660', (348, 359))	('TP53', 'Gene', (180, 184))	('NF2', 'Gene', '4771', (254, 257))	('tumor', 'Disease', (185, 190))	('P95', 'Gene', (113, 116))	('c.839G > C', 'Mutation', 'rs121912660', (335, 345))	('NF2', 'Gene', (254, 257))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (89, 111))	('rat', 'Species', '10116', (22, 25))	('c.553G > T/p.Glu185Ter', 'Var', (259, 281))	('NF2', 'Gene', '4771', (165, 168))	('P95', 'Gene', '4683', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('c.839G > C/p.p.Arg280Thr', 'Var', (335, 359))	('cosm254987', 'Chemical', '-', (361, 371))	('TP53', 'Gene', (329, 333))	('NF2', 'Gene', (165, 168))	('BAP1', 'Gene', '8314', (170, 174))	('Ter', 'cellular_component', 'GO:0097047', ('278', '281'))	('TP53', 'Gene', '7157', (180, 184))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('papillary mesothelioma', 'Disease', (89, 111))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('BAP1', 'Gene', (170, 174))	('p.Glu185Ter', 'Mutation', 'p.E185X', (270, 281))	('TP53', 'Gene', '7157', (329, 333))
113947	29527515	Culture heterogeneity was evidenced in one of the patient (P236_cells) by immunofluorescence analysis, revealing that not all cells stained for podoplanin (D2-40), Ki-67, nuclear YAP, or nuclear calretinin, while all cells expressed N-cadherin (Figure 1D).	('Ki-67', 'Var', (164, 169))	('cadherin', 'molecular_function', 'GO:0008014', ('235', '243'))	('YAP', 'Gene', (179, 182))	('N-cadherin', 'Gene', (233, 243))	('podoplanin', 'Gene', '10630', (144, 154))	('calretinin', 'Gene', '794', (195, 205))	('N-cadherin', 'Gene', '1000', (233, 243))	('nuclear', 'Protein', (171, 178))	('podoplanin', 'Gene', (144, 154))	('YAP', 'Gene', '10413', (179, 182))	('calretinin', 'Gene', (195, 205))	('patient', 'Species', '9606', (50, 57))
113953	29527515	Using this approach, we successfully generated a chemoresistant model for primary cells derived from patient P236 (Figure 2B) but not for primary cells derived from patient P95 (Figure S3 in Supplementary Material).	('chemoresistant model', 'CPA', (49, 69))	('P95', 'Gene', '4683', (173, 176))	('patient', 'Species', '9606', (165, 172))	('rat', 'Species', '10116', (41, 44))	('P95', 'Gene', (173, 176))	('patient', 'Species', '9606', (101, 108))	('P236', 'Var', (109, 113))
113980	29527515	This is consistent with the presence of the gain of function p53 mutation observed in this patient.	('p53', 'Gene', (61, 64))	('gain of function', 'PosReg', (44, 60))	('mutation', 'Var', (65, 73))	('p53', 'Gene', '7157', (61, 64))	('patient', 'Species', '9606', (91, 98))
113983	29527515	However, datamining the catalog of somatic mutations in cancer (COSMIC, ), we found that TP53 mutations are described in 2/24 (8%) epithelioid mesothelioma.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('described', 'Reg', (108, 117))	('epithelioid mesothelioma', 'Disease', (131, 155))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (131, 155))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
113985	29527515	Because we now show that a resistant phenotype against cisplatin/pemetrexed is present before chemotherapy, we infer that intrinsic properties of the tumor, including gain of function of TP53, deletion of NF2, and CDKN2A participate to the evolution of resistant cells toward EMT.	('deletion', 'Var', (193, 201))	('CDKN2A', 'Gene', (214, 220))	('TP53', 'Gene', '7157', (187, 191))	('CDKN2A', 'Gene', '1029', (214, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('gain of function', 'PosReg', (167, 183))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TP53', 'Gene', (187, 191))	('pemetrexed', 'Chemical', 'MESH:D000068437', (65, 75))	('NF2', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('EMT', 'biological_process', 'GO:0001837', ('276', '279'))	('tumor', 'Disease', (150, 155))	('NF2', 'Gene', '4771', (205, 208))
113986	29527515	The tumor from the second patient (P236) was of epithelioid morphology, maintaining the same histotype throughout the course of the disease and displayed absence of gross genetic abnormalities.	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (26, 33))	('genetic abnormalities', 'Disease', 'MESH:D030342', (171, 192))	('genetic abnormalities', 'Disease', (171, 192))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('P236', 'Var', (35, 39))
113992	29527515	Thy1 overexpression suppresses cell proliferation in ovarian and nasopharyngeal cancer, however, Thy1 expression in cancer stem-cells has mostly been associated with chemoresistance and increased tumor-initiating properties.	('tumor', 'Disease', (196, 201))	('chemoresistance', 'CPA', (166, 181))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'Var', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('cancer', 'Disease', (80, 86))	('associated', 'Reg', (150, 160))	('Thy1', 'Gene', '7070', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Thy1', 'Gene', '7070', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cancer', 'Disease', (116, 122))	('cell proliferation', 'CPA', (31, 49))	('Thy1', 'Gene', (97, 101))	('ovarian and nasopharyngeal cancer', 'Disease', 'MESH:D009303', (53, 86))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))	('Thy1', 'Gene', (0, 4))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (65, 86))	('rat', 'Species', '10116', (43, 46))	('suppresses', 'NegReg', (20, 30))
113995	29527515	A significant correlation between expression of lncRNA RP11-334E6.12 and developmental processes has been documented in esophageal cancer; overexpression has been documented in triple negative breast cancer.	('breast cancer', 'Disease', (193, 206))	('RP11', 'Gene', (55, 59))	('overexpression', 'PosReg', (139, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('RP11', 'Gene', '26121', (55, 59))	('developmental processes', 'CPA', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('lncRNA', 'Var', (48, 54))	('esophageal cancer', 'Disease', (120, 137))
114092	29454314	The first example from Grigoriu and colleagues took patients with a positive (> 1 nM/L) mesothelin at baseline receiving chemotherapy and immunotherapy (n = 40).	('mesothelin', 'Gene', (88, 98))	('mesothelin', 'Gene', '10232', (88, 98))	('> 1 nM/L', 'Var', (78, 86))	('patients', 'Species', '9606', (52, 60))
114100	29454314	Wheatley-Price and colleagues performed a post-hoc analysis of mesothelin values from a cohort of 42 patients using absolute (5 mmol) and relative (10%) changes and their correlation with survival, finding that relative changes were more accurate.	('patients', 'Species', '9606', (101, 109))	('mesothelin', 'Gene', (63, 73))	('changes', 'Var', (153, 160))	('mesothelin', 'Gene', '10232', (63, 73))
114115	29454314	Worsening renal function has been shown to falsely elevate mesothelin levels.	('mesothelin', 'Gene', '10232', (59, 69))	('elevate', 'PosReg', (51, 58))	('Worsening', 'Var', (0, 9))	('Worsening renal function', 'Phenotype', 'HP:0012622', (0, 24))	('mesothelin', 'Gene', (59, 69))
114163	26011724	Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms.	('Peroxide', 'Chemical', 'MESH:D010545', (24, 32))	('cancer', 'Disease', (216, 222))	('mito', 'Species', '262676', (252, 256))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (132, 154))	('tumor', 'Disease', (298, 303))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (266, 283))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('enhances', 'PosReg', (229, 237))	('Combinatorial', 'Var', (48, 61))	('Dysregulation', 'Var', (155, 168))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('Peroxiredoxin 3', 'Gene', (75, 90))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (132, 154))	('metabolism', 'biological_process', 'GO:0008152', ('202', '212'))	('Disabling', 'Var', (0, 9))	('Peroxiredoxin 3', 'Gene', '10935', (75, 90))	('Malignant Mesothelioma', 'Disease', (132, 154))	('Mitochondrial Peroxide Metabolism', 'MPA', (10, 43))	('production of mitochondrial hydrogen peroxide', 'MPA', (238, 283))	('Metabolism', 'biological_process', 'GO:0008152', ('33', '43'))
114165	26011724	Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers.	('GV', 'Chemical', 'MESH:D005840', (278, 280))	('cysteine', 'Chemical', 'MESH:D003545', (160, 168))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (6, 28))	('targeting', 'Var', (202, 211))	('TRX2', 'Gene', '25828', (231, 235))	('peroxidatic', 'MPA', (134, 145))	('thiostrepton', 'Chemical', 'MESH:D013883', (60, 72))	('disables', 'NegReg', (91, 99))	('oxidoreductase', 'Gene', '7296', (216, 230))	('increasing', 'PosReg', (307, 317))	('malignant mesothelioma', 'Disease', (6, 28))	('oxidoreductase', 'Gene', (216, 230))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (6, 28))	('TRX2', 'Gene', (231, 235))	('homodimers', 'MPA', (181, 191))	('potentiates', 'PosReg', (282, 293))	('PRX3', 'Gene', (100, 104))	('levels of disulfide-bonded', 'MPA', (318, 344))	('triphenylmethane', 'Chemical', 'MESH:C046945', (245, 261))	('gentian violet', 'Chemical', 'MESH:D005840', (262, 276))	('disulfide', 'Chemical', 'MESH:D004220', (328, 337))
114167	26011724	Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS.	('PRX3', 'Gene', (30, 34))	('mesothelioma', 'Disease', (43, 55))	('reduces', 'NegReg', (35, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('rat', 'Species', '10116', (68, 71))	('sensitivity to TS', 'CPA', (79, 96))	('knockdown', 'Var', (17, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
114170	26011724	Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (275, 287))	('targeting', 'Var', (167, 176))	('GV', 'Chemical', 'MESH:D005840', (117, 119))	('mesothelioma', 'Disease', (234, 246))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (46, 63))	('mito', 'Species', '262676', (32, 36))	('rat', 'Species', '10116', (133, 136))	('rat', 'Species', '10116', (214, 217))	('malignancies', 'Disease', (275, 287))	('human', 'Species', '9606', (269, 274))	('mesothelioma', 'Disease', 'MESH:D008654', (234, 246))	('PRX3', 'Gene', (177, 181))
114174	26011724	Reversible oxidation of specific cysteine residues has been shown to modify the structure, function and subcellular distribution of numerous proteins.	('subcellular distribution of numerous', 'MPA', (104, 140))	('proteins', 'Protein', (141, 149))	('cysteine', 'Chemical', 'MESH:D003545', (33, 41))	('oxidation', 'Var', (11, 20))	('structure', 'MPA', (80, 89))	('function', 'MPA', (91, 99))	('modify', 'Reg', (69, 75))	('cysteine', 'Protein', (33, 41))
114176	26011724	Moderate levels of H2O2 support proliferation, while higher levels create a pro-oxidant environment leading to activation of stress response pathways, damage of cellular macromolecules and cell death.	('activation', 'PosReg', (111, 121))	('cellular macromolecules', 'MPA', (161, 184))	('H2O2', 'Chemical', 'MESH:D006861', (19, 23))	('H2O2', 'Var', (19, 23))	('rat', 'Species', '10116', (39, 42))	('damage', 'MPA', (151, 157))	('cell death', 'CPA', (189, 199))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('rat', 'Species', '10116', (4, 7))	('stress response pathways', 'Pathway', (125, 149))
114178	26011724	Because this phenotypic adaptation is not limited to a specific subset of oncogenes and tumor suppressor genes, exploiting perturbations in the metabolism of mitochondrial and cytosolic-derived oxidants has been proposed to be a viable therapeutic target in a variety of human cancers.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('human', 'Species', '9606', (271, 276))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('metabolism', 'biological_process', 'GO:0008152', ('144', '154'))	('cancers', 'Disease', (277, 284))	('perturbations', 'Var', (123, 136))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mito', 'Species', '262676', (158, 162))	('metabolism', 'MPA', (144, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
114181	26011724	Mutations in mitochondrial DNA do indeed promote tumorigenesis, but mitochondria from tumor cells generally have only subtle alterations in energy transfer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mitochondrial DNA', 'Gene', (13, 30))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('13', '30'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (86, 91))	('rat', 'Species', '10116', (129, 132))	('tumor', 'Disease', (49, 54))	('mito', 'Species', '262676', (68, 72))	('promote', 'PosReg', (41, 48))	('mitochondria', 'cellular_component', 'GO:0005739', ('68', '80'))	('Mutations', 'Var', (0, 9))	('energy transfer', 'MPA', (140, 155))	('mito', 'Species', '262676', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
114191	26011724	For example, PRX3 expression in MCF-7 and MDA-MB-231 breast cancer cells promotes cell cycle progression, while silencing PRX3 impairs cell proliferation.	('PRX3', 'Gene', (13, 17))	('PRX3', 'Gene', (122, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (42, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('impairs', 'NegReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('silencing', 'Var', (112, 121))	('cell proliferation', 'CPA', (135, 153))	('rat', 'Species', '10116', (147, 150))	('promotes', 'PosReg', (73, 81))	('cell cycle progression', 'CPA', (82, 104))	('MCF-7', 'CellLine', 'CVCL:0031', (32, 37))	('breast cancer', 'Disease', (53, 66))
114193	26011724	Recently, mitochondrial oxidants were shown to be essential for tumorigenesis mediated by activated K-RAS, which induces ROS-dependent cell senescence in normal cells.	('induces', 'Reg', (113, 120))	('senescence', 'biological_process', 'GO:0010149', ('140', '150'))	('tumor', 'Disease', (64, 69))	('K-RAS', 'Gene', '3845', (100, 105))	('K-RAS', 'Gene', (100, 105))	('ROS-dependent cell senescence', 'MPA', (121, 150))	('activated', 'Var', (90, 99))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mito', 'Species', '262676', (10, 14))
114199	26011724	Treatment of MM cells with TS leads to stable, non-reducible and irreversible modification to PRX3, inhibits expression of FOXM1, increases mitochondrial oxidant levels, hyperactivates ERK1/2 and induces cell death, all in a redox-dependent manner.	('ERK1', 'molecular_function', 'GO:0004707', ('185', '189'))	('cell death', 'biological_process', 'GO:0008219', ('204', '214'))	('expression', 'MPA', (109, 119))	('inhibits', 'NegReg', (100, 108))	('induces', 'Reg', (196, 203))	('FOXM1', 'Gene', '2305', (123, 128))	('modification', 'Var', (78, 90))	('increases', 'PosReg', (130, 139))	('ERK1/2', 'Gene', (185, 191))	('ERK1/2', 'Gene', '5595;5594', (185, 191))	('PRX3', 'Gene', (94, 98))	('FOXM1', 'Gene', (123, 128))	('hyperactivates', 'PosReg', (170, 184))	('cell death', 'CPA', (204, 214))	('mito', 'Species', '262676', (140, 144))	('mitochondrial oxidant levels', 'MPA', (140, 168))
114202	26011724	We propose adduction of specific cysteine residues in PRX3 by TS inactivates its peroxidase activity, thereby compromising adaptive responses that permit mesothelioma cells to tolerate a pro-oxidant state.	('inactivates', 'NegReg', (65, 76))	('mesothelioma', 'Disease', (154, 166))	('rat', 'Species', '10116', (180, 183))	('peroxidase', 'Enzyme', (81, 91))	('adaptive responses', 'CPA', (123, 141))	('cysteine', 'Chemical', 'MESH:D003545', (33, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('adduction', 'Var', (11, 20))	('PRX3', 'Gene', (54, 58))	('compromising', 'NegReg', (110, 122))	('peroxidase activity', 'molecular_function', 'GO:0004601', ('81', '100'))
114204	26011724	Evaluation of the effects of TS and GV, alone or together, in a SCID mouse xenograft model of human MM indicates combinatorial targeting of the PRX3 antioxidant network is a feasible strategy for managing a wide variety of tumors characterized by dysregulation of mitochondrial metabolism that results in high oxidant production.	('mitochondrial metabolism', 'MPA', (264, 288))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('SCID', 'Disease', (64, 68))	('mito', 'Species', '262676', (264, 268))	('tumors', 'Disease', (223, 229))	('SCID', 'Disease', 'MESH:D053632', (64, 68))	('mouse', 'Species', '10090', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('metabolism', 'biological_process', 'GO:0008152', ('278', '288'))	('high oxidant production', 'MPA', (305, 328))	('dysregulation', 'Var', (247, 260))	('results in', 'Reg', (294, 304))	('human', 'Species', '9606', (94, 99))	('dysregulation of mitochondrial metabolism', 'Phenotype', 'HP:0003287', (247, 288))	('rat', 'Species', '10116', (185, 188))	('GV', 'Chemical', 'MESH:D005840', (36, 38))
114209	26011724	Under reducing and denaturing conditions cellular PRX3 migrates as ~23 kDa monomers, but in extracts from cells treated with TS modified PRX3 migrates at ~35-40 kDa, the apparent molecular weight of PRX3 homodimers.	('rat', 'Species', '10116', (145, 148))	('rat', 'Species', '10116', (58, 61))	('PRX3', 'Gene', (137, 141))	('modified', 'Var', (128, 136))
114235	26011724	Human mitochondrial PRX3 contains three cysteine residues: the peroxidatic cysteine at position 108 (Cys108), the resolving cysteine at position 229 (Cys229), and a highly conserved but non-catalytic cysteine at position 127 (Cys127).	('Cys127', 'Chemical', '-', (226, 232))	('Human', 'Species', '9606', (0, 5))	('cysteine', 'Chemical', 'MESH:D003545', (124, 132))	('cysteine', 'Chemical', 'MESH:D003545', (200, 208))	('Cys108', 'Chemical', '-', (101, 107))	('cysteine', 'Chemical', 'MESH:D003545', (40, 48))	('Cys229', 'Chemical', '-', (150, 156))	('cysteine', 'Chemical', 'MESH:D003545', (75, 83))	('Cys108', 'Var', (101, 107))	('Cys229', 'Var', (150, 156))	('mito', 'Species', '262676', (6, 10))
114237	26011724	We next investigated TS-induced modifications to rPRX3 mutants where specific cysteine residues corresponding to Cys108, Cys229 and Cys127 were replaced with serine.	('mutants', 'Var', (55, 62))	('rPRX3', 'Gene', (49, 54))	('Cys127 were replaced with serine', 'SUBSTITUTION', 'None', (132, 164))	('rPRX3', 'Gene', '64371', (49, 54))	('Cys229 and Cys127 were replaced with serine', 'SUBSTITUTION', 'None', (121, 164))	('Cys127 were replaced with serine', 'Var', (132, 164))	('cysteine', 'Chemical', 'MESH:D003545', (78, 86))	('Cys108', 'Var', (113, 119))
114239	26011724	Incubation of the Cys108 and Cys229 serine mutants significantly reduced the levels of modification to rPRX3 by TS (Fig 3B, lanes 1-2 and 5-6), whereas the Cys127 mutant showed TS induced modifications equal to that of wild type PRX3 (Fig 3B lanes 3-4).	('Cys108', 'Chemical', '-', (18, 24))	('reduced', 'NegReg', (65, 72))	('Cys229 serine', 'Mutation', 'p.C229S', (29, 42))	('Cys108', 'Var', (18, 24))	('rPRX3', 'Gene', (103, 108))	('modification', 'MPA', (87, 99))	('levels', 'MPA', (77, 83))	('rPRX3', 'Gene', '64371', (103, 108))	('Cys127', 'Chemical', '-', (156, 162))	('Cys229 serine mutants', 'Var', (29, 50))	('Cys127', 'Var', (156, 162))
114240	26011724	In order to test the hypothesis that the dimeric form of PRX3 is more reactive with TS, we utilized an engineered dimer of PRX3, S139E/A142E (EE Mut).	('A142E', 'Mutation', 'p.A142E', (135, 140))	('S139E', 'SUBSTITUTION', 'None', (129, 134))	('PRX3', 'Gene', (123, 127))	('S139E', 'Var', (129, 134))
114242	26011724	The amount of non-reducible dimer formed upon addition of TS was greater in the EE mutant than in WT Prx3 (Fig 3C), indicating that HMW oligomer formation is not required to form the TS adduct and that the TS adduct does not form across the dimer-dimer interface.	('mutant', 'Var', (83, 89))	('greater', 'PosReg', (65, 72))	('HM', 'CellLine', 'CVCL:M679', (132, 134))	('Prx3', 'Gene', (101, 105))	('non-reducible dimer formed', 'MPA', (14, 40))	('Prx3', 'Gene', '10935', (101, 105))	('formation', 'biological_process', 'GO:0009058', ('145', '154'))
114245	26011724	Peptides were observed in the TS-treated sample that agreed with the predicted molecular weight for single TS adducts with Cys127 and Cys229 (S1 Table).	('Cys127', 'Chemical', '-', (123, 129))	('Cys229', 'Var', (134, 140))	('Cys127', 'Var', (123, 129))	('Cys229', 'Chemical', '-', (134, 140))
114246	26011724	Importantly, we were able to directly observe a peptide in the TS sample that corresponds to a single TS molecule linked to both the Cys108 and Cys229 containing peptides (Fig 3E, obs MW = 7970.2, predicted MW = 7971.0); this peptide-TS complex was not observed in the DMSO control.	('DMSO', 'Chemical', 'MESH:D004121', (269, 273))	('Cys229 containing', 'Var', (144, 161))	('peptides', 'Chemical', 'MESH:D010455', (162, 170))	('Cys108', 'Chemical', '-', (133, 139))	('Cys229', 'Chemical', '-', (144, 150))	('Cys108', 'Var', (133, 139))
114247	26011724	This data supports that TS is able to irreversibly react with all three cysteines in Prx3, but that the irreducible dimer formation occurs through the reaction of TS with Cys108 and Cys229.	('Cys229', 'Var', (182, 188))	('Cys108', 'Var', (171, 177))	('cysteines', 'Chemical', 'MESH:D003545', (72, 81))	('Prx3', 'Gene', (85, 89))	('Prx3', 'Gene', '10935', (85, 89))	('formation', 'biological_process', 'GO:0009058', ('122', '131'))	('Cys108', 'Chemical', '-', (171, 177))	('dimer formation', 'MPA', (116, 131))	('Cys229', 'Chemical', '-', (182, 188))
114251	26011724	FLAG-tagged PRX3 lacking the Cys108 (lanes 5-8), and Cys229 (lanes 9-12) were not modified by TS, although the TS-adduct was observed for endogenous PRX3 (lanes 1-4).	('lacking', 'NegReg', (17, 24))	('Cys108', 'Chemical', '-', (29, 35))	('Cys229', 'Chemical', '-', (53, 59))	('Cys108', 'Var', (29, 35))	('Cys229', 'Var', (53, 59))	('PRX3', 'Gene', (12, 16))
114252	26011724	Altogether, the data from the analysis of Cys variants of PRX3, either as recombinant proteins or cellular expression constructs, supports the conclusion that an active PRX3 catalytic cycle is required.	('variants', 'Var', (46, 54))	('Cys', 'Chemical', 'MESH:D003545', (42, 45))	('PRX3', 'Gene', (58, 62))
114253	26011724	Moreover, TS-adduct formation with the PRX3 dimer can crosslink Cys108 and Cys229.	('crosslink Cys108', 'Var', (54, 70))	('Cys108', 'Chemical', '-', (64, 70))	('Cys108', 'Var', (64, 70))	('Cys229', 'Chemical', '-', (75, 81))	('TS-adduct', 'MPA', (10, 19))	('Cys229', 'Var', (75, 81))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))
114259	26011724	The EC50 of TS in HM and H2373 MM cells was 1.2 muM, ~7 times lower than primary HMCs with an EC50 of 8.1 muM and ~25 times lower than that observed with immortalized LP9 mesothelial cells (EC50 = 30.1 muM).	('muM', 'Gene', '56925', (106, 109))	('muM', 'Gene', '56925', (202, 205))	('H2373 MM', 'Var', (25, 33))	('muM', 'Gene', '56925', (48, 51))	('muM', 'Gene', (106, 109))	('muM', 'Gene', (202, 205))	('HM', 'CellLine', 'CVCL:M679', (18, 20))	('muM', 'Gene', (48, 51))	('H2373 MM', 'CellLine', 'CVCL:A533', (25, 33))	('HM', 'CellLine', 'CVCL:M679', (81, 83))
114266	26011724	Transfection of HM cells with siRNA to PRX3 resulted in lower cell density (Fig 5B), and stable expression of shRNA to PRX3 reduced HM and H2373 MM cell proliferation as compared to vector controls (Fig 5C and S3A Fig), as has been reported for breast cancer cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('reduced', 'NegReg', (124, 131))	('shRNA to', 'Var', (110, 118))	('rat', 'Species', '10116', (160, 163))	('HM', 'CellLine', 'CVCL:M679', (132, 134))	('cell density', 'CPA', (62, 74))	('lower', 'NegReg', (56, 61))	('H2373 MM', 'CellLine', 'CVCL:A533', (139, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('HM', 'CellLine', 'CVCL:M679', (16, 18))	('reduced HM', 'Phenotype', 'HP:0011905', (124, 134))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('PRX3', 'Gene', (119, 123))	('breast cancer', 'Disease', (245, 258))
114300	26011724	Because tumor cells generally produce high levels of oxidants, most often as a consequence of perturbations in energy metabolism, they require adaptive responses to survive and benefit from a pro-oxidative state.	('perturbations', 'Var', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('metabolism', 'biological_process', 'GO:0008152', ('118', '128'))	('tumor', 'Disease', (8, 13))	('consequence', 'Reg', (79, 90))	('energy metabolism', 'MPA', (111, 128))
114302	26011724	Given that it is a common feature of many tumor types, oxidant metabolism has emerged as an important therapeutic target, with accentuation of oxidant production that overwhelms antioxidant reserve capacity showing the most clinical promise.	('oxidant', 'MPA', (143, 150))	('tumor', 'Disease', (42, 47))	('antioxidant reserve', 'MPA', (178, 197))	('metabolism', 'biological_process', 'GO:0008152', ('63', '73'))	('accentuation', 'Var', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('accentuation of oxidant production', 'Phenotype', 'HP:0025464', (127, 161))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
114311	26011724	TS increases the production of hydrogen peroxide in isolated mitochondria respiring on succinate (Fig 1), a response consistent with inactivation of PRX3 peroxidase activity via adduction of the peroxidatic and resolving cysteine residues, Cys108 and Cys229, (Figs 2 and 3) within the PRX3 dimer.	('Cys229', 'Var', (251, 257))	('activity', 'MPA', (165, 173))	('Cys108', 'Chemical', '-', (240, 246))	('production of hydrogen peroxide', 'MPA', (17, 48))	('increases', 'PosReg', (3, 12))	('adduction', 'Interaction', (178, 187))	('succinate', 'Chemical', 'MESH:D019802', (87, 96))	('Cys108', 'Var', (240, 246))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (31, 48))	('peroxidase activity', 'molecular_function', 'GO:0004601', ('154', '173'))	('cysteine', 'Chemical', 'MESH:D003545', (221, 229))	('Cys229', 'Chemical', '-', (251, 257))	('PRX3 peroxidase', 'Enzyme', (149, 164))	('mitochondria', 'cellular_component', 'GO:0005739', ('61', '73'))	('mito', 'Species', '262676', (61, 65))	('inactivation', 'NegReg', (133, 145))
114312	26011724	Our data suggest a model for the modification of PRX3 by TS that provides a physiological basis for its selective effects on tumor cells (Fig 7).	('modification', 'Var', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PRX3', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))
114336	26011724	As for other cell types, knockdown of PRX3 impedes the proliferation of HM cells (Fig 5).	('HM', 'CellLine', 'CVCL:M679', (72, 74))	('impedes', 'NegReg', (43, 50))	('PRX3', 'Gene', (38, 42))	('proliferation of HM cells', 'CPA', (55, 80))	('rat', 'Species', '10116', (62, 65))	('knockdown', 'Var', (25, 34))
114337	26011724	Even accounting for reduced rates of proliferation, shPRX3 HM cells were significantly less sensitive to TS (Fig 5), and expression of catalase in this background restored cell proliferation without restoring sensitivity to TS.	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('HM', 'CellLine', 'CVCL:M679', (59, 61))	('rat', 'Species', '10116', (184, 187))	('cell proliferation', 'CPA', (172, 190))	('catalase', 'Gene', (135, 143))	('rat', 'Species', '10116', (44, 47))	('restored', 'PosReg', (163, 171))	('catalase', 'Gene', '847', (135, 143))	('expression', 'Var', (121, 131))	('less', 'NegReg', (87, 91))	('rat', 'Species', '10116', (28, 31))
114344	26011724	In agreement with our in vitro findings that inhibition of TRX2 with GV potentiates PRX3 adduction (Fig 2) and sensitizes MM cells to TS, administrating a combination of TS and GV led to the largest reduction in tumor volume in vivo (Fig 6).	('potentiates', 'PosReg', (72, 83))	('TRX2', 'Gene', (59, 63))	('TRX2', 'Gene', '25828', (59, 63))	('PRX3 adduction', 'MPA', (84, 98))	('rat', 'Species', '10116', (146, 149))	('GV', 'Chemical', 'MESH:D005840', (69, 71))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('GV', 'Chemical', 'MESH:D005840', (177, 179))	('inhibition', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('reduction', 'NegReg', (199, 208))	('tumor', 'Disease', (212, 217))
114347	26011724	Detection of the modified form of PRX3 in xenograft MM tumors from animals treated with 50 mg/kg TS provides evidence that the mechanism of action in vivo is similar to that in vitro.	('MM tumors', 'Disease', (52, 61))	('PRX3', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('modified', 'Var', (17, 25))	('MM tumors', 'Disease', 'MESH:D009369', (52, 61))
114348	26011724	If so, the modified form of PRX3 may prove to be a useful biomarker for clinically approved agents like arsenic trioxide that promote mitochondrial oxidative stress and enhance the anti-cancer activity of TS.	('PRX3', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('promote', 'PosReg', (126, 133))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (104, 120))	('enhance', 'PosReg', (169, 176))	('modified', 'Var', (11, 19))	('mitochondrial oxidative stress', 'MPA', (134, 164))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('mito', 'Species', '262676', (134, 138))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
114372	26011724	cDNA was prepared from total RNA using the High Capacity cDNA Reverse Transcription kit following the manufacturers protocol (Life Technologies) and gene expression levels were determined using Assay on Demand TaqMan primers for PRX3 (Hs00428953_g1), FOXM1 (Hs01073586_g1), and HPRT1 (Hs02800695_m1) as a housekeeping control.	('Hs02800695_m1', 'Var', (285, 298))	('Reverse Transcription', 'biological_process', 'GO:0001171', ('62', '83'))	('Hs00428953_g1', 'Var', (235, 248))	('HPRT1', 'Gene', '3251', (278, 283))	('HPRT', 'molecular_function', 'GO:0004422', ('278', '282'))	('HPRT1', 'Gene', (278, 283))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('FOXM1', 'Gene', '2305', (251, 256))	('Hs01073586_g1', 'Var', (258, 271))	('gene expression', 'biological_process', 'GO:0010467', ('149', '164'))	('FOXM1', 'Gene', (251, 256))
114387	26011724	Membranes were prepared for antibody addition following standard protocols and incubated at 4 C overnight with the indicated primary antibodies: PRX3 (1:2000, Ab Frontier, Seoul, Korea), FOXM1 K-19 (1:500, Santa Cruz Biotechnology, Dallas, TX) and actin (1:5000, Millipore, Billerica, MA).	('antibody', 'molecular_function', 'GO:0003823', ('28', '36'))	('FOXM1', 'Gene', '2305', (187, 192))	('FOXM1', 'Gene', (187, 192))	('antibody', 'cellular_component', 'GO:0042571', ('28', '36'))	('PRX3', 'Gene', (145, 149))	('1:2000', 'Var', (151, 157))	('antibody', 'cellular_component', 'GO:0019814', ('28', '36'))	('antibody', 'cellular_component', 'GO:0019815', ('28', '36'))
114404	26011724	The resultant protein (residues 62-256) contained a non-cleavable, N-terminal His-tag.	('His', 'Chemical', 'MESH:D006639', (78, 81))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('residues 62-256', 'Var', (23, 38))	('non-cleavable', 'MPA', (52, 65))
114405	26011724	The Cys to Ser variants (C108S, C127S, and C229S) were generated using the QuickChange protocol and the appropriate primers (Stratagene).	('Ser', 'Chemical', 'MESH:D012694', (11, 14))	('C229S', 'SUBSTITUTION', 'None', (43, 48))	('C127S', 'Mutation', 'p.C127S', (32, 37))	('Ser', 'cellular_component', 'GO:0005790', ('11', '14'))	('C108S', 'Var', (25, 30))	('C127S', 'Var', (32, 37))	('rat', 'Species', '10116', (127, 130))	('C229S', 'Var', (43, 48))	('C108S', 'Mutation', 'p.C108S', (25, 30))	('rat', 'Species', '10116', (59, 62))	('Cys', 'Chemical', 'MESH:D003545', (4, 7))
114408	26011724	A dimeric Prx3 variant was created by introducing two charged residues into the dimer-dimer interface (S139E/A142E), as was previously done with human Prx1.	('Prx1', 'Gene', (151, 155))	('introducing', 'Reg', (38, 49))	('Prx1', 'Gene', '5052', (151, 155))	('S139E', 'Var', (103, 108))	('Prx3', 'Gene', '10935', (10, 14))	('human', 'Species', '9606', (145, 150))	('Prx3', 'Gene', (10, 14))	('S139E', 'SUBSTITUTION', 'None', (103, 108))	('A142E', 'Mutation', 'p.A142E', (109, 114))
114409	26011724	The His-tag of the S139E/A142E variant (EE Mut) was removed by digestion with biotinylated thrombin (Novagen).	('S139E', 'SUBSTITUTION', 'None', (19, 24))	('A142E', 'Mutation', 'p.A142E', (25, 30))	('His', 'Chemical', 'MESH:D006639', (4, 7))	('thrombin', 'Gene', (91, 99))	('S139E', 'Var', (19, 24))	('digestion', 'biological_process', 'GO:0007586', ('63', '72'))	('thrombin', 'Gene', '2147', (91, 99))
114410	26011724	Comparable amounts of thiostrepton adducts were observed in control reactions with either non-tagged or tagged wild-type Prx3.	('Prx3', 'Gene', '10935', (121, 125))	('thiostrepton', 'Chemical', 'MESH:D013883', (22, 34))	('Prx3', 'Gene', (121, 125))	('tagged', 'Var', (104, 110))
114430	26011724	IHC was performed using antibodies to FOXM1 C-20 (Santa Cruz Biotechnology), and PRX3 (Ab Frontier) according to the manufacturers' specifications; incubations with these antibodies were performed for half an hour.	('FOXM1', 'Gene', '2305', (38, 43))	('FOXM1', 'Gene', (38, 43))	('PRX3', 'Gene', (81, 85))	('antibodies', 'Var', (24, 34))
114450	21139928	In addition, a Phase III trial where 456 patients was assigned randomly to cisplatin 75 mg/m2 alone or with pemetrexed 500 mg/m2 indicated that supplementation with folic acid and vitamin B12 resulted in improved survival time, TTPD, response rates and significantly reduced treatment related toxicity when compared to non-supplemented patients.	('survival time', 'CPA', (213, 226))	('supplementation', 'Var', (144, 159))	('vitamin B12', 'Chemical', 'MESH:D014805', (180, 191))	('folic acid', 'Chemical', 'MESH:D005492', (165, 175))	('toxicity', 'Disease', 'MESH:D064420', (293, 301))	('response rates', 'CPA', (234, 248))	('toxicity', 'Disease', (293, 301))	('improved', 'PosReg', (204, 212))	('TTPD', 'CPA', (228, 232))	('reduced', 'NegReg', (267, 274))
114457	31442913	Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival.	('rat', 'Species', '10116', (15, 18))	('inverse', 'NegReg', (57, 64))	('CA9', 'Gene', (90, 93))	('high', 'Var', (85, 89))	('CA9', 'Gene', '768', (90, 93))	('expression', 'MPA', (94, 104))	('survival', 'CPA', (109, 117))
114460	31442913	CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL.	('rat', 'Species', '10116', (71, 74))	('FPN1', 'Gene', (142, 146))	('viability', 'CPA', (54, 63))	('S4', 'Var', (31, 33))	('CA9', 'Gene', (0, 3))	('FTL', 'Gene', '2512', (185, 188))	('overexpression', 'PosReg', (106, 120))	('migration of MM cells', 'CPA', (68, 89))	('downregulation', 'NegReg', (163, 177))	('U104', 'Var', (38, 42))	('FPN1', 'Gene', '30061', (142, 146))	('CA9', 'Gene', '768', (0, 3))	('FTH', 'Gene', (181, 184))	('SLC40A1', 'Gene', '30061', (147, 154))	('TFRC', 'Gene', '7037', (124, 128))	('FTH', 'Gene', '2495', (181, 184))	('suppression', 'NegReg', (4, 15))	('U104', 'Chemical', 'MESH:C585353', (38, 42))	('SLC40A1', 'Gene', (147, 154))	('TFRC', 'Gene', (124, 128))	('decreased', 'NegReg', (44, 53))	('FTL', 'Gene', (185, 188))
114461	31442913	Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2- and lipid peroxidation.	('peroxides', 'MPA', (184, 193))	('autophagy', 'biological_process', 'GO:0006914', ('60', '69'))	('inhibition', 'Var', (147, 157))	('CA9', 'Gene', (143, 146))	('O2', 'Chemical', 'MESH:D013481', (209, 211))	('lipid peroxidation', 'MPA', (217, 235))	('increased', 'PosReg', (75, 84))	('CA9', 'Gene', '768', (143, 146))	('mitochondria', 'cellular_component', 'GO:0005739', ('110', '122'))	('mitochondrial O2-', 'MPA', (195, 212))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('25', '46'))	('catalytic', 'MPA', (85, 94))	('autophagy', 'CPA', (60, 69))	('autophagy', 'biological_process', 'GO:0016236', ('60', '69'))	('mitochondrial fission', 'CPA', (25, 46))	('peroxides', 'Chemical', 'MESH:D010545', (184, 193))	('enhanced', 'PosReg', (51, 59))	('Fe(II)', 'Chemical', 'MESH:D007501', (95, 101))	('increased', 'PosReg', (174, 183))
114489	31442913	CA9 inhibitors, S4 (5577) and U104 (4540) were from Tocris Bioscience (Bristol, UK), which were dissolved in dimethyl sulfoxide (DMSO).	('DMSO', 'Chemical', 'MESH:D004121', (129, 133))	('U104 (4540', 'Var', (30, 40))	('CA9', 'Gene', '768', (0, 3))	('CA9', 'Gene', (0, 3))	('U104', 'Chemical', 'MESH:C585353', (30, 34))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (109, 127))
114498	31442913	Rabbit monoclonal anti-IRP1/IRP2 (20272S/37135), rabbit monoclonal anti-LAMP1 (9091), rabbit monoclonal anti-LC3B (3868) and rabbit polyclonal anti-cleaved caspase-3 (9661) antibodies were from Cell Signaling (Danvers, MA).	('IRP1', 'Gene', '48', (23, 27))	('rabbit', 'Species', '9986', (86, 92))	('rabbit', 'Species', '9986', (49, 55))	('20272S/37135', 'Var', (34, 46))	('LC3B', 'Gene', '81631', (109, 113))	('Signaling', 'biological_process', 'GO:0023052', ('199', '208'))	('LAMP1', 'Gene', '3916', (72, 77))	('IRP1', 'Gene', (23, 27))	('IRP2', 'Gene', (28, 32))	('LAMP1', 'Gene', (72, 77))	('LC3B', 'Gene', (109, 113))	('IRP2', 'Gene', '3658', (28, 32))	('Rabbit', 'Species', '9986', (0, 6))	('rabbit', 'Species', '9986', (125, 131))
114504	31442913	The dilution of primary antibodies used was as follows: anti-CA9 (1:2000), anti-HIF-1alpha (1:1000), anti-transferrin receptor-1 (1:2000), anti-IRP1/IRP2 (1:2000), anti-ferritin light/heavy chain (1:1000), anti-SLC40A1 (1:500), anti-LC3B (1:1000), anti-LAMP-1 (1:1000), anti-cleaved caspase-3 (1:500) and anti-beta-actin (1:2000).	('CA9', 'Gene', '768', (61, 64))	('transferrin', 'Gene', (106, 117))	('LAMP-1', 'Gene', (253, 259))	('LAMP-1', 'Gene', '3916', (253, 259))	('beta-actin', 'Gene', '728378', (310, 320))	('transferrin', 'Gene', '7018', (106, 117))	('LC3B', 'Gene', (233, 237))	('LC3B', 'Gene', '81631', (233, 237))	('HIF-1alpha', 'Gene', '3091', (80, 90))	('IRP1', 'Gene', (144, 148))	('IRP2', 'Gene', (149, 153))	('IRP2', 'Gene', '3658', (149, 153))	('IRP1', 'Gene', '48', (144, 148))	('SLC40A1', 'Gene', '30061', (211, 218))	('SLC40A1', 'Gene', (211, 218))	('beta-actin', 'Gene', (310, 320))	('CA9', 'Gene', (61, 64))	('HIF-1alpha', 'Gene', (80, 90))	('anti-ferritin', 'Var', (164, 177))
114517	31442913	Cells (5 x 104) were cultured in normoxia on 35-mm glass bottom dish for 16 h at 37  C. After treatment with CA9 inhibitors under hypoxia for 48 h, cells were stained with MitoTracker Red in FluoroBrite DMEM for 30 min in normoxia.	('Mito', 'Species', '262676', (172, 176))	('CA9', 'Gene', '768', (109, 112))	('hypoxia', 'Disease', (130, 137))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('inhibitors', 'Var', (113, 123))	('FluoroBrite DMEM', 'Chemical', 'MESH:C009096', (191, 207))	('CA9', 'Gene', (109, 112))
114527	31442913	Cells (5 x 104) were seeded in 6-well plate and cultured in normoxia for 16 h. Two silencer select siRNAs to human CA9 (Invitrogen; s2270 and s224790) and one negative control siRNA (Invitrogen; 4390844) were used.	('human', 'Species', '9606', (109, 114))	('s224790', 'Var', (142, 149))	('CA9', 'Gene', '768', (115, 118))	('CA9', 'Gene', (115, 118))
114552	31442913	To study the significance of CA9 expression in MM cells, we treated ACC-Meso-1 cells under hypoxia with two distinct CA9-specific inhibitors, U104 and S4.	('U104', 'Var', (142, 146))	('hypoxia', 'Disease', (91, 98))	('CA9', 'Gene', (117, 120))	('U104', 'Chemical', 'MESH:C585353', (142, 146))	('CA9', 'Gene', '768', (117, 120))	('CA9', 'Gene', (29, 32))	('CA9', 'Gene', '768', (29, 32))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
114553	31442913	S4 or U104 treatment significantly (P < 0.001; both S4 and U104) decreased cell viability of ACC-Meso-1 cells at 48 and 72 h post treatment whereas vehicle treatment (DMSO) showed no effect on proliferation (Fig.	('U104', 'Var', (6, 10))	('cell viability of ACC-Meso-1 cells', 'CPA', (75, 109))	('decreased', 'NegReg', (65, 74))	('DMSO', 'Chemical', 'MESH:D004121', (167, 171))	('rat', 'Species', '10116', (200, 203))	('U104', 'Chemical', 'MESH:C585353', (6, 10))	('U104', 'Chemical', 'MESH:C585353', (59, 63))	('U104', 'Var', (59, 63))
114554	31442913	Both S4 and U104 revealed antiproliferative effects (P < 0.001 and P < 0.01, respectively) on Met-5A cells though the effects were milder than in ACC-Meso-1 cells (Fig.	('rat', 'Species', '10116', (37, 40))	('U104', 'Var', (12, 16))	('antiproliferative effects', 'CPA', (26, 51))	('Met-5A', 'Chemical', 'MESH:C034758', (94, 100))	('U104', 'Chemical', 'MESH:C585353', (12, 16))
114556	31442913	In contrast to vehicle treatment, S4 or U104 treatment under hypoxia dose-dependently (40 and 75 muM) reduced migration of ACC-Meso-1 cells at 24 h (Fig.	('hypoxia', 'Disease', 'MESH:D000860', (61, 68))	('migration', 'CPA', (110, 119))	('muM', 'Gene', '56925', (97, 100))	('hypoxia', 'Disease', (61, 68))	('U104', 'Var', (40, 44))	('rat', 'Species', '10116', (113, 116))	('muM', 'Gene', (97, 100))	('U104', 'Chemical', 'MESH:C585353', (40, 44))	('reduced', 'NegReg', (102, 109))
114559	31442913	S4 or U104 treatment in ACC-Meso-1 cells showed a dose-dependent decrease in CA9 expression under hypoxia.	('U104', 'Var', (6, 10))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('U104', 'Chemical', 'MESH:C585353', (6, 10))	('decrease', 'NegReg', (65, 73))	('CA9', 'Gene', '768', (77, 80))	('CA9', 'Gene', (77, 80))	('expression', 'MPA', (81, 91))
114563	31442913	S4 or U104 treatment in ACC-Meso-1 cells significantly increased the level of catalytic Fe(II) (P < 0.01 and P < 0.05, S4 and U104, respectively) (Fig.	('U104', 'Var', (6, 10))	('increased', 'PosReg', (55, 64))	('U104', 'Chemical', 'MESH:C585353', (6, 10))	('U104', 'Chemical', 'MESH:C585353', (126, 130))	('Fe(II)', 'Chemical', 'MESH:D007501', (88, 94))	('U104', 'Var', (126, 130))
114565	31442913	We also performed siRNA-induced CA9 knockdown in ACC-Meso-1 cells under hypoxia.	('knockdown', 'Var', (36, 45))	('CA9', 'Gene', (32, 35))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('CA9', 'Gene', '768', (32, 35))
114573	31442913	We also found increased (P < 0.01 and P < 0.05; S4 and U104, respectively) transcription of DRP1, encoding dynamin-related protein to catalyze the mitochondrial fission, after S4 (40 muM) or U104 (75 muM) treatment under hypoxia for 48 h (Fig.	('increased', 'PosReg', (14, 23))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('hypoxia', 'Disease', (221, 228))	('U104', 'Var', (55, 59))	('DRP1', 'Gene', (92, 96))	('DRP1', 'Gene', '10059', (92, 96))	('muM', 'Gene', '56925', (183, 186))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('147', '168'))	('U104', 'Chemical', 'MESH:C585353', (55, 59))	('muM', 'Gene', '56925', (200, 203))	('U104', 'Chemical', 'MESH:C585353', (191, 195))	('muM', 'Gene', (183, 186))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))	('hypoxia', 'Disease', 'MESH:D000860', (221, 228))	('muM', 'Gene', (200, 203))	('transcription', 'MPA', (75, 88))
114575	31442913	A significant (P < 0.001) increase in merged staining area (yellow) of Mito and LysoTracker was detected in S4-treated ACC-Meso-1 cells, which was rare in untreated control group under hypoxia for 48 h (Fig.	('S4-treated', 'Var', (108, 118))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('Mito', 'Species', '262676', (71, 75))	('merged staining area', 'MPA', (38, 58))	('increase', 'PosReg', (26, 34))
114579	31442913	Increased expression of both LAMP-1 and LC3B-II (lipidated form) were observed in a dose-dependent manner in response to S4 or U104 treatment in ACC-Meso-1 cells under hypoxia for 48 h (Fig.	('U104', 'Chemical', 'MESH:C585353', (127, 131))	('LAMP-1', 'Gene', '3916', (29, 35))	('LC3B', 'Gene', '81631', (40, 44))	('expression', 'MPA', (10, 20))	('hypoxia', 'Disease', (168, 175))	('hypoxia', 'Disease', 'MESH:D000860', (168, 175))	('Increased', 'PosReg', (0, 9))	('U104', 'Var', (127, 131))	('LC3B', 'Gene', (40, 44))	('LAMP-1', 'Gene', (29, 35))
114582	31442913	Both S4 and U104-treated ACC-Meso-1 cells showed a significant (P < 0.05 and P < 0.01; S4 and U104, respectively) increase in late apoptotic cells (Annexin V-FITC+/PI+; shown as B+/+) under hypoxia (Fig.	('late apoptotic cells', 'CPA', (126, 146))	('hypoxia', 'Disease', (190, 197))	('hypoxia', 'Disease', 'MESH:D000860', (190, 197))	('increase', 'PosReg', (114, 122))	('Annexin V', 'Gene', '308', (148, 157))	('U104', 'Var', (94, 98))	('Annexin V', 'Gene', (148, 157))	('FITC', 'Chemical', 'MESH:D016650', (158, 162))	('U104', 'Chemical', 'MESH:C585353', (94, 98))	('U104', 'Chemical', 'MESH:C585353', (12, 16))
114583	31442913	U104-treated MM cells also revealed a significant (P < 0.05) increase in early apoptotic cells (Annexin V-FITC+/PI-, shown as B+/-) whereas S4 did not.	('early apoptotic cells', 'CPA', (73, 94))	('U104', 'Chemical', 'MESH:C585353', (0, 4))	('Annexin V', 'Gene', '308', (96, 105))	('Annexin V', 'Gene', (96, 105))	('FITC', 'Chemical', 'MESH:D016650', (106, 110))	('U104-treated', 'Var', (0, 12))
114584	31442913	Treatment with S4 or U104 (75 muM) not only induced TUNEL-positive cells with nuclear fragmentation but also increase in cleaved caspase-3 in ACC-Meso-1 cells cultured under hypoxia (Fig.	('TUNEL-positive cells', 'CPA', (52, 72))	('cleaved caspase-3', 'MPA', (121, 138))	('muM', 'Gene', (30, 33))	('U104', 'Chemical', 'MESH:C585353', (21, 25))	('hypoxia', 'Disease', (174, 181))	('nuclear fragmentation', 'CPA', (78, 99))	('increase', 'PosReg', (109, 117))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('muM', 'Gene', '56925', (30, 33))	('induced', 'PosReg', (44, 51))	('U104', 'Var', (21, 25))
114587	31442913	To study the association of ferroptosis, ferroptotic (Fer-1) and apoptotic (Z-VAD) inhibitors as well as an iron chelator (DFO) were co-treated with S4 or U104 in ACC-Meso-1 cells under hypoxia.	('DFO', 'Chemical', 'MESH:D003676', (123, 126))	('hypoxia', 'Disease', (186, 193))	('U104', 'Var', (155, 159))	('ferroptosis', 'biological_process', 'GO:0097707', ('28', '39'))	('iron', 'Chemical', 'MESH:D007501', (108, 112))	('U104', 'Chemical', 'MESH:C585353', (155, 159))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))
114589	31442913	Fer-1 (3 muM) was significantly effective against S4 and U104 treatment (P < 0.05 and P < 0.01, respectively).	('U104', 'Chemical', 'MESH:C585353', (57, 61))	('muM', 'Gene', '56925', (9, 12))	('U104', 'Var', (57, 61))	('muM', 'Gene', (9, 12))
114612	31442913	Interestingly, the alterations in expression of iron metabolism-associated genes were opposite in MM cells between hypoxia only and CA9 inhibition under hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('expression', 'MPA', (34, 44))	('inhibition', 'Var', (136, 146))	('iron', 'Chemical', 'MESH:D007501', (48, 52))	('rat', 'Species', '10116', (23, 26))	('metabolism', 'biological_process', 'GO:0008152', ('53', '63'))	('CA9', 'Gene', (132, 135))	('CA9', 'Gene', '768', (132, 135))	('iron metabolism-associated genes', 'Gene', (48, 80))	('hypoxia', 'Disease', (153, 160))	('hypoxia', 'Disease', (115, 122))	('hypoxia', 'Disease', 'MESH:D000860', (153, 160))
114617	31442913	However, in the case of CA9 inhibition with simultaneous hypoxia, MM cells responded to a situation of further increase in catalytic Fe(II) as if they lack iron, requiring more (seeking high iron intake and low storage with tight regulation).	('Fe(II)', 'Chemical', 'MESH:D007501', (133, 139))	('increase', 'PosReg', (111, 119))	('lack', 'NegReg', (151, 155))	('regulation', 'biological_process', 'GO:0065007', ('230', '240'))	('hypoxia', 'Disease', (57, 64))	('CA9', 'Gene', '768', (24, 27))	('CA9', 'Gene', (24, 27))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('inhibition', 'Var', (28, 38))	('iron', 'Chemical', 'MESH:D007501', (191, 195))	('iron', 'Chemical', 'MESH:D007501', (156, 160))	('iron', 'MPA', (156, 160))	('storage', 'biological_process', 'GO:0051235', ('211', '218'))
114623	31442913	Based on the results, we further analyzed the modes of MM cell death after CA9 inhibition under hypoxia, and found that this is a mixed cell death of apoptosis and ferroptosis through autophagic process.	('MM cell death', 'Disease', (55, 68))	('cell death', 'biological_process', 'GO:0008219', ('136', '146'))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('inhibition', 'Var', (79, 89))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('ferroptosis', 'biological_process', 'GO:0097707', ('164', '175'))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('CA9', 'Gene', '768', (75, 78))	('CA9', 'Gene', (75, 78))	('MM cell death', 'Disease', 'MESH:D003643', (55, 68))
114761	27223434	GSK3052230 demonstrated antiproliferative activity across a panel of mesothelioma cell lines and inhibited growth of tumor xenografts in mice.	('rat', 'Species', '10116', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('tumor', 'Disease', (117, 122))	('mesothelioma', 'Disease', (69, 81))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('GSK3052230', 'Var', (0, 10))	('inhibited', 'NegReg', (97, 106))	('rat', 'Species', '10116', (35, 38))	('antiproliferative activity', 'CPA', (24, 50))	('mice', 'Species', '10090', (137, 141))
114763	27223434	GSK3052230 inhibited MAPK signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo.	('phospho-S6 levels', 'MPA', (78, 95))	('ERK', 'Gene', '2048', (70, 73))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('ERK', 'Gene', (70, 73))	('MAPK signaling', 'biological_process', 'GO:0000165', ('21', '35'))	('decreased', 'NegReg', (52, 61))	('GSK3052230', 'Var', (0, 10))	('ERK', 'molecular_function', 'GO:0004707', ('70', '73'))	('inhibited', 'NegReg', (11, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('21', '25'))	('MAPK', 'MPA', (21, 25))
114765	27223434	These data support the role of GSK3052230 in effectively targeting FGF-FGFR autocrine signaling in mesothelioma, demonstrate its impact on tumor growth and angiogenesis, and provide a rationale for the current clinical evaluation of this molecule in mesothelioma patients.	('mesothelioma', 'Disease', 'MESH:D008654', (250, 262))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('rat', 'Species', '10116', (184, 187))	('tumor', 'Disease', (139, 144))	('FGF-FGFR', 'Gene', (67, 75))	('rat', 'Species', '10116', (120, 123))	('autocrine signaling', 'MPA', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('angiogenesis', 'biological_process', 'GO:0001525', ('156', '168'))	('impact', 'Reg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('GSK', 'molecular_function', 'GO:0050321', ('31', '34'))	('GSK3052230', 'Var', (31, 41))	('angiogenesis', 'CPA', (156, 168))	('patients', 'Species', '9606', (263, 271))	('mesothelioma', 'Disease', (250, 262))	('autocrine signaling', 'biological_process', 'GO:0035425', ('76', '95'))	('mesothelioma', 'Disease', (99, 111))
114768	27223434	A number of FGF/FGFR genomic alterations have been identified and are largely cancer specific, but the mechanisms by which they drive FGF signaling can be classified as ligand-independent (receptor gene amplifications, mutations, gene fusions) or ligand-dependent (ligand and/or receptor gene amplifications, overexpression, alternative splicing, autocrine and paracrine signaling).	('splicing', 'biological_process', 'GO:0045292', ('337', '345'))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('paracrine signaling', 'biological_process', 'GO:0038001', ('361', '380'))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('cancer', 'Disease', (78, 84))	('FGF signaling', 'MPA', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('alterations', 'Var', (29, 40))	('rat', 'Species', '10116', (33, 36))	('FGF/FGFR', 'Gene', (12, 20))	('ligand', 'molecular_function', 'GO:0005488', ('169', '175'))	('ligand', 'molecular_function', 'GO:0005488', ('247', '253'))	('ligand', 'molecular_function', 'GO:0005488', ('265', '271'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (219, 228))	('drive', 'Reg', (128, 133))
114770	27223434	GSK3052230 is a soluble fusion protein consisting of the extracellular domains of the human FGFR1 alpha-IIIc isoform linked to the modified hinge and native Fc regions of human immunoglobulin G1 (IgG1).	('FGFR1', 'Gene', (92, 97))	('soluble', 'cellular_component', 'GO:0005625', ('16', '23'))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('177', '191'))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('IgG1', 'cellular_component', 'GO:0071735', ('196', '200'))	('FGFR1', 'Gene', '2260', (92, 97))	('human', 'Species', '9606', (86, 91))	('GSK3052230', 'Var', (0, 10))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('human', 'Species', '9606', (171, 176))
114771	27223434	GSK3052230 acts as a fusion protein "trap" that sequesters FGFs, neutralizing their ability to bind to and activate FGFRs, particularly FGFR1.	('ability', 'MPA', (84, 91))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('FGFR1', 'Gene', (136, 141))	('FGFs', 'Protein', (59, 63))	('FGFR1', 'Gene', '2260', (136, 141))	('FGFRs', 'Protein', (116, 121))	('activate', 'PosReg', (107, 115))	('GSK3052230', 'Var', (0, 10))	('bind', 'Interaction', (95, 99))	('neutralizing', 'NegReg', (65, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
114773	27223434	Thus, the unique FGF binding profile of GSK3052230 should avoid the potential on-target toxicities associated with small molecule pan FGFR kinase inhibitors, such as hyperphosphatemia and retinal, nail, and skin changes [reviewed in ref.	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (166, 183))	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (166, 183))	('toxicities', 'Disease', 'MESH:D064420', (88, 98))	('GSK3052230', 'Var', (40, 50))	('toxicities', 'Disease', (88, 98))	('hyperphosphatemia', 'Disease', (166, 183))	('FGF binding', 'molecular_function', 'GO:0017134', ('17', '28'))	('nail', 'Disease', (197, 201))	('skin changes', 'Phenotype', 'HP:0000951', (207, 219))	('retinal', 'Disease', (188, 195))	('skin changes', 'Disease', (207, 219))
114774	27223434	GSK3052230 has been shown to inhibit tumor growth in several cell line-derived xenograft and patient-derived xenograft (PDX) tumor models, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer models, and response to GSK3052230 positively correlated with overexpression of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4 RNA levels.	('FGFR2', 'Gene', '2263', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('FGFR1', 'Gene', '2260', (149, 154))	('overexpression', 'PosReg', (276, 290))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('GSK', 'molecular_function', 'GO:0050321', ('238', '241'))	('ETV4', 'Gene', '2118', (327, 331))	('endometrial cancer', 'Phenotype', 'HP:0012114', (195, 213))	('FGF2', 'Gene', (294, 298))	('FGFR', 'molecular_function', 'GO:0005007', ('307', '311'))	('FGFR1', 'Gene', '2260', (307, 312))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('lung cancer', 'Disease', (165, 176))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('endometrial cancer', 'Disease', (195, 213))	('FGFR3c', 'MPA', (315, 321))	('FGFR1', 'Gene', (149, 154))	('endometrial cancer', 'Disease', 'MESH:D016889', (195, 213))	('GSK3052230', 'Var', (238, 248))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('inhibit', 'NegReg', (29, 36))	('FGF18', 'Gene', (300, 305))	('patient', 'Species', '9606', (93, 100))	('GSK3052230', 'Var', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('FGFR1', 'Gene', (307, 312))	('RNA', 'cellular_component', 'GO:0005562', ('332', '335'))	('FGFR2', 'Gene', (181, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('FGF18', 'Gene', '8817', (300, 305))	('FGFR', 'molecular_function', 'GO:0005007', ('315', '319'))	('FGFR', 'molecular_function', 'GO:0005007', ('181', '185'))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (37, 42))	('FGF2', 'Gene', '2247', (294, 298))	('ETV4', 'Gene', (327, 331))
114779	27223434	Here, we provide evidence using a targeted therapy approach in several preclinical models that mesothelioma cell lines and tumors are particularly sensitive to inhibition of FGF-FGFR autocrine signaling by GSK3052230.	('autocrine signaling', 'MPA', (183, 202))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('autocrine signaling', 'biological_process', 'GO:0035425', ('183', '202'))	('inhibition', 'NegReg', (160, 170))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('GSK3052230', 'Var', (206, 216))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('FGF-FGFR', 'Gene', (174, 182))	('GSK', 'molecular_function', 'GO:0050321', ('206', '209'))	('mesothelioma', 'Disease', (95, 107))
114782	27223434	We hypothesized that by trapping ligands of the FGF family, GSK3052230 will inhibit tumor cell proliferation and/or inhibit tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('inhibit', 'NegReg', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (124, 129))	('GSK3052230', 'Var', (60, 70))	('tumor', 'Disease', (84, 89))	('GSK', 'molecular_function', 'GO:0050321', ('60', '63'))	('angiogenesis', 'biological_process', 'GO:0001525', ('130', '142'))	('rat', 'Species', '10116', (102, 105))	('inhibit', 'NegReg', (116, 123))	('FGF', 'Gene', (48, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
114783	27223434	To test this, two FGF pathway inhibitors, GSK3052230 and NVP-BGJ398, a small molecule pan FGFR kinase inhibitor, were screened in an anchorage-independent methylcellulose (AIMC) assay for their effects on the growth of a panel of 23 mesothelioma and lung cancer cell lines spanning various histologies.	('NVP-BGJ398', 'Gene', (57, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('FGF pathway', 'Gene', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('methylcellulose', 'Chemical', 'MESH:D008747', (155, 170))	('mesothelioma', 'Disease', (233, 245))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('growth', 'MPA', (209, 215))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('95', '111'))	('BGJ398', 'Chemical', 'MESH:C568950', (61, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (233, 245))	('GSK3052230', 'Var', (42, 52))	('effects', 'Reg', (194, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))	('lung cancer', 'Disease', (250, 261))
114785	27223434	Three of the sensitive lung cancer cell lines, DMS 53, DMS 114, and NCI-H520, harbored FGFR1 amplification and were previously shown to respond to GSK3052230 treatment.	('amplification', 'Var', (93, 106))	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('FGFR1', 'Gene', (87, 92))	('FGFR1', 'Gene', '2260', (87, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('GSK', 'molecular_function', 'GO:0050321', ('147', '150'))
114788	27223434	Previous work demonstrated that FGFR1 genomic amplification and increased FGF2 mRNA levels correlated with response to GSK3052230 in tumor xenograft models.	('FGF2', 'Gene', (74, 78))	('mRNA levels', 'MPA', (79, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR1', 'Gene', (32, 37))	('genomic amplification', 'Var', (38, 59))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('FGFR1', 'Gene', '2260', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('rat', 'Species', '10116', (21, 24))	('FGF2', 'Gene', '2247', (74, 78))	('tumor', 'Disease', (133, 138))	('increased', 'PosReg', (64, 73))	('response', 'MPA', (107, 115))	('GSK', 'molecular_function', 'GO:0050321', ('119', '122'))
114795	27223434	Inhibition of FGF/FGFR downstream signaling by GSK3052230 was tested in NCI-H226 and MSTO-211H mesothelioma cells stimulated with either FGF2 or other growth factors known to activate receptor tyrosine kinases (RTKs).	('NCI-H226', 'CellLine', 'CVCL:1544', (72, 80))	('FGF2', 'Gene', (137, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('GSK3052230', 'Var', (47, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGF2', 'Gene', '2247', (137, 141))	('GSK', 'molecular_function', 'GO:0050321', ('47', '50'))	('mesothelioma', 'Disease', (95, 107))
114796	27223434	GSK3052230 effectively inhibited MAPK signaling, evidenced by a reduction of phospho-ERK and phospho-S6 levels in FGF2-stimulated cells (Figure 2A).	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('inhibited', 'NegReg', (23, 32))	('MAPK signaling', 'MPA', (33, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('FGF2', 'Gene', '2247', (114, 118))	('ERK', 'Gene', (85, 88))	('ERK', 'Gene', '2048', (85, 88))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('reduction', 'NegReg', (64, 73))	('MAPK signaling', 'biological_process', 'GO:0000165', ('33', '47'))	('GSK3052230', 'Var', (0, 10))	('phospho-S6 levels', 'MPA', (93, 110))	('FGF2', 'Gene', (114, 118))
114798	27223434	Interestingly, while treatment with GSK3052230 caused a slight reduction in phosphorylation of EGFR and MET upon acute growth factor stimulation, no changes to downstream signaling occurred.	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('GSK3052230', 'Var', (36, 46))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('GSK', 'molecular_function', 'GO:0050321', ('36', '39'))	('phosphorylation', 'MPA', (76, 91))	('reduction', 'NegReg', (63, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', '1956', (95, 99))	('MET', 'MPA', (104, 107))	('EGFR', 'Gene', (95, 99))
114800	27223434	When GSK3052230 was compared with NVP-BGJ398, both molecules effectively inhibited phospho-ERK and phospho-S6 levels under serum-starved and FGF2-stimulated conditions (Figure 2B and 2C).	('FGF2', 'Gene', '2247', (141, 145))	('ERK', 'Gene', '2048', (91, 94))	('GSK3052230', 'Var', (5, 15))	('ERK', 'Gene', (91, 94))	('FGF2', 'Gene', (141, 145))	('inhibited', 'NegReg', (73, 82))	('GSK', 'molecular_function', 'GO:0050321', ('5', '8'))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))	('BGJ398', 'Chemical', 'MESH:C568950', (38, 44))
114801	27223434	Similar results were observed in lung cancer cells that harbor FGFR1 amplification (Supplementary Figure 4).	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('amplification', 'Var', (69, 82))	('lung cancer', 'Disease', (33, 44))
114803	27223434	At all time points tested, phospho-ERK levels were reduced by both GSK3052230 and NVP-BGJ398 when compared to DMSO-treated cells (Figure 2D).	('ERK', 'molecular_function', 'GO:0004707', ('35', '38'))	('GSK3052230', 'Var', (67, 77))	('reduced', 'NegReg', (51, 58))	('BGJ398', 'Chemical', 'MESH:C568950', (86, 92))	('GSK', 'molecular_function', 'GO:0050321', ('67', '70'))	('DMSO', 'Chemical', 'MESH:D004121', (110, 114))	('ERK', 'Gene', '2048', (35, 38))	('ERK', 'Gene', (35, 38))
114804	27223434	To assess the effects of GSK3052230 on tumor growth, female SCID mice bearing subcutaneous NCI-H226 and MSTO-211H tumor xenografts were treated with vehicle or GSK3052230 at 1.024, 5.12, or 25.6 mg/kg three times per week for 4 weeks.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('SCID', 'Disease', 'MESH:D053632', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SCID', 'Disease', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mice', 'Species', '10090', (65, 69))	('GSK3052230', 'Var', (160, 170))	('GSK', 'molecular_function', 'GO:0050321', ('160', '163'))	('NCI-H226', 'CellLine', 'CVCL:1544', (91, 99))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('GSK', 'molecular_function', 'GO:0050321', ('25', '28'))	('tumor', 'Disease', (39, 44))
114805	27223434	GSK3052230 was well tolerated in both tumor models as assessed by body weight changes (Supplementary Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('GSK3052230', 'Var', (0, 10))	('rat', 'Species', '10116', (24, 27))
114806	27223434	GSK3052230 administered at both 5.12 and 25.6 mg/kg caused significant tumor growth inhibition (TGI), 57% and 78%, respectively, compared to the vehicle control group in NCI-H226 tumor xenografts (Figure 3A).	('NCI-H226 tumor', 'Disease', (170, 184))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('NCI-H226 tumor', 'Disease', 'MESH:D009369', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GSK3052230', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (179, 184))
114807	27223434	In MSTO-211H xenografts, GSK3052230 administered at 5.12 mg/kg did not significantly inhibit tumor growth (20% TGI), but the highest dose of GSK3052230 caused 50% TGI compared to the vehicle control group (Figure 3B).	('GSK', 'molecular_function', 'GO:0050321', ('141', '144'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('GSK', 'molecular_function', 'GO:0050321', ('25', '28'))	('TGI', 'Disease', (163, 166))	('GSK3052230', 'Var', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
114808	27223434	These results are consistent with the observed effects of this molecule in vitro, where NCI-H226 cells were more sensitive to GSK3052230 than MSTO-211H cells.	('sensitive', 'MPA', (113, 122))	('GSK', 'molecular_function', 'GO:0050321', ('126', '129'))	('GSK3052230', 'Var', (126, 136))	('NCI-H226', 'CellLine', 'CVCL:1544', (88, 96))
114810	27223434	DUSP6, ETV1, and ETV4 mRNA levels were modestly reduced after GSK3052230 treatment, but none of the effects were statistically significant (Supplemental Figure 6B).	('ETV4', 'Gene', (17, 21))	('DUSP6', 'Gene', '1848', (0, 5))	('GSK3052230 treatment', 'Var', (62, 82))	('GSK', 'molecular_function', 'GO:0050321', ('62', '65'))	('reduced', 'NegReg', (48, 55))	('ETV4', 'Gene', '2118', (17, 21))	('ETV1', 'Gene', (7, 11))	('ETV1', 'Gene', '2115', (7, 11))	('DUSP6', 'Gene', (0, 5))
114812	27223434	Phospho-ERK levels were reduced by ~50% with GSK3052230 (25.6 mg/kg) treatment at day 3 but rebounded back to levels observed in vehicle-treated tumors after 14 days despite detectable levels of GSK3052230 in the tumors (Figure 3D; Supplementary Figure 6C).	('ERK', 'molecular_function', 'GO:0004707', ('8', '11'))	('GSK', 'molecular_function', 'GO:0050321', ('195', '198'))	('ERK', 'Gene', (8, 11))	('tumors', 'Disease', (213, 219))	('reduced', 'NegReg', (24, 31))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('ERK', 'Gene', '2048', (8, 11))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('GSK', 'molecular_function', 'GO:0050321', ('45', '48'))	('tumors', 'Disease', (145, 151))	('GSK3052230', 'Var', (195, 205))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('GSK3052230', 'Var', (45, 55))
114813	27223434	To explore the effects of GSK3052230 on angiogenesis and more specifically, tumor vessel formation, NCI-H226 tumors were tested by immunohistochemistry (IHC) for expression of the mouse endothelial cell protein, MECA-32, upon GSK3052230 treatment (Figure 4A).	('GSK', 'molecular_function', 'GO:0050321', ('26', '29'))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))	('tumor', 'Disease', (109, 114))	('angiogenesis', 'biological_process', 'GO:0001525', ('40', '52'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('GSK', 'molecular_function', 'GO:0050321', ('226', '229'))	('mouse', 'Species', '10090', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GSK3052230', 'Var', (226, 236))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
114816	27223434	While no differences were found between groups for the inner region, blood vessel density was significantly lower in the GSK3052230-treated group compared to the vehicle group for both the outer region and the whole tumor mass (Figure 4B).	('tumor', 'Disease', (216, 221))	('GSK3052230-treated', 'Var', (121, 139))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('lower', 'NegReg', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('blood vessel density', 'CPA', (69, 89))	('GSK', 'molecular_function', 'GO:0050321', ('121', '124'))
114817	27223434	To get an understanding of how GSK3052230 treatment affects tumor blood flow and perfusion, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed.	('DCE', 'Chemical', 'MESH:C024565', (146, 149))	('perfusion', 'MPA', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('GSK', 'molecular_function', 'GO:0050321', ('31', '34'))	('tumor', 'Disease', (60, 65))	('affects', 'Reg', (52, 59))	('GSK3052230', 'Var', (31, 41))
114821	27223434	The ability of GSK3052230 to inhibit tumor vessel formation yet have no effect on blood flow and perfusion highlight the complexity and unique role of FGF biology in tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('GSK', 'molecular_function', 'GO:0050321', ('15', '18'))	('inhibit', 'NegReg', (29, 36))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('angiogenesis', 'biological_process', 'GO:0001525', ('172', '184'))	('GSK3052230', 'Var', (15, 25))
114823	27223434	NCI-H1703 is a squamous non-small cell lung cancer (NSCLC) cell line that harbors both FGFR1 and PDGFRA amplifications.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (24, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('PDGFRA', 'Gene', (97, 103))	('amplifications', 'Var', (104, 118))	('FGFR1', 'Gene', (87, 92))	('squamous non-small cell lung cancer', 'Disease', (15, 50))	('FGFR1', 'Gene', '2260', (87, 92))	('PDGFRA', 'Gene', '5156', (97, 103))	('NCI-H1703', 'CellLine', 'CVCL:1490', (0, 9))	('squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (15, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (28, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
114827	27223434	This study also demonstrated that GSK3052230 is effective in inhibiting tumor growth of FGF2/FGFR1-overexpressing mesothelioma xenografts.	('FGF2', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibiting', 'NegReg', (61, 71))	('tumor', 'Disease', (72, 77))	('rat', 'Species', '10116', (23, 26))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('GSK3052230', 'Var', (34, 44))	('mesothelioma', 'Disease', (114, 126))	('FGF2', 'Gene', '2247', (88, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('FGFR1', 'Gene', (93, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('FGFR1', 'Gene', '2260', (93, 98))
114828	27223434	These effects on tumor growth are at least in part due to the ability of GSK3052230 to inhibit MAPK signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('decreased', 'NegReg', (126, 135))	('tumor', 'Disease', (17, 22))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('MAPK', 'MPA', (95, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('95', '109'))	('ERK', 'Gene', '2048', (144, 147))	('GSK', 'molecular_function', 'GO:0050321', ('73', '76'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('GSK3052230', 'Var', (73, 83))	('ERK', 'Gene', (144, 147))	('inhibit', 'NegReg', (87, 94))
114830	27223434	After three days of treatment at the highest dose of GSK3052230, a 50% decrease in phospho-ERK protein levels was observed.	('GSK3052230', 'Var', (53, 63))	('decrease', 'NegReg', (71, 79))	('ERK', 'Gene', '2048', (91, 94))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('ERK', 'Gene', (91, 94))	('GSK', 'molecular_function', 'GO:0050321', ('53', '56'))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))
114832	27223434	An additional caveat to consider is the possibility that other FGFs that are not inhibited or weakly inhibited by GSK3052230 could be secreted by the tumor or by cells in the tumor microenvironment and contribute to FGFR downstream signaling.	('tumor', 'Disease', (175, 180))	('GSK3052230', 'Var', (114, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('contribute', 'Reg', (202, 212))	('GSK', 'molecular_function', 'GO:0050321', ('114', '117'))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (150, 155))
114837	27223434	The data presented here supports the current clinical evaluation of GSK3052230 in previously untreated mesothelioma patients (NCT01868022).	('GSK', 'molecular_function', 'GO:0050321', ('68', '71'))	('patients', 'Species', '9606', (116, 124))	('mesothelioma', 'Disease', (103, 115))	('GSK3052230', 'Var', (68, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))
114841	27223434	This would allow for broader testing of GSK3052230 across previously untested tumor types where FGF-FGFR autocrine signaling occurs and potentially provide additional benefit to patients with unmet clinical needs.	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (178, 186))	('GSK3052230', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('autocrine signaling', 'biological_process', 'GO:0035425', ('105', '124'))	('tumor', 'Disease', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))
114853	27223434	Once tumors reached ~150-300 mm3, mice were randomized (n = 8/group for NCI-H226 study; n = 10/group for MSTO-211H study) and treated with vehicle (0.9% saline) or GSK3052230 at 1.024, 5.12 or 25.6 mg/kg by intraperitoneal (bolus) injection three times per week for 4 weeks.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('NCI-H226', 'CellLine', 'CVCL:1544', (72, 80))	('mice', 'Species', '10090', (34, 38))	('GSK', 'molecular_function', 'GO:0050321', ('164', '167'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('GSK3052230', 'Var', (164, 174))	('saline', 'Chemical', 'MESH:D012965', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
114858	27223434	Membranes were blocked for one hour using Licor Odyssey Blocking Buffer (Lincoln, NE) before immunoblotting using the following antibodies (all from Cell Signaling Technology, Danvers, MA, USA): pEGFR (#3777), total EGFR (#2239), pMet (#3077), total Met (#3127), pAKT (#4060), total AKT (#9272), pERK (#9101), total ERK (#4695), pS6 (#2211), and total S6 (#2317).	('#2211', 'Var', (334, 339))	('ERK', 'Gene', (297, 300))	('EGFR', 'molecular_function', 'GO:0005006', ('216', '220'))	('EGFR', 'Gene', '1956', (196, 200))	('AKT', 'Gene', '207', (264, 267))	('#3077', 'Var', (236, 241))	('EGFR', 'Gene', (216, 220))	('ERK', 'Gene', '2048', (297, 300))	('#2317', 'Var', (356, 361))	('pERK', 'Gene', '9451', (296, 300))	('pERK', 'Gene', (296, 300))	('pS6', 'Gene', (329, 332))	('AKT', 'Gene', (283, 286))	('#4060', 'Var', (269, 274))	('EGFR', 'Gene', '1956', (216, 220))	('Signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('ERK', 'Gene', (316, 319))	('ERK', 'molecular_function', 'GO:0004707', ('316', '319'))	('EGFR', 'Gene', (196, 200))	('pS6', 'Gene', '338413', (329, 332))	('AKT', 'Gene', (264, 267))	('AKT', 'Gene', '207', (283, 286))	('#9101', 'Var', (302, 307))	('#9272', 'Var', (288, 293))	('#4695', 'Var', (321, 326))	('ERK', 'Gene', '2048', (316, 319))
114862	27223434	The following primer/probe sets (all from Thermo Fisher) were used: DUSP6 (Hs04329643_s1), ETV1 (Hs0095195_m1), ETV4 (Hs00385910_m1), ETV5 (Hs00927557_m1), and beta-actin (Hs99999903).	('Hs00385910_m1', 'Var', (118, 131))	('ETV4', 'Gene', (112, 116))	('ETV1', 'Gene', (91, 95))	('ETV1', 'Gene', '2115', (91, 95))	('beta-actin', 'Gene', '728378', (160, 170))	('Hs0095195_m1', 'Var', (97, 109))	('ETV4', 'Gene', '2118', (112, 116))	('beta-actin', 'Gene', (160, 170))	('Hs00927557_m1', 'Var', (140, 153))	('Hs04329643_s1', 'Var', (75, 88))	('ETV5', 'Gene', '2119', (134, 138))	('DUSP6', 'Gene', '1848', (68, 73))	('ETV5', 'Gene', (134, 138))	('DUSP6', 'Gene', (68, 73))	('Hs99999903', 'Var', (172, 182))
114893	27312399	In addition, asbestos may cause non-neoplastic diseases, including asbestosis and pleural effusions and plaques.	('cause', 'Reg', (26, 31))	('asbestosis and pleural effusions', 'Disease', 'MESH:D010996', (67, 99))	('non-neoplastic diseases', 'Disease', 'MESH:D000073296', (32, 55))	('pleural effusions', 'Phenotype', 'HP:0002202', (82, 99))	('non-neoplastic diseases', 'Disease', (32, 55))	('plaques', 'Disease', (104, 111))	('asbestos', 'Chemical', 'MESH:D001194', (67, 75))	('asbestos', 'Var', (13, 21))	('asbestos', 'Chemical', 'MESH:D001194', (13, 21))
115021	23324131	The combination of cisplatin and pemetrexed has shown to improve the objective response rate and to prolong median overall survival of patients with MPM versus cisplatin alone (41% vs 16.7%, 12.1 vs 9.3 months) within the context of a prospective, randomized, phase III clinical trial  .	('prolong', 'PosReg', (100, 107))	('patients', 'Species', '9606', (135, 143))	('improve', 'PosReg', (57, 64))	('overall survival', 'MPA', (115, 131))	('objective response', 'CPA', (69, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('MPM', 'Var', (149, 152))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('pemetrexed', 'Chemical', 'MESH:D000068437', (33, 43))
115161	21964533	The anti-angiogenic AZD2171 has modest single agent activity in MPM.	('AZD2171', 'Chemical', 'MESH:C500926', (20, 27))	('MPM', 'Disease', (64, 67))	('AZD2171', 'Var', (20, 27))	('MPM', 'Chemical', '-', (64, 67))
115162	21964533	However, several patient tumors were exquisitely sensitive to AZD2171.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('AZD2171', 'Chemical', 'MESH:C500926', (62, 69))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('patient', 'Species', '9606', (17, 24))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('AZD2171', 'Var', (62, 69))
115164	21964533	This study provides a rationale for further testing of AZD2171 with chemotherapy in MPM.	('AZD2171', 'Var', (55, 62))	('MPM', 'Chemical', '-', (84, 87))	('AZD2171', 'Chemical', 'MESH:C500926', (55, 62))	('MPM', 'Disease', (84, 87))
115179	21964533	AZD2171 (Cediranib; AstraZeneca Pharmaceuticals,Wilmington, DE) is an orally active, potent, tyrosine kinase inhibitor (TKI) of VEGFR-1,-2 and -3 at nanomolar concentrations, as well as c-Kit and PDGFR-beta.	('AZD2171', 'Chemical', 'MESH:C500926', (0, 7))	('c-Kit', 'Gene', '3815', (186, 191))	('VEGFR-1,-2 and -3', 'Gene', '2321;3791;2324', (128, 145))	('PDGFR-beta', 'Gene', '5159', (196, 206))	('PDGFR-beta', 'Gene', (196, 206))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('102', '118'))	('Cediranib', 'Chemical', 'MESH:C500926', (9, 18))	('c-Kit', 'Gene', (186, 191))	('AZD2171', 'Var', (0, 7))
115181	21964533	AZD2171 has single agent anti-tumor activity (partial responses and disease stabilization) in a number of solid tumors including ovarian cancer, alveolar soft tissue sarcoma, gastric cancer, biliary cancer, pancreatic cancer, CRC, prostate, RCC, breast cancer, thyroid cancer and NSCLC.	('biliary cancer', 'Disease', 'MESH:D001661', (191, 205))	('prostate', 'Disease', (231, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('thyroid cancer', 'Disease', 'MESH:D013964', (261, 275))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (175, 189))	('CRC', 'Disease', (226, 229))	('RCC', 'Disease', (241, 244))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (207, 224))	('thyroid cancer', 'Phenotype', 'HP:0002890', (261, 275))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('alveolar soft tissue sarcoma', 'Phenotype', 'HP:0012218', (145, 173))	('alveolar soft tissue sarcoma', 'Disease', 'MESH:D012509', (145, 173))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('alveolar soft tissue sarcoma', 'Disease', (145, 173))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('AZD2171', 'Var', (0, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('solid tumors', 'Disease', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ovarian cancer', 'Disease', (129, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (207, 224))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('AZD2171', 'Chemical', 'MESH:C500926', (0, 7))	('thyroid cancer', 'Disease', (261, 275))	('pancreatic cancer', 'Disease', (207, 224))	('gastric cancer', 'Disease', (175, 189))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('NSCLC', 'Disease', (280, 285))	('tumor', 'Disease', (30, 35))	('biliary cancer', 'Disease', (191, 205))
115231	21964533	In the second line setting, AZD2171 showed modest clinical activity as a single agent, with 9% of patients having had objective tumor responses, including 2 with marked shrinkage of bulky tumors.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('AZD2171', 'Var', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('AZD2171', 'Chemical', 'MESH:C500926', (28, 35))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
115239	21964533	PDGF-mediated signaling by AZD2171 may have played a role in the anti-tumor activity noted in the current study.	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('AZD2171', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('AZD2171', 'Chemical', 'MESH:C500926', (27, 34))	('tumor', 'Disease', (70, 75))	('PDGF', 'molecular_function', 'GO:0005161', ('0', '4'))	('PDGF-mediated signaling', 'MPA', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
115247	21964533	The safety profile of AZD2171 as a second line agent in MPM was similar to that already reported for this and other VEGF receptor tyrosine kinase inhibitors.	('VEGF', 'Gene', '7422', (116, 120))	('MPM', 'Disease', (56, 59))	('MPM', 'Chemical', '-', (56, 59))	('AZD2171', 'Var', (22, 29))	('VEGF', 'Gene', (116, 120))	('AZD2171', 'Chemical', 'MESH:C500926', (22, 29))
115255	21964533	Both VEGF and PDGF contribute to increased TIFP, while inhibitors of VEGF and/or PDGF signaling can reduce TIFP and augment chemotherapy effects in vivo.	('VEGF', 'Gene', (69, 73))	('TIFP', 'MPA', (43, 47))	('augment', 'NegReg', (116, 123))	('VEGF', 'Gene', (5, 9))	('VEGF', 'Gene', '7422', (69, 73))	('PDGF', 'molecular_function', 'GO:0005161', ('14', '18'))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('chemotherapy effects', 'CPA', (124, 144))	('increased', 'PosReg', (33, 42))	('PDGF', 'molecular_function', 'GO:0005161', ('81', '85'))	('TIFP', 'MPA', (107, 111))	('inhibitors', 'Var', (55, 65))	('reduce', 'NegReg', (100, 106))	('VEGF', 'Gene', '7422', (5, 9))
115257	21964533	The addition of AZD2171 to cytotoxic chemotherapy in solid tumors is feasible as shown in a number of phase I studies, and an augmentation of the effect of chemotherapy by AZD2171 was reported in a randomized phase II study in NSCLC, where the addition of AZD2171 45 mg daily to Taxol plus Carboplatin resulted in improved tumor responses and PFS for AZD2171 compared with placebo with chemotherapy.	('AZD2171', 'Chemical', 'MESH:C500926', (172, 179))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('solid tumors', 'Disease', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('PFS', 'CPA', (343, 346))	('AZD2171', 'Var', (351, 358))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('AZD2171', 'Chemical', 'MESH:C500926', (256, 263))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NSCLC', 'Disease', (227, 232))	('solid tumors', 'Disease', 'MESH:D009369', (53, 65))	('AZD2171', 'Chemical', 'MESH:C500926', (351, 358))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('AZD2171', 'Chemical', 'MESH:C500926', (16, 23))	('Taxol', 'Chemical', 'MESH:D017239', (279, 284))	('tumor', 'Disease', (323, 328))	('improved', 'PosReg', (314, 322))	('Carboplatin', 'Chemical', 'MESH:D016190', (290, 301))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
115262	21964533	Given the signal of activity of single agent AZD2171 in second line MPM reported here, and the potential of anti-angiogenics to augment the activity of cytotoxic chemotherapy, the Southwest Oncology Group has initiated a Phase I/randomized Phase II clinical trial of pemetrexed plus cisplatin with or without AZD2171 for first-line treatment of MPM.	('AZD2171', 'Chemical', 'MESH:C500926', (45, 52))	('Oncology', 'Phenotype', 'HP:0002664', (190, 198))	('AZD2171', 'Var', (45, 52))	('AZD2171', 'Chemical', 'MESH:C500926', (309, 316))	('MPM', 'Chemical', '-', (345, 348))	('cisplatin', 'Chemical', 'MESH:D002945', (283, 292))	('MPM', 'Chemical', '-', (68, 71))	('pemetrexed', 'Chemical', 'MESH:D000068437', (267, 277))	('MPM', 'Disease', (345, 348))
115269	9460997	Amplification of KRAS2 was detected in two adenocarcinomas by Southern blot analysis.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('adenocarcinomas', 'Disease', (43, 58))	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('KRAS2', 'Gene', (17, 22))	('KRAS2', 'Gene', '3845', (17, 22))	('adenocarcinomas', 'Disease', 'MESH:D000230', (43, 58))
115281	30856277	Both NK cells and ILC3 expressed functional PD-1, moreover, both tumor samples and malignant PE-derived tumor cell lines were PD-L1+ suggesting that the interaction between PD-1+ILC and PD-L1+tumor cells may hamper antitumor immune responses mediated by NK and ILC.	('PD-L1+tumor', 'Disease', (186, 197))	('malignant PE', 'Disease', 'MESH:D016066', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PE', 'Phenotype', 'HP:0002202', (93, 95))	('tumor', 'Disease', (219, 224))	('hamper', 'NegReg', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('PD-L1+tumor', 'Disease', 'MESH:C536029', (186, 197))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (104, 109))	('interaction', 'Interaction', (153, 164))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('malignant PE', 'Disease', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PD-1+ILC', 'Var', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
115308	30856277	In order to evaluate the functional activity of PD-1, lymphocytes derived from PE were incubated with P815 cell line (a FcgammaR+ mastocytoma murine cell line) in the presence of anti-NKp46 (BAB281 clone, IgG1), anti-NKp30 (AZ20 clone, IgG1) and anti-NKp44 (Z231 clone, IgG1) mAbs in combination or not with anti-PD-1 mAb (PD1.3.1.3 clone, IgG2b).	('IgG1', 'Gene', '16017', (270, 274))	('mastocytoma', 'Disease', (130, 141))	('NKp30', 'Gene', (217, 222))	('IgG2b', 'Gene', (340, 345))	('IgG1', 'cellular_component', 'GO:0071735', ('205', '209'))	('IgG1', 'cellular_component', 'GO:0071735', ('236', '240'))	('IgG1', 'cellular_component', 'GO:0071735', ('270', '274'))	('IgG1', 'Gene', '16017', (205, 209))	('IgG2b', 'Gene', '16016', (340, 345))	('murine', 'Species', '10090', (142, 148))	('PD1', 'Gene', (323, 326))	('IgG1', 'Gene', (270, 274))	('PE', 'Disease', 'MESH:D010996', (79, 81))	('NKp30', 'Gene', '259197', (217, 222))	('IgG1', 'Gene', '16017', (236, 240))	('IgG1', 'Gene', (205, 209))	('NKp44', 'Gene', (251, 256))	('PE', 'Phenotype', 'HP:0002202', (79, 81))	('anti-NKp46', 'Var', (179, 189))	('NKp44', 'Gene', '9436', (251, 256))	('PD1', 'Gene', '5133', (323, 326))	('IgG1', 'Gene', (236, 240))	('mastocytoma', 'Disease', 'MESH:D034801', (130, 141))	('IgG2b', 'cellular_component', 'GO:0071735', ('340', '345'))
115347	30856277	As shown in Figure 5 d, mAb-mediated cross-linking of the activating natural cytotoxic receptors (NCRs) including NKp46, NKp44 and NKp30, induced cytokine production by both NK cells and NCR+ILC3.	('NKp30', 'Gene', '259197', (131, 136))	('cross-linking', 'Var', (37, 50))	('NKp44', 'Gene', '9436', (121, 126))	('NCR', 'Gene', '4827', (187, 190))	('NCR', 'Gene', (187, 190))	('NKp44', 'Gene', (121, 126))	('NKp30', 'Gene', (131, 136))	('cytokine production', 'MPA', (146, 165))	('NKp46', 'Var', (114, 119))	('NCR', 'Gene', '4827', (98, 101))	('induced', 'Reg', (138, 145))	('NCR', 'Gene', (98, 101))	('cytokine production', 'biological_process', 'GO:0001816', ('146', '165'))
115351	30856277	These data support the notion that induction of the PD-1 pathway may affect the anti-tumor activity of mPE-NK cells and -ILC3, thus favoring mechanisms of immune escape.	('tumor', 'Disease', (85, 90))	('affect', 'Reg', (69, 75))	('favoring', 'PosReg', (132, 140))	('induction', 'Var', (35, 44))	('PD-1', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mPE', 'Disease', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mPE', 'Disease', 'MESH:D016066', (103, 106))	('PE', 'Phenotype', 'HP:0002202', (104, 106))
115393	30370397	There are multiple mesothelin-targeted agents in clinical development, including chimeric antibody, antibody-drug conjugate, chimeric antigen receptor T-cell therapy, and mesothelin-based vaccine.	('antibody', 'molecular_function', 'GO:0003823', ('90', '98'))	('chimeric', 'Var', (125, 133))	('antibody', 'molecular_function', 'GO:0003823', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019814', ('90', '98'))	('mesothelin', 'Gene', (171, 181))	('antibody', 'cellular_component', 'GO:0042571', ('90', '98'))	('mesothelin', 'Gene', (19, 29))	('antibody', 'cellular_component', 'GO:0019814', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019815', ('90', '98'))	('antibody', 'cellular_component', 'GO:0042571', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019815', ('100', '108'))	('mesothelin', 'Gene', '10232', (19, 29))	('mesothelin', 'Gene', '10232', (171, 181))
115409	30370397	The second trial was a pilot phase II study of SS1P with the addition of a pentostatin and cyclophosphamide immune depletion regimen to decrease antibody response to SS1P in patients with refractory MM (NCT01362790).	('antibody', 'cellular_component', 'GO:0019815', ('145', '153'))	('antibody response', 'MPA', (145, 162))	('antibody', 'cellular_component', 'GO:0019814', ('145', '153'))	('decrease', 'NegReg', (136, 144))	('antibody', 'molecular_function', 'GO:0003823', ('145', '153'))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (91, 107))	('patients', 'Species', '9606', (174, 182))	('antibody', 'cellular_component', 'GO:0042571', ('145', '153'))	('pentostatin', 'Chemical', 'MESH:D015649', (75, 86))	('NCT01362790', 'Var', (203, 214))
115445	30370397	In the second trial of 10 patients with refractory MM with immunotoxin SS1P and an immune depletion regimen of pentostatin and cyclophosphamide, major cancer regressions were observed and were attributed primarily to the activities of SS1P.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pentostatin', 'Chemical', 'MESH:D015649', (111, 122))	('SS1P', 'Var', (71, 75))	('patients', 'Species', '9606', (26, 34))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (127, 143))	('cancer', 'Disease', (151, 157))	('regressions', 'NegReg', (158, 169))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
115545	28358042	The panel includes: DPAS (special stain for mucins), CKMNF116, WT-1, CK5/6, and Calretinin.	('mucin', 'Gene', (44, 49))	('CK5/6', 'Gene', (69, 74))	('Calretinin', 'Gene', (80, 90))	('Calretinin', 'Gene', '794', (80, 90))	('CK5/6', 'Gene', '3852', (69, 74))	('CKMNF116', 'Var', (53, 61))	('mucin', 'Gene', '100508689', (44, 49))
115568	28358042	In case La0086, the clinical diagnosis on an adjacent section was epithelioid DMM, but in contrast FTIR imaging classified it as biphasic, with a majority of sarcomatoid cells.	('sarcomatoid', 'Disease', 'MESH:C538614', (158, 169))	('epithelioid DMM', 'Disease', (66, 81))	('La0086', 'Var', (8, 14))	('sarcomatoid', 'Disease', (158, 169))	('DMM', 'Chemical', '-', (78, 81))
115687	24297392	Next, we assessed the contribution of enhanced Bid activation to synergistic effect of SBL and TRAIL by the knock-down of Bid.	('TRAIL', 'Gene', (95, 100))	('Bid', 'Gene', (47, 50))	('Bid', 'Gene', '637', (47, 50))	('Bid', 'Gene', (122, 125))	('knock-down', 'Var', (108, 118))	('Bid', 'Gene', '637', (122, 125))	('TRAIL', 'Gene', '8743', (95, 100))	('SBL', 'Chemical', '-', (87, 90))
115706	24297392	In one pathway the activated caspase-8 directly activates effector caspases such as caspase-3, in another pathway activated caspase-8 evokes mitochondrial perturbation through cleavage of Bid, and signal of apoptosis is amplified between caspase activation, mitochondria perturbation and Bid truncation.	('caspase', 'Gene', (67, 74))	('caspase', 'Gene', (84, 91))	('caspase', 'Gene', (29, 36))	('caspase-8', 'Gene', (124, 133))	('caspase', 'Gene', '841;842', (124, 131))	('caspase', 'Gene', '841;842', (67, 74))	('caspase', 'Gene', '841;842', (84, 91))	('caspase', 'Gene', '841;842', (29, 36))	('truncation', 'Var', (292, 302))	('mitochondria', 'cellular_component', 'GO:0005739', ('258', '270'))	('Bid', 'Gene', (288, 291))	('Bid', 'Gene', '637', (188, 191))	('cleavage', 'MPA', (176, 184))	('caspase-3', 'Gene', '836', (84, 93))	('caspase-8', 'Gene', '841', (29, 38))	('caspases', 'Gene', (67, 75))	('caspase', 'Gene', (238, 245))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('caspase-3', 'Gene', (84, 93))	('evokes', 'Reg', (134, 140))	('caspase-8', 'Gene', '841', (124, 133))	('caspases', 'Gene', '841;842', (67, 75))	('caspase', 'Gene', '841;842', (238, 245))	('caspase activation', 'biological_process', 'GO:0006919', ('238', '256'))	('Bid', 'Gene', '637', (288, 291))	('Bid', 'Gene', (188, 191))	('caspase-8', 'Gene', (29, 38))	('mitochondrial perturbation', 'MPA', (141, 167))	('caspase', 'Gene', (124, 131))	('activates', 'PosReg', (48, 57))
115708	24297392	Etoposide was reported to sensitize malignant mesothelioma M28 cells to TRAIL-induced apoptosis, and this synergic effect requires amplification of death signals by cleavege of Bid, suggesting that M28 cells belong to type II cells.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (36, 58))	('Bid', 'Gene', (177, 180))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (36, 58))	('TRAIL', 'Gene', '8743', (72, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('malignant mesothelioma', 'Disease', (36, 58))	('cleavege', 'Var', (165, 173))	('sensitize', 'Reg', (26, 35))	('TRAIL', 'Gene', (72, 77))	('Bid', 'Gene', '637', (177, 180))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
115711	24297392	Our results also suggested that H28 cells belong to type II cells, because the cleavage of Bid enhances the apoptotic signals.	('Bid', 'Gene', (91, 94))	('Bid', 'Gene', '637', (91, 94))	('enhances', 'PosReg', (95, 103))	('cleavage', 'Var', (79, 87))	('apoptotic signals', 'CPA', (108, 125))
115712	24297392	Interestingly, Abayasiriwardana et al reported that anisomycin, a translation inhibitor, lowers threshold for mitochondrial perturbation through Bim, and suggested that the contribution of JNK for the stability of Bim.	('anisomycin', 'Chemical', 'MESH:D000841', (52, 62))	('JNK', 'Gene', '5599', (189, 192))	('lowers', 'NegReg', (89, 95))	('Bim', 'Gene', '10018', (214, 217))	('translation', 'biological_process', 'GO:0006412', ('66', '77'))	('anisomycin', 'Var', (52, 62))	('Bim', 'Gene', (145, 148))	('Bim', 'Gene', '10018', (145, 148))	('JNK', 'Gene', (189, 192))	('threshold for mitochondrial perturbation', 'MPA', (96, 136))	('JNK', 'molecular_function', 'GO:0004705', ('189', '192'))	('Bim', 'Gene', (214, 217))
115721	24297392	Eventually, apoptotic signal is amplified by amplification loop consisted of caspase activation and mitochondria perturbation and truncation of Bid.	('caspase', 'Gene', (77, 84))	('mitochondria', 'cellular_component', 'GO:0005739', ('100', '112'))	('mitochondria perturbation', 'MPA', (100, 125))	('caspase activation', 'biological_process', 'GO:0006919', ('77', '95'))	('apoptotic signal', 'CPA', (12, 28))	('activation', 'PosReg', (85, 95))	('truncation', 'Var', (130, 140))	('Bid', 'Gene', (144, 147))	('caspase', 'Gene', '841;842', (77, 84))	('amplified', 'PosReg', (32, 41))	('Bid', 'Gene', '637', (144, 147))	('amplification', 'Var', (45, 58))
115731	30417500	In addition, the disruption of FGFR2 in the NF2-KO cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK, c-Jun, and Rb.	('NF2', 'Gene', '4771', (44, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('JNK', 'molecular_function', 'GO:0004705', ('133', '136'))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('suppressed', 'NegReg', (62, 72))	('cell proliferation', 'CPA', (73, 91))	('disruption', 'Var', (17, 27))	('NF2', 'Gene', (44, 47))	('c-Jun', 'MPA', (138, 143))	('phosphorylation levels of JNK', 'MPA', (107, 136))	('Rb', 'Phenotype', 'HP:0009919', (149, 151))
115736	30417500	Homozygous CDKN2A deletions are a poor prognostic indicator for patients with MPM.14, 15, 16 Deletion of NF2 is associated with increased cell proliferation, invasiveness, spreading, and migration.17, 18 However, the molecular mechanism by which normal mesothelial cells acquire a carcinogenic phenotype in humans is not well understood.	('invasiveness', 'CPA', (158, 170))	('humans', 'Species', '9606', (307, 313))	('patients', 'Species', '9606', (64, 72))	('carcinogenic', 'Disease', 'MESH:D063646', (281, 293))	('Deletion', 'Var', (93, 101))	('carcinogenic', 'Disease', (281, 293))	('NF2', 'Gene', (105, 108))	('deletions', 'Var', (18, 27))	('cell proliferation', 'CPA', (138, 156))	('CDKN2A', 'Gene', (11, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('migration.17', 'CPA', (187, 199))	('CDKN2A', 'Gene', '1029', (11, 17))	('NF2', 'Gene', '4771', (105, 108))
115748	30417500	Two sh oligonucleotides were designed for the target sequence of the hairpin loop of YAP (sh1, 5'-TTCTATGTTCATTCCATCTCC-3'; sh2, 5'-GAGTTCTGACATCCTTAAT-3').	('sh2', 'Var', (124, 127))	('YAP', 'Gene', '10413', (85, 88))	('oligonucleotides', 'Chemical', 'MESH:D009841', (7, 23))	('sh1', 'Var', (90, 93))	('YAP', 'Gene', (85, 88))
115763	30417500	DNA sequencing analysis showed that the NF2-KO cell clones possessed frameshift mutations, which harbored either 200-bp (NF2-KO #1) or 22-bp (NF2-KO #2) deletions in the NF2 gene (Figure 1A).	('NF2', 'Gene', '4771', (170, 173))	('NF2', 'Gene', '4771', (40, 43))	('frameshift mutations', 'Var', (69, 89))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('NF2', 'Gene', (142, 145))	('NF2', 'Gene', (121, 124))	('NF2', 'Gene', (170, 173))	('NF2', 'Gene', (40, 43))	('NF2', 'Gene', '4771', (142, 145))	('NF2', 'Gene', '4771', (121, 124))	('deletions', 'Var', (153, 162))
115770	30417500	We found that rescuing NF2 in the NF2-KO cells significantly suppressed the cell proliferation, colony formation, migration, and wound-healing activities induced by NF2 mutation (Figure 2).	('wound-healing activities', 'CPA', (129, 153))	('suppressed', 'NegReg', (61, 71))	('mutation', 'Var', (169, 177))	('NF2', 'Gene', (34, 37))	('NF2', 'Gene', (165, 168))	('NF2', 'Gene', '4771', (23, 26))	('wound-healing', 'biological_process', 'GO:0042060', ('129', '142'))	('migration', 'CPA', (114, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('cell proliferation', 'CPA', (76, 94))	('NF2', 'Gene', '4771', (34, 37))	('NF2', 'Gene', '4771', (165, 168))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('colony formation', 'CPA', (96, 112))	('NF2', 'Gene', (23, 26))
115771	30417500	These results suggest that NF2 inactivation enhances the proliferation, clonogenicity, and migration of normal mesothelial cells.	('NF2', 'Gene', (27, 30))	('inactivation', 'Var', (31, 43))	('enhances', 'PosReg', (44, 52))	('NF2', 'Gene', '4771', (27, 30))	('migration of normal mesothelial cells', 'CPA', (91, 128))	('clonogenicity', 'CPA', (72, 85))	('proliferation', 'CPA', (57, 70))
115793	30417500	Additionally, knockout of NF2 in other normal mesothelial cell lines, HOMC-A4, and HOMC-D4 substantially increased the FGFR2 protein levels (Figure 5C).	('NF2', 'Gene', '4771', (26, 29))	('FGFR2', 'Gene', '2263', (119, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('HOMC-A4', 'CellLine', 'CVCL:Z622', (70, 77))	('increased', 'PosReg', (105, 114))	('HOMC-D4', 'Chemical', '-', (83, 90))	('NF2', 'Gene', (26, 29))	('knockout', 'Var', (14, 22))	('FGFR2', 'Gene', (119, 124))
115800	30417500	In addition, disruption of FGFR2 in NF2-KO cells suppressed the NF2 knockout-induced migration and wound healing activities of NF2/FGFR2-DKO cells (Figures 6C,D).	('NF2', 'Gene', (127, 130))	('NF2', 'Gene', '4771', (36, 39))	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('FGFR2', 'Gene', (131, 136))	('wound healing', 'biological_process', 'GO:0042060', ('99', '112'))	('NF2', 'Gene', '4771', (64, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('disruption', 'Var', (13, 23))	('wound healing activities', 'CPA', (99, 123))	('FGFR2', 'Gene', '2263', (131, 136))	('NF2', 'Gene', '4771', (127, 130))	('NF2', 'Gene', (36, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('suppressed', 'NegReg', (49, 59))	('migration', 'CPA', (85, 94))	('NF2', 'Gene', (64, 67))
115803	30417500	These results indicate the possibility that FGFR2 could play important role in the proliferation of mesothelioma cells with NF2 mutation.	('NF2', 'Gene', (124, 127))	('mutation', 'Var', (128, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('NF2', 'Gene', '4771', (124, 127))
115808	30417500	We also found that the phosphorylation level of c-Jun increased after exogenous YAP expression, whereas it decreased following YAP knockdown (Figure S3).	('phosphorylation level', 'MPA', (23, 44))	('YAP', 'Gene', (127, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('exogenous', 'Var', (70, 79))	('YAP', 'Gene', '10413', (80, 83))	('increased', 'PosReg', (54, 63))	('expression', 'Species', '29278', (84, 94))	('YAP', 'Gene', '10413', (127, 130))	('-Jun increased', 'Phenotype', 'HP:0003138', (49, 63))	('YAP', 'Gene', (80, 83))
115811	30417500	Interestingly, the rate of positivity for FGFR2 signals in the NF2-negative MPM tissues (11 of 12 tissues, 91.7%) was significantly higher than that in the NF2-positive MPM tissues (2 of 11 tissues, 18.2%; Figure 8).	('FGFR2', 'Gene', (42, 47))	('higher', 'PosReg', (132, 138))	('FGFR2', 'Gene', '2263', (42, 47))	('NF2', 'Gene', (63, 66))	('positivity', 'Var', (27, 37))	('NF2', 'Gene', (156, 159))	('NF2', 'Gene', '4771', (63, 66))	('NF2', 'Gene', '4771', (156, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
115813	30417500	Notably, overall survival in the MPM patients with high FGFR2 expression was shorter than in those with low FGFR2 expression in both datasets (Figure S4B).	('FGFR', 'molecular_function', 'GO:0005007', ('56', '60'))	('expression', 'Species', '29278', (62, 72))	('FGFR2', 'Gene', (56, 61))	('FGFR2', 'Gene', '2263', (56, 61))	('patients', 'Species', '9606', (37, 45))	('FGFR2', 'Gene', (108, 113))	('overall survival', 'MPA', (9, 25))	('MPM', 'Disease', (33, 36))	('FGFR2', 'Gene', '2263', (108, 113))	('expression', 'Species', '29278', (114, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('high', 'Var', (51, 55))	('shorter', 'NegReg', (77, 84))	('expression', 'Var', (62, 72))
115816	30417500	In this study, we generated NF2 knockout isogenic cell clones using a human immortalized normal mesothelial cell line, MeT-5A, and showed that the loss of NF2 enhances cell proliferation with global gene expression changes.	('NF2', 'Gene', (155, 158))	('cell proliferation', 'CPA', (168, 186))	('NF2', 'Gene', (28, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('human', 'Species', '9606', (70, 75))	('NF2', 'Gene', '4771', (155, 158))	('expression', 'Species', '29278', (204, 214))	('NF2', 'Gene', '4771', (28, 31))	('enhances', 'PosReg', (159, 167))	('loss', 'Var', (147, 151))	('gene expression', 'biological_process', 'GO:0010467', ('199', '214'))
115818	30417500	Furthermore, we showed that the loss of FGFR2 attenuates the proliferation of NF2-KO MeT-5A cells.	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('NF2', 'Gene', '4771', (78, 81))	('loss', 'Var', (32, 36))	('FGFR2', 'Gene', (40, 45))	('attenuates', 'NegReg', (46, 56))	('FGFR2', 'Gene', '2263', (40, 45))	('proliferation', 'CPA', (61, 74))	('NF2', 'Gene', (78, 81))
115819	30417500	Our cellular model presented here is the first to reveal the gene expression profile under complete disruption of NF2 in human normal mesothelial cells.	('NF2', 'Gene', (114, 117))	('expression', 'Species', '29278', (66, 76))	('human', 'Species', '9606', (121, 126))	('disruption', 'Var', (100, 110))	('NF2', 'Gene', '4771', (114, 117))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
115826	30417500	In other normal mesothelial cell lines HOMC-A4 and HOMC-D4, we also found that knockout of NF2 causes a substantial increase in FGFR2 protein level.	('HOMC-A4', 'CellLine', 'CVCL:Z622', (39, 46))	('FGFR2', 'Gene', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR2', 'Gene', '2263', (128, 133))	('NF2', 'Gene', (91, 94))	('increase', 'PosReg', (116, 124))	('HOMC-D4', 'Chemical', '-', (51, 58))	('knockout', 'Var', (79, 87))	('NF2', 'Gene', '4771', (91, 94))
115829	30417500	Furthermore, knockout of FGFR2 in NF2-KO cells led to retardation of cell growth, accompanied by decreases in the phosphorylation of JNK, c-Jun, and Rb, as well as the expression of CDK2.	('NF2', 'Gene', (34, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('retardation', 'Disease', 'MESH:D008607', (54, 65))	('JNK', 'MPA', (133, 136))	('expression', 'MPA', (168, 178))	('CDK2', 'Protein', (182, 186))	('c-Jun', 'MPA', (138, 143))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))	('FGFR2', 'Gene', (25, 30))	('JNK', 'molecular_function', 'GO:0004705', ('133', '136'))	('retardation', 'Disease', (54, 65))	('decreases', 'NegReg', (97, 106))	('cell growth', 'CPA', (69, 80))	('expression', 'Species', '29278', (168, 178))	('FGFR2', 'Gene', '2263', (25, 30))	('knockout', 'Var', (13, 21))	('NF2', 'Gene', '4771', (34, 37))	('CDK', 'molecular_function', 'GO:0004693', ('182', '185'))	('phosphorylation', 'MPA', (114, 129))	('Rb', 'Phenotype', 'HP:0009919', (149, 151))
115831	30417500	A transcription factor in the downstream of NF2 signaling, YAP/TAZ, was reported to be critical for the carcinogenesis of mesothelial cells with NF2 loss.30, 31 Our previous study reported c-Jun amplification in a panel of MPM tumors.42 In this study, we observed that overexpression of constitutively active YAP mutant does not alter the FGFR2 protein level in the NF2-KO clone, whereas it increases the phosphorylation levels of c-Jun and cyclin D1.	('YAP', 'Gene', (309, 312))	('NF2', 'Gene', '4771', (366, 369))	('mutant', 'Var', (313, 319))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('transcription factor', 'molecular_function', 'GO:0000981', ('2', '22'))	('FGFR2', 'Gene', '2263', (339, 344))	('NF2', 'Gene', (366, 369))	('cyclin', 'molecular_function', 'GO:0016538', ('441', '447'))	('increases', 'PosReg', (391, 400))	('MPM tumors', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'Species', '29278', (273, 283))	('YAP', 'Gene', '10413', (309, 312))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('NF2', 'Gene', '4771', (44, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('339', '343'))	('YAP', 'Gene', (59, 62))	('MPM tumors', 'Disease', (223, 233))	('protein', 'cellular_component', 'GO:0003675', ('345', '352'))	('phosphorylation', 'biological_process', 'GO:0016310', ('405', '420'))	('NF2', 'Gene', (44, 47))	('NF2', 'Gene', '4771', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('2', '15'))	('carcinogenesis', 'Disease', (104, 118))	('NF2', 'Gene', (145, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('YAP', 'Gene', '10413', (59, 62))	('FGFR2', 'Gene', (339, 344))
115834	30417500	Further studies are necessary to clarify the molecular mechanism by which loss of NF2 increases FGFR2 expression in mesothelial cells.	('FGFR2', 'Gene', (96, 101))	('expression', 'Species', '29278', (102, 112))	('NF2', 'Gene', '4771', (82, 85))	('expression', 'MPA', (102, 112))	('FGFR2', 'Gene', '2263', (96, 101))	('increases', 'PosReg', (86, 95))	('loss', 'Var', (74, 78))	('NF2', 'Gene', (82, 85))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
115836	30417500	The CRISPR/Cas9-mediated loss of NF2 enhanced the proliferation of cells and the expression of FGFR2, the subsequent disruption of which significantly suppressed the phosphorylation of cell cycle-related molecules as well as enhanced the proliferation of the cells.	('NF2', 'Gene', '4771', (33, 36))	('cell', 'Protein', (185, 189))	('disruption', 'Var', (117, 127))	('NF2', 'Gene', (33, 36))	('expression', 'MPA', (81, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('185', '195'))	('suppressed', 'NegReg', (151, 161))	('phosphorylation', 'MPA', (166, 181))	('Cas', 'cellular_component', 'GO:0005650', ('11', '14'))	('expression', 'Species', '29278', (81, 91))	('enhanced', 'PosReg', (37, 45))	('FGFR2', 'Gene', (95, 100))	('proliferation of the cells', 'CPA', (238, 264))	('loss', 'Var', (25, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('proliferation of cells', 'CPA', (50, 72))	('enhanced', 'PosReg', (225, 233))	('FGFR2', 'Gene', '2263', (95, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))
115841	28811252	Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (128, 150))	('ALCAM', 'Gene', (14, 19))	('CD274', 'Gene', (39, 44))	('shorter', 'NegReg', (69, 76))	('pleural mesothelioma', 'Disease', (99, 119))	('PD-L1', 'Gene', (32, 37))	('malignant mesothelioma', 'Disease', (128, 150))	('PD-L1', 'Gene', '29126', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('aggressive tumor', 'Disease', 'MESH:D001523', (177, 193))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (128, 150))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (99, 119))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (99, 119))	('CD274', 'Gene', '29126', (39, 44))	('ALCAM', 'Gene', '214', (14, 19))	('aggressive tumor', 'Disease', (177, 193))	('CD166', 'Var', (21, 26))	('mesothelioma of the pleura', 'Disease', (138, 164))	('mesothelioma of the pleura', 'Disease', 'MESH:D008654', (138, 164))
115893	28811252	Significant association was detected between PD-L1 positivity in TAIs and ALCAM expression (P < .01) or PD-L1 expression (P < .01) on tumor cells (Table 2 and Supplementary Table S1).	('PD-L1', 'Gene', '29126', (45, 50))	('PD-L1', 'Gene', '29126', (104, 109))	('positivity', 'Var', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('PD-L1', 'Gene', (45, 50))	('expression', 'MPA', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('PD-L1', 'Gene', (104, 109))
115897	28811252	Survival was significantly shorter for patients with mesothelioma expressing ALCAM on the cell membrane (7.0 months median vs 22.5 months without ALCAM expression or cytoplasmic labeling only; P < .01; Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('patients', 'Species', '9606', (39, 47))	('shorter', 'NegReg', (27, 34))	('Survival', 'MPA', (0, 8))	('ALCAM', 'Var', (77, 82))	('cell membrane', 'cellular_component', 'GO:0005886', ('90', '103'))	('mesothelioma', 'Disease', (53, 65))
115899	28811252	The patients with mesothelioma co-expressing ALCAM and PD-L1 showed the shortest survival (median 4 months vs 36.0 months without ALCAM or PD-L1; P < .01; Fig.	('shortest', 'NegReg', (72, 80))	('PD-L1', 'Gene', (139, 144))	('ALCAM', 'Var', (45, 50))	('PD-L1', 'Gene', '29126', (55, 60))	('mesothelioma', 'Disease', (18, 30))	('PD-L1', 'Gene', '29126', (139, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (55, 60))
115910	28811252	In nude mice with mesothelioma cell transplants, disturbance of the homophilic ALCAM interaction on the cell membrane significantly prolongs survival.	('prolongs', 'PosReg', (132, 140))	('mesothelioma', 'Disease', (18, 30))	('disturbance', 'Var', (49, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('nude mice', 'Species', '10090', (3, 12))	('cell membrane', 'cellular_component', 'GO:0005886', ('104', '117'))	('survival', 'CPA', (141, 149))
115913	28811252	Actually, in our preliminary study, patients with mesotheliomas expressing ALCAM on the cell membrane showed significantly shorter survival than those carrying tumors expressing no ALCAM (P < .01) or cytoplasmic ALCAM (P = .01).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('shorter', 'NegReg', (123, 130))	('patients', 'Species', '9606', (36, 44))	('cell membrane', 'cellular_component', 'GO:0005886', ('88', '101'))	('mesotheliomas', 'Disease', 'MESH:D008654', (50, 63))	('mesotheliomas', 'Disease', (50, 63))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('ALCAM', 'Var', (75, 80))	('tumors', 'Disease', (160, 166))	('survival', 'CPA', (131, 139))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
115922	28811252	At the time of submission of this manuscript, some clinical trials (such as NCT02497508 and NCT02716272) were in progress to assess PD-L1/PD-1 immune checkpoint inhibitors in patients with mesothelioma.	('NCT02716272', 'Var', (92, 103))	('PD-L1', 'Gene', (132, 137))	('mesothelioma', 'Disease', (189, 201))	('PD-L1', 'Gene', '29126', (132, 137))	('patients', 'Species', '9606', (175, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('clinical', 'Species', '191496', (51, 59))
115933	28811252	Indeed, mesotheliomas co-expressing ALCAM and PD-L1 were associated with the shortest survival (median only 4 months), indicating additive negative effects of ALCAM and PD-L1 expression.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', (169, 174))	('survival', 'MPA', (86, 94))	('PD-L1', 'Gene', '29126', (46, 51))	('PD-L1', 'Gene', '29126', (169, 174))	('shortest', 'NegReg', (77, 85))	('mesotheliomas', 'Disease', 'MESH:D008654', (8, 21))	('mesotheliomas', 'Disease', (8, 21))	('co-expressing', 'Var', (22, 35))	('ALCAM', 'Gene', (36, 41))
115940	28811252	In conclusion, the present study demonstrated that expression of ALCAM and PD-L1 in malignant pleural mesothelioma is associated with shorter survival.	('ALCAM', 'Gene', (65, 70))	('PD-L1', 'Gene', (75, 80))	('PD-L1', 'Gene', '29126', (75, 80))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (94, 114))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (84, 114))	('expression', 'Var', (51, 61))	('shorter', 'NegReg', (134, 141))	('malignant pleural mesothelioma', 'Disease', (84, 114))
116077	28185434	Tumor cells internalize Rho-eNPs an order of magnitude faster than healthy cells (98% uptake v. 2% uptake after 2 hours of incubation, respectively) (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('uptake', 'biological_process', 'GO:0098657', ('86', '92'))	('internalize', 'MPA', (12, 23))	('uptake', 'biological_process', 'GO:0098657', ('99', '105'))	('uptake', 'biological_process', 'GO:0098739', ('99', '105'))	('uptake', 'biological_process', 'GO:0098739', ('86', '92'))	('Rho-eNPs', 'Var', (24, 32))	('Rho-eNPs', 'Chemical', '-', (24, 32))	('faster', 'PosReg', (55, 61))
116125	28185434	Treatment with PTX-eNPs resulted in a profound decrease in the degree of tumor recurrence as compared to treatment with Taxol (0% v. 40%, respectively) (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Taxol', 'Chemical', 'MESH:D017239', (120, 125))	('decrease', 'NegReg', (47, 55))	('PTX-eNPs', 'Chemical', '-', (15, 23))	('tumor', 'Disease', (73, 78))	('PTX-eNPs', 'Var', (15, 23))
116174	28185434	HFR-eNPs were neither grossly nor histologically evident in any major organs including the heart, lungs, brain, liver, spleen, pancreas, stomach, intestines, or kidneys.	('pancreas', 'Disease', (127, 135))	('HFR-eNPs', 'Var', (0, 8))	('pancreas', 'Disease', 'MESH:D010190', (127, 135))
116191	28185434	Third, the in vitro results were confirmed in vivo by treating animals bearing established intraperitoneal mesothelioma tumors with either unloaded-eNPs (experimental), PLGA-NPs (non-swelling, generic nanoparticle control) or saline (no nanoparticle control), followed two days later by an intraperitoneal injection of Taxol.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (107, 126))	('saline', 'Chemical', 'MESH:D012965', (226, 232))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (96, 119))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (107, 126))	('Taxol', 'Chemical', 'MESH:D017239', (319, 324))	('intraperitoneal mesothelioma', 'Phenotype', 'HP:0100003', (91, 119))	('intraperitoneal mesothelioma', 'Disease', (91, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('intraperitoneal mesothelioma', 'Disease', 'MESH:D008654', (91, 119))	('mesothelioma tumors', 'Disease', (107, 126))	('PLGA-NPs', 'Var', (169, 177))
116660	20379224	Several preclinical studies have shown the ablative effects of 131I in tumor xenografts, which suggests that NIS may be a potent tool to combine with radiotherapy for treatment of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('131I', 'Chemical', 'MESH:C000614965', (63, 67))	('NIS', 'Gene', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('131I', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mesothelioma', 'Disease', (180, 192))	('tumor', 'Disease', (71, 76))	('NIS', 'Gene', '6528', (109, 112))
116671	19753302	The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002).	('MMP', 'molecular_function', 'GO:0004235', ('62', '65'))	('death', 'Disease', 'MESH:D003643', (32, 37))	('MMp', 'molecular_function', 'GO:0004235', ('127', '130'))	('death', 'Disease', (32, 37))	('patients', 'Species', '9606', (44, 52))	('low', 'Var', (58, 61))	('lower', 'NegReg', (97, 102))	('patients', 'Species', '9606', (108, 116))	('MMp14', 'Gene', (127, 132))	('MMP14', 'Gene', (62, 67))	('MMp14', 'Gene', '4323', (127, 132))
116724	19753302	Data in vitro seems to confirm their role in cancer, since their knockdown can decrease tumourigenicity.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('decrease', 'NegReg', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('knockdown', 'Var', (65, 74))	('cancer', 'Disease', (45, 51))
116776	19753302	In particular, since secretory or membrane proteins might be especially useful for diagnostic aims and, possibly for therapeutic purposes, we focused our attention on MMP14 (MT1-MMP), LAMA5 and LAMC2.	('LAMA5', 'Gene', (184, 189))	('MT1-MMP', 'Gene', (174, 181))	('MMP', 'molecular_function', 'GO:0004235', ('167', '170'))	('MT1-MMP', 'Gene', '4323', (174, 181))	('MT1', 'molecular_function', 'GO:0043834', ('174', '177'))	('LAMA5', 'Gene', '3911', (184, 189))	('LAMC2', 'Gene', (194, 199))	('LAMC2', 'Gene', '3918', (194, 199))	('membrane', 'cellular_component', 'GO:0016020', ('34', '42'))	('MMP', 'molecular_function', 'GO:0004235', ('178', '181'))	('MT1', 'molecular_function', 'GO:0043791', ('174', '177'))	('MT1', 'molecular_function', 'GO:0047152', ('174', '177'))	('MMP14', 'Var', (167, 172))
116802	19753302	The median survival in patients with low MMP14 expression was clearly longer than in those patients with high MMP14 expression (24 months vs 5 months).	('MMP', 'molecular_function', 'GO:0004235', ('41', '44'))	('patients', 'Species', '9606', (91, 99))	('MMP', 'molecular_function', 'GO:0004235', ('110', '113'))	('patients', 'Species', '9606', (23, 31))	('longer', 'PosReg', (70, 76))	('low MMP14 expression', 'Var', (37, 57))
116804	19753302	In Figure 7 is depicted a Kaplan-Meier survival plot for all patients showing a statistically significant association between high MMP14 expression and poor outcome.	('MMP14', 'Gene', (131, 136))	('expression', 'MPA', (137, 147))	('MMP', 'molecular_function', 'GO:0004235', ('131', '134'))	('patients', 'Species', '9606', (61, 69))	('high', 'Var', (126, 130))
116843	19753302	Finally, to better determine the role of MMP-14 as MM biomarker, our research group is actually working on the identification of MMP14 in the blood of MM patients.	('MMP', 'molecular_function', 'GO:0004235', ('41', '44'))	('patients', 'Species', '9606', (154, 162))	('MMP-14', 'Gene', (41, 47))	('MMP-14', 'Gene', '4323', (41, 47))	('MMP14', 'Var', (129, 134))	('MMP', 'molecular_function', 'GO:0004235', ('129', '132'))
116869	31783178	As this study evaluated patients of any age and only those with peritoneal mesothelioma, we decided to systemically assess the presence of ALK translocations in young mesothelioma patients (40 years or younger) regardless of site of origin of their mesothelioma.	('ALK', 'Gene', (139, 142))	('mesothelioma', 'Disease', 'MESH:D008654', (249, 261))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('mesothelioma', 'Disease', (249, 261))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (64, 87))	('patients', 'Species', '9606', (180, 188))	('peritoneal mesothelioma', 'Disease', (64, 87))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (64, 87))	('ALK', 'Gene', '238', (139, 142))	('mesothelioma', 'Disease', (75, 87))	('patients', 'Species', '9606', (24, 32))	('translocations', 'Var', (143, 157))	('mesothelioma', 'Disease', (167, 179))
116871	31783178	The patients selected for evaluation of ALK translocations were enrolled on the prospective NIH MNH protocol (clinicaltrials.gov # ).	('ALK', 'Gene', (40, 43))	('ALK', 'Gene', '238', (40, 43))	('patients', 'Species', '9606', (4, 12))	('translocations', 'Var', (44, 58))
116918	31783178	Targeted therapy, with tyrosine kinase inhibitors (TKI) that bind the receptor tyrosine kinase domain of the ALK protein, have been shown to be efficacious in cancers harboring these mutations and are approved for treatment.	('cancers', 'Disease', (159, 166))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('ALK', 'Gene', (109, 112))	('mutations', 'Var', (183, 192))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ALK', 'Gene', '238', (109, 112))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
116919	31783178	Although one of our patients who received crizotinib did not respond to it, a recent case report of a 13 year old female with peritoneal mesothelioma carrying the ALK-STRN rearrangement showed dramatic response to the ALK inhibitor ceritinib.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (126, 149))	('ALK', 'Gene', (218, 221))	('rearrangement', 'Var', (172, 185))	('ALK', 'Gene', '238', (163, 166))	('STRN', 'Gene', '6801', (167, 171))	('ceritinib', 'Chemical', 'MESH:C586847', (232, 241))	('patients', 'Species', '9606', (20, 28))	('ALK', 'Gene', '238', (218, 221))	('crizotinib', 'Chemical', 'MESH:D000077547', (42, 52))	('response', 'MPA', (202, 210))	('STRN', 'Gene', (167, 171))	('peritoneal mesothelioma', 'Disease', (126, 149))	('ALK', 'Gene', (163, 166))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (126, 149))
116920	31783178	Given the benefits in the 5% of lung adenocarcinoma patients who harbor this mutation, it is routinely recommended that patients undergo testing for this mutation.	('mutation', 'Var', (77, 85))	('lung adenocarcinoma', 'Disease', (32, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (32, 51))	('patients', 'Species', '9606', (120, 128))	('benefits', 'PosReg', (10, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))	('patients', 'Species', '9606', (52, 60))
116944	31788420	The pathogenesis of mesothelioma is a very low grade chronic inflammatory reaction to the asbestos fibres, which over many years leads to collective mutations leading to the mesothelioma.	('mesothelioma', 'Disease', (174, 186))	('leading to', 'Reg', (159, 169))	('mutations', 'Var', (149, 158))	('mesothelioma', 'Disease', (20, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (174, 186))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('pathogenesis', 'biological_process', 'GO:0009405', ('4', '16'))
116947	31788420	The chronic inflammation and reduce immune surveillance allow a mutated gene (eg ras) to survive and develop further mutations, aided by growth factors.	('inflammation', 'Disease', 'MESH:D007249', (12, 24))	('inflammation', 'Disease', (12, 24))	('inflammation', 'biological_process', 'GO:0006954', ('12', '24'))	('eg ras', 'Gene', (78, 84))	('mutated', 'Var', (64, 71))	('reduce immune surveillance', 'Phenotype', 'HP:0002721', (29, 55))
116957	22028491	Proliferation, migration, clonogenicity and tumorigenicity of MPM cells either exhibiting knock-down of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments.	('3-deazaneplanocin A', 'Chemical', 'MESH:C048460', (131, 150))	('PM', 'Phenotype', 'HP:0100003', (63, 65))	('EZH2', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('migration', 'CPA', (15, 24))	('DZNep', 'Chemical', 'MESH:C048460', (152, 157))	('murine', 'Species', '10090', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('knock-down', 'Var', (90, 100))	('clonogenicity', 'CPA', (26, 39))	('tumor', 'Disease', (44, 49))
116958	22028491	Micro-array and qRT-PCR techniques were used to examine gene expression profiles mediated by knock-down of EZH2 or EED, or DZNep.	('DZNep', 'Chemical', 'MESH:C048460', (123, 128))	('DZNep', 'Gene', (123, 128))	('EZH2', 'Gene', (107, 111))	('knock-down', 'Var', (93, 103))	('EED', 'Gene', (115, 118))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))
116962	22028491	Common as well as differential gene expression profiles were observed following knock-down of PRC-2 members or DZNep treatment.	('PRC-2 members', 'Gene', (94, 107))	('DZNep', 'Chemical', 'MESH:C048460', (111, 116))	('knock-down', 'Var', (80, 90))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))
116968	22028491	For example, changes in chromosomal copy number, as well as miRNA expression correlate with global and site-specific alterations in DNA methylation in these neoplasms.	('DNA methylation', 'MPA', (132, 147))	('alterations', 'Reg', (117, 128))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('miRNA expression', 'MPA', (60, 76))	('changes', 'Reg', (13, 20))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('DNA methylation', 'biological_process', 'GO:0006306', ('132', '147'))	('chromosomal copy number', 'Var', (24, 47))	('neoplasms', 'Disease', 'MESH:D009369', (157, 166))	('neoplasms', 'Disease', (157, 166))
116970	22028491	H28, H2052, and H2452 MPM cell lines were obtained from American Type Culture Collection (Manassas, VA), and cultured in RPMI 10% FCS with Pen/Strep (complete media).	('H2452', 'Var', (16, 21))	('PM', 'Phenotype', 'HP:0100003', (23, 25))	('Pen', 'Gene', (139, 142))	('H2452 MPM', 'CellLine', 'CVCL:1553', (16, 25))	('Pen', 'Gene', '27344', (139, 142))	('RPMI', 'Chemical', '-', (121, 125))	('H2052', 'CellLine', 'CVCL:1518', (5, 10))	('PM', 'Phenotype', 'HP:0100003', (122, 124))
116978	22028491	Equal amounts of miRNA were converted into cDNA using miR-101, miR-26a, miR-26b, and RNU44 RT primers (Applied Biosystems), according to the manufacturer's protocol.	('miR-26a', 'Gene', '407015', (63, 70))	('RNU44', 'Gene', (85, 90))	('miR-26a', 'Gene', (63, 70))	('miR-101', 'Chemical', '-', (54, 61))	('miR-101', 'Var', (54, 61))	('RNU44', 'Gene', '26806', (85, 90))	('miR-26b', 'Gene', '407017', (72, 79))	('miR-26b', 'Gene', (72, 79))
116993	22028491	Affymetrix U133 2.0 plus microarrays were used to examine global gene expression profiles, and specifically identify genes encoding PcG proteins in MES1-4, H28, H2052, and H2452 MPM cells relative to LP9 and NMES1.	('NMES1', 'Gene', (208, 213))	('H2052', 'CellLine', 'CVCL:1518', (161, 166))	('H2452 MPM', 'Var', (172, 181))	('PM', 'Phenotype', 'HP:0100003', (179, 181))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('H2052', 'Var', (161, 166))	('NMES1', 'Gene', '84419', (208, 213))	('H2452 MPM', 'CellLine', 'CVCL:1553', (172, 181))
116994	22028491	Consistent with previous studies pertaining to gene expression analysis of MPM, unsupervised hierarchical cluster analysis of triplicate samples for each cell line demonstrated that gene expression profiles in MPM lines were distinctly different than those observed in NMES1 and LP9 cells (Figure 1A).	('gene expression', 'biological_process', 'GO:0010467', ('182', '197'))	('NMES1', 'Gene', '84419', (269, 274))	('MPM', 'Var', (210, 213))	('PM', 'Phenotype', 'HP:0100003', (76, 78))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('gene expression profiles', 'MPA', (182, 206))	('PM', 'Phenotype', 'HP:0100003', (211, 213))	('different', 'Reg', (236, 245))	('NMES1', 'Gene', (269, 274))
117010	22028491	Additional experiments were performed to examine if aberrant PRC-2 activity directly contributes to the malignant phenotype of mesothelioma cells.	('mesothelioma', 'Disease', (127, 139))	('PRC-2', 'Protein', (61, 66))	('contributes', 'Reg', (85, 96))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('activity', 'MPA', (67, 75))	('aberrant', 'Var', (52, 60))
117012	22028491	Additional experiments were performed to ascertain if knock-down of EZH2 or EED inhibited clonogenicity and tumorigenicity of MPM cells.	('EZH2', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('knock-down', 'Var', (54, 64))	('PM', 'Phenotype', 'HP:0100003', (127, 129))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('clonogenicity', 'CPA', (90, 103))	('tumor', 'Disease', (108, 113))	('inhibited', 'NegReg', (80, 89))	('EED', 'Gene', (76, 79))
117013	22028491	Similarly, knock-down of EZH2 and EED decreased clonogenicity of H2452 cells by 40% and 57%, respectively (Figure 4C).	('decreased', 'NegReg', (38, 47))	('EZH2', 'Gene', (25, 29))	('H2452', 'CellLine', 'CVCL:1553', (65, 70))	('knock-down', 'Var', (11, 21))	('clonogenicity of H2452 cells', 'CPA', (48, 76))
117014	22028491	Subsequent experiments revealed that knock-down of EZH2 or EED modestly delayed tumor take, and significantly decreased size and volume of subcutaneous MES1 xenografts in nude mice (Figure 4D).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EZH2', 'Gene', (51, 55))	('delayed', 'NegReg', (72, 79))	('decreased', 'NegReg', (110, 119))	('tumor', 'Disease', (80, 85))	('nude mice', 'Species', '10090', (171, 180))	('EED', 'Gene', (59, 62))	('knock-down', 'Var', (37, 47))
117015	22028491	Consistent with results from immunoblot, proliferation and migration experiments, the effects of knock-down of EED on clonogenicity and tumorigenicity were more pronounced then those observed following EZH2 knock-down in MPM cells.	('pronounced', 'PosReg', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('clonogenicity', 'CPA', (118, 131))	('PM', 'Phenotype', 'HP:0100003', (222, 224))	('knock-down', 'Var', (97, 107))	('EED', 'Gene', (111, 114))	('tumor', 'Disease', (136, 141))
117017	22028491	Preliminary experiments revealed that DZNep inhibited proliferation of MPM cells, with the effects tending to plateau off at high doses, suggestive of cytostasis rather than cell death (Supplementary Figure 5A); consistent with these findings, Apo-BrdU analysis revealed that the growth inhibitory effects of DZNep (as well as EZH2 or EED knock-downs) were not associated with increased apoptosis (data not shown).	('DZNep', 'Var', (309, 314))	('growth inhibitory', 'CPA', (280, 297))	('cell death', 'biological_process', 'GO:0008219', ('174', '184'))	('DZNep', 'Chemical', 'MESH:C048460', (38, 43))	('inhibited', 'NegReg', (44, 53))	('DZNep', 'Chemical', 'MESH:C048460', (309, 314))	('PM', 'Phenotype', 'HP:0100003', (72, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('387', '396'))	('apoptosis', 'biological_process', 'GO:0097194', ('387', '396'))
117021	22028491	Furthermore, DZNep significantly diminished soft agar clonogenicity of MES1 and H2452 cells (Figure 5C).	('diminished', 'NegReg', (33, 43))	('DZNep', 'Chemical', 'MESH:C048460', (13, 18))	('DZNep', 'Var', (13, 18))	('soft agar clonogenicity', 'CPA', (44, 67))	('H2452', 'CellLine', 'CVCL:1553', (80, 85))
117022	22028491	Additional experiments were performed to examine if DZNep could inhibit growth of established MPM xenografts.	('DZNep', 'Var', (52, 57))	('growth of established MPM xenografts', 'CPA', (72, 108))	('inhibit', 'NegReg', (64, 71))	('DZNep', 'Chemical', 'MESH:C048460', (52, 57))	('PM', 'Phenotype', 'HP:0100003', (95, 97))
117029	22028491	Subsequent qRT-PCR experiments confirmed up-regulation of NF1, FOXD3, FHIT, HIC1, p21, and RASSF1A in MES1 and/or H28 cells following knock-down of EZH2 or EED (Supplementary Table 3).	('NF1', 'Gene', '4763', (58, 61))	('knock-down', 'Var', (134, 144))	('RASSF1A', 'Gene', '11186', (91, 98))	('FHIT', 'Gene', (70, 74))	('FHIT', 'Gene', '2272', (70, 74))	('FOXD3', 'Gene', (63, 68))	('p21', 'Gene', '1026', (82, 85))	('HIC1', 'Gene', (76, 80))	('NF1', 'Gene', (58, 61))	('RASSF1A', 'Gene', (91, 98))	('FOXD3', 'Gene', '27022', (63, 68))	('p21', 'Gene', (82, 85))	('up-regulation', 'PosReg', (41, 54))	('HIC1', 'Gene', '3090', (76, 80))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))
117030	22028491	In general, the magnitude of induction of these tumor suppressor genes was more pronounced in EED knock-down cells relative to EZH2 knock-downs.	('induction', 'MPA', (29, 38))	('knock-down', 'Var', (98, 108))	('tumor', 'Disease', (48, 53))	('EED knock-down', 'Var', (94, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))
117033	22028491	Collectively, these data suggest that the growth inhibitory effects of targeted disruption of PRC-2 or DZNep treatment in MPM cells are mediated, at least in part, by up-regulation of several tumor suppressors that are known to modulate pluripotency, cell cycle progression and apoptosis in cancer cells.	('regulation', 'biological_process', 'GO:0065007', ('170', '180'))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('DZNep', 'Chemical', 'MESH:C048460', (103, 108))	('modulate', 'Reg', (228, 236))	('up-regulation', 'PosReg', (167, 180))	('PM', 'Phenotype', 'HP:0100003', (123, 125))	('cell cycle progression', 'CPA', (251, 273))	('pluripotency', 'Disease', 'None', (237, 249))	('apoptosis', 'biological_process', 'GO:0097194', ('278', '287'))	('apoptosis', 'biological_process', 'GO:0006915', ('278', '287'))	('growth inhibitory effects', 'MPA', (42, 67))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', (291, 297))	('PRC-2', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('DZNep treatment', 'Gene', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cell cycle', 'biological_process', 'GO:0007049', ('251', '261'))	('disruption', 'Var', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('pluripotency', 'Disease', (237, 249))
117034	22028491	Chromatin immunoprecipitation (ChIP) experiments were undertaken to ascertain if activation of tumor suppressor genes in MES1 and H28 cells by DZNep was attributable to depletion of PRC-2 as evidenced by decreased H3K27Me3 levels within the respective promoters.	('DZNep', 'Var', (143, 148))	('depletion', 'MPA', (169, 178))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('H3K27Me3 levels', 'MPA', (214, 229))	('DZNep', 'Chemical', 'MESH:C048460', (143, 148))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('PRC-2', 'Gene', (182, 187))	('activation', 'PosReg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('decreased', 'NegReg', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
117035	22028491	As shown in Figure 6A, H3K27Me3 levels within the promoters of RASSFIA and HIC-1 (putative stem cell polycomb target genes) were markedly decreased in cells exhibiting knock-down of EZH2 or EED, relative to control cells.	('EED', 'Gene', (190, 193))	('knock-down', 'Var', (168, 178))	('decreased', 'NegReg', (138, 147))	('EZH2', 'Gene', (182, 186))	('H3K27Me3 levels', 'MPA', (23, 38))	('HIC-1', 'Gene', '3090', (75, 80))	('HIC-1', 'Gene', (75, 80))
117039	22028491	Using criteria of >1.5 fold change and p <0.05 for drug treatment relative to untreated controls, 940 and 513 genes were modulated by DZNep in MES1 and H28, respectively, of which 122 overlapped.	('DZNep', 'Var', (134, 139))	('MES1', 'Gene', (143, 147))	('modulated', 'Reg', (121, 130))	('DZNep', 'Chemical', 'MESH:C048460', (134, 139))
117040	22028491	Using criteria of >1.5 fold change and more stringent adjusted p values, 830 and 435 genes were differentially modulated by DZNep in MES1 and H28, respectively (Figure 6B); 55% of differentially expressed genes were up-regulated by DZNep.	('DZNep', 'Var', (124, 129))	('DZNep', 'Var', (232, 237))	('DZNep', 'Chemical', 'MESH:C048460', (124, 129))	('DZNep', 'Chemical', 'MESH:C048460', (232, 237))	('up-regulated', 'PosReg', (216, 228))
117041	22028491	Only 11 genes were significantly modulated in both cell lines by DZNep, of which only three were simultaneously up- or down-regulated (Supplementary Table 4), suggesting significant differences in underlying histology or genotype.	('DZNep', 'Var', (65, 70))	('up-', 'PosReg', (112, 115))	('down-regulated', 'NegReg', (119, 133))	('modulated', 'Reg', (33, 42))	('DZNep', 'Chemical', 'MESH:C048460', (65, 70))
117043	22028491	PcG proteins have emerged as critical epigenetic mediators of pluripotency and differentiation of stem cells, as well as aberrant gene repression during malignant transformation.	('pluripotency', 'Disease', (62, 74))	('pluripotency', 'Disease', 'None', (62, 74))	('aberrant gene repression', 'Var', (121, 145))
117044	22028491	The initiation complex, PRC-2, containing EZH2, SUZ12, PCL, and EED subunits, mediates trimethylation of H3K27.	('PCL', 'Gene', '5252', (55, 58))	('EZH2', 'Var', (42, 46))	('SUZ12', 'Gene', '23512', (48, 53))	('PCL', 'Gene', (55, 58))	('SUZ12', 'Gene', (48, 53))	('trimethylation', 'MPA', (87, 101))	('H3K27', 'Protein', (105, 110))	('mediates', 'Reg', (78, 86))
117049	22028491	Knock-down of EZH2 or EED significantly inhibited the malignant phenotype of mesothelioma cells in vitro and in vivo.	('EED', 'Gene', (22, 25))	('mesothelioma', 'Disease', (77, 89))	('inhibited', 'NegReg', (40, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('EZH2', 'Gene', (14, 18))	('Knock-down', 'Var', (0, 10))
117056	22028491	The majority of MPM exhibit disruption of Rb as well as p53-mediated pathways due to allelic loss, or epigenetic silencing of p16/p14.	('epigenetic silencing', 'Var', (102, 122))	('p14', 'Gene', (130, 133))	('p16', 'Gene', '1029', (126, 129))	('MPM', 'Disease', (16, 19))	('p53', 'Gene', (56, 59))	('p14', 'Gene', '1029', (130, 133))	('p16', 'Gene', (126, 129))	('p53', 'Gene', '7157', (56, 59))	('allelic loss', 'Disease', 'MESH:C566065', (85, 97))	('allelic loss', 'Disease', (85, 97))	('disruption', 'Reg', (28, 38))	('PM', 'Phenotype', 'HP:0100003', (17, 19))
117058	22028491	Our preliminary analysis indicated that miR-101 and miR-26a are down-regulated in primary MPM relative to normal pleura, suggesting that dysregulation of micro-RNAs also contributes to over-expression of EZH2 in these neoplasms.	('dysregulation', 'Var', (137, 150))	('down-regulated', 'NegReg', (64, 78))	('micro-RNAs', 'Protein', (154, 164))	('neoplasms', 'Phenotype', 'HP:0002664', (218, 227))	('over-expression', 'PosReg', (185, 200))	('miR-26a', 'Gene', '407015', (52, 59))	('miR-101', 'Chemical', '-', (40, 47))	('neoplasms', 'Disease', 'MESH:D009369', (218, 227))	('miR-26a', 'Gene', (52, 59))	('neoplasms', 'Disease', (218, 227))	('PM', 'Phenotype', 'HP:0100003', (91, 93))	('EZH2', 'Gene', (204, 208))
117062	22028491	Direct binding of the WD40 domain of EED is critical for histone methyltransferase activity of the PRC-2 complex, and placement of the repressive mark H3K27Me3 in murine embryonic fibroblasts and Drosophila melanogaster embryos.	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('Drosophila melanogaster embryos', 'Disease', (196, 227))	('H3K27Me3', 'Var', (151, 159))	('EED', 'Gene', (37, 40))	('activity', 'MPA', (83, 91))	('PRC-2 complex', 'cellular_component', 'GO:0035098', ('99', '112'))	('histone methyltransferase activity', 'molecular_function', 'GO:0008469', ('57', '91'))	('histone methyltransferase activity', 'molecular_function', 'GO:0042054', ('57', '91'))	('Drosophila melanogaster embryos', 'Disease', 'MESH:D020964', (196, 227))	('histone methyltransferase', 'Enzyme', (57, 82))	('murine', 'Species', '10090', (163, 169))
117067	22028491	Furthermore, DZNep induces differentiation of cancer stem cells by caspase dependent degradation of NANOG and OCT4.	('OCT4', 'Gene', (110, 114))	('DZNep', 'Chemical', 'MESH:C048460', (13, 18))	('DZNep', 'Var', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('degradation', 'biological_process', 'GO:0009056', ('85', '96'))	('cancer', 'Disease', (46, 52))	('OCT4', 'Gene', '5460', (110, 114))	('NANOG', 'Gene', '79923', (100, 105))	('degradation', 'MPA', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('NANOG', 'Gene', (100, 105))	('induces', 'Reg', (19, 26))	('differentiation', 'CPA', (27, 42))
117068	22028491	Our analysis revealed that DZNep depleted EZH2, EED, and H3K27Me3, and up-regulated several tumor suppressor genes including p21 and RASSF1A that were also activated following knock-down of EZH2 or EED in MPM cells, suggesting that the cytotoxic effects of DZNep are attributable at least in part to inhibition of PRC-2 activity.	('activated', 'PosReg', (156, 165))	('RASSF1A', 'Gene', (133, 140))	('p21', 'Gene', '1026', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('EZH2', 'Gene', (42, 46))	('up-regulated', 'PosReg', (71, 83))	('EED', 'Protein', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('knock-down', 'Var', (176, 186))	('p21', 'Gene', (125, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('depleted', 'NegReg', (33, 41))	('PM', 'Phenotype', 'HP:0100003', (206, 208))	('DZNep', 'Chemical', 'MESH:C048460', (27, 32))	('RASSF1A', 'Gene', '11186', (133, 140))	('DZNep', 'Chemical', 'MESH:C048460', (257, 262))	('tumor', 'Disease', (92, 97))	('H3K27Me3', 'Protein', (57, 65))
117069	22028491	Consistent with this notion, DZNep mediated growth inhibition without apoptosis in MPM cells; similar results were observed following knock-down of EZH2 and EED in these cells.	('knock-down', 'Var', (134, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('growth inhibition', 'CPA', (44, 61))	('EZH2', 'Gene', (148, 152))	('PM', 'Phenotype', 'HP:0100003', (84, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('DZNep', 'Chemical', 'MESH:C048460', (29, 34))
117070	22028491	These findings are in accordance with recent observations that knock-down of EZH2 induces cellular senescence in melanoma cells in part by up-regulation of p21, and delays G2/M transition without inducing apoptosis in ER-negative breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('p21', 'Gene', '1026', (156, 159))	('breast cancer', 'Disease', (230, 243))	('knock-down', 'Var', (63, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('205', '214'))	('apoptosis', 'biological_process', 'GO:0006915', ('205', '214'))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('cellular senescence', 'CPA', (90, 109))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('p21', 'Gene', (156, 159))	('cellular senescence', 'biological_process', 'GO:0090398', ('90', '109'))	('EZH2', 'Gene', (77, 81))	('induces', 'Reg', (82, 89))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('up-regulation', 'PosReg', (139, 152))	('delays', 'NegReg', (165, 171))	('G2/M transition', 'CPA', (172, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))
117071	22028491	On the other hand, our current findings do not conclusively implicate depletion of PRC-2 as the major mechanism by which DZNep inhibits the malignant phenotype of pleural mesothelioma cells.	('inhibits', 'NegReg', (127, 135))	('PRC-2', 'Gene', (83, 88))	('DZNep', 'Var', (121, 126))	('DZNep', 'Chemical', 'MESH:C048460', (121, 126))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (163, 183))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (163, 183))	('pleural mesothelioma', 'Disease', (163, 183))
117072	22028491	Indeed, our highly stringent microarray analysis suggests that DZNep mediates pleiotropic effects in mesotheliomas, which may vary depending on histologic subtype or genotype of these neoplasms.	('DZNep', 'Var', (63, 68))	('DZNep', 'Chemical', 'MESH:C048460', (63, 68))	('neoplasms', 'Disease', 'MESH:D009369', (184, 193))	('neoplasms', 'Disease', (184, 193))	('mesotheliomas', 'Disease', 'MESH:D008654', (101, 114))	('mesotheliomas', 'Disease', (101, 114))	('neoplasms', 'Phenotype', 'HP:0002664', (184, 193))
117080	22028491	Collectively these data demonstrate that aberrant PcG protein expression contributes to the pathogenesis of mesotheliomas, and suggest that targeting PRC-2 expression/activity may be a novel strategy for the treatment and possible prevention of these neoplasms.	('PRC-2', 'Gene', (150, 155))	('aberrant', 'Var', (41, 49))	('neoplasms', 'Disease', 'MESH:D009369', (251, 260))	('PcG protein', 'Protein', (50, 61))	('neoplasms', 'Disease', (251, 260))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('expression', 'MPA', (62, 72))	('mesotheliomas', 'Disease', 'MESH:D008654', (108, 121))	('pathogenesis', 'biological_process', 'GO:0009405', ('92', '104'))	('contributes', 'Reg', (73, 84))	('mesotheliomas', 'Disease', (108, 121))	('neoplasms', 'Phenotype', 'HP:0002664', (251, 260))
117120	25013421	Many studies have demonstrated the presence of SV40 in pleural mesotheliomas through the use of various techniques, and animal studies have demonstrated a clear association of up to 60% of developing mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('mesothelioma', 'Disease', (63, 75))	('SV40', 'Species', '1891767', (47, 51))	('presence', 'Reg', (35, 43))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (55, 76))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (55, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('SV40', 'Var', (47, 51))	('mesothelioma', 'Disease', (200, 212))	('pleural mesotheliomas', 'Disease', (55, 76))
117121	25013421	However SV40 DNA has not been as well studied in mesotheliomas of the tunica vaginalis as it has been in its pleural counterpart.	('mesotheliomas of the tunica vaginalis', 'Disease', (49, 86))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('SV40', 'Species', '1891767', (8, 12))	('mesotheliomas of the tunica vaginalis', 'Disease', 'MESH:D008654', (49, 86))	('SV40 DNA', 'Var', (8, 16))
117277	24405424	Typically, rho < 0.40 indicates poor reproducibility, 0.4 <= rho < 0.75 indicates fair to good reproducibility, and rho > 0.75 indicates excellent reproducibility (Rosner,).	('rho < 0.40', 'Var', (11, 21))	('reproducibility', 'MPA', (37, 52))	('0.4 <= rho', 'Var', (54, 64))	('g', 'Gene', '1', (90, 91))	('rho > 0.75', 'Var', (116, 126))
117525	31819191	Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells.	('Loss-of-function', 'NegReg', (0, 16))	('BRCA-associated protein 1', 'Gene', (30, 55))	('metabolic', 'MPA', (94, 103))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (17, 26))	('BRCA-associated protein 1', 'Gene', '8314', (30, 55))
117534	31819191	Although environmental exposure to asbestos is a major driver of MPM carcinogenesis, recent studies have revealed an important role for germline or somatic mutations in the BRCA-associated protein 1 (BAP1) gene.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('asbestos', 'Chemical', 'MESH:D001194', (35, 43))	('mutations', 'Var', (156, 165))	('BAP1', 'Gene', '8314', (200, 204))	('BRCA-associated protein 1', 'Gene', '8314', (173, 198))	('iron', 'Chemical', 'MESH:D007501', (12, 16))	('BAP1', 'Gene', (200, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('BRCA-associated protein 1', 'Gene', (173, 198))	('carcinogenesis', 'Disease', (69, 83))
117535	31819191	BAP1 loss-of-function mutations are present in families predisposed to mesothelioma and in 60% of patients with sporadic mesothelioma.	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (112, 133))	('patients', 'Species', '9606', (98, 106))	('sporadic mesothelioma', 'Disease', 'MESH:D008654', (112, 133))	('mesothelioma', 'Disease', (121, 133))	('mutations', 'Var', (22, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('BAP1', 'Gene', '8314', (0, 4))	('sporadic mesothelioma', 'Disease', (112, 133))	('loss-of-function', 'NegReg', (5, 21))
117536	31819191	As BAP1 is implicated in many cellular processes, including DNA repair and apoptosis, its mutation may act in co-operation with environmental exposure to asbestos to drive MPM carcinogenesis.	('BAP1', 'Gene', '8314', (3, 7))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('BAP1', 'Gene', (3, 7))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))	('MPM', 'Disease', (172, 175))	('rat', 'Species', '10116', (116, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('DNA repair', 'biological_process', 'GO:0006281', ('60', '70'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('implicated', 'Reg', (11, 21))	('mutation', 'Var', (90, 98))	('carcinogenesis', 'Disease', (176, 190))	('asbestos', 'Chemical', 'MESH:D001194', (154, 162))
117537	31819191	While MPM arising in the context of germline BAP1 mutations occurs in younger patients and is characterised by a better prognosis, sporadic MPM is in most cases refractory to therapy.	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (78, 86))	('MPM', 'Disease', (6, 9))	('germline', 'Var', (36, 44))	('BAP1', 'Gene', '8314', (45, 49))
117541	31819191	H2O2 can then be converted into H2O by catalases, glutathione peroxidases (GPXs) or thioredoxin peroxidase (TrxP), or reacts with free Fe2+ to form the hydroxyl radical (OH ) through the Fenton and Haber-Weiss reactions.	('thioredoxin', 'molecular_function', 'GO:0000008', ('84', '95'))	('H2O', 'Chemical', '-', (0, 3))	('reacts', 'Reg', (118, 124))	('Fe2+', 'Chemical', '-', (135, 139))	('H2O', 'Chemical', '-', (32, 35))	('thioredoxin', 'molecular_function', 'GO:0030508', ('84', '95'))	('hydroxyl radical', 'Chemical', 'MESH:D017665', (152, 168))	('glutathione', 'Chemical', 'MESH:D005978', (50, 61))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))
117558	31819191	Conversely, the non-carcinogenic silicate mineral fibre palygorskite failed to induce inflammation when injected into the peritoneum of transgenic mice expressing SV40 TAg in mesothelial cells (MexTAg) and Balb/c mice.	('mice', 'Species', '10090', (147, 151))	('inflammation', 'Disease', (86, 98))	('mice', 'Species', '10090', (213, 217))	('carcinogenic', 'Disease', 'MESH:D063646', (20, 32))	('carcinogenic', 'Disease', (20, 32))	('SV40 TAg', 'Var', (163, 171))	('transgenic mice', 'Species', '10090', (136, 151))	('palygorskite', 'Chemical', 'MESH:C026325', (56, 68))	('silicate', 'Chemical', 'MESH:D017640', (33, 41))	('inflammation', 'biological_process', 'GO:0006954', ('86', '98'))	('inflammation', 'Disease', 'MESH:D007249', (86, 98))
117560	31819191	The authors demonstrated that crocidolite and H2O2 provoke necrosis of normal mesothelial cells and release of HMGB1 in culture media, which induce TNF-alpha secretion by macrophages.	('necrosis', 'Disease', (59, 67))	('TNF-alpha', 'Gene', '7124', (148, 157))	('necrosis', 'biological_process', 'GO:0001906', ('59', '67'))	('induce', 'Reg', (141, 147))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('rat', 'Species', '10116', (19, 22))	('TNF-alpha', 'Gene', (148, 157))	('necrosis', 'Disease', 'MESH:D009336', (59, 67))	('HMGB1', 'Gene', (111, 116))	('necrosis', 'biological_process', 'GO:0070265', ('59', '67'))	('release', 'MPA', (100, 107))	('necrosis', 'biological_process', 'GO:0008219', ('59', '67'))	('necrosis', 'biological_process', 'GO:0019835', ('59', '67'))	('TNF-alpha secretion', 'biological_process', 'GO:1990774', ('148', '167'))	('necrosis', 'biological_process', 'GO:0008220', ('59', '67'))	('crocidolite', 'Chemical', 'MESH:D017638', (30, 41))
117562	31819191	HMGB1 activity is regulated by the oxidised/reduced status of three cysteine residues (C23, C45 and C106).	('activity', 'MPA', (6, 14))	('oxidised/reduced', 'MPA', (35, 51))	('HMGB1', 'Gene', (0, 5))	('C106', 'Var', (100, 104))	('C45', 'MPA', (92, 95))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('C23', 'Var', (87, 90))
117563	31819191	Its chemoattractant function requires all cysteine residues to be reduced, while a disulfide bond between C23 and C45 favours its binding to Toll-like receptor 4 (TLR4) and induction of cytokine release by macrophages.	('disulfide', 'Chemical', 'MESH:D004220', (83, 92))	('cysteine', 'Chemical', 'MESH:D003545', (42, 50))	('cysteine residues', 'MPA', (42, 59))	('TLR4', 'Gene', '7099', (163, 167))	('binding', 'molecular_function', 'GO:0005488', ('130', '137'))	('Toll-like receptor 4', 'Gene', '7099', (141, 161))	('cytokine release', 'MPA', (186, 202))	('TLR4', 'Gene', (163, 167))	('C23', 'Var', (106, 109))	('C45', 'Var', (114, 117))	('binding', 'Interaction', (130, 137))	('disulfide bond', 'MPA', (83, 97))	('Toll-like receptor 4', 'Gene', (141, 161))	('favours', 'PosReg', (118, 125))
117590	31819191	Crosstalk between ROS and TGF-beta has been described, with ROS in the extracellular space capable of inducing activation of TGF-beta.	('activation', 'PosReg', (111, 121))	('TGF-beta', 'Gene', (125, 133))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS', 'Var', (60, 63))	('TGF-beta', 'Gene', (26, 34))	('extracellular space', 'cellular_component', 'GO:0005615', ('71', '90'))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
117598	31819191	TGF-beta1 was shown to induce the expression of NOX4 in human peritoneal mesothelial cells, while NOX4 knockdown reduced TGF-beta1-induced EMT.	('NOX4', 'Gene', '50507', (48, 52))	('NOX4', 'Gene', (98, 102))	('expression', 'MPA', (34, 44))	('induce', 'PosReg', (23, 29))	('TGF-beta1', 'Gene', '7040', (121, 130))	('TGF-beta1', 'Gene', (121, 130))	('human', 'Species', '9606', (56, 61))	('NOX4', 'Gene', (48, 52))	('NOX4', 'Gene', '50507', (98, 102))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('reduced', 'NegReg', (113, 120))	('TGF-beta1', 'Gene', '7040', (0, 9))	('knockdown', 'Var', (103, 112))	('TGF-beta1', 'Gene', (0, 9))
117618	31819191	Interestingly, PTEN is inactivated by H2O2 through oxidation of cysteine residues.	('H2O2', 'Var', (38, 42))	('oxidation', 'MPA', (51, 60))	('PTEN', 'Gene', (15, 19))	('cysteine', 'Chemical', 'MESH:D003545', (64, 72))	('PTEN', 'Gene', '5728', (15, 19))	('cysteine residues', 'MPA', (64, 81))	('inactivated', 'NegReg', (23, 34))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
117628	31819191	Greater ROS accumulation was related to higher sensitivity to cisplatin, and this effect was abrogated by treatment with the ROS scavenger NAC, while knockdown of glutathione-S-transferase enhanced this effect.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('ROS', 'MPA', (8, 11))	('higher', 'PosReg', (40, 46))	('NAC', 'Chemical', 'MESH:D000111', (139, 142))	('knockdown', 'Var', (150, 159))	('glutathione', 'Chemical', 'MESH:D005978', (163, 174))	('NAC', 'cellular_component', 'GO:0005854', ('139', '142'))	('ROS', 'Chemical', 'MESH:D017382', (125, 128))	('ROS', 'Chemical', 'MESH:D017382', (8, 11))	('accumulation', 'PosReg', (12, 24))	('sensitivity to cisplatin', 'MPA', (47, 71))
117638	31819191	O2 deficiency, such as the hypoxic conditions found in tumour masses, results in HIF-1alpha accumulation, dimerisation with HIF-1beta to form the HIF-1 transcription factor and activation of gene transcription.	('HIF-1', 'Gene', '3091', (81, 86))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))	('O2', 'Chemical', 'MESH:D010100', (0, 2))	('HIF-1', 'Gene', (81, 86))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (27, 45))	('HIF-1alpha', 'Gene', '3091', (81, 91))	('activation', 'PosReg', (177, 187))	('hypoxic conditions', 'Disease', (27, 45))	('tumour masses', 'Disease', 'MESH:C536030', (55, 68))	('HIF-1beta', 'Gene', '3091', (124, 133))	('deficiency', 'Var', (3, 13))	('tumour masses', 'Disease', (55, 68))	('HIF-1alpha', 'Gene', (81, 91))	('transcription', 'biological_process', 'GO:0006351', ('196', '209'))	('transcription factor', 'molecular_function', 'GO:0000981', ('152', '172'))	('HIF-1', 'Gene', '3091', (146, 151))	('HIF-1', 'Gene', '3091', (124, 129))	('HIF-1', 'Gene', (146, 151))	('HIF-1', 'Gene', (124, 129))	('dimerisation', 'MPA', (106, 118))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('gene transcription', 'MPA', (191, 209))	('HIF-1beta', 'Gene', (124, 133))	('accumulation', 'PosReg', (92, 104))
117642	31819191	ROS can increase HIF-1alpha transcription and translation through the PI3K-AKT-mTOR pathway and can induce, also in normoxic conditions, HIF-1alpha stabilisation through inhibition of prolyl-4-hydroxylases (PHD).	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('PHD', 'molecular_function', 'GO:0050175', ('207', '210'))	('HIF-1alpha', 'Gene', '3091', (17, 27))	('HIF-1alpha', 'Gene', '3091', (137, 147))	('AKT', 'Gene', (75, 78))	('translation', 'biological_process', 'GO:0006412', ('46', '57'))	('PHD', 'Disease', (207, 210))	('mTOR', 'Gene', (79, 83))	('ROS', 'Var', (0, 3))	('transcription', 'biological_process', 'GO:0006351', ('28', '41'))	('transcription', 'MPA', (28, 41))	('stabilisation', 'MPA', (148, 161))	('HIF-1alpha', 'Gene', (137, 147))	('PHD', 'Disease', 'MESH:D011547', (207, 210))	('HIF-1alpha', 'Gene', (17, 27))	('translation', 'MPA', (46, 57))	('increase', 'PosReg', (8, 16))	('mTOR', 'Gene', '2475', (79, 83))	('AKT', 'Gene', '207', (75, 78))	('inhibition', 'NegReg', (170, 180))	('induce', 'PosReg', (100, 106))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
117645	31819191	Moreover, the authors demonstrated that inhibition of both HIF-1alpha and mTOR decreased 18F-FDG uptake in MPM cell lines.	('inhibition', 'Var', (40, 50))	('18F-FDG', 'Chemical', 'MESH:D019788', (89, 96))	('HIF-1alpha', 'Gene', (59, 69))	('18F-FDG uptake', 'MPA', (89, 103))	('decreased', 'NegReg', (79, 88))	('rat', 'Species', '10116', (29, 32))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('HIF-1alpha', 'Gene', '3091', (59, 69))
117646	31819191	Furthermore, loss-of-function mutations in the BAP1 gene profoundly affect the levels of metabolites connected to glycolysis and tricarboxylic acid  (TCA) cycle, with a reduction in mitochondrial respiration and an increase in glucose consumption and lactate production.	('lactate production', 'MPA', (251, 269))	('mitochondrial respiration', 'MPA', (182, 207))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (129, 147))	('BAP1', 'Gene', '8314', (47, 51))	('TCA) cycle', 'biological_process', 'GO:0006099', ('150', '160'))	('lactate', 'Chemical', 'MESH:D019344', (251, 258))	('BAP1', 'Gene', (47, 51))	('glucose', 'Chemical', 'MESH:D005947', (227, 234))	('TCA', 'Chemical', 'MESH:D014233', (150, 153))	('respiration', 'biological_process', 'GO:0007585', ('196', '207'))	('reduction', 'NegReg', (169, 178))	('respiration', 'biological_process', 'GO:0045333', ('196', '207'))	('mutations', 'Var', (30, 39))	('glycolysis', 'biological_process', 'GO:0006096', ('114', '124'))	('loss-of-function', 'NegReg', (13, 29))	('rat', 'Species', '10116', (201, 204))	('glucose consumption', 'MPA', (227, 246))	('levels of metabolites connected', 'MPA', (79, 110))	('increase', 'PosReg', (215, 223))
117647	31819191	These alterations lead to acidification of the tumour microenvironment and promote the polarisation of tumour-associated macrophages towards a M2 phenotype, resulting in an immune-suppressive milieu that favours malignant transformation.	('alterations', 'Var', (6, 17))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('favours', 'PosReg', (204, 211))	('polarisation', 'MPA', (87, 99))	('promote', 'PosReg', (75, 82))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', (47, 53))	('malignant transformation', 'CPA', (212, 236))	('rat', 'Species', '10116', (10, 13))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('acidification', 'biological_process', 'GO:0045851', ('26', '39'))	('immune-suppressive milieu', 'MPA', (173, 198))	('acidification', 'MPA', (26, 39))	('lead to', 'Reg', (18, 25))	('tumour', 'Disease', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
117648	31819191	Thus, through its effects on the metabolic profile of mesothelial cells, loss of BAP1 promotes a favourable niche for malignant transformation and tumour progression.	('loss', 'Var', (73, 77))	('BAP1', 'Gene', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('effects', 'Reg', (18, 25))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('promotes', 'PosReg', (86, 94))	('tumour', 'Disease', (147, 153))	('BAP1', 'Gene', '8314', (81, 85))
117652	31819191	Consistent with this notion, low/absent BAP1 activity is associated with decreased activity of the ETC, resulting in a more glycolytic, "Warburg-like" metabolic profile (Fig.	('activity', 'MPA', (45, 53))	('activity', 'MPA', (83, 91))	('decreased', 'NegReg', (73, 82))	('more', 'PosReg', (119, 123))	('glycolytic', 'MPA', (124, 134))	('BAP1', 'Gene', '8314', (40, 44))	('low/absent', 'Var', (29, 39))	('low/absent', 'NegReg', (29, 39))	('BAP1', 'Gene', (40, 44))
117658	31819191	The acquired cisplatin resistance was associated with profoundly altered bioenergetic features of the cells, including a decrease in the oxygen consumption rate, an alteration that was accompanied by a reduction in mitochondrial content and decreased expression of proteins involved in mitochondrial biogenesis.	('rat', 'Species', '10116', (169, 172))	('altered', 'Reg', (65, 72))	('rat', 'Species', '10116', (156, 159))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('decreased', 'NegReg', (241, 250))	('oxygen consumption rate', 'MPA', (137, 160))	('expression of', 'MPA', (251, 264))	('cisplatin', 'Var', (13, 22))	('decrease', 'NegReg', (121, 129))	('mitochondrial content', 'MPA', (215, 236))	('bioenergetic', 'MPA', (73, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('reduction', 'NegReg', (202, 211))
117666	31819191	Another interesting metabolic alteration is found in a subset of MPM patients carrying the deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A locus, a frequent target of deletion in MPM.	('CDKN2A', 'Gene', '1029', (179, 185))	('MTAP', 'Gene', (142, 146))	('deletion', 'Var', (91, 99))	('MTAP', 'Gene', '4507', (142, 146))	('methylthioadenosine phosphorylase', 'Gene', (107, 140))	('MPM', 'Disease', (65, 68))	('methylthioadenosine phosphorylase', 'Gene', '4507', (107, 140))	('rat', 'Species', '10116', (34, 37))	('patients', 'Species', '9606', (69, 77))	('CDKN2A', 'Gene', (179, 185))
117669	31819191	Although inhibitors of purine biosynthesis are predicted to be synthetically lethal in cancers with defects in MTAP, at least in vitro, this effect may be bypassed if tumour cells take up adenine from the microenvironment.	('MTAP', 'Gene', (111, 115))	('cancers', 'Disease', (87, 94))	('defects', 'Var', (100, 107))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('iron', 'Chemical', 'MESH:D007501', (213, 217))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', (167, 173))	('MTAP', 'Gene', '4507', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('purine', 'Chemical', 'MESH:C030985', (23, 29))	('biosynthesis', 'biological_process', 'GO:0009058', ('30', '42'))	('adenine', 'Chemical', 'MESH:D000225', (188, 195))	('inhibitors', 'Var', (9, 19))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
117672	31819191	It will be interesting to assess whether loss of MTAP could be a predictive marker of response of MPM patients to PRMT inhibitors.	('loss', 'Var', (41, 45))	('MTAP', 'Gene', '4507', (49, 53))	('patients', 'Species', '9606', (102, 110))	('MPM', 'Disease', (98, 101))	('MTAP', 'Gene', (49, 53))
117674	31819191	4), which are involved in mRNA processing, suggesting that PRMT5 inhibitors may also produce major changes in the pattern of mRNA expression.	('changes', 'Reg', (99, 106))	('mRNA processing', 'biological_process', 'GO:0006397', ('26', '41'))	('pattern', 'MPA', (114, 121))	('inhibitors', 'Var', (65, 75))	('mRNA expression', 'MPA', (125, 140))	('PRMT5', 'Gene', (59, 64))	('PRMT5', 'Gene', '10419', (59, 64))
117675	31819191	Interestingly, intraperitoneal injections of asbestos in Nf2+ /- mice result in the development of mesothelioma that recapitulate many of the molecular features of human MPM, including deletions of the CDKN2A locus that span nearby loci.	('asbestos', 'Chemical', 'MESH:D001194', (45, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('human', 'Species', '9606', (164, 169))	('mice', 'Species', '10090', (65, 69))	('deletions', 'Var', (185, 194))	('CDKN2A', 'Gene', '1029', (202, 208))	('CDKN2A', 'Gene', (202, 208))	('mesothelioma', 'Disease', (99, 111))
117677	31819191	Another potentially interesting alteration observed in MPM patients is the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), a key enzyme in arginine biosynthesis.	('argininosuccinate synthetase 1', 'Gene', '445', (99, 129))	('ASS1', 'Gene', '445', (131, 135))	('arginine biosynthesis', 'biological_process', 'GO:0006526', ('154', '175'))	('rat', 'Species', '10116', (36, 39))	('ASS1', 'Gene', (131, 135))	('arginine', 'Chemical', 'MESH:D001120', (154, 162))	('patients', 'Species', '9606', (59, 67))	('epigenetic silencing', 'Var', (75, 95))	('argininosuccinate synthetase 1', 'Gene', (99, 129))	('MPM', 'Disease', (55, 58))
117678	31819191	Loss of ASS1 makes MPM cells dependent on exogenous arginine, a metabolic hallmark that may be exploited therapeutically.	('ASS1', 'Gene', '445', (8, 12))	('ASS1', 'Gene', (8, 12))	('dependent', 'Reg', (29, 38))	('arginine', 'Chemical', 'MESH:D001120', (52, 60))	('Loss', 'Var', (0, 4))
117679	31819191	This possibility is supported by a recent study showing that pegylated arginine deiminase (ADI PEG20), an enzyme that destroys circulating arginine, produced a modest but significant increase in progression-free survival in patients with ASS1-deficient advanced MPM.	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('increase', 'PosReg', (183, 191))	('pegylated', 'Var', (61, 70))	('ASS1', 'Gene', (238, 242))	('circulating arginine', 'MPA', (127, 147))	('ASS1', 'Gene', '445', (238, 242))	('patients', 'Species', '9606', (224, 232))	('arginine', 'Chemical', 'MESH:D001120', (139, 147))	('progression-free survival', 'CPA', (195, 220))
117689	31819191	MPM with loss-of-function mutations of BAP1 may be selectively targeted using inhibitors of histone deacetylases (HDAC), histone methyltransferase (histone-lysine-N-methyltransferase enzyme: EZH2), poly ADP ribose polymerase (PARP) or ribonucleotide reductase regulatory subunit M1.	('poly ADP ribose polymerase', 'Gene', '142', (198, 224))	('PARP', 'Gene', (226, 230))	('poly ADP ribose polymerase', 'Gene', (198, 224))	('mutations', 'Var', (26, 35))	('EZH2', 'Gene', (191, 195))	('BAP1', 'Gene', '8314', (39, 43))	('PARP', 'Gene', '142', (226, 230))	('EZH2', 'Gene', '2146', (191, 195))	('loss-of-function', 'NegReg', (9, 25))	('BAP1', 'Gene', (39, 43))
117690	31819191	Loss of MTAP is also interesting, as it potentially generates a condition of synthetic lethality.	('rat', 'Species', '10116', (56, 59))	('MTAP', 'Gene', (8, 12))	('MTAP', 'Gene', '4507', (8, 12))	('synthetic lethality', 'MPA', (77, 96))	('Loss', 'Var', (0, 4))
117691	31819191	Genetic (or epigenetic) alterations in this gene are likely to serve as useful predictive markers to stratify MPM patients with the aim of defining a subset that would be eligible for treatments with inhibitors of PRMT5 or other methyltransferases that may be affected by the accumulation of MTA.	('methyltransferases', 'Enzyme', (229, 247))	('rat', 'Species', '10116', (103, 106))	('alterations', 'Var', (24, 35))	('MTA', 'Chemical', 'MESH:C008500', (292, 295))	('PRMT5', 'Gene', (214, 219))	('rat', 'Species', '10116', (28, 31))	('PRMT5', 'Gene', '10419', (214, 219))	('patients', 'Species', '9606', (114, 122))	('MPM', 'Disease', (110, 113))
117744	31681739	In the ceRNA networks, GAS1RR, AXIN2, AC017104.1, RASSF8-AS1, CGN, MIR4458HG, has-miR-125b-5p, LINC01105, and CASP9 were significantly associated with overall survival in mesothelioma.	('mesothelioma', 'Disease', (171, 183))	('LINC01105', 'Gene', '150622', (95, 104))	('CASP9', 'Gene', (110, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('CGN', 'Gene', '57530', (62, 65))	('AC017104', 'Chemical', 'MESH:C576651', (38, 46))	('CASP9', 'Gene', '842', (110, 115))	('RASSF8-AS1', 'Gene', (50, 60))	('GAS1RR', 'Gene', (23, 29))	('AXIN2', 'Gene', (31, 36))	('GAS', 'molecular_function', 'GO:0034005', ('23', '26'))	('GAS1RR', 'Gene', '100506834', (23, 29))	('MIR4458HG', 'Gene', '100505738', (67, 76))	('MIR4458HG', 'Gene', (67, 76))	('overall', 'MPA', (151, 158))	('RASSF8-AS1', 'Gene', '100506451;11228;5729', (50, 60))	('CGN', 'Gene', (62, 65))	('AC017104.1', 'Var', (38, 48))	('associated with', 'Reg', (135, 150))	('has-miR-125b-5p', 'Var', (78, 93))	('LINC01105', 'Gene', (95, 104))
117751	31681739	Tumor cells with low RASSF8 expression had higher migratory ability and promoted lymph angiogenesis both in vitro and in vivo (Zhang et al.,).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (43, 49))	('lymph angiogenesis', 'CPA', (81, 99))	('RASSF8', 'Gene', '11228', (21, 27))	('angiogenesis', 'biological_process', 'GO:0001525', ('87', '99'))	('low', 'Var', (17, 20))	('RASSF8', 'Gene', (21, 27))	('promoted', 'PosReg', (72, 80))	('migratory ability', 'CPA', (50, 67))
117774	31681739	The WNT/beta-catenin pathway also has an impact on thymocyte development, especially in the double-negative to double-positive transition and positive/negative selection progress (Pongracz et al.,; Yu et al.,; Kovalovsky et al.,; Shen et al.,).	('thymocyte development', 'CPA', (51, 72))	('positive/negative', 'Var', (142, 159))	('impact', 'Reg', (41, 47))	('men', 'Species', '9606', (68, 71))	('WNT/beta-catenin pathway', 'Pathway', (4, 28))
117775	31681739	confirmed the expression of stabilized beta-catenin accelerated the production of CD8 single-positive thymocytes using a transgenic mouse strain (Yu et al.,), which indicated that AXIN2 may be negatively associated with CD8 T cells, and our study indeed proved that.	('expression', 'Var', (14, 24))	('CD8', 'Gene', (82, 85))	('production', 'MPA', (68, 78))	('CD8', 'Gene', '925', (82, 85))	('CD8', 'Gene', (220, 223))	('beta-catenin', 'Protein', (39, 51))	('CD8', 'Gene', '925', (220, 223))	('negatively', 'NegReg', (193, 203))	('mouse', 'Species', '10090', (132, 137))	('associated', 'Interaction', (204, 214))	('accelerated', 'PosReg', (52, 63))
117780	31681739	In clinical analysis, high expression of CGN showed higher survival probability in the UALCAN database (Figure S6), and high expression of AXIN2, CASP9, and CGN indicated higher overall survival in the PROGgeneV2 database (Figure S4).	('high expression', 'Var', (22, 37))	('CASP9', 'Gene', (146, 151))	('higher', 'PosReg', (171, 177))	('CASP9', 'Gene', '842', (146, 151))	('survival', 'CPA', (59, 67))	('CGN', 'Gene', (157, 160))	('CGN', 'Gene', (41, 44))	('CGN', 'Gene', '57530', (157, 160))	('higher', 'PosReg', (52, 58))	('CGN', 'Gene', '57530', (41, 44))	('AXIN2', 'Gene', (139, 144))
117799	27853379	FAS and FASL genetic polymorphisms impact on clinical outcome of malignant pleural mesothelioma FAS-670 A>G (rs1800682) and FASL-844 C>T (rs763110) polymorphisms have been previously correlated with clinical outcome of non-small cell lung cancer (NSCLC) and breast and bladder cancers.	('NSCLC', 'Disease', (247, 252))	('rs1800682', 'Mutation', 'rs1800682', (109, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('FASL', 'Gene', '356', (124, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (247, 252))	('impact', 'Reg', (35, 41))	('FASL', 'Gene', (8, 12))	('rs763110', 'Mutation', 'rs763110', (138, 146))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (65, 95))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('FASL', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (75, 95))	('correlated', 'Reg', (183, 193))	('bladder cancers', 'Phenotype', 'HP:0009725', (269, 284))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (219, 245))	('polymorphisms', 'Var', (148, 161))	('NSCLC', 'Disease', 'MESH:D002289', (247, 252))	('malignant pleural mesothelioma', 'Disease', (65, 95))	('non-small cell lung cancer', 'Disease', (219, 245))	('FASL', 'Gene', '356', (8, 12))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (258, 284))
117806	27853379	Stratified Cox regression showed that the carriers of FASL-844 CT/TT genotypes were still more susceptible to disease progression than carriers of FASL-844 CC genotype (adjusted HR =3.77, 95% CI: 1.34-10.62, P=0.012).	('susceptible', 'Reg', (95, 106))	('disease progression', 'CPA', (110, 129))	('Cox', 'Gene', (11, 14))	('FASL', 'Gene', (54, 58))	('FASL', 'Gene', '356', (147, 151))	('Cox', 'Gene', '1351', (11, 14))	('FASL', 'Gene', (147, 151))	('FASL', 'Gene', '356', (54, 58))	('CT/TT', 'Var', (63, 68))
117807	27853379	The results of this study suggest that FASL-844 C/T polymorphism could predict PFS in MPM patients receiving platinum-based chemotherapy; therefore, this should be further evaluated as a potential marker for the prediction of clinical outcome in patients with MPM.	('MPM', 'Chemical', '-', (86, 89))	('FASL-844', 'Gene', (39, 47))	('patients', 'Species', '9606', (246, 254))	('platinum', 'Chemical', 'MESH:D010984', (109, 117))	('polymorphism', 'Var', (52, 64))	('predict', 'Reg', (71, 78))	('MPM', 'Chemical', '-', (260, 263))	('MPM', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('PFS', 'Disease', (79, 82))
117820	27853379	FAS-670 A>G and FASL-844 C>T are two polymorphisms located in the promoter region of FAS and FASL genes, respectively, and affect their expression levels.	('FASL', 'Gene', '356', (16, 20))	('FAS', 'Chemical', 'MESH:C038178', (93, 96))	('FASL', 'Gene', (16, 20))	('FAS', 'Chemical', 'MESH:C038178', (16, 19))	('FAS', 'Gene', (85, 88))	('FAS-670 A>G', 'Var', (0, 11))	('FASL', 'Gene', '356', (93, 97))	('FAS', 'Chemical', 'MESH:C038178', (85, 88))	('affect', 'Reg', (123, 129))	('expression levels', 'MPA', (136, 153))	('FASL', 'Gene', (93, 97))	('FAS', 'Chemical', 'MESH:C038178', (0, 3))
117851	27853379	No difference was observed between FASL-844 CC genotype versus FASL-844 CT/TT genotypes (P=0.98) and also between FAS-670 AA genotype versus FAS-670 AG/GG genotypes (P=0.49).	('FAS', 'Chemical', 'MESH:C038178', (141, 144))	('FAS', 'Chemical', 'MESH:C038178', (35, 38))	('FAS', 'Chemical', 'MESH:C038178', (114, 117))	('FAS', 'Chemical', 'MESH:C038178', (63, 66))	('FAS-670 AA', 'Var', (114, 124))	('FASL', 'Gene', '356', (63, 67))	('FASL', 'Gene', '356', (35, 39))	('FASL', 'Gene', (63, 67))	('FASL', 'Gene', (35, 39))
117857	27853379	No significant association was observed between OS rate at 18 months and FASL-844 C>T (log-rank: 0.27; P=0.60) and FAS 670 A>G polymorphisms (log-rank: 1.75; P=0.19) (Table 2).	('FAS', 'Chemical', 'MESH:C038178', (73, 76))	('FAS', 'Chemical', 'MESH:C038178', (115, 118))	('FAS 670 A>G', 'Var', (115, 126))	('670 A>G', 'Mutation', 'rs1800682', (119, 126))	('FASL-844', 'Gene', (73, 81))
117864	27853379	This is the first study to examine the role of FAS-670 A>G and FASL-844 C>T polymorphisms in MPM setting.	('MPM', 'Disease', (93, 96))	('FAS-670', 'Var', (47, 54))	('MPM', 'Chemical', '-', (93, 96))	('FASL-844', 'Gene', (63, 71))
117868	27853379	The current knowledge on the association between FASL-844 C>T and clinical outcome in NSCLC is variable.	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('FASL-844 C>T', 'Var', (49, 61))
117872	27853379	Interestingly, Mahfoudh et al showed that carriers of C-allele are associated with better prognosis in Tunisian breast cancer patients who are similar to the population's ethnicity being from the North African region.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('C-allele', 'Var', (54, 62))	('patients', 'Species', '9606', (126, 134))	('better', 'PosReg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
117881	27853379	In conclusion, the results of this study demonstrate a role of FASL-844 C>T polymorphism as a tumor progression predictor in MPM Egyptian patients treated with platinum-based therapy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MPM', 'Chemical', '-', (125, 128))	('FASL-844', 'Gene', (63, 71))	('tumor', 'Disease', (94, 99))	('polymorphism', 'Var', (76, 88))	('platinum', 'Chemical', 'MESH:D010984', (160, 168))	('patients', 'Species', '9606', (138, 146))
118015	24130923	Inhibition of key proteins in signal transduction pathways, inhibition of transcription factor, modulation of cell-cycle regulation, and induction of apoptosis have been studied as target strategies for understanding carcinogenesis-related mechanisms and cancer prevention.	('signal transduction pathways', 'Pathway', (30, 58))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('signal transduction', 'biological_process', 'GO:0007165', ('30', '49'))	('transcription factor', 'molecular_function', 'GO:0000981', ('74', '94'))	('carcinogenesis', 'Disease', 'MESH:D063646', (217, 231))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('137', '159'))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('carcinogenesis', 'Disease', (217, 231))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('110', '131'))
118158	28100259	In addition, three subcutaneous and orthotopic DMPM xenograft models were used to examine the effect of miR-34a on tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR-34a', 'Var', (104, 111))	('DMPM', 'Chemical', '-', (47, 51))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
118163	28100259	Our preclinical data showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease.	('miR-34a', 'Gene', (70, 77))	('miR-34a-replacement', 'Var', (204, 223))	('immunodeficient', 'Disease', 'MESH:D007153', (130, 145))	('immunodeficient', 'Disease', (130, 145))	('clinical', 'Species', '191496', (7, 15))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('invasion', 'CPA', (106, 114))	('DMPM', 'Chemical', '-', (81, 85))	('mice', 'Species', '10090', (146, 150))	('growth', 'CPA', (120, 126))	('DMPM cell proliferation', 'CPA', (81, 104))	('clinical', 'Species', '191496', (182, 190))
118172	28100259	Deregulated miRNA expression and/or function have been observed in a variety of human solid and hematological tumors and have been causatively linked to the pathogenesis of cancer.	('linked', 'Reg', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('pathogenesis', 'biological_process', 'GO:0009405', ('157', '169'))	('Deregulated', 'Var', (0, 11))	('hematological tumors', 'Disease', (96, 116))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('hematological tumors', 'Disease', 'MESH:D006402', (96, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('function', 'MPA', (36, 44))	('observed', 'Reg', (55, 63))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
118175	28100259	Its expression has been found to be decreased in a variety of human tumors due to DNA copy number loss or epigenetic silencing through aberrant CpG methylation.	('epigenetic silencing', 'Var', (106, 126))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('expression', 'MPA', (4, 14))	('copy number loss', 'Disease', (86, 102))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('copy number loss', 'Disease', 'MESH:D016388', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('aberrant', 'Var', (135, 143))	('CpG', 'Protein', (144, 147))	('DNA', 'Gene', (82, 85))	('decreased', 'NegReg', (36, 45))
118181	28100259	Here, we report that miR-34a is down-regulated in DMPM clinical specimens and demonstrate that miR-34a replacement in a unique collection of in-house-developed human DMPM experimental models inhibits cell proliferation and invasion and impairs tumor growth formation in SCID mice, mainly as a consequence of c-MET and AXL inhibition.	('miR-34a', 'Gene', (21, 28))	('DMPM', 'Chemical', '-', (50, 54))	('mice', 'Species', '10090', (275, 279))	('cell proliferation', 'CPA', (200, 218))	('down-regulated', 'NegReg', (32, 46))	('formation', 'biological_process', 'GO:0009058', ('257', '266'))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('clinical', 'Species', '191496', (55, 63))	('inhibition', 'NegReg', (322, 332))	('human', 'Species', '9606', (160, 165))	('DMPM', 'Chemical', '-', (166, 170))	('SCID', 'Disease', 'MESH:D053632', (270, 274))	('cell proliferation', 'biological_process', 'GO:0008283', ('200', '218'))	('AXL', 'MPA', (318, 321))	('invasion', 'CPA', (223, 231))	('miR-34a', 'Gene', (95, 102))	('impairs tumor', 'Disease', 'MESH:D015417', (236, 249))	('impairs tumor', 'Disease', (236, 249))	('SCID', 'Disease', (270, 274))	('replacement', 'Var', (103, 114))	('inhibits', 'NegReg', (191, 199))	('c-MET', 'Protein', (308, 313))
118183	28100259	Moreover, we provide evidence of persistent activation of ERK1/2 and AKT as a possible cytoprotective mechanism to RTK inhibition by miR-34a.	('AKT', 'Gene', (69, 72))	('activation', 'PosReg', (44, 54))	('ERK1/2', 'Pathway', (58, 64))	('AKT', 'Gene', '207', (69, 72))	('ERK1', 'molecular_function', 'GO:0004707', ('58', '62'))	('miR-34a', 'Var', (133, 140))
118192	28100259	Mature miRNA expression was assayed by miScript Primer Assays specific for miR-34a (MS00003318) and normalized on SNORD48 (MS00007511) (QIAGEN).	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('SNORD48', 'Gene', '26801', (114, 121))	('MS00003318', 'Var', (84, 94))	('SNORD48', 'Gene', (114, 121))	('miR', 'Gene', '220972', (7, 10))	('miR', 'Gene', (7, 10))	('MS00007511', 'Var', (123, 133))
118214	28100259	Volume inhibition percentage (TVI%) in tumors derived from miR-34a- over Neg-transfected cells was calculated as follows: TVI% = 100 - (mean miR-34a TV/mean Neg TV x 100).	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('TVI', 'Chemical', '-', (122, 125))	('miR-34a', 'Var', (141, 148))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TVI', 'Chemical', '-', (30, 33))	('tumors', 'Disease', (39, 45))
118234	28100259	A reduced abundance of phospho-ERK1/2 and phospho-AKT was appreciable in STO cells at 72 and 96 h after transfection with miR-34a mimic (Fig.	('AKT', 'Gene', '207', (50, 53))	('reduced', 'NegReg', (2, 9))	('AKT', 'Gene', (50, 53))	('ERK1', 'molecular_function', 'GO:0004707', ('31', '35'))	('miR-34a', 'Var', (122, 129))
118236	28100259	To assess whether activation of AKT or MAPK/ERK1/2 signaling pathways, which is a well-known mechanism of resistance to RTK inhibitors, could also represent a cytoprotective mechanism to the oncosuppessive effects of miR-34a, we exposed miRNA-reconstituted MesoII cells to subtoxic concentrations of small-molecule AKT (A6730) and MEK1 (CI-1040) inhibitors (Fig.	('MEK1', 'molecular_function', 'GO:0004708', ('331', '335'))	('A6730', 'Chemical', '-', (320, 325))	('MEK1', 'Gene', (331, 335))	('ERK1', 'molecular_function', 'GO:0004707', ('44', '48'))	('AKT', 'Gene', '207', (32, 35))	('CI-1040', 'Chemical', 'MESH:C120227', (337, 344))	('A6730', 'Var', (320, 325))	('miR', 'Gene', '220972', (237, 240))	('AKT', 'Gene', (32, 35))	('miR', 'Gene', (237, 240))	('AKT', 'Gene', '207', (315, 318))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('miR', 'Gene', '220972', (217, 220))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('miR', 'Gene', (217, 220))	('MEK1', 'Gene', '5604', (331, 335))	('MAPK/ERK1/2 signaling pathways', 'Pathway', (39, 69))	('AKT', 'Gene', (315, 318))
118237	28100259	Interestingly, inactivating ERK1/2 or impeding the reactivation of AKT only slightly affected MesoII response to miR-34a, whereas the concomitant blockade of the two pathways, made the sensitivity profile of MesoII cells superimposable on that of the inherently sensitive STO cell line (Fig.	('impeding', 'NegReg', (38, 46))	('reactivation', 'MPA', (51, 63))	('AKT', 'Gene', '207', (67, 70))	('inactivating', 'Var', (15, 27))	('AKT', 'Gene', (67, 70))	('affected', 'Reg', (85, 93))	('ERK1/2', 'Protein', (28, 34))	('ERK1', 'molecular_function', 'GO:0004707', ('28', '32'))
118243	28100259	Moreover, AXL silencing did not inhibit AKT and ERK1/2 signaling pathways similarly to miR-34a reconstitution (Additional file 2: Figure S2).	('silencing', 'Var', (14, 23))	('inhibit', 'NegReg', (32, 39))	('AKT', 'Gene', '207', (40, 43))	('ERK1', 'molecular_function', 'GO:0004707', ('48', '52'))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('AKT', 'Gene', (40, 43))
118248	28100259	Interestingly, miR-34a ectopic expression consistently reduced FAK posphorylation at Y576/577 in STO, MesoII, and MP115 cell models, suggesting that miR-34a-induced inhibition of cell invasion can occur regardless of MAPK and AKT activation (Fig.	('AKT', 'Gene', (226, 229))	('miR-34a-induced', 'Var', (149, 164))	('cell invasion', 'CPA', (179, 192))	('reduced', 'NegReg', (55, 62))	('ectopic expression', 'Var', (23, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('217', '221'))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('miR-34a', 'Gene', (15, 22))	('FAK', 'Gene', (63, 66))	('AKT', 'Gene', '207', (226, 229))	('FAK', 'Gene', '5747', (63, 66))	('inhibition', 'NegReg', (165, 175))
118250	28100259	Indeed, antibody array results obtained in conditioned medium of miR-34a-reconstituted cells (at 72 h following transfection) showed a reduced secretion of the urokinase-type plasminogen activator (uPA), which plays a major role in promoting angiogenesis, together with and increased release of maspin, a member of the serine protease inhibitor (serpin) superfamily, which exerts antiangiogenic effects through the inhibition of both the growth and migration of endothelial cells (Fig.	('maspin', 'Gene', '5268', (295, 301))	('growth', 'CPA', (438, 444))	('angiogenesis', 'biological_process', 'GO:0001525', ('242', '254'))	('secretion', 'biological_process', 'GO:0046903', ('143', '152'))	('serpin', 'molecular_function', 'GO:0004868', ('346', '352'))	('maspin', 'Gene', (295, 301))	('migration of endothelial cells', 'CPA', (449, 479))	('antibody', 'cellular_component', 'GO:0019815', ('8', '16'))	('uPA', 'Gene', (198, 201))	('uPA', 'molecular_function', 'GO:0008243', ('198', '201'))	('secretion', 'MPA', (143, 152))	('uPA', 'Gene', '5328', (198, 201))	('miR-34a-reconstituted', 'Var', (65, 86))	('antibody', 'cellular_component', 'GO:0019814', ('8', '16'))	('urokinase-type plasminogen activator', 'Gene', (160, 196))	('inhibition', 'NegReg', (415, 425))	('reduced', 'NegReg', (135, 142))	('promoting', 'PosReg', (232, 241))	('urokinase-type plasminogen activator', 'molecular_function', 'GO:0008243', ('160', '196'))	('angiogenesis', 'CPA', (242, 254))	('urokinase-type plasminogen activator', 'Gene', '5328', (160, 196))	('antibody', 'molecular_function', 'GO:0003823', ('8', '16'))	('antibody', 'cellular_component', 'GO:0042571', ('8', '16'))
118254	28100259	Results indicate that miR-34a consistently impaired the growth of all s.c. xenograft models, with maximum tumor volume inhibitions ranging from 57 to 98% (Fig.	('growth', 'CPA', (56, 62))	('impaired', 'NegReg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR-34a', 'Var', (22, 29))	('tumor', 'Disease', (106, 111))
118259	28100259	miR-34a ectopic expression did not influence the take of MP8 cells but markedly reduced their growth, as indicated by a significantly reduced tumor weight (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ectopic expression', 'Var', (8, 26))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('reduced', 'NegReg', (80, 87))	('reduced', 'NegReg', (134, 141))	('miR-34a', 'Gene', (0, 7))	('growth', 'MPA', (94, 100))
118262	28100259	We also illustrated that miR-34a exerts oncosuppressive functions in our tumor models, consistent to what previously observed in a variety of human tumor types.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('miR-34a', 'Var', (25, 32))	('oncosuppressive functions', 'MPA', (40, 65))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (148, 153))	('human', 'Species', '9606', (142, 147))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
118265	28100259	Noteworthy, DMPM cell feedback to AXL and c-MET down-regulation induced by miR-34a reconstitution is to directly activate ERK1/2 and AKT survival signaling cascades rather than up-regulate the expression levels of the receptors, thus ensuring a more prompt counter-response.	('down-regulation', 'NegReg', (48, 63))	('DMPM', 'Chemical', '-', (12, 16))	('ERK1/2', 'Pathway', (122, 128))	('AKT', 'Gene', '207', (133, 136))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('miR-34a', 'Gene', (75, 82))	('ERK1', 'molecular_function', 'GO:0004707', ('122', '126'))	('c-MET', 'MPA', (42, 47))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('AXL', 'MPA', (34, 37))	('AKT', 'Gene', (133, 136))	('activate', 'PosReg', (113, 121))	('reconstitution', 'Var', (83, 97))
118270	28100259	In addition, the delayed pro-apoptotic and cytotoxic effects observed in MesoII cells following miR-34a reconstitution are consistent with the finding that, unlike other epithelioid cell lines, they carry a mutant p53.	('mutant', 'Var', (207, 213))	('p53', 'Gene', (214, 217))	('p53', 'Gene', '7157', (214, 217))	('cytotoxic effects', 'CPA', (43, 60))
118271	28100259	A novel mechanism of miR-34a-dependent AKT inhibition has been recently proposed by Wang et al..	('inhibition', 'NegReg', (43, 53))	('miR-34a-dependent', 'Var', (21, 38))	('AKT', 'Gene', (39, 42))	('AKT', 'Gene', '207', (39, 42))
118272	28100259	In this study, miR-34a is reported to inhibit Bmi-1 by targeting c-Myc in gastric cancer cells, resulting in a PTEN-dependent reduction of phospho-AKT.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Bmi-1', 'Gene', (46, 51))	('PTEN', 'Gene', (111, 115))	('c-Myc', 'Gene', (65, 70))	('PTEN', 'Gene', '5728', (111, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('gastric cancer', 'Disease', (74, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('miR-34a', 'Var', (15, 22))	('Bmi-1', 'Gene', '648', (46, 51))	('AKT', 'Gene', '207', (147, 150))	('reduction', 'NegReg', (126, 135))	('c-Myc', 'Gene', '4609', (65, 70))	('inhibit', 'NegReg', (38, 45))	('targeting', 'Reg', (55, 64))	('AKT', 'Gene', (147, 150))
118275	28100259	Interestingly, miR-34a induced a remarkable antitumor activity in the three cell lines (STO, MesoII and MP8) able to generate tumors following xenotransplantation into immunodeficient mice.	('tumors', 'Disease', (126, 132))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('immunodeficient', 'Disease', 'MESH:D007153', (168, 183))	('immunodeficient', 'Disease', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mice', 'Species', '10090', (184, 188))	('miR-34a', 'Var', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
118277	28100259	Specifically, miR-34a significantly inhibited the take of STO cells, with only one mouse developing small tumor nodules in the abdominal cavity.	('miR-34a', 'Var', (14, 21))	('inhibited', 'NegReg', (36, 45))	('mouse', 'Species', '10090', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('take of STO cells', 'CPA', (50, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('small tumor nodules', 'Phenotype', 'HP:0002732', (100, 119))	('tumor', 'Disease', (106, 111))
118279	28100259	Unfortunately, the inability of MP115:the only biphasic DMPM model in our panel:to grow in vivo prevented us to assess whether the in vitro cytostatic effect consequent to miR-34a reconstitution, which was paralleled by the induction of a senescence-like phenotype possibly sustained by ATK activation, may result or not in tumor growth impairment.	('miR-34a', 'Var', (172, 179))	('tumor growth impairment', 'Disease', 'MESH:D006130', (324, 347))	('tumor growth impairment', 'Disease', (324, 347))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('growth impairment', 'Phenotype', 'HP:0001510', (330, 347))	('senescence', 'biological_process', 'GO:0010149', ('239', '249'))	('DMPM', 'Chemical', '-', (56, 60))
118280	28100259	However, the significantly reduced invasive potential induced by miR-34a in DMPM cell lines through the inhibition of FAK signaling could primarily contribute to the antitumor effect observed in the xenograft models.	('inhibition', 'NegReg', (104, 114))	('FAK', 'Gene', (118, 121))	('reduced', 'NegReg', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('FAK', 'Gene', '5747', (118, 121))	('miR-34a', 'Var', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('invasive potential', 'CPA', (35, 53))	('tumor', 'Disease', (170, 175))	('FAK', 'molecular_function', 'GO:0004717', ('118', '121'))	('DMPM', 'Chemical', '-', (76, 80))
118281	28100259	for miR-34a reconstituted HepG2 hepatocellular carcinoma cells.	('miR-34a', 'Var', (4, 11))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (32, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('hepatocellular carcinoma', 'Disease', (32, 56))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (32, 56))	('HepG2', 'CellLine', 'CVCL:0027', (26, 31))
118282	28100259	Interestingly, our evidence indicating that miR-34a ectopic expression impairs the secretion of angiogenesis-related factors by MesoII cells strongly suggests that the antitumor effect observed in both s.c. and ortothopic xenograft models can also rely on miRNA-induced modification of tumor microenvironment, making it less favorable to tumor growth.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', '220972', (256, 259))	('miR', 'Gene', (44, 47))	('miR', 'Gene', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('secretion of angiogenesis-related factors', 'MPA', (83, 124))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('tumor', 'Disease', (172, 177))	('angiogenesis', 'biological_process', 'GO:0001525', ('96', '108'))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (338, 343))	('secretion', 'biological_process', 'GO:0046903', ('83', '92'))	('ectopic expression', 'Var', (52, 70))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('impairs', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (338, 343))
118294	26078352	Today a new man-made material, carbon nanotubes, has arisen as a concern; carbon nanotubes may display 'asbestos-like' pathogenicity with mesothelioma induction potential.	('asbestos', 'Chemical', 'MESH:D001194', (104, 112))	('carbon', 'Chemical', 'MESH:D002244', (31, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))	('mesothelioma', 'Disease', (138, 150))	('carbon', 'Chemical', 'MESH:D002244', (74, 80))	('man', 'Species', '9606', (12, 15))	('carbon nanotubes', 'Var', (74, 90))
118343	26078352	These substitutions have been reported as the sites of spontaneous oncogene expression and may be largely responsible for the onset of carcinogenesis and cell proliferation, ultimately leading to cancer manifestation.	('substitutions', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('carcinogenesis', 'Disease', (135, 149))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('man', 'Species', '9606', (203, 206))	('cancer', 'Disease', (196, 202))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('leading to', 'Reg', (185, 195))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))
118344	26078352	Most of the necessary mutations occur early during cancer development, also resulting in processes such as chronic inflammation, together providing the environment to expand and select malignant clones.	('chronic inflammation', 'Disease', (107, 127))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('iron', 'Chemical', 'MESH:D007501', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (22, 31))	('resulting in', 'Reg', (76, 88))	('cancer', 'Disease', (51, 57))	('chronic inflammation', 'Disease', 'MESH:D007249', (107, 127))
118350	26078352	ROS may attack biological macromolecules such as membrane lipids and lead to their peroxidation.	('ROS', 'Var', (0, 3))	('membrane', 'cellular_component', 'GO:0016020', ('49', '57'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('membrane', 'Protein', (49, 57))	('peroxidation', 'MPA', (83, 95))	('lead to', 'Reg', (69, 76))	('attack', 'Reg', (8, 14))	('lipids', 'Chemical', 'MESH:D008055', (58, 64))
118358	26078352	Interestingly,  NO also attenuates H2O2-induced lipid peroxidation and pulmonary artery endothelial cell injury, suggesting that it has antioxidant functions.	('pulmonary artery endothelial cell injury', 'Disease', 'MESH:D055370', (71, 111))	('attenuates', 'NegReg', (24, 34))	('lipid', 'Chemical', 'MESH:D008055', (48, 53))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('pulmonary artery endothelial cell injury', 'Disease', (71, 111))	('O2-', 'Chemical', '-', (37, 40))	('H2O2-induced', 'Var', (35, 47))
118361	26078352	This effect was reduced by the NOS inhibitor, NG-monomethyl-L-arginine.	('NG-monomethyl-L-arginine', 'Chemical', 'MESH:D019323', (46, 70))	('NG-monomethyl-L-arginine', 'Var', (46, 70))	('NOS inhibitor', 'biological_process', 'GO:0051001', ('31', '44'))	('reduced', 'NegReg', (16, 23))
118374	26078352	The mouse peritoneal cavity has been used as a model of direct mesothelial exposure, and much greater inflammatory responses were evidenced in mice exposed to high doses of long fibres than in those exposed to shorter fibres.	('mouse', 'Species', '10090', (4, 9))	('greater', 'PosReg', (94, 101))	('inflammatory responses', 'CPA', (102, 124))	('long fibres', 'Var', (173, 184))	('mice', 'Species', '10090', (143, 147))
118385	26078352	A hallmark of the "tumor promotion" is the modulation of gene expression resulting in increased cell number either through cell division and/or decrease in apoptotic cell death.	('gene expression', 'MPA', (57, 72))	('increased', 'PosReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('decrease', 'NegReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cell number', 'CPA', (96, 107))	('modulation', 'Var', (43, 53))	('cell division', 'CPA', (123, 136))	('tumor', 'Disease', (19, 24))	('apoptotic cell death', 'CPA', (156, 176))
118386	26078352	Following additional chemical insults or through multiple divisions and acquisition of mutations in the preneoplastic focal lesions, the formation of benign and/or malignant neoplasms can occur during the progression stage.	('neoplasms', 'Disease', 'MESH:D009369', (174, 183))	('neoplasms', 'Disease', (174, 183))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('neoplasms', 'Phenotype', 'HP:0002664', (174, 183))	('mutations', 'Var', (87, 96))
118399	26078352	The occurrence of multiple, recurrent cytogenetic deletions suggests that loss or inactivation of tumor suppressor genes is critical to the development and progression of mesothelioma.	('mesothelioma', 'Disease', (171, 183))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('loss', 'NegReg', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('tumor', 'Disease', (98, 103))	('inactivation', 'NegReg', (82, 94))	('deletions', 'Var', (50, 59))
118401	26078352	Among the known cytogenetic changes, the most frequent is the loss of p16/CDKN2A-p14ARF at 9p21(by homozygous deletion), adversely affecting both Rb and p53 pathways, respectively.	('loss', 'Var', (62, 66))	('p14ARF', 'Gene', (81, 87))	('p16', 'Gene', '1029', (70, 73))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('p14ARF', 'Gene', '1029', (81, 87))	('affecting', 'Reg', (131, 140))	('p16', 'Gene', (70, 73))
118402	26078352	NF2 (merlin), a tumor suppressor located at 22q12, is also frequently altered in mesotheliomas (by an inactivating mutation coupled with allelic loss).	('altered', 'Reg', (70, 77))	('NF2', 'Gene', (0, 3))	('inactivating mutation', 'Var', (102, 123))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('NF2', 'Gene', '4771', (0, 3))	('merlin', 'Gene', '4771', (5, 11))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('mesotheliomas', 'Disease', 'MESH:D008654', (81, 94))	('mesotheliomas', 'Disease', (81, 94))	('merlin', 'Gene', (5, 11))
118423	26078352	Consequently, ROS potentiate the survival pathways in MM.	('ROS', 'Var', (14, 17))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('potentiate', 'PosReg', (18, 28))	('survival pathways', 'CPA', (33, 50))
118436	26078352	NF-kB triggers the activation of a number of genes involved in cell proliferation and apoptosis, including cytokines, growth factors, and adhesion molecules as well as proto-oncogenes such as c-myc.	('c-myc', 'Gene', '4609', (192, 197))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('rat', 'Species', '10116', (75, 78))	('c-myc', 'Gene', (192, 197))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('activation', 'PosReg', (19, 29))	('NF-kB', 'Var', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
118438	26078352	Kinases, such as protein kinase C (PKC), can also be activated by H2O2 and redox cycling quinones.	('H2O2', 'Var', (66, 70))	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('activated', 'PosReg', (53, 62))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('quinones', 'Chemical', 'MESH:D011809', (89, 97))	('H2O2', 'Chemical', 'MESH:D006861', (66, 70))
118447	26078352	Exposure of cells to H2O2 increases MMP-2 activation via a receptor tyrosine kinases/PI3-kinase/NF-kappaB activation.	('activation', 'MPA', (42, 52))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('96', '116'))	('MMP-2', 'Gene', '4313', (36, 41))	('NF-kappaB', 'Gene', '4790', (96, 105))	('MMP-2', 'molecular_function', 'GO:0004228', ('36', '41'))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('H2O2', 'Var', (21, 25))	('activation', 'PosReg', (106, 116))	('NF-kappaB', 'Gene', (96, 105))	('MMP-2', 'Gene', (36, 41))
118469	26078352	Tight regulation of the dynamic equilibrium between proangiogenic and antiangiogenic factors is critical to health, as an imbalance in either direction contributes to a wide range of pathological conditions from atherosclerosis to cancer.	('atherosclerosis to cancer', 'Disease', 'MESH:D050197', (212, 237))	('contributes to', 'Reg', (152, 166))	('imbalance', 'Var', (122, 131))	('atherosclerosis', 'Phenotype', 'HP:0002621', (212, 227))	('atherosclerosis to cancer', 'Disease', (212, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('imbalance', 'Phenotype', 'HP:0002172', (122, 131))	('regulation', 'biological_process', 'GO:0065007', ('6', '16'))
118476	26078352	ROS can induce cell death by apoptosis, necrosis, and autophagy.	('apoptosis', 'CPA', (29, 38))	('ROS', 'Var', (0, 3))	('necrosis', 'biological_process', 'GO:0070265', ('40', '48'))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('necrosis', 'biological_process', 'GO:0019835', ('40', '48'))	('cell death', 'biological_process', 'GO:0008219', ('15', '25'))	('necrosis', 'biological_process', 'GO:0008220', ('40', '48'))	('autophagy', 'CPA', (54, 63))	('necrosis', 'biological_process', 'GO:0001906', ('40', '48'))	('induce', 'Reg', (8, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('necrosis', 'Disease', (40, 48))	('cell death', 'CPA', (15, 25))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))	('necrosis', 'biological_process', 'GO:0008219', ('40', '48'))	('necrosis', 'Disease', 'MESH:D009336', (40, 48))
118478	26078352	Both extrinsic and intrinsic pathways of apoptosis depend on ROS.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('ROS', 'Var', (61, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('intrinsic pathways', 'Pathway', (19, 37))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
118490	26078352	Poly-ADP-ribose polymerase (PARP), a nuclear enzyme, is activated by DNA strand breaks.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('PARP', 'Gene', (28, 32))	('DNA strand breaks', 'Var', (69, 86))	('activated', 'PosReg', (56, 65))	('PARP', 'Gene', '142', (28, 32))	('Poly-ADP-ribose polymerase', 'Gene', (0, 26))	('Poly-ADP-ribose polymerase', 'Gene', '142', (0, 26))
118502	26078352	Moreover, ROS cause DNA damage and aneuploidy.	('DNA damage', 'CPA', (20, 30))	('aneuploidy', 'Disease', (35, 45))	('ROS', 'Var', (10, 13))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('cause', 'Reg', (14, 19))	('aneuploidy', 'Disease', 'MESH:D000782', (35, 45))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))
118503	26078352	TNF-alpha activates NF-kappaB, a survival pathway that allows some mesothelial cells undergoing asbestos-induced DNA damage to survive, thereby creating a pool of aneuploid mesothelial cells with the potential to develop into cancer cells.	('develop', 'CPA', (213, 220))	('TNF-alpha', 'Gene', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('NF-kappaB', 'Gene', '4790', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('aneuploid', 'Var', (163, 172))	('cancer', 'Disease', (226, 232))	('NF-kappaB', 'Gene', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('TNF-alpha', 'Gene', '7124', (0, 9))	('asbestos', 'Chemical', 'MESH:D001194', (96, 104))
118534	26078352	As such, manipulating ROS levels by redox modulation seems to be a feasible way to selectively kill cancer cells with less toxicity to normal cells.	('man', 'Species', '9606', (9, 12))	('toxicity', 'Disease', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('manipulating', 'Var', (9, 21))
118568	26078352	In human (H2373, H2452, H2461, and H226) and murine (AB12) MM cells, curcumin inhibited cell growth in a dose- and time-dependent manner, while pre-treatment of MM cells with curcumin enhanced cisplatin efficacy.	('human', 'Species', '9606', (3, 8))	('man', 'Species', '9606', (130, 133))	('H2452', 'CellLine', 'CVCL:1553', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('enhanced', 'PosReg', (184, 192))	('H2373', 'Var', (10, 15))	('H2373', 'CellLine', 'CVCL:A533', (10, 15))	('H2452', 'Var', (17, 22))	('cell growth', 'CPA', (88, 99))	('pre', 'molecular_function', 'GO:0003904', ('144', '147'))	('murine', 'Species', '10090', (45, 51))	('H226', 'Var', (35, 39))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('H2461', 'Var', (24, 29))	('curcumin', 'Chemical', 'MESH:D003474', (175, 183))	('H2461', 'CellLine', 'CVCL:A536', (24, 29))	('man', 'Species', '9606', (5, 8))	('inhibited', 'NegReg', (78, 87))	('curcumin', 'Chemical', 'MESH:D003474', (69, 77))
118583	24966347	Non-Amplified FGFR1 is a Growth Driver in Malignant Pleural Mesothelioma Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly impacted by small molecule-based targeted therapeutics.	('Non-Amplified', 'Var', (0, 13))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (42, 72))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (73, 103))	('Mesothelioma Malignant', 'Phenotype', 'HP:0100001', (60, 82))	('Malignant pleural mesothelioma', 'Disease', (73, 103))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FGFR1', 'Gene', '2260', (14, 19))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (83, 103))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('Malignant Pleural Mesothelioma', 'Disease', (42, 72))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (52, 72))	('associated', 'Reg', (113, 123))
118599	24966347	While gain-of-function mutations in EGFR are exceedingly rare in MPM, epidermal growth factor receptor (EGFR) is highly expressed in as many as 97% of tumors.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('70', '93'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('EGFR', 'Gene', (104, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('epidermal growth factor receptor', 'Gene', (70, 102))	('EGFR', 'Gene', '1956', (36, 40))	('mutations', 'Var', (23, 32))	('epidermal growth factor receptor', 'Gene', '1956', (70, 102))	('MPM', 'Disease', (65, 68))	('gain-of-function', 'PosReg', (6, 22))	('EGFR', 'Gene', (36, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('EGFR', 'Gene', '1956', (104, 108))
118603	24966347	Deregulation of the FGFR signaling pathways is observed in various tumor types through multiple mechanisms.	('FGFR signaling pathways', 'Pathway', (20, 43))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))
118604	24966347	Activating mutations occur in FGFR2 and FGFR3 leading to constitutive dimerization in bladder, endometrial and squamous cell lung cancers.	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (111, 137))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('FGFR3', 'Gene', (40, 45))	('squamous cell lung cancers', 'Disease', (111, 137))	('constitutive dimerization', 'MPA', (57, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('endometrial', 'Disease', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('FGFR2', 'Gene', (30, 35))	('FGFR2', 'Gene', '2263', (30, 35))	('FGFR3', 'Gene', '2261', (40, 45))	('bladder', 'Disease', (86, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('lung cancers', 'Phenotype', 'HP:0100526', (125, 137))
118605	24966347	Chromosomal translocations in FGFR genes have also been observed in various malignancies.	('malignancies', 'Disease', (76, 88))	('observed', 'Reg', (56, 64))	('Chromosomal translocations', 'Var', (0, 26))	('FGFR genes', 'Gene', (30, 40))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))
118606	24966347	Amplification of FGFR2 is commonly seen in gastric cancers and FGFR1 in breast cancer, squamous cell lung cancers and HNSCC (FGFR1).	('FGFR1', 'Gene', '2260', (125, 130))	('lung cancers', 'Phenotype', 'HP:0100526', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('FGFR1', 'Gene', (63, 68))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancers', 'Disease', 'MESH:D013274', (43, 58))	('gastric cancers', 'Disease', (43, 58))	('gastric cancers', 'Phenotype', 'HP:0012126', (43, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('FGFR1', 'Gene', (125, 130))	('FGFR2', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HNSCC', 'Disease', (118, 123))	('seen', 'Reg', (35, 39))	('FGFR1', 'Gene', '2260', (63, 68))	('FGFR2', 'Gene', '2263', (17, 22))	('Amplification', 'Var', (0, 13))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (87, 113))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('squamous cell lung cancers', 'Disease', (87, 113))
118607	24966347	The increase in FGFR1 gene copy number is especially relevant to lung cancer and serves as the key biomarker for patient recruitment to two open trials of FGFR-specific TKIs in solid tumors (NCT01004224 and NCT00979134).	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('patient', 'Species', '9606', (113, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR1', 'Gene', '2260', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('solid tumors', 'Disease', 'MESH:D009369', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('copy number', 'Var', (27, 38))	('solid tumors', 'Disease', (177, 189))	('FGFR1', 'Gene', (16, 21))
118612	24966347	H28, H513, H2052, H2452, MSTO211H, and Met5A cells were obtained from ATCC (Manassas, VA) and passaged less than 6 months after receipt for completion of the studies.	('H2452', 'CellLine', 'CVCL:1553', (18, 23))	('H2452', 'Var', (18, 23))	('MSTO211H', 'CellLine', 'CVCL:1430', (25, 33))	('H513', 'CellLine', 'CVCL:A570', (5, 9))	('H2052', 'Var', (11, 16))
118626	24966347	Aliquots of the cell lysates containing 150 microg of protein were submitted to SDS-PAGE and immunoblotted for FGFR1 (Origene, Rockville, MD, #TA301021) or FGFR2 (sc-122), FGFR3 (sc-13121) and NaK-ATPase alpha-subunit (sc-21712) (Santa Cruz Biotechnology).	('FGFR1', 'Gene', '2260', (111, 116))	('FGFR3', 'Gene', '2261', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('SDS', 'Chemical', 'MESH:D012967', (80, 83))	('sc-13121', 'Var', (179, 187))	('NaK-ATPase alpha-subunit', 'Protein', (193, 217))	('FGFR3', 'Gene', (172, 177))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('FGFR2', 'Gene', (156, 161))	('FGFR2', 'Gene', '2263', (156, 161))	('FGFR1', 'Gene', (111, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('156', '160'))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))
118637	24966347	Distinct FGFR1-targeting shRNAs (clone IDs TRCN0000121185 and TRCN0000121186) in the pLKO.1 lentiviral vector were obtained from University of Colorado Cancer Center Functional Genomics shared resource.	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('FGFR1', 'Gene', '2260', (9, 14))	('TRCN0000121186', 'Var', (62, 76))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('FGFR1', 'Gene', (9, 14))
118655	24966347	The mixture of the FGFR1 DNP probe (Ventana Medical Systems, Inc.) and the chromosome 8 DIG probe (Ventana Medical Systems, Inc.) was denatured at 80 C for 12 minutes and subsequently hybridized for 6 hours at 44 C. Probes were detected using the respective antibodies and visualized with a chromogenic reagent conjugated antibody, resulting in a black signal for FGFR1 (ultraView SISH DNP Detection Kit, Ventana Medical Systems, Inc.) as well as a chromogenic reagent conjugated antibody detection kit, resulting in a red signal for chromosome 8 (ultraView Red ISH Detection Kit, Ventana Medical Systems, Inc.).	('antibody', 'cellular_component', 'GO:0019814', ('480', '488'))	('antibody', 'cellular_component', 'GO:0019815', ('322', '330'))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('SISH', 'Disease', (381, 385))	('black signal', 'MPA', (347, 359))	('FGFR1', 'Gene', '2260', (19, 24))	('FGFR1', 'Gene', (364, 369))	('antibody', 'molecular_function', 'GO:0003823', ('480', '488'))	('antibody', 'cellular_component', 'GO:0019814', ('322', '330'))	('antibody', 'cellular_component', 'GO:0042571', ('480', '488'))	('Probes', 'Var', (216, 222))	('mixture', 'Var', (4, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('534', '544'))	('antibody', 'molecular_function', 'GO:0003823', ('322', '330'))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('red signal', 'MPA', (519, 529))	('antibody', 'cellular_component', 'GO:0019815', ('480', '488'))	('FGFR1', 'Gene', (19, 24))	('antibody', 'cellular_component', 'GO:0042571', ('322', '330'))	('FGFR', 'molecular_function', 'GO:0005007', ('364', '368'))	('FGFR1', 'Gene', '2260', (364, 369))	('SISH', 'Disease', 'None', (381, 385))	('DNP', 'Var', (25, 28))
118666	24966347	To validate these gene expression findings, a panel of 7 mesothelioma cell lines was employed for cell and molecular studies where five (H28, H226, H290, H513, and H2052) represent the epithelioid histology of MPM and two (H2452, MSTO211H) represent the biphasic variant.	('mesothelioma', 'Disease', (57, 69))	('H513', 'CellLine', 'CVCL:A570', (154, 158))	('H290', 'Var', (148, 152))	('H513', 'Var', (154, 158))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('H2452', 'Var', (223, 228))	('H2452', 'CellLine', 'CVCL:1553', (223, 228))	('H290', 'CellLine', 'CVCL:A555', (148, 152))	('MSTO211H', 'CellLine', 'CVCL:1430', (230, 238))	('MPM', 'Disease', (210, 213))	('H2052', 'Var', (164, 169))	('H28', 'Var', (137, 140))	('H226', 'CellLine', 'CVCL:J621', (142, 146))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))
118669	24966347	Because FGFR1 gene copy number gain has been identified as a mechanism for increased FGFR1 expression in lung squamous cell carcinomas and HNSCC, the FGFR1 gene amplification status was measured in the mesothelioma cell lines using a fluorescence in situ hybridization (FISH) assay (see Materials and Methods).	('expression', 'MPA', (91, 101))	('copy number', 'Var', (19, 30))	('mesothelioma', 'Disease', (202, 214))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('FGFR1', 'Gene', '2260', (85, 90))	('FGFR1', 'Gene', (8, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('FGFR1', 'Gene', (150, 155))	('increased FGFR1', 'Phenotype', 'HP:0030269', (75, 90))	('increased FGFR1 expression', 'Phenotype', 'HP:0030269', (75, 101))	('increased', 'PosReg', (75, 84))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (105, 134))	('FGFR1', 'Gene', (85, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('FGFR1', 'Gene', '2260', (8, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('lung squamous cell carcinomas', 'Disease', (105, 134))	('gain', 'PosReg', (31, 35))	('FGFR1', 'Gene', '2260', (150, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (110, 134))
118697	24966347	As shown in Figure 2C, FP-1039 potently inhibited anchorage-independent growth of H226 and H2452 cells and more modestly the growth of MSTO211H cells.	('H2452', 'CellLine', 'CVCL:1553', (91, 96))	('MSTO211H', 'CellLine', 'CVCL:1430', (135, 143))	('anchorage-independent growth', 'CPA', (50, 78))	('inhibited', 'NegReg', (40, 49))	('H226', 'CellLine', 'CVCL:J621', (82, 86))	('FP-1039', 'Var', (23, 30))
118713	24966347	RNAi-mediated silencing of FGFR1 inhibited clonogenic growth of two FGFR1-expressing MPM cell lines, H226 and MSTO211H (Fig.	('clonogenic growth', 'CPA', (43, 60))	('silencing', 'Var', (14, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', (27, 32))	('FGFR1', 'Gene', '2260', (68, 73))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('FGFR1', 'Gene', '2260', (27, 32))	('H226', 'CellLine', 'CVCL:J621', (101, 105))	('inhibited', 'NegReg', (33, 42))	('MSTO211H', 'CellLine', 'CVCL:1430', (110, 118))
118717	24966347	FGFR1 is under extensive evaluation as a therapeutic target in NSCLC, especially of the squamous cell histology, based on the frequent gene amplification or copy number gain that has been established in these cancers.	('NSCLC', 'Disease', (63, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('copy number gain', 'Var', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
118722	24966347	Thus, distinct from squamous cell lung cancers and HNSCC, increased FGFR1 is not necessarily associated with gene amplification.	('increased', 'PosReg', (58, 67))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('FGFR1', 'Gene', (68, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('increased FGFR1', 'Phenotype', 'HP:0030269', (58, 73))	('FGFR1', 'Gene', '2260', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (34, 46))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (20, 46))	('gene amplification', 'Var', (109, 127))	('squamous cell lung cancers', 'Disease', (20, 46))
118723	24966347	This observation has obvious implications for future testing of the efficacy of FGFR TKIs in MPM patients since the biomarker being deployed for enrolling cancer patients in clinical trials of the FGFR-specific TKIs, BGJ-398 (NCT01004224) and AZD4547 (NCT00979134), is increased FGFR1 gene copy number.	('patients', 'Species', '9606', (162, 170))	('NCT01004224', 'Var', (226, 237))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('FGFR', 'molecular_function', 'GO:0005007', ('197', '201'))	('FGFR', 'molecular_function', 'GO:0005007', ('279', '283'))	('FGFR1', 'Gene', (279, 284))	('AZD4547', 'Var', (243, 250))	('increased FGFR1', 'Phenotype', 'HP:0030269', (269, 284))	('FGFR1', 'Gene', '2260', (279, 284))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('patients', 'Species', '9606', (97, 105))
118726	24966347	In this trial, lung cancer patients of all histologies are enrolled for ponatinib treatment based on tumor positivity for FGFR1 mRNA assessed by in situ hybridization, gene copy number gain by SISH or positivity for both FGFR1 mRNA and gene copy number gain.	('gene copy number gain', 'Var', (236, 257))	('gene copy number', 'Var', (168, 184))	('ponatinib', 'Chemical', 'MESH:C545373', (72, 81))	('lung cancer', 'Disease', (15, 26))	('FGFR1', 'Gene', (221, 226))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))	('gain', 'PosReg', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('FGFR1', 'Gene', '2260', (122, 127))	('patients', 'Species', '9606', (27, 35))	('SISH', 'Disease', 'None', (193, 197))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('positivity', 'Var', (201, 211))	('FGFR1', 'Gene', '2260', (221, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('FGFR1', 'Gene', (122, 127))	('tumor', 'Disease', (101, 106))	('SISH', 'Disease', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('221', '225'))
118731	24966347	The clinical experience with gefitinib and erlotinib in EGFR mutant lung cancer patients and crizotinib in ALK-rearranged lung cancer patients provides precedent for the limitations associated with TKI monotherapy due to acquired resistance.	('patients', 'Species', '9606', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('EGFR', 'Gene', '1956', (56, 60))	('patients', 'Species', '9606', (134, 142))	('erlotinib', 'Chemical', 'MESH:D000069347', (43, 52))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('crizotinib', 'Chemical', 'MESH:D000077547', (93, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('ALK', 'Gene', '238', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gefitinib', 'Chemical', 'MESH:D000077156', (29, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('ALK', 'Gene', (107, 110))	('lung cancer', 'Disease', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('EGFR', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
118733	24966347	In addition to prevention of acquired resistance, combinations of TKIs may disrupt the function of RTK co-activation networks that are generally active in cancer cells and MPM specifically.	('TKIs', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('RTK', 'Gene', (99, 102))	('disrupt', 'NegReg', (75, 82))	('function', 'MPA', (87, 95))	('combinations', 'Var', (50, 62))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('RTK', 'Gene', '5979', (99, 102))
118756	24089446	In accordance with these observations, nab-paclitaxel, the first therapeutic agent developed by the nab  technology (Celgene), showed improved drug delivery, safety, and efficacy compared with the conventional solvent-based paclitaxel in various solid tumors.	('efficacy', 'MPA', (170, 178))	('improved', 'PosReg', (134, 142))	('nab-paclitaxel', 'Var', (39, 53))	('solid tumors', 'Disease', 'MESH:D009369', (246, 258))	('paclitaxel', 'Chemical', 'MESH:D017239', (224, 234))	('nab', 'Chemical', '-', (39, 42))	('Celgene', 'Chemical', 'MESH:D013792', (117, 124))	('safety', 'CPA', (158, 164))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('nab', 'Chemical', '-', (100, 103))	('solid tumors', 'Disease', (246, 258))	('drug delivery', 'MPA', (143, 156))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))
118757	24089446	In preclinical studies, nab-rapamycin has shown an excellent efficacy and safety profile; it reduced cell viability and decreased downstream signaling in various xenograft cancer models, including pancreatic, colorectal, multiple myeloma, and breast cancer.	('multiple myeloma', 'Disease', 'MESH:D009101', (221, 237))	('pancreatic', 'Disease', (197, 207))	('nab-rapamycin', 'Var', (24, 37))	('decreased', 'NegReg', (120, 129))	('downstream signaling', 'MPA', (130, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('colorectal', 'Disease', (209, 219))	('colorectal', 'Disease', 'MESH:D015179', (209, 219))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('multiple myeloma', 'Disease', (221, 237))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('breast cancer', 'Disease', (243, 256))	('xenograft cancer', 'Disease', (162, 178))	('nab-rapamycin', 'Chemical', '-', (24, 37))	('xenograft cancer', 'Disease', 'MESH:D009369', (162, 178))	('pancreatic', 'Disease', 'MESH:D010195', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('multiple myeloma', 'Phenotype', 'HP:0006775', (221, 237))	('reduced', 'NegReg', (93, 100))	('cell viability', 'CPA', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
118800	24089446	Whole blood for pharmacodynamics evaluation was collected only during cycle 1 at 4 time points: C1 D1 (pretreatment), C1 D2, C1 D4, and C1 D8 (immediately prior to next dose) in an 8 mL cell preparation tube with sodium citrate (Becton, Dickinson and Company, Franklin Lakes, NJ).	('C1 D4', 'Var', (125, 130))	('sodium citrate', 'Chemical', 'MESH:D000077559', (213, 227))	('C1 D8', 'Var', (136, 141))	('C1 D2', 'Var', (118, 123))	('C1 D1', 'Var', (96, 101))	('rat', 'Species', '10116', (196, 199))	('rat', 'Species', '10116', (223, 226))
118806	24089446	A total of 135 proteins and 21 replicates were analyzed, including S6 S240/244, S6 S235/236, S6KT389, 4EBP1 T37/46, and 4EBP1 T70.	('S6 S240/244', 'Var', (67, 78))	('S6 S235/236', 'Var', (80, 91))	('S6KT389', 'Var', (93, 100))	('4EBP1', 'Gene', '1978', (120, 125))	('4EBP1', 'Gene', '1978', (102, 107))	('4EBP1', 'Gene', (102, 107))	('4EBP1', 'Gene', (120, 125))
118829	24089446	Specifically, at the MTD (100 mg/m2), all 7 patients experienced at least 1 TRAE of any grades, and the most common AEs were mucositis and fatigue (5 patients, 71% each).	('100 mg/m2', 'Var', (26, 35))	('mucositis and fatigue', 'Disease', 'MESH:D005221', (125, 146))	('patients', 'Species', '9606', (44, 52))	('TRAE', 'Disease', (76, 80))	('experienced', 'Reg', (53, 64))	('AEs', 'Chemical', '-', (116, 119))	('patients', 'Species', '9606', (150, 158))	('fatigue', 'Phenotype', 'HP:0012378', (139, 146))
118847	24089446	There was a rapid decline in whole blood levels of rapamycin in the first 2 hours following the 30-minute infusion of nab-rapamycin, which was followed by a slower elimination phase (Table 3 and Figure 1).	('nab-rapamycin', 'Chemical', '-', (118, 131))	('nab-rapamycin', 'Var', (118, 131))	('whole blood levels', 'MPA', (29, 47))	('decline', 'NegReg', (18, 25))	('rapamycin', 'Chemical', 'MESH:D020123', (122, 131))	('rapamycin', 'Chemical', 'MESH:D020123', (51, 60))
118862	24089446	The MSD phosphoprotein assays revealed very low baseline expression of S6 S240/244 and 4EBP T37/46 in pretreatment PBMC samples, thus we were unable to assess regulation by nab-rapamycin treatment.	('low', 'NegReg', (44, 47))	('S6 S240/244', 'Var', (71, 82))	('4EBP T37/46', 'Var', (87, 98))	('MSD', 'Disease', (4, 7))	('nab-rapamycin', 'Chemical', '-', (173, 186))	('MSD', 'Disease', 'MESH:D052517', (4, 7))	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('baseline expression', 'MPA', (48, 67))	('nab', 'Chemical', '-', (143, 146))	('nab', 'Chemical', '-', (173, 176))
118864	24089446	nab-Rapamycin treatment was associated with a significant decrease of S6K T389 on D2 with persistent inhibition at D8 (Figure 3A and 3B) at all doses.	('decrease', 'NegReg', (58, 66))	('nab-Rapamycin', 'Chemical', '-', (0, 13))	('S6K T389', 'Var', (70, 78))
118865	24089446	nab-Rapamycin treatment was associated with significant decrease of 4EBP1 T70 levels on D2 and D4, but with recovery by D8 (Figure 3A and 3C).	('nab-Rapamycin', 'Var', (0, 13))	('nab-Rapamycin', 'Chemical', '-', (0, 13))	('4EBP1', 'Gene', '1978', (68, 73))	('decrease', 'NegReg', (56, 64))	('4EBP1', 'Gene', (68, 73))
118867	24089446	These results demonstrate that nab-rapamycin has a dose-dependent effect on mTOR signaling, with pathway inhibition being seen at 56.25 mg/m2 and higher doses.	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('mTOR signaling', 'MPA', (76, 90))	('rat', 'Species', '10116', (21, 24))	('nab-rapamycin', 'Chemical', '-', (31, 44))	('nab-rapamycin', 'Var', (31, 44))
118868	24089446	The duration of inhibition differs between downstream targets, and is longer for S6K T389 than for 4EBP1 T70.	('rat', 'Species', '10116', (6, 9))	('4EBP1', 'Gene', '1978', (99, 104))	('4EBP1', 'Gene', (99, 104))	('S6K T389', 'Var', (81, 89))
118872	24089446	The results of this phase 1 dose-finding study demonstrated that the MTD for nab-rapamycin in patients with advanced nonhematologic malignancies was 100 mg/m2, which produced favorable safety profile without the DLTs typically observed with rapalogs.	('patients', 'Species', '9606', (94, 102))	('nab-rapamycin', 'Chemical', '-', (77, 90))	('nab-rapamycin', 'Var', (77, 90))	('rat', 'Species', '10116', (54, 57))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('malignancies', 'Disease', (132, 144))
118874	24089446	mTOR inhibitors can produce potentially life-threatening pneumonitis, but no pneumonitis was observed in this study.	('pneumonitis', 'Disease', (57, 68))	('inhibitors', 'Var', (5, 15))	('pneumonitis', 'Disease', (77, 88))	('pneumonitis', 'Disease', 'MESH:D011014', (77, 88))	('pneumonitis', 'Disease', 'MESH:D011014', (57, 68))	('mTOR', 'Gene', (0, 4))	('produce', 'Reg', (20, 27))
118889	24089446	In accordance with this expectation, molecular analysis of the tumor biopsy from the patient with mesothelioma revealed a single-nucleotide polymorphism that has been associated with PI3K/AKT/mTOR pathway activation.	('tumor', 'Disease', (63, 68))	('patient', 'Species', '9606', (85, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('activation', 'PosReg', (205, 215))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('AKT', 'Gene', '207', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('single-nucleotide polymorphism', 'Var', (122, 152))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (167, 177))	('AKT', 'Gene', (188, 191))	('mesothelioma', 'Disease', (98, 110))
118900	24089446	Importantly, at doses of 56.25 mg/m2 and above, the suppression of S6K T389 and 4EBP1 T70 was maintained for several days after administration suggesting that weekly dosing of nab-rapamycin at the established MTD (100 mg/m2) may be adequate in suppressing these relevant biological targets.	('4EBP1', 'Gene', '1978', (80, 85))	('S6K', 'Var', (67, 70))	('4EBP1', 'Gene', (80, 85))	('rat', 'Species', '10116', (136, 139))	('nab-rapamycin', 'Chemical', '-', (176, 189))
118904	24089446	Studies of either sunitinib or sorafenib in combination with mTOR inhibitors, such as rapamycin (NCT00555256),), temsirolimus (NCT01122615) or everolimus (NCT00422344) have been promising, however, the added toxicity of combination therapies may be concerning.	('NCT00422344', 'Var', (155, 166))	('sorafenib', 'Chemical', 'MESH:D000077157', (31, 40))	('sunitinib', 'Chemical', 'MESH:D000077210', (18, 27))	('NCT00555256', 'Var', (97, 108))	('temsirolimus', 'Chemical', 'MESH:C401859', (113, 125))	('everolimus', 'Chemical', 'MESH:D000068338', (143, 153))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('toxicity', 'Disease', (208, 216))	('NCT01122615', 'Var', (127, 138))	('rapamycin', 'Chemical', 'MESH:D020123', (86, 95))
118907	24089446	Taken together, nab-rapamycin as single agent was well tolerated with preliminary evidence of response and SD in this difficult-to-treat patient population with unresectable advanced nonhematologic malignancies, and should be considered for further study both as single agent and in synergistic combinations.	('nab-rapamycin', 'Chemical', '-', (16, 29))	('nab-rapamycin', 'Var', (16, 29))	('patient', 'Species', '9606', (137, 144))	('malignancies', 'Disease', (198, 210))	('rat', 'Species', '10116', (59, 62))	('malignancies', 'Disease', 'MESH:D009369', (198, 210))
118911	24089446	mTOR inhibitors can produce potentially life-threatening pneumonitis, yet no pneumonitis was observed in this study.	('pneumonitis', 'Disease', (57, 68))	('inhibitors', 'Var', (5, 15))	('pneumonitis', 'Disease', (77, 88))	('pneumonitis', 'Disease', 'MESH:D011014', (77, 88))	('pneumonitis', 'Disease', 'MESH:D011014', (57, 68))	('mTOR', 'Gene', (0, 4))	('produce', 'Reg', (20, 27))
118914	24089446	nab-Rapamycin produced a fairly dose-proportional Cmax and AUC increase, and significantly inhibited mTOR targets.	('increase', 'PosReg', (63, 71))	('Cmax', 'MPA', (50, 54))	('inhibited', 'NegReg', (91, 100))	('nab-Rapamycin', 'Var', (0, 13))	('mTOR targets', 'MPA', (101, 113))	('nab-Rapamycin', 'Chemical', '-', (0, 13))	('AUC', 'MPA', (59, 62))
118953	23937772	HT1080FAP are HT1080 cells stably transfected with human FAP and HT1080PA are mock-transfected HT1080 cells.	('HT1080PA', 'CellLine', 'CVCL:0317', (65, 73))	('HT1080', 'CellLine', 'CVCL:0317', (14, 20))	('HT1080FAP', 'Var', (0, 9))	('HT1080', 'CellLine', 'CVCL:0317', (95, 101))	('human', 'Species', '9606', (51, 56))	('HT1080', 'CellLine', 'CVCL:0317', (0, 6))	('HT1080', 'CellLine', 'CVCL:0317', (65, 71))	('HT1080PA', 'Var', (65, 73))
118957	23937772	To enable in vivo imaging, HT1080FAP and HT1080PA cells were stably transfected with a D-firefly luciferase encoding plasmid (pGL4.26 plasmid, Promega, Dubendorf, Switzerland which was kindly provided by Martin Pruschy, University Hospital Zurich, Switzerland) using Fugene transfection reagent (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer's protocol.	('pGL4', 'Gene', (126, 130))	('pGL4', 'Gene', '6390', (126, 130))	('HT1080FAP', 'Var', (27, 36))	('pGL', 'molecular_function', 'GO:0004598', ('126', '129'))	('HT1080PA', 'Var', (41, 49))	('HT1080PA', 'CellLine', 'CVCL:0317', (41, 49))
118959	23937772	Finally, a stable HT1080FAP-luc and HT1080PA-luc clone were selected that exhibited high luciferase activity and maintained this over months even when cultured in the absence of Hygromycin B.	('luciferase activity', 'molecular_function', 'GO:0047077', ('89', '108'))	('HT1080PA-luc', 'Var', (36, 48))	('HT1080PA', 'CellLine', 'CVCL:0317', (36, 44))	('Hygromycin B', 'Chemical', 'MESH:D006921', (178, 190))	('luciferase activity', 'molecular_function', 'GO:0045289', ('89', '108'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('89', '108'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('89', '108'))	('luciferase', 'Enzyme', (89, 99))	('luciferase activity', 'molecular_function', 'GO:0050397', ('89', '108'))	('activity', 'MPA', (100, 108))
118968	23937772	The variant heavy and the variant light chain of humanized F19 have been converted into a scFv fragment and were flanked with NcoI and BamHI restriction sites.	('F19', 'Gene', (59, 62))	('human', 'Species', '9606', (49, 54))	('scFv', 'Gene', '652070', (90, 94))	('scFv', 'Gene', (90, 94))	('variant', 'Var', (4, 11))
118971	23937772	Furthermore, the CD28 binding domain for lck was corrupted by site directed mutagenesis to avoid IL-2 release and subsequent persistence of Treg cells.	('lck', 'Gene', '3932', (41, 44))	('CD28', 'Gene', (17, 21))	('mutagenesis', 'biological_process', 'GO:0006280', ('76', '87'))	('mutagenesis', 'Var', (76, 87))	('IL-2', 'Gene', '3558', (97, 101))	('avoid', 'NegReg', (91, 96))	('IL-2', 'molecular_function', 'GO:0005134', ('97', '101'))	('IL-2', 'Gene', (97, 101))	('CD28', 'Gene', '940', (17, 21))	('binding', 'molecular_function', 'GO:0005488', ('22', '29'))	('lck', 'Gene', (41, 44))
118974	23937772	It displays the same genetic modifications in the downstream CH2/CH3 and CD28 lck domains.	('CH2/CH3', 'Protein', (61, 68))	('modifications', 'Var', (29, 42))	('lck', 'Gene', (78, 81))	('CD28', 'Gene', (73, 77))	('lck', 'Gene', '3932', (78, 81))	('CD28', 'Gene', '940', (73, 77))
118979	23937772	CD8+ T cells were expanded for 2 more days in R10 plus 100 IU/ml IL-2 before harvest and subsequent application in experiments.	('IL-2', 'Gene', '3558', (65, 69))	('IL-2', 'molecular_function', 'GO:0005134', ('65', '69'))	('IL-2', 'Gene', (65, 69))	('R10', 'Var', (46, 49))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))
118990	23937772	HT1080FAP-luc, HT1080PA-luc, MSTO-211H, T2-1B and primary rheumatoid fibroblasts served as target cells for anti-FAP-F19- CD28/CD3zeta and anti-NY-ESO-1-T1- CD28/CD3zeta re-directed T cells.	('NY-ESO-1', 'Gene', (144, 152))	('HT1080PA-luc', 'Var', (15, 27))	('CD3zeta', 'Gene', (127, 134))	('CD3zeta', 'Gene', '919', (162, 169))	('CD28', 'Gene', (122, 126))	('CD28', 'Gene', (157, 161))	('HT1080PA', 'CellLine', 'CVCL:0317', (15, 23))	('rheumatoid', 'Disease', 'MESH:D001172', (58, 68))	('CD28', 'Gene', '940', (122, 126))	('CD28', 'Gene', '940', (157, 161))	('MSTO-211', 'CellLine', 'CVCL:1430', (29, 37))	('CD3zeta', 'Gene', (162, 169))	('CD3zeta', 'Gene', '919', (127, 134))	('rheumatoid', 'Disease', (58, 68))	('NY-ESO-1', 'Gene', '246100', (144, 152))
118993	23937772	HT1080FAP-luc tumor cells (106 cells per mouse) were co-injected intraperitoneally with re-directed T cells at an effector to target ratio of 5:1.	('tumor', 'Disease', (14, 19))	('mouse', 'Species', '10090', (41, 46))	('HT1080FAP-luc', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
119019	23937772	Since we observed reduced IL-2 production we investigated the ability of anti-FAP-F19- CD28/CD3zeta re-directed T cells to proliferate in the absence of exogenous IL-2.	('IL-2', 'Gene', (26, 30))	('IL-2', 'molecular_function', 'GO:0005134', ('163', '167'))	('CD3zeta', 'Gene', (92, 99))	('IL-2', 'molecular_function', 'GO:0005134', ('26', '30'))	('reduced', 'NegReg', (18, 25))	('IL-2', 'Gene', '3558', (163, 167))	('CD28', 'Gene', (87, 91))	('IL-2', 'Gene', (163, 167))	('CD3zeta', 'Gene', '919', (92, 99))	('anti-FAP-F19-', 'Var', (73, 86))	('IL-2', 'Gene', '3558', (26, 30))	('CD28', 'Gene', '940', (87, 91))	('IL-2 production', 'biological_process', 'GO:0032623', ('26', '41'))
119021	23937772	To investigate the longevity of re-directed T cells without cytokine support we analyzed the in vitro survival of anti-FAP-F19- CD28/CD3zeta re-directed T cells with or without supplementation of 100 IU/ml IL-2 employing live/dead staining of CD8+ T cells.	('CD28', 'Gene', '940', (128, 132))	('CD3zeta', 'Gene', (133, 140))	('CD8', 'Gene', (243, 246))	('IL-2', 'Gene', '3558', (206, 210))	('CD8', 'Gene', '925', (243, 246))	('CD3zeta', 'Gene', '919', (133, 140))	('IL-2', 'Gene', (206, 210))	('IL-2', 'molecular_function', 'GO:0005134', ('206', '210'))	('CD28', 'Gene', (128, 132))	('anti-FAP-F19-', 'Var', (114, 127))
119035	23937772	Injection of HT1080FAP-luc cells into the peritoneum resulted in progressively growing tumors and mice had to be euthanized within three weeks in accordance to predefined end-points (data not shown).	('HT1080FAP-luc', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('mice', 'Species', '10090', (98, 102))
119037	23937772	A significant delay and/or protection of tumor outgrowth was detected in the group treated with anti-FAP re-directed T cells, whereas the tumor grew progressively in the control group injected with NY-ESO-1- re-directed T cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (41, 46))	('NY-ESO-1', 'Gene', (198, 206))	('anti-FAP re-directed T cells', 'Var', (96, 124))	('NY-ESO-1', 'Gene', '246100', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
119041	23937772	The survival after injection of anti-FAP re-directed T cells was significantly longer compared to the control group treated with anti-NY-ESO-1 re-directed T cells (p = 0.007).	('survival', 'CPA', (4, 12))	('longer', 'PosReg', (79, 85))	('anti-FAP', 'Var', (32, 40))	('NY-ESO-1', 'Gene', '246100', (134, 142))	('NY-ESO-1', 'Gene', (134, 142))
119069	23937772	The clinical course of patients with X-linked immunodeficiency after gene transfer in hematopoietic stem cells resulted in the development of leukemia in 4 out of 9 cases.	('gene transfer', 'Var', (69, 82))	('X-linked immunodeficiency', 'Disease', (37, 62))	('patients', 'Species', '9606', (23, 31))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('immunodeficiency', 'Phenotype', 'HP:0002721', (46, 62))	('X-linked immunodeficiency', 'Disease', 'MESH:D053632', (37, 62))	('leukemia', 'Disease', 'MESH:D007938', (142, 150))	('leukemia', 'Disease', (142, 150))	('resulted in', 'Reg', (111, 122))
119088	19555512	Biotin-labeled, cell surface CD26 translocated into the nucleus constantly, and this translocation was enhanced with 1F7 treatment but not with 5F8.	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('cell surface', 'cellular_component', 'GO:0009986', ('16', '28'))	('translocated into the nucleus', 'MPA', (34, 63))	('enhanced', 'PosReg', (103, 111))	('1F7 treatment', 'Var', (117, 130))	('CD26', 'Protein', (29, 33))	('nucleus', 'cellular_component', 'GO:0005634', ('56', '63'))	('5F8', 'Chemical', '-', (144, 147))
119092	19555512	This extracellular domain possesses the activity of a membrane-associated ectopeptidase known as dipeptidyl peptidase (DPP) IV that preferentially cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine in the penultimate position.	('dipeptides', 'Chemical', 'MESH:D004151', (166, 176))	('dipeptidyl peptidase (DPP) IV', 'Gene', (97, 126))	('preferentially', 'PosReg', (132, 146))	('extracellular', 'cellular_component', 'GO:0005576', ('5', '18'))	('cleaves N-terminal dipeptides', 'MPA', (147, 176))	('L-alanine', 'Var', (213, 222))	('L-proline', 'Var', (200, 209))	('L-proline', 'Chemical', 'MESH:D011392', (200, 209))	('activity', 'MPA', (40, 48))	('dipeptidyl peptidase (DPP) IV', 'Gene', '1803', (97, 126))	('membrane', 'cellular_component', 'GO:0016020', ('54', '62'))	('L-alanine', 'Chemical', 'MESH:D000409', (213, 222))
119105	19555512	CD26 expression was also observed in the nuclear, membrane and cytoplasmic fractions of J/CD26 cells, but not in any fractions of J/Wt cells (known to be CD26-negative cells at both the protein and mRNA level) (Fig.	('J/CD26', 'Var', (88, 94))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('CD26', 'Gene', (0, 4))	('J/Wt', 'CellLine', 'CVCL:6411', (130, 134))	('nuclear, membrane', 'cellular_component', 'GO:0031965', ('41', '58'))
119117	19555512	CD26 levels in the nuclear fraction of J/CD26 cells were found to be at a peak within one hour of treatment with 1F7, but not 5F8 or IgG1 (Fig.	('5F8', 'Chemical', '-', (126, 129))	('1F7', 'Var', (113, 116))	('IgG1', 'cellular_component', 'GO:0071735', ('133', '137'))	('CD26 levels', 'MPA', (0, 11))
119119	19555512	1F7 reportedly inhibits the cellular proliferation of T-cells in vitro, while no such inhibitory effect has been observed with 5F8.	('cellular proliferation of T-cells', 'CPA', (28, 61))	('1F7', 'Var', (0, 3))	('inhibits', 'NegReg', (15, 23))	('5F8', 'Chemical', '-', (127, 130))
119125	19555512	As a result, like J/CD26 cells, biotin-CD26 increased in the nuclear fraction of Karpas 299 cells following stimulation with 1F7, compared with IgG1 (Fig.	('IgG1', 'cellular_component', 'GO:0071735', ('144', '148'))	('1F7', 'Var', (125, 128))	('increased', 'PosReg', (44, 53))	('biotin', 'Chemical', 'MESH:D001710', (32, 38))	('biotin-CD26', 'MPA', (32, 43))
119129	19555512	The biotin-1F7 enhanced CD26 translocation into the nuclear fraction from the membrane fraction (Fig.	('biotin', 'Chemical', 'MESH:D001710', (4, 10))	('CD26', 'Protein', (24, 28))	('biotin-1F7', 'Var', (4, 14))	('enhanced', 'PosReg', (15, 23))	('membrane fraction', 'cellular_component', 'GO:0005624', ('78', '95'))
119132	19555512	There is no evidence that CD26 functions as transcriptional regulator, but a study which silenced CD26 using small interfering RNA showed an increase in basic FGF in prostate cancer cells in vitro .	('prostate cancer', 'Disease', (166, 181))	('basic FGF', 'MPA', (153, 162))	('silenced', 'Var', (89, 97))	('increase', 'PosReg', (141, 149))	('CD26', 'Gene', (98, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (166, 181))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
119134	19555512	We observed that CD26 was constantly present in the nucleus of CD26+ cancer cells and the nuclear translocation of CD26 from cell surface was augmented by the treatment with anti-CD26 monoclonal antibody with anti-tumor effect in epitope-specific manner.	('cell surface', 'cellular_component', 'GO:0009986', ('125', '137'))	('CD26', 'Gene', (115, 119))	('antibody', 'molecular_function', 'GO:0003823', ('195', '203'))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('augmented', 'PosReg', (142, 151))	('nucleus', 'cellular_component', 'GO:0005634', ('52', '59'))	('nuclear translocation', 'MPA', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('antibody', 'cellular_component', 'GO:0019814', ('195', '203'))	('anti-CD26', 'Var', (174, 183))	('antibody', 'cellular_component', 'GO:0042571', ('195', '203'))	('tumor', 'Disease', (214, 219))	('anti-CD26', 'Gene', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('antibody', 'cellular_component', 'GO:0019815', ('195', '203'))	('cancer', 'Disease', (69, 75))
119174	32643039	Luminal narrowing of the airway can lead to atelectasis, bronchiectasis, and mucous plugging (Fig.	('lead to', 'Reg', (36, 43))	('mucous plugging', 'Disease', (77, 92))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('bronchiectasis', 'Phenotype', 'HP:0002110', (57, 71))	('mucous', 'cellular_component', 'GO:0070701', ('77', '83'))	('Luminal', 'Var', (0, 7))	('atelectasis', 'Disease', (44, 55))	('bronchiectasis', 'Disease', (57, 71))	('atelectasis', 'Phenotype', 'HP:0100750', (44, 55))
119273	32643039	While typically asymptomatic, if the lesion is large, patients can present with dysphagia, obstruction, cough, and chest pain.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('dysphagia', 'Disease', (80, 89))	('cough', 'Disease', (104, 109))	('obstruction', 'Disease', 'MESH:D000402', (91, 102))	('patients', 'Species', '9606', (54, 62))	('chest pain', 'Phenotype', 'HP:0100749', (115, 125))	('dysphagia', 'Phenotype', 'HP:0002015', (80, 89))	('obstruction', 'Disease', (91, 102))	('cough', 'Disease', 'MESH:D003371', (104, 109))	('chest pain', 'Disease', 'MESH:D002637', (115, 125))	('lesion', 'Var', (37, 43))	('dysphagia', 'Disease', 'MESH:D003680', (80, 89))	('cough', 'Phenotype', 'HP:0012735', (104, 109))	('chest pain', 'Disease', (115, 125))
119452	29468082	The peptide sequence of the calcitonin precursor is composed of the signalling peptide (amino acids 1-25), propeptide (amino acids 25-82), calcitonin protein (amino acids 85-116) and katacalcin protein (amino acids 121-141) (Erickson et al.	('katacalcin', 'Gene', (183, 193))	('calcitonin', 'Gene', '796', (28, 38))	('propeptide', 'Chemical', '-', (107, 117))	('calcitonin', 'Gene', (28, 38))	('calcitonin', 'Gene', '796', (139, 149))	('signalling', 'biological_process', 'GO:0023052', ('68', '78'))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('amino', 'Var', (119, 124))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('katacalcin', 'Gene', '796', (183, 193))	('calcitonin', 'Gene', (139, 149))
119540	24595274	In a variety of tumour models, antagonists of alphavbeta3 reduced the number of tumour blood vessels, leading to tumour regression and suppressed invasion.	('tumour', 'Disease', (80, 86))	('antagonists', 'Var', (31, 42))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('beta3', 'Gene', '1934', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', (16, 22))	('beta3', 'Gene', (52, 57))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour regression', 'Disease', (113, 130))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour regression', 'Disease', 'MESH:D009365', (113, 130))	('suppressed', 'NegReg', (135, 145))	('reduced', 'NegReg', (58, 65))	('invasion', 'CPA', (146, 154))
119547	24595274	Aberrant integrin expression, notably of alphavbeta3, has been associated with tumour invasion and metastasis.	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (63, 73))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('beta3', 'Gene', '1934', (47, 52))	('integrin', 'Protein', (9, 17))	('expression', 'MPA', (18, 28))	('metastasis', 'CPA', (99, 109))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('beta3', 'Gene', (47, 52))	('tumour', 'Disease', (79, 85))
119551	24595274	Aberrant integrin alphav expression thus appears significant for MPM and cilengitide may have clinical potential for its treatment.	('Aberrant', 'Var', (0, 8))	('integrin alphav', 'Protein', (9, 24))	('MPM', 'Disease', (65, 68))	('significant', 'Reg', (49, 60))	('MPM', 'Chemical', '-', (65, 68))
119555	24595274	These effects were partially reproduced by down-regulation of beta3 and beta5 integrins by gene knockdown, consistent with the actions of cilengitide.	('knockdown', 'Var', (96, 105))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('beta3 and beta5', 'Gene', '1934', (62, 77))	('down-regulation', 'NegReg', (43, 58))
119594	24595274	Silencing the integrin beta5 gene ITGB5 with 1 nM siRNA resulted in substantial down-regulation of alphavbeta5 expression (Figure S7A).	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('integrin beta5', 'Gene', '3693', (14, 28))	('integrin beta5', 'Gene', (14, 28))	('beta5', 'Gene', '10382', (23, 28))	('beta5', 'Gene', '10382', (105, 110))	('beta5', 'Gene', (23, 28))	('beta5', 'Gene', (105, 110))	('Silencing', 'Var', (0, 9))	('ITGB5', 'Gene', '3693', (34, 39))	('ITGB5', 'Gene', (34, 39))	('down-regulation', 'NegReg', (80, 95))
119596	24595274	Moreover, as observed with cilengitide treatment, ITGB5 knockdown suppressed invasion into collagen matrix by cells from H28 spheroids (Figure 6B).	('invasion into collagen matrix by cells', 'CPA', (77, 115))	('ITGB5', 'Gene', (50, 55))	('suppressed', 'NegReg', (66, 76))	('ITGB5', 'Gene', '3693', (50, 55))	('collagen', 'molecular_function', 'GO:0005202', ('91', '99'))	('knockdown', 'Var', (56, 65))
119598	24595274	Knocking down ITGB3 with 1 nM siRNA did not affect H28 cell proliferation (not shown).	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('ITGB3', 'Gene', '3690', (14, 19))	('ITGB3', 'Gene', (14, 19))	('H28 cell proliferation', 'CPA', (51, 73))	('Knocking', 'Var', (0, 8))
119608	24595274	Cilengitide was also shown to induce cell detachment rather than direct cytotoxicity in a study of pediatric glioma cell lines, where it did not inhibit growth of normally adherent cells that were cultured under non-adherent conditions.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('glioma', 'Disease', 'MESH:D005910', (109, 115))	('Cilengitide', 'Var', (0, 11))	('cell detachment', 'CPA', (37, 52))	('glioma', 'Disease', (109, 115))	('cytotoxicity', 'Disease', (72, 84))	('induce', 'Reg', (30, 36))
119616	24595274	Many cancers have aberrant alphavbeta3 expression, which is known to be associated with invasion and metastasis.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('beta3', 'Gene', '1934', (33, 38))	('aberrant', 'Var', (18, 26))	('cancers', 'Disease', (5, 12))	('associated', 'Reg', (72, 82))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('beta3', 'Gene', (33, 38))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
119625	24595274	The role of alphavbeta3 and alphavbeta5 in MPM responses to cilengitide was confirmed by gene knockdown of the respective beta subunit genes ITGB3 and ITGB5.	('knockdown', 'Var', (94, 103))	('beta5', 'Gene', (34, 39))	('ITGB5', 'Gene', (151, 156))	('ITGB5', 'Gene', '3693', (151, 156))	('beta3', 'Gene', (18, 23))	('MPM', 'Chemical', '-', (43, 46))	('MPM responses to', 'MPA', (43, 59))	('ITGB3', 'Gene', '3690', (141, 146))	('ITGB3', 'Gene', (141, 146))	('beta3', 'Gene', '1934', (18, 23))	('beta5', 'Gene', '10382', (34, 39))
119628	24595274	The ITGB3 and ITGB5 knockdowns in the MPM cells were deliberately performed with a low, non-toxic concentration of siRNA (1 nM) to exclude non-specific toxicities of the siRNA oligonucleotide.	('MPM', 'Chemical', '-', (38, 41))	('ITGB5', 'Gene', (14, 19))	('ITGB5', 'Gene', '3693', (14, 19))	('ITGB3', 'Gene', '3690', (4, 9))	('ITGB3', 'Gene', (4, 9))	('toxicities', 'Disease', (152, 162))	('knockdowns', 'Var', (20, 30))	('oligonucleotide', 'Chemical', 'MESH:D009841', (176, 191))	('toxicities', 'Disease', 'MESH:D064420', (152, 162))
119629	24595274	At higher concentrations of siRNA growth inhibition did occur (results not shown) but it is not clear whether this is related to silencing of ITGB3 or ITGB5.	('ITGB5', 'Gene', (151, 156))	('ITGB5', 'Gene', '3693', (151, 156))	('silencing', 'Var', (129, 138))	('ITGB3', 'Gene', '3690', (142, 147))	('ITGB3', 'Gene', (142, 147))
119750	33489524	Moreover, histopathology report was positive for pan CK, CK7, calretinin, focally weakly for D2-40 and CD56.	('CK', 'Gene', '51727', (57, 59))	('calretinin', 'Gene', (62, 72))	('CD56', 'Gene', '4684', (103, 107))	('CK', 'Gene', '51727', (53, 55))	('D2-40', 'Var', (93, 98))	('CD56', 'Gene', (103, 107))	('calretinin', 'Gene', '794', (62, 72))	('positive', 'Reg', (36, 44))
119863	29719620	We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments.	('ACC-MESO-4', 'Gene', (182, 192))	('rat', 'Species', '10116', (71, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('blocked', 'NegReg', (214, 221))	('ACC-MESO-4', 'Chemical', '-', (182, 192))	('mesothelioma', 'Disease', (145, 157))	('human', 'Species', '9606', (139, 144))	('migration/invasion', 'CPA', (68, 86))	('rat', 'Species', '10116', (49, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('FG-3019', 'Var', (227, 234))
119867	29719620	Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts.	('mesothelioma', 'Disease', (116, 128))	('inhibited', 'NegReg', (53, 62))	('apoptosis', 'CPA', (98, 107))	('FG-3019', 'Var', (36, 43))	('rat', 'Species', '10116', (74, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('proliferation', 'CPA', (67, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('induced', 'Reg', (90, 97))
119905	29719620	To determine if FG-3019 (100 mug/ml) inhibits the tumorigenic properties of mesothelioma cells alone, or if it enhances the activity of PEM (1 muM), the response of mesothelioma cells to the therapeutic agents was monitored in several different assays.	('muM', 'Gene', '56925', (143, 146))	('mesothelioma', 'Disease', (165, 177))	('FG-3019', 'Var', (16, 23))	('muM', 'Gene', (143, 146))	('activity', 'MPA', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('mesothelioma', 'Disease', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mug', 'molecular_function', 'GO:0043739', ('29', '32'))	('inhibits', 'NegReg', (37, 45))	('enhances', 'PosReg', (111, 119))	('tumor', 'Disease', (50, 55))	('PEM', 'Chemical', 'MESH:D000068437', (136, 139))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
119911	29719620	In the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to detect apoptosis, FG-3019 alone induced apoptosis in ACC-MESO-4 (P < 0.01) and NCI-H290 (P < 0.05) but not in Y-MESO-8D (Figure 2B).	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('FG-3019', 'Var', (103, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('Terminal deoxynucleotidyl transferase', 'Gene', '1791', (7, 44))	('Terminal deoxynucleotidyl transferase', 'Gene', (7, 44))	('NCI-H290', 'CellLine', 'CVCL:A555', (164, 172))	('Y-MESO-8D', 'Chemical', '-', (195, 204))	('apoptosis', 'CPA', (125, 134))	('dUTP', 'Chemical', 'MESH:C027078', (45, 49))	('ACC-MESO-4', 'Chemical', '-', (138, 148))
119912	29719620	There was no significant difference between IgG + PEM and FG-3019 + PEM (Supplementary Figure 1B) although PEM induced a higher percentage of apoptosis than FG-3019 monotherapy (Figure 2B).	('PEM', 'Chemical', 'MESH:D000068437', (107, 110))	('PEM', 'Var', (107, 110))	('PEM', 'Chemical', 'MESH:D000068437', (50, 53))	('PEM', 'Chemical', 'MESH:D000068437', (68, 71))	('apoptosis', 'CPA', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))
119913	29719620	In the migration assay, only the FG-3019 + PEM group using ACC-MESO-4 cells exhibited decreased cell migration, indicating an increase in response by this combination (P < 0.01; Figure 2C).	('cell migration', 'biological_process', 'GO:0016477', ('96', '110'))	('ACC-MESO-4', 'Chemical', '-', (59, 69))	('cell migration', 'CPA', (96, 110))	('decreased', 'NegReg', (86, 95))	('PEM', 'Chemical', 'MESH:D000068437', (43, 46))	('FG-3019 +', 'Var', (33, 42))	('increase', 'PosReg', (126, 134))	('rat', 'Species', '10116', (10, 13))	('response', 'MPA', (138, 146))	('rat', 'Species', '10116', (104, 107))
119915	29719620	In the adhesion assay, FG-3019 alone inhibited cell adhesion, which was significantly enhanced in combination with PEM (P < 0.05; Figure 2D).	('adhesion', 'CPA', (7, 15))	('inhibited', 'NegReg', (37, 46))	('PEM', 'Chemical', 'MESH:D000068437', (115, 118))	('FG-3019', 'Var', (23, 30))	('enhanced', 'PosReg', (86, 94))	('cell adhesion', 'biological_process', 'GO:0007155', ('47', '60'))	('cell adhesion', 'CPA', (47, 60))
119924	29719620	Proliferation, migration and invasion of mesothelioma cells were significantly promoted by the presence of NHLF in all the three cell lines (P < 0.05; Figure 3A-3C).	('rat', 'Species', '10116', (18, 21))	('mesothelioma', 'Disease', (41, 53))	('migration', 'CPA', (15, 24))	('presence', 'Var', (95, 103))	('promoted', 'PosReg', (79, 87))	('rat', 'Species', '10116', (7, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('Proliferation', 'CPA', (0, 13))	('NHLF', 'Gene', (107, 111))
119925	29719620	The co-culture effect in transwell permeable support systems for migration and invasion was greater in ACC-MESO-4 than in the other cell lines; ACC-MESO-4, >20-fold; Y-MESO-8D and NCI-H290, ~2-fold (Figure 3B and 3C).	('migration', 'CPA', (65, 74))	('Y-MESO-8D', 'Chemical', '-', (166, 175))	('NCI-H290', 'CellLine', 'CVCL:A555', (180, 188))	('ACC-MESO-4', 'Chemical', '-', (144, 154))	('rat', 'Species', '10116', (68, 71))	('invasion', 'CPA', (79, 87))	('ACC-MESO-4', 'Chemical', '-', (103, 113))	('ACC-MESO-4', 'Var', (103, 113))
119935	29719620	The migration or invasion of each of the cell lines was enhanced by rhCTGF, although statistical significance was not achieved for NCI-H290 cells in the migration assay and for Y-MESO-8D in the invasion assay (Supplementary Figure 3B and 3C).	('rat', 'Species', '10116', (156, 159))	('Y-MESO-8D', 'Chemical', '-', (177, 186))	('enhanced', 'PosReg', (56, 64))	('rat', 'Species', '10116', (7, 10))	('rhCTGF', 'Var', (68, 74))	('invasion of each', 'CPA', (17, 33))	('NCI-H290', 'CellLine', 'CVCL:A555', (131, 139))	('migration', 'CPA', (4, 13))
119942	29719620	There was a trend for the combination of FG-3019 + PEM to inhibit invasion into the opposite pleural cavity in comparison to IgG alone (P = 0.091, Supplementary Figure 4B).	('PEM', 'Chemical', 'MESH:D000068437', (51, 54))	('PEM', 'Gene', (51, 54))	('pleural', 'Disease', 'MESH:D010995', (93, 100))	('FG-3019 +', 'Var', (41, 50))	('pleural', 'Disease', (93, 100))	('inhibit', 'NegReg', (58, 65))
119943	29719620	The average tumor weight was significantly lower in the FG-3019 group than in the IgG group (P < 0.05; Figure 4B).	('FG-3019', 'Var', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('lower', 'NegReg', (43, 48))
119944	29719620	The average tumor weight was significantly lower in FG-3019 + PEM group than in the IgG group (P < 0.001) or in the IgG + PEM group (P < 0.05), demonstrating an enhanced effect.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('rat', 'Species', '10116', (151, 154))	('tumor', 'Disease', (12, 17))	('PEM', 'Chemical', 'MESH:D000068437', (62, 65))	('FG-3019 + PEM', 'Var', (52, 65))	('PEM', 'Chemical', 'MESH:D000068437', (122, 125))	('lower', 'NegReg', (43, 48))
119951	29719620	FG-3019 + PEM showed a tendency to suppress CTGF expression and decreased tumor-associated fibrosis (Figure 5A-5C).	('PEM', 'Chemical', 'MESH:D000068437', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CTGF', 'Protein', (44, 48))	('tumor', 'Disease', (74, 79))	('FG-3019 + PEM', 'Var', (0, 13))	('fibrosis', 'Disease', 'MESH:D005355', (91, 99))	('fibrosis', 'Disease', (91, 99))	('suppress', 'NegReg', (35, 43))	('decreased', 'NegReg', (64, 73))
119952	29719620	Vascular density was not significantly altered by FG-3019 and/or PEM (Supplementary Figure 4C).	('Vascular density', 'CPA', (0, 16))	('PEM', 'Chemical', 'MESH:D000068437', (65, 68))	('FG-3019', 'Var', (50, 57))
119955	29719620	This effect was strongest in the FG-3019 + PEM group, in which XIAP expression was significantly lower than that after monotherapy either with FG-3019 or PEM.	('XIAP', 'Gene', (63, 67))	('PEM', 'Chemical', 'MESH:D000068437', (154, 157))	('PEM', 'Chemical', 'MESH:D000068437', (43, 46))	('lower', 'NegReg', (97, 102))	('FG-3019 +', 'Var', (33, 42))
119959	29719620	The observation that FG-3019 exhibited more significant anti-cancer effect in vivo than in vitro suggests that matricellular proteins like CTGF may require distinct microenvironmental factors or conditions that are difficult to be replicated in cell culture experiments.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FG-3019', 'Var', (21, 28))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
119977	29719620	In comparison to the control group, FG-3019 or FG-3019 + PEM attenuated tumor growth, and there were a few cases of complete growth inhibition.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FG-3019', 'Var', (36, 43))	('PEM', 'Chemical', 'MESH:D000068437', (57, 60))	('attenuated tumor', 'Disease', (61, 77))	('attenuated tumor', 'Disease', 'MESH:C538265', (61, 77))	('FG-3019 +', 'Var', (47, 56))
119978	29719620	One interpretation of these results is that the mesothelioma cells did not engraft (not implanted efficiently) because FG-3019 prevented anchorage establishment by inhibiting CTGF.	('CTGF', 'MPA', (175, 179))	('inhibiting', 'NegReg', (164, 174))	('prevented', 'NegReg', (127, 136))	('mesothelioma', 'Disease', (48, 60))	('FG-3019', 'Var', (119, 126))	('anchorage establishment', 'CPA', (137, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))
119980	29719620	For the tumors in which anchorage was established, FG-3019 inhibited proliferation and induced apoptosis both of mesothelioma cells and stromal cells, which probably resulted in a decreased tumor mass.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('apoptosis', 'CPA', (95, 104))	('inhibited', 'NegReg', (59, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('tumors', 'Disease', (8, 14))	('mesothelioma', 'Disease', (113, 125))	('FG-3019', 'Var', (51, 58))	('proliferation', 'CPA', (69, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('induced', 'Reg', (87, 94))	('decreased', 'NegReg', (180, 189))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('rat', 'Species', '10116', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
119986	29719620	In a genetically engineered mouse model of PDAC, FG-3019 sensitized tumor cells to gemcitabine-induced apoptosis by inhibiting expression of XIAP.	('tumor', 'Disease', (68, 73))	('inhibiting', 'NegReg', (116, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('mouse', 'Species', '10090', (28, 33))	('XIAP', 'Protein', (141, 145))	('expression', 'MPA', (127, 137))	('FG-3019', 'Var', (49, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('PDAC', 'Chemical', '-', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sensitized', 'Reg', (57, 67))
119987	29719620	Inhibition of BMP or of TGF-beta receptors has been shown to downregulate the expression of XIAP.	('TGF-beta', 'Gene', (24, 32))	('expression', 'MPA', (78, 88))	('BMP', 'Gene', (14, 17))	('downregulate', 'NegReg', (61, 73))	('Inhibition', 'Var', (0, 10))	('XIAP', 'Gene', (92, 96))	('BMP', 'Gene', '649', (14, 17))	('TGF-beta', 'Gene', '7040', (24, 32))
119990	29719620	Western blot analysis also revealed that the combination of FG-3019 and PEM resulted in a greater decrease of XIAP expression than the monotherapy.	('XIAP expression', 'MPA', (110, 125))	('decrease', 'NegReg', (98, 106))	('PEM', 'Chemical', 'MESH:D000068437', (72, 75))	('FG-3019', 'Var', (60, 67))	('PEM', 'Gene', (72, 75))	('combination', 'Interaction', (45, 56))
120068	27453164	Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations.	('mutations', 'Var', (112, 121))	('BRCA1 associated protein 1', 'Gene', '8314', (85, 111))	('BRCA1 associated protein 1', 'Gene', (85, 111))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))
120069	27453164	Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers.	('asbestos', 'Chemical', 'MESH:D001194', (203, 211))	('variants', 'Var', (103, 111))	('BRCA1 associated protein 1', 'Gene', '8314', (49, 75))	('BRCA1 associated protein 1', 'Gene', (49, 75))	('influence', 'Reg', (121, 130))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
120091	27453164	Multiple tumor types develop in family members who inherit BAP1 mutations; in addition, laboratory studies suggest that the incidence of MM may be increased upon exposure to asbestos, possibly even at levels too low to cause MM among the population at large.	('Multiple tumor', 'Disease', 'MESH:D009369', (0, 14))	('increased', 'PosReg', (147, 156))	('BAP1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (64, 73))	('asbestos', 'Chemical', 'MESH:D001194', (174, 182))	('Multiple tumor', 'Disease', (0, 14))
120102	27453164	In subsequent studies, the team found that germline mutations in the BAP1 gene caused a novel cancer syndrome characterized by extremely high incidences of MM and uveal melanoma (UM) and, less frequently, other cancers.	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('germline mutations', 'Var', (43, 61))	('cancer syndrome', 'Disease', (94, 109))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('BAP1', 'Gene', (69, 73))	('cancers', 'Disease', (211, 218))	('caused', 'Reg', (79, 85))	('uveal melanoma', 'Disease', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer syndrome', 'Disease', 'MESH:D009369', (94, 109))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
120105	27453164	At least one malignancy has developed in all carriers of germline BAP1 mutations who are older than 55 years studied so far, and multiple cancers have developed in many of them.	('germline', 'Var', (57, 65))	('malignancy', 'Disease', (13, 23))	('man', 'Species', '9606', (164, 167))	('multiple cancers', 'Disease', (129, 145))	('BAP1', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('multiple cancers', 'Disease', 'MESH:D009369', (129, 145))	('malignancy', 'Disease', 'MESH:D009369', (13, 23))
120112	27453164	In the 18th century, the couple immigrated to the United States and their descendants spread throughout the country, with carriers of the mutation affected by multiple malignancies.	('multiple malignancies', 'Disease', 'MESH:D009369', (159, 180))	('mutation', 'Var', (138, 146))	('multiple malignancies', 'Disease', (159, 180))
120145	27453164	MM caused by environmental exposure and/or reported in those with BAP1 genetic mutations are more likely to be found in younger individuals and to have equal sex and pleural/peritoneal distributions.	('BAP1', 'Gene', (66, 70))	('pleura', 'Disease', 'MESH:D054363', (166, 172))	('genetic mutations', 'Var', (71, 88))	('pleura', 'Disease', (166, 172))
120156	27453164	in China reported a similar or higher percentage of erroneous diagnoses of MM that were often related to inadequate specimens: diagnoses based on cytologic examination or fine-needle aspiration rather than larger biopsy, diagnoses that were not supported by an adequate set of immunostains, or diagnoses made by pathologists or coroners (in the United States) who rarely see these malignancies.	('erroneous', 'Var', (52, 61))	('malignancies', 'Disease', (381, 393))	('aspiration', 'Phenotype', 'HP:0002835', (183, 193))	('malignancies', 'Disease', 'MESH:D009369', (381, 393))
120202	27453164	A retrospective review of 663 patients who underwent an operation at three MM centers in the United States compared EPP with P/D and found that patients who underwent P/D had better survival than those who underwent EPP and that perioperative morbidity and mortality was greater after EPP.	('better', 'PosReg', (175, 181))	('patients', 'Species', '9606', (144, 152))	('survival', 'CPA', (182, 190))	('patients', 'Species', '9606', (30, 38))	('P/D', 'Var', (167, 170))
120210	27453164	PCB improved both progression-free survival (hazard risk = 0.61, p < 0.0001) and OS over PC (hazard risk = 0.77, p = 0.0167).	('improved', 'PosReg', (4, 12))	('OS over PC', 'CPA', (81, 91))	('progression-free survival', 'CPA', (18, 43))	('PCB', 'Var', (0, 3))	('PC', 'Chemical', '-', (89, 91))	('PC', 'Chemical', '-', (0, 2))	('PCB', 'Chemical', '-', (0, 3))
120225	27453164	The finding that BAP1 heterozygosity renders mice susceptible to low amounts of asbestos that rarely cause MM in wild-type mice supports the biologic plausibility for a similar activity in humans.	('heterozygosity', 'Var', (22, 36))	('mice', 'Species', '10090', (45, 49))	('asbestos', 'Chemical', 'MESH:D001194', (80, 88))	('BAP1', 'Gene', (17, 21))	('mice', 'Species', '10090', (123, 127))	('humans', 'Species', '9606', (189, 195))
120226	27453164	To date, none of the patients with MM who are germline carriers of BAP1 mutations have had a history of occupational exposure to asbestos, indicating that MM can develop in these individuals with undetectable levels of exposure.	('patients', 'Species', '9606', (21, 29))	('mutations', 'Var', (72, 81))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('BAP1', 'Gene', (67, 71))
120228	27453164	showing that BAP1+/- mice exposed to 3 microg of asbestos have a higher incidence of MM than control mice, it is anticipated that carriers of germline BAP1 mutations may be more sensitive than the population at large to low amounts of asbestos and NOA.	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('BAP1', 'Gene', (151, 155))	('mutations', 'Var', (156, 165))	('mice', 'Species', '10090', (21, 25))	('mice', 'Species', '10090', (101, 105))	('asbestos', 'Chemical', 'MESH:D001194', (235, 243))	('NOA', 'Chemical', '-', (248, 251))
120229	27453164	It is therefore a reasonable precaution for germline carriers of the BAP1 mutation to consider avoiding jobs associated with any possible asbestos exposure, including low levels of exposure, and avoiding residing in areas where asbestos and NOA are known to be present in the environment.	('mutation', 'Var', (74, 82))	('asbestos', 'Chemical', 'MESH:D001194', (138, 146))	('BAP1', 'Gene', (69, 73))	('asbestos', 'Chemical', 'MESH:D001194', (228, 236))	('NOA', 'Chemical', '-', (241, 244))
120253	27453164	are independently validated, total HMGB1 could provide a useful blood biomarker to identify individuals who have been exposed to asbestos and are thus at risk for development of MM, and, among them, hyperacetylated HMGB1 could provide a blood biomarker to detect those in whom MM has developed.	('HMGB1', 'Gene', (215, 220))	('HMGB1', 'Gene', '3146', (215, 220))	('hyperacetylated', 'Var', (199, 214))	('HMGB1', 'Gene', (35, 40))	('HMGB1', 'Gene', '3146', (35, 40))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))
120258	27453164	The group supported screening for BAP1 germline mutations in families with high-risk features, such as three or more cases of any of the following cancers within two generations: MM, UM, renal cell carcinoma, and cholangiocarcinoma.	('renal cell carcinoma', 'Disease', (187, 207))	('germline mutations', 'Var', (39, 57))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('BAP1', 'Gene', (34, 38))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (213, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (213, 231))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('cholangiocarcinoma', 'Disease', (213, 231))
120261	27453164	Thus, it was proposed that children may benefit from genetic testing, as those who are found to have inherited BAP1 mutations may benefit from screening for melanoma.	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('benefit', 'PosReg', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('children', 'Species', '9606', (27, 35))
120262	27453164	In summary, the group was in support of medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for UM at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (382, 388))	('people', 'Species', '9606', (70, 76))	('BAP1', 'Gene', (416, 420))	('mutations', 'Var', (421, 430))	('BAP1', 'Gene', (97, 101))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))
120356	23860535	Poor prognosis is associated with poor ECOG PS, high WBC count, male sex, probable diagnosis of MPM and sarcomatous histology.	('sarcomatous histology', 'Phenotype', 'HP:0100242', (104, 125))	('high WBC count', 'Phenotype', 'HP:0020059', (48, 62))	('sarcomatous', 'Disease', (104, 115))	('MPM', 'Disease', (96, 99))	('sarcomatous', 'Disease', 'MESH:D018316', (104, 115))	('high', 'Var', (48, 52))
120440	21942912	The mAbs (and their antigens) include bevacizumab/Avastin  (vascular endothelial growth factor A [VEGF-A]), IMC-1121B (VEGF receptor 2), cetuximab/Erbitux  (epidermal growth factor receptor), cixutumumab (insulin-like growth factor 1 receptor [IGF-1R]), AVE1642 (IGF-1R), BIIB022 (IGF-1R), MEDI-575 (platelet-derived growth factor receptor), CT-011 (Programmed Death-1), CP 675,206/tremelimumab (cytotoxic T Lymphocyte antigen 4), RO5323441 (placenta growth factor or PGF), and HGS1012/mapatumumab (TRAIL-R1).	('RO5323441', 'Var', (431, 440))	('Lymphocyte antigen', 'molecular_function', 'GO:0005557', ('408', '426'))	('IGF-1R', 'Gene', '3480', (263, 269))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('205', '231'))	('IGF-1R', 'Gene', (263, 269))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('60', '94'))	('epidermal growth factor receptor', 'Gene', (157, 189))	('VEGF-A', 'Gene', (98, 104))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (205, 242))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('157', '180'))	('epidermal growth factor receptor', 'Gene', '1956', (157, 189))	('TRAIL-R1', 'Gene', '8797', (499, 507))	('placenta growth factor', 'Gene', (442, 464))	('PGF', 'Gene', '5228', (468, 471))	('vascular endothelial growth factor A', 'Gene', '7422', (60, 96))	('VEGF-A', 'Gene', '7422', (98, 104))	('PGF', 'Gene', (468, 471))	('IGF-1R', 'Gene', (244, 250))	('IGF-1R', 'Gene', '3480', (244, 250))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('300', '330'))	('IGF-1R', 'Gene', '3480', (281, 287))	('IGF-1R', 'Gene', (281, 287))	('placenta growth factor', 'Gene', '5228', (442, 464))	('TRAIL-R1', 'Gene', (499, 507))	('insulin-like growth factor 1 receptor', 'Gene', (205, 242))	('vascular endothelial growth factor A', 'Gene', (60, 96))
120448	21942912	My laboratory recently analyzed the mesothelin protein in CCA by immunohistochemistry (IHC), Western blot, and flow cytometry, and found that SS1P, a recombinant anti-mesothelin immunotoxin currently being evaluated in clinical trials for mesothelioma, had remarkable single agent activity against CCA.	('CCA', 'Phenotype', 'HP:0030153', (298, 301))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (239, 251))	('CCA', 'Disease', (298, 301))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('SS1P', 'Chemical', 'MESH:C474515', (142, 146))	('mesothelioma', 'Disease', (239, 251))	('SS1P', 'Var', (142, 146))
120454	21942912	Based on the GPC3 protein sequence, we predicted serine 560 as a cleavage site in GPC3 for GPI anchorage.	('serine 560', 'Var', (49, 59))	('GPC3', 'Gene', (82, 86))	('serine', 'Chemical', 'MESH:D012694', (49, 55))	('GPI', 'Chemical', 'MESH:D017261', (91, 94))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
120455	21942912	Furin cleavage between Arg358 and Ser359 is important in GPC3's modulation of cell survival and Wnt signalling in zebrafish, but it is not important in HCC cell growth.	('HCC', 'Gene', '619501', (152, 155))	('signalling', 'biological_process', 'GO:0023052', ('100', '110'))	('GPC3', 'Gene', (57, 61))	('Ser', 'cellular_component', 'GO:0005790', ('34', '37'))	('HCC', 'Phenotype', 'HP:0001402', (152, 155))	('Ser359', 'Var', (34, 40))	('Furin', 'Gene', (0, 5))	('zebrafish', 'Species', '7955', (114, 123))	('Arg358', 'Var', (23, 29))	('cell survival', 'CPA', (78, 91))	('Wnt', 'Gene', (96, 99))	('cell growth', 'biological_process', 'GO:0016049', ('156', '167'))	('HCC', 'Gene', (152, 155))	('Ser359', 'Chemical', '-', (34, 40))	('Furin', 'Gene', '566557', (0, 5))	('Arg358', 'Chemical', '-', (23, 29))	('Wnt', 'Gene', '7471;22408;89780;22416;22418', (96, 99))
120457	21942912	The sequence R355-Q356-Y357-R358 in GPC3 fits the convertase recognition motif.	('GPC3', 'Gene', (36, 40))	('fits', 'Disease', 'MESH:D012640', (41, 45))	('fits', 'Disease', (41, 45))	('R355-Q356-Y357-R358', 'Var', (13, 32))
120465	21942912	Mutations in GPC3 result in Simpson-Golabi-Behmel syndrome (SGBS), an X-linked condition characterised by pre- and postnatal overgrowth.	('SGBS', 'Disease', 'MESH:C537340', (60, 64))	('SGBS', 'Disease', (60, 64))	('Simpson-Golabi-Behmel syndrome', 'Disease', 'MESH:C537340', (28, 58))	('pre', 'molecular_function', 'GO:0003904', ('106', '109'))	('GPC3', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('Simpson-Golabi-Behmel syndrome', 'Disease', (28, 58))	('overgrowth', 'Phenotype', 'HP:0001548', (125, 135))	('result in', 'Reg', (18, 27))
120479	21942912	They also showed how the effects of SULF2 can upregulate GPC3 expression and tumor growth in nude mouse xenografts.	('upregulate', 'PosReg', (46, 56))	('expression', 'MPA', (62, 72))	('GPC3', 'Protein', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('effects', 'Var', (25, 32))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', (77, 82))
120480	21942912	Interestingly, they showed that GPC3 stimulated the Wnt/beta-catenin signalling pathway.	('stimulated', 'PosReg', (37, 47))	('Wnt', 'Gene', '7471;22408;89780;22416;22418', (52, 55))	('GPC3', 'Var', (32, 36))	('signalling pathway', 'biological_process', 'GO:0007165', ('69', '87'))	('Wnt', 'Gene', (52, 55))
120488	21942912	Recently, we generated a recombinant sGPC3DeltaGPI-human IgG constant fragment (Fc) fusion protein and confirmed that it inhibited the growth of HCC (unpublished data).	('growth', 'MPA', (135, 141))	('HCC', 'Gene', (145, 148))	('human', 'Species', '9606', (51, 56))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('sGPC3DeltaGPI-human', 'Var', (37, 56))	('HCC', 'Gene', '619501', (145, 148))	('GPI', 'Chemical', 'MESH:D017261', (47, 50))	('inhibited', 'NegReg', (121, 130))	('HCC', 'Phenotype', 'HP:0001402', (145, 148))
120497	21942912	Because of the finding that GPC3-positive HCC patients have a significantly lower 5-year survival rate than GPC3-negative HCC patients, GPC3 expression is correlated with poor prognosis in HCC.	('GPC3', 'Var', (136, 140))	('patients', 'Species', '9606', (46, 54))	('HCC', 'Gene', (122, 125))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('HCC', 'Gene', (189, 192))	('HCC', 'Gene', (42, 45))	('HCC', 'Gene', '619501', (122, 125))	('lower', 'NegReg', (76, 81))	('patients', 'Species', '9606', (126, 134))	('HCC', 'Gene', '619501', (189, 192))	('HCC', 'Gene', '619501', (42, 45))	('5-year survival', 'MPA', (82, 97))	('HCC', 'Phenotype', 'HP:0001402', (189, 192))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
120506	21942912	made a form of GPC3 protein lacking the GPI anchor region in Chinese hamster ovary (CHO) cells and used the recombinant protein as an immunogen to obtain two mAbs: A1836A for the N-terminus of GPC3 and GPC3-C02 for the C-terminus.	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('hamster ovary', 'Disease', 'MESH:D010051', (69, 82))	('lacking', 'NegReg', (28, 35))	('CHO', 'molecular_function', 'GO:0043848', ('84', '87'))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('GPI', 'Chemical', 'MESH:D017261', (40, 43))	('A1836A', 'Var', (164, 170))	('hamster ovary', 'Disease', (69, 82))	('CHO', 'CellLine', 'CVCL:0213', (84, 87))
120512	21942912	It has been suggested that an anti-GPC3 antibody may increase the susceptibility of HCC to chemotherapeutic agents.	('HCC', 'Gene', '619501', (84, 87))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('anti-GPC3', 'Var', (30, 39))	('increase', 'PosReg', (53, 61))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('HCC', 'Gene', (84, 87))
120526	21942912	There is a predicted furin cleavage site at Arg295.	('furin', 'Gene', (21, 26))	('Arg295', 'Chemical', '-', (44, 50))	('furin', 'Gene', '5045', (21, 26))	('Arg295', 'Var', (44, 50))
120527	21942912	Unlike GPC3, mesothelin has a common Arg residue at the P2 position (294) of the furin cleavage motif (R292-F293-R294-R295) for what may be potentially efficient cleavage.	('R292-F293-R294-R295', 'Var', (103, 122))	('R292-F293', 'CellLine', 'CVCL:6642', (103, 112))	('cleavage', 'MPA', (162, 170))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('furin', 'Gene', '5045', (81, 86))	('furin', 'Gene', (81, 86))
120553	21942912	Mesothelin RNA expression is also induced by Li+, an inhibitor of glycogen synthase kinase (GSK)-3beta that mimics Wnt-1.	('Mesothelin', 'Gene', '10232', (0, 10))	('GSK', 'molecular_function', 'GO:0050321', ('92', '95'))	('Mesothelin', 'Gene', (0, 10))	('Li+', 'Var', (45, 48))	('RNA', 'cellular_component', 'GO:0005562', ('11', '14'))
120557	21942912	They found that expression of mesothelin increased pancreatic tumor cell proliferation and migration, and increased tumor volume in the nude mouse xenograft model.	('increased', 'PosReg', (41, 50))	('expression', 'Var', (16, 26))	('pancreatic tumor', 'Disease', 'MESH:D010190', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mouse', 'Species', '10090', (141, 146))	('mesothelin', 'Gene', (30, 40))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('migration', 'CPA', (91, 100))	('pancreatic tumor', 'Disease', (51, 67))	('increased', 'PosReg', (106, 115))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
120558	21942912	Silencing of mesothelin inhibited cell proliferation and migration in cancer cells, and tumor progression in vivo.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cell proliferation', 'CPA', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mesothelin', 'Gene', (13, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('cancer', 'Disease', (70, 76))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
120562	21942912	Conversely, silencing mesothelin reduced the IL-6 level.	('silencing', 'Var', (12, 21))	('IL-6', 'molecular_function', 'GO:0005138', ('45', '49'))	('IL-6', 'Gene', (45, 49))	('mesothelin', 'Protein', (22, 32))	('reduced', 'NegReg', (33, 40))	('IL-6', 'Gene', '3569', (45, 49))
120583	21942912	Pre-clinical studies have shown that SS1P is cytotoxic to cell lines expressing mesothelin and causes complete regression of mesothelin expressing tumor xenografts in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('mesothelin', 'Protein', (125, 135))	('SS1P', 'Chemical', 'MESH:C474515', (37, 41))	('SS1P', 'Var', (37, 41))	('nude mice', 'Species', '10090', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('regression', 'NegReg', (111, 121))
120586	21942912	Mesothelioma cells grown as monolayers or as spheroids expressed comparable levels of mesothelin; however, spheroids were at least 100-fold less affected by SS1P.	('SS1P', 'Chemical', 'MESH:C474515', (157, 161))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('Mesothelioma', 'Disease', (0, 12))	('SS1P', 'Var', (157, 161))
120589	21942912	Moreover, we found that small interfering RNA silencing and antibody inhibition targeting E-cadherin enhanced SS1P immunotoxin therapy in vitro.	('small interfering RNA silencing', 'Var', (24, 55))	('antibody', 'molecular_function', 'GO:0003823', ('60', '68'))	('SS1P immunotoxin therapy', 'MPA', (110, 134))	('antibody', 'cellular_component', 'GO:0042571', ('60', '68'))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('enhanced', 'PosReg', (101, 109))	('antibody', 'cellular_component', 'GO:0019815', ('60', '68'))	('RNA', 'cellular_component', 'GO:0005562', ('42', '45'))	('SS1P', 'Chemical', 'MESH:C474515', (110, 114))	('antibody', 'cellular_component', 'GO:0019814', ('60', '68'))	('E-cadherin', 'Gene', (90, 100))	('E-cadherin', 'Gene', '999', (90, 100))
120592	21942912	LMB-H226-GL can consistently form solid tumors in the peritoneum of mice.	('mice', 'Species', '10090', (68, 72))	('LMB-H226-GL', 'CellLine', 'CVCL:J621', (0, 11))	('solid tumors', 'Disease', (34, 46))	('solid tumors', 'Disease', 'MESH:D009369', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('LMB-H226-GL', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
120612	21942912	The m912 mAb binds cell surface-associated mesothelin and lyses A431/H9 cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells (PBMC) isolated from healthy donors, most likely by ADCC.	('ADCC', 'biological_process', 'GO:0001788', ('217', '221'))	('H9', 'CellLine', 'CVCL:1240', (69, 71))	('m912', 'Var', (4, 8))	('cell surface', 'cellular_component', 'GO:0009986', ('19', '31'))	('A431', 'CellLine', 'CVCL:0037', (64, 68))	('binds', 'Interaction', (13, 18))
120751	32549902	Many scientists have documented the predominance of short chrysotile fibers in cases of mesothelioma, contradicting the thought that chrysotile is not associated with the development of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (186, 198))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('short', 'Var', (52, 57))	('mesothelioma', 'Disease', (186, 198))	('mesothelioma', 'Disease', (88, 100))
120786	28704762	Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6.	('cyclin-dependent kinase (CDK) 4/6', 'Gene', '1019;1021', (157, 190))	('PD-0332991', 'Chemical', 'MESH:C500026', (112, 122))	('CDK', 'molecular_function', 'GO:0004693', ('182', '185'))	('palbociclib', 'Chemical', 'MESH:C500026', (99, 110))	('tested', 'Reg', (63, 69))	('alterations', 'Var', (34, 45))	('cyclin', 'molecular_function', 'GO:0016538', ('157', '163'))
120804	28704762	Deletion of the CDKN2A/ARF locus facilitates cell cycle progression, escape from apoptosis and immortalization.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('cell cycle progression', 'CPA', (45, 67))	('CDKN2A', 'Gene', (16, 22))	('ARF', 'Disease', 'MESH:D058186', (23, 26))	('CDKN2A', 'Gene', '1029', (16, 22))	('ARF', 'Disease', (23, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('immortalization', 'CPA', (95, 110))	('cell cycle', 'biological_process', 'GO:0007049', ('45', '55'))	('facilitates', 'PosReg', (33, 44))	('escape from apoptosis', 'CPA', (69, 90))	('Deletion', 'Var', (0, 8))
120808	28704762	Considering the high frequency of deletion of CDKN2A/ARF in MPM, we investigated the effect of palbocilib on a panel of MPM cell lines and on cells obtained from pleural effusion of MPM patients.	('CDKN2A', 'Gene', (46, 52))	('ARF', 'Disease', 'MESH:D058186', (53, 56))	('patients', 'Species', '9606', (186, 194))	('MPM', 'Disease', (60, 63))	('palbocilib', 'Chemical', '-', (95, 105))	('CDKN2A', 'Gene', '1029', (46, 52))	('ARF', 'Disease', (53, 56))	('pleural effusion', 'Phenotype', 'HP:0002202', (162, 178))	('deletion', 'Var', (34, 42))	('pleural effusion of MPM', 'Disease', 'MESH:D010996', (162, 185))	('investigated', 'Reg', (68, 80))	('pleural effusion of MPM', 'Disease', (162, 185))
120813	28704762	In particular, we tested the effect of the combination with NVP-BEZ235, a reversible competitive inhibitor of the ATP-binding site of both class I PI3K and mTOR, and NVP-BYL719, a specific inhibitor of the p110alpha subunit of class I PI3K.	('p110alpha', 'Gene', (206, 215))	('p110alpha', 'Gene', '5290', (206, 215))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (60, 70))	('mTOR', 'Gene', (156, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('235', '239'))	('mTOR', 'Gene', '2475', (156, 160))	('ATP-binding', 'molecular_function', 'GO:0005524', ('114', '125'))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('NVP-BYL719', 'Var', (166, 176))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('NVP-BEZ235', 'Var', (60, 70))	('tested', 'Reg', (18, 24))
120816	28704762	ZS-LP e MG-LP primary cell lines were obtained from two patients (both male, 66 years for ZS-LP, 62 years for MG-LP) affected by mesothelioma biphasic histotype of stage T4 N0 for ZS-LP and T3 N0 for MG-LP, diagnosed at the Department of Pathology -University/Hospital of Parma.	('MG-LP', 'Chemical', '-', (110, 115))	('ZS-LP', 'Chemical', '-', (0, 5))	('patients', 'Species', '9606', (56, 64))	('MG-LP', 'Chemical', '-', (8, 13))	('mesothelioma biphasic', 'Disease', 'MESH:D008654', (129, 150))	('ZS-LP', 'Chemical', '-', (90, 95))	('ZS-LP', 'Chemical', '-', (180, 185))	('T3 N0', 'Var', (190, 195))	('MG-LP', 'Chemical', '-', (200, 205))	('mesothelioma biphasic', 'Disease', (129, 150))
120831	28704762	Primer for CDKN2A (QT00089964), HPRT1 (QT00059066) and PGK1 (QT00013776) were purchased from Qiagen.	('HPRT1', 'Gene', (32, 37))	('PGK1', 'Gene', '5230', (55, 59))	('CDKN2A', 'Gene', '1029', (11, 17))	('PGK', 'molecular_function', 'GO:0004618', ('55', '58'))	('HPRT', 'molecular_function', 'GO:0004422', ('32', '36'))	('HPRT1', 'Gene', '3251', (32, 37))	('QT00013776', 'Var', (61, 71))	('QT00089964', 'Var', (19, 29))	('CDKN2A', 'Gene', (11, 17))	('PGK1', 'Gene', (55, 59))	('QT00059066', 'Var', (39, 49))
120837	28704762	The TruSight Cancer kit (Illumina Inc., San Diego, CA) was used to analyze cell lines for 94 genes and 284 single nucleotide polymorphisms (SNPs) associated with a predisposition towards various cancers.	('TruSight Cancer', 'Disease', (4, 19))	('single nucleotide polymorphisms', 'Var', (107, 138))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('TruSight Cancer', 'Disease', 'MESH:D009369', (4, 19))	('associated with', 'Reg', (146, 161))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
120845	28704762	In addition, we found BAP1 gene deletion in MG-LP cells, PMS2 gene (involved in DNA repair mechanism) deletion in ZS-LP cells, and XPC (involved in repair damaged DNA) and CHRNA3 (associated with an increased risk to develop lung cancer) variants in both primary cell lines.	('deletion', 'Var', (32, 40))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('CHRNA3', 'Gene', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('PMS2', 'Gene', '5395', (57, 61))	('MG-LP', 'Chemical', '-', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('variants', 'Var', (238, 246))	('deletion', 'Var', (102, 110))	('BAP1', 'Gene', '8314', (22, 26))	('XPC', 'Gene', '7508', (131, 134))	('XPC', 'Gene', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ZS-LP', 'Chemical', '-', (114, 119))	('PMS2', 'Gene', (57, 61))	('BAP1', 'Gene', (22, 26))	('lung cancer', 'Disease', (225, 236))	('CHRNA3', 'Gene', '1136', (172, 178))
120848	28704762	As shown in Figure 2A, palbociclib induced a significant blockade of the progression from G1 to S phase of the cell cycle in all MPM sensitive cells; by contrast, the distribution among the cell cycle phases was unchanged in insensitive MDA-MB-468 cells.	('MPM', 'Var', (129, 132))	('S phase', 'biological_process', 'GO:0051320', ('96', '103'))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (237, 247))	('progression', 'MPA', (73, 84))	('cell cycle', 'biological_process', 'GO:0007049', ('111', '121'))	('blockade', 'NegReg', (57, 65))	('palbociclib', 'Chemical', 'MESH:C500026', (23, 34))	('cell cycle', 'biological_process', 'GO:0007049', ('190', '200'))
120864	28704762	Moreover, the percentage of senescent cells was further increased after palbociclib/PI3Ki sequential treatment in comparison with palbociclib alone (60-90% versus 30-40%) in all the analyzed cell models (Figure 4, C and D).	('palbociclib/PI3Ki', 'Var', (72, 89))	('palbociclib', 'Chemical', 'MESH:C500026', (72, 83))	('increased', 'PosReg', (56, 65))	('palbociclib', 'Chemical', 'MESH:C500026', (130, 141))	('senescent cells', 'CPA', (28, 43))
120871	28704762	After such a prolonged treatment, cell growth was blocked irreversibly and the senescent phenotype was maintained both in MSTO-211H cells (Figure 5B) as well as in H28 cells (Supplementary Figure 4) only when the cells were exposed to the sequential combined treatment.	('cell growth', 'biological_process', 'GO:0016049', ('34', '45'))	('senescent phenotype', 'CPA', (79, 98))	('MSTO-211H', 'CellLine', 'CVCL:1430', (122, 131))	('cell growth', 'CPA', (34, 45))	('MSTO-211H', 'Var', (122, 131))
120872	28704762	Conversely, cells treated with palbociclib or PI3K inhibitors alone showed a recovery of cell proliferation and hence a reduction of the percentage of senescent cells after drug removal, indicating that the effects induced by palbociclib or PI3K inhibitors were reversible even after a prolonged treatment.	('palbociclib', 'Chemical', 'MESH:C500026', (226, 237))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('cell proliferation', 'CPA', (89, 107))	('percentage of senescent cells', 'CPA', (137, 166))	('palbociclib', 'Chemical', 'MESH:C500026', (31, 42))	('reduction', 'NegReg', (120, 129))	('PI3K', 'molecular_function', 'GO:0016303', ('241', '245'))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('inhibitors', 'Var', (51, 61))
120873	28704762	In addition, most of the alterations involved in MPM oncogenesis are due to inactivation of tumor suppressor genes, rather than driver mutations in oncogenic genes, thus making the development of new therapies more difficult.	('alterations', 'Var', (25, 36))	('oncogenesis', 'biological_process', 'GO:0007048', ('53', '64'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inactivation', 'NegReg', (76, 88))	('MPM', 'Disease', (49, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))
120875	28704762	Our findings demonstrate that CDKN2A/ARF gene alterations represent an attractive target for MPM treatment.	('CDKN2A', 'Gene', (30, 36))	('ARF', 'Disease', 'MESH:D058186', (37, 40))	('alterations', 'Var', (46, 57))	('ARF', 'Disease', (37, 40))	('CDKN2A', 'Gene', '1029', (30, 36))	('MPM', 'Disease', (93, 96))
120879	28704762	By NGS analysis we identified additional mutations in primary cell cultures in genes involved in DNA repair (PMS2, XPC) and associated with the risk of lung cancer development (CHRNA3); however these alterations did not affected palbociclib sensitivity.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CHRNA3', 'Gene', (177, 183))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('DNA repair', 'biological_process', 'GO:0006281', ('97', '107'))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('XPC', 'Gene', (115, 118))	('associated', 'Reg', (124, 134))	('CHRNA3', 'Gene', '1136', (177, 183))	('palbociclib', 'Chemical', 'MESH:C500026', (229, 240))	('XPC', 'Gene', '7508', (115, 118))	('PMS2', 'Gene', (109, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('PMS2', 'Gene', '5395', (109, 113))	('lung cancer', 'Disease', (152, 163))
120881	28704762	It has been reported that inhibition of CDK4/6 can induce cellular quiescence or senescence, depending on the tumor cell type.	('cellular quiescence', 'biological_process', 'GO:0044838', ('58', '77'))	('inhibition', 'Var', (26, 36))	('cellular quiescence', 'CPA', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('senescence', 'CPA', (81, 91))	('tumor', 'Disease', (110, 115))	('induce', 'Reg', (51, 57))	('CDK4/6', 'Gene', (40, 46))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('senescence', 'biological_process', 'GO:0010149', ('81', '91'))	('CDK4/6', 'Gene', '1019;1021', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
120887	28704762	In addition, it has been demonstrated in liposarcoma cells that the loss of MDM2 together with the expression of ATRX are involved in the induction of a senescent phenotype; interestingly, MDM2 was shown to regulate senescence in a p53-independent manner, through direct ubiquitination of a senescence-activating protein (SAP).	('SAP', 'Gene', (322, 325))	('senescence-activating protein', 'Gene', (291, 320))	('involved', 'Reg', (122, 130))	('p53', 'Gene', (232, 235))	('MDM2', 'Gene', '4193', (189, 193))	('MDM2', 'Gene', (76, 80))	('senescence', 'MPA', (216, 226))	('ubiquitination', 'MPA', (271, 285))	('liposarcoma', 'Disease', (41, 52))	('loss', 'Var', (68, 72))	('MDM2', 'Gene', '4193', (76, 80))	('ATRX', 'Gene', (113, 117))	('senescence', 'biological_process', 'GO:0010149', ('216', '226'))	('ATRX', 'Gene', '546', (113, 117))	('protein', 'cellular_component', 'GO:0003675', ('313', '320'))	('senescence', 'biological_process', 'GO:0010149', ('291', '301'))	('regulate', 'Reg', (207, 215))	('liposarcoma', 'Phenotype', 'HP:0012034', (41, 52))	('SAP', 'Gene', '4068', (322, 325))	('p53', 'Gene', '7157', (232, 235))	('senescence-activating protein', 'Gene', '4068', (291, 320))	('MDM2', 'Gene', (189, 193))	('liposarcoma', 'Disease', 'MESH:D008080', (41, 52))
120892	28704762	In particular, myc depletion has been demonstrated to favor the emergence of a senescent phenotype associated with oncogene over-expression independently of p53.	('senescent phenotype', 'CPA', (79, 98))	('depletion', 'Var', (19, 28))	('p53', 'Gene', '7157', (157, 160))	('oncogene', 'Gene', (115, 123))	('over-expression', 'PosReg', (124, 139))	('myc', 'Gene', (15, 18))	('p53', 'Gene', (157, 160))	('myc', 'Gene', '4609', (15, 18))
120894	28704762	Indeed, we demonstrated that palbocilcib activates AKT and its downstream target mTOR, which in turn has been shown to initiate senescence in the presence of p21 and elevated cyclin D1.	('palbocilcib', 'Chemical', '-', (29, 40))	('AKT', 'Gene', (51, 54))	('palbocilcib', 'Var', (29, 40))	('senescence', 'MPA', (128, 138))	('cyclin D1', 'Gene', '595', (175, 184))	('senescence', 'biological_process', 'GO:0010149', ('128', '138'))	('cyclin', 'molecular_function', 'GO:0016538', ('175', '181'))	('cyclin D1', 'Gene', (175, 184))	('mTOR', 'Gene', (81, 85))	('p21', 'Gene', '1026', (158, 161))	('mTOR', 'Gene', '2475', (81, 85))	('p21', 'Gene', (158, 161))	('AKT', 'Gene', '207', (51, 54))	('elevated', 'PosReg', (166, 174))	('activates', 'PosReg', (41, 50))
120897	28704762	In the cytoplasm, hyper-phosphorylated Rb directly binds Sin1, a component of mTORC2 complex, thus inhibiting the complex activity.	('Sin1', 'Gene', (57, 61))	('complex activity', 'MPA', (114, 130))	('inhibiting', 'NegReg', (99, 109))	('binds', 'Interaction', (51, 56))	('mTORC2', 'cellular_component', 'GO:0031932', ('78', '84'))	('mTORC2', 'Gene', (78, 84))	('cytoplasm', 'cellular_component', 'GO:0005737', ('7', '16'))	('mTORC2', 'Gene', '74343', (78, 84))	('Sin1', 'Gene', '79109', (57, 61))	('hyper-phosphorylated', 'Var', (18, 38))
120903	28704762	Apoptosis induction was also observed in mantle cell lymphoma after treatment with ON123300, a dual inhibitor of CDK4 and PI3K-delta and was ascribed to the inhibition of FOXO1 activation.	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (41, 61))	('PI3K-delta', 'Gene', '5293', (122, 132))	('FOXO1', 'Gene', '2308', (171, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('PI3K-delta', 'Gene', (122, 132))	('mantle cell lymphoma', 'Disease', (41, 61))	('cell lymphoma', 'Phenotype', 'HP:0012191', (48, 61))	('FOXO1', 'Gene', (171, 176))	('CDK4', 'Gene', (113, 117))	('CDK4', 'Gene', '1019', (113, 117))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('ON123300', 'Var', (83, 91))	('Apoptosis', 'CPA', (0, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('ON123300', 'Chemical', 'MESH:C000594117', (83, 91))
120912	28704762	Considering that loss of CDKN2A/ARF is a common alteration in MPM, our study is the first demonstrating the effectiveness of palbociclib in this tumor.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ARF', 'Disease', 'MESH:D058186', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ARF', 'Disease', (32, 35))	('tumor', 'Disease', (145, 150))	('palbociclib', 'Chemical', 'MESH:C500026', (125, 136))	('MPM', 'Disease', (62, 65))	('CDKN2A', 'Gene', (25, 31))	('loss', 'Var', (17, 21))	('CDKN2A', 'Gene', '1029', (25, 31))
121157	29473898	The International Agency for Research Cancer has stated that asbestos causes malignant mesothelioma and cancer of the lung, larynx and ovary.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer of the lung', 'Disease', (104, 122))	('cancer of the lung', 'Phenotype', 'HP:0100526', (104, 122))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer', 'Disease', (38, 44))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (77, 99))	('malignant mesothelioma', 'Disease', (77, 99))	('causes', 'Reg', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('asbestos', 'Var', (61, 69))	('cancer of the lung', 'Disease', 'MESH:D008175', (104, 122))	('asbestos', 'Chemical', 'MESH:D001194', (61, 69))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (77, 99))
121319	29473898	Hospitalisation data is also collected and reported for pleural plaques with and without the presence of asbestos (ICD code J92.0 and J92.9).	('J92.9', 'CellLine', 'CVCL:8607', (134, 139))	('pleural', 'Disease', 'MESH:D010995', (56, 63))	('pleural', 'Disease', (56, 63))	('asbestos', 'Chemical', 'MESH:D001194', (105, 113))	('J92.9', 'Var', (134, 139))
121381	28403901	Variant isoforms of CD44 specially, CD44 v6-v10 are overexpressed in both human and animal neoplasms indicating its implication in cancer progression, whereas its removal is associated with inhibition of tumor growth.	('cancer', 'Disease', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('CD44', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CD44', 'Gene', '960', (20, 24))	('implication', 'Reg', (116, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('tumor', 'Disease', (204, 209))	('v6-v10', 'Var', (41, 47))	('CD44', 'Gene', '960', (36, 40))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('CD44', 'Gene', (20, 24))	('human', 'Species', '9606', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('neoplasms', 'Disease', 'MESH:D009369', (91, 100))	('Variant', 'Var', (0, 7))	('neoplasms', 'Disease', (91, 100))
121390	28403901	After immunological activation, T lymphocytes and other leukocytes transiently upregulate CD44 isoforms expressing variant exons designated as CD44v.	('CD44', 'Gene', (90, 94))	('CD44', 'Gene', '960', (143, 147))	('variant exons', 'Var', (115, 128))	('CD44', 'Gene', (143, 147))	('upregulate', 'PosReg', (79, 89))	('CD44', 'Gene', '960', (90, 94))
121397	28403901	introduced the term "hyaluronan" in 1986 to conform with the international nomenclature of polysaccharides to include the different forms this molecule can take such as the acid form, hyaluronic, and the salt form, sodium hyaluronate.. HA is a non-sulfated, linear GAG consisting of repeating disaccharides of (ss, 1-4)-glucoronic acid (GlcUA) and (ss, 1-3)-N-acetyl glucosamine (GlcNAc).	('(ss, 1-3)-N-acetyl glucosamine', 'Chemical', '-', (348, 378))	('GlcUA', 'Chemical', '-', (337, 342))	('ss', 'Var', (311, 313))	('HA', 'Chemical', 'MESH:D006820', (236, 238))	('hyaluronan', 'Chemical', 'MESH:D006820', (21, 31))	('ss', 'Var', (349, 351))	('(ss, 1-4)-glucoronic acid', 'Chemical', '-', (310, 335))	('sodium hyaluronate', 'Chemical', 'MESH:D006820', (215, 233))	('GAG', 'Chemical', 'MESH:D006025', (265, 268))	('polysaccharides', 'Chemical', 'MESH:D011134', (91, 106))	('GlcNAc', 'Chemical', 'MESH:D000117', (380, 386))	('disaccharides', 'Chemical', 'MESH:D004187', (293, 306))
121415	28403901	Notably, it was found that silencing of CD44 significantly abrogated the HA-mediated cellular effects in the 2 MPM cell lines indicating the essential role of CD44/HA binding in modulating migration and proliferation of mesothelioma cells.	('CD44', 'Gene', (159, 163))	('CD44', 'Gene', (40, 44))	('silencing', 'Var', (27, 36))	('modulating', 'Reg', (178, 188))	('mesothelioma', 'Disease', (220, 232))	('proliferation', 'CPA', (203, 216))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('HA', 'Chemical', 'MESH:D006820', (73, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (220, 232))	('binding', 'Interaction', (167, 174))	('CD44', 'Gene', '960', (159, 163))	('cellular', 'CPA', (85, 93))	('CD44', 'Gene', '960', (40, 44))	('abrogated', 'NegReg', (59, 68))	('HA', 'Chemical', 'MESH:D006820', (164, 166))	('migration', 'CPA', (189, 198))
121418	28403901	In this work, CD44 neutralization profoundly reduced LMWHA binding to MMC (malignant mesothelima cells) illustrating that the interaction between CD44 and HA components transmit regulatory signals conferring locomotion and proliferation of MMC and, thus, show their participation in the expansion of tumor.	('neutralization', 'Var', (19, 33))	('proliferation', 'CPA', (223, 236))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('interaction', 'Interaction', (126, 137))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('binding', 'Interaction', (59, 66))	('HA', 'Chemical', 'MESH:D006820', (155, 157))	('MMC', 'Chemical', '-', (240, 243))	('locomotion', 'biological_process', 'GO:0040011', ('208', '218'))	('CD44', 'Gene', '960', (14, 18))	('CD44', 'Gene', (14, 18))	('LMWHA', 'Chemical', '-', (53, 58))	('locomotion', 'CPA', (208, 218))	('reduced', 'NegReg', (45, 52))	('HA', 'Chemical', 'MESH:D006820', (56, 58))	('tumor', 'Disease', (300, 305))	('malignant mesothelima', 'Phenotype', 'HP:0100001', (75, 96))	('LMWHA', 'Protein', (53, 58))	('transmit', 'Reg', (169, 177))	('CD44', 'Gene', '960', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('MMC', 'Chemical', '-', (70, 73))	('CD44', 'Gene', (146, 150))
121426	28403901	Tajima and coworkers presented evidence that the insertion of OPN gene in stable transfected ACC-MESO-1/OPN cell line upregulated the multidrug resistance through the mechanism of enhanced HA binding.	('OPN', 'Gene', (62, 65))	('OPN', 'Gene', '6696', (104, 107))	('HA binding', 'Interaction', (189, 199))	('OPN', 'Gene', '6696', (62, 65))	('HA', 'Chemical', 'MESH:D006820', (189, 191))	('drug resistance', 'Phenotype', 'HP:0020174', (139, 154))	('OPN', 'Gene', (104, 107))	('enhanced', 'PosReg', (180, 188))	('binding', 'molecular_function', 'GO:0005488', ('192', '199'))	('upregulated', 'PosReg', (118, 129))	('multidrug resistance', 'MPA', (134, 154))	('insertion', 'Var', (49, 58))
121472	28403901	For instance, the side population (SP) associated with CD105, SP, CD9, CD24 and CD26 were used in MPM cells lines and mesothelioma-derived primary cells to identify the presence of a CSC subpopulation.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('SP', 'Chemical', '-', (62, 64))	('SP', 'Chemical', '-', (35, 37))	('CD24', 'Gene', '100133941', (71, 75))	('CD24', 'Gene', (71, 75))	('CD105', 'Var', (55, 60))	('CD9', 'Gene', '928', (66, 69))	('CD9', 'Gene', (66, 69))	('mesothelioma', 'Disease', (118, 130))	('CD26', 'Gene', '1803', (80, 84))	('CD26', 'Gene', (80, 84))
121475	28403901	Using an activated cell sorting (FACS)-based assay, we also measured high percentages of CD44+ cells in the following MPM cell lines: H28 - 48.5%; H2052 - 57.6% and Meso4 - 50.2% relative to the entire cell population sustaining the presence of a putative CSC subpopulation (Cortes-Dericks et al., unpublished report).	('H2052 - 57.6', 'Var', (147, 159))	('H28 -', 'Var', (134, 139))	('CD44', 'Gene', '960', (89, 93))	('CD44', 'Gene', (89, 93))	('Meso4', 'Chemical', '-', (165, 170))
121508	28403901	In this context, the incorporation of CD44 in the combined mesothelin/HA may even generate a reliable diagnosis, which warrants an extensive validation.	('incorporation', 'Var', (21, 34))	('mesothelin', 'Gene', '10232', (59, 69))	('generate', 'Reg', (82, 90))	('HA', 'Chemical', 'MESH:D006820', (70, 72))	('CD44', 'Gene', '960', (38, 42))	('CD44', 'Gene', (38, 42))	('mesothelin', 'Gene', (59, 69))
121558	24260587	The p40 and p35 subunits of murine IL12 were connected with flexible linker (Ser4Gly)3. scFv (SS1) was fused to the p35 subunit of IL12 through flexible linker (GSADGG) and IL12-SS1 (Fv), which contains Flag and 8 His tag at the C-terminal.	('SS1', 'Gene', '3123', (178, 181))	('p35', 'cellular_component', 'GO:0070745', ('116', '119'))	('p35', 'Gene', (12, 15))	('SS1', 'Gene', (94, 97))	('p40', 'cellular_component', 'GO:0070743', ('4', '7'))	('p35', 'Gene', (116, 119))	('IL12', 'Gene', (131, 135))	('p35', 'Gene', '16159', (12, 15))	('p40', 'cellular_component', 'GO:0043514', ('4', '7'))	('p35', 'cellular_component', 'GO:0070745', ('12', '15'))	('p35', 'Gene', '16159', (116, 119))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('murine', 'Species', '10090', (28, 34))	('Ser4Gly', 'Var', (77, 84))	('p35', 'cellular_component', 'GO:0043514', ('116', '119'))	('IL12', 'molecular_function', 'GO:0005143', ('35', '39'))	('p35', 'cellular_component', 'GO:0043514', ('12', '15'))	('SS1', 'Gene', (178, 181))	('GSADGG', 'Chemical', '-', (161, 167))	('SS1', 'Gene', '3123', (94, 97))	('Ser4Gly', 'SUBSTITUTION', 'None', (77, 84))	('IL12', 'molecular_function', 'GO:0005143', ('131', '135'))	('p40', 'Gene', (4, 7))	('IL12', 'molecular_function', 'GO:0005143', ('173', '177'))	('p40', 'Gene', '16160', (4, 7))	('scFv', 'Gene', '652070', (88, 92))	('scFv', 'Gene', (88, 92))
121606	24260587	The p40 and p35 subunits of murine IL12 were connected by flexible linker (Ser4Gly)3.	('p35', 'Gene', '16159', (12, 15))	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('p40', 'cellular_component', 'GO:0043514', ('4', '7'))	('p40', 'Gene', (4, 7))	('p35', 'cellular_component', 'GO:0070745', ('12', '15'))	('IL12', 'Gene', (35, 39))	('p35', 'cellular_component', 'GO:0043514', ('12', '15'))	('p35', 'Gene', (12, 15))	('Ser4Gly', 'SUBSTITUTION', 'None', (75, 82))	('murine', 'Species', '10090', (28, 34))	('p40', 'Gene', '16160', (4, 7))	('p40', 'cellular_component', 'GO:0070743', ('4', '7'))	('Ser4Gly', 'Var', (75, 82))	('IL12', 'molecular_function', 'GO:0005143', ('35', '39'))
121619	24260587	In particular, the binding was stronger in H9, an A431 line highly expressing MSLN on the cell surface, than in A431 which is mesothelin-negative.	('A431', 'CellLine', 'CVCL:0037', (112, 116))	('MSLN', 'Var', (78, 82))	('cell surface', 'cellular_component', 'GO:0009986', ('90', '102'))	('stronger', 'PosReg', (31, 39))	('binding', 'molecular_function', 'GO:0005488', ('19', '26'))	('H9', 'CellLine', 'CVCL:1240', (43, 45))	('binding', 'Interaction', (19, 26))	('A431', 'CellLine', 'CVCL:0037', (50, 54))
121623	24260587	The 20-fold loss of IL12-SS1 (Fv) binding affinity for mesothelin may attribute to the potential interference of single-chain IL12 with SS1.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('SS1', 'Gene', '3123', (136, 139))	('SS1', 'Gene', '3123', (25, 28))	('IL12', 'Gene', (126, 130))	('SS1', 'Gene', (136, 139))	('SS1', 'Gene', (25, 28))	('loss', 'NegReg', (12, 16))	('IL12', 'molecular_function', 'GO:0005143', ('126', '130'))	('IL12', 'molecular_function', 'GO:0005143', ('20', '24'))	('binding affinity', 'Interaction', (34, 50))	('single-chain', 'Var', (113, 125))
121631	24260587	Several studies with tumor specific antibodies fused with IL12 have been reported, including: anti-CD30 antibody for Hodgkin's lymphoma, anti-HER2 antibody for HER2-expressing tumors, and anti-extra-domain B (ED-B) of fibronectin for tumor vessels, IL12-huBC1, and IL12-L19.	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (117, 135))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (21, 26))	('IL12', 'molecular_function', 'GO:0005143', ('249', '253'))	('HER2', 'Gene', '13866', (142, 146))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (117, 135))	('CD30', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('antibody', 'molecular_function', 'GO:0003823', ('147', '155'))	('antibody', 'molecular_function', 'GO:0003823', ('104', '112'))	('CD30', 'Gene', '21941', (99, 103))	('tumor', 'Disease', (176, 181))	('antibody', 'cellular_component', 'GO:0042571', ('147', '155'))	('antibody', 'cellular_component', 'GO:0042571', ('104', '112'))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	("Hodgkin's lymphoma", 'Disease', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('HER2', 'Gene', (160, 164))	('IL12', 'molecular_function', 'GO:0005143', ('265', '269'))	('anti-extra-domain B', 'Var', (188, 207))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('antibody', 'cellular_component', 'GO:0019815', ('104', '112'))	('antibody', 'cellular_component', 'GO:0019815', ('147', '155'))	('HER2', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('IL12', 'molecular_function', 'GO:0005143', ('58', '62'))	('HER2', 'Gene', '13866', (160, 164))	('antibody', 'cellular_component', 'GO:0019814', ('104', '112'))	('antibody', 'cellular_component', 'GO:0019814', ('147', '155'))
121636	24260587	A significant dose-dependent increase in the induction of IFN-gamma by treatment with either IL12 or IL12-SS1 (Fv) was noted (Figure 3B).	('SS1', 'Gene', '3123', (106, 109))	('IL12', 'molecular_function', 'GO:0005143', ('93', '97'))	('IL12', 'Var', (93, 97))	('SS1', 'Gene', (106, 109))	('increase', 'PosReg', (29, 37))	('IL12', 'molecular_function', 'GO:0005143', ('101', '105'))	('induction', 'MPA', (45, 54))
121663	24260587	Furthermore, our animal testing showed that the immunocytokine exhibited inhibition of human malignant mesothelioma grown in the peritoneal cavity of nude mice.	('malignant mesothelioma', 'Disease', (93, 115))	('immunocytokine', 'Var', (48, 62))	('inhibition', 'NegReg', (73, 83))	('human', 'Species', '9606', (87, 92))	('nude mice', 'Species', '10090', (150, 159))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (93, 115))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (93, 115))
121672	21594647	Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells.	('growth', 'MPA', (146, 152))	('human', 'Species', '9606', (168, 173))	('H2461', 'Var', (189, 194))	('H2373', 'Var', (175, 180))	('suppression', 'NegReg', (153, 164))	('H2373', 'CellLine', 'CVCL:A533', (175, 180))	('curcumin', 'Chemical', 'MESH:D003474', (127, 135))	('H2452', 'Var', (182, 187))	('H2452', 'CellLine', 'CVCL:1553', (182, 187))	('H2461', 'CellLine', 'CVCL:A536', (189, 194))	('H226', 'Var', (200, 204))	('murine', 'Species', '10090', (210, 216))
121683	21594647	Simian virus 40 (SV40)-dependent Akt signaling has been shown to drive mesothelial cell transformation after asbestos exposure and knockdown of receptor tyrosine kinase EphB4 was found to reduce phosphorylation of Akt in murine model of mesothelioma.	('Akt', 'Gene', '207', (33, 36))	('drive', 'PosReg', (65, 70))	('Akt', 'Gene', (214, 217))	('EphB4', 'Gene', (169, 174))	('EphB4', 'Gene', '2050', (169, 174))	('murine', 'Species', '10090', (221, 227))	('knockdown', 'Var', (131, 140))	('Akt', 'Gene', '207', (214, 217))	('reduce', 'NegReg', (188, 194))	('Simian virus 40', 'Species', '1891767', (0, 15))	('receptor tyrosine kinase', 'Gene', '5979', (144, 168))	('Akt signaling', 'biological_process', 'GO:0043491', ('33', '46'))	('SV40', 'Species', '1891767', (17, 21))	('mesothelial cell transformation', 'CPA', (71, 102))	('receptor tyrosine kinase', 'Gene', (144, 168))	('mesothelioma', 'Disease', (237, 249))	('phosphorylation', 'MPA', (195, 210))	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('Akt', 'Gene', (33, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))
121692	21594647	Acombination of curcumin and cisplatin were superior in suppressing growth of the MPM cells in vitro.	('Acombination', 'Var', (0, 12))	('curcumin', 'Chemical', 'MESH:D003474', (16, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('growth of the MPM cells in vitro', 'CPA', (68, 100))	('suppressing', 'NegReg', (56, 67))
121709	21594647	MPM (H2373, H2452, H2461, H226 and AB12) cells (5 x 103) were seeded in a 96-well culture plate and subsequently treated with indicated agents at different concentrations for noted times.	('H2452', 'Var', (12, 17))	('H2461', 'CellLine', 'CVCL:A536', (19, 24))	('H2461', 'Var', (19, 24))	('H2373', 'CellLine', 'CVCL:A533', (5, 10))	('H2373', 'Var', (5, 10))	('H2452', 'CellLine', 'CVCL:1553', (12, 17))
121730	21594647	As a first step, we determined the effects of curcumin on the growth of human MPM (H2373, H2452, H2461, and H226) as well as AB12 murine MPM cells.	('H2461', 'CellLine', 'CVCL:A536', (97, 102))	('murine', 'Species', '10090', (130, 136))	('human', 'Species', '9606', (72, 77))	('H2373', 'CellLine', 'CVCL:A533', (83, 88))	('H2461', 'Var', (97, 102))	('H2452', 'Var', (90, 95))	('H2452', 'CellLine', 'CVCL:1553', (90, 95))	('H226', 'Var', (108, 112))	('curcumin', 'Chemical', 'MESH:D003474', (46, 54))
121739	21594647	Since 20 microM dose of curcumin for 48-h treatment period caused ~ 60%, ~60%, ~50%, and ~30% inhibition of H2373, H2452, H2461, and H226 MPM cell growth, respectively, (Fig.	('inhibition', 'NegReg', (94, 104))	('curcumin', 'Chemical', 'MESH:D003474', (24, 32))	('H226', 'Var', (133, 137))	('H226 MPM', 'CellLine', 'CVCL:D527', (133, 141))	('H2373', 'Var', (108, 113))	('H2373', 'CellLine', 'CVCL:A533', (108, 113))	('H2452', 'Var', (115, 120))	('H2461', 'CellLine', 'CVCL:A536', (122, 127))	('H2452', 'CellLine', 'CVCL:1553', (115, 120))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('H2461', 'Var', (122, 127))
121747	21594647	Moreover, MPM cells treated with a combination of curcumin and cisplatin had significant accumulation in the apoptotic (sub G0) fractions while undergoing a drastic reduction in cell numbers in the G0/ G1 phase (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('accumulation', 'PosReg', (89, 101))	('curcumin', 'Chemical', 'MESH:D003474', (50, 58))	('reduction', 'NegReg', (165, 174))	('cisplatin', 'Var', (63, 72))	('G1 phase', 'biological_process', 'GO:0051318', ('202', '210'))
121801	21594647	Because alterations in apoptosis-signaling pathways often contribute to MPM growth and survival, we undertook an in vitro and gene-array-based profiling to identify novel transducers of apoptosis signaling that may be activated/induced by curcumin.	('apoptosis-signaling pathways', 'Pathway', (23, 51))	('curcumin', 'Chemical', 'MESH:D003474', (239, 247))	('MPM growth', 'CPA', (72, 82))	('alterations', 'Var', (8, 19))	('contribute', 'Reg', (58, 68))	('survival', 'CPA', (87, 95))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('186', '205'))	('apoptosis-signaling', 'biological_process', 'GO:0006915', ('23', '42'))
121847	22710680	It is not possible to identify and exclude welders specifically from the industry categories used by CAREX for these exposure estimates, and evidence suggests that other unidentified carcinogenic agents in welding fume may also be contributing to the observed lung cancer risk, or that synergism between the known risk agents may be operating to raise the risk in welders to above that observed in workers exposed to the agents separately (see below).	('lung cancer', 'Disease', (260, 271))	('synergism', 'Var', (286, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (260, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('raise', 'PosReg', (346, 351))	('carcinogenic', 'Disease', 'MESH:D063646', (183, 195))	('contributing', 'Reg', (231, 243))	('lung cancer', 'Disease', 'MESH:D008175', (260, 271))	('carcinogenic', 'Disease', (183, 195))
121942	22710680	The most consistent evidence of an increased risk for lung cancer occurred in nickel refining, particularly those with high exposures in the past because of, now obsolete, operations.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('nickel', 'Chemical', 'MESH:D009532', (78, 84))	('nickel refining', 'Var', (78, 93))
122038	22710680	Although legislation in Britain has now banned smoking in all work places (as well as in public places), thus reducing ETS exposure, exposure in the past will continue to cause work-related lung and laryngeal cancer for some time in the future.	('cause', 'Reg', (171, 176))	('exposure', 'Var', (133, 141))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (199, 215))	('ETS exposure', 'MPA', (119, 131))	('lung and laryngeal cancer', 'Disease', 'MESH:D007822', (190, 215))	('reducing', 'NegReg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
122041	20804550	COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma.	('mesothelioma', 'Disease', (120, 132))	('decreased', 'NegReg', (63, 72))	('immunotherapy', 'CPA', (26, 39))	('improves', 'PosReg', (17, 25))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('COX-2', 'Gene', '19225', (0, 5))	('inhibition', 'Var', (6, 16))	('COX-2', 'Gene', (0, 5))
122067	20804550	Therefore, high expression of COX-2 has been correlated with poor prognosis in cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('COX-2', 'Gene', (30, 35))	('high', 'Var', (11, 15))	('expression', 'MPA', (16, 26))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
122127	20804550	We found that Ly6c expression was lower on the Gr-1low MDSC with a high SSC (subset 1) in contrast to the Gr-1low MDSC with low SSC (subset 2).	('high', 'Var', (67, 71))	('Gr-1', 'Gene', '546644', (47, 51))	('Gr-1', 'Gene', '546644', (106, 110))	('lower', 'NegReg', (34, 39))	('Gr-1', 'Gene', (47, 51))	('Gr-1', 'Gene', (106, 110))	('Ly6c', 'Gene', '17067', (14, 18))	('Ly6c', 'Gene', (14, 18))
122146	20804550	Ten days after tumour injection, the absolute number of MDSC was significantly lower in mice receiving celecoxib diet compared with mice receiving control diet.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour', 'Disease', (15, 21))	('lower', 'NegReg', (79, 84))	('celecoxib diet', 'Var', (103, 117))	('celecoxib', 'Chemical', 'MESH:D000068579', (103, 112))	('mice', 'Species', '10090', (132, 136))	('mice', 'Species', '10090', (88, 92))
122156	20804550	It has been shown that MDSC can down regulated the zeta-chain on T cells by ROS production in the lymphoid organs and thereby induce T cell tolerance.	('T cell tolerance', 'CPA', (133, 149))	('induce', 'PosReg', (126, 132))	('zeta-chain', 'MPA', (51, 61))	('ROS production', 'MPA', (76, 90))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('MDSC', 'Var', (23, 27))	('down regulated', 'NegReg', (32, 46))
122160	20804550	Analyzing ROS production by all myeloid cells revealed that ROS production was decreased in celecoxib treated mice compared to untreated animals (Figure 3).	('celecoxib', 'Var', (92, 101))	('ROS production', 'MPA', (60, 74))	('decreased', 'NegReg', (79, 88))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('mice', 'Species', '10090', (110, 114))	('celecoxib', 'Chemical', 'MESH:D000068579', (92, 101))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
122169	20804550	Additionally, tumour-derived PGE2 was decreased in the peritoneal wash of mice receiving celecoxib diet compared to animals on control diet.	('tumour', 'Disease', (14, 20))	('decreased', 'NegReg', (38, 47))	('celecoxib', 'Chemical', 'MESH:D000068579', (89, 98))	('celecoxib', 'Var', (89, 98))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('mice', 'Species', '10090', (74, 78))	('PGE2', 'Chemical', 'MESH:D015232', (29, 33))
122185	20804550	Production of IFN-gamma and granzyme B was significantly increased after DC-treatment.	('IFN-gamma', 'Gene', (14, 23))	('granzyme B', 'Gene', (28, 38))	('DC-treatment', 'Var', (73, 85))	('Production', 'MPA', (0, 10))	('IFN-gamma', 'Gene', '15978', (14, 23))	('granzyme B', 'Gene', '14939', (28, 38))	('increased', 'PosReg', (57, 66))
122187	20804550	In conclusion, these data show that anti-tumour responses induced by DC-treatment, are affected by suppressive cells in the spleen of tumour-bearing mice.	('tumour-bearing', 'Disease', (134, 148))	('tumour-bearing', 'Disease', 'MESH:C565129', (134, 148))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('DC-treatment', 'Var', (69, 81))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('tumour', 'Disease', (134, 140))	('affected', 'Reg', (87, 95))	('mice', 'Species', '10090', (149, 153))	('tumour', 'Disease', (41, 47))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
122200	20804550	We show that dietary administration of celecoxib leads to a significant decrease in the number and suppressive function of immature myeloid cells in the spleens and tumours of tumour-bearing mice.	('tumours of tumour', 'Disease', 'MESH:D009369', (165, 182))	('celecoxib', 'Var', (39, 48))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('number', 'CPA', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours of tumour', 'Disease', (165, 182))	('tumour-bearing', 'Disease', 'MESH:C565129', (176, 190))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('mice', 'Species', '10090', (191, 195))	('tumour-bearing', 'Disease', (176, 190))	('decrease', 'NegReg', (72, 80))	('celecoxib', 'Chemical', 'MESH:D000068579', (39, 48))	('suppressive function of immature myeloid cells', 'CPA', (99, 145))
122207	20804550	However, our data provides evidence that PMN-MDSC do play a significant role in tumour-induced immune suppression, since PMN-MDSC are most capable of producing ROS and thereby contribute to the induction of tolerance.	('tumour', 'Disease', (80, 86))	('tolerance', 'CPA', (207, 216))	('PMN', 'biological_process', 'GO:0034727', ('121', '124'))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('ROS', 'Chemical', 'MESH:D017382', (160, 163))	('PMN', 'biological_process', 'GO:0034727', ('41', '44'))	('ROS', 'Protein', (160, 163))	('contribute', 'Reg', (176, 186))	('PMN-MDSC', 'Var', (121, 129))
122243	20804550	COX-2 over-expression was found in the majority of mesothelioma (73% epithelial mesothelioma, 50% of mix-variants and 37% sarcomatoid mesothelioma).	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('mesothelioma', 'Disease', (134, 146))	('over-expression', 'PosReg', (6, 21))	('sarcomatoid mesothelioma', 'Disease', (122, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('mesothelioma', 'Disease', (51, 63))	('mix-variants', 'Var', (101, 113))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('mesothelioma', 'Disease', (80, 92))	('COX-2', 'Gene', (0, 5))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (122, 146))
122262	31569615	We used benign mesothelial MeT-5A cells as controls and the MPM cell lines M14K (epithelioid), MSTO (biphasic), and ZL34 (sarcomatoid).	('MPM', 'Disease', 'MESH:C562839', (60, 63))	('MPM', 'Disease', (60, 63))	('benign mesothelial MeT', 'Chemical', 'MESH:C432845', (8, 30))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('M14K', 'SUBSTITUTION', 'None', (75, 79))	('sarcoma', 'Disease', (122, 129))	('MeT-5A', 'Chemical', 'MESH:C520288', (27, 33))	('M14K', 'Var', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
122264	31569615	Doublet treatment reduced the invasive capacity of spheroids of cell lines into collagenous matrices, while Cisplatin lowered the invasion of the MSTO and ZL34 cell lines, and Pemetrexed lowered the invasion of MeT-5A and ZL34 cell lines.	('Cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('Cisplatin', 'Var', (108, 117))	('invasion', 'CPA', (130, 138))	('reduced', 'NegReg', (18, 25))	('MeT-5A', 'Chemical', 'MESH:C520288', (211, 217))	('invasion', 'CPA', (199, 207))	('lowered', 'NegReg', (118, 125))	('lowered', 'NegReg', (187, 194))
122265	31569615	Treatment with Pemetrexed or the combination significantly reduced the collagen gel contraction of all cell lines, while Cisplatin treatment affected only the MeT-5A and M14K cells.	('collagen', 'molecular_function', 'GO:0005202', ('71', '79'))	('collagen gel contraction', 'CPA', (71, 95))	('MeT-5A', 'Chemical', 'MESH:C520288', (159, 165))	('reduced', 'NegReg', (59, 66))	('M14K', 'SUBSTITUTION', 'None', (170, 174))	('M14K', 'Var', (170, 174))	('Cisplatin', 'Chemical', 'MESH:D002945', (121, 130))
122290	31569615	In M14K cells, the cell viability was significantly reduced by all drug treatments, while Pem treated groups had significantly reduced cell viability compared to CPDD alone (Con: 100.0 +- 4.42%, CPDD: 63.83 +- 1.45%, Pem: 21.84 +- 3.34%, CPDD+Pem: 21.02 +- 1.79%; p < 0.001).	('M14K', 'Var', (3, 7))	('CPDD', 'Gene', '882', (195, 199))	('CPDD', 'Gene', (238, 242))	('reduced', 'NegReg', (52, 59))	('M14K', 'SUBSTITUTION', 'None', (3, 7))	('CPDD', 'Gene', '882', (162, 166))	('cell viability', 'CPA', (135, 149))	('CPDD', 'Gene', '882', (238, 242))	('CPDD', 'Gene', (195, 199))	('reduced', 'NegReg', (127, 134))	('CPDD', 'Gene', (162, 166))	('cell viability', 'CPA', (19, 33))
122294	31569615	In M14K cells, the mean spheroid perimeter was significantly reduced in the Pem treated groups (Con: 98.44 +- 2.56%, CPDD: 104.0 +- 3.57%, Pem: 74.25 +- 2.70%, CPDD+Pem: 78.87 +- 2.33%; p < 0.001).	('M14K', 'Var', (3, 7))	('CPDD', 'Gene', (160, 164))	('CPDD', 'Gene', '882', (117, 121))	('CPDD', 'Gene', '882', (160, 164))	('reduced', 'NegReg', (61, 68))	('CPDD', 'Gene', (117, 121))	('M14K', 'SUBSTITUTION', 'None', (3, 7))
122296	31569615	Finally, in ZL34 cells as in M14K cells, the mean spheroid perimeter was significantly reduced in the Pem treated groups (Con: 100 +- 1.81%, CPDD: 97.55 +- 1.04%, Pem: 77.58 +- 0.99%, CPDD+Pem: 78.10 +- 1.87%; p < 0.001).	('CPDD', 'Gene', (141, 145))	('CPDD', 'Gene', (184, 188))	('reduced', 'NegReg', (87, 94))	('M14K', 'SUBSTITUTION', 'None', (29, 33))	('CPDD', 'Gene', '882', (141, 145))	('M14K', 'Var', (29, 33))	('CPDD', 'Gene', '882', (184, 188))	('spheroid perimeter', 'CPA', (50, 68))
122299	31569615	The M14K invasion inside the collagen matrix was significantly reduced when treated with CPDD+Pem, and CPDD+Pem significantly reduced the invasion compared to Pem (Con: 100.0 +- 9.76%, CPDD: 75.93 +- 4.40%, Pem: 95.3 +- 6.63%, CPDD+Pem: 64.61 +- 5.41%; p < 0.001).	('CPDD', 'Gene', (227, 231))	('M14K', 'SUBSTITUTION', 'None', (4, 8))	('M14K', 'Var', (4, 8))	('CPDD', 'Gene', '882', (89, 93))	('reduced', 'NegReg', (63, 70))	('CPDD', 'Gene', '882', (185, 189))	('collagen', 'molecular_function', 'GO:0005202', ('29', '37'))	('CPDD', 'Gene', '882', (103, 107))	('CPDD', 'Gene', '882', (227, 231))	('CPDD', 'Gene', (89, 93))	('invasion', 'CPA', (138, 146))	('CPDD', 'Gene', (185, 189))	('CPDD', 'Gene', (103, 107))	('reduced', 'NegReg', (126, 133))
122302	31569615	Regarding MeT-5A and M14K, the mean gel area was significantly higher with all treatments (MeT-5A: Con: 100.0 +- 0.94%, CPDD: 116.1 +- 3.54%, Pem: 119.8 +- 3.64%, CPDD+Pem: 123.0 +- 3.28%; p < 0.001), (M14K: Con: 100.0 +- 2.31%, CPDD: 127.9 +- 2.08%, Pem: 157.9 +- 11.73%, CPDD+Pem: 160.3 +- 8.63%; p < 0.001).	('CPDD', 'Gene', '882', (120, 124))	('MeT-5A', 'Chemical', 'MESH:C520288', (10, 16))	('CPDD', 'Gene', (229, 233))	('M14K', 'SUBSTITUTION', 'None', (21, 25))	('CPDD', 'Gene', (163, 167))	('MeT-5A', 'Chemical', 'MESH:C520288', (91, 97))	('CPDD', 'Gene', (273, 277))	('CPDD', 'Gene', (120, 124))	('M14K', 'Var', (21, 25))	('CPDD', 'Gene', '882', (229, 233))	('CPDD', 'Gene', '882', (163, 167))	('gel area', 'MPA', (36, 44))	('M14K', 'SUBSTITUTION', 'None', (202, 206))	('higher', 'PosReg', (63, 69))	('M14K', 'Var', (202, 206))	('CPDD', 'Gene', '882', (273, 277))
122307	31569615	Under the scope of the above, we evaluated the effects of CPDD and Pem in the context of MPM cell viability, tumor spheroid formation, tumor spheroid invasion, and collagen gel contraction in MeT-5A, M14K, MSTO, and ZL34 cell lines.	('collagen', 'molecular_function', 'GO:0005202', ('164', '172'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('M14K', 'SUBSTITUTION', 'None', (200, 204))	('CPDD', 'Gene', '882', (58, 62))	('MPM', 'Disease', 'MESH:C562839', (89, 92))	('M14K', 'Var', (200, 204))	('tumor', 'Disease', (135, 140))	('collagen gel contraction', 'CPA', (164, 188))	('tumor spheroid invasion', 'Disease', (135, 158))	('MPM', 'Disease', (89, 92))	('tumor spheroid invasion', 'Disease', 'MESH:D009361', (135, 158))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MeT-5A', 'Chemical', 'MESH:C520288', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CPDD', 'Gene', (58, 62))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
122317	31569615	With respect to spheroid formation, all treatments reduced the perimeter of MeT-5A and MSTO spheroids, while M14K and ZL34 spheroids were smaller only when treated with Pem or the combination of the drugs.	('reduced', 'NegReg', (51, 58))	('perimeter', 'CPA', (63, 72))	('M14K', 'SUBSTITUTION', 'None', (109, 113))	('MSTO spheroids', 'CPA', (87, 101))	('formation', 'biological_process', 'GO:0009058', ('25', '34'))	('MeT-5A', 'CPA', (76, 82))	('M14K', 'Var', (109, 113))	('MeT-5A', 'Chemical', 'MESH:C520288', (76, 82))
122321	31569615	We have shown that spheroids from all cell lines were affected by Pem treatments (Pem or CPDD+Pem), while CPDD did not reduce the perimeter of the spheroids of M14K and ZL34 cells.	('affected', 'Reg', (54, 62))	('CPDD', 'Gene', '882', (89, 93))	('M14K', 'SUBSTITUTION', 'None', (160, 164))	('spheroids', 'CPA', (19, 28))	('CPDD', 'Gene', (106, 110))	('M14K', 'Var', (160, 164))	('CPDD', 'Gene', (89, 93))	('CPDD', 'Gene', '882', (106, 110))
122322	31569615	This suggests that the process of spheroid formation of M14K and ZL34 cells is resistant to CPDD treatment.	('M14K', 'SUBSTITUTION', 'None', (56, 60))	('CPDD', 'Gene', (92, 96))	('M14K', 'Var', (56, 60))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('CPDD', 'Gene', '882', (92, 96))
122336	31569615	CPDD only decreased the contraction of MeT-5A and M14K cells, while the combined treatment of CPDD and Pem decreased the gel contraction in all cell lines.	('gel contraction', 'CPA', (121, 136))	('contraction', 'CPA', (24, 35))	('CPDD', 'Gene', (94, 98))	('decreased', 'NegReg', (10, 19))	('CPDD', 'Gene', '882', (0, 4))	('M14K', 'SUBSTITUTION', 'None', (50, 54))	('MeT-5A', 'Chemical', 'MESH:C520288', (39, 45))	('M14K', 'Var', (50, 54))	('decreased', 'NegReg', (107, 116))	('CPDD', 'Gene', '882', (94, 98))	('CPDD', 'Gene', (0, 4))
122339	31569615	The human cell lines MeT-5A (benign immortalized mesothelial cells), M14K (epithelioid MPM), MSTO (biphasic MPM) and ZL34 (sarcomatoid MPM) were used and were kindly provided by Prof. Ioannis Kalomenidis (National and Kapodistrian University of Athens, Athens, Greece).	('MPM', 'Disease', 'MESH:C562839', (135, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('MPM', 'Disease', (135, 138))	('human', 'Species', '9606', (4, 9))	('MPM', 'Disease', 'MESH:C562839', (87, 90))	('M14K', 'Var', (69, 73))	('M14K', 'SUBSTITUTION', 'None', (69, 73))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('lines MeT-5A', 'Chemical', 'MESH:C061502', (15, 27))	('MPM', 'Disease', (108, 111))	('MPM', 'Disease', (87, 90))	('MPM', 'Disease', 'MESH:C562839', (108, 111))	('sarcoma', 'Disease', (123, 130))
122371	29335598	Specifically, recent studies have demonstrated that dysregulation of specific miRNAs can lead to drug resistance in different cancers, and modulation of these miRNAs using miRNA mimics or antagomiRs can have therapeutic impact on regulatory networks and signaling pathways, thereby sensitizing neoplastic cells to chemotherapy.	('drug resistance', 'MPA', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('drug resistance', 'biological_process', 'GO:0042493', ('97', '112'))	('signaling pathways', 'Pathway', (254, 272))	('regulatory networks', 'Pathway', (230, 249))	('lead to', 'Reg', (89, 96))	('signaling', 'biological_process', 'GO:0023052', ('254', '263'))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('modulation', 'Var', (139, 149))	('drug resistance', 'Phenotype', 'HP:0020174', (97, 112))	('dysregulation', 'Var', (52, 65))	('impact', 'Reg', (220, 226))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('drug resistance', 'biological_process', 'GO:0009315', ('97', '112'))	('sensitizing', 'Reg', (282, 293))
122392	29335598	The two probes (8042830 and 8084064) for MTHFD2 showed highly significant differential expression with concordant direction of effect (p = 7.62 x 10-4 and p = 1.56 x 10-3, respectively), as was observed in the LCLs following treatment with pemetrexed.	('8084064', 'Var', (28, 35))	('MTHFD2', 'Gene', '10797', (41, 47))	('expression', 'MPA', (87, 97))	('8042830', 'Var', (16, 23))	('pemetrexed', 'Chemical', 'MESH:D000068437', (240, 250))	('MTHFD2', 'Gene', (41, 47))
122393	29335598	Similarly, a probe (7930120) for SUFU was differentially expressed with consistent direction of effect (p = 1.64 x 10-3), as was observed in the LCLs.	('SUFU', 'Gene', '51684', (33, 37))	('SUFU', 'Gene', (33, 37))	('7930120', 'Var', (20, 27))
122401	29335598	MTHFD2 inhibition has been shown to enhance the apoptotic effects of methotrexate (MTX; another antifolate that has a similar mechanism to pemetrexed) in several cancer cell lines, and appeared to be a rational selection for further study.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('methotrexate', 'Chemical', 'MESH:D008727', (69, 81))	('apoptotic effects', 'CPA', (48, 65))	('cancer', 'Disease', (162, 168))	('MTHFD2', 'Gene', '10797', (0, 6))	('folate', 'Chemical', 'MESH:D005492', (100, 106))	('MTX', 'Chemical', 'MESH:D008727', (83, 86))	('inhibition', 'Var', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('enhance', 'PosReg', (36, 43))	('MTHFD2', 'Gene', (0, 6))	('pemetrexed', 'Chemical', 'MESH:D000068437', (139, 149))
122402	29335598	Molecular profiling analysis of lung adenocarcinoma samples (N = 230 patients) from TCGA indicates that alterations in MTHFD2 and in two thiol proteases, UCHL1 and UCHL3, in the form of amplification or mRNA upregulation, are associated with shorter median survival (although drug regimen is not reported in this dataset).	('median survival', 'MPA', (250, 265))	('alterations', 'Var', (104, 115))	('MTHFD2', 'Gene', '10797', (119, 125))	('UCHL3', 'Gene', '7347', (164, 169))	('mRNA', 'MPA', (203, 207))	('lung adenocarcinoma', 'Disease', (32, 51))	('UCHL1', 'Gene', '7345', (154, 159))	('upregulation', 'PosReg', (208, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (32, 51))	('UCHL3', 'Gene', (164, 169))	('shorter', 'NegReg', (242, 249))	('MTHFD2', 'Gene', (119, 125))	('UCHL1', 'Gene', (154, 159))	('patients', 'Species', '9606', (69, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
122403	29335598	Among the lung adenocarcinoma samples, 7% (17 out of 230 patients) showed MTHFD2 alterations (amplification, mutation, or mRNA upregulation).	('lung adenocarcinoma', 'Disease', (10, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (10, 29))	('patients', 'Species', '9606', (57, 65))	('alterations', 'Reg', (81, 92))	('mRNA', 'MPA', (122, 126))	('MTHFD2', 'Gene', (74, 80))	('upregulation', 'PosReg', (127, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (10, 29))	('MTHFD2', 'Gene', '10797', (74, 80))	('mutation', 'Var', (109, 117))
122405	29335598	Of the 17 cases with MTHFD2 alterations, 8 were deceased with median month survival of 23.36 months.	('MTHFD2', 'Gene', '10797', (21, 27))	('MTHFD2', 'Gene', (21, 27))	('alterations', 'Var', (28, 39))
122406	29335598	TCGA data for lung adenocarcinoma showed amplifications in 13% of the cases for thiol proteases UCHL1 and UCHL3.	('UCHL3', 'Gene', '7347', (106, 111))	('lung adenocarcinoma', 'Disease', (14, 33))	('UCHL1', 'Gene', (96, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('UCHL3', 'Gene', (106, 111))	('amplifications', 'Var', (41, 55))	('UCHL1', 'Gene', '7345', (96, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
122414	29335598	Our in vitro findings support a role for MTHFD2 in determining the cellular response of LCLs and A549 cells to pemetrexed, while molecular profiling analysis of 230 lung adenocarcinoma patients from TCGA indicates that amplification or upregulation of MTHFD2 is associated with shorter survival.	('amplification', 'Var', (219, 232))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (165, 184))	('MTHFD2', 'Gene', '10797', (41, 47))	('MTHFD2', 'Gene', (252, 258))	('shorter', 'NegReg', (278, 285))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('MTHFD2', 'Gene', '10797', (252, 258))	('upregulation', 'PosReg', (236, 248))	('pemetrexed', 'Chemical', 'MESH:D000068437', (111, 121))	('patients', 'Species', '9606', (185, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (165, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('MTHFD2', 'Gene', (41, 47))	('lung adenocarcinoma', 'Disease', (165, 184))
122421	29335598	One recent randomized clinical trial examining the efficacy of pemetrexed against malignant pleural mesothelioma indicated that patients with at least one risk allele at the MTHFD1 nonsynonymous polymorphism rs2236225 exhibited a significantly lower response rate and shorter progression-free survival than non-carriers.	('malignant pleural mesothelioma', 'Disease', (82, 112))	('rs2236225', 'Var', (208, 217))	('rs2236225', 'Mutation', 'rs2236225', (208, 217))	('MTHFD1', 'Gene', (174, 180))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (82, 112))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (92, 112))	('response', 'MPA', (250, 258))	('lower', 'NegReg', (244, 249))	('shorter', 'NegReg', (268, 275))	('progression-free survival', 'CPA', (276, 301))	('pemetrexed', 'Chemical', 'MESH:D000068437', (63, 73))	('MTHFD1', 'Gene', '4522', (174, 180))	('patients', 'Species', '9606', (128, 136))
122437	29335598	Specifically, the expression levels of our top hit, hsa-miR-1244, have been shown to decrease in A549 and NCI-H522 cells, as well as patient-derived tumor samples after cisplatin treatment, with the overall survival times of cisplatin-treated patients being longer for those who had high miR-1244 expression.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('miR-1244', 'Gene', '100302285', (288, 296))	('hsa-miR-1244', 'Gene', '100302285', (52, 64))	('longer', 'PosReg', (258, 264))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('miR-1244', 'Gene', (56, 64))	('patients', 'Species', '9606', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('decrease', 'NegReg', (85, 93))	('miR-1244', 'Gene', '100302285', (56, 64))	('high', 'Var', (283, 287))	('patient', 'Species', '9606', (133, 140))	('hsa-miR-1244', 'Gene', (52, 64))	('NCI-H522', 'CellLine', 'CVCL:1567', (106, 114))	('miR-1244', 'Gene', (288, 296))	('expression levels', 'MPA', (18, 35))	('patient', 'Species', '9606', (243, 250))	('cisplatin', 'Chemical', 'MESH:D002945', (225, 234))	('tumor', 'Disease', (149, 154))	('expression', 'MPA', (297, 307))
122442	29335598	Notably, a common BIM deletion has been shown to confer intrinsic resistance to tyrosine kinase inhibitors in NSCLC cell lines and to be associated with shorter progression-free survival in EGFR-driven NSCLC.	('resistance to tyrosine kinase inhibitors', 'MPA', (66, 106))	('BIM', 'Gene', '10018', (18, 21))	('BIM', 'Gene', (18, 21))	('progression-free survival', 'CPA', (161, 186))	('NSCLC', 'Disease', (202, 207))	('EGFR', 'Gene', '1956', (190, 194))	('deletion', 'Var', (22, 30))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('shorter', 'NegReg', (153, 160))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('EGFR', 'Gene', (190, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
122444	29335598	For example, in the human breast carcinoma cell line MCF7 (luminal A molecular subtype), 5-FU was found to significantly alter the global expression profile of miRNA with 42 out of 871 human miRNAs differentially expressed.	('miRNA', 'MPA', (160, 165))	('5-FU', 'Var', (89, 93))	('human', 'Species', '9606', (20, 25))	('human', 'Species', '9606', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('breast carcinoma', 'Phenotype', 'HP:0003002', (26, 42))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('MCF7', 'CellLine', 'CVCL:0031', (53, 57))	('global expression profile', 'MPA', (131, 156))	('alter', 'Reg', (121, 126))	('breast carcinoma', 'Disease', 'MESH:D001943', (26, 42))	('breast carcinoma', 'Disease', (26, 42))
122452	29335598	This is particularly noteworthy given recent findings on the use of the proteasome inhibitor bortezomib in combination with pemetrexed in malignant pleural mesothelioma, in which bortezomib was found to increase the cytotoxicity of pemetrexed in a concentration-dependent manner.	('proteasome', 'cellular_component', 'GO:0000502', ('72', '82'))	('bortezomib', 'Chemical', 'MESH:D000069286', (179, 189))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (138, 168))	('malignant pleural mesothelioma', 'Disease', (138, 168))	('bortezomib', 'Var', (179, 189))	('cytotoxicity', 'Disease', (216, 228))	('proteasome', 'molecular_function', 'GO:0004299', ('72', '82'))	('cytotoxicity', 'Disease', 'MESH:D064420', (216, 228))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (148, 168))	('bortezomib', 'Chemical', 'MESH:D000069286', (93, 103))	('pemetrexed', 'Chemical', 'MESH:D000068437', (124, 134))	('increase', 'PosReg', (203, 211))	('pemetrexed', 'Chemical', 'MESH:D000068437', (232, 242))
122457	29335598	Histone acetylation/deacetylation is an essential aspect of gene regulation, and the inhibition of histone deacetylases (HDACs) has been recently shown to augment the antineoplastic effects of pemetrexed against multiple NSCLC cell lines in vitro and in patient-derived xenograft mouse models in vivo through induction of apoptosis and autophagy.	('apoptosis', 'CPA', (322, 331))	('autophagy', 'biological_process', 'GO:0006914', ('336', '345'))	('augment', 'PosReg', (155, 162))	('inhibition', 'Var', (85, 95))	('NSCLC', 'Disease', (221, 226))	('autophagy', 'biological_process', 'GO:0016236', ('336', '345'))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('antineoplastic effects', 'CPA', (167, 189))	('patient', 'Species', '9606', (254, 261))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('Histone acetylation', 'biological_process', 'GO:0016573', ('0', '19'))	('autophagy', 'CPA', (336, 345))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('309', '331'))	('mouse', 'Species', '10090', (280, 285))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))	('pemetrexed', 'Chemical', 'MESH:D000068437', (193, 203))
122466	29335598	Five of the cell lines (GM07055, GM11994, GM11995, GM12813, and GM12762) were more sensitive to pemetrexed (0.5 microM), defined by having 41-57% cell survival following treatment.	('GM11994', 'Var', (33, 40))	('GM12762', 'Var', (64, 71))	('GM07055', 'Var', (24, 31))	('pemetrexed', 'Chemical', 'MESH:D000068437', (96, 106))	('sensitive', 'MPA', (83, 92))	('GM12813', 'Var', (51, 58))	('GM11995', 'Var', (42, 49))
122467	29335598	LCLs that were more resistant to pemetrexed were defined by 87-105% cell survival following the same treatment, and included GM06994, GM07022, GM07034, GM12044, GM12144, and GM12873.	('cell survival', 'CPA', (68, 81))	('GM12873', 'Var', (174, 181))	('GM07022', 'Var', (134, 141))	('GM12044', 'Var', (152, 159))	('GM06994', 'Var', (125, 132))	('GM07034', 'Var', (143, 150))	('GM12144', 'Var', (161, 168))	('pemetrexed', 'Chemical', 'MESH:D000068437', (33, 43))
122490	29335598	For those genes that were differentially expressed in both LCLs and EA.hy 926 cells after pemetrexed exposure, we considered the proportion of TCGA cases in which the gene was found to be altered through amplification, mutation, or mRNA upregulation using cBioPortal for Cancer Genomics.	('EA.hy 926', 'CellLine', 'CVCL:3901', (68, 77))	('amplification', 'Var', (204, 217))	('mRNA', 'MPA', (232, 236))	('mutation', 'Var', (219, 227))	('Cancer', 'Phenotype', 'HP:0002664', (271, 277))	('TCGA', 'Gene', (143, 147))	('pemetrexed', 'Chemical', 'MESH:D000068437', (90, 100))	('altered', 'Reg', (188, 195))	('upregulation', 'PosReg', (237, 249))
122548	29132390	MSTO-211H (also referred to as MSTO) is representative of the biphasic histologic subtype of mesothelioma, and VAMT is derived from the sarcomatoid histologic subtype.	('sarcomatoid', 'Disease', 'MESH:C538614', (136, 147))	('sarcomatoid histologic subtype', 'Phenotype', 'HP:0100242', (136, 166))	('VAMT', 'Chemical', '-', (111, 115))	('mesothelioma', 'Disease', (93, 105))	('sarcomatoid', 'Disease', (136, 147))	('MSTO-211H', 'CellLine', 'CVCL:1430', (0, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('MSTO-211H', 'Var', (0, 9))
122550	29132390	We have previously noted that TNT formation in MSTO and VAMT cells is upregulated in conditions of metabolic and physiological stress, such as a low-serum, hyperglycemic microenvironment; actin is uniformly present throughout the length of these TNTs, and ezrin and ZO-1 localize at the bases of TNTs in these cells; MSTO TNTs facilitate intercellular transfer of molecular cargo such as mitochondria and Golgi vesicles; and formation of TNTs in these cells can be suppressed via inhibition of mTOR.	('TNTs', 'Gene', (438, 442))	('inhibition', 'Var', (480, 490))	('TNTs', 'Gene', '7138', (246, 250))	('VAMT', 'Chemical', '-', (56, 60))	('TNT', 'Gene', (246, 249))	('TNT', 'Gene', '7138', (322, 325))	('TNT', 'Gene', (438, 441))	('MSTO', 'Var', (317, 321))	('TNT', 'Gene', '7138', (296, 299))	('intercellular transfer of molecular cargo', 'MPA', (338, 379))	('TNTs', 'Gene', (246, 250))	('TNTs', 'Gene', '7138', (322, 326))	('Golgi', 'cellular_component', 'GO:0005794', ('405', '410'))	('mTOR', 'Gene', (494, 498))	('TNT', 'Gene', (30, 33))	('TNTs', 'Gene', (322, 326))	('formation', 'biological_process', 'GO:0009058', ('425', '434'))	('TNT', 'Gene', '7138', (438, 441))	('TNT', 'Gene', '7138', (246, 249))	('facilitate', 'PosReg', (327, 337))	('mitochondria', 'cellular_component', 'GO:0005739', ('388', '400'))	('mTOR', 'Gene', '2475', (494, 498))	('TNTs', 'Gene', '7138', (296, 300))	('TNT', 'Gene', (322, 325))	('cargo', 'molecular_function', 'GO:0140355', ('374', '379'))	('TNTs', 'Gene', '7138', (438, 442))	('TNT', 'Gene', (296, 299))	('TNT', 'Gene', '7138', (30, 33))	('TNTs', 'Gene', (296, 300))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))
122652	29100432	Positive expression of MSLN, CA125, and WT1 were demonstrated in 93%, 75%, and 97% of epithelioid MPM cases, and 57%, 33%, and 98% of non-epithelioid MPM cases, respectively.	('CA125', 'Gene', '94025', (29, 34))	('MSLN', 'Var', (23, 27))	('epithelioid MPM', 'Disease', (86, 101))	('CA125', 'Gene', (29, 34))
122658	29100432	Recent comprehensive genomic analysis of transcriptomes and exomes from patient MPM samples have identified significantly mutated genes, recurrent mutations, gene fusions, and splicing alterations.	('patient', 'Species', '9606', (72, 79))	('mutations', 'Var', (147, 156))	('mutated', 'Reg', (122, 129))	('splicing', 'biological_process', 'GO:0045292', ('176', '184'))
122669	29100432	Other investigators have been conducting MSLN-targeted CAR T-cell therapy clinical trials with systemic administration of CAR T cells (NCT01583686, NCT02159716, NCT01355965, and NCT02930993).	('CAR', 'cellular_component', 'GO:0005826', ('55', '58'))	('CAR', 'Gene', (122, 125))	('NCT01583686', 'Var', (135, 146))	('CAR', 'Gene', '9970', (122, 125))	('CAR', 'Gene', (55, 58))	('NCT02930993', 'Var', (178, 189))	('NCT02159716', 'Var', (148, 159))	('CAR', 'Gene', '9970', (55, 58))	('NCT01355965', 'Var', (161, 172))	('CAR', 'cellular_component', 'GO:0005826', ('122', '125'))
122686	29100432	Distribution >=50% of MSLN-, CA125-, and WT1-positive tumor cells were observed in 84%, 20%, and 72% of epithelioid MPM cases, respectively.	('CA125', 'Gene', (29, 34))	('MSLN-', 'Var', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('epithelioid MPM', 'Disease', (104, 119))	('CA125', 'Gene', '94025', (29, 34))	('tumor', 'Disease', (54, 59))
122689	29100432	Distribution >=50% of MSLN-, CA125-, and WT1-positive tumor cells were observed in 25%, 6%, and 45% of non-epithelioid MPM cases, respectively.	('non-epithelioid MPM', 'Disease', (103, 122))	('CA125', 'Gene', (29, 34))	('MSLN-', 'Var', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CA125', 'Gene', '94025', (29, 34))	('tumor', 'Disease', (54, 59))
122691	29100432	Expression of either MSLN or CA125 was demonstrated in 96% of epithelioid and 57% of non-epithelioid MPM cases.	('CA125', 'Gene', '94025', (29, 34))	('MSLN', 'Var', (21, 25))	('epithelioid', 'Disease', (62, 73))	('CA125', 'Gene', (29, 34))
122707	29100432	For all patients (n = 269), 197 (73%) patients had >=50% MSLN distribution and 36 (13%) patients had >=50% WT1 distribution without >=50% MSLN distribution.	('>=50', 'Var', (51, 55))	('patients', 'Species', '9606', (88, 96))	('MSLN', 'Var', (57, 61))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (8, 16))
122710	29100432	These findings, combined with the survival benefits shown in MPM patients with MSLN-, CA125-, and WT1-specific immune responses, provide the rationale for the development of targeted therapies.	('patients', 'Species', '9606', (65, 73))	('MSLN-', 'Var', (79, 84))	('CA125', 'Gene', (86, 91))	('CA125', 'Gene', '94025', (86, 91))
122711	29100432	Furthermore, published evidence has shown that antigen-specific spontaneous immune response are beneficial for different solid malignancies:MSLN in pancreatic cancer, CA125 in ovarian cancer, and WT1 in mesothelioma :and has driven us to explore the expression of these antigens on MPM.	('CA125', 'Gene', '94025', (167, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (148, 165))	('solid malignancies', 'Disease', (121, 139))	('immune response', 'biological_process', 'GO:0006955', ('76', '91'))	('mesothelioma', 'Disease', (203, 215))	('pancreatic cancer', 'Disease', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (148, 165))	('MSLN', 'Var', (140, 144))	('CA125', 'Gene', (167, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('mesothelioma', 'Disease', 'MESH:D008654', (203, 215))	('solid malignancies', 'Disease', 'MESH:D009369', (121, 139))	('ovarian cancer', 'Disease', (176, 190))
122714	29100432	Additionally, we have reported that epithelioid MPM with pleomorphic features was associated with aggressive behavior and a similar survival rate to non-epithelioid MPM.	('pleomorphic features', 'Var', (57, 77))	('associated', 'Reg', (82, 92))	('aggressive behavior', 'Disease', (98, 117))	('aggressive behavior', 'Disease', 'MESH:D001523', (98, 117))	('aggressive behavior', 'biological_process', 'GO:0002118', ('98', '117'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (98, 117))	('epithelioid MPM', 'Disease', (36, 51))
122745	29100432	Sections were stained using a Ventana Discovery XT automated immunohistochemical stainer (Ventana, Tucson, AZ) for MSLN (5B2, MAb, Vector; diluted at 1:50), CA125 (OC125, MAb, Ventana; pre-diluted), and WT1 (C19, PAb, Santa Cruz; diluted at 1:2000) for IHC analysis.	('pre', 'molecular_function', 'GO:0003904', ('185', '188'))	('MSLN', 'Var', (115, 119))	('CA125', 'Gene', '94025', (157, 162))	('CA125', 'Gene', (157, 162))
122841	33300108	In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio.	('colony formation assays', 'CPA', (196, 219))	('proliferation', 'CPA', (34, 47))	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('ERK', 'molecular_function', 'GO:0004707', ('273', '276'))	('ERK', 'molecular_function', 'GO:0004707', ('263', '266'))	('formation', 'biological_process', 'GO:0009058', ('203', '212'))	('F-araA', 'Chemical', 'MESH:C024352', (15, 21))	('F-araA', 'Var', (15, 21))	('MPM', 'Chemical', '-', (88, 91))	('reduced', 'NegReg', (22, 29))	('colony formation ability', 'CPA', (56, 80))
122842	33300108	We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively).	('rs2295890', 'Mutation', 'rs2295890', (161, 170))	('F-araA', 'Chemical', 'MESH:C024352', (35, 41))	('DCK', 'Gene', (83, 86))	('rs2295890', 'Var', (161, 170))	('rs11544786', 'Var', (146, 156))	('NT5E', 'Gene', (91, 95))	('DCK', 'Gene', '1633', (83, 86))	('rs11544786', 'Mutation', 'rs11544786', (146, 156))	('NT5E', 'Chemical', '-', (91, 95))
122875	33300108	Genetic variants in NT5E (rs2295890) and DCK (rs11544786) were screened using PCR followed by sequencing.	('rs2295890', 'Var', (26, 35))	('NT5E', 'Chemical', '-', (20, 24))	('rs11544786', 'Var', (46, 56))	('DCK', 'Gene', '1633', (41, 44))	('NT5E', 'Gene', (20, 24))	('DCK', 'Gene', (41, 44))	('rs2295890', 'Mutation', 'rs2295890', (26, 35))	('rs11544786', 'Mutation', 'rs11544786', (46, 56))
122886	33300108	We bought from Cell Signaling Technology (Danvers, MA, USA) the primary antibodies for STAT1 (#9172, Polyclonal Rabbit), Erk1/2 (#4695 T, p44/42 MAPK (Erk1/2) (137F5) Monoclonal Rabbit), phospho-Erk1/2 (#4370S, Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP  Monoclonal Rabbit).	('Erk1/2', 'Gene', (232, 238))	('Erk1/2', 'Gene', '5595;5594', (151, 157))	('Erk1/2', 'Gene', '5595;5594', (121, 127))	('Erk1/2', 'Gene', (195, 201))	('Erk1', 'molecular_function', 'GO:0004707', ('151', '155'))	('#4370S', 'Var', (203, 209))	('STAT1', 'Gene', (87, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('226', '230'))	('Erk1', 'molecular_function', 'GO:0004707', ('121', '125'))	('MAPK', 'molecular_function', 'GO:0004707', ('145', '149'))	('Erk1/2', 'Gene', (151, 157))	('Erk1/2', 'Gene', (121, 127))	('STAT1', 'Gene', '6772', (87, 92))	('Erk1/2', 'Gene', '5595;5594', (232, 238))	('Erk1', 'molecular_function', 'GO:0004707', ('232', '236'))	('Erk1', 'molecular_function', 'GO:0004707', ('195', '199'))	('Signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('Erk1/2', 'Gene', '5595;5594', (195, 201))
122902	33300108	The EC50s were 46.26 muM, 5.01 muM, 5.46 muM, 9.30 muM, and 7.12 muM for MeT-5A, Mero-14, Mero-25, IST-Mes-2, and MSTO-211H, respectively.	('Mero-14', 'Chemical', '-', (81, 88))	('MSTO-211H', 'Chemical', '-', (114, 123))	('Mero-25', 'Var', (90, 97))	('IST-Mes-', 'Chemical', '-', (99, 107))	('MeT-5A', 'Var', (73, 79))	('MeT-5A', 'Chemical', '-', (73, 79))	('Mero-25', 'Chemical', '-', (90, 97))
122915	33300108	In addition, RIS treatment reduced the viability of MMP1 cells by approximately 20% at 25 muM, again showing reduced activity as compared to F-araA [Supplemental Fig.	('reduced', 'NegReg', (27, 34))	('activity', 'MPA', (117, 125))	('RIS', 'Chemical', 'MESH:D000068296', (13, 16))	('MMP1', 'molecular_function', 'GO:0004232', ('52', '56'))	('MMP1', 'Gene', '4312', (52, 56))	('RIS', 'Var', (13, 16))	('MMP1', 'Gene', (52, 56))	('F-araA', 'Chemical', 'MESH:C024352', (141, 147))	('viability', 'CPA', (39, 48))
122916	33300108	We also observed that F-araA induced cytotoxic effects of the same order of magnitude as cisplatin, a known chemotherapeutic agent used in the cure of MPM and employed here as a control.	('MPM', 'Chemical', '-', (151, 154))	('F-araA', 'Chemical', 'MESH:C024352', (22, 28))	('cytotoxic effects', 'CPA', (37, 54))	('F-araA', 'Var', (22, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))
122923	33300108	Significantly at 1 muM F-araA, we observed decreased proliferation rates (up to -90%) of all MPM cell lines, statistically significant at 24, 48, and 72 h, when compared with their respective controls (vehicle).	('MPM', 'Chemical', '-', (93, 96))	('F-araA', 'Chemical', 'MESH:C024352', (23, 29))	('proliferation rates', 'CPA', (53, 72))	('F-araA', 'Var', (23, 29))	('decreased', 'NegReg', (43, 52))
122934	33300108	We observed that 1 muM F-araA caused a statistically significant decrease of colonies in the malignant cell lines only [Supplemental Fig.	('F-araA', 'Var', (23, 29))	('F-araA', 'Chemical', 'MESH:C024352', (23, 29))	('decrease', 'NegReg', (65, 73))	('colonies in the malignant cell lines only', 'CPA', (77, 118))
122948	33300108	In addition, we verified whether the response to F-araA could be related to genetic polymorphisms in NT5E and DCK, thus we genotyped rs2295890 (G > C) within NT5E and rs11544786 (C > T) within DCK.	('DCK', 'Gene', '1633', (110, 113))	('rs11544786 (C > T', 'Var', (167, 184))	('rs2295890', 'Mutation', 'rs2295890', (133, 142))	('F-araA', 'Chemical', 'MESH:C024352', (49, 55))	('DCK', 'Gene', '1633', (193, 196))	('DCK', 'Gene', (110, 113))	('NT5E', 'Chemical', '-', (158, 162))	('rs11544786', 'Mutation', 'rs11544786', (167, 177))	('DCK', 'Gene', (193, 196))	('rs2295890 (G > C', 'Var', (133, 149))	('NT5E', 'Chemical', '-', (101, 105))	('NT5E', 'Gene', (158, 162))
123014	31878926	In addition, contrary to the opinion expressed by Vimercati et al., there is considerable evidence that in addition to asbestos and some other fibers such as erionite, ionizing radiation increases the risk of malignant mesothelioma (e.g.,).	('ionizing radiation', 'Var', (168, 186))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (209, 231))	('ionizing radiation increases', 'Phenotype', 'HP:0011133', (168, 196))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (209, 231))	('erionite', 'Chemical', 'MESH:C083174', (158, 166))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('malignant mesothelioma', 'Disease', (209, 231))
123052	26870384	A pilot non-randomised study suggested that patients treated with IPC spent significantly fewer days in hospital (for any causes) from procedure to death than those pleurodesed.	('patients', 'Species', '9606', (44, 52))	('days', 'MPA', (96, 100))	('fewer', 'NegReg', (90, 95))	('IPC', 'Var', (66, 69))	('death', 'Disease', 'MESH:D003643', (148, 153))	('death', 'Disease', (148, 153))	('IPC', 'Chemical', '-', (66, 69))
123207	24639000	EPP leaves less residual tumor cells compared with P/D; however, it often results in high mortality/morbidity, severe depression of cardiorespiratory function, and poor quality of life.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('depression of cardiorespiratory function', 'Disease', (118, 158))	('tumor', 'Disease', (25, 30))	('depression of cardiorespiratory function', 'Disease', 'MESH:D000275', (118, 158))	('depression', 'Phenotype', 'HP:0000716', (118, 128))	('results', 'Reg', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('EPP', 'Var', (0, 3))
123217	24639000	Furthermore, Lucklatz and others reported that P/D combined with postoperative adjuvant therapy provided better survival compared with EPP, irrespective of factors such as advanced disease or surgically less fit patients.	('better', 'PosReg', (105, 111))	('patients', 'Species', '9606', (212, 220))	('advanced disease', 'Disease', (172, 188))	('survival', 'MPA', (112, 120))	('advanced disease', 'Disease', 'MESH:D020178', (172, 188))	('P/D', 'Var', (47, 50))
123222	24639000	Accordingly, survival after recurrence was longer in patients who underwent P/D than in those who underwent EPP.	('survival', 'MPA', (13, 21))	('longer', 'PosReg', (43, 49))	('P/D', 'Var', (76, 79))	('patients', 'Species', '9606', (53, 61))
123223	24639000	Third, because of better cardiopulmonary reserve, patients who undergo P/D are more equipped to fend off postoperative nononcological disorders such as pneumonia and cardiac failure compared with those who undergo EPP.	('patients', 'Species', '9606', (50, 58))	('pneumonia', 'Disease', (152, 161))	('pneumonia', 'Disease', 'MESH:D011014', (152, 161))	('cardiac failure', 'Phenotype', 'HP:0001635', (166, 181))	('cardiac failure', 'Disease', 'MESH:D006333', (166, 181))	('P/D', 'Var', (71, 74))	('pneumonia', 'Phenotype', 'HP:0002090', (152, 161))	('cardiac failure', 'Disease', (166, 181))
123229	24639000	First, does P/D allow part of the pleura to be left behind as long as it contains no macroscopic tumor?	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('pleura', 'Disease', (34, 40))	('pleura', 'Disease', 'MESH:D054363', (34, 40))	('tumor', 'Disease', (97, 102))	('P/D', 'Var', (12, 15))
123350	32650433	The 30-day mortality was significantly higher in patients receiving EPP than in those receiving extended P/D according to the meta-analysis (OR: 0.53 (95% confidence interval (CI): 0.33, 0.85); p < 0.01, I2 = 0%).	('higher', 'PosReg', (39, 45))	('mortality', 'Disease', 'MESH:D003643', (11, 20))	('EPP', 'Chemical', '-', (68, 71))	('patients', 'Species', '9606', (49, 57))	('EPP', 'Var', (68, 71))	('mortality', 'Disease', (11, 20))
123352	32650433	Although the morbidity was also significantly higher in patients receiving EPP than in those receiving extended P/D (OR: 0.37 (95% CI: 0.26, 0.54); p < 0.01, I2 = 64%), heterogeneity was detected (Figure 3).	('morbidity', 'MPA', (13, 22))	('patients', 'Species', '9606', (56, 64))	('higher', 'PosReg', (46, 52))	('EPP', 'Chemical', '-', (75, 78))	('EPP', 'Var', (75, 78))
123357	32650433	The 30-day mortality was significantly higher in patients receiving EPP than in those receiving P/D according to a meta-analysis (OR: 0.26 (95% CI: 0.13, 0.52); p < 0.01, I2 = 0%).	('higher', 'PosReg', (39, 45))	('mortality', 'Disease', 'MESH:D003643', (11, 20))	('EPP', 'Chemical', '-', (68, 71))	('patients', 'Species', '9606', (49, 57))	('EPP', 'Var', (68, 71))	('mortality', 'Disease', (11, 20))
123359	32650433	The morbidity was also significantly higher in patients receiving EPP than in those receiving P/D (OR: 0.42 (95% CI: 0.25, 0.71); p < 0.01, I2 = 0%) (Figure 4).	('EPP', 'Var', (66, 69))	('higher', 'PosReg', (37, 43))	('patients', 'Species', '9606', (47, 55))	('EPP', 'Chemical', '-', (66, 69))	('morbidity', 'MPA', (4, 13))
123381	32650433	The trial showed that EPP within trimodal treatment brought no marked benefits and likely even harmed the patient, even based on limited data.	('harmed', 'NegReg', (95, 101))	('EPP', 'Chemical', '-', (22, 25))	('patient', 'Species', '9606', (106, 113))	('EPP', 'Var', (22, 25))
123389	32650433	Extended P/D for MPM did not improve the overall health-related QOL and actually showed a negative influence on the pulmonary function in performance status (PS) 0 patients.	('MPM', 'Var', (17, 20))	('patients', 'Species', '9606', (164, 172))	('negative', 'NegReg', (90, 98))	('pulmonary function', 'MPA', (116, 134))
123394	32650433	Although the postoperative pulmonary function after P/D for MPM was not significantly decreased compared with before surgery (median FEV1.0%: 87.1% to 70.0% and FVC%: 86.5% to 68.2%), the postoperative pulmonary function after EPP for MPM was significantly decreased (median FEV1.0%: 78.0% to 49.3% and FVC%: 76.8% to 48.0%).	('EPP', 'Var', (227, 230))	('pulmonary function', 'CPA', (202, 220))	('EPP', 'Chemical', '-', (227, 230))	('decreased', 'NegReg', (257, 266))
123396	32650433	Although there has been no prospective randomized controlled trial focusing on surgical methods for MPM, P/D seems to be superior to EPP in terms of the postoperative pulmonary function.	('EPP', 'Chemical', '-', (133, 136))	('P/D', 'Var', (105, 108))	('pulmonary function', 'CPA', (167, 185))
123398	32650433	P/D showed a significantly better median overall survival and 30-day postoperative mortality than EPP.	('P/D', 'Var', (0, 3))	('better', 'PosReg', (27, 33))	('mortality', 'Disease', 'MESH:D003643', (83, 92))	('EPP', 'Chemical', '-', (98, 101))	('mortality', 'Disease', (83, 92))
123405	32650433	They measured the QOL using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and concluded that patients receiving P/D had a higher postoperative QOL than those receiving EPP, although at a limited level of evidence.	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('EPP', 'Chemical', '-', (201, 204))	('P/D', 'Var', (145, 148))	('QOL', 'MPA', (176, 179))	('postoperative', 'MPA', (162, 175))	('patients', 'Species', '9606', (126, 134))	('higher', 'PosReg', (155, 161))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', (84, 90))
123414	32650433	The 30-day mortality rates of extended P/D vs. EPP and P/D vs. EPP were 3.19% vs. 7.65% (p < 0.01) and 1.85% vs. 7.34% (p < 0.01), respectively.	('P/D', 'Var', (55, 58))	('EPP', 'Chemical', '-', (47, 50))	('mortality', 'Disease', 'MESH:D003643', (11, 20))	('EPP', 'Chemical', '-', (63, 66))	('mortality', 'Disease', (11, 20))
123419	32650433	Although the morbidity was also significantly higher in patients receiving EPP than in those receiving extended P/D, a literature search revealed that the morbidity of patients receiving EPP was similar to that of patients receiving extended P/D.	('morbidity', 'MPA', (13, 22))	('patients', 'Species', '9606', (56, 64))	('EPP', 'Chemical', '-', (187, 190))	('patients', 'Species', '9606', (214, 222))	('higher', 'PosReg', (46, 52))	('EPP', 'Chemical', '-', (75, 78))	('EPP', 'Var', (187, 190))	('patients', 'Species', '9606', (168, 176))
123463	32650433	Microsatellite instability (MSI) arises from inactivation of any of several mismatch repair (MMR) genes:mutL homolog 1 gene (MLH1), PMS1 homolog 2, mismatch repair system component gene (PMS2), mutS homolog 2 gene (MSH2), and mutS homolog 6 gene (MSH6):resulting in failure to repair the routine errors which occur during replication of short repeats in a DNA sequence.	('inactivation', 'Var', (45, 57))	('Microsatellite instability', 'Disease', (0, 26))	('PMS2', 'Gene', (187, 191))	('MLH1', 'Gene', (125, 129))	('MSH2', 'Gene', '4436', (215, 219))	('mismatch repair', 'biological_process', 'GO:0006298', ('148', '163'))	('MLH1', 'Gene', '4292', (125, 129))	('mutL homolog 1', 'Gene', (104, 118))	('mutS homolog 6', 'Gene', (226, 240))	('mutL homolog 1', 'Gene', '4292', (104, 118))	('mutS homolog 2', 'Gene', (194, 208))	('DNA', 'cellular_component', 'GO:0005574', ('356', '359'))	('PMS2', 'Gene', '5395', (187, 191))	('MSH6', 'Gene', (247, 251))	('MMR', 'biological_process', 'GO:0006298', ('93', '96'))	('MSH6', 'Gene', '2956', (247, 251))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('mutS homolog 2', 'Gene', '4436', (194, 208))	('mismatch repair', 'biological_process', 'GO:0006298', ('76', '91'))	('mutS homolog 6', 'Gene', '2956', (226, 240))	('MSH2', 'Gene', (215, 219))
123465	32650433	The MSI-high status is thought to inactivate tumor suppressor genes, accumulate many genetic mutations and promote cancer development.	('cancer', 'Disease', (115, 121))	('MSI-high', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (93, 102))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('accumulate', 'PosReg', (69, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumor', 'Disease', (45, 50))	('inactivate', 'NegReg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('genetic mutations', 'Var', (85, 102))	('promote', 'PosReg', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
123468	32650433	On the other hand, it was reported that somatic mutations occurred in a number of tumor suppressor genes, such as cyclin-dependent kinase inhibitor 2A gene (CDKN2A), neurofibromin 2 (merlin) gene (NF2) and breast cancer susceptibility gene 1 (BRCA1)-associated protein 1 gene (BAP1).	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (114, 150))	('merlin', 'Gene', '4771', (183, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('BAP1', 'Gene', '8314', (277, 281))	('CDKN2A', 'Gene', '1029', (157, 163))	('tumor', 'Disease', (82, 87))	('mutations', 'Var', (48, 57))	('occurred', 'Reg', (58, 66))	('NF2', 'Gene', '4771', (197, 200))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (114, 150))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('131', '147'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer susceptibility gene 1 (BRCA1)-associated protein 1', 'Gene', '8314', (213, 270))	('NF2', 'Gene', (197, 200))	('BAP1', 'Gene', (277, 281))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('114', '147'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('merlin', 'Gene', (183, 189))	('neurofibromin 2', 'Gene', '4771', (166, 181))	('neurofibromin 2', 'Gene', (166, 181))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('CDKN2A', 'Gene', (157, 163))	('protein', 'cellular_component', 'GO:0003675', ('261', '268'))
123475	32650433	This study is the first to compare the mortality, morbidity and MST separately for EPP vs. P/D and EPP vs. extended P/D.	('EPP', 'Chemical', '-', (83, 86))	('mortality', 'Disease', (39, 48))	('EPP', 'Chemical', '-', (99, 102))	('EPP', 'Var', (99, 102))	('EPP', 'Disease', (83, 86))	('mortality', 'Disease', 'MESH:D003643', (39, 48))
123589	30345394	Mice with a Wt1 deletion in the epicardium develop peripheral oedema, pericardial haemorrhage, and heart wall thinning resulting from impaired EMT.	('pericardial haemorrhage', 'Disease', (70, 93))	('pericardial haemorrhage', 'Phenotype', 'HP:0001698', (70, 93))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('pericardial haemorrhage', 'Disease', 'MESH:D006470', (70, 93))	('deletion', 'Var', (16, 24))	('Wt1', 'Gene', '22431', (12, 15))	('peripheral oedema', 'Disease', 'MESH:D004487', (51, 68))	('oedema', 'Phenotype', 'HP:0000969', (62, 68))	('peripheral oedema', 'Phenotype', 'HP:0012398', (51, 68))	('Mice', 'Species', '10090', (0, 4))	('peripheral oedema', 'Disease', (51, 68))	('Wt1', 'Gene', (12, 15))	('heart wall thinning', 'CPA', (99, 118))
123590	30345394	In line with this, epicardial Wt1 knockouts have reduced epicardial expression of the key EMT activators Snail and Slug, and show reduced expression of the mesenchymal marker Vimentin.	('Vimentin', 'Gene', '22352', (175, 183))	('Snail', 'Gene', (105, 110))	('Vimentin', 'cellular_component', 'GO:0045098', ('175', '183'))	('epicardial expression', 'MPA', (57, 78))	('reduced', 'NegReg', (49, 56))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('Slug', 'Gene', '20583', (115, 119))	('Vimentin', 'cellular_component', 'GO:0045099', ('175', '183'))	('reduced', 'NegReg', (130, 137))	('knockouts', 'Var', (34, 43))	('expression', 'MPA', (138, 148))	('Vimentin', 'Gene', (175, 183))	('Wt1', 'Gene', '22431', (30, 33))	('Slug', 'Gene', (115, 119))	('Snail', 'Gene', '20613', (105, 110))	('Wt1', 'Gene', (30, 33))
123600	30345394	Differentiation of epicardial cells is also regulated by retinoid X receptor alpha (RXRalpha), as epicardial-selective knockouts have impaired EMT that disrupts coronary arteriogenesis and obviates myocardial compaction.	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('EMT', 'CPA', (143, 146))	('RXRalpha', 'Gene', (84, 92))	('impaired', 'NegReg', (134, 142))	('myocardial compaction', 'CPA', (198, 219))	('coronary arteriogenesis', 'CPA', (161, 184))	('obviates', 'NegReg', (189, 197))	('arteriogenesis', 'biological_process', 'GO:0048844', ('170', '184'))	('disrupts', 'NegReg', (152, 160))	('knockouts', 'Var', (119, 128))	('retinoid X receptor alpha', 'Gene', (57, 82))	('RXRalpha', 'Gene', '20181', (84, 92))	('retinoid X receptor alpha', 'Gene', '20181', (57, 82))
123602	30345394	and its co-factor Friend of GATA 2 (Fog2) deficiency results in embryonic death in mice due to vascular defects and myocardial thinning.	('vascular defects', 'Disease', 'MESH:D000783', (95, 111))	('Friend of GATA 2', 'Gene', (18, 34))	('embryonic death', 'Disease', 'MESH:D003643', (64, 79))	('deficiency', 'Var', (42, 52))	('embryonic death', 'Disease', (64, 79))	('Fog2', 'Gene', (36, 40))	('Friend of GATA 2', 'Gene', '22762', (18, 34))	('mice', 'Species', '10090', (83, 87))	('myocardial thinning', 'CPA', (116, 135))	('Fog2', 'Gene', '22762', (36, 40))	('vascular defects', 'Disease', (95, 111))
123604	30345394	Mouse mutants defective in the Notch effector RBPjkappa show premature EMT in the form of ectopic patches of alpha-smooth-muscle-actin (alpha-SMA) at the venous pole of the heart, but show no alterations in expression of WT1, TBX18, GATA4, and RALDH2 (ref.	('alpha-smooth-muscle-actin', 'Gene', '11475', (109, 134))	('GATA4', 'Gene', '14463', (233, 238))	('mutants', 'Var', (6, 13))	('EMT', 'biological_process', 'GO:0001837', ('71', '74'))	('ectopic patches', 'MPA', (90, 105))	('RALDH2', 'Gene', '19378', (244, 250))	('alpha-smooth-muscle-actin', 'Gene', (109, 134))	('TBX18', 'Gene', (226, 231))	('RALDH2', 'Gene', (244, 250))	('Notch', 'Gene', '4851;18128', (31, 36))	('Notch', 'Gene', (31, 36))	('TBX18', 'Gene', '76365', (226, 231))	('alpha-SMA', 'Gene', (136, 145))	('Mouse', 'Species', '10090', (0, 5))	('alpha-SMA', 'Gene', '11475', (136, 145))	('GATA4', 'Gene', (233, 238))
123605	30345394	Wt1-specific Notch1 knockouts display severe defects due to defective EMT, leading to embryonic lethality in some cases.	('EMT', 'CPA', (70, 73))	('embryonic lethality', 'Disease', 'MESH:D020964', (86, 105))	('EMT', 'biological_process', 'GO:0001837', ('70', '73'))	('Wt1', 'Gene', (0, 3))	('embryonic lethality', 'Disease', (86, 105))	('knockouts', 'Var', (20, 29))	('Wt1', 'Gene', '22431', (0, 3))	('Notch1', 'Gene', (13, 19))
123614	30345394	Consequently, many of the transgenic lines where EMT genes are knocked out show liver phenotypes in addition to heart phenotypes.	('show', 'Reg', (75, 79))	('knocked out', 'Var', (63, 74))	('liver phenotypes', 'MPA', (80, 96))	('EMT', 'biological_process', 'GO:0001837', ('49', '52'))	('transgenic', 'Species', '10090', (26, 36))	('heart', 'MPA', (112, 117))	('EMT genes', 'Gene', (49, 58))
123616	30345394	Similarly, coelomic epithelium from the septum transversum requires Wt1-driven WNT/beta-catenin, and loss of beta-catenin in the coelomic epithelium and stellate cells expressing TWIST2 causes abnormal activation of stellate cells in embryonic livers.	('Wt1', 'Gene', (68, 71))	('beta-catenin', 'Protein', (109, 121))	('loss', 'Var', (101, 105))	('TWIST2', 'Gene', '13345', (179, 185))	('septum', 'cellular_component', 'GO:0030428', ('40', '46'))	('TWIST2', 'Gene', (179, 185))	('activation', 'PosReg', (202, 212))	('Wt1', 'Gene', '22431', (68, 71))	('stellate cells', 'CPA', (216, 230))
123620	30345394	knockouts have an increased activation state of hepatic stellate cells, with abnormally high expression of alpha-SMA and deposition of ECM, reminiscent of myofibroblastic differentiation.	('deposition', 'MPA', (121, 131))	('increased', 'PosReg', (18, 27))	('high', 'PosReg', (88, 92))	('activation', 'MPA', (28, 38))	('alpha-SMA', 'Gene', '11475', (107, 116))	('expression', 'MPA', (93, 103))	('knockouts', 'Var', (0, 9))	('alpha-SMA', 'Gene', (107, 116))
123623	30345394	By E10.5, the adrenogonadal primordium splits into the adrenal and gonadal primordia that will continue to differentiate separately.	('E10.5', 'Var', (3, 8))	('gonadal primordia', 'Disease', (67, 84))	('gonadal primordia', 'Disease', 'MESH:D006058', (67, 84))
123632	30345394	Tbx18 null mice appear to have defective EMT in that they develop ectopic patches of fibroblasts along the developing gonads, and Tcf21 knockouts lack a distinct mesenchymal compartment.	('Tbx18', 'Gene', (0, 5))	('Tcf21', 'Gene', '21412', (130, 135))	('Tbx18', 'Gene', '76365', (0, 5))	('ectopic patches of fibroblasts along the', 'CPA', (66, 106))	('Tcf21', 'Gene', (130, 135))	('lack', 'NegReg', (146, 150))	('mice', 'Species', '10090', (11, 15))	('knockouts', 'Var', (136, 145))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))
123635	30345394	Similarly, Fog2 mutants have abnormal gonads through impaired thickening of the genital ridge.	('Fog2', 'Gene', '22762', (11, 15))	('Fog2', 'Gene', (11, 15))	('impaired', 'NegReg', (53, 61))	('mutants', 'Var', (16, 23))	('thickening of the genital ridge', 'CPA', (62, 93))
123638	30345394	Consequently, disruption of SF1 expression results in delayed and decreased EMT, disrupted cell ingression during the formation of the genital ridges, and consequently fewer SF1+ gonadal precursor cells and gonad size.	('gonad size', 'CPA', (207, 217))	('cell ingression', 'CPA', (91, 106))	('SF1', 'Gene', (28, 31))	('EMT', 'CPA', (76, 79))	('decreased', 'NegReg', (66, 75))	('disrupted', 'NegReg', (81, 90))	('SF1', 'Gene', '22668', (28, 31))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('decreased EMT', 'Phenotype', 'HP:0032198', (66, 79))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('disruption', 'Var', (14, 24))	('SF1', 'Gene', (174, 177))	('fewer', 'NegReg', (168, 173))	('SF1', 'Gene', '22668', (174, 177))
123642	30345394	In XY mice, knocking out Wt1 after sex determination results in disruption of developing seminiferous tubules through the aberrant differentiation and development of Sertoli cells.	('knocking out', 'Var', (12, 24))	('development of Sertoli cells', 'CPA', (151, 179))	('sex determination', 'biological_process', 'GO:0007530', ('35', '52'))	('mice', 'Species', '10090', (6, 10))	('Wt1', 'Gene', (25, 28))	('disruption', 'NegReg', (64, 74))	('aberrant differentiation', 'CPA', (122, 146))	('Sertoli cells', 'Phenotype', 'HP:0100619', (166, 179))	('Wt1', 'Gene', '22431', (25, 28))
123643	30345394	Sertoli-specific Wt1 mutants also show abnormal PMC and Leydig development.	('mutants', 'Var', (21, 28))	('Wt1', 'Gene', '22431', (17, 20))	('Wt1', 'Gene', (17, 20))
123645	30345394	In the absence of WT1, high SF1 expression leads undifferentiated somatic cells to develop into steroidogenic cells of the gonads (Leydig and Theca cells in the testis and ovaries, respectively), leading to structural impairments.	('leads', 'Reg', (43, 48))	('high', 'Var', (23, 27))	('SF1', 'Gene', (28, 31))	('ovaries', 'Disease', (172, 179))	('SF1', 'Gene', '22668', (28, 31))	('structural impairments', 'CPA', (207, 229))	('ovaries', 'Disease', 'MESH:D010051', (172, 179))
123653	30345394	Lineage-tracing studies have confirmed that by E11.5, WT1+, MSLN+ and Notch1+ coelomic epithelium cells covering the lungs migrate inward to give rise to alpha-SMA+ fibroblast and smooth muscle cells that make up both arteries and veins in the vascular wall, or those positioned circumferentially around the airways.	('smooth muscle cells', 'CPA', (180, 199))	('MSLN+', 'Var', (60, 65))	('Notch1+', 'Var', (70, 77))	('E11.5', 'Var', (47, 52))	('alpha-SMA', 'Gene', (154, 163))	('give rise to', 'Reg', (141, 153))	('alpha-SMA', 'Gene', '11475', (154, 163))
123655	30345394	Defects in Gata4 or its co-factor Fog2 cause lung lobulation abnormalities, which can be attributed to growth delay and abnormal branching morphogenesis.	('cause', 'Reg', (39, 44))	('Fog2', 'Gene', '22762', (34, 38))	('Fog2', 'Gene', (34, 38))	('lung lobulation abnormalities', 'Disease', (45, 74))	('Gata4', 'Gene', '14463', (11, 16))	('lung lobulation abnormalities', 'Disease', 'MESH:D000069337', (45, 74))	('Gata4', 'Gene', (11, 16))	('Defects', 'Var', (0, 7))	('growth delay', 'Phenotype', 'HP:0001510', (103, 115))	('branching morphogenesis', 'biological_process', 'GO:0001763', ('129', '152'))
123656	30345394	Internally, Gata4 mutants show dilated distal airways and patches of thickened mesenchyme, characterized as ectopic expression of alpha-SMA in the mesothelial and submesothelial layer.	('patches', 'CPA', (58, 65))	('mutants', 'Var', (18, 25))	('Gata4', 'Gene', '14463', (12, 17))	('distal airways', 'CPA', (39, 53))	('alpha-SMA', 'Gene', (130, 139))	('Gata4', 'Gene', (12, 17))	('thickened', 'PosReg', (69, 78))	('alpha-SMA', 'Gene', '11475', (130, 139))
123658	30345394	These results suggest defects in GATA4 expression perturb coelomic epithelium-driven EMT during lung morphogenesis, presumably through impaired signalling from the mesothelium to the underlying endoderm.	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('impaired', 'NegReg', (135, 143))	('GATA4', 'Gene', (33, 38))	('defects', 'Var', (22, 29))	('GATA4', 'Gene', '14463', (33, 38))	('lung morphogenesis', 'biological_process', 'GO:0060425', ('96', '114'))	('signalling', 'biological_process', 'GO:0023052', ('144', '154'))	('lung morphogenesis', 'CPA', (96, 114))	('coelomic epithelium-driven EMT', 'CPA', (58, 88))	('perturb', 'NegReg', (50, 57))	('signalling', 'MPA', (144, 154))
123659	30345394	Similarly, coelomic epithelium-selective (Dermo1+) beta-catenin mutants show impaired lung growth as early as E12.5, primarily through reduced mesenchymal expansion, and defective Notch signalling in Dermo1+ RBPjkappa mutants results in impaired vascular, but not bronchial smooth muscle differentiation.	('lung growth', 'biological_process', 'GO:0060437', ('86', '97'))	('Dermo1', 'Gene', '13345', (42, 48))	('mesenchymal expansion', 'CPA', (143, 164))	('Dermo1', 'Gene', (42, 48))	('Dermo1', 'Gene', '13345', (200, 206))	('Notch', 'Gene', (180, 185))	('Notch', 'Gene', '4851;18128', (180, 185))	('impaired lung growth', 'Disease', 'MESH:D006130', (77, 97))	('reduced', 'NegReg', (135, 142))	('defective', 'Var', (170, 179))	('signalling', 'biological_process', 'GO:0023052', ('186', '196'))	('mutants', 'Var', (64, 71))	('impaired lung growth', 'Disease', (77, 97))	('mutants', 'Var', (218, 225))	('Dermo1', 'Gene', (200, 206))	('impaired vascular', 'Disease', 'MESH:D002561', (237, 254))	('impaired vascular', 'Disease', (237, 254))	('bronchial smooth muscle differentiation', 'CPA', (264, 303))
123661	30345394	Raldh2 mutant mice or lung explants treated with the pan-RXR inverse agonist BMS493 have perturbed lung bud formation.	('RXR', 'molecular_function', 'GO:0004879', ('57', '60'))	('mutant', 'Var', (7, 13))	('lung bud formation', 'CPA', (99, 117))	('mice', 'Species', '10090', (14, 18))	('Raldh2', 'Gene', '19378', (0, 6))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('Raldh2', 'Gene', (0, 6))	('perturbed', 'NegReg', (89, 98))
123662	30345394	Wt1 and Raldh2 mutants initially form a pleuropericardial fold, but do not fuse with the coelomic epithelial lining of the lung hilus, and Tbx18 knockout mice fail to develop the pleuropericardial membranes at all.	('mice', 'Species', '10090', (154, 158))	('Wt1', 'Gene', (0, 3))	('Raldh2', 'Gene', '19378', (8, 14))	('mutants', 'Var', (15, 22))	('Tbx18', 'Gene', (139, 144))	('form', 'Reg', (33, 37))	('Raldh2', 'Gene', (8, 14))	('Wt1', 'Gene', '22431', (0, 3))	('Tbx18', 'Gene', '76365', (139, 144))
123666	30345394	Wt1-dependent EZH2 knockouts display uncontrolled EMT in the coelomic epithelium, and develop multiple heart and lung abnormalities by generating ectopic patches of smooth muscle around E14.5 (ref.	('lung abnormalities', 'Disease', (113, 131))	('knockouts', 'Var', (19, 28))	('multiple heart', 'Phenotype', 'HP:0001640', (94, 108))	('develop', 'PosReg', (86, 93))	('EZH2', 'Gene', '14056', (14, 18))	('EZH2', 'Gene', (14, 18))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('Wt1', 'Gene', (0, 3))	('lung abnormalities', 'Phenotype', 'HP:0002088', (113, 131))	('heart', 'Disease', (103, 108))	('ectopic', 'MPA', (146, 153))	('lung abnormalities', 'Disease', 'MESH:D008171', (113, 131))	('Wt1', 'Gene', '22431', (0, 3))
123673	30345394	Epicardium-specific inhibition of these coelomic epithelial genes significantly diminishes cardiac fibrosis.	('inhibition', 'Var', (20, 30))	('diminishes', 'NegReg', (80, 90))	('fibrosis', 'Disease', 'MESH:D005355', (99, 107))	('fibrosis', 'Disease', (99, 107))
123676	30345394	In adult zebrafish, a species with robust regenerative potential after injury, genetic depletion of the epicardium after experimentally resecting parts of the heart ventricle inhibits cardiomyocyte proliferation and delays muscle regeneration.	('cardiomyocyte proliferation', 'CPA', (184, 211))	('cardiomyocyte proliferation', 'biological_process', 'GO:0060038', ('184', '211'))	('genetic depletion', 'Var', (79, 96))	('delays', 'NegReg', (216, 222))	('muscle regeneration', 'CPA', (223, 242))	('zebrafish', 'Species', '7955', (9, 18))	('regeneration', 'biological_process', 'GO:0031099', ('230', '242'))	('inhibits', 'NegReg', (175, 183))
123677	30345394	Similarly, disruption of thymosin beta4-mediated paracrine signalling towards the epicardium impairs smooth muscle cell development in mice, and its expression facilitates vascular repair following myocardial infarction.	('smooth muscle cell development', 'CPA', (101, 131))	('thymosin beta4', 'Gene', (25, 39))	('myocardial infarction', 'Phenotype', 'HP:0001658', (198, 219))	('myocardial infarction', 'Disease', 'MESH:D009203', (198, 219))	('muscle cell development', 'biological_process', 'GO:0055001', ('108', '131'))	('vascular repair', 'CPA', (172, 187))	('thymosin beta4', 'Gene', '19241', (25, 39))	('paracrine signalling', 'biological_process', 'GO:0038001', ('49', '69'))	('mice', 'Species', '10090', (135, 139))	('disruption', 'Var', (11, 21))	('impairs', 'NegReg', (93, 100))	('myocardial infarction', 'Disease', (198, 219))	('facilitates', 'PosReg', (160, 171))	('expression', 'Var', (149, 159))
123678	30345394	It is worth mentioning that not every cardiac injury model shows evidence for epicardial EMT, for example, in the pressure overload model through constriction of the ascending aortus.	('cardiac injury', 'Disease', 'MESH:D006331', (38, 52))	('constriction', 'Var', (146, 158))	('ascending aortus', 'Phenotype', 'HP:0004970', (166, 182))	('constriction', 'cellular_component', 'GO:0005702', ('146', '158'))	('cardiac injury', 'Disease', (38, 52))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))	('pressure', 'MPA', (114, 122))
123685	30345394	The mechanism by which MSLN promotes fibrosis presumably acts through its antagonistic actions on a TGFbetaR1 inhibitory complex called thymocyte antigen 1 (ref.	('MSLN', 'Var', (23, 27))	('promotes', 'PosReg', (28, 36))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('100', '108'))	('fibrosis', 'Disease', 'MESH:D005355', (37, 45))	('fibrosis', 'Disease', (37, 45))
123708	30345394	Consequently, mice treated with the TGF-betaRII targeting miRNA miR-18a-5p have reduced (sub-)PF after bleomycin administration.	('miRNA miR-18a-5p', 'Var', (58, 74))	('bleomycin', 'Chemical', 'MESH:D001761', (103, 112))	('TGF-beta', 'Gene', '21803', (36, 44))	('mice', 'Species', '10090', (14, 18))	('reduced', 'NegReg', (80, 87))	('TGF-beta', 'Gene', (36, 44))
123712	30345394	Mice subjected to Streptococcus pneumoniae develop empyema accompanied by alpha-SMA+ expression in the pleura, pleural thickening and reduced lung function, which can inhibited by GSK-3beta antagonist 9ING41 (ref.	('lung function', 'CPA', (142, 155))	('pleural thickening', 'Phenotype', 'HP:0031944', (111, 129))	('Streptococcus pneumoniae', 'Var', (18, 42))	('alpha-SMA', 'Gene', (74, 83))	('alpha-SMA', 'Gene', '11475', (74, 83))	('pleural', 'Disease', 'MESH:D010995', (111, 118))	('GSK', 'molecular_function', 'GO:0050321', ('180', '183'))	('pleural', 'Disease', (111, 118))	('reduced', 'NegReg', (134, 141))	('Mice', 'Species', '10090', (0, 4))	('empyema', 'Disease', 'MESH:D004653', (51, 58))	('empyema', 'Disease', (51, 58))
123720	30345394	Adenoviral transmission of intrapleural TGF-beta1 induces progressive PF of the viscera and underlying parenchyma, with strong cytokeratin and alpha-SMA in both tissue compartments.	('alpha-SMA', 'Gene', '11475', (143, 152))	('Adenoviral transmission', 'Var', (0, 23))	('pleural', 'Disease', 'MESH:D010995', (32, 39))	('TGF-beta1', 'Gene', '21803', (40, 49))	('alpha-SMA', 'Gene', (143, 152))	('pleural', 'Disease', (32, 39))	('TGF-beta1', 'Gene', (40, 49))	('induces', 'Reg', (50, 57))
123722	30345394	Damage to mesothelium covering the three cavity walls or the internal organs induces the development of fibrosis on their surfaces that can attach to neighbouring healthy tissues, termed adhesions (Fig.	('Damage', 'Var', (0, 6))	('fibrosis', 'Disease', 'MESH:D005355', (104, 112))	('fibrosis', 'Disease', (104, 112))	('induces', 'Reg', (77, 84))
123764	30345394	Exosomes may contain growth factors used to directly modify the mesothelium, or matrixmetalloproteases (MMPs) to disrupt the basement membrane, and is not restricted to gastric cancer: CD63+, CD44+, MSLN+, or MMP1+ exosomes have been found in ovarian cancer as well.	('CD63', 'Gene', (185, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (243, 257))	('CD44', 'Gene', (192, 196))	('MMP1', 'Gene', (209, 213))	('CD63', 'Gene', '12512', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('MMPs', 'Gene', '17386;17393;17395;17386', (104, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('CD44', 'Gene', '12505', (192, 196))	('disrupt', 'NegReg', (113, 120))	('ovarian cancer', 'Disease', (243, 257))	('basement membrane', 'cellular_component', 'GO:0005604', ('125', '142'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (243, 257))	('MMP1', 'molecular_function', 'GO:0004232', ('209', '213'))	('gastric cancer', 'Disease', (169, 183))	('MMP1', 'Gene', '17386', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('MSLN+', 'Var', (199, 204))	('MMPs', 'Gene', (104, 108))
123767	30345394	Consequently, knockdown of these pathways effectively inhibits cancer invasion.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('knockdown', 'Var', (14, 23))	('inhibits', 'NegReg', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
123793	30345394	It would be important to determine whether patients receiving therapies targeting MSLN and WT1 have equally reduced risks of developing additional diseases such as ischaemia, chronic fibrosis, and adhesions.	('adhesions', 'Disease', (197, 206))	('reduced', 'NegReg', (108, 115))	('patients', 'Species', '9606', (43, 51))	('MSLN', 'Var', (82, 86))	('ischaemia', 'Disease', (164, 173))	('ischaemia', 'Disease', 'MESH:D007511', (164, 173))	('fibrosis', 'Disease', 'MESH:D005355', (183, 191))	('fibrosis', 'Disease', (183, 191))
123797	30098293	Phase I clinical trials in thoracic surgery have demonstrated that IFI with second window indocyanine green (TumorGlow ) can identify sub-centimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while use of a folate receptor-targeted near-infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression.	('indocyanine green', 'Chemical', 'MESH:D007208', (90, 107))	('tumors', 'Disease', (326, 332))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('folate', 'Chemical', 'MESH:D005492', (230, 236))	('anterior mediastinal masses', 'Disease', (168, 195))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('mesothelioma', 'Disease', (201, 213))	('folate', 'Chemical', 'MESH:D005492', (338, 344))	('sub-centimeter', 'Var', (134, 148))	('Tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (201, 213))
123835	30098293	We directly compared OTL38 and EC17 in several controlled experiments in vitro using cadaveric human lungs and in vivo using murine flank tumors and confirmed that OTL38 had decreased auto-fluorescence and increased depth of penetration compared to EC17.	('decreased', 'NegReg', (174, 183))	('human', 'Species', '9606', (95, 100))	('flank tumors', 'Disease', (132, 144))	('increased', 'PosReg', (206, 215))	('flank tumors', 'Disease', 'MESH:D021501', (132, 144))	('auto-fluorescence', 'MPA', (184, 201))	('OTL38', 'Var', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('murine', 'Species', '10090', (125, 131))	('depth of penetration', 'CPA', (216, 236))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
123876	30098293	In a follow-up study of IFI with OTL38 for pulmonary squamous cell carcinomas, approximately 70% (9/13) of nodules accumulated OTL38.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (53, 77))	('accumulated', 'PosReg', (115, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('pulmonary squamous cell carcinomas', 'Disease', (43, 77))	('OTL38', 'Var', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('pulmonary squamous cell carcinomas', 'Disease', 'MESH:D002294', (43, 77))
124128	21660062	In MSTO-211H, H2052, and H2452 human malignant mesothelioma cells, the percentage of GFP-expressing cells quickly increased in a logarithmic manner and reached > 80 % within 15 days and > 90 % within 18 days after virus inoculation, and then remained stable thereafter.	('H2052', 'Var', (14, 19))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (37, 59))	('increased', 'PosReg', (114, 123))	('human', 'Species', '9606', (31, 36))	('malignant mesothelioma', 'Disease', (37, 59))	('H2452', 'Var', (25, 30))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (37, 59))	('MSTO-211H', 'Chemical', '-', (3, 12))
124134	21660062	The fluorescence intensities were normalized to the tumor volumes and found to be highly increased in RCR-GFP-injected tumors compared to LV-GFP-injected tumors (Figure 2b), indicating efficient RCR spread in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('RCR spread', 'CPA', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (215, 221))	('tumor', 'Disease', (154, 159))	('tumors', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('RCR-GFP-injected', 'Var', (102, 118))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (215, 220))	('increased', 'PosReg', (89, 98))	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('fluorescence intensities', 'MPA', (4, 28))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
124135	21660062	On Day 19, tumors were harvested, immediately digested with collagenase into cell suspensions, and the percentage of GFP-positive cells was 5.5 +- 2.9 % with LV-GFP vs. 95.8 +- 6.5 % with RCR-GFP by flow cytometry.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('LV-GFP', 'Var', (158, 164))
124139	21660062	In malignant mesothelioma cell lines (MSTO-211H, H2052, and H2452), decreased cell viability was observed in a 5FC-dose-dependent manner (Figure 3b).	('decreased', 'NegReg', (68, 77))	('H2052', 'Var', (49, 54))	('H2452', 'Var', (60, 65))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (3, 25))	('5FC', 'Chemical', 'MESH:D005437', (111, 114))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (3, 25))	('MSTO-211H', 'Chemical', '-', (38, 47))	('malignant mesothelioma', 'Disease', (3, 25))	('cell viability', 'CPA', (78, 92))
124143	21660062	As shown in Figure 4, subcutaneous tumors treated with RCR-GFP showed no obvious inhibition of tumor growth after 5FC administration, as compared with the PBS control group.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (22, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('5FC', 'Chemical', 'MESH:D005437', (114, 117))	('inhibition', 'NegReg', (81, 91))	('PBS', 'Chemical', 'MESH:D007854', (155, 158))	('tumor', 'Disease', (35, 40))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (22, 40))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RCR-GFP', 'Var', (55, 62))	('tumor', 'Disease', (95, 100))
124144	21660062	In contrast, the growth of RCR-CD transduced tumors was significantly inhibited by 5FC treatment (P<0.01 after Day 21).	('growth', 'CPA', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('RCR-CD', 'Chemical', '-', (27, 33))	('tumors', 'Disease', (45, 51))	('5FC', 'Chemical', 'MESH:D005437', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('5FC treatment', 'Var', (83, 96))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('inhibited', 'NegReg', (70, 79))
124164	21660062	RCR has the capability to permanently integrate into the genome of the host tumor cell and will continue to produce progeny virus transcribed from the integrated copy whether the infected tumor cell itself continues to divide or not.	('integrated', 'Var', (151, 161))	('host tumor', 'Disease', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('infected tumor', 'Disease', 'MESH:D009369', (179, 193))	('infected tumor', 'Disease', (179, 193))	('host tumor', 'Disease', 'MESH:D006086', (71, 81))
124196	21157517	These findings clearly indicate that crystalline silica causes dysregulation and/or disturbance of the human immune system, particularly autoimmunity.	('human immune system', 'CPA', (103, 122))	('silica', 'Chemical', 'MESH:D012822', (49, 55))	('human', 'Species', '9606', (103, 108))	('autoimmunity', 'Phenotype', 'HP:0002960', (137, 149))	('crystalline', 'Var', (37, 48))	('dysregulation', 'MPA', (63, 76))	('autoimmunity', 'Disease', (137, 149))	('causes', 'Reg', (56, 62))	('disturbance', 'MPA', (84, 95))	('autoimmunity', 'Disease', 'MESH:D001327', (137, 149))
124248	21351265	Using the more sensitive detection method of quantitative RT-PCR on an independent series of tumors, we validated the specificity of these alterations in 100 malignant pleural mesotheliomas and 32 lung adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alterations', 'Var', (139, 150))	('lung adenocarcinomas', 'Disease', (197, 217))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (197, 217))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (168, 189))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('malignant pleural mesotheliomas', 'Disease', (158, 189))	('rat', 'Species', '10116', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (197, 217))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (168, 188))	('tumors', 'Disease', (93, 99))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (158, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (197, 216))
124258	21351265	It is clear that miRNAs play an essential regulatory role in healthy cells and miRNA gene clustering and families ensure functional redundancy and safeguards against single mutations resulting in a dysregulation of key pathways.	('dysregulation', 'MPA', (198, 211))	('miR', 'Gene', '220972', (17, 20))	('key pathways', 'Pathway', (215, 227))	('miR', 'Gene', (17, 20))	('mutations', 'Var', (173, 182))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))
124274	21351265	TaqMan miRNA Assays (Applied Biosystems) were used to quantify mature miRNA expression for the chosen candidate miRNAs: hsa-miR-200a* (part # 4373273) hsa-miR-200c (part # 4395411), hsa-miR-200b (part # 4395362), hsa-miR-203 (part # 4373095), hsa-miR-141 (part # 4373137), hsa-miR-429-(part # 4373203) and hsa-miR-205 (part # 4373093) and the reference non-coding RNAs RNU44 (part # 4373384), RNU48 (part # 4373383).	('miR-205', 'Gene', '406988', (310, 317))	('miR', 'Gene', (277, 280))	('miR-200a', 'Gene', (124, 132))	('miR-203', 'Gene', (217, 224))	('miR', 'Gene', (155, 158))	('miR', 'Gene', (70, 73))	('miR-200c', 'Gene', (155, 163))	('part # 4395411', 'Var', (165, 179))	('miR', 'Gene', (124, 127))	('hsa-miR-429', 'Gene', (273, 284))	('miR-200b', 'Gene', '406984', (186, 194))	('miR-141', 'Gene', '406933', (247, 254))	('miR', 'Gene', '220972', (186, 189))	('hsa-miR-429', 'Gene', '554210', (273, 284))	('miR', 'Gene', '220972', (247, 250))	('part # 4373137', 'Var', (256, 270))	('miR', 'Gene', '220972', (217, 220))	('miR-141', 'Gene', (247, 254))	('miR-203', 'Gene', '406986', (217, 224))	('part # 4373093', 'Var', (319, 333))	('miR', 'Gene', (186, 189))	('RNU48', 'Gene', (393, 398))	('miR-205', 'Gene', (310, 317))	('RNU48', 'Gene', '26801', (393, 398))	('miR', 'Gene', '220972', (112, 115))	('part # 4373273', 'Var', (135, 149))	('miR', 'Gene', '220972', (7, 10))	('miR', 'Gene', (247, 250))	('miR-200a', 'Gene', '406983', (124, 132))	('miR', 'Gene', (217, 220))	('RNU44', 'Gene', (369, 374))	('miR-200c', 'Gene', '406985', (155, 163))	('miR-200b', 'Gene', (186, 194))	('miR', 'Gene', '220972', (310, 313))	('miR', 'Gene', (112, 115))	('miR', 'Gene', '220972', (277, 280))	('miR', 'Gene', (7, 10))	('RNU44', 'Gene', '26806', (369, 374))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', '220972', (124, 127))	('part # 4373384', 'Var', (376, 390))	('miR', 'Gene', (310, 313))
124318	21351265	MiRNA are being used clinically to aid in the diagnosis of this disease, although there is little experimental literature detailing the identification of differentially altered miRNA, or the biological pathways predicted to be affected by miRNA expression alterations.	('miR', 'Gene', (239, 242))	('rat', 'Species', '10116', (115, 118))	('miR', 'Gene', '220972', (239, 242))	('rat', 'Species', '10116', (260, 263))	('alterations', 'Var', (256, 267))	('miR', 'Gene', '220972', (177, 180))	('miR', 'Gene', (177, 180))
124342	21351265	This clustering, combined with evidence that distinct methylation alterations predict MPM, indicates epigenetic silencing as a possible mechanism of repression.	('epigenetic silencing', 'Var', (101, 121))	('rat', 'Species', '10116', (70, 73))	('MPM', 'Gene', (86, 89))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))
124343	21351265	Indeed, the expression of miR-203 from a fragile region of chromosome 14 has been shown to be modulated by loss of heterozygocity and through hypermethylation in some acute lymphoblastic leukemias.	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (167, 196))	('acute lymphoblastic leukemias', 'Disease', (167, 196))	('modulated', 'Reg', (94, 103))	('loss', 'NegReg', (107, 111))	('miR-203', 'Gene', (26, 33))	('hypermethylation', 'Var', (142, 158))	('leukemias', 'Phenotype', 'HP:0001909', (187, 196))	('miR-203', 'Gene', '406986', (26, 33))	('acute lymphoblastic leukemias', 'Disease', 'MESH:D054198', (167, 196))	('expression', 'MPA', (12, 22))	('heterozygocity', 'MPA', (115, 129))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (173, 196))
124360	21351265	In conjunction with a disruption in the beta-catenin degradation pathway, the loss of this adhesion molecule may elevate wnt signaling by allowing translocation of beta-catenin to the nucleus.	('allowing', 'Reg', (138, 146))	('beta-catenin', 'Gene', (164, 176))	('wnt', 'Gene', '35975', (121, 124))	('wnt', 'Gene', (121, 124))	('beta-catenin', 'Gene', '1499', (164, 176))	('nucleus', 'cellular_component', 'GO:0005634', ('184', '191'))	('beta-catenin', 'Gene', (40, 52))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('loss', 'Var', (78, 82))	('beta-catenin', 'Gene', '1499', (40, 52))	('degradation', 'biological_process', 'GO:0009056', ('53', '64'))	('elevate', 'PosReg', (113, 120))
124361	21351265	Interestingly, dysregulation of non-miRNA regulators of the wnt signaling pathway has been reported in the metastases lung adenocarcinoma.	('metastases lung adenocarcinoma', 'Disease', (107, 137))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('wnt', 'Gene', '35975', (60, 63))	('metastases lung adenocarcinoma', 'Disease', 'MESH:D009362', (107, 137))	('wnt', 'Gene', (60, 63))	('reported', 'Reg', (91, 99))	('wnt signaling pathway', 'biological_process', 'GO:0016055', ('60', '81'))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))	('dysregulation', 'Var', (15, 28))
124362	21351265	In this case, disruption of the WNT/TCF signaling occurs through the transcription factors LEF1 and HOXB9 and promotes invasion and colonization of multiple organ types, and is not associated with primary lung adenocarcinoma.	('LEF1', 'Gene', '51176', (91, 95))	('HOXB9', 'Gene', '3219', (100, 105))	('HOXB9', 'Gene', (100, 105))	('invasion', 'CPA', (119, 127))	('primary lung adenocarcinoma', 'Disease', (197, 224))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('LEF1', 'Gene', (91, 95))	('colonization of multiple organ types', 'CPA', (132, 168))	('WNT', 'Gene', '35975', (32, 35))	('WNT', 'Gene', (32, 35))	('promotes', 'PosReg', (110, 118))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (197, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('disruption', 'Var', (14, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (205, 224))
124404	32253443	To avoid sparse data problems, we fitted conditional regression models using age categories (<55, 55-59, 60-64, 65-69, 70-74, 75-79, and >=80 years) as the adjustment set.	('age', 'Gene', (77, 80))	('age', 'Gene', '5973', (77, 80))	('men', 'Species', '9606', (162, 165))	('<55', 'Var', (93, 96))
124500	32100581	The antitumor mechanism of RVS is likely to be anti-angiogenesis: it inhibits the proliferation and migratory activity of cells normally recruited via vascular endothelial growth factor.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('angiogenesis', 'biological_process', 'GO:0001525', ('52', '64'))	('inhibits', 'NegReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('151', '185'))	('RVS', 'Var', (27, 30))
124522	30060843	BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (153, 169))	('uveal and mucosal melanoma', 'Phenotype', 'HP:0007716', (143, 169))	('BAP1', 'Gene', (0, 4))	('loss', 'NegReg', (46, 50))	('humans', 'Species', '9606', (89, 95))	('mutations', 'Var', (22, 31))	('mucosal melanoma', 'Disease', (153, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('nBAP1', 'Gene', (68, 73))	('expression', 'MPA', (75, 85))	('loss of function', 'NegReg', (5, 21))
124538	30060843	BAP1 has been shown to undergo both somatic and germline mutation, the latter underpinning a familial cancer predisposition syndrome.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', (0, 4))	('familial cancer', 'Disease', (93, 108))	('germline mutation', 'Var', (48, 65))	('underpinning', 'Reg', (78, 90))	('familial cancer', 'Disease', 'MESH:D009369', (93, 108))
124540	30060843	In humans, loss of nuclear BAP1 (nBAP1) is common in oral mucosal and uveal melanoma, but uncommon in cutaneous melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('nBAP1', 'Gene', (33, 38))	('loss', 'Var', (11, 15))	('oral mucosal', 'Disease', (53, 65))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('humans', 'Species', '9606', (3, 9))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
124541	30060843	In uveal melanoma, mutation of the BAP1 gene is associated with loss of nBAP1 expression, which has been proposed as a surrogate clinical marker.	('nBAP1', 'Gene', (72, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('expression', 'MPA', (78, 88))	('mutation', 'Var', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('loss', 'NegReg', (64, 68))	('BAP1', 'Gene', (35, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
124549	30060843	Specifically, we hypothesized that loss of nBAP1 in canine oral and uveal melanoma would be associated with a poorer prognosis.	('loss', 'Var', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('nBAP1', 'Gene', (43, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))	('associated', 'Reg', (92, 102))	('canine', 'Species', '9615', (52, 58))
124554	30060843	UCDK9M3 and UCDK9M4 are from primary oral mucosal melanomas, UCDK9M2 and UCDK9M5 are from lymph node metastases of oral mucosal melanoma and UCDK9M1 was derived from a skin metastasis of an oral mucosal melanoma.	('UCDK9M5', 'Var', (73, 80))	('M4', 'CellLine', 'CVCL:U812', (17, 19))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('metastases of oral mucosal melanoma', 'Disease', 'MESH:D009362', (101, 136))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (37, 58))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (37, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('oral mucosal melanoma', 'Disease', (190, 211))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (190, 211))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('UCDK9M2', 'Var', (61, 68))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (115, 136))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('oral mucosal melanomas', 'Disease', (37, 59))	('metastases of oral mucosal melanoma', 'Disease', (101, 136))
124613	30060843	Lack of nBAP1 protein expression is associated with loss of function mutations of BAP1 and is common in several human cancers such as uveal and oral mucosal melanoma and malignant mesothelioma.	('mutations', 'Var', (69, 78))	('BAP1', 'Gene', (82, 86))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (170, 192))	('nBAP1', 'Gene', (8, 13))	('protein', 'Protein', (14, 21))	('malignant mesothelioma', 'Disease', (170, 192))	('Lack', 'NegReg', (0, 4))	('uveal and oral mucosal melanoma', 'Disease', 'MESH:C536494', (134, 165))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('loss of function', 'NegReg', (52, 68))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (170, 192))	('human', 'Species', '9606', (112, 117))	('expression', 'MPA', (22, 32))
124617	30060843	This study was performed in the same laboratory using the same technique as a previous study that reported that loss of nBAP1 is associated with a poorer outcome in human uveal melanoma.	('human', 'Species', '9606', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('nBAP1', 'Gene', (120, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))	('uveal melanoma', 'Disease', (171, 185))	('loss', 'Var', (112, 116))
124618	30060843	Moreover, the work presented here was performed contemporaneously with, and with the same methodology as, a follow-up study (to) in this laboratory, which confirmed the prognostic significance of loss of nBAP-1 in human uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('nBAP-1', 'Gene', (204, 210))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('human', 'Species', '9606', (214, 219))	('loss', 'Var', (196, 200))
124620	30060843	Furthermore, the absence of nBAP1 protein expression is indicative of the presence of a BAP1 mutation in human cancers such as malignant mesothelioma and uveal melanoma, as well as Spitz melanoma.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('protein', 'Protein', (34, 41))	('melanoma', 'Disease', (160, 168))	('expression', 'MPA', (42, 52))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (127, 149))	('human', 'Species', '9606', (105, 110))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('BAP1', 'Gene', (88, 92))	('nBAP1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('malignant mesothelioma', 'Disease', (127, 149))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('cancers', 'Disease', (111, 118))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (127, 149))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('absence', 'NegReg', (17, 24))	('mutation', 'Var', (93, 101))	('presence', 'Reg', (74, 82))
124624	30060843	demonstrated that missense mutations within the catalytic domain of BAP1 reduced tumour suppressor activity, but not protein expression, in a human NSCLC cell line.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('NSCLC', 'Disease', (148, 153))	('reduced', 'NegReg', (73, 80))	('missense mutations', 'Var', (18, 36))	('human', 'Species', '9606', (142, 147))	('tumour', 'Disease', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('BAP1', 'Gene', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
124625	30060843	Of note, although BAP1 knockout mice develop a myelodysplastic disorder with features of chronic myelomonocytic leukaemia (CMML), in human CMML, mutation of BAP1 is rare but that of the BAP1 interacting protein ASXL1 is very common.	('chronic myelomonocytic leukaemia', 'Disease', (89, 121))	('myelodysplastic disorder', 'Phenotype', 'HP:0002863', (47, 71))	('chronic myelomonocytic leukaemia', 'Disease', 'MESH:D015477', (89, 121))	('myelodysplastic disorder', 'Disease', 'MESH:D009190', (47, 71))	('chronic myelomonocytic leukaemia', 'Phenotype', 'HP:0012325', (89, 121))	('ASXL1', 'Gene', '171023', (211, 216))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('human', 'Species', '9606', (133, 138))	('mutation', 'Var', (145, 153))	('BAP1', 'Gene', (157, 161))	('CMML', 'Disease', 'MESH:D054429', (123, 127))	('ASXL1', 'Gene', (211, 216))	('mice', 'Species', '10090', (32, 36))	('CMML', 'Disease', (123, 127))	('CMML', 'Phenotype', 'HP:0012325', (123, 127))	('CMML', 'Disease', 'MESH:D054429', (139, 143))	('CMML', 'Disease', (139, 143))	('CMML', 'Phenotype', 'HP:0012325', (139, 143))	('myelodysplastic disorder', 'Disease', (47, 71))
124648	29152082	To target mesothelin expressing cancers, we have developed a new RIT (LMB-100, previously named RG7787) in which a humanized Fab is attached to a 24 kDa fragment of Pseudomonas exotoxin A containing mutations in B and T cell epitopes designed to lower immunogenicity and decrease non-specific side effects.	('mesothelin', 'Gene', (10, 20))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('immunogenicity', 'MPA', (252, 266))	('Fab', 'Gene', (125, 128))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('mesothelin', 'Gene', '10232', (10, 20))	('decrease', 'NegReg', (271, 279))	('human', 'Species', '9606', (115, 120))	('non-specific side effects', 'MPA', (280, 305))	('LMB', 'Chemical', 'MESH:C038753', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (199, 208))	('RIT', 'Chemical', '-', (65, 68))	('Fab', 'Gene', '2187', (125, 128))	('lower', 'NegReg', (246, 251))
124675	29152082	The killing of cells by LMB-100 is complex and involves binding of LMB-100 to mesothelin on the cell membrane, internalization by endocytosis, release of the toxin from the Fab by furin, trafficking to the endoplasmic reticulum, transfer to the cytosol where elongation factor-2 (EF2) is located, ADP-ribosylation and inactivation of EF2, arrest of protein synthesis, degradation of rapidly turning over proteins like MCL-1, activation of BAK and initiation of the apoptotic cascade.	('Fab', 'Gene', (173, 176))	('furin', 'Gene', (180, 185))	('degradation', 'biological_process', 'GO:0009056', ('368', '379'))	('arrest', 'MPA', (339, 345))	('mesothelin', 'Gene', (78, 88))	('EF2', 'Gene', (280, 283))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('protein synthesis', 'MPA', (349, 366))	('cytosol', 'cellular_component', 'GO:0005829', ('245', '252'))	('cell membrane', 'cellular_component', 'GO:0005886', ('96', '109'))	('EF2', 'Gene', (334, 337))	('elongation factor-2', 'Gene', (259, 278))	('EF2', 'Gene', '1938', (280, 283))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('206', '227'))	('MCL-1', 'Gene', '4170', (418, 423))	('mesothelin', 'Gene', '10232', (78, 88))	('EF2', 'Gene', '1938', (334, 337))	('degradation', 'MPA', (368, 379))	('ADP-ribosylation', 'Var', (297, 313))	('LMB', 'Chemical', 'MESH:C038753', (24, 27))	('endocytosis', 'biological_process', 'GO:0006897', ('130', '141'))	('Fab', 'Gene', '2187', (173, 176))	('BAK', 'Gene', (439, 442))	('inactivation', 'Var', (318, 330))	('MCL-1', 'Gene', (418, 423))	('elongation factor-2', 'Gene', '1938', (259, 278))	('BAK', 'Gene', '578', (439, 442))	('rapidly turning over proteins', 'MPA', (383, 412))	('furin', 'Gene', '5045', (180, 185))	('ADP', 'Chemical', 'MESH:D000244', (297, 300))	('LMB', 'Chemical', 'MESH:C038753', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('349', '356'))	('protein synthesis', 'biological_process', 'GO:0006412', ('349', '366'))
124700	29152082	LMB-100, as expected, caused a fall in MCL-1 and in BNIP3L and enhanced PARP cleavage.	('fall', 'NegReg', (31, 35))	('LMB', 'Chemical', 'MESH:C038753', (0, 3))	('LMB-100', 'Var', (0, 7))	('enhanced', 'PosReg', (63, 71))	('PARP', 'Gene', '142', (72, 76))	('BNIP3L', 'Gene', (52, 58))	('BNIP3L', 'Gene', '665', (52, 58))	('MCL-1', 'Gene', (39, 44))	('MCL-1', 'Gene', '4170', (39, 44))	('PARP', 'Gene', (72, 76))	('fall', 'Phenotype', 'HP:0002527', (31, 35))
124719	29152082	Also, TNFR1B was increased in KLM1cells and TNFR11B was increased in MKN28.	('increased', 'PosReg', (17, 26))	('TNF', 'Gene', '7124', (44, 47))	('KLM1cells', 'Var', (30, 39))	('increased', 'PosReg', (56, 65))	('TNF', 'Gene', '7124', (6, 9))	('TNFR1B', 'Gene', (6, 12))	('MKN28', 'Chemical', '-', (69, 74))	('TNF', 'Gene', (44, 47))	('TNFR1B', 'Gene', '7133', (6, 12))	('TNF', 'Gene', (6, 9))	('MKN28', 'Var', (69, 74))
124758	23980201	Alterations in these pathways in turn trigger molecular responses that stimulate cell proliferation and promote tumor survival and progression.	('cell proliferation', 'CPA', (81, 99))	('progression', 'CPA', (131, 142))	('stimulate', 'PosReg', (71, 80))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promote', 'PosReg', (104, 111))	('trigger', 'Reg', (38, 45))	('tumor', 'Disease', (112, 117))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (93, 96))
124781	23980201	Molecular alterations in human mesothelioma associated with asbestos exposure have been an area of intense interest, and a topic of several recent reviews and gene expression profile targeted publications; gene expression profiling and mutation analysis of these tumors in humans has revealed a variety of genetic alterations including mutations in tumor suppressor genes (TP53, WT1, NF2 and PTEN) or cell cycle genes (CDKN2A/2B and CDKN2C), and alterations in proteins associated with tumorigenesis (COL3, CCL2, LGALS).	('cell cycle', 'biological_process', 'GO:0007049', ('401', '411'))	('CCL2', 'Gene', (507, 511))	('CDKN2A/2B', 'Gene', '1029', (419, 428))	('rat', 'Species', '10116', (318, 321))	('asbestos', 'Chemical', 'MESH:D001194', (60, 68))	('gene expression', 'biological_process', 'GO:0010467', ('206', '221'))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('TP53', 'Gene', '7157', (373, 377))	('PTEN', 'Gene', (392, 396))	('human', 'Species', '9606', (25, 30))	('tumor', 'Disease', (263, 268))	('CCL2', 'Gene', '6347', (507, 511))	('CDKN2A/2B', 'Gene', (419, 428))	('tumor', 'Disease', (486, 491))	('rat', 'Species', '10116', (450, 453))	('rat', 'Species', '10116', (14, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('349', '365'))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('humans', 'Species', '9606', (273, 279))	('NF2', 'Gene', '4771', (384, 387))	('PTEN', 'Gene', '5728', (392, 396))	('CDKN2C', 'Gene', (433, 439))	('mesothelioma', 'Disease', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (486, 491))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('NF2', 'Gene', (384, 387))	('WT1', 'Gene', (379, 382))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor suppressor', 'biological_process', 'GO:0051726', ('349', '365'))	('alterations', 'Reg', (446, 457))	('TP53', 'Gene', (373, 377))	('tumor', 'Disease', (349, 354))	('gene expression', 'biological_process', 'GO:0010467', ('159', '174'))	('proteins', 'Protein', (461, 469))	('CCL', 'molecular_function', 'GO:0044101', ('507', '510'))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (486, 491))	('mutations', 'Var', (336, 345))	('WT1', 'Gene', '7490', (379, 382))	('tumors', 'Disease', (263, 269))	('human', 'Species', '9606', (273, 278))	('CDKN2C', 'Gene', '1031', (433, 439))
124803	23980201	To determine this normalized value, 2-(DeltaDeltaCt) values were compared between target and calibrator samples, where the changes in crossing threshold (DeltaCt) = CtTarget gene - Ct18S RNA, and DeltaDeltaCt = DeltaCtcontrol - DeltaCttarget.	('changes', 'Var', (123, 130))	('rat', 'Species', '10116', (98, 101))	('DeltaDeltaCt', 'Var', (196, 208))	('RNA', 'cellular_component', 'GO:0005562', ('187', '190'))
124826	23980201	These alterations in gene expression represent dysregulation of cell growth and proliferation pathways in mesothelial cells leading to transformation and oncogenesis in F344/N rat spontaneous mesotheliomas.	('alterations', 'Var', (6, 17))	('mesotheliomas', 'Disease', (192, 205))	('dysregulation', 'Reg', (47, 60))	('rat', 'Species', '10116', (176, 179))	('oncogenesis', 'CPA', (154, 165))	('proliferation', 'CPA', (80, 93))	('transformation', 'CPA', (135, 149))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('oncogenesis', 'biological_process', 'GO:0007048', ('154', '165'))	('cell growth', 'CPA', (64, 75))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (87, 90))	('mesotheliomas', 'Disease', 'MESH:D008654', (192, 205))
124839	23980201	Alterations in tumor suppressor genes and oncogenes are key genetic factors related to tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('tumor', 'Disease', (15, 20))	('rat', 'Species', '10116', (4, 7))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('oncogenes', 'Gene', (42, 51))	('related', 'Reg', (76, 83))
124845	23980201	Alterations in tumor suppressor genes, oncogenes, and apoptosis mediators have a profound effect on the expression of downstream cellular growth factors and the inflammatory response, two other significantly represented categories of altered gene expression in this study.	('effect', 'Reg', (90, 96))	('growth factor', 'Gene', '79215', (138, 151))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('gene expression', 'biological_process', 'GO:0010467', ('242', '257'))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('oncogenes', 'Gene', (39, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('growth factor', 'Gene', (138, 151))	('tumor', 'Disease', (15, 20))	('expression', 'MPA', (104, 114))	('cellular growth', 'biological_process', 'GO:0016049', ('129', '144'))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('inflammatory response', 'biological_process', 'GO:0006954', ('161', '182'))	('rat', 'Species', '10116', (4, 7))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('inflammatory response', 'CPA', (161, 182))
124862	23980201	Alterations in EpCAM interfere with cadherin-mediated cell to cell adhesion, and cytoplasmic and nuclear translocation of its intercellular domain (EpICD) is associated with stimulation of cell proliferation.	('rat', 'Species', '10116', (201, 204))	('stimulation', 'PosReg', (174, 185))	('cadherin', 'Gene', '29182', (36, 44))	('cadherin', 'Gene', (36, 44))	('Alterations', 'Var', (0, 11))	('EpCAM', 'Gene', (15, 20))	('cell proliferation', 'CPA', (189, 207))	('interfere', 'NegReg', (21, 30))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('174', '207'))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('cell adhesion', 'biological_process', 'GO:0007155', ('62', '75'))	('rat', 'Species', '10116', (4, 7))
124870	23980201	This response could be attributed to chronic inflammation, cancer-related inflammation, dysregulation of mesothelial cell function, and/or intrinsic genetic events.	('inflammation', 'Disease', (45, 57))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('inflammation', 'biological_process', 'GO:0006954', ('45', '57'))	('mesothelial cell function', 'CPA', (105, 130))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('dysregulation', 'Var', (88, 101))	('inflammation', 'biological_process', 'GO:0006954', ('74', '86'))
124877	23980201	In terms of non-asbestos etiologies in human mesothelioma, many of these are also associated with inflammatory processes in the lung (SV40 viral infection, exposure to radiation or chemical agents; whereas others, such as germline mutations in BRCA1-Associated Protein 1 (BAP1) (; Testa et al.	('associated', 'Reg', (82, 92))	('mesothelioma', 'Disease', (45, 57))	('SV40 viral infection', 'Disease', (134, 154))	('germline mutations', 'Var', (222, 240))	('viral infection', 'biological_process', 'GO:0016032', ('139', '154'))	('BAP1', 'Gene', (272, 276))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('SV40 viral infection', 'Disease', 'MESH:D001102', (134, 154))	('asbestos', 'Chemical', 'MESH:D001194', (16, 24))	('human', 'Species', '9606', (39, 44))
124896	23980201	This study shows that there is dysregulation of numerous genes in overlapping pathways including those associated with cellular proliferation and survival, inflammation and immune system dysregulation, inhibition of apoptosis, and dysregulation of oncogenes, tumor suppressor and embryonic genes in the process of spontaneous mesotheliomagenesis.	('inflammation', 'Disease', 'MESH:D007249', (156, 168))	('rat', 'Species', '10116', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('mesothelioma', 'Disease', 'MESH:D008654', (326, 338))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('259', '275'))	('inflammation', 'Disease', (156, 168))	('apoptosis', 'CPA', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor suppressor', 'biological_process', 'GO:0051726', ('259', '275'))	('dysregulation', 'Var', (31, 44))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('202', '225'))	('tumor', 'Disease', (259, 264))	('oncogenes', 'Gene', (248, 257))	('dysregulation', 'Var', (231, 244))	('mesothelioma', 'Disease', (326, 338))	('inflammation', 'biological_process', 'GO:0006954', ('156', '168'))
124926	27512676	Other strains of oncolytic HSV, such as G207, NV1020, and NV1066, that code for fluorescent proteins have also been used to treat and image primary tumors and metastases of mesothelioma in vivo.	('metastases of mesothelioma', 'Disease', 'MESH:D009362', (159, 185))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('NV1066', 'Var', (58, 64))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('oncolytic HSV', 'Disease', 'MESH:C536395', (17, 30))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('metastases of mesothelioma', 'Disease', (159, 185))	('oncolytic HSV', 'Disease', (17, 30))
124928	27512676	JX-594, also known as pexastimogene devacirepvec (Pexa-Vec), is another oncolytic virus expected to be tested in a Phase III clinical trial for patients with hepatocellular carcinoma.	('Pexa-Vec', 'Chemical', '-', (50, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('JX-594', 'Chemical', '-', (0, 6))	('patients', 'Species', '9606', (144, 152))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('hepatocellular carcinoma', 'Disease', (158, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('JX-594', 'Var', (0, 6))
124954	27512676	Indeed, we recently described - in tumor cells derived from 22 patients with MPM - how type I interferon deficiencies could discriminate between patients who would be susceptible to oncolytic MV virotherapy and those who would be resistant to this type of treatment (Achard et al, unpublished data, 2015).	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MV', 'Species', '11234', (192, 194))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('discriminate', 'Reg', (124, 136))	('tumor', 'Disease', (35, 40))	('deficiencies', 'Var', (105, 117))	('patients', 'Species', '9606', (63, 71))	('MPM - how', 'Gene', (77, 86))
124987	27512676	This same group previously reported that MV encoding the interferon-beta gene induced immune cell infiltration - mainly macrophages - into human MM xenografts and the associated microenvironment.	('MV', 'Species', '11234', (41, 43))	('induced', 'Reg', (78, 85))	('MV encoding', 'Var', (41, 52))	('human', 'Species', '9606', (139, 144))	('immune cell infiltration', 'CPA', (86, 110))
124996	27512676	It was first shown that the stress response induced by cisplatin in cell lines derived from epithelioid, sarcomatoid, or biphasic MM could potentiate the replication and cytotoxicity of the oncolytic HSVs NV1066 in vitro.	('cytotoxicity', 'Disease', (170, 182))	('sarcomatoid', 'Disease', 'MESH:C538614', (105, 116))	('stress', 'MPA', (28, 34))	('oncolytic HSV', 'Disease', 'MESH:C536395', (190, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('sarcomatoid', 'Disease', (105, 116))	('oncolytic HSV', 'Disease', (190, 203))	('potentiate', 'PosReg', (139, 149))	('cisplatin', 'Var', (55, 64))
125000	27512676	The antitumor effects of epigenetic drugs have been widely demonstrated for the treatment of hematological cancers, but more work is needed to define their use for solid tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('hematological cancers', 'Disease', 'MESH:D009369', (93, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('solid tumors', 'Disease', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (170, 175))	('hematological cancers', 'Disease', (93, 114))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Disease', (8, 13))	('solid tumors', 'Disease', 'MESH:D009369', (164, 176))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('epigenetic drugs', 'Var', (25, 41))
125001	27512676	Indeed, inhibitors of histone deacetylases have been demonstrated to synergize with certain oncolytic viruses such as VSV to infect refractory primary tumors by dampening the type I interferon response.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('VSV to infect refractory primary tumors', 'Disease', 'MESH:D000069279', (118, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('histone deacetylases', 'Protein', (22, 42))	('dampening', 'NegReg', (161, 170))	('VSV to infect refractory primary tumors', 'Disease', (118, 157))	('type I interferon response', 'MPA', (175, 201))	('inhibitors', 'Var', (8, 18))
125172	33923944	Childhood leukemia may occur due to chromosomal translocation of a pre-leukemic clone, in which the genes are rearranged and may be triggered by exposure to environmental factors such as benzene.	('benzene', 'Chemical', 'MESH:D001554', (187, 194))	('occur due to', 'Reg', (23, 35))	('men', 'Species', '9606', (164, 167))	('leukemia', 'Phenotype', 'HP:0001909', (10, 18))	('Childhood leukemia', 'Disease', 'MESH:D007938', (0, 18))	('pre', 'molecular_function', 'GO:0003904', ('67', '70'))	('chromosomal translocation', 'Var', (36, 61))	('Childhood leukemia', 'Disease', (0, 18))
125225	33688945	Annual follow-up is by CT of the abdomen and pelvis together with tumour markers, namely carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125 and CA19-9.	('carcinoembryonic', 'Disease', (89, 105))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('carcinoembryonic', 'Disease', 'None', (89, 105))	('men', 'Species', '9606', (37, 40))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('carbohydrate antigen (CA) 125', 'Gene', (121, 150))	('tumour', 'Disease', (66, 72))	('CA19-9', 'Var', (155, 161))	('carbohydrate antigen (CA) 125', 'Gene', '94025', (121, 150))
125293	33546236	Environmental carcinogens can cause specific genetic and epigenetic changes in lung tissue, leading to aberrant functions of lung cancer oncogenes and tumor suppressor genes.	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('aberrant', 'Var', (103, 111))	('epigenetic', 'Var', (57, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('functions', 'MPA', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
125339	33546236	Thus, Carter and colleagues demonstrated an important role in the production of H2O2 by the mitochondria of alveolar macrophages using an animal model of asbestosis.	('asbestosis', 'Disease', 'MESH:D001195', (154, 164))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('H2O2', 'Var', (80, 84))	('asbestosis', 'Disease', (154, 164))	('mitochondria', 'cellular_component', 'GO:0005739', ('92', '104'))
125341	33546236	The fc mtDNA copy number changes in different types of malignant neoplasias, including lung cancer.	('malignant neoplasias', 'Disease', 'MESH:D009369', (55, 75))	('mtDNA', 'cellular_component', 'GO:0000262', ('7', '12'))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('copy number', 'Var', (13, 24))	('changes', 'Reg', (25, 32))	('neoplasias', 'Phenotype', 'HP:0002664', (65, 75))	('malignant neoplasias', 'Disease', (55, 75))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('fc mtDNA', 'Gene', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mtDNA', 'Gene', (7, 12))
125372	33546236	In addition, it was found that overexpression of miR-155-5p significantly extended the malignant phenotype of lung cancer cells, including cell growth, colony formation, migration, invasion, and antiapoptotic effects.	('colony formation', 'CPA', (152, 168))	('miR-155-5p', 'Var', (49, 59))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cell growth', 'biological_process', 'GO:0016049', ('139', '150'))	('migration', 'CPA', (170, 179))	('extended', 'PosReg', (74, 82))	('cell growth', 'CPA', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('formation', 'biological_process', 'GO:0009058', ('159', '168'))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('malignant phenotype of', 'CPA', (87, 109))	('antiapoptotic effects', 'CPA', (195, 216))	('invasion', 'CPA', (181, 189))	('overexpression', 'PosReg', (31, 45))
125379	33546236	Interestingly, some TP53 mutations, which were previously associated with oncogenic progression, suppress the expression of some microRNAs.	('microRNAs', 'Protein', (129, 138))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('suppress', 'NegReg', (97, 105))	('expression', 'MPA', (110, 120))	('TP53', 'Gene', '7157', (20, 24))
125392	33546236	After knockdown of miR-103, the number of apoptotic cells increased, the expression level of the proapoptotic protein Bax increased, and the level of the antiapoptotic protein Bcl-2 decreased in A549 and H23 cell lines.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('Bax', 'Gene', (118, 121))	('miR-103', 'Chemical', '-', (19, 26))	('increased', 'PosReg', (58, 67))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('Bcl-2', 'Gene', (176, 181))	('decreased', 'NegReg', (182, 191))	('Bcl-2', 'Gene', '596', (176, 181))	('Bcl-2', 'molecular_function', 'GO:0015283', ('176', '181'))	('H23', 'CellLine', 'CVCL:1547', (204, 207))	('expression level of', 'MPA', (73, 92))	('miR-103', 'Gene', (19, 26))	('Bax', 'Gene', '581', (118, 121))	('knockdown', 'Var', (6, 15))	('increased', 'PosReg', (122, 131))	('A549', 'CellLine', 'CVCL:0023', (195, 199))
125393	33546236	In addition, the level of FBW7 protein was increased after the miR-103 knockdown.	('miR-103', 'Gene', (63, 70))	('protein', 'Protein', (31, 38))	('FBW7', 'Gene', '55294', (26, 30))	('level', 'MPA', (17, 22))	('knockdown', 'Var', (71, 80))	('FBW7', 'Gene', (26, 30))	('miR-103', 'Chemical', '-', (63, 70))	('increased', 'PosReg', (43, 52))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))
125407	33546236	Studies have shown that PM2.5 treatment can cause cell apoptosis, cell necrosis, autophagy, DNA damage, mitochondrial damage, and gene mutations in respiratory tract tissues.	('men', 'Species', '9606', (35, 38))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('mitochondrial damage', 'CPA', (104, 124))	('necrosis', 'biological_process', 'GO:0008220', ('71', '79'))	('cell apoptosis', 'CPA', (50, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('necrosis', 'Disease', 'MESH:D009336', (71, 79))	('PM2.5 treatment', 'Var', (24, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('necrosis', 'biological_process', 'GO:0070265', ('71', '79'))	('necrosis', 'Disease', (71, 79))	('necrosis', 'biological_process', 'GO:0019835', ('71', '79'))	('DNA damage', 'CPA', (92, 102))	('necrosis', 'biological_process', 'GO:0001906', ('71', '79'))	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('gene', 'CPA', (130, 134))	('cause', 'Reg', (44, 49))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('necrosis', 'biological_process', 'GO:0008219', ('71', '79'))	('autophagy', 'CPA', (81, 90))
125414	33546236	High miR-98 expression patients showed longer average survival than low miR-98 expression patients.	('miR-98', 'Gene', (72, 78))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (23, 31))	('miR-98', 'Gene', '407054', (5, 11))	('miR-98', 'Gene', (5, 11))	('patients', 'Species', '9606', (90, 98))	('miR-98', 'Gene', '407054', (72, 78))	('longer', 'PosReg', (39, 45))
125415	33546236	Inhibited miR-98 activated PAK1 (P21-activated protein kinase 1), a biomarker of pulmonary cancer, which promotes NSCLC cell proliferation, migration, and invasion.	('pulmonary cancer', 'Phenotype', 'HP:0100526', (81, 97))	('promotes', 'PosReg', (105, 113))	('pulmonary cancer', 'Disease', (81, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('P21-activated protein kinase 1', 'Gene', '5058', (33, 63))	('PAK1', 'Gene', '5058', (27, 31))	('NSCLC', 'Disease', (114, 119))	('pulmonary cancer', 'Disease', 'MESH:D008175', (81, 97))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('invasion', 'CPA', (155, 163))	('PAK1', 'Gene', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Inhibited', 'Var', (0, 9))	('miR-98', 'Gene', (10, 16))	('miR-98', 'Gene', '407054', (10, 16))	('migration', 'CPA', (140, 149))	('P21-activated protein kinase 1', 'Gene', (33, 63))
125421	33546236	A mimic miR-128 significantly suppressed the expression of vascular endothelial growth factor (VEGF)-C. The overexpression of miR-128 in NSCLC cells and human endothelial vein umbilical cells caused a reduction expression of VEGF-A, vascular endothelial growth factor receptor 2, and VEGFR-3, essential factors critical for cancer angiogenesis and lymphangiogenesis, and slightly declined the phosphorylation of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and p38 signaling pathways.	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('348', '365'))	('angiogenesis', 'biological_process', 'GO:0001525', ('331', '343'))	('NSCLC', 'Disease', (137, 142))	('miR-128', 'Chemical', '-', (126, 133))	('VEGFR-3', 'Gene', '2324', (284, 291))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('233', '267'))	('p38', 'Gene', '1398', (486, 489))	('human', 'Species', '9606', (153, 158))	('extracellular signal-regulated kinase', 'Pathway', (412, 449))	('VEGF', 'Gene', '7422', (225, 229))	('VEGF-A', 'Gene', (225, 231))	('signaling', 'biological_process', 'GO:0023052', ('490', '499'))	('phosphorylation', 'biological_process', 'GO:0016310', ('393', '408'))	('reduction', 'NegReg', (201, 210))	('VEGF', 'Gene', (225, 229))	('declined', 'NegReg', (380, 388))	('p38', 'Gene', (486, 489))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (233, 278))	('extracellular', 'cellular_component', 'GO:0005576', ('412', '425'))	('VEGFR-3', 'Gene', (284, 291))	('cancer', 'Disease', (324, 330))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('VEGF-A', 'Gene', '7422', (225, 231))	('miR-128', 'Var', (126, 133))	('phosphorylation', 'MPA', (393, 408))	('miR-128', 'Chemical', '-', (8, 15))	('VEGF', 'Gene', '7422', (284, 288))	('VEGF', 'Gene', '7422', (95, 99))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('59', '93'))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('VEGF', 'Gene', (284, 288))	('vascular endothelial growth factor receptor 2', 'Gene', (233, 278))	('phosphatidylinositol 3-kinase', 'Pathway', (451, 480))	('VEGF', 'Gene', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
125423	33546236	miR-135a decreased angiogenesis-related factors VEGF, bFGF, and IL-8 in A549 cells by inhibiting IGF-1.	('bFGF', 'Gene', (54, 58))	('IL-8', 'Gene', '3576', (64, 68))	('IGF-1', 'Gene', (97, 102))	('VEGF', 'Gene', (48, 52))	('miR-135a', 'Var', (0, 8))	('IGF-1', 'Gene', '3479', (97, 102))	('IL-8', 'Gene', (64, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('19', '31'))	('miR-135a', 'Chemical', '-', (0, 8))	('inhibiting', 'NegReg', (86, 96))	('VEGF', 'Gene', '7422', (48, 52))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('decreased', 'NegReg', (9, 18))	('IL-8', 'molecular_function', 'GO:0005153', ('64', '68'))	('bFGF', 'Gene', '2247', (54, 58))
125449	33546236	CORO1C knockdown significantly reduced the ability of cells to grow and metastasize in gastric and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('reduced', 'NegReg', (31, 38))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('gastric', 'Disease', (87, 94))	('CORO1C', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('CORO1C', 'Gene', '23603', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
125460	33546236	Overexpression of miR-652-3p was found in tumor tissues of patients with NSCLC and was significantly higher in patients with lymph node metastases.	('tumor', 'Disease', (42, 47))	('miR-652-3p', 'Var', (18, 28))	('higher', 'PosReg', (101, 107))	('NSCLC', 'Disease', (73, 78))	('metastases', 'Disease', (136, 146))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('patients', 'Species', '9606', (111, 119))
125461	33546236	The probable mechanism of metastasis is the binding of miR-652-3p mRNA of the Lgl1 protein, which promotes cell adhesion and inhibits cell migration by suppressing the expression of MMP2 and MMP14 and re-expression of E-cadherin.	('MMP14', 'Gene', '4323', (191, 196))	('MMP14', 'Gene', (191, 196))	('MMP2', 'Gene', '4313', (182, 186))	('binding', 'Interaction', (44, 51))	('re-expression', 'PosReg', (201, 214))	('expression', 'MPA', (168, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('220', '228'))	('E-cadherin', 'Gene', (218, 228))	('E-cadherin', 'Gene', '999', (218, 228))	('inhibits', 'NegReg', (125, 133))	('cell adhesion', 'biological_process', 'GO:0007155', ('107', '120'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('MMP', 'molecular_function', 'GO:0004235', ('191', '194'))	('miR-652-3p mRNA', 'Var', (55, 70))	('promotes', 'PosReg', (98, 106))	('Lgl1', 'Gene', (78, 82))	('cell adhesion', 'CPA', (107, 120))	('cell migration', 'biological_process', 'GO:0016477', ('134', '148'))	('cell migration', 'CPA', (134, 148))	('suppressing', 'NegReg', (152, 163))	('MMP2', 'molecular_function', 'GO:0004228', ('182', '186'))	('MMP2', 'Gene', (182, 186))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('Lgl1', 'Gene', '3996', (78, 82))
125467	33546236	Asbestos-related lung cancer has been made of a result of various mutations, lesions caused by DNA-damaging ROS.	('mutations', 'Var', (66, 75))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('ROS', 'Chemical', 'MESH:D017382', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))
125469	33546236	An example miR-138 knockdown facilitates DNA damage repair, while miR-138 overexpression inhibits DNA damage repair in small-cell lung cancer (SCLC) cells due to a decrease in the level of H2AX expression, and as a result of miR-138 overexpression, reduction of cell growth and a significant inhibition on cell-cycle progression was detected.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('DNA damage repair', 'MPA', (98, 115))	('inhibits', 'NegReg', (89, 97))	('DNA damage repair', 'MPA', (41, 58))	('SCLC', 'Disease', 'MESH:D018288', (143, 147))	('miR-138', 'Chemical', '-', (66, 73))	('miR-138', 'Chemical', '-', (11, 18))	('cell-cycle progression', 'CPA', (306, 328))	('facilitates', 'PosReg', (29, 40))	('miR-138', 'Chemical', '-', (225, 232))	('cell growth', 'biological_process', 'GO:0016049', ('262', '273'))	('knockdown', 'Var', (19, 28))	('reduction', 'NegReg', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('overexpression', 'PosReg', (233, 247))	('decrease', 'NegReg', (164, 172))	('cell-cycle', 'biological_process', 'GO:0007049', ('306', '316'))	('cell growth', 'CPA', (262, 273))	('miR-138', 'Var', (11, 18))	('miR-138', 'Gene', (66, 73))	('SCLC', 'Disease', (143, 147))	('miR-138', 'Gene', (225, 232))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (119, 141))	('H2AX', 'Gene', (189, 193))	('small-cell lung cancer', 'Disease', (119, 141))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('expression', 'MPA', (194, 204))	('H2AX', 'Gene', '3014', (189, 193))
125473	33546236	have shown that miR-24-3p suppressed homology-directed DNA repair by inhibition of BRCA1 expression in the cells of parenchymal lung tissue.	('miR-24-3p', 'Var', (16, 25))	('expression', 'MPA', (89, 99))	('suppressed', 'NegReg', (26, 36))	('BRCA1', 'Gene', '672', (83, 88))	('BRCA1', 'Gene', (83, 88))	('homology-directed DNA repair', 'MPA', (37, 65))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('DNA repair', 'biological_process', 'GO:0006281', ('55', '65'))	('miR-24-3p', 'Chemical', '-', (16, 25))	('inhibition', 'NegReg', (69, 79))
125477	33546236	have shown that miR-125b-5p, miR-21-5p and miR-222-3p expression inversely correlates to PARP1 mRNA expression.	('miR-222', 'Gene', '407007', (43, 50))	('miR-21-5p', 'Gene', (29, 38))	('miR-21-5p', 'Gene', '406997', (29, 38))	('miR-125b-5p', 'Var', (16, 27))	('miR-222', 'Gene', (43, 50))	('PARP1', 'Gene', '142', (89, 94))	('PARP1', 'Gene', (89, 94))
125484	33546236	The level of free-circulating microRNA hsa-miR-19b-3p was significantly higher in groups of patients with lung cancer compared with healthy individuals.	('free-circulating', 'MPA', (13, 29))	('level', 'MPA', (4, 9))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('hsa', 'Gene', '213', (39, 42))	('patients', 'Species', '9606', (92, 100))	('microRNA', 'Var', (30, 38))	('hsa', 'Gene', (39, 42))	('higher', 'PosReg', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
125491	33546236	Thus, it was shown that asbestos causes the overexpression of seven microRNAs (miR-374a, miR-24-1, let-7d, Let-7e, miR-199b-5p, miR-331-3p, and miR-96) in lung tumors (Figure 1), and five microRNAs (miR-939, miR-671-5p, miR-605, miR-1224-5p, and miR-202) demonstrate reduced expression under the influence of asbestos.	('miR-605', 'Gene', '693190', (220, 227))	('miR-331-3p', 'Var', (128, 138))	('miR-374a', 'Gene', (79, 87))	('miR-939', 'Gene', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('miR-96', 'Gene', (144, 150))	('miR-1224', 'Gene', (229, 237))	('miR-202', 'Gene', '574448', (246, 253))	('miR-939', 'Gene', '100126351', (199, 206))	('miR-199b-5p', 'Var', (115, 126))	('miR-605', 'Gene', (220, 227))	('miR-671', 'Gene', (208, 215))	('overexpression', 'PosReg', (44, 58))	('miR-96', 'Gene', '407053', (144, 150))	('Let-7e', 'Gene', (107, 113))	('miR-24-1', 'Gene', '407012', (89, 97))	('miR-1224', 'Gene', '100187716', (229, 237))	('lung tumors', 'Disease', 'MESH:D008175', (155, 166))	('let-7d', 'Gene', '406886', (99, 105))	('lung tumors', 'Phenotype', 'HP:0100526', (155, 166))	('miR-374a', 'Gene', '442919', (79, 87))	('miR-671', 'Gene', '768213', (208, 215))	('asbestos', 'Chemical', 'MESH:D001194', (309, 317))	('asbestos', 'Chemical', 'MESH:D001194', (24, 32))	('miR-24-1', 'Gene', (89, 97))	('lung tumor', 'Phenotype', 'HP:0100526', (155, 165))	('Let-7e', 'Gene', '406887', (107, 113))	('expression', 'MPA', (275, 285))	('let-7d', 'Gene', (99, 105))	('miR-202', 'Gene', (246, 253))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('lung tumors', 'Disease', (155, 166))
125495	33546236	Epigenetic changes and cross-linking between cancer and stroma can induce miR-126 repression to facilitate tumor formation, angiogenesis, and invasion.	('miR-126', 'Gene', '406913', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('miR-126', 'Gene', (74, 81))	('facilitate', 'PosReg', (96, 106))	('tumor', 'Disease', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('Epigenetic changes', 'Var', (0, 18))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('induce', 'Reg', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('angiogenesis', 'CPA', (124, 136))	('cancer', 'Disease', (45, 51))	('invasion', 'CPA', (142, 150))
125500	33546236	They found thirteen microRNAs associated with asbestos, and, among them, eight microRNAs were overexpressed: miR-148b, miR-374a, miR-24-1, Let-7d, Let-7e, miR-199b-5p, miR-331-3p, and miR-96 and five were downregulated: miR-939, miR-671-5p, miR-605, miR-1224-5p, and miR-202.	('miR-671', 'Gene', '768213', (229, 236))	('miR-96', 'Gene', (184, 190))	('miR-331-3p', 'Var', (168, 178))	('Let-7e', 'Gene', '406887', (147, 153))	('miR-374a', 'Gene', (119, 127))	('miR-1224', 'Gene', '100187716', (250, 258))	('Let-7d', 'Gene', (139, 145))	('miR-24-1', 'Gene', '407012', (129, 137))	('miR-96', 'Gene', '407053', (184, 190))	('miR-605', 'Gene', '693190', (241, 248))	('miR-148b', 'Gene', '442892', (109, 117))	('miR-939', 'Gene', (220, 227))	('miR-148b', 'Gene', (109, 117))	('miR-202', 'Gene', (267, 274))	('Let-7d', 'Gene', '406886', (139, 145))	('miR-24-1', 'Gene', (129, 137))	('miR-939', 'Gene', '100126351', (220, 227))	('miR-605', 'Gene', (241, 248))	('miR-671', 'Gene', (229, 236))	('miR-374a', 'Gene', '442919', (119, 127))	('Let-7e', 'Gene', (147, 153))	('miR-1224', 'Gene', (250, 258))	('miR-202', 'Gene', '574448', (267, 274))	('asbestos', 'Chemical', 'MESH:D001194', (46, 54))	('miR-199b-5p', 'Var', (155, 166))
125503	33546236	A link between the hypermethylation of promotor DNA and inflammation has been shown in many forms of cancer, including asbestos-related lung cancer.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('inflammation', 'Disease', (56, 68))	('link', 'Reg', (2, 6))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('shown', 'Reg', (78, 83))	('hypermethylation', 'Var', (19, 35))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('inflammation', 'biological_process', 'GO:0006954', ('56', '68'))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('cancer', 'Disease', (141, 147))	('lung cancer', 'Disease', (136, 147))
125504	33546236	Molecular genetic analysis have shown changes in the number of DNA copies, changes in the profiles of many microRNAs, and dysregulation of the expression of certain genes in asbestos-associated lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('changes', 'Reg', (75, 82))	('dysregulation', 'Var', (122, 135))	('expression', 'MPA', (143, 153))	('profiles', 'MPA', (90, 98))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('changes', 'Reg', (38, 45))	('asbestos', 'Chemical', 'MESH:D001194', (174, 182))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('lung cancer', 'Disease', (194, 205))
125517	33546236	After transfection of miR-30d to the NCI-H2452 cell line, a percentage difference in G1/S/G2 stages was not found; however, the overall rate of apoptosis increased.	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('transfection', 'Var', (6, 18))	('S/G2', 'Var', (88, 92))	('apoptosis', 'CPA', (144, 153))	('miR-30d', 'Gene', (22, 29))	('NCI-H2452', 'CellLine', 'CVCL:1553', (37, 46))	('S/G2', 'SUBSTITUTION', 'None', (88, 92))	('miR-30d', 'Gene', '407033', (22, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))
125521	33546236	The aberrant expression of miR-30a in lung cancer stimulated the expression of myocyte enhancer factor 2D (MEF2D) protein.	('miR-30a', 'Gene', '407029', (27, 34))	('lung cancer', 'Disease', (38, 49))	('myocyte enhancer factor 2D', 'Gene', (79, 105))	('MEF2D', 'Gene', '4209', (107, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('myocyte enhancer factor 2D', 'Gene', '4209', (79, 105))	('miR-30a', 'Gene', (27, 34))	('MEF2D', 'Gene', (107, 112))	('stimulated', 'PosReg', (50, 60))	('aberrant expression', 'Var', (4, 23))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('expression', 'MPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))
125527	33546236	Researchers found that aberrant methylation and silence of miR-34b and miR-34c were observed in asbestos-induced pleural mesothelioma.	('miR-34c', 'Gene', '407042', (71, 78))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (113, 133))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (113, 133))	('miR-34c', 'Gene', (71, 78))	('observed', 'Reg', (84, 92))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('pleural mesothelioma', 'Disease', (113, 133))	('methylation', 'MPA', (32, 43))	('silence', 'NegReg', (48, 55))	('miR-34b', 'Gene', (59, 66))	('miR-34b', 'Gene', '407041', (59, 66))	('aberrant', 'Var', (23, 31))	('asbestos', 'Chemical', 'MESH:D001194', (96, 104))
125530	33546236	ELK1, in turn, controlled miR-34a expression by direct activation of the promoter, and miR-34a returned to suppress AXL mRNA.	('suppress', 'NegReg', (107, 115))	('expression', 'MPA', (34, 44))	('promoter', 'MPA', (73, 81))	('miR-34a', 'Var', (87, 94))	('AXL', 'Gene', '558', (116, 119))	('miR-34a', 'Gene', (26, 33))	('AXL', 'Gene', (116, 119))	('ELK1', 'Gene', (0, 4))	('ELK1', 'Gene', '2002', (0, 4))	('activation', 'PosReg', (55, 65))
125536	33546236	As a result of DSB, changes occur in the chromatin structure, which leads to phosphorylation of the nucleosomal protein H2A and further damage repair.	('phosphorylation', 'MPA', (77, 92))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('leads', 'Reg', (68, 73))	('nucleosomal protein H2A', 'Protein', (100, 123))	('DSB', 'Var', (15, 18))	('damage', 'MPA', (136, 142))	('chromatin', 'MPA', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('changes', 'Reg', (20, 27))	('DSB', 'Chemical', '-', (15, 18))
125545	33546236	Histone H2AX has been identified as a target for miR-138.	('miR-138', 'Chemical', '-', (49, 56))	('miR-138', 'Var', (49, 56))	('Histone H2AX', 'Gene', '3014', (0, 12))	('Histone H2AX', 'Gene', (0, 12))
125564	24392351	On transcriptomic level, syndecan-1 modulation results in profound effects on genes involved in regulation of cell growth Syndecans are transmembrane proteoglycans (PGs) composed of a core protein to which growth factor binding glycosaminoglycan (GAG) side chains are attached.	('core', 'cellular_component', 'GO:0019013', ('184', '188'))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('syndecan-1', 'Gene', '6382', (25, 35))	('transmembrane', 'cellular_component', 'GO:0016021', ('136', '149'))	('genes', 'Gene', (78, 83))	('GAG', 'Chemical', 'MESH:D006025', (247, 250))	('syndecan-1', 'Gene', (25, 35))	('effects', 'Reg', (67, 74))	('growth factor binding', 'molecular_function', 'GO:0019838', ('206', '227'))	('modulation', 'Var', (36, 46))	('regulation of cell growth', 'biological_process', 'GO:0001558', ('96', '121'))	('transmembrane', 'cellular_component', 'GO:0044214', ('136', '149'))	('syndecan', 'molecular_function', 'GO:0015023', ('25', '33'))
125581	24392351	Cell surface HSPGs can themselves participate in regulation of metalloproteinases, anchoring them to the cell surface via the GAG chains, and particularly for syndecan-1 it was demonstrated that the HS chains on the core protein suppresses shedding, giving an additional explanation on the above mentioned role of heparanase in this process.	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('syndecan', 'molecular_function', 'GO:0015023', ('159', '167'))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('heparanase', 'Gene', (314, 324))	('core', 'cellular_component', 'GO:0019013', ('216', '220'))	('shedding', 'MPA', (240, 248))	('GAG', 'Chemical', 'MESH:D006025', (126, 129))	('syndecan-1', 'Gene', '6382', (159, 169))	('HS', 'Chemical', 'MESH:D006497', (199, 201))	('suppresses', 'NegReg', (229, 239))	('HS', 'Chemical', 'MESH:D006497', (13, 15))	('anchoring', 'molecular_function', 'GO:0043495', ('83', '92'))	('heparanase', 'Gene', '10855', (314, 324))	('syndecan-1', 'Gene', (159, 169))	('cell surface', 'cellular_component', 'GO:0009986', ('105', '117'))	('HS chains', 'Var', (199, 208))
125592	24392351	The minimal structural requirement for nuclear translocation is the RMKKK sequence at the cytoplasmic tail of syndecan-1 serving as a nuclear localization signal (NLS).	('RMKKK sequence', 'Var', (68, 82))	('syndecan-1', 'Gene', '6382', (110, 120))	('syndecan', 'molecular_function', 'GO:0015023', ('110', '118'))	('localization', 'biological_process', 'GO:0051179', ('142', '154'))	('syndecan-1', 'Gene', (110, 120))	('N', 'Chemical', 'MESH:D009584', (163, 164))
125664	24392351	Studies using different model organisms with one or more HS biosynthetical genes knocked out, show distinct severe developmental disorders and phenotypic deficiencies.	('HS', 'Chemical', 'MESH:D006497', (57, 59))	('phenotypic deficiencies', 'Disease', (143, 166))	('knocked', 'Var', (81, 88))	('developmental disorders', 'Disease', (115, 138))	('phenotypic deficiencies', 'Disease', 'MESH:C536030', (143, 166))	('developmental disorders', 'Disease', 'MESH:D002658', (115, 138))
125667	24392351	These enzymes may interact as evidenced by studies in different model organisms (fruit fly, nematode, zebra fish, mouse) where knockdown of one of these enzymes is followed by direct and indirect effects, affecting the other enzymes from the HS biosynthetic machinery [for review see ].	('zebra fish', 'Species', '7955', (102, 112))	('affecting', 'Reg', (205, 214))	('fruit fly', 'Species', '7227', (81, 90))	('HS', 'Chemical', 'MESH:D006497', (242, 244))	('mouse', 'Species', '10090', (114, 119))	('knockdown', 'Var', (127, 136))
125668	24392351	Experiments with mice lacking NDST1 and/or NDST2 has shown that the HS N-sulfation is not limited by the total amount of active NDST enzymes; in mice deficient in C5 epimerase the HS N-sulfation is increased; and compensatory effects of 6-O-sulfation for 2-O sulfation were noticed.	('deficient', 'Var', (150, 159))	('HS', 'Chemical', 'MESH:D006497', (68, 70))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('sulfation', 'biological_process', 'GO:0051923', ('259', '268'))	('sulfation', 'biological_process', 'GO:0051923', ('185', '194'))	('sulfation', 'Chemical', '-', (185, 194))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('sulfation', 'Chemical', '-', (73, 82))	('sulfation', 'Chemical', '-', (241, 250))	('NDST2', 'Gene', (43, 48))	('2-O', 'Chemical', 'MESH:C030514', (255, 258))	('sulfation', 'biological_process', 'GO:0051923', ('73', '82'))	('mice', 'Species', '10090', (17, 21))	('NDST2', 'Gene', '17423', (43, 48))	('HS N-sulfation', 'MPA', (180, 194))	('mice', 'Species', '10090', (145, 149))	('HS', 'Chemical', 'MESH:D006497', (180, 182))	('N', 'Chemical', 'MESH:D009584', (183, 184))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('C5 epimerase', 'Enzyme', (163, 175))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('increased', 'PosReg', (198, 207))	('sulfation', 'Chemical', '-', (259, 268))	('6-O', 'Chemical', '-', (237, 240))	('sulfation', 'biological_process', 'GO:0051923', ('241', '250'))
125678	24392351	Moreover, upon SULF-2 knockdown, SULF-1 is able to compensate its effect, while double knockouts showed synergistic co-operativity, resulting in a supraadditive effect and increased amount of 6-O disaccharides.	('amount of 6-O disaccharides', 'MPA', (182, 209))	('SULF-1', 'Gene', '23213', (33, 39))	('increased', 'PosReg', (172, 181))	('SULF-1', 'Gene', (33, 39))	('SULF-2', 'Gene', '55959', (15, 21))	('supraadditive effect', 'MPA', (147, 167))	('knockdown', 'Var', (22, 31))	('6-O disaccharides', 'Chemical', '-', (192, 209))	('SULF-2', 'Gene', (15, 21))
125682	24392351	Thus changes in the expression of one gene will affect the whole HS biosynthetic machinery of the cell.	('changes', 'Var', (5, 12))	('affect', 'Reg', (48, 54))	('whole HS biosynthetic machinery of the cell', 'MPA', (59, 102))	('HS', 'Chemical', 'MESH:D006497', (65, 67))
125705	24392351	Furthermore, modulation of syndecan-1 affects the biological behavior of mesenchymal tumor cells and this involves genes regulating cell growth, cell cycle progression, adhesion, migration, and extracellular matrix organization; orchestrated in a complex network of signaling pathways.	('syndecan-1', 'Gene', '6382', (27, 37))	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('cell growth', 'CPA', (132, 143))	('mesenchymal tumor', 'Disease', (73, 90))	('cell growth', 'biological_process', 'GO:0016049', ('132', '143'))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('194', '227'))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (73, 90))	('cell cycle', 'CPA', (145, 155))	('syndecan-1', 'Gene', (27, 37))	('signaling', 'biological_process', 'GO:0023052', ('266', '275'))	('adhesion', 'CPA', (169, 177))	('affects', 'Reg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('modulation', 'Var', (13, 23))	('migration', 'CPA', (179, 188))	('syndecan', 'molecular_function', 'GO:0015023', ('27', '35'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('194', '214'))
125708	24392351	Thus, in tumors with elevated syndecan-1 level such as multiple myeloma or breast adenocarcinoma, applicable approaches comprise anti-syndecan-1 antibodies, knockdown of syndecan-1, competitive inhibitors or anti-angiogenic agents.	('multiple myeloma', 'Disease', 'MESH:D009101', (55, 71))	('syndecan-1', 'Gene', (30, 40))	('syndecan-1', 'Gene', '6382', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (75, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('multiple myeloma', 'Disease', (55, 71))	('breast adenocarcinoma', 'Disease', (75, 96))	('syndecan', 'molecular_function', 'GO:0015023', ('170', '178'))	('syndecan-1', 'Gene', (170, 180))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (75, 96))	('syndecan', 'molecular_function', 'GO:0015023', ('134', '142'))	('syndecan-1', 'Gene', '6382', (170, 180))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('syndecan-1', 'Gene', (134, 144))	('multiple myeloma', 'Phenotype', 'HP:0006775', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('knockdown', 'Var', (157, 166))	('syndecan-1', 'Gene', '6382', (134, 144))	('tumors', 'Disease', (9, 15))	('syndecan', 'molecular_function', 'GO:0015023', ('30', '38'))
125735	24137394	An epidermal growth factor receptor (EGFR) activating mutation was detected in the cytological examination (deletion in exon 19).	('deletion in exon', 'Var', (108, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'Gene', (37, 41))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('3', '26'))	('epidermal growth factor receptor', 'Gene', '1956', (3, 35))	('EGFR', 'Gene', '1956', (37, 41))	('activating', 'PosReg', (43, 53))	('epidermal growth factor receptor', 'Gene', (3, 35))
125746	24137394	A double mutation was detected consisting of an activating mutation (exon 19 deletion) and an acquired resistance mutation (exon 20 T790M).	('T790M', 'Var', (132, 137))	('activating', 'PosReg', (48, 58))	('T790M', 'Mutation', 'rs121434569', (132, 137))	('exon', 'Var', (69, 73))
125787	24137394	EGFR mutations were identified involving a mutation in exon 18, G719S.	('EGFR', 'Gene', (0, 4))	('G719S', 'Var', (64, 69))	('G719S', 'Mutation', 'rs28929495', (64, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
125808	24137394	In the present study, using a cytological examination, the patient from Case 1 was identified to harbor an EGFR-activating mutation (deletion in exon 19).	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', '1956', (107, 111))	('patient', 'Species', '9606', (59, 66))	('EGFR', 'Gene', (107, 111))	('deletion in exon', 'Var', (133, 149))
125809	24137394	Currently, there is no published evidence with regard to the frequency of EGFR-activating mutations in patients with lung adenocarcinoma and secondary PC.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('secondary PC', 'Disease', (141, 153))	('mutations', 'Var', (90, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('EGFR', 'Gene', '1956', (74, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('patients', 'Species', '9606', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('EGFR', 'Gene', (74, 78))	('lung adenocarcinoma', 'Disease', (117, 136))
125810	24137394	In a multivariate analysis of the incidence of EGFR mutations, including the presence or absence of brain or bone metastases, Rosell et al identified no association between the prognosis and the location of the metastasis.	('mutations', 'Var', (52, 61))	('metastases', 'Disease', (114, 124))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
125811	24137394	In this study, we have presented the first case to be published in the literature that describes a primary lung adenocarcinoma with peritoneal metastasis and an EGFR mutation (deletion in exon 19) (Case 1).	('EGFR', 'Gene', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('primary lung adenocarcinoma', 'Disease', (99, 126))	('deletion in exon 19', 'Var', (176, 195))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 126))	('EGFR', 'Gene', '1956', (161, 165))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('161', '165'))
125812	24137394	In patients with advanced non-small cell lung cancer, activating mutations in the EGFR gene confer hypersensitivity to the tyrosine kinase inhibitors, gefitinib and erlotinib.	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (26, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (26, 52))	('gefitinib', 'Chemical', 'MESH:D000077156', (151, 160))	('hypersensitivity', 'biological_process', 'GO:0002524', ('99', '115'))	('activating mutations', 'Var', (54, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('non-small cell lung cancer', 'Disease', (26, 52))	('hypersensitivity to the', 'Disease', (99, 122))	('patients', 'Species', '9606', (3, 11))	('erlotinib', 'Chemical', 'MESH:D000069347', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (30, 52))	('EGFR', 'Gene', '1956', (82, 86))	('hypersensitivity to the', 'Disease', 'MESH:D004342', (99, 122))
125814	24137394	The patient then presented with a peritoneal progression and a second biopsy was planned to rule out acquired resistant EGFR mutations.	('mutations', 'Var', (125, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('peritoneal progression', 'CPA', (34, 56))	('patient', 'Species', '9606', (4, 11))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (120, 124))
125815	24137394	A double mutation was detected, consisting of an activating mutation (exon 19 deletion) and an acquired resistance mutation (exon 20 T790M).	('T790M', 'Mutation', 'rs121434569', (133, 138))	('T790M', 'Var', (133, 138))	('activating', 'PosReg', (49, 59))
125817	24137394	Case 4 also involved an EGFR mutation in exon 18, but the patient responded poorly to anti-EGFR.	('EGFR', 'Gene', '1956', (24, 28))	('mutation', 'Var', (29, 37))	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (24, 28))	('patient', 'Species', '9606', (58, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('involved', 'Reg', (12, 20))	('EGFR', 'Gene', '1956', (91, 95))
125818	24137394	Su et al have published a lung cancer and PC study in which four patients presented with EGFR mutations and were treated with the EGFR tyrosine kinase inhibitor, gefitinib.	('presented', 'Reg', (74, 83))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutations', 'Var', (94, 103))	('gefitinib', 'Chemical', 'MESH:D000077156', (162, 171))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('144', '160'))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
125820	24137394	Therefore, according to these data, activating EGFR mutations in lung carcinoma, even in cases with peritoneal disease, are considered positive predictors of anti-EGFR therapy.	('mutations', 'Var', (52, 61))	('lung carcinoma', 'Disease', (65, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('EGFR', 'Gene', (163, 167))	('peritoneal disease', 'Disease', 'MESH:D010532', (100, 118))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('peritoneal disease', 'Disease', (100, 118))	('lung carcinoma', 'Disease', 'MESH:D008175', (65, 79))	('activating', 'PosReg', (36, 46))	('EGFR', 'Gene', (47, 51))
125848	19707441	The superior activity of ranpirnase on tumor cells, compared with normal cells, has been explained molecularly by an elegant in vitro study by Iordanov et al (2000b), in which the authors investigated whether ranpirnase activates two signal-transduction pathways commonly stimulated by conventional chemo- and radio-therapy, ie, the stress-activated protein kinase (SAPK) and the nuclear factor-kB (NFkB) pathways.	('signal-transduction', 'biological_process', 'GO:0007165', ('234', '253'))	('signal-transduction pathways', 'Pathway', (234, 262))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('ranpirnase', 'Var', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('350', '357'))	('activity', 'MPA', (13, 21))	('tumor', 'Disease', (39, 44))	('SAPK', 'molecular_function', 'GO:0004707', ('366', '370'))	('activates', 'PosReg', (220, 229))
125849	19707441	Ranpirnase proved to be a potent activator of SAPK1 (JNK-1 and -2) and SAPK2 (p38 MAP kinase), but not NFkB; using explanted fibroblasts from mice containing targeted disruption of both jnk-1 and -2 alleles, the authors found that JNKs are important mediators of ranpirnase-induced cytotoxicity.	('JNK-1 and -2', 'Gene', '26419;26420', (53, 65))	('jnk-1 and -2', 'Gene', '26419;26420', (186, 198))	('SAPK1', 'molecular_function', 'GO:0004705', ('46', '51'))	('JNK', 'molecular_function', 'GO:0004705', ('53', '56'))	('disruption', 'Var', (167, 177))	('cytotoxicity', 'Disease', 'MESH:D064420', (282, 294))	('jnk', 'molecular_function', 'GO:0004705', ('186', '189'))	('mice', 'Species', '10090', (142, 146))	('p38', 'Gene', '26416', (78, 81))	('SAPK1', 'Gene', '26419', (46, 51))	('p38', 'Gene', (78, 81))	('SAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('SAPK2', 'Gene', (71, 76))	('SAPK2', 'Gene', '19094', (71, 76))	('cytotoxicity', 'Disease', (282, 294))	('SAPK1', 'Gene', (46, 51))	('MAP', 'molecular_function', 'GO:0004239', ('82', '85'))
125990	27549627	We demonstrate that long and short mesotheliomagenic CNT-7 injected in the peritoneal cavity of rats induced, like asbestos, an early and selective accumulation of monocytic cells (CD11b/cint and His48hi) which possess the ability to suppress polyclonal activation of T lymphocytes and correspond to M-MDSC.	('suppress polyclonal activation of T lymphocytes', 'Phenotype', 'HP:0005419', (234, 281))	('mesothelioma', 'Disease', (35, 47))	('polyclonal', 'MPA', (243, 253))	('His48hi', 'Var', (196, 203))	('T lymphocytes', 'CPA', (268, 281))	('asbestos', 'Chemical', 'MESH:D001194', (115, 123))	('rats', 'Species', '10116', (96, 100))	('CNT-7', 'Gene', (53, 58))	('rat', 'Species', '10116', (96, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('His48', 'Chemical', '-', (196, 201))	('suppress', 'NegReg', (234, 242))	('rat', 'Species', '10116', (10, 13))	('CD11b/cint', 'Var', (181, 191))
126021	27549627	Short CNT-7 also induced mesotheliomas although to a lesser extent than the long ones (Fig.	('mesotheliomas', 'Disease', 'MESH:D008654', (25, 38))	('mesotheliomas', 'Disease', (25, 38))	('Short', 'Var', (0, 5))	('induced', 'Reg', (17, 24))	('CNT-7', 'Gene', (6, 11))
126033	27549627	In contrast, mesotheliomas were not associated with an increased proportion of neutrophils (CD11b/cint and His48int) (Fig.	('mesotheliomas', 'Disease', 'MESH:D008654', (13, 26))	('mesotheliomas', 'Disease', (13, 26))	('CD11b/cint', 'Var', (92, 102))	('His48int', 'Var', (107, 115))	('His48int', 'Chemical', '-', (107, 115))
126034	27549627	1d) and macrophages (CD11b/chigh and His48int) (Fig.	('His48int', 'Chemical', '-', (37, 45))	('His48int', 'Var', (37, 45))	('CD11b/chigh', 'Var', (21, 32))
126052	27549627	We found that while the proportions of monocytic and neutrophilic cells were increased after CNT-7 and asbestos injections (Additional file 1: Figure S5 A-C), these cells did not possess a significant and persistent immunosuppressive activity (Additional file 1: Figure S5 D-G).	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('CNT-7', 'Gene', (93, 98))	('injections', 'Var', (112, 122))	('increased', 'PosReg', (77, 86))
126056	27549627	We further evaluated the specificity of the early M-MDSC accumulation by comparing their influx at early time points (days 1 and 7) after a single injection of different agents inducing mesotheliomas (CNT-7, asbestos, 2 mg) or not (silica 2 mg, LPS dose 5 mug) in Wistar rats.	('mug', 'molecular_function', 'GO:0043739', ('256', '259'))	('CNT-7', 'Var', (201, 206))	('mesotheliomas', 'Disease', 'MESH:D008654', (186, 199))	('mesotheliomas', 'Disease', (186, 199))	('LPS', 'Disease', (245, 248))	('silica', 'Chemical', 'MESH:D012822', (232, 238))	('asbestos', 'Chemical', 'MESH:D001194', (208, 216))	('LPS', 'Disease', 'MESH:C536528', (245, 248))	('inducing', 'Reg', (177, 185))	('Wistar rats', 'Species', '10116', (264, 275))
126081	27549627	It remains, however, to determine whether regulatory Rp-1+ PMN-MDSC infiltrate mesotheliomas in long-term studies with CNT-treated rats as proposed in other models.	('mesotheliomas', 'Disease', 'MESH:D008654', (79, 92))	('rat', 'Species', '10116', (131, 134))	('PMN', 'biological_process', 'GO:0034727', ('59', '62'))	('mesotheliomas', 'Disease', (79, 92))	('rat', 'Species', '10116', (74, 77))	('infiltrate', 'Reg', (68, 78))	('Rp-1+ PMN-MDSC', 'Var', (53, 67))	('rats', 'Species', '10116', (131, 135))
126085	27549627	Early in the neoplastic process, neutrophils trigger genomic instability, produce a favorable environment for tumor growth, and promote angiogenesis.	('neoplastic process', 'Phenotype', 'HP:0002664', (13, 31))	('genomic instability', 'CPA', (53, 72))	('tumor', 'Disease', (110, 115))	('angiogenesis', 'CPA', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('angiogenesis', 'biological_process', 'GO:0001525', ('136', '148'))	('promote', 'PosReg', (128, 135))	('neutrophils', 'Var', (33, 44))	('trigger', 'Reg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
126110	27549627	The experiment was terminated after 12 months when the majority of the animals injected with CNT-7 or short CNT-7 had developed tumors.	('CNT-7', 'Gene', (93, 98))	('short CNT-7', 'Var', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
126122	27549627	Mouse peritoneal cells were stained by the following antibodies: CD45-PerCp Cy5.5 (clone 30-F11), CD11b-BV 421 (clone M1/70), Ly6G-FITC (clone 1A8) from BD Biosciences (Erembodegem, Belgium), CCR2-PE (clone 475301) from R&D Systems and isotype controls (clone R35-95, A95-1) from BD Biosciences.	('Ly6G', 'Gene', '546644', (126, 130))	('Erembodegem', 'Disease', 'None', (169, 180))	('FITC', 'Chemical', 'MESH:D016650', (131, 135))	('M1/70', 'Gene', (118, 123))	('Erembodegem', 'Disease', (169, 180))	('CD11b-BV 421', 'Var', (98, 110))	('CCR', 'molecular_function', 'GO:0043880', ('192', '195'))	('Mouse', 'Species', '10090', (0, 5))	('Ly6G', 'Gene', (126, 130))	('M1/70', 'Gene', '22238', (118, 123))
126129	27549627	Splenocytes were cultured in the presence of increasing ratios of rat or mouse purified peritoneal cells and stimulated with anti-CD3 (anti-rat clone G4.18, anti-mouse clone 145-2C11, 5 mug/ml, BD Biosciences) and anti-CD28 (anti-rat clone JJ319, anti-mouse clone 37.51, 2 mug/ml, BD Biosciences) antibodies.	('CD3', 'Gene', (130, 133))	('mouse', 'Species', '10090', (252, 257))	('rat', 'Species', '10116', (56, 59))	('mouse', 'Species', '10090', (162, 167))	('CD3', 'Gene', '28134', (130, 133))	('mug', 'molecular_function', 'GO:0043739', ('273', '276'))	('mug', 'molecular_function', 'GO:0043739', ('186', '189'))	('mouse', 'Species', '10090', (73, 78))	('anti-CD28', 'Var', (214, 223))	('JJ319', 'CellLine', 'CVCL:D605', (240, 245))	('rat', 'Species', '10116', (140, 143))	('rat', 'Species', '10116', (230, 233))	('rat', 'Species', '10116', (66, 69))
126133	21998702	H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects.	('H258', 'Var', (9, 13))	('H342', 'Var', (0, 4))	('H342', 'Chemical', 'MESH:C017807', (0, 4))	('H258', 'Chemical', 'MESH:D006690', (9, 13))
126134	21998702	For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies.	('H342', 'Var', (72, 76))	('H342', 'Chemical', 'MESH:C017807', (72, 76))	('transgene', 'Protein', (97, 106))	('H258', 'Chemical', 'MESH:D006690', (81, 85))	('induce', 'Reg', (90, 96))	('H342', 'Var', (13, 17))	('H258', 'Chemical', 'MESH:D006690', (27, 31))	('H342', 'Chemical', 'MESH:C017807', (13, 17))	('H258', 'Var', (81, 85))	('overexpression', 'PosReg', (107, 121))
126137	21998702	H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins.	('caspase-3', 'Gene', '836', (104, 113))	('cleavage', 'MPA', (172, 180))	('mitochondrial translocation', 'biological_process', 'GO:0030150', ('139', '166'))	('caspase-3', 'Gene', (104, 113))	('activation', 'PosReg', (114, 124))	('apoptosis', 'CPA', (13, 22))	('cytochrome c', 'molecular_function', 'GO:0045155', ('126', '138'))	('mitochondrial translocation', 'biological_process', 'GO:0006628', ('139', '166'))	('H342', 'Chemical', 'MESH:C017807', (0, 4))	('cytochrome c', 'Gene', '54205', (126, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('mitochondrial translocation', 'biological_process', 'GO:0006626', ('139', '166'))	('apoptosis-associated', 'Protein', (184, 204))	('cytochrome c', 'molecular_function', 'GO:0009461', ('126', '138'))	('H342-induced', 'Var', (0, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('cytochrome c', 'Gene', (126, 138))
126139	21998702	Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects.	('H342', 'Chemical', 'MESH:C017807', (65, 69))	('gene expression', 'biological_process', 'GO:0010467', ('20', '35'))	('H258', 'Var', (56, 60))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('H258', 'Chemical', 'MESH:D006690', (56, 60))	('H342', 'Var', (65, 69))
126147	21998702	Initial studies show that H258 possesses activity against L1210 murine leukemia and several promising experiments in solid tumors have led to the use of this compound in phase I clinical trials in human.	('leukemia', 'Disease', (71, 79))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('H258', 'Chemical', 'MESH:D006690', (26, 30))	('murine', 'Species', '10090', (64, 70))	('solid tumors', 'Disease', (117, 129))	('L1210', 'Var', (58, 63))	('H258', 'Gene', (26, 30))	('human', 'Species', '9606', (197, 202))	('solid tumors', 'Disease', 'MESH:D009369', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))
126149	21998702	Further data demonstrate that H342, but not H258, is a potent apoptotic inducer of different types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('H258', 'Chemical', 'MESH:D006690', (44, 48))	('apoptotic', 'CPA', (62, 71))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('H342', 'Var', (30, 34))	('H342', 'Chemical', 'MESH:C017807', (30, 34))
126150	21998702	Even so, H342 and H258 share some similar biological effects due to their similar thermodynamic properties.	('H342', 'Var', (9, 13))	('H258', 'Chemical', 'MESH:D006690', (18, 22))	('H342', 'Chemical', 'MESH:C017807', (9, 13))	('H258', 'Var', (18, 22))
126151	21998702	For example, H342 and H258 poison topoisomerase I, inhibit other DNA processing proteins in in vitro studies, and affect the cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('125', '135'))	('poison', 'NegReg', (27, 33))	('cell cycle', 'CPA', (125, 135))	('affect', 'Reg', (114, 120))	('H258', 'Chemical', 'MESH:D006690', (22, 26))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('topoisomerase', 'molecular_function', 'GO:0003917', ('34', '47'))	('H342', 'Var', (13, 17))	('H258', 'Var', (22, 26))	('H342', 'Chemical', 'MESH:C017807', (13, 17))	('topoisomerase', 'molecular_function', 'GO:0003918', ('34', '47'))	('DNA processing', 'Protein', (65, 79))	('inhibit', 'NegReg', (51, 58))	('topoisomerase I', 'Enzyme', (34, 49))
126153	21998702	Intriguingly, both H258 and H342 can enhance transgene overexpression in in vitro studies.	('H342', 'Var', (28, 32))	('H258', 'Chemical', 'MESH:D006690', (19, 23))	('H342', 'Chemical', 'MESH:C017807', (28, 32))	('H258', 'Var', (19, 23))	('transgene overexpression', 'MPA', (45, 69))	('enhance', 'PosReg', (37, 44))
126156	21998702	Large numbers of protein-DNA cross-links and DNA strand breaks can be detected in H342-, but not, H258-treated cells.	('protein-DNA cross-links', 'Protein', (17, 40))	('H342-', 'Var', (82, 87))	('H258', 'Chemical', 'MESH:D006690', (98, 102))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('H342', 'Chemical', 'MESH:C017807', (82, 86))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))
126157	21998702	Early studies revealed that H342 causes rapid cell death once sufficient dye enters the nucleus of a cell.	('H342', 'Var', (28, 32))	('cell death', 'CPA', (46, 56))	('H342', 'Chemical', 'MESH:C017807', (28, 32))	('nucleus', 'cellular_component', 'GO:0005634', ('88', '95'))	('cell death', 'biological_process', 'GO:0008219', ('46', '56'))
126158	21998702	But, our later studies show that the key difference of intracellular effects between the two dyes is that H342, but not H258, is a potent apoptotic inducer in different types of cancer cell lines and species.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('H258', 'Chemical', 'MESH:D006690', (120, 124))	('intracellular', 'cellular_component', 'GO:0005622', ('55', '68'))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('apoptotic', 'CPA', (138, 147))	('H342', 'Var', (106, 110))	('H342', 'Chemical', 'MESH:C017807', (106, 110))
126160	21998702	In chemical structure, H342 has a 4-ethyoxy substitution on the phenyl ring that its parent compound H258 does not, thus enhancing its membrane permeability.	('enhancing', 'PosReg', (121, 130))	('H342', 'Var', (23, 27))	('membrane', 'cellular_component', 'GO:0016020', ('135', '143'))	('H342', 'Chemical', 'MESH:C017807', (23, 27))	('membrane permeability', 'MPA', (135, 156))	('H258', 'Chemical', 'MESH:D006690', (101, 105))
126164	21998702	Our results show differential global gene expression profiles with individually unique gene expression signatures induced by H258 and H342.	('gene expression', 'biological_process', 'GO:0010467', ('87', '102'))	('H258', 'Var', (125, 129))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('H342', 'Var', (134, 138))	('H342', 'Chemical', 'MESH:C017807', (134, 138))	('H258', 'Chemical', 'MESH:D006690', (125, 129))
126168	21998702	Therefore, the present study has highlighted the new insights into molecular and pharmacokinetic mechanisms that cause diverse biological effects of Hoechst 33342 and Hoechst 33258, which can aid in the discovery of more advanced and efficient cancer treatments.	('Hoechst', 'Var', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (149, 162))	('Hoechst 33258', 'Chemical', 'MESH:D006690', (167, 180))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
126169	21998702	To test whether or not H342 may trigger cell death in malignant pleural mesothelioma (MPM) cells, seven MPM cell lines have been employed in this study.	('cell death', 'biological_process', 'GO:0008219', ('40', '50'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (64, 84))	('malignant pleural mesothelioma', 'Disease', (54, 84))	('H342', 'Var', (23, 27))	('H342', 'Chemical', 'MESH:C017807', (23, 27))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (54, 84))
126170	21998702	Cell viability results indicate that H342 significantly induces cell death in all seven mesothelioma cell lines in dose-dependent manners by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Figure 1A).	('3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (146, 206))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('cell death', 'CPA', (64, 74))	('H342', 'Var', (37, 41))	('MTT', 'Chemical', 'MESH:C070243', (141, 144))	('induces', 'Reg', (56, 63))	('H342', 'Chemical', 'MESH:C017807', (37, 41))	('mesothelioma', 'Disease', (88, 100))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))
126171	21998702	To determine the nature of this death in mesothelioma cells induced by H342, we have used fluorescent staining assay, Western blot, and caspase-3 activity assay to test cell morphological changes, caspase-3 activity, and expression of apoptosis-associated proteins during the cell death of H2373 mesothelioma cells treated by H342 for different times.	('caspase-3', 'Gene', '836', (136, 145))	('activity', 'MPA', (207, 215))	('caspase-3', 'Gene', (136, 145))	('cell death', 'biological_process', 'GO:0008219', ('276', '286'))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('136', '154'))	('H2373', 'CellLine', 'CVCL:A533', (290, 295))	('mesothelioma', 'Disease', (41, 53))	('mesothelioma', 'Disease', (296, 308))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (296, 308))	('H342', 'Chemical', 'MESH:C017807', (326, 330))	('caspase-3', 'Gene', '836', (197, 206))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('197', '215'))	('caspase-3', 'Gene', (197, 206))	('H342', 'Chemical', 'MESH:C017807', (71, 75))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('136', '154'))	('test', 'Reg', (164, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('H342', 'Var', (71, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('197', '215'))
126173	21998702	The apoptotic nature of this death has been further confirmed by measurement of caspase activation, translocation of cytochrome c, and levels of apoptosis-associated proteins in H2373 cells treated for different intervals with 36 microM H342.	('cytochrome c', 'Gene', (117, 129))	('H342', 'Var', (237, 241))	('H342', 'Chemical', 'MESH:C017807', (237, 241))	('cytochrome c', 'molecular_function', 'GO:0009461', ('117', '129'))	('H2373', 'CellLine', 'CVCL:A533', (178, 183))	('levels of apoptosis-associated', 'MPA', (135, 165))	('cytochrome c', 'Gene', '54205', (117, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('117', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('caspase activation', 'biological_process', 'GO:0006919', ('80', '98'))	('caspase', 'Protein', (80, 87))
126176	21998702	To determine the pharmacokinetic relationship between H342 and H258, we postulate that H342 and H258 share the same transport system due to their similarities in chemical structure.	('H342', 'Chemical', 'MESH:C017807', (87, 91))	('transport', 'biological_process', 'GO:0006810', ('116', '125'))	('H342', 'Chemical', 'MESH:C017807', (54, 58))	('H258', 'Chemical', 'MESH:D006690', (96, 100))	('H258', 'Chemical', 'MESH:D006690', (63, 67))	('H342', 'Var', (87, 91))	('H258', 'Var', (96, 100))
126179	21998702	In contrast, cell viability, as determined by MTT assay, reveals that H258 decreases H342-induced apoptosis by 33% to 57% in a dose-dependent manner (Figure 4A).	('H258', 'Var', (70, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('H342-induced', 'Gene', (85, 97))	('H258', 'Chemical', 'MESH:D006690', (70, 74))	('H342', 'Chemical', 'MESH:C017807', (85, 89))	('decreases', 'NegReg', (75, 84))	('MTT', 'Chemical', 'MESH:C070243', (46, 49))
126180	21998702	Morphological data indicate combined treatment of H342 and H258 delays cell morphological changes at least for two hours when compared to H342 treatment alone or H258-pretreated group, suggesting H258 effectively delays the entry of H342 into cells (Figure 3).	('delays', 'NegReg', (64, 70))	('H342', 'Chemical', 'MESH:C017807', (233, 237))	('delays', 'NegReg', (213, 219))	('H342', 'Chemical', 'MESH:C017807', (138, 142))	('H342', 'Chemical', 'MESH:C017807', (50, 54))	('H258', 'Chemical', 'MESH:D006690', (196, 200))	('cell morphological changes', 'CPA', (71, 97))	('H258', 'Chemical', 'MESH:D006690', (59, 63))	('H258', 'Var', (196, 200))	('H258', 'Chemical', 'MESH:D006690', (162, 166))	('entry', 'MPA', (224, 229))
126190	21998702	We have analyzed a total of 4 genes: 2 genes that are up-regulated in H342-treated H2373 mesothelioma cells (Fos, JMJD7) and 2 genes that are down-regulated (SNIP1, SMAD6) (Figure 6).	('mesothelioma', 'Disease', (89, 101))	('JMJD7', 'Gene', '100137047', (114, 119))	('H342', 'Chemical', 'MESH:C017807', (70, 74))	('SMAD6', 'Gene', '4091', (165, 170))	('SNIP1', 'Gene', (158, 163))	('H2373', 'CellLine', 'CVCL:A533', (83, 88))	('H342-treated', 'Var', (70, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('up-regulated', 'PosReg', (54, 66))	('SNIP1', 'Gene', '79753', (158, 163))	('Fos', 'Gene', '2353', (109, 112))	('SMAD6', 'Gene', (165, 170))	('JMJD7', 'Gene', (114, 119))	('Fos', 'Gene', (109, 112))
126193	21998702	Figure 7A and 7B show the downregulated gene expression of CTCF, TFAM and COX19 induced by 36 microM H342 treatment for 3 hour, indicating the potential molecular basis of chromatin and mitochondria dysfunction in H342-treated cells.	('downregulated', 'NegReg', (26, 39))	('H342', 'Var', (101, 105))	('COX19', 'Gene', '90639', (74, 79))	('gene expression', 'MPA', (40, 55))	('CTCF', 'Gene', (59, 63))	('H342', 'Chemical', 'MESH:C017807', (101, 105))	('gene expression', 'biological_process', 'GO:0010467', ('40', '55'))	('TFAM', 'Gene', '7019', (65, 69))	('COX19', 'Gene', (74, 79))	('CTCF', 'Gene', '10664', (59, 63))	('H342', 'Chemical', 'MESH:C017807', (214, 218))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (186, 210))	('TFAM', 'Gene', (65, 69))	('mitochondria dysfunction', 'Disease', (186, 210))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('mitochondria', 'cellular_component', 'GO:0005739', ('186', '198'))
126194	21998702	Figure 7C is a schematic diagram of H342-induced mitochondria dysfunction through SNIP1 and COX19.	('H342-induced', 'Var', (36, 48))	('SNIP1', 'Gene', (82, 87))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (49, 73))	('COX19', 'Gene', '90639', (92, 97))	('mitochondria dysfunction', 'Disease', (49, 73))	('SNIP1', 'Gene', '79753', (82, 87))	('H342', 'Chemical', 'MESH:C017807', (36, 40))	('mitochondria', 'cellular_component', 'GO:0005739', ('49', '61'))	('COX19', 'Gene', (92, 97))
126202	21998702	In contrast to the H258-downregulated gene expression profile, H342 mainly targets nuclear processes, in particular, transcription regulation (30%).	('H342', 'Chemical', 'MESH:C017807', (63, 67))	('H258', 'Chemical', 'MESH:D006690', (19, 23))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('nuclear processes', 'MPA', (83, 100))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('H342', 'Var', (63, 67))	('transcription regulation', 'MPA', (117, 141))
126204	21998702	H258-upregulated and H342-downregulated genes that involve transcription regulation are the signatures of differential global gene expression profiles induced by H342 and H258.	('H342', 'Var', (162, 166))	('H342', 'Chemical', 'MESH:C017807', (162, 166))	('transcription', 'biological_process', 'GO:0006351', ('59', '72'))	('H258', 'Chemical', 'MESH:D006690', (171, 175))	('H258', 'Chemical', 'MESH:D006690', (0, 4))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('H258', 'Var', (171, 175))	('H258-upregulated', 'PosReg', (0, 16))	('H342', 'Chemical', 'MESH:C017807', (21, 25))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))
126207	21998702	Of the 10 enriched pathways for H342-downregulated genes (Table 2), 9, except for the vitamin D receptor, overlap with the pathways for H258-upregulated genes.	('vitamin D receptor', 'Gene', (86, 104))	('H342-downregulated', 'Var', (32, 50))	('H258', 'Chemical', 'MESH:D006690', (136, 140))	('H342', 'Chemical', 'MESH:C017807', (32, 36))	('vitamin D receptor', 'Gene', '7421', (86, 104))
126217	21998702	Degradation of PARP impairs the DNA repair process, whereas c-IAP1, c-IAP2 and survivin downregulation disarms their antiapoptotic capacity, thus enhancing the apoptosis process.	('DNA repair process', 'CPA', (32, 50))	('survivin', 'Protein', (79, 87))	('c-IAP2', 'Gene', '330', (68, 74))	('Degradation', 'Var', (0, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('PARP', 'Gene', '142', (15, 19))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('enhancing', 'PosReg', (146, 155))	('apoptosis process', 'CPA', (160, 177))	('c-IAP1', 'Gene', (60, 66))	('impairs', 'NegReg', (20, 27))	('antiapoptotic capacity', 'MPA', (117, 139))	('downregulation disarms', 'NegReg', (88, 110))	('c-IAP1', 'Gene', '329', (60, 66))	('DNA repair', 'biological_process', 'GO:0006281', ('32', '42'))	('PARP', 'Gene', (15, 19))	('c-IAP2', 'Gene', (68, 74))
126220	21998702	Overall, H342-induced apoptosis is an intrinsic pathway-dependent apoptosis that is characterized by not only a morphological hallmark, but also the key biochemical features of apoptosis, including mitochondrial membrane potential, externalization of membrane phophoatidylserine, DNA fragmentation, activation of caspase 3 associated with cytochrome c release (Figure 1C), and cleaved caspase 3 substrates (Figure 1D).	('membrane', 'cellular_component', 'GO:0016020', ('251', '259'))	('activation', 'PosReg', (299, 309))	('caspase 3', 'Gene', (385, 394))	('externalization of membrane phophoatidylserine', 'MPA', (232, 278))	('caspase 3', 'Gene', '836', (385, 394))	('cytochrome c', 'Gene', (339, 351))	('cytochrome c', 'molecular_function', 'GO:0009461', ('339', '351'))	('H342', 'Chemical', 'MESH:C017807', (9, 13))	('mitochondrial membrane potential', 'MPA', (198, 230))	('DNA', 'cellular_component', 'GO:0005574', ('280', '283'))	('DNA fragmentation', 'MPA', (280, 297))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('198', '220'))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('caspase 3', 'Gene', (313, 322))	('H342-induced', 'Var', (9, 21))	('caspase 3', 'Gene', '836', (313, 322))	('cytochrome c', 'Gene', '54205', (339, 351))	('apoptosis', 'Disease', (22, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('339', '351'))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('280', '297'))
126221	21998702	Moreover, H342-induced apoptosis is also associated with dysfunctions of Lactate oxidation and fatty acid anabolism.	('Lactate oxidation', 'biological_process', 'GO:0019516', ('73', '90'))	('H342', 'Chemical', 'MESH:C017807', (10, 14))	('fatty acid anabolism', 'biological_process', 'GO:0006633', ('95', '115'))	('associated', 'Reg', (41, 51))	('apoptosis', 'CPA', (23, 32))	('dysfunctions of Lactate oxidation', 'Disease', 'MESH:D004194', (57, 90))	('dysfunctions of Lactate oxidation', 'Disease', (57, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('fatty acid anabolism', 'MPA', (95, 115))	('fatty acid', 'Chemical', 'MESH:D005227', (95, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('H342-induced', 'Var', (10, 22))
126226	21998702	In the present study, H342 acts as a potent apoptotic inducer in mesothelioma cell lines, which indicates that MBs may hold promise as a novel therapeutic approach for MPM treatment.	('mesothelioma', 'Disease', (65, 77))	('apoptotic', 'CPA', (44, 53))	('MPM', 'Disease', (168, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('H342', 'Var', (22, 26))	('H342', 'Chemical', 'MESH:C017807', (22, 26))
126235	21998702	Antagonism between Hoechst dyes and among Hoechst dyes and other components of the media may imply that there is existence of a mediated transport mechanism involving Hoechst uptake.	('Hoechst uptake', 'MPA', (167, 181))	('Antagonism', 'Var', (0, 10))	('Hoechst', 'Chemical', '-', (19, 26))	('Hoechst dyes', 'Chemical', '-', (42, 54))	('uptake', 'biological_process', 'GO:0098657', ('175', '181'))	('uptake', 'biological_process', 'GO:0098739', ('175', '181'))	('Hoechst', 'Chemical', '-', (167, 174))	('Hoechst', 'Chemical', '-', (42, 49))	('transport', 'biological_process', 'GO:0006810', ('137', '146'))	('Hoechst dyes', 'Chemical', '-', (19, 31))
126241	21998702	Consistent with H342-response gene expression signature, H342-induced apoptosis is not related to de novo synthesis of RNA and proteins, which is associated with rapid degradation of multiple critical proteins such as replication protein A, TATA box binding protein, fatty acid synthase.	('fatty acid synthase', 'Gene', (267, 286))	('synthesis', 'biological_process', 'GO:0009058', ('106', '115'))	('degradation', 'biological_process', 'GO:0009056', ('168', '179'))	('TATA box binding protein', 'Gene', '6908', (241, 265))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('H342-induced', 'Var', (57, 69))	('replication protein A', 'cellular_component', 'GO:0005662', ('218', '239'))	('fatty acid synthase', 'Gene', '2194', (267, 286))	('binding', 'molecular_function', 'GO:0005488', ('250', '257'))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('H342', 'Chemical', 'MESH:C017807', (57, 61))	('TATA box binding protein', 'Gene', (241, 265))	('H342', 'Chemical', 'MESH:C017807', (16, 20))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('apoptosis', 'CPA', (70, 79))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
126244	21998702	Of the 10 enriched pathways for 148 H342-downregulated genes of transcription regulation, 9 (except for the vitamin D receptor) overlap with the pathways for H258-upregulated genes of transcription regulation in enriched pathway analysis of the signatures of these two dyes, demonstrating their sharing similar primary targets.	('vitamin D receptor', 'Gene', (108, 126))	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('H342-downregulated', 'Var', (36, 54))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('H342', 'Chemical', 'MESH:C017807', (36, 40))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('H258', 'Chemical', 'MESH:D006690', (158, 162))	('regulation', 'biological_process', 'GO:0065007', ('198', '208'))	('vitamin D receptor', 'Gene', '7421', (108, 126))
126245	21998702	Since H342-downregulated genes of transcription regulation involve some critical pathways for cell survival and development such as Notch and TGF-beta, etc (Tables 2) H342 like other DNA minor groove binders may be unnecessarily over-targeting many vital genes in the cells, which results in extreme intolerance.	('TGF-beta', 'Gene', '7040', (142, 150))	('TGF-beta', 'Gene', (142, 150))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('results in', 'Reg', (281, 291))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('over-targeting', 'PosReg', (229, 243))	('groove', 'cellular_component', 'GO:0097610', ('193', '199'))	('H342', 'Var', (167, 171))	('H342-downregulated', 'Gene', (6, 24))	('extreme intolerance', 'MPA', (292, 311))	('H342', 'Chemical', 'MESH:C017807', (167, 171))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('H342', 'Chemical', 'MESH:C017807', (6, 10))
126246	21998702	Therefore, choosing some pathways targeted by H342 for pathway-targeted cancer therapy may be a way to minimize cytotoxicity and maximize therapeutic effectiveness of DNA minor groove binders.	('minimize', 'NegReg', (103, 111))	('cytotoxicity', 'Disease', (112, 124))	('H342', 'Var', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('groove', 'cellular_component', 'GO:0097610', ('177', '183'))	('H342', 'Chemical', 'MESH:C017807', (46, 50))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
126352	31360386	Patients who receive either P/D or EPP are also recommended to have a mediastinal node dissection.	('mediastinal node', 'Disease', (70, 86))	('EPP', 'Var', (35, 38))	('Patients', 'Species', '9606', (0, 8))
126363	31360386	We also evaluated the cost of procedures performed during a hospital stay, which included 32.30 video-assisted thoracic surgery (VATS), 32.50 EPP, 34.51 P/D, 33.20 thoracoscopic biopsy, 34.20 thoracoscopic pleural biopsy, and 34.91 thoracentesis.	('P/D', 'Var', (153, 156))	('pleural', 'Disease', (206, 213))	('pleural', 'Disease', 'MESH:D010995', (206, 213))
126446	25608772	Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04).	('CD10', 'molecular_function', 'GO:0004245', ('44', '48'))	('epithelioid tumor', 'Disease', (188, 205))	('epithelioid tumor', 'Disease', 'MESH:D012509', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('positive', 'Var', (35, 43))	('patients', 'Species', '9606', (21, 29))	('patients', 'Species', '9606', (100, 108))	('CD10', 'Gene', '4311', (44, 48))	('CD10', 'Gene', (44, 48))	('patients', 'Species', '9606', (174, 182))	('CD10', 'Gene', (123, 127))	('CD10', 'molecular_function', 'GO:0004245', ('123', '127'))	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (146, 154))	('CD10', 'Gene', '4311', (123, 127))	('shorter', 'NegReg', (78, 85))	('expression', 'Var', (49, 59))
126491	25608772	Among the patients with early-stage disease (stage I-II; n = 46), OS was significantly shorter for patients with positive CD10 expression (n = 21; median OS 16.3 months) than for patients with negative CD10 expression (n = 25; 36.4 months; p = 0.008), although this result was determined from a small number of patients.	('positive', 'Var', (113, 121))	('CD10', 'Gene', (202, 206))	('CD10', 'Gene', '4311', (122, 126))	('patients', 'Species', '9606', (99, 107))	('shorter', 'NegReg', (87, 94))	('patients', 'Species', '9606', (311, 319))	('CD10', 'molecular_function', 'GO:0004245', ('122', '126'))	('CD10', 'molecular_function', 'GO:0004245', ('202', '206'))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (10, 18))	('expression', 'Var', (127, 137))	('CD10', 'Gene', (122, 126))	('CD10', 'Gene', '4311', (202, 206))
126500	25608772	Among all patients with epithelioid and non-epithelioid mesothelioma (n = 176), OS for patients with positive CD10 expression (n = 90) was significantly shorter (median 9.8 months) than that for patients with negative CD10 expression (n = 86; 16.9 months; p = 0.001) (Fig.	('CD10', 'Gene', (110, 114))	('CD10', 'Gene', '4311', (110, 114))	('CD10', 'molecular_function', 'GO:0004245', ('110', '114'))	('patients', 'Species', '9606', (87, 95))	('non-epithelioid mesothelioma', 'Disease', 'MESH:D008654', (40, 68))	('shorter', 'NegReg', (153, 160))	('CD10', 'Gene', (218, 222))	('patients', 'Species', '9606', (195, 203))	('CD10', 'Gene', '4311', (218, 222))	('CD10', 'molecular_function', 'GO:0004245', ('218', '222'))	('patients', 'Species', '9606', (10, 18))	('positive', 'Var', (101, 109))	('non-epithelioid mesothelioma', 'Disease', (40, 68))
126501	25608772	On multivariate analysis of all patients, positive CD10 expression was an independent factor of prognosis (HR 1.48; p = 0.019) (Table 3).	('CD10', 'Gene', '4311', (51, 55))	('patients', 'Species', '9606', (32, 40))	('positive', 'Var', (42, 50))	('expression', 'MPA', (56, 66))	('CD10', 'molecular_function', 'GO:0004245', ('51', '55'))	('CD10', 'Gene', (51, 55))
126520	25608772	Another potential limitation in this study, which used a tissue microarray, is that CD10-negative tumors might be focally positive if they are stained with whole-tissue blocks; however, when whole-tissue blocks were used in a previous study, the total rate of CD10 positivity was 54 % for malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (289, 311))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('malignant mesothelioma', 'Disease', (289, 311))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('CD10', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('positivity', 'Var', (265, 275))	('CD10', 'molecular_function', 'GO:0004245', ('84', '88'))	('CD10', 'Gene', '4311', (84, 88))	('CD10', 'Gene', (260, 264))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (289, 311))	('CD10', 'molecular_function', 'GO:0004245', ('260', '264'))	('CD10', 'Gene', '4311', (260, 264))
126523	25608772	In malignant pleural mesothelioma, expression of CD10 correlates with aggressive histologic types and high mitotic activity, and is an independent predictor of patient survival.	('CD10', 'Gene', '4311', (49, 53))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (13, 33))	('malignant pleural mesothelioma', 'Disease', (3, 33))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (3, 33))	('CD10', 'molecular_function', 'GO:0004245', ('49', '53'))	('patient', 'Species', '9606', (160, 167))	('expression', 'Var', (35, 45))	('CD10', 'Gene', (49, 53))
126590	22634117	Patients were considered for second CRS HIPEC if they had an initial R0, R1 or R2a resection, had a complete recovery from prior systemic chemotherapy or radiation treatments, were ECOG 0, 1 or 2, had disease considered to be resectable based upon imaging, and had no extra-abdominal disease.	('abdominal disease', 'Disease', 'MESH:D015746', (274, 291))	('abdominal disease', 'Disease', (274, 291))	('CRS', 'Disease', (36, 39))	('CRS', 'Disease', 'MESH:D003398', (36, 39))	('R2a', 'Var', (79, 82))	('Patients', 'Species', '9606', (0, 8))
126591	22634117	Selected patients with R2b and R2c were considered for second procedures if all disease near bowel and bile ducts was considered resectable.	('patients', 'Species', '9606', (9, 17))	('R2b', 'Var', (23, 26))	('bowel', 'Disease', 'MESH:D015212', (93, 98))	('bowel', 'Disease', (93, 98))	('R2c', 'Var', (31, 34))
126600	22634117	Of the 27 patients who had an R0-R1 resection during their first CRS/HIPEC, 16 (59.3%) had an R0-R1 resection during the repeat CRS/HIPEC, 6 (22.2%) had an R2a resection, while 5 (18.7%) had an R2b-R2c resection status.	('CRS', 'Disease', (128, 131))	('CRS', 'Disease', 'MESH:D003398', (65, 68))	('CRS', 'Disease', 'MESH:D003398', (128, 131))	('R0-R1', 'Var', (94, 99))	('patients', 'Species', '9606', (10, 18))	('CRS', 'Disease', (65, 68))
126601	22634117	Of the 25 patients who had an R2a resection during their first CRS/HIPEC, 9 (36%) had an R0-R1 resection during the repeat CRS/HIPEC, 9 (36%) had an R2a resection, while 7 (18.7%) had an R2b-R2c resection status.	('CRS', 'Disease', 'MESH:D003398', (63, 66))	('CRS', 'Disease', (123, 126))	('CRS', 'Disease', 'MESH:D003398', (123, 126))	('patients', 'Species', '9606', (10, 18))	('CRS', 'Disease', (63, 66))	('R2a', 'Var', (30, 33))
126602	22634117	Of the 10 patients who had an R2b-R2c resection during their first CRS/HIPEC, 2 (20%) had an R0-R1 resection during the repeat CRS/HIPEC, 1 (10%) had an R2a resection, while 7 (70%) had an R2b-R2c resection status.	('CRS', 'Disease', 'MESH:D003398', (127, 130))	('R2b-R2c resection', 'Var', (30, 47))	('CRS', 'Disease', (67, 70))	('CRS', 'Disease', 'MESH:D003398', (67, 70))	('CRS', 'Disease', (127, 130))	('patients', 'Species', '9606', (10, 18))
126609	22634117	Patients who had an R0-R1 resection status had a significantly better median survival: 55.7 months compared to 20.3 and 15.5 months, respectively for patients who had an R2a or R2b-R2c, respectively (p=0.027), as shown in Figure 1.	('R2b-R2c', 'Var', (177, 184))	('R0-R1 resection', 'Var', (20, 35))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (150, 158))	('R2a', 'Var', (170, 173))
126621	22634117	Our prior accumulated experience with initial CRS/HIPEC has demonstrated that long-term survival was adversely influenced by increased volume of disease, R2 status of resection, high ECOG, poor nutrition and high grade of the primary tumor.	('R2 status', 'Var', (154, 163))	('tumor', 'Disease', (234, 239))	('CRS', 'Disease', (46, 49))	('high ECOG', 'Var', (178, 187))	('CRS', 'Disease', 'MESH:D003398', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('high grade', 'Var', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
126744	23077450	Thus, our research on patients with mesothelioma confirmed that the nucleotide excision repair (NER) pathway polymorphisms influence platinum-treatment efficacy and toxicity and that ribonucleotide reductase subunit 1 (RRM1) polymorphisms as well as haplotypes are associated with gemcitabine treatment efficacy and toxicity.	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('RRM1', 'Gene', '6240', (219, 223))	('platinum-treatment efficacy', 'CPA', (133, 160))	('NER', 'biological_process', 'GO:0006289', ('96', '99'))	('gemcitabine', 'Chemical', 'MESH:C056507', (281, 292))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('68', '94'))	('toxicity', 'Disease', 'MESH:D064420', (165, 173))	('patients', 'Species', '9606', (22, 30))	('toxicity', 'Disease', 'MESH:D064420', (316, 324))	('RRM1', 'Gene', (219, 223))	('toxicity', 'Disease', (165, 173))	('platinum', 'Chemical', 'MESH:D010984', (133, 141))	('toxicity', 'Disease', (316, 324))	('nucleotide', 'Pathway', (68, 78))	('polymorphisms', 'Var', (109, 122))	('associated', 'Reg', (265, 275))	('influence', 'Reg', (123, 132))	('mesothelioma', 'Disease', (36, 48))	('polymorphisms', 'Var', (225, 238))
126821	33499323	Based on this dataset, we observed that, whilst HAS1 and HAS2 (Figure 8) expression seemed not to be correlated to patients' survival, the HAS3 expression level was negatively correlated to life expectancy in MPM patients (Figure 8): survival rate of patients with high HAS3 expression was lower than of the ones with low expression (p < 0.01), as illustrated in The Cancer Genome Atlas (TCGA dataset).	('HAS3', 'Gene', '3038', (270, 274))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (213, 221))	('survival rate', 'CPA', (234, 247))	('lower', 'NegReg', (290, 295))	('HAS2', 'Gene', (57, 61))	('HAS3', 'Gene', (139, 143))	('Cancer', 'Phenotype', 'HP:0002664', (367, 373))	('MPM', 'Chemical', '-', (209, 212))	('patients', 'Species', '9606', (115, 123))	('HAS3', 'Gene', (270, 274))	('Cancer', 'Disease', (367, 373))	('HAS1', 'Gene', (48, 52))	('HAS2', 'Gene', '3037', (57, 61))	('HAS3', 'Gene', '3038', (139, 143))	('Cancer', 'Disease', 'MESH:D009369', (367, 373))	('expression', 'MPA', (275, 285))	('HAS1', 'Gene', '3036', (48, 52))	('high', 'Var', (265, 269))
126887	33499323	In colabeling experiments, the following antibodies were used together with HABP: alpha-vimentin (1:40), alpha-calnexin (1:1000), alpha-Rab11a (1:1000), alpha-EEA1 (1:200), alpha-LAMP1 (1:50), alpha-TGN (1:100).	('LAMP1', 'Gene', '3916', (179, 184))	('vimentin', 'cellular_component', 'GO:0045098', ('88', '96'))	('calnexin', 'Gene', '821', (111, 119))	('EEA1', 'Gene', '8411', (159, 163))	('HABP', 'Gene', (76, 80))	('1:1000', 'Var', (121, 127))	('vimentin', 'Gene', '7431', (88, 96))	('calnexin', 'Gene', (111, 119))	('TGN', 'cellular_component', 'GO:0005802', ('199', '202'))	('LAMP1', 'Gene', (179, 184))	('HABP', 'Gene', '3026', (76, 80))	('1:40', 'Var', (98, 102))	('vimentin', 'Gene', (88, 96))	('EEA1', 'Gene', (159, 163))	('vimentin', 'cellular_component', 'GO:0045099', ('88', '96'))	('1:1000', 'Var', (144, 150))
126897	33499323	After neutralization of the endogenous peroxidase with 3% v/v H2O2 and Fc blocking by a specific protein block (Novocastra, Leica Biosystems), the samples were incubated ON at 4  C with the HAS1, HAS2, HAS3 and C1q primary antibodies.	('C1q', 'cellular_component', 'GO:0062167', ('211', '214'))	('H2O2', 'Chemical', 'MESH:D006861', (62, 66))	('H2O2', 'Var', (62, 66))	('C1q', 'Gene', '712', (211, 214))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('HAS1', 'Gene', '3036', (190, 194))	('HAS1', 'Gene', (190, 194))	('HAS2', 'Gene', (196, 200))	('C1q', 'Gene', (211, 214))	('HAS2', 'Gene', '3037', (196, 200))	('HAS3', 'Gene', (202, 206))	('HAS3', 'Gene', '3038', (202, 206))
126955	31033201	Mesothelioma with mutated p53 genotype, EHMES-1 and JMN-1B cells were provided by Dr. Hironobu Hamada (Hiroshima University, Japan) (Nakataki et al., 2006).	('mutated', 'Var', (18, 25))	('p53', 'Gene', (26, 29))	('JMN-1B', 'CellLine', 'CVCL:M006', (52, 58))	('p53', 'Gene', '7157', (26, 29))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
126960	31033201	Chemicals used in the present study were purchased as follows: PEM (Eli Lilly, Indianapolis, IN, USA), A769662 (Catalogue number: ab120335), PF4708671 (ab141993), compound C (ab120843, Abcam, Cambridge, UK), nutlin-3a (S8059, Selleck, Houston, TX, USA), MK-2206 (CT-MK2206, ChemieTek, Indianapolis, IN, USA) and rapamycin (R8781, Sigma-Aldrich, St. Louis, MO, USA).	('PEM', 'Chemical', 'MESH:D000068437', (63, 66))	('PF4708671', 'Var', (141, 150))	('A769662', 'Chemical', 'MESH:C512408', (103, 110))	('rapamycin', 'Chemical', 'MESH:D020123', (312, 321))	('MK-2206', 'Chemical', '-', (254, 261))	('PF4708671', 'Chemical', 'MESH:C552719', (141, 150))	('ab120843', 'Var', (175, 183))	('R8781', 'Var', (323, 328))
126962	31033201	The protein was transferred to a nitrocellulose membrane and hybridized with antibody against AMPKalpha (catalog number: #2532), phosphorylated AMPKalpha at Thr 172 (#2535), 4E-BP1 (#9452), phosphorylated 4E-BP1 at Thr 37/46 (#9459), p70S6K (#9202), phosphorylated p70S6K at Thr389 (#9205), phosphorylated p53 at Ser 15 (#9284), AKT (#9272), phosphorylated AKT at Ser 473 (#9271), ACC at Ser 79 (#3661), actin (#4970) (Cell Signaling, Danvers, MA, USA), phosphorylated H2AX at Ser 139 (#613401) (BioLegend, San Diego, CA, USA), p53 (Ab-6, clone DO-1) and tubulin-alpha (clone DM1A, Thermo Fisher Scientific, Fremont, CA, USA) followed by an appropriate second antibody.	('AKT', 'Gene', (357, 360))	('AMPK', 'Gene', (94, 98))	('antibody', 'molecular_function', 'GO:0003823', ('660', '668'))	('4E-BP1', 'Gene', '1978', (174, 180))	('membrane', 'cellular_component', 'GO:0016020', ('48', '56'))	('p53', 'Gene', (306, 309))	('antibody', 'cellular_component', 'GO:0042571', ('660', '668'))	('Signaling', 'biological_process', 'GO:0023052', ('424', '433'))	('Ser', 'cellular_component', 'GO:0005790', ('364', '367'))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('Ser', 'cellular_component', 'GO:0005790', ('477', '480'))	('4E-BP1', 'Gene', '1978', (205, 211))	('Ser', 'cellular_component', 'GO:0005790', ('313', '316'))	('Ser', 'cellular_component', 'GO:0005790', ('388', '391'))	('AKT', 'Gene', '207', (357, 360))	('H2AX', 'Gene', (469, 473))	('p70S6K', 'Gene', '6198', (234, 240))	('4E-BP1', 'Gene', (174, 180))	('p70S6K', 'Gene', '6198', (265, 271))	('antibody', 'cellular_component', 'GO:0019815', ('660', '668'))	('AKT', 'Gene', (329, 332))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('Ab-6', 'Gene', '100132406', (533, 537))	('Ab-6', 'Gene', (533, 537))	('4E-BP1', 'Gene', (205, 211))	('H2AX', 'Gene', '3014', (469, 473))	('ACC', 'Gene', '31', (381, 384))	('AMPK', 'Gene', (144, 148))	('p53', 'Gene', '7157', (528, 531))	('AMPK', 'Gene', '5564', (144, 148))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('antibody', 'cellular_component', 'GO:0019814', ('660', '668'))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('ACC', 'Gene', (381, 384))	('#613401', 'Var', (486, 493))	('p53', 'Gene', '7157', (306, 309))	('AKT', 'Gene', '207', (329, 332))	('p70S6K', 'Gene', (234, 240))	('p53', 'Gene', (528, 531))	('p70S6K', 'Gene', (265, 271))	('AMPK', 'Gene', '5564', (94, 98))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
126964	31033201	We established PEM-resistant mesothelioma, H28-PEM, H226-PEM, 211H-PEM and H2452-PEM cells from the parent cells NCI-H28, NCI-H226, MSTO-211H and NCI-H2452, respectively, and showed the PEM resistance with a colony-forming assay (Kitazono-Saitoh et al., 2012).	('NCI-H2452', 'CellLine', 'CVCL:1553', (146, 155))	('PEM', 'Chemical', 'MESH:D000068437', (47, 50))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('H2452-PEM', 'Var', (75, 84))	('PEM', 'Chemical', 'MESH:D000068437', (67, 70))	('PEM', 'Chemical', 'MESH:D000068437', (15, 18))	('H226-PEM', 'CellLine', 'CVCL:J621', (52, 60))	('PEM', 'Chemical', 'MESH:D000068437', (186, 189))	('PEM', 'Chemical', 'MESH:D000068437', (81, 84))	('PEM', 'Chemical', 'MESH:D000068437', (57, 60))	('NCI-H226', 'CellLine', 'CVCL:1544', (122, 130))	('H2452-PEM', 'CellLine', 'CVCL:1553', (75, 84))	('mesothelioma', 'Disease', (29, 41))	('PEM-resistant', 'Disease', (15, 28))
126968	31033201	We previously reported that 211H-PEM and H2452-PEM cells elevated TS and GARFT transcripts in comparison with the respective parent cells, whereas H28-PEM and H226-PEM cells did not up-regulate transcripts of the PEM-related enzymes including DHFR, and the expression levels were rather lower than those of parent cells (Kitazono-Saitoh et al., 2012).	('DHFR', 'molecular_function', 'GO:0004146', ('243', '247'))	('H2452-PEM', 'CellLine', 'CVCL:1553', (41, 50))	('PEM', 'Chemical', 'MESH:D000068437', (47, 50))	('H226-PEM', 'CellLine', 'CVCL:J621', (159, 167))	('GARFT transcripts', 'MPA', (73, 90))	('elevated', 'PosReg', (57, 65))	('DHFR', 'Gene', (243, 247))	('DHFR', 'Gene', '1719', (243, 247))	('TS', 'Gene', '7298', (66, 68))	('PEM', 'Chemical', 'MESH:D000068437', (33, 36))	('PEM', 'Chemical', 'MESH:D000068437', (213, 216))	('PEM', 'Chemical', 'MESH:D000068437', (164, 167))	('211H-PEM', 'Var', (28, 36))	('PEM', 'Chemical', 'MESH:D000068437', (151, 154))	('H2452-PEM', 'Var', (41, 50))
126971	31033201	AMPKalpha expression remained the same between the paired cells, but phosphorylated AMPKalpha level was greater in H28-PEM and H226-PEM cells than in their parent cells.	('H226-PEM', 'Var', (127, 135))	('AMPK', 'Gene', '5564', (84, 88))	('PEM', 'Chemical', 'MESH:D000068437', (132, 135))	('AMPK', 'Gene', (84, 88))	('greater', 'PosReg', (104, 111))	('H28-PEM', 'Var', (115, 122))	('AMPK', 'Gene', '5564', (0, 4))	('PEM', 'Chemical', 'MESH:D000068437', (119, 122))	('AMPK', 'Gene', (0, 4))	('H226-PEM', 'CellLine', 'CVCL:J621', (127, 135))
126972	31033201	The phosphorylation level in H2452-PEM cells also increased in comparison with that in the parent cells, but the level in 211H-PEM cells was lower than that in the parent cells.	('H2452-PEM', 'Var', (29, 38))	('PEM', 'Chemical', 'MESH:D000068437', (35, 38))	('increased', 'PosReg', (50, 59))	('H2452-PEM', 'CellLine', 'CVCL:1553', (29, 38))	('phosphorylation level', 'MPA', (4, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('PEM', 'Chemical', 'MESH:D000068437', (127, 130))
126980	31033201	Expression of AKT which interacted with AMPK and was activated with PEM was not different between the paired cells, whereas phosphorylated AKT was enhanced in H28-PEM and H2452-PEM cells in comparison with their parent cells.	('AKT', 'Gene', '207', (14, 17))	('enhanced', 'PosReg', (147, 155))	('AMPK', 'Gene', (40, 44))	('AKT', 'Gene', (14, 17))	('AKT', 'Gene', '207', (139, 142))	('Expression', 'MPA', (0, 10))	('H28-PEM', 'Var', (159, 166))	('phosphorylated', 'MPA', (124, 138))	('PEM', 'Chemical', 'MESH:D000068437', (177, 180))	('PEM', 'Chemical', 'MESH:D000068437', (163, 166))	('AMPK', 'Gene', '5564', (40, 44))	('H2452-PEM', 'Var', (171, 180))	('AMPK', 'molecular_function', 'GO:0050405', ('40', '44'))	('AMPK', 'molecular_function', 'GO:0004691', ('40', '44'))	('AKT', 'Gene', (139, 142))	('PEM', 'Chemical', 'MESH:D000068437', (68, 71))	('AMPK', 'molecular_function', 'GO:0047322', ('40', '44'))	('H2452-PEM', 'CellLine', 'CVCL:1553', (171, 180))
126981	31033201	The phosphorylation in H226-PEM and 211H-PEM cells was rather down-regulated.	('PEM', 'Chemical', 'MESH:D000068437', (28, 31))	('down-regulated', 'NegReg', (62, 76))	('phosphorylation', 'MPA', (4, 19))	('H226-PEM', 'CellLine', 'CVCL:J621', (23, 31))	('H226-PEM', 'Var', (23, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('PEM', 'Chemical', 'MESH:D000068437', (41, 44))
126983	31033201	Expression of p53 and the phosphorylation increased in H28-PEM cells compared with the parent cells, but other cells did not show up-regulated expression.	('increased', 'PosReg', (42, 51))	('PEM', 'Chemical', 'MESH:D000068437', (59, 62))	('p53', 'Gene', (14, 17))	('H28-PEM', 'Var', (55, 62))	('Expression', 'MPA', (0, 10))	('p53', 'Gene', '7157', (14, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('phosphorylation', 'MPA', (26, 41))
126984	31033201	NCI-2452 and the PEM-resistant cells expressed truncated p53 with a lower molecular weight than the authentic one, as previously reported (Di Marzo et al., 2014).	('lower', 'NegReg', (68, 73))	('p53', 'Gene', (57, 60))	('PEM', 'Chemical', 'MESH:D000068437', (17, 20))	('truncated', 'Var', (47, 56))	('molecular weight', 'MPA', (74, 90))	('p53', 'Gene', '7157', (57, 60))
127002	31033201	The poor responses of AKT, p53 and H2AX in H226-PME cells were probably attributable to greater PEM resistance than in H28-PEM cells (Fig.	('PEM', 'Chemical', 'MESH:D000068437', (96, 99))	('H2AX', 'Gene', '3014', (35, 39))	('p53', 'Gene', '7157', (27, 30))	('AKT', 'Gene', '207', (22, 25))	('H226-PME', 'Var', (43, 51))	('H2AX', 'Gene', (35, 39))	('AKT', 'Gene', (22, 25))	('H226-PME', 'CellLine', 'CVCL:J621', (43, 51))	('greater', 'PosReg', (88, 95))	('PEM', 'Chemical', 'MESH:D000068437', (123, 126))	('p53', 'Gene', (27, 30))
127009	31033201	We examined whether activated AMPK increased PEM resistance with A769662, an AMPK activating agent (Fig.	('PEM', 'Chemical', 'MESH:D000068437', (45, 48))	('A769662', 'Chemical', 'MESH:C512408', (65, 72))	('increased', 'PosReg', (35, 44))	('AMPK', 'molecular_function', 'GO:0004691', ('30', '34'))	('AMPK', 'molecular_function', 'GO:0050405', ('30', '34'))	('AMPK', 'Gene', '5564', (77, 81))	('AMPK', 'Gene', (77, 81))	('AMPK', 'Gene', (30, 34))	('AMPK', 'molecular_function', 'GO:0050405', ('77', '81'))	('AMPK', 'molecular_function', 'GO:0047322', ('30', '34'))	('AMPK', 'Gene', '5564', (30, 34))	('A769662', 'Var', (65, 72))	('PEM resistance', 'MPA', (45, 59))	('AMPK', 'molecular_function', 'GO:0004691', ('77', '81'))	('AMPK', 'molecular_function', 'GO:0047322', ('77', '81'))
127011	31033201	A769662 at 50 and 100 mum produced little effect on the viability, but both parent cells treated with the AMPK activator increased resistance to PEM.	('AMPK', 'molecular_function', 'GO:0004691', ('106', '110'))	('PEM', 'Chemical', 'MESH:D000068437', (145, 148))	('increased', 'PosReg', (121, 130))	('AMPK', 'molecular_function', 'GO:0047322', ('106', '110'))	('A769662', 'Var', (0, 7))	('AMPK', 'Gene', '5564', (106, 110))	('AMPK', 'Gene', (106, 110))	('resistance to PEM', 'MPA', (131, 148))	('A769662', 'Chemical', 'MESH:C512408', (0, 7))	('AMPK', 'molecular_function', 'GO:0050405', ('106', '110'))
127012	31033201	IC50 values of A769662-treated cells were greater than those of untreated cells.	('A769662', 'Chemical', 'MESH:C512408', (15, 22))	('greater', 'PosReg', (42, 49))	('IC50 values', 'MPA', (0, 11))	('A769662-treated', 'Var', (15, 30))
127013	31033201	We next examined the effects of A769662 on AMPK and the related pathways (Fig.	('AMPK', 'molecular_function', 'GO:0004691', ('43', '47'))	('AMPK', 'molecular_function', 'GO:0047322', ('43', '47'))	('A769662', 'Chemical', 'MESH:C512408', (32, 39))	('AMPK', 'Gene', '5564', (43, 47))	('AMPK', 'Gene', (43, 47))	('AMPK', 'molecular_function', 'GO:0050405', ('43', '47'))	('A769662', 'Var', (32, 39))
127015	31033201	A769662-treated cells increased phosphorylation of AMPK in both cells but up-regulated p70S6K phosphorylation was transient in cells treated at 100 mum.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('AMPK', 'molecular_function', 'GO:0047322', ('51', '55'))	('AMPK', 'molecular_function', 'GO:0050405', ('51', '55'))	('AMPK', 'molecular_function', 'GO:0004691', ('51', '55'))	('A769662-treated', 'Var', (0, 15))	('up-regulated', 'PosReg', (74, 86))	('increased', 'PosReg', (22, 31))	('AMPK', 'Gene', (51, 55))	('AMPK', 'Gene', '5564', (51, 55))	('A769662', 'Chemical', 'MESH:C512408', (0, 7))	('p70S6K', 'Gene', (87, 93))	('phosphorylation', 'MPA', (32, 47))	('p70S6K', 'Gene', '6198', (87, 93))
127022	31033201	We next examined whether an AMPK inhibitor, compound C, suppressed the PEM resistance of H28-PEM and H226-PEM (Fig.	('PEM', 'Chemical', 'MESH:D000068437', (106, 109))	('PEM resistance', 'CPA', (71, 85))	('PEM', 'Chemical', 'MESH:D000068437', (93, 96))	('PEM', 'Chemical', 'MESH:D000068437', (71, 74))	('suppressed', 'NegReg', (56, 66))	('H226-PEM', 'CellLine', 'CVCL:J621', (101, 109))	('AMPK', 'molecular_function', 'GO:0047322', ('28', '32'))	('H226-PEM', 'Var', (101, 109))	('AMPK', 'molecular_function', 'GO:0050405', ('28', '32'))	('AMPK', 'molecular_function', 'GO:0004691', ('28', '32'))	('AMPK', 'Gene', (28, 32))	('AMPK', 'Gene', '5564', (28, 32))
127032	31033201	AMPK inhibition in general activated mTORC1 pathways and compound C consequently mediated increase of p70S6K phosphorylation.	('increase', 'PosReg', (90, 98))	('inhibition', 'Var', (5, 15))	('mTORC1', 'Gene', (37, 43))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('p70S6K', 'Gene', '6198', (102, 108))	('p70S6K', 'Gene', (102, 108))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('AMPK', 'Gene', '5564', (0, 4))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('mTORC1', 'cellular_component', 'GO:0031931', ('37', '43'))	('AMPK', 'Gene', (0, 4))	('mTORC1', 'Gene', '382056', (37, 43))	('activated', 'PosReg', (27, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))
127033	31033201	A769662 and compound C influenced PEM sensitivity in opposite ways, but p70S6K phosphorylation was up-regulated in both cases, suggesting that phosphorylation of p70S6K was unrelated to PEM sensitivity.	('PEM', 'Chemical', 'MESH:D000068437', (34, 37))	('p70S6K', 'Gene', '6198', (162, 168))	('A769662', 'Var', (0, 7))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('PEM', 'Chemical', 'MESH:D000068437', (186, 189))	('phosphorylation', 'MPA', (79, 94))	('influenced', 'Reg', (23, 33))	('up-regulated', 'PosReg', (99, 111))	('p70S6K', 'Gene', (72, 78))	('A769662', 'Chemical', 'MESH:C512408', (0, 7))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('p70S6K', 'Gene', '6198', (72, 78))	('p70S6K', 'Gene', (162, 168))
127037	31033201	Rapamycin by itself inhibited viability of H28-PEM and H226-PEM, but did not affect PEM sensitivity of H28-PEM cells or increased PEM resistance in H226-PEM cells.	('viability', 'CPA', (30, 39))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('H226-PEM', 'CellLine', 'CVCL:J621', (55, 63))	('PEM', 'Chemical', 'MESH:D000068437', (107, 110))	('H226-PEM', 'Var', (55, 63))	('H226-PEM', 'CellLine', 'CVCL:J621', (148, 156))	('PEM', 'Chemical', 'MESH:D000068437', (153, 156))	('inhibited', 'NegReg', (20, 29))	('PEM', 'Chemical', 'MESH:D000068437', (84, 87))	('PEM', 'Chemical', 'MESH:D000068437', (60, 63))	('PEM', 'Chemical', 'MESH:D000068437', (47, 50))	('increased', 'PosReg', (120, 129))	('PEM', 'Chemical', 'MESH:D000068437', (130, 133))
127039	31033201	Rapamycin-mediated effects on AMPK and 4E-BP1 were marginal, with a slight increase of AMPK phosphorylation in H226-PEM.	('AMPK', 'molecular_function', 'GO:0050405', ('87', '91'))	('AMPK', 'molecular_function', 'GO:0004691', ('87', '91'))	('AMPK', 'molecular_function', 'GO:0004691', ('30', '34'))	('AMPK', 'molecular_function', 'GO:0050405', ('30', '34'))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('H226-PEM', 'Var', (111, 119))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('4E-BP1', 'Gene', (39, 45))	('H226-PEM', 'CellLine', 'CVCL:J621', (111, 119))	('AMPK', 'Gene', (30, 34))	('AMPK', 'molecular_function', 'GO:0047322', ('87', '91'))	('AMPK', 'molecular_function', 'GO:0047322', ('30', '34'))	('AMPK', 'Gene', '5564', (30, 34))	('increase', 'PosReg', (75, 83))	('AMPK', 'Gene', (87, 91))	('AMPK', 'Gene', '5564', (87, 91))	('4E-BP1', 'Gene', '1978', (39, 45))
127042	31033201	We also examined PF4708671, a different type of p70S6K inhibitor, and showed that the agent decreased viability of H28-PEM and H226-PEM cells but did not influence the PEM sensitivity (Fig.	('viability', 'CPA', (102, 111))	('PF4708671', 'Var', (17, 26))	('PF4708671', 'Chemical', 'MESH:C552719', (17, 26))	('PEM', 'Chemical', 'MESH:D000068437', (132, 135))	('p70S6K', 'Gene', '6198', (48, 54))	('p70S6K', 'Gene', (48, 54))	('PEM', 'Chemical', 'MESH:D000068437', (119, 122))	('decreased', 'NegReg', (92, 101))	('PEM', 'Chemical', 'MESH:D000068437', (168, 171))	('H226-PEM', 'CellLine', 'CVCL:J621', (127, 135))
127043	31033201	PF4708671 decreased p70S6K phosphorylation levels despite increased p70S6K expression, probably due to compensation for decreased p70S6K activity (Fig.	('decreased', 'NegReg', (120, 129))	('p70S6K', 'Gene', (130, 136))	('increased p70S6K expression', 'Phenotype', 'HP:0003240', (58, 85))	('decreased', 'NegReg', (10, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('increased', 'PosReg', (58, 67))	('p70S6K', 'Gene', '6198', (130, 136))	('p70S6K', 'Gene', (20, 26))	('p70S6K', 'Gene', (68, 74))	('p70S6K', 'Gene', '6198', (20, 26))	('p70S6K', 'Gene', '6198', (68, 74))	('PF4708671', 'Var', (0, 9))	('expression', 'MPA', (75, 85))	('PF4708671', 'Chemical', 'MESH:C552719', (0, 9))
127045	31033201	These data showed that PF4708671 was specific to p70S6K and reciprocally augmented AMPK and AKT activities due to a feedback effect, as we detected the same changes in rapamycin-treated cells.	('augmented', 'PosReg', (73, 82))	('rapamycin', 'Chemical', 'MESH:D020123', (168, 177))	('AKT', 'Gene', '207', (92, 95))	('AMPK', 'molecular_function', 'GO:0004691', ('83', '87'))	('p70S6K', 'Gene', (49, 55))	('AMPK', 'molecular_function', 'GO:0050405', ('83', '87'))	('PF4708671', 'Var', (23, 32))	('AMPK', 'Gene', '5564', (83, 87))	('p70S6K', 'Gene', '6198', (49, 55))	('AKT', 'Gene', (92, 95))	('PF4708671', 'Chemical', 'MESH:C552719', (23, 32))	('AMPK', 'Gene', (83, 87))	('AMPK', 'molecular_function', 'GO:0047322', ('83', '87'))
127049	31033201	1B) and that A769662, an AMPK activator, phosphorylated AKT in H28-PEM cells (Fig.	('AKT', 'Gene', '207', (56, 59))	('A769662', 'Var', (13, 20))	('PEM', 'Chemical', 'MESH:D000068437', (67, 70))	('AKT', 'Gene', (56, 59))	('AMPK', 'Gene', (25, 29))	('AMPK', 'Gene', '5564', (25, 29))	('AMPK', 'molecular_function', 'GO:0050405', ('25', '29'))	('A769662', 'Chemical', 'MESH:C512408', (13, 20))	('AMPK', 'molecular_function', 'GO:0004691', ('25', '29'))	('AMPK', 'molecular_function', 'GO:0047322', ('25', '29'))
127052	31033201	Both cells treated with MK-2206 decreased phosphorylated AKT with variable levels but did not influence AMPK phosphorylation (Fig.	('AMPK', 'molecular_function', 'GO:0047322', ('104', '108'))	('phosphorylated', 'MPA', (42, 56))	('AMPK', 'Gene', '5564', (104, 108))	('MK-2206', 'Var', (24, 31))	('AKT', 'Gene', '207', (57, 60))	('MK-2206', 'Chemical', '-', (24, 31))	('AMPK', 'molecular_function', 'GO:0004691', ('104', '108'))	('AMPK', 'molecular_function', 'GO:0050405', ('104', '108'))	('AMPK', 'Gene', (104, 108))	('decreased', 'NegReg', (32, 41))	('AKT', 'Gene', (57, 60))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))
127074	31033201	Mesothelioma with mutated p53 genotype, EHMES-1 and JMN-1B cells, and mesothelium-derived Met-5A cells expressing dominant-negative p53, showed augmented phosphorylation of AMPK when they were treated with PEM (Fig.	('augmented', 'PosReg', (144, 153))	('phosphorylation', 'MPA', (154, 169))	('mutated', 'Var', (18, 25))	('AMPK', 'Gene', '5564', (173, 177))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('AMPK', 'Gene', (173, 177))	('phosphorylation', 'biological_process', 'GO:0016310', ('154', '169'))	('AMPK', 'molecular_function', 'GO:0004691', ('173', '177'))	('AMPK', 'molecular_function', 'GO:0050405', ('173', '177'))	('p53', 'Gene', (26, 29))	('JMN-1B', 'CellLine', 'CVCL:M006', (52, 58))	('p53', 'Gene', '7157', (26, 29))	('AMPK', 'molecular_function', 'GO:0047322', ('173', '177'))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('PEM', 'Chemical', 'MESH:D000068437', (206, 209))
127079	31033201	We also demonstrated that an AMPK activator decreased PEM sensitivity and the inhibitor increased the sensitivity, whereas p70S6K inhibitors did not influence the PEM sensitivity.	('sensitivity', 'MPA', (102, 113))	('AMPK', 'Gene', (29, 33))	('PEM', 'Chemical', 'MESH:D000068437', (163, 166))	('AMPK', 'Gene', '5564', (29, 33))	('p70S6K', 'Gene', (123, 129))	('AMPK', 'molecular_function', 'GO:0047322', ('29', '33'))	('increased', 'PosReg', (88, 97))	('p70S6K', 'Gene', '6198', (123, 129))	('AMPK', 'molecular_function', 'GO:0050405', ('29', '33'))	('PEM', 'Chemical', 'MESH:D000068437', (54, 57))	('AMPK', 'molecular_function', 'GO:0004691', ('29', '33'))	('inhibitor', 'Var', (78, 87))	('PEM sensitivity', 'MPA', (54, 69))	('decreased', 'NegReg', (44, 53))
127091	31033201	In fact, rapamycin and PF4708671 augmented AKT and AMPK phosphorylation depending on cells, and nutlin-3a also increased phosphorylation levels of AMPK in all the cells and AKT in H28-PEM cells.	('AKT', 'Gene', '207', (43, 46))	('AMPK', 'molecular_function', 'GO:0047322', ('147', '151'))	('AKT', 'Gene', (173, 176))	('AMPK', 'Gene', (147, 151))	('AMPK', 'Gene', (51, 55))	('AMPK', 'Gene', '5564', (147, 151))	('AMPK', 'Gene', '5564', (51, 55))	('augmented', 'PosReg', (33, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('rapamycin', 'Chemical', 'MESH:D020123', (9, 18))	('AMPK', 'molecular_function', 'GO:0050405', ('51', '55'))	('phosphorylation levels', 'MPA', (121, 143))	('PF4708671', 'Chemical', 'MESH:C552719', (23, 32))	('AKT', 'Gene', '207', (173, 176))	('AMPK', 'molecular_function', 'GO:0050405', ('147', '151'))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('PEM', 'Chemical', 'MESH:D000068437', (184, 187))	('AMPK', 'molecular_function', 'GO:0004691', ('51', '55'))	('AKT', 'Gene', (43, 46))	('AMPK', 'molecular_function', 'GO:0004691', ('147', '151'))	('increased', 'PosReg', (111, 120))	('PF4708671', 'Var', (23, 32))	('AMPK', 'molecular_function', 'GO:0047322', ('51', '55'))
127092	31033201	Moreover, A769662 phosphorylated AKT and to less of extent p70S6K, and increased p53 expression in NCI-H226 cells.	('expression', 'MPA', (85, 95))	('A769662', 'Chemical', 'MESH:C512408', (10, 17))	('AKT', 'Gene', '207', (33, 36))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('increased', 'PosReg', (71, 80))	('A769662', 'Var', (10, 17))	('p70S6K', 'Gene', (59, 65))	('AKT', 'Gene', (33, 36))	('p70S6K', 'Gene', '6198', (59, 65))	('NCI-H226', 'CellLine', 'CVCL:1544', (99, 107))
127108	31033201	The current study, however, showed that an AKT inhibitor, MK-2206, did not influence AMPK or p70S6K phosphorylation or PEM sensitivity.	('AMPK', 'molecular_function', 'GO:0050405', ('85', '89'))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('MK-2206', 'Chemical', '-', (58, 65))	('AMPK', 'molecular_function', 'GO:0004691', ('85', '89'))	('AKT', 'Gene', '207', (43, 46))	('AMPK', 'molecular_function', 'GO:0047322', ('85', '89'))	('AMPK', 'Gene', (85, 89))	('AMPK', 'Gene', '5564', (85, 89))	('AKT', 'Gene', (43, 46))	('PEM', 'Chemical', 'MESH:D000068437', (119, 122))	('p70S6K', 'Gene', (93, 99))	('p70S6K', 'Gene', '6198', (93, 99))	('MK-2206', 'Var', (58, 65))
127111	31033201	The AMPK activation was also induced with PEM even in cells bearing mutated p53 genotype or expressing dominant p53 under no DNA damage.	('AMPK', 'molecular_function', 'GO:0047322', ('4', '8'))	('induced', 'Reg', (29, 36))	('PEM', 'Chemical', 'MESH:D000068437', (42, 45))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('AMPK', 'molecular_function', 'GO:0050405', ('4', '8'))	('AMPK', 'Gene', (4, 8))	('p53', 'Gene', (112, 115))	('AMPK', 'Gene', '5564', (4, 8))	('AMPK', 'molecular_function', 'GO:0004691', ('4', '8'))	('mutated', 'Var', (68, 75))	('p53', 'Gene', '7157', (112, 115))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))
127246	29615010	MPM Malignant pleural mesothelioma MT Medical thoracoscopy SD standard deviation L.L.X., Y.Y., Z.W., X.J.W, Z.H.T.	('SD', 'Disease', 'MESH:D029461', (59, 61))	('Malignant pleural mesothelioma', 'Disease', (4, 34))	('Z.H.T', 'CellLine', 'CVCL:J056', (108, 113))	('Z.W.', 'Var', (95, 99))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (14, 34))	('MPM', 'Chemical', '-', (0, 3))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (4, 34))
127251	26437366	Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone.	('Ezh2', 'Gene', (33, 37))	('Ezh2', 'Gene', '14056', (33, 37))	('Conditional deletion', 'Var', (0, 20))	('abrogates', 'NegReg', (46, 55))	('Bap1', 'Gene', (24, 28))	('myeloid progenitor expansion', 'CPA', (60, 88))	('Bap1', 'Gene', (100, 104))	('loss', 'NegReg', (105, 109))
127253	26437366	Genomic studies have identified somatic mutations in the tumor suppressors ASXL1 and BAP1 in different malignancies.	('BAP1', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('ASXL1', 'Gene', (75, 80))	('mutations', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ASXL1', 'Gene', '228790', (75, 80))	('malignancies', 'Disease', (103, 115))	('tumor', 'Disease', (57, 62))
127254	26437366	Inactivating mutations in ASXL1 are most common in myeloid malignancies, whereas recurrent BAP1 mutations are commonly observed in mesothelioma, renal cell carcinoma, and metastatic uveal melanoma suggesting BAP1 and ASXL1 have distinct roles in tumor suppression.	('ASXL1', 'Gene', '228790', (217, 222))	('BAP1', 'Gene', (91, 95))	('observed', 'Reg', (119, 127))	('mesothelioma', 'Disease', (131, 143))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('ASXL1', 'Gene', '228790', (26, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))	('mutations', 'Var', (96, 105))	('Inactivating mutations', 'Var', (0, 22))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('myeloid malignancies', 'Disease', 'MESH:D009369', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Disease', (145, 165))	('myeloid malignancies', 'Disease', (51, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('tumor', 'Disease', (246, 251))	('ASXL1', 'Gene', (217, 222))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('common', 'Reg', (41, 47))	('uveal melanoma', 'Disease', (182, 196))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('ASXL1', 'Gene', (26, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))
127265	26437366	These data demonstrate that loss of Asxl1 and Bap1 have opposite effects on gene regulation.	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('loss', 'Var', (28, 32))	('gene regulation', 'MPA', (76, 91))	('Asxl1', 'Gene', (36, 41))	('Bap1', 'Gene', (46, 50))	('Asxl1', 'Gene', '228790', (36, 41))
127266	26437366	ASXL1 directly interacts with the PRC2 complex and ASXL1 depletion reduces global and site-specific H3K27me3.	('ASXL1', 'Gene', (51, 56))	('depletion', 'Var', (57, 66))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('34', '46'))	('ASXL1', 'Gene', '228790', (51, 56))	('H3K27me3', 'Protein', (100, 108))	('ASXL1', 'Gene', (0, 5))	('reduces', 'NegReg', (67, 74))	('ASXL1', 'Gene', '228790', (0, 5))	('global and', 'MPA', (75, 85))
127268	26437366	Chromatin immunoprecipitation sequencing (ChIP-Seq) revealed a global increase in H3K27me3 broad domains and H3K27me3 "spreading" into nearby loci in Bap1 KO mice, as illustrated within the HoxA locus (Fig.	('H3K27me3', 'Protein', (82, 90))	('increase', 'PosReg', (70, 78))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('mice', 'Species', '10090', (158, 162))	('HoxA', 'Gene', '111336', (190, 194))	('Bap1', 'Var', (150, 154))	('HoxA', 'Gene', (190, 194))
127269	26437366	BAP1 silencing increased H3K27me3 and re-expression of BAP1 in Bap1-deficient cells, but not a deubiquitinase-deficient BAP1 allele, reduced H3K27me3 levels (Supplementary Fig.	('deubiquitinase', 'molecular_function', 'GO:0004843', ('95', '109'))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', (55, 59))	('silencing', 'Var', (5, 14))	('deubiquitinase-deficient', 'Disease', (95, 119))	('increased', 'PosReg', (15, 24))	('deubiquitinase-deficient', 'Disease', 'MESH:D007153', (95, 119))	('reduced', 'NegReg', (133, 140))	('H3K27me3 levels', 'MPA', (141, 156))	('H3K27me3', 'MPA', (25, 33))
127271	26437366	Ezh2 deletion reduced H3K27me3 levels in Bap1/Ezh2-deficient mice compared to Bap1-knockout mice (Fig.	('Ezh2', 'Gene', '14056', (46, 50))	('reduced', 'NegReg', (14, 21))	('deletion', 'Var', (5, 13))	('H3K27me3 levels', 'MPA', (22, 37))	('mice', 'Species', '10090', (61, 65))	('Ezh2', 'Gene', (0, 4))	('Ezh2', 'Gene', '14056', (0, 4))	('mice', 'Species', '10090', (92, 96))	('Ezh2', 'Gene', (46, 50))
127272	26437366	Ezh2 deletion abrogated the myeloid malignancy induced by Bap1 loss, with reduced splenomegaly, leukocytosis and anemia (Fig.	('splenomegaly', 'Phenotype', 'HP:0001744', (82, 94))	('deletion', 'Var', (5, 13))	('reduced splenomegaly', 'Disease', 'MESH:D013163', (74, 94))	('myeloid malignancy', 'Disease', 'MESH:D009369', (28, 46))	('Ezh2', 'Gene', (0, 4))	('Bap1', 'Gene', (58, 62))	('Ezh2', 'Gene', '14056', (0, 4))	('leukocytosis and anemia', 'Disease', 'MESH:D007964', (96, 119))	('leukocytosis', 'Phenotype', 'HP:0001974', (96, 108))	('myeloid malignancy', 'Disease', (28, 46))	('abrogated', 'NegReg', (14, 23))	('anemia', 'Phenotype', 'HP:0001903', (113, 119))	('loss', 'NegReg', (63, 67))	('reduced splenomegaly', 'Disease', (74, 94))
127274	26437366	Consistent with the genetic data, treatment of Bap1 KO mice with the small molecule EZH2 inhibitor EPZ011989decreased H3K27me3, splenomegaly, and white blood cell counts (Supplementary Fig.	('white blood cell counts', 'CPA', (146, 169))	('splenomegaly', 'Disease', (128, 140))	('mice', 'Species', '10090', (55, 59))	('splenomegaly', 'Disease', 'MESH:D013163', (128, 140))	('splenomegaly', 'Phenotype', 'HP:0001744', (128, 140))	('H3K27me3', 'Protein', (118, 126))	('EPZ011989decreased', 'Var', (99, 117))
127280	26437366	Expression of BAP1, but not ASXL1, increased H4K20me1 at the EZH2 locus (Supplementary Fig.	('BAP1', 'Gene', (14, 18))	('H4K20me1', 'Var', (45, 53))	('ASXL1', 'Gene', (28, 33))	('ASXL1', 'Gene', '228790', (28, 33))
127290	26437366	EZH2 silencing induced apoptosis in BAP1-mutant mesothelioma cell lines, whereas wild-type cells continued to proliferate (Fig.	('induced', 'Reg', (15, 22))	('BAP1-mutant', 'Var', (36, 47))	('apoptosis', 'CPA', (23, 32))	('EZH2', 'Gene', (0, 4))	('mesothelioma', 'Disease', (48, 60))	('silencing', 'Var', (5, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('BAP1-mutant', 'Gene', (36, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))
127291	26437366	EZH2 silencing abrogated in vivo tumor formation of BAP1-mutant but not wild-type cell lines (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EZH2', 'Gene', (0, 4))	('abrogated', 'NegReg', (15, 24))	('BAP1-mutant', 'Gene', (52, 63))	('silencing', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('tumor', 'Disease', (33, 38))
127292	26437366	EZH2 inhibition significantly reduced BAP1-mutant tumor size compared to vehicle treated mice, whereas wild-type tumors were less responsive to EZH2 inhibition (Fig.	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', (113, 119))	('inhibition', 'Var', (5, 15))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('EZH2', 'Gene', (0, 4))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('reduced', 'NegReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BAP1-mutant', 'Gene', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
127296	26437366	Our data resonate with recent studies suggesting a role for PRC2 inhibition in SWI/SNF-mutant rhabdoid tumors and analyses showing BAP1 mutations are mutually exclusive with mutations in the SWI/SNF complex.	('inhibition', 'NegReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('191', '206'))	('SWI/SNF-mutant', 'Var', (79, 93))	('mutations', 'Var', (136, 145))	('PRC2', 'Gene', (60, 64))	('BAP1', 'Gene', (131, 135))	('rhabdoid tumors', 'Disease', (94, 109))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (94, 109))	('SWI/SNF-mutant', 'Gene', (79, 93))
127304	26437366	These mice were subsequently crossed to the IFN-alpha-inducible Mx1-cre transgenic mice (The Jackson Laboratory) to assess the effects of inducible loss of Bap1 in the hematopoietic system.	('loss', 'Var', (148, 152))	('mice', 'Species', '10090', (6, 10))	('Mx1', 'Gene', '17857', (64, 67))	('IFN-alpha', 'Gene', (44, 53))	('mice', 'Species', '10090', (83, 87))	('IFN-alpha', 'Gene', '111654', (44, 53))	('Mx1', 'Gene', (64, 67))	('Bap1', 'Gene', (156, 160))	('transgenic mice', 'Species', '10090', (72, 87))
127307	26437366	Mx-cre Bap1f/f conditional and Bap1f/f control mice received four intraperitoneal injections of polyI:polyC of 200 muL of a 1 mg/mL solution.	('Bap1f/f', 'Var', (7, 14))	('polyI:polyC', 'Var', (96, 107))	('mice', 'Species', '10090', (47, 51))
127311	26437366	When tumors reached a size of approximately 60-80mm3, we began treatment with either vehicle (0.5% NaCMC+0.1% Tween-80 in water) or EPZ011989.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('NaCMC', 'Chemical', '-', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('EPZ011989', 'Var', (132, 141))	('Tween-80', 'Chemical', 'MESH:D011136', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
127312	26437366	Either EPZ011989 or vehicle were given orally BID at a concentration of 500 mg/kg for the duration of the experiment.	('EPZ011989', 'Var', (7, 16))	('BID', 'Gene', '12122', (46, 49))	('BID', 'Gene', (46, 49))
127316	26437366	Five animals per group were treated orally with either vehicle (described above) or 500 mg/kg EPZ011989 BID for 16 days.	('EPZ011989', 'Var', (94, 103))	('BID', 'Gene', '12122', (104, 107))	('BID', 'Gene', (104, 107))
127336	26437366	Antibodies used included: BAP1 (C-4; Santa Cruz sc-28383; 1:1000), EZH2 (Active Motif, 39933, Active Motif, 39901, or Millipore, 07-689;1:10,000), SUZ12 (Abcam, Ab12073, 1:1000), ASXL1 (N-13; Santa Cruz sc-85283, 1:1000), L3MBTL2 (Active Motif, 39569, 1:1000), Myc-Tag (Cell Signaling, 2276; 1:2000), SETD8 (ab3798, 1:1000), Tubulin (Sigma, T9026, 1:10,000), H3K27me3 (Abcam, 6002 or Millipore, 07-449, 1:1000), H3 (Abcam, Ab1791, 1:10,000), and H4K20me1 (Abcam, Ab9051, 1:1000).	('H3K27me3', 'Var', (359, 367))	('SUZ12', 'Gene', '52615', (147, 152))	('Tubulin', 'Protein', (325, 332))	('SUZ12', 'Gene', (147, 152))	('H4K20me1', 'Var', (446, 454))	('C-4', 'Gene', '12268', (32, 35))	('ASXL1', 'Gene', (179, 184))	('Signaling', 'biological_process', 'GO:0023052', ('275', '284'))	('C-4', 'Gene', (32, 35))	('ASXL1', 'Gene', '228790', (179, 184))
127348	26437366	Sequences for the short-hairpins were as follows: human BAP1 (TRC Oligo IDs: TRCN0000078702 and TRCN0000078698), mouse BAP1 (TRCN0000030719 and TRCN0000030720), human L3MBTL2 (TRCN0000021724 and TRCN0000021726) and a control pLKO.1-puromycin vector encoding an shRNA for luciferase (shLUC).	('TRCN0000030719', 'Disease', (125, 139))	('human', 'Species', '9606', (161, 166))	('TRCN0000021724', 'Var', (176, 190))	('TRCN0000030719', 'Disease', 'None', (125, 139))	('1-puromycin', 'Chemical', '-', (230, 241))	('TRCN0000021726', 'Var', (195, 209))	('human', 'Species', '9606', (50, 55))	('mouse', 'Species', '10090', (113, 118))
127371	23379358	We investigated whether aberrant Hh activation may play a role in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('aberrant', 'Var', (24, 32))	('mesothelioma', 'Disease', (66, 78))
127376	23379358	Our data strongly support that Hh signaling deregulation plays critical roles in proliferation of mesothelioma, and consistently exerts significant impact on prognosis of the disease.	('impact', 'Reg', (148, 154))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('deregulation', 'Var', (44, 56))	('mesothelioma', 'Disease', (98, 110))
127382	23379358	The pathogenic mechanisms underlying mesothelioma involve deregulation of multiple signaling pathways, including activation of multiple receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, the TNF-alpha / NF-kappaB survival pathway, Wnt signaling, and loss of tumor suppressors such as Neurofibromatosis type 2(NF2), p16INK4A, and p14ARF-.	('p16INK4A', 'Gene', '1029', (495, 503))	('epidermal growth factor receptor', 'Gene', (174, 206))	('TNF-alpha', 'Gene', (371, 380))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('loss of tumor', 'Disease', (430, 443))	('epidermal growth factor receptor', 'Gene', '1956', (174, 206))	('Neurofibromatosis type 2', 'Disease', 'MESH:C537392', (464, 488))	('deregulations', 'Var', (245, 258))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('signaling', 'biological_process', 'GO:0023052', ('415', '424'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('174', '197'))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('activation', 'PosReg', (113, 123))	('EGFR', 'Gene', (208, 212))	('p14ARF', 'Gene', '1029', (509, 515))	('NF2', 'Gene', '4771', (489, 492))	('PI3K', 'molecular_function', 'GO:0016303', ('337', '341'))	('MAPK', 'molecular_function', 'GO:0004707', ('296', '300'))	('Wnt signaling', 'Pathway', (411, 424))	('NF2', 'Gene', (489, 492))	('loss of tumor', 'Disease', 'MESH:D009369', (430, 443))	('protein', 'cellular_component', 'GO:0003675', ('280', '287'))	('EGFR', 'Gene', '1956', (208, 212))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (464, 481))	('tumor', 'Phenotype', 'HP:0002664', (438, 443))	('AKT signaling', 'biological_process', 'GO:0043491', ('343', '356'))	('p16INK4A', 'Gene', (495, 503))	('Neurofibromatosis type 2', 'Disease', (464, 488))	('TNF-alpha', 'Gene', '7124', (371, 380))	('mesothelioma', 'Disease', (37, 49))	('p14ARF', 'Gene', (509, 515))	('MET', 'Gene', (225, 228))
127383	23379358	It has been recently reported that sonic hedgehog (Hh) signaling, another important pathway during development and tumorigenesis, is aberrantly activated in MPM, and inhibition of hedgehog signaling suppresses tumor growth.	('hedgehog', 'Gene', '42737', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('hedgehog', 'Gene', (41, 49))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (210, 215))	('suppresses', 'NegReg', (199, 209))	('activated', 'PosReg', (144, 153))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('hedgehog', 'Gene', (180, 188))	('hedgehog', 'Gene', '42737', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('inhibition', 'Var', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
127384	23379358	Deregulated Hedgehog (Hh) pathway activation has been implicated in several human cancers including glioma, basal cell carcinoma, medulloblastoma, lung, breast, pancreatic and gastric cancers -.	('glioma', 'Disease', (100, 106))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (108, 128))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancers', 'Disease', (82, 89))	('activation', 'PosReg', (34, 44))	('Hedgehog', 'Gene', '42737', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (108, 128))	('Deregulated', 'Var', (0, 11))	('cancers', 'Disease', (184, 191))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Hedgehog', 'Gene', (12, 20))	('gastric cancers', 'Phenotype', 'HP:0012126', (176, 191))	('medulloblastoma', 'Disease', 'MESH:D008527', (130, 145))	('pancreatic and gastric cancers', 'Disease', 'MESH:D010190', (161, 191))	('medulloblastoma', 'Phenotype', 'HP:0002885', (130, 145))	('basal cell carcinoma', 'Disease', (108, 128))	('breast', 'Disease', (153, 159))	('medulloblastoma', 'Disease', (130, 145))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('lung', 'Disease', (147, 151))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('implicated', 'Reg', (54, 64))	('human', 'Species', '9606', (76, 81))
127388	23379358	Targeted inhibition of aberrant Hh signaling leads to suppression of cancer stem cells awakened and propelled by inappropriate Hh signaling.	('inhibition', 'NegReg', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('Hh signaling', 'MPA', (127, 139))	('suppression', 'NegReg', (54, 65))	('propelled', 'CPA', (100, 109))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('aberrant', 'Var', (23, 31))	('cancer', 'Disease', (69, 75))
127397	23379358	Mesothelioma cell lines NCI-H28, REN, and H290 were cultured in RPMI 1640 (Life Technology, Carlsbad, CA) supplemented with 10% FBS and penicillin (100 IU/ml) and streptomycin (100 ug/ml), at 37 C in a humid incubator with 5% CO2.	('streptomycin', 'Chemical', 'MESH:D013307', (163, 175))	('FBS', 'Disease', (128, 131))	('H290', 'CellLine', 'CVCL:A555', (42, 46))	('penicillin', 'Chemical', 'MESH:D010406', (136, 146))	('100 ug/ml', 'Var', (177, 186))	('REN', 'Gene', (33, 36))	('FBS', 'Disease', 'MESH:D005198', (128, 131))	('CO2', 'Chemical', '-', (226, 229))	('REN', 'Gene', '403838', (33, 36))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
127434	23379358	As deregulated Hh signaling pathway has been implicated in many different types of cancer, and inhibition of Hh signaling leads to suppression of tumor growth, we addressed whether Hh signaling plays critical roles in proliferation of mesothelioma cells.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mesothelioma', 'Disease', 'MESH:D008654', (235, 247))	('inhibition', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('deregulated', 'Var', (3, 14))	('suppression', 'NegReg', (131, 142))	('implicated', 'Reg', (45, 55))	('tumor', 'Disease', (146, 151))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('Hh signaling pathway', 'biological_process', 'GO:0007224', ('15', '35'))	('Hh signaling pathway', 'Pathway', (15, 35))	('signaling', 'biological_process', 'GO:0023052', ('184', '193'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mesothelioma', 'Disease', (235, 247))	('cancer', 'Disease', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
127437	23379358	These data indicate that aberrant Hh activation plays critical roles in tumor cell proliferation in mesothelioma, consistent with recent data by Shi Y et al.. Taken together, our results demonstrated a strong association between higher SMO and SHH expression levels with poorer overall survival.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('expression levels', 'MPA', (248, 265))	('higher', 'PosReg', (229, 235))	('SHH', 'Gene', (244, 247))	('tumor', 'Disease', (72, 77))	('aberrant', 'Var', (25, 33))	('mesothelioma', 'Disease', (100, 112))	('SHH', 'Gene', '6469', (244, 247))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('SMO', 'Gene', '6608', (236, 239))	('SMO', 'Gene', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
127438	23379358	Furthermore, we showed inhibition of Hh signaling blocked cell proliferation in multiple mesothelioma cell lines, strongly supporting that aberrant Hh signaling is essential for tumor growth in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('tumor', 'Disease', (178, 183))	('mesothelioma', 'Disease', (89, 101))	('inhibition', 'Var', (23, 33))	('blocked', 'NegReg', (50, 57))	('cell proliferation', 'CPA', (58, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('mesothelioma', 'Disease', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('aberrant', 'Var', (139, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
127439	32271879	Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice Badhai et al.	('deletion', 'Var', (9, 17))	('Bap1', 'Gene', (21, 25))	('Nf2', 'Gene', (27, 30))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (66, 88))	('Cdkn2ab', 'Gene', (36, 43))	('Bap1', 'Gene', '104416', (21, 25))	('Nf2', 'Gene', '18016', (27, 30))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (66, 88))	('malignant mesothelioma', 'Disease', (66, 88))
127440	32271879	describe a mouse model of mesothelioma with combined deletion of Bap1, Nf2, and Cdkn2ab that shows rapid onset and recapitulates human mesothelioma including its response to the standard treatment.	('mesothelioma', 'Disease', (26, 38))	('Nf2', 'Gene', (71, 74))	('Cdkn2a', 'Gene', (80, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('mouse', 'Species', '10090', (11, 16))	('Bap1', 'Gene', (65, 69))	('deletion', 'Var', (53, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('mesothelioma', 'Disease', (135, 147))	('human', 'Species', '9606', (129, 134))	('Cdkn2a', 'Gene', '12578', (80, 86))
127442	32271879	We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM.	('Bap1', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('disruption', 'Var', (73, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('mouse', 'Species', '10090', (18, 23))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (34, 56))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (34, 56))	('Cdkn2a', 'Gene', '12578', (106, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('Cdkn2a', 'Gene', (106, 112))	('malignant mesothelioma', 'Disease', (34, 56))	('human', 'Species', '9606', (191, 196))	('Nf2', 'Gene', (97, 100))
127443	32271879	Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients.	('patients', 'Species', '9606', (203, 211))	('leads to', 'Reg', (80, 88))	('human', 'Species', '9606', (197, 202))	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))	('Inactivation', 'Var', (0, 12))
127445	32271879	Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption.	('deletion', 'Var', (5, 13))	('Cdkn2a', 'Gene', '12578', (109, 115))	('Bap1', 'Gene', (0, 4))	('MM development', 'CPA', (67, 81))	('Cdkn2a', 'Gene', (109, 115))	('accelerates', 'PosReg', (55, 66))
127450	32271879	The genomic landscape of MM shows frequent inactivation of the CDKN2AB locus that encodes for the p16INK4A, p15INK4B, and p14ARF cell cycle inhibitor proteins and the Neurofibromatosis Type 2 (NF2) tumor suppressor gene.	('p15INK4B', 'Gene', (108, 116))	('CDKN2A', 'Gene', '1029', (63, 69))	('Neurofibromatosis Type 2', 'Gene', '18016', (167, 191))	('tumor suppressor', 'biological_process', 'GO:0051726', ('198', '214'))	('Neurofibromatosis Type 2', 'Gene', (167, 191))	('p16INK4A', 'Gene', (98, 106))	('p16INK4A', 'Gene', '12578', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('p15INK4B', 'Gene', '12579', (108, 116))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (167, 184))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('198', '214'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('p14ARF', 'Var', (122, 128))	('tumor', 'Disease', (198, 203))	('CDKN2A', 'Gene', (63, 69))	('inactivation', 'Var', (43, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))
127451	32271879	BAP1, encoding a nuclear deubiquitinase, was found to be mutated or deleted in multiple cancers, including ~60% of human MM.	('deubiquitinase', 'molecular_function', 'GO:0004843', ('25', '39'))	('deleted', 'Var', (68, 75))	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('human', 'Species', '9606', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutated', 'Var', (57, 64))
127457	32271879	Deregulation of the Polycomb repressive system is implicated in many cancers.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('implicated', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('Polycomb', 'Gene', '12416', (20, 28))	('Polycomb', 'Gene', (20, 28))	('cancers', 'Disease', (69, 76))
127460	32271879	We previously reported that simultaneous inactivation of Nf2 and Trp53 in the mesothelial lining of the thoracic cavity of mice gives rise to mesothelioma.	('Trp53', 'Gene', (65, 70))	('Nf2', 'Gene', (57, 60))	('inactivation', 'Var', (41, 53))	('Trp53', 'Gene', '22059', (65, 70))	('mesothelioma', 'Disease', (142, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('mice', 'Species', '10090', (123, 127))
127461	32271879	In addition, depleting Cdkn2a further accelerated tumor development.	('depleting', 'Var', (13, 22))	('Cdkn2a', 'Gene', '12578', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Cdkn2a', 'Gene', (23, 29))	('accelerated', 'PosReg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
127468	32271879	Mice in which Nf2, Cdkn2ab (hereafter NC) were deleted but with functional Bap1 alleles gave rise to mesothelioma in 75% of the mice, whereas the remaining 25% succumbed from other tumors such as histiocytic sarcoma and lymphoma (Table S1).	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('Bap1', 'Gene', (75, 79))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('Cdkn2a', 'Gene', '12578', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Cdkn2a', 'Gene', (19, 25))	('mice', 'Species', '10090', (128, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (220, 228))	('mesothelioma', 'Disease', (101, 113))	('alleles', 'Var', (80, 87))	('Mice', 'Species', '10090', (0, 4))	('Nf2', 'Gene', (14, 17))	('gave rise to', 'Reg', (88, 100))	('histiocytic sarcoma and lymphoma', 'Disease', 'MESH:D054747', (196, 228))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
127470	32271879	The median survival of mice homozygously deleted for NC was 190 d. The additional heterozygous or homozygous loss of Bap1 reduced the median survival to 140 and 85 d, respectively (Fig.	('loss', 'Var', (109, 113))	('reduced', 'NegReg', (122, 129))	('Bap1', 'Gene', (117, 121))	('mice', 'Species', '10090', (23, 27))
127471	32271879	S1 F), similar to analysis reported using the TCGA mesothelioma patient with BAP1, NF2, and CDKN2A alterations.	('CDKN2A', 'Gene', (92, 98))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', '1029', (92, 98))	('mesothelioma', 'Disease', (51, 63))	('alterations', 'Var', (99, 110))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))
127476	32271879	The tumor burden in the esophagus of BNC mice is significantly higher than that seen in NC mice, whereas the tumor burden is similar in other organs of the thoracic cavity (Fig.	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (91, 95))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('higher', 'PosReg', (63, 69))	('BNC', 'Var', (37, 40))	('tumor', 'Disease', (109, 114))
127484	32271879	To understand the relative contribution of deletion of each of the Bap1, Nf2, Cdkn2a, and Cdkn2b alleles to mesothelioma development, we developed single and compound models with various combinations of inactivated alleles (Table S1).	('deletion', 'Var', (43, 51))	('mesothelioma', 'Disease', (108, 120))	('Cdkn2a', 'Gene', '12578', (78, 84))	('Cdkn2b', 'Gene', (90, 96))	('Cdkn2a', 'Gene', (78, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('Nf2', 'Gene', (73, 76))	('Cdkn2b', 'Gene', '12579', (90, 96))	('Bap1', 'Gene', (67, 71))
127485	32271879	Deletion of Bap1 alone in the thoracic cavity in a cohort of 20 mice did not result in mesothelioma during the lifetime of the mice (monitored for up to 700 d) except in one heterozygous floxed mouse (Fig.	('mice', 'Species', '10090', (127, 131))	('mesothelioma', 'Disease', (87, 99))	('result in', 'Reg', (77, 86))	('mouse', 'Species', '10090', (194, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('Bap1', 'Gene', (12, 16))	('mice', 'Species', '10090', (64, 68))	('Deletion', 'Var', (0, 8))
127486	32271879	Previously, we reported that genetic deletion of Nf2 or Cdkn2a alone does not induce mesothelioma.	('induce', 'Reg', (78, 84))	('mesothelioma', 'Disease', (85, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('Nf2', 'Gene', (49, 52))	('genetic deletion', 'Var', (29, 45))	('Cdkn2a', 'Gene', '12578', (56, 62))	('Cdkn2a', 'Gene', (56, 62))
127487	32271879	The compound models with deletion of Bap1, Nf2, and Cdkn2a (Ink4a/Arf conditional; hereafter BNCa) and Nf2 together with Cdkn2a (hereafter NCa) gives rise to mesothelioma in mice with median survival of 114 and 244 d, respectively (Fig.	('Ink4a/Arf', 'Gene', '12578', (60, 69))	('Ink4a/Arf', 'Gene', (60, 69))	('Nf2', 'Gene', (43, 46))	('mice', 'Species', '10090', (174, 178))	('mesothelioma', 'Disease', (158, 170))	('deletion', 'Var', (25, 33))	('Cdkn2a', 'Gene', '12578', (121, 127))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('Cdkn2a', 'Gene', '12578', (52, 58))	('Cdkn2a', 'Gene', (52, 58))	('Cdkn2a', 'Gene', (121, 127))	('Bap1', 'Gene', (37, 41))
127490	32271879	Collectively, these mouse models show a strong MM accelerating effect of Bap1 loss in conjunction with the deletion of Nf2 and Cdkn2a/Cdkn2ab.	('Nf2', 'Gene', (119, 122))	('Bap1', 'Gene', (73, 77))	('Cdkn2a', 'Gene', '12578', (134, 140))	('Cdkn2a', 'Gene', (134, 140))	('Cdkn2a', 'Gene', '12578', (127, 133))	('loss', 'NegReg', (78, 82))	('Cdkn2a', 'Gene', (127, 133))	('deletion', 'Var', (107, 115))	('mouse', 'Species', '10090', (20, 25))
127499	32271879	Interestingly, our BNC mesothelioma model, which is exclusively based on engineered tumor suppressor gene deletions, closely mimics this inflammatory phenotype.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('deletions', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('tumor', 'Disease', (84, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('mesothelioma', 'Disease', (23, 35))
127507	32271879	However, our results show that even without asbestos exposure and associated DNA damage, the combined deletion of the tumor suppressors Bap1, Nf2, and Cdkn2ab creates a mesothelioma-specific microenvironment that enables a similar immunophenotype (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('Bap1', 'Gene', (136, 140))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('deletion', 'Var', (102, 110))	('tumor', 'Disease', (118, 123))	('Cdkn2a', 'Gene', '12578', (151, 157))	('mesothelioma', 'Disease', (169, 181))	('Nf2', 'Gene', (142, 145))	('asbestos', 'Chemical', 'MESH:D001194', (44, 52))	('Cdkn2a', 'Gene', (151, 157))
127510	32271879	To determine whether BAP1 depletion confers a distinct drug response profile, we assessed the response of BAP1-deficient and -proficient cell lines to PI3K inhibition, gamma-radiation, and poly(ADP-ribose) ploymerase (PARP) inhibition.	('inhibition', 'NegReg', (156, 166))	('depletion', 'Var', (26, 35))	('poly(ADP-ribose) ploymerase', 'Gene', (189, 216))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('BAP1-deficient', 'Gene', (106, 120))	('PI3K', 'Pathway', (151, 155))	('poly(ADP-ribose) ploymerase', 'Gene', '11545', (189, 216))
127516	32271879	Bap1 deletion causes increased sensitivity of mesothelioma cells to gamma-radiation and PARP inhibition, a feature seen in multiple human BAP1-deficient cell types (; Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('increased', 'PosReg', (21, 30))	('deletion', 'Var', (5, 13))	('sensitivity', 'MPA', (31, 42))	('Bap1', 'Gene', (0, 4))	('mesothelioma', 'Disease', (46, 58))	('human', 'Species', '9606', (132, 137))	('PARP', 'MPA', (88, 92))
127517	32271879	We reasoned that loss of BAP1 may contribute to the extent of copy number alterations seen in mesothelioma given its role in DNA damage repair.	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('BAP1', 'Gene', (25, 29))	('copy number alterations', 'Var', (62, 85))	('mesothelioma', 'Disease', (94, 106))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('loss', 'Var', (17, 21))
127522	32271879	We started administration of cisplatin and pemetrexed 6 wk after deletion of BNC alleles.	('pemetrexed', 'Chemical', 'MESH:D000068437', (43, 53))	('BNC', 'Gene', (77, 80))	('deletion', 'Var', (65, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))
127534	32271879	Loss of tumor suppressor BAP1 causes EZH2-dependent myeloid transformation and promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program.	('RNF2', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor suppressor', 'biological_process', 'GO:0051726', ('8', '24'))	('apoptotic program', 'biological_process', 'GO:0006915', ('148', '165'))	('myeloid transformation', 'CPA', (52, 74))	('RNF2', 'Gene', '19821', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('8', '24'))	('promotes', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (8, 13))	('Loss', 'Var', (0, 4))	('EZH2', 'Gene', '14056', (37, 41))	('EZH2', 'Gene', (37, 41))
127535	32271879	Epigenetic modulation, in particular by EZH2, may play a critical role in MM with BAP1 loss.	('loss', 'NegReg', (87, 91))	('BAP1', 'Gene', (82, 86))	('Epigenetic modulation', 'Var', (0, 21))	('EZH2', 'Gene', '14056', (40, 44))	('EZH2', 'Gene', (40, 44))
127536	32271879	Indeed, we observed that loss of BAP1 results in elevated EZH2 expression and increased H3K27me3 levels, and knock-down of Ezh2 leads to decreased H3K27me3 levels in BNC cells (Fig.	('knock-down', 'Var', (109, 119))	('loss', 'Var', (25, 29))	('H3K27me3 levels', 'MPA', (88, 103))	('Ezh2', 'Gene', (123, 127))	('Ezh2', 'Gene', '14056', (123, 127))	('expression', 'MPA', (63, 73))	('EZH2', 'Gene', (58, 62))	('EZH2', 'Gene', '14056', (58, 62))	('increased', 'PosReg', (78, 87))	('BAP1', 'Gene', (33, 37))	('H3K27me3 levels', 'MPA', (147, 162))	('elevated', 'PosReg', (49, 57))	('decreased', 'NegReg', (137, 146))
127540	32271879	Collectively, our data point to a situation in which BAP1 depletion in mesothelioma promotes polycomb-mediated gene repression, a tumor-promoting event seen in many tumor settings.	('mesothelioma', 'Disease', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('polycomb', 'Gene', '12416', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('polycomb', 'Gene', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('depletion', 'Var', (58, 67))	('BAP1', 'Gene', (53, 57))	('tumor', 'Disease', (130, 135))	('promotes', 'PosReg', (84, 92))	('tumor', 'Disease', (165, 170))
127544	32271879	This offers the possibility of investigating the underlying tumor suppressor pathways that are connected to increased Polycomb repression upon loss of Bap1.	('Polycomb', 'Gene', '12416', (118, 126))	('Polycomb', 'Gene', (118, 126))	('Bap1', 'Gene', (151, 155))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('increased', 'PosReg', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('loss', 'Var', (143, 147))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
127565	32271879	We put the mice on tumor watch after deletion of floxed alleles by Adeno-CMV-Cre.	('deletion', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Disease', (19, 24))
127571	32271879	IHC was performed for proteins such as WT-1, cytokeratins, CK8, vimentin, F4/80, TTF-1, MYF4, CD68, CD3, CD4, CD45R, and FOXP3.	('CD68', 'Var', (94, 98))	('MYF4', 'Gene', (88, 92))	('MYF4', 'Gene', '17928', (88, 92))	('CD3', 'Gene', (100, 103))	('TTF-1', 'Gene', '22130', (81, 86))	('vimentin', 'cellular_component', 'GO:0045099', ('64', '72'))	('F4/80', 'Gene', (74, 79))	('CD3', 'Gene', '12501', (100, 103))	('F4/80', 'Gene', '13733', (74, 79))	('vimentin', 'cellular_component', 'GO:0045098', ('64', '72'))	('TTF-1', 'Gene', (81, 86))
127572	32271879	Signaling pathways were examined by IHC with the following antibodies: p-EGFR, p-S6, p-AKT, and p-ERK.	('p-S6', 'Var', (79, 83))	('EGFR', 'Gene', '13649', (73, 77))	('p-AKT', 'Var', (85, 90))	('ERK', 'molecular_function', 'GO:0004707', ('98', '101'))	('EGFR', 'Gene', (73, 77))	('ERK', 'Gene', (98, 101))	('Signaling', 'biological_process', 'GO:0023052', ('0', '9'))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('ERK', 'Gene', '26413', (98, 101))
127577	32271879	IHC was performed with the following antibodies: p-S6, p-AKT, p-ERK, CD68, CD3, FOXP3, cytokeratins, WT1, and podoplanin.	('CD3', 'Gene', '12501', (75, 78))	('p-S6', 'Var', (49, 53))	('FOXP3', 'Gene', (80, 85))	('ERK', 'Gene', (64, 67))	('CD68', 'Var', (69, 73))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))	('p-AKT', 'Var', (55, 60))	('ERK', 'Gene', '26413', (64, 67))	('WT1', 'Gene', '22431', (101, 104))	('CD3', 'Gene', (75, 78))	('WT1', 'Gene', (101, 104))
127578	32271879	To knock down Ezh2 expression in mesothelioma cells, we used dox-inducible FH1-tUTG-RNAi vectors containing the following targeting sequence: Ezh2-tetKD-A, 5'-GCAAAGCTTGCATTCATTTCA-3'.	('FH1', 'Gene', '14194', (75, 78))	('FH1', 'Gene', (75, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('RNAi', 'biological_process', 'GO:0016246', ('84', '88'))	('Ezh2', 'Gene', (14, 18))	('Ezh2', 'Gene', '14056', (14, 18))	('Ezh2', 'Gene', (142, 146))	('knock', 'Var', (3, 8))	('Ezh2', 'Gene', '14056', (142, 146))	('mesothelioma', 'Disease', (33, 45))	('dox', 'Chemical', 'MESH:D004317', (61, 64))
127591	32271879	We selected patients from TCGA mesothelioma cohorts with combined BAP1, NF2, and CDKN2A alterations and history of asbestos exposure.	('patients', 'Species', '9606', (12, 20))	('CDKN2A', 'Gene', (81, 87))	('mesothelioma', 'Disease', (31, 43))	('asbestos', 'Chemical', 'MESH:D001194', (115, 123))	('NF2', 'Gene', (72, 75))	('alterations', 'Var', (88, 99))	('BAP1', 'Gene', (66, 70))	('CDKN2A', 'Gene', '1029', (81, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))
127726	28652992	The immunohistochemical profile of this neoplasm includes positivity for cytokeratin 7 and 5/6, calretinin, EMA, D2-40, and thrombomodulin, and negativity for cytokeratin 20, BerEP4, B72.3, MOC-31, and Leu-M1.	('thrombomodulin', 'Protein', (124, 138))	('calretinin', 'Gene', (96, 106))	('cytokeratin 20', 'Gene', (159, 173))	('positivity', 'Var', (58, 68))	('cytokeratin 7 and 5/6', 'Gene', '3855;3852', (73, 94))	('negativity', 'Var', (144, 154))	('MOC-31', 'Gene', (190, 196))	('cytokeratin 20', 'Gene', '54474', (159, 173))	('neoplasm', 'Disease', (40, 48))	('calretinin', 'Gene', '794', (96, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (40, 48))	('neoplasm', 'Disease', 'MESH:D009369', (40, 48))	('B72.3', 'Gene', (183, 188))
127729	28652992	Positivity for calretinin differentiates mesothelioma from adenocarcinoma, and the negativity for BerEP4 stands for mesothelioma versus adenocarcinoma.	('mesothelioma', 'Disease', (116, 128))	('differentiates', 'Reg', (26, 40))	('mesothelioma versus adenocarcinoma', 'Disease', 'MESH:D008654', (116, 150))	('adenocarcinoma', 'Disease', (136, 150))	('calretinin', 'Gene', (15, 25))	('mesothelioma', 'Disease', (41, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (136, 150))	('adenocarcinoma', 'Disease', (59, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('Positivity', 'Var', (0, 10))	('mesothelioma versus adenocarcinoma', 'Disease', (116, 150))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('calretinin', 'Gene', '794', (15, 25))
127925	25917934	For patients with advanced-stage HL, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on the following seven adverse factors: age more than 45 years, male gender, stage IV disease, albumin level below 4.0 g/dl, haemoglobin level below 10.5 g/dl, white blood cell count more than 15,000/mm3, absolute lymphocytic count less than 600/mm3 or a lymphocyte count less than 8 % of the total WBC count.	('less', 'NegReg', (400, 404))	('albumin level', 'MPA', (263, 276))	('lymphocyte count less than 8 %', 'Phenotype', 'HP:0001888', (423, 453))	('HL', 'Phenotype', 'HP:0012189', (33, 35))	('patients', 'Species', '9606', (4, 12))	('below', 'Var', (277, 282))	('less', 'NegReg', (440, 444))
127940	25917934	FDG-PET positivity at the treatment completion is an adverse prognostic factor for disease-free survival.	('FDG-PET', 'Gene', (0, 7))	('FDG', 'Chemical', '-', (0, 3))	('disease-free survival', 'CPA', (83, 104))	('positivity', 'Var', (8, 18))
128019	25917934	Anthracyclines cause dose-dependent cardiac toxicity that can produce irreversible cardiomyopathy.	('cardiomyopathy', 'Disease', (83, 97))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('cardiac toxicity', 'Disease', 'MESH:D066126', (36, 52))	('cardiac toxicity', 'Disease', (36, 52))	('irreversible', 'Disease', (70, 82))	('produce', 'Reg', (62, 69))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (83, 97))	('cardiomyopathy', 'Disease', 'MESH:D009202', (83, 97))	('Anthracyclines', 'Var', (0, 14))
128035	25917934	Cyclophosphamide can cause pulmonary haemorrhage and diffuse alveolar damage.	('pulmonary haemorrhage', 'Disease', (27, 48))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('diffuse', 'Disease', (53, 60))	('alveolar damage', 'Disease', 'MESH:C536591', (61, 76))	('pulmonary haemorrhage', 'Phenotype', 'HP:0040223', (27, 48))	('cause', 'Reg', (21, 26))	('pulmonary haemorrhage', 'Disease', 'MESH:D006470', (27, 48))	('alveolar damage', 'Disease', (61, 76))	('Cyclophosphamide', 'Var', (0, 16))
128091	22537085	has shown that development of mesothelioma by crocidolite asbestos was accelerated in this mutant mouse.	('accelerated', 'PosReg', (71, 82))	('mesothelioma by crocidolite asbestos', 'Disease', (30, 66))	('rat', 'Species', '10116', (77, 80))	('mesothelioma by crocidolite asbestos', 'Disease', 'MESH:D008654', (30, 66))	('mouse', 'Species', '10090', (98, 103))	('mutant', 'Var', (91, 97))	('development', 'CPA', (15, 26))
128093	22537085	Here, we applied the same fiber to p53+/- mice at doses of 1/10, 1/100, and 1/1000 of the dose used in the previous study (i.e.	('mice', 'Species', '10090', (42, 46))	('p53', 'Gene', '22060', (35, 38))	('p53', 'Gene', (35, 38))	('1/100', 'Var', (65, 70))
128135	22537085	The present study showed a dose-dependent induction of mesothelioma by the mum-MWCNT from 1/1000 of the dose of our previous study (i.e.	('mesothelioma', 'Disease', (55, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('mum-MWCNT', 'Var', (75, 84))	('MWCNT', 'Chemical', '-', (79, 84))
128158	22537085	In conclusion, mum-MWCNT was mesotheliomagenic in the p53+/- mouse peritoneal cavity model in a dose-dependent manner from as low as 3 mug per mouse or approximately 106 fibers per mouse.	('mum-MWCNT', 'Var', (15, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('mouse', 'Species', '10090', (143, 148))	('MWCNT', 'Chemical', '-', (19, 24))	('p53', 'Gene', (54, 57))	('mouse', 'Species', '10090', (181, 186))	('mug', 'molecular_function', 'GO:0043739', ('135', '138'))	('mouse', 'Species', '10090', (61, 66))	('mesothelioma', 'Disease', (29, 41))	('p53', 'Gene', '22060', (54, 57))	('man', 'Species', '9606', (111, 114))
128249	22768319	Intelectin-1 staining is an excellent means of performing a differential diagnosis of MPM, not only due to its specificity for MPM but also due to the evidently higher positive proportion of MPMs (Table S1).	('Intelectin-1', 'Gene', '55600', (0, 12))	('MPM', 'Disease', (127, 130))	('MPMs', 'Var', (191, 195))	('Intelectin-1', 'Gene', (0, 12))	('higher', 'PosReg', (161, 167))	('MPM', 'Disease', (86, 89))
128376	21534084	Further, as noted by the Institute of Medicine and National Research Council's recent review of the NIOSH roadmap for research on asbestos fibers: These changes in mineral names far outpace the ability of the rulemaking and legislative processes in the United States and have caused considerable confusion and misunderstanding, as is evident in recent legal actions relating to asbestos contamination in Libby, Montana.	('asbestos', 'Chemical', 'MESH:D001194', (378, 386))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('confusion', 'Phenotype', 'HP:0001289', (296, 305))	('caused', 'Reg', (276, 282))	('asbestos', 'Chemical', 'MESH:D001194', (130, 138))	('changes', 'Var', (153, 160))
128584	30883000	q12w in patients with malignant mesothelioma showed signs of efficacy.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (22, 44))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (22, 44))	('malignant mesothelioma', 'Disease', (22, 44))	('q12w', 'Var', (0, 4))	('patients', 'Species', '9606', (8, 16))
128586	30883000	A second study (NCT01655888) of similar design (open-label, single-arm) was later conducted by the same investigator6 with a higher dose intensity (10 mg/kg q4w for up to week 24 followed by q12w until disease progression or unacceptable toxicity).	('toxicity', 'Disease', 'MESH:D064420', (238, 246))	('toxicity', 'Disease', (238, 246))	('10 mg/kg', 'Var', (148, 156))
128654	30883000	When the single-dose experimental arm shows a clinically relevant benefit over standard of care, as in the case of trastuzumab in gastric cancer24 or trastuzumab-DM1 in breast cancer,25 a post hoc analysis of E-R26, 27 was also conducted to decide whether nonresponders could have benefited from a higher dose.	('cancer', 'Disease', (138, 144))	('trastuzumab', 'Chemical', 'MESH:D000068878', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('trastuzumab-DM1', 'Var', (150, 165))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('men', 'Species', '9606', (27, 30))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('breast cancer', 'Disease', (169, 182))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('trastuzumab', 'Chemical', 'MESH:D000068878', (150, 161))
128663	30883000	Based on the biology of malignant tumors, these factors are expected to relate to OS regardless of tremelimumab exposure, and any imbalance in these baseline factors when grouping by exposure status may result in a confounding effect, making the E-R only "apparent."	('malignant tumors', 'Disease', 'MESH:D018198', (24, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tremelimumab', 'Chemical', 'MESH:C520704', (99, 111))	('imbalance', 'Var', (130, 139))	('confounding', 'MPA', (215, 226))	('malignant tumors', 'Disease', (24, 40))	('result in', 'Reg', (203, 212))	('relate', 'Reg', (72, 78))	('imbalance', 'Phenotype', 'HP:0002172', (130, 139))	('OS', 'Chemical', '-', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
128799	29113559	To date, 17 studies from the NTP have reported xenobiotic-induced mesotheliomas in F344 rats; the F344 rat is particularly sensitive to developing this tumor type and is the only rodent strain reported to develop mesothelioma following xenobiotic exposure by a route other than peritoneal injection.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mesothelioma', 'Disease', (213, 225))	('mesotheliomas', 'Disease', 'MESH:D008654', (66, 79))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Disease', (152, 157))	('mesotheliomas', 'Disease', (66, 79))	('mesothelioma', 'Disease', (66, 78))	('xenobiotic-', 'Phenotype', 'HP:0031838', (47, 58))	('develop', 'PosReg', (205, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (213, 225))	('NTP', 'Chemical', '-', (29, 32))	('F344', 'Var', (98, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('rats', 'Species', '10116', (88, 92))
128825	29113559	The causative frame-disrupting mutations of the DMD gene precludes the full translation of its protein product, dystrophin, causing progressive muscle disease.	('mutations', 'Var', (31, 40))	('causing', 'Reg', (124, 131))	('frame-disrupting', 'Reg', (14, 30))	('full translation', 'MPA', (71, 87))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('precludes', 'NegReg', (57, 66))	('translation', 'biological_process', 'GO:0006412', ('76', '87'))	('muscle disease', 'Disease', (144, 158))	('muscle disease', 'Disease', 'MESH:D009135', (144, 158))	('DMD gene', 'Gene', (48, 56))
128901	29113559	A classic seminoma would be positive for OCT4 and D2-40 whereas a spermatocytic tumor would be negative for both.	('seminoma', 'Disease', 'MESH:D018239', (10, 18))	('spermatocytic tumor', 'Disease', 'MESH:C563236', (66, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('positive', 'Reg', (28, 36))	('seminoma', 'Disease', (10, 18))	('D2-40', 'Var', (50, 55))	('OCT4', 'Protein', (41, 45))	('spermatocytic tumor', 'Disease', (66, 85))
129173	18672314	The MET receptor and its ligand HGF (hepatocyte growth factor) play important roles in cell growth, survival and migration, and dysregulation of the HGF-MET pathway leads to oncogenic changes including tumor proliferation, angiogenesis and metastasis.	('metastasis', 'CPA', (240, 250))	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('hepatocyte growth factor', 'Gene', '3082', (37, 61))	('tumor', 'Disease', (202, 207))	('ligand', 'molecular_function', 'GO:0005488', ('25', '31'))	('leads to', 'Reg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('37', '61'))	('oncogenic changes', 'CPA', (174, 191))	('HGF-MET', 'Gene', (149, 156))	('hepatocyte growth factor', 'Gene', (37, 61))	('dysregulation', 'Var', (128, 141))	('angiogenesis', 'CPA', (223, 235))	('angiogenesis', 'biological_process', 'GO:0001525', ('223', '235'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
129174	18672314	In small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), and malignant pleural mesothelioma (MPM), MET is dysregulated via overexpression, constitutive activation, gene amplification, ligand-dependent activation, mutation or epigenetic mechanisms.	('SCLC', 'Gene', (63, 67))	('SCLC', 'Gene', '7864', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('mutation', 'Var', (226, 234))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('small cell lung cancer', 'Disease', 'MESH:D055752', (38, 60))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (74, 104))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (34, 60))	('MET', 'Gene', (112, 115))	('NSCLC', 'Disease', (62, 67))	('ligand', 'molecular_function', 'GO:0005488', ('197', '203'))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('SCLC', 'Gene', '7864', (27, 31))	('SCLC', 'Gene', (27, 31))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (84, 104))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (34, 60))	('epigenetic mechanisms', 'Var', (238, 259))	('overexpression', 'PosReg', (136, 150))	('small cell lung cancer', 'Disease', 'MESH:D055752', (3, 25))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('malignant pleural mesothelioma', 'Disease', (74, 104))	('small cell lung cancer', 'Disease', (3, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('gene amplification', 'Var', (177, 195))	('non small cell lung cancer', 'Disease', (34, 60))
129182	18672314	The function of MET in human tumors can be enhanced by mutation or amplification of this receptor, leading to oncogenic changes including cell proliferation, reduced apoptosis, angiogenesis, altered cytoskeletal function and metastasis.	('enhanced', 'PosReg', (43, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('altered', 'Reg', (191, 198))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('cell proliferation', 'CPA', (138, 156))	('amplification', 'Var', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('angiogenesis', 'CPA', (177, 189))	('human', 'Species', '9606', (23, 28))	('tumors', 'Disease', (29, 35))	('reduced', 'NegReg', (158, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('mutation', 'Var', (55, 63))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('function', 'MPA', (4, 12))	('angiogenesis', 'biological_process', 'GO:0001525', ('177', '189'))	('metastasis', 'CPA', (225, 235))	('cytoskeletal function', 'CPA', (199, 220))	('apoptosis', 'CPA', (166, 175))
129186	18672314	Phosphorylation of S985 negatively regulates kinase activity and phosphorylation of Y1003 recruits c-Cbl, which monoubiquinates MET and interacts with endophilin, targeting MET for internalization and degradation.	('kinase activity', 'MPA', (45, 60))	('negatively', 'NegReg', (24, 34))	('MET', 'MPA', (173, 176))	('c-Cbl', 'Gene', (99, 104))	('degradation', 'MPA', (201, 212))	('c-Cbl', 'Gene', '867', (99, 104))	('kinase activity', 'molecular_function', 'GO:0016301', ('45', '60'))	('internalization', 'MPA', (181, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('Y1003', 'Var', (84, 89))	('interacts', 'Interaction', (136, 145))	('S985', 'Var', (19, 23))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('regulates', 'Reg', (35, 44))	('targeting', 'Reg', (163, 172))	('degradation', 'biological_process', 'GO:0009056', ('201', '212'))
129187	18672314	The TK domain contains numerous tyrosine phosphorylation sites: Y1230, Y1234 and Y1235 are involved in autophosphorylation and initiation of tyrosine kinase activity; Y1313 assists in activation of P13K and recruitment of p85; Y1349 and Y1356 are multi-substrate docking sites for SH2 (Src homology-2), PTB (phosphotyrosine binding) and MDB (MET binding domain)-containing proteins; Y1365 is involved in cell morphogenesis.	('p85', 'Gene', (222, 225))	('P13K', 'Mutation', 'p.P13K', (198, 202))	('tyrosine kinase', 'Gene', '7294', (141, 156))	('MDB', 'Disease', 'MESH:D008527', (337, 340))	('phosphotyrosine binding', 'molecular_function', 'GO:0001784', ('308', '331'))	('Y1313', 'Var', (167, 172))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('tyrosine', 'Chemical', 'MESH:D014443', (141, 149))	('cell morphogenesis', 'biological_process', 'GO:0000902', ('404', '422'))	('binding', 'molecular_function', 'GO:0005488', ('346', '353'))	('Y1234', 'Var', (71, 76))	('Y1230', 'Var', (64, 69))	('tyrosine', 'Chemical', 'MESH:D014443', (315, 323))	('Y1365', 'Var', (383, 388))	('P13K', 'Enzyme', (198, 202))	('kinase activity', 'molecular_function', 'GO:0016301', ('150', '165'))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (308, 323))	('TK', 'Gene', '7294', (4, 6))	('p85', 'Gene', '8874', (222, 225))	('MDB', 'Disease', (337, 340))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('tyrosine kinase', 'Gene', (141, 156))	('Y1235', 'Var', (81, 86))
129199	18672314	Mutation or amplification of the MET gene has been shown in various cancer types, and introduction of Met or HGF transgenes into murine germ cells induces neoplastic growth.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('HGF', 'Gene', (109, 112))	('transgenes', 'Var', (113, 123))	('induces', 'Reg', (147, 154))	('Mutation', 'Var', (0, 8))	('amplification', 'Var', (12, 25))	('murine', 'Species', '10090', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('Met', 'Gene', (102, 105))	('neoplastic growth', 'CPA', (155, 172))	('MET', 'Gene', (33, 36))
129200	18672314	First, the regulation of MET may be altered via overexpression, constitutive kinase activation, gene amplification, paracrine/autocrine activation via HGF, MET mutation or epigenetic mechanisms (tumor secreted growth factors, hypoxia, other oncogenes).	('mutation', 'Var', (160, 168))	('tumor', 'Disease', (195, 200))	('activation', 'PosReg', (84, 94))	('HGF', 'Gene', (151, 154))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('MET', 'Gene', (25, 28))	('paracrine/autocrine', 'MPA', (116, 135))	('hypoxia', 'Disease', (226, 233))	('hypoxia', 'Disease', 'MESH:D000860', (226, 233))	('altered', 'Reg', (36, 43))	('overexpression', 'PosReg', (48, 62))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('regulation', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('epigenetic', 'Var', (172, 182))	('constitutive kinase', 'MPA', (64, 83))
129202	18672314	When subcategorized, 67% of adenocarcinomas, 60% of carcinoids, 57% of large cell carcinomas, 57% of squamous cell carcinomas and 25% of SCLCs strongly expressed MET.	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('carcinoid', 'Phenotype', 'HP:0100570', (52, 61))	('MET', 'Var', (162, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (101, 125))	('carcinoids', 'Disease', (52, 62))	('adenocarcinomas', 'Disease', 'MESH:D000230', (28, 43))	('adenocarcinomas', 'Disease', (28, 43))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('carcinoids', 'Phenotype', 'HP:0100570', (52, 62))	('large cell carcinomas', 'Phenotype', 'HP:0030360', (71, 92))	('SCLC', 'Gene', '7864', (137, 141))	('squamous cell carcinomas', 'Disease', (101, 125))	('SCLC', 'Gene', (137, 141))	('cell carcinomas', 'Disease', 'MESH:C538614', (110, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('cell carcinomas', 'Disease', (77, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cell carcinomas', 'Disease', 'MESH:C538614', (77, 92))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (71, 91))
129203	18672314	When assessing for functional activity with p-MET staining, 44% of adenocarcinomas, 86% of large cell, 71% of squamous cell, 40% of carcinoids and 100% of SCLCs demonstrated MET phosphorylation at the Y1003 c-Cbl binding site; 33% of adenocarcinomas, 57% of large cell and 50% of SCLCs demonstrated MET autophosphorylation at the Y1230/1234/1235 site.	('MET autophosphorylation', 'MPA', (299, 322))	('Y1230/1234/1235', 'Var', (330, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('binding', 'molecular_function', 'GO:0005488', ('213', '220'))	('MET phosphorylation', 'MPA', (174, 193))	('carcinoid', 'Phenotype', 'HP:0100570', (132, 141))	('adenocarcinomas', 'Disease', 'MESH:D000230', (67, 82))	('adenocarcinomas', 'Disease', (67, 82))	('c-Cbl', 'Gene', (207, 212))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('adenocarcinomas', 'Disease', 'MESH:D000230', (234, 249))	('adenocarcinomas', 'Disease', (234, 249))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('SCLC', 'Gene', (155, 159))	('SCLC', 'Gene', '7864', (155, 159))	('SCLC', 'Gene', (280, 284))	('SCLC', 'Gene', '7864', (280, 284))	('carcinoids', 'Phenotype', 'HP:0100570', (132, 142))	('c-Cbl', 'Gene', '867', (207, 212))
129208	18672314	Fourth, MET gene mutation or amplification may promote tumorigenesis, such as the germline missense mutation in hereditary papillary renal cell carcinoma, TK domain mutations, JM domain mutations, and sema domain mutations.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('amplification', 'Var', (29, 42))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (123, 153))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('hereditary papillary renal cell carcinoma', 'Disease', (112, 153))	('promote', 'PosReg', (47, 54))	('sema', 'Gene', '7869', (201, 205))	('tumor', 'Disease', (55, 60))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (112, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('TK', 'Gene', '7294', (155, 157))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('MET', 'Gene', (8, 11))	('sema', 'Gene', (201, 205))	('missense mutation', 'Var', (91, 108))
129213	18672314	There have been over 20 mutations identified in MET, most frequently they are missense mutations located in the TK domain, although mutations in a number of other domains have been identified.	('mutations', 'Var', (24, 33))	('missense mutations', 'Var', (78, 96))	('TK', 'Gene', '7294', (112, 114))
129214	18672314	[see Figure 1b] Mutations in the Sema domain affect binding to HGF, those in the JM domain affect the actin cytoskeleton, cell motility and migration.	('affect', 'Reg', (45, 51))	('actin cytoskeleton', 'MPA', (102, 120))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('102', '120'))	('cell motility', 'biological_process', 'GO:0048870', ('122', '135'))	('cell motility', 'CPA', (122, 135))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('HGF', 'Protein', (63, 66))	('Sema', 'Gene', (33, 37))	('Mutations', 'Var', (16, 25))	('Sema', 'Gene', '7869', (33, 37))	('affect', 'Reg', (91, 97))	('binding', 'Interaction', (52, 59))	('migration', 'CPA', (140, 149))
129215	18672314	Mutations in the TK domain facilitate oligomerization and activate c-Met in the absence of HGF.	('facilitate', 'PosReg', (27, 37))	('activate', 'PosReg', (58, 66))	('TK', 'Gene', '7294', (17, 19))	('c-Met', 'Gene', (67, 72))	('Mutations', 'Var', (0, 9))	('oligomerization', 'MPA', (38, 53))	('c-Met', 'Gene', '4233', (67, 72))
129219	18672314	Two unique JM domain missense mutations were identified: R988C was found in 2 cells lines with extensive stage SCLC, and T1010I was found in 1 cell line.	('T1010I', 'Var', (121, 127))	('R988C', 'Var', (57, 62))	('SCLC', 'Gene', (111, 115))	('R988C', 'Mutation', 'p.R988C', (57, 62))	('SCLC', 'Gene', '7864', (111, 115))	('T1010I', 'Mutation', 'p.T1010I', (121, 127))
129221	18672314	Both R988C and T1010I cells showed less cell-spreading and less cell-adhesion than wild type MET cells.	('cell-adhesion', 'biological_process', 'GO:0007155', ('64', '77'))	('cell-spreading', 'CPA', (40, 54))	('less', 'NegReg', (35, 39))	('R988C', 'Var', (5, 10))	('R988C', 'Mutation', 'p.R988C', (5, 10))	('T1010I', 'Var', (15, 21))	('less', 'NegReg', (59, 63))	('cell-adhesion', 'CPA', (64, 77))	('T1010I', 'Mutation', 'p.T1010I', (15, 21))
129223	18672314	T1010I cells showed increased motility and migration and R988C cells had a higher percentage of migration.	('increased', 'PosReg', (20, 29))	('migration', 'CPA', (96, 105))	('T1010I', 'Var', (0, 6))	('R988C', 'Var', (57, 62))	('higher', 'PosReg', (75, 81))	('R988C', 'Mutation', 'p.R988C', (57, 62))	('T1010I', 'Mutation', 'p.T1010I', (0, 6))	('migration', 'CPA', (43, 52))	('motility', 'CPA', (30, 38))
129224	18672314	One unique Sema domain missense somatic mutation was also identified: E168D was found in 1 cell line and may have a role in tumor progression via aberrant semaphorin signaling.	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('E168D', 'Var', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('E168D', 'Mutation', 'p.E168D', (70, 75))	('sema', 'Gene', '7869', (155, 159))	('tumor', 'Disease', (124, 129))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('role', 'Reg', (116, 120))	('sema', 'Gene', (155, 159))	('Sema', 'Gene', (11, 15))	('Sema', 'Gene', '7869', (11, 15))
129225	18672314	Of note, there has been a previously reported homozygous deletion of 3p21.3 where sema 3B and 3F are located.	('deletion', 'Var', (57, 65))	('sema 3B and 3F', 'Gene', '7869;6405', (82, 96))	('3p21.3', 'Gene', (69, 75))
129231	18672314	MET mutations have also been documented in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (43, 69))	('MET mutations', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('documented', 'Reg', (29, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (47, 69))	('non-small cell lung cancer', 'Disease', (43, 69))	('mutations', 'Var', (4, 13))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (43, 69))
129233	18672314	Three JM domain mutations were identified: R988C was found in 1 cell line, both R988C and T1010I were found in 1 tissue, and S1058P was found in 1 tissue.	('S1058P', 'Var', (125, 131))	('T1010I', 'Var', (90, 96))	('R988C', 'Var', (43, 48))	('S1058P', 'Mutation', 'p.S1058P', (125, 131))	('R988C', 'Mutation', 'p.R988C', (43, 48))	('T1010I', 'Mutation', 'p.T1010I', (90, 96))	('R988C', 'Var', (80, 85))	('R988C', 'Mutation', 'p.R988C', (80, 85))
129234	18672314	Four sema domain missense mutations were identified: E168D was found in 1 tissue, L229F was found in 1 tissue, S323G was found in 1 tissue, and N375S was found in 3 tissues.	('L229F', 'Mutation', 'p.L229F', (82, 87))	('N375S', 'Mutation', 'rs33917957', (144, 149))	('E168D', 'Var', (53, 58))	('S323G', 'Mutation', 'p.S323G', (111, 116))	('E168D', 'Mutation', 'p.E168D', (53, 58))	('sema', 'Gene', '7869', (5, 9))	('S323G', 'Var', (111, 116))	('N375S', 'Var', (144, 149))	('L229F', 'Var', (82, 87))	('sema', 'Gene', (5, 9))
129241	18672314	MET amplification has also been documented in lung cancer, especially after treatment with tyrosine kinase inhibitors.	('tyrosine kinase', 'Gene', (91, 106))	('MET amplification', 'Var', (0, 17))	('documented', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('tyrosine kinase', 'Gene', '7294', (91, 106))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
129247	18672314	Hence, amplification of the MET oncogene allows tumors to potentially overcome therapeutic inhibition of growth signals.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('inhibition of growth', 'biological_process', 'GO:0045926', ('91', '111'))	('MET', 'Gene', (28, 31))	('amplification', 'Var', (7, 20))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
129248	18672314	Amplification of focal adhesion signaling molecules such as paxillin has also been demonstrated in lung cancer.	('focal adhesion', 'cellular_component', 'GO:0005925', ('17', '31'))	('Amplification', 'Var', (0, 13))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('paxillin', 'Gene', '5829', (60, 68))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('paxillin', 'Gene', (60, 68))	('focal adhesion', 'Protein', (17, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
129250	18672314	In analysis of tissue from 66 NSCLC patients, increased copy numbers of both paxillin and MET were found in 17% of large cell carcinomas, 8% of adenocarcinomas and 13% of squamous cell carcinomas.	('large cell carcinomas', 'Phenotype', 'HP:0030360', (115, 136))	('cell carcinomas', 'Disease', 'MESH:C538614', (180, 195))	('found', 'Reg', (99, 104))	('cell carcinomas', 'Disease', (121, 136))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('cell carcinomas', 'Disease', 'MESH:C538614', (121, 136))	('patients', 'Species', '9606', (36, 44))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (171, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('NSCLC', 'Disease', (30, 35))	('copy numbers', 'Var', (56, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('adenocarcinomas', 'Disease', 'MESH:D000230', (144, 159))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (171, 195))	('adenocarcinomas', 'Disease', (144, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (115, 135))	('paxillin', 'Gene', '5829', (77, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('squamous cell carcinomas', 'Disease', (171, 195))	('increased', 'PosReg', (46, 55))	('MET', 'Gene', (90, 93))	('paxillin', 'Gene', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
129251	18672314	Furthermore, 21 paxillin mutations were found among 9.4% of lung cancers studied, more frequently in large cell carcinoma (18.4%) than adenocarcinoma (8.6%), squamous cell carcinoma (6%), or small cell carcinoma (0%).	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('lung cancers', 'Phenotype', 'HP:0100526', (60, 72))	('cell carcinoma', 'Disease', 'MESH:C538614', (197, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('mutations', 'Var', (25, 34))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('cell carcinoma', 'Disease', 'MESH:C538614', (107, 121))	('small cell carcinoma', 'Disease', (191, 211))	('small cell carcinoma', 'Disease', 'MESH:D018288', (191, 211))	('paxillin', 'Gene', '5829', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (101, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('found', 'Reg', (40, 45))	('cell carcinoma', 'Disease', 'MESH:C538614', (167, 181))	('paxillin', 'Gene', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('squamous cell carcinoma', 'Disease', (158, 181))	('lung cancers', 'Disease', 'MESH:D008175', (60, 72))	('adenocarcinoma', 'Disease', (135, 149))	('lung cancers', 'Disease', (60, 72))	('cell carcinoma', 'Disease', (107, 121))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (191, 211))
129255	18672314	Most recently, a similar role for MET in malignant pleural mesothelioma has been demonstrated.	('MET', 'Var', (34, 37))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (51, 71))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (41, 71))	('malignant pleural mesothelioma', 'Disease', (41, 71))
129257	18672314	Two JM domain mutations were identified: T1010I was present in 2 cell lines, and G1085X was present in 1 tissue.	('T1010I', 'Var', (41, 47))	('T1010I', 'Mutation', 'p.T1010I', (41, 47))	('G1085X', 'Mutation', 'p.G1085X', (81, 87))	('G1085X', 'Var', (81, 87))
129258	18672314	Of note, the 2 MPM cell lines with the T1010I mutation exhibited the most dramatic reduction of cell growth with the small molecule inhibitor SU11274.	('T1010I', 'Mutation', 'p.T1010I', (39, 45))	('cell growth', 'biological_process', 'GO:0016049', ('96', '107'))	('T1010I', 'Var', (39, 45))	('reduction', 'NegReg', (83, 92))	('SU11274', 'Chemical', 'MESH:C478479', (142, 149))	('cell growth', 'CPA', (96, 107))
129259	18672314	Three sema domain mutations were identified: N375S, M431V and N454I, each present in 1 tissue.	('N454I', 'Mutation', 'p.N454I', (62, 67))	('N375S', 'Var', (45, 50))	('M431V', 'Mutation', 'p.M431V', (52, 57))	('N375S', 'Mutation', 'rs33917957', (45, 50))	('sema', 'Gene', '7869', (6, 10))	('sema', 'Gene', (6, 10))	('M431V', 'Var', (52, 57))	('N454I', 'Var', (62, 67))
129262	18672314	The growth of these three lines (plus another that was not sensitive to HGF) was inhibited by the small molecule SU11274.	('growth', 'CPA', (4, 10))	('SU11274', 'Var', (113, 120))	('SU11274', 'Chemical', 'MESH:C478479', (113, 120))	('inhibited', 'NegReg', (81, 90))
129264	18672314	Similar to the effects of siRNA in NSCLC, siRNA in MPM also downregulated MET expression, with resulting inhibition of cell growth, viability and migration.	('NSCLC', 'Disease', (35, 40))	('inhibition', 'NegReg', (105, 115))	('cell growth', 'CPA', (119, 130))	('siRNA', 'Var', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('MET expression', 'MPA', (74, 88))	('downregulated', 'NegReg', (60, 73))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('105', '130'))
129281	18672314	Specific anti-MET miRNAs include mir-1/206, mir-199a, mir-34 and mir-23; anti-HGF miRNAs include mir-26 and mir-190.	('mir-1/206', 'Var', (33, 42))	('mir-34', 'Gene', '407040', (54, 60))	('mir-190', 'Gene', (108, 115))	('mir-190', 'Gene', '406965', (108, 115))	('mir-199a', 'Var', (44, 52))	('mir-26', 'Var', (97, 103))	('mir-34', 'Gene', (54, 60))	('mir-23', 'Var', (65, 71))
129294	18672314	In NIH3T3 cells expressing HGF or MET mutations, geldanamycin down-regulated MET protein expression, inhibited HGF-dependent motility and invasion, and blocked transformation of this cell line.	('blocked', 'NegReg', (152, 159))	('NIH3T3', 'CellLine', 'CVCL:0594', (3, 9))	('down-regulated', 'NegReg', (62, 76))	('MET', 'Gene', (34, 37))	('mutations', 'Var', (38, 47))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('transformation', 'CPA', (160, 174))	('geldanamycin', 'Chemical', 'MESH:C001277', (49, 61))	('invasion', 'CPA', (138, 146))	('inhibited', 'NegReg', (101, 110))	('MET protein', 'Protein', (77, 88))
129304	18672314	AMG102 (Amgen, Inc) is a fully human IgG2 monoclonal antibody that binds and neutralizes SF/HGF preventing its binding to c-MET and activation of this pathway.	('preventing', 'NegReg', (96, 106))	('neutralizes', 'Var', (77, 88))	('c-MET', 'Gene', '4233', (122, 127))	('IgG2', 'cellular_component', 'GO:0071735', ('37', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('53', '61'))	('antibody', 'cellular_component', 'GO:0019814', ('53', '61'))	('human', 'Species', '9606', (31, 36))	('SF/HGF', 'Gene', (89, 95))	('binding', 'Interaction', (111, 118))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('antibody', 'cellular_component', 'GO:0042571', ('53', '61'))	('binds', 'Interaction', (67, 72))	('c-MET', 'Gene', (122, 127))	('antibody', 'cellular_component', 'GO:0019815', ('53', '61'))	('SF/HGF', 'Gene', '3082', (89, 95))
129311	18672314	They locally delivered the uncleavable pro-HGF using lentivirus vectors in mice and found that substitution of uncleavable pro-HGF for normal HGF inhibited HGF-mediated MET activation, tumor growth, angiogenesis and metastasis.	('tumor', 'Disease', (185, 190))	('mice', 'Species', '10090', (75, 79))	('substitution', 'Var', (95, 107))	('HGF-mediated', 'Protein', (156, 168))	('angiogenesis', 'CPA', (199, 211))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('inhibited', 'NegReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('metastasis', 'CPA', (216, 226))	('angiogenesis', 'biological_process', 'GO:0001525', ('199', '211'))
129313	18672314	RTK inhibition: The inhibition of receptor tyrosine kinases by small molecules is already used in therapy of human tumors, and is epitomized by the following targeted therapies: imatinib for Bcr-Abl in CML and mutant c-Kit in GIST; trastuzumab in Her-2 overexpressing breast ca; bevacizumab in colorectal ca; gefitinib in certain NSCLCs.	('mutant', 'Var', (210, 216))	('gefitinib', 'Chemical', 'MESH:D000077156', (309, 318))	('Bcr-Abl', 'Gene', '25', (191, 198))	('Her-2', 'Gene', (247, 252))	('colorectal ca', 'Disease', (294, 307))	('receptor tyrosine kinase', 'Gene', '5979', (34, 58))	('breast ca', 'Disease', (268, 277))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('NSCLC', 'Disease', 'MESH:D002289', (330, 335))	('c-Kit', 'Gene', '3815', (217, 222))	('RTK', 'Gene', (0, 3))	('imatinib', 'Chemical', 'MESH:D000068877', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('receptor tyrosine kinase', 'Gene', (34, 58))	('RTK', 'Gene', '5979', (0, 3))	('NSCLC', 'Disease', (330, 335))	('c-Kit', 'Gene', (217, 222))	('tumors', 'Disease', (115, 121))	('Bcr-Abl', 'Gene', (191, 198))	('trastuzumab', 'Chemical', 'MESH:D000068878', (232, 243))	('bevacizumab', 'Chemical', 'MESH:D000068258', (279, 290))	('human', 'Species', '9606', (109, 114))	('CML', 'Disease', 'MESH:D015464', (202, 205))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('CML', 'Disease', (202, 205))	('Her-2', 'Gene', '2064', (247, 252))
129316	18672314	One small molecule inhibitor currently undergoing in vitro testing is SU11274 (Sugen, Inc.), and functions by blocking autophosphorylation of MET at sites required for downstream signaling including the P13K, AKT, mTOR pathways.	('P13K', 'Pathway', (203, 207))	('autophosphorylation', 'MPA', (119, 138))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('blocking', 'NegReg', (110, 118))	('AKT', 'Pathway', (209, 212))	('MET', 'Protein', (142, 145))	('mTOR', 'Gene', (214, 218))	('mTOR', 'Gene', '2475', (214, 218))	('SU11274', 'Var', (70, 77))	('P13K', 'Mutation', 'p.P13K', (203, 207))	('SU11274', 'Chemical', 'MESH:C478479', (70, 77))
129322	18672314	A second promising small molecule in inhibitor, PHA665752 (Pfizer, Inc.), has been shown effective in vitro in SCLC, NSCLC and MPM.	('NSCLC', 'Disease', (117, 122))	('SCLC', 'Gene', (111, 115))	('SCLC', 'Gene', '7864', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('SCLC', 'Gene', '7864', (118, 122))	('MPM', 'Disease', (127, 130))	('SCLC', 'Gene', (118, 122))	('PHA665752', 'Var', (48, 57))	('PHA665752', 'Chemical', 'MESH:C480541', (48, 57))
129324	18672314	Puri et al studied the effects of PHA665752 in mouse xenografts, and found that NCI-H69-derived SCLC tumor nodules treated with PHA665752 for three weeks became clinically undetectable in 50% of the mice, and tumor volume was reduced by 99%.	('tumor', 'Disease', (209, 214))	('NCI-H69', 'CellLine', 'CVCL:1579', (80, 87))	('mice', 'Species', '10090', (199, 203))	('PHA665752', 'Chemical', 'MESH:C480541', (128, 137))	('mouse', 'Species', '10090', (47, 52))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SCLC tumor', 'Disease', 'MESH:D018288', (96, 106))	('SCLC tumor', 'Disease', (96, 106))	('PHA665752', 'Chemical', 'MESH:C480541', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('undetectable', 'NegReg', (172, 184))	('PHA665752', 'Var', (128, 137))	('reduced', 'NegReg', (226, 233))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
129327	18672314	An antiangiogenic effect was also demonstrated, as PHA665752 treatment resulted in greater than 85% reduction in CD31 staining, which corresponds to a reduction in vasculature.	('reduction', 'NegReg', (100, 109))	('vasculature', 'MPA', (164, 175))	('CD31', 'Gene', (113, 117))	('antiangiogenic', 'MPA', (3, 17))	('CD31', 'Gene', '5175', (113, 117))	('PHA665752', 'Var', (51, 60))	('reduction', 'NegReg', (151, 160))	('PHA665752', 'Chemical', 'MESH:C480541', (51, 60))
129329	18672314	PHA665752 was shown to cooperate with rapamycin by reducing growth, inducing apoptosis and cell cycle arrest, and inhibiting constitutive cell motility of BaF3 TPR-MET- and c-MET-expressing H441 NSCLC cells.	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('TPR', 'Gene', (160, 163))	('TPR', 'Gene', '7175', (160, 163))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('apoptosis', 'CPA', (77, 86))	('inhibiting', 'NegReg', (114, 124))	('c-MET', 'Gene', '4233', (173, 178))	('NSCLC', 'Disease', (195, 200))	('cell motility', 'biological_process', 'GO:0048870', ('138', '151'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('BaF3', 'CellLine', 'CVCL:0161', (155, 159))	('PHA665752', 'Var', (0, 9))	('c-MET', 'Gene', (173, 178))	('rapamycin', 'Chemical', 'MESH:D020123', (38, 47))	('cell cycle arrest', 'CPA', (91, 108))	('constitutive cell motility', 'CPA', (125, 151))	('inducing', 'Reg', (68, 76))	('reducing', 'NegReg', (51, 59))	('PHA665752', 'Chemical', 'MESH:C480541', (0, 9))	('growth', 'CPA', (60, 66))
129333	18672314	In in vitro studies of lung cancer cell lines, NCI-H69 cells expressing the R988C mutation demonstrated decreased MET phosphorylation after treatment with PF2341066, and NCI-H441 cells demonstrated decreased HGF-stimulated migration and invasion.	('R988C', 'Var', (76, 81))	('lung cancer', 'Disease', (23, 34))	('R988C', 'Mutation', 'p.R988C', (76, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('PF2341066', 'Chemical', 'MESH:D000077547', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('NCI-H69', 'CellLine', 'CVCL:1579', (47, 54))	('decreased', 'NegReg', (104, 113))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('PF2341066', 'Var', (155, 164))	('MET phosphorylation', 'MPA', (114, 133))	('invasion', 'CPA', (237, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('decreased', 'NegReg', (198, 207))	('NCI-H441', 'CellLine', 'CVCL:1561', (170, 178))
129334	18672314	In mouse xenografts of human NCI-H441 NSCLC cells, mean tumor volume decreased by 43% after 38 days of PF2341066 treatment.	('PF2341066', 'Chemical', 'MESH:D000077547', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mouse', 'Species', '10090', (3, 8))	('decreased', 'NegReg', (69, 78))	('tumor', 'Disease', (56, 61))	('PF2341066', 'Var', (103, 112))	('human', 'Species', '9606', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('NCI-H441 NSCLC', 'CellLine', 'CVCL:1561', (29, 43))
129336	18672314	Further studies of PF2341066-treated gastric carcinoma GTL-16 cells demonstrated decreased mitosis, increased apoptosis, decreased angiogenesis and decreased phosphorylation of MET, Akt, Erk, PLClambda1 and STAT5.	('angiogenesis', 'CPA', (131, 143))	('PLClambda1', 'Gene', (192, 202))	('Akt', 'Gene', '207', (182, 185))	('PF2341066', 'Chemical', 'MESH:D000077547', (19, 28))	('decreased', 'NegReg', (121, 130))	('decreased mitosis', 'Disease', 'MESH:D012021', (81, 98))	('Erk', 'molecular_function', 'GO:0004707', ('187', '190'))	('apoptosis', 'CPA', (110, 119))	('phosphorylation', 'MPA', (158, 173))	('angiogenesis', 'biological_process', 'GO:0001525', ('131', '143'))	('STAT5', 'Gene', '6776', (207, 212))	('decreased mitosis', 'Disease', (81, 98))	('STAT5', 'Gene', (207, 212))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('gastric carcinoma', 'Disease', 'MESH:D013274', (37, 54))	('gastric carcinoma', 'Disease', (37, 54))	('decreased', 'NegReg', (148, 157))	('mitosis', 'biological_process', 'GO:0000278', ('91', '98'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (37, 54))	('GTL-16', 'CellLine', 'CVCL:7668', (55, 61))	('MET', 'Pathway', (177, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('PF2341066-treated', 'Var', (19, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('Erk', 'Gene', (187, 190))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('Erk', 'Gene', '5594', (187, 190))	('Akt', 'Gene', (182, 185))
129353	18672314	At the time of presentation, a total of 21 patients had been enrolled, five with activating MET mutations and 16 with wild type MET.	('patients', 'Species', '9606', (43, 51))	('activating', 'PosReg', (81, 91))	('MET mutations', 'Var', (92, 105))
129364	18672314	K252a is a staurosoporine analog and an ATP-competitive MET kinase and serine/threonine kinase inhibitor that modulates wild type and mutant (M1268T) MET-dependent function and dissemination of tumor cells in vivo.	('ATP', 'Chemical', 'MESH:D000255', (40, 43))	('MET-dependent function', 'MPA', (150, 172))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('88', '104'))	('M1268T', 'SUBSTITUTION', 'None', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('K252a', 'Var', (0, 5))	('modulates', 'Reg', (110, 119))	('tumor', 'Disease', (194, 199))	('M1268T', 'Var', (142, 148))	('staurosoporine', 'Chemical', '-', (11, 25))
129374	33874885	After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8+ T cells with fluorescence-labeled anti-CD3, anti-CD8, anti-CD45RA, anti-CD45RO, anti-CD25, and anti-granzyme B antibodies using flow cytometry.	('CD45RO', 'Gene', (173, 179))	('CD8', 'Gene', (150, 153))	('granzyme B', 'Gene', '3002', (201, 211))	('CD8', 'Gene', '925', (150, 153))	('CD45RA', 'Gene', (160, 166))	('CD8', 'Gene', (96, 99))	('CD25', 'Gene', '3559', (186, 190))	('CD45RA', 'Gene', '5788', (160, 166))	('anti-CD3', 'Var', (135, 143))	('CD45RO', 'Gene', '5788', (173, 179))	('granzyme B', 'Gene', (201, 211))	('CD8', 'Gene', '925', (96, 99))	('CD25', 'Gene', (186, 190))
129388	33874885	Mutagenicity or carcinogenicity of asbestos is believed to cause malignant mesothelioma.	('malignant mesothelioma', 'Disease', (65, 87))	('asbestos', 'Chemical', 'MESH:D001194', (35, 43))	('cause', 'Reg', (59, 64))	('Mutagenicity', 'Var', (0, 12))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (65, 87))	('carcinogenicity', 'CPA', (16, 31))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (65, 87))
129452	33874885	These findings indicate that supplementation with IL-15 has the potential to improve the suppressed function of CTLs following exposure to asbestos, although it did not restore the asbestos-induced suppression of mature CTL differentiation following antigen stimulation.	('improve', 'PosReg', (77, 84))	('supplementation', 'Var', (29, 44))	('IL-15', 'Gene', (50, 55))	('asbestos', 'Chemical', 'MESH:D001194', (181, 189))	('IL-15', 'molecular_function', 'GO:0016170', ('50', '55'))	('CTLs', 'Protein', (112, 116))	('asbestos', 'Chemical', 'MESH:D001194', (139, 147))	('suppressed function', 'MPA', (89, 108))
129461	33874885	As shown in another study, IL-15-/- mice have increased lung metastasis, whereas IL-15 TG mice and IL-15-treated C57BL/6 mice have decreased lung metastasis compared with control.	('lung metastasis', 'CPA', (56, 71))	('increased', 'PosReg', (46, 55))	('IL-15', 'molecular_function', 'GO:0016170', ('99', '104'))	('decreased', 'NegReg', (131, 140))	('mice', 'Species', '10090', (90, 94))	('mice', 'Species', '10090', (121, 125))	('decreased lung', 'Phenotype', 'HP:0002089', (131, 145))	('IL-15', 'molecular_function', 'GO:0016170', ('81', '86'))	('mice', 'Species', '10090', (36, 40))	('IL-15', 'molecular_function', 'GO:0016170', ('27', '32'))	('IL-15-/-', 'Var', (27, 35))	('lung metastasis', 'CPA', (141, 156))
129488	33874885	Those macrophage, dendritic, NK, and NKT cells activated by exogenous IL-15 might contribute to enhanced function in non-proliferating CD8+ lymphocytes as well as proliferating cells in an indirect manner.	('CD8', 'Gene', '925', (135, 138))	('enhanced', 'PosReg', (96, 104))	('exogenous', 'Var', (60, 69))	('CD8', 'Gene', (135, 138))	('function', 'MPA', (105, 113))	('IL-15', 'molecular_function', 'GO:0016170', ('70', '75'))
129494	33874885	In our previous study, it was found that exogenous supplementation of IL-2 could augment the cytotoxicity of asbestos-exposed CD8+ lymphocytes and percentage of granzyme B+ cells during MLR culture, which represents an in vitro model for the immune response that includes initiation and clonal expansion, but not expansion of naive cells or maintenance of memory cells.	('immune response', 'biological_process', 'GO:0006955', ('242', '257'))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('exogenous', 'Var', (41, 50))	('IL-2', 'molecular_function', 'GO:0005134', ('70', '74'))	('granzyme B', 'Gene', (161, 171))	('CD8', 'Gene', (126, 129))	('IL-2', 'Gene', '3558', (70, 74))	('CD8', 'Gene', '925', (126, 129))	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('memory', 'biological_process', 'GO:0007613', ('356', '362'))	('IL-2', 'Gene', (70, 74))	('granzyme B', 'Gene', '3002', (161, 171))	('cytotoxicity', 'Disease', (93, 105))	('augment', 'PosReg', (81, 88))
129512	31554354	Many types of malignancy are caused by errant metastatic cells from nearby organs (lung, liver, stomach, or ovary) occupying serous cavities.	('malignancy', 'Disease', (14, 24))	('errant', 'Var', (39, 45))	('malignancy', 'Disease', 'MESH:D009369', (14, 24))	('caused by', 'Reg', (29, 38))
129550	31554354	Ber-EP4 is an adenocarcinoma marker for which the respective expression of Ber-EP4 was no staining, +- < 10%, 1+ and 2+ in 3/60 (5.0%), 2/60 (3.3%), 17/60 (28.3%) and 38/60 (63.3%) cases of adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (190, 204))	('Ber', 'biological_process', 'GO:0006284', ('0', '3'))	('Ber', 'biological_process', 'GO:0006284', ('75', '78'))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('EP4', 'Gene', '5734', (79, 82))	('adenocarcinoma', 'Disease', (14, 28))	('adenocarcinoma', 'Disease', (190, 204))	('EP4', 'Gene', (4, 7))	('EP4', 'Gene', '5734', (4, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('EP4', 'Gene', (79, 82))	('+- < 10%', 'Var', (100, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
129759	26208479	In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype.	('AKT1', 'Gene', '207', (45, 49))	('AKT1', 'Gene', (45, 49))	('silencing', 'Var', (32, 41))	('spindle', 'cellular_component', 'GO:0005819', ('53', '60'))	('promotes', 'PosReg', (87, 95))	('shift toward an epithelioid phenotype', 'MPA', (100, 137))
129760	26208479	Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor beta (ERbeta) expression.	('estrogen receptor beta', 'Gene', '2100', (151, 173))	('MCT4', 'Gene', '9123', (89, 93))	('silencing', 'Var', (18, 27))	('AKT1', 'Gene', (13, 17))	('Basigin', 'Gene', '682', (118, 125))	('Basigin', 'Gene', (118, 125))	('induction', 'Reg', (138, 147))	('lactate', 'Chemical', 'MESH:D019344', (68, 75))	('MCT4', 'Gene', (89, 93))	('expression', 'MPA', (183, 193))	('MCT', 'biological_process', 'GO:0120197', ('89', '92'))	('AKT1', 'Gene', '207', (13, 17))	('decreased', 'NegReg', (40, 49))	('expression', 'MPA', (50, 60))	('estrogen receptor beta', 'Gene', (151, 173))
129772	26208479	Once activated, PI3K and its downstream effector AKT1 not only provide strong growth and survival signals to tumor cells, but also exert profound effects on their metabolism.	('AKT1', 'Gene', '207', (49, 53))	('metabolism', 'biological_process', 'GO:0008152', ('163', '173'))	('metabolism', 'MPA', (163, 173))	('effects', 'Reg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('AKT1', 'Gene', (49, 53))	('survival signals', 'CPA', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))	('growth', 'CPA', (78, 84))	('PI3K', 'Var', (16, 20))	('tumor', 'Disease', (109, 114))
129795	26208479	In contrast, overexpressing AKT1 in REN cells induced a more spindle-like phenotype (Figure 1B).	('spindle-like phenotype', 'CPA', (61, 83))	('AKT1', 'Gene', '207', (28, 32))	('REN', 'Gene', (36, 39))	('spindle', 'cellular_component', 'GO:0005819', ('61', '68'))	('AKT1', 'Gene', (28, 32))	('overexpressing', 'Var', (13, 27))	('REN', 'Gene', '5972', (36, 39))
129796	26208479	As shown in Figure 1C, ERbeta was significantly induced both at mRNA and protein levels in AKT1 silenced MSTO-211H cells, whereas ERbeta expression was significantly inhibited by AKT1 overexpression in REN cells (Figure 1D).	('AKT1', 'Gene', '207', (91, 95))	('AKT1', 'Gene', (91, 95))	('AKT1', 'Gene', (179, 183))	('silenced', 'Var', (96, 104))	('REN', 'Gene', '5972', (202, 205))	('MSTO-211H', 'CellLine', 'CVCL:1430', (105, 114))	('induced', 'PosReg', (48, 55))	('ERbeta', 'Gene', (23, 29))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('REN', 'Gene', (202, 205))	('AKT1', 'Gene', '207', (179, 183))
129798	26208479	In particular, the expression of the SLC16A3 and CD147 genes was significantly down-regulated in AKT1 silenced MSTO-211H cells and significantly up-regulated in REN cells overexpressing AKT1 (Figure 1E, 1F).	('expression', 'MPA', (19, 29))	('REN', 'Gene', '5972', (161, 164))	('up-regulated', 'PosReg', (145, 157))	('down-regulated', 'NegReg', (79, 93))	('AKT1', 'Gene', '207', (186, 190))	('AKT1', 'Gene', '207', (97, 101))	('AKT1', 'Gene', (97, 101))	('REN', 'Gene', (161, 164))	('AKT1', 'Gene', (186, 190))	('CD147', 'Gene', (49, 54))	('silenced', 'Var', (102, 110))	('MSTO-211H', 'CellLine', 'CVCL:1430', (111, 120))	('SLC16A3', 'Gene', (37, 44))
129803	26208479	In addition, silencing of SLC16A3 in normoxic MSTO-211H cells induced similar epithelioid-like phenotype as AKT1 silencing (see Figure 2A and 1A).	('MSTO-211H', 'CellLine', 'CVCL:1430', (46, 55))	('AKT1', 'Gene', '207', (108, 112))	('AKT1', 'Gene', (108, 112))	('SLC16A3', 'Gene', (26, 33))	('silencing', 'Var', (13, 22))
129807	26208479	SLC16A1 silencing resulted in changed cellular phenotype from epithelioid to spindle-like (Figure 3E, 3F), decreased intracellular lactate content (Figure 3E), and decreased ERbeta expression (Figure 3G, 3H).	('lactate', 'Chemical', 'MESH:D019344', (131, 138))	('decreased', 'NegReg', (164, 173))	('cellular phenotype', 'MPA', (38, 56))	('ERbeta expression', 'MPA', (174, 191))	('intracellular lactate content', 'MPA', (117, 146))	('silencing', 'Var', (8, 17))	('spindle', 'cellular_component', 'GO:0005819', ('77', '84'))	('decreased', 'NegReg', (107, 116))	('changed', 'Reg', (30, 37))	('SLC16A1', 'Gene', (0, 7))	('intracellular', 'cellular_component', 'GO:0005622', ('117', '130'))	('SLC16A1', 'Gene', '6566', (0, 7))
129810	26208479	As expected and in agreement with previously published data, KB9520 significantly reduced the cell growth of MSTO-211H cells cultivated in hypoxic conditions (Figure 4A, 4B).	('KB9520', 'Chemical', '-', (61, 67))	('KB9520', 'Var', (61, 67))	('MSTO-211H', 'CellLine', 'CVCL:1430', (109, 118))	('hypoxic conditions', 'Disease', (139, 157))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('reduced', 'NegReg', (82, 89))	('hypoxic conditions', 'Disease', 'MESH:D009135', (139, 157))	('cell growth', 'CPA', (94, 105))
129811	26208479	Similar sensitivity and growth inhibitory effect of KB9520 was also observed in MSTO-211H cells, silenced for SLC16A3 gene expression in normoxia (data not shown).	('SLC16A3', 'Gene', (110, 117))	('KB9520', 'Chemical', '-', (52, 58))	('growth', 'MPA', (24, 30))	('KB9520', 'Var', (52, 58))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (80, 89))
129814	26208479	Interestingly, by RT-PCR and Western blot analysis, we observed a transient induction of ERbeta expression between the third and fifth day of spheroid growth, that was sustained until the ninth day only in those treated with KB9520 (Figure 4C).	('KB9520', 'Chemical', '-', (225, 231))	('ERbeta', 'Gene', (89, 95))	('expression', 'MPA', (96, 106))	('KB9520', 'Var', (225, 231))
129815	26208479	Furthermore, treatment of spheroids with KB9520 for nine days resulted in a significant growth inhibition and lactate accumulation (Figure 4D).	('growth inhibition', 'CPA', (88, 105))	('lactate accumulation', 'CPA', (110, 130))	('KB9520', 'Chemical', '-', (41, 47))	('KB9520', 'Var', (41, 47))	('lactate', 'Chemical', 'MESH:D019344', (110, 117))
129816	26208479	By RT-PCR, we documented that at the end of the KB9520 treatment the expression of the EPAS1, SLC16A3, CD147 genes were down-regulated, whereas SLC16A1 expression remained unaffected (Figure 4E).	('down-regulated', 'NegReg', (120, 134))	('EPAS1', 'Gene', '2034', (87, 92))	('SLC16A3', 'Gene', (94, 101))	('expression', 'MPA', (69, 79))	('EPAS1', 'Gene', (87, 92))	('KB9520', 'Chemical', '-', (48, 54))	('SLC16A1', 'Gene', (144, 151))	('KB9520', 'Var', (48, 54))	('SLC16A1', 'Gene', '6566', (144, 151))	('CD147', 'Gene', (103, 108))
129822	26208479	Starting from 10 days of treatment, we observed a reduction in tumor growth in the group treated with KB9520 as compared to the vehicle treated animals, an effect that was maintained until the end of the experiment (Figure 5A).	('tumor', 'Disease', (63, 68))	('reduction', 'NegReg', (50, 59))	('KB9520', 'Chemical', '-', (102, 108))	('KB9520', 'Var', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
129825	26208479	By RT-PCR of tumor samples, we documented that KB9520 treatment decreased the expression of the SLC16A3 and CD147 genes and increased the expression of the CDH1 gene.	('tumor', 'Disease', (13, 18))	('CD147', 'Gene', (108, 113))	('KB9520', 'Chemical', '-', (47, 53))	('expression', 'MPA', (78, 88))	('KB9520', 'Var', (47, 53))	('increased', 'PosReg', (124, 133))	('CDH1', 'Gene', (156, 160))	('SLC16A3', 'Gene', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('expression', 'MPA', (138, 148))	('CDH1', 'Gene', '999', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('decreased', 'NegReg', (64, 73))
129827	26208479	By RT-PCR and Western blot analysis, we also observed that tumor samples from mice treated with KB9520 had increased ERbeta expression both at mRNA and protein levels compared to vehicle treated animals (Figure 5C, 5D).	('increased ERbeta', 'Phenotype', 'HP:0003141', (107, 123))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('increased', 'PosReg', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('KB9520', 'Chemical', '-', (96, 102))	('KB9520', 'Var', (96, 102))	('ERbeta', 'Protein', (117, 123))	('mice', 'Species', '10090', (78, 82))
129828	26208479	Moreover, the level of phosphorylated AKT was significantly lower in tumor cells from KB9520 treated mice compared to vehicle animals (Figure 5E).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('level of phosphorylated', 'MPA', (14, 37))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (101, 105))	('KB9520 treated', 'Var', (86, 100))	('KB9520', 'Chemical', '-', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('lower', 'NegReg', (60, 65))
129830	26208479	We therefore decided to analyze the expression of SIRT1 in MSTO-211H tumors recovered from mice; SIRT1 expression was reduced in tumors from KB9520 treated mice (Figure 5B).	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SIRT1', 'Gene', (97, 102))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('expression', 'MPA', (103, 113))	('reduced', 'NegReg', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MSTO-211H', 'CellLine', 'CVCL:1430', (59, 68))	('tumors', 'Disease', (69, 75))	('KB9520 treated', 'Var', (141, 155))	('KB9520', 'Chemical', '-', (141, 147))	('mice', 'Species', '10090', (156, 160))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
129831	26208479	Similar AKT1 post-translational modifications and SIRT1 down-regulation were also observed in KB9520 treated MSTO-211H cells cultivated in hypoxic conditions (Supplementary Figure S2).	('KB9520', 'Var', (94, 100))	('down-regulation', 'NegReg', (56, 71))	('MSTO-211H', 'CellLine', 'CVCL:1430', (109, 118))	('SIRT1', 'Gene', (50, 55))	('hypoxic conditions', 'Disease', (139, 157))	('AKT1', 'Gene', '207', (8, 12))	('regulation', 'biological_process', 'GO:0065007', ('61', '71'))	('hypoxic conditions', 'Disease', 'MESH:D009135', (139, 157))	('KB9520', 'Chemical', '-', (94, 100))	('AKT1', 'Gene', (8, 12))
129837	26208479	AKT1 modulation in vitro led to marked changes in the cell morphology and, consistent with this, in CDH1 expression, suggesting a role for the AKT1 isoform in epithelial-mesenchymal transition (EMT) and in the reciprocal mesenchymal-epithelial transition (MET).	('cell morphology', 'CPA', (54, 69))	('AKT1', 'Gene', (143, 147))	('AKT1', 'Gene', '207', (0, 4))	('CDH1', 'Gene', (100, 104))	('AKT1', 'Gene', (0, 4))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('159', '192'))	('CDH1', 'Gene', '999', (100, 104))	('EMT', 'biological_process', 'GO:0001837', ('194', '197'))	('changes', 'Reg', (39, 46))	('epithelial-mesenchymal transition', 'CPA', (159, 192))	('reciprocal mesenchymal-epithelial transition', 'CPA', (210, 254))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('221', '254'))	('modulation', 'Var', (5, 15))	('AKT1', 'Gene', '207', (143, 147))
129838	26208479	Interestingly, the observed changes in cell morphology in response to AKT1 modulation resembled those previously reported following ERbeta expression modulation in the same cell types.	('cell morphology', 'CPA', (39, 54))	('AKT1', 'Gene', '207', (70, 74))	('AKT1', 'Gene', (70, 74))	('modulation', 'Var', (75, 85))	('changes', 'Reg', (28, 35))
129852	26208479	Here we provide data that the increase in intracellular lactate content induced ERbeta expression in MSTO-211H cells, as evidenced by addition of lactate to the growth medium, or its increase due to knock-down of MCT4 expression or by culturing cells in hypoxic condition.	('MSTO-211H', 'CellLine', 'CVCL:1430', (101, 110))	('ERbeta', 'Gene', (80, 86))	('increase', 'PosReg', (183, 191))	('lactate', 'MPA', (146, 153))	('knock-down', 'Var', (199, 209))	('lactate', 'Chemical', 'MESH:D019344', (146, 153))	('intracellular lactate content', 'MPA', (42, 71))	('MCT', 'biological_process', 'GO:0120197', ('213', '216'))	('MCT4', 'Gene', (213, 217))	('increase', 'PosReg', (30, 38))	('hypoxic condition', 'Disease', 'MESH:D009135', (254, 271))	('hypoxic condition', 'Disease', (254, 271))	('intracellular', 'cellular_component', 'GO:0005622', ('42', '55'))	('lactate', 'Chemical', 'MESH:D019344', (56, 63))	('MCT4', 'Gene', '9123', (213, 217))
129859	26208479	In contrast, when ERbeta was activated by its selective agonist KB9520, its expression was maintained and cell growth significantly inhibited.	('inhibited', 'NegReg', (132, 141))	('activated', 'PosReg', (29, 38))	('ERbeta', 'Gene', (18, 24))	('KB9520', 'Chemical', '-', (64, 70))	('KB9520', 'Var', (64, 70))	('expression', 'MPA', (76, 86))	('cell growth', 'CPA', (106, 117))	('cell growth', 'biological_process', 'GO:0016049', ('106', '117'))
129860	26208479	In spheroids treated with KB9520, SLC16A3 and CD147 expression were down-regulated, causing an increase in intracellular lactate that could in part explain the maintenance of ERbeta expression.	('CD147', 'Gene', (46, 51))	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('KB9520', 'Var', (26, 32))	('KB9520', 'Chemical', '-', (26, 32))	('down-regulated', 'NegReg', (68, 82))	('SLC16A3', 'Gene', (34, 41))	('increase', 'PosReg', (95, 103))	('intracellular lactate', 'MPA', (107, 128))	('lactate', 'Chemical', 'MESH:D019344', (121, 128))
129865	26208479	It has been reported that acetylation blocks binding of AKT and PDK1 to PIP(3), thereby preventing its membrane localization and phosphorylation whereas deacetylation by SIRT1 promotes AKT activation.	('membrane', 'cellular_component', 'GO:0016020', ('103', '111'))	('acetylation', 'MPA', (26, 37))	('phosphorylation', 'MPA', (129, 144))	('PDK1', 'Gene', (64, 68))	('binding', 'Interaction', (45, 52))	('preventing', 'NegReg', (88, 98))	('membrane localization', 'MPA', (103, 124))	('blocks', 'NegReg', (38, 44))	('PIP', 'Gene', (72, 75))	('AKT', 'Gene', (56, 59))	('PIP', 'Gene', '5304', (72, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('129', '144'))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('PDK1', 'molecular_function', 'GO:0004740', ('64', '68'))	('localization', 'biological_process', 'GO:0051179', ('112', '124'))	('deacetylation', 'Var', (153, 166))	('PDK1', 'Gene', '5163', (64, 68))
129866	26208479	Mice injected with cells expressing a mutated AKT that mimicked a constitutively acetylated form of AKT, developed smaller tumors than those injected with cells expressing wild-type AKT.	('mutated', 'Var', (38, 45))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('AKT', 'Gene', (46, 49))	('smaller', 'NegReg', (115, 122))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
129869	26208479	Collectively, the presented data suggest that metabolic changes can promote, via epigenetic modulations, ERbeta expression in ER negative cells and that its expression and tumor suppressive function are maintained by its selective ligand activation (Figure 6).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('expression', 'MPA', (157, 167))	('promote', 'PosReg', (68, 75))	('tumor', 'Disease', (172, 177))	('epigenetic modulations', 'Var', (81, 103))	('ERbeta', 'Protein', (105, 111))	('metabolic', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('ligand', 'molecular_function', 'GO:0005488', ('231', '237'))	('expression', 'MPA', (112, 122))
129929	24502396	Moreover, crosslinking of CD26 and CD3 with solid-phase immobilized monoclonal antibodies (mAbs) can induce T cell costimulation and IL-2 production by CD26+ T cells .	('crosslinking', 'Var', (10, 22))	('IL-2 production', 'biological_process', 'GO:0032623', ('133', '148'))	('T cell costimulation', 'biological_process', 'GO:0031295', ('108', '128'))	('CD3', 'Gene', (35, 38))	('IL-2', 'molecular_function', 'GO:0005134', ('133', '137'))	('IL-2', 'Gene', (133, 137))	('IL-2', 'Gene', '3558', (133, 137))	('T cell costimulation', 'CPA', (108, 128))	('induce', 'PosReg', (101, 107))
129933	24502396	More recently, we have shown that humanized anti-CD26 mAb appears to be a promising novel therapy for the clinical control of graft-versus-host disease (GVHD) in a xenogeneic GVHD murine model .	('GVHD', 'Disease', 'MESH:D006086', (153, 157))	('human', 'Species', '9606', (34, 39))	('murine', 'Species', '10090', (180, 186))	('graft-versus-host disease', 'Disease', 'MESH:D006086', (126, 151))	('GVHD', 'Disease', (153, 157))	('anti-CD26', 'Var', (44, 53))	('GVHD', 'Disease', 'MESH:D006086', (175, 179))	('clinical', 'Species', '191496', (106, 114))	('GVHD', 'Disease', (175, 179))	('graft-versus-host disease', 'Disease', (126, 151))
129935	24502396	We have shown that administration of anti-CD26 mAb resulted in both in vitro and in vivo inhibition of tumor cell growth, migration and invasion, and enhanced survival of mouse xenograft models inoculated with T-lymphoma, renal cell carcinoma or malignant mesothelioma .	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (246, 268))	('malignant mesothelioma', 'Disease', (246, 268))	('mouse', 'Species', '10090', (171, 176))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (222, 242))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (246, 268))	('T-lymphoma', 'Disease', 'MESH:D016399', (210, 220))	('cell growth', 'biological_process', 'GO:0016049', ('109', '120'))	('enhanced', 'PosReg', (150, 158))	('tumor', 'Disease', (103, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (212, 220))	('invasion', 'CPA', (136, 144))	('T-lymphoma', 'Disease', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('anti-CD26', 'Var', (37, 46))	('T-lymphoma', 'Phenotype', 'HP:0012190', (210, 220))	('survival', 'CPA', (159, 167))	('inhibition', 'NegReg', (89, 99))	('renal cell carcinoma', 'Disease', (222, 242))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (222, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
129954	24502396	Each CD26 deletion construct in pcDL-SRalpha was co-transfected with pEB6-CAG-GFP into COS-7 cells using Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (105, 123))	('CD26', 'Gene', (5, 9))	('COS-7', 'CellLine', 'CVCL:0224', (87, 92))	('deletion', 'Var', (10, 18))
129956	24502396	Briefly, the expression vector RcSRalpha-26d3-9, which contains a deletion of the coding sequence for amino acids 3-9 of CD26, was transfected into a dihydrofolate reductase deficit Chinese hamster ovary (CHO) cell line, DXB-11 by electroporation, together with pMT-2 providing the dihydrofolate reductase gene.	('reductase deficit Chinese hamster ovary', 'Disease', 'MESH:C562377', (164, 203))	('CHO', 'molecular_function', 'GO:0043848', ('205', '208'))	('reductase deficit Chinese hamster ovary', 'Disease', (164, 203))	('pMT', 'molecular_function', 'GO:0030736', ('262', '265'))	('DXB-11', 'Chemical', '-', (221, 227))	('CHO', 'CellLine', 'CVCL:0213', (205, 208))	('CD26', 'Gene', (121, 125))	('deletion', 'Var', (66, 74))
129976	24502396	Antigen retrieval was performed by 1) autoclaving in 10 mM citrate buffer (pH 6.0) for 20 min at 120 C, 2) 0.05% trypsin for 15 min at 37 C, 3) 0.02% proteinase K for 10 min at 37 C, or 4) boiling in 10 mM citrate buffer (pH 6.0) for 10 min at 100 C, and the sections were treated with 0.3% H2O2 in methanol for 10 min at RT to inactivate endogenous peroxidase, then treated with 2.5% horse serum (Vector Laboratories, Burlingame, CA) for 10 min at RT to block non-specific binding of the secondary horse antibody.	('inactivate', 'Var', (328, 338))	('boiling', 'Phenotype', 'HP:0020083', (189, 196))	('antibody', 'cellular_component', 'GO:0019814', ('505', '513'))	('antibody', 'molecular_function', 'GO:0003823', ('505', '513'))	('binding', 'molecular_function', 'GO:0005488', ('474', '481'))	('horse', 'Species', '9796', (385, 390))	('horse', 'Species', '9796', (499, 504))	('endogenous', 'Enzyme', (339, 349))	('block', 'NegReg', (455, 460))	('antibody', 'cellular_component', 'GO:0042571', ('505', '513'))	('antibody', 'cellular_component', 'GO:0019815', ('505', '513'))	('proteinase', 'molecular_function', 'GO:0004175', ('150', '160'))	('non-specific binding', 'Interaction', (461, 481))
129988	24502396	When sCD26 was denatured in urea buffer, the absorbance of 5F8, which cannot detect denatured CD26 in formalin-fixed tissues, was apparently decreased, while the absorbance of commercial mAb (purchased from MBL) or pAb (purchased from R&D Systems) was comparatively maintained (Figure  2).	('MBL', 'Gene', (207, 210))	('absorbance', 'MPA', (45, 55))	('absorbance', 'MPA', (162, 172))	('MBL', 'Gene', '50639', (207, 210))	('decreased', 'NegReg', (141, 150))	('formalin', 'Chemical', 'MESH:D005557', (102, 110))	('pAb', 'Chemical', '-', (215, 218))	('denatured', 'Var', (15, 24))	('urea', 'Chemical', 'MESH:D014508', (28, 32))
130006	24502396	As shown in Figure  4 (representative histograms are shown in Additional file 1: Figure S2), binding of YS110 or 1F7 to CD26 was completely blocked by YS110 while the binding of 5F8 to CD26 was hardly affected, indicating that YS110 was sufficiently bound to CD26.	('CD26', 'Protein', (120, 124))	('YS110', 'Var', (151, 156))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('YS110', 'Var', (104, 109))	('binding', 'Interaction', (93, 100))	('blocked', 'NegReg', (140, 147))	('1F7', 'Var', (113, 116))	('YS110', 'Chemical', '-', (227, 232))	('YS110', 'Chemical', '-', (104, 109))	('YS110', 'Chemical', '-', (151, 156))
130007	24502396	Although binding of clone 1, 11, 16 or 19 to CD26 was hardly affected by YS110 pretreatment, binding of clone 5 was partially inhibited, and binding of clone 18 was completely inhibited by YS110 (Figure  4 and Additional file 1: Figure S2).	('YS110', 'Chemical', '-', (73, 78))	('binding', 'Interaction', (141, 148))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('inhibited', 'NegReg', (126, 135))	('YS110', 'Chemical', '-', (189, 194))	('binding', 'Interaction', (93, 100))	('binding', 'molecular_function', 'GO:0005488', ('141', '148'))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('binding', 'Interaction', (9, 16))	('inhibited', 'NegReg', (176, 185))	('YS110', 'Var', (189, 194))
130008	24502396	Taken together, these data suggest that clone 19 was capable of detecting denatured CD26 in formalin-fixed tissue sections with the most reliable staining pattern and intensity, exhibited no cross-reactivity with YS110, and was suitable for analysis of CD26 expression on clinical samples following the administration of YS110.	('YS110', 'Chemical', '-', (321, 326))	('clinical samples', 'Species', '191496', (272, 288))	('CD26', 'Gene', (84, 88))	('formalin', 'Chemical', 'MESH:D005557', (92, 100))	('YS110', 'Chemical', '-', (213, 218))	('detecting', 'Reg', (64, 73))	('denatured', 'Var', (74, 83))
130013	24502396	As shown in Additional file 1: Figure S3, binding of 4G8 to CD26 was completely blocked by clone 19, and binding of YS110 to CD26 was completely inhibited by clone 18 and partially inhibited by clone 5, consistent with the results shown in Figures  4 and 5.	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('blocked', 'NegReg', (80, 87))	('YS110', 'Chemical', '-', (116, 121))	('CD26', 'Gene', (60, 64))	('inhibited', 'NegReg', (181, 190))	('binding', 'Interaction', (42, 49))	('YS110', 'Var', (116, 121))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('binding', 'Interaction', (105, 112))	('inhibited', 'NegReg', (145, 154))
130015	24502396	To further confirm the epitope involved in binding of clone 18 and 19 to human CD26, we tested the ability of these two mAbs to bind to CD26 deletion mutants by flow cytometry .	('bind', 'Interaction', (128, 132))	('tested', 'Reg', (88, 94))	('CD26', 'Gene', (136, 140))	('human', 'Species', '9606', (73, 78))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('deletion mutants', 'Var', (141, 157))
130016	24502396	We first tested the binding of the previously developed anti-human CD26 mAbs, 4G8, 1F7, or 5F8 to confirm the expression pattern of CD26 deletion mutants on COS-7 cells.	('COS-7', 'CellLine', 'CVCL:0224', (157, 162))	('binding', 'Interaction', (20, 27))	('deletion mutants', 'Var', (137, 153))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('human', 'Species', '9606', (61, 66))	('CD26', 'Gene', (132, 136))	('tested', 'Reg', (9, 15))
130017	24502396	We then analyzed the binding of YS110, clone 18 and clone 19 to the CD26 deletion mutants.	('binding', 'Interaction', (21, 28))	('YS110', 'Chemical', '-', (32, 37))	('CD26', 'Gene', (68, 72))	('deletion mutants', 'Var', (73, 89))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))
130018	24502396	As shown in Figure  6 (representative histograms are shown in Additional file 1: Figure S4), both YS110 and clone 18 recognized full length CD26, the 1-739th AAs region of CD26, the 1-577th AAs region of CD26, the 1-449th AAs region of CD26 and the 1-358th AAs region of CD26, but lost the ability to recognize the CD26 molecule with deletion from the 248th AA, suggesting that the sequence of the 248-358th AAs region on CD26 might be important for binding of YS110 and clone 18.	('YS110', 'Chemical', '-', (98, 103))	('AAs', 'Chemical', 'MESH:D000596', (190, 193))	('ability', 'MPA', (290, 297))	('AAs', 'Chemical', 'MESH:D000596', (408, 411))	('AAs', 'Chemical', 'MESH:D000596', (222, 225))	('AAs', 'Chemical', 'MESH:D000596', (158, 161))	('AAs', 'Chemical', 'MESH:D000596', (257, 260))	('binding', 'molecular_function', 'GO:0005488', ('450', '457'))	('deletion', 'Var', (334, 342))	('YS110', 'Chemical', '-', (461, 466))
130020	24502396	Taken together, results from the cross-blocking studies and those involving CD26 deletion mutants strongly suggest that the epitope defined by clone 19 may be located between the 1-247th AAs region, and the epitope defined by clone 18 between the 248-358th AAs region, being almost identical to YS110.	('CD26', 'Gene', (76, 80))	('mutants', 'Var', (90, 97))	('YS110', 'Chemical', '-', (295, 300))	('deletion mutants', 'Var', (81, 97))	('AAs', 'Chemical', 'MESH:D000596', (257, 260))	('AAs', 'Chemical', 'MESH:D000596', (187, 190))
130028	24502396	Furthermore, the overall survival of patients with CD26-positive GISTs is worse than that of patients with CD26-negative GISTs, suggesting that CD26 appears to be a reliable biomarker of malignant GIST of the stomach .	('malignant GIST of the stomach', 'Phenotype', 'HP:0006753', (187, 216))	('patients', 'Species', '9606', (37, 45))	('CD26', 'Var', (144, 148))	('CD26-positive', 'Var', (51, 64))	('worse', 'NegReg', (74, 79))	('patients', 'Species', '9606', (93, 101))
130062	21961533	Conversely, patients having tumors with high ERCC1 expression and thus functional NER and also HRR (homologous recombination repair) systems were found to have a better overall survival, since such tumors are assumed to be less unstable and dedifferentiated (so-called ERCC1 paradoxon).	('high', 'Var', (40, 44))	('ERCC1', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('expression', 'MPA', (51, 61))	('HRR', 'biological_process', 'GO:0000724', ('95', '98'))	('tumors', 'Disease', (198, 204))	('patients', 'Species', '9606', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('homologous recombination', 'biological_process', 'GO:0035825', ('100', '124'))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('better', 'PosReg', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('overall survival', 'CPA', (169, 185))	('tumors', 'Disease', (28, 34))	('ERCC1', 'Gene', '2067', (269, 274))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('ERCC1', 'Gene', '2067', (45, 50))	('ERCC1', 'Gene', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('NER', 'biological_process', 'GO:0006289', ('82', '85'))
130172	33233407	The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR).	('MPM', 'Disease', (162, 165))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (93, 109))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('cg03546163', 'Gene', (110, 120))	('inflammation', 'biological_process', 'GO:0006954', ('218', '230'))	('LMR', 'Chemical', '-', (282, 285))	('inflammation', 'Disease', 'MESH:D007249', (218, 230))	('inflammation', 'Disease', (218, 230))	('cg03546163', 'Chemical', '-', (110, 120))	('patients', 'Species', '9606', (166, 174))	('methylation', 'Var', (67, 78))
130173	33233407	Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases.	('overall survival', 'MPA', (117, 133))	('FKBP5', 'Gene', '2289', (76, 81))	('FKBP5', 'Gene', (76, 81))	('FKBP', 'molecular_function', 'GO:0030051', ('76', '80'))	('MPM', 'Disease', (142, 145))	('associated with', 'Reg', (101, 116))	('epigenetic changes', 'Var', (50, 68))
130177	33233407	Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 x 10-9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5'UTR region of the FKBP5 gene.	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('methylation', 'MPA', (165, 176))	('cg03546163', 'Var', (194, 204))	('FKBP5', 'Gene', '2289', (242, 247))	('FKBP5', 'Gene', (242, 247))	('FKBP', 'molecular_function', 'GO:0030051', ('242', '246'))	('cg03546163', 'Chemical', '-', (194, 204))	('OS-related', 'Disease', (141, 151))
130179	33233407	Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm >= 0.45 (mean: 243 versus 534 days; p value< 0.001).	('cg03546163', 'Chemical', '-', (30, 40))	('poor', 'NegReg', (59, 63))	('cg03546163', 'Var', (30, 40))	('survival', 'MPA', (64, 72))
130180	33233407	Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases.	('FKBP5', 'Gene', '2289', (26, 31))	('associated with', 'Reg', (51, 66))	('FKBP5', 'Gene', (26, 31))	('MPM', 'Disease', (73, 76))	('Epigenetic changes', 'Var', (0, 18))	('FKBP', 'molecular_function', 'GO:0030051', ('26', '30'))
130186	33233407	Recent research on the pathogenesis of MPM indicated that (i) both genetic and epigenetic alterations contribute to asbestos-induced tumorigenesis, (ii) inflammation-based prognostic scores that include lymphocyte counts are associated with survival.	('inflammation', 'Disease', 'MESH:D007249', (153, 165))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('inflammation', 'biological_process', 'GO:0006954', ('153', '165'))	('pathogenesis', 'biological_process', 'GO:0009405', ('23', '35'))	('inflammation', 'Disease', (153, 165))	('MPM', 'Disease', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('contribute', 'Reg', (102, 112))	('tumor', 'Disease', (133, 138))	('epigenetic alterations', 'Var', (79, 101))	('associated with', 'Reg', (225, 240))	('asbestos', 'Chemical', 'MESH:D001194', (116, 124))	('asbestos-induced', 'Disease', (116, 132))
43371	33233407	The BAP1-tumor predisposition syndrome is the most studied genetic condition associated with MPM development and is caused by mutations in the BRCA1-associated protein 1 (BAP1) gene.	('BAP1', 'Gene', (171, 175))	('BRCA1-associated protein 1', 'Gene', '8314', (143, 169))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('BRCA1-associated protein 1', 'Gene', (143, 169))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('caused by', 'Reg', (116, 125))	('tumor', 'Disease', (9, 14))	('BAP1', 'Gene', '8314', (171, 175))	('mutations', 'Var', (126, 135))	('BAP1', 'Gene', '8314', (4, 8))
130189	33233407	While genetic markers may differ from case to case in most cancer patients (i.e., each patient may carry a different mutation within the same gene), different subjects show variable levels of epigenetic biomarkers in specific target regions and different tissues depending on disease status.	('carry', 'Reg', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patient', 'Species', '9606', (66, 73))	('patient', 'Species', '9606', (87, 94))	('mutation', 'Var', (117, 125))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('epigenetic biomarkers', 'MPA', (192, 213))	('patients', 'Species', '9606', (66, 74))
130195	33233407	EWAS revealed a statistically significant hypo-methylated single-CpG (cg03546163) in the FKBP5 gene in the low survival group after Bonferroni post-hoc correction (Figure 1).	('hypo-methylated', 'PosReg', (42, 57))	('FKBP5', 'Gene', '2289', (89, 94))	('FKBP', 'molecular_function', 'GO:0030051', ('89', '93'))	('cg03546163', 'Var', (70, 80))	('cg03546163', 'Chemical', '-', (70, 80))	('low', 'NegReg', (107, 110))	('FKBP5', 'Gene', (89, 94))
130198	33233407	Patients with DNAm < 0.45 at the cg03546163 had significantly poorer survival compared with subjects with DNAm >= 0.45 (mean, 243 versus 534 days; p value < 0.001).	('cg03546163', 'Chemical', '-', (33, 43))	('cg03546163', 'Var', (33, 43))	('poorer', 'NegReg', (62, 68))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (69, 77))
130200	33233407	The multivariate analysis showed that cg03546163 DNAm at FKBP5 was independently associated with OS.	('cg03546163 DNAm', 'Var', (38, 53))	('FKBP', 'molecular_function', 'GO:0030051', ('57', '61'))	('FKBP5', 'Gene', '2289', (57, 62))	('cg03546163', 'Chemical', '-', (38, 48))	('FKBP5', 'Gene', (57, 62))	('associated', 'Reg', (81, 91))
130201	33233407	Kaplan-Meier curves revealed that a decrease of methylation at cg03546163 (<0.45) was significantly associated with worse OS (HR = 2.14 p value < 0.0001) (Figure 2a).	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('methylation', 'MPA', (48, 59))	('cg03546163', 'Chemical', '-', (63, 73))	('decrease', 'NegReg', (36, 44))	('worse OS', 'Disease', (116, 124))	('cg03546163', 'Var', (63, 73))
130202	33233407	Patients with LMR < 2.86 had significantly poorer survival compared with patients with LMR >= 2.86 (mean, 310 versus 528 days; p value < 0.001).	('LMR < 2.86', 'Var', (14, 24))	('LMR', 'Chemical', '-', (14, 17))	('survival', 'MPA', (50, 58))	('LMR', 'Chemical', '-', (87, 90))	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (43, 49))	('patients', 'Species', '9606', (73, 81))
130206	33233407	The statistically significant association between cg03546163 DNAm and OS was confirmed in an independent sample of patients (replication) and using a different targeted DNAm analysis technique (validation).	('cg03546163', 'Chemical', '-', (50, 60))	('patients', 'Species', '9606', (115, 123))	('significant association', 'Reg', (18, 41))	('cg03546163 DNAm', 'Var', (50, 65))
130207	33233407	Patients with below median OS had significantly lower DNAm at the cg03546163 compared with those with above median OS (mean, 188 versus 786 days; p value < 0.001).	('lower', 'NegReg', (48, 53))	('cg03546163', 'Var', (66, 76))	('Patients', 'Species', '9606', (0, 8))	('cg03546163', 'Chemical', '-', (66, 76))	('DNAm', 'MPA', (54, 58))
130208	33233407	The 1st Quartile was 113 versus 482 days and the 3rd Quartile was 262 versus 862 days comparing patients with DNAm difference (reference above median OS, MD: -0.04, 95%CI: -0.07 -0.01, p value: 0.04) at the cg03546163.	('DNAm difference', 'MPA', (110, 125))	('patients', 'Species', '9606', (96, 104))	('cg03546163', 'Var', (207, 217))	('cg03546163', 'Chemical', '-', (207, 217))
130209	33233407	The multivariate analysis confirmed that cg03546163 DNAm at FKBP5 was independently associated with OS.	('cg03546163 DNAm', 'Var', (41, 56))	('FKBP5', 'Gene', '2289', (60, 65))	('cg03546163', 'Chemical', '-', (41, 51))	('associated', 'Reg', (84, 94))	('FKBP5', 'Gene', (60, 65))	('FKBP', 'molecular_function', 'GO:0030051', ('60', '64'))
130210	33233407	A growing number of studies reported on the identification of epigenetic prognostic biomarkers in several cancers.	('epigenetic', 'Var', (62, 72))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
130212	33233407	The main result was the hypomethylation of a single CpG (cg03546163) in the 5' UTR region of the FKBP5 gene in patients with poorer survival compared to patients with longer survival; it also showed to be an independent marker of prognosis in MPM patients.	('FKBP', 'molecular_function', 'GO:0030051', ('97', '101'))	('FKBP5', 'Gene', '2289', (97, 102))	('patients', 'Species', '9606', (153, 161))	('cg03546163', 'Chemical', '-', (57, 67))	('MPM', 'Disease', (243, 246))	('poorer', 'NegReg', (125, 131))	('FKBP5', 'Gene', (97, 102))	('cg03546163', 'Var', (57, 67))	('hypomethylation', 'Var', (24, 39))	('patients', 'Species', '9606', (247, 255))	('patients', 'Species', '9606', (111, 119))
130218	33233407	Kaplan-Meier survival curves for MPM patients highlighted cg03546163 methylation at FKBP5 gene as a prognostic factor superior to the LMR score.	('FKBP5', 'Gene', '2289', (84, 89))	('patients', 'Species', '9606', (37, 45))	('FKBP', 'molecular_function', 'GO:0030051', ('84', '88'))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('MPM', 'Disease', (33, 36))	('cg03546163', 'Chemical', '-', (58, 68))	('FKBP5', 'Gene', (84, 89))	('cg03546163 methylation', 'Var', (58, 80))	('LMR', 'Chemical', '-', (134, 137))
130221	33233407	Interestingly, in a recent study on the Behcet's disease (BD) hypomethylation in the 5'UTR region (including cg03546163) of FKBP5 characterized cases was demonstrated and it was strongly associated with high gene expression, suggesting a possible role of DNA methylation in the pathogenesis.	('FKBP5', 'Gene', '2289', (124, 129))	('BD', 'Disease', 'MESH:D001528', (58, 60))	('hypomethylation', 'Var', (62, 77))	('high gene expression', 'MPA', (203, 223))	('DNA methylation', 'biological_process', 'GO:0006306', ('255', '270'))	('cg03546163', 'Chemical', '-', (109, 119))	('FKBP5', 'Gene', (124, 129))	('gene expression', 'biological_process', 'GO:0010467', ('208', '223'))	('cg03546163', 'Var', (109, 119))	('pathogenesis', 'biological_process', 'GO:0009405', ('278', '290'))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('associated', 'Reg', (187, 197))	('FKBP', 'molecular_function', 'GO:0030051', ('124', '128'))	("Behcet's disease", 'Disease', (40, 56))
130255	33233407	In the case of cg03546163 the measured methylation level is the average between two CpG sites located very close (Figure S1).	('cg03546163', 'Chemical', '-', (15, 25))	('methylation level', 'MPA', (39, 56))	('cg03546163', 'Var', (15, 25))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))
130257	33233407	The amplicon for cg03546163 (chr6:35,654,364) encompasses 196bp (chr6:35,654,222-chr6:35,654,418 (GRCh37/hg19)) and PCR was performed on 10 ng of converted DNA using the following primers: Our results suggest the potential use of DNAm analysis in blood to develop noninvasive tests for prognostic evaluation in MPM; our study is the first to demonstrate that a single CpG in FKBP5 gene is an independent marker of prognosis in patients with MPM and is superior to the LMR inflammation-based prognostic score.	('FKBP5', 'Gene', '2289', (375, 380))	('inflammation', 'Disease', 'MESH:D007249', (472, 484))	('MPM', 'Disease', (441, 444))	('patients', 'Species', '9606', (427, 435))	('FKBP', 'molecular_function', 'GO:0030051', ('375', '379'))	('FKBP5', 'Gene', (375, 380))	('inflammation', 'Disease', (472, 484))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('LMR', 'Chemical', '-', (468, 471))	('cg03546163', 'Chemical', '-', (17, 27))	('CpG', 'Var', (368, 371))	('inflammation', 'biological_process', 'GO:0006954', ('472', '484'))
130259	33233407	Knowledge of epigenetic changes has provided new therapeutic opportunities against cancer.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('epigenetic changes', 'Var', (13, 31))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))
130261	33233407	In this context, we reported epigenetic deregulations in blood samples from MPM patients in relation to OS, paving the road to both patients' stratification and the possible discovery of new combined therapeutic options in MPM.	('epigenetic deregulations', 'Var', (29, 53))	('MPM', 'Disease', (76, 79))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (80, 88))
130262	33233407	Noninvasively obtained, methylation-based biomarkers detected in blood cells from cancer patients offer significant practical advantages, being promising and dynamic prognostic markers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('methylation-based', 'Var', (24, 41))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (89, 97))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))
130284	30449771	The BRAF V600E mutation was detected in the resected primary tumor using two molecular methods: real-time polymerase chain reaction and direct sequencing.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
130285	30449771	Consequently, the oral administration of vemurafenib (960 mg twice daily), a competitive kinase inhibitor with activity against BRAF kinase mutations such as V600E, was initiated.	('V600E', 'Var', (158, 163))	('vemurafenib', 'Chemical', 'MESH:D000077484', (41, 52))	('V600E', 'Mutation', 'rs113488022', (158, 163))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('89', '105'))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', (128, 132))
130312	30449771	We therefore did not evaluate the BRCA1-associated protein 1 (BAP1) mutation status of the sample, as mutations in this gene are associated with both melanoma and a wide range of other cancers, such as lung cancer, meningioma, mesothelioma, and renal cell carcinoma.	('associated', 'Reg', (129, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('mesothelioma', 'Disease', (227, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('cancers', 'Disease', (185, 192))	('BAP1', 'Gene', '8314', (62, 66))	('BRCA1-associated protein 1', 'Gene', '8314', (34, 60))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (245, 265))	('melanoma', 'Disease', (150, 158))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('meningioma', 'Disease', (215, 225))	('BRCA1-associated protein 1', 'Gene', (34, 60))	('lung cancer', 'Disease', (202, 213))	('meningioma', 'Phenotype', 'HP:0002858', (215, 225))	('BAP1', 'Gene', (62, 66))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('renal cell carcinoma', 'Disease', (245, 265))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (245, 265))	('meningioma', 'Disease', 'MESH:D008577', (215, 225))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
130330	30911668	A recent French study (PRODIGE 7) shows that, at 60 days, major morbidity (grade 3-4-5 of the Dindo classification) was higher for patients who received CRS+HIPEC (24.1 %) than patients with CRS only (13.6 %) (p=0.03).	('patients', 'Species', '9606', (131, 139))	('CRS+HIPEC', 'Var', (153, 162))	('patients', 'Species', '9606', (177, 185))	('higher', 'PosReg', (120, 126))	('CRS', 'Chemical', '-', (191, 194))	('CRS', 'Chemical', '-', (153, 156))
130337	30911668	O2- and 1O2 create cell death with two mechanism: direct mechanism (necrosis and apoptosis) and indirect mechanism (microvascular damage, and antitumor immune responses) (Figure 1).	('necrosis', 'biological_process', 'GO:0070265', ('68', '76'))	('1O2', 'Var', (8, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('necrosis', 'biological_process', 'GO:0008219', ('68', '76'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('necrosis', 'Disease', 'MESH:D009336', (68, 76))	('necrosis', 'biological_process', 'GO:0019835', ('68', '76'))	('cell death', 'biological_process', 'GO:0008219', ('19', '29'))	('tumor', 'Disease', (146, 151))	('necrosis', 'biological_process', 'GO:0001906', ('68', '76'))	('necrosis', 'biological_process', 'GO:0008220', ('68', '76'))	('O2-', 'Var', (0, 3))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('necrosis', 'Disease', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
130344	30911668	Furthermore, NPs can bypass drug efflux pumps, thus evading multidrug resistance and achieving significantly higher drug accumulation into the tumoral cells compared to IP therapy with the unformulated free drugs.	('evading', 'Reg', (52, 59))	('efflux', 'biological_process', 'GO:0140352', ('33', '39'))	('higher', 'PosReg', (109, 115))	('tumoral', 'Disease', (143, 150))	('tumoral', 'Disease', 'MESH:D009369', (143, 150))	('NPs', 'Var', (13, 16))	('drug efflux pumps', 'MPA', (28, 45))	('efflux', 'biological_process', 'GO:0140115', ('33', '39'))	('multidrug resistance', 'MPA', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
130385	30911668	Guyon shown that PDT with HAL induced rhabdomyolysis, intestinal necrosis and liver function test anomalies, leading to death in 2 out of 34 rats.	('necrosis', 'biological_process', 'GO:0008219', ('65', '73'))	('necrosis', 'biological_process', 'GO:0019835', ('65', '73'))	('rhabdomyolysis', 'Disease', 'MESH:D012206', (38, 52))	('necrosis', 'biological_process', 'GO:0008220', ('65', '73'))	('PDT', 'Var', (17, 20))	('necrosis', 'biological_process', 'GO:0001906', ('65', '73'))	('rhabdomyolysis', 'Disease', (38, 52))	('liver function test anomalies', 'CPA', (78, 107))	('intestinal necrosis', 'Disease', (54, 73))	('rats', 'Species', '10116', (141, 145))	('intestinal necrosis', 'Disease', 'MESH:D009336', (54, 73))	('rhabdomyolysis', 'Phenotype', 'HP:0003201', (38, 52))	('HAL', 'Chemical', 'MESH:C419924', (26, 29))	('liver function test anomalies', 'Phenotype', 'HP:0002910', (78, 107))	('necrosis', 'biological_process', 'GO:0070265', ('65', '73'))
130400	30911668	There were an increased number of postoperative pleural effusions in patients undergoing PDT, compared to those just being explored (CRS/PDT-: 3/15 (20 %) vs CRS+PDT: 23/39 (59 %), p=0.01).	('PDT', 'Var', (89, 92))	('CRS', 'Chemical', '-', (158, 161))	('postoperative pleural effusions', 'Disease', (34, 65))	('postoperative pleural effusions', 'Disease', 'MESH:D010996', (34, 65))	('pleural effusions', 'Phenotype', 'HP:0002202', (48, 65))	('patients', 'Species', '9606', (69, 77))	('CRS', 'Chemical', '-', (133, 136))
130457	30911668	The number of annexin V/PI double-positive cancer cells in the group that received PTT was twice as high as that of the other groups (p=0.0024, NIR+pSGNs vs control; p=0.007, NOR+pSGNs vs NIR only; p=0.0034, NIR+pSGNs vs pSGNs only).	('NOR', 'cellular_component', 'GO:0005731', ('175', '178'))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('annexin V', 'Gene', (14, 23))	('PTT', 'Var', (83, 86))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('PTT', 'Chemical', '-', (83, 86))	('annexin V', 'Gene', '308', (14, 23))
130460	30911668	The group treated with anti-human CD47 conjugated pSGNs and NIR laser irradiation had the strongest therapeutic effect on the human ovarian cancer cell xenograft model.	('CD47', 'Gene', '961', (34, 38))	('human', 'CPA', (126, 131))	('ovarian cancer', 'Disease', (132, 146))	('anti-human', 'Var', (23, 33))	('human', 'Species', '9606', (126, 131))	('CD47', 'Gene', (34, 38))	('human', 'Species', '9606', (28, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))
130563	29805789	18F-FDG imaging was performed to rule out malignancy; it revealed highly increased uptake of 18F-FDG in the RA, the pericardium adjacent to the RV and RA (Fig.	('increased', 'PosReg', (73, 82))	('18F-FDG', 'Var', (93, 100))	('malignancy', 'Disease', (42, 52))	('18F-FDG', 'Chemical', '-', (0, 7))	('uptake', 'biological_process', 'GO:0098739', ('83', '89'))	('uptake', 'biological_process', 'GO:0098657', ('83', '89'))	('uptake', 'MPA', (83, 89))	('18F-FDG', 'Chemical', '-', (93, 100))	('malignancy', 'Disease', 'MESH:D009369', (42, 52))
130593	24722292	Inhibition of AKT reduced the transcriptional activity of beta-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment.	('AKT', 'Protein', (14, 17))	('clonogenic death', 'Disease', (138, 154))	('reduced', 'NegReg', (18, 25))	('pemetrexed', 'Chemical', 'MESH:D000068437', (161, 171))	('senescence', 'biological_process', 'GO:0010149', ('119', '129'))	('Inhibition', 'Var', (0, 10))	('beta-catenin-dependent', 'Protein', (58, 80))	('transcriptional activity', 'MPA', (30, 54))	('clonogenic death', 'Disease', 'MESH:D003643', (138, 154))	('sensitized', 'Reg', (95, 105))
130608	24722292	This study expands what is known on the function of CSF-1R in non-hematopoietic neoplasms and suggests that interference with the signaling of the CSF-1Rpos cells may overcome the chemoresistance of MPM.	('chemoresistance', 'CPA', (180, 195))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (66, 89))	('CSF-1', 'molecular_function', 'GO:0005011', ('147', '152'))	('neoplasms', 'Disease', (80, 89))	('neoplasms', 'Disease', 'MESH:D009369', (80, 89))	('CSF-1Rpos', 'Gene', (147, 156))	('MPM', 'Disease', (199, 202))	('interference', 'Var', (108, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (80, 89))	('overcome', 'PosReg', (167, 175))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('CSF-1', 'molecular_function', 'GO:0005011', ('52', '57'))
130654	24722292	This was functionally relevant, as western blotting revealed high enrichment of the purified CSF-1Rpos cells for phospho-STAT3 (Tyr705), phospho-NF-kappaB (p-p65-Ser536) and phospho-AKT (Ser473).	('Ser', 'cellular_component', 'GO:0005790', ('187', '190'))	('Ser', 'cellular_component', 'GO:0005790', ('162', '165'))	('Ser536', 'Chemical', '-', (162, 168))	('Ser473', 'Var', (187, 193))	('Ser473', 'Chemical', '-', (187, 193))	('Tyr705', 'Var', (128, 134))	('Tyr705', 'Chemical', '-', (128, 134))	('p65', 'Gene', (158, 161))	('CSF-1', 'molecular_function', 'GO:0005011', ('93', '98'))	('p65', 'Gene', '5970', (158, 161))
130658	24722292	We evaluated the effect of two naturally occurring, polyfunctional NF-kappaB/STAT3 inhibitors, namely parthenolide and butein (2',3,4,4'-tetrahydroxychalcone), and two more specific AKT and ERK small-molecule inhibitors, namely LY294002 (PI3K/AKT) and U0126 (MEK1/2-ERK1/2).	('MEK1', 'molecular_function', 'GO:0004708', ('259', '263'))	('MEK1/2', 'Gene', '5604;5605', (259, 265))	('MEK1/2', 'Gene', (259, 265))	('ERK', 'Gene', (266, 269))	('butein', 'Chemical', 'MESH:C040918', (119, 125))	('PI3', 'Gene', '5266', (238, 241))	('U0126', 'Chemical', 'MESH:C113580', (252, 257))	('LY294002', 'Chemical', 'MESH:C085911', (228, 236))	('U0126', 'Var', (252, 257))	('parthenolide', 'Chemical', 'MESH:C002669', (102, 114))	('ERK1', 'molecular_function', 'GO:0004707', ('266', '270'))	('PI3', 'Gene', (238, 241))	('ERK', 'Gene', '5594', (190, 193))	("2',3,4,4'-tetrahydroxychalcone", 'Chemical', 'MESH:C040918', (127, 157))	('AKT', 'Pathway', (182, 185))	('ERK', 'Gene', '5594', (266, 269))	('ERK', 'molecular_function', 'GO:0004707', ('190', '193'))	('PI3K', 'molecular_function', 'GO:0016303', ('238', '242'))	('ERK', 'Gene', (190, 193))	('ERK1/2', 'Gene', (266, 272))	('ERK1/2', 'Gene', '5595;5594', (266, 272))	('LY294002', 'Var', (228, 236))
130661	24722292	Staining of the treated cells for SA-beta-galactosidase (beta-gal) activity showed that the lack of BrdU incorporation was mainly due to senescence, with the LY294002 treatment eliciting the highest number of senescent cells (Figure 4e).	('LY294002', 'Var', (158, 166))	('BrdU', 'Chemical', 'MESH:D001973', (100, 104))	('SA-beta-gal', 'Chemical', '-', (34, 45))	('BrdU', 'MPA', (100, 104))	('LY294002', 'Chemical', 'MESH:C085911', (158, 166))	('senescence', 'CPA', (137, 147))	('eliciting', 'Reg', (177, 186))	('senescence', 'biological_process', 'GO:0010149', ('137', '147'))
130662	24722292	This correlated with the upregulation of p21 in the LY294002 CSF-1Rpos-treated cells, which was further increased in the pemetrexed-treated samples (Figure 5f).	('p21', 'Gene', (41, 44))	('p21', 'Gene', '644914', (41, 44))	('CSF-1', 'molecular_function', 'GO:0005011', ('61', '66'))	('increased', 'PosReg', (104, 113))	('LY294002', 'Var', (52, 60))	('pemetrexed', 'Chemical', 'MESH:D000068437', (121, 131))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))	('upregulation', 'PosReg', (25, 37))
130663	24722292	We found that the expression of CA-CSF-1R triggered changes in cell morphology and growth kinetics by conferring to the LP9 cells, a epithelial, loosely adherent phenotype and a much faster growth rate (as compared with the empty-vector-infected ones: EV-LP9) (Figure 6a, upper and lower panels, respectively).	('CA-CSF-1R', 'Gene', (32, 41))	('growth', 'CPA', (83, 89))	('faster', 'PosReg', (183, 189))	('cell morphology', 'CPA', (63, 78))	('EV', 'Chemical', '-', (252, 254))	('growth rate', 'CPA', (190, 201))	('CSF-1', 'molecular_function', 'GO:0005011', ('35', '40'))	('changes', 'Reg', (52, 59))	('expression', 'Var', (18, 28))
130669	24722292	Phosphorylation of GSK3beta at serine 9 inactivates this kinase activity and causes stabilization and nuclear localization of beta-catenin from the plasma membrane to the cytoplasm and the nucleus, where the latter acts as a transcription cofactor for developmentally regulated genes.	('cytoplasm', 'cellular_component', 'GO:0005737', ('171', '180'))	('causes', 'Reg', (77, 83))	('stabilization', 'MPA', (84, 97))	('nucleus', 'cellular_component', 'GO:0005634', ('189', '196'))	('kinase activity', 'MPA', (57, 72))	('GSK', 'molecular_function', 'GO:0050321', ('19', '22'))	('Phosphorylation', 'Var', (0, 15))	('GSK3beta', 'Gene', (19, 27))	('plasma membrane', 'cellular_component', 'GO:0005886', ('148', '163'))	('serine', 'Chemical', 'MESH:D012694', (31, 37))	('localization', 'biological_process', 'GO:0051179', ('110', '122'))	('inactivates', 'NegReg', (40, 51))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('transcription', 'biological_process', 'GO:0006351', ('225', '238'))	('GSK3beta', 'Gene', '2932', (19, 27))	('beta-catenin', 'Protein', (126, 138))	('nuclear localization', 'MPA', (102, 122))	('kinase activity', 'molecular_function', 'GO:0016301', ('57', '72'))
130670	24722292	To assess whether the nuclear-localized beta-catenin was functional, we transfected beta-catenin-responsive reporter vectors, containing wild-type or mutated TCF-binding sites, in both empty vector (EV) and CA-CSF-1R-expressing cells.	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('CSF-1', 'molecular_function', 'GO:0005011', ('210', '215'))	('EV', 'Chemical', '-', (199, 201))	('mutated', 'Var', (150, 157))	('TCF', 'Gene', (158, 161))	('TCF', 'Gene', '3172', (158, 161))
130673	24722292	Notably, pretreatment of CA-CSF1R-LP9 cells with LY294002 strongly increased the number of senescent cells in both vehicle- and pemetrexed-treated cells (Figure 6f, lower panel) and only slightly increased the number of apoptotic cells (Supplementary Figure 5C).	('LY294002', 'Var', (49, 57))	('senescent cells', 'CPA', (91, 106))	('CSF1R', 'Gene', '1436', (28, 33))	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('increased', 'PosReg', (67, 76))	('CSF1', 'molecular_function', 'GO:0005011', ('28', '32'))	('CSF1R', 'Gene', (28, 33))	('pemetrexed', 'Chemical', 'MESH:D000068437', (128, 138))
130675	24722292	LY294002 treatment was accompanied by the upregulation of p21 and downregulation of c-MYC proteins in both vehicle- and pemetrexed-treated samples, as revealed by western blotting (Figure 6f, lower panel).	('LY294002', 'Var', (0, 8))	('c-MYC', 'Gene', '4609', (84, 89))	('p21', 'Gene', (58, 61))	('pemetrexed', 'Chemical', 'MESH:D000068437', (120, 130))	('p21', 'Gene', '644914', (58, 61))	('c-MYC', 'Gene', (84, 89))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('downregulation', 'NegReg', (66, 80))	('upregulation', 'PosReg', (42, 54))
130689	24722292	In detail, AKT inhibition indeed counteracted the bypass of senescence induced by the expression of active CSF-1R in pemetrexed-treated mesothelial cells, thereby restoring their chemosensitivity.	('inhibition', 'NegReg', (15, 25))	('restoring', 'PosReg', (163, 172))	('CSF-1', 'molecular_function', 'GO:0005011', ('107', '112'))	('chemosensitivity', 'MPA', (179, 195))	('pemetrexed', 'Chemical', 'MESH:D000068437', (117, 127))	('AKT', 'Pathway', (11, 14))	('CSF-1R', 'Gene', (107, 113))	('expression', 'Var', (86, 96))	('senescence', 'biological_process', 'GO:0010149', ('60', '70'))
130691	24722292	We have recently shown that functional interaction of STAT3 and NF-kappaB impinges on mesothelioma resistance to pemetrexed by modulating EMT-associated genes and that butein abated the resistance of mesothelioma cells by decreasing the pSTAT3-NF-kappaB interaction.	('EMT-associated genes', 'Gene', (138, 158))	('interaction', 'Interaction', (254, 265))	('mesothelioma cell', 'Disease', (200, 217))	('abated', 'NegReg', (175, 181))	('interaction', 'Interaction', (39, 50))	('mesothelioma', 'Disease', (200, 212))	('mesothelioma cell', 'Disease', 'MESH:D008654', (200, 217))	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('modulating', 'Reg', (127, 137))	('pemetrexed', 'Chemical', 'MESH:D000068437', (113, 123))	('butein', 'Var', (168, 174))	('impinges', 'Reg', (74, 82))	('decreasing', 'NegReg', (222, 232))	('EMT', 'biological_process', 'GO:0001837', ('138', '141'))	('pSTAT3-NF-kappaB', 'Protein', (237, 253))	('mesothelioma', 'Disease', (86, 98))	('resistance', 'CPA', (186, 196))	('butein', 'Chemical', 'MESH:C040918', (168, 174))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
130705	24722292	Recombinant human M-CSF receptor (Sino Biological, Daxing, China), recombinant human M-CSF (BioLegend, San Diego, CA, USA), recombinant human IL-34 (BioLegend), pemetrexed (Eli Lilly and Company, Indianapolis, IN, USA), LY294002 (Cell Signaling Technology, Danvers, MA, USA), U0126 (Cell Signaling Technology), parthenolide (Sigma) and butein (Santa Cruz Technology, Dallas, TX, USA) were dissolved according to the manufacturer's instructions.	('LY294002', 'Var', (220, 228))	('human', 'Species', '9606', (136, 141))	('IL-34', 'Gene', '146433', (142, 147))	('M-CSF', 'Gene', (85, 90))	('human', 'Species', '9606', (79, 84))	('Signaling', 'biological_process', 'GO:0023052', ('288', '297'))	('Signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('M-CSF', 'Gene', (18, 23))	('M-CSF', 'Gene', '1435', (18, 23))	('U0126', 'Chemical', 'MESH:C113580', (276, 281))	('pemetrexed', 'Chemical', 'MESH:D000068437', (161, 171))	('IL-34', 'Gene', (142, 147))	('human', 'Species', '9606', (12, 17))	('LY294002', 'Chemical', 'MESH:C085911', (220, 228))	('butein', 'Chemical', 'MESH:C040918', (336, 342))	('parthenolide', 'Chemical', 'MESH:C002669', (311, 323))	('M-CSF', 'Gene', '1435', (85, 90))
130722	24722292	Plasmids of TOP-FLASH (with three repeats of the TCF-binding site) or FOP-FLASH (with three repeats of a mutated TCF-binding site) were transfected into cells treated with LY294002 according to the manufacturer's instructions.	('TCF', 'Gene', (49, 52))	('LY294002', 'Var', (172, 180))	('TCF', 'Gene', '3172', (49, 52))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('FOP-', 'Phenotype', 'HP:0500062', (70, 74))	('LY294002', 'Chemical', 'MESH:C085911', (172, 180))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('TCF', 'Gene', (113, 116))	('TCF', 'Gene', '3172', (113, 116))
130739	23638030	In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cell-surface', 'cellular_component', 'GO:0009986', ('99', '111'))	('YS110', 'Var', (121, 126))	('CD26', 'Protein', (112, 116))	('YS110', 'Var', (55, 60))	('cancer', 'Disease', (130, 136))	('nuclear translocation', 'MPA', (69, 90))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('YS110', 'Chemical', '-', (121, 126))	('YS110', 'Chemical', '-', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
130740	23638030	It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis.	('nucleus', 'cellular_component', 'GO:0005634', ('58', '65'))	('CD26', 'Gene', (22, 26))	('YS110', 'Var', (31, 36))	('YS110', 'Chemical', '-', (31, 36))
130741	23638030	In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis.	('nucleus', 'cellular_component', 'GO:0005634', ('63', '70'))	('caveolin-dependent endocytosis', 'biological_process', 'GO:0072584', ('75', '105'))	('YS110', 'Var', (15, 20))	('translocated into the nucleus', 'MPA', (41, 70))	('caveolin-dependent endocytosis', 'MPA', (75, 105))	('CD26', 'Protein', (32, 36))	('YS110', 'Chemical', '-', (15, 20))
130744	23638030	Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment.	('nuclear transport', 'MPA', (26, 43))	('POLR2A', 'Gene', (151, 157))	('deletion mutants', 'Var', (113, 129))	('CD26', 'Gene', (133, 137))	('POLR2A', 'Gene', '5430', (151, 157))	('endocytosis', 'biological_process', 'GO:0006897', ('73', '84'))	('impaired', 'NegReg', (17, 25))	('nuclear transport', 'biological_process', 'GO:0051169', ('26', '43'))	('YS110', 'Chemical', '-', (180, 185))
130749	23638030	We have previously developed anti-CD26 mAbs that exhibit unambiguous inhibitory effects against the growth of cultured cells and xenografted tumors.	('inhibitory effects', 'MPA', (69, 87))	('anti-CD26', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('anti-CD26', 'Gene', (29, 38))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('growth of cultured cells', 'CPA', (100, 124))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))
130751	23638030	As it has a human IgG1 backbone, YS110 can efficiently mediate the recruitment to tumors of human immune effector cells, including natural killer (NK) cells, that express Fc receptors at the cell membrane, in a process of antibody-dependent cellular cytotoxicity (ADCC).	('tumors', 'Disease', (82, 88))	('IgG1', 'cellular_component', 'GO:0071735', ('18', '22'))	('antibody', 'molecular_function', 'GO:0003823', ('222', '230'))	('antibody', 'cellular_component', 'GO:0042571', ('222', '230'))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('IgG1', 'Gene', (18, 22))	('YS110', 'Var', (33, 38))	('YS110', 'Chemical', '-', (33, 38))	('Fc receptors', 'Protein', (171, 183))	('antibody', 'cellular_component', 'GO:0019815', ('222', '230'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cell membrane', 'cellular_component', 'GO:0005886', ('191', '204'))	('human', 'Species', '9606', (92, 97))	('cytotoxicity', 'Disease', (250, 262))	('ADCC', 'biological_process', 'GO:0001788', ('264', '268'))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('222', '262'))	('antibody', 'cellular_component', 'GO:0019814', ('222', '230'))	('cytotoxicity', 'Disease', 'MESH:D064420', (250, 262))	('human', 'Species', '9606', (12, 17))	('IgG1', 'Gene', '16017', (18, 22))
130755	23638030	In keeping with this, although there is no information on the signaling pathway associated with CD26, YS110 treatment also results in direct inhibitory effects on the proliferation of malignant mesothelioma cells.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (184, 206))	('YS110', 'Chemical', '-', (102, 107))	('malignant mesothelioma', 'Disease', (184, 206))	('inhibitory effects', 'NegReg', (141, 159))	('signaling pathway', 'biological_process', 'GO:0007165', ('62', '79'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (184, 206))	('proliferation', 'CPA', (167, 180))	('YS110', 'Var', (102, 107))
130761	23638030	Therefore, we hypothesized that nuclear localization of CD26 is functionally related to the antitumor process following treatment with YS110.	('CD26', 'Gene', (56, 60))	('localization', 'biological_process', 'GO:0051179', ('40', '52'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('YS110', 'Var', (135, 140))	('related', 'Reg', (77, 84))	('tumor', 'Disease', (96, 101))	('nuclear localization', 'MPA', (32, 52))	('YS110', 'Chemical', '-', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
130762	23638030	In this study, we demonstrated that nuclear translocation of CD26 and YS110 contributed to growth inhibition of malignant mesothelioma cells after YS110 treatment.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (112, 134))	('YS110', 'Var', (147, 152))	('YS110', 'Var', (70, 75))	('growth inhibition', 'CPA', (91, 108))	('CD26', 'Gene', (61, 65))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (112, 134))	('malignant mesothelioma', 'Disease', (112, 134))	('nuclear translocation', 'MPA', (36, 57))	('YS110', 'Chemical', '-', (147, 152))	('YS110', 'Chemical', '-', (70, 75))
130765	23638030	Furthermore, blocking the nuclear trafficking of CD26 and YS110 prevented both the nuclear translocation of these two proteins and the YS110-induced transcriptional repression of the POLR2A gene.	('prevented', 'NegReg', (64, 73))	('YS110-induced', 'Var', (135, 148))	('transcriptional', 'MPA', (149, 164))	('POLR2A', 'Gene', (183, 189))	('YS110', 'Chemical', '-', (58, 63))	('CD26', 'Protein', (49, 53))	('YS110', 'Chemical', '-', (135, 140))	('nuclear translocation of these', 'MPA', (83, 113))	('POLR2A', 'Gene', '5430', (183, 189))	('nuclear trafficking', 'MPA', (26, 45))
130770	23638030	The PCR primers were: CD26wt, 5'-CCG GAA TTC AAT GAA GAC ACC GTGG-3' and 5'-CGG GAT CCT CAA GGT AAA GAG AAA CA-3'; CD267-766, 5'-CCG GAA TTC AGT TCT TCT GGG ACT GC-3' and 5'-CGG GAT CCT CAA GGT AAA GAG AAA CA-3'; CD261-500, 5'-CCG GAA TTC AAT GAA GAC ACC GTGG-3' and 5'-CCG GAA TTC TCA CAA AGC TGA ATTG-3'; and CD261-629, 5'-CCG GAA TTC AAT GAA GAC ACC GTGG-3' and 5'-CGG GAT CCT CAC CAG CCC CAA ATTG-3'.	('CCT', 'Gene', (84, 87))	('AAT', 'molecular_function', 'GO:0004069', ('239', '242'))	('AGT', 'Gene', (141, 144))	('AGT', 'Gene', '183', (141, 144))	('CD261-500', 'Var', (213, 222))	('CCT', 'Gene', (182, 185))	('CCT', 'Gene', '907', (376, 379))	('AAT', 'molecular_function', 'GO:0004069', ('45', '48'))	('AAT', 'molecular_function', 'GO:0004069', ('337', '340'))	('CCT', 'Gene', '907', (84, 87))	('CD261-629', 'Var', (311, 320))	('CCT', 'Gene', '907', (182, 185))	('CCT', 'Gene', (376, 379))	('CCC', 'cellular_component', 'GO:0030896', ('388', '391'))
130826	23638030	Over 4 h after treatment with Alexa-YS110, the number of cells retaining Alexa-YS110 in the nucleus was apparently decreased (Fig.	('Alexa-YS110', 'Var', (30, 41))	('Alexa-YS110', 'Chemical', '-', (73, 84))	('decreased', 'NegReg', (115, 124))	('nucleus', 'cellular_component', 'GO:0005634', ('92', '99'))	('Alexa-YS110', 'Var', (73, 84))	('Alexa-YS110', 'Chemical', '-', (30, 41))
130836	23638030	Similarly, co-localization of CD26 and YS110 was also observed by immunoelectron microscopic analysis using different sized immunogold particles (15 nm for CD26, 30 nm for YS110) (Fig.	('YS110', 'Chemical', '-', (39, 44))	('15 nm', 'Var', (146, 151))	('YS110', 'Var', (39, 44))	('YS110', 'Chemical', '-', (172, 177))	('CD26', 'Var', (156, 160))	('localization', 'biological_process', 'GO:0051179', ('14', '26'))
130846	23638030	S2B), suggesting that YS110 and 1F7 induced nuclear translocation of CD26 in cancer cells.	('YS110', 'Chemical', '-', (22, 27))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('1F7', 'Var', (32, 35))	('YS110', 'Var', (22, 27))	('CD26', 'Protein', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('nuclear translocation', 'MPA', (44, 65))
130847	23638030	To evaluate the relevance of the nuclear localization of CD26 to the nuclear trafficking of YS110, various CD26 deletion mutants were generated to specify the domain of CD26 that was essential for its nuclear localization (Fig.	('YS110', 'Chemical', '-', (92, 97))	('CD26', 'Gene', (169, 173))	('deletion mutants', 'Var', (112, 128))	('mutants', 'Var', (121, 128))	('localization', 'biological_process', 'GO:0051179', ('41', '53'))	('CD26', 'Gene', (107, 111))	('localization', 'biological_process', 'GO:0051179', ('209', '221'))
130849	23638030	In contrast, the two partial C-terminal extracellular region-depleted forms (CD261-500 and CD261-629) were not detected in the nuclear fraction, although their cell-surface expression and capacity to bind to YS110 were confirmed (Fig.	('YS110', 'Chemical', '-', (208, 213))	('bind', 'Interaction', (200, 204))	('extracellular region', 'cellular_component', 'GO:0005576', ('40', '60'))	('cell-surface', 'cellular_component', 'GO:0009986', ('160', '172'))	('CD261-629', 'Var', (91, 100))	('CD261-500', 'Var', (77, 86))
130858	23638030	These data suggest that antitumor mAbs (YS110 and 1F7) bind to cell-surface CD26, and thereafter are translocated to the nucleus.	('cell-surface', 'cellular_component', 'GO:0009986', ('63', '75'))	('bind', 'Interaction', (55, 59))	('tumor', 'Disease', (28, 33))	('YS110', 'Chemical', '-', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('YS110', 'Var', (40, 45))	('CD26', 'Protein', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('nucleus', 'cellular_component', 'GO:0005634', ('121', '128'))
130861	23638030	To this end, three different endocytotic tracers were employed: Alexa488-labeled transferrin (Alexa-Tf) for the clathrin pathway, Alexa488-labeled cholera toxin B (Alexa-CtxB) for the caveolin pathway, and FITC-dextran for macropinocytosis.	('Alexa488-labeled', 'Var', (130, 146))	('FITC-dextran', 'Chemical', 'MESH:C015219', (206, 218))	('macropinocytosis', 'biological_process', 'GO:0044351', ('223', '239'))	('caveolin pathway', 'Pathway', (184, 200))	('Alexa-CtxB', 'Chemical', '-', (164, 174))	('Alexa488', 'Chemical', '-', (64, 72))	('Alexa-Tf', 'Chemical', '-', (94, 102))	('transferrin', 'Gene', '7018', (81, 92))	('clathrin pathway', 'Pathway', (112, 128))	('transferrin', 'Gene', (81, 92))	('Alexa488', 'Chemical', '-', (130, 138))
130864	23638030	Furthermore, consistent with previous evidence that cell-surface CD26 associates with caveolin-1 at the lipid/raft domain, YS110 was found to colocalize with caveolin-1, but not with clathrin heavy chain (CHC), which is a key component of the clathrin pathway (Fig.	('associates', 'Interaction', (70, 80))	('caveolin-1', 'Gene', '857', (158, 168))	('caveolin-1', 'Gene', (86, 96))	('CHC', 'Gene', (205, 208))	('lipid/raft', 'cellular_component', 'GO:0045121', ('104', '114'))	('caveolin-1', 'Gene', '857', (86, 96))	('clathrin heavy chain', 'Gene', '1213', (183, 203))	('YS110', 'Chemical', '-', (123, 128))	('clathrin heavy chain', 'Gene', (183, 203))	('CHC', 'Gene', '1213', (205, 208))	('CD26', 'Gene', (65, 69))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('caveolin-1', 'Gene', (158, 168))	('cell-surface', 'cellular_component', 'GO:0009986', ('52', '64'))	('YS110', 'Var', (123, 128))
130867	23638030	When JMN cells were depleted of caveolin-1 by transfection with small interfering RNA (siRNA) for caveolin-1 mRNA, significant reductions in both endocytosis and nuclear localization of YS110 were observed in JMN cells treated with Alexa-YS110 (Fig.	('endocytosis', 'MPA', (146, 157))	('RNA', 'cellular_component', 'GO:0005562', ('82', '85'))	('endocytosis', 'biological_process', 'GO:0006897', ('146', '157'))	('MN', 'CellLine', 'CVCL:U508', (210, 212))	('YS110', 'Var', (186, 191))	('MN', 'CellLine', 'CVCL:U508', (6, 8))	('nuclear localization', 'MPA', (162, 182))	('localization', 'biological_process', 'GO:0051179', ('170', '182'))	('caveolin-1', 'Gene', (32, 42))	('Alexa-YS110', 'Chemical', '-', (232, 243))	('caveolin-1', 'Gene', (98, 108))	('reductions', 'NegReg', (127, 137))	('caveolin-1', 'Gene', '857', (32, 42))	('caveolin-1', 'Gene', '857', (98, 108))	('YS110', 'Chemical', '-', (238, 243))	('YS110', 'Chemical', '-', (186, 191))
130868	23638030	However, there was no significant difference in the distribution of YS110 between cells treated with control siRNA or siRNA for CHC (Fig.	('YS110', 'Var', (68, 73))	('YS110', 'Chemical', '-', (68, 73))	('CHC', 'Gene', (128, 131))	('CHC', 'Gene', '1213', (128, 131))
130869	23638030	Accordingly, disruption of caveolae formation with nystatin, an inhibitor of the caveolin pathway that binds to cholesterol, markedly impaired both the endocytosis and nuclear localization of CD26 and YS110 in YS110-treated cells (Fig.	('YS110', 'Chemical', '-', (201, 206))	('CD26', 'Protein', (192, 196))	('nuclear localization', 'MPA', (168, 188))	('impaired both the endocytosis', 'Disease', (134, 163))	('cholesterol', 'Chemical', 'MESH:D002784', (112, 123))	('formation', 'biological_process', 'GO:0009058', ('36', '45'))	('disruption', 'Var', (13, 23))	('endocytosis', 'biological_process', 'GO:0006897', ('152', '163'))	('nystatin', 'Chemical', 'MESH:D009761', (51, 59))	('YS110', 'Var', (201, 206))	('caveolae', 'cellular_component', 'GO:0005901', ('27', '35'))	('YS110', 'Chemical', '-', (210, 215))	('impaired both the endocytosis', 'Disease', 'MESH:D009422', (134, 163))	('localization', 'biological_process', 'GO:0051179', ('176', '188'))
130872	23638030	These results indicated that caveolin-dependent endocytosis is required for the nuclear translocation of CD26 and YS110.	('YS110', 'Var', (114, 119))	('YS110', 'Chemical', '-', (114, 119))	('CD26', 'Protein', (105, 109))	('caveolin-dependent endocytosis', 'biological_process', 'GO:0072584', ('29', '59'))
130877	23638030	YS110-EEA1 complex in the nucleus was also observed by electron microscopy with the respective immunogold particle-conjugated antibodies (15 nm for EEA1, 30 nm for YS110) (Fig.	('15 nm', 'Var', (138, 143))	('YS110', 'Chemical', '-', (0, 5))	('EEA1', 'Gene', '8411', (148, 152))	('YS110', 'Chemical', '-', (164, 169))	('EEA1', 'Gene', (6, 10))	('EEA1', 'Gene', (148, 152))	('nucleus', 'cellular_component', 'GO:0005634', ('26', '33'))	('EEA1', 'Gene', '8411', (6, 10))	('YS110', 'Var', (164, 169))
130882	23638030	In a similar model, we confirmed that administration of YS110 apparently reduced the tumorigenicity of JMN and MSTO/clone12 (MSTO/CD26) cells (Fig.	('tumor', 'Disease', (85, 90))	('YS110', 'Var', (56, 61))	('reduced', 'NegReg', (73, 80))	('MN', 'CellLine', 'CVCL:U508', (104, 106))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('YS110', 'Chemical', '-', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
130883	23638030	Direct intra-tumoral injection of Alexa-YS110 into the center of the JMN tumors resulted in the nuclear accumulation of Alexa-YS110, as observed in tumor sections from the mice 1 h (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('JMN tumors', 'Disease', 'MESH:D009369', (69, 79))	('intra-tumoral', 'Disease', 'MESH:D009369', (7, 20))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Alexa-YS110', 'Chemical', '-', (120, 131))	('Alexa-YS110', 'Var', (120, 131))	('mice', 'Species', '10090', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('nuclear accumulation', 'MPA', (96, 116))	('JMN tumors', 'Disease', (69, 79))	('tumor', 'Disease', (73, 78))	('Alexa-YS110', 'Chemical', '-', (34, 45))	('intra-tumoral', 'Disease', (7, 20))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
130888	23638030	From these results, we conclude that CD26 and YS110 are translocated to the nucleus of CD26-positive cancer cells as a result of treatment with YS110.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('translocated', 'MPA', (56, 68))	('cancer', 'Disease', (101, 107))	('CD26', 'Gene', (37, 41))	('YS110', 'Chemical', '-', (144, 149))	('nucleus', 'cellular_component', 'GO:0005634', ('76', '83'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('YS110', 'Chemical', '-', (46, 51))	('YS110', 'Var', (144, 149))
130894	23638030	ChIP analysis using primers flanking CAS162 revealed that the interaction between CD26 and CAS162 was dramatically increased in JMN cells treated with YS110, as compared to those treated with control IgG1 (Fig.	('interaction', 'Interaction', (62, 73))	('MN', 'CellLine', 'CVCL:U508', (129, 131))	('YS110', 'Var', (151, 156))	('increased', 'PosReg', (115, 124))	('CAS162', 'Chemical', '-', (37, 43))	('CAS162', 'Gene', (91, 97))	('CAS162', 'Chemical', '-', (91, 97))	('CAS', 'cellular_component', 'GO:0005650', ('37', '40'))	('CD26', 'Gene', (82, 86))	('IgG1', 'Gene', (200, 204))	('IgG1', 'cellular_component', 'GO:0071735', ('200', '204'))	('YS110', 'Chemical', '-', (151, 156))	('CAS', 'cellular_component', 'GO:0005650', ('91', '94'))	('IgG1', 'Gene', '16017', (200, 204))
130895	23638030	The small amount of PCR product in control goat IgG-immunoprecipitant from the YS110-treated cells was likely due to the binding of YS110 to protein G sepharose on the dynabeads (Fig.	('due', 'Reg', (110, 113))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('goat', 'Species', '9925', (43, 47))	('YS110', 'Var', (132, 137))	('YS110', 'Chemical', '-', (79, 84))	('protein G sepharose', 'Protein', (141, 160))	('binding', 'Interaction', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('sepharose', 'Chemical', 'MESH:D012685', (151, 160))	('YS110', 'Chemical', '-', (132, 137))
130901	23638030	In contrast to transfection with control vector, transfection with CAS162 reporter significantly increased luciferase activity in several cancer cell lines: two malignant mesothelioma lines (MSTO, JMN); and two hepatocellular carcinoma cell lines (Li7, Kim1) (Fig.	('Li7', 'CellLine', 'CVCL:3840', (248, 251))	('cancer', 'Disease', (138, 144))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (211, 235))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CAS162', 'Chemical', '-', (67, 73))	('activity', 'MPA', (118, 126))	('malignant mesothelioma lines', 'Disease', 'MESH:C562839', (161, 189))	('malignant mesothelioma lines', 'Disease', (161, 189))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (211, 235))	('MN', 'CellLine', 'CVCL:U508', (198, 200))	('luciferase', 'Enzyme', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('CAS', 'cellular_component', 'GO:0005650', ('67', '70'))	('increased', 'PosReg', (97, 106))	('luciferase activity', 'molecular_function', 'GO:0047077', ('107', '126'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (161, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('luciferase activity', 'molecular_function', 'GO:0045289', ('107', '126'))	('hepatocellular carcinoma', 'Disease', (211, 235))	('Kim1', 'Gene', '26762', (253, 257))	('luciferase activity', 'molecular_function', 'GO:0047712', ('107', '126'))	('transfection', 'Var', (49, 61))	('Kim1', 'Gene', (253, 257))	('luciferase activity', 'molecular_function', 'GO:0050248', ('107', '126'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('107', '126'))
130908	23638030	Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis for POLR2A mRNA showed a significant reduction in POLR2A expression in JMN cells after treatment with YS110 or 1F7, compared with controls (Fig.	('YS110', 'Var', (182, 187))	('reduction', 'NegReg', (117, 126))	('POLR2A', 'Gene', '5430', (130, 136))	('expression', 'MPA', (137, 147))	('reverse transcription', 'biological_process', 'GO:0001171', ('13', '34'))	('POLR2A', 'Gene', (84, 90))	('YS110', 'Chemical', '-', (182, 187))	('POLR2A', 'Gene', (130, 136))	('MN', 'CellLine', 'CVCL:U508', (152, 154))	('POLR2A', 'Gene', '5430', (84, 90))
130909	23638030	Concomitantly, Western blot analysis also revealed that YS110 treatment decreased the levels of POLR2A protein in the cells (Fig.	('POLR2A', 'Gene', (96, 102))	('YS110', 'Var', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('decreased', 'NegReg', (72, 81))	('POLR2A', 'Gene', '5430', (96, 102))	('YS110', 'Chemical', '-', (56, 61))
130912	23638030	Thus, antitumor CD26 mAbs (YS110 and 1F7) appeared to induce suppression of POLR2A expression at both the mRNA and protein levels.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('YS110', 'Var', (27, 32))	('tumor', 'Disease', (10, 15))	('POLR2A', 'Gene', (76, 82))	('POLR2A', 'Gene', '5430', (76, 82))	('suppression', 'NegReg', (61, 72))	('YS110', 'Chemical', '-', (27, 32))	('expression', 'MPA', (83, 93))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
130914	23638030	qRT-PCR analysis showed that YS110-induced transcriptional repression of POLR2A was significantly over-ridden by nystatin treatment (Fig.	('over-ridden', 'PosReg', (98, 109))	('nystatin', 'Chemical', 'MESH:D009761', (113, 121))	('transcriptional repression', 'MPA', (43, 69))	('POLR2A', 'Gene', (73, 79))	('YS110-induced', 'Var', (29, 42))	('POLR2A', 'Gene', '5430', (73, 79))	('YS110', 'Chemical', '-', (29, 34))
130915	23638030	Furthermore, given that the CD261-629 mutant did not enter the nucleus, Li7 cells were transfected with control vector, CD26wt, or CD261-629, and expression of POLR2A mRNA after IgG1 or YS110 treatment was compared by qRT-PCR.	('IgG1', 'Gene', (178, 182))	('nucleus', 'cellular_component', 'GO:0005634', ('63', '70'))	('CD261-629', 'Var', (131, 140))	('Li7', 'CellLine', 'CVCL:3840', (72, 75))	('IgG1', 'cellular_component', 'GO:0071735', ('178', '182'))	('POLR2A', 'Gene', (160, 166))	('IgG1', 'Gene', '16017', (178, 182))	('POLR2A', 'Gene', '5430', (160, 166))	('CD261-629', 'Var', (28, 37))	('YS110', 'Chemical', '-', (186, 191))
130916	23638030	In CD26wt-expressing Li7 cells, POLR2A expression was significantly decreased after YS110 treatment, compared with control (Fig.	('decreased', 'NegReg', (68, 77))	('YS110', 'Var', (84, 89))	('POLR2A', 'Gene', (32, 38))	('expression', 'MPA', (39, 49))	('Li7', 'CellLine', 'CVCL:3840', (21, 24))	('YS110', 'Chemical', '-', (84, 89))	('POLR2A', 'Gene', '5430', (32, 38))
130920	23638030	Pepsin digestion of YS110 leads to truncation of the Fc region to yield the F(ab')2 form of YS110 (Fig.	('YS110', 'Chemical', '-', (92, 97))	('YS110', 'Chemical', '-', (20, 25))	('YS110', 'Var', (92, 97))	('digestion', 'biological_process', 'GO:0007586', ('7', '16'))	('truncation of the', 'MPA', (35, 52))
130921	23638030	Treatment with the F(ab')2 form of YS110 markedly decreased the levels of POLR2A transcript in JMN cells, which was similar to the result obtained with the original form of YS110 (Fig.	('MN', 'CellLine', 'CVCL:U508', (96, 98))	('YS110', 'Var', (35, 40))	('decreased', 'NegReg', (50, 59))	('POLR2A', 'Gene', (74, 80))	('YS110', 'Chemical', '-', (35, 40))	('YS110', 'Chemical', '-', (173, 178))	('POLR2A', 'Gene', '5430', (74, 80))
130934	23638030	In this study, we examined the significance of the nuclear localization of CD26 in its role as a mAb therapy for CD26-positive cancers, and showed that nuclear translocation of CD26 induced by YS110 treatment reduces cell growth through transcriptional repression of the POLR2A gene.	('POLR2A', 'Gene', (271, 277))	('YS110', 'Chemical', '-', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CD26', 'Gene', (177, 181))	('POLR2A', 'Gene', '5430', (271, 277))	('nuclear translocation', 'MPA', (152, 173))	('cell growth', 'biological_process', 'GO:0016049', ('217', '228'))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cell growth', 'CPA', (217, 228))	('YS110', 'Var', (193, 198))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('localization', 'biological_process', 'GO:0051179', ('59', '71'))	('cancers', 'Disease', (127, 134))	('reduces', 'NegReg', (209, 216))	('transcriptional', 'MPA', (237, 252))
130935	23638030	Furthermore, we found that YS110 is itself translocated to the nucleus by a mechanism that depends on the C-terminus of CD26 (Fig.	('YS110', 'Var', (27, 32))	('nucleus', 'cellular_component', 'GO:0005634', ('63', '70'))	('CD26', 'Gene', (120, 124))	('C-terminus', 'MPA', (106, 116))	('YS110', 'Chemical', '-', (27, 32))	('translocated', 'MPA', (43, 55))
130946	23638030	The present study showed that YS110 colocalized with EEA1, both in the cytoplasm and in the nucleus, and that transfection with a dominant-negative mutant of Rab5A, a master regulator of endosome biogenesis, prevented the nuclear translocation of YS110 (Fig.	('EEA1', 'Gene', (53, 57))	('YS110', 'Var', (247, 252))	('Rab5A', 'Gene', '5868', (158, 163))	('YS110', 'Chemical', '-', (30, 35))	('Rab5A', 'Gene', (158, 163))	('mutant', 'Var', (148, 154))	('endosome', 'cellular_component', 'GO:0005768', ('187', '195'))	('YS110', 'Chemical', '-', (247, 252))	('EEA1', 'Gene', '8411', (53, 57))	('nucleus', 'cellular_component', 'GO:0005634', ('92', '99'))	('prevented', 'NegReg', (208, 217))	('cytoplasm', 'cellular_component', 'GO:0005737', ('71', '80'))	('nuclear translocation', 'MPA', (222, 243))
130947	23638030	Furthermore, impairment of caveolin-dependent endocytosis inhibited the nuclear entry of both CD26 and YS110, and subsequent suppression of POLR2A, suggesting that the caveolin-dependent endocytic pathway is required for nuclear translocation of CD26 and YS110.	('YS110', 'Var', (103, 108))	('POLR2A', 'Gene', '5430', (140, 146))	('nuclear entry', 'MPA', (72, 85))	('suppression', 'NegReg', (125, 136))	('YS110', 'Chemical', '-', (255, 260))	('YS110', 'Chemical', '-', (103, 108))	('inhibited', 'NegReg', (58, 67))	('impairment', 'NegReg', (13, 23))	('caveolin-dependent endocytosis', 'biological_process', 'GO:0072584', ('27', '57'))	('POLR2A', 'Gene', (140, 146))	('CD26', 'Protein', (94, 98))	('caveolin-dependent endocytosis', 'MPA', (27, 57))
130948	23638030	Given that CD26 contains no putative nuclear localization signal (NLS) sequence, and that nuclear trafficking of CD26 and YS110 relies on the C-terminal extracellular domain of CD26 (Fig.	('localization', 'biological_process', 'GO:0051179', ('45', '57'))	('NLS', 'Disease', 'MESH:C536405', (66, 69))	('YS110', 'Chemical', '-', (122, 127))	('NLS', 'Disease', (66, 69))	('CD26', 'Gene', (113, 117))	('nuclear trafficking', 'MPA', (90, 109))	('nuclear localization', 'MPA', (37, 57))	('extracellular', 'cellular_component', 'GO:0005576', ('153', '166'))	('YS110', 'Var', (122, 127))	('relies', 'Reg', (128, 134))
130951	23638030	In support of this, the present data showed that YS110-induced nuclear induction of CD26 did not occur in some non-neoplastic cell lines, such as HEK293 cells transfected with full-length CD26, and normal human T lymphocytes with expression of CD26 on the cell surface and in the nucleus (data not shown).	('CD26', 'Gene', (84, 88))	('YS110-induced', 'Var', (49, 62))	('nuclear', 'MPA', (63, 70))	('293 cells', 'CellLine', 'CVCL:0045', (149, 158))	('cell surface', 'cellular_component', 'GO:0009986', ('256', '268'))	('human', 'Species', '9606', (205, 210))	('YS110', 'Chemical', '-', (49, 54))	('HEK293', 'CellLine', 'CVCL:0045', (146, 152))	('nucleus', 'cellular_component', 'GO:0005634', ('280', '287'))
130959	23638030	The present study revealed that in contrast to this ErbB2-Herceptin axis, YS110 treatment abundantly augments nuclear localization of CD26, and consequently suppresses POLR2A expression, leading to inhibition of malignant mesothelioma cell growth.	('POLR2A', 'Gene', (168, 174))	('expression', 'MPA', (175, 185))	('inhibition', 'NegReg', (198, 208))	('nuclear localization', 'MPA', (110, 130))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (212, 234))	('localization', 'biological_process', 'GO:0051179', ('118', '130'))	('POLR2A', 'Gene', '5430', (168, 174))	('CD26', 'Protein', (134, 138))	('YS110', 'Var', (74, 79))	('ErbB2', 'Gene', (52, 57))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (212, 234))	('suppresses', 'NegReg', (157, 167))	('cell growth', 'biological_process', 'GO:0016049', ('235', '246'))	('malignant mesothelioma', 'Disease', (212, 234))	('ErbB2', 'Gene', '2064', (52, 57))	('augments', 'NegReg', (101, 109))	('YS110', 'Chemical', '-', (74, 79))
130965	23638030	The mechanism of anti-tumor machinery for YS100 and the current chemotherapeutic agents is different.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('YS100', 'Var', (42, 47))
130966	23638030	Thus, combination between YS110 and standard therapy may have synergistic effects and enhance the treatment against malignant mesothelioma.	('YS110', 'Chemical', '-', (26, 31))	('synergistic effects', 'MPA', (62, 81))	('enhance', 'PosReg', (86, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (116, 138))	('treatment', 'CPA', (98, 107))	('malignant mesothelioma', 'Disease', (116, 138))	('combination', 'Interaction', (6, 17))	('YS110', 'Var', (26, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (116, 138))
130971	23638030	This implies that YS110 and 1F7 may target specific intra-nuclear components, such as genomic DNA and transcription factors.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('YS110', 'Var', (18, 23))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('target', 'Reg', (36, 42))	('YS110', 'Chemical', '-', (18, 23))
130972	23638030	In addition to these antibodies, there have been previous reports on the nuclear localization of mAbs directed against cell-surface antigens, including ME425 (against EGF receptor) and Br 15-6A (carbohydrate Y determinant).	('carbohydrate', 'Chemical', 'MESH:D002241', (195, 207))	('EGF', 'molecular_function', 'GO:0005154', ('167', '170'))	('ME425', 'Var', (152, 157))	('EGF receptor', 'Protein', (167, 179))	('nuclear localization', 'MPA', (73, 93))	('cell-surface antigen', 'Gene', '963', (119, 139))	('localization', 'biological_process', 'GO:0051179', ('81', '93'))	('cell-surface antigen', 'Gene', (119, 139))	('cell-surface', 'cellular_component', 'GO:0009986', ('119', '131'))
130975	23638030	Given that YS110 has a direct anti-proliferative effect on cancer cells, including malignant mesothelioma cells, these findings highlight the potential of rational therapy against CD26-positive cancers, not only through immunological ADCC and complementary activation effects, but also by direct inhibition of cancer cell growth.	('ADCC', 'biological_process', 'GO:0001788', ('234', '238'))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', (310, 316))	('YS110', 'Var', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('YS110', 'Chemical', '-', (11, 16))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (83, 105))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('anti-proliferative', 'MPA', (30, 48))	('CD26-positive', 'Gene', (180, 193))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('malignant mesothelioma', 'Disease', (83, 105))	('cancer', 'Disease', (194, 200))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cell growth', 'biological_process', 'GO:0016049', ('317', '328'))	('cancer', 'Disease', (59, 65))
130977	22952676	Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments.	('leads to', 'Reg', (140, 148))	('renal cell carcinoma', 'Disease', (169, 189))	('RCC', 'Disease', (191, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('ferric', 'Var', (34, 40))	('ferric nitrilotriacetate', 'Chemical', 'MESH:C020326', (34, 58))	('rat', 'Species', '10116', (24, 27))
130980	22952676	Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo.	('rat', 'Species', '10116', (76, 79))	('cause', 'Reg', (111, 116))	('Deletions', 'Var', (0, 9))	('rat', 'Species', '10116', (137, 140))
131003	22952676	A whole genome frequency analysis with 15 samples identified recurrent regions of a copy number aberration in the Fe-NTA-induced RCCs ( Fig.	('Fe-NTA-induced', 'Gene', (114, 128))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('Fe-NTA', 'Chemical', 'MESH:C020326', (114, 120))	('RCC', 'Disease', (129, 132))	('copy number aberration', 'Var', (84, 106))	('rat', 'Species', '10116', (100, 103))
131006	22952676	Shutdown of p16/p19 and p15 mRNA expression was confirmed in the samples that contained a homozygous deletion at the Cdkn2a/2b locus ( Figs.	('deletion', 'Var', (101, 109))	('p16', 'Gene', '1029', (12, 15))	('p15', 'Gene', (24, 27))	('p19', 'Gene', (16, 19))	('p15', 'Gene', '1030', (24, 27))	('p19', 'cellular_component', 'GO:0070743', ('16', '19'))	('Cdkn2a/2b', 'Gene', (117, 126))	('p19', 'Gene', '1029', (16, 19))	('p16', 'Gene', (12, 15))
131007	22952676	In samples with a hemizygous deletion at the Cdkn2a locus (i.e., FB32-4, FB28-7), p16 and p19 expressions were downregulated, presumably because the promoter regions of the remaining alleles were methylated.	('deletion', 'Var', (29, 37))	('p19', 'Gene', (90, 93))	('p16', 'Gene', (82, 85))	('expressions', 'MPA', (94, 105))	('p19', 'cellular_component', 'GO:0070743', ('90', '93'))	('downregulated', 'NegReg', (111, 124))	('p19', 'Gene', '1029', (90, 93))	('p16', 'Gene', '1029', (82, 85))	('Cdkn2a', 'Gene', (45, 51))
131008	22952676	However, some of the samples with either a hemizygous or no deletion (e.g., FB14-3; BF51-1; FB14-6; FB30-5 and FB33-7) showed a marked overexpression of p16 and p19.	('FB30-5', 'Var', (100, 106))	('FB33-7', 'Var', (111, 117))	('p19', 'Gene', '1029', (161, 164))	('p16', 'Gene', '1029', (153, 156))	('p19', 'Gene', (161, 164))	('p19', 'cellular_component', 'GO:0070743', ('161', '164'))	('p16', 'Gene', (153, 156))	('overexpression', 'PosReg', (135, 149))
131010	22952676	A greater than 5-fold increase in Met mRNA expression was observed in 6 samples among the 9 tumors that contained a genomic amplification of Met ( Fig.	('Met mRNA expression', 'MPA', (34, 53))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('increase', 'PosReg', (22, 30))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('Met', 'Var', (141, 144))
131011	22952676	Collectively, regarding chromosomal aberrations at these two cancer-related loci, every examined carcinoma including the two cell lines contained either the Met amplification or the Cdkn2a/2b deletion ( Table 1  ,   Figs.	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('contained', 'Reg', (136, 145))	('cancer', 'Disease', (61, 67))	('rat', 'Species', '10116', (40, 43))	('Cdkn2a/2b', 'Gene', (182, 191))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (24, 47))	('carcinoma', 'Disease', (97, 106))	('deletion', 'Var', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
131014	22952676	We examined the associations between genetic alterations and various RCC traits including those summarized in  Table 1 .	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('associations', 'Interaction', (16, 28))	('genetic alterations', 'Var', (37, 56))	('rat', 'Species', '10116', (49, 52))
131016	22952676	Furthermore, a hierarchical clustering of tumors based on whole patterns of chromosomal changes revealed that a group of large tumors (i.e., FB7-7, FB30-5 and FB33-7) corresponded to a distinct cluster ( Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('FB33-7', 'Var', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('FB30-5', 'Var', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('FB7-7', 'Var', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
131020	22952676	We found that Fe-NTA-induced rat RCC was most similar to human RCCs, followed by human malignant mesothelioma ( Figs.	('RCC', 'Disease', (63, 66))	('malignant mesothelioma', 'Disease', (87, 109))	('Fe-NTA-induced', 'Var', (14, 28))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('rat', 'Species', '10116', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (87, 109))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (87, 109))	('human', 'Species', '9606', (81, 86))	('human', 'Species', '9606', (57, 62))	('Fe-NTA', 'Chemical', 'MESH:C020326', (14, 20))
131024	22952676	During the carcinogenic process of such tumors, chromosomal instability is thought to contribute as a driving factor.	('chromosomal instability', 'Var', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('chromosomal instability', 'Phenotype', 'HP:0040012', (48, 71))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('carcinogenic', 'Disease', 'MESH:D063646', (11, 23))	('carcinogenic', 'Disease', (11, 23))	('tumors', 'Disease', (40, 46))
131025	22952676	Among wild-type rodent carcinogenesis models, however, few models report using primary tumor samples extensive genetic alterations because of chromosomal instability.	('carcinogenesis', 'Disease', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('chromosomal instability', 'Var', (142, 165))	('tumor', 'Disease', (87, 92))	('rat', 'Species', '10116', (123, 126))	('chromosomal instability', 'Phenotype', 'HP:0040012', (142, 165))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (23, 37))
131037	22952676	We previously demonstrated that cells with a hemizygous deletion at Cdkn2a appear as early as a few weeks after initiating a Fe-NTA administration.	('deletion', 'Var', (56, 64))	('Cdkn2a', 'Gene', (68, 74))	('rat', 'Species', '10116', (21, 24))	('rat', 'Species', '10116', (140, 143))	('Fe-NTA', 'Chemical', 'MESH:C020326', (125, 131))
131043	22952676	The frequent deletion of the Cdkn2a/2b locus is observed in the rat peritoneal mesothelioma, an iron overload-associated tumor, induced either by another iron compound (ferric saccharate) or by asbestos.	('iron', 'Chemical', 'MESH:D007501', (154, 158))	('iron', 'Chemical', 'MESH:D007501', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mesothelioma', 'Disease', (79, 91))	('tumor', 'Disease', (121, 126))	('deletion', 'Var', (13, 21))	('rat', 'Species', '10116', (64, 67))	('rat', 'Species', '10116', (182, 185))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('asbestos', 'Chemical', 'MESH:D001194', (194, 202))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (68, 91))	('ferric saccharate', 'Chemical', 'MESH:D000077605', (169, 186))	('Cdkn2a/2b', 'Gene', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
131045	22952676	The same genetic alteration is observed in rat mesothelioma induced by multi-walled carbon nanotubes, in which iron involvement is not yet established.	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('rat', 'Species', '10116', (43, 46))	('iron', 'Chemical', 'MESH:D007501', (111, 115))	('multi-walled', 'Var', (71, 83))	('rat', 'Species', '10116', (21, 24))	('carbon', 'Chemical', 'MESH:D002244', (84, 90))	('mesothelioma', 'Disease', (47, 59))
131050	22952676	This can be an unsuccessful attempt to stop cell proliferation in the case of downstream Rb dysregulation or may represent an alternative mechanism for modulating unidentified pathways.	('dysregulation', 'Var', (92, 105))	('rat', 'Species', '10116', (56, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('modulating', 'Reg', (152, 162))
131052	22952676	Various human cancers, such as glioblastoma and non-small cell lung cancer, are reported to harbor amplifications in chromosome 7.	('cancers', 'Disease', (14, 21))	('amplifications', 'Var', (99, 113))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (48, 74))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (48, 74))	('human', 'Species', '9606', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('non-small cell lung cancer', 'Disease', (48, 74))
131057	22952676	4B ), and was associated with amplification and overexpression of Zbtb38 located on chromosome 8 (Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('Zbtb38', 'Gene', '253461', (66, 72))	('amplification', 'Var', (30, 43))	('associated', 'Reg', (14, 24))	('overexpression', 'PosReg', (48, 62))	('Zbtb38', 'Gene', (66, 72))
131069	22952676	In this renal carcinogenesis model, preferred alterations were deletion; Cdkn2A/2B deletion and Met amplification were the major target gene modifications.	('Cdkn2A', 'Gene', (73, 79))	('rat', 'Species', '10116', (50, 53))	('Cdkn2A', 'Gene', '1029', (73, 79))	('renal carcinogenesis', 'Disease', (8, 28))	('deletion', 'Var', (63, 71))	('deletion', 'Var', (83, 91))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (8, 28))
131085	22952676	The GEO accession numbers for the data sets are GSE7599 (hPDAC), GSE7603 (hTALL), GSE9177 (hGBM) and GSE22237 (hMM).	('GSE9177', 'Var', (82, 89))	('GSE7599', 'Chemical', '-', (48, 55))	('GSE22237', 'Var', (101, 109))	('GSE7599', 'Var', (48, 55))	('GSE7603', 'Var', (65, 72))	('GSE7603', 'Chemical', '-', (65, 72))
131270	24733537	We performed a comprehensive FISH study for the detection of chromosomal translocations and deletions in formalin-fixed and paraffin-embedded (FFPE) tumor specimens arranged in TMA format.	('paraffin', 'Chemical', 'MESH:D010232', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('formalin', 'Chemical', 'MESH:D005557', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('TMA', 'Chemical', '-', (177, 180))	('deletions', 'Var', (92, 101))
131271	24733537	We analyzed 46 B-cell lymphoma (B-NHL) specimens with known karyotypes for translocations of IGH-, BCL2-, BCL6- and MYC-genes.	('MYC-genes', 'Gene', (116, 125))	('IGH-', 'Gene', (93, 97))	('cell lymphoma', 'Phenotype', 'HP:0012191', (17, 30))	('lymphoma', 'Disease', 'MESH:D008223', (22, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('BCL2', 'molecular_function', 'GO:0015283', ('99', '103'))	('BCL6-', 'Gene', (106, 111))	('BCL2-', 'Gene', (99, 104))	('translocations', 'Var', (75, 89))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (15, 30))	('lymphoma', 'Disease', (22, 30))
131272	24733537	Locus-specific DNA probes were used for the detection of deletions in chromosome bands 6q21 and 9p21 in 62 follicular lymphomas (FL) and six malignant mesothelioma (MM) samples, respectively.	('deletions', 'Var', (57, 66))	('malignant mesothelioma', 'Disease', (141, 163))	('follicular lymphomas', 'Disease', 'MESH:D008224', (107, 127))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (141, 163))	('follicular lymphomas', 'Disease', (107, 127))	('lymphomas', 'Phenotype', 'HP:0002665', (118, 127))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (141, 163))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('9p21', 'Gene', (96, 100))
131276	24733537	A variety of methods are available for the detection of genetic aberrations in the routine diagnostic work-up of tumor specimens.	('genetic aberrations', 'Var', (56, 75))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
131280	24733537	FISH on TMAs facilitate an expeditious analysis of specific genetic alterations in up to hundred tumor samples on a single slide, therefore enormously reducing costs and execution time, while keeping the experimental procedure constant.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('reducing', 'NegReg', (151, 159))	('tumor', 'Disease', (97, 102))	('genetic alterations', 'Var', (60, 79))	('TMAs', 'Chemical', '-', (8, 12))
131281	24733537	A number of these high-throughput studies have been performed on tumor specimens and it is generally agreed that translocations and gene amplifications can be readily detected in FFPE TMA formats.	('tumor', 'Disease', (65, 70))	('translocations', 'Var', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TMA', 'Chemical', '-', (184, 187))
131285	24733537	locus-specific DNA-probes in order to detect numerical aberrations, especially deletions, on FFPE TMA tumors of 62 B-NHL and six malignant mesothelioma samples.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (129, 151))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('FFPE TMA tumors', 'Disease', (93, 108))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('deletions', 'Var', (79, 88))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (129, 151))	('FFPE TMA tumors', 'Disease', 'MESH:D009369', (93, 108))	('malignant mesothelioma', 'Disease', (129, 151))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
131294	24733537	Translocations involving BCL2 on chromosome 18q21 were observed in five lymphomas by chromosome banding, one of them with an unbalanced translocation without identifiable partner.	('lymphomas', 'Disease', (72, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('Translocations', 'Var', (0, 14))	('lymphomas', 'Disease', 'MESH:D008223', (72, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('BCL2', 'molecular_function', 'GO:0015283', ('25', '29'))	('lymphomas', 'Phenotype', 'HP:0002665', (72, 81))	('BCL2 on', 'Gene', (25, 32))	('observed', 'Reg', (55, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))
131295	24733537	FISH analysis with the BCL2 break-apart probe disclosed breaks at 18q21 in all these cases and, additionally, in one tumor sample without obvious translocation in the karyotype (Table S1).	('BCL2', 'molecular_function', 'GO:0015283', ('23', '27'))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('breaks at 18q21', 'Var', (56, 71))
131296	24733537	Translocations affecting 3q27 were revealed in six tumor samples by karyotyping (two of them with unidentified translocation partners).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Translocations', 'Var', (0, 14))	('3q27', 'Gene', (25, 29))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
131298	24733537	In addition, FISH revealed chromosomal breaks involving the BCL6 gene in five B-NHL patients without aberrant chromosome 3q27 region by banding (Table S1).	('chromosomal breaks', 'Var', (27, 45))	('BCL6 gene', 'Gene', (60, 69))	('patients', 'Species', '9606', (84, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (27, 45))	('B-NHL', 'Disease', (78, 83))
131299	24733537	Translocations involving 8q24 harboring the MYC gene locus were observed in three cases by karyotyping, and in all tumors a MYC-break was evident also upon hybridization with the MYC break-apart probe.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Translocations', 'Var', (0, 14))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('MYC gene', 'Gene', (44, 52))
131308	24733537	All 26 tumor samples with deletions of the ATG5 locus as verified by FISH and the remaining 35 samples with deletion signals below the cut-off level were then analyzed by qPCR.	('deletions', 'Var', (26, 35))	('tumor', 'Disease', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('ATG5', 'Gene', (43, 47))
131309	24733537	None of the samples investigated harbored deletions of the ATG5 gene by FISH neither on TMA nor on whole tissue sections (showing only sectioning artefacts with signal constellations indicative of deletions not exceeding 29%).	('TMA', 'Chemical', '-', (88, 91))	('deletions', 'Var', (42, 51))	('ATG5', 'Gene', (59, 63))
131310	24733537	In conclusion, reliable results obtained by FISH analysis could not be reproducibly validated by qPCR, either because of an inadequate content of tumor cells showing deletions in the specimens, or - in theory - due to underlying genetic aberrations affecting the reference gene loci and thus the appropriate evaluation of qPCR results in the tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumor', 'Disease', (342, 347))	('deletions', 'Var', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
131314	24733537	Moreover, these studies used different DNA probes for either amplifications or translocations on various tumor entities without adjusting the results to data available from alternative cytogenetic approaches.	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('translocations', 'Var', (79, 93))	('tumor', 'Disease', (105, 110))
131316	24733537	Thus, we analyzed 46 B-NHL samples with known karyotypes spotted on TMAs for hallmark lymphoma-associated translocations of the IGH-, BCL2, BCL6- and MYC-genes.	('TMAs', 'Chemical', '-', (68, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('IGH-', 'Gene', (128, 132))	('BCL2', 'Gene', (134, 138))	('MYC-genes', 'Gene', (150, 159))	('BCL6-', 'Gene', (140, 145))	('translocations', 'Var', (106, 120))	('hallmark lymphoma', 'Disease', 'MESH:D008223', (77, 94))	('BCL2', 'molecular_function', 'GO:0015283', ('134', '138'))	('hallmark lymphoma', 'Disease', (77, 94))
131328	24733537	In lymphomas, deletions are often representing secondary aberrations that may not be present in the entire tumor cell population, but only in tumor subclones.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('lymphomas', 'Disease', 'MESH:D008223', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('lymphomas', 'Phenotype', 'HP:0002665', (3, 12))	('deletions', 'Var', (14, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('lymphomas', 'Disease', (3, 12))
131329	24733537	In order to address this question, we established an experimental set-up allowing for the exact definition of the number of cells harboring deletions in FFPE tissue, and performed a rigorous analysis comparing FISH in TMA-format and on whole tissue sections with both chromosome banding and qPCR in order to identify the best-suited approach for the detection of numeric alterations in FFPE tumor samples.	('tumor', 'Disease', (391, 396))	('TMA', 'Chemical', '-', (218, 221))	('deletions', 'Var', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('chromosome', 'cellular_component', 'GO:0005694', ('268', '278'))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))
131333	24733537	Interestingly, qPCR could validate the FISH results only in samples with biallelic deletions and in specimens with monoallelic deletions, but a high tumor cell content, although the qPCR approach had been successfully established in an experimental model set up.	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('biallelic deletions', 'Var', (73, 92))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (149, 154))
131336	24733537	This caveat obviously turned up in three MM tumor sample, that was deletion-positive when referred to HBB, but not to MAL as internal control.	('MM tumor', 'Disease', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletion-positive', 'Var', (67, 84))	('MM tumor', 'Disease', 'MESH:D009369', (41, 49))
131339	24733537	When carefully considering these aspects, FISH is a highly reliable and reproducible method allowing for the rapid detection of deletions on TMAs the sensitivity of which obviously exceeds that of a qPCR approach.	('TMAs', 'Chemical', '-', (141, 145))	('deletions', 'Var', (128, 137))	('TMAs', 'Gene', (141, 145))
131346	24733537	To obtain insight into the reliability of testing numerical genetic alterations (especially deletions) in FFPE tissues, mantle cell lymphoma cell lines REC1 and JVM2 (DSMZ, Braunschweig, Germany) were utilized.	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('mantle cell lymphoma', 'Disease', (120, 140))	('cell lymphoma', 'Phenotype', 'HP:0012191', (127, 140))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (120, 140))	('deletions', 'Var', (92, 101))
131347	24733537	Cell lines were cultured in RPMI-1640 medium (Life Technologies, Darmstadt, Germany), supplemented with 10% heat inactivated fetal bovine serum, 50 microg/ml streptomycin and penicillin (Life Technologies) and maintained in a humidified 95% air - 5% CO2 atmosphere at 37 C. In an experimental setting, REC1 cells were serially spiked into JVM2 cell suspensions to obtain suspensions with a defined content of CDKN2A-deleted cells (0%, 25%, 50%, 75%, 100% cells with deletion of CDKN2A).	('bovine', 'Species', '9913', (131, 137))	('CDKN2A', 'Gene', (478, 484))	('deletion', 'Var', (466, 474))
131427	23115483	M6G has a greater analgesic potency than morphine itself while M3G is a non-analgesic.	('analgesic potency', 'MPA', (18, 35))	('M6G', 'Var', (0, 3))	('morphine', 'Chemical', 'MESH:D009020', (41, 49))
131583	23115483	In a study of NSCLC, patients treated with zoledronic acid had a significantly reduced incidence of skeletal related events.	('NSCLC', 'Disease', (14, 19))	('reduced', 'NegReg', (79, 86))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('skeletal related events', 'CPA', (100, 123))	('patients', 'Species', '9606', (21, 29))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('zoledronic', 'Var', (43, 53))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (43, 58))
131755	21569526	Genes Associated With Prognosis After Surgery For Malignant Pleural Mesothelioma Promote Tumor Cell Survival In Vitro Mesothelioma is an aggressive neoplasm with few effective treatments, one being cytoreductive surgery.	('Malignant Pleural Mesothelioma Promote Tumor', 'Disease', (50, 94))	('Tumor', 'Phenotype', 'HP:0002664', (89, 94))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (137, 156))	('Genes', 'Var', (0, 5))	('Mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('aggressive neoplasm', 'Disease', (137, 156))	('Mesothelioma', 'Disease', (118, 130))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (60, 80))	('Malignant Pleural Mesothelioma Promote Tumor', 'Disease', 'MESH:C562839', (50, 94))	('Mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (148, 156))	('Mesothelioma', 'Disease', (68, 80))
131786	21569526	A single siRNA molecule was used for each positive control gene: KIF11 (siRNA ID #105925), PLK1 (siRNA ID #213548).	('KIF11', 'Gene', (65, 70))	('KIF11', 'Gene', '3832', (65, 70))	('PLK1', 'Gene', (91, 95))	('siRNA ID #213548', 'Var', (97, 113))	('PLK1', 'Gene', '5347', (91, 95))
131787	21569526	Positive control genes were chosen to monitor the performance of the assay as each gene is widely known to affect both mitosis and apoptosis.	('affect', 'Reg', (107, 113))	('gene', 'Var', (83, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('mitosis', 'Disease', (119, 126))	('mitosis', 'Disease', 'None', (119, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('apoptosis', 'CPA', (131, 140))	('mitosis', 'biological_process', 'GO:0000278', ('119', '126'))
131788	21569526	Three structurally distinct siRNA molecules were separately used for each experimental gene to confirm specificity of effect: ARHGDIA (siRNA IDs #119694, #119695, #119907), COBLL1 (siRNA IDs #136636, #136637, #136638), PKM2 (siRNA IDs #285, #286, #287), TM4SF1 (siRNA IDs #144307, #144308, #144309).	('PKM2', 'Gene', (219, 223))	('#144309', 'Var', (290, 297))	('#119695', 'Var', (154, 161))	('PKM2', 'Gene', '5315', (219, 223))	('#144308', 'Var', (281, 288))	('#119907', 'Var', (163, 170))	('#136638', 'Var', (209, 216))
131805	21569526	For reasons that were not immediately clear, a slightly more efficient knockdown was achieved in tumor cells (Figure 1B), as reflected by modestly reduced variability and lower overall mRNA levels.	('mRNA levels', 'MPA', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('knockdown', 'Var', (71, 80))	('tumor', 'Disease', (97, 102))	('variability', 'MPA', (155, 166))	('reduced', 'NegReg', (147, 154))	('lower', 'NegReg', (171, 176))
131806	21569526	Knockdown of ARHGDIA, COBLL1, and TM4SF1 resulted in increased levels of apoptosis in normal cells (ARHGDIA only) and tumor cells (ARHGDIA, COBLL1, TM4SF1) relative to negative controls.	('levels', 'MPA', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TM4SF1', 'Var', (34, 40))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', (118, 123))	('apoptosis', 'MPA', (73, 82))	('ARHGDIA', 'Gene', (13, 20))	('COBLL1', 'Gene', (22, 28))
131808	21569526	A representative image is shown in Figure 2 for ARHGDIA knockdown in tumor cells.	('ARHGDIA', 'Gene', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('knockdown', 'Var', (56, 65))
131810	21569526	Despite a clear mitotic arrest after knockdown of positive control genes, as expected no statistically significant changes were observed in the Mitotic Index for any experimental gene relative to negative controls (data not shown).	('mitotic arrest', 'Disease', (16, 30))	('mitotic arrest', 'Disease', 'MESH:D006323', (16, 30))	('knockdown', 'Var', (37, 46))
131812	21569526	A representative image is shown in Figure 4 for ARHGDIA knockdown in tumor cells.	('ARHGDIA', 'Gene', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('knockdown', 'Var', (56, 65))
131816	21569526	We established the Hoechst-based Condensed Chromatin Index as an apoptotic indicator secondary to the detection of cleaved lamin A, a well established molecular marker.	('Hoechst', 'Chemical', '-', (19, 26))	('Chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('cleaved', 'Var', (115, 122))	('lamin A', 'Protein', (123, 130))
131823	21569526	Given the known role of apoptosis in determining tissue morphology during normal embryonic development and the results of the current study, it is reasonable to hypothesize that inappropriate expression in tumor cells acts to prevent programmed cell death and promotes tumor cell survival.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('inappropriate', 'Var', (178, 191))	('tumor', 'Disease', (206, 211))	('promotes', 'PosReg', (260, 268))	('prevent', 'NegReg', (226, 233))	('tumor', 'Disease', (269, 274))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('programmed cell death', 'biological_process', 'GO:0012501', ('234', '255'))	('programmed cell death', 'CPA', (234, 255))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
131832	21569526	However, as would be expected in a scenario of reduced metabolic activity and decreased proliferation, knockdown of PKM2 was associated with a modest (~15-20%) decrease in cell number (via the Cell Number Index, as a surrogate measure of proliferation) in two of three experiments employing different siRNA molecules, although the results were not statistically significant due primarily to excessive variability.	('PKM2', 'Gene', (116, 120))	('decrease', 'NegReg', (160, 168))	('PKM2', 'Gene', '5315', (116, 120))	('cell number', 'CPA', (172, 183))	('knockdown', 'Var', (103, 112))
131867	33540554	In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women.	('low', 'Var', (38, 41))	('RERG', 'Gene', '85004', (42, 46))	('women', 'Species', '9606', (122, 127))	('death', 'Disease', 'MESH:D003643', (110, 115))	('RERG', 'Gene', (42, 46))	('death', 'Disease', (110, 115))
131871	33540554	MPM exhibits a strong sex bias in terms of distribution (M:F = 4:1), likely due to occupational exposure and women with MPM have consistently demonstrated a significant survival advantage, even when controlling for other known prognostic factors including age, stage, and histologic subtype (ranging from epithelioid to sarcomatoid differentiation with increasingly poor prognosis).	('survival', 'CPA', (169, 177))	('MPM', 'Var', (120, 123))	('sarcomatoid differentiation', 'Disease', (320, 347))	('advantage', 'PosReg', (178, 187))	('women', 'Species', '9606', (109, 114))	('epithelioid', 'Disease', (305, 316))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (320, 347))
131873	33540554	For example, some sex-related differences in typical MPM molecular features, such as mutation of CDKN2A and TP53, have already been described.	('CDKN2A', 'Gene', (97, 103))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('CDKN2A', 'Gene', '1029', (97, 103))	('mutation', 'Var', (85, 93))
131886	33540554	Overall survival (OS) was longer among patients with high RERG expression (above the median level) compared to patients whose tumors had low RERG expression in both Sentrix (median OS 12.8 versus 6.5 months, HR = 2.37, p = 0.014) and Codelink (median OS 40.7 versus 6.9 months, HR = 4.8, p < 0.001) datasets (Figure 1A,B, respectively).	('longer', 'PosReg', (26, 32))	('RERG', 'Gene', '85004', (141, 145))	('tumors', 'Disease', (126, 132))	('high', 'Var', (53, 57))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('RERG', 'Gene', '85004', (58, 62))	('RERG', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Overall survival', 'MPA', (0, 16))	('RERG', 'Gene', (141, 145))	('patients', 'Species', '9606', (111, 119))
131908	33540554	Nevertheless, OS following surgery-based multimodality therapy was found to be significantly longer in female patients whose tumors expressed high levels of RERG, whereas no significant association was observed in men.	('men', 'Species', '9606', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('RERG', 'Gene', '85004', (157, 161))	('RERG', 'Gene', (157, 161))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('high', 'Var', (142, 146))	('longer', 'PosReg', (93, 99))	('patients', 'Species', '9606', (110, 118))
131913	33540554	In breast cancer, high RERG protein expression was associated with longer disease-specific survival and distant metastasis-free interval independently of other prognostic variables.	('RERG', 'Gene', '85004', (23, 27))	('RERG', 'Gene', (23, 27))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('disease-specific survival', 'CPA', (74, 99))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('high', 'Var', (18, 22))	('distant metastasis-free interval', 'CPA', (104, 136))	('expression', 'MPA', (36, 46))	('longer', 'PosReg', (67, 73))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
131922	33540554	High DDX3X expression has been also associated with aggressive phenotype in human malignancies.	('DDX3X', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('malignancies', 'Disease', (82, 94))	('human', 'Species', '9606', (76, 81))	('DDX3X', 'Gene', '1654', (5, 10))	('associated', 'Reg', (36, 46))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
131923	33540554	Pathway analyses of women with high RERG expression vs. women with low RERG levels showed that several pathways associated with cell cycle and integrins were downregulated in women with high levels of RERG.	('RERG', 'Gene', '85004', (71, 75))	('RERG', 'Gene', (71, 75))	('downregulated', 'NegReg', (158, 171))	('cell cycle', 'biological_process', 'GO:0007049', ('128', '138'))	('women', 'Species', '9606', (20, 25))	('cell cycle', 'CPA', (128, 138))	('women', 'Species', '9606', (175, 180))	('RERG', 'Gene', '85004', (201, 205))	('RERG', 'Gene', (201, 205))	('RERG', 'Gene', '85004', (36, 40))	('high', 'Var', (186, 190))	('women', 'Species', '9606', (56, 61))	('RERG', 'Gene', (36, 40))
131949	33540554	Specifically, three differential expression comparisons between (1) tumors expressing high RERG vs. tumors exhibiting low RERG in women, (2) men and women; (3) tumors of women expressing high RERG vs. all the other samples, were performed using respective linear models and Empirical Bayes modulated t-statistics as described in the limma manual.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('RERG', 'Gene', (91, 95))	('RERG', 'Gene', (122, 126))	('RERG', 'Gene', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('RERG', 'Gene', '85004', (91, 95))	('RERG', 'Gene', '85004', (122, 126))	('RERG', 'Gene', '85004', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('high', 'Var', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('men', 'Species', '9606', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('men', 'Species', '9606', (141, 144))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('women', 'Species', '9606', (149, 154))	('tumors', 'Disease', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('men', 'Species', '9606', (172, 175))	('women', 'Species', '9606', (170, 175))	('tumors', 'Disease', (68, 74))	('women', 'Species', '9606', (130, 135))	('men', 'Species', '9606', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
131973	32154179	In small studies with CTLA-4 inhibitors there is evidence for response in some patients, but it fails to show a better PFS and OS compared to best supportive care in a randomized study.	('inhibitors', 'Var', (29, 39))	('CTLA-4', 'Gene', '1493', (22, 28))	('CTLA-4', 'Gene', (22, 28))	('patients', 'Species', '9606', (79, 87))	('OS', 'Chemical', '-', (127, 129))
132058	32154179	In several studies, PD-L1 expression was correlated with response to PD-L1 inhibitors, with or without CTLA-4 inhibitors.	('expression', 'MPA', (26, 36))	('PD-L1', 'Gene', '29126', (69, 74))	('CTLA-4', 'Gene', (103, 109))	('inhibitors', 'Var', (75, 85))	('response', 'MPA', (57, 65))	('PD-L1', 'Gene', '29126', (20, 25))	('PD-L1', 'Gene', (20, 25))	('CTLA-4', 'Gene', '1493', (103, 109))	('correlated', 'Reg', (41, 51))	('PD-L1', 'Gene', (69, 74))
132067	32154179	MPM is also known to have an increased suppressive immune environment, with a high amount of CD4+, FOXP3, and CD25+RO+ TILs.	('FOXP3', 'Gene', (99, 104))	('CD25+RO+', 'Var', (110, 118))	('FOXP3', 'Gene', '50943', (99, 104))	('CD4', 'Gene', (93, 96))	('MPM', 'Disease', 'MESH:C562839', (0, 3))	('CD4', 'Gene', '920', (93, 96))	('MPM', 'Disease', (0, 3))	('suppressive immune environment', 'Phenotype', 'HP:0002721', (39, 69))	('suppressive immune environment', 'MPA', (39, 69))
132104	32154179	As in NSCLC, PD-L1 positive patients, especially the non-epithelioid group, seem to have a better outcome compared to PD-L1 negative patients.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('PD-L1', 'Gene', (118, 123))	('patients', 'Species', '9606', (133, 141))	('PD-L1', 'Gene', '29126', (118, 123))	('PD-L1', 'Gene', (13, 18))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', (6, 11))	('positive', 'Var', (19, 27))	('PD-L1', 'Gene', '29126', (13, 18))
132171	29915796	Ovarian serous borderline tumour is usually confined to the ovary and has an indolent course; however, certain clinicopathological features, such as the presence of a micropapillary pattern, microinvasion and extraovarian implants have been linked to a more aggressive disease.	('linked', 'Reg', (241, 247))	('Ovarian serous borderline tumour', 'Disease', (0, 32))	('ovary', 'Disease', (60, 65))	('extraovarian implants', 'CPA', (209, 230))	('Ovarian serous borderline tumour', 'Disease', 'MESH:D010051', (0, 32))	('ovary', 'Disease', 'MESH:D010051', (60, 65))	('aggressive disease', 'Disease', 'MESH:D001523', (258, 276))	('aggressive disease', 'Disease', (258, 276))	('microinvasion', 'Var', (191, 204))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
132303	28210155	Similar to the literature reporting associations between dosimetric factors and esophagitis, an association was found between clinically significant weight loss and the maximum dose to the esophagus, and the absolute esophageal length receiving doses of 40 Gy, 50 Gy, and 60 Gy.	('weight loss', 'Disease', 'MESH:D015431', (149, 160))	('esophagitis', 'Phenotype', 'HP:0100633', (80, 91))	('esophagitis', 'Disease', (80, 91))	('50 Gy', 'Var', (261, 266))	('esophagitis', 'Disease', 'MESH:D004941', (80, 91))	('weight loss', 'Disease', (149, 160))	('weight loss', 'Phenotype', 'HP:0001824', (149, 160))
132407	24243779	In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1.	('germline mutation', 'Var', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (64, 72))	('BAP1', 'Gene', '8314', (135, 139))	('hereditary cancer', 'Disease', 'MESH:D009369', (92, 109))	('BAP1', 'Gene', (135, 139))	('hereditary cancer', 'Disease', (92, 109))
132409	24243779	We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1.	('pGln684*; c.1182C>G', 'Var', (77, 96))	('c.2050 C>T', 'Mutation', 'rs387906848', (65, 75))	('BAP1', 'Gene', (154, 158))	('pathogenic', 'Reg', (43, 53))	('c.1882_1885delTCAC', 'Var', (113, 131))	('p.Tyr394*', 'Mutation', 'p.Y394*', (98, 107))	('Ser', 'cellular_component', 'GO:0005790', ('136', '139'))	('patients', 'Species', '9606', (20, 28))	('c.2050 C>T', 'Var', (65, 75))	('p. Ser628Profs*8', 'Var', (133, 149))	('c.1182C>G', 'Var', (87, 96))	('p.Tyr394*', 'Var', (98, 107))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (113, 131))	('BAP1', 'Gene', '8314', (154, 158))	('Ser628Profs', 'Chemical', '-', (136, 147))	('c.1182C>G', 'Mutation', 'c.1182C>G', (87, 96))
132412	24243779	The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('CM', 'Disease', 'MESH:D009202', (121, 123))	('mesothelioma', 'Disease', (107, 119))	('germline', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (67, 71))	('association', 'Reg', (38, 49))	('mutation', 'Var', (72, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('BAP1', 'Gene', (67, 71))
132415	24243779	Germline mutations in the BAP1 gene have been identified in a small number of families with hereditary cancers.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hereditary cancers', 'Disease', (92, 110))	('hereditary cancers', 'Disease', 'MESH:D009369', (92, 110))	('BAP1', 'Gene', '8314', (26, 30))	('identified', 'Reg', (46, 56))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
132420	24243779	Proper characterization of the phenotype is crucial to define diagnostic criteria and design management and follow-up protocols for patients with germline BAP1 mutations.	('BAP1', 'Gene', '8314', (155, 159))	('mutations', 'Var', (160, 169))	('BAP1', 'Gene', (155, 159))	('men', 'Species', '9606', (99, 102))	('patients', 'Species', '9606', (132, 140))
132421	24243779	In the following study, we report three additional patients with germline BAP1 mutations, including one presenting with metastatic adenocarcinoma likely from a cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('germline', 'Var', (65, 73))	('BAP1', 'Gene', '8314', (74, 78))	('adenocarcinoma', 'Disease', (131, 145))	('patients', 'Species', '9606', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cholangiocarcinoma', 'Disease', (160, 178))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
132432	24243779	Immunohistochemistry was carried out on tumor tissues from FUM103 (III.1) and FUM064 (III-12).	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FUM064', 'Var', (78, 84))
132437	24243779	Out of the 50 patients tested, we identified three with pathogenic mutations in BAP1 and 4 with variants of uncertain significance: c.2057-4G>T (rs149499021) in two different patients, both c.2057-22A>C (rs144083199) and c.*45C>G (rs56898787) in a third patient and c. 932-58_59delTG in a fourth patient (Table 1).	('rs56898787', 'Var', (231, 241))	('c. 932-58_59delTG', 'Mutation', 'c.932-58_59delTG', (266, 283))	('c.2057-22A>C (rs144083199', 'Var', (190, 215))	('BAP1', 'Gene', '8314', (80, 84))	('rs144083199', 'Var', (204, 215))	('c. 932-58_59delTG', 'Var', (266, 283))	('patients', 'Species', '9606', (14, 22))	('c.2057-22A>C', 'Mutation', 'rs144083199', (190, 202))	('rs149499021', 'Var', (145, 156))	('c.2057-4G>T', 'Mutation', 'rs149499021', (132, 143))	('c.2057-4G>T (rs149499021', 'Var', (132, 156))	('patient', 'Species', '9606', (175, 182))	('rs149499021', 'Mutation', 'rs149499021', (145, 156))	('patient', 'Species', '9606', (254, 261))	('BAP1', 'Gene', (80, 84))	('rs56898787', 'Mutation', 'rs56898787', (231, 241))	('patient', 'Species', '9606', (14, 21))	('pathogenic', 'Reg', (56, 66))	('c.*45C>G', 'Mutation', 'rs56898787', (221, 229))	('c.*45C>G (rs56898787', 'Var', (221, 241))	('patient', 'Species', '9606', (296, 303))	('patients', 'Species', '9606', (175, 183))	('rs144083199', 'Mutation', 'rs144083199', (204, 215))
132438	24243779	A germline truncating mutation (c.2050 C>T, p.Gln684*) of BAP1 was identified in the proband (IV.1), who presented with UM (age 41), an epithelial malignancy of unknown origin at the porta hepatis with distant metastasis (age 42) and an unclassified spindle cell proliferation in her thigh (age 42).	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('malignancy', 'Disease', (147, 157))	('p.Gln684*', 'Var', (44, 53))	('BAP1', 'Gene', (58, 62))	('c.2050 C>T', 'Mutation', 'rs387906848', (32, 42))	('spindle', 'cellular_component', 'GO:0005819', ('250', '257'))	('cell proliferation', 'biological_process', 'GO:0008283', ('258', '276'))	('distant metastasis', 'CPA', (202, 220))	('epithelial malignancy', 'Phenotype', 'HP:0031492', (136, 157))	('BAP1', 'Gene', '8314', (58, 62))	('c.2050 C>T', 'Var', (32, 42))	('unclassified spindle cell proliferation in', 'CPA', (237, 279))	('p.Gln684*', 'Mutation', 'rs387906848', (44, 53))
132441	24243779	A paternal cousin once-removed (III-12) presenting with peritoneal papillary tumor was also positive for the same mutation; thus, making their parents and the proband's paternal grandmother obligate carriers of the same mutation.	('mutation', 'Var', (114, 122))	('papillary tumor', 'Disease', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('papillary tumor', 'Disease', 'MESH:D002291', (67, 82))
132447	24243779	2B) with strong expression in nontumor tissue suggesting biallelic inactivation of BAP1 in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('biallelic', 'Var', (57, 66))	('BAP1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('BAP1', 'Gene', '8314', (83, 87))
132449	24243779	A germline truncating mutation c.1182C>G, p.Tyr394* was identified in the proband (III.1) who presented with a metastatic adenocarcinoma to the rib and a hepatic focal lesion.	('adenocarcinoma', 'Disease', (122, 136))	('hepatic focal lesion', 'Disease', 'MESH:D056486', (154, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('p.Tyr394*', 'Var', (42, 51))	('c.1182C>G', 'Var', (31, 40))	('p.Tyr394*', 'Mutation', 'p.Y394*', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('c.1182C>G', 'Mutation', 'c.1182C>G', (31, 40))	('hepatic focal lesion', 'Disease', (154, 174))
132460	24243779	A germline frameshift mutation c.1882_1885delTCAC, p. Ser628Profs*8in BAP1 was identified in the index case, her son and a great maternal aunt, who presented with invasive breast cancer (Figs.	('Ser628Profs', 'Chemical', '-', (54, 65))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (31, 49))	('p. Ser628Profs*8in', 'Var', (51, 69))	('invasive breast cancer', 'Disease', 'MESH:D001943', (163, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', '8314', (70, 74))	('c.1882_1885delTCAC', 'Var', (31, 49))	('invasive breast cancer', 'Disease', (163, 185))	('Ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('BAP1', 'Gene', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))
132464	24243779	The association of germline BAP1 mutation with increased risks for UM, mesothelioma, CM, RCC, and MBAITs is now fairly well established.	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('MBAITs', 'Disease', (98, 104))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('CM', 'Disease', 'MESH:D009202', (85, 87))	('germline', 'Var', (19, 27))
132466	24243779	In the present study, we report three new families with germline pathogenic mutations in BAP1.	('BAP1', 'Gene', '8314', (89, 93))	('mutations', 'Var', (76, 85))	('BAP1', 'Gene', (89, 93))
132467	24243779	One of the mutations (p.Q684*) has been previously reported in another hereditary mesothelioma/UM family.	('mesothelioma', 'Disease', (82, 94))	('p.Q684*', 'Mutation', 'rs387906848', (22, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('reported', 'Reg', (51, 59))	('p.Q684*', 'Var', (22, 29))
132468	24243779	The two other mutations (p.Tyr394* and p. Ser628Profs*8) have not been previously reported.	('p.Tyr394*', 'Mutation', 'p.Y394*', (25, 34))	('p.Tyr394*', 'Var', (25, 34))	('Ser628Profs', 'Chemical', '-', (42, 53))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('p. Ser628Profs*', 'Var', (39, 54))
132469	24243779	Cancers reported in patients with germline BAP1 mutation in our study included cancers associated with BAP1 hereditary cancer predisposition syndrome, such as UM, CM, RCC and mesothelioma, as well as, other cancers such as hepatic cholangiocarcinoma and breast carcinoma.	('BAP1', 'Gene', '8314', (103, 107))	('hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 249))	('BAP1', 'Gene', (43, 47))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('germline', 'Var', (34, 42))	('CM', 'Disease', 'MESH:D009202', (163, 165))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('BAP1', 'Gene', (103, 107))	('hereditary cancer', 'Disease', (108, 125))	('breast carcinoma', 'Disease', 'MESH:D001943', (254, 270))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', (79, 86))	('mesothelioma', 'Disease', (175, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (231, 249))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hereditary cancer', 'Disease', 'MESH:D009369', (108, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('BAP1', 'Gene', '8314', (43, 47))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (48, 56))	('RCC', 'Disease', (167, 170))	('breast carcinoma', 'Phenotype', 'HP:0003002', (254, 270))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('breast carcinoma', 'Disease', (254, 270))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('hepatic cholangiocarcinoma', 'Disease', (223, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
132479	24243779	WDPM has been recently reported by another group in two siblings with germline mutation in BAP1.	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (91, 95))	('WDPM', 'Disease', (0, 4))	('germline mutation', 'Var', (70, 87))
132482	24243779	An earlier study by our group suggested that the frequency of germline mutation in BAP1 is low (1/53) in patients with UM, even in those with strong personal or family histories of cancer.	('germline mutation', 'Var', (62, 79))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('BAP1', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('BAP1', 'Gene', '8314', (83, 87))
132484	24243779	Whether other cancers seen in other mutation carriers in these families are coincidental or due to the mutation has yet to be definitively established.	('cancers', 'Disease', (14, 21))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (103, 111))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
132485	24243779	Germline mutation in BAP1 has been observed in one patient in our study as well as reported in a few high-risk breast cancer families suggesting that breast cancer could be part of the phenotype.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('BAP1', 'Gene', (21, 25))	('breast cancer', 'Disease', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('observed', 'Reg', (35, 43))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('patient', 'Species', '9606', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('Germline mutation', 'Var', (0, 17))	('BAP1', 'Gene', '8314', (21, 25))
132488	24243779	Nevertheless, it appears clear that carrying a BAP1 germline mutation puts an individual at significantly increased risk of cancer.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BAP1', 'Gene', '8314', (47, 51))	('germline mutation', 'Var', (52, 69))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('BAP1', 'Gene', (47, 51))
132493	24243779	The high frequency of germline BAP1 mutations in patients presenting with metastatic disease suggests that UM is more aggressive in these patients.	('metastatic disease', 'Disease', (74, 92))	('BAP1', 'Gene', '8314', (31, 35))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (31, 35))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (138, 146))
132495	24243779	In conclusion, germline BAP1 mutations appear to predispose patients to an increasing spectrum of cancers including UM, CM, mesothelioma, and RCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('predispose', 'Reg', (49, 59))	('BAP1', 'Gene', (24, 28))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('mesothelioma', 'Disease', (124, 136))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('CM', 'Disease', 'MESH:D009202', (120, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (24, 28))
132498	24243779	Finally, the current evidence justifies establishment of surveillance protocols for early diagnosis of UM and CM in patients with germline mutation in BAP1.	('men', 'Species', '9606', (49, 52))	('BAP1', 'Gene', (151, 155))	('patients', 'Species', '9606', (116, 124))	('CM', 'Disease', 'MESH:D009202', (110, 112))	('germline mutation', 'Var', (130, 147))	('BAP1', 'Gene', '8314', (151, 155))
132501	23976967	Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) play an important functional role in cancer biology.	('aberrant expression', 'Var', (36, 55))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('long non-coding RNAs', 'Protein', (59, 79))	('al', 'Chemical', 'MESH:D000535', (116, 118))
132518	23976967	Altered expression of lncRNAs has been implicated in a myriad of biological processes including normal tissue development and cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('implicated', 'Reg', (39, 49))	('lncRNAs', 'Gene', (22, 29))	('al', 'Chemical', 'MESH:D000535', (100, 102))	('Altered', 'Var', (0, 7))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('al', 'Chemical', 'MESH:D000535', (73, 75))	('normal tissue development', 'CPA', (96, 121))	('expression', 'MPA', (8, 18))	('tissue development', 'biological_process', 'GO:0009888', ('103', '121'))
132519	23976967	Accumulating evidence suggests that their aberrant expression plays important functional roles in cancer biology.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('aberrant expression', 'Var', (42, 61))	('al', 'Chemical', 'MESH:D000535', (86, 88))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
132520	23976967	For example high expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with metastases and poor outcome in patients with NSCLC, and is thought to have an important role in alternative splicing and pre-mRNA processing.	('pre', 'molecular_function', 'GO:0003904', ('241', '244'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('al', 'Chemical', 'MESH:D000535', (216, 218))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('high', 'Var', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('MALAT1', 'Gene', '378938', (87, 93))	('patients', 'Species', '9606', (151, 159))	('metastases', 'Disease', (120, 130))	('associated with', 'Reg', (104, 119))	('splicing', 'biological_process', 'GO:0045292', ('228', '236'))	('mRNA processing', 'biological_process', 'GO:0006397', ('245', '260'))	('MALAT1', 'Gene', (87, 93))	('metastasis associated lung adenocarcinoma transcript 1', 'Gene', '378938', (31, 85))	('metastases', 'Disease', 'MESH:D009362', (120, 130))	('NSCLC', 'Disease', (165, 170))
132534	23976967	The MPM cell lines consisted of a combination of epithelioid (VMC20, VMC23, VMC6, H226, H28, REN, H2052, H2452, 1988, CLAB) and biphasic (VMC40, MM05, MSTO-211H) subtypes.	('H2452', 'Var', (105, 110))	('REN', 'Gene', (93, 96))	('H226', 'CellLine', 'CVCL:J621', (82, 86))	('H2052', 'Var', (98, 103))	('REN', 'Gene', '5972', (93, 96))	('H2052', 'CellLine', 'CVCL:1518', (98, 103))
132588	23976967	identified aberrant expression of CDKN2A, TK1, MYC and STMN1  Further confirmation in MPM cell lines also confirmed dysregulation of TSM4SF1, STMN1, IFI16, CDKN3 and ARHGDIG .	('STMN1', 'Gene', (55, 60))	('TK1', 'Gene', (42, 45))	('TK1', 'Gene', '7083', (42, 45))	('aberrant', 'Var', (11, 19))	('MYC', 'Gene', '4609', (47, 50))	('CDKN2A', 'Gene', (34, 40))	('TSM4SF1', 'Gene', (133, 140))	('IFI16', 'Gene', '3428', (149, 154))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN3', 'Gene', (156, 161))	('ARHGDIG', 'Gene', (166, 173))	('ARHGDIG', 'Gene', '398', (166, 173))	('STMN1', 'Gene', '3925', (142, 147))	('IFI16', 'Gene', (149, 154))	('al', 'Chemical', 'MESH:D000535', (101, 103))	('MYC', 'Gene', (47, 50))	('CDKN3', 'Gene', '1033', (156, 161))	('STMN1', 'Gene', (142, 147))	('dysregulation', 'MPA', (116, 129))	('STMN1', 'Gene', '3925', (55, 60))
132598	23976967	AK130977 and AX746718 were both found to be down-regulated via both microarray and RT-qPCR (AK130977 Microarray (MA)  = -5.207, RT-qPCR  = -1.6; AX746718 MA  = -3.37, RT-qPCR  = -4.6), with AK130977 demonstrating fairly small changes using RT-qPCR.	('al', 'Chemical', 'MESH:D000535', (222, 224))	('down-regulated', 'NegReg', (44, 58))	('AX746718', 'Var', (13, 21))
132599	23976967	Similarly, BX648695, AK129685, EF177379, AK054908, AK130275, AF268386 and NR_003584 all demonstrated consistent up-regulation using both microarrays and RT-qPCR.	('EF177379', 'Var', (31, 39))	('AK129685', 'Var', (21, 29))	('AF268386', 'Var', (61, 69))	('AK130275', 'Var', (51, 59))	('NR_003584', 'Var', (74, 83))	('AK054908', 'Var', (41, 49))	('regulation', 'biological_process', 'GO:0065007', ('115', '125'))	('BX648695', 'Var', (11, 19))	('up-regulation', 'PosReg', (112, 125))	('al', 'Chemical', 'MESH:D000535', (84, 86))
132601	23976967	High levels were also observed for AK130977 (average 25-fold upregulation; 10/10 cell lines >4-fold differences in expression) and AF268386 (38-fold upregulation; 7/10 cell lines >5-fold differences).The remaining candidates AK130275, AK054908, AK129685 and NR_003584 also demonstrated moderate levels of up-regulation (3-6 fold) although not all cell lines demonstrated overexpression.	('al', 'Chemical', 'MESH:D000535', (17, 19))	('AK054908', 'Var', (235, 243))	('al', 'Chemical', 'MESH:D000535', (330, 332))	('al', 'Chemical', 'MESH:D000535', (268, 270))	('up-regulation', 'PosReg', (305, 318))	('AK130275', 'Var', (225, 233))	('regulation', 'biological_process', 'GO:0065007', ('308', '318'))	('al', 'Chemical', 'MESH:D000535', (343, 345))	('AK129685', 'Var', (245, 253))	('NR_003584', 'Gene', (258, 267))
132605	23976967	AK130275, AK129685, EF177379 and AF268386 all demonstrated >-2-fold expression differences in MPM compared to benign pleura without reaching significance (AK130275 - 3.3 fold, MWU P = 0.345; AK129685 - 3.2 fold, MWU P = 0.659; EF177379 - 2.8 fold, MWU P = 0.186; AF268386 - 2.17 fold, MWU P = 0.950).	('AK129685 -', 'Var', (191, 201))	('AF268386 -', 'Var', (263, 273))	('EF177379', 'Var', (20, 28))	('al', 'Chemical', 'MESH:D000535', (42, 44))	('AK130275', 'Var', (0, 8))	('AF268386', 'Var', (33, 41))	('AK129685', 'Var', (10, 18))	('EF177379 -', 'Var', (227, 237))	('differences', 'Reg', (79, 90))	('MPM', 'MPA', (94, 97))
132606	23976967	Receiver operating characteristic (ROC) curve analysis showed that BX648695 could discriminate benign pleura and MPM with an accuracy of 93%, sensitivity 78.6% and specificity 100% (AUC 0.93, 95% confidence interval 0.793-1.064, P = 0.023; Figure 2b).	('al', 'Chemical', 'MESH:D000535', (48, 50))	('MPM', 'Disease', (113, 116))	('al', 'Chemical', 'MESH:D000535', (213, 215))	('BX648695', 'Var', (67, 75))
132607	23976967	Similarly NR_003584 could discriminate benign pleura and MPM with an accuracy of 90.5%, sensitivity 78.5% and specificity 100% (AUC 0.905, 95% confidence interval 0.752-1.057, P = 0.033; Figure 2a).	('MPM', 'Disease', (57, 60))	('NR_003584', 'Var', (10, 19))	('benign pleura', 'Disease', (39, 52))	('al', 'Chemical', 'MESH:D000535', (160, 162))
132618	23976967	Higher expression of AK054908 was significantly associated with metastasis in the ipsilateral bronchopulmonary/hilar lymph nodes (N1 status; AK054908 P = 0.005; Figure 2d) with a trend for higher expression also observed in AF268386 (P = 0.071).	('AK054908', 'Var', (21, 29))	('expression', 'MPA', (7, 17))	('associated with', 'Reg', (48, 63))	('al', 'Chemical', 'MESH:D000535', (207, 209))	('AK054908', 'Var', (141, 149))	('al', 'Chemical', 'MESH:D000535', (91, 93))
132619	23976967	Significantly lower levels of AK130275 and AF268386 were observed in patients receiving induction chemotherapy (AK130275 induction chemotherapy  = 0.763 vs. no chemotherapy 1.578, P = 0.002; AF268386 induction chemotherapy  = 0.956 vs. no chemotherapy 1.685, P = 0.033).	('patients', 'Species', '9606', (69, 77))	('lower', 'NegReg', (14, 19))	('AF268386', 'Var', (191, 199))	('AF268386', 'Var', (43, 51))
132623	23976967	When stratified by treatment with/without induction chemotherapy, patients with higher EF177379 levels had better overall survival when they did not receive induction chemotherapy (Log-Rank P = 0.019, median survival low expression  = 9.5 month versus high expression 19.7 months).	('better', 'PosReg', (107, 113))	('EF177379', 'Var', (87, 95))	('overall', 'MPA', (114, 121))	('al', 'Chemical', 'MESH:D000535', (118, 120))	('al', 'Chemical', 'MESH:D000535', (214, 216))	('al', 'Chemical', 'MESH:D000535', (128, 130))	('patients', 'Species', '9606', (66, 74))
132626	23976967	In addition, >50% of mRNAs were associated with phosphoproteins (P = 0.003; 56% genes) and alternative splicing (P = 0.024; 52%).	('mRNAs', 'Var', (21, 26))	('alternative splicing', 'Var', (91, 111))	('associated', 'Reg', (32, 42))	('phosphoproteins', 'Protein', (48, 63))	('al', 'Chemical', 'MESH:D000535', (91, 93))	('splicing', 'biological_process', 'GO:0045292', ('103', '111'))
132627	23976967	For BX648695, 22 unique genes were co-expressed and were associated with muscle system processes (P = 0.047), calcium ion binding (P = 0.024), metal ion binding (P = 0.019) and phosphoproteins (P = 0.016).	('BX648695', 'Var', (4, 12))	('metal ion binding', 'molecular_function', 'GO:0046872', ('143', '160'))	('metal', 'Chemical', 'MESH:D008670', (143, 148))	('calcium', 'Chemical', 'MESH:D002118', (110, 117))	('calcium ion binding', 'molecular_function', 'GO:0005509', ('110', '129'))	('muscle system processes', 'CPA', (73, 96))	('metal', 'Protein', (143, 148))	('calcium ion', 'MPA', (110, 121))	('associated', 'Reg', (57, 67))
132628	23976967	AF268386 co-expressed mRNAs were significantly associated with actin-filament based processes (P = 0.049), glycolipid metabolism (P = 0.045), cell proliferation (P = 0.025), cell cycle (P = 0.025), ganglioside metabolic processes (P = 0.012), and Rho GTPase binding (P = 0.051) with some of these processes demonstrating a greater than 10-fold over-enrichment.	('cell cycle', 'CPA', (174, 184))	('Rho', 'Protein', (247, 250))	('binding', 'Interaction', (258, 265))	('glycolipid', 'Chemical', 'MESH:D006017', (107, 117))	('glycolipid metabolism', 'biological_process', 'GO:0006664', ('107', '128'))	('Rho GTPase binding', 'molecular_function', 'GO:0017048', ('247', '265'))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('mRNAs', 'Var', (22, 27))	('ganglioside metabolic processes', 'MPA', (198, 229))	('actin-filament based processes', 'MPA', (63, 93))	('cell proliferation', 'CPA', (142, 160))	('AF268386', 'Var', (0, 8))	('cell cycle', 'biological_process', 'GO:0007049', ('174', '184'))	('ganglioside', 'Chemical', 'MESH:D005732', (198, 209))	('associated', 'Reg', (47, 57))	('glycolipid metabolism', 'MPA', (107, 128))	('actin-filament', 'cellular_component', 'GO:0005884', ('63', '77'))
132629	23976967	EF177379 (NEAT1) was found to be co-expressed with 139 mRNAs involved in processes including cell cycle (P<.001), apoptosis (P<0.001), cell death (P = 0.01), regulation of cyclin-dependent protein kinases (P = 0.046), cell cycle arrest (P = 0.028), M phase (P = 0.018) and cytoskeleton reorganisation (P = 0.021).	('cytoskeleton reorganisation', 'CPA', (273, 300))	('cyclin', 'molecular_function', 'GO:0016538', ('172', '178'))	('NEAT1', 'Gene', (10, 15))	('M phase', 'biological_process', 'GO:0000279', ('249', '256'))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('EF177379', 'Var', (0, 8))	('cell cycle', 'biological_process', 'GO:0007049', ('93', '103'))	('cell death', 'CPA', (135, 145))	('regulation', 'biological_process', 'GO:0065007', ('158', '168'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('218', '235'))	('NEAT1', 'Gene', '283131', (10, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('cell cycle arrest', 'CPA', (218, 235))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('apoptosis', 'CPA', (114, 123))	('cyclin-dependent', 'Enzyme', (172, 188))	('M phase', 'CPA', (249, 256))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('273', '285'))	('cell cycle', 'CPA', (93, 103))	('cell death', 'biological_process', 'GO:0008219', ('135', '145'))
132631	23976967	Finally, mRNAs co-expressed with NR_003584 were associated with enrichment of cellular processes including cell cycle (P<0.001), apoptosis (P = 0.002), actin cytoskeleton organisation (P<0.001), mitotic cell cycle (P<0.001), regulation of protein kinase activity (P = 0.004), regulation of transferase activity (P = 0.006), cell division (P = 0.021), regulation of phosphorylation (P = 0.021), regulation of phosphate metabolism (P = 0.026), and cell morphogenesis (P = 0.046).	('cell morphogenesis', 'CPA', (446, 464))	('associated', 'Reg', (48, 58))	('regulation of transferase activity', 'biological_process', 'GO:0051338', ('276', '310'))	('protein', 'Protein', (239, 246))	('cell cycle', 'biological_process', 'GO:0007049', ('107', '117'))	('regulation', 'MPA', (351, 361))	('regulation of phosphate metabolism', 'biological_process', 'GO:0019220', ('394', '428'))	('regulation of phosphorylation', 'biological_process', 'GO:0042325', ('351', '380'))	('cell division', 'biological_process', 'GO:0051301', ('324', '337'))	('mitotic cell cycle', 'CPA', (195, 213))	('cellular processes', 'CPA', (78, 96))	('cell morphogenesis', 'biological_process', 'GO:0000902', ('446', '464'))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('152', '170'))	('apoptosis', 'CPA', (129, 138))	('NR_003584', 'Var', (33, 42))	('actin cytoskeleton organisation', 'CPA', (152, 183))	('transferase activity', 'molecular_function', 'GO:0016740', ('290', '310'))	('al', 'Chemical', 'MESH:D000535', (3, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('cell division', 'CPA', (324, 337))	('cell cycle', 'CPA', (107, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('actin cytoskeleton organisation', 'biological_process', 'GO:0030036', ('152', '183'))	('regulation of protein kinase activity', 'biological_process', 'GO:0045859', ('225', '262'))	('protein kinase activity', 'molecular_function', 'GO:0004672', ('239', '262'))	('regulation', 'MPA', (394, 404))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('195', '213'))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
132632	23976967	Since the realisation that non-coding regions of the genome are functional and not "junk" as previously thought, there have been numerous studies linking changes in long noncoding RNA (lncRNA) expression to cancer prompting an increasing interest in the use of lncRNAs as potential disease biomarkers.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('al', 'Chemical', 'MESH:D000535', (72, 74))	('cancer', 'Disease', (207, 213))	('lncRNA', 'Gene', (185, 191))	('changes', 'Var', (154, 161))	('al', 'Chemical', 'MESH:D000535', (279, 281))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('al', 'Chemical', 'MESH:D000535', (12, 14))	('RNA', 'cellular_component', 'GO:0005562', ('178', '181'))
132639	23976967	We identified a panel of nine lncRNAs, six which were biologically validated in cell lines and MPM tissues (AK130275, AK129685, EF177379, BX648695, NR_003584 and AF268386) and seemed to be diagnostic.	('NR_003584', 'Var', (148, 157))	('al', 'Chemical', 'MESH:D000535', (62, 64))	('EF177379', 'Var', (128, 136))	('BX648695', 'Var', (138, 146))	('AK130275', 'Var', (108, 116))	('AK129685', 'Var', (118, 126))	('al', 'Chemical', 'MESH:D000535', (68, 70))	('AF268386', 'Var', (162, 170))
132643	23976967	The lncRNA EF177379 (NEAT1), is located on 11q13.1, a region reported to be amplified in MPM.	('NEAT1', 'Gene', (21, 26))	('NEAT1', 'Gene', '283131', (21, 26))	('EF177379', 'Var', (11, 19))
132647	23976967	It is also tempting to speculate that its expression may also be regulated by copy number gains.	('al', 'Chemical', 'MESH:D000535', (6, 8))	('expression', 'MPA', (42, 52))	('al', 'Chemical', 'MESH:D000535', (57, 59))	('regulated', 'Reg', (65, 74))	('copy number gains', 'Var', (78, 95))
132648	23976967	AK130275 is a bidirectional lncRNA located antisense to PAX8, a transcription factor expressed at high levels in the thyroid, that has an essential role in cell proliferation.	('al', 'Chemical', 'MESH:D000535', (25, 27))	('AK130275', 'Var', (0, 8))	('al', 'Chemical', 'MESH:D000535', (145, 147))	('PAX8', 'Gene', '7849', (56, 60))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('transcription factor', 'molecular_function', 'GO:0000981', ('64', '84'))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('PAX8', 'Gene', (56, 60))
132652	23976967	Considering its close proximity to PAX8, it is possible that AK130275 may regulate expression of PAX8 by stabilizing the corresponding mRNA or exert its own functional effects.	('AK130275', 'Var', (61, 69))	('regulate', 'Reg', (74, 82))	('functional', 'MPA', (157, 167))	('mRNA', 'MPA', (135, 139))	('al', 'Chemical', 'MESH:D000535', (165, 167))	('PAX8', 'Gene', '7849', (97, 101))	('PAX8', 'Gene', '7849', (35, 39))	('PAX8', 'Gene', (35, 39))	('expression', 'MPA', (83, 93))	('PAX8', 'Gene', (97, 101))	('stabilizing', 'Reg', (105, 116))
132654	23976967	Thus AK130275 could be potentially useful for the differential diagnosis of primary and metastatic pleural mesothelioma.	('primary', 'Disease', (76, 83))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (99, 119))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (99, 119))	('al', 'Chemical', 'MESH:D000535', (104, 106))	('pleural mesothelioma', 'Disease', (99, 119))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('AK130275', 'Var', (5, 13))	('al', 'Chemical', 'MESH:D000535', (60, 62))
132655	23976967	AK054908, also known as the small nucleolar RNA host gene 7 (SNHG7), has been described as a 3'UTR/bidirectional lncRNA and is thought to encode the smaller snoRNAs, SNORA43 and SNORA17.	('small nucleolar RNA host gene 7', 'Gene', '84973', (28, 59))	('al', 'Chemical', 'MESH:D000535', (151, 153))	('al', 'Chemical', 'MESH:D000535', (110, 112))	('al', 'Chemical', 'MESH:D000535', (10, 12))	('SNORA43', 'Gene', (166, 173))	('AK054908', 'Var', (0, 8))	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('28', '47'))	('SNHG7', 'Gene', '84973', (61, 66))	('SNORA17', 'Gene', (178, 185))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('28', '47'))	('small nucleolar RNA host gene 7', 'Gene', (28, 59))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('SNHG7', 'Gene', (61, 66))	('SNORA43', 'Gene', '677824', (166, 173))	('SNORA17', 'Gene', '677804', (178, 185))
132659	23976967	In mesothelioma, inhibition of this pathway has been shown to inhibit cell invasion, motility and spreading.	('spreading', 'CPA', (98, 107))	('mesothelioma', 'Disease', (3, 15))	('cell invasion', 'CPA', (70, 83))	('inhibition', 'Var', (17, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('inhibit', 'NegReg', (62, 69))
132663	23976967	Epigenetic changes including DNA methylation have been well reported in MPM with hypermethylation of E-Cadherin (ECAD; 71.4%), fragile histidine triad (FHIT; 78%), the secreted frizzled related protein family (SFRPs), RASSF1A (19.5%), DAPK (20%) and RARB (55.8%) all being implicated in MPM.	('E-Cadherin', 'Gene', (101, 111))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('FHIT', 'Gene', '2272', (152, 156))	('hypermethylation', 'Var', (81, 97))	('ECAD', 'Gene', '999', (113, 117))	('MPM', 'Disease', (72, 75))	('DAPK', 'Gene', '1612', (235, 239))	('RASSF1A', 'Gene', '11186', (218, 225))	('Cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('ECAD', 'Gene', (113, 117))	('RARB', 'Gene', (250, 254))	('triad', 'cellular_component', 'GO:0030315', ('145', '150'))	('RARB', 'Gene', '5915', (250, 254))	('RASSF1A', 'Gene', (218, 225))	('E-Cadherin', 'Gene', '999', (101, 111))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('FHIT', 'Gene', (152, 156))	('DNA methylation', 'MPA', (29, 44))	('histidine', 'Chemical', 'MESH:D006639', (135, 144))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('al', 'Chemical', 'MESH:D000535', (263, 265))	('DAPK', 'Gene', (235, 239))
132673	23976967	In muscle differentiation, linc-MD1 contains recognition sites for miR-133 and miR-135 with its depletion found to reduce levels of two predicted targets of miR-133 and miR-135, MAML1 and MEF2C .	('MEF2C', 'Gene', '4208', (188, 193))	('MEF2C', 'Gene', (188, 193))	('linc-MD1', 'Gene', '101154644', (27, 35))	('linc-MD1', 'Gene', (27, 35))	('miR-133', 'Var', (157, 164))	('miR-133', 'Var', (67, 74))	('depletion', 'MPA', (96, 105))	('levels', 'MPA', (122, 128))	('MAML1', 'Gene', (178, 183))	('miR-135', 'Gene', (79, 86))	('reduce', 'NegReg', (115, 121))	('miR-135', 'Var', (169, 176))	('MAML1', 'Gene', '9794', (178, 183))
132674	23976967	This suggests that linc-MD1 may act as a decoy for miR-133 and miR-135.	('linc-MD1', 'Gene', (19, 27))	('miR-133', 'Var', (51, 58))	('linc-MD1', 'Gene', '101154644', (19, 27))	('miR-135', 'Var', (63, 70))
132685	23976967	Our profiling studies revealed that AK130275, AK129685, EF177379, BX648695, NR_003584 and AF268386 are substantially up-regulated in MPM tumours compared to benign pleura, and are detectable in both FFPE and fresh-frozen MPM tissues.	('AF268386', 'Var', (90, 98))	('NR_003584', 'Var', (76, 85))	('up-regulated', 'PosReg', (117, 129))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('MPM tumours', 'Disease', 'MESH:D009369', (133, 144))	('BX648695', 'Var', (66, 74))	('al', 'Chemical', 'MESH:D000535', (112, 114))	('EF177379', 'Var', (56, 64))	('AK130275', 'Var', (36, 44))	('AK129685', 'Var', (46, 54))	('MPM tumours', 'Disease', (133, 144))	('al', 'Chemical', 'MESH:D000535', (26, 28))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
132700	33065998	Mutations in RAPGEF6 (p = 0.03) and ACTG1 (p = 0.02) were associated with the non-epithelioid subtype, and mutations in BAP1 (p = 0.04) were related to progression-free survival (PFS) > 6 months.	('progression-free', 'Disease', (152, 168))	('mutations', 'Var', (107, 116))	('associated', 'Reg', (58, 68))	('ACTG1', 'Gene', '71', (36, 41))	('RAPGEF6', 'Gene', '51735', (13, 20))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (120, 124))	('RAPGEF6', 'Gene', (13, 20))	('ACTG1', 'Gene', (36, 41))	('related', 'Reg', (141, 148))	('non-epithelioid subtype', 'Disease', (78, 101))	('BAP1', 'Gene', (120, 124))
132701	33065998	Conclusions: In the Ramucirumab Mesothelioma clinical trial (RAMES), mutation of the gene BAP1 is related to a prolonged PFS for patients treated with platinum/pemetrexed regimens (p = 0.04).	('pemetrexed', 'Chemical', 'MESH:D000068437', (160, 170))	('patients', 'Species', '9606', (129, 137))	('BAP1', 'Gene', '8314', (90, 94))	('Ramucirumab', 'Chemical', 'MESH:C543333', (20, 31))	('Mesothelioma', 'Disease', (32, 44))	('Mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('mutation', 'Var', (69, 77))	('prolonged', 'PosReg', (111, 120))	('PFS', 'MPA', (121, 124))	('BAP1', 'Gene', (90, 94))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))
132706	33065998	The subsequent discovery of an MPM risk in family members who are heterozygous for inherited/germline BAP1 mutations underscores the role of genetic alterations in this disease.	('BAP1', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('rat', 'Species', '10116', (153, 156))	('BAP1', 'Gene', '8314', (102, 106))	('MPM', 'Disease', (31, 34))
132708	33065998	Loss-of-function mutations in the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), the neurofibromin 2 gene (NF2), and the BRCA1-associated protein-1 gene (BAP1) have been reported in MPM.	('Loss-of-function', 'NegReg', (0, 16))	('MPM', 'Disease', (187, 190))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('51', '67'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('34', '67'))	('BAP1', 'Gene', '8314', (159, 163))	('CDKN2A', 'Gene', (77, 83))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('BRCA1-associated protein-1', 'Gene', (126, 152))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (34, 70))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (34, 70))	('CDKN2A', 'Gene', '1029', (77, 83))	('neurofibromin 2', 'Gene', '4771', (90, 105))	('NF2', 'Gene', (112, 115))	('BAP1', 'Gene', (159, 163))	('mutations', 'Var', (17, 26))	('BRCA1-associated protein-1', 'Gene', '8314', (126, 152))	('neurofibromin 2', 'Gene', (90, 105))
132738	33065998	We found a significant correlation between number of mutations and PFS1 in our cohort.	('PFS1', 'Gene', (67, 71))	('PFS1', 'Chemical', '-', (67, 71))	('mutations', 'Var', (53, 62))
132740	33065998	The number of mutated genes was positively associated with higher tumor stage (p = 0.025).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutated genes', 'Var', (14, 27))	('number', 'Var', (4, 10))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
132744	33065998	Genetic alterations in RAPGEF6 (p = 0.035) and ACTG1 (p = 0.027) were more frequent in the sarcomatoid and biphasic subtype of MPM as compared with the epithelioid subtype (Figure 3).	('sarcomatoid', 'Disease', 'MESH:C538614', (91, 102))	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (12, 15))	('RAPGEF6', 'Gene', '51735', (23, 30))	('biphasic subtype', 'Disease', (107, 123))	('RAPGEF6', 'Gene', (23, 30))	('frequent', 'Reg', (75, 83))	('ACTG1', 'Gene', '71', (47, 52))	('MPM', 'Disease', (127, 130))	('sarcomatoid', 'Disease', (91, 102))	('ACTG1', 'Gene', (47, 52))
132745	33065998	BAP1 variants (p = 0.04) were associated with a longer PFS after platinum/pemetrexed first-line treatment (PFS1) (Figure 4A,B).	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('BAP1', 'Gene', (0, 4))	('pemetrexed', 'Chemical', 'MESH:D000068437', (74, 84))	('PFS1', 'Chemical', '-', (107, 111))	('PFS', 'MPA', (55, 58))	('variants', 'Var', (5, 13))	('BAP1', 'Gene', '8314', (0, 4))
132746	33065998	In addition, CUL1 and DHFR mutations were related to the epithelioid subtype, Stage III, and PFS1 > 6 months, but this correlation was not statistically significant.	('Stage III', 'Disease', (78, 87))	('mutations', 'Var', (27, 36))	('DHFR', 'molecular_function', 'GO:0004146', ('22', '26'))	('CUL1', 'Gene', '8454', (13, 17))	('DHFR', 'Gene', (22, 26))	('PFS1', 'Chemical', '-', (93, 97))	('DHFR', 'Gene', '1719', (22, 26))	('related', 'Reg', (42, 49))	('CUL1', 'Gene', (13, 17))	('epithelioid subtype', 'Disease', (57, 76))
132748	33065998	Cluster 1 was defined by a high incidence of MXRA5 mutations, cluster 2 included the majority of MPM cases mutated in BAP1, NF2, NOD2, or RAPGEF6, cluster 3 was comprised of 91% of MPM cases mutated in PIK3CB, and cluster 4 included the majority of MPMs mutated in RDX and more than 80% of cases mutated in ACTG1 (Figure 5).	('RAPGEF6', 'Gene', (138, 145))	('mutations', 'Var', (51, 60))	('ACTG1', 'Gene', '71', (307, 312))	('NF2', 'Gene', (124, 127))	('MXRA5', 'Gene', '25878', (45, 50))	('PIK3CB', 'Gene', (202, 208))	('ACTG1', 'Gene', (307, 312))	('mutated', 'Var', (107, 114))	('PIK3CB', 'Gene', '5291', (202, 208))	('BAP1', 'Gene', '8314', (118, 122))	('NOD2', 'Gene', '64127', (129, 133))	('RDX', 'Gene', (265, 268))	('NOD2', 'Gene', (129, 133))	('MXRA5', 'Gene', (45, 50))	('BAP1', 'Gene', (118, 122))	('RAPGEF6', 'Gene', '51735', (138, 145))	('RDX', 'Gene', '5962', (265, 268))
132753	33065998	Exome analysis revealed that BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, STDB1, and DDX51 were the most frequently mutated genes in MPM.	('RYR', 'cellular_component', 'GO:1990425', ('66', '69'))	('RYR2', 'Gene', '6262', (66, 70))	('TP53', 'Gene', '7157', (40, 44))	('CFAP45', 'Gene', '25790', (72, 78))	('DDX3X', 'Gene', (53, 58))	('CFAP45', 'Gene', (72, 78))	('BAP1', 'Gene', '8314', (29, 33))	('DDX51', 'Gene', (91, 96))	('SETD2', 'Gene', (46, 51))	('DDX51', 'Gene', '317781', (91, 96))	('TP53', 'Gene', (40, 44))	('DDX3X', 'Gene', '1654', (53, 58))	('SETD2', 'Gene', '29072', (46, 51))	('mutated', 'Var', (122, 129))	('BAP1', 'Gene', (29, 33))	('ULK2', 'Gene', '9706', (60, 64))	('MPM', 'Disease', (139, 142))	('ULK2', 'Gene', (60, 64))	('RYR2', 'Gene', (66, 70))
132765	33065998	In addition, the number of mutated genes was positively associated with higher tumor stage and metastatic disease.	('number', 'Var', (17, 23))	('mutated genes', 'Var', (27, 40))	('metastatic disease', 'CPA', (95, 113))	('tumor', 'Disease', (79, 84))	('associated', 'Reg', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
132776	33065998	We also found genetic alterations in several genes that might play a role in MPM pathogenesis and progression.	('genetic alterations', 'Var', (14, 33))	('MPM', 'Disease', (77, 80))	('rat', 'Species', '10116', (26, 29))	('genes', 'Gene', (45, 50))	('pathogenesis', 'biological_process', 'GO:0009405', ('81', '93'))
132784	33065998	Inactivating mutations in the NF2 gene have been reported in 35-40% of MPM patients.	('MPM', 'Disease', (71, 74))	('reported', 'Reg', (49, 57))	('patients', 'Species', '9606', (75, 83))	('Inactivating mutations', 'Var', (0, 22))	('NF2', 'Gene', (30, 33))
132785	33065998	In our study, RDX mutations were more frequent in non-epithelioid histotypes and in the population of patients with asbestos exposure, while NF2 variants were more frequently found in patients with epithelioid tumors.	('RDX', 'Gene', '5962', (14, 17))	('non-epithelioid', 'Disease', (50, 65))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('epithelioid tumors', 'Disease', (198, 216))	('patients', 'Species', '9606', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('variants', 'Var', (145, 153))	('asbestos', 'Chemical', 'MESH:D001194', (116, 124))	('RDX', 'Gene', (14, 17))	('found', 'Reg', (175, 180))	('frequent', 'Reg', (38, 46))	('epithelioid tumors', 'Disease', 'MESH:D012509', (198, 216))	('mutations', 'Var', (18, 27))
132787	33065998	However, although not statistically significant, RDX was more frequently mutated in patients with metastatic disease, in agreement with its possible role as a pro-metastatic gene.	('RDX', 'Gene', '5962', (49, 52))	('metastatic disease', 'Disease', (98, 116))	('mutated', 'Var', (73, 80))	('patients', 'Species', '9606', (84, 92))	('RDX', 'Gene', (49, 52))
132791	33065998	In our study, MXRA5 was more frequently mutated in Stage III tumors, epithelioid histotypes, and patients with PFS1 > 6 months.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('epithelioid histotypes', 'Disease', (69, 91))	('PFS1', 'Chemical', '-', (111, 115))	('MXRA5', 'Gene', '25878', (14, 19))	('MXRA5', 'Gene', (14, 19))	('mutated', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (97, 105))
132794	33065998	Following platinum chemotherapy, overall survival was significantly longer for patients with loss-of-function mutations in BAP1 and DNA repair genes compared with patients with no such mutations.	('BAP1', 'Gene', (123, 127))	('patients', 'Species', '9606', (163, 171))	('mutations', 'Var', (110, 119))	('longer', 'PosReg', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('overall', 'MPA', (33, 40))	('DNA repair genes', 'Gene', (132, 148))	('loss-of-function', 'NegReg', (93, 109))	('BAP1', 'Gene', '8314', (123, 127))	('patients', 'Species', '9606', (79, 87))	('DNA repair', 'biological_process', 'GO:0006281', ('132', '142'))	('platinum', 'Chemical', 'MESH:D010984', (10, 18))
132796	33065998	Inactivating mutations in BAP1 can be found in 23% of mesotheliomas.	('BAP1', 'Gene', (26, 30))	('Inactivating mutations', 'Var', (0, 22))	('mesotheliomas', 'Disease', (54, 67))	('mesotheliomas', 'Disease', 'MESH:D008654', (54, 67))	('BAP1', 'Gene', '8314', (26, 30))	('found', 'Reg', (38, 43))
132797	33065998	Since 2011, over 600 articles have evaluated the role of BAP1 mutations in mesothelioma and in other cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('BAP1', 'Gene', '8314', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mesothelioma', 'Disease', (75, 87))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
132800	33065998	BAP1 germline mutations have been also associated with an increased risk of mesothelioma.	('BAP1', 'Gene', (0, 4))	('germline mutations', 'Var', (5, 23))	('mesothelioma', 'Disease', (76, 88))	('associated', 'Reg', (39, 49))	('BAP1', 'Gene', '8314', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))
132801	33065998	In this regard, mesotheliomas in carriers of BAP1 mutations are almost exclusively of the epithelioid type, are well differentiated, and have an overall nonaggressive morphology, consistent with prolonged survival (i.e., oval cells with bland nuclei, rare mitoses, no necrosis).	('necrosis', 'biological_process', 'GO:0001906', ('268', '276'))	('BAP1', 'Gene', (45, 49))	('necrosis', 'Disease', (268, 276))	('mutations', 'Var', (50, 59))	('necrosis', 'biological_process', 'GO:0070265', ('268', '276'))	('BAP1', 'Gene', '8314', (45, 49))	('necrosis', 'biological_process', 'GO:0008219', ('268', '276'))	('necrosis', 'Disease', 'MESH:D009336', (268, 276))	('oval cells with bland nuclei', 'Phenotype', 'HP:0004445', (221, 249))	('necrosis', 'biological_process', 'GO:0019835', ('268', '276'))	('mesotheliomas', 'Disease', 'MESH:D008654', (16, 29))	('necrosis', 'biological_process', 'GO:0008220', ('268', '276'))	('mesotheliomas', 'Disease', (16, 29))
132802	33065998	We had no available whole blood of non-involved tissue from BAP1 mutant tumors to assess the germline or somatic origin of BAP1 mutations.	('BAP1', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutant', 'Var', (65, 71))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', (60, 64))
132803	33065998	However, the majority of BAP1 variants had allelic frequency < 50%, suggesting a somatic origin.	('BAP1', 'Gene', '8314', (25, 29))	('variants', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))
132814	33065998	Both CUL1 and DHFR variants have been identified at a high frequency in patients with PFS1 > 6 months and in epithelioid and Stage III tumors, possibly correlating with a good prognosis, in contrast to other scientific evidence.	('identified', 'Reg', (38, 48))	('PFS1', 'Chemical', '-', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('DHFR', 'molecular_function', 'GO:0004146', ('14', '18'))	('CUL1', 'Gene', (5, 9))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('DHFR', 'Gene', (14, 18))	('epithelioid', 'Disease', (109, 120))	('CUL1', 'Gene', '8454', (5, 9))	('DHFR', 'Gene', '1719', (14, 18))	('variants', 'Var', (19, 27))	('patients', 'Species', '9606', (72, 80))
132892	30410729	This mutation has also found to be linked to the development of BAP1 cancer syndrome, characterized by an increased incidence of malignant mesothelioma, uveal and cutaneous melanoma, and melanocytic BAP1-mutated atypical intradermal tumors , .	('linked', 'Reg', (35, 41))	('uveal', 'Disease', (153, 158))	('malignant mesothelioma', 'Disease', (129, 151))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('BAP1', 'Gene', (64, 68))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('cancer syndrome', 'Disease', 'MESH:D009369', (69, 84))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('cutaneous melanoma', 'Disease', (163, 181))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (163, 181))	('intradermal tumors', 'Disease', 'MESH:D018330', (221, 239))	('cancer', 'Disease', (69, 75))	('cancer syndrome', 'Disease', (69, 84))	('intradermal tumors', 'Disease', (221, 239))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (129, 151))	('mutation', 'Var', (5, 13))
132923	23626673	Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk.	('ETV1', 'Gene', '2115', (133, 137))	('MMP14', 'Gene', '4323', (148, 153))	('THRB', 'Gene', '7068', (109, 113))	('MMP14', 'Gene', (148, 153))	('SLC7A14', 'Gene', (100, 107))	('increase', 'PosReg', (189, 197))	('ADAMTS2', 'Gene', '9509', (124, 131))	('alterations', 'Var', (71, 82))	('MMP', 'molecular_function', 'GO:0004235', ('148', '151'))	('ADAMTS2', 'Gene', (124, 131))	('PVT1', 'Gene', (139, 143))	('THRB', 'Gene', (109, 113))	('MPM', 'Disease', (201, 204))	('ETV1', 'Gene', (133, 137))	('CEBP350', 'Gene', (115, 122))	('PVT1', 'Gene', '5820', (139, 143))	('SLC7A14', 'Gene', '57709', (100, 107))	('mesothelioma', 'Disease', (86, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
132924	23626673	Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28).	('increase', 'PosReg', (270, 278))	('variants', 'Var', (74, 82))	('asbestos', 'Chemical', 'MESH:D001194', (282, 290))
132935	23626673	Dominant mutations in the BAP1 (BRCA1-associated protein 1) gene were recently reported to cause a new, rare cancer-prone syndrome that renders the individual susceptible to mesothelioma and melanoma, among others.	('BAP1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('cancer', 'Disease', (109, 115))	('BRCA1-associated protein 1', 'Gene', '8314', (32, 58))	('Dominant mutations', 'Var', (0, 18))	('BRCA1-associated protein 1', 'Gene', (32, 58))	('BAP1', 'Gene', '8314', (26, 30))	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (174, 199))
132938	23626673	The most significant haplotype associations were found in the chromosomal region 3p24.2, where the THRB gene is located (P = 2.04x10-7), and in 19q13.42 (P = 7.02x1 0-7) (Table S3), strengthening the importance of these chromosomal regions.	('haplotype', 'Var', (21, 30))	('chromosomal region', 'cellular_component', 'GO:0098687', ('62', '80'))	('THRB', 'Gene', '7068', (99, 103))	('THRB', 'Gene', (99, 103))
132944	23626673	Gene expression analysis on lymphocytes from Italian healthy subjects (Text S1) showed a possible expression Quantitative Trait Locus (eQTL) for the PVT1 (rs7841347) gene (non-parametric Kruskal-Wallis test P<0.001) (Figure 4).	('PVT1', 'Gene', '5820', (149, 153))	('rs7841347', 'Mutation', 'rs7841347', (155, 164))	('rs7841347', 'Var', (155, 164))	('PVT1', 'Gene', (149, 153))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
132945	23626673	However, expression analysis from Italian healthy subjects pleural tissue stratified by PVT1 rs7841347 genotypes did not show any gradient, although a statistically significant difference (P = 0.01) was found (Figure S4).	('PVT1', 'Gene', '5820', (88, 92))	('rs7841347', 'Var', (93, 102))	('pleura', 'Disease', (59, 65))	('rs7841347', 'Mutation', 'rs7841347', (93, 102))	('pleura', 'Disease', 'MESH:D054363', (59, 65))	('PVT1', 'Gene', (88, 92))
132952	23626673	Another Italian genotyped top-signal (rs7632718) is located in the SLC7A14 (solute carrier family 7 member 14) gene, which lies on 3q26.2, which was one of the replicating regions in the Australian study.	('solute carrier family 7 member 14', 'Gene', (76, 109))	('SLC7A14', 'Gene', (67, 74))	('rs7632718', 'Mutation', 'rs7632718', (38, 47))	('carrier', 'molecular_function', 'GO:0005215', ('83', '90'))	('solute carrier family 7 member 14', 'Gene', '57709', (76, 109))	('rs7632718', 'Var', (38, 47))	('SLC7A14', 'Gene', '57709', (67, 74))
132958	23626673	A functional variant (rs378854) in chromosomal region 8q24 that modulates PVT1 expression has been associated with prostate cancer.	('prostate cancer', 'Disease', (115, 130))	('expression', 'MPA', (79, 89))	('PVT1', 'Gene', '5820', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs378854', 'Var', (22, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('chromosomal region', 'cellular_component', 'GO:0098687', ('35', '53'))	('rs378854', 'Mutation', 'rs378854', (22, 30))	('associated', 'Reg', (99, 109))	('PVT1', 'Gene', (74, 78))
132959	23626673	In vitro, the rs378854-G allele has been associated with reduced binding of the transcription factor YY1, a putative tumor suppressor, and with repressed global transcription in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (178, 193))	('rs378854', 'Mutation', 'rs378854', (14, 22))	('global transcription', 'MPA', (154, 174))	('prostate cancer', 'Disease', (178, 193))	('transcription', 'biological_process', 'GO:0006351', ('80', '93'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('reduced', 'NegReg', (57, 64))	('transcription factor', 'molecular_function', 'GO:0000981', ('80', '100'))	('binding', 'Interaction', (65, 72))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('repressed', 'PosReg', (144, 153))	('YY1', 'Gene', '7528', (101, 104))	('YY1', 'Gene', (101, 104))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs378854-G', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (178, 193))
132975	23626673	Most of the top-signals we identified were located in chromosomal regions reported to harbor aberrant alterations in mesothelioma, and cause an at most 2-3 fold increase in MPM risk.	('MPM', 'Disease', (173, 176))	('alterations', 'Var', (102, 113))	('mesothelioma', 'Disease', (117, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('increase', 'PosReg', (161, 169))
132976	23626673	Moreover, asbestos exposure in our study was associated with a remarkable increase in MPM risk, which became even more evident when the contribution of genetic factors was taken into account, with a significant improvement of asbestos exposure risk estimation.	('asbestos', 'Chemical', 'MESH:D001194', (10, 18))	('increase', 'PosReg', (74, 82))	('asbestos', 'Var', (10, 18))	('MPM', 'Disease', (86, 89))	('asbestos', 'Chemical', 'MESH:D001194', (226, 234))
132999	23626673	SNPs included in the second multivariate model were selected among the top 20 markers (12 genotyped and 8 imputed), excluding 4 SNPs (rs4290865, rs1354252, rs1072577, rs10519201) because of negative internal replication between Casale Monferrato and pooled Turin-Genoa studies, and 6 SNPs (rs742109, rs1508805, rs9536579, rs5756444, rs6897549, rs71365421) because they did not replicate in the Australian study on the regional analysis and were not intragenic.	('rs9536579', 'Var', (311, 320))	('rs1508805', 'Mutation', 'rs1508805', (300, 309))	('rs1354252', 'Var', (145, 154))	('rs71365421', 'Mutation', 'rs71365421', (344, 354))	('rs1354252', 'Mutation', 'rs1354252', (145, 154))	('rs6897549', 'Mutation', 'rs6897549', (333, 342))	('rs1072577', 'Mutation', 'rs1072577', (156, 165))	('negative', 'NegReg', (190, 198))	('rs5756444', 'Var', (322, 331))	('rs71365421', 'Var', (344, 354))	('rs1508805', 'Var', (300, 309))	('rs1072577', 'Var', (156, 165))	('rs10519201', 'Mutation', 'rs10519201', (167, 177))	('rs10519201', 'Var', (167, 177))	('rs742109', 'Var', (290, 298))	('rs5756444', 'Mutation', 'rs5756444', (322, 331))	('rs4290865', 'Var', (134, 143))	('rs742109', 'Mutation', 'rs742109', (290, 298))	('rs6897549', 'Var', (333, 342))	('rs4290865', 'Mutation', 'rs4290865', (134, 143))	('rs9536579', 'Mutation', 'rs9536579', (311, 320))
133000	23626673	A GSEA (File S1) was performed on the genes in which the top SNPs are located (9 genes out of 20 signals): PVT1 (gene ID 5820), CEP350 (ID 9857), THRB (ID 7068), ETV1 (ID 2115), C9orf46 (also known as PLGRKT; ID 55848), MMP14 (ID 4323), ADAMTS2 (ID 9509), SLC7A14 (ID 57709), SHC4 (ID 399694).	('CEP', 'molecular_function', 'GO:0047849', ('128', '131'))	('SHC4', 'Gene', (276, 280))	('ID 399694', 'Var', (282, 291))	('ID 57709', 'Var', (265, 273))	('ETV1', 'Gene', (162, 166))	('THRB', 'Gene', (146, 150))	('ADAMTS2', 'Gene', '9509', (237, 244))	('SLC7A14', 'Gene', '57709', (256, 263))	('C9orf46', 'Gene', (178, 185))	('PLGRKT', 'Gene', (201, 207))	('ADAMTS2', 'Gene', (237, 244))	('MMP14', 'Gene', '4323', (220, 225))	('GSEA', 'Chemical', '-', (2, 6))	('MMP14', 'Gene', (220, 225))	('ETV1', 'Gene', '2115', (162, 166))	('ID 9857', 'Var', (136, 143))	('ID 9509', 'Var', (246, 253))	('SLC7A14', 'Gene', (256, 263))	('THRB', 'Gene', '7068', (146, 150))	('PVT1', 'Gene', (107, 111))	('C9orf46', 'Gene', '55848', (178, 185))	('PVT1', 'Gene', '5820', (107, 111))	('ID 4323', 'Var', (227, 234))	('PLGRKT', 'Gene', '55848', (201, 207))	('SHC4', 'Gene', '399694', (276, 280))	('CEP350', 'Gene', (128, 134))	('MMP', 'molecular_function', 'GO:0004235', ('220', '223'))	('CEP350', 'Gene', '9857', (128, 134))
133078	19644223	It is, therefore, suggested that ferritin in lung tissue incorporates preferentially ions with larger radii such as Rb+, Ra2+, Ba2+, UO22+ and Th4+.	('Th4+', 'Var', (143, 147))	('Rb+', 'Chemical', 'MESH:D012413', (116, 119))	('preferentially', 'PosReg', (70, 84))	('UO22+', 'Var', (133, 138))	('Th4+', 'Chemical', '-', (143, 147))	('Ba2+', 'MPA', (127, 131))	('Ra2+', 'MPA', (121, 125))	('Ra2+', 'Chemical', '-', (121, 125))	('Ba2+', 'Chemical', 'MESH:C080430', (127, 131))	('Rb+', 'MPA', (116, 119))	('UO22', 'Chemical', '-', (133, 137))
133079	19644223	This suggestion is also supported by the systematic increase of LREE3+ relative to HREE3+ with increasing iron abundance.	('increase', 'PosReg', (52, 60))	('iron', 'Chemical', 'MESH:D007501', (106, 110))	('LREE3+', 'Var', (64, 70))
133100	19644223	226Ra is the fifth daughter nuclide of the 238U-206Pb decay chain and has a half-life of 1600 years.	('226Ra', 'Var', (0, 5))	('Ra', 'Chemical', 'MESH:D011883', (3, 5))	('Pb', 'Chemical', 'MESH:D007854', (51, 53))	('238U-206Pb', 'Var', (43, 53))
133103	19644223	Thus, the integrated alpha-particles emitted through the decay chain from 226Ra to 210Pb, are highly effective in damaging tissues within the lung, in comparison to the case of inhaled radon progeny decay which have been previously proposed for the association of radon and lung cancer.	('lung cancer', 'Disease', (274, 285))	('Pb', 'Chemical', 'MESH:D007854', (86, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('226Ra to 210Pb', 'Var', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Ra', 'Chemical', 'MESH:D011883', (77, 79))	('lung cancer', 'Disease', 'MESH:D008175', (274, 285))	('damaging', 'Reg', (114, 122))
133139	19802384	We conclude that syndecan-1 and FGF-2, but not FGFR-1 share a common transport route and co-localize with heparanase in the nucleus, and this transport is mediated by the RMKKK motif in syndecan-1.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('nucleus', 'cellular_component', 'GO:0005634', ('124', '131'))	('FGF-2', 'Gene', (32, 37))	('FGF-2', 'Gene', '2247', (32, 37))	('heparanase', 'Gene', '10855', (106, 116))	('transport route', 'MPA', (69, 84))	('transport', 'biological_process', 'GO:0006810', ('142', '151'))	('syndecan', 'molecular_function', 'GO:0015023', ('17', '25'))	('FGFR-1', 'Gene', (47, 53))	('RMKKK motif', 'Var', (171, 182))	('FGFR-1', 'Gene', '2260', (47, 53))	('transport', 'biological_process', 'GO:0006810', ('69', '78'))	('syndecan', 'molecular_function', 'GO:0015023', ('186', '194'))	('heparanase', 'Gene', (106, 116))	('mediated by', 'Reg', (155, 166))	('co-localize', 'MPA', (89, 100))
133146	19802384	Experimental studies show that cleavage of the HS chain may generate oligosaccharide sequences, which can either inhibit or potentiate the effect of the GFs.	('cleavage', 'Var', (31, 39))	('inhibit', 'NegReg', (113, 120))	('HS', 'Chemical', 'MESH:D006497', (47, 49))	('potentiate', 'PosReg', (124, 134))	('oligosaccharide sequences', 'MPA', (69, 94))	('HS chain', 'Protein', (47, 55))	('oligosaccharide', 'Chemical', 'MESH:D009844', (69, 84))
133155	19802384	In our previous work, double staining experiments clearly demonstrated that syndecan-1 is structurally linked to the intracellular microtubule system in all phases of cell division, and that inhibition of microtubule polymerization by vinblastine treatment hampers the nuclear translocation of syndecan-1.	('microtubule polymerization', 'MPA', (205, 231))	('inhibition', 'Var', (191, 201))	('syndecan', 'molecular_function', 'GO:0015023', ('76', '84'))	('cell division', 'biological_process', 'GO:0051301', ('167', '180'))	('syndecan', 'molecular_function', 'GO:0015023', ('294', '302'))	('vinblastine', 'Chemical', 'MESH:D014747', (235, 246))	('nuclear translocation', 'MPA', (269, 290))	('microtubule', 'cellular_component', 'GO:0005874', ('131', '142'))	('intracellular', 'cellular_component', 'GO:0005622', ('117', '130'))	('hampers', 'NegReg', (257, 264))	('microtubule', 'cellular_component', 'GO:0005874', ('205', '216'))	('inhibition of microtubule polymerization', 'biological_process', 'GO:0031115', ('191', '231'))
133181	19802384	Doxorubicin is a chemotherapeutic agent known to cause cellular damage via a number of mechanisms including inhibition of topoisomerase II, nucleotide intercalation, free radical formation and inhibition of DNA replication.	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('inhibition', 'NegReg', (108, 118))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('topoisomerase II', 'Enzyme', (122, 138))	('inhibition', 'NegReg', (193, 203))	('free radical formation', 'MPA', (166, 188))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('DNA replication', 'CPA', (207, 222))	('cellular damage', 'CPA', (55, 70))	('nucleotide', 'Var', (140, 150))	('inhibition of DNA replication', 'biological_process', 'GO:0008156', ('193', '222'))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('122', '138'))
133192	19802384	The RMKKK sequence of syndecan-1 corresponding to Arg - Met -Lys - Lys - Lys was subjected to site directed mutagenesis by GenScript Corporation (NJ, USA) to generate three mutants.	('syndecan-1', 'Gene', (22, 32))	('Arg - Met -Lys - Lys - Lys', 'Var', (50, 76))	('syndecan', 'molecular_function', 'GO:0015023', ('22', '30'))	('Lys', 'Chemical', 'MESH:D008239', (73, 76))	('Lys', 'Chemical', 'MESH:D008239', (67, 70))	('Arg', 'Chemical', 'MESH:D001120', (50, 53))	('mutagenesis', 'biological_process', 'GO:0006280', ('108', '119'))	('Lys', 'Chemical', 'MESH:D008239', (61, 64))
133193	19802384	These were mutant 1, Ala - Met - Leu - Lys - Lys (AMLKK); mutant 2, Ala - Met - Lys - Leu - Lys (AMKLK); and mutant 3, Arg - Met -Leu - Leu - Lys (RMLLK).	('Ala - Met - Lys - Leu - Lys', 'Var', (68, 95))	('Arg - Met -Leu - Leu - Lys', 'Var', (119, 145))	('Arg - Met -Leu - Leu - Lys', 'Chemical', '-', (119, 145))	('Ala - Met - Lys - Leu - Lys', 'Chemical', '-', (68, 95))	('Ala - Met - Leu - Lys - Lys', 'Chemical', '-', (21, 48))	('Ala - Met - Leu - Lys - Lys', 'Var', (21, 48))
133205	19802384	Double labeling experiments showed that both FGF-2 ( Figure 3A ) and syndecan-1 ( Figure 3B ) strictly co-localized with the depolymerized tubulin; furthermore, that tubulin depolymerization completely hampered the nuclear translocation of both syndecan-1 and FGF-2.	('tubulin', 'Protein', (166, 173))	('hampered', 'NegReg', (202, 210))	('FGF-2', 'Gene', (260, 265))	('FGF-2', 'Gene', '2247', (260, 265))	('syndecan', 'molecular_function', 'GO:0015023', ('69', '77'))	('depolymerization', 'Var', (174, 190))	('syndecan-1 ( Figure 3B', 'Gene', '6382', (69, 91))	('nuclear translocation', 'MPA', (215, 236))	('FGF-2', 'Gene', '2247', (45, 50))	('syndecan', 'molecular_function', 'GO:0015023', ('245', '253'))	('FGF-2', 'Gene', (45, 50))
133219	19802384	In cells transfected to express the RMKKK mutant 1 (Ala - Met - Leu - Lys - Lys, AMLKK) or mutant 2 (Ala - Met - Lys - Leu - Lys, AMKLK), both containing alanine instead of arginine, the proportion of cells with a nuclear positivity for EGFP signal was reduced by up to 50% compared to wide type RMKKK ( Figure 7 ).	('mutant', 'Var', (42, 48))	('arginine', 'Chemical', 'MESH:D001120', (173, 181))	('Ala - Met - Lys - Leu - Lys', 'Var', (101, 128))	('reduced', 'NegReg', (253, 260))	('Ala - Met - Leu - Lys - Lys', 'Chemical', '-', (52, 79))	('alanine', 'Chemical', 'MESH:D000409', (154, 161))	('Ala - Met - Lys - Leu - Lys', 'Chemical', '-', (101, 128))
133220	19802384	The replacement of two of the three lysines with leucines, but retention of the arginine, in mutant 3 (Arg - Met -Leu - Leu - Lys, RMLLK), did not significantly affect the nuclear localization.	('nuclear localization', 'MPA', (172, 192))	('retention', 'biological_process', 'GO:0051235', ('63', '72'))	('Arg - Met -Leu - Leu - Lys', 'Var', (103, 129))	('Arg - Met -Leu - Leu - Lys', 'Chemical', '-', (103, 129))	('leucines', 'Chemical', 'MESH:D007930', (49, 57))	('lysines', 'Chemical', 'MESH:D008239', (36, 43))	('arginine', 'Chemical', 'MESH:D001120', (80, 88))	('localization', 'biological_process', 'GO:0051179', ('180', '192'))
133232	19802384	Tubulin depolymerization prevents the nuclear transport of FGF-2 and syndecan-1 ( Figure 3A, B ), and the fact that both components co-localize with the depolymerized tubulin indicates stable associations between them.	('depolymerization', 'Var', (8, 24))	('nuclear transport', 'biological_process', 'GO:0051169', ('38', '55'))	('nuclear transport', 'MPA', (38, 55))	('syndecan', 'molecular_function', 'GO:0015023', ('69', '77'))	('FGF-2', 'Gene', (59, 64))	('prevents', 'NegReg', (25, 33))	('syndecan-1', 'Gene', (69, 79))	('FGF-2', 'Gene', '2247', (59, 64))	('associations', 'Interaction', (192, 204))
133237	19802384	Furthermore, replacement of the one arginine is sufficient to substantially decrease the nuclear accumulation of the mutated fusion proteins.	('replacement', 'Var', (13, 24))	('decrease', 'NegReg', (76, 84))	('arginine', 'Chemical', 'MESH:D001120', (36, 44))
133238	19802384	The mutants 1 and 2 share a common arginine mutation and give a dramatic decrease of nuclear translocation, which indicates that arginine is most crucial for this function ( Figure 7 ).	('arginine', 'Chemical', 'MESH:D001120', (129, 137))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('decrease', 'NegReg', (73, 81))	('nuclear translocation', 'MPA', (85, 106))	('arginine mutation', 'Var', (35, 52))
133256	32138788	Recent technological advances have enabled the analyses of alterations in gene-based structure or function in a comprehensive, high-throughput fashion showing that each tumor type typically exhibits distinct constellations of genetic alterations targeting one or more key cellular pathways that regulate cell growth and proliferation, evasion of the immune system, and other aspects of cancer behavior.	('alterations', 'Var', (234, 245))	('alterations', 'Var', (59, 70))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('targeting', 'Reg', (246, 255))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('regulate', 'Reg', (295, 303))	('cancer', 'Disease', (386, 392))	('cell growth', 'biological_process', 'GO:0016049', ('304', '315'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cell growth', 'CPA', (304, 315))	('evasion', 'MPA', (335, 342))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('genetic alterations', 'Var', (226, 245))
133261	32138788	By the use of C3H/HeJ and C57BL/10ScCr mice, carrying mutations of the LPS gene, in 1998 Beutler demonstrated that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex.	('TLR4', 'Gene', (157, 161))	('mammalian', 'Species', '9606', (210, 219))	('HeJ', 'CellLine', 'CVCL:0030', (18, 21))	('LPS', 'Gene', (220, 223))	('mice', 'Species', '10090', (39, 43))	('mutations', 'Var', (54, 63))	('membrane', 'cellular_component', 'GO:0016020', ('175', '183'))	('LPS', 'Gene', '21898', (71, 74))	('TLR4', 'Gene', '7099', (157, 161))	('LPS', 'Gene', (71, 74))	('mammalian', 'Species', '9606', (126, 135))	('LPS', 'Gene', '21898', (220, 223))	('LPS receptor complex', 'cellular_component', 'GO:0046696', ('220', '240'))
133262	32138788	In fact, he showed that destructive mutations of Tlr4 gene predispose to the development of Gram-negative sepsis, while leaving most aspects of immune function intact.	('leaving', 'Reg', (120, 127))	('Tlr4', 'Gene', (49, 53))	('predispose', 'Reg', (59, 69))	('sepsis', 'Phenotype', 'HP:0100806', (106, 112))	('sepsis', 'Disease', (106, 112))	('mutations', 'Var', (36, 45))	('sepsis', 'Disease', 'MESH:D018805', (106, 112))	('Tlr4', 'Gene', '7099', (49, 53))
133263	32138788	In these studies, using the mutagen agent N-ethyl-N-nitrosourea (ENU), Beutler's laboratory randomly generated a number of germline mutations in mouse models, detected about 200 mutations altering innate immune response and finally isolated them by positional cloning.	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (42, 63))	('innate immune', 'MPA', (197, 210))	('mutations', 'Var', (132, 141))	('mouse', 'Species', '10090', (145, 150))	('innate immune response', 'biological_process', 'GO:0045087', ('197', '219'))	('mutations', 'Var', (178, 187))	('altering', 'Reg', (188, 196))
133266	32138788	This is a very exciting story running from approximately 25 years regarding the discovery of BAP1 mutations that define a novel cancer syndrome.	('BAP1', 'Gene', '8314', (93, 97))	('cancer syndrome', 'Disease', (128, 143))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BAP1', 'Gene', (93, 97))	('cancer syndrome', 'Disease', 'MESH:D009369', (128, 143))
133270	32138788	To shed light on this aspect, in 2001 Carbone's team begun to study two US families affected by mesothelioma without a story of environmental exposure to carcinogenic fibers and demonstrated that all affected family members carried inherited germline mutations of the BAP1 gene.	('BAP1', 'Gene', '8314', (268, 272))	('Carbone', 'Chemical', 'MESH:D002244', (38, 45))	('carried', 'Reg', (224, 231))	('mesothelioma', 'Disease', (96, 108))	('germline mutations', 'Var', (242, 260))	('carcinogenic fibers', 'Disease', 'MESH:D004916', (154, 173))	('carcinogenic fibers', 'Disease', (154, 173))	('BAP1', 'Gene', (268, 272))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))
133271	32138788	Germline BAP1 mutations-affected family members developed multiple malignancies, predominantly mesotheliomas and uveal melanomas, and less frequently skin melanomas and other tumors.	('tumors', 'Disease', (175, 181))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('multiple malignancies', 'Disease', 'MESH:C536827', (58, 79))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('BAP1', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('skin melanomas', 'Disease', (150, 164))	('skin melanomas', 'Disease', 'MESH:D008545', (150, 164))	('uveal melanomas', 'Disease', 'MESH:C536494', (113, 128))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('mesotheliomas', 'Disease', (95, 108))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('mutations-affected', 'Var', (14, 32))	('mesotheliomas', 'Disease', 'MESH:D008654', (95, 108))	('multiple malignancies', 'Disease', (58, 79))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('uveal melanomas', 'Disease', (113, 128))	('uveal melanomas', 'Phenotype', 'HP:0007716', (113, 128))	('BAP1', 'Gene', '8314', (9, 13))	('developed', 'Reg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
133276	32138788	In fact, BAP-1 mutation inhibits asbestos-induced cell death, ensuring the viability of cancerogenic clones.	('mutation', 'Var', (15, 23))	('cancer', 'Disease', (88, 94))	('BAP-1', 'Gene', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cell death', 'biological_process', 'GO:0008219', ('50', '60'))	('inhibits', 'NegReg', (24, 32))	('asbestos-induced cell death', 'CPA', (33, 60))	('asbestos', 'Chemical', 'MESH:D001194', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BAP-1', 'Gene', '8314', (9, 14))
133280	32138788	Current therapies extend the survival of mesothelioma patients only to ~ 1 year, whereas carriers of germline BAP1 mutations have an average survival of 5 years, an amount of time that significantly exceeded the benefit of any currently available therapy, thus suggesting that germline BAP1 mutations could be exploited as a prognostic factor.	('mutations', 'Var', (115, 124))	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', '8314', (286, 290))	('mesothelioma', 'Disease', (41, 53))	('patients', 'Species', '9606', (54, 62))	('BAP1', 'Gene', (110, 114))	('BAP1', 'Gene', (286, 290))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))
133281	32138788	The clinical translation of this discovery is the possibility to perform genotyping of patients and their relatives to identify carriers of germline mutations for screening programs and to conduct genomic studies on tumor biopsies to identify actionable mutations.	('tumor', 'Disease', (216, 221))	('mutations', 'Var', (149, 158))	('translation', 'biological_process', 'GO:0006412', ('13', '24'))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('patients', 'Species', '9606', (87, 95))
133285	32138788	Overall, specific tumor mutations are identified followed by the synthesis of new antigens (peptides, miRNAs) or collections of platforms combined according to the individual's tumor model.	('tumor', 'Disease', (18, 23))	('synthesis', 'biological_process', 'GO:0009058', ('65', '74'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
133298	32138788	Pepe showed some results obtained by SiRe, a panel which covers 568 mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRa) involved in NSCLC, gastrointestinal stromal tumor, colorectal carcinoma and melanoma.	('EGFR', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (110, 114))	('NRAS', 'Gene', (104, 108))	('KRAS', 'Gene', '3845', (98, 102))	('BRAF', 'Gene', (110, 114))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (152, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))	('cKIT', 'Gene', '3815', (116, 120))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (152, 182))	('KRAS', 'Gene', (98, 102))	('EGFR', 'Gene', '1956', (92, 96))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('gastrointestinal stromal tumor', 'Disease', (152, 182))	('Pepe', 'Gene', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('Pepe', 'Gene', '5185', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('cKIT', 'Gene', (116, 120))	('NRAS', 'Gene', '4893', (104, 108))	('NSCLC', 'Disease', (145, 150))	('colorectal carcinoma', 'Disease', (184, 204))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (184, 204))	('mutations', 'Var', (68, 77))	('melanoma', 'Disease', (209, 217))	('PDGFRa', 'Gene', '5156', (125, 131))	('PDGFRa', 'Gene', (125, 131))
133309	32138788	Manipulating the ratio between the two cytokines reverses the resistance to IL-4, changing the macrophages activation.	('IL-4', 'Gene', '3565', (76, 80))	('macrophages activation', 'MPA', (95, 117))	('Manipulating', 'Var', (0, 12))	('changing', 'Reg', (82, 90))	('IL-4', 'molecular_function', 'GO:0005136', ('76', '80'))	('IL-4', 'Gene', (76, 80))
133310	32138788	In the context of PDAC, Ostuni groups' highlighted that TAMs epigenetically up- or down-regulate the expression of inflammatory-related genes in response to different cytokine, alone or in combination.	('epigenetically', 'Var', (61, 75))	('TAMs', 'Chemical', 'MESH:D013629', (56, 60))	('response to different cytokine', 'MPA', (145, 175))	('down-regulate', 'NegReg', (83, 96))	('up-', 'PosReg', (76, 79))	('PDAC', 'Disease', 'MESH:D021441', (18, 22))	('expression', 'MPA', (101, 111))	('PDAC', 'Disease', (18, 22))	('PDAC', 'Phenotype', 'HP:0006725', (18, 22))	('inflammatory-related genes', 'Gene', (115, 141))
133317	32138788	Tumor heterogeneity is frequently seen as the result of genetic evolution but additional mechanisms such as epigenetic modifications, transcriptional changes and alterations in protein levels or protein modifications in the tumor cells and/or the microenvironment also play a major role.	('transcriptional', 'Var', (134, 149))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('alterations', 'Reg', (162, 173))	('protein modifications', 'MPA', (195, 216))	('protein levels', 'MPA', (177, 191))	('tumor', 'Disease', (224, 229))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('epigenetic modifications', 'Var', (108, 132))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
133329	32138788	In summary, single-cell transcriptomic with high sensitivity detection of mutations provide insights into cellular and molecular mechanisms of resistance of CML-SCs to therapy and could be useful for predicting and monitoring therapy response and for the identification of new and more effective treatment to improve clinical outcome of this disease.	('CML', 'Disease', 'MESH:D015464', (157, 160))	('CML', 'Phenotype', 'HP:0005506', (157, 160))	('mutations', 'Var', (74, 83))	('CML', 'Disease', (157, 160))	('SCs', 'molecular_function', 'GO:0004776', ('161', '164'))
133331	32138788	Indeed, previous data have highlighted mutation or deletion of genes implicated in DNA damage response in 22% of MM patients.	('MM', 'Disease', 'MESH:D009101', (113, 115))	('mutation', 'Var', (39, 47))	('DNA damage response', 'biological_process', 'GO:0006974', ('83', '102'))	('patients', 'Species', '9606', (116, 124))	('genes', 'Gene', (63, 68))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('deletion', 'Var', (51, 59))
133335	32138788	Interestingly, experiments performed by Caracciolo and coworkers have shown that knockdown of LIG3 reduces MM cells viability, suggesting that neoplastic plasma cells are dependent on LIG3-driven repair.	('LIG3', 'Gene', '3980', (94, 98))	('LIG3', 'Gene', '3980', (184, 188))	('MM', 'Disease', 'MESH:D009101', (107, 109))	('knockdown', 'Var', (81, 90))	('LIG3', 'Gene', (94, 98))	('LIG3', 'Gene', (184, 188))	('reduces', 'NegReg', (99, 106))
133343	32138788	Indeed, loss of DIS3 increases DNA:RNA hybrids and impairs DSB repair, inducing a BRCAness status and accumulation of mutations.	('inducing', 'Reg', (71, 79))	('increases', 'PosReg', (21, 30))	('accumulation', 'PosReg', (102, 114))	('DNA:RNA hybrids', 'CPA', (31, 46))	('mutations', 'MPA', (118, 127))	('DIS3', 'Gene', '22894', (16, 20))	('BRCAness status', 'Disease', 'MESH:D013226', (82, 97))	('DIS3', 'Gene', (16, 20))	('loss', 'Var', (8, 12))	('impairs', 'NegReg', (51, 58))	('DSB', 'Disease', (59, 62))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('BRCAness status', 'Disease', (82, 97))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
133345	32138788	Furthermore, Tonon has provided an essential contribution to the topic of tumor resistance to treatments: tumors cells may exhibit a reversible drug-tolerance, induced by epigenetic changes in phenotypically distinct subpopulations of cells, which allows survival of the tumor and further tumor evolution and progression after the initial elimination of the tumor bulk and suspension of the treatment.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('allows', 'Reg', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Disease', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('epigenetic', 'Var', (171, 181))	('survival', 'CPA', (255, 263))
133350	32138788	PanNETs and PanNEC differ also in term of genetic alterations being PanNEC genetically characterized by TP53 and RB1 inactivation while PanNETs are more heterogeneous.	('PanNEC', 'Disease', 'MESH:D018278', (12, 18))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('PanNETs', 'Disease', 'MESH:D018358', (136, 143))	('PanNETs', 'Disease', (0, 7))	('PanNEC', 'Disease', (12, 18))	('inactivation', 'Var', (117, 129))	('PanNETs', 'Disease', 'MESH:D018358', (0, 7))	('RB1', 'Gene', (113, 116))	('PanNEC', 'Disease', 'MESH:D018278', (68, 74))	('PanNEC', 'Disease', (68, 74))	('PanNETs', 'Disease', (136, 143))	('RB1', 'Gene', '5925', (113, 116))
133352	32138788	Mafficini summarized several sets of potential targets, including Wnt pathway, cell cycle regulation, PI3K/mTOR, Chromatin remodeling, homologous recombination and DNA single base repairs.	('DNA single base repairs', 'Var', (164, 187))	('cell cycle', 'CPA', (79, 89))	('mTOR', 'Gene', (107, 111))	('homologous recombination', 'biological_process', 'GO:0035825', ('135', '159'))	('mTOR', 'Gene', '2475', (107, 111))	('Wnt pathway', 'Pathway', (66, 77))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('79', '100'))	('Chromatin remodeling', 'biological_process', 'GO:0006338', ('113', '133'))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('Chromatin', 'cellular_component', 'GO:0000785', ('113', '122'))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('homologous', 'Var', (135, 145))
133357	32138788	Another issue highlighted by ultradeep sequencing is the intratumor heterogeneity, and the presence of low abundance mutations which may confer clonal resistance to therapy.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
133370	32138788	ZNF281 silencing significantly increases cell death upon chemotherapy in vitro by regulating XRCC2 and XRCC4, two genes that take part in homologous recombination and non-homologous end joining, respectively.	('cell death upon chemotherapy', 'CPA', (41, 69))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('increases', 'PosReg', (31, 40))	('XRCC4', 'Gene', (103, 108))	('XRCC4', 'Gene', '7518', (103, 108))	('XRCC2', 'Gene', '7516', (93, 98))	('homologous recombination', 'biological_process', 'GO:0035825', ('138', '162'))	('ZNF281', 'Gene', '23528', (0, 6))	('XRCC2', 'Gene', (93, 98))	('silencing', 'Var', (7, 16))	('ZNF281', 'Gene', (0, 6))
133373	32138788	Silencing of ZNF281 induces neuronal differentiation of NB cells while its ectopic expression causes the opposite effect.	('induces', 'Reg', (20, 27))	('ZNF281', 'Gene', '23528', (13, 19))	('NB', 'Phenotype', 'HP:0003006', (56, 58))	('NB', 'Disease', 'MESH:D009447', (56, 58))	('ZNF281', 'Gene', (13, 19))	('neuronal differentiation', 'CPA', (28, 52))	('Silencing', 'Var', (0, 9))
133385	32138788	In conclusion Melino's lab results define a late ZNF281-dependent regulatory step of NHEJ complex assembly at DNA lesions supporting its additional role as marker for cancer patients' stratification for therapeutic approaches in NB treatment.	('ZNF281', 'Gene', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('NB', 'Disease', 'MESH:D009447', (229, 231))	('NHEJ', 'biological_process', 'GO:0006303', ('85', '89'))	('NHEJ complex', 'cellular_component', 'GO:0070419', ('85', '97'))	('cancer', 'Disease', (167, 173))	('patients', 'Species', '9606', (174, 182))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ZNF281', 'Gene', '23528', (49, 55))	('lesions', 'Var', (114, 121))	('NB', 'Phenotype', 'HP:0003006', (229, 231))
133416	32138788	Transfer of human T cells expressing the costimulated MOv19-BBzeta CAR mediated tumor regression in immuno-deficient mice bearing large, established FRalpha(+) human cancer.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BBzeta', 'Chemical', '-', (60, 66))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('immuno-deficient', 'Disease', (100, 116))	('immuno-deficient', 'Disease', 'MESH:D000163', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (117, 121))	('human', 'Species', '9606', (12, 17))	('MOv19-BBzeta', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CAR', 'cellular_component', 'GO:0005826', ('67', '70'))	('human', 'Species', '9606', (160, 165))
133436	27042127	Antibodies against CTLA-4 and against PD-1, alone or in combination, have been shown to be the most promising.	('PD-1', 'Gene', (38, 42))	('Antibodies', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (38, 42))	('CTLA-4', 'Gene', (19, 25))
133450	27042127	The model that depicts anti-CTLA-4 antibodies directly blocking the inhibitory signals on T-cells, inactivating the brakes to enhance antitumor activity, is in collusion with the fact that B7 expression is very low in the tumor environment.	('brakes', 'MPA', (116, 122))	('blocking', 'NegReg', (55, 63))	('enhance', 'PosReg', (126, 133))	('tumor', 'Disease', (138, 143))	('inactivating', 'NegReg', (99, 111))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('inhibitory signals on T-cells', 'MPA', (68, 97))	('anti-CTLA-4', 'Gene', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('antibodies', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
133455	27042127	The effectiveness of anti-CTLA-4 antibodies in a microenvironment deprived of B7 stimulatory coreceptor can also be explained by an enhanced infiltration of tumor-specific T-cells from tumor-draining lymph nodes.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (185, 190))	('infiltration', 'CPA', (141, 153))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('anti-CTLA-4', 'Gene', (21, 32))	('enhanced', 'PosReg', (132, 140))	('anti-CTLA-4 antibodies', 'Var', (21, 43))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('antibodies', 'Var', (33, 43))
133457	27042127	Tregs express high levels of CTLA-4 coreceptor, and it has been shown that the administration of anti-CTLA-4 antibodies decreases the ratio of Tregs to effector T-cells, leading to an increased antitumor T-cell activity.	('ratio', 'MPA', (134, 139))	('anti-CTLA-4', 'Gene', (97, 108))	('antibodies', 'Var', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('increased', 'PosReg', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('decreases', 'NegReg', (120, 129))	('anti-CTLA-4 antibodies', 'Var', (97, 119))
133458	27042127	The mechanism that mediates anti-CTLA-4-induced Treg depletion is still unknown, although the involvement of macrophage Fcgamma receptor (FcgammaR) responses has been proposed to play a fundamental role in it.	('Fcgamma receptor', 'Gene', '2209', (120, 136))	('FcgammaR', 'Gene', '2209', (138, 146))	('anti-CTLA-4-induced', 'Var', (28, 47))	('depletion', 'MPA', (53, 62))	('FcgammaR', 'Gene', (138, 146))	('Fcgamma receptor', 'Gene', (120, 136))
133463	27042127	At the same time, Canniff et al revealed how the effects of tremelimumab were independent of the disease stage or the cancer type, and that the antibody enhanced the IL-2 production in T-cells from healthy individuals and from cancer patients with solid tumors, including ovarian, renal, prostate, rectal, melanoma, and Hodgkin's/non-Hodgkin's lymphoma.	('IL-2', 'molecular_function', 'GO:0005134', ('166', '170'))	('IL-2', 'Gene', '3558', (166, 170))	('renal', 'Disease', (281, 286))	('antibody', 'cellular_component', 'GO:0019814', ('144', '152'))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('enhanced', 'PosReg', (153, 161))	('rectal', 'Disease', (298, 304))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('IL-2 production', 'biological_process', 'GO:0032623', ('166', '181'))	('patients', 'Species', '9606', (234, 242))	('antibody', 'Var', (144, 152))	('antibody', 'molecular_function', 'GO:0003823', ('144', '152'))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (330, 352))	('cancer', 'Disease', (118, 124))	('tremelimumab', 'Chemical', 'MESH:C520704', (60, 72))	('antibody', 'cellular_component', 'GO:0042571', ('144', '152'))	('ovarian', 'Disease', (272, 279))	('solid tumors', 'Disease', (248, 260))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('IL-2', 'Gene', (166, 170))	('cancer', 'Disease', (227, 233))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (334, 352))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	("Hodgkin's/non-Hodgkin's lymphoma", 'Disease', (320, 352))	('prostate', 'Disease', (288, 296))	('melanoma', 'Disease', (306, 314))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lymphoma', 'Phenotype', 'HP:0002665', (344, 352))	('antibody', 'cellular_component', 'GO:0019815', ('144', '152'))	("Hodgkin's/non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (320, 352))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('solid tumors', 'Disease', 'MESH:D009369', (248, 260))
133474	27042127	The most common AEs in this study were diarrhea, rash, pruritus, fatigue, and nausea, all of them being more frequent on the 10 mg/kg arm.	('diarrhea', 'Disease', (39, 47))	('nausea', 'Disease', (78, 84))	('nausea', 'Disease', 'MESH:D009325', (78, 84))	('diarrhea', 'Disease', 'MESH:D003967', (39, 47))	('fatigue', 'Disease', (65, 72))	('pruritus', 'Phenotype', 'HP:0000989', (55, 63))	('10 mg/kg', 'Var', (125, 133))	('fatigue', 'Phenotype', 'HP:0012378', (65, 72))	('rash', 'Disease', 'MESH:D005076', (49, 53))	('pruritus', 'Disease', 'MESH:D011537', (55, 63))	('pruritus', 'Disease', (55, 63))	('rash', 'Disease', (49, 53))	('rash', 'Phenotype', 'HP:0000988', (49, 53))	('diarrhea', 'Phenotype', 'HP:0002014', (39, 47))	('fatigue', 'Disease', 'MESH:D005221', (65, 72))	('nausea', 'Phenotype', 'HP:0002018', (78, 84))
133496	27042127	The novelty of this clinical trial was the study of tremelimumab as an antiviral: tremelimumab decreased the median values in viral load in all the patients; however, six patients with lower viral load showed mutations in the hypervariable region 1 of hepatitis C virus.	('decreased', 'NegReg', (95, 104))	('patients', 'Species', '9606', (148, 156))	('viral load', 'MPA', (126, 136))	('tremelimumab', 'Chemical', 'MESH:C520704', (82, 94))	('hepatitis C virus', 'Species', '11103', (252, 269))	('patients', 'Species', '9606', (171, 179))	('hepatitis', 'Phenotype', 'HP:0012115', (252, 261))	('mutations', 'Var', (209, 218))	('tremelimumab', 'Chemical', 'MESH:C520704', (52, 64))
133522	27042127	Millard et al carried out a study with 17 patients with melanoma and one patient with mesothelioma, prostate, non-small-cell lung, and pancreatic cancer, with a combination of tremelimumab plus 6 mg/kg, 10 mg/kg, or 15 mg/kg PF-3512676, an oligonucleotide agonist of the toll-like receptor-9.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('toll-like receptor-9', 'Gene', (271, 291))	('oligonucleotide', 'Chemical', 'MESH:D009841', (240, 255))	('pancreatic cancer', 'Disease', (135, 152))	('mesothelioma', 'Disease', (86, 98))	('patient', 'Species', '9606', (42, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('PF', 'Chemical', 'MESH:C002997', (225, 227))	('toll-like receptor-9', 'Gene', '54106', (271, 291))	('patient', 'Species', '9606', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PF-3512676', 'Var', (225, 235))	('patients', 'Species', '9606', (42, 50))	('tremelimumab', 'Chemical', 'MESH:C520704', (176, 188))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
133565	27042127	Moreover, there were also interactions between tremelimumab and the invariant natural killer cells (iNKTs) implicated in both innate and adaptive immune responses: the iNKT-CD4+ and iNKT-CD8+ presented a higher effector memory phenotype than the iNKT-double-negative iNKT cells (iNKT-DN) after treatment.	('tremelimumab', 'Chemical', 'MESH:C520704', (47, 59))	('effector memory phenotype', 'CPA', (211, 236))	('iNKT-CD4+', 'Var', (168, 177))	('CD8', 'Gene', (187, 190))	('CD8', 'Gene', '925', (187, 190))	('memory', 'biological_process', 'GO:0007613', ('220', '226'))	('higher', 'PosReg', (204, 210))
133570	27042127	In the study with patients having hepatocarcinoma and chronic hepatitis C, tremelimumab induced an expansion of virus-specific IFN-gamma lymphocytes, Tregs (defined as CD4+ FoxP3+ cells only), and a transient expansion of peptides.	('Tregs', 'CPA', (150, 155))	('peptides', 'MPA', (222, 230))	('tremelimumab', 'Chemical', 'MESH:C520704', (75, 87))	('hepatitis', 'Phenotype', 'HP:0012115', (62, 71))	('hepatocarcinoma and chronic hepatitis C', 'Disease', 'MESH:D019698', (34, 73))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (54, 71))	('expansion', 'PosReg', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('patients', 'Species', '9606', (18, 26))	('tremelimumab', 'Var', (75, 87))
133575	27042127	There was a better survival of patients with CD4+ICOS+ T-cells circulating over a value of 54 cells/muL and 26 cells/muL at days 30 and 26, respectively.	('CD4+ICOS+', 'Var', (45, 54))	('muL', 'Gene', '4591', (100, 103))	('muL', 'Gene', '4591', (117, 120))	('patients', 'Species', '9606', (31, 39))	('muL', 'Gene', (117, 120))	('muL', 'Gene', (100, 103))	('better', 'PosReg', (12, 18))
133579	27042127	The milestone of long-term cancer survivals in patients treated with anti-CTLA-4 antibodies opened a door to immune therapy with immune checkpoint inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('antibodies', 'Var', (81, 91))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('anti-CTLA-4', 'Gene', (69, 80))	('anti-CTLA-4 antibodies', 'Var', (69, 91))
133582	27042127	The use of anti-CTLA-4 antibodies, including tremelimumab, leads to strong immune-related side effects, although the majority of them are treatable.	('anti-CTLA-4', 'Gene', (11, 22))	('anti-CTLA-4', 'Var', (11, 22))	('immune-related', 'MPA', (75, 89))	('tremelimumab', 'Chemical', 'MESH:C520704', (45, 57))
133629	32391074	C1407C3 mouse IgG2a control mAb was injected at the same times and doses.	('IgG2a', 'cellular_component', 'GO:0071735', ('14', '19'))	('IgG2a', 'Gene', (14, 19))	('C1407C3', 'Var', (0, 7))	('mouse', 'Species', '10090', (8, 13))	('IgG2a', 'Gene', '668478', (14, 19))
133661	32391074	IFN-gamma neutralization resulted in a suppression of LDV-induced preventive effect as complete as NK cell depletion (Fig.	('suppression', 'NegReg', (39, 50))	('neutralization', 'Var', (10, 24))	('LDV', 'Species', '11048', (54, 57))
133676	32391074	This and other observations that experimental LDV infection reduces the development of other cancer types through activation of the immune system rather than through direct oncolytic effect may thus support the hypothesis that modulation of the immune microenvironment by some pathogens leads to enhancement of immunosurveillance capacity of the infected host against some cancer types.	('modulation', 'Var', (227, 237))	('enhancement', 'PosReg', (296, 307))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('infected', 'Disease', (346, 354))	('cancer', 'Disease', (373, 379))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('LDV', 'Species', '11048', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('immunosurveillance capacity', 'CPA', (311, 338))	('infection', 'Disease', (50, 59))	('reduces', 'NegReg', (60, 67))	('infection', 'Disease', 'MESH:D007239', (50, 59))	('infected', 'Disease', 'MESH:D007239', (346, 354))
133741	30349836	Other etiologies include para-exposure, such as laundering the clothes of an exposed person, therapeutic irradiation, chronic inflammatory peritonitis, and simian virus-40.	('simian', 'Var', (156, 162))	('inflammatory peritonitis', 'Disease', 'MESH:D010534', (126, 150))	('inflammatory peritonitis', 'Disease', (126, 150))	('para-exposure', 'Disease', (25, 38))	('peritonitis', 'Phenotype', 'HP:0002586', (139, 150))	('simian virus-40', 'Species', '1891767', (156, 171))	('person', 'Species', '9606', (85, 91))
133781	26968202	The vector used in this trial, originally called SCH 721015 (Ad.hIFN-alpha2b), is a clinical-grade, serotype 5, E1/partial E3-deleted replication-incompetent adenovirus with insertion of the human IFN-alpha2b gene in the E1 region of the adenoviral genome.	('IFN', 'Gene', (197, 200))	('IFN', 'Gene', '3439', (65, 68))	('insertion', 'Var', (174, 183))	('human', 'Species', '9606', (191, 196))	('IFN', 'Gene', '3439', (197, 200))	('IFN', 'Gene', (65, 68))
133825	26968202	Most patients experienced only expected mild toxicities from the vector and transgene expression, including cytokine release syndrome, nausea, fatigue, anemia, lymphopenia (grade 3-4), and hypoalbuminemia (Table 2A).	('fatigue', 'Phenotype', 'HP:0012378', (143, 150))	('toxicities', 'Disease', (45, 55))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (189, 204))	('anemia', 'Phenotype', 'HP:0001903', (152, 158))	('nausea', 'Phenotype', 'HP:0002018', (135, 141))	('lymphopenia', 'Disease', 'MESH:D008231', (160, 171))	('anemia', 'Disease', (152, 158))	('patients', 'Species', '9606', (5, 13))	('hypoalbuminemia', 'Disease', (189, 204))	('nausea', 'Disease', (135, 141))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (189, 204))	('fatigue', 'Disease', 'MESH:D005221', (143, 150))	('cytokine release syndrome', 'Disease', (108, 133))	('transgene', 'Var', (76, 85))	('nausea', 'Disease', 'MESH:D009325', (135, 141))	('lymphopenia', 'Disease', (160, 171))	('anemia', 'Disease', 'MESH:D000740', (152, 158))	('lymphopenia', 'Phenotype', 'HP:0001888', (160, 171))	('toxicities', 'Disease', 'MESH:D064420', (45, 55))	('fatigue', 'Disease', (143, 150))
133840	26968202	All but two of the deceased patients died of progressive disease, with one patient dying from esophageal perforation status post proton-beam radiotherapy (5 months) and another from a BAP-1 deficiency-related metastatic uveal melanoma (40 months).	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('BAP-1', 'Gene', (184, 189))	('esophageal perforation status', 'Disease', (94, 123))	('patient', 'Species', '9606', (28, 35))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('deficiency-related', 'Var', (190, 208))	('patients', 'Species', '9606', (28, 36))	('patient', 'Species', '9606', (75, 82))	('BAP-1', 'Gene', '8314', (184, 189))
133970	27026891	Growth of MSTO-211H cells in vitro was faster than that of EHMES-10 cells, which was attributable to greater tumor weights of MSTO-211H cells than EHMES-10 cells.	('EHMES-10', 'CellLine', 'CVCL:M208', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('greater', 'PosReg', (101, 108))	('MSTO-211H', 'CellLine', 'CVCL:1430', (126, 135))	('MSTO-211H', 'CellLine', 'CVCL:1430', (10, 19))	('faster', 'PosReg', (39, 45))	('Growth', 'CPA', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('EHMES-10', 'CellLine', 'CVCL:M208', (147, 155))	('tumor', 'Disease', (109, 114))	('MSTO-211H', 'Var', (126, 135))
133982	27026891	Consequently, gammadelta Taucells bearing the Vgamma9 Vdelta2 T cell receptors were activated by ZOL-treated cells (Benzaid et al.)	('Vdelta2 T', 'CellLine', 'CVCL:0042', (54, 63))	('ZOL', 'Chemical', 'MESH:D000077211', (97, 100))	('Vgamma9', 'Var', (46, 53))	('activated', 'PosReg', (84, 93))
134046	27026891	conducted a clinical trial for patients with peritoneal dissemination by administering Vgamma9 Vdelta2 T cells and 1 mg of ZOL into the peritoneal cavity to activate the gammadelta T cells.	('activate', 'PosReg', (157, 165))	('ZOL', 'Chemical', 'MESH:D000077211', (123, 126))	('patients', 'Species', '9606', (31, 39))	('Vgamma9', 'Var', (87, 94))	('Vdelta2 T', 'CellLine', 'CVCL:0042', (95, 104))
134202	24039630	Based on these results, they developed a prediction model where patients who have tumor > 5 cm in the epigastric region and have nodular thickening of the small bowel with mesentery involvement have a 100% probability of a suboptimal resection, whereas patients who lack these two CT scan findings have a 94% probability of adequate cytoreduction.	('small bowel', 'Disease', 'MESH:D015212', (155, 166))	('suboptimal resection', 'CPA', (223, 243))	('men', 'Species', '9606', (189, 192))	('patients', 'Species', '9606', (64, 72))	('small bowel', 'Disease', (155, 166))	('patients', 'Species', '9606', (253, 261))	('nodular thickening', 'Var', (129, 147))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
134229	19221091	As the first step in evaluating the therapeutic potential of MCAM-targeting antibodies, we performed single-photon emission computed tomography studies using the anti-MCAM scFv and found that it recognizes mesothelioma organotypic xenografts in vivo.	('mesothelioma', 'Disease', (206, 218))	('scFv', 'Gene', '652070', (172, 176))	('scFv', 'Gene', (172, 176))	('anti-MCAM', 'Var', (162, 171))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('anti-MCAM', 'Gene', (162, 171))
134257	19221091	Reagents for scFv purification and characterization: nitrilotriacetic acid-nickel (Ni-NTA) agarose beads (Qiagen, Hilden, Germany), EZ-Link Sulfo-NHS-LC-Biotin (Pierce, Rockfold, IL), and streptavidin Qdot 705 conjugate (Invitrogen).	('scFv', 'Gene', '652070', (13, 17))	('agarose', 'Chemical', 'MESH:D012685', (91, 98))	('scFv', 'Gene', (13, 17))	('EZ-Link Sulfo-NHS-LC-Biotin', 'Chemical', '-', (132, 159))	('Qdot 705', 'Chemical', '-', (201, 209))	('EZ-Link', 'Var', (132, 139))	('Ni-NTA', 'Chemical', '-', (83, 89))	('nitrilotriacetic acid-nickel', 'Chemical', '-', (53, 81))
134279	19221091	A near infrared fluorescent nanometer crystal with a polymer shell directly coupled to streptavidin (Qdot streptavidin 705 conjugate, Invitrogen) was conjugated to the anti-MCAM scFv or control scFv in two steps.	('anti-MCAM', 'Var', (168, 177))	('scFv', 'Gene', '652070', (178, 182))	('scFv', 'Gene', (178, 182))	('scFv', 'Gene', (194, 198))	('scFv', 'Gene', '652070', (194, 198))
134304	19221091	We used a similar strategy (Figure 1) to identify the M1-targeted mesothelioma antigen using the M1 phage antibody as the "bait" to select binding clones from the yeast surface cDNA display library by FACS.	('antibody', 'cellular_component', 'GO:0042571', ('106', '114'))	('antibody', 'cellular_component', 'GO:0019815', ('106', '114'))	('mesothelioma', 'Disease', (66, 78))	('antibody', 'cellular_component', 'GO:0019814', ('106', '114'))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('antibody', 'molecular_function', 'GO:0003823', ('106', '114'))	('clones', 'Var', (147, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('yeast', 'Species', '4932', (163, 168))
134320	19221091	The cells bound by the anti-MCAM scFv were confirmed to be mesothelioma cells by cytokeratin stain (Figure 5A).	('mesothelioma', 'Disease', (59, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('scFv', 'Gene', '652070', (33, 37))	('scFv', 'Gene', (33, 37))	('anti-MCAM', 'Var', (23, 32))
134324	19221091	Mice carrying peritoneally-implanted human mesothelioma tissues were injected with either 99mTc-labeled anti-MCAM M1 scFv or a 99mTc-labeled control scFv and imaged with SPECT/CT.	('mesothelioma', 'Disease', (43, 55))	('scFv', 'Gene', (117, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('scFv', 'Gene', '652070', (117, 121))	('scFv', 'Gene', '652070', (149, 153))	('anti-MCAM', 'Var', (104, 113))	('scFv', 'Gene', (149, 153))	('human', 'Species', '9606', (37, 42))	('Mice', 'Species', '10090', (0, 4))
134329	19221091	Next, we performed biodistribution studies using the 99mTc-labeled anti-MCAM and control scFvs.	('anti-MCAM', 'Var', (67, 76))	('scFv', 'Gene', '652070', (89, 93))	('scFv', 'Gene', (89, 93))
134331	19221091	The anti-MCAM scFv showed higher tumor accumulation in mice carrying mesothelioma tissue xenografts than the control scFv (Figure 6A), demonstrating targeting specificity of the anti-MCAM scFv.	('scFv', 'Gene', (14, 18))	('higher', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('anti-MCAM', 'Var', (4, 13))	('scFv', 'Gene', '652070', (14, 18))	('scFv', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('scFv', 'Gene', '652070', (117, 121))	('mesothelioma', 'Disease', (69, 81))	('mice', 'Species', '10090', (55, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('tumor', 'Disease', (33, 38))	('scFv', 'Gene', '652070', (188, 192))	('scFv', 'Gene', (188, 192))
134350	19221091	Using human tumor fragments cultured ex vivo, we showed that the anti-MCAM scFv penetrates the tumor fragments and homes specifically to primary mesothelioma cells.	('human', 'Species', '9606', (6, 11))	('scFv', 'Gene', '652070', (75, 79))	('anti-MCAM', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mesothelioma', 'Disease', (145, 157))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (137, 157))	('tumor', 'Disease', (12, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))	('tumor', 'Disease', (95, 100))	('scFv', 'Gene', (75, 79))
134352	19221091	The in vivo biodistribution of the anti-MCAM M1 scFv was evaluated in a novel mesothelioma organotypic xenograft model using SPECT/CT.	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('scFv', 'Gene', '652070', (48, 52))	('scFv', 'Gene', (48, 52))	('anti-MCAM', 'Var', (35, 44))	('mesothelioma', 'Disease', (78, 90))
134354	19221091	We found that the anti-MCAM M1 scFv, but not the control scFv, preferentially accumulated in mesothelioma xenografts compared to surrounding soft tissues, demonstrating its potential in noninvasive imaging and targeted immunotherapy.	('mesothelioma xenografts', 'Disease', 'MESH:D008654', (93, 116))	('mesothelioma xenografts', 'Disease', (93, 116))	('preferentially', 'PosReg', (63, 77))	('scFv', 'Gene', '652070', (57, 61))	('scFv', 'Gene', (31, 35))	('anti-MCAM', 'Var', (18, 27))	('scFv', 'Gene', '652070', (31, 35))	('accumulated', 'PosReg', (78, 89))	('scFv', 'Gene', (57, 61))
134387	30941737	Inhibition of COX-2 has been reported to reverse malignant behaviour such as antiapoptosis, angiogenesis and invasion and epidemiological evidence suggests that regular use of COX-2 inhibitors may reduce the risk of several cancers.	('COX-2', 'Gene', '5743', (14, 19))	('behaviour', 'biological_process', 'GO:0007610', ('59', '68'))	('invasion', 'CPA', (109, 117))	('COX-2', 'Gene', (14, 19))	('reduce', 'NegReg', (197, 203))	('COX-2', 'Gene', '5743', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('angiogenesis', 'CPA', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('inhibitors', 'Var', (182, 192))	('Inhibition', 'Var', (0, 10))	('antiapoptosis', 'CPA', (77, 90))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('malignant behaviour', 'CPA', (49, 68))	('cancers', 'Disease', (224, 231))	('angiogenesis', 'biological_process', 'GO:0001525', ('92', '104'))	('COX-2', 'Gene', (176, 181))
134388	30941737	We have previously shown using immunohistochemistry (IHC) that COX-2 is overexpressed in MPM and that the specific COX-2 inhibitor DuP-697 can potentiate the in vitro cytotoxic effects of pemetrexed in MPM cell lines.	('DuP-697', 'Var', (131, 138))	('COX-2', 'Gene', (115, 120))	('COX-2', 'Gene', '5743', (115, 120))	('DuP-697', 'Chemical', 'MESH:C064874', (131, 138))	('potentiate', 'PosReg', (143, 153))	('pemetrexed', 'Chemical', 'MESH:D000068437', (188, 198))	('MPM', 'Chemical', '-', (89, 92))	('MPM', 'Chemical', '-', (202, 205))	('COX-2', 'Gene', (63, 68))	('COX-2', 'Gene', '5743', (63, 68))
134389	30941737	Functional interactions between COX-2 and LOX enzymes have been identified and, of the three known LOX isoenzymes (5-LOX, 12-LOX and 15-LOX), 5-LOX and 12-LOX have also been implicated in carcinogenesis.	('12-LOX', 'Gene', (152, 158))	('12-LOX', 'Gene', (122, 128))	('12-LOX', 'Gene', '239', (152, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('interactions', 'Interaction', (11, 23))	('15-LOX', 'Gene', (133, 139))	('COX-2', 'Gene', (32, 37))	('COX-2', 'Gene', '5743', (32, 37))	('carcinogenesis', 'Disease', (188, 202))	('15-LOX', 'Gene', '246', (133, 139))	('12-LOX', 'Gene', '239', (122, 128))	('5-LOX', 'Var', (142, 147))	('implicated', 'Reg', (174, 184))
134395	30941737	The expression of 5-LOX and 12-LOX has been associated with carcinogenesis in various solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('carcinogenesis', 'Disease', (60, 74))	('12-LOX', 'Gene', (28, 34))	('5-LOX', 'Var', (18, 23))	('12-LOX', 'Gene', '239', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('associated with', 'Reg', (44, 59))
134409	30941737	Incubations with anti 5-LOX (#ab169755, Abcam) or anti 12-LOX (#ab23678, Abcam) antibodies were performed using a dilution of 1:100 for 2 h. Negative (antibody-omitted) control and positive control slides, which consisted of archival colorectal cancer tissue, were included in each batch.	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('antibody', 'cellular_component', 'GO:0042571', ('151', '159'))	('#ab169755', 'Var', (29, 38))	('antibody', 'cellular_component', 'GO:0019815', ('151', '159'))	('archival colorectal cancer', 'Disease', 'MESH:D015179', (225, 251))	('archival colorectal cancer', 'Disease', (225, 251))	('antibody', 'cellular_component', 'GO:0019814', ('151', '159'))	('#ab23678', 'Var', (63, 71))	('12-LOX', 'Gene', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('antibody', 'molecular_function', 'GO:0003823', ('151', '159'))	('12-LOX', 'Gene', '239', (55, 61))
134420	30941737	Membranes were blocked in 5% non-fat milk before samples were probed for 2 h with the anti 5-LOX antibody (#ab39347, Abcam) at a final concentration of 1:250 and the anti 12-LOX antibody (#ab23678, Abcam) at a final concentration of 1:500.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('antibody', 'molecular_function', 'GO:0003823', ('178', '186'))	('12-LOX', 'Gene', (171, 177))	('#ab39347', 'Var', (107, 115))	('12-LOX', 'Gene', '239', (171, 177))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('#ab23678', 'Var', (188, 196))	('antibody', 'cellular_component', 'GO:0042571', ('178', '186'))	('antibody', 'cellular_component', 'GO:0019815', ('178', '186'))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('antibody', 'cellular_component', 'GO:0019814', ('178', '186'))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))
134433	30941737	Overall, the expression of 5-LOX was not associated with survival (p = 0.640), however when considering only the sarcomatoid subtype the positive expression of 5-LOX was significantly associated with improved survival (median survival 4.2 months versus 1 month in 5-LOX negative cases; p = 0.028) (online resource 1).	('5-LOX', 'Var', (160, 165))	('sarcomatoid', 'Disease', 'MESH:C538614', (113, 124))	('improved', 'PosReg', (200, 208))	('sarcomatoid', 'Disease', (113, 124))	('survival', 'MPA', (209, 217))
134438	30941737	In univariate analysis cases demonstrating a COX-2 positive /12-LOX negative status or co-expression of COX-2 with 12-LOX were associated with longer survival (online resource 1).	('12-LOX', 'Gene', (61, 67))	('COX-2', 'Gene', (104, 109))	('COX-2', 'Gene', '5743', (45, 50))	('COX-2', 'Gene', '5743', (104, 109))	('12-LOX', 'Gene', '239', (61, 67))	('longer', 'PosReg', (143, 149))	('co-expression', 'Var', (87, 100))	('12-LOX', 'Gene', (115, 121))	('12-LOX', 'Gene', '239', (115, 121))	('COX-2', 'Gene', (45, 50))
134452	30941737	The co-expression of COX-2 with 5-LOX was associated with improved survival in this cohort and, in the sarcomatoid subtype only, the expression of 5-LOX was associated with improved prognosis however these preliminary findings require further confirmation using a larger number of cases.	('COX-2', 'Gene', '5743', (21, 26))	('improved', 'PosReg', (58, 66))	('co-expression', 'Var', (4, 17))	('sarcomatoid', 'Disease', (103, 114))	('survival', 'MPA', (67, 75))	('improved', 'PosReg', (173, 181))	('sarcomatoid', 'Disease', 'MESH:C538614', (103, 114))	('COX-2', 'Gene', (21, 26))
134589	29068368	While there no village in Nevsehir that has recorded asbestos exposure, the presence of erionite in the Cappadocia region also increased the risk for MM in this city.	('erionite', 'Chemical', 'MESH:C083174', (88, 96))	('MM in', 'Disease', (150, 155))	('presence', 'Var', (76, 84))	('asbestos', 'Chemical', 'MESH:D001194', (53, 61))
134614	28348450	A Novel Panel of Serum Biomarkers for MPM Diagnosis Exposure to asbestos is the main cause of malignant pleural mesothelioma (MPM), a highly aggressive cancer of the pleura.	('MPM', 'Chemical', '-', (38, 41))	('aggressive cancer', 'Disease', 'MESH:D009369', (141, 158))	('cancer of the pleura', 'Phenotype', 'HP:0100527', (152, 172))	('aggressive cancer', 'Disease', (141, 158))	('cause', 'Reg', (85, 90))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (94, 124))	('Exposure', 'Var', (52, 60))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (104, 124))	('malignant pleural mesothelioma', 'Disease', (94, 124))	('asbestos', 'Chemical', 'MESH:D001194', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MPM', 'Chemical', '-', (126, 129))
134650	28348450	E95422Hu), and TIMP3 ELISA kit by Abcam (cat.	('cat', 'molecular_function', 'GO:0004096', ('41', '44'))	('TIMP3', 'Gene', '7078', (15, 20))	('E95422Hu', 'Var', (0, 8))	('TIMP3', 'Gene', (15, 20))
134731	27091358	Molecular testing performed on the PAC showed negativity for EGFR, KRAS/NRAS/BRAF gene mutations and ALK fusion protein.	('NRAS', 'Gene', (72, 76))	('ALK', 'Gene', (101, 104))	('PAC', 'Phenotype', 'HP:0030078', (35, 38))	('BRAF', 'Gene', '673', (77, 81))	('NRAS', 'Gene', '4893', (72, 76))	('PAC', 'Phenotype', 'HP:0006699', (35, 38))	('KRAS', 'Gene', (67, 71))	('BRAF', 'Gene', (77, 81))	('ALK', 'Gene', '238', (101, 104))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('KRAS', 'Gene', '3845', (67, 71))	('EGFR', 'Gene', '1956', (61, 65))	('mutations', 'Var', (87, 96))	('EGFR', 'Gene', (61, 65))
134743	27091358	PAC had somatic mutation of ERBB4 (300 fs, 301 fs) and STK11 (E65G), as well as TP53 (P72R) and KDR (Q472H) with the possibility of the germline mutations.	('STK11', 'Gene', '6794', (55, 60))	('PAC', 'Phenotype', 'HP:0030078', (0, 3))	('KDR', 'Gene', (96, 99))	('PAC', 'Phenotype', 'HP:0006699', (0, 3))	('ERBB4', 'Gene', '2066', (28, 33))	('TP53', 'Gene', '7157', (80, 84))	('P72R', 'Mutation', 'rs1042522', (86, 90))	('TP53', 'Gene', (80, 84))	('STK11', 'molecular_function', 'GO:0033868', ('55', '60'))	('ERBB4', 'Gene', (28, 33))	('E65G', 'Var', (62, 66))	('STK11', 'Gene', (55, 60))	('KDR', 'Gene', '3791', (96, 99))	('Q472H', 'Mutation', 'rs1870377', (101, 106))	('E65G', 'Mutation', 'p.E65G', (62, 66))	('P72R', 'Var', (86, 90))
134750	27091358	Deletion of 9p21, encoding the CDK inhibitors, p16INK4a, p14ARF and p15INK4b, has been observed in up to 80 % of mesotheliomas.	('mesotheliomas', 'Disease', (113, 126))	('p15INK4b', 'Gene', '1030', (68, 76))	('p14ARF', 'Gene', (57, 63))	('p15INK4b', 'Gene', (68, 76))	('9p21', 'Gene', (12, 16))	('p16INK4a', 'Gene', (47, 55))	('p14ARF', 'Gene', '1029', (57, 63))	('p16INK4a', 'Gene', '1029', (47, 55))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('mesotheliomas', 'Disease', 'MESH:D008654', (113, 126))	('observed', 'Reg', (87, 95))	('Deletion', 'Var', (0, 8))
134752	27091358	Allelic loss of NF2, located at 22q12.2, has been reported in up to 70 % of mesotheliomas.	('NF2', 'Gene', '4771', (16, 19))	('mesotheliomas', 'Disease', 'MESH:D008654', (76, 89))	('Allelic loss', 'Var', (0, 12))	('NF2', 'Gene', (16, 19))	('mesotheliomas', 'Disease', (76, 89))	('reported', 'Reg', (50, 58))
134753	27091358	Loss of chromosome 17p13.1, encoding the p53 gene TP53, is also a common and important change in mesothelioma.	('p53', 'Gene', '7157', (41, 44))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('TP53', 'Gene', '7157', (50, 54))	('mesothelioma', 'Disease', (97, 109))	('TP53', 'Gene', (50, 54))	('Loss', 'Var', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('p53', 'Gene', (41, 44))
134758	27091358	An investigation of LOH and TP53 mutation by Inamura et al.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))
134767	27091358	CA19-9 carbohydrate antigen 19-9 CEA carcinoembryonic antigen CN copy number CNA copy number alteration CT computed tomography CYFRA cytokeratin fragment FFPE formalin-fixed paraffin-embedded IHC immunohistochemistry LOH loss of heterozygosity MPM malignant pleural mesothelioma NGS next-generation sequencing NSE neuron-specific enolase PAC primary pulmonary adenocarcinoma Pro-GRP pro-gastrin-releasing peptide SCC squamous cell carcinoma antigen	('Pro-GRP', 'Gene', (375, 382))	('loss', 'Var', (221, 225))	('pro-gastrin-releasing peptide', 'Gene', '2922', (383, 412))	('carcinoma', 'Phenotype', 'HP:0030731', (431, 440))	('squamous cell carcinoma', 'Disease', (417, 440))	('NSE', 'Gene', '2026', (310, 313))	('formalin', 'Chemical', 'MESH:D005557', (159, 167))	('primary pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (342, 374))	('NSE', 'Gene', (310, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('primary pulmonary adenocarcinoma', 'Disease', (342, 374))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (248, 278))	('carcinoembryonic antigen', 'Gene', (37, 61))	('SCC', 'Gene', '6317', (413, 416))	('pro-gastrin-releasing peptide', 'Gene', (383, 412))	('PAC', 'Phenotype', 'HP:0030078', (338, 341))	('SCC', 'Gene', (413, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (417, 440))	('CEA', 'Gene', (33, 36))	('neuron-specific enolase', 'Gene', (314, 337))	('Pro-GRP', 'Gene', '2922', (375, 382))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (258, 278))	('paraffin', 'Chemical', 'MESH:D010232', (174, 182))	('carcinoembryonic antigen', 'Gene', '1084', (37, 61))	('neuron-specific enolase', 'Gene', '2026', (314, 337))	('PAC', 'Phenotype', 'HP:0006699', (338, 341))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (350, 374))	('malignant pleural mesothelioma', 'Disease', (248, 278))	('CEA', 'Gene', '1084', (33, 36))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (417, 440))
134829	22371455	We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MPM', 'Disease', (56, 59))	('tumor', 'Disease', (63, 68))	('aggressiveness', 'Disease', (105, 119))	('promote', 'PosReg', (30, 37))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (105, 119))	('MSLN', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('metastases', 'Disease', (137, 147))	('aggressiveness', 'Disease', 'MESH:D001523', (105, 119))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
134832	22371455	MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells.	('MMP secretion', 'biological_process', 'GO:1990773', ('47', '60'))	('promotes', 'PosReg', (16, 24))	('MMP secretion', 'CPA', (47, 60))	('MPM cell invasion', 'CPA', (25, 42))	('expression', 'Var', (5, 15))	('human', 'Species', '9606', (69, 74))	('MMP', 'molecular_function', 'GO:0004235', ('47', '50'))	('MSLN', 'Gene', (0, 4))	('murine', 'Species', '10090', (79, 85))
134836	22371455	Our data provide evidence elucidating a biological role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN-expressing MPM.	('MMP-9', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('MSLN-expressing', 'Var', (126, 141))	('MMP-9', 'molecular_function', 'GO:0004229', ('106', '111'))	('promoting', 'PosReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('expression', 'MPA', (112, 122))
134846	22371455	We demonstrate for the first time that MSLN promotes MMP-9 expression as well as tumor invasion shown by MSLN forced overexpression and confirmed by shRNA knockdown experiments in mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('promotes', 'PosReg', (44, 52))	('MMP-9', 'molecular_function', 'GO:0004229', ('53', '58'))	('MSLN', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('expression', 'MPA', (59, 69))	('overexpression', 'PosReg', (117, 131))	('mesothelioma', 'Disease', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('rat', 'Species', '10116', (10, 13))	('MMP-9', 'Protein', (53, 58))	('tumor', 'Disease', (81, 86))
134848	22371455	With this model, we demonstrate that MSLN-expressing MPM cells are invasive, express MMP-9 on the invasive tumor edge, and decrease overall survival independent of tumor cell proliferation or metastasis.	('MMP-9', 'Gene', (85, 90))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('overall survival', 'MPA', (132, 148))	('decrease', 'NegReg', (123, 131))	('MSLN-expressing', 'Var', (37, 52))	('tumor', 'Disease', (107, 112))	('MMP-9', 'molecular_function', 'GO:0004229', ('85', '90'))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('rat', 'Species', '10116', (182, 185))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('express', 'Reg', (77, 84))
134899	22371455	Similarly, we observed no differences in morphology or log-phase growth rates between AB12 cells transfected with control scramble shRNA or MSLN-specific shRNA (data not shown).	('MSLN-specific', 'Var', (140, 153))	('log-phase growth rates', 'CPA', (55, 77))	('rat', 'Species', '10116', (72, 75))
134902	22371455	MSLN overexpression in MSTO-211H significantly increased cell migration(2.56-fold, p<0.001) and invasion(1.54-fold, p<0.001) compared to non-MSLN expressing MPM cells (Fig.	('MSTO-211H', 'Chemical', '-', (23, 32))	('overexpression', 'PosReg', (5, 19))	('invasion', 'CPA', (96, 104))	('increased', 'PosReg', (47, 56))	('cell migration', 'biological_process', 'GO:0016477', ('57', '71'))	('MSTO-211H', 'Var', (23, 32))	('cell migration', 'CPA', (57, 71))	('rat', 'Species', '10116', (65, 68))
134904	22371455	These results demonstrate that MSLN overexpression promotes invasion in MPM cells.	('MSLN', 'Gene', (31, 35))	('invasion', 'CPA', (60, 68))	('promotes', 'PosReg', (51, 59))	('rat', 'Species', '10116', (21, 24))	('overexpression', 'Var', (36, 50))
134922	22371455	Serial BLI was used to monitor tumors in mice and revealed no differences in tumor burden between tumors with or without MSLN expression at any point in disease progression (Fig.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (41, 45))	('tumors', 'Disease', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('expression', 'Var', (126, 136))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (77, 82))	('MSLN', 'Gene', (121, 125))
134923	22371455	Despite equivalent tumor progression rates and tumor burden, mice with MSLN-expressing MPM experienced significantly decreased survival compared to mice with MSLN-negative tumors (29 vs. 37 days, p=0.001; Fig.	('MSLN-expressing', 'Var', (71, 86))	('survival', 'CPA', (127, 135))	('tumor', 'Disease', (172, 177))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mice', 'Species', '10090', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('MPM', 'Gene', (87, 90))	('rat', 'Species', '10116', (37, 40))	('decreased', 'NegReg', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
134924	22371455	These results of decreased survival with MSLN expression were reproduced in our syngeneic orthotopic MPM model using BALB/c mice with murine AB12 MPM cells.	('expression', 'Var', (46, 56))	('decreased', 'NegReg', (17, 26))	('mice', 'Species', '10090', (124, 128))	('murine', 'Species', '10090', (134, 140))	('MSLN', 'Gene', (41, 45))
134927	22371455	We observed decreased survival of mice inoculated with these high MSLN expressing AB12 cells compared to AB12 wild-type cells (24 vs 30 days, p=0.005; Supplemental Figure 1).	('AB12', 'Gene', (82, 86))	('survival', 'CPA', (22, 30))	('mice', 'Species', '10090', (34, 38))	('high MSLN expressing', 'Var', (61, 81))	('decreased', 'NegReg', (12, 21))
134947	22371455	Tumors that are known to express MSLN including MPM, pancreatic, and serous ovarian cancers are characterized by locoregional aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (126, 140))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MSLN', 'Var', (33, 37))	('aggressiveness', 'Disease', (126, 140))	('pancreatic', 'Disease', (53, 63))	('pancreatic', 'Disease', 'MESH:D010195', (53, 63))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('aggressiveness', 'Phenotype', 'HP:0000718', (126, 140))	('Tumors', 'Disease', (0, 6))	('serous ovarian cancers', 'Disease', (69, 91))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancers', 'Phenotype', 'HP:0100615', (76, 91))	('MPM', 'Disease', (48, 51))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (69, 91))
134953	22371455	In this study, we have shown that MSLN overexpression increases tumor cell MMP secretion, whereas shRNA knockdown of MSLN decreases MMP secretion in mesothelioma(Fig.	('MMP', 'molecular_function', 'GO:0004235', ('75', '78'))	('MMP secretion', 'biological_process', 'GO:1990773', ('132', '145'))	('MSLN decreases MMP secretion in mesothelioma', 'Disease', 'MESH:D008654', (117, 161))	('MSLN overexpression increases tumor', 'Disease', (34, 69))	('MSLN decreases MMP secretion in mesothelioma', 'Disease', (117, 161))	('MSLN overexpression increases tumor', 'Disease', 'MESH:D009369', (34, 69))	('MMP', 'molecular_function', 'GO:0004235', ('132', '135'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('MMP secretion', 'biological_process', 'GO:1990773', ('75', '88'))	('knockdown', 'Var', (104, 113))
134970	22371455	Perturbations in Wnt1/beta-catenin or Ras pathways lead to the expression of MSLN in mammary and pancreatic adenocarcinomas.	('beta-catenin', 'Gene', '1499', (22, 34))	('Wnt1', 'Gene', (17, 21))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (97, 123))	('pancreatic adenocarcinomas', 'Disease', (97, 123))	('MSLN', 'Gene', (77, 81))	('expression', 'MPA', (63, 73))	('lead to', 'Reg', (51, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Ras pathways', 'Pathway', (38, 50))	('beta-catenin', 'Gene', (22, 34))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (97, 123))	('Perturbations', 'Var', (0, 13))	('Wnt1', 'Gene', '7471', (17, 21))	('mammary', 'Disease', (85, 92))
134997	33753750	They examined 25 potential driver genes and found a high rate of non-synonymous mutation in BAP1, confirmed frequent inactivating mutations in NF2, and described missense mutations in LATS1 and LATS2.	('LATS2', 'Gene', (194, 199))	('LATS2', 'Gene', '26524', (194, 199))	('LATS1', 'Gene', '9113', (184, 189))	('non-synonymous', 'MPA', (65, 79))	('inactivating', 'MPA', (117, 129))	('NF2', 'Gene', '4771', (143, 146))	('missense mutations', 'Var', (162, 180))	('BAP1', 'Gene', '8314', (92, 96))	('NF2', 'Gene', (143, 146))	('BAP1', 'Gene', (92, 96))	('LATS1', 'Gene', (184, 189))
135001	33753750	The Cancer Genome Atlas' (TCGA) comprehensive integrated genomic study of MPM, reported by Dr. Hmeljak and colleagues in 2018, identified prognostic molecular subsets independent of histology, and also defined a novel subtype with extensive loss of heterozygosity and mutations in TP53 and SETDB1.	('loss', 'NegReg', (241, 245))	('SETDB1', 'Gene', (290, 296))	('mutations', 'Var', (268, 277))	('MPM', 'Disease', (74, 77))	('SETDB1', 'Gene', '9869', (290, 296))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('TP53', 'Gene', '7157', (281, 285))	('TP53', 'Gene', (281, 285))
135014	33753750	Homozygous deletion of CDKN2A/B and MTAP occurred only as clonal events.	('CDKN2A/B', 'Gene', (23, 31))	('MTAP', 'Gene', (36, 40))	('CDKN2A/B', 'Gene', '1029;1030', (23, 31))	('MTAP', 'Gene', '4507', (36, 40))	('deletion', 'Var', (11, 19))
135017	33753750	High clonal copy number burden was associated with greater systemic inflammation as measured by neutrophil:lymphocyte and platelet:lymphocyte ratios.	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('systemic', 'CPA', (59, 67))	('High clonal copy number burden', 'Var', (0, 30))	('greater', 'PosReg', (51, 58))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('inflammation', 'Disease', (68, 80))
135019	33753750	Highly branched tumors also had higher neoantigen burden which is associated with immunoediting via HLA loss of heterozygosity and can lead to immune escape.	('lead to', 'Reg', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('higher', 'PosReg', (32, 38))	('immune escape', 'MPA', (143, 156))	('loss of', 'NegReg', (104, 111))	('neoantigen burden', 'MPA', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('Highly branched', 'Var', (0, 15))
135023	33753750	In other cancers, biomarkers have been identified that predict a patient's response to drugs; for instance, larotrectinib for TRK fusion-positive cancers.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('larotrectinib', 'Var', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TRK', 'Gene', (126, 129))	('patient', 'Species', '9606', (65, 72))	('TRK', 'Gene', '4914', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('larotrectinib', 'Chemical', 'MESH:C000609083', (108, 121))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
135081	33388517	However, there are GISTs that have a mutation of platelet-derived growth factor receptor alpha (PDGFRA) instead of c-KIT and therefore they do not show the characteristic CD117 positive immunostaining.	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (49, 94))	('GIST', 'Phenotype', 'HP:0100723', (19, 23))	('platelet-derived growth factor receptor alpha', 'Gene', (49, 94))	('PDGFRA', 'Gene', (96, 102))	('mutation', 'Var', (37, 45))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('49', '79'))	('PDGFRA', 'Gene', '5156', (96, 102))	('c-KIT', 'Gene', (115, 120))	('c-KIT', 'Gene', '3815', (115, 120))	('CD117', 'Gene', (171, 176))	('CD117', 'Gene', '3815', (171, 176))	('KIT', 'molecular_function', 'GO:0005020', ('117', '120'))
135082	33388517	The mutation analysis of c-KIT and PDGFRA is useful for confirming CD117 negative GIST.	('GIST', 'Phenotype', 'HP:0100723', (82, 86))	('PDGFRA', 'Gene', (35, 41))	('PDGFRA', 'Gene', '5156', (35, 41))	('c-KIT', 'Gene', (25, 30))	('mutation', 'Var', (4, 12))	('c-KIT', 'Gene', '3815', (25, 30))	('CD117', 'Gene', '3815', (67, 72))	('CD117', 'Gene', (67, 72))	('KIT', 'molecular_function', 'GO:0005020', ('27', '30'))
135083	33388517	reported an E-GIST of abdominal wall in a 40 years old patient with 24 cm sized tumor with low mitotic index (1/50 HPFs), in which tumor cells showed positivity for CD117, CD99, CD34, vimentin, and actin.	('positivity', 'Var', (150, 160))	('vimentin', 'cellular_component', 'GO:0045099', ('184', '192'))	('CD99', 'Gene', '4267', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('actin', 'Protein', (198, 203))	('GIST', 'Phenotype', 'HP:0100723', (14, 18))	('tumor', 'Disease', (131, 136))	('CD34', 'Gene', (178, 182))	('CD117', 'Gene', '3815', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('vimentin', 'Gene', '7431', (184, 192))	('vimentin', 'Gene', (184, 192))	('patient', 'Species', '9606', (55, 62))	('CD117', 'Gene', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('vimentin', 'cellular_component', 'GO:0045098', ('184', '192'))	('tumor', 'Disease', (80, 85))	('CD34', 'Gene', '947', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CD99', 'Gene', (172, 176))
135093	33388517	Though mesothelioma may resemble E-GIST in H&E stain, they are positive with calretinin, WT-1, cytokeratin 5/6, and D2-40 but are negative with CD 117 and CD34.	('CD34', 'Gene', (155, 159))	('are', 'Reg', (59, 62))	('H&E', 'Chemical', '-', (43, 46))	('with', 'Protein', (72, 76))	('cytokeratin 5/6', 'Gene', '3852', (95, 110))	('and', 'Var', (112, 115))	('cytokeratin 5/6', 'Gene', (95, 110))	('calretinin', 'Gene', '794', (77, 87))	('GIST', 'Phenotype', 'HP:0100723', (35, 39))	('CD 117', 'Gene', (144, 150))	('WT-1', 'Gene', (89, 93))	('mesothelioma', 'Disease', (7, 19))	('CD 117', 'Gene', '3815', (144, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (7, 19))	('WT-1', 'Gene', '7490', (89, 93))	('calretinin', 'Gene', (77, 87))	('CD34', 'Gene', '947', (155, 159))
135123	31998326	For influenza virus infections: 8-10 week-old female mice received an intravenous injection of 1 x 104 OT-I CD45.1+ CD8+ T cells from an uninfected OT-I female mouse of 8-10 weeks of age; 3 h later, mice were anesthetized with 2.5% isoflurane gas and were infected intranasally with influenza virus strain A/WSN/33 expressing OVA(257-264)(WSN-OVA(I); a gift from D. Topham, University of Rochester Medical Center).	('influenza virus infections', 'Disease', 'MESH:D007251', (4, 30))	('CD8', 'Gene', (116, 119))	('mice', 'Species', '10090', (199, 203))	('WSN', 'Gene', (308, 311))	('WSN', 'Gene', (339, 342))	('257-264', 'Var', (330, 337))	('WSN', 'Gene', '7489', (308, 311))	('WSN', 'Gene', '7489', (339, 342))	('isoflurane', 'Chemical', 'MESH:D007530', (232, 242))	('influenza virus', 'Species', '11309', (283, 298))	('CD8', 'Gene', '925', (116, 119))	('influenza virus infections', 'Disease', (4, 30))	('influenza virus', 'Species', '11309', (4, 19))	('mouse', 'Species', '10090', (160, 165))	('mice', 'Species', '10090', (53, 57))
135160	31998326	The frequency of donor OT-I T cells expressing Ki-67 was significantly less in day 22 intratumoral donor OT-I T cells compared to day 15 donor T cells [96.26 +- 1.5 % day 15 vs. 48.44 +- 20.29 % day 22; p < 0.001], indicating that fewer cells were proliferating at the later time point (Figures 1E,F).	('Ki-67', 'Var', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('less', 'NegReg', (71, 75))	('donor', 'Species', '9606', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('donor', 'Species', '9606', (17, 22))	('donor', 'Species', '9606', (137, 142))	('tumor', 'Disease', (91, 96))
135207	31998326	It is clear that intrinsic molecular pathways including signaling initiated by ligation of other surface molecules such as CD160, TIM-3, and CTLA-4 promote T cell inhibition and play a central role in T cell exhaustion.	('T cell inhibition', 'CPA', (156, 173))	('CTLA-4', 'Gene', (141, 147))	('CD160', 'Gene', (123, 128))	('TIM-3', 'Gene', '84868', (130, 135))	('CD160', 'Gene', '11126', (123, 128))	('ligation', 'Var', (79, 87))	('promote', 'PosReg', (148, 155))	('TIM-3', 'Gene', (130, 135))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (201, 218))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
135228	31998326	Conversely, donor OT-I T cells within the spleens of AE17sOVA mesothelioma-bearing mice did not display an exhausted phenotype, while T cells in the tumor DLN showed a partially exhausted phenotype when mice were challenged with AE17sOVA mesothelioma tumor cells.	('mesothelioma', 'Disease', 'MESH:D008654', (238, 250))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('mice', 'Species', '10090', (203, 207))	('AE17sOVA', 'Var', (53, 61))	('donor', 'Species', '9606', (12, 17))	('mesothelioma', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (238, 256))	('mice', 'Species', '10090', (83, 87))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (238, 256))	('tumor', 'Disease', (149, 154))	('mesothelioma', 'Disease', (238, 250))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('mesothelioma tumor', 'Disease', (238, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
135244	31998326	Like B16-OVA, we also believe that AE17sOVA tumors experience the loss of OVA-antigen over time, as we have found lower OVA expression levels in large tumors (unpublished data) and this loss could be reflective of immune evasion in response to SIINFEKL-specific CTLs.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('loss', 'NegReg', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('immune evasion', 'biological_process', 'GO:0051842', ('214', '228'))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('immune evasion', 'biological_process', 'GO:0042783', ('214', '228'))	('AE17sOVA', 'Var', (35, 43))	('lower', 'NegReg', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('OVA expression levels', 'MPA', (120, 141))
135333	31867277	Monocytes migrate toward malignant pleural fluid or mesothelioma cell line supernatant and neutralizing antibodies to CCL2 or CCR2 substantially reduce this migration in Transwell experiments.	('CCR', 'molecular_function', 'GO:0043880', ('126', '129'))	('CCR2', 'Gene', '729230', (126, 130))	('malignant pleural fluid or mesothelioma', 'Disease', (25, 64))	('neutralizing antibodies', 'Var', (91, 114))	('CCR2', 'Gene', (126, 130))	('CCL', 'molecular_function', 'GO:0044101', ('118', '121'))	('migration', 'CPA', (157, 166))	('CCL2', 'Gene', (118, 122))	('reduce', 'NegReg', (145, 151))	('malignant pleural fluid or mesothelioma', 'Disease', 'MESH:C562839', (25, 64))	('pleural fluid', 'Phenotype', 'HP:0002202', (35, 48))
135360	31867277	Although next generation sequencing of mesothelioma originally identified few neoepitope generating mutations, more recently mate-pair seq based analysis has identified higher numbers of neoepitope generating mutations which were probably from chromosomal rearrangements missed by NGS.	('neoepitope', 'Var', (187, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('mutations', 'Var', (209, 218))	('mesothelioma', 'Disease', (39, 51))
135362	31867277	While neoantigens may prompt T-cell activation and proliferation, various checkpoint molecules are also evident in the mesothelioma microenvironment and are discussed in more detail elsewhere in this issue.	('iron', 'Chemical', 'MESH:D007501', (140, 144))	('neoantigens', 'Var', (6, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('activation', 'PosReg', (36, 46))	('proliferation', 'CPA', (51, 64))	('T-cell activation', 'biological_process', 'GO:0042110', ('29', '46'))	('T-cell', 'CPA', (29, 35))	('mesothelioma', 'Disease', (119, 131))
135364	31867277	Of interest, PD-L1 expression is associated with a higher objective response rate to nivolumab but is not entirely predictive of response.	('nivolumab', 'Chemical', 'MESH:D000077594', (85, 94))	('expression', 'Var', (19, 29))	('PD-L1', 'Gene', (13, 18))	('objective response rate', 'MPA', (58, 81))	('higher', 'PosReg', (51, 57))
135377	31867277	Only one comparatively small study demonstrated a poorer prognosis in multivariate analyses of low CD8+ T-cell counts.	('CD8', 'Gene', (99, 102))	('low', 'Var', (95, 98))	('CD8', 'Gene', '925', (99, 102))	('low CD8+ T-cell count', 'Phenotype', 'HP:0005415', (95, 116))	('low CD8+ T-cell counts', 'Phenotype', 'HP:0005415', (95, 117))
135378	31867277	Interestingly, low CD8+ T-cell count was also a poor prognostic factor in patients undergoing extrapleural pneumonectomy.	('CD8', 'Gene', (19, 22))	('low', 'Var', (15, 18))	('CD8', 'Gene', '925', (19, 22))	('patients', 'Species', '9606', (74, 82))	('low CD8+ T-cell count', 'Phenotype', 'HP:0005415', (15, 36))
135392	31867277	Other modifications such as mutating the CAR CD3zeta Immunoreceptor Tyrosine-Based Activation Motifs have also been shown to prevent exhaustion in other disease models, and these principles are likely to be applicable to mesothelioma.	('mutating', 'Var', (28, 36))	('CD3zeta', 'Gene', (45, 52))	('Tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('mesothelioma', 'Disease', (221, 233))	('CAR', 'cellular_component', 'GO:0005826', ('41', '44'))	('exhaustion', 'MPA', (133, 143))	('prevent', 'NegReg', (125, 132))	('CD3zeta', 'Gene', '919', (45, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))
135403	31867277	Free radical species can also affect T-cell function by nitration of the T-cell receptor, downregulation of CD3zeta, and H2O2-mediated reduction in cytokine production.	('CD3zeta', 'Gene', '919', (108, 115))	('H2O2-mediated', 'Var', (121, 134))	('reduction', 'NegReg', (135, 144))	('H2O2', 'Chemical', 'MESH:D006861', (121, 125))	('reduction in cytokine production', 'Phenotype', 'HP:0031407', (135, 167))	('CD3zeta', 'Gene', (108, 115))	('nitration', 'Var', (56, 65))	('cytokine production', 'MPA', (148, 167))	('cytokine production', 'biological_process', 'GO:0001816', ('148', '167'))	('affect', 'Reg', (30, 36))	('downregulation', 'NegReg', (90, 104))	('T-cell receptor', 'Protein', (73, 88))	('T-cell function', 'CPA', (37, 52))
135427	31867277	Mast cells have been detected in mesothelioma tumors treated with IL-2 and high counts of tryptase-positive mast cells has been associated with a better prognosis but this is awaiting further confirmation.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mesothelioma tumors', 'Disease', (33, 52))	('IL-2', 'Gene', '3558', (66, 70))	('high', 'Var', (75, 79))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (33, 51))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (33, 52))	('IL-2', 'Gene', (66, 70))	('IL-2', 'molecular_function', 'GO:0005134', ('66', '70'))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mesothelioma tumors', 'Disease', 'MESH:D008654', (33, 52))
135459	31330086	These examples demonstrate how the identification of key mutations can clearly benefit a larger number of selected cancer patients, and illustrate the need to include a molecular taxonomy when establishing effective treatment plans.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
135480	31330086	Similar to other cancers, Src inhibition has been shown to reduce proliferation, migration and invasion in PDAC cell lines, as well as inhibits tumour progression and metastasis in vivo 43, 53, 54, 55, 56, 57.	('invasion', 'CPA', (95, 103))	('Src', 'Gene', (26, 29))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('inhibition', 'Var', (30, 40))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('proliferation', 'CPA', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('PDAC', 'Disease', (107, 111))	('tumour', 'Disease', (144, 150))	('reduce', 'NegReg', (59, 65))	('cancers', 'Disease', (17, 24))	('inhibits', 'NegReg', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('migration', 'CPA', (81, 90))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('PDAC', 'Disease', 'MESH:D021441', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
135481	31330086	Src can also promote the progression of PDAC by reducing tumour response to gemcitabine, one of the current standards of care chemotherapies for this cancer 58.	('PDAC', 'Disease', (40, 44))	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('PDAC', 'Disease', 'MESH:D021441', (40, 44))	('response to gemcitabine', 'biological_process', 'GO:0036272', ('64', '87'))	('tumour', 'Disease', (57, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (76, 87))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('Src', 'Var', (0, 3))	('promote', 'PosReg', (13, 20))	('reducing', 'NegReg', (48, 56))	('cancer', 'Disease', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
135488	31330086	In PDAC specifically, overexpression of integrin alphanubeta3/alphanubeta6 has been previously shown to associate with poor survival of patients as well as lymph node metastasis 59, 72, and recent findings indicate that the stromal localisation and levels of active alpha5beta1-integrin and FAK can identify two readily distinguishable desmoplastic phenotypes in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('alphanubeta3/alphanubeta6', 'Var', (49, 74))	('overexpression', 'PosReg', (22, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (363, 380))	('patients', 'Species', '9606', (136, 144))	('PDAC', 'Disease', 'MESH:D021441', (3, 7))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('pancreatic cancer', 'Disease', 'MESH:D010190', (363, 380))	('FAK', 'molecular_function', 'GO:0004717', ('291', '294'))	('PDAC', 'Disease', (3, 7))	('pancreatic cancer', 'Disease', (363, 380))	('localisation', 'biological_process', 'GO:0051179', ('232', '244'))
135499	31330086	PI 3-kinase (PI3K) signalling is another relevant, tumour-promoting and potentially druggable effector network activated through FAK/SFK 97, 98, 99.	('FAK/SFK 97', 'Var', (129, 139))	('PI 3-kinase', 'Gene', '5290', (0, 11))	('FAK', 'molecular_function', 'GO:0004717', ('129', '132'))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('signalling', 'biological_process', 'GO:0023052', ('19', '29'))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('PI 3-kinase', 'Gene', (0, 11))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('tumour', 'Disease', (51, 57))
135505	31330086	Furthermore, Akt signalling is present in preneoplastic lesions during pancreatic carcinogenesis induced by mutated Kras, and is associated with progression towards higher grade tumours and poorer patient survival 99, 107, 108, 109.	('mutated', 'Var', (108, 115))	('associated with', 'Reg', (129, 144))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (71, 96))	('patient', 'Species', '9606', (197, 204))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('Akt', 'Gene', '207', (13, 16))	('Kras', 'Gene', (116, 120))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('signalling', 'biological_process', 'GO:0023052', ('17', '27'))	('Kras', 'Gene', '3845', (116, 120))	('tumours', 'Disease', (178, 185))	('Akt', 'Gene', (13, 16))	('pancreatic carcinogenesis', 'Disease', (71, 96))
135506	31330086	Historically, the documented cases of activating Src mutations are rare, with only one major study in colon cancer documenting 12% of cases with a truncating mutation at codon 531 110, which when functionally validated, was shown to lead to increased Src specificity and transformation of NIH 3T3 cells.	('truncating mutation at codon 531 110', 'Var', (147, 183))	('increased', 'PosReg', (241, 250))	('transformation', 'CPA', (271, 285))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('colon cancer', 'Disease', (102, 114))	('Src specificity', 'MPA', (251, 266))
135509	31330086	In PDAC specifically, examination of multidimensional publically available cancer genomics datasets (TCGA, PanCan Atlas and QCMG cohorts) revealed that Src mutations occur at a frequency of less than 2% (Fig.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', (75, 81))	('Src', 'Gene', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('PDAC', 'Disease', 'MESH:D021441', (3, 7))	('PDAC', 'Disease', (3, 7))
135512	31330086	Several cancers, including glioblastoma, show modifications of the integrin pattern to be associated with tumour progression and poor patient survival, including alpha6beta4, alpha6beta1, alphavbeta6 and alphavbeta3 119.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('alpha6beta1', 'Var', (175, 186))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('alphavbeta6', 'Var', (188, 199))	('modifications', 'Reg', (46, 59))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('glioblastoma', 'Disease', (27, 39))	('associated', 'Reg', (90, 100))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('alphavbeta3 119', 'Var', (204, 219))	('tumour', 'Disease', (106, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('patient', 'Species', '9606', (134, 141))	('alpha6beta4', 'Var', (162, 173))
135513	31330086	An early sequencing study demonstrated a positive association between mutations in subunit alpha7 (encoded by ITGA7 gene), identified in 57% of prostate cancers, and increased cancer recurrence 120.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('prostate cancer', 'Phenotype', 'HP:0012125', (144, 159))	('prostate cancers', 'Disease', 'MESH:D011471', (144, 160))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (153, 159))	('increased', 'PosReg', (166, 175))	('ITGA7', 'Gene', '3679', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('prostate cancers', 'Phenotype', 'HP:0012125', (144, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('prostate cancers', 'Disease', (144, 160))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('ITGA7', 'Gene', (110, 115))
135517	31330086	Similar results have also been seen with alpha2beta1 in breast cancer, and alpha6beta4/ alpha6beta1 in oesophageal carcinoma 59.	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (103, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('alpha6beta4/ alpha6beta1', 'Var', (75, 99))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('alpha2beta1', 'Var', (41, 52))	('breast cancer', 'Disease', (56, 69))	('oesophageal carcinoma', 'Disease', (103, 124))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (103, 124))
135518	31330086	In PDAC, early sequencing studies identified genetic alterations in the integrin signalling pathway (ITGA4, ITGA9, ITGA11, LAMA1, LAMA4, LAMA5, FN1 and ILK) in 67% of tumours 18.	('signalling pathway', 'biological_process', 'GO:0007165', ('81', '99'))	('LAMA1', 'Gene', (123, 128))	('FN1', 'Gene', '2335', (144, 147))	('ITGA11', 'Gene', '22801', (115, 121))	('PDAC', 'Disease', 'MESH:D021441', (3, 7))	('PDAC', 'Disease', (3, 7))	('LAMA4', 'Gene', (130, 135))	('ITGA4', 'Gene', '3676', (101, 106))	('FN1', 'Gene', (144, 147))	('tumours', 'Disease', (167, 174))	('ITGA9', 'Gene', (108, 113))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('LAMA4', 'Gene', '3910', (130, 135))	('ITGA4', 'Gene', (101, 106))	('ILK', 'Gene', (152, 155))	('ILK', 'Gene', '3611', (152, 155))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('LAMA1', 'Gene', '284217', (123, 128))	('LAMA5', 'Gene', (137, 142))	('genetic alterations', 'Var', (45, 64))	('ITGA11', 'Gene', (115, 121))	('LAMA5', 'Gene', '3911', (137, 142))	('ITGA9', 'Gene', '3680', (108, 113))	('integrin signalling pathway', 'Pathway', (72, 99))
135522	31330086	An alternate mechanism involving a mutation in TP53 is thought to promote integrin alpha6beta4-mediated tumour cell survival 125.	('TP53', 'Gene', (47, 51))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('promote', 'PosReg', (66, 73))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('TP53', 'Gene', '7157', (47, 51))	('mutation', 'Var', (35, 43))	('tumour', 'Disease', (104, 110))
135524	31330086	Of > 7000 tumours examined, 63% harboured nonsilent somatic mutations or copy number alterations within the PI3K/AKT/mTOR pathway 127.	('tumours', 'Disease', (10, 17))	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('AKT', 'Gene', '207', (113, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('copy number alterations', 'Var', (73, 96))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('AKT', 'Gene', (113, 116))
135525	31330086	In PDAC specifically, ~ 17% of tumours carried alterations, the majority of which involved gene amplification, and this finding is consistent across multiple cohorts 114, 115 (Fig.	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('gene amplification', 'MPA', (91, 109))	('PDAC', 'Disease', 'MESH:D021441', (3, 7))	('PDAC', 'Disease', (3, 7))	('alterations', 'Var', (47, 58))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))
135526	31330086	The PI3KCA gene mutations present in 3-5% of pancreatic cancer patients can act as activating mutations initiating pancreatic tumour formation 129.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Disease', (45, 62))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (115, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('PI3KCA gene', 'Gene', (4, 15))	('patients', 'Species', '9606', (63, 71))	('pancreatic tumour', 'Disease', 'MESH:D010190', (115, 132))	('pancreatic tumour', 'Disease', (115, 132))
135527	31330086	Further, inactivating aberrations in PTEN (negative regulator of PI3K/PI3K pathway) occur in up to 70% of human PDAC, and have been shown to activate the tumour-promoting stromal and immune cell components that shape the PDAC TME 130.	('PDAC', 'Disease', (221, 225))	('PDAC', 'Phenotype', 'HP:0006725', (221, 225))	('human', 'Species', '9606', (106, 111))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('PDAC', 'Disease', 'MESH:D021441', (112, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('PDAC', 'Disease', (112, 116))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('PTEN', 'Gene', (37, 41))	('tumour', 'Disease', (154, 160))	('PTEN', 'Gene', '5728', (37, 41))	('activate', 'PosReg', (141, 149))	('PDAC', 'Disease', 'MESH:D021441', (221, 225))	('inactivating aberrations', 'Var', (9, 33))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
135530	31330086	Although mutations at the NF2 locus are rare (~ 10%) in human PDAC 12, 19, Merlin expression is lost in > 40% of PDAC and is negatively correlated with tumour stage, regional lymph node metastasis and differentiation 134.	('PDAC', 'Disease', 'MESH:D021441', (113, 117))	('Merlin', 'Gene', '4771', (75, 81))	('PDAC', 'Disease', (113, 117))	('mutations', 'Var', (9, 18))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))	('expression', 'MPA', (82, 92))	('human', 'Species', '9606', (56, 61))	('correlated', 'Reg', (136, 146))	('differentiation 134', 'CPA', (201, 220))	('regional lymph node metastasis', 'CPA', (166, 196))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('Merlin', 'Gene', (75, 81))	('PDAC', 'Disease', 'MESH:D021441', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('PDAC', 'Disease', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('NF2', 'Gene', '4771', (26, 29))	('tumour', 'Disease', (152, 158))	('negatively', 'NegReg', (125, 135))	('lost', 'NegReg', (96, 100))	('NF2', 'Gene', (26, 29))
135534	31330086	Importantly, moving forward, the integration of DNA copy-number alterations, methylome, mRNA and protein, metabolomics and clinical information may help to further delineate the extent of Src signalling deregulation in pancreatic and other cancers, and could potentially lay the foundation for more accurate and rapid implementation of therapeutic inhibitors of Src as personalised cancer therapeutics.	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (382, 388))	('cancer', 'Disease', (240, 246))	('copy-number alterations', 'Var', (52, 75))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('cancers', 'Disease', (240, 247))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('pancreatic', 'Disease', (219, 229))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('signalling', 'biological_process', 'GO:0023052', ('192', '202'))	('Src signalling deregulation', 'MPA', (188, 215))
135546	31330086	The rationale behind this includes the finding that Src is associated with increased chemoresistance in PDAC, and that inhibition of Src can overcome resistance to gemcitabine 58, 137, 143.	('gemcitabine', 'Chemical', 'MESH:C056507', (164, 175))	('Src', 'Gene', (133, 136))	('inhibition', 'Var', (119, 129))	('resistance', 'MPA', (150, 160))	('PDAC', 'Disease', (104, 108))	('chemoresistance', 'CPA', (85, 100))	('PDAC', 'Disease', 'MESH:D021441', (104, 108))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('increased', 'PosReg', (75, 84))	('Src', 'Var', (52, 55))
135548	31330086	Src inhibition can also increase oxaliplatin activity, and inhibit oxaliplatin-induced Src activation 137.	('increase', 'PosReg', (24, 32))	('oxaliplatin', 'Chemical', 'MESH:C030110', (67, 78))	('Src', 'Protein', (0, 3))	('oxaliplatin', 'Chemical', 'MESH:C030110', (33, 44))	('inhibition', 'Var', (4, 14))	('oxaliplatin-induced Src activation 137', 'MPA', (67, 105))	('inhibit', 'NegReg', (59, 66))	('oxaliplatin activity', 'MPA', (33, 53))
135583	31330086	Inhibition of FAK decreased PDAC cell growth and migration in vitro 191, 192, and limited pancreatic tumour progression in vivo, doubling the survival in the p48-Cre;LSL-KrasG12D;Trp53flox/+ (KPC) mouse model of PDAC 25, 193, 194.	('decreased', 'NegReg', (18, 27))	('pancreatic tumour', 'Disease', (90, 107))	('PDAC', 'Phenotype', 'HP:0006725', (212, 216))	('p48', 'Gene', (158, 161))	('cell growth', 'biological_process', 'GO:0016049', ('33', '44'))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('Trp53', 'Gene', '22059', (179, 184))	('p48', 'Gene', '16391', (158, 161))	('mouse', 'Species', '10090', (197, 202))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('Trp53', 'Gene', (179, 184))	('PDAC', 'Disease', 'MESH:D021441', (212, 216))	('PDAC', 'Disease', (212, 216))	('PDAC', 'Disease', (28, 32))	('Inhibition', 'Var', (0, 10))	('FAK', 'molecular_function', 'GO:0004717', ('14', '17'))	('limited', 'NegReg', (82, 89))	('pancreatic tumour', 'Disease', 'MESH:D010190', (90, 107))	('Kras', 'Gene', '3845', (170, 174))	('FAK', 'Gene', (14, 17))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (90, 107))	('PDAC', 'Disease', 'MESH:D021441', (28, 32))	('doubling', 'PosReg', (129, 137))	('Kras', 'Gene', (170, 174))
135586	31330086	In addition, FAK inhibitors such as PF-00562271 are well tolerated and hence show significant promise for the treatment of PDAC 131, 196.	('PDAC', 'Disease', 'MESH:D021441', (123, 127))	('PDAC', 'Disease', (123, 127))	('PDAC', 'Phenotype', 'HP:0006725', (123, 127))	('PF-00562271', 'Var', (36, 47))	('PF-00562271', 'Chemical', 'MESH:C573150', (36, 47))	('FAK', 'molecular_function', 'GO:0004717', ('13', '16'))
135588	31330086	This is supported by positive data from two phase I studies (NCT01138033, NCT01938443) in advanced solid tumours, where improved response to the FAK inhibitor GSK2256098 was observed in Merlin-negative mesothelioma 131, 133.	('Merlin', 'Gene', '4771', (186, 192))	('improved', 'PosReg', (120, 128))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('GSK2256098', 'Var', (159, 169))	('FAK', 'molecular_function', 'GO:0004717', ('145', '148'))	('mesothelioma', 'Disease', (202, 214))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('NCT01138033', 'Var', (61, 72))	('response', 'MPA', (129, 137))	('solid tumours', 'Disease', 'MESH:D009369', (99, 112))	('NCT01938443', 'Chemical', 'MESH:C079985', (74, 85))	('solid tumours', 'Disease', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('Merlin', 'Gene', (186, 192))	('GSK', 'molecular_function', 'GO:0050321', ('159', '162'))
135592	31330086	These studies also differ in terms of their patient selection and cohort size, with the larger COMMAND trial 132 being a prospective study examining defactinib efficacy as a maintenance therapy in chemo-responsive advanced MPM, whereas the smaller phase I and Ib studies of the GSK2256098 compound examined efficacy in advanced chemo-resistant solid tumours, including mesothelioma.	('defactinib', 'Var', (149, 159))	('mesothelioma', 'Disease', 'MESH:D008654', (369, 381))	('chemo-resistant solid tumours', 'Disease', 'MESH:D009369', (328, 357))	('patient', 'Species', '9606', (44, 51))	('chemo-resistant solid tumours', 'Disease', (328, 357))	('tumours', 'Phenotype', 'HP:0002664', (350, 357))	('GSK', 'molecular_function', 'GO:0050321', ('278', '281'))	('MPM', 'Disease', 'MESH:C562839', (223, 226))	('MPM', 'Disease', (223, 226))	('mesothelioma', 'Disease', (369, 381))	('tumour', 'Phenotype', 'HP:0002664', (350, 356))
135599	31330086	Newer ROCK inhibitors (such as ripasudil, CCT129254 or AT13148), are currently being trialled, and utilise a similar 'priming' 92, 93 or intermittent regime 201.	('CCT129254', 'Var', (42, 51))	('CCT129254', 'Chemical', 'MESH:C043232', (42, 51))	('AT13148', 'Var', (55, 62))
135600	31330086	The rationale behind this novel treatment scheduling involves modulating or 'loosening' the ECM, via ROCK inhibition, prior to chemotherapy administration in order to improve chemotherapy drug perfusion and reduce toxicity 92.	('reduce', 'NegReg', (207, 213))	('ROCK', 'MPA', (101, 105))	("'loosening", 'NegReg', (76, 86))	('improve', 'PosReg', (167, 174))	('chemotherapy drug perfusion', 'MPA', (175, 202))	('toxicity', 'Disease', 'MESH:D064420', (214, 222))	('toxicity', 'Disease', (214, 222))	('modulating', 'Var', (62, 72))	("'loosening'", 'Phenotype', 'HP:0100036', (76, 87))
135605	31330086	For example, inhibition of mTORC1 drives activation of PI3K-, AKT- or ERK pathways 205, which in turn limits the efficacy of mTORC-inhibitors as targeted therapies 206.	('PI3K-', 'Pathway', (55, 60))	('AKT', 'Gene', (62, 65))	('mTOR', 'Gene', '2475', (125, 129))	('ERK', 'Gene', (70, 73))	('mTORC1', 'Gene', '382056', (27, 33))	('mTORC1', 'cellular_component', 'GO:0031931', ('27', '33'))	('mTOR', 'Gene', (125, 129))	('efficacy', 'MPA', (113, 121))	('inhibition', 'Var', (13, 23))	('ERK', 'molecular_function', 'GO:0004707', ('70', '73'))	('activation', 'PosReg', (41, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('AKT', 'Gene', '207', (62, 65))	('mTORC1', 'Gene', (27, 33))	('limits', 'NegReg', (102, 108))	('mTOR', 'Gene', '2475', (27, 31))	('mTOR', 'Gene', (27, 31))	('ERK', 'Gene', '5594', (70, 73))
135607	31330086	However there is still some debate as to whether blocking mTORC1/2 leads to the adaptive activation of the PI3K-AKT pathway 209, and consequently whether multiple targeting of this network is required to effectively interfere with both branches of adaptive signalling and to elicit a durable therapeutic response.	('signalling', 'biological_process', 'GO:0023052', ('257', '267'))	('mTORC1/2', 'Gene', '74343;382056', (58, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('AKT', 'Gene', '207', (112, 115))	('blocking', 'Var', (49, 57))	('mTORC1/2', 'Gene', (58, 66))	('activation', 'PosReg', (89, 99))	('mTORC1', 'cellular_component', 'GO:0031931', ('58', '64'))	('AKT', 'Gene', (112, 115))
135608	31330086	The combination of Cyclin-dependent Kinase (CDK) inhibitors with PI3K pathway inhibition has been shown to inhibit tumour growth and metastasis in a variety of cancers including PDAC 210, 211, with a need for molecular stratification into responsive subtypes 212.	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('PDAC', 'Disease', 'MESH:D021441', (178, 182))	('inhibitors', 'Var', (49, 59))	('PDAC', 'Disease', (178, 182))	('tumour growth', 'Disease', 'MESH:D006130', (115, 128))	('Cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('Cyclin-dependent', 'Protein', (19, 35))	('cancers', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('combination', 'Interaction', (4, 15))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('tumour growth', 'Disease', (115, 128))	('PDAC', 'Phenotype', 'HP:0006725', (178, 182))	('PI3K pathway', 'Pathway', (65, 77))	('inhibit', 'NegReg', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('CDK', 'Gene', (44, 47))
135612	31330086	Synergy has previously been shown between a MEK-inhibitor and PI3K/mTOR inhibitor in a lung cancer model, where inhibition of MEK/ERK was shown to stabilise BIM, and PI3K/AKT inhibition upregulated PUMA via FOXO, all of which are key mediators of apoptosis 215, 216.	('MEK', 'Gene', '5609', (126, 129))	('ERK', 'Gene', '5594', (130, 133))	('mTOR', 'Gene', (67, 71))	('lung cancer', 'Disease', (87, 98))	('MEK', 'Gene', '5609', (44, 47))	('inhibition', 'Var', (112, 122))	('inhibition', 'Var', (175, 185))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('MEK', 'Gene', (126, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('mTOR', 'Gene', '2475', (67, 71))	('ERK', 'Gene', (130, 133))	('PUMA', 'MPA', (198, 202))	('MEK', 'Gene', (44, 47))	('ERK', 'molecular_function', 'GO:0004707', ('130', '133'))	('AKT', 'Gene', (171, 174))	('upregulated', 'PosReg', (186, 197))	('BIM', 'MPA', (157, 160))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('166', '170'))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('AKT', 'Gene', '207', (171, 174))
135622	31330086	Clinical trials of further integrin antagonists, including intetumumab, volociximab, ATN-161 (Ac-PHSCN-NH2 peptide), abituzumab and etaracizumab, all of which are antibodies or peptide mimetics, have largely yielded no improvements in patient progression-free or overall survival (Table 2) 235, 236; however, specific studies in colon cancer suggest that their antitumour activity may be linked to the presence of a biomarker 237, and, alternatively, may specifically inhibit the progression of bone-associated metastases in prostate cancer 238.	('abituzumab and etaracizumab', 'Disease', 'None', (117, 144))	('patient', 'Species', '9606', (235, 242))	('tumour', 'Disease', (365, 371))	('progression', 'CPA', (480, 491))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('presence', 'Var', (402, 410))	('colon cancer', 'Phenotype', 'HP:0003003', (329, 341))	('colon cancer', 'Disease', 'MESH:D015179', (329, 341))	('ATN-161', 'Chemical', 'MESH:C057315', (85, 92))	('metastases in prostate cancer', 'Disease', 'MESH:D011471', (511, 540))	('prostate cancer', 'Phenotype', 'HP:0012125', (525, 540))	('metastases in prostate cancer', 'Disease', (511, 540))	('tumour', 'Phenotype', 'HP:0002664', (365, 371))	('colon cancer', 'Disease', (329, 341))	('tumour', 'Disease', 'MESH:D009369', (365, 371))	('inhibit', 'NegReg', (468, 475))	('Ac-PHSCN-NH2', 'Chemical', 'MESH:C404392', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (534, 540))
135631	31330086	Of note, mutant P53 has been shown to regulate alpha5beta1 signalling and EGFR, which suggests there may also be potential for molecular stratification 245.	('signalling', 'biological_process', 'GO:0023052', ('59', '69'))	('P53', 'Gene', '7157', (16, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('mutant', 'Var', (9, 15))	('EGFR', 'Gene', '1956', (74, 78))	('regulate', 'Reg', (38, 46))	('alpha5beta1 signalling', 'MPA', (47, 69))	('EGFR', 'Gene', (74, 78))	('P53', 'Gene', (16, 19))
135638	31330086	Clinical studies of PEGPH20 are also promising with phase II data already demonstrating significant efficacy of this agent when combined with chemotherapy, effect particularly prominent in patients with HA-high tumours 248, highlighting the potential utility of intratumoural HA as a predictive biomarker of response 248, 249, 250.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('tumour', 'Disease', (211, 217))	('tumours', 'Disease', (211, 218))	('tumour', 'Disease', (267, 273))	('PEGPH20', 'Chemical', 'MESH:C588234', (20, 27))	('PEGPH20', 'Var', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('patients', 'Species', '9606', (189, 197))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('tumour', 'Disease', 'MESH:D009369', (267, 273))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
135641	31330086	Consequently several phase II/III clinical trials are now investigating further the clinical efficacy of PEGPH20, in combination with standard of care chemotherapies (Table 2) (NCT02487277, NCT02715804), or immune checkpoint inhibition (NCT03481920; NCT03634332, NCT03193190) in HA-high molecular subgroups of PDAC 248, 255.	('NCT02487277', 'Var', (177, 188))	('PDAC', 'Disease', (310, 314))	('NCT03634332', 'Chemical', 'MESH:C079985', (250, 261))	('PDAC', 'Phenotype', 'HP:0006725', (310, 314))	('NCT03193190', 'Var', (263, 274))	('NCT03481920; NCT03634332', 'Var', (237, 261))	('NCT03634332', 'Var', (250, 261))	('NCT02487277', 'Chemical', 'MESH:C079985', (177, 188))	('NCT02715804', 'Chemical', 'MESH:C079985', (190, 201))	('PDAC', 'Disease', 'MESH:D021441', (310, 314))	('PEGPH20', 'Chemical', 'MESH:C588234', (105, 112))
135660	31207975	Also genetic factors, such as germline variants of BAP-1 Tumor suppressor gene, have been hypothesized to play a role as high-risk factors in the susceptibility to develop malignant mesothelioma in asbestos-exposed subjects.	('malignant mesothelioma', 'Disease', (172, 194))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('BAP-1', 'Gene', (51, 56))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (172, 194))	('asbestos', 'Chemical', 'MESH:D001194', (198, 206))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (172, 194))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('Tumor', 'Phenotype', 'HP:0002664', (57, 62))	('germline variants', 'Var', (30, 47))
135682	31207975	The monitoring of VOCs in gaseous exhaled breath could represent a new frontier in medical early diagnosis of cancer diseases because tumor growth is mainly accompanied by gene and/or protein changes that may lead to peroxidation of the cell membrane species and, hence, to the release of VOCs.	('cell membrane', 'cellular_component', 'GO:0005886', ('237', '250'))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('lead to', 'Reg', (209, 216))	('changes', 'Var', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('peroxidation of the cell membrane species', 'MPA', (217, 258))	('cancer diseases', 'Disease', (110, 125))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('release of VOCs', 'MPA', (278, 293))	('cancer diseases', 'Disease', 'MESH:D009369', (110, 125))	('tumor', 'Disease', (134, 139))
135695	31207975	VOCs are chemically ionized by well-defined reagent ions (i.e., H3O+, NO+ or O2+) and transformed in characteristic product ions allowing both detection and quantification.	('ionized', 'Disease', 'MESH:D004194', (20, 27))	('ionized', 'Disease', (20, 27))	('NO+', 'Var', (70, 73))	('H3O+', 'Var', (64, 68))	('H3O+', 'Chemical', 'MESH:C027727', (64, 68))	('O2+', 'Chemical', 'MESH:D010100', (77, 80))
135711	31207975	Several papers in literature showed that asbestos fibers linked to high iron concentrations could directly induce oxidative stress and generate reactive oxygen species (ROS) and nitrogen species (RNS), which determine lipid peroxidation with consequent formation of saturated hydrocarbons and aldehydes.	('RNS', 'Chemical', 'MESH:D011886', (196, 199))	('saturated hydrocarbons', 'MPA', (266, 288))	('iron', 'Chemical', 'MESH:D007501', (72, 76))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (144, 167))	('lipid', 'Chemical', 'MESH:D008055', (218, 223))	('hydrocarbons', 'Chemical', 'MESH:D006838', (276, 288))	('aldehydes', 'Chemical', 'MESH:D000447', (293, 302))	('oxidative stress', 'MPA', (114, 130))	('lipid peroxidation', 'MPA', (218, 236))	('nitrogen species', 'MPA', (178, 194))	('asbestos', 'Chemical', 'MESH:D001194', (41, 49))	('formation', 'biological_process', 'GO:0009058', ('253', '262'))	('oxidative stress', 'Phenotype', 'HP:0025464', (114, 130))	('determine', 'Reg', (208, 217))	('reactive oxygen species', 'MPA', (144, 167))	('high', 'Var', (67, 71))	('induce', 'Reg', (107, 113))	('nitrogen', 'Chemical', 'MESH:D009584', (178, 186))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))
135816	24466195	Consistent with these findings was the fact that gene transfer of CD26 into CD26-negative MSTO-211H cells reduced CD9 expression.	('MSTO-211H', 'CellLine', 'CVCL:1430', (90, 99))	('gene transfer', 'Var', (49, 62))	('CD26', 'Gene', (66, 70))	('CD9 expression', 'MPA', (114, 128))	('reduced', 'NegReg', (106, 113))
135818	24466195	Finally, gene depletion of CD9 resulted in elevated protein levels and tyrosine phosphorylation of FAK and Cas-L, which are downstream of beta1 integrin, while depletion of CD26 led to a reduction in the levels of these molecules.	('beta1 integrin', 'Gene', '3688', (138, 152))	('FAK', 'Gene', (99, 102))	('FAK', 'Gene', '5747', (99, 102))	('elevated', 'PosReg', (43, 51))	('Cas-L', 'Gene', '4739', (107, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('Cas-L', 'Gene', (107, 112))	('FAK', 'molecular_function', 'GO:0004717', ('99', '102'))	('CD9', 'Gene', (27, 30))	('beta1 integrin', 'Gene', (138, 152))	('Cas', 'cellular_component', 'GO:0005650', ('107', '110'))	('gene depletion', 'Var', (9, 23))	('tyrosine phosphorylation', 'MPA', (71, 95))	('tyrosine', 'Chemical', 'MESH:D014443', (71, 79))	('protein levels', 'MPA', (52, 66))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
135819	24466195	Collectively, our findings suggest that CD26 potentiates tumor cell invasion through its interaction with alpha5beta1 integrin, and CD9 negatively regulates tumor cell invasion by reducing the level of CD26-alpha5beta1 integrin complex through an inverse correlation between CD9 and CD26 expression.	('CD26', 'Gene', (283, 287))	('CD26-alpha5beta1', 'Gene', '1803', (202, 218))	('alpha5beta1 integrin complex', 'cellular_component', 'GO:0034674', ('207', '235'))	('CD9', 'Gene', (275, 278))	('beta1 integrin', 'Gene', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CD9', 'Gene', (132, 135))	('beta1 integrin', 'Gene', '3688', (112, 126))	('regulates', 'Reg', (147, 156))	('negatively', 'NegReg', (136, 146))	('level', 'MPA', (193, 198))	('tumor', 'Disease', (57, 62))	('potentiates', 'PosReg', (45, 56))	('beta1 integrin', 'Gene', (213, 227))	('CD26-alpha5beta1', 'Gene', (202, 218))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('reducing', 'NegReg', (180, 188))	('beta1 integrin', 'Gene', '3688', (213, 227))	('CD26', 'Var', (40, 44))	('tumor', 'Disease', (157, 162))	('interaction', 'Interaction', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
135824	24466195	CD26 is a 110-kDa cell surface glycoprotein with known dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) activity in its extracellular domain and is capable of cleaving N-terminal dipeptides with either L-proline or L-alanine at the penultimate position.	('dipeptidyl peptidase IV', 'Gene', '1803', (55, 78))	('cell surface', 'cellular_component', 'GO:0009986', ('18', '30'))	('L-alanine', 'Var', (211, 220))	('dipeptides', 'Chemical', 'MESH:D004151', (175, 185))	('dipeptidyl peptidase IV', 'Gene', (55, 78))	('CD26', 'Gene', (0, 4))	('DPPIV', 'Gene', (80, 85))	('L-proline', 'Chemical', 'MESH:D011392', (198, 207))	('L-alanine', 'Chemical', 'MESH:D000409', (211, 220))	('cleaving N-terminal dipeptides', 'MPA', (155, 185))	('extracellular', 'cellular_component', 'GO:0005576', ('116', '129'))	('dipeptidyl peptidase IV', 'molecular_function', 'GO:0004274', ('55', '78'))	('DPPIV', 'Gene', '1803', (80, 85))
135830	24466195	Anti-CD26 monoclonal antibody (mAb) treatment resulted in both in vitro and in vivo antitumor activity against several tumor types, including lymphoma and renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (155, 175))	('tumor', 'Disease', (119, 124))	('antibody', 'cellular_component', 'GO:0019815', ('21', '29'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('lymphoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (142, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('antibody', 'cellular_component', 'GO:0019814', ('21', '29'))	('antibody', 'molecular_function', 'GO:0003823', ('21', '29'))	('Anti-CD26', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (142, 150))	('antibody', 'cellular_component', 'GO:0042571', ('21', '29'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (88, 93))
135832	24466195	Importantly, humanized anti-CD26 antibody inhibited growth of malignant mesothelioma cells and induced long-term survival of tumor-transplanted immunodeficient mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('human', 'Species', '9606', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('anti-CD26', 'Var', (23, 32))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('long-term survival', 'CPA', (103, 121))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (62, 84))	('tumor', 'Disease', (125, 130))	('anti-CD26', 'Gene', (23, 32))	('inhibited', 'NegReg', (42, 51))	('mice', 'Species', '10090', (160, 164))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (62, 84))	('induced', 'PosReg', (95, 102))	('malignant mesothelioma', 'Disease', (62, 84))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))
135835	24466195	Clinicopathologic findings indicated that CD9 may be a predictor for better prognosis in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('CD9', 'Var', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', (89, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))
135876	24466195	We first analyzed antigenic modulation induced by the addition of anti-CD26 mAbin these mesothelioma cells as described previously.	('anti-CD26', 'Var', (66, 75))	('mesothelioma', 'Disease', (88, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))
135879	24466195	Similar results were also seen in the mesothelioma cell line NCI-H2452 transduced with CD26 or CD9 siRNA (Figure S1B).	('mesothelioma', 'Disease', (38, 50))	('NCI-H2452', 'CellLine', 'CVCL:1553', (61, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (38, 50))	('CD26', 'Var', (87, 91))
135881	24466195	CD26+CD9- cells showed higher invasion activity than that of CD26+CD9+ cells, suggesting that CD9 may suppress tumor cell invasion.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CD9', 'Var', (94, 97))	('higher', 'PosReg', (23, 29))	('invasion activity', 'CPA', (30, 47))	('tumor', 'Disease', (111, 116))	('suppress', 'NegReg', (102, 110))
135883	24466195	Although the exact nature of the CD26 and CD9 association was not elucidated in the report, our current data clearly demonstrate that CD26+CD9+ cells exhibit higher invasive activity than CD26-CD9+ cells, suggesting that CD26 may potentiate tumor cell invasiveness.	('CD26+CD9+', 'Var', (134, 143))	('tumor', 'Disease', (241, 246))	('invasive activity', 'CPA', (165, 182))	('higher', 'PosReg', (158, 164))	('potentiate', 'PosReg', (230, 240))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
135884	24466195	With our previous data suggesting that CD26 potentiates tumor cell invasiveness, we further evaluated the effect of overexpression and gene depletion of CD26 on invasiveness and motility of MSTO-CD26(+) and MESO1 cells.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CD26', 'Gene', (153, 157))	('tumor', 'Disease', (56, 61))	('potentiates', 'PosReg', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD26', 'Var', (39, 43))
135885	24466195	These results indicate that CD26 may confer greater tumor cell invasiveness and motility.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('CD26', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('greater', 'PosReg', (44, 51))
135892	24466195	Meanwhile, treatment with anti-CD26 mAb led to co-modulation of alpha5beta1, but not alpha6beta1 integrin, in MESO1 and MSTO-CD26 (+) cells (data not shown).	('co-modulation', 'MPA', (47, 60))	('anti-CD26', 'Var', (26, 35))	('beta1', 'Gene', (91, 96))	('beta1', 'Gene', '3779', (70, 75))	('beta1 integrin', 'Gene', '3688', (91, 105))	('beta1', 'Gene', '3779', (91, 96))	('beta1 integrin', 'Gene', (91, 105))	('beta1', 'Gene', (70, 75))
135893	24466195	Additional analysis of the interaction between alpha5beta1 integrin and CD26 showed that transfection of CD26 cDNA into MSTO-Wild cells increased the level of alpha5beta1 expression (Figure 5A).	('beta1', 'Gene', '3779', (165, 170))	('transfection', 'Var', (89, 101))	('beta1', 'Gene', (53, 58))	('beta1 integrin', 'Gene', '3688', (53, 67))	('beta1', 'Gene', (165, 170))	('increased', 'PosReg', (136, 145))	('beta1', 'Gene', '3779', (53, 58))	('beta1 integrin', 'Gene', (53, 67))	('CD26', 'Var', (105, 109))
135894	24466195	Immunoprecipitation analysis indicated that alpha5beta1 integrin co-precipitated with CD26, but not with CD9 in MESO1 and MSTO-CD26 (+) cells (Figure 5B).	('CD26', 'Var', (86, 90))	('beta1 integrin', 'Gene', (50, 64))	('beta1 integrin', 'Gene', '3688', (50, 64))
135901	24466195	On the other hand, siRNA-mediated depletion of CD9 augmented the expression of CD26 and alpha5beta1 integrin, as detected by immunoblotting (Figure 6B).	('beta1 integrin', 'Gene', '3688', (94, 108))	('beta1 integrin', 'Gene', (94, 108))	('CD9', 'Gene', (47, 50))	('augmented', 'PosReg', (51, 60))	('CD26', 'Protein', (79, 83))	('depletion', 'Var', (34, 43))	('expression', 'MPA', (65, 75))
135902	24466195	Since CD9 itself does not associate with alpha5 integrin (Figure 5B), it is plausible that down-regulation or perturbation of CD9 may augment CD26 expression in an inverse manner, and the resultant increased level of the CD26-alpha5beta1 complex likely contributes to enhanced invasive potential.	('invasive potential', 'CPA', (277, 295))	('expression', 'MPA', (147, 157))	('down-regulation', 'NegReg', (91, 106))	('enhanced', 'PosReg', (268, 276))	('CD9', 'Gene', (126, 129))	('increased', 'PosReg', (198, 207))	('CD26-alpha5beta1', 'Gene', '1803', (221, 237))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('CD26', 'Protein', (142, 146))	('CD26-alpha5beta1', 'Gene', (221, 237))	('augment', 'PosReg', (134, 141))	('perturbation', 'Var', (110, 122))	('level', 'MPA', (208, 213))
135903	24466195	Since CD9 overexpression led to decreased CD26 expression and suppression of tumor cell invasion (Figure 4E), we next determined the effect of CD9 overexpression on alpha5beta1 integrin expression.	('suppression', 'NegReg', (62, 73))	('overexpression', 'Var', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('beta1 integrin', 'Gene', '3688', (171, 185))	('expression', 'MPA', (47, 57))	('CD26', 'Protein', (42, 46))	('CD9', 'Gene', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('decreased', 'NegReg', (32, 41))	('beta1 integrin', 'Gene', (171, 185))
135909	24466195	CD26 depletion by siRNA resulted in decreased expression of FAK and Cas-L, while CD9 depletion augmented FAK and Cas-L level in MESO1 and MSTO-CD26 (+) cells (Figure 6D).	('FAK', 'Gene', (105, 108))	('Cas-L', 'Gene', (113, 118))	('depletion', 'Var', (5, 14))	('Cas-L', 'Gene', '4739', (68, 73))	('Cas-L', 'Gene', '4739', (113, 118))	('FAK', 'Gene', '5747', (105, 108))	('FAK', 'Gene', (60, 63))	('Cas-L', 'Gene', (68, 73))	('FAK', 'Gene', '5747', (60, 63))	('FAK', 'molecular_function', 'GO:0004717', ('105', '108'))	('depletion', 'Var', (85, 94))	('augmented', 'PosReg', (95, 104))	('FAK', 'molecular_function', 'GO:0004717', ('60', '63'))	('Cas', 'cellular_component', 'GO:0005650', ('113', '116'))	('expression', 'MPA', (46, 56))	('Cas', 'cellular_component', 'GO:0005650', ('68', '71'))	('decreased', 'NegReg', (36, 45))
135911	24466195	Since CD9 depletion led to increased CD26 expression (Figure 2B, Figure 6B, and Figure S1) and promoted invasiveness and motility (Figure 4C and Figure S2C), we evaluated the effect of CD9 depletion on tyrosine phosphorylation levels of FAK and Cas-L. As shown in Figure 6E, CD9 depletion led to increased FAK and Cas-L tyrosine phosphorylation in mesothelioma cells, indicating that CD26 and CD9 may regulate the overall protein level and tyrosine-phosphorylation of beta1 integrin-related signaling molecules as well as the expression of alpha5beta1 integrin.	('protein level', 'MPA', (422, 435))	('Cas', 'cellular_component', 'GO:0005650', ('314', '317'))	('expression', 'MPA', (526, 536))	('Cas-L', 'Gene', (314, 319))	('CD9', 'Gene', (393, 396))	('Cas-L', 'Gene', '4739', (245, 250))	('FAK', 'Gene', (306, 309))	('protein', 'cellular_component', 'GO:0003675', ('422', '429'))	('regulate', 'Reg', (401, 409))	('FAK', 'molecular_function', 'GO:0004717', ('237', '240'))	('signaling', 'biological_process', 'GO:0023052', ('491', '500'))	('Cas', 'cellular_component', 'GO:0005650', ('245', '248'))	('FAK', 'molecular_function', 'GO:0004717', ('306', '309'))	('tyrosine', 'Chemical', 'MESH:D014443', (202, 210))	('FAK', 'Gene', '5747', (306, 309))	('tyrosine', 'Chemical', 'MESH:D014443', (440, 448))	('increased', 'PosReg', (296, 305))	('tyrosine-phosphorylation', 'MPA', (440, 464))	('beta1 integrin', 'Gene', (468, 482))	('beta1 integrin', 'Gene', (546, 560))	('mesothelioma', 'Disease', (348, 360))	('FAK', 'Gene', (237, 240))	('Cas-L', 'Gene', '4739', (314, 319))	('depletion', 'Var', (279, 288))	('Cas-L', 'Gene', (245, 250))	('mesothelioma', 'Disease', 'MESH:D008654', (348, 360))	('beta1 integrin', 'Gene', '3688', (468, 482))	('beta1 integrin', 'Gene', '3688', (546, 560))	('phosphorylation', 'biological_process', 'GO:0016310', ('329', '344'))	('phosphorylation', 'biological_process', 'GO:0016310', ('211', '226'))	('tyrosine', 'Chemical', 'MESH:D014443', (320, 328))	('FAK', 'Gene', '5747', (237, 240))	('phosphorylation', 'biological_process', 'GO:0016310', ('449', '464'))
135914	24466195	In MSTO-CD26(+) cells, anti-CD26 mAb inhibited tumor cell invasiveness.	('inhibited', 'NegReg', (37, 46))	('anti-CD26', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
135916	24466195	CD26-depletion with shRNA inhibited in vitro tumor cell growth of MESO1 cells (Figure 7B).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cell growth', 'biological_process', 'GO:0016049', ('51', '62'))	('inhibited', 'NegReg', (26, 35))	('tumor', 'Disease', (45, 50))	('CD26-depletion', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
135917	24466195	In contrast to the enhanced effects on invasiveness by CD9-depletion, gene-depletion of CD9 inhibited tumor growth (Figure 7B).	('CD9', 'Gene', (88, 91))	('inhibited', 'NegReg', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('gene-depletion', 'Var', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
135920	24466195	Moreover, combined treatment with anti-CD26 mAb and anti-CD9 mAb resulted in enhanced inhibition of tumor growth in these cell lines (Figure 7C).	('anti-CD9', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('enhanced', 'PosReg', (77, 85))	('tumor', 'Disease', (100, 105))	('anti-CD26', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('inhibition', 'NegReg', (86, 96))
135921	24466195	In mouse xenograft study, depletion of CD26 or CD9 by shRNA inhibited in vivo tumor growth (Figure 7D), and combined depletion of CD26 and CD9 caused prominent suppression of tumor growth in vivo (Figure 7D).	('CD26', 'Var', (130, 134))	('tumor', 'Disease', (175, 180))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('inhibited', 'NegReg', (60, 69))	('suppression', 'NegReg', (160, 171))	('depletion', 'MPA', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('depletion', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (78, 83))	('CD9', 'Var', (139, 142))	('CD26', 'Var', (39, 43))	('CD9', 'Var', (47, 50))
135922	24466195	Similarly, anti-CD26 mAb or anti-CD9 mAb inhibited tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('anti-CD9', 'Var', (28, 36))	('inhibited', 'NegReg', (41, 50))	('anti-CD26', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
135923	24466195	Furthermore, combined treatment with anti-CD26 mAb and anti-CD9 mAb resulted in marked inhibition of tumor growth in vivo.	('inhibition', 'NegReg', (87, 97))	('anti-CD26', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('combined', 'Interaction', (13, 21))	('anti-CD9', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
135925	24466195	Meanwhile, these molecules exhibited opposite effects on invasion and migration of mesothelioma cells, with CD26 having an enhancing effect and CD9 showing a suppressing effect.	('invasion', 'CPA', (57, 65))	('enhancing', 'PosReg', (123, 132))	('suppressing', 'NegReg', (158, 169))	('CD9', 'Var', (144, 147))	('mesothelioma', 'Disease', (83, 95))	('CD26', 'Protein', (108, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))
135927	24466195	Finally, perturbation of CD26 or CD9 expression resulted in changes of the overall protein and tyrosine-phosphorylation levels of FAK and Cas-L, the beta1 integrin-mediated signaling molecules involved in cell adhesion and migration.	('beta1 integrin', 'Gene', '3688', (149, 163))	('FAK', 'molecular_function', 'GO:0004717', ('130', '133'))	('CD9', 'Gene', (33, 36))	('perturbation', 'Var', (9, 21))	('changes', 'Reg', (60, 67))	('Cas-L', 'Gene', (138, 143))	('Cas-L', 'Gene', '4739', (138, 143))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('tyrosine-phosphorylation levels', 'MPA', (95, 126))	('FAK', 'Gene', (130, 133))	('FAK', 'Gene', '5747', (130, 133))	('beta1 integrin', 'Gene', (149, 163))	('CD26', 'Gene', (25, 29))	('tyrosine', 'Chemical', 'MESH:D014443', (95, 103))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('cell adhesion', 'biological_process', 'GO:0007155', ('205', '218'))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('Cas', 'cellular_component', 'GO:0005650', ('138', '141'))
135940	24466195	In human colon cancer, CD26 was identified as a novel marker for cancer stem cells, and injection of CD26+ cells into SCID mice resulted in the development of distant metastasis, indicating the metastatic capacity of the CD26+ cells.	('distant metastasis', 'CPA', (159, 177))	('SCID', 'Disease', (118, 122))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('CD26+ cells', 'Var', (101, 112))	('cancer', 'Disease', (15, 21))	('human', 'Species', '9606', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('colon cancer', 'Disease', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SCID', 'Disease', 'MESH:D053632', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mice', 'Species', '10090', (123, 127))
135948	24466195	Several molecular mechanisms involved in CD9-mediated suppression of metastasis have been reported, including modification of beta1 integrin and inhibition of WAVE2.	('metastasis', 'CPA', (69, 79))	('WAVE2', 'Gene', '10163', (159, 164))	('beta1 integrin', 'Gene', '3688', (126, 140))	('suppression', 'NegReg', (54, 65))	('CD9-mediated', 'Gene', (41, 53))	('modification', 'Var', (110, 122))	('WAVE2', 'Gene', (159, 164))	('beta1 integrin', 'Gene', (126, 140))	('inhibition', 'NegReg', (145, 155))
135951	24466195	Therefore, combined application of anti-CD26 and anti-CD9 mAb is likely a promising therapeutic strategy for malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (109, 131))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (109, 131))	('malignant mesothelioma', 'Disease', (109, 131))	('anti-CD26', 'Var', (35, 44))	('anti-CD9', 'Var', (49, 57))
135952	24466195	In conclusion, our present study demonstrates that the interaction between CD26 and CD9 mediates mesothelioma behavior, while suggesting that CD26 and CD9 would be promising biomarkers as well as molecular targets for the future treatment of malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (242, 264))	('CD9', 'Gene', (84, 87))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (242, 264))	('CD26', 'Gene', (75, 79))	('mesothelioma behavior', 'Disease', (97, 118))	('interaction', 'Interaction', (55, 66))	('malignant mesothelioma', 'Disease', (242, 264))	('mediates', 'Reg', (88, 96))	('mesothelioma behavior', 'Disease', 'MESH:D008654', (97, 118))	('CD26', 'Var', (142, 146))
135966	23977343	The majority of mesothelioma has a deletion in the INK4A/ARF locus which encodes the p14 ARF and the p16 INK4A genes, but possesses the wild-type p53 gene.	('INK4A/ARF', 'Gene', (51, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (16, 28))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('INK4A/ARF', 'Gene', '1029', (51, 60))	('p14 ARF', 'Gene', '1029', (85, 92))	('p16 INK4A', 'Gene', '1029', (101, 110))	('mesothelioma', 'Disease', (16, 28))	('deletion', 'Var', (35, 43))	('p14 ARF', 'Gene', (85, 92))	('p16 INK4A', 'Gene', (101, 110))
135967	23977343	Deletion of p16INK4A increases cyclin-dependent kinase 4/6 activities, which subsequently induces pRb phosphorylation and cell cycle progression.	('increases', 'PosReg', (21, 30))	('cyclin', 'molecular_function', 'GO:0016538', ('31', '37'))	('activities', 'MPA', (59, 69))	('p16', 'Gene', '1029', (12, 15))	('cyclin-dependent kinase 4/6', 'Enzyme', (31, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('induces', 'Reg', (90, 97))	('pRb phosphorylation', 'MPA', (98, 117))	('p16', 'Gene', (12, 15))	('cell cycle progression', 'CPA', (122, 144))	('Deletion', 'Var', (0, 8))
135968	23977343	In contrast, deficiency of p14ARF augments Mdm2 activities and consequently down-regulates p53 expression, which may render mesothelioma cells resistant to chemotherapeutic agents.	('activities', 'MPA', (48, 58))	('p14ARF', 'Gene', '1029', (27, 33))	('Mdm2', 'Gene', (43, 47))	('deficiency', 'Var', (13, 23))	('mesothelioma', 'Disease', (124, 136))	('p14ARF', 'Gene', (27, 33))	('p53', 'Gene', (91, 94))	('render', 'Reg', (117, 123))	('down-regulates', 'NegReg', (76, 90))	('augments', 'PosReg', (34, 42))	('Mdm2', 'Gene', '4193', (43, 47))	('p53', 'Gene', '7157', (91, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('expression', 'MPA', (95, 105))
135987	23977343	All the mesothelioma cells used were defective of p14 and p16 expressions due to either loss of the transcription or deletion of the genomic DNA (Figure S1), and sequencing data confirmed that they possessed the wild-type p53 gene.	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('defective', 'NegReg', (37, 46))	('p16', 'Gene', (58, 61))	('loss', 'NegReg', (88, 92))	('transcription', 'MPA', (100, 113))	('mesothelioma', 'Disease', (8, 20))	('p16', 'Gene', '1029', (58, 61))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('p14', 'Gene', (50, 53))	('p53', 'Gene', '7157', (222, 225))	('p53', 'Gene', (222, 225))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('p14', 'Gene', '1029', (50, 53))	('deletion', 'Var', (117, 125))
136013	23977343	The cell cycle changes, increased S- and G2/M-phase populations and then sub-G1 fractions, were greater with IFN-beta treatments than with IFN-alpha treatments.	('treatments', 'Var', (118, 128))	('IFN-alpha', 'Gene', '3439', (139, 148))	('sub-G1 fractions', 'CPA', (73, 89))	('IFN-alpha', 'Gene', (139, 148))	('IFN-beta', 'Gene', (109, 117))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('cell cycle changes', 'CPA', (4, 22))	('IFN-beta', 'Gene', '3456', (109, 117))	('increased', 'PosReg', (24, 33))	('M-phase', 'biological_process', 'GO:0000279', ('44', '51'))
136022	23977343	Cell cycle analyses after IFN-beta treatments showed that NCI-H2052 cells increased S- and G2/M-phase fractions but less significantly augmented sub-G1 population, whereas NCI-H28 cells increased S-phase and then sub-G1 fractions (Table 1).	('M-phase', 'biological_process', 'GO:0000279', ('94', '101'))	('NCI-H2052', 'Var', (58, 67))	('IFN-beta', 'Gene', '3456', (26, 34))	('S-phase', 'biological_process', 'GO:0051320', ('196', '203'))	('IFN-beta', 'Gene', (26, 34))	('increased', 'PosReg', (74, 83))	('NCI-H28', 'CellLine', 'CVCL:1555', (172, 179))	('NCI-H2052', 'CellLine', 'CVCL:1518', (58, 67))	('sub-G1 population', 'CPA', (145, 162))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
136047	23977343	Interestingly, Met-5A cells of mesothelium origin were positive for IL-28Ralpha in contrast to mesothelioma cells, suggesting that IL-28Ralpha expression was activated by a process of immortalization due to expressed SV40 T antigen or was lost during tumorigenesis of mesothelial cells.	('tumor', 'Disease', (251, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('expression', 'MPA', (143, 153))	('IL-28Ralpha', 'Gene', '163702', (68, 79))	('activated', 'PosReg', (158, 167))	('IL-28Ralpha', 'Gene', (131, 142))	('IL-28Ralpha', 'Gene', '163702', (131, 142))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('217', '231'))	('IL-28', 'molecular_function', 'GO:0032003', ('68', '73'))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('IL-28', 'molecular_function', 'GO:0032003', ('131', '136'))	('IL-28Ralpha', 'Gene', (68, 79))	('SV40', 'Var', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('mesothelioma', 'Disease', (95, 107))
136057	23977343	The lack of cell death in type I IFNs-treated Met-5A cells can be associated with the relative insensitivity to type III IFNs because Met-5A cells showed low proliferation activity compared with mesothelioma cells.	('mesothelioma', 'Disease', (195, 207))	('low', 'NegReg', (154, 157))	('insensitivity to type III', 'Phenotype', 'HP:0001976', (95, 120))	('IFN', 'Gene', (33, 36))	('cell death', 'biological_process', 'GO:0008219', ('12', '22'))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('IFN', 'Gene', '3439', (121, 124))	('Met-5A', 'Var', (134, 140))	('proliferation activity', 'CPA', (158, 180))	('IFN', 'Gene', (121, 124))	('IFN', 'Gene', '3439', (33, 36))
136069	23977343	Our previous study also showed that CDDP treatments increased endogenous p53 levels in mesothelioma cells, and the susceptibility to CDDP was augmented by forced p53 expression.	('forced', 'Var', (155, 161))	('expression', 'Var', (166, 176))	('increased', 'PosReg', (52, 61))	('p53', 'Gene', (162, 165))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('mesothelioma', 'Disease', (87, 99))	('p53', 'Gene', '7157', (162, 165))	('CDDP', 'Chemical', 'MESH:D002945', (36, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))
136077	23977343	It is currently unknown as to the p14 involvement in the type I IFNs-mediated apoptosis, but difference of genetic backgrounds, such as defective 16 expression and aberrant signal pathways often found in mesothelioma, can be responsible.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('p14', 'Gene', (34, 37))	('IFN', 'Gene', '3439', (64, 67))	('p14', 'Gene', '1029', (34, 37))	('IFN', 'Gene', (64, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('mesothelioma', 'Disease', (204, 216))	('mesothelioma', 'Disease', 'MESH:D008654', (204, 216))	('defective', 'Var', (136, 145))
136100	30479770	Inhalation of asbestos fibres can cause malignant mesothelioma of the pleura, which typically manifests 30-40 years after first exposure, with longer periods possibly seen with lower levels of exposure 5.	('Inhalation', 'Var', (0, 10))	('malignant mesothelioma of the pleura', 'Disease', (40, 76))	('asbestos', 'Chemical', 'MESH:D001194', (14, 22))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (40, 62))	('cause', 'Reg', (34, 39))	('malignant mesothelioma of the pleura', 'Disease', 'MESH:C562839', (40, 76))
136158	26218750	In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong.	('Cul4A', 'Gene', (45, 50))	('rat', 'Species', '10116', (155, 158))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('increased', 'PosReg', (35, 44))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (9, 28))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('mesothelioma tumours', 'Disease', (9, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('copy number', 'Var', (51, 62))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (9, 29))
136159	26218750	Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines.	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('Cul4A', 'Gene', (39, 44))	('copy number', 'Var', (45, 56))	('increased', 'PosReg', (61, 70))	('mesothelioma', 'Disease', (80, 92))	('human', 'Species', '9606', (74, 79))
136167	26218750	Increased Cul4A copy number and Cul4A overexpression have been reported in various human cancers, and its oncogenic role has been reported in vivo and in mesothelioma cells.	('copy number', 'Var', (16, 27))	('mesothelioma', 'Disease', (154, 166))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('Cul4A', 'Gene', (32, 37))	('overexpression', 'PosReg', (38, 52))	('cancers', 'Disease', (89, 96))	('Increased', 'PosReg', (0, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('Cul4A', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
136171	26218750	In recent studies of the importance of Gli1 expression in mesothelioma tumours, Gli1 transcription and protein expression were increased significantly in mesothelioma tumours when compared to normal pleural tissues, and high Gli1 expression was significantly associated with poor survival.	('mesothelioma tumours', 'Disease', 'MESH:D008654', (154, 174))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('Gli1', 'Gene', (225, 229))	('high', 'Var', (220, 224))	('associated', 'Reg', (259, 269))	('Gli1', 'Gene', '2735', (80, 84))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (58, 78))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('mesothelioma tumours', 'Disease', (154, 174))	('Gli1', 'Gene', '2735', (39, 43))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('transcription', 'MPA', (85, 98))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (154, 173))	('protein expression', 'MPA', (103, 121))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (58, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('poor survival', 'CPA', (275, 288))	('mesothelioma tumours', 'Disease', (58, 78))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('Gli1', 'Gene', (80, 84))	('Gli1', 'Gene', (39, 43))	('Gli1', 'Gene', '2735', (225, 229))	('increased', 'PosReg', (127, 136))
136172	26218750	Inhibition of Gli1 by siRNA or small molecular inhibitors was shown to suppress mesothelioma cell growth in vitro and in a xenograft model.	('small molecular inhibitors', 'Var', (31, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('cell growth', 'biological_process', 'GO:0016049', ('93', '104'))	('Gli1', 'Gene', '2735', (14, 18))	('Inhibition', 'Var', (0, 10))	('mesothelioma', 'Disease', (80, 92))	('suppress', 'NegReg', (71, 79))	('Gli1', 'Gene', (14, 18))
136207	26218750	Cell lysates were then immunoblotted using anti-Gli1 (ab49314; Abcam), anti-mTOR (#2983; Cell Signaling, Beverly, MA) or anti-beta-actin (#4970; Cell Signaling) antibodies.	('#2983', 'Var', (82, 87))	('Gli1', 'Gene', (48, 52))	('anti-mTOR', 'Var', (71, 80))	('Gli1', 'Gene', '2735', (48, 52))	('Signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('beta-actin', 'Gene', '728378', (126, 136))	('beta-actin', 'Gene', (126, 136))	('Signaling', 'biological_process', 'GO:0023052', ('94', '103'))
136209	26218750	To measure Gli-mediated Hh transcriptional activity, the luciferase reporter constructs, 8x wild-type Gli binding site (8x Gliwt Luc) or 8x mutant Gli binding site (8x Glimut Luc) plasmids, a human Gli1 expression vector (pcDNA3.1-Gli1), and Cul4A siRNA or control siRNA were co-transfected into NSCLC H1299 cells in a 24-well plate.	('Gli', 'Gene', '2735', (168, 171))	('Gli1', 'Gene', '2735', (231, 235))	('Gli', 'Gene', '2735', (231, 234))	('Gli', 'Gene', (168, 171))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('human', 'Species', '9606', (192, 197))	('Gli', 'Gene', (231, 234))	('NSCLC H1299', 'CellLine', 'CVCL:0060', (296, 307))	('Gli1', 'Gene', '2735', (198, 202))	('Gli', 'Gene', '2735', (198, 201))	('Gli', 'Gene', '2735', (102, 105))	('Gli1', 'Gene', (231, 235))	('Gli', 'Gene', (198, 201))	('Gli', 'Gene', (102, 105))	('mutant', 'Var', (140, 146))	('Gli', 'Gene', '2735', (123, 126))	('Gli', 'Gene', '2735', (147, 150))	('Gli', 'Gene', '2735', (11, 14))	('Gli1', 'Gene', (198, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (296, 301))	('binding', 'molecular_function', 'GO:0005488', ('151', '158'))	('Gli', 'Gene', (123, 126))	('Gli', 'Gene', (147, 150))	('Gli', 'Gene', (11, 14))
136225	26218750	Our results showed a 72.2% concurrency of increased Cul4A copy number and Cul4A protein overexpression in the identical mesothelioma patient samples (Table S1), suggesting that the increased Cul4A copy number may contribute to the increased Cul4A expression in the mesothelioma tumours.	('copy number', 'Var', (197, 208))	('mesothelioma', 'Disease', (120, 132))	('mesothelioma tumours', 'Disease', (265, 285))	('expression', 'MPA', (247, 257))	('patient', 'Species', '9606', (133, 140))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('mesothelioma', 'Disease', (265, 277))	('increased', 'PosReg', (231, 240))	('Cul4A', 'Gene', (191, 196))	('mesothelioma', 'Disease', 'MESH:D008654', (265, 277))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (265, 285))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('tumours', 'Phenotype', 'HP:0002664', (278, 285))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (265, 284))	('increased', 'PosReg', (181, 190))	('Cul4A', 'Gene', (241, 246))
136231	26218750	Since these results indicated that Cul4A copy number is increased in most of the analysed mesothelioma cell lines, we next analysed Cul4A protein expression in these cell lines using IHC.	('Cul4A', 'Gene', (35, 40))	('increased', 'PosReg', (56, 65))	('mesothelioma', 'Disease', (90, 102))	('copy number', 'Var', (41, 52))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
136251	26218750	Among 14 mesothelioma samples with weak Cul4A expression, 28.6% showed negative Gli1 expression and 50% showed weak Gli1 expression.	('Gli1', 'Gene', '2735', (116, 120))	('expression', 'MPA', (85, 95))	('expression', 'Var', (46, 56))	('weak', 'NegReg', (111, 115))	('Gli1', 'Gene', (80, 84))	('Cul4A', 'Gene', (40, 45))	('mesothelioma', 'Disease', (9, 21))	('Gli1', 'Gene', '2735', (80, 84))	('Gli1', 'Gene', (116, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (9, 21))	('negative', 'NegReg', (71, 79))
136256	26218750	Three mesothelioma cell lines (MS-1, H2452 and 211H) with increased Cul4A copy number were treated with Cul4A siRNA for 48 hr and greater than 90% reduction in Cul4A mRNA was detected in all cell lines when compared to controls (*P < 0.05, t-test; Fig.	('mRNA', 'MPA', (166, 170))	('mesothelioma', 'Disease', (6, 18))	('copy number', 'Var', (74, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('Cul4A', 'Gene', (68, 73))	('reduction', 'NegReg', (147, 156))	('H2452', 'CellLine', 'CVCL:1553', (37, 42))
136257	26218750	When Gli1 mRNA expression in the cell lysates was analysed using qRT-PCR, all the mesothelioma cell lines showed decreased Gli1 expression levels after Cul4A knockdown (P < 0.05, t-test; Fig.	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('expression levels', 'MPA', (128, 145))	('Gli1', 'Gene', (5, 9))	('knockdown', 'Var', (158, 167))	('Gli1', 'Gene', (123, 127))	('Gli1', 'Gene', '2735', (5, 9))	('decreased', 'NegReg', (113, 122))	('Gli1', 'Gene', '2735', (123, 127))
136262	26218750	Silencing of Cul4A by siRNA resulted in a significant decrease of Gli reporter activity in H1299 cells, compared with that treated with non-targeting siRNA (control; *P < 0.05, t-test).	('decrease', 'NegReg', (54, 62))	('Gli', 'Gene', (66, 69))	('Gli', 'Gene', '2735', (66, 69))	('H1299', 'CellLine', 'CVCL:0060', (91, 96))	('Cul4A', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
136266	26218750	Protein expression of Gli1 was decreased in all three cell lines after Cul4A knockdown (Fig.	('Gli1', 'Gene', '2735', (22, 26))	('Protein expression', 'MPA', (0, 18))	('decreased', 'NegReg', (31, 40))	('knockdown', 'Var', (77, 86))	('Cul4A', 'Gene', (71, 76))	('Gli1', 'Gene', (22, 26))
136268	26218750	Quantitative analysis of western blotting images showed that both Gli1 and mTOR protein levels were decreased after Cul4A knockdown in the mesothelioma cells (Fig.	('Gli1', 'Gene', (66, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('Gli1', 'Gene', '2735', (66, 70))	('knockdown', 'Var', (122, 131))	('Cul4A', 'Gene', (116, 121))	('decreased', 'NegReg', (100, 109))	('mesothelioma', 'Disease', (139, 151))	('mTOR protein levels', 'MPA', (75, 94))
136273	26218750	Our study shows that in mesothelioma tumours and human mesothelioma cell lines, Cul4A is overexpressed and Cul4A copy number is increased.	('Cul4A', 'Gene', (107, 112))	('mesothelioma tumours', 'Disease', (24, 44))	('Cul4A', 'Gene', (80, 85))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('copy number', 'Var', (113, 124))	('mesothelioma', 'Disease', (24, 36))	('mesothelioma', 'Disease', (55, 67))	('human', 'Species', '9606', (49, 54))	('increased', 'PosReg', (128, 137))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (24, 44))	('mesothelioma', 'Disease', 'MESH:D008654', (24, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (24, 43))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('overexpressed', 'PosReg', (89, 102))
136274	26218750	Moreover, in 72.2% mesothelioma tumours with increased Cul4A copy number, Cul4A expression was moderate to strong.	('mesothelioma tumours', 'Disease', 'MESH:D008654', (19, 39))	('copy number', 'Var', (61, 72))	('Cul4A', 'Gene', (55, 60))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (19, 38))	('increased', 'PosReg', (45, 54))	('rat', 'Species', '10116', (99, 102))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('mesothelioma tumours', 'Disease', (19, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))
136275	26218750	Therefore, increased Cul4A copy number appears to, at least in part, contribute to increased Cul4A expression in mesothelioma tumours and in mesothelioma cells.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('expression', 'MPA', (99, 109))	('Cul4A', 'Gene', (93, 98))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (113, 132))	('increased', 'PosReg', (83, 92))	('increased', 'PosReg', (11, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (113, 133))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('mesothelioma', 'Disease', (141, 153))	('copy number', 'Var', (27, 38))	('mesothelioma tumours', 'Disease', (113, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('mesothelioma', 'Disease', (113, 125))	('Cul4A', 'Gene', (21, 26))
136277	26218750	These findings suggest that Cul4A overexpression may contribute to Gli1 expression in the mesothelioma cells, and inhibiting Cul4A leads to Gli1 decrease in these cells.	('Gli1', 'Gene', '2735', (140, 144))	('Cul4A', 'Gene', (125, 130))	('contribute', 'Reg', (53, 63))	('overexpression', 'PosReg', (34, 48))	('expression', 'MPA', (72, 82))	('Gli1', 'Gene', (67, 71))	('mesothelioma', 'Disease', (90, 102))	('inhibiting', 'Var', (114, 124))	('decrease', 'NegReg', (145, 153))	('Gli1', 'Gene', (140, 144))	('Gli1', 'Gene', '2735', (67, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
136278	26218750	To further our understanding on the association of Cul4A and Gli1 expression in mesothelioma cells, we analysed mTOR expression after Cul4A knockdown by siRNA and mTOR expression was decreased.	('Gli1', 'Gene', '2735', (61, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('Cul4A', 'Gene', (134, 139))	('mTOR expression', 'MPA', (112, 127))	('mesothelioma', 'Disease', (80, 92))	('Gli1', 'Gene', (61, 65))	('mTOR', 'MPA', (163, 167))	('analysed', 'Reg', (103, 111))	('knockdown', 'Var', (140, 149))
136280	26218750	Increased Cul4A copy number has been reported in several human cancers.	('copy number', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('Cul4A', 'Gene', (10, 15))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
136281	26218750	We have previously shown that Cul4A copy number and protein expression are both increased in human mesothelioma cells.	('copy number', 'Var', (36, 47))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('protein expression', 'MPA', (52, 70))	('increased', 'PosReg', (80, 89))	('human', 'Species', '9606', (93, 98))	('Cul4A', 'Gene', (30, 35))	('mesothelioma', 'Disease', (99, 111))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
136287	26218750	Cul4A was shown to promote migration and invasion of tumour cells in vitro and induce the growth and metastasis of tumour cells in vivo , suggesting that Cul4A can regulate epithelial-mesenchymal transition (EMT) and promote metastasis of tumour cells.	('promote', 'PosReg', (19, 26))	('tumour', 'Disease', (53, 59))	('growth', 'CPA', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('metastasis of tumour', 'Disease', 'MESH:D009362', (225, 245))	('metastasis of tumour', 'Disease', (101, 121))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))	('rat', 'Species', '10116', (30, 33))	('regulate', 'Reg', (164, 172))	('metastasis of tumour', 'Disease', (225, 245))	('Cul4A', 'Var', (154, 159))	('EMT', 'biological_process', 'GO:0001837', ('208', '211'))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('migration', 'CPA', (27, 36))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('173', '206'))	('promote', 'PosReg', (217, 224))	('tumour', 'Disease', (239, 245))	('metastasis of tumour', 'Disease', 'MESH:D009362', (101, 121))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('epithelial-mesenchymal transition', 'CPA', (173, 206))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
136291	26218750	By associating with betaTrCP, Cul4A has been shown to mediate proteolysis of REDD1, an inhibitor of mTOR signalling.	('proteolysis', 'biological_process', 'GO:0006508', ('62', '73'))	('betaTrCP', 'Gene', (20, 28))	('betaTrCP', 'Gene', '8945', (20, 28))	('signalling', 'biological_process', 'GO:0023052', ('105', '115'))	('Cul4A', 'Var', (30, 35))	('REDD1', 'Gene', '54541', (77, 82))	('proteolysis', 'MPA', (62, 73))	('REDD1', 'Gene', (77, 82))	('mediate', 'Reg', (54, 61))
136292	26218750	By associating with FBXW5, Cul4A has been shown to mediate proteolysis of TSC2, another mTOR signalling inhibitor.	('mediate', 'Reg', (51, 58))	('proteolysis', 'biological_process', 'GO:0006508', ('59', '70'))	('signalling', 'biological_process', 'GO:0023052', ('93', '103'))	('FBXW5', 'Gene', '54461', (20, 25))	('TSC2', 'Gene', '7249', (74, 78))	('TSC2', 'Gene', (74, 78))	('FBXW5', 'Gene', (20, 25))	('proteolysis', 'MPA', (59, 70))	('Cul4A', 'Var', (27, 32))
136299	26218750	We have also observed decreased transcriptional activities of SMO and Gli1 in mesothelioma H28 cells after Cul4A knockdown by siRNA (data not shown), suggesting that SMO is in part involved in the Cul4A-mediated Gli1 expression.	('SMO', 'Gene', (62, 65))	('Cul4A', 'Gene', (107, 112))	('Gli1', 'Gene', '2735', (212, 216))	('Gli1', 'Gene', (70, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('SMO', 'Gene', '6608', (166, 169))	('SMO', 'Gene', '6608', (62, 65))	('SMO', 'Gene', (166, 169))	('Gli1', 'Gene', '2735', (70, 74))	('knockdown', 'Var', (113, 122))	('Gli1', 'Gene', (212, 216))	('transcriptional activities', 'MPA', (32, 58))	('mesothelioma', 'Disease', (78, 90))	('decreased', 'NegReg', (22, 31))
136302	26218750	In this study, knocking-down Cul4A expression by using siRNA showed that Gli1 mRNA level and Gli1 protein level were both decreased in the treated mesothelioma cells, suggesting that inhibiting Cul4A decreased Gli1 expression.	('Gli1', 'Gene', (210, 214))	('mesothelioma', 'Disease', (147, 159))	('Gli1', 'Gene', '2735', (210, 214))	('Gli1', 'Gene', (73, 77))	('Cul4A', 'Gene', (29, 34))	('Gli1', 'Gene', (93, 97))	('knocking-down', 'Var', (15, 28))	('Gli1', 'Gene', '2735', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('inhibiting', 'Var', (183, 193))	('decreased', 'NegReg', (200, 209))	('Gli1', 'Gene', '2735', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('decreased', 'NegReg', (122, 131))	('expression', 'MPA', (215, 225))
136310	26218750	Studies also shown that Gli1 inhibition induces cell-cycle arrest by promoting p21 transcriptional activity in human cancer cells.	('p21', 'Protein', (79, 82))	('Gli1', 'Gene', (24, 28))	('promoting', 'PosReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Gli1', 'Gene', '2735', (24, 28))	('human', 'Species', '9606', (111, 116))	('arrest', 'Disease', (59, 65))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('48', '65'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('inhibition', 'Var', (29, 39))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
136312	26218750	The increased Cul4A copy number and its association with Gli1 regulation in mesothelioma cells highlight Cul4A as a possible new therapeutic target for mesothelioma tumours.	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (152, 172))	('mesothelioma tumours', 'Disease', (152, 172))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('copy number', 'Var', (20, 31))	('mesothelioma', 'Disease', (76, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))	('mesothelioma', 'Disease', (152, 164))	('Gli1', 'Gene', (57, 61))	('Cul4A', 'Gene', (14, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('association', 'Interaction', (40, 51))	('increased', 'PosReg', (4, 13))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (152, 171))	('Gli1', 'Gene', '2735', (57, 61))
136313	26218750	Cul4A can be a potential target for developing anti-mesothelioma therapeutics because (i) Cul4A is amplified and overexpressed in mesothelioma tumours and cell lines as shown in this study and others, (ii) overexpressing Cul4A induces tumourigenesis in a mouse model and (iii) knockdown of Cul4A expression reduces mesothelioma cell growth.	('mesothelioma', 'Disease', (315, 327))	('Cul4A', 'Gene', (221, 226))	('mouse', 'Species', '10090', (255, 260))	('mesothelioma', 'Disease', (52, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (315, 327))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('overexpressing', 'PosReg', (206, 220))	('mesothelioma', 'Disease', (130, 142))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (130, 150))	('tumour', 'Disease', (235, 241))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (130, 149))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('Cul4A', 'Gene', (290, 295))	('mesothelioma tumours', 'Disease', (130, 150))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('cell growth', 'biological_process', 'GO:0016049', ('328', '339'))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('knockdown', 'Var', (277, 286))	('reduces', 'NegReg', (307, 314))	('tumour', 'Disease', (143, 149))
136315	26218750	Moreover, a proteasome inhibitor Bortezomib (also known as Velcade or PS-341) that targets ubiquitin-proteasome system has been approved for the treatment of multiple myeloma and mantle cell lymphoma, and a small molecule MLN4924 that attenuates Cullin activity has entered phase I clinical trials for haematological and solid tumour malignancies.	('multiple myeloma', 'Phenotype', 'HP:0006775', (158, 174))	('PS-341', 'Chemical', 'MESH:D000069286', (70, 76))	('tumour malignancies', 'Disease', 'MESH:D009369', (327, 346))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (179, 199))	('proteasome', 'molecular_function', 'GO:0004299', ('12', '22'))	('mantle cell lymphoma', 'Disease', (179, 199))	('proteasome', 'molecular_function', 'GO:0004299', ('101', '111'))	('Cullin', 'Gene', (246, 252))	('ubiquitin', 'molecular_function', 'GO:0031386', ('91', '100'))	('Velcade', 'Chemical', 'MESH:D000069286', (59, 66))	('attenuates', 'NegReg', (235, 245))	('multiple myeloma', 'Disease', 'MESH:D009101', (158, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('proteasome', 'cellular_component', 'GO:0000502', ('101', '111'))	('proteasome', 'cellular_component', 'GO:0000502', ('12', '22'))	('activity', 'MPA', (253, 261))	('cell lymphoma', 'Phenotype', 'HP:0012191', (186, 199))	('tumour malignancies', 'Disease', (327, 346))	('multiple myeloma', 'Disease', (158, 174))	('tumour', 'Phenotype', 'HP:0002664', (327, 333))	('MLN4924', 'Var', (222, 229))	('ubiquitin-proteasome system', 'MPA', (91, 118))	('Cullin', 'Gene', '143384', (246, 252))	('Bortezomib', 'Chemical', 'MESH:D000069286', (33, 43))
136319	26218750	This may be an underestimate, given that (i) FISH analysis of clinical tissue sections was done in interphase, (ii) visualizing the locations of FISH probes in clinical tissue sections is difficult and (iii) 6/6 of mesothelioma cell lines showed increased Cul4A copy number (3-4 copies) by FISH (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (215, 227))	('interphase', 'biological_process', 'GO:0051325', ('99', '109'))	('Cul4A', 'Gene', (256, 261))	('increased', 'PosReg', (246, 255))	('copy number', 'Var', (262, 273))	('mesothelioma', 'Disease', (215, 227))
136321	26218750	In conclusion, our results suggest Cul4A overexpression, driven by increased Cul4A copy number, in mesothelioma tumours and in mesothelioma cells.	('mesothelioma', 'Disease', (127, 139))	('Cul4A', 'Gene', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (99, 119))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (99, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('Cul4A', 'Gene', (77, 82))	('increased', 'PosReg', (67, 76))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mesothelioma tumours', 'Disease', (99, 119))	('copy number', 'Var', (83, 94))	('overexpression', 'PosReg', (41, 55))	('mesothelioma', 'Disease', (99, 111))
136346	21970874	Similarly, phase II studies of the antiangiogenic agents SU5416, vatalanib, thalidomide and sorafenib demonstrated only modest activity as monotherapy, hence being comparable to other single agents in this disease.	('SU5416', 'Chemical', 'MESH:C116890', (57, 63))	('vatalanib', 'Chemical', 'MESH:C404768', (65, 74))	('SU5416', 'Var', (57, 63))	('sorafenib', 'Chemical', 'MESH:D000077157', (92, 101))	('thalidomide', 'Chemical', 'MESH:D013792', (76, 87))	('activity', 'MPA', (127, 135))
136357	21970874	The MPM cells were characterised for EGFR and k-Ras mutations.	('mutations', 'Var', (52, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('k-Ras', 'Gene', (46, 51))	('EGFR', 'Gene', '1956', (37, 41))	('k-Ras', 'Gene', '3845', (46, 51))	('EGFR', 'Gene', (37, 41))
136358	21970874	Furthermore, we evaluated the AKT1-SNP4-G/A (rs#1130233) polymorphism, related to gefitinib resistance, as well as polymorphisms that may influence pemetrexed sensitivity, such as the methylenetetrahydrofolate reductase (MTHFR) MTHFR-C677T (rs#1801133) and the reduced folate carrier (RFC) RFC-G80A (rs#1051266), and carboplatin activity, such as the DNA repair systems excision-repair cross-complementing-group-1 (ERCC1), and xeroderma-pigmentosum group-D (XPD) polymorphisms ERCC1-C118T (rs#11615), XPDAsp312Asn (rs#1799793) and XPDLys751Gln (rs#13181).	('folate', 'Chemical', 'MESH:D005492', (203, 209))	('ERCC1', 'Gene', '2067', (415, 420))	('rs#11615', 'Var', (490, 498))	('XPD', 'Gene', (458, 461))	('MTHFR', 'Gene', '4524', (228, 233))	('pemetrexed', 'Chemical', 'MESH:D000068437', (148, 158))	('MTHFR', 'Gene', (221, 226))	('rs#1799793', 'Var', (515, 525))	('ERCC1', 'Gene', (415, 420))	('AKT1', 'Gene', '207', (30, 34))	('ERCC1', 'Gene', '2067', (477, 482))	('XPD', 'Gene', '2068', (501, 504))	('carrier', 'molecular_function', 'GO:0005215', ('276', '283'))	('excision-repair cross-complementing-group-1', 'Gene', (370, 413))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (184, 219))	('XPD', 'Gene', '2068', (531, 534))	('xeroderma-pigmentosum group-D', 'Gene', (427, 456))	('MTHFR', 'Gene', (228, 233))	('rs#', 'Var', (241, 244))	('AKT1', 'Gene', (30, 34))	('RFC', 'Phenotype', 'HP:0100507', (285, 288))	('ERCC1', 'Gene', (477, 482))	('DNA', 'cellular_component', 'GO:0005574', ('351', '354'))	('methylenetetrahydrofolate reductase', 'Gene', (184, 219))	('C677T', 'Mutation', 'rs1801133', (234, 239))	('carboplatin', 'Chemical', 'MESH:D016190', (317, 328))	('xeroderma-pigmentosum group-D', 'Gene', '2068', (427, 456))	('gefitinib', 'Chemical', 'MESH:D000077156', (82, 91))	('reduced folate carrier', 'Phenotype', 'HP:0100507', (261, 283))	('influence', 'Reg', (138, 147))	('XPD', 'Gene', '2068', (458, 461))	('XPD', 'Gene', (501, 504))	('excision-repair cross-complementing-group-1', 'Gene', '2067', (370, 413))	('folate', 'Chemical', 'MESH:D005492', (269, 275))	('DNA repair', 'biological_process', 'GO:0006281', ('351', '361'))	('MTHFR', 'Gene', '4524', (221, 226))	('RFC', 'Phenotype', 'HP:0100507', (290, 293))	('C118T', 'Mutation', 'rs11615', (483, 488))	('XPD', 'Gene', (531, 534))	('G80A', 'Mutation', 'rs986893901', (294, 298))
136365	21970874	The cytotoxicity of these combinations was compared with the cytotoxicity of each drug alone using the combination index (CI), where CI<0.9, CI=0.9-1.1 and CI>1.1 indicated synergistic, additive and antagonistic effects, respectively.	('cytotoxicity', 'Disease', (61, 73))	('CI=0.9-1.1', 'Var', (141, 151))	('CI>', 'Var', (156, 159))	('CI<0.9', 'Var', (133, 139))	('cytotoxicity', 'Disease', (4, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
136371	21970874	Gene expression of the following key determinants of drug sensitivity was assessed by RT-PCR: EGFR (NM_005228.3), VEGFR-2 (NM_002253.2), RET (NM_020363.4) ERCC1 (NM_001983), XPD (NM_000400), thymidylate synthase (TS; NM_0010711), dihydrofolate reductase (DHFR; NM_000791), glycinamide ribonucleotide formyltransferase (GARFT; NM_000819), RFC (NM_194255.1) and folyl-polyglutamate synthetase (FPGS; NM_004957).	('NM_000400', 'Var', (179, 188))	('ERCC1', 'Gene', (155, 160))	('glycinamide ribonucleotide formyltransferase', 'Gene', '2618', (273, 317))	('NM_001983', 'Var', (162, 171))	('folyl-polyglutamate synthetase', 'Gene', (360, 390))	('EGFR', 'Gene', (115, 119))	('DHFR', 'Gene', (255, 259))	('dihydrofolate reductase', 'Gene', '1719', (230, 253))	('GARFT', 'Gene', '2618', (319, 324))	('GARFT', 'Gene', (319, 324))	('NM_020363.4', 'Var', (142, 153))	('EGFR', 'Gene', '1956', (94, 98))	('VEGFR-2', 'Gene', '3791', (114, 121))	('RET', 'Gene', (137, 140))	('TS', 'Gene', '7298', (213, 215))	('DHFR', 'Gene', '1719', (255, 259))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('XPD', 'Gene', '2068', (174, 177))	('drug sensitivity', 'Phenotype', 'HP:0020174', (53, 69))	('EGFR', 'Gene', '1956', (115, 119))	('NM_194255.1', 'Var', (343, 354))	('VEGFR-2', 'Gene', (114, 121))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('folyl-polyglutamate synthetase', 'Gene', '2356', (360, 390))	('thymidylate synthase', 'Gene', (191, 211))	('dihydrofolate reductase', 'Gene', (230, 253))	('RFC', 'Phenotype', 'HP:0100507', (338, 341))	('thymidylate synthase', 'Gene', '7298', (191, 211))	('glycinamide ribonucleotide formyltransferase', 'Gene', (273, 317))	('EGFR', 'Gene', (94, 98))	('ERCC1', 'Gene', '2067', (155, 160))	('DHFR', 'molecular_function', 'GO:0004146', ('255', '259'))	('FPGS', 'Gene', (392, 396))	('FPGS', 'Gene', '2356', (392, 396))	('RET', 'Gene', '5979', (137, 140))	('XPD', 'Gene', (174, 177))
136401	21970874	MSTO-211H cells harbouring the XPD-Asp312Asn/Lys751Gln genotypes were the most drug-sensitive cells, whereas H28 cells bearing the XPD-Asp312Asp/Lys751Lys genotypes were the most inherently drug resistant to both carboplatin and pemetrexed.	('drug-sensitive', 'MPA', (79, 93))	('carboplatin', 'Chemical', 'MESH:D016190', (213, 224))	('pemetrexed', 'Chemical', 'MESH:D000068437', (229, 239))	('XPD', 'Gene', (31, 34))	('Asp312Asn', 'Var', (35, 44))	('Lys751Lys', 'Chemical', '-', (145, 154))	('Lys751Gln', 'SUBSTITUTION', 'None', (45, 54))	('Asp312Asn', 'SUBSTITUTION', 'None', (35, 44))	('MSTO-211H', 'CellLine', 'CVCL:1430', (0, 9))	('XPD', 'Gene', '2068', (31, 34))	('XPD', 'Gene', (131, 134))	('Lys751Gln', 'Var', (45, 54))	('XPD', 'Gene', '2068', (131, 134))
136412	21970874	Both the carboplatin and vandetanib combinations reduced the IC50 values of pemetrexed in the studied cell lines.	('IC50 values', 'MPA', (61, 72))	('reduced', 'NegReg', (49, 56))	('vandetanib', 'Chemical', 'MESH:C452423', (25, 35))	('pemetrexed', 'Chemical', 'MESH:D000068437', (76, 86))	('combinations', 'Var', (36, 48))	('carboplatin', 'Chemical', 'MESH:D016190', (9, 20))
136418	21970874	In contrast, pemetrexed increased the fraction of cells in the S-phase; this increment was most pronounced in MSTO-211H and H2052 (1.6- and 1.9-fold, respectively).	('MSTO-211H', 'CellLine', 'CVCL:1430', (110, 119))	('S-phase', 'biological_process', 'GO:0051320', ('63', '70'))	('H2052', 'Var', (124, 129))	('MSTO-211H', 'Var', (110, 119))	('pemetrexed', 'Chemical', 'MESH:D000068437', (13, 23))	('H2052', 'Chemical', '-', (124, 129))	('increased', 'PosReg', (24, 33))
136425	21970874	Expectedly, vandetanib significantly suppressed EGFR phosphorylation at the tyrosine residue pY1173, with percentages of reduction of phospho-EGFR ranging up to -74.3% in H28 cells.	('vandetanib', 'Chemical', 'MESH:C452423', (12, 22))	('EGFR', 'Gene', '1956', (48, 52))	('tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (142, 146))	('EGFR', 'Gene', (48, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('pY1173', 'Var', (93, 99))	('suppressed', 'NegReg', (37, 47))
136438	21970874	Similarly, both vandetanib and its combinations significantly reduced E2F-1 mRNA levels in MPM cells, and the modifications in TS and E2F-1 expression levels after vandetanib and vandetanib combinations were correlated (R2=0.87).	('E2F-1 mRNA levels', 'MPA', (70, 87))	('expression', 'MPA', (140, 150))	('vandetanib', 'Chemical', 'MESH:C452423', (179, 189))	('TS', 'Gene', '7298', (127, 129))	('vandetanib', 'Chemical', 'MESH:C452423', (164, 174))	('combinations', 'Var', (35, 47))	('vandetanib', 'Chemical', 'MESH:C452423', (16, 26))	('combinations', 'Var', (190, 202))	('reduced', 'NegReg', (62, 69))
136473	21970874	These findings are in agreement with previous preclinical studies, showing a prominent activity of EGFR inhibitors in mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('EGFR', 'Gene', (99, 103))	('activity', 'MPA', (87, 95))	('mesothelioma', 'Disease', (118, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', '1956', (99, 103))	('inhibitors', 'Var', (104, 114))
136503	21970874	In this regard, transfection of gastric cells with a cyclin D1 antisense oligodeoxynucleotide reduced TS mRNA and significantly increased 5-FU and methotrexate sensitivity.	('reduced', 'NegReg', (94, 101))	('increased', 'PosReg', (128, 137))	('cyclin D1', 'Gene', '595', (53, 62))	('5-FU', 'Chemical', 'MESH:D005472', (138, 142))	('TS', 'Gene', '7298', (102, 104))	('cyclin D1', 'Gene', (53, 62))	('gastric', 'Disease', 'MESH:D013274', (32, 39))	('gastric', 'Disease', (32, 39))	('antisense', 'Var', (63, 72))	('cyclin', 'molecular_function', 'GO:0016538', ('53', '59'))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (73, 93))	('methotrexate', 'Chemical', 'MESH:D008727', (147, 159))
136505	21970874	Due to the accelerated rate of DNA replication in neoplastic cells, disruption of folate metabolism and consequent depletion of cellular nucleotide pools causes impaired DNA synthesis and repair.	('folate metabolism', 'biological_process', 'GO:0046655', ('82', '99'))	('DNA synthesis', 'MPA', (170, 183))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('folate metabolism', 'MPA', (82, 99))	('folate', 'Chemical', 'MESH:D005492', (82, 88))	('disruption', 'Var', (68, 78))	('DNA replication', 'biological_process', 'GO:0006260', ('31', '46'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('impaired', 'NegReg', (161, 169))	('accelerated', 'PosReg', (11, 22))	('repair', 'MPA', (188, 194))	('DNA synthesis', 'biological_process', 'GO:0071897', ('170', '183'))	('rate', 'MPA', (23, 27))	('depletion of cellular nucleotide pools', 'MPA', (115, 153))
136506	21970874	Furthermore, folate deficiency has been shown to act synergistically with alkylating agents to increase DNA strand breaks and mutations as a result of impaired DNA excision repair.	('DNA strand breaks', 'MPA', (104, 121))	('folate', 'Chemical', 'MESH:D005492', (13, 19))	('DNA excision', 'biological_process', 'GO:0044349', ('160', '172'))	('deficiency', 'Var', (20, 30))	('increase', 'PosReg', (95, 103))	('DNA excision repair', 'MPA', (160, 179))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('impaired', 'NegReg', (151, 159))	('folate deficiency', 'Phenotype', 'HP:0100507', (13, 30))	('mutations', 'Var', (126, 135))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))
136611	33208866	Accordingly, regulators of actomyosin contractility and Rho-ROCK signaling in cancer cells have become the main target of drugs that target cell motility ("migrastatics") and showed promising effects both in vitro and in vivo in a variety of cancer types including lung, breast and prostate cancer.	('drugs', 'Var', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (282, 297))	('lung', 'Disease', (265, 269))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cell motility', 'CPA', (140, 153))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (271, 297))	('myosin', 'Gene', '79784', (31, 37))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', (78, 84))	('actomyosin', 'cellular_component', 'GO:0042641', ('27', '37'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (242, 248))	('cell motility', 'biological_process', 'GO:0048870', ('140', '153'))	('myosin', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('effects', 'Reg', (192, 199))
136616	33208866	In such long term cultures around half of the cell lines established from MPM patients form macroscopic nodules (Supplementary Table S1), similar to nodules appearing on the pleural surfaces of mesothelioma patients and in orthotopic models of certain mesothelioma cell lines (Fig.	('mesothelioma', 'Disease', (252, 264))	('patients', 'Species', '9606', (207, 215))	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('patients', 'Species', '9606', (78, 86))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('mesothelioma', 'Disease', (194, 206))	('MPM', 'Var', (74, 77))
136633	33208866	The compound Y27632 is a specific inhibitor of Rho kinase (ROCK), which is a prominent myosin activator.	('myosin', 'Gene', (87, 93))	('Y27632', 'Chemical', 'MESH:C108830', (13, 19))	('myosin', 'Gene', '79784', (87, 93))	('Y27632', 'Var', (13, 19))
136634	33208866	Both Y27632 and blebbistatin substantially reduce or completely abrogate the formation of intracellular stress cables (Fig.	('reduce', 'NegReg', (43, 49))	('Y27632', 'Var', (5, 11))	('blebbistatin', 'Chemical', 'MESH:C472645', (16, 28))	('abrogate', 'NegReg', (64, 72))	('intracellular', 'cellular_component', 'GO:0005622', ('90', '103'))	('formation of intracellular stress cables', 'MPA', (77, 117))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('Y27632', 'Chemical', 'MESH:C108830', (5, 11))
136637	33208866	Administration of Y27632 reduces contractility by 50% and 40% in SPC111 (Fig.	('reduces', 'NegReg', (25, 32))	('Y27632', 'Chemical', 'MESH:C108830', (18, 24))	('contractility', 'MPA', (33, 46))	('SPC', 'molecular_function', 'GO:0009004', ('65', '68'))	('Y27632', 'Var', (18, 24))
136645	33208866	To relate cell movements and external forces acting on a cell we envision the following process: when a cell-substrate connection breaks, the same mechanical load is distributed along the remaining adhesion complexes.	('breaks', 'Var', (130, 136))	('actin', 'Gene', '40444', (45, 50))	('actin', 'Gene', (45, 50))
136654	33208866	Previous investigations particularly in non-tumorous cells described an IC50 lower than M for both blebbistatin and Y27632.	('Y27632', 'Var', (116, 122))	('IC50', 'MPA', (72, 76))	('tumorous', 'Disease', 'MESH:D009369', (44, 52))	('tumorous', 'Disease', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('blebbistatin', 'Chemical', 'MESH:C472645', (99, 111))	('Y27632', 'Chemical', 'MESH:C108830', (116, 122))
136666	33208866	Still, interfering with actomyosin contractility has emerged as a novel therapeutic approach in various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('interfering', 'Var', (7, 18))	('actomyosin', 'cellular_component', 'GO:0042641', ('24', '34'))	('myosin', 'Gene', (28, 34))	('malignancies', 'Disease', (104, 116))	('myosin', 'Gene', '79784', (28, 34))
136675	33208866	The non-MPM tumor cell lines MEWO, A375, DLD-1, HT29, SW1417, HCT116, A549, CRL5922, CRL2066, H1650, U87, U373, A172 and T98 were purchased from the ATCC.	('CRL2066', 'Var', (85, 92))	('HT29', 'CellLine', 'CVCL:0320', (48, 52))	('SW1417', 'CellLine', 'CVCL:1717', (54, 60))	('HCT116', 'CellLine', 'CVCL:0291', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('H1650', 'Var', (94, 99))	('A375', 'CellLine', 'CVCL:0132', (35, 39))	('U87', 'CellLine', 'CVCL:0022', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
136679	33208866	Genetical characterization of MPM cell lines was carried out by identification of alterations in TERT promoter region, BAP1, TP53 and NF2 described in.	('TERT', 'Gene', '7015', (97, 101))	('TP53', 'Gene', '7157', (125, 129))	('NF2', 'Gene', '4771', (134, 137))	('TP53', 'Gene', (125, 129))	('BAP1', 'Gene', '8314', (119, 123))	('TERT', 'Gene', (97, 101))	('alterations', 'Var', (82, 93))	('NF2', 'Gene', (134, 137))	('BAP1', 'Gene', (119, 123))
136689	33208866	To interfere with normal actomyosin function, we utilized Y27632, the rho kinase (ROCK) inhibitor (Merck Millipore) and Blebbistatin (Merck Millipore), an inhibitor of actomyosin crosslinking.	('Blebbistatin', 'Chemical', 'MESH:C472645', (120, 132))	('Y27632', 'Chemical', 'MESH:C108830', (58, 64))	('actomyosin', 'cellular_component', 'GO:0042641', ('168', '178'))	('myosin', 'Gene', (172, 178))	('actomyosin', 'cellular_component', 'GO:0042641', ('25', '35'))	('myosin', 'Gene', '79784', (172, 178))	('Y27632', 'Var', (58, 64))	('myosin', 'Gene', (29, 35))	('myosin', 'Gene', '79784', (29, 35))
136697	33208866	Filamentous actin was stained either by Phalloidin-TRITC (P1951, Sigma), or Phalloidin-FITC (P5282, Sigma).	('actin', 'Gene', (12, 17))	('P1951', 'Var', (58, 63))	('Phalloidin-TRITC', 'Chemical', '-', (40, 56))	('Filamentous actin', 'cellular_component', 'GO:0031941', ('0', '17'))	('Phalloidin-FITC', 'Chemical', '-', (76, 91))	('actin', 'Gene', '40444', (12, 17))	('P5282', 'Var', (93, 98))
136724	32039010	However, MPM carcinogenesis and outcome are influenced by many factors: BRCA-associated protein 1 (BAP1) expression status, CDKN2A and neurofibromatosis type 2 (NF2) tumor suppressor inactivation, overexpression of growth factors such as vascular endothelial growth factor (VEGF), mesothelin (MSLN) promoter methylation, and Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/mTOR pathway activation.	('CDKN2A', 'Gene', (124, 130))	('BAP1', 'Gene', (99, 103))	('NF2', 'Gene', (161, 164))	('MPM', 'Disease', (9, 12))	('vascular endothelial growth factor', 'Gene', '7422', (238, 272))	('overexpression', 'PosReg', (197, 211))	('MPM', 'Disease', 'MESH:C562839', (9, 12))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (135, 152))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('VEGF', 'Gene', (274, 278))	('BRCA-associated protein 1', 'Gene', (72, 97))	('vascular endothelial growth factor', 'Gene', (238, 272))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('neurofibromatosis type 2', 'Gene', '4771', (135, 159))	('CDKN2A', 'Gene', '1029', (124, 130))	('mesothelin', 'Gene', (281, 291))	('BRCA-associated protein 1', 'Gene', '8314', (72, 97))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('238', '272'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (366, 386))	('protein', 'cellular_component', 'GO:0003675', ('347', '354'))	('methylation', 'biological_process', 'GO:0032259', ('308', '319'))	('mTOR', 'Gene', (396, 400))	('tumor', 'Disease', (166, 171))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('inactivation', 'Var', (183, 195))	('BAP1', 'Gene', '8314', (99, 103))	('mesothelin', 'Gene', '10232', (281, 291))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mTOR', 'Gene', '2475', (396, 400))	('NF2', 'Gene', '4771', (161, 164))	('influenced', 'Reg', (44, 54))	('activation', 'PosReg', (409, 419))	('neurofibromatosis type 2', 'Gene', (135, 159))	('MSLN', 'Gene', (293, 297))	('VEGF', 'Gene', '7422', (274, 278))
136742	32039010	A phase Ib study indicates that a combination of GSK3052230 plus cisplatin-pemetrexed-CT leads to an ORR of 44% and to a median PFS of 7.4 months with limited adverse events.	('GSK3052230', 'Var', (49, 59))	('ORR', 'MPA', (101, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('GSK', 'molecular_function', 'GO:0050321', ('49', '52'))
136744	32039010	ASS1 deficiency is twice more frequent in the biphasic/sarcomatoid histotypes than in the epithelioid subtype.	('sarcomatoid', 'Disease', (55, 66))	('deficiency', 'Var', (5, 15))	('sarcomatoid', 'Disease', 'MESH:D002292', (55, 66))	('ASS1', 'Gene', '445', (0, 4))	('ASS1', 'Gene', (0, 4))
136747	32039010	The ATOMIC-Meso phase III trial (NCT02709512) is recruiting patients with ASS1 gene loss.	('patients', 'Species', '9606', (60, 68))	('gene', 'Var', (79, 83))	('loss', 'NegReg', (84, 88))	('ASS1', 'Gene', (74, 78))	('ASS1', 'Gene', '445', (74, 78))
136750	32039010	Inherited loss-of-function mutations in BAP1 predispose to multiple carcinomas, including mesothelioma.	('mutations', 'Var', (27, 36))	('multiple carcinomas', 'Disease', 'MESH:C537656', (59, 78))	('multiple carcinomas', 'Disease', (59, 78))	('loss-of-function', 'NegReg', (10, 26))	('BAP1', 'Gene', '8314', (40, 44))	('mesothelioma', 'Disease', (90, 102))	('BAP1', 'Gene', (40, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
136751	32039010	Interestingly, MPM patients with germline mutated BAP1 or with genetic alterations in other DNA repair genes and treated with platinum CT showed a significantly longer median OS than patients devoid of the same mutations.	('genetic alterations', 'Var', (63, 82))	('MPM', 'Disease', (15, 18))	('patients', 'Species', '9606', (19, 27))	('MPM', 'Disease', 'MESH:C562839', (15, 18))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('germline mutated', 'Var', (33, 49))	('BAP1', 'Gene', '8314', (50, 54))	('DNA repair', 'biological_process', 'GO:0006281', ('92', '102'))	('longer', 'PosReg', (161, 167))	('BAP1', 'Gene', (50, 54))	('platinum', 'Chemical', 'MESH:D010984', (126, 134))	('median', 'MPA', (168, 174))	('patients', 'Species', '9606', (183, 191))
136753	32039010	Accordingly, as already suggested by Srinivasan et al., the homologous repair (HR) component PARP-1 would be an excellent target for a synthetic lethality approach, given that MPM cells are frequently characterized by HR deficiency and unrepaired DNA damage accumulation due to the aforementioned BAP1 mutations.	('MPM', 'Disease', (176, 179))	('mutations', 'Var', (302, 311))	('deficiency', 'NegReg', (221, 231))	('PARP-1', 'Gene', (93, 99))	('accumulation', 'PosReg', (258, 270))	('PARP-1', 'Gene', '142', (93, 99))	('BAP1', 'Gene', '8314', (297, 301))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('BAP1', 'Gene', (297, 301))	('MPM', 'Disease', 'MESH:C562839', (176, 179))
136809	32039010	The phase I trial NCT01675765 evaluated the sequential administration of the cancer vaccine CRS-207, an attenuated form of Listeria monocytogenes expressing MSLN, with or without cyclophosphamide followed by consolidation CT, to stimulate an innate and adaptive immunity against MSLN-expressing cells.	('stimulate', 'PosReg', (229, 238))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('MSLN', 'Var', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (179, 195))	('Listeria monocytogenes', 'Species', '1639', (123, 145))
136829	30719319	Furthermore, p16 deletions were specifically detected by fluorescence in situ hybridization, and electron microscopy showed numerous, significantly elongated microvilli.	('microvilli', 'cellular_component', 'GO:0005902', ('158', '168'))	('p16', 'Gene', (13, 16))	('deletions', 'Var', (17, 26))	('elongated', 'PosReg', (148, 157))	('p16', 'Gene', '1029', (13, 16))
136862	30719319	Furthermore, p16 deletions were specifically detected by FISH (Figure 3(c)), but electron microscopy also showed numerous, significantly elongated microvilli (Figure 3(d)).	('elongated', 'PosReg', (137, 146))	('p16', 'Gene', (13, 16))	('deletions', 'Var', (17, 26))	('p16', 'Gene', '1029', (13, 16))	('microvilli', 'cellular_component', 'GO:0005902', ('147', '157'))
136868	30719319	Furthermore, the other useful method for discriminating LMPM was presented as the detection of homozygous deletion of p16 using FISH.	('p16', 'Gene', '1029', (118, 121))	('p16', 'Gene', (118, 121))	('deletion', 'Var', (106, 114))
136869	30719319	It is well known that p16 is located on 21.3 region of the short arm of chromosome 9 (9p21.3), and the homozygous deletion of p16 has been identified in up to 86% of epithelioid-type MPM cases.	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('p16', 'Gene', (126, 129))	('p16', 'Gene', '1029', (22, 25))	('epithelioid-type MPM', 'Disease', (166, 186))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('identified', 'Reg', (139, 149))	('p16', 'Gene', '1029', (126, 129))	('p16', 'Gene', (22, 25))	('deletion', 'Var', (114, 122))
136910	28182302	In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice.	('transfection', 'Var', (19, 31))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('Ki-67-positive', 'Protein', (114, 128))	('increase', 'PosReg', (88, 96))	('PDPN', 'Gene', (35, 39))	('progression', 'CPA', (171, 182))	('SCID', 'Disease', 'MESH:D053632', (206, 210))	('SCID', 'Disease', (206, 210))	('PDPN-low', 'Gene', (43, 51))	('mice', 'Species', '10090', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('SCID', 'Phenotype', 'HP:0004430', (206, 210))	('tumor', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('promoted', 'PosReg', (162, 170))
136921	28182302	The procedure for Western blotting was as previously described.11 The primary antibodies (Ab) used were anti- PDPN Ab (AngioBio Co.), anti-E-cadherin Ab (Cell Signaling), anti-N-cadherin Ab (Cell Signaling), anti-Vimentin Ab (Cell Signaling), anti-GAPDH Ab (Trevigen), and anti-beta-actin Ab (Cell Signaling).	('E-cadherin', 'Gene', (139, 149))	('cadherin', 'molecular_function', 'GO:0008014', ('178', '186'))	('Vimentin', 'cellular_component', 'GO:0045098', ('213', '221'))	('Signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('Vimentin', 'Gene', '7431', (213, 221))	('anti-beta-actin', 'Var', (273, 288))	('E-cadherin', 'Gene', '999', (139, 149))	('Vimentin', 'cellular_component', 'GO:0045099', ('213', '221'))	('anti-N-cadherin Ab', 'Protein', (171, 189))	('Signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('Signaling', 'biological_process', 'GO:0023052', ('298', '307'))	('Vimentin', 'Gene', (213, 221))	('anti-GAPDH', 'Var', (243, 253))	('Signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
136928	28182302	Tumor cells were transfected with siRNAs against PDPN (Stealth siRNAs: HSS116395, HSS116397, HSS173792) or Stealth RNAi-negative control low GC Duplex #3 (Invitrogen) introduced into cells using Lipofectamine RNAiMAX (Invitrogen) according to the manufacturer's instructions.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PDPN', 'Gene', (49, 53))	('HSS116395', 'Var', (71, 80))	('HSS173792', 'Var', (93, 102))	('RNAi', 'biological_process', 'GO:0016246', ('115', '119'))	('Lipofectamine', 'Chemical', 'MESH:C086724', (195, 208))	('HSS116397', 'Var', (82, 91))
136933	28182302	Formalin-fixed paraffin-embedded tumor sections were subjected to antigen retrieval and endogenous peroxidase blocking, and sections were incubated with primary antibody (Ab), anti-Ki-67 Ab (Dako), or anti-Yes-associated protein 1 (YAP1) Ab (Cell Signaling) at 4 C overnight.	('antibody', 'cellular_component', 'GO:0019814', ('161', '169'))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('antibody', 'molecular_function', 'GO:0003823', ('161', '169'))	('anti-Ki-67', 'Var', (176, 186))	('Signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('anti-Yes-associated protein 1', 'Gene', '10413', (201, 230))	('YAP1', 'Gene', '10413', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('antibody', 'cellular_component', 'GO:0042571', ('161', '169'))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('anti-Yes-associated protein 1', 'Gene', (201, 230))	('tumor', 'Disease', (33, 38))	('antibody', 'cellular_component', 'GO:0019815', ('161', '169'))	('YAP1', 'Gene', (232, 236))
136942	28182302	In order to determine the role of PDPN in MPM cell lines, PDPN was knocked down with siRNA in 2 cell lines expressing high levels of PDPN (H226 and H2452).	('H226', 'CellLine', 'CVCL:J621', (139, 143))	('PDPN', 'Gene', (58, 62))	('knocked', 'Var', (67, 74))
136944	28182302	When PDPN was stably knocked down with shRNA in H226, motility was inhibited (Fig.	('inhibited', 'NegReg', (67, 76))	('knocked down', 'Var', (21, 33))	('H226', 'CellLine', 'CVCL:J621', (48, 52))	('motility', 'CPA', (54, 62))	('PDPN', 'Gene', (5, 9))
136946	28182302	Transfection of PDPN into MSTO-211H cells resulted in increased RhoA-GTP binding (Fig.	('GTP binding', 'molecular_function', 'GO:0005525', ('69', '80'))	('increased', 'PosReg', (54, 63))	('GTP', 'Chemical', 'MESH:D006160', (69, 72))	('Transfection', 'Var', (0, 12))	('RhoA', 'Gene', (64, 68))	('PDPN', 'Gene', (16, 20))	('RhoA', 'Gene', '387', (64, 68))
136947	28182302	Conversely, knocking down PDPN with specific siRNA in H226 cells resulted in decreased RhoA-GTP binding (Fig.	('H226', 'CellLine', 'CVCL:J621', (54, 58))	('GTP', 'Chemical', 'MESH:D006160', (92, 95))	('RhoA', 'Gene', '387', (87, 91))	('GTP binding', 'molecular_function', 'GO:0005525', ('92', '103'))	('RhoA', 'Gene', (87, 91))	('knocking down', 'Var', (12, 25))	('PDPN', 'Gene', (26, 30))	('decreased', 'NegReg', (77, 86))
136951	28182302	In H226 cells, tumor progression (the intrathoracic tumor burden) was inhibited by the knockdown of PDPN with shRNA (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PDPN', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('H226', 'CellLine', 'CVCL:J621', (3, 7))	('inhibited', 'NegReg', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('knockdown', 'Var', (87, 96))
136952	28182302	In contrast, tumor progression was promoted by transfection of PDPN into MSTO-211H cells, and mice had a significantly reduced survival time (Fig.	('tumor', 'Disease', (13, 18))	('transfection', 'Var', (47, 59))	('survival time', 'CPA', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('promoted', 'PosReg', (35, 43))	('mice', 'Species', '10090', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('reduced', 'NegReg', (119, 126))	('PDPN', 'Var', (63, 67))
136955	28182302	In another cell line expressing low levels of PDPN (H290), transfection of the PDPN gene resulted in enhanced tumor progression in a model of orthotopic implantation and an increased number of Ki-67-positive proliferating cells (Fig.	('PDPN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('transfection', 'Var', (59, 71))	('increased', 'PosReg', (173, 182))	('enhanced', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
136960	28182302	In contrast, knockdown of PDPN enhanced contact inhibition in H226 cells (Fig.	('contact inhibition', 'biological_process', 'GO:0060242', ('40', '58'))	('contact inhibition', 'CPA', (40, 58))	('enhanced', 'PosReg', (31, 39))	('H226', 'CellLine', 'CVCL:J621', (62, 66))	('PDPN', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
136966	28182302	Moreover, PDPN knockdown in H226 cells resulted in increased E-cadherin expression, whereas transfection of PDPN into MSTO-211H cells resulted in decreased E-cadherin expression (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('63', '71'))	('PDPN', 'Gene', (10, 14))	('knockdown', 'Var', (15, 24))	('E-cadherin', 'Gene', (61, 71))	('increased', 'PosReg', (51, 60))	('E-cadherin', 'Gene', (156, 166))	('E-cadherin', 'Gene', '999', (156, 166))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('decreased', 'NegReg', (146, 155))	('E-cadherin', 'Gene', '999', (61, 71))	('H226', 'CellLine', 'CVCL:J621', (28, 32))
136970	28182302	Increased motility due to PDPN was noted in various types of cells, including breast cancer cells, pancreatic beta cell carcinoma,20 and cells derived from the kidney.21 This view is uncontested, but there is still debate as to whether motility increased by PDPN occurs via induction of an epithelial-mesenchymal transition (EMT) or not.20, 21 In the present study, PDPN expression in MPM cells did cause a decrease in E-cadherin expression but it did not necessarily trigger an increase in vimentin (Fig.	('decrease', 'NegReg', (407, 415))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('vimentin', 'Gene', (491, 499))	('PDPN expression', 'Var', (366, 381))	('vimentin', 'cellular_component', 'GO:0045099', ('491', '499'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('290', '323'))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pancreatic beta cell carcinoma', 'Disease', 'MESH:D007340', (99, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('421', '429'))	('E-cadherin', 'Gene', (419, 429))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('vimentin', 'cellular_component', 'GO:0045098', ('491', '499'))	('EMT', 'biological_process', 'GO:0001837', ('325', '328'))	('pancreatic beta cell carcinoma', 'Disease', (99, 129))	('vimentin', 'Gene', '7431', (491, 499))	('breast cancer', 'Disease', (78, 91))	('E-cadherin', 'Gene', '999', (419, 429))
137003	27259231	Asbestos exposure entails inhalation of mineral fibers and their accumulation in the lungs, where they cause a variety of adverse effects that include production of reactive oxygen species (ROS), chromosome damage, disturbance of mitosis, gene mutations, alteration of growth factor signaling, defects in the apoptotic machinery, deregulation of methylation status, chronic inflammation, phagocytosis, and aberrant microRNA (miRNA, miR) expression.	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('miR', 'Gene', '220972', (425, 428))	('methylation', 'biological_process', 'GO:0032259', ('346', '357'))	('miR', 'Gene', '220972', (432, 435))	('chromosome damage', 'CPA', (196, 213))	('growth factor', 'CPA', (269, 282))	('aberrant', 'Var', (406, 414))	('methylation', 'MPA', (346, 357))	('signaling', 'biological_process', 'GO:0023052', ('283', '292'))	('miR', 'Gene', (425, 428))	('deregulation', 'Reg', (330, 342))	('miR', 'Gene', (432, 435))	('mitosis', 'biological_process', 'GO:0000278', ('230', '237'))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('disturbance of mitosis', 'Disease', (215, 237))	('inflammation', 'biological_process', 'GO:0006954', ('374', '386'))	('phagocytosis', 'biological_process', 'GO:0006909', ('388', '400'))	('apoptotic machinery', 'CPA', (309, 328))	('defects', 'Reg', (294, 301))	('inflammation', 'Disease', 'MESH:D007249', (374, 386))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (165, 188))	('alteration', 'Reg', (255, 265))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('phagocytosis', 'CPA', (388, 400))	('disturbance of mitosis', 'Disease', 'MESH:D010468', (215, 237))	('inflammation', 'Disease', (374, 386))
137004	27259231	In the lung parenchyma, asbestos can cause non-malignant inflammatory diseases such as permanent fibrosis (asbestosis) and accumulation of asbestos bodies, which are composed of fibers coated with iron-containing protein.	('asbestos bodies', 'Phenotype', 'HP:0011002', (139, 154))	('asbestos', 'Var', (24, 32))	('lung parenchyma', 'Disease', 'MESH:D010195', (7, 22))	('asbestos', 'Chemical', 'MESH:D001194', (24, 32))	('asbestos', 'Chemical', 'MESH:D001194', (107, 115))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('non-malignant inflammatory diseases', 'Disease', (43, 78))	('asbestosis', 'Disease', 'MESH:D001195', (107, 117))	('asbestos bodies', 'Disease', 'MESH:D001195', (139, 154))	('fibrosis', 'Disease', 'MESH:D005355', (97, 105))	('fibrosis', 'Disease', (97, 105))	('asbestos bodies', 'Disease', (139, 154))	('lung parenchyma', 'Disease', (7, 22))	('iron', 'Chemical', 'MESH:D007501', (197, 201))	('asbestos', 'Chemical', 'MESH:D001194', (139, 147))	('asbestosis', 'Disease', (107, 117))	('cause', 'Reg', (37, 42))
137017	27259231	In the latter subjects, MM, uveal melanoma and other cancers have also been related to genetic predisposing factors such as germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1).	('germline mutations', 'Var', (124, 142))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('BRCA1 associated protein-1', 'Gene', (164, 190))	('BAP1', 'Gene', (192, 196))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA1 associated protein-1', 'Gene', '8314', (164, 190))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('BAP1', 'Gene', '8314', (192, 196))	('uveal melanoma', 'Phenotype', 'HP:0007716', (28, 42))	('uveal melanoma', 'Disease', (28, 42))	('related', 'Reg', (76, 83))
137024	27259231	Advanced stage, poor differentiation, co-morbidities, advanced age, failure to undergo surgical resection, and male gender are associated with a poorer prognosis.	('poor', 'Var', (16, 20))	('failure', 'Disease', 'MESH:D017093', (68, 75))	('failure', 'Disease', (68, 75))
137069	27259231	It has also been reported that miR-23a and miR-27a modulation in MM induce silencing of ZIC1, a potential tumor suppressor gene involved in apoptosis.	('miR-23a', 'Gene', (31, 38))	('modulation', 'Var', (51, 61))	('ZIC1', 'Gene', '7545', (88, 92))	('ZIC1', 'Gene', (88, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('miR-27a', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('miR-23a', 'Gene', '407010', (31, 38))	('miR-27a', 'Gene', '407018', (43, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('silencing', 'MPA', (75, 84))	('tumor', 'Disease', (106, 111))
137071	27259231	Its frequent copy number gain in MM cell lines, combined with miR-1204 depletion at the same locus, promotes overexpression of anti-apoptotic genes and the malignant phenotype.	('miR-1', 'Gene', (62, 67))	('gain', 'PosReg', (25, 29))	('anti-apoptotic genes', 'Gene', (127, 147))	('copy number', 'Var', (13, 24))	('promotes', 'PosReg', (100, 108))	('overexpression', 'MPA', (109, 123))	('miR-1', 'Gene', '79187', (62, 67))	('malignant phenotype', 'CPA', (156, 175))
137075	27259231	Finally, restoration of miR-193a-3p levels has been reported to inhibit MM cell growth and xenograft tumors in vivo.	('miR-1', 'Gene', (24, 29))	('xenograft tumors', 'Disease', (91, 107))	('MM cell growth', 'CPA', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-1', 'Gene', '79187', (24, 29))	('restoration', 'Var', (9, 20))	('inhibit', 'NegReg', (64, 71))	('xenograft tumors', 'Disease', 'MESH:D009369', (91, 107))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
137076	27259231	Similar to protein-coding genes, miRNA-encoding genes are also affected by epigenetic changes.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('epigenetic changes', 'Var', (75, 93))	('affected', 'Reg', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))
137092	27259231	SV40 large-T antigen complexes with p53 and leads to activation of insulin-like growth factor-I promoter and eventually to stimulation of malignant mesothelial cell growth.	('insulin-like growth factor-I promoter', 'Gene', (67, 104))	('stimulation', 'PosReg', (123, 134))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('67', '93'))	('activation', 'PosReg', (53, 63))	('malignant mesothelial cell growth', 'CPA', (138, 171))	('complexes', 'Interaction', (21, 30))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('SV40', 'Species', '1891767', (0, 4))	('SV40', 'Var', (0, 4))	('factor-I', 'molecular_function', 'GO:0003818', ('87', '95'))	('cell growth', 'biological_process', 'GO:0016049', ('160', '171'))
137101	27259231	Deregulation of mir-1266 gene family miRNAs has been related to recurrence and metastasis in patients with estrogen receptor-positive breast cancer, gastric cancer growth and invasion, and psoriasis vulgaris.	('miR', 'Gene', '220972', (37, 40))	('related', 'Reg', (53, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('psoriasis vulgaris', 'Disease', 'MESH:D011565', (189, 207))	('patients', 'Species', '9606', (93, 101))	('recurrence', 'Disease', (64, 74))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('gastric cancer', 'Disease', (149, 163))	('breast cancer', 'Disease', (134, 147))	('miR', 'Gene', (37, 40))	('psoriasis', 'Phenotype', 'HP:0003765', (189, 198))	('mir-126', 'Gene', '406913', (16, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('psoriasis vulgaris', 'Disease', (189, 207))	('invasion', 'CPA', (175, 183))	('mir-126', 'Gene', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Deregulation', 'Var', (0, 12))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('metastasis', 'CPA', (79, 89))
137104	27259231	Indeed, the presence and expression of SV40 in MM and the absence of SV40-like DNA sequences in patients not exposed to the virus have been reported by several groups.	('expression', 'MPA', (25, 35))	('SV40', 'Species', '1891767', (39, 43))	('SV40', 'Var', (39, 43))	('patients', 'Species', '9606', (96, 104))	('SV40', 'Species', '1891767', (69, 73))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
137105	27259231	SV40 may actually contribute to the development of those MM forms that are not due to asbestos exposure, and facilitate asbestos-mediated carcinogenicity.	('asbestos', 'Chemical', 'MESH:D001194', (86, 94))	('carcinogenic', 'Disease', 'MESH:D063646', (138, 150))	('men', 'Species', '9606', (43, 46))	('carcinogenic', 'Disease', (138, 150))	('SV40', 'Species', '1891767', (0, 4))	('SV40', 'Var', (0, 4))	('asbestos', 'Chemical', 'MESH:D001194', (120, 128))	('facilitate', 'PosReg', (109, 119))	('contribute', 'Reg', (18, 28))
137119	27259231	MiRNA quantification approaches also differed widely and included real-time quantitative PCR, qRT-PCR array, microarray, in situ hybridization-based assays, and variants thereof.	('MiR', 'Gene', (0, 3))	('variants', 'Var', (161, 169))	('MiR', 'Gene', '220972', (0, 3))
137186	27259231	1p36, 9p21, 3p, 4q, 6q, 14q32, 17p13, and 22q12 deletions), and instability has been related to underexpression of tumor suppressor genes, the miRNAs targeting them are also conceivably candidate biomarkers for MM.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('tumor', 'Disease', (115, 120))	('instability', 'MPA', (64, 75))	('underexpression', 'MPA', (96, 111))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('1p36', 'Var', (0, 4))
137187	27259231	Several significant miRNAs identified in our study map to the above loci or to fragile genomic regions (Table 2), and might be down- or up-regulated due to accumulation of acquired chromosomal losses or gains and other copy number changes.	('chromosomal losses', 'Var', (181, 199))	('down-', 'NegReg', (127, 132))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('up-regulated', 'PosReg', (136, 148))	('gains', 'PosReg', (203, 208))
137206	27259231	Methylation-induced silencing has been shown by various functional studies to induce downregulation of clustered miR-34b and miR-34c.	('miR-34c', 'Gene', '407042', (125, 132))	('miR-34c', 'Gene', (125, 132))	('downregulation', 'NegReg', (85, 99))	('miR-34b', 'Gene', (113, 120))	('miR-34b', 'Gene', '407041', (113, 120))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Methylation-induced', 'Var', (0, 19))	('silencing', 'NegReg', (20, 29))
137222	27259231	In the "pollution exposure" set, miR-126 downregulation has been detected in leukocytes as an effect of particulate matter, black carbon, organic carbon, and SO42-; the latter ions are found in the atmosphere as aerosols produced by fossil fuel and biomass combustion.	('miR-126', 'Gene', (33, 40))	('black carbon', 'Var', (124, 136))	('SO42', 'Chemical', '-', (158, 162))	('downregulation', 'NegReg', (41, 55))	('carbon', 'Chemical', 'MESH:D002244', (146, 152))	('carbon', 'Chemical', 'MESH:D002244', (130, 136))	('organic carbon', 'Var', (138, 152))	('miR-126', 'Gene', '406913', (33, 40))
137245	27259231	Moreover, re-expression of miR-126 reduced tumor cell migration and invasion in colon cancer, and both mature forms of mir-126 hindered metastasis progression by reducing inflammatory monocyte and mesenchymal stem cell recruitment to the site of the primary tumors.	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('hindered', 'NegReg', (127, 135))	('reduced', 'NegReg', (35, 42))	('tumor', 'Disease', (258, 263))	('colon cancer', 'Disease', (80, 92))	('invasion', 'CPA', (68, 76))	('miR-126', 'Gene', (27, 34))	('re-expression', 'Var', (10, 23))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('primary tumors', 'Disease', 'MESH:D009369', (250, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mir-126', 'Gene', '406913', (119, 126))	('miR-126', 'Gene', '406913', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metastasis progression', 'CPA', (136, 158))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))	('mir-126', 'Gene', (119, 126))	('reducing', 'NegReg', (162, 170))	('primary tumors', 'Disease', (250, 264))	('men', 'Species', '9606', (226, 229))
137250	27259231	In this context, low levels of specific miRNAs or the genetic alteration of key components in miRNA processing can compromise the immune response and lead to tumor formation.	('lead to', 'Reg', (150, 157))	('tumor', 'Disease', (158, 163))	('genetic alteration', 'Var', (54, 72))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('immune response', 'CPA', (130, 145))	('immune response', 'biological_process', 'GO:0006955', ('130', '145'))	('miR', 'Gene', '220972', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('miR', 'Gene', (94, 97))	('miRNA processing', 'biological_process', 'GO:0035196', ('94', '110'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('compromise', 'NegReg', (115, 125))
137443	25999306	This study indicates that CRS-207 is effective in prevention of growth of malignant mesothelioma in mice.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (74, 96))	('mice', 'Species', '10090', (100, 104))	('malignant mesothelioma', 'Disease', (74, 96))	('growth', 'MPA', (64, 70))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (74, 96))	('CRS-207', 'Var', (26, 33))	('CRS', 'Chemical', 'MESH:D002857', (26, 29))
137450	25999306	These data provide proof of principle that CRS-207 can generate an immune response to slow tumor growth.	('CRS-207', 'Var', (43, 50))	('immune response', 'MPA', (67, 82))	('immune response', 'biological_process', 'GO:0006955', ('67', '82'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('CRS', 'Chemical', 'MESH:D002857', (43, 46))
137463	25999306	When tumor reached ~300 mm3 in mice, 90% of the tumor was resected and mice were given an additional dose of CRS-207 or ANZ-100.	('mice', 'Species', '10090', (71, 75))	('ANZ-100', 'Chemical', '-', (120, 127))	('CRS', 'Chemical', 'MESH:D002857', (109, 112))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (31, 35))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CRS-207', 'Var', (109, 116))
137464	25999306	Recurrent tumor growth was monitored after surgery and it was observed that CRS-207 significantly inhibited tumor growth (397 +- 103 mm3) compared to ANZ-100 at post-operative day 18 (1047 +- 258 mm3) (p = 0.002) [Figure 4].	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('inhibited', 'NegReg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('CRS-207', 'Var', (76, 83))	('CRS', 'Chemical', 'MESH:D002857', (76, 79))	('ANZ-100', 'Chemical', '-', (150, 157))
137466	25999306	To more precisely define this role in our model, mice with recurrent AE17 flank tumors after surgery were randomized to four groups: (1) ANZ-100 (control), (2) ANZ-100 with CD8 T-cell depletion, (3) CRS-207, or (4) CRS-207 with CD8 T-cell depletion.	('ANZ-100', 'Chemical', '-', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CRS', 'Chemical', 'MESH:D002857', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mice', 'Species', '10090', (49, 53))	('flank tumors', 'Disease', 'MESH:D021501', (74, 86))	('ANZ-100', 'Var', (160, 167))	('flank tumors', 'Disease', (74, 86))	('ANZ-100', 'Chemical', '-', (160, 167))	('AE17', 'Gene', (69, 73))	('CRS', 'Chemical', 'MESH:D002857', (215, 218))
137467	25999306	Although mice receiving CRS-207 had smaller nodules after 14 days of tumor growth, effects were negated in the presence of CD8 T-cell depletion (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CRS-207', 'Var', (24, 31))	('tumor', 'Disease', (69, 74))	('nodules', 'MPA', (44, 51))	('CRS', 'Chemical', 'MESH:D002857', (24, 27))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('smaller', 'NegReg', (36, 43))
137471	25999306	We found that CD8 T-cells obtained from mice receiving CRS-207 were better able to neutralize AE17 cells as compared to mice receiving ANZ-100 (p=0.02) (Fig.	('mice', 'Species', '10090', (120, 124))	('CRS', 'Chemical', 'MESH:D002857', (55, 58))	('CRS-207', 'Var', (55, 62))	('ANZ-100', 'Chemical', '-', (135, 142))	('mice', 'Species', '10090', (40, 44))	('neutralize AE17 cells', 'MPA', (83, 104))
137498	25999306	Finally, we expand upon the concept of a synergy between surgery and immunotherapy, demonstrating that debulking of tumor restores the antitumor efficacy of vaccine-based immunotherapy for MPM by reducing systemic MDSC populations.	('S', 'Chemical', 'MESH:D013455', (216, 217))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('reducing', 'NegReg', (196, 204))	('systemic MDSC populations', 'CPA', (205, 230))	('debulking', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('restores', 'PosReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('P', 'Chemical', 'MESH:D010758', (190, 191))	('tumor', 'Disease', (116, 121))
137520	25403819	Mesothelioma cells stained positive for calretinin, D2-40, CAM5.2, vimentin, and myoglobin, but were negative for PE-10, TTF-1, and CEA.	('calretinin', 'Gene', '794', (40, 50))	('CEA', 'Gene', (132, 135))	('D2-40', 'Var', (52, 57))	('TTF-1', 'Gene', (121, 126))	('positive', 'Reg', (27, 35))	('CEA', 'Gene', '5670', (132, 135))	('vimentin', 'Protein', (67, 75))	('TTF-1', 'Gene', '7270', (121, 126))	('myoglobin', 'Protein', (81, 90))	('calretinin', 'Gene', (40, 50))	('CAM5.2', 'Gene', (59, 65))	('vimentin', 'cellular_component', 'GO:0045099', ('67', '75'))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('vimentin', 'cellular_component', 'GO:0045098', ('67', '75'))
137524	25403819	reported that P/D combined with hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy was well tolerated and associated with low morbidity and mortality.	('povidone-iodine', 'Chemical', 'MESH:D011206', (65, 80))	('hyperthermic pleural lavage', 'Disease', 'MESH:D010995', (32, 59))	('P/D', 'Var', (14, 17))	('hyperthermic pleural lavage', 'Disease', (32, 59))
137525	25403819	On the other hand, retrospective analysis of the International Association for the Study of Lung Cancer Mesothelioma database showed no difference in the median survival time between EPP and P/D, except in stage I patients, in whom EPP conferred a substantial survival benefit.	('patients', 'Species', '9606', (214, 222))	('Lung Cancer Mesothelioma', 'Disease', (92, 116))	('Cancer Mesothelioma', 'Phenotype', 'HP:0100001', (97, 116))	('Lung Cancer', 'Phenotype', 'HP:0100526', (92, 103))	('EPP', 'Var', (232, 235))	('Lung Cancer Mesothelioma', 'Disease', 'MESH:D008175', (92, 116))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
137544	25221930	ARQ 197 alone mainly induced apoptosis (20+-2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression.	('apoptosis', 'CPA', (29, 38))	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('suppression', 'NegReg', (72, 83))	('suppressed', 'NegReg', (122, 132))	('ARQ 197', 'Chemical', 'MESH:C551661', (0, 7))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('MAPK', 'Protein', (87, 91))	('induced', 'Reg', (21, 28))	('ARQ 197', 'Var', (0, 7))	('activity', 'MPA', (92, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('cell cycle progression', 'CPA', (133, 155))
137545	25221930	Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase.	('GDC-0980', 'Var', (5, 13))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('activities', 'MPA', (48, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('NVP-BEZ235', 'Var', (18, 28))	('AKT', 'Gene', (124, 127))	('GDC-0980', 'Chemical', 'MESH:C569670', (5, 13))	('inhibited', 'NegReg', (38, 47))	('mTOR', 'Pathway', (71, 75))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (18, 28))	('PI3K', 'Pathway', (62, 66))	('AKT', 'Gene', '207', (124, 127))
137548	25221930	Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.	('MPM tumor', 'Disease', (155, 164))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (53, 63))	('ARQ 197/NVP-BEZ235', 'Var', (45, 63))	('ARQ 197', 'Chemical', 'MESH:C551661', (68, 75))	('GDC-0980', 'Chemical', 'MESH:C569670', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ARQ', 'Var', (68, 71))	('suppressing', 'NegReg', (143, 154))	('MPM tumor', 'Disease', 'MESH:D009369', (155, 164))	('motility', 'CPA', (176, 184))	('ARQ 197', 'Chemical', 'MESH:C551661', (45, 52))
137554	25221930	HGF (hepatocyte growth factor)/MET signaling pathway is associated with acquired resistance to EGFR inhibitors in EGFR mutant non-small cell lung cancers.	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (126, 153))	('cell lung cancers', 'Disease', 'MESH:D008175', (136, 153))	('hepatocyte growth factor', 'Gene', '3082', (5, 29))	('associated', 'Reg', (56, 66))	('cell lung cancers', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('EGFR', 'Gene', '1956', (95, 99))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('5', '29'))	('hepatocyte growth factor', 'Gene', (5, 29))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (130, 153))	('HGF', 'Gene', '3082', (0, 3))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('mutant', 'Var', (119, 125))	('MET signaling pathway', 'biological_process', 'GO:0048012', ('31', '52'))	('HGF', 'Gene', (0, 3))	('lung cancers', 'Phenotype', 'HP:0100526', (141, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('EGFR', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
137556	25221930	We previously reported that MET is overexpressed and mutated in a variety of malignancies including MPM.	('malignancies', 'Disease', (77, 89))	('mutated', 'Var', (53, 60))	('MET', 'Gene', (28, 31))	('MPM', 'Disease', (100, 103))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
137557	25221930	Using several mesothelioma cell lines, our group showed that the small molecule MET inhibitor SU11274 suppresses cell proliferation.	('cell proliferation', 'CPA', (113, 131))	('mesothelioma', 'Disease', (14, 26))	('suppresses', 'NegReg', (102, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (14, 26))	('SU11274', 'Var', (94, 101))	('SU11274', 'Chemical', 'MESH:C478479', (94, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))
137562	25221930	The p110alpha catalytic subunit of PI3K and its constitutively bound regulatory subunit p85 are usually overexpressed and acquire frequent gain-of-function mutations in MPM.	('gain-of-function', 'PosReg', (139, 155))	('mutations', 'Var', (156, 165))	('MPM', 'Gene', (169, 172))	('p85', 'Gene', '5296', (88, 91))	('p110alpha', 'Gene', (4, 13))	('p110alpha', 'Gene', '5290', (4, 13))	('p85', 'Gene', (88, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
137563	25221930	The phosphatidyl-inositol-3,4,5-trisphosphate (PIP3) generated by the PI3K at the cell membrane recruits PH domain containing proteins such as PDK1 and AKT to the plasma membrane resulting in activation of mTOR complexes.	('mTOR', 'Pathway', (206, 210))	('PIP3', 'Chemical', '-', (47, 51))	('AKT', 'Gene', '207', (152, 155))	('PH domain containing proteins', 'Protein', (105, 134))	('PDK1', 'Gene', '5163', (143, 147))	('PDK1', 'Gene', (143, 147))	('PDK1', 'molecular_function', 'GO:0004740', ('143', '147'))	('AKT', 'Gene', (152, 155))	('PI3K', 'Var', (70, 74))	('activation', 'PosReg', (192, 202))	('cell membrane', 'cellular_component', 'GO:0005886', ('82', '95'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('163', '178'))	('phosphatidyl-inositol-3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (4, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
137565	25221930	Several inhibitors that target either PI3K alone or PI3K/mTOR are currently in phase I cancer clinical trials.	('cancer', 'Disease', (87, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))	('PI3K/mTOR', 'Var', (52, 61))
137567	25221930	Studies have shown that both NVP-BEZ235 and GDC-0980 significantly inhibit PI3K and mTOR activity, and tumor growth in many preclinical cancer models.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (29, 39))	('inhibit', 'NegReg', (67, 74))	('tumor', 'Disease', (103, 108))	('GDC-0980', 'Chemical', 'MESH:C569670', (44, 52))	('PI3K', 'Pathway', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('NVP-BEZ235', 'Var', (29, 39))	('cancer', 'Disease', (136, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))	('mTOR activity', 'CPA', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GDC-0980', 'Gene', (44, 52))
137571	25221930	Antibodies for p110alpha, p-85, AKT, p-AKT Thr308, p-AKT ser473, S6, p-S6 Ser235/236, cleaved PARP, total PARP, cyclin D1, p-MET (1234/1235) and anti-MAPK antibodies (ERK and p-ERK) were from Cell Signaling (Danvers, MA).	('ERK', 'molecular_function', 'GO:0004707', ('177', '180'))	('PARP', 'Gene', '142', (94, 98))	('Ser235', 'Chemical', '-', (74, 80))	('p110alpha', 'Gene', (15, 24))	('p110alpha', 'Gene', '5290', (15, 24))	('cyclin D1', 'Gene', (112, 121))	('cleaved', 'MPA', (86, 93))	('Thr308', 'Chemical', '-', (43, 49))	('p-ERK', 'Gene', '9451', (175, 180))	('PARP', 'Gene', (94, 98))	('AKT', 'Gene', (39, 42))	('p-MET (1234/1235', 'Var', (123, 139))	('p-ERK', 'Gene', (175, 180))	('AKT', 'Gene', '207', (32, 35))	('cyclin D1', 'Gene', '595', (112, 121))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('PARP', 'Gene', '142', (106, 110))	('p-85', 'Gene', (26, 30))	('AKT', 'Gene', (53, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('150', '154'))	('PARP', 'Gene', (106, 110))	('AKT', 'Gene', '207', (39, 42))	('Signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('ERK', 'molecular_function', 'GO:0004707', ('167', '170'))	('cyclin', 'molecular_function', 'GO:0016538', ('112', '118'))	('p-S6 Ser235/236', 'Var', (69, 84))	('ser', 'cellular_component', 'GO:0005790', ('57', '60'))	('p-85', 'Gene', '5296', (26, 30))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', (32, 35))	('ser473', 'Chemical', '-', (57, 63))
137572	25221930	Antibodies against total Met, p-MET (pY1349 and pY1003) and Alexa Fluor Phalloidin 594 were from Invitrogen (Grand Island, NY).	('pY1003', 'Var', (48, 54))	('Alexa Fluor Phalloidin 594', 'Chemical', '-', (60, 86))	('pY1349', 'Var', (37, 43))
137577	25221930	Crizotinib, GDC-0941, GDC-0980, ARQ 197 and NVP-BEZ235 were purchased from Selleck (Houston, TX).	('GDC-0941', 'Var', (12, 20))	('GDC-0980', 'Var', (22, 30))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (44, 54))	('GDC-0941', 'Chemical', 'MESH:C532162', (12, 20))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('GDC-0980', 'Chemical', 'MESH:C569670', (22, 30))	('ARQ 197', 'Chemical', 'MESH:C551661', (32, 39))
137579	25221930	Seven human mesothelioma cell lines (H2596, H513, H2461, H2052, H2452, H28 and H2373) and one nonmalignant transformed mesothelioma control cell line (Met-5A) were obtained from American Type Culture Collection (ATCC) (Manassas, VA).	('human', 'Species', '9606', (6, 11))	('H2596', 'Var', (37, 42))	('H2596', 'CellLine', 'CVCL:A546', (37, 42))	('H2452', 'Var', (64, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('H2452', 'CellLine', 'CVCL:1553', (64, 69))	('H2373', 'CellLine', 'CVCL:A533', (79, 84))	('H2052', 'Var', (57, 62))	('H2461', 'CellLine', 'CVCL:A536', (50, 55))	('mesothelioma', 'Disease', (12, 24))	('mesothelioma', 'Disease', (119, 131))	('H2052', 'CellLine', 'CVCL:1518', (57, 62))	('H513', 'CellLine', 'CVCL:A570', (44, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))
137591	25221930	IHC was done using CD31, MET, p-MET and p-AKT antibodies as described previously.	('AKT', 'Gene', (42, 45))	('p-MET', 'Var', (30, 35))	('AKT', 'Gene', '207', (42, 45))	('CD31', 'Var', (19, 23))	('MET', 'Var', (25, 28))
137612	25221930	2A , cell viability was significantly decreased in all the MPM cell lines in response to ARQ 197 but not in Met-5A.	('ARQ 197', 'Chemical', 'MESH:C551661', (89, 96))	('decreased', 'NegReg', (38, 47))	('cell viability', 'CPA', (5, 19))	('ARQ 197', 'Var', (89, 96))
137615	25221930	In the case of the PI3K/mTOR dual inhibitor GDC-0980, the Met-5A cells demonstrated higher levels of cell viability (IC50 0.96 microM) in comparison to three out of the four MPM cell lines tested.	('GDC-0980', 'Var', (44, 52))	('GDC-0980', 'Chemical', 'MESH:C569670', (44, 52))	('cell viability', 'CPA', (101, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('19', '23'))	('higher', 'PosReg', (84, 90))
137616	25221930	The IC50s for H2596, H2052 and H513 ranged from 0.08 to 0.3 microM.	('50s', 'Species', '1214577', (6, 9))	('H2052', 'CellLine', 'CVCL:1518', (21, 26))	('H513', 'CellLine', 'CVCL:A570', (31, 35))	('H513', 'Var', (31, 35))	('H2596', 'Var', (14, 19))	('H2596', 'CellLine', 'CVCL:A546', (14, 19))	('H2052', 'Var', (21, 26))
137618	25221930	On the other hand, all the five cell lines were sensitive to NVP-BEZ235 and the IC50s ranged from 0.003 to 0.030 microM, with Met-5A being the least sensitive ( Fig.	('50s', 'Species', '1214577', (82, 85))	('NVP-BEZ235', 'Var', (61, 71))	('sensitive', 'Reg', (48, 57))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (61, 71))
137622	25221930	The combination of ARQ 197/NVP-BEZ 235 had significant synergistic effect on the suppression of the growth of H513.	('ARQ 197', 'Chemical', 'MESH:C551661', (19, 26))	('ARQ', 'Var', (19, 22))	('combination', 'Var', (4, 15))	('H513', 'CellLine', 'CVCL:A570', (110, 114))	('suppression', 'NegReg', (81, 92))	('growth', 'MPA', (100, 106))
137623	25221930	The combination of ARQ 197/GDC-0980 on the other hand showed greater synergistic effect in H2596 compared to H513 cells in inhibiting cell growth.	('ARQ 197', 'Chemical', 'MESH:C551661', (19, 26))	('synergistic effect', 'MPA', (69, 87))	('inhibiting', 'NegReg', (123, 133))	('197/GDC-0980', 'Var', (23, 35))	('cell growth', 'biological_process', 'GO:0016049', ('134', '145'))	('H2596', 'CellLine', 'CVCL:A546', (91, 96))	('cell growth', 'CPA', (134, 145))	('GDC-0980', 'Chemical', 'MESH:C569670', (27, 35))	('H513', 'CellLine', 'CVCL:A570', (109, 113))	('ARQ 197/GDC-0980', 'Var', (19, 35))
137630	25221930	The levels of cyclin D1, which is a G0/G1 cell cycle regulator were decreased in cells treated with ARQ 197, GDC-0980 or NVP-BEZ235, in a dose dependent manner.	('cyclin', 'molecular_function', 'GO:0016538', ('14', '20'))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('42', '62'))	('levels', 'MPA', (4, 10))	('GDC-0980', 'Var', (109, 117))	('decreased', 'NegReg', (68, 77))	('NVP-BEZ235', 'Var', (121, 131))	('ARQ 197', 'Gene', (100, 107))	('GDC-0980', 'Chemical', 'MESH:C569670', (109, 117))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (121, 131))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('42', '62'))	('ARQ 197', 'Chemical', 'MESH:C551661', (100, 107))	('cyclin D1', 'Gene', '595', (14, 23))	('cyclin D1', 'Gene', (14, 23))
137632	25221930	However, the combination of ARQ 197/GDC-0980 and ARQ 197/NVP-BEZ235 induced the largest decrease in cyclin D1.	('decrease', 'NegReg', (88, 96))	('cyclin D1', 'Gene', (100, 109))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (57, 67))	('ARQ 197/NVP-BEZ235', 'Var', (49, 67))	('ARQ 197/GDC-0980', 'Var', (28, 44))	('GDC-0980', 'Chemical', 'MESH:C569670', (36, 44))	('ARQ 197', 'Chemical', 'MESH:C551661', (28, 35))	('cyclin', 'molecular_function', 'GO:0016538', ('100', '106'))	('ARQ 197', 'Chemical', 'MESH:C551661', (49, 56))	('cyclin D1', 'Gene', '595', (100, 109))
137633	25221930	The combinatorial treatment of ARQ 197/GDC-0980 and ARQ 197/NVP-BEZ235 however induced significant levels of cleaved PARP in both MPM cell lines.	('PARP', 'Gene', '142', (117, 121))	('ARQ 197/NVP-BEZ235', 'Var', (52, 70))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (60, 70))	('ARQ 197/GDC-0980', 'Var', (31, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (39, 47))	('ARQ 197', 'Chemical', 'MESH:C551661', (31, 38))	('PARP', 'Gene', (117, 121))	('induced', 'Reg', (79, 86))	('ARQ 197', 'Chemical', 'MESH:C551661', (52, 59))
137634	25221930	Individual treatment with GDC-0980 or NVP-BEZ235 had little effect as evidenced from cleaved PARP levels ( Fig.	('PARP', 'Gene', '142', (93, 97))	('GDC-0980', 'Var', (26, 34))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (38, 48))	('GDC-0980', 'Chemical', 'MESH:C569670', (26, 34))	('PARP', 'Gene', (93, 97))	('NVP-BEZ235', 'Var', (38, 48))
137642	25221930	The phosphorylation status of MET downstream targets such as PI3K (p85), FAK and paxillin also showed dose related decreases.	('PI3K', 'Var', (61, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('decreases', 'NegReg', (115, 124))	('p85', 'Gene', '5296', (67, 70))	('FAK', 'molecular_function', 'GO:0004717', ('73', '76'))	('paxillin', 'Gene', '5829', (81, 89))	('p85', 'Gene', (67, 70))	('FAK', 'Gene', (73, 76))	('FAK', 'Gene', '5747', (73, 76))	('paxillin', 'Gene', (81, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('phosphorylation status', 'MPA', (4, 26))
137644	25221930	With p-MET 1234/1235, there was a clear-cut inhibition in phosphorylation of MET in H513 cells, but less so in H2596 cells.	('phosphorylation', 'MPA', (58, 73))	('inhibition', 'NegReg', (44, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('MET', 'Protein', (77, 80))	('H513', 'CellLine', 'CVCL:A570', (84, 88))	('p-MET 1234/1235', 'Var', (5, 20))	('H2596', 'CellLine', 'CVCL:A546', (111, 116))
137645	25221930	Although with p-MET pY1349 and pY1003 antibodies results are less significant, it showed the same trend in H513 cells.	('p-MET pY1349', 'Var', (14, 26))	('H513', 'CellLine', 'CVCL:A570', (107, 111))	('pY1003 antibodies', 'Var', (31, 48))
137651	25221930	The activation of ribosomal S6 kinase, that is immediately downstream of mTOR, was effectively inhibited by both NVP-BEZ235 and GDC-0980; however ARQ 197 had a suppressive effect only at the highest concentration tested in H513 but not in H2596 cells ( Fig.	('H2596', 'CellLine', 'CVCL:A546', (239, 244))	('activation', 'MPA', (4, 14))	('inhibited', 'NegReg', (95, 104))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (113, 123))	('ribosomal S6 kinase', 'Enzyme', (18, 37))	('H513', 'CellLine', 'CVCL:A570', (223, 227))	('ARQ 197', 'Chemical', 'MESH:C551661', (146, 153))	('ARQ', 'Var', (146, 149))	('GDC-0980', 'Chemical', 'MESH:C569670', (128, 136))
137654	25221930	As expected from the immunoblot results, ARQ 197 had a less dramatic effect on PIP3 production compared to NVP-BEZ235 or GDC-0980.	('GDC-0980', 'Chemical', 'MESH:C569670', (121, 129))	('ARQ 197', 'Chemical', 'MESH:C551661', (41, 48))	('PIP3 production', 'MPA', (79, 94))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (107, 117))	('PIP3', 'Chemical', '-', (79, 83))	('ARQ 197', 'Var', (41, 48))
137655	25221930	GDC-0980 showed the largest inhibition of PIP3 production, even at low concentration (0.1 microM).	('PIP3 production', 'MPA', (42, 57))	('GDC-0980', 'Var', (0, 8))	('PIP3', 'Chemical', '-', (42, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))	('inhibition', 'NegReg', (28, 38))
137656	25221930	Taken together, the PI3K/mTOR inhibitors, more than ARQ 197 appear to efficiently suppress the growth providing signals mediated through AKT and S6 kinase while ARQ 197 suppressed cell motility and induced apoptosis.	('cell motility', 'biological_process', 'GO:0048870', ('180', '193'))	('ARQ', 'Gene', (52, 55))	('PI3K', 'molecular_function', 'GO:0016303', ('20', '24'))	('induced', 'Reg', (198, 205))	('apoptosis', 'CPA', (206, 215))	('ARQ 197', 'Var', (161, 168))	('growth providing signals mediated', 'MPA', (95, 128))	('ARQ 197', 'Chemical', 'MESH:C551661', (161, 168))	('AKT', 'Gene', '207', (137, 140))	('ARQ 197', 'Chemical', 'MESH:C551661', (52, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('cell motility', 'CPA', (180, 193))	('suppress', 'NegReg', (82, 90))	('suppressed', 'NegReg', (169, 179))	('AKT', 'Gene', (137, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('S6 kinase', 'Pathway', (145, 154))
137660	25221930	Although treatment with ARQ 197 or GDC-0980 alone inhibited tumor growth, the effect of GDC-0980 was far greater than ARQ 197 ( Fig.	('GDC-0980', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('GDC-0980', 'Chemical', 'MESH:C569670', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ARQ 197', 'Chemical', 'MESH:C551661', (24, 31))	('ARQ 197', 'Chemical', 'MESH:C551661', (118, 125))	('tumor', 'Disease', (60, 65))	('GDC-0980', 'Chemical', 'MESH:C569670', (35, 43))	('inhibited', 'NegReg', (50, 59))
137663	25221930	The combination of ARQ 197/GDC-0980 had a more significant effect on suppression of tumor growth compared to any single drug (p<0.001).	('ARQ 197/GDC-0980', 'Gene', (19, 35))	('ARQ 197', 'Chemical', 'MESH:C551661', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('suppression', 'NegReg', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('197/GDC-0980', 'Gene', (23, 35))	('combination', 'Var', (4, 15))	('tumor', 'Disease', (84, 89))	('GDC-0980', 'Chemical', 'MESH:C569670', (27, 35))
137664	25221930	The average tumor volume was less in mice treated with ARQ 197/GDC-0980, followed GDC-0980 and ARQ 197 groups ( Fig.	('ARQ 197', 'Chemical', 'MESH:C551661', (95, 102))	('less', 'NegReg', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('GDC-0980', 'Chemical', 'MESH:C569670', (82, 90))	('ARQ 197/GDC-0980', 'Var', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ARQ 197', 'Chemical', 'MESH:C551661', (55, 62))	('tumor', 'Disease', (12, 17))	('GDC-0980', 'Chemical', 'MESH:C569670', (63, 71))	('mice', 'Species', '10090', (37, 41))
137666	25221930	Tumor sections from vehicle control, ARQ 197, GDC-0980 and combination treated mice were immunostained with p-MET, total MET, CD31 and p-AKT.	('p-MET', 'Var', (108, 113))	('total MET', 'Var', (115, 124))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ARQ 197', 'Chemical', 'MESH:C551661', (37, 44))	('CD31', 'Var', (126, 130))	('GDC-0980', 'Chemical', 'MESH:C569670', (46, 54))	('mice', 'Species', '10090', (79, 83))	('AKT', 'Gene', '207', (137, 140))	('AKT', 'Gene', (137, 140))
137668	25221930	CD31, an indicator of angiogenesis was also decreased in the both MET and PI3K/mTOR inhibitor treated mice as compared to vehicle treated mice ( Fig.	('mice', 'Species', '10090', (102, 106))	('MET', 'Var', (66, 69))	('angiogenesis', 'biological_process', 'GO:0001525', ('22', '34'))	('mice', 'Species', '10090', (138, 142))	('angiogenesis', 'CPA', (22, 34))	('PI3K/mTOR', 'Gene', (74, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('CD31', 'MPA', (0, 4))	('decreased', 'NegReg', (44, 53))
137672	25221930	The combination of ARQ 197 with either GDC-0980 or NVP-BEZ235 had a strong synergistic suppressive effect on MPM cell viability ( Fig.	('MPM cell viability', 'CPA', (109, 127))	('ARQ 197', 'Chemical', 'MESH:C551661', (19, 26))	('GDC-0980', 'Var', (39, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (39, 47))	('ARQ 197', 'Gene', (19, 26))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (51, 61))	('combination', 'Interaction', (4, 15))	('suppressive', 'NegReg', (87, 98))
137674	25221930	ARQ 197, exhibited strong inhibition of MET autophosphorylation (Y1234-1235) in H513 cells, but not in H2596 cells.	('inhibition', 'NegReg', (26, 36))	('ARQ 197', 'Chemical', 'MESH:C551661', (0, 7))	('MET autophosphorylation', 'MPA', (40, 63))	('Y1234-1235', 'Var', (65, 75))	('H513', 'CellLine', 'CVCL:A570', (80, 84))	('H2596', 'CellLine', 'CVCL:A546', (103, 108))
137676	25221930	ARQ 197 also had a strong suppressive effect on HGF induced MAPK activation ( Fig.	('suppressive', 'NegReg', (26, 37))	('HGF', 'Gene', (48, 51))	('ARQ 197', 'Chemical', 'MESH:C551661', (0, 7))	('ARQ 197', 'Var', (0, 7))	('MAPK activation', 'biological_process', 'GO:0000187', ('60', '75'))	('HGF', 'Gene', '3082', (48, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('60', '64'))
137681	25221930	In addition, PI3K/mTOR inhibitors were more effective in suppressing the phosphorylation of AKT and S6 kinases and production of PIP3 compared to the MET inhibitor.	('PIP3', 'Chemical', '-', (129, 133))	('production of PIP3', 'MPA', (115, 133))	('S6 kinases', 'Pathway', (100, 110))	('AKT', 'Gene', '207', (92, 95))	('PI3K/mTOR', 'Var', (13, 22))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('phosphorylation', 'MPA', (73, 88))	('AKT', 'Gene', (92, 95))	('suppressing', 'NegReg', (57, 68))
137683	25221930	Here, we have shown that key MET downstream signaling molecules including PI3K (p85 and p110alpha subunits), AKT and phospho-AKT are also expressed in majority of the cell lines tested.	('AKT', 'Gene', '207', (125, 128))	('AKT', 'Gene', '207', (109, 112))	('p85', 'Gene', '5296', (80, 83))	('p110alpha', 'Gene', (88, 97))	('AKT', 'Gene', (125, 128))	('p110alpha', 'Gene', '5290', (88, 97))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('p85', 'Gene', (80, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('PI3K', 'Var', (74, 78))	('AKT', 'Gene', (109, 112))
137685	25221930	In addition to overexpression of MET in MPM, we previously identified mutations within the MET semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced form exon 10 deletion.	('N454I', 'Var', (132, 137))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('144', '157'))	('M431V', 'SUBSTITUTION', 'None', (121, 126))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('144', '157'))	('N375S', 'Var', (114, 119))	('N375S', 'Mutation', 'rs33917957', (114, 119))	('N454I', 'Mutation', 'p.N454I', (132, 137))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('144', '157'))	('T1010I', 'Var', (166, 172))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('144', '157'))	('M431V', 'Var', (121, 126))	('G1085X', 'Mutation', 'p.G1085X', (177, 183))	('T1010I', 'Mutation', 'p.T1010I', (166, 172))	('MET', 'Gene', (91, 94))	('G1085X', 'Var', (177, 183))
137686	25221930	The cell lines H513 and H2596 harbor the T1010I mutation and exhibited the most dramatic reduction of cell growth when treated with the MET inhibitor SU11274.	('T1010I', 'Var', (41, 47))	('SU11274', 'Chemical', 'MESH:C478479', (150, 157))	('T1010I', 'Mutation', 'p.T1010I', (41, 47))	('reduction', 'NegReg', (89, 98))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('H2596', 'CellLine', 'CVCL:A546', (24, 29))	('cell growth', 'CPA', (102, 113))	('H513', 'CellLine', 'CVCL:A570', (15, 19))
137688	25221930	Cell viability was decreased in all mesothelioma cell lines tested in response to ARQ 197, with those harboring the T1010I MET mutation (H513 and H2596) showing the greatest sensitivity.	('H513', 'CellLine', 'CVCL:A570', (137, 141))	('T1010I', 'Mutation', 'p.T1010I', (116, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('ARQ 197', 'Chemical', 'MESH:C551661', (82, 89))	('Cell viability', 'CPA', (0, 14))	('T1010I', 'Var', (116, 122))	('mesothelioma', 'Disease', (36, 48))	('decreased', 'NegReg', (19, 28))	('H2596', 'CellLine', 'CVCL:A546', (146, 151))
137693	25221930	ARQ 197 was observed to disrupt microtubule assembly and induce cell cycle arrest in these cells.	('disrupt', 'NegReg', (24, 31))	('microtubule assembly', 'biological_process', 'GO:0046785', ('32', '52'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('ARQ 197', 'Chemical', 'MESH:C551661', (0, 7))	('ARQ 197', 'Var', (0, 7))	('microtubule', 'cellular_component', 'GO:0005874', ('32', '43'))	('induce', 'Reg', (57, 63))	('microtubule assembly', 'MPA', (32, 52))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))	('cell cycle arrest', 'CPA', (64, 81))
137697	25221930	Using other p-MET antibodies (pY1349 and pY1003) it showed the same trend in H513 cells, and in H2596 it inhibited phosphorylation of MET at higher concentration.	('pY1349', 'Var', (30, 36))	('inhibited', 'NegReg', (105, 114))	('pY1003', 'Var', (41, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('phosphorylation', 'MPA', (115, 130))	('MET at higher concentration', 'MPA', (134, 161))	('H2596', 'CellLine', 'CVCL:A546', (96, 101))	('H513', 'CellLine', 'CVCL:A570', (77, 81))
137701	25221930	Moreover, our data on the effect of ARQ 197 on cell viability is in agreement with our previous report on the effect of SU11274, another MET kinase inhibitor, on MPM cell viability and growth (4).	('ARQ 197', 'Chemical', 'MESH:C551661', (36, 43))	('SU11274', 'Var', (120, 127))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('141', '157'))	('SU11274', 'Chemical', 'MESH:C478479', (120, 127))	('ARQ 197', 'Gene', (36, 43))
137702	25221930	In addition, that study also demonstrated that MET knockdown using specific siRNA in MPM cells induced significant apoptosis that mirrors our present finding that ARQ 197 also induces apoptosis in MPM cells ( Figure 5B-D ).	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'CPA', (115, 124))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('induces', 'Reg', (176, 183))	('ARQ 197', 'Chemical', 'MESH:C551661', (163, 170))	('ARQ 197', 'Var', (163, 170))	('knockdown', 'Var', (51, 60))
137705	25221930	Our studies show that ARQ 197 inhibited phosphorylation of paxillin thereby attesting to the ability of ARQ 197 to adversely affect the cytoskeleton either through MET dependent or independent pathways.	('paxillin', 'Gene', (59, 67))	('cytoskeleton', 'MPA', (136, 148))	('paxillin', 'Gene', '5829', (59, 67))	('affect', 'Reg', (125, 131))	('ARQ', 'Gene', (22, 25))	('ARQ 197', 'Chemical', 'MESH:C551661', (22, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('inhibited', 'NegReg', (30, 39))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('136', '148'))	('ARQ 197', 'Chemical', 'MESH:C551661', (104, 111))	('ARQ 197', 'Var', (104, 111))	('phosphorylation', 'MPA', (40, 55))
137707	25221930	Here we also demonstrated that treatment of H2596 and H513 MPM cells had a dramatic inhibitory effect on suppression of HGF induced MAPK and paxillin phosphorylation thereby explaining the underlying mechanism in ARQ 197 mediated suppression of cell motility seen in the above two MPM cell lines.	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('H513 MPM', 'Var', (54, 62))	('paxillin', 'Gene', '5829', (141, 149))	('H2596', 'Var', (44, 49))	('HGF', 'Gene', (120, 123))	('H2596', 'CellLine', 'CVCL:A546', (44, 49))	('paxillin', 'Gene', (141, 149))	('cell motility', 'biological_process', 'GO:0048870', ('245', '258'))	('ARQ 197', 'Chemical', 'MESH:C551661', (213, 220))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('HGF', 'Gene', '3082', (120, 123))	('suppression', 'NegReg', (105, 116))	('H513 MPM', 'CellLine', 'CVCL:A570', (54, 62))	('cell motility', 'CPA', (245, 258))	('MAPK', 'Protein', (132, 136))
137715	25221930	In the present study, we initially determined the efficacy of PI3K first generation and second-generation inhibitors such as wortmanin, LY294002 and GDC-0941to curb MPM cell growth without much success (data not shown) and therefore shifted the focus to PI3K/mTOR dual inhibitors.	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('MPM cell growth', 'CPA', (165, 180))	('curb', 'NegReg', (160, 164))	('cell growth', 'biological_process', 'GO:0016049', ('169', '180'))	('LY294002', 'Chemical', 'MESH:C085911', (136, 144))	('GDC-0941to', 'Chemical', '-', (149, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('254', '258'))	('wortmanin', 'Chemical', '-', (125, 134))	('GDC-0941to', 'Var', (149, 159))	('LY294002', 'Var', (136, 144))
137716	25221930	GDC-0980 was reported to be a potent inhibitor of breast, prostate and lung cancer cell growth and was much less effective against melanoma and pancreatic cancers, most likely due to the presence of highly active KRAS and BRAF usually encountered in these cancers.	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('cancers', 'Disease', (256, 263))	('pancreatic cancers', 'Disease', 'MESH:D010190', (144, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('BRAF', 'Gene', '673', (222, 226))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('BRAF', 'Gene', (222, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('GDC-0980', 'Var', (0, 8))	('breast', 'Disease', (50, 56))	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))	('less', 'NegReg', (108, 112))	('KRAS', 'Gene', '3845', (213, 217))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (144, 162))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibitor', 'NegReg', (37, 46))	('pancreatic cancers', 'Disease', (144, 162))	('prostate', 'Disease', (58, 66))	('lung cancer', 'Disease', (71, 82))	('KRAS', 'Gene', (213, 217))
137717	25221930	GDC-0980 was shown to induce G1 cell cycle arrest followed by apoptosis in certain cancer cell lines.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (32, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('GDC-0980', 'Var', (0, 8))	('apoptosis', 'CPA', (62, 71))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('32', '49'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))	('G1 cell cycle arrest', 'CPA', (29, 49))	('cancer', 'Disease', (83, 89))
137723	25221930	Using glioma cells, it was shown that NVP-BEZ235 specifically inhibited PI3K/mTOR signaling; an observation supported by suppressed activity of AKT, and S6K1.	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('AKT', 'Gene', (144, 147))	('activity', 'MPA', (132, 140))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (38, 48))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('suppressed', 'NegReg', (121, 131))	('inhibited', 'NegReg', (62, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('PI3K/mTOR signaling', 'Pathway', (72, 91))	('AKT', 'Gene', '207', (144, 147))	('glioma', 'Disease', (6, 12))	('NVP-BEZ235', 'Var', (38, 48))
137725	25221930	For instance, both NVP-BEZ235 and GDC-0980 effectively suppressed AKT and S6K phosphorylation and production of PIP3 in a dose dependent manner ( Fig.	('AKT', 'Gene', (66, 69))	('PIP3', 'Chemical', '-', (112, 116))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (19, 29))	('GDC-0980', 'Var', (34, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('suppressed', 'NegReg', (55, 65))	('production of PIP3', 'MPA', (98, 116))	('S6K phosphorylation', 'CPA', (74, 93))	('NVP-BEZ235', 'Var', (19, 29))	('GDC-0980', 'Chemical', 'MESH:C569670', (34, 42))	('AKT', 'Gene', '207', (66, 69))
137726	25221930	It has been observed that inhibition of mTOR results in enhanced cancer cell death.	('inhibition', 'Var', (26, 36))	('mTOR', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('enhanced', 'PosReg', (56, 64))	('cell death', 'biological_process', 'GO:0008219', ('72', '82'))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
137727	25221930	In glioma cells, in addition to inducing G0/G1 cell cycle arrest, NVP-BEZ235 was also observed to enhance autophagy.	('enhance', 'PosReg', (98, 105))	('NVP-BEZ235', 'Var', (66, 76))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('autophagy', 'biological_process', 'GO:0006914', ('106', '115'))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('inducing', 'PosReg', (32, 40))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (66, 76))	('glioma', 'Disease', (3, 9))	('G0/G1 cell cycle arrest', 'CPA', (41, 64))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('47', '64'))	('autophagy', 'CPA', (106, 115))	('autophagy', 'biological_process', 'GO:0016236', ('106', '115'))
137729	25221930	MET inhibition was also observed to enhance autophagy in gastric adenoma cells.	('MET', 'Protein', (0, 3))	('autophagy', 'biological_process', 'GO:0016236', ('44', '53'))	('gastric adenoma', 'Disease', (57, 72))	('gastric adenoma', 'Disease', 'MESH:D000236', (57, 72))	('inhibition', 'Var', (4, 14))	('autophagy', 'biological_process', 'GO:0006914', ('44', '53'))	('autophagy', 'CPA', (44, 53))	('enhance', 'PosReg', (36, 43))
137730	25221930	In our hands, NVP-BEZ235 showed significant synergy in killing MPM cells when combined with ARQ 197 ( Fig.	('ARQ 197', 'Chemical', 'MESH:C551661', (92, 99))	('MPM cells', 'CPA', (63, 72))	('NVP-BEZ235', 'Var', (14, 24))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (14, 24))
137733	25221930	A recent investigation reported significant synergistic inhibitory effect on MPM cell growth with combined treatment of MEK inhibitor U0126 and the PI3K inhibitor LY 294002 in vitro and in vivo mouse models.	('MEK', 'Gene', (120, 123))	('inhibitor U0126', 'Var', (124, 139))	('U0126', 'Var', (134, 139))	('mouse', 'Species', '10090', (194, 199))	('MPM cell growth', 'CPA', (77, 92))	('inhibitory', 'NegReg', (56, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('MEK', 'Gene', '17242', (120, 123))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('U0126', 'Chemical', 'MESH:C113580', (134, 139))	('LY 294002', 'Chemical', 'MESH:C085911', (163, 172))
137735	25221930	In summary, using MPM cell lines and a mouse xenograft model, we have clearly demonstrated the advantage of the combinatorial targeting of MET and PI3K/mTOR in MPM.	('MPM', 'Disease', (160, 163))	('MET', 'Var', (139, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('mouse', 'Species', '10090', (39, 44))	('PI3K/mTOR', 'Var', (147, 156))
137784	19304273	A recent survey of 3978 indoor samples from 752 buildings that were the subject of litigation stemming from alleged asbestos exposure noted the following: (1) the average concentration of airborne asbestos 5 mum long or longer was 0.00012 fibers/cm3, (2) 99.9% of all samples contained less than 0.01 fibers/cm3, and (3) no asbestos was detected in 90% of the buildings when the analysis was restricted to optically detected fibers (>=5 mum long; >=0.25 mum wide).	('airborne asbestos', 'Disease', 'MESH:D001195', (188, 205))	('airborne asbestos', 'Disease', (188, 205))	('0.00012', 'Var', (231, 238))	('asbestos', 'Chemical', 'MESH:D001194', (197, 205))	('asbestos', 'Chemical', 'MESH:D001194', (324, 332))	('rat', 'Species', '10116', (178, 181))	('asbestos', 'Chemical', 'MESH:D001194', (116, 124))
137803	19304273	It is generally agreed that the presence of asbestosis significantly increases the risk of lung cancer in a manner that is similar in patients with other forms of pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF).	('asbestosis', 'Disease', 'MESH:D001195', (44, 54))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (205, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('increases', 'PosReg', (69, 78))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (194, 223))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pulmonary fibrosis', 'Disease', (163, 181))	('presence', 'Var', (32, 40))	('patients', 'Species', '9606', (134, 142))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('asbestosis', 'Disease', (44, 54))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (163, 181))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (163, 181))	('idiopathic pulmonary fibrosis', 'Disease', (194, 223))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (205, 223))	('lung cancer', 'Disease', (91, 102))
137809	19304273	Asbestos-exposed workers can have mutations in the k-ras gene at codon 12 in lung cancers without radiographic asbestosis, which suggests that these 2 events are not necessarily linked.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('asbestosis', 'Disease', (111, 121))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('k-ras', 'Gene', '3845', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('k-ras', 'Gene', (51, 56))	('asbestosis', 'Disease', 'MESH:D001195', (111, 121))	('lung cancers', 'Disease', (77, 89))	('mutations', 'Var', (34, 43))
137817	19304273	Although as noted above, chrysotile-induced malignancies are associated with at least a hundred-fold higher lung fiber concentration as compared with amphiboles, chrysotile can promote iron-derived free radical formation in vitro, can injure lung target cells, and can induce asbestosis, lung cancer, and mesothelioma in humans.	('promote', 'PosReg', (177, 184))	('lung cancer', 'Disease', 'MESH:D008175', (288, 299))	('mesothelioma', 'Disease', (305, 317))	('lung cancer', 'Phenotype', 'HP:0100526', (288, 299))	('lung target cells', 'CPA', (242, 259))	('mesothelioma', 'Disease', 'MESH:D008654', (305, 317))	('injure', 'Reg', (235, 241))	('rat', 'Species', '10116', (126, 129))	('asbestosis', 'Disease', 'MESH:D001195', (276, 286))	('lung fiber concentration', 'MPA', (108, 132))	('chrysotile', 'Var', (162, 172))	('higher', 'PosReg', (101, 107))	('induce', 'Reg', (269, 275))	('humans', 'Species', '9606', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('lung cancer', 'Disease', (288, 299))	('iron', 'Chemical', 'MESH:D007501', (185, 189))	('malignancies', 'Disease', (44, 56))	('iron-derived free radical formation', 'MPA', (185, 220))	('asbestosis', 'Disease', (276, 286))	('formation', 'biological_process', 'GO:0009058', ('211', '220'))
137827	19304273	Interestingly, the silencing of FHC using small interfering RNA promotes apoptosis in MM cells.	('promotes', 'PosReg', (64, 72))	('FHC', 'Gene', (32, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('RNA', 'cellular_component', 'GO:0005562', ('60', '63'))	('silencing', 'Var', (19, 28))	('apoptosis in MM cells', 'CPA', (73, 94))	('small', 'Protein', (42, 47))	('FHC', 'Gene', '2495', (32, 35))
137840	19304273	Not surprisingly, the most common mutations in human tumors involve the p53 gene family members.	('p53', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('human', 'Species', '9606', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', (53, 59))
137844	19304273	Tumor-derived p53 mutants that block the interaction between p53 and Bcl-xl cause a "double hit" on the mitochondria-regulated apoptotic pathway by preventing both the transcriptional-dependent and direct mitochondrial effects of p53.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('interaction', 'Interaction', (41, 52))	('p53', 'Gene', (14, 17))	('preventing', 'NegReg', (148, 158))	('mutants', 'Var', (18, 25))	('Bcl-xl', 'Gene', '598', (69, 75))	('transcriptional-dependent', 'MPA', (168, 193))	('mitochondria-regulated apoptotic pathway', 'Pathway', (104, 144))	('direct mitochondrial effects', 'MPA', (198, 226))	('Bcl-xl', 'Gene', (69, 75))
137848	19304273	First, altered p53 expression is implicated in the pathophysiology of pulmonary fibrosis, which includes that caused by asbestos exposure as well as asbestos-associated malignancies.	('altered', 'Var', (7, 14))	('expression', 'MPA', (19, 29))	('malignancies', 'Disease', (169, 181))	('implicated', 'Reg', (33, 43))	('pulmonary fibrosis', 'Disease', (70, 88))	('asbestos', 'Chemical', 'MESH:D001194', (149, 157))	('p53', 'Gene', (15, 18))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (70, 88))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (70, 88))	('malignancies', 'Disease', 'MESH:D009369', (169, 181))	('asbestos', 'Chemical', 'MESH:D001194', (120, 128))
137851	19304273	Second, crocidolite asbestos promotes p53 gene mutations predominantly in exons 9 through 11 in BALB/c-3T3 cells.	('p53 gene', 'Gene', (38, 46))	('crocidolite asbestos', 'Chemical', 'MESH:D017638', (8, 28))	('T3', 'CellLine', 'CVCL:0594', (104, 106))	('mutations', 'Var', (47, 56))
137852	19304273	Third, asbestos induces p53 and p21CIP1/WAF1/SD11 (p21) expression in lung epithelial and mesothelial cells that can result in cell cycle arrest.	('WAF1/SD11', 'Gene', (40, 49))	('asbestos', 'Chemical', 'MESH:D001194', (7, 15))	('cell cycle arrest', 'CPA', (127, 144))	('WAF1/SD11', 'Gene', '1026', (40, 49))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('127', '144'))	('induces', 'Reg', (16, 23))	('p53', 'Var', (24, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (127, 144))	('p21CIP1', 'Gene', (32, 39))	('result in', 'Reg', (117, 126))	('p21CIP1', 'Gene', '1026', (32, 39))
137853	19304273	p21 is a downstream family of proteins (p21, p27, and p57) expressed during a p53 genotoxic stress response that results in cell cycle arrest to allow time for DNA repair.	('p57', 'Gene', (54, 57))	('DNA repair', 'MPA', (160, 170))	('cell cycle arrest', 'CPA', (124, 141))	('DNA repair', 'biological_process', 'GO:0006281', ('160', '170'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('124', '141'))	('p21', 'Var', (40, 43))	('p27', 'Gene', '3429', (45, 48))	('p27', 'Gene', (45, 48))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('p57', 'Gene', '1028', (54, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
137854	19304273	The importance of targeting p21 has recently been suggested by studies showing that p21 regulates lifespan in telomerase-deficient mice prone to premature aging, augments pulmonary inflammation caused by oxidative stress, and mediates transforming growth factor-beta (TGF-beta)-induced pulmonary inflammation and fibrosis that occurs via tumor necrosis factor-alpha (TNF-alpha) signaling.	('necrosis', 'biological_process', 'GO:0019835', ('344', '352'))	('necrosis', 'biological_process', 'GO:0001906', ('344', '352'))	('augments pulmonary inflammation', 'Disease', (162, 193))	('tumor necrosis factor-alpha', 'Gene', (338, 365))	('fibrosis', 'Disease', 'MESH:D005355', (313, 321))	('fibrosis', 'Disease', (313, 321))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('235', '266'))	('pulmonary inflammation', 'Disease', (286, 308))	('aging', 'biological_process', 'GO:0007568', ('155', '160'))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (286, 308))	('lifespan', 'CPA', (98, 106))	('mice', 'Species', '10090', (131, 135))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('tumor necrosis factor-alpha', 'Gene', '21926', (338, 365))	('necrosis', 'biological_process', 'GO:0008219', ('344', '352'))	('regulates', 'Reg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('augments pulmonary inflammation', 'Disease', 'MESH:D011014', (162, 193))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (171, 193))	('mediates', 'Reg', (226, 234))	('inflammation', 'biological_process', 'GO:0006954', ('296', '308'))	('necrosis', 'biological_process', 'GO:0008220', ('344', '352'))	('p21', 'Var', (84, 87))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('338', '359'))	('signaling', 'biological_process', 'GO:0023052', ('378', '387'))	('inflammation', 'biological_process', 'GO:0006954', ('181', '193'))	('necrosis', 'biological_process', 'GO:0070265', ('344', '352'))
137864	19304273	In murine lung epithelium, the disruption of MAPK-1 using a dominant-negative transgene targeted to the bronchiolar epithelium with the CC10 promoter inhibits asbestos-induced proliferation and procollagen gene expression.	('rat', 'Species', '10116', (183, 186))	('asbestos', 'Chemical', 'MESH:D001194', (159, 167))	('MAPK-1', 'Gene', (45, 51))	('CC10', 'Gene', '22287', (136, 140))	('asbestos-induced proliferation', 'CPA', (159, 189))	('CC10', 'Gene', (136, 140))	('murine', 'Species', '10090', (3, 9))	('procollagen gene', 'Gene', (194, 210))	('disruption', 'Var', (31, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('gene expression', 'biological_process', 'GO:0010467', ('206', '221'))	('MAPK-1', 'Gene', '26413', (45, 51))	('inhibits', 'NegReg', (150, 158))
137865	19304273	Inactivation of the Akt and MAPK pathways mediates asbestos-induced AEC apoptosis, which is a potentially crucial step for promoting a fibrotic response.	('promoting', 'PosReg', (123, 132))	('asbestos', 'Chemical', 'MESH:D001194', (51, 59))	('mediates', 'Reg', (42, 50))	('AEC', 'Disease', (68, 71))	('MAPK pathways', 'Pathway', (28, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('Akt', 'Gene', '207', (20, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('28', '32'))	('Akt', 'Gene', (20, 23))	('Inactivation', 'Var', (0, 12))
137867	19304273	A provocative recent study showed that mTOR increases survival of MM cells and that rapamycin (a mTOR inhibitor) or silencing p-S6K (a major downstream target of mTOR), can each augment cell death of these otherwise apoptosis-resistant MM cells.	('cell death', 'biological_process', 'GO:0008219', ('186', '196'))	('mTOR', 'Gene', (162, 166))	('augment', 'PosReg', (178, 185))	('mTOR', 'Gene', '2475', (162, 166))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('p-S6K', 'Gene', (126, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('216', '225'))	('mTOR', 'Gene', (39, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('216', '225'))	('mTOR', 'Gene', '2475', (39, 43))	('cell death', 'CPA', (186, 196))	('silencing', 'Var', (116, 125))	('p-S6K', 'Gene', '6198', (126, 131))	('increases', 'PosReg', (44, 53))	('men', 'Species', '9606', (181, 184))	('survival', 'CPA', (54, 62))
137868	19304273	Thus, the targeted disruption of MKP-3 or activated p38 in macrophages to limit TNF-alpha gene expression or regulating Akt/MAPK/mTOR signaling in the lung epithelium or in MM cells are novel approaches that merit additional study.	('TNF-alpha', 'Protein', (80, 89))	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('p38', 'Gene', (52, 55))	('disruption', 'Var', (19, 29))	('Akt', 'Gene', '207', (120, 123))	('MKP-3', 'Gene', '1848', (33, 38))	('MKP-3', 'Gene', (33, 38))	('mTOR', 'Gene', '2475', (129, 133))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('mTOR', 'Gene', (129, 133))	('p38', 'Gene', '1432', (52, 55))	('limit', 'NegReg', (74, 79))	('Akt', 'Gene', (120, 123))	('expression', 'MPA', (95, 105))
137870	19304273	In animal models of asbestosis, the development of fibrosis directly correlates with TNF-alpha levels, and TNF-alpha receptor knockout mice are protected against asbestosis.	('asbestosis', 'Disease', (162, 172))	('asbestosis', 'Disease', 'MESH:D001195', (20, 30))	('fibrosis', 'Disease', (51, 59))	('knockout', 'Var', (126, 134))	('fibrosis', 'Disease', 'MESH:D005355', (51, 59))	('asbestosis', 'Disease', (20, 30))	('mice', 'Species', '10090', (135, 139))	('men', 'Species', '9606', (43, 46))	('asbestosis', 'Disease', 'MESH:D001195', (162, 172))	('TNF-alpha levels', 'MPA', (85, 101))
137873	19304273	Using transgenic (Tg) mice expressing an inhibitory kappaB (IkappaB) mutant resistant to phosphorylation-induced degradation and targeted to the bronchiolar epithelium via the CC10 promoter in a murine model of asbestosis, Tg(+) mice exposed to asbestos had less BALF inflammatory cytokine levels (eg, KC, IL-6, and IL-1beta) and reduced levels of bronchiolar and distal epithelial proliferation as compared with Tg(-) mice.	('CC10', 'Gene', (176, 180))	('IL-1', 'molecular_function', 'GO:0005149', ('316', '320'))	('asbestosis', 'Disease', (211, 221))	('mice', 'Species', '10090', (419, 423))	('asbestos', 'Chemical', 'MESH:D001194', (211, 219))	('IL-1beta', 'Gene', '16176', (316, 324))	('CC10', 'Gene', '22287', (176, 180))	('mice', 'Species', '10090', (22, 26))	('IL-1beta', 'Gene', (316, 324))	('murine', 'Species', '10090', (195, 201))	('BALF inflammatory cytokine levels', 'MPA', (263, 296))	('IL-6', 'Gene', (306, 310))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('IL-6', 'Gene', '16193', (306, 310))	('asbestosis', 'Disease', 'MESH:D001195', (211, 221))	('reduced', 'NegReg', (330, 337))	('mutant', 'Var', (69, 75))	('asbestos', 'Chemical', 'MESH:D001194', (245, 253))	('levels of bronchiolar and', 'MPA', (338, 363))	('IL-6', 'molecular_function', 'GO:0005138', ('306', '310'))	('mice', 'Species', '10090', (229, 233))	('rat', 'Species', '10116', (389, 392))	('less', 'NegReg', (258, 262))
137879	19304273	Notably, asbestos-induced inflammatory cell lung recruitment, cytokine production (IL-1beta and KC), and silicosis are all reduced in mice deficient in Nalp3, ASC, or caspase-1.	('deficient', 'Var', (139, 148))	('mice', 'Species', '10090', (134, 138))	('cytokine production', 'biological_process', 'GO:0001816', ('62', '81'))	('asbestos-induced', 'CPA', (9, 25))	('inflammatory cell lung recruitment', 'CPA', (26, 60))	('men', 'Species', '9606', (56, 59))	('IL-1beta', 'Gene', '16176', (83, 91))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('silicosis', 'Disease', 'MESH:D012829', (105, 114))	('IL-1', 'molecular_function', 'GO:0005149', ('83', '87'))	('silicosis', 'Disease', (105, 114))	('IL-1beta', 'Gene', (83, 91))	('reduced', 'NegReg', (123, 130))
137884	19304273	Notably, asbestos-induced gremlin expression could be blocked by inhibitors of the TGF-beta receptor or the MAPK pathway as well as by exogenously administered BMP-7, which is known to prevent TGF-beta-induced EMT and fibrosis in the kidney and liver.	('EMT', 'CPA', (210, 213))	('BMP-7', 'Gene', (160, 165))	('expression', 'MPA', (34, 44))	('blocked', 'NegReg', (54, 61))	('MAPK pathway', 'Pathway', (108, 120))	('gremlin', 'Gene', '26585', (26, 33))	('EMT', 'biological_process', 'GO:0001837', ('210', '213'))	('BMP-7', 'Gene', '655', (160, 165))	('fibrosis in the kidney', 'Phenotype', 'HP:0030760', (218, 240))	('fibrosis in the kidney', 'Disease', (218, 240))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('fibrosis in the kidney', 'Disease', 'MESH:D005355', (218, 240))	('inhibitors', 'Var', (65, 75))	('TGF-beta receptor', 'Gene', (83, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('gremlin', 'Gene', (26, 33))
137886	19304273	Also, restoration of lung BMP signaling activity is a novel therapeutic approach worthy of additional investigation.	('restoration', 'Var', (6, 17))	('BMP', 'Gene', '649', (26, 29))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('rat', 'Species', '10116', (11, 14))	('BMP', 'Gene', (26, 29))
137901	32979832	Hong Kong Research Grant Council (T11-709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.	('HKU AIDS', 'Disease', (374, 382))	('HKU AIDS', 'Disease', 'MESH:D000163', (374, 382))	('17114114', 'Var', (99, 107))	('ANR', 'molecular_function', 'GO:0033729', ('195', '198'))	('17122915', 'Var', (86, 94))	('11100752', 'Var', (154, 162))	('AIDS', 'Disease', (378, 382))	('AIDS', 'Disease', 'MESH:D000163', (378, 382))	('16150662', 'Var', (174, 182))
137905	32979832	Depletion of MDSCs reduced infection and boosted T cell function in vivo.	('MDSCs reduced infection', 'Disease', (13, 36))	('MDSCs reduced infection', 'Disease', 'MESH:D007239', (13, 36))	('boosted', 'PosReg', (41, 48))	('Depletion', 'Var', (0, 9))	('T cell function', 'CPA', (49, 64))
137913	32979832	Following vaccination, we detected up to 21% of p24 tetramer-positive CD8+ T cells in the mouse spleen, and these exhibited broad reactivity, polyfunctionality and cytotoxicity.	('CD8+ T cells', 'CPA', (70, 82))	('p24', 'Var', (48, 51))	('mouse', 'Species', '10090', (90, 95))	('cytotoxicity', 'Disease', (164, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (164, 176))
137915	32979832	However, our results indicated that despite effective initial memory CD8+ T cell reactivation, there was a rapid expansion of MDSCs within 7 days post-infection (dpi), which profoundly subverted the memory CD8+ T cell response both in terms of number and function at a very early stage of infection, resulted in viral persistence.	('MDSCs', 'Var', (126, 131))	('subverted', 'NegReg', (185, 194))	('-infection', 'Disease', 'MESH:D007239', (150, 160))	('memory', 'biological_process', 'GO:0007613', ('62', '68'))	('resulted in', 'Reg', (300, 311))	('-infection', 'Disease', (150, 160))	('memory', 'biological_process', 'GO:0007613', ('199', '205'))	('viral persistence', 'MPA', (312, 329))
137935	32979832	Lymphoid architecture is integral to induction and maintenance of immune responses, and EcoHIV infection resulted in slight splenic disorganization at 12 wpi, with a higher proportion of F4/80+ myeloid cells and a corresponding loss of T cells (Fig.	('splenic disorganization', 'CPA', (124, 147))	('higher', 'PosReg', (166, 172))	('loss of T', 'Disease', 'MESH:D014786', (228, 237))	('infection', 'Var', (95, 104))	('loss of T', 'Disease', (228, 237))	('EcoHIV', 'Gene', (88, 94))
137940	32979832	pDCs are the most potent type I interferon (IFN-I)-producing cells in response to viral infection in humans and mice, and provide critical resistance to infection by limiting viral spread and by activating multiple innate and adaptive immune cells.	('activating', 'PosReg', (195, 205))	('viral infection', 'biological_process', 'GO:0016032', ('82', '97'))	('humans', 'Species', '9606', (101, 107))	('limiting', 'NegReg', (166, 174))	('viral', 'CPA', (175, 180))	('pDCs', 'Var', (0, 4))
137945	32979832	We have previously reported that sPD1-p24fc elicited functional antigen-specific CD8+ T cells can eliminate MDSCs through apoptosis in a malignant mesothelioma mouse model.	('MDSCs', 'Disease', (108, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (137, 159))	('apoptosis', 'CPA', (122, 131))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (137, 159))	('eliminate', 'NegReg', (98, 107))	('sPD1-p24fc', 'Var', (33, 43))	('malignant mesothelioma', 'Disease', (137, 159))
137948	32979832	The number of p24+ cDC, a population that do not express ly6c, were also significantly reduced in the blood of depleted mice (Fig.	('ly6c', 'Gene', '17067', (57, 61))	('p24+ cDC', 'Var', (14, 22))	('reduced', 'NegReg', (87, 94))	('ly6c', 'Gene', (57, 61))
137953	32979832	Previous studies using models of acute and chronic LCMV infection, the ARM and C13 strains, respectively, induced accumulation of Ly6Chi monocytes and Gr1hi neutrophils in lymphoid organs and blood during the first three days.	('lymphoid organs', 'Disease', (172, 187))	('LCMV infection', 'Disease', (51, 65))	('accumulation', 'PosReg', (114, 126))	('LCMV infection', 'Disease', 'MESH:D007239', (51, 65))	('lymphoid organs', 'Disease', 'MESH:D000072717', (172, 187))	('Gr1hi', 'CPA', (151, 156))	('Ly6Chi', 'Var', (130, 136))
138050	33093271	In addition, N-acetylcysteine reduced ROS production and improved DeltaPsim loss and cell death that were caused by apigenin.	('apigenin', 'Chemical', 'MESH:D047310', (116, 124))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (13, 29))	('DeltaPsim loss and cell death', 'Disease', 'MESH:D003643', (66, 95))	('ROS production', 'MPA', (38, 52))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('N-acetylcysteine', 'Var', (13, 29))	('reduced', 'NegReg', (30, 37))	('improved', 'PosReg', (57, 65))	('reduced ROS production', 'Phenotype', 'HP:0025464', (30, 52))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))
138064	33093271	Deregulation of many molecules that regulate apoptosis, such as intrinsic pathway (bcl-2 family, PI3K-Akt and Wnt signalings), or extrinsic pathway (TRAIL, NF-kB and ERK1/2 signalings) has been shown in MM tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('ERK1', 'molecular_function', 'GO:0004707', ('166', '170'))	('Deregulation', 'Var', (0, 12))	('Akt', 'Gene', '207', (102, 105))	('bcl-2', 'molecular_function', 'GO:0015283', ('83', '88'))	('tumor', 'Disease', (206, 211))	('PI3K', 'molecular_function', 'GO:0016303', ('97', '101'))	('bcl-2', 'Gene', (83, 88))	('TRAIL', 'Gene', '8743', (149, 154))	('ERK1/2', 'Gene', (166, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('ERK1/2', 'Gene', '5595;5594', (166, 172))	('bcl-2', 'Gene', '596', (83, 88))	('TRAIL', 'Gene', (149, 154))	('Akt', 'Gene', (102, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
138095	33093271	9542), and cleaved PARP (catalog no.	('PARP', 'Gene', (19, 23))	('cleaved', 'Var', (11, 18))	('PARP', 'Gene', '1302', (19, 23))
138132	33093271	1D, apigenin increased the phosphorylation of ATMSer1981, ATRSer428, CHK1Ser345, and CHK2Thr68 as well as histone H2A.XSer139, a DSB marker, suggesting that apigenin could cause DSB and activate the ATM/ATR signaling pathway.	('ATM', 'Gene', '472', (199, 202))	('DSB', 'Chemical', '-', (178, 181))	('ATR', 'Gene', '545', (58, 61))	('ATM', 'Gene', '472', (46, 49))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('CHK2', 'Gene', '11200', (85, 89))	('ATR', 'Gene', '545', (203, 206))	('DSB', 'Chemical', '-', (129, 132))	('XSer139', 'Chemical', '-', (118, 125))	('ATM', 'Gene', (199, 202))	('activate', 'PosReg', (186, 194))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('ATM', 'Gene', (46, 49))	('apigenin', 'Chemical', 'MESH:D047310', (157, 165))	('signaling pathway', 'biological_process', 'GO:0007165', ('207', '224'))	('DSB', 'Disease', (178, 181))	('ATR', 'Gene', (58, 61))	('CHK1', 'Gene', (69, 73))	('ATR', 'Gene', (203, 206))	('cause', 'PosReg', (172, 177))	('apigenin', 'Chemical', 'MESH:D047310', (4, 12))	('CHK2', 'Gene', (85, 89))	('apigenin', 'Var', (157, 165))	('CHK1', 'Gene', '1111', (69, 73))
138141	33093271	DeltaPsim loss after apigenin treatment was higher in MSTO-211H cells compared to H-2452 cells (Fig.	('MSTO-211H', 'CellLine', 'CVCL:1430', (54, 63))	('H-2452', 'CellLine', 'CVCL:1553', (82, 88))	('apigenin', 'Chemical', 'MESH:D047310', (21, 29))	('DeltaPsim loss', 'Disease', (0, 14))	('higher', 'PosReg', (44, 50))	('MSTO-211H', 'Var', (54, 63))	('DeltaPsim loss', 'Disease', 'MESH:D014786', (0, 14))
138148	33093271	Given the observation that excess ROS was linked to increased cytotoxicity, the effect of ROS scavenging on apigenin-treated cells was evaluated.	('cytotoxicity', 'Disease', 'MESH:D064420', (62, 74))	('ROS', 'Var', (34, 37))	('increased', 'PosReg', (52, 61))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('apigenin', 'Chemical', 'MESH:D047310', (108, 116))	('ROS', 'Chemical', 'MESH:D017382', (90, 93))	('cytotoxicity', 'Disease', (62, 74))
138201	31755214	Inhibition of CDK7 by siRNA decreased the YAP protein level and the GTIIC reporter activity in the MPM cell lines 211H, H290 and H2052.	('decreased', 'NegReg', (28, 37))	('CDK7', 'Gene', '1022', (14, 18))	('YAP', 'Gene', (42, 45))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('GTIIC reporter activity', 'MPA', (68, 91))	('MPM', 'Chemical', '-', (99, 102))	('Inhibition', 'Var', (0, 10))	('CDK7', 'Gene', (14, 18))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('YAP', 'Gene', '10413', (42, 45))	('H290', 'CellLine', 'CVCL:A555', (120, 124))
138202	31755214	Degradation of the YAP protein was accelerated after CDK7 knockdown in 211H, H290 and H2052 cells.	('Degradation', 'MPA', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('CDK7', 'Gene', (53, 57))	('YAP', 'Gene', '10413', (19, 22))	('CDK7', 'Gene', '1022', (53, 57))	('YAP', 'Gene', (19, 22))	('accelerated', 'PosReg', (35, 46))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('H290', 'CellLine', 'CVCL:A555', (77, 81))	('knockdown', 'Var', (58, 67))
138203	31755214	Inhibition of CDK7 reduced tumour cell migration and invasion, as well as tumorsphere formation ability.	('CDK7', 'Gene', (14, 18))	('CDK7', 'Gene', '1022', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('cell migration', 'biological_process', 'GO:0016477', ('34', '48'))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (19, 26))	('tumorsphere formation ability', 'CPA', (74, 103))	('tumour', 'Disease', (27, 33))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))
138206	31755214	Our results suggest that CDK7 inhibition reduces the YAP protein level by promoting its degradation and suppresses the migration and invasion of MPM cells.	('suppresses', 'NegReg', (104, 114))	('CDK7', 'Gene', '1022', (25, 29))	('MPM', 'Chemical', '-', (145, 148))	('inhibition', 'Var', (30, 40))	('reduces', 'NegReg', (41, 48))	('YAP', 'Gene', '10413', (53, 56))	('degradation', 'MPA', (88, 99))	('promoting', 'PosReg', (74, 83))	('YAP', 'Gene', (53, 56))	('CDK7', 'Gene', (25, 29))	('degradation', 'biological_process', 'GO:0009056', ('88', '99'))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))
138216	31755214	Here, we hypothesized that CDK7 inhibition down-regulates YAP expression and sought to answer whether CDK7 is involved in regulating YAP expression in human MPM.	('CDK7', 'Gene', '1022', (102, 106))	('down-regulates', 'NegReg', (43, 57))	('YAP', 'Gene', (58, 61))	('inhibition', 'Var', (32, 42))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('CDK7', 'Gene', '1022', (27, 31))	('human', 'Species', '9606', (151, 156))	('YAP', 'Gene', '10413', (133, 136))	('CDK7', 'Gene', (102, 106))	('YAP', 'Gene', '10413', (58, 61))	('CDK7', 'Gene', (27, 31))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('MPM', 'Chemical', '-', (157, 160))	('YAP', 'Gene', (133, 136))
138217	31755214	The human MPM cell lines 211H (biphasic), H290 (unknown), H2452 (epithelial), H2052 (sarcomatoid), MS-1 (epithelial) and H28 (sarcomatoid) were obtained from the American Type Culture Collection.	('sarcomatoid', 'Disease', (126, 137))	('MPM', 'Chemical', '-', (10, 13))	('human', 'Species', '9606', (4, 9))	('sarcomatoid', 'Disease', 'MESH:C538614', (85, 96))	('H290', 'CellLine', 'CVCL:A555', (42, 46))	('H2452', 'CellLine', 'CVCL:1553', (58, 63))	('sarcomatoid', 'Disease', 'MESH:C538614', (126, 137))	('H2052', 'Var', (78, 83))	('sarcomatoid', 'Disease', (85, 96))
138247	31755214	Antibodies used for co-IP included a YAP antibody (Cat#14074, Cell Signaling) and IgG antibody (Cat#2729, Cell Signaling).	('YAP', 'Gene', '10413', (37, 40))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('Cat', 'molecular_function', 'GO:0004096', ('96', '99'))	('Signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('IgG antibody', 'Phenotype', 'HP:0003237', (82, 94))	('IgG antibody', 'cellular_component', 'GO:0071736', ('82', '94'))	('Cat', 'molecular_function', 'GO:0004096', ('51', '54'))	('Cat#2729', 'Var', (96, 104))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))	('YAP', 'Gene', (37, 40))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('Cat#14074', 'Var', (51, 60))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))	('Signaling', 'biological_process', 'GO:0023052', ('111', '120'))
138261	31755214	Phosphorylation of YAP (S127) through LATS1/2 promotes YAP translocation from the nucleus to the cytoplasm followed by YAP protein degradation.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('YAP', 'Gene', (55, 58))	('LATS1/2', 'Gene', '9113;26524', (38, 45))	('Phosphorylation', 'Var', (0, 15))	('nucleus', 'cellular_component', 'GO:0005634', ('82', '89'))	('YAP', 'Gene', '10413', (119, 122))	('YAP', 'Gene', '10413', (19, 22))	('S127', 'Var', (24, 28))	('YAP', 'Gene', '10413', (55, 58))	('cytoplasm', 'cellular_component', 'GO:0005737', ('97', '106'))	('translocation', 'MPA', (59, 72))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('LATS1/2', 'Gene', (38, 45))	('YAP', 'Gene', (19, 22))	('protein degradation', 'biological_process', 'GO:0030163', ('123', '142'))	('promotes', 'PosReg', (46, 54))	('YAP', 'Gene', (119, 122))
138266	31755214	Compared with that of the cells treated with control siRNA, the reporter activity of these three cell lines decreased significantly after CDK7 silencing (Figure 3A-C, P < .05).	('CDK7', 'Gene', (138, 142))	('CDK', 'molecular_function', 'GO:0004693', ('138', '141'))	('CDK7', 'Gene', '1022', (138, 142))	('reporter activity', 'MPA', (64, 81))	('decreased', 'NegReg', (108, 117))	('silencing', 'Var', (143, 152))
138267	31755214	We next investigated whether inhibition of CDK7 influences YAP protein levels.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('YAP', 'Gene', (59, 62))	('CDK7', 'Gene', (43, 47))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('YAP', 'Gene', '10413', (59, 62))	('inhibition', 'Var', (29, 39))	('CDK7', 'Gene', '1022', (43, 47))
138281	31755214	These results suggested that inhibition of CDK7 promoted YAP protein degradation in MPM cell lines.	('promoted', 'PosReg', (48, 56))	('CDK7', 'Gene', (43, 47))	('YAP', 'Gene', '10413', (57, 60))	('MPM', 'Chemical', '-', (84, 87))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('protein degradation', 'biological_process', 'GO:0030163', ('61', '80'))	('YAP', 'Gene', (57, 60))	('inhibition', 'Var', (29, 39))	('CDK7', 'Gene', '1022', (43, 47))
138282	31755214	The results of the transwell invasion assay showed that knockdown of CDK7 significantly decreased the invasion ability of 211H, H2052 and H290 cells to 57.5%, 63.4% and 52.1%, respectively, normalized to the number of cells treated with control siRNA (P < .001) (Figure 5A-D).	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('invasion ability', 'CPA', (102, 118))	('CDK7', 'Gene', '1022', (69, 73))	('H290', 'CellLine', 'CVCL:A555', (138, 142))	('decreased', 'NegReg', (88, 97))	('CDK7', 'Gene', (69, 73))	('knockdown', 'Var', (56, 65))
138285	31755214	In 10 000 H290 cells treated with THZ1, the average compact sphere decreased significantly to 12 (Figure 5E-G) (P < .001).	('H290', 'CellLine', 'CVCL:A555', (10, 14))	('THZ1', 'Chemical', '-', (34, 38))	('compact sphere', 'CPA', (52, 66))	('THZ1', 'Var', (34, 38))	('decreased', 'NegReg', (67, 76))
138288	31755214	The CDK7 siRNA targeting the 3'UTR was used to knockdown CDK7, and the CDK7 plasmid DNA was used to overexpress CDK7.	('CDK7', 'Gene', '1022', (4, 8))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('CDK7', 'Gene', '1022', (57, 61))	('CDK7', 'Gene', (71, 75))	('CDK7', 'Gene', (57, 61))	('knockdown', 'Var', (47, 56))	('CDK7', 'Gene', (112, 116))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('CDK', 'molecular_function', 'GO:0004693', ('57', '60'))	('CDK7', 'Gene', '1022', (71, 75))	('CDK7', 'Gene', (4, 8))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))	('CDK7', 'Gene', '1022', (112, 116))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
138289	31755214	After CDK7 inhibition, the YAP protein level was reduced in both cell lines (Figure 6A,B), similar to what occurred after CDK7 inhibition using a pooled CDK7 siRNA.	('YAP', 'Gene', (27, 30))	('CDK7', 'Gene', '1022', (122, 126))	('YAP', 'Gene', '10413', (27, 30))	('CDK7', 'Gene', (153, 157))	('CDK7', 'Gene', '1022', (6, 10))	('reduced', 'NegReg', (49, 56))	('CDK', 'molecular_function', 'GO:0004693', ('6', '9'))	('CDK7', 'Gene', (122, 126))	('inhibition', 'Var', (11, 21))	('CDK7', 'Gene', '1022', (153, 157))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('CDK', 'molecular_function', 'GO:0004693', ('122', '125'))	('CDK7', 'Gene', (6, 10))	('CDK', 'molecular_function', 'GO:0004693', ('153', '156'))
138299	31755214	Several lines of evidence support that CDK7 inhibition down-regulates YAP protein expression in MPM cells.	('MPM', 'Chemical', '-', (96, 99))	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('YAP', 'Gene', '10413', (70, 73))	('inhibition', 'Var', (44, 54))	('YAP', 'Gene', (70, 73))	('CDK7', 'Gene', (39, 43))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('down-regulates', 'NegReg', (55, 69))	('CDK7', 'Gene', '1022', (39, 43))
138301	31755214	Second, inhibition of CDK7 decreased the YAP protein expression level and the GTIIC reporter activity of the Hippo pathway in MPM cell lines.	('YAP', 'Gene', (41, 44))	('decreased', 'NegReg', (27, 36))	('Hippo pathway', 'Pathway', (109, 122))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('GTIIC reporter activity', 'MPA', (78, 101))	('CDK7', 'Gene', (22, 26))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('inhibition', 'Var', (8, 18))	('CDK7', 'Gene', '1022', (22, 26))	('YAP', 'Gene', '10413', (41, 44))	('MPM', 'Chemical', '-', (126, 129))
138304	31755214	Fourth, inhibition of CDK7 reduced the migration, invasion and tumorsphere formation ability of 211H, H290 and H2052 cells.	('reduced', 'NegReg', (27, 34))	('invasion', 'CPA', (50, 58))	('H290', 'CellLine', 'CVCL:A555', (102, 106))	('tumorsphere formation ability', 'CPA', (63, 92))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('CDK7', 'Gene', (22, 26))	('migration', 'CPA', (39, 48))	('inhibition', 'Var', (8, 18))	('CDK7', 'Gene', '1022', (22, 26))
138317	31755214	In the Hippo pathway, YAP is negatively regulated by MST1, MST2, LATS1 and LATS2 kinases26, 27, 28, 29, 30 through modulated phosphorylation events of kinase cascade in most situations.	('MST2', 'Gene', (59, 63))	('modulated', 'Reg', (115, 124))	('YAP', 'Gene', '10413', (22, 25))	('LATS1', 'Gene', '9113', (65, 70))	('LATS2', 'Gene', (75, 80))	('LATS2', 'Gene', '26524', (75, 80))	('MST2', 'Gene', '6788', (59, 63))	('MST1', 'Gene', '4485', (53, 57))	('negatively', 'NegReg', (29, 39))	('LATS1', 'Gene', (65, 70))	('MST1', 'Gene', (53, 57))	('phosphorylation', 'MPA', (125, 140))	('Hippo pathway', 'Pathway', (7, 20))	('YAP', 'Gene', (22, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('kinases26', 'Var', (81, 90))
138321	31755214	The acceleration of YAP protein degradation may not be related to NF2 mutation and LAST2 deletion because this phenomenon exists in 211H, H290 and H2052 cell lines.	('acceleration', 'PosReg', (4, 16))	('NF2', 'Gene', (66, 69))	('YAP', 'Gene', (20, 23))	('H290', 'CellLine', 'CVCL:A555', (138, 142))	('NF2', 'Gene', '4771', (66, 69))	('YAP', 'Gene', '10413', (20, 23))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('mutation', 'Var', (70, 78))	('protein degradation', 'biological_process', 'GO:0030163', ('24', '43'))
138326	31755214	H2052 (sarcomatoid) and 211H (biphasic) have a mesenchymal phenotype that has invasion ability.	('H2052', 'Var', (0, 5))	('sarcomatoid', 'Disease', (7, 18))	('sarcomatoid', 'Disease', 'MESH:C538614', (7, 18))	('invasion ability', 'CPA', (78, 94))
138327	31755214	We analysed two EMT markers (Snail and MMP9) with Western blotting in H2052 shControl cells and H2052 shCDK7 cells and found no dramatic differences at the protein level (data not shown).	('H2052', 'Var', (96, 101))	('MMP9', 'Gene', '4318', (39, 43))	('CDK7', 'Gene', '1022', (104, 108))	('EMT', 'biological_process', 'GO:0001837', ('16', '19'))	('MMP9', 'molecular_function', 'GO:0004229', ('39', '43'))	('MMP9', 'Gene', (39, 43))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('CDK7', 'Gene', (104, 108))	('Snail', 'Gene', '6615', (29, 34))	('Snail', 'Gene', (29, 34))
138330	31755214	This finding indicated that, in MPM, the inhibition of CDK7 may suppress tumour development at least in part through the suppression of cancer stem cells.	('suppression', 'NegReg', (121, 132))	('tumour', 'Disease', (73, 79))	('CDK7', 'Gene', '1022', (55, 59))	('suppress', 'NegReg', (64, 72))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('MPM', 'Chemical', '-', (32, 35))	('inhibition', 'Var', (41, 51))	('cancer', 'Disease', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('CDK', 'molecular_function', 'GO:0004693', ('55', '58'))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('CDK7', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
138334	31755214	Taken together, the results of our study suggest that CDK7 inhibition down-regulates YAP expression via promoting its degradation and suppresses the migration and invasion of MPM cells.	('expression', 'MPA', (89, 99))	('promoting', 'PosReg', (104, 113))	('degradation', 'MPA', (118, 129))	('suppresses', 'NegReg', (134, 144))	('YAP', 'Gene', '10413', (85, 88))	('CDK7', 'Gene', (54, 58))	('down-regulates', 'NegReg', (70, 84))	('degradation', 'biological_process', 'GO:0009056', ('118', '129'))	('inhibition', 'Var', (59, 69))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))	('CDK7', 'Gene', '1022', (54, 58))	('YAP', 'Gene', (85, 88))	('MPM', 'Chemical', '-', (175, 178))
138419	28619093	Fifteen patients with mesothelioma received up to six 21-day cycles of pemetrexed plus cisplatin chemotherapy and anti-CD40 (CP-870,893).	('pemetrexed', 'Chemical', 'MESH:D000068437', (71, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('anti-CD40', 'Var', (114, 123))	('mesothelioma', 'Disease', (22, 34))	('CP-870', 'Chemical', '-', (125, 131))	('mesothelioma', 'Disease', 'MESH:D008654', (22, 34))	('patients', 'Species', '9606', (8, 16))
138424	28619093	A higher than average proportion of BDCA-3+ dendritic cells was associated with poorer overall survival at both the second (p = 0.008) and third (p = 0.014) dose of anti-CD40.	('BDCA-3', 'Gene', (36, 42))	('higher', 'PosReg', (2, 8))	('poorer', 'NegReg', (80, 86))	('anti-CD40', 'Var', (165, 174))	('BDCA-3', 'Gene', '7056', (36, 42))	('overall survival', 'MPA', (87, 103))
138430	28619093	Extensive preclinical studies of anti-CD40 therapy have shown efficacy in various tumour model systems, and several clinical agents targeting the CD40 signalling axis have been or are currently under investigation.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('signalling', 'biological_process', 'GO:0023052', ('151', '161'))	('anti-CD40 therapy', 'Var', (33, 50))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))
138433	28619093	Agonistic anti-CD40 can synergise with chemotherapy and cure advanced tumours in mice, especially when administered after chemotherapy.	('mice', 'Species', '10090', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('anti-CD40', 'Var', (10, 19))	('cure', 'NegReg', (56, 60))	('tumours', 'Disease', (70, 77))
138440	28619093	Weekly CP-870,893 monotherapy halved circulating lymphocyte concentrations after 48 h before returning to pre-treatment levels; this depletion was not observed when dosing occurred every three weeks.	('pre', 'molecular_function', 'GO:0003904', ('106', '109'))	('monotherapy', 'Var', (18, 29))	('circulating lymphocyte concentrations', 'MPA', (37, 74))	('halved', 'NegReg', (30, 36))	('halved circulating lymphocyte concentrations', 'Phenotype', 'HP:0001888', (30, 74))	('CP-870', 'Chemical', '-', (7, 13))
138469	28619093	CD4+ T cells were identified by positive staining for CD3-V450 and CD4-APCH7, and negative for a lineage cocktail of CD19-V500, CD14-V500 and LIVE/DEAD Fixable Aqua viability stain.	('CD19', 'Gene', '930', (117, 121))	('CD4', 'Gene', '920', (0, 3))	('CD14-V500', 'Gene', '929', (128, 137))	('CD4', 'Gene', (67, 70))	('CD3-V450', 'Var', (54, 62))	('CD4', 'Gene', '920', (67, 70))	('CD14-V500', 'Gene', (128, 137))	('CD19', 'Gene', (117, 121))	('CD4', 'Gene', (0, 3))
138472	28619093	CD8+ T cells were identified by positive staining for CD3-V450 and CD8-APC-H7, and negative for a lineage cocktail of CD19-V500, CD14-V500 and LIVE/DEAD Fixable Aqua viability stain.	('CD19', 'Gene', (118, 122))	('CD8-APC-H7', 'Disease', 'MESH:C563824', (67, 77))	('CD8-APC-H7', 'Disease', (67, 77))	('CD14-V500', 'Gene', '929', (129, 138))	('CD3-V450', 'Var', (54, 62))	('CD19', 'Gene', '930', (118, 122))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('CD14-V500', 'Gene', (129, 138))	('CD8', 'Gene', (67, 70))	('APC', 'cellular_component', 'GO:0005680', ('71', '74'))	('CD8', 'Gene', '925', (67, 70))
138510	28619093	Overall, CD4+ T cells exhibited a broadly similar profile for fluctuations in proliferation and activation as CD8+ T cells, with significant reductions in the proportion of both Ki67+ and ICOS+ cells at Day 8 of each cycle, one week following chemotherapy (Fig.	('reductions', 'NegReg', (141, 151))	('ICOS', 'Gene', (188, 192))	('Ki67', 'Chemical', '-', (178, 182))	('ICOS', 'Gene', '29851', (188, 192))	('Ki67+', 'Var', (178, 183))	('CD8', 'Gene', (110, 113))	('CD4', 'Gene', (9, 12))	('CD4', 'Gene', '920', (9, 12))	('CD8', 'Gene', '925', (110, 113))	('activation', 'CPA', (96, 106))
138516	28619093	Given that activating anti-CD40 has strong preclinical and early clinical evidence of efficacy, we undertook this study of systemic immune parameters to establish the pattern of changes induced by this agent in the context of chemotherapy, and to undertake an exploratory analysis of any correlation between these changes and patient outcomes.	('anti-CD40', 'Var', (22, 31))	('patient', 'Species', '9606', (326, 333))	('activating', 'PosReg', (11, 21))
138531	28619093	Weekly CP-870,893 monotherapy has been shown to reduce lymphocyte concentrations in peripheral blood to below 50% of baseline counts two days after treatment at MTD, followed by rebound to pretreatment levels, although this has not been observed for less frequent dosing schedules.	('lymphocyte concentrations in peripheral', 'MPA', (55, 94))	('monotherapy', 'Var', (18, 29))	('reduce lymphocyte', 'Phenotype', 'HP:0001888', (48, 65))	('reduce', 'NegReg', (48, 54))	('CP-870', 'Chemical', '-', (7, 13))
138535	28619093	Our exploratory analyses of the relationship between immunological parameters and patient outcomes highlighted a potential relationship between either higher-than-median BDCA-2 + DC% of PBMC at baseline, or lower-than-median BDCA-3 + % at C2D8 and C3D8, and longer patient survival.	('BDCA-3', 'Gene', (225, 231))	('lower-than-median', 'NegReg', (207, 224))	('patient', 'Species', '9606', (82, 89))	('BDCA-2', 'Gene', '170482', (170, 176))	('longer', 'PosReg', (258, 264))	('C2D8', 'Var', (239, 243))	('patient', 'Species', '9606', (265, 272))	('BDCA-2', 'Gene', (170, 176))	('BDCA-3', 'Gene', '7056', (225, 231))	('C3D8', 'Var', (248, 252))
138536	28619093	Mechanistically, it is possible that a higher proportion of BDCA-2+ DC at baseline indicates a larger number of target cells available for the action of anti-CD40 therapy, potentially giving a useful prognostic indicator for those patients likely to achieve better responses.	('BDCA-2', 'Gene', (60, 66))	('anti-CD40', 'Var', (153, 162))	('patients', 'Species', '9606', (231, 239))	('BDCA-2', 'Gene', '170482', (60, 66))
138538	28619093	However, it may be that these BDCA-3+ are migrating out of the peripheral blood and into other tissues, potentially as a result of anti-CD40 inducing the maturation of these cells, and may therefore be indicative of those patients achieving better responses.	('BDCA-3', 'Gene', (30, 36))	('inducing', 'PosReg', (141, 149))	('patients', 'Species', '9606', (222, 230))	('maturation', 'CPA', (154, 164))	('anti-CD40', 'Var', (131, 140))	('BDCA-3', 'Gene', '7056', (30, 36))
138540	28619093	The postulated mechanism of CP-870,893 action is to increase APC-mediated CD8+ T cell activation and it may be that those patients with higher-than-median CD8 activation prior to treatment have an immune landscape that is already predisposed toward this outcome; thus, addition of anti-CD40 is sufficient to tip the balance further in favour of a better anti-tumour response in those individuals.	('tumour', 'Disease', (359, 365))	('CD8', 'Gene', '925', (74, 77))	('T cell activation', 'biological_process', 'GO:0042110', ('79', '96'))	('increase', 'PosReg', (52, 60))	('APC', 'cellular_component', 'GO:0005680', ('61', '64'))	('anti-CD40', 'Var', (281, 290))	('patients', 'Species', '9606', (122, 130))	('CD8', 'Gene', (155, 158))	('tumour', 'Phenotype', 'HP:0002664', (359, 365))	('tumour', 'Disease', 'MESH:D009369', (359, 365))	('CD8', 'Gene', '925', (155, 158))	('CP-870', 'Chemical', '-', (28, 34))	('CD8', 'Gene', (74, 77))
138559	28464864	We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene.	('MSTO-211H', 'CellLine', 'CVCL:1430', (87, 96))	('metformin', 'Chemical', 'MESH:D008687', (39, 48))	('nutlin-3a', 'Chemical', 'MESH:C482205', (67, 76))	('nutlin-3a', 'Chemical', 'MESH:C482205', (53, 62))	('EHMES-10', 'CellLine', 'CVCL:M208', (131, 139))	('nutlin-3a', 'Var', (67, 76))	('p53', 'Gene', (178, 181))	('NCI-H28', 'CellLine', 'CVCL:1555', (101, 108))	('p53', 'Gene', '7157', (178, 181))
138577	28464864	The p14 defect in mesothelioma facilitated ubiquitin-mediated p53 degradation since p14 blocked a MDM2 action which degraded p53 through the ubiquitination-proteasome pathway.	('proteasome', 'cellular_component', 'GO:0000502', ('156', '166'))	('p14', 'Gene', '1029', (4, 7))	('p14', 'Gene', (84, 87))	('ubiquitin', 'molecular_function', 'GO:0031386', ('43', '52'))	('p53', 'Gene', '7157', (62, 65))	('proteasome pathway', 'biological_process', 'GO:0043161', ('156', '174'))	('p14', 'Gene', (4, 7))	('MDM2', 'Gene', (98, 102))	('mesothelioma', 'Disease', (18, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('p53', 'Gene', (62, 65))	('MDM2', 'Gene', '4193', (98, 102))	('p53', 'Gene', '7157', (125, 128))	('facilitated', 'PosReg', (31, 42))	('degraded', 'NegReg', (116, 124))	('defect', 'Var', (8, 14))	('proteasome', 'molecular_function', 'GO:0004299', ('156', '166'))	('p53', 'Gene', (125, 128))	('blocked', 'NegReg', (88, 95))	('degradation', 'biological_process', 'GO:0009056', ('66', '77'))	('p14', 'Gene', '1029', (84, 87))
138592	28464864	The p53 genotypes of JMN-1B and EHMES-1 cells are mutated and those of the others including Met-5A are wild-type.	('JMN-1B', 'Disease', 'MESH:C565748', (21, 27))	('p53', 'Gene', '7157', (4, 7))	('mutated', 'Var', (50, 57))	('JMN-1B', 'Disease', (21, 27))	('p53', 'Gene', (4, 7))
138593	28464864	All the mesothelioma cells with the wild-type p53 except Met-5A showed defective p14ARF and p16INK4A expression due to either lack of the transcription or deletion of the corresponding genomic DNA, whereas Met-5A cells had the p14 ARF and p16 INKA genes but lost the p53 functions because of SV40 T antigen expressed.	('p16', 'Gene', (92, 95))	('p16', 'Gene', '1029', (92, 95))	('p14 ARF', 'Gene', '1029', (227, 234))	('mesothelioma', 'Disease', (8, 20))	('p53', 'Gene', '7157', (46, 49))	('deletion', 'Var', (155, 163))	('p14ARF', 'Gene', '1029', (81, 87))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('p16', 'Gene', (239, 242))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('defective', 'NegReg', (71, 80))	('p53', 'Gene', (46, 49))	('transcription', 'MPA', (138, 151))	('p53', 'Gene', '7157', (267, 270))	('p16', 'Gene', '1029', (239, 242))	('lack', 'NegReg', (126, 130))	('p14ARF', 'Gene', (81, 87))	('p14 ARF', 'Gene', (227, 234))	('p16INK4A', 'Gene', (92, 100))	('p53', 'Gene', (267, 270))	('p16INK4A', 'Gene', '1029', (92, 100))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('292', '306'))	('expression', 'MPA', (101, 111))
138604	28464864	EHMES-1 and JMN-1B cells with mutated p53 gene, NCI-H2452 cells with truncated p53 protein that cannot induce p21, and Met-5A cells with a loss of p53 functions by expressed SV40 T antigen that inactivated p53, were consequently classified as a non-functional p53 group and the others as a functional p53 group.	('mutated', 'Var', (30, 37))	('p53', 'Gene', '7157', (301, 304))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('174', '188'))	('p53', 'Gene', '7157', (206, 209))	('p53', 'Gene', '7157', (79, 82))	('loss', 'NegReg', (139, 143))	('p53', 'Gene', (301, 304))	('p21', 'Gene', (110, 113))	('p21', 'Gene', '644914', (110, 113))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('p53', 'Gene', '7157', (260, 263))	('p53', 'Gene', (206, 209))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (38, 41))	('JMN-1B', 'Disease', (12, 18))	('p53', 'Gene', (260, 263))	('p53', 'Gene', '7157', (147, 150))	('NCI-H2452', 'CellLine', 'CVCL:1553', (48, 57))	('p53', 'Gene', (38, 41))	('functions', 'MPA', (151, 160))	('JMN-1B', 'Disease', 'MESH:C565748', (12, 18))	('p53', 'Gene', (147, 150))
138649	28464864	MSTO-211H cells were prone to be arrested at G1 phase followed by increased sub-G1 populations, while NCI-H28 cells were likely to be arrested at G2/M phase.	('increased', 'PosReg', (66, 75))	('NCI-H28', 'CellLine', 'CVCL:1555', (102, 109))	('sub-G1 populations', 'CPA', (76, 94))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (0, 15))	('M phase', 'biological_process', 'GO:0000279', ('149', '156'))	('MSTO-211H', 'Var', (0, 9))	('G1 phase', 'biological_process', 'GO:0051318', ('45', '53'))
138666	28464864	Cleaved caspase-3 levels were induced in MSTO-211H and to a lesser extent in NCI-H28 cells but not in EHMES-10 cells.	('NCI-H28', 'CellLine', 'CVCL:1555', (77, 84))	('induced', 'Reg', (30, 37))	('caspase-3', 'Gene', (8, 17))	('MSTO-211H', 'Var', (41, 50))	('caspase-3', 'Gene', '836', (8, 17))	('EHMES-10', 'CellLine', 'CVCL:M208', (102, 110))	('MSTO-211H', 'CellLine', 'CVCL:1430', (41, 50))
138723	28464864	Furthermore, metformin rather down-regulated nutlin-3a-induced effects.	('down-regulated', 'NegReg', (30, 44))	('metformin', 'Var', (13, 22))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('nutlin-3a-induced effects', 'MPA', (45, 70))	('nutlin-3a', 'Chemical', 'MESH:C482205', (45, 54))
138727	28464864	In contrast, cell cycle analyses showed increased sub-G1 populations in EHMES-10 cells but not in NCI-H28 cells.	('EHMES-10', 'CellLine', 'CVCL:M208', (72, 80))	('NCI-H28', 'CellLine', 'CVCL:1555', (98, 105))	('EHMES-10', 'Var', (72, 80))	('increased', 'PosReg', (40, 49))	('sub-G1 populations', 'CPA', (50, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('13', '23'))
138731	28464864	We also found that the down-regulated Atg-5 was irrelevant to AMPK activation since an AMPK activator, A769662, did not influence the Atg-5 expression (Additional file 5: Figure S4A).	('Atg-5', 'Gene', (134, 139))	('AMPK', 'molecular_function', 'GO:0047322', ('62', '66'))	('AMPK', 'molecular_function', 'GO:0050405', ('87', '91'))	('AMPK', 'Gene', (62, 66))	('Atg-5', 'Gene', (38, 43))	('Atg-5', 'Gene', '9474', (134, 139))	('AMPK', 'molecular_function', 'GO:0004691', ('87', '91'))	('A769662', 'Var', (103, 110))	('AMPK', 'Gene', '5563', (62, 66))	('AMPK', 'Gene', '5563', (87, 91))	('AMPK', 'molecular_function', 'GO:0050405', ('62', '66'))	('Atg-5', 'Gene', '9474', (38, 43))	('AMPK', 'molecular_function', 'GO:0047322', ('87', '91'))	('AMPK', 'molecular_function', 'GO:0004691', ('62', '66'))	('AMPK', 'Gene', (87, 91))
138739	28464864	Mesothelioma has another frequent genetic alternations, mutations of NF2 and those of the downstream genes found in about 50% of the clinical specimens.	('mutations', 'Var', (56, 65))	('NF2', 'Gene', (69, 72))	('NF2', 'Gene', '4771', (69, 72))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
138740	28464864	The loss of functions caused by these mutation led to activation of the Hippo pathway, and the activation augmented the mTOR downstream pathways.	('activation', 'PosReg', (54, 64))	('mutation', 'Var', (38, 46))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (120, 124))	('Hippo pathway', 'Pathway', (72, 85))	('loss of functions', 'NegReg', (4, 21))
138745	28464864	Furthermore, metformin negated nutlin-3a-induced activation of p53 and the AMPK pathways, and induced non-apoptotic pathways in MSTO-211H cells.	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('AMPK', 'Gene', '5563', (75, 79))	('metformin', 'Var', (13, 22))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (128, 143))	('AMPK', 'molecular_function', 'GO:0004691', ('75', '79'))	('AMPK', 'molecular_function', 'GO:0050405', ('75', '79'))	('AMPK', 'Gene', (75, 79))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('negated', 'NegReg', (23, 30))	('AMPK', 'molecular_function', 'GO:0047322', ('75', '79'))	('non-apoptotic pathways', 'Pathway', (102, 124))	('induced', 'Reg', (94, 101))	('nutlin-3a', 'Chemical', 'MESH:C482205', (31, 40))	('activation', 'PosReg', (49, 59))
138749	28464864	Combination of an mTOR inhibitor and an agent to augment p53 levels is therefore a suitable therapeutic strategy for mesothelioma with the NF2 mutation and loss of p53 functions.	('mTOR', 'Gene', (18, 22))	('functions', 'MPA', (168, 177))	('NF2', 'Gene', '4771', (139, 142))	('mTOR', 'Gene', '2475', (18, 22))	('mesothelioma', 'Disease', (117, 129))	('augment', 'PosReg', (49, 56))	('loss', 'NegReg', (156, 160))	('mutation', 'Var', (143, 151))	('NF2', 'Gene', (139, 142))	('p53', 'Gene', (57, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('p53', 'Gene', (164, 167))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', '7157', (164, 167))
138750	28464864	Previous studies also showed that metformin up-regulated p53 levels through inhibited mTOR pathways and augmentation of p53 suppressed the mTOR activity.	('mTOR', 'Gene', '2475', (86, 90))	('p53', 'Gene', '7157', (120, 123))	('mTOR', 'Gene', (86, 90))	('mTOR', 'Gene', (139, 143))	('mTOR', 'Gene', '2475', (139, 143))	('metformin', 'Chemical', 'MESH:D008687', (34, 43))	('p53', 'Gene', (120, 123))	('up-regulated', 'PosReg', (44, 56))	('p53', 'Gene', (57, 60))	('suppressed', 'NegReg', (124, 134))	('inhibited', 'NegReg', (76, 85))	('p53', 'Gene', '7157', (57, 60))	('augmentation', 'Var', (104, 116))
138900	25757056	Studies from the literature also show the modulated levels of IL-10 in asbestos exposed population and MM patients suggesting a role of IL-10 in the pathobiology of asbestos-induced diseases.	('asbestos', 'Chemical', 'MESH:D001194', (165, 173))	('IL-10', 'Gene', (136, 141))	('IL-10', 'Gene', '3586', (62, 67))	('IL-10', 'molecular_function', 'GO:0005141', ('136', '141'))	('patients', 'Species', '9606', (106, 114))	('IL-10', 'molecular_function', 'GO:0005141', ('62', '67'))	('IL-10', 'Gene', (62, 67))	('asbestos', 'Chemical', 'MESH:D001194', (71, 79))	('modulated', 'Var', (42, 51))	('asbestos-induced diseases', 'Disease', (165, 190))	('levels', 'MPA', (52, 58))	('IL-10', 'Gene', '3586', (136, 141))	('asbestos-induced diseases', 'Disease', 'MESH:D001195', (165, 190))
138945	26664569	Recently, WWTR1/CAMTA1 gene fusion has been reported as a genetic abnormality, which may help in distinguishing PEHE from other vascular tumors such as epitheliod hemangioma and epitheliod angiosarcoma, especially on small biopsy samples.	('CAMTA1', 'Gene', (16, 22))	('fusion', 'Var', (28, 34))	('PEHE', 'Disease', (112, 116))	('genetic abnormality', 'Disease', 'MESH:D030342', (58, 77))	('WWTR1', 'Gene', (10, 15))	('vascular tumors', 'Disease', (128, 143))	('EHE', 'Phenotype', 'HP:0032060', (113, 116))	('genetic abnormality', 'Disease', (58, 77))	('vascular tumor', 'Phenotype', 'HP:0100742', (128, 142))	('vascular tumors', 'Phenotype', 'HP:0100742', (128, 143))	('epitheliod hemangioma', 'Phenotype', 'HP:0032060', (152, 173))	('epitheliod angiosarcoma', 'Disease', 'MESH:D006394', (178, 201))	('help', 'Reg', (89, 93))	('CAMTA1', 'Gene', '23261', (16, 22))	('vascular tumors', 'Disease', 'MESH:D019043', (128, 143))	('epitheliod hemangioma', 'Disease', 'MESH:D006391', (152, 173))	('epitheliod angiosarcoma', 'Disease', (178, 201))	('hemangioma', 'Phenotype', 'HP:0001028', (163, 173))	('WWTR1', 'Gene', '25937', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('epitheliod hemangioma', 'Disease', (152, 173))	('angiosarcoma', 'Phenotype', 'HP:0200058', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
139055	22989046	After comparing the sum of the average duration of automatic + manual correction for each site and software with the total time needed to get the Vref, we can conclude the following: 1) for prostate patients, MIM was the software that obtained the most gain in time (55 min), while the average gain was 31 min and 41 min with ABAS and VelocityAI respectively; 2) for the H&N site, ABAS was the most time saving software with an average gain of 1 hour and 23 min; MIM can save 1 hour and 4 min, and VelocityAI 45 min; 3) for the mesothelioma cases, the average obtained gain was 22 min with both ABAS and MIM, and 15 min with Velocity.	('the', 'Disease', (524, 527))	('both', 'Var', (590, 594))	('mesothelioma', 'Disease', 'MESH:D008654', (528, 540))	('and', 'Var', (600, 603))	('N', 'Chemical', 'MESH:D009584', (373, 374))	('patients', 'Species', '9606', (199, 207))	('mesothelioma', 'Disease', (528, 540))
139062	22989046	The need to replan and adapt treatment for internal anatomy variations due to tumor shrinkage and shape deformation   has increased over the years in order to make better use of highly conformal treatment techniques.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('variations', 'Var', (60, 70))	('tumor', 'Disease', (78, 83))
139123	21317924	Hsa-miR-17* mimic transfection decreased cell invasion by 31-48% in all cell lines (p <= 0.004) compared to controls, while hsa-30c inhibitor expression decreased cell invasion by 81 - 96% in all cell lines (p <= 0.001) compared to controls (Fig.	('cell invasion', 'CPA', (41, 54))	('decreased', 'NegReg', (31, 40))	('Hsa-miR-17', 'Gene', (0, 10))	('Hsa-miR-17', 'Gene', '406952', (0, 10))	('decreased', 'NegReg', (153, 162))	('transfection', 'Var', (18, 30))	('cell invasion', 'CPA', (163, 176))
139166	21317924	Soini has reported that all mesothelioma cell lines are positive for bcl-X, and other investigators have demonstrated that introduction of antisense oligonucleotides specific to Bcl-xL mRNA, can sensitize MPM cells to chemotherapeutic agents.	('antisense', 'Var', (139, 148))	('Bcl-xL', 'Gene', '598', (178, 184))	('bcl-X', 'Gene', '598', (69, 74))	('oligonucleotides', 'Chemical', 'MESH:D009841', (149, 165))	('MPM cells', 'CPA', (205, 214))	('mesothelioma', 'Disease', (28, 40))	('Bcl-xL', 'Gene', (178, 184))	('MPM', 'Chemical', '-', (205, 208))	('sensitize', 'Reg', (195, 204))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))	('bcl-X', 'Gene', (69, 74))
139167	21317924	Additionally, the growth of established mouse flank human tumor xenografts is reduced with intra-tumor administration of antisense oligoncleotides to BCL-x.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('BCL-x', 'Gene', '598', (150, 155))	('BCL-x', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('intra-tumor', 'Disease', 'MESH:D009369', (91, 102))	('growth', 'CPA', (18, 24))	('human', 'Species', '9606', (52, 57))	('antisense oligoncleotides', 'Var', (121, 146))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('reduced', 'NegReg', (78, 85))	('intra-tumor', 'Disease', (91, 102))	('mouse', 'Species', '10090', (40, 45))
139169	21317924	As detailed above, miR-17c* and inhibitor of miR-30 suppressed expression of these genes in our MPM cell lines, possibly explaining enhanced sensitivity of chemotherapy drugs when used in combination with Onconase.	('miR', 'Gene', '220972', (19, 22))	('MPM', 'Chemical', '-', (96, 99))	('miR', 'Gene', (19, 22))	('sensitivity', 'MPA', (141, 152))	('expression', 'MPA', (63, 73))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('miR-17', 'Gene', (19, 25))	('suppressed', 'NegReg', (52, 62))	('enhanced', 'PosReg', (132, 140))	('miR-17', 'Gene', '406952', (19, 25))	('inhibitor', 'Var', (32, 41))
139173	21317924	Inhibition of ABC transporters has been proven to be an efficacious technique for improvements in cancer therapy, and currently tyrosine kinase inhibitors are being investigated due to their preferential inhibition of these multidrug resistant transmembrane proteins.	('ABC transporters', 'Gene', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('transmembrane', 'cellular_component', 'GO:0044214', ('244', '257'))	('cancer', 'Disease', (98, 104))	('Inhibition', 'Var', (0, 10))	('transmembrane', 'cellular_component', 'GO:0016021', ('244', '257'))
139199	21317924	Oligonucleotides miRIDIAN hsa-miR-17* mimic (C-300486-05) and hsa-miR-30c inhibitor (IH-300542-07) were purchased from Dharmacon RNAi Technologies (Lafayette, CO).	('miR', 'Gene', '220972', (30, 33))	('RNAi', 'biological_process', 'GO:0016246', ('129', '133'))	('miR', 'Gene', (30, 33))	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('C', 'Chemical', 'MESH:D002244', (159, 160))	('hsa-miR-17', 'Gene', '406952', (26, 36))	('miR', 'Gene', '220972', (17, 20))	('miR-30c', 'Gene', (66, 73))	('miR', 'Gene', (17, 20))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('miR', 'Gene', (66, 69))	('C-300486-05', 'Var', (45, 56))	('miR-30c', 'Gene', '407031', (66, 73))	('miR', 'Gene', '220972', (66, 69))	('hsa-miR-17', 'Gene', (26, 36))
139247	32872534	Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease.	('Mesothelioma Malignant', 'Phenotype', 'HP:0100001', (109, 131))	('Mutations', 'Var', (57, 66))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (101, 121))	('Pleural Mesothelioma', 'Phenotype', 'HP:0100002', (132, 152))	('Malignant Pleural Mesothelioma', 'Disease', (122, 152))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (91, 121))	('Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (122, 152))	('Biphasic Malignant Pleural Mesothelioma', 'Disease', 'MESH:C562839', (82, 121))	('Biphasic Malignant Pleural Mesothelioma', 'Disease', (82, 121))
139253	32872534	Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component.	('MXRA5', 'Gene', '25878', (13, 18))	('NOD2', 'Gene', (34, 38))	('MXRA5', 'Gene', (13, 18))	('associated', 'Reg', (70, 80))	('sarcomatoid component', 'Disease', (176, 197))	('Mutations', 'Var', (0, 9))	('sarcomatoid component', 'Disease', 'MESH:C538614', (176, 197))	('biph-MPM', 'Chemical', '-', (86, 94))	('biph-MPM', 'Disease', (86, 94))	('NOD2', 'Gene', '64127', (34, 38))
139254	32872534	Mutations in NOD2 and XRCC6 correlated with patients' survival.	('NOD2', 'Gene', (13, 17))	('patients', 'Species', '9606', (44, 52))	('XRCC6', 'Gene', (22, 27))	('correlated with', 'Reg', (28, 43))	('Mutations', 'Var', (0, 9))	('NOD2', 'Gene', '64127', (13, 17))	('XRCC6', 'Gene', '2547', (22, 27))
139280	32872534	Surprisingly, RDX has the highest prevalence of protein-altering mutations in our cohort (29/69, 42%) followed by MXRA5 which was mutated in 40.6% of analyzed samples (n = 28).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('protein-altering', 'MPA', (48, 64))	('RDX', 'Gene', '5962', (14, 17))	('MXRA5', 'Gene', '25878', (114, 119))	('RDX', 'Gene', (14, 17))	('MXRA5', 'Gene', (114, 119))	('mutations', 'Var', (65, 74))
139281	32872534	We found 42 mutations for RDX and 47 for MXRA5.	('RDX', 'Gene', (26, 29))	('mutations', 'Var', (12, 21))	('MXRA5', 'Gene', '25878', (41, 46))	('RDX', 'Gene', '5962', (26, 29))	('MXRA5', 'Gene', (41, 46))
139282	32872534	Of these the vast majority were missense variants (97.2% RDX, 93.3% MXRA5).	('missense variants', 'Var', (32, 49))	('RDX', 'Gene', (57, 60))	('MXRA5', 'Gene', (68, 73))	('RDX', 'Gene', '5962', (57, 60))	('MXRA5', 'Gene', '25878', (68, 73))
139284	32872534	BAP1 and NF2 mutations were detected in 21.7% (n = 15) and 18.8% (n = 13) of samples respectively, in line with previous reports that describe these as the most frequent mutated genes in MPM.	('BAP1', 'Gene', (0, 4))	('MPM', 'Gene', (187, 190))	('detected', 'Reg', (28, 36))	('NF2', 'Gene', (9, 12))	('mutations', 'Var', (13, 22))	('BAP1', 'Gene', '8314', (0, 4))	('NF2', 'Gene', '4771', (9, 12))
139285	32872534	Mutations in TP53, CUL1, PIK3CA and TAOK, which were previously reported to be variably mutated in MPM, were observed with frequency in line with previous reports.	('TP53', 'Gene', (13, 17))	('PIK3CA', 'Gene', (25, 31))	('CUL1', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (25, 31))	('CUL1', 'Gene', '8454', (19, 23))	('TAOK', 'Gene', (36, 40))	('TP53', 'Gene', '7157', (13, 17))
139288	32872534	While mutations in RDX are quite homogeneously distributed in the two subsets, mutations in MXRA5 and NOD2 are significantly associated with biph-MPM (p = 0.050 and p = 0.018 respectively).	('NOD2', 'Gene', (102, 106))	('MXRA5', 'Gene', (92, 97))	('RDX', 'Gene', (19, 22))	('mutations', 'Var', (79, 88))	('RDX', 'Gene', '5962', (19, 22))	('associated with', 'Reg', (125, 140))	('NOD2', 'Gene', '64127', (102, 106))	('MXRA5', 'Gene', '25878', (92, 97))	('biph-MPM', 'Chemical', '-', (141, 149))	('mutations', 'Var', (6, 15))	('biph-MPM', 'Disease', (141, 149))
139289	32872534	MXRA5 is mutated in 51.3% (20/39) of biph-MPM vs. 26.7% (8/30) of e-MPM.	('biph-MPM', 'Chemical', '-', (37, 45))	('MXRA5', 'Gene', '25878', (0, 5))	('biph-MPM', 'Disease', (37, 45))	('MXRA5', 'Gene', (0, 5))	('mutated', 'Var', (9, 16))	('e-MPM', 'Chemical', '-', (66, 71))
139290	32872534	Mutations in NOD2 are observed in 25.6% (10/39) of biph-MPM vs. 3.3% (1/30) of e-MPM.	('NOD2', 'Gene', (13, 17))	('observed', 'Reg', (22, 30))	('Mutations', 'Var', (0, 9))	('NOD2', 'Gene', '64127', (13, 17))	('biph-MPM', 'Chemical', '-', (51, 59))	('biph-MPM', 'Disease', (51, 59))	('e-MPM', 'Chemical', '-', (79, 84))
139291	32872534	Even if not significant, mutations in CDH8 and XRCC6 showed a positive trend of association with the biph-MPM subset.	('mutations', 'Var', (25, 34))	('biph-MPM subset', 'Disease', (101, 116))	('CDH8', 'Gene', (38, 42))	('XRCC6', 'Gene', (47, 52))	('CDH8', 'Gene', '1006', (38, 42))	('biph-MPM', 'Chemical', '-', (101, 109))	('association', 'Reg', (80, 91))	('XRCC6', 'Gene', '2547', (47, 52))
139292	32872534	By contrast, mutations in ACTG1 (p = 0.002), TAOK1 (p = 0.077) and PIK3CA (p = 0.090) were more frequent in the e-MPM samples as compared with the other subtype.	('PIK3CA', 'Gene', '5290', (67, 73))	('TAOK1', 'Gene', '57551', (45, 50))	('TAOK1', 'Gene', (45, 50))	('e-MPM', 'Disease', (112, 117))	('e-MPM', 'Chemical', '-', (112, 117))	('ACTG1', 'Gene', '71', (26, 31))	('frequent', 'Reg', (96, 104))	('ACTG1', 'Gene', (26, 31))	('mutations', 'Var', (13, 22))	('PIK3CA', 'Gene', (67, 73))
139294	32872534	In particular, mutations in MRXA5 and NOD2 were equally occur in sMPM as in biph-MPM even if with slightly different frequencies.	('MRXA5', 'Gene', (28, 33))	('NOD2', 'Gene', (38, 42))	('mutations', 'Var', (15, 24))	('biph-MPM', 'Chemical', '-', (76, 84))	('occur', 'Reg', (56, 61))	('NOD2', 'Gene', '64127', (38, 42))	('sMPM', 'Disease', (65, 69))
139295	32872534	By contrast mutations in CDH8 and XRCC6 were detected exclusively in the biph-MPM samples (Table S5).	('detected', 'Reg', (45, 53))	('CDH8', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('XRCC6', 'Gene', '2547', (34, 39))	('biph-MPM', 'Chemical', '-', (73, 81))	('CDH8', 'Gene', '1006', (25, 29))	('biph-MPM', 'Disease', (73, 81))	('XRCC6', 'Gene', (34, 39))
139298	32872534	Mutations in MXRA5 were significantly associated with an increased s-MPM component, indicating that these mutations may be part of the progression process that lead to transdifferentiation of epithelioid MPM cells into the sarcomatoid phenotype.	('lead to', 'Reg', (160, 167))	('s-MPM component', 'MPA', (67, 82))	('sarcomatoid', 'Disease', 'MESH:C538614', (223, 234))	('epithelioid MPM', 'Disease', (192, 207))	('MXRA5', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('increased', 'PosReg', (57, 66))	('transdifferentiation', 'biological_process', 'GO:0060290', ('168', '188'))	('MXRA5', 'Gene', '25878', (13, 18))	('sarcomatoid', 'Disease', (223, 234))
139304	32872534	To this end, we investigated the potential correlation of mutations in MXRA5, NOD2, CDH8 and XRCC6 (that display the highest association with this histotype) with survival within the set of 39 biph-MPM included in our cohort.	('mutations', 'Var', (58, 67))	('MXRA5', 'Gene', (71, 76))	('CDH8', 'Gene', '1006', (84, 88))	('XRCC6', 'Gene', '2547', (93, 98))	('NOD2', 'Gene', '64127', (78, 82))	('CDH8', 'Gene', (84, 88))	('investigated', 'Reg', (16, 28))	('MXRA5', 'Gene', '25878', (71, 76))	('XRCC6', 'Gene', (93, 98))	('biph-MPM', 'Chemical', '-', (193, 201))	('NOD2', 'Gene', (78, 82))
139310	32872534	Mutations in XRCC6 and high value of performance status significantly correlated with reduced survival in both univariate and multivariate analysis.	('reduced', 'NegReg', (86, 93))	('XRCC6', 'Gene', '2547', (13, 18))	('survival', 'MPA', (94, 102))	('Mutations', 'Var', (0, 9))	('XRCC6', 'Gene', (13, 18))
139311	32872534	By contrast, mutations in NOD2 do not correlate with survival probability in the univariate analysis but, when considered in a multivariable model, show a significant protective effect on patients' survival (Table 3).	('patients', 'Species', '9606', (188, 196))	('mutations', 'Var', (13, 22))	('NOD2', 'Gene', '64127', (26, 30))	('NOD2', 'Gene', (26, 30))
139312	32872534	In fact, Kaplan-Meier plots showed that in patients with a favorable performance status, mutations in NOD2 are associated to an increased survival while mutations in XRCC6 had a significant negative effect on the outcome of these patients which was comparable with the effect determined by an unfavorable PS.	('NOD2', 'Gene', (102, 106))	('XRCC6', 'Gene', (166, 171))	('survival', 'MPA', (138, 146))	('mutations', 'Var', (153, 162))	('patients', 'Species', '9606', (43, 51))	('increased', 'PosReg', (128, 137))	('patients', 'Species', '9606', (230, 238))	('NOD2', 'Gene', '64127', (102, 106))	('mutations', 'Var', (89, 98))	('XRCC6', 'Gene', '2547', (166, 171))
139325	32872534	Both in the training and validation set, mutations in MXRA5 and NOD2 are significantly associated with the biph-MPM while alterations in XRCC6 and CDH8 seem to be enriched in this subset of MPM.	('CDH8', 'Gene', (147, 151))	('mutations', 'Var', (41, 50))	('MXRA5', 'Gene', (54, 59))	('XRCC6', 'Gene', '2547', (137, 142))	('associated', 'Reg', (87, 97))	('NOD2', 'Gene', '64127', (64, 68))	('CDH8', 'Gene', '1006', (147, 151))	('biph-MPM', 'Chemical', '-', (107, 115))	('biph-MPM', 'Disease', (107, 115))	('XRCC6', 'Gene', (137, 142))	('NOD2', 'Gene', (64, 68))	('MXRA5', 'Gene', '25878', (54, 59))
139327	32872534	Mutations in MXRA5 were previously described in MPM.	('described', 'Reg', (35, 44))	('MXRA5', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('MPM', 'Disease', (48, 51))	('MXRA5', 'Gene', '25878', (13, 18))
139329	32872534	Besides MPM, mutations in MXRA5 were previously reported in liposarcoma, colon and lung cancer.	('liposarcoma', 'Disease', (60, 71))	('MXRA5', 'Gene', (26, 31))	('colon and lung cancer', 'Disease', 'MESH:D008175', (73, 94))	('reported', 'Reg', (48, 56))	('liposarcoma', 'Phenotype', 'HP:0012034', (60, 71))	('liposarcoma', 'Disease', 'MESH:D008080', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (13, 22))	('MXRA5', 'Gene', '25878', (26, 31))
139330	32872534	The fact that mutations in MXRA5 may be associated with transition from e- to s- phenotype is further confirmed by the positive association we observed with the s-component percentage in the tumor.	('MXRA5', 'Gene', '25878', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('MXRA5', 'Gene', (27, 32))	('mutations', 'Var', (14, 23))	('associated', 'Reg', (40, 50))
139333	32872534	Its function within the immune-system is intriguing since, our survival analysis indicated that mutations in NOD2 have a protective role in MPM being associated with improved survival probability independently of the PS.	('improved', 'PosReg', (166, 174))	('NOD2', 'Gene', '64127', (109, 113))	('MPM', 'Disease', (140, 143))	('NOD2', 'Gene', (109, 113))	('survival', 'MPA', (175, 183))	('mutations', 'Var', (96, 105))
139336	32872534	Our data seem to indicate that mutations in XRCC6 may be relevant in dictating biph-MPM prognosis.	('dictating', 'Reg', (69, 78))	('mutations', 'Var', (31, 40))	('XRCC6', 'Gene', '2547', (44, 49))	('biph-MPM', 'Chemical', '-', (79, 87))	('XRCC6', 'Gene', (44, 49))	('biph-MPM', 'Disease', (79, 87))
139337	32872534	Taking into consideration the role of XRCC6 and its relevance in maintaining DNA homeostasis, it is not surprising that mutations in this gene may be associated with increased DNA damage and therefore increased aggressiveness, as it has already been shown in other cancers.	('associated', 'Reg', (150, 160))	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('aggressiveness', 'Phenotype', 'HP:0000718', (211, 225))	('increased', 'PosReg', (201, 210))	('increased', 'PosReg', (166, 175))	('XRCC6', 'Gene', '2547', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('homeostasis', 'biological_process', 'GO:0042592', ('81', '92'))	('XRCC6', 'Gene', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('mutations', 'Var', (120, 129))	('aggressiveness', 'Disease', 'MESH:D001523', (211, 225))	('cancers', 'Disease', (265, 272))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('aggressiveness', 'Disease', (211, 225))	('DNA damage', 'MPA', (176, 186))
139357	32872534	Furthermore, we showed that genetic analysis at the time of diagnosis may improve risk-based stratification of patients adding information to the evaluation of clinical features that, like performance status, condition patient outcome.	('improve', 'PosReg', (74, 81))	('performance', 'Disease', (189, 200))	('patient', 'Species', '9606', (219, 226))	('genetic analysis', 'Var', (28, 44))	('patient', 'Species', '9606', (111, 118))	('condition', 'Reg', (209, 218))	('risk-based stratification', 'MPA', (82, 107))	('patients', 'Species', '9606', (111, 119))
139633	27830073	An 18F-fluorodeoxyglucose (FDG)-PET/CT scan showed FDG accumulation in the right pleural lesion, right hilar lymph node, and mediastinal lymph node.	('FDG', 'Chemical', 'MESH:D019788', (51, 54))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (3, 25))	('FDG', 'Var', (51, 54))	('right pleural lesion', 'Disease', 'MESH:D010995', (75, 95))	('right pleural lesion', 'Disease', (75, 95))	('FDG', 'Chemical', 'MESH:D019788', (27, 30))
139701	26185765	Combined Analysis of SNP Array Data Identifies Novel CNV Candidates and Pathways in Ependymoma and Mesothelioma Copy number variation is a class of structural genomic modifications that includes the gain and loss of a specific genomic region, which may include an entire gene.	('loss', 'NegReg', (208, 212))	('Ependymoma', 'Phenotype', 'HP:0002888', (84, 94))	('Copy number variation', 'Var', (112, 133))	('Ependymoma and Mesothelioma', 'Disease', 'MESH:D004806', (84, 111))
139703	26185765	In this study, we combined two different open-source packages into an innovative strategy to identify novel copy number variations and pathways associated with cancer.	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('copy number variations', 'Var', (108, 130))
139705	26185765	We detected previously described and novel copy number variations that are associated with cancer chemotherapy resistance.	('cancer', 'Disease', (91, 97))	('copy number variations', 'Var', (43, 65))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (75, 85))
139707	26185765	In conclusion, we present a novel strategy using open-source software to identify copy number variations and altered pathways associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('altered', 'Reg', (109, 116))	('copy number variations', 'Var', (82, 104))	('cancer', 'Disease', (142, 148))
139727	26185765	For example, we identified CTNND2 amplification in 2 patients within the 5p amplified region using CGHcall (Table 1).	('amplification', 'Var', (34, 47))	('CTNND2', 'Gene', '1501', (27, 33))	('patients', 'Species', '9606', (53, 61))	('CTNND2', 'Gene', (27, 33))
139735	26185765	The ADORA1 gene was present in extra copies in 87% of the patients who presented amplifications at the 1q region.	('patients', 'Species', '9606', (58, 66))	('ADORA1', 'Gene', '134', (4, 10))	('ADORA1', 'Gene', (4, 10))	('amplifications', 'Var', (81, 95))
139738	26185765	In the 20q region, we identified the amplification of the cadherin gene CDH22 in 13 patients (when using CGHcall) and 4 patients (while using DNAcopy).	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('patients', 'Species', '9606', (84, 92))	('amplification', 'Var', (37, 50))	('CDH22', 'Gene', (72, 77))	('CDH22', 'Gene', '64405', (72, 77))	('patients', 'Species', '9606', (120, 128))
139743	26185765	We used Cytoscape to evaluate which genes would be affected by the impact of the genes with CNVs in the negative regulation of synaptic transmission, glutamatergic pathway and we found three clusters (Figure 4).	('glutamatergic pathway', 'Pathway', (150, 171))	('negative regulation of synaptic transmission, glutamatergic', 'biological_process', 'GO:0051967', ('104', '163'))	('genes', 'Var', (81, 86))	('CNVs', 'Gene', (92, 96))	('negative regulation', 'MPA', (104, 123))	('synaptic transmission', 'MPA', (127, 148))	('glutamate', 'Chemical', 'MESH:D018698', (150, 159))
139747	26185765	When we used the CGHcall package, we also identified two patients with extra copies of the CTNND2 gene, which encodes a protein that promotes the disruption of the adhesion protein E-cadherin, favoring cell migration and therefore cancer metastasis.	('promotes', 'PosReg', (133, 141))	('CTNND2', 'Gene', (91, 97))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('cell migration', 'CPA', (202, 216))	('patients', 'Species', '9606', (57, 65))	('favoring', 'PosReg', (193, 201))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('E-cadherin', 'Gene', (181, 191))	('extra copies', 'Var', (71, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('183', '191'))	('cancer metastasis', 'Disease', (231, 248))	('disruption', 'MPA', (146, 156))	('CTNND2', 'Gene', '1501', (91, 97))	('E-cadherin', 'Gene', '999', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cell migration', 'biological_process', 'GO:0016477', ('202', '216'))	('cancer metastasis', 'Disease', 'MESH:D009362', (231, 248))
139748	26185765	Christensen and colleagues identified ten lost chromosomal arms in mesothelioma patients.	('patients', 'Species', '9606', (80, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('chromosomal arms', 'Var', (47, 63))	('lost', 'NegReg', (42, 46))	('mesothelioma', 'Disease', (67, 79))
139753	26185765	Cadherins are important tight junction molecules and the absence of these molecules can promote cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer metastasis', 'Disease', (96, 113))	('promote', 'PosReg', (88, 95))	('absence', 'Var', (57, 64))	('Cadherins', 'Protein', (0, 9))	('tight junction', 'cellular_component', 'GO:0070160', ('24', '38'))	('cancer metastasis', 'Disease', 'MESH:D009362', (96, 113))
139754	26185765	We observed the loss of the NCAM gene in 4 patients: this can affect cell-matrix adhesion and stimulate cell migration (Tables 1 and 2).	('affect', 'Reg', (62, 68))	('NCAM', 'Gene', '4684', (28, 32))	('NCAM', 'Gene', (28, 32))	('patients', 'Species', '9606', (43, 51))	('cell migration', 'CPA', (104, 118))	('cell-matrix adhesion', 'CPA', (69, 89))	('cell migration', 'biological_process', 'GO:0016477', ('104', '118'))	('loss', 'Var', (16, 20))	('cell-matrix adhesion', 'biological_process', 'GO:0007160', ('69', '89'))	('stimulate', 'PosReg', (94, 103))
139755	26185765	CNVs in adhesion genes may alter pathways implicated in cell adhesion, as our GSEA using the KEGG and GO databases suggests (Table 3 and Figure 2).	('cell adhesion', 'biological_process', 'GO:0007155', ('56', '69'))	('GSEA', 'Chemical', '-', (78, 82))	('alter', 'Reg', (27, 32))	('adhesion genes', 'Gene', (8, 22))	('CNVs', 'Var', (0, 4))	('pathways', 'Pathway', (33, 41))
139759	26185765	Additionally, our combined approach detected CNV events at other genes associated with mesothelioma: lost copies of LATS1 (associated with hippo signaling) and NF2 (a tumor suppressor) and the amplification of the YAP gene, responsible for encoding a protein that activates transcription factors.	('LATS1', 'Gene', (116, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('167', '183'))	('amplification', 'Var', (193, 206))	('mesothelioma', 'Disease', (87, 99))	('YAP', 'Gene', '10413', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('hippo signaling', 'biological_process', 'GO:0035329', ('139', '154'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('NF2', 'Gene', (160, 163))	('LATS1', 'Gene', '9113', (116, 121))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('transcription', 'biological_process', 'GO:0006351', ('274', '287'))	('lost', 'NegReg', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('YAP', 'Gene', (214, 217))	('tumor', 'Disease', (167, 172))	('NF2', 'Gene', '4771', (160, 163))
139760	26185765	On the ependymoma dataset, we noticed that combining CGHcall and DNAcopy increased our ability to detect amplifications in the 1q chromosomal arm for most of patients, corroborating the original findings.	('increased', 'PosReg', (73, 82))	('amplifications', 'Var', (105, 119))	('ependymoma', 'Disease', (7, 17))	('ependymoma', 'Phenotype', 'HP:0002888', (7, 17))	('patients', 'Species', '9606', (158, 166))	('ependymoma', 'Disease', 'MESH:D004806', (7, 17))
139762	26185765	We identified amplifications in the 1q25 region in 7 patients as well as in the gene QSOX1 with the analysis through CGHcall.	('amplifications', 'Var', (14, 28))	('patients', 'Species', '9606', (53, 61))	('QSOX1', 'Gene', (85, 90))	('QSOX1', 'Gene', '5768', (85, 90))
139764	26185765	In the breast cancer MCF-7 cell line, the silencing of the ADORA1 gene decreases the endogenous estrogen receptor-alpha (ER-alpha) levels and causes a decline in cell proliferation.	('silencing', 'Var', (42, 51))	('decreases', 'NegReg', (71, 80))	('ER-alpha', 'Gene', '2099', (121, 129))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('MCF-7', 'CellLine', 'CVCL:0031', (21, 26))	('estrogen receptor-alpha', 'Gene', (96, 119))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cell proliferation', 'CPA', (162, 180))	('breast cancer', 'Disease', (7, 20))	('ADORA1', 'Gene', '134', (59, 65))	('ADORA1', 'Gene', (59, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('162', '180'))	('ER-alpha', 'Gene', (121, 129))	('estrogen receptor-alpha', 'Gene', '2099', (96, 119))	('decline', 'NegReg', (151, 158))
139774	26185765	We noticed that SLC7A11, one of the system x c - genes, was amplified in 5 patients, which is evidence for the role of glutamate in ependymoma.	('SLC7A11', 'Gene', '23657', (16, 23))	('ependymoma', 'Phenotype', 'HP:0002888', (132, 142))	('glutamate', 'Chemical', 'MESH:D018698', (119, 128))	('ependymoma', 'Disease', 'MESH:D004806', (132, 142))	('patients', 'Species', '9606', (75, 83))	('ependymoma', 'Disease', (132, 142))	('amplified', 'Var', (60, 69))	('SLC7A11', 'Gene', (16, 23))
139780	26185765	We also detected extra copies of the CDH22 gene in 13 patients with CGHcall and in 9 patients with DNAcopy.	('patients', 'Species', '9606', (54, 62))	('detected', 'Reg', (8, 16))	('patients', 'Species', '9606', (85, 93))	('CGHcall', 'Disease', (68, 75))	('extra copies', 'Var', (17, 29))	('CDH22', 'Gene', (37, 42))	('CDH22', 'Gene', '64405', (37, 42))
139789	24884875	Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDHhighCD44+ phenotype and sphere-forming capacity Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs).	('pleural mesothelioma', 'Disease', 'MESH:D008654', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (39, 59))	('malignant pleural mesothelioma', 'Disease', (157, 187))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (167, 187))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (167, 187))	('sphere-forming capacity', 'CPA', (104, 127))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('patient', 'Species', '9606', (216, 223))	('ALDHhighCD44+', 'Var', (76, 89))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (29, 59))	('cancer', 'Disease', (272, 278))	('malignant pleural mesothelioma', 'Disease', (29, 59))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (157, 187))
139793	24884875	Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation.	('ALDH', 'Gene', (36, 40))	('reductions', 'NegReg', (108, 118))	('diethylaminobenzaldehyde', 'Chemical', '-', (52, 76))	('DEAB', 'Chemical', '-', (78, 82))	('diethylaminobenzaldehyde', 'Var', (52, 76))	('drug sensitivity', 'Phenotype', 'HP:0020174', (13, 29))	('ALDH', 'molecular_function', 'GO:0004030', ('36', '40'))	('drug sensitivity', 'Disease', (13, 29))	('cell viability', 'CPA', (122, 136))
139794	24884875	At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDHhigh and ALDHlow fractions of the three MPM cell lines.	('cisplatin', 'Var', (29, 38))	('chemoresistance', 'CPA', (201, 216))	('mRNA expression levels', 'MPA', (81, 103))	('ALDH1A2', 'Gene', '8854', (108, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('ALDH', 'molecular_function', 'GO:0004030', ('108', '112'))	('DEAB', 'Chemical', '-', (41, 45))	('upregulated', 'PosReg', (69, 80))	('ALDH1A2', 'Gene', (108, 115))	('CD44', 'Gene', '960', (138, 142))	('ALDH', 'molecular_function', 'GO:0004030', ('117', '121'))	('ALDH1A3', 'Gene', (117, 124))	('ALDH1A3', 'Gene', '220', (117, 124))	('CD44', 'Gene', (138, 142))
139837	24884875	As has been described in a number of studies in solid tumours, we used the flow cytometry-based Aldefluor assay (Figure 2B) to select ALDHhigh and ALDHlow subpopulations in order to demarcate a non-CSC from a CSC-like cell population in MPM cell lines, and determine the potential role of the former in chemoresistance.	('ALDHhigh', 'Var', (134, 142))	('ALDHlow', 'Var', (147, 154))	('solid tumours', 'Disease', 'MESH:D009369', (48, 61))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('solid tumours', 'Disease', (48, 61))
139840	24884875	The ALDHlow fractions also co-expressed CD44 although at much lower frequencies in H28 (1.8%), H2052 (2.0%) and Meso4 (1.1%) relative to all cancer cells.	('CD44', 'Gene', (40, 44))	('H28', 'Chemical', '-', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('H2052', 'Chemical', '-', (95, 100))	('Meso4', 'Chemical', '-', (112, 117))	('lower', 'NegReg', (62, 67))	('H2052', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('CD44', 'Gene', '960', (40, 44))	('cancer', 'Disease', (141, 147))
139843	24884875	Notably, the spheres generated by the ALDHhigh fractions in all of the cell lines grew faster, were larger and more robust under mechanical agitations compared with those derived from the ALDHlow cells and non-treated controls.	('agitations', 'Phenotype', 'HP:0000713', (140, 150))	('faster', 'PosReg', (87, 93))	('ALDHhigh', 'Var', (38, 46))	('agitations', 'Disease', 'MESH:D011595', (140, 150))	('grew', 'CPA', (82, 86))	('agitations', 'Disease', (140, 150))
139845	24884875	After 48- and 72-h treatments with the IC50 cisplatin: H28high 28 muM, H28low 8 muM; H2052high 83 muM, H2052low 27 muM; Meso4high 27 muM, Meso4low 9 muM (see Additional file 1), ALDH activity was determined by FACS analysis and compared with those of the non-treated cells.	('muM', 'Gene', '56925', (66, 69))	('H2052', 'Chemical', '-', (85, 90))	('muM', 'Gene', '56925', (115, 118))	('muM', 'Gene', (66, 69))	('IC50', 'Var', (39, 43))	('muM', 'Gene', (115, 118))	('muM', 'Gene', '56925', (98, 101))	('muM', 'Gene', (98, 101))	('Meso4', 'Chemical', '-', (138, 143))	('muM', 'Gene', '56925', (149, 152))	('H28low', 'Var', (71, 77))	('H28', 'Chemical', '-', (71, 74))	('muM', 'Gene', '56925', (80, 83))	('muM', 'Gene', (149, 152))	('H2052', 'Chemical', '-', (103, 108))	('muM', 'Gene', '56925', (133, 136))	('muM', 'Gene', (80, 83))	('muM', 'Gene', (133, 136))	('H28', 'Chemical', '-', (55, 58))	('H28high', 'Var', (55, 62))	('Meso4', 'Chemical', '-', (120, 125))	('ALDH', 'molecular_function', 'GO:0004030', ('178', '182'))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('ALDH', 'MPA', (178, 182))
139848	24884875	Our data show that the drug resistance of both ALDHhigh and ALDHlow fractions of the MPM cell lines varies in response to cisplatin treatment, plausibly due to the differences in the pathological subtype given that both H28 and Meso4 are of a predominantly epitheloid phenotype and H2052 is sarcomatoid.	('H28', 'Chemical', '-', (220, 223))	('H2052', 'Var', (282, 287))	('response to cisplatin', 'biological_process', 'GO:0072718', ('110', '131'))	('drug resistance', 'biological_process', 'GO:0009315', ('23', '38'))	('drug resistance', 'biological_process', 'GO:0042493', ('23', '38'))	('drug resistance', 'MPA', (23, 38))	('Meso4', 'Chemical', '-', (228, 233))	('sarcomatoid', 'Disease', (291, 302))	('H2052', 'Chemical', '-', (282, 287))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('drug resistance', 'Phenotype', 'HP:0020174', (23, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('H28', 'Var', (220, 223))	('sarcomatoid', 'Disease', 'MESH:C538614', (291, 302))
139851	24884875	In H2052, 100% elimination of the sphere-forming population was observed after 48 h of drug treatment, but unexpectedly re-appeared after 72 h (Figure 4E).	('H2052', 'Var', (3, 8))	('H2052', 'Chemical', '-', (3, 8))	('sphere-forming population', 'CPA', (34, 59))	('elimination', 'NegReg', (15, 26))
139855	24884875	We hypothesized that specific inhibition of ALDH by DEAB may sensitize the ALDH-sorted fractions of the three MPM cell lines as DEAB has been shown to inhibit ALDH in breast, leukemia and lung cancer cell lines, as well as the ALDHhigh/CD44+ cells in breast cancer.	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DEAB', 'Var', (128, 132))	('inhibit', 'NegReg', (151, 158))	('ALDH', 'molecular_function', 'GO:0004030', ('159', '163'))	('ALDH', 'molecular_function', 'GO:0004030', ('44', '48'))	('ALDH', 'MPA', (159, 163))	('leukemia and lung cancer', 'Disease', 'MESH:D008175', (175, 199))	('inhibition', 'NegReg', (30, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('breast cancer', 'Disease', (251, 264))	('DEAB', 'Chemical', '-', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('CD44', 'Gene', '960', (236, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('ALDH', 'molecular_function', 'GO:0004030', ('75', '79'))	('CD44', 'Gene', (236, 240))	('DEAB', 'Chemical', '-', (128, 132))
139858	24884875	No decrease in sphere formation was found in H28 after 48 h of cisplatin + DEAB treatment compared with the cisplatin alone-treated cells (Figure 5D); H2052 maintained the absence of spheres, and the sphere-forming cells were totally eliminated in Meso4.	('H2052', 'Var', (151, 156))	('H28', 'Chemical', '-', (45, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('DEAB', 'Chemical', '-', (75, 79))	('absence', 'MPA', (172, 179))	('H2052', 'Chemical', '-', (151, 156))	('eliminated', 'NegReg', (234, 244))	('Meso4', 'Chemical', '-', (248, 253))	('sphere-forming cells', 'CPA', (200, 220))
139869	24884875	Importantly, CD44 significantly increased in both ALDH- sorted fractions of H2052 and the Meso4ALDHhigh fraction (Figure 6E-F).	('Meso4', 'Chemical', '-', (90, 95))	('H2052', 'Var', (76, 81))	('CD44', 'Gene', '960', (13, 17))	('ALDH', 'molecular_function', 'GO:0004030', ('50', '54'))	('CD44', 'Gene', (13, 17))	('increased', 'PosReg', (32, 41))	('H2052', 'Chemical', '-', (76, 81))
139877	24884875	also found that ALDHbr/+and ALDHlow/- cells repopulated stem cell heterogeneity, formed spheroids and generated tumours in epithelial and malignant melanoma.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('ALDHlow/-', 'Gene', (28, 37))	('malignant melanoma', 'Phenotype', 'HP:0002861', (138, 156))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (112, 119))	('ALDHbr/+and', 'Var', (16, 27))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('malignant melanoma', 'Disease', 'MESH:D008545', (138, 156))	('malignant melanoma', 'Disease', (138, 156))
139901	24884875	We observed an upregulation of ALDH1A2 in H28 and ALDH1A3 in H2052 and Meso4 in the cisplatin + DEAB-resistant cells of the ALDH-sorted fractions of the three MPM cell lines, indicating the implication of these two isozymes in conveying resistance to cisplatin and DEAB.	('ALDH1A3', 'Gene', (50, 57))	('ALDH', 'molecular_function', 'GO:0004030', ('31', '35'))	('DEAB', 'Chemical', '-', (265, 269))	('H2052', 'Chemical', '-', (61, 66))	('ALDH1A2', 'Gene', '8854', (31, 38))	('ALDH', 'molecular_function', 'GO:0004030', ('124', '128'))	('cisplatin', 'Chemical', 'MESH:D002945', (251, 260))	('H28', 'Chemical', '-', (42, 45))	('ALDH1A3', 'Gene', '220', (50, 57))	('upregulation', 'PosReg', (15, 27))	('ALDH1A2', 'Gene', (31, 38))	('H2052', 'Var', (61, 66))	('Meso4', 'Chemical', '-', (71, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('ALDH', 'molecular_function', 'GO:0004030', ('50', '54'))	('DEAB', 'Chemical', '-', (96, 100))
139905	24884875	Notably, inhibition of ALDH activity cannot sensitize the ALDHhghCD44+ cells to drug treatment.	('ALDH', 'molecular_function', 'GO:0004030', ('23', '27'))	('ALDH', 'Protein', (23, 27))	('activity', 'MPA', (28, 36))	('CD44', 'Gene', '960', (65, 69))	('inhibition', 'Var', (9, 19))	('CD44', 'Gene', (65, 69))
139907	24884875	Our data also demonstrate that the double expression of ALDH and CD44 rather than ALDH alone better delineates a chemoresistant, sphere-forming cell populations in the tested MPM cell lines.	('ALDH', 'molecular_function', 'GO:0004030', ('56', '60'))	('delineates', 'Reg', (100, 110))	('double expression', 'Var', (35, 52))	('CD44', 'Gene', '960', (65, 69))	('ALDH', 'molecular_function', 'GO:0004030', ('82', '86'))	('ALDH', 'Gene', (56, 60))	('CD44', 'Gene', (65, 69))
139942	23256650	Immunohistochemistry will be positive for cytokeratin and mesothelial origin markers calretinin and D2-40.	('D2-40', 'Var', (100, 105))	('calretinin', 'Gene', '794', (85, 95))	('calretinin', 'Gene', (85, 95))
140036	32155978	Examples of variability of sources of phytochemicals comprise hydroxylation in the liver that cause secondary oxidation products as well as reduction, dihydroxylation and demethylation, that are performed by gut bacteria and are responsible for the formation of more biologically active metabolites.	('dihydroxylation', 'MPA', (151, 166))	('demethylation', 'biological_process', 'GO:0070988', ('171', '184'))	('secondary oxidation products', 'MPA', (100, 128))	('hydroxylation', 'Var', (62, 75))	('formation', 'biological_process', 'GO:0009058', ('249', '258'))	('demethylation', 'MPA', (171, 184))	('hydroxyl', 'Chemical', 'MESH:D017665', (62, 70))	('reduction', 'MPA', (140, 149))	('hydroxyl', 'Chemical', 'MESH:D017665', (153, 161))
140084	32155978	investigated the effects of curcumin on the human derived MM cell line ACC-MESO-1 and found that the dose-dependent reduced cell viability caused by curcumin was not attributable to apoptosis but to autophagy, as also demonstrated by the detection of autophagosomes on electron microscopy.	('human', 'Species', '9606', (44, 49))	('MM', 'Disease', 'MESH:C562839', (58, 60))	('autophagy', 'CPA', (199, 208))	('curcumin', 'Var', (149, 157))	('autophagy', 'biological_process', 'GO:0006914', ('199', '208'))	('rat', 'Species', '10116', (225, 228))	('cell viability', 'CPA', (124, 138))	('curcumin', 'Chemical', 'MESH:D003474', (28, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('reduced', 'NegReg', (116, 123))	('autophagy', 'biological_process', 'GO:0016236', ('199', '208'))	('curcumin', 'Chemical', 'MESH:D003474', (149, 157))
140134	32098830	The accumulation of genetic aberrations can induce malignancies.	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('genetic aberrations', 'Var', (20, 39))	('malignancies', 'Disease', (51, 63))	('induce', 'Reg', (44, 50))
140136	32098830	The results revealed frequent mutations in BAP1, CDKN2A, NF2, TP53, LATS2 and SETD2.	('BAP1', 'Gene', (43, 47))	('CDKN2A', 'Gene', '1029', (49, 55))	('TP53', 'Gene', '7157', (62, 66))	('SETD2', 'Gene', '29072', (78, 83))	('NF2', 'Gene', '4771', (57, 60))	('TP53', 'Gene', (62, 66))	('LATS2', 'Gene', (68, 73))	('SETD2', 'Gene', (78, 83))	('LATS2', 'Gene', '26524', (68, 73))	('BAP1', 'Gene', '8314', (43, 47))	('mutations', 'Var', (30, 39))	('NF2', 'Gene', (57, 60))	('CDKN2A', 'Gene', (49, 55))
140137	32098830	Recently, a considerably higher number of genetic alterations in mesotheliomas has been detected than that detected by NGS, including point mutations, minute deletions and copy number changes.	('mesotheliomas', 'Disease', 'MESH:D008654', (65, 78))	('point mutations', 'Var', (134, 149))	('mesotheliomas', 'Disease', (65, 78))	('copy number changes', 'Var', (172, 191))	('minute deletions', 'Var', (151, 167))
140138	32098830	Furthermore, the vast array of genetic alterations in mesothelioma may lead to producing neoantigens, which correlate with the clonal expansion of tumor-infiltrating T lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('lead', 'Reg', (71, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('producing neoantigens', 'MPA', (79, 100))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mesothelioma', 'Disease', (54, 66))	('genetic alterations', 'Var', (31, 50))
140146	32098830	In a melanoma model, PD-1 blockade increased the proportion of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide.	('recognition', 'MPA', (157, 168))	('increased', 'PosReg', (35, 44))	('increased', 'PosReg', (147, 156))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('PD-1', 'Gene', (21, 25))	('melanoma', 'Disease', (5, 13))	('blockade', 'Var', (26, 34))	('PD-1', 'Gene', '5133', (21, 25))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('degranulation', 'MPA', (121, 134))
140147	32098830	The increased frequency and absolute number of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, and not decreased apoptosis.	('blockade', 'Var', (77, 85))	('augmented', 'PosReg', (100, 109))	('PD-1', 'Gene', (72, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('PD-1', 'Gene', '5133', (72, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('increased', 'PosReg', (4, 13))
140187	32098830	Following these trials, a randomized phase IIb study, the DETERMINE study, revealed that tremelimumab failed to significantly prolong OS compared with that of placebo, in 571 patients with previously treated malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (208, 230))	('malignant mesothelioma', 'Disease', (208, 230))	('tremelimumab', 'Chemical', 'MESH:C520704', (89, 101))	('patients', 'Species', '9606', (175, 183))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (208, 230))	('prolong', 'PosReg', (126, 133))	('tremelimumab', 'Var', (89, 101))
140206	32098830	Overall, anti-PD-1 antibodies exhibited promising results when used alone as a salvage therapy after the first-line chemotherapy.	('PD-1', 'Gene', '5133', (14, 18))	('antibodies', 'Var', (19, 29))	('PD-1', 'Gene', (14, 18))
140245	30873867	By immunohistochemistry, the tumor cells are positive for WT-1, calretinin, and focally for D2-40, while BAP-1 is retained.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BAP-1', 'Gene', '8314', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('positive', 'Reg', (45, 53))	('WT-1', 'Gene', (58, 62))	('tumor', 'Disease', (29, 34))	('BAP-1', 'Gene', (105, 110))	('calretinin', 'Protein', (64, 74))	('D2-40', 'Var', (92, 97))	('WT-1', 'Gene', '7490', (58, 62))
140398	28794394	Two four-week inhalation studies of MWCNTs and SWCNTs showed no inflammation in the rats' lungs with maximum concentrations of 0.37 mg/m3 and 0.13 mg/m3, respectively,.	('SWCNT', 'Chemical', '-', (47, 52))	('MWCNTs', 'Chemical', '-', (36, 42))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('inflammation', 'Disease', (64, 76))	('0.37 mg/m3', 'Var', (127, 137))	('inflammation', 'biological_process', 'GO:0006954', ('64', '76'))	('rats', 'Species', '10116', (84, 88))
140406	28794394	However, pulmonary inflammation induced by short fibers tend to be less persistence than that induced by long fibers in intratracheal instillation studies.	('short fibers', 'Var', (43, 55))	('pulmonary inflammation', 'Disease', (9, 31))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (9, 31))	('inflammation', 'biological_process', 'GO:0006954', ('19', '31'))
140437	28794394	Gene damage in the lungs is considered to play a key role in the transformation and proliferation of cells (especially epithelial cells) as an abnormality of restoration following lung injury.	('lung injury', 'Disease', 'MESH:D055370', (180, 191))	('Gene damage', 'Var', (0, 11))	('lung injury', 'Disease', (180, 191))
140438	28794394	Most CNT studies showed the results of genotoxicity in an acute phase following exposure and induced the formation of DNA breakage, micronuclei, and mutations in the lungs after inhalation and intratracheal instillation.	('micronuclei', 'Var', (132, 143))	('toxicity', 'Disease', (43, 51))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('mutations', 'Var', (149, 158))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))
140444	28794394	K-ras mutation plays an important role in the signal transduction of epidermal growth factor receptor and is one of the representative oncogenic driver mutations.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('69', '92'))	('epidermal growth factor receptor', 'Gene', (69, 101))	('epidermal growth factor receptor', 'Gene', '13649', (69, 101))	('mutation', 'Var', (6, 14))	('signal transduction', 'MPA', (46, 65))	('K-ras', 'Gene', '16653', (0, 5))	('K-ras', 'Gene', (0, 5))	('signal transduction', 'biological_process', 'GO:0007165', ('46', '65'))
140445	28794394	The pharyngeal aspiration of SWCNTs and CNFs in mice increased the incidence of K-ras oncogene mutations in the lungs at 1 year post exposure.	('K-ras', 'Gene', '16653', (80, 85))	('aspiration', 'Phenotype', 'HP:0002835', (15, 25))	('K-ras', 'Gene', (80, 85))	('mice', 'Species', '10090', (48, 52))	('mutations', 'Var', (95, 104))	('SWCNT', 'Chemical', '-', (29, 34))
140448	28794394	Gene damage is also reported to be associated with reactive oxygen species (ROS),.	('Gene damage', 'Var', (0, 11))	('associated', 'Reg', (35, 45))	('reactive oxygen species', 'MPA', (51, 74))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (51, 74))
140449	28794394	MWCNTs induced the mutation of hypoxanthine phosphoribosyltransferase (HPRT) genes in Chinese hamster lung fibroblasts through ROS.	('HPRT', 'molecular_function', 'GO:0004422', ('71', '75'))	('mutation', 'Var', (19, 27))	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('Chinese hamster', 'Species', '10029', (86, 101))	('HPRT', 'Gene', (71, 75))	('HPRT', 'Gene', '100769768', (71, 75))	('MWCNTs', 'Chemical', '-', (0, 6))	('hypoxanthine phosphoribosyltransferase', 'Gene', (31, 69))	('hypoxanthine phosphoribosyltransferase', 'Gene', '100769768', (31, 69))
140602	25035576	In rats, a fibroma of desmoid type (also known as fibromatosis-type) has been described as postoperative lesion in Bhd gene mutant rats (Kouchi et al.	('fibroma', 'Phenotype', 'HP:0010614', (11, 18))	('Bhd', 'Gene', '303185', (115, 118))	('fibroma of desmoid type', 'Disease', (11, 34))	('mutant', 'Var', (124, 130))	('fibroma', 'Phenotype', 'HP:0010614', (50, 57))	('fibromatosis-type', 'Disease', 'MESH:D005350', (50, 67))	('fibroma of desmoid type', 'Disease', 'MESH:C535944', (11, 34))	('Bhd', 'Gene', (115, 118))	('fibroma of desmoid', 'Phenotype', 'HP:0100245', (11, 29))	('fibromatosis-type', 'Disease', (50, 67))
140673	24455327	Immunohistochemistry showed the cells stained positively for CK5, CK6, Calretinin, WT1, CK7, and CD9 with weakly focally positive staining for BerEP4 and NSE.	('Calretinin', 'Gene', '794', (71, 81))	('NSE', 'Gene', (154, 157))	('CK6', 'Var', (66, 69))	('CK5', 'Gene', (61, 64))	('CK7', 'Gene', (88, 91))	('WT1', 'Gene', '7490', (83, 86))	('CK7', 'Gene', '3855', (88, 91))	('Calretinin', 'Gene', (71, 81))	('WT1', 'Gene', (83, 86))	('CK5', 'Gene', '3852', (61, 64))	('CD9', 'Gene', (97, 100))	('NSE', 'Gene', '2026', (154, 157))	('CD9', 'Gene', '928', (97, 100))
140738	32392897	Detection of homozygous deletion of the CDKN2A(p16) gene compared to BAP1 loss through fluorescence in situ hybridization (FISH) on the spindle cell component could be useful to separate ambiguous cases from benign florid stromal reaction and distinguish true sarcomatoid component of biphasic MPM.	('sarcomatoid component of biphasic', 'Disease', 'MESH:C538614', (260, 293))	('BAP1', 'Gene', (69, 73))	('p16', 'Gene', (47, 50))	('CDKN2A', 'Gene', (40, 46))	('CDKN2A', 'Gene', '1029', (40, 46))	('sarcomatoid component of biphasic', 'Disease', (260, 293))	('deletion', 'Var', (24, 32))	('MPM', 'Chemical', '-', (294, 297))	('p16', 'Gene', '1029', (47, 50))	('spindle', 'cellular_component', 'GO:0005819', ('136', '143'))	('BAP1', 'Gene', '8314', (69, 73))
140756	32392897	Similarly, high expression of PTEN (Phosphatase and tensin homolog), which is known to be implicated in EMT in cancer, acts as positive prognostic factor.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Phosphatase and tensin homolog', 'Gene', '5728', (36, 66))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('36', '66'))	('high', 'Var', (11, 15))	('cancer', 'Disease', (111, 117))	('PTEN', 'Gene', (30, 34))	('Phosphatase', 'molecular_function', 'GO:0016791', ('36', '47'))	('PTEN', 'Gene', '5728', (30, 34))	('EMT', 'biological_process', 'GO:0001837', ('104', '107'))
140766	32392897	Mutations in oncogenes known to be driver of epithelial-derived solid cancers are extremely rare as next generation sequencing (NGS) deep studies have shown although sometimes with small number of samples (22 MPMs and matched blood samples) and they seem to be not prognostically relevant in the disease.	('solid cancers', 'Disease', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('solid cancers', 'Disease', 'MESH:D009369', (64, 77))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('MPM', 'Chemical', '-', (209, 212))
140771	32392897	Although TP53 is vital for the integrity of the genome and thus its mutation can lead to a variety of cancers, TP53 mutations do not characteristically lead to MPM.	('MPM', 'Disease', (160, 163))	('lead to', 'Reg', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', '7157', (111, 115))	('mutation', 'Var', (68, 76))	('MPM', 'Chemical', '-', (160, 163))	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (116, 125))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('lead to', 'Reg', (152, 159))
140774	32392897	Deletions of 3p21 region, enclosing BAP1 gene are also reported in 33 MPM bioptic samples.	('BAP1', 'Gene', (36, 40))	('MPM', 'Chemical', '-', (70, 73))	('BAP1', 'Gene', '8314', (36, 40))	('Deletions', 'Var', (0, 9))
140776	32392897	Roughly 40% of mesotheliomas have an NF2 mutation, causing hypophosphorylation of the YAP (Yes-Associated Protein) transcriptional coactivator.	('NF2', 'Gene', '4771', (37, 40))	('causing', 'Reg', (51, 58))	('YAP', 'Gene', (86, 89))	('mesotheliomas', 'Disease', 'MESH:D008654', (15, 28))	('mutation', 'Var', (41, 49))	('hypophosphorylation', 'MPA', (59, 78))	('mesotheliomas', 'Disease', (15, 28))	('NF2', 'Gene', (37, 40))	('YAP', 'Gene', '10413', (86, 89))
140779	32392897	MPM is one of a few cancers (it has been demonstrated on 12 out of 14 MPM samples) that harbor mutations in Hippo pathway genes.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('MPM', 'Chemical', '-', (70, 73))	('MPM', 'Disease', (0, 3))	('Hippo pathway genes', 'Gene', (108, 127))	('mutations', 'Var', (95, 104))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('MPM', 'Chemical', '-', (0, 3))
140780	32392897	Thus, it would be expected that some patients with mesothelioma would show an activating mutation in TAZ, however in vivo evidence of such mutations is lacking.	('activating', 'PosReg', (78, 88))	('patients', 'Species', '9606', (37, 45))	('mutation', 'Var', (89, 97))	('mesothelioma', 'Disease', (51, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('TAZ', 'Gene', '6901', (101, 104))	('TAZ', 'Gene', (101, 104))
140783	32392897	A germ-line mutation in BAP1 is thought to cause a syndrome that includes mesothelioma, uveal and cutaneous melanoma as well as other neoplasms.	('syndrome', 'Disease', (51, 59))	('cause', 'Reg', (43, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('BAP1', 'Gene', (24, 28))	('neoplasms', 'Phenotype', 'HP:0002664', (134, 143))	('neoplasms', 'Disease', 'MESH:D009369', (134, 143))	('neoplasms', 'Disease', (134, 143))	('cutaneous melanoma', 'Disease', (98, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('uveal', 'Disease', (88, 93))	('mutation', 'Var', (12, 20))	('mesothelioma', 'Disease', (74, 86))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('BAP1', 'Gene', '8314', (24, 28))
140784	32392897	When several family members all get mesothelioma, despite only one member of the family working near asbestos, the high incidence can be explained by the transmission of the fibers on the skin and clothes of the one family member to the other members; however, genetic analysis suggests BAP1 mutations may induce augmented susceptibility (Figure 1).	('mutations', 'Var', (292, 301))	('men', 'Species', '9606', (316, 319))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('augmented', 'PosReg', (313, 322))	('asbestos', 'Chemical', 'MESH:D001194', (101, 109))	('susceptibility', 'MPA', (323, 337))	('BAP1', 'Gene', '8314', (287, 291))	('mesothelioma', 'Disease', (36, 48))	('BAP1', 'Gene', (287, 291))
140785	32392897	Interestingly, BAP1 mutations seem to prime for epithelial MPM more than any other type, which has important implications for screening and prognosis.	('BAP1', 'Gene', '8314', (15, 19))	('prime', 'Reg', (38, 43))	('epithelial', 'Disease', (48, 58))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('MPM', 'Chemical', '-', (59, 62))
140786	32392897	Signal transduction pathways and growth factors that stimulate cell survival and proliferation are commonly mutated in cancer cells.	('mutated', 'Var', (108, 115))	('cell survival', 'CPA', (63, 76))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('Signal transduction', 'biological_process', 'GO:0007165', ('0', '19'))	('cancer', 'Disease', (119, 125))	('proliferation', 'CPA', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
140789	32392897	The HGF-receptor MET has been reported to be activated in MPM due to overexpressed, not related to the occurrence of MET genetic lesions: (i) MET gene amplification are very infrequent and (ii) mutations in MET gene were not found in MPM by recent NGS studies supporting that MET mutations are really rare.	('HGF-receptor', 'Gene', '4233', (4, 16))	('mutations', 'Var', (194, 203))	('HGF-receptor', 'Gene', (4, 16))	('MET', 'Gene', (207, 210))	('MPM', 'Chemical', '-', (58, 61))	('MPM', 'Chemical', '-', (234, 237))
140793	32392897	In mice combinatorial deletions of Bap1, Nf2, and Cdkn2a result in aggressive mesotheliomas, defined by stem cell-like potential.	('deletions', 'Var', (22, 31))	('aggressive mesotheliomas', 'Disease', (67, 91))	('Cdkn2a', 'Gene', '12578', (50, 56))	('mice', 'Species', '10090', (3, 7))	('result in', 'Reg', (57, 66))	('Bap1', 'Gene', '104416', (35, 39))	('Cdkn2a', 'Gene', (50, 56))	('Nf2', 'Gene', (41, 44))	('Bap1', 'Gene', (35, 39))	('aggressive mesotheliomas', 'Disease', 'MESH:D008654', (67, 91))	('Nf2', 'Gene', '18016', (41, 44))
140799	32392897	Single nucleotide variants were firstly detected on four MPM frozen samples compared to one lung adenocarcinoma and one normal lung sample through pyrosequencing analysis.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('Single nucleotide variants', 'Var', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', (92, 111))	('MPM', 'Chemical', '-', (57, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))
140821	32392897	Similarly, the expression of miR-625-3p was reported to be significantly higher in plasma/serum of 30 MPM patients and allowed to discriminate between cases and controls, defined as 14 healthy subjects and 10 subjects with asbestosis.	('asbestosis', 'Disease', 'MESH:D001195', (223, 233))	('expression', 'MPA', (15, 25))	('higher', 'PosReg', (73, 79))	('patients', 'Species', '9606', (106, 114))	('MPM', 'Chemical', '-', (102, 105))	('asbestosis', 'Disease', (223, 233))	('miR-625-3p', 'Var', (29, 39))
140834	32392897	The endpoint of asbestos-induced damage is the generation of an inflammatory microenvironment that may support tumor growth in individuals with predisposition, for instance due to loss of BAP1.	('support', 'PosReg', (103, 110))	('BAP1', 'Gene', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('loss', 'Var', (180, 184))	('tumor', 'Disease', (111, 116))	('BAP1', 'Gene', '8314', (188, 192))	('asbestos', 'Chemical', 'MESH:D001194', (16, 24))	('men', 'Species', '9606', (89, 92))
140835	32392897	demonstrated, by analyzing samples from 198 patients, that a significant proportion of them carry germline mutations in cancer susceptibility genes, as BAP1, CDKN2A, TMEM127, VHL and WT1.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (107, 116))	('patients', 'Species', '9606', (44, 52))	('TMEM127', 'Gene', (166, 173))	('TMEM127', 'Gene', '55654', (166, 173))	('BAP1', 'Gene', '8314', (152, 156))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('CDKN2A', 'Gene', (158, 164))	('WT1', 'Gene', '7490', (183, 186))	('VHL', 'Gene', (175, 178))	('BAP1', 'Gene', (152, 156))	('VHL', 'Gene', '7428', (175, 178))	('CDKN2A', 'Gene', '1029', (158, 164))	('WT1', 'Gene', (183, 186))
140836	32392897	Moreover, it appears that mutations in two genes involved in DNA repair, XRCC1 and XRCC3, along with the GSTM1 (Glutathione S-Transferase Mu 1) antioxidant/detoxifying protein, increase susceptibility in this patient population, as demonstrated on more than 220 MPM samples and matched controls.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('MPM', 'Chemical', '-', (262, 265))	('patient', 'Species', '9606', (209, 216))	('Glutathione S-Transferase Mu 1', 'Gene', (112, 142))	('GSTM1', 'Gene', '2944', (105, 110))	('susceptibility', 'MPA', (186, 200))	('increase', 'PosReg', (177, 185))	('Glutathione S-Transferase Mu 1', 'Gene', '2944', (112, 142))	('mutations', 'Var', (26, 35))	('GSTM1', 'Gene', (105, 110))	('XRCC3', 'Gene', (83, 88))	('XRCC1', 'Gene', '7515', (73, 78))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('DNA repair', 'biological_process', 'GO:0006281', ('61', '71'))	('XRCC3', 'Gene', '7517', (83, 88))	('XRCC1', 'Gene', (73, 78))
140872	32392897	Overall, they found that MPM TILs were consistently hypofunctional, mainly associated with higher numbers of CD4 regulatory Tregs and with expression of TIGIT.	('higher', 'PosReg', (91, 97))	('TIGIT', 'Gene', (153, 158))	('MPM', 'Var', (25, 28))	('CD4', 'Gene', (109, 112))	('CD4', 'Gene', '920', (109, 112))	('MPM', 'Chemical', '-', (25, 28))
140873	32392897	The considerable immunophenotypic variability is coherent to the variable responses obtained in MPM by PD-L1 inhibitors, although other factors are involved: (i) the abundance of infiltrating lymphocytes; (ii) co-expression of multiple inhibitory receptors on T cells; (iii) the influence of MDSCs and tumor-associated macrophages.	('MPM', 'Chemical', '-', (96, 99))	('PD-L1', 'Gene', '29126', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', (302, 307))	('co-expression', 'Var', (210, 223))	('PD-L1', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
140884	32392897	Notably, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival in a cohort of 79 MPM tumor samples and 26 normal pleura.	('MPM', 'Chemical', '-', (83, 86))	('PE', 'Phenotype', 'HP:0002202', (39, 41))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', (126, 131))	('BDNF', 'Gene', '627', (14, 18))	('high', 'Var', (9, 13))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patient', 'Species', '9606', (87, 94))	('shorter', 'NegReg', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BDNF', 'Gene', (14, 18))	('MPM', 'Chemical', '-', (122, 125))	('MPM', 'Disease', (83, 86))
140887	32392897	Within respect to MPM, the MiR-625-3p has been found in the serum which has high stability and thus high diagnostic potential in a cohort of 15 MPM samples matched with 14 normal cases, weather the validation cohort was defined by 30 MPM and 10 asbestosis cases, respectively.	('MPM', 'Chemical', '-', (18, 21))	('MPM', 'Chemical', '-', (144, 147))	('asbestosis', 'Disease', (245, 255))	('asbestosis', 'Disease', 'MESH:D001195', (245, 255))	('MPM', 'Chemical', '-', (234, 237))	('MiR-625-3p', 'Var', (27, 37))	('stability', 'MPA', (81, 90))
140906	32392897	Particular attention should be paid to lymph node involvement; they should be sampled during the procedure and their positivity drastically reduces survival.	('survival', 'MPA', (148, 156))	('positivity', 'Var', (117, 127))	('men', 'Species', '9606', (57, 60))	('reduces', 'NegReg', (140, 147))
140929	32392897	MPM cells are less capable of synthesizing arginine, thus depleting available arginine with pegylated-arginine deiminase (ADI-PEG20) prolonged progression free survival (PFS) in one study performed after a screening of 201 patients which allowed the identification of 68 with advanced ASS1-deficient malignant pleural mesothelioma.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('progression free survival', 'CPA', (143, 168))	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('ASS1-deficient malignant pleural mesothelioma', 'Disease', (285, 330))	('arginine', 'Chemical', 'MESH:D001120', (102, 110))	('PE', 'Phenotype', 'HP:0002202', (126, 128))	('depleting', 'Var', (58, 67))	('prolonged', 'PosReg', (133, 142))	('MPM', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (223, 231))	('ASS1-deficient malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (285, 330))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (310, 330))
140930	32392897	As previously mentioned, BAP1 is a tumor suppressor and mutations in BAP1 are important in MPM pathogenesis, especially in MPM associated with familial clusters.	('BAP1', 'Gene', (25, 29))	('familial clusters', 'Disease', (143, 160))	('BAP1', 'Gene', '8314', (69, 73))	('mutations', 'Var', (56, 65))	('associated', 'Reg', (127, 137))	('tumor', 'Disease', (35, 40))	('MPM', 'Chemical', '-', (91, 94))	('important', 'Reg', (78, 87))	('MPM', 'Chemical', '-', (123, 126))	('pathogenesis', 'biological_process', 'GO:0009405', ('95', '107'))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MPM', 'Disease', (91, 94))	('BAP1', 'Gene', (69, 73))	('MPM', 'Disease', (123, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('BAP1', 'Gene', '8314', (25, 29))	('men', 'Species', '9606', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))
140932	32392897	In animal studies on MPM with BAP1 mutations, inhibiting EZH2 halted MPM progression, thus posing a potential therapeutic target.	('EZH2', 'Gene', (57, 61))	('inhibiting', 'NegReg', (46, 56))	('MPM', 'Chemical', '-', (69, 72))	('BAP1', 'Gene', (30, 34))	('MPM', 'Chemical', '-', (21, 24))	('halted', 'NegReg', (62, 68))	('MPM', 'Disease', (69, 72))	('BAP1', 'Gene', '8314', (30, 34))	('EZH2', 'Gene', '2146', (57, 61))	('mutations', 'Var', (35, 44))
140933	32392897	Continuing with treatments in the epigenetic pathway, the DNA methyl transferase (DNMT) inhibitor dihydro-5-azacytidine had a small clinical effect in MPM in 29 evaluated cases in absence of correlation to the presence of p16INK4a methylation.	('dihydro-5-azacytidine', 'Chemical', 'MESH:C013938', (98, 119))	('methylation', 'biological_process', 'GO:0032259', ('231', '242'))	('p16INK4a', 'Gene', (222, 230))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNMT', 'Gene', '1786', (82, 86))	('DNA methyl transferase', 'Gene', (58, 80))	('DNMT', 'Gene', (82, 86))	('p16INK4a', 'Gene', '1029', (222, 230))	('MPM', 'Disease', (151, 154))	('MPM', 'Chemical', '-', (151, 154))	('dihydro-5-azacytidine', 'Var', (98, 119))	('DNA methyl transferase', 'Gene', '1786', (58, 80))	('men', 'Species', '9606', (21, 24))
140939	32392897	Apart from statins, other potential therapies targeting the NF2/Merlin pathway include MLN4924, which is an enzyme that stops the activation of YAP1 in MPM cells with NF2 mutations.	('YAP1', 'Gene', (144, 148))	('YAP1', 'Gene', '10413', (144, 148))	('NF2', 'Gene', '4771', (60, 63))	('MPM', 'Chemical', '-', (152, 155))	('NF2', 'Gene', '4771', (167, 170))	('MLN4924', 'Var', (87, 94))	('Merlin', 'Gene', (64, 70))	('Merlin', 'Gene', '4771', (64, 70))	('NF2', 'Gene', (60, 63))	('mutations', 'Var', (171, 180))	('NF2', 'Gene', (167, 170))	('activation', 'MPA', (130, 140))	('MLN4924', 'Chemical', 'MESH:C539933', (87, 94))
140940	32392897	MLN4924 plus an mTOR/PI3K inhibitor showed promising effects in both in vitro and in vivo studies.	('MLN4924', 'Var', (0, 7))	('PI3K', 'molecular_function', 'GO:0016303', ('21', '25'))	('mTOR', 'Gene', '2475', (16, 20))	('mTOR', 'Gene', (16, 20))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
140955	32392897	Although a relevant number of genomic alterations are known to drive epithelial carcinogenesis, very few data have been reported regarding MPM onset.	('epithelial carcinogenesis', 'Disease', (69, 94))	('epithelial carcinogenesis', 'Disease', 'MESH:D063646', (69, 94))	('drive', 'Reg', (63, 68))	('MPM', 'Chemical', '-', (139, 142))	('alterations', 'Var', (38, 49))
140960	32392897	Manipulations of the inflammatory tumor stroma will render MPM susceptible to therapy with checkpoint inhibitors that have shown relevant results in other solid and aggressive tumors as lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('tumor stroma', 'Disease', 'MESH:D009369', (34, 46))	('tumor stroma', 'Disease', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('aggressive tumors', 'Disease', 'MESH:D001523', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('Manipulations', 'Var', (0, 13))	('MPM', 'Chemical', '-', (59, 62))	('aggressive tumors', 'Disease', (165, 182))
140987	32213105	The release of DM4 into the tumor microenvironment leads to bystander killing of neighboring dividing cells.	('tumor', 'Disease', (28, 33))	('leads to', 'Reg', (51, 59))	('bystander killing of neighboring dividing cells', 'CPA', (60, 107))	('release', 'MPA', (4, 11))	('DM4', 'Chemical', 'MESH:D008453', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('DM4', 'Var', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
140991	32213105	The anetumab ravtansine dose was escalated in 10 cohorts: 0.15, 0.3, 0.6, 1.2, 2.4, 3.6, 4.5, 5.5, 6.5, and 7.5 mg/kg once every 3 weeks.	('anetumab', 'Gene', (4, 12))	('0.3', 'Var', (64, 67))	('anetumab', 'Chemical', '-', (4, 12))	('ravtansine', 'Chemical', 'MESH:D008453', (13, 23))	('0.6', 'Var', (69, 72))
141032	32213105	The peak concentrations of both occurred at 1.5 hours; peak plasma concentrations of DM4 and DM4-Me were generally observed around 5 hours and 8 hours after the start of the anetumab ravtansine infusion, respectively.	('DM4-Me', 'Var', (93, 99))	('ravtansine', 'Chemical', 'MESH:D008453', (183, 193))	('DM4-Me', 'Chemical', '-', (93, 99))	('anetumab', 'Chemical', '-', (174, 182))	('DM4', 'Chemical', 'MESH:D008453', (93, 96))	('DM4', 'Chemical', 'MESH:D008453', (85, 88))	('DM4', 'Var', (85, 88))
141033	32213105	The average half-lives of anetumab ravtansine, DM4-Me, and DM4 were 5.5, 5.6, and 2.9 days, respectively, and no analytes accumulated after once-every-3-weeks dosing.	('DM4', 'Chemical', 'MESH:D008453', (59, 62))	('DM4', 'Var', (59, 62))	('anetumab', 'Gene', (26, 34))	('ravtansine', 'Chemical', 'MESH:D008453', (35, 45))	('DM4-Me', 'Var', (47, 53))	('anetumab', 'Chemical', '-', (26, 34))	('DM4-Me', 'Chemical', '-', (47, 53))	('DM4', 'Chemical', 'MESH:D008453', (47, 50))
141060	32213105	Similarly, 5 patients with ovarian cancer with high mesothelin expression received treatment of > 200 days (1 received 6.5 mg/kg once every 3 weeks, and 4 received 2.2 mg/kg once per week; Fig 3D).	('ovarian cancer', 'Disease', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('high', 'Var', (47, 51))	('patients', 'Species', '9606', (13, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('mesothelin', 'Gene', '10232', (52, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('mesothelin', 'Gene', (52, 62))
141083	32213105	On the basis of all the findings from the phase I study of anetumab ravtansine, several additional clinical trials are underway (ClinicalTrials.gov identifiers: NCT02751918, NCT03455556, NCT03126630, and NCT03102320) to evaluate the safety, tolerability, and activity of anetumab ravtansine as monotherapy or in combination with standard of care in a variety of mesothelin-expressing solid tumors.	('mesothelin', 'Gene', (362, 372))	('tumors', 'Phenotype', 'HP:0002664', (390, 396))	('NCT03102320', 'Var', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('anetumab', 'Chemical', '-', (271, 279))	('ravtansine', 'Chemical', 'MESH:D008453', (280, 290))	('tumors', 'Disease', 'MESH:D009369', (390, 396))	('mesothelin', 'Gene', '10232', (362, 372))	('anetumab', 'Chemical', '-', (59, 67))	('ravtansine', 'Chemical', 'MESH:D008453', (68, 78))	('tumors', 'Disease', (390, 396))
141086	32213105	Research Funding: Aduro Biotech (Inst), Morphotek (Inst), Bayer (Inst), TCR2 Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Mesothelin domain-specific monoclonal antibodies and use thereof (Patent No.	('TCR', 'cellular_component', 'GO:0042101', ('72', '75'))	('Mesothelin', 'Gene', (146, 156))	('domain-specific', 'Var', (157, 172))	('Mesothelin', 'Gene', '10232', (146, 156))	('TCR', 'biological_process', 'GO:0006283', ('72', '75'))
141105	32033319	Inactivation of p16 appears to promote the pathogenesis of many tumor types, including mesothelioma, breast cancer, pancreatic cancer, non-small cell lung cancer, esophageal cancer, and head and neck cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (135, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Disease', (174, 180))	('promote', 'PosReg', (31, 38))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (186, 206))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('breast cancer', 'Disease', (101, 114))	('pancreatic cancer', 'Disease', (116, 133))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('pathogenesis', 'biological_process', 'GO:0009405', ('43', '55'))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('non-small cell lung cancer', 'Disease', (135, 161))	('p16', 'Gene', '1029', (16, 19))	('mesothelioma', 'Disease', (87, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', (108, 114))	('head and neck cancer', 'Disease', 'MESH:D006258', (186, 206))	('tumor', 'Disease', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('neck', 'cellular_component', 'GO:0044326', ('195', '199'))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (135, 161))	('cancer', 'Disease', (200, 206))
141107	32033319	Deletion of the 9p21 locus that encodes p16 was deleted in 35/40 cases (88%) in one study.	('p16', 'Gene', (40, 43))	('p16', 'Gene', '1029', (40, 43))	('deleted', 'Var', (48, 55))	('Deletion', 'Var', (0, 8))
141136	32033319	The Kaplan-Meier curves for overall survival of patients with each cancer with mRNA panel expression for z-scores > 2 vs. tumors with z-scores < 2 are shown in Figure 2A.	('z-scores > 2', 'Var', (105, 117))	('tumors', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('patients', 'Species', '9606', (48, 56))
141137	32033319	Overall survival was significantly higher for patients with tumors exhibiting z-scores < 2 in hepatocellular carcinoma and mesothelioma, but overall survival was not higher for patients with pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('patients', 'Species', '9606', (46, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('z-scores < 2', 'Var', (78, 90))	('pancreatic cancer', 'Disease', (191, 208))	('hepatocellular carcinoma', 'Disease', (94, 118))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (191, 208))	('mesothelioma', 'Disease', (123, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Overall survival', 'MPA', (0, 16))	('higher', 'PosReg', (35, 41))	('tumors', 'Disease', (60, 66))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (94, 118))	('patients', 'Species', '9606', (177, 185))	('pancreatic cancer', 'Disease', 'MESH:D010190', (191, 208))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
141139	32033319	The Kaplan-Meier curves for progression-free survival of patients with cancers expressing the target mRNA with z-scores > 2 vs. tumors with z-scores < 2 are shown in Figure 2B.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('z-scores > 2', 'Var', (111, 123))
141140	32033319	In contrast to the overall survival curves, alteration of mRNA expression of the selected gene set was not associated with progression-free survival for any of the cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('alteration', 'Var', (44, 54))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('mRNA expression', 'MPA', (58, 73))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))
141142	32033319	Unexpectedly, the top 3 copy number variants for both mesothelioma and pancreatic cancer were the same: CDKN2A (encoding p16INK4a), CDKN2B (encoding p15INK4b), MTAP (encoding methylthioadenosine phosphorylase), DMRTA1 (doublesex and mab-3 related transcription factor 1), and LINC01239 (long intergenic non-protein coding RNA 1239).	('p16INK4a', 'Gene', '1029', (121, 129))	('p15INK4b', 'Gene', '1030', (149, 157))	('DMRTA1', 'Gene', (211, 217))	('transcription', 'biological_process', 'GO:0006351', ('247', '260'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('p15INK4b', 'Gene', (149, 157))	('MTAP', 'Gene', (160, 164))	('methylthioadenosine phosphorylase', 'Gene', (175, 208))	('MTAP', 'Gene', '4507', (160, 164))	('CDKN2A', 'Gene', (104, 110))	('DMRTA1', 'Gene', '1761', (211, 217))	('RNA', 'cellular_component', 'GO:0005562', ('322', '325'))	('CDKN2B', 'Gene', (132, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('LINC01239', 'Gene', '441389', (276, 285))	('transcription factor', 'molecular_function', 'GO:0000981', ('247', '267'))	('doublesex and mab-3 related transcription factor 1', 'Gene', '1761', (219, 269))	('p16INK4a', 'Gene', (121, 129))	('CDKN2A', 'Gene', '1029', (104, 110))	('mesothelioma and pancreatic cancer', 'Disease', 'MESH:D010190', (54, 88))	('CDKN2B', 'Gene', '1030', (132, 138))	('methylthioadenosine phosphorylase', 'Gene', '4507', (175, 208))	('variants', 'Var', (36, 44))	('LINC01239', 'Gene', (276, 285))	('protein', 'cellular_component', 'GO:0003675', ('307', '314'))
141144	32033319	The interferon alpha gene alterations observed are likely because they cluster near band 9q21 that is proximal to the locus of CDKN2A, which was included in the screened gene set and is commonly deleted in both cancer sets.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('interferon alpha gene', 'Gene', (4, 25))	('alterations', 'Var', (26, 37))	('CDKN2A', 'Gene', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('CDKN2A', 'Gene', '1029', (127, 133))
141148	32033319	The top 3 genes with mutations in pancreatic cancer included RAS and TP53, as expected, in addition to SMAD4 (SMAD family member 4).	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('SMAD family member 4', 'Gene', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('SMAD4', 'Gene', '4089', (103, 108))	('SMAD family member 4', 'Gene', '4089', (110, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('SMAD4', 'Gene', (103, 108))	('RAS', 'Gene', (61, 64))	('pancreatic cancer', 'Disease', (34, 51))	('mutations', 'Var', (21, 30))
141149	32033319	For mesothelioma, the top genes with mutations were BAP1 (BRCA-associated protein 1), NF2 (neurofibromin 2), and SETD2 (SET domain containing 2, histone lysine methyltransferase).	('NF2', 'Gene', (86, 89))	('neurofibromin 2', 'Gene', '4771', (91, 106))	('BRCA-associated protein 1', 'Gene', '8314', (58, 83))	('BAP1', 'Gene', '8314', (52, 56))	('mesothelioma', 'Disease', (4, 16))	('SET domain containing 2', 'Gene', '29072', (120, 143))	('SETD2', 'Gene', '29072', (113, 118))	('neurofibromin 2', 'Gene', (91, 106))	('BRCA-associated protein 1', 'Gene', (58, 83))	('SET domain containing 2', 'Gene', (120, 143))	('mutations', 'Var', (37, 46))	('SETD2', 'Gene', (113, 118))	('BAP1', 'Gene', (52, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('NF2', 'Gene', '4771', (86, 89))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))
141151	32033319	For hepatocellular carcinoma, the top gene mutations were TP53, CTNNB1 (catenin beta 1), and TTN (titin).	('hepatocellular carcinoma', 'Disease', (4, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (4, 28))	('catenin beta 1', 'Gene', (72, 86))	('CTNNB1', 'Gene', (64, 70))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('titin', 'Gene', '7273', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutations', 'Var', (43, 52))	('TTN', 'Gene', (93, 96))	('CTNNB1', 'Gene', '1499', (64, 70))	('titin', 'Gene', (98, 103))	('catenin beta 1', 'Gene', '1499', (72, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (4, 28))	('TTN', 'Gene', '7273', (93, 96))
141215	26500734	KL-6 has been the established serum and immunohistochemical marker for diagnosing interstitial lung diseases and is widely applied to clinical practice.	('lung diseases', 'Phenotype', 'HP:0002088', (95, 108))	('interstitial lung diseases', 'Disease', 'MESH:D017563', (82, 108))	('KL-6', 'Var', (0, 4))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (82, 107))	('lung disease', 'Phenotype', 'HP:0002088', (95, 107))	('interstitial lung diseases', 'Phenotype', 'HP:0006530', (82, 108))	('interstitial lung diseases', 'Disease', (82, 108))
141229	26500734	A recent large scale case-control study has further confirmed that serum KL-6 is associated with subsequent lung cancer among patients with interstitial lung disease.	('associated with', 'Reg', (81, 96))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('interstitial lung disease', 'Disease', (140, 165))	('lung disease', 'Phenotype', 'HP:0002088', (153, 165))	('KL-6', 'Gene', (73, 77))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('patients', 'Species', '9606', (126, 134))	('serum', 'Var', (67, 72))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (140, 165))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('interstitial lung disease', 'Disease', 'MESH:D017563', (140, 165))
141413	31921422	Therefore, dysfunction of LOX and the LOXL family contributes to various types of diseases including liver fibrosis, cardiovascular disease, and cancer.	('cancer', 'Disease', (145, 151))	('LOX', 'Gene', '4015', (38, 41))	('cardiovascular disease', 'Disease', (117, 139))	('LOXL', 'Gene', (38, 42))	('dysfunction', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (117, 139))	('LOX', 'Gene', (38, 41))	('fibrosis', 'Disease', 'MESH:D005355', (107, 115))	('contributes', 'Reg', (50, 61))	('fibrosis', 'Disease', (107, 115))	('LOX', 'Gene', '4015', (26, 29))	('cardiovascular disease', 'Disease', 'MESH:D002318', (117, 139))	('liver fibrosis', 'Phenotype', 'HP:0001395', (101, 115))	('LOX', 'Gene', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('LOXL', 'Gene', '4016', (38, 42))
141456	31463062	In contrast, preclinical and clinical studies showed that aberrant MSLN expression on tumor cells plays an important role in promoting proliferation and invasion.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('invasion', 'CPA', (153, 161))	('MSLN', 'Gene', (67, 71))	('tumor', 'Disease', (86, 91))	('promoting', 'PosReg', (125, 134))	('aberrant', 'Var', (58, 66))	('proliferation', 'CPA', (135, 148))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
141465	31463062	Chang and colleagues found that MSLN was present in 10 of 15 nonmucinous ovarian cancers and absent in all 4 mucinous ovarian cancers examined.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('MSLN', 'Var', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('15 nonmucinous ovarian cancers', 'Disease', 'MESH:D010051', (58, 88))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('mucinous ovarian cancers', 'Disease', 'MESH:D010051', (109, 133))	('15 nonmucinous ovarian cancers', 'Disease', (58, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('mucinous ovarian cancers', 'Disease', 'MESH:D010051', (64, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian cancers', 'Phenotype', 'HP:0100615', (73, 88))	('ovarian cancers', 'Phenotype', 'HP:0100615', (118, 133))	('mucinous ovarian cancers', 'Disease', (109, 133))
141467	31463062	This was in line with the results of another independent study that confirmed MSLN reactivity in all 44 epithelioid mesotheliomas and in the epithelial components of 3 biphasic mesotheliomas, but not in any of 8 sarcomatous mesotheliomas examined.	('epithelioid mesotheliomas', 'Disease', (104, 129))	('biphasic mesotheliomas', 'Disease', (168, 190))	('MSLN', 'Gene', (78, 82))	('biphasic mesotheliomas', 'Disease', 'MESH:D008654', (168, 190))	('sarcomatous mesotheliomas', 'Disease', 'MESH:D008654', (212, 237))	('sarcomatous mesotheliomas', 'Disease', (212, 237))	('reactivity', 'Var', (83, 93))	('epithelioid mesotheliomas', 'Disease', 'MESH:D008654', (104, 129))
141478	31463062	The production of SMRP could be associated with abnormal splicing, which results in a secreted form or its cleavage from the membrane by the TNFalpha-converting enzyme ADAM17.	('results in', 'Reg', (73, 83))	('cleavage from the membrane', 'MPA', (107, 133))	('secreted', 'MPA', (86, 94))	('ADAM17', 'Gene', '6868', (168, 174))	('abnormal', 'Var', (48, 56))	('SMRP', 'Gene', '10232', (18, 22))	('splicing', 'biological_process', 'GO:0045292', ('57', '65'))	('SMRP', 'Gene', (18, 22))	('ADAM17', 'Gene', (168, 174))	('membrane', 'cellular_component', 'GO:0016020', ('125', '133'))
141487	31463062	The fusion of the PE38 portion to SS1 resulted in a recombinant immunotoxin (RIT) termed SS1P, which enters cells by receptor-mediated endocytosis and induces apoptosis by inactivating elongation factor 2 to impede protein synthesis.	('impede', 'NegReg', (208, 214))	('RIT', 'Chemical', '-', (77, 80))	('receptor-mediated endocytosis', 'biological_process', 'GO:0006898', ('117', '146'))	('SS1', 'Gene', '3123', (89, 92))	('induces', 'PosReg', (151, 158))	('SS1', 'Gene', '3123', (34, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('protein synthesis', 'biological_process', 'GO:0006412', ('215', '232'))	('fusion', 'Var', (4, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('elongation factor 2', 'Gene', '1938', (185, 204))	('elongation factor 2', 'Gene', (185, 204))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('inactivating', 'NegReg', (172, 184))	('SS1', 'Gene', (89, 92))	('receptor-mediated endocytosis', 'MPA', (117, 146))	('protein synthesis', 'MPA', (215, 232))	('SS1', 'Gene', (34, 37))	('apoptosis', 'CPA', (159, 168))
141529	31463062	BAY94-9343 showed dose-dependent anti-tumor efficacy and bystander effects in xenogeneic tumor models.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('xenogeneic tumor', 'Disease', 'MESH:D009369', (78, 94))	('BAY94-9343', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('xenogeneic tumor', 'Disease', (78, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
141535	31463062	In another clinical trial (NCT01469793), DMOT4039A was administered to 71 patients with pancreatic cancer (n = 40) or ovarian cancer (n = 31).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ovarian cancer', 'Disease', (118, 132))	('DMOT4039A', 'Var', (41, 50))	('patients', 'Species', '9606', (74, 82))	('DMOT4039A', 'Chemical', '-', (41, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('pancreatic cancer', 'Disease', (88, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))
141537	31463062	Hyperglycemia (grade 3) and hypophosphatemia (grade 3) were observed in 2 patients treated with DMOT4039A every 3 weeks at a dosage of 2.8 mg/kg but no DLTs were observed in patients treated with other dosages.	('Hyperglycemia', 'Disease', 'MESH:D006943', (0, 13))	('DMOT4039A', 'Var', (96, 105))	('Hyperglycemia', 'Disease', (0, 13))	('DMOT4039A', 'Chemical', '-', (96, 105))	('patients', 'Species', '9606', (74, 82))	('hypophosphatemia', 'Disease', 'MESH:D017674', (28, 44))	('patients', 'Species', '9606', (174, 182))	('hypophosphatemia', 'Phenotype', 'HP:0002148', (28, 44))	('Hyperglycemia', 'Phenotype', 'HP:0003074', (0, 13))	('hypophosphatemia', 'Disease', (28, 44))
141540	31463062	Six patients (4 ovarian cancer; 2 pancreatic cancer) treated with DMOT4039A at 2.4 to 2.8 mg/kg had a PR.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('DMOT4039A', 'Var', (66, 75))	('ovarian cancer', 'Disease', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('DMOT4039A', 'Chemical', '-', (66, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('patients', 'Species', '9606', (4, 12))	('ovarian cancer', 'Phenotype', 'HP:0100615', (16, 30))	('pancreatic cancer', 'Disease', (34, 51))	('ovarian cancer', 'Disease', 'MESH:D010051', (16, 30))
141550	31463062	BAY2287411, a thorium-227-labeled antibody-chelator conjugate, was administered to patients with tumors known to express MSLN to evaluate the safety, tolerability, maximum tolerated dose, PK, anti-tumor activity and recommended dose for further clinical development (NCT03507452).	('BAY2287411', 'Var', (0, 10))	('antibody', 'cellular_component', 'GO:0019814', ('34', '42'))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('antibody', 'cellular_component', 'GO:0042571', ('34', '42'))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('antibody', 'cellular_component', 'GO:0019815', ('34', '42'))	('tumors', 'Disease', (97, 103))	('thorium', 'Chemical', 'MESH:D013910', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('BAY2287411', 'Chemical', '-', (0, 10))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('antibody', 'molecular_function', 'GO:0003823', ('34', '42'))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', (197, 202))	('MSLN', 'Gene', (121, 125))
141552	31463062	A recent study demonstrated that the combination of BAY2287411 with the damage response inhibitors ATRi and PARPi resulted in synergistic activity and increased anti-tumor efficacy.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('increased', 'PosReg', (151, 160))	('BAY2287411', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('combination', 'Interaction', (37, 48))	('tumor', 'Disease', (166, 171))	('synergistic activity', 'MPA', (126, 146))	('BAY2287411', 'Chemical', '-', (52, 62))
141555	31463062	NCI-H292 tumor growth was impeded in mice implanted with human PBMCs and treated with HPN536.	('impeded', 'NegReg', (26, 33))	('NCI-H292 tumor', 'Disease', 'MESH:D009369', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('NCI-H292 tumor', 'Disease', (0, 14))	('HPN536', 'Var', (86, 92))	('human', 'Species', '9606', (57, 62))	('mice', 'Species', '10090', (37, 41))
141568	31463062	Sixty-one patients who received CRS-207 and Cy/GVAX had longer overall survival (6.1 months) than 29 patients treated with Cy/GVAX alone (3.9 months).	('overall survival', 'MPA', (63, 79))	('patients', 'Species', '9606', (101, 109))	('GVAX', 'Chemical', '-', (126, 130))	('GVAX', 'Chemical', '-', (47, 51))	('Cy', 'Chemical', 'MESH:D003545', (44, 46))	('longer', 'PosReg', (56, 62))	('CRS-207', 'Var', (32, 39))	('patients', 'Species', '9606', (10, 18))	('Cy', 'Chemical', 'MESH:D003545', (123, 125))
141570	31463062	The overall survival was 3.8 months for the cohort treated with Cy/GVAX + CRS-207, 5.4 months for the cohort treated with CRS-207 alone, and 4.6 months for the cohort treated with chemotherapy (NCT02004262).	('Cy', 'Chemical', 'MESH:D003545', (64, 66))	('CRS-207', 'Var', (74, 81))	('GVAX', 'Chemical', '-', (67, 71))	('Cy/GVAX + CRS-207', 'Var', (64, 81))
141571	31463062	JNJ-64041757 (previously referred to as ADU-214) is a live-attenuated, double-deleted (LADD) Listeria monocytogenes strain used as a potential treatment for NSCLC that was engineered by Aduro Biotech, Inc. in 2014.	('JNJ-64041757', 'Var', (0, 12))	('NSCLC', 'Disease', (157, 162))	('Listeria monocytogenes', 'Species', '1639', (93, 115))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
141572	31463062	However, two clinical trials that attempted to evaluate its efficacy alone or in combination with nivolumab were both terminated due to a lack of clinical benefit (NCT02592967 and NCT03371381).	('NCT02592967', 'Var', (164, 175))	('NCT03371381', 'Var', (180, 191))	('nivolumab', 'Chemical', 'MESH:D000077594', (98, 107))
141601	31463062	Recent preclinical studies showed that PD-1/PD-L1 blockade or CRISPR/Cas9-mediated PD-1 disruption could rescue MSLN-targeted CAR-T cell responses in vivo.	('PD-1', 'Gene', (39, 43))	('PD-1', 'Gene', '6139', (39, 43))	('PD-1', 'Gene', '6139', (83, 87))	('PD-1', 'Gene', (83, 87))	('PD-L1', 'Gene', (44, 49))	('CAR', 'cellular_component', 'GO:0005826', ('126', '129'))	('rescue', 'PosReg', (105, 111))	('Cas', 'cellular_component', 'GO:0005650', ('69', '72'))	('MSLN-targeted', 'Disease', (112, 125))	('PD-L1', 'Gene', '29126', (44, 49))	('disruption', 'Var', (88, 98))
141602	31463062	Based on this, CAR-T cells engineered to express immune checkpoint antibodies (CTLA-4 and PD-1) or to knock out PD-1 are being evaluated in clinical trials (NCT03030001, NCT03182803, NCT03615313, NCT03545815, and NCT03747965).	('NCT03545815', 'Var', (196, 207))	('PD-1', 'Gene', (112, 116))	('NCT03030001', 'Var', (157, 168))	('NCT03747965', 'Var', (213, 224))	('CTLA-4', 'Gene', (79, 85))	('NCT03182803', 'Var', (170, 181))	('NCT03615313', 'Var', (183, 194))	('CAR', 'cellular_component', 'GO:0005826', ('15', '18'))	('PD-1', 'Gene', '6139', (90, 94))	('PD-1', 'Gene', (90, 94))	('CTLA-4', 'Gene', '1493', (79, 85))	('PD-1', 'Gene', '6139', (112, 116))
141620	31463062	Notably, MSLN-targeting CAR-T cells were able to lyse primary tumor cells and elicit a systemic antitumor immune response by inducing epitope spreading.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('elicit', 'Reg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (100, 105))	('CAR', 'cellular_component', 'GO:0005826', ('24', '27'))	('epitope spreading', 'MPA', (134, 151))	('tumor', 'Disease', (62, 67))	('inducing', 'Reg', (125, 133))	('MSLN-targeting', 'Var', (9, 23))	('lyse', 'CPA', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('immune response', 'biological_process', 'GO:0006955', ('106', '121'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
141632	31463062	CAR-T cells were administered intrapleurally, intratumorally, or by vascular interventional mediated injection (NCT02414269, NCT02706782, NCT02959151, NCT03267173, and NCT03198052).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NCT03198052', 'Var', (168, 179))	('NCT02959151', 'Var', (138, 149))	('tumor', 'Disease', (51, 56))	('NCT02414269', 'Var', (112, 123))	('CAR', 'cellular_component', 'GO:0005826', ('0', '3'))	('NCT03267173', 'Var', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('NCT02706782', 'Var', (125, 136))
141780	30664644	By knocking down key enzymes of the RNAi pathway, we generated trophozoites expressing their entire repertoire of VSPs.	('VSP', 'Gene', '13035', (114, 117))	('VSP', 'Gene', (114, 117))	('knocking', 'Var', (3, 11))	('RNAi', 'biological_process', 'GO:0016246', ('36', '40'))
141809	30664644	Using a panel of reporter HEK293 cells constitutively expressing human TLRs, DeltaVSP1267 was able to signal through TLR-4 and, to a lesser extent, through TLR-2 (Fig.	('HEK293', 'CellLine', 'CVCL:0045', (26, 32))	('human', 'Species', '9606', (65, 70))	('DeltaVSP1267', 'Var', (77, 89))	('DeltaVSP1267', 'Chemical', '-', (77, 89))	('TLR-4', 'Gene', (117, 122))	('TLR-2', 'Gene', (156, 161))	('signal', 'Reg', (102, 108))	('TLR-2', 'Gene', '7097', (156, 161))
141812	30664644	DeltaVSP1267 induced a significant up-regulation of the expression of CD40 and CD86 co-stimulatory molecules and this activation was not observed when BMDCs from TLR-4 KO mice were used (Fig.	('CD40', 'Gene', '21939', (70, 74))	('mice', 'Species', '10090', (171, 175))	('up-regulation', 'PosReg', (35, 48))	('CD40', 'Gene', (70, 74))	('DeltaVSP1267', 'Var', (0, 12))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('expression', 'MPA', (56, 66))	('CD86', 'Gene', (79, 83))	('CD86', 'Gene', '12524', (79, 83))	('DeltaVSP1267', 'Chemical', '-', (0, 12))
141820	30664644	Additionally, VSP pseudotyping enhanced binding and uptake of VLPs by BMDCs (Fig.	('VLPs', 'Protein', (62, 66))	('VSP', 'Gene', '13035', (14, 17))	('pseudotyping', 'Var', (18, 30))	('VSP', 'Gene', (14, 17))	('enhanced', 'PosReg', (31, 39))	('uptake', 'MPA', (52, 58))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('uptake', 'biological_process', 'GO:0098657', ('52', '58'))	('uptake', 'biological_process', 'GO:0098739', ('52', '58'))	('binding', 'Interaction', (40, 47))
141824	30664644	4d, e), indicating that the presence of VSPs on VLPs improved VLP immunogenicity in a TLR-4 dependent manner.	('presence', 'Var', (28, 36))	('VSP', 'Gene', '13035', (40, 43))	('VLP', 'cellular_component', 'GO:0000943', ('62', '65'))	('VLP immunogenicity', 'MPA', (62, 80))	('VSP', 'Gene', (40, 43))	('improved', 'PosReg', (53, 61))
141856	30664644	Antibodies generated by oral vaccination were capable of neutralizing influenza A H1N1 virus from infecting MDCK cells in vitro (Fig.	('H1N1', 'Gene', (82, 86))	('neutralizing', 'Var', (57, 69))	('A H1N1', 'Species', '41857', (80, 86))	('influenza', 'Species', '11309', (70, 79))	('MDCK', 'CellLine', 'CVCL:0422', (108, 112))	('influenza A H1N1', 'Gene', (70, 86))
141912	30664644	BALB/c, C57BL/6, and C57BL/10ScNJ (TLR-4 KO) mice (6-8 week-old) of both sexes were obtained from the Facultad de Ciencias Veterinarias, Universidad Nacional de la Plata (Argentina) and housed in the vivarium of the CIDIE under specific pathogen-free (SPF) conditions in microisolator cages (Techniplast, Italy); they were cared for following NIH guidelines for laboratory animals.	('C57BL/10ScNJ', 'Var', (21, 33))	('de Ciencias Veterinarias', 'Disease', 'MESH:D005862', (111, 135))	('de Ciencias Veterinarias', 'Disease', (111, 135))	('mice', 'Species', '10090', (45, 49))
141925	30664644	A mouse-adapted variant strain (muH5N1) obtained from an avian H5N1 virus (A/crested eagle/Belgium/1/2004) was obtained by five passages by lung-to-lung, after that, the muH5N1 rapidly caused the death of naive mice and began to propagate stably in lungs.	('caused', 'Reg', (185, 191))	('H5N1', 'Species', '102793', (34, 38))	('death', 'Disease', 'MESH:D003643', (196, 201))	('death', 'Disease', (196, 201))	('H5N1', 'Species', '102793', (63, 67))	('muH5N1', 'Var', (170, 176))	('H5N1', 'Species', '102793', (172, 176))	('mice', 'Species', '10090', (211, 215))	('mouse', 'Species', '10090', (2, 7))	('crested eagle', 'Species', '252789', (77, 90))
142005	30664644	constructed and validated the insect expression plasmids and generated the recombinant DeltaVSPs; A.S. generated monoclonal antibodies; P.R.G., R.R.T., A.H.T., and J.P.P.	('R.R.T.', 'Var', (144, 150))	('VSP', 'Gene', '13035', (92, 95))	('P.R.G.', 'Var', (136, 142))	('VSP', 'Gene', (92, 95))	('A.H.T.', 'Var', (152, 158))
142067	30510551	Indeed, mice deficient for IL-10 developed exaggerated acute inflammation but limited lung fibrosis in response to silica.	('lung fibrosis', 'Disease', 'MESH:D005355', (86, 99))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('silica', 'Chemical', 'MESH:D012822', (115, 121))	('response to silica', 'biological_process', 'GO:0034021', ('103', '121'))	('lung fibrosis', 'Disease', (86, 99))	('deficient', 'Var', (13, 22))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('exaggerated', 'PosReg', (43, 54))	('lung fibrosis', 'Phenotype', 'HP:0002206', (86, 99))	('IL-10', 'Gene', (27, 32))	('limited', 'NegReg', (78, 85))	('mice', 'Species', '10090', (8, 12))	('IL-10', 'molecular_function', 'GO:0005141', ('27', '32'))
142102	30510551	There is, indeed, a growing body of evidence showing that nanoparticles also display strong immunosuppressive effects.	('immunosuppressive effects', 'CPA', (92, 117))	('nanoparticles', 'Var', (58, 71))	('Th', 'Chemical', 'MESH:D013910', (0, 2))
142117	30510551	Mechanistic studies investigating the effects of nanoparticles on T-lymphocyte immunosuppressive lineage commitment revealed that nanoparticles (carbon, grapheme, and iron) directly interfere with autophagy, ROS production, NFkappaB-nuclear translocation or antigen processing by dendritic cells.	('autophagy', 'biological_process', 'GO:0016236', ('197', '206'))	('antigen processing', 'CPA', (258, 276))	('carbon', 'Chemical', 'MESH:D002244', (145, 151))	('NFkappaB', 'Gene', (224, 232))	('autophagy', 'CPA', (197, 206))	('nanoparticles', 'Var', (130, 143))	('autophagy', 'biological_process', 'GO:0006914', ('197', '206'))	('antigen processing', 'biological_process', 'GO:0019882', ('258', '276'))	('ROS', 'Chemical', '-', (208, 211))	('interfere', 'NegReg', (182, 191))	('NFkappaB', 'Gene', '18033', (224, 232))	('iron', 'Chemical', 'MESH:D007501', (167, 171))	('ROS', 'Protein', (208, 211))
142351	23639003	By 3 weeks post-implantation, glandular structures were apparent in the periphery of the sample signifying growth of the implanted tumor and these glands were surrounded by vessels staining strongly for msCD34, but huCD31(+) vessels were not detectable.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('growth', 'CPA', (107, 113))	('glandular structures', 'CPA', (30, 50))	('tumor', 'Disease', (131, 136))	('CD31', 'Gene', (217, 221))	('CD31', 'Gene', '5175', (217, 221))	('msCD34', 'Var', (203, 209))
142358	23639003	Immunofluorescence staining was performed on frozen sections using either anti-msCD31 or anti-huCD34 to determine the origin of perfused vessels.	('CD31', 'Gene', '5175', (81, 85))	('anti-huCD34', 'Var', (89, 100))	('CD31', 'Gene', (81, 85))
142402	21479131	LMB-H226-GL was found to be able to consistently form solid tumors in the peritoneum of mice.	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('mice', 'Species', '10090', (88, 92))	('LMB-H226-GL', 'Var', (0, 11))	('LMB-H226-GL', 'Chemical', '-', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
142435	21479131	We found that all of the mice with tumor burdens had significant response upon SS1P treatment, as evidenced by in vivo imaging and necropsy observance, which strongly supports the role that SS1P may have as a potent anti-mesothelioma drug candidate.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mice', 'Species', '10090', (25, 29))	('SS1P', 'Chemical', 'MESH:C474515', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SS1P', 'Var', (190, 194))	('tumor', 'Disease', (35, 40))	('mesothelioma', 'Disease', (221, 233))	('SS1P', 'Chemical', 'MESH:C474515', (79, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))
142473	21479131	No differences were observed in mesothelin expression levels between NCI-H226 and LMB-H226-GL (Fig.	('LMB-H226-GL', 'Var', (82, 93))	('NCI-H226', 'CellLine', 'CVCL:1544', (69, 77))	('mesothelin expression levels', 'MPA', (32, 60))	('LMB-H226-GL', 'Chemical', '-', (82, 93))
142513	21479131	We found that SS1P bound to the remaining tumor cells and killed them with similar activity when tested in vitro as tumor monolayers (data not shown).	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SS1P', 'Chemical', 'MESH:C474515', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('bound', 'Interaction', (19, 24))	('SS1P', 'Var', (14, 18))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
71834	21479131	Mesothelioma cells grown as monolayers or as spheroids expressed comparable levels of mesothelin; however, spheroids were at least 100 times less affected by SS1P.	('SS1P', 'Chemical', 'MESH:C474515', (158, 162))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('SS1P', 'Var', (158, 162))
142530	21162719	Stage was T1b N0 M0 (according to International Mesothelioma Interest Group 1995).	('Mesothelioma', 'Disease', (48, 60))	('Mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('T1b N0 M0', 'Var', (10, 19))
142625	20601329	In addition, studies reporting a high prevalence of SV40 DNA in human tumors were based on molecular assays that are prone to false-positive results.	('human', 'Species', '9606', (64, 69))	('false', 'biological_process', 'GO:0071877', ('126', '131'))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('false', 'biological_process', 'GO:0071878', ('126', '131'))	('SV40 DNA', 'Var', (52, 60))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('SV40', 'Species', '1891767', (52, 56))
142643	20601329	There is general agreement among scientists and physicians, and widespread support from agencies in countries around the world, that chrysotile causes various cancers, including mesothelioma and lung cancer .	('cancers', 'Disease', (159, 166))	('mesothelioma and lung cancer', 'Disease', 'MESH:D008175', (178, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('causes', 'Reg', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('chrysotile', 'Var', (133, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('men', 'Species', '9606', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
142706	18442377	Our patient, a 63-year-old woman, initially presented in 1992 with a T1N0M0 invasive ductal carcinoma of the left breast, which was treated with quadrantectomy, post-operative radiotherapy and adjuvant tamoxifen for 5 years.	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (76, 101))	('T1N0M0', 'Var', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('patient', 'Species', '9606', (4, 11))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (85, 101))	('invasive ductal carcinoma', 'Disease', (76, 101))	('woman', 'Species', '9606', (27, 32))	('tamoxifen', 'Chemical', 'MESH:D013629', (202, 211))
142753	30357853	To stain surface markers, cells were incubated in the dark at 4  C for 1h with 1:50 dilutions of the following antibodies (all obtained from Thermo Fisher): eFluor 450-CD45 (clone 30-F11), PE-CD11b (clone M1/70), PE-Cy7-Ly6C (clone HK1.4), PerCP-eFluor710 (clone 1A8).	('M1/70', 'Gene', '22238', (205, 210))	('CD45', 'Gene', (168, 172))	('Ly6C', 'Gene', '17067', (220, 224))	('M1/70', 'Gene', (205, 210))	('HK1', 'molecular_function', 'GO:0004673', ('232', '235'))	('CD45', 'Gene', '19264', (168, 172))	('PE-CD11b', 'Var', (189, 197))	('PerCP-eFluor710', 'Var', (240, 255))	('Ly6C', 'Gene', (220, 224))
142758	30357853	Figure 2B demonstrates that Ly6G antibody successfully depleted neutrophils as detected by flow cytometric phenotyping of the neutrophil population via a Ly6C antibody (Ly6Cmid cells).	('Ly6Cmid', 'CellLine', 'CVCL:8802', (169, 176))	('depleted neutrophils', 'Phenotype', 'HP:0001875', (55, 75))	('Ly6G antibody', 'Var', (28, 41))	('antibody', 'cellular_component', 'GO:0042571', ('159', '167'))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('antibody', 'cellular_component', 'GO:0019815', ('159', '167'))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('depleted', 'NegReg', (55, 63))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('antibody', 'cellular_component', 'GO:0019814', ('159', '167'))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('159', '167'))	('neutrophils', 'CPA', (64, 75))
142790	24003413	Hemoptysis due to SFT as well as hypertrophic osteoarthropathy secondary to SFT of the lung has also been reported.	('Hemoptysis', 'Disease', (0, 10))	('SFT', 'Disease', (18, 21))	('Hemoptysis', 'Phenotype', 'HP:0002105', (0, 10))	('SFT', 'Var', (76, 79))	('hypertrophic osteoarthropathy', 'Disease', 'MESH:D010004', (33, 62))	('hypertrophic osteoarthropathy', 'Disease', (33, 62))
142933	22312496	However, with 4-hydroxyifosfamide, considerable variation in the levels of plasma and peritoneal fluid hydroxyifosfamide occurred.	('occurred', 'Reg', (121, 129))	('hydroxyifosfamide', 'Chemical', '-', (103, 120))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (86, 102))	('4-hydroxyifosfamide', 'Chemical', 'MESH:C039771', (14, 33))	('hydroxyifosfamide', 'Chemical', '-', (16, 33))	('4-hydroxyifosfamide', 'Var', (14, 33))
143116	30485442	EPP can leave less residual tumor cells compared with ePD; however, it often results in high morbidity and even mortality rates, severe depression of cardiorespiratory function, and poor quality of life.	('cardiorespiratory function', 'MPA', (150, 176))	('morbidity', 'CPA', (93, 102))	('depression', 'Disease', 'MESH:D003866', (136, 146))	('results in', 'Reg', (77, 87))	('depression', 'Phenotype', 'HP:0000716', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('EPP', 'Var', (0, 3))	('depression', 'Disease', (136, 146))
143181	30651596	Interestingly, ADAM10 depletion was associated with decreased tumour progression as shown by biophotonic imaging measurements (Fig.	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('ADAM10', 'Gene', (15, 21))	('depletion', 'Var', (22, 31))	('decreased tumour', 'Disease', 'MESH:D009369', (52, 68))	('decreased tumour', 'Disease', (52, 68))
143182	30651596	To further validate the impact of ADAM10 on mesothelioma cell properties, AB12 as well as PM27 cells were treated with a pharmacological selective ADAM10 inhibitor, GI254023X [6,23], and their phenotypes were analysed accordingly.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('ADAM10', 'Gene', (147, 153))	('GI254023X', 'Chemical', 'MESH:C555398', (165, 174))	('mesothelioma', 'Disease', (44, 56))	('GI254023X', 'Var', (165, 174))
143184	30651596	5b), GI254023X-treated mouse mesothelioma cells displayed weaker migratory properties in transwell chambers as compared to vehicle-treated cells (Fig.	('GI254023X-treated', 'Var', (5, 22))	('GI254023X', 'Chemical', 'MESH:C555398', (5, 14))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('migratory properties in transwell chambers', 'CPA', (65, 107))	('weaker', 'NegReg', (58, 64))	('mouse', 'Species', '10090', (23, 28))	('mesothelioma', 'Disease', (29, 41))
143185	30651596	Similarly, GI254023X-treated mouse mesothelioma cells showed a significantly decreased migration in a scratch assay (at 4, 6 and 8 h) (Fig.	('mesothelioma', 'Disease', (35, 47))	('migration in a scratch assay', 'CPA', (87, 115))	('mouse', 'Species', '10090', (29, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('GI254023X-treated', 'Var', (11, 28))	('GI254023X', 'Chemical', 'MESH:C555398', (11, 20))	('decreased', 'NegReg', (77, 86))
143186	30651596	Invasion of AB12 and PM27 cells measured in spheroid assay was also significantly decreased after GI254023X treatment (Fig.	('decreased', 'NegReg', (82, 91))	('Invasion of AB12', 'CPA', (0, 16))	('GI254023X', 'Chemical', 'MESH:C555398', (98, 107))	('GI254023X', 'Var', (98, 107))
143191	30651596	Treatment of AB12 and PM27 cells with GI254023X also reduced NTF secretion (Fig.	('GI254023X', 'Var', (38, 47))	('NTF secretion', 'MPA', (61, 74))	('reduced', 'NegReg', (53, 60))	('GI254023X', 'Chemical', 'MESH:C555398', (38, 47))	('secretion', 'biological_process', 'GO:0046903', ('65', '74'))
143201	30651596	Interestingly, mesothelioma H28 cell migration measured in transwell chambers and in a scratch assay was significantly decreased in siADAM10-treated H28 cells as compared to siScramble-treated H28 cells (Fig.	('H28', 'Gene', '15061', (193, 196))	('H28', 'Gene', (28, 31))	('decreased', 'NegReg', (119, 128))	('H28', 'Gene', (149, 152))	('siADAM10-treated', 'Var', (132, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('cell migration', 'biological_process', 'GO:0016477', ('32', '46'))	('H28', 'Gene', '15061', (28, 31))	('H28', 'Gene', (193, 196))	('mesothelioma', 'Disease', (15, 27))	('H28', 'Gene', '15061', (149, 152))
143220	30651596	In MPM, we showed that mesothelioma cell (AB12, PM27 and H28) proliferation is not modified when ADAM10 is targeted with shADAM10, GI254023X or siADAM10.	('GI254023X', 'Chemical', 'MESH:C555398', (131, 140))	('mesothelioma', 'Disease', (23, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (23, 35))	('GI254023X', 'Var', (131, 140))	('targeted', 'Reg', (107, 115))	('H28', 'Gene', '15061', (57, 60))	('H28', 'Gene', (57, 60))	('ADAM10', 'Gene', (97, 103))
143222	30651596	Importantly, we could demonstrate using different experimental settings (transwell chambers, wound healing and spheroid assays), different mouse and human mesothelioma cells as well as different ADAM10 inhibition strategies (shADAM10, GI254023X or siADAM10) that ADAM10 enhances migration and invasion of mesothelioma cells.	('ADAM10', 'Gene', (263, 269))	('mesothelioma', 'Disease', (305, 317))	('wound healing', 'biological_process', 'GO:0042060', ('93', '106'))	('mesothelioma', 'Disease', (155, 167))	('GI254023X', 'Chemical', 'MESH:C555398', (235, 244))	('enhances', 'PosReg', (270, 278))	('ADAM10', 'Gene', (195, 201))	('mesothelioma', 'Disease', 'MESH:D008654', (305, 317))	('mouse', 'Species', '10090', (139, 144))	('GI254023X', 'Var', (235, 244))	('human', 'Species', '9606', (149, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('inhibition', 'NegReg', (202, 212))
143224	30651596	Indeed, bioluminescence imaging and macroscopic analysis of tumours at the time of sacrifice revealed that tumours developed after intrapleural injection of shADAM10-treated AB12 cells are significantly smaller as compared to tumours developed after injection of shCtls-treated cells.	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('shADAM10-treated', 'Var', (157, 173))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('bioluminescence', 'biological_process', 'GO:0008218', ('8', '23'))	('smaller', 'NegReg', (203, 210))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
143226	30651596	GI254023X, blocking ADAM10 catalytic activity, drastically reduced MPM cell migration and invasion indicating that ADAM10-related molecular mechanisms underlying the regulation of MPM cancer cell migration and invasion are dependent on the metalloprotease domain activity.	('cancer', 'Disease', (184, 190))	('reduced', 'NegReg', (59, 66))	('regulation', 'biological_process', 'GO:0065007', ('166', '176'))	('ADAM10', 'Gene', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('MPM cell migration', 'CPA', (67, 85))	('GI254023X', 'Chemical', 'MESH:C555398', (0, 9))	('cell migration', 'biological_process', 'GO:0016477', ('191', '205'))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('27', '45'))	('catalytic activity', 'MPA', (27, 45))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('GI254023X', 'Var', (0, 9))	('invasion', 'CPA', (90, 98))
143228	30651596	In line with previous data, the extracellular domain of N-cadherin has been described to promote cell motility of squamous epithelial cells and to be a stimulating agent of endothelial and glioblastoma cell migration.	('stimulating', 'Reg', (152, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('cell motility', 'biological_process', 'GO:0048870', ('97', '110'))	('promote', 'PosReg', (89, 96))	('extracellular', 'cellular_component', 'GO:0005576', ('32', '45'))	('N-cadherin', 'Gene', (56, 66))	('glioblastoma', 'Disease', (189, 201))	('N-cadherin', 'Gene', '12558', (56, 66))	('cell motility', 'CPA', (97, 110))	('extracellular domain', 'Var', (32, 52))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('cell migration', 'biological_process', 'GO:0016477', ('202', '216'))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))
143245	30651596	GI254023X (Sigma-Aldrich), ionomycin (Sigma-Aldrich) and PD173074 (Abcam, Cambridge, UK) were prepared in DMSO (vehicle).	('ionomycin', 'Chemical', 'MESH:D015759', (27, 36))	('PD173074', 'Chemical', 'MESH:C115711', (57, 65))	('PD173074', 'Var', (57, 65))	('DMSO', 'Chemical', 'MESH:D004121', (106, 110))	('GI254023X', 'Chemical', 'MESH:C555398', (0, 9))	('GI254023X', 'Var', (0, 9))
143246	30651596	For assays in presence of GI254023X or vehicle, mesothelioma cells were pretreated 16 h before the experiment.	('GI254023X', 'Var', (26, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('mesothelioma', 'Disease', (48, 60))	('GI254023X', 'Chemical', 'MESH:C555398', (26, 35))
143249	30651596	Lentiviral transfer shRNA plasmids directed against mouse ADAM10 (TRCN0000031848, TRCN0000031844) and non-target control shRNA were purchased from Sigma-Aldrich (SHC005 and SHC012).	('TRCN0000031848', 'Var', (66, 80))	('mouse', 'Species', '10090', (52, 57))	('TRCN0000031844', 'Var', (82, 96))
143259	30651596	A surgical incision was made into the right chest wall followed by an injection of cells in the pleural cavity through an intercostal space (1.5 x 106 AB12 cells or 106 PM27 cells in 200 microl serum-free medium).	('pleural cavity', 'Disease', (96, 110))	('pleural cavity', 'Disease', 'MESH:D010995', (96, 110))	('1.5', 'Var', (141, 144))
143272	30651596	PM27 cells (2 x 104cells/100 microl) were cultured on microscopy slides during 24 h, fixed, permeabilized and incubated for 1 h with following primary antibodies: rabbit anti-mesothelin (250519, Abbiotec; 1/200); rabbit anti-keratin5 (PRB-160P, Covance; 1/100); guinea pig anti-vimentin (2220900801, Quartett; 1/250).	('rabbit', 'Species', '9986', (163, 169))	('vimentin', 'Gene', (278, 286))	('guinea pig', 'Species', '10141', (262, 272))	('vimentin', 'cellular_component', 'GO:0045099', ('278', '286'))	('vimentin', 'cellular_component', 'GO:0045098', ('278', '286'))	('mesothelin', 'Gene', (175, 185))	('mesothelin', 'Gene', '56047', (175, 185))	('2220900801', 'Var', (288, 298))	('rabbit', 'Species', '9986', (213, 219))	('250519', 'Var', (187, 193))	('vimentin', 'Gene', '22352', (278, 286))
143282	30651596	The cells were treated with ionomycin (5 microM or 3 microM for H28 cells) or vehicle during 2 h, in presence or not of GI254023X (5 microM).	('GI254023X', 'Chemical', 'MESH:C555398', (120, 129))	('H28', 'Gene', '15061', (64, 67))	('H28', 'Gene', (64, 67))	('ionomycin', 'Chemical', 'MESH:D015759', (28, 37))	('GI254023X', 'Var', (120, 129))
143285	30651596	In some assays, GI254023X (5 microM), PD173074 (5 microM) or vehicles were added.	('PD173074', 'Chemical', 'MESH:C115711', (38, 46))	('GI254023X', 'Chemical', 'MESH:C555398', (16, 25))	('GI254023X', 'Var', (16, 25))	('PD173074', 'Var', (38, 46))
143310	31406207	Of note, the study indicated very low expression levels of tumor suppressor miRNAs in MM such as miR-16-5p, miR-15, miR-31, and let-7a, to name a few.	('expression levels', 'MPA', (38, 55))	('5p', 'Chemical', '-', (104, 106))	('tumor suppressor', 'Gene', '7248', (59, 75))	('let-7a', 'Var', (128, 134))	('miR-31', 'Gene', '407035', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-16', 'Gene', (97, 103))	('low', 'NegReg', (34, 37))	('miR-16', 'Gene', '51573', (97, 103))	('tumor suppressor', 'Gene', (59, 75))	('miR-31', 'Gene', (116, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('miR-15', 'Var', (108, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
143311	31406207	Furthermore, diagnostic value of miRNAs in asbestos exposure and MM has also been proposed Notably, as per our knowledge only one current research article looks at the miRNA signature associated with circulating extracellular vesicle (EV) miRNAs in MM patients, and found that miR-103a-3p and miR-30e-3p were discriminatory for MM from asbestos-exposed patients with no cancer.	('asbestos', 'Chemical', 'MESH:D001194', (336, 344))	('miR-30e', 'Gene', (293, 300))	('patients', 'Species', '9606', (252, 260))	('patients', 'Species', '9606', (353, 361))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('extracellular vesicle', 'cellular_component', 'GO:1903561', ('212', '233'))	('cancer', 'Disease', (370, 376))	('miR-103a-3p', 'Var', (277, 288))	('asbestos', 'Chemical', 'MESH:D001194', (43, 51))	('miR-30e', 'Gene', '407034', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))
143320	31406207	We chose to validate the exosomal miRNA expression levels of 3 upregulated (miR-16-5p, miR-222-3p, miR-30a-5p) and one down regulated (miR-31-5p) miRNA by qRTPCR (Fig.	('down regulated', 'NegReg', (119, 133))	('miR-30a', 'Gene', (99, 106))	('5p', 'Chemical', '-', (142, 144))	('5p', 'Chemical', '-', (83, 85))	('miR-31', 'Gene', '407035', (135, 141))	('miR-16', 'Gene', (76, 82))	('miR-31', 'Gene', (135, 141))	('upregulated', 'PosReg', (63, 74))	('miR-30a', 'Gene', '407029', (99, 106))	('miR-16', 'Gene', '51573', (76, 82))	('5p', 'Chemical', '-', (107, 109))	('miR-222-3p', 'Var', (87, 97))
143322	31406207	1B) that miR-16-5p, miR-222-3p, and miR-30a-5p are upregulated in exosomes from both epithelioid subtypes, Hmeso and H2595.	('miR-30a', 'Gene', (36, 43))	('5p', 'Chemical', '-', (16, 18))	('miR-30a', 'Gene', '407029', (36, 43))	('miR-222-3p', 'Var', (20, 30))	('5p', 'Chemical', '-', (44, 46))	('miR-16', 'Gene', (9, 15))	('upregulated', 'PosReg', (51, 62))	('Hmeso', 'Chemical', '-', (107, 112))	('miR-16', 'Gene', '51573', (9, 15))
143324	31406207	miR-31a-5p was significantly decreased in all MM cancer exosomes.	('miR-31a-5p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('MM cancer', 'Disease', 'MESH:D009369', (46, 55))	('decreased', 'NegReg', (29, 38))	('MM cancer', 'Disease', (46, 55))	('miR-31a-5p', 'Chemical', '-', (0, 10))
143325	31406207	Treatment of Hmeso MM cells with small molecule inhibitors GW4869 (GW, 40 microM) or combination of Bisindolylmaleimide-I (10 microM) with Chloramidine (50 microM) (B&C), for 72 hours, resulted in significant reductions in exosome secretion from both treatment groups (Fig.	('significant', 'NegReg', (197, 208))	('GW4869', 'Chemical', 'MESH:C468773', (59, 65))	('secretion', 'biological_process', 'GO:0046903', ('231', '240'))	('GW', 'Chemical', 'MESH:C468773', (67, 69))	('Hmeso', 'Chemical', '-', (13, 18))	('exosome', 'cellular_component', 'GO:0070062', ('223', '230'))	('GW4869', 'Var', (59, 65))	('Bisindolylmaleimide-I', 'Chemical', 'MESH:C070515', (100, 121))	('in exosome', 'MPA', (220, 230))	('Chloramidine', 'Chemical', 'MESH:C558727', (139, 151))	('GW', 'Chemical', 'MESH:C468773', (59, 61))
143329	31406207	For further validation, we measured 4 other exosomally secreted miRNAs that were initially identified by microarray, and found that exosome inhibition also leads to reduced levels of exosomal miR-222-3p, miR-30a-5p, miR31-5p, and let-7e-5p (Fig.	('exosome', 'cellular_component', 'GO:0070062', ('132', '139'))	('let-7e-5p', 'Var', (230, 239))	('exosome', 'MPA', (132, 139))	('5p', 'Chemical', '-', (212, 214))	('miR-30a', 'Gene', '407029', (204, 211))	('5p', 'Chemical', '-', (222, 224))	('exosomal miR-222-3p', 'MPA', (183, 202))	('inhibition', 'NegReg', (140, 150))	('miR31', 'Gene', (216, 221))	('5p', 'Chemical', '-', (237, 239))	('miR-30a', 'Gene', (204, 211))	('reduced', 'NegReg', (165, 172))	('miR31', 'Gene', '407035', (216, 221))
143339	31406207	3G), although cisplatin does, and that BCL2 levels are significantly reduced upon exosome inhibition and increased with cisplatin (Fig.	('exosome inhibition', 'MPA', (82, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('reduced', 'NegReg', (69, 76))	('BCL2', 'molecular_function', 'GO:0015283', ('39', '43'))	('cisplatin', 'Var', (120, 129))	('exosome', 'cellular_component', 'GO:0070062', ('82', '89'))	('BCL2', 'Gene', '596', (39, 43))	('increased', 'PosReg', (105, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('BCL2', 'Gene', (39, 43))
143341	31406207	Additionally, the migratory and invasive capacity for both Hmeso and H2373 cells was significantly reduced upon inhibition of exosome secretion (Supplementary Fig.	('inhibition', 'Var', (112, 122))	('exosome', 'cellular_component', 'GO:0070062', ('126', '133'))	('exosome secretion', 'MPA', (126, 143))	('secretion', 'biological_process', 'GO:0046903', ('134', '143'))	('Hmeso', 'Chemical', '-', (59, 64))	('reduced', 'NegReg', (99, 106))
143354	31406207	This result also coincided with significantly reduced viable Hmeso cells after miR-16 transfection alone as well as with cisplatin (Fig.	('Hmeso', 'Chemical', '-', (61, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('miR-16', 'Gene', (79, 85))	('reduced', 'NegReg', (46, 53))	('miR-16', 'Gene', '51573', (79, 85))	('transfection', 'Var', (86, 98))	('viable Hmeso cells', 'CPA', (54, 72))
143357	31406207	The observation of decreased levels of miR-16-5p in exosomes from transfected cells, suggests two possibilities; either secretion of exosomes is inhibited in response to transfection or loading of miR-16-5p into exosomes is decreased.	('decreased', 'NegReg', (19, 28))	('secretion of exosomes', 'MPA', (120, 141))	('5p', 'Chemical', '-', (204, 206))	('5p', 'Chemical', '-', (46, 48))	('decreased', 'NegReg', (224, 233))	('miR-16', 'Gene', '51573', (39, 45))	('secretion', 'biological_process', 'GO:0046903', ('120', '129'))	('miR-16', 'Gene', (197, 203))	('loading', 'MPA', (186, 193))	('miR-16', 'Gene', (39, 45))	('miR-16', 'Gene', '51573', (197, 203))	('transfection', 'Var', (170, 182))	('inhibited', 'NegReg', (145, 154))
143379	31406207	The low miR-16-5p in MM tumor cells observed by us and others could be attributed to its increased secretion via exosomes, as opposed to common loss of tumor suppressors via mutation and deletion.	('MM tumor', 'Disease', (21, 29))	('deletion', 'Var', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'Gene', (152, 168))	('MM tumor', 'Disease', 'MESH:D009369', (21, 29))	('mutation', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('secretion', 'biological_process', 'GO:0046903', ('99', '108'))	('tumor suppressor', 'Gene', '7248', (152, 168))	('5p', 'Chemical', '-', (15, 17))	('miR-16', 'Gene', (8, 14))	('low', 'NegReg', (4, 7))	('miR-16', 'Gene', '51573', (8, 14))	('increased', 'PosReg', (89, 98))	('secretion via exosomes', 'MPA', (99, 121))
143382	31406207	The neutral sphingolmyelinase-2 inhibitor GW4869, which blocks ceramide production that is needed to bud exosomes inward at the endosomal surface, has been indicated as a useful avenue for blocking exosome secretion as well as increasing the efficacy/reducing chemotherapeutic drug resistance to cisplatin.	('secretion', 'biological_process', 'GO:0046903', ('206', '215'))	('cisplatin', 'Chemical', 'MESH:D002945', (296, 305))	('drug resistance', 'Phenotype', 'HP:0020174', (277, 292))	('exosome', 'cellular_component', 'GO:0070062', ('198', '205'))	('blocking', 'NegReg', (189, 197))	('ceramide', 'Chemical', 'MESH:D002518', (63, 71))	('GW4869', 'Var', (42, 48))	('drug resistance', 'biological_process', 'GO:0042493', ('277', '292'))	('drug resistance', 'biological_process', 'GO:0009315', ('277', '292'))	('increasing', 'PosReg', (227, 237))	('exosome secretion', 'MPA', (198, 215))	('efficacy/reducing', 'NegReg', (242, 259))	('GW4869', 'Chemical', 'MESH:C468773', (42, 48))
143383	31406207	Further, a combination of two small molecules bisindolylmaleimide-I and chloramidine have also been shown to reduce exosome secretion from cells and increase chemotherapeutic retention.	('bisindolylmaleimide-I', 'Var', (46, 67))	('bisindolylmaleimide-I', 'Chemical', 'MESH:C070515', (46, 67))	('increase', 'PosReg', (149, 157))	('reduce', 'NegReg', (109, 115))	('secretion', 'biological_process', 'GO:0046903', ('124', '133'))	('exosome', 'cellular_component', 'GO:0070062', ('116', '123'))	('retention', 'biological_process', 'GO:0051235', ('175', '184'))	('chemotherapeutic retention', 'CPA', (158, 184))	('chloramidine', 'Chemical', 'MESH:C558727', (72, 84))	('exosome secretion from cells', 'MPA', (116, 144))
143410	31406207	Based on our results thus far, we have drawn together a proposed mechanism that may be involved where HuR promotes miR-16-5p loading into exosomes, meaning that siHuR knockdown of HuR protein levels leads to reduced exosomal miR-16-5p, and hence increased miR-16-5p in the cell.	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('HuR', 'Gene', '1994', (163, 166))	('HuR', 'Gene', '1994', (102, 105))	('HuR', 'Gene', '1994', (180, 183))	('miR-16', 'Gene', (115, 121))	('5p', 'Chemical', '-', (122, 124))	('reduced', 'NegReg', (208, 215))	('5p', 'Chemical', '-', (232, 234))	('5p', 'Chemical', '-', (263, 265))	('knockdown', 'Var', (167, 176))	('miR-16', 'Gene', '51573', (115, 121))	('miR-16', 'Gene', (225, 231))	('miR-16', 'Gene', (256, 262))	('HuR', 'Gene', (102, 105))	('HuR', 'Gene', (180, 183))	('HuR', 'Gene', (163, 166))	('increased', 'PosReg', (246, 255))	('miR-16', 'Gene', '51573', (225, 231))	('miR-16', 'Gene', '51573', (256, 262))
143412	31406207	Because miR-16-5p upregulation by transfection does not affect exosome secretion by particle number, we know that this effect is limited to the packaging process of exosome cargo.	('upregulation', 'PosReg', (18, 30))	('exosome', 'cellular_component', 'GO:0070062', ('63', '70'))	('exosome', 'cellular_component', 'GO:0070062', ('165', '172'))	('exosome secretion', 'MPA', (63, 80))	('5p', 'Chemical', '-', (15, 17))	('miR-16', 'Gene', (8, 14))	('transfection', 'Var', (34, 46))	('secretion', 'biological_process', 'GO:0046903', ('71', '80'))	('miR-16', 'Gene', '51573', (8, 14))	('cargo', 'molecular_function', 'GO:0140355', ('173', '178'))
143432	31406207	We used TaqMan Assays on Demand primers and probes for human miRNAs miR-16-5p, miR-30a-5p, miR-222-3p, and miR-31-5p, and for internal control miRNA cel-miR-39-3p (Thermo Fisher) was used.	('5p', 'Chemical', '-', (87, 89))	('miR-16', 'Gene', (68, 74))	('miR-30a', 'Gene', '407029', (79, 86))	('miR-222-3p', 'Var', (91, 101))	('5p', 'Chemical', '-', (114, 116))	('miR-31', 'Gene', (107, 113))	('miR-16', 'Gene', '51573', (68, 74))	('5p', 'Chemical', '-', (75, 77))	('human', 'Species', '9606', (55, 60))	('miR-30a', 'Gene', (79, 86))	('miR-31', 'Gene', '407035', (107, 113))
143439	31406207	On-Target plus Non-Targeting small-interfering RNA (siRNA) (scrambled control) or On-Target plus SMARTpool human ELAV1 (HuR) siRNA (100 nmol/L, Dharmacon, Lafayette, CO) were transfected into 95% confluent cells using Lipofectamine RNAiMAX (Invitrogen), following the manufacturer's protocol.	('HuR', 'Gene', '1994', (120, 123))	('small-interfering', 'Var', (29, 46))	('ELAV1', 'Gene', '1994', (113, 118))	('human', 'Species', '9606', (107, 112))	('Lipofectamine', 'Chemical', 'MESH:C086724', (218, 231))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('ELAV1', 'Gene', (113, 118))	('HuR', 'Gene', (120, 123))
143440	31406207	The efficiency of HuR protein knockdown was determined by Western blot analysis after 48 hr.	('HuR', 'Gene', (18, 21))	('HuR', 'Gene', '1994', (18, 21))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('knockdown', 'Var', (30, 39))
143452	29094504	Restoration of miR-15/16 led to dose-dependent growth inhibition in MPM cell lines, which significantly correlated with their sensitivity to FGFR inhibition.	('Restoration', 'Var', (0, 11))	('growth inhibition', 'CPA', (47, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('miR-15/16', 'Gene', '51573', (15, 24))	('miR-15/16', 'Gene', (15, 24))
143459	29094504	As classical malignant drivers such as mutated EGFR or Raf are uncommon in MPM, treatments specifically targeting these mutations are ineffective in this disease (Dubey et al., 2010; Garland et al., 2007; Govindan et al., 2005).	('MPM', 'Disease', (75, 78))	('Raf', 'Gene', '22882', (55, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('47', '51'))	('mutated', 'Var', (39, 46))	('Raf', 'Gene', (55, 58))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
143460	29094504	Instead, genomic analysis has revealed genetic deletions in MPM largely in genes considered to be tumor suppressive, such as P16/CDKN2A and NF2 (Jaurand and Fleury-Feith, 2005), which are not easily targetable.	('P16', 'Gene', '1029', (125, 128))	('deletions', 'Var', (47, 56))	('Fleury-Feith', 'Disease', (157, 169))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('CDKN2A', 'Gene', (129, 135))	('NF2', 'Gene', '4771', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Fleury-Feith', 'Disease', 'None', (157, 169))	('CDKN2A', 'Gene', '1029', (129, 135))	('P16', 'Gene', (125, 128))	('tumor', 'Disease', (98, 103))	('MPM largely', 'Gene', (60, 71))	('NF2', 'Gene', (140, 143))
143461	29094504	Hyperactivation of FGF receptors and downstream pathways has been associated with tumor progression, therapy resistance, and poor prognosis (Korc and Friesel, 2009).	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('therapy resistance', 'CPA', (101, 119))	('Hyperactivation', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('FGF receptors', 'Protein', (19, 32))	('tumor', 'Disease', (82, 87))
143486	29094504	The mutated FGFR1 constructs were generated by site-directed mutagenesis.	('mutated', 'Var', (4, 11))	('FGFR1', 'Gene', (12, 17))	('FGFR1', 'Gene', '2260', (12, 17))	('mutagenesis', 'biological_process', 'GO:0006280', ('61', '72'))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
143489	29094504	Immunodetection was performed using antibodies against FGFR1 (D8E4 XP, #9740, Cell Signaling; 1 : 1000) and FGFR4 (H-121, sc-9006, Santa Cruz, Dallas, TX, USA; 1 : 1000).	('FGFR1', 'Gene', '2260', (55, 60))	('Signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('Cell Signaling', 'MPA', (78, 92))	('FGFR4', 'Gene', '2264', (108, 113))	('FGFR4', 'Gene', (108, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('FGFR1', 'Gene', (55, 60))	('H-121', 'Var', (115, 120))
143509	29094504	The strongest effect was seen in MSTO, SPC212, and P31 cells, while VMC20, M38K, SPC111 as well as the control mesothelial cell lines MeT-5A and LP9 were only moderately affected.	('SPC', 'molecular_function', 'GO:0009004', ('39', '42'))	('SPC212', 'Var', (39, 45))	('SPC', 'molecular_function', 'GO:0009004', ('81', '84'))	('P31', 'Gene', (51, 54))	('P31', 'Gene', '529', (51, 54))	('M38K', 'Var', (75, 79))	('M38K', 'SUBSTITUTION', 'None', (75, 79))	('SPC212', 'CellLine', 'CVCL:D312', (39, 45))
143511	29094504	We previously reported that FGFR1 inhibition reduces MPM tumor growth in vitro and in vivo (Schelch et al., 2014).	('inhibition', 'Var', (34, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('reduces', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('FGFR1', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FGFR1', 'Gene', '2260', (28, 33))	('tumor', 'Disease', (57, 62))
143512	29094504	In our panel of MPM cell lines, MTT assays using the small-molecule-specific FGFR1 inhibitor PD166866 showed a dose-dependent decrease in cell viability reflecting the effects seen by miRNA mimics (Fig.	('FGFR1', 'Gene', (77, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('FGFR1', 'Gene', '2260', (77, 82))	('PD166866', 'Chemical', 'MESH:C113399', (93, 101))	('cell viability', 'CPA', (138, 152))	('decrease', 'NegReg', (126, 134))	('inhibitor PD166866', 'Var', (83, 101))	('PD166866', 'Var', (93, 101))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
143522	29094504	In addition to miR-15a, -15b, and -16, miR-195, and miR-424:additional members of this family:as well other microRNAs predicted to target various members of the FGF axis:miR-23a, miR-24, and miR-223:were also downregulated upon FGF pathway activation.	('miR-23a', 'Gene', '407010', (170, 177))	('miR-223', 'Gene', '407008', (191, 198))	('miR-23a', 'Gene', (170, 177))	('FGF pathway', 'Pathway', (228, 239))	('miR-424', 'Gene', (52, 59))	('downregulated', 'NegReg', (209, 222))	('miR-24', 'Var', (179, 185))	('miR-15a', 'Gene', '406948', (15, 22))	('miR-424', 'Gene', '494336', (52, 59))	('miR-223', 'Gene', (191, 198))	('miR-15a', 'Gene', (15, 22))	('miR-195', 'Gene', (39, 46))	('miR-195', 'Gene', '406971', (39, 46))
143523	29094504	In contrast, miR-93, miR-103, miR-137, and miR-193a-3p, which are not involved in the regulation of the FGF axis, remained largely unchanged (Fig.	('miR-93', 'Gene', '407051', (13, 19))	('miR-93', 'Gene', (13, 19))	('miR-193a-3p', 'Var', (43, 54))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('miR-137', 'Gene', (30, 37))	('miR-137', 'Gene', '406928', (30, 37))	('miR-103', 'Var', (21, 28))
143525	29094504	This model would suggest that, conversely, inhibition of FGF signals could partially rescue miR-15/16 expression.	('miR-15/16', 'Gene', '51573', (92, 101))	('miR-15/16', 'Gene', (92, 101))	('inhibition', 'Var', (43, 53))	('expression', 'MPA', (102, 112))	('rescue', 'NegReg', (85, 91))
143526	29094504	Therefore, we treated the three sensitive cell lines with the FGFR1 inhibitor PD166866 as well as the multikinase inhibitor ponatinib, which inhibits FGFR1-4, Abl, PDGFRA, and Src, and assessed the expression of miR-15/16.	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('Abl', 'Gene', '25', (159, 162))	('Src', 'Gene', '6714', (176, 179))	('PDGFRA', 'Gene', '5156', (164, 170))	('PDGFRA', 'Gene', (164, 170))	('FGFR1', 'Gene', (150, 155))	('miR-15/16', 'Gene', (212, 221))	('inhibits', 'NegReg', (141, 149))	('FGFR1', 'Gene', (62, 67))	('PD166866', 'Chemical', 'MESH:C113399', (78, 86))	('expression', 'MPA', (198, 208))	('miR-15/16', 'Gene', '51573', (212, 221))	('Abl', 'Gene', (159, 162))	('ponatinib', 'Chemical', 'MESH:C545373', (124, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('PD166866', 'Var', (78, 86))	('FGFR1', 'Gene', '2260', (150, 155))	('Src', 'Gene', (176, 179))	('FGFR1', 'Gene', '2260', (62, 67))
143529	29094504	Indeed, we have previously demonstrated that restoration of miR-16 is feasible in MPM models and results in growth suppression in vitro and in vivo (Reid et al., 2013) and several groups including our own have established FGFR inhibition as viable anti-MPM strategy (Blackwell et al., 2016; Marek et al., 2014; Schelch et al., 2014).	('FGFR', 'Gene', (222, 226))	('miR-16', 'Gene', '51573', (60, 66))	('restoration', 'Var', (45, 56))	('growth suppression', 'CPA', (108, 126))	('miR-16', 'Gene', (60, 66))	('inhibition', 'NegReg', (227, 237))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))
143530	29094504	The combination of mimic expression with the FGFR1 inhibitor PD166866 reached a higher total growth inhibition compared with each treatment alone.	('PD166866', 'Chemical', 'MESH:C113399', (61, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', '2260', (45, 50))	('mimic expression', 'Var', (19, 35))
143536	29094504	Therefore, we next tested the FGFR1 inhibitor PD166866 as well as the multikinase inhibitor ponatinib in combination with venetoclax and obatoclax.	('obatoclax', 'Chemical', 'MESH:C520962', (137, 146))	('FGFR1', 'Gene', (30, 35))	('tested', 'Reg', (19, 25))	('ponatinib', 'Chemical', 'MESH:C545373', (92, 101))	('inhibitor PD166866', 'Var', (36, 54))	('PD166866', 'Chemical', 'MESH:C113399', (46, 54))	('FGFR1', 'Gene', '2260', (30, 35))	('venetoclax', 'Chemical', 'MESH:C579720', (122, 132))	('PD166866', 'Var', (46, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))
143540	29094504	In the other combination settings, where calculation of CI values was not possible, effects stronger than the predicted value (PV, indicated as red bars) of additive interactions were observed at concentrations of 1 mum PD166866 or 100 nm ponatinib in combination with 50 nm obatoclax or 10 mum venetoclax (Figs 6C and S5).	('PD166866', 'Chemical', 'MESH:C113399', (220, 228))	('ponatinib', 'Chemical', 'MESH:C545373', (239, 248))	('venetoclax', 'Chemical', 'MESH:C579720', (295, 305))	('ponatinib', 'Gene', (239, 248))	('obatoclax', 'Chemical', 'MESH:C520962', (275, 284))	('PD166866', 'Var', (220, 228))
143558	29094504	Therefore, the miR-16 suppletion approach needs further investigation for tumors characterized with mutated or dysregulated FGF signaling.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('miR-16', 'Gene', '51573', (15, 21))	('mutated', 'Var', (100, 107))	('dysregulated', 'Var', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('miR-16', 'Gene', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
143560	29094504	Multiple members of the miR-15/16 family may be targeted with microRNA mimics, whereas FGFRs and Bcl-2 have the advantage of being druggable.	('Bcl-2', 'Gene', (97, 102))	('Bcl-2', 'Gene', '596', (97, 102))	('miR-15/16', 'Gene', '51573', (24, 33))	('miR-15/16', 'Gene', (24, 33))	('Bcl-2', 'molecular_function', 'GO:0015283', ('97', '102'))	('microRNA', 'Var', (62, 70))
143562	29094504	In mesothelioma, a phase lll study using the multi-RTK inhibitor nintedanib (NCT01907100) and a phase lb trial using the FGFR ligand trap GSK3052230 in combination with first-line chemotherapy (NCT01868022) are ongoing.	('FGFR ligand', 'molecular_function', 'GO:0005104', ('121', '132'))	('nintedanib', 'Chemical', 'MESH:C530716', (65, 75))	('mesothelioma', 'Disease', (3, 15))	('NCT01907100', 'Var', (77, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('GSK', 'molecular_function', 'GO:0050321', ('138', '141'))
143565	29094504	For example, a trial of the EZH2 inhibitor in the context of BAP1 loss-of-function mutation (NCT02860286) is currently recruiting.	('BAP1', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (28, 32))	('loss-of-function', 'NegReg', (66, 82))	('EZH2', 'Gene', (28, 32))	('NCT02860286', 'Var', (93, 104))	('BAP1', 'Gene', '8314', (61, 65))
143566	29094504	Similarly, our characterization of the impact of microRNA expression changes on MPM biology led us to identify the synergistic effect of combining inhibitors of FGFR1 and Bcl-2, two independent targets of the miR-15/16 pathway.	('FGFR1', 'Gene', (161, 166))	('miR-15/16', 'Gene', '51573', (209, 218))	('miR-15/16', 'Gene', (209, 218))	('FGFR1', 'Gene', '2260', (161, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('171', '176'))	('inhibitors', 'Var', (147, 157))	('Bcl-2', 'Gene', (171, 176))	('Bcl-2', 'Gene', '596', (171, 176))
143588	25410479	Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes.	('rats', 'Species', '10116', (64, 68))	('mesotheliomas', 'Disease', 'MESH:D008654', (42, 55))	('mesotheliomas', 'Disease', (42, 55))	('MWCNT', 'Chemical', '-', (82, 87))	('MWCNT D -', 'Var', (82, 91))
143637	25410479	At the end of the experimental time after 24 months, mortality was 56% in the MWCNT D low-dose group, 76% in the amosite asbestos group, and 34% in the negative control group.	('MWCNT', 'Chemical', '-', (78, 83))	('MWCNT D', 'Gene', (78, 85))	('low-dose', 'Var', (86, 94))	('amosite asbestos', 'Chemical', 'MESH:D017639', (113, 129))
143677	25410479	Malignant mesotheliomas of the epithelioid type occurred occasionally in the MWCNT groups B high, C low and high, D low and high, and in the amosite asbestos group.	('Malignant mesotheliomas of the epithelioid type', 'Disease', (0, 47))	('MWCNT', 'Chemical', '-', (77, 82))	('Malignant mesotheliomas', 'Phenotype', 'HP:0100001', (0, 23))	('amosite asbestos', 'Chemical', 'MESH:D017639', (141, 157))	('D low', 'Var', (114, 119))	('Malignant mesotheliomas of the epithelioid type', 'Disease', 'MESH:C562839', (0, 47))
143739	25410479	The kinetic behavior of bent MWCNTs is most probably different from that of straight MWCNTs, which might influence clearance half-times.	('bent', 'Var', (24, 28))	('influence', 'Reg', (105, 114))	('MWCNT', 'Chemical', '-', (29, 34))	('clearance', 'MPA', (115, 124))	('MWCNT', 'Chemical', '-', (85, 90))
143741	25410479	In contrast, thick NT115- and NT145-MWCNTs with a diameter of 150 nm and a length of 4.88 or 4.34 mum, respectively, and tangled NTtngl nanotubes with diameters of 2 to 20 nm and a length of 3 mum were less toxic.	('mum', 'Gene', '56925', (193, 196))	('mum', 'Gene', (193, 196))	('mum', 'Gene', '56925', (98, 101))	('mum', 'Gene', (98, 101))	('MWCNT', 'Chemical', '-', (36, 41))	('NT145-MWCNTs', 'Var', (30, 42))	('NTtngl', 'Protein', (129, 135))
143764	25410479	For the pleural cavity, Donaldson and co-workers assumed a risk of asbestos-like pathogenicity for nanotubes that are longer than 5 mum.	('mum', 'Gene', (132, 135))	('pleural', 'Disease', 'MESH:D010995', (8, 15))	('asbestos-like pathogenicity', 'Disease', (67, 94))	('pleural', 'Disease', (8, 15))	('asbestos', 'Chemical', 'MESH:D001194', (67, 75))	('nanotubes', 'Var', (99, 108))	('mum', 'Gene', '56925', (132, 135))
143767	25410479	In the mesothelioma samples, whose signal intensity at the Cdkn2a/2b locus was largely lower than -1, they found homozygous deletion of the gene.	('lower', 'NegReg', (87, 92))	('mesothelioma', 'Disease', (7, 19))	('signal intensity', 'MPA', (35, 51))	('deletion', 'Var', (124, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (7, 19))	('Cdkn2a', 'Gene', '25163', (59, 65))	('Cdkn2a', 'Gene', (59, 65))
143768	25410479	Furthermore, they detected deletion of this gene locus also in their asbestos-induced mesothelioma samples.	('asbestos', 'Chemical', 'MESH:D001194', (69, 77))	('detected', 'Reg', (18, 26))	('mesothelioma', 'Disease', (86, 98))	('deletion', 'Var', (27, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
143778	25410479	A nanotube length of more than 15 to 20 micrometers, preventing clearance from the serosal cavities because of limited stoma size and leading to frustrated phagocytosis and subsequent chronic inflammation, seems to be one mechanism of mesothelioma induction, however, it is probably not the only pathway.	('inflammation', 'biological_process', 'GO:0006954', ('192', '204'))	('frustrated phagocytosis', 'CPA', (145, 168))	('stoma', 'Disease', (119, 124))	('mesothelioma', 'Disease', 'MESH:D008654', (235, 247))	('preventing', 'NegReg', (53, 63))	('nanotube', 'Var', (2, 10))	('rat', 'Species', '10116', (150, 153))	('inflammation', 'Disease', 'MESH:D007249', (192, 204))	('inflammation', 'Disease', (192, 204))	('mesothelioma', 'Disease', (235, 247))	('clearance', 'CPA', (64, 73))	('stoma', 'Disease', 'None', (119, 124))	('phagocytosis', 'biological_process', 'GO:0006909', ('156', '168'))
143800	25410479	In our study, the histological features of the MWCNT-induced mesotheliomas and the reaction patterns of the immunohistochemical markers were congruent with those observed for amosite asbestos-induced mesotheliomas.	('asbestos-induced mesotheliomas', 'Disease', 'MESH:D008654', (183, 213))	('mesotheliomas', 'Disease', 'MESH:D008654', (200, 213))	('amosite asbestos', 'Chemical', 'MESH:D017639', (175, 191))	('mesotheliomas', 'Disease', (200, 213))	('MWCNT', 'Chemical', '-', (47, 52))	('mesotheliomas', 'Disease', 'MESH:D008654', (61, 74))	('asbestos-induced mesotheliomas', 'Disease', (183, 213))	('mesotheliomas', 'Disease', (61, 74))	('MWCNT-induced', 'Var', (47, 60))
143894	24594996	High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('High expression', 'Var', (0, 15))	('CD74', 'Gene', (19, 23))	('mesothelioma', 'Disease', (80, 92))	('prolonged OS', 'Disease', (64, 76))	('patients', 'Species', '9606', (93, 101))
143949	24594996	Cox regression analysis of the joint influence of the predictors (gender, age, calretinin expression, CD74 expression, and MIF expression) showed that calretinin (medium/high vs none/low) expression, CD74 (medium/high vs none/low) expression, gender (female vs male), and age (>63 years vs<=63 years) are independent prognosticators (Table 3).	('calretinin', 'Gene', (151, 161))	('CD74', 'Gene', (200, 204))	('calretinin', 'Gene', '794', (79, 89))	('medium/high', 'Var', (163, 174))	('calretinin', 'Gene', '794', (151, 161))	('calretinin', 'Gene', (79, 89))
143959	24594996	Migration inhibitory factor was also positively correlated with calretinin, CD74, D2-40, and PTEN (Supplementary Figure S2).	('PTEN', 'Gene', (93, 97))	('correlated', 'Interaction', (48, 58))	('PTEN', 'Gene', '5728', (93, 97))	('Migration inhibitory factor', 'MPA', (0, 27))	('calretinin', 'Gene', '794', (64, 74))	('CD74', 'Var', (76, 80))	('men', 'Species', '9606', (105, 108))	('calretinin', 'Gene', (64, 74))
143963	24594996	Indeed, MIF has been shown to have an important role in favouring tumorigenesis, and several research groups have shown a correlation between MIF and prognosis in hepatocellular carcinomas, gastric, ovarian, breast, colon, prostate, and non-small cell lung cancers.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (237, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (237, 264))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (163, 188))	('lung cancers', 'Phenotype', 'HP:0100526', (252, 264))	('prostate', 'Disease', (223, 231))	('hepatocellular carcinomas', 'Disease', (163, 188))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (241, 263))	('colon', 'Disease', (216, 221))	('MIF', 'Var', (142, 145))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (241, 264))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (237, 264))	('breast', 'Disease', (208, 214))	('gastric', 'Disease', (190, 197))	('tumorigenesis', 'CPA', (66, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))	('ovarian', 'Disease', (199, 206))	('ovarian', 'Disease', 'MESH:D010051', (199, 206))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (163, 188))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('correlation', 'Reg', (122, 133))	('non-small cell lung cancers', 'Disease', (237, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
143968	24594996	Our results confirmed Kao et al's findings in which calretinin positivity is associated with improved survivals.	('calretinin', 'Gene', (52, 62))	('improved', 'PosReg', (93, 101))	('survivals', 'CPA', (102, 111))	('positivity', 'Var', (63, 73))	('calretinin', 'Gene', '794', (52, 62))
143973	24594996	In some cancers (gastric, hepatocellular, prostate, ovarian, breast, colon, and non-small cell lung cancers), high expression levels of MIF and/or CD74 correlate with poor prognoses.	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('breast', 'Disease', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('gastric', 'Disease', (17, 24))	('cancers', 'Disease', (8, 15))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (84, 107))	('ovarian', 'Disease', (52, 59))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (80, 107))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('ovarian', 'Disease', 'MESH:D010051', (52, 59))	('hepatocellular', 'Disease', (26, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('lung cancers', 'Phenotype', 'HP:0100526', (95, 107))	('expression levels', 'MPA', (115, 132))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('non-small cell lung cancers', 'Disease', (80, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (84, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colon', 'Disease', (69, 74))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (80, 106))	('MIF', 'Protein', (136, 139))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (80, 107))	('prostate', 'Disease', (42, 50))	('CD74', 'Var', (147, 151))
143980	24594996	Activation of the AMPK pathway in some cancer cells has been shown to decrease cell proliferation, cell viability, and their metastatic potential, whereas inactivation of this pathway contributes to carcinogenesis in hepatic nodular foci.	('carcinogenesis in hepatic nodular foci', 'Disease', 'MESH:D020518', (199, 237))	('contributes', 'Reg', (184, 195))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cell proliferation', 'CPA', (79, 97))	('AMPK', 'molecular_function', 'GO:0047322', ('18', '22'))	('AMPK', 'molecular_function', 'GO:0004691', ('18', '22'))	('inactivation', 'Var', (155, 167))	('metastatic potential', 'CPA', (125, 145))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('AMPK', 'Gene', '5563', (18, 22))	('decrease', 'NegReg', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('hepatic nodular foci', 'Phenotype', 'HP:0011954', (217, 237))	('AMPK', 'Gene', (18, 22))	('cell viability', 'CPA', (99, 113))	('carcinogenesis in hepatic nodular foci', 'Disease', (199, 237))	('AMPK', 'molecular_function', 'GO:0050405', ('18', '22'))
143981	24594996	Furthermore, underexpression of AMPK-alpha2 was found to be associated with an undifferentiated cellular phenotype and poor prognosis, while patients with high expression of AMPK had a better prognosis in ovarian carcinoma and non-small cell lung cancer.	('underexpression', 'Var', (13, 28))	('AMPK', 'molecular_function', 'GO:0004691', ('174', '178'))	('AMPK-alpha2', 'Gene', (32, 43))	('AMPK', 'molecular_function', 'GO:0004691', ('32', '36'))	('AMPK', 'Gene', '5563', (32, 36))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (227, 253))	('AMPK-alpha2', 'Gene', '5563', (32, 43))	('AMPK', 'molecular_function', 'GO:0047322', ('174', '178'))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('AMPK', 'molecular_function', 'GO:0047322', ('32', '36'))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (205, 222))	('AMPK', 'Gene', (32, 36))	('undifferentiated cellular', 'MPA', (79, 104))	('ovarian carcinoma', 'Disease', (205, 222))	('AMPK', 'Gene', '5563', (174, 178))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (231, 253))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (227, 253))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (205, 222))	('AMPK', 'molecular_function', 'GO:0050405', ('174', '178'))	('AMPK', 'molecular_function', 'GO:0050405', ('32', '36'))	('AMPK', 'Gene', (174, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('non-small cell lung cancer', 'Disease', (227, 253))
143985	24594996	Our analyses suggest that the epithelial differentiation state is characterised by high levels of calretinin, MIF/CD74, podoplanin (D2-40) and the inhibitor of Akt signalling pathway PTEN and low level of periostin.	('periostin', 'Gene', (205, 214))	('epithelial differentiation', 'CPA', (30, 56))	('Akt', 'Gene', '207', (160, 163))	('calretinin', 'Gene', '794', (98, 108))	('PTEN', 'Gene', (183, 187))	('podoplanin', 'Gene', '10630', (120, 130))	('periostin', 'Gene', '10631', (205, 214))	('PTEN', 'Gene', '5728', (183, 187))	('Akt', 'Gene', (160, 163))	('podoplanin', 'Gene', (120, 130))	('MIF/CD74', 'Var', (110, 118))	('calretinin', 'Gene', (98, 108))	('signalling pathway', 'biological_process', 'GO:0007165', ('164', '182'))
144013	24624305	All parameters were improved among P/D patients with the exception of postoperative pain, which was similar in the two groups.	('improved', 'PosReg', (20, 28))	('postoperative pain', 'Disease', 'MESH:D010149', (70, 88))	('P/D', 'Var', (35, 38))	('pain', 'Phenotype', 'HP:0012531', (84, 88))	('postoperative pain', 'Disease', (70, 88))
144052	33613924	The patient received 3 cycles of well tolerated full dose pemetrexed (500 mg/m2) and cisplatin (100 mg/m2) with a partial response according to RECIST1.1 criteria.	('patient', 'Species', '9606', (4, 11))	('100 mg/m2', 'Var', (96, 105))	('pemetrexed', 'Chemical', 'MESH:D000068437', (58, 68))	('500 mg/m2', 'Var', (70, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
144087	33045471	The MPC subpopulation, MSLN+ and CD90+, were upregulated in ASB compared to HD suggesting an early role in pleural damage from asbestos.	('MPC', 'Chemical', '-', (4, 7))	('HD', 'Disease', 'MESH:D006816', (76, 78))	('MSLN+', 'Var', (23, 28))	('ASB', 'Chemical', 'MESH:D001194', (60, 63))	('pleural damage', 'Disease', 'MESH:D010995', (107, 121))	('ASB', 'Disease', (60, 63))	('upregulated', 'PosReg', (45, 56))	('pleural damage', 'Disease', (107, 121))	('CD90+', 'Var', (33, 38))	('asbestos', 'Chemical', 'MESH:D001194', (127, 135))
144088	33045471	The MPC subpopulation, MSLN+ and CD34+, in contrast, were detected in advanced MPM and associated with markers of poor prognosis, suggesting a predominant role during cancer progression.	('MPC', 'Chemical', '-', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('MSLN+', 'Var', (23, 28))	('CD34+', 'Var', (33, 38))	('cancer', 'Disease', (167, 173))	('associated', 'Reg', (87, 97))	('MPM', 'Disease', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
144116	33045471	In our preliminary work, we attempted to detect CD34+, CD90+, and mesothelin (MSLN)+ MPC in blood as previously described using flow cytometry.	('CD34+', 'Var', (48, 53))	('MPC', 'Chemical', '-', (85, 88))	('CD90+', 'Var', (55, 60))
144119	33045471	Our prior strategies generally focused on the detection of circulating tumor cells (CTC); however, the detection of MPCs as a screening approach provides significant advantages over CTC analysis for two reasons: (1) MPCs are more abundant than CTCs and, (2) MPCs are likely overexpressed much earlier in the disease.	('MPCs', 'Var', (216, 220))	('MPCs', 'Chemical', 'MESH:C070638', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('MPCs', 'Chemical', 'MESH:C070638', (258, 262))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('MPCs', 'Chemical', 'MESH:C070638', (216, 220))
144147	33045471	Cells were then washed with a solution containing 0.1% Tween 20 (P9416, Sigma-Aldrich, USA) and 1% Bovine Serum Albumin (BSA) (A7906, Sigma-Aldrich, USA) in PBS.	('A7906', 'Var', (127, 132))	('Tween 20', 'Chemical', 'MESH:D011136', (55, 63))	('P9416', 'Chemical', '-', (65, 70))	('P9416', 'Var', (65, 70))	('PBS', 'Chemical', '-', (157, 160))
144148	33045471	The captured cells were then immunostained with 200microL of an antibody cocktail containing either 2mg/mL of anti-CD34 AF488 (bs-8996R-A488, Bioss Antibodies, USA), 2mg/mL of anti-CD90 AF555 (bs-0778R-A555, Bioss Antibodies, USA), and 0.6 mg/mL anti-CD45 APC (17-0451-83, Invitrogen, USA) for mice-related samples or 1mg/mL of anti-CD34 AF488 (ab195013, Abcam, Canada), 0.5mg/mL of anti-CD90 AF555 (bs-10430R-A555, Bioss Antibodies, USA), and 1.2% v/v of anti-CD45 APC (555485, BD Biosciences, USA) for human-related samples.	('APC', 'Disease', 'MESH:D011125', (466, 469))	('human', 'Species', '9606', (504, 509))	('APC', 'Disease', (466, 469))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('APC', 'Disease', (256, 259))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('anti-CD34', 'Var', (328, 337))	('APC', 'cellular_component', 'GO:0005680', ('256', '259'))	('APC', 'cellular_component', 'GO:0005680', ('466', '469'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('mice', 'Species', '10090', (294, 298))	('APC', 'Disease', 'MESH:D011125', (256, 259))
144151	33045471	Fluorescent images were obtained in the channels corresponding to DAPI, AF488, AF555, and APC.	('APC', 'cellular_component', 'GO:0005680', ('90', '93'))	('DAPI', 'Chemical', 'MESH:C007293', (66, 70))	('AF488', 'Var', (72, 77))	('APC', 'Disease', 'MESH:D011125', (90, 93))	('APC', 'Disease', (90, 93))	('AF555', 'Var', (79, 84))
144162	33045471	To determine the analytical sensitivity of the device, the capture efficiency of the MesoFind device was determined by introducing RN5, H2052, and H2452 cells into the chip and the proportion of MSLN+ cells captured on-chip were reported as capture efficiency (supplementary figure 1).	('H2052', 'Var', (136, 141))	('MesoFind', 'Chemical', '-', (85, 93))	('H2452', 'Var', (147, 152))	('H2452', 'Chemical', '-', (147, 152))
144167	33045471	Due to the large degree of heterogeneity in mesothelioma, we anticipated the existence of heterogeneous subpopulations of MPC with variable expression of MSLN+, CD34+, and CD90+ in circulation (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('CD90+', 'Var', (172, 177))	('MSLN+', 'Var', (154, 159))	('CD34+', 'Var', (161, 166))	('MPC', 'Chemical', '-', (122, 125))	('mesothelioma', 'Disease', (44, 56))
144168	33045471	For simplicity, we distinguish the variable CD34 and CD90-expressing MPC through the presence or absence of signal under immunofluorescent imaging.	('CD34', 'Var', (44, 48))	('MPC', 'Chemical', '-', (69, 72))	('CD90-expressing', 'Gene', (53, 68))
144169	33045471	Hence, the contributing MPC subpopulations for our analysis are segregated based on following phenotypes: MSLN+ CD34+ CD90+, MSLN+ CD34- CD90+, MSLN+ CD34+ CD90-, MSLN+ CD34+, and MSLN+ CD90+.	('MSLN+ CD34+ CD90-', 'Var', (144, 161))	('MSLN+ CD34+', 'Var', (163, 174))	('MPC', 'Chemical', '-', (24, 27))	('MSLN+ CD34+ CD90+', 'Var', (106, 123))	('MSLN+ CD34- CD90+', 'Var', (125, 142))	('MSLN+ CD90+', 'Var', (180, 191))
144174	33045471	This optimal threshold was reached at 0.5mL/h, where the total recovery was maximized in mouse mesothelioma cells lines (RN5 104 +- 6%) and human mesothelioma cell lines (H2052 97 +- 2%, H2452 98 +- 6%) spiked in healthy human blood (Fig.	('human', 'Species', '9606', (140, 145))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('H2452', 'Chemical', '-', (187, 192))	('human', 'Species', '9606', (221, 226))	('mesothelioma', 'Disease', (146, 158))	('H2052', 'Var', (171, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (146, 158))	('H2452', 'Var', (187, 192))	('mouse', 'Species', '10090', (89, 94))	('mesothelioma', 'Disease', (95, 107))
144175	33045471	To distinguish between MPC subpopulations and leukocytes, we performed immunofluorescent staining with DAPI, CD34 (AF488), CD90 (AF555), and CD45 (APC) on-chip.	('APC', 'cellular_component', 'GO:0005680', ('147', '150'))	('APC', 'Disease', 'MESH:D011125', (147, 150))	('CD34', 'Var', (109, 113))	('DAPI', 'Chemical', 'MESH:C007293', (103, 107))	('CD90', 'Var', (123, 127))	('APC', 'Disease', (147, 150))	('MPC', 'Chemical', '-', (23, 26))	('CD45', 'Var', (141, 145))
144189	33045471	Overall, there was a noticeable increase in the total number of traditional MPCs (MSLN+ CD34+ CD90+ CD45-) in whole blood for the ASB and MPM group compared to healthy donors (Fig.	('increase', 'PosReg', (32, 40))	('ASB', 'Chemical', 'MESH:D001194', (130, 133))	('MSLN+ CD34+ CD90+ CD45-', 'Var', (82, 105))	('MPCs', 'Chemical', 'MESH:C070638', (76, 80))	('MPM', 'Var', (138, 141))
144197	33045471	After evaluating an EI threshold value for all subpopulations, the MPC subtype with MSLN+ CD90- CD34+ CD45- marker expression had the most distinct EI between ASB and MPM with a clinical sensitivity of 81% and specificity of 70% (Fig.	('MPC', 'Chemical', '-', (67, 70))	('MPM', 'Disease', (167, 170))	('ASB', 'Chemical', 'MESH:D001194', (159, 162))	('MSLN+ CD90- CD34+ CD45- marker', 'Var', (84, 114))	('ASB', 'Disease', (159, 162))
144199	33045471	On the other hand, MSLN+ CD90+ CD34- CD45- MPC subpopulations elicit higher mesothelin response in ASB individuals compared to HD, which suggests the early involvement of these MPC subtypes in tissue repair and maintenance (Fig.	('mesothelin response', 'MPA', (76, 95))	('ASB', 'Chemical', 'MESH:D001194', (99, 102))	('MPC', 'Chemical', '-', (177, 180))	('MPC', 'Chemical', '-', (43, 46))	('MSLN+ CD90+ CD34- CD45-', 'Var', (19, 42))	('HD', 'Disease', 'MESH:D006816', (127, 129))	('higher', 'PosReg', (69, 75))
144206	33045471	The MPC subpopulation of MSLN+ CD90+ CD45- displayed a marked increase in mesothelin expression for epithelioid MPM compared to biphasic MPM (Fig.	('MPC', 'Chemical', '-', (4, 7))	('mesothelin expression', 'MPA', (74, 95))	('MSLN+ CD90+ CD45-', 'Var', (25, 42))	('increase', 'PosReg', (62, 70))
144216	33045471	Overall, these findings demonstrate that circulating MSLN+ CD90+ CD45- MPC subtype increases with pleural damage related to asbestos and continues to rise during the early development of mesothelioma, while MSLN+ CD34+ CD45- MPC subtype starts rising with established MPM and are associated with more advanced mesothelioma (Fig.	('rise', 'PosReg', (150, 154))	('increases', 'PosReg', (83, 92))	('MSLN+ CD34+', 'Var', (207, 218))	('asbestos', 'Chemical', 'MESH:D001194', (124, 132))	('MPC', 'Chemical', '-', (71, 74))	('MPC', 'Chemical', '-', (225, 228))	('mesothelioma', 'Disease', (187, 199))	('mesothelioma', 'Disease', (310, 322))	('pleural damage', 'Disease', 'MESH:D010995', (98, 112))	('pleural damage', 'Disease', (98, 112))	('associated with', 'Reg', (280, 295))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (310, 322))
144228	33045471	Two MPC subtypes, MSLN+ CD90+ CD34- CD45- and MSLN+ CD90- CD34+ CD45-, had a different profile in the blood depending on the exposure to asbestos and presence of advanced mesothelioma.	('mesothelioma', 'Disease', (171, 183))	('MPC', 'Chemical', '-', (4, 7))	('mesothelioma', 'Disease', 'MESH:D008654', (171, 183))	('MSLN+ CD90+ CD34- CD45-', 'Var', (18, 41))	('MSLN+ CD90- CD34+ CD45-', 'Var', (46, 69))	('asbestos', 'Chemical', 'MESH:D001194', (137, 145))
144229	33045471	MSLN+ CD90+ CD34- CD45- exhibited a much greater level of mesothelin in asbestos-exposed individuals compared to healthy controls, even before malignancy.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('MSLN+ CD90+ CD34- CD45-', 'Var', (0, 23))	('malignancy', 'Disease', (143, 153))	('greater', 'PosReg', (41, 48))	('asbestos', 'Chemical', 'MESH:D001194', (72, 80))	('level', 'MPA', (49, 54))
144231	33045471	These findings suggest that CD90+ MPC have an early role in the recruitment of inflammatory cells after pleural damage.	('recruitment of inflammatory cells', 'MPA', (64, 97))	('pleural damage', 'Disease', 'MESH:D010995', (104, 118))	('pleural damage', 'Disease', (104, 118))	('CD90+ MPC', 'Var', (28, 37))	('MPC', 'Chemical', '-', (34, 37))
144234	33045471	In contrast, MSLN+ CD90- CD34+ CD45- are more relevant in the context of mesothelioma since this MPC subtype is extremely low in the absence of mesothelioma despite asbestos exposure, but significantly elevated in MPM and associated with markers of advanced disease characterized by high SUV on PET scan and lymph node metastasis on biopsy.	('MSLN+ CD90- CD34+ CD45-', 'Var', (13, 36))	('associated with', 'Reg', (222, 237))	('mesothelioma', 'Disease', (144, 156))	('MPC', 'Chemical', '-', (97, 100))	('mesothelioma', 'Disease', (73, 85))	('MPM', 'Disease', (214, 217))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('elevated', 'PosReg', (202, 210))	('asbestos', 'Chemical', 'MESH:D001194', (165, 173))
144235	33045471	It is not clear whether the CD34+ MPC subtypes are contributing to disease progression or simply a bystander related to malignancy.	('malignancy', 'Disease', (120, 130))	('CD34+ MPC', 'Var', (28, 37))	('contributing', 'Reg', (51, 63))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('MPC', 'Chemical', '-', (34, 37))
144236	33045471	MSLN+ CD90- CD34+ CD45- MPC subtype could potentially be helpful to monitor tumor response after therapeutic interventions and act as a predictive marker for cancer progression or recurrence.	('MPC', 'Chemical', '-', (24, 27))	('MSLN+ CD90- CD34+ CD45-', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
144251	31828040	A clear example of this occurs in follicular lymphoma where chromosomal re-arrangements result in Bcl2 overexpression, allowing escape from apoptosis and tolerance to undesired generation of otherwise physiological mutations and double strand breaks necessary to produce the variability necessary for antigen recognition site by immunoglobulin.	('Bcl2', 'Gene', '596', (98, 102))	('apoptosis', 'CPA', (140, 149))	('lymphoma', 'Disease', (45, 53))	('mutations', 'Var', (215, 224))	('lymphoma', 'Disease', 'MESH:D008223', (45, 53))	('Bcl2', 'molecular_function', 'GO:0015283', ('98', '102'))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('overexpression', 'PosReg', (103, 117))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('329', '343'))	('escape', 'CPA', (128, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('Bcl2', 'Gene', (98, 102))	('double strand breaks', 'Var', (229, 249))
144272	31828040	Taking into account all this information, a mesothelial cell losing BAP1 function becomes resistant to ROS and ferroptosis, while mesothelial cells losing NF2 function become "primed" for ferroptosis, while loss of p16 expression will be associated with impaired senescence-driven ferroptosis resistance.	('NF2', 'Gene', (155, 158))	('expression', 'MPA', (219, 229))	('resistant', 'MPA', (90, 99))	('loss', 'Var', (207, 211))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('senescence', 'biological_process', 'GO:0010149', ('261', '271'))	('p16', 'Gene', '1029', (215, 218))	('ferroptosis', 'biological_process', 'GO:0097707', ('279', '290'))	('BAP1', 'Gene', '8314', (68, 72))	('impaired senescence-driven ferroptosis', 'MPA', (254, 292))	('NF2', 'Gene', '4771', (155, 158))	('ferroptosis', 'biological_process', 'GO:0097707', ('111', '122'))	('BAP1', 'Gene', (68, 72))	('ferroptosis', 'biological_process', 'GO:0097707', ('186', '197'))	('p16', 'Gene', (215, 218))
144280	31828040	Collectively, these observations suggest that tumors with alterations in both pathways, NF2 and BAP1, which occur in a significant fraction of MPM patients according to TCGA data (Figure 1B), might be more resistant to ferroptosis.	('NF2', 'Gene', '4771', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BAP1', 'Gene', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('MPM', 'Disease', (143, 146))	('ferroptosis', 'biological_process', 'GO:0097707', ('219', '230'))	('patients', 'Species', '9606', (147, 155))	('NF2', 'Gene', (88, 91))	('tumors', 'Disease', (46, 52))	('BAP1', 'Gene', '8314', (96, 100))	('alterations', 'Var', (58, 69))
144286	31828040	Remarkably, in a recent study ferroptosis was observed in cells treated with some open-chain epothilones small molecules in a manner similar to that of erastin.	('epothilones', 'Chemical', 'MESH:D034261', (93, 104))	('ferroptosis', 'Disease', (30, 41))	('erastin', 'Chemical', 'MESH:C477224', (152, 159))	('small molecules', 'Var', (105, 120))	('ferroptosis', 'biological_process', 'GO:0097707', ('30', '41'))
144288	31828040	Given the propensity of mesenchymal cells to be sensitive to ferroptosis induction, it is tempting to suggest that mesothelioma patients with high S-score might benefit from this novel therapy.	('benefit', 'PosReg', (161, 168))	('mesothelioma', 'Disease', (115, 127))	('ferroptosis', 'biological_process', 'GO:0097707', ('61', '72'))	('high', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('S-score', 'Gene', (147, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (115, 127))
144295	30669483	In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed.	('mesothelioma', 'Disease', (45, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('mutant', 'Var', (99, 105))	('human', 'Species', '9606', (39, 44))	('BAP1', 'Gene', (78, 82))
144296	30669483	The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('BAP1', 'Gene', (4, 8))	('mutant', 'Var', (9, 15))	('less', 'NegReg', (41, 45))	('sensitive', 'MPA', (46, 55))
144297	30669483	Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine.	('BAP1', 'Gene', (13, 17))	('gemcitabine', 'Chemical', 'MESH:C056507', (69, 80))	('resistance', 'MPA', (42, 52))	('increased', 'PosReg', (32, 41))	('Silencing', 'Var', (0, 9))
144298	30669483	Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells.	('G1 phase', 'biological_process', 'GO:0051318', ('59', '67'))	('accumulation', 'PosReg', (68, 80))	('S-phase', 'MPA', (123, 130))	('mutant', 'Var', (151, 157))	('gemcitabine', 'Chemical', 'MESH:C056507', (35, 46))	('S-phase', 'biological_process', 'GO:0051320', ('123', '130'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('increased', 'PosReg', (106, 115))	('Sub-G1 phase', 'CPA', (55, 67))
144299	30669483	Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('mutant', 'Var', (118, 124))	('BAP1', 'Gene', (101, 105))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('BAP1', 'Gene', (113, 117))
144301	30669483	Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('decreased', 'NegReg', (14, 23))	('BAP1', 'Gene', (107, 111))	('double-strand breaks', 'MPA', (50, 70))	('gemcitabine', 'Chemical', 'MESH:C056507', (87, 98))	('DNA damage', 'MPA', (24, 34))	('mutant', 'Var', (112, 118))
144308	30669483	Among the latest advances towards better understanding of this tumour, the discovery of BAP1 gene mutations in MMe cells is one of the most intriguing due to potential translational implications.	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (98, 107))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('BAP1', 'Gene', (88, 92))	('tumour', 'Disease', (63, 69))
144311	30669483	Knockout of BAP1 in HeLa cervical cancer and renal cancer cells exposed to ionising radiation resulted in increased cell death.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('renal cancer', 'Disease', (45, 57))	('cell death', 'CPA', (116, 126))	('cell death', 'biological_process', 'GO:0008219', ('116', '126'))	('renal cancer', 'Phenotype', 'HP:0009726', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal cancer', 'Disease', 'MESH:D007680', (45, 57))	('Knockout', 'Var', (0, 8))	('HeLa cervical cancer', 'Disease', (20, 40))	('HeLa cervical cancer', 'Disease', 'MESH:D002583', (20, 40))	('BAP1', 'Gene', (12, 16))
144313	30669483	Loss of BAP1 due to mutations and deletions has been reported in various cancers including lung, renal, breast, uveal melanoma, and MMe.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('cancers', 'Disease', (73, 80))	('lung', 'Disease', (91, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('breast', 'Disease', (104, 110))	('deletions', 'Var', (34, 43))	('MMe', 'Disease', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('renal', 'Disease', (97, 102))	('uveal melanoma', 'Disease', (112, 126))	('Loss', 'NegReg', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('BAP1', 'Gene', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('mutations', 'Var', (20, 29))
144314	30669483	reported somatic BAP1 mutations in malignant pleural mesothelioma and Testa et al also found MMe patients with germline BAP1 mutations in the same year.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (45, 65))	('malignant pleural mesothelioma', 'Disease', (35, 65))	('mutations', 'Var', (22, 31))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (35, 65))	('BAP1', 'Gene', (17, 21))	('patients', 'Species', '9606', (97, 105))
144316	30669483	BAP1 mutations are associated with worse prognosis in uveal and cutaneous melanoma and renal cell carcinoma whereas they mark better outcomes for MMe patients.	('cutaneous melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 107))	('BAP1', 'Gene', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('patients', 'Species', '9606', (150, 158))	('uveal', 'Disease', (54, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))
144317	30669483	The findings of this research are of high significance for clinical practice as they could be used to stratify MMe patients prior to treatment and avoid the use of a toxic drug as second line therapy that is unlikely to be effective in BAP1 mutant patients.	('patients', 'Species', '9606', (115, 123))	('mutant', 'Var', (241, 247))	('MMe', 'Disease', (111, 114))	('patients', 'Species', '9606', (248, 256))	('BAP1', 'Gene', (236, 240))
144318	30669483	Here, evidence has been provided that supports the view that BAP1 inactivation in MMe cells confers resistance to gemcitabine and provides further insight into the role of BAP1 in the cell cycle, cell death and DNA repair mechanisms in MMe cells.	('BAP1', 'Gene', (61, 65))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('resistance to gemcitabine', 'MPA', (100, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('inactivation', 'Var', (66, 78))	('cell cycle', 'biological_process', 'GO:0007049', ('184', '194'))	('DNA repair', 'biological_process', 'GO:0006281', ('211', '221'))	('cell death', 'biological_process', 'GO:0008219', ('196', '206'))
144322	30669483	Silencing of BAP1 expression in BAP1 WT PPM-Mill and REN cells:demonstrated using Western blot analysis and qRT-PCR (Figure 1B):led to a significant reduction in sensitivity to gemcitabine (Figure 1C).	('BAP1', 'Gene', (13, 17))	('reduction', 'NegReg', (149, 158))	('sensitivity to gemcitabine', 'MPA', (162, 188))	('REN', 'Gene', (53, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (177, 188))	('Silencing', 'Var', (0, 9))	('REN', 'Gene', '5972', (53, 56))
144325	30669483	Results demonstrated a significant increase of the percentage of cells in the Sub-G1 phase after gemcitabine treatment for PPM-Mill (Figure 2A) and REN (Figure 2B) cell lines (BAP1 WT) to a greater level than in Phi (Figure 2C) and Rob (Figure 2D) cells (BAP1 mutant) (Figure 2, compare Sub-G1 phase cell populations).	('G1 phase', 'biological_process', 'GO:0051318', ('291', '299'))	('increase', 'PosReg', (35, 43))	('cells in the Sub-G1 phase', 'CPA', (65, 90))	('REN', 'Gene', (148, 151))	('G1 phase', 'biological_process', 'GO:0051318', ('82', '90'))	('Phi', 'Gene', '2821', (212, 215))	('Phi', 'Gene', (212, 215))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('REN', 'Gene', '5972', (148, 151))	('PPM-Mill', 'Var', (123, 131))
144328	30669483	Notably, these results indicate that gemcitabine induced more cell death in the BAP1 WT cells compared to BAP1 mutant cells.	('mutant', 'Var', (111, 117))	('cell death', 'CPA', (62, 72))	('gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))
144332	30669483	Late apoptotic cell population significantly increased by approximately 6-fold in PPM-Mill cells and 2-fold in REN cells, whereas there was no significant increase in Phi and Rob cell lines (Figure 3A,B, compared to Figure 3C,D).	('increased', 'PosReg', (45, 54))	('REN', 'Gene', (111, 114))	('Phi', 'Gene', (167, 170))	('Phi', 'Gene', '2821', (167, 170))	('REN', 'Gene', '5972', (111, 114))	('Late apoptotic cell population', 'CPA', (0, 30))	('PPM-Mill', 'Var', (82, 90))
144334	30669483	DNA damage was assessed in BAP1 WT (Figure 4A,B) and BAP1 mutated cell lines (Figure 4C,D) treated with gemcitabine (0.1 microM) for 24 h. Increased DNA double-strand breaks and gamma-Eta2Alpha.Chi phosphorylation were evident in gemcitabine-treated compared to non-treated PPM-Mill cells, whereas no ATM phosphorylation was detected in these cells under the same conditions.	('ATM', 'Gene', (301, 304))	('gemcitabine', 'Chemical', 'MESH:C056507', (230, 241))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('gemcitabine-treated', 'Var', (230, 249))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('ATM', 'Gene', '472', (301, 304))	('phosphorylation', 'biological_process', 'GO:0016310', ('305', '320'))	('gamma-Eta2Alpha.Chi phosphorylation', 'CPA', (178, 213))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))
144338	30669483	Malignant mesothelioma cells with functional BAP1 were more sensitive to gemcitabine treatment compared to cells bearing mutated and non-functional BAP1.	('functional', 'Var', (34, 44))	('BAP1', 'Gene', (45, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('more', 'PosReg', (55, 59))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))	('sensitive to gemcitabine treatment', 'MPA', (60, 94))
144339	30669483	The results obtained from the analysis of cell viability indicate that functional BAP1 results in a better response to gemcitabine, that its status differentially affects the cell cycle progression in gemcitabine-treated versus non-treated cells and that BAP1 inactivation is linked to decreased DNA damage response after gemcitabine treatment.	('gemcitabine', 'Chemical', 'MESH:C056507', (322, 333))	('gemcitabine', 'Chemical', 'MESH:C056507', (119, 130))	('BAP1', 'Gene', (82, 86))	('inactivation', 'Var', (260, 272))	('response to gemcitabine', 'MPA', (107, 130))	('BAP1', 'Gene', (255, 259))	('DNA', 'cellular_component', 'GO:0005574', ('296', '299'))	('better', 'PosReg', (100, 106))	('cell cycle', 'biological_process', 'GO:0007049', ('175', '185'))	('decreased', 'NegReg', (286, 295))	('DNA damage response', 'biological_process', 'GO:0006974', ('296', '315'))	('gemcitabine', 'Chemical', 'MESH:C056507', (201, 212))	('cell cycle progression', 'CPA', (175, 197))	('DNA damage response', 'MPA', (296, 315))	('affects', 'Reg', (163, 170))	('functional', 'Var', (71, 81))	('response to gemcitabine', 'biological_process', 'GO:0036272', ('107', '130'))
144343	30669483	Increased NF-kappaB transcriptional activity and consequent repression of hCNT1 expression in BAP1 defective cells offers a potential explanation of the observed gemcitabine resistance in BAP1 mutant cells.	('BAP1', 'Gene', (188, 192))	('transcriptional activity', 'MPA', (20, 44))	('hCNT1', 'Gene', (74, 79))	('NF-kappaB', 'Gene', '4790', (10, 19))	('repression', 'NegReg', (60, 70))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('mutant', 'Var', (193, 199))	('Increased', 'PosReg', (0, 9))	('NF-kappaB', 'Gene', (10, 19))	('hCNT1', 'Gene', '9154', (74, 79))
144347	30669483	In uveal melanoma cells, BAP1 knockdown causes G1 arrest most likely through HCF1-mediated effects that involve histone deubiquitination and effects on E2F1-dependent transcription.	('HCF1', 'Gene', (77, 81))	('E2F1', 'Gene', '1869', (152, 156))	('causes', 'Reg', (40, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('BAP1', 'Gene', (25, 29))	('effects', 'Reg', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('E2F1', 'Gene', (152, 156))	('G1 arrest', 'Disease', (47, 56))	('histone deubiquitination', 'MPA', (112, 136))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('HCF1', 'Gene', '3054', (77, 81))	('histone deubiquitination', 'biological_process', 'GO:0016578', ('112', '136'))	('knockdown', 'Var', (30, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
144351	30669483	In uveal melanoma cells, depletion of BAP1 resulted in a 20-40% reduction in cell cycle progression; however, it seems that this change was of a transient nature.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('BAP1', 'Gene', (38, 42))	('reduction', 'NegReg', (64, 73))	('cell cycle progression', 'CPA', (77, 99))	('depletion', 'Var', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
144356	30669483	It is intriguing therefore to hypothesise that BAP1 could cause cell death through apoptosis, necrosis or necroptosis which needs to be investigated further in order to evaluate potential therapeutic targets involved in this pathway such as RIPK1, which can be inhibited through Necrostatin-1.	('necroptosis', 'biological_process', 'GO:0097528', ('106', '117'))	('necrosis', 'biological_process', 'GO:0008219', ('94', '102'))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('RIPK1', 'Gene', (241, 246))	('apoptosis', 'CPA', (83, 92))	('necrosis', 'Disease', 'MESH:D009336', (94, 102))	('necrosis', 'biological_process', 'GO:0008220', ('94', '102'))	('RIPK1', 'Gene', '8737', (241, 246))	('BAP1', 'Var', (47, 51))	('necroptosis', 'CPA', (106, 117))	('cell death', 'CPA', (64, 74))	('necrosis', 'Disease', (94, 102))	('necrosis', 'biological_process', 'GO:0070265', ('94', '102'))	('necrosis', 'biological_process', 'GO:0019835', ('94', '102'))	('necrosis', 'biological_process', 'GO:0001906', ('94', '102'))	('cause', 'Reg', (58, 63))	('necroptosis', 'biological_process', 'GO:0070266', ('106', '117'))
144361	30669483	In cholangiocarcinoma, low BAP1 status conferred greater sensitivity to gemcitabine.	('cholangiocarcinoma', 'Disease', (3, 21))	('greater', 'PosReg', (49, 56))	('low', 'Var', (23, 26))	('BAP1', 'Gene', (27, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('sensitivity to gemcitabine', 'MPA', (57, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))
144362	30669483	The results presented herein demonstrate that in BAP1 WT cells gemcitabine induced an increase in DNA double strand breaks, whereas in cells with mutant BAP1 gemcitabine did not have the same effect.	('gemcitabine', 'Chemical', 'MESH:C056507', (158, 169))	('increase', 'PosReg', (86, 94))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('mutant', 'Var', (146, 152))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('BAP1', 'Gene', (153, 157))	('DNA double strand breaks', 'MPA', (98, 122))
144363	30669483	These differences are potentially due to specific dual role that BAP1 has in mesothelioma compared to other types of cancer, where BAP1 mutations increase predisposition to this cancer, but certain mutations can be associated with longer survival.	('BAP1', 'Gene', (131, 135))	('mesothelioma', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('increase', 'PosReg', (146, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (117, 123))
144365	30669483	The augmented resistance of mutated BAP1 cells seems to go against the clinical evidence that patients with MMe carrying BAP1 mutations survive longer.	('augmented', 'PosReg', (4, 13))	('resistance', 'MPA', (14, 24))	('patients', 'Species', '9606', (94, 102))	('BAP1', 'Gene', (121, 125))	('mutations', 'Var', (126, 135))
144367	30669483	The different sensitivity to DNA damage between BAP1 mutant and WT also suggests BAP1 status could be the basis of selection of patients for treatment with poly ADP ribose polymerase (PARP) inhibitors, given that patients with BAP1 mutated or BAP1 WT (less sensitive and more sensitive to DNA damage respectively) are likely to respond differently to this type of inhibitors.	('BAP1', 'Gene', (243, 247))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('PARP', 'Gene', '142', (184, 188))	('mutated', 'Var', (232, 239))	('BAP1', 'Gene', (48, 52))	('poly ADP ribose polymerase', 'Gene', (156, 182))	('BAP1', 'Gene', (227, 231))	('poly ADP ribose polymerase', 'Gene', '142', (156, 182))	('DNA', 'cellular_component', 'GO:0005574', ('289', '292'))	('mutant', 'Var', (53, 59))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (128, 136))	('PARP', 'Gene', (184, 188))
144368	30669483	Finally, it has been already proposed that defective DNA repair leads to chromosomal instability and higher mutational load, which potentially provides a rationale for patient stratification with regard to immunotherapy, according to BAP1 status.	('chromosomal instability', 'MPA', (73, 96))	('leads', 'Reg', (64, 69))	('higher', 'PosReg', (101, 107))	('patient', 'Species', '9606', (168, 175))	('chromosomal instability', 'Phenotype', 'HP:0040012', (73, 96))	('DNA repair', 'biological_process', 'GO:0006281', ('53', '63'))	('DNA repair', 'Gene', (53, 63))	('mutational load', 'MPA', (108, 123))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('defective', 'Var', (43, 52))
144537	22778767	However, during this period, tumour cells may undergo mutations caused by their genetic instability, potentially generating variants that can escape the immune system, by either evading the induction of an immune response or by inhibiting antitumour responses via a variety of immune suppressive mechanisms.	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('tumour', 'Disease', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('variants', 'Var', (124, 132))	('tumour', 'Disease', (243, 249))	('evading', 'NegReg', (178, 185))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('immune response', 'biological_process', 'GO:0006955', ('206', '221'))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('inhibiting', 'NegReg', (228, 238))	('induction', 'MPA', (190, 199))
144577	22778767	PA2024 consists of a prostate antigen, prostatic acid phosphatase that is fused to GM-CSF, an immune-cell activator.	('phosphatase', 'molecular_function', 'GO:0016791', ('54', '65'))	('GM-CSF', 'Gene', (83, 89))	('prostatic acid phosphatase', 'Gene', '55', (39, 65))	('prostatic acid phosphatase', 'Gene', (39, 65))	('GM-CSF', 'Gene', '1437', (83, 89))	('PA2024', 'Var', (0, 6))
144599	22778767	Therefore, combating immunosuppression through modulation of these cell types will be an important key to increase the efficacy of immunotherapy and should lead to better prognosis for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('modulation', 'Var', (47, 57))	('increase', 'PosReg', (106, 114))	('cancer', 'Disease', (185, 191))	('lead', 'Reg', (156, 160))
144605	22778767	MDSCs can inhibit the antitumour immune response in several ways.	('MDSCs', 'Var', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('immune response', 'biological_process', 'GO:0006955', ('33', '48'))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('inhibit', 'NegReg', (10, 17))
144614	22778767	MDSCs can indirectly enhance immune suppression via the induction of Tregs.	('MDSCs', 'Var', (0, 5))	('enhance', 'PosReg', (21, 28))	('immune suppression', 'CPA', (29, 47))	('Tregs', 'CPA', (69, 74))	('Tregs', 'Chemical', '-', (69, 74))
144617	22778767	The treatment of tumour-bearing mice with 5FU led to a decrease in the number of MDSC in the spleens and tumour beds of animals whereas no significant effect on T cells, NK cells, DCs, or B cells was noted.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('MDSC', 'CPA', (81, 85))	('5FU', 'Var', (42, 45))	('DC', 'Gene', '20299', (180, 182))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('tumour', 'Disease', (105, 111))	('men', 'Species', '9606', (9, 12))	('decrease', 'NegReg', (55, 63))	('mice', 'Species', '10090', (32, 36))	('tumour', 'Disease', (17, 23))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('5FU', 'Chemical', 'MESH:D005472', (42, 45))
144621	22778767	The production of ROS by MDSCs, which is responsible for most of the adverse effects on T cells, is highly depending upon cyclooxygenase-2 (COX-2) enzyme activity.	('enzyme activity', 'molecular_function', 'GO:0003824', ('147', '162'))	('MDSCs', 'Var', (25, 30))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('COX-2', 'Gene', (140, 145))	('cyclooxygenase-2', 'Gene', '5743', (122, 138))	('cyclooxygenase-2', 'Gene', (122, 138))	('COX-2', 'Gene', '5743', (140, 145))
144662	22778767	A recent study revealed that activation of macrophages by the infusion of antibodies against CD40 may induce macrophage-mediated tumour regression in 30% of cases in both a mouse model for pancreatic cancer and in patients with pancreatic cancer.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('pancreatic cancer', 'Disease', (189, 206))	('activation', 'PosReg', (29, 39))	('CD40', 'Gene', '21939', (93, 97))	('patients', 'Species', '9606', (214, 222))	('pancreatic cancer', 'Disease', 'MESH:D010190', (189, 206))	('antibodies', 'Var', (74, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CD40', 'Gene', (93, 97))	('tumour regression', 'Disease', (129, 146))	('mouse', 'Species', '10090', (173, 178))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (189, 206))	('pancreatic cancer', 'Disease', (228, 245))	('tumour regression', 'Disease', 'MESH:D009365', (129, 146))	('pancreatic cancer', 'Disease', 'MESH:D010190', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
144664	22778767	Blockade of TGF-beta has been shown to enhance tumour vaccine efficacy, but at this moment the exact mechanism has not been unravelled yet.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('TGF-beta', 'Gene', '7040', (12, 20))	('men', 'Species', '9606', (86, 89))	('Blockade', 'Var', (0, 8))	('TGF-beta', 'Gene', (12, 20))	('tumour', 'Disease', (47, 53))	('enhance', 'PosReg', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
144665	22778767	Since CCL2 plays a major role in the recruitment of TAMs, anti-CCL2 would be a logical step in preventing this recruitment.	('CCL', 'molecular_function', 'GO:0044101', ('6', '9'))	('CCL', 'molecular_function', 'GO:0044101', ('63', '66'))	('men', 'Species', '9606', (118, 121))	('recruitment', 'MPA', (37, 48))	('men', 'Species', '9606', (44, 47))	('anti-CCL2', 'Var', (58, 67))	('TAMs', 'Chemical', 'MESH:D013629', (52, 56))
144713	22778767	Our data showed that metronomic administration of low-dose CTX has a strong immune-modulating effect in vivo.	('immune-modulating', 'MPA', (76, 93))	('low-dose', 'Var', (50, 58))	('CTX', 'Disease', (59, 62))	('CTX', 'Disease', 'MESH:D019294', (59, 62))
144720	22778767	Recently, p300 was found to be an important target for modulation of host Foxp3+ Treg functions, and an inhibition of p300 using a small molecule inhibitor, C646 (p300i), impaired Foxp3 acetylation and inhibited Treg function.	('Treg function', 'CPA', (212, 225))	('p300', 'Gene', '2033', (163, 167))	('Foxp3', 'Gene', '50943', (180, 185))	('acetylation', 'MPA', (186, 197))	('p300', 'Gene', '2033', (118, 122))	('p300', 'Gene', (10, 14))	('Foxp3', 'Gene', (180, 185))	('Foxp3', 'Gene', '50943', (74, 79))	('impaired', 'NegReg', (171, 179))	('Foxp3', 'Gene', (74, 79))	('inhibition', 'Var', (104, 114))	('p300', 'Gene', (118, 122))	('p300', 'Gene', (163, 167))	('inhibited', 'NegReg', (202, 211))	('p300', 'Gene', '2033', (10, 14))
144753	21620512	The prognosis is worse in male patients and in patients with extensive disease, poor performance status, elevated white-cell counts, anemia, thrombocytosis, sarcomatoid histologic findings, or high standardized uptake value ratios on Positron Emission Tomography (PET).	('high', 'Var', (193, 197))	('worse', 'Reg', (17, 22))	('elevated', 'PosReg', (105, 113))	('elevated white-cell counts', 'Phenotype', 'HP:0001974', (105, 131))	('thrombocytosis', 'Disease', (141, 155))	('sarcomatoid histologic findings', 'Phenotype', 'HP:0100242', (157, 188))	('sarcomatoid', 'Disease', 'MESH:C538614', (157, 168))	('patients', 'Species', '9606', (47, 55))	('thrombocytosis', 'Disease', 'MESH:D013922', (141, 155))	('anemia', 'Disease', (133, 139))	('uptake', 'biological_process', 'GO:0098657', ('211', '217'))	('patients', 'Species', '9606', (31, 39))	('thrombocytosis', 'Phenotype', 'HP:0001894', (141, 155))	('anemia', 'Disease', 'MESH:D000740', (133, 139))	('uptake', 'biological_process', 'GO:0098739', ('211', '217'))	('sarcomatoid', 'Disease', (157, 168))	('anemia', 'Phenotype', 'HP:0001903', (133, 139))	('standardized uptake value ratios', 'MPA', (198, 230))
144842	21620512	The results of these clinical trials demonstrate that EGFR inhibitors have no efficacy in pleural mesothelioma, which is most likely due to absence of sensitizing mutations in the EGFR tyrosine kinase domain.	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('mutations', 'Var', (163, 172))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (90, 110))	('EGFR', 'Gene', '1956', (54, 58))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (90, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('EGFR', 'Gene', (54, 58))	('pleural mesothelioma', 'Disease', (90, 110))
144900	21620512	Cell cycle G2 checkpoint abrogation is an attractive strategy for sensitizing cancer cells to DNA-damaging anticancer agents without increasing adverse effects on normal cells.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('abrogation', 'Var', (25, 35))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
144913	21620512	In preclinical studies, SS1P is cytotoxic to mesothelin expressing cell lines and causes regression of mesothelin expressing tumor xenografts in nude mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('nude mice', 'Species', '10090', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('SS1P', 'Var', (24, 28))	('SS1P', 'Chemical', 'MESH:C474515', (24, 28))	('regression', 'CPA', (89, 99))
144919	21620512	Since SS1P given as bolus infusion has a prolonged half-life, approximately 8 hours, and the continuous infusion showed no significant benefit over bolus dosing, the bolus infusion schedule has been adopted for future clinical trials.	('half-life', 'MPA', (51, 60))	('SS1P', 'Var', (6, 10))	('SS1P', 'Chemical', 'MESH:C474515', (6, 10))
144924	21620512	MORAb-009 kills mesothelin expressing cell lines via antibody dependent cellular cytotoxicity and it inhibits the binding of mesothelin to CA-125.	('cytotoxicity', 'Disease', (81, 93))	('mesothelin', 'Protein', (125, 135))	('antibody', 'molecular_function', 'GO:0003823', ('53', '61'))	('antibody', 'cellular_component', 'GO:0019814', ('53', '61'))	('CA-125', 'Gene', (139, 145))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('CA-125', 'Gene', '94025', (139, 145))	('binding', 'Interaction', (114, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('inhibits', 'NegReg', (101, 109))	('antibody dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('53', '93'))	('antibody', 'cellular_component', 'GO:0019815', ('53', '61'))	('antibody', 'cellular_component', 'GO:0042571', ('53', '61'))	('MORAb-009', 'Chemical', 'MESH:C526187', (0, 9))	('MORAb-009', 'Var', (0, 9))
144934	21620512	Based on the tolerability and immune activation, CRS-207 may be an attractive agent to treat mesothelioma either alone or in combination with other agents.	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('CRS', 'Chemical', 'MESH:D002857', (49, 52))	('mesothelioma', 'Disease', (93, 105))	('CRS-207', 'Var', (49, 56))
144939	21620512	The trial demonstrated proof of principle with 11/20 patients having transfer of the HSVtk gene into their tumors and 2 patients had a long term survival over 6.5 years.	('HSVtk', 'Gene', (85, 90))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (120, 128))	('transfer', 'Var', (69, 77))
144942	21620512	The trial demonstrated gene transfer, humoral antitumor immune responses, and disease stability in 3 of 10 patients at 2 months after a single dose of Ad.IFN-beta.	('IFN-beta', 'Gene', '3456', (154, 162))	('IFN-beta', 'Gene', (154, 162))	('disease stability', 'CPA', (78, 95))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Disease', (50, 55))	('gene', 'Var', (23, 27))
144956	19330256	AMP may present local recurrence, but it has no potential for malignant transformation.	('local recurrence', 'CPA', (16, 32))	('AMP', 'Chemical', '-', (0, 3))	('AMP', 'Var', (0, 3))
144997	19330256	Immunohistochemistry revealed positivity for calretinin, which labels mesothelial cells in 60 to 100% of cases and rarely labels adenocarcinomas (0 to 28%).	('adenocarcinomas', 'Disease', (129, 144))	('positivity', 'Var', (30, 40))	('calretinin', 'Gene', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('calretinin', 'Gene', '794', (45, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('adenocarcinomas', 'Disease', 'MESH:D000230', (129, 144))
145000	19330256	Thus, negativity of this marker is of no help for differentiation between adenomatoid tumors and adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('adenocarcinomas', 'Disease', 'MESH:D000230', (97, 112))	('negativity', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinomas', 'Disease', (97, 112))	('adenomatoid tumors', 'Disease', (74, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (74, 92))
145157	31399037	Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('viability', 'CPA', (27, 36))	('Dropwort', 'Var', (9, 17))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (101, 111))	('affected', 'Reg', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Cisplatin', 'Chemical', 'MESH:D002945', (87, 96))
145174	31399037	MPM is one of a few cancers that harbor mutations in Hippo pathway genes.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (40, 49))	('MPM', 'Disease', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('Hippo pathway genes', 'Gene', (53, 72))
145175	31399037	Accordingly to the COSMIC database, the genes that are most frequently mutated in MPM are loss of function mutations of tumor suppressor genes such as cyclin dependent kinase inhibitor 2A gene (CDNKN2A), TP53, Neurofibromin 2 (NF2) and BRACA1 associated protein gene 1 (BAP1).	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('151', '184'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('loss of function', 'NegReg', (90, 106))	('BAP1', 'Gene', (270, 274))	('TP53', 'Gene', (204, 208))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (151, 187))	('CDNKN2A', 'Gene', (194, 201))	('tumor', 'Disease', (120, 125))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('168', '184'))	('Neurofibromin 2', 'Gene', '4771', (210, 225))	('TP53', 'Gene', '7157', (204, 208))	('BRACA1 associated protein gene 1', 'Gene', '8314', (236, 268))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Neurofibromin 2', 'Gene', (210, 225))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('NF2', 'Gene', '4771', (227, 230))	('mutations', 'Var', (107, 116))	('NF2', 'Gene', (227, 230))	('BAP1', 'Gene', '8314', (270, 274))	('cyclin dependent kinase inhibitor 2A', 'Gene', (151, 187))	('MPM', 'Disease', (82, 85))	('BRACA1 associated protein gene 1', 'Gene', (236, 268))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
145176	31399037	Transcriptome and whole-exome sequencing have revealed that NF2 is frequently mutated in tissues of MPM patients together with a copy number loss and/or loss of expression of NF2, LATS1 and LATS2.	('NF2', 'Gene', '4771', (60, 63))	('LATS2', 'Gene', '26524', (190, 195))	('expression', 'MPA', (161, 171))	('loss of', 'NegReg', (153, 160))	('NF2', 'Gene', '4771', (175, 178))	('patients', 'Species', '9606', (104, 112))	('NF2', 'Gene', (60, 63))	('mutated', 'Var', (78, 85))	('MPM', 'Disease', (100, 103))	('NF2', 'Gene', (175, 178))	('LATS1', 'Gene', (180, 185))	('LATS2', 'Gene', (190, 195))	('LATS1', 'Gene', '9113', (180, 185))
145178	31399037	The inactivation of NF2 and LATS2 in MPM prevents the phosphorylation of the transcriptional co-activators YAP/TAZ at Serine 127.	('Serine', 'Chemical', 'MESH:D012694', (118, 124))	('inactivation', 'Var', (4, 16))	('NF2', 'Gene', (20, 23))	('YAP', 'Gene', (107, 110))	('prevents', 'NegReg', (41, 49))	('LATS2', 'Gene', (28, 33))	('NF2', 'Gene', '4771', (20, 23))	('LATS2', 'Gene', '26524', (28, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('YAP', 'Gene', '10413', (107, 110))	('phosphorylation', 'MPA', (54, 69))
145201	31399037	Aliquots of cells were incubated for 15 min with Annexin V FITC (0.2 mug/ml) (Abcam, ab-63,556) and PI (5 mg/ml) (Invitrogen).	('0.2', 'Var', (65, 68))	('Annexin V', 'Gene', '308', (49, 58))	('Annexin V', 'Gene', (49, 58))	('mug', 'molecular_function', 'GO:0043739', ('69', '72'))
145289	31399037	5c, MSTO-211H cells exhibited a reduction in the phospho protein levels of mTOR, p70S6 and S6 after 24 h of treatment with 50 mug/ml of Fil.v.	('p70S6', 'Var', (81, 86))	('mug', 'molecular_function', 'GO:0043739', ('126', '129'))	('reduction', 'NegReg', (32, 41))	('MSTO-211H', 'CellLine', 'CVCL:1430', (4, 13))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('mTOR', 'Gene', (75, 79))	('phospho protein levels', 'MPA', (49, 71))	('mTOR', 'Gene', '2475', (75, 79))
145299	31399037	YAP and TAZ are transcriptional co-activators that interact with the TEAD family of transcription factors and their aberrant activity leads to unrestrained cell proliferation, in several cancers types, including MPM.	('leads to', 'Reg', (134, 142))	('YAP', 'Gene', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('aberrant activity', 'Var', (116, 133))	('unrestrained cell proliferation', 'CPA', (143, 174))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('MPM', 'Disease', (212, 215))	('YAP', 'Gene', '10413', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))
145304	31399037	Furthermore, we observed a similar reduction of phosphorylation on NF-KappaB on Ser-865 and Ser-869 and of the Focal Adhesion Kinase (FAK) on p-Tyr-397 (Fig.	('NF-KappaB', 'Protein', (67, 76))	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('p-Tyr-397', 'Var', (142, 151))	('Ser-865', 'Var', (80, 87))	('Ser-869', 'Var', (92, 99))	('FAK', 'Gene', '5747', (134, 137))	('Ser', 'cellular_component', 'GO:0005790', ('92', '95'))	('Focal Adhesion Kinase', 'Gene', '5747', (111, 132))	('phosphorylation', 'MPA', (48, 63))	('FAK', 'Gene', (134, 137))	('Ser', 'Chemical', 'MESH:D012694', (80, 83))	('FAK', 'molecular_function', 'GO:0004717', ('134', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('Focal Adhesion', 'cellular_component', 'GO:0005925', ('111', '125'))	('Ser', 'Chemical', 'MESH:D012694', (92, 95))	('Focal Adhesion Kinase', 'Gene', (111, 132))	('reduction', 'NegReg', (35, 44))	('Tyr', 'Chemical', 'MESH:D014443', (144, 147))
145354	31399037	In particular, silencing of YAP and TAZ caused increased effects of Fil.v.	('Fil.v', 'MPA', (68, 73))	('effects', 'MPA', (57, 64))	('YAP', 'Gene', (28, 31))	('silencing', 'Var', (15, 24))	('increased', 'PosReg', (47, 56))	('YAP', 'Gene', '10413', (28, 31))
145363	31399037	Emerging lines of evidence link metabolic alterations and mTOR aberrant activation with sustained pro-tumorigenic activities of the HIPPO tumor suppressor pathway.	('activation', 'PosReg', (72, 82))	('mTOR', 'Gene', (58, 62))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('aberrant', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mTOR', 'Gene', '2475', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
145366	31399037	This double inactivation of two tumor suppressors leads to the aberrant activation of the two HIPPO oncogenic transducers, YAP and TAZ, which enhance the transcriptional activity of TEAD family of potent transcription factors.	('activation', 'PosReg', (72, 82))	('transcriptional activity', 'MPA', (154, 178))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('YAP', 'Gene', '10413', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('transcription', 'biological_process', 'GO:0006351', ('204', '217'))	('HIPPO oncogenic transducers', 'Gene', (94, 121))	('enhance', 'PosReg', (142, 149))	('double inactivation', 'Var', (5, 24))	('tumor', 'Disease', (32, 37))	('YAP', 'Gene', (123, 126))
145367	31399037	Excessive nuclear accumulation of YAP/TAZ is critical for its oncogenic co-transcriptional activity; thereby compounds that re-localize YAP/TAZ to the cytoplasm strongly impair their pro-tumorigenic activities in various cancers.	('YAP', 'Gene', (136, 139))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('YAP', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('compounds', 'Var', (109, 118))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cytoplasm', 'cellular_component', 'GO:0005737', ('151', '160'))	('tumor', 'Disease', (187, 192))	('YAP', 'Gene', '10413', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('YAP', 'Gene', '10413', (34, 37))	('impair', 'NegReg', (170, 176))
145407	29184420	The overexpression of MSLN activates multiple intracellular pathways, including nuclear factor-kappaB (NFkappaB), MAPK, and PI3K pathways, with the consequent promotion of cell proliferation, migration, and metastasis to distal sites and the inhibition of apoptosis.	('intracellular pathways', 'Pathway', (46, 68))	('PI3K', 'molecular_function', 'GO:0016303', ('124', '128'))	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('MAPK', 'Pathway', (114, 118))	('nuclear factor-kappaB', 'Gene', (80, 101))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('242', '265'))	('promotion', 'PosReg', (159, 168))	('MSLN', 'Var', (22, 26))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('overexpression', 'PosReg', (4, 18))	('PI3K pathways', 'Pathway', (124, 137))	('NFkappaB', 'Gene', '4790', (103, 111))	('metastasis to distal sites', 'CPA', (207, 233))	('activates', 'PosReg', (27, 36))	('apoptosis', 'CPA', (256, 265))	('cell proliferation', 'CPA', (172, 190))	('intracellular', 'cellular_component', 'GO:0005622', ('46', '59'))	('NFkappaB', 'Gene', (103, 111))	('nuclear factor-kappaB', 'Gene', '4790', (80, 101))	('migration', 'CPA', (192, 201))
145425	29184420	At the same time, their studies revealed the presence of MSLN in other adenocarcinomas of the biliary tract.	('adenocarcinomas of the biliary tract', 'Disease', (71, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('presence', 'Reg', (45, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('MSLN', 'Var', (57, 61))	('adenocarcinomas of the biliary tract', 'Disease', 'MESH:D001661', (71, 107))
145434	29184420	These results are consistent with data published by Bayoglu et al and Parinyanitikul et al, who, respectively, reported a prevalence of 42.3% and 34% of patients expressing MSLN in TNBC.	('MSLN', 'Var', (173, 177))	('BC', 'Phenotype', 'HP:0003002', (183, 185))	('TNBC', 'Gene', (181, 185))	('patients', 'Species', '9606', (153, 161))
145488	29184420	Two early Phase I mono-centric studies were conducted with the objective of investigating in vivo distribution and safety of 111In radio-labeled amatuximab in MSLN-expressing cancers (NCT01521325 and NCT01413451).	('NCT01521325', 'Var', (184, 195))	('NCT01413451', 'Var', (200, 211))	('111In', 'Chemical', 'MESH:C000615551', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('amatuximab', 'Chemical', 'MESH:C526187', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
145500	29184420	Two initial Phase I-II studies, started in June 2016, are recruiting patients with malignant mesothelioma (NCT02798536) and pretreated patients with pancreatic adenocarcinoma (NCT02810418).	('malignant mesothelioma', 'Disease', (83, 105))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (149, 174))	('patients', 'Species', '9606', (135, 143))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (83, 105))	('patients', 'Species', '9606', (69, 77))	('NCT02798536', 'Var', (107, 118))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (149, 174))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (83, 105))	('pancreatic adenocarcinoma', 'Disease', (149, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))
145506	29184420	Although they are not yet recruiting patients, they intend to combine GVAX/CRS-207 with nivolumab (NCT02243371) or CRS-207 with epacodostat, an inhibitor of indolamine 2,3-dioxygenase (NCT03006302), and this study started in June 2017, with the aim of improving survival in the same setting.	('survival', 'MPA', (262, 270))	('CRS-207', 'Chemical', '-', (75, 82))	('nivolumab', 'Chemical', 'MESH:D000077594', (88, 97))	('GVAX', 'Chemical', '-', (70, 74))	('patients', 'Species', '9606', (37, 45))	('NCT02243371', 'Var', (99, 110))	('improving', 'PosReg', (252, 261))	('NCT03006302', 'Var', (185, 196))	('indolamine 2,3-dioxygenase', 'Gene', '3620', (157, 183))	('CRS-207', 'Chemical', '-', (115, 122))
145518	29184420	Anetumab has reached Phase II of clinical development as a single agent in PC (NCT03023722) and lung cancer (NCT02839681), and these two studies just started to recruit patients (May and June 2017, respectively).	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('patients', 'Species', '9606', (169, 177))	('PC', 'Phenotype', 'HP:0002894', (75, 77))	('Anetumab', 'Chemical', '-', (0, 8))	('Anetumab', 'Gene', (0, 8))	('NCT02839681', 'Var', (109, 120))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
145521	29184420	After binding the ADC to the specific biological antigen, the complex MSLN-ADC is then internalized, and the free form is released into the cytosol, which induces G2/M-phase growth arrest, cell death, and apoptosis.	('death', 'Disease', (194, 199))	('apoptosis', 'CPA', (205, 214))	('binding', 'molecular_function', 'GO:0005488', ('6', '13'))	('apoptosis', 'biological_process', 'GO:0006915', ('205', '214'))	('M-phase', 'biological_process', 'GO:0000279', ('166', '173'))	('apoptosis', 'biological_process', 'GO:0097194', ('205', '214'))	('binding', 'Interaction', (6, 13))	('growth arrest', 'Disease', 'MESH:D006323', (174, 187))	('induces', 'Reg', (155, 162))	('growth arrest', 'Disease', (174, 187))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('MSLN-ADC', 'Var', (70, 78))	('cytosol', 'cellular_component', 'GO:0005829', ('140', '147'))	('death', 'Disease', 'MESH:D003643', (194, 199))	('growth arrest', 'Phenotype', 'HP:0001510', (174, 187))
145522	29184420	The specific antiproliferative activity in vitro and its potent antitumor activity in xenograft cancer models encourage researchers to test DMOT4039A in clinical trials.	('tumor', 'Disease', (68, 73))	('DMOT4039A', 'Chemical', '-', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('DMOT4039A', 'Var', (140, 149))	('antiproliferative activity', 'CPA', (13, 39))
145523	29184420	A multicenter, open-label, Phase I study is planned to assess the safety, tolerability, and PK of DMOT4039A in patients with unresectable PC or platinum-resistant OC (NCT01469793).	('unresectable PC', 'Disease', (125, 140))	('DMOT4039A', 'Chemical', '-', (98, 107))	('DMOT4039A', 'Var', (98, 107))	('platinum', 'Chemical', 'MESH:D010984', (144, 152))	('OC', 'Phenotype', 'HP:0100615', (163, 165))	('PC', 'Phenotype', 'HP:0002894', (138, 140))	('patients', 'Species', '9606', (111, 119))
145531	29184420	An initial first Phase I study planned to investigate the safety and tolerability of BMS-986148 in combination with nivolumab, with the principal aim of highlighting the most hazardous AEs and SAEs (NCT02341625).	('nivolumab', 'Chemical', 'MESH:D000077594', (116, 125))	('BMS-986148', 'Gene', (85, 95))	('NCT02341625', 'Var', (199, 210))
145563	29184420	Antibodies against MSLN have a more efficient anti-tumor activity when they are conjugated with a cytotoxic molecule compared to the unconjugated drug, as demonstrated in pre-clinical and clinical studies.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Antibodies', 'Var', (0, 10))	('MSLN', 'Gene', (19, 23))	('tumor', 'Disease', (51, 56))	('pre', 'molecular_function', 'GO:0003904', ('171', '174'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
145564	29184420	DM4, conjugated with anetumab, performs its cytotoxic activity mainly against rapidly replicating cells, reducing systemic toxicity, and, thus, widening its therapeutic window.	('widening', 'PosReg', (144, 152))	('rapidly', 'CPA', (78, 85))	('toxicity', 'Disease', (123, 131))	('DM4', 'Chemical', 'MESH:D008453', (0, 3))	('DM4', 'Var', (0, 3))	('therapeutic window', 'MPA', (157, 175))	('cytotoxic activity', 'CPA', (44, 62))	('anetumab', 'Chemical', '-', (21, 29))	('reducing', 'NegReg', (105, 113))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))
145754	19935800	DeLong et al (2005) also reported a lower number of these cells in the pleural effusions from seven MPM patients, comparing with those from lung or breast cancer patients.	('patients', 'Species', '9606', (162, 170))	('lower', 'NegReg', (36, 41))	('pleural effusions', 'Disease', (71, 88))	('pleural effusions', 'Disease', 'MESH:D010996', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pleural effusions', 'Phenotype', 'HP:0002202', (71, 88))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('MPM', 'Var', (100, 103))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('patients', 'Species', '9606', (104, 112))
145767	19935800	They also showed that high levels of CD8+ lymphocytes were associated with a better prognosis and with a lower incidence of mediastinal lymph node metastasis.	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (124, 157))	('CD8', 'Gene', (37, 40))	('high levels', 'Var', (22, 33))	('CD8', 'Gene', '925', (37, 40))
145795	11875694	There was a trend towards improved response rate (54% vs 33%), improved median survival (9.7 months vs 7.5 months) and improved 1 year survival (42% vs 18%) in patients who received both chemotherapy and SRL172 compared to those in the chemotherapy alone group.	('patients', 'Species', '9606', (160, 168))	('improved', 'PosReg', (63, 71))	('SRL172', 'Var', (204, 210))	('response', 'CPA', (35, 43))	('improved', 'PosReg', (119, 127))	('improved', 'PosReg', (26, 34))	('median', 'MPA', (72, 78))
145799	11875694	The rationale behind this new study was that SRL172 in the tumour or in the pleural cavity could result in an increased concentration of the immunologically active compound in the vicinity of the tumour, thus causing an inflammatory reaction which could potentiate the anti-tumour killing at the tumour site.	('inflammatory reaction', 'CPA', (220, 241))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('increased', 'PosReg', (110, 119))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('tumour', 'Disease', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('tumour', 'Disease', 'MESH:D009369', (274, 280))	('tumour', 'Disease', (274, 280))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('potentiate', 'PosReg', (254, 264))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('pleural', 'Disease', 'MESH:D010995', (76, 83))	('tumour', 'Disease', 'MESH:D009369', (296, 302))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('pleural', 'Disease', (76, 83))	('tumour', 'Disease', (59, 65))	('causing', 'Reg', (209, 216))	('tumour', 'Disease', (296, 302))	('concentration of the', 'MPA', (120, 140))	('SRL172', 'Var', (45, 51))
145861	11875694	SRL172 has been reported to increase interleulin 2 (IL-2) production in peripheral blood monocytes in patients with melanoma (Maraveyas et al, 1999) and we had also demonstrated that it leads to NK activation in vitro (KV Bromelow et al, in preparation).	('increase', 'PosReg', (28, 36))	('IL-2', 'molecular_function', 'GO:0005134', ('52', '56'))	('patients', 'Species', '9606', (102, 110))	('IL-2) production', 'biological_process', 'GO:0032623', ('52', '68'))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('interleulin 2 (IL-2', 'Gene', '3558', (37, 56))	('leads to', 'Reg', (186, 194))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('NK activation', 'MPA', (195, 208))	('SRL172', 'Var', (0, 6))
145867	11875694	On the other hand, a significant decrease in the proportion of IL-4 producing CD3+ T cells (Th2) as well as an increase in NK activation was recorded in the peripheral blood after SRL172 and chemotherapy irrespective of the clinical response.	('activation', 'MPA', (126, 136))	('increase', 'PosReg', (111, 119))	('SRL172', 'Var', (180, 186))	('decrease', 'NegReg', (33, 41))	('IL-4', 'Gene', (63, 67))	('IL-4', 'molecular_function', 'GO:0005136', ('63', '67'))	('IL-4', 'Gene', '3565', (63, 67))
145892	33533181	Moreover, this region showed increased uptake on F18-FDG-PET.	('F18-FDG', 'Chemical', 'MESH:D019788', (49, 56))	('uptake', 'MPA', (39, 45))	('increased', 'PosReg', (29, 38))	('uptake', 'biological_process', 'GO:0098657', ('39', '45'))	('uptake', 'biological_process', 'GO:0098739', ('39', '45'))	('F18-FDG-PET', 'Var', (49, 60))
145941	31475103	These authors found a strong correlation between radiological responses (measured by CT scans according to modified RECIST criteria) and SMRP variations.	('SMRP', 'Gene', (137, 141))	('variations', 'Var', (142, 152))	('SMRP', 'Gene', '10232', (137, 141))
145977	31475103	Transformed MPM cells actively secrete acetylated HMGB1, which promotes cell proliferation and invasiveness in an autocrine manner.	('HMGB1', 'Gene', (50, 55))	('HMGB1', 'Gene', '3146', (50, 55))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('promotes', 'PosReg', (63, 71))	('invasiveness', 'CPA', (95, 107))	('cell proliferation', 'CPA', (72, 90))	('acetylated', 'Var', (39, 49))
145982	31475103	Although these results were obtained with a small number of subjects, they provide groundwork for future investigations on larger cohorts aimed at validating acetylated HMGB1 as an early diagnostic marker.	('HMGB1', 'Gene', (169, 174))	('HMGB1', 'Gene', '3146', (169, 174))	('acetylated', 'Var', (158, 168))
145986	31475103	Setting a cut-off at 460 pg/ml, these authors showed a strong correlation between high serum VEGF and shorter patient survival.	('shorter', 'NegReg', (102, 109))	('VEGF', 'Gene', (93, 97))	('high', 'Var', (82, 86))	('VEGF', 'Gene', '7422', (93, 97))	('patient', 'Species', '9606', (110, 117))
146016	31475103	It must be noted that in this study, the authors used different normalizer RNAs for plasma (miR-146) and tissue (U6, RNU44, RNU48).	('RNU48', 'Gene', (124, 129))	('RNU44', 'Gene', '26806', (117, 122))	('RNU48', 'Gene', '26801', (124, 129))	('miR', 'Gene', '220972', (92, 95))	('RNU44', 'Gene', (117, 122))	('miR', 'Gene', (92, 95))	('U6', 'Var', (113, 115))
146038	31475103	Cancer patients commonly exhibit a higher concentration of cfDNA that contains the mutations found in the tumor.	('mutations', 'Var', (83, 92))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('higher', 'PosReg', (35, 41))	('patients', 'Species', '9606', (7, 15))	('tumor', 'Disease', (106, 111))
146039	31475103	The detection of ctDNA variants in MPM holds promise as a potential biomarker for the diagnosis and stratification of MPM patients.	('variants', 'Var', (23, 31))	('patients', 'Species', '9606', (122, 130))	('MPM', 'Gene', (35, 38))	('MPM', 'Disease', (118, 121))
146044	31475103	on a large cohort of MPM tissue samples revealed mutations in the BAP1, NF2, TP53, SETd2, DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51 genes.	('RYR', 'cellular_component', 'GO:1990425', ('103', '106'))	('DDX3X', 'Gene', '1654', (90, 95))	('SETDB1', 'Gene', (117, 123))	('BAP1', 'Gene', (66, 70))	('ULK2', 'Gene', '9706', (97, 101))	('RYR2', 'Gene', (103, 107))	('NF2', 'Gene', '4771', (72, 75))	('TP53', 'Gene', (77, 81))	('SETDB1', 'Gene', '9869', (117, 123))	('mutations', 'Var', (49, 58))	('ULK2', 'Gene', (97, 101))	('RYR2', 'Gene', '6262', (103, 107))	('NF2', 'Gene', (72, 75))	('DDX51', 'Gene', (129, 134))	('DDX51', 'Gene', '317781', (129, 134))	('CFAP45', 'Gene', '25790', (109, 115))	('CFAP45', 'Gene', (109, 115))	('TP53', 'Gene', '7157', (77, 81))	('DDX3X', 'Gene', (90, 95))	('BAP1', 'Gene', '8314', (66, 70))	('SETd2', 'Gene', '29072', (83, 88))	('SETd2', 'Gene', (83, 88))
146055	31475103	The authors identified seven top DM-CpGs, three of which were hypomethylated (FOXK1, MYB, and TAF4) and four hypermethylated (CXCR6/FYCO1, TAP1, MORC2, and LIME1).	('LIME1', 'Gene', (156, 161))	('FOXK1', 'Gene', (78, 83))	('LIME1', 'Gene', '54923', (156, 161))	('MORC2', 'Gene', (145, 150))	('FYCO1', 'Gene', '79443', (132, 137))	('CXCR6', 'Gene', (126, 131))	('CXCR6', 'Gene', '10663', (126, 131))	('MYB', 'Gene', '4602', (85, 88))	('FYCO1', 'Gene', (132, 137))	('TAF4', 'Gene', '6874', (94, 98))	('TAF4', 'Gene', (94, 98))	('TAP1', 'Gene', (139, 143))	('MYB', 'Gene', (85, 88))	('FOXK1', 'Gene', '221937', (78, 83))	('MORC2', 'Gene', '22880', (145, 150))	('hypomethylated', 'Var', (62, 76))	('TAP1', 'Gene', '6890', (139, 143))
146096	31092657	Previous preclinical studies demonstrated that DCBI has the capacity to slow down tumour growth, although tumour load has an important role in survival.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('DCBI', 'Var', (47, 51))	('slow down', 'NegReg', (72, 81))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('tumour', 'Disease', (106, 112))	('DCBI', 'Chemical', '-', (47, 51))
146122	31092657	Patients must have adequate bone marrow reserve before DCBI treatment; absolute neutrophil count >1.0x109/l, platelet count >100x109/l and haemoglobin >6.0 mmol/L.	('>100x109/l', 'Var', (124, 134))	('haemoglobin', 'MPA', (139, 150))	('DCBI', 'Chemical', '-', (55, 59))	('Patients', 'Species', '9606', (0, 8))	('platelet count', 'CPA', (109, 123))
146292	29085180	Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM.	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('aggressive disease', 'Disease', 'MESH:D001523', (69, 87))	('associated', 'Reg', (32, 42))	('BAP1', 'Gene', (9, 13))	('aggressive disease', 'Disease', (69, 87))
146293	29085180	Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('improved', 'PosReg', (59, 67))	('BAP1', 'Gene', '8314', (9, 13))	('malignancies', 'Disease', (102, 114))	('survival', 'MPA', (68, 76))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
146295	29085180	BAP1 mutation was found in 58% of histology and 59% of cytology specimens.	('found', 'Reg', (18, 23))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))	('BAP1', 'Gene', (0, 4))
146298	29085180	We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients.	('patients', 'Species', '9606', (155, 163))	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))
146307	29085180	Recent evidence has shown that BAP1 plays a role in modulation of calcium-induced apoptosis, and consequently mutation may result in accumulation of DNA-damaged cells and greater susceptibility to development of malignancy.	('DNA-damaged cells', 'MPA', (149, 166))	('malignancy', 'Disease', 'MESH:D009369', (212, 222))	('BAP1', 'Gene', '8314', (31, 35))	('malignancy', 'Disease', (212, 222))	('calcium-induced apoptosis', 'CPA', (66, 91))	('modulation', 'MPA', (52, 62))	('BAP1', 'Gene', (31, 35))	('mutation', 'Var', (110, 118))	('result in', 'Reg', (123, 132))	('calcium', 'Chemical', 'MESH:D002118', (66, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('accumulation', 'PosReg', (133, 145))
146308	29085180	Most published mutations result in a truncated protein or mRNA decay, and the site of the mutation has no known association with the resulting cancer type.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (15, 24))	('truncated protein', 'MPA', (37, 54))	('mRNA decay', 'MPA', (58, 68))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mRNA decay', 'biological_process', 'GO:0006402', ('58', '68'))	('result in', 'Reg', (25, 34))
146309	29085180	BAP1 knockdown in vitro has resulted in decreased cell proliferation and mediation of apoptosis in MSTO211H, HMeso, and H2373 mesothelioma cell lines, and reintroduction of wild-type BAP1 in BAP1-null cell line NCI-H226 promoted cell growth, yet another study reported that this was counterbalanced by increased apoptosis, indicating that the consequences of in vitro manipulation may be cell type dependent.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('knockdown', 'Var', (5, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('BAP1', 'Gene', (183, 187))	('BAP1', 'Gene', (191, 195))	('cell proliferation', 'CPA', (50, 68))	('BAP1', 'Gene', (0, 4))	('NCI-H226', 'CellLine', 'CVCL:1544', (211, 219))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('promoted', 'PosReg', (220, 228))	('cell growth', 'biological_process', 'GO:0016049', ('229', '240'))	('decreased', 'NegReg', (40, 49))	('HMeso', 'Chemical', '-', (109, 114))	('H2373', 'CellLine', 'CVCL:A533', (120, 125))	('cell growth', 'CPA', (229, 240))	('reintroduction', 'Var', (155, 169))	('BAP1', 'Gene', '8314', (183, 187))	('mesothelioma', 'Disease', (126, 138))	('BAP1', 'Gene', '8314', (191, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('312', '321'))	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('312', '321'))	('BAP1', 'Gene', '8314', (0, 4))
146310	29085180	Additionally, in vivo evidence in nude mice has shown that injection of NCI-H226 (BAP1 negative) cells confers less tumorigenicity when these cells are infected with lentivirus carrying wild-type BAP1 compared to the mutated BAP1, further indicating its role in tumour suppression.	('BAP1', 'Gene', (196, 200))	('BAP1', 'Gene', (82, 86))	('NCI-H226', 'CellLine', 'CVCL:1544', (72, 80))	('nude mice', 'Species', '10090', (34, 43))	('BAP1', 'Gene', '8314', (82, 86))	('tumour suppression', 'Disease', (262, 280))	('NCI-H226', 'Gene', (72, 80))	('BAP1', 'Gene', '8314', (225, 229))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('tumour suppression', 'Disease', 'OMIM:146850', (262, 280))	('BAP1', 'Gene', '8314', (196, 200))	('BAP1', 'Gene', (225, 229))	('tumorigenicity', 'MPA', (116, 130))	('mutated', 'Var', (217, 224))	('less', 'NegReg', (111, 115))
146311	29085180	Mutations of BAP1 may be sporadic or familial.	('BAP1', 'Gene', '8314', (13, 17))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', (13, 17))
146312	29085180	Germline mutations in BAP1 have been observed in families with a high frequency of MM, associated with earlier age of onset, among other malignancies such as uveal, ocular, and cutaneous melanoma.	('Germline mutations', 'Var', (0, 18))	('uveal', 'Disease', (158, 163))	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('observed', 'Reg', (37, 45))	('malignancies', 'Disease', (137, 149))	('cutaneous melanoma', 'Disease', (177, 195))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (177, 195))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (177, 195))	('BAP1', 'Gene', '8314', (22, 26))	('ocular', 'Disease', (165, 171))	('BAP1', 'Gene', (22, 26))
146316	29085180	A number of associated mutations have been identified as candidate genes in MM, particularly those involved with regulation of hypoxia-inducible factor (HIF1alpha) and VEGF.	('hypoxia', 'Disease', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('VEGF', 'Gene', '7422', (168, 172))	('mutations', 'Var', (23, 32))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('HIF1alpha', 'Gene', (153, 162))	('VEGF', 'Gene', (168, 172))	('HIF1alpha', 'Gene', '3091', (153, 162))
146318	29085180	Mutations in VHL have been detected in MM samples, along with other mutations at 3p21 such as SETD2 and PBRM1.	('SETD2', 'Gene', (94, 99))	('VHL', 'Disease', (13, 16))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('SETD2', 'Gene', '29072', (94, 99))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (104, 109))	('PBRM1', 'Gene', (104, 109))	('detected', 'Reg', (27, 35))
146320	29085180	Consequently, immunohistochemistry is thought to be the most reliable method for detection of BAP1 mutation.	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', '8314', (94, 98))	('mutation', 'Var', (99, 107))
146321	29085180	Loss or mutation of BAP1 can be visualised in most cases as undetectable nuclear immunoreactivity in immunohistochemistry studies.	('undetectable', 'NegReg', (60, 72))	('BAP1', 'Gene', (20, 24))	('Loss', 'NegReg', (0, 4))	('mutation', 'Var', (8, 16))	('BAP1', 'Gene', '8314', (20, 24))
146323	29085180	In MM however, loss of BAP1 expression detected by immunohistochemistry has shown contradictory prognostic implications, with some studies reporting improved patient outcomes with loss of BAP1 expression, suggesting a protective mechanism in disease development, and others reporting no change in patient survival.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (188, 192))	('patient', 'Species', '9606', (158, 165))	('loss', 'Var', (180, 184))	('loss', 'NegReg', (15, 19))	('BAP1', 'Gene', '8314', (23, 27))	('improved', 'PosReg', (149, 157))	('BAP1', 'Gene', '8314', (188, 192))	('expression', 'MPA', (193, 203))	('patient', 'Species', '9606', (297, 304))
146360	29085180	For the surgical sections, median survival times were 6 months (95% CI, 4.3-7.7 months) and 11 months (6.9-15.1 months) for negative and positive BAP1 expression, respectively (Figure 1(a)).	('positive', 'Var', (137, 145))	('BAP1', 'Gene', '8314', (146, 150))	('BAP1', 'Gene', (146, 150))
146361	29085180	Median survival times for cytology sections alone were 8 months (95% CI, 5.6-10.4 months) and 9 months (5.7-12.3 months) for negative and positive BAP1 expression, respectively (Figure 1(b)).	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', (147, 151))	('positive', 'Var', (138, 146))
146367	29085180	As expected, ELISA data showed adverse prognostic outcomes for patients with high VEGFA concentrations (p = 0.005).	('high', 'Var', (77, 81))	('VEGFA', 'Gene', (82, 87))	('VEGFA', 'Gene', '7422', (82, 87))	('patients', 'Species', '9606', (63, 71))
146370	29085180	Regardless of conflicting evidence and theories on prognostication, it is evident that BAP1 is commonly mutated in MM.	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (87, 91))	('mutated', 'Var', (104, 111))
146373	29085180	There is evidence for BAP1 activity in the cytoplasm, and normal mesothelial cells may show nuclear and weaker cytoplasmic labelling; but cytoplasmic labelling in isolation indicates mutated inactive BAP1.	('mutated', 'Var', (183, 190))	('BAP1', 'Gene', '8314', (200, 204))	('cytoplasm', 'cellular_component', 'GO:0005737', ('43', '52'))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (200, 204))	('BAP1', 'Gene', (22, 26))
146384	29085180	The current study used immunohistochemistry for detection of mutation, in the absence of sequencing and/or qPCR, but this may not detect all BAP1 mutations, as reported by us in a case of MM and uveal melanoma and another study in the case of uveal melanoma alone, where loss of heterogeneity did not result in loss of BAP1 protein expression.	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (146, 155))	('uveal melanoma', 'Disease', 'MESH:C536494', (243, 257))	('BAP1', 'Gene', (319, 323))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('BAP1', 'Gene', (141, 145))	('protein', 'cellular_component', 'GO:0003675', ('324', '331'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (195, 209))	('uveal melanoma', 'Disease', 'MESH:C536494', (195, 209))	('uveal melanoma', 'Phenotype', 'HP:0007716', (243, 257))	('uveal melanoma', 'Disease', (243, 257))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('uveal melanoma', 'Disease', (195, 209))	('BAP1', 'Gene', '8314', (319, 323))
146390	29085180	While there has been limited evidence of a link between molecular pathways, BAP1 mutation has coincided with VHL mutation in clear cell renal cell carcinoma (ccRCC).	('VHL', 'Disease', (109, 112))	('mutation', 'Var', (113, 121))	('coincided', 'Reg', (94, 103))	('VHL', 'Disease', 'MESH:D006623', (109, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (136, 156))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (125, 156))	('BAP1', 'Gene', '8314', (76, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('mutation', 'Var', (81, 89))	('renal cell carcinoma', 'Disease', (136, 156))	('BAP1', 'Gene', (76, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (136, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
146393	29085180	Recent evidence reports that transient BAP1 mutation increases the sensitivity of MM cell lines to HDAC inhibitors, as opposed to long-term BAP1 loss where adaptation had reduced sensitivity.	('mutation', 'Var', (44, 52))	('BAP1', 'Gene', (140, 144))	('sensitivity', 'MPA', (67, 78))	('BAP1', 'Gene', '8314', (39, 43))	('increases', 'PosReg', (53, 62))	('BAP1', 'Gene', '8314', (140, 144))	('BAP1', 'Gene', (39, 43))
146398	29085180	In addition, our cohort has a higher mean age at diagnosis in comparison to many studies, which may indicate acquired BAP1 mutation in comparison to germline mutations.	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (118, 122))	('mutation', 'Var', (123, 131))
146400	29085180	The mechanism of MM development in patients with germline BAP1 mutation is unknown, but it has been suggested that BAP1 mutation predisposes to augmented sensitivity to asbestos-mediated carcinogenicity.	('augmented', 'PosReg', (144, 153))	('BAP1', 'Gene', '8314', (115, 119))	('BAP1', 'Gene', (58, 62))	('sensitivity to asbestos-mediated carcinogenicity', 'MPA', (154, 202))	('mutation', 'Var', (120, 128))	('BAP1', 'Gene', (115, 119))	('asbestos', 'Chemical', 'MESH:D001194', (169, 177))	('patients', 'Species', '9606', (35, 43))	('BAP1', 'Gene', '8314', (58, 62))
146411	20151039	Aberrations resulting in point mutations, genome rearrangements, and insertions/deletions (indels) have been linked to tumorigenesis.	('tumor', 'Disease', (119, 124))	('insertions/deletions', 'Var', (69, 89))	('point mutations', 'Var', (25, 40))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('genome rearrangements', 'Var', (42, 63))	('linked', 'Reg', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
146430	20151039	GMAP's algorithm for approximate alignment of the cDNA to these mapped regions allows for local mismatches, cDNA insertions, and genomic insertions.	('GMAP', 'Gene', (0, 4))	('insertions', 'Var', (113, 123))	('GMAP', 'Gene', '51083', (0, 4))	('cDNA', 'Gene', (108, 112))	('mismatches', 'Var', (96, 106))
146443	20151039	GMAP and GSNAP provide essential mapping and alignment for short read data, and these results are used for identification of variants.	('GMAP', 'Gene', '51083', (0, 4))	('GMAP', 'Gene', (0, 4))	('variants', 'Var', (125, 133))
146447	20151039	Alpheus was successfully used to determine candidate causal single nucleotide variants (SNVs) in malignant pleural mesothelioma (MPM) tissues, an asbestos-related, rapidly fatal cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (97, 127))	('single nucleotide variants', 'Var', (60, 86))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('malignant pleural mesothelioma', 'Disease', (97, 127))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (107, 127))
146455	20151039	54 of 69 nsV tested within the mesothelioma tissue were present in the genomic DNA, indicating polymorphisms and not mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('mesothelioma', 'Disease', (31, 43))	('polymorphisms', 'Var', (95, 108))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
146456	20151039	The remaining 15 nsV were tumor-specific relating to somatic mutations (n = 7), RNA editing (n = 1), loss of heterozygosity due to chromosomal deletions (n = 3), and epigenetic silencing (n = 3).	('chromosomal deletions', 'Var', (131, 152))	('loss', 'NegReg', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RNA', 'MPA', (80, 83))	('epigenetic silencing', 'Var', (166, 186))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('RNA editing', 'biological_process', 'GO:0009451', ('80', '91'))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
146458	20151039	Three of the mutations were present in 4-6% of a larger cohort of MPM tissues; COL5A2 mutation in 3 of 53 (c2773t, NM_000393.3); UQCRC1 mutation in 3 of 53 (g851a, NM_003365.2) and MXRA5 mutation in 2 of 53 (c7862a, NM_015419.1).	('c7862a', 'Var', (208, 214))	('MXRA5', 'Gene', '25878', (181, 186))	('c2773t', 'Var', (107, 113))	('UQCRC1', 'Gene', (129, 135))	('UQCRC1', 'Gene', '7384', (129, 135))	('COL5A2', 'Gene', '1290', (79, 85))	('COL5A2', 'Gene', (79, 85))	('MXRA5', 'Gene', (181, 186))	('g851a', 'Var', (157, 162))	('mutation', 'Var', (86, 94))
146485	20151039	ANOVA Analysis of variation cSNV Coding SNV indels Insertions/deletions MPM Malignant pleural mesothelioma                nsV              Non-synonymous genetic variations SRA NCBI Short Read Archive PCA Principal components analysis ribo(-) Ribominus SNPs Single nucleotide polymorphisms SNVs Single nucleotide variants sV Synonymous variant WGSS Whole genome shotgun sequencing WTSS Whole transcriptome shotgun sequencing	('SRA', 'Chemical', '-', (173, 176))	('Insertions/deletions', 'Var', (51, 71))	('Malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (76, 106))	('Malignant pleural mesothelioma', 'Disease', (76, 106))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (86, 106))	('Single nucleotide variants', 'Var', (295, 321))
146495	31917456	In our cohort, seafaring was associated with a higher overall incidence of cancer compared to the general population.	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('seafaring', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
146603	32816946	The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape.	('dasatinib', 'Chemical', 'MESH:D000069439', (134, 143))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
146610	32816946	Recent studies from MPM patients carrying germline mutations in tumor suppressor genes such as BAP1 or DNA repair genes have shown improved survival results.	('DNA repair', 'biological_process', 'GO:0006281', ('103', '113'))	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('BAP1', 'Gene', (95, 99))	('survival', 'CPA', (140, 148))	('patients', 'Species', '9606', (24, 32))	('DNA repair genes', 'Gene', (103, 119))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('improved', 'PosReg', (131, 139))	('BAP1', 'Gene', '8314', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('germline mutations', 'Var', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
146614	32816946	Using a multi-region sequencing approach, our group and others have previously delineated the genomic, epigenetic and transcriptomic ITH architecture of non-small cell lung cancers (NSCLCs) and demonstrated that complex molecular ITH was associated with inferior clinical outcomes.	('lung cancers', 'Disease', (168, 180))	('NSCLCs', 'Disease', 'MESH:D002289', (182, 188))	('NSCLCs', 'Phenotype', 'HP:0030358', (182, 188))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('complex', 'Var', (212, 219))	('lung cancers', 'Disease', 'MESH:D008175', (168, 180))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('NSCLCs', 'Disease', (182, 188))
146629	32816946	Next, we applied following mutation filtering criteria: (i) sequencing depth >= 50 for tumor and >= 30 for normal, (ii) tumor allele frequency >= 5% for single nucleotide variants and >= 10% for INDELs, and (iii) normal allele frequency < 1%.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('single nucleotide variants', 'Var', (153, 179))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (120, 125))
146631	32816946	We defined copy number gains and losses in all tumor samples using +log21.5 for gain and -log21.5 for loss respectively.	('losses', 'NegReg', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('copy number', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
146632	32816946	Since the signal to noise ratio of SCNA could be reduced in the samples with lower tumor purity, we obtained purity-adjusted log2 ratios by log2 ((original copy ratio-1)/purity+1) if any of the paired samples from the same patients passed the original log2 thresholds of +log21.5 and -log21.5.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('signal to noise ratio', 'MPA', (10, 31))	('reduced', 'NegReg', (49, 56))	('tumor', 'Disease', (83, 88))	('+log21.5', 'Var', (271, 279))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
146641	32816946	A total of 5,021 non-synonymous mutations (Supplementary Data) were detected in 69 tumor regions with a median total mutational burden (TMB) of 0.65/Mb, consistent with that from TCGA MPM cohort (0.65/Mb, p=0.35).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('non-synonymous mutations', 'Var', (17, 41))	('TMB', 'Chemical', '-', (136, 139))	('tumor', 'Disease', (83, 88))	('detected', 'Reg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
146643	32816946	The median proportion of shared mutations between any pair of tumor regions was 80% (43% to 90%) prior to and 83% (71%-88%) post-dasatinib treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mutations', 'Var', (32, 41))	('dasatinib', 'Chemical', 'MESH:D000069439', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
146646	32816946	We further predicted neoantigens from these somatic mutations, but did not observe significant changes in total predicted neoantigen burden or proportion of neoantigens shared by different regions within the same tumors before and after dasatinib treatment (Supplementary Fig.	('mutations', 'Var', (52, 61))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('dasatinib', 'Chemical', 'MESH:D000069439', (237, 246))	('neoantigen burden', 'MPA', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('neoantigens', 'MPA', (21, 32))
146649	32816946	1) suggesting these mutations may have been early genomic events during clonal evolution of these MPM tumors.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('MPM', 'Disease', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mutations', 'Var', (20, 29))
146650	32816946	However, two NF2 mutations were heterogeneous mutations.	('NF2', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('NF2', 'Gene', '4771', (13, 16))
146651	32816946	A NF2 stop-gain mutation was detected in both pre-treatment specimens but was missing in one of the post-treatment tumor specimens from patient M4 and a NF2 non-synonymous mutation (p.G123X) was identified in 1 of the 3 pre-treatment tumor specimens and 1 of 6 post-treatment specimens from patient M11 suggesting these two NF2 mutations may be later subclonal mutations in patients M4 and M11.	('NF2', 'Gene', '4771', (153, 156))	('patient', 'Species', '9606', (136, 143))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (115, 120))	('p.G123X', 'Var', (182, 189))	('NF2', 'Gene', (153, 156))	('NF2', 'Gene', '4771', (324, 327))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('p.G123X', 'Mutation', 'p.G123X', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('NF2', 'Gene', (324, 327))	('patient', 'Species', '9606', (374, 381))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pre', 'molecular_function', 'GO:0003904', ('220', '223'))	('NF2', 'Gene', '4771', (2, 5))	('patient', 'Species', '9606', (291, 298))	('NF2', 'Gene', (2, 5))	('mutations', 'Var', (328, 337))	('patients', 'Species', '9606', (374, 382))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))
146662	32816946	S6, different regions within the same tumors showed a high level of homogeneity of SCNAs in cancer genes including deletions of BAP1, CDKN2A and an amplification of NTRK3.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('NTRK3', 'Gene', (165, 170))	('tumors', 'Disease', (38, 44))	('cancer', 'Disease', (92, 98))	('BAP1', 'Gene', '8314', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('CDKN2A', 'Gene', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('BAP1', 'Gene', (128, 132))	('NTRK3', 'Gene', '4916', (165, 170))	('CDKN2A', 'Gene', '1029', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('deletions', 'Var', (115, 124))
146676	32816946	Importantly, patients with higher T cell clonality in post-dasatinib treated MPM tumors, had significantly longer overall survival (OS) (Fig.	('overall survival', 'MPA', (114, 130))	('MPM', 'Disease', (77, 80))	('tumors', 'Disease', (81, 87))	('T cell clonality', 'Var', (34, 50))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('dasatinib', 'Chemical', 'MESH:D000069439', (59, 68))	('patients', 'Species', '9606', (13, 21))	('longer', 'PosReg', (107, 113))	('higher', 'PosReg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
146686	32816946	By multi-region WES, we revealed relatively homogenous genomic ITH pattern in this cohort of MPM with the majority of mutations and SCNAs including canonical cancer genes alterations present across all the regions of the same MPM tumors.	('MPM', 'Disease', (93, 96))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('alterations', 'Var', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
146689	32816946	One plausible explanation for the homogenous genomic landscape in MPM is that the majority of these mutations are very early molecular events during MPM evolution that have had occurred before these tumors have spread locally.	('mutations', 'Var', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
146691	32816946	Nevertheless, these data indicate that single biopsy analysis might be sufficient to identify the majority of known cancer gene mutations in MPM.	('MPM', 'Gene', (141, 144))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
146701	32816946	A recent study by Mansfield et al demonstrated that inter- or intra-chromosomal rearrangements in a pattern of chromothripsis generated the junctions of genes and noncoding DNA with neoantigenic potential in MPM.	('junctions', 'Var', (140, 149))	('chromothripsis', 'Disease', (111, 125))	('chromothripsis', 'Disease', 'MESH:D000072837', (111, 125))	('rearrangements', 'Var', (80, 94))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))
146702	32816946	Chromothripsis-like genome alterations could be heterogeneous and lead to vastly heterogenous neoantigen profiles in different regions of MPM and subsequent heterogeneous T cell response.	('Chromothripsis', 'Disease', 'MESH:D000072837', (0, 14))	('heterogeneous', 'MPA', (157, 170))	('heterogenous neoantigen profiles', 'MPA', (81, 113))	('lead to', 'Reg', (66, 73))	('Chromothripsis', 'Disease', (0, 14))	('alterations', 'Var', (27, 38))
146710	32816946	However, patients who with decreased p-SrcTyr419 post-dasatinib treatment had improved PFS suggesting dasatinib may benefit some MPM patients.	('patients', 'Species', '9606', (9, 17))	('p-SrcTyr419', 'Var', (37, 48))	('dasatinib', 'Chemical', 'MESH:D000069439', (102, 111))	('MPM', 'Disease', (129, 132))	('patients', 'Species', '9606', (133, 141))	('PFS', 'MPA', (87, 90))	('improved', 'PosReg', (78, 86))	('dasatinib', 'Chemical', 'MESH:D000069439', (54, 63))
146715	32816946	These results are in line with previous findings that those molecular alterations from on-treatment biopsies were superior than pretreatment biopsies regarding the association with benefit from receiving ICB treatment in patients with melanoma.	('alterations', 'Var', (70, 81))	('patients', 'Species', '9606', (221, 229))	('ICB', 'Chemical', '-', (204, 207))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Disease', (235, 243))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))
146740	30654090	The role of multimodality therapy; involving surgery with adjuvant radiation and/or chemotherapy, has been established to improve clinical outcomes for patients who have received EPP or P/D.	('EPP', 'Var', (179, 182))	('P/D', 'Var', (186, 189))	('patients', 'Species', '9606', (152, 160))	('improve', 'PosReg', (122, 129))
146775	30654090	Median values of the dosimetric parameters for patients that developed grade >= 3 RP versus those that did not (Table 3) revealed a statistically significant difference in the absolute and percentage volume of the ipsilateral lung spared of 20Gy and 30Gy but not 40Gy.	('20Gy', 'Var', (241, 245))	('30Gy', 'Var', (250, 254))	('patients', 'Species', '9606', (47, 55))
146862	27841316	MPM487 is a malignant pleural mesothelioma xenograft with biphasic morphology established in our laboratory from patient derived cells (obtained from the Mesothelioma Biobank-Pathology Dept., SS Antonio e Biagio General Hospital, Alessandria, Italy) and maintained by serial passages in nude mice.	('patient', 'Species', '9606', (113, 120))	('malignant pleural mesothelioma xenograft', 'Disease', (12, 52))	('nude mice', 'Species', '10090', (287, 296))	('MPM487', 'Var', (0, 6))	('malignant pleural mesothelioma xenograft', 'Disease', 'MESH:C562839', (12, 52))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (22, 42))	('Mesothelioma', 'Disease', (154, 166))	('Mesothelioma', 'Disease', 'MESH:D008654', (154, 166))
146863	27841316	Six to seven-week-old female NCr-Nu/Nu mice (from Envigo, Udine, Italy) were inoculated subcutaneously with tumor fragments of MPM487.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('MPM487', 'Var', (127, 133))	('mice', 'Species', '10090', (39, 43))
146890	22935333	Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (80, 102))	('malignant mesothelioma', 'Disease', (80, 102))	('melanocytic tumors', 'Disease', (113, 131))	('neoplasms', 'Disease', (142, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('neoplasms', 'Disease', 'MESH:D009369', (142, 151))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('BAP1', 'Gene', '8314', (9, 13))	('associated', 'Reg', (43, 53))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (80, 102))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('melanocytic tumors', 'Disease', 'MESH:D009508', (113, 131))
146891	22935333	To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.	('BAP1', 'Gene', (252, 256))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (257, 266))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (289, 311))	('BAP1', 'Gene', (45, 49))	('malignant mesothelioma', 'Disease', (289, 311))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', '8314', (252, 256))	('melanocytic tumors', 'Disease', 'MESH:D009508', (183, 201))	('predispose', 'Reg', (64, 74))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (289, 311))	('melanocytic tumors', 'Disease', (183, 201))	('BAP1', 'Gene', '8314', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
146892	22935333	Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations.	('BAP1', 'Gene', '8314', (135, 139))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))
146893	22935333	We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson chi2 test or two-tailed Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BAP1', 'Gene', (63, 67))	('mutation', 'Var', (136, 144))	('germline', 'Var', (122, 130))	('cancer', 'Disease', (95, 101))	('BAP1', 'Gene', '8314', (131, 135))	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (63, 67))
146894	22935333	Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs).	('melanocytic tumors', 'Disease', 'MESH:D009508', (161, 179))	('melanocytic tumors', 'Disease', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('Melanocytic tumors', 'Disease', (0, 18))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', '8314', (246, 250))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('BAP1', 'Gene', '8314', (387, 391))	('p.Gln684*', 'Var', (110, 119))	('Melanocytic tumors', 'Disease', 'MESH:D009508', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('atypical', 'Disease', (321, 329))	('BAP1', 'Gene', (246, 250))	('BAP1', 'Gene', (387, 391))	('BAP1', 'Gene', (95, 99))	('melanocytic tumors', 'Disease', 'MESH:D009508', (330, 348))	('p.Gln684*', 'Mutation', 'p.Q684*', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('melanocytic tumors', 'Disease', (330, 348))	('p.Pro147fs*48', 'Mutation', 'p.P147fsX48', (261, 274))	('tumors', 'Phenotype', 'HP:0002664', (342, 348))	('p.Pro147fs*48', 'Var', (261, 274))	('intradermal tumors', 'Disease', 'MESH:D018330', (409, 427))	('intradermal tumors', 'Disease', (409, 427))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))
146897	22935333	Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers.	('cancer syndrome', 'Disease', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('BAP1', 'Gene', (9, 13))	('cutaneous melanoma', 'Disease', (125, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (85, 107))	('mutations', 'Var', (14, 23))	('MBAITs', 'Disease', (148, 154))	('associated', 'Reg', (28, 38))	('malignant mesothelioma', 'Disease', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer syndrome', 'Disease', 'MESH:D009369', (52, 67))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (85, 107))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('cancers', 'Disease', (178, 185))	('uveal melanoma', 'Disease', (109, 123))
146898	22935333	MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('BAP1', 'Gene', '8314', (87, 91))	('cancers', 'Disease', (153, 160))	('germline', 'Var', (78, 86))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
146899	22935333	Hereditary cancer syndromes are caused by mutations in genes conferring high relative risks of cancer among carriers.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Hereditary cancer', 'Disease', 'MESH:D009369', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('caused by', 'Reg', (32, 41))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer syndrome', 'Disease', 'MESH:D009369', (11, 26))	('cancer', 'Disease', (11, 17))	('cancer syndrome', 'Disease', (11, 26))	('mutations', 'Var', (42, 51))	('Hereditary cancer', 'Disease', (0, 17))
146904	22935333	We recently identified two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma (MM) and possibly other cancers.	('malignant mesothelioma', 'Disease', (107, 129))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (107, 129))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('cancers', 'Disease', (154, 161))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (107, 129))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
146905	22935333	In parallel with our study, Wiesner and colleagues reported germline BAP1 mutations in two unrelated families with "atypical melanocytic tumors" and other cancers.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('melanocytic tumors', 'Disease', (125, 143))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))	('BAP1', 'Gene', '8314', (69, 73))
146906	22935333	In a subsequent paper, Wiesner and colleagues called the same melanocytic lesions "atypical Spitz tumors" (ASTs), but noted that in contrast to ASTs these lesions had a different histology and were characterized by the presence of both BAP1 and BRAF mutations.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('AST', 'Gene', (144, 147))	('AST', 'Gene', (107, 110))	('presence', 'Reg', (219, 227))	('AST', 'Gene', '26503', (144, 147))	('melanocytic lesions "atypical Spitz tumors', 'Disease', 'MESH:D018332', (62, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BAP1', 'Gene', '8314', (236, 240))	('mutations', 'Var', (250, 259))	('melanocytic lesions "atypical Spitz tumors', 'Disease', (62, 104))	('AST', 'Gene', '26503', (107, 110))	('BAP1', 'Gene', (236, 240))
146907	22935333	BRAF mutations are indeed common in melanocytic nevi (80%) and in cutaneous melanomas (CMs) (65%) but are rare in ASTs.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('nevi', 'Phenotype', 'HP:0003764', (48, 52))	('melanocytic nevi', 'Disease', (36, 52))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (66, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (66, 85))	('CMs', 'Phenotype', 'HP:0012056', (87, 90))	('CM', 'Disease', 'MESH:D009202', (87, 89))	('AST', 'Gene', (114, 117))	('mutations', 'Var', (5, 14))	('cutaneous melanomas', 'Disease', (66, 85))	('common', 'Reg', (26, 32))	('BRAF', 'Gene', '673', (0, 4))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (36, 52))	('AST', 'Gene', '26503', (114, 117))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
146908	22935333	Other investigators independently confirmed the association of germline BAP1 mutations and other cancers in additional families.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('BAP1', 'Gene', '8314', (72, 76))	('association', 'Interaction', (48, 59))	('germline', 'Var', (63, 71))	('BAP1', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (77, 86))
146910	22935333	To verify if germline BAP1 mutations are associated with distinct syndromes or with a single syndrome exhibiting a wide phenotypic range, we first investigated the presence of melanocytic tumors in our two families and compared them to those published in the literature, and then conducted a pooled analysis of individuals from studies reporting BAP1-mutated families to compare cancer risk in the 63 mutated vs the 55 non-mutated individuals from those families.	('BAP1', 'Gene', (346, 350))	('cancer', 'Disease', (379, 385))	('mutations', 'Var', (27, 36))	('associated', 'Reg', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('melanocytic tumors', 'Disease', (176, 194))	('melanocytic tumors', 'Disease', 'MESH:D009508', (176, 194))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', '8314', (346, 350))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('BAP1', 'Gene', (22, 26))
146911	22935333	We demonstrate that germline BAP1 mutations are associated with a novel cancer syndrome characterized by MM, uveal melanoma (UVM), CM, MBAITs and possibly by other tumors.	('cancer syndrome', 'Disease', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cancer syndrome', 'Disease', 'MESH:D009369', (72, 87))	('tumors', 'Disease', (164, 170))	('associated', 'Reg', (48, 58))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('CM', 'Disease', 'MESH:D009202', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('UVM', 'Phenotype', 'HP:0007716', (125, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('BAP1', 'Gene', '8314', (29, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('MBAITs', 'Disease', (135, 141))
146916	22935333	BRAF (exon15) mutations were detected by multiplex PCR amplification of tumor DNA, followed by automated fluorescent labeling, hybridization to a BioFilmChip Microarray, and signal detection using the AutoGenomics INFINITY Analyzer (AutoGenomics).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (14, 23))
146918	22935333	The inclusion criteria were: at least two generations and five members tested for germline BAP1 mutations, one positive germline BAP1 mutation found in at least one member of the family, and cancer status assessed for each of the tested members.	('germline', 'Var', (82, 90))	('BAP1', 'Gene', (91, 95))	('tested', 'Reg', (71, 77))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('BAP1', 'Gene', '8314', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (129, 133))	('mutations', 'Var', (96, 105))
146919	22935333	We asked the authors of the four selected papers for additional data: we collected gender, age of death or age of last follow up, germline BAP1 mutation result, all diagnosed cancers, and age of each cancer diagnosis.	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('mutation result', 'Var', (144, 159))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('germline', 'Var', (130, 138))	('cancers', 'Disease', (175, 182))	('cancer', 'Disease', (175, 181))	('BAP1', 'Gene', '8314', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('BAP1', 'Gene', (139, 143))	('cancer', 'Disease', (200, 206))
146920	22935333	To assess if germline BAP1 mutations were associated with an increased risk of cancer or MBAITs, we built two cohorts from these families: one cohort constituting 63 germline BAP1-mutated patients and the second cohort constituting 55 non-mutated patients.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (247, 255))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', '8314', (175, 179))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('BAP1', 'Gene', (22, 26))
146932	22935333	Of the five members of L family, four (80%) carried the germline BAP1 mutation (p.Gln684*).	('BAP1', 'Gene', '8314', (65, 69))	('p.Gln684*', 'Var', (80, 89))	('BAP1', 'Gene', (65, 69))	('p.Gln684*', 'Mutation', 'p.Q684*', (80, 89))
146934	22935333	All of the seven members of W family carried the germline BAP1 mutations (p.Pro147fs*48).	('BAP1', 'Gene', (58, 62))	('p.Pro147fs*48', 'Mutation', 'p.P147fsX48', (74, 87))	('p.Pro147fs*48', 'Var', (74, 87))	('BAP1', 'Gene', '8314', (58, 62))
146938	22935333	The mean ages of follow up were comparable in both cohorts (53.2 years, 95%CI: 49.0-57.4 in the BAP1 mutated cohort, 51.0 years, 95%CI: 46.3-55.8 in the non-mutated cohort).	('BAP1', 'Gene', (96, 100))	('mutated', 'Var', (101, 108))	('BAP1', 'Gene', '8314', (96, 100))
146940	22935333	At this time we do not have an explanation for this finding, although it appears possible that BAP1 mutation may carry a higher risk of lethality in utero for males.	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', (95, 99))	('lethality', 'MPA', (136, 145))
146943	22935333	The odds ratio (OR) of cancer risk in the germline BAP1-mutated cohort versus the non-mutated cohort was 17.39 (95% CI: 6.07-49.83).	('BAP1', 'Gene', (51, 55))	('germline', 'Var', (42, 50))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BAP1', 'Gene', '8314', (51, 55))
146947	22935333	To avoid the overestimation of the cancer risks estimates usually due to publication bias in meta-analyses, we chose to compare BAP1 mutated vs non-mutated patients from the same families.	('patients', 'Species', '9606', (156, 164))	('BAP1', 'Gene', '8314', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BAP1', 'Gene', (128, 132))	('mutated', 'Var', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
146948	22935333	We demonstrate that germline BAP1 mutations are associated with a significant increased overall risk of cancer and particularly of MM, UVM and CM (Table 2).	('CM', 'Disease', 'MESH:D009202', (143, 145))	('UVM', 'Phenotype', 'HP:0007716', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BAP1', 'Gene', '8314', (29, 33))	('UVM', 'Disease', (135, 138))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', (29, 33))
146950	22935333	Our results reveal that germline BAP1 mutations cause a novel autosomal dominant hereditary cancer syndrome, the BAP1 cancer syndrome, characterized predominantly by MM, UVM, CM and by MBAITs and possibly by other cancers.	('CM', 'Disease', 'MESH:D009202', (175, 177))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('UVM', 'Phenotype', 'HP:0007716', (170, 173))	('cancers', 'Disease', (214, 221))	('BAP1', 'Gene', '8314', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cause', 'Reg', (48, 53))	('BAP1', 'Gene', '8314', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('autosomal dominant hereditary cancer syndrome, the BAP1 cancer syndrome', 'Disease', 'MESH:D009386', (62, 133))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('BAP1', 'Gene', (113, 117))	('UVM', 'Disease', (170, 173))
146956	22935333	MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing CM, UVM and MM.	('BAP1', 'Gene', '8314', (87, 91))	('UVM', 'Phenotype', 'HP:0007716', (146, 149))	('germline', 'Var', (78, 86))	('developing', 'PosReg', (131, 141))	('BAP1', 'Gene', (87, 91))	('UVM', 'Disease', (146, 149))	('mutations', 'Var', (92, 101))	('CM', 'Disease', 'MESH:D009202', (142, 144))
146957	22935333	We identified MBAITs among the majority of germline BAP1 mutation carriers in the L and W families.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))
146958	22935333	Our meta-analysis demonstrates that the prevalence of MBAITs is significantly higher in germline BAP1 mutation carriers compared to controls.	('BAP1', 'Gene', '8314', (97, 101))	('MBAITs', 'Disease', (54, 60))	('mutation', 'Var', (102, 110))	('higher', 'PosReg', (78, 84))	('BAP1', 'Gene', (97, 101))
146962	22935333	Instead, the tumors found in these BAP1 mutated patients show large epithelioid clonal cells (that resemble those found in Spitz nevus and in ASTs) but these cells are present only in the dermis (there is no epidermal component).	('tumors', 'Disease', (13, 19))	('AST', 'Gene', (142, 145))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('nevus', 'Phenotype', 'HP:0003764', (129, 134))	('BAP1', 'Gene', '8314', (35, 39))	('Spitz nevus', 'Disease', (123, 134))	('mutated', 'Var', (40, 47))	('AST', 'Gene', '26503', (142, 145))	('BAP1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('patients', 'Species', '9606', (48, 56))
146967	22935333	At the molecular level, these lesions are characterized by BAP1 inactivation and almost always by concurrent BRAF mutation, features that are not found in Spitz and ASTs.	('AST', 'Gene', (165, 168))	('BRAF', 'Gene', (109, 113))	('BAP1', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (109, 113))	('AST', 'Gene', '26503', (165, 168))	('mutation', 'Var', (114, 122))	('BAP1', 'Gene', '8314', (59, 63))	('inactivation', 'NegReg', (64, 76))
146972	22935333	Therefore, we believe that if we continue to lump different melanocytic lesions (such as MBAITs) under the umbrella term of AST we will miss an opportunity to help pathologists to identify and classify this subgroup and to guide clinicians in selecting patients who may need testing for BAP1 mutations.	('mutations', 'Var', (292, 301))	('melanocytic lesions', 'Disease', 'MESH:D009508', (60, 79))	('melanocytic lesions', 'Disease', (60, 79))	('AST', 'Gene', (124, 127))	('patients', 'Species', '9606', (253, 261))	('AST', 'Gene', '26503', (124, 127))	('BAP1', 'Gene', '8314', (287, 291))	('BAP1', 'Gene', (287, 291))
146975	22935333	Along the guidelines used for FAMM-P families we advise families with hereditary BAP1 mutation to have family members tested for mutant gene carrier status at the age of ten and, if positive, to begin routine screening with a total body dermatological examination as family members may develop melanoma at an early age.	('carrier', 'molecular_function', 'GO:0005215', ('141', '148'))	('BAP1', 'Gene', (81, 85))	('develop', 'PosReg', (286, 293))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (81, 85))
146980	22935333	Detection of BRAF mutations may help diagnose this condition in cases of inconclusive BAP1 staining.	('BAP1', 'Gene', '8314', (86, 90))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (18, 27))
146981	22935333	Next, genetic counseling should be offered and germline DNA should be tested for BAP1 mutations to identify individuals and families at higher risk for one or more of the neoplasms associated with the BAP1 cancer syndrome.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', '8314', (201, 205))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('BAP1', 'Gene', (201, 205))	('cancer syndrome', 'Disease', 'MESH:D009369', (206, 221))	('cancer syndrome', 'Disease', (206, 221))	('BAP1', 'Gene', '8314', (81, 85))	('neoplasms', 'Disease', (171, 180))
146982	22935333	Germline BAP1 mutation carriers can be targeted for early detection and therapy that is associated with either a cure or improved prognosis.	('BAP1', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('BAP1', 'Gene', '8314', (9, 13))
147047	19829978	Studies performed in rats showed that smoking enhances susceptibility to mesothelioma in animals with a history of asbestos exposure.	('enhances', 'PosReg', (46, 54))	('rats', 'Species', '10116', (21, 25))	('asbestos', 'Chemical', 'MESH:D001194', (115, 123))	('mesothelioma', 'Disease', (73, 85))	('susceptibility', 'MPA', (55, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('smoking', 'Var', (38, 45))
147065	19829978	Treatment with pemetrexed and cisplatin may reduce the rate of disease progression, while smoking cessation and early intervention with supplemental oxygen for hypoxemia may assist in symptom management.	('disease progression', 'CPA', (63, 82))	('reduce', 'NegReg', (44, 50))	('cisplatin', 'Var', (30, 39))	('man', 'Species', '9606', (192, 195))	('rate', 'MPA', (55, 59))	('hypoxemia', 'Disease', 'MESH:D000860', (160, 169))	('oxygen', 'Chemical', 'MESH:D010100', (149, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('pemetrexed', 'Chemical', 'MESH:D000068437', (15, 25))	('hypoxemia', 'Disease', (160, 169))	('hypoxemia', 'Phenotype', 'HP:0012418', (160, 169))
147122	32050546	Moreover, particular polymorphisms within the MSLN gene were found to be related with high levels in healthy subjects.	('MSLN', 'Gene', (46, 50))	('MSLN', 'Gene', '10232', (46, 50))	('polymorphisms', 'Var', (21, 34))	('related', 'Reg', (73, 80))
147138	32050546	Possible mechanisms of cancer-related VOC emissions include (1) persistent oxidative stress-induced lipid peroxidation of polyunsaturated fatty acids (PUFAs) (i.e., emission of alkanes, alkenes and aldehydes following cell- and mitochondrial-membrane perturbations by ROS attacks) (2) induction of cytochrome p-450 enzymes by environmental carcinogens and ROS molecules (3) overexpression of cytochrome p-450 enzymes in several tumor types, such as breast tumors, (4) cancer cell metabolism shift from oxidative phosphorylation to aerobic glycolysis, (5) molecular alterations in oncogenes and tumor suppressor genes.	('breast tumors', 'Phenotype', 'HP:0100013', (449, 462))	('cytochrome p-450', 'Gene', '4051', (392, 408))	('lipid', 'Chemical', 'MESH:D008055', (100, 105))	('tumor suppressor', 'biological_process', 'GO:0051726', ('594', '610'))	('tumor', 'Phenotype', 'HP:0002664', (428, 433))	('cytochrome p-450', 'molecular_function', 'GO:0005490', ('392', '408'))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('breast tumors, (4) cancer', 'Disease', 'MESH:D001943', (449, 474))	('cytochrome p-450', 'molecular_function', 'GO:0019825', ('392', '408'))	('metabolism', 'biological_process', 'GO:0008152', ('480', '490'))	('cytochrome p-450', 'molecular_function', 'GO:0005490', ('298', '314'))	('tumor', 'Phenotype', 'HP:0002664', (594, 599))	('ROS', 'Chemical', '-', (356, 359))	('cytochrome p-450', 'molecular_function', 'GO:0019825', ('298', '314'))	('ROS', 'Chemical', '-', (268, 271))	('oncogenes', 'Gene', (580, 589))	('tumor', 'Disease', (456, 461))	('environmental carcinogens', 'Disease', 'MESH:D018876', (326, 351))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('502', '527'))	('cancer', 'Disease', (468, 474))	('tumor', 'Disease', 'MESH:D009369', (456, 461))	('cancer', 'Phenotype', 'HP:0002664', (468, 474))	('tumors', 'Phenotype', 'HP:0002664', (456, 462))	('cancer', 'Disease', (23, 29))	('tumor', 'Disease', (428, 433))	('cytochrome p-450', 'Gene', (298, 314))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mitochondrial-membrane', 'cellular_component', 'GO:0031966', ('228', '250'))	('glycolysis', 'biological_process', 'GO:0006096', ('539', '549'))	('tumor', 'Disease', (594, 599))	('environmental carcinogens', 'Disease', (326, 351))	('tumor', 'Disease', 'MESH:D009369', (428, 433))	('cytochrome p-450', 'Gene', (392, 408))	('oxidative stress', 'Phenotype', 'HP:0025464', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (456, 461))	('cytochrome p-450', 'Gene', '4051', (298, 314))	('molecular alterations', 'Var', (555, 576))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('594', '610'))	('tumor', 'Disease', 'MESH:D009369', (594, 599))	('cancer', 'Disease', 'MESH:D009369', (468, 474))
147245	32050546	The studies involved in this review identified some compounds (i.e, cyclohexane, P3, P5, P50, P71, diethyl ether, limonene, nonanal, VOC IK 1287) that can be indicative of MPM development in an asbestos-exposed population.	('P50', 'Gene', (89, 92))	('P50', 'Gene', '4790', (89, 92))	('nonanal', 'Chemical', 'MESH:C008664', (124, 131))	('limonene', 'Chemical', 'MESH:D000077222', (114, 122))	('P71', 'Gene', (94, 97))	('P71', 'Gene', '57541', (94, 97))	('MPM', 'Disease', (172, 175))	('diethyl ether', 'Chemical', 'MESH:D004986', (99, 112))	('asbestos', 'Chemical', 'MESH:D001194', (194, 202))	('MPM', 'Disease', 'MESH:C562839', (172, 175))	('cyclohexane', 'Var', (68, 79))	('cyclohexane', 'Chemical', 'MESH:C506365', (68, 79))
147290	30906657	Increased inflammatory cytokines may induce liver and kidney damage, for example elevated IL-6 is associated with iron accumulation leading to oxidative tissue damage.	('IL-6', 'Gene', (90, 94))	('kidney damage', 'Disease', (54, 67))	('IL-6', 'Gene', '16193', (90, 94))	('kidney damage', 'Phenotype', 'HP:0000112', (54, 67))	('oxidative tissue damage', 'MPA', (143, 166))	('elevated IL-6', 'Phenotype', 'HP:0030783', (81, 94))	('kidney damage', 'Disease', 'MESH:D007674', (54, 67))	('iron', 'Chemical', 'MESH:D007501', (114, 118))	('induce', 'Reg', (37, 43))	('elevated', 'Var', (81, 89))	('IL-6', 'molecular_function', 'GO:0005138', ('90', '94'))	('associated', 'Reg', (98, 108))	('iron accumulation', 'MPA', (114, 131))	('Increased inflammatory cytokines', 'Phenotype', 'HP:0012649', (0, 32))
147327	30906657	Finally, depletion studies confirmed that even though T cells in young mice could not prevent tumor development, they could restrain tumor growth, as in the absence of CD4+ or CD8+ T cells tumors grew faster (Figure 4C).	('CD8', 'Gene', '925', (176, 179))	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('CD4', 'Gene', '12504', (168, 171))	('men', 'Species', '9606', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('CD8', 'Gene', (176, 179))	('tumors', 'Disease', (189, 195))	('absence', 'Var', (157, 164))	('tumor', 'Disease', (133, 138))	('CD4', 'Gene', (168, 171))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('restrain', 'NegReg', (124, 132))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', (94, 99))	('faster', 'PosReg', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
147329	30906657	Interestingly, depletion of CD8+ T cells in elderly mice significantly slowed tumor growth (Figure 4D), suggesting that these cells become immunosuppressive with aging.	('depletion', 'Var', (15, 24))	('slowed', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mice', 'Species', '10090', (52, 56))	('CD8', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('aging', 'biological_process', 'GO:0007568', ('162', '167'))	('CD8', 'Gene', '925', (28, 31))
147394	30906657	In fact, cisplatin appeared to numerically re-focus the tumor-infiltrating response back onto the dominant SIINFEKL epitope.	('cisplatin', 'Var', (9, 18))	('dominant SIINFEKL epitope', 'Disease', 'MESH:D017827', (98, 123))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('re-focus', 'PosReg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('dominant SIINFEKL epitope', 'Disease', (98, 123))
147444	30906657	Samples were blocked with CD16/32 (Biolegend) for 30 minutes at 4 C in the dark and the following anti-mouse primary antibodies and pentamers incubated for 1 hour at 4 C in the dark: anti-CD3-APC-Cy7 (clone 1452C11, BD), anti-CD8alpha-PerCP-Cy5 (clone 53-6.7, BD), SIINFEKL-PE (ProImmune), KVVRFDKL-APC (ProImmune) and B220-PE-Cy7 (RA3-6B2, Biolegend).	('CD3', 'Gene', (188, 191))	('SIINFEKL', 'Disease', (265, 273))	('KVVRFDKL-APC', 'Disease', 'MESH:D011125', (290, 302))	('CD8', 'Gene', (226, 229))	('CD3', 'Gene', '12501', (188, 191))	('mouse', 'Species', '10090', (103, 108))	('KVVRFDKL-APC', 'Disease', (290, 302))	('CD8', 'Gene', '925', (226, 229))	('APC', 'cellular_component', 'GO:0005680', ('299', '302'))	('SIINFEKL', 'Disease', 'None', (265, 273))	('clone 1452C11', 'Var', (201, 214))	('APC', 'cellular_component', 'GO:0005680', ('192', '195'))
147464	29575535	Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma Although tumour PD-L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD-L1 axis in various cancers, the regulation of PD-L1 (CD274) expression is unclear.	('CD274', 'Gene', '29126', (140, 145))	('CD274', 'Gene', '29126', (59, 64))	('tumour PD-L1', 'Disease', 'MESH:D010300', (126, 138))	('expression', 'MPA', (66, 76))	('CD274', 'Gene', (300, 305))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('down-regulates', 'NegReg', (37, 51))	('PD1', 'Gene', '5133', (240, 243))	('tumour PD-L1', 'Disease', (126, 138))	('PD-L1', 'Gene', (133, 138))	('yes-associated protein', 'Gene', (14, 36))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('CD274', 'Gene', (59, 64))	('PD-L1', 'Gene', (244, 249))	('CD274', 'Gene', (140, 145))	('pleural mesothelioma', 'Disease', (96, 116))	('PD-L1', 'Gene', '29126', (133, 138))	('human', 'Species', '9606', (80, 85))	('regulation', 'biological_process', 'GO:0065007', ('279', '289'))	('PD-L1', 'Gene', '29126', (244, 249))	('PD-L1', 'Gene', (293, 298))	('PD-L1', 'Gene', '29126', (293, 298))	('Inhibition', 'Var', (0, 10))	('PD-L1', 'Gene', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('PD-L1', 'Gene', '29126', (52, 57))	('PD1', 'Gene', (240, 243))	('cancers', 'Disease', (266, 273))	('yes-associated protein', 'Gene', '10413', (14, 36))	('CD274', 'Gene', '29126', (300, 305))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (96, 116))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (96, 116))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
147468	29575535	In H2052 and 211H cells, PD-L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD-L1 protein and mRNA expression.	('PD-L1', 'Gene', '29126', (158, 163))	('increased', 'PosReg', (65, 74))	('H2052', 'CellLine', 'CVCL:1518', (3, 8))	('PD-L1', 'Gene', '29126', (25, 30))	('small interfering', 'Var', (126, 143))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('decreased', 'NegReg', (148, 157))	('YAP', 'Gene', '10413', (109, 112))	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('PD-L1', 'Gene', (158, 163))	('YAP', 'Gene', (109, 112))	('decreased PD', 'Phenotype', 'HP:0032198', (148, 160))	('PD-L1', 'Gene', (25, 30))	('mRNA expression', 'MPA', (176, 191))
147472	29575535	We conclude that PD-L1 is correlated with YAP expression, and inhibition of YAP down-regulates PD-L1 expression in human MPM.	('PD-L1', 'Gene', '29126', (17, 22))	('YAP', 'Gene', '10413', (76, 79))	('YAP', 'Gene', (42, 45))	('YAP', 'Gene', (76, 79))	('human', 'Species', '9606', (115, 120))	('PD-L1', 'Gene', (95, 100))	('inhibition', 'Var', (62, 72))	('PD-L1', 'Gene', (17, 22))	('down-regulates', 'NegReg', (80, 94))	('expression', 'MPA', (101, 111))	('YAP', 'Gene', '10413', (42, 45))	('PD-L1', 'Gene', '29126', (95, 100))
147475	29575535	Yes-associated protein (YAP) is a key oncogenic mediator in the Hippo signalling pathway and promotes tumorigenesis, invasion, metastasis and drug resistance in several cancers.14, 15, 16, 17, 18 YAP has also been identified in human MPM and is correlated with tumorigenesis and cancer development, suggesting YAP is a therapeutic target for treating advanced unresectable MPM.19, 20, 21 YAP regulates tumour-associated immune cells such as myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs).22, 23 YAP may be involved in the immune checkpoint.22, 23 Here, we sought to investigate whether YAP is involved in the regulation of PD-L1 expression of human MPM and whether inhibition of YAP down-regulates PD-L1 expression in human MPM.	('cancers', 'Disease', (169, 176))	('Yes-associated protein', 'Gene', (0, 22))	('YAP', 'Gene', (714, 717))	('YAP', 'Gene', (24, 27))	('cancer', 'Disease', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (402, 408))	('tumour', 'Disease', 'MESH:D009369', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('YAP', 'Gene', (310, 313))	('YAP', 'Gene', '10413', (621, 624))	('tumour', 'Disease', (402, 408))	('regulation', 'biological_process', 'GO:0065007', ('644', '654'))	('cancer', 'Disease', (279, 285))	('YAP', 'Gene', (196, 199))	('PD-L1', 'Gene', (658, 663))	('YAP', 'Gene', (530, 533))	('expression', 'MPA', (739, 749))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('down-regulates', 'NegReg', (718, 732))	('YAP', 'Gene', '10413', (388, 391))	('PD-L1', 'Gene', '29126', (658, 663))	('inhibition', 'Var', (700, 710))	('YAP', 'Gene', '10413', (24, 27))	('tumour', 'Phenotype', 'HP:0002664', (486, 492))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('YAP', 'Gene', '10413', (714, 717))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('YAP', 'Gene', '10413', (310, 313))	('tumour', 'Disease', 'MESH:D009369', (486, 492))	('Yes-associated protein', 'Gene', '10413', (0, 22))	('tumour', 'Disease', (486, 492))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('drug resistance', 'biological_process', 'GO:0009315', ('142', '157'))	('human', 'Species', '9606', (753, 758))	('drug resistance', 'biological_process', 'GO:0042493', ('142', '157'))	('YAP', 'Gene', '10413', (196, 199))	('human', 'Species', '9606', (228, 233))	('metastasis', 'Disease', (127, 137))	('YAP', 'Gene', (621, 624))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('signalling pathway', 'biological_process', 'GO:0007165', ('70', '88'))	('YAP', 'Gene', '10413', (530, 533))	('PD-L1', 'Gene', (733, 738))	('drug resistance', 'Phenotype', 'HP:0020174', (142, 157))	('PD-L1', 'Gene', '29126', (733, 738))	('human', 'Species', '9606', (678, 683))	('metastasis', 'Disease', 'MESH:D009362', (127, 137))	('YAP', 'Gene', (388, 391))
147510	29575535	Western blotting showed that H2052 and 211H cells had increased PD-L1 protein expression compared to the other 3 cell lines (H290, MS-1 and H28).	('MS-1 and H28', 'Gene', '4397', (131, 143))	('increased PD', 'Phenotype', 'HP:0008151', (54, 66))	('expression', 'MPA', (78, 88))	('H2052', 'Var', (29, 34))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('increased', 'PosReg', (54, 63))	('H290', 'CellLine', 'CVCL:A555', (125, 129))	('PD-L1', 'Gene', (64, 69))	('H2052', 'CellLine', 'CVCL:1518', (29, 34))	('PD-L1', 'Gene', '29126', (64, 69))
147513	29575535	Real-time PCR showed that H2052 and 211H cells had 6-fold higher PD-L1 (CD274) mRNA expression than LP-9, H290, MS-1, H28 and H2452 cells (P < .001) (Figure 1C).	('H290', 'CellLine', 'CVCL:A555', (106, 110))	('H2452', 'CellLine', 'CVCL:1553', (126, 131))	('CD274', 'Gene', '29126', (72, 77))	('LP', 'Chemical', 'MESH:D008070', (100, 102))	('PD-L1', 'Gene', (65, 70))	('H2052', 'Var', (26, 31))	('higher', 'PosReg', (58, 64))	('mRNA expression', 'MPA', (79, 94))	('H2052', 'CellLine', 'CVCL:1518', (26, 31))	('PD-L1', 'Gene', '29126', (65, 70))	('CD274', 'Gene', (72, 77))
147517	29575535	The growth rate of cells with high YAP and PD-L1 expression (H2052 and 211H) was much higher than cells with low PD-L1 expression (Figure S1B).	('YAP', 'Gene', (35, 38))	('growth rate', 'CPA', (4, 15))	('PD-L1', 'Gene', '29126', (43, 48))	('PD-L1', 'Gene', (113, 118))	('PD-L1', 'Gene', (43, 48))	('211H', 'Var', (71, 75))	('PD-L1', 'Gene', '29126', (113, 118))	('H2052', 'Var', (61, 66))	('higher', 'PosReg', (86, 92))	('YAP', 'Gene', '10413', (35, 38))	('H2052', 'CellLine', 'CVCL:1518', (61, 66))
147518	29575535	Our results indicate that H2052 and 211H cells had increased PD-L1 protein expression and that PD-L1 mRNA expression is greater in the 2 cell lines than in other mesothelioma cell lines.	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('increased', 'PosReg', (51, 60))	('PD-L1', 'Gene', (61, 66))	('PD-L1', 'Gene', (95, 100))	('mesothelioma', 'Disease', (162, 174))	('PD-L1', 'Gene', '29126', (61, 66))	('H2052', 'Var', (26, 31))	('increased PD', 'Phenotype', 'HP:0008151', (51, 63))	('H2052', 'CellLine', 'CVCL:1518', (26, 31))	('PD-L1', 'Gene', '29126', (95, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))	('mRNA expression', 'MPA', (101, 116))
147520	29575535	After YAP knockdown by YAP siRNA in both cell lines, PD-L1 protein expression decreased in both cell lines, as shown by Western blotting (Figure 2A).	('PD-L1', 'Gene', (53, 58))	('YAP', 'Gene', (6, 9))	('protein', 'Protein', (59, 66))	('YAP', 'Gene', '10413', (23, 26))	('PD-L1', 'Gene', '29126', (53, 58))	('YAP', 'Gene', '10413', (6, 9))	('YAP', 'Gene', (23, 26))	('decreased', 'NegReg', (78, 87))	('knockdown', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
147522	29575535	Finally, transcriptional activities of YAP downstream genes AREG and CTGF were significantly decreased in H2052 and 211H cells after YAP knockdown by YAP siRNA (Figure 2H,I).	('H2052', 'CellLine', 'CVCL:1518', (106, 111))	('CTGF', 'Gene', (69, 73))	('YAP', 'Gene', '10413', (133, 136))	('AREG', 'Gene', (60, 64))	('YAP', 'Gene', '10413', (150, 153))	('decreased', 'NegReg', (93, 102))	('YAP', 'Gene', '10413', (39, 42))	('AREG', 'Gene', '374', (60, 64))	('knockdown', 'Var', (137, 146))	('transcriptional activities', 'MPA', (9, 35))	('YAP', 'Gene', (150, 153))	('YAP', 'Gene', (39, 42))	('YAP', 'Gene', (133, 136))	('CTGF', 'Gene', '1490', (69, 73))
147523	29575535	Our results indicate that YAP knockdown by YAP siRNA decreased PD-L1 expression at both protein and mRNA levels in mesothelioma H2052 and 211H cells.	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('decreased', 'NegReg', (53, 62))	('YAP', 'Gene', '10413', (26, 29))	('YAP', 'Gene', '10413', (43, 46))	('expression', 'MPA', (69, 79))	('mesothelioma H2052', 'Disease', 'MESH:D008654', (115, 133))	('PD-L1', 'Gene', (63, 68))	('mesothelioma H2052', 'Disease', (115, 133))	('knockdown', 'Var', (30, 39))	('YAP', 'Gene', (43, 46))	('YAP', 'Gene', (26, 29))	('decreased PD', 'Phenotype', 'HP:0032198', (53, 65))	('PD-L1', 'Gene', '29126', (63, 68))
147542	29575535	YAP staining in the nucleus was negative (-) in 15.7% of the samples, weak (+) in 30.0% and moderate to strong (++/+++) in 54.3% (Figure 6D,F,H,L,N,P, Table 1).	('++/+++', 'Var', (112, 118))	('YAP', 'Gene', (0, 3))	('YAP', 'Gene', '10413', (0, 3))	('nucleus', 'cellular_component', 'GO:0005634', ('20', '27'))
147551	29575535	Our study showed this coexpression in 31.4% (22/70) of MPM samples and that the PD-L1-positive ratio was higher in moderate to strong nucleus YAP staining samples than in negative to weak nucleus YAP staining samples (P < .05, chi-square).	('YAP', 'Gene', '10413', (142, 145))	('PD-L1', 'Gene', (80, 85))	('higher', 'PosReg', (105, 111))	('YAP', 'Gene', (142, 145))	('nucleus', 'cellular_component', 'GO:0005634', ('188', '195'))	('PD-L1', 'Gene', '29126', (80, 85))	('YAP', 'Gene', '10413', (196, 199))	('MPM', 'Disease', (55, 58))	('nucleus', 'cellular_component', 'GO:0005634', ('134', '141'))	('moderate', 'Var', (115, 123))	('YAP', 'Gene', (196, 199))
147557	29575535	We previously reported that YAP is frequently activated in human MPM and suggested YAP as a potential therapeutic target.20, 21 Our current study shows that inhibition of YAP down-regulates PD-L1 expression in H2052 and 211H cells.	('YAP', 'Gene', '10413', (83, 86))	('human', 'Species', '9606', (59, 64))	('down-regulates', 'NegReg', (175, 189))	('PD-L1', 'Gene', (190, 195))	('YAP', 'Gene', (83, 86))	('PD-L1', 'Gene', '29126', (190, 195))	('YAP', 'Gene', (28, 31))	('expression', 'MPA', (196, 206))	('inhibition', 'Var', (157, 167))	('YAP', 'Gene', '10413', (171, 174))	('H2052', 'CellLine', 'CVCL:1518', (210, 215))	('YAP', 'Gene', '10413', (28, 31))	('YAP', 'Gene', (171, 174))
147559	29575535	Moreover, we recently reported a correlation between YAP and EGFR/extracellular signal-regulated kinase (ERK) signalling pathways in human NSCLC cells with EGFR mutation.16, 17 We showed that inhibiting the EGFR/ERK signalling pathway decreased YAP expression in EGFR-mutant human NSCLC cells.	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('YAP', 'Gene', (245, 248))	('signalling', 'biological_process', 'GO:0023052', ('110', '120'))	('ERK', 'Gene', '5595;5594;5595', (212, 215))	('expression', 'MPA', (249, 259))	('signalling pathway', 'biological_process', 'GO:0007165', ('216', '234'))	('EGFR', 'Gene', '1956', (156, 160))	('ERK', 'Gene', (105, 108))	('EGFR', 'Gene', (207, 211))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('YAP', 'Gene', (53, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('human', 'Species', '9606', (133, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('263', '267'))	('EGFR', 'Gene', (263, 267))	('EGFR', 'Gene', '1956', (61, 65))	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('NSCLC', 'Disease', 'MESH:D002289', (281, 286))	('YAP', 'Gene', '10413', (245, 248))	('extracellular', 'cellular_component', 'GO:0005576', ('66', '79'))	('ERK', 'Gene', '5595;5594;5595', (105, 108))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', (281, 286))	('decreased', 'NegReg', (235, 244))	('ERK', 'molecular_function', 'GO:0004707', ('212', '215'))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (281, 286))	('EGFR', 'Gene', '1956', (207, 211))	('human', 'Species', '9606', (275, 280))	('YAP', 'Gene', '10413', (53, 56))	('EGFR', 'Gene', (156, 160))	('EGFR', 'Gene', '1956', (263, 267))	('inhibiting', 'Var', (192, 202))	('ERK', 'Gene', (212, 215))	('EGFR', 'Gene', (61, 65))
147562	29575535	YAP is one of the factors that regulate PD-L1 expression, and other factors may be involved in regulating PD-L1 expression in various cancers.29, 30, 31, 32 For example, TAZ, another mediator of the Hippo signalling, was reported to contribute to PD-L1 regulation in human lung cancer cells.29  To our knowledge, our study is the first to show that inhibition of YAP down-regulates PD-L1 expression in human MPM.	('YAP', 'Gene', (0, 3))	('PD-L1', 'Gene', '29126', (382, 387))	('lung cancer', 'Disease', 'MESH:D008175', (273, 284))	('PD-L1', 'Gene', (247, 252))	('YAP', 'Gene', (363, 366))	('signalling', 'biological_process', 'GO:0023052', ('205', '215'))	('PD-L1', 'Gene', '29126', (247, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (273, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('PD-L1', 'Gene', (40, 45))	('cancers', 'Disease', (134, 141))	('YAP', 'Gene', '10413', (0, 3))	('PD-L1', 'Gene', '29126', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TAZ', 'Gene', '6901', (170, 173))	('TAZ', 'Gene', (170, 173))	('regulation', 'biological_process', 'GO:0065007', ('253', '263'))	('expression', 'MPA', (388, 398))	('inhibition', 'Var', (349, 359))	('YAP', 'Gene', '10413', (363, 366))	('human', 'Species', '9606', (267, 272))	('lung cancer', 'Disease', (273, 284))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('down-regulates', 'NegReg', (367, 381))	('human', 'Species', '9606', (402, 407))	('PD-L1', 'Gene', (106, 111))	('PD-L1', 'Gene', '29126', (106, 111))	('PD-L1', 'Gene', (382, 387))
147585	29699510	For example, activation of natural killer T cells, depletion of regulatory T (Treg) cells, or systemic blockade of the immune checkpoint inhibitory regulator of T-cell immunity CTLA-4, between cycles of chemotherapy, was shown to inhibit cancer cell repopulation by enhancing specific antitumor immunity in murine mesothelioma.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('cancer', 'Disease', (238, 244))	('enhancing', 'PosReg', (266, 275))	('mesothelioma', 'Disease', 'MESH:D008654', (314, 326))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('CTLA-4', 'Gene', '12477', (177, 183))	('murine', 'Species', '10090', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Disease', (289, 294))	('CTLA-4', 'Gene', (177, 183))	('activation', 'PosReg', (13, 23))	('inhibit', 'NegReg', (230, 237))	('mesothelioma', 'Disease', (314, 326))	('blockade', 'Var', (103, 111))	('depletion', 'Var', (51, 60))
147644	29699510	Only in the groups treated with cisplatin, a decrease of non-green cells, i.e., a higher fraction of GFP+ cells was evident (Fig.	('non-green cells', 'CPA', (57, 72))	('cisplatin', 'Var', (32, 41))	('higher', 'PosReg', (82, 88))	('decrease', 'NegReg', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('GFP+ cells', 'CPA', (101, 111))
147696	29699510	Modified DCs may be a promising therapy for treating drug-resistant cancer cells as well as CSC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Modified', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('CSC', 'Disease', (92, 95))
147721	29069806	From the aforementioned results, BAP1 inactivation is expected to affect transcription regulation, either through direct gene expression dysregulation or chromatin structure perturbation.	('transcription regulation', 'MPA', (73, 97))	('affect', 'Reg', (66, 72))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('inactivation', 'Var', (38, 50))	('BAP1', 'Gene', '8314', (33, 37))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('BAP1', 'Gene', (33, 37))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))
147743	29069806	Finally, a high number of proteins involved in detoxification, anti-oxidation, and / or being NRF2 targets were found significantly over-expressed by SILAC/MS in a pCDH1_BAP1wt expression context, suggesting an increased intra-cellular ROS level (Supplementary Figure 2C).	('BAP1wt', 'Gene', (170, 176))	('pCDH1', 'Gene', (164, 169))	('NRF2', 'Gene', '4780', (94, 98))	('increased intra-cellular ROS level', 'Phenotype', 'HP:0025464', (211, 245))	('NRF2', 'Gene', (94, 98))	('SILAC/MS', 'Var', (150, 158))	('pCDH1', 'Gene', '5097', (164, 169))	('increased', 'PosReg', (211, 220))	('over-expressed', 'PosReg', (132, 146))	('detoxification', 'biological_process', 'GO:0098754', ('47', '61'))	('ROS', 'Chemical', 'MESH:D017382', (236, 239))	('BAP1wt', 'Gene', '8314', (170, 176))	('proteins', 'Protein', (26, 34))
147745	29069806	In order to confirm the phenotypes predicted by IPA on the SILAC-based proteomics data and to determine the involvement of BAP1 catalytic activity, NCI-H226 and QR (also known as MPM_33) mesothelioma cell lines were complemented with pBABE retroviral vector alone (EV), pBABE expressing a wild-type BAP1 protein (BAP1wt), or the same vector expressing a catalytically dead BAP1 protein carrying the C91S point mutation (BAP1C91S) (Supplementary Figure 3A&3B).This mutation specifically affects the catalytic cysteine and prevents BAP1 deubiquitinase activity.	('EV', 'Chemical', '-', (265, 267))	('protein', 'cellular_component', 'GO:0003675', ('378', '385'))	('BAP1', 'Gene', '8314', (420, 424))	('C91S', 'Mutation', 'p.C91S', (424, 428))	('catalytic activity', 'molecular_function', 'GO:0003824', ('128', '146'))	('BAP1', 'Gene', (373, 377))	('prevents', 'Enzyme', (521, 529))	('BAP1', 'Gene', '8314', (299, 303))	('C91S', 'Mutation', 'p.C91S', (399, 403))	('NCI-H226', 'CellLine', 'CVCL:1544', (148, 156))	('BAP1', 'Gene', '8314', (530, 534))	('the catalytic', 'MPA', (494, 507))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', (420, 424))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('535', '558'))	('BAP1', 'Gene', '8314', (313, 317))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('BAP1', 'Gene', (299, 303))	('BAP1', 'Gene', (530, 534))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('535', '558'))	('specifically', 'Reg', (473, 485))	('BAP1', 'Gene', (123, 127))	('and', 'NegReg', (517, 520))	('BAP1', 'Gene', (313, 317))	('BAP1wt', 'Gene', '8314', (313, 319))	('mesothelioma', 'Disease', (187, 199))	('BAP1', 'Gene', '8314', (373, 377))	('.This', 'Var', (458, 463))	('BAP1wt', 'Gene', (313, 319))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))
147749	29069806	Immunofluorescence revealed an expected CDH2 membrane localization in control EV cells and upon expression of BAP1C91S.	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('CDH2', 'Gene', (40, 44))	('CDH2', 'Gene', '1000', (40, 44))	('BAP1C91S', 'Var', (110, 118))	('membrane', 'cellular_component', 'GO:0016020', ('45', '53'))	('EV', 'Chemical', '-', (78, 80))
147763	29069806	Of note, the expression of BAP1C91S resulted in a decrease of respiratory capacities in NCI-H226 cell line compared to the empty vector, Figure 3E, p<0.05), while EV and BAP1C91S have similar respiratory capacities in QR cell line (Figure 3F).	('respiratory capacities', 'MPA', (62, 84))	('EV', 'Chemical', '-', (163, 165))	('BAP1C91S', 'Var', (27, 35))	('NCI-H226', 'CellLine', 'CVCL:1544', (88, 96))	('decrease', 'NegReg', (50, 58))
147768	29069806	Of note, the expression of BAP1C91S resulted in a significant increase of ROS level in NCI-H226 cell line compared to the empty vector (p<0.05; Figure 4B) while EV and BAP1C91S have similar ROS levels in QR cell line (Figure 4A&4B).	('BAP1C91S', 'Var', (27, 35))	('increase of ROS level', 'Phenotype', 'HP:0025464', (62, 83))	('NCI-H226', 'CellLine', 'CVCL:1544', (87, 95))	('EV', 'Chemical', '-', (161, 163))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('ROS level', 'MPA', (74, 83))	('increase', 'PosReg', (62, 70))
147770	29069806	CAT expression measured by qPCR confirmed a 1.5-fold and 3-fold increased expression level associated with BAP1wt expression compared to either EV or mutant BAP1C91S expressing cells in NCI-H226 and QR, respectively (Figure 4C).	('CAT', 'molecular_function', 'GO:0004096', ('0', '3'))	('NCI-H226', 'CellLine', 'CVCL:1544', (186, 194))	('BAP1C91S', 'Gene', (157, 165))	('BAP1wt', 'Gene', '8314', (107, 113))	('BAP1wt', 'Gene', (107, 113))	('expression level', 'MPA', (74, 90))	('EV', 'Chemical', '-', (144, 146))	('increased', 'PosReg', (64, 73))	('mutant', 'Var', (150, 156))
147772	29069806	NCI-H226 expressing EV or mutant BAP1C91S showed significantly lower intracellular ROS levels compared to BAP1wt (p<0.05; Figure 4B), and ROS levels did not fluctuate under antioxidant treatment (Supplementary Figure 7), and EV and mutant BAP1C91S expressing NCI-H226 show similar level of ROS management proteins.	('intracellular ROS levels', 'MPA', (69, 93))	('BAP1C91S', 'Gene', (33, 41))	('lower', 'NegReg', (63, 68))	('BAP1wt', 'Gene', '8314', (106, 112))	('ROS management proteins', 'MPA', (290, 313))	('EV', 'Chemical', '-', (225, 227))	('NCI-H226', 'CellLine', 'CVCL:1544', (259, 267))	('NCI-H226', 'Gene', (259, 267))	('BAP1wt', 'Gene', (106, 112))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('EV', 'Chemical', '-', (20, 22))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('NCI-H226', 'CellLine', 'CVCL:1544', (0, 8))	('mutant', 'Var', (26, 32))	('ROS', 'Chemical', 'MESH:D017382', (290, 293))
147780	29069806	Importantly, BAP1wt expressing cells were significantly more affected by H2O2 treatment than control EV cells (p<0.05, Figure 4E).	('H2O2', 'Chemical', 'MESH:D006861', (73, 77))	('H2O2', 'Var', (73, 77))	('BAP1wt', 'Gene', '8314', (13, 19))	('EV', 'Chemical', '-', (101, 103))	('affected', 'Reg', (61, 69))	('BAP1wt', 'Gene', (13, 19))
147782	29069806	After 400muM H2O2, BAP1wt cells had a 50% survival rate and EV cells had 15% survival rate, which is a 3-fold difference (p<0.01, Figure 4F).	('BAP1wt', 'Gene', (19, 25))	('EV', 'Chemical', '-', (60, 62))	('muM', 'Gene', '56925', (9, 12))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('H2O2', 'Var', (13, 17))	('BAP1wt', 'Gene', '8314', (19, 25))	('muM', 'Gene', (9, 12))
147794	29069806	Hence, no consistent transcriptional signature has been associated to BAP1 inactivation among the BAP1-associated tumors, although histone H2A deubiquitination and interactions with numerous transcriptomic factors are strongly supported by an abundant literature.	('BAP1', 'Gene', (98, 102))	('inactivation', 'Var', (75, 87))	('histone H2A', 'Protein', (131, 142))	('deubiquitination', 'biological_process', 'GO:0016579', ('143', '159'))	('BAP1', 'Gene', '8314', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('interactions', 'Interaction', (164, 176))	('BAP1', 'Gene', (70, 74))	('tumors', 'Disease', (114, 120))	('deubiquitination', 'MPA', (143, 159))	('BAP1', 'Gene', '8314', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
147796	29069806	Parallel investigation of transcriptomic and proteomic consequences of BAP1 expression modulation revealed major protein dysregulations.	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('modulation', 'Var', (87, 97))	('BAP1', 'Gene', '8314', (71, 75))	('protein dysregulations', 'MPA', (113, 135))	('BAP1', 'Gene', (71, 75))
147801	29069806	However, mutant BAP1 expression led to some phenotypic differences, suggesting that the catalytically inactive BAP1 may maintain some biological activities - possibly a scaffold or a dominant negative protein.	('BAP1', 'Gene', '8314', (111, 115))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('mutant', 'Var', (9, 15))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (16, 20))	('biological activities', 'MPA', (134, 155))	('BAP1', 'Gene', (16, 20))
147810	29069806	Interestingly, our results suggest that mesothelioma cells expressing wild-type BAP1 are more aggressive, which is consistent with clinical studies associating BAP1 expression with worse prognosis in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('aggressive', 'CPA', (94, 104))	('BAP1', 'Gene', '8314', (160, 164))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', (160, 164))	('mesothelioma', 'Disease', (200, 212))	('BAP1', 'Gene', (80, 84))	('mesothelioma', 'Disease', (40, 52))	('wild-type', 'Var', (70, 79))
147812	29069806	Interestingly, morphologic changes were also observed after BAP1 expression modulation in uveal melanoma cell lines, although no loss of cellular identity was observed in our study.	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('modulation', 'Var', (76, 86))	('uveal melanoma', 'Disease', (90, 104))	('expression modulation', 'Var', (65, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('BAP1', 'Gene', '8314', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BAP1', 'Gene', (60, 64))
147829	29069806	In uveal melanoma, BAP1 inactivation is associated with metastasis development and worse prognosis.	('uveal melanoma', 'Disease', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('inactivation', 'Var', (24, 36))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (19, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('associated', 'Reg', (40, 50))	('metastasis development', 'CPA', (56, 78))
147830	29069806	In clear cell renal cell carcinoma, BAP1 inactivation defines a specific subtype of cancer of worse prognosis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('cancer', 'Disease', (84, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('inactivation', 'Var', (41, 53))	('BAP1', 'Gene', '8314', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('BAP1', 'Gene', (36, 40))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
147831	29069806	Interestingly, in mesothelioma, BAP1 inactivation is associated with less aggressive tumors and a better outcome.	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('BAP1', 'Gene', '8314', (32, 36))	('aggressive tumors', 'Disease', (74, 91))	('mesothelioma', 'Disease', (18, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('BAP1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('inactivation', 'Var', (37, 49))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
147834	29069806	Antioxidant treatment partially abrogated the phenotypes, supporting the sensing and/or management of ROS as the most direct function altered by BAP1 expression modulation, cellular morphology and respiration defects most likely being at least in part consequence of increased intracellular oxidative stress.	('modulation', 'Var', (161, 171))	('intracellular', 'cellular_component', 'GO:0005622', ('277', '290'))	('expression modulation', 'Var', (150, 171))	('ROS', 'Chemical', 'MESH:D017382', (102, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (291, 307))	('respiration', 'biological_process', 'GO:0045333', ('197', '208'))	('respiration', 'MPA', (197, 208))	('BAP1', 'Gene', '8314', (145, 149))	('altered', 'Reg', (134, 141))	('BAP1', 'Gene', (145, 149))	('respiration', 'biological_process', 'GO:0007585', ('197', '208'))
147861	29069806	We set carbamidomethyl cysteine, oxidation of methionine, N-terminal acetylation, heavy 13C615N2-Lysine (Lys8) and 13C615N4-Arginine (Arg10) as variable modifications.	('Arg10', 'Chemical', '-', (134, 139))	('methionine', 'Chemical', 'MESH:D008715', (46, 56))	('N-terminal acetylation', 'MPA', (58, 80))	('Lys8', 'Chemical', '-', (105, 109))	('carbamidomethyl cysteine', 'Chemical', 'MESH:C034636', (7, 31))	('oxidation', 'MPA', (33, 42))	('13C615N2-Lysine', 'Chemical', '-', (88, 103))	('13C615N2-Lysine', 'Var', (88, 103))	('13C615N4-Arginine', 'Var', (115, 132))	('13C615N4-Arginine', 'Chemical', '-', (115, 132))
147939	23486267	Additionally, low TS levels have been shown to predict better outcomes in patients with non-squamous non-small cell lung cancer treated with Pem.	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (74, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('non-squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (88, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('better', 'PosReg', (55, 61))	('non-squamous non-small cell lung cancer', 'Disease', (88, 127))	('low', 'Var', (14, 17))	('TS', 'Gene', '7298', (18, 20))	('Pem', 'Chemical', 'MESH:D000068437', (141, 144))
147998	23486267	We did not find a significant association between high and low FPGS expression and median TTP (p = 0.77), median OS (p = 0.43) or DCR (p = 0.95).	('median TTP', 'Disease', (83, 93))	('DCR', 'Chemical', '-', (130, 133))	('median OS', 'Disease', (106, 115))	('low', 'NegReg', (59, 62))	('FPGS', 'Gene', (63, 67))	('FPGS', 'Gene', '2356', (63, 67))	('DCR', 'Disease', (130, 133))	('OS', 'Chemical', '-', (113, 115))	('high', 'Var', (50, 54))
148001	23486267	In patients with a high FPGS/TS ratio there was a higher TTP (7.5 months vs. 6 months; p = 0.10), OS (13 months vs. 12 months; p = 0.43), and DCR (76.3% vs. 64.9%; p = 0.27) but these differences were not statistically significant.	('high', 'Var', (19, 23))	('higher', 'PosReg', (50, 56))	('DCR', 'MPA', (142, 145))	('OS', 'Chemical', '-', (98, 100))	('FPGS', 'Gene', (24, 28))	('FPGS', 'Gene', '2356', (24, 28))	('patients', 'Species', '9606', (3, 11))	('TTP', 'MPA', (57, 60))	('TS', 'Gene', '7298', (29, 31))	('DCR', 'Chemical', '-', (142, 145))
148018	23486267	Although the median TTP (8 months vs 6 months) and OS (14 months vs 11 months) were longer in our low TS versus high TS group, these differences did not reach statistical significance.	('OS', 'Chemical', '-', (51, 53))	('low', 'Var', (98, 101))	('TS', 'Gene', '7298', (102, 104))	('TS', 'Gene', '7298', (117, 119))	('TTP', 'MPA', (20, 23))
148106	15700034	Nevertheless, the absence of viral infection was confirmed by PCR with two sets of primers (orf 26 and orf 75) (not shown).	('viral infection', 'Disease', 'MESH:D001102', (29, 44))	('viral infection', 'biological_process', 'GO:0016032', ('29', '44'))	('orf', 'Var', (103, 106))	('viral infection', 'Disease', (29, 44))
148132	15700034	However, immunodetection of SV40 Tag is not commonly recognised as a diagnostic marker enabling the distinction between mesothelioma and adenocarcinoma, or between mesothelioma and reactive mesothelial hyperplasia (Jasani, 1999).	('SV40 Tag', 'Var', (28, 36))	('mesothelioma', 'Disease', (120, 132))	('adenocarcinoma', 'Disease', (137, 151))	('mesothelial hyperplasia', 'Disease', (190, 213))	('mesothelioma', 'Disease', (164, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('adenocarcinoma', 'Disease', 'MESH:D000230', (137, 151))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('SV40', 'Species', '1891767', (28, 32))	('mesothelial hyperplasia', 'Disease', 'MESH:D018301', (190, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
148253	30924615	Furthermore, manipulation of non-friable asbestos-containing products may also release asbestos in the short term, resulting in high personal exposures, as it has been shown for auto mechanics.	('asbestos', 'Chemical', 'MESH:D001194', (41, 49))	('asbestos', 'Chemical', 'MESH:D001194', (87, 95))	('release asbestos', 'MPA', (79, 95))	('manipulation', 'Var', (13, 25))	('personal exposures', 'MPA', (133, 151))	('person', 'Species', '9606', (133, 139))
148324	30924615	An ethnographic study conducted in Bari (Southern Italy), where the A/C plant Fibronit was operative from 1935 to 1989, has shown that the absence of risk perception of asbestos dangers among the general citizenry and in public discourses worsened the seriousness of contamination and prolonged its impact on citizens' health.	('rat', 'Species', '10116', (94, 97))	('seriousness', 'MPA', (252, 263))	('absence', 'Var', (139, 146))	('worsened', 'NegReg', (239, 247))	('prolonged', 'PosReg', (285, 294))	('asbestos', 'Chemical', 'MESH:D001194', (169, 177))	('contamination', 'MPA', (267, 280))
148374	26284517	We found that a subset of mesothelioma spheroids is sensitive to GDC-0980 alone and to its combination with chemotherapy.	('mesothelioma', 'Disease', (26, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (26, 48))	('GDC-0980', 'Var', (65, 73))	('sensitive', 'Reg', (52, 61))	('GDC-0980', 'Chemical', 'MESH:C569670', (65, 73))
148375	26284517	Instead, sensitivity to GDC-0980 correlated with the presence of constitutive ATG13 puncta, a feature of autophagy, a cellular program that supports cells under stress.	('correlated', 'Reg', (33, 43))	('ATG13', 'Gene', (78, 83))	('GDC-0980', 'Var', (24, 32))	('ATG13', 'Gene', '9776', (78, 83))	('autophagy', 'biological_process', 'GO:0016236', ('105', '114'))	('GDC-0980', 'Chemical', 'MESH:C569670', (24, 32))	('autophagy', 'biological_process', 'GO:0006914', ('105', '114'))
148376	26284517	In tumor fragment spheroids grown from 21 tumors, we also found a subset (n = 11) that was sensitive to GDC-0980, a sensitivity that also correlated with the presence of ATG13 puncta.	('GDC-0980', 'Chemical', 'MESH:C569670', (104, 112))	('sensitive', 'Reg', (91, 100))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ATG13', 'Gene', (170, 175))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('ATG13', 'Gene', '9776', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('GDC-0980', 'Var', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
148379	26284517	In summary, we show that GDC-0980 is effective in mesothelioma 3D models that display ATG13 puncta, and that blockade of autophagy increases their response to chemotherapy.	('ATG13', 'Gene', (86, 91))	('autophagy', 'biological_process', 'GO:0016236', ('121', '130'))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('ATG13', 'Gene', '9776', (86, 91))	('autophagy', 'CPA', (121, 130))	('autophagy', 'biological_process', 'GO:0006914', ('121', '130'))	('increases', 'PosReg', (131, 140))	('GDC-0980', 'Var', (25, 33))	('response', 'MPA', (147, 155))	('mesothelioma', 'Disease', (50, 62))	('GDC-0980', 'Chemical', 'MESH:C569670', (25, 33))	('blockade', 'Var', (109, 117))
148385	26284517	We have previously tested several inhibitors of the PI3K/Akt (LY294002 and wortmannin) and mTOR (rapamycin) pathways or both (PI-103), by using 3D mesothelioma models grown from cell lines (multicellular spheroids) and actual tumor (tumor fragment spheroids).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('wortmannin', 'Chemical', 'MESH:D000077191', (75, 85))	('mesothelioma', 'Disease', (147, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('PI3K/Akt', 'Pathway', (52, 60))	('tested', 'Reg', (19, 25))	('LY294002', 'Var', (62, 70))	('tumor', 'Disease', (233, 238))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('actual tumor', 'Disease', 'MESH:D009369', (219, 231))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('LY294002', 'Chemical', 'MESH:C085911', (62, 70))	('actual tumor', 'Disease', (219, 231))	('rapamycin', 'Chemical', 'MESH:D020123', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (226, 231))	('mTOR', 'Pathway', (91, 95))
148387	26284517	GDC-0980 has also been shown to be effective in in vitro studies of mesothelioma, in combination with a MET inhibitor.	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))	('mesothelioma', 'Disease', (68, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('GDC-0980', 'Var', (0, 8))
148391	26284517	Indeed, GDC-0980 has been reported, like other PI3K/mTOR inhibitors, to induce autophagy; nonetheless, little is known about how autophagy is altered by GDC-0980 in 3D.	('GDC-0980', 'Var', (153, 161))	('autophagy', 'CPA', (79, 88))	('GDC-0980', 'Chemical', 'MESH:C569670', (8, 16))	('GDC-0980', 'Chemical', 'MESH:C569670', (153, 161))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))
148392	26284517	In the present work, we demonstrate that GDC-0980 is active in a subset of mesotheliomas, regardless of the activation of the Akt/mTOR pathway.	('GDC-0980', 'Var', (41, 49))	('GDC-0980', 'Chemical', 'MESH:C569670', (41, 49))	('Akt/mTOR pathway', 'Pathway', (126, 142))	('mesotheliomas', 'Disease', 'MESH:D008654', (75, 88))	('mesotheliomas', 'Disease', (75, 88))
148393	26284517	In this sensitive subset, autophagy is induced by GDC-0980 and its inhibition further sensitizes these spheroids to chemotherapy.	('autophagy', 'biological_process', 'GO:0006914', ('26', '35'))	('GDC-0980', 'Var', (50, 58))	('inhibition', 'NegReg', (67, 77))	('induced', 'Reg', (39, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (50, 58))	('autophagy', 'CPA', (26, 35))	('autophagy', 'biological_process', 'GO:0016236', ('26', '35'))
148400	26284517	Bortezomib (25 nM), GDC-0980 (1 muM) and vorinostat (5 muM) were from Selleck Chem (Boston, MA, USA).	('muM', 'Gene', '56925', (55, 58))	('vorinostat', 'Chemical', 'MESH:D000077337', (41, 51))	('Bortezomib', 'Chemical', 'MESH:D000069286', (0, 10))	('GDC-0980', 'Var', (20, 28))	('muM', 'Gene', '56925', (32, 35))	('muM', 'Gene', (55, 58))	('GDC-0980', 'Chemical', 'MESH:C569670', (20, 28))	('muM', 'Gene', (32, 35))
148414	26284517	LC3 (#L7543) and tubulin (#T-6074) antibodies were from Sigma-Aldrich (St. Louis, MO, USA).	('LC3', 'Gene', '84557', (0, 3))	('#L7543', 'Var', (5, 11))	('LC3', 'Gene', (0, 3))	('#T-6074', 'Var', (26, 33))	('tubulin', 'Protein', (17, 24))
148415	26284517	P-AKTSer473 (#4060), P-S6KThr389 (#9234), P-ERK (#4370), Bid (#2002), ATG5 (#12994), ATG7 (#8558) and cleaved caspase 3 (#9661) antibodies were from Cell Signaling (Danver MA, USA).	('P-ERK', 'Gene', (42, 47))	('Bid', 'Gene', '637', (57, 60))	('Ser473', 'Chemical', '-', (5, 11))	('P-ERK', 'Gene', '9451', (42, 47))	('P-AKTSer473 (#4060', 'Var', (0, 18))	('#4370', 'Var', (49, 54))	('#9661', 'Var', (121, 126))	('ATG5', 'Gene', '9474', (70, 74))	('ATG7', 'Gene', '10533', (85, 89))	('caspase 3', 'Gene', (110, 119))	('Bid', 'Gene', (57, 60))	('caspase 3', 'Gene', '836', (110, 119))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('P-S6KThr389 (#9234', 'Var', (21, 39))	('#9234', 'Var', (34, 39))	('Signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('#4060', 'Var', (13, 18))	('ATG5', 'Gene', (70, 74))	('ATG7', 'Gene', (85, 89))	('#12994', 'Var', (76, 82))
148419	26284517	Control (12935-400), Bim (s195011), Bid (s1986), ATG5 (HSS114104) and ATG7 (s20651) siRNA were purchased from Life Technologies (Carlsbad, CA, USA).	('Bid', 'Gene', (36, 39))	('ATG7', 'Gene', (70, 74))	('s195011', 'Var', (26, 33))	('Bim', 'Gene', (21, 24))	('HSS114104', 'Var', (55, 64))	('Bim', 'Gene', '10018', (21, 24))	('ATG5', 'Gene', (49, 53))	('ATG7', 'Gene', '10533', (70, 74))	('ATG5', 'Gene', '9474', (49, 53))	('12935-400', 'Var', (9, 18))	('s1986', 'Var', (41, 46))	('Bid', 'Gene', '637', (36, 39))
148431	26284517	The secondary antibodies for cleaved caspase 3 (#A11010 goat anti-rabbit AlexaFluor 546, Life Technologies, Carlsbad, CA, USA) and cytokeratin (RPN1001V biotinylated sheep anti-mouse, GE Healthcare and #A6374 NeutrAvidin streptavidin-conjugated oregon green-Life Technologies, Carlsbad, CA) both 1:200, were incubated for 60 min at RT in a humidified chamber.	('sheep', 'Species', '9940', (166, 171))	('AlexaFluor 546', 'Chemical', 'MESH:C481052', (73, 87))	('caspase 3', 'Gene', (37, 46))	('mouse', 'Species', '10090', (177, 182))	('#A11010', 'Var', (48, 55))	('caspase 3', 'Gene', '836', (37, 46))	('goat', 'Species', '9925', (56, 60))	('rabbit', 'Species', '9986', (66, 72))
148436	26284517	Spheroids with an apoptotic response both to GDC-0980 alone (compared to control) and to the combination of GDC-0980 plus chemotherapy (compared to chemotherapy alone) were considered sensitive to GDC-0980.	('GDC-0980', 'Chemical', 'MESH:C569670', (197, 205))	('apoptotic', 'CPA', (18, 27))	('GDC-0980', 'Var', (45, 53))	('GDC-0980', 'Chemical', 'MESH:C569670', (45, 53))	('GDC-0980', 'Chemical', 'MESH:C569670', (108, 116))
148438	26284517	Slides were then incubated overnight with an ATG13 antibody (1:100, #13468, Cell Signaling, Danvers, MA, USA), then washed 3 times in TBS-Tween and incubated 1.5 h at RT with a goat anti-rabbit-AlexaFluor 546 secondary antibody (#A11010, Life Technologies, Carlsbad, CA, USA).	('antibody', 'cellular_component', 'GO:0019814', ('219', '227'))	('ATG13', 'Gene', (45, 50))	('goat', 'Species', '9925', (177, 181))	('antibody', 'cellular_component', 'GO:0042571', ('51', '59'))	('ATG13', 'Gene', '9776', (45, 50))	('rabbit', 'Species', '9986', (187, 193))	('antibody', 'cellular_component', 'GO:0019815', ('219', '227'))	('antibody', 'cellular_component', 'GO:0019815', ('51', '59'))	('antibody', 'molecular_function', 'GO:0003823', ('219', '227'))	('antibody', 'cellular_component', 'GO:0042571', ('219', '227'))	('antibody', 'cellular_component', 'GO:0019814', ('51', '59'))	('AlexaFluor 546', 'Chemical', 'MESH:C481052', (194, 208))	('Signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('antibody', 'molecular_function', 'GO:0003823', ('51', '59'))	('TBS-Tween', 'Chemical', '-', (134, 143))	('#A11010', 'Var', (229, 236))
148442	26284517	Primary antibodies for ATG13 (1:100, #13468, Cell signaling, Danvers, MA, USA) and pan-cytokeratin (1:200:M3515 clone AE1/AE3, DAKO, Carpinteria, CA, USA) were incubated in a humidified chamber at 4 C overnight.	('AE3', 'Gene', (122, 125))	('1:200:M3515 clone', 'Var', (100, 117))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('ATG13', 'Gene', (23, 28))	('AE1', 'Gene', (118, 121))	('AE3', 'Gene', '6508', (122, 125))	('AE1', 'Gene', '6521', (118, 121))	('ATG13', 'Gene', '9776', (23, 28))
148443	26284517	The secondary antibodies for ATG13 (#A11010 goat anti-rabbit AlexaFluor 546, Life Technologies, Carlsbad, CA, USA) and cytokeratin (#RPN1001V biotinylated sheep anti-mouse, GE Healthcare and #A6374 NeutrAvidin streptavidin-conjugated Oregon green-Life Technologies, Carlsbad, CA) both 1:200, were incubated for 60 min at RT in a humidified chamber.	('sheep', 'Species', '9940', (155, 160))	('goat', 'Species', '9925', (44, 48))	('#RPN1001V', 'Var', (132, 141))	('ATG13', 'Gene', (29, 34))	('#A6374', 'Var', (191, 197))	('ATG13', 'Gene', '9776', (29, 34))	('mouse', 'Species', '10090', (166, 171))	('rabbit', 'Species', '9986', (54, 60))	('AlexaFluor 546', 'Chemical', 'MESH:C481052', (61, 75))	('#A11010', 'Var', (36, 43))
148447	26284517	Paraffin sections (5 mum) were stained for 2 h at RT with antibodies for Bim (1:200 #559685BD, Pharmingen, San Jose, CA), P-AKTSer473 and P-S6KThr389 (1:100 #4060, 1:100 #9234, Cell Signaling, Danver MA, USA), Ki67 (1:200, #ab15580, Abcam, Cambridge, MA, USA), GLUT-1 and IRS-1 (1:500 PA5-16793, 1:800 PA5-29667, Thermo Scientific, Waltham, MA, USA) and visualized with a HRP/DAB Envision plus Kit (#K4010, Dako, Carpinteria, CA).	('GLUT-1', 'Gene', '6513', (261, 267))	('IRS-1', 'Gene', (272, 277))	('P-S6KThr389', 'Var', (138, 149))	('Ser473', 'Chemical', '-', (127, 133))	('P-AKTSer473', 'Var', (122, 133))	('mum', 'Gene', '56925', (21, 24))	('Signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('IRS-1', 'Gene', '3667', (272, 277))	('Bim', 'Gene', (73, 76))	('Bim', 'Gene', '10018', (73, 76))	('mum', 'Gene', (21, 24))	('GLUT-1', 'Gene', (261, 267))
148453	26284517	Unenhanced CT scans for attenuation correction and anatomic co-registration were performed first, from the patient's head to the mid thighs, using the following acquisition parameters: 140kVp, 75-120mA (varying according to the patient's weight), 0.5 sec per CT rotation, a pitch of 1.375:1, and a reconstructed slice thickness of 3.75 mm.	('140kVp', 'Var', (185, 191))	('patient', 'Species', '9606', (107, 114))	('patient', 'Species', '9606', (228, 235))	('75-120mA', 'Var', (193, 201))
148465	26284517	We treated monolayers and spheroids with GDC-0980 alone or in combination with the current standard of therapy for mesothelioma, cisplatin plus pemetrexed, or with a proteasome inhibitor, bortezomib.	('bortezomib', 'Chemical', 'MESH:D000069286', (188, 198))	('GDC-0980', 'Var', (41, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('pemetrexed', 'Chemical', 'MESH:D000068437', (144, 154))	('mesothelioma', 'Disease', (115, 127))	('proteasome', 'cellular_component', 'GO:0000502', ('166', '176'))	('GDC-0980', 'Chemical', 'MESH:C569670', (41, 49))	('proteasome', 'molecular_function', 'GO:0004299', ('166', '176'))	('mesothelioma', 'Disease', 'MESH:D008654', (115, 127))
148475	26284517	As found in multicellular spheroids, we identified a group of tumors sensitive to GDC-0980 (n = 11) and another group resistant (n = 10) (Fig 2 - additional images in S2 Fig).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('GDC-0980', 'Var', (82, 90))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('GDC-0980', 'Chemical', 'MESH:C569670', (82, 90))
148478	26284517	First, we confirmed that GDC-0980 inhibited P-Akt in M28 and REN monolayers and spheroids (Fig 3A).	('GDC-0980', 'Chemical', 'MESH:C569670', (25, 33))	('P-Akt', 'Pathway', (44, 49))	('inhibited', 'NegReg', (34, 43))	('GDC-0980', 'Var', (25, 33))
148479	26284517	Then, we studied the 6 cell lines as multicellular spheroids to compare their response to GDC-0980 with the levels of P-Akt Ser473, P-S6K Thr389 and, as a representative from another pathway, P-ERK.	('P-ERK', 'Gene', (192, 197))	('Thr389', 'Chemical', '-', (138, 144))	('GDC-0980', 'Chemical', 'MESH:C569670', (90, 98))	('Ser', 'cellular_component', 'GO:0005790', ('124', '127'))	('P-S6K', 'Gene', '6198', (132, 137))	('Ser473', 'Var', (124, 130))	('Ser473', 'Chemical', '-', (124, 130))	('P-ERK', 'Gene', '9451', (192, 197))	('P-S6K', 'Gene', (132, 137))	('ERK', 'molecular_function', 'GO:0004707', ('194', '197'))	('GDC-0980', 'Var', (90, 98))
148483	26284517	In addition, we also found no correlation between the response to GDC-0980 and several measures of the PI3K/mTOR pathway: P-S6K Thr389 (a target of mTOR), GLUT-1 (a measure of Akt activity on glycolysis), Ki67 (a marker of cell proliferation), or IRS-1 (regulated by Akt and mTOR) (S3 Fig).	('IRS-1', 'Gene', (247, 252))	('Thr389', 'Chemical', '-', (128, 134))	('GLUT-1', 'Gene', (155, 161))	('GDC-0980', 'Chemical', 'MESH:C569670', (66, 74))	('GLUT-1', 'Gene', '6513', (155, 161))	('glycolysis', 'biological_process', 'GO:0006096', ('192', '202'))	('P-S6K', 'Gene', '6198', (122, 127))	('PI3K/mTOR pathway', 'Pathway', (103, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('223', '241'))	('GDC-0980', 'Var', (66, 74))	('IRS-1', 'Gene', '3667', (247, 252))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('P-S6K', 'Gene', (122, 127))
148486	26284517	Thus, the apoptotic response to GDC-0980 in the tumor fragment spheroid model did not clearly relate to the activity of the PI3K/mTOR pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('124', '128'))	('tumor', 'Disease', (48, 53))	('GDC-0980', 'Chemical', 'MESH:C569670', (32, 40))	('PI3K/mTOR pathway', 'Pathway', (124, 141))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('GDC-0980', 'Var', (32, 40))
148488	26284517	Indeed, the response to GDC-0980, bortezomib or the combination was completely blocked by zVAD-fmk as early as 8 h of treatment (Fig 4A-additional data in S4 Fig), a result confirmed also by another group in pancreatic cancer.	('response', 'MPA', (12, 20))	('bortezomib', 'Chemical', 'MESH:D000069286', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('bortezomib', 'Gene', (34, 44))	('pancreatic cancer', 'Disease', (208, 225))	('zVAD-fmk', 'Chemical', 'MESH:C096713', (90, 98))	('GDC-0980', 'Gene', (24, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('blocked', 'NegReg', (79, 86))	('GDC-0980', 'Chemical', 'MESH:C569670', (24, 32))	('zVAD-fmk', 'Var', (90, 98))
148490	26284517	This suggests that GDC-0980 induces apoptosis without the requirement for Bim or Bid.	('Bid', 'Gene', (81, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('Bim', 'Gene', '10018', (74, 77))	('GDC-0980', 'Var', (19, 27))	('Bid', 'Gene', '637', (81, 84))	('GDC-0980', 'Chemical', 'MESH:C569670', (19, 27))	('apoptosis', 'CPA', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('Bim', 'Gene', (74, 77))
148496	26284517	In tumor fragment spheroids also, GDC-0980 increased autophagy, as shown by the formation of LC3 puncta, only in the sensitive group (S6 Fig).	('autophagy', 'biological_process', 'GO:0016236', ('53', '62'))	('tumor', 'Disease', (3, 8))	('LC3', 'Gene', '84557', (93, 96))	('autophagy', 'biological_process', 'GO:0006914', ('53', '62'))	('GDC-0980', 'Var', (34, 42))	('autophagy', 'CPA', (53, 62))	('LC3', 'Gene', (93, 96))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('increased', 'PosReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('GDC-0980', 'Chemical', 'MESH:C569670', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
148497	26284517	Altogether these results suggest that autophagy is responsive to PI3K/Akt blockade only in the spheroids sensitive to GDC-0980 and that its induction might be involved in the response to GDC-0980.	('GDC-0980', 'Chemical', 'MESH:C569670', (118, 126))	('GDC-0980', 'Chemical', 'MESH:C569670', (187, 195))	('PI3K/Akt', 'Protein', (65, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('autophagy', 'biological_process', 'GO:0016236', ('38', '47'))	('GDC-0980', 'Var', (118, 126))	('autophagy', 'CPA', (38, 47))	('autophagy', 'biological_process', 'GO:0006914', ('38', '47'))
148515	26284517	In this study, we have identified subsets of mesothelioma that are sensitive to GDC-0980, a novel dual PI3K/mTOR inhibitor currently in clinical trials.	('GDC-0980', 'Var', (80, 88))	('mesothelioma', 'Disease', (45, 57))	('GDC-0980', 'Chemical', 'MESH:C569670', (80, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('sensitive', 'Reg', (67, 76))
148525	26284517	After GDC-0980, both autophagy and cell death increase; either the autophagy is counteracting the stress and acting in a survival capacity or is itself inducing death.	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('autophagy', 'CPA', (21, 30))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('cell death', 'biological_process', 'GO:0008219', ('35', '45'))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('GDC-0980', 'Var', (6, 14))	('autophagy', 'CPA', (67, 76))	('cell death', 'CPA', (35, 45))	('GDC-0980', 'Chemical', 'MESH:C569670', (6, 14))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
148527	26284517	On the other hand, in the other group of tumors that are resistant to GDC-0980, autophagy does not respond to PI3K/mTOR inhibition and the inhibition of autophagy has no effect on cell survival.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('autophagy', 'biological_process', 'GO:0006914', ('153', '162'))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('autophagy', 'CPA', (80, 89))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('GDC-0980', 'Var', (70, 78))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))	('autophagy', 'biological_process', 'GO:0016236', ('153', '162'))
148531	26284517	Interestingly, despite the lack of correlation with the phosphorylation of Akt/mTOR, the response to GDC-0980 did correlate with autophagy, as measured by the presence of ATG13 puncta.	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('GDC-0980', 'Chemical', 'MESH:C569670', (101, 109))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('ATG13', 'Gene', (171, 176))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('autophagy', 'CPA', (129, 138))	('ATG13', 'Gene', '9776', (171, 176))	('GDC-0980', 'Var', (101, 109))
148532	26284517	To our knowledge, this is the first time that sensitivity to GDC-0980 has been shown to be associated with autophagic activity, either in cell lines or importantly in tumor samples studied ex vivo.	('GDC-0980', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('GDC-0980', 'Chemical', 'MESH:C569670', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('sensitivity', 'Var', (46, 57))	('autophagic activity', 'CPA', (107, 126))	('tumor', 'Disease', (167, 172))	('associated', 'Reg', (91, 101))
148538	26284517	In this study, we have shown for the first time that GDC-0980 is active in a subset of mesotheliomas, which can be identified by the presence of ATG13 puncta.	('ATG13', 'Gene', (145, 150))	('GDC-0980', 'Var', (53, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (87, 100))	('mesotheliomas', 'Disease', (87, 100))	('GDC-0980', 'Chemical', 'MESH:C569670', (53, 61))	('ATG13', 'Gene', '9776', (145, 150))
148539	26284517	By studying 3D models of mesothelioma, we have found that, whereas all spheroids demonstrated basal autophagy, only the sensitive spheroids displayed ATG13 puncta at baseline, increased autophagy in response to GDC-0980 and became more chemoresponsive with inhibition of autophagy.	('GDC-0980', 'Var', (211, 219))	('autophagy', 'biological_process', 'GO:0016236', ('271', '280'))	('increased', 'PosReg', (176, 185))	('autophagy', 'biological_process', 'GO:0016236', ('186', '195'))	('autophagy', 'biological_process', 'GO:0006914', ('271', '280'))	('GDC-0980', 'Chemical', 'MESH:C569670', (211, 219))	('autophagy', 'CPA', (186, 195))	('mesothelioma', 'Disease', (25, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('autophagy', 'biological_process', 'GO:0006914', ('186', '195'))	('ATG13', 'Gene', (150, 155))	('autophagy', 'biological_process', 'GO:0016236', ('100', '109'))	('ATG13', 'Gene', '9776', (150, 155))	('autophagy', 'biological_process', 'GO:0006914', ('100', '109'))
148569	23788949	Clinically staged T4 (with malignant pericardial tamponade) N2M0, surgery was deemed inappropriate for the patient and he received 30-Gy palliative radiotherapy for the primary tumor and mediastinum.	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('N2M0', 'Var', (60, 64))	('patient', 'Species', '9606', (107, 114))	('tumor', 'Disease', (177, 182))
148621	19755995	Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity Potency, immunogenicity, and toxicity are three problems that limit the use of targeted toxins in solid tumour therapy.	('mesothelioma', 'Disease', (130, 142))	('immunogenicity', 'MPA', (99, 113))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('toxicity', 'Disease', (181, 189))	('EGF4KDEL 7Mut', 'Var', (27, 40))	('solid tumour', 'Disease', 'MESH:D009369', (250, 262))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('EGF', 'molecular_function', 'GO:0005154', ('27', '30'))	('modification', 'Var', (11, 23))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('ligand', 'molecular_function', 'GO:0005488', ('61', '67'))	('solid tumour', 'Disease', (250, 262))	('decreased', 'NegReg', (89, 98))
148623	19755995	Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGF4KDEL 7Mut.	('Immunogenicity', 'MPA', (0, 14))	('EGF', 'Gene', (120, 123))	('EGF', 'molecular_function', 'GO:0005154', ('120', '123'))	('EGF', 'Gene', '1950', (120, 123))	('mutating', 'Var', (30, 38))
148624	19755995	In vitro, bispecific EGF4KDEL showed superior anti-mesothelioma activity compared with its monospecific counterparts.	('EGF', 'molecular_function', 'GO:0005154', ('21', '24'))	('mesothelioma', 'Disease', (51, 63))	('EGF', 'Gene', (21, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('EGF', 'Gene', '1950', (21, 24))	('bispecific', 'Var', (10, 20))
148634	19755995	PE38 is used for cytotoxin construction because a single molecule delivered to the cytosol is sufficient to bring about cell killing by catalysing ADP ribosylation of elongation factor 2 (EF-2) leading to irreversible inhibition of protein synthesis and cell death (Pastan et al, 1992).	('EF-2', 'Gene', (188, 192))	('protein synthesis', 'biological_process', 'GO:0006412', ('232', '249'))	('ADP', 'Var', (147, 150))	('cell death', 'biological_process', 'GO:0008219', ('254', '264'))	('elongation factor 2', 'Gene', '1938', (167, 186))	('inhibition', 'NegReg', (218, 228))	('elongation factor 2', 'Gene', (167, 186))	('cell killing', 'CPA', (120, 132))	('protein synthesis', 'MPA', (232, 249))	('cytosol', 'cellular_component', 'GO:0005829', ('83', '90'))	('cell death', 'CPA', (254, 264))	('protein', 'cellular_component', 'GO:0003675', ('232', '239'))	('EF-2', 'Gene', '1938', (188, 192))	('cell killing', 'biological_process', 'GO:0001906', ('120', '132'))
148635	19755995	Further studies have shown that modifying PE38 by adding a Lys-Asp-Glu-Leu (KDEL) C-terminal signal that prevents secretion of luminal endoplasmic reticulum (ER) proteins increased ER accumulation and enhanced potency of targeted toxins (Kreitman and Pastan, 1995).	('secretion of luminal endoplasmic', 'MPA', (114, 146))	('Lys', 'Chemical', 'MESH:D008239', (59, 62))	('prevents', 'NegReg', (105, 113))	('modifying', 'Var', (32, 41))	('PE38', 'Gene', (42, 46))	('ER accumulation', 'MPA', (181, 196))	('Asp', 'Chemical', 'MESH:D001224', (63, 66))	('Glu', 'Chemical', 'MESH:D018698', (67, 70))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('135', '156'))	('Leu', 'Chemical', 'MESH:D007930', (71, 74))	('potency', 'MPA', (210, 217))	('enhanced', 'PosReg', (201, 209))	('increased', 'PosReg', (171, 180))	('secretion', 'biological_process', 'GO:0046903', ('114', '123'))
148636	19755995	The advantage of ligand-directed toxins is that PE38KDEL-mediated cytotoxicity requires specific ligand-receptor binding and subsequent internalisation.	('ligand', 'molecular_function', 'GO:0005488', ('17', '23'))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('internalisation', 'MPA', (136, 151))	('PE38KDEL-mediated', 'Var', (48, 65))	('receptor binding', 'molecular_function', 'GO:0005102', ('104', '120'))	('cytotoxicity', 'Disease', (66, 78))	('ligand', 'molecular_function', 'GO:0005488', ('97', '103'))	('binding', 'Interaction', (113, 120))
148643	19755995	Targeting solid tumours with ligand-directed cytotoxins has been hampered by problems with immunogenicity as effective therapy often requires multiple treatments resulting in the generation of neutralising antibodies, mostly against the PE38 portion of the molecule (Hassan et al, 2004).	('PE38', 'Var', (237, 241))	('ligand', 'molecular_function', 'GO:0005488', ('29', '35'))	('solid tumours', 'Disease', 'MESH:D009369', (10, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('solid tumours', 'Disease', (10, 23))
148644	19755995	Subsequently, they described a series of mutations that did not alter the catalytic activity of PE38 yet nearly eliminated the immune response of mice (Onda et al, 2008).	('mutations', 'Var', (41, 50))	('eliminated', 'NegReg', (112, 122))	('immune response of mice', 'CPA', (127, 150))	('mice', 'Species', '10090', (146, 150))	('catalytic activity', 'molecular_function', 'GO:0003824', ('74', '92'))	('immune response', 'biological_process', 'GO:0006955', ('127', '142'))
148652	19755995	The fully assembled fusion gene (from 5' end to 3' end) consisted of an Nco1 restriction site, an ATG initiation codon, the genes for human EGF and circularly permutated human IL-4 linked by a 20 amino-acid segment of human muscle aldolase (HMA), the 7 amino-acid EASGGPE linker and the first 362 amino acids of the PE molecule with KDEL replacing the REDLK at the C terminus, a NotI restriction site at the 3' end of the construct.	('human', 'Species', '9606', (134, 139))	('Nco1', 'Gene', (72, 76))	('EGF', 'molecular_function', 'GO:0005154', ('140', '143'))	('EGF', 'Gene', (140, 143))	('HMA', 'Chemical', '-', (241, 244))	('KDEL replacing', 'Var', (333, 347))	('human', 'Species', '9606', (170, 175))	('human', 'Species', '9606', (218, 223))	('IL-4', 'molecular_function', 'GO:0005136', ('176', '180'))	('EGF', 'Gene', '1950', (140, 143))	('IL-4', 'Gene', (176, 180))	('IL-4', 'Gene', '3565', (176, 180))
148656	19755995	To create an EGF4KDEL molecule with decreased immunogenicity, eight amino acids representing the seven major epitopes on PE38 (Onda et al, 2008) were mutated using the QuickChange Site-Directed Mutagenesis Kit (Stratagene.	('Mutagenesis', 'biological_process', 'GO:0006280', ('194', '205'))	('EGF', 'Gene', (13, 16))	('EGF', 'molecular_function', 'GO:0005154', ('13', '16'))	('EGF', 'Gene', '1950', (13, 16))	('mutated', 'Var', (150, 157))
148657	19755995	The following amino acids were altered: R490A, R513A, R467A, E548S, K590S, R432G, Q332S, R313A and confirmed with DNA sequencing.	('R513A', 'Var', (47, 52))	('R432G', 'Mutation', 'p.R432G', (75, 80))	('K590S', 'Mutation', 'p.K590S', (68, 73))	('R313A', 'Mutation', 'p.R313A', (89, 94))	('E548S', 'Mutation', 'p.E548S', (61, 66))	('E548S', 'Var', (61, 66))	('R467A', 'Mutation', 'p.R467A', (54, 59))	('R490A', 'Mutation', 'p.R490A', (40, 45))	('K590S', 'Var', (68, 73))	('Q332S', 'Mutation', 'p.Q332S', (82, 87))	('R467A', 'Var', (54, 59))	('R490A', 'Var', (40, 45))	('R313A', 'Var', (89, 94))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('Q332S', 'Var', (82, 87))	('R513A', 'Mutation', 'p.R513A', (47, 52))	('R432G', 'Var', (75, 80))
148658	19755995	Genes for monospecific cytotoxins splicing mutated PE38(KDEL) to human EGF (EGFKDEL) and mutated human IL-4 (cpIL4KDEL) were created using the same techniques.	('EGF', 'Gene', (71, 74))	('human', 'Species', '9606', (65, 70))	('EGF', 'Gene', '1950', (76, 79))	('human', 'Species', '9606', (97, 102))	('EGF', 'Gene', '1950', (71, 74))	('PE38(KDEL', 'Var', (51, 60))	('IL-4', 'molecular_function', 'GO:0005136', ('103', '107'))	('IL-4', 'Gene', (103, 107))	('EGF', 'molecular_function', 'GO:0005154', ('71', '74'))	('EGF', 'Gene', (76, 79))	('splicing', 'biological_process', 'GO:0045292', ('34', '42'))	('IL-4', 'Gene', '3565', (103, 107))
148659	19755995	BIC3KDEL, a bispecific immunotoxin-targeting T-cell surface marker CD3, was made by replacing the DT390 portion of the BIC3 molecule described previously with PE38(KDEL) (Vallera et al, 2005a).	('BIC3', 'Gene', (119, 123))	('BIC3KDEL', 'Chemical', '-', (0, 8))	('BIC3KDEL', 'Var', (0, 8))	('cell surface', 'cellular_component', 'GO:0009986', ('47', '59'))	('PE38(KDEL', 'Var', (159, 168))	('CD3', 'Gene', (67, 70))	('CD3', 'Gene', '12501', (67, 70))
148669	19755995	Each clone used in this study, H2373/Luc/GFP and H513/Luc/GFP, retained identical morphological and biological properties to the specific parental cell line.	('H2373/Luc/GFP', 'Var', (31, 44))	('H513', 'CellLine', 'CVCL:A570', (49, 53))	('H2373', 'CellLine', 'CVCL:A533', (31, 36))	('H513/Luc/GFP', 'Var', (49, 61))
148687	19755995	Briefly, 5 mug of purified recombinant PE38KDEL was added to each well of a 96-well microtiter plate and adhered overnight at 4 C. Unbound protein was washed away with PBS-T and blocking was performed for 1 h with 5% milk/PBS-T. Serum samples were diluted in 1 : 10 000 and 100 mul of each was added to appropriate wells in triplicate.	('PE38KDEL', 'Var', (39, 47))	('mug', 'molecular_function', 'GO:0043739', ('11', '14'))	('PBS-T', 'Disease', (168, 173))	('PBS-T', 'Disease', 'MESH:D011535', (222, 227))	('PBS-T', 'Disease', 'MESH:D011535', (168, 173))	('PBS-T', 'Disease', (222, 227))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
148707	19755995	Figure 1A shows that EGF4KDEL had impressive activity against H2373 as indicated by IC50 value of 1.3 x 10-5 nM.	('activity', 'MPA', (45, 53))	('EGF', 'molecular_function', 'GO:0005154', ('21', '24'))	('EGF', 'Gene', (21, 24))	('H2373', 'CellLine', 'CVCL:A533', (62, 67))	('H2373', 'Var', (62, 67))	('EGF', 'Gene', '1950', (21, 24))
148709	19755995	BIC3KDEL, a PE38(KDEL)-containing agent targeting the T-cell-specific CD3 molecule, had no effect on H2373 cells revealing the specificity of toxin-mediated cell killing.	('BIC3KDEL', 'Chemical', '-', (0, 8))	('BIC3KDEL', 'Var', (0, 8))	('H2373', 'CellLine', 'CVCL:A533', (101, 106))	('CD3', 'Gene', (70, 73))	('CD3', 'Gene', '12501', (70, 73))	('cell killing', 'biological_process', 'GO:0001906', ('157', '169'))
148713	19755995	To show EGF4KDEL specificity, we incubated EGFR- and IL-4R- HBP-MLT leukaemic T cells with varying concentrations of both EGF4KDEL and BIC3KDEL.	('EGF', 'Gene', '1950', (122, 125))	('EGF', 'Gene', '1950', (8, 11))	('EGF', 'molecular_function', 'GO:0005154', ('8', '11'))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('EGF', 'Gene', (43, 46))	('IL-4R', 'molecular_function', 'GO:0004913', ('53', '58'))	('HBP-MLT leukaemic T', 'Disease', 'MESH:D001260', (60, 79))	('EGF', 'Gene', '1950', (43, 46))	('EGF', 'molecular_function', 'GO:0005154', ('122', '125'))	('EGF', 'Gene', (122, 125))	('EGF', 'Gene', (8, 11))	('BIC3KDEL', 'Var', (135, 143))	('BIC3KDEL', 'Chemical', '-', (135, 143))	('HBP-MLT leukaemic T', 'Disease', (60, 79))
148714	19755995	Figure 1C shows that while BIC3KDEL possesses excellent cytotoxicity towards these CD3+ cells, EGF4KDEL had no effect on cell proliferation.	('EGF', 'Gene', (95, 98))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('EGF', 'molecular_function', 'GO:0005154', ('95', '98'))	('BIC3KDEL', 'Chemical', '-', (27, 35))	('EGF', 'Gene', '1950', (95, 98))	('CD3', 'Gene', (83, 86))	('BIC3KDEL', 'Var', (27, 35))	('CD3', 'Gene', '12501', (83, 86))	('cytotoxicity', 'Disease', (56, 68))
148736	19755995	To prove the necessity of toxin-mediated killing, additional mice were treated with EGF4, a bispecific ligand devoid of a PE38(KDEL) and the B-cell-targeting agent 2219KDEL made with the same PE38(KDEL) construct as EGF4KDEL.	('EGF', 'molecular_function', 'GO:0005154', ('84', '87'))	('EGF', 'molecular_function', 'GO:0005154', ('216', '219'))	('mice', 'Species', '10090', (61, 65))	('EGF', 'Gene', (84, 87))	('2219KDEL', 'Var', (164, 172))	('EGF', 'Gene', '1950', (84, 87))	('EGF', 'Gene', (216, 219))	('ligand', 'molecular_function', 'GO:0005488', ('103', '109'))	('EGF', 'Gene', '1950', (216, 219))
148739	19755995	Whereas the untreated animals have diffuse GFP-positive H2373 tumour colonies, minimal tumours are seen in treated mice.	('tumours', 'Disease', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour colonies', 'Disease', (62, 77))	('H2373', 'Var', (56, 61))	('H2373', 'CellLine', 'CVCL:A533', (56, 61))	('tumour colonies', 'Disease', 'MESH:D009369', (62, 77))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('mice', 'Species', '10090', (115, 119))	('tumours', 'Disease', 'MESH:D009369', (87, 94))
148768	19755995	Upon identifying seven major reactive epitopes, they proved that mutations could be made to these regions without compromising tumour cell killing (Onda et al, 2008).	('cell killing', 'biological_process', 'GO:0001906', ('134', '146'))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', (127, 133))	('mutations', 'Var', (65, 74))
148776	19755995	Onda and Pastan have tested sera from patients receiving non-mutated PE38-targeted toxins and found that their anti-PE38 antibodies bind to the same seven B-cell epitopes defined by the mouse studies and eliminated in EGF4KDEL 7mut (Onda et al, 2008).	('anti-PE38', 'Var', (111, 120))	('EGF', 'Gene', (218, 221))	('mouse', 'Species', '10090', (186, 191))	('EGF', 'Gene', '1950', (218, 221))	('patients', 'Species', '9606', (38, 46))	('EGF', 'molecular_function', 'GO:0005154', ('218', '221'))	('sera', 'molecular_function', 'GO:0004617', ('28', '32'))
148781	19755995	Additional studies may show that incorporation of similar mutations into EGF4KDEL 7Mut can further enhance its already potent anti-tumour activity.	('mutations', 'Var', (58, 67))	('tumour', 'Disease', (131, 137))	('EGF', 'Gene', '1950', (73, 76))	('EGF', 'molecular_function', 'GO:0005154', ('73', '76'))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('EGF', 'Gene', (73, 76))	('enhance', 'PosReg', (99, 106))
148796	19755995	This inconsistency of response is likely because of the fact that few MM tumours possess the activating EGFR mutations that correlate with tyrosine kinase inhibitor efficacy (Cortese et al, 2006).	('EGFR', 'Gene', (104, 108))	('MM tumours', 'Disease', (70, 80))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('148', '164'))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('activating', 'PosReg', (93, 103))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (109, 118))	('MM tumours', 'Disease', 'MESH:D009369', (70, 80))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tyrosine kinase inhibitor efficacy', 'MPA', (139, 173))
148799	19755995	Numerous preclinical studies have shown the potent anti-tumour activity of a monospecific cytotoxin composed of IL-4 linked to PE38 (Kreitman et al, 1994; Shimamura et al, 2007).	('IL-4', 'molecular_function', 'GO:0005136', ('112', '116'))	('IL-4', 'Gene', (112, 116))	('IL-4', 'Gene', '3565', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))	('PE38', 'Var', (127, 131))
148803	19755995	By introducing the firefly luciferase gene into H2373 and H513 we were able to monitor the effect of treatment on tumour burden on a weekly basis using a highly sensitive and well-validated bioluminescent imaging technology that directly correlates with actual tumour volume (Jenkins et al, 2003).	('H2373', 'CellLine', 'CVCL:A533', (48, 53))	('H513', 'CellLine', 'CVCL:A570', (58, 62))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('tumour burden', 'Disease', (114, 127))	('H513', 'Var', (58, 62))	('H2373', 'Var', (48, 53))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('actual tumour', 'Disease', (254, 267))	('actual tumour', 'Disease', 'MESH:D009369', (254, 267))	('tumour burden', 'Disease', 'MESH:D009369', (114, 127))
148814	19755995	More importantly, we reduced in vivo drug toxicity and by introducing a series of amino-acid substitutions, we were able to decrease the immunogenicity of EGF4KDEL 7Mut and ultimately improve its potential for use in a clinical setting for MM therapy.	('reduced', 'NegReg', (21, 28))	('EGF', 'Gene', '1950', (155, 158))	('substitutions', 'Var', (93, 106))	('immunogenicity', 'MPA', (137, 151))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('toxicity', 'Disease', (42, 50))	('EGF', 'Gene', (155, 158))	('decrease', 'NegReg', (124, 132))	('improve', 'PosReg', (184, 191))	('EGF', 'molecular_function', 'GO:0005154', ('155', '158'))
148879	18397527	These include glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTTM1), cytochrome P450 1A1 (CYP1A1), N-acetyltransferase 2 (NAT2), and microsomal epoxide hydrolase (mEH) gene polymorphisms.	('glutathione S-transferase M1', 'Gene', (14, 42))	('mEH', 'Gene', (185, 188))	('cytochrome P450 1A1', 'Gene', (91, 110))	('CYP1A1', 'Gene', '1543', (112, 118))	('glutathione S-transferase T1', 'Gene', '2952', (52, 80))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('91', '106'))	('cytochrome P450 1A1', 'Gene', '1543', (91, 110))	('mEH', 'molecular_function', 'GO:0033961', ('185', '188'))	('GSTM1', 'Gene', (44, 49))	('mEH', 'Gene', '13849', (185, 188))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('91', '106'))	('NAT2', 'Gene', '10', (144, 148))	('microsomal epoxide hydrolase', 'Gene', '2052', (155, 183))	('NAT2', 'Gene', (144, 148))	('microsomal epoxide hydrolase', 'Gene', (155, 183))	('N-acetyltransferase 2', 'Gene', (121, 142))	('polymorphisms', 'Var', (195, 208))	('N-acetyltransferase 2', 'Gene', '10', (121, 142))	('GSTM1', 'Gene', '2944', (44, 49))	('CYP1A1', 'Gene', (112, 118))	('GSTTM1', 'Gene', (82, 88))	('glutathione S-transferase T1', 'Gene', (52, 80))	('glutathione S-transferase M1', 'Gene', '2944', (14, 42))
148926	31270394	Here we show that EphB4 expression in malignant mesothelioma cells is markedly decreased upon neutralization of cancer-secreted IGF-II.	('neutralization', 'Var', (94, 108))	('cancer', 'Disease', (112, 118))	('expression', 'MPA', (24, 34))	('decreased', 'NegReg', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (38, 60))	('EphB4', 'Gene', (18, 23))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('malignant mesothelioma', 'Disease', (38, 60))
148944	31270394	This is consistent with previously described high molecular weight (HMW) variants originating through combined retention of the IGF-II pre-pro-peptide domain E and its cell-specific O-glycosylation.	('pre', 'molecular_function', 'GO:0003904', ('135', '138'))	('variants', 'Var', (73, 81))	('IGF-II', 'Gene', (128, 134))	('glycosylation', 'biological_process', 'GO:0070085', ('184', '197'))	('retention', 'biological_process', 'GO:0051235', ('111', '120'))	('peptide', 'Chemical', 'MESH:D010455', (143, 150))
148945	31270394	These HMW variants have been shown to bear the capability to bind and activate the IRA and the IGFIR while showing less affinity for other IGF-II binding proteins.	('IGFIR', 'Gene', (95, 100))	('IGF-II binding', 'molecular_function', 'GO:0031995', ('139', '153'))	('variants', 'Var', (10, 18))	('activate', 'PosReg', (70, 78))	('bind', 'Interaction', (61, 65))	('IGFIR', 'Gene', '3480', (95, 100))	('IRA', 'Protein', (83, 86))
148962	31270394	We then acutely stimulated (3 min) these cell lines following overnight serum starvation using both a non-supra-physiological concentration of human synthetic IGF-II (10 nM) as well as a supra-physiological concentration (50 nM).	('10 nM', 'Var', (167, 172))	('human', 'Species', '9606', (143, 148))	('IGF-II', 'Gene', (159, 165))
148966	31270394	Interestingly, we found that the last C-terminus residue of EphB4 corresponding to tyrosine 987 is, so far, the only tyrosine found phosphorylated in vivo by large scale phospho-proteomic screening.	('tyrosine', 'Chemical', 'MESH:D014443', (83, 91))	('tyrosine', 'Chemical', 'MESH:D014443', (117, 125))	('EphB4', 'Gene', (60, 65))	('tyrosine 987', 'Var', (83, 95))
148971	31270394	4b is indeed Tyrosine 987 and confirmed the observation that the Insulin Receptor A (IRA) but not the IGF1R mediates such effect.	('IGF1R', 'Gene', (102, 107))	('Tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('IGF1R', 'Gene', '3480', (102, 107))	('Tyrosine 987', 'Var', (13, 25))	('Insulin', 'molecular_function', 'GO:0016088', ('65', '72'))
148973	31270394	The demonstration that EphB4 Y987 phosphorylation is a target of autocrine IGF-II-IRA signaling axis prompted us to look at other PTMs possibly linked to the observed IGF-II-induced degradation rescue effect.	('IGF-II-', 'Gene', (167, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('EphB4', 'Gene', (23, 28))	('PTMs', 'Gene', (130, 134))	('Y987', 'Chemical', '-', (29, 33))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('IGF-II-', 'Gene', '3481', (75, 82))	('degradation', 'biological_process', 'GO:0009056', ('182', '193'))	('IGF-II-', 'Gene', '3481', (167, 174))	('Y987', 'Var', (29, 33))	('IGF-II-', 'Gene', (75, 82))	('degradation', 'MPA', (182, 193))	('PTMs', 'Gene', '5763', (130, 134))
148986	31270394	The type of Lysine ubiquitination, namely on Lys48 versus Lys63, has been linked to degradative versus regulatory properties of the protein targeted by ubiquitination as reviewed in ref..	('ubiquitin', 'Gene', (152, 161))	('Lysine', 'Chemical', 'MESH:D008239', (12, 18))	('degradative', 'MPA', (84, 95))	('ubiquitin', 'Gene', '176718', (152, 161))	('ubiquitin', 'Gene', (19, 28))	('ubiquitin', 'Gene', '176718', (19, 28))	('Lys63', 'Var', (58, 63))	('Lys48', 'Chemical', '-', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('Lys63', 'Chemical', '-', (58, 63))	('Lys48', 'Var', (45, 50))	('linked', 'Reg', (74, 80))
148988	31270394	5c, both Ub-K48 and Ub-K63 appear to play a role in EphB4 protein regulation by IGF-II.	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('Ub-K48', 'Var', (9, 15))	('Ub', 'Chemical', '-', (20, 22))	('play', 'Reg', (37, 41))	('IGF-II', 'Gene', (80, 86))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('Ub-K63', 'Var', (20, 26))	('EphB4', 'Gene', (52, 57))	('K63', 'Chemical', '-', (23, 26))	('Ub', 'Chemical', '-', (9, 11))
148989	31270394	K63 was the most prominent type of ubiquitination associated to EphB4 in the cell model studied.	('K63', 'Chemical', '-', (0, 3))	('ubiquitin', 'Gene', (35, 44))	('ubiquitin', 'Gene', '176718', (35, 44))	('K63', 'Var', (0, 3))	('EphB4', 'Gene', (64, 69))
148990	31270394	In all cases, ubiquitination was clearly increased upon block of the IGF-II autocrine stimuli confirming the inversely related trend between ubiquitination versus its Tyr987 phosphorylation.	('ubiquitin', 'Gene', (14, 23))	('ubiquitin', 'Gene', '176718', (14, 23))	('increased', 'PosReg', (41, 50))	('ubiquitin', 'Gene', (141, 150))	('ubiquitin', 'Gene', '176718', (141, 150))	('IGF-II', 'Gene', (69, 75))	('block', 'Var', (56, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('Tyr987', 'Chemical', '-', (167, 173))
148994	31270394	Worth noticing, the identified motif contains Lysine 973 which has been found ubiquitinated in vivo.	('Lysine 973', 'Var', (46, 56))	('Lysine', 'Chemical', 'MESH:D008239', (46, 52))	('ubiquitin', 'Gene', (78, 87))	('ubiquitin', 'Gene', '176718', (78, 87))
148997	31270394	A further phylogenetic comparison of the immediate upstream region to the tyrosine 987 in human EphB4 was conducted via pBlast using EphB4 protein sequences from both mammalian and non-mammalian orthologues with regards to the identified UBX-like motif and at the light of the observed inverted pattern of tyrosine phosphorylation versus ubiquitination in this specific aa stretch that might narrow down our interest in potential mechanisms regulated by Tyrosine 987 phosphorylation or its phylogenetic counterpart.	('Tyrosine', 'Var', (454, 462))	('phosphorylation', 'biological_process', 'GO:0016310', ('467', '482'))	('ubiquitin', 'Gene', (338, 347))	('ubiquitin', 'Gene', '176718', (338, 347))	('tyrosine', 'Chemical', 'MESH:D014443', (306, 314))	('tyrosine', 'Chemical', 'MESH:D014443', (74, 82))	('human', 'Species', '9606', (90, 95))	('mammalian', 'Species', '9606', (167, 176))	('phosphorylation', 'biological_process', 'GO:0016310', ('315', '330'))	('Tyrosine', 'Chemical', 'MESH:D014443', (454, 462))	('mammalian', 'Species', '9606', (185, 194))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
149012	31270394	The fact that EphB4 IGF-II-dependent phosphorylation modifications observed in this study precede the drop in de novo synthesized protein levels provide a required cause/effect association between the observed phosphorylation changes and the decrease in EphB4 steady-state levels.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('phosphorylation', 'MPA', (37, 52))	('IGF-II-', 'Gene', (20, 27))	('phosphorylation', 'MPA', (210, 225))	('IGF-II-', 'Gene', '3481', (20, 27))	('EphB4', 'Gene', (14, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('210', '225'))	('modifications', 'Var', (53, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('EphB4', 'MPA', (254, 259))	('decrease', 'NegReg', (242, 250))
149015	31270394	The present study identifies EphB4 intracellular last residue, Tyrosine 987, as the specific target of the autocrine IGF-II signal in cancer and it links its phosphorylation status with the protein stability and overall lifespan of EphB4 expression.	('Tyrosine 987', 'Var', (63, 75))	('EphB4', 'Gene', (232, 237))	('protein', 'MPA', (190, 197))	('phosphorylation', 'MPA', (158, 173))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('intracellular', 'cellular_component', 'GO:0005622', ('35', '48'))	('Tyrosine', 'Chemical', 'MESH:D014443', (63, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('EphB4', 'Gene', (29, 34))
149018	31270394	A review of the known in vivo modified amino acid residues on the EphB4 intracellular portion via UniProt search suggests that Lys973 could play a role in the observed ubiquitination/degradation trend due to its proximity to Tyr987 as part of a novel phosphodegron spanning the last 30 c-terminal amino acids of EphB4.	('Lys973', 'Var', (127, 133))	('Lys973', 'Chemical', '-', (127, 133))	('Tyr987', 'Var', (225, 231))	('ubiquitin', 'Gene', (168, 177))	('EphB4', 'Gene', (312, 317))	('ubiquitin', 'Gene', '176718', (168, 177))	('degradation', 'biological_process', 'GO:0009056', ('183', '194'))	('Tyr987', 'Chemical', '-', (225, 231))	('intracellular', 'cellular_component', 'GO:0005622', ('72', '85'))
149022	31270394	These Ub-branched variants have been involved in ubiquitin-mediated degradation and protein unfolding processes, respectively.	('protein unfolding', 'CPA', (84, 101))	('ubiquitin', 'molecular_function', 'GO:0031386', ('49', '58'))	('protein unfolding', 'biological_process', 'GO:0043335', ('84', '101'))	('ubiquitin', 'Gene', '176718', (49, 58))	('Ub', 'Chemical', '-', (6, 8))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('ubiquitin', 'Gene', (49, 58))	('variants', 'Var', (18, 26))	('degradation', 'biological_process', 'GO:0009056', ('68', '79'))	('involved', 'Reg', (37, 45))
149023	31270394	In fact, the Tyr987 dephosphorylated form, which rapidly degrades was found to bear a more compact structure than the respective phosphorylated version as also suggested by solvent accessibility.	('Tyr987', 'Chemical', '-', (13, 19))	('compact structure', 'MPA', (91, 108))	('Tyr987 dephosphorylated', 'Var', (13, 36))
149024	31270394	The opposite increased accessibility of Lys973 and the UBX/Znf-like motif suggested by the molecular dynamic analysis upon phosphorylation of Tyr987 associating with a decrease in ubiquitination and degradation of the EphB4 protein could be explained by the consensual phosphorylation of Threonine 976 as a permissive event following phosphorylation of Tyrosine 987 towards the molecular regulation of EphB4 protein by autocrine IGF-II.	('regulation', 'biological_process', 'GO:0065007', ('388', '398'))	('degradation', 'MPA', (199, 210))	('Tyr987', 'Chemical', '-', (142, 148))	('EphB4', 'Gene', (218, 223))	('Lys973', 'Chemical', '-', (40, 46))	('increased', 'PosReg', (13, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('269', '284'))	('ubiquitin', 'Gene', (180, 189))	('Tyrosine', 'Chemical', 'MESH:D014443', (353, 361))	('Threonine', 'Chemical', 'MESH:D013912', (288, 297))	('degradation', 'biological_process', 'GO:0009056', ('199', '210'))	('phosphorylation', 'biological_process', 'GO:0016310', ('334', '349'))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('ubiquitin', 'Gene', '176718', (180, 189))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('accessibility', 'MPA', (23, 36))	('protein', 'cellular_component', 'GO:0003675', ('408', '415'))	('EphB4', 'Gene', (402, 407))	('Tyrosine 987', 'Var', (353, 365))	('decrease', 'NegReg', (168, 176))	('Lys973', 'Var', (40, 46))
149025	31270394	According to this model, supported by the dynamic modeling results, a second IGF-II regulated (threonine) kinase would be required upon increased accessibility of Thr976 triggered by Tyr987 phosphorylation.	('Tyr987', 'Chemical', '-', (183, 189))	('phosphorylation', 'biological_process', 'GO:0016310', ('190', '205'))	('Tyr987 phosphorylation', 'Var', (183, 205))	('Thr976', 'Chemical', '-', (163, 169))	('increased', 'PosReg', (136, 145))	('IGF-II', 'Gene', (77, 83))	('accessibility', 'MPA', (146, 159))
149026	31270394	Threonine 976 has indeed also been described to be an in-vivo phosphorylated residue in EphB4 and is located two residues downstream Lys973.	('Threonine', 'Chemical', 'MESH:D013912', (0, 9))	('Lys973', 'Chemical', '-', (133, 139))	('Threonine 976', 'Var', (0, 13))	('EphB4', 'Gene', (88, 93))
149027	31270394	In this local context, phosphorylation of Thr976, due to the additional negative charge and the ensuing repulsive interaction, would prevent ubiquitin priming of EphB4 Lys973 by specific ubiquitin-binding factors.	('Lys973', 'Chemical', '-', (168, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('ubiquitin', 'Gene', (141, 150))	('ubiquitin', 'Gene', '176718', (141, 150))	('ubiquitin-binding', 'molecular_function', 'GO:0043130', ('187', '204'))	('prevent', 'NegReg', (133, 140))	('ubiquitin', 'molecular_function', 'GO:0031386', ('141', '150'))	('Thr976', 'Chemical', '-', (42, 48))	('phosphorylation', 'Var', (23, 38))	('ubiquitin', 'Gene', (187, 196))	('ubiquitin', 'Gene', '176718', (187, 196))	('Thr976', 'Var', (42, 48))	('EphB4', 'Gene', (162, 167))	('negative charge', 'MPA', (72, 87))	('repulsive interaction', 'MPA', (104, 125))	('Lys973', 'Var', (168, 174))
149028	31270394	At present the proposed model for a Tyr987/Thr976 double phosphorylation by IGF-II towards the regulation of the described EphB4 bona-fide phosphodegron, while fully fitting with the present findings, will requires further experimental confirmatory work.	('Tyr987/Thr976', 'Var', (36, 49))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('IGF-II', 'Gene', (76, 82))	('Tyr987', 'Chemical', '-', (36, 42))	('EphB4', 'Gene', (123, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('Thr976', 'Chemical', '-', (43, 49))
149037	31270394	However, under such cultural conditions (hypoxic, serum-containing and growth-factor rich), the neutralization of secreted IGF-II was able to significantly downregulate EphB4 as well as VEGF-A suggesting a major role for IGF-II as a mediator of HIF effects in malignant mesothelioma cells.	('EphB4', 'Gene', (169, 174))	('IGF-II', 'Gene', (123, 129))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (260, 282))	('malignant mesothelioma', 'Disease', (260, 282))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (260, 282))	('VEGF-A', 'Gene', '7422', (186, 192))	('VEGF-A', 'Gene', (186, 192))	('neutralization', 'Var', (96, 110))	('downregulate', 'NegReg', (156, 168))
149061	31270394	The specificity of the detected signal for EphB4 Y987 phosphorylation (the only tyrosine present in the synthetic peptide) was further strengthened by performing a parallel in vitro reaction using a synthetic peptide bearing a Y987- > L single residue replacement and considering any visible signal as the non-specific background.	('EphB4', 'Gene', (43, 48))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('peptide', 'Chemical', 'MESH:D010455', (209, 216))	('Y987', 'Var', (49, 53))	('strengthened', 'PosReg', (135, 147))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Y987- > L', 'Var', (227, 236))	('Y987- > L', 'Mutation', 'p.Y987L', (227, 236))	('Y987', 'Chemical', '-', (227, 231))	('Y987', 'Chemical', '-', (49, 53))	('peptide', 'Chemical', 'MESH:D010455', (114, 121))	('phosphorylation', 'MPA', (54, 69))
149081	33072611	A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('cancer', 'Disease', (160, 166))	('TSG', 'Gene', (139, 142))	('tumor', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('TSG', 'Gene', '57045', (139, 142))	('translation', 'biological_process', 'GO:0006412', ('62', '73'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('alterations', 'Var', (100, 111))
149091	33072611	Comprehensive genomic studies have revealed frequent deletions or loss-of-function mutations of tumor suppressor genes (TSGs) in MPM, most often cyclin-dependent kinase inhibitor 2A (CDKN2A), BRCA1 associated protein-1 (BAP1) and neurofibromatosis type 2 (NF2) (Figure 1A), for which direct targeting has proven difficult, contrasted to oncogene-driven malignancies that benefit from a vast majority of molecular targeted anti-cancer drugs.	('deletions', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('145', '178'))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('162', '178'))	('BAP1', 'Gene', '8314', (220, 224))	('neurofibromatosis type 2', 'Gene', '4771', (230, 254))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (145, 181))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('BRCA1 associated protein-1', 'Gene', (192, 218))	('loss-of-function', 'NegReg', (66, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('CDKN2A', 'Gene', (183, 189))	('TSG', 'Gene', '57045', (120, 123))	('cancer', 'Disease', (427, 433))	('BAP1', 'Gene', (220, 224))	('tumor', 'Disease', (96, 101))	('MPM', 'Chemical', '-', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BRCA1 associated protein-1', 'Gene', '8314', (192, 218))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TSG', 'Gene', (120, 123))	('malignancies', 'Disease', 'MESH:D009369', (353, 365))	('mutations', 'Var', (83, 92))	('NF2', 'Gene', '4771', (256, 259))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('neurofibromatosis type 2', 'Gene', (230, 254))	('malignancies', 'Disease', (353, 365))	('NF2', 'Gene', (256, 259))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (230, 247))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (145, 181))
149092	33072611	However, aberrant cancer genome rewires biochemical networks, leading to synthetic lethal or collateral vulnerabilities that are contextually linked with specific genetic alterations, providing alternative approaches for targeting TSG-driven MPM (Figure 2).	('collateral', 'CPA', (93, 103))	('MPM', 'Chemical', '-', (242, 245))	('TSG', 'Gene', (231, 234))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('synthetic lethal', 'MPA', (73, 89))	('aberrant', 'Var', (9, 17))	('TSG', 'Gene', '57045', (231, 234))	('rewires', 'Reg', (32, 39))	('leading to', 'Reg', (62, 72))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
149096	33072611	Cdkn2a inactivation is a key driver of MPM in a conditional mouse model, and CDKN2A loss is associated with shorter survival in patients with MPM.	('MPM', 'Chemical', '-', (142, 145))	('CDKN2A', 'Gene', (77, 83))	('inactivation', 'Var', (7, 19))	('loss', 'NegReg', (84, 88))	('shorter', 'NegReg', (108, 115))	('mouse', 'Species', '10090', (60, 65))	('MPM', 'Chemical', '-', (39, 42))	('survival', 'MPA', (116, 124))	('Cdkn2a', 'Gene', '12578', (0, 6))	('MPM', 'Disease', (142, 145))	('Cdkn2a', 'Gene', (0, 6))	('patients', 'Species', '9606', (128, 136))
149097	33072611	CDKN2A encodes two important tumor suppressor proteins via alternative open reading frames, p16Ink4a and p14Arf that govern the activity of the retinoblastoma (pRb) and p53 pathways, respectively.	('p16Ink4a', 'Var', (92, 100))	('activity', 'MPA', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (144, 158))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('p14Arf', 'Gene', (105, 111))	('p14Arf', 'Gene', '1029', (105, 111))	('govern', 'Reg', (117, 123))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('tumor', 'Disease', (29, 34))	('CDKN2A', 'Gene', (0, 6))	('retinoblastoma', 'Disease', 'MESH:D012175', (144, 158))	('retinoblastoma', 'Disease', (144, 158))	('p53 pathways', 'Pathway', (169, 181))
149098	33072611	While the absence of p16Ink4a, an inhibitor of cyclin-dependent kinases 4/6 (CDK4/6)-mediated phosphorylation of pRb, abrogates the G1/S cell-cycle arrest and promotes aberrant proliferation, functional loss of p14Arf, a central negative regulator of mouse double minute 2 homolog (MDM2), suppresses apoptosis by escape from p53-mediated anti-tumor surveillance (Figure 1B).	('abrogates', 'NegReg', (118, 127))	('mouse double minute 2 homolog', 'Gene', (251, 280))	('MDM2', 'Gene', (282, 286))	('cyclin', 'molecular_function', 'GO:0016538', ('47', '53'))	('apoptosis', 'CPA', (300, 309))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))	('suppresses', 'NegReg', (289, 299))	('aberrant proliferation', 'CPA', (168, 190))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('escape', 'NegReg', (313, 319))	('p14Arf', 'Gene', '1029', (211, 217))	('apoptosis', 'biological_process', 'GO:0097194', ('300', '309'))	('arrest', 'Disease', (148, 154))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('300', '309'))	('tumor', 'Disease', (343, 348))	('loss', 'Var', (203, 207))	('MDM2', 'Gene', '17246', (282, 286))	('p16Ink4a', 'Var', (21, 29))	('promotes', 'PosReg', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('mouse double minute 2 homolog', 'Gene', '17246', (251, 280))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('p14Arf', 'Gene', (211, 217))
149103	33072611	Strikingly, in around 30% MPM cases CDKN2A alterations co-occur with biallelic deletion in type I interferon (IFN-I; mainly IFN-alpha and IFN-beta) locus.	('IFN-alpha', 'Gene', (124, 133))	('CDKN2A', 'Gene', (36, 42))	('MPM', 'Disease', (26, 29))	('IFN-beta', 'Gene', '3439', (138, 146))	('MPM', 'Chemical', '-', (26, 29))	('alterations', 'Var', (43, 54))	('IFN-beta', 'Gene', (138, 146))	('IFN-alpha', 'Gene', '3439', (124, 133))
149106	33072611	Germline mutations in BAP1 causes a predisposition syndrome with increased risk to renal cell carcinoma, MPM and uveal melanoma.	('Germline mutations', 'Var', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MPM', 'Disease', (105, 108))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (83, 103))	('MPM', 'Chemical', '-', (105, 108))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('causes', 'Reg', (27, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('BAP1', 'Gene', '8314', (22, 26))	('renal cell carcinoma', 'Disease', (83, 103))	('uveal melanoma', 'Disease', (113, 127))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('BAP1', 'Gene', (22, 26))
149107	33072611	BAP1 is also frequently inactivated by somatic mutations and loss of the 3p21.1 locus in MPM (Figure 1A).	('BAP1', 'Gene', (0, 4))	('inactivated', 'NegReg', (24, 35))	('3p21.1', 'Gene', (73, 79))	('MPM', 'Chemical', '-', (89, 92))	('MPM', 'Gene', (89, 92))	('BAP1', 'Gene', '8314', (0, 4))	('loss', 'Var', (61, 65))
149108	33072611	Other mechanisms leading to inactivation of BAP1 includes chromosomal rearrangements, gene fusion and splice alterations.	('inactivation', 'Var', (28, 40))	('gene fusion', 'Var', (86, 97))	('BAP1', 'Gene', '8314', (44, 48))	('splice alterations', 'Var', (102, 120))	('chromosomal rearrangements', 'Var', (58, 84))	('BAP1', 'Gene', (44, 48))
149109	33072611	As a component of the polycomb repressive deubiquitinase (PR-DUB) complex, BAP1 deletion causes defects in homologous recombination (HR), contributed by failure to deubiquitinate histone H2A on chromatin, which eventually leads to accumulation of DNA mutations and chromosomal aberrations.	('leads to', 'Reg', (222, 230))	('failure', 'NegReg', (153, 160))	('deletion', 'Var', (80, 88))	('BAP1', 'Gene', (75, 79))	('BAP1', 'Gene', '8314', (75, 79))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('42', '56'))	('homologous recombination', 'MPA', (107, 131))	('PR-DUB) complex', 'cellular_component', 'GO:0035517', ('58', '73'))	('chromatin', 'cellular_component', 'GO:0000785', ('194', '203'))	('histone H2A', 'Protein', (179, 190))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('DNA mutations', 'MPA', (247, 260))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (265, 288))	('accumulation', 'PosReg', (231, 243))	('deubiquitinate', 'MPA', (164, 178))	('homologous recombination', 'biological_process', 'GO:0035825', ('107', '131'))	('defects', 'NegReg', (96, 103))	('chromosomal aberrations', 'CPA', (265, 288))
149114	33072611	The heterozygous germline BAP1 mutations were reported to increase aerobic glycolysis, also known as the "Warburg effect," due to impaired mitochondrial respiration, suggesting a role for BAP1 in metabolism.	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', (188, 192))	('mutations', 'Var', (31, 40))	('increase', 'PosReg', (58, 66))	('aerobic glycolysis', 'MPA', (67, 85))	('glycolysis', 'biological_process', 'GO:0006096', ('75', '85'))	('BAP1', 'Gene', '8314', (188, 192))	('mitochondrial respiration', 'MPA', (139, 164))	('impaired', 'NegReg', (130, 138))	('BAP1', 'Gene', '8314', (26, 30))
149115	33072611	Indeed, recent evidence has indicated that loss of BAP1 promotes cellular adaptability to metabolic stress by impairing ER stress gene regulatory network (e.g., ATF3 and CHOP) and ferroptosis via modulating SLC7AL11.	('CHOP', 'Gene', (170, 174))	('cellular adaptability to metabolic stress', 'MPA', (65, 106))	('BAP1', 'Gene', (51, 55))	('modulating', 'Reg', (196, 206))	('SLC7AL11', 'MPA', (207, 215))	('ER stress gene regulatory network', 'MPA', (120, 153))	('ATF3', 'Gene', '467', (161, 165))	('impairing', 'NegReg', (110, 119))	('ferroptosis', 'CPA', (180, 191))	('CHOP', 'Gene', '1649', (170, 174))	('promotes', 'PosReg', (56, 64))	('ferroptosis', 'biological_process', 'GO:0097707', ('180', '191'))	('loss', 'Var', (43, 47))	('ATF3', 'Gene', (161, 165))	('BAP1', 'Gene', '8314', (51, 55))
149119	33072611	Importantly, recent studies indicate that BAP1 loss in MPM prioritizes the enhancer of zeste homolog 2 (EZH2)-targeted therapy, suggesting that aberrant expression of EZH2, known to lead to uncontrolled cell proliferation and tumorigenesis, might be an inherent feature enabled by the suppression of BAP1.	('BAP1', 'Gene', '8314', (42, 46))	('MPM', 'Chemical', '-', (55, 58))	('EZH2', 'Gene', (167, 171))	('BAP1', 'Gene', '8314', (300, 304))	('aberrant', 'Var', (144, 152))	('EZH2', 'Gene', '2146', (104, 108))	('BAP1', 'Gene', (42, 46))	('EZH2', 'Gene', (104, 108))	('BAP1', 'Gene', (300, 304))	('loss', 'NegReg', (47, 51))	('enhancer of zeste homolog 2', 'Gene', '2146', (75, 102))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('enhancer of zeste homolog 2', 'Gene', (75, 102))	('EZH2', 'Gene', '2146', (167, 171))	('tumor', 'Disease', (226, 231))
149122	33072611	Surprisingly, several studies have revealed that BAP1 mutaions in MPM are associated with favorable prognosis in patients.	('MPM', 'Chemical', '-', (66, 69))	('mutaions', 'Var', (54, 62))	('BAP1', 'Gene', (49, 53))	('patients', 'Species', '9606', (113, 121))	('MPM', 'Gene', (66, 69))	('BAP1', 'Gene', '8314', (49, 53))
149124	33072611	In addition, BAP1 deletion is linked with fewer chromosome arm gain and loss, as well as less somatic copy number alterations (SCNAs).	('fewer', 'NegReg', (42, 47))	('BAP1', 'Gene', (13, 17))	('loss', 'NegReg', (72, 76))	('somatic copy number alterations', 'CPA', (94, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('BAP1', 'Gene', '8314', (13, 17))	('less', 'NegReg', (89, 93))	('deletion', 'Var', (18, 26))	('chromosome arm gain', 'CPA', (48, 67))
149130	33072611	In addition to NF2 mutations (Figure 1A), gene fusion and chromosomal rearrangements also result in nonfunctional NF2 and therefore inactivates Hippo pathway in MPM.	('inactivates', 'NegReg', (132, 143))	('NF2', 'Gene', (114, 117))	('mutations', 'Var', (19, 28))	('Hippo pathway', 'Pathway', (144, 157))	('gene fusion', 'Var', (42, 53))	('NF2', 'Gene', (15, 18))	('nonfunctional', 'MPA', (100, 113))	('NF2', 'Gene', '4771', (114, 117))	('MPM', 'Chemical', '-', (161, 164))	('NF2', 'Gene', '4771', (15, 18))	('result in', 'Reg', (90, 99))
149131	33072611	In addition, other components of the Hippo pathway, such as LATS2, are also frequently inactivated in MPM, which inactivates the Hippo pathway as well.	('MPM', 'Var', (102, 105))	('Hippo pathway', 'Pathway', (37, 50))	('LATS2', 'Gene', (60, 65))	('Hippo pathway', 'Pathway', (129, 142))	('LATS2', 'Gene', '26524', (60, 65))	('inactivated', 'NegReg', (87, 98))	('inactivates', 'NegReg', (113, 124))	('MPM', 'Chemical', '-', (102, 105))
149132	33072611	LATS2 alterations (mutations, copy loss) occur in about 11% of MPM patients, and LATS2-deficient MPM might have similar vulnerabilities as those where the Hippo pathway is inactivated via other mechanisms.	('copy loss', 'Var', (30, 39))	('MPM', 'Chemical', '-', (63, 66))	('patients', 'Species', '9606', (67, 75))	('LATS2', 'Gene', (0, 5))	('LATS2', 'Gene', (81, 86))	('MPM', 'Chemical', '-', (97, 100))	('LATS2', 'Gene', '26524', (0, 5))	('LATS2', 'Gene', '26524', (81, 86))	('mutations', 'Var', (19, 28))	('MPM', 'Disease', (63, 66))	('alterations', 'Reg', (6, 17))	('MPM', 'Disease', (97, 100))
149133	33072611	In particular, MPM with co-occuring mutations in LATS2 and NF2 has been reported to rely on an altered mTOR/PI3K/AKT signaling, and therefore highly sensitive to PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases.	('MPM', 'Disease', (15, 18))	('mTOR', 'Gene', (103, 107))	('NF2', 'Gene', (59, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('216', '220'))	('mTOR', 'Gene', '2475', (225, 229))	('MPM', 'Chemical', '-', (15, 18))	('AKT', 'Gene', '207', (113, 116))	('mutations', 'Var', (36, 45))	('NF2', 'Gene', '4771', (59, 62))	('mTOR', 'Gene', (225, 229))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('AKT signaling', 'biological_process', 'GO:0043491', ('113', '126'))	('altered', 'Reg', (95, 102))	('PF-04691502', 'Chemical', 'MESH:C570662', (162, 173))	('AKT', 'Gene', (113, 116))	('LATS2', 'Gene', (49, 54))	('LATS2', 'Gene', '26524', (49, 54))	('mTOR', 'Gene', '2475', (103, 107))
149134	33072611	Finally, gene fusions involving LIFR, encoding a metastasis suppressor, was identified as an additional mechanism that inactivates Hippo pathway in MPM.	('MPM', 'Disease', (148, 151))	('LIFR', 'Gene', '3977', (32, 36))	('LIFR', 'Gene', (32, 36))	('MPM', 'Chemical', '-', (148, 151))	('gene fusions', 'Var', (9, 21))	('inactivates', 'NegReg', (119, 130))	('Hippo pathway', 'Pathway', (131, 144))
149135	33072611	The disrupted Hippo pathway constitutively activates oncogenic YAP/TAZ, which in turn transcriptionally activates cancer-promoting genes through interaction with TEA/ATTS domain (TEAD) transcription factors.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('activates', 'PosReg', (104, 113))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('YAP', 'Gene', (63, 66))	('Hippo', 'Gene', (14, 19))	('interaction', 'Interaction', (145, 156))	('activates', 'PosReg', (43, 52))	('YAP', 'Gene', '10413', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disrupted', 'Var', (4, 13))	('cancer', 'Disease', (114, 120))
149138	33072611	Further, inhibition of YAP/TAZ was reported to compensatorially activate the MAPK pathway and, as a consequence, co-targeting YAP/TAZ and MEK, a key constituent of the MAPK signaling cascade, synergizes in suppressing the growth of NF2-deficient tumors, providing a rational combination strategy for NF2-mutant MPM.	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('MAPK signaling', 'biological_process', 'GO:0000165', ('168', '182'))	('YAP', 'Gene', (23, 26))	('inhibition', 'Var', (9, 19))	('tumors', 'Disease', (246, 252))	('YAP', 'Gene', (126, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('77', '81'))	('MEK', 'Gene', '5609', (138, 141))	('NF2', 'Gene', '4771', (300, 303))	('co-targeting', 'Var', (113, 125))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('YAP', 'Gene', '10413', (23, 26))	('NF2', 'Gene', (300, 303))	('MPM', 'Chemical', '-', (311, 314))	('signaling cascade', 'biological_process', 'GO:0007165', ('173', '190'))	('MEK', 'Gene', (138, 141))	('YAP', 'Gene', '10413', (126, 129))	('NF2', 'Gene', '4771', (232, 235))	('activate', 'PosReg', (64, 72))	('growth', 'MPA', (222, 228))	('suppressing', 'NegReg', (206, 217))	('NF2', 'Gene', (232, 235))	('MAPK pathway', 'Pathway', (77, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('168', '172'))
149139	33072611	Finally, NF2/Merlin inactivation has been associated with upregulation of the focal adhesion kinase (FAK) activity in mesothelioma.	('FAK', 'Gene', (101, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('FAK', 'Gene', '5747', (101, 104))	('FAK', 'molecular_function', 'GO:0004717', ('101', '104'))	('inactivation', 'Var', (20, 32))	('Merlin', 'Gene', (13, 19))	('focal adhesion', 'cellular_component', 'GO:0005925', ('78', '92'))	('NF2', 'Gene', (9, 12))	('Merlin', 'Gene', '4771', (13, 19))	('mesothelioma', 'Disease', (118, 130))	('FA', 'Phenotype', 'HP:0001994', (101, 103))	('focal adhesion kinase', 'Gene', '5747', (78, 99))	('NF2', 'Gene', '4771', (9, 12))	('activity', 'MPA', (106, 114))	('upregulation', 'PosReg', (58, 70))	('focal adhesion kinase', 'Gene', (78, 99))
149145	33072611	In addition to the TSGs (CDKN2A, BAP1, and NF2) described above, several other genes, e.g., TP53 (tumor protein p53), LATS2, SETD2 (SET domain containing 2) and oncogenic changes in the TERT (telomerase reverse transcriptase) promoter are also altered by at non-negligible frequencies in MPM.	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('TP53', 'Gene', (92, 96))	('BAP1', 'Gene', (33, 37))	('tumor', 'Disease', (98, 103))	('transcriptase', 'molecular_function', 'GO:0003968', ('211', '224'))	('SET domain containing 2', 'Gene', '29072', (132, 155))	('TSG', 'Gene', '57045', (19, 22))	('telomerase reverse transcriptase', 'Gene', (192, 224))	('transcriptase', 'molecular_function', 'GO:0034062', ('211', '224'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TSG', 'Gene', (19, 22))	('TERT', 'Gene', (186, 190))	('TERT', 'Gene', '7015', (186, 190))	('LATS2', 'Gene', (118, 123))	('LATS2', 'Gene', '26524', (118, 123))	('telomerase reverse transcriptase', 'Gene', '7015', (192, 224))	('SET domain containing 2', 'Gene', (132, 155))	('oncogenic changes', 'CPA', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MPM', 'Chemical', '-', (288, 291))	('TP53', 'Gene', '7157', (92, 96))	('transcriptase', 'molecular_function', 'GO:0003899', ('211', '224'))	('SETD2', 'Gene', (125, 130))	('NF2', 'Gene', '4771', (43, 46))	('BAP1', 'Gene', '8314', (33, 37))	('SETD2', 'Gene', '29072', (125, 130))	('NF2', 'Gene', (43, 46))	('MPM', 'Var', (288, 291))
149148	33072611	We and others have shown that inactivation of CDKN2A/2B and TP53 renders MPM cell particularly sensitive to G2 checkpoint inhibition, e.g., CBP501 (a peptide with G2 checkpoint-abrogating activity) and AZD1775 (selective inhibitor of the G2 checkpoint kinase WEE1).	('AZD1775', 'Var', (202, 209))	('MPM', 'Chemical', '-', (73, 76))	('inactivation', 'Var', (30, 42))	('WEE1', 'Gene', (259, 263))	('AZD1775', 'Chemical', 'MESH:C549567', (202, 209))	('WEE1', 'Gene', '7465', (259, 263))	('CBP', 'molecular_function', 'GO:0008140', ('140', '143'))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('CDKN2A/2B', 'Gene', (46, 55))	('CBP501', 'Var', (140, 146))	('sensitive', 'Reg', (95, 104))
149149	33072611	Genetic alterations (mutation, gene fusion and splice alteration) in SETD2, an epigenetic tumor suppressor involved in histone methylation, are detected in more than 8% of MPM cases.	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('SETD2', 'Gene', '29072', (69, 74))	('MPM', 'Disease', (172, 175))	('splice alteration', 'Var', (47, 64))	('SETD2', 'Gene', (69, 74))	('histone methylation', 'biological_process', 'GO:0016571', ('119', '138'))	('MPM', 'Chemical', '-', (172, 175))	('detected', 'Reg', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
149150	33072611	SETD2-deficient MPM may respond favorably to inhibitors of histone methyltransferase EZH2.	('histone methyltransferase', 'Gene', (59, 84))	('EZH2', 'Gene', '2146', (85, 89))	('EZH2', 'Gene', (85, 89))	('SETD2', 'Gene', '29072', (0, 5))	('MPM', 'Chemical', '-', (16, 19))	('respond', 'Reg', (24, 31))	('SETD2', 'Gene', (0, 5))	('inhibitors', 'Var', (45, 55))	('histone methyltransferase', 'Gene', '56979', (59, 84))
149153	33072611	As expected, MPM cells carrying TERT promoter mutations show increased sensitivity to telomerase inhibition than those with wide-type TERT, indicating that targeting telomerase activity might be a promising treatment strategy for this MPM subset.	('TERT', 'Gene', '7015', (32, 36))	('mutations', 'Var', (46, 55))	('telomerase activity', 'molecular_function', 'GO:0003720', ('166', '185'))	('TERT', 'Gene', (134, 138))	('increased', 'PosReg', (61, 70))	('TERT', 'Gene', '7015', (134, 138))	('MPM', 'Chemical', '-', (13, 16))	('MPM', 'Chemical', '-', (235, 238))	('sensitivity', 'MPA', (71, 82))	('TERT', 'Gene', (32, 36))
149172	33072611	The UPR is mediated by three effector arms: double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1alpha (IRE1alpha), and activating transcription factor 6 (ATF6).	('ATF6', 'Gene', (203, 207))	('double-stranded', 'Var', (44, 59))	('transcription', 'biological_process', 'GO:0006351', ('179', '192'))	('PERK', 'Gene', (111, 115))	('transcription factor', 'molecular_function', 'GO:0000981', ('179', '199'))	('RNA', 'cellular_component', 'GO:0005562', ('60', '63'))	('IRE1alpha', 'Gene', (152, 161))	('IRE1alpha', 'Gene', '2081', (152, 161))	('activating transcription factor 6', 'Gene', '22926', (168, 201))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('activating transcription factor 6', 'Gene', (168, 201))	('PERK', 'Gene', '9451', (111, 115))	('ATF6', 'Gene', '22926', (203, 207))
149179	33072611	Consistently, we have recently showed that deregulated ER stress/UPR is a characteristic feature of MPM, and that therapeutic modulation of the signaling impairs the growth of MPM cells and overcomes resistance to standard chemotherapy.	('MPM', 'Disease', (176, 179))	('deregulated ER stress/UPR', 'MPA', (43, 68))	('impairs', 'NegReg', (154, 161))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('MPM', 'Chemical', '-', (176, 179))	('growth', 'CPA', (166, 172))	('overcomes', 'NegReg', (190, 199))	('modulation', 'Var', (126, 136))	('MPM', 'Disease', (100, 103))	('MPM', 'Chemical', '-', (100, 103))
149201	33072611	Mesothelioma stem cells (MSCs) might be responsible for tumor repopulation after chemoradiation in murine mesothelioma, and cisplatin-resistant, CSC-like subpopulations could be enriched by aldehyde dehydrogenase (ALDH)high and CD44+ in mesothelioma cell lines.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ALDH', 'molecular_function', 'GO:0004030', ('214', '218'))	('mesothelioma', 'Disease', (106, 118))	('responsible', 'Reg', (40, 51))	('ALDH', 'Gene', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('murine', 'Species', '10090', (99, 105))	('tumor', 'Disease', (56, 61))	('mesothelioma', 'Disease', (237, 249))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('MSCs', 'molecular_function', 'GO:0043854', ('25', '29'))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('CD44+', 'Var', (228, 233))	('high', 'Var', (219, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
149204	33072611	Compelling evidence suggests that DDR protects against genomic instability and affects responses to genotoxic agents, although loss of some elements involved in DNA repair pathways is predisposed to malignancy.	('malignancy', 'Disease', (199, 209))	('DDR', 'Chemical', '-', (34, 37))	('malignancy', 'Disease', 'MESH:D009369', (199, 209))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('responses to genotoxic agents', 'MPA', (87, 116))	('DNA repair', 'biological_process', 'GO:0006281', ('161', '171'))	('affects', 'Reg', (79, 86))	('loss', 'Var', (127, 131))	('genomic instability', 'MPA', (55, 74))
149206	33072611	MPM patients with germline mutations in BAP1 or other DNA repair genes (CHEK2, PALB2, BRCA2, and MLH1) show increased sensitivity to cytotoxic chemotherapy due to impaired DDR.	('germline mutations', 'Var', (18, 36))	('PALB2', 'Gene', '79728', (79, 84))	('BAP1', 'Gene', (40, 44))	('DDR', 'MPA', (172, 175))	('DDR', 'Chemical', '-', (172, 175))	('impaired', 'NegReg', (163, 171))	('increased', 'PosReg', (108, 117))	('patients', 'Species', '9606', (4, 12))	('BRCA2', 'Gene', (86, 91))	('CHEK2', 'Gene', (72, 77))	('sensitivity', 'MPA', (118, 129))	('MLH1', 'Gene', (97, 101))	('DNA repair', 'biological_process', 'GO:0006281', ('54', '64'))	('CHEK2', 'Gene', '11200', (72, 77))	('BRCA2', 'Gene', '675', (86, 91))	('BAP1', 'Gene', '8314', (40, 44))	('PALB2', 'Gene', (79, 84))	('MLH1', 'Gene', '4292', (97, 101))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('MPM', 'Chemical', '-', (0, 3))
149208	33072611	Notably, p53 signaling is frequently inactivated in MPM, a consequence of TP53 mutaions (6-16% in MPM) and, more often, of inactivating alterations in CDKN2A, which depletes p14Arf and promotes proteasome-mediated degradation of p53.	('alterations', 'Var', (136, 147))	('inactivating alterations', 'Var', (123, 147))	('TP53', 'Gene', (74, 78))	('p14Arf', 'Gene', (174, 180))	('p53 signaling', 'MPA', (9, 22))	('MPM', 'Chemical', '-', (52, 55))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('promotes', 'PosReg', (185, 193))	('CDKN2A', 'Gene', (151, 157))	('mutaions', 'Var', (79, 87))	('proteasome', 'molecular_function', 'GO:0004299', ('194', '204'))	('degradation', 'biological_process', 'GO:0009056', ('214', '225'))	('depletes', 'NegReg', (165, 173))	('MPM', 'Chemical', '-', (98, 101))	('MPM', 'Disease', (52, 55))	('proteasome-mediated degradation', 'MPA', (194, 225))	('proteasome', 'cellular_component', 'GO:0000502', ('194', '204'))	('TP53', 'Gene', '7157', (74, 78))	('p14Arf', 'Gene', '1029', (174, 180))	('inactivated', 'NegReg', (37, 48))
149209	33072611	Consequently, p53 deficient MPM cells might have greater dependence on G2/M checkpoint to protect the toxicity of chemotherapy, and abrogation of the G2/M checkpoint activity, e.g., WEE1 inhibition, sensitizes MPM cells to chemotherapy.	('MPM', 'Chemical', '-', (210, 213))	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('toxicity', 'Disease', (102, 110))	('MPM', 'Chemical', '-', (28, 31))	('inhibition', 'NegReg', (187, 197))	('p53', 'Gene', (14, 17))	('abrogation', 'Var', (132, 142))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('150', '165'))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('71', '86'))	('WEE1', 'Gene', '7465', (182, 186))	('sensitizes', 'Reg', (199, 209))	('deficient', 'Var', (18, 27))	('WEE1', 'Gene', (182, 186))
149221	33072611	CRISPR screens of genome and customized sgRNA libraries in numerous disease models have identified novel oncogenic drivers and cancer dependencies, synthetic lethal interactions with mutant RAS and BRAF and mechanisms of resistance to anti-cancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRAF', 'Gene', '673', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('interactions', 'Interaction', (165, 177))	('numerous disease', 'Disease', (59, 75))	('BRAF', 'Gene', (198, 202))	('mutant', 'Var', (183, 189))	('cancer', 'Disease', (127, 133))	('cancer dependencies', 'Disease', 'MESH:D009369', (127, 146))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('numerous disease', 'Disease', 'MESH:D003141', (59, 75))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer dependencies', 'Disease', (127, 146))	('RAS', 'Gene', (190, 193))	('cancer', 'Disease', (240, 246))
149222	33072611	CRISPR-based functional genomics in MPM is still at its infancy, we recently screened MPM kinome and delineated that deregulated G2-M checkpoint activity dictates MPM response to chemotherapy.	('dictates', 'Reg', (154, 162))	('MPM response to chemotherapy', 'MPA', (163, 191))	('MPM', 'Chemical', '-', (86, 89))	('G2-M checkpoint', 'biological_process', 'GO:0000075', ('129', '144'))	('MPM', 'Chemical', '-', (163, 166))	('G2-M checkpoint activity', 'MPA', (129, 153))	('MPM', 'Chemical', '-', (36, 39))	('deregulated', 'Var', (117, 128))
149229	33072611	Unlike many other solid tumors, MPM is characterized by overwhelming prevalence of loss of function alterations in tumor suppressor genes, for which direct pharmacological targeting proves difficult.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MPM', 'Disease', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', (115, 120))	('MPM', 'Chemical', '-', (32, 35))	('loss of function', 'NegReg', (83, 99))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('alterations', 'Var', (100, 111))
149231	33072611	Recent studies have identified previously unappreciated vulnerabilities contextually linked with aberrant TSGs and dependencies acquired during cancer development and drug resistance, which provides unprecedented insights into MPM pathobiology and may bring about unprecedented hopes for the development of biomarker-guided precision medicine for the disease (Figure 3).	('drug resistance', 'biological_process', 'GO:0042493', ('167', '182'))	('TSG', 'Gene', '57045', (106, 109))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('MPM', 'Chemical', '-', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('aberrant', 'Var', (97, 105))	('drug resistance', 'biological_process', 'GO:0009315', ('167', '182'))	('TSG', 'Gene', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
149265	32033266	Already at d1C2, all patients showed a statistically significant (p < 0.001) increase in the sPD-L1 levels, with respect to baseline, that was maintained in the course of treatment with median values of sPD-L1 concentration and fold change vs. baseline (FC) at each investigated time-point ranging from 1.52 ng/mL (d1C2) to 1.76 ng/mL (d1C5), and from 22.71 (d1C2) to 27.28 (d1C3), respectively (Figure 1, Table 1).	('PD-L1', 'Gene', (94, 99))	('d1C2', 'Var', (11, 15))	('PD-L1', 'Gene', '29126', (204, 209))	('PD-L1', 'Gene', '29126', (94, 99))	('patients', 'Species', '9606', (21, 29))	('increase', 'PosReg', (77, 85))	('PD-L1', 'Gene', (204, 209))
149269	32033266	No association between OS and concentration of sPD-L1 resulted at d1C3 (Figure 2c; Table S1).	('PD-L1', 'Gene', (48, 53))	('OS', 'Chemical', '-', (23, 25))	('PD-L1', 'Gene', '29126', (48, 53))	('d1C3', 'Var', (66, 70))
149276	32033266	In the course of treatment, a significant negative correlation was identified between sPD-L1 and the absolute eosinophil count (AEC) at d1C2 (r = -0.34, p = 0.04) and d1C5 (r = -0.45, p = 0.02) (Figure 4d,e; Table S2).	('PD-L1', 'Gene', (87, 92))	('d1C5', 'Var', (167, 171))	('PD-L1', 'Gene', '29126', (87, 92))	('negative', 'NegReg', (42, 50))
149282	32033266	Consistently, median values of sPD-L1 FC increased at each investigated time-point vs. baseline, ranging from 18.25 at d1C4 to 43.9 at d1C3.	('d1C3', 'Var', (135, 139))	('increased', 'PosReg', (41, 50))	('PD-L1', 'Gene', (32, 37))	('PD-L1', 'Gene', '29126', (32, 37))	('d1C4', 'Var', (119, 123))
149283	32033266	Patients treated with anti-CTLA-4 mAbs, by contrast, did not show any significant modulation in sPD-L1 serum levels during treatment, with median values of sPD-L1 FC ranging from 0.85 at d1C4 to 1.76 at d1C3 (Figure 5; Table 2).	('CTLA-4', 'Gene', (27, 33))	('PD-L1', 'Gene', '29126', (97, 102))	('CTLA-4', 'Gene', '1493', (27, 33))	('PD-L1', 'Gene', (157, 162))	('d1C4', 'Var', (187, 191))	('d1C3', 'Var', (203, 207))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', '29126', (157, 162))	('PD-L1', 'Gene', (97, 102))
149285	32033266	Results showed that median values of sPD-L1 FC, in these patients, did not significantly change between baseline and the following administration cycles, ranging from 1.05 at d1C3 and d1C4 to 1.12 at d1C2 (Table 3).	('patients', 'Species', '9606', (57, 65))	('d1C4', 'Var', (184, 188))	('d1C3', 'Var', (175, 179))	('PD-L1', 'Gene', (38, 43))	('PD-L1', 'Gene', '29126', (38, 43))
149288	32033266	Consistently, median values of sPD-L1 FC increased at each investigated time-point vs. baseline, ranging from 19.77 at d1C4 to 28.58 at d1C3 (Figure 6; Table 4).	('PD-L1', 'Gene', (32, 37))	('PD-L1', 'Gene', '29126', (32, 37))	('d1C3', 'Var', (136, 140))	('d1C4', 'Var', (119, 123))
149290	32033266	Patients with concentration levels below the identified cut-offs showed a longer survival only at d1C2 and d1C5 (p = 0.01) (Figure 7; Table S3).	('d1C5', 'Var', (107, 111))	('longer', 'PosReg', (74, 80))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (81, 89))	('d1C2', 'Var', (98, 102))
149318	32033266	This evidence suggests that the increase of sPD-L1 was specifically associated with the blockade of PD-L1 and not generally to the blockade of PD-1/PD-L1 pathway or other immune check-point molecules.	('blockade', 'Var', (88, 96))	('PD-1', 'Gene', (143, 147))	('PD-1', 'Gene', '5133', (143, 147))	('increase', 'PosReg', (32, 40))	('PD-L1', 'Gene', '29126', (100, 105))	('PD-L1', 'Gene', '29126', (148, 153))	('PD-L1', 'Gene', '29126', (45, 50))	('PD-L1', 'Gene', (148, 153))	('PD-L1', 'Gene', (100, 105))	('PD-L1', 'Gene', (45, 50))
149355	30060501	High-throughput analyses have uncovered key genomic and epigenomic alterations driving malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (87, 109))	('malignant mesothelioma', 'Disease', (87, 109))	('epigenomic alterations', 'Var', (56, 78))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (87, 109))
149383	30060501	Oxidative DNA damage, if not properly repaired, is highly mutagenic and can trigger genomic instability, a primary enabling characteristic of cancer formation that is detectable by high-throughput techniques (Figure 1a).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (142, 148))	('Oxidative', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('genomic instability', 'CPA', (84, 103))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('trigger', 'Reg', (76, 83))
149385	30060501	Within such environments, chronic oxidative stress accelerates the pace of genetic mutation, giving rise to cancer with alarming efficacy and speed.	('giving rise', 'Reg', (93, 104))	('oxidative stress', 'Phenotype', 'HP:0025464', (34, 50))	('genetic mutation', 'Var', (75, 91))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('accelerates', 'PosReg', (51, 62))	('pace', 'MPA', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
149396	30060501	Moreover, frequent DNA-level alterations:specifically copy-number losses:affecting CDKN2A, NF2, EP300, SETD2, PBRM1, and BAP1 have been detected in copy-number data from TCGA and additional cohorts.	('CDKN2A', 'Gene', '1029', (83, 89))	('BAP1', 'Gene', (121, 125))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('EP300', 'Gene', (96, 101))	('CDKN2A', 'Gene', (83, 89))	('EP300', 'Gene', '2033', (96, 101))	('SETD2', 'Gene', '29072', (103, 108))	('NF2', 'Gene', (91, 94))	('SETD2', 'Gene', (103, 108))	('copy-number losses', 'Var', (54, 72))	('PBRM1', 'Gene', (110, 115))	('PBRM1', 'Gene', '55193', (110, 115))	('NF2', 'Gene', '4771', (91, 94))
149398	30060501	Whole-exome sequencing analyses have also identified frequent alterations affecting BAP1, NF2, and CDKN2A (located in chromosomal regions 3p21, 22q12, and 9p21) by somatic mutations and/or copy-number alterations (Figure 2b).	('CDKN2A', 'Gene', (99, 105))	('NF2', 'Gene', '4771', (90, 93))	('NF2', 'Gene', (90, 93))	('CDKN2A', 'Gene', '1029', (99, 105))	('p21', 'Gene', (156, 159))	('copy-number alterations', 'Var', (189, 212))	('p21', 'Gene', '644914', (156, 159))	('p21', 'Gene', (139, 142))	('BAP1', 'Gene', (84, 88))	('p21', 'Gene', '644914', (139, 142))
149402	30060501	The authors describe two novel genomic alterations preferentially occurring in peritoneal mesothelioma (amplification of 15q26.2 and deletion of 8p11.22).	('peritoneal mesothelioma', 'Disease', (79, 102))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (79, 102))	('amplification of', 'Var', (104, 120))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (79, 102))	('15q26.2', 'Gene', (121, 128))	('deletion of', 'Var', (133, 144))
149403	30060501	Analysis of average methylation and copy number alterations in the 87 samples of the TCGA-MESO cohort confirms these previously-described genome-wide alterations in mesothelioma, such as the prevalent copy-number loss of chromosomal region 22q12 (Figure 2a).	('mesothelioma', 'Disease', (165, 177))	('chromosomal region', 'cellular_component', 'GO:0098687', ('221', '239'))	('copy-number loss', 'Var', (201, 217))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))
149404	30060501	Furthermore, the most recent analysis of mesothelioma samples (TCGA-MPM) suggests up to 57% of samples with alterations in BAP1, collectively confirming that BAP1 is the most frequently altered gene in mesothelioma.	('BAP1', 'Gene', (123, 127))	('alterations', 'Var', (108, 119))	('mesothelioma', 'Disease', (202, 214))	('mesothelioma', 'Disease', (41, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))
149408	30060501	A more in-depth analysis of the correlation between genetic and epigenetic changes in mesothelioma identified that methylation status and copy-number were significantly associated in the TGFB2 and GDF10 genes.	('GDF10', 'Gene', (197, 202))	('copy-number', 'Var', (138, 149))	('GDF10', 'Gene', '2662', (197, 202))	('mesothelioma', 'Disease', (86, 98))	('methylation', 'MPA', (115, 126))	('associated', 'Reg', (169, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('TGFB2', 'Gene', '7042', (187, 192))	('TGFB2', 'Gene', (187, 192))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
149414	30060501	However, as both sporadic and familial MPM has a high prevalence of inactivating BAP1 mutations, this epigenetic axis may be critical to mesothelioma carcinogenesis.	('mutations', 'Var', (86, 95))	('mesothelioma carcinogenesis', 'Disease', (137, 164))	('familial MPM', 'Disease', (30, 42))	('BAP1', 'Gene', (81, 85))	('mesothelioma carcinogenesis', 'Disease', 'MESH:D063646', (137, 164))	('inactivating', 'MPA', (68, 80))
149416	30060501	Collectively, these results suggest not only the importance of epigenetic regulation in mesothelioma biology, but also highlight the potential utility of epigenetic-based therapies such as EZH2 inhibitors.	('epigenetic regulation', 'Var', (63, 84))	('mesothelioma', 'Disease', (88, 100))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))
149417	30060501	To investigate the role of epigenetic alterations contributing to tumor heterogeneity, Kim et al.	('tumor', 'Disease', (66, 71))	('epigenetic alterations', 'Var', (27, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))
149419	30060501	Epigenetic alterations and consequent transcriptomic changes in the BNC1, RPS6KA3, TWSG1, and DUSP15 genes were characteristic features found in the side population cells and likely to participate in defining tumor heterogeneity.	('Epigenetic alterations', 'Var', (0, 22))	('DUSP15', 'Gene', (94, 100))	('TWSG1', 'Gene', '57045', (83, 88))	('BNC1', 'Gene', '646', (68, 72))	('tumor', 'Disease', (209, 214))	('TWSG1', 'Gene', (83, 88))	('RPS6KA3', 'Gene', (74, 81))	('transcriptomic', 'MPA', (38, 52))	('DUSP15', 'Gene', '128853', (94, 100))	('RPS6KA3', 'Gene', '6197', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BNC1', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('participate', 'Reg', (185, 196))
149422	30060501	Germline mutations in the BAP1 gene are one of the most significant factors that lead to the development of mesothelioma.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('lead to', 'Reg', (81, 88))	('mesothelioma', 'Disease', (108, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))
149423	30060501	For example, analysis of 407 pleural mesothelioma cases and 389 controls with a comprehensive history of asbestos exposure revealed an increased risk of abnormalities in chromosomal region 7p22.2, which includes the gene encoding Forkhead box protein K1 (FOXK1) that is known to interact with BAP1.	('FOXK1', 'Gene', '221937', (255, 260))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('pleural mesothelioma', 'Disease', (29, 49))	('Forkhead box protein K1', 'Gene', '221937', (230, 253))	('chromosomal region', 'cellular_component', 'GO:0098687', ('170', '188'))	('abnormalities', 'Var', (153, 166))	('FOXK1', 'Gene', (255, 260))	('asbestos', 'Chemical', 'MESH:D001194', (105, 113))	('Forkhead box protein K1', 'Gene', (230, 253))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (29, 49))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (29, 49))
149425	30060501	In Western Australia, a large study (428 cases and 1269 controls) identified variants located in the CRTAM, SDK1, and RASGRF2 genes that were significantly associated with malignant mesothelioma risk.	('malignant mesothelioma', 'Disease', (172, 194))	('variants', 'Var', (77, 85))	('RASGRF2', 'Gene', '5924', (118, 125))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (172, 194))	('CRTAM', 'Gene', '56253', (101, 106))	('SDK1', 'Gene', (108, 112))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (172, 194))	('CRTAM', 'Gene', (101, 106))	('associated with', 'Reg', (156, 171))	('RASGRF2', 'Gene', (118, 125))	('SDK1', 'Gene', '221935', (108, 112))
149426	30060501	In cases like these, it is common to focus on the interactions between exposure to a specific environmental carcinogen (e.g., asbestos) and single-nucleotide polymorphisms (SNPs) emerging from previous GWAS studies.	('interactions', 'Interaction', (50, 62))	('single-nucleotide polymorphisms', 'Var', (140, 171))	('asbestos', 'Chemical', 'MESH:D001194', (126, 134))
149427	30060501	For instance, these approaches have revealed the synergistic effect between asbestos exposure and rs1508805, rs2501618, and rs5756444 genetic variations.	('rs2501618', 'Var', (109, 118))	('rs1508805', 'Var', (98, 107))	('rs2501618', 'Mutation', 'rs2501618', (109, 118))	('rs5756444', 'Var', (124, 133))	('asbestos', 'Chemical', 'MESH:D001194', (76, 84))	('rs1508805', 'Mutation', 'rs1508805', (98, 107))	('rs5756444', 'Mutation', 'rs5756444', (124, 133))
149430	30060501	The discovery of the role of BAP1 mutations in malignant mesothelioma is an example of the combination between classical genetic methods and novel high-throughput technologies to discover causal relationships between genotype and phenotype.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (47, 69))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (47, 69))	('malignant mesothelioma', 'Disease', (47, 69))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
149434	30060501	However, BAP1 mutations are also found in other types of tumors, thus its alteration is not exclusive to mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mesothelioma', 'Disease', (105, 117))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
149436	30060501	In fact, BAP1 has been shown to be affected in both alleles by copy-number losses and mutations in 42% of tumors.	('mutations', 'Var', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('copy-number losses', 'Var', (63, 81))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('affected', 'Reg', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', (9, 13))
149437	30060501	Additionally, the high frequency of mutation in BAP1, as well as NF2 and TP53 was confirmed in multi-omic analysis of human malignant and matched non-malignant samples.	('TP53', 'Gene', '7157', (73, 77))	('NF2', 'Gene', (65, 68))	('TP53', 'Gene', (73, 77))	('BAP1', 'Gene', (48, 52))	('NF2', 'Gene', '4771', (65, 68))	('human', 'Species', '9606', (118, 123))	('mutation', 'Var', (36, 44))
149438	30060501	Interestingly, it has been shown that germline mutations in Bap1 can induce epigenetic deregulation of the Rb protein in mice, facilitating the development of malignant mesothelioma.	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('malignant mesothelioma', 'Disease', (159, 181))	('induce', 'Reg', (69, 75))	('epigenetic deregulation', 'MPA', (76, 99))	('Rb protein', 'Protein', (107, 117))	('Bap1', 'Gene', '104416', (60, 64))	('mice', 'Species', '10090', (121, 125))	('germline mutations', 'Var', (38, 56))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (159, 181))	('Bap1', 'Gene', (60, 64))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (159, 181))
149440	30060501	Additional studies have suggested that BAP1 mutations could be further exploited for MPM epigenetic therapy, since BAP1 function stabilizes BRCA1 and promotes recruitment of the polycomb deubiquitylase complex to DNA damage sites.	('recruitment', 'MPA', (159, 170))	('BRCA1', 'Gene', (140, 145))	('promotes', 'PosReg', (150, 158))	('BAP1', 'Gene', (115, 119))	('stabilizes', 'NegReg', (129, 139))	('mutations', 'Var', (44, 53))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('187', '201'))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('BRCA1', 'Gene', '672', (140, 145))	('function', 'Var', (120, 128))	('BAP1', 'Gene', (39, 43))
149441	30060501	Deletion of 9p21 is a common event in malignant mesothelioma.	('p21', 'Gene', '644914', (13, 16))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (38, 60))	('Deletion', 'Var', (0, 8))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (38, 60))	('p21', 'Gene', (13, 16))	('malignant mesothelioma', 'Disease', (38, 60))
149444	30060501	Deletion of CDKN2A is commonly assessed through fluorescence in-situ hybridization (FISH), which is widely used as a molecular diagnostic tool in malignant mesothelioma.	('CDKN2A', 'Gene', (12, 18))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (146, 168))	('malignant mesothelioma', 'Disease', (146, 168))	('CDKN2A', 'Gene', '1029', (12, 18))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (146, 168))	('Deletion', 'Var', (0, 8))
149445	30060501	Deletion of CDKN2A occurs in up to 80% of pleural mesothelioma cases, and the frequency is higher in sarcomatoid tumors.	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (101, 119))	('CDKN2A', 'Gene', (12, 18))	('occurs', 'Reg', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('CDKN2A', 'Gene', '1029', (12, 18))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (42, 62))	('higher', 'Reg', (91, 97))	('sarcomatoid tumors', 'Disease', (101, 119))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (42, 62))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('pleural mesothelioma', 'Disease', (42, 62))	('Deletion', 'Var', (0, 8))
149447	30060501	Recent studies indicate that while a positive identification of CDKN2A deletion is consistent with malignant mesothelioma, the lack of deletion does not preclude disease diagnosis.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (99, 121))	('CDKN2A', 'Gene', (64, 70))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (99, 121))	('deletion', 'Var', (71, 79))	('CDKN2A', 'Gene', '1029', (64, 70))	('malignant mesothelioma', 'Disease', (99, 121))
149448	30060501	Additionally, deletion of CDKN2A is not useful in distinguishing mesothelioma from metastatic lung tumors, a common clinical problem in mesothelioma diagnosis.	('mesothelioma', 'Disease', (136, 148))	('lung tumors', 'Phenotype', 'HP:0100526', (94, 105))	('CDKN2A', 'Gene', (26, 32))	('mesothelioma', 'Disease', (65, 77))	('lung tumors', 'Disease', 'MESH:D008175', (94, 105))	('CDKN2A', 'Gene', '1029', (26, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (136, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('deletion', 'Var', (14, 22))	('lung tumors', 'Disease', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
149449	30060501	Initial studies using RNA pyrosequencing techniques, revealed multiple types of genetic alterations commonly occurring in malignant mesotheliomas, including somatic mutations, gene deletions, gene silencing, and RNA editing.	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (122, 145))	('malignant mesotheliomas', 'Disease', (122, 145))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('gene deletions', 'Var', (176, 190))	('RNA editing', 'biological_process', 'GO:0009451', ('212', '223'))	('gene silencing', 'Var', (192, 206))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (122, 144))	('RNA', 'cellular_component', 'GO:0005562', ('212', '215'))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (122, 145))	('gene silencing', 'biological_process', 'GO:0016458', ('192', '206'))	('RNA', 'MPA', (212, 215))
149452	30060501	Several genes encoding for members of this pathway, including NF2, RASSF1/2/6, LATS1/2, and FAT1 were affected by mutations, copy number changes or loss of expression.	('LATS1', 'Gene', '9113', (79, 84))	('RASSF1/2/6', 'Gene', '11186;9770;166824', (67, 77))	('mutations', 'Var', (114, 123))	('affected', 'Reg', (102, 110))	('NF2', 'Gene', '4771', (62, 65))	('FAT1', 'Gene', '2195', (92, 96))	('loss of', 'NegReg', (148, 155))	('copy number changes', 'Var', (125, 144))	('FAT1', 'Gene', (92, 96))	('LATS1', 'Gene', (79, 84))	('expression', 'MPA', (156, 166))	('RASSF1/2/6', 'Gene', (67, 77))	('NF2', 'Gene', (62, 65))
149453	30060501	Moreover, YAP1:a downstream effector of the Hippo signaling pathway:is also activated in mesothelioma as a result of DNA amplifications and has been proposed as one of the few clinically actionable options in mesothelioma.	('activated', 'PosReg', (76, 85))	('YAP1', 'Gene', (10, 14))	('mesothelioma', 'Disease', (89, 101))	('mesothelioma', 'Disease', (209, 221))	('YAP1', 'Gene', '10413', (10, 14))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('44', '67'))	('DNA amplifications', 'Var', (117, 135))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
149454	30060501	Additionally, analysis of the newly released TCGA-MPM cohort revealed focal deletions in numerous genes, including BAP1, SETD2, PBRM1, LATS1, PTPRD, CDKN2A, and MTAP, as well as a lack of genomic disruptions involving targetable genes and signaling pathways such as MAPK and PI3K/AKT.	('CDKN2A', 'Gene', '1029', (149, 155))	('AKT', 'Gene', '207', (280, 283))	('MTAP', 'Gene', (161, 165))	('PTPRD', 'Gene', (142, 147))	('deletions', 'Var', (76, 85))	('SETD2', 'Gene', (121, 126))	('MTAP', 'Gene', '4507', (161, 165))	('PBRM1', 'Gene', '55193', (128, 133))	('PTPRD', 'Gene', '5789', (142, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('275', '279'))	('SETD2', 'Gene', '29072', (121, 126))	('LATS1', 'Gene', (135, 140))	('PBRM1', 'Gene', (128, 133))	('LATS1', 'Gene', '9113', (135, 140))	('MAPK', 'Pathway', (266, 270))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('AKT', 'Gene', (280, 283))	('CDKN2A', 'Gene', (149, 155))	('BAP1', 'Gene', (115, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('266', '270'))
149461	30060501	It is inactivated by mutation in ~40% of malignant mesothelioma, and this loss of function promotes invasiveness.	('promotes', 'PosReg', (91, 99))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (41, 63))	('mutation', 'Var', (21, 29))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (41, 63))	('invasiveness', 'CPA', (100, 112))	('malignant mesothelioma', 'Disease', (41, 63))
149463	30060501	It has been proposed that this feature can be therapeutically exploited, since mesothelial cells can be sensitized to FAK inhibition by the loss of NF2.	('FAK', 'Gene', (118, 121))	('FAK', 'Gene', '5747', (118, 121))	('NF2', 'Gene', (148, 151))	('FAK', 'molecular_function', 'GO:0004717', ('118', '121'))	('NF2', 'Gene', '4771', (148, 151))	('loss', 'Var', (140, 144))
149473	30060501	Some of the deregulated miRNAs identified had been previously detected as disrupted in other cancer types, affecting pathways related to cell cycle regulation, proliferation and migration; others were shown to map to genomic locations known to be deleted or gained in malignant mesothelioma.	('cancer', 'Disease', (93, 99))	('malignant mesothelioma', 'Disease', (268, 290))	('gained', 'PosReg', (258, 264))	('deleted', 'Var', (247, 254))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cell cycle', 'CPA', (137, 147))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('137', '158'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (268, 290))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (268, 290))	('proliferation', 'CPA', (160, 173))	('pathways', 'Pathway', (117, 125))	('miR', 'Gene', '220972', (24, 27))	('affecting', 'Reg', (107, 116))	('miR', 'Gene', (24, 27))	('migration', 'CPA', (178, 187))
149489	30060501	For example, loss of miR-31 that is located at 9p21.3:a region frequently lost in MPM:has been shown to be significantly associated with poor prognosis and a short time to tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('miR-31', 'Gene', (21, 27))	('tumor', 'Disease', (172, 177))	('associated', 'Reg', (121, 131))	('p21', 'Gene', (48, 51))	('p21', 'Gene', '644914', (48, 51))	('miR-31', 'Gene', '407035', (21, 27))	('loss', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
149513	30060501	Recent analyses have begun to elucidate the most frequent alterations that may drive mesothelioma development, uncovering disrupted genes with well-known roles in human cancer development.	('mesothelioma', 'Disease', (85, 97))	('cancer', 'Disease', (169, 175))	('drive', 'Reg', (79, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human', 'Species', '9606', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('alterations', 'Var', (58, 69))
149523	27884852	Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls.	('pleurodesis', 'Disease', 'None', (119, 130))	('fibulin-3', 'Gene', '2202', (35, 44))	('MPM', 'Var', (161, 164))	('pleural', 'Disease', 'MESH:D010995', (104, 111))	('pleural', 'Disease', (104, 111))	('pleural', 'Disease', 'MESH:D010995', (201, 208))	('pleurodesis', 'Disease', (119, 130))	('fibulin-3', 'Gene', (35, 44))	('asbestos', 'Chemical', 'MESH:D001194', (225, 233))	('patients', 'Species', '9606', (147, 155))	('non-MPM pleural disease', 'Disease', (193, 216))	('patients', 'Species', '9606', (179, 187))	('pleural disease', 'Phenotype', 'HP:0002103', (201, 216))	('pleural', 'Disease', (201, 208))	('non-MPM pleural disease', 'Disease', 'MESH:D010995', (193, 216))
149541	27884852	Previous studies have demonstrated that blood levels of single proteins, including mesothelin,  megakaryocyte potentiating factor (MPF) and osteopontin, are higher in patients with MPM than in asbestos-exposed controls (AECs) and patients with secondary pleural malignancies.	('mesothelin', 'Gene', (83, 93))	('pleural malignancies', 'Disease', 'MESH:D016066', (254, 274))	('asbestos', 'Chemical', 'MESH:D001194', (193, 201))	('patients', 'Species', '9606', (167, 175))	('MPF', 'Gene', '10232', (131, 134))	('mesothelin', 'Gene', '10232', (83, 93))	('MPM', 'Var', (181, 184))	('patients', 'Species', '9606', (230, 238))	('osteopontin', 'Gene', '6696', (140, 151))	('pleural malignancies', 'Disease', (254, 274))	('higher', 'PosReg', (157, 163))	('megakaryocyte potentiating factor', 'Gene', '10232', (96, 129))	('osteopontin', 'Gene', (140, 151))	('MPF', 'Gene', (131, 134))	('megakaryocyte potentiating factor', 'Gene', (96, 129))	('blood levels of', 'MPA', (40, 55))
149669	25231400	In tumor xenograft studies, combination treatment with amatuximab plus chemotherapy led to a greater reduction in the growth of mesothelin-expressing tumors than either amatuximab or chemotherapy alone.	('tumors', 'Disease', (150, 156))	('amatuximab', 'Chemical', 'MESH:C526187', (169, 179))	('reduction', 'NegReg', (101, 110))	('mesothelin', 'Gene', (128, 138))	('tumor', 'Disease', (3, 8))	('men', 'Species', '9606', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('mesothelin', 'Gene', '10232', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('amatuximab', 'Var', (55, 65))	('growth', 'MPA', (118, 124))	('amatuximab', 'Chemical', 'MESH:C526187', (55, 65))	('tumor', 'Disease', (150, 155))
149677	25231400	Eligibility criteria included age >= 18 years, epithelial type or biphasic (mixed) MPM with low sarcomatous content, radiographically measurable disease, Karnofsky performance status (KPS) score of >=70, adequate bone marrow reserve [absolute neutrophil count (ANC) >=1.5 x 109/L; platelet count >=100 x 109/L; hemoglobin >= 9 g/dL], hepatic function [bilirubin <=1.5 times the upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) <=2.5 x ULN; alkaline phosphatase <=3.0 x ULN], and normal renal function (serum creatinine <=2.0 mg/dL and a calculated creatinine clearance >=60 ml/min) based on the standard Cockcroft and Gault formula.	('hepatic function', 'MPA', (334, 350))	('renal function', 'MPA', (526, 540))	('creatinine', 'Chemical', 'MESH:D003404', (548, 558))	('alanine transaminase', 'MPA', (407, 427))	('ALT', 'molecular_function', 'GO:0004021', ('429', '432'))	('>=1.5', 'Var', (266, 271))	('low sarcomatous', 'Disease', (92, 107))	('low sarcomatous', 'Disease', 'MESH:D018316', (92, 107))	('alkaline phosphatase', 'MPA', (480, 500))	('creatinine clearance', 'MPA', (588, 608))	('creatinine', 'Chemical', 'MESH:D003404', (588, 598))	('phosphatase', 'molecular_function', 'GO:0016791', ('489', '500'))	('aspartate transaminase', 'MPA', (438, 460))	('>=100', 'Var', (296, 301))	('man', 'Species', '9606', (170, 173))
149733	25231400	A similar association was observed with pre-treatment MPF wherein patients with low levels at baseline had superior OS compared to those with high levels [18.5 months (95% CI: 13.2, not reached) vs. 12.8 months (95% CI: 11.3, 16.0)] (Figure 2C) and CA125 [20.7 months (95% CI: 10.7, not reached) vs. 13.3 months (95% CI: 11.6, 18.2)] (Figure 2D).	('men', 'Species', '9606', (49, 52))	('MPF', 'Gene', (54, 57))	('CA125', 'Gene', (249, 254))	('CA125', 'Gene', '94025', (249, 254))	('pre', 'molecular_function', 'GO:0003904', ('40', '43'))	('MPF', 'Gene', '10232', (54, 57))	('low levels', 'Var', (80, 90))	('patients', 'Species', '9606', (66, 74))
149746	25231400	For example, the phase III trial of cisplatin and pemetrexed had more patients with poor performance status (48% patients with KPS 70/80 vs. 30% in our trial) and unfavorable histology (22% with mixed or sarcomatoid histology vs. 11% mixed histology in our trial).	('patients', 'Species', '9606', (70, 78))	('pemetrexed', 'Chemical', 'MESH:D000068437', (50, 60))	('KPS 70/80', 'Var', (127, 136))	('patients', 'Species', '9606', (113, 121))	('sarcomatoid', 'Disease', (204, 215))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (204, 225))	('sarcomatoid', 'Disease', 'MESH:C538614', (204, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('mixed', 'Disease', (195, 200))	('man', 'Species', '9606', (95, 98))
149752	25231400	Although the full extent of the mechanism of action of amatuximab and its synergy with chemotherapy is not known, amatuximab elicits antibody-dependent cellular cytotoxicity (ADCC) against mesothelin expressing tumor cell lines and inhibits heterotypic cell adhesion of mesothelin positive tumor cells to CA125 expressing tumor cells.	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('133', '173'))	('cytotoxicity', 'Disease', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('ADCC', 'biological_process', 'GO:0001788', ('175', '179'))	('tumor', 'Disease', (211, 216))	('cytotoxicity', 'Disease', 'MESH:D064420', (161, 173))	('mesothelin', 'Gene', '10232', (270, 280))	('mesothelin', 'Gene', (189, 199))	('tumor', 'Disease', (290, 295))	('amatuximab', 'Var', (114, 124))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CA125', 'Gene', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('amatuximab', 'Chemical', 'MESH:C526187', (114, 124))	('tumor', 'Disease', (322, 327))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('mesothelin', 'Gene', '10232', (189, 199))	('elicits', 'Reg', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cell adhesion', 'biological_process', 'GO:0007155', ('253', '266'))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('CA125', 'Gene', '94025', (305, 310))	('inhibits', 'NegReg', (232, 240))	('heterotypic cell adhesion', 'CPA', (241, 266))	('mesothelin', 'Gene', (270, 280))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('amatuximab', 'Chemical', 'MESH:C526187', (55, 65))
149803	24195451	Mortality data were drawn from the records of the National Statistics Institute (Instituto Nacional de Estadistica/INE) for the study period (1976-2010), and corresponded to deaths coded as malignant pleural neoplasm, namely, codes 163 (International Classification of Diseases-9th Revision/ICD-9) and C38.4, C45.0 (ICD-10).	('codes 163', 'Var', (226, 235))	('malignant pleural neoplasm', 'Disease', 'MESH:D010997', (190, 216))	('death', 'Disease', 'MESH:D003643', (174, 179))	('death', 'Disease', (174, 179))	('C45.0', 'Var', (309, 314))	('C38.4', 'Var', (302, 307))	('malignant pleural neoplasm', 'Disease', (190, 216))	('neoplasm', 'Phenotype', 'HP:0002664', (208, 216))	('pleural neoplasm', 'Phenotype', 'HP:0100527', (200, 216))
149975	31732616	These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('inhibition', 'Var', (27, 37))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('mesothelioma', 'Disease', (93, 105))
149994	31732616	Antibodies for caspase-3 (9665), caspase-8 (9746), caspase-9 (9502), LATS1-P (9157), LATS1 (9153), YAP1-P (13008), YAP1 (4912), TAZ (4883), TEAD (13295) and Snail (3895) were purchased from Cell Signaling Technologies (Danvers, MA).	('caspase-9', 'Gene', (51, 60))	('Snail', 'Gene', (157, 162))	('9153', 'Var', (92, 96))	('caspase-3', 'Gene', '836', (15, 24))	('caspase-3', 'Gene', (15, 24))	('Snail', 'Gene', '6615', (157, 162))	('LATS1', 'Gene', (85, 90))	('caspase-8', 'Gene', (33, 42))	('9665', 'Var', (26, 30))	('9502', 'Var', (62, 66))	('LATS1', 'Gene', '9113', (85, 90))	('caspase-9', 'Gene', '842', (51, 60))	('LATS1', 'Gene', (69, 74))	('LATS1', 'Gene', '9113', (69, 74))	('caspase-8', 'Gene', '841', (33, 42))	('Signaling', 'biological_process', 'GO:0023052', ('195', '204'))
149995	31732616	Peroxidase-conjugated anti mouse IgG (NA931V) and anti-rabbit IgG (NA934V) were obtained from GE Healthcare (Buckinghamshire, UK), and anti-goat IgG (PA1-28664) was obtained from Invitrogen (Carlsbad, CA).	('NA931V', 'Var', (38, 44))	('NA934V', 'Var', (67, 73))	('NA934V', 'Chemical', '-', (67, 73))	('NA931V', 'Chemical', '-', (38, 44))
150032	31732616	1H/I), and this is associated with reduced LATS1, LATS1-P, YAP1, YAP1-P, and procaspase-8 and -9 (Fig.	('reduced', 'NegReg', (35, 42))	('LATS1', 'Gene', (43, 48))	('1H/I', 'SUBSTITUTION', 'None', (0, 4))	('LATS1', 'Gene', (50, 55))	('LATS1', 'Gene', '9113', (43, 48))	('1H/I', 'Var', (0, 4))	('LATS1', 'Gene', '9113', (50, 55))	('caspase-8 and -9', 'Gene', '841;842', (80, 96))
150036	31732616	2B/C/D show that CA3 treatment reduces the size and number of pre-formed Meso-1 cell spheroids, and suppresses matrigel invasion and migration.	('2B/C', 'SUBSTITUTION', 'None', (0, 4))	('Meso-1', 'Gene', '21407', (73, 79))	('CA3', 'Var', (17, 20))	('pre', 'molecular_function', 'GO:0003904', ('62', '65'))	('Meso-1', 'Gene', (73, 79))	('2B/C', 'Var', (0, 4))	('reduces', 'NegReg', (31, 38))	('suppresses', 'NegReg', (100, 110))
150037	31732616	Moreover, CA3 reduces LATS1, LATS1-P, YAP1, YAP1-P, TAZ and pan-TEAD signaling (Fig.	('LATS1', 'Gene', (29, 34))	('LATS1', 'Gene', (22, 27))	('LATS1', 'Gene', '9113', (29, 34))	('CA3', 'Var', (10, 13))	('LATS1', 'Gene', '9113', (22, 27))	('reduces', 'NegReg', (14, 21))	('YAP1', 'MPA', (38, 42))	('YAP1-P', 'MPA', (44, 50))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('TAZ', 'MPA', (52, 55))	('pan-TEAD signaling', 'MPA', (60, 78))
150038	31732616	In addition, CA3 reduces procaspase-3, -8 and -9, and PARP level, and increases the level of cleaved (active) caspase-8 and -9 and PARP (Fig.	('CA3', 'Var', (13, 16))	('reduces', 'NegReg', (17, 24))	('increases', 'PosReg', (70, 79))	('caspase-8 and -9', 'Gene', '841;842', (110, 126))	('PARP', 'Gene', '1302', (131, 135))	('PARP', 'Gene', '1302', (54, 58))	('procaspase-3, -8 and -9', 'Gene', '836', (25, 48))	('PARP', 'Gene', (131, 135))	('PARP', 'Gene', (54, 58))
150039	31732616	2G/H/I show that CA3 treatment of NCI-Meso-17 cells causes destruction of pre-formed spheroids, and suppresses matrigel invasion and migration.	('2G/H', 'SUBSTITUTION', 'None', (0, 4))	('2G/H', 'Var', (0, 4))	('Meso-1', 'Gene', '21407', (38, 44))	('Meso-1', 'Gene', (38, 44))	('suppresses', 'NegReg', (100, 110))	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))
150046	31732616	3A/B shows that verteporfin produces a dose-dependent reduction in tumor formation.	('3A/B', 'SUBSTITUTION', 'None', (0, 4))	('verteporfin', 'Chemical', 'MESH:D000077362', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('reduction', 'NegReg', (54, 63))	('3A/B', 'Var', (0, 4))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
150052	31732616	CA3 also reduces tumor formation (Fig.	('tumor', 'Disease', (17, 22))	('CA3', 'Var', (0, 3))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduces', 'NegReg', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
150057	31732616	If YAP1 has a key role in maintaining mesothelioma cancer cell function, YAP1 knockdown should reduce MCS cell survival and overexpression of constitutively active YAP1, YAP(S127A), should antagonize verteporfin and CA3 action.	('reduce', 'NegReg', (95, 101))	('YAP', 'Gene', '10413', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (38, 57))	('YAP', 'Gene', (164, 167))	('mesothelioma cancer', 'Disease', 'MESH:D009369', (38, 57))	('MCS', 'cellular_component', 'GO:0044232', ('102', '105'))	('YAP', 'Gene', '10413', (73, 76))	('MCS cell survival', 'CPA', (102, 119))	('reduce MCS', 'Phenotype', 'HP:0025066', (95, 105))	('antagonize', 'NegReg', (189, 199))	('YAP', 'Gene', (3, 6))	('mesothelioma cancer', 'Disease', (38, 57))	('YAP', 'Gene', '10413', (164, 167))	('YAP', 'Gene', (170, 173))	('S127A', 'Mutation', 'rs762471803', (174, 179))	('knockdown', 'Var', (78, 87))	('YAP', 'Gene', (73, 76))	('YAP', 'Gene', '10413', (3, 6))	('verteporfin', 'Chemical', 'MESH:D000077362', (200, 211))
150059	31732616	4A/B show that YAP1 knockdown reduces Meso-1 and NCI-Meso-17 cell matrigel invasion.	('Meso-1', 'Gene', '21407', (53, 59))	('Meso-1', 'Gene', (53, 59))	('4A/B', 'SUBSTITUTION', 'None', (0, 4))	('Meso-1', 'Gene', '21407', (38, 44))	('Meso-1', 'Gene', (38, 44))	('YAP1', 'Gene', (15, 19))	('4A/B', 'Var', (0, 4))	('knockdown', 'Var', (20, 29))	('reduces', 'NegReg', (30, 37))
150063	31732616	4C/D), but this is not suprising since inhibitor treatment suppresses YAP1 level.	('suppresses', 'NegReg', (59, 69))	('4C/D', 'Var', (0, 4))	('YAP1 level', 'MPA', (70, 80))	('4C/D', 'SUBSTITUTION', 'None', (0, 4))
150075	31732616	Moreover, expression of constitutively active YAP1 angatonizes veteporfin and CA3 suppression of matrigel invasion, suggesting that loss of YAP1 is a requirement for action of these agents.	('angatonizes', 'Var', (51, 62))	('matrigel invasion', 'CPA', (97, 114))	('veteporfin', 'Chemical', '-', (63, 73))	('YAP1', 'Gene', (46, 50))	('suppression', 'NegReg', (82, 93))
150093	31732616	CA3 also suppresses tumor formation and this is associated with reduced YAP1, TAZ and pan-TEAD levels.	('TAZ', 'MPA', (78, 81))	('CA3', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('pan-TEAD levels', 'MPA', (86, 101))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('reduced', 'NegReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('YAP1', 'MPA', (72, 76))	('tumor', 'Disease', (20, 25))	('suppresses', 'NegReg', (9, 19))
150097	31732616	Verteporfin and CA3 also reduce Slug and Snail, which are positive regulators of EMT, suggesting that verteporfin suppresses tumor cell EMT.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('Verteporfin', 'Chemical', 'MESH:D000077362', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Slug', 'Gene', (32, 36))	('tumor', 'Disease', (125, 130))	('verteporfin', 'Var', (102, 113))	('Snail', 'Gene', (41, 46))	('reduce', 'NegReg', (25, 31))	('verteporfin', 'Chemical', 'MESH:D000077362', (102, 113))	('Slug', 'Gene', '6591', (32, 36))	('EMT', 'biological_process', 'GO:0001837', ('81', '84'))	('Snail', 'Gene', '6615', (41, 46))	('suppresses', 'NegReg', (114, 124))
150157	31096539	The results of immunohistochemistry showed that the 3 molecules Calretinin, D2-40, CK were positive, while p53, EMA were negative (Table 2).	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('Calretinin', 'Gene', '794', (64, 74))	('D2-40', 'Var', (76, 81))	('Calretinin', 'Gene', (64, 74))
150170	31096539	Our case presented as Calretinin, D2-40 positive and p53, EMA negative, which was consistent with the literature reports.	('Calretinin', 'Gene', '794', (22, 32))	('negative', 'NegReg', (62, 70))	('D2-40 positive', 'Var', (34, 48))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('Calretinin', 'Gene', (22, 32))
150190	26889976	Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01).	('low SPARC', 'Var', (91, 100))	('higher', 'PosReg', (67, 73))	('patients', 'Species', '9606', (77, 85))
150223	26889976	These included Selenoprotein P (qy-e01007; Qayee-Bio for Life Science, Shanghai, China), Tetranectin (E80350Hu; Uscn Life Science Inc, Wuhan, China) and SPARC (E90791Hu; Uscn Life Science Inc).	('Tetranectin', 'Gene', '7123', (89, 100))	('Selenoprotein P', 'Gene', '6414', (15, 30))	('qy-e01007;', 'Var', (32, 42))	('Selenoprotein P', 'Gene', (15, 30))	('E80350Hu;', 'Var', (102, 111))	('E90791Hu;', 'Var', (160, 169))	('Tetranectin', 'Gene', (89, 100))
150259	26889976	The median OS was significantly higher in patients with SPARC-low (19.0 months; 95% CI: 12.1-25.9 months) compared with SPARC-high patients (8.8 months; 95% CI: 7.8-9.9 months, P=0.01; Figure 1A).	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (42, 50))	('SPARC-low', 'Var', (56, 65))	('higher', 'PosReg', (32, 38))
150260	26889976	Using the multivariate Cox proportional hazard Regression model, incorporating all the above factors, SPARC remained an independent prognostic factor, with low SPARC level being associated with longer survival (HR: 1.55; P=0.05; Table 2).	('low', 'Var', (156, 159))	('SPARC', 'MPA', (160, 165))	('longer', 'PosReg', (194, 200))	('rat', 'Species', '10116', (72, 75))
150264	26889976	We found both the SPARC IHC scores to be significantly higher in MPM tumour cells (P=0.001) and MPM stromal fibroblasts (P<0.001) compared with respective scores in the normal mesothelium (Figure 2C and D).	('MPM', 'Var', (96, 99))	('MPM tumour', 'Disease', 'MESH:D009369', (65, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('higher', 'PosReg', (55, 61))	('MPM tumour', 'Disease', (65, 75))	('SPARC', 'MPA', (18, 23))
150269	26889976	In addition, low stromal SPARC (<=50%) was associated with longer survival (10.9 vs 7.6 months; P=0.001; Figure 2E) while there was no association between tumoral SPARC and patient survival (P=0.71).	('survival', 'MPA', (66, 74))	('low', 'NegReg', (13, 16))	('patient', 'Species', '9606', (173, 180))	('stromal SPARC', 'CPA', (17, 30))	('longer', 'PosReg', (59, 65))	('tumoral', 'Disease', (155, 162))	('tumoral', 'Disease', 'MESH:D009369', (155, 162))	('<=50%', 'Var', (32, 37))
150314	26889976	Furthermore, we validated the independent prognostic importance of circulating SPARC in a large retrospective series of MPM patients.	('MPM', 'Disease', (120, 123))	('patients', 'Species', '9606', (124, 132))	('circulating', 'Var', (67, 78))
150329	31608237	In mesothelioma cell lines, SIRT3 and SIRT5 exerted pro-survival trends.	('pro-survival', 'biological_process', 'GO:0043066', ('52', '64'))	('mesothelioma', 'Disease', (3, 15))	('SIRT3', 'Var', (28, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))
150346	31608237	The effects of silencing of the nuclear SIRT1 vs. the mitochondrial SIRT3 and SIRT5 family members on cell viability were analyzed in the human osteosarcoma (U2OS) and mesothelioma (Mero-14 and REN) cell lines.	('osteosarcoma', 'Disease', (144, 156))	('mesothelioma', 'Disease', (168, 180))	('osteosarcoma', 'Phenotype', 'HP:0002669', (144, 156))	('human', 'Species', '9606', (138, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (144, 156))	('REN', 'Gene', (194, 197))	('silencing', 'Var', (15, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (168, 180))	('REN', 'Gene', '5972', (194, 197))
150349	31608237	Silencing of the nuclear SIRT1 significantly increased cell viability in U2OS cells (Figure 1A, compare bars 1-6 to 7-12), whereas silencing of the mitochondrial SIRT3 and SIRT5 did not affect cell survival in the absence of treatment (Figure 1A, compare bar 1 to bars 13 and 19, respectively).	('increased', 'PosReg', (45, 54))	('cell viability', 'CPA', (55, 69))	('to 7', 'Species', '1214577', (113, 117))	('Silencing', 'Var', (0, 9))	('SIRT1', 'Gene', (25, 30))
150351	31608237	On the contrary, silencing of the mitochondrial SIRT3 and SIRT5 in U2OS cells led to decreased cell viability upon etoposide treatment (Figure 1A, compare bars 3, 4 to 15, 16 and 21, 22 respectively).	('etoposide', 'Chemical', 'MESH:D005047', (115, 124))	('decreased', 'NegReg', (85, 94))	('SIRT5', 'Gene', (58, 63))	('mitochondrial SIRT3', 'Enzyme', (34, 53))	('silencing', 'Var', (17, 26))	('cell viability', 'CPA', (95, 109))
150357	31608237	The effects of silencing of sirtuin family members on cell viability were also tested in the REN cell line which differs from Mero-14 in terms of expression of crucial genes involved in cancer cell viability and response to cytotoxic drugs including p53.	('REN', 'Gene', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('silencing', 'Var', (15, 24))	('REN', 'Gene', '5972', (93, 96))	('p53', 'Gene', (250, 253))	('p53', 'Gene', '7157', (250, 253))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
150358	31608237	Substantial and statistically significant downregulation of cell viability was observed in REN cells treated with the studied drugs, however silencing of SIRT1, SIRT3, and SIRT5 did not exert significant effects (Figure 1C) although downward trend was observed in SIRT3 and SIRT5 silenced cells.	('cell viability', 'CPA', (60, 74))	('silencing', 'Var', (141, 150))	('REN', 'Gene', (91, 94))	('downregulation', 'NegReg', (42, 56))	('SIRT1', 'Gene', (154, 159))	('REN', 'Gene', '5972', (91, 94))
150359	31608237	In summary, silencing of SIRT1 led to increased U2OS cell viability in all conditions tested and SIRT5 silencing resulted in decreased cell viability in etoposide treated U2OS cells.	('decreased', 'NegReg', (125, 134))	('SIRT5', 'Gene', (97, 102))	('SIRT1', 'Gene', (25, 30))	('cell viability', 'CPA', (135, 149))	('silencing', 'Var', (12, 21))	('U2OS cell viability', 'CPA', (48, 67))	('etoposide', 'Chemical', 'MESH:D005047', (153, 162))	('silencing', 'NegReg', (103, 112))	('increased', 'PosReg', (38, 47))
150362	31608237	In U2OS cells, SIRT1 silencing increased SIRT3 protein levels in rotenone treated cells (Figure 2Aii, compare bars 2 and 6) and SIRT5 protein levels in etoposide treated cells (Figure 2Aiii, compare bar 3 to 7).	('SIRT3 protein levels', 'MPA', (41, 61))	('increased SIRT3 protein levels', 'Phenotype', 'HP:0003240', (31, 61))	('etoposide', 'Chemical', 'MESH:D005047', (152, 161))	('SIRT1', 'Gene', (15, 20))	('increased', 'PosReg', (31, 40))	('SIRT5 protein levels', 'MPA', (128, 148))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('to 7', 'Species', '1214577', (205, 209))	('rotenone', 'Chemical', 'MESH:D012402', (65, 73))	('silencing', 'Var', (21, 30))
150363	31608237	In Mero-14 cells, SIRT1 silencing decreased SIRT3 protein levels in rotenone and etoposide treated cells (Figure 2Bii, compare bars 2 and 3 with bars 6 and 7).	('decreased', 'NegReg', (34, 43))	('rotenone', 'Chemical', 'MESH:D012402', (68, 76))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('etoposide', 'Chemical', 'MESH:D005047', (81, 90))	('SIRT3 protein levels', 'MPA', (44, 64))	('SIRT1', 'Gene', (18, 23))	('silencing', 'Var', (24, 33))
150364	31608237	In REN cells, SIRT1 silencing increased SIRT3 protein levels in rotenone treated cells (Figure 2Cii, compare bar 2 to 6) and SIRT5 protein levels in etoposide and resveratrol treated cells (Figure 2Ciii, compare bars 3 and 4 to 7 and 8).	('REN', 'Gene', '5972', (3, 6))	('etoposide', 'Chemical', 'MESH:D005047', (149, 158))	('rotenone', 'Chemical', 'MESH:D012402', (64, 72))	('increased SIRT3 protein levels', 'Phenotype', 'HP:0003240', (30, 60))	('REN', 'Gene', (3, 6))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('SIRT5 protein levels', 'MPA', (125, 145))	('SIRT1', 'Gene', (14, 19))	('increased', 'PosReg', (30, 39))	('SIRT3 protein levels', 'MPA', (40, 60))	('to 7', 'Species', '1214577', (225, 229))	('silencing', 'Var', (20, 29))	('resveratrol', 'Chemical', 'MESH:C059514', (163, 174))
150365	31608237	In U2OS cells, SIRT3 silencing increased SIRT5 protein levels in untreated and rotenone treated cells (Figure 3Aiii, compare bars 1 and 2 to 5 and 6).	('SIRT5 protein levels', 'MPA', (41, 61))	('increased', 'PosReg', (31, 40))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('SIRT3', 'Gene', (15, 20))	('rotenone', 'Chemical', 'MESH:D012402', (79, 87))	('silencing', 'Var', (21, 30))
150366	31608237	In Mero-14 cells, SIRT3 silencing increased SIRT1 protein levels in untreated cells (Figure 3Bi, compare bar 1 to 5) and decreased SIRT5 protein levels in etoposide and resveratrol treated cells (Figure 3Biii, compare bars 3 and 4 to 7 and 8).	('Biii', 'Gene', (204, 208))	('SIRT3', 'Gene', (18, 23))	('etoposide', 'Chemical', 'MESH:D005047', (155, 164))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('decreased', 'NegReg', (121, 130))	('etoposide', 'MPA', (155, 164))	('SIRT1 protein levels', 'MPA', (44, 64))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('SIRT5 protein levels', 'MPA', (131, 151))	('Biii', 'Gene', '774', (204, 208))	('resveratrol', 'Chemical', 'MESH:C059514', (169, 180))	('increased', 'PosReg', (34, 43))	('to 7', 'Species', '1214577', (231, 235))	('increased SIRT1 protein levels', 'Phenotype', 'HP:0003240', (34, 64))	('silencing', 'Var', (24, 33))
150367	31608237	Silencing of SIRT3 had no major effect in REN cells (Figure 3C).	('Silencing', 'Var', (0, 9))	('SIRT3', 'Gene', (13, 18))	('REN', 'Gene', (42, 45))	('REN', 'Gene', '5972', (42, 45))
150368	31608237	In Mero-14 cells, SIRT5 silencing increased SIRT1 levels in the untreated and resveratrol treated cells and SIRT3 protein levels in resveratrol treated cells (Figures 4Bi,ii, compare bars 1 to 5 and 4 to 8, respectively).	('SIRT5', 'Gene', (18, 23))	('resveratrol', 'Chemical', 'MESH:C059514', (78, 89))	('SIRT1 levels', 'MPA', (44, 56))	('SIRT3 protein levels', 'MPA', (108, 128))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('resveratrol', 'Chemical', 'MESH:C059514', (132, 143))	('increased', 'PosReg', (34, 43))	('silencing', 'Var', (24, 33))
150369	31608237	In REN cells, SIRT5 silencing decreased SIRT3 protein levels in untreated, rotenone, and etoposide treated cells (Figure 4Cii, compare bars 1, 2, and 3 to 5, 6, and 7).	('SIRT5', 'Gene', (14, 19))	('silencing', 'Var', (20, 29))	('REN', 'Gene', '5972', (3, 6))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('rotenone', 'Chemical', 'MESH:D012402', (75, 83))	('REN', 'Gene', (3, 6))	('etoposide', 'Chemical', 'MESH:D005047', (89, 98))	('SIRT3 protein levels', 'MPA', (40, 60))	('decreased', 'NegReg', (30, 39))
150374	31608237	In REN cells carrying silenced SIRT1, the LC3II/LC3I ratio was upregulated in etoposide and resveratrol treated cells (Figure 5Cii, compare bars 3 and 4 to 7 and 8).	('resveratrol', 'Chemical', 'MESH:C059514', (92, 103))	('SIRT1', 'Gene', (31, 36))	('REN', 'Gene', '5972', (3, 6))	('etoposide', 'Chemical', 'MESH:D005047', (78, 87))	('upregulated', 'PosReg', (63, 74))	('LC3II/LC3I', 'MPA', (42, 52))	('REN', 'Gene', (3, 6))	('to 7', 'Species', '1214577', (153, 157))	('silenced', 'Var', (22, 30))
150375	31608237	SIRT3 silencing led to downregulation of beclin-1 in U2OS cells treated with rotenone and etoposide (Figure 6Ai, compare bars 2 and 3 to 6 and 7).	('downregulation', 'NegReg', (23, 37))	('beclin-1', 'Gene', '8678', (41, 49))	('etoposide', 'Chemical', 'MESH:D005047', (90, 99))	('rotenone', 'Chemical', 'MESH:D012402', (77, 85))	('silencing', 'Var', (6, 15))	('SIRT3', 'Gene', (0, 5))	('beclin-1', 'Gene', (41, 49))
150376	31608237	SIRT3 silencing down regulated the LC3II/LC3I ratio in untreated U2OS cells (Figure 6Aii, compare bar 1 to 5), whereas upregulation of this ratio was observed in the resveratrol treated SIRT3 silenced cells (Figure 6Aii, compare bar 4 to 8).	('LC3II/LC3I ratio', 'MPA', (35, 51))	('resveratrol', 'Chemical', 'MESH:C059514', (166, 177))	('down regulated', 'NegReg', (16, 30))	('silencing', 'Var', (6, 15))	('SIRT3', 'Gene', (0, 5))
150381	31608237	Beclin-1 protein levels and LC3II/LC3I ratio were downregulated in SIRT5 silenced untreated, rotenone, or etoposide treated U2OS cells (Figures 7Ai,ii, compare bars 1, 2, and 3 to 5, 6, and 7, respectively).	('rotenone', 'Chemical', 'MESH:D012402', (93, 101))	('LC3II/LC3I ratio', 'MPA', (28, 44))	('Beclin-1', 'Gene', (0, 8))	('Beclin-1', 'Gene', '8678', (0, 8))	('silenced', 'Var', (73, 81))	('etoposide', 'Chemical', 'MESH:D005047', (106, 115))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('downregulated', 'NegReg', (50, 63))	('SIRT5', 'Gene', (67, 72))
150384	31608237	In REN cells, SIRT5 silencing downregulated beclin-1 protein levels in resveratrol treated cells (Figure 7Ci, compare bar 4 to 8).	('resveratrol', 'Chemical', 'MESH:C059514', (71, 82))	('downregulated', 'NegReg', (30, 43))	('SIRT5', 'Gene', (14, 19))	('REN', 'Gene', '5972', (3, 6))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('REN', 'Gene', (3, 6))	('beclin-1', 'Gene', (44, 52))	('silencing', 'Var', (20, 29))	('beclin-1', 'Gene', '8678', (44, 52))
150389	31608237	SIRT3 silencing led to inhibition of autophagy in U2OS cells treated with etoposide or resveratrol (Figure 8B, compare bars 3 and 4 to 11 and 12), whereas SIRT5 silencing resulted in inhibition of autophagy in resveratrol treated U2OS cells (Figure 8B, compare bar 4 to 16).	('inhibition', 'NegReg', (183, 193))	('SIRT5', 'Gene', (155, 160))	('autophagy', 'biological_process', 'GO:0016236', ('197', '206'))	('inhibition', 'NegReg', (23, 33))	('autophagy', 'CPA', (197, 206))	('etoposide', 'Chemical', 'MESH:D005047', (74, 83))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('resveratrol', 'Chemical', 'MESH:C059514', (210, 221))	('silencing', 'NegReg', (161, 170))	('autophagy', 'CPA', (37, 46))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))	('autophagy', 'biological_process', 'GO:0006914', ('197', '206'))	('resveratrol', 'Chemical', 'MESH:C059514', (87, 98))	('silencing', 'Var', (6, 15))	('SIRT3', 'Gene', (0, 5))
150399	31608237	In breast cancer and mouse myoblasts cells SIRT5 silencing increases ammonia-induced autophagy through control of glutamine metabolism and mitophagy.	('glutamine', 'Chemical', 'MESH:C578860', (114, 123))	('glutamine metabolism', 'MPA', (114, 134))	('silencing', 'Var', (49, 58))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('autophagy', 'biological_process', 'GO:0016236', ('85', '94'))	('mouse', 'Species', '10090', (21, 26))	('ammonia', 'Chemical', 'MESH:D000641', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('autophagy', 'biological_process', 'GO:0006914', ('85', '94'))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('114', '134'))	('ammonia-induced', 'MPA', (69, 84))	('mitophagy', 'biological_process', 'GO:0000422', ('139', '148'))	('SIRT5', 'Gene', (43, 48))	('mitophagy', 'CPA', (139, 148))	('mitophagy', 'biological_process', 'GO:0000423', ('139', '148'))	('increases', 'PosReg', (59, 68))
150402	31608237	SIRT1 silencing in U2OS cells led to pro-survival outcome whereas silencing of this sirtuin family member in Mero-14 and REN cells did not have significant effect.	('REN', 'Gene', (121, 124))	('pro-survival', 'biological_process', 'GO:0043066', ('37', '49'))	('SIRT1', 'Gene', (0, 5))	('REN', 'Gene', '5972', (121, 124))	('pro-survival outcome', 'CPA', (37, 57))	('silencing', 'Var', (6, 15))
150452	27624915	For mesothelin staining experiments, normal tissue TMA sections were obtained from Folio (cat# ARY0HH0213, Powell, OH), normal peritoneum and pleura TMAs from Pantomics (cat# GIP541, LUP541, Richmond, CA), multiple tumor TMA from Pantomics (cat# MTU391, Richmond, CA) malignant mesothelioma from MyBioSource (cat# MBS640483, San Diego, CA).	('malignant mesothelioma', 'Disease', (268, 290))	('cat# MTU391', 'Var', (241, 252))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (268, 290))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cat', 'molecular_function', 'GO:0004096', ('309', '312'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (268, 290))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cat', 'molecular_function', 'GO:0004096', ('241', '244'))	('pleura TMAs', 'Disease', (142, 153))	('pleura TMAs', 'Disease', 'MESH:D054363', (142, 153))	('cat# MBS640483', 'Var', (309, 323))	('cat', 'molecular_function', 'GO:0004096', ('170', '173'))	('tumor', 'Disease', (215, 220))	('GIP', 'molecular_function', 'GO:0005095', ('175', '178'))	('cat', 'molecular_function', 'GO:0004096', ('90', '93'))
150491	27624915	Multivariate analysis accounting for grade and extent of resection revealed infiltration with CD20+ cells was independently predictive of improved progression free survival (HR 0.966 per CD20+ cell in core, p = 0.041, Table 3).	('progression free survival', 'CPA', (147, 172))	('core', 'cellular_component', 'GO:0019013', ('201', '205'))	('improved', 'PosReg', (138, 146))	('CD20', 'Gene', (187, 191))	('CD20', 'Gene', '931', (187, 191))	('CD20', 'Gene', (94, 98))	('CD20', 'Gene', '931', (94, 98))	('infiltration', 'Var', (76, 88))
150506	27624915	If the degree of PD-L1 expression is predictive of poor survival only among grade II/III tumors, this effect may not be detectable in a series consisting of mostly grade I tumors, as the prognostic impact maybe diluted.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PD-L1', 'Gene', '29126', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('poor survival', 'NegReg', (51, 64))	('III tumors', 'Disease', (85, 95))	('PD-L1', 'Gene', (17, 22))	('expression', 'Var', (23, 33))	('I tumors', 'Disease', 'MESH:D009369', (170, 178))	('I tumors', 'Disease', (170, 178))	('III tumors', 'Disease', 'MESH:D009369', (85, 95))	('I tumors', 'Disease', 'MESH:D009369', (87, 95))
150554	24598211	Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for both cell lines.	('apoptotic death', 'CPA', (58, 73))	('caspase-3', 'Gene', '836', (14, 23))	('cleavage', 'Var', (28, 36))	('caspase-3', 'Gene', (14, 23))	('PARP', 'Gene', (40, 44))
150570	24598211	The p53 protein is a transcription factor that normally inhibits cell growth and stimulates cell death in response to myriad stressors, including DNA damage (induced by either UV or chemical agents such as hydrogen peroxide), oxidative stress, and deregulated oncogene expression.	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (206, 223))	('protein', 'Protein', (8, 15))	('inhibits', 'NegReg', (56, 64))	('cell growth', 'CPA', (65, 76))	('DNA damage', 'MPA', (146, 156))	('stimulates', 'PosReg', (81, 91))	('oncogene', 'Gene', (260, 268))	('deregulated', 'Var', (248, 259))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('oxidative stress', 'Phenotype', 'HP:0025464', (226, 242))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('expression', 'MPA', (269, 279))	('cell death', 'biological_process', 'GO:0008219', ('92', '102'))	('cell death', 'CPA', (92, 102))	('p53', 'Gene', '7157', (4, 7))	('transcription factor', 'molecular_function', 'GO:0000981', ('21', '41'))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('p53', 'Gene', (4, 7))
150609	24598211	The G1 peak was increased in CF-treated HCT-116 cells.	('increased', 'PosReg', (16, 25))	('CF-treated', 'Var', (29, 39))	('G1 peak', 'MPA', (4, 11))	('HCT-116', 'CellLine', 'CVCL:0291', (40, 47))
150652	24598211	Interestingly, wild-type p53 expression was detected in 47% of colorectal adenocarcinomas, and approximately 70-80% of mesothelioma cells, although having the wild-type p53 gene, show a homologous deletion at the INK4A/ARF locus containing the p14ARF and the p16INK4A genes, which consequently leads to decreased p53 functions despite the wild-type genotype.	('p53', 'Gene', (25, 28))	('p16INK4A', 'Gene', (259, 267))	('colorectal adenocarcinomas', 'Disease', (63, 89))	('p53', 'Gene', '7157', (25, 28))	('deletion', 'Var', (197, 205))	('INK4A/ARF', 'Gene', '1029', (213, 222))	('p14ARF', 'Gene', '1029', (244, 250))	('p53', 'Gene', (313, 316))	('p53', 'Gene', '7157', (313, 316))	('decreased', 'NegReg', (303, 312))	('p53', 'Gene', (169, 172))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('p16INK4A', 'Gene', '1029', (259, 267))	('p53', 'Gene', '7157', (169, 172))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (63, 89))	('INK4A/ARF', 'Gene', (213, 222))	('p14ARF', 'Gene', (244, 250))	('mesothelioma', 'Disease', (119, 131))
150657	24598211	Studies using conventional c-myc transgenic mice, in which the oncogene is constitutively expressed in a given cell type by means of a tissue-specific promoter, have supported the view that deregulated c-myc, as an initial event, is important for the formation of certain cancers, albeit with a long latency.	('deregulated', 'Var', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('c-myc', 'Gene', '4609', (202, 207))	('c-myc', 'Gene', '4609', (27, 32))	('c-myc', 'Gene', (202, 207))	('c-myc', 'Gene', (27, 32))	('transgenic mice', 'Species', '10090', (33, 48))	('formation', 'biological_process', 'GO:0009058', ('251', '260'))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (272, 279))
150662	24598211	Akt is hyperactivated in a wide range of human tumours as a result of constitutive activation of growth receptors, mutation of PI3K, and inactivation or loss of PTEN phosphatise.	('PI3K', 'Protein', (127, 131))	('activation', 'PosReg', (83, 93))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('loss', 'NegReg', (153, 157))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('human', 'Species', '9606', (41, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('127', '131'))	('activation of growth', 'biological_process', 'GO:0045927', ('83', '103'))	('Akt', 'Gene', '207', (0, 3))	('growth receptors', 'Protein', (97, 113))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('PTEN', 'Gene', (161, 165))	('mutation', 'Var', (115, 123))	('Akt', 'Gene', (0, 3))	('PTEN', 'Gene', '5728', (161, 165))	('inactivation', 'NegReg', (137, 149))	('hyperactivated', 'PosReg', (7, 21))
150676	24690739	Gene-array based analyses revealed that DSF-Cu suppressed cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10.	('DSF-Cu', 'Var', (40, 46))	('suppressed', 'NegReg', (47, 57))	('matrix metallopeptidase 3', 'Gene', (111, 136))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('DSF-Cu', 'Chemical', '-', (40, 46))	('metastasis-promoting genes', 'Gene', (74, 100))	('cell growth', 'CPA', (58, 69))
150680	24690739	Although podoplanin expression often correlates with metastatic disease and poor prognosis, phosphorylation of serines in cytoplasmic domain of podoplanin has recently been shown to interfere with cellular motility and migration signaling.	('serines', 'Chemical', 'MESH:D012694', (111, 118))	('metastatic disease', 'Disease', (53, 71))	('correlates with', 'Reg', (37, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('cellular motility', 'CPA', (197, 214))	('rat', 'Species', '10116', (222, 225))	('phosphorylation', 'Var', (92, 107))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('interfere', 'NegReg', (182, 191))	('podoplanin', 'Gene', (144, 154))	('podoplanin', 'Gene', (9, 19))
150681	24690739	Post-translational modification of podoplanin and cleavage of vimentin by DSF-Cu underscore a metastasis inhibitory property of this agent and together with our in vivo studies underscore its potential as an anti-MPM agent.	('DSF-Cu', 'Gene', (74, 80))	('metastasis inhibitory', 'MPA', (94, 115))	('cleavage', 'MPA', (50, 58))	('vimentin', 'cellular_component', 'GO:0045098', ('62', '70'))	('vimentin', 'Gene', (62, 70))	('Post-translational modification', 'Var', (0, 31))	('DSF-Cu', 'Chemical', '-', (74, 80))	('vimentin', 'cellular_component', 'GO:0045099', ('62', '70'))	('Post-translational modification', 'biological_process', 'GO:0043687', ('0', '31'))	('vimentin', 'Gene', '22352', (62, 70))
150687	24690739	Disulfiram (DSF) is a member of the dithiocarbamate family comprising a broad class of molecules possessing an R1R2NC(S)SR3 functional group, which gives them the ability to complex metals and react with sulfhydryl groups.	('R1R2NC', 'Var', (111, 117))	('complex', 'Interaction', (174, 181))	('DSF', 'Chemical', 'MESH:D004221', (12, 15))	('Disulfiram', 'Chemical', 'MESH:D004221', (0, 10))	('react', 'Interaction', (193, 198))	('dithiocarbamate', 'Chemical', '-', (36, 51))	('ability', 'MPA', (163, 170))
150695	24690739	Although DSF-Cu stimulated activation of pro-apoptotic SAPKs, and caspase-9, -3, our gene-array-based analysis revealed that DSF-Cu suppressed expression of cell growth and metastasis transducers such as matrix metallopeptidase 3 and 10.	('DSF-Cu', 'Chemical', '-', (125, 131))	('cell growth', 'biological_process', 'GO:0016049', ('157', '168'))	('expression', 'MPA', (143, 153))	('DSF-Cu', 'Chemical', '-', (9, 15))	('caspase-9', 'Gene', '12371', (66, 75))	('DSF-Cu', 'Var', (125, 131))	('cell growth', 'CPA', (157, 168))	('caspase-9', 'Gene', (66, 75))	('suppressed', 'NegReg', (132, 142))
150712	24690739	Anti-p38, phospho-p38, PARP, ABIN1, IkappaBalpha, and IkappaBbeta rabbit polyclonal antibodies, caspase-3, and phospho-JNK (threonine183/tyrosine 185) G9 mouse monoclonal antibodies were obtained from Cell Signaling Technology (Beverly, MA).	('PARP', 'Gene', (23, 27))	('threonine183/tyrosine', 'SUBSTITUTION', 'None', (124, 145))	('JNK', 'Gene', (119, 122))	('p38', 'Gene', (5, 8))	('Signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('threonine183/tyrosine', 'Var', (124, 145))	('JNK', 'molecular_function', 'GO:0004705', ('119', '122'))	('IkappaBbeta', 'Gene', '18036', (54, 65))	('rabbit', 'Species', '9986', (66, 72))	('ABIN1', 'Gene', '57783', (29, 34))	('JNK', 'Gene', '26419', (119, 122))	('IkappaBbeta', 'Gene', (54, 65))	('IkappaBalpha', 'Gene', (36, 48))	('p38', 'Gene', '26416', (5, 8))	('ABIN1', 'Gene', (29, 34))	('p38', 'Gene', (18, 21))	('mouse', 'Species', '10090', (154, 159))	('PARP', 'Gene', '11545', (23, 27))	('p38', 'Gene', '26416', (18, 21))	('IkappaBalpha', 'Gene', '18035', (36, 48))
150744	24690739	As shown in figure 1, DSF-Cu inhibited cell proliferation in all tested cell lines.	('inhibited', 'NegReg', (29, 38))	('DSF-Cu', 'Chemical', '-', (22, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('cell proliferation in', 'CPA', (39, 60))	('DSF-Cu', 'Var', (22, 28))	('rat', 'Species', '10116', (51, 54))
150747	24690739	Since the MPM cells utilized here are representative of the epitheliod (H2461 and H2595), sacromatoid (H2373), and biphasic (H2452) tumor histologic origins, and the treatments with DSF-Cu significantly inhibited viabilities of most of these cells, the data would suggest for potential utility of this agent to target a diverse histotypes of MPM tumors.	('MPM tumors', 'Disease', 'MESH:D009369', (342, 352))	('H2595', 'CellLine', 'CVCL:A545', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('H2461', 'CellLine', 'CVCL:A536', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('DSF-Cu', 'Gene', (182, 188))	('H2373', 'CellLine', 'CVCL:A533', (103, 108))	('inhibited', 'NegReg', (203, 212))	('viabilities', 'CPA', (213, 224))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('H2452', 'CellLine', 'CVCL:1553', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('MPM tumors', 'Disease', (342, 352))	('H2452', 'Var', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (346, 352))	('DSF-Cu', 'Chemical', '-', (182, 188))	('tumor', 'Disease', (346, 351))
150751	24690739	Treatment of murine MPM cells with DSF-Cu resulted in increased number of TUNEL-positive cells (Figure 2B).	('DSF-Cu', 'Chemical', '-', (35, 41))	('TUNEL-positive cells', 'CPA', (74, 94))	('increased', 'PosReg', (54, 63))	('murine', 'Species', '10090', (13, 19))	('DSF-Cu', 'Var', (35, 41))
150754	24690739	As expected, DSF-Cu stimulated caspase-3 activation in a dose-dependent manner in H226, H-Meso and AB12 MPM cells (Figure 2C).	('caspase-3', 'Protein', (31, 40))	('DSF-Cu', 'Var', (13, 19))	('H226', 'CellLine', 'CVCL:J621', (82, 86))	('activation', 'PosReg', (41, 51))	('DSF-Cu', 'Chemical', '-', (13, 19))	('H-Meso', 'Chemical', '-', (88, 94))
150760	24690739	Consistent with the fact that inhibition of proteasome often results in apoptosis induction, DSF-Cu exposure also promoted PARP1 cleavage in a dose-dependent manner in different MPM cells (Figure 3A).	('PARP1', 'Gene', '11545', (123, 128))	('inhibition', 'Var', (30, 40))	('DSF-Cu', 'Chemical', '-', (93, 99))	('proteasome', 'molecular_function', 'GO:0004299', ('44', '54'))	('proteasome', 'cellular_component', 'GO:0000502', ('44', '54'))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('apoptosis', 'CPA', (72, 81))	('promoted', 'PosReg', (114, 122))	('PARP1', 'Gene', (123, 128))
150761	24690739	Together with the data in figure 2, these findings suggest that DSF-Cu suppresses MPM cell growth in part by inhibiting proteasome and activating intrinsic apoptosis signaling involving caspases 9 and 3.	('proteasome', 'MPA', (120, 130))	('inhibiting', 'NegReg', (109, 119))	('DSF-Cu', 'Var', (64, 70))	('caspases', 'Gene', '835;841;12370;12371', (186, 194))	('suppresses', 'NegReg', (71, 81))	('cell growth', 'biological_process', 'GO:0016049', ('86', '97'))	('intrinsic apoptosis', 'biological_process', 'GO:0097193', ('146', '165'))	('proteasome', 'cellular_component', 'GO:0000502', ('120', '130'))	('proteasome', 'molecular_function', 'GO:0004299', ('120', '130'))	('activating', 'PosReg', (135, 145))	('DSF-Cu', 'Chemical', '-', (64, 70))	('MPM cell growth', 'CPA', (82, 97))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('156', '175'))	('caspases', 'Gene', (186, 194))	('intrinsic apoptosis signaling', 'MPA', (146, 175))
150774	24690739	IGFBP7 signaling are often associated with cell growth suppression, and elevated expression of SULF1 has also been shown to inhibit HBEGF-dependent co-receptor functions of cell surface heparan sulfate proteoglycans (HSPGs) in hepatic and esophageal squamous cell cancer cells.	('elevated', 'PosReg', (72, 80))	('SULF1', 'Gene', (95, 100))	('IGFBP7', 'Gene', (0, 6))	('cell surface', 'cellular_component', 'GO:0009986', ('173', '185'))	('esophageal squamous cell cancer', 'Disease', (239, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('associated', 'Reg', (27, 37))	('expression', 'Var', (81, 91))	('HBEGF', 'Gene', (132, 137))	('HBEGF', 'Gene', '15200', (132, 137))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (250, 270))	('cell growth suppression', 'CPA', (43, 66))	('signaling', 'biological_process', 'GO:0023052', ('7', '16'))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (239, 270))	('inhibit', 'NegReg', (124, 131))	('cell growth', 'biological_process', 'GO:0016049', ('43', '54'))
150782	24690739	The data revealed that DSF-Cu treatments not only induced expression of cyclin-dependent kinase inhibitor p27Kip1, it also caused increased expression of CARP-1 in a dose-dependent manner in both the murine and human MPM cells (Figure 5).	('p27Kip1', 'Var', (106, 113))	('induced', 'Reg', (50, 57))	('CARP-1', 'Gene', '112360', (154, 160))	('expression', 'MPA', (140, 150))	('expression', 'MPA', (58, 68))	('CARP-1', 'Gene', (154, 160))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('72', '105'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('89', '105'))	('DSF-Cu', 'Chemical', '-', (23, 29))	('increased', 'PosReg', (130, 139))	('human', 'Species', '9606', (211, 216))	('murine', 'Species', '10090', (200, 206))
150783	24690739	Since deprivation of serum growth factors results in elevated CARP-1 levels, elevated levels of CARP-1 and p27Kip1 by DSF-Cu then would underscore for a cell-cycle inhibitory property of this compound.	('elevated', 'PosReg', (53, 61))	('CARP-1', 'Gene', '112360', (62, 68))	('CARP-1', 'Gene', '112360', (96, 102))	('DSF-Cu', 'Chemical', '-', (118, 124))	('p27Kip1', 'Var', (107, 114))	('cell-cycle', 'biological_process', 'GO:0007049', ('153', '163'))	('CARP-1', 'Gene', (62, 68))	('CARP-1', 'Gene', (96, 102))
150785	24690739	Therefore, it is likely that p27Kip1 expression in the presence of lower doses of DSF-Cu would provoke MPM cell cycle arrest, and continued expression of p27Kip1 and stimulation of CARP-1 at higher doses of DSF-Cu further exacerbates cell cycle arrest, while elevated levels of CARP-1, SULF1, and activation of JNK/p38 SAPKs in the presence of higher doses of DSF-Cu concomitantly signal for apoptosis in MPM cells.	('DSF-Cu', 'Chemical', '-', (207, 213))	('CARP-1', 'Gene', (181, 187))	('JNK', 'molecular_function', 'GO:0004705', ('311', '314'))	('p38', 'Gene', '26416', (315, 318))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('107', '124'))	('CARP-1', 'Gene', '112360', (181, 187))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('234', '251'))	('apoptosis', 'CPA', (392, 401))	('MPM cell cycle arrest', 'CPA', (103, 124))	('cell cycle arrest', 'CPA', (234, 251))	('provoke', 'PosReg', (95, 102))	('DSF-Cu', 'Chemical', '-', (360, 366))	('p27Kip1', 'Var', (29, 36))	('CARP-1', 'Gene', (278, 284))	('p27Kip1', 'Var', (154, 161))	('CARP-1', 'Gene', '112360', (278, 284))	('apoptosis', 'biological_process', 'GO:0097194', ('392', '401'))	('JNK', 'Gene', (311, 314))	('apoptosis', 'biological_process', 'GO:0006915', ('392', '401'))	('p38', 'Gene', (315, 318))	('exacerbates', 'PosReg', (222, 233))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (234, 251))	('DSF-Cu', 'Chemical', '-', (82, 88))	('signal', 'Reg', (381, 387))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (107, 124))	('JNK', 'Gene', '26419', (311, 314))
150788	24690739	Exposure of glioblastoma and breast cancer cells to DSF-Cu has previously been shown to attenuate transcriptional activation functions of NF-kappaB.	('DSF-Cu', 'Chemical', '-', (52, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('NF-kappaB', 'Gene', '18033', (138, 147))	('DSF-Cu', 'Var', (52, 58))	('transcriptional activation functions', 'MPA', (98, 134))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (12, 24))	('glioblastoma', 'Disease', (12, 24))	('attenuate', 'NegReg', (88, 97))	('breast cancer', 'Disease', (29, 42))	('NF-kappaB', 'Gene', (138, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
150795	24690739	In addition, DSF-Cu treatments also caused increased expression of ABIN1 and 2 proteins in a dose-dependent manner in both the MPM cell lines (Figure 6).	('DSF-Cu', 'Var', (13, 19))	('ABIN1 and 2', 'Gene', '57783;231130', (67, 78))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))	('DSF-Cu', 'Chemical', '-', (13, 19))
150806	24690739	Both the D2-40 and NZ-1.2 antibodies showed a robust increase in a ~100 kDa peptide in lysates derived from DSF-Cu-treated cells (Figure S1).	('NZ-1.2', 'Gene', (19, 25))	('increase', 'PosReg', (53, 61))	('D2-40', 'Var', (9, 14))	('DSF-Cu', 'Chemical', '-', (108, 114))
150807	24690739	These data suggest that DSF-Cu treatments likely cause further post-translational modifications of the MPM cell surface podoplanin protein that collectively result in podoplanin peptides of 75 kDa and higher sizes.	('result in', 'Reg', (157, 166))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('cell surface', 'cellular_component', 'GO:0009986', ('107', '119'))	('modifications', 'Var', (82, 95))	('DSF-Cu', 'Chemical', '-', (24, 30))	('podoplanin', 'MPA', (167, 177))
150808	24690739	A recent report demonstrated PKA phosphorylation of the serines in the intracellular region of podoplanin that resulted in diminished cell motility and migration signaling by podoplanin.	('rat', 'Species', '10116', (155, 158))	('cell motility', 'biological_process', 'GO:0048870', ('134', '147'))	('PKA', 'molecular_function', 'GO:0004691', ('29', '32'))	('migration', 'CPA', (152, 161))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('cell motility', 'CPA', (134, 147))	('PKA', 'cellular_component', 'GO:0005952', ('29', '32'))	('intracellular', 'cellular_component', 'GO:0005622', ('71', '84'))	('diminished', 'NegReg', (123, 133))	('rat', 'Species', '10116', (23, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('PKA', 'Var', (29, 32))	('serines', 'Chemical', 'MESH:D012694', (56, 63))
150811	24690739	Since Lysine63-linked ubiquitination often prevents degradation of the target proteins by the proteasome, and the fact that DSF-Cu inhibits proteasome and was also found to elevate cellular levels of ubiquitinated proteins (see figure 3), it is likely that the DSF-Cu treatments stimulate phosphorylation of podoplanin to inhibit its signaling for cell motility, while the Lysine63-linked ubiquitination contributes to a persistent and elevated levels of inactive podoplanin.	('ubiquitinated proteins', 'MPA', (200, 222))	('proteasome', 'cellular_component', 'GO:0000502', ('140', '150'))	('levels', 'MPA', (445, 451))	('DSF-Cu', 'Chemical', '-', (261, 267))	('Lysine63', 'Chemical', '-', (373, 381))	('cellular levels', 'MPA', (181, 196))	('cell motility', 'biological_process', 'GO:0048870', ('348', '361'))	('signaling for', 'MPA', (334, 347))	('phosphorylation', 'biological_process', 'GO:0016310', ('289', '304'))	('signaling', 'biological_process', 'GO:0023052', ('334', '343'))	('proteasome', 'molecular_function', 'GO:0004299', ('94', '104'))	('degradation', 'MPA', (52, 63))	('Lysine63', 'Chemical', '-', (6, 14))	('DSF-Cu', 'Chemical', '-', (124, 130))	('prevents', 'NegReg', (43, 51))	('elevate', 'NegReg', (173, 180))	('inhibit', 'NegReg', (322, 329))	('proteasome', 'cellular_component', 'GO:0000502', ('94', '104'))	('inhibits', 'NegReg', (131, 139))	('DSF-Cu', 'Var', (124, 130))	('degradation', 'biological_process', 'GO:0009056', ('52', '63'))	('elevated', 'PosReg', (436, 444))	('proteasome', 'MPA', (140, 150))	('proteasome', 'molecular_function', 'GO:0004299', ('140', '150'))	('phosphorylation', 'MPA', (289, 304))	('Lysine63-linked', 'Var', (6, 21))
150816	24690739	To investigate whether DSF-Cu inhibits MPM tumor growth, we implanted murine mesothelioma AB12 cells (0.5x106) subcutaneously into the right flanks of female Balb/c mice.	('mesothelioma', 'Disease', (77, 89))	('mice', 'Species', '10090', (165, 169))	('DSF-Cu', 'Var', (23, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('DSF-Cu', 'Chemical', '-', (23, 29))	('tumor', 'Disease', (43, 48))	('murine', 'Species', '10090', (70, 76))	('inhibits', 'NegReg', (30, 38))
150824	24690739	The TUNEL staining indicated an increase in the number of apoptotic cells in a representative tumor from mouse treated with DSF-Cu when compared with the corresponding vehicle-treated control (Figure 8C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('apoptotic cells', 'CPA', (58, 73))	('DSF-Cu', 'Chemical', '-', (124, 130))	('increase', 'PosReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('DSF-Cu', 'Var', (124, 130))	('mouse', 'Species', '10090', (105, 110))
150825	24690739	Consistent with the in vitro data in figures 2 and 6, increased apoptosis, and elevated levels of p27Kip1 and CARP-1 was also evident in a representative tumor that was derived from a mouse treated with DSF-Cu (Figure 8C).	('CARP-1', 'Gene', (110, 116))	('levels', 'MPA', (88, 94))	('apoptosis', 'CPA', (64, 73))	('CARP-1', 'Gene', '112360', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mouse', 'Species', '10090', (184, 189))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('elevated', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('elevated levels of p27Kip1', 'Phenotype', 'HP:0003240', (79, 105))	('DSF-Cu', 'Chemical', '-', (203, 209))	('p27Kip1', 'Var', (98, 105))	('tumor', 'Disease', (154, 159))
150835	24690739	Of note are our proof-of-concept findings that DSF-Cu effectively inhibited growth of the MPM cells that were derived from the three different clinical histotypes of this malignancy.	('DSF-Cu', 'Var', (47, 53))	('growth', 'CPA', (76, 82))	('DSF-Cu', 'Chemical', '-', (47, 53))	('inhibited', 'NegReg', (66, 75))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('malignancy', 'Disease', (171, 181))
150845	24690739	Given that expression of both the podoplanin and vimentin proteins are often associated with poor prognosis in MPM and other cancers, cleavage of vimentin and post-translational modifications of podoplanin (phosphorylation and lys63-linked ubiquitination), and together with reduced expression of MMP3 and 10 proteins, would collectively suggest for MPM invasion and metastasis inhibitory properties of DSF-Cu.	('vimentin', 'Gene', (146, 154))	('MPM', 'Disease', (350, 353))	('lys63', 'Chemical', '-', (227, 232))	('vimentin', 'cellular_component', 'GO:0045099', ('146', '154'))	('MPM', 'Disease', (111, 114))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('MMP3', 'Gene', (297, 301))	('vimentin', 'Gene', (49, 57))	('vimentin', 'Gene', '22352', (146, 154))	('vimentin', 'cellular_component', 'GO:0045099', ('49', '57'))	('DSF-Cu', 'Chemical', '-', (403, 409))	('phosphorylation', 'biological_process', 'GO:0016310', ('207', '222'))	('vimentin', 'Gene', '22352', (49, 57))	('associated', 'Reg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('podoplanin', 'Gene', (195, 205))	('MMP3', 'Gene', '17392', (297, 301))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('vimentin', 'cellular_component', 'GO:0045098', ('146', '154'))	('cancers', 'Disease', (125, 132))	('MMP3', 'molecular_function', 'GO:0004248', ('297', '301'))	('vimentin', 'cellular_component', 'GO:0045098', ('49', '57'))	('metastasis', 'CPA', (367, 377))	('cleavage', 'Var', (134, 142))
150857	24690739	It is to be noted however that DSF-Cu caused elevated levels of cell cycle inhibitory p27Kip1 at lower doses while the levels of CARP-1 and SULF1 proteins were induced in MPM cells treated with higher doses of DSF-Cu.	('CARP-1', 'Gene', '112360', (129, 135))	('DSF-Cu', 'Chemical', '-', (31, 37))	('elevated levels of cell cycle inhibitory p27Kip1', 'Phenotype', 'HP:0003240', (45, 93))	('CARP-1', 'Gene', (129, 135))	('DSF-Cu', 'Var', (31, 37))	('cell cycle inhibitory p27Kip1', 'MPA', (64, 93))	('levels', 'MPA', (54, 60))	('elevated', 'PosReg', (45, 53))	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('DSF-Cu', 'Chemical', '-', (210, 216))
150863	24690739	DSF-Cu however was effective in suppressing murine MPM allograft growth, in part by stimulating expression of CARP-1, p27Kip1 and apoptosis (figure 8).	('stimulating', 'PosReg', (84, 95))	('DSF-Cu', 'Chemical', '-', (0, 6))	('CARP-1', 'Gene', (110, 116))	('apoptosis', 'CPA', (130, 139))	('murine', 'Species', '10090', (44, 50))	('expression', 'MPA', (96, 106))	('CARP-1', 'Gene', '112360', (110, 116))	('p27Kip1', 'Var', (118, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('suppressing', 'NegReg', (32, 43))
150868	22912669	WA inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in increased levels of ubiquitinated proteins and pro-apoptotic proteasome target proteins (p21, Bax, IkappaBalpha).	('proteasome', 'molecular_function', 'GO:0004299', ('126', '136'))	('proteasome', 'cellular_component', 'GO:0000502', ('126', '136'))	('chymotryptic activity of the proteasome', 'MPA', (97, 136))	('p21', 'Var', (243, 246))	('IkappaBalpha', 'Gene', '4792', (253, 265))	('proteasome', 'molecular_function', 'GO:0004299', ('215', '225'))	('proteasome', 'cellular_component', 'GO:0000502', ('215', '225'))	('decreasing', 'NegReg', (82, 92))	('IkappaBalpha', 'Gene', (253, 265))	('inhibited', 'NegReg', (3, 12))	('patient', 'Species', '9606', (45, 52))	('murine', 'Species', '10090', (27, 33))	('levels of ubiquitinated proteins', 'MPA', (164, 196))	('increased', 'PosReg', (154, 163))	('growth', 'CPA', (13, 19))
150872	22912669	Knock-down of CARP-1, on the other hand, interfered with MPM growth inhibitory effects of WA.	('CARP-1', 'Gene', (14, 20))	('interfered', 'NegReg', (41, 51))	('CARP-1', 'Gene', '80196', (14, 20))	('Knock-down', 'Var', (0, 10))	('MPM', 'MPA', (57, 60))
150967	30476945	These were identified using ICD-10 codes for suicide (X60-X84 and Y87.0) and open verdicts (Y10-Y34 [excluding Y33.9, which is now called U309] and Y87.2 [event of undetermined intent]) and their International Classification of Diseases, Ninth Revision (ICD-9) equivalents: E950-E959 for suicide and self-inflicted injury and E980-E989 (excluding E988.8) for undetermined death.	('suicide', 'Disease', (288, 295))	('Y87.2', 'Var', (148, 153))	('open verdicts', 'Disease', (77, 90))	('injury', 'Disease', 'MESH:D058186', (315, 321))	('X60-X84', 'Var', (54, 61))	('E950-E959', 'Var', (274, 283))	('E988.8', 'CellLine', 'CVCL:V789', (347, 353))	('open verdicts', 'Disease', 'MESH:D005597', (77, 90))	('Y10-Y34', 'Var', (92, 99))	('E980-E989', 'Var', (326, 335))	('injury', 'Disease', (315, 321))
151055	30952634	Computational and experimental studies showed that inhibition of tumor-secreted factors effectively halts microtumor migration despite tumor-to-tumor variation in migration kinetics, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it.	('variation', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor-to-tumor', 'Disease', (272, 286))	('hypoxia', 'Disease', 'MESH:D000860', (203, 210))	('tumor', 'Disease', (281, 286))	('hypoxia', 'Disease', (325, 332))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('halts', 'NegReg', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor-to-tumor', 'Disease', (135, 149))	('tumor-to-tumor', 'Disease', 'MESH:D009369', (272, 286))	('tumor', 'Disease', (144, 149))	('hypoxia', 'Disease', 'MESH:D000860', (325, 332))	('migration', 'CPA', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor-to-tumor', 'Disease', 'MESH:D009369', (135, 149))	('hypoxia', 'Disease', (203, 210))
151064	30952634	For example, hypoxia is known to contribute to hypoxic secretome and activate several transcription factors and epigenetic modifications.	('transcription', 'Protein', (86, 99))	('contribute', 'Reg', (33, 43))	('epigenetic modifications', 'Var', (112, 136))	('hypoxic secretome', 'MPA', (47, 64))	('activate', 'PosReg', (69, 77))	('transcription', 'biological_process', 'GO:0006351', ('86', '99'))	('hypoxia', 'Disease', (13, 20))	('hypoxia', 'Disease', 'MESH:D000860', (13, 20))
151081	30952634	All antibodies were purchased from Santa Cruz Biotechnology (California, USA) except anti-Vimentin (MA3-745), anti-beta actin (MA5-15739) from Thermo Scientific Inc. (Rockford, USA); anti-ERK (9102S) and, anti-pERK (4370P) from Cell signaling Technologies Inc. (Massachusetts, USA); anti-HIF1-alpha (GTX127309) from GenTex (California, USA) and anti-Fibronectin (610077) from BD Biosciences (California, USA).	('HIF1-alpha', 'Gene', '3091', (288, 298))	('Vimentin', 'cellular_component', 'GO:0045099', ('90', '98'))	('ERK', 'Gene', '5594', (211, 214))	('signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('pERK', 'Gene', '9451', (210, 214))	('ERK', 'Gene', (211, 214))	('pERK', 'Gene', (210, 214))	('HIF1-alpha', 'Gene', (288, 298))	('Fibronectin', 'Gene', '2335', (350, 361))	('ERK', 'Gene', '5594', (188, 191))	('Fibronectin', 'Gene', (350, 361))	('Vimentin', 'cellular_component', 'GO:0045098', ('90', '98'))	('beta actin', 'Gene', (115, 125))	('610077', 'Var', (363, 369))	('ERK', 'Gene', (188, 191))	('beta actin', 'Gene', '728378', (115, 125))	('ERK', 'molecular_function', 'GO:0004707', ('188', '191'))
151167	30952634	In our previous work, HIF-1alpha knockdown in large microtumors either by siRNA or pharmacological inhibition from day 1 downregulated expression of mesenchymal markers and suppressed migration in large microtumors, suggesting possible role of hypoxic pre-conditioning and HIF-1alpha stabilization in migration as suggested by others.	('HIF-1alpha', 'Gene', '3091', (273, 283))	('pre', 'molecular_function', 'GO:0003904', ('252', '255'))	('HIF-1alpha', 'Gene', (22, 32))	('downregulated', 'NegReg', (121, 134))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('mesenchymal markers', 'Protein', (149, 168))	('HIF-1alpha', 'Gene', (273, 283))	('expression', 'MPA', (135, 145))	('suppressed', 'NegReg', (173, 183))	('knockdown', 'Var', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('HIF-1alpha', 'Gene', '3091', (22, 32))	('migration', 'CPA', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (208, 214))	('tumors', 'Disease', (57, 63))
151198	30952634	Western blots revealed increased levels of sE-CAD and FN in 600/CM compared to small non-migratory mBC microtumors (Fig.	('mBC microtumors', 'Disease', 'None', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('600/CM', 'Var', (60, 66))	('sE-CAD', 'MPA', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('increased', 'PosReg', (23, 32))	('sE-CAD', 'Chemical', '-', (43, 49))	('mBC microtumors', 'Disease', (99, 114))	('FN', 'Gene', '2335', (54, 56))
151245	30952634	Interestingly, HIF-1alpha inhibition from D1-6 or D3-6 inhibited microtumor migration significantly (only 3 and 11 out of 290 microtumors showed migration) (Fig.	('D1-6', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('HIF-1alpha', 'Gene', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (70, 75))	('inhibition', 'NegReg', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('D3-6', 'Var', (50, 54))	('tumor', 'Disease', (131, 136))	('D1-6', 'Gene', '25802;28503;1735;397;1238', (42, 46))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('inhibited', 'NegReg', (55, 64))	('HIF-1alpha', 'Gene', '3091', (15, 25))
151255	30952634	Early HIF-1alpha inhibition also reduced pERK expression significantly compared to untreated control (Fig.	('HIF-1alpha', 'Gene', (6, 16))	('pERK', 'Gene', (41, 45))	('pERK', 'Gene', '9451', (41, 45))	('inhibition', 'Var', (17, 27))	('HIF-1alpha', 'Gene', '3091', (6, 16))	('reduced', 'NegReg', (33, 40))
151256	30952634	Although D4-6 HIF-1alpha inhibition reduced FN (both secreted in the CM and intracellular), this late inhibition could not reduce MMP9 and VIM expression (Fig.	('VIM', 'Gene', '7431', (139, 142))	('HIF-1alpha', 'Gene', (14, 24))	('FN', 'Gene', '2335', (44, 46))	('MMP9', 'molecular_function', 'GO:0004229', ('130', '134'))	('VIM', 'Gene', (139, 142))	('inhibition', 'Var', (25, 35))	('reduced', 'NegReg', (36, 43))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('MMP9', 'Gene', (130, 134))	('intracellular', 'cellular_component', 'GO:0005622', ('76', '89'))	('MMP9', 'Gene', '4318', (130, 134))
151270	30952634	Although few microtumors treated with anti-sE-CAD antibody on D4-6 exhibited some migration (that was started before the treatment), the distance and extent of migration was significantly lower (38.4 +- 6.5mum and <25%, respectively) (Fig.	('antibody', 'cellular_component', 'GO:0019815', ('50', '58'))	('lower', 'NegReg', (188, 193))	('antibody', 'cellular_component', 'GO:0019814', ('50', '58'))	('antibody', 'molecular_function', 'GO:0003823', ('50', '58'))	('migration', 'CPA', (160, 169))	('anti-sE-CAD', 'Var', (38, 49))	('migration', 'CPA', (82, 91))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('antibody', 'cellular_component', 'GO:0042571', ('50', '58'))	('sE-CAD', 'Chemical', '-', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
151281	30952634	Additionally, we blocked sE-CAD shedding in 600mum microtumors by broad MMP inhibitor, GM6001 (20muM) on day 1 (T<Tcritical) or day 4 (T>Tcritical).	('GM6001', 'Var', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('sE-CAD', 'Chemical', '-', (25, 31))	('tumors', 'Disease', (56, 62))	('blocked', 'NegReg', (17, 24))	('GM6001', 'Chemical', 'MESH:C078131', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MMP', 'molecular_function', 'GO:0004235', ('72', '75'))	('sE-CAD shedding', 'CPA', (25, 40))
151282	30952634	MMP inhibition reduced sE-CAD shedding and secreted FN levels in the CM at both treatment times (Fig.	('FN', 'Gene', '2335', (52, 54))	('MMP', 'Protein', (0, 3))	('sE-CAD shedding', 'CPA', (23, 38))	('inhibition', 'Var', (4, 14))	('reduced', 'NegReg', (15, 22))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('sE-CAD', 'Chemical', '-', (23, 29))
151286	30952634	MMP inhibition also reduced pERK/ERK ratio and ERK activation (Fig.	('reduced', 'NegReg', (20, 27))	('ERK', 'Gene', '5594', (29, 32))	('ERK', 'Gene', '5594', (33, 36))	('MMP', 'Protein', (0, 3))	('ERK', 'Gene', (29, 32))	('pERK', 'Gene', (28, 32))	('inhibition', 'Var', (4, 14))	('ERK', 'Gene', (33, 36))	('activation', 'MPA', (51, 61))	('ERK', 'Gene', '5594', (47, 50))	('pERK', 'Gene', '9451', (28, 32))	('ERK', 'molecular_function', 'GO:0004707', ('47', '50'))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('ERK', 'Gene', (47, 50))
151294	30952634	Consequently, inhibiting HIF-1alpha is only effective before Tcritical, which varies from tumor to tumor.	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('inhibiting', 'Var', (14, 24))	('tumor', 'Disease', (90, 95))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('HIF-1alpha', 'Gene', (25, 35))
151359	30157247	Researchers using alpha-lactalbumin without oleic acid as a control for in vitro HAMLET and BAMLET experiments have found no toxicity of alpha-lactalbumin towards cancer cells, whereas others found a reduction in cell viability of approximately 10%.	('cell viability', 'CPA', (213, 227))	('reduction', 'NegReg', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('oleic acid', 'Chemical', 'MESH:D019301', (44, 54))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('toxicity', 'Disease', (125, 133))	('alpha-lactalbumin', 'Var', (137, 154))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
151410	30157247	All BLASTP searches returned a result of no significant similarity found, with the exception of three sequenced S. pneumoniae isolates (identified in NCBI protein database as CVY60247, COE43039, and CJL04251).	('S. pneumoniae', 'Species', '1313', (112, 125))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('CJL04251', 'Var', (199, 207))	('CVY60247', 'Var', (175, 183))
151421	30157247	Twenty-three of the twenty-four tested combinations of ATP synthase gene in cell line pairs exhibited downregulation of which seven were statistically significant (encompassing all 4 cell lines tested) (Table C in S1 File).	('ATP synthase', 'molecular_function', 'GO:0016468', ('55', '67'))	('downregulation', 'NegReg', (102, 116))	('ATP', 'Gene', '51761', (55, 58))	('ATP', 'Gene', (55, 58))	('combinations', 'Var', (39, 51))	('ATP synthase', 'molecular_function', 'GO:0016467', ('55', '67'))
151426	30157247	The SAXS data for high oleic acid content BAMLET and BLAGLET species exhibit the now classical liprotide characteristics of a non-sharp first minimum and a well-developed secondary maximum (Fig 3) which indicate that the structure is that of a liprotide having an oleic acid core and disordered protein shell.	('liprotide', 'Chemical', '-', (95, 104))	('core', 'cellular_component', 'GO:0019013', ('275', '279'))	('disordered', 'Disease', 'MESH:D030342', (284, 294))	('liprotide', 'Chemical', '-', (244, 253))	('high oleic acid content', 'Phenotype', 'HP:0025626', (18, 41))	('oleic acid', 'Chemical', 'MESH:D019301', (23, 33))	('protein', 'cellular_component', 'GO:0003675', ('295', '302'))	('disordered', 'Disease', (284, 294))	('oleic acid', 'Chemical', 'MESH:D019301', (264, 274))	('high oleic acid content', 'Var', (18, 41))
151459	30157247	If this irreversibility is due to unpaired disulphide bonds between cysteines of neighbouring beta-lactoglobulin molecules, then oleic acid inhibits the formation of these neighbouring bonds.	('inhibits', 'NegReg', (140, 148))	('mole', 'Phenotype', 'HP:0003764', (113, 117))	('disulphide', 'Chemical', '-', (43, 53))	('unpaired', 'Var', (34, 42))	('beta-lactoglobulin', 'Gene', '280838', (94, 112))	('cysteines', 'Chemical', 'MESH:D003545', (68, 77))	('beta-lactoglobulin', 'Gene', (94, 112))	('due', 'Reg', (27, 30))	('oleic acid', 'Chemical', 'MESH:D019301', (129, 139))	('formation', 'biological_process', 'GO:0009058', ('153', '162'))
151474	30157247	We show that although mesothelioma cells are more sensitive to BAMLET in the absence of serum, BAMLET is nonetheless able to kill mesothelioma cells even when blood serum components are present.	('mesothelioma', 'Disease', (130, 142))	('mesothelioma', 'Disease', (22, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (22, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('BAMLET', 'Var', (95, 101))
151516	30157247	Further investigations would be to see if removing these nucleoside transporters removes sensitivity to BAMLET, and a possible confounding issue for such investigations would be that some inhibitors of membrane channels and transporters also deactivate BAMLET by causing oleic acid to precipitate out of the complex (eg.	('sensitivity', 'MPA', (89, 100))	('BAMLET', 'Gene', (253, 259))	('precipitate out', 'MPA', (285, 300))	('removing', 'Var', (42, 50))	('membrane', 'cellular_component', 'GO:0016020', ('202', '210'))	('deactivate', 'NegReg', (242, 252))	('causing', 'Reg', (263, 270))	('oleic acid', 'MPA', (271, 281))	('oleic acid', 'Chemical', 'MESH:D019301', (271, 281))	('removes', 'NegReg', (81, 88))
151520	30157247	Oleic acid's one unsaturated cis double-bond is responsible for a kink in oleic acid structure, a characteristic that promotes softening, disordering and disruption of the lipid bilayer.	('disruption', 'MPA', (154, 164))	('kink', 'Var', (66, 70))	('oleic acid structure', 'MPA', (74, 94))	('rat', 'Species', '10116', (23, 26))	('Oleic acid', 'Chemical', 'MESH:D019301', (0, 10))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('oleic acid', 'Chemical', 'MESH:D019301', (74, 84))	('promotes', 'PosReg', (118, 126))	('disordering', 'MPA', (138, 149))	('softening', 'CPA', (127, 136))	('responsible', 'Reg', (48, 59))
151525	30157247	These results echo previous findings that HAMLET is just as cytotoxic towards apoptosis-resistant cells (p53 mutant and bcl-2 overexpressing) as for their respective apoptosis-sensitive parental cell lines, and BAMLET is just as cytotoxic towards TRAIL-resistant cell lines as for TRAIL-sensitive cell lines.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('TRAIL', 'Gene', (281, 286))	('TRAIL', 'Gene', '8743', (247, 252))	('bcl-2', 'Gene', (120, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('TRAIL', 'Gene', '8743', (281, 286))	('TRAIL', 'Gene', (247, 252))	('bcl-2', 'Gene', '596', (120, 125))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('mutant', 'Var', (109, 115))	('apoptosis-resistant cells', 'CPA', (78, 103))	('bcl-2', 'molecular_function', 'GO:0015283', ('120', '125'))
151534	30157247	It is the increased amount of oleic acid present in the solubilised, activated state that is mainly responsible for the increased cytotoxicity of the higher oleic acid content BAMLETs and BLAGLETs compared to the lower oleic acid content complexes.	('increased amount of oleic acid present', 'Phenotype', 'HP:0025626', (10, 48))	('higher oleic acid content', 'Var', (150, 175))	('cytotoxicity', 'Disease', (130, 142))	('oleic acid', 'Chemical', 'MESH:D019301', (30, 40))	('oleic acid', 'Chemical', 'MESH:D019301', (157, 167))	('cytotoxicity', 'Disease', 'MESH:D064420', (130, 142))	('oleic acid', 'Chemical', 'MESH:D019301', (219, 229))	('increased', 'PosReg', (120, 129))
151558	30157247	The human malignant pleural mesothelioma cell lines H28, H226, H2052, H2452, MSTO, and the immortalised human mesothelial cell line MeT5A were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA).	('human', 'Species', '9606', (4, 9))	('H226', 'CellLine', 'CVCL:J621', (57, 61))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (20, 40))	('human', 'Species', '9606', (104, 109))	('H2452', 'CellLine', 'CVCL:1553', (70, 75))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (20, 40))	('H2452', 'Var', (70, 75))	('pleural mesothelioma', 'Disease', (20, 40))
151562	30157247	The mesothelioma types represented are epithelioid (REN, H28, H226, H2452, H2052, VMC20, VMC23 and VMC33) and biphasic (MM05, MSTO and VMC40).	('MM05', 'Var', (120, 124))	('REN', 'Gene', (52, 55))	('mesothelioma', 'Disease', (4, 16))	('H2452', 'Var', (68, 73))	('H2452', 'CellLine', 'CVCL:1553', (68, 73))	('H2052', 'Var', (75, 80))	('biphasic', 'Disease', (110, 118))	('REN', 'Gene', '5972', (52, 55))	('epithelioid', 'Disease', (39, 50))	('H226', 'Var', (62, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('H226', 'CellLine', 'CVCL:J621', (62, 66))
151580	30157247	The sigmoid function used was:  where A is the left asymptote (viability at treatment concentration of 0, B is the right asymptote (viability at highest treatment concentration), xmid the transition point (TC50), scale is an x-axis scale parameter impacting slope of the transition, and x is log10 of the BAMLET concentration (thus rendering the curve symmetrical and suitable for modelling using log-likelihood).	('rat', 'Species', '10116', (170, 173))	('rat', 'Species', '10116', (319, 322))	('xmid', 'Var', (179, 183))	('impacting', 'NegReg', (248, 257))	('rat', 'Species', '10116', (93, 96))
151599	30157247	The NCBI Nucleotide identifiers of genome sequences from which ATP synthase genes were obtained are NC_008533.1 (S. pneumoniae D39), CP014326.1 (Streptococcus mitis strain SVGS_061), NC_002737.2 (Streptococcus pyogeneM1 GAS), CP009685.1 (Escherichia coli str.	('CP009685.1', 'Var', (226, 236))	('ATP synthase', 'molecular_function', 'GO:0016467', ('63', '75'))	('CP014326.1', 'Var', (133, 143))	('Streptococcus', 'Species', '28037', (196, 209))	('ATP synthase', 'molecular_function', 'GO:0016468', ('63', '75'))	('NC_002737.2', 'Var', (183, 194))	('ATP', 'Gene', (63, 66))	('ATP', 'Gene', '51761', (63, 66))	('Streptococcus mitis', 'Species', '28037', (145, 164))	('NC_008533.1', 'Var', (100, 111))	('Streptococcus', 'Species', '28037', (145, 158))	('S. pneumoniae D39', 'Species', '373153', (113, 130))	('GAS', 'molecular_function', 'GO:0034005', ('220', '223'))
151601	30157247	Kp52.145), CP007224.1 (Pseudomonas aeruginosa PA96), and CP009756.1 (Enterobacter cloacae strain GGT036).	('Pseudomonas aeruginosa PA96', 'Species', '1457392', (23, 50))	('Enterobacter cloacae', 'Species', '550', (69, 89))	('CP009756.1', 'Var', (57, 67))	('CP007224.1', 'Var', (11, 21))
151629	29721201	Increasing evidence indicates that aberrant activation of the developmental EMT program contributes to tumor invasion, metastatic dissemination and acquisition of therapeutic resistance.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('activation', 'PosReg', (44, 54))	('aberrant', 'Var', (35, 43))	('acquisition', 'CPA', (148, 159))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('developmental EMT program', 'CPA', (62, 87))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('and', 'Chemical', 'MESH:C019152', (144, 147))	('metastatic dissemination', 'CPA', (119, 143))
151639	29721201	We selected for our experiment three cell lines, representative of different mesothelioma subtypes: H2452, epithelial mesothelioma, H28, sarcomatoid mesothelioma, and MSTO, biphasic mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('mesothelioma', 'Disease', (77, 89))	('epithelial mesothelioma', 'Disease', 'MESH:D008654', (107, 130))	('and', 'Chemical', 'MESH:C019152', (163, 166))	('sarcomatoid mesothelioma', 'Disease', (137, 161))	('mesothelioma', 'Disease', (182, 194))	('biphasic mesothelioma', 'Disease', (173, 194))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (173, 194))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('H2452', 'Var', (100, 105))	('mesothelioma', 'Disease', (118, 130))	('mesothelioma', 'Disease', (149, 161))	('H2452', 'CellLine', 'CVCL:1553', (100, 105))	('sarcomatoid mesothelioma', 'Disease', 'MESH:C538614', (137, 161))	('epithelial mesothelioma', 'Disease', (107, 130))
151645	29721201	Following Kp-10 treatment at the range dose 0.001, 0.01, 0.1 nM, cells seemed to loose their aggressiveness and probably their high metastatic abilities; in fact our results displayed a strongly reduction to the > 80% of cell invasion in presence of Kp-10 (Figure 2C) than the control cells without Kp-10 treatment.	('and', 'Chemical', 'MESH:C019152', (108, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (93, 107))	('high metastatic abilities', 'CPA', (127, 152))	('aggressiveness', 'Disease', 'MESH:D001523', (93, 107))	('loose', 'NegReg', (81, 86))	('reduction', 'NegReg', (195, 204))	('cell invasion', 'CPA', (221, 234))	('Kp-10', 'Var', (250, 255))	('aggressiveness', 'Disease', (93, 107))
151647	29721201	In particular, with a dose of Kp-10 0.1 nM migration ability of mesothelioma cells decreased to about 50% in H2452 cells and about 60% in H28 and MSTO if compared to untreated controls (Figure 3A, 3C).	('migration ability', 'CPA', (43, 60))	('and', 'Chemical', 'MESH:C019152', (142, 145))	('H2452', 'CellLine', 'CVCL:1553', (109, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('decreased', 'NegReg', (83, 92))	('Kp-10 0.1', 'Var', (30, 39))	('mesothelioma', 'Disease', (64, 76))	('and', 'Chemical', 'MESH:C019152', (121, 124))
151649	29721201	Surprisingly we obtained a stronger effect in terms of inhibition of proliferation (Figure 2B), invasion (Figure 2D) and formation of colonies after treatment with FTM080 (Figure 3B) demonstrating that the anti-metastatic effect could be enhanced using a synthetic molecule.	('formation of colonies', 'CPA', (121, 142))	('and', 'Chemical', 'MESH:C019152', (117, 120))	('invasion', 'CPA', (96, 104))	('FTM080', 'Var', (164, 170))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('inhibition', 'NegReg', (55, 65))	('FTM080', 'Chemical', '-', (164, 170))
151654	29721201	The analysis revealed a strong over expression of the epithelial element: an Ep-Cam increase of 27% and 15%, in H28 and H2452 respectively, was observed following Kp-10 treatment than the control cells, indicating that the presence of Kisspeptin is associated with epithelial phenotype and thus favors a less aggressive behavior than the more aggressive mesenchymal one.	('aggressive behavior', 'Phenotype', 'HP:0000718', (309, 328))	('and', 'Chemical', 'MESH:C019152', (286, 289))	('Ep-Cam', 'Gene', (77, 83))	('presence', 'Var', (223, 231))	('less aggressive behavior', 'CPA', (304, 328))	('H2452', 'CellLine', 'CVCL:1553', (120, 125))	('favors', 'PosReg', (295, 301))	('Ep-Cam', 'Gene', '4072', (77, 83))	('and', 'Chemical', 'MESH:C019152', (116, 119))	('aggressive behavior', 'biological_process', 'GO:0002118', ('309', '328'))	('epithelial', 'Disease', (265, 275))	('and', 'Chemical', 'MESH:C019152', (100, 103))
151664	29721201	Several studies have shown that Kp-10 is completely degraded in murine serum within 1 hour; in contrast FTM080, the pentapeptide agonist that exhibits equipotent GPR54 activation to Kp-10, has a half-life in murine serum of 6.6 hours and offers more stability under physiological conditions.	('GPR54', 'Gene', (162, 167))	('murine', 'Species', '10090', (208, 214))	('FTM080', 'Chemical', '-', (104, 110))	('murine', 'Species', '10090', (64, 70))	('and', 'Chemical', 'MESH:C019152', (234, 237))	('GPR54', 'Gene', '84634', (162, 167))	('stability', 'MPA', (250, 259))	('FTM080', 'Var', (104, 110))
151680	29721201	This evidence suggests that the presence of Kisspeptin favors the maintenance of the epithelial phenotype, that is, a less aggressive behavior of cancerous cells.	('cancerous', 'Disease', (146, 155))	('Kisspeptin', 'Gene', (44, 54))	('cancerous', 'Disease', 'MESH:D009369', (146, 155))	('aggressive behavior', 'biological_process', 'GO:0002118', ('123', '142'))	('presence', 'Var', (32, 40))	('aggressive behavior', 'Phenotype', 'HP:0000718', (123, 142))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('favors', 'PosReg', (55, 61))
151686	29721201	In our experiments, performed on H28 and H2452 cell lines, we observed remarkable reductions in MMP-2 and MMP-9 after 0.1 nM of Kp-10 as evidenced by gelatin zymography analysis.	('MMP-9', 'Gene', (106, 111))	('and', 'Chemical', 'MESH:C019152', (37, 40))	('MMP-2', 'Gene', (96, 101))	('MMP-9', 'molecular_function', 'GO:0004229', ('106', '111'))	('Kp-10', 'Var', (128, 133))	('reductions', 'NegReg', (82, 92))	('H2452', 'CellLine', 'CVCL:1553', (41, 46))	('and', 'Chemical', 'MESH:C019152', (102, 105))	('MMP-2', 'molecular_function', 'GO:0004228', ('96', '101'))	('MMP-9', 'Gene', '4318', (106, 111))	('0.1 nM', 'Var', (118, 124))	('MMP-2', 'Gene', '4313', (96, 101))
151692	29721201	The result obtained was very satisfactory: in fact the analysis performed on the human Alu sequences clearly showed that mice receiving FTM080 had human Alu quantity reduced by more than 5 times the mice they did not receive type of treatment.	('human', 'Species', '9606', (147, 152))	('mice', 'Species', '10090', (199, 203))	('reduced', 'NegReg', (166, 173))	('mice', 'Species', '10090', (121, 125))	('human Alu quantity', 'MPA', (147, 165))	('FTM080', 'Var', (136, 142))	('FTM080', 'Chemical', '-', (136, 142))	('human', 'Species', '9606', (81, 86))
151721	29721201	FTM080: 98 mg, overall yield: 82 %, purity: >= 95%, tR 20.55 min, HRMS (ESI-MS): Calculated: 799,40553 for C41H52FN10O6 [M+H]+, found: 799.40516.	('FTM080', 'Chemical', '-', (0, 6))	('ESI-MS', 'Disease', (72, 78))	('ESI-MS', 'Disease', 'MESH:D009103', (72, 78))	('C41H52FN10O6', 'Chemical', '-', (107, 119))	('C41H52FN10O6 [', 'Var', (107, 121))
151732	29721201	Briefly, cells were seeded onto the membrane of the upper chamber of the Transwell chambers at a concentration of 5x104/ml in 500 mul of RPMI medium and were treated with the indicated concentrations of drugs for 72 hours [0.001, 0.01, 0.1 nM of Kp-10 and 0.01, 0.1, 1 muM of FTM080].	('and', 'Chemical', 'MESH:C019152', (149, 152))	('and', 'Chemical', 'MESH:C019152', (252, 255))	('0.01', 'Var', (256, 260))	('Kp-10', 'Var', (246, 251))	('0.01', 'Var', (230, 234))	('FTM080', 'Chemical', '-', (276, 282))	('membrane', 'cellular_component', 'GO:0016020', ('36', '44'))	('RPMI medium', 'Chemical', '-', (137, 148))
151738	29721201	Cells were seeded on 6-well tissue culture dishes at 300 cells/well and treated with 0.001, 0.01, 0.1 nM of Kp-10 and 0.01, 0.1, 1 muM of FTM080.	('and', 'Chemical', 'MESH:C019152', (114, 117))	('0.01', 'Var', (92, 96))	('FTM080', 'Chemical', '-', (138, 144))	('0.1 nM', 'Var', (98, 104))	('Kp-10', 'Var', (108, 113))	('and', 'Chemical', 'MESH:C019152', (68, 71))	('0.001', 'Var', (85, 90))
151790	29191582	The type of mesothelioma was classified as pleural (ICD-O-3 site codes: C384, C342, C349) and non-pleural.	('pleural', 'Disease', (43, 50))	('pleural', 'Disease', (98, 105))	('non-pleural', 'Disease', 'MESH:D010995', (94, 105))	('mesothelioma', 'Disease', (12, 24))	('non-pleural', 'Disease', (94, 105))	('C342', 'Var', (78, 82))	('C349', 'Var', (84, 88))	('pleural', 'Disease', 'MESH:D010995', (98, 105))	('pleural', 'Disease', 'MESH:D010995', (43, 50))	('C384', 'Var', (72, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))
151791	29191582	Body mass index (BMI) was calculated based on height and weight ("usual weight" or if that was unavailable "weight at diagnosis") and then categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), obese (>30) and unknown.	('overweight', 'Phenotype', 'HP:0025502', (195, 205))	('obese', 'Disease', (219, 224))	('<18.5', 'Var', (167, 172))	('obese', 'Disease', 'MESH:D009765', (219, 224))
151839	29191582	Consistent with previous reports, epithelioid histology, receipt of systemic therapy, and surgery were all associated with improved outcomes in pleural mesothelioma patients.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (144, 164))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (144, 164))	('epithelioid', 'Var', (34, 45))	('patients', 'Species', '9606', (165, 173))	('pleural mesothelioma', 'Disease', (144, 164))	('improved', 'PosReg', (123, 131))	('outcomes', 'MPA', (132, 140))
151952	24754309	Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 muM.	('malignant pleural mesothelioma', 'Disease', (167, 197))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (59, 89))	('HUHS1015', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('NCI-H2052', 'CellLine', 'CVCL:1518', (229, 238))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (69, 89))	('naftopidil', 'Chemical', 'MESH:C064357', (112, 122))	('NCI-H28', 'CellLine', 'CVCL:1555', (220, 227))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (69, 89))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (167, 197))	('muM', 'Gene', '56925', (374, 377))	('reduced', 'NegReg', (141, 148))	('malignant pleural mesothelioma', 'Disease', (59, 89))	('muM', 'Gene', (374, 377))	('cisplatin', 'Chemical', 'MESH:D002945', (331, 340))	('cell viability', 'CPA', (149, 163))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (177, 197))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (177, 197))	('paclitaxel', 'Chemical', 'MESH:D017239', (317, 327))	('MSTO-211H', 'CellLine', 'CVCL:1430', (209, 218))	('NCI-H2452', 'CellLine', 'CVCL:1553', (244, 253))
151953	24754309	HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells.	('necrosis', 'biological_process', 'GO:0070265', ('22', '30'))	('necrosis', 'Disease', 'MESH:D009336', (22, 30))	('necrosis', 'biological_process', 'GO:0008219', ('22', '30'))	('necrosis', 'biological_process', 'GO:0019835', ('22', '30'))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('necrosis', 'biological_process', 'GO:0001906', ('22', '30'))	('necrosis', 'biological_process', 'GO:0008220', ('22', '30'))	('NCI-H2052', 'CellLine', 'CVCL:1518', (62, 71))	('necrosis', 'Disease', (22, 30))	('HUHS1015', 'Var', (0, 8))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (48, 57))
151954	24754309	HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('Noxa', 'Gene', '5366', (60, 64))	('HUHS1015-induced', 'Var', (110, 126))	('upregulated', 'PosReg', (9, 20))	('Noxa', 'Gene', (60, 64))	('NCI-H2052', 'CellLine', 'CVCL:1518', (82, 91))	('HUHS1015', 'Gene', (0, 8))	('mitochondrial apoptosis', 'CPA', (127, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (68, 77))	('expression', 'MPA', (21, 31))
151955	24754309	HUHS1015 clearly suppressed tumor growth in mice inoculated with NCI-H2052 cells.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('suppressed', 'NegReg', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('NCI-H2052', 'CellLine', 'CVCL:1518', (65, 74))	('HUHS1015', 'Var', (0, 8))	('mice', 'Species', '10090', (44, 48))
151956	24754309	Taken together, the results of the present study indicate that HUHS1015 could be developed as an effective anticancer drug for treatment of malignant pleural mesothelioma.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (150, 170))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (140, 170))	('malignant pleural mesothelioma', 'Disease', (140, 170))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HUHS1015', 'Var', (63, 71))
151959	24754309	We have found that naftopidil induces apoptosis in malignant mesothelioma cells by activating caspase-8 and the effector caspase-3, regardless of alpha1-adrenoceptor blocking.	('caspase-3', 'Gene', (121, 130))	('malignant mesothelioma', 'Disease', (51, 73))	('caspase-3', 'Gene', '836', (121, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'CPA', (38, 47))	('caspase-8', 'Gene', (94, 103))	('alpha1-adrenoceptor', 'molecular_function', 'GO:0004937', ('146', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('naftopidil', 'Var', (19, 29))	('caspase-8', 'Gene', '841', (94, 103))	('activating', 'PosReg', (83, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (51, 73))	('naftopidil', 'Chemical', 'MESH:C064357', (19, 29))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (51, 73))
151961	24754309	HUHS1015 induced apoptosis of not only human malignant mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452 cells but also lung cancer cell lines A549, SBC-3, and Lu-65 cells, hepatoma cell lines HepG2 and HuH-7 cells, gastric cancer cell lines MKN-28 and MKN-45 cells, and bladder cancer cell lines 253J, 5637, KK-47, TCCSUP, T24, and UM-UC-3 cells, prostate cancer cell lines DU145, LNCap, and PC-3 cells, and renal cancer cell lines ACHN, RCC4-VHL, and 786-O cells.	('renal cancer', 'Phenotype', 'HP:0009726', (428, 440))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('RCC4-VHL', 'Disease', 'MESH:D006623', (458, 466))	('DU145', 'CellLine', 'CVCL:0105', (394, 399))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('MSTO-211H', 'CellLine', 'CVCL:1430', (79, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (235, 249))	('hepatoma', 'Disease', 'MESH:D006528', (192, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (367, 382))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('renal cancer', 'Disease', 'MESH:D007680', (428, 440))	('bladder cancer', 'Phenotype', 'HP:0009725', (290, 304))	('prostate cancer', 'Phenotype', 'HP:0012125', (367, 382))	('LNCap', 'CellLine', 'CVCL:0395', (401, 406))	('prostate cancer', 'Disease', (367, 382))	('HepG2', 'CellLine', 'CVCL:0027', (212, 217))	('UM-UC-3', 'CellLine', 'CVCL:1783', (352, 359))	('human', 'Species', '9606', (39, 44))	('HuH-7', 'CellLine', 'CVCL:0336', (222, 227))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (45, 67))	('gastric cancer', 'Disease', (235, 249))	('apoptosis', 'biological_process', 'GO:0097194', ('17', '26'))	('NCI-H2452', 'CellLine', 'CVCL:1553', (114, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('17', '26'))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('hepatoma', 'Disease', (192, 200))	('NCI-H28', 'CellLine', 'CVCL:1555', (90, 97))	('HUHS1015', 'Var', (0, 8))	('RCC4-VHL', 'Disease', (458, 466))	('PC-3', 'CellLine', 'CVCL:0035', (412, 416))	('lung cancer', 'Disease', (139, 150))	('malignant mesothelioma', 'Disease', (45, 67))	('MSTO-211H', 'Var', (79, 88))	('NCI-H2052', 'CellLine', 'CVCL:1518', (99, 108))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (235, 249))	('bladder cancer', 'Disease', 'MESH:D001749', (290, 304))	('bladder cancer', 'Disease', (290, 304))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (45, 67))	('renal cancer', 'Disease', (428, 440))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
151962	24754309	The present study aimed to assess whether HUHS1015 could be developed as a promising drug for treatment of malignant pleural mesothelioma.	('HUHS1015', 'Var', (42, 50))	('malignant pleural mesothelioma', 'Disease', (107, 137))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (107, 137))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (117, 137))
151969	24754309	Before and after 24-h treatment with HUHS1015 (15 muM) or paclitaxel (15 muM), MSTO-211H and NCI-H2052 cells were suspended in a binding buffer and stained with both PI and annexin V-FITC, and loaded on a flow cytometer (FACSCalibur) available for FL1 (annexin V) and FL2 (PI) bivariate analysis.	('FL1', 'Gene', '100306940', (248, 251))	('muM', 'Gene', '56925', (73, 76))	('HUHS1015', 'Var', (37, 45))	('annexin V', 'Gene', '308', (253, 262))	('annexin V', 'Gene', (173, 182))	('muM', 'Gene', (73, 76))	('annexin V', 'Gene', '308', (173, 182))	('muM', 'Gene', '56925', (50, 53))	('MSTO-211H', 'CellLine', 'CVCL:1430', (79, 88))	('annexin V', 'Gene', (253, 262))	('FL2', 'Chemical', '-', (268, 271))	('binding', 'molecular_function', 'GO:0005488', ('129', '136'))	('FL1', 'Gene', (248, 251))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))	('muM', 'Gene', (50, 53))	('NCI-H2052', 'CellLine', 'CVCL:1518', (93, 102))
151980	24754309	HUHS1015 reduced the cell viability of all the investigated malignant pleural mesothelioma cell lines, MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, in a concentration (1-100 muM)-dependent manner; a drastic effect was found at concentrations more than 30 muM, with the viability reaching almost 0% of basal levels at 100 muM (Fig.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (60, 90))	('muM', 'Gene', (322, 325))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (70, 90))	('muM', 'Gene', '56925', (256, 259))	('NCI-H2452', 'CellLine', 'CVCL:1553', (138, 147))	('malignant pleural mesothelioma', 'Disease', (60, 90))	('cell viability', 'CPA', (21, 35))	('muM', 'Gene', (175, 178))	('muM', 'Gene', '56925', (322, 325))	('NCI-H2052', 'CellLine', 'CVCL:1518', (123, 132))	('reduced', 'NegReg', (9, 16))	('MSTO-211H', 'CellLine', 'CVCL:1430', (103, 112))	('NCI-H28', 'CellLine', 'CVCL:1555', (114, 121))	('HUHS1015', 'Var', (0, 8))	('muM', 'Gene', (256, 259))	('muM', 'Gene', '56925', (175, 178))
151984	24754309	In the cell cycle analysis by flow cytometry, HUHS1015 increases the proportion of sub-G1 phase NCI-H2052 and MSTO-211H cells (Fig.	('MSTO-211H', 'CellLine', 'CVCL:1430', (110, 119))	('G1 phase', 'biological_process', 'GO:0051318', ('87', '95'))	('cell cycle', 'biological_process', 'GO:0007049', ('7', '17'))	('HUHS1015', 'Var', (46, 54))	('increases', 'PosReg', (55, 64))	('sub-G1 phase NCI-H2052', 'CPA', (83, 105))	('NCI-H2052', 'CellLine', 'CVCL:1518', (96, 105))	('MSTO-211H cells', 'CPA', (110, 125))
151985	24754309	HUHS1015 (10 muM) increased the proportion of the G1 and S phases of cell cycling and decreased that of the G2/M phase in NCI-H2052 cells (Fig.	('increased', 'PosReg', (18, 27))	('muM', 'Gene', (13, 16))	('M phase', 'biological_process', 'GO:0000279', ('111', '118'))	('NCI-H2052', 'CellLine', 'CVCL:1518', (122, 131))	('decreased', 'NegReg', (86, 95))	('HUHS1015', 'Var', (0, 8))	('muM', 'Gene', '56925', (13, 16))	('G2/M', 'MPA', (108, 112))
151995	24754309	In this assay, each population of PI-positive and annexin V-negative, PI-negative and annexin V-positive, or PI-positive and annexin V-positive cells corresponded to primary necrosis, early apoptosis, and late apoptosis/secondary necrosis, respectively.	('necrosis', 'biological_process', 'GO:0008220', ('174', '182'))	('necrosis', 'biological_process', 'GO:0070265', ('230', '238'))	('necrosis', 'Disease', 'MESH:D009336', (174, 182))	('necrosis', 'Disease', 'MESH:D009336', (230, 238))	('necrosis', 'biological_process', 'GO:0019835', ('230', '238'))	('necrosis', 'biological_process', 'GO:0001906', ('230', '238'))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('necrosis', 'biological_process', 'GO:0070265', ('174', '182'))	('necrosis', 'Disease', (230, 238))	('necrosis', 'Disease', (174, 182))	('necrosis', 'biological_process', 'GO:0019835', ('174', '182'))	('early apoptosis', 'CPA', (184, 199))	('secondary necrosis', 'Phenotype', 'HP:0010885', (220, 238))	('necrosis', 'biological_process', 'GO:0001906', ('174', '182'))	('annexin V', 'Gene', (125, 134))	('annexin V', 'Gene', (86, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('annexin V', 'Gene', '308', (86, 95))	('annexin V', 'Gene', '308', (125, 134))	('necrosis', 'biological_process', 'GO:0008219', ('230', '238'))	('annexin V', 'Gene', (50, 59))	('necrosis', 'biological_process', 'GO:0008219', ('174', '182'))	('PI-positive', 'Var', (34, 45))	('annexin V', 'Gene', '308', (50, 59))	('necrosis', 'biological_process', 'GO:0008220', ('230', '238'))
151996	24754309	HUHS1015 (15 muM) increased the populations of PI-positive and annexin V-negative, PI-negative and annexin V-positive, and PI-positive and annexin V-positive cells both in NCI-H2052 (Fig.	('annexin V', 'Gene', (63, 72))	('annexin V', 'Gene', '308', (63, 72))	('increased', 'PosReg', (18, 27))	('HUHS1015', 'Var', (0, 8))	('muM', 'Gene', (13, 16))	('annexin V', 'Gene', '308', (139, 148))	('annexin V', 'Gene', (139, 148))	('NCI-H2052', 'CellLine', 'CVCL:1518', (172, 181))	('annexin V', 'Gene', '308', (99, 108))	('annexin V', 'Gene', (99, 108))	('muM', 'Gene', '56925', (13, 16))
151998	24754309	4d,e), suggesting that HUHS1015 induces both necrosis and apoptosis of NCI-H2052 and MSTO-211H cells.	('necrosis', 'biological_process', 'GO:0001906', ('45', '53'))	('necrosis', 'Disease', (45, 53))	('necrosis', 'biological_process', 'GO:0008220', ('45', '53'))	('NCI-H2052', 'CellLine', 'CVCL:1518', (71, 80))	('MSTO-211H', 'CellLine', 'CVCL:1430', (85, 94))	('HUHS1015', 'Var', (23, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('necrosis', 'Disease', 'MESH:D009336', (45, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('necrosis', 'biological_process', 'GO:0070265', ('45', '53'))	('necrosis', 'biological_process', 'GO:0008219', ('45', '53'))	('apoptosis', 'CPA', (58, 67))	('necrosis', 'biological_process', 'GO:0019835', ('45', '53'))	('induces', 'Reg', (32, 39))
152007	24754309	Collectively, these results suggest that HUHS1015 induces mitochondria-mediated apoptosis of NCI-H2052 and MSTO-211H cells.	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('mitochondria', 'cellular_component', 'GO:0005739', ('58', '70'))	('NCI-H2052', 'CellLine', 'CVCL:1518', (93, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (107, 116))	('mitochondria-mediated apoptosis', 'MPA', (58, 89))	('induces', 'Reg', (50, 57))	('HUHS1015', 'Var', (41, 49))
152015	24754309	Intraperitoneal injection with HUHS1015 at a dose of 9.15 mg/kg, corresponding to approximately 25 muM, twice a week significantly inhibited NCI-H2052 cell growth compared with that for control mice without HUHS1015 (P < 0.001, Fisher's protected least significant difference test) (Fig.	('muM', 'Gene', (99, 102))	('NCI-H2052 cell growth', 'CPA', (141, 162))	('NCI-H2052', 'CellLine', 'CVCL:1518', (141, 150))	('mice', 'Species', '10090', (194, 198))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('muM', 'Gene', '56925', (99, 102))	('inhibited', 'NegReg', (131, 140))	('HUHS1015', 'Var', (31, 39))
152017	24754309	These results indicate that HUHS1015 could exert its beneficial anticancer effect on malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (85, 115))	('HUHS1015', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('anticancer effect', 'CPA', (64, 81))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (95, 115))	('malignant pleural mesothelioma', 'Disease', (85, 115))	('beneficial', 'PosReg', (53, 63))
152018	24754309	In the present study, HUHS1015 reduced cell viability in all the investigated malignant pleural mesothelioma cell lines in a concentration (1-100 muM)-dependent manner, reaching almost 0% of basal levels at 100 muM.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (88, 108))	('reduced', 'NegReg', (31, 38))	('muM', 'Gene', '56925', (146, 149))	('muM', 'Gene', '56925', (211, 214))	('HUHS1015', 'Var', (22, 30))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (78, 108))	('cell viability', 'CPA', (39, 53))	('muM', 'Gene', (146, 149))	('muM', 'Gene', (211, 214))	('malignant pleural mesothelioma', 'Disease', (78, 108))
152023	24754309	HUHS1015 increased the proportion of the sub-G1 phase of cell cycling in NCI-H2052 and MSTO-211H cells.	('sub-G1 phase', 'CPA', (41, 53))	('increased', 'PosReg', (9, 18))	('NCI-H2052', 'CellLine', 'CVCL:1518', (73, 82))	('MSTO-211H', 'CellLine', 'CVCL:1430', (87, 96))	('HUHS1015', 'Var', (0, 8))	('G1 phase', 'biological_process', 'GO:0051318', ('45', '53'))
152024	24754309	In addition, HUHS1015 increased the proportion of the G1 and S phases of cell cycling in NCI-H2052 cells, but such effect was not found in MSTO-211H cells.	('HUHS1015', 'Var', (13, 21))	('increased', 'PosReg', (22, 31))	('MSTO-211H', 'CellLine', 'CVCL:1430', (139, 148))	('NCI-H2052', 'CellLine', 'CVCL:1518', (89, 98))
152025	24754309	This suggests that HUHS1015 induces cell cycle arrest at the G1 and S phases in NCI-H2052 cells, but not in MSTO-211H cells.	('NCI-H2052', 'CellLine', 'CVCL:1518', (80, 89))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('36', '53'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('induces', 'Reg', (28, 35))	('HUHS1015', 'Var', (19, 27))	('MSTO-211H', 'CellLine', 'CVCL:1430', (108, 117))
152029	24754309	HUHS1015 increased the population of PI-positive and annexin V-negative, PI-negative and annexin V-positive, and PI-positive and annexin V-positive cells in NCI-H2052 and MSTO-211H cells, which corresponds to primary necrosis, early apoptosis, and late apoptosis/secondary necrosis, respectively.	('necrosis', 'biological_process', 'GO:0001906', ('217', '225'))	('necrosis', 'biological_process', 'GO:0001906', ('273', '281'))	('necrosis', 'Disease', (217, 225))	('annexin V', 'Gene', '308', (89, 98))	('NCI-H2052', 'CellLine', 'CVCL:1518', (157, 166))	('apoptosis', 'biological_process', 'GO:0006915', ('233', '242'))	('annexin V', 'Gene', (53, 62))	('necrosis', 'biological_process', 'GO:0008219', ('217', '225'))	('necrosis', 'biological_process', 'GO:0008219', ('273', '281'))	('apoptosis', 'biological_process', 'GO:0097194', ('253', '262'))	('apoptosis', 'biological_process', 'GO:0006915', ('253', '262'))	('secondary necrosis', 'Phenotype', 'HP:0010885', (263, 281))	('MSTO-211H', 'CellLine', 'CVCL:1430', (171, 180))	('increased', 'PosReg', (9, 18))	('annexin V', 'Gene', '308', (53, 62))	('annexin V', 'Gene', (129, 138))	('HUHS1015', 'Var', (0, 8))	('necrosis', 'Disease', 'MESH:D009336', (273, 281))	('PI-positive', 'Var', (37, 48))	('necrosis', 'biological_process', 'GO:0008220', ('217', '225'))	('necrosis', 'biological_process', 'GO:0008220', ('273', '281'))	('annexin V', 'Gene', '308', (129, 138))	('necrosis', 'Disease', 'MESH:D009336', (217, 225))	('necrosis', 'Disease', (273, 281))	('apoptosis', 'biological_process', 'GO:0097194', ('233', '242'))	('necrosis', 'biological_process', 'GO:0070265', ('217', '225'))	('necrosis', 'biological_process', 'GO:0070265', ('273', '281'))	('necrosis', 'biological_process', 'GO:0019835', ('217', '225'))	('necrosis', 'biological_process', 'GO:0019835', ('273', '281'))	('annexin V', 'Gene', (89, 98))
152031	24754309	Taken together, these results indicate that HUHS1015 and paclitaxel could induce both necrosis and apoptosis of malignant pleural mesothelioma cells.	('induce', 'PosReg', (74, 80))	('necrosis', 'biological_process', 'GO:0019835', ('86', '94'))	('malignant pleural mesothelioma', 'Disease', (112, 142))	('necrosis', 'biological_process', 'GO:0001906', ('86', '94'))	('necrosis', 'biological_process', 'GO:0008220', ('86', '94'))	('necrosis', 'Disease', (86, 94))	('apoptosis', 'CPA', (99, 108))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (122, 142))	('HUHS1015', 'Var', (44, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('necrosis', 'Disease', 'MESH:D009336', (86, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('necrosis', 'biological_process', 'GO:0070265', ('86', '94'))	('necrosis', 'biological_process', 'GO:0008219', ('86', '94'))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (112, 142))
152036	24754309	Overall, HUHS1015 appears to induce apoptosis of malignant pleural mesothelioma cells through the mitochondria-mediated pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('mitochondria', 'cellular_component', 'GO:0005739', ('98', '110'))	('apoptosis', 'CPA', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('HUHS1015', 'Var', (9, 17))	('mitochondria-mediated pathway', 'Pathway', (98, 127))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (59, 79))	('malignant pleural mesothelioma', 'Disease', (49, 79))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (49, 79))	('induce', 'PosReg', (29, 35))
152038	24754309	In the in vivo experiments using mice inoculated with NCI-H2052 cells, HUHS1015 strongly suppressed tumor growth, and the survival rate was 100% 8 weeks after the start of HUHS1015 injections.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NCI-H2052', 'CellLine', 'CVCL:1518', (54, 63))	('suppressed', 'NegReg', (89, 99))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (33, 37))	('HUHS1015', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
152039	24754309	This suggests that HUHS1015 has the potential to effectively suppress proliferation of malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (87, 117))	('proliferation', 'CPA', (70, 83))	('suppress', 'NegReg', (61, 69))	('HUHS1015', 'Var', (19, 27))	('malignant pleural mesothelioma', 'Disease', (87, 117))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (97, 117))
152040	24754309	In summary, the results of the present study show that HUHS1015 induces apoptosis of malignant pleural mesothelioma cells, possibly mediated through mitochondria, and in part, cell cycle arrest, thereby leading to suppression of tumor proliferation.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (85, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (176, 193))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('induces', 'Reg', (64, 71))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (95, 115))	('malignant pleural mesothelioma', 'Disease', (85, 115))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('176', '193'))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cell cycle arrest', 'CPA', (176, 193))	('mitochondria', 'cellular_component', 'GO:0005739', ('149', '161'))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('tumor', 'Disease', (229, 234))	('suppression', 'NegReg', (214, 225))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('apoptosis', 'CPA', (72, 81))	('HUHS1015', 'Var', (55, 63))
152043	21723781	We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study.	('patients', 'Species', '9606', (44, 52))	('trimodal', 'Chemical', '-', (115, 123))	('EPP', 'Var', (83, 86))	('Mesothelioma', 'Disease', (139, 151))	('Mesothelioma', 'Disease', 'MESH:D008654', (139, 151))
152094	21723781	Between Oct 1, 2005 and Nov 3, 2008, 112 patients were registered, of whom 50 were subsequently randomly assigned to EPP (n=24) or to no EPP (n=26; figure 2).	('Oct 1', 'Gene', '5451', (8, 13))	('patients', 'Species', '9606', (41, 49))	('EPP', 'Var', (117, 120))	('Oct 1', 'Gene', (8, 13))
152167	21723781	The MARS trial was rigorously done, with the final decision that a patient was eligible for randomisation within MARS made in discussions by the MARS virtual multidisciplinary team and the allocation to EPP or no EPP made within the ICR-CTSU.	('CTSU', 'Gene', '1515', (237, 241))	('EPP', 'Var', (203, 206))	('patient', 'Species', '9606', (67, 74))	('CTSU', 'Gene', (237, 241))
152176	19638575	In a similar analysis restricted to tumors, methylation profile classes significantly predicted tumor type (P < 0.0001).	('methylation', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', (96, 101))	('predicted', 'Reg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))
152179	19638575	Using the CpG loci with significant differential methylation in a pathways analysis revealed significant enrichment of methylated gene-loci in Cell Cycle Regulation, DNA Damage Response, PTEN Signaling, and Apoptosis Signaling pathways in lung adenocarcinoma when compared to mesothelioma.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('Apoptosis Signaling pathways', 'Pathway', (207, 235))	('mesothelioma', 'Disease', 'MESH:D008654', (276, 288))	('methylated', 'Var', (119, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (239, 258))	('PTEN', 'Gene', (187, 191))	('DNA Damage Response', 'biological_process', 'GO:0006974', ('166', '185'))	('Signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('DNA Damage Response', 'MPA', (166, 185))	('PTEN', 'Gene', '5728', (187, 191))	('Cell Cycle Regulation', 'biological_process', 'GO:0051726', ('143', '164'))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('lung adenocarcinoma', 'Disease', (239, 258))	('mesothelioma', 'Disease', (276, 288))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (239, 258))	('Cell', 'MPA', (143, 147))	('Apoptosis Signaling', 'biological_process', 'GO:0006915', ('207', '226'))
152186	19638575	It is well recognized that promoter DNA hypermethylation is a mechanism of stable control of transcription, and an important contributor to carcinogenesis.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('promoter DNA hypermethylation', 'Var', (27, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('carcinogenesis', 'Disease', (140, 154))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('36', '56'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))
152191	19638575	Our previous work has demonstrated hundreds of differentially methylated CpG loci in pleural mesothelioma compared to non-diseased pleura.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (85, 105))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (85, 105))	('pleural mesothelioma', 'Disease', (85, 105))	('differentially methylated', 'Var', (47, 72))	('CpG loci', 'Gene', (73, 81))
152194	19638575	Using one of the largest case series studies of these diseases and focusing on epigenetic alteration, we demonstrate that methylation profiling can differentiate lung adenocarcinoma, mesothelioma, and non-malignant tissues.	('methylation', 'Var', (122, 133))	('lung adenocarcinoma', 'Disease', (162, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (162, 181))	('mesothelioma', 'Disease', (183, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (162, 181))
152220	19638575	Methylation classes significantly predicted of tumor type (P < 0.0001).	('predicted', 'Reg', (34, 43))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
152229	19638575	Lung adenocarcinomas had six pathways with significant enrichment (Fisher's P < 0.05) of methylated gene-loci versus mesothelioma including Cell Cycle Regulation, DNA Damage Response, PTEN Signaling, and Apoptosis Signaling.	('Signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('adenocarcinomas', 'Disease', (5, 20))	('PTEN', 'Gene', (184, 188))	('methylated', 'Var', (89, 99))	('Cell Cycle Regulation', 'biological_process', 'GO:0051726', ('140', '161'))	('mesothelioma', 'Disease', (117, 129))	('Cell Cycle', 'CPA', (140, 150))	('PTEN', 'Gene', '5728', (184, 188))	('Apoptosis Signaling', 'biological_process', 'GO:0006915', ('204', '223'))	('DNA Damage Response', 'biological_process', 'GO:0006974', ('163', '182'))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('Lung adenocarcinomas', 'Phenotype', 'HP:0030078', (0, 20))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('adenocarcinomas', 'Disease', 'MESH:D000230', (5, 20))
152239	19638575	In an analysis restricted to tumors, we demonstrated the great extent to which CpG methylation varies between mesothelioma and lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mesothelioma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 146))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('methylation', 'Var', (83, 94))	('tumors', 'Disease', (29, 35))	('varies', 'Reg', (95, 101))
152245	19638575	Significant smoking-related and asbestos-related methylation-induced gene inactivation events have been described in lung adenocarcinoma and mesothelioma respectively.	('lung adenocarcinoma and mesothelioma', 'Disease', 'MESH:D000077192', (117, 153))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('methylation-induced', 'Var', (49, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('gene', 'MPA', (69, 73))
152247	19638575	In a locus-by-locus analysis of tumor samples, over one thousand CpG loci were differentially methylated between tumor types.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('differentially', 'Reg', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('methylated', 'Var', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CpG loci', 'Gene', (65, 73))	('tumor', 'Disease', (32, 37))
152253	19638575	Pathways analysis of differentially methylated CpG loci suggested that there is significant, tumor-type-specific enrichment for methylation-based silencing of genes in specific pathways.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('methylation-based', 'Var', (128, 145))	('tumor', 'Disease', (93, 98))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('genes', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
152255	19638575	For example, the enrichment for methylation inactivation of differential cytokine signaling pathway genes (IL-6 Signaling in lung adenocarcinoma and Fc Epsilon Signaling in mesothelioma) could represent a differential immune-regulated inflammatory response to the primary carcinogens of tobacco smoke and asbestos for these tumors.	('mesothelioma', 'Disease', 'MESH:D008654', (173, 185))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('methylation inactivation', 'Var', (32, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('Fc Epsilon Signaling', 'MPA', (149, 169))	('signaling pathway', 'biological_process', 'GO:0007165', ('82', '99'))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumors', 'Disease', (324, 330))	('asbestos', 'Chemical', 'MESH:D001194', (305, 313))	('inflammatory response', 'biological_process', 'GO:0006954', ('235', '256'))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('Signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('Signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('lung adenocarcinoma', 'Disease', (125, 144))	('tobacco', 'Species', '4097', (287, 294))	('IL-6', 'molecular_function', 'GO:0005138', ('107', '111'))	('mesothelioma', 'Disease', (173, 185))
152257	19638575	Alternatively, but not mutually exclusively, the epigenetic status of the genes in these pathways in the stem cells that give rise to these tissues could differ, contributing to the observed differences between these tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('differences', 'MPA', (191, 202))	('epigenetic status', 'Var', (49, 66))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('contributing', 'Reg', (162, 174))
152281	12189542	All had adequate haematological parameters (total leucocyte count >3.0x109 l-1; granulocyte count >1.5x109 l-1; platelet count >100x109 l-1; and haemoglobin >10 g dl-1), adequate renal function (serum creatinine <120 mumol l-1), and adequate hepatic function (total bilirubin <1.5xupper limit of normal (ULN); alanine transaminase and alkaline phosphatase <3xULN).	('>100x109 l-1', 'Var', (127, 139))	('phosphatase', 'molecular_function', 'GO:0016791', ('344', '355'))	('creatinine', 'Chemical', 'MESH:D003404', (201, 211))	('renal function', 'MPA', (179, 193))	('bilirubin', 'Chemical', 'MESH:D001663', (266, 275))	('>3.0x109', 'Var', (66, 74))
152301	12189542	Serum creatinine >150 mumol l-1 led to treatment delay.	('creatinine', 'Chemical', 'MESH:D003404', (6, 16))	('Serum creatinine', 'MPA', (0, 16))	('>150', 'Var', (17, 21))	('treatment', 'Disease', (39, 48))
152386	12189542	There is, however, some consensus that schedules using cisplatin 100 mg m-2 on day 1 of a 28 day cycle are less able to deliver the full dose of gemcitabine due to frequent dose omissions and reductions for haematological toxicity on day 15 (Abratt et al, 1998).	('toxicity', 'Disease', 'MESH:D064420', (222, 230))	('less', 'NegReg', (107, 111))	('toxicity', 'Disease', (222, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('dose', 'MPA', (173, 177))	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('reductions', 'NegReg', (192, 202))	('cisplatin', 'Var', (55, 64))
152448	31773090	It was found that three of the PC organoids contained homozygous deletions of the gene encoding chromodomain helicase DNA binding protein 1 (CHD1), which is the second most commonly deleted gene in prostate cancer.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('DNA binding', 'molecular_function', 'GO:0003677', ('118', '129'))	('prostate cancer', 'Disease', (198, 213))	('PC', 'Phenotype', 'HP:0012125', (31, 33))	('PC', 'Disease', 'MESH:D011471', (31, 33))	('chromodomain helicase DNA binding protein 1', 'Gene', (96, 139))	('CHD1', 'Gene', (141, 145))	('deletions', 'Var', (65, 74))	('chromodomain helicase DNA binding protein 1', 'Gene', '1105', (96, 139))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('prostate cancer', 'Disease', 'MESH:D011471', (198, 213))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))	('CHD1', 'Gene', '1105', (141, 145))
152449	31773090	In addition, six of the seven PC organoid lines contained homozygous deletions of PTEN, and one of the PC organoids harbored an amplification of the gene encoding androgen receptor (AR), which is found in approximately 50% of CRPC.	('PC', 'Disease', 'MESH:D011471', (30, 32))	('PTEN', 'Gene', '5728', (82, 86))	('androgen receptor', 'Gene', (163, 180))	('PC', 'Phenotype', 'HP:0012125', (103, 105))	('PC', 'Disease', 'MESH:D011471', (103, 105))	('deletions', 'Var', (69, 78))	('androgen receptor', 'Gene', '367', (163, 180))	('PTEN', 'Gene', (82, 86))	('PC', 'Phenotype', 'HP:0012125', (228, 230))	('AR', 'Gene', '367', (182, 184))	('PC', 'Disease', 'MESH:D011471', (228, 230))	('PC', 'Phenotype', 'HP:0012125', (30, 32))
152451	31773090	Four PC organoids had mutations in TP53 gene, which is the most commonly mutated gene in CRPC.	('PC', 'Disease', 'MESH:D011471', (5, 7))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('PC', 'Phenotype', 'HP:0012125', (5, 7))	('mutations', 'Var', (22, 31))	('PC', 'Phenotype', 'HP:0012125', (91, 93))	('PC', 'Disease', 'MESH:D011471', (91, 93))
152452	31773090	The PC organoid that was derived from circulating tumor cells, rather than the metastatic biopsies, harbored a mutation in the SPOP gene, which encodes an E3 ubiquitin ligase and is the most commonly mutated gene in primary prostate cancers.	('SPOP', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('primary prostate cancers', 'Disease', 'MESH:D011471', (216, 240))	('ubiquitin', 'molecular_function', 'GO:0031386', ('158', '167'))	('prostate cancer', 'Phenotype', 'HP:0012125', (224, 239))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('PC', 'Phenotype', 'HP:0012125', (4, 6))	('PC', 'Disease', 'MESH:D011471', (4, 6))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('prostate cancers', 'Phenotype', 'HP:0012125', (224, 240))	('SPOP', 'Gene', '8405', (127, 131))	('mutation', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('primary prostate cancers', 'Disease', (216, 240))
152456	31773090	The PC organoid that harbored an AR amplification was extremely sensitive to enzalutamide, with an IC-50 of approximately 50 nmol/L, in comparison with the PC organoids that were lacking this amplification and were, as expected, resistant to this agent.	('PC', 'Disease', 'MESH:D011471', (156, 158))	('AR', 'Gene', '367', (33, 35))	('sensitive', 'MPA', (64, 73))	('amplification', 'Var', (36, 49))	('PC', 'Disease', 'MESH:D011471', (4, 6))	('PC', 'Phenotype', 'HP:0012125', (4, 6))	('PC', 'Phenotype', 'HP:0012125', (156, 158))	('enzalutamide', 'Chemical', 'MESH:C540278', (77, 89))
152458	31773090	It was also found that the PC organoid line, which harbored both the PTEN and PIK3R1 mutations, was sensitive to everolimus and BKM-120, in keeping with the targets of these drugs.	('PIK3R1', 'Gene', (78, 84))	('PTEN', 'Gene', '5728', (69, 73))	('PC', 'Phenotype', 'HP:0012125', (27, 29))	('everolimus', 'Chemical', 'MESH:C107135', (113, 123))	('mutations', 'Var', (85, 94))	('PC', 'Disease', 'MESH:D011471', (27, 29))	('sensitive', 'MPA', (100, 109))	('PIK3R1', 'Gene', '5295', (78, 84))	('PTEN', 'Gene', (69, 73))
152476	31773090	Similarly, the mutant BRCA1/2 signature of the BC organoids correlated well with their sensitivity to PARPi.	('PARP', 'Gene', (102, 106))	('BC', 'Phenotype', 'HP:0003002', (47, 49))	('BRCA1', 'Gene', '672', (22, 27))	('PARP', 'Gene', '1302', (102, 106))	('BC', 'Disease', 'MESH:D001943', (47, 49))	('mutant', 'Var', (15, 21))	('BRCA1', 'Gene', (22, 27))
152484	31773090	Among the 69 PDAC organoids with patient clinical data available, 96% had KRAS mutation, and 88% harbored TP53 mutations as well as numerous mutations in genes like CDKN2A and SMAD4.	('mutations', 'Var', (111, 120))	('patient', 'Species', '9606', (33, 40))	('PDAC', 'Phenotype', 'HP:0006725', (13, 17))	('SMAD4', 'Gene', '4089', (176, 181))	('PDAC', 'Disease', 'MESH:D021441', (13, 17))	('PDAC', 'Disease', (13, 17))	('CDKN2A', 'Gene', (165, 171))	('KRAS', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))	('KRAS', 'Gene', '3845', (74, 78))	('CDKN2A', 'Gene', '1029', (165, 171))	('SMAD4', 'Gene', (176, 181))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
152485	31773090	On average, 97.43% of the mutations that were detected in the primary tumor specimen were also detected in the organoids.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (26, 35))	('men', 'Species', '9606', (81, 84))	('detected', 'Reg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
152506	31773090	The research team also investigated whether or not the cultured organoids could serve as models for phenotypes associated with the two most frequently seen mutations in ductal pancreatic cancer, mutant KRAS and TP53.	('pancreatic cancer', 'Disease', (176, 193))	('TP53', 'Gene', '7157', (211, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('KRAS', 'Gene', '3845', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('TP53', 'Gene', (211, 215))	('KRAS', 'Gene', (202, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('mutant', 'Var', (195, 201))
152507	31773090	Both mutant KRAS and TP53-infected cells had higher proliferation rates compared to the negative control.	('TP53', 'Gene', (21, 25))	('proliferation rates', 'CPA', (52, 71))	('KRAS', 'Gene', (12, 16))	('mutant', 'Var', (5, 11))	('KRAS', 'Gene', '3845', (12, 16))	('higher', 'PosReg', (45, 51))	('TP53', 'Gene', '7157', (21, 25))
152513	31773090	However, positive results were found when targeted therapies were utilized, and organoids and parental tumors alike that harbored the EZH2 mutation responded well to UNC1999, an inhibitor of EZH2, when combined with gemcitabine.	('parental tumors', 'Disease', 'MESH:D063129', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('responded', 'MPA', (148, 157))	('parental tumors', 'Disease', (94, 109))	('mutation', 'Var', (139, 147))	('gemcitabine', 'Chemical', 'MESH:C056507', (216, 227))	('EZH2', 'Gene', '2146', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('EZH2', 'Gene', (134, 138))	('EZH2', 'Gene', (191, 195))	('EZH2', 'Gene', '2146', (191, 195))
152524	31773090	Whole-genome profiling of the paired EGD and surgical organoids, as well as the whole-tumor lysates, demonstrated fewer copy number variation.	('tumor', 'Disease', (86, 91))	('copy number', 'Var', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
152525	31773090	PCR assays identified similar KRAS alterations in the primary tumor and paired organoids.	('alterations', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PC', 'Phenotype', 'HP:0012125', (0, 2))	('KRAS', 'Gene', '3845', (30, 34))	('tumor', 'Disease', (62, 67))	('PC', 'Disease', 'MESH:D011471', (0, 2))	('KRAS', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
152526	31773090	This finding highlights the ability of this method to maintain genetic alterations from primary tumor to both surgical and endoscopic organoids.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('genetic alterations', 'Var', (63, 82))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
152537	31773090	The authors first confirmed the validity of using organoids as tumor models via analyzing histology, immunohistochemistry, genome sequencing, copy number alterations, and 3-day drug screening assays.	('tumor', 'Disease', (63, 68))	('copy number alterations', 'Var', (142, 165))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
152576	31773090	Next-generation sequencing studies were also conducted, which found mutations that corresponded with the parental tissue, for example CTNNB1 missense mutations in HCC, TP53 frameshift mutations in CHC, and KRAS mutations in both CC and CHC.	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('CC', 'Disease', 'MESH:D018281', (164, 166))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('KRAS', 'Gene', '3845', (206, 210))	('CHC', 'Gene', (236, 239))	('CHC', 'Gene', (197, 200))	('CTNNB1', 'Gene', (134, 140))	('CC', 'Phenotype', 'HP:0030153', (229, 231))	('frameshift mutations', 'Var', (173, 193))	('CTNNB1', 'Gene', '1499', (134, 140))	('missense mutations', 'Var', (141, 159))	('CC', 'Phenotype', 'HP:0030153', (164, 166))	('HCC', 'Disease', 'MESH:D006528', (163, 166))	('CC', 'Disease', 'MESH:D018281', (229, 231))	('KRAS', 'Gene', (206, 210))	('HCC', 'Disease', (163, 166))
152579	31773090	Drug testing was performed on the tumor organoids utilizing the following clinically relevant compounds: Taselisib, Gemcitabine, AZD8931, SCH772984, and Dasatinib.	('Dasatinib', 'Chemical', 'MESH:C488369', (153, 162))	('Gemcitabine', 'Chemical', 'MESH:C056507', (116, 127))	('tumor', 'Disease', (34, 39))	('AZD8931', 'Var', (129, 136))	('SCH772984', 'Var', (138, 147))	('AZD8931', 'Chemical', 'MESH:C548875', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('SCH772984', 'Chemical', 'MESH:C587178', (138, 147))
152580	31773090	Interestingly, the research team found that treatment with SCH772984, an ERK1/2 inhibitor, leads to significant suppression of organoid formation via selectively inhibiting ERK-phosphorylation in HCC and CC organoids.	('CC', 'Phenotype', 'HP:0030153', (204, 206))	('phosphorylation', 'biological_process', 'GO:0016310', ('177', '192'))	('ERK1', 'molecular_function', 'GO:0004707', ('73', '77'))	('CC', 'Phenotype', 'HP:0030153', (197, 199))	('ERK', 'molecular_function', 'GO:0004707', ('173', '176'))	('CC', 'Disease', 'MESH:D018281', (204, 206))	('CC', 'Disease', 'MESH:D018281', (197, 199))	('inhibiting', 'NegReg', (162, 172))	('suppression', 'NegReg', (112, 123))	('ERK', 'Gene', '5594', (73, 76))	('men', 'Species', '9606', (49, 52))	('SCH772984', 'Var', (59, 68))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('HCC', 'Disease', (196, 199))	('SCH772984', 'Chemical', 'MESH:C587178', (59, 68))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('ERK', 'Gene', '5594', (173, 176))	('ERK', 'Gene', (73, 76))	('ERK', 'Gene', (173, 176))	('HCC', 'Disease', 'MESH:D006528', (196, 199))	('organoid formation', 'MPA', (127, 145))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))
152593	31773090	Eighty percentage of the organoids showed TP53 mutations.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
152594	31773090	The main esophageal adenocarcinoma driver mutations (CDKN2A, KCNQ3, and PIK3CA) were also maintained in the organoids.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (9, 34))	('esophageal adenocarcinoma', 'Disease', (9, 34))	('CDKN2A', 'Gene', (53, 59))	('KCNQ3', 'Gene', '3786', (61, 66))	('CDKN2A', 'Gene', '1029', (53, 59))	('PIK3CA', 'Gene', (72, 78))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (9, 34))	('PIK3CA', 'Gene', '5290', (72, 78))	('mutations', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('KCNQ3', 'Gene', (61, 66))
152595	31773090	However, a higher frequency of driver mutations was found in organoids than in the parental tumors, possibly due to the pure tumor cellularity of the organoids.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('pure', 'molecular_function', 'GO:0034023', ('120', '124'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (92, 97))	('mutations', 'Var', (38, 47))	('parental tumors', 'Disease', 'MESH:D063129', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('parental tumors', 'Disease', (83, 98))
152598	31773090	The organoid genomes were relatively stable, showing less than 25% increase in the total number of mutations, none of which influenced the various cancer drivers.	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))
152612	31773090	For example, the organoids contained mutations most commonly seen in nonmuscle-invasive bladder cancers, including ARID1A, KMT2C, KMT2D, KDM6A, and FGFR3.	('nonmuscle-invasive bladder cancers', 'Disease', (69, 103))	('ARID1A', 'Gene', '8289', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('KMT2C', 'Gene', '58508', (123, 128))	('KMT2C', 'Gene', (123, 128))	('FGFR3', 'Gene', (148, 153))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('KDM6A', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('KMT2D', 'Gene', '8085', (130, 135))	('FGFR3', 'Gene', '2261', (148, 153))	('bladder cancers', 'Phenotype', 'HP:0009725', (88, 103))	('nonmuscle-invasive bladder', 'Phenotype', 'HP:0000011', (69, 95))	('mutations', 'Var', (37, 46))	('invasive bladder', 'Phenotype', 'HP:0100645', (79, 95))	('nonmuscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (69, 103))	('KDM6A', 'Gene', '7403', (137, 142))	('KMT2D', 'Gene', (130, 135))	('ARID1A', 'Gene', (115, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('148', '152'))
152613	31773090	Interestingly, only 33% of the organoids derived from muscle-invasive bladder cancers harbored TP53 mutations, compared to the reported frequency of 50% in this subpopulation.	('mutations', 'Var', (100, 109))	('invasive bladder', 'Phenotype', 'HP:0100645', (61, 77))	('bladder cancers', 'Phenotype', 'HP:0009725', (70, 85))	('muscle-invasive bladder cancers', 'Disease', (54, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('muscle-invasive bladder cancers', 'Disease', 'MESH:D001749', (54, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('harbored', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
152614	31773090	The rates of Rb mutations in organoids were lower than patient tumors as well.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (16, 25))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('patient', 'Species', '9606', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
152618	31773090	For example, two organoids that are sensitive to the treatment of MEK inhibitor trametinib and ERK inhibitor SCH772984 also contain activating mutations in the FGFR3 gene.	('FGFR3', 'Gene', (160, 165))	('ERK', 'Gene', '5594', (95, 98))	('ERK', 'Gene', (95, 98))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))	('SCH772984', 'Chemical', 'MESH:C587178', (109, 118))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))	('FGFR3', 'Gene', '2261', (160, 165))	('trametinib', 'Chemical', 'MESH:C560077', (80, 90))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('activating', 'PosReg', (132, 142))	('men', 'Species', '9606', (58, 61))	('mutations', 'Var', (143, 152))
152770	30072395	miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells.	('inhibition', 'Var', (53, 63))	('miR-24-3p', 'Gene', (67, 76))	('growth', 'MPA', (85, 91))	('GTP', 'Chemical', 'MESH:D006160', (35, 38))	('reduced', 'NegReg', (77, 84))	('Rho-GTP activity', 'MPA', (31, 47))
152773	30072395	Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('cingulin', 'Gene', (44, 52))	('miR-24-3p', 'Var', (30, 39))	('inhibits', 'NegReg', (84, 92))	('GTP', 'Chemical', 'MESH:D006160', (97, 100))	('Rho-GTP', 'MPA', (93, 100))	('tight junction', 'cellular_component', 'GO:0070160', ('56', '70'))	('cingulin', 'Gene', '57530', (44, 52))
152788	30072395	We suggest that miR-24-3p shows oncogenic properties in MPM, and hypothesize that our miRNA screen may unveil relevant connections in cancer studies.	('miR-24-3p', 'Var', (16, 25))	('MPM', 'Disease', (56, 59))	('oncogenic', 'MPA', (32, 41))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
152831	30072395	The plasmids containing wild-type (Cat# HmiT088611-MT06) or mutant (Cat# CS-HmiT088611-MT06) Luc-CGN 3' UTR, wild-type (Cat# HmiT064331-MT06) or mutant (Cat# CS-HmiT064331-MT06) Luc-CXADR 3' UTR and wild-type (Cat# HmiT010922-MT06-01) or mutant (Cat# CS-HmiT010922--MT06-01) Luc-BCAM 3' UTR were synthesized (GeneCopoeia) and used in luciferase reporter assays.	('Cat', 'molecular_function', 'GO:0004096', ('68', '71'))	('BCAM', 'Gene', (279, 283))	('CXADR', 'Gene', (182, 187))	('Cat', 'molecular_function', 'GO:0004096', ('35', '38'))	('Cat', 'molecular_function', 'GO:0004096', ('246', '249'))	('HmiT010922--MT06-01', 'CellLine', 'CVCL:6F14', (254, 273))	('CXADR', 'Gene', '1525', (182, 187))	('Cat# CS-HmiT010922', 'Var', (246, 264))	('BCAM', 'Gene', '4059', (279, 283))	('Cat', 'molecular_function', 'GO:0004096', ('120', '123'))	('Cat', 'molecular_function', 'GO:0004096', ('153', '156'))	('HmiT010922-MT06-01', 'CellLine', 'CVCL:6F14', (215, 233))	('Cat', 'molecular_function', 'GO:0004096', ('210', '213'))	('mutant (Cat# CS-HmiT088611-MT06', 'Var', (60, 91))	('CGN', 'Gene', (97, 100))	('CGN', 'Gene', '57530', (97, 100))
152841	30072395	Finally, ratio of EDTA-treated/EDTA untreated miRNA polysome occupancy indicates that a restricted set of miRNAs dramatically changes its distribution, like miR-15a-5p, miR-16-5p, miR-24-3p, miR-191-5p and let-7g-5p (Figure 1C).	('EDTA', 'Chemical', 'MESH:D004492', (18, 22))	('distribution', 'MPA', (138, 150))	('EDTA', 'Chemical', 'MESH:D004492', (31, 35))	('let-7g-5p', 'Var', (206, 215))	('polysome', 'cellular_component', 'GO:0005844', ('52', '60'))	('miR-191-5p', 'Gene', '100302129', (191, 201))	('changes', 'Reg', (126, 133))	('miR-191-5p', 'Gene', (191, 201))	('miR-15a-5p', 'Var', (157, 167))	('miR-16', 'Gene', (169, 175))	('miR-24-3p', 'Var', (180, 189))	('miR-16', 'Gene', '51573', (169, 175))
152842	30072395	Notably, three of these miRNAs were already linked to MPM through previous analysis, miR-15/16 and miR-191-5p.	('miR-15/16', 'Var', (85, 94))	('MPM', 'Disease', (54, 57))	('linked', 'Reg', (44, 50))	('miR-191-5p', 'Gene', (99, 109))	('miR-191-5p', 'Gene', '100302129', (99, 109))
152844	30072395	The most significant polysome enriched miRNAs (miR-15a-5p, miR-16-5p, miR-24-3p, miR-191-5p and let-7g-5p) were commonly predicted to regulate genes in the cell cycle and in the TCR pathway (Supplementary Figure S1E).	('cell cycle', 'biological_process', 'GO:0007049', ('156', '166'))	('let-7g-5p', 'Var', (96, 105))	('TCR pathway', 'Pathway', (178, 189))	('regulate', 'Reg', (134, 142))	('miR-16', 'Gene', (59, 65))	('miR-15a-5p', 'Var', (47, 57))	('genes', 'Gene', (143, 148))	('miR-16', 'Gene', '51573', (59, 65))	('TCR', 'cellular_component', 'GO:0042101', ('178', '181'))	('miR-191-5p', 'Gene', (81, 91))	('miR-24-3p', 'Var', (70, 79))	('cell cycle', 'CPA', (156, 166))	('miR-191-5p', 'Gene', '100302129', (81, 91))	('TCR', 'biological_process', 'GO:0006283', ('178', '181'))	('polysome', 'cellular_component', 'GO:0005844', ('21', '29'))
152846	30072395	miR-24-3p was the only one not previously identified in MPM tumors by other approaches and was further analyzed.	('miR-24-3p', 'Var', (0, 9))	('MPM tumors', 'Disease', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MPM tumors', 'Disease', 'MESH:D009369', (56, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
152849	30072395	We found that miR-24-3p is expressed above the control in all primary mesothelioma cells analyzed (Figure 2B), as well in other tumor cell lines (Supplementary Figure S2).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miR-24-3p', 'Var', (14, 23))	('mesothelioma', 'Disease', (70, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))
152852	30072395	Next, we investigated the migratory role of miR-24-3p in MCF-7 cells, a metastatic breast cancer cell line, analyzing both miR-24-3p knockdown and overexpression.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR-24-3p', 'Var', (123, 132))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('MCF-7', 'CellLine', 'CVCL:0031', (57, 62))
152858	30072395	At autopsy, we observed a consistent reduction of metastasis formation and intraperitoneal hemorrhage in mice injected with REN cells depleted of miR-24-3p (Figure 4B).	('hemorrhage', 'Disease', 'MESH:D006470', (91, 101))	('metastasis formation', 'CPA', (50, 70))	('depleted', 'NegReg', (134, 142))	('reduction', 'NegReg', (37, 46))	('miR-24-3p', 'Var', (146, 155))	('hemorrhage', 'Disease', (91, 101))	('mice', 'Species', '10090', (105, 109))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))
152859	30072395	We measured total body, tumor mass and diaphragm weight and found that knockdown of miR-24-3p causes a significant reduction in tumor volume in vivo (Figure 4C and Supplementary Table S1).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('reduction', 'NegReg', (115, 124))	('tumor', 'Disease', (24, 29))	('knockdown', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('miR-24-3p', 'Gene', (84, 93))
152860	30072395	Several properties of malignant progression and migration have been attributed to aberrant signaling through RHO-GTPase proteins.	('migration', 'CPA', (48, 57))	('signaling', 'MPA', (91, 100))	('GTP', 'Chemical', 'MESH:D006160', (113, 116))	('malignant progression', 'CPA', (22, 43))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('RHO-GTPase proteins', 'Protein', (109, 128))	('aberrant', 'Var', (82, 90))
152862	30072395	We investigated RhoA activity in cells depleted for miR-24-3p or overexpressing it.	('investigated', 'Reg', (3, 15))	('miR-24-3p', 'Var', (52, 61))	('RhoA', 'Gene', (16, 20))	('RhoA', 'Gene', '387', (16, 20))
152863	30072395	RhoA-GTP pulldown assays showed that miR-24-3p knockdown causes a reduction of RhoA activity, in REN cells (Figure 5A), whereas miR-24-3p overexpression in MeT-5A cells caused an increment of RhoA activity (Figure 5B).	('RhoA', 'Gene', '387', (192, 196))	('RhoA', 'Gene', '387', (0, 4))	('GTP', 'Chemical', 'MESH:D006160', (5, 8))	('RhoA', 'Gene', '387', (79, 83))	('knockdown', 'Var', (47, 56))	('RhoA', 'Gene', (192, 196))	('RhoA', 'Gene', (0, 4))	('miR-24-3p', 'Gene', (37, 46))	('RhoA', 'Gene', (79, 83))	('reduction', 'NegReg', (66, 75))
152867	30072395	To bring order in this scenario we clustered, by Gene Ontology analysis, differentially expressed genes in functional groups and we observed that miR-24-3p modulates several mRNAs involved in cell adhesion and migration in REN and MM98 cells (Figure 6A).	('cell adhesion', 'CPA', (192, 205))	('Gene Ontology', 'biological_process', 'GO:0003673', ('49', '62'))	('mRNAs involved', 'MPA', (174, 188))	('modulates', 'Reg', (156, 165))	('miR-24-3p', 'Var', (146, 155))	('cell adhesion', 'biological_process', 'GO:0007155', ('192', '205'))	('MM98', 'CellLine', 'CVCL:V748', (231, 235))
152869	30072395	Thus, we shortlisted 33 genes that are bona fide direct targets of miR-24-3p (Supplementary Figure S5B).	('S5B', 'Gene', '5711', (99, 102))	('miR-24-3p', 'Var', (67, 76))	('S5B', 'Gene', (99, 102))	('genes', 'Gene', (24, 29))
152873	30072395	Our RNAseq data indicate that miR-24-3p hits relevant biological pathways in cancer, including cell motility and migration.	('biological pathways', 'Pathway', (54, 73))	('hits', 'Reg', (40, 44))	('cell motility', 'CPA', (95, 108))	('miR-24-3p', 'Var', (30, 39))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cell motility', 'biological_process', 'GO:0048870', ('95', '108'))	('migration', 'CPA', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
152876	30072395	In support of this idea, miR-24-3p expression in 293T cells is able to specifically decrease the activity of a luciferase reporter gene fused to the wild-type 3' UTR of CGN, whereas the presence of a mutant form of CGN 3' UTR has no effect on the luciferase activity (Figure 6B right).	('decrease', 'NegReg', (84, 92))	('CGN', 'Gene', (169, 172))	('luciferase activity', 'molecular_function', 'GO:0047077', ('247', '266'))	('activity', 'MPA', (258, 266))	('CGN', 'Gene', (215, 218))	('CGN', 'Gene', '57530', (169, 172))	('CGN', 'Gene', '57530', (215, 218))	('293T', 'CellLine', 'CVCL:0063', (49, 53))	('luciferase reporter gene', 'Enzyme', (111, 135))	('luciferase activity', 'molecular_function', 'GO:0047712', ('247', '266'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('247', '266'))	('activity', 'MPA', (97, 105))	('luciferase activity', 'molecular_function', 'GO:0050397', ('247', '266'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('247', '266'))	('miR-24-3p expression', 'Var', (25, 45))	('fused', 'Var', (136, 141))
152878	30072395	Next, we validated the changes of cingulin, BCAM and CXADR mRNAs in REN, MM98 and MSTO-211H cells, after miR-24-3p partial depletion (Fig.	('BCAM', 'Gene', '4059', (44, 48))	('changes', 'Reg', (23, 30))	('cingulin', 'Gene', '57530', (34, 42))	('MSTO-211H', 'CellLine', 'CVCL:1430', (82, 91))	('cingulin', 'Gene', (34, 42))	('MM98', 'CellLine', 'CVCL:V748', (73, 77))	('BCAM', 'Gene', (44, 48))	('CXADR', 'Gene', (53, 58))	('partial depletion', 'Var', (115, 132))	('CXADR', 'Gene', '1525', (53, 58))
152882	30072395	As expected, we found that miR-24-3p reduction induces an increase in cingulin protein levels in REN, MM98 and MSTO-211H (Figure 6F).	('increase', 'PosReg', (58, 66))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('cingulin', 'Gene', '57530', (70, 78))	('cingulin', 'Gene', (70, 78))	('miR-24-3p reduction', 'Var', (27, 46))	('MSTO-211H', 'CellLine', 'CVCL:1430', (111, 120))	('MM98', 'CellLine', 'CVCL:V748', (102, 106))
152884	30072395	The total loss of cingulin protein in miR-24-3p overexpression conditions (Figure 6H), combined with a partial reduction of cingulin mRNA transcript levels, suggests that, as hypothesized, miR-24-3p is able to regulate cingulin expression first at the translation level, and subsequently at the mRNA stability level (Supplementary Figure S5F).	('reduction', 'NegReg', (111, 120))	('translation', 'biological_process', 'GO:0006412', ('252', '263'))	('cingulin', 'Gene', '57530', (219, 227))	('cingulin', 'Gene', (219, 227))	('miR-24-3p', 'Var', (38, 47))	('cingulin', 'Gene', '57530', (18, 26))	('cingulin', 'Gene', '57530', (124, 132))	('cingulin', 'Gene', (18, 26))	('regulate', 'Reg', (210, 218))	('cingulin', 'Gene', (124, 132))	('loss', 'NegReg', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
152886	30072395	We analyzed cingulin mRNA distribution along the polysomal profile of normal or miR-24-3p knockdown REN cells and found that reduced levels of miR-24-3p cause an accumulation of cingulin mRNA in highly translating polysomes (Figure 7B).	('cingulin', 'Gene', '57530', (178, 186))	('cingulin', 'Gene', (178, 186))	('miR-24-3p', 'Var', (143, 152))	('reduced', 'NegReg', (125, 132))	('accumulation', 'PosReg', (162, 174))	('cingulin', 'Gene', '57530', (12, 20))	('cingulin', 'Gene', (12, 20))
152889	30072395	Next, we investigated the distribution of cingulin mRNA in MeT-5A cells that expressed miR-24-3p, compared to control.	('miR-24-3p', 'Var', (87, 96))	('cingulin', 'Gene', '57530', (42, 50))	('cingulin', 'Gene', (42, 50))
152891	30072395	Data show that cingulin mRNA has a shorter half-life in cells with increased miR-24-3p.	('miR-24-3p', 'Var', (77, 86))	('shorter', 'NegReg', (35, 42))	('increased', 'PosReg', (67, 76))	('cingulin', 'Gene', '57530', (15, 23))	('cingulin', 'Gene', (15, 23))
152892	30072395	Finally, the striking regulation of cingulin driven by miR-24-3p led us to address whether cingulin expression is related to the survival of MPM patients.	('cingulin', 'Gene', (91, 99))	('patients', 'Species', '9606', (145, 153))	('miR-24-3p', 'Var', (55, 64))	('MPM', 'Disease', (141, 144))	('cingulin', 'Gene', '57530', (36, 44))	('regulation', 'biological_process', 'GO:0065007', ('22', '32'))	('cingulin', 'Gene', (36, 44))	('related', 'Reg', (114, 121))	('cingulin', 'Gene', '57530', (91, 99))
152896	30072395	In addition, we identified miR-24-3p, a polysome-associated miRNA, which is expressed in MPM and in other solid tumors.	('solid tumors', 'Disease', (106, 118))	('polysome', 'cellular_component', 'GO:0005844', ('40', '48'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-24-3p', 'Var', (27, 36))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
152899	30072395	Our experiments identified, beside miR-24-3p, let-7 and miR-191-5p, which are well established in connection to cancer.	('miR-191-5p', 'Gene', (56, 66))	('cancer', 'Disease', (112, 118))	('miR-191-5p', 'Gene', '100302129', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('miR-24-3p', 'Var', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('let-7', 'Gene', (46, 51))
152903	30072395	According to the literature, miR-24-3p has been described either as a pro-oncogenic or as a tumor suppressor.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('miR-24-3p', 'Var', (29, 38))
152904	30072395	In the past, reports of a tumor suppressor role for miR-24-3p relied on the use of a mimic miRNA in cells normally devoid of it, without parallel down-regulation experiments.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('miR-24-3p', 'Var', (52, 61))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
152905	30072395	We conclude that in physiological conditions, miR-24-3p positively regulates migratory properties, rather than suppressing cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('regulates', 'Reg', (67, 76))	('migratory properties', 'CPA', (77, 97))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('miR-24-3p', 'Var', (46, 55))
152906	30072395	Supporting the conclusion of miR-24-3p acting as an oncogenic facilitator, PRECOG analysis showed that the expression of the vast majority of the common targets of miR-24-3p in MPM, is down-regulated in the progression of most tumors.	('down-regulated', 'NegReg', (185, 199))	('miR-24-3p', 'Var', (164, 173))	('MPM', 'Gene', (177, 180))	('tumors', 'Disease', (227, 233))	('expression', 'MPA', (107, 117))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
152908	30072395	As we have shown in Figure 7, cingulin protein is annihilated by miR-24-3p, but its mRNA is not.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('cingulin', 'Gene', '57530', (30, 38))	('cingulin', 'Gene', (30, 38))	('miR-24-3p', 'Var', (65, 74))	('annihilated', 'NegReg', (50, 61))
152911	30072395	Interfering with the Rho-kinase pathway may inhibit migration and invasion of NSCLC.	('Rho-kinase pathway', 'Pathway', (21, 39))	('Interfering', 'Var', (0, 11))	('inhibit', 'NegReg', (44, 51))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
152912	30072395	Hyperactivation of the Rho pathway is generally associated with more aggressive tumour properties and RhoA expression is associated with a significant reduction of survival of MPM patients.	('MPM', 'Disease', (176, 179))	('more', 'PosReg', (64, 68))	('aggressive tumour', 'Disease', (69, 86))	('Rho pathway', 'Pathway', (23, 34))	('survival', 'CPA', (164, 172))	('Hyperactivation', 'Var', (0, 15))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('RhoA', 'Gene', (102, 106))	('aggressive tumour', 'Disease', 'MESH:D001523', (69, 86))	('expression', 'Var', (107, 117))	('RhoA', 'Gene', '387', (102, 106))	('reduction', 'NegReg', (151, 160))	('patients', 'Species', '9606', (180, 188))
152913	30072395	miR-24-3p controls RhoA activity through at least one target, cingulin.	('controls', 'Reg', (10, 18))	('miR-24-3p', 'Var', (0, 9))	('RhoA', 'Gene', (19, 23))	('cingulin', 'Gene', '57530', (62, 70))	('cingulin', 'Gene', (62, 70))	('RhoA', 'Gene', '387', (19, 23))
152915	30072395	Besides cingulin, discussed above, also CXADR, a transmembrane protein involved in TJ structure and function, is regulated by miR-24-3p and is essential for TJ integrity.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('transmembrane', 'cellular_component', 'GO:0016021', ('49', '62'))	('miR-24-3p', 'Var', (126, 135))	('regulated', 'Reg', (113, 122))	('cingulin', 'Gene', '57530', (8, 16))	('cingulin', 'Gene', (8, 16))	('CXADR', 'Gene', (40, 45))	('transmembrane', 'cellular_component', 'GO:0044214', ('49', '62'))	('CXADR', 'Gene', '1525', (40, 45))
152916	30072395	Even if miR-24-3p affects migration in all tested cells, including the MCF-7 metastatic breast cancer cells, its primary identification in mesothelioma is intriguing.	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('miR-24-3p', 'Var', (8, 17))	('MCF-7', 'CellLine', 'CVCL:0031', (71, 76))	('migration', 'CPA', (26, 35))	('mesothelioma', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('affects', 'Reg', (18, 25))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
152920	30072395	In summary, with our study we propose an original approach for identifying novel miRNAs with relevant function in cancer biology and we suggest that miR-24-3p expression is relevant for cancer progression and metastasization.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-24-3p', 'Var', (149, 158))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
152932	27134571	We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases.	('human', 'Species', '9606', (20, 25))	('CD26', 'Gene', (64, 68))	('CD26', 'Gene', '1803', (64, 68))	('YS110', 'Chemical', '-', (50, 55))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('YS110', 'Var', (50, 55))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))
152934	27134571	We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules.	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('147', '167'))	('cell cycle', 'biological_process', 'GO:0007049', ('125', '135'))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('YS110', 'Var', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('147', '167'))	('NCI-H2452', 'CellLine', 'CVCL:1553', (74, 83))	('tumor', 'Disease', (29, 34))	('YS110', 'Chemical', '-', (45, 50))	('MN', 'CellLine', 'CVCL:U508', (89, 91))
152935	27134571	In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('YS110', 'Var', (52, 57))	('pemetrexed', 'Chemical', 'MESH:D000068437', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('YS110', 'Chemical', '-', (52, 57))	('PMX', 'Chemical', 'MESH:D000068437', (91, 94))	('tumor', 'Disease', (67, 72))
152936	27134571	YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment.	('waf1', 'Gene', (245, 249))	('cyclin B1', 'Gene', '891', (268, 277))	('cyclin B1', 'Gene', (268, 277))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('216', '236'))	('cell', 'MPA', (216, 220))	('waf1', 'Gene', '1026', (245, 249))	('YS110', 'Chemical', '-', (186, 191))	('NCI-H2452 cells', 'CellLine', 'CVCL:1553', (38, 53))	('YS110', 'Var', (298, 303))	('p21', 'Gene', (237, 240))	('YS110', 'Chemical', '-', (298, 303))	('M phase', 'biological_process', 'GO:0000279', ('141', '148'))	('cyclin', 'molecular_function', 'GO:0016538', ('268', '274'))	('YS110', 'Chemical', '-', (0, 5))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('216', '236'))	('p21', 'Gene', '1026', (237, 240))	('increased', 'PosReg', (254, 263))	('decreased', 'NegReg', (282, 291))
152937	27134571	Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated.	('Ser216', 'Chemical', '-', (60, 66))	('cdc25C', 'Gene', '995', (52, 58))	('cdc2', 'Gene', '983', (35, 39))	('Inhibitory phosphorylation', 'MPA', (0, 26))	('Tyr15', 'Chemical', '-', (41, 46))	('cdc25C', 'Gene', (52, 58))	('Ser216', 'Var', (60, 66))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('cdc2', 'Gene', (52, 56))	('cdc2', 'Gene', (35, 39))	('elevated', 'PosReg', (73, 81))	('cdc2', 'Gene', '983', (52, 56))
152938	27134571	Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment.	('Thr202/Tyr204', 'Var', (80, 93))	('MAPK', 'Gene', (47, 51))	('p38', 'Gene', '5594', (43, 46))	('ERK1/2', 'Gene', (72, 78))	('Thr180', 'Chemical', '-', (53, 59))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('ERK1/2', 'Gene', '5595;5594', (72, 78))	('ERK1', 'molecular_function', 'GO:0004707', ('72', '76'))	('augmented', 'PosReg', (100, 109))	('Thr180/Tyr182', 'Var', (53, 66))	('Thr202', 'Chemical', '-', (80, 86))	('Tyr182', 'Chemical', '-', (60, 66))	('Tyr204', 'Chemical', '-', (87, 93))	('p38', 'Gene', (43, 46))	('YS110', 'Chemical', '-', (124, 129))	('activating phosphorylation', 'MPA', (13, 39))	('MAPK', 'Gene', '5595;5594;5595', (47, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
152939	27134571	PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.	('PMX', 'Chemical', 'MESH:D000068437', (0, 3))	('MIB-1', 'Gene', (171, 176))	('cell surface', 'cellular_component', 'GO:0009986', ('39', '51'))	('YS110', 'Var', (80, 85))	('expression', 'MPA', (25, 35))	('MIB-1', 'Gene', '57534', (171, 176))	('PMX', 'Chemical', 'MESH:D000068437', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD26', 'Gene', (20, 24))	('CD26', 'Gene', '1803', (20, 24))	('reduction', 'NegReg', (154, 163))	('tumor', 'Disease', (112, 117))	('YS110', 'Chemical', '-', (80, 85))	('inhibited', 'NegReg', (94, 103))	('induced', 'Reg', (12, 19))
152940	27134571	This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.	('cell cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('regulation', 'Reg', (165, 175))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('G2/M cell cycle delay', 'CPA', (135, 156))	('YS110', 'Chemical', '-', (110, 115))	('YS110', 'Var', (110, 115))	('CD26', 'Gene', (85, 89))	('anti-proliferative', 'MPA', (34, 52))	('human', 'Species', '9606', (70, 75))	('CD26', 'Gene', '1803', (85, 89))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('quantity', 'MPA', (179, 187))	('activity', 'MPA', (192, 200))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('cell cycle', 'biological_process', 'GO:0007049', ('212', '222'))
152944	27134571	EPP followed by high-dose radiation therapy (RT) has been shown to prolong median survival to 33.8 months in patients with Stage 1 and Stage 2 MM but survival remained 10 months in patients with Stage 3 and Stage 4 MM.	('median survival', 'MPA', (75, 90))	('patients', 'Species', '9606', (109, 117))	('prolong', 'PosReg', (67, 74))	('patients', 'Species', '9606', (181, 189))	('EPP', 'Var', (0, 3))
152958	27134571	We have previously reported the anti-tumor effects of YS110 against MM cells.	('YS110', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('MM cells', 'CPA', (68, 76))	('YS110', 'Var', (54, 59))
152965	27134571	YS110 inhibited growth of YS110 with G2/M cell cycle arrest and altered the expression or phosphorylation state of cell cycle molecules.	('growth', 'MPA', (16, 22))	('YS110', 'Chemical', '-', (26, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('YS110', 'Chemical', '-', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (53, 59))	('arrest', 'Disease', (53, 59))	('expression', 'MPA', (76, 86))	('inhibited', 'NegReg', (6, 15))	('cell cycle', 'biological_process', 'GO:0007049', ('115', '125'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('42', '59'))	('phosphorylation state', 'MPA', (90, 111))	('YS110', 'Var', (26, 31))	('altered', 'Reg', (64, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))	('YS110', 'Var', (0, 5))
152968	27134571	YS110 inhibits proliferation of the mesothelioma cell line NCI-H2452 in a concentration-dependent manner (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('inhibits', 'NegReg', (6, 14))	('YS110', 'Chemical', '-', (0, 5))	('proliferation', 'CPA', (15, 28))	('mesothelioma', 'Disease', (36, 48))	('NCI-H2452', 'CellLine', 'CVCL:1553', (59, 68))	('YS110', 'Var', (0, 5))
152973	27134571	On the average of ten experiments, the percentage of G2/M phase cells were significantly increased after YS110 treatment (p < 0.05) (Fig.	('YS110', 'Chemical', '-', (105, 110))	('M phase', 'biological_process', 'GO:0000279', ('56', '63'))	('G2/M phase cells', 'CPA', (53, 69))	('YS110', 'Var', (105, 110))	('increased', 'PosReg', (89, 98))
152974	27134571	Furthermore, in another CD26 positive MM cell line NCI-H28, the percentage of cells in G2/M phase increased by 5 % on the average after YS110 treatment though its significance could not be proved statistically (data not shown).	('YS110', 'Chemical', '-', (136, 141))	('CD26', 'Gene', '1803', (24, 28))	('increased', 'PosReg', (98, 107))	('NCI-H28', 'CellLine', 'CVCL:1555', (51, 58))	('YS110', 'Var', (136, 141))	('CD26', 'Gene', (24, 28))	('M phase', 'biological_process', 'GO:0000279', ('90', '97'))
152975	27134571	We investigated the alterations caused by YS110 treatment in the quantity and activation state of cell cycle regulators responsible for G2/M transition.	('cell cycle', 'biological_process', 'GO:0007049', ('98', '108'))	('YS110', 'Chemical', '-', (42, 47))	('YS110', 'Var', (42, 47))	('activation', 'MPA', (78, 88))
152978	27134571	Cdc25C phosphorylated on Ser216 is known to be sequestrated into cytoplasm and refrained from contact with cdc2.	('cdc2', 'Gene', '983', (107, 111))	('Cdc25C', 'Gene', '995', (0, 6))	('Ser216', 'Chemical', '-', (25, 31))	('Ser', 'cellular_component', 'GO:0005790', ('25', '28'))	('cdc2', 'Gene', (107, 111))	('Ser216', 'Var', (25, 31))	('cytoplasm', 'cellular_component', 'GO:0005737', ('65', '74'))	('Cdc25C', 'Gene', (0, 6))
152982	27134571	Activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were elevated 24 h after YS110 treatment (Fig.	('p38', 'Gene', '5594', (30, 33))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('Tyr204', 'Chemical', '-', (74, 80))	('MAPK', 'Gene', '5595;5594;5595', (34, 38))	('ERK1/2', 'Gene', (59, 65))	('Activating phosphorylation', 'MPA', (0, 26))	('ERK1/2', 'Gene', '5595;5594', (59, 65))	('MAPK', 'Gene', (34, 38))	('Thr180', 'Chemical', '-', (40, 46))	('Thr202/Tyr204', 'Var', (67, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('Thr180/Tyr182', 'Var', (40, 53))	('p38', 'Gene', (30, 33))	('Tyr182', 'Chemical', '-', (47, 53))	('YS110', 'Chemical', '-', (107, 112))	('Thr202', 'Chemical', '-', (67, 73))	('ERK1', 'molecular_function', 'GO:0004707', ('59', '63'))	('elevated', 'PosReg', (87, 95))
152984	27134571	While the p38 inhibitor SB203580 failed to block G2/M arrest caused by YS110 (data not shown), the MEK1/2 inhibitor U0126 blocked G2/M arrest caused by YS110 according to cell cycle analysis using flowcytometry (Fig.	('YS110', 'Chemical', '-', (71, 76))	('M arrest', 'Disease', (52, 60))	('YS110', 'Var', (152, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('171', '181'))	('M arrest', 'Disease', 'MESH:D006323', (133, 141))	('MEK1', 'molecular_function', 'GO:0004708', ('99', '103'))	('SB203580', 'Chemical', 'MESH:C093642', (24, 32))	('p38', 'Gene', '5594', (10, 13))	('M arrest', 'Disease', (133, 141))	('MEK1/2', 'Gene', '5604;5605', (99, 105))	('M arrest', 'Disease', 'MESH:D006323', (52, 60))	('MEK1/2', 'Gene', (99, 105))	('YS110', 'Chemical', '-', (152, 157))	('U0126', 'Chemical', 'MESH:C113580', (116, 121))	('p38', 'Gene', (10, 13))
152992	27134571	Tumor size in mice treated with both YS110 and PMX was smaller than mice treated with only YS110 or PMX (data not shown).	('mice', 'Species', '10090', (68, 72))	('PMX', 'Chemical', 'MESH:D000068437', (100, 103))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('YS110', 'Chemical', '-', (37, 42))	('YS110', 'Chemical', '-', (91, 96))	('mice', 'Species', '10090', (14, 18))	('smaller', 'NegReg', (55, 62))	('Tumor size', 'CPA', (0, 10))	('YS110', 'Var', (37, 42))	('PMX', 'Chemical', 'MESH:D000068437', (47, 50))	('PMX', 'Var', (47, 50))
152993	27134571	The weight of tumors with YS110 treatment was insignificantly reduced (Fig.	('YS110', 'Chemical', '-', (26, 31))	('YS110 treatment', 'Var', (26, 41))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('reduced', 'NegReg', (62, 69))
152994	27134571	PMX treatment induced a significant reduction in tumor weight (p < 0.05); the combination of YS110 and PMX treatment synergistically reduced tumor weight compared with YS110 single treatment and PMX single treatment (p < 0.05).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PMX', 'Chemical', 'MESH:D000068437', (195, 198))	('PMX', 'Chemical', 'MESH:D000068437', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('YS110', 'Var', (93, 98))	('PMX', 'Chemical', 'MESH:D000068437', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PMX', 'Gene', (103, 106))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (49, 54))	('YS110', 'Chemical', '-', (168, 173))	('reduction in tumor', 'Disease', 'MESH:D009369', (36, 54))	('YS110', 'Chemical', '-', (93, 98))	('reduction in tumor', 'Disease', (36, 54))	('reduced', 'NegReg', (133, 140))
152996	27134571	The MIB-1 index was significantly decreased in tumors after YS110 or PMX single treatment compared with controls (p < 0.05; Fig.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('MIB-1', 'Gene', (4, 9))	('YS110', 'Chemical', '-', (60, 65))	('decreased', 'NegReg', (34, 43))	('PMX', 'Chemical', 'MESH:D000068437', (69, 72))	('index', 'MPA', (10, 15))	('MIB-1', 'Gene', '57534', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('YS110', 'Var', (60, 65))
152997	27134571	Combinatory treatment with YS110 and PMX significantly reduced the MIB-1 index compared to single treatment (p < 0.05; Fig.	('YS110', 'Var', (27, 32))	('reduced', 'NegReg', (55, 62))	('MIB-1', 'Gene', '57534', (67, 72))	('YS110', 'Chemical', '-', (27, 32))	('PMX', 'Chemical', 'MESH:D000068437', (37, 40))	('MIB-1', 'Gene', (67, 72))
153005	27134571	The number of Ki-67 positive nuclei was decreased after combined treatment of YS110 and PMX and the necrotic area is indicated by an asterisk (Fig.	('YS110', 'Chemical', '-', (78, 83))	('Ki-67', 'Gene', (14, 19))	('necrotic', 'Disease', 'MESH:D009336', (100, 108))	('YS110', 'Var', (78, 83))	('PMX', 'Chemical', 'MESH:D000068437', (88, 91))	('PMX', 'Var', (88, 91))	('decreased', 'NegReg', (40, 49))	('necrotic', 'Disease', (100, 108))
153007	27134571	We expected YS110 to cause ADCC to eliminate CD26 positive MM cells.	('ADCC', 'Disease', (27, 31))	('eliminate', 'NegReg', (35, 44))	('YS110', 'Chemical', '-', (12, 17))	('ADCC', 'biological_process', 'GO:0001788', ('27', '31'))	('CD26', 'Gene', (45, 49))	('YS110', 'Var', (12, 17))	('CD26', 'Gene', '1803', (45, 49))
153008	27134571	In addition to the ADCC effect, YS110 demonstrated direct anti-proliferative effects in vitro against CD26-positive MM cell lines.	('ADCC', 'biological_process', 'GO:0001788', ('19', '23'))	('YS110', 'Chemical', '-', (32, 37))	('CD26', 'Gene', '1803', (102, 106))	('CD26', 'Gene', (102, 106))	('YS110', 'Var', (32, 37))	('anti-proliferative effects', 'CPA', (58, 84))
153009	27134571	We proposed that investigation into the molecular mechanisms of the direct anti-proliferative effect against MM cells would be beneficial for both understanding anti-tumor effect of YS110, as well as uncover the underlying mechanism its proliferation and progression.	('YS110', 'Var', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('YS110', 'Chemical', '-', (182, 187))
153010	27134571	Although the direct anti-proliferative effect of YS110 is limited to a repression rate of approximately 20 % in vitro, the molecular mechanism was associated with the proliferative signal transduction system and cell cycle.	('anti-proliferative', 'NegReg', (20, 38))	('YS110', 'Var', (49, 54))	('signal transduction', 'biological_process', 'GO:0007165', ('181', '200'))	('YS110', 'Chemical', '-', (49, 54))	('cell cycle', 'biological_process', 'GO:0007049', ('212', '222'))
153011	27134571	Cell cycle analysis revealed that YS110 caused significant delay of the G2/M transition.	('delay', 'NegReg', (59, 64))	('YS110', 'Chemical', '-', (34, 39))	('G2/M transition', 'CPA', (72, 87))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('YS110', 'Var', (34, 39))
153015	27134571	At 24 h after treatment with YS110, inhibitory phosphorylation of cdc2 and its upstream regulator cdc25C were elevated.	('inhibitory phosphorylation', 'MPA', (36, 62))	('cdc2', 'Gene', (98, 102))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('YS110', 'Var', (29, 34))	('cdc2', 'Gene', '983', (98, 102))	('YS110', 'Chemical', '-', (29, 34))	('cdc2', 'Gene', (66, 70))	('cdc2', 'Gene', '983', (66, 70))	('cdc25C', 'Gene', '995', (98, 104))	('elevated', 'PosReg', (110, 118))	('cdc25C', 'Gene', (98, 104))
153016	27134571	Phosphorylation of Cdc25C on Ser216 is sequestrated into the cytoplasm and therefore restrained from contact with nuclear cdc2.	('cdc2', 'Gene', (122, 126))	('Cdc25C', 'Gene', (19, 25))	('Phosphorylation', 'MPA', (0, 15))	('cdc2', 'Gene', '983', (122, 126))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Cdc25C', 'Gene', '995', (19, 25))	('Ser216', 'Chemical', '-', (29, 35))	('restrained', 'NegReg', (85, 95))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('61', '70'))	('Ser216', 'Var', (29, 35))
153019	27134571	To determine the upstream regulator of the altered cdc25C phosphorylation state caused by YS110, we investigated several molecules known to regulate cdc25C.	('cdc25C', 'Gene', '995', (51, 57))	('cdc25C', 'Gene', '995', (149, 155))	('YS110', 'Var', (90, 95))	('cdc25C', 'Gene', (51, 57))	('cdc25C', 'Gene', (149, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('YS110', 'Chemical', '-', (90, 95))
153020	27134571	24 h after YS110 treatment, activated phosphorylation levels of p38 MAPK (Thr180/Thy182) and ERK 1/2 (Thr202/Tyr204) were elevated.	('ERK 1/2', 'Gene', (93, 100))	('Tyr204', 'Chemical', '-', (109, 115))	('MAPK', 'Gene', '5595;5594;5595', (68, 72))	('Thr202', 'Chemical', '-', (102, 108))	('ERK 1', 'molecular_function', 'GO:0004707', ('93', '98'))	('p38', 'Gene', '5594', (64, 67))	('Thr180', 'Chemical', '-', (74, 80))	('elevated', 'PosReg', (122, 130))	('Thr202/Tyr204', 'Var', (102, 115))	('p38', 'Gene', (64, 67))	('Thr180/Thy182', 'Var', (74, 87))	('YS110', 'Chemical', '-', (11, 16))	('activated phosphorylation levels', 'MPA', (28, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('ERK 1/2', 'Gene', '5595;5594', (93, 100))	('MAPK', 'Gene', (68, 72))
153021	27134571	Inhibitor assays indicated that YS110 treatment activated the ERK signal pathway, but not the p38MAPK pathway, which induced G2/M delay.	('YS110', 'Chemical', '-', (32, 37))	('activated', 'PosReg', (48, 57))	('YS110 treatment', 'Var', (32, 47))	('ERK', 'Gene', '5594', (62, 65))	('ERK', 'molecular_function', 'GO:0004707', ('62', '65'))	('ERK', 'Gene', (62, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))
153023	27134571	Although ERK1/2 activation is associated with cell survival and proliferation, a number of studies have shown that activation of ERK1/2 can mediate cell cycle arrest and cell death depending on the stimuli and cell types involved.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (148, 165))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('148', '165'))	('ERK1', 'molecular_function', 'GO:0004707', ('9', '13'))	('ERK1', 'molecular_function', 'GO:0004707', ('129', '133'))	('arrest', 'Disease', (159, 165))	('ERK1/2', 'Gene', (9, 15))	('ERK1/2', 'Gene', '5595;5594', (9, 15))	('activation', 'Var', (115, 125))	('ERK1/2', 'Gene', '5595;5594', (129, 135))	('cell death', 'biological_process', 'GO:0008219', ('170', '180'))	('ERK1/2', 'Gene', (129, 135))	('cell death', 'CPA', (170, 180))
153030	27134571	Previously, we reported that YS110 induces intra-nuclear transportation of CD26.	('intra-nuclear transportation', 'MPA', (43, 71))	('CD26', 'Gene', (75, 79))	('CD26', 'Gene', '1803', (75, 79))	('YS110', 'Var', (29, 34))	('induces', 'Reg', (35, 42))	('YS110', 'Chemical', '-', (29, 34))
153040	27134571	As a result, anti-tumor effects were significantly shown in xenografted tumors with YS110 and PMX combined treatment compared to tumors with single treatment of YS110 or PMX, which was accompanied by a significantly reduced MIB-1 index.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (129, 135))	('PMX', 'Var', (94, 97))	('tumors', 'Disease', (72, 78))	('tumor', 'Disease', (129, 134))	('reduced', 'NegReg', (216, 223))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (18, 23))	('YS110', 'Chemical', '-', (161, 166))	('PMX', 'Chemical', 'MESH:D000068437', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('MIB-1', 'Gene', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('MIB-1', 'Gene', '57534', (224, 229))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('YS110', 'Var', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PMX', 'Chemical', 'MESH:D000068437', (170, 173))	('YS110', 'Chemical', '-', (84, 89))
153041	27134571	The combined treatment with YS110 and PMX showed a tendency to retard both G1/S and G2/M transition; however, significant differences of G1/S or G2/M proportion were not seen between YS110 plus PMX treatment and YS110 or PMX single treatment (data not shown).	('YS110', 'Chemical', '-', (183, 188))	('PMX', 'Chemical', 'MESH:D000068437', (38, 41))	('G1/S', 'CPA', (75, 79))	('YS110', 'Chemical', '-', (212, 217))	('retard', 'NegReg', (63, 69))	('YS110', 'Var', (183, 188))	('YS110', 'Chemical', '-', (28, 33))	('PMX', 'Chemical', 'MESH:D000068437', (221, 224))	('PMX', 'Chemical', 'MESH:D000068437', (194, 197))	('YS110', 'Var', (28, 33))	('G2/M transition', 'CPA', (84, 99))
153044	27134571	This is the first report of a novel anti-proliferative mechanism of a humanized anti-CD26 monoclonal antibody YS110 causing G2/M cell cycle delay through ERK1/2 phosphorylation and identifying PMX as a CD26 inducer.	('phosphorylation', 'MPA', (161, 176))	('CD26', 'Gene', (202, 206))	('CD26', 'Gene', (85, 89))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('ERK1', 'molecular_function', 'GO:0004707', ('154', '158'))	('ERK1/2', 'Gene', (154, 160))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))	('G2/M cell cycle delay', 'CPA', (124, 145))	('CD26', 'Gene', '1803', (85, 89))	('CD26', 'Gene', '1803', (202, 206))	('human', 'Species', '9606', (70, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('161', '176'))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('anti-proliferative', 'MPA', (36, 54))	('PMX', 'Chemical', 'MESH:D000068437', (193, 196))	('YS110', 'Var', (110, 115))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('YS110', 'Chemical', '-', (110, 115))	('ERK1/2', 'Gene', '5595;5594', (154, 160))
153045	27134571	Humanized anti-CD26 monoclonal antibody YS110 suppressed proliferation of CD26 positive MM cell lines through a novel mechanism causing G2/M cell cycle delay through ERK1/2 phosphorylation.	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('G2/M cell cycle delay', 'CPA', (136, 157))	('CD26', 'Gene', '1803', (15, 19))	('ERK1', 'molecular_function', 'GO:0004707', ('166', '170'))	('CD26', 'Gene', (74, 78))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('phosphorylation', 'MPA', (173, 188))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('suppressed', 'NegReg', (46, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('173', '188'))	('ERK1/2', 'Gene', (166, 172))	('ERK1/2', 'Gene', '5595;5594', (166, 172))	('YS110', 'Var', (40, 45))	('CD26', 'Gene', (15, 19))	('CD26', 'Gene', '1803', (74, 78))	('YS110', 'Chemical', '-', (40, 45))	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('proliferation', 'CPA', (57, 70))
153077	23721559	The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling.	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('inhibition', 'NegReg', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EphB4', 'Gene', (4, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('sEphB4-HSA', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('Src', 'Gene', (155, 158))	('Src', 'Gene', '6714', (155, 158))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('tumor', 'Disease', (78, 83))	('inhibit', 'NegReg', (70, 77))	('sEphB4-HSA', 'Chemical', '-', (20, 30))
153078	23721559	Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression.	('sEphB4-HSA', 'Var', (15, 25))	('antibody', 'cellular_component', 'GO:0042571', ('44', '52'))	('sEphB4-HSA', 'Chemical', '-', (15, 25))	('VEGF', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (54, 65))	('antibody', 'cellular_component', 'GO:0019815', ('44', '52'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('antibody', 'cellular_component', 'GO:0019814', ('44', '52'))	('antibody', 'molecular_function', 'GO:0003823', ('44', '52'))	('VEGF', 'Gene', '7422', (39, 43))	('tumor', 'Disease', (120, 125))
153090	23721559	In tumor angiogenesis, loss of Ephrin-B2 leads both to significantly reduced tumor vessel density and to tumor growth.	('angiogenesis', 'biological_process', 'GO:0001525', ('9', '21'))	('Ephrin-B2', 'Gene', '1948', (31, 40))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', (105, 110))	('Ephrin-B2', 'Gene', (31, 40))	('reduced', 'NegReg', (69, 76))	('Ephrin', 'molecular_function', 'GO:0005106', ('31', '37'))	('Ephrin', 'molecular_function', 'GO:0046875', ('31', '37'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('loss', 'Var', (23, 27))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
153099	23721559	sEphB4-HSA induces cell death in MPM tumor xenografts in vivo and down-regulates major signaling pathways including PI3K and Src.	('sEphB4-HSA', 'Chemical', '-', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('sEphB4-HSA', 'Var', (0, 10))	('cell death', 'biological_process', 'GO:0008219', ('19', '29'))	('cell death', 'CPA', (19, 29))	('Src', 'Gene', '6714', (125, 128))	('MPM tumor', 'Disease', (33, 42))	('major signaling pathways', 'Pathway', (81, 105))	('down-regulates', 'NegReg', (66, 80))	('PI3K', 'Pathway', (116, 120))	('MPM tumor', 'Disease', 'MESH:D009369', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Src', 'Gene', (125, 128))	('PI3K', 'molecular_function', 'GO:0016303', ('116', '120'))
153100	23721559	In addition, we demonstrate that the combination of sEphB4-HSA and VEGF antibody has superior efficacy than either single agent alone, leading to complete tumor regression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('antibody', 'cellular_component', 'GO:0042571', ('72', '80'))	('sEphB4-HSA', 'Chemical', '-', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('antibody', 'molecular_function', 'GO:0003823', ('72', '80'))	('antibody', 'cellular_component', 'GO:0019815', ('72', '80'))	('tumor', 'Disease', (155, 160))	('VEGF', 'Gene', (67, 71))	('antibody', 'cellular_component', 'GO:0019814', ('72', '80'))	('sEphB4-HSA', 'Var', (52, 62))	('VEGF', 'Gene', '7422', (67, 71))
153104	23721559	Phosphorylated AKT (Ser473), S6 (Ser235/Ser236) and Src (Tyr416) antibodies were from Cell Signaling, Ki67 antibody was from Abcam, CD31 and NG2 antibodies were from BD Biosciences, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) fluorescent kit was from Promega.	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('Ser236', 'Chemical', '-', (40, 46))	('NG2', 'Gene', '1464', (141, 144))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('AKT', 'Gene', (15, 18))	('dUTP', 'Chemical', 'MESH:C027078', (233, 237))	('antibody', 'cellular_component', 'GO:0019814', ('107', '115'))	('CD31', 'Gene', '5175', (132, 136))	('Tyr416', 'Chemical', '-', (57, 63))	('antibody', 'molecular_function', 'GO:0003823', ('107', '115'))	('AKT', 'Gene', '207', (15, 18))	('antibody', 'cellular_component', 'GO:0019815', ('107', '115'))	('antibody', 'cellular_component', 'GO:0042571', ('107', '115'))	('terminal deoxynucleotidyl transferase', 'Gene', '1791', (186, 223))	('Ser235/Ser236', 'Var', (33, 46))	('Src', 'Gene', (52, 55))	('CD31', 'Gene', (132, 136))	('Signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('terminal deoxynucleotidyl transferase', 'Gene', (186, 223))	('NG2', 'Gene', (141, 144))	('Ser', 'cellular_component', 'GO:0005790', ('40', '43'))	('Ser473', 'Var', (20, 26))	('Ser473', 'Chemical', '-', (20, 26))	('Src', 'Gene', '6714', (52, 55))	('Ser235', 'Chemical', '-', (33, 39))
153130	23721559	Utilizing anti-sense oligonucleotides against EphB4, we had previously reported decreased survival of mesothelioma cell lines.	('mesothelioma', 'Disease', (102, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('oligonucleotides', 'Chemical', 'MESH:D009841', (21, 37))	('decreased', 'NegReg', (80, 89))	('survival', 'CPA', (90, 98))	('EphB4', 'Gene', (46, 51))	('anti-sense oligonucleotides', 'Var', (10, 37))
153133	23721559	After 25 days of treatment, mice receiving sEphB4-HSA had a 66% reduction in tumor volume (Figure 2A, P < 0.02) compared to control group, and a 20% regression from the starting tumor volume (P < 0.05).	('regression', 'NegReg', (149, 159))	('tumor', 'Disease', (178, 183))	('sEphB4-HSA', 'Var', (43, 53))	('mice', 'Species', '10090', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('sEphB4-HSA', 'Chemical', '-', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('reduction', 'NegReg', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
153134	23721559	Thus, blockade of EphB4 activation inhibited tumor angiogenesis and mesothelioma cell proliferation and also induced mesothelioma cell apoptosis in vivo.	('mesothelioma', 'Disease', (68, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mesothelioma', 'Disease', (117, 129))	('tumor', 'Disease', (45, 50))	('induced', 'Reg', (109, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('angiogenesis', 'biological_process', 'GO:0001525', ('51', '63'))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('blockade', 'Var', (6, 14))	('EphB4', 'Gene', (18, 23))	('inhibited', 'NegReg', (35, 44))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
153137	23721559	sEphB4-HSA also reduced phosphorylation of Src, which signals downstream of Ephrin-B2 activation.	('sEphB4-HSA', 'Chemical', '-', (0, 10))	('Ephrin-B2', 'Gene', '1948', (76, 85))	('Src', 'Gene', (43, 46))	('Src', 'Gene', '6714', (43, 46))	('Ephrin', 'molecular_function', 'GO:0046875', ('76', '82'))	('Ephrin', 'molecular_function', 'GO:0005106', ('76', '82'))	('Ephrin-B2', 'Gene', (76, 85))	('reduced', 'NegReg', (16, 23))	('phosphorylation', 'MPA', (24, 39))	('sEphB4-HSA', 'Var', (0, 10))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
153146	23721559	Since tumors went to complete remission after combinatorial treatment of sEphB4-HSA and Bevacizumab, we had no tumor tissues for analysis.	('sEphB4-HSA', 'Var', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('sEphB4-HSA', 'Chemical', '-', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
153149	23721559	sEphB4-HSA had much greater inhibition of tumor vessel density than Bevacizumab, which is consistent with our previous study in Kaposi's Sarcoma.	('sEphB4-HSA', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (42, 47))	("Kaposi's Sarcoma", 'Disease', (128, 144))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (68, 79))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('inhibition', 'NegReg', (28, 38))	('sEphB4-HSA', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	("Kaposi's Sarcoma", 'Disease', 'MESH:D012514', (128, 144))
153150	23721559	However, tumor growth inhibitions after 3 weeks of treatment with sEphB4-HSA and Bevacizumab were similar (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('sEphB4-HSA', 'Chemical', '-', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (81, 92))	('tumor', 'Disease', (9, 14))	('sEphB4-HSA', 'Var', (66, 76))
153152	23721559	We also observed that vessels in Bevacizumab-treated tumors appeared normal in caliber while sEphB4-HSA led to not only significantly reduced vessel density, but also markedly reduced vessel length, vessel caliber, and pericyte recruitment (measured by co-localization of NG2-positive pericytes and CD31-positive endothelial cell; P < 0.002) compared to Bevacizumab treatment.	('sEphB4-HSA', 'Chemical', '-', (93, 103))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('pericyte recruitment', 'CPA', (219, 239))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (354, 365))	('CD31', 'Gene', '5175', (299, 303))	('sEphB4-HSA', 'Var', (93, 103))	('reduced', 'NegReg', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('reduced', 'NegReg', (134, 141))	('vessel caliber', 'CPA', (199, 213))	('tumors', 'Disease', (53, 59))	('vessel density', 'CPA', (142, 156))	('NG2', 'Gene', (272, 275))	('vessel length', 'CPA', (184, 197))	('localization', 'biological_process', 'GO:0051179', ('256', '268'))	('CD31', 'Gene', (299, 303))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (33, 44))	('NG2', 'Gene', '1464', (272, 275))
153156	23721559	First, since Ephrin-B2 binds directly to VEGFRs and its activation is required for VEGFR activation, EphB4-Ephrin-B2 blockade will inhibit VEGF-induced signaling.	('Ephrin', 'molecular_function', 'GO:0005106', ('107', '113'))	('VEGF', 'Gene', '7422', (83, 87))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('VEGF', 'Gene', '7422', (139, 143))	('VEGF', 'Gene', (83, 87))	('VEGF', 'Gene', '7422', (41, 45))	('VEGF', 'Gene', (139, 143))	('VEGFR', 'Gene', '3791', (83, 88))	('Ephrin', 'molecular_function', 'GO:0046875', ('13', '19'))	('VEGFR', 'Gene', (83, 88))	('Ephrin-B2', 'Gene', '1948', (13, 22))	('VEGF', 'Gene', (41, 45))	('Ephrin-B2', 'Gene', '1948', (107, 116))	('Ephrin', 'molecular_function', 'GO:0046875', ('107', '113'))	('Ephrin-B2', 'Gene', (13, 22))	('inhibit', 'NegReg', (131, 138))	('Ephrin-B2', 'Gene', (107, 116))	('VEGFR', 'Gene', '3791', (41, 46))	('Ephrin', 'molecular_function', 'GO:0005106', ('13', '19'))	('blockade', 'Var', (117, 125))	('VEGFR', 'Gene', (41, 46))
153159	23721559	When sEphB4-HSA and Bevacizumab were combined, vessel density is further decreased (P < 0.01 compared to Bevacizumab alone), along with diminished pericyte recruitment (P < 0.05 compared to Bevacizumab alone).	('diminished', 'NegReg', (136, 146))	('decreased', 'NegReg', (73, 82))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (190, 201))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (105, 116))	('vessel density', 'CPA', (47, 61))	('sEphB4-HSA', 'Var', (5, 15))	('sEphB4-HSA', 'Chemical', '-', (5, 15))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (20, 31))	('pericyte recruitment', 'CPA', (147, 167))
153169	23721559	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/13/269/prepub This work was in part supported by SBIR grants (1R43 CA 171538-01 and 1R43 CA 168158-01) to VK, mesothelioma Foundation of America to PSG and DOD to RS.	('mesothelioma', 'Disease', 'MESH:D008654', (214, 226))	('PSG', 'Gene', (252, 255))	('1R43 CA 168158-01', 'Var', (188, 205))	('PSG', 'cellular_component', 'GO:0034515', ('252', '255'))	('PSG', 'Gene', '5673', (252, 255))	('1R43', 'Var', (166, 170))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))	('mesothelioma', 'Disease', (214, 226))
153170	23031505	NLRP1 polymorphisms in patients with asbestos-associated mesothelioma An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors.	('malignant mesothelioma', 'Disease', (97, 119))	('mesothelioma', 'Disease', (57, 69))	('patients', 'Species', '9606', (23, 31))	('asbestos', 'Chemical', 'MESH:D001194', (162, 170))	('polymorphisms', 'Var', (6, 19))	('mesothelioma', 'Disease', (107, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('patients', 'Species', '9606', (134, 142))	('NLRP1', 'Gene', '22861', (0, 5))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (97, 119))	('NLRP1', 'Gene', (0, 5))	('asbestos', 'Chemical', 'MESH:D001194', (37, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (97, 119))
153174	23031505	This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM.	('NLRP1', 'Gene', '22861', (62, 67))	('asbestos-induced mesothelioma', 'Disease', (118, 147))	('polymorphisms', 'Var', (68, 81))	('NLRP3', 'Gene', (52, 57))	('NLRP1', 'Gene', (62, 67))	('NLRP3', 'Gene', '114548', (52, 57))	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (118, 147))
153175	23031505	134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms.	('patients', 'Species', '9606', (12, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('asbestos', 'Chemical', 'MESH:D001194', (179, 187))	('rs35829419', 'Var', (258, 268))	('NLRP1', 'Gene', '22861', (214, 219))	('rs12150220', 'Mutation', 'rs12150220', (235, 245))	('rs2670660', 'Mutation', 'rs2670660', (221, 230))	('NLRP1', 'Gene', (214, 219))	('NLRP3', 'Gene', (251, 256))	('rs12150220', 'Var', (235, 245))	('rs35829419', 'Mutation', 'rs35829419', (258, 268))	('asbestos', 'Chemical', 'MESH:D001194', (92, 100))	('rs10754558', 'Mutation', 'rs10754558', (273, 283))	('rs10754558', 'Var', (273, 283))	('NLRP3', 'Gene', '114548', (251, 256))	('mesothelioma', 'Disease', (39, 51))	('rs2670660', 'Var', (221, 230))
153176	23031505	While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('NLRP3', 'Gene', (6, 11))	('mesothelioma', 'Disease', (240, 252))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('rs12150220', 'Mutation', 'rs12150220', (64, 74))	('rs12150220', 'Var', (64, 74))	('NLRP3', 'Gene', '114548', (6, 11))	('NLRP1', 'Gene', '22861', (58, 63))	('MMAE', 'Disease', (119, 123))	('mesothelioma', 'Disease', (40, 52))	('NLRP1', 'Gene', (58, 63))
153177	23031505	This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52).	('NLRP1', 'Gene', '22861', (35, 40))	('NLRP1', 'Gene', '22861', (80, 85))	('NLRP1', 'Gene', (35, 40))	('NLRP1', 'Gene', (80, 85))	('rs2670660', 'Mutation', 'rs2670660', (41, 50))	('rs12150220', 'Mutation', 'rs12150220', (86, 96))	('rs2670660', 'Var', (41, 50))	('rs12150220', 'Var', (86, 96))
153187	23031505	In addition, polymorphisms in NLRP3 gene have been recently associated with chronic inflammatory diseases, autoimmune disorders and infections.	('inflammatory diseases', 'Disease', (84, 105))	('NLRP3', 'Gene', (30, 35))	('autoimmune disorders and infections', 'Disease', 'MESH:D001327', (107, 142))	('polymorphisms', 'Var', (13, 26))	('NLRP3', 'Gene', '114548', (30, 35))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (107, 127))	('inflammatory diseases', 'Disease', 'MESH:D007249', (84, 105))	('associated', 'Reg', (60, 70))
153188	23031505	Moreover other two SNPs in NLRP1, a gene that codifying for another inflammasome receptor, have been recently reported to contribute to the immune response in lung epithelial cells and alveolar macrophages.	('SNPs', 'Var', (19, 23))	('NLRP1', 'Gene', (27, 32))	('immune response', 'CPA', (140, 155))	('contribute', 'Reg', (122, 132))	('immune response', 'biological_process', 'GO:0006955', ('140', '155'))	('NLRP1', 'Gene', '22861', (27, 32))
153189	23031505	Taking in account the previously reported association between variants in NLRP3 gene and an impaired IL-1 production as well as the role of IL-1 driven inflammation in asbestos lung fibrosis and mesothelioma, the aim of this study was to evaluate the impact of the NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in a cohort of MM patients from a North-Eastern Italy area hyperendemic for malignant pleural mesothelioma.	('IL-1', 'molecular_function', 'GO:0005149', ('101', '105'))	('mesothelioma', 'Disease', (195, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('mesothelioma', 'Disease', (455, 467))	('NLRP1', 'Gene', '22861', (275, 280))	('malignant pleural mesothelioma', 'Disease', (437, 467))	('lung fibrosis', 'Phenotype', 'HP:0002206', (177, 190))	('mesothelioma', 'Disease', 'MESH:D008654', (455, 467))	('patients', 'Species', '9606', (379, 387))	('NLRP1', 'Gene', (275, 280))	('IL-1', 'Gene', (101, 105))	('IL-1', 'Gene', '3553', (101, 105))	('NLRP3', 'Gene', (74, 79))	('IL-1', 'Gene', (140, 144))	('inflammation in asbestos lung fibrosis', 'Disease', (152, 190))	('IL-1', 'molecular_function', 'GO:0005149', ('140', '144'))	('NLRP3', 'Gene', '114548', (74, 79))	('IL-1', 'Gene', '3553', (140, 144))	('mesothelioma', 'Disease', (348, 360))	('IL-1 production', 'biological_process', 'GO:0032612', ('101', '116'))	('NLRP3', 'Gene', (265, 270))	('inflammation in asbestos lung fibrosis', 'Disease', 'MESH:D011014', (152, 190))	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (331, 360))	('mesothelioma', 'Disease', 'MESH:D008654', (348, 360))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (437, 467))	('asbestos-induced mesothelioma', 'Disease', (331, 360))	('NLRP3', 'Gene', '114548', (265, 270))	('variants', 'Var', (62, 70))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (447, 467))	('inflammation', 'biological_process', 'GO:0006954', ('152', '164'))
153191	23031505	We analyzed NLRP3 rs35829419, rs10754558 SNPs and NLRP1 rs2670660, rs12150220 SNPs in 134 Italian patients with mesothelioma, in 256 healthy controls and in 101 individuals exposed to asbestos with no mesothelioma at the age of the enrollment.	('rs12150220', 'Mutation', 'rs12150220', (67, 77))	('rs12150220 SNPs', 'Var', (67, 82))	('rs2670660', 'Mutation', 'rs2670660', (56, 65))	('NLRP3', 'Gene', '114548', (12, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('patients', 'Species', '9606', (98, 106))	('asbestos', 'Chemical', 'MESH:D001194', (184, 192))	('mesothelioma', 'Disease', (112, 124))	('mesothelioma', 'Disease', (201, 213))	('NLRP1', 'Gene', '22861', (50, 55))	('rs35829419', 'Var', (18, 28))	('rs10754558', 'Mutation', 'rs10754558', (30, 40))	('rs2670660', 'Var', (56, 65))	('rs10754558 SNPs', 'Var', (30, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (201, 213))	('rs35829419', 'Mutation', 'rs35829419', (18, 28))	('NLRP1', 'Gene', (50, 55))	('NLRP3', 'Gene', (12, 17))
153192	23031505	The rs2670660 and rs12150220 NLRP1 SNPs as well as rs35829419 and rs10754558 NLRP3 were not in linkage disequilibrium in all the tested groups (r2<0.9).	('rs10754558', 'Mutation', 'rs10754558', (66, 76))	('NLRP3', 'Gene', (77, 82))	('rs2670660', 'Mutation', 'rs2670660', (4, 13))	('rs10754558', 'Var', (66, 76))	('NLRP1', 'Gene', '22861', (29, 34))	('NLRP1', 'Gene', (29, 34))	('NLRP3', 'Gene', '114548', (77, 82))	('rs2670660', 'Var', (4, 13))	('rs35829419', 'Var', (51, 61))	('rs12150220', 'Mutation', 'rs12150220', (18, 28))	('rs35829419', 'Mutation', 'rs35829419', (51, 61))	('rs12150220', 'Var', (18, 28))
153195	23031505	The NLRP1 rs2670660 G allele was more frequent in MMAE than in HCAE (0.55 versus 0.43), although not significant different after Bonferroni correction (p=0.027).	('rs2670660', 'Mutation', 'rs2670660', (10, 19))	('HCAE', 'Disease', (63, 67))	('MMAE', 'Disease', (50, 54))	('NLRP1', 'Gene', '22861', (4, 9))	('rs2670660 G', 'Var', (10, 21))	('NLRP1', 'Gene', (4, 9))
153196	23031505	The NLRP1 rs12150220 T allele was significantly more frequent in MMAE patients (0.55) than in HCAE (0.41) (p=0.011; OR=1.79; 95%CI=1.13-2.85) (Table 2).	('rs12150220 T', 'Var', (10, 22))	('patients', 'Species', '9606', (70, 78))	('MMAE', 'Disease', (65, 69))	('NLRP1', 'Gene', '22861', (4, 9))	('rs12150220', 'Mutation', 'rs12150220', (10, 20))	('NLRP1', 'Gene', (4, 9))
153198	23031505	In particular the haplotype A-A SNPs was significantly less frequent in MMAE patients than in HCAE (0.40 versus 0.56; p=0.004; OR=0.52; 95% CI=0.33-0.83).	('patients', 'Species', '9606', (77, 85))	('MMAE', 'Disease', (72, 76))	('less', 'NegReg', (55, 59))	('haplotype A-A SNPs', 'Var', (18, 36))
153203	23031505	In a previous study we have reported the presence of SV40 in 22% of MM patients from a North-Eastern Italy area massively exposed to asbestos in the past, suggesting that an association between SV40 infection and asbestos exposure, as co-morbidity factor, seem to exist.	('SV40 infection', 'Disease', 'MESH:D007239', (194, 208))	('SV40', 'Species', '1891767', (194, 198))	('patients', 'Species', '9606', (71, 79))	('SV40', 'Species', '1891767', (53, 57))	('SV40', 'Var', (53, 57))	('SV40 infection', 'Disease', (194, 208))	('asbestos', 'Chemical', 'MESH:D001194', (133, 141))	('asbestos', 'Chemical', 'MESH:D001194', (213, 221))
153205	23031505	In this study we considered the hypothesis of an association between known NLRP3 single nucleotide variations and asbestos-induced mesothelioma.	('NLRP3', 'Gene', (75, 80))	('single nucleotide variations', 'Var', (81, 109))	('NLRP3', 'Gene', '114548', (75, 80))	('association', 'Interaction', (49, 60))	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (114, 143))	('asbestos-induced mesothelioma', 'Disease', (114, 143))
153207	23031505	Thus, we hypothesized that SNPs influencing the ability to activate the inflammasome and IL-1ss secretion, could affect the response to asbestos, the entity of asbestos-induced inflammation and, finally, the predisposition to develop mesothelioma.	('secretion', 'biological_process', 'GO:0046903', ('96', '105'))	('inflammation', 'Disease', 'MESH:D007249', (177, 189))	('IL-1', 'Gene', '3553', (89, 93))	('mesothelioma', 'Disease', (234, 246))	('activate', 'PosReg', (59, 67))	('IL-1', 'molecular_function', 'GO:0005149', ('89', '93'))	('inflammation', 'Disease', (177, 189))	('inflammasome', 'MPA', (72, 84))	('asbestos', 'Chemical', 'MESH:D001194', (160, 168))	('SNPs', 'Var', (27, 31))	('affect', 'Reg', (113, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (234, 246))	('response to asbestos', 'MPA', (124, 144))	('inflammation', 'biological_process', 'GO:0006954', ('177', '189'))	('asbestos', 'Chemical', 'MESH:D001194', (136, 144))	('IL-1', 'Gene', (89, 93))
153211	23031505	Notably, our data showed that the rs2670660 and rs12150220 polymorphisms in NLRP1 gene were not associated to the mesothelioma.	('rs2670660', 'Mutation', 'rs2670660', (34, 43))	('NLRP1', 'Gene', (76, 81))	('NLRP1', 'Gene', '22861', (76, 81))	('associated', 'Reg', (96, 106))	('rs12150220', 'Mutation', 'rs12150220', (48, 58))	('mesothelioma', 'Disease', (114, 126))	('rs2670660', 'Var', (34, 43))	('rs12150220', 'Var', (48, 58))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))
153214	23031505	The deregulation of NLRP1 inflammasome could contribute to the formation of the pro-tumor micro-environment both influencing the transformation of the lung tissue cells and/or inducing high levels of IL-1ss that contribute to growth and metastatic spread in experimental and human cancers.	('growth', 'CPA', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('IL-1', 'molecular_function', 'GO:0005149', ('200', '204'))	('inducing', 'Reg', (176, 184))	('NLRP1', 'Gene', '22861', (20, 25))	('transformation of the lung tissue cells', 'CPA', (129, 168))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('NLRP1', 'Gene', (20, 25))	('cancers', 'Disease', (281, 288))	('contribute', 'Reg', (45, 55))	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('metastatic spread', 'CPA', (237, 254))	('influencing', 'Reg', (113, 124))	('deregulation', 'Var', (4, 16))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('human', 'Species', '9606', (275, 280))	('IL-1', 'Gene', (200, 204))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('IL-1', 'Gene', '3553', (200, 204))
153216	23031505	It could be hypothesized that the rs2670660 G allele and rs12150220 T allele affect the level of NLRP1 expression, its function and the balance between cell surviving and apoptosis after injury influencing the mechanism of cell transformation.	('rs2670660', 'Mutation', 'rs2670660', (34, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('function', 'MPA', (119, 127))	('NLRP1', 'Gene', '22861', (97, 102))	('rs12150220', 'Mutation', 'rs12150220', (57, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('NLRP1', 'Gene', (97, 102))	('expression', 'MPA', (103, 113))	('rs2670660 G', 'Var', (34, 45))	('affect', 'Reg', (77, 83))	('rs12150220 T', 'Var', (57, 69))	('level', 'MPA', (88, 93))
153217	23031505	Although the frequency of rs2670660 and rs12150220 polymorphism in the general population is relatively high, it does not exist any functional information about this variant.	('rs12150220', 'Var', (40, 50))	('rs2670660', 'Var', (26, 35))	('rs2670660', 'Mutation', 'rs2670660', (26, 35))	('rs12150220', 'Mutation', 'rs12150220', (40, 50))
153218	23031505	However we believe that this strong association between the rs12150220 polymorphism in NLRP1 and asbestos-mesothelioma development emphasizes once more the role of inflammation and inflammasome in tumorigenesis events.	('inflammation', 'Disease', (164, 176))	('NLRP1', 'Gene', '22861', (87, 92))	('inflammation', 'biological_process', 'GO:0006954', ('164', '176'))	('rs12150220', 'Mutation', 'rs12150220', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('asbestos-mesothelioma', 'Disease', 'MESH:D008654', (97, 118))	('rs12150220', 'Var', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('asbestos-mesothelioma', 'Disease', (97, 118))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('tumor', 'Disease', (197, 202))	('NLRP1', 'Gene', (87, 92))
153226	23031505	We analyzed 2 SNPs (rs35829419 and rs10754558) in NLRP3 and 2 SNP (rs2670660 and rs12150220) in the NLRP1 genes.	('rs2670660', 'Var', (67, 76))	('NLRP3', 'Gene', (50, 55))	('rs35829419', 'Var', (20, 30))	('NLRP1', 'Gene', (100, 105))	('rs10754558', 'Mutation', 'rs10754558', (35, 45))	('rs12150220', 'Mutation', 'rs12150220', (81, 91))	('rs10754558', 'Var', (35, 45))	('rs12150220', 'Var', (81, 91))	('rs35829419', 'Mutation', 'rs35829419', (20, 30))	('NLRP3', 'Gene', '114548', (50, 55))	('rs2670660', 'Mutation', 'rs2670660', (67, 76))	('NLRP1', 'Gene', '22861', (100, 105))
153241	21534085	The obvious commonality in environmental exposures to "naturally occurring asbestos" (NOA), occupational exposure to REMP from asbestos mining, manufacturing, uses, and para-occupational or domestic exposures is that inhalation of REMP, given sufficient quality, quantity and individual susceptibility, induce disease in humans.	('inhalation', 'Var', (217, 227))	('REMP', 'Chemical', '-', (231, 235))	('para-occupational', 'Disease', 'MESH:D009784', (169, 186))	('para-occupational', 'Disease', (169, 186))	('disease', 'Disease', (310, 317))	('humans', 'Species', '9606', (321, 327))	('induce', 'Reg', (303, 309))	('REMP', 'Chemical', '-', (117, 121))	('asbestos', 'Chemical', 'MESH:D001194', (127, 135))	('asbestos', 'Chemical', 'MESH:D001194', (75, 83))	('iron', 'Chemical', 'MESH:D007501', (30, 34))
153310	21534085	The presently known potential toxicity determinants of fibrous dusts are divided into physical and chemical characteristics of the dusts and molecular features that include inherent surface characteristics including effective or bioavailable surface areas, charges, chemically reactive sites, variations of elemental composition, and an array of changes induced by contributions/alterations of these features in biosystems.	('toxicity', 'Disease', 'MESH:D064420', (30, 38))	('chemically', 'MPA', (266, 276))	('toxicity', 'Disease', (30, 38))	('changes', 'Reg', (346, 353))	('rat', 'Species', '10116', (383, 386))	('contributions/alterations', 'Var', (365, 390))	('variations', 'Var', (293, 303))	('elemental composition', 'MPA', (307, 328))
153359	21534085	These alterations, while useful in producing altered particle size distributions, may have also produced alterations of the surface/chemical makeup of the materials used in the exposures when compared to the exposures to these particles in a less unaltered (more natural) state.	('particle size distributions', 'MPA', (53, 80))	('alterations', 'Var', (6, 17))	('altered', 'Reg', (45, 52))	('rat', 'Species', '10116', (109, 112))	('alterations', 'Reg', (105, 116))	('surface/chemical makeup', 'MPA', (124, 147))	('rat', 'Species', '10116', (10, 13))
153388	21534085	As with the TiO2 example earlier, differences in REMP widths exert large impacts on number of particles or total particle effective surface areas per unit mass of test samples.	('TiO2', 'Chemical', 'MESH:C009495', (12, 16))	('number of particles', 'MPA', (84, 103))	('REMP', 'Chemical', '-', (49, 53))	('impacts', 'Reg', (73, 80))	('differences', 'Var', (34, 45))
153462	21534085	This is precisely what found when they investigated the effects of various proteins on the uptake of NIEHS crocidolite asbestos (amphibole with a nominal composition (Na2Fe3+2Fe2+3Si8O22 (OH)2) by rabbit pleural mesothelial cells.	('Na2Fe3+2Fe2+3Si8O22', 'Var', (167, 186))	('O2', 'Chemical', '-', (183, 185))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('Si', 'Chemical', 'MESH:D012825', (180, 182))	('rabbit', 'Species', '9986', (197, 203))	('Fe', 'Chemical', 'MESH:D007501', (170, 172))	('uptake', 'MPA', (91, 97))	('NIEHS crocidolite', 'Chemical', '-', (101, 118))	('Fe', 'Chemical', 'MESH:D007501', (175, 177))	('amphibole', 'Chemical', 'MESH:D017636', (129, 138))	('uptake', 'biological_process', 'GO:0098739', ('91', '97'))	('uptake', 'biological_process', 'GO:0098657', ('91', '97'))
153481	21534085	Systematic substitution of Al atoms for Si gives rise to an overall negative charge on the framework tetrahedra.	('Al', 'Chemical', 'MESH:D000535', (27, 29))	('substitution', 'Var', (11, 23))	('Si', 'Chemical', 'MESH:D012825', (40, 42))	('negative', 'NegReg', (68, 76))
153496	21534085	observed homolytic and heterolytic cleavage of chemical bonds on the surface of silicates after grinding, which produces distorted siloxane bridges, peroxide bridges, silica radicals, Si+ or Si-O- surface charges, Si-O2  peroxyradical, and Si+O2 -.	('peroxide', 'Chemical', 'MESH:D010545', (149, 157))	('silicates', 'Chemical', 'MESH:D017640', (80, 89))	('silica', 'MPA', (167, 173))	('siloxane', 'Chemical', 'MESH:D012833', (131, 139))	('Si', 'Chemical', 'MESH:D012825', (184, 186))	('Si-O2', 'Chemical', 'MESH:D012822', (214, 219))	('Si+O2 -', 'Var', (240, 247))	('Si+', 'Var', (184, 187))	('Si-O2  peroxyradical', 'Var', (214, 234))	('Si', 'Chemical', 'MESH:D012825', (240, 242))	('Si+', 'Chemical', 'MESH:D012825', (240, 243))	('Si', 'Chemical', 'MESH:D012825', (191, 193))	('peroxide bridges', 'MPA', (149, 165))	('Si', 'Chemical', 'MESH:D012825', (214, 216))	('Si+', 'Chemical', 'MESH:D012825', (184, 187))	('siloxane bridges', 'Protein', (131, 147))	('O2 -', 'Chemical', '-', (243, 247))	('silica', 'Chemical', 'MESH:D012822', (167, 173))	('chemical', 'Protein', (47, 55))	('silica', 'Chemical', 'MESH:D012822', (80, 86))
153531	21534085	This damage leads to mutations from the misincorporation of bases during replication of the damaged DNA if the damage is not repaired by enzymes synthesized by cells for that purpose.	('rat', 'Species', '10116', (50, 53))	('misincorporation of bases', 'MPA', (40, 65))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('leads to', 'Reg', (12, 20))	('mutations', 'Var', (21, 30))
153540	21534085	What role these damaged proteins may play in development of cancer is not understood, but modification of function of proteins, such as glutathione (GSH) or glutathione peroxidase (GSPx), or DNA repair enzymes may compromise the cell's ability to defend itself against an assault by ROS.	('glutathione', 'Chemical', 'MESH:D005978', (136, 147))	('DNA repair', 'biological_process', 'GO:0006281', ('191', '201'))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('GSH', 'Chemical', '-', (149, 152))	('glutathione', 'Chemical', 'MESH:D005978', (157, 168))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('defend itself', 'CPA', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ROS', 'Chemical', 'MESH:D017382', (283, 286))	('modification of', 'Var', (90, 105))	('compromise', 'NegReg', (214, 224))
153567	21534085	Little Fe was mobilized from NIEHS long or short fiber chrysotile, none from tremolite, and no Fe was mobilized from erionite from Rome, OR.	('mobilized', 'MPA', (14, 23))	('Fe', 'Chemical', 'MESH:D007501', (95, 97))	('Fe', 'Chemical', 'MESH:D007501', (7, 9))	('erionite', 'Chemical', 'MESH:C083174', (117, 125))	('short fiber', 'Var', (43, 54))
153603	21534085	Analysis of blood from hemochromatosis patients contains citrate-chelated Fe, and it is well known that citrate-chelated Fe produces damage to biomolecules in the presence of a reductant, such as ascorbate.	('ascorbate', 'Chemical', 'MESH:D001205', (196, 205))	('hemochromatosis', 'Disease', (23, 38))	('citrate', 'Chemical', 'MESH:D019343', (104, 111))	('patients', 'Species', '9606', (39, 47))	('damage', 'MPA', (133, 139))	('hemochromatosis', 'Disease', 'MESH:D006432', (23, 38))	('Fe', 'Chemical', 'MESH:D007501', (74, 76))	('citrate', 'Chemical', 'MESH:D019343', (57, 64))	('citrate-chelated Fe', 'MPA', (57, 76))	('citrate-chelated', 'Var', (104, 120))	('Fe', 'Chemical', 'MESH:D007501', (121, 123))
153609	21534085	Thus, increasing LMW Fe in lung or mesothelial cells after inhalation of asbestos may pose a risk for cancer.	('LMW Fe', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('asbestos', 'Chemical', 'MESH:D001194', (73, 81))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('increasing', 'PosReg', (6, 16))	('LMW', 'Chemical', '-', (17, 20))	('Fe', 'Chemical', 'MESH:D007501', (21, 23))
153612	21534085	The LMW Fe from asbestos is likely to pose an increased risk for cancer, as it does for other disease conditions where it is found.	('Fe', 'Chemical', 'MESH:D007501', (8, 10))	('LMW Fe', 'Var', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('asbestos', 'Chemical', 'MESH:D001194', (16, 24))	('LMW', 'Chemical', '-', (4, 7))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
153723	21534085	Studies focusing on the mechanism for these events in human lung epithelial cells (A549) showed that exposure to crocidolite resulted in intracellular Fe mobilization from the fibers and a fall in intracellular GSH from the cells (independent of Fe, but requiring endocytosis).	('intracellular', 'cellular_component', 'GO:0005622', ('137', '150'))	('endocytosis', 'biological_process', 'GO:0006897', ('264', '275'))	('intracellular GSH from the', 'MPA', (197, 223))	('crocidolite', 'Chemical', 'MESH:D017638', (113, 124))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('Fe', 'Chemical', 'MESH:D007501', (246, 248))	('Fe', 'Chemical', 'MESH:D007501', (151, 153))	('GSH', 'Chemical', '-', (211, 214))	('fall', 'Phenotype', 'HP:0002527', (189, 193))	('crocidolite', 'Var', (113, 124))	('intracellular Fe mobilization from the', 'MPA', (137, 175))	('intracellular', 'cellular_component', 'GO:0005622', ('197', '210'))	('human', 'Species', '9606', (54, 59))	('fall', 'NegReg', (189, 193))
153749	29946373	Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('epigenetic drugs', 'Var', (33, 49))	('cytotoxicity', 'Disease', (158, 170))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('DNA methylation', 'biological_process', 'GO:0006306', ('64', '79'))	('histone', 'Protein', (83, 90))	('histone acetylation', 'biological_process', 'GO:0016573', ('83', '102'))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))
153771	29946373	Even if epigenetic drugs are efficient especially as a treatment of hematopoietic cancers such as leukemia, they display poor clinical benefits on solid tumors.	('leukemia', 'Disease', (98, 106))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('epigenetic drugs', 'Var', (8, 24))	('leukemia', 'Disease', 'MESH:D007938', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hematopoietic cancers', 'Disease', (68, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (68, 89))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
153780	29946373	Recently, it was demonstrated that hypomethylating agent can induce interferon pathway through activation of endogenous retroviral elements in colorectal, breast, and ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (167, 181))	('hypomethylating agent', 'Var', (35, 56))	('induce', 'PosReg', (61, 67))	('breast', 'Disease', (155, 161))	('activation', 'PosReg', (95, 105))	('ovarian cancer', 'Disease', (167, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('interferon pathway', 'Pathway', (68, 86))	('colorectal', 'Disease', (143, 153))	('endogenous retroviral elements', 'MPA', (109, 139))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
153804	29946373	The aim of our strategy is to induce an anti-tumor immune response to cure malignant pleural mesothelioma by using combinations of epigenetic drugs including HDACi.	('HDAC', 'Gene', '9734', (158, 162))	('malignant pleural mesothelioma', 'Disease', (75, 105))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('epigenetic', 'Var', (131, 141))	('tumor', 'Disease', (45, 50))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (85, 105))	('combinations', 'Interaction', (115, 127))	('immune response', 'biological_process', 'GO:0006955', ('51', '66'))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (75, 105))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('HDAC', 'Gene', (158, 162))
153859	29946373	FoxP3, a strong marker of Treg, is well-known to be regulated by methylation, and recent study suggests that CD16 expression could also be regulated by methylation.	('regulated', 'Reg', (139, 148))	('FoxP3', 'Gene', (0, 5))	('CD16', 'Gene', '2214', (109, 113))	('CD16', 'Gene', (109, 113))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('expression', 'MPA', (114, 124))	('methylation', 'Var', (152, 163))	('FoxP3', 'Gene', '50943', (0, 5))
153884	29946373	The PD-1/PD-L1 axis is of particular interest regarding the impressive results observed in clinic with anti-PD-1 blocking antibody.	('antibody', 'cellular_component', 'GO:0042571', ('122', '130'))	('PD-L1', 'Gene', '29126', (9, 14))	('antibody', 'cellular_component', 'GO:0019815', ('122', '130'))	('anti-PD-1', 'Var', (103, 112))	('antibody', 'cellular_component', 'GO:0019814', ('122', '130'))	('antibody', 'molecular_function', 'GO:0003823', ('122', '130'))	('PD-L1', 'Gene', (9, 14))
153888	29946373	This observation suggests that epigenetic regulation of CTA expression and PD-L1 could be associated.	('epigenetic regulation', 'Var', (31, 52))	('PD-L1', 'Gene', (75, 80))	('CTA', 'Chemical', '-', (56, 59))	('associated', 'Reg', (90, 100))	('CTA', 'Protein', (56, 59))	('PD-L1', 'Gene', '29126', (75, 80))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))
153891	29946373	Indeed, this HDACi is active at nanomolar concentrations and at concentrations which induce gene expression, NODH is moderately toxic for lymphocytes when combined with decitabine (25% of cell death).	('NODH', 'Chemical', '-', (109, 113))	('gene expression', 'MPA', (92, 107))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('decitabine', 'Chemical', 'MESH:D000077209', (169, 179))	('cell death', 'biological_process', 'GO:0008219', ('188', '198'))	('HDAC', 'Gene', (13, 17))	('NODH', 'Var', (109, 113))	('HDAC', 'Gene', '9734', (13, 17))
153923	24492162	In addition, inhibition of PDGF/PDGF-R pathway enhances tumor vascular uptake of chemotherapy by decreasing tumor interstitial fluid pressure (IFP).	('decreasing', 'NegReg', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (56, 61))	('uptake', 'biological_process', 'GO:0098657', ('71', '77'))	('uptake', 'biological_process', 'GO:0098739', ('71', '77'))	('tumor', 'Disease', (108, 113))	('enhances', 'PosReg', (47, 55))	('PD', 'Disease', 'MESH:D010300', (27, 29))	('PDGF', 'molecular_function', 'GO:0005161', ('32', '36'))	('PDGF', 'molecular_function', 'GO:0005161', ('27', '31'))	('PD', 'Disease', 'MESH:D010300', (32, 34))
153926	24492162	We hypothesized that inhibition of PDGF pathway in combination with cisplatin-pemetrexed in chemo-naive MPM patients would show a clinical benefit and embarked on a phase I clinical trial.	('cisplatin-pemetrexed', 'Chemical', '-', (68, 88))	('inhibition', 'Var', (21, 31))	('PD', 'Disease', 'MESH:D010300', (35, 37))	('benefit', 'PosReg', (139, 146))	('patients', 'Species', '9606', (108, 116))	('PDGF', 'molecular_function', 'GO:0005161', ('35', '39'))	('MPM', 'Disease', (104, 107))
153952	24492162	Gene copy number analysis was done in approximately 50 nuclei per tumor in at least four areas, and the selection of the area was guided by H&E-stained section.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('Gene copy number analysis', 'Var', (0, 25))	('H&E', 'Chemical', 'MESH:D006371', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
153987	24492162	Our initial hypothesis that PDGFR inhibition has a synergistic role with systemic chemotherapy, has been well-supported by data from preclinical models.	('inhibition', 'Var', (34, 44))	('PDGFR', 'Gene', (28, 33))	('PDGFR', 'Gene', '5159', (28, 33))
154031	27619223	Tumor ingrowth into the neural structures of the brachial plexus and the intercostal or paravertebral structures can also cause neuropathic pain.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cause', 'Reg', (122, 127))	('neuropathic pain', 'Disease', (128, 144))	('Tumor', 'Var', (0, 5))	('neuropathic pain', 'Disease', 'MESH:D009437', (128, 144))	('pain', 'Phenotype', 'HP:0012531', (140, 144))
154110	33000251	Of these, hsa-miR-193a-5p and hsa-miR-551b-5p demonstrated higher expression in MPM-derived EVcap50/220.	('EVcap50', 'Chemical', '-', (92, 99))	('hsa-miR-551b', 'Gene', (30, 42))	('expression', 'MPA', (66, 76))	('hsa-miR-551b', 'Gene', '693136', (30, 42))	('hsa-miR-193a-5p', 'Var', (10, 25))	('higher', 'PosReg', (59, 65))
154111	33000251	Our data suggest that hsa-miR-193a-5p and hsa-miR-551b-5p in EVcap50/220 could be diagnostic markers for MPM.	('MPM', 'Disease', (105, 108))	('hsa-miR-193a-5p', 'Var', (22, 37))	('EVcap50', 'Chemical', '-', (61, 68))	('hsa-miR-551b', 'Gene', (42, 54))	('hsa-miR-551b', 'Gene', '693136', (42, 54))
154137	33000251	In the same way, MeT-4728-5p, MeT-193a-5p and MeT-551b-5p cells expressing hsa-miR-4728-5p, hsa-miR-193a-5p and hsa-miR-551b-5p, respectively, were obtained by infection and selection with MeT-5A cells.	('MeT', 'Gene', (30, 33))	('MeT', 'Gene', '79811', (189, 192))	('infection', 'Disease', 'MESH:D007239', (160, 169))	('hsa-miR-551b', 'Gene', (112, 124))	('MeT', 'Gene', (17, 20))	('hsa-miR-193a-5p', 'Var', (92, 107))	('MeT', 'Gene', (189, 192))	('hsa-miR-551b', 'Gene', '693136', (112, 124))	('MeT', 'Gene', '79811', (46, 49))	('infection', 'Disease', (160, 169))	('MeT', 'Gene', '79811', (30, 33))	('hsa-miR-4728', 'Gene', '100616132', (75, 87))	('MeT', 'Gene', '79811', (17, 20))	('MeT', 'Gene', (46, 49))	('hsa-miR-4728', 'Gene', (75, 87))
154170	33000251	Primer sequences used to analyze human miRNAs and gene expression via qPCR were provided by the following sources: miR-4728-5p, Thermo Fisher Scientific, Inc., 461811_mat; miR-193a-5p, Thermo Fisher Scientific, Inc., 002281; miR-551b-5p, Thermo Fisher Scientific, Inc., 002346; U6, Thermo Fisher Scientific, Inc., 001973.	('miR-193a-5p', 'Var', (172, 183))	('461811_mat', 'Var', (160, 170))	('mat', 'molecular_function', 'GO:0004314', ('167', '170'))	('miR-4728', 'Gene', '100616132', (115, 123))	('miR-4728', 'Gene', (115, 123))	('human', 'Species', '9606', (33, 38))	('miR-551b', 'Gene', (225, 233))	('miR-551b', 'Gene', '693136', (225, 233))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))
154201	33000251	From the results of the microarray, 390 and 502 EV50-miRNAs were detected in MeT-5A and all six MPM cell lines, respectively.	('EV50-miRNAs', 'Var', (48, 59))	('MeT', 'Gene', '79811', (77, 80))	('MeT', 'Gene', (77, 80))
154203	33000251	On the other hand, 123 EV50-miRNAs were detected in MPM cells but not in MeT-5A cells.	('MeT', 'Gene', (73, 76))	('MeT', 'Gene', '79811', (73, 76))	('EV50-miRNAs', 'Var', (23, 34))
154223	33000251	Based on our analysis on diameter, form, specific proteins, and inclusion of miRNAs, the isolated EVcap50/220 and EVrev50/220 were considered structurally to be EVs.	('EVcap50', 'Chemical', '-', (98, 105))	('EVcap50/220', 'Var', (98, 109))	('EVrev50/220', 'Var', (114, 125))
154237	33000251	In order to investigate the effect of EV50-miRNA uptake on gene expression of cells, MeT-5A cells overexpressing hsa-miR-193a-5p or hsa-miR-551b-5p were established.	('uptake', 'biological_process', 'GO:0098657', ('49', '55'))	('uptake', 'biological_process', 'GO:0098739', ('49', '55'))	('MeT', 'Gene', (85, 88))	('hsa-miR-193a-5p', 'Var', (113, 128))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('MeT', 'Gene', '79811', (85, 88))	('hsa-miR-551b', 'Gene', (132, 144))	('hsa-miR-551b', 'Gene', '693136', (132, 144))
154239	33000251	Genes whose expression was commonly suppressed by hsa-miR-193a-5p and hsa-miR-551b-5p were analyzed using pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG).	('suppressed', 'NegReg', (36, 46))	('hsa-miR-551b', 'Gene', '693136', (70, 82))	('hsa-miR-193a-5p', 'Var', (50, 65))	('hsa-miR-551b', 'Gene', (70, 82))	('expression', 'MPA', (12, 22))
154242	33000251	PARD3 is associated with tight junctions and adherens junctions, and our results showed that PARD3 mRNA could be repressed by both hsa-miR-193a-5p and hsa-miR-551b-5p.	('hsa-miR-193a-5p', 'Var', (131, 146))	('PARD3', 'Gene', (0, 5))	('PARD3', 'Gene', '56288', (93, 98))	('PARD3', 'Gene', (93, 98))	('hsa-miR-551b', 'Gene', (151, 163))	('hsa-miR-551b', 'Gene', '693136', (151, 163))	('mRNA', 'MPA', (99, 103))	('PARD3', 'Gene', '56288', (0, 5))
154247	33000251	In our study, hsa-miR-193a-5p and hsa-miR-551b-5p suppressed genes associated with tight junctions, which may contribute to metastasis in MPM cells.	('hsa-miR-193a-5p', 'Var', (14, 29))	('genes', 'MPA', (61, 66))	('suppressed', 'NegReg', (50, 60))	('metastasis', 'CPA', (124, 134))	('hsa-miR-551b', 'Gene', (34, 46))	('hsa-miR-551b', 'Gene', '693136', (34, 46))	('contribute', 'Reg', (110, 120))	('MPM', 'Disease', (138, 141))
154249	33000251	Our results indicated that six EV50-miRNAs in blood and pleural effusions may serve as novel diagnostic markers for MPM.	('pleural effusions', 'Phenotype', 'HP:0002202', (56, 73))	('EV50-miRNAs', 'Var', (31, 42))	('MPM', 'Disease', (116, 119))	('pleural effusion', 'Phenotype', 'HP:0002202', (56, 72))	('pleural effusions', 'Disease', (56, 73))	('pleural effusions', 'Disease', 'MESH:D010996', (56, 73))
154250	33000251	In particular, since the expression of hsa-miR-193a-5p and hsa-miR-551b-5p are high in MPM-derived EVs, these are very promising diagnostic markers.	('hsa-miR-551b', 'Gene', '693136', (59, 71))	('expression', 'MPA', (25, 35))	('hsa-miR-551b', 'Gene', (59, 71))	('hsa-miR-193a-5p', 'Var', (39, 54))
154255	33000251	Among them, hsa-miR-193a-5p and hsa-miR-551b-5p strongly inhibited expression of genes related to cell-cell interactions and cell-matrix interactions in normal cells.	('hsa-miR-551b', 'Gene', '693136', (32, 44))	('inhibited', 'NegReg', (57, 66))	('hsa-miR-193a-5p', 'Var', (12, 27))	('hsa-miR-551b', 'Gene', (32, 44))	('expression of genes', 'MPA', (67, 86))
154256	33000251	These results suggest that hsa-miR-193a-5p and hsa-miR-551b-5b may contribute to invasion of MPM cells, and may help elucidate the mechanism of malignant acquisition of MPM.	('hsa-miR-551b', 'Gene', (47, 59))	('invasion', 'CPA', (81, 89))	('hsa-miR-551b', 'Gene', '693136', (47, 59))	('hsa-miR-193a-5p', 'Var', (27, 42))	('contribute', 'PosReg', (67, 77))
154260	32325837	Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1 The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined.	('Melanoma', 'Disease', (40, 48))	('ACD', 'Gene', '65057', (105, 108))	('POT1', 'Gene', (125, 129))	('Pathogenic', 'Reg', (82, 92))	('ATM', 'Gene', '472', (110, 113))	('BAP1', 'Gene', '8314', (115, 119))	('melanoma', 'Disease', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('Variants', 'Var', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('Melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', (115, 119))	('Melanoma', 'Disease', 'MESH:D008545', (40, 48))	('ATM', 'Gene', (110, 113))	('ACD', 'Gene', (105, 108))
154262	32325837	We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1.	('cutaneous melanoma', 'Disease', (104, 122))	('variants', 'Var', (202, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('BAP1', 'Gene', '8314', (214, 218))	('POT1', 'Gene', (151, 155))	('BAP1', 'Gene', (145, 149))	('POT1', 'Gene', '25913', (228, 232))	('ACD', 'Gene', (157, 160))	('variants', 'Var', (57, 65))	('TERF2IP', 'Gene', (172, 179))	('BAP1', 'Gene', (214, 218))	('BAP1 and 4', 'Gene', '8314', (214, 224))	('POT1', 'Gene', (228, 232))	('TERF2IP', 'Gene', '54386', (172, 179))	('pathogenic', 'Reg', (24, 34))	('MITF', 'Gene', '4286', (162, 166))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('ACD', 'Gene', '65057', (157, 160))	('BAP1', 'Gene', '8314', (145, 149))	('POT1', 'Gene', '25913', (151, 155))	('MITF', 'Gene', (162, 166))
154263	32325837	We also found four deleterious and five likely deleterious variants in ATM (3.3%).	('ATM', 'Gene', (71, 74))	('variants', 'Var', (59, 67))	('ATM', 'Gene', '472', (71, 74))
154264	32325837	Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%.	('ATM', 'Gene', '472', (52, 55))	('variants', 'Var', (40, 48))	('ATM', 'Gene', (52, 55))	('increased', 'PosReg', (56, 65))
154266	32325837	To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('ATM', 'Gene', (60, 63))	('variants', 'Var', (76, 84))	('ATM', 'Gene', '472', (60, 63))
154270	32325837	Germline pathogenic variants in CDKN2A/ARF have been found in 20-45% of familial CM cases and in 11-19% of multiple primary melanomas (MPM) from the Italian population, characterized by a high prevalence of CDKN2A pathogenetic variants often associated with pancreatic cancer (PC) and other cancers.	('variants', 'Var', (20, 28))	('melanomas', 'Disease', 'MESH:D008545', (124, 133))	('variants', 'Var', (227, 235))	('melanomas', 'Disease', (124, 133))	('CDKN2A/ARF', 'Gene', '1029', (32, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (258, 275))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('pancreatic cancer', 'Disease', (258, 275))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('CDKN2A', 'Gene', (207, 213))	('CDKN2A', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('associated', 'Reg', (242, 252))	('CDKN2A/ARF', 'Gene', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('CDKN2A', 'Gene', '1029', (207, 213))	('found', 'Reg', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('familial CM', 'Disease', (72, 83))	('cancers', 'Disease', (291, 298))	('CDKN2A', 'Gene', '1029', (32, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (258, 275))	('familial CM', 'Disease', 'MESH:D020936', (72, 83))
154271	32325837	Conversely, a small number of families carrying pathogenic variants in CDK4 have been described worldwide, including some Italian families.	('variants', 'Var', (59, 67))	('CDK4', 'Gene', (71, 75))	('CDK4', 'Gene', '1019', (71, 75))	('pathogenic', 'Reg', (48, 58))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
154274	32325837	Recently, novel rare high-risk variants have been identified in BAP1 (BRCA1 associated protein 1), POT1 (protection of telomeres 1), ACD (adrenocortical dysplasia), TERF2IP (telomeric repeat-binding factor-2 interacting protein), and the TERT (telomerase reverse transcriptase) promoter primarily by whole exome sequencing (WES) studies, although differences in terms of prevalence have been reported across studies.	('TERT', 'Gene', '7015', (238, 242))	('transcriptase', 'molecular_function', 'GO:0034062', ('263', '276'))	('telomerase reverse transcriptase', 'Gene', '7015', (244, 276))	('BRCA1 associated protein 1', 'Gene', '8314', (70, 96))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('ACD', 'Gene', (133, 136))	('BAP1', 'Gene', (64, 68))	('TERF2IP', 'Gene', (165, 172))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('transcriptase', 'molecular_function', 'GO:0003899', ('263', '276'))	('variants', 'Var', (31, 39))	('POT1', 'Gene', '25913', (99, 103))	('TERF2IP', 'Gene', '54386', (165, 172))	('BRCA1 associated protein 1', 'Gene', (70, 96))	('adrenocortical dysplasia', 'Gene', (138, 162))	('ACD', 'Gene', '65057', (133, 136))	('telomerase reverse transcriptase', 'Gene', (244, 276))	('telomeric repeat-binding', 'molecular_function', 'GO:0042162', ('174', '198'))	('POT1', 'Gene', (99, 103))	('BAP1', 'Gene', '8314', (64, 68))	('adrenocortical dysplasia', 'Gene', '65057', (138, 162))	('transcriptase', 'molecular_function', 'GO:0003968', ('263', '276'))	('TERT', 'Gene', (238, 242))
154277	32325837	Namely, carriers of the MITF p.Glu318Lys variant have a greater than fivefold increased risk of developing melanoma, especially MPM, with specific dermatological and dermoscopic features and with renal cell carcinoma (RCC) or both compared with non-carriers.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('p.Glu318Lys', 'Mutation', 'rs149617956', (29, 40))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('renal cell carcinoma', 'Disease', (196, 216))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('MITF', 'Gene', '4286', (24, 28))	('RCC', 'Disease', (218, 221))	('p.Glu318Lys', 'Var', (29, 40))	('MITF', 'Gene', (24, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('MPM', 'Disease', (128, 131))
154280	32325837	Further, in families with pathogenic variants in novel susceptibility genes, CM is part of a broader multi-cancer syndrome.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('multi-cancer syndrome', 'Disease', (101, 122))	('multi-cancer syndrome', 'Disease', 'MESH:D009369', (101, 122))	('pathogenic', 'Reg', (26, 36))	('variants', 'Var', (37, 45))
154281	32325837	In addition to CM, the tumor spectrum of BAP1 pathogenic variants includes uveal melanoma (UM), mesothelioma, basal cell carcinoma (BCC), renal cell carcinoma (RCC), and BAP1-inactivated melanocytic tumors (BIMTs), which together constitute the BAP1-tumor predisposition syndrome (BAP1-TPDS).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('BAP1', 'Gene', (281, 285))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (110, 130))	('BAP1', 'Gene', (41, 45))	('BAP1-tumor predisposition syndrome', 'Disease', (245, 279))	('BAP1', 'Gene', '8314', (245, 249))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('melanoma', 'Disease', (81, 89))	('tumor', 'Disease', (250, 255))	('renal cell carcinoma', 'Disease', (138, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('basal cell carcinoma', 'Disease', (110, 130))	('mesothelioma', 'Disease', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', (245, 249))	('variants', 'Var', (57, 65))	('tumor', 'Disease', (199, 204))	('BAP1', 'Gene', '8314', (170, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('RCC', 'Disease', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('melanocytic tumors', 'Disease', (187, 205))	('melanocytic tumors', 'Disease', 'MESH:D009508', (187, 205))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('tumor', 'Disease', (23, 28))	('BAP1', 'Gene', '8314', (281, 285))	('BAP1', 'Gene', '8314', (41, 45))	('BAP1-tumor predisposition syndrome', 'Disease', 'OMIM:614327', (245, 279))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 158))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (110, 130))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('BAP1', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
154282	32325837	Moreover, POT1 pathogenic variants predispose to glioma, thyroid cancer, cardiac angiosarcoma, and colorectal cancer.	('cardiac angiosarcoma', 'Disease', (73, 93))	('angiosarcoma', 'Phenotype', 'HP:0200058', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('predispose', 'Reg', (35, 45))	('colorectal cancer', 'Disease', (99, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (57, 71))	('thyroid cancer', 'Disease', (57, 71))	('cardiac angiosarcoma', 'Disease', 'MESH:D006338', (73, 93))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('thyroid cancer', 'Disease', 'MESH:D013964', (57, 71))	('variants', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('POT1', 'Gene', '25913', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('POT1', 'Gene', (10, 14))	('glioma', 'Disease', (49, 55))
154283	32325837	Lastly, ACD and TERF2IP, as well as TERT promoter variants, are associated not only with early onset and multiple CM, but also with other cancers, although these latter associations are not yet conclusively defined.	('associated', 'Reg', (64, 74))	('TERT', 'Gene', '7015', (36, 40))	('TERF2IP', 'Gene', (16, 23))	('multiple CM', 'Disease', (105, 116))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('early onset', 'Disease', (89, 100))	('ACD', 'Gene', (8, 11))	('variants', 'Var', (50, 58))	('TERF2IP', 'Gene', '54386', (16, 23))	('ACD', 'Gene', '65057', (8, 11))	('TERT', 'Gene', (36, 40))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
154284	32325837	Pathogenic variants in the above-mentioned genes appear to be extremely rare in the context of non-syndromic familial aggregation (i.e., a familial clustering of only one type of cancer, such as CM).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('variants', 'Var', (11, 19))	('syndromic familial aggregation', 'Disease', 'MESH:D001791', (99, 129))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('syndromic familial aggregation', 'Disease', (99, 129))	('cancer', 'Disease', (179, 185))
154285	32325837	Conversely, recent exome sequencing studies on PC-only families identified pathogenic variants in the ATM (ataxia-telangiectasia mutated) and PALB2 (partner and localizer of BRCA2) genes.	('BRCA2', 'Gene', '675', (174, 179))	('telangiectasia', 'Phenotype', 'HP:0001009', (114, 128))	('pathogenic', 'Reg', (75, 85))	('ataxia', 'Phenotype', 'HP:0001251', (107, 113))	('variants', 'Var', (86, 94))	('ATM (ataxia-telangiectasia mutated', 'Gene', '472', (102, 136))	('BRCA2', 'Gene', (174, 179))	('PALB2', 'Gene', '79728', (142, 147))	('PALB2', 'Gene', (142, 147))
154286	32325837	ATM is a known intermediate penetrance cancer predisposition gene, as heterozygous carriers of ATM germline pathogenic variants are at increased risk of developing several types of malignancies, including breast cancer (BC) and PC.	('ATM', 'Gene', (95, 98))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('ATM', 'Gene', (0, 3))	('ATM', 'Gene', '472', (95, 98))	('cancer', 'Disease', (212, 218))	('malignancies', 'Disease', (181, 193))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('variants', 'Var', (119, 127))	('breast cancer', 'Disease', (205, 218))	('ATM', 'Gene', '472', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
154288	32325837	In a recent WES study on PC cases from CDKN2A-positive and negative CM families, ATM loss-of-function (LOF) variants were mostly observed in CDKN2A-negative PC patients.	('CDKN2A', 'Gene', '1029', (141, 147))	('patients', 'Species', '9606', (160, 168))	('CDKN2A', 'Gene', (39, 45))	('ATM', 'Gene', (81, 84))	('loss-of-function', 'NegReg', (85, 101))	('CDKN2A', 'Gene', '1029', (39, 45))	('variants', 'Var', (108, 116))	('ATM', 'Gene', '472', (81, 84))	('CDKN2A', 'Gene', (141, 147))
154289	32325837	In another WES study, a potentially deleterious missense variant in ATM detected in a CM family co-segregated with CM in three affected members whose mother developed PC.	('ATM', 'Gene', '472', (68, 71))	('deleterious', 'Reg', (36, 47))	('ATM', 'Gene', (68, 71))	('missense variant', 'Var', (48, 64))
154293	32325837	Under the hypothesis that part of the aggregation of PC seen in our CM families could be ascribed to variants in ATM and PALB2, we decided to include these genes in our panel, with the purpose of investigating their potential role in CM predisposition.	('PALB2', 'Gene', (121, 126))	('ATM', 'Gene', (113, 116))	('variants', 'Var', (101, 109))	('ATM', 'Gene', '472', (113, 116))	('PALB2', 'Gene', '79728', (121, 126))
154294	32325837	To determine the sensitivity and specificity of our next-generation sequencing (NGS) platform and bioinformatics algorithm, we first sequenced 10 DNA samples with known CDKN2A/ARF, CDK4, and MC1R germline variants previously found through SS.	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('MC1R', 'Gene', '4157', (191, 195))	('CDKN2A/ARF', 'Gene', '1029', (169, 179))	('variants', 'Var', (205, 213))	('CDK4', 'Gene', (181, 185))	('MC1R', 'Gene', (191, 195))	('CDK4', 'Gene', '1019', (181, 185))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))	('CDKN2A/ARF', 'Gene', (169, 179))
154296	32325837	A 100% concordance in single-nucleotide polymorphisms (SNPs) detection in CDKN2A/ARF and MC1R was observed.	('MC1R', 'Gene', '4157', (89, 93))	('CDKN2A/ARF', 'Gene', (74, 84))	('MC1R', 'Gene', (89, 93))	('single-nucleotide polymorphisms', 'Var', (22, 53))	('CDKN2A/ARF', 'Gene', '1029', (74, 84))
154297	32325837	Out of 273 probands who underwent gene panel testing, we identified 16 (5.9%) pathogenetic or likely pathogenic variants in established high/intermediate penetrance CM susceptibility genes such as BAP1 (2.2%; n = 6), POT1 (0.7%; n = 2), ACD (0.37%; n = 1), and MITF (2.6%; n = 7).	('ACD', 'Gene', (237, 240))	('ACD', 'Gene', '65057', (237, 240))	('BAP1', 'Gene', '8314', (197, 201))	('pathogenetic', 'Reg', (78, 90))	('POT1', 'Gene', (217, 221))	('POT1', 'Gene', '25913', (217, 221))	('MITF', 'Gene', '4286', (261, 265))	('MITF', 'Gene', (261, 265))	('BAP1', 'Gene', (197, 201))	('variants', 'Var', (112, 120))
154299	32325837	In addition, we found four deleterious variants and five potentially deleterious variants (3.3%) as well as six rare VUS in ATM, whereas no rare variants were found in PALB2.	('ATM', 'Gene', '472', (124, 127))	('PALB2', 'Gene', (168, 173))	('PALB2', 'Gene', '79728', (168, 173))	('ATM', 'Gene', (124, 127))	('variants', 'Var', (39, 47))
154300	32325837	Overall, we identified six variants, five frameshift and one non-sense, which were classified as pathogenic, as well as one VUS in the BAP1 gene.	('BAP1', 'Gene', '8314', (135, 139))	('frameshift', 'Var', (42, 52))	('BAP1', 'Gene', (135, 139))
154301	32325837	All families with LOF variants showed the typical features of the BAP1-TPDS (OMIM 614327) as well as multiple cases of CM (Table 1).	('BAP1', 'Gene', (66, 70))	('variants', 'Var', (22, 30))	('BAP1', 'Gene', '8314', (66, 70))
154302	32325837	The patient with the novel c.1337delA variant developed a spitzoid CM at the age of 41, as well as a further CM and two dysplastic nevi:one classified as spitzoid:at the age of 43.	('c.1337delA', 'Mutation', 'c.1337delA', (27, 37))	('patient', 'Species', '9606', (4, 11))	('spitzoid CM', 'Disease', (58, 69))	('developed', 'PosReg', (46, 55))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('dysplastic nevi', 'Disease', (120, 135))	('dysplastic nevi', 'Disease', 'MESH:D004416', (120, 135))	('c.1337delA', 'Var', (27, 37))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (120, 135))
154303	32325837	The second novel variant, c.1777dupC, which is predicted to cause a truncated protein after 50 amino acids, was found in a young patient diagnosed with an atypical Spitz nevus/tumor with loss of BAP1 expression and with a second-degree relative deceased owing to RCC at the age of 46.	('atypical Spitz nevus', 'Phenotype', 'HP:0001062', (155, 175))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BAP1', 'Gene', (195, 199))	('truncated', 'MPA', (68, 77))	('loss', 'NegReg', (187, 191))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('tumor', 'Disease', (176, 181))	('c.1777dupC', 'Var', (26, 36))	('RCC', 'Disease', (263, 266))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('c.1777dupC', 'Mutation', 'c.1777dupC', (26, 36))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('expression', 'MPA', (200, 210))	('BAP1', 'Gene', '8314', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('patient', 'Species', '9606', (129, 136))
154304	32325837	The patient with c.799_800delCA developed CM and had a brother previously diagnosed with three CMs and a mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('CMs', 'Disease', (95, 98))	('patient', 'Species', '9606', (4, 11))	('c.799_800delCA', 'Var', (17, 31))	('developed', 'PosReg', (32, 41))	('mesothelioma', 'Disease', (105, 117))	('CMs', 'Disease', 'MESH:C564254', (95, 98))	('c.799_800delCA', 'Mutation', 'c.799_800delCA', (17, 31))
154307	32325837	Additionally, in a patient diagnosed with CM at the age of 52, we identified a missense BAP1 variant, c.1507T>C p.(Phe503Leu), which was found in The Genome Aggregation Database (gnomAD) with a very low frequency in the non-Finnish European population (f = 3.99e-6).	('c.1507T>C', 'Mutation', 'rs745959970', (102, 111))	('patient', 'Species', '9606', (19, 26))	('BAP1', 'Gene', '8314', (88, 92))	('p.(Phe503Leu', 'Var', (112, 124))	('p.(Phe503Leu)', 'SUBSTITUTION', 'None', (112, 125))	('BAP1', 'Gene', (88, 92))
154308	32325837	The patient's sister developed CM at the age of 23, but segregation in the family could not be verified as BAP1 germline status was only available for the proband, the family history was not suggestive for a BAP1 mutation, and the variant was thus classified as VUS.	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', '8314', (208, 212))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', (107, 111))	('mutation', 'Var', (213, 221))	('BAP1', 'Gene', (208, 212))
154310	32325837	The c.255+1G>A novel variant, involving the same canonical splice site of a variant functionally described by Potrony et al., was found in a patient who developed three CMs and several dysplastic nevi, as well as in his unaffected mother and sister.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (185, 200))	('dysplastic nevi', 'Disease', 'MESH:D004416', (185, 200))	('CMs', 'Disease', (169, 172))	('c.255+1G>A', 'Mutation', 'c.255+1G>A', (4, 14))	('c.255+1G>A', 'Var', (4, 14))	('patient', 'Species', '9606', (141, 148))	('CMs', 'Disease', 'MESH:C564254', (169, 172))	('dysplastic nevi', 'Disease', (185, 200))	('nevi', 'Phenotype', 'HP:0003764', (196, 200))
154311	32325837	The c.1687-1G>A variant, which was predicted to be pathogenic by the MaxEntScan algorithm, and was previously shown to affect transcript splicing by RT-PCR and sequencing by Robles-Espinoza et al., was found in a family with two CM cases and an RCC case.	('c.1687-1G>A', 'Mutation', 'rs587777473', (4, 15))	('RCC', 'Disease', (245, 248))	('transcript splicing', 'MPA', (126, 145))	('splicing', 'biological_process', 'GO:0045292', ('137', '145'))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('affect', 'Reg', (119, 125))	('c.1687-1G>A', 'Var', (4, 15))
154312	32325837	Three of the six POT1 missense variants (c.158C>T, c.280C>A, and c.314C>T) were located in the DNA binding domain (OB1).	('c.158C>T', 'Var', (41, 49))	('c.314C>T', 'Var', (65, 73))	('POT1', 'Gene', '25913', (17, 21))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('DNA binding', 'molecular_function', 'GO:0003677', ('95', '106'))	('POT1', 'Gene', (17, 21))	('c.314C>T', 'Mutation', 'rs754742811', (65, 73))	('c.158C>T', 'Mutation', 'c.158C>T', (41, 49))	('c.280C>A', 'Mutation', 'rs769908514', (51, 59))	('c.280C>A', 'Var', (51, 59))
154313	32325837	c.158C>T p.(Thr53Ile), predicted to be pathogenic by in silico analysis, was detected in two different CM families: one included individuals with glioblastoma and PC, while the second was a CM-only family, with two affected CM members.	('p.(Thr53Ile', 'Var', (9, 20))	('p.(Thr53Ile)', 'SUBSTITUTION', 'None', (9, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('c.158C>T', 'Mutation', 'c.158C>T', (0, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('glioblastoma', 'Disease', (146, 158))
154314	32325837	The c.280C>A p.(Gln94Lys) variant, which, according to A.J.	('c.280C>A', 'Var', (4, 12))	('p.(Gln94Lys)', 'SUBSTITUTION', 'None', (13, 25))	('c.280C>A', 'Mutation', 'rs769908514', (4, 12))	('p.(Gln94Lys', 'Var', (13, 24))
154316	32325837	The third variant, c.314C>T p.(Thr105Met), is phylogenetically highly conserved (suggesting that this threonine has an essential role in protein function) and was found in a MPM proband who also developed a dysplastic nevus and whose nephew had an atypical Spitz lesion.	('c.314C>T', 'Mutation', 'rs754742811', (19, 27))	('p.(Thr105Met)', 'SUBSTITUTION', 'None', (28, 41))	('nevus', 'Phenotype', 'HP:0003764', (218, 223))	('p.(Thr105Met', 'Var', (28, 40))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (207, 223))	('c.314C>T', 'Var', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('Spitz lesion', 'Disease', (257, 269))	('dysplastic', 'Disease', (207, 217))	('threonine', 'Chemical', 'MESH:D013912', (102, 111))	('dysplastic', 'Disease', 'MESH:D004416', (207, 217))	('developed', 'PosReg', (195, 204))
154317	32325837	Of the remaining missense variants, c.809G>A p.(Ser270Asn) was found in a patient with more than 50 melanocytic nevi who developed nine CMs and was diagnosed with multiple myeloma at the age of 54.	('patient', 'Species', '9606', (74, 81))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (100, 116))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('CMs', 'Disease', 'MESH:C564254', (136, 139))	('p.(Ser270Asn', 'Var', (45, 57))	('multiple myeloma', 'Phenotype', 'HP:0006775', (163, 179))	('multiple myeloma', 'Disease', 'MESH:D009101', (163, 179))	('multiple myeloma', 'Disease', (163, 179))	('c.809G>A', 'Mutation', 'rs587777477', (36, 44))	('CMs', 'Disease', (136, 139))	('diagnosed', 'Reg', (148, 157))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('c.809G>A', 'Var', (36, 44))	('p.(Ser270Asn)', 'SUBSTITUTION', 'None', (45, 58))
154320	32325837	The last missense variant, c.1400C> p.(Ser467Leu), was found in a patient who developed two CMs and whose mother developed a CM at the age of 50 and a glioblastoma at the age of 79.	('CMs', 'Disease', (92, 95))	('glioblastoma', 'Disease', (151, 163))	('patient', 'Species', '9606', (66, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('CMs', 'Disease', 'MESH:C564254', (92, 95))	('p.(Ser467Leu)', 'SUBSTITUTION', 'None', (36, 49))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('p.(Ser467Leu', 'Var', (36, 48))
154321	32325837	We found the c.866_867delCT frameshift variant in ACD that leads to a premature truncating protein in a patient affected by multiple CM and with a family history of CM and a relative who died of PC at the age of 55.	('ACD', 'Gene', '65057', (50, 53))	('c.866_867delCT frameshift', 'Var', (13, 38))	('leads to', 'Reg', (59, 67))	('premature truncating protein', 'MPA', (70, 98))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('patient', 'Species', '9606', (104, 111))	('ACD', 'Gene', (50, 53))	('c.866_867delCT', 'Mutation', 'rs777476880', (13, 27))
154322	32325837	Additionally, an MPM patient, with no family history of CM, had a VUS in the TERF2IP gene, c.258C>G p.(Asp86Glu).	('patient', 'Species', '9606', (21, 28))	('p.(Asp86Glu)', 'SUBSTITUTION', 'None', (100, 112))	('TERF2IP', 'Gene', (77, 84))	('p.(Asp86Glu', 'Var', (100, 111))	('c.258C>G', 'Mutation', 'rs752446617', (91, 99))	('TERF2IP', 'Gene', '54386', (77, 84))
154323	32325837	None of the 273 probands carried the c.-57T>G or other germline pathogenic TERT promoter variants.	('c.-57T>G', 'Var', (37, 45))	('c.-57T>G', 'Mutation', 'c.-57T>G', (37, 45))	('TERT', 'Gene', '7015', (75, 79))	('TERT', 'Gene', (75, 79))
154324	32325837	The MITF c.952G>A p.(Glu318Lys) risk variant was detected in 7 out 273 probands, four of whom had a history of MPMs and dysplastic nevi, one was also affected by RCC, and another who had a second degree relative also diagnosed with CM.	('detected', 'Reg', (49, 57))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (18, 31))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('dysplastic nevi', 'Disease', (120, 135))	('c.952G>A', 'Mutation', 'rs149617956', (9, 17))	('MPMs', 'Disease', (111, 115))	('dysplastic nevi', 'Disease', 'MESH:D004416', (120, 135))	('p.(Glu318Lys', 'Var', (18, 30))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (120, 135))
154325	32325837	Nine potentially pathogenic (four deleterious and five potentially deleterious variants) and six VUS were found in ATM.	('ATM', 'Gene', (115, 118))	('pathogenic', 'Reg', (17, 27))	('variants', 'Var', (79, 87))	('ATM', 'Gene', '472', (115, 118))
154326	32325837	c.3275C>A p.(Ser1092Ter) was detected in a CM proband with a second degree relative affected by PC.	('c.3275C>A', 'Var', (0, 9))	('p.(Ser1092Ter)', 'SUBSTITUTION', 'None', (10, 24))	('p.(Ser1092Ter', 'Var', (10, 23))	('Ter', 'cellular_component', 'GO:0097047', ('20', '23'))	('Ser', 'cellular_component', 'GO:0005790', ('13', '16'))	('c.3275C>A', 'Mutation', 'c.3275C>A', (0, 9))
154327	32325837	Three frameshift variants, predicted to cause truncated proteins owing to premature stop codons, were detected in families with MPM, UM, and other cancers (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('frameshift variants', 'Var', (6, 25))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('detected', 'Reg', (102, 110))	('cancers', 'Disease', (147, 154))	('MPM', 'Disease', (128, 131))	('truncated', 'MPA', (46, 55))
154328	32325837	Of these, c.4451delT was found in a proband who was treated 10 years earlier with cyclosporine and radiotherapy for a Hodgkin's lymphoma, and subsequently developed three CMs, two at the age of 45 and one at age 46.	('c.4451delT', 'Mutation', 'c.4451delT', (10, 20))	('CMs', 'Disease', 'MESH:C564254', (171, 174))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (118, 136))	('CMs', 'Disease', (171, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('cyclosporine', 'Chemical', 'MESH:D016572', (82, 94))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (118, 136))	('c.4451delT', 'Var', (10, 20))	("Hodgkin's lymphoma", 'Disease', (118, 136))
154330	32325837	In consideration of personal and family history, the presence of the ATM variant was reported to the proband in a research context, with emphasis on the uncertainty about the role of ATM in melanoma and PC development and the absence of a standardized surveillance protocol.	('ATM', 'Gene', '472', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('ATM', 'Gene', '472', (183, 186))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('ATM', 'Gene', (69, 72))	('ATM', 'Gene', (183, 186))	('variant', 'Var', (73, 80))
154335	32325837	c.5979_5983delTAAAG, which causes a premature stop codon after 23 aa, was found in a proband who developed two Ums at the age of 41 and a CM 10 years later.	('causes', 'Reg', (27, 33))	('premature stop codon', 'MPA', (36, 56))	('c.5979_5983delTAAAG', 'Mutation', 'rs876660134', (0, 19))	('c.5979_5983delTAAAG', 'Var', (0, 19))
154336	32325837	The last frameshift variant, c.8319_8323dupTGTCC, was found in a woman who developed two CMs at the ages of 48 and one at 53, as well one BCC and a BC (at the ages of 49 and 53, respectively).	('c.8319_8323dupTGTCC', 'Var', (29, 48))	('CMs', 'Disease', (89, 92))	('woman', 'Species', '9606', (65, 70))	('c.8319_8323dupTGTCC', 'Mutation', 'rs1060501552', (29, 48))	('CMs', 'Disease', 'MESH:C564254', (89, 92))
154339	32325837	The first one, a CM patient diagnosed at the age of 47, belonged to a family in which the variant co-segregated with the sister (CM at the age of 43) and their father developed prostate, bladder, colon cancer, and UM (at the ages of 70, 71, 72, and 74, respectively).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('bladder', 'Disease', (187, 194))	('prostate', 'Disease', (177, 185))	('colon cancer', 'Phenotype', 'HP:0003003', (196, 208))	('colon cancer', 'Disease', 'MESH:D015179', (196, 208))	('patient', 'Species', '9606', (20, 27))	('colon cancer', 'Disease', (196, 208))	('variant', 'Var', (90, 97))
154340	32325837	The second proband harboring the p.(Arg1917Thr) variant was an apparently sporadic MPM patient, with no other tumor in the family.	('p.(Arg1917Thr)', 'SUBSTITUTION', 'None', (33, 47))	('p.(Arg1917Thr', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patient', 'Species', '9606', (87, 94))	('MPM', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
154341	32325837	This patient was also a carrier of a MITF p.(Glu318Lys) variant.	('patient', 'Species', '9606', (5, 12))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (42, 55))	('carrier', 'molecular_function', 'GO:0005215', ('24', '31'))	('MITF', 'Gene', '4286', (37, 41))	('MITF', 'Gene', (37, 41))	('p.(Glu318Lys', 'Var', (42, 54))
154343	32325837	We did not find previously undetected pathogenic variants in CDK4 and CDKN2A/ARF, although we included regulatory regions, for example, the whole CDKN2A/ARF 5'UTR, as we recently showed that nearly half of the rare 5'UTR germline variants are potentially pathogenic, owing to their impact on CDKN2A/ARF internal ribosome entry site (IRES)-mediated translation.	("ARF 5'UTR", 'Gene', '381', (153, 162))	('ribosome', 'cellular_component', 'GO:0005840', ('312', '320'))	("5'UTR", 'Gene', (215, 220))	('variants', 'Var', (230, 238))	('CDKN2A/ARF', 'Gene', '1029', (292, 302))	('CDKN2A/ARF', 'Gene', '1029', (70, 80))	('CDK', 'molecular_function', 'GO:0004693', ('61', '64'))	('translation', 'biological_process', 'GO:0006412', ('348', '359'))	('CDK4', 'Gene', (61, 65))	('CDKN2A/ARF', 'Gene', (292, 302))	('CDKN2A/ARF', 'Gene', (70, 80))	('impact', 'Reg', (282, 288))	('CDK4', 'Gene', '1019', (61, 65))	('CDKN2A/ARF', 'Gene', '1029', (146, 156))	('internal ribosome entry site', 'MPA', (303, 331))	('CDKN2A/ARF', 'Gene', (146, 156))	('pathogenic', 'Reg', (255, 265))	("ARF 5'UTR", 'Gene', (153, 162))
154345	32325837	Initial findings of pathogenic variants in POT1, however, considered the second most frequently mutated high penetrance gene after CDKN2A/ARF, showed a higher frequency, probably owing to the presence of founders in the studied populations.	('variants', 'Var', (31, 39))	('POT1', 'Gene', '25913', (43, 47))	('POT1', 'Gene', (43, 47))	('CDKN2A/ARF', 'Gene', '1029', (131, 141))	('CDKN2A/ARF', 'Gene', (131, 141))	('pathogenic', 'Reg', (20, 30))
154346	32325837	Currently, pathogenic variants in recently identified CM predisposition genes are detected at a frequency similar to that of pathogenic CDK4 variants, which was routinely screened in familial and MPM patients together with CDKN2A/ARF.	('patients', 'Species', '9606', (200, 208))	('CDKN2A/ARF', 'Gene', '1029', (223, 233))	('CDK4', 'Gene', (136, 140))	('CDKN2A/ARF', 'Gene', (223, 233))	('CDK4', 'Gene', '1019', (136, 140))	('variants', 'Var', (141, 149))	('CDK', 'molecular_function', 'GO:0004693', ('136', '139'))	('variants', 'Var', (22, 30))
154350	32325837	We also included ATM and PALB2 for research purposes, excluding them from the clinical report, under the assumption that their variants could play a role in families with known cancer associations, that is, CM and PC.	('variants', 'Var', (127, 135))	('play', 'Reg', (142, 146))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('role', 'Reg', (149, 153))	('ATM', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PALB2', 'Gene', '79728', (25, 30))	('PALB2', 'Gene', (25, 30))	('ATM', 'Gene', '472', (17, 20))
154351	32325837	Overall, the detection yield of pathogenic/likely pathogenic variants in established melanoma risk genes was 5.86%.	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('variants', 'Var', (61, 69))	('pathogenic/likely', 'Reg', (32, 49))
154352	32325837	When deleterious and potentially deleterious ATM variants were also included, the detection yield rose to 9.16%, the highest estimate described so far to our knowledge.	('ATM', 'Gene', (45, 48))	('rose', 'PosReg', (98, 102))	('ATM', 'Gene', '472', (45, 48))	('variants', 'Var', (49, 57))
154353	32325837	However, the association between variants in ATM, mostly known for being associated with a low-intermediate risk of other cancers, and CM risk is not yet clearly established.	('ATM', 'Gene', '472', (45, 48))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('ATM', 'Gene', (45, 48))	('variants', 'Var', (33, 41))
154354	32325837	Further, the detection of a pathogenic variant in a gene such as BAP1, which is related to a complex syndrome that includes several potentially lethal cancers, should be reported to aid clinical management, even though the complete tumor spectrum and related tumor-specific penetrance and surveillance recommendations are not definitively drawn.	('BAP1', 'Gene', '8314', (65, 69))	('aid', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('BAP1', 'Gene', (65, 69))	('variant', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('aid', 'Gene', '57379', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('tumor', 'Disease', (259, 264))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('tumor', 'Disease', (232, 237))	('pathogenic', 'Reg', (28, 38))	('cancers', 'Disease', (151, 158))
154358	32325837	For patients with MITF p.(Glu318Lys), based on the association of a higher risk of MPM, dysplastic nevi, and RCC, and on the basis of our data, we propose the inclusion of this gene in clinical diagnostic testing and suggest that an annual abdominal ultrasound should be integrated with the dermatological surveillance for the carriers, even though tailored surveillance for cancers other than CM is not standardized.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('dysplastic nevi', 'Disease', (88, 103))	('p.(Glu318Lys', 'Var', (23, 35))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('dysplastic nevi', 'Disease', 'MESH:D004416', (88, 103))	('RCC', 'Disease', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (88, 103))	('patients', 'Species', '9606', (4, 12))	('MITF', 'Gene', '4286', (18, 22))	('MITF', 'Gene', (18, 22))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (23, 36))	('cancers', 'Disease', (375, 382))	('MPM', 'Disease', (83, 86))
154359	32325837	Specific recommendations are not yet available for multiple variants/genes such as POT1 variants.	('variants', 'Var', (88, 96))	('POT1', 'Gene', (83, 87))	('POT1', 'Gene', '25913', (83, 87))
154361	32325837	Interestingly, our study cohort showed a higher rate of ATM variants than that reported in recent WES and WGS studies that included melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('ATM', 'Gene', '472', (56, 59))	('variants', 'Var', (60, 68))	('ATM', 'Gene', (56, 59))
154364	32325837	The finding of ATM LOF variants in our study cohort is in line with previous findings on the association between ATM and CM/PC risk.	('ATM', 'Gene', (15, 18))	('ATM', 'Gene', (113, 116))	('LOF', 'NegReg', (19, 22))	('ATM', 'Gene', '472', (15, 18))	('ATM', 'Gene', '472', (113, 116))	('variants', 'Var', (23, 31))	('CM/PC', 'Disease', (121, 126))
154365	32325837	In fact, four deleterious and five potentially deleterious variants were found, three of them in melanoma-prone families that also included PC cases.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('variants', 'Var', (59, 67))	('melanoma', 'Disease', (97, 105))
154369	32325837	found no variants in POT1, and occurrence of UM and mesothelioma in three BAP1 positive families in a large multigene panel study of 451 Dutch families with an overall diagnostic yield of 4%, principally explained by the identification of 15 MITF positive families (3.3%).	('MITF', 'Gene', '4286', (242, 246))	('MITF', 'Gene', (242, 246))	('POT1', 'Gene', '25913', (21, 25))	('mesothelioma', 'Disease', (52, 64))	('BAP1', 'Gene', '8314', (74, 78))	('POT1', 'Gene', (21, 25))	('variants', 'Var', (9, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('BAP1', 'Gene', (74, 78))
154370	32325837	Casula et al., in a cohort of Italian MPM patients, used a panel containing the same genes we tested (with the exception of MITF), and found a lower pathogenic variant rate, considering the American College of Medical Genetics on Genomics (ACMG) variant classification (3%).	('variant', 'Var', (160, 167))	('pathogenic', 'MPA', (149, 159))	('lower', 'NegReg', (143, 148))	('MITF', 'Gene', '4286', (124, 128))	('MITF', 'Gene', (124, 128))	('patients', 'Species', '9606', (42, 50))
154371	32325837	CDKN2A pathogenic variants were also less frequent (3.84%).	('variants', 'Var', (18, 26))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
154381	32325837	Variants were classified as pathogenic, likely pathogenic, VUS, likely benign, or benign based on the published ACMG recommendations, for known melanoma genes.	('Variants', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('pathogenic', 'Reg', (28, 38))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
154387	32325837	To verify whether the variant c.255+1G>A alters splicing in POT1, as described in Potrony et al., in which they tested the variant c.255G>A, we isolated total RNA from lymphoblastoid cells with TRIzol (Invitrogen, Carlsbad, CA, USA) and cDNA synthesis was performed with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystem, Foster City, CA, USA) using random primers.	('variant c.255+1G>A', 'Var', (22, 40))	('c.255+1G>A', 'Mutation', 'c.255+1G>A', (30, 40))	('c.255+1G>A', 'Var', (30, 40))	('c.255G>A', 'Mutation', 'rs747851551', (131, 139))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('POT1', 'Gene', '25913', (60, 64))	('Reverse Transcription', 'biological_process', 'GO:0001171', ('294', '315'))	('POT1', 'Gene', (60, 64))	('alters', 'Reg', (41, 47))	('TRIzol', 'Chemical', 'MESH:C411644', (194, 200))	('synthesis', 'biological_process', 'GO:0009058', ('242', '251'))	('RNA', 'cellular_component', 'GO:0005562', ('159', '162'))	('c.255G>A', 'Var', (131, 139))
154393	32325837	To the best of our knowledge, this is the first study to report a high percentage of deleterious ATM variants in melanoma families (3.3%).	('ATM', 'Gene', '472', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('variants', 'Var', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('ATM', 'Gene', (97, 100))
154394	32325837	In fact, the finding of ATM deleterious or potentially deleterious variants in nearly 3.3% of our families, and an additional 2.2% of rare VUS, has led to a multicenter international collaboration, currently ongoing, to define the role of ATM as a susceptibility gene to CM.	('ATM', 'Gene', '472', (24, 27))	('ATM', 'Gene', (239, 242))	('ATM', 'Gene', (24, 27))	('ATM', 'Gene', '472', (239, 242))	('variants', 'Var', (67, 75))
154396	32325837	The following are available online at , Figure S1: Pedigree diagrams from the families carrying loss of function variants in BAP1, POT1, ATM, ACD genes; Figure S2: Pedigree diagram from the family with the rare c.799_800delCA BAP1 germline variant.	('c.799_800delCA', 'Var', (211, 225))	('POT1', 'Gene', (131, 135))	('BAP1', 'Gene', (226, 230))	('BAP1', 'Gene', '8314', (125, 129))	('ATM', 'Gene', (137, 140))	('BAP1', 'Gene', (125, 129))	('ACD', 'Gene', (142, 145))	('c.799_800delCA', 'Mutation', 'c.799_800delCA', (211, 225))	('ACD', 'Gene', '65057', (142, 145))	('ATM', 'Gene', '472', (137, 140))	('variants', 'Var', (113, 121))	('BAP1', 'Gene', '8314', (226, 230))	('POT1', 'Gene', '25913', (131, 135))
154397	32325837	; writing:review and editing L.P., B.D., V.A., I.V., S.M., R.L.S., M.G., F.G., S.S. (Stefania Sciallero), M.A.G., W.B.	('F.G.', 'Var', (73, 77))	('Stefania Sciallero', 'Disease', (85, 103))	('Stefania Sciallero', 'Disease', 'None', (85, 103))	('M.G.', 'Var', (67, 71))	('M.A.G.', 'Var', (106, 112))	('S.S.', 'Var', (79, 83))
154398	32325837	; acquisition, analysis, and interpretation of data, L.P., V.A., B.D., I.V., G.C., M.M., G.S., M.A.P., G.P., M.G.T., E.S., M.G., P.C., G.M., S.M., S.S. (Serena Sestini), R.D., V.Z., R.L.S., I.S., A.B., L.M., F.G., S.S. (Stefania Sciallero), F.C., E.T.T., F.S., P.Q., A.M.G., W.B.	('F.S.', 'Var', (255, 259))	('P.Q.', 'Var', (261, 265))	('F.C.', 'Var', (241, 245))	('Stefania Sciallero', 'Disease', 'None', (220, 238))	('Stefania Sciallero', 'Disease', (220, 238))
154400	30739911	MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients.	('malignant pleural mesothelioma', 'Disease', (77, 107))	('MST1', 'Gene', (0, 4))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (343, 373))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (77, 107))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (353, 373))	('malignant pleural mesothelioma', 'Disease', (343, 373))	('Mesothelioma', 'Disease', (153, 165))	('Mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('Cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('methylation', 'Var', (25, 36))	('patients', 'Species', '9606', (63, 71))	('patients', 'Species', '9606', (380, 388))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('MPM', 'Disease', (375, 378))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (87, 107))	('MST1', 'Gene', '4485', (0, 4))	('MPM', 'Disease', 'MESH:C562839', (375, 378))	('cisplatin', 'Chemical', 'MESH:D002945', (294, 303))
154402	30739911	MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.	('MST1', 'Gene', (0, 4))	('human', 'Species', '9606', (127, 132))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('YAP/TAZ', 'Mutation', 'YAP/TAZ', (87, 94))	('inactivation', 'Var', (5, 17))	('MST1', 'Gene', '4485', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
154403	30739911	STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022).	('methylation', 'Var', (26, 37))	('MST1', 'Gene', (6, 10))	('STK4', 'Gene', (0, 4))	('STK4', 'Gene', '6789', (0, 4))	('patients', 'Species', '9606', (61, 69))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('STK4', 'molecular_function', 'GO:0050369', ('0', '4'))	('MST1', 'Gene', '4485', (6, 10))	('poorer', 'Disease', (96, 102))
154404	30739911	MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines.	('MST1', 'Gene', (0, 4))	('YAP', 'Gene', '10413', (162, 165))	('invasion', 'CPA', (92, 100))	('reduced', 'NegReg', (18, 25))	('TAZ', 'NegReg', (184, 187))	('YAP', 'Gene', (162, 165))	('cellular basal apoptotic activity', 'CPA', (26, 59))	('retention', 'biological_process', 'GO:0051235', ('200', '209'))	('soft agar', 'CPA', (106, 115))	('increasing', 'PosReg', (66, 76))	('inactivation', 'Var', (5, 17))	('MST1', 'Gene', '4485', (0, 4))	('proliferation', 'CPA', (77, 90))
154405	30739911	YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.	('YAP', 'Gene', (0, 3))	('decreased', 'NegReg', (14, 23))	('MST1', 'Gene', '4485', (36, 40))	('MST1', 'Gene', (36, 40))	('invasion of', 'CPA', (24, 35))	('YAP', 'Gene', '10413', (0, 3))	('silencing', 'Var', (4, 13))
154415	30739911	Several studies suggest that Hippo signalling pathway deregulation is involved in pleural carcinogenesis, since the RASSF1A tumour suppressor gene, an upstream negative regulator of the pathway, is frequently methylated and inactivated in MPM.	('RASSF1A', 'Gene', (116, 123))	('pleural carcinogenesis', 'Disease', (82, 104))	('MPM', 'Disease', 'MESH:C562839', (239, 242))	('inactivated', 'NegReg', (224, 235))	('MPM', 'Disease', (239, 242))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('RASSF1A', 'Gene', '11186', (116, 123))	('signalling pathway', 'biological_process', 'GO:0007165', ('35', '53'))	('deregulation', 'Var', (54, 66))	('Hippo signalling pathway', 'Pathway', (29, 53))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('pleural carcinogenesis', 'Disease', 'MESH:D063646', (82, 104))	('tumour', 'Disease', (124, 130))
154417	30739911	By transfecting cells with RNAi-MST1, we further reported that MST1 inactivation increases proliferation, invasion, and cell colony formation of MPM cell lines while decreasing their basal apoptotic activity.	('decreasing', 'NegReg', (166, 176))	('MST1', 'Gene', (63, 67))	('basal apoptotic activity', 'CPA', (183, 207))	('cell colony formation', 'CPA', (120, 141))	('MST1', 'Gene', '4485', (32, 36))	('MPM', 'Disease', 'MESH:C562839', (145, 148))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('invasion', 'CPA', (106, 114))	('MST1', 'Gene', (32, 36))	('RNAi', 'biological_process', 'GO:0016246', ('27', '31'))	('proliferation', 'CPA', (91, 104))	('MPM', 'Disease', (145, 148))	('inactivation', 'Var', (68, 80))	('MST1', 'Gene', '4485', (63, 67))	('increases', 'PosReg', (81, 90))
154426	30739911	Whole-cell protein extracts were prepared as previously described, and proteins were detected by immunoblotting with the primary antibody from cell signalling (E-Cadherin, MST1, YAP/TAZ, P-Ser127YAP, GAPDH, vimentin), diluted to 1:1000 in Tween (0.1%)-tris-buffered saline buffer and horseradish peroxidase-conjugated secondary antibody, and then revealed by enhanced chemiluminescence using the ECL kit (Promega ).	('P-Ser127YAP', 'Var', (187, 198))	('Ser', 'cellular_component', 'GO:0005790', ('189', '192'))	('MST1', 'Gene', (172, 176))	('E-Cadherin', 'Gene', '999', (160, 170))	('GAPDH', 'Gene', '2597', (200, 205))	('antibody', 'molecular_function', 'GO:0003823', ('328', '336'))	('enhanced', 'PosReg', (359, 367))	('signalling', 'biological_process', 'GO:0023052', ('148', '158'))	('antibody', 'cellular_component', 'GO:0042571', ('328', '336'))	('antibody', 'cellular_component', 'GO:0019815', ('129', '137'))	('vimentin', 'Gene', '7431', (207, 215))	('vimentin', 'Gene', (207, 215))	('GAPDH', 'Gene', (200, 205))	('MST1', 'Gene', '4485', (172, 176))	('Cadherin', 'molecular_function', 'GO:0008014', ('162', '170'))	('E-Cadherin', 'Gene', (160, 170))	('antibody', 'cellular_component', 'GO:0019814', ('129', '137'))	('vimentin', 'cellular_component', 'GO:0045098', ('207', '215'))	('antibody', 'cellular_component', 'GO:0019815', ('328', '336'))	('chemiluminescence', 'MPA', (368, 385))	('Tween', 'Chemical', 'MESH:D011136', (239, 244))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))	('P-Ser127YAP', 'Chemical', 'MESH:C530429', (187, 198))	('vimentin', 'cellular_component', 'GO:0045099', ('207', '215'))	('antibody', 'molecular_function', 'GO:0003823', ('129', '137'))	('horseradish', 'Species', '3704', (284, 295))	('antibody', 'cellular_component', 'GO:0019814', ('328', '336'))	('antibody', 'cellular_component', 'GO:0042571', ('129', '137'))	('YAP/TAZ', 'Mutation', 'YAP/TAZ', (178, 185))
154438	30739911	RASSF1A, RASSF2A, RASSF6, and RASSF10 were found to be methylated in 11.1%, 14.5%, 21.5%, and 4.4% of samples, respectively, while no sample exhibited any RASSF5, MST2, LATS1, or LATS2 methylation.	('RASSF1A', 'Gene', (0, 7))	('LATS1', 'Gene', (169, 174))	('RASSF5', 'Gene', '83593', (155, 161))	('LATS1', 'Gene', '9113', (169, 174))	('RASSF6', 'Gene', '166824', (18, 24))	('RASSF5', 'Gene', (155, 161))	('LATS2', 'Gene', (179, 184))	('LATS2', 'Gene', '26524', (179, 184))	('methylation', 'biological_process', 'GO:0032259', ('185', '196'))	('RASSF1A', 'Gene', '11186', (0, 7))	('RASSF10', 'Gene', '644943', (30, 37))	('methylated', 'Var', (55, 65))	('RASSF6', 'Gene', (18, 24))	('RASSF2A', 'Gene', (9, 16))	('RASSF10', 'Gene', (30, 37))
154441	30739911	In univariate analysis, the median OS of patients with methylated MST1 promoter was 1.4 times lower than that of patients with unmethylated MST1 promoter (13.0 versus 19.3 months, HR: 2.40, 95% CI (1.48-3.90), p < 0.001) (Fig.	('MST1', 'Gene', (66, 70))	('patients', 'Species', '9606', (113, 121))	('patients', 'Species', '9606', (41, 49))	('methylated', 'Var', (55, 65))	('lower', 'NegReg', (94, 99))	('MST1', 'Gene', '4485', (140, 144))	('MST1', 'Gene', (140, 144))	('MST1', 'Gene', '4485', (66, 70))
154442	30739911	Moreover, univariate analyses showed that methylation of MST1 gene predicted worse survival in each treatment group separately, with HR = 2.29 (95% CI 1.13-4.65), p = 0.021 for the chemotherapy arm and 2.50 (95% CI 1.27-4.90), p = 0.0079 for the bevacizumab arm (Figure S2).	('MST1', 'Gene', '4485', (57, 61))	('methylation', 'Var', (42, 53))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('MST1', 'Gene', (57, 61))	('worse', 'NegReg', (77, 82))
154443	30739911	1b), and validated by a bootstrap procedure: MST1 methylation was significantly associated with worse OS in 59% of 1000 bootstrapped samples, with an optimism corrected c-index of 0.67.	('worse OS', 'Disease', (96, 104))	('MST1', 'Gene', (45, 49))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('associated', 'Reg', (80, 90))	('MST1', 'Gene', '4485', (45, 49))	('methylation', 'Var', (50, 61))
154445	30739911	Finally, MST1 inactivation did not significantly predict PFS for MPM patients, although there was a correlating trend of a deleterious impact (HR: 1.53, 95% CI (0.95-2.46), p = 0.082 in univariate analysis).	('MST1', 'Gene', '4485', (9, 13))	('inactivation', 'Var', (14, 26))	('MST1', 'Gene', (9, 13))	('MPM', 'Disease', (65, 68))	('patients', 'Species', '9606', (69, 77))	('MPM', 'Disease', 'MESH:C562839', (65, 68))	('PFS', 'Disease', (57, 60))
154446	30739911	Since MST1 methylation status was the only alteration found to significantly influence prognosis in our large series of MPM patients, we focussed our functional mesothelial cell studies on this protein's role.	('MST1', 'Gene', (6, 10))	('influence', 'Reg', (77, 86))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('prognosis', 'MPA', (87, 96))	('MPM', 'Disease', 'MESH:C562839', (120, 123))	('methylation', 'Var', (11, 22))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('MPM', 'Disease', (120, 123))	('MST1', 'Gene', '4485', (6, 10))	('patients', 'Species', '9606', (124, 132))
154454	30739911	2c) (as H2052 and H28, data not shown) appeared significantly modified, and MST1 knockdown cells exhibited more cytoplasmic extensions than mock-transfected cells.	('cytoplasmic extensions', 'CPA', (112, 134))	('MST1', 'Gene', '4485', (76, 80))	('MST1', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('H2052', 'CellLine', 'CVCL:1518', (8, 13))	('more', 'PosReg', (107, 111))	('H28', 'Chemical', 'MESH:C414365', (18, 21))
154457	30739911	2d), thus suggesting an increased ability for cell migration upon MST1 knockdown.	('cell migration', 'biological_process', 'GO:0016477', ('46', '60'))	('MST1', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))	('cell migration', 'CPA', (46, 60))	('increased', 'PosReg', (24, 33))	('MST1', 'Gene', '4485', (66, 70))
154458	30739911	We observed that MST1 depletion significantly increased the ability of MSTO-211H, H2452 (Fig.	('H2452', 'CellLine', 'CVCL:1553', (82, 87))	('increased', 'PosReg', (46, 55))	('depletion', 'Var', (22, 31))	('MSTO-211H', 'Chemical', 'MESH:C073773', (71, 80))	('MST1', 'Gene', '4485', (17, 21))	('MST1', 'Gene', (17, 21))
154460	30739911	Moreover, colony formation on soft agar was increased by MST1 depletion in MSTO-211H, H2452 (Fig.	('increased', 'PosReg', (44, 53))	('MST1', 'Gene', '4485', (57, 61))	('colony formation on soft agar', 'CPA', (10, 39))	('depletion', 'Var', (62, 71))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('H2452', 'CellLine', 'CVCL:1553', (86, 91))	('MST1', 'Gene', (57, 61))	('MSTO-211H', 'Chemical', 'MESH:C073773', (75, 84))
154470	30739911	It should be noted that in MSTO-211H cells, cells with LATS1 kinase inactivation, the Hippo pathway remains functional as demonstrated by the increase of phosphorylation on the serine 127 of YAP with increasing cell density (Figure S4A) and the concomitant decrease in intensity of nuclear YAP (Figure S4B), LATS1 inactivation being probably compensated by another NDR kinases.	('serine', 'Chemical', 'MESH:C047902', (177, 183))	('LATS1', 'Gene', '9113', (55, 60))	('increase', 'PosReg', (142, 150))	('YAP', 'Gene', '10413', (191, 194))	('YAP', 'Gene', '10413', (290, 293))	('LATS1', 'Gene', (308, 313))	('phosphorylation', 'biological_process', 'GO:0016310', ('154', '169'))	('LATS1', 'Gene', '9113', (308, 313))	('NDR', 'Gene', '11329', (365, 368))	('decrease', 'NegReg', (257, 265))	('phosphorylation on the serine 127', 'MPA', (154, 187))	('NDR', 'Gene', (365, 368))	('YAP', 'Gene', (191, 194))	('LATS1', 'Gene', (55, 60))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (27, 42))	('YAP', 'Gene', (290, 293))	('inactivation', 'Var', (68, 80))	('Hippo pathway', 'Pathway', (86, 99))
154471	30739911	By using immunocytochemistry, we actually found that MST1 depletion led to nuclear YAP accumulation, suggesting a decrease in YAP phosphorylation.	('YAP', 'Gene', '10413', (83, 86))	('YAP', 'Gene', (126, 129))	('YAP', 'Gene', (83, 86))	('MST1', 'Gene', '4485', (53, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('130', '145'))	('MST1', 'Gene', (53, 57))	('depletion', 'Var', (58, 67))	('YAP', 'Gene', '10413', (126, 129))	('decrease', 'NegReg', (114, 122))
154483	30739911	By silencing YAP in MST1-depleted MSTO-211H or H2452 cells, in line with such hypothesis, we were finally able to decrease their invasion through Matrigel  (Fig.	('silencing', 'Var', (3, 12))	('MST1', 'Gene', (20, 24))	('H2452', 'CellLine', 'CVCL:1553', (47, 52))	('invasion through Matrigel', 'CPA', (129, 154))	('YAP', 'Gene', '10413', (13, 16))	('decrease', 'NegReg', (114, 122))	('YAP', 'Gene', (13, 16))	('MST1', 'Gene', '4485', (20, 24))	('MSTO-211H', 'Chemical', 'MESH:C073773', (34, 43))
154488	30739911	While MST1 inactivation had not previously been evidenced in MPM, our findings are in line with the reports of frequent genetic alterations of Hippo pathway members recently revealed in MPM and support the concept that Hippo pathway alterations are key events in pleural carcinogenesis.,27, Interestingly, our study further revealed that the hypermethylation of MST1 promoter is associated with significantly worse OS for MPM patients, which is consistent with its tumour suppressor function and biomarker potential status.	('MST1', 'Gene', '4485', (362, 366))	('worse', 'NegReg', (409, 414))	('tumour', 'Disease', 'MESH:D009369', (465, 471))	('MST1', 'Gene', (6, 10))	('MPM', 'Disease', 'MESH:C562839', (186, 189))	('MPM', 'Disease', (186, 189))	('MST1', 'Gene', (362, 366))	('MPM', 'Disease', (61, 64))	('MPM', 'Disease', 'MESH:C562839', (422, 425))	('tumour', 'Disease', (465, 471))	('MPM', 'Disease', (422, 425))	('pleural carcinogenesis', 'Disease', 'MESH:D063646', (263, 285))	('MPM', 'Disease', 'MESH:C562839', (61, 64))	('patients', 'Species', '9606', (426, 434))	('MST1', 'Gene', '4485', (6, 10))	('hypermethylation', 'Var', (342, 358))	('tumour', 'Phenotype', 'HP:0002664', (465, 471))	('pleural carcinogenesis', 'Disease', (263, 285))
154494	30739911	In line with such reports, our study found that the nuclear YAP accumulation induced by MST1 depletion is consistent with a P-Ser127YAP decrease in MST1-depleted cells with ANKDR1 and Cyr61 gene transcription increase, supporting the fact that YAP accumulated under its active form in the nucleus.	('transcription', 'biological_process', 'GO:0006351', ('195', '208'))	('MST1', 'Gene', '4485', (148, 152))	('Ser', 'cellular_component', 'GO:0005790', ('126', '129'))	('YAP', 'Gene', (244, 247))	('YAP', 'Gene', (132, 135))	('Cyr61', 'Gene', '3491', (184, 189))	('MST1', 'Gene', (88, 92))	('YAP', 'Gene', (60, 63))	('P-Ser127YAP', 'Chemical', 'MESH:C530429', (124, 135))	('increase', 'PosReg', (209, 217))	('YAP', 'Gene', '10413', (244, 247))	('ANKDR1', 'Gene', (173, 179))	('Cyr61', 'Gene', (184, 189))	('YAP', 'Gene', '10413', (132, 135))	('MST1', 'Gene', (148, 152))	('MST1', 'Gene', '4485', (88, 92))	('decrease', 'NegReg', (136, 144))	('YAP', 'Gene', '10413', (60, 63))	('nucleus', 'cellular_component', 'GO:0005634', ('289', '296'))	('depletion', 'Var', (93, 102))
154495	30739911	We also revealed that YAP inactivation in MST1-depleted cells was able to fully reverse their ability to invade Matrigel .	('MST1', 'Gene', (42, 46))	('inactivation', 'Var', (26, 38))	('YAP', 'Gene', '10413', (22, 25))	('YAP', 'Gene', (22, 25))	('MST1', 'Gene', '4485', (42, 46))
154497	30739911	That loss of MST1 expression involving YAP has already been reported in the literature, as has the involvement of YAP in the tumour progression of MPM, yet our study was the first to identify Hippo kinase inactivation leading to YAP deregulation.	('YAP', 'Gene', '10413', (114, 117))	('tumour', 'Disease', (125, 131))	('YAP', 'Gene', (114, 117))	('YAP', 'Gene', '10413', (229, 232))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('YAP', 'Gene', '10413', (39, 42))	('MPM', 'Disease', 'MESH:C562839', (147, 150))	('loss', 'NegReg', (5, 9))	('MPM', 'Disease', (147, 150))	('YAP', 'Gene', (229, 232))	('MST1', 'Gene', '4485', (13, 17))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('YAP', 'Gene', (39, 42))	('inactivation', 'Var', (205, 217))	('MST1', 'Gene', (13, 17))	('deregulation', 'MPA', (233, 245))
154499	30739911	In line with our results, another team recently reported that YAP inactivation in the MSTO-211H cells, which contain an inactive kinase-truncated LATS1 fusion protein and thus a constitutively nuclear active YAP by wild-type LATS1 kinase overexpression leading to YAP phosphorylation, was able to restore YAP to its cytoplasmic location, consisting of a surrogate marker for its functional inactivation .	('YAP', 'Gene', '10413', (264, 267))	('LATS1', 'Gene', '9113', (225, 230))	('LATS1', 'Gene', '9113', (146, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('268', '283'))	('YAP', 'Gene', '10413', (208, 211))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('YAP', 'Gene', (264, 267))	('YAP', 'Gene', '10413', (305, 308))	('inactivation', 'Var', (66, 78))	('YAP', 'Gene', (305, 308))	('YAP', 'Gene', (208, 211))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (86, 101))	('YAP', 'Gene', '10413', (62, 65))	('restore', 'PosReg', (297, 304))	('LATS1', 'Gene', (146, 151))	('LATS1', 'Gene', (225, 230))	('YAP', 'Gene', (62, 65))
154501	30739911	Similarly, another team recently experimented with H2452 cells with wild-type LATS1, using YAP RNAi-mediated knockdown, demonstrating that such YAP depletion also inhibited the growth of H2452 mesothelial cells and significantly suppressed Hippo pathway transcriptional activity, with decreased invasion, tumorosphere formation, and impaired stem cell self-renewal capacity.	('stem cell self-renewal capacity', 'CPA', (342, 373))	('YAP', 'Gene', (144, 147))	('growth', 'CPA', (177, 183))	('inhibited', 'NegReg', (163, 172))	('transcriptional', 'MPA', (254, 269))	('Hippo pathway', 'Pathway', (240, 253))	('YAP', 'Gene', (91, 94))	('YAP', 'Gene', '10413', (144, 147))	('tumorosphere formation', 'CPA', (305, 327))	('suppressed', 'NegReg', (229, 239))	('LATS1', 'Gene', (78, 83))	('LATS1', 'Gene', '9113', (78, 83))	('decreased', 'NegReg', (285, 294))	('invasion', 'CPA', (295, 303))	('RNAi', 'biological_process', 'GO:0016246', ('95', '99'))	('H2452', 'CellLine', 'CVCL:1553', (187, 192))	('YAP', 'Gene', '10413', (91, 94))	('formation', 'biological_process', 'GO:0009058', ('318', '327'))	('H2452', 'CellLine', 'CVCL:1553', (51, 56))	('impaired', 'NegReg', (333, 341))	('depletion', 'Var', (148, 157))
154512	29085453	Overall, this data suggests that KP-MM-8 may be considered as a cancer/testis-like antigen and KP-MM-5 as an immunogenic tumor antigen in MM patients.	('KP-MM-8', 'Var', (33, 40))	('KP-MM-5', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', (64, 70))	('tumor', 'Disease', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('patients', 'Species', '9606', (141, 149))	('tumor antigen', 'molecular_function', 'GO:0008222', ('121', '134'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
154560	29085453	Seroreactivity testing of 7 phage clones, consisting of KP-MM-2, KP-MM-5, KP-MM-6, KP-MM-7, KP-MM-8, KP-MM-9 and KP-MM-12, was performed using the sera of 8 MM patients and 8 healthy donors by phage plaque assay (Fig.	('KP-MM-9', 'Var', (101, 108))	('KP-MM-8', 'Var', (92, 99))	('patients', 'Species', '9606', (160, 168))	('KP-MM-6', 'Var', (74, 81))	('KP-MM-5', 'Var', (65, 72))	('sera', 'molecular_function', 'GO:0004617', ('147', '151'))	('KP-MM-7', 'Var', (83, 90))
154566	29085453	Notably, 6 of the 16 identified genes (KP-MM-6, KP-MM-7, KP-MM-12, KP-MM-13, KP-MM-14 and KP-MM-19) belonged to the zinc finger gene family.	('KP-MM-12', 'Var', (57, 65))	('KP-MM-6', 'Var', (39, 46))	('KP-MM-13', 'Var', (67, 75))	('belonged', 'Reg', (100, 108))	('KP-MM-7', 'Var', (48, 55))	('KP-MM-14 and KP-MM-19', 'Disease', 'MESH:C535488', (77, 98))
154768	15496233	When performing this function on the mesothelioma dataset, epidermal growth factor receptor (EGFR) inhibitors in combination with eniluracil and topoisomerase II inhibitors are identified as a possible combination treatment for mesothelioma based upon relatively high expression of their molecular targets EGFR, Dihydropyrimidine dehydrogenase and topoisomerase II respectively.	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', '1956', (306, 310))	('mesothelioma', 'Disease', 'MESH:D008654', (228, 240))	('inhibitors', 'Var', (99, 109))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('145', '161'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('59', '82'))	('EGFR', 'Gene', (93, 97))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('348', '364'))	('EGFR', 'Gene', (306, 310))	('eniluracil', 'Chemical', 'MESH:C073482', (130, 140))	('mesothelioma', 'Disease', (37, 49))	('mesothelioma', 'Disease', (228, 240))	('EGFR', 'molecular_function', 'GO:0005006', ('306', '310'))
154771	15496233	Recently, it was shown that lung carcinomas from a subset of patients that possess activating mutations in the EGFR are most responsive to Iressa.	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('mutations', 'Var', (94, 103))	('EGFR', 'Gene', '1956', (111, 115))	('lung carcinomas', 'Disease', (28, 43))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', (111, 115))	('responsive to Iressa', 'MPA', (125, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('lung carcinomas', 'Disease', 'MESH:D008175', (28, 43))	('activating', 'PosReg', (83, 93))
154773	15496233	The following discussion will focus on a high-throughput means by which we assess the functional significance of target gene/protein disruption in murine models of various human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (178, 190))	('malignancies', 'Disease', (178, 190))	('disruption', 'Var', (133, 143))	('human', 'Species', '9606', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('murine', 'Species', '10090', (147, 153))
154776	15496233	This system was developed to allow us to target the delivery of gene-specific siRNA to tumor and/or endothelial cells in vivo, such that the effect that target gene disruption has on tumor growth, metastasis and angiogenesis can be directly assessed.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('angiogenesis', 'CPA', (212, 224))	('metastasis', 'CPA', (197, 207))	('tumor', 'Disease', (183, 188))	('disruption', 'Var', (165, 175))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('angiogenesis', 'biological_process', 'GO:0001525', ('212', '224'))
154853	27462362	We asked for information from the registry on all cases of cancer with ICD-10 code C45 mesothelioma (the accurate location was read from the decimal figure, pleura, peritoneum, and other and unspecified sites), and ICD-O codes 9050, 9051, 9052, and 9053, mesothelioma, with the behaviour code /3, malignant, primary site.	('mesothelioma', 'Disease', (255, 267))	('mesothelioma', 'Disease', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('behaviour', 'biological_process', 'GO:0007610', ('278', '287'))	('mesothelioma', 'Disease', 'MESH:D008654', (255, 267))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('C45', 'Var', (83, 86))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('unspecified', 'Species', '32644', (191, 202))
154861	27462362	Information on the volume of annual import of asbestos and goods containing asbestos was obtained from Statistics Iceland, according to Customs Tariff, the Directorate of Customs, codes under 2524, 6811, 6812, 6813, and 8708 with mention of asbestos, and corresponding codes from older versions of the Customs Tariffs.	('men', 'Species', '9606', (230, 233))	('6812', 'Var', (204, 208))	('asbestos', 'Chemical', 'MESH:D001194', (241, 249))	('asbestos', 'Chemical', 'MESH:D001194', (76, 84))	('asbestos', 'Chemical', 'MESH:D001194', (46, 54))	('codes', 'Var', (180, 185))	('6813', 'Var', (210, 214))	('6811', 'Var', (198, 202))
154873	27462362	Malignant mesothelioma NOS (M-9050/3) is the dominant histological type for both genders.	('Malignant mesothelioma NOS', 'Disease', (0, 26))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma NOS', 'Disease', 'MESH:C562839', (0, 26))	('M-9050/3', 'Var', (28, 36))
154890	27462362	There is sufficient evidence that asbestos exposure causes lung, larynx and ovarian cancer, and limited evidence that it causes colorectal, pharynx and stomach cancers.	('colorectal', 'Disease', (128, 138))	('lung', 'Disease', (59, 63))	('ovarian cancer', 'Disease', (76, 90))	('stomach cancers', 'Disease', (152, 167))	('larynx', 'Disease', (65, 71))	('stomach cancers', 'Disease', 'MESH:D013274', (152, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('stomach cancers', 'Phenotype', 'HP:0012126', (152, 167))	('causes', 'Reg', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pharynx', 'Disease', (140, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('asbestos', 'Var', (34, 42))	('asbestos', 'Chemical', 'MESH:D001194', (34, 42))
154909	21956388	BAP1 is a tumor suppressor gene located on chromosome 3p21 in a region that shows loss or deletions in numerous cancers, including lung and breast cancer, as well as uveal melanoma and mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('numerous cancers', 'Disease', (103, 119))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (10, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('loss', 'NegReg', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('deletions', 'Var', (90, 99))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('breast cancer', 'Disease', (140, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (166, 197))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('lung', 'Disease', (131, 135))	('numerous cancers', 'Disease', 'MESH:D009369', (103, 119))	('BAP1', 'Gene', '8314', (0, 4))
154911	21956388	Harbour et al found inactivating somatic mutations of BAP1 in 47% (28/60) (Table 1) of uveal melanoma with a much higher frequency of somatic mutations (27/34, 79%) in metastasizing uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('uveal melanoma', 'Disease', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('BAP1', 'Gene', '8314', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('inactivating', 'Var', (20, 32))	('BAP1', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))	('uveal melanoma', 'Disease', (182, 196))
154914	21956388	In this issue, Wiesner, Bastian, Speicher and colleagues and Testa, Carbone, and colleagues provide further links between BAP1, uveal melanoma and mesothelioma by reporting on germline mutations of BAP1 in two putatively distinct cancer-related syndromes characterized predominantly by melanocytic tumors or mesothelioma, respectively, plus uveal melanoma in both disorders.	('mesothelioma', 'Disease', (147, 159))	('BAP1', 'Gene', (122, 126))	('melanocytic tumors', 'Disease', (286, 304))	('BAP1', 'Gene', '8314', (198, 202))	('melanocytic tumors', 'Disease', 'MESH:D009508', (286, 304))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('cancer', 'Disease', (230, 236))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (128, 159))	('BAP1', 'Gene', (198, 202))	('uveal melanoma', 'Disease', 'MESH:C536494', (341, 355))	('melanoma', 'Phenotype', 'HP:0002861', (347, 355))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('uveal melanoma', 'Disease', (341, 355))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('uveal melanoma', 'Disease', (128, 142))	('BAP1', 'Gene', '8314', (122, 126))	('mesothelioma', 'Disease', (308, 320))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('germline mutations', 'Var', (176, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (341, 355))	('mesothelioma', 'Disease', 'MESH:D008654', (308, 320))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
154915	21956388	Wiesner et al identified co-segregating germline mutations of BAP1 in two families (1 and 2) with multiple members with melanocytic tumors that ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that had features that overlapped with cutaneous melanoma.	('cutaneous melanoma', 'Disease', (271, 289))	('BAP1', 'Gene', '8314', (62, 66))	('melanocytic tumors', 'Disease', (120, 138))	('melanocytic tumors', 'Disease', 'MESH:D009508', (120, 138))	('germline mutations', 'Var', (40, 58))	('nevi to atypical melanocytic proliferations', 'Phenotype', 'HP:0000995', (188, 231))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (271, 289))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (271, 289))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BAP1', 'Gene', (62, 66))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (205, 231))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('epithelioid nevi', 'Disease', (176, 192))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('nevi', 'Phenotype', 'HP:0003764', (188, 192))	('atypical melanocytic proliferations', 'Phenotype', 'HP:0001062', (196, 231))	('melanocytic proliferations', 'Disease', (205, 231))
154918	21956388	Examination of a subset of the familial melanocytic tumors revealed that the majority of tumors showed biallelic inactivation of BAP1 by various somatic alterations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('biallelic inactivation', 'Var', (103, 125))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BAP1', 'Gene', '8314', (129, 133))	('familial melanocytic tumors', 'Disease', 'MESH:C536819', (31, 58))	('BAP1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('familial melanocytic tumors', 'Disease', (31, 58))
154919	21956388	Testa et al discovered co-segregating germline mutations in BAP1 in two families (L and W) with 5 or more members with mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('mesothelioma', 'Disease', (119, 131))	('BAP1', 'Gene', '8314', (60, 64))	('germline mutations', 'Var', (38, 56))	('BAP1', 'Gene', (60, 64))
154921	21956388	The families also had multiple members with various malignancies including two members with uveal melanoma in family L. Somatic alterations of the familial mesothelioma tumors indicated biallelic inactivation of BAP1.	('familial mesothelioma tumors', 'Disease', (147, 175))	('BAP1', 'Gene', (212, 216))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (156, 175))	('biallelic inactivation', 'Var', (186, 208))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('malignancies', 'Disease', (52, 64))	('BAP1', 'Gene', '8314', (212, 216))	('familial mesothelioma tumors', 'Disease', 'MESH:D008654', (147, 175))
154922	21956388	Testa et al also sequenced BAP1 in germline DNAs from 26 sporadic mesothelioma cases and uncovered two inactivating frameshift mutations in patients subsequently found to have had uveal melanoma.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (57, 78))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('uveal melanoma', 'Disease', (180, 194))	('BAP1', 'Gene', (27, 31))	('mesothelioma', 'Disease', (66, 78))	('patients', 'Species', '9606', (140, 148))	('frameshift mutations', 'Var', (116, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('BAP1', 'Gene', '8314', (27, 31))
154925	21956388	Several cancers including cutaneous melanoma (n=3), non-melanoma skin (n=2), ovarian (n=1), breast (n=1), renal (n=1), and pancreatic (n=1) cancer occurred in family members who inherited their family's inactivating BAP1 mutation.	('inactivating', 'Var', (203, 215))	('BAP1', 'Gene', (216, 220))	('pancreatic', 'Disease', 'MESH:D010195', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('breast', 'Disease', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancer', 'Disease', (8, 14))	('cancers', 'Disease', (8, 15))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('non-melanoma skin', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('pancreatic', 'Disease', (123, 133))	('non-melanoma skin', 'Disease', 'MESH:D008545', (52, 69))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('ovarian', 'Disease', (77, 84))	('cancer', 'Disease', (140, 146))	('BAP1', 'Gene', '8314', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutation', 'Var', (221, 229))	('cutaneous melanoma', 'Disease', (26, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (26, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (26, 44))	('occurred', 'Reg', (147, 155))	('renal', 'Disease', (106, 111))
154926	21956388	Whether these cancers are part of the spectrum of tumors related to germline BAP1 mutations requires additional study.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('BAP1', 'Gene', (77, 81))
154927	21956388	Data from COSMIC (Catalogue Of Somatic Mutations In Cancer) showed low frequencies of somatic BAP1 mutations in several of the observed tumors including breast (0.4%), ovarian (3.4%), and pancreatic (0.0%) cancer (table 1).	('tumors', 'Disease', (136, 142))	('ovarian', 'Disease', (168, 175))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BAP1', 'Gene', '8314', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast', 'Disease', (153, 159))	('pancreatic', 'Disease', 'MESH:D010195', (188, 198))	('mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('pancreatic', 'Disease', (188, 198))	('BAP1', 'Gene', (94, 98))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
154928	21956388	In addition, Wiesner et al showed that five percent (3/60) of primary melanomas originating from acral skin (n=15), mucosa (n=15), or skin with (n=15) or without chronic sun damage had somatic BAP1 mutations.	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('BAP1', 'Gene', '8314', (193, 197))	('mutations', 'Var', (198, 207))	('sun damage', 'Phenotype', 'HP:0000992', (170, 180))	('BAP1', 'Gene', (193, 197))	('melanomas', 'Disease', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
154929	21956388	Finally, lung cancer, which was one of the first cancers originally reported to have BAP1 somatic mutations, also had very few somatic mutations (0.6%) suggesting that another gene in the 3p21 region may be implicated in some of the cancers that show loss/deletion in this region.	('BAP1', 'Gene', (85, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('implicated', 'Reg', (207, 217))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('mutations', 'Var', (98, 107))	('loss/deletion', 'NegReg', (251, 264))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('BAP1', 'Gene', '8314', (85, 89))	('lung cancer', 'Disease', (9, 20))	('cancers', 'Disease', (49, 56))
154933	21956388	Harbour et al hypothesized that biallelic loss of BAP1 was a key event in uveal melanoma metastasis.	('uveal melanoma metastasis', 'Disease', (74, 99))	('biallelic', 'Var', (32, 41))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (74, 99))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (50, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('loss', 'NegReg', (42, 46))
154934	21956388	The current studies suggest a potentially more complex scenario that may depend on various combinations of the tissue of origin, environmental exposures, functional consequences of the BAP1 mutations, and mechanisms of inactivation of the second BAP1 allele.	('BAP1', 'Gene', (246, 250))	('BAP1', 'Gene', (185, 189))	('mutations', 'Var', (190, 199))	('BAP1', 'Gene', '8314', (246, 250))	('BAP1', 'Gene', '8314', (185, 189))
154938	21956388	Given its complexity, different germline mutations in BAP1 may predispose to divergent tumor types.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('germline mutations', 'Var', (32, 50))	('predispose', 'Reg', (63, 73))	('tumor', 'Disease', (87, 92))	('BAP1', 'Gene', '8314', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('BAP1', 'Gene', (54, 58))
154939	21956388	For what tumor types do germline mutations of BAP1 increase susceptibility?	('increase', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', '8314', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('germline mutations', 'Var', (24, 42))	('BAP1', 'Gene', (46, 50))	('susceptibility', 'MPA', (60, 74))
154944	23371858	Antibodies against mesothelin have been shown to act via immunotoxin-based inhibition of tumor growth and induction of antibody-dependent cellular cytotoxicity (ADCC).	('Antibodies', 'Var', (0, 10))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('119', '159'))	('antibody', 'cellular_component', 'GO:0019815', ('119', '127'))	('antibody', 'cellular_component', 'GO:0042571', ('119', '127'))	('inhibition', 'NegReg', (75, 85))	('cytotoxicity', 'Disease', (147, 159))	('antibody', 'cellular_component', 'GO:0019814', ('119', '127'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mesothelin', 'Gene', (19, 29))	('antibody', 'molecular_function', 'GO:0003823', ('119', '127'))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('ADCC', 'biological_process', 'GO:0001788', ('161', '165'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
154947	23371858	SD1 recognizes a conformational epitope at the C-terminal end (residues 539-588) of mesothelin close to the cell surface.	('residues 539-588', 'Var', (63, 79))	('SD1', 'Gene', (0, 3))	('cell surface', 'cellular_component', 'GO:0009986', ('108', '120'))	('SD1', 'Gene', '57306', (0, 3))
155059	23371858	In contrast, the control single-domain antibody and HN1 showed no activity at the same concentrations, indicating that targeting to the C-terminal epitope of SD1 is capable of inducing CDC.	('SD1', 'Gene', (158, 161))	('antibody', 'molecular_function', 'GO:0003823', ('39', '47'))	('inducing', 'PosReg', (176, 184))	('SD1', 'Gene', '57306', (158, 161))	('antibody', 'cellular_component', 'GO:0042571', ('39', '47'))	('targeting', 'Var', (119, 128))	('antibody', 'cellular_component', 'GO:0019815', ('39', '47'))	('CDC', 'MPA', (185, 188))	('antibody', 'cellular_component', 'GO:0019814', ('39', '47'))
155093	23371858	Our data demonstrate that CDC triggered by SD1-hFc depends on the specific new epitope because the HN1 human IgG (specific for the N-terminus of mesothelin, Region I, far from the cell surface) does not exhibit CDC activity and cannot recruit C1q to cancer cells.	('cell surface', 'cellular_component', 'GO:0009986', ('180', '192'))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('SD1', 'Gene', '57306', (43, 46))	('human', 'Species', '9606', (103, 108))	('C1q', 'cellular_component', 'GO:0062167', ('243', '246'))	('cancer', 'Disease', (250, 256))	('CDC', 'Disease', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('C1q', 'Gene', '712', (243, 246))	('C1q', 'Gene', (243, 246))	('HN1 human', 'Var', (99, 108))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('SD1', 'Gene', (43, 46))
155098	23371858	MORAb-009 is the only anti-mesothelin antibody currently being evaluated in clinical trials and should be compared to SD1.	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('SD1', 'Gene', (118, 121))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('SD1', 'Gene', '57306', (118, 121))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))	('MORAb-009', 'Var', (0, 9))
155103	23371858	Human single-domain antibodies are attractive candidates for cancer therapy.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('single-domain antibodies', 'Var', (6, 30))
155175	23486268	The predominant cause for manual editing of lung segmentations was erroneous inclusion of segmented bowel gas.	('erroneous', 'Var', (67, 76))	('segmented bowel gas', 'Disease', (90, 109))	('segmented bowel gas', 'Disease', 'MESH:C537538', (90, 109))	('lung segmentation', 'Phenotype', 'HP:0002101', (44, 61))
155184	23486268	The performance of the full multivariate model trained and tested on the same patient cohort was 0.692, 0.680, and 0.670 for the models using linear thickness measurements, disease volume measurements, and normalized lung volume measurements, respectively, along with the same clinical covariates.	('patient', 'Species', '9606', (78, 85))	('0.670', 'Var', (115, 120))	('0.680', 'Var', (104, 109))
155273	23503999	The prognosis depends firstly on the resectability of the tumor, secondly on its size, and then, in decreasing order of importance, on the mitotic count, polymorphism, and necrosis within the tumor.	('necrosis', 'biological_process', 'GO:0019835', ('172', '180'))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (192, 197))	('polymorphism', 'Var', (154, 166))	('necrosis', 'biological_process', 'GO:0008220', ('172', '180'))	('necrosis', 'biological_process', 'GO:0001906', ('172', '180'))	('necrosis within the tumor', 'Disease', (172, 197))	('necrosis within the tumor', 'Disease', 'MESH:D001929', (172, 197))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('necrosis', 'biological_process', 'GO:0070265', ('172', '180'))	('necrosis', 'biological_process', 'GO:0008219', ('172', '180'))
155338	21807578	An in-depth review of the existing literature suggests a role for mutagenesis in asbestos-induced neoplastic diseases but not in non-neoplastic diseases.	('neoplastic diseases', 'Disease', (98, 117))	('neoplastic disease', 'Phenotype', 'HP:0002664', (98, 116))	('non-neoplastic diseases', 'Disease', 'MESH:D000073296', (129, 152))	('neoplastic disease', 'Phenotype', 'HP:0002664', (133, 151))	('non-neoplastic diseases', 'Disease', (129, 152))	('neoplastic diseases', 'Disease', 'MESH:D009386', (133, 152))	('neoplastic diseases', 'Disease', 'MESH:D009386', (98, 117))	('mutagenesis', 'biological_process', 'GO:0006280', ('66', '77'))	('asbestos', 'Chemical', 'MESH:D001194', (81, 89))	('mutagenesis', 'Var', (66, 77))
155339	21807578	Thus, mutagenicity is one MOA for asbestos-induced neoplastic diseases, although this does not rule out a role for inflammation, cellular toxicity, and oxidative stress.	('neoplastic disease', 'Phenotype', 'HP:0002664', (51, 69))	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('mutagenicity', 'Var', (6, 18))	('inflammation', 'Disease', (115, 127))	('neoplastic diseases', 'Disease', 'MESH:D009386', (51, 70))	('toxicity', 'Disease', 'MESH:D064420', (138, 146))	('neoplastic diseases', 'Disease', (51, 70))	('toxicity', 'Disease', (138, 146))	('oxidative stress', 'Phenotype', 'HP:0025464', (152, 168))	('asbestos', 'Chemical', 'MESH:D001194', (34, 42))
155351	21807578	Further, there is a need to better understand a) the potential for fiber-induced mutations that influence cancer, b) relevant mechanisms of translocation of different fiber types to extrapulmonary sites, c) health effects outside of the respiratory tract and pleural tissue, and d) the role of population variability and sensitivity to asbestos-induced adverse health end points.	('asbestos', 'Chemical', 'MESH:D001194', (336, 344))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('pleural', 'Disease', 'MESH:D010995', (259, 266))	('mutations', 'Var', (81, 90))	('influence', 'Reg', (96, 105))	('pleural', 'Disease', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
155372	21807578	Further, although existing data suggest that alterations in gene expression and epigenetic effects may contribute to some types of asbestos fibers inducing disease, more research is needed to fully understand the complex and overlapping signaling pathways involved in these effects, including ROS production, DNA damage and repair and p53 activation, cell death (apoptosis or necrosis), and inflammation.	('alterations', 'Var', (45, 56))	('cell death', 'biological_process', 'GO:0008219', ('351', '361'))	('necrosis', 'biological_process', 'GO:0070265', ('376', '384'))	('disease', 'Disease', (156, 163))	('cell death', 'CPA', (351, 361))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('necrosis', 'biological_process', 'GO:0019835', ('376', '384'))	('p53', 'Gene', (335, 338))	('necrosis', 'biological_process', 'GO:0001906', ('376', '384'))	('ROS', 'MPA', (293, 296))	('ROS', 'Chemical', 'MESH:D017382', (293, 296))	('asbestos', 'Chemical', 'MESH:D001194', (131, 139))	('inflammation', 'Disease', 'MESH:D007249', (391, 403))	('inflammation', 'biological_process', 'GO:0006954', ('391', '403'))	('signaling', 'biological_process', 'GO:0023052', ('237', '246'))	('gene expression', 'MPA', (60, 75))	('necrosis', 'biological_process', 'GO:0008219', ('376', '384'))	('necrosis', 'Disease', 'MESH:D009336', (376, 384))	('contribute', 'Reg', (103, 113))	('inflammation', 'Disease', (391, 403))	('epigenetic effects', 'Var', (80, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('363', '372'))	('apoptosis', 'biological_process', 'GO:0006915', ('363', '372'))	('necrosis', 'Disease', (376, 384))	('activation', 'PosReg', (339, 349))	('p53', 'Gene', '7157', (335, 338))	('DNA', 'cellular_component', 'GO:0005574', ('309', '312'))	('necrosis', 'biological_process', 'GO:0008220', ('376', '384'))
155460	30499156	Finally, the CTC-chip enabled sensitive detection of CTCs in peripheral blood sampled from MPM patients, which provided a significant diagnostic performance in discrimination of "unresectable" disease from "resectable" disease and a significant prognostic value in MPM patients.	('MPM', 'Disease', (265, 268))	('patients', 'Species', '9606', (269, 277))	('CTCs', 'Var', (53, 57))	('patients', 'Species', '9606', (95, 103))
155490	29246008	Patients who received HITHOC had significantly longer median survival length compared to the patients without HITHOC (Hedges's g = 0.384 +- 0.105, 95% CI: 0.178~0.591, P < 0.001).	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (47, 53))	('patients', 'Species', '9606', (93, 101))	('HITHOC', 'Var', (22, 28))
155491	29246008	The findings of the current study suggested that HITHOC is one of the safe and effective therapies in prolonging patients' median survival time and extending recurrence free interval.	('extending', 'PosReg', (148, 157))	('patients', 'Species', '9606', (113, 121))	('HITHOC', 'Var', (49, 55))	('prolonging', 'PosReg', (102, 112))	('recurrence free interval', 'CPA', (158, 182))
155495	29246008	However, significant proportion of patients have relapse of the disease following EPP or P/D and they usually die within a few months.	('patients', 'Species', '9606', (35, 43))	('EPP', 'Var', (82, 85))	('P/D', 'Var', (89, 92))
155531	29246008	Most of the 21 articles included in the current study reported that HITHOC as one of the multimodality therapies could prolong patients' median survival time although one study indicated that HITHOC had no advantage in the treatment of malignant mesothelioma.	('HITHOC', 'Var', (68, 74))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (236, 258))	('patients', 'Species', '9606', (127, 135))	('prolong', 'PosReg', (119, 126))	('malignant mesothelioma', 'Disease', (236, 258))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (236, 258))
155537	29246008	Protein denaturation of cancer cell leads to an increase in the rate of tumor cell apoptosis through affecting cell membrane cytoskeleton, DNA synthesis and membrane permeability.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('membrane', 'cellular_component', 'GO:0016020', ('157', '165'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('139', '152'))	('cancer', 'Disease', (24, 30))	('affecting', 'Reg', (101, 110))	('Protein denaturation', 'biological_process', 'GO:0030164', ('0', '20'))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('cell', 'MPA', (111, 115))	('membrane permeability', 'MPA', (157, 178))	('tumor', 'Disease', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('125', '137'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('DNA synthesis', 'MPA', (139, 152))	('cell membrane', 'cellular_component', 'GO:0005886', ('111', '124'))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('denaturation', 'Var', (8, 20))	('increase', 'PosReg', (48, 56))
155540	29246008	While surgical procedure of EPP or P/D on MPM may cause morbidities of adverse effects such as bronchopleural fistula, diaphragm rupture or laryngeal nerve dysfunction, HITHOC per se did not cause such adverse effects.	('cause', 'Reg', (50, 55))	('bronchopleural fistula', 'Disease', (95, 117))	('P/D', 'Var', (35, 38))	('laryngeal nerve dysfunction', 'Disease', (140, 167))	('laryngeal nerve dysfunction', 'Disease', 'MESH:D061224', (140, 167))	('rupture', 'Disease', (129, 136))	('bronchopleural fistula', 'Disease', 'MESH:D005402', (95, 117))	('rupture', 'Disease', 'MESH:D012421', (129, 136))
155546	29246008	Taken together, EPP or P/D plus hyperthermic intrathoracic chemotherapy significantly prolong patients overall survival time and extend recurrence free interval of the patients MPM.	('prolong', 'PosReg', (86, 93))	('extend', 'PosReg', (129, 135))	('patients', 'Species', '9606', (94, 102))	('recurrence free interval', 'CPA', (136, 160))	('EPP', 'Var', (16, 19))	('patients', 'Species', '9606', (168, 176))	('P/D', 'Var', (23, 26))
155637	26381550	This analysis provides some evidence that Minnesota taconite mining workers are at higher risk for mesothelioma, and other cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('Minnesota', 'Var', (42, 51))	('mesothelioma', 'Disease', (99, 111))
155709	25268063	The surgical biopsy specimens were well-preserved and showed calretinin positivity in both the chest wall and liver nodule.	('calretinin', 'Gene', '794', (61, 71))	('calretinin', 'Gene', (61, 71))	('positivity', 'Var', (72, 82))
155711	25268063	CD10 positivity is seen in 81% of RCC cases and can be a helpful diagnostic marker of RCC as well.	('CD10', 'Gene', '4311', (0, 4))	('positivity', 'Var', (5, 15))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('CD10', 'molecular_function', 'GO:0004245', ('0', '4'))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('CD10', 'Gene', (0, 4))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('RCC', 'Disease', (34, 37))
155753	25460485	Significant results of laboratory tests on admission were as follows: hemoglobin = 7.5 g/dL, hematocrit = 23.8%, INR = 1.4, alkaline phosphatase (ALP) = 227 IU/L (normal range 40-150), total proteins = 9.1 g/dL (normal range 6.7-8.8), albumin = 2.3 g/dL (normal range 3.5-5), C-reactive protein = 67 mg/L (normal range <5), carcinoembryonic antigen (CEA) = 1.9 mug/L (normal range <5), a-fetoprotein (AFP) = 2.4 mug/L (normal range <20), Ca19-9 <2 U/mL (normal range <37), Ca125 = 259.7 U/mL (normal range <35), Ca15-3 = 69 U/mL (normal range <30).	('ALP', 'Gene', (146, 149))	('mug', 'molecular_function', 'GO:0043739', ('412', '415'))	('mug', 'molecular_function', 'GO:0043739', ('361', '364'))	('Ca15-3', 'Gene', (512, 518))	('ALP', 'Gene', '250', (146, 149))	('alkaline phosphatase', 'Gene', '250', (124, 144))	('Ca125 = 259.7', 'Var', (473, 486))	('carcinoembryonic', 'Disease', (324, 340))	('alkaline phosphatase', 'Gene', (124, 144))	('CEA', 'Gene', '1048', (350, 353))	('protein', 'cellular_component', 'GO:0003675', ('287', '294'))	('Ca19-9', 'CellLine', 'CVCL:X558', (438, 444))	('carcinoembryonic', 'Disease', 'None', (324, 340))	('CEA', 'Gene', (350, 353))	('Ca15-3', 'Gene', '4582', (512, 518))	('Ca19-9 <2 U/mL', 'Var', (438, 452))	('phosphatase', 'molecular_function', 'GO:0016791', ('133', '144'))
155786	20160038	Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was demonstrated through downregulation of DNA methyltransferases as well as upregulation of demethylating genes.	('demethylating genes', 'Gene', (179, 198))	('upregulation', 'PosReg', (163, 175))	('DNA methyltransferases', 'Enzyme', (129, 151))	('hsa-miR-29c*', 'Gene', '407026', (69, 81))	('mediated', 'Reg', (57, 65))	('epigenetic', 'Var', (16, 26))	('mesothelioma', 'Disease', (41, 53))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('hsa-miR-29c*', 'Gene', (69, 81))	('downregulation', 'NegReg', (111, 125))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))
155841	20160038	Colony formation was significantly inhibited with transfection of miR- 29c* resulting in smaller and fewer colonies, with the most impressive results recorded with H-2595.	('fewer', 'NegReg', (101, 106))	('miR- 29c', 'Gene', (66, 74))	('inhibited', 'NegReg', (35, 44))	('miR- 29c', 'Gene', '407026', (66, 74))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('Colony formation', 'CPA', (0, 16))	('transfection', 'Var', (50, 62))
155853	20160038	The results of the in vitro functional assays in which the miR is expressed in MM cell lines are entirely consistent with the clinical findings that the expression of this miR decreases the tumors proliferative, migration and invasive potential.	('invasive potential', 'CPA', (226, 244))	('expression', 'Var', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('miR', 'Gene', '220972', (172, 175))	('decreases the tumors', 'Disease', 'MESH:D009369', (176, 196))	('miR', 'Gene', (172, 175))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('decreases the tumors', 'Disease', (176, 196))
155870	20160038	In myoblasts, miR-29 is repressed by NF-kB, and in primary rhabdomyosarcomas that possess impaired differentiation, miR-29 is epigenetically silenced by an activated NF-kB pathway.	('primary rhabdomyosarcomas', 'Disease', (51, 76))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))	('primary rhabdomyosarcomas', 'Disease', 'MESH:D012208', (51, 76))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (59, 76))	('NF-kB pathway', 'Pathway', (166, 179))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('epigenetically silenced', 'Var', (126, 149))
155877	20160038	Most recently, B7-H3 protein expression was found to be inversely correlated with miR-29 levels in cell lines and tumor tissues, and knock-in and knockdown of miR-29a results in down-and up-regulation, respectively, of B7-H3 protein expression.	('B7-H3', 'Gene', '80381', (15, 20))	('down-and', 'NegReg', (178, 186))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('knockdown', 'Var', (146, 155))	('miR', 'Gene', '220972', (82, 85))	('miR-29a', 'Gene', (159, 166))	('miR-29a', 'Gene', '407021', (159, 166))	('tumor', 'Disease', (114, 119))	('miR', 'Gene', '220972', (159, 162))	('B7-H3', 'Gene', '80381', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('B7-H3', 'Gene', (15, 20))	('miR', 'Gene', (82, 85))	('regulation', 'biological_process', 'GO:0065007', ('190', '200'))	('knock-in', 'Var', (133, 141))	('miR', 'Gene', (159, 162))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('up-regulation', 'PosReg', (187, 200))	('B7-H3', 'Gene', (219, 224))	('protein', 'Protein', (225, 232))
155880	20160038	One of the primary methods for genetic damage by asbestos involves promoter methylation, and various genes have been found to be methylated in mesothelioma at varying frequencies.	('mesothelioma', 'Disease', (143, 155))	('methylated', 'Var', (129, 139))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('promoter methylation', 'MPA', (67, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('genetic damage', 'Disease', 'MESH:D030342', (31, 45))	('genetic damage', 'Disease', (31, 45))
155882	20160038	Nonetheless, high expression of the microRNA was able to significantly increase survival within both the asbestos and non-asbestos exposed cohorts.	('survival', 'CPA', (80, 88))	('high expression', 'Var', (13, 28))	('microRNA', 'Protein', (36, 44))	('increase', 'PosReg', (71, 79))	('asbestos', 'Chemical', 'MESH:D001194', (105, 113))	('asbestos', 'Chemical', 'MESH:D001194', (122, 130))
155903	33578808	Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells.	('MN', 'CellLine', 'CVCL:U508', (102, 104))	('PMN-MDSC', 'Var', (101, 109))	('melanoma lesions', 'Disease', 'MESH:D008545', (54, 70))	('pre', 'molecular_function', 'GO:0003904', ('75', '78'))	('infiltration of', 'CPA', (38, 53))	('melanoma lesions', 'Disease', (54, 70))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('PMN', 'biological_process', 'GO:0034727', ('101', '104'))	('reduced', 'NegReg', (26, 33))	('accumulation', 'PosReg', (139, 151))
155904	33578808	Conclusions: We provide evidence for the tumor-promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PMN', 'biological_process', 'GO:0034727', ('71', '74'))	('tumor', 'Disease', (41, 46))	('PMN-MDSC', 'Var', (71, 79))	('MN', 'CellLine', 'CVCL:U508', (72, 74))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('melanoma', 'Disease', (142, 150))
155907	33578808	Melanoma is currently treated with targeted therapy against mutations in the serine/threonine-protein kinase B-Raf (BRAF) or mitogen-activated protein kinase (MEK), which leads to tumor regression in up to 90% of patients.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('serine/threonine-protein kinase B-Raf', 'Gene', '673', (77, 114))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('BRAF', 'Gene', '673', (116, 120))	('mitogen-activated protein kinase', 'Gene', (125, 157))	('Melanoma', 'Disease', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('tumor', 'Disease', (180, 185))	('MEK', 'Gene', (159, 162))	('BRAF', 'Gene', (116, 120))	('mitogen-activated protein kinase', 'Gene', '5609', (125, 157))	('MEK', 'Gene', '5609', (159, 162))	('patients', 'Species', '9606', (213, 221))	('serine/threonine-protein kinase B-Raf', 'Gene', (77, 114))	('mutations', 'Var', (60, 69))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
155908	33578808	Furthermore, the therapy with immune checkpoint inhibitors, in particular with antibodies against programmed cell death protein (PD)-1, resulted in a strong increase in the overall survival of advanced melanoma patients.	('patients', 'Species', '9606', (211, 219))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('programmed cell death', 'biological_process', 'GO:0012501', ('98', '119'))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('programmed cell death protein (PD)-1', 'Gene', '5133', (98, 134))	('antibodies', 'Var', (79, 89))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('increase', 'PosReg', (157, 165))
155913	33578808	The main feature of MDSC is a strong capacity to inhibit anti-tumor reactivity of effector T and NK cells by various mechanisms.	('MDSC', 'Var', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('inhibit', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
155918	33578808	In addition, MDSC were reported to induce the development of FoxP3+ regulatory T cells (Treg) in tumor bearing host and to subvert tumor associated macrophages into M2 cells in a cell-contact dependent manner.	('development', 'CPA', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('FoxP3', 'Gene', '20371', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (131, 136))	('subvert', 'NegReg', (123, 130))	('induce', 'PosReg', (35, 41))	('MDSC', 'Var', (13, 17))	('M2', 'CellLine', 'CVCL:U035', (165, 167))	('FoxP3', 'Gene', (61, 66))
155922	33578808	In melanoma bearing mice, PMN-MDSC have been shown to produce hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta that stimulate epithelial to mesenchymal transition (EMT) and dissemination of tumor cells.	('EMT', 'biological_process', 'GO:0001837', ('188', '191'))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('150', '186'))	('HGF', 'Gene', '15234', (88, 91))	('epithelial', 'CPA', (150, 160))	('transforming growth factor (TGF)-beta', 'Gene', '21802', (97, 134))	('mice', 'Species', '10090', (20, 24))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('HGF', 'Gene', (88, 91))	('hepatocyte growth factor', 'Gene', '15234', (62, 86))	('PMN-MDSC', 'Var', (26, 34))	('stimulate', 'PosReg', (140, 149))	('tumor', 'Disease', (214, 219))	('hepatocyte growth factor', 'Gene', (62, 86))	('MN', 'CellLine', 'CVCL:U508', (27, 29))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('62', '86'))	('PMN', 'biological_process', 'GO:0034727', ('26', '29'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
155931	33578808	The frequency of PMN-MDSC was found to be significantly higher in LN, spleen and peripheral blood of tumor bearing mice compared to their non-suppressive counterpart in these organs from healthy animals (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PMN-MDSC', 'Var', (17, 25))	('MN', 'CellLine', 'CVCL:U508', (18, 20))	('PMN', 'biological_process', 'GO:0034727', ('17', '20'))	('higher', 'PosReg', (56, 62))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
155935	33578808	Recent studies with injected AB12 mesothelioma cells suggested a critical role of PMN-MDSC in contrast to M-MDSC in suppressing the anti-tumor response.	('tumor', 'Disease', (137, 142))	('PMN-MDSC', 'Var', (82, 90))	('mesothelioma', 'Disease', (34, 46))	('suppressing', 'NegReg', (116, 127))	('MN', 'CellLine', 'CVCL:U508', (83, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('PMN', 'biological_process', 'GO:0034727', ('82', '85'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
155936	33578808	To corroborate our observations, we analyzed the tumor infiltrating MDSC subpopulations in a mouse mesothelioma model and found similar tendencies regarding the enrichment of PMN- (Figure 1E) and M-MDSC (Figure S2B) as in the melanoma microenvironment.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('M-MDSC', 'Var', (196, 202))	('MN', 'CellLine', 'CVCL:U508', (176, 178))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mouse', 'Species', '10090', (93, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('PMN', 'biological_process', 'GO:0034727', ('175', '178'))	('tumor', 'Disease', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('mesothelioma', 'Disease', (99, 111))
155937	33578808	To compare the immunosuppressive pattern of PMN-MDSC and M-MDSC, we determined the frequency of PD-L1, CD39, and CD73 and the level of their expression (detected as mean fluorescence intensity, MFI) in skin tumors of RET transgenic mice.	('PMN', 'biological_process', 'GO:0034727', ('44', '47'))	('MN', 'CellLine', 'CVCL:U508', (45, 47))	('skin tumors', 'Disease', 'MESH:D012878', (202, 213))	('transgenic mice', 'Species', '10090', (221, 236))	('CD3', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('PD-L1', 'Gene', (96, 101))	('skin tumor', 'Phenotype', 'HP:0008069', (202, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('skin tumors', 'Phenotype', 'HP:0008069', (202, 213))	('CD73', 'Var', (113, 117))	('CD3', 'Gene', '12501', (103, 106))	('skin tumors', 'Disease', (202, 213))
155938	33578808	In contrast, the frequency of CD39+ and especially CD73+ cells was significantly higher within PMN- than M-MDSC (Figure 2A and Figure S3).	('MN', 'CellLine', 'CVCL:U508', (96, 98))	('CD3', 'Gene', '12501', (30, 33))	('higher', 'PosReg', (81, 87))	('PMN', 'biological_process', 'GO:0034727', ('95', '98'))	('CD73+ cells', 'Var', (51, 62))	('CD3', 'Gene', (30, 33))
155945	33578808	However, M-MDSC displayed a significantly higher level of CCR2, CCR4, CCR5, and CXCR4 than PMN-MDSC (Figure 3A).	('CCR', 'molecular_function', 'GO:0043880', ('58', '61'))	('CCR', 'molecular_function', 'GO:0043880', ('64', '67'))	('CXCR4', 'Gene', (80, 85))	('CCR4', 'Gene', '12773', (64, 68))	('CCR4', 'Gene', (64, 68))	('PMN', 'biological_process', 'GO:0034727', ('91', '94'))	('M-MDSC', 'Var', (9, 15))	('CCR2', 'Gene', '12772', (58, 62))	('higher', 'PosReg', (42, 48))	('CCR2', 'Gene', (58, 62))	('CCR5', 'Gene', (70, 74))	('CXCR4', 'molecular_function', 'GO:0038147', ('80', '85'))	('MN', 'CellLine', 'CVCL:U508', (92, 94))	('CCR', 'molecular_function', 'GO:0043880', ('70', '73'))	('CXCR4', 'Gene', '12767', (80, 85))	('CCR5', 'Gene', '12774', (70, 74))
155948	33578808	In addition, CCR2 expression level was significantly lower on PMN-MDSC than on M-MDSC (Figure 3B).	('CCR2', 'Gene', '12772', (13, 17))	('expression level', 'MPA', (18, 34))	('PMN', 'biological_process', 'GO:0034727', ('62', '65'))	('MN', 'CellLine', 'CVCL:U508', (63, 65))	('CCR2', 'Gene', (13, 17))	('CCR', 'molecular_function', 'GO:0043880', ('13', '16'))	('PMN-MDSC', 'Var', (62, 70))	('lower', 'NegReg', (53, 58))
155969	33578808	Tumor bearing RET transgenic mice were treated with the CXCR2 inhibitor SB265610, which led to a significant survival benefit as compared to mice treated with the DMSO solution (control group) (Figure 5A).	('DMSO', 'Chemical', 'MESH:D004121', (163, 167))	('transgenic mice', 'Species', '10090', (18, 33))	('CXCR2 inhibitor', 'MPA', (56, 71))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SB265610', 'Var', (72, 80))	('benefit', 'PosReg', (118, 125))	('mice', 'Species', '10090', (141, 145))	('SB265610', 'Chemical', 'MESH:C549500', (72, 80))	('mice', 'Species', '10090', (29, 33))	('survival', 'CPA', (109, 117))
155970	33578808	The observed anti-tumor effect was indicated also by a decrease in tumor weight upon anti-CXCR2 therapy (Figure 5B).	('anti-CXCR2', 'Var', (85, 95))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decrease', 'NegReg', (55, 63))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
155978	33578808	Interestingly, PMN-MDSC frequencies in the BM and peripheral blood were not significantly altered upon the therapy, indicating that anti-CXCR2 therapy could inhibit PMN-MDSC migration to the tumor without affecting their amounts at the systemic level (Figure S9).	('PMN', 'biological_process', 'GO:0034727', ('165', '168'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('PMN-MDSC', 'MPA', (165, 173))	('PMN', 'biological_process', 'GO:0034727', ('15', '18'))	('inhibit', 'NegReg', (157, 164))	('tumor', 'Disease', (191, 196))	('anti-CXCR2', 'Var', (132, 142))	('MN', 'CellLine', 'CVCL:U508', (166, 168))	('MN', 'CellLine', 'CVCL:U508', (16, 18))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))
155980	33578808	It was found that PMN-MDSC significantly reduced the production of IFN-gamma and IL-16, indicating an inhibition of NK cell activity (Figure 5G,H).	('PMN', 'biological_process', 'GO:0034727', ('18', '21'))	('IL-16', 'Gene', (81, 86))	('reduced', 'NegReg', (41, 48))	('IFN-gamma', 'Gene', '15978', (67, 76))	('IL-16', 'Gene', '16170', (81, 86))	('IFN-gamma', 'Gene', (67, 76))	('inhibition', 'NegReg', (102, 112))	('NK cell activity', 'CPA', (116, 132))	('PMN-MDSC', 'Var', (18, 26))	('MN', 'CellLine', 'CVCL:U508', (19, 21))	('IL-16', 'molecular_function', 'GO:0045514', ('81', '86'))
155992	33578808	Observing further the development of metastases in mice receiving anti-CXCR2 therapy, we found that they had less macroscopic metastatic nodules in lungs and liver than in mice without the inhibition of PMN-MDSC recruitment (Figure 7G).	('PMN', 'biological_process', 'GO:0034727', ('203', '206'))	('mice', 'Species', '10090', (51, 55))	('less', 'NegReg', (109, 113))	('anti-CXCR2', 'Var', (66, 76))	('metastases', 'Disease', (37, 47))	('MN', 'CellLine', 'CVCL:U508', (204, 206))	('mice', 'Species', '10090', (172, 176))	('macroscopic metastatic nodules', 'CPA', (114, 144))	('metastases', 'Disease', 'MESH:D009362', (37, 47))
155996	33578808	Interestingly, the accumulation of melanoma infiltrating MDSC in this transgenic mouse model was primarily caused by an enrichment of PMN-MDSC, while the frequency of M-MDSC remained constant during tumor progression.	('tumor', 'Disease', (199, 204))	('transgenic', 'Species', '10090', (70, 80))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('PMN', 'biological_process', 'GO:0034727', ('134', '137'))	('MN', 'CellLine', 'CVCL:U508', (135, 137))	('PMN-MDSC', 'Var', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mouse', 'Species', '10090', (81, 86))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
156004	33578808	However, significantly larger proportion of PMN-MDSC displayed ectonucleotidase CD39 and CD73 than that of M-MDSC.	('PMN', 'biological_process', 'GO:0034727', ('44', '47'))	('CD73', 'Var', (89, 93))	('MN', 'CellLine', 'CVCL:U508', (45, 47))	('CD3', 'Gene', (80, 83))	('CD3', 'Gene', '12501', (80, 83))
156005	33578808	Since CD39 and CD73 can convert ATP into adenosine that inhibits T cell functions, their predominant expression on PMN-MDSC suggests a more important role of adenosine in immunosuppressive activity of this MDSC subset.	('adenosine', 'Chemical', 'MESH:D000241', (41, 50))	('CD3', 'Gene', (6, 9))	('inhibits', 'NegReg', (56, 64))	('CD3', 'Gene', '12501', (6, 9))	('PMN', 'biological_process', 'GO:0034727', ('115', '118'))	('T cell functions', 'CPA', (65, 81))	('adenosine', 'Chemical', 'MESH:D000241', (158, 167))	('CD73', 'Var', (15, 19))	('MN', 'CellLine', 'CVCL:U508', (116, 118))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))
156007	33578808	In addition, high CD39/CD73 co-expression on circulating MDSC has been shown to be associated with the progression of non-small-cell lung carcinoma (NSCLC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (118, 147))	('high', 'Var', (13, 17))	('NSCLC', 'Disease', (149, 154))	('CD3', 'Gene', (18, 21))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (122, 147))	('lung carcinoma', 'Disease', 'MESH:D008175', (133, 147))	('associated with', 'Reg', (83, 98))	('CD3', 'Gene', '12501', (18, 21))	('lung carcinoma', 'Disease', (133, 147))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
156011	33578808	For example, M-MDSC have been shown to exert their immunosuppressive capacity via the immune-regulatory TIM-3/galectin-9 pathway that could mediate the resistance to PD-1 blockade in NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('galectin', 'molecular_function', 'GO:0001577', ('110', '118'))	('M-MDSC', 'Var', (13, 19))	('PD-1 blockade', 'Disease', (166, 179))	('galectin-9', 'Gene', '3965', (110, 120))	('TIM-3', 'Gene', (104, 109))	('NSCLC', 'Disease', (183, 188))	('PD-1 blockade', 'Disease', 'MESH:D010300', (166, 179))	('TIM-3', 'Gene', '84868', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('immunosuppressive capacity', 'MPA', (51, 77))	('galectin-9', 'Gene', (110, 120))	('patients', 'Species', '9606', (189, 197))
156042	33578808	Therefore, by targeting the CXCR2 receptor we were able to impair PMN-MDSC migration to the melanoma microenvironment.	('impair', 'NegReg', (59, 65))	('targeting', 'Var', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('PMN-MDSC migration', 'CPA', (66, 84))	('melanoma', 'Disease', (92, 100))	('PMN', 'biological_process', 'GO:0034727', ('66', '69'))	('MN', 'CellLine', 'CVCL:U508', (67, 69))
156045	33578808	Importantly, NK cells demonstrated higher sensitivity to the immunosuppression mediated by PMN-MDSC as compared to M-MDSC, indicating a critical impact of PMN-MDSC in the inhibition of anti-tumor functions of NK cells.	('PMN', 'biological_process', 'GO:0034727', ('155', '158'))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('PMN-MDSC', 'Var', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PMN', 'biological_process', 'GO:0034727', ('91', '94'))	('tumor', 'Disease', (190, 195))	('MN', 'CellLine', 'CVCL:U508', (156, 158))	('MN', 'CellLine', 'CVCL:U508', (92, 94))
156070	33578808	To induce T cell proliferation, the plate was coated with 100 microL of an anti-CD28 and anti-CD3 mAb (both eBioscience, Inc., San Diego, CA, USA) in PBS for 3 h at 37  C and 5% CO2.	('T cell proliferation', 'biological_process', 'GO:0042098', ('10', '30'))	('CO2', 'Chemical', 'MESH:D002245', (178, 181))	('PBS', 'Chemical', 'MESH:D007854', (150, 153))	('induce', 'PosReg', (3, 9))	('CA', 'Gene', '12310', (138, 140))	('CD3', 'Gene', (94, 97))	('T cell proliferation', 'CPA', (10, 30))	('CD3', 'Gene', '12501', (94, 97))	('anti-CD28', 'Var', (75, 84))
156144	28434399	Patients experienced a longer median overall survival (OS) with nivolumab (9.2 months, 95% CI 7.3-13.3) versus previous standard-of-care chemotherapy: docetaxel (6.0 months, 95% CI 5.1-7.3) (HR = 0.59, 95% CI 0.44-0.79, p = 0.00025).	('docetaxel', 'Chemical', 'MESH:D000077143', (151, 160))	('longer', 'PosReg', (23, 29))	('OS', 'Gene', '17451', (55, 57))	('nivolumab', 'Chemical', 'MESH:D000077594', (64, 73))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (37, 53))	('nivolumab', 'Var', (64, 73))
156145	28434399	One-year OS was also higher with nivolumab (42%, 95% CI 34-50) compared to docetaxel (24%, 95% CI 17-31).	('nivolumab', 'Var', (33, 42))	('OS', 'Gene', '17451', (9, 11))	('higher', 'PosReg', (21, 27))	('docetaxel', 'Chemical', 'MESH:D000077143', (75, 84))	('nivolumab', 'Chemical', 'MESH:D000077594', (33, 42))
156146	28434399	Median duration of response (DOR) was higher with nivolumab (not reached, 95% CI 2.9-20.5+) compared to docetaxel (8.4 (1.4+-15.2+)).	('nivolumab', 'Var', (50, 59))	('docetaxel', 'Chemical', 'MESH:D000077143', (104, 113))	('higher', 'PosReg', (38, 44))	('nivolumab', 'Chemical', 'MESH:D000077594', (50, 59))
156147	28434399	Median progression-free survival (PFS) was longer with nivolumab (3.5 months, 95% CI 2.1-4.9) compared to docetaxel (2.8 months, 95% CI 2.1-3.5) (HR = 0.62, 95% CI 0.47-0.81, p = 0.0004).	('longer', 'PosReg', (43, 49))	('progression-free survival', 'CPA', (7, 32))	('nivolumab', 'Var', (55, 64))	('docetaxel', 'Chemical', 'MESH:D000077143', (106, 115))	('nivolumab', 'Chemical', 'MESH:D000077594', (55, 64))
156148	28434399	This was reflected in a 1-year PFS that was higher with nivolumab (21%, 95% CI 14-28) compared to docetaxel (6%, 95% CI 3-12).	('nivolumab', 'Var', (56, 65))	('higher', 'PosReg', (44, 50))	('PFS', 'MPA', (31, 34))	('nivolumab', 'Chemical', 'MESH:D000077594', (56, 65))	('docetaxel', 'Chemical', 'MESH:D000077143', (98, 107))
156149	28434399	Finally, median overall response rate (ORR) was higher with nivolumab compared to docetaxel (20 versus 9%, p = 0.0083).	('nivolumab', 'Chemical', 'MESH:D000077594', (60, 69))	('higher', 'PosReg', (48, 54))	('docetaxel', 'Chemical', 'MESH:D000077143', (82, 91))	('nivolumab', 'Var', (60, 69))
156155	28434399	One-year OS was higher with nivolumab (50.5%, 95% CI 44.6-56.1) compared to docetaxel (39.0%, 95% CI 33.3-44.6) as well.	('higher', 'PosReg', (16, 22))	('docetaxel', 'Chemical', 'MESH:D000077143', (76, 85))	('OS', 'Gene', '17451', (9, 11))	('nivolumab', 'Chemical', 'MESH:D000077594', (28, 37))	('nivolumab', 'Var', (28, 37))
156156	28434399	Median ORR was higher with nivolumab compared to docetaxel (19.2 versus 12.4%; p = 0.0235; HR = 0.92, 95% CI 0.77-1.11, p = 0.393).	('nivolumab', 'Var', (27, 36))	('higher', 'PosReg', (15, 21))	('ORR', 'MPA', (7, 10))	('docetaxel', 'Chemical', 'MESH:D000077143', (49, 58))	('nivolumab', 'Chemical', 'MESH:D000077594', (27, 36))
156164	28434399	Patients with tumors expressing at least 50% PD-L1 expression had significantly longer OS with pembrolizumab 2 mg/kg versus docetaxel (median 14.9 versus 8.2 months; HR = 0.54, 95% CI 0.38-0.77; p = 0.0002) and with pembrolizumab 10 mg/kg versus docetaxel (median 17.3 versus 8.2 months; HR = 0.50, 95% CI 0.36-0.70; p < 0.0001).	('pembrolizumab', 'Chemical', 'MESH:C582435', (216, 229))	('OS', 'Gene', '17451', (87, 89))	('docetaxel', 'Chemical', 'MESH:D000077143', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('pembrolizumab', 'Chemical', 'MESH:C582435', (95, 108))	('longer', 'PosReg', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('docetaxel', 'Chemical', 'MESH:D000077143', (246, 255))	('expression', 'Var', (51, 61))	('PD-L1', 'Gene', (45, 50))
156179	28434399	The Cancer Genome Atlas (TCGA) has detected gene mutations that are potentially amenable to targeted therapy in SQ NSCLC.	('mutations', 'Var', (49, 58))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer Genome Atlas', 'Disease', (4, 23))	('SCLC', 'Phenotype', 'HP:0030357', (116, 120))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
156204	28434399	Several trials have examined these PD-1/PD-L1 inhibitors in combination with chemotherapy or CTLA-4 inhibitors (Tables 2 and 3).	('PD-1', 'Gene', (35, 39))	('PD-1', 'Gene', '5133', (35, 39))	('inhibitors', 'Var', (46, 56))
156240	28434399	Rate of discontinuation was higher with the ipilimumab arm at 18% and five treatment-related deaths versus 2% and two treatment-related deaths with the placebo arm.	('discontinuation', 'MPA', (8, 23))	('ipilimumab', 'Chemical', 'MESH:D000074324', (44, 54))	('ipilimumab', 'Var', (44, 54))
156244	28434399	Grade 3-4 TrAEs occurred at a rate of 13% with nivo3, 30% with nivo1 + ipi3, and 19% with nivo3 + ipi1.	('ipi1', 'Gene', '54881', (98, 102))	('ipi3', 'Chemical', '-', (71, 75))	('nivo1 + ipi3', 'Var', (63, 75))	('nivo3', 'Chemical', '-', (90, 95))	('nivo1', 'Chemical', '-', (63, 68))	('Grade 3-4 TrAEs', 'Disease', (0, 15))	('nivo3', 'Var', (47, 52))	('nivo3', 'Chemical', '-', (47, 52))	('ipi1', 'Gene', (98, 102))
156247	28434399	Two patients treated with nivo1 + ipi3 died from grade 5 TrAEs of myasthenia gravis and worsening renal failure while one patient treated with nivo3 + ipi1 died from treatment-related pneumonitis.	('renal failure', 'Phenotype', 'HP:0000083', (98, 111))	('myasthenia gravis', 'Disease', (66, 83))	('ipi1', 'Gene', '54881', (151, 155))	('renal failure', 'Disease', 'MESH:D051437', (98, 111))	('patient', 'Species', '9606', (122, 129))	('ipi3', 'Chemical', '-', (34, 38))	('pneumonitis', 'Disease', (184, 195))	('renal failure', 'Disease', (98, 111))	('patient', 'Species', '9606', (4, 11))	('worsening renal failure', 'Phenotype', 'HP:0012622', (88, 111))	('myasthenia gravis', 'Disease', 'MESH:D009157', (66, 83))	('pneumonitis', 'Disease', 'MESH:D011014', (184, 195))	('patients', 'Species', '9606', (4, 12))	('myasthenia', 'Phenotype', 'HP:0003473', (66, 76))	('nivo3', 'Chemical', '-', (143, 148))	('ipi1', 'Gene', (151, 155))	('nivo1 + ipi3', 'Var', (26, 38))	('nivo1', 'Chemical', '-', (26, 31))
156290	28434399	This vaccine will be selected for adenocarcinoma tumor antigens and transfected to secrete gp96-Ig to the patient's antigen presenting cells (APCs) leading to increased cytotoxic CD8+ TILs.	('TIL', 'Gene', (184, 187))	('adenocarcinoma tumor', 'Disease', 'MESH:D000230', (34, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CD8', 'Gene', (179, 182))	('patient', 'Species', '9606', (106, 113))	('increased', 'PosReg', (159, 168))	('APC', 'Disease', 'MESH:D011125', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('TIL', 'Gene', '7096', (184, 187))	('adenocarcinoma tumor', 'Disease', (34, 54))	('CD8', 'Gene', '925', (179, 182))	('APC', 'Disease', (142, 145))	('gp96-Ig', 'Var', (91, 98))
156296	28434399	In animal models, blocking histone deacetylation with entinostat has been shown to decrease the activity of Tregs and suppressor T cells leading to increased T cell activation.	('T cell activation', 'biological_process', 'GO:0042110', ('158', '175'))	('activity', 'MPA', (96, 104))	('histone deacetylation', 'Protein', (27, 48))	('increased', 'PosReg', (148, 157))	('increased T cell', 'Phenotype', 'HP:0100828', (148, 164))	('suppressor T cells', 'CPA', (118, 136))	('blocking', 'Var', (18, 26))	('decrease', 'NegReg', (83, 91))	('Tregs', 'CPA', (108, 113))	('entinostat', 'Chemical', 'MESH:C118739', (54, 64))	('histone deacetylation', 'biological_process', 'GO:0016575', ('27', '48'))	('T cell activation', 'CPA', (158, 175))
156303	28434399	PI3K-gamma has been shown to increase the immunosuppressive effects of myeloid cells in the tumor microenvironment, and inhibition of this molecule has shown decreased tumor growth in preclinical studies.	('PI3K-gamma', 'Gene', '5294', (0, 10))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('decreased', 'NegReg', (158, 167))	('tumor', 'Disease', (168, 173))	('inhibition', 'Var', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increase', 'PosReg', (29, 37))	('immunosuppressive effects', 'MPA', (42, 67))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('PI3K-gamma', 'Gene', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
156312	28434399	Interestingly, small studies utilizing whole-exome sequencing in patients who initially responded to PD-1 checkpoint inhibition and then progressed found mutations involving interferon pathway genes.	('interferon', 'Pathway', (174, 184))	('patients', 'Species', '9606', (65, 73))	('PD-1', 'Gene', (101, 105))	('mutations', 'Var', (154, 163))	('PD-1', 'Gene', '5133', (101, 105))
156313	28434399	Loss of function mutations and truncating mutations were seen in JAK1, JAK2, and B2M proteins associated with the interferon signaling pathways.	('B2M', 'Gene', (81, 84))	('JAK2', 'Gene', '3717', (71, 75))	('proteins', 'Protein', (85, 93))	('B2M', 'Gene', '567', (81, 84))	('JAK', 'molecular_function', 'GO:0004713', ('65', '68'))	('JAK2', 'Gene', (71, 75))	('truncating mutations', 'Var', (31, 51))	('JAK', 'molecular_function', 'GO:0004713', ('71', '74'))	('Loss of function', 'NegReg', (0, 16))	('interferon signaling pathways', 'Pathway', (114, 143))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('JAK1', 'Gene', (65, 69))	('JAK1', 'Gene', '3716', (65, 69))	('mutations', 'Var', (17, 26))
156330	28434399	This has led to the FDA approval of pembrolizumab in the first-line setting for tumors with >50% PD-L1 positivity and established a new standard of care.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('positivity', 'Var', (103, 113))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('pembrolizumab', 'Chemical', 'MESH:C582435', (36, 49))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('PD-L1', 'Gene', (97, 102))
156365	26202904	Recent studies have identified germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) which can predispose to mesothelioma.	('BAP1', 'Gene', (99, 103))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('predispose', 'Reg', (115, 125))	('BRCA1 associated protein-1', 'Gene', '8314', (71, 97))	('BAP1', 'Gene', '8314', (99, 103))	('germline mutations', 'Var', (31, 49))	('mesothelioma', 'Disease', (129, 141))	('BRCA1 associated protein-1', 'Gene', (71, 97))
156366	26202904	Mesothelioma occurring in germline BAP1 mutation carriers have been reported to be less aggressive clinically and associated with prolonged survival compared with sporadic mesothelioma.	('mutation', 'Var', (40, 48))	('germline', 'Var', (26, 34))	('sporadic mesothelioma', 'Disease', 'MESH:D008654', (163, 184))	('BAP1', 'Gene', '8314', (35, 39))	('aggressive', 'CPA', (88, 98))	('sporadic mesothelioma', 'Disease', (163, 184))	('BAP1', 'Gene', (35, 39))	('less', 'NegReg', (83, 87))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (163, 184))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
156367	26202904	In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for the development of several other tumors including uveal melanoma, cutaneous melanoma, renal cell cancers and possibly other cancers.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('cancers', 'Disease', (186, 193))	('uveal melanoma', 'Disease', (139, 153))	('renal cell cancers', 'Disease', (175, 193))	('BAP1', 'Gene', '8314', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('BAP1', 'Gene', (38, 42))	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mesothelioma', 'Disease', (15, 27))	('tumors', 'Disease', (122, 128))	('renal cell cancers', 'Disease', 'MESH:C538614', (175, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('mutations', 'Var', (43, 52))	('susceptibility', 'Reg', (70, 84))
156407	26202904	Germline BAP1 mutations were first described in mesothelioma families with no heavy exposure to carcinogens which are known to cause a high incidence of mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('cause', 'Reg', (127, 132))	('mesothelioma', 'Disease', (48, 60))	('BAP1', 'Gene', '8314', (9, 13))	('mesothelioma', 'Disease', (153, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
156408	26202904	Germline BAP1 mutation carriers have an exceptionally high incidence of malignancies, including mesothelioma and uveal melanoma whereas family members who do not carry these mutations do not develop these malignancies.	('mesothelioma', 'Disease', (96, 108))	('BAP1', 'Gene', '8314', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('malignancies', 'Disease', 'MESH:D009369', (205, 217))	('mutation', 'Var', (14, 22))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('uveal melanoma', 'Disease', (113, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('malignancies', 'Disease', (72, 84))	('BAP1', 'Gene', (9, 13))	('malignancies', 'Disease', (205, 217))
156409	26202904	Germline BAP1 mutation carriers are thought to be highly susceptible to mesothelioma even at modest levels of asbestos exposure that would be considerably less tumorigenic in the general population.	('susceptible', 'Reg', (57, 68))	('asbestos', 'Chemical', 'MESH:D001194', (110, 118))	('BAP1', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('BAP1', 'Gene', '8314', (9, 13))	('mesothelioma', 'Disease', (72, 84))	('mutation', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
156580	20412567	The first hypothesis considers that asbestos has played an important role in the industrial development of the study area and therefore it continues to cause a poorly defined and quantified morbidity and mortality by means of a current or past inhalation of asbestos fibres.	('asbestos', 'Chemical', 'MESH:D001194', (258, 266))	('asbestos', 'Var', (36, 44))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('men', 'Species', '9606', (99, 102))	('cause', 'Reg', (152, 157))
156603	20412567	The fieldworker will undertake every three months a comprehensive search for every computerised new case of primary care and hospital discharge reports with the relevant ICD 10 codes (J61; J92.0; C45).	('ICD', 'Disease', (170, 173))	('J61; J92.0; C45', 'Var', (184, 199))	('ICD', 'Disease', 'OMIM:252500', (170, 173))
156822	31398954	YS110 has an inhibitory activity against the CD26-positive tumor growth via the immunological and direct pathway, such as intra-nuclear transportation of CD26 and YS110, and suppressed transcription of RNA polymerase II (Pol II) subunit POLR2A.	('inhibitory activity', 'MPA', (13, 32))	('POLR2A', 'Gene', (237, 243))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('tumor', 'Disease', (59, 64))	('intra-nuclear transportation', 'MPA', (122, 150))	('transcription', 'MPA', (185, 198))	('YS110', 'Chemical', '-', (0, 5))	('POLR2A', 'Gene', '5430', (237, 243))	('suppressed', 'NegReg', (174, 184))	('YS110', 'Var', (163, 168))	('CD26', 'Gene', (154, 158))	('RNA', 'cellular_component', 'GO:0005562', ('202', '205'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('YS110', 'Var', (0, 5))	('YS110', 'Chemical', '-', (163, 168))
156826	31398954	Y-TR1 showed significant cytotoxicity against CD26-positive cell lines but not CD26-negative counterparts in a dose-dependent manner via suppression of mRNA synthesis by impairment of the Pol II activity.	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('mRNA synthesis', 'MPA', (152, 166))	('mRNA synthesis', 'biological_process', 'GO:0009299', ('152', '166'))	('Pol II', 'Enzyme', (188, 194))	('cytotoxicity', 'Disease', (25, 37))	('impairment', 'NegReg', (170, 180))	('Y-TR1', 'Var', (0, 5))	('suppression', 'NegReg', (137, 148))	('activity', 'MPA', (195, 203))
156827	31398954	The tumors in xenografted mice administered Y-TR1 was smaller than that of the unconjugated YS110 treated mice without severe toxicity.	('YS110', 'Chemical', '-', (92, 97))	('mice', 'Species', '10090', (106, 110))	('toxicity', 'Disease', 'MESH:D064420', (126, 134))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('toxicity', 'Disease', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Y-TR1', 'Var', (44, 49))	('smaller', 'NegReg', (54, 61))	('mice', 'Species', '10090', (26, 30))
156829	31398954	The Y-TR1 is a unique antitumor ADC and functions against Pol II.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Pol', 'Protein', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Y-TR1', 'Var', (4, 9))
156833	31398954	We have already generated anti-CD26 monoclonal antibodies (mAbs) that have certain inhibitory effects against the growth of tumor cells and xenografted tumors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('anti-CD26', 'Var', (26, 35))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', (152, 157))	('inhibitory effects', 'MPA', (83, 101))	('anti-CD26', 'Gene', (26, 35))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
156836	31398954	As a result, anti-CD26 mAbs are well tolerated up to 6 mg/kg Q1W, which has been defined as RP2D, with encouraging prolonged disease stabilizations observed in a number of patients with advanced/refractory mesothelioma.	('mesothelioma', 'Disease', (206, 218))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('anti-CD26', 'Var', (13, 22))	('advanced/refractory', 'Disease', (186, 205))	('patients', 'Species', '9606', (172, 180))
156843	31398954	We have previously showed that the nuclear localization of CD26 is functionally involved in the anti-tumor process following the YS110 treatment and that the nuclear translocation of CD26 and YS110 contributes to growth inhibition of malignant mesothelioma cells after the YS110 treatment.	('nuclear localization', 'MPA', (35, 55))	('YS110', 'Chemical', '-', (273, 278))	('CD26', 'Gene', (183, 187))	('nuclear translocation', 'MPA', (158, 179))	('YS110', 'Chemical', '-', (129, 134))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (234, 256))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('YS110', 'Chemical', '-', (192, 197))	('localization', 'biological_process', 'GO:0051179', ('43', '55'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (234, 256))	('CD26', 'Gene', (59, 63))	('growth inhibition', 'CPA', (213, 230))	('involved', 'Reg', (80, 88))	('malignant mesothelioma', 'Disease', (234, 256))	('YS110', 'Var', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
156846	31398954	Furthermore, the impairing nuclear translocation of CD26 and YS110 prevented both the nuclear translocation of these two proteins and the YS110-induced transcriptional repression of the POLR2A gene.	('prevented', 'NegReg', (67, 76))	('YS110-induced', 'Var', (138, 151))	('nuclear translocation of these two', 'MPA', (86, 120))	('POLR2A', 'Gene', (186, 192))	('YS110', 'Chemical', '-', (61, 66))	('nuclear translocation', 'MPA', (27, 48))	('transcriptional', 'MPA', (152, 167))	('CD26', 'Var', (52, 56))	('YS110', 'Chemical', '-', (138, 143))	('POLR2A', 'Gene', '5430', (186, 192))	('YS110', 'Var', (61, 66))	('impairing', 'NegReg', (17, 26))
156849	31398954	It may be a reasonable strategy that the YS110 treatment specifically induces internalization of both CD26 and Y-TR1 into the nucleus from the cell surface in cancer cells but not in normal CD26-positive cells, such as the endothelium or lymphocytes, and then, YS110 suppresses the POLR2A transcription, and TR-1 inhibits TFIIH and POLII, which leads to additive or synergistic anti-tumor effects.	('internalization', 'MPA', (78, 93))	('POLR2A', 'Gene', '5430', (282, 288))	('induces', 'Reg', (70, 77))	('TR-1', 'Gene', (308, 312))	('cell surface', 'cellular_component', 'GO:0009986', ('143', '155'))	('cancer', 'Disease', (159, 165))	('nucleus', 'cellular_component', 'GO:0005634', ('126', '133'))	('POLR2A', 'Gene', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (383, 388))	('TR-1', 'Gene', '80835', (308, 312))	('tumor', 'Disease', 'MESH:D009369', (383, 388))	('inhibits', 'NegReg', (313, 321))	('YS110', 'Var', (41, 46))	('YS110', 'Chemical', '-', (41, 46))	('TFIIH', 'Gene', '2071', (322, 327))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('transcription', 'biological_process', 'GO:0006351', ('289', '302'))	('suppresses', 'NegReg', (267, 277))	('YS110', 'Var', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('transcription', 'MPA', (289, 302))	('YS110', 'Chemical', '-', (261, 266))	('TFIIH', 'Gene', (322, 327))
156857	31398954	The intact masses of unconjugated YS110 and Y-TR1 (SMCC) measured by the MALDI-TOF mass analysis were 147,012.7 and 151,815.6, respectively (Figure 3A,B).	('YS110', 'Chemical', '-', (34, 39))	('Y-TR1', 'Var', (44, 49))	('SMCC', 'Chemical', 'MESH:C025285', (51, 55))	('YS110', 'Var', (34, 39))
156861	31398954	The Y-TR1 showed dose-dependent cytotoxicity against CD26-positive MM and leukemia cell lines (Figure 4A,C-E).	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('Y-TR1', 'Var', (4, 9))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('CD26-positive MM', 'CPA', (53, 69))	('cytotoxicity', 'Disease', (32, 44))	('leukemia', 'Disease', (74, 82))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
156867	31398954	Against CD26-positive cells (MSTO clone12, JMN, Jurkat CD26 (+)), Y-TR1 showed remarkably higher cytotoxicity than the unconjugated YS110.	('cytotoxicity', 'Disease', (97, 109))	('Y-TR1', 'Var', (66, 71))	('cytotoxicity', 'Disease', 'MESH:D064420', (97, 109))	('higher', 'PosReg', (90, 96))	('MN', 'CellLine', 'CVCL:U508', (44, 46))	('YS110', 'Chemical', '-', (132, 137))	('Jurkat CD26', 'CellLine', 'CVCL:0065', (48, 59))
156870	31398954	In vitro cytotoxicity against CD26-positive non-cancer cells (primary dermal human microvascular endothelial cells, dHMVECs) was also tested, and Y-TR1 showed less cytotoxicity than against CD26-positive malignant cell lines significantly (Figure 4E).	('less', 'NegReg', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Y-TR1', 'Var', (146, 151))	('cytotoxicity', 'Disease', 'MESH:D064420', (9, 21))	('non-cancer', 'Disease', (44, 54))	('cytotoxicity', 'Disease', (164, 176))	('non-cancer', 'Disease', 'MESH:D009369', (44, 54))	('cytotoxicity', 'Disease', (9, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (164, 176))	('human', 'Species', '9606', (77, 82))
156871	31398954	Y-TR1's equivalent of free TR-1 was calculated by IC50 of Y-TR1 (approximately 15 microg/mL = 99 nM) and unconjugated TR-1 (250 nM) against the MSTO clone12 cell line.	('TR-1', 'Gene', '80835', (118, 122))	('TR-1', 'Gene', (118, 122))	('Y-TR1', 'Var', (58, 63))	('TR-1', 'Gene', (27, 31))	('TR-1', 'Gene', '80835', (27, 31))
156877	31398954	To confirm that the cytotoxic effect of Y-TR1 is caused by RNA polymerase II repression as with triptolide, heat shock induction of HSP70, which is dependent on the RNA polymerase activity, was evaluated.	('RNA polymerase activity', 'molecular_function', 'GO:0034062', ('165', '188'))	('RNA polymerase activity', 'molecular_function', 'GO:0097747', ('165', '188'))	('RNA polymerase', 'Protein', (59, 73))	('repression', 'NegReg', (77, 87))	('cytotoxic effect', 'MPA', (20, 36))	('RNA', 'cellular_component', 'GO:0005562', ('165', '168'))	('triptolide', 'Chemical', 'MESH:C001899', (96, 106))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('shock', 'Phenotype', 'HP:0031273', (113, 118))	('Y-TR1', 'Var', (40, 45))
156879	31398954	The in vivo efficacy of Y-TR1 compared with the unconjugated YS110 in the NOD/SCID mouse xenograft model using the CD26-positive MM cell line JMN.	('SCID', 'Disease', 'MESH:D053632', (78, 82))	('SCID', 'Disease', (78, 82))	('YS110', 'Chemical', '-', (61, 66))	('NOD', 'Gene', '1822', (74, 77))	('mouse', 'Species', '10090', (83, 88))	('NOD', 'Gene', (74, 77))	('Y-TR1', 'Var', (24, 29))	('MN', 'CellLine', 'CVCL:U508', (143, 145))
156881	31398954	The mean tumor volume of the Y-TR1 group (4 mg/kg weight, total 36 mg/kg Y-TR1 intraperitoneally) was significantly lower (p < 0.05) than the control or the YS110 group (Figure 6A).	('lower', 'NegReg', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('YS110', 'Chemical', '-', (157, 162))	('Y-TR1', 'Var', (29, 34))	('tumor', 'Disease', (9, 14))
156882	31398954	The mean tumor volume of the YS110 group (4 mg/kg weight, total 36 mg/kg Y-TR1 intraperitoneally) was not significantly altered compared with the control (Figure 6A).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('YS110', 'Var', (29, 34))	('tumor', 'Disease', (9, 14))	('YS110', 'Chemical', '-', (29, 34))
156884	31398954	There were no clinical manifestations in mice treated with YS110 or Y-TR1.	('YS110', 'Chemical', '-', (59, 64))	('Y-TR1', 'Var', (68, 73))	('mice', 'Species', '10090', (41, 45))	('YS110', 'Var', (59, 64))
156885	31398954	The mean body weight of the mice of each group at sacrifice was not significantly different in mice treated with YS110 or Y-TR1 (Supplementary Figure S2A).	('mice', 'Species', '10090', (95, 99))	('mice', 'Species', '10090', (28, 32))	('YS110', 'Chemical', '-', (113, 118))	('Y-TR1', 'Var', (122, 127))	('YS110', 'Var', (113, 118))
156887	31398954	On the other hand, the mean tumor weight of the YS110 only group and the Y-TR1 group (8 mg/kg weight, total 72 mg/kg of YS110 or Y-TR1 intraperitoneally) was significantly lower (p < 0.05 or p < 0.025) than that of the control group (Figure 6B).	('tumor', 'Disease', (28, 33))	('YS110', 'Chemical', '-', (120, 125))	('lower', 'NegReg', (172, 177))	('YS110', 'Chemical', '-', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('YS110', 'Var', (48, 53))
156888	31398954	Furthermore, the mean tumor weight of the Y-TR1 group was significantly lower (p < 0.05) than that of the YS110 only group (Figure 6B).	('Y-TR1', 'Var', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('YS110', 'Chemical', '-', (106, 111))	('lower', 'NegReg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
156890	31398954	As a result, a decreased number of MIB-1-positive cells in Y-TR1-treated tumors was shown compared to IgG1- or YS110-treated tumors (Figure 6C).	('YS110-treated tumors', 'Disease', 'MESH:D019553', (111, 131))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('IgG1', 'Gene', '16017', (102, 106))	('Y-TR1-treated', 'Var', (59, 72))	('tumors', 'Disease', (125, 131))	('YS110-treated tumors', 'Disease', (111, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('MIB-1', 'Gene', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('decreased', 'NegReg', (15, 24))	('tumors', 'Disease', (73, 79))	('IgG1', 'cellular_component', 'GO:0071735', ('102', '106'))	('IgG1', 'Gene', (102, 106))	('MIB-1', 'Gene', '57534', (35, 40))
156896	31398954	reported that cancer cells with hemizygous TP53 deletion were vulnerable to further suppression of such genes.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('deletion', 'Var', (48, 56))
156901	31398954	It was shown that low doses of the alpha-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumor regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('antibody', 'cellular_component', 'GO:0019815', ('108', '116'))	('epithelial cell adhesion molecule', 'Gene', (66, 99))	('cell adhesion', 'biological_process', 'GO:0007155', ('77', '90'))	('colorectal cancer', 'Disease', (176, 193))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('EpCAM', 'Gene', '17075', (101, 106))	('alpha-amanitin', 'Chemical', 'MESH:D053959', (35, 49))	('antibody', 'cellular_component', 'GO:0019814', ('108', '116'))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('77', '99'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('EpCAM', 'Gene', (101, 106))	('deletion', 'Var', (210, 218))	('antibody', 'molecular_function', 'GO:0003823', ('108', '116'))	('POLR2A', 'Gene', '5430', (222, 228))	('tumor', 'Disease', (134, 139))	('mouse', 'Species', '10090', (154, 159))	('antibody', 'cellular_component', 'GO:0042571', ('108', '116'))	('epithelial cell adhesion molecule', 'Gene', '17075', (66, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('POLR2A', 'Gene', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('human', 'Species', '9606', (170, 175))
156909	31398954	Herein it revealed that in contrast to this ErbB2-Herceptin line, the YS110 treatment abundantly induces nuclear localization of CD26 and in consequentially suppresses POLR2A expression, leading to inhibition of tumor cell growth.	('localization', 'biological_process', 'GO:0051179', ('113', '125'))	('CD26', 'Protein', (129, 133))	('expression', 'MPA', (175, 185))	('ErbB2', 'Gene', (44, 49))	('YS110', 'Var', (70, 75))	('inhibition', 'NegReg', (198, 208))	('POLR2A', 'Gene', '5430', (168, 174))	('nuclear localization', 'MPA', (105, 125))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('ErbB2', 'Gene', '2064', (44, 49))	('suppresses', 'NegReg', (157, 167))	('induces', 'PosReg', (97, 104))	('YS110', 'Chemical', '-', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cell growth', 'biological_process', 'GO:0016049', ('218', '229'))	('POLR2A', 'Gene', (168, 174))	('tumor', 'Disease', (212, 217))
156922	31398954	Furthermore, YS110 retards directly cell cycling of cancer cells at both G1/s and G2/M.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('retards', 'Disease', (19, 26))	('cell cycling', 'CPA', (36, 48))	('YS110', 'Chemical', '-', (13, 18))	('retards', 'Disease', 'MESH:D008607', (19, 26))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('YS110', 'Var', (13, 18))
156926	31398954	As a result, the clinical application of Y-TR1 may be expected at 6 mg/kg body weight in accord with the concentration of YS110 in the phase I clinical trial without toxicity of TR1 because the LD50 of Y-TR1 is estranged from the calculated LD50 of TR-1.	('Y-TR1', 'Var', (202, 207))	('YS110', 'Chemical', '-', (122, 127))	('TR-1', 'Gene', '80835', (249, 253))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('toxicity', 'Disease', (166, 174))	('TR-1', 'Gene', (249, 253))
156952	31398954	In brief, 5 x 103 MSTO-wt, MSTO-clone12, JMN, Jurkat CD26(-), and Jurkat CD26(+) cultured in 96-well plates in the RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS), ABPC(100 mug/mL), Streptomycin(100 mug/mL) with Triptolide (ranging from 0 nM to 100 nM), TR-1 (ranging from 0 nM to 1000 nM), YS110 (ranging from 0 microg/mL to 100 microg/mL), or Y-TR1 (ranging from 0 microg/mL to 100 microg/mL) for 48 h at 37  C, 5% CO2.	('FBS', 'Disease', 'MESH:D005198', (191, 194))	('Triptolide', 'Chemical', 'MESH:C001899', (245, 255))	('MN', 'CellLine', 'CVCL:U508', (42, 44))	('mug', 'molecular_function', 'GO:0043739', ('232', '235'))	('Jurkat CD26', 'CellLine', 'CVCL:0065', (46, 57))	('mug', 'molecular_function', 'GO:0043739', ('206', '209'))	('FBS', 'Disease', (191, 194))	('Streptomycin', 'Chemical', 'MESH:D013307', (215, 227))	('TR-1', 'Gene', '80835', (287, 291))	('Jurkat CD26', 'CellLine', 'CVCL:0065', (66, 77))	('ranging', 'Var', (257, 264))	('YS110', 'Chemical', '-', (324, 329))	('CO2', 'Chemical', '-', (450, 453))	('TR-1', 'Gene', (287, 291))	('bovine', 'Species', '9913', (177, 183))	('RPMI', 'Chemical', '-', (115, 119))
156970	31398954	From the day of transplantation, the YS110, 14D10 and Y-TR1 groups received 4 or 8 mg/kg/dose of YS110, 14D10 or Y-TR1 intraperitoneally three times a week, for a total of nine doses.	('14D10', 'Var', (104, 109))	('YS110', 'Chemical', '-', (37, 42))	('YS110', 'Var', (97, 102))	('Y-TR1', 'Var', (113, 118))	('YS110', 'Chemical', '-', (97, 102))
156981	31398954	Induction of nuclear localization of CD26 by Y-TR1 promotes transcriptional repression of the POLR2A gene, furthermore the internalization of YS110-TR1 compound into the nucleus may inhibit TFIIH, resulting in impaired cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('internalization', 'MPA', (123, 138))	('transcriptional repression', 'MPA', (60, 86))	('POLR2A', 'Gene', (94, 100))	('localization', 'biological_process', 'GO:0051179', ('21', '33'))	('cell growth', 'biological_process', 'GO:0016049', ('226', '237'))	('promotes', 'PosReg', (51, 59))	('inhibit', 'NegReg', (182, 189))	('YS110-TR1', 'Var', (142, 151))	('TFIIH', 'Gene', (190, 195))	('impaired cancer', 'Disease', 'MESH:D009422', (210, 225))	('TFIIH', 'Gene', '2071', (190, 195))	('YS110', 'Chemical', '-', (142, 147))	('POLR2A', 'Gene', '5430', (94, 100))	('nucleus', 'cellular_component', 'GO:0005634', ('170', '177'))	('nuclear localization', 'MPA', (13, 33))	('impaired cancer', 'Disease', (210, 225))
156982	31398954	PCT/JP2016/076542 cancer treatment composition combining the anti-CD26 antibody and other anticancer agent.	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('anti-CD26', 'Var', (61, 70))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
156986	31398954	), a Grant-in-Aid for Scientific Research (B) (23390086 and 16H04714 to T.Y.	('Aid', 'Gene', '57379', (14, 17))	('23390086', 'Var', (47, 55))	('Aid', 'Gene', (14, 17))	('16H04714', 'Var', (60, 68))
156989	29731861	Analysis of YAP1 and TAZ expression by immunohistochemical staining in malignant mesothelioma and reactive mesothelial cells Gene mutations are involved in the development of malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (175, 197))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (71, 93))	('TAZ', 'Gene', (21, 24))	('TAZ', 'Gene', '6901', (21, 24))	('involved', 'Reg', (144, 152))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (175, 197))	('malignant mesothelioma', 'Disease', (71, 93))	('malignant mesothelioma', 'Disease', (175, 197))	('YAP1', 'Gene', (12, 16))	('mutations', 'Var', (130, 139))	('YAP1', 'Gene', '10413', (12, 16))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (71, 93))	('men', 'Species', '9606', (167, 170))
156991	29731861	Previously, the utility of detecting the loss of BAP1 by immunohistochemistry (IHC) and p16-deletion by fluorescence in situ hybridization has been identified in several studies.	('p16', 'Gene', (88, 91))	('loss', 'Var', (41, 45))	('BAP1', 'Gene', (49, 53))	('p16', 'Gene', '1029', (88, 91))	('BAP1', 'Gene', '51411', (49, 53))
156992	29731861	The present study aimed to evaluate the expression of yes-associated protein 1 (YAP1) and tafazzin (TAZ) protein, which are associated with NF2 gene mutations, in malignant mesothelioma (MM) and reactive mesothelial cells (RMCs).	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (163, 185))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('mutations', 'Var', (149, 158))	('tafazzin', 'Gene', '6901', (90, 98))	('malignant mesothelioma', 'Disease', (163, 185))	('TAZ', 'Gene', '6901', (100, 103))	('YAP1', 'Gene', (80, 84))	('associated', 'Reg', (124, 134))	('YAP1', 'Gene', '10413', (80, 84))	('TAZ', 'Gene', (100, 103))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (163, 185))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('NF2', 'Gene', (140, 143))	('tafazzin', 'Gene', (90, 98))
156995	29731861	Positivity for YAP1 was identified 27/31 MM and 15/33 RMC samples.	('YAP1', 'Gene', '10413', (15, 19))	('YAP1', 'Gene', (15, 19))	('Positivity', 'Var', (0, 10))
156996	29731861	Positivity for TAZ was identified in 28/31 MM and 18/33 RMC samples.	('TAZ', 'Gene', '6901', (15, 18))	('TAZ', 'Gene', (15, 18))	('Positivity', 'Var', (0, 10))
157003	29731861	Previous studies suggest that detection of 9p21 homozygous deletion using fluorescence in situ hybridization (FISH) and loss of BAP1 by IHC analysis is useful for diagnosing MM.	('9p21', 'Gene', (43, 47))	('BAP1', 'Gene', (128, 132))	('loss', 'Var', (120, 124))	('BAP1', 'Gene', '51411', (128, 132))
157010	29731861	Hippo signaling inactivation leads to constitutive YAP1/TAZ activation.	('YAP1', 'Gene', (51, 55))	('YAP1', 'Gene', '10413', (51, 55))	('activation', 'PosReg', (60, 70))	('inactivation', 'Var', (16, 28))	('TAZ', 'Gene', '6901', (56, 59))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))	('TAZ', 'Gene', (56, 59))	('Hippo', 'Protein', (0, 5))
157011	29731861	Overexpression of YAP1 and an inactivating mutation of LATS2 have been identified in MM.	('inactivating mutation', 'Var', (30, 51))	('YAP1', 'Gene', (18, 22))	('YAP1', 'Gene', '10413', (18, 22))	('LATS2', 'Gene', (55, 60))	('LATS2', 'Gene', '26524', (55, 60))
157017	29731861	PP1 efficiently dephosphorylates Ser-89 and Ser-311 in TAZ in vitro.	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('PP1', 'Gene', (0, 3))	('TAZ', 'Gene', '6901', (55, 58))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('TAZ', 'Gene', (55, 58))	('Ser-89', 'Var', (33, 39))	('Ser', 'Chemical', 'MESH:D012694', (33, 36))	('Ser', 'Chemical', 'MESH:D012694', (44, 47))	('Ser-311', 'Var', (44, 51))	('PP1', 'Gene', '5464', (0, 3))
157064	29731861	However, despite the high specificity of p16 homozygous deletion and loss of BAP1, their sensitivity was low.	('loss', 'NegReg', (69, 73))	('p16', 'Gene', (41, 44))	('BAP1', 'Gene', '51411', (77, 81))	('homozygous deletion', 'Var', (45, 64))	('BAP1', 'Gene', (77, 81))	('p16', 'Gene', '1029', (41, 44))
157065	29731861	Asbestos-exposed NF2 knockout mice exhibit accelerated MM tumor formation; therefore, it is possible that the inactivation of NF2 is important in the development of MM.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mice', 'Species', '10090', (30, 34))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('MM tumor', 'Disease', (55, 63))	('accelerated', 'PosReg', (43, 54))	('MM tumor', 'Disease', 'MESH:D009369', (55, 63))	('inactivation', 'Var', (110, 122))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('men', 'Species', '9606', (157, 160))	('NF2', 'Gene', (126, 129))
157080	29731861	Additionally, NF2 gene mutations are involved in an alternative pathway that differ from p16 and BAP1, thus these markers may aid in distinguishing MM from RMC.	('p16', 'Gene', (89, 92))	('BAP1', 'Gene', '51411', (97, 101))	('RMC', 'Disease', (156, 159))	('aid', 'Gene', (126, 129))	('mutations', 'Var', (23, 32))	('BAP1', 'Gene', (97, 101))	('p16', 'Gene', '1029', (89, 92))	('aid', 'Gene', '57379', (126, 129))	('NF2 gene', 'Gene', (14, 22))	('involved', 'Reg', (37, 45))
157108	28968974	Additionally, another factor important for viral tropism of cancer cells are deficiencies in the innate antiviral response pathway in cancer cells that elevates permissiveness for viral replication and spread selectively within tumors compared to normal cells.	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('spread', 'CPA', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tropism', 'biological_process', 'GO:0009606', ('49', '56'))	('cancer', 'Disease', (134, 140))	('elevates', 'PosReg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('viral tropism of cancer', 'Disease', (43, 66))	('viral replication', 'biological_process', 'GO:0008166', ('180', '197'))	('tumors', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('viral replication', 'biological_process', 'GO:0019079', ('180', '197'))	('viral replication', 'biological_process', 'GO:0019058', ('180', '197'))	('deficiencies', 'Var', (77, 89))	('viral tropism of cancer', 'Disease', 'MESH:D009369', (43, 66))	('antiviral response', 'biological_process', 'GO:0051607', ('104', '122'))	('permissiveness for viral replication', 'MPA', (161, 197))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
157132	28968974	Three MM cell lines were either treated with MV-GFP (MOI of 1.0) or left untreated for 48 hours and cells were subjected to Annexin V measurement (Figure 2B).	('MV-GFP', 'Var', (45, 51))	('MV', 'Species', '11234', (45, 47))	('Annexin V', 'Gene', '308', (124, 133))	('Annexin V', 'Gene', (124, 133))
157159	28968974	However, for H2596 the diminishment between MV and the combined treatment was slight compared to MV-CEA alone (Figure 4A).	('CEA', 'Gene', (100, 103))	('H2596', 'Var', (13, 18))	('H2596', 'Chemical', '-', (13, 18))	('MV', 'Species', '11234', (97, 99))	('MV', 'Species', '11234', (44, 46))	('CEA', 'Gene', '1048', (100, 103))
157164	28968974	These results together indicate that in the presence of limiting and diminished levels of eIF4E the mesothelioma cells are rendered less sensitive to oncolytic viral effects of MV-CEA.	('less', 'NegReg', (132, 136))	('CEA', 'Gene', (180, 183))	('CEA', 'Gene', '1048', (180, 183))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('MV', 'Species', '11234', (177, 179))	('diminished', 'NegReg', (69, 79))	('eIF4', 'cellular_component', 'GO:0008304', ('90', '94'))	('eIF4E', 'Var', (90, 95))	('sensitive to oncolytic viral effects', 'MPA', (137, 173))
157165	28968974	Further, if repressing cap-mediated translation by reducing eIF4E levels attenuates measles virus cytotoxicity, then forcing mesothelioma cells to produce an endogenous repressor protein of eIF4E, 4E-BP1, should also result in a similar decreased sensitivity to measles virus oncolysis.	('cytotoxicity', 'Disease', (98, 110))	('measles virus', 'Species', '11234', (262, 275))	('translation', 'biological_process', 'GO:0006412', ('36', '47'))	('eIF4E', 'MPA', (60, 65))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('eIF4', 'cellular_component', 'GO:0008304', ('190', '194'))	('4E-BP1', 'Gene', '1978', (197, 203))	('eIF4', 'cellular_component', 'GO:0008304', ('60', '64'))	('measles virus', 'Species', '11234', (84, 97))	('cap', 'Chemical', '-', (23, 26))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('decreased', 'NegReg', (237, 246))	('sensitivity to measles', 'Phenotype', 'HP:0020088', (247, 269))	('sensitivity to measles virus oncolysis', 'MPA', (247, 285))	('attenuates', 'NegReg', (73, 83))	('4E-BP1', 'Gene', (197, 203))	('eIF4E', 'Var', (190, 195))	('measles', 'CPA', (84, 91))	('reducing', 'NegReg', (51, 59))	('mesothelioma', 'Disease', (125, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (125, 137))
157175	28968974	The average CI for the 6 different drug combinations for cell line H2373 was slightly antagonistic (1.12), for H2596 was moderately antagonistic (1.31), for H2461 was antagonistic (2.18) and for H513 was strongly antagonistic (8.31).	('H2596', 'Chemical', '-', (111, 116))	('H513', 'CellLine', 'CVCL:A570', (195, 199))	('H2461', 'CellLine', 'CVCL:A536', (157, 162))	('H2373', 'CellLine', 'CVCL:A533', (67, 72))	('H2596', 'Var', (111, 116))	('H2461', 'Var', (157, 162))
157179	28968974	To assess the impact that IGF-I stimulation has on the activation of MV oncolysis, three MM cell lines were left untreated or treated with IGF-I (5 nM), MV-GFP (MOI 0.1) or treated with both agents (Figure 5A) and cell viability measured 24 hours later.	('IGF-I', 'Gene', '3479', (26, 31))	('IGF-I', 'Gene', (139, 144))	('MV', 'Species', '11234', (69, 71))	('MV', 'Species', '11234', (153, 155))	('IGF-I', 'Gene', (26, 31))	('MV-GFP', 'Var', (153, 159))	('IGF-I', 'Gene', '3479', (139, 144))
157180	28968974	In all cell lines the cell viability was significantly reduced to a greater extent in the presence of IGF-I when treated with MV-GFP than in cells treated with MV-GFP but in the absence of IGF-I.	('IGF-I', 'Gene', '3479', (102, 107))	('MV-GFP', 'Var', (126, 132))	('presence', 'Var', (90, 98))	('reduced', 'NegReg', (55, 62))	('IGF-I', 'Gene', '3479', (189, 194))	('IGF-I', 'Gene', (102, 107))	('IGF-I', 'Gene', (189, 194))	('cell viability', 'CPA', (22, 36))	('MV', 'Species', '11234', (160, 162))	('MV', 'Species', '11234', (126, 128))
157182	28968974	In most examples the oncogenic potential of deranged eIF4F hyperactivity is connected to eIF4E activity, which is the rate-limiting element of the translation initiation complex.	('translation initiation complex', 'cellular_component', 'GO:0070992', ('147', '177'))	('eIF4F', 'Gene', '1981', (53, 58))	('eIF4', 'cellular_component', 'GO:0008304', ('89', '93'))	('oncogenic potential', 'CPA', (21, 40))	('deranged', 'Var', (44, 52))	('hyperactivity', 'Disease', 'MESH:D006948', (59, 72))	('translation initiation', 'biological_process', 'GO:0006413', ('147', '169'))	('activity', 'MPA', (95, 103))	('eIF4F', 'cellular_component', 'GO:0016281', ('53', '58'))	('eIF4E', 'Protein', (89, 94))	('hyperactivity', 'Disease', (59, 72))	('hyperactivity', 'Phenotype', 'HP:0000752', (59, 72))	('eIF4F', 'Gene', (53, 58))
157183	28968974	Moreover, in NIH-3T3 cells, ectopic overexpression of eIF4E was revealed to be oncogenic driving tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('NIH-3T3', 'CellLine', 'CVCL:0594', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('eIF4E', 'Gene', (54, 59))	('ectopic', 'Var', (28, 35))	('eIF4', 'cellular_component', 'GO:0008304', ('54', '58'))
157187	28968974	These results indicate elevated cap-meditated translation for MeT-5A producing ectopic meIF4E.	('cap-meditated translation', 'MPA', (32, 57))	('elevated', 'PosReg', (23, 31))	('ectopic', 'Var', (79, 86))	('cap', 'Chemical', '-', (32, 35))	('meIF4E', 'Gene', (87, 93))	('translation', 'biological_process', 'GO:0006412', ('46', '57'))
157189	28968974	MeT-5A cells expressing ectopic meIF4E were significantly more sensitive to MV-Edm than cells not producing ectopic meIF4E at each MOI employed (Figure 5B).	('meIF4E', 'Var', (32, 38))	('sensitive to MV-Edm', 'MPA', (63, 82))	('MV', 'Species', '11234', (76, 78))	('more', 'PosReg', (58, 62))	('ectopic meIF4E', 'Var', (24, 38))
157191	28968974	CEA marker emitted into the medium following MV-CEA infection of MeT-5A cells expressing ectopic meIF4E increased significantly compared to MV-CEA infected MeT-5A cells not expressing meIF4E (Figure 5D).	('CEA', 'Gene', (48, 51))	('increased', 'PosReg', (104, 113))	('MV', 'Species', '11234', (45, 47))	('CEA', 'Gene', '1048', (143, 146))	('MV', 'Species', '11234', (140, 142))	('CEA', 'Gene', '1048', (0, 3))	('ectopic meIF4E', 'Var', (89, 103))	('CEA', 'Gene', (143, 146))	('CEA', 'Gene', (0, 3))	('CEA', 'Gene', '1048', (48, 51))	('meIF4E', 'Var', (97, 103))
157200	28968974	While the elevated levels of CD46 can enhance the malignant phenotype in cancer it also engenders the tumor cells more sensitive to infection by MV-Edm potentiating cell killing.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('potentiating', 'PosReg', (152, 164))	('cell killing', 'CPA', (165, 177))	('enhance', 'PosReg', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MV', 'Species', '11234', (145, 147))	('cell killing', 'biological_process', 'GO:0001906', ('165', '177'))	('CD46', 'Var', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('more', 'PosReg', (114, 118))
157235	28968974	The protein bands for eIF4E and eIF4GI were normalized to their respective densities found in the MeT-5A empty vector sample.	('eIF4GI', 'Gene', '1981', (32, 38))	('eIF4GI', 'Gene', (32, 38))	('eIF4', 'cellular_component', 'GO:0008304', ('32', '36'))	('eIF4E', 'Var', (22, 27))	('eIF4', 'cellular_component', 'GO:0008304', ('22', '26'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
157237	28968974	Ten or twelve percent SDS-PAGE was used for PARP and eIF4E proteins, respectively.	('PARP', 'Gene', (44, 48))	('eIF4E', 'Var', (53, 58))	('SDS', 'Chemical', 'MESH:D012967', (22, 25))	('PARP', 'Gene', '142', (44, 48))	('eIF4', 'cellular_component', 'GO:0008304', ('53', '57'))
157299	28790855	DT undergoes the following steps to kill cells (Figure 2): 1) DT is proteolytically cleaved outside the cell between Arg193 and Ser194, which is within a disulfide loop formed by Cys186 and Cys201.	('Cys201', 'Var', (190, 196))	('Cys201', 'Chemical', '-', (190, 196))	('Cys186', 'Var', (179, 185))	('Ser194', 'Chemical', '-', (128, 134))	('Ser194', 'Var', (128, 134))	('Cys186', 'Chemical', '-', (179, 185))	('Ser', 'cellular_component', 'GO:0005790', ('128', '131'))	('disulfide', 'Chemical', 'MESH:D004220', (154, 163))	('Arg193', 'Var', (117, 123))	('Arg193', 'Chemical', '-', (117, 123))
157307	28790855	Keppler et al indicated that a PE-based RIT, B3(Fv)-PE38, kills MCF-7 breast cancer cell line by 2 mechanisms: one is due to the inhibition of protein synthesis caused by inactivation of EF-2 and the other requires caspase activation.	('protein synthesis', 'biological_process', 'GO:0006412', ('143', '160'))	('inactivation', 'Var', (171, 183))	('EF-2', 'Gene', '1938', (187, 191))	('caspase activation', 'biological_process', 'GO:0006919', ('215', '233'))	('PE', 'Chemical', '-', (52, 54))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (64, 83))	('PE', 'Chemical', '-', (31, 33))	('MCF-7 breast cancer', 'Disease', (64, 83))	('protein synthesis', 'MPA', (143, 160))	('EF-2', 'Gene', (187, 191))	('inhibition', 'NegReg', (129, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
157316	28790855	Plant toxins have been reported to prevent the association of EF-1 and EF-2 with the ribosomal subunit by removing the base of A4324 in 28s ribosomal RNA (rRNA).	('EF-2', 'Gene', (71, 75))	('A4324', 'Var', (127, 132))	('ribosomal RNA', 'molecular_function', 'GO:0005566', ('140', '153'))	('EF-2', 'Gene', '1938', (71, 75))	('base', 'MPA', (119, 123))	('ribosomal RNA', 'molecular_function', 'GO:0003735', ('140', '153'))	('removing', 'NegReg', (106, 114))	('ribosomal subunit', 'cellular_component', 'GO:0044391', ('85', '102'))	('ribosomal RNA', 'cellular_component', 'GO:0005840', ('140', '153'))	('association', 'Interaction', (47, 58))
157321	28790855	IL-2R, which binds the IL-2 with high affinity, is composed of 3 subunits (alpha [CD25], beta [CD122], and gamma [CD132]).	('IL-2', 'Gene', (23, 27))	('IL-2', 'molecular_function', 'GO:0005134', ('23', '27'))	('IL-2', 'Gene', (0, 4))	('CD25', 'Gene', (82, 86))	('IL-2R', 'Gene', (0, 5))	('IL-2', 'Gene', '3558', (0, 4))	('IL-2R', 'Gene', '3559', (0, 5))	('CD25', 'Gene', '3559', (82, 86))	('IL-2', 'Gene', '3558', (23, 27))	('IL-2R', 'molecular_function', 'GO:0004911', ('0', '5'))	('beta [CD122]', 'Var', (89, 101))
157373	28790855	Bell et al evaluated the effect of depleting activated T cells with RFT5-dgA through an in vitro model of acute HIV infection, and the results showed that RFT5-dgA inhibited viral production by activated CD25+ HIV-infected cells and suppressed the breed of infection to uninfected T cells.	('HIV-infected', 'Disease', (210, 222))	('RFT5-dgA', 'Var', (155, 163))	('HIV infection', 'Disease', 'MESH:D015658', (112, 125))	('suppressed', 'NegReg', (233, 243))	('infection to uninfected T', 'Disease', 'MESH:D001260', (257, 282))	('CD25', 'Gene', '3559', (204, 208))	('HIV-infected', 'Disease', 'MESH:D015658', (210, 222))	('inhibited', 'NegReg', (164, 173))	('viral production', 'MPA', (174, 190))	('infection to uninfected T', 'Disease', (257, 282))	('HIV infection', 'Disease', (112, 125))	('CD25', 'Gene', (204, 208))
157375	28790855	In these mice, 40 mug of RFT5-dgA decreased the diameter of >60% of solid Hodgkin and Reed-Sternberg (H-RS) tumors and inhibited the growth of HL in the majority of the treated mice.	('RFT5-dgA', 'Var', (25, 33))	('H-RS) tumors', 'Disease', 'MESH:D041441', (102, 114))	('decreased', 'NegReg', (34, 43))	('solid Hodgkin', 'Disease', 'MESH:D006689', (68, 81))	('growth', 'MPA', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('solid Hodgkin', 'Disease', (68, 81))	('mug', 'molecular_function', 'GO:0043739', ('18', '21'))	('diameter', 'MPA', (48, 56))	('inhibited', 'NegReg', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mice', 'Species', '10090', (9, 13))	('mice', 'Species', '10090', (177, 181))
157382	28790855	In conclusion, RFT5-dgA showed encouraging efficacy at a dose level, and multiple cycles of treatment could be given without cumulative toxicities.	('RFT5-dgA', 'Var', (15, 23))	('toxicities', 'Disease', 'MESH:D064420', (136, 146))	('toxicities', 'Disease', (136, 146))
157390	28790855	Eleven of 16 patients receiving 2 or more cycles produced anti-ricin antibodies or anti-mouse antibodies, and the side effect in this study remained moderate and related to VLS.	('patients', 'Species', '9606', (13, 21))	('anti-ricin', 'Protein', (58, 68))	('anti-mouse', 'Var', (83, 93))	('his', 'Chemical', 'MESH:D006639', (130, 133))	('mouse', 'Species', '10090', (88, 93))	('ricin', 'molecular_function', 'GO:0030598', ('63', '68'))	('VLS', 'Disease', (173, 176))
157399	28790855	Anti-B4-bR has been shown to be highly cytotoxic for B4-positive cells, and the cytotoxicity is restricted to these cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('Anti-B4-bR', 'Var', (0, 10))	('cytotoxic', 'CPA', (39, 48))	('cytotoxicity', 'Disease', (80, 92))
157400	28790855	Thirty-four patients with relapsed or refractory B-cell neoplasms (twenty-six NHL, four CLL, four ALL) received 7-day continuous infusion of anti-B4-bR at dose levels ranging from 10 to 70 mg/kg/d.	('B-cell neoplasms', 'Disease', (49, 65))	('patients', 'Species', '9606', (12, 20))	('B-cell neoplasms', 'Phenotype', 'HP:0012191', (49, 65))	('anti-B4-bR', 'Var', (141, 151))	('B-cell neoplasms', 'Disease', 'MESH:D016393', (49, 65))	('neoplasms', 'Phenotype', 'HP:0002664', (56, 65))
157403	28790855	Another Phase I trial that enrolled 25 patients with refractory B-cell malignancies was conducted to detail the toxicity and clinical response data when anti-B4-bR was administered as daily bolus infusions for 5 consecutive days.	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('toxicity', 'Disease', (112, 120))	('patients', 'Species', '9606', (39, 47))	('malignancies', 'Disease', (71, 83))	('anti-B4-bR', 'Var', (153, 163))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
157414	28790855	Almost 25% of patients on the bolus infusion regimen and 30% on the continuous infusion regimen developed antibody against mouse Ig and/or ricin A chain antibody.	('ricin', 'molecular_function', 'GO:0030598', ('139', '144'))	('antibody', 'cellular_component', 'GO:0042571', ('106', '114'))	('mouse', 'Species', '10090', (123, 128))	('ricin A chain antibody', 'Protein', (139, 161))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('antibody', 'cellular_component', 'GO:0019815', ('106', '114'))	('ricin A', 'Chemical', '-', (139, 146))	('antibody', 'cellular_component', 'GO:0019814', ('106', '114'))	('mouse Ig', 'Protein', (123, 131))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('106', '114'))	('antibody', 'Var', (106, 114))	('patients', 'Species', '9606', (14, 22))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))
157479	28790855	Combotox is a 1:1 mixture of HD37-dgA and RFB4-dgA, which are RITs that target the CD19 and CD22 antigens, respectively.	('CD22', 'Gene', (92, 96))	('RFB4-dgA', 'Var', (42, 50))	('HD', 'Disease', 'MESH:D006816', (29, 31))	('CD22', 'Gene', '933', (92, 96))	('RITs', 'Chemical', '-', (62, 66))	('CD19', 'Gene', (83, 87))	('Combotox', 'Chemical', 'MESH:C577568', (0, 8))	('CD19', 'Gene', '930', (83, 87))
157480	28790855	A previous Phase I trial showed that RFB4-dgA induced 24% PRs and 1 long-lasting CR by continuous infusion regimen.	('PRs', 'CPA', (58, 61))	('CR', 'Chemical', '-', (81, 83))	('RFB4-dgA', 'Var', (37, 45))
157489	28790855	Combotox, the mixture of HD37-dgA and RFB4-dgA, can bind to and kill human precursor-B-ALL blasts in vitro, and the combination was more effective than either RIT alone.	('bind', 'Interaction', (52, 56))	('RFB4-dgA', 'Var', (38, 46))	('human', 'Species', '9606', (69, 74))	('kill', 'NegReg', (64, 68))	('Combotox', 'Chemical', 'MESH:C577568', (0, 8))	('HD', 'Disease', 'MESH:D006816', (25, 27))
157503	28790855	Ki-4.dgA was 5 times more potent in vitro than other anti-CD30 dgA-RITs tested previously and showed high efficacy in the treatment of human HL in SCID mice.	('CD30', 'Gene', '943', (58, 62))	('RITs', 'Chemical', '-', (67, 71))	('Ki-4.dgA', 'Var', (0, 8))	('human HL', 'Disease', (135, 143))	('SCID', 'Disease', 'MESH:D053632', (147, 151))	('SCID', 'Disease', (147, 151))	('human', 'Species', '9606', (135, 140))	('mice', 'Species', '10090', (152, 156))	('CD30', 'Gene', (58, 62))
157504	28790855	Therefore, ki-4.dgA was selected for a Phase I trial in patients with refractory CD30+ HL and NHL.	('patients', 'Species', '9606', (56, 64))	('ki-4.dgA', 'Var', (11, 19))	('NHL', 'Disease', (94, 97))	('ki-4', 'Chemical', 'MESH:D013645', (11, 15))	('CD30', 'Gene', '943', (81, 85))	('CD30', 'Gene', (81, 85))
157513	28790855	In a Phase I trial of refractory myeloid leukemias, HUM-195/Rgel induced a 38%-50% decrease in peripheral blood blasts or bone marrow blasts in 7 of 28 patients, and there was no CR or PR.	('myeloid leukemias', 'Disease', 'MESH:D007951', (33, 50))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('myeloid leukemias', 'Disease', (33, 50))	('decrease', 'NegReg', (83, 91))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (33, 50))	('HUM-195/Rgel', 'Var', (52, 64))	('patients', 'Species', '9606', (152, 160))	('leukemias', 'Phenotype', 'HP:0001909', (41, 50))	('peripheral blood blasts', 'CPA', (95, 118))	('CR', 'Chemical', '-', (179, 181))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (33, 49))
157550	28790855	One of 6 patients, who received the maximum dose level of SS1P, had DLT because of the reversible VLS.	('patients', 'Species', '9606', (9, 17))	('SS1P', 'Chemical', 'MESH:C474515', (58, 62))	('SS1P', 'Var', (58, 62))	('DLT', 'Disease', (68, 71))
157560	28790855	Grade 3 toxicities associated with SS1P included fatigue, hypoalbuminemia, back pain, and hypotension.	('pain', 'Phenotype', 'HP:0012531', (80, 84))	('hypotension', 'Disease', (90, 101))	('SS1P', 'Var', (35, 39))	('back pain', 'Disease', 'MESH:D001416', (75, 84))	('hypotension', 'Phenotype', 'HP:0002615', (90, 101))	('fatigue', 'Disease', (49, 56))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (58, 73))	('toxicities', 'Disease', (8, 18))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (58, 73))	('fatigue', 'Phenotype', 'HP:0012378', (49, 56))	('hypoalbuminemia', 'Disease', (58, 73))	('back pain', 'Disease', (75, 84))	('toxicities', 'Disease', 'MESH:D064420', (8, 18))	('hypotension', 'Disease', 'MESH:D007022', (90, 101))	('back pain', 'Phenotype', 'HP:0003418', (75, 84))	('fatigue', 'Disease', 'MESH:D005221', (49, 56))	('SS1P', 'Chemical', 'MESH:C474515', (35, 39))
157583	28790855	ERB-38 is an RIT composed of the Fv portion of Mab e23 that reacts with ErbB2, fused to PE38, a truncated form of PE.	('ERB', 'Gene', (0, 3))	('PE', 'Chemical', '-', (114, 116))	('ERB', 'Gene', '2100', (0, 3))	('PE38', 'Var', (88, 92))	('PE', 'Chemical', '-', (88, 90))
157605	28790855	BR96 binds to the LeY carbohydrate antigen that is overexpressed on the surface of many human solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (88, 93))	('binds', 'Interaction', (5, 10))	('LeY carbohydrate antigen', 'Protein', (18, 42))	('solid tumors', 'Disease', (94, 106))	('carbohydrate', 'Chemical', 'MESH:D002241', (22, 34))	('BR96', 'Var', (0, 4))
157616	28790855	NBI-3001 was highly cytotoxic to glioblastoma cell lines and made CRs in murine xenografts of human glioma in all the animals.	('CRs', 'Chemical', '-', (66, 69))	('glioma', 'Disease', (100, 106))	('glioblastoma', 'Disease', (33, 45))	('murine', 'Species', '10090', (73, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('human', 'Species', '9606', (94, 99))	('NBI-3001', 'Var', (0, 8))
157630	28790855	Although the majority of patients developed antibodies against the toxin portion of VB4-845, VB4-845 therapy was safe and without the most adverse events.	('VB4-845', 'Var', (93, 100))	('developed antibodies', 'Reg', (34, 54))	('VB4-845', 'Gene', (84, 91))	('patients', 'Species', '9606', (25, 33))
157645	28790855	And last, ADCs can cause off-target toxicity due to inappropriate payload, but RITs do not have this problem.	('cause', 'Reg', (19, 24))	('his', 'Chemical', 'MESH:D006639', (97, 100))	('inappropriate payload', 'MPA', (52, 73))	('ADCs', 'Var', (10, 14))	('RITs', 'Chemical', '-', (79, 83))	('toxicity', 'Disease', 'MESH:D064420', (36, 44))	('toxicity', 'Disease', (36, 44))
157653	28790855	Studies have shown that PE binds directly to endothelial cells, while truncated PE requires a ligand that reacts with the endothelium and a mutant form of PE showed less VLS.	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('PE', 'Chemical', '-', (24, 26))	('PE', 'Chemical', '-', (155, 157))	('PE', 'Chemical', '-', (80, 82))	('less', 'NegReg', (165, 169))	('VLS', 'MPA', (170, 173))	('mutant', 'Var', (140, 146))
157654	28790855	In addition, mutant toxins that lack enzymatic activity do not cause VLS, suggesting that VLS is an off-target effect of RITs.	('mutant', 'Var', (13, 19))	('VLS', 'Disease', (69, 72))	('RITs', 'Chemical', '-', (121, 125))
157659	28790855	In addition to mutations of short amino acid motifs of toxin part, patients receiving premedication with dexamethasone have also been shown to have less severe VLS.	('less', 'NegReg', (148, 152))	('patients', 'Species', '9606', (67, 75))	('VLS', 'Disease', (160, 163))	('mutations', 'Var', (15, 24))	('dexamethasone', 'Chemical', 'MESH:D003907', (105, 118))
157685	28790855	PEGylation also prolongs the circulation of RIT by reducing renal clearance.	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('renal clearance', 'MPA', (60, 75))	('prolongs', 'PosReg', (16, 24))	('reducing', 'NegReg', (51, 59))	('circulation of RIT', 'MPA', (29, 47))	('PEGylation', 'Var', (0, 10))	('reducing renal clearance', 'Phenotype', 'HP:0012213', (51, 75))
157689	28790855	The variant RIT, which with a deletion of domain II and 7-point mutations that modified human B-cell epitopes, had significantly reduced reactivity with human antisera and retained cytotoxic and antitumor activity.	('tumor', 'Disease', (199, 204))	('cytotoxic', 'CPA', (181, 190))	('reactivity', 'MPA', (137, 147))	('deletion', 'Var', (30, 38))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('human', 'Species', '9606', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('reduced', 'NegReg', (129, 136))
157692	28790855	All these approaches were widely used in the production of new RITs, especially the deletion of domain II of PE toxin and modification of human B- or T-cell epitopes (Figure 3).	('PE', 'Chemical', '-', (109, 111))	('modification', 'Reg', (122, 134))	('human', 'Species', '9606', (138, 143))	('RITs', 'Chemical', '-', (63, 67))	('deletion of', 'Var', (84, 95))
157694	28790855	So we constructed an RIT with small molecules that consisted of a PE38 toxin and 17 amino acids of amidated gastrin.	('gastrin', 'Gene', (108, 115))	('PE38', 'Var', (66, 70))	('gastrin', 'Gene', '2520', (108, 115))	('PE', 'Chemical', '-', (66, 68))
157697	28790855	Serial modifications have been used to reduce nonspecific toxicities, to increase stability and to improve targeted cellular killing.	('reduce', 'NegReg', (39, 45))	('modifications', 'Var', (7, 20))	('improve', 'PosReg', (99, 106))	('increase', 'PosReg', (73, 81))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('targeted cellular killing', 'CPA', (107, 132))	('stability', 'MPA', (82, 91))	('toxicities', 'Disease', (58, 68))
157698	28790855	Onda et al developed the less immunogenic PE by engineering variant of the toxin.	('engineering variant', 'Var', (48, 67))	('variant', 'Var', (60, 67))	('PE', 'Chemical', '-', (42, 44))
157734	25970771	Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('alters', 'Reg', (32, 38))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('12', '26'))	('BAP1', 'Gene', (27, 31))	('regulation', 'biological_process', 'GO:0065007', ('213', '223'))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mesothelioma', 'Disease', (97, 109))	('cancer', 'Disease', (182, 188))	('class', 'MPA', (39, 44))	('expression', 'MPA', (67, 77))	('HDAC', 'Gene', (119, 123))	('Loss', 'Var', (0, 4))	('HDAC', 'Gene', '9734', (119, 123))	('BAP1', 'Gene', '8314', (27, 31))
157738	25970771	Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('BAP1', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('inactivation', 'Var', (155, 167))	('BAP1', 'Gene', (42, 46))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('HDAC2', 'Gene', (11, 16))	('downregulated', 'NegReg', (96, 109))	('mesothelioma', 'Disease', (113, 125))
157753	25970771	In breast or osteoscarcoma cells HDAC1, but not HDAC2, was required for proliferation and its depletion led to cell cycle arrest and apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('led to', 'Reg', (104, 110))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('apoptosis', 'CPA', (133, 142))	('breast or osteoscarcoma', 'Disease', 'MESH:D001943', (3, 26))	('breast or osteoscarcoma', 'Disease', (3, 26))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('depletion', 'Var', (94, 103))	('arrest', 'Disease', (122, 128))
157774	25970771	Whilst USP33 or USPL1 depletion increased the HDAC2/HDAC1 ratio, we identified USP27X and the tumor suppressor BAP1 as DUBs whose depletion lead to the most significant decrease in the HDAC2/HDAC1 ratio.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('USP33', 'Gene', '23032', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('decrease', 'NegReg', (169, 177))	('HDAC2/HDAC1 ratio', 'MPA', (46, 63))	('USPL1', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('USP', 'molecular_function', 'GO:0051748', ('7', '10'))	('depletion', 'Var', (22, 31))	('USPL1', 'Gene', '10208', (16, 21))	('tumor', 'Disease', (94, 99))	('USP27X', 'Gene', (79, 85))	('USP', 'molecular_function', 'GO:0051748', ('79', '82'))	('USP33', 'Gene', (7, 12))	('increased', 'PosReg', (32, 41))	('HDAC2/HDAC1 ratio', 'MPA', (185, 202))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('USP27X', 'Gene', '389856', (79, 85))
157779	25970771	BAP1 knockdown elicited this same switch in HDAC2/HDAC1 expression in two other NSCLC cell lines (Figure 2C), which endogenously express these HDACs at different levels (Figure 1B).	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('BAP1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('HDAC', 'Gene', (50, 54))	('NSCLC', 'Disease', (80, 85))	('HDAC', 'Gene', '9734', (50, 54))	('HDAC', 'Gene', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('HDAC', 'Gene', (143, 147))	('HDAC', 'Gene', '9734', (44, 48))	('elicited', 'Reg', (15, 23))	('HDAC', 'Gene', '9734', (143, 147))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))
157780	25970771	As loss of BAP1 function is implicated in a high proportion of mesothelioma, we next asked whether we could recapitulate this effect in MSTO-211H cells, which were derived from a grade 4 biphasic mesothelioma and retain wild-type BAP1 expression.	('loss', 'Var', (3, 7))	('rad', 'Gene', '6236', (180, 183))	('mesothelioma', 'Disease', (196, 208))	('biphasic mesothelioma', 'Disease', (187, 208))	('mesothelioma', 'Disease', (63, 75))	('MSTO-211H', 'CellLine', 'CVCL:1430', (136, 145))	('rad', 'Gene', (180, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('BAP1', 'Gene', (11, 15))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('implicated', 'Reg', (28, 38))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (187, 208))
157782	25970771	In light of the effect of transient BAP1 depletion on HDAC expression, we hypothesized that variation in the endogenous expression of BAP1 in cancer cells may also influence HDAC levels.	('HDAC', 'Gene', '9734', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('BAP1', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('HDAC', 'Gene', (54, 58))	('influence', 'Reg', (164, 173))	('HDAC', 'Gene', '9734', (54, 58))	('HDAC', 'Gene', (174, 178))	('variation', 'Var', (92, 101))	('cancer', 'Disease', (142, 148))
157787	25970771	The MeT-5A cell line is derived from normal lung mesothelium, whilst the mesothelioma cell lines have differing BAP1 genetic status: NCI-H2052 and MSTO-211H cells retain genetically wild-type BAP1, NCI-H28 and NCI-H226 cells are BAP1 null, and NCI-H2452 cells have an inactivating mutation in the BAP1 catalytic domain.	('NCI-H2052', 'CellLine', 'CVCL:1518', (133, 142))	('mesothelioma', 'Disease', (73, 85))	('MSTO-211H', 'CellLine', 'CVCL:1430', (147, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('inactivating mutation in', 'Var', (268, 292))	('NCI-H226', 'CellLine', 'CVCL:1544', (210, 218))	('BAP1', 'Gene', (297, 301))	('NCI-H2452', 'CellLine', 'CVCL:1553', (244, 253))
157793	25970771	We first assessed whether inhibition of the proteasome led to accumulation of HDACs (Figure 4A).	('inhibition', 'Var', (26, 36))	('proteasome', 'molecular_function', 'GO:0004299', ('44', '54'))	('accumulation', 'PosReg', (62, 74))	('proteasome', 'cellular_component', 'GO:0000502', ('44', '54'))	('HDAC', 'Gene', (78, 82))	('HDAC', 'Gene', '9734', (78, 82))
157807	25970771	While HDAC1 depletion had little effect, depletion of HDAC2 significantly reduced cell viability, suggesting that MSTO-211H cells are dependent on HDAC2 for survival (Figure 6B, DMSO).	('cell viability', 'CPA', (82, 96))	('MSTO-211H', 'CellLine', 'CVCL:1430', (114, 123))	('depletion', 'Var', (41, 50))	('DMSO', 'Chemical', 'MESH:D004121', (178, 182))	('reduced', 'NegReg', (74, 81))
157811	25970771	Importantly, BAP1 knockdown also increased sensitivity to HDAC inhibition in a similar fashion, decreasing cell survival with both vorinostat and mocetinostat.	('knockdown', 'Var', (18, 27))	('BAP1', 'Gene', (13, 17))	('HDAC', 'Gene', (58, 62))	('mocetinostat', 'Chemical', 'MESH:C523184', (146, 158))	('HDAC', 'Gene', '9734', (58, 62))	('cell survival', 'CPA', (107, 120))	('vorinostat', 'Chemical', 'MESH:D000077337', (131, 141))	('increased', 'PosReg', (33, 42))	('decreasing', 'NegReg', (96, 106))
157817	25970771	In conclusion, loss of BAP1 in cell line models of thoracic malignancies alters expression of HDAC2.	('BAP1', 'Gene', (23, 27))	('malignancies', 'Disease', (60, 72))	('loss', 'Var', (15, 19))	('expression', 'MPA', (80, 90))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('HDAC2', 'Gene', (94, 99))	('alters', 'Reg', (73, 79))
157821	25970771	In fact, somatic BAP1 mutation occurs in only around 1% of lung adenocarcinoma, but is far more prevalent in uveal melanoma, mesothelioma and renal clear cell carcinoma.	('prevalent', 'Reg', (96, 105))	('mutation', 'Var', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('mesothelioma and renal clear cell carcinoma', 'Disease', 'MESH:C538614', (125, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))	('BAP1', 'Gene', (17, 21))
157822	25970771	Germline BAP1 mutation underpins a cancer predisposition syndrome and BAP1 protein expression is reportedly lost in around 50% of NSCLC, colon carcinoma, uveal melanoma and kidney cancers.	('colon carcinoma', 'Disease', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('uveal melanoma and kidney cancers', 'Disease', 'MESH:C536494', (154, 187))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('expression', 'MPA', (83, 93))	('BAP1', 'Gene', (9, 13))	('colon carcinoma', 'Disease', 'MESH:D015179', (137, 152))	('underpins', 'Reg', (23, 32))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('lost', 'NegReg', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cancer', 'Disease', (180, 186))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('BAP1', 'Gene', (70, 74))	('protein', 'Protein', (75, 82))	('NSCLC', 'Disease', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('mutation', 'Var', (14, 22))	('kidney cancers', 'Phenotype', 'HP:0009726', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (35, 41))
157829	25970771	Up to 80% of mesothelioma are directly attributable to asbestos exposure and it was recently shown that mice with heterozygous germline BAP1 knockout were predisposed to develop mesothelioma upon asbestos exposure.	('mesothelioma', 'Disease', (13, 25))	('BAP1', 'Gene', (136, 140))	('asbestos', 'Chemical', 'MESH:D001194', (55, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('mice', 'Species', '10090', (104, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('develop', 'PosReg', (170, 177))	('asbestos', 'Chemical', 'MESH:D001194', (196, 204))	('mesothelioma', 'Disease', (178, 190))	('knockout', 'Var', (141, 149))
157830	25970771	Interestingly, somatic BAP1 mutation is reported to be more common in current or ex-smokers who develop mesothelioma and could conceivably compound HDAC2 instability in response to cigarette smoke.	('BAP1', 'Gene', (23, 27))	('compound', 'Reg', (139, 147))	('develop', 'PosReg', (96, 103))	('mesothelioma', 'Disease', (104, 116))	('mutation', 'Var', (28, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))
157832	25970771	Clinically BAP1 mutation was initially linked to more aggressive, metastasizing uveal melanoma, whilst subsequent cell models suggested that BAP1 loss induces a stem cell-like phenotype.	('loss', 'NegReg', (146, 150))	('mutation', 'Var', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('induces', 'Reg', (151, 158))	('BAP1', 'Gene', (141, 145))	('linked', 'Reg', (39, 45))	('BAP1', 'Gene', (11, 15))	('stem cell-like', 'CPA', (161, 175))
157833	25970771	In mesothelioma, BAP1 loss is more common in a clinical sub-group that exhibit less evidence of EMT, but on asbestos exposure BAP1+/- mice develop more aggressive tumors, that invade other organs, than their wild-type littermates.	('EMT', 'Gene', (96, 99))	('mice', 'Species', '10090', (134, 138))	('BAP1+/-', 'Var', (126, 133))	('aggressive tumors', 'Disease', (152, 169))	('asbestos', 'Chemical', 'MESH:D001194', (108, 116))	('mesothelioma', 'Disease', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EMT', 'Gene', '16428', (96, 99))	('loss', 'NegReg', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('develop', 'PosReg', (139, 146))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('aggressive tumors', 'Disease', 'MESH:D001523', (152, 169))	('BAP1', 'Gene', (17, 21))
157835	25970771	Indeed uveal melanoma cells stably expressing BAP1 shRNA show no difference in their in vitro or in vivo growth kinetics and BAP1+/- mice do not spontaneously develop tumors.	('uveal melanoma', 'Disease', (7, 21))	('mice', 'Species', '10090', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('BAP1 shRNA', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
157836	25970771	Indeed, on transient BAP1 depletion in MSTO-211H cells, we observed an approximate 50% reduction in viable cell number, comparable with previous data for this cell line.	('depletion', 'Var', (26, 35))	('BAP1', 'Gene', (21, 25))	('MSTO-211H', 'CellLine', 'CVCL:1430', (39, 48))	('viable cell number', 'CPA', (100, 118))	('reduction', 'NegReg', (87, 96))
157841	25970771	As BAP1 interacts with BRCA1, PARP inhibitors might also exhibit synthetic lethality with BAP1 mutation.	('PARP', 'Gene', '1302', (30, 34))	('PARP', 'Gene', (30, 34))	('interacts', 'Reg', (8, 17))	('mutation', 'Var', (95, 103))	('BAP1', 'Gene', (90, 94))	('BRCA1', 'Gene', '672', (23, 28))	('BRCA1', 'Gene', (23, 28))
157848	25970771	The need to stratify NSCLC patients based on EGFR mutation for EGFR inhibitor clinical trials highlights the importance of identifying biomarkers that can predict for response.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (45, 49))	('NSCLC', 'Disease', (21, 26))	('EGFR', 'Gene', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('SCLC', 'Phenotype', 'HP:0030357', (22, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
157849	25970771	We found that despite the effect on HDAC2 expression, loss of BAP1 does not impact on total cellular HDAC activity, suggesting the compensatory increase in HDAC1 maintains cellular HDAC activity.	('HDAC', 'Gene', (101, 105))	('HDAC', 'Gene', (36, 40))	('BAP1', 'Gene', (62, 66))	('HDAC', 'Gene', (156, 160))	('HDAC', 'Gene', '9734', (101, 105))	('HDAC', 'Gene', '9734', (36, 40))	('HDAC', 'Gene', '9734', (156, 160))	('loss', 'Var', (54, 58))	('HDAC', 'Gene', (181, 185))	('increase', 'PosReg', (144, 152))	('HDAC', 'Gene', '9734', (181, 185))
157850	25970771	This is consistent with other reports of the HDAC relationship, for example in mice with targeted inactivation of either HDAC1 or HDAC2 in the epidermis, there is reciprocal upregulation of the opposite isoenzyme with no reduction in total HDAC activity.	('HDAC', 'Gene', (240, 244))	('inactivation', 'Var', (98, 110))	('HDAC', 'Gene', '9734', (240, 244))	('HDAC', 'Gene', (121, 125))	('mice', 'Species', '10090', (79, 83))	('HDAC', 'Gene', '9734', (121, 125))	('upregulation', 'PosReg', (174, 186))	('HDAC', 'Gene', (130, 134))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (130, 134))	('HDAC', 'Gene', '9734', (45, 49))
157857	25970771	In uveal melanoma cell lines, HDAC inhibitors partially rescue the loss of melanocytic differentiation associated with BAP1 depletion.	('BAP1', 'Gene', (119, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('loss of melanocytic', 'Disease', 'MESH:D009508', (67, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('HDAC', 'Gene', (30, 34))	('depletion', 'Var', (124, 133))	('HDAC', 'Gene', '9734', (30, 34))	('uveal melanoma', 'Disease', (3, 17))	('loss of melanocytic', 'Disease', (67, 86))
157858	25970771	Furthermore, stable BAP1 depletion in a uveal melanoma cell line leads to sensitization to the HDAC inhibitor valproic acid and decreased viability.	('BAP1', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('decreased', 'NegReg', (128, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('depletion', 'Var', (25, 34))	('valproic acid', 'Chemical', 'MESH:D014635', (110, 123))	('sensitization', 'biological_process', 'GO:0046960', ('74', '87'))	('HDAC', 'Gene', (95, 99))	('HDAC', 'Gene', '9734', (95, 99))	('viability', 'MPA', (138, 147))
157861	25970771	Indeed, our data suggest that cells adapt to genetic BAP1 loss, such that sensitivity to HDAC inhibitors is reduced.	('HDAC', 'Gene', (89, 93))	('loss', 'NegReg', (58, 62))	('HDAC', 'Gene', '9734', (89, 93))	('reduced', 'NegReg', (108, 115))	('genetic', 'Var', (45, 52))	('BAP1', 'Gene', (53, 57))
157862	25970771	While our findings will need to be confirmed in other models, this is potentially of clinical significance, as HDAC inhibitors are currently being investigated in clinical trials for uveal melanoma in which BAP1 mutations are common.	('HDAC', 'Gene', (111, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (183, 197))	('uveal melanoma', 'Disease', 'MESH:C536494', (183, 197))	('HDAC', 'Gene', '9734', (111, 115))	('uveal melanoma', 'Disease', (183, 197))	('BAP1', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))
157867	25970771	The transformed normal mesothelial cell line MeT-5A (ATCC) was cultured in Medium 199 with added 10% FBS, 2% HEPES, 0.1% Trace Elements B, 0.02% (100 mug/ml) EGF, 0.028% (1 mg/ml) Hydrocortisone, 0.05% (10 mg/ml) Insulin, and 0.01% (2 mg/ml) selenium acid.	('HEPES', 'Chemical', 'MESH:D006531', (109, 114))	('EGF', 'molecular_function', 'GO:0005154', ('158', '161'))	('Hydrocortisone', 'Chemical', 'MESH:D006854', (180, 194))	('mug', 'molecular_function', 'GO:0043739', ('150', '153'))	('FBS', 'Disease', (101, 104))	('Insulin', 'molecular_function', 'GO:0016088', ('213', '220'))	('FBS', 'Disease', 'MESH:D005198', (101, 104))	('0.02', 'Var', (139, 143))	('selenium acid', 'Chemical', '-', (242, 255))
157895	24747001	We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization (FISH) and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome.	('gain', 'PosReg', (63, 67))	('patient', 'Species', '9606', (206, 213))	('PDGFR', 'Gene', (39, 44))	('PDGFR', 'Gene', '5159', (39, 44))	('PDGFRB', 'Gene', '5159', (39, 45))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('PDGFRB', 'Gene', (39, 45))	('copy number', 'Var', (51, 62))	('PDGFR', 'Gene', (123, 128))	('PDGFR', 'Gene', '5159', (123, 128))
157919	24747001	Several of the analyses provide conflicting information and there have been no prior studies that evaluated PDGFRB gene copy number gain (CNG) and its prognostic value in MPM.	('PDGFRB', 'Gene', '5159', (108, 114))	('copy number', 'Var', (120, 131))	('gain', 'PosReg', (132, 136))	('PDGFRB', 'Gene', (108, 114))	('MPM', 'Disease', (171, 174))
157927	24747001	Immunohistochemical biomarkers for PDGFRalpha, PDGFRbeta and p-PDGFRbeta, and fluorescence in situ hybridization (FISH) were performed for analysis of PDGFRB gene copy number gain (CNG).	('PDGFRB', 'Gene', (151, 157))	('PDGFRalpha', 'Gene', '5156', (35, 45))	('PDGFRbeta', 'Gene', '5159', (47, 56))	('PDGFRalpha', 'Gene', (35, 45))	('PDGFRbeta', 'Gene', (47, 56))	('PDGFRbeta', 'Gene', '5159', (63, 72))	('copy number', 'Var', (163, 174))	('gain', 'PosReg', (175, 179))	('PDGFRB', 'Gene', '5159', (151, 157))	('PDGFRbeta', 'Gene', (63, 72))
153952	24747001	Gene copy number analysis was done in approximately 50 nuclei per tumor in at least four areas, and the selection of the area was guided by H&E-stained section.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('Gene copy number analysis', 'Var', (0, 25))	('H&E', 'Chemical', 'MESH:D006371', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
157952	24747001	Patients with PDGFRB gene CNG in > 10% of cells had lower median expression of cytoplasmic p-PDGFRbeta (p=0.029).	('PDGFRbeta', 'Gene', (93, 102))	('PDGFRB', 'Gene', '5159', (14, 20))	('CNG', 'Var', (26, 29))	('lower', 'NegReg', (52, 57))	('PDGFRB', 'Gene', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (65, 75))	('PDGFRbeta', 'Gene', '5159', (93, 102))
157953	24747001	Patients with PDGFRB gene CNG in > 40% of cells had a higher median expression of cytoplasmic PDGFRbeta (p=0.04).	('higher', 'PosReg', (54, 60))	('expression', 'MPA', (68, 78))	('PDGFRB', 'Gene', '5159', (14, 20))	('PDGFRbeta', 'Gene', (94, 103))	('CNG', 'Var', (26, 29))	('PDGFRB', 'Gene', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('PDGFRbeta', 'Gene', '5159', (94, 103))
157958	24747001	For patients who had PDGFRB CNG > 40% of cells, the RFS was improved compared to patients with PDGFRB <40% CNG [HR 0.25 (95% CI 0.09, 0.72), p=0.0096] (see Figure 1A).	('PDGFRB', 'Gene', '5159', (21, 27))	('RFS', 'MPA', (52, 55))	('PDGFRB', 'Gene', (21, 27))	('patients', 'Species', '9606', (81, 89))	('CNG > 40%', 'Var', (28, 37))	('patients', 'Species', '9606', (4, 12))	('improved', 'PosReg', (60, 68))	('PDGFRB', 'Gene', (95, 101))	('PDGFRB', 'Gene', '5159', (95, 101))
157966	24747001	Other reports have noted the presence of increased PDGFRB copy number gain in mesothelioma; from the publically available data from the Progenetix database (www.progenetix.org), they report that 13 out of 20 (65%) mesotheliomas with copy number variations demonstrated gain of the PDGFRB gene region (5q33.1), as well as the CSFR1 gene region (5q32).	('PDGFRB', 'Gene', '5159', (51, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (214, 226))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('PDGFRB', 'Gene', (51, 57))	('gain', 'PosReg', (269, 273))	('mesotheliomas', 'Disease', 'MESH:D008654', (214, 227))	('mesotheliomas', 'Disease', (214, 227))	('PDGFRB', 'Gene', '5159', (281, 287))	('CSFR1 gene', 'Gene', (325, 335))	('copy number variations', 'Var', (233, 255))	('mesothelioma', 'Disease', (214, 226))	('mesothelioma', 'Disease', (78, 90))	('PDGFRB', 'Gene', (281, 287))
157967	24747001	Future studies such as from The Cancer Genome Atlas (TCGA) Project will be crucial in determining the precise incidence of PDGFRB copy number gain.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (32, 51))	('copy number', 'Var', (130, 141))	('PDGFRB', 'Gene', (123, 129))	('Cancer Genome Atlas', 'Disease', (32, 51))	('PDGFRB', 'Gene', '5159', (123, 129))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
157974	24747001	This mechanism is supported by an analysis showing that inhibition of PDGFR tyrosine kinase activity via imatinib mesylate causes a contrary response by decreasing pericyte coverage and increasing tumor cell proliferation.	('PDGFR', 'Gene', (70, 75))	('decreasing', 'NegReg', (153, 163))	('PDGFR', 'Gene', '5159', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('kinase activity', 'molecular_function', 'GO:0016301', ('85', '100'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('inhibition', 'Var', (56, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (105, 122))	('pericyte coverage', 'CPA', (164, 181))	('tumor', 'Disease', (197, 202))	('increasing', 'PosReg', (186, 196))
157996	24926549	Survival was significantly decreased for patients whose tumors expressed B7-H1 (5 months median, 2-9.5 months interquartile range) compared to those whose tumors did not (14.5 months, 9.25-19 months; p<0.0001).	('B7-H1', 'Var', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('decreased', 'NegReg', (27, 36))	('Survival', 'MPA', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (56, 62))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
157998	24926549	B7-H1 is expressed in a substantial proportion of malignant pleural mesotheliomas and is associated with poor survival.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (60, 80))	('malignant pleural mesotheliomas', 'Disease', (50, 81))	('B7-H1', 'Var', (0, 5))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (50, 81))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (60, 81))
158024	24926549	Of the patients who expressed B7-H1 the median percent of B7-H1 positive neoplastic cells was 35% (10-70% interquartile range).	('patients', 'Species', '9606', (7, 15))	('B7-H1', 'Gene', (58, 63))	('B7-H1', 'Var', (30, 35))
158026	24926549	Additionally, all sarcomatoid mesotheliomas besides a single desmoplastic subtype were in the B7-H1 positive group.	('B7-H1', 'Var', (94, 99))	('sarcomatoid mesotheliomas', 'Disease', 'MESH:C538614', (18, 43))	('sarcomatoid mesotheliomas', 'Disease', (18, 43))
158027	24926549	Conversely, there were fewer epithelioid mesotheliomas in the B7-H1 positive group (n=14, 33% of the B7-H1 positive group) than the B7-H1 negative group (n=54, 84%; p<0.0001 of the B7-H1 negative group).	('epithelioid mesotheliomas', 'Disease', 'MESH:D008654', (29, 54))	('B7-H1 positive', 'Var', (62, 76))	('fewer', 'NegReg', (23, 28))	('epithelioid mesotheliomas', 'Disease', (29, 54))	('B7-H1', 'Var', (101, 106))
158032	24926549	Survival was significantly shorter for patients with B7-H1 expression (5 months median, 2-9.5 months interquartile range) than those without B7-H1 expression (14.5 months, 9.25-19 months; p<0.0001; Figure 2).	('Survival', 'MPA', (0, 8))	('B7-H1 expression', 'Var', (53, 69))	('patients', 'Species', '9606', (39, 47))	('shorter', 'NegReg', (27, 34))
158034	24926549	There was no difference in survival between patients with cytoplasmic B7-H1 expression and patients with any membranous expression (p=0.44).	('patients', 'Species', '9606', (44, 52))	('cytoplasmic', 'Var', (58, 69))	('patients', 'Species', '9606', (91, 99))	('B7-H1', 'Protein', (70, 75))
158038	24926549	Immune surveillance is a critical component of tumor growth control and tumor-infiltrating CD3+ and CD8+ lymphocytes have been associated with improved survival in many tumor types including MPM.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('improved', 'PosReg', (143, 151))	('MPM', 'Disease', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (72, 77))	('CD3+', 'Var', (91, 95))	('CD8', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('CD8', 'Gene', '925', (100, 103))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('survival', 'CPA', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (47, 52))
158048	24926549	Tumor expression of B7-H1 is a poor prognostic feature in esophageal carcinoma, gastric carcinoma, hepatocellular carcinoma, pancreatic carcinoma, renal cell carcinoma and ovarian carcinoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))	('gastric carcinoma', 'Disease', 'MESH:D013274', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (172, 189))	('gastric carcinoma', 'Disease', (80, 97))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('B7-H1', 'Var', (20, 25))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (58, 78))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (125, 145))	('hepatocellular carcinoma', 'Disease', (99, 123))	('pancreatic carcinoma', 'Disease', (125, 145))	('esophageal carcinoma', 'Disease', (58, 78))	('renal cell carcinoma and ovarian carcinoma', 'Disease', 'MESH:C538614', (147, 189))
158086	22953164	Polycyclic aromatic hydrocarbons (PAHs) have also been reported to cause respiratory cancers.	('cause', 'Reg', (67, 72))	('PAHs', 'Chemical', 'MESH:D011084', (34, 38))	('Polycyclic', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('respiratory cancers', 'Disease', 'MESH:D012131', (73, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('respiratory cancers', 'Disease', (73, 92))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))
158173	33023139	MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM.	('ABBV', 'Chemical', '-', (57, 61))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('ABBV-221', 'Var', (57, 65))	('ABBV-322', 'Chemical', '-', (70, 78))	('ABBV-322', 'Var', (70, 78))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('MAb806', 'Chemical', 'MESH:C518939', (0, 6))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('ABBV', 'Chemical', '-', (70, 74))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('ABT', 'Chemical', 'MESH:C002502', (48, 51))
158178	33023139	ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ABBV-322', 'Chemical', '-', (12, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('tumor', 'Disease', (45, 50))	('mAb806', 'Chemical', 'MESH:C518939', (101, 107))	('ABBV-322', 'Var', (12, 20))	('mAb806', 'Gene', (101, 107))	('ABT', 'Chemical', 'MESH:C002502', (0, 3))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('ABT-414', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
158189	33023139	The monoclonal antibody 806 (mAb806) is a novel anti-EGFR antibody that selectively targets a unique epitope of the EGFR only exposed on overexpressed, mutant or ligand-activated forms of the EGFR.	('epitope', 'MPA', (101, 108))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('mAb806', 'Chemical', 'MESH:C518939', (29, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('EGFR', 'Gene', (192, 196))	('antibody', 'molecular_function', 'GO:0003823', ('58', '66'))	('antibody', 'cellular_component', 'GO:0042571', ('58', '66'))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('mutant', 'Var', (152, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('116', '120'))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('192', '196'))	('ligand', 'molecular_function', 'GO:0005488', ('162', '168'))	('antibody', 'cellular_component', 'GO:0019815', ('58', '66'))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (53, 57))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('antibody', 'cellular_component', 'GO:0019814', ('58', '66'))	('EGFR', 'Gene', (116, 120))
158195	33023139	ABBV-322 is another mAb806-ADC derivative, comprised of the nonaffinity matured version of ABT-806 engineered to include an S238C point mutation that permits site-specific conjugation to a DNA minor groove crosslinking agent, pyrrolobenzodiazepine (PBD), via a cathepsin-cleavable Val-Ala linker with a DAR of two (Supplementary Figure S1).	('PBD', 'Chemical', 'MESH:C438462', (249, 252))	('pyrrolobenzodiazepine', 'Chemical', 'MESH:C438462', (226, 247))	('conjugation', 'Interaction', (172, 183))	('Ala', 'Chemical', 'MESH:D000409', (285, 288))	('S238C', 'Mutation', 'p.S238C', (124, 129))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('ABT-806', 'Chemical', 'MESH:C000604456', (91, 98))	('conjugation', 'biological_process', 'GO:0000746', ('172', '183'))	('groove', 'cellular_component', 'GO:0097610', ('199', '205'))	('S238C', 'Var', (124, 129))	('Val', 'Chemical', 'MESH:D014633', (281, 284))	('ABBV-322', 'Chemical', '-', (0, 8))	('ABT-806', 'Gene', (91, 98))	('mAb806', 'Chemical', 'MESH:C518939', (20, 26))
158197	33023139	We also performed quantitative biodistribution and imaging of radiolabeled mAb806 to establish tumor drug concentrations in vivo and imaging properties of 89Zr-ch806, a chimeric form of mAb806 (ch806).	('89Zr-ch806', 'Var', (155, 165))	('89Zr-ch806', 'Chemical', '-', (155, 165))	('mAb806', 'Chemical', 'MESH:C518939', (186, 192))	('ch806', 'Chemical', '-', (194, 199))	('ch806', 'Chemical', '-', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mAb806', 'Chemical', 'MESH:C518939', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
158205	33023139	ABT-414 and ABBV-221 resulted in significant tumor growth inhibitions compared to cetuximab (p < 0.05) and had equivalent efficacies compared to cisplatin (Figure 2).	('ABBV-221', 'Var', (12, 20))	('ABBV', 'Chemical', '-', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('cetuximab', 'Chemical', 'MESH:D000068818', (82, 91))	('ABT', 'Chemical', 'MESH:C002502', (0, 3))	('ABT-414', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
158209	33023139	Treatment with mAb806-ADCs resulted in significant tumor growth inhibition compared to the ADC control (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mAb806-ADCs', 'Var', (15, 26))	('mAb806', 'Chemical', 'MESH:C518939', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
158212	33023139	However, mice treated with mAb806-ADCs had significantly longer survival until the need for euthanasia for the study endpoints compared to the cisplatin-treated mice (p < 0.05) and the ADC-MMAF control group (p < 0.0015) (Figure 3).	('longer', 'PosReg', (57, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('survival', 'CPA', (64, 72))	('mice', 'Species', '10090', (161, 165))	('MMAF', 'Chemical', 'MESH:C513576', (189, 193))	('mAb806', 'Chemical', 'MESH:C518939', (27, 33))	('mice', 'Species', '10090', (9, 13))	('mAb806-ADCs', 'Var', (27, 38))
158220	33023139	ABBV-322 resulted in significant tumor growth inhibition compared to the ADC-PBD control (Figure 4).	('ABBV-322', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('ABBV-322', 'Chemical', '-', (0, 8))	('ADC-PBD', 'Chemical', '-', (73, 80))
158222	33023139	The median survival of mice in the ABBV-322 arm was significantly longer compared to the ADC control group (150 vs. 122 days, respectively; p = 0.018).	('ABBV-322', 'Var', (35, 43))	('ABBV-322', 'Chemical', '-', (35, 43))	('longer', 'PosReg', (66, 72))	('mice', 'Species', '10090', (23, 27))
158225	33023139	There was no significant tumor growth inhibition by ABBV-322 compared to the ADC control and no significant difference in the median survivals for both treatment groups (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('ABBV-322', 'Chemical', '-', (52, 60))	('tumor', 'Disease', (25, 30))	('ABBV-322', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
158226	33023139	Quantitative biodistribution and imaging of mAb806 uptake (89Zr-ch806) were performed to allow the correlation of mAb806 concentrations in MM tumors and to establish 89Zr-806 as a noninvasive imaging biomarker of 806 expression in MM tumors.	('89Zr-ch806', 'Chemical', '-', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MM tumors', 'Disease', 'MESH:D009369', (139, 148))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('MM tumors', 'Disease', (139, 148))	('MM tumors', 'Disease', (231, 240))	('MM tumors', 'Disease', 'MESH:D009369', (231, 240))	('uptake', 'biological_process', 'GO:0098739', ('51', '57'))	('mAb806', 'Chemical', 'MESH:C518939', (114, 120))	('uptake', 'biological_process', 'GO:0098657', ('51', '57'))	('89Zr-806', 'Var', (166, 174))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('89Zr-806', 'Chemical', '-', (166, 174))	('mAb806', 'Gene', (114, 120))	('mAb806', 'Chemical', 'MESH:C518939', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
158227	33023139	A Scatchard analysis indicated that the 89Zr-ch806 had a Ka of 0.376 x 109 M-1, and the number of antibody binding sites per cell was 2.5 x 106.	('antibody', 'cellular_component', 'GO:0019815', ('98', '106'))	('antibody', 'cellular_component', 'GO:0019814', ('98', '106'))	('89Zr-ch806', 'Chemical', '-', (40, 50))	('antibody', 'molecular_function', 'GO:0003823', ('98', '106'))	('89Zr-ch806', 'Var', (40, 50))	('binding', 'Interaction', (107, 114))	('antibody', 'cellular_component', 'GO:0042571', ('98', '106'))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
158231	33023139	89Zr-ch806 demonstrated selective tumor uptake in 806-positive MSTO-221 tumors in BALB/c nu/nu mice, with normal tissues demonstrating clearance patterns typical of a radiolabeled intact humanized antibody.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mice', 'Species', '10090', (95, 99))	('tumors', 'Disease', (72, 78))	('tumor', 'Disease', (34, 39))	('antibody', 'cellular_component', 'GO:0019815', ('197', '205'))	('L', 'Gene', '21832', (84, 85))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('uptake', 'biological_process', 'GO:0098657', ('40', '46'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('89Zr-ch806', 'Var', (0, 10))	('tumor', 'Disease', (72, 77))	('antibody', 'cellular_component', 'GO:0019814', ('197', '205'))	('uptake', 'biological_process', 'GO:0098739', ('40', '46'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('MSTO-221', 'Gene', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('antibody', 'molecular_function', 'GO:0003823', ('197', '205'))	('human', 'Species', '9606', (187, 192))	('89Zr-ch806', 'Chemical', '-', (0, 10))	('antibody', 'cellular_component', 'GO:0042571', ('197', '205'))
158233	33023139	PET imaging showed a high uptake of 89Zr-ch806 in the tumors (Figure 6), and some bone, spleen and liver uptakes were observed, most likely due to the blood pool activity and catabolism of the free 89Zr-chelate.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('uptake', 'MPA', (26, 32))	('89Zr', 'Chemical', 'MESH:C000615502', (36, 40))	('89Zr-ch806', 'Var', (36, 46))	('89Zr', 'Chemical', 'MESH:C000615502', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('89Zr-ch806', 'Chemical', '-', (36, 46))	('catabolism', 'biological_process', 'GO:0009056', ('175', '185'))	('catabolism', 'MPA', (175, 185))	('uptake', 'biological_process', 'GO:0098657', ('26', '32'))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('uptake', 'biological_process', 'GO:0098739', ('26', '32'))	('tumors', 'Disease', (54, 60))
158235	33023139	Treatments with ABT-414, ABBV-221 and ABBV-322 resulted in significant tumor growth inhibition in EGFR-overexpressing cell lines in vitro, as well as in their derived xenografts and PDX models with high EGFR and mAb806 epitope expression.	('EGFR', 'Gene', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (203, 207))	('mAb806', 'Chemical', 'MESH:C518939', (212, 218))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('mAb806', 'Gene', (212, 218))	('ABT', 'Chemical', 'MESH:C002502', (16, 19))	('ABBV-322', 'Var', (38, 46))	('EGFR', 'Gene', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ABBV', 'Chemical', '-', (25, 29))	('ABT-414', 'Var', (16, 23))	('ABBV', 'Chemical', '-', (38, 42))	('ABBV-221', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('EGFR', 'Gene', '1956', (98, 102))	('tumor', 'Disease', (71, 76))	('ABBV-322', 'Chemical', '-', (38, 46))
158239	33023139	89Zr-ch806 was stable in the serum at 37  C with a retention of immunoreactivity, radiochemical purity and construct integrity for up to seven days and showed targeting of 806-positive tumors on PET/MRI imaging.	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('retention', 'biological_process', 'GO:0051235', ('51', '60'))	('89Zr-ch806', 'Chemical', '-', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('89Zr-ch806', 'Var', (0, 10))
158240	33023139	The splenic and bone uptakes seen with 89Zr-ch806 were a result of catabolized free 89Zr and similar to that seen with other 89Zr-labeled antibodies.	('catabolized free 89Zr', 'MPA', (67, 88))	('89Zr', 'Chemical', 'MESH:C000615502', (125, 129))	('89Zr-ch806', 'Var', (39, 49))	('89Zr-ch806', 'Chemical', '-', (39, 49))	('89Zr', 'Chemical', 'MESH:C000615502', (84, 88))	('89Zr', 'Chemical', 'MESH:C000615502', (39, 43))
158243	33023139	We have previously reported that mAb806-ADC has markedly superior antitumor efficacy in animal models compared to antibody alone and the drug alone at similar concentrations.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('antibody', 'cellular_component', 'GO:0019815', ('114', '122'))	('tumor', 'Disease', (70, 75))	('mAb806', 'Chemical', 'MESH:C518939', (33, 39))	('superior', 'PosReg', (57, 65))	('antibody', 'cellular_component', 'GO:0019814', ('114', '122'))	('antibody', 'molecular_function', 'GO:0003823', ('114', '122'))	('antibody', 'cellular_component', 'GO:0042571', ('114', '122'))	('mAb806-ADC', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
158249	33023139	Our results also confirm that the deliverable concentration of mAb806 to MM can be measured by PET imaging and may assist with comparing the ADC concentration in tumors to therapeutic responses in clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mAb806', 'Chemical', 'MESH:C518939', (63, 69))	('mAb806', 'Var', (63, 69))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
158251	33023139	Mesothelin-targeted therapies involving anti-mesothelin immunotoxins (SSP1), chimeric anti-mesothelin antibodies (amatuximab) and mesothelin-directed antibody-drug conjugates (anetumab ravtansine) have shown phase I efficacy, but these were not replicated in the later phase studies.	('mesothelin', 'Gene', '10232', (130, 140))	('Mesothelin', 'Gene', '10232', (0, 10))	('antibody', 'cellular_component', 'GO:0019815', ('150', '158'))	('Mesothelin', 'Gene', (0, 10))	('mesothelin', 'Gene', '10232', (45, 55))	('antibody', 'cellular_component', 'GO:0019814', ('150', '158'))	('antibody', 'molecular_function', 'GO:0003823', ('150', '158'))	('SSP1', 'Gene', (70, 74))	('SSP1', 'Gene', '26054', (70, 74))	('mesothelin', 'Gene', (130, 140))	('mesothelin', 'Gene', (91, 101))	('chimeric', 'Var', (77, 85))	('antibody', 'cellular_component', 'GO:0042571', ('150', '158'))	('ravtansine', 'Chemical', 'MESH:D008453', (185, 195))	('mesothelin', 'Gene', '10232', (91, 101))	('amatuximab', 'Chemical', 'MESH:C526187', (114, 124))	('anetumab', 'Chemical', '-', (176, 184))	('mesothelin', 'Gene', (45, 55))
158267	33023139	Cells (4 x 104) were incubated for 1 hour with 10-mug/mL mAb806, mAb528 or IgG1 isotype control antibody.	('mAb806', 'Gene', (57, 63))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('mAb528', 'Var', (65, 71))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('mAb806', 'Chemical', 'MESH:C518939', (57, 63))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('IgG1', 'cellular_component', 'GO:0071735', ('75', '79'))	('mug', 'molecular_function', 'GO:0043739', ('50', '53'))	('mL', 'Gene', '21832', (54, 56))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))
158271	33023139	The primary antibodies used included rabbit anti-human EGFR (#4267, Cell Signalling, Danvers, MA, USA) at 1:1000 dilution, mouse anti-human EGFR-806:mAb806 (Ludwig Institute for Cancer Research (LICR), Olivia-Newton John Cancer Research Institute (ONJCRI)) at 3 mg/mL and mouse anti-human actin (#3700, Cell Signalling, Danvers, MA, USA) at 1:1000 dilution.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (140, 144))	('mAb806', 'Var', (149, 155))	('mAb806', 'Chemical', 'MESH:C518939', (149, 155))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Olivia-Newton John Cancer', 'Disease', 'MESH:D009369', (202, 227))	('L', 'Gene', '21832', (157, 158))	('Olivia-Newton John Cancer', 'Disease', (202, 227))	('Cancer', 'Disease', 'MESH:D009369', (221, 227))	('Cancer', 'Disease', (178, 184))	('Signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('human', 'Species', '9606', (49, 54))	('L', 'Gene', '21832', (195, 196))	('EGFR', 'Gene', '1956', (140, 144))	('human', 'Species', '9606', (134, 139))	('#3700', 'Var', (296, 301))	('EGFR', 'Gene', (55, 59))	('L', 'Gene', '21832', (266, 267))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('human', 'Species', '9606', (283, 288))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mouse', 'Species', '10090', (272, 277))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('mouse', 'Species', '10090', (123, 128))	('Signalling', 'biological_process', 'GO:0023052', ('308', '318'))	('mL', 'Gene', '21832', (265, 267))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('Cancer', 'Disease', (221, 227))
158272	33023139	The secondary antibodies included goat anti-rabbit Ig (A2554, Sigma-Aldrich, St. Louis, MO, USA) at 1:3000 dilution and goat anti-mouse Ig (A6154, Sigma-Aldrich, St. Louis, MO, USA) at 1:3000 dilution.	('L', 'Gene', '21832', (166, 167))	('A6154', 'Var', (140, 145))	('L', 'Gene', '21832', (81, 82))	('A2554', 'Var', (55, 60))	('mouse', 'Species', '10090', (130, 135))
158292	33023139	Chimeric anti-EGFR antibody ch806 was chelated with the bifunctional metal ion chelator p-isothiocyanatobenzyldesferrioxamine (Df; Macrocyclics Inc., Dallas, TX, USA) at a 3.0-fold molar excess, as previously described.	('ch806', 'Chemical', '-', (28, 33))	('-fold molar', 'Phenotype', 'HP:0011093', (175, 186))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('antibody', 'cellular_component', 'GO:0019815', ('19', '27'))	('metal', 'Chemical', 'MESH:D008670', (69, 74))	('ch806', 'Var', (28, 33))	('antibody', 'cellular_component', 'GO:0019814', ('19', '27'))	('antibody', 'molecular_function', 'GO:0003823', ('19', '27'))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('antibody', 'cellular_component', 'GO:0042571', ('19', '27'))	('p-isothiocyanatobenzyldesferrioxamine', 'Chemical', 'MESH:C549125', (88, 125))
158351	30879467	Histopathological and immunohistochemical examinations of the resected specimens were positive for CD34, CD31, D2-40, and calretinin, which confirmed epithelioid mesothelioma (Fig.	('calretinin', 'Gene', '794', (122, 132))	('D2-40', 'Var', (111, 116))	('CD31', 'Gene', (105, 109))	('CD34', 'Gene', '947', (99, 103))	('CD31', 'Gene', '5175', (105, 109))	('epithelioid mesothelioma', 'Disease', (150, 174))	('CD34', 'Gene', (99, 103))	('calretinin', 'Gene', (122, 132))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (150, 174))
158383	30863365	In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis.	('MST1R', 'Gene', (62, 67))	('high positivity', 'Var', (36, 51))	('patient', 'Species', '9606', (19, 26))
158386	30863365	Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004.	('LCRF-0004', 'Chemical', 'MESH:C000605132', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('LCRF-0004', 'Chemical', 'MESH:C000605132', (5, 14))	('tumor', 'Disease', (60, 65))	('BMS-777607', 'Var', (93, 103))
158394	30863365	Several studies have demonstrated that c-MET, Axl, EGFR, ErbB2, ErbB3, IGF1R, and PDGFRbeta RTKs are active in MPM, and that targeting c-MET has anti-proliferative activity in this disease.	('RTK', 'Gene', '5979', (92, 95))	('ErbB3', 'Gene', (64, 69))	('EGFR', 'Gene', (51, 55))	('ErbB2', 'Gene', '2064', (57, 62))	('PDGFRbeta', 'Gene', (82, 91))	('c-MET', 'Gene', '4233', (135, 140))	('Axl', 'Gene', '558', (46, 49))	('c-MET', 'Gene', '4233', (39, 44))	('MPM', 'Disease', (111, 114))	('Axl', 'Gene', (46, 49))	('PDGFRbeta', 'Gene', '5159', (82, 91))	('c-MET', 'Gene', (135, 140))	('c-MET', 'Gene', (39, 44))	('ErbB3', 'Gene', '2065', (64, 69))	('IGF1R', 'Gene', '3480', (71, 76))	('EGFR', 'Gene', '1956', (51, 55))	('ErbB2', 'Gene', (57, 62))	('IGF1R', 'Gene', (71, 76))	('targeting', 'Var', (125, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('RTK', 'Gene', (92, 95))	('anti-proliferative activity', 'CPA', (145, 172))
158398	30863365	A number of MST1R (RON) transcripts have been identified, with the two most common having been identified in normal and cancerous tissues including breast, prostate and lung, coding for either full-length MST1R (RON) (flMST1R) or a shorter transcript called short-form (sfMST1R).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancerous', 'Disease', (120, 129))	('MST1R', 'Gene', (12, 17))	('MST1R', 'Var', (205, 210))	('cancerous', 'Disease', 'MESH:D009369', (120, 129))
158399	30863365	sfMST1R is constitutively phosphorylated and results in a more aggressive cancer phenotype in breast cancer.	('breast cancer', 'Disease', (94, 107))	('aggressive cancer', 'Disease', 'MESH:D009369', (63, 80))	('aggressive cancer', 'Disease', (63, 80))	('sfMST1R', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('more', 'PosReg', (58, 62))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('results in', 'Reg', (45, 55))
158400	30863365	A number of additional MST1R (RON) variants have been identified, many of which are constitutively active and have oncogenic potential including RONDelta165 (also known as DeltaRON), RONDelta160, and RONDelta155 amongst others.	('RONDelta165', 'Var', (145, 156))	('DeltaRON', 'Chemical', '-', (172, 180))	('MST1R', 'Gene', (23, 28))	('variants', 'Var', (35, 43))
158406	30863365	Altered TAM signaling is thought to contribute to chronic inflammatory and autoimmune disease in humans, and is strongly associated with cancer progression, metastasis, and resistance to targeted therapies.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('autoimmune disease', 'Disease', (75, 93))	('TAM', 'Chemical', 'MESH:D013629', (8, 11))	('TAM', 'Protein', (8, 11))	('contribute', 'Reg', (36, 46))	('humans', 'Species', '9606', (97, 103))	('signaling', 'biological_process', 'GO:0023052', ('12', '21'))	('associated', 'Reg', (121, 131))	('Altered', 'Var', (0, 7))	('autoimmune disease', 'Disease', 'MESH:D001327', (75, 93))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('autoimmune disease', 'Phenotype', 'HP:0002960', (75, 93))	('cancer', 'Disease', (137, 143))	('metastasis', 'CPA', (157, 167))
158410	30863365	For example, the dual MET/MST1R (RON) kinase inhibitor, LY2801653 which is a type-II ATP competitive, slow-off inhibitor binding to the kinase domains of these RTKs, decreased tumor growth and angiogenesis in the lung cancer setting and demonstrated greater efficacy than crizotinib.	('LY2801653', 'Chemical', 'MESH:C586252', (56, 65))	('ATP', 'Chemical', 'MESH:D000255', (85, 88))	('decreased tumor', 'Disease', 'MESH:D009369', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('angiogenesis', 'CPA', (193, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('38', '54'))	('RTK', 'Gene', (160, 163))	('decreased tumor', 'Disease', (166, 181))	('lung cancer', 'Disease', (213, 224))	('crizotinib', 'Chemical', 'MESH:D000077547', (272, 282))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('angiogenesis', 'biological_process', 'GO:0001525', ('193', '205'))	('LY2801653', 'Var', (56, 65))	('RTK', 'Gene', '5979', (160, 163))
158419	30863365	Both fl and sfMST1R were robustly detected in the majority of MPM cell lines at the mRNA level (Figure 1B), similar to the expression of C-MET, TYRO3 and AXL (Figure 1B).	('AXL', 'Gene', '558', (154, 157))	('C-MET', 'Gene', (137, 142))	('TYRO3', 'Gene', '7301', (144, 149))	('C-MET', 'Gene', '4233', (137, 142))	('AXL', 'Gene', (154, 157))	('sfMST1R', 'Var', (12, 19))	('TYRO3', 'Gene', (144, 149))
158420	30863365	Additionally, a number MST1R (RON) beta chain isoforms were detected at the protein level such as p110 and p80 (Supplementary Figure 1B).	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (112, 135))	('p80', 'Gene', (107, 110))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('detected', 'Reg', (60, 68))	('p80', 'Gene', '8161', (107, 110))	('MST1R', 'Gene', (23, 28))	('p110', 'Var', (98, 102))	('Supplementary Figure 1B', 'Disease', (112, 135))
158421	30863365	Strong expression of both sfMST1R and flMST1R mRNA was also observed in fresh-frozen surgically resected mesotheliomas across all histological subtypes (n = 17), which was greater than that observed in resected benign tissues (n = 5) (Figure 2A, Additional File: Figure S2A).	('flMST1R', 'Var', (38, 45))	('mesotheliomas', 'Disease', 'MESH:D008654', (105, 118))	('mesotheliomas', 'Disease', (105, 118))	('sfMST1R', 'Var', (26, 33))
158425	30863365	As mutations within the tyrosine kinase domain of MST1R have been identified in Merkel cell carcinoma and Gastroesophageal adenocarcinoma, we screened DNA from our panel of MPM cell lines and the 17 fresh-frozen surgical samples for the presence of the R1018G or R1194H mutations.	('Merkel cell carcinoma and Gastroesophageal adenocarcinoma', 'Disease', 'MESH:D015266', (80, 137))	('R1018G', 'Mutation', 'p.R1018G', (253, 259))	('identified', 'Reg', (66, 76))	('R1018G', 'Var', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('R1194H', 'Mutation', 'rs560835056', (263, 269))	('R1194H', 'Var', (263, 269))	('MST1R', 'Gene', (50, 55))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
158426	30863365	We also examined our panel of MPM cell lines and tumors for the presence of MET exon 14 skipping, and again no mutations were observed (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MET exon 14 skipping', 'Var', (76, 96))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
158440	30863365	Based on global staining intensity dichotomized closest to the median into low and high, high expression of MST1R (RON) was found to be an independent prognosticator for survival based on Cox regression survival analysis (log rank p = 0.014, 14 vs. 11 months) (Figure 4A).	('Cox', 'Gene', '1351', (188, 191))	('high', 'Var', (89, 93))	('MST1R', 'Gene', (108, 113))	('Cox', 'Gene', (188, 191))
158442	30863365	Like MST1R (RON), high MST1 expression was found to be an independent prognostic factor for longer survival (log rank p = 0.015, 14 vs. 11 months).	('expression', 'MPA', (28, 38))	('MST1', 'Gene', '4485', (5, 9))	('MST1', 'Gene', '4485', (23, 27))	('MST1', 'Gene', (5, 9))	('high', 'Var', (18, 22))	('MST1', 'Gene', (23, 27))	('longer', 'PosReg', (92, 98))
158444	30863365	On multivariate analysis, only high expression of MST1 remained significantly associated with increased survival.	('associated', 'Reg', (78, 88))	('survival', 'MPA', (104, 112))	('MST1', 'Gene', '4485', (50, 54))	('increased', 'PosReg', (94, 103))	('MST1', 'Gene', (50, 54))	('high expression', 'Var', (31, 46))
158448	30863365	In agreement with our data, high expression of MST1R (P < 0.022), or MST1 (P < 0.05) was associated with better overall survival, which remained significant (P < 0.008) under multivariate analysis (Figure S5).	('better', 'PosReg', (105, 111))	('MST1', 'Gene', (69, 73))	('MST1', 'Gene', '4485', (47, 51))	('high expression', 'Var', (28, 43))	('MST1', 'Gene', (47, 51))	('overall', 'MPA', (112, 119))	('MST1', 'Gene', '4485', (69, 73))
158482	30863365	Consequently, targeted disruption of this "addicted" oncogene/pathway leads to growth arrest and programmed cell death.	('programmed cell death', 'CPA', (97, 118))	('growth arrest', 'Phenotype', 'HP:0001510', (79, 92))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('disruption', 'Var', (23, 33))	('arrest', 'Disease', (86, 92))	('programmed cell death', 'biological_process', 'GO:0012501', ('95', '116'))
158500	30863365	Given that JU77 cells seem to have a constitutive activation of the RON MET TAM pathways due to the expression of the sfMSTR1 variant (Figure 1 and Figure S1), it could be argued that the responses to MST1 observed in this cell line (Figure S7) do not truly reflect signaling functionality for this axis compared to the responses observed for NCI-H226, and that cell lines with different activation states of the pathway could instead have been used to test the molecules to ensure that JU77 and NCI-H226 are not "special cases," or alternatively, cell lines with similar activation states or characteristics could have been used to confirm the results.	('RON MET TAM pathways', 'Pathway', (68, 88))	('MST1', 'Gene', '4485', (201, 205))	('TAM', 'Chemical', 'MESH:D013629', (76, 79))	('MST1', 'Gene', (201, 205))	('NCI-H226', 'CellLine', 'CVCL:1544', (496, 504))	('activation', 'PosReg', (50, 60))	('NCI-H226', 'CellLine', 'CVCL:1544', (343, 351))	('sfMSTR1', 'Gene', (118, 125))	('variant', 'Var', (126, 133))	('signaling', 'biological_process', 'GO:0023052', ('266', '275'))
158512	30863365	The poor responses observed by Narnatumab or NRWHE may be because both of these target elements of the MST1R (RON) receptor at the extracellular or cell membrane level, and as MST1R (RON) has several truncated receptor variants (lacking extracellular elements) including the constitutively active oncogenic sfMST1R, this may have limited their efficacy.	('extracellular', 'cellular_component', 'GO:0005576', ('237', '250'))	('variants', 'Var', (219, 227))	('extracellular', 'cellular_component', 'GO:0005576', ('131', '144'))	('Narnatumab', 'Chemical', '-', (31, 41))	('MST1R (RON) receptor', 'Gene', (103, 123))	('cell membrane', 'cellular_component', 'GO:0005886', ('148', '161'))	('MST1R (RON) receptor', 'Gene', '4486', (103, 123))
158514	30863365	BMS-777607 significantly reduced the proliferative capacity of REN and NCI-H226, whilst having no obvious effect on LP9 cells (Figure 5C).	('proliferative capacity', 'CPA', (37, 59))	('reduced', 'NegReg', (25, 32))	('REN', 'Gene', '5972', (63, 66))	('NCI-H226', 'CellLine', 'CVCL:1544', (71, 79))	('BMS-777607', 'Var', (0, 10))	('NCI-H226', 'Gene', (71, 79))	('REN', 'Gene', (63, 66))
158526	30863365	For example, it was found that silencing RON in pancreatic cancer cell lines leads to upregulation of c-Met expression and activity, whilst another study has demonstrated that oncogenic addition to c-Met requires co-expression of constitutively activated RON that was dependent on transphosphorylation by c-Met.	('silencing', 'Var', (31, 40))	('upregulation', 'PosReg', (86, 98))	('pancreatic cancer', 'Disease', (48, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('c-Met', 'Gene', (198, 203))	('RON', 'Protein', (41, 44))	('c-Met', 'Gene', (305, 310))	('c-Met', 'Gene', '4233', (198, 203))	('expression', 'MPA', (108, 118))	('c-Met', 'Gene', '4233', (305, 310))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('activity', 'MPA', (123, 131))	('c-Met', 'Gene', (102, 107))	('c-Met', 'Gene', '4233', (102, 107))
158534	30863365	Indeed, while BMS-777607 is marketed as a c-MET inhibitor, one recent study utilized it to therapeutically target AXL in a model of glioblastoma.	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('AXL', 'Gene', (114, 117))	('c-MET', 'Gene', '4233', (42, 47))	('AXL', 'Gene', '558', (114, 117))	('c-MET', 'Gene', (42, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('BMS-777607', 'Var', (14, 24))
158550	30863365	The following MPM cell lines were used in the study: LP9, Met5A, NCI-H2596, MMP, MMB, NCI-H2052, NCI-H28, Ju77, One58, RS-5, DM-3, ACC-MESO-1, ACC-MESO-4, Y-MESO-8D, Y-MESO-9, Y-MESO-12, Y-MESO-14, REN, NCI-H226, and MSTO-211H.	('REN', 'Gene', '5972', (198, 201))	('MMP', 'molecular_function', 'GO:0004235', ('76', '79'))	('Y-MESO-9', 'Chemical', '-', (166, 174))	('NCI-H2596', 'CellLine', 'CVCL:A546', (65, 74))	('REN', 'Gene', (198, 201))	('ACC-MESO-4', 'Chemical', '-', (143, 153))	('Y-MESO-14', 'Var', (187, 196))	('NCI-H2052', 'CellLine', 'CVCL:1518', (86, 95))	('Y-MESO-12', 'Chemical', '-', (176, 185))	('NCI-H226', 'CellLine', 'CVCL:1544', (203, 211))	('ACC-MESO-1', 'Chemical', '-', (131, 141))
158575	30863365	Following overnight incubation, cells were treated for 24 or 48 h with human recombinant MST1 (0-250 ng/mL), LCRF-0004 (0-200 nM), RON8 (200-1,000 ng/mL), or NRWHE (25-200 ng/mL) or combinations of drug as appropriate.	('MST1', 'Gene', (89, 93))	('MST1', 'Gene', '4485', (89, 93))	('LCRF-0004', 'Chemical', 'MESH:C000605132', (109, 118))	('200-1,000', 'Var', (137, 146))	('human', 'Species', '9606', (71, 76))
158579	30863365	Cells were treated for 24-72 h with human recombinant MST1 (250 ng/mL) and LCRF-0004 (200 nM) alone or in combination.	('250', 'Var', (60, 63))	('MST1', 'Gene', '4485', (54, 58))	('MST1', 'Gene', (54, 58))	('human', 'Species', '9606', (36, 41))	('LCRF-0004', 'Chemical', 'MESH:C000605132', (75, 84))
158581	30863365	Cells were treated for 24-48 h with human recombinant MST1 (250 ng/mL) and LCRF-0004 (200 nM) alone or in combination.	('250', 'Var', (60, 63))	('MST1', 'Gene', '4485', (54, 58))	('MST1', 'Gene', (54, 58))	('human', 'Species', '9606', (36, 41))	('LCRF-0004', 'Chemical', 'MESH:C000605132', (75, 84))
158699	28053943	New technologies made it possible to preserve certain viral genes required for the antineoplastic effect and to knock out genes responsible for viral specific pathogenicity and undesirable toxicity.	('toxicity', 'Disease', 'MESH:D064420', (189, 197))	('knock', 'Var', (112, 117))	('toxicity', 'Disease', (189, 197))
158737	28053943	Although a previous study with oncolytic vaccinia virus coding GMCSF reported elevated serum levels of GMCSF and white blood cells, preclinical testing of Ad5/3-D24-GMCSF revealed undetectable systemic GMCSF and white blood cells, which was indicative of restricted GMCSF release only at the site of viral infection and replication.	('serum levels', 'MPA', (87, 99))	('oncolytic vaccinia virus', 'Disease', 'MESH:D014615', (31, 55))	('coding', 'Var', (56, 62))	('viral infection', 'Disease', (300, 315))	('GMCSF', 'Gene', (165, 170))	('oncolytic vaccinia virus', 'Disease', (31, 55))	('viral infection', 'Disease', 'MESH:D001102', (300, 315))	('clinical', 'Species', '191496', (135, 143))	('GMCSF', 'Gene', '1437', (266, 271))	('GMCSF', 'Gene', '1437', (202, 207))	('viral infection', 'biological_process', 'GO:0016032', ('300', '315'))	('GMCSF', 'Gene', (266, 271))	('GMCSF', 'Gene', (202, 207))	('GMCSF', 'Gene', '1437', (63, 68))	('GMCSF', 'Gene', '1437', (103, 108))	('elevated', 'PosReg', (78, 86))	('GMCSF', 'Gene', (63, 68))	('Ad5/3-D24-GMCSF', 'Gene', (155, 170))	('GMCSF', 'Gene', (103, 108))	('GMCSF', 'Gene', '1437', (165, 170))	('Ad5/3-D24-GMCSF', 'Gene', '1437', (155, 170))
158774	28053943	Thus, the phenomenon of expressing more CD46 in tumor cells as compared to their normal tissue counterparts represents a mechanism developmentally acquired by cancer cells via mutations to prevent complement-mediated lytic activity by the normal host immune system but at the same time make cancer cells more susceptible to infection by MV vaccine strains.	('cancer', 'Disease', (159, 165))	('mutations', 'Var', (176, 185))	('tumor', 'Disease', (48, 53))	('more', 'PosReg', (304, 308))	('MV', 'Species', '11234', (337, 339))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('CD46', 'Gene', (40, 44))	('make', 'Reg', (286, 290))	('susceptible', 'Interaction', (309, 320))	('CD46', 'Gene', '4179', (40, 44))	('prevent', 'NegReg', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('complement-mediated lytic activity', 'MPA', (197, 231))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
158794	28053943	MV-mIFNb expression enhanced the infiltration of CD68-positive immune cells two to four times greater than MV-GFP 7 days after subcutaneous MV injection into the flank of tumor-bearing nude mice.	('MV', 'Species', '11234', (0, 2))	('expression', 'Var', (9, 19))	('enhanced', 'PosReg', (20, 28))	('mIFNb', 'Gene', '15977', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('MV', 'Species', '11234', (107, 109))	('infiltration of CD68-positive immune cells', 'CPA', (33, 75))	('nude mice', 'Species', '10090', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('MV', 'Species', '11234', (140, 142))	('mIFNb', 'Gene', (3, 8))
158799	28053943	A median survival of 45 days was reported in mice treated with MV-GFP and MV-GFP-NIS (P<0.001), and a median survival of just 20 days was reported in control animals treated with PBS only.	('mice', 'Species', '10090', (45, 49))	('NIS', 'Gene', (81, 84))	('MV', 'Species', '11234', (63, 65))	('MV-GFP', 'Var', (63, 69))	('MV', 'Species', '11234', (74, 76))	('PBS', 'Chemical', '-', (179, 182))	('NIS', 'Gene', '6528', (81, 84))
158807	28053943	NDV infection induces the host to secrete certain cytokines including interferons and TNF, which are responsible for the migration of NK cells, monocytes, macrophages, and sensitized T-cells to tumor microenvironment, resulting in subsequent oncolysis.	('TNF', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('NDV', 'Species', '11176', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('infection', 'Var', (4, 13))	('tumor', 'Disease', (194, 199))	('NDV', 'Gene', (0, 3))	('oncolysis', 'MPA', (242, 251))	('secrete', 'MPA', (34, 41))
158858	22253921	Only two of 49 miRNAs, miR-20a (p = 0.0101) and miR-103 (p = 0.0303), showed a significant down-regulation in MM.	('miR-20a', 'Gene', '406982', (23, 30))	('miR-103', 'Var', (48, 55))	('down-regulation', 'NegReg', (91, 106))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('miR-103', 'Chemical', '-', (48, 55))	('miR-20a', 'Gene', (23, 30))
158862	22253921	Using normalized Ct values of miR-20a the median value and interquartile range (IQR) were 0.668 (IQR 0.659-0.676) for MMP and 0.682 (IQR 0.657-0.695) for AEC, but the observed difference was not significant (data not shown).	('miR-20a', 'Gene', (30, 37))	('miR-20a', 'Gene', '406982', (30, 37))	('AEC', 'Disease', (154, 157))	('MMP', 'Disease', (118, 121))	('MMP', 'molecular_function', 'GO:0004235', ('118', '121'))	('0.682', 'Var', (126, 131))
158866	22253921	Median value of miR-103 was 0.611 (IQR 0.602-0.620) for epithelioid mesothelioma and 0.612 (IQR 0.610-0.614) for biphasic mesothelioma (Figure 4).	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (113, 134))	('epithelioid mesothelioma', 'Disease', (56, 80))	('miR-103', 'Gene', (16, 23))	('biphasic mesothelioma', 'Disease', (113, 134))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (56, 80))	('0.612', 'Var', (85, 90))	('miR-103', 'Chemical', '-', (16, 23))
158872	22253921	Regarding the smoking status the median value of miR-103 was 0.629 (IQR 0.622-0.642) for smokers, 0.624 (IQR 0.612-0.635) for ex-smokers, and 0.621 (IQR 0.612-0.634) for non-smokers, (Figure 6 B).	('miR-103', 'Gene', (49, 56))	('miR-103', 'Chemical', '-', (49, 56))	('0.624', 'Var', (98, 103))
158894	22253921	For example, miR-103 and miR-107 are described as possible prognostic markers in esophageal carcinoma.	('esophageal carcinoma', 'Disease', (81, 101))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (81, 101))	('miR-103', 'Chemical', '-', (13, 20))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('miR-107', 'Gene', '406901', (25, 32))	('miR-103', 'Var', (13, 20))	('miR-107', 'Gene', (25, 32))
158910	22253921	In comparison to miR-126 (73% sensitivity and 74% specificity), miR-103 shows a comparable specificity but slightly higher sensitivity.	('miR-103', 'Chemical', '-', (64, 71))	('miR-126', 'Gene', '406913', (17, 24))	('higher', 'PosReg', (116, 122))	('miR-126', 'Gene', (17, 24))	('miR-103', 'Var', (64, 71))
158999	30501113	Representative images of the tumor and normal tissue biodistribution of 67Ga-nimotuzumab are shown in Figure 2.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('nimotuzumab', 'Chemical', 'MESH:C501466', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('67Ga-nimotuzumab', 'Var', (72, 88))
159019	30501113	It has been reported that the use of a molar ratio 1:10 (antibody/DTPA) results in a chelation of about two groups of DTPA per antibody, other groups have reported between 0.9 to 5 DTPAs per antibody molecule; this difference can be attributed to the number of lysines in the structure and those available to react.	('antibody', 'cellular_component', 'GO:0019815', ('191', '199'))	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019815', ('127', '135'))	('lysines', 'Chemical', 'MESH:D008239', (261, 268))	('DTPA', 'Chemical', 'MESH:D004369', (118, 122))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019814', ('191', '199'))	('antibody', 'molecular_function', 'GO:0003823', ('191', '199'))	('antibody', 'cellular_component', 'GO:0019814', ('127', '135'))	('antibody', 'molecular_function', 'GO:0003823', ('127', '135'))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('DTPA', 'Chemical', 'MESH:D004369', (181, 185))	('chelation', 'MPA', (85, 94))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('molar', 'Var', (39, 44))	('antibody', 'cellular_component', 'GO:0042571', ('191', '199'))	('DTPA', 'Chemical', 'MESH:D004369', (66, 70))	('antibody', 'cellular_component', 'GO:0042571', ('127', '135'))
159035	30501113	Because 67GaCl3 does not have a specific target in the body, its small size facilitates its clearance through the kidneys, which is the main route of elimination for small water-soluble molecules with low molecular weight.	('facilitates', 'PosReg', (76, 87))	('67GaCl3', 'Chemical', '-', (8, 15))	('soluble', 'cellular_component', 'GO:0005625', ('178', '185'))	('water', 'Chemical', 'MESH:D014867', (172, 177))	('67GaCl3', 'Var', (8, 15))	('clearance', 'MPA', (92, 101))
159038	30501113	In contrast, it has been reported that nimotuzumab is not directly excreted in the urine or metabolized by the microsomal hepatic system, maybe as result of its high molecular weight (150,000 kDa).	('150,000 kDa', 'Var', (184, 195))	('nimotuzumab', 'Chemical', 'MESH:C501466', (39, 50))	('nimotuzumab', 'Gene', (39, 50))
159040	30501113	In our experiment, the inhomogeneous tumor uptake of 67Ga-nimotuzumab was observed in the mesothelioma xenografts (Figure 3 and Figure 4).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('67Ga-nimotuzumab', 'Var', (53, 69))	('nimotuzumab', 'Chemical', 'MESH:C501466', (58, 69))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('uptake', 'biological_process', 'GO:0098657', ('43', '49'))	('uptake', 'biological_process', 'GO:0098739', ('43', '49'))	('mesothelioma xenografts', 'Disease', 'MESH:D008654', (90, 113))	('mesothelioma xenografts', 'Disease', (90, 113))
159043	30501113	The use of beta-particle emitter radionuclides (177Lu, 131I, 188Re) in the radiolabeling of nimotuzumab could promote its use as a radioimmunotherapeutic agent for the treatment of malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (181, 211))	('nimotuzumab', 'Gene', (92, 103))	('131I', 'Chemical', 'MESH:C000614965', (55, 59))	('177Lu', 'Var', (48, 53))	('malignant pleural mesothelioma', 'Disease', (181, 211))	('nimotuzumab', 'Chemical', 'MESH:C501466', (92, 103))	('radionuclide', 'Chemical', 'MESH:D011868', (33, 45))	('promote', 'PosReg', (110, 117))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (191, 211))
159078	30501113	The results of the biodistribution and specific uptake of 67Ga-nimotuzumab in mesothelioma xenografts are valuable and will motivate further imaging studies to explore its potential use as a theranostic biomarker in clinical studies of patients with malignant pleural mesothelioma.	('malignant pleural mesothelioma', 'Disease', (250, 280))	('uptake', 'biological_process', 'GO:0098739', ('48', '54'))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (260, 280))	('uptake', 'biological_process', 'GO:0098657', ('48', '54'))	('patients', 'Species', '9606', (236, 244))	('mesothelioma xenografts', 'Disease', (78, 101))	('67Ga-nimotuzumab', 'Var', (58, 74))	('mesothelioma xenografts', 'Disease', 'MESH:D008654', (78, 101))	('nimotuzumab', 'Chemical', 'MESH:C501466', (63, 74))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (250, 280))
159079	30501113	This work was partially financed by PAPIIT-UNAM research grants (IN-225014 and IN209916), CONACyT grant (154557) and institutional research resources from the Mexican National Cancer Institute.	('154557', 'Var', (105, 111))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('Cancer', 'Disease', (176, 182))	('IN209916', 'Var', (79, 87))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))
159130	28426148	However, the deformation of the pleural volume during the surgery, when the pleural cavity is opened impacts the light fluence delivered to the tumor as well as the fluence to the organs-at-risk and thus reduces the treatment efficacy.	('impacts', 'Reg', (101, 108))	('tumor', 'Disease', (144, 149))	('fluence', 'MPA', (165, 172))	('deformation', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('reduces', 'NegReg', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('treatment efficacy', 'CPA', (216, 234))	('light fluence delivered', 'MPA', (113, 136))
159237	27853672	PE is subsequently transferred to the cytosol, where it ADP-ribosylates and inactivates elongation factor-2 (EF-2).	('inactivates', 'NegReg', (76, 87))	('EF-2', 'Gene', '1938', (109, 113))	('elongation factor-2', 'Gene', '1938', (88, 107))	('cytosol', 'cellular_component', 'GO:0005829', ('38', '45'))	('EF-2', 'Gene', (109, 113))	('ADP-ribosylates', 'Var', (56, 71))	('elongation factor-2', 'Gene', (88, 107))
159243	27853672	In vitro, SS1P is a potent anticancer agent as a single agent.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('SS1P', 'Chemical', 'MESH:C474515', (10, 14))	('cancer', 'Disease', (31, 37))	('SS1P', 'Var', (10, 14))
159261	27853672	Overall, continuous infusion of SS1P had no significant benefit over the bolus injection in patients with refractory solid cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SS1P', 'Chemical', 'MESH:C474515', (32, 36))	('SS1P', 'Var', (32, 36))	('patients', 'Species', '9606', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('solid cancers', 'Disease', (117, 130))	('solid cancers', 'Disease', 'MESH:D009369', (117, 130))
159267	27853672	SS1P in combination with cisplatin/pemetrexed was safe and well tolerated in this preliminary assessment with Grade 3 hypoalbuminemia, back pain and hypotension being the main toxicities associated with SS1P at the MTD of 45 mug/kg.	('back pain', 'Disease', (135, 144))	('toxicities', 'Disease', 'MESH:D064420', (176, 186))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (118, 133))	('hypoalbuminemia', 'Disease', (118, 133))	('toxicities', 'Disease', (176, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))	('pemetrexed', 'Chemical', 'MESH:D000068437', (35, 45))	('SS1P', 'Chemical', 'MESH:C474515', (203, 207))	('hypotension', 'Disease', (149, 160))	('back pain', 'Phenotype', 'HP:0003418', (135, 144))	('rat', 'Species', '10116', (68, 71))	('SS1P', 'Var', (203, 207))	('back pain', 'Disease', 'MESH:D001416', (135, 144))	('hypotension', 'Disease', 'MESH:D007022', (149, 160))	('mug', 'molecular_function', 'GO:0043739', ('225', '228'))	('hypotension', 'Phenotype', 'HP:0002615', (149, 160))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (118, 133))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('pain', 'Phenotype', 'HP:0012531', (140, 144))
159270	27853672	Modification of the SS1P structure is being considered to minimize its immunogenicity and allow for more extended administration.	('SS1P', 'Gene', (20, 24))	('immunogenicity', 'MPA', (71, 85))	('Modification', 'Var', (0, 12))	('rat', 'Species', '10116', (122, 125))	('SS1P', 'Chemical', 'MESH:C474515', (20, 24))
159276	27853672	also re-engineered the targeting moiety from mouse dsFv to humanized Fab and de-immunized the effector moiety PE24 to generate a new immunotoxin RG7787 [huSS1(Fab)-LR-GGS-LO10-PE24].	('human', 'Species', '9606', (59, 64))	('mouse', 'Species', '10090', (45, 50))	('SS1', 'Gene', '3123', (155, 158))	('Fab', 'Gene', '2187', (69, 72))	('Fab', 'Gene', '2187', (159, 162))	('rat', 'Species', '10116', (122, 125))	('SS1', 'Gene', (155, 158))	('Fab', 'Gene', (159, 162))	('RG7787', 'Var', (145, 151))	('Fab', 'Gene', (69, 72))
159277	27853672	Differences in domain structure between SS1P and RG7787 are shown in (Fig.	('SS1P', 'Chemical', 'MESH:C474515', (40, 44))	('domain structure', 'MPA', (15, 31))	('RG7787', 'Var', (49, 55))	('Differences', 'Reg', (0, 11))
159279	27853672	Replacing domain II of PE in the RG7787 fusion protein by a furin cleavable peptide linker eliminates B-cell as well as major T-cell epitopes.	('furin', 'Gene', (60, 65))	('eliminates', 'NegReg', (91, 101))	('RG7787', 'Gene', (33, 39))	('B-cell', 'CPA', (102, 108))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('Replacing', 'Var', (0, 9))	('furin', 'Gene', '5045', (60, 65))
159280	27853672	In vitro, RG7787 produced >95% cell killing of the HCC70 and SUM149 human breast cancer cell lines with IC50 < 100 pM.	('breast cancer', 'Disease', (74, 87))	('human', 'Species', '9606', (68, 73))	('cell killing', 'CPA', (31, 43))	('cell killing', 'biological_process', 'GO:0001906', ('31', '43'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('RG7787', 'Var', (10, 16))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
159281	27853672	RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 with activity in the subnanomolar range.	('activity', 'MPA', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('gastric cancer', 'Disease', (34, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('RG7787', 'Var', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
159282	27853672	Furthermore, RG7787 was significantly more active than SS1P in GUMC108, KLM-1, and Panc 3.014 cells.	('Panc 3.014', 'CellLine', 'CVCL:E298', (83, 93))	('more', 'PosReg', (38, 42))	('RG7787', 'Var', (13, 19))	('active', 'MPA', (43, 49))	('SS1P', 'Chemical', 'MESH:C474515', (55, 59))
159283	27853672	In a nude mouse model, RG7787 treatment resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001).	('decrease', 'NegReg', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('volumes', 'MPA', (96, 103))	('mouse', 'Species', '10090', (10, 15))	('HCC70 xenograft tumors', 'Disease', 'MESH:D009369', (107, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('decrease', 'NegReg', (154, 162))	('RG7787', 'Var', (23, 29))	('MKN28 tumors', 'Disease', 'MESH:D009369', (166, 178))	('MKN28 tumors', 'Disease', (166, 178))	('HCC70 xenograft tumors', 'Disease', (107, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
159285	27853672	enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both).	('paclitaxel', 'Chemical', 'MESH:D017239', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('HCC70', 'Var', (72, 77))	('MKN28', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('reduction', 'NegReg', (41, 50))
159290	27853672	Interestingly, despite very comparable pharmacokinetic properties of the two molecules, RG7787 was found to be up to 10-fold better tolerated in different animal species.	('better', 'PosReg', (125, 131))	('rat', 'Species', '10116', (136, 139))	('RG7787', 'Var', (88, 94))
159291	27853672	For instance, in female Wistar Furth rats, SS1P at 2 mg/kg caused massive hepatotoxicity and VLS, whereas even a 5-fold higher dose of RG7787 did not.	('hepatotoxicity', 'Disease', 'MESH:D056486', (74, 88))	('SS1P', 'Chemical', 'MESH:C474515', (43, 47))	('VLS', 'MPA', (93, 96))	('SS1P', 'Var', (43, 47))	('hepatotoxicity', 'Disease', (74, 88))	('rats', 'Species', '10116', (37, 41))
159304	27853672	It has been shown that the binding properties of MF-T are not altered by the presence of CA125.	('binding', 'molecular_function', 'GO:0005488', ('27', '34'))	('MF-T', 'Disease', (49, 53))	('MF-T', 'Disease', 'MESH:D001260', (49, 53))	('CA125', 'Gene', '94025', (89, 94))	('binding', 'Interaction', (27, 34))	('presence', 'Var', (77, 85))	('CA125', 'Gene', (89, 94))
159350	27853672	In vivo, cleavable 7D9-mc-vc-PAB-MMAE was more efficacious than both MMAF ADCs against OVCAR3 tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mc-vc-PAB', 'Chemical', '-', (23, 32))	('7D9-mc-vc-PAB-MMAE', 'Var', (19, 37))	('-mc', 'Chemical', '-', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
159353	27853672	This may be due to its lysosomal metabolite Cys-mc-MMAF having a slower diffusion into the cytoplasm to exert cytotoxic effects than the free MMAF or MMAE resulting from the valine-citrulline cleavage.	('Cys-mc-MMAF', 'Var', (44, 55))	('cytoplasm', 'cellular_component', 'GO:0005737', ('91', '100'))	('valine-citrulline', 'Chemical', '-', (174, 191))	('diffusion', 'MPA', (72, 81))	('slower', 'NegReg', (65, 71))	('mc-MMAF', 'Chemical', '-', (48, 55))
159358	27853672	The ADC h7D9.v3-mc-vc-PAB-MMAE inhibited the proliferation of mesothelin-expressing cells with an IC50 of 0.32 nM to 20 nM depending on the levels of mesothelin on cancer cells.	('rat', 'Species', '10116', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('proliferation of mesothelin-expressing cells', 'CPA', (45, 89))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('h7D9.v3-mc-vc-PAB-MMAE', 'Var', (8, 30))	('mc-vc-PAB', 'Chemical', '-', (16, 25))	('-mc', 'Chemical', '-', (15, 18))	('inhibited', 'NegReg', (31, 40))
159359	27853672	A phase I study of ADC DMOT4039A [ADC composed of a humanized IgG1 anti-mesothelin antibody and monomethyl auristatin E (MMAE)] is ongoing in patients with unresectable pancreatic (PANC) or platinum-resistant ovarian cancer (OV).	('antibody', 'molecular_function', 'GO:0003823', ('83', '91'))	('ovarian cancer', 'Disease', 'MESH:D010051', (209, 223))	('monomethyl auristatin E', 'Chemical', 'MESH:C495575', (96, 119))	('antibody', 'cellular_component', 'GO:0042571', ('83', '91'))	('ADC', 'Gene', (19, 22))	('DMOT4039A', 'Chemical', '-', (23, 32))	('pancreatic', 'Disease', 'MESH:D010195', (169, 179))	('antibody', 'cellular_component', 'GO:0019815', ('83', '91'))	('DMOT4039A', 'Var', (23, 32))	('ovarian cancer', 'Disease', (209, 223))	('IgG1', 'Gene', '16017', (62, 66))	('ovarian cancer', 'Phenotype', 'HP:0100615', (209, 223))	('pancreatic', 'Disease', (169, 179))	('antibody', 'cellular_component', 'GO:0019814', ('83', '91'))	('IgG1', 'Gene', (62, 66))	('human', 'Species', '9606', (52, 57))	('patients', 'Species', '9606', (142, 150))	('IgG1', 'cellular_component', 'GO:0071735', ('62', '66'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
159360	27853672	DMOT4039A (0.2-2.8 mg/kg) was given q3w to cancer patients.	('DMOT4039A', 'Chemical', '-', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('DMOT4039A', 'Var', (0, 9))
159367	27853672	Mesothelin expression was IHC 2+/3+ in 64% of PANC patients and 91% of OV patients, in part due to diagnostic selection for enrollment in expansion cohorts.	('PANC', 'Disease', (46, 50))	('patients', 'Species', '9606', (74, 82))	('expression', 'MPA', (11, 21))	('Mesothelin', 'Protein', (0, 10))	('patients', 'Species', '9606', (51, 59))	('IHC', 'Var', (26, 29))
159369	27853672	ADC DMOT4039A, at 2.4 mg/kg q3w, showed clinical activity in both PANC and OV cancers expressing mesothelin levels at IHC 2/3+, with a tolerable safety profile.	('DMOT4039A', 'Chemical', '-', (4, 13))	('OV cancers', 'Disease', 'MESH:D009369', (75, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('OV cancers', 'Disease', (75, 85))	('PANC', 'Disease', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mesothelin levels', 'MPA', (97, 114))	('DMOT4039A', 'Var', (4, 13))
159399	27853672	The main toxicities with ADCs conjugated to microtubule inhibitors (MMAE or DM1) were observed in the bone marrow, as evidenced by decreases in neutrophils, lymphocyte, reticulocytes, and platelets, and in liver.	('microtubule', 'cellular_component', 'GO:0005874', ('44', '55'))	('neutrophils', 'CPA', (144, 155))	('toxicities', 'Disease', (9, 19))	('DM1', 'Gene', '28509', (76, 79))	('lymphocyte', 'CPA', (157, 167))	('ADCs', 'Var', (25, 29))	('decreases', 'NegReg', (131, 140))	('reticulocytes', 'CPA', (169, 182))	('platelets', 'CPA', (188, 197))	('toxicities', 'Disease', 'MESH:D064420', (9, 19))	('DM1', 'Gene', (76, 79))
159400	27853672	Ocular toxicity was also reported with ADCs containing DM4.	('Ocular toxicity', 'Disease', (0, 15))	('DM4', 'Chemical', 'MESH:D008453', (55, 58))	('DM4', 'Var', (55, 58))	('Ocular toxicity', 'Disease', 'MESH:D005128', (0, 15))
159441	27110327	The most prevalent finding in the mesothelioma group was pleural thickening seen in 88.2% (n = 15) followed by loculated effusion in 58.8%, and thickening of interlobar fissure in 47.1% (Figure 2, 3 and 4).	('pleural', 'Disease', (57, 64))	('effusion', 'Disease', 'MESH:D010996', (121, 129))	('mesothelioma', 'Disease', (34, 46))	('pleural thickening', 'Phenotype', 'HP:0031944', (57, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('effusion', 'Disease', (121, 129))	('thickening', 'Var', (144, 154))	('pleural', 'Disease', 'MESH:D010995', (57, 64))
159461	27110327	in their study in 2000 on 117 mesothelioma patients reported that pleural effusion (89%), pleural thickening (82%), mediastinal pleural involvement (66%), and thickening of the interlobar fissure (53%) are the most common CT findings in mesothelioma patients (7).	('mesothelioma', 'Disease', (30, 42))	('pleural effusion', 'Disease', 'MESH:D010996', (66, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (30, 42))	('pleural involvement', 'Disease', 'MESH:D010995', (128, 147))	('pleural thickening', 'Phenotype', 'HP:0031944', (90, 108))	('pleural', 'Disease', 'MESH:D010995', (66, 73))	('pleural', 'Disease', (66, 73))	('pleural', 'Disease', 'MESH:D010995', (90, 97))	('pleural effusion', 'Phenotype', 'HP:0002202', (66, 82))	('pleural', 'Disease', (90, 97))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (250, 258))	('pleural', 'Disease', 'MESH:D010995', (128, 135))	('pleural', 'Disease', (128, 135))	('thickening', 'Var', (159, 169))	('pleural effusion', 'Disease', (66, 82))	('mesothelioma', 'Disease', (237, 249))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('pleural involvement', 'Disease', (128, 147))
159463	27110327	named unilateral pleural effusion, nodular pleural thickening, and thickening of interlobar fissure the key CT finding of MPM.	('pleural effusion', 'Disease', (17, 33))	('pleural effusion', 'Phenotype', 'HP:0002202', (17, 33))	('nodular pleural', 'Disease', 'MESH:D020518', (35, 50))	('thickening', 'Var', (67, 77))	('pleural thickening', 'Phenotype', 'HP:0031944', (43, 61))	('nodular pleural', 'Disease', (35, 50))	('pleural effusion', 'Disease', 'MESH:D010996', (17, 33))
159468	27110327	Comparing the two groups, pleural thickening (P = 0.05) and thickening of the interlobar fissure (P = 0.02) are more prevalent in malignant mesothelioma; therefore, they can be considered as important parameters in favor of malignant mesothelioma.	('pleural', 'Disease', (26, 33))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (224, 246))	('malignant mesothelioma', 'Disease', (224, 246))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (130, 152))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (130, 152))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (224, 246))	('malignant mesothelioma', 'Disease', (130, 152))	('pleural thickening', 'Phenotype', 'HP:0031944', (26, 44))	('thickening', 'Var', (60, 70))	('pleural', 'Disease', 'MESH:D010995', (26, 33))
159486	26364129	A genetic factor predisposing to MM was recently discovered, namely germline mutation of the BAP1 (BRCA1-associated protein 1) gene in two families with a high incidence of MM and only modest exposure to asbestos.	('BAP1', 'Gene', '8314', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('germline mutation', 'Var', (68, 85))	('asbestos', 'Chemical', 'MESH:D001194', (204, 212))	('BAP1', 'Gene', (93, 97))	('BRCA1-associated protein 1', 'Gene', '8314', (99, 125))	('BRCA1-associated protein 1', 'Gene', (99, 125))
159487	26364129	The association of germline BAP1 mutations with familial MM has been confirmed in a series of recent reports.	('BAP1', 'Gene', '8314', (28, 32))	('mutations', 'Var', (33, 42))	('BAP1', 'Gene', (28, 32))	('familial MM', 'Disease', (48, 59))
159488	26364129	Germline BAP1 mutations have also been repeatedly associated with other tumor types, including uveal melanomas, cutaneous melanomas, benign melanocytic tumors, kidney cancers, and basal cell carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('uveal melanomas', 'Disease', (95, 110))	('uveal melanomas', 'Phenotype', 'HP:0007716', (95, 110))	('basal cell carcinomas', 'Disease', (180, 201))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (180, 201))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('BAP1', 'Gene', (9, 13))	('cutaneous melanomas', 'Disease', (112, 131))	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('benign melanocytic tumors', 'Disease', (133, 158))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumor', 'Disease', (152, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('kidney cancers', 'Disease', 'MESH:D007680', (160, 174))	('mutations', 'Var', (14, 23))	('kidney cancers', 'Disease', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor', 'Disease', (72, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (95, 110))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('kidney cancers', 'Phenotype', 'HP:0009726', (160, 174))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (180, 201))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('BAP1', 'Gene', '8314', (9, 13))	('benign melanocytic tumors', 'Disease', 'MESH:D009508', (133, 158))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('associated', 'Reg', (50, 60))
159489	26364129	Somatic mutations and/or deletions have been described in MMs of both individuals with germline BAP1 mutations and in sporadic cases lacking a germline mutation.	('BAP1', 'Gene', (96, 100))	('deletions', 'Var', (25, 34))	('mutations', 'Var', (101, 110))	('BAP1', 'Gene', '8314', (96, 100))
159490	26364129	found biallelic gene alterations, including homozygous deletions of part or all of the BAP1 gene as well as sequence-level mutations, in 61% of sporadic MMs.	('BAP1', 'Gene', '8314', (87, 91))	('MMs', 'Disease', (153, 156))	('homozygous deletions', 'Var', (44, 64))	('BAP1', 'Gene', (87, 91))
159491	26364129	Subsequent studies with newer next generation and multiplex ligation-dependent probe amplification (MLPA) platforms confirmed a similarly high incidence of BAP1 mutations in this disease.	('BAP1', 'Gene', (156, 160))	('mutations', 'Var', (161, 170))	('BAP1', 'Gene', '8314', (156, 160))
159492	26364129	Based on the reported connection between familial MM and inheritance of a BAP1 mutation, we decided to analyze the BAP1 status in a family with many cases of pleural MM and asbestos exposure.	('BAP1', 'Gene', '8314', (115, 119))	('asbestos', 'Chemical', 'MESH:D001194', (173, 181))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (115, 119))	('mutation', 'Var', (79, 87))	('pleural MM', 'Disease', 'MESH:D010995', (158, 168))	('pleural MM', 'Disease', (158, 168))	('BAP1', 'Gene', (74, 78))
159506	26364129	Our main goal was to identify a predisposing (germline) mutation in this family, but unfortunately peripheral blood samples were unavailable; therefore, sequence analysis was performed on three FFPE specimens and one pleural fluid sample from a total of four MM cases.	('predisposing', 'Reg', (32, 44))	('mutation', 'Var', (56, 64))	('men', 'Species', '9606', (204, 207))	('pleural fluid', 'Phenotype', 'HP:0002202', (217, 230))
159514	26364129	To assess the possibility of a heterozygous or homozygous deletion of all or part of the BAP1 gene, MLPA studies were perfomed on the pleural effusion from subject III-5 by myGenomics (Alpharetta, GA) using a commercially available BAP1 MLPA kit (P417, MRC-Holland, Amsterdam, Netherlands).	('BAP1', 'Gene', (232, 236))	('BAP1', 'Gene', (89, 93))	('pleural effusion', 'Disease', 'MESH:D010996', (134, 150))	('pleural effusion', 'Phenotype', 'HP:0002202', (134, 150))	('pleural effusion', 'Disease', (134, 150))	('Alpharetta', 'Chemical', '-', (185, 195))	('BAP1', 'Gene', '8314', (232, 236))	('deletion', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (89, 93))
159515	26364129	To ascertain the potential involvement of a BAP1 mutation, Sanger sequencing was performed on samples from family members III-1, III-2, III-5, and III-7.	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', '8314', (44, 48))	('involvement', 'Reg', (27, 38))	('BAP1', 'Gene', (44, 48))	('men', 'Species', '9606', (34, 37))
159516	26364129	MLPA analysis of the pleural effusion from case III-5, consisting of mostly normal cells, revealed no deletions in BAP1.	('pleural effusion', 'Disease', 'MESH:D010996', (21, 37))	('pleural effusion', 'Disease', (21, 37))	('pleural effusion', 'Phenotype', 'HP:0002202', (21, 37))	('deletions', 'Var', (102, 111))	('BAP1', 'Gene', '8314', (115, 119))	('BAP1', 'Gene', (115, 119))
159528	26364129	Recent studies have revealed germline mutations of BAP1 in familial MM.	('BAP1', 'Gene', (51, 55))	('familial MM', 'Disease', (59, 70))	('BAP1', 'Gene', '8314', (51, 55))	('germline mutations', 'Var', (29, 47))
159530	26364129	Thus, while sequencing of BAP1 in MMs from individuals III-1 and III-7 did not reveal any mutation, loss of nuclear BAP1 staining in these two samples, and in tumor from III-17 - which was not sequenced, may have occurred via somatic deletions of the gene, which would not be identified by Sanger sequencing.	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('deletions', 'Var', (234, 243))	('tumor', 'Disease', (159, 164))	('BAP1', 'Gene', '8314', (26, 30))	('staining', 'MPA', (121, 129))	('BAP1', 'Gene', '8314', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('loss', 'NegReg', (100, 104))
159531	26364129	Alternatively, somatic epigenetic silencing of BAP1 may have occurred in these cases.	('occurred', 'Reg', (61, 69))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (47, 51))	('epigenetic silencing', 'Var', (23, 43))
159539	26364129	Since germline BAP1 mutations have been shown to be involved in a tumor syndrome consisting of not just MM but also other tumor types such as cutaneous melanoma, and given that germline mutations of CDKN2A mutations have been identified in some families with a high incidence of cutaneous melanoma, sequencing of CDKN2A was performed in one case (III-5) to determine whether a germline CDKN2A mutation might be responsible for the high incidence of MM in this family.	('CDKN2A', 'Gene', (386, 392))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('cutaneous melanoma', 'Disease', (279, 297))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (279, 297))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (279, 297))	('BAP1', 'Gene', '8314', (15, 19))	('CDKN2A', 'Gene', (313, 319))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (66, 71))	('CDKN2A', 'Gene', '1029', (386, 392))	('cutaneous melanoma', 'Disease', (142, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (142, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('CDKN2A', 'Gene', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BAP1', 'Gene', (15, 19))	('CDKN2A', 'Gene', '1029', (313, 319))	('CDKN2A', 'Gene', '1029', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('involved', 'Reg', (52, 60))
159542	26364129	Since somatic mutations of TP53 occur in ~15% of MMs, and germline mutation of TP53 predisposes to a variety of cancers in patients with Li-Fraumeni Syndrome, we also searched for mutations in this gene in MMs from four members of the family reported here.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('TP53', 'Gene', '7157', (79, 83))	('Li-Fraumeni Syndrome', 'Disease', (137, 157))	('TP53', 'Gene', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('predisposes to', 'Reg', (84, 98))	('patients', 'Species', '9606', (123, 131))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('MMs', 'Disease', (49, 52))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (137, 157))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (14, 23))
159544	26364129	In summary, an inherited BAP1 mutation does not appear to be involved in the high incidence of MM in the family reported here.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))
159577	25186961	Mice were inoculated subcutaneously (s.c.) with 5x105 AB1-HA cells in a total volume of 100 mul PBS on the right hand flank unless otherwise stated.	('5x105', 'Var', (48, 53))	('AB1-HA', 'Gene', (54, 60))	('Mice', 'Species', '10090', (0, 4))	('PBS', 'Chemical', 'MESH:D007854', (96, 99))
159614	25186961	Similarly, CD4 depletion during vaccination prevented any vaccine induce delay in tumor growth prior to surgery.	('depletion', 'Var', (15, 24))	('prevented', 'NegReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('delay', 'NegReg', (73, 78))	('CD4', 'Protein', (11, 14))	('tumor', 'Disease', (82, 87))
159616	25186961	Further experiments confirmed that CD4 depletion either prior to surgery, or during vaccination was sufficient to eradicate tumor in 50% (5/10) of treated animals and this could be increased to 70% (7/10) when vaccination was combined with surgery (Figure 2B), demonstrating that vaccination with CD4 depletion significantly enhances survival compared to surgery alone.	('depletion', 'Var', (301, 310))	('depletion', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('enhances', 'PosReg', (325, 333))	('tumor', 'Disease', (124, 129))	('survival', 'CPA', (334, 342))	('eradicate', 'NegReg', (114, 123))
159621	25186961	The proportion of CD4 and CD8 (as a percentage of total CD3+ lymphocytes) and FoxP3 + CD4+ regulatory T cells (Treg, as a proportion of total CD4+ T cells) was as expected, the same in all groups at baseline (day 7) and remained unchanged throughout the experiment in all non-CD4 depleted groups (Figure 3).	('FoxP3', 'Gene', (78, 83))	('FoxP3', 'Gene', '20371', (78, 83))	('CD8', 'Gene', '925', (26, 29))	('CD4', 'Var', (18, 21))	('CD3', 'Gene', (56, 59))	('CD3', 'Gene', '12501', (56, 59))	('CD8', 'Gene', (26, 29))
159622	25186961	In contrast, the proportion of CD4+ T cells and Treg were significantly depleted upon anti-CD4 mAb treatment (p < 0.0001), correlating with a significant increase in the proportion and activation status of CD8 T cells (Figure 3C-D, p < 0.0001).	('activation', 'CPA', (185, 195))	('CD8', 'Gene', (206, 209))	('CD8', 'Gene', '925', (206, 209))	('depleted', 'NegReg', (72, 80))	('increase', 'PosReg', (154, 162))	('anti-CD4', 'Var', (86, 94))
159643	25186961	Furthermore, depletion of CD4 T cells during vaccination produced complete tumor eradication and established immunological memory that could protect against subsequent tumor growth.	('immunological memory', 'CPA', (109, 129))	('memory', 'biological_process', 'GO:0007613', ('123', '129'))	('tumor', 'Disease', (168, 173))	('depletion', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CD4 T', 'Protein', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
159644	25186961	These results suggest that prior to performing debulking surgery, administration of an immunotherapy consisting of transient CD4 T cell, or more specifically Treg depletion combined with anti-tumor vaccination is an effective therapeutic strategy to enhance survival.	('depletion', 'Var', (163, 172))	('tumor', 'Disease', (192, 197))	('survival', 'CPA', (258, 266))	('CD4', 'Gene', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('enhance', 'PosReg', (250, 257))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
159849	30328620	Risk factors for local recurrence include anastomotic leak, non-R0 resection, intraoperative tumor perforation, high-grade pathology, and lack of adjuvant therapies.	('local', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('anastomotic leak', 'Disease', 'MESH:D057868', (42, 58))	('high-grade', 'Var', (112, 122))	('intraoperative tumor', 'Disease', 'MESH:D007431', (78, 98))	('intraoperative tumor', 'Disease', (78, 98))	('non-R0', 'Var', (60, 66))	('anastomotic leak', 'Disease', (42, 58))
159873	30328620	A review of 583 patients with locally recurrent rectal cancer who underwent surgery (approximately 60% R0) reported 5-year OS of 44%, 26%, and 10% for R0, R1, and R2 resections, respectively.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (16, 24))	('rectal cancer', 'Disease', 'MESH:D012004', (48, 61))	('rectal cancer', 'Disease', (48, 61))	('rectal cancer', 'Phenotype', 'HP:0100743', (48, 61))	('R2 resections', 'Var', (163, 176))
159887	30328620	LRR within the breast parenchyma is associated with better survival than extramammary LRR (hazard ratio [HR] 2.58 versus 5.85; 5-year OS 60% versus 24%).	('LRR', 'Var', (0, 3))	('better', 'PosReg', (52, 58))	('breast parenchyma', 'Disease', (15, 32))	('breast parenchyma', 'Disease', 'MESH:D061325', (15, 32))	('survival', 'MPA', (59, 67))
159910	30328620	In a phase I/II trial of 44 patients treated with P/D and HIOC (high-dose cisplatin), median OS and DFS were 18 months and 9 months, respectively, but 54% of patients still experienced LRR.	('experienced', 'Reg', (173, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('P/D', 'Var', (50, 53))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (28, 36))	('LRR', 'Disease', (185, 188))
159932	30328620	A trial with 975 resectable NSCLC patients reported that sublobar resection, stage >IA, squamous or large cell histology, and presence of lymphovascular invasion were independently associated with higher rates of LRR on multivariate analysis.	('NSCLC', 'Disease', (28, 33))	('sublobar', 'Var', (57, 65))	('stage', 'Disease', (77, 82))	('higher', 'PosReg', (197, 203))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('lymphovascular invasion', 'Disease', (138, 161))	('squamous or large cell histology', 'Var', (88, 120))	('lymphovascular invasion', 'Disease', 'MESH:D009361', (138, 161))	('patients', 'Species', '9606', (34, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('LRR', 'Disease', (213, 216))
159942	30328620	tyrosine kinase inhibitors for EGFR mutated cancer, BRAF inhibitors, ROS1 inhibitors, etc) and immunotherapy agents (pembrolizumab, nivolumab, ipilimumab, atezolizumab, etc) are being used to treat more advanced NSCLC and thus are being used in cases of non-resectable LRR.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('EGFR', 'Gene', '1956', (31, 35))	('cancer', 'Disease', (44, 50))	('ROS1', 'Gene', (69, 73))	('EGFR', 'Gene', (31, 35))	('tyrosine', 'Chemical', 'None', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutated', 'Var', (36, 43))	('ROS1', 'Gene', '6098', (69, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('non-resectable LRR', 'Disease', (254, 272))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('NSCLC', 'Disease', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
159962	30328620	Patients most likely to derive benefit from re-resection are those with longer disease-free intervals, no history of tumor rupture at initial operation, low-grade tumors, and unifocal recurrences.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor rupture', 'Disease', (117, 130))	('tumor rupture', 'Disease', 'MESH:D012421', (117, 130))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('low-grade', 'Var', (153, 162))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
159978	30328620	While ligand-targeting has shown enhanced anti-tumor efficacy in vivo, its use in clinical studies has thus far been limited by a combination of tumor-dependent physiological barriers and formulation stability.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ligand', 'molecular_function', 'GO:0005488', ('6', '12'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ligand-targeting', 'Var', (6, 22))	('tumor', 'Disease', (47, 52))	('enhanced', 'PosReg', (33, 41))
159982	30328620	Although clinical studies of liposomal agents for treatment of LRR are limited, PEGylated liposomal doxorubicin exhibits a better safety profile than non-liposomal doxorubicin and in a phase II trial of elderly and cardiotoxicity-prone patients with high-risk breast cancer, liposomal doxorubicin resulted in a 5-year PFS of 58%.	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('cardiotoxicity', 'Disease', (215, 229))	('breast cancer', 'Disease', (260, 273))	('doxorubicin', 'Chemical', 'MESH:D004317', (164, 175))	('PEG', 'Chemical', 'MESH:D011092', (80, 83))	('patients', 'Species', '9606', (236, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('PEGylated', 'Var', (80, 89))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('cardiotoxicity', 'Disease', 'MESH:D066126', (215, 229))	('doxorubicin', 'Chemical', 'MESH:D004317', (285, 296))	('liposomal', 'Var', (275, 284))
159993	30328620	Furthermore, radiotherapy alters the tumor microenvironment immune-cell composition, vasculature, and cell-signaling to enhance intra-tumoral accumulation of NP and the presence of NP may also enhance the efficacy of ionizing radiotherapy.	('enhance', 'PosReg', (120, 127))	('ionizing radiotherapy', 'CPA', (217, 238))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('intra-tumoral', 'Disease', 'MESH:D009369', (128, 141))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('intra-tumoral', 'Disease', (128, 141))	('presence', 'Var', (169, 177))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('enhance', 'PosReg', (193, 200))	('tumor', 'Disease', (134, 139))
160021	30305100	This finding suggests for the first time that loss of RASSF1A expression could be a potential biomarker for TNTs formation, such TNTs facilitating intercellular communication favoring multistep progression of bronchial epithelial cells toward overt malignancy.	('TNTs', 'Chemical', '-', (108, 112))	('RASSF1A', 'Gene', '11186', (54, 61))	('TNTs', 'Chemical', '-', (129, 133))	('loss', 'Var', (46, 50))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('intercellular communication', 'MPA', (147, 174))	('RASSF1A', 'Gene', (54, 61))	('facilitating', 'Reg', (134, 146))	('malignancy', 'Disease', 'MESH:D009369', (249, 259))	('malignancy', 'Disease', (249, 259))
160024	30305100	In Non-Small Cell Lung Cancer (NSCLC), RASSF1A inactivation is also an independent marker of poor prognosis.	('inactivation', 'Var', (47, 59))	('RASSF1A', 'Gene', '11186', (39, 46))	('NSCLC', 'Disease', (31, 36))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Non-Small Cell Lung Cancer', 'Disease', (3, 29))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (3, 29))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (3, 29))	('RASSF1A', 'Gene', (39, 46))	('Lung Cancer', 'Phenotype', 'HP:0100526', (18, 29))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (7, 29))
160025	30305100	RASSF1A depletion underlies tumor initiation and progression since inducing epithelial to mesenchymal transition (EMT) in human bronchial cell lines with a pro-metastatic phenotype sustained by both i) guanine nucleotide exchange factor 1 (GEF-H1) inactivation and subsequent RhoB (a putative anti-metastatic small GTPase) inactivation and ii) nuclear accumulation of the active form of the Hippo pathway transcriptional cofactor YAP (Yes-associated protein).	('human', 'Species', '9606', (122, 127))	('Yes-associated protein', 'Gene', '10413', (435, 457))	('inactivation', 'Var', (323, 335))	('protein', 'cellular_component', 'GO:0003675', ('450', '457'))	('YAP', 'Gene', '10413', (430, 433))	('GEF-H1', 'Gene', '9181', (240, 246))	('tumor initiation', 'Disease', 'MESH:D009369', (28, 44))	('nuclear accumulation', 'MPA', (344, 364))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('76', '112'))	('tumor initiation', 'Disease', (28, 44))	('GEF', 'molecular_function', 'GO:0005085', ('240', '243'))	('epithelial to mesenchymal transition', 'CPA', (76, 112))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Yes-associated protein', 'Gene', (435, 457))	('GEF-H1', 'Gene', (240, 246))	('pro-metastatic', 'CPA', (156, 170))	('inactivation', 'Var', (248, 260))	('RASSF1A', 'Gene', '11186', (0, 7))	('YAP', 'Gene', (430, 433))	('RASSF1A', 'Gene', (0, 7))	('RhoB', 'Gene', '388', (276, 280))	('inducing', 'Reg', (67, 75))	('RhoB', 'Gene', (276, 280))	('EMT', 'biological_process', 'GO:0001837', ('114', '117'))
160026	30305100	Among long and narrow cytoplasmic extensions induced by RASSF1A depletion, some did not seem to contact the substratum, which distinguish these structures from mesenchymal morphology or other cell extensions such as filopodia.	('RASSF1A', 'Gene', (56, 63))	('depletion', 'Var', (64, 73))	('rat', 'Species', '10116', (113, 116))	('RASSF1A', 'Gene', '11186', (56, 63))
160035	30305100	Finally, the alteration of cell-cell junctions, which occurs after RASSF1A depletion or the disruption of gap junction upon EMT, is thought to support the intercellular communication via TNTs.	('disruption', 'Var', (92, 102))	('intercellular communication', 'MPA', (155, 182))	('TNTs', 'Chemical', '-', (187, 191))	('depletion', 'Var', (75, 84))	('rat', 'Species', '10116', (17, 20))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('RASSF1A', 'Gene', (67, 74))	('support', 'PosReg', (143, 150))	('cell-cell junctions', 'CPA', (27, 46))	('gap junction', 'cellular_component', 'GO:0005921', ('106', '118'))	('alteration', 'Reg', (13, 23))	('RASSF1A', 'Gene', '11186', (67, 74))
160041	30305100	Moreover, the transfer of mitochondria via TNT have been shown to enhance chemo-resistance between cancer cell populations.	('TNT', 'Chemical', '-', (43, 46))	('enhance', 'PosReg', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mitochondria', 'MPA', (26, 38))	('mitochondria', 'cellular_component', 'GO:0005739', ('26', '38'))	('cancer', 'Disease', (99, 105))	('transfer', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TNT', 'Gene', (43, 46))
160043	30305100	In this regard and given the role of RASSF1A in microtubules stabilization, actin organization and maintenance of epithelial phenotype, we sought to determine how depletion of RASSF1A could affect TNTs formation.	('depletion', 'Var', (163, 172))	('TNTs formation', 'CPA', (197, 211))	('RASSF1A', 'Gene', '11186', (37, 44))	('affect', 'Reg', (190, 196))	('TNTs', 'Chemical', '-', (197, 201))	('formation', 'biological_process', 'GO:0009058', ('202', '211'))	('RASSF1A', 'Gene', (176, 183))	('RASSF1A', 'Gene', '11186', (176, 183))	('RASSF1A', 'Gene', (37, 44))
160045	30305100	We employed RASSF1A specific RNAi or a wild-type RASSF1A encoding expression plasmid to assess the consequence of RASSF1A depletion or rescuing on TNTs formation.	('RASSF1A', 'Gene', '11186', (12, 19))	('depletion', 'NegReg', (122, 131))	('RASSF1A', 'Gene', (49, 56))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('RASSF1A', 'Gene', (114, 121))	('RASSF1A', 'Gene', (12, 19))	('RASSF1A', 'Gene', '11186', (49, 56))	('TNTs', 'Chemical', '-', (147, 151))	('RNAi', 'biological_process', 'GO:0016246', ('29', '33'))	('rescuing', 'Var', (135, 143))	('RASSF1A', 'Gene', '11186', (114, 121))
160047	30305100	Furthermore, we looked for additional key proteins, which are perturbed by loss of RASSF1A and could play a role in TNT formation.	('TNT', 'Chemical', '-', (116, 119))	('RASSF1A', 'Gene', (83, 90))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('RASSF1A', 'Gene', '11186', (83, 90))	('loss', 'Var', (75, 79))
160120	30305100	To confirm whether influencing RASSF1A expression in vitro could also modulate the occurrence of TNTs formation, RASSF1A knockdown or re-expression was achieved, respectively, in two cell lines with wild type expression of RASSF1A (HBEC-3 and H2452), and two other cell lines (H28 and A549), which RASSF1A epigenetic silencing (Additional file 1: Figure S1A and Additional file 6: Table S1).	('modulate', 'Reg', (70, 78))	('TNTs', 'Chemical', '-', (97, 101))	('A549', 'CellLine', 'CVCL:0023', (285, 289))	('RASSF1A', 'Gene', (223, 230))	('RASSF1A', 'Gene', (31, 38))	('RASSF1A', 'Gene', '11186', (113, 120))	('H2452', 'CellLine', 'CVCL:1553', (243, 248))	('RASSF1A', 'Gene', '11186', (298, 305))	('epigenetic silencing', 'Var', (306, 326))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('RASSF1A', 'Gene', '11186', (31, 38))	('HBEC-3', 'CellLine', 'CVCL:X491', (232, 238))	('RASSF1A', 'Gene', '11186', (223, 230))	('RASSF1A', 'Gene', (113, 120))	('RASSF1A', 'Gene', (298, 305))
160122	30305100	Besides, after RASSF1A depletion, the mean cell-to-cell length of TNT-1 was 1.5 fold higher and could reach up to about 250 mum in length, while control HBEC-3 cells transfected with non-relevant siRNA exhibited TNT-1 reaching not more than 170 mum in length (p < 0.01, Fig.	('depletion', 'Var', (23, 32))	('higher', 'PosReg', (85, 91))	('mum', 'Gene', (245, 248))	('TNT', 'Chemical', '-', (66, 69))	('RASSF1A', 'Gene', '11186', (15, 22))	('TNT', 'Chemical', '-', (212, 215))	('mum', 'Gene', '56925', (245, 248))	('cell-to-cell length', 'CPA', (43, 62))	('TNT-1', 'Gene', (66, 71))	('HBEC-3', 'CellLine', 'CVCL:X491', (153, 159))	('mum', 'Gene', '56925', (124, 127))	('RASSF1A', 'Gene', (15, 22))	('mum', 'Gene', (124, 127))
160124	30305100	The same result was also observed in malignant mesothelioma H2452 cells line after RASSF1A depletion (Additional file 1: Figure S2D, Fig.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (37, 59))	('H2452', 'CellLine', 'CVCL:1553', (60, 65))	('depletion', 'Var', (91, 100))	('RASSF1A', 'Gene', (83, 90))	('malignant mesothelioma', 'Disease', (37, 59))	('RASSF1A', 'Gene', '11186', (83, 90))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (37, 59))
160125	30305100	Next, we investigated whether RASSF1A depletion was able to induce functional TNT-1, which allow long distance communication between cells.	('TNT-1', 'Gene', (78, 83))	('RASSF1A', 'Gene', '11186', (30, 37))	('TNT', 'Chemical', '-', (78, 81))	('depletion', 'Var', (38, 47))	('RASSF1A', 'Gene', (30, 37))	('induce', 'Reg', (60, 66))
160129	30305100	Concordantly, transfection of the plasmid encoding wild type RASSF1A in malignant mesothelioma H28 cell line and lung epithelial A549 (Additional file 1: Figure S2F), decreased significantly not only TNT-1 formation, but also their length and intracellular transfers of mitochondria, compared to the cells transfected with the control plasmid (Fig.	('malignant mesothelioma', 'Disease', (72, 94))	('TNT-1 formation', 'MPA', (200, 215))	('RASSF1A', 'Gene', (61, 68))	('mitochondria', 'cellular_component', 'GO:0005739', ('270', '282'))	('length', 'MPA', (232, 238))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('RASSF1A', 'Gene', '11186', (61, 68))	('intracellular', 'cellular_component', 'GO:0005622', ('243', '256'))	('transfection', 'Var', (14, 26))	('lung epithelial A549', 'Disease', (113, 133))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (72, 94))	('lung epithelial A549', 'Disease', 'MESH:D002277', (113, 133))	('intracellular transfers of mitochondria', 'MPA', (243, 282))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (72, 94))	('TNT', 'Chemical', '-', (200, 203))	('decreased', 'NegReg', (167, 176))
160130	30305100	Taken together, these data provide evidence of the role of RASSF1A in TNTs formation and support the existence of a specific signaling pathway, which leads to an increase of functional TNT-1 after RASSF1A depletion.	('depletion', 'Var', (205, 214))	('TNTs', 'Chemical', '-', (70, 74))	('RASSF1A', 'Gene', '11186', (197, 204))	('TNT-1', 'Protein', (185, 190))	('increase', 'PosReg', (162, 170))	('signaling pathway', 'biological_process', 'GO:0007165', ('125', '142'))	('functional', 'MPA', (174, 184))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('RASSF1A', 'Gene', (59, 66))	('TNT', 'Chemical', '-', (185, 188))	('TNT', 'Chemical', '-', (70, 73))	('RASSF1A', 'Gene', '11186', (59, 66))	('RASSF1A', 'Gene', (197, 204))	('TNTs formation', 'CPA', (70, 84))
160137	30305100	As stated earlier in the cells cultured in standard medium conditions (10% fetal bovine serum and normoxic environment), RASSF1A depletion did increase the number of TNT-1.	('depletion', 'Var', (129, 138))	('RASSF1A', 'Gene', '11186', (121, 128))	('RASSF1A', 'Gene', (121, 128))	('TNT', 'Chemical', '-', (166, 169))	('TNT-1', 'CPA', (166, 171))	('increase', 'PosReg', (143, 151))	('bovine', 'Species', '9913', (81, 87))
160138	30305100	In either hypoxic environment or in the cells exposed to serum deprivation, RASSF1A depletion still enhanced significantly TNT-1 formation compared to the cells transfected with control RNAi (Fig.	('RASSF1A', 'Gene', '11186', (76, 83))	('depletion', 'Var', (84, 93))	('TNT', 'Chemical', '-', (123, 126))	('hypoxic', 'Disease', (10, 17))	('hypoxic', 'Disease', 'MESH:D000860', (10, 17))	('enhanced', 'PosReg', (100, 108))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('RNAi', 'biological_process', 'GO:0016246', ('186', '190'))	('TNT-1 formation', 'MPA', (123, 138))	('RASSF1A', 'Gene', (76, 83))
160139	30305100	These data suggest that RASSF1A promoter methylation, observed at the early pre-invasive stage of cancer development, may actually be beneficial for cell survival during environmental or metabolic stresses.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('promoter', 'MPA', (32, 40))	('RASSF1A', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('methylation', 'Var', (41, 52))	('cell survival', 'CPA', (149, 162))	('pre', 'molecular_function', 'GO:0003904', ('76', '79'))	('cancer', 'Disease', (98, 104))	('RASSF1A', 'Gene', '11186', (24, 31))	('beneficial', 'PosReg', (134, 144))
160140	30305100	We then sought to determine whether RASSF1A depletion increased the number and length of the functional TNTs by influencing cytoskeletal elements.	('influencing', 'Reg', (112, 123))	('RASSF1A', 'Gene', '11186', (36, 43))	('depletion', 'Var', (44, 53))	('cytoskeletal elements', 'MPA', (124, 145))	('increased', 'PosReg', (54, 63))	('RASSF1A', 'Gene', (36, 43))	('TNTs', 'Chemical', '-', (104, 108))
160145	30305100	We also sought to study the role of other cytoskeletal components, and 48 h after RASSF1A knockdown, HBEC-3 cells were incubated with cytoskeleton disrupting drugs during 24 h, before fixation.	('knockdown', 'Var', (90, 99))	('RASSF1A', 'Gene', '11186', (82, 89))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('134', '146'))	('HBEC-3', 'CellLine', 'CVCL:X491', (101, 107))	('RASSF1A', 'Gene', (82, 89))
160146	30305100	Despite the well-known role of RASSF1A in microtubules stabilization, stabilization of the microtubule by paclitaxel (10 nM) or their depolymerization with nocodazole (10 muM) did not affect the enhancement of TNT-1 formation induced by RASSF1A knockdown (Fig.	('RASSF1A', 'Gene', (237, 244))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))	('microtubules', 'MPA', (42, 54))	('muM', 'Gene', (171, 174))	('nocodazole', 'Chemical', 'MESH:D015739', (156, 166))	('RASSF1A', 'Gene', (31, 38))	('knockdown', 'Var', (245, 254))	('RASSF1A', 'Gene', '11186', (237, 244))	('TNT', 'Chemical', '-', (210, 213))	('RASSF1A', 'Gene', '11186', (31, 38))	('formation', 'biological_process', 'GO:0009058', ('216', '225'))	('muM', 'Gene', '56925', (171, 174))	('microtubule', 'cellular_component', 'GO:0005874', ('91', '102'))	('enhancement', 'PosReg', (195, 206))	('TNT-1 formation', 'MPA', (210, 225))
160148	30305100	We also find that RASSF1A knockdown reduced the mRNA expression of Myosin 9 and 10 heavy chains mRNAs and increased the expression of Myosin 9 light chain transcript (Fig.	('Myosin 9', 'Gene', (134, 142))	('expression', 'MPA', (120, 130))	('Myosin 9', 'Gene', '4627', (134, 142))	('RASSF1A', 'Gene', (18, 25))	('knockdown', 'Var', (26, 35))	('reduced', 'NegReg', (36, 43))	('mRNA expression', 'MPA', (48, 63))	('Myosin 9', 'Gene', (67, 75))	('increased', 'PosReg', (106, 115))	('RASSF1A', 'Gene', '11186', (18, 25))	('Myosin 9', 'Gene', '4627', (67, 75))
160153	30305100	5a), confirmed that RASSF1A depletion did increase the number of vesicles (Fig.	('RASSF1A', 'Gene', (20, 27))	('depletion', 'Var', (28, 37))	('RASSF1A', 'Gene', '11186', (20, 27))	('number of vesicles', 'MPA', (55, 73))	('increase', 'PosReg', (42, 50))
160154	30305100	To our surprise, the quantification of the exosome released in culture media by RASSF1A knockdown cells did not differ from the control cells (Fig.	('exosome', 'cellular_component', 'GO:0070062', ('43', '50'))	('RASSF1A', 'Gene', '11186', (80, 87))	('RASSF1A', 'Gene', (80, 87))	('knockdown', 'Var', (88, 97))
160161	30305100	Recently, our group demonstrated that RASSF1A depletion inhibits the anti-metastatic RhoB GTPase via phosphorylation and inactivation of GEF-H1, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors.	('RASSF1-hypermethylated lung tumors', 'Disease', (201, 235))	('RASSF1A', 'Gene', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('inhibits', 'NegReg', (56, 64))	('GEF', 'molecular_function', 'GO:0005085', ('137', '140'))	('lung tumors', 'Phenotype', 'HP:0100526', (224, 235))	('GEF-H1', 'Gene', '9181', (137, 143))	('RhoB', 'Gene', '388', (85, 89))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('RhoB', 'Gene', (85, 89))	('RASSF1-hypermethylated lung tumors', 'Disease', 'MESH:D008175', (201, 235))	('inactivation', 'NegReg', (121, 133))	('GEF-H1', 'Gene', (137, 143))	('GTPase', 'Enzyme', (90, 96))	('rat', 'Species', '10116', (27, 30))	('phosphorylation', 'MPA', (101, 116))	('depletion', 'Var', (46, 55))	('RASSF1A', 'Gene', '11186', (38, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))
160165	30305100	In line with our hypothesis, in both cell types, GEF-H1 depletion significantly elevated the TNT-1 formation in control cells, comparable to the level of TNT-1 number in the cells depleted for RASSF1A (Fig.	('TNT', 'Chemical', '-', (154, 157))	('RASSF1A', 'Gene', '11186', (193, 200))	('GEF-H1', 'Gene', '9181', (49, 55))	('TNT-1 formation', 'MPA', (93, 108))	('elevated', 'PosReg', (80, 88))	('GEF', 'molecular_function', 'GO:0005085', ('49', '52'))	('GEF-H1', 'Gene', (49, 55))	('TNT', 'Chemical', '-', (93, 96))	('depletion', 'Var', (56, 65))	('RASSF1A', 'Gene', (193, 200))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))
160167	30305100	Furthermore, it is known in the literature that loss of GEF-H1 induces the accumulation of Rab11, a small GTPase regulating exocytosis at the plasma membrane.	('Rab11', 'Gene', (91, 96))	('loss', 'Var', (48, 52))	('GEF-H1', 'Gene', '9181', (56, 62))	('GEF', 'molecular_function', 'GO:0005085', ('56', '59'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('142', '157'))	('rat', 'Species', '10116', (36, 39))	('GEF-H1', 'Gene', (56, 62))	('Rab11', 'Gene', '8766', (91, 96))	('exocytosis', 'biological_process', 'GO:0006887', ('124', '134'))	('accumulation', 'PosReg', (75, 87))
160172	30305100	Hence, by using both Rab11a and Rab11b RNAi in HBEC-3 and H2452 cell lines (Additional file 1: Figure S2H-J), we observed that loss of Rab11a or Rab11b induced a clear and significant reduction in the number of TNT-1 in RASSF1A-knockdown cells, compared with cells treated with siRASSF1A alone (Fig.	('HBEC-3', 'CellLine', 'CVCL:X491', (47, 53))	('RASSF1A', 'Gene', (220, 227))	('Rab11a', 'Gene', '8766', (135, 141))	('RNAi', 'biological_process', 'GO:0016246', ('39', '43'))	('RASSF1A', 'Gene', '11186', (280, 287))	('Rab11b', 'Gene', (32, 38))	('RASSF1A', 'Gene', (280, 287))	('Rab11a', 'Gene', (135, 141))	('TNT', 'Chemical', '-', (211, 214))	('reduction', 'NegReg', (184, 193))	('Rab11a', 'Gene', '8766', (21, 27))	('Rab11b', 'Gene', '9230', (145, 151))	('Rab11b', 'Gene', (145, 151))	('H2452', 'CellLine', 'CVCL:1553', (58, 63))	('RASSF1A', 'Gene', '11186', (220, 227))	('Rab11a', 'Gene', (21, 27))	('Rab11b', 'Gene', '9230', (32, 38))	('loss', 'Var', (127, 131))	('TNT-1', 'Gene', (211, 216))
160174	30305100	Consistent with above data, confocal and time-lapse imaging showed that loss of GEF-H1 in HBEC-3 cell line, led to an increased number of double positive cells, indicative of effective organelle transfer (Fig.	('GEF-H1', 'Gene', '9181', (80, 86))	('GEF', 'molecular_function', 'GO:0005085', ('80', '83'))	('GEF-H1', 'Gene', (80, 86))	('HBEC-3', 'CellLine', 'CVCL:X491', (90, 96))	('double positive', 'MPA', (138, 153))	('loss', 'Var', (72, 76))	('organelle', 'cellular_component', 'GO:0043226', ('185', '194'))
160178	30305100	We previously showed that the loss of expression of the tumor suppressor gene RASSF1A was a factor of poor prognosis in patient with non-small cell lung cancer since the inactivation of RASSF1A, by altering both the Hippo and Rho signaling pathways, led to the acquisition of a metastatic phenotype by the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (306, 311))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor suppressor', 'Gene', (56, 72))	('RASSF1A', 'Gene', '11186', (186, 193))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (133, 159))	('patient', 'Species', '9606', (120, 127))	('inactivation', 'Var', (170, 182))	('acquisition', 'PosReg', (261, 272))	('RASSF1A', 'Gene', (186, 193))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('metastatic', 'CPA', (278, 288))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor suppressor', 'Gene', '7248', (56, 72))	('tumor', 'Disease', (56, 61))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (133, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('RASSF1A', 'Gene', '11186', (78, 85))	('led to', 'Reg', (250, 256))	('altering', 'Reg', (198, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('non-small cell lung cancer', 'Disease', (133, 159))	('RASSF1A', 'Gene', (78, 85))	('Rho signaling pathways', 'Pathway', (226, 248))
160179	30305100	Here, we hypothesized that the RASSF1A knockdown could also affect intercellular communication via tunneling nanotubes (TNTs), since TNT-1 contains actin and microtubules, two elements of the cytoskeleton influenced by RASSF1A cell content.	('RASSF1A', 'Gene', (219, 226))	('TNT', 'Chemical', '-', (133, 136))	('TNT', 'Chemical', '-', (120, 123))	('knockdown', 'Var', (39, 48))	('RASSF1A', 'Gene', (31, 38))	('RASSF1A', 'Gene', '11186', (219, 226))	('RASSF1A', 'Gene', '11186', (31, 38))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('192', '204'))	('TNTs', 'Chemical', '-', (120, 124))	('affect', 'Reg', (60, 66))	('tunneling nanotubes', 'CPA', (99, 118))	('intercellular communication', 'CPA', (67, 94))
160186	30305100	Only H1975 cell line, despite a normal expression of RASSF1A, exhibited numerous numbers of TNTs formation which could be explained by the activating mutation of PI3K on these cells, since PI3K was previously implicated in TNTs induction.	('activating', 'PosReg', (139, 149))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('PI3K', 'molecular_function', 'GO:0016303', ('189', '193'))	('mutation', 'Var', (150, 158))	('TNTs', 'Chemical', '-', (92, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('H1975', 'CellLine', 'CVCL:1511', (5, 10))	('RASSF1A', 'Gene', (53, 60))	('PI3K', 'Gene', (162, 166))	('TNTs', 'Chemical', '-', (223, 227))	('RASSF1A', 'Gene', '11186', (53, 60))	('TNTs formation', 'CPA', (92, 106))
160188	30305100	Indeed, while microtubule and actin are the main building blocks of TNTs genesis and stabilization, we provide evidence that TNT-1 induced by RASSF1A silencing in bronchial epithelial or mesothelial cells did not depend on microtubules since TNT-1 were insusceptible to either pharmacologic stabilization of microtubules by paclitaxel or further depolymerization by nocodazole (Fig.	('TNT', 'Chemical', '-', (68, 71))	('paclitaxel', 'Chemical', 'MESH:D017239', (324, 334))	('nocodazole', 'Chemical', 'MESH:D015739', (366, 376))	('RASSF1A', 'Gene', (142, 149))	('TNTs', 'Chemical', '-', (68, 72))	('silencing', 'Var', (150, 159))	('TNT-1', 'Gene', (125, 130))	('TNT', 'Chemical', '-', (242, 245))	('TNT', 'Chemical', '-', (125, 128))	('microtubule', 'cellular_component', 'GO:0005874', ('14', '25'))	('RASSF1A', 'Gene', '11186', (142, 149))
160191	30305100	RASSF1A depletion enhanced synergistically the effects of blebbistatin to drive extension of TNTs protrusions (Fig.	('effects', 'MPA', (47, 54))	('RASSF1A', 'Gene', (0, 7))	('depletion', 'Var', (8, 17))	('blebbistatin', 'Chemical', 'MESH:C472645', (58, 70))	('TNTs', 'Chemical', '-', (93, 97))	('enhanced', 'PosReg', (18, 26))	('RASSF1A', 'Gene', '11186', (0, 7))
160193	30305100	A potential explanation for these results might come from our previous data where RASSF1A depletion was found to influence actin structure through modulating both Rho GTPase and LIMK/Cofilin signaling pathways, proteins largely linked to modulation of actomyosin assembly.	('myosin', 'Gene', (256, 262))	('modulating', 'Reg', (147, 157))	('actin structure', 'MPA', (123, 138))	('Rho GTPase', 'Pathway', (163, 173))	('Cofilin', 'Gene', (183, 190))	('RASSF1A', 'Gene', '11186', (82, 89))	('myosin', 'Gene', '79784', (256, 262))	('Cofilin', 'Gene', '1072', (183, 190))	('LIMK', 'Gene', (178, 182))	('influence', 'Reg', (113, 122))	('actomyosin', 'cellular_component', 'GO:0042641', ('252', '262'))	('LIMK', 'Gene', '3984', (178, 182))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('depletion', 'Var', (90, 99))	('RASSF1A', 'Gene', (82, 89))
160198	30305100	The TNTs induced by the loss of RASSF1A in bronchial epithelial or mesothelial cells are functional and allow the exchange of organelles and in particular of mitochondrial, lysosome or endoplasmic reticulum between cells (Fig.	('loss', 'Var', (24, 28))	('RASSF1A', 'Gene', '11186', (32, 39))	('exchange of organelles', 'MPA', (114, 136))	('RASSF1A', 'Gene', (32, 39))	('allow', 'Reg', (104, 109))	('lysosome', 'cellular_component', 'GO:0005764', ('173', '181'))	('TNTs', 'Chemical', '-', (4, 8))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('185', '206'))
160199	30305100	As RASSF1A methylation occurs at the early stage of numerous human cancers and its inactivation is associated with more aggressive tumor phenotype, increase of TNT-1 formation in the absence of RASSF1A, could act by stimulating metabolic adaptation of cancer cells at the early stage, and could further participate to the emergence of resistance during drug treatment.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('metabolic adaptation', 'CPA', (228, 248))	('inactivation', 'NegReg', (83, 95))	('RASSF1A', 'Gene', '11186', (3, 10))	('formation', 'biological_process', 'GO:0009058', ('166', '175'))	('participate', 'Reg', (303, 314))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RASSF1A', 'Gene', (3, 10))	('increase', 'PosReg', (148, 156))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('RASSF1A', 'Gene', '11186', (194, 201))	('RASSF1A', 'Gene', (194, 201))	('aggressive tumor', 'Disease', 'MESH:D001523', (120, 136))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('cancer', 'Disease', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('methylation', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('human', 'Species', '9606', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (67, 73))	('cancers', 'Disease', (67, 74))	('aggressive tumor', 'Disease', (120, 136))	('stimulating', 'PosReg', (216, 227))	('TNT-1 formation', 'MPA', (160, 175))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TNT', 'Chemical', '-', (160, 163))	('absence', 'NegReg', (183, 190))
160207	30305100	Considering this result and in line with previous reports, we postulated that the increase of secretion or uptake of exosomes after RASSF1A knockdown could also be introduced as potential chemotactic stimuli acting as paracrine effectors to induce TNT formation.	('secretion', 'biological_process', 'GO:0046903', ('94', '103'))	('uptake of exosomes', 'MPA', (107, 125))	('formation', 'biological_process', 'GO:0009058', ('252', '261'))	('uptake', 'biological_process', 'GO:0098657', ('107', '113'))	('RASSF1A', 'Gene', (132, 139))	('TNT', 'Chemical', '-', (248, 251))	('increase', 'PosReg', (82, 90))	('secretion', 'MPA', (94, 103))	('knockdown', 'Var', (140, 149))	('RASSF1A', 'Gene', '11186', (132, 139))	('uptake', 'biological_process', 'GO:0098739', ('107', '113'))
160213	30305100	Our group has previously demonstrated that RASSF1A knockdown can induce EMT and increase of invasiveness, at least in part, through GEF-H1 inactivation.	('rat', 'Species', '10116', (32, 35))	('GEF-H1', 'Gene', '9181', (132, 138))	('RASSF1A', 'Gene', '11186', (43, 50))	('knockdown', 'Var', (51, 60))	('increase', 'PosReg', (80, 88))	('GEF', 'molecular_function', 'GO:0005085', ('132', '135'))	('EMT', 'CPA', (72, 75))	('EMT', 'biological_process', 'GO:0001837', ('72', '75'))	('induce', 'PosReg', (65, 71))	('GEF-H1', 'Gene', (132, 138))	('invasiveness', 'CPA', (92, 104))	('inactivation', 'NegReg', (139, 151))	('RASSF1A', 'Gene', (43, 50))
160215	30305100	Using confocal and time-lapse imaging, we reported that GEF-H1 depletion actually increased both TNTs formation and intercellular transfer between the cells (Fig.	('TNTs formation', 'MPA', (97, 111))	('intercellular transfer between', 'CPA', (116, 146))	('GEF-H1', 'Gene', '9181', (56, 62))	('TNTs', 'Chemical', '-', (97, 101))	('GEF', 'molecular_function', 'GO:0005085', ('56', '59'))	('GEF-H1', 'Gene', (56, 62))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('depletion', 'Var', (63, 72))	('increased', 'PosReg', (82, 91))
160217	30305100	While previously described in Hela cells, we confirmed here in bronchial epithelial or pleural mesothelial cells that GEF-H1 depletion did induce Rab11 accumulation (Additional file 1: Figure S3).	('Rab11', 'Gene', '8766', (146, 151))	('GEF-H1', 'Gene', '9181', (118, 124))	('pleural', 'Disease', 'MESH:D010995', (87, 94))	('GEF-H1', 'Gene', (118, 124))	('induce', 'Reg', (139, 145))	('pleural', 'Disease', (87, 94))	('Rab11', 'Gene', (146, 151))	('depletion', 'Var', (125, 134))	('Hela cells', 'CellLine', 'CVCL:0030', (30, 40))	('GEF', 'molecular_function', 'GO:0005085', ('118', '121'))
160218	30305100	However, from our results, we suggest that GEF-H1 depletion increase exosome secretion, whereas, Pathak et al., indicate a negative role for GEH-H1 depletion in regulation of exocytosis.	('exosome', 'cellular_component', 'GO:0070062', ('69', '76'))	('exosome secretion', 'MPA', (69, 86))	('regulation of exocytosis', 'biological_process', 'GO:0017157', ('161', '185'))	('GEF-H1', 'Gene', '9181', (43, 49))	('increase', 'PosReg', (60, 68))	('GEF', 'molecular_function', 'GO:0005085', ('43', '46'))	('GEF-H1', 'Gene', (43, 49))	('GEH', 'molecular_function', 'GO:0004806', ('141', '144'))	('secretion', 'biological_process', 'GO:0046903', ('77', '86'))	('depletion', 'Var', (50, 59))
160223	30305100	On the other hands, Rab11 knockdown in RASSF1A-depleted cells, actually decreased the induction of TNTs and subsequent organelle transfer.	('TNTs', 'MPA', (99, 103))	('organelle', 'cellular_component', 'GO:0043226', ('119', '128'))	('RASSF1A', 'Gene', '11186', (39, 46))	('Rab11', 'Gene', (20, 25))	('decreased', 'NegReg', (72, 81))	('knockdown', 'Var', (26, 35))	('induction', 'MPA', (86, 95))	('TNTs', 'Chemical', '-', (99, 103))	('RASSF1A', 'Gene', (39, 46))	('Rab11', 'Gene', '8766', (20, 25))
160225	30305100	Thus, decrease of GEF-H1 activity, in addition to Rab11 accumulation after RASSF1A knockdown, induces the increase of TNTs formation, possibly by altering exocytosis.	('TNTs formation', 'MPA', (118, 132))	('Rab11', 'Gene', (50, 55))	('exocytosis', 'MPA', (155, 165))	('RASSF1A', 'Gene', '11186', (75, 82))	('GEF-H1', 'Gene', '9181', (18, 24))	('TNTs', 'Chemical', '-', (118, 122))	('GEF-H1', 'Gene', (18, 24))	('decrease', 'NegReg', (6, 14))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))	('GEF', 'molecular_function', 'GO:0005085', ('18', '21'))	('altering', 'Reg', (146, 154))	('accumulation', 'PosReg', (56, 68))	('RASSF1A', 'Gene', (75, 82))	('Rab11', 'Gene', '8766', (50, 55))	('increase', 'PosReg', (106, 114))	('exocytosis', 'biological_process', 'GO:0006887', ('155', '165'))	('knockdown', 'Var', (83, 92))	('activity', 'MPA', (25, 33))
160226	30305100	In agreement with the role of exocytosis in TNTs formation reported here and by others, it is interesting to note that accumulation of Rab11 induced by GEF-H1 depletion was previously shown to regulates exocytosis at the plasma membrane.	('regulates', 'Reg', (193, 202))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('exocytosis', 'biological_process', 'GO:0006887', ('30', '40'))	('TNTs', 'Chemical', '-', (44, 48))	('Rab11', 'Gene', '8766', (135, 140))	('GEF-H1', 'Gene', '9181', (152, 158))	('GEF', 'molecular_function', 'GO:0005085', ('152', '155'))	('GEF-H1', 'Gene', (152, 158))	('Rab11', 'Gene', (135, 140))	('plasma membrane', 'cellular_component', 'GO:0005886', ('221', '236'))	('exocytosis', 'biological_process', 'GO:0006887', ('203', '213'))	('accumulation', 'PosReg', (119, 131))	('exocytosis at the plasma membrane', 'MPA', (203, 236))	('depletion', 'Var', (159, 168))
160227	30305100	Taken together, we provide evidence here that RASSF1A depletion increased the number and length of functional TNTs.	('depletion', 'Var', (54, 63))	('RASSF1A', 'Gene', '11186', (46, 53))	('increased', 'PosReg', (64, 73))	('RASSF1A', 'Gene', (46, 53))	('TNTs', 'Chemical', '-', (110, 114))
160228	30305100	It occurred mechanistically because of i) increase of vimentin expression upon the induction of EMT ii) loss of actomyosin network through modulating both Rho GTPase and LIMK/Cofilin signaling pathways and iii) control of exosome release possibly by inducing GEF-H1 inactivation and RAB11 upregulation (Fig.	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('inducing', 'Reg', (250, 258))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('inactivation', 'Var', (266, 278))	('exosome', 'cellular_component', 'GO:0070062', ('222', '229'))	('EMT', 'Gene', (96, 99))	('vimentin', 'cellular_component', 'GO:0045098', ('54', '62'))	('GEF', 'molecular_function', 'GO:0005085', ('259', '262'))	('exosome release', 'MPA', (222, 237))	('LIMK', 'Gene', '3984', (170, 174))	('Cofilin', 'Gene', '1072', (175, 182))	('loss', 'NegReg', (104, 108))	('actomyosin', 'cellular_component', 'GO:0042641', ('112', '122'))	('myosin', 'Gene', '79784', (116, 122))	('vimentin', 'Gene', '7431', (54, 62))	('GEF-H1', 'Gene', '9181', (259, 265))	('expression', 'MPA', (63, 73))	('LIMK', 'Gene', (170, 174))	('RAB11', 'Gene', (283, 288))	('vimentin', 'Gene', (54, 62))	('vimentin', 'cellular_component', 'GO:0045099', ('54', '62'))	('increase', 'PosReg', (42, 50))	('upregulation', 'PosReg', (289, 301))	('RAB11', 'Gene', '8766', (283, 288))	('GEF-H1', 'Gene', (259, 265))	('modulating', 'Reg', (139, 149))	('Cofilin', 'Gene', (175, 182))	('myosin', 'Gene', (116, 122))
160230	30305100	Thus, we postulate that RASSF1A methylation within the complex and heterogeneous tumor microenvironment would allow the cancer cells to transmit cytoplasmic components (proteins and genetic material) over a long-range distance through TNTs to neighbor cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('methylation', 'Var', (32, 43))	('TNTs', 'Chemical', '-', (235, 239))	('cancer', 'Disease', (120, 126))	('RASSF1A', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('RASSF1A', 'Gene', '11186', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('allow', 'Reg', (110, 115))	('tumor', 'Disease', (81, 86))	('transmit', 'MPA', (136, 144))
160301	24918816	As a consequence, clinical uncertainty often results in suboptimal or excessively toxic treatments, which ultimately may lead to poorer outcomes as compared with younger patients.	('suboptimal', 'Var', (56, 66))	('results in', 'Reg', (45, 55))	('patients', 'Species', '9606', (170, 178))
160399	21383961	The PKC-beta isoform is a key component in the VEGF/VEGFR signaling cascade, and inhibiting PKC-beta results in reduced tumor vascularization that ultimately leads to tumor regression.	('PKC', 'molecular_function', 'GO:0004697', ('92', '95'))	('PKC-beta', 'Gene', (92, 100))	('leads to', 'Reg', (158, 166))	('PKC-beta', 'Gene', '5579', (92, 100))	('PKC-beta', 'Gene', (4, 12))	('VEGFR', 'Gene', '3791', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PKC-beta', 'Gene', '5579', (4, 12))	('PKC', 'molecular_function', 'GO:0004697', ('4', '7'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('reduced', 'NegReg', (112, 119))	('signaling cascade', 'biological_process', 'GO:0007165', ('58', '75'))	('inhibiting', 'Var', (81, 91))	('VEGFR', 'Gene', (52, 57))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (120, 125))
160400	21383961	Furthermore, inhibition of angiogenesis has been shown to confer a survival benefit in a phase III trial in non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('non-small cell lung cancer', 'Disease', (108, 134))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('13', '39'))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('inhibition', 'Var', (13, 23))	('survival benefit', 'CPA', (67, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('angiogenesis', 'CPA', (27, 39))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (108, 134))	('NSCLC', 'Disease', (136, 141))	('SCLC', 'Phenotype', 'HP:0030357', (137, 141))
160403	21383961	Enzastaurin (LY317615) is a non-cyclic bisindolylmaleimide that competitively inhibits the ATP binding site of PKC-beta, resulting in the inhibition of its kinase activity.	('inhibition', 'NegReg', (138, 148))	('PKC', 'molecular_function', 'GO:0004697', ('111', '114'))	('LY317615', 'Chemical', 'MESH:C504878', (13, 21))	('ATP binding site', 'Interaction', (91, 107))	('kinase activity', 'MPA', (156, 171))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('LY317615', 'Var', (13, 21))	('cyclic bisindolylmaleimide', 'Chemical', '-', (32, 58))	('kinase activity', 'molecular_function', 'GO:0016301', ('156', '171'))	('PKC-beta', 'Gene', (111, 119))	('inhibits', 'NegReg', (78, 86))	('PKC-beta', 'Gene', '5579', (111, 119))	('ATP', 'Chemical', 'MESH:D000255', (91, 94))	('ATP binding', 'molecular_function', 'GO:0005524', ('91', '102'))
160410	21383961	We have previously shown that human lung cancer specific c-Met mutant transgenic C. elegans (transgenic animals) suffered from an abnormal vulval development, vulval hyperplasia and lower fecundity that are exaggerated upon addition of nicotine to the culture medium.	('lung cancer', 'Disease', (36, 47))	('human', 'Species', '9606', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('vulval hyperplasia', 'Disease', (159, 177))	('mutant', 'Var', (63, 69))	('lower', 'NegReg', (182, 187))	('vulval', 'MPA', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('fecundity', 'CPA', (188, 197))	('nicotine', 'Chemical', 'MESH:D009538', (236, 244))	('vulval hyperplasia', 'Disease', 'MESH:D006965', (159, 177))	('c-Met', 'Gene', (57, 62))	('c-Met', 'Gene', '4233', (57, 62))	('C. elegans', 'Species', '6239', (81, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('vulval development', 'biological_process', 'GO:0040025', ('139', '157'))
160429	21383961	H2452 (SAR), H2691 (EPI), H2461 (EPI), H513 (EPI), H2596 (SAR), H2373 (SAR), H28 (SAR), MSTO-211H (biphasic), H2052 (SAR), non-malignant mesothelial cells (Met5A) and human umbilical vein endothelial cells (HUVEC) were obtained as previously described and cultured as described.	('H513', 'Var', (39, 43))	('H2373', 'Var', (64, 69))	('H2373', 'CellLine', 'CVCL:A533', (64, 69))	('H2691', 'CellLine', 'CVCL:A551', (13, 18))	('H2596', 'CellLine', 'CVCL:A546', (51, 56))	('H2596', 'Var', (51, 56))	('H2052', 'Chemical', '-', (110, 115))	('human', 'Species', '9606', (167, 172))	('H2461', 'Var', (26, 31))	('H2691', 'Var', (13, 18))
160444	21383961	H2452 (SAR), H2691 (EPI), H2461 (EPI), H513 (EPI), H2596 (SAR), H2373 (SAR), H28 (SAR), MSTO-211H (biphasic), H2052 (SAR) and non-malignant mesothelial cells (Met5A) expressed similar amounts of PKC-beta1 and PKC-beta2.	('H513', 'Var', (39, 43))	('H2373', 'Var', (64, 69))	('H2452', 'Var', (0, 5))	('H2373', 'CellLine', 'CVCL:A533', (64, 69))	('PKC-beta', 'Gene', '5579', (209, 217))	('PKC-beta', 'Gene', (195, 203))	('PKC-beta', 'Gene', (209, 217))	('PKC-beta', 'Gene', '5579', (195, 203))	('H2691', 'CellLine', 'CVCL:A551', (13, 18))	('PKC', 'molecular_function', 'GO:0004697', ('195', '198'))	('PKC', 'molecular_function', 'GO:0004697', ('209', '212'))	('H2596', 'Var', (51, 56))	('H2052', 'Chemical', '-', (110, 115))	('H2596', 'CellLine', 'CVCL:A546', (51, 56))	('H2461', 'Var', (26, 31))	('H2691', 'Var', (13, 18))
160458	21383961	The Met5A control cells showed a robust cell survival at a wide range of enzastaurin concentrations (data not shown), as compared with H2052, MSTO, H513, H2373, H2452, H2691, and H2461 malignant mesothelioma cell lines.	('enzastaurin', 'Chemical', 'MESH:C504878', (73, 84))	('H2373', 'CellLine', 'CVCL:A533', (154, 159))	('H2052', 'Var', (135, 140))	('H2461 malignant mesothelioma', 'Disease', 'MESH:C562839', (179, 207))	('H2691', 'CellLine', 'CVCL:A551', (168, 173))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (185, 207))	('H2052', 'Chemical', '-', (135, 140))	('H2461 malignant mesothelioma', 'Disease', (179, 207))	('cell survival', 'CPA', (40, 53))
160459	21383961	Of the cell lines examined, H2461 showed the highest sensitivity to enzastaurin, whereas H2052 was relatively less sensitive.	('sensitivity to enzastaurin', 'MPA', (53, 79))	('enzastaurin', 'Chemical', 'MESH:C504878', (68, 79))	('H2052', 'Chemical', '-', (89, 94))	('H2461', 'Var', (28, 33))
160464	21383961	However, the cell viability in the various mesothelioma cell lines when treated with enzastaurin and/or KRN633 was significantly lower compared to the controls [Figure 2b].	('mesothelioma', 'Disease', (43, 55))	('cell viability', 'CPA', (13, 27))	('KRN633', 'Chemical', 'MESH:C508488', (104, 110))	('KRN633', 'Var', (104, 110))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('enzastaurin', 'Chemical', 'MESH:C504878', (85, 96))	('lower', 'NegReg', (129, 134))
160468	21383961	Our results showed that in mesothelioma H2461 cell line, there was significant phosphorylation of VEGFR-2 (Y951), PKC-beta2 (T642) and AKT (S473) in response to VEGF.	('T642', 'Var', (125, 129))	('VEGFR-2', 'Gene', (98, 105))	('AKT', 'Gene', '207', (135, 138))	('Y951', 'Var', (107, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('mesothelioma H2461', 'Disease', 'MESH:D008654', (27, 45))	('AKT', 'Gene', (135, 138))	('phosphorylation', 'MPA', (79, 94))	('PKC', 'molecular_function', 'GO:0004697', ('114', '117'))	('PKC-beta', 'Gene', '5579', (114, 122))	('PKC-beta', 'Gene', (114, 122))	('VEGFR-2', 'Gene', '3791', (98, 105))	('mesothelioma H2461', 'Disease', (27, 45))	('S473', 'Var', (140, 144))
160469	21383961	Treatment with KRN633 or enzastaurin alone demonstrated considerable inhibition of the phosphorylation of above three proteins, and in addition, the combination of the two drugs resulted in additive inhibition in H2461 but not in Met5A cells.	('H2461', 'Var', (213, 218))	('KRN633', 'Chemical', 'MESH:C508488', (15, 21))	('phosphorylation', 'MPA', (87, 102))	('combination', 'Interaction', (149, 160))	('enzastaurin', 'Chemical', 'MESH:C504878', (25, 36))	('inhibition', 'NegReg', (69, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
160475	21383961	In order to develop novel therapeutics, we investigated the role of PKC pathway that is triggered by ligation of VEGFR-2.	('VEGFR-2', 'Gene', (113, 120))	('PKC pathway', 'Pathway', (68, 79))	('ligation', 'Var', (101, 109))	('VEGFR-2', 'Gene', '3791', (113, 120))	('triggered', 'Reg', (88, 97))	('PKC', 'molecular_function', 'GO:0004697', ('68', '71'))
160476	21383961	We show here that the RTK VEGFR-2, its natural ligand VEGF, the downstream targets PKC-beta1 and -beta2, as well as AKT were overexpressed and/or highly active in MPM.	('PKC', 'molecular_function', 'GO:0004697', ('83', '86'))	('RTK', 'Var', (22, 25))	('overexpressed', 'PosReg', (125, 138))	('active', 'MPA', (153, 159))	('VEGFR-2', 'Gene', '3791', (26, 33))	('PKC-beta', 'Gene', (83, 91))	('AKT', 'Gene', '207', (116, 119))	('PKC-beta', 'Gene', '5579', (83, 91))	('ligand', 'molecular_function', 'GO:0005488', ('47', '53'))	('MPM', 'Disease', (163, 166))	('AKT', 'Gene', (116, 119))	('VEGFR-2', 'Gene', (26, 33))
160483	21383961	Based on the mutational and amplification analysis of PKC-beta2 gene in MPM (9 cell lines and 33 tumor tissues), there was no amplification seen of PKC-beta2; however, in two different tumor tissues, there were synonymous single nucleotide variants (SNVs), 119/T7TC: Pro and 1770C7CT: Gly.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PKC-beta', 'Gene', '5579', (54, 62))	('Pro', 'Chemical', 'MESH:D011392', (267, 270))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('1770C7CT: Gly', 'Var', (275, 288))	('PKC', 'molecular_function', 'GO:0004697', ('54', '57'))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Gly', 'Chemical', 'MESH:D005998', (285, 288))	('PKC-beta', 'Gene', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PKC', 'molecular_function', 'GO:0004697', ('148', '151'))	('PKC-beta', 'Gene', '5579', (148, 156))	('PKC-beta', 'Gene', (54, 62))	('T7TC', 'Mutation', 'c.7T>TC', (261, 265))
160492	21383961	Assuming that both drugs are equally efficacious in targeting their respective kinases, the underlying mechanism behind enzastaurin efficacy could be that PKC is downstream of several RTKs including VEGFR, and therefore, inhibition of PKC could in turn inhibit multiple growth factor signaling pathways that contribute to growth and survival of MPM cells.	('inhibition', 'Var', (221, 231))	('VEGFR', 'Gene', '3791', (199, 204))	('inhibit', 'NegReg', (253, 260))	('growth factor signaling pathways', 'Pathway', (270, 302))	('signaling', 'biological_process', 'GO:0023052', ('284', '293'))	('VEGFR', 'Gene', (199, 204))	('enzastaurin', 'Chemical', 'MESH:C504878', (120, 131))	('PKC', 'molecular_function', 'GO:0004697', ('235', '238'))	('growth', 'CPA', (322, 328))	('PKC', 'molecular_function', 'GO:0004697', ('155', '158'))	('PKC', 'Enzyme', (235, 238))
160631	17450227	Quartz is known to cause silicosis (another pneumoconiosis), although only one worker in this cohort died from silicosis.	('cause', 'Reg', (19, 24))	('silicosis', 'Disease', 'MESH:D012829', (25, 34))	('silicosis', 'Disease', (111, 120))	('silicosis', 'Disease', (25, 34))	('silicosis', 'Disease', 'MESH:D012829', (111, 120))	('pneumoconiosis', 'Disease', 'MESH:D011009', (44, 58))	('pneumoconiosis', 'Disease', (44, 58))	('Quartz', 'Var', (0, 6))
160656	30317900	We hypothesized that p53+/- mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs.	('p53+/-', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mice', 'Species', '10090', (28, 32))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('lung tumor', 'Disease', (57, 67))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))	('susceptible', 'Reg', (42, 53))
160659	30317900	In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/- and p53+/+ mice.	('hyperplasia', 'Disease', 'MESH:D006965', (150, 161))	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('mice', 'Species', '10090', (212, 216))	('granuloma', 'Phenotype', 'HP:0032252', (70, 79))	('p53+/+', 'Var', (205, 211))	('granulomas', 'Phenotype', 'HP:0032252', (70, 80))	('granulomas', 'Disease', (70, 80))	('p53+/-', 'Var', (194, 200))	('hyperplasia', 'Disease', (150, 161))	('granulomas', 'Disease', 'MESH:D006099', (70, 80))	('greater', 'PosReg', (84, 91))
160660	30317900	A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/- mice compared to p53+/+ mice.	('p53+/-', 'Var', (76, 82))	('CD3', 'Gene', '28134', (39, 42))	('mice', 'Species', '10090', (83, 87))	('mice', 'Species', '10090', (107, 111))	('larger', 'PosReg', (17, 23))	('CD45R', 'Gene', (32, 37))	('CD3', 'Gene', (39, 42))	('CD45R', 'Gene', '19264', (32, 37))
160661	30317900	Importantly, p53+/- mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice.	('granulomas', 'Disease', 'MESH:D006099', (36, 46))	('larger', 'PosReg', (29, 35))	('mice', 'Species', '10090', (20, 24))	('granuloma', 'Phenotype', 'HP:0032252', (36, 45))	('mice', 'Species', '10090', (88, 92))	('granulomas', 'Phenotype', 'HP:0032252', (36, 46))	('p53+/-', 'Var', (13, 19))	('granulomas', 'Disease', (36, 46))
160687	30317900	Genetic alterations also play a part in the development of pulmonary diseases like lung cancer, mesothelioma and fibrosis.	('fibrosis', 'Disease', (113, 121))	('Genetic alterations', 'Var', (0, 19))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('rat', 'Species', '10116', (12, 15))	('mesothelioma', 'Disease', (96, 108))	('pulmonary diseases', 'Disease', (59, 77))	('pulmonary diseases', 'Disease', 'MESH:D008171', (59, 77))	('lung cancer', 'Disease', (83, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('play', 'Reg', (25, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('fibrosis', 'Disease', 'MESH:D005355', (113, 121))
160690	30317900	Mutation of either p53 allele can lead to loss of both function and proliferation control, potentially resulting in fibrosis or cancer.	('fibrosis', 'Disease', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('fibrosis', 'Disease', 'MESH:D005355', (116, 124))	('cancer', 'Disease', (128, 134))	('rat', 'Species', '10116', (75, 78))	('Mutation', 'Var', (0, 8))	('resulting in', 'Reg', (103, 115))	('proliferation control', 'CPA', (68, 89))	('function', 'MPA', (55, 63))	('p53', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('loss', 'NegReg', (42, 46))
160691	30317900	Some disease states are associated with alteration of p53; for example, samples taken from patients with idiopathic pulmonary fibrosis (IPF) have high p53 mutation incidences.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (116, 134))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (105, 134))	('patients', 'Species', '9606', (91, 99))	('IPF', 'Disease', 'MESH:D054990', (136, 139))	('rat', 'Species', '10116', (44, 47))	('idiopathic pulmonary fibrosis', 'Disease', (105, 134))	('IPF', 'Disease', (136, 139))	('mutation', 'Var', (155, 163))	('p53', 'Gene', (151, 154))
160692	30317900	Furthermore, the majority of IPF patients with overexpression of p53 have been found to have multiple point mutations in the p53 gene.	('patients', 'Species', '9606', (33, 41))	('point mutations', 'Var', (102, 117))	('overexpression', 'PosReg', (47, 61))	('p53', 'Gene', (125, 128))	('IPF', 'Disease', (29, 32))	('IPF', 'Disease', 'MESH:D054990', (29, 32))
160694	30317900	Knock-down or knock-out of p53 can increase tumor incidence and burden associated with decreased life span of the genetically modified mice.	('life span', 'CPA', (97, 106))	('increase', 'PosReg', (35, 43))	('decreased', 'NegReg', (87, 96))	('burden', 'CPA', (64, 70))	('Knock-down', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mice', 'Species', '10090', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('knock-out', 'Var', (14, 23))	('tumor', 'Disease', (44, 49))	('p53', 'Gene', (27, 30))
160697	30317900	Therefore, p53 is a crucial regulator of cellular homeostasis, and alterations of p53 may result in the promotion of disease states in the lung.	('promotion', 'PosReg', (104, 113))	('rat', 'Species', '10116', (71, 74))	('disease states', 'Disease', (117, 131))	('alterations', 'Var', (67, 78))	('result', 'Reg', (90, 96))	('p53', 'Gene', (82, 85))	('cellular homeostasis', 'biological_process', 'GO:0019725', ('41', '61'))
160702	30317900	While mesothelioma was not observed in p53+/- mice exposed to either tMWCNTs or rMWCNTs, we discovered that p53+/- mice were susceptible to MWCNT-induced granuloma formation and the formation of tertiary lymphoid tissue in lung tissue.	('granuloma', 'Disease', 'MESH:D006099', (154, 163))	('mesothelioma', 'Disease', (6, 18))	('p53+/-', 'Var', (108, 114))	('granuloma formation', 'biological_process', 'GO:0002432', ('154', '173'))	('granuloma', 'Disease', (154, 163))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('granuloma', 'Phenotype', 'HP:0032252', (154, 163))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (115, 119))	('formation', 'biological_process', 'GO:0009058', ('182', '191'))	('susceptible', 'Reg', (125, 136))
160703	30317900	Moreover, rMWNCTs caused significantly larger granulomas compared to tMWCNTs in wild type (p53+/+) mice and p53+/- mice.	('mice', 'Species', '10090', (99, 103))	('granulomas', 'Disease', 'MESH:D006099', (46, 56))	('granuloma', 'Phenotype', 'HP:0032252', (46, 55))	('larger', 'PosReg', (39, 45))	('rMWNCTs', 'Var', (10, 17))	('granulomas', 'Phenotype', 'HP:0032252', (46, 56))	('granulomas', 'Disease', (46, 56))	('mice', 'Species', '10090', (115, 119))
160713	30317900	Only two mice from the p53+/- rMWCNT group did not survive the entirety of the study, one died following the 4th and final dose and the other was euthanized due to the development of a debilitating sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (198, 205))	('debilitating sarcoma', 'Phenotype', 'HP:0030448', (185, 205))	('sarcoma', 'Disease', (198, 205))	('mice', 'Species', '10090', (9, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('p53+/-', 'Var', (23, 29))
160744	30317900	Of note, the rMWCNTs, but not the tMWCNTs, protrude from macrophages indicating frustrated phagocytosis (Fig.	('frustrated phagocytosis', 'CPA', (80, 103))	('rat', 'Species', '10116', (85, 88))	('protrude', 'Reg', (43, 51))	('rMWCNTs', 'Var', (13, 20))	('phagocytosis', 'biological_process', 'GO:0006909', ('91', '103'))
160748	30317900	Though there was a slight increase in neutrophil cell counts from the lungs of p53+/+ mice with rMWCNT exposure, this increase was not significant (data not shown).	('p53+/+', 'Var', (79, 85))	('rMWCNT', 'Var', (96, 102))	('neutrophil cell counts', 'CPA', (38, 60))	('mice', 'Species', '10090', (86, 90))	('increase', 'PosReg', (26, 34))
160750	30317900	Cytokine levels of osteopontin (OPN), TGF-beta1, and PDGF-BB in the BALF were not significantly increased by either MWCNT type or different between p53+/+ and p53+/- mice at the chronic endpoint evaluated in this study (data not shown).	('TGF-beta1', 'Gene', '21803', (38, 47))	('TGF-beta1', 'Gene', (38, 47))	('OPN', 'Gene', '20750', (32, 35))	('p53+/+', 'Var', (148, 154))	('osteopontin', 'Gene', '20750', (19, 30))	('Cytokine levels', 'MPA', (0, 15))	('PDGF', 'molecular_function', 'GO:0005161', ('53', '57'))	('mice', 'Species', '10090', (166, 170))	('osteopontin', 'Gene', (19, 30))	('OPN', 'Gene', (32, 35))	('PDGF-BB', 'Gene', (53, 60))
160752	30317900	There was a trend towards larger granuloma number and total granuloma area in t- or rMWCNT-exposed p53+/- mice compared to p53+/+ mice, although this difference was not statistically significant (Fig.	('mice', 'Species', '10090', (130, 134))	('mice', 'Species', '10090', (106, 110))	('granuloma', 'Phenotype', 'HP:0032252', (33, 42))	('larger', 'PosReg', (26, 32))	('granuloma number and total granuloma area', 'Disease', 'MESH:D006099', (33, 74))	('granuloma', 'Phenotype', 'HP:0032252', (60, 69))	('p53+/-', 'Var', (99, 105))
160757	30317900	Foci of iBALT were observed near bronchioles with adjacent granulomas in the lungs of both p53+/+ and p53+/- mice exposed to rMWCNTs but not tMWCNTs (Fig.	('granulomas', 'Phenotype', 'HP:0032252', (59, 69))	('granulomas', 'Disease', (59, 69))	('granulomas', 'Disease', 'MESH:D006099', (59, 69))	('mice', 'Species', '10090', (109, 113))	('granuloma', 'Phenotype', 'HP:0032252', (59, 68))	('rMWCNTs', 'Var', (125, 132))
160758	30317900	Of note, there were significantly more granulomas adjacent to lymphoid tissue in the rMWCNT-exposed mouse lungs compared to the tMWCNT-exposed mouse lungs, and there was no notable difference between genotypes (Fig 3D).	('mouse', 'Species', '10090', (143, 148))	('mouse', 'Species', '10090', (100, 105))	('granuloma', 'Phenotype', 'HP:0032252', (39, 48))	('more', 'PosReg', (34, 38))	('granulomas', 'Phenotype', 'HP:0032252', (39, 49))	('granulomas', 'Disease', (39, 49))	('rMWCNT-exposed', 'Var', (85, 99))	('granulomas', 'Disease', 'MESH:D006099', (39, 49))
160762	30317900	The total number of lymphoid aggregates (iBALT and ELT) in tMWCNT-exposed mice was similar to that seen in the control animals, although there was a trend for increased numbers of lymphoid aggregates in p53+/- mice compared to p53+/+ (Fig.	('mice', 'Species', '10090', (74, 78))	('increased', 'PosReg', (159, 168))	('mice', 'Species', '10090', (210, 214))	('p53+/-', 'Var', (203, 209))
160763	30317900	The percent of the lung occupied by lymphoid tissue, as measured by semi-quantitative morphometry, was significantly greater in control p53+/- mice compared to control p53+/+ mice, but was not further increased by tMWCNT or rMWCNT treatment (Fig.	('p53+/-', 'Var', (136, 142))	('mice', 'Species', '10090', (175, 179))	('mice', 'Species', '10090', (143, 147))	('greater', 'PosReg', (117, 124))
160764	30317900	Taken together, these data suggest that while rMWCNTs increased the number of lymphoid aggregates, the area of lung occupied by these lymphoid structures was greater in p53+/- mouse lungs primarily due to constitutive iBALT in the absence of MWCNT exposure (Fig 4 E-F).	('p53+/-', 'Var', (169, 175))	('greater', 'PosReg', (158, 165))	('mouse', 'Species', '10090', (176, 181))
160773	30317900	About 25% of the p53+/+ and 15% of the p53+/- granulomas resulting from rMWCNT-exposure included BrdU positive cells compared to only 5% of either p53+/+ or p53+/- tMWCNT-resulting lung granulomas (Fig.	('granulomas', 'Disease', 'MESH:D006099', (46, 56))	('lung granulomas', 'Disease', (181, 196))	('granuloma', 'Phenotype', 'HP:0032252', (186, 195))	('granuloma', 'Phenotype', 'HP:0032252', (46, 55))	('lung granulomas', 'Disease', 'MESH:D016726', (181, 196))	('granulomas', 'Phenotype', 'HP:0032252', (186, 196))	('granulomas', 'Disease', (186, 196))	('BrdU', 'Chemical', 'MESH:D001973', (97, 101))	('p53+/-', 'Var', (39, 45))	('rMWCNT-exposure', 'Var', (72, 87))	('granulomas', 'Disease', (46, 56))	('BrdU', 'CPA', (97, 101))	('granulomas', 'Disease', 'MESH:D006099', (186, 196))	('granulomas', 'Phenotype', 'HP:0032252', (46, 56))	('lung granulomas', 'Phenotype', 'HP:0030250', (181, 196))
160774	30317900	Bronchiolar epithelial hyperplastic lesions were observed in the lungs of both p53+/+ and p53+/- mice exposed to rMWCNTs, but were rarely observed in tMWCNT-exposed mouse lungs (Fig.	('mouse', 'Species', '10090', (165, 170))	('Bronchiolar epithelial hyperplastic lesions', 'Disease', 'MESH:D002282', (0, 43))	('p53+/-', 'Var', (90, 96))	('mice', 'Species', '10090', (97, 101))	('Bronchiolar epithelial hyperplastic lesions', 'Disease', (0, 43))
160776	30317900	Quantification of BrdU-positive epithelial cells along the first bronchoalveolar duct bifurcation revealed increased proliferation in rMWCNT-exposed p53+/+ and p53+/- mouse airway epithelial cells compared to control or tMWCNT treatment groups (Fig 7B).	('rat', 'Species', '10116', (124, 127))	('p53+/+', 'Var', (149, 155))	('proliferation', 'CPA', (117, 130))	('increased', 'PosReg', (107, 116))	('p53+/-', 'Var', (160, 166))	('BrdU', 'Chemical', 'MESH:D001973', (18, 22))	('rMWCNT-exposed', 'Var', (134, 148))	('mouse', 'Species', '10090', (167, 172))
160777	30317900	There were also occasional aggregates of plasma cells near airways of rMWCNT-exposed mice, which were not seen in the control or tMWCNT-exposed mouse lungs.	('mice', 'Species', '10090', (85, 89))	('mouse', 'Species', '10090', (144, 149))	('aggregates', 'CPA', (27, 37))	('rMWCNT-exposed', 'Var', (70, 84))
160788	30317900	The Sircol assay showed no difference in total collagen content from the lungs of p53+/+ versus p53+/- mice (Fig.	('collagen content', 'MPA', (47, 63))	('collagen', 'molecular_function', 'GO:0005202', ('47', '55'))	('mice', 'Species', '10090', (103, 107))	('Sircol', 'Chemical', 'None', (4, 10))	('p53+/+', 'Var', (82, 88))
160789	30317900	While p53+/- mice had significantly greater lung collagen content compared to p53+/+ mice in the rMWCNT treatment group, this was due to a reduction in total lung collagen content in p53+/+ mice exposed to rMWCNT.	('mice', 'Species', '10090', (85, 89))	('mice', 'Species', '10090', (13, 17))	('reduction', 'NegReg', (139, 148))	('p53+/+', 'Var', (183, 189))	('collagen', 'molecular_function', 'GO:0005202', ('163', '171'))	('greater', 'PosReg', (36, 43))	('lung collagen content', 'MPA', (44, 65))	('mice', 'Species', '10090', (190, 194))	('collagen', 'molecular_function', 'GO:0005202', ('49', '57'))	('lung collagen content', 'MPA', (158, 179))
160790	30317900	No evidence of pleural inflammation or mesothelioma was found in either p53+/+ or p53+/- mice after careful examination of 3 H&E-stained sections per lung (data not shown).	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('pleural inflammation', 'Disease', (15, 35))	('inflammation', 'biological_process', 'GO:0006954', ('23', '35'))	('pleural inflammation', 'Disease', 'MESH:D007249', (15, 35))	('mice', 'Species', '10090', (89, 93))	('p53+/-', 'Var', (82, 88))	('mesothelioma', 'Disease', (39, 51))	('p53+/+', 'Var', (72, 78))
160792	30317900	Because rMWCNTs have been classified as a Group 2B possible human carcinogen, we postulated that chronic exposure to these rod-like nanotubes would cause lung cancer or mesothelioma in p53+/- but not wild type p53+/+ mice.	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('lung cancer', 'Disease', (154, 165))	('p53+/-', 'Var', (185, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('mice', 'Species', '10090', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cause', 'Reg', (148, 153))	('mesothelioma', 'Disease', (169, 181))	('human', 'Species', '9606', (60, 65))
160793	30317900	No MWCNT related lung tumors or mesothelioma were observed in p53+/- mice, although rMWCNTs caused focal bronchiolar epithelial hyperplasia in p53+/- mouse lungs.	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('rMWCNTs', 'Var', (84, 91))	('lung tumor', 'Phenotype', 'HP:0100526', (17, 27))	('lung tumors', 'Phenotype', 'HP:0100526', (17, 28))	('lung tumors', 'Disease', (17, 28))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mesothelioma', 'Disease', (32, 44))	('bronchiolar epithelial hyperplasia', 'Disease', 'MESH:D002282', (105, 139))	('bronchiolar epithelial hyperplasia', 'Disease', (105, 139))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mouse', 'Species', '10090', (150, 155))	('lung tumors', 'Disease', 'MESH:D008175', (17, 28))
160796	30317900	Interestingly, we observed that rMWCNTs, but not tMWCNTs, stimulated iBALT formation in p53+/+ mice and iBALT was spontaneously generated in the lungs of p53+/- mice.	('mice', 'Species', '10090', (161, 165))	('mice', 'Species', '10090', (95, 99))	('rat', 'Species', '10116', (132, 135))	('iBALT formation', 'MPA', (69, 84))	('p53+/+', 'Var', (88, 94))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('stimulated', 'PosReg', (58, 68))
160797	30317900	Also, p53+/- mice exhibited significantly larger lung area obscured by lymphoid aggregates compared to p53+/+ mice.	('mice', 'Species', '10090', (13, 17))	('p53+/-', 'Var', (6, 12))	('mice', 'Species', '10090', (110, 114))	('lung area obscured by lymphoid aggregates', 'CPA', (49, 90))	('larger', 'PosReg', (42, 48))
160800	30317900	The observation of increased BrdU-positive cells in granulomas from p53+/+ or p53+/- mice after chronic exposure to rMWCNT is indicative of continual injury and/or immune stimulation.	('mice', 'Species', '10090', (85, 89))	('granuloma', 'Phenotype', 'HP:0032252', (52, 61))	('granulomas', 'Phenotype', 'HP:0032252', (52, 62))	('granulomas', 'Disease', (52, 62))	('granulomas', 'Disease', 'MESH:D006099', (52, 62))	('increased', 'PosReg', (19, 28))	('p53+/+', 'Var', (68, 74))	('p53+/-', 'Var', (78, 84))	('BrdU', 'Chemical', 'MESH:D001973', (29, 33))	('BrdU-positive', 'Protein', (29, 42))
160801	30317900	We observed that T cells were integrated into the granulomas induced by rMWCNTs (Fig.	('granuloma', 'Phenotype', 'HP:0032252', (50, 59))	('granulomas', 'Disease', 'MESH:D006099', (50, 60))	('rMWCNTs', 'Var', (72, 79))	('granulomas', 'Phenotype', 'HP:0032252', (50, 60))	('rat', 'Species', '10116', (35, 38))	('granulomas', 'Disease', (50, 60))
160806	30317900	The early development of this tissue is driven by IL-1alpha, and IL-1-receptor deficient mice fail to develop iBALT following exposure to either aluminum salts, silica, or viruses.	('IL-1-receptor', 'Gene', (65, 78))	('aluminum', 'Chemical', 'MESH:D000535', (145, 153))	('silica', 'Chemical', 'MESH:D012822', (161, 167))	('mice', 'Species', '10090', (89, 93))	('IL-1alpha', 'Gene', (50, 59))	('deficient', 'Var', (79, 88))	('IL-1alpha', 'Gene', '16175', (50, 59))	('IL-1', 'molecular_function', 'GO:0005149', ('65', '69'))	('IL-1', 'molecular_function', 'GO:0005149', ('50', '54'))	('iBALT', 'MPA', (110, 115))
160814	30317900	It is possible that the increased iBALT formations observed in p53+/- mice in the present study could result in an altered immune microenvironment that could favor tumor development.	('tumor', 'Disease', (164, 169))	('p53+/-', 'Var', (63, 69))	('iBALT formations', 'CPA', (34, 50))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('favor', 'PosReg', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('increased', 'PosReg', (24, 33))
160816	30317900	In our study, the observation of BrdU-positive macrophages in granulomatous formations resulting from rMWCNT- and not from tMWCNT-exposure lends itself to suggest that chronic injury by rMWCNTs could signal macrophage replenishment.	('BrdU', 'Chemical', 'MESH:D001973', (33, 37))	('granuloma', 'Disease', 'MESH:D006099', (62, 71))	('chronic injury', 'Disease', 'MESH:D020208', (168, 182))	('granuloma', 'Disease', (62, 71))	('rMWCNT-', 'Var', (102, 109))	('macrophage replenishment', 'CPA', (207, 231))	('chronic injury', 'Disease', (168, 182))	('granuloma', 'Phenotype', 'HP:0032252', (62, 71))
160819	30317900	Interestingly, alveolar macrophages from the lungs of p53+/+ or p53+/- mice exposed to tMWCNTs contained crystalline bodies, but these bodies were not observed in macrophages from mice exposed to rMWCNTs.	('mice', 'Species', '10090', (71, 75))	('p53+/-', 'Var', (64, 70))	('mice', 'Species', '10090', (180, 184))	('p53+/+', 'Var', (54, 60))
160824	30317900	A major issue that we sought to address in this study was to determine if p53+/- mice, a mouse model that is susceptible to tumor development, would develop mesothelioma after pulmonary exposure to MWCNTs.	('mesothelioma', 'Disease', (157, 169))	('mice', 'Species', '10090', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('develop', 'PosReg', (149, 156))	('tumor', 'Disease', (124, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (157, 169))	('p53+/-', 'Var', (74, 80))	('mouse', 'Species', '10090', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
160825	30317900	Previous studies of p53+/- mice injected intraperitoneally with asbestos or rMWCNTs demonstrated more rapid development of mesotheliomas resulting from MWCNT compared to asbestos.	('mesotheliomas', 'Disease', 'MESH:D008654', (123, 136))	('MWCNT', 'Var', (152, 157))	('mesotheliomas', 'Disease', (123, 136))	('rat', 'Species', '10116', (91, 94))	('mice', 'Species', '10090', (27, 31))	('asbestos or rMWCNTs', 'Disease', (64, 83))	('asbestos or rMWCNTs', 'Disease', 'MESH:D001195', (64, 83))
160826	30317900	We did not observe mesothelioma or other exposure-related neoplasms 11 months following the initial dose delivered by oropharyngeal aspiration in either wild type or p53+/- mice.	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('neoplasms', 'Disease', 'MESH:D009369', (58, 67))	('neoplasms', 'Disease', (58, 67))	('aspiration', 'Phenotype', 'HP:0002835', (132, 142))	('p53+/-', 'Var', (166, 172))	('rat', 'Species', '10116', (136, 139))	('mesothelioma', 'Disease', (19, 31))	('mice', 'Species', '10090', (173, 177))
160841	30317900	For example, rMWCNTs or crocidolite, a rigid type of asbestos, both resulted in mesothelioma when injected intraperitoneally in C57BL/6 mice or Wistar rats and progression of mesothelioma in these animals was coupled with an accumulation of monocytic cells that suppressed polyclonal activation of lymphocytes 12 months following exposure.	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('mesothelioma', 'Disease', (175, 187))	('mice', 'Species', '10090', (136, 140))	('resulted in', 'Reg', (68, 79))	('crocidolite', 'Chemical', 'MESH:D017638', (24, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('Wistar rats', 'Species', '10116', (144, 155))	('rMWCNTs', 'Var', (13, 20))	('mesothelioma', 'Disease', (80, 92))	('accumulation', 'PosReg', (225, 237))	('crocidolite', 'Var', (24, 35))	('polyclonal activation of lymphocytes', 'MPA', (273, 309))
160850	30317900	A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in the lungs of p53+/- mice compared to p53+/+ mice and these mice had larger granulomas induced by either tMWCNTs or rMWCNTs as compared to p53+/+ mice, with rMWCNTs causing the most prominent granuloma formation.	('granuloma', 'Disease', 'MESH:D006099', (151, 160))	('granulomas', 'Disease', 'MESH:D006099', (151, 161))	('granuloma', 'Disease', 'MESH:D006099', (267, 276))	('p53+/-', 'Var', (89, 95))	('granuloma', 'Disease', (151, 160))	('CD45R', 'Gene', (32, 37))	('CD45R', 'Gene', '19264', (32, 37))	('granuloma', 'Disease', (267, 276))	('mice', 'Species', '10090', (96, 100))	('granuloma formation', 'biological_process', 'GO:0002432', ('267', '286'))	('granulomas', 'Disease', (151, 161))	('CD3', 'Gene', (39, 42))	('granuloma', 'Phenotype', 'HP:0032252', (151, 160))	('mice', 'Species', '10090', (120, 124))	('granulomas', 'Phenotype', 'HP:0032252', (151, 161))	('CD3', 'Gene', '28134', (39, 42))	('granuloma', 'Phenotype', 'HP:0032252', (267, 276))	('mice', 'Species', '10090', (221, 225))	('mice', 'Species', '10090', (135, 139))
160851	30317900	While no lung or pleural tumors were observed in p53+/- mice after chronic MWCNT exposure, rMWCNTs caused greater epithelial cell hyperplasia in terminal bronchioles in both p53+/- and p53+/+ mice.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('pleural tumors', 'Disease', (17, 31))	('rMWCNTs', 'Var', (91, 98))	('greater', 'PosReg', (106, 113))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('hyperplasia', 'Disease', (130, 141))	('pleural tumors', 'Disease', 'MESH:D010997', (17, 31))	('mice', 'Species', '10090', (56, 60))	('hyperplasia', 'Disease', 'MESH:D006965', (130, 141))
160855	28978163	Increasing studies indicate that loss of BRCA1-associated protein 1 (BAP1) detected by immunohistochemistry (IHC) is a useful diagnostic marker for MM.	('BRCA1-associated protein 1', 'Gene', '8314', (41, 67))	('BAP1', 'Gene', (69, 73))	('BRCA1-associated protein 1', 'Gene', (41, 67))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('loss', 'Var', (33, 37))	('BAP1', 'Gene', '8314', (69, 73))
160858	28978163	Results indicated that loss of BAP1 sustained a pooled sensitivity of 0.56 (95% CI, 0.50-0.62), specificity of 1.00 (95% CI, 0.95-1.00), PLR of 548.82 (95% CI, 11.31-2.7 x 104), NLR of 0.44 (95% CI, 0.39-0.50), DOR of 1247.78 (95% CI, 25.08 -6.2 x 104) in discriminating MM from non-MM.	('loss', 'Var', (23, 27))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (31, 35))
160862	28978163	Current meta-analysis indicates that detection of BAP1 by IHC is a useful diagnostic marker for MM.	('BAP1', 'Gene', (50, 54))	('detection', 'Var', (37, 46))	('BAP1', 'Gene', '8314', (50, 54))
160863	28978163	Loss of BAP1 almost provides confirming diagnosis for MM, while positive staining for BAP1 is not enough to exclude non-MM.	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (86, 90))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
160870	28978163	The BRCA1-associated protein 1 (BAP1) gene, located on chromosome 3p21.1, is a tumour suppressor gene, and germline BAP1 mutations have been found in association with hereditary cancer syndrome.	('BAP1', 'Gene', (116, 120))	('BRCA1-associated protein 1', 'Gene', (4, 30))	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('BAP1', 'Gene', '8314', (32, 36))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (167, 193))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('association', 'Reg', (150, 161))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', '8314', (116, 120))	('hereditary cancer syndrome', 'Disease', (167, 193))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('tumour', 'Disease', (79, 85))	('BRCA1-associated protein 1', 'Gene', '8314', (4, 30))	('found', 'Reg', (141, 146))
160871	28978163	Loss of BAP1 is frequently observed in MM and has been proven to increase the risk of MM.	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))
160901	28978163	Loss of BAP1 is responsible for the process of malignant mesothelioma, and the homozygous deletion of BAP1 are associated with loss of IHC staining, thus leading to the high specificity of BAP1 in IHC.	('BAP1', 'Gene', '8314', (189, 193))	('deletion', 'Var', (90, 98))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (47, 69))	('BAP1', 'Gene', (102, 106))	('specificity', 'MPA', (174, 185))	('loss of IHC', 'Disease', (127, 138))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (47, 69))	('BAP1', 'Gene', (189, 193))	('BAP1', 'Gene', '8314', (8, 12))	('IHC', 'Disease', (197, 200))	('loss of IHC', 'Disease', 'MESH:D015431', (127, 138))	('malignant mesothelioma', 'Disease', (47, 69))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', '8314', (102, 106))	('Loss', 'Var', (0, 4))
160904	28978163	The results from our meta-analysis showed that the utility of BAP1 as a marker in the diagnosis of MM harbored a pooled sensitivity of 0.56 at a specificity of 1.00, meaning that loss of BAP1 immunostaining almost could rule in MM, but ruling BAP1 out as a marker seems to be premature.	('BAP1', 'Gene', (243, 247))	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', '8314', (187, 191))	('BAP1', 'Gene', (62, 66))	('BAP1', 'Gene', (187, 191))	('BAP1', 'Gene', '8314', (243, 247))	('rule in', 'Reg', (220, 227))	('loss', 'Var', (179, 183))
160906	28978163	Of note, cells expressing one wild-type copy of BAP1 retained IHC staining, and detection of BAP1 loss may be feasible for homozygous deletion of the BAP1.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', (150, 154))	('BAP1', 'Gene', (48, 52))	('loss', 'NegReg', (98, 102))	('deletion', 'Var', (134, 142))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', '8314', (150, 154))
160907	28978163	However, somatic BAP1 mutations have also been found and initialized in the neoplasm of sporadic MM, which does not always cause the loss of IHC staining.	('loss of IHC', 'Disease', (133, 144))	('neoplasm', 'Disease', (76, 84))	('sporadic MM', 'Disease', (88, 99))	('neoplasm', 'Disease', 'MESH:D009369', (76, 84))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('loss of IHC', 'Disease', 'MESH:D015431', (133, 144))	('BAP1', 'Gene', (17, 21))
160908	28978163	The BAP1 antibody (C-4, Santa Cruz) is predicted to detect wild-type BAP1 and mutant forms, and the mutant forms might not be differentiated from wild-type, thus affecting the true positive in diagnosing MM.	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('BAP1', 'Gene', '8314', (69, 73))	('mutant', 'Var', (100, 106))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', (69, 73))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('C-4', 'Gene', '720', (19, 22))	('affecting', 'Reg', (162, 171))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('diagnosing', 'Reg', (193, 203))	('mutant', 'Var', (78, 84))	('BAP1', 'Gene', '8314', (4, 8))	('C-4', 'Gene', (19, 22))
160920	28978163	A study reported that loss of BAP1 is rare in SMM.	('BAP1', 'Gene', '8314', (30, 34))	('SMM', 'Disease', (46, 49))	('BAP1', 'Gene', (30, 34))	('loss', 'Var', (22, 26))
160924	28978163	Therefore, BAP1 harbors a better diagnostic performance in diagnosing EMM when compared with the other two subtypes, and loss of BAP1 is more inclined to support an EMM diagnosis.	('EMM', 'Disease', (70, 73))	('BAP1', 'Gene', '8314', (11, 15))	('loss', 'Var', (121, 125))	('BAP1', 'Gene', '8314', (129, 133))	('EMM diagnosis', 'CPA', (165, 178))	('BAP1', 'Gene', (11, 15))	('BAP1', 'Gene', (129, 133))	('support', 'Reg', (154, 161))
160927	28978163	Subgroup analysis concluded that the detection of BAP1 in histological specimens had better diagnostic performance than cytological ones; and 3.)	('detection', 'Var', (37, 46))	('men', 'Species', '9606', (76, 79))	('BAP1', 'Gene', '8314', (50, 54))	('diagnostic', 'MPA', (92, 102))	('BAP1', 'Gene', (50, 54))
160954	27098557	Our studies have directly demonstrated that in rats MWCNT administered to the lung by the trans-tracheal intrapulmonary spraying (TIPS) method, an apposite antecedent to costly aerosol inhalation studies, translocated to the pleural cavity and caused marked inflammatory reactions, accumulations of macrophages phagocytosing the MWCNT fibers, and hyperplastic proliferation of the visceral mesothelium.11, 16 Importantly, pleural translocation and induction of lesions in the lung and pleura by MWCNT administered to the lung was size and shape dependent.16 Based on these findings, we conducted the present study to investigate the possibility that MWCNT-N administered to the lung is carcinogenic to the pleura and lung.	('MWCNT-N', 'Chemical', '-', (650, 657))	('pleural', 'Disease', (422, 429))	('MWCNT', 'Chemical', '-', (495, 500))	('carcinogenic to the pleura', 'Disease', (686, 712))	('MWCNT', 'Chemical', '-', (52, 57))	('MWCNT', 'Chemical', '-', (650, 655))	('carcinogenic to the pleura', 'Disease', 'MESH:D054363', (686, 712))	('rat', 'Species', '10116', (47, 50))	('MWCNT-N', 'Var', (650, 657))	('rat', 'Species', '10116', (33, 36))	('pleural', 'Disease', 'MESH:D010995', (225, 232))	('rat', 'Species', '10116', (367, 370))	('MWCNT', 'Chemical', '-', (329, 334))	('pleural', 'Disease', (225, 232))	('pleural', 'Disease', 'MESH:D010995', (422, 429))	('rats', 'Species', '10116', (47, 51))
161040	27098557	The primary objective of the present study was to determine whether administration of MWCNT-N via the airway to the rat lung using the TIPS method, an apposite antecedent to costly aerosol inhalation studies, was carcinogenic to the lung or pleural tissues.	('rat', 'Species', '10116', (76, 79))	('MWCNT-N', 'Var', (86, 93))	('MWCNT-N', 'Chemical', '-', (86, 93))	('rat', 'Species', '10116', (116, 119))	('carcinogenic to the lung or pleural', 'Disease', (213, 248))	('carcinogenic to the lung or pleural', 'Disease', 'MESH:D010995', (213, 248))
161087	26191485	The clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells.	('c-Met', 'Gene', (143, 148))	('HGF', 'Gene', '3082', (139, 142))	('NK4', 'Gene', '9235', (105, 108))	('dephosphorylation', 'biological_process', 'GO:0016311', ('170', '187'))	('dephosphorylation', 'MPA', (170, 187))	('HGF', 'Gene', (139, 142))	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('antibody', 'Var', (88, 96))	('mesothelioma', 'Disease', (200, 212))	('c-Met', 'Gene', '4233', (191, 196))	('NK4', 'Gene', (72, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('NK4', 'Gene', '9235', (72, 75))	('c-Met', 'Gene', '4233', (143, 148))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('inhibition', 'NegReg', (114, 124))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('c-Met', 'Gene', (191, 196))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))	('NK4', 'Gene', (105, 108))
161101	26191485	Biochemical analyses demonstrated aberrant growth signaling with enhanced angiogenesis in mesothelioma, which suggests that blocking these signal pathways is a therapeutic strategy.	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('aberrant', 'Var', (34, 42))	('angiogenesis', 'CPA', (74, 86))	('enhanced', 'PosReg', (65, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('aberrant growth', 'Phenotype', 'HP:0001507', (34, 49))	('mesothelioma', 'Disease', (90, 102))	('growth', 'CPA', (43, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
161106	26191485	Previous studies showed that the HGF/c-Met pathway played a crucial role in tumor invasion and metastasis, and blocking the pathway suppressed tumor infiltration into neighboring tissues (Matsumoto and Nakamura).	('HGF', 'Gene', (33, 36))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HGF', 'Gene', '3082', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('blocking', 'Var', (111, 119))	('c-Met', 'Gene', (37, 42))	('metastasis', 'CPA', (95, 105))	('c-Met', 'Gene', '4233', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('suppressed', 'NegReg', (132, 142))
161129	26191485	The study includes a dose escalation schedule with Ad-NK4 at 1 x 1010, 1 x 1011 or 1 x 1012 vp per person and a single injection for each dose group consisting of 3 patients.	('1 x 1011', 'Var', (71, 79))	('NK4', 'Gene', '9235', (54, 57))	('1 x 1012', 'Var', (83, 91))	('patients', 'Species', '9606', (165, 173))	('person', 'Species', '9606', (99, 105))	('NK4', 'Gene', (54, 57))
161217	24762959	Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates.	('signalling', 'biological_process', 'GO:0023052', ('207', '217'))	('RAD', 'biological_process', 'GO:1990116', ('58', '61'))	('AKT', 'Gene', (69, 72))	('RAD', 'Gene', (58, 61))	('RTK', 'Gene', '5979', (188, 191))	('mesothelioma proliferation', 'Disease', (107, 133))	('viability', 'CPA', (138, 147))	('RAD', 'Gene', '6236', (58, 61))	('PI3', 'Gene', (18, 21))	('mesothelioma proliferation', 'Disease', 'MESH:D008654', (107, 133))	('mTOR', 'Gene', (23, 27))	('BEZ235', 'Chemical', 'MESH:C531198', (31, 37))	('mTOR', 'Gene', '2475', (23, 27))	('PI3', 'Gene', '5266', (18, 21))	('RTK', 'Gene', (188, 191))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('AKT', 'Gene', '207', (69, 72))	('knockdown', 'Var', (73, 82))
161229	24762959	The MET inhibitor PHA-665752 exerts antiproliferative effects in mesothelioma cell lines by inhibiting MET-dependent PI3K/AKT and RAF/MAPK.	('PHA-665752', 'Var', (18, 28))	('MAPK', 'Gene', (134, 138))	('PI3', 'Gene', (117, 120))	('RAF', 'Gene', '22882', (130, 133))	('mesothelioma', 'Disease', (65, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('134', '138'))	('antiproliferative effects', 'MPA', (36, 61))	('AKT', 'Gene', '207', (122, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('PI3', 'Gene', '5266', (117, 120))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('MAPK', 'Gene', '5603', (134, 138))	('RAF', 'Gene', (130, 133))	('inhibiting', 'NegReg', (92, 102))	('AKT', 'Gene', (122, 125))
161231	24762959	In addition, high AXL expression is associated with better prognosis in mesothelioma patients.	('AXL', 'Gene', (18, 21))	('high', 'Var', (13, 17))	('patients', 'Species', '9606', (85, 93))	('mesothelioma', 'Disease', (72, 84))	('AXL', 'Gene', '558', (18, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
161243	24762959	Gefitinib, LY294002, U0126, GDC0941, and everolimus (RAD001) were obtained from LC Labs (Woburn, MA, USA).	('U0126', 'Chemical', 'MESH:C113580', (21, 26))	('RAD', 'Gene', '6236', (53, 56))	('LY294002', 'Var', (11, 19))	('GDC0941', 'Chemical', 'MESH:C532162', (28, 35))	('RAD', 'biological_process', 'GO:1990116', ('53', '56'))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('U0126', 'Var', (21, 26))	('LY294002', 'Chemical', 'MESH:C085911', (11, 19))	('RAD', 'Gene', (53, 56))	('everolimus', 'Chemical', 'MESH:D000068338', (41, 51))
161244	24762959	PHA-665752 was from Tocris Biosciences (St Louis, MO, USA).	('Tocris Biosciences', 'Disease', (20, 38))	('Tocris Biosciences', 'Disease', 'None', (20, 38))	('PHA-665752', 'Var', (0, 10))
161265	24762959	Mesothelioma cells including MESO924, MESO257, MESO296, and MESO428, and normal mesothelial cells 97-510 were plated at 3000 and 10 000 cells per well, respectively, in a 96-well flat-bottomed plate (Falcon, Lincoln, NJ, USA) and cultured in media for 24 h before being treated with different inhibitors, which included gefitinib (1 muM), PHA665752 (1 muM), BEZ235 (10, 25, 50, 100, 500, and 1000 nM), GDC0941 (0.5, 1, 2.5, 5, and 10 muM), RAD001 (20 nM), and U0126 (10 muM), or AXL shRNA.	('GDC0941', 'Chemical', 'MESH:C532162', (402, 409))	('PHA665752', 'Var', (339, 348))	('muM', 'Gene', '56925', (352, 355))	('BEZ235', 'Chemical', 'MESH:C531198', (358, 364))	('muM', 'Gene', (352, 355))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('AXL', 'Gene', '558', (479, 482))	('muM', 'Gene', '56925', (470, 473))	('0.5', 'Var', (411, 414))	('muM', 'Gene', (470, 473))	('muM', 'Gene', '56925', (333, 336))	('RAD', 'Gene', '6236', (440, 443))	('MESO257', 'Chemical', '-', (38, 45))	('muM', 'Gene', (333, 336))	('RAD', 'biological_process', 'GO:1990116', ('440', '443'))	('AXL', 'Gene', (479, 482))	('MESO296', 'Chemical', '-', (47, 54))	('U0126', 'Chemical', 'MESH:C113580', (460, 465))	('10', 'Var', (366, 368))	('gefitinib', 'Chemical', 'MESH:D000077156', (320, 329))	('RAD', 'Gene', (440, 443))	('MESO924', 'Chemical', '-', (29, 36))	('muM', 'Gene', '56925', (434, 437))	('muM', 'Gene', (434, 437))	('MESO428', 'Chemical', '-', (60, 67))
161278	24762959	PI3K inhibition by BEZ235 (10 and 50 nM), GDC0941 (500 and 1000 nM), and LY294002 (10 and 50 muM) substantially inhibited AKT in all mesothelioma cell lines (Figure 2A).	('BEZ235', 'Chemical', 'MESH:C531198', (19, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('inhibited', 'NegReg', (112, 121))	('LY294002', 'Var', (73, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('GDC0941', 'Chemical', 'MESH:C532162', (42, 49))	('PI3', 'Gene', '5266', (0, 3))	('LY294002', 'Chemical', 'MESH:C085911', (73, 81))	('muM', 'Gene', '56925', (93, 96))	('inhibition', 'NegReg', (5, 15))	('muM', 'Gene', (93, 96))	('PI3', 'Gene', (0, 3))	('AKT', 'Gene', '207', (122, 125))	('BEZ235', 'Var', (19, 25))	('mesothelioma', 'Disease', (133, 145))	('500', 'Var', (51, 54))	('AKT', 'Gene', (122, 125))
161280	24762959	LY294002 inhibited AKT effectively, but had unpredictable effects on S6, confirming the nonselective activity of this broadly active PI3K-family inhibitor.	('inhibited', 'NegReg', (9, 18))	('LY294002', 'Var', (0, 8))	('PI3', 'Gene', '5266', (133, 136))	('AKT', 'Gene', '207', (19, 22))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('PI3', 'Gene', (133, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('AKT', 'Gene', (19, 22))
161281	24762959	MEK1/2 inhibition by 10 muM U0126 inhibited MAPK, as expected, in all mesothelioma cell lines but had little impact on S6 phosphorylation (Figure 2A).	('U0126', 'Chemical', 'MESH:C113580', (28, 33))	('MEK1/2', 'Gene', '5604;5605', (0, 6))	('S6 phosphorylation', 'MPA', (119, 137))	('MEK1/2', 'Gene', (0, 6))	('muM', 'Gene', '56925', (24, 27))	('MEK1', 'molecular_function', 'GO:0004708', ('0', '4'))	('inhibited', 'NegReg', (34, 43))	('muM', 'Gene', (24, 27))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('MAPK', 'Gene', '5603', (44, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('mesothelioma', 'Disease', (70, 82))	('U0126', 'Var', (28, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('MAPK', 'Gene', (44, 48))	('inhibition', 'NegReg', (7, 17))
161283	24762959	Dual targeting of PI3K/mTOR with BEZ235 (50 nM) inhibited cell proliferation by 74%, 78%, 64%, and 60% in MESO924, MESO257, MESO296, and MESO428, respectively (Figure 2B).	('MESO296', 'Chemical', '-', (124, 131))	('MESO257', 'Chemical', '-', (115, 122))	('MESO428', 'Chemical', '-', (137, 144))	('cell proliferation', 'CPA', (58, 76))	('MESO924', 'Var', (106, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('MESO257', 'Var', (115, 122))	('mTOR', 'Gene', (23, 27))	('inhibited', 'NegReg', (48, 57))	('MESO296', 'Var', (124, 131))	('mTOR', 'Gene', '2475', (23, 27))	('PI3', 'Gene', '5266', (18, 21))	('MESO924', 'Chemical', '-', (106, 113))	('BEZ235', 'Chemical', 'MESH:C531198', (33, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('PI3', 'Gene', (18, 21))
161284	24762959	Selective PI3K inhibition by GDC0941 resulted in 40-50% inhibition of these mesothelioma cells, and broader PI3K family inhibition with LY294002 markedly decreased cell proliferation in all mesothelioma cell lines (Figure 2B).	('inhibition', 'NegReg', (56, 66))	('inhibition', 'NegReg', (15, 25))	('decreased', 'NegReg', (154, 163))	('PI3', 'Gene', (108, 111))	('PI3', 'Gene', '5266', (10, 13))	('mesothelioma', 'Disease', (76, 88))	('GDC0941', 'Chemical', 'MESH:C532162', (29, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('164', '182'))	('mesothelioma', 'Disease', 'MESH:D008654', (76, 88))	('PI3K', 'molecular_function', 'GO:0016303', ('10', '14'))	('PI3', 'Gene', (10, 13))	('LY294002', 'Var', (136, 144))	('GDC0941', 'Var', (29, 36))	('PI3', 'Gene', '5266', (108, 111))	('mesothelioma', 'Disease', (190, 202))	('mesothelioma', 'Disease', 'MESH:D008654', (190, 202))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('cell proliferation', 'CPA', (164, 182))	('LY294002', 'Chemical', 'MESH:C085911', (136, 144))
161287	24762959	By contrast, PI3K inhibition by BEZ235, GDC0941, and LY294002 had only mild anti-proliferative effects in normal mesothelial cells 97-510 (Figure 2C).	('PI3', 'Gene', '5266', (13, 16))	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('GDC0941', 'Var', (40, 47))	('PI3', 'Gene', (13, 16))	('LY294002', 'Var', (53, 61))	('BEZ235', 'Var', (32, 38))	('GDC0941', 'Chemical', 'MESH:C532162', (40, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('BEZ235', 'Chemical', 'MESH:C531198', (32, 38))
161289	24762959	Cell growth inhibition IC50s at day 3 were 14 and 744 nM for MESO924, and 7 and 356 nM for MESO428, respectively (Figure 2D), suggesting that BEZ235 has more potent anti-proliferative effects in mesotheliomas than GDC0941.	('mesotheliomas', 'Disease', 'MESH:D008654', (195, 208))	('MESO428', 'Chemical', '-', (91, 98))	('50s', 'Species', '1214577', (25, 28))	('mesotheliomas', 'Disease', (195, 208))	('Cell growth', 'biological_process', 'GO:0016049', ('0', '11'))	('BEZ235', 'Var', (142, 148))	('anti-proliferative effects', 'CPA', (165, 191))	('BEZ235', 'Chemical', 'MESH:C531198', (142, 148))	('MESO924', 'Chemical', '-', (61, 68))	('GDC0941', 'Chemical', 'MESH:C532162', (214, 221))
161291	24762959	EGFR, MET, and AXL inhibition by 1 muM gefitinib, 1 muM PHA665752, and AXL shRNA substantially inhibited EGFR, MET, and AXL phosphorylation, respectively, in these cell lines.	('muM', 'Gene', '56925', (35, 38))	('muM', 'Gene', '56925', (52, 55))	('muM', 'Gene', (35, 38))	('AXL', 'Gene', (15, 18))	('gefitinib', 'Chemical', 'MESH:D000077156', (39, 48))	('muM', 'Gene', (52, 55))	('EGFR', 'Gene', (105, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('MET', 'MPA', (111, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('MET', 'MPA', (6, 9))	('AXL', 'Gene', '558', (71, 74))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (105, 109))	('AXL', 'Gene', '558', (120, 123))	('PHA665752', 'Var', (56, 65))	('AXL', 'Gene', '558', (15, 18))	('inhibited', 'NegReg', (95, 104))	('AXL', 'Gene', (71, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('AXL', 'Gene', (120, 123))	('EGFR', 'Gene', '1956', (0, 4))
161296	24762959	We next compared effects of the PI3K/mTOR inhibitor BEZ235 on cell viability, compared with those obtained by direct targeting of EGFR, MET, and AXL.	('AXL', 'Gene', (145, 148))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('BEZ235', 'Var', (52, 58))	('cell viability', 'CPA', (62, 76))	('PI3', 'Gene', (32, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (52, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('mTOR', 'Gene', (37, 41))	('PI3', 'Gene', '5266', (32, 35))	('AXL', 'Gene', '558', (145, 148))	('mTOR', 'Gene', '2475', (37, 41))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
161297	24762959	As shown in Figure 3B, the most striking reduction in cell viability was seen in cells treated with BEZ235 or with concurrent direct targeting of EGFR, MET, and AXL; these approaches resulted in ~70% and ~60% decrease in cell viability, respectively.	('EGFR', 'Gene', '1956', (146, 150))	('BEZ235', 'Var', (100, 106))	('decrease', 'NegReg', (209, 217))	('EGFR', 'Gene', (146, 150))	('AXL', 'Gene', '558', (161, 164))	('BEZ235', 'Chemical', 'MESH:C531198', (100, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('cell viability', 'CPA', (221, 235))	('AXL', 'Gene', (161, 164))	('cell viability', 'CPA', (54, 68))	('reduction', 'NegReg', (41, 50))
161301	24762959	The additive inhibitory effects were seen after treatment with GDC0941/U0126 targeting PI3K and MAPK, RAD/U0126 targeting mTOR and MAPK, or GDC0941/RAD targeting PI3K and mTOR.	('RAD', 'Gene', '6236', (102, 105))	('MAPK', 'Gene', '5603', (131, 135))	('mTOR', 'Gene', (122, 126))	('GDC0941/U0126', 'Var', (63, 76))	('MAPK', 'Gene', (131, 135))	('mTOR', 'Gene', '2475', (171, 175))	('RAD', 'Gene', '6236', (148, 151))	('MAPK', 'Gene', '5603', (96, 100))	('PI3', 'Gene', (162, 165))	('GDC0941', 'Chemical', 'MESH:C532162', (140, 147))	('MAPK', 'Gene', (96, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('PI3', 'Gene', '5266', (87, 90))	('mTOR', 'Gene', '2475', (122, 126))	('U0126', 'Chemical', 'MESH:C113580', (106, 111))	('RAD', 'Gene', (102, 105))	('RAD', 'biological_process', 'GO:1990116', ('102', '105'))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('PI3', 'Gene', '5266', (162, 165))	('RAD', 'Gene', (148, 151))	('PI3', 'Gene', (87, 90))	('GDC0941', 'Chemical', 'MESH:C532162', (63, 70))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('RAD', 'biological_process', 'GO:1990116', ('148', '151'))	('U0126', 'Chemical', 'MESH:C113580', (71, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('mTOR', 'Gene', (171, 175))
161302	24762959	The anti-proliferative effects of combination inhibition of PI3K/mTOR and MAPK by BEZ235/U0126 or GDC0941/RAD/U0126 were comparable with inhibition of PI3K/mTOR (Figure 3C), indicating that PI3K/mTOR signalling has a crucial oncogenic role in mesothelioma.	('mesothelioma', 'Disease', (243, 255))	('BEZ235', 'Chemical', 'MESH:C531198', (82, 88))	('RAD', 'Gene', (106, 109))	('U0126', 'Chemical', 'MESH:C113580', (110, 115))	('PI3', 'Gene', (60, 63))	('mTOR', 'Gene', '2475', (156, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (243, 255))	('MAPK', 'Gene', '5603', (74, 78))	('mTOR', 'Gene', '2475', (195, 199))	('MAPK', 'Gene', (74, 78))	('mTOR', 'Gene', (65, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('PI3', 'Gene', '5266', (151, 154))	('BEZ235/U0126', 'Var', (82, 94))	('RAD', 'biological_process', 'GO:1990116', ('106', '109'))	('GDC0941', 'Chemical', 'MESH:C532162', (98, 105))	('PI3', 'Gene', '5266', (190, 193))	('mTOR', 'Gene', '2475', (65, 69))	('signalling', 'biological_process', 'GO:0023052', ('200', '210'))	('anti-proliferative', 'MPA', (4, 22))	('RAD', 'Gene', '6236', (106, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('190', '194'))	('PI3', 'Gene', (151, 154))	('U0126', 'Chemical', 'MESH:C113580', (89, 94))	('PI3', 'Gene', '5266', (60, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('PI3', 'Gene', (190, 193))	('mTOR', 'Gene', (156, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('mTOR', 'Gene', (195, 199))
161304	24762959	Cell proliferation IC50s at day 3 were 11.8 nM for MESO924, 11.4 nM for MESO257, 12 nM for MESO296, and 10.8 nM for MESO428, suggesting that BEZ235 has potent anti-proliferative effects in mesotheliomas with either spindle-cell components (MESO296 and MESO428) or in those with purely epithelial-type histology (MESO924 and MESO257).	('anti-proliferative effects', 'CPA', (159, 185))	('MESO924', 'Chemical', '-', (51, 58))	('MESO428', 'Var', (252, 259))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('MESO428', 'Chemical', '-', (116, 123))	('mesotheliomas', 'Disease', (189, 202))	('50s', 'Species', '1214577', (21, 24))	('BEZ235', 'Var', (141, 147))	('BEZ235', 'Chemical', 'MESH:C531198', (141, 147))	('MESO296', 'Chemical', '-', (91, 98))	('MESO428', 'Chemical', '-', (252, 259))	('MESO296', 'Var', (240, 247))	('MESO924', 'Chemical', '-', (312, 319))	('MESO257', 'Chemical', '-', (72, 79))	('MESO257', 'Chemical', '-', (324, 331))	('spindle', 'cellular_component', 'GO:0005819', ('215', '222'))	('MESO296', 'Chemical', '-', (240, 247))	('mesotheliomas', 'Disease', 'MESH:D008654', (189, 202))
161305	24762959	Cell-cycle analyses demonstrated a dose-dependent G1 block with decrease in the S-phase population after selective PI3K inhibition by GDC0941 in each of four mesothelioma lines, and after PI3K/mTOR inhibition by BEZ235 in those with epithelial-type histology (MESO924 and MESO257) (Figure 4B).	('mTOR', 'Gene', (193, 197))	('S-phase', 'biological_process', 'GO:0051320', ('80', '87'))	('GDC0941', 'Var', (134, 141))	('block', 'NegReg', (53, 58))	('S-phase population', 'MPA', (80, 98))	('mTOR', 'Gene', '2475', (193, 197))	('PI3', 'Gene', (115, 118))	('mesothelioma lines', 'Disease', (158, 176))	('PI3K', 'molecular_function', 'GO:0016303', ('188', '192'))	('PI3K', 'molecular_function', 'GO:0016303', ('115', '119'))	('Cell-cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('PI3', 'Gene', '5266', (188, 191))	('BEZ235', 'Chemical', 'MESH:C531198', (212, 218))	('MESO924', 'Chemical', '-', (260, 267))	('mesothelioma lines', 'Disease', 'MESH:D008654', (158, 176))	('GDC0941', 'Chemical', 'MESH:C532162', (134, 141))	('decrease', 'NegReg', (64, 72))	('PI3', 'Gene', (188, 191))	('inhibition', 'NegReg', (120, 130))	('MESO257', 'Chemical', '-', (272, 279))	('PI3', 'Gene', '5266', (115, 118))
161308	24762959	Nuclear fragmentation after selective PI3-K inhibition with GDC0941 did not substantially exceed levels seen in control arms in which the cells were exposed to DMSO alone (Figure 4B).	('PI3', 'Gene', (38, 41))	('DMSO', 'Chemical', 'MESH:D004121', (160, 164))	('PI3-K', 'molecular_function', 'GO:0016303', ('38', '43'))	('Nuclear fragmentation', 'CPA', (0, 21))	('PI3', 'Gene', '5266', (38, 41))	('GDC0941', 'Var', (60, 67))	('GDC0941', 'Chemical', 'MESH:C532162', (60, 67))
161309	24762959	In MESO296 and MESO428, mild apoptosis was induced by treatment with BEZ235 and LY294002 (Supplementary Figure 1), which is consistent with the cell-cycle analysis (Figure 4B).	('apoptosis', 'CPA', (29, 38))	('LY294002', 'Chemical', 'MESH:C085911', (80, 88))	('BEZ235', 'Var', (69, 75))	('cell-cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('LY294002', 'Var', (80, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('BEZ235', 'Chemical', 'MESH:C531198', (69, 75))	('MESO296', 'Chemical', '-', (3, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('MESO428', 'Chemical', '-', (15, 22))
161315	24762959	AKT1 and AKT2 knockdown by shRNA, whether singly or in combination, induced expression of p53, MDM2, and p21 (Figure 5B), consistent with AKT-mediated MDM2 functional inactivation, with resultant p53 overexpression and transcriptional activation of MDM2 and p21.	('AKT', 'Gene', (0, 3))	('p53', 'Gene', (90, 93))	('AKT1', 'Gene', (0, 4))	('MDM2', 'Gene', '4193', (95, 99))	('activation', 'PosReg', (235, 245))	('AKT', 'Gene', '207', (9, 12))	('MDM2', 'Gene', (249, 253))	('AKT2', 'Gene', '208', (9, 13))	('AKT', 'Gene', '207', (0, 3))	('transcriptional', 'MPA', (219, 234))	('inactivation', 'NegReg', (167, 179))	('p53', 'Gene', '7157', (196, 199))	('overexpression', 'PosReg', (200, 214))	('MDM2', 'Gene', '4193', (249, 253))	('AKT2', 'Gene', (9, 13))	('AKT', 'Gene', (138, 141))	('MDM2', 'Gene', (151, 155))	('p53', 'Gene', (196, 199))	('AKT1', 'Gene', '207', (0, 4))	('p21', 'Gene', (258, 261))	('p53', 'Gene', '7157', (90, 93))	('p21', 'Gene', '644914', (258, 261))	('MDM2', 'Gene', '4193', (151, 155))	('MDM2', 'Gene', (95, 99))	('AKT', 'Gene', (9, 12))	('p21', 'Gene', (105, 108))	('knockdown', 'Var', (14, 23))	('p21', 'Gene', '644914', (105, 108))	('AKT', 'Gene', '207', (138, 141))
161316	24762959	The AKT1 and AKT2 knockdowns resulted in ~40% inhibition of cell viability (CellTiter-Glo assay), at 3 and 6 days after AKT1 or AKT2 silencing, compared with the empty vector control (Figure 5C).	('AKT2', 'Gene', (128, 132))	('AKT1', 'Gene', '207', (4, 8))	('AKT1', 'Gene', (120, 124))	('inhibition', 'NegReg', (46, 56))	('AKT1', 'Gene', (4, 8))	('AKT2', 'Gene', '208', (128, 132))	('silencing', 'NegReg', (133, 142))	('AKT2', 'Gene', (13, 17))	('AKT2', 'Gene', '208', (13, 17))	('AKT1', 'Gene', '207', (120, 124))	('knockdowns', 'Var', (18, 28))
161317	24762959	The most striking reductions in cell viability (60% and 80%, at days 3 and 6, respectively) were seen after combined PI3K/mTOR inhibition (with BEZ235) or after mTOR inhibition (with RAD001) combined with shRNA knockdown of AKT1 or AKT2 (Figure 5C).	('PI3', 'Gene', (117, 120))	('BEZ235', 'Chemical', 'MESH:C531198', (144, 150))	('RAD', 'Gene', (183, 186))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('inhibition', 'NegReg', (127, 137))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', (161, 165))	('inhibition', 'NegReg', (166, 176))	('knockdown', 'Var', (211, 220))	('cell viability', 'CPA', (32, 46))	('AKT2', 'Gene', '208', (232, 236))	('mTOR', 'Gene', '2475', (122, 126))	('mTOR', 'Gene', '2475', (161, 165))	('AKT1', 'Gene', '207', (224, 228))	('AKT2', 'Gene', (232, 236))	('PI3', 'Gene', '5266', (117, 120))	('RAD', 'Gene', '6236', (183, 186))	('reductions', 'NegReg', (18, 28))	('RAD', 'biological_process', 'GO:1990116', ('183', '186'))	('AKT1', 'Gene', (224, 228))
161321	24762959	In addition, AKT3 knockdown by shRNA also induced expression of p53, MDM2, p21, and p-S6 (Supplementary Figure 5).	('MDM2', 'Gene', '4193', (69, 73))	('knockdown', 'Var', (18, 27))	('p-S6', 'Gene', '338413', (84, 88))	('p53', 'Gene', (64, 67))	('p-S6', 'Gene', (84, 88))	('AKT3', 'Gene', '10000', (13, 17))	('induced', 'Reg', (42, 49))	('p21', 'Gene', (75, 78))	('AKT3', 'Gene', (13, 17))	('MDM2', 'Gene', (69, 73))	('p21', 'Gene', '644914', (75, 78))	('expression', 'MPA', (50, 60))	('p53', 'Gene', '7157', (64, 67))
161345	24762959	Unexpectedly, AKT1, AKT2, and AKT3 knockdown by shRNAs, whether singly or in combination, enhanced mTOR activation (Supplementary Figures 4 and 5), and although the mechanism is unclear, these data provide an additional rationale for dual targeting of AKT and mTOR in mesothelioma.	('AKT1', 'Gene', '207', (14, 18))	('AKT', 'Gene', (252, 255))	('enhanced', 'PosReg', (90, 98))	('AKT', 'Gene', (30, 33))	('AKT2', 'Gene', (20, 24))	('mTOR', 'Gene', (99, 103))	('mTOR', 'Gene', '2475', (260, 264))	('AKT3', 'Gene', '10000', (30, 34))	('AKT', 'Gene', (14, 17))	('shRNAs', 'Gene', (48, 54))	('AKT1', 'Gene', (14, 18))	('mTOR', 'Gene', '2475', (99, 103))	('AKT3', 'Gene', (30, 34))	('knockdown', 'Var', (35, 44))	('AKT', 'Gene', (20, 23))	('AKT', 'Gene', '207', (252, 255))	('AKT', 'Gene', '207', (30, 33))	('AKT', 'Gene', '207', (14, 17))	('mesothelioma', 'Disease', (268, 280))	('AKT', 'Gene', '207', (20, 23))	('mesothelioma', 'Disease', 'MESH:D008654', (268, 280))	('mTOR', 'Gene', (260, 264))	('AKT2', 'Gene', '208', (20, 24))
161347	24762959	The in vitro evidence, here, demonstrates additive effects of AKT1/AKT2 shRNA knockdown and RAD001 mTOR-inhibition in mesothelioma (Figures 4A and 5C).	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('RAD', 'Gene', (92, 95))	('shRNA', 'Gene', (72, 77))	('knockdown', 'Var', (78, 87))	('AKT1', 'Gene', '207', (62, 66))	('RAD', 'Gene', '6236', (92, 95))	('AKT2', 'Gene', (67, 71))	('AKT1', 'Gene', (62, 66))	('mesothelioma', 'Disease', (118, 130))	('AKT2', 'Gene', '208', (67, 71))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))	('RAD', 'biological_process', 'GO:1990116', ('92', '95'))
161349	24762959	PI3K or AKT inhibition in mesothelioma induced p53 expression, associated with upregulation of MDM2 and p21 (Figure 5B and Supplementary Figure 5).	('mesothelioma', 'Disease', (26, 38))	('AKT', 'Gene', '207', (8, 11))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('inhibition', 'Var', (12, 22))	('upregulation', 'PosReg', (79, 91))	('induced', 'Reg', (39, 46))	('AKT', 'Gene', (8, 11))	('p21', 'Gene', (104, 107))	('MDM2', 'Gene', '4193', (95, 99))	('MDM2', 'Gene', (95, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('p21', 'Gene', '644914', (104, 107))	('PI3', 'Gene', '5266', (0, 3))	('expression', 'MPA', (51, 61))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('PI3', 'Gene', (0, 3))
161350	24762959	In addition, a recent study showed that the PI3K/mTOR inhibitor PF-06491502 induced expression of wild-type p53 in head and neck cancer.	('neck', 'cellular_component', 'GO:0044326', ('124', '128'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mTOR', 'Gene', (49, 53))	('neck cancer', 'Disease', 'MESH:D006258', (124, 135))	('neck cancer', 'Disease', (124, 135))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('mTOR', 'Gene', '2475', (49, 53))	('PI3', 'Gene', (44, 47))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('expression', 'MPA', (84, 94))	('PF-06491502', 'Var', (64, 75))	('PI3', 'Gene', '5266', (44, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
161352	24762959	This finding is in keeping with studies showing that AKT physically associates with MDM2 and phosphorylates MDM2 at Ser166 and Ser186, leading to nuclear translocation and degradation of the tumour-suppressor p53, and that activation of MDM2 by AKT in mammary epithelium delays mammary involution and accelerates mammary tumorigenesis.	('MDM2', 'Gene', (84, 88))	('MDM2', 'Gene', '4193', (237, 241))	('AKT', 'Gene', (245, 248))	('MDM2', 'Gene', '4193', (108, 112))	('MDM2', 'Gene', '4193', (84, 88))	('degradation', 'MPA', (172, 183))	('accelerates', 'PosReg', (301, 312))	('leading to', 'Reg', (135, 145))	('activation', 'Var', (223, 233))	('mammary tumorigenesis', 'CPA', (313, 334))	('delays', 'NegReg', (271, 277))	('nuclear translocation', 'MPA', (146, 167))	('Ser', 'cellular_component', 'GO:0005790', ('116', '119'))	('AKT', 'Gene', (53, 56))	('AKT', 'Gene', '207', (245, 248))	('Ser186', 'Chemical', '-', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('MDM2', 'Gene', (108, 112))	('mammary involution', 'CPA', (278, 296))	('p53', 'Gene', '7157', (209, 212))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Disease', (191, 197))	('AKT', 'Gene', '207', (53, 56))	('Ser', 'cellular_component', 'GO:0005790', ('127', '130'))	('degradation', 'biological_process', 'GO:0009056', ('172', '183'))	('p53', 'Gene', (209, 212))	('MDM2', 'Gene', (237, 241))	('Ser166', 'Chemical', '-', (116, 122))
161396	23293508	The deletion of the p16 gene was associated with poor prognosis.	('p16', 'Gene', '1029', (20, 23))	('p16', 'Gene', (20, 23))	('deletion', 'Var', (4, 12))
161451	23293508	Pass and colleagues retrospectively studied 190 patients with MPM, benign asbestos related disease, and healthy subjects without asbestos exposure, and found that serum osteopontin levels were significantly higher in patients with MPM than in patients with asbestosis and healthy non-asbestos exposed subjects but did not appear useful in patients with radiographic evidence of pleural disease as the levels were also elevated in these patients.	('osteopontin', 'Gene', '6696', (169, 180))	('pleural disease', 'Disease', 'MESH:D010995', (378, 393))	('osteopontin', 'Gene', (169, 180))	('patients', 'Species', '9606', (243, 251))	('pleural disease', 'Phenotype', 'HP:0002103', (378, 393))	('asbestosis', 'Disease', 'MESH:D001195', (257, 267))	('patients', 'Species', '9606', (339, 347))	('asbestosis', 'Disease', (257, 267))	('patients', 'Species', '9606', (48, 56))	('asbestos', 'Chemical', 'MESH:D001194', (74, 82))	('asbestos', 'Chemical', 'MESH:D001194', (284, 292))	('patients', 'Species', '9606', (436, 444))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('patients', 'Species', '9606', (217, 225))	('pleural disease', 'Disease', (378, 393))	('MPM', 'Var', (231, 234))	('asbestos', 'Chemical', 'MESH:D001194', (257, 265))	('higher', 'PosReg', (207, 213))
161455	23293508	Although the mean serum osteopontin levels were higher in patients with MPM as compared to the healthy asbestos-exposed group and all patients with benign asbestos related disease, ~14% (72 subjects) had an elevated osteopontin level (>= 64.2 ng/mL) as defined by Pass and colleagues without evidence of MPM (false positive).	('osteopontin', 'Gene', (24, 35))	('osteopontin', 'Gene', (216, 227))	('false', 'biological_process', 'GO:0071877', ('309', '314'))	('elevated', 'PosReg', (207, 215))	('asbestos', 'Chemical', 'MESH:D001194', (155, 163))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('patients', 'Species', '9606', (134, 142))	('false', 'biological_process', 'GO:0071878', ('309', '314'))	('higher', 'PosReg', (48, 54))	('osteopontin', 'Gene', '6696', (216, 227))	('patients', 'Species', '9606', (58, 66))	('MPM', 'Var', (72, 75))	('osteopontin', 'Gene', '6696', (24, 35))
161459	23293508	As reviewed in detail elsewhere a number of potentially useful serum biomarkers in MPM are under investigation including various microRNAs (miRNAs), loss of p16, overexpression of vascular endothelial growth factor (VEGF), and others.	('p16', 'Gene', '1029', (157, 160))	('p16', 'Gene', (157, 160))	('VEGF', 'Gene', '7422', (216, 220))	('loss', 'Var', (149, 153))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('180', '214'))	('vascular endothelial growth factor', 'Gene', (180, 214))	('VEGF', 'Gene', (216, 220))	('overexpression', 'PosReg', (162, 176))	('vascular endothelial growth factor', 'Gene', '7422', (180, 214))	('MPM', 'Disease', (83, 86))
161461	23293508	Busacca and colleagues reported that reduced expression of specific miRNAs (miRNA-17-5p and miRNA-30c) correlated with a better survival in patients with sarcomatoid MPM subtype.	('survival', 'MPA', (128, 136))	('miRNA-17', 'Gene', '406952', (76, 84))	('sarcomatoid MPM subtype', 'Disease', 'MESH:C538614', (154, 177))	('better', 'PosReg', (121, 127))	('expression', 'MPA', (45, 55))	('sarcomatoid MPM subtype', 'Disease', (154, 177))	('miRNA-30c', 'Var', (92, 101))	('patients', 'Species', '9606', (140, 148))	('reduced', 'NegReg', (37, 44))	('miRNA-17', 'Gene', (76, 84))
161481	33599775	Thirteen OCs (ie, arsenic, asbestos, benzene, beryllium, cadmium, chromium, diesel engine exhaust, formaldehyde, nickel, polycyclic aromatic hydrocarbons, silica, sulfuric acid, and trichloroethylene).	('chromium', 'Chemical', 'MESH:D002857', (66, 74))	('asbestos', 'Chemical', 'MESH:D001194', (27, 35))	('OCs', 'Chemical', '-', (9, 12))	('polycyclic', 'Var', (121, 131))	('silica', 'Chemical', 'MESH:D012822', (155, 161))	('benzene', 'Chemical', 'MESH:D001554', (37, 44))	('trichloroethylene', 'Chemical', 'MESH:D014241', (182, 199))	('arsenic', 'Chemical', 'MESH:D001151', (18, 25))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (121, 153))	('beryllium', 'Chemical', 'MESH:D001608', (46, 55))	('sulfuric acid', 'Chemical', 'MESH:C033158', (163, 176))	('formaldehyde', 'MPA', (99, 111))	('cadmium', 'Chemical', 'MESH:D002104', (57, 64))	('formaldehyde', 'Chemical', 'MESH:D005557', (99, 111))	('nickel', 'Chemical', 'MESH:D009532', (113, 119))
161552	33599775	The evolution of summary exposure values by region for the 13 OCs in terms of cancer DALYs with SDI changes and the expected summary exposure value level based on SDI alone are shown in eFigure 6 in the Supplement.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('OCs', 'Chemical', '-', (62, 65))	('men', 'Species', '9606', (209, 212))	('changes', 'Var', (100, 107))
161576	33599775	A Chinese cohort study reported that long-term exposure to low levels of silica (exposure limit <=0.05, <=0.10, or <=0.35 mg/m3) was associated with an increased risk of total and cause-specific mortality (lung cancer: hazard ratio, 1.08; 95% CI, 1.02-1.14).	('mortality', 'Disease', 'MESH:D003643', (195, 204))	('silica', 'Chemical', 'MESH:D012822', (73, 79))	('lung cancer', 'Disease', (206, 217))	('<=0.10', 'Var', (104, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('mortality', 'Disease', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('total', 'CPA', (170, 175))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))
161697	29413759	Interestingly, rare NRAS p.Q61K and EGFR exon 19 deletions were observed in 2 patients.	('p.Q61K', 'Mutation', 'rs121913254', (25, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'Gene', '1956', (36, 40))	('p.Q61K', 'Var', (25, 31))	('NRAS', 'Gene', (20, 24))	('EGFR', 'Gene', (36, 40))	('NRAS', 'Gene', '4893', (20, 24))
161699	29413759	Somatic mutation profiling in MM patients receiving PP therapy revealed genetic alterations in potential therapeutic targets such as NRAS and EGFR.	('genetic alterations', 'Var', (72, 91))	('patients', 'Species', '9606', (33, 41))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('NRAS', 'Gene', (133, 137))	('NRAS', 'Gene', '4893', (133, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))
161703	29413759	BRCA1-associated protein-1 (BAP1) mutations is known to be related to a high rate of MM and MM associated with germline BAP1mutations has a better prognosis of overall 7-fold increased long-term survival compared to sporadic MM.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('BRCA1-associated protein-1', 'Gene', (0, 26))	('BAP1', 'Gene', '8314', (120, 124))	('increased', 'PosReg', (175, 184))	('BRCA1-associated protein-1', 'Gene', '8314', (0, 26))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', (120, 124))
161735	29413759	We detected a mean of 2.8 somatic mutations per tumor (range, 1-8), corresponding to an average of 1.4 mutations per megabase (range, 0.5-4; Figure 2A).	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
161736	29413759	The mutational spectrum in our 9 MM cases was dominated by C>T transitions, which is in line with the results from a previous mesothelioma study.	('mesothelioma', 'Disease', 'MESH:D008654', (126, 138))	('C>T transitions', 'Var', (59, 74))	('mesothelioma', 'Disease', (126, 138))
161737	29413759	The genes that most frequently carried somatic mutations were BAP1 and TP53 (2 out of 12 cases (16.7%)).	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (47, 56))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
161738	29413759	In detail, we found a somatic mutations in BAP1, which resulted in p.Q85R and p.S469Rfs*22 amino acid change (peritoneum -1; pleural -1; Figure 2B).	('BAP1', 'Gene', (43, 47))	('p.Q85R', 'Var', (67, 73))	('pleural -1; Figure 2B', 'Disease', (125, 146))	('p.S469Rfs*22', 'Var', (78, 90))	('pleural -1; Figure 2B', 'Disease', 'MESH:D010995', (125, 146))	('BAP1', 'Gene', '8314', (43, 47))	('p.Q85R', 'Mutation', 'rs773232276', (67, 73))	('resulted in', 'Reg', (55, 66))	('p.S469Rfs*22', 'Mutation', 'p.S469RfsX22', (78, 90))
161739	29413759	Somatic mutations in TP53 were also found at the P53 DNA binding domain (p.Y205C and p.X261_splice) (Figure 2C).	('p.X261_splice', 'Var', (85, 98))	('TP53', 'Gene', (21, 25))	('binding', 'Interaction', (57, 64))	('X261', 'CellLine', 'CVCL:2490', (87, 91))	('found', 'Reg', (36, 41))	('p.Y205C', 'Mutation', 'rs1057520007', (73, 80))	('DNA binding', 'molecular_function', 'GO:0003677', ('53', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('TP53', 'Gene', '7157', (21, 25))
161740	29413759	These two TP53 mutations were observed in pleural mesothelioma.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (42, 62))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (42, 62))	('observed', 'Reg', (30, 38))	('pleural mesothelioma', 'Disease', (42, 62))	('TP53', 'Gene', '7157', (10, 14))
161748	29413759	A novel EGFR exon 19 deletion (p.E746_A750del) was detected in malignant pleural mesothelioma (Figure 4C and D).	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('p.E746_A750del', 'Var', (31, 45))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (63, 93))	('malignant pleural mesothelioma', 'Disease', (63, 93))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (73, 93))	('p.E746_A750del', 'Mutation', 'p.746,750delA', (31, 45))
161751	29413759	We identified somatically recurrent mutations in 2 genes including BAP1 and TP53.	('TP53', 'Gene', '7157', (76, 80))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', (76, 80))	('BAP1', 'Gene', '8314', (67, 71))	('BAP1', 'Gene', (67, 71))
161755	29413759	reported that approximately 60% of MM specimens had somatic mutations in BAP1 and half of the mutations were deletions which were too large to be detected using NGS (ranging from 300 to about 3,000 kb).	('BAP1', 'Gene', '8314', (73, 77))	('deletions', 'Var', (109, 118))	('mutations', 'Var', (94, 103))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (60, 69))
161760	29413759	Most of the somatic mutations in TP53 were observed at recurrent hotspots such as K132N, R273H, V216L, C238F, G244D, G245S, Y234C, R273C, Q331*, A276D, and Q331*.	('Q331*', 'SUBSTITUTION', 'None', (156, 161))	('G244D', 'Var', (110, 115))	('TP53', 'Gene', '7157', (33, 37))	('Q331*', 'Var', (156, 161))	('K132N', 'Var', (82, 87))	('R273C', 'Var', (131, 136))	('V216L', 'Mutation', 'rs730882025', (96, 101))	('V216L', 'Var', (96, 101))	('G244D', 'Mutation', 'rs985033810', (110, 115))	('G245S', 'Mutation', 'rs28934575', (117, 122))	('Y234C', 'Mutation', 'rs587780073', (124, 129))	('A276D', 'Var', (145, 150))	('G245S', 'Var', (117, 122))	('K132N', 'Mutation', 'rs866775781', (82, 87))	('TP53', 'Gene', (33, 37))	('R273H', 'Mutation', 'rs28934576', (89, 94))	('C238F', 'Var', (103, 108))	('Q331*', 'SUBSTITUTION', 'None', (138, 143))	('Y234C', 'Var', (124, 129))	('R273H', 'Var', (89, 94))	('A276D', 'Mutation', 'rs786202082', (145, 150))	('C238F', 'Mutation', 'rs730882005', (103, 108))	('R273C', 'Mutation', 'rs121913343', (131, 136))	('Q331*', 'Var', (138, 143))
161763	29413759	This is the first report of NRAS mutation in mesothelioma.	('NRAS', 'Gene', '4893', (28, 32))	('mutation', 'Var', (33, 41))	('mesothelioma', 'Disease', (45, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('NRAS', 'Gene', (28, 32))
161766	29413759	Mutated NRAS triggers the MAPK signaling cascade through activation of RAF, which in turn activates MEK, thereby triggering ERK phosphorylation and cellular proliferation.	('ERK', 'Gene', (124, 127))	('NRAS', 'Gene', '4893', (8, 12))	('MEK', 'Gene', '5609', (100, 103))	('RAF', 'Gene', '22882', (71, 74))	('MAPK signaling cascade', 'Pathway', (26, 48))	('ERK', 'Gene', '2048', (124, 127))	('signaling cascade', 'biological_process', 'GO:0007165', ('31', '48'))	('MEK', 'Gene', (100, 103))	('activation', 'PosReg', (57, 67))	('RAF', 'Gene', (71, 74))	('NRAS', 'Gene', (8, 12))	('cellular proliferation', 'CPA', (148, 170))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('Mutated', 'Var', (0, 7))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('activates', 'PosReg', (90, 99))	('triggers', 'Reg', (13, 21))	('triggering', 'Reg', (113, 123))	('MAPK signaling', 'biological_process', 'GO:0000165', ('26', '40'))	('ERK', 'molecular_function', 'GO:0004707', ('124', '127'))
161770	29413759	EGFR exon 19 (729-761 amino acid) deletions occur in approximately 50% of NSCLC patients and are well-characterized as a EGFR-tyrosine kinase inhibitor (TKI)-sensitive mutations.	('occur', 'Reg', (44, 49))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('135', '151'))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (121, 125))	('patients', 'Species', '9606', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('deletions', 'Var', (34, 43))	('EGFR', 'Gene', (121, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('NSCLC', 'Disease', (74, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('EGFR', 'Gene', '1956', (0, 4))
161771	29413759	In our current study, EGFR exon 19 deletion (p.E746_A750del) was identified in malignant pleural mesothelioma, which suggests that EGFR TKI could be a potential therapeutic candidate for MM by targeting EGFR exon 19 deletion.	('deletion (p.E746_A750del', 'Var', (35, 59))	('EGFR', 'Gene', '1956', (203, 207))	('p.E746_A750del', 'Var', (45, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('identified', 'Reg', (65, 75))	('EGFR', 'Gene', (203, 207))	('malignant pleural mesothelioma', 'Disease', (79, 109))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (79, 109))	('EGFR', 'Gene', '1956', (131, 135))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (89, 109))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('p.E746_A750del', 'Mutation', 'p.746,750delA', (45, 59))	('EGFR', 'Gene', (22, 26))
161776	29413759	A previous study reported that asbestos exposure is associated with mutations in KRAS and worse prognosis in MM patients.	('KRAS', 'Gene', '3845', (81, 85))	('associated', 'Reg', (52, 62))	('patients', 'Species', '9606', (112, 120))	('KRAS', 'Gene', (81, 85))	('mutations', 'Var', (68, 77))	('asbestos', 'Chemical', 'MESH:D001194', (31, 39))
161779	29413759	We did not find any predictive marker for PP therapy, but found potential actionable targets such as NRAS p.Q61K mutation and EGFR exon 19 deletion.	('p.Q61K mutation', 'Var', (106, 121))	('NRAS', 'Gene', (101, 105))	('EGFR', 'Gene', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('NRAS', 'Gene', '4893', (101, 105))	('p.Q61K', 'Mutation', 'rs121913254', (106, 112))	('EGFR', 'Gene', '1956', (126, 130))
161780	29413759	Further investigations with a larger number of patients including functional studies for potential therapeutic targets with NRAS and EGFR inhibitors are needed.	('NRAS', 'Gene', '4893', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('133', '137'))	('patients', 'Species', '9606', (47, 55))	('EGFR', 'Gene', '1956', (133, 137))	('inhibitors', 'Var', (138, 148))	('EGFR', 'Gene', (133, 137))	('NRAS', 'Gene', (124, 128))
161999	28915695	Consideration of all these observations led to the conclusion that the M5-T1 tumor corresponds to a TNM grading of T4N1M1.	('T4N1M1', 'Disease', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('M5-T1', 'Var', (71, 76))	('M5-T1', 'CellLine', 'CVCL:8289', (71, 76))
162004	28915695	Quantification of the surfaces covered by necrotic cells demonstrated that the extension of necrosis within the invaded omentum was significantly higher after treatment with curcumin (Figures 7E and 7G) compared with treatment with SAHA (Figures 7F and 7G) and with control rats (Figure 7D).	('higher', 'PosReg', (146, 152))	('necrosis', 'biological_process', 'GO:0001906', ('92', '100'))	('necrosis', 'Disease', 'MESH:D009336', (92, 100))	('necrosis', 'biological_process', 'GO:0008219', ('92', '100'))	('necrotic', 'Disease', (42, 50))	('SAHA', 'Chemical', 'MESH:D000077337', (232, 236))	('curcumin', 'Chemical', 'MESH:D003474', (174, 182))	('rat', 'Species', '10116', (274, 277))	('curcumin', 'Var', (174, 182))	('rat', 'Species', '10116', (64, 67))	('necrotic', 'Disease', 'MESH:D009336', (42, 50))	('necrosis', 'biological_process', 'GO:0070265', ('92', '100'))	('extension', 'CPA', (79, 88))	('necrosis', 'biological_process', 'GO:0019835', ('92', '100'))	('necrosis', 'Disease', (92, 100))	('rats', 'Species', '10116', (274, 278))	('necrosis', 'biological_process', 'GO:0008220', ('92', '100'))
162010	28915695	In curcumin-treated rats, the CD8+ cells were distributed everywhere, including at the periphery of necrotic areas, close to dying cells (Figure 8E).	('necrotic areas', 'Disease', 'MESH:D009336', (100, 114))	('rats', 'Species', '10116', (20, 24))	('CD8+', 'Var', (30, 34))	('curcumin', 'Chemical', 'MESH:D003474', (3, 11))	('necrotic areas', 'Disease', (100, 114))
162027	28915695	Further immunohistochemical staining of these areas with anti-CD3 and anti-CD8 monoclonal antibodies revealed that they corresponded to T lymphocytes, and particularly CD8+ T lymphocytes (Supplemental Figure S4A), some of them showing the same morphology as in Figure 9K.	('CD3', 'Gene', (62, 65))	('anti-CD8', 'Var', (70, 78))	('CD3', 'Gene', '12501', (62, 65))
162072	28915695	curcumin injections do not impair the cytotoxic function of NK cells, while they do maintain the level of Th1 regulatory cytokines and enhance the antigen-induced proliferation potential of T cells.	('rat', 'Species', '10116', (170, 173))	('antigen-induced proliferation potential of T cells', 'CPA', (147, 197))	('Th1 regulatory cytokines', 'MPA', (106, 130))	('level', 'MPA', (97, 102))	('curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('injections', 'Var', (9, 19))	('enhance', 'PosReg', (135, 142))
162077	28915695	The latter case could be explained by an increased expression of cancer antigens induced by inhibitors of histone deacetylases (iHDACs), which has previously been documented both in vitro and in vivo.	('increased', 'PosReg', (41, 50))	('inhibitors', 'Var', (92, 102))	('histone', 'Protein', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
162089	28915695	This T-cell-mediated response is evidenced by an increased production of CD8+ T cells in the spleen and their numerous presence, sometimes in contact with isolated tumor cells, both in normal tissues preserved from metastases, and in minute foci of residual tumor cells vicinal to these normal tissues, where these latter present important changes of their morphology.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (258, 263))	('increased', 'PosReg', (49, 58))	('metastases', 'Disease', (215, 225))	('changes', 'Reg', (340, 347))	('metastases', 'Disease', 'MESH:D009362', (215, 225))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('CD8+', 'Var', (73, 77))
162178	28341225	One- and 2-year survival rates were higher for patients receiving IMPRINT (69% and 42% versus 50% and 20% for CONV).	('patients', 'Species', '9606', (47, 55))	('higher', 'PosReg', (36, 42))	('IMPRINT', 'Var', (66, 73))
162180	28341225	On MVA, KPS > 80% (p=0.01), epithelioid histology (p=0.003), MCR (p=0.01) and IMPRINT (p=0.02) were significantly associated with longer OS.	('longer OS', 'Disease', (130, 139))	('associated with', 'Reg', (114, 129))	('KPS > 80%', 'Var', (8, 17))	('epithelioid histology', 'CPA', (28, 49))	('OS', 'Chemical', '-', (137, 139))
162215	28341225	In general, however, IMRT has been shown in mesothelioma and multiple other disease sites to be associated with decreased radiation dose to organs at risk, leading to a decrease in toxicities.	('mesothelioma', 'Disease', 'MESH:D008654', (44, 56))	('decrease', 'NegReg', (169, 177))	('toxicities', 'Disease', 'MESH:D064420', (181, 191))	('IMRT', 'Var', (21, 25))	('toxicities', 'Disease', (181, 191))	('decreased', 'NegReg', (112, 121))	('mesothelioma', 'Disease', (44, 56))	('radiation dose', 'MPA', (122, 136))
162223	28125734	MiRNAs targeting the MSLN mRNA were identified by NGS and miR-21-5p and miR-100-5p were selected for further validation analyses.	('miR-100', 'Gene', (72, 79))	('MSLN', 'Gene', '10232', (21, 25))	('MSLN', 'Gene', (21, 25))	('h', 'Gene', '9464', (105, 106))	('miR-100', 'Gene', '406892', (72, 79))	('miR-21-5p', 'Var', (58, 67))	('h', 'Gene', '9464', (18, 19))
162226	28125734	Moreover, in vitro experiments showed that treatment with miR-21-5p mimic reduced proliferation of MPM cell lines.	('h', 'Gene', '9464', (56, 57))	('h', 'Gene', '9464', (39, 40))	('proliferation of MPM cell lines', 'CPA', (82, 113))	('h', 'Gene', '9464', (32, 33))	('miR-21-5p', 'Var', (58, 67))	('reduced', 'NegReg', (74, 81))
162304	28125734	At 48 hours after transfection, RNA was isolated with Trizol reagent (Sigma-Aldrich, Cat # T9424) and miRNAs levels were measured with TaqMan microRNA Assays (Cat # 4427975, Assay ID 000397 for hsa-miR-21-5p and 000437 for has-miR-100-p) according to manufacturer's protocol.	('miR', 'Gene', (198, 201))	('miR-100', 'Gene', (227, 234))	('miR', 'Gene', (102, 105))	('Cat', 'molecular_function', 'GO:0004096', ('85', '88'))	('h', 'Gene', '9464', (133, 134))	('hsa-miR-21', 'Gene', (194, 204))	('h', 'Gene', '9464', (52, 53))	('h', 'Gene', '9464', (194, 195))	('hsa-miR-21', 'Gene', '406991', (194, 204))	('miR', 'Gene', '22877', (198, 201))	('h', 'Gene', '9464', (82, 83))	('Trizol', 'Chemical', 'MESH:C411644', (54, 60))	('miR', 'Gene', '22877', (102, 105))	('miR', 'Gene', (227, 230))	('miR-100', 'Gene', '406892', (227, 234))	('Cat # 4427975', 'Var', (159, 172))	('miR', 'Gene', '22877', (227, 230))	('h', 'Gene', '9464', (223, 224))	('RNA', 'cellular_component', 'GO:0005562', ('32', '35'))	('Cat', 'molecular_function', 'GO:0004096', ('159', '162'))	('h', 'Gene', '9464', (6, 7))
162314	28125734	Subsequent site-directed mutagenesis reactions were performed with QuikChange Lightning Multi Site-Directed Mutagenesis Kit (Agilent, Cat # 210515), in order to generate a plasmid, referred as "MUT_pmir_MSLN", with mutations in the predicted binding site (in bold in the miRNA seed GATGCTTT).	('h', 'Gene', '9464', (268, 269))	('h', 'Gene', '9464', (72, 73))	('h', 'Gene', '9464', (229, 230))	('h', 'Gene', '9464', (65, 66))	('miR', 'Gene', (271, 274))	('binding', 'molecular_function', 'GO:0005488', ('240', '247'))	('Mutagenesis', 'biological_process', 'GO:0006280', ('108', '119'))	('mutagenesis', 'biological_process', 'GO:0006280', ('25', '36'))	('mutations', 'Var', (215, 224))	('MSLN', 'Gene', '10232', (203, 207))	('Cat', 'molecular_function', 'GO:0004096', ('134', '137'))	('MSLN', 'Gene', (203, 207))	('h', 'Gene', '9464', (81, 82))	('miR', 'Gene', '22877', (271, 274))	('h', 'Gene', '9464', (213, 214))
162367	28125734	Three possible binding sites were predicted for miR-100-5p (one in the 5'UTR and two in the coding region, starting at residues 122, 659 and 910), all with DeltaDeltaG>0.	('DeltaG', 'Mutation', 'c.delG', (161, 167))	('binding', 'molecular_function', 'GO:0005488', ('15', '22'))	('h', 'Gene', '9464', (1, 2))	('miR-100', 'Gene', (48, 55))	('DeltaDeltaG', 'Var', (156, 167))	('h', 'Gene', '9464', (154, 155))	('miR-100', 'Gene', '406892', (48, 55))	('h', 'Gene', '9464', (89, 90))	('h', 'Gene', '9464', (68, 69))
162368	28125734	Regarding CEP170B, miR-21-5p is predicted to anneal once with a DeltaDeltaG of +8.53 kcal/mol, whereas three putative binding sites are predicted for miR-100-5p, two of whom with DeltaDeltaG<0.	('h', 'Gene', '9464', (96, 97))	('CEP', 'molecular_function', 'GO:0047849', ('10', '13'))	('h', 'Gene', '9464', (170, 171))	('miR-100', 'Gene', '406892', (150, 157))	('h', 'Gene', '9464', (104, 105))	('170B', 'Species', '696258', (13, 17))	('DeltaG', 'Mutation', 'c.delG', (184, 190))	('CEP170B', 'Var', (10, 17))	('h', 'Gene', '9464', (177, 178))	('DeltaG', 'Mutation', 'c.delG', (69, 75))	('miR-100', 'Gene', (150, 157))	('h', 'Gene', '9464', (60, 61))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
162371	28125734	A reduction in MSLN protein level was evident after over-expression of miR-21-5p but not of miR-100-5p in all of the cell lines (Fig 2A, 2B, 2C and 2D).	('MSLN', 'Gene', '10232', (15, 19))	('MSLN', 'Gene', (15, 19))	('miR-21-5p', 'Var', (71, 80))	('miR-100', 'Gene', '406892', (92, 99))	('reduction', 'NegReg', (2, 11))	('h', 'Gene', '9464', (114, 115))	('over-expression', 'PosReg', (52, 67))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('miR-100', 'Gene', (92, 99))
162372	28125734	After miR-21-5p mimic transfection, MSLN protein levels significantly decreased to 58% (+-8%), 65% (+-5%), 61% (+-2%) and 54% (+-8%) of that obtained following transfection with the negative control (set to 100%) in Met-5A, Mero-14, MSTO-211H and H2052, respectively.	('MSLN', 'Gene', (36, 40))	('H2052', 'CellLine', 'CVCL:1518', (247, 252))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('transfection', 'Var', (22, 34))	('h', 'Gene', '9464', (176, 177))	('miR-21-5p mimic transfection', 'Var', (6, 34))	('decreased', 'NegReg', (70, 79))	('Mero-14', 'Chemical', '-', (224, 231))	('MSTO-211H', 'CellLine', 'CVCL:1430', (233, 242))	('h', 'Gene', '9464', (137, 138))	('h', 'Gene', '9464', (179, 180))	('MSLN', 'Gene', '10232', (36, 40))
162375	28125734	Following miR-21-5p depletion, MSLN protein levels increased by 33% (+-3.4%, P = 0.01) compared to the negative control (set to 100%) (Fig 3A).	('h', 'Gene', '9464', (100, 101))	('increased', 'PosReg', (51, 60))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('miR-21-5p depletion', 'Var', (10, 29))	('MSLN', 'Gene', '10232', (31, 35))	('MSLN', 'Gene', (31, 35))
162376	28125734	Mero-14 cells were transiently transfected with a luciferase reporter plasmid containing the region of MSLN coding sequence that most likely is target of miR-21-5p (WT_pmir_MSLN) or a reporter with mutations in the predicted binding site (MUT_pmir_MSLN) to validate the direct interaction between miR-21-5p and MSLN suggested by the miR-CATCH.	('h', 'Gene', '9464', (125, 126))	('MSLN', 'Gene', '10232', (311, 315))	('h', 'Gene', '9464', (267, 268))	('miR', 'Gene', '22877', (333, 336))	('MSLN', 'Gene', '10232', (103, 107))	('h', 'Gene', '9464', (46, 47))	('miR', 'Gene', (297, 300))	('h', 'Gene', '9464', (212, 213))	('h', 'Gene', '9464', (196, 197))	('h', 'Gene', '9464', (330, 331))	('miR', 'Gene', (154, 157))	('MSLN', 'Gene', (173, 177))	('Mero-14', 'Chemical', '-', (0, 7))	('mutations', 'Var', (198, 207))	('MSLN', 'Gene', '10232', (173, 177))	('h', 'Gene', '9464', (90, 91))	('miR', 'Gene', '22877', (297, 300))	('miR', 'Gene', '22877', (154, 157))	('MSLN', 'Gene', (248, 252))	('binding', 'molecular_function', 'GO:0005488', ('225', '232'))	('miR', 'Gene', (333, 336))	('MSLN', 'Gene', (311, 315))	('MSLN', 'Gene', '10232', (248, 252))	('MSLN', 'Gene', (103, 107))
162379	28125734	S2 Fig shows that treatment with miR-21-5p mimic led to reduction of MSLN protein levels at each tested time point.	('h', 'Gene', '9464', (14, 15))	('h', 'Gene', '9464', (31, 32))	('miR-21-5p mimic', 'Var', (33, 48))	('h', 'Gene', '9464', (8, 9))	('MSLN', 'Gene', '10232', (69, 73))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('h', 'Gene', '9464', (95, 96))	('MSLN', 'Gene', (69, 73))	('reduction', 'NegReg', (56, 65))
162381	28125734	In MSTO-211H cells miR-21-5p overexpression also decreased cell proliferation compared to the negative control with the most evident reduction (minus 15%, P = 0.048) at 72 h post transfection (Fig 4A, right panel).	('h', 'Gene', '9464', (172, 173))	('h', 'Gene', '9464', (117, 118))	('h', 'Gene', '9464', (204, 205))	('reduction', 'NegReg', (133, 142))	('cell proliferation', 'CPA', (59, 77))	('h', 'Gene', '9464', (114, 115))	('decreased', 'NegReg', (49, 58))	('h', 'Gene', '9464', (91, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (3, 12))	('miR-21-5p overexpression', 'Var', (19, 43))
162382	28125734	Overall, miR-21-5p overexpression led to a significant reduction (P = 0.0069 for Mero-14 and P = 0.0012 for MSTO-211H) in the proliferation rates of both cell lines over time.	('overexpression', 'PosReg', (19, 33))	('miR-21-5p', 'Var', (9, 18))	('proliferation rates', 'CPA', (126, 145))	('Mero-14', 'Chemical', '-', (81, 88))	('reduction', 'NegReg', (55, 64))	('h', 'Gene', '9464', (152, 153))	('MSTO-211H', 'CellLine', 'CVCL:1430', (108, 117))	('h', 'Gene', '9464', (123, 124))
162383	28125734	To delineate the observed effect on cell growth, we performed clonogenic assays on the same MPM cell lines, whose ability to form colonies was strongly decreased by transfection of miR-21-5p mimic, as compared to control-transfected cells (Fig 4B).	('h', 'Gene', '9464', (14, 15))	('cell growth', 'biological_process', 'GO:0016049', ('36', '47'))	('transfection', 'Var', (165, 177))	('h', 'Gene', '9464', (84, 85))	('decreased', 'NegReg', (152, 161))	('h', 'Gene', '9464', (46, 47))	('miR-21-5p mimic', 'Var', (181, 196))	('h', 'Gene', '9464', (109, 110))
162384	28125734	The number of colonies in wells treated with miR-21-5p was significantly decreased to 53% and to 40% in Mero-14 and MSTO-211H cells, respectively (P = 0.0002 for both cell lines).	('decreased', 'NegReg', (73, 82))	('h', 'Gene', '9464', (1, 2))	('MSTO-211H', 'CellLine', 'CVCL:1430', (116, 125))	('h', 'Gene', '9464', (43, 44))	('Mero-14', 'Chemical', '-', (104, 111))	('h', 'Gene', '9464', (165, 166))	('miR-21-5p', 'Var', (45, 54))
162397	28125734	Interestingly, one potential off-target, LRP5L, which has complementarity of 18 out of 19 bases with oligo MSLN_1, was not enriched suggesting that the presence of a single mismatch in the middle of a predicted binding site can abrogate the binding of the oligo and prevent mRNA capture, confirming the observation we reported previously.	('h', 'Gene', '9464', (180, 181))	('h', 'Gene', '9464', (300, 301))	('presence', 'Var', (152, 160))	('h', 'Gene', '9464', (149, 150))	('h', 'Gene', '9464', (54, 55))	('binding', 'Interaction', (211, 218))	('h', 'Gene', '9464', (52, 53))	('h', 'Gene', '9464', (186, 187))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('binding', 'Interaction', (241, 248))	('h', 'Gene', '9464', (99, 100))	('MSLN', 'Gene', (107, 111))	('prevent', 'NegReg', (266, 273))	('LRP5L', 'Gene', (41, 46))	('abrogate', 'NegReg', (228, 236))	('MSLN', 'Gene', '10232', (107, 111))	('h', 'Gene', '9464', (144, 145))	('mRNA capture', 'MPA', (274, 286))	('h', 'Gene', '9464', (49, 50))	('h', 'Gene', '9464', (238, 239))	('h', 'Gene', '9464', (128, 129))	('h', 'Gene', '9464', (253, 254))	('binding', 'molecular_function', 'GO:0005488', ('241', '248'))	('LRP5L', 'Gene', '91355', (41, 46))
162401	28125734	According to our NGS data, the isolation of miR-21-5p and, to a lower extent, of miR-100-5p was significantly higher in MSLN- vs scrambled- captured samples.	('h', 'Gene', '9464', (28, 29))	('MSLN', 'Gene', '10232', (120, 124))	('h', 'Gene', '9464', (110, 111))	('miR-100', 'Gene', '406892', (81, 88))	('MSLN', 'Gene', (120, 124))	('miR-21-5p', 'Var', (44, 53))	('isolation', 'MPA', (31, 40))	('h', 'Gene', '9464', (113, 114))	('miR-100', 'Gene', (81, 88))
162403	28125734	The lack of effect of miR-100-5p could be partially explained by the fact that it is predicted to bind with a stronger affinity to the off-target CEP170B rather than to MSLN mRNA, as shown by our prediction analysis performed with PITA algorithm.	('miR-100', 'Gene', '406892', (22, 29))	('CEP', 'molecular_function', 'GO:0047849', ('146', '149'))	('bind', 'Interaction', (98, 102))	('170B', 'Species', '696258', (149, 153))	('h', 'Gene', '9464', (162, 163))	('h', 'Gene', '9464', (132, 133))	('stronger', 'PosReg', (110, 118))	('h', 'Gene', '9464', (75, 76))	('h', 'Gene', '9464', (106, 107))	('h', 'Gene', '9464', (243, 244))	('h', 'Gene', '9464', (66, 67))	('h', 'Gene', '9464', (1, 2))	('h', 'Gene', '9464', (184, 185))	('CEP170B', 'Var', (146, 153))	('miR-100', 'Gene', (22, 29))	('MSLN', 'Gene', (169, 173))	('h', 'Gene', '9464', (229, 230))	('h', 'Gene', '9464', (157, 158))	('MSLN', 'Gene', '10232', (169, 173))
162404	28125734	Thus, the possible false positive result for miR-100-5p in NGS may have been due to the presence of CEP170B rather than MSLN in the MSLN-captured samples.	('miR-100', 'Gene', (45, 52))	('h', 'Gene', '9464', (7, 8))	('h', 'Gene', '9464', (111, 112))	('MSLN', 'Gene', '10232', (120, 124))	('CEP', 'molecular_function', 'GO:0047849', ('100', '103'))	('h', 'Gene', '9464', (1, 2))	('false', 'biological_process', 'GO:0071877', ('19', '24'))	('MSLN', 'Gene', (120, 124))	('h', 'Gene', '9464', (67, 68))	('miR-100', 'Gene', '406892', (45, 52))	('h', 'Gene', '9464', (116, 117))	('CEP170B', 'Var', (100, 107))	('MSLN', 'Gene', '10232', (132, 136))	('h', 'Gene', '9464', (85, 86))	('false', 'biological_process', 'GO:0071878', ('19', '24'))	('h', 'Gene', '9464', (129, 130))	('MSLN', 'Gene', (132, 136))	('170B', 'Species', '696258', (103, 107))
162406	28125734	The knock down of endogenous miR-21-5p showed a significant increase of MSLN protein levels, further confirming the proposed regulatory mechanism.	('miR-21-5p', 'Var', (29, 38))	('knock down', 'Var', (4, 14))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('h', 'Gene', '9464', (97, 98))	('h', 'Gene', '9464', (1, 2))	('h', 'Gene', '9464', (40, 41))	('increase', 'PosReg', (60, 68))	('h', 'Gene', '9464', (139, 140))	('MSLN', 'Gene', '10232', (72, 76))	('h', 'Gene', '9464', (113, 114))	('MSLN', 'Gene', (72, 76))
162411	28125734	MPM cell lines treated with miR-21-5p mimic showed lower proliferative abilities compared to cells treated with negative controls, both in a classical proliferation assay (SRB) and in the colony formation assay.	('proliferative abilities', 'CPA', (57, 80))	('SRB', 'Gene', '10575', (172, 175))	('h', 'Gene', '9464', (45, 46))	('formation', 'biological_process', 'GO:0009058', ('195', '204'))	('h', 'Gene', '9464', (110, 111))	('SRB', 'Gene', (172, 175))	('lower', 'NegReg', (51, 56))	('miR-21-5p mimic', 'Var', (28, 43))	('h', 'Gene', '9464', (134, 135))	('h', 'Gene', '9464', (26, 27))	('h', 'Gene', '9464', (185, 186))
162418	28125734	The role of miR-21-5p in senescence was beyond the scope of the present study but this and other long-term effects of miR-21-5p could contribute to the more evident response in the clonogenic than in the SRB assay.	('h', 'Gene', '9464', (83, 84))	('h', 'Gene', '9464', (178, 179))	('miR-21-5p', 'Var', (118, 127))	('h', 'Gene', '9464', (48, 49))	('h', 'Gene', '9464', (93, 94))	('h', 'Gene', '9464', (1, 2))	('h', 'Gene', '9464', (149, 150))	('h', 'Gene', '9464', (201, 202))	('h', 'Gene', '9464', (193, 194))	('h', 'Gene', '9464', (61, 62))	('SRB', 'Gene', '10575', (204, 207))	('clonogenic', 'CPA', (181, 191))	('senescence', 'biological_process', 'GO:0010149', ('25', '35'))	('SRB', 'Gene', (204, 207))
162424	28125734	Computational methods suggested that miR-21-5p could play an important role in the development and progression of lung cancer through JAK/STAT, MAPK, Wnt, and PPAR signalling pathways.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('PPAR', 'Gene', (159, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('MAPK', 'Pathway', (144, 148))	('JAK/STAT', 'Pathway', (134, 142))	('h', 'Gene', '9464', (132, 133))	('PPAR', 'Gene', '5465', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('h', 'Gene', '9464', (178, 179))	('miR-21-5p', 'Var', (37, 46))	('h', 'Gene', '9464', (33, 34))	('lung cancer', 'Disease', (114, 125))	('h', 'Gene', '9464', (17, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('JAK', 'molecular_function', 'GO:0004713', ('134', '137'))	('Wnt', 'Gene', (150, 153))	('h', 'Gene', '9464', (80, 81))	('signalling', 'biological_process', 'GO:0023052', ('164', '174'))	('Wnt', 'Gene', '7471', (150, 153))	('h', 'Gene', '9464', (127, 128))
162425	28125734	A number of targets for miR-21-5p have been experimentally validated, including, among the others, PTEN, Bcl2, JAG1, hMSH2, PDCD4.	('h', 'Gene', '9464', (117, 118))	('hMSH', 'molecular_function', 'GO:0018775', ('117', '121'))	('h', 'Gene', '9464', (93, 94))	('Bcl2', 'Gene', '596', (105, 109))	('PDCD4', 'Gene', '27250', (124, 129))	('JAG1', 'Gene', '182', (111, 115))	('Bcl2', 'molecular_function', 'GO:0015283', ('105', '109'))	('JAG1', 'Gene', (111, 115))	('h', 'Gene', '9464', (34, 35))	('h', 'Gene', '9464', (88, 89))	('hMSH2', 'Gene', '4436', (117, 122))	('PTEN', 'Gene', (99, 103))	('miR-21-5p', 'Var', (24, 33))	('PDCD4', 'Gene', (124, 129))	('Bcl2', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (99, 103))	('hMSH2', 'Gene', (117, 122))
162462	27438989	Those patients as defined as R2b and R2c (6 mm or greater in gross residual disease) were not considered to be disease free.	('patients', 'Species', '9606', (6, 14))	('R2c', 'Var', (37, 40))	('R2b', 'Var', (29, 32))
162477	27438989	Several studies have shown that biphasic and undifferentiated/sarcomatoid subtypes have a worsened prognosis and refractory response to chemotherapy compared with the epithelioid morphology.	('sarcomatoid', 'Disease', (62, 73))	('sarcomatoid', 'Disease', 'MESH:C538614', (62, 73))	('biphasic', 'Var', (32, 40))	('prognosis', 'MPA', (99, 108))
162502	24716035	Additionally, it is generally not advisable to aspirate pelvic masses that are suspicious for ovarian malignancy, as rupture of the cyst wall will worsen overall prognosis.	('ovarian malignancy', 'Disease', 'MESH:D010051', (94, 112))	('ovarian malignancy', 'Disease', (94, 112))	('worsen', 'Reg', (147, 153))	('pelvic masses', 'Phenotype', 'HP:0031501', (56, 69))	('cyst wall', 'cellular_component', 'GO:0097570', ('132', '141'))	('rupture', 'Var', (117, 124))	('ovarian malignancy', 'Phenotype', 'HP:0100615', (94, 112))	('pelvic mass', 'Phenotype', 'HP:0031501', (56, 67))
162509	24453997	Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('ASS1', 'Gene', (80, 84))	('HCC', 'Phenotype', 'HP:0001402', (160, 163))	('lymphoma', 'Phenotype', 'HP:0002665', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('argininosuccinate synthetase 1', 'Gene', '445', (48, 78))	('lymphomas', 'Disease', 'MESH:D008223', (216, 225))	('sarcomas', 'Disease', 'MESH:D012509', (202, 210))	('lymphomas', 'Phenotype', 'HP:0002665', (216, 225))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('hepatocellular carcinoma', 'Disease', (134, 158))	('melanoma', 'Disease', (124, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('sarcomas', 'Disease', (202, 210))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('malignancies', 'Disease', (100, 112))	('urological cancers', 'Disease', 'MESH:D014571', (182, 200))	('inactivation', 'Var', (32, 44))	('argininosuccinate synthetase 1', 'Gene', (48, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('urological cancers', 'Disease', (182, 200))	('lymphomas', 'Disease', (216, 225))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
162510	24453997	Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('loss of the tumor', 'Disease', 'MESH:D009369', (64, 81))	('ASS1', 'Gene', (101, 105))	('tumoral dependence', 'Disease', 'MESH:D019966', (117, 135))	('loss of the tumor', 'Disease', (64, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumoral dependence', 'Disease', (117, 135))	('Epigenetic silencing', 'Var', (0, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('arginine', 'Chemical', 'MESH:D001120', (149, 157))
162511	24453997	More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers.	('documented', 'Reg', (65, 75))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('arginine auxotrophic glioblastoma multiforme', 'Disease', 'MESH:D005909', (91, 135))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('arginine auxotrophic glioblastoma multiforme', 'Disease', (91, 135))	('argininosuccinate lyase', 'Gene', '435', (32, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('HCC', 'Disease', (137, 140))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('renal cancers', 'Disease', 'MESH:D007680', (174, 187))	('fumarate hydratase', 'Gene', '2271', (148, 166))	('renal cancers', 'Disease', (174, 187))	('argininosuccinate lyase', 'Gene', (32, 55))	('dysregulation', 'Var', (15, 28))	('fumarate hydratase', 'Gene', (148, 166))
162514	24453997	The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('ADI-PEG20', 'Var', (68, 77))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
162516	24453997	For many human cancers, dysregulation of cellular metabolism is now recognized as a key event in tumor growth and development.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('dysregulation', 'Var', (24, 37))	('cellular metabolism', 'MPA', (41, 60))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('human', 'Species', '9606', (9, 14))	('tumor', 'Disease', (97, 102))	('cancers', 'Disease', (15, 22))	('cellular metabolism', 'biological_process', 'GO:0044237', ('41', '60'))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
162519	24453997	Testing for metabolic genetic drivers such as mutations in Kreb's cycle genes (i.e., fumarate hydratase [FH], succinate dehydrogenase [SDH], isocitrate dehydrogenase-1/2 [IDH 1/2]) is already available, and new PET tracers and antimetabolites are being devised that aim to exploit the differential biochemistry of sugars, lipids and amino acids in normal and malignant cells.	('mutations', 'Var', (46, 55))	('IDH 1/2', 'Gene', (171, 178))	('fumarate hydratase', 'Gene', '2271', (85, 103))	('fumarate hydratase', 'Gene', (85, 103))	('succinate dehydrogenase', 'Gene', '6390', (110, 133))	('SDH', 'Gene', '6390', (135, 138))	('lipids', 'Chemical', 'MESH:D008055', (322, 328))	('succinate dehydrogenase', 'Gene', (110, 133))	('IDH 1/2', 'Gene', '3417;3418', (171, 178))	('SDH', 'Gene', (135, 138))	('sugars', 'Chemical', 'MESH:D000073893', (314, 320))
162523	24453997	As a monotherapy, deamidation of asparagine to aspartate and ammonia by L-asparaginase, led to responses of up to 50% in early studies of patients with chemorefractory leukemia.	('patients', 'Species', '9606', (138, 146))	('chemorefractory leukemia', 'Disease', (152, 176))	('aspartate', 'Chemical', 'MESH:D001224', (47, 56))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('asparagine', 'Chemical', 'MESH:D001216', (33, 43))	('chemorefractory leukemia', 'Disease', 'MESH:D007938', (152, 176))	('ammonia', 'Chemical', 'MESH:D000641', (61, 68))	('deamidation', 'Var', (18, 29))	('L-asparaginase', 'Gene', (72, 86))	('L-asparaginase', 'Gene', '80150', (72, 86))
162530	24453997	Although the data are preliminary, early signs suggest that arginine deprivation has the potential to make an impact across a broad range of human malignancies.	('arginine', 'Chemical', 'MESH:D001120', (60, 68))	('arginine deprivation', 'Var', (60, 80))	('malignancies', 'Disease', (147, 159))	('human', 'Species', '9606', (141, 146))	('impact', 'Reg', (110, 116))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
162535	24453997	Methylation-dependent transcriptional silencing has been shown to drive tumoral ASS1 loss in some tumor types, although other mechanisms may also be involved, including repression of the ASS1 promoter by hypoxia-inducible factor-1alpha detected in melanoma cells.	('melanoma', 'Disease', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumoral ASS1 loss', 'Disease', (72, 89))	('ASS1', 'Gene', (187, 191))	('Methylation-dependent', 'Var', (0, 21))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (204, 235))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('hypoxia-inducible factor-1alpha', 'Gene', (204, 235))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Disease', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('tumoral ASS1 loss', 'Disease', 'MESH:D009369', (72, 89))
162540	24453997	Previously extracellular arginine has been shown to increase DNA synthesis in Burkitt lymphoma cells, and enhance incorporation of glutamine into nucleotides in colorectal cancer cells.	('glutamine', 'Chemical', 'MESH:D005973', (131, 140))	('colorectal cancer', 'Disease', (161, 178))	('DNA synthesis', 'biological_process', 'GO:0071897', ('61', '74'))	('incorporation of glutamine into nucleotides', 'MPA', (114, 157))	('Burkitt lymphoma', 'Disease', (78, 94))	('arginine', 'Chemical', 'MESH:D001120', (25, 33))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (78, 94))	('extracellular', 'Var', (11, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('extracellular', 'cellular_component', 'GO:0005576', ('11', '24'))	('increase', 'PosReg', (52, 60))	('DNA synthesis', 'MPA', (61, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('arginine', 'Var', (25, 33))	('enhance', 'PosReg', (106, 113))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))
162544	24453997	Evidence for crosstalk between glutamine and arginine has also been revealed in studies of melanoma cells exposed to ADI-PEG20.	('glutamine', 'Chemical', 'MESH:D005973', (31, 40))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (117, 126))	('crosstalk', 'Reg', (13, 22))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('arginine', 'Chemical', 'MESH:D001120', (45, 53))	('ADI-PEG20', 'Var', (117, 126))
162552	24453997	On the other hand, there is evidence that methylated ASL contributes to the arginine auxotrophy of glioblastoma multiforme, with loss of ASS1 and ASL conferring greater sensitivity to ADI-PEG20.	('ASL', 'Gene', (146, 149))	('ASL', 'Gene', '435', (146, 149))	('greater', 'PosReg', (161, 168))	('glioblastoma multiforme', 'Disease', (99, 122))	('ASL', 'Gene', (53, 56))	('methylated', 'Var', (42, 52))	('arginine auxotrophy', 'MPA', (76, 95))	('loss', 'NegReg', (129, 133))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (184, 193))	('ASL', 'Gene', '435', (53, 56))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (99, 122))	('ASS1', 'Gene', (137, 141))	('sensitivity', 'MPA', (169, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('arginine', 'Chemical', 'MESH:D001120', (76, 84))	('contributes', 'Reg', (57, 68))
162562	24453997	In addition to the links between exogenous arginine and intracellular glutamine and pyrimidine synthesis described above-which impact directly on the cell cycle-ADI-PEG20 also downregulates mammalian target of rapamycin (mTOR) and modulates phosphoinositide 3-kinase (PI3K) via suppression of phosphatase and tensin homolog (PTEN) in ASS1-negative tumor cells.	('mammalian target of rapamycin', 'Gene', '2475', (190, 219))	('intracellular', 'cellular_component', 'GO:0005622', ('56', '69'))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('phosphatase', 'molecular_function', 'GO:0016791', ('293', '304'))	('PTEN', 'Gene', '5728', (325, 329))	('phosphatase', 'Protein', (293, 304))	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('mammalian target of rapamycin', 'Gene', (190, 219))	('suppression', 'NegReg', (278, 289))	('phosphoinositide 3-kinase', 'Gene', '5295', (241, 266))	('PI3K', 'molecular_function', 'GO:0016303', ('268', '272'))	('tumor', 'Disease', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (161, 170))	('downregulates', 'NegReg', (176, 189))	('mTOR', 'Gene', (221, 225))	('phosphoinositide 3-kinase', 'Gene', (241, 266))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('293', '323'))	('synthesis', 'biological_process', 'GO:0009058', ('95', '104'))	('glutamine', 'Chemical', 'MESH:D005973', (70, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('mTOR', 'Gene', '2475', (221, 225))	('cycle-ADI-PEG20', 'Var', (155, 170))	('modulates', 'Reg', (231, 240))	('PTEN', 'Gene', (325, 329))	('pyrimidine', 'Chemical', 'MESH:C030986', (84, 94))
162566	24453997	Furthermore, arginine deiminase was antiangiogenic and potentiated the effect of radiation in a neuroblastoma mouse model.	('neuroblastoma', 'Disease', (96, 109))	('antiangiogenic', 'CPA', (36, 50))	('arginine', 'Chemical', 'MESH:D001120', (13, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (96, 109))	('mouse', 'Species', '10090', (110, 115))	('arginine deiminase', 'Var', (13, 31))	('neuroblastoma', 'Disease', 'MESH:D009447', (96, 109))	('potentiated', 'PosReg', (55, 66))
162568	24453997	Clearly, arginine-lowering enzymes are likely to impact numerous other pathophysiological pathways and their further characterization will be crucial in optimizing arginine deprivation in the clinic.	('arginine', 'Chemical', 'MESH:D001120', (164, 172))	('arginine', 'Chemical', 'MESH:D001120', (9, 17))	('arginine-lowering', 'Var', (9, 26))	('impact', 'Reg', (49, 55))
162573	24453997	More recently, c-myc has been shown to play a role in the metabolic reprogramming seen during the development of ADI-PEG20 resistance in arginine auxotrophic melanoma cell lines.	('arginine', 'Chemical', 'MESH:D001120', (137, 145))	('auxotrophic melanoma', 'Disease', 'MESH:D008545', (146, 166))	('auxotrophic melanoma', 'Disease', (146, 166))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (113, 122))	('metabolic reprogramming', 'CPA', (58, 81))	('c-myc', 'Gene', '4609', (15, 20))	('ADI-PEG20 resistance', 'Var', (113, 133))	('c-myc', 'Gene', (15, 20))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
162574	24453997	Here, ADI-PEG20-resistant cells exhibited elevated expression of key enzymes in glutaminolysis, glutaminase (GLS1) and glutamine dehydrogenase, and increased glycolytic metabolic activity, resulting in preferential sensitivity to glutamine inhibitors and glycolytic inhibitors, respectively.	('ADI-PEG20-resistant', 'Var', (6, 25))	('preferential', 'PosReg', (202, 214))	('GLS1', 'Gene', (109, 113))	('glycolytic inhibitors', 'MPA', (255, 276))	('increased', 'PosReg', (148, 157))	('glycolytic metabolic activity', 'MPA', (158, 187))	('GLS1', 'Gene', '2744', (109, 113))	('expression', 'MPA', (51, 61))	('glutamine', 'Chemical', 'MESH:D005973', (230, 239))	('glutamine', 'Chemical', 'MESH:D005973', (119, 128))	('elevated', 'PosReg', (42, 50))	('sensitivity to glutamine inhibitors', 'MPA', (215, 250))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (6, 15))
162588	24453997	Indeed, recent work indicates that ADI-PEG20 is synergistic in vitro and in vivo with radiotherapy in pancreatic cancer cells and may have utility in combination with gemcitabine, a known radiosensitizer and potentiator of ADI-PEG20 in pancreatic malignancy.	('pancreatic malignancy', 'Disease', (236, 257))	('gemcitabine', 'Chemical', 'MESH:C056507', (167, 178))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (35, 44))	('pancreatic malignancy', 'Phenotype', 'HP:0002894', (236, 257))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('pancreatic malignancy', 'Disease', 'MESH:D010190', (236, 257))	('ADI-PEG20', 'Var', (35, 44))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (223, 232))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
162589	24453997	We have investigated further the effect of combining ADI-PEG20 with the antifolate drug pemetrexed based on the novel finding that ADI-PEG20 suppresses the pemetrexed target enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR).	('DHFR', 'Gene', (238, 242))	('thymidylate synthase', 'Gene', '7298', (183, 203))	('DHFR', 'Gene', '1719', (238, 242))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (131, 140))	('thymidylate synthase', 'Gene', (183, 203))	('dihydrofolate reductase', 'Gene', '1719', (213, 236))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (53, 62))	('DHFR', 'molecular_function', 'GO:0004146', ('238', '242'))	('ADI-PEG20', 'Var', (131, 140))	('dihydrofolate reductase', 'Gene', (213, 236))	('suppresses', 'NegReg', (141, 151))	('pemetrexed', 'Chemical', 'MESH:D000068437', (88, 98))	('pemetrexed', 'Chemical', 'MESH:D000068437', (156, 166))
162590	24453997	It is noteworthy that high TS expression, in particular, has been linked to poor clinical outcome and resistance to antifolates in several cancers including the bladder, lung, mesothelium, and colon.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('linked', 'Reg', (66, 72))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('bladder', 'Disease', 'MESH:D001745', (161, 168))	('lung', 'Disease', (170, 174))	('resistance', 'MPA', (102, 112))	('mesothelium', 'Disease', (176, 187))	('bladder', 'Disease', (161, 168))	('TS expression', 'MPA', (27, 40))	('colon', 'Disease', (193, 198))
162591	24453997	Moreover, we showed that loss of ASS1 was correlated with high levels of TS and DHFR and predicted for a poor outcome in patients with transitional carcinoma of the bladder.	('DHFR', 'Gene', (80, 84))	('loss', 'Var', (25, 29))	('DHFR', 'Gene', '1719', (80, 84))	('ASS1', 'Gene', (33, 37))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (148, 172))	('carcinoma of the bladder', 'Disease', (148, 172))	('DHFR', 'molecular_function', 'GO:0004146', ('80', '84'))	('patients', 'Species', '9606', (121, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
162592	24453997	Subsequently, we validated that arginine deprivation with ADI-PEG20 potentiated the effect of pemetrexed with enhanced apoptosis as assessed by cleaved poly (ADP-ribose) polymerase and annexin V staining.	('annexin V', 'Gene', (185, 194))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (58, 67))	('arginine', 'MPA', (32, 40))	('deprivation', 'NegReg', (41, 52))	('arginine', 'Chemical', 'MESH:D001120', (32, 40))	('potentiated', 'PosReg', (68, 79))	('ADI-PEG20', 'Var', (58, 67))	('enhanced', 'PosReg', (110, 118))	('apoptosis', 'CPA', (119, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('annexin V', 'Gene', '308', (185, 194))	('pemetrexed', 'Chemical', 'MESH:D000068437', (94, 104))
162595	24453997	first identified loss of ASS1 as one of 9 genes that predicted independently for cisplatin resistance in a microarray retrospective study of patients with ovarian cancer.	('cisplatin resistance', 'MPA', (81, 101))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('ASS1', 'Gene', (25, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('loss', 'Var', (17, 21))	('ovarian cancer', 'Disease', (155, 169))
162597	24453997	In contrast, studies linking ASS1 loss to enhanced platinum salt sensitivity, namely oxaliplatin and human arginase in HCC cell lines, and cisplatin and ADI-PEG20 in melanoma cells, may exploit a prosurvival pathway that depends on NO synthesis derived from exogenous arginine.	('enhanced', 'PosReg', (42, 50))	('HCC', 'Phenotype', 'HP:0001402', (119, 122))	('platinum salt sensitivity', 'MPA', (51, 76))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (85, 96))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('platinum salt', 'Chemical', '-', (51, 64))	('salt sensitivity', 'Phenotype', 'HP:0000127', (60, 76))	('ASS1', 'Gene', (29, 33))	('prosurvival pathway', 'Pathway', (196, 215))	('exploit', 'Reg', (186, 193))	('loss', 'NegReg', (34, 38))	('ADI-PEG20', 'Var', (153, 162))	('synthesis', 'biological_process', 'GO:0009058', ('235', '244'))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (153, 162))	('human', 'Species', '9606', (101, 106))	('cisplatin', 'Var', (139, 148))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('arginine', 'Chemical', 'MESH:D001120', (268, 276))
162604	24453997	ADI-PEG20 therapy also triggers a reciprocal increase in plasma citrulline and a decline in plasma nitrite and nitrate levels due to reduced NO synthesis.	('citrulline', 'Chemical', 'MESH:D002956', (64, 74))	('plasma citrulline', 'MPA', (57, 74))	('NO synthesis', 'MPA', (141, 153))	('nitrite', 'Chemical', 'MESH:D009573', (99, 106))	('decline', 'NegReg', (81, 88))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (0, 9))	('nitrate', 'Chemical', 'MESH:D009566', (111, 118))	('synthesis', 'biological_process', 'GO:0009058', ('144', '153'))	('reduced', 'NegReg', (133, 140))	('ADI-PEG20 therapy', 'Var', (0, 17))	('increase', 'PosReg', (45, 53))
162622	24453997	assessed the effect of arginine deprivation with ADI-PEG20 on metastatic melanoma with both early and late imaging timepoints "using PET."	('melanoma', 'Disease', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (49, 58))	('ADI-PEG20', 'Var', (49, 58))	('arginine', 'Chemical', 'MESH:D001120', (23, 31))
162625	24453997	One of the drawbacks in imaging some arginine auxotrophs such as melanoma, is the apparent increase in glucose uptake following ADI-PEG20 therapy secondary to PTEN loss and PI3K-induced glucose transporter type 1 (GLUT-1) expression.	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('PI3K-induced', 'Var', (173, 185))	('PTEN', 'Gene', '5728', (159, 163))	('loss', 'NegReg', (164, 168))	('glucose uptake', 'biological_process', 'GO:0046323', ('103', '117'))	('GLUT-1', 'Gene', (214, 220))	('GLUT-1', 'Gene', '6513', (214, 220))	('increase', 'PosReg', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('glucose transporter type 1', 'Gene', (186, 212))	('glucose', 'Chemical', 'MESH:D005947', (186, 193))	('glucose uptake', 'MPA', (103, 117))	('ADI-PEG20 therapy', 'Var', (128, 145))	('PTEN', 'Gene', (159, 163))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (128, 137))	('glucose transporter type 1', 'Gene', '6513', (186, 212))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('arginine', 'Chemical', 'MESH:D001120', (37, 45))
162626	24453997	Thus, we and others have explored FLT as an alternative imaging PET tracer and although this does not appear predictive in ASS1-negative melanoma, our studies confirmed robust suppression of FLT uptake following ADI-PEG20 treatment of ASS1-methylated tumors.	('FLT', 'Chemical', '-', (34, 37))	('tumors', 'Disease', (251, 257))	('ADI-PEG20', 'Var', (212, 221))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('suppression', 'NegReg', (176, 187))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('FLT', 'Chemical', '-', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('uptake', 'biological_process', 'GO:0098739', ('195', '201'))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (212, 221))	('FLT uptake', 'MPA', (191, 201))	('uptake', 'biological_process', 'GO:0098657', ('195', '201'))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
162631	24453997	Studies of the doublet of ADI-PEG20 and cisplatin and ADI-PEG20 and docetaxel to date have shown no untoward toxicity other than that ascribed to either agent alone (Bomalaski J, personal communication).	('docetaxel', 'Chemical', 'MESH:D000077143', (68, 77))	('ADI-PEG20', 'Var', (26, 35))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (54, 63))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (26, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('ADI-PEG20', 'Var', (54, 63))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
162632	24453997	Building on the ADAM trial, we have hypothesized that ADI-PEG20 with the standard doublet of cisplatin and pemetrexed may provide a novel way of targeting the heterogeneity and chemoresistance of mesothelioma.	('mesothelioma', 'Disease', (196, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (54, 63))	('pemetrexed', 'Chemical', 'MESH:D000068437', (107, 117))	('ADI-PEG20', 'Var', (54, 63))
162640	24453997	The field is evolving towards combination strategies and it is hoped that arginine-targeted therapies will soon become part of the standard cancer armamentarium.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('arginine-targeted', 'Var', (74, 91))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
162700	22480303	Cytogenetic studies of the smooth muscle tumor of the pleura have revealed contained chromosomal losses at 10q and 13q, which are the most common losses described in soft tissue leiomyosarcomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('tumor', 'Disease', (41, 46))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (178, 193))	('soft tissue leiomyosarcomas', 'Phenotype', 'HP:0030448', (166, 193))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (178, 193))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (178, 192))	('leiomyosarcomas', 'Disease', (178, 193))	('tumor of the pleura', 'Phenotype', 'HP:0100527', (41, 60))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('chromosomal losses', 'Var', (85, 103))
162800	32649003	Benzene and other polycyclic aromatic hydrocarbons as well as polychlorinated biphenyls (which are potential occupational hazards in the aluminum smelting industry, and also may be environmental hazards in Badin as these agents have been detected in Badin site wastewater evaluations ) have been associated with lymphatic and hematopoietic cancers .	('hematopoietic cancers', 'Disease', 'MESH:D009369', (326, 347))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('aluminum', 'Chemical', 'MESH:D000535', (137, 145))	('associated', 'Reg', (296, 306))	('hematopoietic cancers', 'Disease', (326, 347))	('cancers', 'Phenotype', 'HP:0002664', (340, 347))	('polychlorinated', 'Var', (62, 77))	('Benzene', 'Chemical', 'MESH:D001554', (0, 7))	('men', 'Species', '9606', (188, 191))	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (62, 87))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (18, 50))
162850	33324545	If the role of cancer heterocellular signaling via TNTs in the TME is proven to be crucial, then disrupting formation and maintenance of TNTs represents a novel therapeutic approach for ovarian and other similarly invasive peritoneal cancers.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (15, 21))	('invasive peritoneal cancers', 'Disease', 'MESH:D010534', (214, 241))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('invasive peritoneal cancers', 'Disease', (214, 241))	('TNTs', 'Chemical', '-', (137, 141))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('ovarian', 'Disease', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('ovarian', 'Disease', 'MESH:D010049', (186, 193))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('cancer', 'Disease', (234, 240))	('disrupting', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('TNTs', 'Chemical', '-', (51, 55))
162927	33324545	Utilizing gene expression microarrays, they identified candidate genes including tweety-homologue 1 (TTYH1), and associated its presence with the ability to regulate TM-mediated cancer cell invasion and proliferation, whereas downregulation nearly abrogated this effect.	('TTYH1', 'Gene', (101, 106))	('presence', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gene expression', 'biological_process', 'GO:0010467', ('10', '25'))	('TTYH1', 'Gene', '57348', (101, 106))	('tweety-homologue 1', 'Gene', '57348', (81, 99))	('regulate', 'Reg', (157, 165))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tweety-homologue 1', 'Gene', (81, 99))
162969	33324545	This notion may be most pertinent to cancers in which RAS alterations are most prevalent (e.g., pancreatic and colorectal carcinomas); although KRAS is only mutated in <1% of high-grade serous ovarian carcinomas, mutations in KRAS or BRAF and other components of the mitogen-activated protein kinase (MAPK) pathway are more prevalent in low-grade serous and also serous borderline forms of ovarian tumors.	('KRAS', 'Gene', '3845', (226, 230))	('serous ovarian carcinomas', 'Disease', (186, 211))	('protein', 'cellular_component', 'GO:0003675', ('285', '292'))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('low-grade serous', 'Disease', (337, 353))	('ovarian tumors', 'Phenotype', 'HP:0100615', (390, 404))	('KRAS', 'Gene', (226, 230))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (186, 211))	('MAPK', 'molecular_function', 'GO:0004707', ('301', '305'))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('pancreatic and colorectal carcinomas', 'Disease', 'MESH:D015179', (96, 132))	('mutations', 'Var', (213, 222))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (193, 211))	('prevalent', 'Reg', (324, 333))	('KRAS', 'Gene', '3845', (144, 148))	('ovarian tumors', 'Disease', (390, 404))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (193, 210))	('BRAF', 'Gene', '673', (234, 238))	('ovarian tumors', 'Disease', 'MESH:D010051', (390, 404))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (186, 211))	('BRAF', 'Gene', (234, 238))	('KRAS', 'Gene', (144, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('tumors', 'Phenotype', 'HP:0002664', (398, 404))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (398, 403))
163104	29403559	Our previous study identified that Wnt signaling is activated in mesothelioma cells, and that blockade of Wnt signaling may be achieved with antibodies against Wnt-1 or -2, Wnt-1 or -2 small interfering RNAs (siRNAs), or dominant-negative dishevelled (Dvl), leading to suppressed viability or tumorigenesis of mesothelioma cells in athymic mice.	('dishevelled', 'Gene', (239, 250))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('mice', 'Species', '10090', (340, 344))	('dishevelled', 'Gene', '8215', (239, 250))	('Wnt-1 or -2', 'Gene', (160, 171))	('Wnt-1 or -2', 'Gene', '22408;22413', (173, 184))	('mesothelioma', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('Wnt-1 or -2', 'Gene', (173, 184))	('suppressed', 'NegReg', (269, 279))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('small', 'Var', (185, 190))	('mesothelioma', 'Disease', (310, 322))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('antibodies', 'Var', (141, 151))	('mesothelioma', 'Disease', 'MESH:D008654', (310, 322))	('tumor', 'Disease', (293, 298))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('Wnt-1 or -2', 'Gene', '22408;22413', (160, 171))
163105	29403559	Notably, the mesothelioma H28 cell line exhibits Wnt signal activity, which blocks apoptosis, without expression of beta-catenin, due to a homozygous deletion of the beta-catenin gene and activation of the aforementioned non-canonical pathways.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('mesothelioma H28', 'Disease', 'MESH:D008654', (13, 29))	('beta-catenin', 'Gene', (166, 178))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('non-canonical pathways', 'Pathway', (221, 243))	('mesothelioma H28', 'Disease', (13, 29))	('deletion', 'Var', (150, 158))	('beta-catenin', 'Gene', '1499', (166, 178))	('blocks', 'NegReg', (76, 82))	('apoptosis', 'CPA', (83, 92))	('activation', 'PosReg', (188, 198))	('beta-catenin', 'Gene', (116, 128))	('beta-catenin', 'Gene', '1499', (116, 128))
163107	29403559	The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are promising anticancer drugs for the treatment of patients with non-small cell lung cancer (NSCLC) with a specific EGFR mutation.	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('mutation', 'Var', (234, 242))	('afatinib', 'Chemical', 'MESH:D000077716', (103, 111))	('NSCLC', 'Disease', 'MESH:D002289', (206, 211))	('EGFR', 'Gene', '1956', (229, 233))	('gefitinib', 'Chemical', 'MESH:D000077156', (78, 87))	('non-small cell lung cancer', 'Disease', (178, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('EGFR', 'Gene', '1956', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tyrosine kinase', 'Gene', (44, 59))	('cancer', 'Disease', (198, 204))	('EGFR', 'molecular_function', 'GO:0005006', ('229', '233'))	('NSCLC', 'Disease', (206, 211))	('erlotinib', 'Chemical', 'MESH:D000069347', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('NSCLC', 'Phenotype', 'HP:0030358', (206, 211))	('patients', 'Species', '9606', (164, 172))	('tyrosine kinase', 'Gene', '7294', (44, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (178, 204))	('epidermal growth factor receptor', 'Gene', (4, 36))	('EGFR', 'Gene', (229, 233))	('epidermal growth factor receptor', 'Gene', '1956', (4, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (182, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('4', '27'))	('EGFR', 'Gene', (38, 42))	('cancer', 'Disease', (130, 136))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (178, 204))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
163132	29403559	After 24 h of siRNA transfection, 400 cells were spread onto 35-mm dishes with RPMI-1640 medium and 10% FBS, with 5 microM gefitinib or DMSO as a control.	('gefitinib', 'Chemical', 'MESH:D000077156', (123, 132))	('FBS', 'Disease', (104, 107))	('transfection', 'Var', (20, 32))	('DMSO', 'Chemical', 'MESH:D004121', (136, 140))	('FBS', 'Disease', 'MESH:D005198', (104, 107))	('RPMI-1640 medium', 'Chemical', '-', (79, 95))
163138	29403559	Whereas H28 cells expressed no beta-catenin due to a homozygous deletion of the beta-catenin gene, 211H and H2452 cells did.	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('deletion', 'Var', (64, 72))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('H2452', 'CellLine', 'CVCL:1553', (108, 113))
163144	29403559	At 5, 10 or 30 microM gefitinib, the viability of 211H cells were significantly suppressed synergistically with Dvl-3 siRNA transfection compared with that of cells transfected with control siRNA.	('Dvl-3', 'Gene', '1857', (112, 117))	('gefitinib', 'Var', (22, 31))	('viability', 'CPA', (37, 46))	('gefitinib', 'Chemical', 'MESH:D000077156', (22, 31))	('suppressed', 'NegReg', (80, 90))	('Dvl-3', 'Gene', (112, 117))
163146	29403559	Colony counts of 211H, H2452 and H28 cells were significantly decreased following transfection with Dvl-3 siRNA, and were further significantly decreased following treatment with 5 microM gefitinib, compared with respective controls (Fig.	('decreased', 'NegReg', (144, 153))	('transfection', 'Var', (82, 94))	('decreased', 'NegReg', (62, 71))	('Colony counts', 'CPA', (0, 13))	('Dvl-3', 'Gene', (100, 105))	('Dvl-3', 'Gene', '1857', (100, 105))	('gefitinib', 'Chemical', 'MESH:D000077156', (188, 197))	('H2452', 'CellLine', 'CVCL:1553', (23, 28))
163147	29403559	After 48 h of transfection with Dvl-3 siRNA, the population of 211H, H2452 and H28 cells in G1 phase tended to increase (Fig.	('Dvl-3', 'Gene', '1857', (32, 37))	('increase', 'PosReg', (111, 119))	('G1 phase', 'biological_process', 'GO:0051318', ('92', '100'))	('H2452', 'CellLine', 'CVCL:1553', (69, 74))	('H2452', 'Var', (69, 74))	('Dvl-3', 'Gene', (32, 37))
163148	29403559	At a further 24 h after the addition of gefitinib to the medium, after 24 h of transfection with Dvl-3 siRNA, the population of 211H, H2452 and H28 cells in G1 phase tended to increase further, although these results were not statistically significant (P>0.05; Fig.	('G1 phase', 'biological_process', 'GO:0051318', ('157', '165'))	('H28', 'Var', (144, 147))	('H2452', 'CellLine', 'CVCL:1553', (134, 139))	('increase', 'PosReg', (176, 184))	('G1 phase', 'CPA', (157, 165))	('H2452', 'Var', (134, 139))	('Dvl-3', 'Gene', (97, 102))	('gefitinib', 'Chemical', 'MESH:D000077156', (40, 49))	('Dvl-3', 'Gene', '1857', (97, 102))	('211H', 'Var', (128, 132))
163155	29403559	In the present study, inhibition of Dvl-3 enhanced inhibition of viability at 10 microM in all three mesothelioma cell lines.	('inhibition', 'Var', (22, 32))	('inhibition', 'NegReg', (51, 61))	('Dvl-3', 'Gene', (36, 41))	('Dvl-3', 'Gene', '1857', (36, 41))	('mesothelioma', 'Disease', (101, 113))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
163157	29403559	At 30 microM gefitinib, H28 cell viability was markedly decreased, but it was not affected by downregulation of Dvl-3.	('gefitinib', 'Chemical', 'MESH:D000077156', (13, 22))	('H28 cell viability', 'CPA', (24, 42))	('Dvl-3', 'Gene', '1857', (112, 117))	('decreased', 'NegReg', (56, 65))	('gefitinib', 'Var', (13, 22))	('Dvl-3', 'Gene', (112, 117))
163181	29403559	Furthermore, our previous studies demonstrated that mesothelioma cells express Dvl-3 and that the inhibition of Dvl-3 suppressed mesothelioma cell viability, including that of H28 cells, which do not express beta-catenin.	('inhibition', 'Var', (98, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('Dvl-3', 'Gene', '1857', (112, 117))	('Dvl-3', 'Gene', (79, 84))	('Dvl-3', 'Gene', '1857', (79, 84))	('mesothelioma', 'Disease', (52, 64))	('beta-catenin', 'Gene', '1499', (208, 220))	('beta-catenin', 'Gene', (208, 220))	('mesothelioma', 'Disease', (129, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('Dvl-3', 'Gene', (112, 117))	('suppressed', 'NegReg', (118, 128))
163199	29228689	In addition, inhibitors of TGF-beta receptors significantly reduced invasive growth.	('invasive growth', 'CPA', (68, 83))	('invasive growth', 'biological_process', 'GO:0051831', ('68', '83'))	('invasive growth', 'biological_process', 'GO:0044409', ('68', '83'))	('inhibitors', 'Var', (13, 23))	('invasive growth', 'biological_process', 'GO:0007125', ('68', '83'))	('invasive growth', 'biological_process', 'GO:0044412', ('68', '83'))	('reduced', 'NegReg', (60, 67))	('invasive growth', 'biological_process', 'GO:0001404', ('68', '83'))	('invasive growth', 'biological_process', 'GO:0036267', ('68', '83'))	('TGF-beta', 'Gene', '7040', (27, 35))	('TGF-beta', 'Gene', (27, 35))
163221	29228689	BMP-independent functions, such as modulation of VEGFR2-dependent induction of angiogenesis and inhibition of macrophage migration inhibitory factor (MIF), have also been described for gremlin-1.	('MIF', 'Gene', '4282', (150, 153))	('BMP', 'Gene', (0, 3))	('BMP', 'Gene', '649', (0, 3))	('modulation', 'Var', (35, 45))	('VEGFR2', 'Gene', '3791', (49, 55))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('inhibition of macrophage migration', 'biological_process', 'GO:1905522', ('96', '130'))	('MIF', 'Gene', (150, 153))	('macrophage migration inhibitory factor', 'Gene', (110, 148))	('VEGFR2', 'Gene', (49, 55))	('angiogenesis', 'CPA', (79, 91))	('inhibition', 'NegReg', (96, 106))	('macrophage migration inhibitory factor', 'Gene', '4282', (110, 148))
163236	29228689	Gremlin-1 silencing efficiently inhibited both Matrigel and collagen invasion of H2052 cells (Figure 1D, 1E).	('inhibited', 'NegReg', (32, 41))	('Gremlin-1', 'Gene', '26585', (0, 9))	('Gremlin-1', 'Gene', (0, 9))	('collagen', 'molecular_function', 'GO:0005202', ('60', '68'))	('silencing', 'Var', (10, 19))
163238	29228689	In addition, gremlin-1 silencing resulted in downregulation of the expression of the EMT transcription factor SNAI2 (Figure 1F), similar to what we have reported previously in H2052 cells.	('EMT', 'Gene', '3702', (85, 88))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('SNAI2', 'Gene', '6591', (110, 115))	('gremlin-1', 'Gene', (13, 22))	('silencing', 'Var', (23, 32))	('expression', 'Species', '29278', (67, 77))	('downregulation', 'NegReg', (45, 59))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('expression', 'MPA', (67, 77))	('SNAI2', 'Gene', (110, 115))	('transcription factor', 'molecular_function', 'GO:0000981', ('89', '109'))	('EMT', 'Gene', (85, 88))
163249	29228689	We observed that silencing or overexpression of gremlin-1 in mesothelioma cells affected the adhesion of cells in 2D cultures.	('adhesion of cells in 2D cultures', 'CPA', (93, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (61, 73))	('overexpression', 'PosReg', (30, 44))	('gremlin-1', 'Gene', (48, 57))	('mesothelioma', 'Disease', (61, 73))	('silencing', 'Var', (17, 26))	('affected', 'Reg', (80, 88))	('expression', 'Species', '29278', (34, 44))
163250	29228689	Therefore, we used a commercial PCR array to analyze the mRNA expression levels of extracellular matrix and adhesion molecules in gremlin-1 silenced H2052 cells (see Methods).	('extracellular matrix', 'cellular_component', 'GO:0031012', ('83', '103'))	('gremlin-1', 'Gene', (130, 139))	('expression', 'Species', '29278', (62, 72))	('silenced', 'Var', (140, 148))	('mRNA expression levels of extracellular matrix', 'MPA', (57, 103))
163251	29228689	Gremlin-1 silencing reduced the expression of several mesenchymal matrix proteins including FN1, SPARC and TNC (Supplementary Figure 2).	('reduced', 'NegReg', (20, 27))	('Gremlin-1', 'Gene', '26585', (0, 9))	('FN1', 'Gene', (92, 95))	('Gremlin-1', 'Gene', (0, 9))	('TNC', 'Gene', (107, 110))	('SPARC', 'Disease', (97, 102))	('expression', 'Species', '29278', (32, 42))	('expression', 'MPA', (32, 42))	('silencing', 'Var', (10, 19))
163259	29228689	We observed significantly reduced binding of H2052 cells to fibronectin when gremlin-1 was silenced (Figure 3C).	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('gremlin-1', 'Gene', (77, 86))	('binding', 'Interaction', (34, 41))	('fibronectin', 'Gene', '2335', (60, 71))	('reduced', 'NegReg', (26, 33))	('fibronectin', 'Gene', (60, 71))	('silenced', 'Var', (91, 99))
163260	29228689	Gremlin-1 silencing in JL-1 cells decreased migration/invasion through collagen 1 coated inserts.	('collagen', 'molecular_function', 'GO:0005202', ('71', '79'))	('JL-1', 'CellLine', 'CVCL:2080', (23, 27))	('decreased', 'NegReg', (34, 43))	('Gremlin-1', 'Gene', '26585', (0, 9))	('Gremlin-1', 'Gene', (0, 9))	('silencing', 'Var', (10, 19))
163261	29228689	The results suggest that modulation of integrin expression and cell adhesion is linked to gremlin-1 induced change in mesothelioma cell phenotype.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('modulation', 'Var', (25, 35))	('expression', 'Species', '29278', (48, 58))	('cell adhesion', 'CPA', (63, 76))	('cell adhesion', 'biological_process', 'GO:0007155', ('63', '76'))	('change', 'Reg', (108, 114))	('mesothelioma', 'Disease', (118, 130))	('gremlin-1', 'Gene', (90, 99))	('integrin', 'Protein', (39, 47))
163262	29228689	The PCR array revealed also downregulation of the expression of several matrix metalloproteinases in gremlin-1 silenced H2052 cells (Figure 4A).	('silenced', 'Var', (111, 119))	('downregulation', 'NegReg', (28, 42))	('matrix metalloproteinases', 'Enzyme', (72, 97))	('gremlin-1', 'Gene', (101, 110))	('expression', 'Species', '29278', (50, 60))	('expression', 'MPA', (50, 60))
163265	29228689	Quantitative RT-PCR analyses confirmed that several MMPs were downregulated in gremlin-1 silenced H2052 and JL-1 cells.	('silenced', 'Var', (89, 97))	('downregulated', 'NegReg', (62, 75))	('gremlin-1', 'Gene', (79, 88))	('MMPs', 'Gene', (52, 56))	('JL-1', 'CellLine', 'CVCL:2080', (108, 112))	('MMPs', 'Gene', '4313;4318;4323', (52, 56))
163267	29228689	Gelatin zymography assay indicated that MMP-2 and MMP-9 proteins were downregulated in gremlin-1 silenced H2052 cells and that MMP-2 protein levels were upregulated in JP5/grem1 cell conditioned medium (Figure 4C).	('MMP-2', 'Gene', (40, 45))	('MMP-2', 'molecular_function', 'GO:0004228', ('40', '45'))	('MMP-2', 'Gene', (127, 132))	('MMP-2', 'molecular_function', 'GO:0004228', ('127', '132'))	('protein levels', 'MPA', (133, 147))	('proteins', 'Protein', (56, 64))	('gremlin-1', 'Gene', (87, 96))	('silenced', 'Var', (97, 105))	('MMP-2', 'Gene', '4313', (40, 45))	('downregulated', 'NegReg', (70, 83))	('MMP-9', 'Gene', '4318', (50, 55))	('upregulated', 'PosReg', (153, 164))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('MMP-9', 'molecular_function', 'GO:0004229', ('50', '55'))	('MMP-9', 'Gene', (50, 55))	('MMP-2', 'Gene', '4313', (127, 132))
163268	29228689	The invasive growth of H2052 and JP5/grem1 cells into 3D collagen matrix was blocked by broad spectrum MMP inhibitors (GM6001 and BB2516) confirming the role of MMPs in gremlin-1 induced invasive growth (Figure 4D-4E).	('invasive growth', 'biological_process', 'GO:0044409', ('187', '202'))	('invasive growth', 'CPA', (4, 19))	('blocked', 'NegReg', (77, 84))	('invasive growth', 'biological_process', 'GO:0001404', ('187', '202'))	('invasive growth', 'biological_process', 'GO:0007125', ('4', '19'))	('MMPs', 'Gene', '4313;4318;4323', (161, 165))	('invasive growth', 'biological_process', 'GO:0044412', ('187', '202'))	('BB2516', 'Chemical', 'MESH:C100342', (130, 136))	('invasive growth', 'biological_process', 'GO:0036267', ('4', '19'))	('invasive growth', 'biological_process', 'GO:0051831', ('187', '202'))	('collagen', 'molecular_function', 'GO:0005202', ('57', '65'))	('GM6001', 'Var', (119, 125))	('invasive growth', 'biological_process', 'GO:0044409', ('4', '19'))	('invasive growth', 'biological_process', 'GO:0007125', ('187', '202'))	('invasive growth', 'biological_process', 'GO:0036267', ('187', '202'))	('invasive growth', 'biological_process', 'GO:0001404', ('4', '19'))	('GM6001', 'Chemical', 'MESH:C078131', (119, 125))	('MMP', 'molecular_function', 'GO:0004235', ('103', '106'))	('invasive growth', 'biological_process', 'GO:0044412', ('4', '19'))	('invasive growth', 'biological_process', 'GO:0051831', ('4', '19'))	('MMPs', 'Gene', (161, 165))	('invasive growth', 'CPA', (187, 202))
163271	29228689	In addition, many TGF-beta pathway genes were found to be downregulated in gremlin-1 silenced cells.	('silenced', 'Var', (85, 93))	('gremlin-1', 'Gene', (75, 84))	('TGF-beta', 'Gene', (18, 26))	('downregulated', 'NegReg', (58, 71))	('TGF-beta', 'Gene', '7040', (18, 26))
163273	29228689	Gremlin-1 silencing significantly reduced TGFB2 and INHBA expression but did not alter TGFB1 expression in H2052 cells (Figure 5A).	('expression', 'Species', '29278', (58, 68))	('reduced', 'NegReg', (34, 41))	('Gremlin-1', 'Gene', '26585', (0, 9))	('expression', 'MPA', (58, 68))	('Gremlin-1', 'Gene', (0, 9))	('expression', 'Species', '29278', (93, 103))	('TGFB2', 'Gene', (42, 47))	('INHBA', 'Gene', (52, 57))	('silencing', 'Var', (10, 19))
163274	29228689	In JL-1 cells gremlin-1 silencing reduced the expression of all isoforms, TGFB1 being the most downregulated gene.	('reduced', 'NegReg', (34, 41))	('gremlin-1', 'Gene', (14, 23))	('JL-1', 'CellLine', 'CVCL:2080', (3, 7))	('expression', 'Species', '29278', (46, 56))	('expression of all isoforms', 'MPA', (46, 72))	('TGFB1', 'Gene', (74, 79))	('silencing', 'Var', (24, 33))
163277	29228689	BMP-pathway activity was increased and TGF-beta-pathway activity decreased in H2052 cells upon gremlin-1 knockdown (Figure 5B).	('BMP', 'Gene', (0, 3))	('increased', 'PosReg', (25, 34))	('activity', 'MPA', (56, 64))	('decreased', 'NegReg', (65, 74))	('gremlin-1', 'Gene', (95, 104))	('knockdown', 'Var', (105, 114))	('activity', 'MPA', (12, 20))	('TGF-beta', 'Gene', '7040', (39, 47))	('BMP', 'Gene', '649', (0, 3))	('TGF-beta', 'Gene', (39, 47))
163281	29228689	Silencing gremlin-1 in H2052 cells reduced and overexpression of gremlin-1 in JP5 cells increased the secretion of both active and total TGF-beta (Figure 5C).	('TGF-beta', 'Gene', (137, 145))	('overexpression', 'PosReg', (47, 61))	('gremlin-1', 'Gene', (10, 19))	('secretion', 'biological_process', 'GO:0046903', ('102', '111'))	('expression', 'Species', '29278', (51, 61))	('TGF-beta', 'Gene', '7040', (137, 145))	('gremlin-1', 'Gene', (65, 74))	('increased', 'PosReg', (88, 97))	('secretion of', 'MPA', (102, 114))	('Silencing', 'Var', (0, 9))
163283	29228689	We have previously shown that inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc) reduces mesothelioma cell migration and invasive growth in 3D Matrigel matrix.	('invasive growth', 'biological_process', 'GO:0007125', ('150', '165'))	('activin', 'molecular_function', 'GO:0016915', ('77', '84'))	('activin', 'Gene', (44, 51))	('invasive growth', 'biological_process', 'GO:0036267', ('150', '165'))	('activin', 'Gene', '83729', (77, 84))	('activin', 'Gene', '83729', (44, 51))	('invasive growth', 'biological_process', 'GO:0044409', ('150', '165'))	('activin', 'molecular_function', 'GO:0005160', ('44', '51'))	('invasive growth in 3D Matrigel matrix', 'CPA', (150, 187))	('cell migration', 'biological_process', 'GO:0016477', ('131', '145'))	('invasive growth', 'biological_process', 'GO:0044412', ('150', '165'))	('reduces', 'NegReg', (110, 117))	('invasive growth', 'biological_process', 'GO:0001404', ('150', '165'))	('invasive growth', 'biological_process', 'GO:0051831', ('150', '165'))	('activin', 'molecular_function', 'GO:0016915', ('44', '51'))	('soluble', 'cellular_component', 'GO:0005625', ('69', '76'))	('activin', 'molecular_function', 'GO:0005160', ('77', '84'))	('activin', 'Gene', (77, 84))	('inhibition', 'Var', (30, 40))	('mesothelioma cell migration', 'Disease', 'MESH:D008654', (118, 145))	('mesothelioma cell migration', 'Disease', (118, 145))
163285	29228689	Inhibition of activin/TGF-beta pathway receptors (ALK4, ALK5 and ALK-7) by small molecule inhibitors (SB431542 and SB505124) reduced 3D collagen invasion of H2052 and JP5/grem1 cells (Figure 6A) suggesting a role for activin/TGF-beta pathways in gremlin-1 induced invasive growth.	('ALK5', 'Gene', (56, 60))	('TGF-beta', 'Gene', '7040', (225, 233))	('invasive growth', 'biological_process', 'GO:0001404', ('264', '279'))	('activin', 'molecular_function', 'GO:0016915', ('217', '224'))	('invasive growth', 'biological_process', 'GO:0044412', ('264', '279'))	('activin', 'Gene', (217, 224))	('TGF-beta', 'Gene', (22, 30))	('invasive growth', 'biological_process', 'GO:0051831', ('264', '279'))	('activin', 'Gene', '83729', (14, 21))	('ALK-7', 'Gene', (65, 70))	('TGF-beta', 'Gene', (225, 233))	('SB505124', 'Var', (115, 123))	('collagen', 'molecular_function', 'GO:0005202', ('136', '144'))	('activin', 'molecular_function', 'GO:0005160', ('14', '21'))	('activin', 'Gene', '83729', (217, 224))	('invasive growth', 'biological_process', 'GO:0007125', ('264', '279'))	('ALK4', 'Gene', '91', (50, 54))	('SB431542', 'Chemical', 'MESH:C459179', (102, 110))	('invasive growth', 'biological_process', 'GO:0036267', ('264', '279'))	('3D collagen invasion', 'CPA', (133, 153))	('ALK5', 'Gene', '7046', (56, 60))	('activin', 'molecular_function', 'GO:0016915', ('14', '21'))	('SB505124', 'Chemical', 'MESH:C519132', (115, 123))	('activin', 'molecular_function', 'GO:0005160', ('217', '224'))	('ALK4', 'Gene', (50, 54))	('TGF-beta', 'Gene', '7040', (22, 30))	('reduced', 'NegReg', (125, 132))	('invasive growth', 'biological_process', 'GO:0044409', ('264', '279'))	('activin', 'Gene', (14, 21))	('ALK-7', 'Gene', '130399', (65, 70))
163290	29228689	BMP4 expression was increased in gremlin-1 silenced cells and decreased in JP5/grem1 cells as compared to the controls (Figure 7A).	('gremlin-1', 'Gene', (33, 42))	('increased', 'PosReg', (20, 29))	('BMP', 'Gene', (0, 3))	('expression', 'MPA', (5, 15))	('decreased', 'NegReg', (62, 71))	('BMP', 'Gene', '649', (0, 3))	('silenced', 'Var', (43, 51))	('expression', 'Species', '29278', (5, 15))
163291	29228689	In JL-1 gremlin-1 silenced cells BMP2 expression was instead decreased.	('expression', 'Species', '29278', (38, 48))	('BMP2', 'Gene', (33, 37))	('JL-1 gremlin-1', 'Gene', (3, 17))	('silenced', 'Var', (18, 26))	('JL-1', 'CellLine', 'CVCL:2080', (3, 7))	('BMP2', 'Gene', '650', (33, 37))	('decreased', 'NegReg', (61, 70))
163294	29228689	The small molecule ALK2/ALK3 receptor inhibitor LDN193189 blocked BMP-2 mediated induction of BMP-pathway activity in H2052 cells (Figure 7B).	('BMP-2', 'Gene', (66, 71))	('BMP', 'Gene', (66, 69))	('BMP', 'Gene', (94, 97))	('ALK3', 'Gene', '657', (24, 28))	('ALK2', 'Gene', (19, 23))	('blocked', 'NegReg', (58, 65))	('LDN193189', 'Chemical', 'MESH:C554430', (48, 57))	('BMP-2', 'Gene', '650', (66, 71))	('LDN193189', 'Var', (48, 57))	('BMP', 'Gene', '649', (66, 69))	('ALK2', 'Gene', '90', (19, 23))	('ALK3', 'Gene', (24, 28))	('BMP', 'Gene', '649', (94, 97))
163295	29228689	Treatment of mesothelioma cells with LDN193189 for 3 days reduced BMP-pathway activity as expected, but did not induce TGF-beta-pathway activity (Figure 7C).	('mesothelioma', 'Disease', (13, 25))	('BMP', 'Gene', (66, 69))	('LDN193189', 'Var', (37, 46))	('TGF-beta', 'Gene', '7040', (119, 127))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('BMP', 'Gene', '649', (66, 69))	('TGF-beta', 'Gene', (119, 127))	('reduced', 'NegReg', (58, 65))	('LDN193189', 'Chemical', 'MESH:C554430', (37, 46))
163297	29228689	Invasive growth of JP5/ctrl cells into Matrigel (Figure 7E) or collagen (data not shown) matrices was not enhanced by LDN193189 treatment.	('LDN193189', 'Chemical', 'MESH:C554430', (118, 127))	('Invasive growth', 'biological_process', 'GO:0051831', ('0', '15'))	('Invasive growth', 'biological_process', 'GO:0044409', ('0', '15'))	('LDN193189', 'Var', (118, 127))	('Invasive growth', 'CPA', (0, 15))	('Invasive growth', 'biological_process', 'GO:0036267', ('0', '15'))	('Invasive growth', 'biological_process', 'GO:0007125', ('0', '15'))	('collagen', 'molecular_function', 'GO:0005202', ('63', '71'))	('Invasive growth', 'biological_process', 'GO:0001404', ('0', '15'))	('Invasive growth', 'biological_process', 'GO:0044412', ('0', '15'))
163317	29228689	Notably, VEGFA mRNA expression was decreased in gremlin-1 silenced mesothelioma cells and increased in JP5/grem1 cells as compared to the controls (Figure 9C).	('increased', 'PosReg', (90, 99))	('VEGF', 'Gene', (9, 13))	('silenced', 'Var', (58, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('decreased', 'NegReg', (35, 44))	('gremlin-1', 'Gene', (48, 57))	('VEGF', 'Gene', '7422', (9, 13))	('mesothelioma', 'Disease', (67, 79))	('expression', 'Species', '29278', (20, 30))
163331	29228689	In some studies overexpression of gremlin-1 was found to induce proliferation in cultured epithelial or mesenchymal cells.	('gremlin-1', 'Gene', (34, 43))	('proliferation', 'CPA', (64, 77))	('overexpression', 'Var', (16, 30))	('induce', 'PosReg', (57, 63))	('expression', 'Species', '29278', (20, 30))
163332	29228689	Consistent with this, we observed previously that gremlin-1 silencing in H2052 mesothelioma cells reduces proliferation.	('H2052 mesothelioma', 'Disease', 'MESH:D008654', (73, 91))	('reduces', 'NegReg', (98, 105))	('silencing', 'Var', (60, 69))	('H2052 mesothelioma', 'Disease', (73, 91))	('proliferation', 'CPA', (106, 119))	('gremlin-1', 'Gene', (50, 59))
163338	29228689	In vivo studies also suggested that in gremlin-1 overexpressing cells tumor development was slower, but there was a tendency to send metastasis.	('overexpressing', 'Var', (49, 63))	('gremlin-1', 'Gene', (39, 48))	('send metastasis', 'CPA', (128, 143))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('slower', 'NegReg', (92, 98))
163350	29228689	In agreement, inhibition of MMP activity prevented gremlin-1 induced mesothelioma cell invasion into 3D collagen.	('mesothelioma', 'Disease', (69, 81))	('prevented', 'NegReg', (41, 50))	('collagen', 'molecular_function', 'GO:0005202', ('104', '112'))	('MMP', 'Protein', (28, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('inhibition', 'Var', (14, 24))	('MMP', 'molecular_function', 'GO:0004235', ('28', '31'))
163356	29228689	We have previously linked activin signaling to mesothelioma invasive growth in 3D Matrigel; however, inhibition of activin activity was not enough to reduced invasive growth in 3D collagen.	('inhibition', 'Var', (101, 111))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('invasive growth', 'biological_process', 'GO:0044409', ('158', '173'))	('mesothelioma invasive growth', 'Disease', 'MESH:D008654', (47, 75))	('invasive growth', 'biological_process', 'GO:0044412', ('158', '173'))	('invasive growth', 'biological_process', 'GO:0001404', ('158', '173'))	('activin', 'Gene', (115, 122))	('invasive growth', 'biological_process', 'GO:0044409', ('60', '75'))	('activin', 'Gene', (26, 33))	('mesothelioma invasive growth', 'Disease', (47, 75))	('invasive growth', 'biological_process', 'GO:0051831', ('158', '173'))	('invasive growth', 'biological_process', 'GO:0001404', ('60', '75'))	('activin', 'molecular_function', 'GO:0005160', ('26', '33'))	('reduced', 'NegReg', (150, 157))	('activin', 'molecular_function', 'GO:0005160', ('115', '122'))	('invasive growth', 'biological_process', 'GO:0044412', ('60', '75'))	('invasive growth', 'biological_process', 'GO:0051831', ('60', '75'))	('activin', 'Gene', '83729', (115, 122))	('activin', 'Gene', '83729', (26, 33))	('activin', 'molecular_function', 'GO:0016915', ('26', '33'))	('activin', 'molecular_function', 'GO:0016915', ('115', '122'))	('invasive growth', 'biological_process', 'GO:0007125', ('158', '173'))	('collagen', 'molecular_function', 'GO:0005202', ('180', '188'))	('invasive growth', 'biological_process', 'GO:0036267', ('158', '173'))	('invasive growth', 'biological_process', 'GO:0007125', ('60', '75'))	('invasive growth', 'biological_process', 'GO:0036267', ('60', '75'))
163375	29228689	Targeting gremlin-1 in mesothelioma tumor tissue may present a way to decrease chemoresistance and invasive growth by affecting multiple tumorigenic processes including mesenchymal programming and angiogenesis.	('invasive growth', 'biological_process', 'GO:0036267', ('99', '114'))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (23, 41))	('mul', 'Gene', '4591', (128, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('197', '209'))	('mul', 'Gene', (128, 131))	('decrease', 'NegReg', (70, 78))	('tumor', 'Disease', (36, 41))	('affecting', 'Reg', (118, 127))	('invasive growth', 'biological_process', 'GO:0044409', ('99', '114'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('angiogenesis', 'CPA', (197, 209))	('invasive growth', 'biological_process', 'GO:0001404', ('99', '114'))	('mesenchymal programming', 'CPA', (169, 192))	('tumor', 'Disease', (137, 142))	('invasive growth', 'biological_process', 'GO:0044412', ('99', '114'))	('invasive growth', 'biological_process', 'GO:0051831', ('99', '114'))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mesothelioma tumor', 'Disease', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('gremlin-1', 'Gene', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('invasive growth', 'biological_process', 'GO:0007125', ('99', '114'))	('Targeting', 'Var', (0, 9))	('invasive growth', 'CPA', (99, 114))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (23, 41))	('chemoresistance', 'CPA', (79, 94))
163380	29228689	Anti-gremlin-1 antibody was from Origene (TA324077), anti-E-cadherin antibody from BD Biosciences (610182) and anti-beta-tubulin antibody from Santa Cruz (sc-9104).	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('antibody', 'cellular_component', 'GO:0019814', ('129', '137'))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('antibody', 'cellular_component', 'GO:0042571', ('129', '137'))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('129', '137'))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('TA324077', 'Var', (42, 50))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('610182', 'Var', (99, 105))	('antibody', 'cellular_component', 'GO:0019815', ('129', '137'))
163383	29228689	Broad spectrum MMP inhibitors GM6001 and BB2516 were from Calbiochem and used at 10 muM concentration.	('GM6001', 'Var', (30, 36))	('BB2516', 'Gene', (41, 47))	('BB2516', 'Chemical', 'MESH:C100342', (41, 47))	('GM6001', 'Chemical', 'MESH:C078131', (30, 36))	('MMP', 'Gene', (15, 18))	('MMP', 'molecular_function', 'GO:0004235', ('15', '18'))
163384	29228689	TGF-betaR inhibitors SB431542 and SB505124 were from Sigma-Aldrich and used at 10 muM concentration.	('SB505124', 'Var', (34, 42))	('SB505124', 'Chemical', 'MESH:C519132', (34, 42))	('SB431542', 'Chemical', 'MESH:C459179', (21, 29))	('TGF-beta', 'Gene', '7040', (0, 8))	('SB431542', 'Var', (21, 29))	('TGF-beta', 'Gene', (0, 8))
163385	29228689	BMP receptor inhibitor LDN193189 was from Sigma-Aldrich and used at 100 nM concentration.	('BMP', 'Gene', '649', (0, 3))	('LDN193189', 'Var', (23, 32))	('BMP', 'Gene', (0, 3))	('LDN193189', 'Chemical', 'MESH:C554430', (23, 32))
163448	24013775	In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.	('mesothelioma', 'Disease', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lowering', 'NegReg', (41, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('copper', 'Var', (34, 40))	('patient', 'Species', '9606', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('slows', 'NegReg', (116, 121))	('copper', 'Chemical', 'MESH:D003300', (34, 40))	('tumor', 'Disease', (122, 127))	('copper lowering', 'Phenotype', 'HP:0011967', (34, 49))	('rat', 'Species', '10116', (104, 107))
163455	24013775	Copper lowering may modulate tumor blood vessels to normalize them, i.e.	('Copper', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('tumor', 'Disease', (29, 34))	('modulate', 'Reg', (20, 28))	('lowering', 'NegReg', (7, 15))	('Copper lowering', 'Phenotype', 'HP:0011967', (0, 15))
163459	24013775	Beneficial consequences of vessel normalization may be facilitation of immune cell infiltration and/or enhanced immune cell function.	('immune cell infiltration', 'CPA', (71, 95))	('immune cell function', 'CPA', (112, 132))	('rat', 'Species', '10116', (89, 92))	('enhanced', 'PosReg', (103, 111))	('vessel normalization', 'Var', (27, 47))
163515	24013775	For immune cell analysis single cell suspensions were co-stained with APC Cy7-anti-CD3 and PE-anti-CD8 (both from BD Pharmingen), as well as PECy5.5-anti-CD4 and/or PE-anti-CD19 (both from Biolegend), and FACS analyzed.	('FACS', 'Gene', (205, 209))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('PE-anti-CD8', 'Var', (91, 102))	('FACS', 'Gene', '14081', (205, 209))	('CD3', 'Gene', (83, 86))	('CD3', 'Gene', '12501', (83, 86))	('CD4', 'Gene', (154, 157))	('CD4', 'Gene', '12504', (154, 157))
163565	24013775	We then hypothesized that copper lowering may normalize tumor vessels as previously described.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lowering', 'NegReg', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('copper', 'Var', (26, 32))	('copper', 'Chemical', 'MESH:D003300', (26, 32))	('copper lowering', 'Phenotype', 'HP:0011967', (26, 41))	('normalize', 'NegReg', (46, 55))
163620	24013775	Copper depletion induced structural and functional changes in tumor-associated blood vessels.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('depletion', 'Var', (7, 16))	('functional changes', 'CPA', (40, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
163624	24013775	These data are in agreement with an early study using a rabbit brain tumor model in which copper lowering reduced tumor vessel width, as well as the proliferative rate of tumor endothelia, to similar levels seen in healthy brain vessels.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (114, 119))	('tumor endothelia', 'Disease', (171, 187))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('rat', 'Species', '10116', (163, 166))	('rabbit', 'Species', '9986', (56, 62))	('copper', 'Var', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (156, 159))	('brain tumor', 'Phenotype', 'HP:0030692', (63, 74))	('copper lowering', 'Phenotype', 'HP:0011967', (90, 105))	('lowering reduced', 'NegReg', (97, 113))	('brain tumor', 'Disease', 'MESH:D001932', (63, 74))	('brain tumor', 'Disease', (63, 74))	('proliferative rate', 'CPA', (149, 167))	('tumor endothelia', 'Disease', 'MESH:D009369', (171, 187))	('copper', 'Chemical', 'MESH:D003300', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
163635	24013775	Our findings suggest copper lowering modulates tumor blood vessels such that they are transiently 'normalized' to promote immune cell infiltration into the tumor microenvironment.	('copper', 'Chemical', 'MESH:D003300', (21, 27))	('copper lowering', 'Phenotype', 'HP:0011967', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('immune cell infiltration into', 'CPA', (122, 151))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lowering', 'NegReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('copper', 'Var', (21, 27))	('tumor', 'Disease', (156, 161))	('rat', 'Species', '10116', (140, 143))	('modulates', 'Reg', (37, 46))	('tumor', 'Disease', (47, 52))	('promote', 'PosReg', (114, 121))
163636	24013775	We propose that copper lowering is a potentially useful and relatively non-toxic anti-mesothelioma strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve outcomes for mesothelioma patients.	('tumor', 'Disease', (119, 124))	('rat', 'Species', '10116', (101, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (235, 247))	('lowering', 'NegReg', (23, 31))	('patients', 'Species', '9606', (248, 256))	('copper', 'Var', (16, 22))	('copper', 'Chemical', 'MESH:D003300', (16, 22))	('mesothelioma', 'Disease', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('copper lowering', 'Phenotype', 'HP:0011967', (16, 31))	('mesothelioma', 'Disease', (235, 247))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('slows', 'NegReg', (113, 118))
163719	33633208	The slides were then incubated between 30 min and 1 h (depending on which antibody was used at room temperature) with the same primary antibodies used for IHC staining against the immune markers at similar dilutions: CD3 (dilution 1:100), CD8 (dilution 1:25), PD-1 (dilution 1:250), PD-L1 (dilution 1:1500), Foxp3 (dilution 1:50), KI67 (dilution 1:100), CD68 (dilution 1:50), and panCK (dilution 1:100).	('dilution 1:1500', 'Var', (290, 305))	('CD8', 'Gene', (239, 242))	('dilution 1:50', 'Var', (315, 328))	('CD3', 'Gene', '397455', (217, 220))	('CD8', 'Gene', '925', (239, 242))	('dilution', 'Var', (337, 345))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('CD3', 'Gene', (217, 220))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('dilution', 'Var', (360, 368))
163735	33633208	The different ROIs were divided according the expression of panCK or not in tumor-epithelial compartment (groups or nests of malignant cells) and tumor-stroma compartment (represented by the stroma area between tumor cells), respectively (Fig.	('tumor-stroma', 'Disease', 'MESH:D009369', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('panCK', 'Var', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor-stroma', 'Disease', (146, 158))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
163751	33633208	Interestingly, we observed that an only a median of 143.00 cell/mm2 [minimum (min) 0 cell/mm2; maximum (max) 524.14 cell/mm2] of the total panCK+ cells co-expressed KI67, and of those, only a median of 9.03 cell/mm2 (min 0 cell/mm2; max 318.89 cell/mm2) expressed PD-L1 + (panCK + KI67 + PD-L1 +), showing active proliferation of a small number of tumor cells, Table 1.	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('PD-L1', 'Var', (264, 269))	('tumor', 'Disease', (348, 353))
163761	33633208	We also observed that T-cells expressing PD-L1 (CD3 + PD-L1 +), antigen experienced T-cells (CD3 + PD-1 +), and macrophages expressing PD-L1 were relatively close to malignant cells (median distance, 110.32, 176.46, and 161.88 microns, respectively).	('CD3', 'Gene', '397455', (93, 96))	('CD3', 'Gene', (48, 51))	('CD3', 'Gene', (93, 96))	('PD-L1', 'Var', (41, 46))	('CD3', 'Gene', '397455', (48, 51))
163776	33633208	In fact, we observed that malignant cells expressing PD-L1 were spatially closely associated with CD3 + CD8 + cytotoxic T cells and total CD3 + PD-1 + T cells as compared to their PD-L1- counterparts.	('CD3', 'Gene', '397455', (138, 141))	('PD-L1', 'Var', (53, 58))	('CD3', 'Gene', (138, 141))	('associated', 'Interaction', (82, 92))	('CD8', 'Gene', (104, 107))	('CD3', 'Gene', '397455', (98, 101))	('CD8', 'Gene', '925', (104, 107))	('CD3', 'Gene', (98, 101))
163784	33633208	Interestingly, we also observed that malignant cells expressing PD-L1 are closely localized with cytotoxic T-cells (CD3 + CD8 +) and antigen experienced T-cells (CD3 + PD-1 +) while these subsets are less likely to interact with PD-L1 negative malignant cells.	('CD3', 'Gene', '397455', (162, 165))	('CD3', 'Gene', (116, 119))	('CD8', 'Gene', (122, 125))	('CD3', 'Gene', (162, 165))	('PD-L1', 'Var', (64, 69))	('CD8', 'Gene', '925', (122, 125))	('CD3', 'Gene', '397455', (116, 119))
163793	33633208	This study was supported in part by the Scientific and financial support for the CIMAC-CIDC Network provided through the National Cancer Institute (NCI) Cooperative Agreement U24CA224285 of the MD Anderson Cancer Center CIMAC and for the Translational Molecular Pathology Immunoprofiling Laboratory, National Institutes of Health/National Cancer Institute through Cancer Center Support Grant P30CA016672 (used the Institutional Tissue Bank), and SPORE grant 5P50CA070907-18, by the Cancer Prevention and Research Institute of Texas through MIRA RP160688, and by the Lung Cancer Moon Shot at MD Anderson.	('Shot', 'Gene', (583, 587))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Cancer', 'Disease', (339, 345))	('Bank', 'Gene', '55024', (435, 439))	('Cancer', 'Disease', 'MESH:D009369', (364, 370))	('Bank', 'Gene', (435, 439))	('P30CA016672', 'Var', (392, 403))	('Cancer', 'Disease', 'MESH:D009369', (206, 212))	('Cancer', 'Disease', (130, 136))	('Cancer', 'Disease', 'MESH:D009369', (482, 488))	('Cancer', 'Disease', 'MESH:D009369', (339, 345))	('Shot', 'Gene', '6474', (583, 587))	('Lung Cancer', 'Disease', (566, 577))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('Cancer', 'Phenotype', 'HP:0002664', (364, 370))	('Cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Cancer', 'Disease', (571, 577))	('Cancer', 'Phenotype', 'HP:0002664', (482, 488))	('Lung Cancer', 'Disease', 'MESH:D008175', (566, 577))	('Cancer', 'Disease', (482, 488))	('Cancer', 'Phenotype', 'HP:0002664', (339, 345))	('Cancer', 'Disease', (364, 370))	('Cancer', 'Disease', (206, 212))	('Lung Cancer', 'Phenotype', 'HP:0100526', (566, 577))	('Cancer', 'Disease', 'MESH:D009369', (571, 577))
163855	31942091	Reactive Mesothelial proliferation and distinction from adenocarcinoma BerEP4, MOC31, and EMA positivity favors adenocarcinoma; calretinin/desmin positivity favors reactive mesothelial proliferation Reactive mesothelium versus mesothelioma Strong diffuse membranous EMA and loss of BAP1 and MTAP on IHC with or without p16 deletion on FISH are diagnostic of mesothelioma.	('EMA', 'Gene', '4582', (266, 269))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('mesothelioma', 'Disease', (227, 239))	('desmin positivity', 'Phenotype', 'HP:0100300', (139, 156))	('membranous EMA', 'Phenotype', 'HP:0031153', (255, 269))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('EMA', 'Gene', (266, 269))	('EMA', 'Gene', '4582', (90, 93))	('desmin', 'cellular_component', 'GO:0045098', ('139', '145'))	('EMA', 'Gene', (90, 93))	('mesothelioma', 'Disease', (358, 370))	('desmin', 'Gene', (139, 145))	('mesothelioma', 'Disease', 'MESH:D008654', (358, 370))	('deletion', 'Var', (323, 331))	('BAP1', 'Gene', '8314', (282, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('calretinin', 'Gene', (128, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('desmin', 'Gene', '1674', (139, 145))	('adenocarcinoma', 'Disease', (112, 126))	('BAP1', 'Gene', (282, 286))	('MTAP', 'Gene', (291, 295))	('desmin', 'cellular_component', 'GO:0045100', ('139', '145'))	('adenocarcinoma', 'Disease', (56, 70))	('MTAP', 'Gene', '4507', (291, 295))	('calretinin', 'Gene', '794', (128, 138))
163856	31942091	Desmin positivity favors reactive mesothelium.	('Desmin positivity', 'Phenotype', 'HP:0100300', (0, 17))	('positivity', 'Var', (7, 17))	('reactive mesothelium', 'CPA', (25, 45))	('Desmin', 'Gene', '1674', (0, 6))	('Desmin', 'cellular_component', 'GO:0045100', ('0', '6'))	('Desmin', 'cellular_component', 'GO:0045098', ('0', '6'))	('Desmin', 'Gene', (0, 6))
163858	31942091	Tests done: EGFR mutation; ALK and ROS 1 rearrangements and PDL1 expression.	('ROS 1', 'Gene', (35, 40))	('PDL1', 'Gene', '29126', (60, 64))	('PDL1', 'Gene', (60, 64))	('rearrangements', 'Var', (41, 55))	('mutation', 'Var', (17, 25))	('ALK', 'Gene', (27, 30))	('ROS 1', 'Gene', '6098', (35, 40))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', (12, 16))	('ALK', 'Gene', '238', (27, 30))
163860	31942091	EGFR mutation testing Testing for EGFR driver mutations in exons 18, 19, 20, and 21 can be done by real-time polymerase chain reaction (PCR)-based methods using commercially available kits, next-generation sequencing, or digital PCR.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (46, 55))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (34, 38))
163869	31632972	Although a number of actionable mutations have now been identified, a large population of thoracic cancer patients have no therapeutic options outside of first-line chemotherapy.	('thoracic cancer', 'Disease', 'MESH:D009369', (90, 105))	('thoracic cancer', 'Disease', (90, 105))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
163895	31632972	TP53 or p53 mutations were frequent clonal events in both subtypes, while oncogenic ALK translocations were not observed in any tumors.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p53', 'Gene', (8, 11))	('ALK', 'Gene', (84, 87))	('mutations', 'Var', (12, 21))	('p53', 'Gene', '7157', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ALK', 'Gene', '238', (84, 87))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
163896	31632972	As for MPM, next-generation sequencing of 216 MPM patients showed that the tumor suppressors BAP1, NF2, and SETD2 were significantly mutated through gene fusions and splicing alterations.	('MPM', 'Disease', 'MESH:C562839', (46, 49))	('MPM', 'Disease', (46, 49))	('SETD2', 'Gene', (108, 113))	('NF2', 'Gene', '4771', (99, 102))	('BAP1', 'Gene', '8314', (93, 97))	('patients', 'Species', '9606', (50, 58))	('splicing', 'biological_process', 'GO:0045292', ('166', '174'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('MPM', 'Disease', (7, 10))	('MPM', 'Disease', 'MESH:C562839', (7, 10))	('BAP1', 'Gene', (93, 97))	('mutated', 'Var', (133, 140))	('SETD2', 'Gene', '29072', (108, 113))	('splicing alterations', 'Var', (166, 186))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NF2', 'Gene', (99, 102))	('tumor', 'Disease', (75, 80))
163897	31632972	CDKN2A, which encodes the tumor suppressor p16INK4a, is also frequently deleted in up to 75-90% of MPM cases.	('MPM', 'Disease', 'MESH:C562839', (99, 102))	('p16INK4a', 'Gene', (43, 51))	('deleted', 'Var', (72, 79))	('MPM', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('p16INK4a', 'Gene', '1029', (43, 51))	('to 7', 'Species', '1214577', (86, 90))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('CDKN2A', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('CDKN2A', 'Gene', '1029', (0, 6))
163907	31632972	The best known of these are the EGFR tyrosine kinase inhibitors such as erlotinib and osimertinib, which have proved effective for EGFR mutant ADC tumors.	('osimertinib', 'Chemical', 'None', (86, 97))	('ADC', 'Disease', 'MESH:D000230', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('ADC', 'Disease', (143, 146))	('tumors', 'Disease', (147, 153))	('erlotinib', 'Chemical', 'MESH:C400278', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tyrosine', 'Chemical', 'None', (37, 45))	('EGFR', 'Gene', '1956', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('EGFR', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('mutant', 'Var', (136, 142))
163908	31632972	In the ADC TCGA dataset, 21% of patients had EGFR alterations (Figure 1A), although the occurrence of EGFR mutations can vary between populations in ADC and NSCLC as a whole.	('ADC', 'Disease', 'MESH:D000230', (7, 10))	('patients', 'Species', '9606', (32, 40))	('ADC', 'Disease', (7, 10))	('EGFR', 'Gene', (45, 49))	('ADC', 'Disease', 'MESH:D000230', (149, 152))	('alterations', 'Var', (50, 61))	('ADC', 'Disease', (149, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('NSCLC', 'Disease', (157, 162))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('EGFR', 'Gene', '1956', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
163909	31632972	For example, while EGFR mutation can occur in up to 40% of all NSCLC patients of Asian descent, the frequency of mutation in non-Asian NSCLC populations drops to 10-20%.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('NSCLC', 'Disease', (135, 140))	('EGFR', 'Gene', '1956', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('mutation', 'Var', (24, 32))	('EGFR', 'Gene', (19, 23))	('patients', 'Species', '9606', (69, 77))
163911	31632972	ALK inhibitors are similarly effective in patients harboring ALK translocations, present in 2% of all NSCLC patients.	('translocations', 'Var', (65, 79))	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Disease', (102, 107))	('ALK', 'Gene', (61, 64))	('ALK', 'Gene', '238', (61, 64))	('ALK', 'Gene', (0, 3))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (42, 50))	('ALK', 'Gene', '238', (0, 3))
163912	31632972	Alterations of ALK in ADC tumors specifically is found in up to 7% of cases, according to TCGA data (Figure 1A).	('ALK', 'Gene', (15, 18))	('to 7', 'Species', '1214577', (61, 65))	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ALK', 'Gene', '238', (15, 18))	('ADC', 'Disease', 'MESH:D000230', (22, 25))	('ADC', 'Disease', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
163913	31632972	Inhibitors targeting BRAF mutant tumors (3-5% of lung cancers), MET overexpressing tumors (3-4% of ADC cases) and tumors harboring RET fusion proteins (1-2% of NSCLC) are also currently undergoing preclinical and clinical studies.	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('lung cancers', 'Disease', 'MESH:D008175', (49, 61))	('mutant', 'Var', (26, 32))	('NSCLC', 'Disease', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('lung cancers', 'Disease', (49, 61))	('BRAF', 'Gene', '673', (21, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('BRAF', 'Gene', (21, 25))	('lung cancers', 'Phenotype', 'HP:0100526', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ADC', 'Disease', 'MESH:D000230', (99, 102))	('ADC', 'Disease', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', (33, 39))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
163917	31632972	TP53 mutations are a common alteration in SCC patients (33%; Figure 1B), however, existing targeted TP53 treatments have proven ineffective.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', '7157', (0, 4))	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', (100, 104))	('SCC', 'Gene', (42, 45))	('mutations', 'Var', (5, 14))	('SCC', 'Gene', '6317', (42, 45))
163919	31632972	However, despite promising preclinical studies of PIK3CA inhibitors, the benefit of these drugs appears to be negligible in trials with NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('inhibitors', 'Var', (57, 67))	('PIK3CA', 'Gene', (50, 56))	('PIK3CA', 'Gene', '5290', (50, 56))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', (136, 141))
163922	31632972	FGFR1 amplification occurs in 20-25% of SCC cases (; Figure 1B), but again, targeting it in the clinic has provided limited efficacy and its potential as a viable target remains under contention.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('SCC', 'Gene', '6317', (40, 43))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('SCC', 'Gene', (40, 43))
163935	31632972	Although mutations of YBX1 are rare [~1% in all cancers types ], overexpression of YB-1 is found in a wide range of cancers and is often associated with poor prognosis, including NSCLC and MPM.	('cancers', 'Disease', (48, 55))	('associated', 'Reg', (137, 147))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('YBX1', 'Gene', '4904', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('YB-1', 'Gene', (83, 87))	('overexpression', 'PosReg', (65, 79))	('cancers', 'Disease', (116, 123))	('MPM', 'Disease', 'MESH:C562839', (189, 192))	('YBX1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('NSCLC', 'Disease', (179, 184))	('MPM', 'Disease', (189, 192))
163937	31632972	This supports the results of a recent meta-analysis of data from 692 NSCLC patients which found that high YB-1 protein expression significantly correlated with poorer overall survival and clinicopathological features.	('expression', 'MPA', (119, 129))	('NSCLC', 'Disease', (69, 74))	('YB-1', 'Gene', (106, 110))	('patients', 'Species', '9606', (75, 83))	('protein', 'Protein', (111, 118))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('overall survival', 'CPA', (167, 183))	('high', 'Var', (101, 105))	('poorer', 'NegReg', (160, 166))
163941	31632972	While only PIK3CA and SOX2 were significantly co-expressed in the SCC dataset (q < 0.001; Figure 1B), notably, this analysis did not show YBX1 alteration to be significantly associated with the current targetable oncogenes ALK, BRAF or EGFR in ADC (Figure 1A), despite there being a small proportion of tumors that had elevated levels of both YBX1 and EGFR.	('YBX1', 'Gene', '4904', (343, 347))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('SCC', 'Gene', '6317', (66, 69))	('tumors', 'Disease', (303, 309))	('EGFR', 'molecular_function', 'GO:0005006', ('236', '240'))	('SCC', 'Gene', (66, 69))	('associated', 'Reg', (174, 184))	('PIK3CA', 'Gene', (11, 17))	('EGFR', 'Gene', '1956', (236, 240))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('EGFR', 'Gene', (352, 356))	('EGFR', 'molecular_function', 'GO:0005006', ('352', '356'))	('BRAF', 'Gene', '673', (228, 232))	('ADC', 'Disease', 'MESH:D000230', (244, 247))	('BRAF', 'Gene', (228, 232))	('ADC', 'Disease', (244, 247))	('YBX1', 'Gene', (138, 142))	('ALK', 'Gene', '238', (223, 226))	('alteration', 'Var', (143, 153))	('YBX1', 'Gene', '4904', (138, 142))	('EGFR', 'Gene', '1956', (352, 356))	('PIK3CA', 'Gene', '5290', (11, 17))	('YBX1', 'Gene', (343, 347))	('SOX2', 'Gene', '6657', (22, 26))	('SOX2', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('ALK', 'Gene', (223, 226))	('EGFR', 'Gene', (236, 240))
163942	31632972	This suggests that YB-1 deregulation may represent a unique subpopulation of patients that may not have a targetable mutation.	('deregulation', 'Var', (24, 36))	('YB-1', 'Gene', (19, 23))	('patients', 'Species', '9606', (77, 85))
163953	31632972	A study of 105 NSCLC samples showed that YB-1 and EGFR were significantly co-expressed and knockdown of YB-1 in two NSCLC cell lines resulted in reduction of EGFR.	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('EGFR', 'Gene', (158, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('reduction', 'NegReg', (145, 154))	('knockdown', 'Var', (91, 100))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'Gene', '1956', (50, 54))	('NSCLC', 'Disease', (15, 20))	('YB-1', 'Gene', (104, 108))	('EGFR', 'Gene', (50, 54))	('NSCLC', 'Disease', (116, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))
163956	31632972	YB-1 specifically binds to the promoter of cell cycle activators transcription factor E2F1 and transcription factor E2F2 and YB-1 knockdown reduced cell proliferation of a NSCLC cell line in vitro and in vivo.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('E2F1', 'Gene', '1869', (86, 90))	('E2F1', 'Gene', (86, 90))	('NSCLC', 'Disease', (172, 177))	('cell proliferation of a', 'CPA', (148, 171))	('transcription', 'biological_process', 'GO:0006351', ('95', '108'))	('knockdown', 'Var', (130, 139))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('YB-1', 'Gene', (0, 4))	('transcription factor', 'molecular_function', 'GO:0000981', ('95', '115'))	('E2F2', 'Gene', (116, 120))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('transcription factor', 'molecular_function', 'GO:0000981', ('65', '85'))	('cell cycle', 'biological_process', 'GO:0007049', ('43', '53'))	('YB-1', 'Gene', (125, 129))	('reduced', 'NegReg', (140, 147))	('E2F2', 'Gene', '1870', (116, 120))
163959	31632972	These studies demonstrate the important role of YB-1 by showing that its knockdown with siRNA induces G0/G1 cell cycle arrest in vitro and in vivo.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('induces', 'Reg', (94, 101))	('G0/G1 cell cycle arrest', 'CPA', (102, 125))	('YB-1', 'Gene', (48, 52))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('108', '125'))	('knockdown', 'Var', (73, 82))
163960	31632972	Similarly, we have also shown that targeting YB-1 with siRNA can inhibit the growth of MPM cells in vitro.	('YB-1', 'Gene', (45, 49))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('MPM', 'Disease', 'MESH:C562839', (87, 90))	('inhibit', 'NegReg', (65, 72))	('targeting', 'Var', (35, 44))	('MPM', 'Disease', (87, 90))
163963	31632972	It is possible that the removal of Ser102, a site commonly phosphorylated and associated with growth (discussed further in section "Post-Translational Modification in the Control of YB-1 Activity and Localization"), could explain the lack of growth promotion here.	('Ser', 'cellular_component', 'GO:0005790', ('35', '38'))	('growth', 'MPA', (242, 248))	('Ser102', 'Var', (35, 41))	('removal', 'Var', (24, 31))	('Ser', 'Chemical', 'MESH:C530429', (35, 38))
163969	31632972	In support, silencing YB-1 inhibited the invasion and metastasis of lung cancer cells in vitro and in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('YB-1', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('silencing', 'Var', (12, 21))	('inhibited', 'NegReg', (27, 36))	('metastasis of lung cancer', 'Disease', (54, 79))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (54, 79))
163970	31632972	Similarly, knockdown of YB-1 inhibited lung cancer migration and MPM migration and invasion in vitro.	('inhibited', 'NegReg', (29, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('YB-1', 'Gene', (24, 28))	('MPM', 'Disease', (65, 68))	('MPM', 'Disease', 'MESH:C562839', (65, 68))	('knockdown', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
163989	31632972	Supporting this, knockdown of YB-1 in hepatocellular carcinoma cells reduced NANOG and Oct4, as well as alpha-fetoprotein transcript expression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('NANOG', 'Gene', '79923', (77, 82))	('NANOG', 'Gene', (77, 82))	('hepatocellular carcinoma', 'Disease', (38, 62))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (38, 62))	('reduced', 'NegReg', (69, 76))	('Oct4', 'Gene', (87, 91))	('YB-1', 'Gene', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('knockdown', 'Var', (17, 26))	('alpha-fetoprotein transcript expression', 'MPA', (104, 143))	('Oct4', 'Gene', '5460', (87, 91))
163994	31632972	The re-expression of the microRNA miR-382 in osteosarcoma cells significantly decreased the CSC population resulting in reduced relapse after doxorubicin treatment, EMT and metastasis both in vitro and in vivo.	('relapse after doxorubicin', 'MPA', (128, 153))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('miR-382', 'Gene', '494331', (34, 41))	('EMT', 'Gene', (165, 168))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('EMT', 'Gene', '3702', (165, 168))	('metastasis', 'CPA', (173, 183))	('miR-382', 'Gene', (34, 41))	('microRNA', 'Var', (25, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('EMT', 'biological_process', 'GO:0001837', ('165', '168'))	('decreased', 'NegReg', (78, 87))	('CSC population', 'CPA', (92, 106))	('doxorubicin', 'Chemical', 'MESH:D004317', (142, 153))	('reduced', 'NegReg', (120, 127))
163997	31632972	In breast cancer, inhibition of p90 RSK, a major kinase involved in YB-1 phosphorylation; see section "Post-Translational Modification in the Control of YB-1 Activity and Localization") using the small molecule LJI308 eradicated the population of breast CSCs and induced apoptosis in breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('breast CSCs', 'CPA', (247, 258))	('induced', 'Reg', (263, 270))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('p90 RSK', 'Gene', '6195', (32, 39))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('population', 'CPA', (233, 243))	('p90 RSK', 'Gene', (32, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('inhibition', 'Var', (18, 28))	('eradicated', 'NegReg', (218, 228))	('apoptosis', 'CPA', (271, 280))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('breast cancer', 'Disease', (284, 297))
163999	31632972	Furthermore, knockdown of WAVE3, a protein required for nuclear translocation of YB-1, prevented YB-1 mediated transcriptional activation NANOG, SOX2 and Oct4 in breast CSCs.	('WAVE3', 'Gene', (26, 31))	('breast CSCs', 'Disease', (162, 173))	('Oct4', 'Gene', (154, 158))	('SOX2', 'Gene', (145, 149))	('NANOG', 'Gene', '79923', (138, 143))	('prevented', 'NegReg', (87, 96))	('SOX2', 'Gene', '6657', (145, 149))	('NANOG', 'Gene', (138, 143))	('Oct4', 'Gene', '5460', (154, 158))	('WAVE3', 'Gene', '10810', (26, 31))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('knockdown', 'Var', (13, 22))	('YB-1', 'Gene', (97, 101))
164011	31632972	Silencing YB-1 induces cisplatin sensitization in neuroblastoma, esophageal SCC, bladder cancer and melanoma.	('induces', 'Reg', (15, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (50, 63))	('cisplatin sensitization', 'MPA', (23, 46))	('neuroblastoma', 'Disease', (50, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('SCC', 'Gene', (76, 79))	('neuroblastoma', 'Phenotype', 'HP:0003006', (50, 63))	('sensitization', 'biological_process', 'GO:0046960', ('33', '46'))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('YB-1', 'Gene', (10, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('SCC', 'Gene', '6317', (76, 79))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('Silencing', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
164015	31632972	YB-1 knockdown in lung cancer cell lines resulted in LRP downregulation and nuclear staining of YB-1 correlated with LRP expression in 105 NSCLC samples, conferring significantly lower overall survival.	('downregulation', 'NegReg', (57, 71))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('lower', 'NegReg', (179, 184))	('LRP', 'Gene', '9961', (53, 56))	('knockdown', 'Var', (5, 14))	('expression', 'MPA', (121, 131))	('NSCLC', 'Disease', (139, 144))	('LRP', 'Gene', (117, 120))	('YB-1', 'Gene', (96, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('lung cancer', 'Disease', (18, 29))	('overall survival', 'MPA', (185, 201))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LRP', 'Gene', '9961', (117, 120))	('LRP', 'Gene', (53, 56))
164025	31632972	Chronic inflammation caused by asbestos-related oxidative stress is a major driver of MPM carcinogenesis, implying that aberrations in DNA repair machinery in response to oxidization play a role in the progression of many thoracic cancers.	('inflammation', 'Disease', 'MESH:D007249', (8, 20))	('inflammation', 'Disease', (8, 20))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('DNA repair', 'biological_process', 'GO:0006281', ('135', '145'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('role', 'Reg', (190, 194))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('thoracic cancers', 'Disease', (222, 238))	('thoracic cancers', 'Disease', 'MESH:D009369', (222, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('MPM', 'Disease', 'MESH:C562839', (86, 89))	('oxidative stress', 'Phenotype', 'HP:0025464', (48, 64))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('MPM', 'Disease', (86, 89))	('aberrations', 'Var', (120, 131))	('carcinogenesis', 'Disease', (90, 104))	('inflammation', 'biological_process', 'GO:0006954', ('8', '20'))	('play', 'Reg', (183, 187))
164033	31632972	Cross-talk between YB-1 and XPC (an important player in NER which has significance in lung cancer carcinogenesis and is affected by germline mutation in MPM), results in their assembly at DNA damage sites.	('MPM', 'Disease', 'MESH:C562839', (153, 156))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('MPM', 'Disease', (153, 156))	('YB-1 and XPC', 'Gene', '4904;7508', (19, 31))	('lung cancer carcinogenesis', 'Disease', (86, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('N', 'Chemical', 'MESH:D009584', (189, 190))	('assembly', 'MPA', (176, 184))	('germline', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NER', 'biological_process', 'GO:0006289', ('56', '59'))	('lung cancer carcinogenesis', 'Disease', 'MESH:D008175', (86, 112))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('results in', 'Reg', (159, 169))	('affected by', 'Reg', (120, 131))
164038	31632972	A malignant role for exosomes in lung cancer is well documented, where exosomes can induce proliferation, angiogenesis, EMT changes and metastasis.	('EMT', 'Gene', (120, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('EMT', 'Gene', '3702', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('induce', 'PosReg', (84, 90))	('exosomes', 'Var', (71, 79))	('angiogenesis', 'CPA', (106, 118))	('metastasis', 'CPA', (136, 146))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('proliferation', 'CPA', (91, 104))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('lung cancer', 'Disease', (33, 44))
164050	31632972	High YB-1 was also associated with resistance to cisplatin, gemcitabine, docetaxel, dasatinib and gefitinib in this study.	('associated', 'Reg', (19, 29))	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('resistance to cisplatin', 'MPA', (35, 58))	('YB-1', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('docetaxel', 'Chemical', 'MESH:C067311', (73, 82))	('gefitinib', 'Chemical', 'MESH:C419708', (98, 107))	('dasatinib', 'Chemical', 'MESH:C488369', (84, 93))
164053	31632972	As YB-1 is frequently overexpressed in cancer, dysregulation of these controlling systems may play a role in malignant transformation.	('role', 'Reg', (101, 105))	('dysregulation', 'Var', (47, 60))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('malignant transformation', 'CPA', (109, 133))	('overexpressed', 'PosReg', (22, 35))	('YB-1', 'Gene', (3, 7))	('play', 'Reg', (94, 98))
164054	31632972	Several transcription factors have been found to promote YB-1 transcription by binding to motifs in the YBX1 promoter.	('YBX1', 'Gene', (104, 108))	('motifs', 'Var', (90, 96))	('YB-1', 'Gene', (57, 61))	('transcription', 'biological_process', 'GO:0006351', ('8', '21'))	('transcription', 'MPA', (62, 75))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('YBX1', 'Gene', '4904', (104, 108))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('promote', 'PosReg', (49, 56))
164058	31632972	A recent meta-analysis of 572 NSCLC patients showed that high Twist1 expression significantly correlated with poorer patient prognosis, recurrence-free survival and lymph node or other metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('Twist1', 'Gene', (62, 68))	('patients', 'Species', '9606', (36, 44))	('high', 'Var', (57, 61))	('expression', 'MPA', (69, 79))	('recurrence-free survival', 'CPA', (136, 160))	('Twist1', 'Gene', '7291', (62, 68))	('patient prognosis', 'CPA', (117, 134))	('poorer', 'NegReg', (110, 116))	('patient', 'Species', '9606', (117, 124))	('NSCLC', 'Disease', (30, 35))	('lymph node or other metastasis', 'CPA', (165, 195))	('patient', 'Species', '9606', (36, 43))
164070	31632972	This pathway is frequently activated in lung cancer and antagonizing mTOR in such cells has proven to be a potential therapeutic avenue.	('mTOR', 'Gene', '2475', (69, 73))	('mTOR', 'Gene', (69, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('antagonizing', 'Var', (56, 68))	('lung cancer', 'Disease', (40, 51))	('activated', 'PosReg', (27, 36))
164074	31632972	Y-box binding protein-1 is controlled by an autoregulatory feedback loop in which YB-1 binds its own mRNA at two 8 nucleotide motifs at (nt) 1133-1145 and nt 1165-1172, inhibiting translation prior to 40S ribosomal subunit binding (; Figure 2).	('translation', 'biological_process', 'GO:0006412', ('180', '191'))	('binding', 'molecular_function', 'GO:0005488', ('6', '13'))	('translation', 'MPA', (180, 191))	('binding', 'molecular_function', 'GO:0005488', ('223', '230'))	('mRNA', 'Protein', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('YB-1', 'Gene', (82, 86))	('nt 1165-1172', 'Var', (155, 167))	('40S ribosomal subunit', 'cellular_component', 'GO:0022627', ('201', '222'))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('inhibiting', 'NegReg', (169, 179))
164088	31632972	Dysregulation of DANCR and subsequent lowering of miR-216a could represent one mechanism of YB-1 overexpression in thoracic cancer, representing an area which requires further investigation.	('overexpression', 'PosReg', (97, 111))	('YB-1', 'Gene', (92, 96))	('DANCR', 'Gene', (17, 22))	('Dysregulation', 'Var', (0, 13))	('DANCR', 'Gene', '57291', (17, 22))	('miR-216a', 'Gene', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('miR-216a', 'Gene', '406998', (50, 58))	('thoracic cancer', 'Disease', 'MESH:D009369', (115, 130))	('thoracic cancer', 'Disease', (115, 130))	('lowering', 'NegReg', (38, 46))
164091	31632972	Interestingly, GAS5 knockdown did not affect YBX1 mRNA expression, something the authors attribute to possible interactions with other proteins.	('YBX1', 'Gene', (45, 49))	('mRNA expression', 'MPA', (50, 65))	('GAS', 'molecular_function', 'GO:0034005', ('15', '18'))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('YBX1', 'Gene', '4904', (45, 49))	('interactions', 'Interaction', (111, 123))	('GAS5', 'Gene', '60674', (15, 19))	('knockdown', 'Var', (20, 29))	('GAS5', 'Gene', (15, 19))
164093	31632972	However, GAS5 knockdown does not affect YBX1 mRNA expression, as would be expected by an increase in miR-137 availability, so this does not fully explain this relationship.	('increase', 'PosReg', (89, 97))	('miR-137', 'Gene', '406928', (101, 108))	('GAS', 'molecular_function', 'GO:0034005', ('9', '12'))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('YBX1', 'Gene', (40, 44))	('GAS5', 'Gene', '60674', (9, 13))	('miR-137', 'Gene', (101, 108))	('knockdown', 'Var', (14, 23))	('mRNA expression', 'MPA', (45, 60))	('YBX1', 'Gene', '4904', (40, 44))	('GAS5', 'Gene', (9, 13))
164106	31632972	ncRNA therefore play an integral role in the expression and activity of YB-1, and dysregulation of these families is likely to contribute to YB-1 overexpression in cancer.	('dysregulation', 'Var', (82, 95))	('overexpression', 'PosReg', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ncRNA', 'Gene', (0, 5))	('contribute', 'Reg', (127, 137))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('activity', 'MPA', (60, 68))	('ncRNA', 'Gene', '220202', (0, 5))	('YB-1', 'Gene', (141, 145))	('YB-1', 'Gene', (72, 76))
164107	31632972	Ser102 (located in the CSD of YB-1) is currently the most comprehensively studied phosphorylation site.	('CSD', 'Gene', (23, 26))	('Ser102', 'Var', (0, 6))	('CSD', 'Gene', '7045', (23, 26))	('Ser', 'Chemical', 'MESH:C530429', (0, 3))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
164109	31632972	Several additional phosphorylation sites on YB-1 have been identified including Tyr281, which is located within a NLS toward the C-terminal of YB-1 and correlates with the nuclear localization of either a YB-1 C-terminal fragment or full length YB-1 (refer to next section for more detail).	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('nuclear localization', 'MPA', (172, 192))	('NLS', 'Gene', (114, 117))	('YB-1', 'Gene', (44, 48))	('YB-1', 'Gene', (143, 147))	('Tyr281', 'Var', (80, 86))	('NLS', 'Gene', '26227', (114, 117))	('localization', 'biological_process', 'GO:0051179', ('180', '192'))
164110	31632972	Tyr162 on YB-1 is also reportedly phosphorylated by FGFR1, an important oncogenic driver in lung cancer and mesothelioma, however, to our knowledge the significance of this modification has not yet been established.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('mesothelioma', 'Disease', (108, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('YB-1', 'Gene', (10, 14))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('Tyr162', 'Var', (0, 6))
164111	31632972	Ser165 and Ser176 on YB-1 are also phosphorylated, each promoting distinct groups of nuclear factor-kappaB target gene expression.	('Ser', 'cellular_component', 'GO:0005790', ('11', '14'))	('promoting', 'PosReg', (56, 65))	('Ser', 'Chemical', 'MESH:C530429', (0, 3))	('Ser', 'Chemical', 'MESH:C530429', (11, 14))	('groups of', 'MPA', (75, 84))	('YB-1', 'Gene', (21, 25))	('Ser165', 'Var', (0, 6))	('Ser176', 'Chemical', 'MESH:C530429', (11, 17))	('Ser176', 'Var', (11, 17))	('gene expression', 'biological_process', 'GO:0010467', ('114', '129'))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
164113	31632972	In the case of Ser102, it seems that phosphorylation is linked to the hexosamine biosynthetic pathway, in which OGT and O-linked N-acetylglucosamine add or remove N-acetylglucosamine groups to serine or threonine residues, respectively.	('remove', 'NegReg', (156, 162))	('Ser', 'cellular_component', 'GO:0005790', ('15', '18'))	('N-acetylglucosamine groups', 'MPA', (163, 189))	('N-acetylglucosamine', 'Chemical', 'MESH:C014088', (163, 182))	('OGT', 'Gene', (112, 115))	('N-acetylglucosamine', 'Chemical', 'MESH:C014088', (129, 148))	('OGT', 'Gene', '8473', (112, 115))	('threonine', 'Chemical', 'MESH:C061951', (203, 212))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('Ser', 'Chemical', 'MESH:C530429', (15, 18))	('Ser102', 'Var', (15, 21))	('hexosamine', 'Enzyme', (70, 80))	('serine', 'Chemical', 'MESH:C047902', (193, 199))	('hexosamine', 'Chemical', 'MESH:D006595', (70, 80))
164114	31632972	OGT-mediated O-linked glycosylation of YB-1 at Thr216 aids in the phosphorylation of Ser102 and subsequent transcriptional activity of YB-1 in hepatocellular carcinoma (; Figure 3).	('YB-1', 'Gene', (135, 139))	('glycosylation', 'biological_process', 'GO:0070085', ('22', '35'))	('Thr216', 'Var', (47, 53))	('YB-1', 'Gene', (39, 43))	('OGT', 'Gene', (0, 3))	('phosphorylation', 'MPA', (66, 81))	('aids', 'PosReg', (54, 58))	('OGT', 'Gene', '8473', (0, 3))	('transcriptional activity', 'MPA', (107, 131))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (143, 167))	('Thr', 'Chemical', 'MESH:C055175', (47, 50))	('hepatocellular carcinoma', 'Disease', (143, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (143, 167))	('Ser', 'Chemical', 'MESH:C530429', (85, 88))
164117	31632972	One of these sites is a canonical inverted sumoylation site (at amino acids 287-290 within NLS-3), while the other two are non-canonical sites (at 60-63 which is within the CSD and at 151-154, within NLS-1; Figure 3).	('at amino acids 287-290', 'Var', (61, 83))	('sumoylation', 'biological_process', 'GO:0016925', ('43', '54'))	('inverted sumoylation site', 'MPA', (34, 59))	('NLS', 'Gene', '26227', (91, 94))	('NLS', 'Gene', (200, 203))	('NLS-1', 'Gene', '26227', (200, 205))	('NLS', 'Gene', (91, 94))	('at', 'Var', (144, 146))	('CSD', 'Gene', (173, 176))	('CSD', 'Gene', '7045', (173, 176))	('NLS', 'Gene', '26227', (200, 203))	('NLS-1', 'Gene', (200, 205))
164119	31632972	Although one study failed to find a link between night shift work and lung cancer among a cohort of female textile workers in Shanghai, China, preclinical data indicates that disturbance of the circadian clock can promote lung tumor growth in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('promote', 'PosReg', (214, 221))	('lung tumor', 'Disease', (222, 232))	('disturbance', 'Var', (175, 186))	('lung tumor', 'Disease', 'MESH:D008175', (222, 232))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumor', 'Phenotype', 'HP:0100526', (222, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
164120	31632972	Modulation of YB-1 localization in response to light may represent one contributing factor in the observed correlation between circadian rhythm and cancer and warrants further investigation.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('localization', 'biological_process', 'GO:0051179', ('19', '31'))	('localization', 'MPA', (19, 31))	('correlation', 'Interaction', (107, 118))	('YB-1', 'Gene', (14, 18))	('circadian rhythm', 'biological_process', 'GO:0007623', ('127', '143'))
164124	31632972	Lys301/304 of YB-1 can also be acetylated and the amount of acetylated YB-1 is significantly increased in monocytes of hemodialysis patients.	('increased', 'PosReg', (93, 102))	('Lys301/304', 'Var', (0, 10))	('amount', 'MPA', (50, 56))	('YB-1', 'Gene', (14, 18))	('acetylated', 'MPA', (31, 41))	('patients', 'Species', '9606', (132, 140))
164127	31632972	Further supporting this theory, UV irradiated DNA damage stimulates YB-1 ubiquitination at Lys64 (the same lysine residue that is acetylated, above in this section; Figure 3).	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('stimulates', 'PosReg', (57, 67))	('YB-1', 'Gene', (68, 72))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('Lys64', 'Var', (91, 96))	('Lys64', 'Chemical', 'MESH:C063487', (91, 96))	('ubiquitination', 'MPA', (73, 87))	('lysine', 'Chemical', 'MESH:C114808', (107, 113))
164138	31632972	For example, there is evidence showing that YB-1 is phosphorylated at Ser102 by the serine/threonine kinase AKT before being shuttled to the nucleus (; Figures 3, 5).	('AKT', 'Gene', '207', (108, 111))	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('threonine', 'Chemical', 'MESH:C061951', (91, 100))	('YB-1', 'Gene', (44, 48))	('Ser102', 'Var', (70, 76))	('AKT', 'Gene', (108, 111))	('Ser', 'Chemical', 'MESH:C530429', (70, 73))	('nucleus', 'cellular_component', 'GO:0005634', ('141', '148'))	('serine', 'Chemical', 'MESH:C047902', (84, 90))
164140	31632972	However, a recent study found that while ionizing radiation, EGF stimulation and overexpression of the KRAS G12V mutant induced Ser102 phosphorylation of YB-1 in both the nucleus and the cytoplasm, there was no increase in YB-1 expression in nuclear fractions.	('cytoplasm', 'cellular_component', 'GO:0005737', ('187', '196'))	('KRAS', 'Gene', (103, 107))	('EGF', 'molecular_function', 'GO:0005154', ('61', '64'))	('KRAS', 'Gene', '3845', (103, 107))	('Ser102 phosphorylation', 'MPA', (128, 150))	('nucleus', 'cellular_component', 'GO:0005634', ('171', '178'))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('EGF', 'Gene', (61, 64))	('Ser', 'Chemical', 'MESH:C530429', (128, 131))	('induced', 'Reg', (120, 127))	('YB-1', 'Gene', (154, 158))	('EGF', 'Gene', '1950', (61, 64))	('G12V', 'Var', (108, 112))	('G12V', 'SUBSTITUTION', 'None', (108, 112))	('Ser', 'cellular_component', 'GO:0005790', ('128', '131'))
164143	31632972	As mentioned in section "Post-Translational Modification in the Control of YB-1 Activity and Localization," phosphorylation of Thr281 within the NLS 276-292 of YB-1 also correlates with its nuclear translocation, however, it is not yet clear whether this modification is actively involved in YB-1 shuttling.	('YB-1', 'Gene', (160, 164))	('Activity', 'MPA', (80, 88))	('Thr281', 'Var', (127, 133))	('Thr', 'Chemical', 'MESH:C055175', (127, 130))	('NLS', 'Gene', '26227', (145, 148))	('nuclear translocation', 'MPA', (190, 211))	('phosphorylation', 'MPA', (108, 123))	('NLS', 'Gene', (145, 148))
164151	31632972	Serum HMGB1 has shown prognostic relevance as a possible biomarker in MPM.	('MPM', 'Disease', (70, 73))	('HMGB1', 'Gene', (6, 11))	('HMGB1', 'Gene', '3146', (6, 11))	('Ser', 'Chemical', 'MESH:C530429', (0, 3))	('Serum', 'Var', (0, 5))	('MPM', 'Disease', 'MESH:C562839', (70, 73))
164153	31632972	This was first evident in monocytes stimulated with bacterial lipopolysaccharide through an active, non-classical pathway and appears to require the same two lysine residues (Lys301/304) that are the site of adenylation in hemodialysis patients (; Figures 3-5).	('hemodialysis', 'Disease', (223, 235))	('patients', 'Species', '9606', (236, 244))	('Lys301/304', 'Var', (175, 185))	('lysine', 'Chemical', 'MESH:C114808', (158, 164))
164158	31632972	Secretion of YB-1 resulted in depletion of cytoplasmic YB-1, leaving nuclear expression intact (presumably to allow for YB-1-mediated DNA repair), while secreted YB-1 inhibited the growth of neighboring keratinocytes.	('Secretion', 'Var', (0, 9))	('inhibited', 'NegReg', (167, 176))	('YB-1', 'Gene', (13, 17))	('nuclear expression intact', 'MPA', (69, 94))	('depletion', 'MPA', (30, 39))	('YB-1', 'Gene', (55, 59))	('DNA repair', 'biological_process', 'GO:0006281', ('134', '144'))	('growth of neighboring keratinocytes', 'CPA', (181, 216))	('leaving', 'Reg', (61, 68))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
164164	31632972	YB-1 protein has been correlated with poor prognosis previously, supported by a recent meta-analysis of six studies covering data on 692 NSCLC patients, where YB-1 was associated with worse overall survival, tumor stage and depth of invasion.	('NSCLC', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('depth of invasion', 'CPA', (224, 241))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('overall survival', 'CPA', (190, 206))	('YB-1', 'Var', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('worse', 'NegReg', (184, 189))	('YB-1', 'Gene', (0, 4))	('patients', 'Species', '9606', (143, 151))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('tumor', 'Disease', (208, 213))	('protein', 'Protein', (5, 12))
164174	31632972	One study of 44 breast cancer patients with bone metastases found that serum YB-1 was present in 50% of patients and associated with extra-bone metastases and faster bone disease progression.	('bone metastases', 'Disease', (44, 59))	('bone metastases', 'Disease', (139, 154))	('breast cancer', 'Disease', (16, 29))	('bone metastases', 'Disease', 'MESH:D009362', (44, 59))	('YB-1', 'Gene', (77, 81))	('bone disease', 'Disease', (166, 178))	('associated with', 'Reg', (117, 132))	('serum', 'Var', (71, 76))	('patients', 'Species', '9606', (30, 38))	('bone disease', 'Disease', 'MESH:D001847', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('bone metastases', 'Disease', 'MESH:D009362', (139, 154))	('patients', 'Species', '9606', (104, 112))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
164175	31632972	There was a trend toward poorer overall survival in high-YB-1 patients, although a bigger cohort is needed to provide a more definitive answer.	('patients', 'Species', '9606', (62, 70))	('poorer', 'NegReg', (25, 31))	('high-YB-1', 'Var', (52, 61))	('overall survival', 'MPA', (32, 48))
164183	31632972	More pertinently, a phase 1 clinical trial delivering miR-16-based mimics using bacterial minicells (EnGeneIC Dream Vectors) in mesothelioma and advanced NSCLC patients demonstrated the safety and efficacy of miRNA-based therapy, evidencing the potential for miRNA replacement therapy in patients with thoracic cancer.	('miR-16', 'Gene', '51573', (54, 60))	('patients', 'Species', '9606', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('miRNA-based', 'Var', (209, 220))	('thoracic cancer', 'Disease', 'MESH:D009369', (302, 317))	('thoracic cancer', 'Disease', (302, 317))	('patients', 'Species', '9606', (288, 296))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('mesothelioma', 'Disease', (128, 140))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('N', 'Chemical', 'MESH:D009584', (262, 263))	('miR-16', 'Gene', (54, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (128, 140))	('NSCLC', 'Disease', (154, 159))
164202	31632972	Preclinical evidence in other tumors suggests that targeting YB-1 could also benefit immunotherapy in some cases.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('immunotherapy', 'CPA', (85, 98))	('targeting', 'Var', (51, 60))	('YB-1', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('benefit', 'PosReg', (77, 84))
164203	31632972	YB-1 knockdown increased the efficacy of IFN-alpha in renal cell carcinoma cells in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('efficacy', 'MPA', (29, 37))	('knockdown', 'Var', (5, 14))	('renal cell carcinoma', 'Disease', (54, 74))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (54, 74))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (54, 74))	('increased', 'PosReg', (15, 24))	('YB-1', 'Gene', (0, 4))	('IFN-alpha', 'Gene', '3439', (41, 50))	('IFN-alpha', 'Gene', (41, 50))
164209	31632972	In the context of regulatory T-cell depletion, YB-1 immunization enhanced CD8+ response against neuroblastoma cells and conferred significantly higher mouse survival compared to control groups.	('neuroblastoma', 'Disease', (96, 109))	('mouse', 'Species', '10090', (151, 156))	('YB-1', 'Gene', (47, 51))	('mouse survival', 'CPA', (151, 165))	('neuroblastoma', 'Phenotype', 'HP:0003006', (96, 109))	('enhanced', 'PosReg', (65, 73))	('higher', 'PosReg', (144, 150))	('neuroblastoma', 'Disease', 'MESH:D009447', (96, 109))	('immunization', 'Var', (52, 64))
164219	31632972	While there is strong evidence supporting YB-1-driven resistance to platinum chemotherapy in other cancers, a study looking at the effect of YB-1 knockdown on cisplatin or other platinum drug sensitivity in lung cancer or MPM cells is still required.	('knockdown', 'Var', (146, 155))	('drug sensitivity', 'Phenotype', 'HP:0020174', (187, 203))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('MPM', 'Disease', 'MESH:C562839', (222, 225))	('MPM', 'Disease', (222, 225))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('platinum', 'Chemical', 'MESH:D010984', (68, 76))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('YB-1', 'Gene', (141, 145))	('lung cancer', 'Disease', (207, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
164226	31632972	It is also possible that secreted YB-1 could be used as a biomarker down the line, however, studies with larger patient numbers are required to determine this.	('YB-1', 'Gene', (34, 38))	('secreted', 'Var', (25, 33))	('patient', 'Species', '9606', (112, 119))
164236	31118810	The optimal cutoff value of SII was 988.6x109/L.	('SII', 'Disease', (28, 31))	('SII', 'Disease', 'None', (28, 31))	('988.6x109/L', 'Var', (36, 47))
164268	31118810	Parameters were collected as potential prognostic factors including age (<65 or >=65 years), gender (male or female), smoking history (never or ever), Eastern Cooperative Oncology Group performance status (ECOG PS) scores (<2 or >=2 points), primary site of tumor (left or right), pleural effusion (yes or no), weight loss (yes or no), pretreatment SII (<988.6 or >=988.6x109/L) and treatment strategies (best supportive care [BSC] or adjuvant therapies).	('pleural effusion', 'Disease', (281, 297))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('pleural effusion', 'Phenotype', 'HP:0002202', (281, 297))	('SII', 'Disease', 'None', (349, 352))	('<988.6', 'Var', (354, 360))	('tumor', 'Disease', (258, 263))	('weight loss', 'Phenotype', 'HP:0001824', (311, 322))	('Oncology', 'Phenotype', 'HP:0002664', (171, 179))	('weight loss', 'Disease', 'MESH:D015431', (311, 322))	('BSC', 'Chemical', '-', (427, 430))	('pleural effusion', 'Disease', 'MESH:D010996', (281, 297))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('weight loss', 'Disease', (311, 322))	('SII', 'Disease', (349, 352))
164282	31118810	The mean pretreatment SII level of 97 cases was 1275.4+-955.9x109/L (range 247.5-6725.1).	('1275.4+-955.9x109/L', 'Var', (48, 67))	('SII', 'Disease', (22, 25))	('SII', 'Disease', 'None', (22, 25))
164283	31118810	According to the result of ROC analysis, the optimal cut-off value of pretreatment SII was 988.6x109/L (Figure 1, AUC, 0.700; 95% CI, 0.594-0.805; P=0.001).	('SII', 'Disease', 'None', (83, 86))	('988.6x109/L', 'Var', (91, 102))	('SII', 'Disease', (83, 86))
164454	23576561	Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases Recent clinical trials have shown promise in the use of chimeric antigen receptor(CAR)-transduced T cells; however, augmentation of their activity may broaden their clinical utility and improve their efficacy.	('CD8+ T Cells Deficient', 'Phenotype', 'HP:0005415', (41, 63))	('chimeric antigen receptor', 'Gene', (146, 171))	('efficacy', 'MPA', (290, 298))	('Effector Responses', 'CPA', (9, 27))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('augmentation', 'Var', (206, 218))	('CAR', 'cellular_component', 'GO:0005826', ('172', '175'))	('activity', 'MPA', (228, 236))	('Deficient', 'Var', (54, 63))	('chimeric antigen receptor', 'Gene', '12355', (146, 171))	('improve', 'PosReg', (276, 283))
164458	23576561	Consistent with our studies in mice, pharmacologic inhibition of dgks also augments function of primary human T cells transduced with CARs.	('pharmacologic', 'Var', (37, 50))	('augments', 'NegReg', (75, 83))	('dgks', 'Gene', (65, 69))	('human', 'Species', '9606', (104, 109))	('mice', 'Species', '10090', (31, 35))
164461	23576561	Although the extent to which CD8+ T cells are capable of controlling the development and progression of tumorigenesis remains uncertain, it is clear that deficiency of these cells increases the potential for the development of malignancy and that enhanced function of these CD8+ T cells can impart robust anti-tumor responses in both animal model systems and patients.	('malignancy', 'Disease', 'MESH:D009369', (227, 237))	('CD8', 'Gene', (274, 277))	('enhanced', 'PosReg', (247, 255))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('deficiency', 'Var', (154, 164))	('CD8', 'Gene', '925', (29, 32))	('development', 'CPA', (212, 223))	('CD8', 'Gene', '925', (274, 277))	('tumor', 'Disease', (104, 109))	('malignancy', 'Disease', (227, 237))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumor', 'Disease', (310, 315))	('CD8', 'Gene', (29, 32))	('patients', 'Species', '9606', (359, 367))
164473	23576561	We hypothesized that deletion of proteins that limit the strength of TCR signal might overcome this obstacle of impaired CD8+ T cell anti-tumor immunity and impart significantly enhanced anti-tumor functioning in CAR-expressing CD8+ T cells.	('tumor', 'Disease', (192, 197))	('enhanced', 'PosReg', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (138, 143))	('CAR', 'cellular_component', 'GO:0005826', ('213', '216'))	('TCR', 'cellular_component', 'GO:0042101', ('69', '72'))	('deletion', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CD8', 'Gene', '925', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('TCR', 'biological_process', 'GO:0006283', ('69', '72'))	('proteins', 'Protein', (33, 41))	('CD8', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CD8', 'Gene', (228, 231))	('CD8', 'Gene', '925', (228, 231))	('strength', 'MPA', (57, 65))
164477	23576561	Previously, we and others observed that deletion of either dgk isoform potentiates DAG-mediated Ras and ERK activation and augments TCR-induced cytokine production and T cell proliferation.	('TCR', 'biological_process', 'GO:0006283', ('132', '135'))	('augments', 'NegReg', (123, 131))	('ERK', 'Gene', (104, 107))	('T cell proliferation', 'biological_process', 'GO:0042098', ('168', '188'))	('DAG-mediated Ras', 'MPA', (83, 99))	('dgk', 'Gene', (59, 62))	('deletion', 'Var', (40, 48))	('ERK', 'molecular_function', 'GO:0004707', ('104', '107'))	('potentiates', 'PosReg', (71, 82))	('DAG', 'Chemical', 'MESH:D004075', (83, 86))	('TCR-induced cytokine production', 'MPA', (132, 163))	('cytokine production', 'biological_process', 'GO:0001816', ('144', '163'))	('T cell proliferation', 'CPA', (168, 188))	('TCR', 'cellular_component', 'GO:0042101', ('132', '135'))	('ERK', 'Gene', '13844', (104, 107))	('activation', 'PosReg', (108, 118))
164478	23576561	We have found further that deletion of dgkzeta results in improved CD8+ T cell responses by augmenting signaling via the TCR when mice are challenged with a transplantable subcutaneous tumor.	('tumor', 'Disease', (185, 190))	('mice', 'Species', '10090', (130, 134))	('improved', 'PosReg', (58, 66))	('dgkzeta', 'Gene', (39, 46))	('TCR', 'cellular_component', 'GO:0042101', ('121', '124'))	('deletion', 'Var', (27, 35))	('augmenting', 'PosReg', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('TCR', 'biological_process', 'GO:0006283', ('121', '124'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('signaling via the TCR', 'MPA', (103, 124))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (172, 190))	('CD8', 'Gene', (67, 70))	('CD8', 'Gene', '925', (67, 70))
164479	23576561	However, neither the absence of dgkalpha or dgkzeta is sufficient to enable a completely successful anti-tumor response.	('dgkzeta', 'Gene', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('dgkalpha', 'Gene', (32, 40))	('absence', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
164522	23576561	We wondered if the effect of dgkzeta deletion would be improved if, instead of naive T cells, we made use of activated T cells that could potentially confer a more robust anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('deletion', 'Var', (37, 45))	('dgkzeta', 'Gene', (29, 36))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
164531	23576561	These data demonstrate that deficiency of dgkzeta confers enhanced anti-tumor potential in pre-activated T cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (58, 66))	('pre', 'molecular_function', 'GO:0003904', ('91', '94'))	('deficiency', 'Var', (28, 38))	('dgkzeta', 'Gene', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
164533	23576561	Given that deletion of dgkzeta conferred enhanced activity of CD8+ T cells against established tumors but did not appear to be curative, we wondered whether inhibition of dgk function might augment other approaches shown to have efficacy in enhancing T cell responses against tumor.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('enhanced', 'PosReg', (41, 49))	('CD8', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('CD8', 'Gene', '925', (62, 65))	('dgkzeta', 'Gene', (23, 30))	('enhancing', 'PosReg', (241, 250))	('tumor', 'Disease', (276, 281))	('activity', 'MPA', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('deletion', 'Var', (11, 19))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
164540	23576561	2B and 2C), indicating that deletion of dgkzeta enhances the function of CAR-transduced CD8+ T cells against AE17 cells that express both ova and mesothelin.	('CD8', 'Gene', '925', (88, 91))	('function', 'MPA', (61, 69))	('dgkzeta', 'Gene', (40, 47))	('enhances', 'PosReg', (48, 56))	('deletion', 'Var', (28, 36))	('CAR', 'cellular_component', 'GO:0005826', ('73', '76'))	('CD8', 'Gene', (88, 91))
164541	23576561	The finding that deletion of dgkzeta enhanced mesoCAR T cell functional responses suggested that these two strategies may be used together for potentiating CD8+ T cell tumor responses.	('tumor', 'Disease', (168, 173))	('dgkzeta', 'Gene', (29, 36))	('mesoCAR T cell functional responses', 'CPA', (46, 81))	('deletion', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('enhanced', 'PosReg', (37, 45))	('CD8', 'Gene', (156, 159))	('mesoCAR', 'Chemical', '-', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('CD8', 'Gene', '925', (156, 159))
164546	23576561	As observed with deletion of dgkzeta in OT-1 cells, deletion of either dgkalpha or dgkzeta in this population of cells expressing the mesoCAR receptor conferred enhanced cytokine production and cytotoxicity when the T cells were incubated with tumor cells expressing mesothelin (Fig.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('enhanced', 'PosReg', (161, 169))	('cytokine production', 'biological_process', 'GO:0001816', ('170', '189'))	('tumor', 'Disease', (244, 249))	('cytotoxicity', 'Disease', 'MESH:D064420', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('dgkalpha', 'Gene', (71, 79))	('cytotoxicity', 'Disease', (194, 206))	('cytokine production', 'MPA', (170, 189))	('mesoCAR', 'Chemical', '-', (134, 141))	('deletion', 'Var', (52, 60))	('dgkzeta', 'Gene', (83, 90))
164553	23576561	To test whether deletion of dgks enhanced Erk activation downstream of mesoCAR, we then repeated this experiment with mesoCAR-transduced T cells derived from DKO mice.	('Erk', 'Gene', (42, 45))	('deletion', 'Var', (16, 24))	('dgks', 'Gene', (28, 32))	('Erk', 'Gene', '13844', (42, 45))	('mice', 'Species', '10090', (162, 166))	('Erk', 'molecular_function', 'GO:0004707', ('42', '45'))	('mesoCAR', 'Chemical', '-', (118, 125))	('mesoCAR', 'Chemical', '-', (71, 78))	('enhanced', 'PosReg', (33, 41))
164554	23576561	Similar to the enhanced activation of Erk known downstream of the TCR in T cells deficient in dgks, loss of dgks augmented the activation of Erk downstream of mesoCAR (Fig.	('Erk', 'Gene', (38, 41))	('Erk', 'Gene', (141, 144))	('loss', 'Var', (100, 104))	('augmented', 'PosReg', (113, 122))	('TCR', 'biological_process', 'GO:0006283', ('66', '69'))	('activation', 'MPA', (127, 137))	('Erk', 'molecular_function', 'GO:0004707', ('141', '144'))	('Erk', 'Gene', '13844', (141, 144))	('dgks', 'Gene', (108, 112))	('Erk', 'Gene', '13844', (38, 41))	('mesoCAR', 'Chemical', '-', (159, 166))	('TCR', 'cellular_component', 'GO:0042101', ('66', '69'))	('Erk', 'molecular_function', 'GO:0004707', ('38', '41'))
164557	23576561	Together, these data suggest that dgk influences CAR signaling in a manner similar to the TCR and that the combination of CAR expression and dgk deletion could represent an effective strategy for augmenting CD8+ T cell anti-tumor responses.	('augmenting', 'PosReg', (196, 206))	('combination', 'Interaction', (107, 118))	('CD8', 'Gene', '925', (207, 210))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('influences', 'Reg', (38, 48))	('dgk', 'Gene', (141, 144))	('CAR signaling', 'MPA', (49, 62))	('CAR', 'cellular_component', 'GO:0005826', ('122', '125'))	('tumor', 'Disease', (224, 229))	('CAR', 'cellular_component', 'GO:0005826', ('49', '52'))	('TCR', 'cellular_component', 'GO:0042101', ('90', '93'))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('TCR', 'biological_process', 'GO:0006283', ('90', '93'))	('CD8', 'Gene', (207, 210))	('deletion', 'Var', (145, 153))
164558	23576561	We next sought to determine whether deletion of dgk isoforms conferred enhanced anti-tumor responses in vivo making use of the WINN assay.	('tumor', 'Disease', (85, 90))	('enhanced', 'PosReg', (71, 79))	('deletion', 'Var', (36, 44))	('dgk', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
164560	23576561	Although mice that received wt mesoCAR-transduced T cells or T cells lacking a single isoform of dgk were unable to completely control the growth of mesotheliomas, DKO T cells eradicated the mesotheliomas (Fig.	('eradicated', 'NegReg', (176, 186))	('mesoCAR', 'Chemical', '-', (31, 38))	('mesotheliomas', 'Disease', 'MESH:D008654', (191, 204))	('DKO', 'Var', (164, 167))	('mesotheliomas', 'Disease', 'MESH:D008654', (149, 162))	('mesotheliomas', 'Disease', (149, 162))	('mice', 'Species', '10090', (9, 13))	('mesotheliomas', 'Disease', (191, 204))
164561	23576561	5A), indicating that, as suggested by in vitro studies, targeting dgk generates meaningful enhancement of CD8+ T cells against tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('dgk', 'Gene', (66, 69))	('tumor', 'Disease', (127, 132))	('CD8', 'Gene', (106, 109))	('CD8', 'Gene', '925', (106, 109))	('enhancement', 'PosReg', (91, 102))	('targeting', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
164562	23576561	While this experiment offered proof of principle that DKO T cells conferred enhanced in vivo activity against mesothelioma, it did not directly assess whether deletion of dgk isoforms would be capable of limiting the growth of established tumors, which is more representative of how CAR-T cells would be utilized clinically.	('tumors', 'Disease', (239, 245))	('dgk', 'Gene', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('activity', 'MPA', (93, 101))	('mesothelioma', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('enhanced', 'PosReg', (76, 84))	('CAR', 'cellular_component', 'GO:0005826', ('283', '286'))	('deletion', 'Var', (159, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))
164564	23576561	Under these conditions, whereas wt mesoCAR-transduced T cells were ineffective at limiting tumor growth, mesoCAR-transduced T cells deficient in either dgk isoform significantly (p<0.05) decreased the rate of tumor growth (Fig.	('tumor', 'Disease', (209, 214))	('mesoCAR', 'Chemical', '-', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('decreased', 'NegReg', (187, 196))	('tumor', 'Disease', (91, 96))	('deficient', 'Var', (132, 141))	('mesoCAR', 'Chemical', '-', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
164571	23576561	Since we and others have previously shown that deletion of dgks mitigates the induction of anergy, we hypothesized that inhibition of dgks might also diminish the impaired cytotoxicity observed in our assay.	('dgks', 'Gene', (59, 63))	('cytotoxicity', 'Disease', 'MESH:D064420', (172, 184))	('dgks', 'Protein', (134, 138))	('deletion', 'Var', (47, 55))	('diminish', 'NegReg', (150, 158))	('mitigates', 'NegReg', (64, 73))	('cytotoxicity', 'Disease', (172, 184))	('anergy', 'CPA', (91, 97))
164572	23576561	To test this, we incubated mesoCAR T cells with EM-meso cells for 96 hours, and then assessed their ability to lyse target cells in the presence of dgk inhibitors R59022 (DGK1 inhibitor) or R59949 (DGK2 inhibitor).	('dgk', 'Protein', (148, 151))	('R59022', 'Var', (163, 169))	('R59949', 'Var', (190, 196))	('DGK1', 'Gene', (171, 175))	('mesoCAR', 'Chemical', '-', (27, 34))	('DGK2', 'Gene', (198, 202))	('DGK1', 'Gene', '27369', (171, 175))	('DGK2', 'Gene', '27369', (198, 202))
164574	23576561	6A, center and right panels), indicating that, similar to our findings in mice, inhibition of dgk function appears to augment anti-tumor activity of primary human T cells expressing CARs.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('augment', 'NegReg', (118, 125))	('dgk', 'Protein', (94, 97))	('inhibition', 'Var', (80, 90))	('mice', 'Species', '10090', (74, 78))	('human', 'Species', '9606', (157, 162))
164575	23576561	These data also suggest that in addition to augmenting TCR (or CAR)-mediated signaling, blockade of dgk may enhance T cell anti-tumor responses by mitigating antigen-induced unresponsiveness of the effector cells.	('antigen-induced unresponsiveness', 'MPA', (158, 190))	('blockade', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('dgk', 'Gene', (100, 103))	('TCR', 'cellular_component', 'GO:0042101', ('55', '58'))	('enhance', 'PosReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('enhance T cell', 'Phenotype', 'HP:0100828', (108, 122))	('TCR', 'biological_process', 'GO:0006283', ('55', '58'))	('mitigating', 'NegReg', (147, 157))	('augmenting', 'PosReg', (44, 54))	('tumor', 'Disease', (128, 133))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('CAR', 'cellular_component', 'GO:0005826', ('63', '66'))
164581	23576561	As demonstrated before, deletion of either or both dgk isoforms resulted in mesoCAR T cells with enhanced function when compared with wt mesoCAR T cells (Fig.	('mesoCAR', 'Chemical', '-', (137, 144))	('function', 'CPA', (106, 114))	('dgk', 'Gene', (51, 54))	('enhanced', 'PosReg', (97, 105))	('mesoCAR', 'Chemical', '-', (76, 83))	('deletion', 'Var', (24, 32))	('mesoCAR T cells', 'CPA', (76, 91))
164583	23576561	These data suggest that deletion of dgks confers relative resistance to TGFbeta for mesoCAR T cells.	('mesoCAR', 'Chemical', '-', (84, 91))	('resistance', 'MPA', (58, 68))	('deletion', 'Var', (24, 32))	('dgks', 'Gene', (36, 40))
164585	23576561	Collectively our data suggest that deletion of dgks augments effector function of CAR-expressing CD8+ T cells not only by augmenting signaling through the CAR itself but also by reducing sensitivity of the effector cells to physiologically relevant inhibitory signals.	('signaling', 'MPA', (133, 142))	('effector function', 'MPA', (61, 78))	('reducing', 'NegReg', (178, 186))	('CAR', 'cellular_component', 'GO:0005826', ('155', '158'))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('CD8', 'Gene', (97, 100))	('sensitivity', 'MPA', (187, 198))	('augmenting', 'PosReg', (122, 132))	('deletion', 'Var', (35, 43))	('CAR', 'cellular_component', 'GO:0005826', ('82', '85'))	('augments', 'PosReg', (52, 60))	('dgks', 'Gene', (47, 51))	('CD8', 'Gene', '925', (97, 100))
164593	23576561	For instance, antibodies that activate CD40 on APCs upregulate co-stimulatory molecules that help facilitate priming of naive cells.	('antibodies', 'Var', (14, 24))	('CD40', 'Gene', '21939', (39, 43))	('co-stimulatory molecules', 'MPA', (63, 87))	('CD40', 'Gene', (39, 43))	('facilitate', 'PosReg', (98, 108))	('upregulate', 'PosReg', (52, 62))	('priming', 'CPA', (109, 116))
164595	23576561	Inhibition of proteins that negatively regulate signal transduction downstream of the TCR has garnered recent attention as a potential strategy for augmenting T cell responses to malignancy at the time of T cell priming.	('proteins', 'Protein', (14, 22))	('malignancy', 'Disease', (179, 189))	('TCR', 'cellular_component', 'GO:0042101', ('86', '89'))	('augmenting', 'PosReg', (148, 158))	('TCR', 'biological_process', 'GO:0006283', ('86', '89'))	('Inhibition', 'Var', (0, 10))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('signal transduction', 'biological_process', 'GO:0007165', ('48', '67'))
164596	23576561	For instance, deletion of Casitas-B-lineage lymphoma b (cbl-b), an E3 ubiquitin ligase responsible for the degradation of several proteins important in TCR signal transduction, results in T cells with a decreased requirement of co-stimulation at the time of activation and enhanced anti-tumor activity of naive T cells.	('Casitas-B-lineage lymphoma b', 'Gene', '208650', (26, 54))	('TCR', 'cellular_component', 'GO:0042101', ('152', '155'))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('decreased', 'NegReg', (203, 212))	('signal transduction', 'biological_process', 'GO:0007165', ('156', '175'))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cbl-b', 'Gene', (56, 61))	('TCR', 'biological_process', 'GO:0006283', ('152', '155'))	('requirement', 'MPA', (213, 224))	('degradation', 'biological_process', 'GO:0009056', ('107', '118'))	('Casitas-B-lineage lymphoma b', 'Gene', (26, 54))	('T cells', 'CPA', (188, 195))	('ubiquitin', 'molecular_function', 'GO:0031386', ('70', '79'))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('deletion', 'Var', (14, 22))	('cbl-b', 'Gene', '208650', (56, 61))	('enhanced', 'PosReg', (273, 281))
164597	23576561	We had previously demonstrated, similar to cbl-b, that deletion of dgkzeta enhanced the effector functions of naive CD8+ T cells.	('enhanced', 'PosReg', (75, 83))	('dgkzeta', 'Gene', (67, 74))	('CD8', 'Gene', (116, 119))	('cbl-b', 'Gene', '208650', (43, 48))	('CD8', 'Gene', '925', (116, 119))	('deletion', 'Var', (55, 63))	('cbl-b', 'Gene', (43, 48))
164598	23576561	Although deletion of cbl-b and dgkzeta both result in changes downstream of the TCR, dgkzeta and dgkalpha; likely act directly to regulate the threshold for activation of T cells downstream of the TCR.	('TCR', 'biological_process', 'GO:0006283', ('80', '83'))	('TCR', 'biological_process', 'GO:0006283', ('197', '200'))	('result', 'Reg', (44, 50))	('cbl-b', 'Gene', (21, 26))	('changes', 'Reg', (54, 61))	('deletion', 'Var', (9, 17))	('TCR', 'cellular_component', 'GO:0042101', ('197', '200'))	('TCR', 'cellular_component', 'GO:0042101', ('80', '83'))	('dgkzeta', 'Gene', (31, 38))	('cbl-b', 'Gene', '208650', (21, 26))
164602	23576561	In a manner largely consistent with this model, we had previously found that deletion of dgkzeta resulted in a decreased threshold of T cell activation, a finding that correlated with enhanced responses in naive CD8+ T cells.	('threshold', 'MPA', (121, 130))	('T cell activation', 'biological_process', 'GO:0042110', ('134', '151'))	('CD8', 'Gene', (212, 215))	('decreased', 'NegReg', (111, 120))	('dgkzeta', 'Gene', (89, 96))	('deletion', 'Var', (77, 85))	('CD8', 'Gene', '925', (212, 215))	('enhanced', 'PosReg', (184, 192))
164605	23576561	In current clinical trial protocols, human T cells are transduced with lentivirus-expressing CARs in the presence of CD3 and CD28 or CD3 and 41BB (CD137), a process that induces T cell division and activation.	('CD3', 'Var', (117, 120))	('CD137', 'Gene', '3604', (147, 152))	('activation', 'CPA', (198, 208))	('CD28', 'Var', (125, 129))	('T cell division', 'CPA', (178, 193))	('cell division', 'biological_process', 'GO:0051301', ('180', '193'))	('human', 'Species', '9606', (37, 42))	('induces', 'Reg', (170, 177))	('CD137', 'Gene', (147, 152))
164608	23576561	After establishing a retroviral system to efficiently transduce murine T cells, we found, as with TCR signaling, that deletion of dgkzeta augmented Erk activation, a phosphorylation event that occurs downstream of DAG formation, after CAR ligation.	('TCR', 'cellular_component', 'GO:0042101', ('98', '101'))	('DAG', 'Chemical', 'MESH:D004075', (214, 217))	('activation', 'PosReg', (152, 162))	('CAR', 'cellular_component', 'GO:0005826', ('235', '238'))	('formation', 'biological_process', 'GO:0009058', ('218', '227'))	('augmented', 'PosReg', (138, 147))	('TCR', 'biological_process', 'GO:0006283', ('98', '101'))	('dgkzeta', 'Gene', (130, 137))	('Erk', 'Gene', (148, 151))	('Erk', 'molecular_function', 'GO:0004707', ('148', '151'))	('murine', 'Species', '10090', (64, 70))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('Erk', 'Gene', '13844', (148, 151))	('deletion', 'Var', (118, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))
164609	23576561	Deletion of both T cell isoforms of dgk resulted in even greater enhancement of effector functions of mesoCAR-transduced cells and resulted in control of tumor in vivo in tumor-bearing mice.	('enhancement', 'PosReg', (65, 76))	('tumor', 'Disease', (154, 159))	('mesoCAR', 'Chemical', '-', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mice', 'Species', '10090', (185, 189))	('effector functions of mesoCAR-transduced cells', 'CPA', (80, 126))	('dgk', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('Deletion', 'Var', (0, 8))
164613	23576561	TGFbeta is thought to be a key mediator of tumor-mediated inhibition, since it is secreted by a variety of tumors, and inhibition of TGFbeta signaling, through the expression of a dominant negative receptor, results in enhanced tumor-specific activity of cytotoxic lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('enhanced', 'PosReg', (219, 227))	('tumors', 'Disease', (107, 113))	('TGFbeta', 'Gene', (133, 140))	('inhibition', 'Var', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (43, 48))
164615	23576561	Since TGFbeta is known to result in the reduced phosphorylation of Itk, a Tec kinase important in PLCgamma1 activation, and since PLCgamma1 is the protein directly responsible for DAG generation in T cells, one could envision that deletion of dgks might directly subvert this TGFbeta-induced signaling alteration.	('dgks', 'Gene', (243, 247))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('deletion', 'Var', (231, 239))	('Itk', 'Gene', (67, 70))	('PLCgamma1', 'Gene', '18803', (98, 107))	('signaling', 'biological_process', 'GO:0023052', ('292', '301'))	('subvert', 'NegReg', (263, 270))	('PLCgamma1', 'Gene', '18803', (130, 139))	('PLCgamma1', 'Gene', (98, 107))	('phosphorylation', 'MPA', (48, 63))	('reduced', 'NegReg', (40, 47))	('PLCgamma1', 'Gene', (130, 139))	('DAG', 'Chemical', 'MESH:D004075', (180, 183))	('TGFbeta', 'Disease', (6, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('Itk', 'Gene', '16428', (67, 70))
164616	23576561	Future studies will address the potential means by which loss of dgks confers insensitivity to TGFbeta, including direct effects, such as enhanced Ras activation downstream of TCR, and indirect effects, such as increased expression of cytotoxic proteins including FasL and TRAIL.	('TRAIL', 'Gene', (273, 278))	('Ras', 'Protein', (147, 150))	('TGFbeta', 'Gene', (95, 102))	('FasL', 'Gene', '14103', (264, 268))	('TCR', 'biological_process', 'GO:0006283', ('176', '179'))	('TCR', 'cellular_component', 'GO:0042101', ('176', '179'))	('dgks', 'Gene', (65, 69))	('enhanced', 'PosReg', (138, 146))	('FasL', 'Gene', (264, 268))	('increased', 'PosReg', (211, 220))	('expression', 'MPA', (221, 231))	('TRAIL', 'Gene', '22035', (273, 278))	('loss', 'Var', (57, 61))	('activation', 'PosReg', (151, 161))
164617	23576561	We have demonstrated that pharmacologic inhibition of dgks augment the efficacy of human CAR T cells under inhibitory in vitro conditions.	('CAR', 'cellular_component', 'GO:0005826', ('89', '92'))	('efficacy of human CAR T cells', 'CPA', (71, 100))	('pharmacologic', 'Var', (26, 39))	('augment', 'PosReg', (59, 66))	('human', 'Species', '9606', (83, 88))	('dgks', 'Gene', (54, 58))
164619	23576561	We are currently extending our preliminary data in human T cells by developing model systems in which dgk activity is suppressed through decreased dgk expression (e.g., through expression of shRNA specific for dgks), or inhibited dgk function (e.g., through expression of dominant negative forms of dgks).	('dgk', 'Protein', (102, 105))	('function', 'MPA', (234, 242))	('expression', 'MPA', (151, 161))	('dgk', 'Protein', (230, 233))	('human', 'Species', '9606', (51, 56))	('dgk', 'Protein', (147, 150))	('inhibited', 'NegReg', (220, 229))	('dominant', 'Var', (272, 280))	('activity', 'MPA', (106, 114))	('decreased', 'NegReg', (137, 146))	('dgk activity', 'molecular_function', 'GO:0004143', ('102', '114'))	('suppressed', 'NegReg', (118, 128))
164628	23576561	Collectively, our data suggest that targeting dgks, as one means to blunt an endogenous inhibitory response, could be a useful mechanism to improve CAR-based strategies in the treatment of human malignancy.	('endogenous inhibitory response', 'MPA', (77, 107))	('malignancy', 'Disease', (195, 205))	('CAR', 'cellular_component', 'GO:0005826', ('148', '151'))	('human', 'Species', '9606', (189, 194))	('dgks', 'Var', (46, 50))	('blunt', 'NegReg', (68, 73))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))
164784	31057996	MPM has a strong causal relationship with asbestos exposure, and to a lesser extent, prior in-field radiotherapy and the germline breast cancer type 1 susceptibility protein-associated protein-1 mutation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('mutation', 'Var', (195, 203))	('MPM', 'Disease', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
164904	27158561	Epidemiologic studies have established that exposure to asbestos fibers causes pulmonary fibrosis, pleural abnormalities, and malignancies such as bronchogenic carcinoma and mesothelioma, including peritoneal mesothelioma.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('causes', 'Reg', (72, 78))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (198, 221))	('mesothelioma', 'Disease', (209, 221))	('pleural abnormalities', 'Disease', (99, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('pleural abnormalities', 'Disease', 'MESH:D010995', (99, 120))	('mesothelioma', 'Disease', (174, 186))	('pulmonary fibrosis', 'Disease', (79, 97))	('exposure', 'Var', (44, 52))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('bronchogenic carcinoma', 'Disease', 'MESH:D002283', (147, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (174, 186))	('malignancies', 'Disease', (126, 138))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (79, 97))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (79, 97))	('bronchogenic carcinoma', 'Disease', (147, 169))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('pleural abnormalities', 'Phenotype', 'HP:0002103', (99, 120))
164966	27158561	Although mechanistic studies related with GI cancer or GI disorder by asbestos at the cellular level are lacking using epithelial cells of them, expose with asbestos result in change a surface charge, crystallization, morphologic and biochemical changes of epithelium that resemble effects of classical tumor promoters on target cells in both the pulmonary and GIT systems.	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('expose', 'Var', (145, 151))	('GI disorder', 'Disease', 'MESH:D005767', (55, 66))	('surface charge', 'MPA', (185, 199))	('GI cancer', 'Phenotype', 'HP:0007378', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('cancer or GI disorder', 'Phenotype', 'HP:0011024', (45, 66))	('tumor', 'Disease', (303, 308))	('change', 'Reg', (176, 182))	('crystallization', 'MPA', (201, 216))	('GI cancer', 'Disease', (42, 51))	('biochemical changes', 'CPA', (234, 253))	('morphologic', 'CPA', (218, 229))	('GI cancer', 'Disease', 'MESH:D009369', (42, 51))	('GI disorder', 'Disease', (55, 66))	('asbestos', 'Chemical', 'MESH:D001194', (157, 165))
165046	23225411	Each slide was scored for the percent of tumor cells that were positive for mesothelin expression and the intensity of staining (+, mild; ++, moderate; and +++, intense).	('mesothelin', 'Gene', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mesothelin', 'Gene', '10232', (76, 86))	('expression', 'MPA', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('+++', 'Var', (156, 159))
165088	23225411	In addition to SS1P, these early-passage mesothelioma cells were also treated with HB21PE40, an immunotoxin targeting the transferin receptor which is universally expressed on the cell surface of most human cells, that caused >90% cell killing in all cells tested.	('cell surface', 'cellular_component', 'GO:0009986', ('180', '192'))	('mesothelioma', 'Disease', (41, 53))	('cell killing', 'biological_process', 'GO:0001906', ('231', '243'))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('human', 'Species', '9606', (201, 206))	('cell killing', 'CPA', (231, 243))	('HB21PE40', 'Var', (83, 91))
165090	23225411	While BL22 had very little effect on killing tumor cells, treatment with SS1P killed the majority of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('BL22', 'CellLine', 'CVCL:C140', (6, 10))	('SS1P', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
165147	30406026	Aberrant FOXO1 expression has been demonstrated in gastric cancer, lung cancer, osteosarcoma, pancreas cancer, and glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('expression', 'MPA', (15, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('glioblastoma', 'Disease', (115, 127))	('lung cancer', 'Disease', (67, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('pancreas cancer', 'Disease', 'MESH:D010190', (94, 109))	('pancreas cancer', 'Phenotype', 'HP:0002894', (94, 109))	('pancreas cancer', 'Disease', (94, 109))	('gastric cancer', 'Disease', (51, 65))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('osteosarcoma', 'Disease', (80, 92))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('FOXO1', 'Gene', (9, 14))
165176	30406026	Mesothelioma cells transfected with miR-182 or miR-183 inhibitors showed reduced cell proliferation rates compared to cells treated with negative control inhibitor.	('miR-182', 'Gene', (36, 43))	('cell proliferation rates', 'CPA', (81, 105))	('reduced', 'NegReg', (73, 80))	('miR-182', 'Gene', '406958', (36, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('miR-183', 'Gene', '406959', (47, 54))	('miR-183', 'Gene', (47, 54))	('inhibitors', 'Var', (55, 65))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
165177	30406026	Moreover, cells co-transfected with miR-182 and miR-183 inhibitors showed the lowest proliferation rates in 4 subgroups (Negative Control, miR-182 inhibitor, miR-183 inhibitor, miR-182/183 inhibitor) (Figure 2A).	('miR-182', 'Gene', (177, 184))	('miR-183', 'Gene', (48, 55))	('miR-182', 'Gene', (36, 43))	('miR-182', 'Gene', (139, 146))	('lowest', 'NegReg', (78, 84))	('miR-183', 'Gene', '406959', (48, 55))	('miR-182', 'Gene', '406958', (177, 184))	('miR-182', 'Gene', '406958', (139, 146))	('miR-182', 'Gene', '406958', (36, 43))	('miR-183', 'Gene', '406959', (158, 165))	('miR-183', 'Gene', (158, 165))	('inhibitors', 'Var', (56, 66))	('proliferation rates', 'CPA', (85, 104))
165178	30406026	In invasion assay, inhibition of miR-182 significantly reduced cell invasion.	('miR-182', 'Gene', (33, 40))	('inhibition', 'Var', (19, 29))	('reduced', 'NegReg', (55, 62))	('cell invasion', 'CPA', (63, 76))	('miR-182', 'Gene', '406958', (33, 40))
165188	30406026	Furthermore, cells treated with both miR-182 and miR-183 inhibitors showed significant upregulation of FOXO1 expression than cells treated with miR-182 or miR-183 inhibitor alone.	('inhibitors', 'Var', (57, 67))	('miR-182', 'Gene', (37, 44))	('expression', 'MPA', (109, 119))	('miR-183', 'Gene', '406959', (155, 162))	('upregulation', 'PosReg', (87, 99))	('miR-182', 'Gene', (144, 151))	('FOXO1', 'Gene', (103, 108))	('miR-182', 'Gene', '406958', (37, 44))	('miR-182', 'Gene', '406958', (144, 151))	('miR-183', 'Gene', '406959', (49, 56))	('miR-183', 'Gene', (155, 162))	('miR-183', 'Gene', (49, 56))
165193	30406026	However, FOXO1 knockdown inhibited the upregulation of p27 expression but not p21 expression (Figure 4B).	('p21', 'Gene', '644914', (78, 81))	('knockdown', 'Var', (15, 24))	('p27', 'Gene', '3429', (55, 58))	('p27', 'Gene', (55, 58))	('inhibited', 'NegReg', (25, 34))	('FOXO1', 'Gene', (9, 14))	('p21', 'Gene', (78, 81))
165194	30406026	In addition, FOXO1 knockdown reversed the cell invasion-reducing effects of miR-182 and miR-183 inhibitors (Figure 4C).	('miR-182', 'Gene', '406958', (76, 83))	('knockdown', 'Var', (19, 28))	('FOXO1', 'Gene', (13, 18))	('miR-183', 'Gene', '406959', (88, 95))	('miR-183', 'Gene', (88, 95))	('inhibitors', 'Var', (96, 106))	('cell invasion-reducing', 'CPA', (42, 64))	('miR-182', 'Gene', (76, 83))
165224	30406026	FOXO1 knockdown has been demonstrated to promote prostate tumorigenesis and cell invasion properties.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('FOXO1', 'Gene', (0, 5))	('cell invasion properties', 'CPA', (76, 100))	('promote', 'PosReg', (41, 48))	('prostate', 'Disease', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('knockdown', 'Var', (6, 15))
165227	30406026	Results showed that p21 and p27 expression levels were upregulated in mesothelioma cells treated with miR-182 and miR-183 inhibitors, and the observed upregulation of p27 was reversed by FOXO1 knockdown but not p21.	('miR-183', 'Gene', '406959', (114, 121))	('p21', 'Gene', (20, 23))	('miR-183', 'Gene', (114, 121))	('p27', 'Gene', (167, 170))	('p27', 'Gene', '3429', (167, 170))	('p21', 'Gene', '644914', (20, 23))	('inhibitors', 'Var', (122, 132))	('miR-182', 'Gene', (102, 109))	('p27', 'Gene', (28, 31))	('p27', 'Gene', '3429', (28, 31))	('mesothelioma', 'Disease', (70, 82))	('upregulated', 'PosReg', (55, 66))	('p21', 'Gene', (211, 214))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('miR-182', 'Gene', '406958', (102, 109))	('expression levels', 'MPA', (32, 49))	('FOXO1', 'Gene', (187, 192))	('p21', 'Gene', '644914', (211, 214))
165258	29607973	The neoplastic cells were accompanied by nuclear deviation and multinuclear cells, and were diffusely positive for cytokeratin (AE1/AE3) and vimentin, focally positive for D2-40, WT-1, and mesothelin, and negative for calretinin, CEA, and TTF-1 (Fig.	('AE3', 'Gene', '6508', (132, 135))	('positive', 'Reg', (102, 110))	('vimentin', 'Protein', (141, 149))	('calretinin', 'Gene', '794', (218, 228))	('D2-40', 'Var', (172, 177))	('cytokeratin', 'Protein', (115, 126))	('AE1', 'Gene', '6521', (128, 131))	('vimentin', 'cellular_component', 'GO:0045099', ('141', '149'))	('AE1', 'Gene', (128, 131))	('calretinin', 'Gene', (218, 228))	('TTF-1', 'Gene', '7080', (239, 244))	('AE3', 'Gene', (132, 135))	('nuclear deviation', 'CPA', (41, 58))	('TTF-1', 'Gene', (239, 244))	('vimentin', 'cellular_component', 'GO:0045098', ('141', '149'))	('CEA', 'Gene', (230, 233))	('CEA', 'Gene', '1084', (230, 233))
165339	28525370	This model was built from the following hypotheses: H1, In absence of treatment, tumor growth follows a Gompertz model; H2, Endothelial cells are more sensitive to chemotherapy agents than cancer cells; H3, Depleting endothelial cells will affect tumor growth; and H4, Endothelial cells are more genetically stable than cancer cells and therefore less likely to develop resistance to chemotherapy agents.	('affect', 'Reg', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancer', 'Disease', (320, 326))	('tumor', 'Disease', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('Depleting', 'Var', (207, 216))	('tumor', 'Disease', (81, 86))	('cancer', 'Disease', (189, 195))
165351	33562126	We demonstrate that overexpression and silencing of SDC-1 alters the secretion of angiogenic proteins in MM cells.	('secretion', 'biological_process', 'GO:0046903', ('69', '78'))	('alters', 'Reg', (58, 64))	('silencing', 'Var', (39, 48))	('SDC-1', 'Gene', (52, 57))	('se', 'Gene', '6713', (69, 71))
165358	33562126	In the present study, we studied the effect of SDC-1 overexpression and silencing on MM cells ability to secrete angiogenic factors and monitored the downstream effect of SDC-1 modulation on endothelial cells proliferation, wound healing, and tube formation.	('tube formation', 'CPA', (243, 257))	('se', 'Gene', '6713', (105, 107))	('silencing', 'Var', (72, 81))	('wound healing', 'biological_process', 'GO:0042060', ('224', '237'))	('se', 'Gene', '6713', (10, 12))	('tube formation', 'biological_process', 'GO:0035148', ('243', '257'))	('wound healing', 'CPA', (224, 237))
165362	33562126	SDC-1 silencing increased IL8 (1.33 +- 0.06), promoted wound closure, but did not influence the tube formation of endothelial cells.	('promoted', 'PosReg', (46, 54))	('se', 'Gene', '6713', (22, 24))	('SDC-1', 'Gene', (0, 5))	('tube formation', 'biological_process', 'GO:0035148', ('96', '110'))	('IL8', 'Gene', (26, 29))	('IL8', 'Gene', '3576', (26, 29))	('IL8', 'molecular_function', 'GO:0005153', ('26', '29'))	('wound closure', 'CPA', (55, 68))	('silencing', 'Var', (6, 15))
165364	33562126	In conclusion, SDC-1 over-expression affects the angiogenic factor secretion of mesothelioma cells and thereby inhibits endothelial cells proliferation, tube formation, and wound healing.	('se', 'Gene', '6713', (67, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('inhibits', 'NegReg', (111, 119))	('tube formation', 'CPA', (153, 167))	('affects', 'Reg', (37, 44))	('wound healing', 'CPA', (173, 186))	('over-expression', 'Var', (21, 36))	('mesothelioma', 'Disease', (80, 92))	('secretion', 'biological_process', 'GO:0046903', ('67', '76'))	('SDC-1', 'Gene', (15, 20))	('wound healing', 'biological_process', 'GO:0042060', ('173', '186'))	('tube formation', 'biological_process', 'GO:0035148', ('153', '167'))	('endothelial cells proliferation', 'CPA', (120, 151))
165384	33562126	By over-expressing and silencing SDC-1 in mesothelioma cells, we could elicit changes in a wide range of angiogenesis-related proteins secreted to the conditioned media.	('elicit', 'Reg', (71, 77))	('changes', 'Reg', (78, 85))	('mesothelioma', 'Disease', (42, 54))	('angiogenesis-related', 'MPA', (105, 125))	('silencing', 'Var', (23, 32))	('over-expressing', 'PosReg', (3, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('SDC-1', 'Gene', (33, 38))	('se', 'Gene', '6713', (135, 137))
165387	33562126	Modulation of SDC-1 expression elicited different pattern of angiogenesis-related factor secretion, most effect being observed upon SDC-1 overexpression.	('Modulation', 'Var', (0, 10))	('elicited', 'Reg', (31, 39))	('se', 'Gene', '6713', (89, 91))	('se', 'Gene', '6713', (120, 122))	('SDC-1', 'Gene', (14, 19))	('angiogenesis', 'biological_process', 'GO:0001525', ('61', '73'))	('secretion', 'biological_process', 'GO:0046903', ('89', '98'))
165388	33562126	Seven angiogenesis-related proteins were significantly altered by SDC-1 overexpression including angiopoietin-1 (mean fold change +- SD: 0.65 +- 0.07), fibroblast growth factor-4 (FGF-4) (1.45 +- 0.04), hepatocyte growth factor (HGF) (1.33 +- 0.12), neuroglin-1 beta-1(NRG1-beta1) (1.35 +- 0.02), tissue inhibitor of metalloproteinases-1 (TIMP-1) (0.89 +- 0.01), thrombospondin-1 (TSP-1) (0.8 +- 0.04), and transforming growth factor beta-1 (TGF-beta1) (1.35 +- 0.02) (Figure 1A), whereas interleukin 8 (IL-8) (1.33 +- 0.06) was increased upon SDC-1 silencing (Figure 1B).	('transforming growth factor beta-1', 'Gene', (407, 440))	('tissue inhibitor of metalloproteinases-1', 'Gene', (297, 337))	('thrombospondin-1', 'Gene', '7057', (363, 379))	('transforming growth factor beta-1', 'Gene', '7040', (407, 440))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('407', '438'))	('IL-8', 'molecular_function', 'GO:0005153', ('504', '508'))	('hepatocyte', 'MPA', (203, 213))	('angiopoietin-1', 'Gene', '284', (97, 111))	('se', 'Gene', '6713', (332, 334))	('beta1', 'Gene', '597', (274, 279))	('SDC-1', 'Gene', (544, 549))	('beta1', 'Gene', '597', (446, 451))	('angiogenesis-related', 'MPA', (6, 26))	('IL-8', 'Gene', '3576', (504, 508))	('fibroblast growth factor-4', 'Gene', '2249', (152, 178))	('se', 'Gene', '6713', (535, 537))	('angiopoietin-1', 'Gene', (97, 111))	('fibroblast growth factor-4', 'Gene', (152, 178))	('altered', 'Reg', (55, 62))	('angiogenesis', 'biological_process', 'GO:0001525', ('6', '18'))	('thrombospondin-1', 'Gene', (363, 379))	('TIMP-1', 'Gene', (339, 345))	('TIMP-1', 'Gene', '7076', (339, 345))	('HGF', 'Gene', '3082', (229, 232))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('152', '176'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('203', '227'))	('FGF-4', 'Gene', (180, 185))	('TSP-1', 'Gene', (381, 386))	('beta1', 'Gene', (446, 451))	('beta1', 'Gene', (274, 279))	('interleukin 8', 'Gene', '3576', (489, 502))	('TGF-beta1', 'Gene', (442, 451))	('NRG1', 'Gene', (269, 273))	('FGF-4', 'Gene', '2249', (180, 185))	('HGF', 'Gene', (229, 232))	('TSP-1', 'molecular_function', 'GO:0004277', ('381', '386'))	('silencing', 'Var', (550, 559))	('NRG1', 'Gene', '3084', (269, 273))	('IL-8', 'Gene', (504, 508))	('interleukin 8', 'Gene', (489, 502))	('TSP-1', 'Gene', '7057', (381, 386))	('TGF-beta1', 'Gene', '7040', (442, 451))	('tissue inhibitor of metalloproteinases-1', 'Gene', '7076', (297, 337))
165389	33562126	TSP-1 (1.15 +- 0.17) and TIMP-1 (1.08 +- 0.08) increased when the SDC-1 silenced cells conditioned medium was compared to SDC-1 overexpressing cells; ratios of both conditions being calculated relative to their specific control (p < 0.05) (Figure 1C).	('TIMP-1', 'Gene', (25, 31))	('TSP-1', 'Gene', (0, 5))	('se', 'Gene', '6713', (53, 55))	('TSP-1', 'Gene', '7057', (0, 5))	('SDC-1', 'Gene', (66, 71))	('silenced', 'Var', (72, 80))	('TSP-1', 'molecular_function', 'GO:0004277', ('0', '5'))	('TIMP-1', 'Gene', '7076', (25, 31))
165391	33562126	We observed that endothelial cell proliferation was significantly hampered after incubation with conditioned medium from SDC-1 over-expressing cells compared to Human Umbilical Vein Endothelial Cells (HUVEC)cells growing in conditioned medium from control cells.	('Human', 'Species', '9606', (161, 166))	('endothelial cell proliferation', 'biological_process', 'GO:0001935', ('17', '47'))	('se', 'Gene', '6713', (5, 7))	('hampered', 'NegReg', (66, 74))	('Umbilical Vein Endothelial', 'CellLine', 'CVCL:2G60', (167, 193))	('over-expressing', 'Var', (127, 142))	('SDC-1', 'Gene', (121, 126))	('HUVEC', 'CellLine', 'CVCL:2959', (201, 206))	('endothelial cell proliferation', 'CPA', (17, 47))
165394	33562126	The wound area closure in HUVEC cells treated with conditioned medium from SDC-1 over-expressing cells was significantly lower compared to cells treated with conditioned medium form control cells.	('SDC-1', 'Gene', (75, 80))	('over-expressing', 'Var', (81, 96))	('lower', 'NegReg', (121, 126))	('HUVEC', 'CellLine', 'CVCL:2959', (26, 31))	('wound area closure', 'CPA', (4, 22))
165395	33562126	Additionally, the wound area closure in HUVEC cells treated by conditioned medium from SDC-1 silenced cells was significantly higher compared to the cells treated with conditioned medium from scrambled negative control cells (Figure 3A,B).	('wound area closure', 'CPA', (18, 36))	('higher', 'PosReg', (126, 132))	('silenced', 'Var', (93, 101))	('SDC-1', 'Gene', (87, 92))	('HUVEC', 'CellLine', 'CVCL:2959', (40, 45))
165398	33562126	Percentage of covered area by HUVEC cells attracted by SDC-1 over-expressing cells conditioned medium was (12.48 +- 5%; mean +- SD), compared to HUVEC cells incubated with conditioned medium collected from mock control cells (8.45 +- 2.5%) (Supplementary Figure S2).	('over-expressing', 'Var', (61, 76))	('SDC-1', 'Gene', (55, 60))	('HUVEC', 'CellLine', 'CVCL:2959', (145, 150))	('HUVEC', 'CellLine', 'CVCL:2959', (30, 35))
165400	33562126	After 6 h incubation of HUVEC cells with conditioned medium from SDC-1 over-expressing cells, the total tube lengths, number of total branching points, and loops were significantly reduced compared to HUVEC cells that were incubated with medium from control cells (Figure 4A,B).	('over-expressing cells', 'Var', (71, 92))	('reduced', 'NegReg', (181, 188))	('tube lengths', 'CPA', (104, 116))	('HUVEC', 'CellLine', 'CVCL:2959', (24, 29))	('cells', 'Var', (87, 92))	('SDC-1', 'Gene', (65, 70))	('HUVEC', 'CellLine', 'CVCL:2959', (201, 206))	('loops', 'CPA', (156, 161))
165402	33562126	Silencing of SDC-1 did not inhibit the formation of capillary-like structures of HUVEC cells (Supplementary Figure S4).	('SDC-1', 'Gene', (13, 18))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('HUVEC', 'CellLine', 'CVCL:2959', (81, 86))	('Silencing', 'Var', (0, 9))	('inhibit', 'NegReg', (27, 34))
165403	33562126	In order to investigate the role of shed SDC-1 on the tube formation of endothelial cells, we silenced MMP-7 in mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('tube formation', 'biological_process', 'GO:0035148', ('54', '68'))	('MMP-7', 'Gene', (103, 108))	('silenced', 'Var', (94, 102))	('MMP-7', 'molecular_function', 'GO:0004235', ('103', '108'))	('MMP-7', 'Gene', '4316', (103, 108))	('mesothelioma', 'Disease', (112, 124))
165405	33562126	We observed that SDC-1 shedding was decreased by nearly 30% in the supernatant silenced for MMP-7 compared to scrambled control (Supplementary Figure S5B).	('MMP-7', 'Gene', (92, 97))	('se', 'Gene', '6713', (5, 7))	('silenced', 'Var', (79, 87))	('S5B', 'Gene', (150, 153))	('MMP-7', 'Gene', '4316', (92, 97))	('SDC-1', 'Gene', (17, 22))	('MMP-7', 'molecular_function', 'GO:0004235', ('92', '97'))	('se', 'Gene', '6713', (42, 44))	('S5B', 'Gene', '5711', (150, 153))	('shedding', 'MPA', (23, 31))
165419	33562126	In addition, among proteins which were altered by both SDC-1 over-expression and silencing, TIMP-1 and TSP-1 were significantly upregulated upon SDC-1 silencing.	('TSP-1', 'molecular_function', 'GO:0004277', ('103', '108'))	('silencing', 'Var', (151, 160))	('TSP-1', 'Gene', (103, 108))	('TIMP-1', 'Gene', (92, 98))	('TIMP-1', 'Gene', '7076', (92, 98))	('TSP-1', 'Gene', '7057', (103, 108))	('silencing', 'Var', (81, 90))	('SDC-1', 'Gene', (55, 60))	('SDC-1', 'Var', (145, 150))	('upregulated', 'PosReg', (128, 139))
165427	33562126	Taken together, the alterations of angiopoietin-1, TSP-1, and TIMP-1 associated to SDC-1 overexpression collectively led to reduced proliferation, wound closure, and tube formation of HUVEC cells.	('alterations', 'Var', (20, 31))	('angiopoietin-1', 'Gene', (35, 49))	('tube formation', 'biological_process', 'GO:0035148', ('166', '180'))	('angiopoietin-1', 'Gene', '284', (35, 49))	('reduced', 'NegReg', (124, 131))	('tube formation', 'CPA', (166, 180))	('wound closure', 'CPA', (147, 160))	('HUVEC', 'CellLine', 'CVCL:2959', (184, 189))	('proliferation', 'CPA', (132, 145))	('SDC-1', 'Gene', (83, 88))	('TSP-1', 'Gene', (51, 56))	('TSP-1', 'molecular_function', 'GO:0004277', ('51', '56'))	('TSP-1', 'Gene', '7057', (51, 56))	('TIMP-1', 'Gene', (62, 68))	('TIMP-1', 'Gene', '7076', (62, 68))
165431	33562126	The pro-angiogenic factors HGF, NRG1beta1, and FGF4 were, on the other hand, upregulated by the SDC-1 over-expression.	('NRG1beta1', 'Gene', (32, 41))	('FGF4', 'Gene', (47, 51))	('upregulated', 'PosReg', (77, 88))	('over-expression', 'Var', (102, 117))	('HGF', 'Gene', (27, 30))	('FGF4', 'Gene', '2249', (47, 51))	('SDC-1', 'Gene', (96, 101))	('HGF', 'Gene', '3082', (27, 30))
165436	33562126	Although other enzymes could also be involved in SDC-1 shedding, such as MMP-9 or heparanase, we found that silencing of MMP-7 by 45% decreased the SDC-1 shedding nearly 30%.	('heparanase', 'Gene', '10855', (82, 92))	('silencing', 'Var', (108, 117))	('se', 'Gene', '6713', (140, 142))	('MMP-7', 'molecular_function', 'GO:0004235', ('121', '126'))	('MMP-9', 'Gene', '4318', (73, 78))	('MMP-9', 'molecular_function', 'GO:0004229', ('73', '78'))	('MMP-9', 'Gene', (73, 78))	('heparanase', 'Gene', (82, 92))	('SDC-1 shedding', 'MPA', (148, 162))	('se', 'Gene', '6713', (90, 92))	('MMP-7', 'Gene', (121, 126))	('MMP-7', 'Gene', '4316', (121, 126))
165438	33562126	Moreover, MMP7-mediated shedding of SDC-1 affects the activity of alpha2beta1 integrins towards a lower affinity and therefore less cell-matrix interactions which facilitates the cell migration.	('cell-matrix interactions', 'CPA', (132, 156))	('MMP7', 'Gene', '4316', (10, 14))	('SDC-1', 'Gene', (36, 41))	('beta1', 'Gene', '597', (72, 77))	('cell migration', 'biological_process', 'GO:0016477', ('179', '193'))	('MMP7', 'molecular_function', 'GO:0004235', ('10', '14'))	('facilitates', 'PosReg', (163, 174))	('MMP7', 'Gene', (10, 14))	('less', 'NegReg', (127, 131))	('shedding', 'Var', (24, 32))	('activity', 'MPA', (54, 62))	('affects', 'Reg', (42, 49))	('beta1', 'Gene', (72, 77))	('lower', 'NegReg', (98, 103))	('cell migration', 'CPA', (179, 193))
165449	33562126	For instance, chemotherapy resistance in colorectal cancer has been attributed to EGFR phosphorylation and activation of the downstream pathway through growth factor binding ability of heparan sulfate chains existing on shed SDC-1.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('phosphorylation', 'Var', (87, 102))	('EGFR', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('chemotherapy resistance', 'CPA', (14, 37))	('colorectal cancer', 'Disease', (41, 58))	('heparan sulfate', 'Chemical', 'MESH:D006497', (185, 200))	('growth factor binding', 'molecular_function', 'GO:0019838', ('152', '173'))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('downstream pathway', 'Pathway', (125, 143))	('heparan sulfate chains', 'Protein', (185, 207))	('EGFR', 'Gene', '1956', (82, 86))	('activation', 'PosReg', (107, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
165465	33562126	ATCC-CRL-1730) and were grown in F12K medium (Kaighn's Modification of Ham's F-12 Medium, cat.no.ATCC 30-2004).	('cat', 'Gene', (90, 93))	('cat', 'molecular_function', 'GO:0004096', ('90', '93'))	('cat', 'Gene', '847', (90, 93))	('cat', 'Gene', (61, 64))	('F12K', 'SUBSTITUTION', 'None', (33, 37))	('F12K', 'Var', (33, 37))	("Ham's F-12 Medium", 'Chemical', '-', (71, 88))	('cat', 'Gene', '847', (61, 64))
165467	33562126	In order to silence SDC-1, we used three different siRNAs (SDC-1 silencer pre-designed siRNA, s12632, s12633, and s12634) and silencer negative siRNA as a negative control.	('silencer', 'Disease', 'None', (126, 134))	('s12634', 'Var', (114, 120))	('SDC-1', 'Gene', (59, 64))	('silencer', 'Disease', 'None', (65, 73))	('silencer', 'Disease', (126, 134))	('silencer', 'Disease', (65, 73))	('se', 'Gene', '6713', (31, 33))	('s12633', 'Var', (102, 108))	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))	('s12632', 'Var', (94, 100))
165501	33562126	The chemotactic effect of soluble angiogenic factors released from SDC-1 over-expressing or mock control cells was evaluated using a modified two chamber assay with a pore size of 3 mum (Transwell chamber, Corning, NY, USA).	('soluble', 'cellular_component', 'GO:0005625', ('26', '33'))	('se', 'Gene', '6713', (58, 60))	('pore', 'cellular_component', 'GO:0046930', ('167', '171'))	('over-expressing', 'Var', (73, 88))	('SDC-1', 'Gene', (67, 72))
165542	33562126	The following are available online at , Figure S1: SDC-1 mRNA and protein expression level upon SDC-1 overexpression and silencing, Figure S2: Chemotactic directional movement of HUVEC cells toward the conditioned medium of malignant mesothelioma cells overexpressing SDC-1, Figure S3: Number of total nets and total tubes, mean loop area and perimeter, and percentage of covered area by tubes tended to be lower in HUVEC cells incubated with conditioned medium from SDC-1 over-expressing cells compared to corresponding controls, Figure S4: Number of total tube length, total branching points and total loops are not significantly affected in HUVEC cells treated with conditioned medium from SDC-1 silenced cells compared to HUVEC cells treated with conditioned medium from negative silencer control (Sc), Figure S5: MMP-7 expression level of malignant mesothelioma cells after MMP7 silencing and its effect of SDC-1 shedding.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (224, 246))	('silencer', 'Disease', (784, 792))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (844, 866))	('MMP7', 'molecular_function', 'GO:0004235', ('879', '883'))	('HUVEC', 'CellLine', 'CVCL:2959', (416, 421))	('silencer', 'Disease', 'None', (784, 792))	('HUVEC', 'CellLine', 'CVCL:2959', (644, 649))	('MMP7', 'Gene', '4316', (879, 883))	('MMP-7', 'molecular_function', 'GO:0004235', ('818', '823'))	('malignant mesothelioma', 'Disease', (224, 246))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (224, 246))	('MMP-7', 'Gene', (818, 823))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('MMP7', 'Gene', (879, 883))	('silencing', 'Var', (884, 893))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (844, 866))	('HUVEC', 'CellLine', 'CVCL:2959', (179, 184))	('MMP-7', 'Gene', '4316', (818, 823))	('HUVEC', 'CellLine', 'CVCL:2959', (726, 731))	('malignant mesothelioma', 'Disease', (844, 866))
165596	29059207	Although the available chemotherapeutic agents have limited value in malignant mesothelioma treatment, the FDA approved cisplatin-pemetrexed as a first-line therapy in unresectable patients, and has resulted in an improvement in the response rates and overall survival rates in clinical trials.	('malignant mesothelioma', 'Disease', (69, 91))	('cisplatin-pemetrexed', 'Var', (120, 140))	('cisplatin-pemetrexed', 'Chemical', '-', (120, 140))	('response rates', 'CPA', (233, 247))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (69, 91))	('patients', 'Species', '9606', (181, 189))	('improvement', 'PosReg', (214, 225))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (69, 91))
165599	29059207	EnGeneIC Dream Vectors (EDVs) are targeted and drug loaded 400 +- 20 nm, anucleate nanocells derived from gram-negative Salmonella typhimurium, produced as a consequence of mutation of the genes that control bacterial cell division.	('Dream', 'Gene', (9, 14))	('Dream', 'Gene', '30818', (9, 14))	('Salmonella typhimurium', 'Species', '90371', (120, 142))	('cell division', 'biological_process', 'GO:0051301', ('218', '231'))	('mutation', 'Var', (173, 181))
165607	29059207	An in vitro evaluation revealed that MSLN increased cancerous cell proliferation significantly, and silencing the MSLN gene decreased cancer cell proliferation, migration and invasiveness.	('increased', 'PosReg', (42, 51))	('cancerous', 'Disease', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('silencing', 'Var', (100, 109))	('MSLN gene', 'Gene', (114, 123))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('decreased', 'NegReg', (124, 133))	('cancerous', 'Disease', 'MESH:D009369', (52, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('invasiveness', 'CPA', (175, 187))
165653	29059207	Cell surface EGFR was detected with ex633/em670 nm.	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('ex633/em670 nm', 'Var', (36, 50))
165675	29059207	Once the tumours reached ~110 mm3 (Day 11) the mice were randomized into treatment groups which included 5-6 mice per group, as follows: Group 1 -Saline, Group 2 -AmatuxEDV, Group 3 -Non-targetedEDVDox, and Group 4 -AmatuxEDVDox.	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('tumours', 'Disease', (9, 16))	('Dox', 'Chemical', 'MESH:D004317', (225, 228))	('Saline', 'Chemical', 'MESH:D012965', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('-Non-targetedEDVDox', 'Var', (182, 201))	('Dox', 'Chemical', 'MESH:D004317', (198, 201))	('mice', 'Species', '10090', (109, 113))	('mice', 'Species', '10090', (47, 51))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
165722	29059207	Eleven days after tumour subcutaneous-implantation when the volume of the tumours reached ~110 mm3, mice were randomly sorted into four different groups (n = 6 per group): saline control group, AmatuxEDV, Non-targetedEDVDox and AmatuxEDVDox.	('Non-targetedEDVDox', 'Var', (205, 223))	('Dox', 'Chemical', 'MESH:D004317', (220, 223))	('AmatuxEDV', 'Var', (194, 203))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('mice', 'Species', '10090', (100, 104))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('tumour', 'Disease', (74, 80))	('saline', 'Chemical', 'MESH:D012965', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumours', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('AmatuxEDVDox', 'Var', (228, 240))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('Dox', 'Chemical', 'MESH:D004317', (237, 240))	('tumour', 'Disease', (18, 24))
165734	29059207	The Ki67 immunohistochemical staining of tissue sections from excised xenograft tumours from the AmatuxEDVDox treated group showed a significant decrease in the number of proliferating cells, compared to the saline (p < 0.01), AmatuxEDV (p < 0.01) and Non-targetedEDVDox (p < 0.05) treated groups (Fig 6A and 6B).	('Ki67', 'Gene', '17345', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('AmatuxEDVDox', 'Var', (97, 109))	('Dox', 'Chemical', 'MESH:D004317', (267, 270))	('number of proliferating cells', 'CPA', (161, 190))	('Ki67', 'Gene', (4, 8))	('saline', 'Chemical', 'MESH:D012965', (208, 214))	('xenograft tumours', 'Disease', (70, 87))	('decrease', 'NegReg', (145, 153))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('Dox', 'Chemical', 'MESH:D004317', (106, 109))	('xenograft tumours', 'Disease', 'MESH:D009369', (70, 87))
165736	29059207	Statistically, the AmatuxEDVDox treated mice had significantly smaller necrotic areas compared to the saline group, AmatuxEDV and Non-targetedEDVDox (p <= 0.0005, p < 0.01 and p < 0.05, respectively).	('Dox', 'Chemical', 'MESH:D004317', (145, 148))	('Dox', 'Chemical', 'MESH:D004317', (28, 31))	('necrotic areas', 'Disease', (71, 85))	('saline', 'Chemical', 'MESH:D012965', (102, 108))	('smaller', 'NegReg', (63, 70))	('necrotic areas', 'Disease', 'MESH:D009336', (71, 85))	('AmatuxEDVDox', 'Var', (19, 31))	('mice', 'Species', '10090', (40, 44))
165754	29059207	For example, the doxorubicin dose was reduced around 1764-fold with CD3EDVDox compared to that of conventional chemotherapy treatment.	('CD3EDVDox', 'Var', (68, 77))	('doxorubicin dose', 'MPA', (17, 33))	('reduced', 'NegReg', (38, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (17, 28))	('Dox', 'Chemical', 'MESH:D004317', (74, 77))
165757	29059207	We were able to identify necrotic areas in xenograft tumour sections, and observed that tumours from mice treated with AmatuxEDVDox showed significantly smaller areas of necrosis compared to Non-targetedEDVDox (p < 0.05).	('necrosis', 'biological_process', 'GO:0008220', ('170', '178'))	('Dox', 'Chemical', 'MESH:D004317', (206, 209))	('necrotic areas in xenograft tumour', 'Disease', (25, 59))	('mice', 'Species', '10090', (101, 105))	('AmatuxEDVDox', 'Var', (119, 131))	('necrosis', 'biological_process', 'GO:0070265', ('170', '178'))	('necrosis', 'biological_process', 'GO:0019835', ('170', '178'))	('necrosis', 'biological_process', 'GO:0001906', ('170', '178'))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('smaller', 'NegReg', (153, 160))	('necrosis', 'Disease', 'MESH:D009336', (170, 178))	('necrosis', 'biological_process', 'GO:0008219', ('170', '178'))	('Dox', 'Chemical', 'MESH:D004317', (128, 131))	('necrosis', 'Disease', (170, 178))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('necrotic areas in xenograft tumour', 'Disease', 'MESH:D009369', (25, 59))
165772	25632963	In the univariate analysis, low Wnt7A expression was a significant negative factor for overall survival (P=0.043, HR=2.30).	('Wnt7A', 'Gene', (32, 37))	('expression', 'MPA', (38, 48))	('overall', 'MPA', (87, 94))	('Wnt7A', 'Gene', '7476', (32, 37))	('low', 'Var', (28, 31))	('negative', 'NegReg', (67, 75))
165776	25632963	In patients who did not have neoadjuvant chemotherapy, prognosis was significantly more favorable for patients with high Wnt7A expression than for those with low Wnt7A expression (P=0.031).	('Wnt7A', 'Gene', (121, 126))	('prognosis', 'CPA', (55, 64))	('favorable', 'PosReg', (88, 97))	('high', 'Var', (116, 120))	('patients', 'Species', '9606', (102, 110))	('Wnt7A', 'Gene', '7476', (162, 167))	('Wnt7A', 'Gene', '7476', (121, 126))	('patients', 'Species', '9606', (3, 11))	('Wnt7A', 'Gene', (162, 167))
165777	25632963	Among the patients with low Wnt7A-expressing tumors, those who received neoadjuvant chemotherapy had better prognosis than those who did not (P=0.024).	('Wnt7A', 'Gene', '7476', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Wnt7A', 'Gene', (28, 33))	('patients', 'Species', '9606', (10, 18))	('low', 'Var', (24, 27))
165789	25632963	E-cadherin induction by Wnt/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and loss of Wnt7A expression may be important in lung cancer development or progression due to its effects on E-cadherin.	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('lung cancer', 'Disease', (103, 114))	('cadherin', 'molecular_function', 'GO:0008014', ('234', '242'))	('loss', 'Var', (126, 130))	('effects', 'Reg', (221, 228))	('E-cadherin', 'Gene', (232, 242))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', (171, 182))	('E-cadherin', 'Gene', '999', (232, 242))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('Wnt7A', 'Gene', (134, 139))	('men', 'Species', '9606', (190, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('Wnt7A', 'Gene', '7476', (134, 139))	('beta-catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', '1499', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('E-cadherin', 'Gene', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('E-cadherin', 'Gene', '999', (0, 10))
165800	25632963	Hybridization probes and primers (Wnt7A, Hs01114990 m1; GAPDH, Hs00244574 m1) were purchased from Applied Biosystems (ABI).	('Hs00244574 m1', 'Var', (63, 76))	('Wnt7A', 'Gene', '7476', (34, 39))	('GAPDH', 'Gene', '2597', (56, 61))	('GAPDH', 'Gene', (56, 61))	('Hs01114990 m1', 'Var', (41, 54))	('Wnt7A', 'Gene', (34, 39))
165803	25632963	Patients were divided into those with high Wnt7A expression and those with low Wnt7A expression.	('Wnt7A', 'Gene', '7476', (79, 84))	('high', 'Var', (38, 42))	('Wnt7A', 'Gene', (43, 48))	('Patients', 'Species', '9606', (0, 8))	('Wnt7A', 'Gene', '7476', (43, 48))	('Wnt7A', 'Gene', (79, 84))
165812	25632963	Multivariate analysis using a Cox's regression hazard model showed no significant prognostic factors for overall survival, but did show that low Wnt7A expression (P=0.051, HR=2.283) and histological subtype (non-epithelioid, P=0.05, HR=2.898) were likely to be negative prognostic factors for overall survival (Table III).	('Cox', 'Gene', (30, 33))	('Wnt7A', 'Gene', (145, 150))	('expression', 'MPA', (151, 161))	('Wnt7A', 'Gene', '7476', (145, 150))	('low', 'Var', (141, 144))	('Cox', 'Gene', '1351', (30, 33))
165818	25632963	Overall survival was significantly more favorable for patients with high Wnt7A expression than for those with low expression (26.7+-11.1 months vs. 11.8+-4.9; P=0.043, Fig.	('Wnt7A', 'Gene', (73, 78))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (54, 62))	('favorable', 'PosReg', (40, 49))	('Wnt7A', 'Gene', '7476', (73, 78))	('Overall survival', 'CPA', (0, 16))
165832	25632963	However, in patients with low Wnt7A-expressing epithelioid tumors, overall survival was significantly better in those who underwent neoadjuvant chemotherapy than in those who did not (P=0.024; HR=4.31, 95% CI of HR, 1.1 to 16.9; Fig.	('patients', 'Species', '9606', (12, 20))	('epithelioid tumors', 'Disease', 'MESH:D012509', (47, 65))	('better', 'PosReg', (102, 108))	('low', 'Var', (26, 29))	('overall survival', 'MPA', (67, 83))	('epithelioid tumors', 'Disease', (47, 65))	('Wnt7A', 'Gene', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Wnt7A', 'Gene', '7476', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
165833	25632963	In the subset of the 20 patients who received neoadjuvant chemotherapy, overall survival did not differ significantly between those with low Wnt7A vs. high Wnt7A tumors (17.6+-5.25; 95% CI, 7.3 to 27.9 months vs. 34.4+-13.3; 95% CI, 8.2 to 60.5 months, P=0.425; Fig.	('Wnt7A', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Wnt7A', 'Gene', (156, 161))	('Wnt7A', 'Gene', '7476', (141, 146))	('low', 'Var', (137, 140))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Wnt7A', 'Gene', '7476', (156, 161))
165849	25632963	E-cadherin induction by Wnt/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and loss of Wnt7A expression may be important in lung cancer development or progression through its effects on E-cadherin.	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('lung cancer', 'Disease', (103, 114))	('loss', 'Var', (126, 130))	('E-cadherin', 'Gene', (233, 243))	('effects', 'Reg', (222, 229))	('E-cadherin', 'Gene', '999', (233, 243))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', (171, 182))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('Wnt7A', 'Gene', (134, 139))	('men', 'Species', '9606', (190, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('Wnt7A', 'Gene', '7476', (134, 139))	('beta-catenin', 'Gene', (28, 40))	('cadherin', 'molecular_function', 'GO:0008014', ('235', '243'))	('beta-catenin', 'Gene', '1499', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('E-cadherin', 'Gene', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('E-cadherin', 'Gene', '999', (0, 10))
165857	25632963	In our study, Wnt7A expression might have been affected by smoking in normal or precancerous events such K-ras mutation, loss of EGFR mutation, or P53 mutation, even in pleural tissues.	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Wnt7A', 'Gene', '7476', (14, 19))	('K-ras', 'Gene', '3845', (105, 110))	('expression', 'MPA', (20, 30))	('loss', 'NegReg', (121, 125))	('P53', 'Gene', (147, 150))	('affected', 'Reg', (47, 55))	('mutation', 'Var', (134, 142))	('mutation', 'Var', (151, 159))	('K-ras', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('EGFR', 'Gene', '1956', (129, 133))	('P53', 'Gene', '7157', (147, 150))	('mutation', 'Var', (111, 119))	('Wnt7A', 'Gene', (14, 19))	('EGFR', 'Gene', (129, 133))	('cancer', 'Disease', (83, 89))
165871	25632963	These results indicate the patients with low Wnt7A expression do benefit, while patients with high Wnt7A expression do not benefit.	('Wnt7A', 'Gene', '7476', (99, 104))	('patients', 'Species', '9606', (80, 88))	('benefit', 'PosReg', (65, 72))	('Wnt7A', 'Gene', '7476', (45, 50))	('patients', 'Species', '9606', (27, 35))	('low', 'Var', (41, 44))	('Wnt7A', 'Gene', (99, 104))	('Wnt7A', 'Gene', (45, 50))
165873	25632963	Among patients who did not have neoadjuvant chemotherapy, those with high Wnt7A expression had a significantly better prognosis than those with low Wnt7A expression.	('Wnt7A', 'Gene', (74, 79))	('Wnt7A', 'Gene', '7476', (148, 153))	('Wnt7A', 'Gene', '7476', (74, 79))	('patients', 'Species', '9606', (6, 14))	('high', 'Var', (69, 73))	('Wnt7A', 'Gene', (148, 153))
165876	25632963	This means that patients with high Wnt7A expression have better prognosis, and patients with high Wnt7A expression might be more sensitive to neoadjuvant chemotherapy and they could have a better prognosis than those without neoadjuvant chemotherapy.	('Wnt7A', 'Gene', (35, 40))	('sensitive', 'MPA', (129, 138))	('patients', 'Species', '9606', (16, 24))	('Wnt7A', 'Gene', (98, 103))	('Wnt7A', 'Gene', '7476', (35, 40))	('high', 'Var', (30, 34))	('more', 'PosReg', (124, 128))	('patients', 'Species', '9606', (79, 87))	('Wnt7A', 'Gene', '7476', (98, 103))	('better', 'PosReg', (57, 63))	('high', 'Var', (93, 97))
165908	25849448	Immunohistochemistry showed a strong positive expression of calretinin, epithelial membrane antigen, WT1, pan-cytokeratin, thrombomodulin, anti-D240 antibody (D2-40), e-cadherin, and CK 5, 6, and 7.	('thrombomodulin', 'Gene', (123, 137))	('antibody', 'cellular_component', 'GO:0019814', ('149', '157'))	('antibody', 'molecular_function', 'GO:0003823', ('149', '157'))	('calretinin', 'Gene', '794', (60, 70))	('membrane', 'cellular_component', 'GO:0016020', ('83', '91'))	('CK 5', 'Gene', (183, 187))	('epithelial membrane antigen, WT1', 'Gene', '7490', (72, 104))	('antibody', 'cellular_component', 'GO:0042571', ('149', '157'))	('anti-D240', 'Var', (139, 148))	('cadherin', 'molecular_function', 'GO:0008014', ('169', '177'))	('CK 5', 'Gene', '3852', (183, 187))	('calretinin', 'Gene', (60, 70))	('e-cadherin', 'Gene', (167, 177))	('antibody', 'cellular_component', 'GO:0019815', ('149', '157'))	('thrombomodulin', 'Gene', '7056', (123, 137))	('e-cadherin', 'Gene', '999', (167, 177))
165981	25479300	The smoking habits were classified into nonsmokers, ex-smokers, moderate smokers (less than 15 cig/day, less than 8 cigars or 100 g or more pipe tobacco/week), and heavy smokers from the first health examinations.	('tobacco', 'Species', '4097', (145, 152))	('less than', 'Var', (104, 113))	('less than 15 cig/day', 'Var', (82, 102))
166023	25479300	Experiments in animals have indicated genotoxicity at very high doses, but other mechanisms may be more important at lower exposure, for example, epigenetic mechanisms and enhancing the delivery of polycyclic aromatic hydrocarbons into cells.	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (198, 230))	('epigenetic', 'Var', (146, 156))	('enhancing', 'PosReg', (172, 181))	('delivery of polycyclic aromatic hydrocarbons into', 'MPA', (186, 235))	('men', 'Species', '9606', (6, 9))
166056	20736856	Other eligibility criteria included: ECOG PS 0 or 1, measurable disease, no therapeutic anticoagulation, no currently active second malignancy (completed treatment with <30% risk of relapse) other than non-melanoma skin cancers and carcinoma in situ of the cervix, and lab values reflective of adequate organ function (granulocytes >=1500/mm3, platelets >=100,000/mm3, total bilirubin <=1.5 X upper limit of normal (ULN), AST <=2.5 xULN, creatinine<=1.5 X ULN, INR <1.5).	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('carcinoma', 'Disease', (232, 241))	('INR', 'MPA', (461, 464))	('AST', 'Gene', (422, 425))	('upper limit of normal', 'MPA', (393, 414))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('granulocytes', 'Var', (319, 331))	('creatinine', 'MPA', (438, 448))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (202, 227))	('carcinoma', 'Disease', 'MESH:D002277', (232, 241))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (232, 249))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('malignancy', 'Disease', (132, 142))	('non-melanoma skin cancers', 'Disease', (202, 227))	('AST', 'Gene', '26503', (422, 425))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('total bilirubin', 'MPA', (369, 384))	('skin cancers', 'Phenotype', 'HP:0008069', (215, 227))
166065	20736856	Secondary endpoints included i) overall survival and progression free survival, ii) toxicities, and iii) correlation of BRAF mutations and p-ERK1/2 expression with anti-tumor activity.	('progression free survival', 'CPA', (53, 78))	('mutations', 'Var', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('p-ERK1/2', 'Gene', (139, 147))	('toxicities', 'Disease', (84, 94))	('BRAF', 'Gene', '673', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BRAF', 'Gene', (120, 124))	('tumor', 'Disease', (169, 174))	('ERK1', 'molecular_function', 'GO:0004707', ('141', '145'))	('toxicities', 'Disease', 'MESH:D064420', (84, 94))	('correlation', 'Interaction', (105, 116))
166115	20736856	Hence cancers with low levels of p-ERK 1/2 may in general be less aggressive and thus be associated with a better outcome.	('low levels', 'Var', (19, 29))	('aggressive', 'CPA', (66, 76))	('ERK 1', 'molecular_function', 'GO:0004707', ('35', '40'))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('less', 'NegReg', (61, 65))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('ERK 1/2', 'Gene', '5595;5594', (35, 42))	('cancers', 'Disease', (6, 13))	('ERK 1/2', 'Gene', (35, 42))
166210	29755689	The stringent control of RTKs is often abrogated in tumor cells: gene mutations, amplifications, overexpression and gene fusions result in constitutive activation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('gene mutations', 'Var', (65, 79))	('amplifications', 'Var', (81, 95))	('tumor', 'Disease', (52, 57))	('result in', 'Reg', (129, 138))	('constitutive activation', 'MPA', (139, 162))	('overexpression', 'Var', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('gene fusions', 'Var', (116, 128))
166212	29755689	Crizotinib (PF02341066) is a potent, orally bioavailable, well tolerated, small molecule inhibitor of ALK, ROS1 and MET.	('MET', 'Protein', (116, 119))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ALK', 'Gene', (102, 105))	('ROS1', 'Gene', (107, 111))	('ROS1', 'Gene', '6098', (107, 111))	('ALK', 'Gene', '238', (102, 105))	('PF02341066', 'Var', (12, 22))
166217	29755689	had minimal activity in MPM and was poorly tolerated, and single-agent EGFR or MET inhibition was clinically ineffective in MPM patients, despite high expression of EGFR and MET (NCT01861301).	('EGFR', 'Gene', (165, 169))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('activity', 'MPA', (12, 20))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'molecular_function', 'GO:0005006', ('165', '169'))	('MPM', 'Disease', (24, 27))	('patients', 'Species', '9606', (128, 136))	('EGFR', 'Gene', (71, 75))	('MET', 'Var', (174, 177))	('MPM', 'Disease', (124, 127))	('EGFR', 'Gene', '1956', (165, 169))
166218	29755689	Deletion of the tumor suppressor NF2 seen in 40-50% of MPM leads to aberrant activation of the serine/threonine protein kinase mTOR.	('NF2', 'Gene', '4771', (33, 36))	('mTOR', 'Gene', '2475', (127, 131))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('activation', 'PosReg', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('tumor', 'Disease', (16, 21))	('NF2', 'Gene', (33, 36))	('mTOR', 'Gene', (127, 131))	('Deletion', 'Var', (0, 8))
166223	29755689	Inhibition of mTOR by rapamycin or its derivatives (sirolimus, temsirolimus, everolimus) suppressed mesothelioma cell growth in pre-clinical models, but was not effective in clinical trials: everolimus showed no therapeutic benefit in unselected MPM patients and a small group of patients selected for NF2 deletion (NCT01024946).	('mTOR', 'Gene', '2475', (14, 18))	('temsirolimus', 'Chemical', 'MESH:C401859', (63, 75))	('MPM', 'Disease', (246, 249))	('suppressed', 'NegReg', (89, 99))	('rapamycin', 'Gene', '74370', (22, 31))	('NF2', 'Gene', '4771', (302, 305))	('sirolimus', 'Chemical', 'MESH:D020123', (52, 61))	('deletion (NCT01024946', 'Var', (306, 327))	('NF2', 'Gene', (302, 305))	('cell growth', 'biological_process', 'GO:0016049', ('113', '124'))	('NCT01024946', 'Var', (316, 327))	('sirolimus', 'Chemical', 'MESH:D020123', (66, 75))	('patients', 'Species', '9606', (280, 288))	('patients', 'Species', '9606', (250, 258))	('everolimus', 'Chemical', 'MESH:D000068338', (191, 201))	('mTOR', 'Gene', (14, 18))	('rapamycin', 'Gene', (22, 31))	('pre', 'molecular_function', 'GO:0003904', ('128', '131'))	('mesothelioma', 'Disease', (100, 112))	('everolimus', 'Chemical', 'MESH:D000068338', (77, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))
166224	29755689	These disappointing results are most probably due to adverse AKT activation: Inhibiting mTORC1 releases the negative feedback on PI3K/AKT signaling and increases AKT activation (Figure 1), which may promote cell survival and prevent apoptosis.	('AKT', 'Gene', '207', (162, 165))	('negative feedback', 'MPA', (108, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('Inhibiting', 'Var', (77, 87))	('mTORC1', 'cellular_component', 'GO:0031931', ('88', '94'))	('AKT', 'Gene', (134, 137))	('mTORC1', 'Gene', (88, 94))	('increases', 'PosReg', (152, 161))	('promote', 'PosReg', (199, 206))	('cell survival', 'CPA', (207, 220))	('AKT', 'Gene', (61, 64))	('mTORC1', 'Gene', '382056', (88, 94))	('AKT', 'Gene', (162, 165))	('apoptosis', 'CPA', (233, 242))	('AKT', 'Gene', '207', (134, 137))	('releases', 'PosReg', (95, 103))	('prevent', 'NegReg', (225, 232))	('activation', 'PosReg', (166, 176))	('AKT', 'Gene', '207', (61, 64))	('AKT signaling', 'biological_process', 'GO:0043491', ('134', '147'))	('apoptosis', 'biological_process', 'GO:0097194', ('233', '242'))	('apoptosis', 'biological_process', 'GO:0006915', ('233', '242'))
166225	29755689	Moreover, mTORC1 inhibition induces autophagy, helping to maintain cancer cell survival.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('mTORC1', 'Gene', '382056', (10, 16))	('inhibition', 'Var', (17, 27))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('maintain', 'PosReg', (58, 66))	('induces', 'Reg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mTORC1', 'cellular_component', 'GO:0031931', ('10', '16'))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('autophagy', 'CPA', (36, 45))	('mTORC1', 'Gene', (10, 16))
166226	29755689	We postulated, therefore, that co-targeting of mTOR and RTK signaling pathways may result in greater therapeutic benefit via simultaneous inhibition of mTORC1, RAS/MEK/MAPK and STAT signaling and simultaneous suppression of rapamycin-induced AKT activation.	('MEK', 'Gene', '5609', (164, 167))	('therapeutic benefit', 'CPA', (101, 120))	('rapamycin', 'Gene', (224, 233))	('STAT', 'MPA', (177, 181))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))	('MEK', 'Gene', (164, 167))	('mTOR', 'Gene', (152, 156))	('AKT', 'Gene', (242, 245))	('rapamycin', 'Gene', '74370', (224, 233))	('mTORC1', 'Gene', (152, 158))	('activation', 'PosReg', (246, 256))	('mTOR', 'Gene', '2475', (152, 156))	('mTOR', 'Gene', (47, 51))	('suppression', 'NegReg', (209, 220))	('mTORC1', 'Gene', '382056', (152, 158))	('AKT', 'Gene', '207', (242, 245))	('inhibition', 'NegReg', (138, 148))	('mTORC1', 'cellular_component', 'GO:0031931', ('152', '158'))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('co-targeting', 'Var', (31, 43))	('mTOR', 'Gene', '2475', (47, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('168', '172'))
166229	29755689	We also found that the combined use of rapamycin and crizotinib was more effective than rapamycin as single-agent in suppressing tumor growth in a patient-derived mesothelioma graft with co-activated ALK and mTOR pathways.	('rapamycin', 'Gene', '74370', (88, 97))	('crizotinib', 'Chemical', 'MESH:D000077547', (53, 63))	('rapamycin', 'Gene', '74370', (39, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('patient', 'Species', '9606', (147, 154))	('rapamycin', 'Gene', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mesothelioma', 'Disease', (163, 175))	('suppressing', 'NegReg', (117, 128))	('mTOR', 'Gene', (208, 212))	('mTOR', 'Gene', '2475', (208, 212))	('crizotinib', 'Var', (53, 63))	('ALK', 'Gene', '238', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('rapamycin', 'Gene', (88, 97))	('ALK', 'Gene', (200, 203))
166237	29755689	Because up-regulated ALK expression is frequently associated with mutations in the kinase domain in neuroblastoma, we examined ALK exons 20-29 for mutations in all cases with ALK protein expression.	('neuroblastoma', 'Disease', (100, 113))	('ALK', 'Gene', '238', (21, 24))	('ALK', 'Gene', (175, 178))	('expression', 'MPA', (25, 35))	('neuroblastoma', 'Phenotype', 'HP:0003006', (100, 113))	('up-regulated', 'PosReg', (8, 20))	('ALK', 'Gene', (21, 24))	('ALK', 'Gene', (127, 130))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('neuroblastoma', 'Disease', 'MESH:D009447', (100, 113))	('ALK', 'Gene', '238', (127, 130))	('ALK', 'Gene', '238', (175, 178))	('mutations in', 'Var', (66, 78))
166270	29755689	It has been reported that mTOR is the main negative regulator of autophagy and that crizotinib induces autophagy in ALK-positive tumors.	('crizotinib', 'Chemical', 'MESH:D000077547', (84, 94))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('autophagy', 'CPA', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('autophagy', 'biological_process', 'GO:0016236', ('65', '74'))	('autophagy', 'biological_process', 'GO:0006914', ('65', '74'))	('crizotinib', 'Var', (84, 94))	('autophagy', 'biological_process', 'GO:0016236', ('103', '112'))	('ALK', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mTOR', 'Gene', (26, 30))	('mTOR', 'Gene', '2475', (26, 30))	('autophagy', 'biological_process', 'GO:0006914', ('103', '112'))	('ALK', 'Gene', '238', (116, 119))	('induces', 'Reg', (95, 102))
166271	29755689	Indeed, we observed autophagy induction by rapamycin and crizotinib in the mTOR/ALK-positive mesothelioma graft model, evidenced by the accumulation of LC3B in autophagosomes: 9.1% and 7.7% autophagosome-positive cells in the rapamycin and crizotinib groups, respectively, versus 2.5% in the control group.	('rapamycin', 'Gene', (43, 52))	('rapamycin', 'Gene', '74370', (226, 235))	('mTOR', 'Gene', (75, 79))	('rapamycin', 'Gene', '74370', (43, 52))	('autophagosome', 'cellular_component', 'GO:0005776', ('190', '203'))	('LC3B', 'Gene', (152, 156))	('mTOR', 'Gene', '2475', (75, 79))	('autophagy', 'biological_process', 'GO:0016236', ('20', '29'))	('autophagy', 'CPA', (20, 29))	('accumulation', 'PosReg', (136, 148))	('LC3B', 'Gene', '81631', (152, 156))	('crizotinib', 'Chemical', 'MESH:D000077547', (57, 67))	('crizotinib', 'Var', (57, 67))	('crizotinib', 'Chemical', 'MESH:D000077547', (240, 250))	('rapamycin', 'Gene', (226, 235))	('autophagy', 'biological_process', 'GO:0006914', ('20', '29'))	('mesothelioma', 'Disease', (93, 105))	('ALK', 'Gene', '238', (80, 83))	('autophagosome-positive cells', 'CPA', (190, 218))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('ALK', 'Gene', (80, 83))
166284	29755689	In lung adenocarcinoma and anaplastic large-cell lymphoma, ALK is activated by the expression of chimeric proteins containing the ALK kinase domain, whereas ALK activation in neuroblastoma (NB) and rhabdomyosarcoma (RMS) results in the overexpression of wildtype or mutated transcripts.	('wildtype', 'MPA', (254, 262))	('ALK', 'Gene', (157, 160))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('mutated transcripts', 'MPA', (266, 285))	('lung adenocarcinoma', 'Disease', (3, 22))	('neuroblastoma', 'Phenotype', 'HP:0003006', (175, 188))	('ALK', 'Gene', '238', (59, 62))	('ALK', 'Gene', (59, 62))	('activated', 'PosReg', (66, 75))	('ALK', 'Gene', '238', (130, 133))	('cell lymphoma', 'Phenotype', 'HP:0012191', (44, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('chimeric', 'Var', (97, 105))	('RMS', 'Phenotype', 'HP:0002859', (216, 219))	('ALK', 'Gene', (130, 133))	('lymphoma', 'Disease', (49, 57))	('overexpression', 'MPA', (236, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('lymphoma', 'Disease', 'MESH:D008223', (49, 57))	('NB', 'Phenotype', 'HP:0003006', (190, 192))	('neuroblastoma (NB) and rhabdomyosarcoma', 'Disease', 'MESH:D009447', (175, 214))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (27, 57))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (198, 214))	('ALK', 'Gene', '238', (157, 160))
166287	29755689	Upregulated expression in our MPM cohort was independent of a copy number increase and no activating mutations were seen, while ALK activation in NB and RMS is often associated with copy number gains (NB, RMS) and kinase-domain mutations (NB).	('activation', 'PosReg', (132, 142))	('NB', 'Phenotype', 'HP:0003006', (146, 148))	('copy number gains', 'Var', (182, 199))	('ALK', 'Gene', '238', (128, 131))	('NB', 'Phenotype', 'HP:0003006', (201, 203))	('NB', 'Phenotype', 'HP:0003006', (239, 241))	('kinase-domain mutations', 'Var', (214, 237))	('RMS', 'Disease', (153, 156))	('ALK', 'Gene', (128, 131))	('expression', 'MPA', (12, 22))	('RMS', 'Phenotype', 'HP:0002859', (205, 208))	('RMS', 'Phenotype', 'HP:0002859', (153, 156))
166288	29755689	Of interest, recent studies of NB tumor cells have demonstrated that (1) microRNAs (miR-96, miR-424-5p, miR-503-5p) were involved in regulating ALK expression, and (2) intragenic non-CpG methylation was inversely associated with the amount of ALK transcripts.	('ALK', 'Gene', '238', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ALK', 'Gene', (243, 246))	('miR-503-5p', 'Var', (104, 114))	('miR-96', 'Gene', '407053', (84, 90))	('miR-96', 'Gene', (84, 90))	('miR-424-5p', 'Var', (92, 102))	('NB tumor', 'Disease', 'MESH:D009369', (31, 39))	('ALK', 'Gene', (144, 147))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('NB', 'Phenotype', 'HP:0003006', (31, 33))	('ALK', 'Gene', '238', (243, 246))	('expression', 'MPA', (148, 158))	('NB tumor', 'Disease', (31, 39))
166289	29755689	Similarly, ALK overexpression in MPM might be mediated by microRNAs and/or demethylation of intragenic non-CpG sites.	('overexpression', 'PosReg', (15, 29))	('demethylation', 'Var', (75, 88))	('mediated by', 'Reg', (46, 57))	('MPM', 'Disease', (33, 36))	('ALK', 'Gene', (11, 14))	('demethylation', 'biological_process', 'GO:0070988', ('75', '88'))	('microRNAs', 'Var', (58, 67))	('ALK', 'Gene', '238', (11, 14))
166294	29755689	Specific ALK inhibitors were shown to inhibit the growth of NB and RMS cells overexpressing wildtype or mutated ALK in vitro and in xenograft models, and crizotinib is currently being tested for the treatment of NB and RMS (NCT00939770, NCT01524926, NCT01121588).	('ALK', 'Gene', (9, 12))	('growth', 'MPA', (50, 56))	('mutated', 'Var', (104, 111))	('ALK', 'Gene', (112, 115))	('NB', 'Phenotype', 'HP:0003006', (60, 62))	('ALK', 'Gene', '238', (112, 115))	('inhibitors', 'Var', (13, 23))	('crizotinib', 'Chemical', 'MESH:D000077547', (154, 164))	('NB', 'Phenotype', 'HP:0003006', (212, 214))	('ALK', 'Gene', '238', (9, 12))	('RMS', 'Phenotype', 'HP:0002859', (219, 222))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('NCT00939770', 'Var', (224, 235))	('inhibit', 'NegReg', (38, 45))
166297	29755689	In general, failure to achieve tumor growth inhibition by crizotinib could be due to mutations in the ALK kinase domain that effect inhibitor binding or increase ALK catalytic activity or ALK gene amplification both observed in therapy-resistant lung cancer.	('effect', 'Reg', (125, 131))	('ALK', 'Gene', (188, 191))	('ALK', 'Gene', (102, 105))	('inhibitor', 'MPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('failure', 'Disease', 'MESH:D017093', (12, 19))	('ALK', 'Gene', '238', (162, 165))	('lung cancer', 'Disease', 'MESH:D008175', (246, 257))	('crizotinib', 'Chemical', 'MESH:D000077547', (58, 68))	('lung cancer', 'Disease', (246, 257))	('ALK', 'Gene', (162, 165))	('catalytic activity', 'MPA', (166, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))	('mutations', 'Var', (85, 94))	('failure', 'Disease', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Disease', (31, 36))	('increase', 'PosReg', (153, 161))	('catalytic activity', 'molecular_function', 'GO:0003824', ('166', '184'))	('binding', 'Interaction', (142, 149))	('ALK', 'Gene', '238', (102, 105))	('ALK', 'Gene', '238', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
166302	29755689	In exactly the same way, rapamycin sensitized crizotinib-resistant EML4-ALK+ lung cancer cells to ALK inhibition: Crizotinib alone did not affect ALK and AKT activity, but blocked the feedback activation from mTOR to AKT, when administered together with rapamycin.	('crizotinib', 'Chemical', 'MESH:D000077547', (46, 56))	('Crizotinib', 'Chemical', 'MESH:D000077547', (114, 124))	('blocked', 'NegReg', (172, 179))	('mTOR', 'Gene', (209, 213))	('AKT', 'Gene', '207', (217, 220))	('lung cancer', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('feedback activation', 'MPA', (184, 203))	('ALK', 'Gene', '238', (146, 149))	('rapamycin', 'Gene', (254, 263))	('rapamycin', 'Gene', (25, 34))	('AKT', 'Gene', (154, 157))	('mTOR', 'Gene', '2475', (209, 213))	('ALK', 'Gene', '238', (98, 101))	('Crizotinib', 'Var', (114, 124))	('ALK', 'Gene', (146, 149))	('EML4', 'Gene', (67, 71))	('EML4', 'Gene', '27436', (67, 71))	('ALK', 'Gene', (98, 101))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('rapamycin', 'Gene', '74370', (254, 263))	('rapamycin', 'Gene', '74370', (25, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('AKT', 'Gene', (217, 220))	('AKT', 'Gene', '207', (154, 157))	('ALK', 'Gene', '238', (72, 75))	('ALK', 'Gene', (72, 75))
166304	29755689	It has been reported that aberrant mTOR signaling increases the expression of various growth factors including RTK ligands.	('aberrant', 'Var', (26, 34))	('expression', 'MPA', (64, 74))	('mTOR', 'Gene', (35, 39))	('mTOR', 'Gene', '2475', (35, 39))	('increases', 'PosReg', (50, 59))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))
166306	29755689	Hence, it seems highly probable that mTOR inactivation sensitized the tumor to crizotinib by suppressing mTOR triggered bypass signaling.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('tumor', 'Disease', (70, 75))	('inactivation', 'Var', (42, 54))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('crizotinib', 'Chemical', 'MESH:D000077547', (79, 89))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))	('suppressing', 'NegReg', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
166325	29755689	Instead, rapamycin and rapamycin/crizotinib co-treatment induced caspase-independent, necrotic cell death, indicated by (1) PARP-1 cleavage into 40-70-kD fragments, which appears specifically when PARP-1 is digested with calpain in the context of necrosis, and (2) histomorphological features characteristic of necrosis: loss of cell membrane integrity, chromatin condensation and vacuolization of the cytoplasm.	('chromatin', 'cellular_component', 'GO:0000785', ('354', '363'))	('necrosis', 'Disease', 'MESH:D009336', (311, 319))	('PARP-1', 'Gene', '142', (124, 130))	('cytoplasm', 'cellular_component', 'GO:0005737', ('402', '411'))	('necrosis', 'biological_process', 'GO:0008220', ('311', '319'))	('rapamycin', 'Gene', (9, 18))	('necrosis', 'Disease', (311, 319))	('vacuolization of the', 'CPA', (381, 401))	('cell membrane', 'cellular_component', 'GO:0005886', ('329', '342'))	('necrosis', 'biological_process', 'GO:0008219', ('247', '255'))	('necrosis', 'biological_process', 'GO:0070265', ('311', '319'))	('necrotic cell death', 'Disease', (86, 105))	('cell membrane integrity', 'CPA', (329, 352))	('PARP-1', 'Gene', (197, 203))	('co-treatment', 'Var', (44, 56))	('loss', 'NegReg', (321, 325))	('necrosis', 'biological_process', 'GO:0019835', ('311', '319'))	('necrosis', 'biological_process', 'GO:0001906', ('311', '319'))	('rapamycin', 'Gene', (23, 32))	('rapamycin', 'Gene', '74370', (9, 18))	('crizotinib', 'Chemical', 'MESH:D000077547', (33, 43))	('necrotic cell death', 'biological_process', 'GO:0070265', ('86', '105'))	('PARP-1', 'Gene', (124, 130))	('necrotic cell death', 'Disease', 'MESH:D003643', (86, 105))	('necrosis', 'biological_process', 'GO:0008220', ('247', '255'))	('chromatin condensation', 'CPA', (354, 376))	('necrosis', 'Disease', 'MESH:D009336', (247, 255))	('rapamycin', 'Gene', '74370', (23, 32))	('necrosis', 'biological_process', 'GO:0070265', ('247', '255'))	('necrosis', 'biological_process', 'GO:0019835', ('247', '255'))	('necrosis', 'biological_process', 'GO:0008219', ('311', '319'))	('PARP-1', 'Gene', '142', (197, 203))	('necrosis', 'biological_process', 'GO:0001906', ('247', '255'))	('necrosis', 'Disease', (247, 255))
166330	29755689	Consistent with the observations made by others that specific PI3K/mTOR inhibitors induce autophagy in MPM cells, we also observed autophagy induction when mTOR/ALK-positive MPM tumors were treated with rapamycin.	('induce', 'Reg', (83, 89))	('mTOR', 'Gene', '2475', (156, 160))	('mTOR', 'Gene', (67, 71))	('rapamycin', 'Gene', '74370', (203, 212))	('autophagy', 'biological_process', 'GO:0016236', ('131', '140'))	('inhibitors', 'Var', (72, 82))	('autophagy', 'biological_process', 'GO:0006914', ('90', '99'))	('mTOR', 'Gene', '2475', (67, 71))	('ALK', 'Gene', '238', (161, 164))	('autophagy', 'biological_process', 'GO:0006914', ('131', '140'))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('ALK', 'Gene', (161, 164))	('autophagy', 'CPA', (131, 140))	('MPM tumors', 'Disease', 'MESH:D009369', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('MPM tumors', 'Disease', (174, 184))	('autophagy', 'CPA', (90, 99))	('rapamycin', 'Gene', (203, 212))	('mTOR', 'Gene', (156, 160))	('autophagy', 'biological_process', 'GO:0016236', ('90', '99'))
166340	29755689	Antibodies to detect MET (D1C2), mTOR (7C10), LC3B, PARP, Caspase 3, Cyclin D1, phospho-ALK (Tyr1604), phospho-MET (Tyr1234/1235), AKT, phospho-AKT (Ser473), phospho-MAPK (Tyr202/204), 4EBP1, phospho-4EBP1 (Thr37/46), S6K, phospho-S6K (Ser371), RPS6, phospho-RPS6 (Ser235/236), STAT3, phospho-STAT3 (Tyr705) were from Cell Signaling (Danvers, MA, USA).	('AKT', 'Gene', '207', (131, 134))	('4EBP1', 'Gene', '1978', (200, 205))	('AKT', 'Gene', (144, 147))	('STAT3', 'Gene', (278, 283))	('RPS6', 'Gene', '6194', (259, 263))	('Ser235/236', 'Var', (265, 275))	('S6K', 'Gene', (231, 234))	('4EBP1', 'Gene', '1978', (185, 190))	('Ser', 'cellular_component', 'GO:0005790', ('236', '239'))	('Caspase 3', 'Gene', '836', (58, 67))	('RPS6', 'Gene', (245, 249))	('STAT3', 'Gene', '6774', (278, 283))	('Signaling', 'biological_process', 'GO:0023052', ('323', '332'))	('PARP', 'Gene', '142', (52, 56))	('STAT3', 'Gene', (293, 298))	('mTOR', 'Gene', (33, 37))	('Ser', 'cellular_component', 'GO:0005790', ('149', '152'))	('PARP', 'Gene', (52, 56))	('RPS6', 'Gene', (259, 263))	('Tyr1604', 'Chemical', '-', (93, 100))	('Cyclin D1', 'Gene', '595', (69, 78))	('AKT', 'Gene', '207', (144, 147))	('4EBP1', 'Gene', (185, 190))	('Cyclin D1', 'Gene', (69, 78))	('S6K', 'Gene', '6198', (218, 221))	('STAT3', 'Gene', '6774', (293, 298))	('mTOR', 'Gene', '2475', (33, 37))	('4EBP1', 'Gene', (200, 205))	('AKT', 'Gene', (131, 134))	('Ser', 'cellular_component', 'GO:0005790', ('265', '268'))	('Caspase 3', 'Gene', (58, 67))	('Cyclin', 'molecular_function', 'GO:0016538', ('69', '75'))	('ALK', 'Gene', '238', (88, 91))	('LC3B', 'Gene', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('S6K', 'Gene', '6198', (231, 234))	('ALK', 'Gene', (88, 91))	('Tyr705', 'Var', (300, 306))	('LC3B', 'Gene', '81631', (46, 50))	('RPS6', 'Gene', '6194', (245, 249))	('S6K', 'Gene', (218, 221))
166378	27736841	Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53 Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions.	('mesothelioma', 'Disease', (77, 89))	('FAK', 'Gene', (16, 19))	('p53', 'Gene', (124, 127))	('patient', 'Species', '9606', (150, 157))	('FAK', 'Gene', '5747', (16, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('Improved', 'PosReg', (128, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('anti-proliferative effects', 'MPA', (47, 73))	('MDM2', 'Gene', '4193', (24, 28))	('MDM2', 'Gene', (24, 28))	('reactivation', 'Var', (108, 120))	('FAK', 'molecular_function', 'GO:0004717', ('16', '19'))	('mesothelioma', 'Disease', (137, 149))
166387	27736841	However, FAK regulation of mesothelioma proliferation was not restricted to p53-dependent pathways, as demonstrated by immunoblots after FAK knockdown in JMN1B mesothelioma cells, which have mutant/inactivated p53, compared with four mesothelioma cell lines with nonmutant p53.	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('mesothelioma', 'Disease', (27, 39))	('mesothelioma proliferation', 'Disease', (27, 53))	('FAK', 'molecular_function', 'GO:0004717', ('9', '12'))	('mesothelioma', 'Disease', (234, 246))	('mesothelioma proliferation', 'Disease', 'MESH:D008654', (27, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('FAK', 'molecular_function', 'GO:0004717', ('137', '140'))	('mesothelioma', 'Disease', (160, 172))	('mesothelioma', 'Disease', 'MESH:D008654', (234, 246))	('mutant/inactivated', 'Var', (191, 209))	('p53', 'Gene', (210, 213))	('mutant/inactivated', 'NegReg', (191, 209))
166388	27736841	Our results also indicate that NF2 regulates the interaction of FAK-p53 and MDM2-p53.	('NF2', 'Gene', (31, 34))	('FAK', 'molecular_function', 'GO:0004717', ('64', '67'))	('interaction', 'Interaction', (49, 60))	('MDM2-p53', 'Gene', (76, 84))	('NF2', 'Gene', '4771', (31, 34))	('FAK-p53', 'Var', (64, 71))	('regulates', 'Reg', (35, 44))
166393	27736841	A better understanding of mesothelioma biology - including the function of highly recurrent mutations such as NF2 and BAP1, and key growth factor signalling pathways - will likely be useful in identifying biologically rational targets for novel therapies.	('mesothelioma', 'Disease', (26, 38))	('NF2', 'Gene', (110, 113))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('signalling', 'biological_process', 'GO:0023052', ('146', '156'))	('mutations', 'Var', (92, 101))	('BAP1', 'Gene', '8314', (118, 122))	('NF2', 'Gene', '4771', (110, 113))	('BAP1', 'Gene', (118, 122))
166397	27736841	The effects of FAK on tumour growth in mice suggest that FAK may influence the formation, growth, and metastasis of tumours.	('FAK', 'Var', (57, 60))	('tumour growth', 'Disease', 'MESH:D006130', (22, 35))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('metastasis of tumours', 'Disease', (102, 123))	('growth', 'CPA', (90, 96))	('FAK', 'molecular_function', 'GO:0004717', ('15', '18'))	('formation', 'CPA', (79, 88))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('metastasis of tumours', 'Disease', 'MESH:D009362', (102, 123))	('influence', 'Reg', (65, 74))	('FAK', 'molecular_function', 'GO:0004717', ('57', '60'))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumour growth', 'Disease', (22, 35))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('mice', 'Species', '10090', (39, 43))
166400	27736841	Recently, studies of direct interaction of the N-terminal domain of FAK with the N-terminal transactivation domain of p53, particularly at the 7-amino-acid site in the proline-rich region of the p53 N-terminal domain, indicated that FAK can suppress p53-mediated apoptosis and inhibit the transcriptional activity of p53.	('FAK', 'molecular_function', 'GO:0004717', ('233', '236'))	('suppress', 'NegReg', (241, 249))	('FAK', 'molecular_function', 'GO:0004717', ('68', '71'))	('transactivation', 'biological_process', 'GO:2000144', ('92', '107'))	('FAK', 'Var', (233, 236))	('proline', 'Chemical', 'MESH:D011392', (168, 175))	('inhibit', 'NegReg', (277, 284))	('transcriptional activity', 'MPA', (289, 313))	('apoptosis', 'biological_process', 'GO:0097194', ('263', '272'))	('apoptosis', 'biological_process', 'GO:0006915', ('263', '272'))	('p53-mediated apoptosis', 'CPA', (250, 272))	('7-amino-acid', 'Chemical', '-', (143, 155))	('p53', 'Protein', (317, 320))
166407	27736841	TP53 mutations are seen infrequently in mesothelioma.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('mutations', 'Var', (5, 14))	('mesothelioma', 'Disease', (40, 52))
166409	27736841	Suppressor of cytokine signalling 3 (SOCS3) overexpression showed anti-proliferative effects in mesotheliomas via multiple signalling pathways including JAK/STAT3 and FAK/p53.	('signalling', 'biological_process', 'GO:0023052', ('123', '133'))	('SOCS3', 'Gene', (37, 42))	('anti-proliferative', 'NegReg', (66, 84))	('FAK', 'molecular_function', 'GO:0004717', ('167', '170'))	('mesotheliomas', 'Disease', 'MESH:D008654', (96, 109))	('Suppressor of cytokine signalling 3', 'Gene', '9021', (0, 35))	('mesotheliomas', 'Disease', (96, 109))	('Suppressor of cytokine signalling 3', 'Gene', (0, 35))	('STAT3', 'Gene', '6774', (157, 162))	('JAK', 'molecular_function', 'GO:0004713', ('153', '156'))	('signalling', 'biological_process', 'GO:0023052', ('23', '33'))	('STAT3', 'Gene', (157, 162))	('SOCS3', 'Gene', '9021', (37, 42))	('overexpression', 'Var', (44, 58))
166419	27736841	Polyclonal antibodies to phospho-p53 (Ser15) and phospho-NF2 (Ser518) were from Cell Signaling Technology (Beverly, MA, USA).	('Ser', 'cellular_component', 'GO:0005790', ('62', '65'))	('Ser518', 'Chemical', '-', (62, 68))	('Ser15', 'Chemical', '-', (38, 43))	('NF2', 'Gene', '4771', (57, 60))	('Ser', 'cellular_component', 'GO:0005790', ('38', '41'))	('Signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('NF2', 'Gene', (57, 60))	('Ser518', 'Var', (62, 68))
166448	27736841	Well-validated shRNAs were used for FAK and NF2 knockdowns.	('NF2', 'Gene', '4771', (44, 47))	('FAK', 'molecular_function', 'GO:0004717', ('36', '39'))	('NF2', 'Gene', (44, 47))	('knockdowns', 'Var', (48, 58))
166452	27736841	MESO924, MESO257, MESO296, MESO428, JMN1B, and stably infected MESO257 with NF2 shRNA knockdown were plated at 3000 cells per well in a 96-well flat-bottomed plate (Falcon, Lincoln, NJ, USA) and cultured in RPMI 1640 for 24 h before transduction with lentiviral empty vector or FAK shRNA, or treatment with MDM2 inhibitor nutlin-3 and FAK inhibitor PF562271, or 48 h before treatment with nutlin-3 after FAK shRNA transduction.	('MESO296', 'Chemical', '-', (18, 25))	('transduction', 'biological_process', 'GO:0009293', ('414', '426'))	('transduction', 'biological_process', 'GO:0009293', ('233', '245'))	('MESO257', 'Chemical', '-', (9, 16))	('nutlin-3', 'Chemical', 'MESH:C482205', (389, 397))	('NF2', 'Gene', (76, 79))	('MESO428', 'Chemical', '-', (27, 34))	('FAK', 'molecular_function', 'GO:0004717', ('278', '281'))	('FAK', 'molecular_function', 'GO:0004717', ('404', '407'))	('NF2', 'Gene', '4771', (76, 79))	('PF562271', 'Chemical', '-', (349, 357))	('FAK', 'molecular_function', 'GO:0004717', ('335', '338'))	('nutlin-3', 'Chemical', 'MESH:C482205', (322, 330))	('MESO924', 'Chemical', '-', (0, 7))	('MESO257', 'Chemical', '-', (63, 70))	('MDM2', 'Gene', (307, 311))	('PF562271', 'Var', (349, 357))
166457	27736841	The NF2 mutation was validated by sequencing.	('NF2', 'Gene', '4771', (4, 7))	('NF2', 'Gene', (4, 7))	('mutation', 'Var', (8, 16))
166460	27736841	Mass spectrometry analysis of the ~130 kDa band cut from a Coomassie-stained gel identified the FAK non-receptor tyrosine kinase.	('FAK', 'Var', (96, 99))	('receptor tyrosine kinase', 'Gene', (104, 128))	('receptor tyrosine kinase', 'Gene', '5979', (104, 128))	('FAK', 'molecular_function', 'GO:0004717', ('96', '99'))	('Coomassie', 'Chemical', '-', (59, 68))
166462	27736841	FAK and p53 were expressed in most mesotheliomas, with especially strong expression of p53 in JMN1B and one frozen tumour, both of which have been found to contain TP53 missense mutations (JMN1B: G245S; MESO96-975: A159V) (Figure 2).	('TP53', 'Gene', '7157', (164, 168))	('G245S', 'Var', (196, 201))	('TP53', 'Gene', (164, 168))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('p53', 'Gene', (87, 90))	('mesotheliomas', 'Disease', 'MESH:D008654', (35, 48))	('mesotheliomas', 'Disease', (35, 48))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('A159V', 'Mutation', 'p.A159V', (215, 220))	('G245S', 'Mutation', 'rs28934575', (196, 201))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('missense mutations', 'Var', (169, 187))	('tumour', 'Disease', (115, 121))
166463	27736841	Focal adhesion kinase (phospho-FAK Y397) was constitutively activated in all mesotheliomas.	('phospho-FAK', 'Var', (23, 34))	('activated', 'PosReg', (60, 69))	('Focal adhesion', 'cellular_component', 'GO:0005925', ('0', '14'))	('Focal adhesion kinase', 'Gene', (0, 21))	('mesotheliomas', 'Disease', 'MESH:D008654', (77, 90))	('FAK', 'molecular_function', 'GO:0004717', ('31', '34'))	('Focal adhesion kinase', 'Gene', '5747', (0, 21))	('mesotheliomas', 'Disease', (77, 90))
166466	27736841	The p53 immunoprecipitations revealed a dominant FAK 130 kDa band in five mesothelioma cell lines, which was confirmed by FAK immunostaining in FAK immunoprecipitations (Figure 3).	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('FAK', 'molecular_function', 'GO:0004717', ('49', '52'))	('FAK', 'Var', (49, 52))	('FAK', 'molecular_function', 'GO:0004717', ('144', '147'))	('FAK', 'molecular_function', 'GO:0004717', ('122', '125'))	('mesothelioma', 'Disease', (74, 86))
166467	27736841	The FAK shRNA-mediated knockdown resulted in ~60-70% inhibition of FAK protein expression in MESO257 at 48 h and 96 h post infection (Figure 4A).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('inhibition', 'NegReg', (53, 63))	('knockdown', 'Var', (23, 32))	('FAK', 'molecular_function', 'GO:0004717', ('67', '70'))	('protein', 'Protein', (71, 78))	('FAK', 'molecular_function', 'GO:0004717', ('4', '7'))	('h post infection', 'Disease', 'MESH:D017169', (116, 132))	('h post infection', 'Disease', (116, 132))	('FAK', 'Gene', (67, 70))	('MESO257', 'Chemical', '-', (93, 100))
166468	27736841	Treatment with FAK inhibitor PF562271 decreased expression of phospho-FAK, phospho-MDM2, and MDM2 in MESO257 and MESO296 in a dose-dependent manner (Figure 4B and Supplementary Figure 1).	('decreased', 'NegReg', (38, 47))	('MESO257', 'Chemical', '-', (101, 108))	('FAK', 'molecular_function', 'GO:0004717', ('15', '18'))	('expression', 'MPA', (48, 58))	('MESO296', 'Chemical', '-', (113, 120))	('PF562271', 'Chemical', '-', (29, 37))	('PF562271', 'Var', (29, 37))	('MDM2', 'Gene', (93, 97))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))
166471	27736841	The expression of MDM2, p53, and phospho-p53 increased in a dose-dependent manner after treatment with nutlin-3 in cells with wild type p53 (MESO924, MESO257, MESO296, and MESO428).	('p53', 'Gene', (24, 27))	('MESO296', 'Chemical', '-', (159, 166))	('MESO924', 'Chemical', '-', (141, 148))	('increased', 'PosReg', (45, 54))	('MESO257', 'Chemical', '-', (150, 157))	('nutlin-3', 'Chemical', 'MESH:C482205', (103, 111))	('expression', 'MPA', (4, 14))	('MESO428', 'Chemical', '-', (172, 179))	('phospho-p53', 'Var', (33, 44))	('MESO428', 'Var', (172, 179))	('MESO257', 'Var', (150, 157))	('MESO924', 'Var', (141, 148))	('MDM2', 'Gene', (18, 22))	('MESO296', 'Var', (159, 166))
166475	27736841	However, FAK shRNA knockdown inhibited cyclin A proliferation marker expression in JMN1B cells (Figure 5A).	('cyclin A', 'Gene', (39, 47))	('inhibited', 'NegReg', (29, 38))	('cyclin A', 'Gene', '890', (39, 47))	('knockdown', 'Var', (19, 28))	('FAK', 'molecular_function', 'GO:0004717', ('9', '12'))	('cyclin', 'molecular_function', 'GO:0016538', ('39', '45'))
166476	27736841	FAK knockdown in wild-type p53 mesothelioma cell lines MESO924, MESO257, MESO296, and MESO428 resulted in ~15-35% inhibition of cell viability at 3 days after FAK silencing, compared with an empty vector control (Figure 5B).	('inhibition', 'NegReg', (114, 124))	('silencing', 'NegReg', (163, 172))	('MESO296', 'Chemical', '-', (73, 80))	('MESO924', 'Chemical', '-', (55, 62))	('MESO257', 'Chemical', '-', (64, 71))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('mesothelioma', 'Disease', (31, 43))	('MESO428', 'Chemical', '-', (86, 93))	('cell viability', 'CPA', (128, 142))	('FAK', 'Gene', (0, 3))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('FAK', 'Gene', (159, 162))	('knockdown', 'Var', (4, 13))	('FAK', 'molecular_function', 'GO:0004717', ('159', '162'))
166478	27736841	However, viability was little affected in p53 mutant JMN1B cells after treatment with nutlin-3 (Figure 5B).	('p53', 'Gene', (42, 45))	('mutant', 'Var', (46, 52))	('nutlin-3', 'Chemical', 'MESH:C482205', (86, 94))
166480	27736841	Treatment with PF562271 showed profound anti-proliferative effects at day 6 in all the five mesothelioma cell lines (Figure 5C).	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('PF562271', 'Chemical', '-', (15, 23))	('anti-proliferative', 'NegReg', (40, 58))	('PF562271', 'Var', (15, 23))	('mesothelioma', 'Disease', (92, 104))
166482	27736841	The FAK knockdown in all the five mesothelioma cell lines resulted in G1 arrest.	('knockdown', 'Var', (8, 17))	('mesothelioma', 'Disease', (34, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('resulted in', 'Reg', (58, 69))	('FAK', 'Gene', (4, 7))	('FAK', 'molecular_function', 'GO:0004717', ('4', '7'))	('G1 arrest', 'CPA', (70, 79))
166485	27736841	The observations of mild upregulation of p53 by FAK shRNA knockdown in MESO257 (Figure 5A) with strong NF2 expression (Figure 2), as compared with strong induction of p53 expression after FAK knockdown in NF2-null mesothelioma cell lines (Figure 5A), suggests that the FAK-p53 interaction is regulated by NF2.	('FAK', 'molecular_function', 'GO:0004717', ('48', '51'))	('FAK', 'molecular_function', 'GO:0004717', ('188', '191'))	('MESO257', 'Chemical', '-', (71, 78))	('FAK', 'molecular_function', 'GO:0004717', ('269', '272'))	('NF2', 'Gene', (103, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (214, 226))	('p53', 'Gene', (41, 44))	('interaction', 'Interaction', (277, 288))	('NF2', 'Gene', (205, 208))	('NF2', 'Gene', (305, 308))	('NF2', 'Gene', '4771', (103, 106))	('NF2', 'Gene', '4771', (305, 308))	('knockdown', 'Var', (58, 67))	('mesothelioma', 'Disease', (214, 226))	('upregulation', 'PosReg', (25, 37))	('NF2', 'Gene', '4771', (205, 208))
166486	27736841	The NF2 overexpression (wild-type and constitutive activated mutation NF2 S518A) inhibits FAK phosphorylation in NF2-null mesothelioma cell line (MESO924), but not loss-of-function mutant NF2 S518D (Supplementary Figure 2), which is in keeping with previous evidence for regulation of FAK activity by NF2.	('inhibits', 'NegReg', (81, 89))	('NF2', 'Gene', '4771', (301, 304))	('MESO924', 'Chemical', '-', (146, 153))	('regulation', 'biological_process', 'GO:0065007', ('271', '281'))	('mutation', 'Var', (61, 69))	('NF2', 'Gene', (301, 304))	('mesothelioma', 'Disease', (122, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('NF2', 'Gene', '4771', (188, 191))	('FAK', 'molecular_function', 'GO:0004717', ('285', '288'))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('S518A', 'Var', (74, 79))	('NF2', 'Gene', (188, 191))	('NF2', 'Gene', '4771', (70, 73))	('S518A', 'Mutation', 'rs867074714', (74, 79))	('S518D', 'Mutation', 'p.S518D', (192, 197))	('NF2', 'Gene', (70, 73))	('NF2', 'Gene', '4771', (4, 7))	('FAK', 'molecular_function', 'GO:0004717', ('90', '93'))	('NF2', 'Gene', (4, 7))	('overexpression', 'PosReg', (8, 22))	('NF2', 'Gene', '4771', (113, 116))	('FAK phosphorylation', 'MPA', (90, 109))	('NF2', 'Gene', (113, 116))
166491	27736841	The NF2, p53, and MDM2 are predominantly nuclear and partial FAK nuclear localisation was also confirmed by immunoblot (Figure 6B).	('FAK', 'molecular_function', 'GO:0004717', ('61', '64'))	('MDM2', 'Var', (18, 22))	('NF2', 'Gene', '4771', (4, 7))	('localisation', 'biological_process', 'GO:0051179', ('73', '85'))	('NF2', 'Gene', (4, 7))
166494	27736841	The NF2 and FAK shRNA knockdowns resulted in greater than 50% and 60% inhibition of expression of their targets.	('inhibition', 'NegReg', (70, 80))	('knockdowns', 'Var', (22, 32))	('NF2', 'Gene', '4771', (4, 7))	('FAK', 'molecular_function', 'GO:0004717', ('12', '15'))	('expression', 'MPA', (84, 94))	('NF2', 'Gene', (4, 7))
166495	27736841	The NF2 shRNA knockdown induced p53, p21, and MDM2 expression, and FAK silencing resulted in upregulation of p53, p21, and p27.	('upregulation', 'PosReg', (93, 105))	('p27', 'Gene', '3429', (123, 126))	('p27', 'Gene', (123, 126))	('induced', 'PosReg', (24, 31))	('p21', 'Gene', (114, 117))	('p53', 'Protein', (32, 35))	('FAK', 'molecular_function', 'GO:0004717', ('67', '70'))	('p53', 'Protein', (109, 112))	('p21', 'Gene', '644914', (114, 117))	('NF2', 'Gene', '4771', (4, 7))	('expression', 'MPA', (51, 61))	('knockdown', 'Var', (14, 23))	('p21', 'Gene', (37, 40))	('p21', 'Gene', '644914', (37, 40))	('MDM2', 'Gene', (46, 50))	('NF2', 'Gene', (4, 7))
166496	27736841	The combination of FAK and NF2 shRNA knockdowns increased p53, MDM2, p21, and p27 expression two- to three-fold, which was greater than the level after either intervention alone (Figure 6C).	('p27', 'Gene', '3429', (78, 81))	('p27', 'Gene', (78, 81))	('NF2', 'Gene', (27, 30))	('knockdowns', 'Var', (37, 47))	('increased', 'PosReg', (48, 57))	('expression', 'MPA', (82, 92))	('p21', 'Gene', (69, 72))	('FAK', 'Gene', (19, 22))	('NF2', 'Gene', '4771', (27, 30))	('p21', 'Gene', '644914', (69, 72))	('p53', 'Gene', (58, 61))	('MDM2', 'Gene', (63, 67))	('FAK', 'molecular_function', 'GO:0004717', ('19', '22'))
166497	27736841	Furthermore, we investigated p53 and p21 expression in nuclear, cytoplasmic, and membrane fractions after NF2 knockdown (Figure 6D).	('knockdown', 'Var', (110, 119))	('p21', 'Gene', '644914', (37, 40))	('p53', 'Gene', (29, 32))	('NF2', 'Gene', '4771', (106, 109))	('investigated', 'Reg', (16, 28))	('p21', 'Gene', (37, 40))	('membrane', 'cellular_component', 'GO:0016020', ('81', '89'))	('NF2', 'Gene', (106, 109))
166498	27736841	The NF2 shRNA knockdown induced p53 in each of these subcellular fractions, at levels comparable to those in the total cell lysate.	('knockdown', 'Var', (14, 23))	('NF2', 'Gene', '4771', (4, 7))	('p53', 'MPA', (32, 35))	('induced', 'Reg', (24, 31))	('NF2', 'Gene', (4, 7))
166500	27736841	In addition, NF2-positive MESO257 cells demonstrated increased sensitivity to FAK shRNA after NF2 knockdown (Figure 6E).	('MESO257', 'Chemical', '-', (26, 33))	('NF2', 'Gene', '4771', (13, 16))	('NF2', 'Gene', (94, 97))	('knockdown', 'Var', (98, 107))	('FAK', 'molecular_function', 'GO:0004717', ('78', '81'))	('increased', 'PosReg', (53, 62))	('NF2', 'Gene', '4771', (94, 97))	('NF2', 'Gene', (13, 16))	('sensitivity to FAK shRNA', 'MPA', (63, 87))
166506	27736841	Inactivating TP53 mutations are found in approximately 50% of human tumours.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (13, 17))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('human', 'Species', '9606', (62, 67))	('Inactivating', 'Var', (0, 12))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
166507	27736841	However, TP53 mutations are seen less frequently in mesothelioma.	('mesothelioma', 'Disease', (52, 64))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('mutations', 'Var', (14, 23))
166508	27736841	Previous studies have suggested that p53 activity is potentially lost in mesothelioma because of p14ARF inactivation and the effects of the SV40 large T antigen.	('inactivation', 'NegReg', (104, 116))	('p14ARF', 'Gene', '1029', (97, 103))	('mesothelioma', 'Disease', (73, 85))	('SV40 large T', 'Var', (140, 152))	('p53', 'Protein', (37, 40))	('lost', 'NegReg', (65, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('activity', 'MPA', (41, 49))	('p14ARF', 'Gene', (97, 103))
166512	27736841	The interaction of tyrosine kinases and the p53 family was first reported by investigating the association of c-Abl and p73alpha in apoptosis.	('association', 'Interaction', (95, 106))	('apoptosis', 'CPA', (132, 141))	('interaction', 'Interaction', (4, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('c-Abl', 'Gene', (110, 115))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('p73alpha', 'Var', (120, 128))	('c-Abl', 'Gene', '25', (110, 115))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))
166515	27736841	In previous studies, we developed and validated a functional proteomic approach including double phosphotyrosine and panRTK immuno-affinity purification, coupled to tandem mass spectrometry in various tumour tissues or cell lines.	('tumour', 'Disease', (201, 207))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (97, 112))	('RTK', 'Gene', '5979', (120, 123))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('double phosphotyrosine', 'Var', (90, 112))	('RTK', 'Gene', (120, 123))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
166518	27736841	In addition, normal p53 expression in most mesothelioma samples confirmed that TP53 mutations are infrequent in these cancers (Figure 2).	('mesothelioma', 'Disease', (43, 55))	('cancers', 'Disease', (118, 125))	('TP53', 'Gene', '7157', (79, 83))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('TP53', 'Gene', (79, 83))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (84, 93))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
166522	27736841	Further studies showed that FAK inhibition at high concentration of PF562271 (5 muM) induced p53 expression because of inhibition of MDM2 and phospho-MDM2 expression (Figure 4B).	('FAK', 'molecular_function', 'GO:0004717', ('28', '31'))	('MDM2', 'Protein', (133, 137))	('p53', 'Gene', (93, 96))	('inhibition', 'NegReg', (119, 129))	('muM', 'Gene', '56925', (80, 83))	('phospho-MDM2', 'MPA', (142, 154))	('PF562271', 'Chemical', '-', (68, 76))	('induced', 'PosReg', (85, 92))	('muM', 'Gene', (80, 83))	('expression', 'MPA', (97, 107))	('PF562271', 'Var', (68, 76))
166524	27736841	In the current study, we show increased expression and phosphorylation of p53, and decreased viability in a dose-dependent manner after treatment with nutlin-3 in wild-type p53 cell lines (Figure 5A and B), indicating that inhibition of MDM2-p53 interaction has an important biological function in mesothelioma.	('expression', 'MPA', (40, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('mesothelioma', 'Disease', 'MESH:D008654', (298, 310))	('decreased', 'NegReg', (83, 92))	('inhibition', 'Var', (223, 233))	('p53', 'Gene', (74, 77))	('phosphorylation', 'MPA', (55, 70))	('interaction', 'Interaction', (246, 257))	('increased', 'PosReg', (30, 39))	('viability', 'MPA', (93, 102))	('nutlin-3', 'Chemical', 'MESH:C482205', (151, 159))	('mesothelioma', 'Disease', (298, 310))
166529	27736841	In the present study, in NF2-null MESO924, overexpression of mutant NF2 S518A, which mimics constitutively phosphorylated NF2 and functions equivalently to wild-type NF2, partially inhibited FAK activity, while overexpression of mutant, nonfunctional NF2 S518D, did not inhibit FAK activity (Supplementary Figure 2).	('NF2', 'Gene', (122, 125))	('NF2', 'Gene', (25, 28))	('NF2', 'Gene', '4771', (166, 169))	('MESO924', 'Chemical', '-', (34, 41))	('NF2', 'Gene', (166, 169))	('NF2', 'Gene', '4771', (251, 254))	('FAK', 'molecular_function', 'GO:0004717', ('191', '194'))	('FAK activity', 'MPA', (191, 203))	('NF2', 'Gene', (251, 254))	('NF2', 'Gene', '4771', (68, 71))	('S518D', 'Mutation', 'p.S518D', (255, 260))	('FAK', 'molecular_function', 'GO:0004717', ('278', '281'))	('mutant', 'Var', (61, 67))	('NF2', 'Gene', (68, 71))	('S518A', 'Var', (72, 77))	('inhibited', 'NegReg', (181, 190))	('NF2', 'Gene', '4771', (122, 125))	('NF2', 'Gene', '4771', (25, 28))	('S518A', 'Mutation', 'rs867074714', (72, 77))
166531	27736841	After treatment with nutlin-3, the FAK inhibitor PF562271, or FAK shRNA knockdown, upregulation of p53 and phospho-p53, and reduction of cell viability were least pronounced in NF2-positive MESO257 as compared with NF2-inactivated cell lines (Figure 5A-C), NF2 knockdown resulted in the accumulation of p53-p21 in nucleus and cytoplasm (Figure 6D), and NF2-positive MESO257 cells showed increased sensitivity to FAK shRNA after NF2 knockdown (Figure 6E), indicating that the presence of NF2 regulates MDM2-p53 and FAK-p53 interactions.	('FAK', 'molecular_function', 'GO:0004717', ('62', '65'))	('knockdown', 'Var', (261, 270))	('NF2', 'Gene', (487, 490))	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('FAK', 'molecular_function', 'GO:0004717', ('412', '415'))	('MDM2-p53', 'Protein', (501, 509))	('NF2', 'Gene', (215, 218))	('FAK', 'molecular_function', 'GO:0004717', ('514', '517'))	('nucleus', 'cellular_component', 'GO:0005634', ('314', '321'))	('MESO257', 'Chemical', '-', (190, 197))	('NF2', 'Gene', '4771', (428, 431))	('NF2', 'Gene', (428, 431))	('accumulation', 'PosReg', (287, 299))	('p21', 'Gene', (307, 310))	('PF562271', 'Var', (49, 57))	('NF2', 'Gene', '4771', (353, 356))	('p21', 'Gene', '644914', (307, 310))	('NF2', 'Gene', '4771', (257, 260))	('NF2', 'Gene', '4771', (177, 180))	('PF562271', 'Chemical', '-', (49, 57))	('NF2', 'Gene', (353, 356))	('NF2', 'Gene', (257, 260))	('nutlin-3', 'Chemical', 'MESH:C482205', (21, 29))	('cytoplasm', 'cellular_component', 'GO:0005737', ('326', '335'))	('NF2', 'Gene', '4771', (487, 490))	('MESO257', 'Chemical', '-', (366, 373))	('NF2', 'Gene', (177, 180))	('interactions', 'Interaction', (522, 534))	('regulates', 'Reg', (491, 500))	('NF2', 'Gene', '4771', (215, 218))
166533	27736841	NF2-null mesothelioma cells have been found to have weak cell-cell adhesions, which results in FAK leaving focal contact sites, increasing the cytoplasmic pool of FAK and enhancing FAK nuclear accumulation.	('NF2', 'Gene', (0, 3))	('increasing', 'PosReg', (128, 138))	('FAK', 'molecular_function', 'GO:0004717', ('95', '98'))	('weak', 'NegReg', (52, 56))	('enhancing', 'PosReg', (171, 180))	('cytoplasmic pool of FAK', 'MPA', (143, 166))	('NF2', 'Gene', '4771', (0, 3))	('focal contact', 'cellular_component', 'GO:0005925', ('107', '120'))	('cell-cell adhesions', 'CPA', (57, 76))	('mesothelioma', 'Disease', (9, 21))	('FAK nuclear accumulation', 'CPA', (181, 205))	('FAK', 'molecular_function', 'GO:0004717', ('181', '184'))	('FAK', 'molecular_function', 'GO:0004717', ('163', '166'))	('FAK', 'Var', (95, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (9, 21))
166534	27736841	These observations establish mechanisms by which FAK knockdown or FAK kinase activity inhibition suppress cell growth via minimising p53 degradation by MDM2 (Figure 4A and B, and Figure 5A), and have greater anti-proliferative effects in NF2-null mesothelioma cell lines (MESO296 and MESO428) than NF2-positive MESO257 cell lines (Figure 5B and C).	('minimising', 'NegReg', (122, 132))	('degradation', 'biological_process', 'GO:0009056', ('137', '148'))	('knockdown', 'Var', (53, 62))	('NF2', 'Gene', (238, 241))	('cell growth', 'CPA', (106, 117))	('FAK', 'Gene', (66, 69))	('kinase activity', 'molecular_function', 'GO:0016301', ('70', '85'))	('MESO296', 'Chemical', '-', (272, 279))	('mesothelioma', 'Disease', (247, 259))	('FAK', 'molecular_function', 'GO:0004717', ('49', '52'))	('mesothelioma', 'Disease', 'MESH:D008654', (247, 259))	('p53', 'Protein', (133, 136))	('cell growth', 'biological_process', 'GO:0016049', ('106', '117'))	('anti-proliferative effects', 'CPA', (208, 234))	('NF2', 'Gene', '4771', (298, 301))	('inhibition suppress', 'NegReg', (86, 105))	('MDM2', 'Var', (152, 156))	('MESO428', 'Chemical', '-', (284, 291))	('NF2', 'Gene', (298, 301))	('MESO257', 'Chemical', '-', (311, 318))	('FAK', 'molecular_function', 'GO:0004717', ('66', '69'))	('greater', 'PosReg', (200, 207))	('NF2', 'Gene', '4771', (238, 241))
166536	27736841	The NF2 shRNA knockdown resulted in the upregulation of p53 and MDM2 in MESO257 (Figure 6C), indicating that NF2 regulates the interaction of MDM2 and p53, and that upregulation of p53 expression by MDM2 inhibition (nutlin-3) is NF2-dependent.	('p53', 'Gene', (181, 184))	('NF2', 'Gene', '4771', (109, 112))	('expression', 'MPA', (185, 195))	('inhibition', 'NegReg', (204, 214))	('knockdown', 'Var', (14, 23))	('upregulation', 'PosReg', (40, 52))	('NF2', 'Gene', (229, 232))	('NF2', 'Gene', '4771', (4, 7))	('MESO257', 'Chemical', '-', (72, 79))	('NF2', 'Gene', (109, 112))	('upregulation', 'PosReg', (165, 177))	('NF2', 'Gene', (4, 7))	('NF2', 'Gene', '4771', (229, 232))	('nutlin-3', 'Chemical', 'MESH:C482205', (216, 224))	('interaction', 'Interaction', (127, 138))
166538	27736841	Thus, additive effects were obtained through coordinated reactivation of p53 by FAK knockdown, which attenuated MDM2-dependent p53 degradation, and by NF2 knockdown, which attenuated the inhibitory effect of MDM2 on p53.	('knockdown', 'Var', (155, 164))	('FAK', 'Gene', (80, 83))	('FAK', 'molecular_function', 'GO:0004717', ('80', '83'))	('p53', 'Gene', (73, 76))	('knockdown', 'Var', (84, 93))	('degradation', 'biological_process', 'GO:0009056', ('131', '142'))	('NF2', 'Gene', '4771', (151, 154))	('attenuated', 'NegReg', (101, 111))	('MDM2-dependent p53 degradation', 'MPA', (112, 142))	('NF2', 'Gene', (151, 154))
166539	27736841	Our data indicate that FAK regulates cell survival via p53-dependent and -independent pathways, which was demonstrated by immunoblots after FAK knockdown in mutant p53 JMN1B cell line and in nonmutant p53 mesothelioma cell lines (MESO924, MESO257, MESO296, and MESO428; Figure 5).	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('p53 JMN1B', 'Gene', (164, 173))	('MESO296', 'Chemical', '-', (248, 255))	('mutant', 'Var', (157, 163))	('MESO257', 'Chemical', '-', (239, 246))	('FAK', 'molecular_function', 'GO:0004717', ('140', '143'))	('MESO428', 'Chemical', '-', (261, 268))	('mesothelioma', 'Disease', (205, 217))	('cell survival', 'CPA', (37, 50))	('FAK', 'molecular_function', 'GO:0004717', ('23', '26'))	('JMN1B', 'Gene', (168, 173))	('MESO924', 'Chemical', '-', (230, 237))
166540	27736841	In addition, we found the dramatic anti-proliferative and apoptotic effects of FAK knockdown in mutant leiomyosarcoma cell lines (data not shown).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (103, 117))	('mutant', 'Var', (96, 102))	('apoptotic', 'CPA', (58, 67))	('leiomyosarcoma', 'Disease', (103, 117))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (103, 117))	('anti-proliferative', 'CPA', (35, 53))	('FAK', 'Gene', (79, 82))	('FAK', 'molecular_function', 'GO:0004717', ('79', '82'))	('knockdown', 'Var', (83, 92))
166541	27736841	The FAK (FAK shRNA or PF562271) and MDM2 (nutlin-3) inhibitors showed anti-proliferative effects in mesothelioma cell lines characterised by a decrease of cyclin A expression, CDK inhibitor p21 upregulation (Figure 5A), reduction of cellular viability (Figure 5B and C), and G1-phase arrest (Figure 5D).	('MDM2', 'Gene', (36, 40))	('cyclin', 'molecular_function', 'GO:0016538', ('155', '161'))	('cyclin A', 'Gene', (155, 163))	('FAK', 'Gene', (4, 7))	('G1-phase', 'biological_process', 'GO:0051318', ('275', '283'))	('FAK', 'molecular_function', 'GO:0004717', ('4', '7'))	('nutlin-3', 'Chemical', 'MESH:C482205', (42, 50))	('PF562271', 'Var', (22, 30))	('PF562271', 'Chemical', '-', (22, 30))	('p21', 'Gene', (190, 193))	('p21', 'Gene', '644914', (190, 193))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('176', '189'))	('FAK', 'molecular_function', 'GO:0004717', ('9', '12'))	('inhibitors', 'Var', (52, 62))	('decrease', 'NegReg', (143, 151))	('upregulation', 'PosReg', (194, 206))	('cellular viability', 'CPA', (233, 251))	('expression', 'MPA', (164, 174))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('reduction', 'NegReg', (220, 229))	('cyclin A', 'Gene', '890', (155, 163))	('anti-proliferative effects', 'CPA', (70, 96))	('G1-phase arrest', 'CPA', (275, 290))
166560	26544728	Molecular pathogenesis of MPM is characterized by several gene mutations, including neurofibromatosis 2 (NF2), BRCA1-associated protein-1 (BAP-1) and deletion of the INK4A/ARF locus (70-80%) where the genes p14/ARF and p16/INK4A are located.	('neurofibromatosis 2', 'Gene', '18016', (84, 103))	('BRCA1-associated protein-1', 'Gene', '104416', (111, 137))	('INK4A', 'Gene', '12578', (223, 228))	('p16', 'Gene', (219, 222))	('BAP-1', 'Gene', '104416', (139, 144))	('INK4A', 'Gene', '12578', (166, 171))	('pathogenesis', 'biological_process', 'GO:0009405', ('10', '22'))	('NF2', 'Gene', '18016', (105, 108))	('BAP-1', 'Gene', (139, 144))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (84, 101))	('deletion', 'Var', (150, 158))	('BRCA1-associated protein-1', 'Gene', (111, 137))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('ARF', 'Gene', (172, 175))	('p14', 'Gene', '20202', (207, 210))	('p14', 'Gene', (207, 210))	('INK4A', 'Gene', (223, 228))	('ARF', 'Gene', (211, 214))	('ARF', 'Gene', '1029', (172, 175))	('p16', 'Gene', '12578', (219, 222))	('INK4A', 'Gene', (166, 171))	('MPM', 'Disease', (26, 29))	('NF2', 'Gene', (105, 108))	('ARF', 'Gene', '1029', (211, 214))	('neurofibromatosis 2', 'Gene', (84, 103))
166567	26544728	In pathological conditions, hypoxia has been proposed as an inducer of MDM2 expression; subsequently, MDM2 could bind and stabilize HIF1alpha, responsible for VEGF transcription.	('HIF1alpha', 'Gene', '3091', (132, 141))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('VEGF', 'Gene', (159, 163))	('stabilize', 'NegReg', (122, 131))	('bind', 'Interaction', (113, 117))	('hypoxia', 'Disease', (28, 35))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('VEGF', 'Gene', '7422', (159, 163))	('HIF1alpha', 'Gene', (132, 141))	('MDM2', 'Var', (102, 106))
166568	26544728	Moreover, inhibition of the MDM2-HIF1alpha interaction reduces VEGF mRNA expression (Figure 1).	('VEGF', 'Gene', (63, 67))	('HIF1alpha', 'Gene', '3091', (33, 42))	('VEGF', 'Gene', '7422', (63, 67))	('reduces', 'NegReg', (55, 62))	('inhibition', 'Var', (10, 20))	('HIF1alpha', 'Gene', (33, 42))	('interaction', 'Interaction', (43, 54))
166591	26544728	Finally, a significant correlation between necrosis and Ki67 was noted (correlation coefficient: 0.43; p: 0.0007).	('necrosis', 'Disease', 'MESH:D009336', (43, 51))	('necrosis', 'biological_process', 'GO:0070265', ('43', '51'))	('necrosis', 'biological_process', 'GO:0008219', ('43', '51'))	('Ki67', 'Var', (56, 60))	('necrosis', 'biological_process', 'GO:0019835', ('43', '51'))	('Ki67', 'Chemical', '-', (56, 60))	('necrosis', 'Disease', (43, 51))	('necrosis', 'biological_process', 'GO:0001906', ('43', '51'))	('necrosis', 'biological_process', 'GO:0008220', ('43', '51'))
166600	26544728	When considering the 'combination score', patients with high levels of MDM2, necrosis and proliferation index showed shorter although not significant OS (p = 0.08) and significantly shorter progression free survival (p = 0.02) (Figure 6).	('necrosis', 'biological_process', 'GO:0070265', ('77', '85'))	('shorter', 'NegReg', (182, 189))	('necrosis', 'biological_process', 'GO:0008219', ('77', '85'))	('necrosis', 'Disease', 'MESH:D009336', (77, 85))	('proliferation', 'CPA', (90, 103))	('necrosis', 'biological_process', 'GO:0019835', ('77', '85'))	('MDM2', 'Gene', (71, 75))	('necrosis', 'biological_process', 'GO:0008220', ('77', '85'))	('shorter', 'NegReg', (117, 124))	('high levels', 'Var', (56, 67))	('necrosis', 'biological_process', 'GO:0001906', ('77', '85'))	('OS', 'Chemical', '-', (150, 152))	('patients', 'Species', '9606', (42, 50))	('progression free survival', 'CPA', (190, 215))	('necrosis', 'Disease', (77, 85))
166604	26544728	Even though mutation and deletion of p53 and pRb tumour suppressor genes occur frequently in a lot of human cancers, they have been rarely described in malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (152, 174))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (152, 174))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('malignant mesothelioma', 'Disease', (152, 174))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('deletion', 'Var', (25, 33))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('human', 'Species', '9606', (102, 107))	('mutation', 'Var', (12, 20))	('pRb', 'Gene', '5925', (45, 48))	('pRb', 'Gene', (45, 48))	('tumour', 'Disease', (49, 55))
166611	26544728	These findings, the evidence of higher effectiveness of MDM2-p53 inhibitors in killing cancer cells overproducing MDM2 protein as a result of MDM2 gene amplification, and MDM2 disregulation in merlin-deficient tumors, suggest a possible role of MDM2 in malignant mesothelioma cancerogenesis and progression.	('higher', 'PosReg', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (253, 275))	('MDM2', 'Gene', (171, 175))	('deficient tumors', 'Disease', 'MESH:D009369', (200, 216))	('merlin', 'Gene', (193, 199))	('amplification', 'Var', (152, 165))	('cancer', 'Disease', (87, 93))	('malignant mesothelioma cancerogenesis', 'Disease', (253, 290))	('cancer', 'Disease', (276, 282))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('malignant mesothelioma cancerogenesis', 'Disease', 'MESH:C562839', (253, 290))	('deficient tumors', 'Disease', (200, 216))	('p53', 'Gene', '7157', (61, 64))	('overproducing', 'PosReg', (100, 113))	('MDM2', 'Gene', (142, 146))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('merlin', 'Gene', '4771', (193, 199))	('p53', 'Gene', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('disregulation', 'Var', (176, 189))
166619	26544728	Recent retrospective data of Next-Generation-Sequencing in 123 MPM tumor samples showed high frequency of mutations in the p53-DNA repair pathway, with high ratio of non synonimous-synonimous variation in TP53 and CDKNA2A suggesting a central role in MPM carcinogenesis and progression.	('non synonimous-synonimous variation', 'Var', (166, 201))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MPM carcinogenesis', 'Disease', 'MESH:D063646', (251, 269))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('CDKNA2A', 'Gene', (214, 221))	('MPM carcinogenesis', 'Disease', (251, 269))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('DNA repair', 'biological_process', 'GO:0006281', ('127', '137'))	('p53', 'Gene', (123, 126))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', (67, 72))	('p53', 'Gene', '7157', (123, 126))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
166620	26544728	However, in line with previous literature data, we observed no p53 mutation across exons 4 through 10 in ten MPM samples (5 epithelioid and 5 sarcomatoid/biphasic), even in those samples with MDM2 overexpression.	('p53', 'Gene', (63, 66))	('mutation', 'Var', (67, 75))	('p53', 'Gene', '7157', (63, 66))	('sarcomatoid', 'Disease', (142, 153))	('sarcomatoid', 'Disease', 'MESH:C538614', (142, 153))
166624	26544728	Our results reported a statistically significant correlation of high proliferation index and necrosis with sarcomatoid/biphasic histology, and of high inflammation with epithelioid subtype.	('high inflammation', 'Disease', (146, 163))	('necrosis', 'biological_process', 'GO:0001906', ('93', '101'))	('high', 'Var', (64, 68))	('inflammation', 'biological_process', 'GO:0006954', ('151', '163'))	('sarcomatoid', 'Disease', (107, 118))	('necrosis', 'Disease', (93, 101))	('necrosis', 'biological_process', 'GO:0070265', ('93', '101'))	('sarcomatoid', 'Disease', 'MESH:C538614', (107, 118))	('necrosis', 'Disease', 'MESH:D009336', (93, 101))	('high inflammation', 'Disease', 'MESH:D007249', (146, 163))	('necrosis', 'biological_process', 'GO:0019835', ('93', '101'))	('necrosis', 'biological_process', 'GO:0008219', ('93', '101'))	('necrosis', 'biological_process', 'GO:0008220', ('93', '101'))
166628	26544728	Thus, from our results, it is tempting to speculate that MDM2, Ki67 and necrosis might be considered as important diagnostic parameters to characterize a more aggressive phenotype of MPM: in fact, when considering the 'combination score', patients with high levels of two out of three markers showed shorter OS and PFS.	('high', 'Var', (253, 257))	('PFS', 'CPA', (315, 318))	('necrosis', 'biological_process', 'GO:0001906', ('72', '80'))	('necrosis', 'biological_process', 'GO:0019835', ('72', '80'))	('necrosis', 'biological_process', 'GO:0008220', ('72', '80'))	('Ki67', 'Chemical', '-', (63, 67))	('necrosis', 'Disease', (72, 80))	('patients', 'Species', '9606', (239, 247))	('shorter', 'NegReg', (300, 307))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('necrosis', 'biological_process', 'GO:0070265', ('72', '80'))	('OS', 'Chemical', '-', (308, 310))	('necrosis', 'biological_process', 'GO:0008219', ('72', '80'))
166631	26544728	Sarcomatoid/biphasic histology, high levels of necrosis and proliferation index were the only features associated with shorter PFS, thus defining a more aggressive and chemoresistant phenotype.	('necrosis', 'biological_process', 'GO:0019835', ('47', '55'))	('necrosis', 'biological_process', 'GO:0001906', ('47', '55'))	('necrosis', 'biological_process', 'GO:0008220', ('47', '55'))	('Sarcomatoid', 'Disease', (0, 11))	('necrosis', 'Disease', 'MESH:D009336', (47, 55))	('Sarcomatoid', 'Disease', 'MESH:C538614', (0, 11))	('necrosis', 'biological_process', 'GO:0008219', ('47', '55'))	('PFS', 'Gene', (127, 130))	('necrosis', 'biological_process', 'GO:0070265', ('47', '55'))	('shorter', 'Var', (119, 126))	('necrosis', 'Disease', (47, 55))	('proliferation index', 'CPA', (60, 79))
166659	26544728	Inflammatory cell characterization was performed by immunohistochemistry (IHC) in 4 mum-thick sections using the following antibodies: anti-CD45 (1:100, Biocare), anti-CD4 (1:200, Dako), anti-CD8 (1:200, Dako) and anti-CD20 (1:200, Dako).	('CD4', 'Gene', (140, 143))	('CD4', 'Gene', (168, 171))	('1:200', 'Var', (197, 202))	('CD4', 'Gene', '920', (168, 171))	('CD45', 'Gene', '5788', (140, 144))	('CD8', 'Gene', (192, 195))	('CD20', 'Gene', '54474', (219, 223))	('CD4', 'Gene', '920', (140, 143))	('CD8', 'Gene', '925', (192, 195))	('CD20', 'Gene', (219, 223))	('CD45', 'Gene', (140, 144))
166662	26544728	The IARC, International Agency for Research on Cancer, dataset also reported 10 TP53 mutated cases in exon 5, 7 and 8.	('Cancer', 'Disease', (47, 53))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutated', 'Var', (85, 92))
166704	24086527	Furthermore, we showed that meloe promoter was hypomethylated in melanomas and melanocytes, and hypermethylated in colon cancer cell lines and mesotheliomas, thus explaining the absence of P-CREB binding in these cell lines.	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('binding', 'Interaction', (196, 203))	('mesotheliomas', 'Disease', 'MESH:D008654', (143, 156))	('colon cancer', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CREB', 'Gene', '1385', (191, 195))	('CREB binding', 'molecular_function', 'GO:0008140', ('191', '203'))	('melanomas', 'Disease', (65, 74))	('CREB', 'Gene', (191, 195))	('hypermethylated', 'Var', (96, 111))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('mesotheliomas', 'Disease', (143, 156))
166718	24086527	Two main mechanisms have been involved in the regulation of tumour antigen expression: regulation by tissue specific transcription factors (TFs), responsible for the expression of differentiation antigens and hypomethylation of the gene promoters in tumour tissues, as reported for cancer germline antigens, such as MAGE, BAGE, GAGE and NY-ESO-1 antigens.	('tumour', 'Disease', 'MESH:D009369', (250, 256))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('tumour', 'Disease', (250, 256))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('tumour', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('expression', 'Species', '29278', (166, 176))	('expression', 'Species', '29278', (75, 85))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('cancer', 'Disease', (282, 288))	('hypomethylation', 'Var', (209, 224))
166719	24086527	Such epigenetic alteration in the cancer cell genome leads to a shared expression of these tumour antigens between different types of cancers, that does not fit with meloe expression profile.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('expression', 'MPA', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('shared', 'Reg', (64, 70))	('epigenetic alteration', 'Var', (5, 26))	('expression', 'Species', '29278', (71, 81))	('expression', 'Species', '29278', (172, 182))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('tumour', 'Disease', (91, 97))	('cancers', 'Disease', (134, 141))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('leads to', 'Reg', (53, 61))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
166720	24086527	Differentiation antigens, in turn, are exclusively expressed in the melanocytic lineage, such as Melan-A, gp100, Tyrosinase or TYRP1.	('gp100', 'Var', (106, 111))	('Tyrosinase', 'Gene', '7299', (113, 123))	('Tyrosinase', 'Gene', (113, 123))
166738	24086527	SOX10 wild type and mutant cDNA (E189X) were a gift from M. Goossens and N. Bondurand (IMRB, Creteil-FRANCE).	('E189X', 'Var', (33, 38))	('SOX10', 'Gene', (0, 5))	('SOX10', 'Gene', '6663', (0, 5))	('E189X', 'Mutation', 'rs74315514', (33, 38))
166743	24086527	ChIP assays were performed with the ChIP-IT  kit (ActiveMotif, La Hulpe-BELGIUM) with the following antibodies: anti-SOX9 (Millipore) and anti-SOX10 (Santa-Cruz), anti-phospho-CREB (Cell-Signalling).	('CREB', 'Gene', '1385', (176, 180))	('anti-SOX9', 'Var', (112, 121))	('SOX10', 'Gene', '6663', (143, 148))	('Signalling', 'biological_process', 'GO:0023052', ('187', '197'))	('SOX10', 'Gene', (143, 148))	('CREB', 'Gene', (176, 180))
166756	24086527	We found two E-boxes (CA [T/C]GTG) consensus sequences (-659 and +495) able to bind MITF, along with ETS (-409), AP1 (-354), SOX (-93), and CREB (-80) consensus sequences.	('MITF', 'Gene', (84, 88))	('CREB', 'Gene', (140, 144))	('AP1', 'cellular_component', 'GO:0005907', ('113', '116'))	('-659', 'Var', (56, 60))	('CREB', 'Gene', '1385', (140, 144))	('bind', 'Interaction', (79, 83))
166759	24086527	Results first show that meloe promoter (from P-1565 to P-415) is as active as Melan-A promoter in melanoma cells (Figure 2B).	('active', 'MPA', (68, 74))	('P-415', 'Var', (55, 60))	('from P-1565', 'Var', (40, 51))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))
166760	24086527	Promoter activity decreased when the region between -415 and -268 (containing ETS and AP1 consensus sequences) was deleted (p<0.01), and was completely abrogated after deletion of the region containing SOX and CREB consensus sequences (P-76) (p<0.001).	('AP1', 'cellular_component', 'GO:0005907', ('86', '89'))	('abrogated', 'NegReg', (152, 161))	('decreased', 'NegReg', (18, 27))	('CREB', 'Gene', (210, 214))	('Promoter activity', 'MPA', (0, 17))	('CREB', 'Gene', '1385', (210, 214))	('deletion', 'Var', (168, 176))
166761	24086527	Mutation of SOX and CREB binding sites entailed a drastic loss of promoter activity (P<0.001).	('promoter activity', 'MPA', (66, 83))	('loss', 'NegReg', (58, 62))	('CREB', 'Gene', (20, 24))	('Mutation', 'Var', (0, 8))	('CREB', 'Gene', '1385', (20, 24))	('CREB binding', 'molecular_function', 'GO:0008140', ('20', '32'))
166770	24086527	The presence of each of these factors restores meloe promoter activity in these cell lines, strongly suggesting their involvement in meloe transcription in melanoma cells (Figure 3B).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('meloe promoter activity', 'MPA', (47, 70))	('restores', 'PosReg', (38, 46))	('presence', 'Var', (4, 12))
166772	24086527	This mutated form (E189X) contains the high-mobility-group binding domain but is defective for the activation of gene transcription.	('gene transcription', 'MPA', (113, 131))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('transcription', 'biological_process', 'GO:0006351', ('118', '131'))	('E189X', 'Var', (19, 24))	('defective', 'NegReg', (81, 90))	('high-mobility-group binding domain', 'MPA', (39, 73))	('E189X', 'Mutation', 'rs74315514', (19, 24))
166784	24086527	On the contrary, most of the CpG motifs of this region, including that of the CREB binding site, are hypermethylated in mesothelioma cells (100% in Meso45 and 77% in Meso163), and in colon carcinoma cells (64% in SW480 and 85% in SW707).	('CREB binding', 'molecular_function', 'GO:0008140', ('78', '90'))	('SW707', 'CellLine', 'CVCL:6230', (230, 235))	('hypermethylated', 'Var', (101, 116))	('mesothelioma', 'Disease', (120, 132))	('CREB', 'Gene', '1385', (78, 82))	('SW480', 'CellLine', 'CVCL:0546', (213, 218))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('colon carcinoma', 'Disease', 'MESH:D015179', (183, 198))	('colon carcinoma', 'Disease', (183, 198))	('CREB', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
166785	24086527	The hypermethylation of the promoter region is consistent with the underexpression of meloe gene in non-melanocytic cells.	('expression', 'Species', '29278', (72, 82))	('meloe gene', 'Gene', (86, 96))	('hypermethylation', 'Var', (4, 20))
166796	24086527	Conversely, SOX and CREB proteins appeared essential for meloe expression as mutations of their specific binding sites completely abrogate promoter activity (Figure 2C).	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('promoter activity', 'MPA', (139, 156))	('expression', 'Species', '29278', (63, 73))	('CREB', 'Gene', (20, 24))	('mutations', 'Var', (77, 86))	('abrogate', 'NegReg', (130, 138))	('CREB', 'Gene', '1385', (20, 24))
166811	24086527	The region from -270 to +544 bp of meloe was almost unmethylated in melanoma cell lines and in melanocytes, and hypermethylated in colon carcinoma cell lines and even more in mesotheliomas (Figure 5).	('colon carcinoma cell lines', 'Disease', 'MESH:D003110', (131, 157))	('mesotheliomas', 'Disease', (175, 188))	('colon carcinoma cell lines', 'Disease', (131, 157))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('hypermethylated', 'Var', (112, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('mesotheliomas', 'Disease', 'MESH:D008654', (175, 188))
166813	24086527	In cancer cells, epigenetic modifications are very frequent, regulating positively or negatively gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('expression', 'Species', '29278', (102, 112))	('negatively', 'NegReg', (86, 96))	('regulating', 'Reg', (61, 71))	('epigenetic modifications', 'Var', (17, 41))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('positively', 'MPA', (72, 82))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
166814	24086527	Many tumours show hypomethylation of their genome, but the hypomethylation of the region of 800bp surrounding meloe transcription start site concerns both melanomas and their normal counterparts and thus appears specific to the melanocytic lineage.	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('hypomethylation', 'Var', (59, 74))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('concerns', 'Reg', (141, 149))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('melanomas', 'Disease', (155, 164))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
166815	24086527	In the same line of thought, a melanoma specific hypomethylation has been described for the first intron of FOXP3 gene, demethylated in regulatory T cell clones and in melanoma cells, compared to other cancer cells such as lung and colorectal carcinoma cells.	('lung', 'Disease', 'MESH:D008171', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('demethylated', 'Var', (120, 132))	('lung', 'Disease', (223, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('FOXP3', 'Gene', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('colorectal carcinoma', 'Disease', (232, 252))	('cancer', 'Disease', (202, 208))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (232, 252))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (31, 39))	('melanoma', 'Disease', (168, 176))	('FOXP3', 'Gene', '50943', (108, 113))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
166920	33516644	In addition, gemcitabine has been found to increase tumour-antigenicity in mesothelioma mouse models by increasing antigen-presenting cell (APC) MHC-expression and promoting cross-presentation of tumour-antigens leading to increased tumour control.	('increased tumour', 'Disease', (223, 239))	('cross-presentation', 'biological_process', 'GO:0042590', ('174', '192'))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('increased tumour', 'Disease', 'MESH:D009369', (223, 239))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', (196, 202))	('tumour', 'Disease', (52, 58))	('mesothelioma', 'Disease', (75, 87))	('promoting', 'PosReg', (164, 173))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('cross-presentation', 'MPA', (174, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('cross-presentation', 'biological_process', 'GO:0002479', ('174', '192'))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('tumour', 'Disease', (233, 239))	('gemcitabine', 'Var', (13, 24))	('cross-presentation', 'biological_process', 'GO:0002480', ('174', '192'))	('APC', 'Disease', 'MESH:D011125', (140, 143))	('APC', 'Disease', (140, 143))	('APC', 'cellular_component', 'GO:0005680', ('140', '143'))	('increase', 'PosReg', (43, 51))	('gemcitabine', 'Chemical', 'MESH:C056507', (13, 24))	('mouse', 'Species', '10090', (88, 93))	('antigen-presenting', 'MPA', (115, 133))	('increasing', 'PosReg', (104, 114))
166935	33516644	JGA reports personal fees and non-financial support from MSD, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from amphera, personal fees from Eli-Lilly, personal fees from Takeda, personal fees from Bayer, personal fees from Roche, personal fees from Astra Zeneca, all outside the submitted work; In addition, JGA has a patent on allogenic tumour cell lysate licensed to amphora (EP2938354A1), a patent combination immunotherapy in cancer (pending), and a patent biomarker for immunotherapy (pending) .	('MSD', 'Disease', (57, 60))	('MSD', 'Disease', 'MESH:D052517', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (464, 470))	('tumour', 'Phenotype', 'HP:0002664', (372, 378))	('EP2938354A1', 'Var', (412, 423))	('cancer', 'Disease', (464, 470))	('cancer', 'Disease', 'MESH:D009369', (464, 470))	('tumour', 'Disease', 'MESH:D009369', (372, 378))	('tumour', 'Disease', (372, 378))
167059	29574645	In particular, in three non-occupationally exposed MM patients, there were 110,000 (resident at a distance of 2000 m) and 1,700,000 (resident at a distance of 200 m) ff/g of dry lung in two men and 2,300,000 ff/g of dry lung in a woman (resident at a distance of 500 m).	('occupation', 'Disease', 'MESH:D009784', (28, 38))	('patients', 'Species', '9606', (54, 62))	('woman', 'Species', '9606', (230, 235))	('ff/g', 'Var', (166, 170))	('dry lung', 'Disease', 'MESH:D008171', (174, 182))	('men', 'Species', '9606', (190, 193))	('occupation', 'Disease', (28, 38))	('dry lung', 'Disease', (174, 182))	('dry lung', 'Disease', 'MESH:D008171', (216, 224))	('dry lung', 'Disease', (216, 224))
167088	29619192	In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (20, 45))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('murine', 'Species', '10090', (3, 9))	('improved', 'PosReg', (204, 212))	('localization', 'biological_process', 'GO:0051179', ('241', '253'))	('peritoneal carcinomatosis', 'Disease', (20, 45))	('PGC-PTX', 'Var', (184, 191))
167103	29619192	It has been previously demonstrated that sub-100 nm particles exhibit effective tumor tissue penetration and retention, while sub-50 nm NPs exhibit poor tumor retention.	('sub-100 nm', 'Var', (41, 51))	('tumor retention', 'Disease', (153, 168))	('retention', 'CPA', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('retention', 'biological_process', 'GO:0051235', ('109', '118'))	('tumor retention', 'Disease', 'MESH:D016055', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('retention', 'biological_process', 'GO:0051235', ('159', '168'))	('tumor tissue penetration', 'CPA', (80, 104))
167106	29619192	However, drug-free NPs composed of poly(benzyl 1,2-glycerol carbonate) (PGC-Bn), the PGC polymer prior to deprotection, exhibit slightly smaller diameters (63.7 +- 7.6 nm) and greater dispersity (0.126 +- 0.043).	('diameters', 'MPA', (145, 154))	('smaller', 'NegReg', (137, 144))	('dispersity', 'MPA', (184, 194))	('greater', 'PosReg', (176, 183))	('poly(benzyl 1,2-glycerol carbonate)', 'Chemical', '-', (35, 70))	('poly', 'Var', (35, 39))
167115	29619192	This observation is consistent with previous reports on the localization of negatively charged NPs to peritoneal tumors following IP administration, and may be attributed to the increased metabolic activity and more rapid NP internalization of tumor cells compared to healthy cells.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('metabolic', 'MPA', (188, 197))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('peritoneal tumors', 'Disease', 'MESH:D010534', (102, 119))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('peritoneal tumors', 'Disease', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('negatively', 'Var', (76, 86))	('increased', 'PosReg', (178, 187))
167121	25653542	They were characterized by immunohistochemistry, growth kinetics, tests for tumorigenicity, EGFR and KRAS gene mutations, ALK gene rearrangement and OncoSeq mutation profiling.	('mutations', 'Var', (111, 120))	('ALK', 'Gene', '238', (122, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('KRAS', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('KRAS', 'Gene', '3845', (101, 105))	('ALK', 'Gene', (122, 125))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
167123	25653542	One of these new cell lines bears EML4-ALK rearrangement variant 2, two lung cancer cell lines bear different KRAS mutations at codon 12, and known single nucleotide polymorphism variants were identified in these cell lines.	('mutations', 'Var', (115, 124))	('ALK', 'Gene', (39, 42))	('KRAS', 'Gene', '3845', (110, 114))	('variant', 'Var', (57, 64))	('lung cancer', 'Disease', (72, 83))	('ALK', 'Gene', '238', (39, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('KRAS', 'Gene', (110, 114))
167126	25653542	Despite knowledge on known therapeutic targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangement, and continuous efforts in clinical trials, lung cancer remains the top cause of cancer morbidity and mortality in most parts of the world.	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('ALK', 'Gene', (134, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('52', '75'))	('anaplastic lymphoma kinase', 'Gene', '238', (106, 132))	('cancer', 'Disease', (207, 213))	('anaplastic lymphoma kinase', 'Gene', (106, 132))	('EGFR', 'Gene', '1956', (86, 90))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (106, 125))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Disease', (202, 213))	('mutations', 'Var', (92, 101))	('epidermal growth factor receptor', 'Gene', (52, 84))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('EGFR', 'Gene', (86, 90))	('ALK', 'Gene', '238', (134, 137))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
167128	25653542	Oncogenic driver mutations have been identified and they are present in mutually exclusive ways in individual lung tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lung tumors', 'Disease', 'MESH:D008175', (110, 121))	('lung tumor', 'Phenotype', 'HP:0100526', (110, 120))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('lung tumors', 'Disease', (110, 121))	('mutations', 'Var', (17, 26))	('lung tumors', 'Phenotype', 'HP:0100526', (110, 121))
167130	25653542	Even with the presence of these molecular targets, however, there are mutant tumors that do not respond to the corresponding targeted agents, or mutant tumors that do respond initially followed subsequently by development of resistance to the corresponding targeted agents.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('mutant', 'Var', (145, 151))	('resistance', 'MPA', (225, 235))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
167131	25653542	A better understanding of the mechanisms of actions of these therapeutic oncogenic driver mutations in lung cancer may allow for identification of new molecular targets for better diagnostics and targeted therapy of lung cancer.	('mutations', 'Var', (90, 99))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', (216, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))
167136	25653542	Mutation profiling was performed to document the single nucleotide polymorphism (SNP) variants of these newly established lung cancer and MPM cell lines.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('variants', 'Var', (86, 94))	('single nucleotide polymorphism', 'Var', (49, 79))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))
167152	25653542	Genomic DNA was extracted from freshly harvested cells, and extracted DNA was analyzed for mutations in exons 18-21 of the EGFR gene and codons 12, 13, and 61 of the KRAS gene by direct sequencing according to previous protocol.	('EGFR', 'Gene', (123, 127))	('mutations in', 'Var', (91, 103))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('KRAS', 'Gene', (166, 170))	('KRAS', 'Gene', '3845', (166, 170))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('EGFR', 'Gene', '1956', (123, 127))
167161	25653542	Reverse transcription-PCR combined with direct sequencing of the PCR products were performed for any cell line with ALK rearrangement with FISH to identify EML4-ALK variants.	('variants', 'Var', (165, 173))	('ALK', 'Gene', (161, 164))	('ALK', 'Gene', (116, 119))	('Reverse transcription', 'biological_process', 'GO:0001171', ('0', '21'))	('ALK', 'Gene', '238', (116, 119))	('ALK', 'Gene', '238', (161, 164))
167176	25653542	The established line was tested to harbor EML4-ALK translocation with variant type 2 of exon 20: exon 20 rearrangement (Table 1).	('ALK', 'Gene', '238', (47, 50))	('ALK', 'Gene', (47, 50))	('variant', 'Var', (70, 77))
167186	25653542	The patient was started on erlotinib and he decided to maintain it despite the fact that EGFR mutation tests came back to show no mutation subsequently.	('EGFR', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))	('patient', 'Species', '9606', (4, 11))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('EGFR', 'Gene', '1956', (89, 93))	('erlotinib', 'Chemical', 'MESH:D000069347', (27, 36))
167194	25653542	FA34, FA44, FA49, and FA98 were derived from pleural fluid adenocarcinoma cells taken from patients who had received prior treatment with either platinum-based chemotherapy (for FA34, FA44, and FA49) or empirical EGFR-TKI treatment (for FA98) before EGFR mutation status was known.	('patients', 'Species', '9606', (91, 99))	('platinum', 'Chemical', 'MESH:D010984', (145, 153))	('EGFR', 'Gene', (213, 217))	('FA44', 'Var', (184, 188))	('FA49', 'Var', (194, 198))	('FA98', 'Chemical', '-', (237, 241))	('EGFR', 'molecular_function', 'GO:0005006', ('250', '254'))	('pleural fluid adenocarcinoma', 'Disease', 'MESH:D010997', (45, 73))	('pleural fluid adenocarcinoma', 'Disease', (45, 73))	('FA98', 'Chemical', '-', (22, 26))	('EGFR', 'Gene', '1956', (250, 254))	('pleural fluid', 'Phenotype', 'HP:0002202', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('EGFR', 'Gene', (250, 254))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('EGFR', 'Gene', '1956', (213, 217))
167200	25653542	Napsin A was stained positive for FA44 but negative for other lung adenocarcinoma cell lines in this report (Figure 3).	('Napsin A', 'Gene', '9476', (0, 8))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Napsin A', 'Gene', (0, 8))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('FA44', 'Var', (34, 38))	('lung adenocarcinoma', 'Disease', (62, 81))
167209	25653542	All of the cell lines were tested wild type for EGFR mutation at exons 18-21.	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('EGFR', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))	('EGFR', 'Gene', '1956', (48, 52))
167210	25653542	FA44 and FA49 were both KRAS mutations at codon 12 with G215T and G219A, respectively.	('G215T', 'Var', (56, 61))	('G215T', 'Mutation', 'c.215G>T', (56, 61))	('KRAS', 'Gene', '3845', (24, 28))	('G219A', 'Var', (66, 71))	('G219A', 'Mutation', 'rs104886027', (66, 71))	('KRAS', 'Gene', (24, 28))
167212	25653542	FISH for ALK rearrangement were tested for all these new cell lines, with FA34 showing ALK rearrangement (Figure 6) according to standard scoring criteria while all the others showed no ALK rearrangement.	('ALK', 'Gene', (9, 12))	('rearrangement', 'Var', (91, 104))	('ALK', 'Gene', (186, 189))	('ALK', 'Gene', '238', (87, 90))	('ALK', 'Gene', '238', (9, 12))	('ALK', 'Gene', '238', (186, 189))	('ALK', 'Gene', (87, 90))
167217	25653542	Numerically, FA34b is near-tetraploid; FA44a, FA49, FA98, and PME1 are near-triploid.	('PME1', 'Gene', '51400', (62, 66))	('FA98', 'Chemical', '-', (52, 56))	('FA34b', 'Var', (13, 18))	('FA44a', 'Var', (39, 44))	('PME1', 'Gene', (62, 66))
167219	25653542	With the SIFT and PROVEAN softwares, detected variants were predicted to have damaging/deleterious or tolerated/neutral effects on the resulting protein structure or functions.	('protein', 'Protein', (145, 152))	('SIFT', 'Disease', (9, 13))	('functions', 'MPA', (166, 175))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('variants', 'Var', (46, 54))	('SIFT', 'Disease', 'None', (9, 13))
167221	25653542	BLM (Bloom syndrome, RecQ helicase-like, NM_000057: exon11: c.C2371T: p.R791C), RECQL4 (NM_004260: exon5: c.G1060A: p.V354I), and ERBB2 (NM_004448: exon27: c.C3508G: p.P1170A) variants were found in FA34 alone.	('c.G1060A', 'Mutation', 'rs753902259', (106, 114))	('ERBB2', 'Gene', '2064', (130, 135))	('c.C3508G', 'Mutation', 'rs1058808', (156, 164))	('c.C2371T', 'Mutation', 'rs55880859', (60, 68))	('p.R791C', 'Mutation', 'rs55880859', (70, 77))	('ERBB2', 'Gene', (130, 135))	('BLM', 'Gene', '641', (0, 3))	('RECQL4', 'Gene', (80, 86))	('p.V354I', 'Mutation', 'rs551940973', (116, 123))	('p.P1170A', 'Mutation', 'rs1058808', (166, 174))	('RECQL4', 'Gene', '9401', (80, 86))	('p.P1170A', 'Var', (166, 174))	('BLM', 'Gene', (0, 3))
167222	25653542	An ATM variant (ATM serine/threonine kinase, NM_000051:exon6:c.G566A:p.R189K) with potential deleterious effects was found in FA44, together with a tolerated variant of EGFR at exon 13 (NM_005228: exon13: c.G1562A: p.R521K), and FLT3 (fms-related tyrosine kinase 3, NM_004119: exon6: c.C680T: p.T227M), and another variant of ERBB2 was found at the same genetic locus as in FA34 above.	('c.G566A:p.R189K', 'Var', (61, 76))	('FLT3', 'Gene', '2322', (229, 233))	('ERBB2', 'Gene', (326, 331))	('c.C680T', 'Mutation', 'rs1933437', (284, 291))	('fms-related tyrosine kinase 3', 'Gene', (235, 264))	('c.G566A:p.R189K', 'SUBSTITUTION', 'None', (61, 76))	('p.R521K', 'Mutation', 'rs2227983', (215, 222))	('ERBB2', 'Gene', '2064', (326, 331))	('fms', 'molecular_function', 'GO:0005011', ('235', '238'))	('ATM', 'Gene', (16, 19))	('p.T227M', 'Mutation', 'rs1933437', (293, 300))	('EGFR', 'Gene', (169, 173))	('FA44', 'Var', (126, 130))	('ATM', 'Gene', '472', (3, 6))	('ATM serine/threonine kinase', 'Gene', (16, 43))	('c.G1562A', 'Mutation', 'rs2227983', (205, 213))	('fms-related tyrosine kinase 3', 'Gene', '2322', (235, 264))	('EGFR', 'Gene', '1956', (169, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('169', '173'))	('ATM', 'Gene', '472', (16, 19))	('FLT3', 'Gene', (229, 233))	('effects', 'Reg', (105, 112))	('ATM', 'Gene', (3, 6))	('ATM serine/threonine kinase', 'Gene', '472', (16, 43))
167225	25653542	The five lung adenocarcinoma and mesothelioma cell lines were newly established from lung cancer and mesothelioma patients with advanced-stage disease, and each of them carries their respective oncogenic driver mutation, including two new lung adenocarcinoma cell lines with two different KRAS mutations at codon 12, and one new lung adenocarcinoma cell line with EML4-ALK translocation.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (239, 258))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KRAS', 'Gene', '3845', (289, 293))	('lung adenocarcinoma', 'Disease', (329, 348))	('KRAS', 'Gene', (289, 293))	('lung cancer', 'Disease', (85, 96))	('ALK', 'Gene', '238', (369, 372))	('mutations', 'Var', (294, 303))	('patients', 'Species', '9606', (114, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (329, 348))	('mesothelioma', 'Disease', (33, 45))	('ALK', 'Gene', (369, 372))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (329, 348))	('lung adenocarcinoma', 'Disease', (9, 28))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('lung adenocarcinoma', 'Disease', (239, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('mesothelioma', 'Disease', (101, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (9, 28))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (239, 258))	('mutation', 'Var', (211, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
167233	25653542	Lung adenocarcinoma cell lines bearing EML4-ALK rearrangement were seldom found in the literature and the more-commonly used ones were NCI-H3122 and DFCI032.	('ALK', 'Gene', (44, 47))	('rearrangement', 'Var', (48, 61))	('ALK', 'Gene', '238', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('NCI-H3122', 'CellLine', 'CVCL:5160', (135, 144))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
167234	25653542	EML4-ALK rearrangement was reported to be more-commonly found in young patients, especially nonsmokers, with lung adenocarcinoma.	('ALK', 'Gene', (5, 8))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('patients', 'Species', '9606', (71, 79))	('lung adenocarcinoma', 'Disease', (109, 128))	('ALK', 'Gene', '238', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('rearrangement', 'Var', (9, 22))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))
167236	25653542	Two different KRAS mutations at codon 12 were found in two lung adenocarcinoma cell lines, FA44 and FA49.	('KRAS', 'Gene', '3845', (14, 18))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('mutations', 'Var', (19, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('KRAS', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))
167238	25653542	KRAS mutant lung cancer cell lines were found in the NCI-H series, namely H23, H358, H441, and H1792, which all bear codon 12 mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('H358', 'CellLine', 'CVCL:1559', (79, 83))	('lung cancer', 'Disease', (12, 23))	('mutations', 'Var', (126, 135))	('KRAS', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('KRAS', 'Gene', '3845', (0, 4))
167242	25653542	Chromosome 13 is known to harbor RB1, a tumor suppressor gene, the deletion of which may contribute to tumor growth in lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('tumor growth in lung cancer', 'Disease', 'MESH:D008175', (103, 130))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('deletion', 'Var', (67, 75))	('contribute', 'Reg', (89, 99))	('tumor growth in lung cancer', 'Disease', (103, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('RB1', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('RB1', 'Gene', '5925', (33, 36))
167243	25653542	Among the 42 genes with mutation or SNP identified from the RainDance OncoSeq panel, there were genes commonly found to be mutated/variant in lung cancer while some other mutant/variants could be the characteristics of individual cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (147, 153))	('mutated/variant', 'Var', (123, 138))
167244	25653542	We used the SIFT and PROVEAN softwares to predict whether these mutations could give rise to damaging or deleterious effects to the resultant expression.	('SIFT', 'Disease', (12, 16))	('SIFT', 'Disease', 'None', (12, 16))	('mutations', 'Var', (64, 73))	('expression', 'MPA', (142, 152))
167248	25653542	The growth of mesothelioma cells has been shown to be affected by aberrant Notch1 signaling.	('affected', 'Reg', (54, 62))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('growth', 'CPA', (4, 10))	('mesothelioma', 'Disease', (14, 26))	('aberrant', 'Var', (66, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (14, 26))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
167249	25653542	The two adenocarcinoma cell lines, FA49 and FA98, as well as PME1 in the mesothelioma cell line, possess variants in Notch1 and could be used as an in vitro model to further study the role of Notch1 in lung adenocarcinoma and mesothelioma cell growth.	('mesothelioma', 'Disease', (226, 238))	('PME1', 'Gene', (61, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (226, 238))	('variants', 'Var', (105, 113))	('PME1', 'Gene', '51400', (61, 65))	('lung adenocarcinoma', 'Disease', (202, 221))	('Notch1', 'Gene', (192, 198))	('cell growth', 'biological_process', 'GO:0016049', ('239', '250'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (8, 22))	('adenocarcinoma', 'Disease', 'MESH:D000230', (207, 221))	('Notch1', 'Gene', '4851', (192, 198))	('mesothelioma', 'Disease', (73, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('Notch1', 'Gene', (117, 123))	('Notch1', 'Gene', '4851', (117, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('FA98', 'Chemical', '-', (44, 48))	('adenocarcinoma', 'Disease', (8, 22))	('adenocarcinoma', 'Disease', (207, 221))
167252	25653542	Mutation or variants of LKB1 have been reported in genomic studies on lung cancers, and the presence of LKB1 mutation may cause dysregulation of these AMPK pathways and thus could result in disinhibition of energy-consuming anabolic processes and eventually promote tumor growth.	('result in', 'Reg', (180, 189))	('disinhibition', 'Phenotype', 'HP:0000734', (190, 203))	('LKB1', 'Gene', '6794', (104, 108))	('disinhibition', 'MPA', (190, 203))	('AMPK', 'molecular_function', 'GO:0004691', ('151', '155'))	('tumor', 'Disease', (266, 271))	('AMPK', 'Gene', '5563', (151, 155))	('energy-consuming anabolic', 'MPA', (207, 232))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('LKB1', 'Gene', '6794', (24, 28))	('AMPK', 'molecular_function', 'GO:0047322', ('151', '155'))	('dysregulation', 'MPA', (128, 141))	('LKB1', 'Gene', (104, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('AMPK', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('presence', 'Var', (92, 100))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('mutation', 'Var', (109, 117))	('LKB1', 'Gene', (24, 28))	('cause', 'Reg', (122, 127))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('variants', 'Var', (12, 20))	('AMPK', 'molecular_function', 'GO:0050405', ('151', '155'))	('promote', 'PosReg', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))
167253	25653542	AXIN2 is another known tumor suppressor gene on the Wnt/beta-catenin pathway and a variant (NM_004655: exon7: c.G1807C: p.A603P) was found in both FA34 and FA98.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('FA98', 'Chemical', '-', (156, 160))	('AXIN2', 'Gene', (0, 5))	('NM_004655', 'Var', (92, 101))	('AXIN2', 'Gene', '8313', (0, 5))	('beta-catenin', 'Gene', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('beta-catenin', 'Gene', '1499', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('c.G1807C', 'Mutation', 'rs145353986', (110, 118))	('tumor', 'Disease', (23, 28))	('p.A603P', 'Mutation', 'rs145353986', (120, 127))	('p.A603P', 'Var', (120, 127))
167254	25653542	AXIN2 polymorphism was reported to be associated with risk of developing lung cancer, at least in Japanese and Turkish groups.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('polymorphism', 'Var', (6, 18))	('associated', 'Reg', (38, 48))	('AXIN2', 'Gene', '8313', (0, 5))	('AXIN2', 'Gene', (0, 5))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
167255	25653542	Two different ERBB2 variants were found in FA34 and FA44, whereas an EGFR variant was also present in FA44.	('EGFR', 'Gene', '1956', (69, 73))	('variants', 'Var', (20, 28))	('EGFR', 'Gene', (69, 73))	('ERBB2', 'Gene', '2064', (14, 19))	('ERBB2', 'Gene', (14, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))
167257	25653542	Both ERBB2 gene (which encodes for HER2) and EGFR mutation at exons 18-21 are major proliferative drivers that activate downstream growth signaling pathways.	('ERBB2', 'Gene', '2064', (5, 10))	('HER2', 'Gene', (35, 39))	('ERBB2', 'Gene', (5, 10))	('EGFR', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (35, 39))	('growth signaling pathways', 'Pathway', (131, 156))	('activate', 'PosReg', (111, 119))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
167258	25653542	However, the ERBB2 variants were found at exon 27, which differs from the mutations at exon 20 that have been found to correlate with clinical characteristics and therapeutic response; the same for EGFR mutation at exon 13 in this study, which was different from the usual region of mutations within exons 18-21.	('ERBB2', 'Gene', '2064', (13, 18))	('EGFR', 'molecular_function', 'GO:0005006', ('198', '202'))	('ERBB2', 'Gene', (13, 18))	('mutation', 'Var', (203, 211))	('EGFR', 'Gene', '1956', (198, 202))	('EGFR', 'Gene', (198, 202))	('variants', 'Var', (19, 27))
167263	25653542	IL21R (interleukin 21 receptor, NM_021798: exon4: c.A238C: p.T80P) was another variant found among these newly established cell lines.	('interleukin 21 receptor', 'Gene', '50615', (7, 30))	('interleukin 21 receptor', 'Gene', (7, 30))	('c.A238C: p.T80P', 'Var', (50, 65))	('p.T80P', 'Mutation', 'rs200577530', (59, 65))	('IL21R', 'Gene', '50615', (0, 5))	('IL21R', 'molecular_function', 'GO:0001532', ('0', '5'))	('IL21R', 'Gene', (0, 5))	('c.A238C', 'Mutation', 'rs200577530', (50, 57))
167264	25653542	Aberrant IL21R may interfere with the action of IL21, which itself could be tumor suppressive.	('IL21R', 'molecular_function', 'GO:0001532', ('9', '14'))	('Aberrant', 'Var', (0, 8))	('IL21R', 'Gene', (9, 14))	('action', 'MPA', (38, 44))	('IL21R', 'Gene', '50615', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IL21', 'Gene', (9, 13))	('tumor', 'Disease', (76, 81))	('IL21', 'Gene', '59067', (48, 52))	('IL21', 'molecular_function', 'GO:0001531', ('48', '52'))	('IL21', 'Gene', '59067', (9, 13))	('interfere', 'NegReg', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('IL21', 'Gene', (48, 52))
167265	25653542	A BRCA1 variant (breast cancer 1, early onset, NM_007297: exon9: c.A2972G: p.E991G) with potential deleterious effects was found in FA34 and PME1.	('p.E991G', 'Mutation', 'rs16941', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('c.A2972G: p.E991G', 'Var', (65, 82))	('PME1', 'Gene', '51400', (141, 145))	('breast cancer', 'Disease', (17, 30))	('p.E991G', 'Var', (75, 82))	('effects', 'Reg', (111, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('BRCA1', 'Gene', '672', (2, 7))	('c.A2972G', 'Mutation', 'rs16941', (65, 73))	('BRCA1', 'Gene', (2, 7))	('PME1', 'Gene', (141, 145))
167267	25653542	In PME1, however, we did identify WRN _ENREF_33 mutations or SNP, which may represent the scant oncogenic genomic changes in mesothelioma.	('PME1', 'Gene', '51400', (3, 7))	('WRN _ENREF_33', 'Gene', (34, 47))	('mesothelioma', 'Disease', (125, 137))	('PME1', 'Gene', (3, 7))	('mesothelioma', 'Disease', 'MESH:D008654', (125, 137))	('mutations', 'Var', (48, 57))
167268	25653542	Although the panel of RainDance Oncoseq was limited to the detection of genetic variants/mutations in a panel of 140 known oncogenic mutations, it served as a screening tool for potential oncogenic targets within those cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('variants/mutations', 'Var', (80, 98))	('cancer', 'Disease', (219, 225))
167270	25653542	Mutations of all these potential therapeutic oncology targets - namely ALK rearrangement, KRAS mutations, ERBB2, Notch1, BRCA1, BLM, and related RecQL4, IL-21R, STK11/P, and ATM - were reported in various frequencies in lung cancer before.	('ERBB2', 'Gene', '2064', (106, 111))	('IL-21R', 'Gene', '50615', (153, 159))	('IL-21R', 'Gene', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('Notch1', 'Gene', (113, 119))	('Notch1', 'Gene', '4851', (113, 119))	('STK11', 'Gene', (161, 166))	('BLM', 'Gene', (128, 131))	('BRCA1', 'Gene', '672', (121, 126))	('lung cancer', 'Disease', (220, 231))	('ATM', 'Gene', (174, 177))	('KRAS', 'Gene', '3845', (90, 94))	('BRCA1', 'Gene', (121, 126))	('mutations', 'Var', (95, 104))	('BLM', 'Gene', '641', (128, 131))	('IL-21R', 'molecular_function', 'GO:0001532', ('153', '159'))	('KRAS', 'Gene', (90, 94))	('STK11', 'Gene', '6794', (161, 166))	('ALK', 'Gene', '238', (71, 74))	('RecQL4', 'Gene', '9401', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('ALK', 'Gene', (71, 74))	('RecQL4', 'Gene', (145, 151))	('ERBB2', 'Gene', (106, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('STK11', 'molecular_function', 'GO:0033868', ('161', '166'))	('oncology', 'Phenotype', 'HP:0002664', (45, 53))	('ATM', 'Gene', '472', (174, 177))
167346	21799700	Identification of very large or giant mesothelial cells displaying nuclear atypia, such as enlargement, irregularity of nuclear contours, is an important diagnostic tool for malignant mesothelioma.	('irregularity', 'Var', (104, 116))	('enlargement', 'Disease', 'MESH:D006529', (91, 102))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (174, 196))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (174, 196))	('enlargement', 'Disease', (91, 102))	('malignant mesothelioma', 'Disease', (174, 196))
167428	30245692	Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks).	('HLA-DR', 'Var', (71, 77))	('CD8', 'Gene', (147, 150))	('CD4 T cells', 'CPA', (48, 59))	('enhanced', 'PosReg', (24, 32))	('PD-1', 'Gene', (79, 83))	('CD8', 'Gene', '925', (147, 150))	('PD-1', 'Gene', '5133', (79, 83))	('enhanced proportions of CD4 T cells', 'Phenotype', 'HP:0032219', (24, 59))
167470	30245692	For flow cytometric analysis, the cells were stained with the following antibodies: anti-CD3-APC-eF780 and anti-CD8-AlexaFLuor700 (eBiosciences), anti-CD4-BV785, anti-CD56-PE-Cy7 and anti-CD69-FITC (BD Biosciences) and anti-CD137-PE (Biolegend).	('CD69', 'Gene', (188, 192))	('anti-CD3-APC-eF780', 'Var', (84, 102))	('CD56', 'Gene', (167, 171))	('CD8', 'Gene', (112, 115))	('CD137', 'Gene', (224, 229))	('CD137', 'Gene', '3604', (224, 229))	('AlexaFLuor700', 'Chemical', '-', (116, 129))	('APC', 'cellular_component', 'GO:0005680', ('93', '96'))	('CD8', 'Gene', '925', (112, 115))	('CD56', 'Gene', '4684', (167, 171))	('anti-CD4-BV785', 'Var', (146, 160))	('Cy7', 'Chemical', '-', (175, 178))	('CD69', 'Gene', '969', (188, 192))
167494	30245692	In summary, these findings show that following autologous DC therapy in mesothelioma patients the frequencies of circulating CD4 T cells expressing HLA-DR, PD-1 or ICOS, as well as CD8 T cells expressing the co-inhibitory receptor LAG3 are significantly increased.	('increased', 'PosReg', (254, 263))	('CD8', 'Gene', (181, 184))	('mesothelioma', 'Disease', (72, 84))	('patients', 'Species', '9606', (85, 93))	('CD8', 'Gene', '925', (181, 184))	('PD-1', 'Gene', '5133', (156, 160))	('HLA-DR', 'Var', (148, 154))	('PD-1', 'Gene', (156, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
167524	30245692	Notably, the best responding patient (#5) in our study showed the highest numbers of HLA-DR+ CD4+ and ICOS+ CD4+ T cells.	('HLA-DR+', 'Var', (85, 92))	('ICOS+', 'CPA', (102, 107))	('patient', 'Species', '9606', (29, 36))
167716	25037982	Fibulin-3 values of >=53 and >=346 ng/mL in plasma and effusions respectively were considered positive for MM.	('>=346 ng/mL', 'Var', (29, 40))	('Fibulin-3', 'Gene', (0, 9))	('Fibulin-3', 'Gene', '2202', (0, 9))
167742	25037982	The AUC for plasma mesothelin of 0.816 (0.755 to 0.867) was significantly higher than for fibulin-3 (p=0.003) (figure 1F).	('AUC', 'MPA', (4, 7))	('higher', 'PosReg', (74, 80))	('fibulin-3', 'Gene', '2202', (90, 99))	('fibulin-3', 'Gene', (90, 99))	('mesothelin', 'Gene', (19, 29))	('0.816', 'Var', (33, 38))	('mesothelin', 'Gene', '10232', (19, 29))
167764	25037982	Increasing age, biphasic or sarcomatoid histology, poor performance status, high haemoglobin, high platelet count, CALGB prognostic group 5 or 6, and absence of active treatment were also negative univariable prognostic predictors.	('high platelet count', 'Phenotype', 'HP:0001894', (94, 113))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (28, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('high haemoglobin', 'Phenotype', 'HP:0001900', (76, 92))	('men', 'Species', '9606', (173, 176))	('high', 'Var', (76, 80))	('biphasic or sarcomatoid', 'Disease', (16, 39))	('biphasic or sarcomatoid', 'Disease', 'MESH:C538614', (16, 39))
167768	25037982	MM patients with low effusion fibulin-3 (<467 ng/mL) survived significantly longer than those with high effusion fibulin-3 (14.1, 95% CI 10.5 to 17.7 vs 7.9, 95% CI 4.9 to 10.9 months, p=0.012) (figure 3).	('low effusion', 'Disease', (17, 29))	('<467', 'Var', (41, 45))	('low effusion', 'Disease', 'MESH:D009800', (17, 29))	('patients', 'Species', '9606', (3, 11))	('fibulin-3', 'Gene', '2202', (113, 122))	('fibulin-3', 'Gene', '2202', (30, 39))	('fibulin-3', 'Gene', (113, 122))	('fibulin-3', 'Gene', (30, 39))
167936	22233924	Their ARLC : mesothelioma ratio varied substantially, from 3.3 (22 mesotheliomas; 423 lung cancers, SMR 1.21) for cumulative exposures below 300 million particles per cubic foot (mpcf)-years to 31 (1 mesothelioma; 47 lung cancers, SMR 2.97) above 1000 mpcf-years.	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('lung cancers', 'Disease', 'MESH:D008175', (217, 229))	('mesotheliomas', 'Disease', 'MESH:D008654', (67, 80))	('mesothelioma', 'Disease', (67, 79))	('SMR', 'Gene', '147719', (100, 103))	('lung cancers', 'Disease', (217, 229))	('SMR', 'Gene', (231, 234))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('mesothelioma', 'Disease', (200, 212))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancers', 'Phenotype', 'HP:0100526', (217, 229))	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('SMR', 'Gene', (100, 103))	('lung cancers', 'Disease', 'MESH:D008175', (86, 98))	('mesothelioma', 'Disease', (13, 25))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('below 300 million', 'Var', (135, 152))	('lung cancers', 'Disease', (86, 98))	('SMR', 'Gene', '147719', (231, 234))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('mesotheliomas', 'Disease', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancers', 'Phenotype', 'HP:0100526', (86, 98))
168036	12771921	Similarly, high pro-MMP-2 (P=0.04) and total MMP-2 (P=0.04) contributed independently to the CALGB prognostic scoring system (P=0.005 and 0.02 respectively).	('MMP-2', 'molecular_function', 'GO:0004228', ('20', '25'))	('MMP-2', 'Gene', (20, 25))	('MMP-2', 'Gene', (45, 50))	('MMP-2', 'Gene', '4313', (20, 25))	('high', 'Var', (11, 15))	('MMP-2', 'molecular_function', 'GO:0004228', ('45', '50'))	('MMP-2', 'Gene', '4313', (45, 50))
168067	12771921	Inhibition of MMPs reduces tumour growth, invasion and angiogenesis in vivo (Maekawa et al, 1999).	('MMPs', 'Gene', '4313;4318;4320;4323', (14, 18))	('angiogenesis', 'CPA', (55, 67))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour growth', 'Disease', (27, 40))	('angiogenesis', 'biological_process', 'GO:0001525', ('55', '67'))	('MMPs', 'Gene', (14, 18))	('tumour growth', 'Disease', 'MESH:D006130', (27, 40))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (42, 50))	('reduces', 'NegReg', (19, 26))
168087	33562138	The activated immune system:especially with regard to its innate blood derived components:proved to be associated with worse patient outcome, late stage of disease, high Ki67 expression and poor treatment response in MPM as shown before by the authors and other research groups.	('expression', 'MPA', (175, 185))	('Ki67', 'Protein', (170, 174))	('high', 'Var', (165, 169))	('patient', 'Species', '9606', (125, 132))	('MPM', 'Disease', (217, 220))
168112	33562138	For MPM, a predominant infiltration of CD8+ and CD4+ T-lymphocytes has been described by various researchers, but also the role of B lymphocytes and Treg is under investigation as described below.	('CD8', 'Gene', (39, 42))	('Treg', 'Chemical', '-', (149, 153))	('CD8', 'Gene', '925', (39, 42))	('MPM', 'Var', (4, 7))	('rat', 'Species', '10116', (29, 32))
168121	33562138	Additionally, high CD4+ T cell count in the tumor correlated with better outcome.	('CD4+ T cell count', 'Var', (19, 36))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('high CD4+ T', 'Phenotype', 'HP:0005407', (14, 25))	('tumor', 'Disease', (44, 49))
168136	33562138	Inhibition of FGF receptor not only showed anti-proliferative effects itself but also a synergism with radiation and cisplatin and might, therefore, serve as a novel therapeutic target in MPM.	('FGF', 'Gene', '2247', (14, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('anti-proliferative effects', 'CPA', (43, 69))	('MPM', 'Disease', (188, 191))	('Inhibition', 'Var', (0, 10))	('FGF', 'Gene', (14, 17))	('rat', 'Species', '10116', (55, 58))
168215	33562138	Additionally, for surgical patients undergoing cytoreductive surgery, high NLR was found to correlate with worse prognosis.	('high', 'Var', (70, 74))	('NLR', 'MPA', (75, 78))	('patients', 'Species', '9606', (27, 35))
168216	33562138	Low LMR, displaying a domination of unspecific monocytes, has been found to be a negative prognostic marker for numerous malignancies as reviewed by Gu et al.. For MPM, comparable results have been published showing that low LMR is associated with adverse prognosis in line with the reported negative prognostic value of elevated monocyte count as mentioned before.	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('malignancies', 'Disease', (121, 133))	('elevated monocyte count', 'Phenotype', 'HP:0012311', (321, 344))	('low LMR', 'Var', (221, 228))
168224	33562138	The proinflammatory cytokine IL-6 is released by various immune cells triggered by IL-1beta and TNF, but also produced by tumor cells directly as also proven for MPM with tumor-promoting effects.	('TNF', 'Gene', (96, 99))	('IL-6', 'Gene', (29, 33))	('TNF', 'Gene', '7124', (96, 99))	('IL-1beta', 'Gene', '3552', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('IL-6', 'Gene', '3569', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('IL-6', 'molecular_function', 'GO:0005138', ('29', '33'))	('IL-1', 'molecular_function', 'GO:0005149', ('83', '87'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('MPM', 'Var', (162, 165))	('IL-1beta', 'Gene', (83, 91))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (122, 127))
168258	33562138	Elevated CAR has been shown to predict poor outcome in acute diseases including sepsis as well as in various malignant diseases.	('acute diseases', 'Disease', 'MESH:D000208', (55, 69))	('malignant diseases', 'Disease', 'MESH:D009369', (109, 127))	('malignant diseases', 'Disease', (109, 127))	('CAR', 'MPA', (9, 12))	('CAR', 'cellular_component', 'GO:0005826', ('9', '12'))	('sepsis', 'Phenotype', 'HP:0100806', (80, 86))	('sepsis', 'Disease', (80, 86))	('acute diseases', 'Disease', (55, 69))	('Elevated', 'Var', (0, 8))	('sepsis', 'Disease', 'MESH:D018805', (80, 86))
168331	30985689	Immunostaining showed almost all the tumor cells were strongly positive for CK-pan, CK5/6, CK7, CK18, CK19, WT1, calretinin, D2-40, and vimentin.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('WT1', 'Gene', '7490', (108, 111))	('CK7', 'Gene', '3855', (91, 94))	('CK19', 'Gene', (102, 106))	('CK19', 'Gene', '3880', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('calretinin', 'Gene', (113, 123))	('vimentin', 'Gene', '7431', (136, 144))	('vimentin', 'cellular_component', 'GO:0045098', ('136', '144'))	('vimentin', 'Gene', (136, 144))	('CK18', 'Gene', (96, 100))	('CK5/6', 'Gene', '3852', (84, 89))	('positive', 'Reg', (63, 71))	('CK18', 'Gene', '3875', (96, 100))	('CK7', 'Gene', (91, 94))	('D2-40', 'Var', (125, 130))	('vimentin', 'cellular_component', 'GO:0045099', ('136', '144'))	('calretinin', 'Gene', '794', (113, 123))	('CK5/6', 'Gene', (84, 89))	('tumor', 'Disease', (37, 42))	('CK-pan', 'Var', (76, 82))	('WT1', 'Gene', (108, 111))
168379	28348451	Recent in vitro experimental evidence showed that asbestos fibers could induce programmed necrosis and inflammation in primary human mesothelial cells.	('human', 'Species', '9606', (127, 132))	('inflammation', 'biological_process', 'GO:0006954', ('103', '115'))	('inflammation', 'Disease', (103, 115))	('necrosis', 'Disease', (90, 98))	('induce', 'Reg', (72, 78))	('asbestos', 'Chemical', 'MESH:D001194', (50, 58))	('asbestos fibers', 'Var', (50, 65))	('programmed necrosis', 'biological_process', 'GO:0070266', ('79', '98'))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))
168387	28348451	Serum HMGB1 was also a prognostic marker for Japanese patients with malignant pleural mesothelioma (MPM).	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (78, 98))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (68, 98))	('malignant pleural mesothelioma', 'Disease', (68, 98))	('HMGB1', 'Gene', (6, 11))	('patients', 'Species', '9606', (54, 62))	('Serum', 'Var', (0, 5))	('MPM', 'Chemical', '-', (100, 103))
168418	28348451	Similarly, HMGB1 levels in the MPM group (median level: 60.23 ng/mL) were also significantly higher than those of the control, AE, and PP groups.	('higher', 'PosReg', (93, 99))	('HMGB1', 'Gene', (11, 16))	('MPM', 'Var', (31, 34))	('AE', 'Chemical', '-', (127, 129))	('MPM', 'Chemical', '-', (31, 34))
168449	28348451	Increasing clinical evidence indicates that extracellular HMGB1 contributes to inflammatory disorders and cancer development.	('contributes', 'Reg', (64, 75))	('extracellular', 'Var', (44, 57))	('extracellular', 'cellular_component', 'GO:0005576', ('44', '57'))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('inflammatory disorders', 'Disease', (79, 101))	('inflammatory disorders', 'Disease', 'MESH:D015212', (79, 101))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
168465	28348451	Furthermore, they determined that hyperacetylated HMGB1, a specific subset of HMGB1 molecules, reliably distinguished MM patients from individuals who were occupationally exposed to asbestos with 100% sensitivity and specificity.	('HMGB1', 'Gene', (50, 55))	('asbestos', 'Chemical', 'MESH:D001194', (182, 190))	('distinguished', 'Reg', (104, 117))	('hyperacetylated', 'Var', (34, 49))	('patients', 'Species', '9606', (121, 129))
168483	28348451	Combining these results, it is likely that extracellular HMGB1 may induce intracellular MMP2 and MMP9 expression in local tissue cells but not their secretions into the blood.	('intracellular', 'cellular_component', 'GO:0005622', ('74', '87'))	('MMP2', 'Gene', '4313', (88, 92))	('MMP2', 'molecular_function', 'GO:0004228', ('88', '92'))	('extracellular', 'Var', (43, 56))	('expression', 'MPA', (102, 112))	('HMGB1', 'Gene', (57, 62))	('MMP9', 'Gene', (97, 101))	('extracellular', 'cellular_component', 'GO:0005576', ('43', '56'))	('MMP9', 'molecular_function', 'GO:0004229', ('97', '101'))	('MMP2', 'Gene', (88, 92))	('induce', 'PosReg', (67, 73))
168489	28348451	For clinical diagnosis, these results indicated that serum HMGB1 is a sensitive and specific biomarker to discriminate asbestosis and MM from healthy or AE individuals.	('asbestosis', 'Disease', 'MESH:D001195', (119, 129))	('HMGB1', 'Gene', (59, 64))	('AE', 'Chemical', '-', (153, 155))	('serum', 'Var', (53, 58))	('asbestosis', 'Disease', (119, 129))
168527	25325012	The GO of the differentially expressed genes of SQ included M/G1 transition and DNA repair, while in KEGG several DNA repair mechanisms where overexpressed.	('DNA repair', 'biological_process', 'GO:0006281', ('114', '124'))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('M/G1', 'SUBSTITUTION', 'None', (60, 64))	('M/G1', 'Var', (60, 64))	('DNA repair', 'CPA', (80, 90))	('SQ', 'Phenotype', 'HP:0002860', (48, 50))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
168550	25325012	Current progress include more efficient chemotherapy compounds for so-called non-squamous carcinomas, including the multifolate inhibitor pemetrexed, and smaller subgroups with molecular changes such as EGFR mutations and ALK rearrangements that significantly predict the effect of biological targeted therapies.	('EGFR', 'Gene', '1956', (203, 207))	('EGFR', 'molecular_function', 'GO:0005006', ('203', '207'))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('mole', 'Phenotype', 'HP:0003764', (177, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('ALK', 'Gene', (222, 225))	('EGFR', 'Gene', (203, 207))	('folate', 'Chemical', 'MESH:D005492', (121, 127))	('mutations', 'Var', (208, 217))	('non-squamous carcinomas', 'Disease', 'MESH:D002294', (77, 100))	('non-squamous carcinomas', 'Disease', (77, 100))	('ALK', 'Gene', '238', (222, 225))	('pemetrexed', 'Chemical', 'MESH:D000068437', (138, 148))
168572	25325012	Cyclins are often upregulated in cancers; however, cyclin D1 has not been shown to be a negative prognostic factor in cancer, cyclin D2 is often methylated and thus downregulated in lung cancer, and cyclin D3 was suggested not to have a profound role in tumorigenesis.	('cyclin D1', 'Gene', (51, 60))	('cancer', 'Disease', (33, 39))	('lung cancer', 'Disease', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cyclin D3', 'Gene', (199, 208))	('cyclin', 'molecular_function', 'GO:0016538', ('199', '205'))	('cyclin D1', 'Gene', '595', (51, 60))	('Cyclins', 'Gene', '891;902', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cyclin D2', 'Gene', '894', (126, 135))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('cancer', 'Disease', (118, 124))	('tumor', 'Disease', (254, 259))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('downregulated', 'NegReg', (165, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Cyclins', 'Gene', (0, 7))	('cyclin D2', 'Gene', (126, 135))	('cyclin D3', 'Gene', '896', (199, 208))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('cancer', 'Disease', (187, 193))	('cyclin', 'molecular_function', 'GO:0016538', ('126', '132'))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('methylated', 'Var', (145, 155))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
168581	25325012	Low TS expression increases the pemetrexed response in vitro and a recent meta-analysis on clinical data showed that both TYMS and TS expression were inversely correlated to the effect of pemetrexed in lung cancer.	('pemetrexed', 'Chemical', 'MESH:D000068437', (32, 42))	('pemetrexed response', 'MPA', (32, 51))	('increases', 'PosReg', (18, 27))	('lung cancer', 'Disease', (202, 213))	('TYMS', 'Gene', '7298', (122, 126))	('pemetrexed', 'Chemical', 'MESH:D000068437', (188, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TS', 'Gene', '7298', (4, 6))	('TS', 'Gene', '7298', (131, 133))	('TYMS', 'Gene', (122, 126))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('Low', 'Var', (0, 3))
168592	25325012	Recently afatinib, a selective, orally bioavailable ERBB family blocker that irreversibly blocks signaling from EGFR, HER2, and ERBB4 showed an increased progression-free survival of EGFR mutated ADs of the lung in a phase III study versus chemotherapy.	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('HER2', 'Gene', (118, 122))	('ERBB4', 'Gene', '2066', (128, 133))	('signaling', 'MPA', (97, 106))	('ERBB', 'Gene', (52, 56))	('mutated', 'Var', (188, 195))	('ERBB4', 'Gene', (128, 133))	('ERBB', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (183, 187))	('blocks', 'NegReg', (90, 96))	('AD', 'Disease', (196, 198))	('ERBB', 'Gene', (128, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('EGFR', 'Gene', (112, 116))	('progression-free survival', 'CPA', (154, 179))	('ERBB', 'Gene', '1956', (128, 132))	('HER2', 'Gene', '2064', (118, 122))	('AD', 'Disease', 'MESH:D000544', (196, 198))	('increased', 'PosReg', (144, 153))	('EGFR', 'Gene', '1956', (183, 187))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('afatinib', 'Chemical', 'MESH:D000077716', (9, 17))	('EGFR', 'Gene', '1956', (112, 116))
168608	25325012	The monoubiquitinated FANCD2/FANCI becomes an active form and interacts with a series of DNA repair proteins and facilitates downstream repair pathways.	('facilitates', 'PosReg', (113, 124))	('FANCI', 'Gene', '55215', (29, 34))	('downstream repair pathways', 'Pathway', (125, 151))	('FANCI', 'Gene', (29, 34))	('FANCD2', 'Gene', '2177', (22, 28))	('DNA repair', 'biological_process', 'GO:0006281', ('89', '99'))	('FANCD2', 'Gene', (22, 28))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('interacts', 'Interaction', (62, 71))	('monoubiquitinated', 'Var', (4, 21))
168613	25325012	Overexpression of NKX2-2 has been shown to predict a more dismal survival.	('NKX2-2', 'Gene', (18, 24))	('NKX2-2', 'Gene', '4821', (18, 24))	('Overexpression', 'Var', (0, 14))
168634	25325012	Loss of this integrin-linked kinase induces failure in the formation of a unitary layer in ILK-deficient vascular smooth muscle cells and also induces abnormal contractility, through the activation of RHOA/ROCK2 that was also overexpressed in normal lung.	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('integrin-linked kinase', 'Gene', '3611', (13, 35))	('ILK', 'Gene', (91, 94))	('induces', 'Reg', (143, 150))	('RHOA', 'Gene', (201, 205))	('activation', 'PosReg', (187, 197))	('contractility', 'MPA', (160, 173))	('integrin-linked kinase', 'Gene', (13, 35))	('ILK', 'Gene', '3611', (91, 94))	('formation of a unitary layer', 'CPA', (59, 87))	('failure', 'NegReg', (44, 51))	('ROCK2', 'Gene', (206, 211))	('Loss', 'Var', (0, 4))	('ROCK2', 'Gene', '9475', (206, 211))	('RHOA', 'Gene', '387', (201, 205))
168643	25325012	Inhibition of the JAM2/JAMB (junctional adhesion molecule) decreases leukocyte infiltration.	('decreases', 'NegReg', (59, 68))	('JAM2', 'Gene', (18, 22))	('JAMB', 'Gene', (23, 27))	('JAM2', 'Gene', '58494', (18, 22))	('JAMB', 'Gene', '58494', (23, 27))	('decreases leukocyte', 'Phenotype', 'HP:0001882', (59, 78))	('leukocyte infiltration', 'CPA', (69, 91))	('Inhibition', 'Var', (0, 10))	('mole', 'Phenotype', 'HP:0003764', (49, 53))
168644	25325012	Vascular endothelial cadherin or CDH5 is a key protein controlling the endothelial barrier and its disruption by specific antibody both amplifies metastasis in normal mice and overcomes the genetic resistance in mice.	('antibody', 'cellular_component', 'GO:0042571', ('122', '130'))	('CDH5', 'Gene', (33, 37))	('mice', 'Species', '10090', (212, 216))	('metastasis', 'CPA', (146, 156))	('disruption', 'Var', (99, 109))	('antibody', 'cellular_component', 'GO:0019815', ('122', '130'))	('genetic resistance', 'CPA', (190, 208))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('antibody', 'cellular_component', 'GO:0019814', ('122', '130'))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('antibody', 'molecular_function', 'GO:0003823', ('122', '130'))	('overcomes', 'NegReg', (176, 185))	('Vascular endothelial cadherin', 'Gene', '12562', (0, 29))	('Vascular endothelial cadherin', 'Gene', (0, 29))	('mice', 'Species', '10090', (167, 171))	('amplifies', 'PosReg', (136, 145))
168653	25325012	Cytokinesis dysregulation also leads to the formation of polyploid and aneuploid cells that are prone to tumor formation.	('dysregulation', 'Var', (12, 25))	('formation', 'biological_process', 'GO:0009058', ('44', '53'))	('Cytokinesis', 'biological_process', 'GO:0000910', ('0', '11'))	('leads to', 'Reg', (31, 39))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
168670	20532500	Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions.	('substituting', 'Var', (93, 105))	('binding', 'molecular_function', 'GO:0005488', ('135', '142'))	('HLA-A', 'Gene', '3105', (125, 130))	('peptides', 'Chemical', 'MESH:D010455', (54, 62))	('HLA-A', 'Gene', (125, 130))
168680	20532500	Although originally described as a tumor suppressor gene, the WT1 proteins appear to be involved in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (100, 105))	('proteins', 'Protein', (66, 74))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('WT1', 'Var', (62, 65))	('involved', 'Reg', (88, 96))
168687	20532500	By using computer prediction analysis, we designed a large number of synthetic peptides derived from WT1 protein sequences in which single or double amino acid substitutions were introduced into the peptides at key HLA A0201 binding positions.	('HLA', 'Gene', '3123', (215, 218))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('peptides', 'Chemical', 'MESH:D010455', (199, 207))	('HLA', 'Gene', (215, 218))	('peptides', 'Chemical', 'MESH:D010455', (79, 87))	('double amino acid substitutions', 'Var', (142, 173))	('binding', 'molecular_function', 'GO:0005488', ('225', '232'))	('introduced', 'Reg', (179, 189))
168698	20532500	The vaccine contains one WT1 heteroclitic peptide to stimulate CD8 responses (WT1-A1), two longer WT1 native peptides to stimulate CD4 responses (WT1-427 long and WT1-331 long) and one longer heteroclitic peptide which could stimulate both CD4 and CD8 cells (WT1-122A1 long).	('WT1-427 long', 'Var', (146, 158))	('WT1 heteroclitic', 'Disease', (25, 41))	('CD4', 'Gene', (240, 243))	('stimulate', 'PosReg', (53, 62))	('CD4', 'Gene', '920', (240, 243))	('CD8 responses', 'CPA', (63, 76))	('CD4', 'Gene', (131, 134))	('CD4', 'Gene', '920', (131, 134))	('peptides', 'Chemical', 'MESH:D010455', (109, 117))	('stimulate', 'PosReg', (225, 234))	('WT1 heteroclitic', 'Disease', 'MESH:D009396', (25, 41))	('CD8 cells', 'CPA', (248, 257))
168705	20532500	Patients were also required to have adequate organ and bone marrow function, including: absolute neutrophil count > 1000/mcL, platelets > 50 K/mcL, total bilirubin <= 2.0 mg/dl, AST and ALT <= 2.5xupper limits of normal, creatinine <= 2.0 mg/dl.	('AST', 'Gene', (178, 181))	('total bilirubin', 'MPA', (148, 163))	('> 50 K/mcL', 'Var', (136, 146))	('AST', 'Gene', '26503', (178, 181))	('ALT', 'CPA', (186, 189))	('creatinine', 'MPA', (221, 231))	('Patients', 'Species', '9606', (0, 8))	('absolute neutrophil count', 'CPA', (88, 113))	('ALT', 'molecular_function', 'GO:0004021', ('186', '189'))	('platelets', 'CPA', (126, 135))	('bilirubin', 'Chemical', 'MESH:D001663', (154, 163))	('creatinine', 'Chemical', 'MESH:D003404', (221, 231))
168752	20532500	A total of 106 cells were resuspended in 50 microl FACS buffer and stained with the following cell surface markers for 30 min at 4 C: Pacific blue-CD3, APC-AF750-CD8 (eBioscience) and ECDCD4 (Beckman Coulter).	('cell surface', 'cellular_component', 'GO:0009986', ('94', '106'))	('CD4', 'Gene', (187, 190))	('APC', 'cellular_component', 'GO:0005680', ('152', '155'))	('CD4', 'Gene', '920', (187, 190))	('APC-AF750-CD8', 'Var', (152, 165))
168775	20532500	CD4 T cell response to immunizing WT1 peptides 331, 427 and 122A1 and the native peptide 122A was directly assessed by unprimed CD4+T cell proliferation.	('122A1', 'Var', (60, 65))	('peptides', 'Chemical', 'MESH:D010455', (38, 46))	('CD4', 'Gene', '920', (0, 3))	('CD4', 'Gene', (128, 131))	('T cell proliferation', 'biological_process', 'GO:0042098', ('132', '152'))	('CD4', 'Gene', '920', (128, 131))	('CD4', 'Gene', (0, 3))
168783	20532500	Among the peptides tested, WT1-331 seemed to be the most immunogenic, as shown by 4 out of 6 patients who had strong responses to the peptide.	('WT1-331', 'Var', (27, 34))	('patients', 'Species', '9606', (93, 101))	('peptides', 'Chemical', 'MESH:D010455', (10, 18))	('responses', 'MPA', (117, 126))
168784	20532500	Two of five patients who responded to 122A1 also showed a weak response to its native peptide 122A (data not shown).	('122A1', 'Var', (38, 43))	('patients', 'Species', '9606', (12, 20))	('response to', 'MPA', (63, 74))
168820	20532500	Representative data from patient 12 show the cytokine production profile from CD3+ CD8+ T cells (Fig.	('cytokine production', 'biological_process', 'GO:0001816', ('45', '64'))	('CD3+ CD8+ T', 'Var', (78, 89))	('patient', 'Species', '9606', (25, 32))	('cytokine production profile', 'MPA', (45, 72))
168823	20532500	Challenging with either WT1-A or WT1-A1 induced a similar cytokine-producing profile, thus indicating that cross reactivity between the two peptides was effectively achieved.	('peptides', 'Chemical', 'MESH:D010455', (140, 148))	('WT1-A1', 'Var', (33, 39))	('cytokine-producing profile', 'MPA', (58, 84))
168851	20532500	CD4 T cell responses did not correlate with particular HLA-DR types, suggesting that such promiscuous peptides could prime CD4 T cell responses in a broader range of patients, compared to the WT1 peptides that have been reported to date.	('peptides', 'Chemical', 'MESH:D010455', (102, 110))	('CD4', 'Gene', '920', (123, 126))	('CD4', 'Gene', (123, 126))	('peptides', 'Var', (102, 110))	('CD4', 'Gene', '920', (0, 3))	('prime', 'PosReg', (117, 122))	('HLA', 'Gene', '3123', (55, 58))	('HLA', 'Gene', (55, 58))	('patients', 'Species', '9606', (166, 174))	('peptides', 'Chemical', 'MESH:D010455', (196, 204))	('CD4', 'Gene', (0, 3))
168853	20532500	Other studies have suggested that CD8+ T cells that secrete both IFN-gamma and TNF-alpha have enhanced cytolytic activity compared with CD8+ T cells that secret IFN-gamma alone.	('TNF-alpha', 'Gene', '7124', (79, 88))	('IFN-gamma', 'Gene', '3458', (65, 74))	('IFN-gamma', 'Gene', (65, 74))	('TNF-alpha', 'Gene', (79, 88))	('cytolytic activity', 'MPA', (103, 121))	('enhanced', 'PosReg', (94, 102))	('IFN-gamma', 'Gene', '3458', (161, 170))	('IFN-gamma', 'Gene', (161, 170))	('secrete', 'Var', (52, 59))
168917	22950644	Results showed that the proportion of ICC associated with HPV-16 and HPV-18 was between 70 and 76% in all world regions except for Asia.	('ICC', 'Disease', (38, 41))	('HPV-16', 'Var', (58, 64))	('associated', 'Reg', (42, 52))	('HPV', 'Species', '10566', (69, 72))	('HPV-16', 'Species', '333760', (58, 64))	('HPV-18', 'Var', (69, 75))	('HPV', 'Species', '10566', (58, 61))
168943	22950644	Overexpression of p16, a cell cycle regulator, in HPV-positive oropharyngeal squamous cell carcinoma results from degradation of pRb by the viral oncoprotein E7; for this reason, p16 positivity at immunohistochemistry has been proposed as a surrogate marker for high-risk HPV infection.	('cell cycle regulator', 'biological_process', 'GO:0051726', ('25', '45'))	('HPV infection', 'Disease', 'MESH:D030361', (272, 285))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('HPV infection', 'Disease', (272, 285))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('25', '45'))	('pRb', 'Gene', (129, 132))	('positivity', 'Var', (183, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (63, 100))	('HPV-positive oropharyngeal squamous cell carcinoma', 'Disease', (50, 100))	('degradation', 'NegReg', (114, 125))	('HPV-positive oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 100))	('degradation', 'biological_process', 'GO:0009056', ('114', '125'))
168944	22950644	However, although some studies indicated a good correspondence between p16 and HPV status (assessed by DNA-ISH or mRNA E6/E7 Real- time PCR), a recent study from the Licitra group in Milan, evaluating an algorithm for the definition of HPV status in oropharyngeal cancer, demonstrated the existence of a cancer subset characterized by p16-positivity and consistently negative HPV-ISH.	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('HPV', 'Species', '10566', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('negative', 'NegReg', (367, 375))	('HPV', 'Species', '10566', (376, 379))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (304, 310))	('HPV', 'Species', '10566', (236, 239))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('Licitra', 'Chemical', '-', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('p16-positivity', 'Var', (335, 349))	('cancer', 'Disease', (264, 270))
168970	22950644	A 17 year prospective cohort study coordinated in Pavia has demonstrated conclusively that HCV genotype 1b was associated with a significant higher risk of developing HCC.	('genotype 1b', 'Var', (95, 106))	('HCC', 'Gene', '619501', (167, 170))	('HCV', 'Gene', (91, 94))	('HCC', 'Gene', (167, 170))
168976	22950644	As previously discussed for cervical cancer, miRNAs may be involved in hepatocellular carcinoma as well.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('involved', 'Reg', (59, 67))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (28, 43))	('miRNAs', 'Var', (45, 51))	('cervical cancer', 'Disease', (28, 43))
168982	22950644	The first speaker, Mauro Tognon (University of Ferrara, Italy), focused the attention on personal data on polyomaviruses, brain tumors and Merkel cell carcinoma.	('polyomaviruses', 'Var', (106, 120))	('Merkel cell carcinoma', 'Disease', (139, 160))	('polyomaviruses', 'Species', '36362', (106, 120))	('brain tumors', 'Disease', 'MESH:D001932', (122, 134))	('brain tumors', 'Phenotype', 'HP:0030692', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('brain tumors', 'Disease', (122, 134))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (139, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
168985	22950644	Expression of SV40 early region RNA was also investigated, and 78% of glioblastoma multiforme cell lines positive for SV40 DNA were found also to express SV40 early region sequences.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (70, 93))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('SV40 DNA', 'Var', (118, 126))	('RNA', 'cellular_component', 'GO:0005562', ('32', '35'))	('glioblastoma multiforme', 'Disease', (70, 93))	('SV40 early', 'Var', (154, 164))
168994	22950644	In a first retrospective Italian study aimed to investigate the presence of SV40 in malignant and normal tissues from mesothelioma patients of this area, Comar and collaborators detected SV40 DNA in approximately 3/19 tumors (15.8%, all positive for asbestos exposure), 3/18 liver and 1/8 of kidney tissues from the same patients.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (321, 329))	('19 tumors', 'Disease', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('SV40 DNA', 'Var', (187, 195))	('mesothelioma', 'Disease', (118, 130))	('19 tumors', 'Disease', 'MESH:D009369', (215, 224))	('asbestos', 'Chemical', 'MESH:D001194', (250, 258))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))
169003	22950644	SV40 large T antigen fragments were found in colon cancer tissues with a prevalence of 6.4%.	('colon cancer', 'Disease', (45, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('SV40', 'Var', (0, 4))	('men', 'Species', '9606', (25, 28))
169005	22950644	Collectively, these studies demonstrate the existence of SV40 and MCPyV sequences, but no JCV and BK, with low prevalence rates in tumor tissues from colon carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (150, 165))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('colon carcinoma', 'Disease', (150, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('SV40', 'Var', (57, 61))	('MCPyV', 'Gene', (66, 71))
169013	22950644	Target of preventive vaccines is neutralization of virus before infection of basal keratinocytes.	('infection', 'Disease', (64, 73))	('neutralization', 'Var', (33, 47))	('infection', 'Disease', 'MESH:D007239', (64, 73))
169033	22950644	SVR is higher in genotype 2 patients, and so these patients have an advantage in the treatment response.	('men', 'Species', '9606', (90, 93))	('genotype 2', 'Var', (17, 27))	('treatment response', 'CPA', (85, 103))	('advantage', 'PosReg', (68, 77))	('higher', 'PosReg', (7, 13))	('SVR', 'MPA', (0, 3))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (28, 36))
169161	22710673	In addition, solar radiation and polycyclic aromatic hydrocarbons have also caused a large number of cancers, mostly non-melanoma skin cancer, in the industry.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (33, 65))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('caused', 'Reg', (76, 82))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (117, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-melanoma skin cancer', 'Disease', (117, 141))	('polycyclic aromatic hydrocarbons', 'Var', (33, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (130, 141))
169198	19746156	The role of TRAIL was supported by data showing that agonistic anti-TRAIL-receptor (DR5) antibodies enhanced the effects of CY in athymic nude mice.	('effects', 'MPA', (113, 120))	('enhanced', 'PosReg', (100, 108))	('antibodies', 'Var', (89, 99))	('CY', 'Chemical', 'MESH:D003520', (124, 126))	('DR5', 'Gene', (84, 87))	('nude mice', 'Species', '10090', (138, 147))
169212	19746156	Preliminary data indicate that several pro-inflammatory genes were upregulated in CY-treated tumors, including type-I IFNs (IFN-alpha4 and IFN-beta1) but also IL-1alpha, IL-19, IL-2 and OX40L (Van der Most, unpublished data).	('OX40L', 'Gene', (186, 191))	('IL-1alpha', 'Gene', (159, 168))	('OX40L', 'Gene', '22164', (186, 191))	('CY-treated', 'Var', (82, 92))	('upregulated', 'PosReg', (67, 78))	('CY', 'Chemical', 'MESH:D003520', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('IL-2', 'Gene', '16183', (177, 181))	('IFN-alpha4', 'Gene', (124, 134))	('IL-2', 'Gene', (177, 181))	('IL-19', 'Gene', (170, 175))	('pro-inflammatory genes', 'Gene', (39, 61))	('IL-2', 'molecular_function', 'GO:0005134', ('177', '181'))	('tumors', 'Disease', (93, 99))	('IL-1', 'molecular_function', 'GO:0005149', ('159', '163'))	('IFN-alpha4', 'Gene', '15967', (124, 134))	('IL-1alpha', 'Gene', '16175', (159, 168))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('IL-19', 'molecular_function', 'GO:0045516', ('170', '175'))	('IL-19', 'Gene', '329244', (170, 175))
169222	19746156	Therefore, the combined data suggest that CY-injection in tumor-bearing mice results in systemic immune activation, consistent with the concept of immunogenic cell death and consistent with previously reported data.	('CY-injection', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cell death', 'biological_process', 'GO:0008219', ('159', '169'))	('CY', 'Chemical', 'MESH:D003520', (42, 44))	('systemic immune activation', 'MPA', (88, 114))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mice', 'Species', '10090', (72, 76))
169227	19746156	We found that the anti-tumor efficacy of CY was only marginally affected by type-I IFN neutralization ( Figure 3B ), indicating that the CY-induced anti-tumor CD8 T cell response was not dependent on IFN-alpha/beta.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CY', 'Chemical', 'MESH:D003520', (137, 139))	('CY', 'Chemical', 'MESH:D003520', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('CD8', 'Gene', (159, 162))	('tumor', 'Disease', (153, 158))	('CD8', 'Gene', '925', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('IFN-alpha/beta', 'Gene', '15977', (200, 214))	('tumor', 'Disease', (23, 28))	('neutralization', 'Var', (87, 101))	('IFN-alpha/beta', 'Gene', (200, 214))
169228	19746156	As a positive control for the efficiency of in vivo IFN-alpha/beta-neutralization, we have shown that poly-I:C-mediated anti-tumor responses were abrogated using this anti-IFN-alpha/beta treatment.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('abrogated', 'NegReg', (146, 155))	('IFN-alpha/beta', 'Gene', '15977', (172, 186))	('poly-I:C-mediated', 'Var', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('IFN-alpha/beta', 'Gene', '15977', (52, 66))	('tumor', 'Disease', (125, 130))	('poly-I:C', 'Chemical', 'MESH:D011070', (102, 110))	('IFN-alpha/beta', 'Gene', (52, 66))	('IFN-alpha/beta', 'Gene', (172, 186))
169238	19746156	We have recently reported similar findings for CD4 T cells and foxp3+ CD4+ regulatory T cells.	('CD4', 'Gene', '12504', (47, 50))	('CD4', 'Gene', (70, 73))	('CD4', 'Gene', '12504', (70, 73))	('foxp3+', 'Var', (63, 69))	('CD4', 'Gene', (47, 50))
169246	19746156	However, both the recovery of tumor-specific transgenic T cells as well as proliferation of these cells (assessed by serial CFSE dilution) were significantly reduced in the draining lymph nodes from CY-treated mice ( Figure 4B ).	('mice', 'Species', '10090', (210, 214))	('CY', 'Chemical', 'MESH:D003520', (199, 201))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('recovery', 'CPA', (18, 26))	('C', 'Chemical', 'MESH:D002244', (199, 200))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CY-treated', 'Var', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('proliferation', 'CPA', (75, 88))	('reduced', 'NegReg', (158, 165))	('tumor', 'Disease', (30, 35))
169262	19746156	Finally, we evaluated the efficacy of CY in IFN-gamma/perforin double knock-out mice and found that combined deficiency of IFN-gamma and perforin completely abrogated the CY-induced anti-tumor effects (9/9 mice, two experiments), consistent with the results from the IFN-gamma-knock-out mice and highlighting the key role of this effector molecule ( Figure 5C ).	('abrogated', 'NegReg', (157, 166))	('tumor', 'Disease', (187, 192))	('IFN-gamma', 'Gene', '15978', (267, 276))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('deficiency', 'Var', (109, 119))	('IFN-gamma', 'Gene', (267, 276))	('CY', 'Chemical', 'MESH:D003520', (38, 40))	('IFN-gamma', 'Gene', '15978', (44, 53))	('C', 'Chemical', 'MESH:D002244', (358, 359))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IFN-gamma', 'Gene', '15978', (123, 132))	('IFN-gamma', 'Gene', (44, 53))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('mice', 'Species', '10090', (287, 291))	('IFN-gamma', 'Gene', (123, 132))	('mice', 'Species', '10090', (206, 210))	('CY-induced', 'MPA', (171, 181))	('mice', 'Species', '10090', (80, 84))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('CY', 'Chemical', 'MESH:D003520', (171, 173))
169275	19746156	Indeed, repetition of the experiment with CY-treatment done at day 7 and anti-DR5 on days 6, 10 and 14 (Figure 7B) confirmed the benefit of anti-DR5 antibodies in combination with CY and also increased efficcy of earlier CY treatment (day 7 instead of 9).	('CY', 'Chemical', 'MESH:D003520', (42, 44))	('CY', 'Chemical', 'MESH:D003520', (180, 182))	('efficcy', 'MPA', (202, 209))	('CY', 'Chemical', 'MESH:D003520', (221, 223))	('antibodies', 'Var', (149, 159))	('benefit', 'PosReg', (129, 136))	('anti-DR5', 'Gene', (140, 148))	('increased', 'PosReg', (192, 201))
169277	19746156	Unfortunately, the CY/anti-DR5 combination treatment was also associated with liver toxicity, preventing us from studying long-term control of tumor growth.	('tumor', 'Disease', (143, 148))	('CY/anti-DR5', 'Var', (19, 30))	('associated', 'Reg', (62, 72))	('liver toxicity', 'Disease', 'MESH:D056486', (78, 92))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('liver toxicity', 'Disease', (78, 92))	('CY', 'Chemical', 'MESH:D003520', (19, 21))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
169294	19746156	Irrespective of the mechanism, type-I IFNs are essential to generate de novo CD8 T cell responses to apoptotic cells and to cross-presented antigens and we hypothesized that CY-associated IFN responses might augment potential anti-tumor CD8 T cell responses.	('CD8', 'Gene', (77, 80))	('CY', 'Chemical', 'MESH:D003520', (174, 176))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('CD8', 'Gene', '925', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('CD8', 'Gene', (237, 240))	('CY-associated', 'Var', (174, 187))	('tumor', 'Disease', (231, 236))	('CD8', 'Gene', '925', (237, 240))	('augment', 'PosReg', (208, 215))
169296	19746156	However, CY-induced anti-tumor responses in our model are clearly less dependent on type-I IFNs, in contrast to the anti-tumor effects of poly-I:C and imiquimod in the same model.	('poly-I:C', 'Chemical', 'MESH:D011070', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (121, 126))	('CY-induced', 'Var', (9, 19))	('CY', 'Chemical', 'MESH:D003520', (9, 11))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('less', 'NegReg', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
169322	19746156	TCR transgenic CL4 mice, expressing a TCR specific for the H-2d-restricted peptide IYSTVASSL (residues 518-526) from the influenza virus A/PR8/8/34 HA protein, were generated and screened as described.	('TCR', 'Gene', '328483', (0, 3))	('H-2d', 'Gene', (59, 63))	('residues 518-526', 'Var', (94, 110))	('TCR', 'Gene', '328483', (38, 41))	('TCR', 'cellular_component', 'GO:0042101', ('38', '41'))	('influenza virus', 'Species', '11309', (121, 136))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('TCR', 'biological_process', 'GO:0006283', ('38', '41'))	('TCR', 'biological_process', 'GO:0006283', ('0', '3'))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('H-2d', 'Gene', '83772', (59, 63))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('TCR', 'cellular_component', 'GO:0042101', ('0', '3'))	('TCR', 'Gene', (0, 3))	('mice', 'Species', '10090', (19, 23))	('TCR', 'Gene', (38, 41))
169334	19746156	The IFN-alpha/beta neutralizing sheep Ig and matching normal sheep Ig were used as described.	('neutralizing', 'Var', (19, 31))	('sheep', 'Species', '9940', (32, 37))	('IFN-alpha/beta', 'Gene', '15977', (4, 18))	('sheep', 'Species', '9940', (61, 66))	('IFN-alpha/beta', 'Gene', (4, 18))
169363	32650215	Among these patients, 152 (76 %) were hospitalized and 66 (33.3 %) died, most of them without undergoing admission to intensive therapy units, suggesting an unexpectedly high mortality among this patient population, Univariate analysis showed that the presence of COPD was associated with the risk of hospitalization and more than one comorbidity with the risk of hospitalization and death.	('patients', 'Species', '9606', (12, 20))	('mortality', 'Disease', 'MESH:D003643', (175, 184))	('COPD', 'Phenotype', 'HP:0006510', (264, 268))	('death', 'Disease', 'MESH:D003643', (384, 389))	('patient', 'Species', '9606', (196, 203))	('death', 'Disease', (384, 389))	('died', 'Disease', 'MESH:D003643', (67, 71))	('mortality', 'Disease', (175, 184))	('COPD', 'Disease', 'MESH:D029424', (264, 268))	('presence', 'Var', (252, 260))	('died', 'Disease', (67, 71))	('hospitalization', 'Disease', (301, 316))	('patient', 'Species', '9606', (12, 19))	('COPD', 'Disease', (264, 268))
169454	32650215	Recommendation: Patients with oncogene driver mutations after progression to a first line TKI are high priority and ideally treatment should not be delayed.	('Patients', 'Species', '9606', (16, 24))	('oncogene driver', 'Gene', (30, 45))	('mutations', 'Var', (46, 55))
169455	32650215	TKIs in second line treatment have demonstrated superior outcomes compared with chemotherapy in multiple scenarios in EGFR, ALK, ROS1 and BRAF mutated population with a considerable impact in ORR and PFS.	('ROS1', 'Gene', '6098', (129, 133))	('ALK', 'Gene', '238', (124, 127))	('BRAF', 'Gene', '673', (138, 142))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('ALK', 'Gene', (124, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('mutated', 'Var', (143, 150))	('BRAF', 'Gene', (138, 142))	('ROS1', 'Gene', (129, 133))
169456	32650215	Additionally, a different toxicity profile predominating symptoms like rash, diarrhea and fatigue predominate in targeted therapy compared with more hematologic toxicity in chemotherapy.	('rash', 'Disease', 'MESH:D005076', (71, 75))	('fatigue', 'Disease', 'MESH:D005221', (90, 97))	('hematologic toxicity', 'Disease', (149, 169))	('diarrhea', 'Disease', (77, 85))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('rash', 'Disease', (71, 75))	('toxicity', 'Disease', (26, 34))	('hematologic toxicity', 'Disease', 'MESH:D006402', (149, 169))	('toxicity', 'Disease', (161, 169))	('diarrhea', 'Disease', 'MESH:D003967', (77, 85))	('fatigue', 'Disease', (90, 97))	('toxicity', 'Disease', 'MESH:D064420', (161, 169))	('rash', 'Phenotype', 'HP:0000988', (71, 75))	('targeted therapy', 'Var', (113, 129))	('fatigue', 'Phenotype', 'HP:0012378', (90, 97))	('diarrhea', 'Phenotype', 'HP:0002014', (77, 85))
169481	32650215	Further, data from the ALK in Lung Cancer Trial of Brigatinib in 1 st Line (ALTA-1 L) showed patients treated with brigatinib and crizotinib presented with G3/4 interstitial lung disease or pneumonitis in 3% and 0.7 % of cases, respectively.	('brigatinib', 'Chemical', 'MESH:C000598580', (115, 125))	('ALK', 'Gene', (23, 26))	('Brigatinib', 'Chemical', 'MESH:C000598580', (51, 61))	('Lung Cancer', 'Phenotype', 'HP:0100526', (30, 41))	('crizotinib', 'Chemical', 'MESH:D000077547', (130, 140))	('pneumonitis', 'Disease', (190, 201))	('Lung Cancer', 'Disease', (30, 41))	('lung disease', 'Disease', (174, 186))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (161, 186))	('ALK', 'Gene', '238', (23, 26))	('pneumonitis', 'Disease', 'MESH:D011014', (190, 201))	('crizotinib', 'Var', (130, 140))	('lung disease', 'Phenotype', 'HP:0002088', (174, 186))	('brigatinib', 'Gene', (115, 125))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lung disease', 'Disease', 'MESH:D008171', (174, 186))	('patients', 'Species', '9606', (93, 101))	('Lung Cancer', 'Disease', 'MESH:D008175', (30, 41))
169486	32650215	There are many trials that have elucidated the activity of third-generation EGFR-TKI inhibitors (osimertinib) and second (alectinib, brigatinib) and third generation ALK inhibitors (lorlatinib) in preventing or delaying the onset of CNS disease, and in leading to intracranial response for patients with preexisting brain metastases.	('CNS disease', 'Disease', 'MESH:D002493', (233, 244))	('brain metastases', 'Disease', 'MESH:D009362', (316, 332))	('patients', 'Species', '9606', (290, 298))	('ALK', 'Gene', '238', (166, 169))	('inhibitors', 'Var', (85, 95))	('brain metastases', 'Disease', (316, 332))	('leading to', 'Reg', (253, 263))	('intracranial response', 'CPA', (264, 285))	('EGFR', 'Gene', '1956', (76, 80))	('brigatinib', 'Chemical', 'MESH:C000598580', (133, 143))	('lorlatinib', 'Chemical', 'MESH:C000590786', (182, 192))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('EGFR', 'Gene', (76, 80))	('osimertinib', 'Chemical', '-', (97, 108))	('CNS disease', 'Disease', (233, 244))	('alectinib', 'Chemical', 'MESH:C582670', (122, 131))	('ALK', 'Gene', (166, 169))	('delaying', 'NegReg', (211, 219))
169757	28033270	A meta-analysis by Chen et al also found elevated LDH to have an adverse impact on OS in patients with osteosarcoma (combined HR: 1.92 [95% CI: 1.53-2.40]).	('OS', 'Chemical', '-', (83, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('LDH', 'MPA', (50, 53))	('patients', 'Species', '9606', (89, 97))	('elevated', 'Var', (41, 49))
169768	28033270	Recently, Le et al reported that inhibition of LDH-A inhibited tumor progression and induced apoptosis via accumulation of reactive oxygen species (ROS) in lymphoma cells.	('inhibition', 'Var', (33, 43))	('tumor', 'Disease', (63, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('inhibited', 'NegReg', (53, 62))	('reactive oxygen species', 'MPA', (123, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('induced', 'Reg', (85, 92))	('accumulation', 'PosReg', (107, 119))	('lymphoma', 'Disease', (156, 164))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('LDH-A', 'Gene', '3939', (47, 52))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (123, 146))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LDH-A', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('apoptosis', 'CPA', (93, 102))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))
169774	28033270	In conclusion, a negative association between high serum LDH level and poor survival outcome in malignant mesothelioma was observed in current meta-analysis.	('high', 'Var', (46, 50))	('malignant mesothelioma', 'Disease', (96, 118))	('negative', 'NegReg', (17, 25))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (96, 118))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (96, 118))
30480	27900005	It has also been demonstrated that low levels of p27 are associated with stathmin upregulation, determining an aggressive phenotype of tumor cells.	('stathmin', 'Gene', '3925', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('stathmin', 'Gene', (73, 81))	('p27', 'Gene', '3429', (49, 52))	('tumor', 'Disease', (135, 140))	('p27', 'Gene', (49, 52))	('upregulation', 'PosReg', (82, 94))	('low levels', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
169870	27900005	Of note, we have previously demonstrated that stathmin expression is useful for the survival of cancer cells carrying a p53 mutant that may be also involved in the drug resistance mechanisms of hematopoietic cells.	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('p53', 'Gene', '7157', (120, 123))	('stathmin', 'Gene', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutant', 'Var', (124, 130))	('stathmin', 'Gene', '3925', (46, 54))	('drug resistance', 'biological_process', 'GO:0009315', ('164', '179'))	('involved', 'Reg', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('p53', 'Gene', (120, 123))	('drug resistance', 'biological_process', 'GO:0042493', ('164', '179'))	('cancer', 'Disease', (96, 102))
169876	25588929	Targeted, massively parallel DNA sequencing and molecular inversion probe microarray analysis revealed a germline TP53 mutation compatible with Li-Fraumeni-like syndrome, somatic mutations of PIK3CA in the endometrial cancer, and a somatic mutation of GNA11 and JAK3 in the PMM.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (206, 224))	('TP53', 'Gene', '7157', (114, 118))	('PIK3CA', 'Gene', '5290', (192, 198))	('JAK3', 'Gene', (262, 266))	('endometrial cancer', 'Disease', (206, 224))	('GNA11', 'Gene', (252, 257))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (144, 169))	('endometrial cancer', 'Disease', 'MESH:D016889', (206, 224))	('mutation', 'Var', (119, 127))	('JAK3', 'Gene', '3718', (262, 266))	('PIK3CA', 'Gene', (192, 198))	('PMM', 'Phenotype', 'HP:0100003', (274, 277))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (179, 188))	('GNA11', 'Gene', '2767', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Li-Fraumeni-like syndrome', 'Disease', (144, 169))	('JAK', 'molecular_function', 'GO:0004713', ('262', '265'))
169877	25588929	Large-scale genomic amplifications and some deletions were found in the endometrial cancer.	('endometrial cancer', 'Disease', (72, 90))	('deletions', 'Var', (44, 53))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('found', 'Reg', (59, 64))
169881	25588929	Identification of germline TP53 mutation further urged us to monitor future development of malignancies in this patient and encourage cancer screening in her family.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('malignancies', 'Disease', (91, 103))	('patient', 'Species', '9606', (112, 119))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutation', 'Var', (32, 40))
169888	25588929	The genetic make-up of the concomitant tumors of this patient was determined, and identification of a germline TP53 mutation indicating Li-Fraumeni-like syndrome in this patient encouraged further screening for this mutation in her family members.	('patient', 'Species', '9606', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (136, 161))	('indicating', 'Reg', (125, 135))	('mutation', 'Var', (116, 124))	('TP53', 'Gene', '7157', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TP53', 'Gene', (111, 115))	('Li-Fraumeni-like syndrome', 'Disease', (136, 161))	('tumors', 'Disease', (39, 45))	('patient', 'Species', '9606', (170, 177))
169904	25588929	She also received concurrent radiation to the pelvis (5040 cGy) with brachytherapy (200 cGy) for cervical extension and positive vaginal margins of the endometrial cancer.	('vagina', 'Disease', 'MESH:D014625', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('vagina', 'Disease', (129, 135))	('cervical', 'Disease', (97, 105))	('endometrial cancer', 'Disease', (152, 170))	('5040 cGy', 'Var', (54, 62))	('200 cGy', 'Var', (84, 91))	('vaginal margin', 'Phenotype', 'HP:0000145', (129, 143))	('endometrial cancer', 'Phenotype', 'HP:0012114', (152, 170))	('endometrial cancer', 'Disease', 'MESH:D016889', (152, 170))
169909	25588929	The TP53 mutation (Pro72Arg) found in blood and both tumors was confirmed with Sanger sequencing.	('TP53', 'Gene', (4, 8))	('Pro72Arg', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', '7157', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('Pro72Arg', 'Mutation', 'rs1042522', (19, 27))	('tumors', 'Disease', (53, 59))
169910	25588929	Of note, among 4 somatic point mutations in this case, only the PIK3CA mutation (c.1624 G > A p.E542K) was detected by both MPS and MIP microarray.	('PIK3CA', 'Gene', (64, 70))	('c.1624 G > A p.E542K', 'Var', (81, 101))	('MIP', 'molecular_function', 'GO:0004243', ('132', '135'))	('MPS', 'Disease', (124, 127))	('PIK3CA', 'Gene', '5290', (64, 70))	('p.E542K', 'Mutation', 'rs121913273', (94, 101))	('c.1624 G > A', 'Mutation', 'rs121913273', (81, 93))	('MPS', 'Disease', 'MESH:D009084', (124, 127))
169911	25588929	Large regions of amplification in chromosomes 1q21.1-1qter, 2, 7, 8, 9, 10, 12, 14q11.2-14pter, 17, 19p13.3-19p12, and 19p13.2-19q13.42, deletions in 18q22.1-18q23, and loss-of-heterozygosity (LOH) in 3p26.3-3p14.1 and 10q22.1-10q26.3 were detected in the endometrial cancer using the Nexus 6 Copy Number software algorithms for the MIP microarray (Figure 2 and Additional file 2).	('deletions', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('MIP', 'molecular_function', 'GO:0004243', ('333', '336'))	('endometrial cancer', 'Disease', (256, 274))	('loss-of-heterozygosity', 'NegReg', (169, 191))	('endometrial cancer', 'Phenotype', 'HP:0012114', (256, 274))	('endometrial cancer', 'Disease', 'MESH:D016889', (256, 274))
169914	25588929	The germline TP53 mutation (Pro72Arg) was compatible with Li-Fraumeni-like syndrome.	('Li-Fraumeni-like syndrome', 'Disease', (58, 83))	('TP53', 'Gene', (13, 17))	('Pro72Arg', 'Mutation', 'rs1042522', (28, 36))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (58, 83))	('TP53', 'Gene', '7157', (13, 17))	('Pro72Arg', 'Var', (28, 36))
169929	25588929	Targeted MPS can detect mutations in 48 cancer related genes (Additional file 1).	('MPS', 'Disease', 'MESH:D009084', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('MPS', 'Disease', (9, 12))	('cancer', 'Disease', (40, 46))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('detect', 'Reg', (17, 23))
169930	25588929	Copy number variations (gains or losses) and LOH in cancer genomes can be further identified using MIP microarrays.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Copy number variations', 'Var', (0, 22))	('MIP', 'molecular_function', 'GO:0004243', ('99', '102'))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
169931	25588929	Her endometrial cancer had somatic cancer mutations in PIK3CA, which is frequently reported in endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (95, 113))	('endometrial cancer', 'Disease', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('endometrial cancer', 'Phenotype', 'HP:0012114', (4, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('endometrial cancer', 'Disease', 'MESH:D016889', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('PIK3CA', 'Gene', (55, 61))	('endometrial cancer', 'Disease', (95, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('PIK3CA', 'Gene', '5290', (55, 61))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (35, 41))	('endometrial cancer', 'Disease', 'MESH:D016889', (95, 113))
169934	25588929	Mutation of GNA11 in uveal melanoma leads to the activation of downstream mitogen-activated protein kinase (MAPK/ERK) pathways.	('uveal melanoma', 'Disease', (21, 35))	('GNA11', 'Gene', '2767', (12, 17))	('GNA11', 'Gene', (12, 17))	('Mutation', 'Var', (0, 8))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('activation', 'PosReg', (49, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
169937	25588929	Germline TP53 mutations have been reported in 80% of families who have classical Li-Fraumeni syndrome, and 20-40% of families who meet the criteria for Li- Fraumeni-like syndrome.	('reported', 'Reg', (34, 42))	('Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (156, 178))	('Fraumeni-like syndrome', 'Disease', (156, 178))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('mutations', 'Var', (14, 23))	('Li-Fraumeni syndrome', 'Disease', (81, 101))
169940	25588929	The Pro72Arg variants of TP53 has been associated with various cancer susceptibility and poor outcomes, such as human papillomavirus 16-positive cervical cancer, laryngeal tumors, head and neck cancers, non-small cell lung cancer, and bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('neck cancers', 'Disease', (189, 201))	('Pro72Arg', 'Mutation', 'rs1042522', (4, 12))	('neck cancers', 'Disease', 'MESH:D006258', (189, 201))	('associated', 'Reg', (39, 49))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (162, 178))	('cancer', 'Disease', (223, 229))	('neck', 'cellular_component', 'GO:0044326', ('189', '193'))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (203, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('human papillomavirus', 'Disease', (112, 132))	('cancer', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TP53', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (207, 229))	('human papillomavirus 16', 'Species', '333760', (112, 135))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (203, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('laryngeal tumors', 'Disease', 'MESH:D007822', (162, 178))	('cervical cancer', 'Disease', 'MESH:D002583', (145, 160))	('head and neck cancers', 'Phenotype', 'HP:0012288', (180, 201))	('cervical cancer', 'Disease', (145, 160))	('cancer', 'Disease', (194, 200))	('bladder cancer', 'Disease', 'MESH:D001749', (235, 249))	('bladder cancer', 'Disease', (235, 249))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('laryngeal tumors', 'Disease', (162, 178))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Pro72Arg', 'Var', (4, 12))	('non-small cell lung cancer', 'Disease', (203, 229))	('TP53', 'Gene', '7157', (25, 29))
169941	25588929	Hisada et al reported an increased risk of developing second cancer in patients with a germline TP53 mutation, with a cumulative probability of 57% of developing a second cancer at 30 years after diagnosis of the first cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('TP53', 'Gene', (96, 100))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('germline', 'Var', (87, 95))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutation', 'Var', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TP53', 'Gene', '7157', (96, 100))
170194	23247629	Multivariate analysis indicated that the following factors were predictive of worse DMFS and OS in those patients receiving EPP+IMRT: non-epithelioid histology, higher nodal status, and lower pretreatment FEV1 tested as a continuous variable (Table 3).	('patients', 'Species', '9606', (105, 113))	('FEV1', 'Phenotype', 'HP:0032342', (205, 209))	('OS', 'Chemical', '-', (93, 95))	('EPP+IMRT', 'Var', (124, 132))	('DMFS', 'Disease', (84, 88))	('DMFS', 'Chemical', '-', (84, 88))
170223	23247629	Finally, consistent with prior reports from our institution and others, we found that patients with sarcomatoid or biphasic histology and mediastinal nodal involvement had substantially reduced survival outcomes with this aggressive technique.	('sarcomatoid', 'Disease', (100, 111))	('survival', 'MPA', (194, 202))	('reduced', 'NegReg', (186, 193))	('biphasic', 'Var', (115, 123))	('sarcomatoid', 'Disease', 'MESH:C538614', (100, 111))	('patients', 'Species', '9606', (86, 94))
170267	24137389	In addition, immunohistochemical staining revealed that the tumor cells were positive for calretinin, Wilms tumor gene-1 (WT-1) and D2-40 (Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('WT-1', 'Gene', (122, 126))	('positive', 'Reg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('calretinin', 'Gene', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('WT-1', 'Gene', '7490', (122, 126))	('Wilms tumor', 'Phenotype', 'HP:0002667', (102, 113))	('tumor', 'Disease', (108, 113))	('Wilms tumor gene-1', 'Gene', '7490', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Wilms tumor gene-1', 'Gene', (102, 120))	('D2-40', 'Var', (132, 137))	('calretinin', 'Gene', '794', (90, 100))	('tumor', 'Disease', (60, 65))
170319	31263030	Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('CRS-207', 'Chemical', '-', (15, 22))	('changes', 'Reg', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (118, 123))	('men', 'Species', '9606', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CRS-207', 'Var', (15, 22))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', (81, 86))
170335	31263030	CRS-207 was constructed using precise deletions of the entire coding sequences for virulence determinants, actin assembly inducing protein A (actA), and internalin B (InlB), by homologous recombination, thus attenuating the pathogenicity of Lm in mice by 1,000-fold as compared with wild-type, while retaining its immunogenicity.	('mice', 'Species', '10090', (247, 251))	('virulence', 'biological_process', 'GO:0016032', ('83', '92'))	('pathogenicity', 'MPA', (224, 237))	('attenuating', 'NegReg', (208, 219))	('deletions', 'Var', (38, 47))	('CRS-207', 'Chemical', '-', (0, 7))	('virulence', 'biological_process', 'GO:0009405', ('83', '92'))	('virulence', 'biological_process', 'GO:0009406', ('83', '92'))	('homologous recombination', 'biological_process', 'GO:0035825', ('177', '201'))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('Lm', 'Species', '1639', (241, 243))
170337	31263030	In clinical trials, over 400 patients with advanced cancer have received CRS-207 alone or in combination with other therapies.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CRS-207', 'Var', (73, 80))	('cancer', 'Disease', (52, 58))	('CRS-207', 'Chemical', '-', (73, 80))
170338	31263030	A phase I study in patients with advanced mesothelioma, non-small-cell lung cancer, ovarian cancer, and pancreatic adenocarcinoma who had previously failed standard therapy revealed that CRS-207 was well tolerated at a dose of 1.0 x 109 colony-forming units (CFU; ref.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('ovarian cancer', 'Disease', (84, 98))	('patients', 'Species', '9606', (19, 27))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('pancreatic adenocarcinoma', 'Disease', (104, 129))	('mesothelioma', 'Disease', (42, 54))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (104, 129))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CRS-207', 'Var', (187, 194))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (104, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('lung cancer', 'Disease', (71, 82))	('CRS-207', 'Chemical', '-', (187, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
170345	31263030	In addition, CRS-207 in combination with chemotherapy induced significant changes in the frequency of circulating immune cell subsets.	('CRS-207', 'Var', (13, 20))	('frequency of circulating immune', 'MPA', (89, 120))	('CRS-207', 'Chemical', '-', (13, 20))	('changes', 'Reg', (74, 81))
170346	31263030	Remodeling in the tumor microenvironment as evidenced by in situ changes in immune cell complexity and effector phenotype was observed following CRS-207 prime infusion.	('tumor', 'Disease', (18, 23))	('CRS-207', 'Var', (145, 152))	('men', 'Species', '9606', (36, 39))	('changes', 'Reg', (65, 72))	('CRS-207', 'Chemical', '-', (145, 152))	('immune cell complexity', 'CPA', (76, 98))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
170391	31263030	Antibodies used were alphaPD-1 (NAT105, Abcam, 1:50), alphaCD3 (SP7, Thermo Scientific, 1:150), alphaRORgt (6F3.1 EMD Millipore, 1:200), alphaCD56 (123C3, Santa Cruz Biotech, 1:25), alphaCD8 (C8/144B, Thermo Scientific, 1:100), alphaT-bet (H210, Santa Cruz Biotech, 1:100), alphaGATA3 (L50-823, BD Biosciences, 1:100), alphaFoxp3 (236A/E7, eBioscience, 1:40), alphaCD20 (0.N.85, Santa Cruz Biotech, 1:1,000), alphaCD45 (H130, Thermo Scientific, 1:100), alphaMesothelin (EPR2685, Abcam, 1:500), alphaTryptase (AA1, Abcam, 1:20,000), alphaCD68 (PG-M1, Abcam, 1:50), alphaCSF1R (SP211, Abcam, 1:150), alphaDC-SIGN (DC-28, Santa Cruz Biotech, 1:100), alphaCD66b (G10F5, eBioscience, 1:600), alphaCD83 (1H4b, Abcam, 1:40), alphaCD163 (10D6, Thermo Scientific, 1:100), alphaMHC class II (SPM288, Novus Biological, 1:100), alphaTbr2 (Eomes) (AB2283, EMD Millipore, 1:1,000), and alphaKi67(SP6, Abcam, 1:500).	('PD', 'Disease', 'MESH:D010300', (26, 28))	('CSF1R', 'Gene', '1436', (569, 574))	('CSF1R', 'Gene', (569, 574))	('CD8', 'Gene', (692, 695))	('PG-M1', 'Gene', (543, 548))	('SP7', 'Gene', (64, 67))	('AA1', 'Gene', '100034700', (509, 512))	('Mesothelin', 'Gene', (458, 468))	('CD163', 'Gene', '9332', (723, 728))	('PG-M1', 'Gene', '5236', (543, 548))	('CD8', 'Gene', '925', (187, 190))	('Ki67', 'Gene', (877, 881))	('AB2283', 'Var', (835, 841))	('SP7', 'Gene', '121340', (64, 67))	('CD163', 'Gene', (723, 728))	('CD8', 'Gene', '925', (692, 695))	('AA1', 'Gene', (509, 512))	('Ki67', 'Gene', '17345', (877, 881))	('Mesothelin', 'Gene', '10232', (458, 468))	('PR', 'Chemical', '-', (471, 473))	('CD8', 'Gene', (187, 190))
170439	31263030	CD8 Tcm (central memory), pDCs (plasmacytoid dendritic cells), and mDCs (myeloid dendritic cells) changed significantly following combination treatment with CRS-207 and chemotherapy.	('memory', 'biological_process', 'GO:0007613', ('17', '23'))	('combination', 'Interaction', (130, 141))	('CRS-207', 'Chemical', '-', (157, 164))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('men', 'Species', '9606', (147, 150))	('CRS-207', 'Var', (157, 164))
170446	31263030	Notably, increased NK cells were detected in posttherapy biopsies, indicating that recruitment of NK cells was facilitated by CRS-207-based immunotherapy in agreement with a previous report.	('men', 'Species', '9606', (90, 93))	('CRS-207-based', 'Var', (126, 139))	('CRS-207', 'Chemical', '-', (126, 133))	('men', 'Species', '9606', (162, 165))	('recruitment', 'CPA', (83, 94))	('facilitated', 'PosReg', (111, 122))
170456	31263030	In this phase Ib clinical trial, administration of CRS-207 was well tolerated, with no additive or cumulative toxicities when combined with standard-of-care pemetrexed and cisplatin chemotherapy in patients with MPM.	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('patients', 'Species', '9606', (198, 206))	('toxicities', 'Disease', (110, 120))	('CRS-207', 'Var', (51, 58))	('pemetrexed', 'Chemical', 'MESH:D000068437', (157, 167))	('CRS-207', 'Chemical', '-', (51, 58))	('MPM', 'Disease', (212, 215))	('toxicities', 'Disease', 'MESH:D064420', (110, 120))	('MPM', 'Chemical', '-', (212, 215))
170458	31263030	The side effects of CRS-207 were similar to what was observed in studies of single-agent CRS-207 and consisted mainly of grade 1 to 2 fever, chills, and nausea following infusion that quickly resolved with supportive care.	('fever', 'Disease', 'MESH:D005334', (134, 139))	('fever', 'Disease', (134, 139))	('CRS-207', 'Var', (20, 27))	('CRS-207', 'Chemical', '-', (89, 96))	('CRS-207', 'Chemical', '-', (20, 27))	('chills', 'Phenotype', 'HP:0025143', (141, 147))	('chills', 'Disease', (141, 147))	('fever', 'Phenotype', 'HP:0001945', (134, 139))	('nausea', 'Phenotype', 'HP:0002018', (153, 159))	('nausea', 'Disease', (153, 159))	('nausea', 'Disease', 'MESH:D009325', (153, 159))
170477	31263030	Notably, among highly infiltrative myeloid populations observed in the MPM tissues, we observed postvaccination increases of CD83+ DCs, as well as decreased presence of CD68+CSF1R+CD163+ macrophages, typically associated with T-cell-suppressive and protumoral (M2) activities.	('CD68+CSF1R+CD163+', 'Var', (169, 186))	('decreased', 'NegReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('MPM', 'Chemical', '-', (71, 74))	('CSF1', 'molecular_function', 'GO:0005011', ('174', '178'))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('increases', 'PosReg', (112, 121))	('tumor', 'Disease', (252, 257))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))
170478	31263030	Based on preclinical mouse modeling studies (Coussens lab, personal communication and manuscript in preparation), we anticipate that alternations in intratumoral immune presence associated with altered effector phenotype facilitate enhanced proliferation and differentiation of CD8+ T cells as revealed by phenotypic effector and Ki67 changes (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mouse', 'Species', '10090', (21, 26))	('Ki67', 'Gene', '17345', (330, 334))	('proliferation', 'CPA', (241, 254))	('facilitate enhanced', 'PosReg', (221, 240))	('alternations', 'Var', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD8', 'Gene', (278, 281))	('Ki67', 'Gene', (330, 334))	('differentiation', 'CPA', (259, 274))	('CD8', 'Gene', '925', (278, 281))	('men', 'Species', '9606', (350, 353))	('tumor', 'Disease', (154, 159))
170481	31263030	These observations together support the notion that CRS-207 prime infusion was sufficient to elicit reprogramming of the tumor immune microenvironment represented by increased in situ presence of activated Ki67+CD8+ T cells, potentially as a consequence of in situ priming of tumor antigens.	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('CD8', 'Gene', '925', (211, 214))	('Ki67', 'Gene', '17345', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('elicit', 'Reg', (93, 99))	('increased', 'PosReg', (166, 175))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', (121, 126))	('CRS-207', 'Var', (52, 59))	('men', 'Species', '9606', (146, 149))	('tumor', 'Disease', (276, 281))	('Ki67', 'Gene', (206, 210))	('CD8', 'Gene', (211, 214))	('CRS-207', 'Chemical', '-', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
170497	30863440	Researchers agree that the tumor microinflammatory state of the body and the body's immune system can significantly affect prognosis, and variations in systemic inflammatory response biomarker levels have been associated with adverse clinical outcome in various malignancies.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('associated with', 'Reg', (210, 225))	('systemic inflammatory response biomarker levels', 'MPA', (152, 199))	('malignancies', 'Disease', 'MESH:D009369', (262, 274))	('affect', 'Reg', (116, 122))	('variations', 'Var', (138, 148))	('inflammatory response', 'biological_process', 'GO:0006954', ('161', '182'))	('prognosis', 'CPA', (123, 132))	('malignancies', 'Disease', (262, 274))
170529	28884745	We examined demographic and clinical characteristics, histologic type, growth patterns, mitotic index, and nuclear grade on hematoxylin and eosin-stained slides, BAP1 protein expression by immunohistochemistry, and CDKN2A and NF2 deletions by fluorescence in situ hybridization.	('eosin', 'Chemical', 'MESH:D004801', (140, 145))	('CDKN2A', 'Gene', (215, 221))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('deletions', 'Var', (230, 239))	('BAP1', 'Gene', '8314', (162, 166))	('CDKN2A', 'Gene', '1029', (215, 221))	('NF2', 'Gene', '4771', (226, 229))	('BAP1', 'Gene', (162, 166))	('hematoxylin', 'Chemical', 'MESH:D006416', (124, 135))	('NF2', 'Gene', (226, 229))
170532	28884745	CDKN2A deletion was less prevalent in young patients (P = 0.01), loss of BAP1 protein expression less frequent in young patients (P = 0.06), and NF2 deletion rates similar between groups (P>0.05 each).	('loss', 'NegReg', (65, 69))	('CDKN2A', 'Gene', '1029', (0, 6))	('BAP1', 'Gene', '8314', (73, 77))	('patients', 'Species', '9606', (44, 52))	('NF2', 'Gene', (145, 148))	('BAP1', 'Gene', (73, 77))	('expression', 'MPA', (86, 96))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('patients', 'Species', '9606', (120, 128))	('NF2', 'Gene', '4771', (145, 148))	('CDKN2A', 'Gene', (0, 6))	('deletion', 'Var', (7, 15))	('less', 'NegReg', (97, 101))
170535	28884745	Young patients with pleural mesothelioma have an equal sex distribution and are more likely to have a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients.	('CDKN2A', 'Gene', (183, 189))	('pleural mesothelioma', 'Disease', (20, 40))	('mantle radiation', 'Disease', (113, 129))	('deletion', 'Var', (190, 198))	('CDKN2A', 'Gene', '1029', (183, 189))	('lower', 'NegReg', (168, 173))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (20, 40))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (20, 40))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (6, 14))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('patients', 'Species', '9606', (210, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))
170546	28884745	We compared clinical features, history of asbestos exposure, personal and familial history of malignancy, CDKN2A and NF2 deletion, and BAP1 protein expression between young and older patients, and compared the results with overall survival.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('NF2', 'Gene', (117, 120))	('malignancy', 'Disease', 'MESH:D009369', (94, 104))	('BAP1', 'Gene', '8314', (135, 139))	('CDKN2A', 'Gene', (106, 112))	('NF2', 'Gene', '4771', (117, 120))	('malignancy', 'Disease', (94, 104))	('BAP1', 'Gene', (135, 139))	('CDKN2A', 'Gene', '1029', (106, 112))	('deletion', 'Var', (121, 129))	('patients', 'Species', '9606', (183, 191))
170554	28884745	Cytogenetic analysis and fluorescence in situ hybridization to evaluate for CDKN2A (p16) and NF2 deletions were performed as part of routine clinical practice at BWH, as previously published.	('CDKN2A', 'Gene', '1029', (76, 82))	('NF2', 'Gene', (93, 96))	('p16', 'Gene', '1029', (84, 87))	('NF2', 'Gene', '4771', (93, 96))	('CDKN2A', 'Gene', (76, 82))	('deletions', 'Var', (97, 106))	('p16', 'Gene', (84, 87))
170580	28884745	Karyotypic analysis was available in eight young patients and demonstrated deletions of chromosome 9 in one patient, chromosome 22 in four patients, and chromosome 3 in one patient, and translocations in two patients.	('patient', 'Species', '9606', (208, 215))	('deletions', 'Var', (75, 84))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (139, 147))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('translocations', 'Var', (186, 200))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('patient', 'Species', '9606', (49, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (49, 57))	('patient', 'Species', '9606', (173, 180))	('patient', 'Species', '9606', (139, 146))
170581	28884745	Thirteen older patients had available karyotypes, demonstrating deletions of chromosomes 9 in seven patients, chromosome 22 in seven patients, chromosome 3 in two patients, and translocations in six patients.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (163, 171))	('deletions', 'Var', (64, 73))	('patients', 'Species', '9606', (133, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('patients', 'Species', '9606', (100, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('patients', 'Species', '9606', (199, 207))	('translocations', 'CPA', (177, 191))
170582	28884745	Genomic losses predominated over genomic gains in 50% of tumors in the study group compared with 62% of tumors in the comparison group.	('gains', 'PosReg', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('losses', 'NegReg', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('Genomic', 'Var', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
170586	28884745	CDKN2A deletion was significantly less frequent in younger than in older patients (17% vs 54%; P = 0.01).	('less', 'NegReg', (34, 38))	('CDKN2A', 'Gene', (0, 6))	('patients', 'Species', '9606', (73, 81))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
170587	28884745	No difference in the prevalence of NF2 deletion was seen between the two groups (67% vs 78%; P = 0.53).	('NF2', 'Gene', '4771', (35, 38))	('deletion', 'Var', (39, 47))	('NF2', 'Gene', (35, 38))
170590	28884745	Next-generation sequencing in the group of older patients showed BAP1 alterations consisting of point mutations, insertions, deletions, copy number variations, or gene rearrangements in 19 of 21 cases with complete absence of BAP1 protein.	('insertions', 'Var', (113, 123))	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (226, 230))	('BAP1', 'Gene', (65, 69))	('men', 'Species', '9606', (177, 180))	('gene rearrangements', 'Var', (163, 182))	('point mutations', 'Var', (96, 111))	('copy number variations', 'Var', (136, 158))	('patients', 'Species', '9606', (49, 57))	('deletions', 'Var', (125, 134))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('BAP1', 'Gene', '8314', (226, 230))
170591	28884745	With the exception of two cases that demonstrated missense mutations of unknown significance, any amount of BAP1 nuclear staining regardless of intensity or distribution was associated with wild-type BAP1 gene status.	('missense mutations', 'Var', (50, 68))	('associated', 'Reg', (174, 184))	('BAP1', 'Gene', '8314', (108, 112))	('BAP1', 'Gene', '8314', (200, 204))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', (200, 204))
170597	28884745	Non-epithelioid histology and mitotic index >4 were significantly associated with a shorter overall survival among young patients (Figures 3 and 4 and Supplementary Table S2).	('Non-epithelioid', 'Disease', (0, 15))	('mitotic index >4', 'Var', (30, 46))	('overall survival', 'MPA', (92, 108))	('shorter', 'NegReg', (84, 91))	('men', 'Species', '9606', (157, 160))	('patients', 'Species', '9606', (121, 129))
170611	28884745	Interestingly, there was a much higher relative prevalence of family history of breast cancer among young than among older pleural mesothelioma patients (Supplementary Table S1), and one patient in the study group had a personal history of invasive ductal carcinoma of the breast at age 28 in the setting of a germline BRCA2 mutation.	('pleural mesothelioma', 'Disease', (123, 143))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('BRCA2', 'Gene', (319, 324))	('breast cancer', 'Disease', (80, 93))	('patient', 'Species', '9606', (144, 151))	('men', 'Species', '9606', (160, 163))	('BRCA2', 'Gene', '675', (319, 324))	('mutation', 'Var', (325, 333))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (123, 143))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (123, 143))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (256, 279))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patient', 'Species', '9606', (187, 194))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (240, 265))	('invasive ductal carcinoma', 'Disease', (240, 265))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (249, 265))	('patients', 'Species', '9606', (144, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
170614	28884745	Although the difference in distribution of histologic mesothelioma types did not reach significance between study and comparison groups, the higher prevalence of biphasic and sarcomatoid mesotheliomas in the comparison group prompted us to examine the remaining histologic and genetic characteristics in epithelioid mesotheliomas separately, as non-epithelioid histology is associated with poor survival and a higher prevalence of CDKN2A alterations.	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('epithelioid mesotheliomas', 'Disease', 'MESH:D008654', (304, 329))	('sarcomatoid mesotheliomas', 'Disease', (175, 200))	('CDKN2A', 'Gene', (431, 437))	('mesothelioma', 'Disease', (316, 328))	('alterations', 'Var', (438, 449))	('CDKN2A', 'Gene', '1029', (431, 437))	('mesothelioma', 'Disease', (187, 199))	('epithelioid mesotheliomas', 'Disease', (304, 329))	('mesothelioma', 'Disease', 'MESH:D008654', (316, 328))	('mesothelioma', 'Disease', (54, 66))	('histologic mesothelioma', 'Phenotype', 'HP:0100001', (43, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))	('sarcomatoid mesotheliomas', 'Disease', 'MESH:C538614', (175, 200))
170616	28884745	Approximately 43-80% of all pleural diffuse malignant mesotheliomas are reported to harbor deletions of the CDKN2A gene and 40-65% have NF2 deletions.	('NF2', 'Gene', (136, 139))	('CDKN2A', 'Gene', '1029', (108, 114))	('pleural diffuse malignant mesotheliomas', 'Disease', (28, 67))	('deletions', 'Var', (91, 100))	('NF2', 'Gene', '4771', (136, 139))	('pleural diffuse malignant mesotheliomas', 'Disease', 'MESH:C562839', (28, 67))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (44, 66))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (44, 67))	('CDKN2A', 'Gene', (108, 114))
170617	28884745	More recently, somatic alterations of the BAP1 gene have also been described in 42-80% pleural mesothelioma patients, and are independent of CDKN2A and NF2 alterations.	('BAP1', 'Gene', '8314', (42, 46))	('pleural mesothelioma', 'Disease', (87, 107))	('CDKN2A', 'Gene', '1029', (141, 147))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (87, 107))	('BAP1', 'Gene', (42, 46))	('NF2', 'Gene', (152, 155))	('NF2', 'Gene', '4771', (152, 155))	('described', 'Reg', (67, 76))	('alterations', 'Var', (23, 34))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (87, 107))	('patients', 'Species', '9606', (108, 116))	('CDKN2A', 'Gene', (141, 147))
170618	28884745	CDKN2A deletion is reported to be associated with asbestos exposure in vitro and in vivo, and has been associated with poor prognosis in multiple studies compared with pleural mesotheliomas without the deletion.	('associated', 'Reg', (34, 44))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (168, 189))	('asbestos', 'Chemical', 'MESH:D001194', (50, 58))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (168, 188))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (168, 189))	('CDKN2A', 'Gene', (0, 6))	('pleural mesotheliomas', 'Disease', (168, 189))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
170619	28884745	Somatic BAP1 abnormalities have not consistently been shown to be associated with asbestos exposure, and have shown variable correlation with overall survival.	('BAP1', 'Gene', '8314', (8, 12))	('associated', 'Reg', (66, 76))	('BAP1', 'Gene', (8, 12))	('asbestos', 'Chemical', 'MESH:D001194', (82, 90))	('abnormalities', 'Var', (13, 26))
170620	28884745	The prognostic significance of NF2 alterations has not been studied in depth.	('NF2', 'Gene', (31, 34))	('alterations', 'Var', (35, 46))	('NF2', 'Gene', '4771', (31, 34))
170621	28884745	54% of pleural mesotheliomas in older patients in our study had CDKN2A deletions, and 76% had losses at the NF2 locus.	('deletions', 'Var', (71, 80))	('losses', 'NegReg', (94, 100))	('NF2', 'Gene', (108, 111))	('CDKN2A', 'Gene', (64, 70))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (7, 27))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (7, 28))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (7, 28))	('CDKN2A', 'Gene', '1029', (64, 70))	('NF2', 'Gene', '4771', (108, 111))	('patients', 'Species', '9606', (38, 46))	('pleural mesotheliomas', 'Disease', (7, 28))
170622	28884745	While the prevalence of NF2 deletion in the study group was not significantly different from the older comparison group, young patients had a much lower prevalence of CDKN2A deletion.	('lower', 'NegReg', (147, 152))	('NF2', 'Gene', (24, 27))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('deletion', 'Var', (174, 182))	('patients', 'Species', '9606', (127, 135))	('NF2', 'Gene', '4771', (24, 27))	('deletion', 'Var', (28, 36))
170623	28884745	Given that germline mutations of the BAP1 gene confer susceptibility to a number of tumors, including pleural diffuse malignant mesothelioma, we also evaluated the possibility that BAP1 alterations may play an important oncogenic role in young pleural mesothelioma patients.	('susceptibility', 'Reg', (54, 68))	('pleural diffuse malignant mesothelioma', 'Disease', (102, 140))	('BAP1', 'Gene', '8314', (181, 185))	('BAP1', 'Gene', (181, 185))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (118, 140))	('pleural diffuse malignant mesothelioma', 'Disease', 'MESH:C562839', (102, 140))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BAP1', 'Gene', '8314', (37, 41))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (244, 264))	('patients', 'Species', '9606', (265, 273))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (244, 264))	('germline mutations', 'Var', (11, 29))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAP1', 'Gene', (37, 41))	('pleural mesothelioma', 'Disease', (244, 264))
170626	28884745	Although the lower prevalence of CDKN2A deletion among young patients could potentially be attributed to a lower prevalence of non-epithelioid histology in the study group, this genomic difference persisted between the study and comparison groups even when epithelioid mesotheliomas were analyzed separately.	('CDKN2A', 'Gene', (33, 39))	('epithelioid mesotheliomas', 'Disease', (257, 282))	('deletion', 'Var', (40, 48))	('CDKN2A', 'Gene', '1029', (33, 39))	('lower', 'NegReg', (107, 112))	('patients', 'Species', '9606', (61, 69))	('epithelioid mesotheliomas', 'Disease', 'MESH:D008654', (257, 282))
170627	28884745	Additionally, while the number of cases with available karyotypic analysis in the current study were few, mesotheliomas in young patients had a slightly lower prevalence of genomic losses than did older patients.	('genomic losses', 'Var', (173, 187))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (203, 211))	('lower', 'NegReg', (153, 158))	('mesotheliomas', 'Disease', 'MESH:D008654', (106, 119))	('mesotheliomas', 'Disease', (106, 119))
170641	28884745	Among young patients with pleural mesothelioma, a higher prevalence of family history of breast cancer, lower prevalence of CDKN2A deletion, potentially lower prevalence of somatic BAP1 alteration, and longer overall survival among epithelioid mesotheliomas suggest that pleural diffuse malignant mesothelioma in patients aged 35 years and younger has unique biological features and may be driven by different oncogenetic events than pleural diffuse malignant mesothelioma in older patients.	('CDKN2A', 'Gene', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('BAP1', 'Gene', '8314', (181, 185))	('patients', 'Species', '9606', (12, 20))	('epithelioid mesotheliomas', 'Disease', 'MESH:D008654', (232, 257))	('pleural mesothelioma', 'Disease', (26, 46))	('CDKN2A', 'Gene', '1029', (124, 130))	('pleural diffuse malignant mesothelioma', 'Disease', 'MESH:C562839', (271, 309))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (482, 490))	('epithelioid mesotheliomas', 'Disease', (232, 257))	('pleural diffuse malignant mesothelioma', 'Disease', (434, 472))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (450, 472))	('patients', 'Species', '9606', (313, 321))	('BAP1', 'Gene', (181, 185))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (26, 46))	('deletion', 'Var', (131, 139))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (26, 46))	('pleural diffuse malignant mesothelioma', 'Disease', (271, 309))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (287, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('pleural diffuse malignant mesothelioma', 'Disease', 'MESH:C562839', (434, 472))
170650	28816162	Dose-volume correlations for heart were RP2+ with VD (35<=D<=47 Gy, V43 strongest at p=0.003), RP3+ with VD (31 <=D<= 45 Gy), RP2+ with DV (5 <=V<= 30%), RP3+ with DV (15 <=V<= 35%) and mean dose.	('31 <=D<=', 'Var', (109, 117))	('DV', 'Chemical', 'MESH:D004028', (164, 166))	('DV', 'Chemical', 'MESH:D004028', (136, 138))	('RP2', 'Gene', (40, 43))	('V43', 'Gene', '28780', (68, 71))	('V43', 'Gene', (68, 71))	('RP3', 'Gene', '22924', (95, 98))	('RP3', 'Gene', '22924', (154, 157))	('RP2', 'Gene', '6102', (40, 43))	('RP2', 'Gene', (126, 129))	('RP2', 'Gene', '6102', (126, 129))	('RP3', 'Gene', (95, 98))	('RP3', 'Gene', (154, 157))
170691	28816162	Heart dosimetric variables were strongly dependent on disease laterality; for right-sided mesothelioma, median MHD was 21.9 Gy (14.06-29.1 Gy) and median V40Gy was 16.8% (14.5-32.3%); for left-sided mesothelioma, MHD was 28.1 Gy (26.9-29.2 Gy) and median V40Gy was 25.5% (9.7-37.6%).	('V40Gy', 'Var', (154, 159))	('mesothelioma', 'Disease', (199, 211))	('MHD', 'Disease', 'None', (111, 114))	('MHD', 'Disease', (111, 114))	('mesothelioma', 'Disease', (90, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (199, 211))	('MHD', 'Disease', 'None', (213, 216))	('MHD', 'Disease', (213, 216))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
170709	28816162	Multivariate metrics based on these variables were x= 0.000224 *PTV + 0.0596*Heart V43 and y=0.000637*PTV + 0.103*Heart D10, where units of PTV, Heart V43Gy and the Heart D10 are cc, %, and Gy respectively.	('PTV', 'cellular_component', 'GO:1990257', ('140', '143'))	('PTV', 'Chemical', '-', (102, 105))	('PTV', 'Chemical', '-', (140, 143))	('y=0.000637*PTV + 0.103*Heart D10', 'Var', (91, 123))	('PTV', 'cellular_component', 'GO:1990257', ('102', '105'))	('V43', 'Gene', '28780', (151, 154))	('V43', 'Gene', (151, 154))	('PTV', 'cellular_component', 'GO:1990257', ('64', '67'))	('V43', 'Gene', '28780', (83, 86))	('PTV', 'Chemical', '-', (64, 67))	('V43', 'Gene', (83, 86))
170836	27871980	Based upon these considerations, doses of 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92 and 2.0 mg furan/kg BW were selected for the 2-year bioassay (Table 1).	('0.044', 'Var', (51, 56))	('0.2', 'Var', (65, 68))	('0.02', 'Var', (45, 49))	('0.92', 'Var', (76, 80))	('furan', 'Chemical', 'MESH:C039281', (92, 97))	('0.44', 'Var', (70, 74))	('rat', 'Species', '10116', (24, 27))	('0.092', 'Var', (58, 63))
170843	27871980	While the NCTR sub-strain differs from the Charles River sub-strain used in the previous furan bioassay, the NCTR F344/N sub-strain has given tumorigenic responses comparable to those of other F344/N sub-strains in previously reported carcinogenicity bioassays (e.g., acrylamide).	('carcinogenic', 'Disease', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('F344/N', 'Var', (114, 120))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('tumor', 'Disease', (142, 147))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('furan', 'Chemical', 'MESH:C039281', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('carcinogenic', 'Disease', 'MESH:D063646', (235, 247))	('acrylamide', 'Chemical', 'MESH:D020106', (268, 278))	('C', 'Chemical', 'MESH:D002244', (11, 12))
170870	27871980	Male F344/N Nctr rats were administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2.0 mg furan/kg BW by gavage in corn oil 5 days/week for 2 years (104 weeks), with interim sacrifices conducted at 9 (36 weeks) and 15 (60 weeks) months (Table 1).	('0.044', 'Var', (49, 54))	('0.092', 'Var', (56, 61))	('rats', 'Species', '10116', (17, 21))	('0.2', 'Var', (63, 66))	('furan', 'Chemical', 'MESH:C039281', (91, 96))	('corn', 'Species', '4577', (116, 120))	('0.44', 'Var', (68, 72))
170882	27871980	Male F344/N Nctr rats had dose-related increases in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.092, 0.2, 0.92, and 2 mg furan/kg BW (Table 2).	('rats', 'Species', '10116', (17, 21))	('0.2', 'Var', (155, 158))	('furan', 'Chemical', 'MESH:C039281', (175, 180))	('0.092', 'Var', (148, 153))	('0.92', 'Var', (160, 164))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('increases', 'PosReg', (39, 48))
170887	27871980	Significant increases in cholangiofibrosis, bile duct subcapsular hyperplasia, and subcapsular fibrosis, chronic inflammation, and pigmentation were observed at 0.44 mg furan/kg BW.	('subcapsular fibrosis', 'Phenotype', 'HP:0000523', (83, 103))	('increases', 'PosReg', (12, 21))	('pigmentation', 'Disease', (131, 143))	('cholangiofibrosis', 'Disease', 'None', (25, 42))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('fibrosis', 'Disease', (34, 42))	('fibrosis', 'Disease', 'MESH:D005355', (34, 42))	('inflammation', 'biological_process', 'GO:0006954', ('113', '125'))	('cholangiofibrosis', 'Disease', (25, 42))	('fibrosis', 'Disease', 'MESH:D005355', (95, 103))	('fibrosis', 'Disease', (95, 103))	('0.44 mg', 'Var', (161, 168))	('pigmentation', 'Disease', 'MESH:D010859', (131, 143))	('inflammation', 'Disease', (113, 125))	('pigmentation', 'biological_process', 'GO:0043473', ('131', '143'))	('hyperplasia', 'Disease', (66, 77))	('bile duct subcapsular hyperplasia', 'Phenotype', 'HP:0006560', (44, 77))	('subcapsular hyperplasia', 'Phenotype', 'HP:0000523', (54, 77))	('hyperplasia', 'Disease', 'MESH:D006965', (66, 77))	('furan', 'Chemical', 'MESH:C039281', (169, 174))
170892	27871980	For example, in the 60-week rats, the incidence of subcapsular fibrosis, chronic inflammation, and pigmentation became significant at 0.2 mg furan/kg BW (as compared to 0.44 mg furan/kg BW at 36 weeks).	('furan', 'Chemical', 'MESH:C039281', (141, 146))	('fibrosis', 'Disease', 'MESH:D005355', (63, 71))	('rats', 'Species', '10116', (28, 32))	('fibrosis', 'Disease', (63, 71))	('inflammation', 'biological_process', 'GO:0006954', ('81', '93'))	('furan', 'Chemical', 'MESH:C039281', (177, 182))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('subcapsular fibrosis', 'Phenotype', 'HP:0000523', (51, 71))	('pigmentation', 'Disease', 'MESH:D010859', (99, 111))	('0.2 mg', 'Var', (134, 140))	('pigmentation', 'Disease', (99, 111))	('pigmentation', 'biological_process', 'GO:0043473', ('99', '111'))
170894	27871980	The incidence of cholangiofibrosis was significantly increased at 0.2 mg furan/kg BW, and a single occurrence was observed at 0.092 mg furan/kg BW.	('cholangiofibrosis', 'Disease', 'None', (17, 34))	('furan', 'Chemical', 'MESH:C039281', (73, 78))	('0.2 mg', 'Var', (66, 72))	('furan', 'Chemical', 'MESH:C039281', (135, 140))	('cholangiofibrosis', 'Disease', (17, 34))	('increased', 'PosReg', (53, 62))
170959	27871980	Promoter region hypermethylation was observed in the tumor suppressor genes p16IKN4a and Rassf1a, and this was accompanied by a decreased expression of Rassf1a.	('Rassf1a', 'Gene', (89, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('hypermethylation', 'Var', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('decreased', 'NegReg', (128, 137))	('Rassf1a', 'Gene', (152, 159))	('expression', 'MPA', (138, 148))	('p16IKN4a', 'Gene', (76, 84))	('tumor', 'Disease', (53, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
170966	27871980	In contrast to Areg and Jag 1, hypermethylation of the promoter region and decreased gene expression was found with Foxe1, which encodes a thyroid-specific forkhead transcription factor that represses transcription of several rat genes, including fibrogenesis-associated Duox2 and Adamts1 genes.	('transcription', 'biological_process', 'GO:0006351', ('165', '178'))	('Jag 1', 'Gene', (24, 29))	('Adamts1', 'Gene', (281, 288))	('fibrogenesis-associated', 'Disease', (247, 270))	('hypermethylation', 'Var', (31, 47))	('Foxe1', 'Gene', '192274', (116, 121))	('transcription', 'biological_process', 'GO:0006351', ('201', '214'))	('Foxe1', 'Gene', (116, 121))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('Areg', 'Gene', (15, 19))	('Adamts1', 'Gene', '79252', (281, 288))	('Jag 1', 'Gene', '29146', (24, 29))	('transcription', 'MPA', (201, 214))	('Duox2', 'Gene', (271, 276))	('rat', 'Species', '10116', (226, 229))	('Areg', 'Gene', '29183', (15, 19))	('Duox2', 'Gene', '79107', (271, 276))	('represses', 'NegReg', (191, 200))	('transcription factor', 'molecular_function', 'GO:0000981', ('165', '185'))
170967	27871980	Therefore, hypermethylation-associated inhibition of Foxe1 expression may cause activation of these genes and stimulation of liver fibrogenesis.	('inhibition', 'Var', (39, 49))	('liver fibrogenesis', 'CPA', (125, 143))	('liver fibrogenesis', 'Phenotype', 'HP:0001395', (125, 143))	('expression', 'MPA', (59, 69))	('stimulation', 'PosReg', (110, 121))	('hypermethylation-associated', 'Var', (11, 38))	('Foxe1', 'Gene', '192274', (53, 58))	('Foxe1', 'Gene', (53, 58))	('activation', 'PosReg', (80, 90))
170968	27871980	These results indicate that gene-specific changes in DNA methylation have functional consequences that may be important for the induction of cholangiofibrosis and subsequently cholangiocarcinoma.	('methylation', 'Var', (57, 68))	('cholangiocarcinoma', 'Disease', (176, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cholangiofibrosis', 'Disease', 'None', (141, 158))	('DNA', 'Protein', (53, 56))	('changes', 'Var', (42, 49))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (176, 194))	('cholangiofibrosis', 'Disease', (141, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (176, 194))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('42', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
171012	26982031	We found that staining for both clone 25 and clone 2B10 was non-specific (especially BD clone 25), while clone 2C10 correctly identified ASS1 in transduced MSTO cells (Fig 3A).	('ASS1', 'Gene', (137, 141))	('clone 2C10', 'Var', (105, 115))	('ASS1', 'Gene', '445', (137, 141))
171041	26982031	ASS1 deficiency has also been associated with platinum resistance; in some studies, the silencing of ASS1 has induced a resistance to platinum-induced cell death while, at the same time, sensitizing to arginine degradation.	('sensitizing', 'PosReg', (187, 198))	('platinum', 'Chemical', 'MESH:D010984', (134, 142))	('ASS1', 'Gene', (101, 105))	('ASS1', 'Gene', '445', (101, 105))	('platinum', 'Chemical', 'MESH:D010984', (46, 54))	('ASS1 deficiency', 'Disease', 'MESH:D007153', (0, 15))	('arginine', 'Chemical', 'MESH:D001120', (202, 210))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('silencing', 'Var', (88, 97))	('arginine degradation', 'biological_process', 'GO:0006527', ('202', '222'))	('ASS1', 'Gene', '445', (0, 4))	('ASS1', 'Gene', (0, 4))	('resistance', 'CPA', (120, 130))	('ASS1 deficiency', 'Disease', (0, 15))
171042	26982031	In the case of mesothelioma with low ASS1 expression, patients have been treated with pegylated arginine deiminase (ADI-PEG20), either alone (ADAM - https://goo.gl/hSNkI7)) or together with chemotherapy (TRAP - http://goo.gl/tiwzGO), to deprive the tumor of arginine; results from these trials are pending.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('low', 'Var', (33, 36))	('arginine', 'Chemical', 'MESH:D001120', (96, 104))	('ASS1', 'Gene', '445', (37, 41))	('ASS1', 'Gene', (37, 41))	('tumor', 'Disease', (249, 254))	('arginine', 'Chemical', 'MESH:D001120', (258, 266))	('mesothelioma', 'Disease', (15, 27))
171057	26982031	If so, then techniques to suppress ASS1 could improve response to chemotherapy and would also render the tumor vulnerable to arginine depletion techniques, such as ADI-PEG20.	('arginine depletion', 'MPA', (125, 143))	('ASS1', 'Gene', (35, 39))	('techniques', 'Var', (12, 22))	('ASS1', 'Gene', '445', (35, 39))	('response to chemotherapy', 'MPA', (54, 78))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('suppress', 'NegReg', (26, 34))	('tumor', 'Disease', (105, 110))	('render', 'Reg', (94, 100))	('arginine', 'Chemical', 'MESH:D001120', (125, 133))	('improve', 'PosReg', (46, 53))
171067	26982031	TaqMan probes for ASS1 (Hs01597989_g1), ANXA4 (Hs00984874_m1), MVP (Hs00245438_m1) and the control beta glucuronidase (GUSB, 4333767T) were from Applied Biosystems (Life Technologies, Carlsbad, CA, USA).	('ASS1', 'Gene', (18, 22))	('Hs00984874_m1', 'Var', (47, 60))	('ASS1', 'Gene', '445', (18, 22))	('beta glucuronidase', 'Gene', '2990', (99, 117))	('beta glucuronidase', 'Gene', (99, 117))	('ANXA4', 'Gene', '307', (40, 45))	('Hs01597989_g1', 'Var', (24, 37))	('MVP', 'Gene', (63, 66))	('GUSB', 'Gene', '2990', (119, 123))	('ANXA4', 'Gene', (40, 45))	('Hs00245438_m1', 'Var', (68, 81))	('MVP', 'Gene', '9961', (63, 66))	('GUSB', 'Gene', (119, 123))
171073	26982031	The following primary antibodies were used: anti-ASS1 (clone 25, 1:500, BD Biosciences, San Jose, CA, USA; clone 2B10, 1:500, Sigma-Aldrich, St. Louis, MO, USA; clone 2C10, 1:500, Millipore, Billerica, MA, USA), anti-alpha-tubulin (#A5441, 1:10,000, Sigma-Aldrich, St. Louis, MO, USA).	('ASS1', 'Gene', (49, 53))	('clone 2C10', 'Var', (161, 171))	('ASS1', 'Gene', '445', (49, 53))
171115	23634900	block to cell differentiation), immortality via genetic instability, enhanced cancer hallmark cell behaviour and in vivo tumour formation.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('enhanced', 'PosReg', (69, 77))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cell differentiation', 'biological_process', 'GO:0030154', ('9', '29'))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('tumour', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('behaviour', 'biological_process', 'GO:0007610', ('99', '108'))	('genetic instability', 'Var', (48, 67))
171144	23634900	SAECs were chosen as an ideal model since aspiration of CNT results in substantial deposition in terminal bronchioles and alveolar region of exposed mice.	('aspiration', 'Var', (42, 52))	('deposition', 'MPA', (83, 93))	('SAECs', 'Chemical', '-', (0, 5))	('mice', 'Species', '10090', (149, 153))	('aspiration', 'Phenotype', 'HP:0002835', (42, 52))
171182	23634900	DEG data from each treatment were uploaded into IPA for Core Analysis (Ingenuity Systems, Redwood City, CA, USA) to determine major alterations in cell functions, gene signalling networks (GSNs) and key genome alterations promoting neoplastic transformation in CNT-exposed cells.	('alterations', 'Var', (210, 221))	('alterations', 'Reg', (132, 143))	('Redwood', 'Species', '28980', (90, 97))	('GSNs', 'Chemical', '-', (189, 193))	('signalling', 'biological_process', 'GO:0023052', ('168', '178'))	('neoplastic transformation', 'CPA', (232, 257))	('cell functions', 'CPA', (147, 161))	('promoting', 'PosReg', (222, 231))
171206	23634900	Both D-SWCNT and D-MWCNT exhibited significantly greater CFE (Figure 2B) and morphological transformation evidenced by Type III foci than DISP control cells (Figure 2C).	('D-SWCNT', 'Var', (5, 12))	('greater', 'PosReg', (49, 56))	('CFE', 'CPA', (57, 60))	('MWCNT', 'Chemical', '-', (19, 24))	('morphological transformation', 'CPA', (77, 105))
171211	23634900	D-SWCNT, D-MWCNT and ASB cells exhibited significantly greater cell proliferation at 48 h compared to SAL, DISP and D-UFCB cells (Figure 3A-1).	('MWCNT', 'Chemical', '-', (11, 16))	('D-SWCNT', 'Var', (0, 7))	('ASB', 'Gene', (21, 24))	('greater', 'PosReg', (55, 62))	('SAL', 'Chemical', 'MESH:D012965', (102, 105))	('cell proliferation at 48 h', 'CPA', (63, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('ASB', 'Gene', '411', (21, 24))
171212	23634900	Similarly, D-SWCNT, D-MWCNT and ASB cells showed a significant increase in live cell number over 48 h compared to SAL and DISP controls.	('increase', 'PosReg', (63, 71))	('SAL', 'Chemical', 'MESH:D012965', (114, 117))	('D-SWCNT', 'Var', (11, 18))	('MWCNT', 'Chemical', '-', (22, 27))	('live cell number', 'CPA', (75, 91))	('ASB', 'Gene', '411', (32, 35))	('ASB', 'Gene', (32, 35))
171219	23634900	Lastly, we assessed angiogenic potential of D-UFCB, D-SWCNT, D-MWCNT and ASB SAECs compared to parental, SAL and DISP control SAECs.	('MWCNT', 'Chemical', '-', (63, 68))	('angiogenic potential', 'CPA', (20, 40))	('ASB', 'Gene', '411', (73, 76))	('SAL', 'Chemical', 'MESH:D012965', (105, 108))	('D-SWCNT', 'Var', (52, 59))	('SAECs', 'Chemical', '-', (126, 131))	('ASB', 'Gene', (73, 76))	('SAECs', 'Chemical', '-', (77, 82))	('D-UFCB', 'Var', (44, 50))
171220	23634900	Conditioned media from D-SWCNT, D-MWCNT, ASB and SAL SAECs caused a significant increase in tube formation while UFCB and parental SAECs exhibited a significant decrease compared to DISP SAECs (Figure 3D).	('ASB', 'Gene', '411', (41, 44))	('D-MWCNT', 'Var', (32, 39))	('SAL', 'Chemical', 'MESH:D012965', (49, 52))	('increase', 'PosReg', (80, 88))	('SAECs', 'Chemical', '-', (131, 136))	('ASB', 'Gene', (41, 44))	('tube formation', 'biological_process', 'GO:0035148', ('92', '106'))	('SAECs', 'Chemical', '-', (187, 192))	('tube formation', 'CPA', (92, 106))	('SAECs', 'Chemical', '-', (53, 58))	('D-SWCNT', 'Var', (23, 30))	('MWCNT', 'Chemical', '-', (34, 39))
171225	23634900	Following mRNA hybridisation and DEG determination, hierarchical clustering (HC) heat map expression signature and PCA showed that D-SWCNT- and D-MWCNT-transformed SAECs possessed the most similar toxicogenomic signatures, which were clearly distinct from ASB cells (Figures 4A and B).	('ASB', 'Gene', (256, 259))	('SAECs', 'Chemical', '-', (164, 169))	('MWCNT', 'Chemical', '-', (146, 151))	('D-SWCNT-', 'Var', (131, 139))	('ASB', 'Gene', '411', (256, 259))	('D-MWCNT-transformed', 'Var', (144, 163))
171231	23634900	Both D-SWCNT and D-MWCNT SAECs displayed large alterations in DEGs associated with cell proliferation, movement, cell death, development and cell-cell signalling (Figure 5A).	('D-SWCNT', 'Var', (5, 12))	('cell-cell signalling', 'CPA', (141, 161))	('cell death', 'CPA', (113, 123))	('movement', 'CPA', (103, 111))	('cell proliferation', 'CPA', (83, 101))	('SAECs', 'Chemical', '-', (25, 30))	('MWCNT', 'Chemical', '-', (19, 24))	('cell death', 'biological_process', 'GO:0008219', ('113', '123'))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('alterations', 'Reg', (47, 58))	('D-MWCNT', 'Var', (17, 24))	('cell-cell signalling', 'biological_process', 'GO:0007267', ('141', '161'))	('DEGs associated', 'MPA', (62, 77))	('development', 'CPA', (125, 136))
171232	23634900	Cell development signalling associated with connective tissue development was predicted as activated in D-SWCNT SAECs (*, Z >= 2).	('connective tissue development', 'biological_process', 'GO:0061448', ('44', '73'))	('signalling', 'biological_process', 'GO:0023052', ('17', '27'))	('Cell development', 'biological_process', 'GO:0048468', ('0', '16'))	('connective tissue development', 'CPA', (44, 73))	('D-SWCNT', 'Var', (104, 111))	('activated', 'PosReg', (91, 100))	('SAECs', 'Chemical', '-', (112, 117))	('Cell', 'Pathway', (0, 4))
171233	23634900	In addition, a majority of cell movement and development signalling in both D-SWCNT and D-MWCNT was associated with decreased gene expression of inflammatory cytokines and chemokines involved with leukocyte recruitment ( ; Z <= -2).	('cell movement', 'CPA', (27, 40))	('gene expression of inflammatory cytokines', 'MPA', (126, 167))	('D-MWCNT', 'Var', (88, 95))	('cell movement', 'biological_process', 'GO:0048870', ('27', '40'))	('MWCNT', 'Chemical', '-', (90, 95))	('cell movement', 'biological_process', 'GO:0006928', ('27', '40'))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('D-SWCNT', 'Var', (76, 83))	('signalling', 'biological_process', 'GO:0023052', ('57', '67'))	('decreased', 'NegReg', (116, 125))	('development signalling', 'CPA', (45, 67))
171242	23634900	Only D-UFCB and ASB cells possessed a substantial number of DEGs associated with DNA recombination and repair.	('DEGs', 'Var', (60, 64))	('DNA recombination', 'biological_process', 'GO:0006310', ('81', '98'))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('ASB', 'Gene', '411', (16, 19))	('ASB', 'Gene', (16, 19))
171243	23634900	ASB SAEC post-translational modification, amino acid metabolism, antigen presentation and molecular transportation were all predicted as activated (*).	('ASB', 'Gene', '411', (0, 3))	('SAEC', 'Chemical', '-', (4, 8))	('antigen presentation', 'biological_process', 'GO:0019882', ('65', '85'))	('antigen presentation', 'MPA', (65, 85))	('ASB', 'Gene', (0, 3))	('post-translational', 'Var', (9, 27))	('molecular transportation', 'CPA', (90, 114))	('post-translational modification', 'biological_process', 'GO:0043687', ('9', '40'))	('metabolism', 'biological_process', 'GO:0008152', ('53', '63'))	('amino acid metabolism', 'MPA', (42, 63))
171249	23634900	Investigation of top-ranked canonical pathways revealed that D-SWCNT SAECs exhibited changes in altered apoptotic, decreased inflammatory (NFKB2, Ikk) and cancer-related signalling (Table III).	('D-SWCNT', 'Var', (61, 68))	('Ikk', 'molecular_function', 'GO:0008384', ('146', '149'))	('NFKB2', 'Gene', (139, 144))	('SAECs', 'Chemical', '-', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inflammatory', 'CPA', (125, 137))	('decreased', 'NegReg', (115, 124))	('signalling', 'biological_process', 'GO:0023052', ('170', '180'))	('apoptotic', 'CPA', (104, 113))	('NFKB2', 'Gene', '4791', (139, 144))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
171259	23634900	Conversely, D-UFCB demonstrated down-regulation of fibrosis (TGFBR1, SMAD2, IL6, VEGF, CSF1, CCL2 and MMP2), WNT pathway and polo-like kinase signaling (APC, CCNB2, PLK, SLK) indicating a reduced ability to proliferate and contribute to a particle-induced fibrotic response.	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('APC', 'Disease', (153, 156))	('APC', 'cellular_component', 'GO:0005680', ('153', '156'))	('down-regulation', 'NegReg', (32, 47))	('MMP2', 'Gene', '4313', (102, 106))	('fibrosis', 'Disease', (51, 59))	('proliferate', 'CPA', (207, 218))	('fibrosis', 'Disease', 'MESH:D005355', (51, 59))	('IL6', 'Gene', (76, 79))	('CSF1', 'Gene', '1435', (87, 91))	('IL6', 'molecular_function', 'GO:0005138', ('76', '79'))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('CSF1', 'molecular_function', 'GO:0005011', ('87', '91'))	('CCNB2', 'Gene', (158, 163))	('SLK', 'Gene', (170, 173))	('PLK', 'Gene', (165, 168))	('TGFBR1', 'Gene', '7046', (61, 67))	('TGFBR1', 'Gene', (61, 67))	('VEGF', 'Gene', '7422', (81, 85))	('SLK', 'Gene', '9748', (170, 173))	('SMAD2', 'Gene', '4087', (69, 74))	('D-UFCB', 'Var', (12, 18))	('MMP2', 'molecular_function', 'GO:0004228', ('102', '106'))	('VEGF', 'Gene', (81, 85))	('WNT pathway', 'Pathway', (109, 120))	('MMP2', 'Gene', (102, 106))	('SMAD2', 'Gene', (69, 74))	('IL6', 'Gene', '3569', (76, 79))	('CCL', 'molecular_function', 'GO:0044101', ('93', '96'))	('CSF1', 'Gene', (87, 91))	('CCNB2', 'Gene', '9133', (158, 163))	('PLK', 'Gene', '5347', (165, 168))	('APC', 'Disease', 'MESH:D011125', (153, 156))
171260	23634900	In summary, both D-SWCNT and D-MWCNT SAECs exhibited altered apoptosis signalling, cancer-related signalling and decreased inflammatory signalling, which differed from ASB and SAL SAEC pro-inflammatory signalling.	('MWCNT', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('SAEC', 'Chemical', '-', (180, 184))	('signalling', 'biological_process', 'GO:0023052', ('71', '81'))	('decreased', 'NegReg', (113, 122))	('SAEC', 'Chemical', '-', (37, 41))	('D-MWCNT', 'Var', (29, 36))	('ASB', 'Gene', (168, 171))	('SAL', 'Chemical', 'MESH:D012965', (176, 179))	('altered', 'Reg', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('signalling', 'biological_process', 'GO:0023052', ('136', '146'))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('signalling', 'biological_process', 'GO:0023052', ('202', '212'))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('SAECs', 'Chemical', '-', (37, 42))	('ASB', 'Gene', '411', (168, 171))	('D-SWCNT', 'Var', (17, 24))	('inflammatory signalling', 'MPA', (123, 146))	('signalling', 'biological_process', 'GO:0023052', ('98', '108'))	('apoptosis signalling', 'CPA', (61, 81))	('cancer', 'Disease', (83, 89))
171271	23634900	Based on aggressive neoplastic-like transformation phenotype and identification of several signalling pathways associated with carcinogenesis, cancer-associated GSNs were constructed in IPA to further identify potential complex signalling pathways in both D-SWCNT and D-MWCNT compared to ASB SAECs.	('D-MWCNT', 'Var', (268, 275))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('signalling', 'biological_process', 'GO:0023052', ('228', '238'))	('SAECs', 'Chemical', '-', (292, 297))	('signalling', 'biological_process', 'GO:0023052', ('91', '101'))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('carcinogenesis', 'Disease', (127, 141))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('MWCNT', 'Chemical', '-', (270, 275))	('ASB', 'Gene', '411', (288, 291))	('D-SWCNT', 'Var', (256, 263))	('ASB', 'Gene', (288, 291))	('GSNs', 'Chemical', '-', (161, 165))
171272	23634900	Large complex pro-cancer networks for both D-SWNCT and D-MWCNT were characterised by proliferation, tissue development, cell movement and suppressed immune signalling, while ASB cell signalling was primarily driven by pro-inflammatory signalling (Figures S3-S5).	('tissue development', 'biological_process', 'GO:0009888', ('100', '118'))	('signalling', 'biological_process', 'GO:0023052', ('183', '193'))	('cell movement', 'biological_process', 'GO:0006928', ('120', '133'))	('ASB', 'Gene', (174, 177))	('tissue development', 'CPA', (100, 118))	('signalling', 'biological_process', 'GO:0023052', ('156', '166'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('signalling', 'biological_process', 'GO:0023052', ('235', '245'))	('D-SWNCT', 'Var', (43, 50))	('MWCNT', 'Chemical', '-', (57, 62))	('immune signalling', 'MPA', (149, 166))	('cell movement', 'biological_process', 'GO:0048870', ('120', '133'))	('suppressed', 'NegReg', (138, 148))	('cell movement', 'CPA', (120, 133))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('D-MWCNT', 'Var', (55, 62))	('ASB', 'Gene', '411', (174, 177))
171279	23634900	Western blot analysis showed that D-SWCNT, D-MWCNT and ASB possessed over-expressed cFOS, c-Myc and PPARgamma levels (Figure 7B), while the tumour suppressors Inhibin alpha and p53 were under-expressed (Figure 7C).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('PPARgamma', 'Gene', '5468', (100, 109))	('MWCNT', 'Chemical', '-', (45, 50))	('c-Myc', 'MPA', (90, 95))	('cFOS', 'Gene', (84, 88))	('ASB', 'Gene', '411', (55, 58))	('p53', 'Gene', (177, 180))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('p53', 'Gene', '7157', (177, 180))	('Inhibin', 'molecular_function', 'GO:0016916', ('159', '166'))	('over-expressed', 'PosReg', (69, 83))	('D-MWCNT', 'Var', (43, 50))	('tumour', 'Disease', (140, 146))	('Inhibin', 'molecular_function', 'GO:0005160', ('159', '166'))	('ASB', 'Gene', (55, 58))	('cFOS', 'Gene', '2353', (84, 88))	('PPARgamma', 'Gene', (100, 109))
171282	23634900	Given caspase 8's prominence in the GSN analyses and known roles in cancer signalling, blots for pro-caspase 8 (57 kD) showed over-expression in D-SWCNT, D-MWCNT and ASB compared to both SAL and DISP control cells.	('caspase 8', 'Gene', '841', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('caspase 8', 'Gene', (6, 15))	('over-expression', 'PosReg', (126, 141))	('signalling', 'biological_process', 'GO:0023052', ('75', '85'))	('GSN', 'Gene', '2934', (36, 39))	('caspase 8', 'Gene', (101, 110))	('SAL', 'Chemical', 'MESH:D012965', (187, 190))	('D-MWCNT', 'Var', (154, 161))	('D-SWCNT', 'Var', (145, 152))	('MWCNT', 'Chemical', '-', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('ASB', 'Gene', '411', (166, 169))	('cancer', 'Disease', (68, 74))	('GSN', 'Gene', (36, 39))	('ASB', 'Gene', (166, 169))	('caspase 8', 'Gene', '841', (6, 15))
171286	23634900	Both p100 and p52 NFKB2 subunits were diminished in D-MWCNT and ASB cells compared to SAL and DISP cells (Figure 7D).	('ASB', 'Gene', (64, 67))	('NFKB2', 'Gene', '4791', (18, 23))	('SAL', 'Chemical', 'MESH:D012965', (86, 89))	('diminished', 'NegReg', (38, 48))	('p52', 'Gene', (14, 17))	('p52', 'Gene', '4791', (14, 17))	('MWCNT', 'Chemical', '-', (54, 59))	('NFKB2', 'Gene', (18, 23))	('p100', 'Var', (5, 9))	('D-MWCNT', 'Disease', (52, 59))	('ASB', 'Gene', '411', (64, 67))
171294	23634900	A preliminary inhalation exposure study recently reported that MWCNT promote lung carcinogenesis in a mouse initiation/promotion tumour model.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (77, 96))	('MWCNT', 'Chemical', '-', (63, 68))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('promote', 'PosReg', (69, 76))	('lung carcinogenesis', 'Disease', (77, 96))	('mouse', 'Species', '10090', (102, 107))	('MWCNT', 'Var', (63, 68))
171391	23634900	These immortalised cell models, however, may represent the in vivo human lung epithelial cell condition since many lung cancers exhibit mutations in p53 and p16.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('p53', 'Gene', (149, 152))	('p16', 'Gene', (157, 160))	('p53', 'Gene', '7157', (149, 152))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('lung cancers', 'Disease', (115, 127))	('mutations', 'Var', (136, 145))	('lung cancers', 'Disease', 'MESH:D008175', (115, 127))	('human', 'Species', '9606', (67, 72))	('p16', 'Gene', '1029', (157, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
171399	23634900	Lastly, subchronic exposure to both D-SWCNT and D-MWCNT resulted in decreased NF-kappaB inflammatory signalling and complement protein expression that could potentially be linked to altered lipid metabolism and PPARG over-expression.	('NF-kappaB', 'Gene', '4790', (78, 87))	('over-expression', 'PosReg', (217, 232))	('decreased', 'NegReg', (68, 77))	('D-MWCNT', 'Var', (48, 55))	('lipid metabolism', 'biological_process', 'GO:0006629', ('190', '206'))	('NF-kappaB', 'Gene', (78, 87))	('signalling', 'biological_process', 'GO:0023052', ('101', '111'))	('PPARG', 'Gene', '5468', (211, 216))	('PPARG', 'Gene', (211, 216))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('complement protein expression', 'MPA', (116, 145))	('lipid', 'Chemical', 'MESH:D008055', (190, 195))	('MWCNT', 'Chemical', '-', (50, 55))	('D-SWCNT', 'Var', (36, 43))
171402	25979873	Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment.	('depleting', 'Var', (44, 53))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('desmoplasia', 'Disease', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('immunosuppressive tumor', 'Disease', (142, 165))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (142, 165))	('desmoplasia', 'Disease', 'None', (16, 27))
171406	25979873	Prior studies established that depletion of FAP+ cells inhibits tumor growth by augmenting anti-tumor immunity.	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibits', 'NegReg', (55, 63))	('FAP+', 'Var', (44, 48))	('tumor', 'Disease', (96, 101))	('augmenting', 'NegReg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('depletion', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
171421	25979873	Based on the tumor-promoting functions and the therapeutic resistance conferred by tumor stroma, it has been hypothesized that destruction of stromal cells and/or disruption of molecular stromal cell/ECM-dependent pathways would inhibit tumor growth and augment efficacy of other therapeutic modalities.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (237, 242))	('destruction', 'Var', (127, 138))	('disruption', 'Reg', (163, 173))	('tumor', 'Disease', (83, 88))	('efficacy', 'CPA', (262, 270))	('inhibit', 'NegReg', (229, 236))	('augment', 'NegReg', (254, 261))	('tumor stroma', 'Disease', 'MESH:D009369', (83, 95))	('molecular stromal cell/ECM-dependent pathways', 'Pathway', (177, 222))	('tumor stroma', 'Disease', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
171425	25979873	Blockade of the HA-CD44 axis inhibited tumor cell proliferation, survival, invasion and epithelial-to-mesenchymal transition (EMT).	('inhibited', 'NegReg', (29, 38))	('CD44', 'Gene', '12505', (19, 23))	('CD44', 'Gene', (19, 23))	('invasion', 'CPA', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Blockade', 'Var', (0, 8))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('EMT', 'biological_process', 'GO:0001837', ('126', '129'))	('survival', 'CPA', (65, 73))	('epithelial-to-mesenchymal transition', 'CPA', (88, 124))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('88', '124'))	('tumor', 'Disease', (39, 44))
171427	25979873	Furthermore, depletion of HA in the tumor stroma induced a transient increase in vessel density and perfusion that facilitated delivery of gemcitabine into tumors, thereby augmenting efficacy of chemotherapy in a highly desmoplastic mouse model of pancreatic ductal adenocarcinoma (PDA).	('tumor stroma', 'Disease', (36, 48))	('vessel', 'MPA', (81, 87))	('depletion', 'Var', (13, 22))	('gemcitabine', 'Chemical', 'MESH:C056507', (139, 150))	('augmenting', 'PosReg', (172, 182))	('tumor stroma', 'Disease', 'MESH:D009369', (36, 48))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (248, 280))	('increase', 'PosReg', (69, 77))	('facilitated', 'PosReg', (115, 126))	('increase in vessel density', 'Phenotype', 'HP:0002634', (69, 95))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('chemotherapy', 'CPA', (195, 207))	('efficacy', 'MPA', (183, 191))	('pancreatic ductal adenocarcinoma', 'Disease', (248, 280))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('delivery', 'MPA', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (248, 280))	('tumors', 'Disease', (156, 162))	('mouse', 'Species', '10090', (233, 238))	('perfusion', 'MPA', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
171434	25979873	Specific ablation of SMA+ myofibroblasts in mouse models of PDA suppressed anti-tumor immunity, enhanced hypoxia and EMT, and reduced survival.	('SMA', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('ablation', 'Var', (9, 17))	('EMT', 'CPA', (117, 120))	('hypoxia', 'Disease', (105, 112))	('enhanced', 'PosReg', (96, 104))	('suppressed', 'NegReg', (64, 74))	('survival', 'CPA', (134, 142))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PDA', 'Disease', (60, 63))	('tumor', 'Disease', (80, 85))	('mouse', 'Species', '10090', (44, 49))	('reduced', 'NegReg', (126, 133))	('SMA', 'Gene', '20589', (21, 24))
171436	25979873	In contrast to the impact of depleting SMA+ myofibroblasts, targeted deletion of FAP+ cells using genetic and immune-based approaches inhibited tumor growth.	('tumor', 'Disease', (144, 149))	('SMA', 'Gene', (39, 42))	('FAP+ cells', 'Gene', (81, 91))	('inhibited', 'NegReg', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('SMA', 'Gene', '20589', (39, 42))	('deletion', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
171438	25979873	Although our mechanistic understanding of the impact of depleting CASCs is still limited, several studies demonstrated that depleting FAP+ CASCs enhanced anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('depleting', 'Var', (124, 133))	('FAP+', 'Gene', (134, 138))	('enhanced', 'PosReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
171456	25979873	Tumor-bearing mice were randomly assigned to three groups that received FAP-CAR or MigR1-transduced (control) mouse T cells or remained untreated.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MigR1-transduced', 'Gene', (83, 99))	('mice', 'Species', '10090', (14, 18))	('mouse T', 'CellLine', 'CVCL:0594', (110, 117))	('CAR', 'cellular_component', 'GO:0005826', ('76', '79'))	('FAP-CAR', 'Var', (72, 79))
171464	25979873	Extensive accumulation of collagen and glycosaminoglycans (GAGs) was evident in 4662 and A549 tumors compared to in AE17.OVA and I45 tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('accumulation', 'PosReg', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('glycosaminoglycans', 'Chemical', 'MESH:D006025', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('collagen', 'molecular_function', 'GO:0005202', ('26', '34'))	('4662', 'Var', (80, 84))	('A549 tumors', 'Disease', (89, 100))	('A549 tumors', 'Disease', 'MESH:D009369', (89, 100))
171483	25979873	In contrast, the stroma in tumors of mice that received MigR1 T cells was similar to that in the untreated control (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MigR1 T cells', 'Var', (56, 69))	('stroma in tumors', 'Disease', 'MESH:D009369', (17, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('stroma in tumors', 'Disease', (17, 33))	('mice', 'Species', '10090', (37, 41))
171485	25979873	These data prompted us to investigate whether FAP+ CASCs might promote tumor growth through immune-independent stromal-dependent mechanisms.	('FAP+', 'Var', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promote', 'PosReg', (63, 70))	('tumor', 'Disease', (71, 76))
171504	25979873	Quantification of CD31+ (endothelial cell) and NG2+ (pericyte) staining indicated that treatment with FAP-CAR T cells resulted in a 53% decrease (p<0.01) in tumor endothelial cells (Fig.	('tumor', 'Disease', (157, 162))	('decrease', 'NegReg', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CAR', 'cellular_component', 'GO:0005826', ('106', '109'))	('NG2', 'Gene', '13003', (47, 50))	('CD31', 'Gene', '18613', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('FAP-CAR T cells', 'Var', (102, 117))	('CD31', 'Gene', (18, 22))	('NG2', 'Gene', (47, 50))
171510	25979873	The effects of conditional FAP+ CASC depletion indicate that these cells are critical for maintenance of desmoplasia.	('FAP+', 'Gene', (27, 31))	('desmoplasia', 'Disease', (105, 116))	('conditional', 'Var', (15, 26))	('desmoplasia', 'Disease', 'None', (105, 116))
171515	25979873	Furthermore, antibody-mediated depletion of either CD4+ or CD8+ T cells did not change tumor growth relative to isotype-treated controls (data not shown).	('antibody', 'molecular_function', 'GO:0003823', ('13', '21'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD4', 'Gene', (51, 54))	('CD4', 'Gene', '12504', (51, 54))	('tumor', 'Disease', (87, 92))	('antibody', 'cellular_component', 'GO:0042571', ('13', '21'))	('antibody', 'cellular_component', 'GO:0019815', ('13', '21'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('antibody', 'cellular_component', 'GO:0019814', ('13', '21'))	('CD8+', 'Var', (59, 63))
171517	25979873	Seven days following the administration of the second dose of T cells, the growth of 4662 PDA was reduced by 36% (p<0.05) in immune-competent C57BL/6 mice that received FAP-CAR T cells relative to the tumors from mice treated with MigR1 T cells (Fig.	('mice', 'Species', '10090', (150, 154))	('growth', 'MPA', (75, 81))	('mice', 'Species', '10090', (213, 217))	('FAP-CAR', 'Var', (169, 176))	('4662', 'Var', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('reduced', 'NegReg', (98, 105))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('CAR', 'cellular_component', 'GO:0005826', ('173', '176'))
171519	25979873	Flow cytometric analysis also demonstrated infiltration of the adoptively transferred GFP+ FAP CAR T cells into 4662 tumors (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GFP+', 'Var', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('CAR', 'cellular_component', 'GO:0005826', ('95', '98'))
171529	25979873	7A) following treatment with FAP-CAR T cells, while HA and versican were reduced by 34-52% (Fig.	('reduced', 'NegReg', (73, 80))	('FAP-CAR T cells', 'Var', (29, 44))	('CAR', 'cellular_component', 'GO:0005826', ('33', '36'))	('versican', 'Gene', '13003', (59, 67))	('versican', 'Gene', (59, 67))
171533	25979873	Clinicopathological studies indicate that accumulation of FAP+ CASCs is associated with tumor progression, metastasis, and predicts poorer outcome in many types of human malignancies, including PDA and colon cancer.	('malignancies', 'Disease', (170, 182))	('metastasis', 'CPA', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PDA', 'Disease', (194, 197))	('human', 'Species', '9606', (164, 169))	('FAP+ CASCs', 'Var', (58, 68))	('accumulation', 'PosReg', (42, 54))	('associated', 'Reg', (72, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('tumor', 'Disease', (88, 93))	('colon cancer', 'Disease', (202, 214))
171535	25979873	Taken together, these data indicate that deleting FAP+ CASCs and SMA+ myofibroblasts can have opposing effects, highlighting the phenotypic and functional heterogeneity of tumor stromal cells.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('SMA', 'Gene', '20589', (65, 68))	('SMA', 'Gene', (65, 68))	('FAP+', 'Gene', (50, 54))	('tumor stroma', 'Disease', 'MESH:D009369', (172, 184))	('deleting', 'Var', (41, 49))	('tumor stroma', 'Disease', (172, 184))
171538	25979873	These mechanisms bode well for combining stromal-targeted CAR T cell therapy with cancer vaccines or immunological checkpoint antagonists such as anti-CTLA-4, anti-PD-1 or anti-PD-L1.	('CTLA-4', 'Gene', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PD-L1', 'Gene', (177, 182))	('cancer', 'Disease', (82, 88))	('PD-L1', 'Gene', '60533', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CAR', 'cellular_component', 'GO:0005826', ('58', '61'))	('anti-PD-1', 'Var', (159, 168))	('CTLA-4', 'Gene', '12477', (151, 157))
171549	25979873	Moreover, FAP-CAR T cell-mediated matrix modification may have augmented anti-tumor immunity by influencing immune cell recruitment and/or motility, as matrix architecture has been shown to regulate intratumoral T cell localization and migration.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('influencing', 'Reg', (96, 107))	('augmented', 'PosReg', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('migration', 'CPA', (236, 245))	('tumor', 'Disease', (204, 209))	('motility', 'CPA', (139, 147))	('cell localization', 'biological_process', 'GO:0051674', ('214', '231'))	('tumor', 'Disease', (78, 83))	('matrix modification', 'Var', (34, 53))	('CAR', 'cellular_component', 'GO:0005826', ('14', '17'))	('regulate', 'Reg', (190, 198))	('immune cell recruitment', 'CPA', (108, 131))
171562	25979873	Instead, tumors that received FAP-CAR T cell treatment exhibited a reduced proliferative index and an increased apoptotic index compared either to MigR1 T cell-treated or untreated tumors.	('apoptotic index', 'CPA', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('increased apoptotic index', 'Phenotype', 'HP:0030887', (102, 127))	('reduced', 'NegReg', (67, 74))	('FAP-CAR', 'Var', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('proliferative index', 'CPA', (75, 94))	('CAR', 'cellular_component', 'GO:0005826', ('34', '37'))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
171564	25979873	Recent studies raised the concern that ablation of FAP+ stromal cells could induce bone marrow hypocellularity and cachexia in mice.	('mice', 'Species', '10090', (127, 131))	('bone marrow hypocellularity', 'Disease', 'MESH:D001855', (83, 110))	('bone marrow hypocellularity', 'Disease', (83, 110))	('cachexia', 'Disease', 'MESH:D002100', (115, 123))	('cachexia', 'Disease', (115, 123))	('ablation', 'Var', (39, 47))	('induce', 'PosReg', (76, 82))	('bone marrow hypocellularity', 'Phenotype', 'HP:0005528', (83, 110))	('cachexia', 'Phenotype', 'HP:0004326', (115, 123))	('FAP+', 'Gene', (51, 55))
171573	25979873	In summary, the results presented herein provide proof-of-concept that, in addition to suppressing adaptive anti-tumor immunity, FAP+ CASCs orchestrate tumor-promoting effects by enhancing tumor angiogenesis and desmoplasia.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('FAP+ CASCs', 'Var', (129, 139))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('enhancing', 'PosReg', (179, 188))	('angiogenesis', 'biological_process', 'GO:0001525', ('195', '207'))	('desmoplasia', 'Disease', 'None', (212, 223))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('desmoplasia', 'Disease', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
171834	25756049	Gee and colleagues identified a panel of miR that were specifically downregulated in MPM (irregardless of histological subtype) compared to lung adenocarcinoma and included miR-141, miR-200a*, miR-200b, miR-200c, miR-203, miR-205, and miR-429.	('miR-200b', 'Gene', (193, 201))	('miR-200c', 'Gene', '406985', (203, 211))	('miR-429', 'Gene', (235, 242))	('downregulated', 'NegReg', (68, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('MPM', 'Disease', (85, 88))	('miR-141', 'Gene', '406933', (173, 180))	('miR-200a*', 'Var', (182, 191))	('miR-205', 'Gene', (222, 229))	('lung adenocarcinoma', 'Disease', (140, 159))	('miR-205', 'Gene', '406988', (222, 229))	('miR-200b', 'Gene', '406984', (193, 201))	('miR-203', 'Gene', (213, 220))	('miR-203', 'Gene', '406986', (213, 220))	('miR-200c', 'Gene', (203, 211))	('miR-429', 'Gene', '554210', (235, 242))	('miR-141', 'Gene', (173, 180))
171842	25756049	It has been shown that SV40 induces HGF/Met receptor activation, telomerase activity, and Notch-1 activation in human mesothelial cells and MPM biopsy samples.	('HGF/Met receptor', 'Protein', (36, 52))	('activation', 'PosReg', (98, 108))	('activation', 'PosReg', (53, 63))	('activity', 'MPA', (76, 84))	('telomerase activity', 'molecular_function', 'GO:0003720', ('65', '84'))	('SV40', 'Var', (23, 27))	('Notch-1', 'Gene', '4851', (90, 97))	('Notch-1', 'Gene', (90, 97))	('telomerase', 'CPA', (65, 75))
171977	32731396	Median survival time of malignant mesothelioma patients with high level of SDC-1 was significantly shorter (2.4 months) compared to patients with low shed SDC-1 level (9.6 months) (p = 0.03) (Figure 4B).	('shorter', 'NegReg', (99, 106))	('SDC-1', 'Gene', (75, 80))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (24, 46))	('patients', 'Species', '9606', (47, 55))	('SDC-1', 'Gene', '6382', (155, 160))	('high level', 'Var', (61, 71))	('SDC-1', 'Gene', (155, 160))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (24, 46))	('patients', 'Species', '9606', (132, 140))	('SDC-1', 'Gene', '6382', (75, 80))	('malignant mesothelioma', 'Disease', (24, 46))
171996	32731396	The corresponding AUCs were 0.99, 0.97, 0.95, 0.94, 0.93, 0.84 and 0.83 for Galectin-1, NRG1-beta1, Osteopontin, Mesothelin, shed SDC-1, VEGF and TIMP-1, respectively, whereas the AUCs were 0.75 and 0.56 for HGF and MMP-7, respectively.	('0.83', 'Var', (67, 71))	('MMP-7', 'Gene', (216, 221))	('Osteopontin', 'Gene', '6696', (100, 111))	('Galectin-1', 'Gene', '3956', (76, 86))	('SDC-1', 'Gene', '6382', (130, 135))	('Osteopontin', 'Gene', (100, 111))	('beta1', 'Gene', (93, 98))	('SDC-1', 'Gene', (130, 135))	('VEGF', 'Gene', '7422', (137, 141))	('beta1', 'Gene', '28881', (93, 98))	('MMP-7', 'molecular_function', 'GO:0004235', ('216', '221'))	('NRG1', 'Gene', (88, 92))	('HGF', 'Gene', '3082', (208, 211))	('Galectin-1', 'Gene', (76, 86))	('NRG1', 'Gene', '3084', (88, 92))	('VEGF', 'Gene', (137, 141))	('MMP-7', 'Gene', '4316', (216, 221))	('Mesothelin', 'Gene', '10232', (113, 123))	('HGF', 'Gene', (208, 211))	('TIMP-1', 'Gene', (146, 152))	('TIMP-1', 'Gene', '7076', (146, 152))	('Galectin', 'molecular_function', 'GO:0001577', ('76', '84'))	('Mesothelin', 'Gene', (113, 123))
172034	30618090	Lung cancer and mesothelioma deaths were identified using codes C34 and C45, respectively.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('mesothelioma deaths', 'Disease', 'MESH:D008654', (16, 35))	('C34', 'Var', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('C45', 'Var', (72, 75))	('mesothelioma deaths', 'Disease', (16, 35))
172118	30300374	Many small molecule inhibitors of Top1 have proven clinically effective, the most potent being the camptothecin (CPT) derivatives (Fig 1).	('Top1', 'Gene', (34, 38))	('inhibitors', 'Var', (20, 30))	('CPT', 'molecular_function', 'GO:0004142', ('113', '116'))	('CPT', 'Chemical', 'MESH:D002166', (113, 116))	('CPT', 'molecular_function', 'GO:0004095', ('113', '116'))	('camptothecin', 'Chemical', 'MESH:D002166', (99, 111))
172123	30300374	HDAC inhibition has been reported to affect cancer cells mainly by a global relaxation of chromatin structure, which contributes to a recovered cell response to chemotherapeutic agents targeting DNA.	('HDAC', 'Gene', (0, 4))	('relaxation', 'NegReg', (76, 86))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('chromatin structure', 'MPA', (90, 109))	('N', 'Chemical', 'MESH:D009584', (196, 197))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
172124	30300374	In this respect, there is a lot of evidence showing that co-treatment with HDAC inhibitors and camptothecin derivatives (such as Topotecan, Irinotecan) synergistically block cell proliferation.	('cell proliferation', 'CPA', (174, 192))	('cell proliferation', 'biological_process', 'GO:0008283', ('174', '192'))	('block', 'NegReg', (168, 173))	('camptothecin', 'Chemical', 'MESH:D002166', (95, 107))	('Irinotecan', 'Chemical', 'MESH:D000077146', (140, 150))	('HDAC', 'Gene', (75, 79))	('HDAC', 'Gene', '9734', (75, 79))	('Topotecan', 'Chemical', 'MESH:D019772', (129, 138))	('inhibitors', 'Var', (80, 90))
172189	30300374	Human primary epithelioid MM288, MM317, MM404, MM473, MM473-Luc; biphasic MM487 and MM491; sarcomatoid MM432 and MM472 mesothelioma cell lines (all from our cell bank collection).	('sarcomatoid', 'Disease', 'MESH:C538614', (91, 102))	('Human', 'Species', '9606', (0, 5))	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('MM288', 'CellLine', 'CVCL:J871', (26, 31))	('MM473', 'Var', (47, 52))	('MM472', 'CellLine', 'CVCL:C845', (113, 118))	('sarcomatoid', 'Disease', (91, 102))	('MM317', 'Var', (33, 38))	('mesothelioma', 'Disease', (119, 131))	('MM404', 'Var', (40, 45))
172192	30300374	All primary mesothelioma cell lines (MM288, MM317, MM404, MM473, MM487, MM491, MM432, MM472) were cultured in F-10 Nutrient Mixture medium supplemented with 10% Foetal Bovine Serum (FBS), 2 mM L-glutamine and gentamicin sulfate.	('Bovine', 'Species', '9913', (168, 174))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (4, 24))	('MM288', 'CellLine', 'CVCL:J871', (37, 42))	('MM472', 'Var', (86, 91))	('N', 'Chemical', 'MESH:D009584', (115, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))	('MM288', 'Var', (37, 42))	('MM404', 'Var', (51, 56))	('mesothelioma', 'Disease', (12, 24))	('MM473', 'Var', (58, 63))	('gentamicin sulfate', 'Chemical', 'MESH:D005839', (209, 227))	('L-glutamine', 'Chemical', 'MESH:D005973', (193, 204))	('MM491', 'Var', (72, 77))	('MM472', 'CellLine', 'CVCL:C845', (86, 91))	('MM432', 'Var', (79, 84))	('MM487', 'Var', (65, 70))	('MM317', 'Var', (44, 49))
172194	30300374	A2780, A2780-Dx, ARH-77, DG-75, Jurkat, KM-H2, HeLa, L-428, NB4, NCI-H60, U937, RAJI, REC-1, RPMI-8226, and U-2932 cells were cultured in RPMI-1640 medium supplemented with 10% FBS, 2 mM L-glutamine and gentamicin sulfate.	('ARH', 'Gene', '26119', (17, 20))	('RPMI-1640 medium', 'Chemical', '-', (138, 154))	('U-2932', 'CellLine', 'CVCL:1896', (108, 114))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('HeLa', 'CellLine', 'CVCL:0030', (47, 51))	('ARH', 'Gene', (17, 20))	('gentamicin sulfate', 'Chemical', 'MESH:D005839', (203, 221))	('L-glutamine', 'Chemical', 'MESH:D005973', (187, 198))	('Jurkat', 'CellLine', 'CVCL:0065', (32, 38))	('U937', 'CellLine', 'CVCL:0007', (74, 78))	('A2780-Dx', 'Var', (7, 15))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('A2780', 'Var', (0, 5))
172214	30300374	Subsequently, the membrane was incubated overnight with primary antibodies: anti-Histone H4 (Millipore, 1:500), anti-acetyl-H4 (Santa Cruz, 1:1000) anti-p21 (Santa Cruz, 1:1000), anti-acetyl-tubulin (abcam, 1:1000), anti-alpha-tubulin (Sigma, 1:5000), anti beta-actin (Sigma, 1:5000) and anti-Topoisomerase 1 (Santa Cruz, 1:500).	('C', 'Chemical', 'MESH:D002244', (316, 317))	('Topoisomerase', 'molecular_function', 'GO:0003918', ('293', '306'))	('anti-alpha-tubulin', 'Var', (216, 234))	('anti-acetyl-tubulin', 'Var', (179, 198))	('Histone H4', 'Gene', '8366', (81, 91))	('membrane', 'cellular_component', 'GO:0016020', ('18', '26'))	('Topoisomerase', 'molecular_function', 'GO:0003917', ('293', '306'))	('anti-acetyl-H4', 'Var', (112, 126))	('beta-actin', 'Gene', '728378', (257, 267))	('p21', 'Gene', (153, 156))	('beta-actin', 'Gene', (257, 267))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('p21', 'Gene', '644914', (153, 156))	('Histone H4', 'Gene', (81, 91))	('C', 'Chemical', 'MESH:D002244', (164, 165))
172234	30300374	Each docking consisted of an initial population of 100 randomly placed individuals, a maximum number of 200 energy evaluations, a mutation rate of 0.02, a crossover rate of 0.80, and an elitism value of 1.	('mutation', 'Var', (130, 138))	('elitism', 'Disease', 'None', (186, 193))	('elitism', 'Disease', (186, 193))
172257	30300374	Compounds 3b and 3d show a hydrogen bond between the nitrogen atom N1 of ring B and R364NH2 residue, which also forms an additional hydrogen bond between R364NH1 and the OH group of the lactone ring E of all five compounds (see Table 1).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('R364NH2', 'Var', (84, 91))	('nitrogen', 'Chemical', 'MESH:D009584', (53, 61))	('hydrogen', 'Chemical', 'MESH:D006859', (132, 140))	('hydrogen', 'Chemical', 'MESH:D006859', (27, 35))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('R364NH2', 'Chemical', '-', (84, 91))	('lactone', 'Chemical', 'MESH:D007783', (186, 193))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('R364NH1', 'Var', (154, 161))
172261	30300374	The interaction pattern of the compound 3d within the binding site is completed by a hydrogen bond between the camptothecin phenolic 10-hydroxy and E356Oepsilon2, an interaction clearly impossible for the other compounds.	('interaction', 'Interaction', (4, 15))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('E356Oepsilon2', 'Var', (148, 161))	('camptothecin', 'Chemical', 'MESH:D002166', (111, 123))	('hydrogen', 'Chemical', 'MESH:D006859', (85, 93))	('hydrogen bond', 'MPA', (85, 98))
172264	30300374	The only interaction common to all the studied compounds is the hydrogen bond between (-1)A113H62 and the oxygen of the oxime group, that only in 3b forms a second hydrogen bond with (-1)A113H61.	('hydrogen', 'Chemical', 'MESH:D006859', (64, 72))	('oxygen', 'Chemical', 'MESH:D010100', (106, 112))	('oxime', 'Chemical', 'MESH:D010091', (120, 125))	('A113H62', 'Var', (90, 97))	('hydrogen', 'Chemical', 'MESH:D006859', (164, 172))	('-1', 'Var', (87, 89))
172265	30300374	The C = O group of the 3a side chain interact with K425NzetaH1, while 3b forms a bidentate bond with both K425NzetaH1 and K425NzetaH2.	('K425NzetaH1', 'Chemical', '-', (106, 117))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('K425NzetaH2', 'Chemical', '-', (122, 133))	('K425NzetaH1', 'Var', (51, 62))	('K425NzetaH1', 'Chemical', '-', (51, 62))	('interact', 'Interaction', (37, 45))	('K425NzetaH1', 'Var', (106, 117))	('K425NzetaH2', 'Var', (122, 133))
172266	30300374	The interaction with K425 is absent in 3c-d and 10, where the C = O group is rotated to form a hydrogen bond with W416Nepsilon1.	('hydrogen', 'Chemical', 'MESH:D006859', (95, 103))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('K425', 'Chemical', '-', (21, 25))	('W416Nepsilon1', 'Var', (114, 127))	('K425', 'Var', (21, 25))	('N', 'Chemical', 'MESH:D009584', (118, 119))
172267	30300374	The interaction of the hydroxyamic NH group with the target is present only for compounds 3a, 3c and 3d, involving however different residues: 3a with Y426O, 3c with E356Oepsilon2, 3d with K354O.	('interaction', 'Interaction', (4, 15))	('K354O', 'Chemical', '-', (189, 194))	('Y426O', 'Chemical', '-', (151, 156))	('E356Oepsilon2', 'Var', (166, 179))	('hydroxyamic', 'Chemical', '-', (23, 34))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('Y426O', 'Var', (151, 156))	('K354O', 'Var', (189, 194))
172268	30300374	Finally, the interaction pattern of the side chains is completed by the interactions of the hydroxamic OH group with the DNA-topoisomerase-I system, present only in 3b, 3c and 3d, but also in this case with different residues: 3b with (-1)A113N7, (-1)A114H61 and K425NzetaH2, 3c with E356N and K354O, 3d with E356Oepsilon2.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('K354O', 'Chemical', '-', (294, 299))	('A114H61', 'Var', (251, 258))	('E356N', 'Var', (284, 289))	('E356Oepsilon2', 'Var', (309, 322))	('N', 'Chemical', 'MESH:D009584', (267, 268))	('N', 'Chemical', 'MESH:D009584', (288, 289))	('topoisomerase', 'molecular_function', 'GO:0003917', ('125', '138'))	('E356N', 'SUBSTITUTION', 'None', (284, 289))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('topoisomerase', 'molecular_function', 'GO:0003918', ('125', '138'))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('K425NzetaH2', 'Chemical', '-', (263, 274))	('interactions', 'Interaction', (72, 84))	('4H', 'Chemical', '-', (254, 256))	('K425NzetaH2', 'Var', (263, 274))	('-1', 'Var', (248, 250))	('K354O', 'Var', (294, 299))
172271	30300374	Their common interactions include a hydrogen bond from the hydroxamic NH towards G154O and two interaction involving the hydroxamic C = O group; a hydrogen bond with H183Hdelta1 and the chelation of the catalytic Zn2+ ion (Table 2).	('hydrogen', 'Chemical', 'MESH:D006859', (36, 44))	('interactions', 'Interaction', (13, 25))	('Zn2+', 'Chemical', 'MESH:D015032', (213, 217))	('chelation', 'MPA', (186, 195))	('G154', 'Chemical', '-', (81, 85))	('hydrogen', 'Chemical', 'MESH:D006859', (147, 155))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('hydrogen bond', 'Interaction', (147, 160))	('G154O', 'Var', (81, 86))	('N', 'Chemical', 'MESH:D009584', (70, 71))
172272	30300374	The residue Y308 is directly involved only in the binding of the compounds having the spacer with n = 5 (3b and 3d), through a hydrogen bond involving Y308O and the C = O group of both compounds, and a further hydrogen bond between Y308O and the hydroxamic OH of the 3d compound alone, which further stabilizes its conformation.	('Y308', 'Chemical', '-', (232, 236))	('hydrogen', 'Interaction', (210, 218))	('Y308O', 'Var', (151, 156))	('Y308', 'Chemical', '-', (151, 155))	('Y308O', 'Chemical', '-', (151, 156))	('hydrogen', 'Chemical', 'MESH:D006859', (127, 135))	('hydrogen', 'Chemical', 'MESH:D006859', (210, 218))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('Y308O', 'Var', (232, 237))	('stabilizes', 'Reg', (300, 310))	('Y308O', 'Chemical', '-', (232, 237))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('Y308', 'Chemical', '-', (12, 16))	('Y308', 'Var', (12, 16))
172273	30300374	Compound 10 still exhibits the interactions with G154 and H146, but there is no hydrogen bond with Y308.	('Y308', 'Chemical', '-', (99, 103))	('G154', 'Var', (49, 53))	('interactions', 'Interaction', (31, 43))	('G154', 'Chemical', '-', (49, 53))	('H146', 'Chemical', '-', (58, 62))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('H146', 'Var', (58, 62))	('hydrogen', 'Chemical', 'MESH:D006859', (80, 88))
172274	30300374	The loss of the interaction with Y308 is almost certainly attributable to the non-optimal spacer length, considering that the same effect is also found in compounds 3a and 3c.	('Y308', 'Var', (33, 37))	('Y308', 'Chemical', '-', (33, 37))	('loss', 'NegReg', (4, 8))	('interaction', 'Interaction', (16, 27))
172275	30300374	Furthermore, unlike 3a-d compounds, in 10 the zinc ion is complexed by the sulfur atom, which also interacts with rings of H145, H146 and Y308, forming three Pi-Sulfur interactions.	('Sulfur', 'Chemical', 'MESH:D013455', (161, 167))	('H146', 'Chemical', '-', (129, 133))	('H145', 'Var', (123, 127))	('forming', 'Reg', (144, 151))	('H146', 'Var', (129, 133))	('sulfur', 'Chemical', 'MESH:D013455', (75, 81))	('Y308', 'Chemical', '-', (138, 142))	('Y308', 'Var', (138, 142))	('complexed', 'Interaction', (58, 67))	('Pi-Sulfur', 'MPA', (158, 167))
172278	30300374	For 3a-c the only observed pi-pi stacking interactions are with the residue Y209 (3a-c), while only 3a is able to form a pi-pi stacking with F210, evidently aided by the shorter linker that forces the camptothecin skeleton to approach the surface.	('pi-pi', 'Var', (27, 32))	('camptothecin', 'Chemical', 'MESH:D002166', (201, 213))	('Y209', 'Var', (76, 80))
172280	30300374	These two structural features provide 3d with the possibility of tightly interacting with the external surface through two strong hydrogen bonds, one between the OH of the lactone E ring and D104Odelta1 and the other between the phenolic 10-hydroxy and E208O.	('lactone', 'Chemical', 'MESH:D007783', (172, 179))	('E208O', 'Var', (253, 258))	('D104Odelta1', 'Chemical', '-', (191, 202))	('hydrogen', 'Chemical', 'MESH:D006859', (130, 138))	('D104Odelta1', 'Var', (191, 202))	('interacting', 'Interaction', (73, 84))
172378	25253633	In cases were these analyses were inconclusive Fluorescence in situ hybridization (FISH) was performed, to identify cell population with aneuploidy and/or homozygous deletion of Cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, coding for the p16INK4A protein.	('p16INK4A', 'Gene', (245, 253))	('deletion', 'Var', (166, 174))	('aneuploidy', 'Disease', 'MESH:D000782', (137, 147))	('p16INK4A', 'Gene', '1029', (245, 253))	('CDKN2A', 'Gene', (216, 222))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('195', '211'))	('aneuploidy', 'Disease', (137, 147))	('CDKN2A', 'Gene', '1029', (216, 222))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('178', '211'))
172423	25253633	Primary cell cultures with a higher ICC score for RRM1 were more resistant to the antimicrotubule agents (except paclitaxel), topotecan, hydroxyurea, gemcitabine, methotrexate, bleomycin and doxorubicin, compared to those with a lower ICC score.	('doxorubicin', 'Chemical', 'MESH:D004317', (191, 202))	('topotecan', 'Chemical', 'MESH:D019772', (126, 135))	('methotrexate', 'Chemical', 'MESH:D008727', (163, 175))	('hydroxyurea', 'Chemical', 'MESH:D006918', (137, 148))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))	('gemcitabine', 'Chemical', 'MESH:C056507', (150, 161))	('RRM1', 'Gene', '6240', (50, 54))	('bleomycin', 'Chemical', 'MESH:D001761', (177, 186))	('RRM1', 'Gene', (50, 54))	('score', 'Var', (40, 45))	('resistant to', 'MPA', (65, 77))	('antimicrotubule agents', 'MPA', (82, 104))
172429	25253633	In six of these a homozygous deletion of 9p21 band could be demonstrated, but presence of this did not correlate to patient data, drug sensitivity of cells or RRM1 and ERCC1 staining.	('deletion', 'Var', (29, 37))	('ERCC1', 'Gene', (168, 173))	('patient', 'Species', '9606', (116, 123))	('ERCC1', 'Gene', '2067', (168, 173))	('drug sensitivity', 'Phenotype', 'HP:0020174', (130, 146))	('RRM1', 'Gene', '6240', (159, 163))	('RRM1', 'Gene', (159, 163))	('9p21', 'Gene', (41, 45))
172494	24655565	The pathogenic mechanisms underlying mesothelioma involve epigenetic gene regulation and deregulation of multiple signaling pathways, including sonic hedgehog signalling, activation of multiple receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, the TNF-alpha/NF-kappaB survival pathway, Wnt signaling, and loss of tumor suppressors such as Neurofibromatosis type 2, p16INK4A, and p14ARF.	('p14ARF', 'Gene', '1029', (560, 566))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('signaling', 'biological_process', 'GO:0023052', ('471', '480'))	('Neurofibromatosis type 2', 'Disease', 'MESH:C537392', (520, 544))	('MAPK', 'molecular_function', 'GO:0004707', ('354', '358'))	('TNF-alpha/NF-kappaB survival pathway', 'Pathway', (429, 465))	('EGFR', 'Gene', '1956', (266, 270))	('p14ARF', 'Gene', (560, 566))	('PI3K', 'molecular_function', 'GO:0016303', ('395', '399'))	('AKT', 'Gene', (401, 404))	('protein', 'cellular_component', 'GO:0003675', ('338', '345'))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('loss of tumor', 'Disease', 'MESH:D009369', (486, 499))	('Wnt signaling', 'Pathway', (467, 480))	('epidermal growth factor receptor', 'Gene', (232, 264))	('sonic', 'Gene', (144, 149))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('232', '255'))	('p16INK4A', 'Gene', (546, 554))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('epidermal growth factor receptor', 'Gene', '1956', (232, 264))	('p16INK4A', 'Gene', '1029', (546, 554))	('AKT signaling', 'biological_process', 'GO:0043491', ('401', '414'))	('deregulations', 'Var', (303, 316))	('activation', 'PosReg', (171, 181))	('AKT', 'Gene', '207', (401, 404))	('EGFR', 'Gene', (266, 270))	('signalling', 'biological_process', 'GO:0023052', ('159', '169'))	('tumor', 'Phenotype', 'HP:0002664', (494, 499))	('mesothelioma', 'Disease', (37, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('266', '270'))	('loss of tumor', 'Disease', (486, 499))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (520, 537))	('Neurofibromatosis type 2', 'Disease', (520, 544))
172499	24655565	Prognosis is poor for all MMs, but sarcomatoid MMs have a particularly poor response rate to treatment: a significant association between high expression of CYP19A1 and sarcomatoid MPMs was found.	('sarcomatoid MMs', 'Disease', (35, 50))	('sarcomatoid MPMs', 'Disease', 'MESH:C538614', (169, 185))	('sarcomatoid MMs', 'Phenotype', 'HP:0100242', (35, 50))	('sarcomatoid MPMs', 'Disease', (169, 185))	('sarcomatoid MMs', 'Disease', 'MESH:C538614', (35, 50))	('CYP19A1', 'Gene', '1588', (157, 164))	('CYP19A1', 'Gene', (157, 164))	('men', 'Species', '9606', (98, 101))	('high', 'Var', (138, 142))
172519	24655565	Upon 24 h exemestane treatment MSTO resulted in a cell cycle arrest in S-phase (Figure 1E).	('arrest', 'Disease', (61, 67))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('S-phase', 'biological_process', 'GO:0051320', ('71', '78'))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('50', '67'))	('men', 'Species', '9606', (26, 29))	('MSTO', 'Var', (31, 35))	('exemestane', 'Chemical', 'MESH:C056516', (10, 20))
172533	24655565	To test this assumption, we silenced CD44 in MSTO and NCI and then investigated the effect on migration.	('CD44', 'Gene', '960', (37, 41))	('CD44', 'Gene', (37, 41))	('silenced', 'Var', (28, 36))	('NCI', 'Gene', (54, 57))	('investigated', 'Reg', (67, 79))	('MSTO', 'Gene', (45, 49))
172534	24655565	The silencing of CD44 in MSTO and NCI inhibited the wound healing confirming the role of CD44 in cell migration (2D).	('CD44', 'Gene', '960', (17, 21))	('wound healing', 'CPA', (52, 65))	('wound healing', 'biological_process', 'GO:0042060', ('52', '65'))	('CD44', 'Gene', '960', (89, 93))	('CD44', 'Gene', (17, 21))	('inhibited', 'NegReg', (38, 47))	('CD44', 'Gene', (89, 93))	('silencing', 'Var', (4, 13))	('MSTO', 'Gene', (25, 29))	('cell migration', 'biological_process', 'GO:0016477', ('97', '111'))
172536	24655565	It is evident that the silencing of CD44 kills both cell lines, consequently, we can deduce that CD44 was essential in the cellular growth.	('cellular growth', 'biological_process', 'GO:0016049', ('123', '138'))	('CD44', 'Gene', (97, 101))	('CD44', 'Gene', (36, 40))	('silencing', 'Var', (23, 32))	('CD44', 'Gene', '960', (97, 101))	('CD44', 'Gene', '960', (36, 40))
172550	24655565	40 days after the end of treatments, 3 mice treated with cisplatin-pemetrexed were dead and only 1 showed a complete reduction in the mass, while in mice treated with exemestane-pemetrexed 1 was dead and 7 showed a complete reduction of the mass.	('reduction', 'NegReg', (117, 126))	('mass', 'MPA', (134, 138))	('mice', 'Species', '10090', (149, 153))	('men', 'Species', '9606', (30, 33))	('exemestane-pemetrexed', 'Chemical', '-', (167, 188))	('cisplatin-pemetrexed', 'Chemical', '-', (57, 77))	('cisplatin-pemetrexed', 'Var', (57, 77))	('mice', 'Species', '10090', (39, 43))
172586	24655565	The silencing of CD44 in MSTO and NCI confirms the importance of CD44 in cell migration and suggests its essential in the response to the drug, although the direct target of exemestane might be a factor upstream of CD44 that in NCI gives it resistance.	('CD44', 'Gene', '960', (215, 219))	('CD44', 'Gene', '960', (17, 21))	('cell migration', 'biological_process', 'GO:0016477', ('73', '87'))	('CD44', 'Gene', (215, 219))	('exemestane', 'Chemical', 'MESH:C056516', (174, 184))	('CD44', 'Gene', (17, 21))	('cell migration', 'CPA', (73, 87))	('CD44', 'Gene', '960', (65, 69))	('resistance', 'MPA', (241, 251))	('silencing', 'Var', (4, 13))	('CD44', 'Gene', (65, 69))
172599	24655565	PI3K phosphorylates AKT (pAkt) which in turn regulates Bcl-xL, anti-apoptotic protein.	('AKT', 'Gene', (20, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('Bcl-xL', 'Gene', '598', (55, 61))	('anti-apoptotic protein', 'MPA', (63, 85))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('regulates', 'Reg', (45, 54))	('AKT', 'Gene', '207', (20, 23))	('Bcl-xL', 'Gene', (55, 61))
172628	24655565	In lung cancer, where studies of CYP19A1 are at a more advanced stage, some clinical studies consider the inhibitors of CYP19A1 an anti-oestrogen.	('lung cancer', 'Disease', (3, 14))	('CYP19A1', 'Gene', '1588', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('CYP19A1', 'Gene', '1588', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('inhibitors', 'Var', (106, 116))	('CYP19A1', 'Gene', (33, 40))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('CYP19A1', 'Gene', (120, 127))
172656	24655565	Cells were incubated with siRNA for 5 hours and then left for 48 hours to achieve knockdown of CD44 protein as measured by immunoblot.	('CD44', 'Gene', '960', (95, 99))	('protein', 'Protein', (100, 107))	('knockdown', 'Var', (82, 91))	('CD44', 'Gene', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))
172897	20175889	Cytogenetic analysis revealed rearrangement of the short arm of chromosome 1, an aberration frequently reported in mesothelioma karyotypes (56% of the cases), as well as rearrangements of the short arm of chromosome 3 that are found in 51% of the cases, deletion accounting for nearly half of them (48%).	('rearrangement', 'Var', (30, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('rearrangements', 'Var', (170, 184))	('mesothelioma', 'Disease', (115, 127))	('short arm', 'Phenotype', 'HP:0009824', (192, 201))	('chromosome', 'cellular_component', 'GO:0005694', ('205', '215'))	('deletion', 'Var', (254, 262))	('short arm', 'Phenotype', 'HP:0009824', (51, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (115, 127))
172898	20175889	Sandberg and Bridge proposed a scheme for the stepwise process of genetic changes leading to the full development of malignant mesothelioma.	('malignant mesothelioma', 'Disease', (117, 139))	('genetic changes', 'Var', (66, 81))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (117, 139))	('leading to', 'Reg', (82, 92))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (117, 139))
172899	20175889	In this scheme a deletion in the short arm of chromosome 3 is a late event and deletion of chromosome 1 is mainly found in metastatic tumors.	('short arm', 'Phenotype', 'HP:0009824', (33, 42))	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('deletion', 'Var', (17, 25))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
172911	20175889	A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells, in osteosarcoma and prostate cancer.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('CD99', 'Gene', '4267', (20, 24))	('human', 'Species', '9606', (68, 73))	('osteosarcoma and prostate cancer', 'Disease', 'MESH:D011471', (98, 130))	('MMP-9', 'molecular_function', 'GO:0004229', ('48', '53'))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('increases', 'PosReg', (25, 34))	('splice variant', 'Var', (2, 16))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('expression', 'MPA', (54, 64))	('MMP-9', 'Gene', '4318', (48, 53))	('breast cancer', 'Disease', (74, 87))	('motility', 'CPA', (35, 43))	('MMP-9', 'Gene', (48, 53))	('CD99', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
172919	20175889	It is already known that Wnt signaling is an osteoinductive signal that promotes differentiation of osteo-progenitors and that, in human mesenchymal stem cell the inhibition of Wnt signaling with recombinant soluble DKK1 induces spontaneous transformation and tumorigenicity.	('spontaneous transformation', 'CPA', (229, 255))	('tumor', 'Disease', (260, 265))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('Wnt', 'Gene', '7471', (25, 28))	('DKK1', 'Gene', '22943', (216, 220))	('DKK1', 'Gene', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('soluble', 'cellular_component', 'GO:0005625', ('208', '215'))	('human', 'Species', '9606', (131, 136))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('Wnt', 'Gene', (25, 28))	('Wnt', 'Gene', '7471', (177, 180))	('soluble', 'Gene', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('induces', 'Reg', (221, 228))	('Wnt', 'Gene', (177, 180))	('inhibition', 'Var', (163, 173))
173085	31417958	Ancillary studies will assess the role of MSI status, EGFR and Ras mutations as predictive of OS and PFS, the role of mesothelin, calretinin and CA-125 as predictive factors of tumor response and will identify new imaging biomarkers of tumor response using radiomics.	('Ras', 'Gene', (63, 66))	('tumor response', 'CPA', (177, 191))	('MSI', 'Gene', '5928', (42, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('mesothelin', 'Gene', (118, 128))	('CA-125', 'Gene', '94025', (145, 151))	('PFS', 'Disease', (101, 104))	('CA-125', 'Gene', (145, 151))	('mutations', 'Var', (67, 76))	('EGFR', 'Gene', '1956', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('mesothelin', 'Gene', '10232', (118, 128))	('EGFR', 'Gene', (54, 58))	('MSI', 'Gene', (42, 45))
173104	29545973	Post-irradiation pericardial malignant mesothelioma with deletion of p16: a case report Malignant mesotheliomas are rather uncommon neoplasms associated primarily with asbestos exposure; however, they may also arise as second primary malignancies after radiation therapy, with a latency period of 15-25 years.	('neoplasms', 'Phenotype', 'HP:0002664', (132, 141))	('asbestos', 'Chemical', 'MESH:D001194', (168, 176))	('malignancies', 'Disease', 'MESH:D009369', (234, 246))	('deletion', 'Var', (57, 65))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (88, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (132, 140))	('Malignant mesotheliomas', 'Phenotype', 'HP:0100001', (88, 111))	('Malignant mesotheliomas', 'Disease', (88, 111))	('neoplasms', 'Disease', (132, 141))	('p16', 'Gene', (69, 72))	('pericardial malignant mesothelioma', 'Disease', (17, 51))	('malignancies', 'Disease', (234, 246))	('pericardial malignant mesothelioma', 'Phenotype', 'HP:0100004', (17, 51))	('neoplasms', 'Disease', 'MESH:D009369', (132, 141))	('Malignant mesotheliomas', 'Disease', 'MESH:C562839', (88, 111))	('pericardial malignant mesothelioma', 'Disease', 'MESH:C562839', (17, 51))	('p16', 'Gene', '1029', (69, 72))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (29, 51))
173115	29545973	Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas.	('malignant mesotheliomas', 'Disease', (122, 145))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (122, 145))	('p16', 'Gene', (53, 56))	('p21', 'Gene', (24, 27))	('p21', 'Gene', '644914', (24, 27))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (122, 144))	('p16', 'Gene', '1029', (53, 56))	('Homozygous', 'Var', (0, 10))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (122, 145))
173117	29545973	Loss of p16/CDKN2A is associated with more aggressive clinical behavior in pleural mesothelioma and may have potential therapeutic applications; however, this issue has not been studied in pericardial mesothelioma.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (75, 95))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (75, 95))	('aggressive clinical behavior', 'CPA', (43, 71))	('p16', 'Gene', '1029', (8, 11))	('CDKN2A', 'Gene', (12, 18))	('pericardial mesothelioma', 'Phenotype', 'HP:0100004', (189, 213))	('pericardial mesothelioma', 'Disease', (189, 213))	('pericardial mesothelioma', 'Disease', 'MESH:D008654', (189, 213))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (43, 71))	('pleural mesothelioma', 'Disease', (75, 95))	('CDKN2A', 'Gene', '1029', (12, 18))	('more', 'PosReg', (38, 42))	('p16', 'Gene', (8, 11))	('associated', 'Reg', (22, 32))	('Loss', 'Var', (0, 4))
173118	29545973	Here we report the first case of pericardial mesothelioma showing homozygous deletion of 9p21.	('p21', 'Gene', (90, 93))	('deletion', 'Var', (77, 85))	('p21', 'Gene', '644914', (90, 93))	('pericardial mesothelioma', 'Phenotype', 'HP:0100004', (33, 57))	('pericardial mesothelioma', 'Disease', (33, 57))	('pericardial mesothelioma', 'Disease', 'MESH:D008654', (33, 57))
173129	29545973	The differential diagnosis included metastatic carcinoma and reactive mesothelial hyperplasia versus malignant mesothelioma; the immunohistochemical stains supported the mesothelial origin of the malignant cells, showing positivity for WT1, CK5/6, and calretinin (Figure 2B, 2C, and 2D), and negativity for BerEP4, B72.3, and MOC31 (not shown).	('positivity', 'Var', (221, 231))	('mesothelial', 'Chemical', '-', (70, 81))	('CK5/6, and calretinin', 'Gene', '794;3852', (241, 262))	('mesothelial', 'Chemical', '-', (170, 181))	('carcinoma', 'Disease', 'MESH:D002277', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('hyperplasia versus malignant mesothelioma', 'Disease', (82, 123))	('mesothelial origin', 'CPA', (170, 188))	('hyperplasia versus malignant mesothelioma', 'Disease', 'MESH:C562839', (82, 123))	('WT1', 'Gene', '7490', (236, 239))	('carcinoma', 'Disease', (47, 56))	('WT1', 'Gene', (236, 239))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (101, 123))
173130	29545973	Interphase FISH analysis with the fluorescently labeled dual colored probe set Vysis LSI CDKN2A spectrum orange probe (red signals) (Abbott Molecular Inc., Des Plaines, IL, USA) (~222kb; chromosome 9: 21, 802, 635-22, 032, 985; includes MTAP, DMSMFH, CDKN2A, MTS1, P16, MLM, and CMM2 genes, respectively); and a control probe from the centromere of chromosome 9 labeled with spectrum green (green signals) demonstrated abnormal signal patterns with increased copies of chromosome 9 and homozygous loss of the 9p21 signals (Figure 3).	('loss', 'NegReg', (497, 501))	('CDKN2A', 'Gene', '1029', (251, 257))	('copies', 'Var', (459, 465))	('p21', 'Gene', '644914', (510, 513))	('CDKN2A', 'Gene', (89, 95))	('increased', 'PosReg', (449, 458))	('centromere', 'cellular_component', 'GO:0000775', ('335', '345'))	('chromosome', 'cellular_component', 'GO:0005694', ('349', '359'))	('MLM', 'Disease', (270, 273))	('MLM', 'Disease', 'OMIM:155600', (270, 273))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('centromere', 'cellular_component', 'GO:0005698', ('335', '345'))	('P16', 'Gene', '1029', (265, 268))	('CDKN2A', 'Gene', '1029', (89, 95))	('MTAP', 'Gene', (237, 241))	('signal patterns', 'MPA', (428, 443))	('MTAP', 'Gene', '4507', (237, 241))	('Interphase', 'biological_process', 'GO:0051325', ('0', '10'))	('P16', 'Gene', (265, 268))	('CDKN2A', 'Gene', (251, 257))	('p21', 'Gene', (510, 513))	('chromosome', 'cellular_component', 'GO:0005694', ('469', '479'))
173133	29545973	The presence of chromosome 9 polysomy (extra centromere signals) is suggestive of an underlying abnormal karyotype, often a marker of complex and heterogeneous chromosomal abnormalities, commonly described in the cytogenetics of multiple myeloma (MM).	('centromere', 'cellular_component', 'GO:0000775', ('45', '55'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (229, 245))	('polysomy', 'Var', (29, 37))	('multiple myeloma', 'Disease', 'MESH:D009101', (229, 245))	('multiple myeloma', 'Disease', (229, 245))	('centromere', 'cellular_component', 'GO:0005698', ('45', '55'))	('chromosomal abnormalities', 'Disease', (160, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (160, 185))
173134	29545973	Molecular changes in mesothelioma with an impact on prognosis and treatment.	('mesothelioma', 'Disease', (21, 33))	('Molecular changes', 'Var', (0, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))
173135	29545973	The invasive nature of this neoplasm, in addition to p16 deletion, supported the diagnosis of malignant mesothelioma over mesothelial hyperplasia.	('neoplasm', 'Disease', (28, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (94, 116))	('p16', 'Gene', (53, 56))	('malignant mesothelioma', 'Disease', (94, 116))	('deletion', 'Var', (57, 65))	('neoplasm', 'Disease', 'MESH:D009369', (28, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (28, 36))	('p16', 'Gene', '1029', (53, 56))	('hyperplasia', 'Disease', (134, 145))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (94, 116))	('hyperplasia', 'Disease', 'MESH:D006965', (134, 145))	('mesothelial', 'Chemical', '-', (122, 133))
173144	29545973	Here we present the first case of post-radiation pericardial mesothelioma with deletion of the p16 gene.	('pericardial mesothelioma', 'Disease', 'MESH:D008654', (49, 73))	('pericardial mesothelioma', 'Phenotype', 'HP:0100004', (49, 73))	('p16', 'Gene', '1029', (95, 98))	('pericardial mesothelioma', 'Disease', (49, 73))	('deletion', 'Var', (79, 87))	('p16', 'Gene', (95, 98))
173154	29545973	What makes the present study unique is the significant finding of an abnormal signal pattern with a homozygous (biallelic) deletion of 9p21.	('p21', 'Gene', (136, 139))	('deletion', 'Var', (123, 131))	('p21', 'Gene', '644914', (136, 139))
173158	29545973	Destabilization of this regulatory mechanism via mutations or deletions in the p16 gene can be seen in a wide variety of tumors.	('p16', 'Gene', '1029', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutations', 'Var', (49, 58))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('deletions', 'Var', (62, 71))	('p16', 'Gene', (79, 82))
173241	28321148	For mesothelioma, a multitude of deregulated miRNAs in tissues and cell lines was described, whereas only three blood-based miRNAs, namely, miR-103a-3p, miR-126, and miR-625-3p, were identified as potential biomarkers.	('deregulated', 'MPA', (33, 44))	('mesothelioma', 'Disease', (4, 16))	('miR-625', 'Gene', (166, 173))	('miR-103a-3p', 'Var', (140, 151))	('miR-126', 'Gene', '406913', (153, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('miR-126', 'Gene', (153, 160))	('miR-625', 'Gene', '693210', (166, 173))
173260	28321148	Individual miRNAs were analyzed using commercial TaqMan microRNA assays (Life Technologies; miR-16 (ID 000391), miR-24 (ID 000402), miR-28-3p (ID 002446), miR-126 (ID 002228), miR-132-3p (ID 000457), miR-146b-5p (ID 001097), miR-625-3p (ID 002432), and U6 snRNA (ID 001973)) according to the manufacturer's instructions.	('ID 001097', 'Var', (213, 222))	('ID 000402', 'Var', (120, 129))	('miR-16', 'Gene', (92, 98))	('miR-28', 'Gene', (132, 138))	('ID 002432', 'Var', (237, 246))	('miR-132-3p', 'Gene', '100302255', (176, 186))	('ID 002446', 'Var', (143, 152))	('miR-625', 'Gene', '693210', (225, 232))	('ID 000391', 'Var', (100, 109))	('miR-126', 'Gene', '406913', (155, 162))	('miR-16', 'Gene', '51573', (92, 98))	('ID 002228', 'Var', (164, 173))	('miR-132-3p', 'Gene', (176, 186))	('miR-146b', 'Gene', (200, 208))	('miR-28', 'Gene', '407020', (132, 138))	('ID 001973', 'Var', (263, 272))	('ID 000457', 'Var', (188, 197))	('miR-126', 'Gene', (155, 162))	('miR-146b', 'Gene', '574447', (200, 208))	('miR-625', 'Gene', (225, 232))
173263	28321148	Corresponding plasma samples were spiked with lysed erythrocytes in order to obtain plasma samples with hemolysis grades of 0%, 0.125%, 0.25%, 0.5%, 1%, and 2%.	('0.125%', 'Var', (128, 134))	('0.25%', 'Var', (136, 141))	('hemolysis', 'Disease', (104, 113))	('hemolysis', 'Disease', 'MESH:D006461', (104, 113))	('0.5%', 'Var', (143, 147))
173272	28321148	Overall, the 40 combinations consisted of 15 different miRNAs (miR-20b, miR-24, miR-28-3p, miR-132-3p, miR-140-3p, miR-146b-5p, miR-155, miR-191, miR-193a-5p, miR-328, miR-331, miR-381, miR-532, miR-628-5p, and miR-660) that were used for further analysis.	('miR-381', 'Gene', (177, 184))	('miR-532', 'Gene', '693124', (186, 193))	('miR-20b', 'Gene', (63, 70))	('miR-155', 'Gene', '406947', (128, 135))	('miR-132-3p', 'Gene', '100302255', (91, 101))	('miR-328', 'Gene', '442901', (159, 166))	('miR-28', 'Gene', '407020', (80, 86))	('miR-140-3p', 'Var', (103, 113))	('miR-146b', 'Gene', (115, 123))	('miR-660', 'Gene', (211, 218))	('miR-24', 'Var', (72, 78))	('miR-381', 'Gene', '494330', (177, 184))	('miR-20b', 'Gene', '574032', (63, 70))	('miR-660', 'Gene', '724030', (211, 218))	('miR-132-3p', 'Gene', (91, 101))	('miR-191', 'Gene', '406966', (137, 144))	('miR-191', 'Gene', (137, 144))	('miR-193a-5p', 'Var', (146, 157))	('miR-28', 'Gene', (80, 86))	('miR-146b', 'Gene', '574447', (115, 123))	('miR-331', 'Gene', (168, 175))	('miR-328', 'Gene', (159, 166))	('miR-628', 'Gene', (195, 202))	('miR-628', 'Gene', '693213', (195, 202))	('miR-155', 'Gene', (128, 135))	('miR-331', 'Gene', '442903', (168, 175))	('miR-532', 'Gene', (186, 193))
173275	28321148	No significant fold changes > 2.0 could be observed for miR-24, miR-28-3p, miR-132-3p, and miR-146b-5p at low hemolysis grades < 0.5% (Figure 2 and Additional File 3).	('miR-132-3p', 'Gene', (75, 85))	('miR-28', 'Gene', (64, 70))	('low hemolysis', 'Disease', (106, 119))	('miR-28', 'Gene', '407020', (64, 70))	('low hemolysis', 'Disease', 'MESH:D006461', (106, 119))	('miR-132-3p', 'Gene', '100302255', (75, 85))	('miR-146b', 'Gene', (91, 99))	('miR-24', 'Var', (56, 62))	('miR-146b', 'Gene', '574447', (91, 99))
173421	28090191	In contrast, the expression level of Vimentin, N-cadherin, Twist, beta-catenin, pGSK3alpha/beta such as mesenchymal markers were decreased by ursolic acid in H2452 and MSTO-211H cells, while Vimentin was not detected in H28 cells.	('Vimentin', 'cellular_component', 'GO:0045098', ('191', '199'))	('beta-catenin', 'Gene', (66, 78))	('Vimentin', 'Gene', (191, 199))	('Twist', 'Gene', (59, 64))	('beta-catenin', 'Gene', '1499', (66, 78))	('ursolic acid', 'Var', (142, 154))	('decreased', 'NegReg', (129, 138))	('H2452', 'CellLine', 'CVCL:1553', (158, 163))	('Vimentin', 'Gene', '7431', (37, 45))	('pGSK3alpha/beta', 'Gene', (80, 95))	('Vimentin', 'cellular_component', 'GO:0045099', ('37', '45'))	('Twist', 'Gene', '7291', (59, 64))	('Vimentin', 'cellular_component', 'GO:0045099', ('191', '199'))	('Vimentin', 'Gene', (37, 45))	('pGSK3alpha', 'Chemical', '-', (80, 90))	('N-cadherin', 'Gene', (47, 57))	('N-cadherin', 'Gene', '1000', (47, 57))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('Vimentin', 'cellular_component', 'GO:0045098', ('37', '45'))	('Vimentin', 'Gene', '7431', (191, 199))	('expression level', 'MPA', (17, 33))	('MSTO-', 'Chemical', '-', (168, 173))	('ursolic acid', 'Chemical', 'MESH:C005466', (142, 154))
173437	28090191	In the current study the underlying antitumor mechanism of ursolic acid was investigated in H28, H2452 and MSTO-211H mesothelioma cells in association with EMT and microRNA let 7b, ursolic acid significantly showed cytoxic and anti-proliferative activity in H28, H2452, MSTO-211H mesothelioma cells, implying that ursolic acid can be a chemotherapeutic agent for MPN.	('H2452', 'CellLine', 'CVCL:1553', (263, 268))	('EMT', 'biological_process', 'GO:0001837', ('156', '159'))	('microRNA let 7b', 'Gene', (164, 179))	('MSTO-', 'Chemical', '-', (270, 275))	('ursolic acid', 'Chemical', 'MESH:C005466', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mesothelioma', 'Disease', (280, 292))	('H2452', 'Var', (263, 268))	('mesothelioma', 'Disease', 'MESH:D008654', (280, 292))	('MPN', 'Gene', '83886', (363, 366))	('ursolic acid', 'Chemical', 'MESH:C005466', (59, 71))	('MSTO-', 'Chemical', '-', (107, 112))	('ursolic acid', 'Chemical', 'MESH:C005466', (314, 326))	('anti-proliferative activity', 'CPA', (227, 254))	('tumor', 'Disease', (40, 45))	('cytoxic', 'CPA', (215, 222))	('microRNA let 7b', 'Gene', '406884', (164, 179))	('mesothelioma', 'Disease', (117, 129))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MPN', 'Gene', (363, 366))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('H2452', 'CellLine', 'CVCL:1553', (97, 102))
173441	28090191	Similarly, previous studies showed that ursolic acid induced apoptosis via inhibition of the Wnt5/beta-catenin pathway in prostate cancer cells and also inhibited the cell growth via AMPK, ER stress or Akt/NF-kB in human bladder cancer cells carcinoma cells.	('ursolic acid', 'Var', (40, 52))	('AMPK', 'molecular_function', 'GO:0050405', ('183', '187'))	('AMPK', 'molecular_function', 'GO:0004691', ('183', '187'))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))	('apoptosis', 'CPA', (61, 70))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('carcinoma', 'Disease', 'MESH:D002277', (242, 251))	('prostate cancer', 'Disease', (122, 137))	('cell growth', 'CPA', (167, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('human', 'Species', '9606', (215, 220))	('inhibited', 'NegReg', (153, 162))	('Akt', 'Gene', (202, 205))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('AMPK', 'molecular_function', 'GO:0047322', ('183', '187'))	('bladder cancer', 'Disease', 'MESH:D001749', (221, 235))	('inhibition', 'NegReg', (75, 85))	('bladder cancer', 'Disease', (221, 235))	('Akt', 'Gene', '207', (202, 205))	('ER stress', 'MPA', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('bladder cancer', 'Phenotype', 'HP:0009725', (221, 235))	('ursolic acid', 'Chemical', 'MESH:C005466', (40, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('beta-catenin', 'Gene', (98, 110))	('carcinoma', 'Disease', (242, 251))	('beta-catenin', 'Gene', '1499', (98, 110))
173512	26976946	However, diagnostic errors may have had a greater impact on, for example, cancer of the liver, which can be difficult to distinguish from hepatic metastasis of malignancies arising in other tissues.	('errors', 'Var', (20, 26))	('hepatic metastasis of malignancies', 'Disease', 'MESH:D009362', (138, 172))	('impact', 'Reg', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('hepatic metastasis of malignancies', 'Disease', (138, 172))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer of the liver', 'Phenotype', 'HP:0002896', (74, 93))
173534	26976946	Applying risk estimates derived from published studies to estimates of the proportion of the national population ever exposed, they calculated population attributable fractions for mortality from sinonasal cancer in men during 2005 of 0.1533 (95%CI 0.0594-0.2912) for wood dust and 0.0668 (95%CI 0.0328-0.1231) for leather dust.	('men', 'Species', '9606', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('0.0668', 'Var', (282, 288))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
173571	24281081	Asbestos fibers may produce a variety of lesions in cellular DNA, such as single-double strand breaks (SSBs-DSBs), intra-interstrand cross-linking, and base damage.	('intra-interstrand', 'Disease', (115, 132))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('single-double', 'Var', (74, 87))	('base', 'Disease', (152, 156))	('produce', 'Reg', (20, 27))
118343	24281081	These substitutions have been reported as the sites of spontaneous oncogene expression and may be largely responsible for the onset of carcinogenesis and cell proliferation, ultimately leading to cancer manifestation.	('substitutions', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('carcinogenesis', 'Disease', (135, 149))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('man', 'Species', '9606', (203, 206))	('cancer', 'Disease', (196, 202))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('leading to', 'Reg', (185, 195))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))
173573	24281081	8OHdG is one of the predominant forms of free radical-induced oxidative lesions, and has therefore been widely used as a biomarker for oxidative stress and carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('carcinogenesis', 'Disease', (156, 170))	('free radical-induced oxidative lesions', 'MPA', (41, 79))	('free radical', 'Chemical', 'MESH:D005609', (41, 53))	('8OHdG', 'Chemical', 'MESH:C067134', (0, 5))	('8OHdG', 'Var', (0, 5))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
173600	24281081	Heritable differences in host resistance to genetic changes may be identified at different phases of the carcinogenic process, i.e., DNA repair capacity, chromosome stability, cytogenetic changes, modified gene expression, mutation spectra in tumours or pre-cancerous cells.	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('modified', 'Var', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('pre', 'molecular_function', 'GO:0003904', ('254', '257'))	('cancerous', 'Disease', 'MESH:D009369', (258, 267))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('tumours', 'Disease', 'MESH:D009369', (243, 250))	('tumours', 'Disease', (243, 250))	('mutation', 'Var', (223, 231))	('gene expression', 'biological_process', 'GO:0010467', ('206', '221'))	('chromosome stability', 'CPA', (154, 174))	('carcinogenic process', 'Disease', (105, 125))	('DNA repair', 'biological_process', 'GO:0006281', ('133', '143'))	('DNA repair capacity', 'CPA', (133, 152))	('cancerous', 'Disease', (258, 267))	('carcinogenic process', 'Disease', 'MESH:D009385', (105, 125))
173614	24281081	Recent evidence suggests the usefulness of a micronucleus test as a screening test for carriers of specific mutations in evaluating cancer susceptibility.	('micronucleus', 'cellular_component', 'GO:0031040', ('45', '57'))	('cancer', 'Disease', (132, 138))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
173630	24281081	In summary, standard markers such as hyaluronic acid, various cytokeratin fragments (CYFRA 21.1, TPA) and other cancer antigens (CA 15.3, CA 125 or CA 19.9 or CEA) are not sensitive or specific enough and cannot be used in clinic practice.	('CEA', 'Gene', (159, 162))	('TPA', 'molecular_function', 'GO:0031299', ('97', '100'))	('cancer', 'Disease', (112, 118))	('TPA', 'Gene', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('CA 19.9', 'Var', (148, 155))	('TPA', 'Gene', '5327', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (37, 52))	('CEA', 'Gene', '1048', (159, 162))
173695	24281081	Deregulation of epigenetic transcriptional control (aberrant promoter DNA hypermethylation and histone acethylation) is a fundamental feature of human malignancies.	('epigenetic transcriptional control', 'MPA', (16, 50))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('70', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('human', 'Species', '9606', (145, 150))	('aberrant', 'Var', (52, 60))	('malignancies', 'Disease', (151, 163))	('transcriptional control', 'biological_process', 'GO:0006355', ('27', '50'))	('promoter DNA hypermethylation', 'MPA', (61, 90))
173696	24281081	In lung cancer and mesothelioma, a number of genes involved in carcinogenesis have been demonstrated to be hypermethylated, implicating epigenomic changes in the aetiology of these cancers.	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('hypermethylated', 'Var', (107, 122))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('cancers', 'Disease', (181, 188))	('mesothelioma', 'Disease', (19, 31))	('carcinogenesis', 'Disease', (63, 77))
173697	24281081	Hypermethylated genes have also been associated with lung cancer recurrence, indicating epigenomic regulation of metastasis.	('Hypermethylated genes', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('associated', 'Reg', (37, 47))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))
173701	24281081	There is increasing evidence that hypermethylation of CpG islands can be one of the most prevalent molecular markers for human cancers (epigenetic biomarkers).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('hypermethylation', 'Var', (34, 50))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('prevalent', 'Reg', (89, 98))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
173706	24281081	miRNAs were found to regulate post-transcriptionally the expression of target genes and may behave as oncogenes or tumour suppressors.	('expression', 'MPA', (57, 67))	('regulate', 'Reg', (21, 29))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('miRNAs', 'Var', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))
173750	24281081	High expression of COX-2 in MM specimens was demonstrated to be an independent predictor of poor prognosis.	('COX-2', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('COX-2', 'Gene', '4513', (19, 24))
173754	24281081	Some efficacy has been reportedfor SU5416, an inhibitor of the VEGF receptor (VEGFR) Flk-1, but this was hampered by an excessive risk of thrombosis.	('Flk-1', 'Gene', (85, 90))	('SU5416', 'Var', (35, 41))	('VEGF receptor', 'Gene', '3791', (63, 76))	('thrombosis', 'Disease', (138, 148))	('VEGFR', 'Gene', (78, 83))	('VEGF receptor', 'Gene', (63, 76))	('Flk-1', 'Gene', '3791', (85, 90))	('thrombosis', 'Disease', 'MESH:D013927', (138, 148))	('VEGFR', 'Gene', '3791', (78, 83))	('SU5416', 'Chemical', 'MESH:C116890', (35, 41))
173798	23412101	Mesothelial cells generate large quantities of surface glycoproteins to help lubricate the pleural space, and so dysregulation of their synthesis is likely to be associated with ER stress.	('synthesis', 'MPA', (136, 145))	('synthesis', 'biological_process', 'GO:0009058', ('136', '145'))	('rat', 'Species', '10116', (22, 25))	('dysregulation', 'Var', (113, 126))	('associated', 'Reg', (162, 172))	('ER stress', 'Disease', (178, 187))	('pleural', 'Disease', 'MESH:D010995', (91, 98))	('surface glycoproteins', 'Protein', (47, 68))	('pleural', 'Disease', (91, 98))
173804	23412101	We chose to measure protein expression of CHOP, GADD34 and BiP in formalin-fixed paraffin-embedded (FFPE) samples, because CHOP and GADD34 have both been linked with the toxic consequences of ER stress, whereas BiP levels are known to correlate with cytoprotection.	('GADD34', 'Var', (132, 138))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('linked', 'Reg', (154, 160))	('formalin', 'Chemical', 'MESH:D005557', (66, 74))	('paraffin', 'Chemical', 'MESH:D010232', (81, 89))
173855	23412101	This may prove useful in patient stratification and the development of anticancer strategies aimed at modulating ER stress, for example, the use of proteasome inhibitors and newer agents such as inhibitors of HSP90.	('HSP90', 'Protein', (209, 214))	('proteasome', 'molecular_function', 'GO:0004299', ('148', '158'))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('rat', 'Species', '10116', (84, 87))	('cancer', 'Disease', (75, 81))	('inhibitors', 'Var', (195, 205))	('patient', 'Species', '9606', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rat', 'Species', '10116', (35, 38))	('proteasome', 'cellular_component', 'GO:0000502', ('148', '158'))
173869	32517181	Finally, germline mutations in the BRCA1, BRCA2, TP53 or CDKN2A genes also represent risk factors for around 5% of PDAC patients.	('PDAC', 'Disease', (115, 119))	('TP53', 'Gene', '7157', (49, 53))	('CDKN2A', 'Gene', (57, 63))	('TP53', 'Gene', (49, 53))	('BRCA2', 'Gene', '675', (42, 47))	('BRCA1', 'Gene', '672', (35, 40))	('CDKN2A', 'Gene', '1029', (57, 63))	('risk factors', 'Reg', (85, 97))	('PDAC', 'Chemical', '-', (115, 119))	('BRCA1', 'Gene', (35, 40))	('patients', 'Species', '9606', (120, 128))	('BRCA2', 'Gene', (42, 47))	('germline mutations', 'Var', (9, 27))
173885	32517181	Indeed, MSLN gene inactivation did not reveal any developmental, anatomical nor histological abnormalities:no detectable phenotype is thus mirrored by the absence of mesothelin gene.	('histological abnormalities', 'Phenotype', 'HP:0002664', (80, 106))	('mesothelin', 'Gene', (166, 176))	('inactivation', 'Var', (18, 30))	('mesothelin', 'Gene', '10232', (166, 176))	('absence', 'NegReg', (155, 162))	('men', 'Species', '9606', (57, 60))
173887	32517181	MUC16 is a type-I transmembrane protein composed of a glycosylated extracellular N-terminal domain, tandem repeat domains and a C-terminal domain.	('MUC16', 'Gene', '94025', (0, 5))	('tandem repeat domains', 'Var', (100, 121))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('extracellular', 'cellular_component', 'GO:0005576', ('67', '80'))	('MUC16', 'Gene', (0, 5))	('transmembrane', 'cellular_component', 'GO:0044214', ('18', '31'))	('transmembrane', 'cellular_component', 'GO:0016021', ('18', '31'))
173889	32517181	Overexpression of MUC16 has also been reported in several types of cancer including PDAC.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('PDAC', 'Disease', (84, 88))	('cancer', 'Disease', (67, 73))	('MUC16', 'Gene', '94025', (18, 23))	('reported', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Overexpression', 'Var', (0, 14))	('PDAC', 'Chemical', '-', (84, 88))	('MUC16', 'Gene', (18, 23))
173891	32517181	indeed reported that MUC16 knockdown not only slows-down in vitro proliferation and colony formation of tumorigenic PDAC cells (Capan-1 and colo-357), but also hampers in vivo tumorigenic potential:with reduced formation of pancreatic tumors and decreased metastatic dissemination.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('slows-down', 'NegReg', (46, 56))	('reduced', 'NegReg', (203, 210))	('PDAC', 'Chemical', '-', (116, 120))	('MUC16', 'Gene', (21, 26))	('pancreatic tumors', 'Disease', 'MESH:D010190', (224, 241))	('pancreatic tumors', 'Disease', (224, 241))	('hampers', 'NegReg', (160, 167))	('Capan-1', 'CellLine', 'CVCL:0237', (128, 135))	('tumor', 'Disease', (176, 181))	('colony formation', 'CPA', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('decreased', 'NegReg', (246, 255))	('formation', 'CPA', (211, 220))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('knockdown', 'Var', (27, 36))	('tumor', 'Disease', (104, 109))	('colo', 'Species', '307630', (84, 88))	('metastatic dissemination', 'CPA', (256, 280))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('colo', 'Species', '307630', (140, 144))	('MUC16', 'Gene', '94025', (21, 26))	('formation', 'biological_process', 'GO:0009058', ('211', '220'))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (224, 241))	('tumor', 'Disease', (235, 240))
173903	32517181	MSLN also activates NFkappaB, which results in an increased IL-6 expression and cell proliferation, via an autocrine IL-6/sIL-6R trans-signaling.	('IL-6', 'Gene', '3569', (117, 121))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('IL-6', 'Gene', '3569', (60, 64))	('IL-6', 'Gene', '3569', (123, 127))	('NFkappaB', 'Gene', '4790', (20, 28))	('IL-6', 'Gene', (117, 121))	('IL-6', 'Gene', (60, 64))	('increased', 'PosReg', (50, 59))	('NFkappaB', 'Gene', (20, 28))	('IL-6', 'Gene', (123, 127))	('cell proliferation', 'CPA', (80, 98))	('expression', 'MPA', (65, 75))	('IL-6', 'molecular_function', 'GO:0005138', ('117', '121'))	('sIL', 'Gene', (122, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('activates', 'PosReg', (10, 19))	('sIL', 'Gene', '6491', (122, 125))	('increased IL-6', 'Phenotype', 'HP:0030783', (50, 64))	('MSLN', 'Var', (0, 4))
173904	32517181	The pro-proliferative effect of MSLN also involved ERK and PI3K/Akt pathways.	('ERK', 'Gene', (51, 54))	('pro-proliferative effect', 'MPA', (4, 28))	('MSLN', 'Var', (32, 36))	('Akt', 'Gene', '207', (64, 67))	('Akt', 'Gene', (64, 67))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('ERK', 'Gene', '5594', (51, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
173905	32517181	Indeed, silencing of MSLN in PDAC BxPC-3 cells decreased ERK1 (but not ERK2) and AKT activities that may probably explain its anti-proliferative effects considering the prominent role of ERK and AKT pathways during cell proliferation and metastasis processes.	('ERK1', 'Gene', '5595', (57, 61))	('ERK', 'Gene', (187, 190))	('AKT', 'Gene', '207', (81, 84))	('silencing', 'Var', (8, 17))	('MSLN', 'Gene', (21, 25))	('PDAC', 'Chemical', '-', (29, 33))	('ERK', 'Gene', '5594', (71, 74))	('ERK', 'Gene', '5594', (57, 60))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('cell proliferation', 'biological_process', 'GO:0008283', ('215', '233'))	('ERK', 'molecular_function', 'GO:0004707', ('187', '190'))	('decreased', 'NegReg', (47, 56))	('AKT', 'Gene', (195, 198))	('ERK', 'Gene', (71, 74))	('ERK2', 'Gene', '5594', (71, 75))	('AKT', 'Gene', (81, 84))	('ERK', 'Gene', (57, 60))	('BxPC-3', 'CellLine', 'CVCL:0186', (34, 40))	('ERK', 'Gene', '5594', (187, 190))	('ERK2', 'molecular_function', 'GO:0004707', ('71', '75'))	('ERK2', 'Gene', (71, 75))	('ERK1', 'Gene', (57, 61))	('AKT', 'Gene', '207', (195, 198))
173907	32517181	In PDAC, MSLN decreases BAX and augments BCL-2, leading then to enhanced cell proliferation.	('men', 'Species', '9606', (35, 38))	('MSLN', 'Var', (9, 13))	('decreases', 'NegReg', (14, 23))	('PDAC', 'Chemical', '-', (3, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('BCL-2', 'molecular_function', 'GO:0015283', ('41', '46'))	('BCL-2', 'Gene', '596', (41, 46))	('BAX', 'Gene', (24, 27))	('BAX', 'Gene', '581', (24, 27))	('BCL-2', 'Gene', (41, 46))	('cell proliferation', 'CPA', (73, 91))	('augments', 'NegReg', (32, 40))	('enhanced', 'PosReg', (64, 72))
173915	32517181	MUC16-expressing PDAC treated with MSLN indeed displayed increased MMP-7 expression and invasive capacity, thus proposing that the MMP-7 induction and increased invasive potential could actually stem from the MSLN-MUC16 molecular interaction.	('MMP-7', 'molecular_function', 'GO:0004235', ('67', '72'))	('increased', 'PosReg', (151, 160))	('MMP-7', 'Gene', '4316', (131, 136))	('MMP-7', 'Gene', (67, 72))	('MUC16', 'Gene', '94025', (0, 5))	('MMP-7', 'molecular_function', 'GO:0004235', ('131', '136'))	('MMP-7', 'Gene', '4316', (67, 72))	('invasive potential', 'CPA', (161, 179))	('invasive capacity', 'CPA', (88, 105))	('MUC16', 'Gene', (214, 219))	('expression', 'MPA', (73, 83))	('MUC16', 'Gene', '94025', (214, 219))	('increased', 'PosReg', (57, 66))	('MMP-7', 'Gene', (131, 136))	('MUC16', 'Gene', (0, 5))	('PDAC', 'Chemical', '-', (17, 21))	('MSLN', 'Var', (35, 39))
173917	32517181	Indeed, MSLN was shown to stimulate the expressions of ALDH, SNAIL, SLUG and TWIST, while decreasing expression of E-cadherin in lung carcinoma and mesothelioma cell lines.	('expressions', 'MPA', (40, 51))	('MSLN', 'Var', (8, 12))	('stimulate', 'PosReg', (26, 35))	('lung carcinoma', 'Disease', 'MESH:D008175', (129, 143))	('SNAIL', 'Gene', '6615', (61, 66))	('SNAIL', 'Gene', (61, 66))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('TWIST', 'Gene', (77, 82))	('ALDH', 'Gene', (55, 59))	('decreasing', 'NegReg', (90, 100))	('SLUG', 'Gene', '6591', (68, 72))	('SLUG', 'Gene', (68, 72))	('TWIST', 'Gene', '7291', (77, 82))	('lung carcinoma', 'Disease', (129, 143))	('mesothelioma', 'Disease', (148, 160))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('ALDH', 'molecular_function', 'GO:0004030', ('55', '59'))	('expression', 'MPA', (101, 111))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
173919	32517181	Finally, MSLN-expressing tumors were also evidenced to be associated with a significant increase of microvascular density in newly formed pancreatic metastatic tissues:this would suggest a new potential role held by MSLN in promoting angiogenesis.	('promoting', 'PosReg', (224, 233))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('pancreatic', 'Disease', (138, 148))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('increase', 'PosReg', (88, 96))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('MSLN', 'Var', (216, 220))	('angiogenesis', 'biological_process', 'GO:0001525', ('234', '246'))	('angiogenesis', 'CPA', (234, 246))	('pancreatic', 'Disease', 'MESH:D010195', (138, 148))
173920	32517181	Inhibition of MSLN in mesothelioma cell lines has been shown to restore cell sensitivity after exposure to cisplatin.	('restore', 'PosReg', (64, 71))	('mesothelioma', 'Disease', (22, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (22, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('cell sensitivity', 'CPA', (72, 88))	('MSLN', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))
173932	32517181	MSLN and MUC16 co-expression, assessed by immunohistochemistry, was reported to be associated with increased tumor cell invasiveness and metastasis, and poor clinical outcomes of PDAC patients.	('MUC16', 'Gene', (9, 14))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MUC16', 'Gene', '94025', (9, 14))	('associated', 'Reg', (83, 93))	('MSLN', 'Gene', (0, 4))	('increased', 'PosReg', (99, 108))	('co-expression', 'Var', (15, 28))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('PDAC', 'Chemical', '-', (179, 183))	('tumor', 'Disease', (109, 114))
173946	32517181	Finally, single-chain variant antibodies as well as single-domain antibodies demonstrating optimal pharmacokinetics have recently been validated for preclinical imaging of MSLN-expressing tumors, and will therefore deserve to be fully considered for further clinical development.	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', (188, 194))	('single-chain', 'Var', (9, 21))	('men', 'Species', '9606', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
173951	32517181	The fusion of SS1 to a Pseudomonas exotoxin (PE38) resulted in the recombinant immunotoxin (RIT) called SS1P.	('SS1', 'Gene', '3123', (14, 17))	('SS1', 'Gene', '3123', (104, 107))	('fusion', 'Var', (4, 10))	('SS1', 'Gene', (14, 17))	('SS1', 'Gene', (104, 107))
173963	32517181	LMB-100/RG7787, a re-engineered version of SS1P combining SS1 Fab with the truncated and deimmunized PE24 moiety, was shown to restrict tumorigenicity both in vitro and in vivo using preclinical models of PDAC.	('SS1', 'Gene', '3123', (43, 46))	('SS1', 'Gene', '3123', (58, 61))	('PE24', 'Chemical', '-', (101, 105))	('SS1', 'Gene', (43, 46))	('SS1', 'Gene', (58, 61))	('PDAC', 'Chemical', '-', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('LMB', 'Chemical', '-', (0, 3))	('tumor', 'Disease', (136, 141))	('LMB-100/RG7787', 'Var', (0, 14))	('restrict', 'NegReg', (127, 135))
173964	32517181	Similarly, its combination with taxanes, actinomycin D and panobinostat were also associated with increased anti-tumor activities in both mesothelioma and PDAC preclinical models:LMB-100/RG7787 is then currently under clinical trial for these types of cancer (NCT02810418).	('panobinostat', 'Chemical', 'MESH:D000077767', (59, 71))	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('taxanes', 'Chemical', 'MESH:D043823', (32, 39))	('cancer', 'Disease', (252, 258))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))	('PDAC', 'Chemical', '-', (155, 159))	('mesothelioma', 'Disease', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('increased', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LMB', 'Chemical', '-', (179, 182))	('actinomycin D', 'Chemical', 'MESH:D003609', (41, 54))	('LMB-100/RG7787', 'Var', (179, 193))
173977	32517181	DMOT4039A is a humanized anti-MSLN mAb fused to monomethyl auristatin (MMAE), an anti-mitotic agent that blocks the polymerization of tubulin.	('DMOT4039A', 'Chemical', '-', (0, 9))	('monomethyl auristatin', 'Chemical', '-', (48, 69))	('tubulin', 'Protein', (134, 141))	('polymerization', 'MPA', (116, 130))	('human', 'Species', '9606', (15, 20))	('DMOT4039A', 'Var', (0, 9))
173978	32517181	A single-dose of DMOT4039A prevented tumor growth in a dose-dependent manner in murine models of ovarian cancer, PDAC and mesothelioma, as well as in mice bearing patient-derived tumor xenografts.	('mice', 'Species', '10090', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DMOT4039A', 'Chemical', '-', (17, 26))	('PDAC', 'Disease', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DMOT4039A', 'Var', (17, 26))	('mesothelioma', 'Disease', (122, 134))	('mesothelioma', 'Disease', 'MESH:D008654', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PDAC', 'Chemical', '-', (113, 117))	('tumor', 'Disease', (179, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('patient', 'Species', '9606', (163, 170))	('ovarian cancer', 'Disease', (97, 111))	('prevented', 'NegReg', (27, 36))	('tumor', 'Disease', (37, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('murine', 'Species', '10090', (80, 86))
174022	32517181	In a phase I clinical study, 6 patients with metastatic PDAC were intravenously injected with anti-MSLN CAR-T cells twice per week during three weeks, and no side effects or dose-limiting toxicities were reported.	('toxicities', 'Disease', 'MESH:D064420', (188, 198))	('anti-MSLN', 'Var', (94, 103))	('PDAC', 'Chemical', '-', (56, 60))	('CAR-T', 'Chemical', '-', (104, 109))	('patients', 'Species', '9606', (31, 39))	('toxicities', 'Disease', (188, 198))	('CAR', 'cellular_component', 'GO:0005826', ('104', '107'))
174024	32517181	As preclinical studies demonstrated the higher persistence of regionally injected CAR-T cells, several clinical studies are presently exploiting the possibility to infuse CAR-T cells in PDAC through vascular intervention in order (1) to potentiate the drug concentration of the tumor site, and (2) to reduce the potential off-target side effects (NCT02706782, NCT03267173).	('drug concentration of', 'MPA', (252, 273))	('CAR-T', 'Chemical', '-', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('NCT03267173', 'Var', (360, 371))	('reduce', 'NegReg', (301, 307))	('CAR-T', 'Chemical', '-', (171, 176))	('tumor', 'Disease', (278, 283))	('potentiate', 'PosReg', (237, 247))	('PDAC', 'Chemical', '-', (186, 190))	('CAR', 'cellular_component', 'GO:0005826', ('82', '85'))	('NCT02706782', 'Var', (347, 358))	('CAR', 'cellular_component', 'GO:0005826', ('171', '174'))	('tumor', 'Disease', 'MESH:D009369', (278, 283))
174025	32517181	Finally, the safety and efficacy of CTLA-4 and PD-1 expressing MSLN-CAR-T cells are currently in clinical evaluation in MSLN-expressing PDAC patients (NCT03615313, NCT03182803) (Table 1).	('MSLN-expressing', 'Disease', (120, 135))	('CAR', 'cellular_component', 'GO:0005826', ('68', '71'))	('PDAC', 'Disease', (136, 140))	('CTLA-4', 'Gene', (36, 42))	('CTLA-4', 'Gene', '397286', (36, 42))	('NCT03182803', 'Var', (164, 175))	('NCT03615313', 'Var', (151, 162))	('PDAC', 'Chemical', '-', (136, 140))	('MSLN-CAR-T', 'CellLine', 'CVCL:4140', (63, 73))	('patients', 'Species', '9606', (141, 149))
174045	26429628	Neonatal B6C3F1/Tk+/- mice treated on postnatal days 1, 8, and 15 with glycidamide have an increased mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase gene in splenic T-lymphocytes.	('hypoxanthine-guanine phosphoribosyltransferase', 'Gene', (125, 171))	('hypoxanthine-guanine phosphoribosyltransferase', 'Gene', '15452', (125, 171))	('mutant', 'Var', (101, 107))	('glycidamide', 'Chemical', 'MESH:C071834', (71, 82))	('mice', 'Species', '10090', (22, 26))
174048	26429628	In the experiment, C57BL/6J Min/+ mice, a strain susceptible to intestinal neoplasia, and their wild-type littermates were administered subcutaneous injections of 10 or 50 mg glycidamide per kg body weight (bw) at one and two weeks after birth.	('intestinal neoplasia', 'Disease', (64, 84))	('mice', 'Species', '10090', (34, 38))	('glycidamide', 'Chemical', 'MESH:C071834', (175, 186))	('intestinal neoplasia', 'Disease', 'MESH:D009369', (64, 84))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('C57BL/6J', 'Var', (19, 27))
174051	26429628	In the study, male B6C3F1 mice injected intraperitoneally with 0.70 mmol glycidamide per kg bw on postnatal days 1, 8, and 15 had a significant increase in hepatocellular tumors that was associated with A   G and A   T mutations at codon 61 of the H-ras oncogene.	('T mutations at', 'Var', (217, 231))	('H-ras', 'Gene', '15461', (248, 253))	('increase in hepatocellular tumors', 'Disease', 'MESH:D006528', (144, 177))	('increase in hepatocellular tumors', 'Disease', (144, 177))	('H-ras', 'Gene', (248, 253))	('hepatocellular tumors', 'Phenotype', 'HP:0001402', (156, 177))	('glycidamide', 'Chemical', 'MESH:C071834', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('mice', 'Species', '10090', (26, 30))
174059	26429628	The administration of either 3.52 mM glycidamide or 3.52 mM acrylamide in the drinking water resulted in hind limb paresis and decreased body weight.	('glycidamide', 'Chemical', 'MESH:C071834', (37, 48))	('decreased', 'NegReg', (127, 136))	('body weight', 'CPA', (137, 148))	('drinking water', 'Chemical', 'MESH:D060766', (78, 92))	('acrylamide', 'Chemical', 'MESH:D020106', (60, 70))	('3.52 mM', 'Var', (52, 59))	('hind limb paresis', 'CPA', (105, 122))	('decreased body weight', 'Phenotype', 'HP:0004325', (127, 148))	('3.52 mM', 'Var', (29, 36))
174062	26429628	Since one of the goals of this study was to compare acrylamide with glycidamide, a high dose of 0.70 mM glycidamide was selected for the chronic two-year drinking water study, with the remaining doses being 0.0, 0.0875, 0.175, and 0.35 mM glycidamide.	('0.0875', 'Var', (212, 218))	('glycidamide', 'Chemical', 'MESH:C071834', (68, 79))	('glycidamide', 'Chemical', 'MESH:C071834', (239, 250))	('drinking water', 'Chemical', 'MESH:D060766', (154, 168))	('0.35', 'Var', (231, 235))	('glycidamide', 'Chemical', 'MESH:C071834', (104, 115))	('acrylamide', 'Chemical', 'MESH:D020106', (52, 62))	('0.175', 'Var', (220, 225))	('0.0', 'Var', (207, 210))
174085	26429628	Groups of 48 male and 48 female B6C3F1 mice and 48 male and 48 female F344/N rats were administered 0, 0.0875, 0.175, 0.35, and 0.70 mM glycidamide in the drinking water for two years.	('0.0875', 'Var', (103, 109))	('glycidamide', 'Chemical', 'MESH:C071834', (136, 147))	('0.35', 'Var', (118, 122))	('drinking water', 'Chemical', 'MESH:D060766', (155, 169))	('rats', 'Species', '10116', (77, 81))	('0.175', 'Var', (111, 116))	('mice', 'Species', '10090', (39, 43))
174088	26429628	Pair-wise comparisons indicated that treatment with 0.70 mM glycidamide resulted in significant decreases in body weight gain beginning at week 8 in male rats.	('glycidamide', 'Chemical', 'MESH:C071834', (60, 71))	('decreases', 'NegReg', (96, 105))	('weight gain', 'Disease', (114, 125))	('rats', 'Species', '10116', (154, 158))	('glycidamide', 'Var', (60, 71))	('0.70 mM glycidamide', 'Var', (52, 71))	('decreases in body weight', 'Phenotype', 'HP:0004325', (96, 120))	('weight gain', 'Disease', 'MESH:D015430', (114, 125))	('weight gain', 'Phenotype', 'HP:0004324', (114, 125))
174089	26429628	In female rats, treatment with 0.175, 0.35, or 0.70 mM glycidamide resulted in significant decreases in body weight gain beginning at week 4.	('0.35', 'Var', (38, 42))	('weight gain', 'Disease', 'MESH:D015430', (109, 120))	('rats', 'Species', '10116', (10, 14))	('weight gain', 'Phenotype', 'HP:0004324', (109, 120))	('weight gain', 'Disease', (109, 120))	('decreases in body weight', 'Phenotype', 'HP:0004325', (91, 115))	('glycidamide', 'Chemical', 'MESH:C071834', (55, 66))	('0.70 mM', 'Var', (47, 54))	('decreases', 'NegReg', (91, 100))	('0.175', 'Var', (31, 36))
174094	26429628	In female B6C3F1 mice, there was a dose-related increasing trend in water consumption beginning at week 76, with water consumption in the 0.70 mM glycidamide group being significantly greater than in the control group beginning at week 80 (Supplementary Figure S5B).	('mice', 'Species', '10090', (17, 21))	('water', 'Chemical', 'MESH:D014867', (68, 73))	('water', 'Chemical', 'MESH:D014867', (113, 118))	('water consumption', 'MPA', (68, 85))	('increasing', 'PosReg', (48, 58))	('glycidamide', 'Chemical', 'MESH:C071834', (146, 157))	('greater', 'PosReg', (184, 191))	('0.70 mM glycidamide', 'Var', (138, 157))
174095	26429628	The mean amount of glycidamide consumed by male B6C3F1 mice, calculated at four-week intervals, for the entire two-year experiment was 1.20, 2.65, 5.13, and 9.55 mg glycidamide per kg bw per day for the 0.0875, 0.175, 0.35, and 0.70 mM glycidamide dose groups, respectively.	('0.175', 'Var', (211, 216))	('glycidamide', 'Chemical', 'MESH:C071834', (165, 176))	('mice', 'Species', '10090', (55, 59))	('glycidamide', 'Chemical', 'MESH:C071834', (236, 247))	('glycidamide', 'Chemical', 'MESH:C071834', (19, 30))	('0.0875', 'Var', (203, 209))
174098	26429628	The mean amount of glycidamide consumed by male F344/N rats, calculated at four-week intervals, for the entire two-year experiment was 0.39, 0.79, 1.56, and 3.34 mg glycidamide per kg bw per day for the 0.0875, 0.175, 0.35, and 0.70 mM glycidamide dose groups, respectively.	('0.175', 'Var', (211, 216))	('rats', 'Species', '10116', (55, 59))	('glycidamide', 'Chemical', 'MESH:C071834', (165, 176))	('glycidamide', 'Chemical', 'MESH:C071834', (236, 247))	('glycidamide', 'Chemical', 'MESH:C071834', (19, 30))	('0.0875', 'Var', (203, 209))
174104	26429628	Male and female B6C3F1 mice administered glycidamide in the drinking water had dose-related increases in Harderian gland adenoma, with the incidences being significant in both sexes at all doses of glycidamide (Table 1).	('glycidamide', 'Chemical', 'MESH:C071834', (198, 209))	('Harderian gland adenoma', 'Disease', 'MESH:D000236', (105, 128))	('drinking water', 'Chemical', 'MESH:D060766', (60, 74))	('glycidamide', 'Chemical', 'MESH:C071834', (41, 52))	('glycidamide', 'Var', (41, 52))	('Harderian gland adenoma', 'Disease', (105, 128))	('increases', 'PosReg', (92, 101))	('mice', 'Species', '10090', (23, 27))
174105	26429628	Harderian gland adenocarcinoma was also observed in one male mouse administered 0.70 mM glycidamide and one female mouse administered 0.175 mM glycidamide.	('glycidamide', 'Chemical', 'MESH:C071834', (88, 99))	('glycidamide', 'Chemical', 'MESH:C071834', (143, 154))	('observed', 'Reg', (40, 48))	('mouse', 'Species', '10090', (115, 120))	('0.70 mM', 'Var', (80, 87))	('Harderian gland adenocarcinoma', 'Disease', (0, 30))	('mouse', 'Species', '10090', (61, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('Harderian gland adenocarcinoma', 'Disease', 'MESH:D000230', (0, 30))
174110	26429628	Male B6C3F1 mice exposed to glycidamide had a dose-related increase in squamous cell papilloma of the skin, with the incidence being significant at 0.70 mM glycidamide (Table 1).	('squamous cell papilloma of the skin', 'Disease', 'MESH:D010212', (71, 106))	('mice', 'Species', '10090', (12, 16))	('papilloma', 'Phenotype', 'HP:0012740', (85, 94))	('glycidamide', 'Chemical', 'MESH:C071834', (28, 39))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (71, 94))	('glycidamide', 'Chemical', 'MESH:C071834', (156, 167))	('squamous cell papilloma of the skin', 'Disease', (71, 106))	('glycidamide', 'Var', (28, 39))	('increase', 'PosReg', (59, 67))
174112	26429628	Female B6C3F1 mice had dose-related increases in malignant mesenchymal skin tumors (fibrosarcoma or combined fibrosarcoma or sarcoma; Table 1).	('mice', 'Species', '10090', (14, 18))	('malignant mesenchymal skin tumors', 'Disease', (49, 82))	('increases', 'PosReg', (36, 45))	('skin tumors', 'Phenotype', 'HP:0008069', (71, 82))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('B6C3F1', 'Var', (7, 13))	('fibrosarcoma or sarcoma', 'Disease', 'MESH:D005354', (109, 132))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('fibrosarcoma', 'Disease', 'MESH:D005354', (109, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('malignant mesenchymal skin tumors', 'Disease', 'MESH:C535700', (49, 82))	('fibrosarcoma', 'Disease', (109, 121))	('fibrosarcoma or sarcoma', 'Disease', (109, 132))	('fibrosarcoma', 'Disease', 'MESH:D005354', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('fibrosarcoma', 'Disease', (84, 96))
174113	26429628	The incidence of fibrosarcoma was significant at 0.70 mM glycidamide and the incidence of combined fibrosarcoma or sarcoma was significant at 0.35 and 0.70 mM glycidamide.	('fibrosarcoma or sarcoma', 'Disease', 'MESH:D005354', (99, 122))	('glycidamide', 'Var', (57, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('fibrosarcoma', 'Disease', (17, 29))	('fibrosarcoma or sarcoma', 'Disease', (99, 122))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (99, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('glycidamide', 'Chemical', 'MESH:C071834', (159, 170))	('fibrosarcoma', 'Disease', 'MESH:D005354', (99, 111))	('0.70 mM glycidamide', 'Var', (49, 68))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (17, 29))	('fibrosarcoma', 'Disease', 'MESH:D005354', (17, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('glycidamide', 'Chemical', 'MESH:C071834', (57, 68))	('fibrosarcoma', 'Disease', (99, 111))
174114	26429628	Female B6C3F1 mice administered glycidamide had dose-related increasing trends in adenoacanthoma, adenocarcinoma, and combined adenoacanthoma or adenocarcinoma of the mammary gland (Table 1).	('adenoacanthoma or adenocarcinoma', 'Disease', (127, 159))	('glycidamide', 'Var', (32, 43))	('adenoacanthoma, adenocarcinoma', 'Disease', 'MESH:D000230', (82, 112))	('mice', 'Species', '10090', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('adenoacanthoma or adenocarcinoma', 'Disease', 'MESH:D000230', (127, 159))	('glycidamide', 'Chemical', 'MESH:C071834', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
174115	26429628	The incidence of adenoacanthoma was increased significantly in the 0.70 mM glycidamide dose group, and the incidence of adenocarcinoma and combined adenoacanthoma or adenocarcinoma was increased significantly in the 0.35 and 0.70 mM glycidamide dose groups.	('adenocarcinoma', 'Disease', (120, 134))	('adenoacanthoma', 'Disease', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('adenoacanthoma or adenocarcinoma', 'Disease', 'MESH:D000230', (148, 180))	('glycidamide', 'Chemical', 'MESH:C071834', (75, 86))	('glycidamide', 'Chemical', 'MESH:C071834', (233, 244))	('adenoacanthoma or adenocarcinoma', 'Disease', (148, 180))	('adenoacanthoma', 'Disease', (17, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (120, 134))	('adenoacanthoma', 'Disease', 'None', (17, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adenocarcinoma', 'Disease', (166, 180))	('adenocarcinoma', 'Disease', 'MESH:D000230', (166, 180))	('0.70', 'Var', (67, 71))	('adenoacanthoma', 'Disease', 'None', (148, 162))
174117	26429628	In both sexes of F344/N rats administered glycidamide in the drinking water, there was a dose-related increasing trend in the incidence of thyroid gland follicular cell adenoma, follicular cell carcinoma, and combined follicular cell adenoma or carcinoma (Table 2).	('drinking water', 'Chemical', 'MESH:D060766', (61, 75))	('follicular cell carcinoma', 'Phenotype', 'HP:0031548', (178, 203))	('follicular cell carcinoma', 'Disease', (178, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('rats', 'Species', '10116', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (234, 254))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (153, 176))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (218, 241))	('thyroid gland follicular cell adenoma', 'Phenotype', 'HP:0011774', (139, 176))	('glycidamide', 'Chemical', 'MESH:C071834', (42, 53))	('follicular cell carcinoma', 'Disease', 'MESH:D018263', (178, 203))	('follicular cell adenoma', 'Disease', (153, 176))	('glycidamide', 'Var', (42, 53))	('follicular cell adenoma', 'Disease', (218, 241))	('adenoma or carcinoma', 'Disease', (234, 254))
174118	26429628	In male F344/N rats, the incidence of follicular cell adenoma, follicular cell carcinoma, and combined follicular cell adenoma or carcinoma was significant at 0.70 mM glycidamide.	('glycidamide', 'Chemical', 'MESH:C071834', (167, 178))	('follicular cell carcinoma', 'Disease', (63, 88))	('0.70 mM', 'Var', (159, 166))	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (119, 139))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (103, 126))	('follicular cell carcinoma', 'Phenotype', 'HP:0031548', (63, 88))	('follicular cell adenoma', 'Disease', (38, 61))	('follicular cell adenoma', 'Disease', (103, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('adenoma or carcinoma', 'Disease', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('follicular cell carcinoma', 'Disease', 'MESH:D018263', (63, 88))	('rats', 'Species', '10116', (15, 19))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (38, 61))
174119	26429628	In female F344/N rats, the incidence of follicular cell adenoma and follicular cell carcinoma was significant at 0.70 mM glycidamide, while the incidence of combined follicular cell adenoma or carcinoma was significant at 0.175, 0.35, and 0.70 mM glycidamide.	('follicular cell adenoma', 'Disease', (166, 189))	('rats', 'Species', '10116', (17, 21))	('follicular cell adenoma', 'Disease', (40, 63))	('0.70 mM glycidamide', 'Var', (113, 132))	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (182, 202))	('glycidamide', 'Chemical', 'MESH:C071834', (247, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('follicular cell carcinoma', 'Disease', 'MESH:D018263', (68, 93))	('glycidamide', 'Chemical', 'MESH:C071834', (121, 132))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (166, 189))	('adenoma or carcinoma', 'Disease', (182, 202))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (40, 63))	('glycidamide', 'Var', (121, 132))	('follicular cell carcinoma', 'Phenotype', 'HP:0031548', (68, 93))	('follicular cell carcinoma', 'Disease', (68, 93))
174120	26429628	The administration of glycidamide was associated with a dose-related increase in squamous cell papilloma of the oral mucosa and tongue and combined squamous cell papilloma or carcinoma of the oral mucosa or tongue in male F344/N rats (Table 2).	('squamous cell papilloma', 'Disease', 'MESH:D010212', (148, 171))	('increase', 'PosReg', (69, 77))	('papilloma', 'Phenotype', 'HP:0012740', (162, 171))	('glycidamide', 'Var', (22, 33))	('rats', 'Species', '10116', (229, 233))	('glycidamide', 'Chemical', 'MESH:C071834', (22, 33))	('carcinoma of the oral mucosa', 'Disease', 'MESH:C565008', (175, 203))	('squamous cell papilloma', 'Disease', 'MESH:D010212', (81, 104))	('papilloma', 'Phenotype', 'HP:0012740', (95, 104))	('carcinoma of the oral mucosa', 'Disease', (175, 203))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (148, 171))	('squamous cell papilloma', 'Disease', (148, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (175, 196))	('squamous cell papilloma of the oral mucosa', 'Disease', (81, 123))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (81, 104))	('squamous cell papilloma of the oral mucosa', 'Disease', 'MESH:D010212', (81, 123))
174121	26429628	The incidence of squamous cell papilloma of the tongue and combined squamous cell papilloma or carcinoma of the oral mucosa or tongue was significant at 0.70 mM glycidamide.	('squamous cell papilloma', 'Disease', (17, 40))	('papilloma', 'Phenotype', 'HP:0012740', (31, 40))	('carcinoma of the oral mucosa', 'Disease', 'MESH:C565008', (95, 123))	('papilloma', 'Phenotype', 'HP:0012740', (82, 91))	('carcinoma of the oral mucosa', 'Disease', (95, 123))	('glycidamide', 'Chemical', 'MESH:C071834', (161, 172))	('0.70 mM', 'Var', (153, 160))	('combined', 'Disease', (59, 67))	('squamous cell papilloma', 'Disease', 'MESH:D010212', (68, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell papilloma', 'Disease', 'MESH:D010212', (17, 40))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (95, 116))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (68, 91))	('squamous cell papilloma', 'Disease', (68, 91))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (17, 40))
174123	26429628	Both sexes of F344/N rats also had dose related increases in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.70 mM glycidamide (Table 2).	('increases', 'PosReg', (48, 57))	('rats', 'Species', '10116', (21, 25))	('glycidamide', 'Chemical', 'MESH:C071834', (165, 176))	('leukemia', 'Disease', (95, 103))	('0.70 mM', 'Var', (157, 164))	('leukemia', 'Disease', 'MESH:D007938', (95, 103))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('F344/N', 'Var', (14, 20))
174125	26429628	The incidence of malignant mesothelioma was significant in the epididymis, testes, and combined testes or epididymis at 0.35 and 0.70 mM glycidamide.	('epididymis', 'Disease', 'MESH:D004823', (106, 116))	('glycidamide', 'Chemical', 'MESH:C071834', (137, 148))	('epididymis', 'Disease', 'MESH:D004823', (63, 73))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (17, 39))	('0.70 mM', 'Var', (129, 136))	('epididymis', 'Disease', (106, 116))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (17, 39))	('malignant mesothelioma', 'Disease', (17, 39))	('combined testes', 'Phenotype', 'HP:0010470', (87, 102))	('epididymis', 'Disease', (63, 73))
174127	26429628	Female F344/N rats exposed to glycidamide in the drinking water had an increased occurrence of fibroadenomas in the mammary gland, with the incidence being significantly increased at all doses (Table 2).	('fibroadenomas', 'Disease', 'MESH:D018226', (95, 108))	('glycidamide', 'Chemical', 'MESH:C071834', (30, 41))	('fibroadenomas', 'Disease', (95, 108))	('rats', 'Species', '10116', (14, 18))	('increased', 'PosReg', (170, 179))	('glycidamide', 'Var', (30, 41))	('drinking water', 'Chemical', 'MESH:D060766', (49, 63))	('fibroadenomas in the mammary gland', 'Phenotype', 'HP:0010619', (95, 129))
174129	26429628	The incidence of clitoral gland carcinoma was significant at 0.35 and 0.70 mM glycidamide, while the occurrence of forestomach squamous cell papilloma was significant at 0.70 mM glycidamide (Table 2).	('clitoral gland carcinoma', 'Disease', 'MESH:D004701', (17, 41))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (127, 150))	('glycidamide', 'Chemical', 'MESH:C071834', (78, 89))	('glycidamide', 'Var', (78, 89))	('clitoral gland', 'Phenotype', 'HP:0008665', (17, 31))	('glycidamide', 'Chemical', 'MESH:C071834', (178, 189))	('clitoral gland carcinoma', 'Disease', (17, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('forestomach squamous cell papilloma', 'Disease', (115, 150))	('0.70 mM glycidamide', 'Var', (70, 89))	('papilloma', 'Phenotype', 'HP:0012740', (141, 150))	('forestomach squamous cell papilloma', 'Disease', 'MESH:D010212', (115, 150))	('0.35', 'Var', (61, 65))
174131	26429628	The incidence of cataracts was increased in the 0.175, 0.35, and 0.70 mM glycidamide dose groups, while the incidence of corneal inflammation was increased at 0.70 mM glycidamide.	('0.70 mM', 'Var', (65, 72))	('glycidamide', 'Chemical', 'MESH:C071834', (167, 178))	('cataracts', 'Phenotype', 'HP:0000518', (17, 26))	('0.35', 'Var', (55, 59))	('glycidamide', 'Chemical', 'MESH:C071834', (73, 84))	('corneal inflammation', 'Phenotype', 'HP:0000491', (121, 141))	('0.175', 'Var', (48, 53))	('corneal inflammation', 'Disease', (121, 141))	('corneal inflammation', 'Disease', 'MESH:D007249', (121, 141))	('cataracts', 'Disease', 'MESH:D002386', (17, 26))	('inflammation', 'biological_process', 'GO:0006954', ('129', '141'))	('cataracts', 'Disease', (17, 26))
174132	26429628	Glycidamide administration resulted in a dose-related increasing trend in epithelium hyperplasia of the forestomach in both sexes of B6C3F1 mice, with the incidence being significant at 0.70 mM glycidamide in male mice and 0.35 mM glycidamide in female mice.	('Glycidamide', 'Chemical', 'MESH:C071834', (0, 11))	('mice', 'Species', '10090', (214, 218))	('mice', 'Species', '10090', (140, 144))	('glycidamide', 'Chemical', 'MESH:C071834', (194, 205))	('hyperplasia of the forestomach', 'Disease', 'MESH:D013274', (85, 115))	('hyperplasia of the forestomach', 'Disease', (85, 115))	('0.70', 'Var', (186, 190))	('mice', 'Species', '10090', (253, 257))	('glycidamide', 'Chemical', 'MESH:C071834', (231, 242))
174133	26429628	Both sexes of B6C3F1 mice also had increasing dose-related trends in hematopoietic cell proliferation of the spleen, with the incidence being significant at 0.35 and 0.70 mM glycidamide.	('B6C3F1', 'Var', (14, 20))	('mice', 'Species', '10090', (21, 25))	('0.70 mM', 'Var', (166, 173))	('glycidamide', 'Chemical', 'MESH:C071834', (174, 185))	('hematopoietic cell proliferation of the spleen', 'CPA', (69, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))
174136	26429628	Drinking water administration of glycidamide to F334/N rats resulted in a dose-related increase in brain gliosis in both sexes (Table 4).	('increase', 'PosReg', (87, 95))	('rats', 'Species', '10116', (55, 59))	('gliosis', 'Phenotype', 'HP:0002171', (105, 112))	('gliosis', 'biological_process', 'GO:0150103', ('105', '112'))	('increase in brain gliosis', 'Phenotype', 'HP:0002171', (87, 112))	('brain gliosis', 'Disease', 'MESH:D005911', (99, 112))	('brain gliosis', 'Disease', (99, 112))	('F334/N', 'Var', (48, 54))	('glycidamide', 'Chemical', 'MESH:C071834', (33, 44))	('Drinking water', 'Chemical', 'MESH:D060766', (0, 14))
174137	26429628	In male rats, the incidence of gliosis was increased in the 0.70 mM glycidamide dose group, while in female rats the incidence was increased at 0.175, 0.35, and 0.70 mM glycidamide.	('glycidamide', 'Chemical', 'MESH:C071834', (68, 79))	('gliosis', 'Disease', 'MESH:D005911', (31, 38))	('gliosis', 'Disease', (31, 38))	('rats', 'Species', '10116', (108, 112))	('0.70 mM', 'Var', (60, 67))	('increased', 'PosReg', (43, 52))	('glycidamide', 'Chemical', 'MESH:C071834', (169, 180))	('rats', 'Species', '10116', (8, 12))	('gliosis', 'Phenotype', 'HP:0002171', (31, 38))	('0.70 mM', 'Var', (161, 168))	('gliosis', 'biological_process', 'GO:0150103', ('31', '38'))
174155	26429628	These results, coupled with the observation that glycidamide and acrylamide give very similar DNA adduct profiles in the lungs of B6C3F1 mice and other strains of mice are consistent with the premise that the lung neoplasms induced in B6C3F1 mice are due to acrylamide being metabolized to glycidamide.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('neoplasms', 'Phenotype', 'HP:0002664', (214, 223))	('mice', 'Species', '10090', (137, 141))	('lung neoplasms', 'Disease', (209, 223))	('lung neoplasms', 'Disease', 'MESH:D008175', (209, 223))	('glycidamide', 'Chemical', 'MESH:C071834', (49, 60))	('B6C3F1', 'Var', (235, 241))	('mice', 'Species', '10090', (163, 167))	('lung neoplasms', 'Phenotype', 'HP:0100526', (209, 223))	('neoplasm', 'Phenotype', 'HP:0002664', (214, 222))	('acrylamide', 'Chemical', 'MESH:D020106', (258, 268))	('mice', 'Species', '10090', (242, 246))	('acrylamide', 'Chemical', 'MESH:D020106', (65, 75))	('glycidamide', 'Chemical', 'MESH:C071834', (290, 301))
174161	26429628	In other studies, high levels of N7-GA-Gua and N3-GA-Ade have been detected in liver DNA from mice treated as adults with glycidamide and an increase in mutant frequency has been observed in the cII transgene in the livers of adult Big Blue mice dosed orally with glycidamide for four weeks.	('N7-GA-Gua', 'Chemical', 'MESH:C093852', (33, 42))	('N3-GA-Ade', 'Var', (47, 56))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('increase', 'PosReg', (141, 149))	('glycidamide', 'Chemical', 'MESH:C071834', (122, 133))	('N3-GA-Ade', 'Chemical', 'MESH:C518583', (47, 56))	('mice', 'Species', '10090', (241, 245))	('mutant frequency', 'MPA', (153, 169))	('N7-GA-Gua', 'Var', (33, 42))	('mice', 'Species', '10090', (94, 98))	('glycidamide', 'Chemical', 'MESH:C071834', (264, 275))	('cII transgene', 'Gene', (195, 208))
174168	26429628	The administration of glycidamide in the drinking water to F344/N rats resulted in significant dose-related decreases in body weight, with the effect being most pronounced in the 0.70 mM glycidamide dose group (Supplementary Figure S2).	('0.70 mM', 'Var', (179, 186))	('decreases in body weight', 'Phenotype', 'HP:0004325', (108, 132))	('decreases', 'NegReg', (108, 117))	('body weight', 'CPA', (121, 132))	('drinking water', 'Chemical', 'MESH:D060766', (41, 55))	('rats', 'Species', '10116', (66, 70))	('glycidamide', 'Chemical', 'MESH:C071834', (187, 198))	('glycidamide', 'Chemical', 'MESH:C071834', (22, 33))
174174	26429628	In male rats, the incidence of combined follicular cell adenoma or carcinoma was significantly increased at 0.70 mM glycidamide and in female rats the incidence was increased significantly at 0.175, 0.35, and 0.70 mM glycidamide (Table 2).	('0.35', 'Var', (199, 203))	('rats', 'Species', '10116', (8, 12))	('follicular cell adenoma', 'Disease', (40, 63))	('adenoma or carcinoma', 'Disease', (56, 76))	('glycidamide', 'Chemical', 'MESH:C071834', (116, 127))	('glycidamide', 'Chemical', 'MESH:C071834', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('rats', 'Species', '10116', (142, 146))	('0.175', 'Var', (192, 197))	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (56, 76))	('follicular cell adenoma', 'Disease', 'MESH:D000236', (40, 63))	('0.70 mM', 'Var', (209, 216))	('increased', 'PosReg', (95, 104))	('0.70 mM glycidamide', 'Var', (108, 127))
174181	26429628	Furthermore, Big Blue rats administered equimolar quantities of acrylamide or glycidamide have increased mutant frequencies at the cII transgene of their thyroid glands.	('glycidamide', 'Chemical', 'MESH:C071834', (78, 89))	('cII transgene', 'Gene', (131, 144))	('acrylamide', 'Chemical', 'MESH:D020106', (64, 74))	('mutant frequencies', 'Var', (105, 123))	('increased', 'PosReg', (95, 104))	('rats', 'Species', '10116', (22, 26))
174186	26429628	In addition to having similar incidences of mammary gland fibroadenomas, female F344 rats administered a single intraperitoneal injection of 0.7 mmol acrylamide or glycidamide per kg body weight form high levels of N7-GA-Gua in their mammary gland DNA, which supports the concept that the fibroadenomas result from a genotoxic mechanism as a consequence of the metabolic conversion of acrylamide to glycidamide.	('N7-GA-Gua', 'Var', (215, 224))	('rats', 'Species', '10116', (85, 89))	('glycidamide', 'Chemical', 'MESH:C071834', (164, 175))	('mammary gland fibroadenomas', 'Phenotype', 'HP:0010619', (44, 71))	('N7-GA-Gua', 'Chemical', 'MESH:C093852', (215, 224))	('fibroadenomas', 'Disease', 'MESH:D018226', (58, 71))	('acrylamide', 'Chemical', 'MESH:D020106', (150, 160))	('mammary gland fibroadenoma', 'Phenotype', 'HP:0010619', (44, 70))	('fibroadenomas', 'Disease', 'MESH:D018226', (289, 302))	('fibroadenomas', 'Disease', (58, 71))	('glycidamide', 'Chemical', 'MESH:C071834', (399, 410))	('DNA', 'cellular_component', 'GO:0005574', ('248', '251'))	('fibroadenomas', 'Disease', (289, 302))	('acrylamide', 'Chemical', 'MESH:D020106', (385, 395))
174190	26429628	Female F344/N rats treated with glycidamide in the drinking water also had increased incidences of clitoral gland carcinoma and oral cavity neoplasms (primarily squamous cell papilloma of the oral mucosa or tongue; Table 2) that, in each of the glycidamide dose groups, exceeded the NCTR historical range for control female F344/N rats.	('increased incidences of clitoral gland', 'Phenotype', 'HP:0008665', (75, 113))	('squamous cell papilloma of the oral mucosa', 'Disease', 'MESH:D010212', (161, 203))	('squamous cell papilloma', 'Phenotype', 'HP:0031021', (161, 184))	('glycidamide', 'Var', (32, 43))	('clitoral gland', 'Phenotype', 'HP:0008665', (99, 113))	('clitoral gland carcinoma and oral cavity neoplasms', 'Disease', 'MESH:D009062', (99, 149))	('oral cavity neoplasms', 'Phenotype', 'HP:0100649', (128, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('rats', 'Species', '10116', (14, 18))	('papilloma', 'Phenotype', 'HP:0012740', (175, 184))	('rats', 'Species', '10116', (331, 335))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('drinking water', 'Chemical', 'MESH:D060766', (51, 65))	('squamous cell papilloma of the oral mucosa', 'Disease', (161, 203))	('glycidamide', 'Chemical', 'MESH:C071834', (32, 43))	('glycidamide', 'Chemical', 'MESH:C071834', (245, 256))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))
174195	26429628	Female F344/N rats treated with 0.70 mM glycidamide had a low, but statistically significant, occurrence of forestomach papilloma (Table 2), the incidence of which exceeded the NCTR historical control range.	('0.70 mM glycidamide', 'Var', (32, 51))	('glycidamide', 'Chemical', 'MESH:C071834', (40, 51))	('glycidamide', 'Var', (40, 51))	('papilloma', 'Phenotype', 'HP:0012740', (120, 129))	('rats', 'Species', '10116', (14, 18))	('forestomach papilloma', 'Disease', 'MESH:D013274', (108, 129))	('forestomach papilloma', 'Disease', (108, 129))
174198	26429628	The incidence of these neoplasms was significant at 0.35 and 0.70 mM glycidamide and exceeded the NCTR historical control range.	('glycidamide', 'MPA', (69, 80))	('0.70', 'Var', (61, 65))	('neoplasms', 'Phenotype', 'HP:0002664', (23, 32))	('0.35', 'Var', (52, 56))	('glycidamide', 'Chemical', 'MESH:C071834', (69, 80))	('neoplasms', 'Disease', (23, 32))	('neoplasm', 'Phenotype', 'HP:0002664', (23, 31))	('neoplasms', 'Disease', 'MESH:D009369', (23, 32))
174226	26429628	Female B6C3F1 mice also had a significantly increased incidence of tumors of the mammary gland and ovary.	('tumors of the mammary gland', 'Phenotype', 'HP:0100013', (67, 94))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('B6C3F1', 'Var', (7, 13))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
174228	26429628	Male F344/N rats also had significant dose-related increases in tumors of the epididymis/testes and heart, while female F344/N rats demonstrated significant increases in tumors of the mammary gland, clitoral gland, and forestomach.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('rats', 'Species', '10116', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors of the mammary gland', 'Phenotype', 'HP:0100013', (170, 197))	('clitoral gland', 'Phenotype', 'HP:0008665', (199, 213))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('increases', 'PosReg', (51, 60))	('F344/N', 'Var', (5, 11))	('rats', 'Species', '10116', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors of the epididymis', 'Disease', 'MESH:D009369', (64, 88))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('increases', 'PosReg', (157, 166))	('clitoral gland', 'CPA', (199, 213))	('tumors', 'Disease', (170, 176))	('tumors of the epididymis', 'Disease', (64, 88))
174232	26429628	These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide in both sexes of both species and that the carcinogenic activity of acrylamide is due to its metabolic conversion into glycidamide.	('glycidamide', 'Chemical', 'MESH:C071834', (239, 250))	('metabolic conversion', 'MPA', (213, 233))	('acrylamide', 'Chemical', 'MESH:D020106', (67, 77))	('carcinogenic', 'Disease', 'MESH:D063646', (163, 175))	('acrylamide', 'Chemical', 'MESH:D020106', (188, 198))	('carcinogenic', 'Disease', (163, 175))	('glycidamide', 'Chemical', 'MESH:C071834', (108, 119))	('acrylamide', 'Var', (188, 198))
174304	24566531	Although both mesothelin and MPF belong to mesothelin family proteins, we noted in the current meta-analysis that the overall diagnostic measures including sensitivity, specificity, PLR, NLR, DOR and AUC of serum MPF were better than those of serum mesothelin.	('MPF', 'Gene', (29, 32))	('MPF', 'Gene', (213, 216))	('mesothelin', 'Gene', (43, 53))	('DOR', 'MPA', (192, 195))	('mesothelin', 'Gene', (249, 259))	('PLR', 'MPA', (182, 185))	('mesothelin', 'Gene', '10232', (14, 24))	('MPF', 'Gene', '10232', (29, 32))	('serum', 'Var', (207, 212))	('mesothelin', 'Gene', '10232', (249, 259))	('PF', 'Phenotype', 'HP:0002202', (214, 216))	('MPF', 'Gene', '10232', (213, 216))	('mesothelin', 'Gene', '10232', (43, 53))	('PF', 'Phenotype', 'HP:0002202', (30, 32))	('mesothelin', 'Gene', (14, 24))
174384	24063788	After adjustment for various prognostic factors in a multivariable model, sensitivity to doxorubicin, synchronous PC and macroscopically radical surgery were independently associated with longer TTP.	('TTP', 'Gene', (195, 198))	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('synchronous PC', 'Disease', (102, 116))	('TTP', 'Gene', '7538', (195, 198))	('associated', 'Reg', (172, 182))	('sensitivity', 'Var', (74, 85))
174449	17331233	Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines Asbestos has been shown to cause chromosomal damage and DNA aberrations.	('Asbestos', 'Var', (88, 96))	('rat', 'Species', '10116', (152, 155))	('chromosomal damage', 'Disease', 'MESH:D004194', (121, 139))	('chromosomal damage', 'Disease', (121, 139))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('DNA aberrations', 'CPA', (144, 159))	('Asbestos', 'Chemical', 'MESH:D001194', (88, 96))	('cause', 'Reg', (115, 120))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))
174481	17331233	The most significant cluster of A549 (cluster 5) contained enrichment of genes located in nine of the 18 previously identified chromosomal regions with copy number changes in asbestos-associated lung cancer, i.e., 11q13, 19p13, 9q34, 16p13, 1p36, 17p13, 5q35, 3p21, and 22q13 (p < 0.01).	('copy number changes', 'Var', (152, 171))	('1p36', 'Var', (241, 245))	('p21', 'Gene', (261, 264))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (195, 206))	('p21', 'Gene', '644914', (261, 264))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))
174523	17331233	Asbestos-associated protein kinase c, delta (PKC-delta)and p-adducin (ADD) were represented in significant clusters in all cell lines and ADD3 was represented in the most significant cluster of all cell lines (Fig 2A, D and 2G).	('ADD3', 'Gene', (138, 142))	('PKC-delta', 'Gene', (45, 54))	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('PKC', 'molecular_function', 'GO:0004697', ('45', '48'))	('ADD3', 'Gene', '27360', (138, 142))	('PKC-delta', 'Gene', '5580', (45, 54))	('protein kinase c', 'Gene', '5580', (20, 36))	('protein kinase c', 'Gene', (20, 36))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('p-adducin', 'Var', (59, 68))
174525	17331233	Furthermore, PKC-delta maps to a chromosomal area closely adjacent to 3p21, a region that has recently been found to be more frequently affected by loss of heterozygosity in asbestos-exposed than in non-exposed lung cancer patients.	('PKC-delta', 'Gene', (13, 22))	('PKC-delta', 'Gene', '5580', (13, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('loss', 'Var', (148, 152))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('p21', 'Gene', (71, 74))	('p21', 'Gene', '644914', (71, 74))	('asbestos', 'Chemical', 'MESH:D001194', (174, 182))	('patients', 'Species', '9606', (223, 231))	('lung cancer', 'Disease', (211, 222))
174545	17331233	The long arm of chromosome 2 contains two fragile sites, FRA2G and FRA2H closely preceding and adjacent, respectively, to the region in the CCA results, suggesting that damage in these areas could cause specific changes in the expression of genes localized between the fragile sites.	('CCA', 'Chemical', '-', (140, 143))	('expression of genes', 'MPA', (227, 246))	('FRA2H', 'Gene', (67, 72))	('FRA2H', 'Gene', '2380', (67, 72))	('FRA2G', 'Gene', '2379', (57, 62))	('FRA2G', 'Gene', (57, 62))	('changes', 'Reg', (212, 219))	('damage', 'Var', (169, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))
174546	17331233	We have previously found fragile sites to be associated with asbestos-related copy number aberrations in lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('rat', 'Species', '10116', (94, 97))	('asbestos-related', 'Disease', (61, 77))	('associated', 'Reg', (45, 55))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('copy number aberrations', 'Var', (78, 101))	('patients', 'Species', '9606', (117, 125))	('asbestos', 'Chemical', 'MESH:D001194', (61, 69))	('lung cancer', 'Disease', (105, 116))
174549	17331233	This could possibly be attributable to the fact that A549 is a malignancy-derived cell line from a lung adenocarcinoma, whereas Beas-2B and MeT5A are SV40-transformed non-malignant cells that may exhibit the early effects of asbestos more clearly.	('A549', 'Var', (53, 57))	('Beas-2B', 'CellLine', 'CVCL:0168', (128, 135))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('malignancy', 'Disease', (63, 73))	('asbestos', 'Chemical', 'MESH:D001194', (225, 233))	('lung adenocarcinoma', 'Disease', (99, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('A549', 'CellLine', 'CVCL:0023', (53, 57))
174615	31028099	Syndecan-2 was measured quantitatively in a subset of pleural fluids (n=179), adapted from a semiquantitative procedure, and using monoclonal primary anti-human antibody developed in rat (LS-C39400) and secondary syndecan-2 polyclonal anti-human antibody developed in rabbit (LS-C39399).	('antibody', 'cellular_component', 'GO:0042571', ('246', '254'))	('rabbit', 'Species', '9986', (268, 274))	('rat', 'Species', '10116', (183, 186))	('antibody', 'cellular_component', 'GO:0019814', ('161', '169'))	('human', 'Species', '9606', (240, 245))	('syndecan', 'molecular_function', 'GO:0015023', ('213', '221'))	('LS-C39399', 'Var', (276, 285))	('antibody', 'molecular_function', 'GO:0003823', ('161', '169'))	('pleural fluid', 'Phenotype', 'HP:0002202', (54, 67))	('antibody', 'cellular_component', 'GO:0019815', ('246', '254'))	('antibody', 'cellular_component', 'GO:0042571', ('161', '169'))	('LS-C39400', 'Var', (188, 197))	('antibody', 'cellular_component', 'GO:0019814', ('246', '254'))	('Syndecan', 'molecular_function', 'GO:0015023', ('0', '8'))	('antibody', 'cellular_component', 'GO:0019815', ('161', '169'))	('human', 'Species', '9606', (155, 160))	('antibody', 'molecular_function', 'GO:0003823', ('246', '254'))	('pleural', 'Disease', 'MESH:D010995', (54, 61))	('pleural', 'Disease', (54, 61))
174703	25598227	Malignant mesothelioma can also occur due to less common causes such as radiation, viruses (e.g., Simian virus 40) and germline mutations in BAP-1.	('BAP-1', 'Gene', (141, 146))	('germline mutations', 'Var', (119, 137))	('Simian virus 40', 'Species', '1891767', (98, 113))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('radiation', 'Disease', 'MESH:D004194', (72, 81))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))	('radiation', 'Disease', (72, 81))
174766	24322529	Completeness of cytoreduction (CC) score assessed the extent of residual disease at the end of surgical resection: CC-0, no visible residual disease; CC-1, residual tumors <=2.5 mm; CC-2, residual tumors 2.5-2.5 cm; CC-3, residual tumors >=2.5 cm.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('<=2.5', 'Var', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (197, 203))	('tumors', 'Disease', (231, 237))
174806	24322529	Molecular targeted therapies against various aberrantly activated growth factor receptors and cellular pathways, involved in tumor invasion and metastasis, are currently being tested in preclinical, phase I, and phase II studies.	('aberrantly', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('growth factor receptors', 'Protein', (66, 89))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cellular pathways', 'Pathway', (94, 111))
174848	19662202	Earlier studies have reported high levels of expression of SV40 DNA or large T antigen protein in MM (reviewed in Shah, 2006), although not all studies reproduced this observation.	('large T antigen protein', 'Protein', (71, 94))	('SV40 DNA', 'Var', (59, 67))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('SV40', 'Species', '1891767', (59, 63))	('expression', 'MPA', (45, 55))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
174849	19662202	The presence of SV40 has been associated with expression of several cancer-associated molecules, the majority of which are discussed below.	('associated', 'Reg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('SV40', 'Species', '1891767', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('SV40', 'Gene', (16, 20))	('cancer', 'Disease', (68, 74))	('presence', 'Var', (4, 12))	('expression', 'MPA', (46, 56))
174850	19662202	The presence of SV40 in MM was shown to be associated with more frequent methylation of the RASSF1 gene, a putative tumor suppressor gene in lung cancer.	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('methylation', 'MPA', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('SV40', 'Species', '1891767', (16, 20))	('lung cancer', 'Disease', (141, 152))	('RASSF1', 'Gene', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('SV40', 'Var', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('tumor', 'Disease', (116, 121))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
174852	19662202	The presence of SV40 has been shown to be associated with higher levels of vascular endothelial growth factor (VEGF), telomerase activity, expression of the cell cycle inhibitor p21WAF1/CIP1, p53 inactivation and activation of the phosphatidylinositol 3-kinase/AKT signaling pathway.	('levels', 'MPA', (65, 71))	('telomerase activity', 'MPA', (118, 137))	('AKT', 'Gene', (261, 264))	('SV40', 'Species', '1891767', (16, 20))	('SV40', 'Var', (16, 20))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('75', '109'))	('p53', 'Gene', (192, 195))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('AKT signaling', 'biological_process', 'GO:0043491', ('261', '274'))	('telomerase activity', 'molecular_function', 'GO:0003720', ('118', '137'))	('AKT', 'Gene', '207', (261, 264))	('signaling pathway', 'biological_process', 'GO:0007165', ('265', '282'))	('vascular endothelial growth factor', 'Gene', '7422', (75, 109))	('activation', 'PosReg', (213, 223))	('VEGF', 'Gene', '7422', (111, 115))	('higher', 'PosReg', (58, 64))	('presence', 'Var', (4, 12))	('p21', 'Gene', (178, 181))	('inactivation', 'NegReg', (196, 208))	('VEGF', 'Gene', (111, 115))	('p21', 'Gene', '644914', (178, 181))	('vascular endothelial growth factor', 'Gene', (75, 109))	('expression', 'MPA', (139, 149))	('p53', 'Gene', '7157', (192, 195))
174895	19662202	However, EGFR mutations were not detected in pleural MM.	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))	('pleural MM', 'Disease', (45, 55))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('pleural MM', 'Disease', 'MESH:D010995', (45, 55))
174897	19662202	EGFR expression correlates with worse survival in MM, but this finding loses significance when histologic type (epithelioid vs. sarcomatoid) is taken into account.	('EGFR', 'Gene', (0, 4))	('sarcomatoid', 'Disease', (128, 139))	('expression', 'Var', (5, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('sarcomatoid', 'Disease', 'MESH:C538614', (128, 139))	('worse', 'NegReg', (32, 37))	('EGFR', 'Gene', '1956', (0, 4))
174913	19662202	Silencing methylation of TNF-related apoptosis-inducing ligand (TRAIL) receptors has been found in various cancers, including clinical specimens and MM cell lines, documenting an important mechanism for the evasion of apoptosis.	('cancers', 'Disease', (107, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('ligand', 'molecular_function', 'GO:0005488', ('56', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('Silencing methylation', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('TNF-related', 'Gene', (25, 36))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
174918	19662202	Survivin levels decreased following treatment with Cisplatin, and treatment with anti-Survivin oligonucleotides resulted in p53 activation and sensitization to apoptosis in the ZL34 cell line.	('activation', 'PosReg', (128, 138))	('apoptosis', 'CPA', (160, 169))	('anti-Survivin', 'Var', (81, 94))	('sensitization', 'Reg', (143, 156))	('p53', 'Gene', (124, 127))	('sensitization', 'biological_process', 'GO:0046960', ('143', '156'))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (95, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('Survivin levels', 'MPA', (0, 15))	('p53', 'Gene', '7157', (124, 127))	('ZL34', 'CellLine', 'CVCL:5906', (177, 181))	('Cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('decreased', 'NegReg', (16, 25))
174920	19662202	c-IAP1 expression was reported to be elevated in pleural MM compared to normal pleura and lung tissue, and antisense targeting of cIAP-1 resulted in caspase 9 cleavage and sensitization to apoptosis in the 94-589 cell line.	('cIAP-1', 'Gene', (130, 136))	('pleural MM', 'Disease', 'MESH:D010995', (49, 59))	('c-IAP1', 'Gene', '329', (0, 6))	('pleural MM', 'Disease', (49, 59))	('elevated', 'PosReg', (37, 45))	('sensitization', 'Reg', (172, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('expression', 'MPA', (7, 17))	('apoptosis', 'CPA', (189, 198))	('antisense targeting', 'Var', (107, 126))	('cleavage', 'MPA', (159, 167))	('cIAP-1', 'Gene', '329', (130, 136))	('sensitization', 'biological_process', 'GO:0046960', ('172', '185'))	('c-IAP1', 'Gene', (0, 6))	('caspase 9', 'Gene', (149, 158))	('caspase 9', 'Gene', '842', (149, 158))
174928	19662202	WT1 is a tumor suppressor gene localized to chromosome 11 that is inactivated through mutation in 10% of Wilms' tumors, a pediatric malignancy of renal origin.	("Wilms' tumors", 'Phenotype', 'HP:0002667', (105, 118))	('inactivated', 'NegReg', (66, 77))	("Wilms' tumors", 'Disease', (105, 118))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (105, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('44', '54'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('WT1', 'Gene', (0, 3))	("Wilms' tumors", 'Disease', 'MESH:D009396', (105, 118))	('malignancy', 'Disease', (132, 142))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('WT1', 'Gene', '7490', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('malignancy of renal', 'Phenotype', 'HP:0009726', (132, 151))	('mutation', 'Var', (86, 94))
174941	19662202	Expression and activation of p38 (phospho-p38, p-p38) was found in the majority of specimens, with less frequent phosphorylation of ERK and JNK (Figure 1-H).	('ERK', 'molecular_function', 'GO:0004707', ('132', '135'))	('activation', 'PosReg', (15, 25))	('JNK', 'molecular_function', 'GO:0004705', ('140', '143'))	('phosphorylation', 'MPA', (113, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('ERK', 'Protein', (132, 135))	('JNK', 'Gene', (140, 143))	('p-p38', 'Var', (47, 52))	('JNK', 'Gene', '5599', (140, 143))
174942	19662202	Recent work has shown that Wnt-1, member of the Wnt family, is involved in inhibition of apoptosis in MM in vitro, and that inhibition of Wnt-1 or its receptor Dishevelled induces apoptosis via JNK activation.	('Wnt-1', 'Gene', '7471', (27, 32))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('75', '98'))	('Wnt', 'Gene', '7471', (48, 51))	('apoptosis', 'CPA', (180, 189))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('induces', 'Reg', (172, 179))	('Wnt', 'Gene', (27, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('Wnt-1', 'Gene', (138, 143))	('Wnt', 'Gene', (138, 141))	('Wnt', 'Gene', '7471', (27, 30))	('activation', 'PosReg', (198, 208))	('Wnt', 'Gene', '7471', (138, 141))	('Wnt-1', 'Gene', (27, 32))	('Wnt-1', 'Gene', '7471', (138, 143))	('JNK', 'Gene', (194, 197))	('apoptosis', 'CPA', (89, 98))	('JNK', 'Gene', '5599', (194, 197))	('JNK', 'molecular_function', 'GO:0004705', ('194', '197'))	('inhibition', 'Var', (124, 134))	('Wnt', 'Gene', (48, 51))
174943	19662202	These data are supported by the frequent inactivation through methylation of several secreted frizzled-related proteins, inhibitors of the Wnt pathway, in MM cell lines and clinical specimens.	('inactivation', 'NegReg', (41, 53))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('Wnt', 'Gene', (139, 142))	('methylation', 'Var', (62, 73))	('Wnt', 'Gene', '7471', (139, 142))
174949	19662202	However, anti-tumor effect was seen with use of soluble type II TGF-beta receptor and interferon-beta in experimental models.	('tumor', 'Disease', (14, 19))	('interferon-beta', 'Gene', (86, 101))	('interferon-beta', 'Gene', '3456', (86, 101))	('TGF-beta receptor', 'Protein', (64, 81))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('soluble type', 'Var', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('soluble', 'cellular_component', 'GO:0005625', ('48', '55'))
174971	19662202	recently reviewed new agents that under evaluation for the treatment of MM, including EGFR, PDGFR, VEGF and HGF inhibitors, inhibitors of mTOR, a downstream molecule of the PI3K/AKT pathway, and inhibitors of the proteasome/ubiquitin pathway.	('AKT', 'Gene', (178, 181))	('mTOR', 'Gene', (138, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('mTOR', 'Gene', '2475', (138, 142))	('proteasome', 'cellular_component', 'GO:0000502', ('213', '223'))	('VEGF', 'Gene', '7422', (99, 103))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('PDGFR', 'Gene', (92, 97))	('PDGFR', 'Gene', '5159', (92, 97))	('EGFR', 'Gene', (86, 90))	('ubiquitin', 'molecular_function', 'GO:0031386', ('224', '233'))	('HGF', 'Gene', (108, 111))	('AKT', 'Gene', '207', (178, 181))	('VEGF', 'Gene', (99, 103))	('HGF', 'Gene', '3082', (108, 111))	('inhibitors', 'Var', (124, 134))	('proteasome', 'molecular_function', 'GO:0004299', ('213', '223'))
175028	33032525	In contrast, PBMCs exposed to CB asbestos during the MLR exhibited markedly decreased cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (86, 98))	('decreased', 'NegReg', (76, 85))	('CB asbestos', 'Chemical', '-', (30, 41))	('cytotoxicity', 'Disease', (86, 98))	('CB asbestos', 'Var', (30, 41))
175044	33032525	These findings indicate that IL-2 insufficiency is not the main cause for the suppressed differentiation of CTLs upon exposure to asbestos, although suppressed CTL function might be recoverable, as summarized in Table 1.	('asbestos', 'Chemical', 'MESH:D001194', (130, 138))	('IL-2', 'molecular_function', 'GO:0005134', ('29', '33'))	('IL-2', 'Gene', '3558', (29, 33))	('IL-2', 'Gene', (29, 33))	('insufficiency', 'Var', (34, 47))
175155	30524884	P/D had no effect on nTregs or aTregs, nor on other circulating lymphocyte and monocyte subsets.	('Tregs', 'Chemical', '-', (22, 27))	('P/D', 'Var', (0, 3))	('Tregs', 'Chemical', '-', (32, 37))	('nTregs', 'CPA', (21, 27))	('aTregs', 'CPA', (31, 37))
175171	30524884	Conflicting results have been published about the effect of mCTX on the suppressive capacity of Tregs; in metastasized breast cancer patients 50 mg cyclophosphamide daily for three months resulted in an initial Treg reduction but a preservation of their suppressive function.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (148, 164))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('mCTX', 'Gene', (60, 64))	('Treg', 'Chemical', '-', (211, 215))	('mCTX', 'Gene', '57276', (60, 64))	('Treg', 'CPA', (211, 215))	('breast cancer', 'Disease', (119, 132))	('patients', 'Species', '9606', (133, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('reduction', 'NegReg', (216, 225))	('suppressive', 'MPA', (254, 265))	('Treg', 'Chemical', '-', (96, 100))	('50 mg cyclophosphamide', 'Var', (142, 164))	('Tregs', 'Chemical', '-', (96, 101))
175344	30333973	Ablation of CSPG4/NG2 in a breast cancer animal model resulted in decreased progression and development of vasculature (Gibby et al.,).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('NG2', 'Gene', (18, 21))	('development of vasculature', 'CPA', (92, 118))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('decreased', 'NegReg', (66, 75))	('Ablation', 'Var', (0, 8))	('NG2', 'Gene', '1464', (18, 21))	('CSPG4', 'Gene', (12, 17))	('CSPG4', 'Gene', '1464', (12, 17))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('progression', 'CPA', (76, 87))
175367	30333973	Interestingly, we found that while the average number of TNTs per cell was significantly lower in the UNC-45A-knockdown group at 24 h and 48 h, by 72 h the reverse was seen, as on average there were more TNTs/cell among the cells in which ~80% of UNC-45A had been suppressed via shRNA knockdown (Figure 6).	('lower', 'NegReg', (89, 94))	('knockdown', 'Var', (285, 294))	('TNTs', 'Chemical', '-', (204, 208))	('shRNA', 'Gene', (279, 284))	('UNC-45A', 'Gene', (102, 109))	('more', 'PosReg', (199, 203))	('TNTs/cell', 'CPA', (204, 213))	('TNTs', 'Chemical', '-', (57, 61))	('UNC-45A', 'Gene', '55898', (102, 109))	('UNC-45A', 'Gene', (247, 254))	('UNC-45A', 'Gene', '55898', (247, 254))
175609	28577209	The detection of MPM CTCs in pleural effusions by flow cytometry showed a superior sensitivity (48%) to standard cytological analysis (15%) (p = 0.03).	('pleural effusions', 'Disease', 'MESH:D010996', (29, 46))	('pleural effusions', 'Phenotype', 'HP:0002202', (29, 46))	('TC', 'Chemical', 'MESH:D013667', (22, 24))	('MPM', 'Var', (17, 20))	('pleural effusion', 'Phenotype', 'HP:0002202', (29, 45))	('pleural effusions', 'Disease', (29, 46))
175633	28577209	Data are presented on a cohort of patients with pleural effusions due to MPM and a cohort of patients with pleural effusions due to other causes.	('pleural effusions', 'Phenotype', 'HP:0002202', (107, 124))	('pleural effusion', 'Phenotype', 'HP:0002202', (48, 64))	('pleural effusions', 'Disease', (48, 65))	('pleural effusions', 'Disease', (107, 124))	('patients', 'Species', '9606', (34, 42))	('pleural effusion', 'Phenotype', 'HP:0002202', (107, 123))	('pleural effusions', 'Disease', 'MESH:D010996', (48, 65))	('MPM', 'Var', (73, 76))	('pleural effusions', 'Phenotype', 'HP:0002202', (48, 65))	('patients', 'Species', '9606', (93, 101))	('pleural effusions', 'Disease', 'MESH:D010996', (107, 124))
175662	28577209	CK+, DAPI+, CD45- and CD34- were considered positive events as described before.	('CD34', 'Gene', '947', (22, 26))	('CD45', 'Gene', (12, 16))	('CD34', 'Gene', (22, 26))	('CK+', 'Var', (0, 3))	('DAPI', 'Chemical', 'MESH:C007293', (5, 9))	('CD45', 'Gene', '5788', (12, 16))
175666	28577209	Cells that were MCAM+, DAPI+, pan-CK+, CD45- and CD34- were considered as putative MPM tumor cells (see gating strategy in Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MPM tumor', 'Disease', 'MESH:D009369', (83, 92))	('CD34', 'Gene', '947', (49, 53))	('MCAM', 'Gene', (16, 20))	('MCAM', 'Gene', '4162', (16, 20))	('CD45', 'Gene', (39, 43))	('DAPI', 'Chemical', 'MESH:C007293', (23, 27))	('CD34', 'Gene', (49, 53))	('MPM tumor', 'Disease', (83, 92))	('pan-CK+', 'Var', (30, 37))	('CD45', 'Gene', '5788', (39, 43))
175669	28577209	Cells that were CD34+, DRAQ5+, MCAM+ and CD45- were defined as CECs, and CECs also expressing CD276 were defined as tumor-associated CECs.	('MCAM', 'Gene', '4162', (31, 35))	('CD34', 'Gene', '947', (16, 20))	('CD276', 'Gene', (94, 99))	('MCAM', 'Gene', (31, 35))	('CD45', 'Gene', '5788', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CD34', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('DRAQ5+', 'Var', (23, 29))	('tumor', 'Disease', (116, 121))	('CD276', 'Gene', '80381', (94, 99))	('CD45', 'Gene', (41, 45))
175727	28577209	Recently, others have reported that p16 FISH and BRCA1-associated protein 1 (BAP1) immunohistochemistry-based assays may improve the sensitivity of pleural effusion cytology, with a sensitivity of 45% to 84% for p16 and of 33% to 74% for BAP1.	('p16', 'Var', (212, 215))	('pleural effusion', 'Disease', 'MESH:D010996', (148, 164))	('pleural effusion', 'Disease', (148, 164))	('p16', 'Var', (36, 39))	('pleural effusion', 'Phenotype', 'HP:0002202', (148, 164))	('improve', 'PosReg', (121, 128))	('BAP1', 'Gene', (77, 81))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('sensitivity', 'MPA', (133, 144))
175732	28577209	There are two possible explanations for this observation: 1) MCAM is a marker for a good prognosis; 2) the presence of MPM tumor cells in pleural effusions is related to an increased chance of response to therapy.	('response', 'CPA', (193, 201))	('MPM tumor', 'Disease', 'MESH:D009369', (119, 128))	('presence', 'Var', (107, 115))	('pleural effusions', 'Phenotype', 'HP:0002202', (138, 155))	('pleural effusion', 'Phenotype', 'HP:0002202', (138, 154))	('MCAM', 'Gene', (61, 65))	('pleural effusions', 'Disease', (138, 155))	('MCAM', 'Gene', '4162', (61, 65))	('MPM tumor', 'Disease', (119, 128))	('pleural effusions', 'Disease', 'MESH:D010996', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
175785	30915265	Specifically, HIPEC with the use of cisplatin chemotherapy has shown to be independently more successful with survival rates versus HIPEC with mitomycin-c chemotherapy .	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('mitomycin-c', 'Chemical', 'MESH:D016685', (143, 154))	('cisplatin', 'Var', (36, 45))	('survival rates', 'CPA', (110, 124))
175827	29968778	Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo Malignant mesothelioma is an aggressive cancer with poor prognosis.	('AKT', 'Gene', (94, 97))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (156, 178))	('aggressive cancer', 'Disease', 'MESH:D009369', (185, 202))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Pirfenidone', 'Chemical', 'MESH:C093844', (0, 11))	('decreases mesothelioma', 'Disease', (12, 34))	('ERK', 'Gene', '5594', (86, 89))	('Pirfenidone', 'Var', (0, 11))	('mesothelioma tumor', 'Disease', (112, 130))	('AKT', 'Gene', '207', (94, 97))	('aggressive cancer', 'Disease', (185, 202))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (156, 178))	('Malignant mesothelioma', 'Disease', (156, 178))	('decreases mesothelioma', 'Disease', 'MESH:D008654', (12, 34))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (112, 130))	('migration', 'CPA', (58, 67))	('ERK', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('regulates', 'Reg', (102, 111))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (112, 130))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('inhibition', 'NegReg', (72, 82))
175832	29968778	Pirfenidone also decreased significantly Transwell migration/invasion and 3D collagen invasion.	('decreased', 'NegReg', (17, 26))	('rat', 'Species', '10116', (54, 57))	('Pirfenidone', 'Chemical', 'MESH:C093844', (0, 11))	('collagen', 'molecular_function', 'GO:0005202', ('77', '85'))	('Transwell migration/invasion', 'CPA', (41, 69))	('3D collagen invasion', 'CPA', (74, 94))	('Pirfenidone', 'Var', (0, 11))
175873	29968778	H2052 cells are able to invade and sprout through the surrounding matrix when embedded into 3D Matrigel.	('H2052', 'CellLine', 'CVCL:1518', (0, 5))	('H2052', 'Var', (0, 5))	('sprout', 'CPA', (35, 41))	('invade', 'CPA', (24, 30))
175877	29968778	We have previously linked high gremlin-1 expression and aberrant TGF-beta/BMP signaling activity to mesothelioma invasive growth.	('TGF-beta', 'Gene', (65, 73))	('mesothelioma invasive growth', 'Disease', 'MESH:D008654', (100, 128))	('invasive growth', 'biological_process', 'GO:0051831', ('113', '128'))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('expression', 'MPA', (41, 51))	('BMP', 'Gene', '649', (74, 77))	('gremlin-1', 'Gene', '26585', (31, 40))	('invasive growth', 'biological_process', 'GO:0007125', ('113', '128'))	('activity', 'MPA', (88, 96))	('aberrant', 'Var', (56, 64))	('invasive growth', 'biological_process', 'GO:0036267', ('113', '128'))	('invasive growth', 'biological_process', 'GO:0044412', ('113', '128'))	('gremlin-1', 'Gene', (31, 40))	('invasive growth', 'biological_process', 'GO:0001404', ('113', '128'))	('mesothelioma invasive growth', 'Disease', (100, 128))	('BMP', 'Gene', (74, 77))	('TGF-beta', 'Gene', '7040', (65, 73))	('invasive growth', 'biological_process', 'GO:0044409', ('113', '128'))
175885	29968778	In contrast to previous observations, these results suggest that at least in mesothelioma cells, the anti-tumor and anti-fibrotic activity mediated by pirfenidone is independent of the canonical TGF-beta signaling.	('TGF-beta', 'Gene', (195, 203))	('mesothelioma', 'Disease', (77, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('pirfenidone', 'Var', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('pirfenidone', 'Chemical', 'MESH:C093844', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TGF-beta', 'Gene', '7040', (195, 203))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('tumor', 'Disease', (106, 111))	('anti-fibrotic activity', 'CPA', (116, 138))
175888	29968778	P-ERK1/2 levels were also analyzed by ELISA and observed to be decreased by pirfenidone, while P-p38 and P-JNK1/2 levels were not altered (Fig.	('P-ERK1/2', 'MPA', (0, 8))	('ERK1', 'molecular_function', 'GO:0004707', ('2', '6'))	('p38', 'Gene', (97, 100))	('decreased', 'NegReg', (63, 72))	('p38', 'Gene', '81649', (97, 100))	('JNK', 'molecular_function', 'GO:0004705', ('107', '110'))	('pirfenidone', 'Var', (76, 87))	('pirfenidone', 'Chemical', 'MESH:C093844', (76, 87))
175906	29968778	In addition, MG132 rescued AKT levels in pirfenidone treated cells.	('MG132', 'Chemical', 'MESH:C072553', (13, 18))	('rescued', 'PosReg', (19, 26))	('AKT', 'Gene', (27, 30))	('MG132', 'Var', (13, 18))	('AKT', 'Gene', '207', (27, 30))	('pirfenidone', 'Chemical', 'MESH:C093844', (41, 52))
175907	29968778	P-CREB levels also increased in TGF-beta treated and non-treated JL-1 cells, however, MG132 was only slightly able to rescue P-CREB levels in pirfenidone treated JL-1 or H2052 cells (Fig.	('CREB', 'Gene', (127, 131))	('CREB', 'Gene', (2, 6))	('TGF-beta', 'Gene', '7040', (32, 40))	('CREB', 'Gene', '1385', (127, 131))	('CREB', 'Gene', '1385', (2, 6))	('MG132', 'Var', (86, 91))	('TGF-beta', 'Gene', (32, 40))	('MG132', 'Chemical', 'MESH:C072553', (86, 91))	('increased', 'PosReg', (19, 28))	('H2052', 'CellLine', 'CVCL:1518', (170, 175))	('pirfenidone', 'Chemical', 'MESH:C093844', (142, 153))
175909	29968778	The results indicate that pirfenidone can decrease AKT and CREB pathways and that proteasome mediated degradation of AKT may play a functional role in mesothelioma cells.	('AKT', 'Gene', '207', (117, 120))	('degradation', 'biological_process', 'GO:0009056', ('102', '113'))	('mesothelioma', 'Disease', (151, 163))	('proteasome mediated degradation', 'MPA', (82, 113))	('pirfenidone', 'Chemical', 'MESH:C093844', (26, 37))	('AKT', 'Gene', (51, 54))	('CREB', 'Gene', (59, 63))	('AKT', 'Gene', '207', (51, 54))	('proteasome', 'cellular_component', 'GO:0000502', ('82', '92'))	('AKT', 'Gene', (117, 120))	('proteasome', 'molecular_function', 'GO:0004299', ('82', '92'))	('mesothelioma', 'Disease', 'MESH:D008654', (151, 163))	('decrease', 'NegReg', (42, 50))	('CREB', 'Gene', '1385', (59, 63))	('pirfenidone', 'Var', (26, 37))
175933	29968778	We have previously shown high expression of FBN1 and FBN2 as well as MMP2 in association with high GREM1 expression in JP5 cells as well as in other mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('expression', 'MPA', (30, 40))	('MMP2', 'Gene', (69, 73))	('GREM1', 'Gene', '26585', (99, 104))	('FBN1', 'Gene', (44, 48))	('GREM1', 'Gene', (99, 104))	('FBN2', 'Gene', '2201', (53, 57))	('mesothelioma', 'Disease', (149, 161))	('FBN1', 'Gene', '2200', (44, 48))	('FBN2', 'Gene', (53, 57))	('MMP2', 'Gene', '4313', (69, 73))	('MMP2', 'molecular_function', 'GO:0004228', ('69', '73'))	('expression', 'MPA', (105, 115))	('high', 'Var', (94, 98))
175949	29968778	In the present study, pirfenidone was found to significantly decrease mesothelioma cell proliferation.	('decrease', 'NegReg', (61, 69))	('rat', 'Species', '10116', (95, 98))	('pirfenidone', 'Chemical', 'MESH:C093844', (22, 33))	('mesothelioma', 'Disease', (70, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('pirfenidone', 'Var', (22, 33))
175951	29968778	This is in agreement with a recent study where pirfenidone and cisplatin in combination was shown to increase cell death in non-small cell lung cancer cells as well as in lung derived cancer-associated fibroblasts.	('cancer', 'Disease', (184, 190))	('non-small cell lung cancer', 'Disease', (124, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pirfenidone', 'Var', (47, 58))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('cell death', 'biological_process', 'GO:0008219', ('110', '120'))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('increase', 'PosReg', (101, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('cancer', 'Disease', (144, 150))	('pirfenidone', 'Chemical', 'MESH:C093844', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cell death', 'CPA', (110, 120))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))
175952	29968778	Mesothelioma cell migration/invasion through collagen matrix as well as invasive growth into 3D collagen were also found decreased by pirfenidone treatment.	('pirfenidone', 'Var', (134, 145))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('collagen', 'molecular_function', 'GO:0005202', ('96', '104'))	('invasive growth', 'biological_process', 'GO:0036267', ('72', '87'))	('invasive growth', 'biological_process', 'GO:0001404', ('72', '87'))	('invasive growth', 'biological_process', 'GO:0044412', ('72', '87'))	('collagen', 'molecular_function', 'GO:0005202', ('45', '53'))	('invasive growth', 'biological_process', 'GO:0044409', ('72', '87'))	('pirfenidone', 'Chemical', 'MESH:C093844', (134, 145))	('decreased', 'NegReg', (121, 130))	('invasive growth', 'biological_process', 'GO:0051831', ('72', '87'))	('rat', 'Species', '10116', (21, 24))	('cell migration', 'biological_process', 'GO:0016477', ('13', '27'))	('invasive growth', 'biological_process', 'GO:0007125', ('72', '87'))	('Mesothelioma', 'Disease', (0, 12))	('invasive growth into 3D collagen', 'CPA', (72, 104))
175953	29968778	indicated that in 3D spheroids cultured from IPF patient lung biopsy cells pirfenidone can reduce invasiveness.	('pirfenidone', 'Var', (75, 86))	('reduce', 'NegReg', (91, 97))	('pirfenidone', 'Chemical', 'MESH:C093844', (75, 86))	('patient', 'Species', '9606', (49, 56))	('invasiveness', 'CPA', (98, 110))
175954	29968778	Pirfenidone was also able to reduce pancreatic stellate cell proliferation and migration/invasion through Matrigel matrix.	('pancreatic stellate cell proliferation', 'biological_process', 'GO:0072343', ('36', '74'))	('Pirfenidone', 'Chemical', 'MESH:C093844', (0, 11))	('rat', 'Species', '10116', (68, 71))	('rat', 'Species', '10116', (82, 85))	('migration/invasion through Matrigel matrix', 'CPA', (79, 121))	('pancreatic stellate', 'Disease', 'MESH:D010195', (36, 55))	('pancreatic stellate', 'Disease', (36, 55))	('Pirfenidone', 'Var', (0, 11))	('reduce', 'NegReg', (29, 35))
175959	29968778	Pirfenidone modulates the properties of IPF fibroblasts and myofibroblasts by reducing proliferation and myofibroblastic appearance at the ultrastructural level and it was recently noted to reduce collagen fibril formation.	('reducing', 'NegReg', (78, 86))	('rat', 'Species', '10116', (94, 97))	('fibril', 'cellular_component', 'GO:0099512', ('206', '212'))	('collagen', 'molecular_function', 'GO:0005202', ('197', '205'))	('collagen fibril formation', 'CPA', (197, 222))	('proliferation', 'CPA', (87, 100))	('Pirfenidone', 'Chemical', 'MESH:C093844', (0, 11))	('reduce', 'NegReg', (190, 196))	('modulates', 'Reg', (12, 21))	('Pirfenidone', 'Var', (0, 11))	('formation', 'biological_process', 'GO:0009058', ('213', '222'))
175962	29968778	In rat proximal tubular epithelial cells pirfenidone was found to reduce ERK phosphorylation, but not p38 or Smad2 phosphorylation, which fully agrees with our current observations.	('reduce ERK', 'Phenotype', 'HP:0000654', (66, 76))	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('ERK', 'Gene', (73, 76))	('pirfenidone', 'Var', (41, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('rat', 'Species', '10116', (3, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('p38', 'Gene', (102, 105))	('pirfenidone', 'Chemical', 'MESH:C093844', (41, 52))	('p38', 'Gene', '81649', (102, 105))	('reduce', 'NegReg', (66, 72))	('ERK', 'Gene', '5594', (73, 76))
175963	29968778	They are also in agreement with our previous studies indicating that mesothelioma cell migration can be reduced with MEK inhibitors.	('reduced', 'NegReg', (104, 111))	('cell migration', 'biological_process', 'GO:0016477', ('82', '96'))	('MEK', 'Gene', (117, 120))	('mesothelioma', 'Disease', (69, 81))	('MEK', 'Gene', '5609', (117, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('inhibitors', 'Var', (121, 131))	('rat', 'Species', '10116', (90, 93))
175964	29968778	Interestingly, pirfenidone was able to significantly reduce AKT levels, likely through regulation of protein stability.	('reduce', 'NegReg', (53, 59))	('regulation of protein stability', 'biological_process', 'GO:0031647', ('87', '118'))	('pirfenidone', 'Chemical', 'MESH:C093844', (15, 26))	('AKT', 'Gene', '207', (60, 63))	('AKT', 'Gene', (60, 63))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('pirfenidone', 'Var', (15, 26))
175965	29968778	In addition, pirfenidone reduced CREB phosphorylation in a time- and concentration-dependent manner.	('reduced', 'NegReg', (25, 32))	('CREB', 'Gene', '1385', (33, 37))	('pirfenidone', 'Var', (13, 24))	('rat', 'Species', '10116', (76, 79))	('pirfenidone', 'Chemical', 'MESH:C093844', (13, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('CREB', 'Gene', (33, 37))
175970	29968778	Our studies are in agreement with previous studies suggesting that pirfenidone can decrease EMT or myofibroblast differentiation by modulating MAPK or AKT pathways in other cell models.	('AKT', 'Gene', (151, 154))	('decrease EMT', 'Phenotype', 'HP:0032198', (83, 95))	('pirfenidone', 'Chemical', 'MESH:C093844', (67, 78))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('myofibroblast differentiation', 'biological_process', 'GO:0036446', ('99', '128'))	('decrease', 'NegReg', (83, 91))	('modulating', 'Reg', (132, 142))	('AKT', 'Gene', '207', (151, 154))	('MAPK', 'Pathway', (143, 147))	('pirfenidone', 'Var', (67, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('EMT or myofibroblast differentiation', 'CPA', (92, 128))
175977	29968778	Along these lines, studies proposed that in mammary tumor models pirfenidone improves the anti-tumor efficacy of doxorubisin, likely through modulation of the tumor microenvironment e.g.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('improves', 'PosReg', (77, 85))	('pirfenidone', 'Var', (65, 76))	('tumor', 'Disease', (159, 164))	('pirfenidone', 'Chemical', 'MESH:C093844', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (95, 100))	('doxorubisin', 'Chemical', '-', (113, 124))
175980	29968778	We performed RNA sequencing of the tumors and found that pirfenidone downregulated the expression of several collagen genes as part of an extracellular matrix organization gene signature.	('collagen genes', 'Gene', (109, 123))	('collagen', 'molecular_function', 'GO:0005202', ('109', '117'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('pirfenidone', 'Chemical', 'MESH:C093844', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('downregulated', 'NegReg', (69, 82))	('expression', 'MPA', (87, 97))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('138', '171'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('138', '158'))	('pirfenidone', 'Var', (57, 68))
175982	29968778	These results suggest that pirfenidone can modulate the tumor microenvironment by reducing fibrotic gene expression.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reducing', 'NegReg', (82, 90))	('fibrotic gene expression', 'MPA', (91, 115))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('tumor', 'Disease', (56, 61))	('pirfenidone', 'Var', (27, 38))	('pirfenidone', 'Chemical', 'MESH:C093844', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
175984	29968778	Consistent with this, in a mammary tumor model pirfenidone decreased interstitial fluid pressure and increased blood vessel functionality leading to better drug delivery.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('drug delivery', 'MPA', (156, 169))	('pirfenidone', 'Var', (47, 58))	('decreased', 'NegReg', (59, 68))	('increased', 'PosReg', (101, 110))	('interstitial fluid pressure', 'MPA', (69, 96))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('pirfenidone', 'Chemical', 'MESH:C093844', (47, 58))	('blood vessel functionality', 'MPA', (111, 137))	('better', 'PosReg', (149, 155))
175987	29968778	In our study, pirfenidone was shown to reduce two major upregulated pathways in mesothelioma and to target both tumor cells and the microenvironment, which makes it a candidate for similar clinical studies.	('reduce', 'NegReg', (39, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('pirfenidone', 'Chemical', 'MESH:C093844', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('pirfenidone', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mesothelioma', 'Disease', (80, 92))	('tumor', 'Disease', (112, 117))	('upregulated', 'PosReg', (56, 67))
175988	29968778	Since mesothelioma is characterized with tumor suppressor gene mutations instead of activation of "druggable" oncogenes, targeting the upregulated signaling pathways presents a therapeutic approach.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mesothelioma', 'Disease', (6, 18))	('tumor', 'Disease', (41, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
175990	29968778	Antibodies used for Western blotting were P-Smad2 (#3108), Smad2 (#5339), P-ERK1/2 (#9101), ERK1/2 (#9107), P-AKT (#9271), P-p70S6K (#108D2) and p70S6K (#2708) from Cell Signaling, P-CREB (RLP0075) and AKT (YT0178) from Immunoway (see Supplementary Fig.	('#5339', 'Var', (66, 71))	('#9107', 'Var', (100, 105))	('AKT', 'Gene', (202, 205))	('#9271', 'Var', (115, 120))	('ERK1', 'molecular_function', 'GO:0004707', ('92', '96'))	('AKT', 'Gene', (110, 113))	('#2708', 'Var', (153, 158))	('#9101', 'Var', (84, 89))	('CREB', 'Gene', (183, 187))	('p70S6K', 'Gene', '6198', (125, 131))	('p70S6K', 'Gene', (125, 131))	('p70S6K', 'Gene', (145, 151))	('AKT', 'Gene', '207', (202, 205))	('CREB', 'Gene', '1385', (183, 187))	('ERK1', 'molecular_function', 'GO:0004707', ('76', '80'))	('Signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('p70S6K', 'Gene', '6198', (145, 151))	('AKT', 'Gene', '207', (110, 113))
176001	29968778	Briefly, cells were seeded into 96-well plates (5.000/well) and treated the next day with different concentrations of pirfenidone, cisplatin, pemetrexed or the inhibitors MK-2206 or PD98059 in medium containing 1% FBS.	('pirfenidone', 'Chemical', 'MESH:C093844', (118, 129))	('PD98059', 'Var', (182, 189))	('FBS', 'Disease', 'MESH:D005198', (214, 217))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('PD98059', 'Chemical', 'MESH:C093973', (182, 189))	('FBS', 'Disease', (214, 217))	('MK-2206', 'Var', (171, 178))	('pemetrexed', 'Chemical', 'MESH:D000068437', (142, 152))	('MK-2206', 'Chemical', 'MESH:C548887', (171, 178))	('rat', 'Species', '10116', (107, 110))
176047	28829357	In fact, in familial mesothelioma, germline bands 3p21 (BAP1) mutations make the members susceptible to the development of cancer even in the presence of low amounts of inhaled asbestos.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('p21', 'Gene', (51, 54))	('familial mesothelioma', 'Phenotype', 'HP:0100001', (12, 33))	('p21', 'Gene', '644914', (51, 54))	('susceptible', 'Reg', (89, 100))	('men', 'Species', '9606', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('BAP1', 'Gene', (56, 60))	('cancer', 'Disease', (123, 129))	('asbestos', 'Chemical', 'MESH:D001194', (177, 185))	('familial mesothelioma', 'Disease', (12, 33))	('familial mesothelioma', 'Disease', 'MESH:D008654', (12, 33))	('mutations', 'Var', (62, 71))
176053	28829357	Deletion of 9p21 is particularly frequent in MM, especially in the biphasic histotype, although this deletion has been reported to be less frequent in peritoneal than in pleura mesothelioma.	('frequent', 'Reg', (33, 41))	('Deletion', 'Var', (0, 8))	('pleura mesothelioma', 'Phenotype', 'HP:0100002', (170, 189))	('pleura mesothelioma', 'Disease', 'MESH:D008654', (170, 189))	('pleura mesothelioma', 'Disease', (170, 189))	('p21', 'Gene', (13, 16))	('p21', 'Gene', '644914', (13, 16))
176055	28829357	Generally, a higher frequency of loss was seen in pleural MM, gains were seen more frequently in peritoneal MM, including regions at 3q, 7q, 8p, 9p, 16p, and 20q.	('16p', 'Var', (149, 152))	('pleural MM', 'Disease', 'MESH:D010995', (50, 60))	('pleural MM', 'Disease', (50, 60))	('peritoneal MM', 'Disease', (97, 110))	('gain', 'Disease', (62, 66))	('gain', 'Disease', 'MESH:D015430', (62, 66))
176070	28829357	By contrast, a middle-aged woman with non-asbestos-related peritoneal mesothelioma, sarcomatoid type, with mutations in NF2 (22q12.1), CDKN2A (9p21), p53 (17p12), and LATS2 (13q12), had an excellent response to treatment.	('LATS2', 'Gene', (167, 172))	('LATS2', 'Gene', '26524', (167, 172))	('NF2', 'Gene', '4771', (120, 123))	('p53', 'Gene', '7157', (150, 153))	('peritoneal mesothelioma', 'Disease', (59, 82))	('NF2', 'Gene', (120, 123))	('men', 'Species', '9606', (216, 219))	('sarcomatoid type', 'Disease', (84, 100))	('p21', 'Gene', (144, 147))	('p21', 'Gene', '644914', (144, 147))	('p53', 'Gene', (150, 153))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (59, 82))	('CDKN2A', 'Gene', (135, 141))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (59, 82))	('woman', 'Species', '9606', (27, 32))	('CDKN2A', 'Gene', '1029', (135, 141))	('sarcomatoid type', 'Disease', 'MESH:C538614', (84, 100))	('mutations', 'Var', (107, 116))
176077	28829357	BAP1 immunohistochemical staining, loss vs. preserved, was not associated with clinical outcome, whereas the CDKN2A and NF2 deletions were negative prognostic markers.	('BAP1', 'Gene', (0, 4))	('loss', 'NegReg', (35, 39))	('CDKN2A', 'Gene', (109, 115))	('NF2', 'Gene', '4771', (120, 123))	('CDKN2A', 'Gene', '1029', (109, 115))	('deletions', 'Var', (124, 133))	('NF2', 'Gene', (120, 123))
176087	28829357	Gelsolin (GSN) can act as a transcriptional cofactor in signal transduction and its own expression and function can be influenced by epigenetic changes.	('GSN', 'Gene', (10, 13))	('epigenetic changes', 'Var', (133, 151))	('Gelsolin', 'Gene', (0, 8))	('influenced', 'Reg', (119, 129))	('function', 'MPA', (103, 111))	('signal transduction', 'biological_process', 'GO:0007165', ('56', '75'))	('GSN', 'Gene', '2934', (10, 13))	('expression', 'MPA', (88, 98))	('Gelsolin', 'Gene', '2934', (0, 8))
176093	28829357	Dysfunction of telomeres plays an important role in cancer initiation and progression.	('cancer initiation', 'Disease', 'MESH:D009369', (52, 69))	('cancer initiation', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Dysfunction', 'Var', (0, 11))
176096	28829357	So, detection of TERT amplification may be useful to reveal an initial mesothelioma but we should also consider that TERT promoter mutations might be associated with inactivation of many cell cycle regulator genes.	('associated', 'Reg', (150, 160))	('mesothelioma', 'Disease', (71, 83))	('mutations', 'Var', (131, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('TERT', 'Gene', (17, 21))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('187', '207'))	('TERT', 'Gene', '7015', (17, 21))	('man', 'Species', '9606', (182, 185))	('TERT', 'Gene', (117, 121))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('187', '207'))	('TERT', 'Gene', '7015', (117, 121))
176100	28829357	Next-generation sequencing (NGS) coupled with bioinformatics analysis of the somatic mutations would allow for the screening of tumor-specific mutated proteins, candidate targets for the design of individualized therapy.	('proteins', 'Protein', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', (128, 133))
176102	28829357	The combination of ralitrexed and oxaliplatin would have a synergistic effect on the early inhibition of DNA synthesis promoted by the mutations described.	('DNA synthesis', 'MPA', (105, 118))	('mutations', 'Var', (135, 144))	('inhibition', 'NegReg', (91, 101))	('ralitrexed', 'Chemical', '-', (19, 29))	('DNA synthesis', 'biological_process', 'GO:0071897', ('105', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (34, 45))
176184	28649123	reported similar frequency distributions of BRCA 1/2 mutation for both ovarian and primary peritoneal carcinoma, further indicating a shared molecular pathogenesis.	('mutation', 'Var', (53, 61))	('pathogenesis', 'biological_process', 'GO:0009405', ('151', '163'))	('primary peritoneal carcinoma', 'Phenotype', 'HP:0030406', (83, 111))	('BRCA 1', 'Gene', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('ovarian and primary peritoneal carcinoma', 'Disease', 'MESH:D010534', (71, 111))	('BRCA 1', 'Gene', '672', (44, 50))
176185	28649123	Carrier status was associated with earlier onset and multifocal disease.	('associated', 'Reg', (19, 29))	('Carrier status', 'Var', (0, 14))	('multifocal disease', 'Disease', (53, 71))	('multifocal disease', 'Disease', 'None', (53, 71))
176189	27623107	Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth.	('GDC-0980', 'Chemical', 'MESH:C569670', (93, 101))	('BKM120', 'Chemical', 'MESH:C571178', (82, 88))	('combination', 'Interaction', (135, 146))	('growth', 'MPA', (181, 187))	('crizotinib', 'Chemical', 'MESH:D000077547', (70, 80))	('GDC-0980', 'Var', (93, 101))	('suppressing', 'NegReg', (169, 180))	('BKM120', 'Var', (82, 88))
176190	27623107	Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('G2-M arrest', 'Disease', (70, 81))	('G2-M arrest', 'Disease', 'MESH:D006323', (70, 81))	('BKM120', 'Var', (15, 21))	('apoptosis', 'CPA', (86, 95))	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))	('BKM120', 'Chemical', 'MESH:C571178', (15, 21))
176191	27623107	Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase.	('decreased', 'NegReg', (95, 104))	('PI3K', 'Pathway', (70, 74))	('phosphorylation', 'MPA', (105, 120))	('inhibited', 'NegReg', (36, 45))	('AKT', 'Gene', '207', (129, 132))	('MET', 'Pathway', (62, 65))	('BKM120', 'Chemical', 'MESH:C571178', (20, 26))	('crizotinib', 'Chemical', 'MESH:D000077547', (5, 15))	('activity', 'MPA', (50, 58))	('ribosomal', 'Enzyme', (137, 146))	('BKM120', 'Var', (20, 26))	('MET', 'Pathway', (124, 127))	('AKT', 'Gene', (129, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
176199	27623107	Previously we demonstrated that the MET/HGF axis is activated in MPM through overexpression, amplification and mutations of MET.	('amplification', 'Var', (93, 106))	('mutations', 'Var', (111, 120))	('overexpression', 'PosReg', (77, 91))	('HGF', 'Gene', '3082', (40, 43))	('MET', 'Gene', (124, 127))	('activated', 'PosReg', (52, 61))	('HGF', 'Gene', (40, 43))
176200	27623107	SU11274, a small molecule inhibitor of MET is known to decrease cell proliferation of mesothelioma cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('mesothelioma', 'Disease', (86, 98))	('decrease', 'NegReg', (55, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('MET', 'Gene', (39, 42))
176201	27623107	Crizotinib (PF02341066, Pfizer) is an orally available, potent, ATP competitive, small molecular inhibitor of MET, anaplastic lymphoma kinase (ALK) and c-Ros Oncogene 1 (ROS1).	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (115, 134))	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('c-Ros Oncogene 1', 'Gene', (152, 168))	('ALK', 'Gene', (143, 146))	('anaplastic lymphoma kinase', 'Gene', '238', (115, 141))	('ROS1', 'Gene', (170, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('PF02341066', 'Var', (12, 22))	('ROS1', 'Gene', '6098', (170, 174))	('ALK', 'Gene', '238', (143, 146))	('c-Ros Oncogene 1', 'Gene', '6098', (152, 168))	('anaplastic lymphoma kinase', 'Gene', (115, 141))
176210	27623107	While single use of BKM120 inhibited growth of MPM tumor in a PDX mouse model, the combined treatment with crizotinib and BKM120 was highly synergistic.	('growth', 'MPA', (37, 43))	('BKM120', 'Chemical', 'MESH:C571178', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mouse', 'Species', '10090', (66, 71))	('BKM120', 'Chemical', 'MESH:C571178', (20, 26))	('MPM tumor', 'Disease', (47, 56))	('crizotinib', 'Chemical', 'MESH:D000077547', (107, 117))	('BKM120', 'Var', (122, 128))	('inhibited', 'NegReg', (27, 36))	('BKM120', 'Var', (20, 26))	('MPM tumor', 'Disease', 'MESH:D009369', (47, 56))
176212	27623107	Most of the MPM cell lines used were sensitive to treatment with BKM120 with IC50 values ranging from 0.79-1.51 muM.	('BKM120', 'Chemical', 'MESH:C571178', (65, 71))	('muM', 'Gene', '56925', (112, 115))	('muM', 'Gene', (112, 115))	('BKM120', 'Var', (65, 71))
176224	27623107	Treatment of MPM cells with either, crizotinib, BKM120 or GDC-0980 significantly decreased migration of cells compared to control cells (crizotinib p < 0.05, BKM120 and GDC-0980 p < 0.001).	('decreased', 'NegReg', (81, 90))	('migration of cells', 'CPA', (91, 109))	('crizotinib', 'Chemical', 'MESH:D000077547', (36, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (169, 177))	('BKM120', 'Chemical', 'MESH:C571178', (158, 164))	('crizotinib', 'Chemical', 'MESH:D000077547', (137, 147))	('GDC-0980', 'Gene', (58, 66))	('BKM120', 'Chemical', 'MESH:C571178', (48, 54))	('GDC-0980', 'Chemical', 'MESH:C569670', (58, 66))	('BKM120', 'Var', (48, 54))
176225	27623107	The combination of crizotinib with either BKM120 or GDC-0980 further decreased cell migration and was significantly synergistic compared to single drug treatment with crizotinib or GDC-0980 (crizotinib Vs BKM120/crizotinib p < 0.001 and GDC-0980 Vs crizotinib/GDC-0980 p < 0.001).	('BKM120', 'Chemical', 'MESH:C571178', (205, 211))	('GDC-0980', 'Chemical', 'MESH:C569670', (52, 60))	('GDC-0980', 'Chemical', 'MESH:C569670', (181, 189))	('crizotinib', 'Chemical', 'MESH:D000077547', (191, 201))	('cell migration', 'CPA', (79, 93))	('crizotinib', 'Chemical', 'MESH:D000077547', (167, 177))	('BKM120', 'Chemical', 'MESH:C571178', (42, 48))	('decreased', 'NegReg', (69, 78))	('crizotinib', 'Chemical', 'MESH:D000077547', (249, 259))	('cell migration', 'biological_process', 'GO:0016477', ('79', '93'))	('crizotinib', 'Chemical', 'MESH:D000077547', (19, 29))	('GDC-0980', 'Chemical', 'MESH:C569670', (260, 268))	('crizotinib', 'Chemical', 'MESH:D000077547', (212, 222))	('GDC-0980', 'Gene', (52, 60))	('BKM120', 'Var', (42, 48))	('GDC-0980', 'Chemical', 'MESH:C569670', (237, 245))
176226	27623107	Treatment with BKM120/crizotinib combination did further inhibit the migration compared to BKM120 alone, but the decrease was not statistically significant.	('BKM120', 'Chemical', 'MESH:C571178', (91, 97))	('crizotinib', 'Chemical', 'MESH:D000077547', (22, 32))	('BKM120/crizotinib', 'Var', (15, 32))	('inhibit', 'NegReg', (57, 64))	('migration', 'CPA', (69, 78))	('BKM120', 'Chemical', 'MESH:C571178', (15, 21))
176227	27623107	Treatment of H2596 cells with crizotinib, BKM120 and GDC-0980 alone had no effect on G2-M arrest in cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('BKM120', 'Chemical', 'MESH:C571178', (42, 48))	('GDC-0980', 'Chemical', 'MESH:C569670', (53, 61))	('crizotinib', 'Chemical', 'MESH:D000077547', (30, 40))	('H2596', 'CellLine', 'CVCL:A546', (13, 18))	('G2-M arrest', 'Disease', (85, 96))	('BKM120', 'Var', (42, 48))	('G2-M arrest', 'Disease', 'MESH:D006323', (85, 96))
176228	27623107	However the combination of BKM120/crizotinib significantly increased the percentage of cells arrested in G2-M phase (crizotinib Vs BKM120/crizotinib p < 0.001) (BKM120 Vs BKM120/crizotinib p < 0.01) (Fig.	('BKM120', 'Chemical', 'MESH:C571178', (171, 177))	('BKM120', 'Chemical', 'MESH:C571178', (27, 33))	('BKM120', 'Chemical', 'MESH:C571178', (161, 167))	('crizotinib', 'Chemical', 'MESH:D000077547', (34, 44))	('M phase', 'biological_process', 'GO:0000279', ('108', '115'))	('BKM120/crizotinib', 'Var', (27, 44))	('crizotinib', 'Chemical', 'MESH:D000077547', (178, 188))	('crizotinib', 'Chemical', 'MESH:D000077547', (117, 127))	('BKM120', 'Chemical', 'MESH:C571178', (131, 137))	('increased', 'PosReg', (59, 68))	('crizotinib', 'Chemical', 'MESH:D000077547', (138, 148))
176231	27623107	While treatment of H2596 cells with crizotinib alone resulted in a 2.5-fold increase (p < 0.001) in the number of apoptotic cells, addition of BKM120 was more effective showing a 4-fold increase, (p < 0.001) while GDC-0980 had no significant effect (Fig.	('BKM120', 'Var', (143, 149))	('H2596', 'CellLine', 'CVCL:A546', (19, 24))	('increase', 'PosReg', (76, 84))	('crizotinib', 'Chemical', 'MESH:D000077547', (36, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (214, 222))	('BKM120', 'Chemical', 'MESH:C571178', (143, 149))
176232	27623107	As expected, the combination of BKM120/crizotinib resulted in more apoptotic cells than crizotinib alone (p < 0.001).	('BKM120', 'Chemical', 'MESH:C571178', (32, 38))	('crizotinib', 'Chemical', 'MESH:D000077547', (39, 49))	('BKM120/crizotinib', 'Var', (32, 49))	('crizotinib', 'Chemical', 'MESH:D000077547', (88, 98))	('more', 'PosReg', (62, 66))	('apoptotic cells', 'CPA', (67, 82))
176235	27623107	Individual treatment of H2596 cells with BKM120 and GDC-0980 at 12 h did not have much effect on the levels of cleaved PARP, however the combination of crizotinib with BKM120 or GDC-0980 had much greater effect than single treatments (Fig.	('BKM120', 'Var', (168, 174))	('BKM120', 'Var', (41, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (52, 60))	('crizotinib', 'Chemical', 'MESH:D000077547', (152, 162))	('PARP', 'Gene', (119, 123))	('GDC-0980', 'Var', (178, 186))	('BKM120', 'Chemical', 'MESH:C571178', (168, 174))	('BKM120', 'Chemical', 'MESH:C571178', (41, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (178, 186))	('PARP', 'Gene', '142', (119, 123))	('H2596', 'CellLine', 'CVCL:A546', (24, 29))
176241	27623107	The activation of ribosomal S6 kinase, a downstream target of mTOR was inhibited by both BKM120 and GDC-0980 in both cell lines.	('mTOR', 'Gene', '2475', (62, 66))	('mTOR', 'Gene', (62, 66))	('inhibited', 'NegReg', (71, 80))	('activation', 'MPA', (4, 14))	('BKM120', 'Chemical', 'MESH:C571178', (89, 95))	('ribosomal S6 kinase', 'Enzyme', (18, 37))	('GDC-0980', 'Chemical', 'MESH:C569670', (100, 108))	('GDC-0980', 'Var', (100, 108))	('BKM120', 'Var', (89, 95))
176243	27623107	Activation of MAPK, a known mediator of cell motility and metastasis, was completely suppressed by crizotinib alone and the combination of crizotinib and BKM120 in H513 cells (Fig.	('crizotinib', 'Chemical', 'MESH:D000077547', (139, 149))	('H513', 'CellLine', 'CVCL:A570', (164, 168))	('BKM120', 'Chemical', 'MESH:C571178', (154, 160))	('suppressed', 'NegReg', (85, 95))	('MAPK', 'Gene', (14, 18))	('crizotinib', 'Chemical', 'MESH:D000077547', (99, 109))	('MAPK', 'molecular_function', 'GO:0004707', ('14', '18'))	('Activation', 'MPA', (0, 10))	('BKM120', 'Var', (154, 160))	('cell motility', 'biological_process', 'GO:0048870', ('40', '53'))
176244	27623107	Our results clearly show that treatment of H2596 cells with crizotinib had very little effect on the activity of PI3K, however BKM120 the class I PI3K inhibitor, significantly decreased PI3K activity.	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('BKM120', 'Var', (127, 133))	('PI3K', 'Enzyme', (186, 190))	('H2596', 'CellLine', 'CVCL:A546', (43, 48))	('crizotinib', 'Chemical', 'MESH:D000077547', (60, 70))	('decreased', 'NegReg', (176, 185))	('BKM120', 'Chemical', 'MESH:C571178', (127, 133))	('activity', 'MPA', (191, 199))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))
176249	27623107	Our results show that for single drug treatment the cells treated with BKM120 formed the least number of colonies (p < 0.001) followed by those treated with GDC-0980 (p < 0.001) and crizotinib (p < 0.001) compared to vehicle treated controls.	('BKM120', 'Chemical', 'MESH:C571178', (71, 77))	('BKM120', 'Var', (71, 77))	('crizotinib', 'Chemical', 'MESH:D000077547', (182, 192))	('GDC-0980', 'Chemical', 'MESH:C569670', (157, 165))	('least', 'NegReg', (89, 94))
176250	27623107	The combination of BKM120/crizotinib significantly decreased the number of colonies compared to either drug alone (p < 0.001).	('BKM120/crizotinib', 'Gene', (19, 36))	('BKM120/crizotinib', 'Var', (19, 36))	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('crizotinib', 'Chemical', 'MESH:D000077547', (26, 36))	('decreased', 'NegReg', (51, 60))	('combination', 'Interaction', (4, 15))
176252	27623107	Our results show the colonies were significantly smaller when cells were treated with BKM120 or GDC-0980 alone compared to the control (p < 0.001).	('BKM120', 'Var', (86, 92))	('colonies', 'CPA', (21, 29))	('smaller', 'NegReg', (49, 56))	('GDC-0980', 'Gene', (96, 104))	('BKM120', 'Chemical', 'MESH:C571178', (86, 92))	('GDC-0980', 'Chemical', 'MESH:C569670', (96, 104))
176254	27623107	The exposure of cells to the combination of BKM120/crizotinib resulted in a further decrease in the size of the colonies compared to crizotinib treatment alone (p < 0.01).	('decrease', 'NegReg', (84, 92))	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('BKM120/crizotinib', 'Var', (44, 61))	('crizotinib', 'Chemical', 'MESH:D000077547', (133, 143))	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))
176256	27623107	Given our earlier results demonstrating cell cycle arrest in BKM120 treated cells, we studied the effect of BKM120 on the dynamics of microtubules.	('cell cycle arrest', 'CPA', (40, 57))	('BKM120', 'Chemical', 'MESH:C571178', (61, 67))	('BKM120', 'Chemical', 'MESH:C571178', (108, 114))	('BKM120', 'Var', (61, 67))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('40', '57'))
176259	27623107	The effect of BKM120 on MPM cells was comparable to Nocodazole as evidenced from disrupted microtubule polymerization (Fig.	('microtubule polymerization', 'MPA', (91, 117))	('BKM120', 'Var', (14, 20))	('Nocodazole', 'Chemical', 'MESH:D015739', (52, 62))	('BKM120', 'Chemical', 'MESH:C571178', (14, 20))	('microtubule polymerization', 'biological_process', 'GO:0046785', ('91', '117'))	('microtubule', 'cellular_component', 'GO:0005874', ('91', '102'))
176262	27623107	At day 17 tumor volumes for the crizotinib and BKM120 groups were not significantly different compared to the vehicle alone treated control (DMSO/NMP-PEG300) group.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('BKM120', 'Chemical', 'MESH:C571178', (47, 53))	('crizotinib', 'Chemical', 'MESH:D000077547', (32, 42))	('tumor', 'Disease', (10, 15))	('NMP', 'Chemical', 'MESH:C038678', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('PEG300', 'Chemical', '-', (150, 156))	('BKM120', 'Var', (47, 53))	('DMSO', 'Chemical', 'MESH:D004121', (141, 145))
176263	27623107	Significantly lower tumor volumes were however observed in the crizotinib/BKM120 group (p <= 0.01).	('BKM120', 'Chemical', 'MESH:C571178', (74, 80))	('lower', 'NegReg', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('crizotinib/BKM120', 'Var', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('crizotinib', 'Chemical', 'MESH:D000077547', (63, 73))	('tumor', 'Disease', (20, 25))
176264	27623107	Analysis of data from Day 0 to Day 17 showed that the crizotinib/BKM120 combination group had significantly lower tumor volume compared to that of the vehicle group (p <= 0.0001) (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('crizotinib/BKM120', 'Var', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('crizotinib', 'Chemical', 'MESH:D000077547', (54, 64))	('tumor', 'Disease', (114, 119))	('BKM120', 'Chemical', 'MESH:C571178', (65, 71))	('lower', 'NegReg', (108, 113))	('crizotinib/BKM120', 'Gene', (54, 71))
176268	27623107	In general combined treatment with MET inhibitor, crizotinib, and PI3K inhibitors, BKM120 or GDC-0980 resulted in a synergistic suppression of MPM cell growth (compare Fig.	('GDC-0980', 'Chemical', 'MESH:C569670', (93, 101))	('crizotinib', 'Chemical', 'MESH:D000077547', (50, 60))	('BKM120', 'Var', (83, 89))	('suppression', 'NegReg', (128, 139))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('cell growth', 'biological_process', 'GO:0016049', ('147', '158'))	('PI3K', 'Gene', (66, 70))	('BKM120', 'Chemical', 'MESH:C571178', (83, 89))	('GDC-0980', 'Var', (93, 101))	('MPM cell growth', 'CPA', (143, 158))
176270	27623107	Once again the maximum apoptotic effect was observed when MPM cells were treated with both crizotinib and BKM120 (Fig.	('BKM120', 'Var', (106, 112))	('BKM120', 'Chemical', 'MESH:C571178', (106, 112))	('crizotinib', 'Chemical', 'MESH:D000077547', (91, 101))	('crizotinib', 'Var', (91, 101))
176271	27623107	Cell motility, a reflection of metastatic potential was also decreased following treatment with crizotinib, BKM120 and GDC-0980 alone, with combination treatments being more effective (Fig.	('GDC-0980', 'Gene', (119, 127))	('crizotinib', 'Gene', (96, 106))	('crizotinib', 'Chemical', 'MESH:D000077547', (96, 106))	('BKM120', 'Var', (108, 114))	('Cell motility', 'biological_process', 'GO:0048870', ('0', '13'))	('Cell motility', 'CPA', (0, 13))	('GDC-0980', 'Chemical', 'MESH:C569670', (119, 127))	('BKM120', 'Chemical', 'MESH:C571178', (108, 114))	('decreased', 'NegReg', (61, 70))	('metastatic potential', 'CPA', (31, 51))
176274	27623107	Single treatment with crizotinib or BKM120 or GDC-0980 significantly reduced the number of colonies in a soft agar assay with the combination of crizotinib/BKM120 being even more effective (Fig.	('BKM120', 'Chemical', 'MESH:C571178', (36, 42))	('reduced', 'NegReg', (69, 76))	('GDC-0980', 'Gene', (46, 54))	('crizotinib', 'Chemical', 'MESH:D000077547', (22, 32))	('GDC-0980', 'Chemical', 'MESH:C569670', (46, 54))	('BKM120', 'Var', (36, 42))	('agar', 'Chemical', 'MESH:D000362', (110, 114))	('crizotinib', 'Chemical', 'MESH:D000077547', (145, 155))	('BKM120', 'Chemical', 'MESH:C571178', (156, 162))
176276	27623107	These results suggest that the combination of MET, PI3K and mTOR inhibition is the most effective in decreasing the transformation potential of MPM cells.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('decreasing', 'NegReg', (101, 111))	('PI3K', 'Var', (51, 55))	('MET', 'Var', (46, 49))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (60, 64))	('transformation potential of MPM cells', 'CPA', (116, 153))
176277	27623107	Finally, using a mesothelioma PDX mouse model, we demonstrated that the combination of crizotinib/BKM120 was more effective than the single drugs alone in inhibiting MPM tumor growth in vivo (Fig.	('MPM tumor', 'Disease', (166, 175))	('mesothelioma', 'Disease', (17, 29))	('mouse', 'Species', '10090', (34, 39))	('crizotinib/BKM120', 'Gene', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('BKM120', 'Chemical', 'MESH:C571178', (98, 104))	('MPM tumor', 'Disease', 'MESH:D009369', (166, 175))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))	('inhibiting', 'NegReg', (155, 165))	('crizotinib/BKM120', 'Var', (87, 104))	('crizotinib', 'Chemical', 'MESH:D000077547', (87, 97))
176283	27623107	In addition, BKM120 and also GDC-0980 were effective in decreasing phosphorylation of AKT and S6 ribosomal kinases which are downstream targets of PI3K.	('AKT', 'Gene', (86, 89))	('BKM120', 'Chemical', 'MESH:C571178', (13, 19))	('GDC-0980', 'Chemical', 'MESH:C569670', (29, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('decreasing', 'NegReg', (56, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('S6 ribosomal kinases', 'Pathway', (94, 114))	('AKT', 'Gene', '207', (86, 89))	('BKM120', 'Var', (13, 19))	('phosphorylation', 'MPA', (67, 82))	('GDC-0980', 'Var', (29, 37))
176284	27623107	BKM120 is known to significantly suppress cell proliferation by decreasing the levels of p-AKT and its action is synergistic when combined with other targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide in multiple cancer cell lines.	('levels', 'MPA', (79, 85))	('cancer', 'Disease', (268, 274))	('temozolomide', 'Chemical', 'MESH:D000077204', (243, 255))	('BKM120', 'Var', (0, 6))	('AKT', 'Gene', '207', (91, 94))	('cell proliferation', 'CPA', (42, 60))	('decreasing', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('AKT', 'Gene', (91, 94))	('suppress', 'NegReg', (33, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('docetaxel', 'Chemical', 'MESH:D000077143', (230, 239))	('cancer', 'Disease', 'MESH:D009369', (268, 274))
176288	27623107	This builds on our previous finding showing synergistic suppressive activity of MET inhibitor ARQ-197 with GDC-0980 in MPM.	('ARQ-197', 'Gene', (94, 101))	('MET inhibitor', 'Var', (80, 93))	('suppressive', 'NegReg', (56, 67))	('GDC-0980', 'Chemical', 'MESH:C569670', (107, 115))
176289	27623107	Cell cycle analysis results showed that treatment with crizotinib and GDC-0980 mostly arrested MPM cells at G0-G1 phase, whereas BKM120 induced cell cycle arrest at G2-M phase.	('G1 phase', 'biological_process', 'GO:0051318', ('111', '119'))	('BKM120', 'Chemical', 'MESH:C571178', (129, 135))	('GDC-0980', 'Chemical', 'MESH:C569670', (70, 78))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('144', '161'))	('MPM cells at G0-G1 phase', 'CPA', (95, 119))	('M phase', 'biological_process', 'GO:0000279', ('168', '175'))	('arrested', 'NegReg', (86, 94))	('BKM120', 'Var', (129, 135))	('crizotinib', 'Chemical', 'MESH:D000077547', (55, 65))	('GDC-0980', 'Gene', (70, 78))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
176291	27623107	Also our studies revealed that both MET and PI3K inhibitors induced apoptosis in MPM cells, while maximum effect was seen with BKM120 (Fig.	('apoptosis', 'CPA', (68, 77))	('BKM120', 'Chemical', 'MESH:C571178', (127, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('MET', 'Var', (36, 39))	('PI3K inhibitors', 'Var', (44, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
176292	27623107	Moreover treatment of MPM cells with both MET and PI3K inhibitors significantly decreased the levels of cyclin-D1, the cell cycle regulator and increased the levels of cleaved-poly (ADP-ribose) polymerase (PARP), a marker of apoptosis (Fig.	('poly (ADP-ribose) polymerase', 'Gene', '142', (176, 204))	('poly (ADP-ribose) polymerase', 'Gene', (176, 204))	('apoptosis', 'biological_process', 'GO:0006915', ('225', '234'))	('MET', 'Var', (42, 45))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('119', '139'))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('PI3K inhibitors', 'Var', (50, 65))	('PARP', 'Gene', (206, 210))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('119', '139'))	('decreased', 'NegReg', (80, 89))	('cyclin-D1', 'Gene', '595', (104, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('104', '110'))	('PARP', 'Gene', '142', (206, 210))	('apoptosis', 'biological_process', 'GO:0097194', ('225', '234'))	('cyclin-D1', 'Gene', (104, 113))	('increased', 'PosReg', (144, 153))
176293	27623107	Both crizotinib and BKM120 are known to induce apoptosis in various cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('BKM120', 'Chemical', 'MESH:C571178', (20, 26))	('crizotinib', 'Chemical', 'MESH:D000077547', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('crizotinib', 'Gene', (5, 15))	('cancer', 'Disease', (68, 74))	('BKM120', 'Var', (20, 26))	('induce', 'PosReg', (40, 46))
176294	27623107	(2013) have demonstrated that BKM120 enhanced TRAIL-induced apoptosis in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('BKM120', 'Chemical', 'MESH:C571178', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TRAIL', 'Gene', '8743', (46, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('lung cancer', 'Disease', (73, 84))	('BKM120', 'Var', (30, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('TRAIL', 'Gene', (46, 51))	('enhanced', 'PosReg', (37, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))
176295	27623107	Another study in hepatocellular carcinoma showed that BKM120 markedly reduced tumor growth mainly via cell cycle arrest than by apoptosis.	('hepatocellular carcinoma', 'Disease', (17, 41))	('reduced', 'NegReg', (70, 77))	('BKM120', 'Chemical', 'MESH:C571178', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('102', '119'))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('BKM120', 'Var', (54, 60))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('tumor', 'Disease', (78, 83))	('cell cycle arrest', 'CPA', (102, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (17, 41))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (17, 41))
176296	27623107	BKM120 also effectively suppressed neuroendocrine tumor cell proliferation and stimulated apoptosis.	('BKM120', 'Var', (0, 6))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (35, 55))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (35, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('suppressed', 'NegReg', (24, 34))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('neuroendocrine tumor', 'Disease', (35, 55))	('stimulated', 'PosReg', (79, 89))	('apoptosis', 'CPA', (90, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
176298	27623107	In addition we have shown that treatment of MPM cells with BKM120 resulted in disruption of microtubule assembly causing mitotic catastrophe cell death (Fig.	('cell death', 'biological_process', 'GO:0008219', ('141', '151'))	('microtubule assembly', 'MPA', (92, 112))	('BKM120', 'Var', (59, 65))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('121', '140'))	('BKM120', 'Chemical', 'MESH:C571178', (59, 65))	('disruption', 'NegReg', (78, 88))	('mitotic catastrophe cell death', 'Disease', 'MESH:D002388', (121, 151))	('microtubule', 'cellular_component', 'GO:0005874', ('92', '103'))	('microtubule assembly', 'biological_process', 'GO:0046785', ('92', '112'))	('mitotic catastrophe cell death', 'Disease', (121, 151))
176300	27623107	Treatment of glioma cells with BKM120 inhibited microtubule dynamics and induced either robust G2-M arrest and apoptosis or mitotic catastrophe.	('glioma', 'Disease', (13, 19))	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('BKM120', 'Var', (31, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('124', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('microtubule', 'cellular_component', 'GO:0005874', ('48', '59'))	('microtubule dynamics', 'MPA', (48, 68))	('inhibited', 'NegReg', (38, 47))	('BKM120', 'Chemical', 'MESH:C571178', (31, 37))	('microtubule dynamics', 'biological_process', 'GO:0000226', ('48', '68'))	('mitotic catastrophe', 'CPA', (124, 143))	('G2-M arrest', 'Disease', (95, 106))	('G2-M arrest', 'Disease', 'MESH:D006323', (95, 106))	('apoptosis', 'CPA', (111, 120))	('induced', 'Reg', (73, 80))
176301	27623107	Finally, using a PDX model we have demonstrated that the combination of crizotinib/ BKM120 is effective in suppressing MPM tumor growth.	('MPM tumor', 'Disease', 'MESH:D009369', (119, 128))	('crizotinib/', 'Var', (72, 83))	('MPM tumor', 'Disease', (119, 128))	('suppressing', 'NegReg', (107, 118))	('crizotinib', 'Chemical', 'MESH:D000077547', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('BKM120', 'Chemical', 'MESH:C571178', (84, 90))
176302	27623107	For instance treatment with BKM120 significantly inhibited tumor growth in vivo and it also showed synergistic cytotoxicity with dexamethasone in dexamethasone sensitive multiple myeloma cells.	('tumor', 'Disease', (59, 64))	('myeloma', 'Disease', 'MESH:D009101', (179, 186))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('multiple myeloma', 'Phenotype', 'HP:0006775', (170, 186))	('BKM120', 'Chemical', 'MESH:C571178', (28, 34))	('myeloma', 'Disease', (179, 186))	('dexamethasone', 'Chemical', 'MESH:D003907', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cytotoxicity', 'Disease', (111, 123))	('dexamethasone', 'Chemical', 'MESH:D003907', (146, 159))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('BKM120', 'Var', (28, 34))
176303	27623107	Moreover, combined treatment of neuroendocrine tumors with BKM120 and MEK inhibitor (PD0325901) was more effective in suppressing tumor growth in a xenograft model.	('neuroendocrine tumors', 'Disease', (32, 53))	('PD0325901', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (32, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('BKM120', 'Chemical', 'MESH:C571178', (59, 65))	('BKM120', 'Gene', (59, 65))	('PD0325901', 'Chemical', 'MESH:C506614', (85, 94))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('suppressing', 'NegReg', (118, 129))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (32, 53))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (47, 52))
176304	27623107	Recently a combination of PI3K/MEK inhibition with BKM120 and PD0325901 was effective in inducing tumor regression in mouse model of cancer that harbored a KRAS mutation.	('inducing', 'NegReg', (89, 97))	('BKM120', 'Var', (51, 57))	('KRAS', 'Gene', (156, 160))	('mutation', 'Var', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('KRAS', 'Gene', '16653', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (133, 139))	('PD0325901', 'Var', (62, 71))	('BKM120', 'Chemical', 'MESH:C571178', (51, 57))	('mouse', 'Species', '10090', (118, 123))	('tumor', 'Disease', (98, 103))	('PD0325901', 'Chemical', 'MESH:C506614', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
176308	27623107	Despite this, the combination of crizotinib/BKM120 did suppress MPM tumor growth.	('MPM tumor', 'Disease', 'MESH:D009369', (64, 73))	('crizotinib', 'Chemical', 'MESH:D000077547', (33, 43))	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('crizotinib/BKM120', 'Var', (33, 50))	('MPM tumor', 'Disease', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppress', 'NegReg', (55, 63))
176311	27623107	BKM120 is a pan inhibitor of all four class I PI3K isoforms and inhibited tumor cells bearing PIK3CA mutations.	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('PIK3CA', 'Gene', (94, 100))	('tumor', 'Disease', (74, 79))	('PIK3CA', 'Gene', '5290', (94, 100))
176316	27623107	AKT, p-AKTser473, S6, p-S6Ser235/236, cyclin D1, cleaved PARP, p-MET (1234/1235), and anti-MAPK antibodies (ERK and p-ERK) were from Cell Signaling (Danvers, MA, USA).	('anti-MAPK', 'Protein', (86, 95))	('AKT', 'Gene', (0, 3))	('AKT', 'Gene', (7, 10))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('ERK', 'molecular_function', 'GO:0004707', ('108', '111'))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('p-S6Ser235/236', 'Var', (22, 36))	('Signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('AKT', 'Gene', '207', (7, 10))	('AKT', 'Gene', '207', (0, 3))	('cyclin D1', 'Gene', (38, 47))	('PARP', 'Gene', '142', (57, 61))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('cyclin D1', 'Gene', '595', (38, 47))	('p-ERK', 'Gene', '9451', (116, 121))	('p-ERK', 'Gene', (116, 121))	('PARP', 'Gene', (57, 61))	('p-MET', 'Var', (63, 68))	('cleaved', 'MPA', (49, 56))
176319	27623107	Mesothelioma cell lines namely H2596, H513, H2461, H2052, H2452, H28 and H2373 and one benign transformed mesothelial control cell line Met-5A, were obtained from American Type Culture Collection (ATCC) (Manassas, VA, USA).	('H2052', 'Var', (51, 56))	('H513', 'CellLine', 'CVCL:A570', (38, 42))	('H2452', 'Var', (58, 63))	('H2052', 'CellLine', 'CVCL:1518', (51, 56))	('H2452', 'CellLine', 'CVCL:1553', (58, 63))	('H2373', 'Var', (73, 78))	('H2373', 'CellLine', 'CVCL:A533', (73, 78))	('H2461', 'CellLine', 'CVCL:A536', (44, 49))	('H2596', 'CellLine', 'CVCL:A546', (31, 36))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('H2461', 'Var', (44, 49))
176354	25277603	KB9520 showed significant anti-proliferative effect in ERbeta positive human malignant pleural mesothelioma cells in vitro.	('pleural mesothelioma', 'Disease', (87, 107))	('anti-proliferative effect', 'CPA', (26, 51))	('KB9520', 'Chemical', '-', (0, 6))	('KB9520', 'Var', (0, 6))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (87, 107))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (87, 107))	('human', 'Species', '9606', (71, 76))
176355	25277603	Selective activation of ERbeta with KB9520 sensitized the cells to treatment with cisplatin, resulting in enhanced growth inhibition and increased apoptosis.	('growth inhibition', 'CPA', (115, 132))	('KB9520', 'Chemical', '-', (36, 42))	('enhanced', 'PosReg', (106, 114))	('KB9520', 'Var', (36, 42))	('men', 'Species', '9606', (72, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('increased', 'PosReg', (137, 146))	('apoptosis', 'CPA', (147, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('activation', 'PosReg', (10, 20))
176357	25277603	Importantly, KB9520 exerted a protective effect to cisplatin toxicity in the non-malignant mesothelium derived MET5A cells.	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('toxicity', 'Disease', (61, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('malignant mesothelium', 'Phenotype', 'HP:0100001', (81, 102))	('KB9520', 'Chemical', '-', (13, 19))	('KB9520', 'Var', (13, 19))	('protective', 'MPA', (30, 40))
176358	25277603	Together, the data presented suggest that selective targeting of ERbeta may be an efficacious stand-alone treatment option and/or become an important add-on to existing malignant mesothelioma therapy.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (169, 191))	('ERbeta', 'Gene', (65, 71))	('selective targeting', 'Var', (42, 61))	('men', 'Species', '9606', (111, 114))	('malignant mesothelioma', 'Disease', (169, 191))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (169, 191))
176375	25277603	In the present study, we characterized the efficacy of KB9520, a selective ERbeta agonist, to inhibit MPM cell growth in vitro and in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('106', '117'))	('KB9520', 'Chemical', '-', (55, 61))	('MPM cell growth', 'CPA', (102, 117))	('KB9520', 'Var', (55, 61))	('inhibit', 'NegReg', (94, 101))
176376	25277603	Moreover, we investigated the possibility of an additive or synergistic effect between KB9520 and the SOC regimen (cisplatin/pemetrexed) for treatment of MPM.	('SOC', 'biological_process', 'GO:0031578', ('102', '105'))	('MPM', 'Disease', (154, 157))	('men', 'Species', '9606', (110, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('men', 'Species', '9606', (146, 149))	('pemetrexed', 'Chemical', 'MESH:D000068437', (125, 135))	('KB9520', 'Chemical', '-', (87, 93))	('KB9520', 'Var', (87, 93))
176378	25277603	KB9520 significantly (p <= 0,05) reduced cell growth and viability in a concentration-dependent manner, with highest efficacy at 10 nM.	('man', 'Species', '9606', (96, 99))	('KB9520', 'Chemical', '-', (0, 6))	('KB9520', 'Var', (0, 6))	('reduced', 'NegReg', (33, 40))	('cell growth', 'CPA', (41, 52))	('cell growth', 'biological_process', 'GO:0016049', ('41', '52'))
176381	25277603	KB9520 significantly (p <= 0,05) inhibited proliferation of the REN and MMB cells, whereas no inhibitory effect was observed in the MET5A cells, despite high endogenous levels of ERbeta.	('KB9520', 'Chemical', '-', (0, 6))	('KB9520', 'Var', (0, 6))	('inhibited', 'NegReg', (33, 42))
176386	25277603	To test if KB9520 influences MPM cell response to chemotherapy in vitro, we explored the effect of adding 10 nM KB9520 to the cisplatin/pemetrexed chemo combination (at their respective IC50 concentrations) on REN cell viability.	('KB9520', 'Chemical', '-', (112, 118))	('KB9520', 'Var', (112, 118))	('pemetrexed', 'Chemical', 'MESH:D000068437', (136, 146))	('influences', 'Reg', (18, 28))	('KB9520', 'Chemical', '-', (11, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))
176387	25277603	As shown in Figure 2A, the triple combination KB9520/cisplatin/pemetrexed (10 nM/100 muM/22 muM, respectively) was superior (p <= 0.05) to either KB9520 or cisplatin/pemetrexed treatment alone.	('KB9520', 'Chemical', '-', (146, 152))	('muM', 'Gene', (85, 88))	('pemetrexed', 'Chemical', 'MESH:D000068437', (166, 176))	('KB9520', 'Chemical', '-', (46, 52))	('muM', 'Gene', (92, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('pemetrexed', 'Chemical', 'MESH:D000068437', (63, 73))	('KB9520/cisplatin/pemetrexed', 'Var', (46, 73))	('muM', 'Gene', '56925', (92, 95))	('men', 'Species', '9606', (182, 185))	('muM', 'Gene', '56925', (85, 88))
176395	25277603	After 21 days of treatment, we observed a statistically significant reduction in tumor growth in the group treated with KB9520 plus cisplatin/pemetrexed as compared to the vehicle, KB9520, and cisplatin/pemetrexed groups, respectively (Figure 2B, C).	('KB9520', 'Chemical', '-', (120, 126))	('KB9520', 'Var', (120, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('men', 'Species', '9606', (22, 25))	('pemetrexed', 'Chemical', 'MESH:D000068437', (203, 213))	('KB9520', 'Chemical', '-', (181, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduction', 'NegReg', (68, 77))	('pemetrexed', 'Chemical', 'MESH:D000068437', (142, 152))	('tumor', 'Disease', (81, 86))
176398	25277603	Since the in vivo plasma half-life of KB9520 is only approximately 1 hour in mice (data not shown) we decided to investigate the biological sustainability and mechanism of action of KB9520 in vitro to better understand its anti-tumorigenic activity and synergism with cisplatin/pemetrexed in vivo.	('mice', 'Species', '10090', (77, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('KB9520', 'Chemical', '-', (182, 188))	('KB9520', 'Chemical', '-', (38, 44))	('pemetrexed', 'Chemical', 'MESH:D000068437', (278, 288))	('KB9520', 'Var', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))
176399	25277603	Firstly, we tested the anti-proliferative response to brief exposures (1, 2, 4, 8, 16 and 24 hours) to 10 nM KB9520 on the ERbeta positive REN cells (Figure 3A).	('KB9520', 'Var', (109, 115))	('KB9520', 'Chemical', '-', (109, 115))	('tested', 'Reg', (12, 18))	('anti-proliferative', 'MPA', (23, 41))
176403	25277603	The largest anti-proliferative effect was, however, observed with the highest KB9520 concentration used.	('KB9520', 'Chemical', '-', (78, 84))	('anti-proliferative effect', 'CPA', (12, 37))	('KB9520', 'Var', (78, 84))
176411	25277603	The most efficacious anti-proliferative effect was observed when KB9520 pre-treatment was combined with the highest concentration of cisplatin (100 muM).	('pre', 'molecular_function', 'GO:0003904', ('72', '75'))	('combined', 'Interaction', (90, 98))	('muM', 'Gene', '56925', (148, 151))	('anti-proliferative effect', 'CPA', (21, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('men', 'Species', '9606', (81, 84))	('KB9520', 'Var', (65, 71))	('muM', 'Gene', (148, 151))	('KB9520', 'Chemical', '-', (65, 71))
176412	25277603	Interestingly, 2 hours pre-treatment with KB9520 in combination with 20 muM cisplatin was as efficacious as 100 muM cisplatin alone.	('muM', 'Gene', (112, 115))	('pre', 'molecular_function', 'GO:0003904', ('23', '26'))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('muM', 'Gene', '56925', (72, 75))	('men', 'Species', '9606', (32, 35))	('KB9520', 'Chemical', '-', (42, 48))	('KB9520', 'Var', (42, 48))	('muM', 'Gene', (72, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('muM', 'Gene', '56925', (112, 115))
176414	25277603	Results of 2 hours pre-treatment with 10 nM KB9520, wash-off and then continued growth in normal medium, or medium supplemented with pemetrexed at different concentrations (range 5-22 muM) for an additional 24 hours are shown.	('men', 'Species', '9606', (28, 31))	('men', 'Species', '9606', (121, 124))	('pemetrexed', 'Chemical', 'MESH:D000068437', (133, 143))	('KB9520', 'Chemical', '-', (44, 50))	('KB9520', 'Var', (44, 50))	('muM', 'Gene', '56925', (184, 187))	('pre', 'molecular_function', 'GO:0003904', ('19', '22'))	('muM', 'Gene', (184, 187))
176418	25277603	In summary, our data suggest that KB9520 acts as a chemosensitizer through ERbeta, increasing the anti-tumorigenic efficacy of cisplatin or the cisplatin/pemetrexed combination on malignant mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant mesothelioma', 'Disease', (180, 202))	('pemetrexed', 'Chemical', 'MESH:D000068437', (154, 164))	('tumor', 'Disease', (103, 108))	('KB9520', 'Chemical', '-', (34, 40))	('KB9520', 'Var', (34, 40))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (180, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (180, 202))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('increasing', 'PosReg', (83, 93))
176421	25277603	Pre-treatment with KB9520 for 2 hours followed by 24 hours cisplatin treatment resulted in significant and efficient block in the G0/G1 phase and inhibition of cells entering the S-phase of the cell cycle compared to any other treatment (data reported in Table 2 represent mean +- s.d.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('KB9520', 'Chemical', '-', (19, 25))	('KB9520', 'Var', (19, 25))	('inhibition', 'NegReg', (146, 156))	('block', 'NegReg', (117, 122))	('cell cycle', 'biological_process', 'GO:0007049', ('194', '204'))	('S-phase', 'biological_process', 'GO:0051320', ('179', '186'))	('men', 'Species', '9606', (9, 12))	('men', 'Species', '9606', (232, 235))	('cells entering the S-phase of the cell cycle', 'CPA', (160, 204))	('G0/G1 phase', 'CPA', (130, 141))	('men', 'Species', '9606', (74, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('G1 phase', 'biological_process', 'GO:0051318', ('133', '141'))
176422	25277603	Moreover, a significant higher percentage of dead cells were found in wells pre-treated with KB9520 followed by cisplatin compared to other treatment regimens.	('men', 'Species', '9606', (145, 148))	('higher', 'PosReg', (24, 30))	('pre', 'molecular_function', 'GO:0003904', ('76', '79'))	('men', 'Species', '9606', (154, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('KB9520', 'Chemical', '-', (93, 99))	('KB9520', 'Var', (93, 99))
176424	25277603	As expected from the cell cycle analysis and percentage of dead cells, 2 hours KB9520 treatment, prior to addition of cisplatin, had the greatest effect on the appearance of cleaved PARP1 (Figure 6A).	('PARP1', 'Gene', '142', (182, 187))	('PARP1', 'Gene', (182, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('men', 'Species', '9606', (91, 94))	('cleaved', 'MPA', (174, 181))	('KB9520', 'Chemical', '-', (79, 85))	('KB9520', 'Var', (79, 85))	('cell cycle', 'biological_process', 'GO:0007049', ('21', '31'))
176427	25277603	As shown in Figure 6A, KB9520 treatment significantly reduced AKT phosphorylation both in the absence and in the presence of cisplatin.	('AKT', 'Gene', (62, 65))	('men', 'Species', '9606', (35, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('KB9520', 'Chemical', '-', (23, 29))	('KB9520', 'Var', (23, 29))	('reduced', 'NegReg', (54, 61))	('AKT', 'Gene', '207', (62, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))
176428	25277603	The mechanism for the combined effect of KB9520 and cisplatin on AKT pathway modulation, PARP1 cleavage and increased cell death needs further studies.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('cell death', 'biological_process', 'GO:0008219', ('118', '128'))	('modulation', 'Reg', (77, 87))	('AKT', 'Gene', (65, 68))	('KB9520', 'Chemical', '-', (41, 47))	('KB9520', 'Var', (41, 47))	('AKT', 'Gene', '207', (65, 68))	('PARP1', 'Gene', '142', (89, 94))	('PARP1', 'Gene', (89, 94))
176432	25277603	As previously described for REN cells, we treated MET5A cells with 10 nM KB9520 for 2 hours followed by wash-off and incubation in normal medium alone or in the presence of three concentrations of cisplatin (25, 50, 100 muM) for additional 24 hours.	('muM', 'Gene', (220, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (197, 206))	('KB9520', 'Chemical', '-', (73, 79))	('KB9520', 'Var', (73, 79))	('muM', 'Gene', '56925', (220, 223))
176433	25277603	As reported in Figure 6B, KB9520 alone had no effect on MET5A cell proliferation or viability, while a protective effect was observed when KB9520 pre-treatment was combined with low concentrations of cisplatin.	('MET5A cell proliferation', 'CPA', (56, 80))	('men', 'Species', '9606', (155, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('pre', 'molecular_function', 'GO:0003904', ('146', '149'))	('KB9520', 'Chemical', '-', (139, 145))	('viability', 'CPA', (84, 93))	('KB9520', 'Var', (139, 145))	('KB9520', 'Chemical', '-', (26, 32))
176435	25277603	Western-blot analysis (Figure 6C) revealed that KB9520 pre-treatment reduced the percentage of cleaved PARP1 in cells exposed to all concentrations of cisplatin, in accordance with data obtained on cell viability.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('PARP1', 'Gene', (103, 108))	('PARP1', 'Gene', '142', (103, 108))	('reduced', 'NegReg', (69, 76))	('KB9520', 'Chemical', '-', (48, 54))	('KB9520', 'Var', (48, 54))	('pre', 'molecular_function', 'GO:0003904', ('55', '58'))	('men', 'Species', '9606', (64, 67))
176436	25277603	Regarding phosphorylated AKT, KB9520 had no effect on basal pAKT levels in the MET5A control cells but it antagonized the cisplatin-mediated inhibition of AKT activation (Figure 6C).	('AKT', 'Gene', (25, 28))	('AKT', 'Gene', (155, 158))	('KB9520', 'Chemical', '-', (30, 36))	('KB9520', 'Var', (30, 36))	('AKT', 'Gene', '207', (61, 64))	('cisplatin-mediated inhibition', 'MPA', (122, 151))	('AKT', 'Gene', '207', (155, 158))	('AKT', 'Gene', '207', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('AKT', 'Gene', (61, 64))	('antagonized', 'NegReg', (106, 117))
176437	25277603	AKT pathway activation is associated with anti-apoptotic effects and cell survival and together with the effects of KB9520 on reduced PARP1 cleavage, this may explain the KB9520-mediated decrease in cisplatin cytotoxicity in the non-malignant MET5A cells.	('AKT', 'Gene', (0, 3))	('KB9520', 'Chemical', '-', (116, 122))	('KB9520-mediated', 'Var', (171, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('KB9520', 'Chemical', '-', (171, 177))	('activation', 'PosReg', (12, 22))	('cytotoxicity', 'Disease', (209, 221))	('AKT', 'Gene', '207', (0, 3))	('cisplatin', 'MPA', (199, 208))	('PARP1', 'Gene', (134, 139))	('PARP1', 'Gene', '142', (134, 139))	('cytotoxicity', 'Disease', 'MESH:D064420', (209, 221))	('decrease', 'NegReg', (187, 195))
176443	25277603	Both KB9520 and E2 displayed bell-shaped responses with growth inhibition at low doses and opposite effect at high doses.	('growth', 'CPA', (56, 62))	('KB9520', 'Chemical', '-', (5, 11))	('inhibition', 'NegReg', (63, 73))	('KB9520', 'Var', (5, 11))
176448	25277603	This time to effect difference between KB9520 and E2 may depend on the different ERbeta conformational change/s induced by KB9520 and E2, respectively, which in turn may have an effect on co-regulatory protein interactions including type of co-regulatory complex, stoichiometry and kinetics.	('effect', 'Reg', (178, 184))	('have', 'Reg', (170, 174))	('KB9520', 'Chemical', '-', (123, 129))	('KB9520', 'Var', (123, 129))	('interactions', 'Interaction', (210, 222))	('co-regulatory protein', 'MPA', (188, 209))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('ERbeta conformational change/s', 'MPA', (81, 111))	('KB9520', 'Chemical', '-', (39, 45))
176452	25277603	Of note though, the non-malignant MET5A cells did respond to KB9520 when stressed by cisplatin.	('respond', 'Reg', (50, 57))	('KB9520', 'Chemical', '-', (61, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('KB9520', 'Var', (61, 67))
176454	25277603	Treatment with KB9520 in combination with cisplatin/pemetrexed in vivo had greater efficacy than either treatment alone and caused a significantly reduced tumor load compared to vehicle treated animals at the end of the treatment period.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('KB9520', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('men', 'Species', '9606', (225, 228))	('pemetrexed', 'Chemical', 'MESH:D000068437', (52, 62))	('men', 'Species', '9606', (5, 8))	('efficacy', 'MPA', (83, 91))	('men', 'Species', '9606', (109, 112))	('reduced', 'NegReg', (147, 154))	('KB9520', 'Chemical', '-', (15, 21))
176455	25277603	Moreover, the triple combination shrunk the tumor volume even below the tumor volume at the start of treatment.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('shrunk', 'PosReg', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('triple combination', 'Var', (14, 32))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (44, 49))	('men', 'Species', '9606', (106, 109))
176456	25277603	Also in a second human malignant mesothelioma cell line, MMP, KB9520 in complex with cisplatin resulted in synergistic growth inhibition compared to KB9520 or cisplatin alone in vitro (data not shown).	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (23, 45))	('human', 'Species', '9606', (17, 22))	('MMP', 'molecular_function', 'GO:0004235', ('57', '60'))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('malignant mesothelioma', 'Disease', (23, 45))	('KB9520', 'Chemical', '-', (62, 68))	('inhibition', 'NegReg', (126, 136))	('KB9520', 'Var', (62, 68))	('KB9520', 'Chemical', '-', (149, 155))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (23, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('synergistic growth', 'MPA', (107, 125))
176457	25277603	Moreover, similar to the effect in REN cells, the combination of KB9520 and cisplatin in the MMP cells decreased the level of phosphorylated AKT and increased the levels of cleaved PARP1 (data not shown).	('level of phosphorylated', 'MPA', (117, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('increased', 'PosReg', (149, 158))	('AKT', 'Gene', (141, 144))	('decreased', 'NegReg', (103, 112))	('MMP', 'molecular_function', 'GO:0004235', ('93', '96'))	('KB9520', 'Var', (65, 71))	('PARP1', 'Gene', '142', (181, 186))	('AKT', 'Gene', '207', (141, 144))	('KB9520', 'Chemical', '-', (65, 71))	('PARP1', 'Gene', (181, 186))
176458	25277603	That a brief exposure of malignant mesothelioma cells to KB9520 (2 hours) elicited a stronger growth inhibitory effect in vitro compared to continuous exposure is suggestive of a hit-and-run mechanism.	('KB9520', 'Chemical', '-', (57, 63))	('malignant mesothelioma', 'Disease', (25, 47))	('growth inhibitory effect', 'MPA', (94, 118))	('KB9520', 'Var', (57, 63))	('stronger', 'PosReg', (85, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (25, 47))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (25, 47))
176459	25277603	The long-lived biological activity of KB9520 (>=24 hours) together with a hit-and-run type of mechanism adds to our understanding of the in vivo tumor inhibitory efficacy of KB9520 despite its short plasma half-life of approximately 1 hour in mice.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('KB9520', 'Chemical', '-', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('KB9520', 'Var', (174, 180))	('KB9520', 'Chemical', '-', (38, 44))	('KB9520', 'Gene', (38, 44))	('tumor', 'Disease', (145, 150))	('mice', 'Species', '10090', (243, 247))
176462	25277603	Here we show that KB9520 significantly reduced pAKT levels both in vitro and in vivo (data not shown), which, at least in part, may explain the observed sensitization to cisplatin cytotoxicity.	('sensitization', 'biological_process', 'GO:0046960', ('153', '166'))	('AKT', 'Gene', (48, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('reduced', 'NegReg', (39, 46))	('KB9520', 'Chemical', '-', (18, 24))	('AKT', 'Gene', '207', (48, 51))	('cytotoxicity', 'Disease', (180, 192))	('KB9520', 'Var', (18, 24))
176464	25277603	Exposure of REN cells to KB9520 prior to cisplatin resulted in synergistic inhibition of malignant mesothelioma cell proliferation and survival whereas the reverse order of drug exposure did not even result in additive efficacy.	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (89, 111))	('inhibition', 'NegReg', (75, 85))	('KB9520', 'Chemical', '-', (25, 31))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (89, 111))	('KB9520', 'Var', (25, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('survival', 'CPA', (135, 143))	('malignant mesothelioma', 'Disease', (89, 111))
176465	25277603	Furthermore, KB9520 preconditioned malignant mesothelioma cells to low-concentration cisplatin cytotoxicity; combination of KB9520 with 20 muM cisplatin was as efficacious as 100 muM cisplatin alone.	('muM', 'Gene', '56925', (179, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('malignant mesothelioma', 'Disease', (35, 57))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (35, 57))	('cytotoxicity', 'Disease', (95, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('muM', 'Gene', (179, 182))	('KB9520', 'Chemical', '-', (13, 19))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (35, 57))	('muM', 'Gene', '56925', (139, 142))	('cytotoxicity', 'Disease', 'MESH:D064420', (95, 107))	('KB9520', 'Chemical', '-', (124, 130))	('combination', 'Var', (109, 120))	('muM', 'Gene', (139, 142))	('KB9520', 'Var', (124, 130))
176466	25277603	Thus, these data imply that KB9520, through ERbeta, acts as a chemosensitizer increasing cisplatin cytotoxicity in human malignant mesothelioma cells.	('cytotoxicity', 'Disease', (99, 111))	('malignant mesothelioma', 'Disease', (121, 143))	('increasing', 'PosReg', (78, 88))	('cytotoxicity', 'Disease', 'MESH:D064420', (99, 111))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (121, 143))	('KB9520', 'Chemical', '-', (28, 34))	('human', 'Species', '9606', (115, 120))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (121, 143))	('KB9520', 'Var', (28, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))
176473	25277603	In summary, in this report we have shown that MPM cell proliferation and tumor growth can be effectively suppressed by selective agonist activation of ERbeta.	('suppressed', 'NegReg', (105, 115))	('agonist', 'Var', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('tumor', 'Disease', (73, 78))	('ERbeta', 'Protein', (151, 157))	('MPM cell proliferation', 'CPA', (46, 68))
176474	25277603	We have also shown that KB9520 acts as a chemosensitizer through activation of ERbeta and that the order of drug administration in combination with cisplatin/pemetrexed is essential for the synergistic efficacy observed in vitro and in vivo.	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('KB9520', 'Chemical', '-', (24, 30))	('pemetrexed', 'Chemical', 'MESH:D000068437', (158, 168))	('KB9520', 'Var', (24, 30))	('activation', 'PosReg', (65, 75))	('ERbeta', 'Protein', (79, 85))
176477	25277603	Thus, combination of KB9520 with SOC (cisplatin/pemetrexed combination) may increase the sensitivity of MPM tumors to the SOC regimen in patients and perhaps result in higher response rates, extended progression free survival (PFS) and prolonged overall survival (OS), without adding toxicity.	('extended', 'PosReg', (191, 199))	('KB9520', 'Chemical', '-', (21, 27))	('SOC', 'biological_process', 'GO:0031578', ('122', '125'))	('men', 'Species', '9606', (130, 133))	('toxicity', 'Disease', 'MESH:D064420', (284, 292))	('sensitivity', 'MPA', (89, 100))	('overall', 'MPA', (246, 253))	('response', 'MPA', (175, 183))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('MPM tumors', 'Disease', 'MESH:D009369', (104, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('prolonged', 'PosReg', (236, 245))	('toxicity', 'Disease', (284, 292))	('increase', 'PosReg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (137, 145))	('MPM tumors', 'Disease', (104, 114))	('pemetrexed', 'Chemical', 'MESH:D000068437', (48, 58))	('SOC', 'biological_process', 'GO:0031578', ('33', '36'))	('KB9520', 'Var', (21, 27))	('higher', 'PosReg', (168, 174))	('progression free survival', 'CPA', (200, 225))
176478	25277603	Furthermore, combination with KB9520 may allow milder SOC (cisplatin) regimen without loss of anti-tumor efficacy and thereby may become an option for patients that cannot tolerate the standard and more aggressive cisplatin/pemetrexed dose regimen.	('tumor', 'Disease', (99, 104))	('men', 'Species', '9606', (244, 247))	('KB9520', 'Chemical', '-', (30, 36))	('KB9520', 'Var', (30, 36))	('patients', 'Species', '9606', (151, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('pemetrexed', 'Chemical', 'MESH:D000068437', (224, 234))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('men', 'Species', '9606', (74, 77))	('SOC', 'biological_process', 'GO:0031578', ('54', '57'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('combination', 'Var', (13, 24))
176530	22314185	Activated VEGFR2-signaling, sometimes by KDR gene mutations found in juvenile capillary hemangiomas and angiosarcomas, is believed to be pathogenetically important.	('KDR', 'Gene', (41, 44))	('hemangioma', 'Phenotype', 'HP:0001028', (88, 98))	('VEGFR2', 'Gene', '3791', (10, 16))	('mutations', 'Var', (50, 59))	('angiosarcoma', 'Phenotype', 'HP:0200058', (104, 116))	('juvenile capillary hemangiomas', 'Disease', (69, 99))	('VEGFR2', 'Gene', (10, 16))	('juvenile capillary hemangiomas', 'Disease', 'MESH:D018324', (69, 99))	('KDR', 'Gene', '3791', (41, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('hemangiomas', 'Phenotype', 'HP:0001028', (88, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('hemangiomas and angiosarcomas', 'Disease', 'MESH:D006394', (88, 117))	('capillary hemangiomas', 'Phenotype', 'HP:0005306', (78, 99))	('angiosarcomas', 'Phenotype', 'HP:0200058', (104, 117))
176652	18606715	Cell killing is associated with decreased Fra-1 and Survivin expression and knock-down of Fra-1 increases cell killing by ranpirnase in a dose-dependent manner, but not by rosiglitazone.	('increases', 'PosReg', (96, 105))	('cell killing', 'CPA', (106, 118))	('Fra-1', 'Gene', (90, 95))	('Cell killing', 'CPA', (0, 12))	('Fra-1', 'Protein', (42, 47))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (172, 185))	('knock-down', 'Var', (76, 86))	('Survivin', 'Gene', '11799', (52, 60))	('Cell killing', 'biological_process', 'GO:0001906', ('0', '12'))	('Survivin', 'Gene', (52, 60))	('cell killing', 'biological_process', 'GO:0001906', ('106', '118'))	('decreased', 'NegReg', (32, 41))	('expression', 'MPA', (61, 71))
176657	18606715	Ectopic expression of Fra-1 in vitro increases the cell motility and metastatic behavior of mammary adenocarcinoma cells and lung epithelial cells.	('metastatic behavior of mammary', 'CPA', (69, 99))	('Ectopic expression', 'Var', (0, 18))	('adenocarcinoma', 'Disease', (100, 114))	('increases', 'PosReg', (37, 46))	('cell motility', 'CPA', (51, 64))	('Fra-1', 'Gene', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cell motility', 'biological_process', 'GO:0048870', ('51', '64'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))
176659	18606715	Fra-1 is a predominant component of the AP-1 complex in asbestos-induced mesothelioma and proliferating rat mesothelioma cells, while overexpression of a dominant negative Fra-1 mutant inhibits the growth of these cells in soft agar.	('mutant', 'Var', (178, 184))	('rat', 'Species', '10116', (97, 100))	('Fra-1', 'Gene', (172, 177))	('AP-1 complex', 'cellular_component', 'GO:0035976', ('40', '52'))	('mesothelioma', 'Disease', (108, 120))	('inhibits', 'NegReg', (185, 193))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('mesothelioma', 'Disease', (73, 85))	('asbestos-induced', 'Disease', (56, 72))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('rat', 'Species', '10116', (104, 107))
176666	18606715	Previously, we reported that in malignant mesothelioma cells with increased kinase activity levels of AKT, both LY294002 and wortmannin (two inhibitors of the phosphatidylinositol 3'-Kinase (PI3K)/AKT pathway) act cooperatively with ranpirnase to inhibit cell growth.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (32, 54))	('AKT', 'Gene', (197, 200))	('cell growth', 'biological_process', 'GO:0016049', ('255', '266'))	('cell growth', 'CPA', (255, 266))	('PI3', 'Gene', '5266', (191, 194))	('AKT', 'Gene', (102, 105))	('mesothelioma', 'Disease', (42, 54))	('kinase activity', 'molecular_function', 'GO:0016301', ('76', '91'))	("phosphatidylinositol 3'-Kinase", 'Gene', '5294', (159, 189))	('wortmannin', 'Chemical', 'MESH:D000077191', (125, 135))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('LY294002', 'Var', (112, 120))	('increased', 'PosReg', (66, 75))	('PI3', 'Gene', (191, 194))	('AKT', 'Gene', '207', (197, 200))	('PI3K', 'molecular_function', 'GO:0016303', ('191', '195'))	('AKT', 'Gene', '207', (102, 105))	('rat', 'Species', '10116', (219, 222))	('LY294002', 'Chemical', 'MESH:C085911', (112, 120))	("phosphatidylinositol 3'-Kinase", 'Gene', (159, 189))	('kinase activity levels', 'MPA', (76, 98))	('inhibit', 'NegReg', (247, 254))
176675	18606715	Stock solution of the PI3K's small molecular inhibitor LY294002 was diluted in dimethyl sulfoxide (DMSO) and used at effective nontoxic concentrations (20muM) (Calbiochem, La Jolla, CA).	('LY294002', 'Var', (55, 63))	('muM', 'Gene', (154, 157))	('PI3', 'Gene', (22, 25))	('DMSO', 'Chemical', 'MESH:D004121', (99, 103))	('rat', 'Species', '10116', (143, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('muM', 'Gene', '56925', (154, 157))	('LY294002', 'Chemical', 'MESH:C085911', (55, 63))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (79, 97))	('PI3', 'Gene', '5266', (22, 25))
176719	18606715	The use of the PI3K inhibitor LY294002 further confirmed the PI3K effect on Fra-1 expression.	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('PI3', 'Gene', '5266', (61, 64))	('expression', 'MPA', (82, 92))	('PI3', 'Gene', (15, 18))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('Fra-1', 'Gene', (76, 81))	('PI3', 'Gene', (61, 64))	('PI3', 'Gene', '5266', (15, 18))	('LY294002', 'Var', (30, 38))
176727	18606715	To directly observe if the knock-down of Fra-1 increased the efficacy of ranpirnase, rosiglitazone, or their combination, cell line H292 (a cell line with high transfection efficiency) was studied.	('Fra-1', 'Gene', (41, 46))	('knock-down', 'Var', (27, 37))	('H292', 'CellLine', 'CVCL:0455', (132, 136))	('efficacy', 'MPA', (61, 69))	('increased', 'PosReg', (47, 56))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (85, 98))
176729	18606715	The knock-down of Fra-1 significantly increased the efficacy of ranpirnase alone at all concentrations, but not rosiglitazone alone.	('Fra-1', 'Gene', (18, 23))	('rat', 'Species', '10116', (95, 98))	('knock-down', 'Var', (4, 14))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (112, 125))	('increased', 'PosReg', (38, 47))	('efficacy', 'MPA', (52, 60))
176734	18606715	Furthermore, we investigated the effect of knocking down Fra-1 on the cell killing and apoptosis found with combinations of ranpirnase with rosiglitazone.	('cell killing', 'biological_process', 'GO:0001906', ('70', '82'))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('knocking down', 'Var', (43, 56))	('cell killing', 'CPA', (70, 82))	('Fra-1', 'Gene', (57, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (140, 153))
176738	18606715	The knock-down of Fra-1 in the cell line H292 further demonstrates that the synergistic effect of the two drugs is partially related to the modulation of Fra-1.	('synergistic effect', 'MPA', (76, 94))	('H292', 'CellLine', 'CVCL:0455', (41, 45))	('rat', 'Species', '10116', (61, 64))	('modulation', 'Var', (140, 150))	('Fra-1', 'Gene', (154, 159))
176765	33674911	Molecular profiling of unique mesothelioma variants resulted in the revision of the histological classification as summarized in the review by Beasley MB and colleagues.	('variants', 'Var', (43, 51))	('mesothelioma', 'Disease', (30, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (30, 42))
176778	33674911	Alexander Marx and colleagues start the section on thymic tumors by reviewing the growing number of recurrent molecular alterations that have been described in thymomas in recent years and that have helped to underpin and confirm the classification approach used by the WHO.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('thymoma', 'Phenotype', 'HP:0100522', (160, 167))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('thymomas', 'Disease', 'MESH:D013945', (160, 168))	('thymomas', 'Disease', (160, 168))	('alterations', 'Var', (120, 131))
176781	33674911	Potentially even more interesting is the recent description of KMT2A-MAML translocations in some type B2 and B3 thymomas and occasional thymic carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('thymoma', 'Phenotype', 'HP:0100522', (112, 119))	('thymic carcinomas', 'Disease', (136, 153))	('thymic carcinomas', 'Disease', 'MESH:D013953', (136, 153))	('translocations', 'Var', (74, 88))	('KMT2A', 'Gene', (63, 68))	('thymomas', 'Disease', 'MESH:D013945', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('thymomas', 'Disease', (112, 120))	('KMT2A', 'Gene', '4297', (63, 68))
176826	29799130	Also in NSCLC, high levels of IL-6 were associated with an increased expression of anti-apoptotic and DNA repair molecules and led to cisplatin resistance.	('led to', 'Reg', (127, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('cisplatin resistance', 'MPA', (134, 154))	('DNA repair', 'biological_process', 'GO:0006281', ('102', '112'))	('expression', 'MPA', (69, 79))	('IL-6', 'Gene', (30, 34))	('NSCLC', 'Disease', (8, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('high levels', 'Var', (15, 26))	('increased', 'PosReg', (59, 68))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('IL-6', 'molecular_function', 'GO:0005138', ('30', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
176901	29799130	Dysregulation of p53 function desensitized human colon carcinoma cells to Photofrin-PDT.	('desensitized', 'NegReg', (30, 42))	('Dysregulation', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('colon carcinoma', 'Disease', 'MESH:D015179', (49, 64))	('colon carcinoma', 'Disease', (49, 64))	('p53', 'Gene', (17, 20))	('human', 'Species', '9606', (43, 48))
176931	29799130	Inhibition of COX-2 led to increased apoptosis, measured as an increase in poly (ADP-ribose) polymerase (PARP) cleavage and decrease in Bcl-2 expression.	('PARP', 'Gene', (105, 109))	('increase', 'PosReg', (63, 71))	('poly (ADP-ribose) polymerase', 'Gene', '142', (75, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('136', '141'))	('PARP', 'Gene', '142', (105, 109))	('poly (ADP-ribose) polymerase', 'Gene', (75, 103))	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (124, 132))	('expression', 'MPA', (142, 152))	('Bcl-2', 'Gene', (136, 141))	('Bcl-2', 'Gene', '596', (136, 141))	('COX-2', 'Gene', (14, 19))
176932	29799130	Moreover, inhibition decreased the expression of inflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta and increased the expression of the anti-inflammatory cytokine IL-10.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('expression', 'MPA', (35, 45))	('necrosis', 'biological_process', 'GO:0070265', ('78', '86'))	('necrosis', 'biological_process', 'GO:0019835', ('78', '86'))	('necrosis', 'biological_process', 'GO:0001906', ('78', '86'))	('inflammatory cytokines', 'MPA', (49, 71))	('expression', 'MPA', (137, 147))	('IL-10', 'Gene', '3586', (182, 187))	('IL-10', 'Gene', (182, 187))	('inhibition', 'Var', (10, 20))	('increased', 'PosReg', (123, 132))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('72', '93'))	('IL-1', 'molecular_function', 'GO:0005149', ('110', '114'))	('necrosis', 'biological_process', 'GO:0008219', ('78', '86'))	('IL-10', 'molecular_function', 'GO:0005141', ('182', '187'))	('IL-1beta', 'Gene', '3553', (110, 118))	('tumor necrosis factor (TNF)-alpha', 'Gene', '7124', (72, 105))	('decreased', 'NegReg', (21, 30))	('anti-inflammatory cytokine', 'MPA', (155, 181))	('IL-1beta', 'Gene', (110, 118))	('necrosis', 'biological_process', 'GO:0008220', ('78', '86'))
176942	29799130	This group also demonstrated that inhibition with the selective COX-2 inhibitor SC58236 significantly improved the ability of naiotaive CD3+ T cells to proliferate in the presence of extracted Treg cells.	('SC58236', 'Var', (80, 87))	('proliferate', 'CPA', (152, 163))	('SC58236', 'Chemical', 'MESH:C119130', (80, 87))	('improved', 'PosReg', (102, 110))
176970	29799130	This model avoids the need to grow tumors to a larger size in groups to receive resection and PDT compared to those to receive PDT alone.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PDT', 'Var', (94, 97))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
176980	29854315	Using a cut-off that yielded 95.58% specificity, measurement of sCD157 in cytology-negative effusions increased sensitivity of malignant pleural mesothelioma diagnosis from 34.42% to 49.18%.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (137, 157))	('malignant pleural mesothelioma', 'Disease', (127, 157))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (127, 157))	('measurement', 'Var', (49, 60))	('CD157', 'Gene', (65, 70))	('CD157', 'Gene', '683', (65, 70))	('increased', 'PosReg', (102, 111))
176998	29854315	CD157 is also expressed in >85% of MPM, and again, high CD157 expression is associated with enhanced tumor aggressiveness and with reduced sensitivity to platinum-based chemotherapy, notably in the biphasic histotype.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (101, 121))	('CD157', 'Gene', (0, 5))	('CD157', 'Gene', '683', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'MPA', (62, 72))	('reduced', 'NegReg', (131, 138))	('enhanced', 'PosReg', (92, 100))	('high', 'Var', (51, 55))	('tumor aggressiveness', 'Disease', (101, 121))	('CD157', 'Gene', (56, 61))	('CD157', 'Gene', '683', (56, 61))	('platinum', 'Chemical', 'MESH:D010984', (154, 162))	('aggressiveness', 'Phenotype', 'HP:0000718', (107, 121))	('sensitivity to platinum-based chemotherapy', 'MPA', (139, 181))
177072	29854315	In view of CD157's pivotal role in cell-matrix interaction, it is tempting to speculate that exosomal CD157 in pleural effusions has the potential to participate to the cross-talk between tumor cells and the surrounding environment, thus influencing tumor behavior.	('tumor', 'Disease', (188, 193))	('pleural effusions', 'Phenotype', 'HP:0002202', (111, 128))	('exosomal', 'Var', (93, 101))	('CD157', 'Gene', (102, 107))	('CD157', 'Gene', '683', (102, 107))	('participate', 'Reg', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('influencing', 'Reg', (238, 249))	('CD157', 'Gene', (11, 16))	('pleural effusion', 'Phenotype', 'HP:0002202', (111, 127))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('pleural effusions', 'Disease', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('CD157', 'Gene', '683', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('pleural effusions', 'Disease', 'MESH:D010996', (111, 128))	('cross-talk', 'Interaction', (169, 179))	('tumor', 'Disease', (250, 255))
177088	29854315	These proteases can cleave CD157 expressed in the stromal, endothelial and inflammatory cells that form the microenvironment.	('CD157', 'Gene', '683', (27, 32))	('CD157', 'Gene', (27, 32))	('cleave', 'Var', (20, 26))
177282	32752156	Interestingly, AB1 (sarcomatoid) and AB22 (epithelioid)-derived tumors were richer in the myeloid compartment (up to 70-80% of CD11b+ cells/total CD45+ cells), (Figure 1D,E,G,H,J).	('CD11b+', 'Var', (127, 133))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('AB1', 'Gene', (15, 18))	('sarcomatoid', 'Disease', 'MESH:C538614', (20, 31))	('AB22', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('sarcomatoid', 'Disease', (20, 31))
177361	32752156	The leukocyte infiltrate analysis of murine AB1, AB12, and AB22 mesothelioma was done with the following mAbs: CD45 PerCP (BD Biosciences, Eysins, Switzerland), CD11b Pacific Blue (Biolegend, San Diego, CA, USA), CD3 BV786 (BD Biosciences), CD4 FITC (eBioscience, San Diego, CA, USA), CD8 PE-Cy7 (BD Biosciences), F480 APC (AbD Serotec), Ly6G PE-Cy7 (BD Biosciences), and Ly6C FITC (BD Biosciences).	('Ly6G', 'Gene', (338, 342))	('CD3', 'Gene', (213, 216))	('Ly6C', 'Gene', (372, 376))	('APC', 'Disease', 'MESH:D011125', (319, 322))	('CD3', 'Gene', '12503', (213, 216))	('Ly6C', 'Gene', '17067', (372, 376))	('murine', 'Species', '10090', (37, 43))	('APC', 'Disease', (319, 322))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('Ly6G', 'Gene', '546644', (338, 342))	('APC', 'cellular_component', 'GO:0005680', ('319', '322'))	('CD8', 'Gene', (285, 288))	('Serotec', 'Chemical', '-', (328, 335))	('CD4 FITC', 'Var', (241, 249))	('CD8', 'Gene', '925', (285, 288))	('rat', 'Species', '10116', (20, 23))	('CD11b Pacific', 'Var', (161, 174))	('mesothelioma', 'Disease', (64, 76))
177380	22889334	A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma Inactivating germ line BRCA1-associated protein-1 (BAP1) mutations have recently been reported in families with uveal or cutaneous malignant melanoma (UMM, CMM), mesothelioma, and meningioma.	('mutations', 'Var', (153, 162))	('BAP1', 'Gene', (10, 14))	('mesothelioma', 'Disease', (258, 270))	('meningioma', 'Disease', 'MESH:D008577', (276, 286))	('mesothelioma', 'Disease', 'MESH:D008654', (258, 270))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (217, 245))	('paraganglioma', 'Disease', (82, 95))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('paraganglioma', 'Disease', 'MESH:D010235', (82, 95))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (217, 245))	('BAP1', 'Gene', '8314', (147, 151))	('BRCA1-associated protein-1', 'Gene', '8314', (119, 145))	('uveal or cutaneous malignant melanoma', 'Phenotype', 'HP:0007716', (208, 245))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('BRCA1-associated protein-1', 'Gene', (119, 145))	('Inactivating', 'NegReg', (96, 108))	('BAP1', 'Gene', '8314', (10, 14))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('meningioma', 'Disease', (276, 286))	('cutaneous melanoma', 'Disease', (58, 76))	('BAP1', 'Gene', (147, 151))	('reported', 'Reg', (182, 190))	('cutaneous malignant melanoma', 'Disease', (217, 245))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('meningioma', 'Phenotype', 'HP:0002858', (276, 286))	('malignant melanoma', 'Phenotype', 'HP:0002861', (227, 245))
177381	22889334	Although apparently predisposing to a wide range of tumors, the exact tumor spectrum associated with germ line BAP1 mutations has yet to be established.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BAP1', 'Gene', '8314', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
177382	22889334	Here, we report a novel germ line BAP1 splice mutation, c.1708C>G (p.Leu570fs*40), in a multiple-case Danish UMM family with a spectrum of other tumors.	('c.1708C>G', 'Var', (56, 65))	('p.Leu570fs*40', 'Mutation', 'p.L570fsX40', (67, 80))	('BAP1', 'Gene', (34, 38))	('c.1708C>G', 'Mutation', 'c.1708C>G', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('BAP1', 'Gene', '8314', (34, 38))
177383	22889334	Whole-exome sequencing identified an apparent missense mutation of BAP1 in UMM, CMM, as well as paraganglioma, breast cancer, and suspected mesothelioma cases in the family.	('paraganglioma', 'Disease', 'MESH:D010235', (96, 109))	('mesothelioma', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutation', 'Var', (46, 63))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('BAP1', 'Gene', '8314', (67, 71))	('paraganglioma', 'Disease', (96, 109))	('breast cancer', 'Disease', (111, 124))	('BAP1', 'Gene', (67, 71))
177384	22889334	Bioinformatic analysis and splicing assays demonstrated that this mutation creates a strong cryptic splice donor, resulting in aberrant splicing and a truncating frameshift of the BAP1 transcript.	('splicing', 'biological_process', 'GO:0045292', ('136', '144'))	('BAP1', 'Gene', '8314', (180, 184))	('splicing', 'MPA', (136, 144))	('BAP1', 'Gene', (180, 184))	('mutation', 'Var', (66, 74))	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('truncating', 'MPA', (151, 161))
177387	22889334	The report of a germ line inactivating mutation of the BRCA1-associated protein-1 (BAP1) in a patient with uveal malignant melanoma (UMM) as a part of the initial discovery of frequent somatic BAP1 mutations in UMM suggested a role for BAP1 in cancer predisposition.	('inactivating mutation', 'Var', (26, 47))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('malignant melanoma', 'Phenotype', 'HP:0002861', (113, 131))	('uveal malignant melanoma', 'Disease', (107, 131))	('mutations', 'Var', (198, 207))	('BAP1', 'Gene', '8314', (236, 240))	('patient', 'Species', '9606', (94, 101))	('BAP1', 'Gene', '8314', (83, 87))	('BAP1', 'Gene', '8314', (193, 197))	('uveal malignant melanoma', 'Disease', 'MESH:C536494', (107, 131))	('BRCA1-associated protein-1', 'Gene', '8314', (55, 81))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('BRCA1-associated protein-1', 'Gene', (55, 81))	('cancer', 'Disease', (244, 250))	('BAP1', 'Gene', (236, 240))	('uveal malignant melanoma', 'Phenotype', 'HP:0007716', (107, 131))	('BAP1', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('BAP1', 'Gene', (193, 197))
177388	22889334	Consistent with this finding, recently identified germ line BAP1 mutations in two families with a syndrome characterized by multiple skin-colored elevated melanocytic tumors, with some individuals also developing UMM or cutaneous malignant melanoma (CMM).	('UMM', 'Disease', (213, 216))	('mutations', 'Var', (65, 74))	('developing', 'Reg', (202, 212))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (220, 248))	('BAP1', 'Gene', '8314', (60, 64))	('melanocytic tumors', 'Disease', (155, 173))	('melanocytic tumors', 'Disease', 'MESH:D009508', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('BAP1', 'Gene', (60, 64))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (220, 248))	('cutaneous malignant melanoma', 'Disease', (220, 248))	('malignant melanoma', 'Phenotype', 'HP:0002861', (230, 248))
177389	22889334	At the same time, reported germ line BAP1 mutations in two families with at least five patients with mesothelioma, as well as individuals diagnosed with other cancers including UMM.	('cancers', 'Disease', (159, 166))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('BAP1', 'Gene', '8314', (37, 41))	('mesothelioma', 'Disease', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('BAP1', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('mutations', 'Var', (42, 51))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
177390	22889334	More recently, described a UMM family with cases of CMM, meningioma, and lung adenocarcinoma carrying a BAP1 mutation.	('BAP1', 'Gene', '8314', (104, 108))	('lung adenocarcinoma', 'Disease', (73, 92))	('meningioma', 'Disease', (57, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('meningioma', 'Phenotype', 'HP:0002858', (57, 67))	('BAP1', 'Gene', (104, 108))	('meningioma', 'Disease', 'MESH:D008577', (57, 67))	('CMM', 'Disease', (52, 55))	('mutation', 'Var', (109, 117))
177391	22889334	Similarly, reported two families with BAP1 mutations co-segregating with both UMM and CMM, as well as four other mutations in sporadic UMM and/or CMM cases.	('BAP1', 'Gene', (38, 42))	('UMM', 'Disease', (78, 81))	('CMM', 'Disease', (86, 89))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', '8314', (38, 42))
177392	22889334	All 14 of the germ line BAP1 mutations reported to date are predicted to result in protein truncation via nonsense mutation, frameshift caused by insertions/deletions, or alteration of a canonical dinucleotide splice donor/acceptor sequences.	('frameshift', 'Var', (125, 135))	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('nonsense mutation', 'Var', (106, 123))	('insertions/deletions', 'Var', (146, 166))	('alteration', 'Reg', (171, 181))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('result', 'Reg', (73, 79))	('protein truncation', 'MPA', (83, 101))	('BAP1', 'Gene', '8314', (24, 28))
177393	22889334	Among them, two families described by report skin-colored melanocytic tumors in all mutation carriers, while carriers from one family and another sporadic case described by Njauw display a similar but distinct nevoid melanoma-like melanocytic proliferations.	('skin-colored melanocytic tumors', 'Disease', (45, 76))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('mutation', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('skin-colored melanocytic tumors', 'Disease', 'MESH:D012878', (45, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
177395	22889334	Here, we report a Danish family with multiple UMM and suspected mesothelioma cases, as well as several other cancers including CMM, breast cancer, and paraganglioma, carrying an apparent missense mutation of BAP1 resulting in the creation of a strong cryptic splice donor, aberrant splicing, and a truncating frameshift of the BAP1 transcript.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('missense mutation', 'Var', (187, 204))	('BAP1', 'Gene', (327, 331))	('splicing', 'MPA', (282, 290))	('BAP1', 'Gene', (208, 212))	('paraganglioma', 'Phenotype', 'HP:0002668', (151, 164))	('splicing', 'biological_process', 'GO:0045292', ('282', '290'))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('mesothelioma', 'Disease', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('cancers', 'Disease', (109, 116))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', (132, 145))	('aberrant', 'MPA', (273, 281))	('BAP1', 'Gene', '8314', (327, 331))	('BAP1', 'Gene', '8314', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('paraganglioma', 'Disease', (151, 164))	('truncating', 'MPA', (298, 308))	('paraganglioma', 'Disease', 'MESH:D010235', (151, 164))
177404	22889334	Among these was a single non-synonymous variant in BAP1 (c.1708C>G, p.Leu570Val), which was also not listed in the sequence derived from approximately 6000 additional human chromosomes annotated by the NHLBI exome project (http://evs.gs.washington.edu/EVS/) or Kaviar (http://db.systemsbiology.net/kaviar/cgi-pub/Kaviar.pl).	('BAP1', 'Gene', (51, 55))	('p.Leu570Val', 'Mutation', 'p.L570V', (68, 79))	('c.1708C>G', 'Var', (57, 66))	('c.1708C>G', 'Mutation', 'c.1708C>G', (57, 66))	('human', 'Species', '9606', (167, 172))	('BAP1', 'Gene', '8314', (51, 55))
177405	22889334	While a conservative leucine to valine change is not consistent with previously reported germ line BAP1 mutations, which were all predicted to result in truncated protein, analysis of the potential effects of the nucleotide change on splicing using the information theory methodology of; https://splice.uwo.ca/) suggested that the variant creates a strong cryptic splice donor site.	('variant', 'Var', (331, 338))	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('leucine', 'Chemical', 'MESH:D007930', (21, 28))	('cryptic splice donor site', 'MPA', (356, 381))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('valine', 'Chemical', 'MESH:D014633', (32, 38))	('leucine', 'Var', (21, 28))	('BAP1', 'Gene', '8314', (99, 103))	('splicing', 'biological_process', 'GO:0045292', ('234', '242'))
177406	22889334	The predicted incorrectly spliced mRNA would be missing 22 bp from the end of exon 13 and would result in a frameshift and truncation 121 amino acids in advance of the normal stop codon (p.Leu570fs*40).	('p.Leu570fs*40', 'Mutation', 'p.L570fsX40', (187, 200))	('frameshift', 'Var', (108, 118))	('truncation', 'MPA', (123, 133))	('p.Leu570fs*40', 'Var', (187, 200))	('result in', 'Reg', (96, 105))
177407	22889334	The c.1708C>G mutation was present in all UMM (III-1, IV-2, and III-8) and CMM (IV-3) cases, the patient with paraganglioma (III-3), the case with both breast cancer and unconfirmed mesothelioma (II-4), the individual with both MFH and a suspected mesothelioma diagnosis (III-12), the case with pulmonary adenocarcinoma (II-1), the unaffected members who volunteered for presymptomatic testing (II-6, III-5, and IV-5), but not in the patient with prolactinoma (IV-4).	('paraganglioma', 'Disease', 'MESH:D010235', (110, 123))	('patient', 'Species', '9606', (97, 104))	('prolactinoma', 'Phenotype', 'HP:0040278', (447, 459))	('c.1708C>G', 'Var', (4, 13))	('mesothelioma', 'Disease', (248, 260))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (248, 260))	('prolactinoma', 'Disease', (447, 459))	('mesothelioma', 'Disease', (182, 194))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('prolactinoma', 'Disease', 'MESH:D015175', (447, 459))	('patient', 'Species', '9606', (434, 441))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (295, 319))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (295, 319))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('pulmonary adenocarcinoma', 'Disease', (295, 319))	('paraganglioma', 'Disease', (110, 123))	('c.1708C>G', 'Mutation', 'c.1708C>G', (4, 13))
177408	22889334	We next performed RT-PCR analysis to evaluate whether aberrant splicing of the BAP1 transcript occurs precisely as predicted in carriers of the c.1708C>G mutation.	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('c.1708C>G', 'Var', (144, 153))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))	('c.1708C>G', 'Mutation', 'c.1708C>G', (144, 153))
177411	22889334	As predicted, blood from individuals harboring the c.1708C>G variant yields both the 124-bp product as well as a second band 22 bp shorter, suggesting that the cryptic splice donor causes aberrant splicing.	('c.1708C>G', 'Var', (51, 60))	('c.1708C>G', 'Mutation', 'c.1708C>G', (51, 60))	('causes', 'Reg', (181, 187))	('splicing', 'biological_process', 'GO:0045292', ('197', '205'))	('splicing', 'MPA', (197, 205))
177412	22889334	Sequencing of the correctly spliced 124-bp product from c.1708C>G heterozygous individuals indicated no detectable trace of the c.1708C>G allele, suggesting that the majority of transcript from the mutant allele is improperly spliced (Fig.	('c.1708C>G', 'Var', (128, 137))	('c.1708C>G', 'Mutation', 'c.1708C>G', (56, 65))	('c.1708C>G', 'Var', (56, 65))	('c.1708C>G', 'Mutation', 'c.1708C>G', (128, 137))
177415	22889334	Another UMM case (III-1) displayed monosomy of chromosome 3, but the DNA was of insufficient quantity to genotype c.1708C>G.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('c.1708C>G', 'Mutation', 'c.1708C>G', (114, 123))	('c.1708C>G', 'Var', (114, 123))	('monosomy', 'MPA', (35, 43))
177416	22889334	BAP1 immunohistochemistry was performed on available archival tumor tissues from carriers of this germ line BAP1 mutation but was not successful.	('mutation', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (108, 112))	('tumor', 'Disease', (62, 67))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
177418	22889334	Of the eight reported multi-cancer families harboring germ line inactivating BAP1 mutations, including the family reported here, three have both UMM and mesothelioma (or suspected mesothelioma).	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('multi-cancer', 'Disease', (22, 34))	('multi-cancer', 'Disease', 'MESH:D009369', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('mesothelioma', 'Disease', (180, 192))	('mesothelioma', 'Disease', (153, 165))	('BAP1', 'Gene', (77, 81))	('UMM', 'Disease', (145, 148))
177420	22889334	Notably, we identified a patient with paraganglioma carrying a germ line BAP1 mutation and showed that the WT BAP1 allele was lost somatically.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (110, 114))	('mutation', 'Var', (78, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (38, 51))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', (110, 114))	('paraganglioma', 'Disease', (38, 51))	('patient', 'Species', '9606', (25, 32))	('paraganglioma', 'Disease', 'MESH:D010235', (38, 51))
177422	22889334	We suggest that BAP1 is truly a broad-spectrum tumor suppressor gene and that multi-cancer families and cases of apparently sporadic paragangliomas warrant screening for germ line BAP1 mutations.	('paragangliomas', 'Disease', (133, 147))	('paragangliomas', 'Disease', 'MESH:D010235', (133, 147))	('tumor', 'Disease', (47, 52))	('multi-cancer', 'Disease', (78, 90))	('paragangliomas', 'Phenotype', 'HP:0002668', (133, 147))	('BAP1', 'Gene', '8314', (180, 184))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('BAP1', 'Gene', '8314', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (180, 184))	('mutations', 'Var', (185, 194))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('paraganglioma', 'Phenotype', 'HP:0002668', (133, 146))	('BAP1', 'Gene', (16, 20))	('multi-cancer', 'Disease', 'MESH:D009369', (78, 90))
177425	22889334	Germ line BAP1 mutations have recently been identified in a few families with melanoma and mesothelioma.	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma and mesothelioma', 'Disease', 'MESH:D008654', (78, 103))	('identified', 'Reg', (44, 54))	('BAP1', 'Gene', '8314', (10, 14))
177426	22889334	We report an apparent missense mutation of BAP1 resulting in aberrant splicing and a truncating frameshift in a family with melanoma, suspected mesothelioma, and paraganglioma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('BAP1', 'Gene', (43, 47))	('melanoma', 'Disease', (124, 132))	('paraganglioma', 'Disease', 'MESH:D010235', (162, 175))	('mesothelioma', 'Disease', (144, 156))	('resulting in', 'Reg', (48, 60))	('BAP1', 'Gene', '8314', (43, 47))	('aberrant splicing', 'MPA', (61, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('truncating', 'MPA', (85, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('missense mutation', 'Var', (22, 39))	('splicing', 'biological_process', 'GO:0045292', ('70', '78'))	('paraganglioma', 'Disease', (162, 175))
177541	30678439	An ICC study of fine needle aspiration of a liver tumor showed Hep Par-1 positivity combined with Ber-EP4 negativity was exclusively observed in hepatocellular carcinoma (Onofre et al., 2007).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('Hep', 'CellLine', 'CVCL:1906', (63, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('liver tumor', 'Disease', 'MESH:D008113', (44, 55))	('observed', 'Reg', (133, 141))	('liver tumor', 'Phenotype', 'HP:0002896', (44, 55))	('liver tumor', 'Disease', (44, 55))	('positivity', 'Var', (73, 83))	('Par-1', 'Gene', '145624', (67, 72))	('Ber', 'biological_process', 'GO:0006284', ('98', '101'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Par-1', 'Gene', (67, 72))	('aspiration', 'Phenotype', 'HP:0002835', (28, 38))
177641	30370398	We focused on African-Americans because previous work demonstrated that tumor mesothelin positivity was significantly associated with triple-negative breast cancer (the subtype most common among African-American women) and poor clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mesothelin', 'Gene', '10232', (78, 88))	('positivity', 'Var', (89, 99))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('tumor', 'Disease', (72, 77))	('breast cancer', 'Disease', (150, 163))	('women', 'Species', '9606', (212, 217))	('mesothelin', 'Gene', (78, 88))	('associated', 'Reg', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
177644	30370398	Patients with high MPF at the time of their diagnosis had a worse outcome than patients with low levels (Fig.	('MPF', 'Gene', (19, 22))	('high', 'Var', (14, 18))	('MPF', 'Gene', '10232', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (79, 87))
177816	29699512	Generally, cells derived from epithelioid and biphasic MM are characterized by higher basal CR expression levels than cells derived from sarcomatoid MM, in particular ZL34 and SPC111 cells, the latter with very low basal CR expression levels.	('SPC', 'molecular_function', 'GO:0009004', ('176', '179'))	('biphasic MM', 'Var', (46, 57))	('sarcomatoid MM', 'Disease', 'MESH:C538614', (137, 151))	('sarcomatoid MM', 'Disease', (137, 151))	('epithelioid', 'Var', (30, 41))	('higher', 'PosReg', (79, 85))	('basal CR expression levels', 'MPA', (86, 112))
177822	29699512	The three changes (1 point mutation (A/T), 2 deletions of either 1 or 2 nucleotides) were present in the sequences of all clones derived from both cell lines, ZL55 and Met-5A, excluding this being PCR artifacts (Additional file 1: Figure S2).	('deletions', 'Var', (45, 54))	('ZL5', 'Gene', (159, 162))	('ZL5', 'Gene', '106633808', (159, 162))
177861	29699512	In MeT-5A, ZL55, ZL5, SPC212, ZL34 and MSTO-211H cells CR levels increased (as also shown in Fig.	('increased', 'PosReg', (65, 74))	('ZL5', 'Gene', (11, 14))	('SPC212', 'Var', (22, 28))	('MSTO-211H', 'CellLine', 'CVCL:1430', (39, 48))	('SPC', 'molecular_function', 'GO:0009004', ('22', '25'))	('ZL5', 'Gene', '106633808', (11, 14))	('SPC212', 'CellLine', 'CVCL:D312', (22, 28))	('ZL5', 'Gene', (17, 20))	('ZL5', 'Gene', '106633808', (17, 20))
177864	29699512	Thus, to directly investigate whether septin 7 acts as a negative transcriptional regulator of CR expression, septin 7 levels were increased by lentiviral infection of MSTO-211H cells with LV-SEPT7.	('increased', 'PosReg', (131, 140))	('SEPT7', 'Gene', (192, 197))	('MSTO-211H', 'CellLine', 'CVCL:1430', (168, 177))	('lentiviral', 'Var', (144, 154))	('SEPT7', 'Gene', '989', (192, 197))	('septin 7 levels', 'MPA', (110, 125))
177874	29699512	Expression patterns for CR and septin 7 showed an almost complete overlap in the mesenchyme of E10.5 mice (Fig.	('septin 7', 'Gene', (31, 39))	('mice', 'Species', '10090', (101, 105))	('E10.5', 'Var', (95, 100))
177877	29699512	Western blots revealed clearly higher levels of septin 7 in mesothelial cells from CR-/- mice compared to WT animals (Fig.	('higher', 'PosReg', (31, 37))	('mice', 'Species', '10090', (89, 93))	('levels', 'MPA', (38, 44))	('CR-/-', 'Var', (83, 88))
177878	29699512	The expression of SV40 Tag/tag was previously shown to substantially increase the proliferation rate of primary mesothelial cells, both from WT and CR-/- mice.	('SV40 Tag/tag', 'Var', (18, 30))	('increase', 'PosReg', (69, 77))	('mice', 'Species', '10090', (154, 158))	('proliferation rate of primary mesothelial cells', 'CPA', (82, 129))	('rat', 'Species', '10116', (89, 92))	('rat', 'Species', '10116', (96, 99))
177907	29699512	lower CR levels are a poor prognostic factor, also deregulated septin expression has been linked to tumor development/growth.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('septin', 'Protein', (63, 69))	('linked', 'Reg', (90, 96))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('expression', 'MPA', (70, 80))	('lower CR levels', 'MPA', (0, 15))	('deregulated', 'Var', (51, 62))
177927	29610630	The patients were recruited from inpatient clinics if they met the following criteria: (1) age >18 years, (2) presence of unilateral pleural effusion of unknown origin after less invasive means of diagnosis, and (3) presence of advanced epidermal growth factor receptor (EGFR) mutation positive nonsmall cell lung cancer (NSCLC), (4) clinical resistance to an EGFR tyrosine kinase inhibitor (TKI) (gefitinib, erlotinib, or afatinib), and (5) undergoing a repeat biopsy for tumor genotyping as part of their routine clinical care.	('epidermal growth factor receptor', 'Gene', (237, 269))	('unilateral pleural effusion', 'Disease', 'MESH:D010996', (122, 149))	('epidermal growth factor receptor', 'Gene', '1956', (237, 269))	('unilateral pleural effusion', 'Disease', (122, 149))	('NSCLC', 'Disease', 'MESH:D002289', (322, 327))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('237', '260'))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('EGFR', 'Gene', (360, 364))	('EGFR', 'Gene', (271, 275))	('NSCLC', 'Disease', (322, 327))	('nonsmall cell lung cancer', 'Disease', (295, 320))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (295, 320))	('EGFR', 'molecular_function', 'GO:0005006', ('271', '275'))	('EGFR', 'molecular_function', 'GO:0005006', ('360', '364'))	('NSCLC', 'Phenotype', 'HP:0030358', (322, 327))	('lung cancer', 'Phenotype', 'HP:0100526', (309, 320))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('pleural effusion', 'Phenotype', 'HP:0002202', (133, 149))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('374', '390'))	('EGFR', 'Gene', '1956', (360, 364))	('EGFR', 'Gene', '1956', (271, 275))	('cancer', 'Disease', (314, 320))	('mutation', 'Var', (277, 285))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (295, 320))
177951	29228566	Six patients with pleural mesothelioma underwent [68Ga]Pentixafor-PET/CT.	('Pentixafor', 'Chemical', 'MESH:C000597686', (55, 65))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (18, 38))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (18, 38))	('patients', 'Species', '9606', (4, 12))	('pleural mesothelioma', 'Disease', (18, 38))	('[68Ga]', 'Var', (49, 55))
177954	29228566	Whereas [18F]FDG-PET depicted active lesions in all patients, [68Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [68Ga]Pentixafor-positive lesions.	('patients', 'Species', '9606', (145, 153))	('[68Ga]Pentixafor-PET/CT', 'Var', (62, 85))	('[18F]FDG-PET', 'Var', (8, 20))	('Pentixafor', 'Chemical', 'MESH:C000597686', (170, 180))	('physiologic tracer distribution', 'MPA', (95, 126))	('Pentixafor', 'Chemical', 'MESH:C000597686', (68, 78))	('FDG', 'Chemical', 'MESH:D019788', (13, 16))	('patients', 'Species', '9606', (52, 60))
177963	29228566	Recently, Wester and co-workers developed [68Ga]Pentixafor ([68Ga]CPCR4.2), a cyclic pentapeptide that enables sensitive and high-contrast imaging of human CXCR4 receptor expression in vivo .	('human', 'Species', '9606', (150, 155))	('CXCR4', 'Gene', '7852', (156, 161))	('CXCR4', 'molecular_function', 'GO:0038147', ('156', '161'))	('CXCR4', 'Gene', (156, 161))	('[68Ga]', 'Var', (42, 48))	('Pentixafor', 'Chemical', 'MESH:C000597686', (48, 58))
178011	29228566	[68Ga]Pentixafor was administered in compliance with The German Medicinal Products Act, AMG  13 2b, and in accordance with the responsible regulatory body (Regierung von Oberfranken).	('Pentixafor', 'Chemical', 'MESH:C000597686', (6, 16))	('Regierung von Oberfranken', 'Disease', (156, 181))	('[68Ga', 'Var', (0, 5))	('Regierung von Oberfranken', 'Disease', 'MESH:D014842', (156, 181))	('AMG', 'Gene', (88, 91))	('AMG', 'Gene', '265', (88, 91))
178113	27822122	We also established that surgery is associated with improved OS, and that chemotherapy modified the effects of surgery.	('surgery', 'Var', (25, 32))	('improved', 'PosReg', (52, 60))	('OS', 'Chemical', '-', (61, 63))
178148	32133285	The first demonstration of benefit from systemic therapy of mesothelioma was in 2003, with the EMPHACIS study showing a modest improvement in overall survival (OS) for patients receiving cisplatin/pemetrexed, over cisplatin alone.	('pemetrexed', 'Chemical', 'MESH:D000068437', (197, 207))	('overall survival', 'MPA', (142, 158))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('cisplatin/pemetrexed', 'Var', (187, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('OS', 'Chemical', '-', (160, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('patients', 'Species', '9606', (168, 176))	('mesothelioma', 'Disease', (60, 72))
178161	32133285	VEGF-A exists as more than 20 splice isoforms, ranging from 121 to 206 kDa molecular weight; the VEFG165 isoform is the most abundant tissue variant.	('VEFG165', 'Var', (97, 104))	('VEGF-A', 'Gene', (0, 6))	('VEGF-A', 'Gene', '7422', (0, 6))
178176	32133285	Preclinical inhibition of VEGF signaling by MAb also decreased tumor vascular permeability in human xenografts implanted into mice.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inhibition', 'Var', (12, 22))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('human', 'Species', '9606', (94, 99))	('inhibition of VEGF signaling', 'biological_process', 'GO:1900747', ('12', '40'))	('decreased', 'NegReg', (53, 62))	('VEGF', 'Protein', (26, 30))
178189	32133285	An increased risk of arterial thromboembolism is also described with anti-angiogenesis therapy while the risk of venous thromboembolism remains controversial with a meta-analysis suggesting no statistically significant increase for bevacizumab compared with control groups (10.9 vs. 9.8%, p = 0,13).	('thromboembolism', 'Disease', (120, 135))	('bevacizumab', 'Chemical', 'MESH:D000068258', (232, 243))	('venous thromboembolism', 'Disease', (113, 135))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('anti-angiogenesis', 'Var', (69, 86))	('thromboembolism', 'Disease', 'MESH:D013923', (30, 45))	('thromboembolism', 'Phenotype', 'HP:0001907', (30, 45))	('thromboembolism', 'Disease', 'MESH:D013923', (120, 135))	('venous thromboembolism', 'Disease', 'MESH:D054556', (113, 135))	('thromboembolism', 'Disease', (30, 45))	('thromboembolism', 'Phenotype', 'HP:0001907', (120, 135))
178282	32133285	Toxicity was also problematic, with the addition of cediranib associated with more anorexia, dehydration, diarrhea, and weight loss.	('anorexia', 'Disease', 'MESH:D000855', (83, 91))	('diarrhea', 'Phenotype', 'HP:0002014', (106, 114))	('anorexia', 'Phenotype', 'HP:0002039', (83, 91))	('dehydration', 'Disease', (93, 104))	('weight loss', 'Disease', (120, 131))	('diarrhea', 'Disease', (106, 114))	('anorexia', 'Disease', (83, 91))	('cediranib', 'Chemical', 'MESH:C500926', (52, 61))	('weight loss', 'Phenotype', 'HP:0001824', (120, 131))	('diarrhea', 'Disease', 'MESH:D003967', (106, 114))	('cediranib', 'Var', (52, 61))	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('addition', 'Var', (40, 48))	('dehydration', 'Phenotype', 'HP:0001944', (93, 104))	('weight loss', 'Disease', 'MESH:D015431', (120, 131))	('dehydration', 'Disease', 'MESH:D003681', (93, 104))
178296	32133285	The prognostic analysis based on VEGF assessed as a continuous variable showed that high VEGF concentrations were associated with worse PFS and OS.	('VEGF', 'Protein', (89, 93))	('high', 'Var', (84, 88))	('concentrations', 'MPA', (94, 108))	('OS', 'Chemical', '-', (144, 146))	('PFS', 'Disease', (136, 139))
178297	32133285	This was confirmed by bootstrap resampling, a smart statistical method for internal validation of biomarkers, VEGF significantly correlating with worse PFS in 891 (89%) of 1,000 theoretical samples generated by bootstrapping, and with OS in 979 (98%) of 1,000 bootstrapped samples, with high optimism corrected concordance index of 0.64 for PFS and 0.65 for OS.	('VEGF', 'Var', (110, 114))	('OS', 'Chemical', '-', (235, 237))	('OS', 'Chemical', '-', (358, 360))	('PFS', 'Disease', (152, 155))
178303	32133285	To summarize what is to date the largest prospective study of serum VEGF in MPM patients, high serum VEGF concentration was clearly a worse prognostic biomarker.	('high', 'Var', (90, 94))	('MPM', 'Disease', (76, 79))	('patients', 'Species', '9606', (80, 88))	('MPM', 'Disease', 'MESH:C562839', (76, 79))
178306	32133285	However, no analysis of the effect of BAP1 mutations is available in this study and the influence of such molecular alterations on sensitivity to bevacizumab-containing triplet remains unknown.	('bevacizumab', 'Chemical', 'MESH:D000068258', (146, 157))	('BAP1', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', '8314', (38, 42))
178385	31905913	In the case of malignant mesothelioma, asbestos is overwhelmingly the singular identifiable causal factor, with only rare cases related to other factors such as erionite or fluoro-edenite fiber inhalation, ionizing radiation (sometimes in association with asbestos exposure), and innate susceptibility factors such as germline mutations affecting the BAP1 gene.	('germline mutations', 'Var', (318, 336))	('fluoro-edenite', 'Chemical', 'MESH:C492470', (173, 187))	('malignant mesothelioma', 'Disease', (15, 37))	('erionite', 'Chemical', 'MESH:C083174', (161, 169))	('BAP1', 'Gene', (351, 355))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (15, 37))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (15, 37))
178405	31905913	paper, Balmes commented that we 'know' that (i) 'asbestos exposure alone is capable of causing lung cancer'; (ii) asbestos and smoking together are associated with at least an additive increased risk of lung cancer; (iii) the presence of asbestosis further increases the risk in both smokers and nonsmokers; and (iv) smoking cessation substantially decreases the lung cancer risk associated with asbestos exposure [italicized text in the original editorial]).	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Disease', (363, 374))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (363, 374))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))	('increases', 'PosReg', (257, 266))	('asbestosis', 'Disease', 'MESH:D001195', (238, 248))	('asbestosis', 'Disease', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Disease', (203, 214))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('lung cancer', 'Disease', 'MESH:D008175', (363, 374))	('presence', 'Var', (226, 234))	('decreases', 'NegReg', (349, 358))	('men', 'Species', '9606', (17, 20))
178411	31905913	However, this criticism is weakened by two factors: (i) the limit p <= 0.05 is an arbitrary statistical convention, and reality often lacks sharp boundaries of this type; and (ii) what is important in this study is the trend from a low to a higher ORLCA with transition from an intermediate fiber count (1.0-5.0); the clinical asbestosis cases were in the heaviest exposure group and that the mild histological fibrosis cases were in the intermediate exposure group:the ORLCAs then become 2.85 and 1.8 respectively, as consistent as possible with the age-adjusted ORLCAs of 2.8 and 1.5 in the original paper and trend testing then yields Chi2 (1 d.f.)	('asbestosis', 'Disease', (327, 337))	('fibrosis', 'Disease', 'MESH:D005355', (411, 419))	('fibrosis', 'Disease', (411, 419))	('Chi2', 'Var', (638, 642))	('asbestosis', 'Disease', 'MESH:D001195', (327, 337))
178438	31905913	found k-ras mutations more frequently in asbestos-exposed lung adenocarcinomas than carcinomas in nonexposed lung; Kettunen et al.	('lung adenocarcinomas than carcinomas', 'Disease', (58, 94))	('k-ras', 'Gene', (6, 11))	('lung adenocarcinomas than carcinomas', 'Disease', 'MESH:C538231', (58, 94))	('k-ras', 'Gene', '3845', (6, 11))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (58, 78))	('mutations', 'Var', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('frequently', 'Reg', (27, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
178439	31905913	found a statistically significant greater frequency of chromosome position 2p16 loss in lung cancers (all cell types) from asbestos exposure compared to nonexposure carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('carcinomas', 'Disease', 'MESH:D002277', (165, 175))	('lung cancers', 'Disease', 'MESH:D008175', (88, 100))	('loss', 'NegReg', (80, 84))	('carcinomas', 'Disease', (165, 175))	('lung cancers', 'Phenotype', 'HP:0100526', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung cancers', 'Disease', (88, 100))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('chromosome', 'Var', (55, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
178451	31905913	Tobacco smoke can act at early stages, inducing genetic alterations, DNA adducts, and mutations in genes critical to cancer formation.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('rat', 'Species', '10116', (60, 63))	('Tobacco', 'Species', '4097', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('genetic alterations', 'MPA', (48, 67))	('DNA adducts', 'MPA', (69, 80))	('cancer', 'Disease', (117, 123))	('inducing', 'Reg', (39, 47))
178453	31905913	It is likely that the chemical basis of tobacco-induced mutations is the oxidation of DNA groups by free radicals.	('tobacco', 'Species', '4097', (40, 47))	('mutations', 'Var', (56, 65))	('oxidation', 'MPA', (73, 82))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))
178472	31905913	Although the number of tumors or the frequency of tumor-bearing animals was higher in the chrysotile + B[a]P than the amosite + B[a]P group, the differences were not significant.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('higher', 'PosReg', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (50, 55))	('chrysotile', 'Var', (90, 100))
178487	31905913	At this stage, this is early and preliminary work, but it is conceivable that in future, mutation signatures associated with different etiologies of lung tumors may be able to verify the mutagenic effect of smoking and/or asbestos exposure in the in causal pathways in the tumor tissue.	('tumor', 'Disease', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('mutation', 'Var', (89, 97))	('lung tumors', 'Disease', 'MESH:D008175', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('lung tumors', 'Phenotype', 'HP:0100526', (149, 160))	('lung tumors', 'Disease', (149, 160))
178489	31905913	investigated k-ras codon 12 mutations among 84 male patients with adenocarcinoma of lung for whom a work history was available, as well as a chest radiograph for all those who had a history of occupational exposure to asbestos.	('adenocarcinoma of lung', 'Disease', (66, 88))	('k-ras', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma of lung', 'Disease', 'MESH:C538231', (66, 88))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (52, 60))	('k-ras', 'Gene', '3845', (13, 18))
178490	31905913	K-ras mutations were more prevalent in patients with a history of occupational asbestos exposure (crude OR = 4.8; 95% CI = 1.5 - 15.4) in comparison to those without asbestos exposure.	('patients', 'Species', '9606', (39, 47))	('prevalent', 'Reg', (26, 35))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('mutations', 'Var', (6, 15))
178492	31905913	An index score that weighted for both the dates of exposure and estimated exposure intensity indicated that subjects with k-ras mutations had significantly greater asbestos exposures than those without such mutations (p < 0.01).	('k-ras', 'Gene', '3845', (122, 127))	('mutations', 'Var', (128, 137))	('greater', 'PosReg', (156, 163))	('asbestos exposures', 'MPA', (164, 182))	('k-ras', 'Gene', (122, 127))
178493	31905913	A supra-additive effect of smoking and asbestos exposure on the percentage of k-ras mutations was shown (Figure 2 in the original).	('mutations', 'Var', (84, 93))	('k-ras', 'Gene', (78, 83))	('k-ras', 'Gene', '3845', (78, 83))
178496	31905913	The findings were considered to suggest 'that asbestos exposure increases the likelihood of mutation at k-ras codon 12 and that this process occurs independently of the induction of interstitial fibrosis.'	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (182, 203))	('mutation', 'Var', (92, 100))	('k-ras', 'Gene', (104, 109))	('k-ras', 'Gene', '3845', (104, 109))	('interstitial fibrosis', 'Disease', (182, 203))	('interstitial fibrosis', 'Disease', 'MESH:D005355', (182, 203))
178497	31905913	In an earlier study, the same group of researchers also found that asbestos exposure (p < 0.01) and a duration of more than 50 years of smoking (p < 0.01) were significantly associated with exon deletion from the fragile histidine triad (FHIT) gene.	('FHIT', 'Gene', (238, 242))	('associated', 'Reg', (174, 184))	('exon deletion', 'Var', (190, 203))	('triad', 'cellular_component', 'GO:0030315', ('231', '236'))	('histidine', 'Chemical', 'MESH:C115717', (221, 230))	('rat', 'Species', '10116', (104, 107))
178598	31766522	For that reason, the investigation of the functional roles of ion channels in cancer development may identify novel approaches for determining tumour prognosis and the discovery that alteration in key Ca2+-transport molecules could underlie pathological changes, might provide promising targets for treatment of tumours.	('tumours', 'Phenotype', 'HP:0002664', (312, 319))	('ion channels', 'molecular_function', 'GO:0022831', ('62', '74'))	('tumour', 'Phenotype', 'HP:0002664', (312, 318))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (312, 318))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumours', 'Disease', 'MESH:D009369', (312, 319))	('transport', 'biological_process', 'GO:0006810', ('206', '215'))	('tumours', 'Disease', (312, 319))	('tumour', 'Disease', (312, 318))	('tumour', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('alteration', 'Var', (183, 193))	('Ca2+-transport molecules', 'MPA', (201, 225))
178611	31766522	In fact, the first direct suggestions that ion channels play a crucial role in carcinogenesis came in the late 1980s, with studies describing that brain cancer cells show uncommon configurations of ion channel functional expression and that blockade by pharmacological inhibitions of some channels can hinder the growth of tumour cells.	('brain cancer', 'Phenotype', 'HP:0030692', (147, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('tumour', 'Phenotype', 'HP:0002664', (323, 329))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hinder', 'NegReg', (302, 308))	('blockade', 'Var', (241, 249))	('ion channels', 'molecular_function', 'GO:0022831', ('43', '55'))	('carcinogenesis', 'Disease', (79, 93))	('growth of tumour cells', 'CPA', (313, 335))
178613	31766522	So, due to the increased knowledge of ion pumps and channels involved in neoplasm growth, tumours can be categorised as a channelopathy, or a disease induced by the disturbed function of ion channels, frequently due to channel expression deregulation (transcriptional channelopathy) or other alterations resultant in transformed function.	('function', 'MPA', (175, 183))	('channelopathy', 'Disease', 'MESH:D053447', (268, 281))	('channelopathy', 'Disease', (122, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (73, 81))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('deregulation', 'Var', (238, 250))	('ion channels', 'molecular_function', 'GO:0022831', ('187', '199'))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('channelopathy', 'Disease', 'MESH:D053447', (122, 135))	('disturbed', 'Var', (165, 174))	('channelopathy', 'Disease', (268, 281))	('neoplasm growth, tumours', 'Disease', 'MESH:D009369', (73, 97))
178619	31766522	Similarly, mutations as well as transformed expression levels of Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA) isoforms have been involved in many tumours, including lung, prostate, and colon cancers.	('mutations', 'Var', (11, 20))	('tumours', 'Disease', (152, 159))	('prostate', 'Disease', (177, 185))	('SERCA', 'Gene', (109, 114))	('SERCA', 'Gene', '489', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('colon cancers', 'Disease', (191, 204))	('colon cancers', 'Phenotype', 'HP:0003003', (191, 204))	('colon cancers', 'Disease', 'MESH:D015179', (191, 204))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('involved', 'Reg', (135, 143))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('lung', 'Disease', (171, 175))
178622	31766522	In particular, they showed the minor expression of miR-17-5p and miR-20a-5p in epithelioid histology.	('miR-17-5p', 'Gene', (51, 60))	('miR-17-5p', 'Gene', '406952', (51, 60))	('miR-20a-5p', 'Var', (65, 75))
178623	31766522	Among the predicted targets of these differentially expressed microRNA families, they identified KCa1.1, a Ca2+-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p.	('KCNMA1', 'Gene', '3778', (171, 177))	('KCa1.1', 'Gene', (97, 103))	('KCNMA1', 'Gene', (171, 177))	('KCa1.1', 'Gene', '3778', (97, 103))	('potassium', 'Chemical', 'MESH:D011188', (122, 131))	('miR-17-5p', 'Var', (199, 208))
178640	31766522	Mutations and deletions determining BAP1 loss have been described in several tumors including lung, breast, melanoma, and mesothelioma.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('mesothelioma', 'Disease', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('breast', 'Disease', (100, 106))	('lung', 'Disease', (94, 98))	('deletions', 'Var', (14, 23))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('BAP1', 'Gene', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('loss', 'NegReg', (41, 45))	('melanoma', 'Disease', (108, 116))
178641	31766522	People with one inactive BAP1 allele (BAP1 tumour predisposition syndrome) have a significantly higher predisposition to cancer, and somatic BAP1 point mutations were present in up to 60% of sporadic mesothelioma.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (191, 212))	('tumour predisposition syndrome', 'Disease', 'MESH:D020022', (43, 73))	('BAP1', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumour predisposition syndrome', 'Disease', (43, 73))	('BAP1', 'Gene', (141, 145))	('People', 'Species', '9606', (0, 6))	('sporadic mesothelioma', 'Disease', 'MESH:D008654', (191, 212))	('sporadic mesothelioma', 'Disease', (191, 212))	('point mutations', 'Var', (146, 161))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (121, 127))
178645	31766522	Therefore, other observations are strongly required to assess the role of BAP1 on mesothelioma biology and with particular attention to drugs used for this cancer such as pemetrexed and platinum-based treatments, as well as to avoid second line treatment with compounds not effective in BAP1 mutant patients.	('mutant', 'Var', (292, 298))	('mesothelioma', 'Disease', (82, 94))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BAP1', 'Gene', (287, 291))
178654	31766522	They also found a reduced level of the Mitochondrial Calcium Uniporter (MCU), highlighting that the alteration of mitochondrial Ca2+ uptake is crucial for the unresponsiveness of mesothelioma cells to apoptotic stimuli, and silencing MCU by RNAi or NaV (sodium orthovanadate) treatment to restore the Ca2+ homeostasis and mesothelioma sensitivity to apoptotic stimuli.	('Ca2+ homeostasis', 'MPA', (301, 317))	('sodium orthovanadate', 'Chemical', 'MESH:D014638', (254, 274))	('homeostasis', 'biological_process', 'GO:0042592', ('306', '317'))	('MCU', 'Gene', (234, 237))	('RNAi', 'biological_process', 'GO:0016246', ('241', '245'))	('MCU', 'Gene', '90550', (234, 237))	('Mitochondrial Calcium Uniporter', 'MPA', (39, 70))	('MCU', 'Gene', (72, 75))	('uptake', 'biological_process', 'GO:0098657', ('133', '139'))	('restore', 'PosReg', (289, 296))	('MCU', 'Gene', '90550', (72, 75))	('uptake', 'biological_process', 'GO:0098739', ('133', '139'))	('NaV', 'Chemical', 'MESH:D012964', (249, 252))	('silencing', 'Var', (224, 233))
178668	29089859	An example is the insertion of the herpes simplex virus thymidine kinase (HSV-TK) gene into cancer cells which are consequently induced to "commit suicide" when in the presence of otherwise non-toxic doses of ganciclovir (GCV).	('herpes simplex', 'Phenotype', 'HP:0012302', (35, 49))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('HSV-TK', 'Gene', (74, 80))	('GCV', 'Chemical', 'MESH:D015774', (222, 225))	('ganciclovir', 'Chemical', 'MESH:D015774', (209, 220))	('insertion', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('induced', 'Reg', (128, 135))
178724	29089859	The cytospin histological analysis of the irradiated PA-STK cells suggests that these cells die by pyknosis, a form of necrosis (Fig.	('necrosis', 'biological_process', 'GO:0008220', ('119', '127'))	('necrosis', 'Disease', 'MESH:D009336', (119, 127))	('STK', 'molecular_function', 'GO:0050359', ('56', '59'))	('pyknosis', 'Var', (99, 107))	('necrosis', 'biological_process', 'GO:0001906', ('119', '127'))	('STK', 'Gene', (56, 59))	('necrosis', 'biological_process', 'GO:0070265', ('119', '127'))	('PA', 'Chemical', 'MESH:D011478', (53, 55))	('STK', 'Gene', '19882', (56, 59))	('pyknosis', 'biological_process', 'GO:0030263', ('99', '107'))	('necrosis', 'Disease', (119, 127))	('necrosis', 'biological_process', 'GO:0008219', ('119', '127'))	('necrosis', 'biological_process', 'GO:0019835', ('119', '127'))
178764	29089859	It is therefore important to establish whether and when the irradiated gene-modified tumor cells would die after irradiation.	('gene-modified', 'Var', (71, 84))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
178799	28545562	Raf kinases (CRAF and BRAF) and the V600E BRAF mutant, along the MAPK pathway, and cell surface RTKs (VEGFR-2 and VEGFR-3, PDGFR-beta, c-KIT, RET, FLT-3, and, with slightly lower potency, FGFR1).	('BRAF', 'Gene', '673', (42, 46))	('FLT-3', 'Gene', '2322', (147, 152))	('FGFR1', 'Gene', '2260', (188, 193))	('BRAF', 'Gene', (42, 46))	('CRAF', 'Gene', '5894', (13, 17))	('CRAF', 'molecular_function', 'GO:0004709', ('13', '17'))	('PDGFR-beta', 'Gene', (123, 133))	('VEGFR-2', 'Gene', (102, 109))	('RET', 'Gene', '5979', (142, 145))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('Raf', 'Gene', (0, 3))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('FLT-3', 'Gene', (147, 152))	('FGFR1', 'Gene', (188, 193))	('BRAF', 'Gene', '673', (22, 26))	('VEGFR-3', 'Gene', '2324', (114, 121))	('BRAF', 'Gene', (22, 26))	('cell surface', 'cellular_component', 'GO:0009986', ('83', '95'))	('RET', 'Gene', (142, 145))	('V600E', 'Var', (36, 41))	('KIT', 'molecular_function', 'GO:0005020', ('137', '140'))	('Raf', 'Gene', '22882', (0, 3))	('PDGFR-beta', 'Gene', '5159', (123, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('188', '192'))	('c-KIT', 'Gene', (135, 140))	('c-KIT', 'Gene', '3815', (135, 140))	('VEGFR-3', 'Gene', (114, 121))	('VEGFR-2', 'Gene', '3791', (102, 109))	('MAPK', 'Pathway', (65, 69))	('CRAF', 'Gene', (13, 17))
178808	28545562	Sorafenib (US Biological) and AZ628 and PD173074 (Sigma-Aldrich) were dissolved in DMSO at 10 mM concentration and stored at -20  C. Drugs were diluted with culture medium to the experimental concentrations, with a maximum 0.1% (v/v) DMSO final concentration.	('PD173074', 'Chemical', 'MESH:C115711', (40, 48))	('DMSO', 'Chemical', 'MESH:D004121', (234, 238))	('AZ628', 'Var', (30, 35))	('AZ628', 'Chemical', 'MESH:C000592454', (30, 35))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('PD173074', 'Var', (40, 48))
178830	28545562	Blots were probed with the following antibodies: phospho-ERK1/2 (Thr201-Tyr204, #9101), phospho-MEK (Ser217/221, #9121), phospho-Akt (Ser473, #9271) phospho-STAT3 (Ser-727, #9134), Mcl-1 (#5453), phospho-FGFR (Tyr653/654, #3476), and FGFR1 (#9740) from Cell Signaling and alpha-tubulin (#T5168; Sigma-Aldrich).	('Mcl-1', 'Gene', '4170', (181, 186))	('alpha-tubulin', 'Gene', (272, 285))	('Ser217/221', 'Var', (101, 111))	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('STAT3', 'Gene', (157, 162))	('FGFR1', 'Gene', '2260', (234, 239))	('#5453', 'Var', (188, 193))	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('Ser', 'cellular_component', 'GO:0005790', ('164', '167'))	('STAT3', 'Gene', '6774', (157, 162))	('Mcl-1', 'Gene', (181, 186))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('#9740', 'Var', (241, 246))	('alpha-tubulin', 'Gene', '10376', (272, 285))	('FGFR1', 'Gene', (234, 239))	('MEK', 'Gene', '5609', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('204', '208'))	('Akt', 'Gene', (129, 132))	('Signaling', 'biological_process', 'GO:0023052', ('258', '267'))	('Tyr653/654', 'Var', (210, 220))	('Akt', 'Gene', '207', (129, 132))	('MEK', 'Gene', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))
178901	28545562	7e), indicating a constitutive activation of FGFR1 that in the absence of exogenous growth factor was likely dependent on autocrine activation by bFGF spontaneously released by the cells; moreover, dose-response curves revealed that MM1 cells display higher sensitivity to PD173074 (IC50 = 6.12 nM) in agreement with the higher amount of bFGF produced by these cells.	('PD173074', 'Var', (273, 281))	('PD173074', 'Chemical', 'MESH:C115711', (273, 281))	('bFGF', 'Gene', '2247', (146, 150))	('bFGF', 'Gene', '2247', (338, 342))	('higher', 'PosReg', (251, 257))	('sensitivity', 'MPA', (258, 269))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('bFGF', 'Gene', (146, 150))	('bFGF', 'Gene', (338, 342))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', '2260', (45, 50))
178902	28545562	Moreover, the inhibitory activity of PD173074 on MPM TICs was not additive with sorafenib effects (data not shown).	('PD173074', 'Chemical', 'MESH:C115711', (37, 45))	('PD173074', 'Var', (37, 45))	('sorafenib', 'Chemical', 'MESH:D000077157', (80, 89))	('TIC', 'Gene', '23550', (53, 56))	('TIC', 'Gene', (53, 56))	('TIC', 'Phenotype', 'HP:0100033', (53, 56))	('TICs', 'Phenotype', 'HP:0100033', (53, 57))
178904	28545562	PD173074 treatment also prevented activation of FGFR1 downstream MAPK pathway signaling, abolishing phospho-ERK1/2 levels in all the three cultures.	('abolishing', 'NegReg', (89, 99))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('phospho-ERK1/2 levels', 'MPA', (100, 121))	('ERK1', 'molecular_function', 'GO:0004707', ('108', '112'))	('PD173074', 'Var', (0, 8))	('prevented', 'NegReg', (24, 33))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('FGFR1', 'Gene', (48, 53))	('FGFR1', 'Gene', '2260', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('MAPK pathway signaling', 'Pathway', (65, 87))
178905	28545562	In particular, PD173074 was able to block both bFGF-induced and basal/constitutive ERK1/2 phosphorylation in MM1 cells, confirming that PD173074 prevents FGFR1-induced ERK1/2 activation (Fig.	('ERK1', 'molecular_function', 'GO:0004707', ('83', '87'))	('PD173074', 'Chemical', 'MESH:C115711', (15, 23))	('bFGF', 'Gene', (47, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('PD173074', 'Var', (136, 144))	('FGFR1', 'Gene', (154, 159))	('ERK1/2', 'Enzyme', (168, 174))	('PD173074', 'Chemical', 'MESH:C115711', (136, 144))	('activation', 'PosReg', (175, 185))	('ERK1', 'molecular_function', 'GO:0004707', ('168', '172'))	('FGFR', 'molecular_function', 'GO:0005007', ('154', '158'))	('FGFR1', 'Gene', '2260', (154, 159))	('bFGF', 'Gene', '2247', (47, 51))
178907	28545562	Western blot experiments in MM1 cells treated with AZ628 (0.1, 1, and 10 muM) showed a significant and concentration-dependent inhibition of MEK phosphorylation, the direct Raf target (around -60% at 1 and 10 muM) and its downstream substrate ERK1/2 (-49% at 10 muM) after EGF stimulation (Fig.	('AZ628', 'Var', (51, 56))	('EGF', 'Gene', (273, 276))	('muM', 'Gene', (209, 212))	('AZ628', 'Chemical', 'MESH:C000592454', (51, 56))	('muM', 'Gene', '56925', (262, 265))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('ERK1', 'molecular_function', 'GO:0004707', ('243', '247'))	('MEK', 'Gene', (141, 144))	('MEK', 'Gene', '5609', (141, 144))	('muM', 'Gene', '56925', (73, 76))	('EGF', 'molecular_function', 'GO:0005154', ('273', '276'))	('muM', 'Gene', (262, 265))	('muM', 'Gene', (73, 76))	('Raf', 'Gene', '22882', (173, 176))	('EGF', 'Gene', '1950', (273, 276))	('inhibition', 'NegReg', (127, 137))	('muM', 'Gene', '56925', (209, 212))	('Raf', 'Gene', (173, 176))
178908	28545562	Thus, in MM1 cells in which sorafenib fails to suppress the EGF-dependent activation of MEK and ERK1/2, AZ628 efficiently impaired the signaling cascade from Raf to MEK and, consequently, to ERK1/2.	('MEK', 'Gene', '5609', (88, 91))	('EGF', 'Gene', (60, 63))	('AZ628', 'Var', (104, 109))	('AZ628', 'Chemical', 'MESH:C000592454', (104, 109))	('signaling cascade', 'biological_process', 'GO:0007165', ('135', '152'))	('MEK', 'Gene', (165, 168))	('MEK', 'Gene', '5609', (165, 168))	('ERK1', 'molecular_function', 'GO:0004707', ('191', '195'))	('Raf', 'Gene', (158, 161))	('EGF', 'Gene', '1950', (60, 63))	('EGF', 'molecular_function', 'GO:0005154', ('60', '63'))	('signaling cascade', 'MPA', (135, 152))	('impaired', 'NegReg', (122, 130))	('MEK', 'Gene', (88, 91))	('ERK1', 'molecular_function', 'GO:0004707', ('96', '100'))	('Raf', 'Gene', '22882', (158, 161))	('sorafenib', 'Chemical', 'MESH:D000077157', (28, 37))
178909	28545562	Moreover, as expected, the sustained EGF-dependent phosphorylation of MEK and ERK1/2 in the sorafenib-responsive MM4 culture was also significantly suppressed (-70 and -80%, respectively) by exposure to AZ628 (Fig.	('ERK1', 'molecular_function', 'GO:0004707', ('78', '82'))	('MM4', 'CellLine', 'CVCL:S405', (113, 116))	('AZ628', 'Chemical', 'MESH:C000592454', (203, 208))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('EGF', 'Gene', (37, 40))	('EGF', 'Gene', '1950', (37, 40))	('MEK', 'Gene', (70, 73))	('phosphorylation', 'MPA', (51, 66))	('ERK1/2', 'Protein', (78, 84))	('sorafenib', 'Chemical', 'MESH:D000077157', (92, 101))	('MEK', 'Gene', '5609', (70, 73))	('EGF', 'molecular_function', 'GO:0005154', ('37', '40'))	('AZ628', 'Var', (203, 208))	('suppressed', 'NegReg', (148, 158))
178951	28545562	AZ628 significantly inhibited EGF-dependent MEK and ERK1/2 phosphorylation in the sorafenib-responsive MM4 TICs.	('EGF', 'Gene', (30, 33))	('TIC', 'Gene', (107, 110))	('EGF', 'molecular_function', 'GO:0005154', ('30', '33'))	('TIC', 'Gene', '23550', (107, 110))	('TIC', 'Phenotype', 'HP:0100033', (107, 110))	('MM4', 'CellLine', 'CVCL:S405', (103, 106))	('EGF', 'Gene', '1950', (30, 33))	('inhibited', 'NegReg', (20, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('AZ628', 'Var', (0, 5))	('ERK1/2', 'Pathway', (52, 58))	('sorafenib', 'Chemical', 'MESH:D000077157', (82, 91))	('AZ628', 'Chemical', 'MESH:C000592454', (0, 5))	('TICs', 'Phenotype', 'HP:0100033', (107, 111))	('MEK', 'Gene', (44, 47))	('MEK', 'Gene', '5609', (44, 47))	('ERK1', 'molecular_function', 'GO:0004707', ('52', '56'))
178952	28545562	These results suggest that modulation of the MAPK pathway is readily achievable in MPM TICs and the low sorafenib efficacy is not due to intrinsic mechanisms of Raf activation.	('MAPK pathway', 'Pathway', (45, 57))	('modulation', 'Var', (27, 37))	('Raf', 'Gene', '22882', (161, 164))	('TIC', 'Gene', '23550', (87, 90))	('sorafenib', 'Chemical', 'MESH:D000077157', (104, 113))	('TIC', 'Gene', (87, 90))	('TICs', 'Phenotype', 'HP:0100033', (87, 91))	('Raf', 'Gene', (161, 164))	('TIC', 'Phenotype', 'HP:0100033', (87, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))
178962	28545562	For example, an aberrant autocrine bFGF circuit is a key component of downstream ERK1/2 activation and tumor aggressiveness in NSLC, breast cancer, head and neck squamous cell carcinoma, and mesothelioma cells, and mediates resistance to RTK inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (148, 185))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (103, 123))	('ERK1/2', 'Gene', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancer', 'Disease', (133, 146))	('activation', 'PosReg', (88, 98))	('bFGF', 'Gene', '2247', (35, 39))	('mesothelioma', 'Disease', (191, 203))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))	('aberrant', 'Var', (16, 24))	('NSLC', 'Disease', (127, 131))	('mesothelioma', 'Disease', 'MESH:D008654', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('bFGF', 'Gene', (35, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('tumor aggressiveness', 'Disease', (103, 123))	('aggressiveness', 'Phenotype', 'HP:0000718', (109, 123))	('neck', 'cellular_component', 'GO:0044326', ('157', '161'))	('autocrine', 'MPA', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
179001	28210162	Mutations in the BAP1 tumor suppressor gene have been associated with a variety of malignancies, and BAP1 is frequently mutated in MPM.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('BAP1', 'Gene', '8314', (101, 105))	('MPM', 'Chemical', '-', (131, 134))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', (101, 105))	('BAP1', 'Gene', '8314', (17, 21))	('tumor', 'Disease', (22, 27))	('malignancies', 'Disease', (83, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('associated', 'Reg', (54, 64))	('BAP1', 'Gene', (17, 21))
179002	28210162	In recent small case series, somatic BAP1 mutations have been reported in 57%-63% of MPM tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('reported', 'Reg', (62, 70))	('BAP1', 'Gene', '8314', (37, 41))	('MPM tumor', 'Disease', (85, 94))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('MPM tumor', 'Disease', 'MESH:D009369', (85, 94))
179003	28210162	Germline BAP1 mutations coupled with somatic loss of the second BAP1 allele were discovered in mesothelioma tumor samples from affected families, in which up to 50% of family members developed MPM despite modest levels of environmental asbestos exposure.	('MPM', 'MPA', (193, 196))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MPM', 'Chemical', '-', (193, 196))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (95, 113))	('BAP1', 'Gene', '8314', (9, 13))	('developed', 'PosReg', (183, 192))	('men', 'Species', '9606', (229, 232))	('BAP1', 'Gene', '8314', (64, 68))	('asbestos', 'Chemical', 'MESH:D001194', (236, 244))	('loss', 'NegReg', (45, 49))	('BAP1', 'Gene', (9, 13))	('mesothelioma tumor', 'Disease', (95, 113))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', (64, 68))
179004	28210162	Germline and somatic BAP1 mutations resulting in a loss of heterozygosity have been associated with a novel tumor predisposition syndrome associated with various other malignancies.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('loss of', 'NegReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BAP1', 'Gene', (21, 25))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (26, 35))	('malignancies', 'Disease', (168, 180))	('associated', 'Reg', (84, 94))	('BAP1', 'Gene', '8314', (21, 25))
179006	28210162	The prevalence of germline BAP1 mutations was 6% in a large asbestos-exposed cohort with both mesothelioma and a family history of cancer.	('cancer', 'Disease', (131, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('BAP1', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (32, 41))	('asbestos', 'Chemical', 'MESH:D001194', (60, 68))	('mesothelioma', 'Disease', (94, 106))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('BAP1', 'Gene', '8314', (27, 31))
179045	28210162	In a multivariate analysis, the CALGB identified the following as independent predictors of poor outcome: pleural primary site, lactate dehydrogenase >500 IU/L, Eastern Cooperative Oncology Group (ECOG) performance status >0, platelet count >400,000/microL, non-epithelial histology, and age >75 years.	('pleural', 'Disease', 'MESH:D010995', (106, 113))	('pleural', 'Disease', (106, 113))	('lactate dehydrogenase', 'MPA', (128, 149))	('>500', 'Var', (150, 154))	('Oncology', 'Phenotype', 'HP:0002664', (181, 189))
179093	28210162	Surgical complications (31% versus 14%) and length of hospital stay (7 versus 3 days) were significantly greater in the VAT-PP patients, whereas the rate of complete resolution of the effusion at 12 months and the quality of life measures were similar in both treatment arms.	('VAT-PP', 'Chemical', '-', (120, 126))	('men', 'Species', '9606', (265, 268))	('patients', 'Species', '9606', (127, 135))	('Surgical complications', 'CPA', (0, 22))	('VAT-PP', 'Var', (120, 126))	('greater', 'PosReg', (105, 112))
179109	28210162	Seven studies including 632 EPP patients and 513 P/D patients were analyzed.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (53, 61))	('513 P/D', 'SUBSTITUTION', 'None', (45, 52))	('513 P/D', 'Var', (45, 52))	('EPP', 'Disease', (28, 31))
179222	31646089	While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses.	('dexamethasone', 'Var', (86, 99))	('hypersensitivity reactions', 'Disease', 'MESH:D004342', (58, 84))	('hypersensitivity reactions', 'Disease', (58, 84))	('dexamethasone', 'Chemical', 'MESH:D003907', (86, 99))	('immune responses', 'CPA', (150, 166))	('depletes', 'NegReg', (100, 108))	('hypersensitivity', 'biological_process', 'GO:0002524', ('58', '74'))	('impacts', 'Reg', (142, 149))
179292	31646089	5-FU, an antimetabolite, can enhance anti-tumour immune responses via depletion of myeloid-derived suppressor cells while cisplatin can sensitize tumour cells to granzyme B-mediated T cell cytotoxicity and enhance antigen presentation by dendritic cells.	('enhance', 'PosReg', (206, 213))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('sensitize', 'Reg', (136, 145))	('tumour', 'Disease', (42, 48))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('enhance', 'PosReg', (29, 36))	('antigen presentation', 'MPA', (214, 234))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('antigen presentation', 'biological_process', 'GO:0019882', ('214', '234'))	('tumour', 'Disease', (146, 152))	('5-FU', 'Chemical', 'MESH:D005472', (0, 4))	('cytotoxicity', 'Disease', (189, 201))	('cytotoxicity', 'Disease', 'MESH:D064420', (189, 201))	('depletion', 'MPA', (70, 79))	('cisplatin', 'Var', (122, 131))	('granzyme B', 'Gene', (162, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('granzyme B', 'Gene', '14939', (162, 172))
179313	31646089	Clinical trial registration numbers with the Australia New Zealand Clinical Trial Registry are ACTRN12609000294257 and ACTRN12609000260224 and all involvement of human subjects complied with the Declaration of Helsinki.	('ACTRN12609000260224', 'Var', (119, 138))	('ACTRN12609000294257', 'Var', (95, 114))	('rat', 'Species', '10116', (200, 203))	('human', 'Species', '9606', (162, 167))	('rat', 'Species', '10116', (21, 24))
179325	31646089	For tumour flow cytometry and therapeutic studies, BALB/cArc and C57BL/6J mice were inoculated s.c. with 5 x 105 AB1 or AE17 mesothelioma tumour cells, respectively.	('mesothelioma tumour', 'Disease', (125, 144))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('mesothelioma tumour', 'Disease', 'MESH:D008654', (125, 144))	('AE17', 'Var', (120, 124))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (125, 144))	('tumour', 'Disease', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('mice', 'Species', '10090', (74, 78))	('tumour', 'Disease', (138, 144))
179359	29848954	Mutations are mainly found in tumor suppressors (COSMIC), but common oncogenes such as PI3K, EGFR, and VEGFR are, if any, rarely found to be mutated in MPM, which limits the choice of targeted inhibitors.	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', (104, 108))	('MPM', 'Chemical', '-', (152, 155))	('EGFR', 'Gene', (93, 97))	('VEGFR', 'Gene', '3791', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('PI3K', 'Disease', (87, 91))	('VEGFR', 'Gene', (103, 108))	('tumor', 'Disease', (30, 35))	('EGFR', 'Gene', '1956', (104, 108))
179362	29848954	One reason for the inefficacy of the treatment regimens is the molecular inter-tumor heterogeneity, describing the diverse mutational (referred to as "genetic" in this review), epigenetic, expressional, and macroscropic (summarized as "phenotypical") changes between patients.	('patients', 'Species', '9606', (267, 275))	('tumor', 'Disease', (79, 84))	('epigenetic', 'Var', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
179364	29848954	In contrast to non-small cell lung cancer, the relatively low number of MPM cases combined with the low prevalence of drug-targetable EGFR mutations in MPM compromises the investigation and use of selective EGFR inhibitors in the treatment of mesothelioma.	('mesothelioma', 'Disease', (243, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (15, 41))	('EGFR', 'Gene', (134, 138))	('MPM', 'Chemical', '-', (152, 155))	('compromises', 'NegReg', (156, 167))	('mutations', 'Var', (139, 148))	('non-small cell lung cancer', 'Disease', (15, 41))	('MPM', 'Chemical', '-', (72, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (243, 255))	('EGFR', 'Gene', '1956', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (19, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('EGFR', 'molecular_function', 'GO:0005006', ('207', '211'))	('EGFR', 'Gene', (207, 211))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (15, 41))	('EGFR', 'Gene', '1956', (134, 138))
179381	29848954	Chromosomal losses are the most frequent alterations in MPM, mostly affecting the chromosomal arms 3p, 9p, and 22q, where, amongst others genes, BAP1, CDKN2A, and NF2 are located, respectively.	('Chromosomal losses', 'Var', (0, 18))	('MPM', 'Gene', (56, 59))	('MPM', 'Chemical', '-', (56, 59))	('NF2', 'Gene', (163, 166))	('affecting', 'Reg', (68, 77))	('BAP1', 'Gene', '8314', (145, 149))	('CDKN2A', 'Gene', '1029', (151, 157))	('CDKN2A', 'Gene', (151, 157))	('NF2', 'Gene', '4771', (163, 166))	('BAP1', 'Gene', (145, 149))
179385	29848954	Although the authors reported a higher number of mutations clustering in exon 13 and 17 of the BAP1 gene, which are the two largest exons, it did not seem that those were common hotspots for BAP1 mutations (COSMIC); there was more of an enrichment found in the N-terminal Ubiquitin Hydrolase domain (COSMIC).	('BAP1', 'Gene', (95, 99))	('mutations', 'Var', (49, 58))	('BAP1', 'Gene', '8314', (191, 195))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('272', '281'))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', (191, 195))	('mutations', 'Var', (196, 205))
179389	29848954	The results from these publications clearly illustrate that, in contrast to e.g., the L858R mutation in EGFR in lung cancer, there are no commonly mutated amino acid positions or "hotspot" regions in any of the genes tested.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('EGFR', 'Gene', (104, 108))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('L858R', 'Var', (86, 91))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('L858R', 'Mutation', 'rs121434568', (86, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('EGFR', 'Gene', '1956', (104, 108))
179392	29848954	Clinical trials inhibiting for example the EGFR receptor in MPM patients using Erlotinib (NCT01592383, NCT00137826, NCT00039182), Gefitinib (NCT00787410, NCT00025207), Vandetanib (NCT00597116), or Cetuximab (NCT00996567) did not reveal any beneficial effects of the treatment.	('NCT00025207', 'Var', (154, 165))	('Vandetanib', 'Chemical', 'MESH:C452423', (168, 178))	('Erlotinib', 'Chemical', 'MESH:D000069347', (79, 88))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('Gefitinib', 'Chemical', 'MESH:D000077156', (130, 139))	('NCT01592383', 'Var', (90, 101))	('Cetuximab', 'Chemical', 'MESH:D000068818', (197, 206))	('NCT00597116', 'Var', (180, 191))	('NCT00039182', 'Var', (116, 127))	('EGFR', 'Gene', '1956', (43, 47))	('MPM', 'Chemical', '-', (60, 63))	('NCT00137826', 'Var', (103, 114))	('EGFR', 'Gene', (43, 47))	('NCT00996567', 'Var', (208, 219))	('NCT00787410', 'Var', (141, 152))
179404	29848954	In our sequencing studies (Oehl et al., manuscript in preparation), we could see EGFR mutations at low allele frequency in the tissues, indicating a subclonal origin.	('mutations', 'Var', (86, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
179409	29848954	In silico modeling of spatial tumor growth suggests that the number of driver gene mutations, as well as the speed of cell turnover, greatly influences the degree of heterogeneity within a tumor.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (189, 194))	('influences', 'Reg', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('heterogeneity', 'MPA', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (30, 35))
179412	29848954	This assay is based on X-chromosome inactivation by methylation and the HUMARA gene which is located on the X-chromosome.	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('23', '48'))	('HUMARA', 'Gene', '367', (72, 78))	('X-chromosome', 'cellular_component', 'GO:0000805', ('23', '35'))	('HUMARA', 'Gene', (72, 78))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('X-chromosome', 'cellular_component', 'GO:0000805', ('108', '120'))
179417	29848954	As described above, a common molecular alteration is the homozygous deletion of CDKN2A (p16) on chromosome 9.	('p16', 'Gene', (88, 91))	('CDKN2A', 'Gene', '1029', (80, 86))	('deletion', 'Var', (68, 76))	('p16', 'Gene', '1029', (88, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('CDKN2A', 'Gene', (80, 86))
179425	29848954	Comparing the allele frequencies of these mutations, they detected some high variant allele frequency mutations in every examined location of the respective tumor, indicative of mutations of early clonal origin.	('tumor', 'Disease', (157, 162))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))
179459	29848954	The lack of purine and pyrimidine results in the inhibition of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, essential elements for cell proliferation and survival.	('pyrimidine', 'Var', (23, 33))	('pyrimidine', 'Chemical', 'MESH:C030986', (23, 33))	('purine', 'MPA', (12, 18))	('lack', 'NegReg', (4, 8))	('RNA) synthesis', 'biological_process', 'GO:0032774', ('113', '127'))	('purine', 'Chemical', 'MESH:C030985', (12, 18))	('ribonucleic acid', 'MPA', (95, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('152', '170'))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('inhibition', 'NegReg', (49, 59))
179465	29848954	In addition to inducing phenotypical changes, DNA damage caused by cisplatin, if incorrectly repaired, can generate novel mutations or chromosome alterations, thereby increasing genetic diversity of tumors.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('tumors', 'Disease', (199, 205))	('genetic', 'MPA', (178, 185))	('increasing', 'PosReg', (167, 177))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('cisplatin', 'Gene', (67, 76))	('mutations', 'Var', (122, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('chromosome alterations', 'CPA', (135, 157))	('generate', 'Reg', (107, 115))
179473	29848954	In our previous study, we compared protein expression of markers of the PI3K-mTOR pathway namely PTEN, p-mTOR, and p-S6 in matched MPM tissues pre- and post- cisplatin-based induction chemotherapy.	('pre', 'molecular_function', 'GO:0003904', ('143', '146'))	('PTEN', 'Gene', (97, 101))	('PTEN', 'Gene', '5728', (97, 101))	('MPM', 'Chemical', '-', (131, 134))	('p-S6', 'Var', (115, 119))	('mTOR', 'Gene', (105, 109))	('protein expression', 'MPA', (35, 53))	('mTOR', 'Gene', '2475', (77, 81))	('mTOR', 'Gene', '2475', (105, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('mTOR', 'Gene', (77, 81))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('compared', 'Reg', (26, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
179474	29848954	Staining of the tissue microarray (TMA) revealed a reduction of protein expression of PTEN, p-mTOR, and p-S6 in the tumor tissues following chemotherapy.	('p-S6', 'Var', (104, 108))	('reduction', 'NegReg', (51, 60))	('PTEN', 'Gene', (86, 90))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('mTOR', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (86, 90))	('mTOR', 'Gene', '2475', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('protein expression', 'MPA', (64, 82))
179495	29848954	MPM SP were however more resistant to cisplatin and expressed increased level of PTCH1, a gene of the sonic hedgehog signaling pathway.	('increased', 'PosReg', (62, 71))	('PTCH1', 'Gene', (81, 86))	('SP', 'Chemical', 'MESH:C000604007', (4, 6))	('MPM', 'Var', (0, 3))	('level', 'MPA', (72, 77))	('MPM', 'Chemical', '-', (0, 3))	('PTCH1', 'Gene', '5727', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('sonic hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('102', '134'))
179501	29848954	Here, they detected MPM CSCs (Aldefluor + cells) with increased tumor initiating potential compared to non-CSCs when implanted into immunodeficient mice.	('tumor', 'Disease', (64, 69))	('increased', 'PosReg', (54, 63))	('mice', 'Species', '10090', (148, 152))	('MPM CSCs', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('immunodeficient', 'Disease', 'MESH:D007153', (132, 147))	('MPM', 'Chemical', '-', (20, 23))	('immunodeficient', 'Disease', (132, 147))
179505	29848954	In a preclinical model, CSCs survive during the treatment with cisplatin and pemetrexed and thus can give rise to a new generation of tumor cell population and create the diversity of recurrent tumor clones that differ from tumor at diagnosis.	('pemetrexed', 'Chemical', 'MESH:D000068437', (77, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('CSCs', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (194, 199))	('give rise to', 'Reg', (101, 113))	('create', 'Reg', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
179522	29848954	Understanding the pathways behind those mutations could then be exploited to develop new therapeutic approaches targeting most, if not all, of the tumor cells.	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))
179531	29848954	However, both studies relied on the detection of mutations that were previously found in the primary cancers of the respective patients, and thus could not identify novel mutations or mutations that were enriched during the treatment course.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('mutations', 'Var', (49, 58))	('cancers', 'Disease', (101, 108))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
179555	29419731	Additionally, asbestos causes malignant diseases such as lung cancer and malignant mesothelioma (MPM).	('asbestos', 'Var', (14, 22))	('asbestos', 'Chemical', 'MESH:D001194', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('causes', 'Reg', (23, 29))	('malignant mesothelioma', 'Disease', (73, 95))	('MPM', 'Chemical', '-', (97, 100))	('malignant diseases', 'Disease', 'MESH:D009369', (30, 48))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('malignant diseases', 'Disease', (30, 48))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (73, 95))	('lung cancer', 'Disease', (57, 68))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (73, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
179564	29419731	Depending on the nature of these various mechanisms at play, asbestos fibers can cause malignant transformation.	('cause', 'Reg', (81, 86))	('malignant transformation', 'CPA', (87, 111))	('asbestos', 'Chemical', 'MESH:D001194', (61, 69))	('asbestos fibers', 'Var', (61, 76))
179587	29419731	Additionally, molecular transient knock-down of FoxO1 in original MT-2 cells resulted in a reduction in the occurrence of apoptosis, and forced expression of FoxO1 in the CA1 subline caused a re-increase in expression of the puma gene.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('knock-down', 'Var', (34, 44))	('apoptosis', 'CPA', (122, 131))	('MT-2', 'molecular_function', 'GO:0043851', ('66', '70'))	('re-increase', 'PosReg', (192, 203))	('reduction', 'NegReg', (91, 100))	('FoxO1', 'Gene', (158, 163))	('MT-2', 'Gene', '4502', (66, 70))	('CA1', 'Gene', '759', (171, 174))	('FoxO1', 'Gene', (48, 53))	('FoxO1', 'Gene', '2308', (48, 53))	('expression', 'MPA', (207, 217))	('FoxO1', 'Gene', '2308', (158, 163))	('CA1', 'Gene', (171, 174))	('MT-2', 'Gene', (66, 70))	('puma gene', 'Gene', (225, 234))
179627	29419731	As previously reported and mentioned above, expression of CXCR3 in CD4+ T cells derived from peripheral blood of asbestos-exposed patients with PP or MPM was reduced.	('MPM', 'Var', (150, 153))	('CXCR3', 'Gene', (58, 63))	('CD4', 'Gene', (67, 70))	('patients', 'Species', '9606', (130, 138))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('CD4', 'Gene', '920', (67, 70))	('MPM', 'Chemical', '-', (150, 153))	('CXCR3', 'Gene', '2833', (58, 63))	('reduced', 'NegReg', (158, 165))
179630	29419731	Thus, in the experiments using peripheral blood CD4+ T cells activated with anti-CD3 and CD28 for five days, IFN-gamma mRNA expression was assayed.	('CD4', 'Gene', (48, 51))	('CD28', 'Gene', (89, 93))	('anti-CD3', 'Var', (76, 84))	('CD4', 'Gene', '920', (48, 51))	('IFN-gamma', 'Gene', '3458', (109, 118))	('IFN-gamma', 'Gene', (109, 118))	('CD28', 'Gene', '940', (89, 93))
179635	29419731	However, one interesting finding was the observed increased expression of IL-6 in asbestos-exposed patients, PP and MPM patients compared with HD.	('expression', 'MPA', (60, 70))	('IL-6', 'Gene', (74, 78))	('increased', 'PosReg', (50, 59))	('MPM', 'Var', (116, 119))	('IL-6', 'Gene', '3569', (74, 78))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (120, 128))	('HD', 'Disease', 'MESH:D006816', (143, 145))	('asbestos', 'Chemical', 'MESH:D001194', (82, 90))	('MPM', 'Chemical', '-', (116, 119))	('IL-6', 'molecular_function', 'GO:0005138', ('74', '78'))
179663	28859932	Data from a multicentre non-randomised study of 663 patients suggests that this less radical approach, which leaves the underlying lung intact, is associated not only with lower rates of intraoperative mortality (7% for EPP compared to 4% for PD), but also with a survival benefit (median overall survival of 12 months for EPP compared to 16 months for PD, p <0.001).	('PD', 'Disease', 'MESH:D010300', (243, 245))	('EPP', 'Var', (323, 326))	('PD', 'Disease', 'MESH:D010300', (353, 355))	('lower', 'NegReg', (172, 177))	('benefit', 'PosReg', (273, 280))	('patients', 'Species', '9606', (52, 60))	('survival', 'MPA', (264, 272))
179688	28859932	IMRT was associated with improved median survival: 14.2 months in irradiated patients versus 10.2 months in the overall cohort.	('improved', 'PosReg', (25, 33))	('patients', 'Species', '9606', (77, 85))	('median survival', 'MPA', (34, 49))	('IMRT', 'Var', (0, 4))
179717	28859932	A variety of radiotherapy techniques were used and median overall survival rates of between 15.5 and 19.9 months are reported, with several studies noting an increase in median survival for patients completing EPP and a further survival benefit in patients completing radiotherapy.	('EPP', 'Var', (210, 213))	('increase', 'PosReg', (158, 166))	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (248, 256))	('median survival', 'MPA', (170, 185))
179800	26000097	In addition, Hsp70 expression is elevated in both pancreatic cancer and osteosarcoma compared to normal cells, and treatement with triptolide or minnelide, a water-soluble prodrug of triptolide, decreases Hsp70 expression and induces apoptosis and cell death in preclinical studies.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('cell death', 'biological_process', 'GO:0008219', ('248', '258'))	('triptolide', 'Chemical', 'MESH:C001899', (183, 193))	('decreases', 'NegReg', (195, 204))	('Hsp70', 'Protein', (205, 210))	('expression', 'MPA', (19, 29))	('soluble', 'cellular_component', 'GO:0005625', ('164', '171'))	('Hsp70', 'Protein', (13, 18))	('treatement', 'Var', (115, 125))	('apoptosis', 'CPA', (234, 243))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('cell death', 'CPA', (248, 258))	('elevated', 'PosReg', (33, 41))	('induces', 'Reg', (226, 233))	('water', 'Chemical', 'MESH:D014867', (158, 163))	('pancreatic cancer', 'Disease', (50, 67))	('triptolide', 'Chemical', 'MESH:C001899', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('minnelide', 'Chemical', 'MESH:C579022', (145, 154))	('osteosarcoma', 'Disease', (72, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('234', '243'))	('apoptosis', 'biological_process', 'GO:0006915', ('234', '243'))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))	('expression', 'MPA', (211, 221))
179826	26000097	In addition, baseline Hsp70 levels were greatest for H2461 cells compared to other MM cell lines (Figure 2A).	('Hsp70', 'Protein', (22, 27))	('H2461', 'Var', (53, 58))	('H2461', 'CellLine', 'CVCL:A536', (53, 58))
179831	26000097	A panel of 4 MM cell lines were either treated with triptolide (125 nM) or minnelide (100 nM) or left untreated for 48 hours and lysates prepared.	('minnelide', 'Chemical', 'MESH:C579022', (75, 84))	('100 nM', 'Var', (86, 92))	('125 nM', 'Var', (64, 70))	('triptolide', 'Chemical', 'MESH:C001899', (52, 62))
179842	26000097	The addition of triptolide treatment enhanced pemetrexed-induced cell death by 30.8% [H513], 29.8% [H2373], 33.6%, [H2461], and 27.2% [H2596] as compared to cells treated with only pemetrexed.	('triptolide', 'Chemical', 'MESH:C001899', (16, 26))	('pemetrexed', 'Chemical', 'MESH:D000068437', (46, 56))	('[H2461]', 'Var', (115, 122))	('[H2373]', 'Var', (99, 106))	('pemetrexed', 'Chemical', 'MESH:D000068437', (181, 191))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('[H513]', 'Var', (85, 91))	('cell death', 'CPA', (65, 75))	('H2461', 'CellLine', 'CVCL:A536', (116, 121))	('enhanced', 'PosReg', (37, 45))
179844	26000097	Further, the addition of triptolide treatment increased gemcitabine-induced cell death by 58.7% [H513], 27.6% [H2373], 37.7%, [H2461], and 45.7% [H2596] as compared to gemcitabine alone.	('[H513]', 'Var', (96, 102))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('increased', 'PosReg', (46, 55))	('triptolide', 'Chemical', 'MESH:C001899', (25, 35))	('gemcitabine', 'Chemical', 'MESH:C056507', (56, 67))	('[H2461]', 'Var', (126, 133))	('[H2373]', 'Var', (110, 117))	('H2461', 'CellLine', 'CVCL:A536', (127, 132))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))
179849	26000097	Significantly reduced tumor volume (p<0.02) at the completion of the experiment was 3.25 fold for H2373 and 7.1 fold for H513.	('H2373', 'Var', (98, 103))	('reduced', 'NegReg', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('H513', 'Var', (121, 125))	('tumor', 'Disease', (22, 27))
179851	26000097	Tumor volumes were found to be significantly different (p<0.05) starting on day 18 and day 20 after tumor implantation for H2373 and H513, respectively.	('H513', 'Var', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('H2373', 'Var', (123, 128))	('tumor', 'Disease', (100, 105))	('different', 'Reg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Tumor volumes', 'CPA', (0, 13))
179858	26000097	Enhanced Hsp70 levels protect cancer cells from apoptosis and cellular pressures linked to amplified growth, aneuploidy, and accumulation of mutant proteins.	('aneuploidy', 'Disease', 'MESH:D000782', (109, 119))	('mutant', 'Var', (141, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('cellular pressures', 'CPA', (62, 80))	('cancer', 'Disease', (30, 36))	('proteins', 'Protein', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('aneuploidy', 'Disease', (109, 119))	('Hsp70', 'Protein', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('Enhanced', 'PosReg', (0, 8))
179862	26000097	A recent study has revealed that the likely mechanism for the decreased levels of Hsp70 is that triptolide induces the upregulation of a microRNA, miR-142-3p, which directly binds to the 3' UTR of Hsp70 mRNA and causes the destruction of Hsp70 mRNA.	('miR-142-3p', 'Var', (147, 157))	('causes', 'Reg', (212, 218))	('upregulation', 'PosReg', (119, 131))	('triptolide', 'Chemical', 'MESH:C001899', (96, 106))	('miR-142-3p', 'Chemical', '-', (147, 157))	('destruction', 'MPA', (223, 234))	('Hsp70', 'Protein', (238, 243))	('binds', 'Interaction', (174, 179))	('Hsp70', 'Protein', (197, 202))
179894	26000097	Cells were seeded as triplicate sets into 6-well plates with 150,000 cells per well for H513, H2373, H2461, and H2596.	('H2596', 'Var', (112, 117))	('H2461', 'CellLine', 'CVCL:A536', (101, 106))	('H2461', 'Var', (101, 106))	('H2373', 'Var', (94, 99))	('H513', 'Var', (88, 92))
179900	26000097	The IC of triptolide for H513 and H2373 was determined by using Compusyn (ComboSyn, Inc., Paramus, NJ).	('H2373', 'Var', (34, 39))	('H513', 'Var', (25, 29))	('triptolide', 'Chemical', 'MESH:C001899', (10, 20))
179953	22472194	Only the CNT samples containing long fibres- NTlong1 and NTlong2 caused a significant increase in IL-1beta and IL-6 concentrations compared to untreated cells.	('IL-6', 'Gene', '3569', (111, 115))	('increase', 'PosReg', (86, 94))	('long fibres- NTlong1', 'Var', (32, 52))	('IL-1beta', 'Gene', (98, 106))	('NTlong2', 'Var', (57, 64))	('IL-1beta', 'Gene', '3553', (98, 106))	('IL-6', 'molecular_function', 'GO:0005138', ('111', '115'))	('IL-1', 'molecular_function', 'GO:0005149', ('98', '102'))	('IL-6', 'Gene', (111, 115))
179954	22472194	NTlong2 did appear to elevate the concentration of TNFalpha, but this elevation was not statistically significant.	('concentration', 'MPA', (34, 47))	('TNFalpha', 'Gene', (51, 59))	('NTlong2', 'Var', (0, 7))	('TNFalpha', 'Gene', '7124', (51, 59))	('elevate', 'PosReg', (22, 29))
179962	22472194	Whilst direct exposure of Met5A cells to the CNT panel had not caused any increases in IL-1beta, treatment with conditioned media from THP-1 cells exposed to LPS, NTlong1 or NTlong2 resulted in approximately two-fold increase in IL-1beta concentration compared with the combined total from both cell types exposed directly as shown by the horizontal lines on the bars (Figure 6A).	('IL-1beta', 'Gene', (229, 237))	('IL-1', 'molecular_function', 'GO:0005149', ('87', '91'))	('increase', 'PosReg', (217, 225))	('LPS', 'Disease', 'MESH:C536528', (158, 161))	('IL-1', 'molecular_function', 'GO:0005149', ('229', '233'))	('NTlong2', 'Var', (174, 181))	('IL-1beta', 'Gene', '3553', (229, 237))	('NTlong1', 'Var', (163, 170))	('THP-1', 'Gene', '2736', (135, 140))	('IL-1beta', 'Gene', '3553', (87, 95))	('THP-1', 'Gene', (135, 140))	('LPS', 'Disease', (158, 161))	('IL-1beta', 'Gene', (87, 95))
179969	22472194	We previously reported that long CNT but not short CNT were capable of causing inflammation in the peritoneal and pleural spaces.	('pleural', 'Disease', 'MESH:D010995', (114, 121))	('causing', 'Reg', (71, 78))	('inflammation', 'biological_process', 'GO:0006954', ('79', '91'))	('pleural', 'Disease', (114, 121))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('inflammation', 'Disease', (79, 91))	('long CNT', 'Var', (28, 36))
180072	32117751	There is abundant evidence that inactivating somatic mutations and deletions of the tumor suppressor genes (TSGs) BAP1, CDKN2A, and NF2 represent the most frequent genetic lesions in human malignant pleural mesothelioma (MPM).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TSG', 'Gene', (108, 111))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (199, 219))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('BAP1', 'Gene', (114, 118))	('MPM', 'Disease', 'MESH:C562839', (221, 224))	('MPM', 'Disease', (221, 224))	('deletions', 'Var', (67, 76))	('malignant pleural mesothelioma', 'Disease', (189, 219))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CDKN2A', 'Gene', (120, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('genetic lesions', 'Disease', (164, 179))	('human', 'Species', '9606', (183, 188))	('inactivating somatic mutations', 'Var', (32, 62))	('NF2', 'Gene', (132, 135))	('genetic lesions', 'Disease', 'MESH:D020022', (164, 179))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (189, 219))	('tumor', 'Disease', (84, 89))	('TSG', 'Gene', '65960', (108, 111))
180077	32117751	In fact, a recent report that compared next-generation sequencing of two series of MPMs:one from The Cancer Genome Atlas (TCGA) and the second from a Harvard series :revealed only four "significantly mutated genes at a false discovery rate of <0.05" common to the two studies: BAP1, NF2, TP53, and SETD2, each of which showed prominent levels of inactivating nonsense, frameshift, and splice-site mutations, consistent with their putative roles as driver loss-of-function lesions in this malignancy.	('BAP1', 'Gene', (277, 281))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('frameshift', 'Var', (369, 379))	('MPM', 'Disease', (83, 86))	('malignancy', 'Disease', (488, 498))	('rat', 'Species', '10116', (235, 238))	('malignancy', 'Disease', 'MESH:D009369', (488, 498))	('inactivating', 'MPA', (346, 358))	('SETD2', 'Gene', (298, 303))	('splice-site', 'MPA', (385, 396))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SETD2', 'Gene', '235626', (298, 303))	('TP53', 'Gene', (288, 292))	('loss-of-function', 'NegReg', (455, 471))	('MPM', 'Disease', 'MESH:C562839', (83, 86))	('rat', 'Species', '10116', (48, 51))	('Cancer', 'Disease', (101, 107))
180078	32117751	In the TCGA data set, focal deletions were found to affect several TSGs, especially CDKN2A, with deep, apparently homozygous deletions occurring in 36/73 (49%) tumors and single-copy losses in 5 others (7%).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CDKN2A', 'Gene', (84, 90))	('TSG', 'Gene', (67, 70))	('deletions', 'Var', (28, 37))	('focal deletions', 'Var', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('single-copy losses', 'Var', (171, 189))	('deletions', 'Var', (125, 134))	('tumors', 'Disease', (160, 166))	('TSG', 'Gene', '65960', (67, 70))	('affect', 'Reg', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
180079	32117751	found copy number losses of CDKN2A in 48/95 (51%) MPMs.	('CDKN2A', 'Gene', (28, 34))	('MPM', 'Disease', 'MESH:C562839', (50, 53))	('MPM', 'Disease', (50, 53))	('copy number losses', 'Var', (6, 24))
180080	32117751	In a deletion mapping analysis, homozygous CDKN2A deletions were identified in 36 of 40 (90%) human MPM cell lines tested, while homozygous deletions of the adjacent locus CDKN2B occurred in most:i.e., 32/36:of these same cell lines.	('CDKN2A', 'Gene', (43, 49))	('CDKN2B', 'Gene', (172, 178))	('human', 'Species', '9606', (94, 99))	('MPM', 'Disease', 'MESH:C562839', (100, 103))	('MPM', 'Disease', (100, 103))	('CDKN2B', 'Gene', '1030', (172, 178))	('deletions', 'Var', (50, 59))
180081	32117751	Experiments in mice have shown that the Cdkn2b also exhibits a tumor suppressor role in MPM, as its deletion concomitant with Cdkn2a further accelerates MPM development (our unpublished results) offering a rationale for the predominant deletion of all three tumor suppressors in this locus in MPM.	('MPM', 'Disease', 'MESH:C562839', (153, 156))	('MPM', 'Disease', (153, 156))	('MPM', 'Disease', 'MESH:C562839', (88, 91))	('tumor', 'Disease', (258, 263))	('MPM', 'Disease', (88, 91))	('rat', 'Species', '10116', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('MPM', 'Disease', (293, 296))	('MPM', 'Disease', 'MESH:C562839', (293, 296))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('Cdkn2b', 'Gene', (40, 46))	('accelerates', 'PosReg', (141, 152))	('deletion', 'Var', (100, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('rat', 'Species', '10116', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
180084	32117751	Moreover, despite a rarity of mutations of PTEN in MPM, earlier immunohistochemical (IHC) studies revealed diminished PTEN protein expression in 16 to 62% of MMs in several studies.	('PTEN protein', 'Protein', (118, 130))	('MMs', 'Chemical', 'MESH:D008741', (158, 161))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('MMs', 'Disease', (158, 161))	('diminished', 'NegReg', (107, 117))	('expression', 'MPA', (131, 141))	('PTEN', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('MPM', 'Disease', 'MESH:C562839', (51, 54))	('protein', 'Protein', (123, 130))	('MPM', 'Disease', (51, 54))
180087	32117751	In view of the prominence of TSG inactivation and the relatively rare oncogenic gain-of-function mutations in MM, high-throughput chemical inhibitor screens and gene expression analyses have been performed in MM cell lines to identify unique vulnerabilities.	('mutations', 'Var', (97, 106))	('TSG', 'Gene', '65960', (29, 32))	('MM', 'Disease', 'MESH:C562839', (110, 112))	('TSG', 'Gene', (29, 32))	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))	('MM', 'Disease', 'MESH:C562839', (209, 211))	('gain-of-function', 'PosReg', (80, 96))
180088	32117751	Chemical screens pointed to increased sensitivity to FGFR inhibitors in a subset of the MPM cell lines.	('increased', 'PosReg', (28, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('FGFR', 'Gene', (53, 57))	('sensitivity', 'MPA', (38, 49))	('MPM', 'Disease', 'MESH:C562839', (88, 91))	('MPM', 'Disease', (88, 91))	('increased sensitivity to FGFR', 'Phenotype', 'HP:0030269', (28, 57))	('inhibitors', 'Var', (58, 68))
180093	32117751	Another vulnerability relates to the co-deletion of CDKN2A and the nearby methylthioadenosine phosphorylase (MTAP) gene, the latter rendering cells dependent on protein arginine methyltransferase (PRMT5).	('methylthioadenosine phosphorylase', 'Gene', (74, 107))	('PRMT5', 'Gene', '27374', (197, 202))	('methylthioadenosine phosphorylase', 'Gene', '66902', (74, 107))	('MTAP', 'Gene', (109, 113))	('protein arginine methyltransferase', 'Gene', (161, 195))	('rendering', 'Reg', (132, 141))	('PRMT5', 'Gene', (197, 202))	('MTAP', 'Gene', '66902', (109, 113))	('protein arginine methyltransferase', 'Gene', '59035', (161, 195))	('CDKN2A', 'Gene', (52, 58))	('co-deletion', 'Var', (37, 48))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
180094	32117751	NF2 depletion leads to dysregulation of the Hippo pathway by activating the transcriptional co-activator YAP1 and its association with the TEAD family of transcription factors, resulting in up-regulation of genes that promote cell proliferation and inhibit cell death.	('promote', 'PosReg', (218, 225))	('cell death', 'CPA', (257, 267))	('depletion', 'Var', (4, 13))	('association', 'Interaction', (118, 129))	('NF2', 'Gene', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('226', '244'))	('up-regulation', 'PosReg', (190, 203))	('Hippo pathway', 'Pathway', (44, 57))	('cell death', 'biological_process', 'GO:0008219', ('257', '267'))	('genes', 'MPA', (207, 212))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('activating', 'PosReg', (61, 71))	('YAP1', 'Gene', '22601', (105, 109))	('dysregulation', 'MPA', (23, 36))	('cell proliferation', 'CPA', (226, 244))	('regulation', 'biological_process', 'GO:0065007', ('193', '203'))	('inhibit', 'NegReg', (249, 256))	('YAP1', 'Gene', (105, 109))	('rat', 'Species', '10116', (238, 241))
180096	32117751	MM also shows overexpression of RTKs such as MET and downstream PI3K, making inhibitors targeting components of this pathway other promising therapies for this disease.	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('MM', 'Disease', 'MESH:C562839', (0, 2))	('MET', 'Var', (45, 48))	('overexpression', 'PosReg', (14, 28))	('PI3K', 'Var', (64, 68))
180107	32117751	Genetically engineered mouse (GEM) models, typically harboring heterozygous whole-body germline mutations, have been used to assess whether loss of TSGs implicated in human MPM accelerate tumor formation.	('tumor', 'Disease', (188, 193))	('MPM', 'Disease', (173, 176))	('rat', 'Species', '10116', (183, 186))	('formation', 'biological_process', 'GO:0009058', ('194', '203'))	('TSG', 'Gene', (148, 151))	('accelerate', 'PosReg', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mouse', 'Species', '10090', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('human', 'Species', '9606', (167, 172))	('TSG', 'Gene', '65960', (148, 151))	('loss', 'Var', (140, 144))	('MPM', 'Disease', 'MESH:C562839', (173, 176))
180110	32117751	Tp53+/- mice developed a high incidence (76%) of MMs (median latency, 44 weeks) vs. a32% of wild type mice (median latency, 67 weeks).	('Tp53+/-', 'Var', (0, 7))	('mice', 'Species', '10090', (102, 106))	('MMs', 'Chemical', 'MESH:D008741', (49, 52))	('MMs', 'Disease', (49, 52))	('mice', 'Species', '10090', (8, 12))
180111	32117751	Only 1/8 (12.5%) Tp53-/- mice had a MM, with others succumbing quickly due to thymic lymphomas or hemangiosarcomas, previously reported to arise spontaneously in Tp53-/- mice.	('lymphomas', 'Phenotype', 'HP:0002665', (85, 94))	('Tp53-/-', 'Var', (17, 24))	('thymic lymphomas', 'Disease', (78, 94))	('mice', 'Species', '10090', (25, 29))	('hemangiosarcomas', 'Disease', (98, 114))	('thymic lymphomas', 'Disease', 'MESH:D013953', (78, 94))	('MM', 'Disease', 'MESH:C562839', (36, 38))	('mice', 'Species', '10090', (170, 174))	('hemangiosarcomas', 'Disease', 'MESH:D006394', (98, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
180115	32117751	Notably, the normal Nf2 allele was deleted in most MMs from the Nf2+/- mice, consistent with biallelic inactivation, which similarly occurs in many human MPMs.	('mice', 'Species', '10090', (71, 75))	('man', 'Species', '9606', (150, 153))	('MPM', 'Disease', (154, 157))	('MMs', 'Chemical', 'MESH:D008741', (51, 54))	('MPM', 'Disease', 'MESH:C562839', (154, 157))	('Nf2+/-', 'Var', (64, 70))	('man', 'Species', '9606', (143, 146))	('human', 'Species', '9606', (148, 153))	('Nf2', 'Gene', (20, 23))
180116	32117751	Moreover, most MM cell lines from the Nf2-deficient mice showed homologous deletions of Cdkn2a/Cdkn2b and activation of Akt, recapitulating events that often occur in human MPM.	('MPM', 'Disease', (173, 176))	('deletions', 'Var', (75, 84))	('mice', 'Species', '10090', (52, 56))	('Akt', 'Gene', '11651', (120, 123))	('Cdkn2a/Cdkn2b', 'Gene', (88, 101))	('MM', 'Disease', 'MESH:C562839', (15, 17))	('human', 'Species', '9606', (167, 172))	('activation', 'PosReg', (106, 116))	('Akt', 'Gene', (120, 123))	('MPM', 'Disease', 'MESH:C562839', (173, 176))
180119	32117751	To test the relative contributions of these genes to MM formation, one study used mice with heterozygous deletions of Cdkn2a exon 1alpha (resulting in loss of p16Ink4a) or exon 1beta (p19Arf), or with a deletion of exon 2 (deleting both p16Ink4a and p19Arf).	('mice', 'Species', '10090', (82, 86))	('Cdkn2a', 'Gene', (118, 124))	('p19', 'cellular_component', 'GO:0070743', ('250', '253'))	('deletions', 'Var', (105, 114))	('exon', 'MPA', (172, 176))	('p16Ink4a', 'Gene', (159, 167))	('p16Ink4a', 'Gene', '12578', (159, 167))	('p16Ink4a', 'Gene', '12578', (237, 245))	('p19', 'cellular_component', 'GO:0070743', ('184', '187'))	('MM', 'Disease', 'MESH:C562839', (53, 55))	('loss', 'NegReg', (151, 155))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('p16Ink4a', 'Gene', (237, 245))
180120	32117751	Both p16Ink4a+/- mice and p19Arf +/- mice injected i.p.	('p16Ink4a', 'Gene', '12578', (5, 13))	('mice', 'Species', '10090', (17, 21))	('p19Arf', 'Var', (26, 32))	('p16Ink4a', 'Gene', (5, 13))	('p19', 'cellular_component', 'GO:0070743', ('26', '29'))	('mice', 'Species', '10090', (37, 41))
180122	32117751	Mice heterozygous for Cdkn2a exon 2 showed a more accelerated rate of asbestos-induced MMs vs. mice deficient for either p16Ink4a or p19Arf separately.	('p16Ink4a', 'Gene', (121, 129))	('Cdkn2a', 'Var', (22, 28))	('accelerated', 'PosReg', (50, 61))	('mice', 'Species', '10090', (95, 99))	('rat', 'Species', '10116', (56, 59))	('p19', 'cellular_component', 'GO:0070743', ('133', '136'))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('MMs', 'Chemical', 'MESH:D008741', (87, 90))	('p16Ink4a', 'Gene', '12578', (121, 129))	('Mice', 'Species', '10090', (0, 4))	('rat', 'Species', '10116', (62, 65))	('rat', 'Species', '10116', (144, 147))	('asbestos-induced MMs', 'Disease', (70, 90))
180123	32117751	Together, these data indicate that each of the Cdkn2a gene products suppresses asbestos-induced MM, and that the combined inactivation of both gene products results in further cooperation to accelerate asbestos-induced MM development and progression.	('asbestos', 'Chemical', 'MESH:D001194', (202, 210))	('MM', 'Disease', 'MESH:C562839', (219, 221))	('asbestos', 'Chemical', 'MESH:D001194', (79, 87))	('inactivation', 'Var', (122, 134))	('MM', 'Disease', 'MESH:C562839', (96, 98))	('rat', 'Species', '10116', (197, 200))	('suppresses', 'NegReg', (68, 78))	('Cdkn2a', 'Gene', (47, 53))	('rat', 'Species', '10116', (181, 184))	('progression', 'CPA', (238, 249))	('accelerate', 'PosReg', (191, 201))
180124	32117751	Early Sanger sequencing studies had revealed point mutations in BAP1 in 20-25% of sporadic human MMs, but subsequent studies of sporadic MMs using various combinations of assays, such as quantitative real-time PCR, targeted comparative genomic hybridization, next generation sequencing, and/or multiplex ligation-dependent probe amplification platforms demonstrated BAP1 alterations in up to 60-65% of MMs.	('BAP1', 'Gene', (366, 370))	('rat', 'Species', '10116', (268, 271))	('MMs', 'Chemical', 'MESH:D008741', (402, 405))	('rat', 'Species', '10116', (229, 232))	('MMs', 'Chemical', 'MESH:D008741', (97, 100))	('point mutations', 'Var', (45, 60))	('MMs', 'Disease', (402, 405))	('rat', 'Species', '10116', (360, 363))	('rat', 'Species', '10116', (375, 378))	('human', 'Species', '9606', (91, 96))	('alterations', 'Reg', (371, 382))	('MMs', 'Disease', (97, 100))	('MMs', 'Chemical', 'MESH:D008741', (137, 140))	('BAP1', 'Gene', (64, 68))
180126	32117751	In addition to somatic changes, it is now well-established that BAP1 mutation carriers are predisposed to MM and a variety of other tumors.	('MM', 'Disease', 'MESH:C562839', (106, 108))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('mutation', 'Var', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('predisposed', 'Reg', (91, 102))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('BAP1', 'Gene', (64, 68))
180127	32117751	The use of Bap1 knockout models has shown that heterozygosity in the germline predisposes to asbestos-induced MM, and similar results were obtained with two knock-in models that harbored different germline mutations that were identical to the ones found in two BAP1 tumor predisposition syndrome (BAP1-TPDS) families that exhibited a very high incidence of MM.	('mutations', 'Var', (206, 215))	('heterozygosity', 'Var', (47, 61))	('Bap1', 'Gene', '104416', (11, 15))	('asbestos', 'Chemical', 'MESH:D001194', (93, 101))	('MM', 'Disease', 'MESH:C562839', (110, 112))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('Bap1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('MM', 'Disease', 'MESH:C562839', (357, 359))
180129	32117751	Collectively, these data indicate that human BAP1 mutation carriers have are more prone to the carcinogenic effects of asbestos, even when exposed to small amounts of these fibers, when compared to the general population.	('carcinogenic', 'Disease', 'MESH:D063646', (95, 107))	('carcinogenic', 'Disease', (95, 107))	('BAP1', 'Gene', (45, 49))	('human', 'Species', '9606', (39, 44))	('prone', 'Reg', (82, 87))	('asbestos', 'Chemical', 'MESH:D001194', (119, 127))	('mutation', 'Var', (50, 58))
180130	32117751	Other work has recently demonstrated cooperation between Nf2 and Cdkn2a in MM development in asbestos-exposed Nf2+/-;Cdkn2a+/- mice, which exhibited significantly hastened tumor onset and disease progression vs. similarly exposed Nf2+/- and wild-type cohorts.	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('asbestos', 'Chemical', 'MESH:D001194', (93, 101))	('hastened', 'NegReg', (163, 171))	('disease progression', 'CPA', (188, 207))	('Cdkn2a+/-', 'Var', (117, 126))	('MM', 'Disease', 'MESH:C562839', (75, 77))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('rat', 'Species', '10116', (42, 45))	('rat', 'Species', '10116', (31, 34))
180131	32117751	These studies also showed that tumors from Nf2+/-;Cdkn2a+/- mice had enhanced metastatic potential and an increased cancer stem cell population, in connection with p53/miR-34a-dependent activation of c-Met.	('Cdkn2a+/-', 'Var', (50, 59))	('mice', 'Species', '10090', (60, 64))	('miR-34a', 'Gene', '723848', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('c-Met', 'Gene', (200, 205))	('tumors', 'Disease', (31, 37))	('enhanced', 'PosReg', (69, 77))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('Nf2+/-;Cdkn2a+/-', 'Var', (43, 59))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('metastatic potential', 'CPA', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('increased', 'PosReg', (106, 115))	('c-Met', 'Gene', '17295', (200, 205))	('miR-34a', 'Gene', (168, 175))
180134	32117751	Exposure of Nf2+/-;Cdkn2a+/- mice to asbestos in the presence of an IL-1 receptor (IL-1R) antagonist known as anakinra resulted in a significant delay MM development compared to that of asbestos-exposed mice given a vehicle control, i.e., 33 vs. ~22.5 weeks, respectively.	('Nf2+/-;Cdkn2a+/-', 'Var', (12, 28))	('Cdkn2a+/-', 'Var', (19, 28))	('development', 'CPA', (154, 165))	('MM', 'Disease', 'MESH:C562839', (151, 153))	('mice', 'Species', '10090', (203, 207))	('asbestos', 'Chemical', 'MESH:D001194', (186, 194))	('delay', 'NegReg', (145, 150))	('IL-1', 'molecular_function', 'GO:0005149', ('68', '72'))	('asbestos', 'Chemical', 'MESH:D001194', (37, 45))	('mice', 'Species', '10090', (29, 33))	('IL-1R', 'molecular_function', 'GO:0004908', ('83', '88'))
180148	32117751	Since specific genetic driver lesions had been repeatedly found to be associated with human MM by the year 2008, particularly alterations of the CDKN2A, NF2, and TP53, Jongsma et al.	('lesions', 'Var', (30, 37))	('TP53', 'Gene', (162, 166))	('human', 'Species', '9606', (86, 91))	('associated', 'Reg', (70, 80))	('rat', 'Species', '10116', (130, 133))	('NF2', 'Gene', (153, 156))	('alterations', 'Var', (126, 137))	('MM', 'Disease', 'MESH:C562839', (92, 94))	('CDKN2A', 'Gene', (145, 151))
180149	32117751	decided to establish whether various genetic alterations affecting the same signaling pathways that are dysregulated in the human disease counterpart might similarly induce MM in rodents in the absence of carcinogenic exposure to asbestos.	('asbestos', 'Chemical', 'MESH:D001194', (230, 238))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('MM', 'Disease', 'MESH:C562839', (173, 175))	('genetic alterations', 'Var', (37, 56))	('human', 'Species', '9606', (124, 129))	('induce', 'Reg', (166, 172))	('carcinogenic', 'Disease', 'MESH:D063646', (205, 217))	('rat', 'Species', '10116', (49, 52))	('carcinogenic', 'Disease', (205, 217))
180150	32117751	Thus, they generated a variety of mutant mice carrying deletions in the Nf2/merlin, p53, and/or Ink4a pathways, hypothesizing that mice with one or more of these combinations might represent an appropriate model of human MM.	('rat', 'Species', '10116', (15, 18))	('mice', 'Species', '10090', (41, 45))	('Ink4a', 'Gene', '12578', (96, 101))	('mice', 'Species', '10090', (131, 135))	('MM', 'Disease', 'MESH:C562839', (221, 223))	('merlin', 'Gene', (76, 82))	('p53', 'Pathway', (84, 87))	('Ink4a', 'Gene', (96, 101))	('human', 'Species', '9606', (215, 220))	('deletions', 'Var', (55, 64))	('merlin', 'Gene', '18016', (76, 82))
180151	32117751	To avoid possible issues such as embryonic lethality due to germline homozygous deletion of one or more targeted genes, mice with conditional knockout (CKO) of various TSGs were used in combination with the Cre-LoxP system.	('mice', 'Species', '10090', (120, 124))	('embryonic lethality', 'Disease', (33, 52))	('deletion', 'Var', (80, 88))	('TSG', 'Gene', '65960', (168, 171))	('CKO', 'Chemical', '-', (152, 155))	('TSG', 'Gene', (168, 171))	('embryonic lethality', 'Disease', 'MESH:D020964', (33, 52))
180157	32117751	However, it remained unclear whether somatic mutations/deletions of BAP1 have a similarly favorable prognosis in sporadic MM, or if somatic BAP1 alterations are a poor prognostic marker, as is the case for uveal melanoma and clear cell renal cell carcinoma.	('rat', 'Species', '10116', (149, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (206, 220))	('uveal melanoma', 'Disease', (206, 220))	('uveal melanoma', 'Disease', 'MESH:C536494', (206, 220))	('clear cell renal cell carcinoma', 'Disease', (225, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (225, 256))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (236, 256))	('mutations/deletions', 'Var', (45, 64))	('BAP1', 'Gene', (68, 72))	('MM', 'Disease', 'MESH:C562839', (122, 124))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (225, 256))
180158	32117751	Furthermore, although most human MMs exhibit somatic alterations of BAP1, NF2, and/or CDKN2A:with 25/74 cases of MPM in the TCGA series having alterations of all three TSGs in combination :it was not known if loss of BAP1 could cooperate with the inactivation of NF2 and/or CDKN2A to initiate a more aggressive form of MM.	('MPM', 'Disease', 'MESH:C562839', (113, 116))	('MPM', 'Disease', (113, 116))	('BAP1', 'Gene', (217, 221))	('TSG', 'Gene', '65960', (168, 171))	('human', 'Species', '9606', (27, 32))	('initiate', 'Reg', (284, 292))	('MM', 'Disease', 'MESH:C562839', (33, 35))	('MMs', 'Chemical', 'MESH:D008741', (33, 36))	('rat', 'Species', '10116', (57, 60))	('TSG', 'Gene', (168, 171))	('rat', 'Species', '10116', (147, 150))	('rat', 'Species', '10116', (233, 236))	('MM', 'Disease', 'MESH:C562839', (319, 321))	('loss', 'Var', (209, 213))
180160	32117751	Various combinations of deletions of Bap1, Cdkn2a, and Nf2 were introduced in the pleural cavity of the mice, focusing on the contribution of Bap1 loss.	('Bap1', 'Gene', '104416', (142, 146))	('Cdkn2a', 'Gene', (43, 49))	('mice', 'Species', '10090', (104, 108))	('deletions', 'Var', (24, 33))	('Bap1', 'Gene', (142, 146))	('Nf2', 'Gene', (55, 58))	('Bap1', 'Gene', '104416', (37, 41))	('Bap1', 'Gene', (37, 41))
180162	32117751	:deletion of Bap1 cooperated with deletion of either Nf2 or Cdkn2a to promote MM formation in about 20% of double-CKO mice.	('Bap1', 'Gene', (13, 17))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('Bap1', 'Gene', '104416', (13, 17))	('deletion', 'Var', (1, 9))	('rat', 'Species', '10116', (23, 26))	('CKO', 'Chemical', '-', (114, 117))	('promote', 'PosReg', (70, 77))	('deletion', 'Var', (34, 42))	('mice', 'Species', '10090', (118, 122))	('MM', 'Disease', 'MESH:C562839', (78, 80))
180164	32117751	Onset of MM was rapid in the triple-CKO mice (median survival, 12 weeks), and tumors from these mice were consistently high-grade and invasive.	('tumors', 'Disease', (78, 84))	('triple-CKO', 'Var', (29, 39))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CKO', 'Chemical', '-', (36, 39))	('invasive', 'CPA', (134, 142))	('MM', 'Disease', 'MESH:C562839', (9, 11))	('mice', 'Species', '10090', (40, 44))	('high-grade', 'CPA', (119, 129))
180168	32117751	The findings suggested that loss of Bap1 contributes to MM progression, at least partially, via loss of PRC2-mediated repression of oncogenic target genes that were identified, suggesting a novel avenue for therapeutic intervention.	('PRC2-mediated', 'Protein', (104, 117))	('loss', 'Var', (28, 32))	('MM', 'Disease', 'MESH:C562839', (56, 58))	('Bap1', 'Gene', '104416', (36, 40))	('Bap1', 'Gene', (36, 40))	('loss', 'NegReg', (96, 100))
180169	32117751	showed that the additional disruption of Cdkn2b further added to the aggressiveness of the resulting MMs, providing also an explanation for the predominance of deletion of the complete CDKN2A-CDKN2B locus in human MM over point mutations in CDKN2A (Badhai et al., submitted).	('point mutations', 'Var', (222, 237))	('Cdkn2b', 'Gene', (41, 47))	('deletion', 'Var', (160, 168))	('aggressiveness', 'Disease', 'MESH:D001523', (69, 83))	('disruption', 'Var', (27, 37))	('MM', 'Disease', 'MESH:C562839', (101, 103))	('CDKN2B', 'Gene', (192, 198))	('MMs', 'Chemical', 'MESH:D008741', (101, 104))	('MM', 'Disease', 'MESH:C562839', (214, 216))	('aggressiveness', 'Disease', (69, 83))	('human', 'Species', '9606', (208, 213))	('CDKN2B', 'Gene', '1030', (192, 198))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
180170	32117751	Because CDKN2A deletions encompassing the sequence encoding p14ARF, a component of the p53 pathway, have been documented in 90% of human MM cell lines and TP53 is altered in about 15% of primary MMs, and because the PI3K/PTEN/AKT pathway is activated in most human MPMs, Sementino et al.	('p14ARF', 'Gene', (60, 66))	('CDKN2A', 'Gene', (8, 14))	('MMs', 'Chemical', 'MESH:D008741', (195, 198))	('PI3K', 'molecular_function', 'GO:0016303', ('216', '220'))	('MM', 'Disease', 'MESH:C562839', (195, 197))	('human', 'Species', '9606', (131, 136))	('p14ARF', 'Gene', '1029', (60, 66))	('human', 'Species', '9606', (259, 264))	('MPM', 'Disease', 'MESH:C562839', (265, 268))	('deletions', 'Var', (15, 24))	('MPM', 'Disease', (265, 268))	('PI3K/PTEN/AKT pathway', 'Pathway', (216, 237))	('MM', 'Disease', 'MESH:C562839', (137, 139))
180171	32117751	decided to determine if alterations affecting the same pathways would also induce MM in mice.	('MM', 'Disease', 'MESH:C562839', (82, 84))	('alterations', 'Var', (24, 35))	('induce', 'Reg', (75, 81))	('mice', 'Species', '10090', (88, 92))	('rat', 'Species', '10116', (28, 31))
180172	32117751	The investigators demonstrated that while neither adeno-Cre-mediated homozygous deletion of Tp53 or Pten alone in the mesothelium was sufficient to induce MM formation, compound deletion of these two TSGs resulted in rapid, aggressive peritoneal and pleural MMs (median latency: 9 and 19 weeks, respectively).	('TSG', 'Gene', '65960', (200, 203))	('deletion', 'Var', (80, 88))	('MM', 'Disease', 'MESH:C562839', (258, 260))	('MM', 'Disease', 'MESH:C562839', (155, 157))	('TSG', 'Gene', (200, 203))	('pleural MMs', 'Disease', (250, 261))	('pleural MMs', 'Disease', 'MESH:D010995', (250, 261))	('induce', 'Reg', (148, 154))	('rat', 'Species', '10116', (25, 28))	('Tp53', 'Gene', (92, 96))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))
180178	32117751	For instance, given that this model has homozygous loss of Tp53, this precludes studies of a drug such as RITA, which reactivates p53's pro-apoptotic function in tumor cells that preserve expression of mutant or wild-type p53.	('reactivates', 'NegReg', (118, 129))	('RITA', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Tp53', 'Gene', (59, 63))	('tumor', 'Disease', (162, 167))	('RITA', 'Gene', '100764', (106, 110))	('p53', 'Gene', (130, 133))	('p53', 'Gene', (222, 225))	('loss', 'NegReg', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('pro-apoptotic', 'MPA', (136, 149))	('mutant', 'Var', (202, 208))
180184	32117751	Due to often long-term in vitro propagation, these cell lines have invariably acquired (epi)genetic alterations that facilitate their propagation in cell culture, resulting in new vulnerabilities and resistance features.	('facilitate', 'PosReg', (117, 127))	('rat', 'Species', '10116', (104, 107))	('resistance features', 'MPA', (200, 219))	('propagation', 'CPA', (134, 145))	('vulnerabilities', 'MPA', (180, 195))	('alterations', 'Var', (100, 111))
180202	32117751	JT has a patent on BAP1 mutation testing and has provided legal consultation regarding the role of germline mutations of BAP1 in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('BAP1', 'Gene', (121, 125))	('mutation', 'Var', (24, 32))	('BAP1', 'Gene', (19, 23))	('mesothelioma', 'Disease', (129, 141))
180285	30370171	According to the assessment results of the WHO, p-aramid fibers have respirable fibers with similar dimensions as carcinogenic fibers and had effects on the lungs in an animal testing.	('p-aramid fibers', 'Var', (48, 63))	('effects', 'Reg', (142, 149))	('carcinogenic fibers', 'Disease', (114, 133))	('respirable fibers', 'MPA', (69, 86))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (114, 133))	('lungs', 'CPA', (157, 162))
180486	27794408	The patient cohort consisted of 16 non-consecutive mesothelioma patients, of whom eight were on treatment (including Vorinostat, Pemetrexed, cisplatin or carboplatin/Pemetrexed, cisplatin/Pemetrexed/CBP501, and GDC-0980) and eight were on observation.	('Pemetrexed', 'Chemical', 'MESH:D000068437', (188, 198))	('carboplatin', 'Chemical', 'MESH:D016190', (154, 165))	('patient', 'Species', '9606', (64, 71))	('patients', 'Species', '9606', (64, 72))	('GDC-0980', 'Chemical', 'MESH:C569670', (211, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('CBP', 'molecular_function', 'GO:0008140', ('199', '202'))	('mesothelioma', 'Disease', (51, 63))	('patient', 'Species', '9606', (4, 11))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (166, 176))	('Vorinostat', 'Chemical', 'MESH:D000077337', (117, 127))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (129, 139))	('cisplatin', 'Var', (141, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
180520	27794408	The authors specifically noted that "further evaluation of these modified criteria should be performed before they can be incorporated routinely into future clinical trials"; nevertheless, modified RECIST almost immediately became the standard for mesothelioma tumor response assessment.	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (248, 266))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('mesothelioma tumor', 'Disease', (248, 266))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (248, 266))	('modified', 'Var', (189, 197))
180598	24928783	Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos.	('Germline Mutation', 'Var', (0, 17))	('Accelerates', 'PosReg', (26, 37))	('Bap1', 'Gene', (21, 25))	('Malignant mesotheliomas', 'Disease', (93, 116))	('Asbestos-Induced Malignant Mesothelioma', 'Disease', (53, 92))	('asbestos', 'Chemical', 'MESH:D001194', (176, 184))	('Malignant mesotheliomas', 'Disease', 'MESH:C562839', (93, 116))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('Asbestos-Induced Malignant Mesothelioma', 'Disease', 'MESH:C562839', (53, 92))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (93, 115))	('Bap1', 'Gene', '104416', (21, 25))
180599	24928783	Germline inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers.	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('Germline inactivating mutations', 'Var', (0, 31))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('predispose', 'Reg', (40, 50))	('BAP1', 'Gene', (35, 39))	('mesothelioma', 'Disease', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
180600	24928783	However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers, are not known.	('mesothelioma', 'Disease', (13, 25))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('BAP1', 'Gene', (174, 178))	('mesothelioma', 'Disease', (158, 170))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('mutation', 'Var', (179, 187))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('malignancy', 'Disease', (45, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('BAP1', 'Gene', (64, 68))
180602	24928783	Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than WT littermates(73% vs. 32%, respectively).	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (59, 88))	('mice', 'Species', '10090', (8, 12))	('Bap1+/-', 'Var', (0, 7))	('asbestos-induced mesothelioma', 'Disease', (59, 88))
180603	24928783	Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice compared to WT animals(median survival, 43 weeks versus 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation.	('proliferation', 'CPA', (213, 226))	('mesotheliomas', 'Disease', 'MESH:D008654', (13, 26))	('mesotheliomas', 'Disease', (13, 26))	('accelerated', 'PosReg', (39, 50))	('increased', 'PosReg', (186, 195))	('Bap1+/-', 'Var', (59, 66))	('invasiveness', 'CPA', (196, 208))	('mice', 'Species', '10090', (67, 71))
180605	24928783	Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Bap1', 'Gene', (70, 74))	('mice', 'Species', '10090', (32, 36))	('cancer', 'Disease', (125, 131))	('biallelic inactivation', 'Var', (44, 66))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
180607	24928783	However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb.	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('mesothelioma', 'Disease', (38, 50))	('mice', 'Species', '10090', (189, 193))	('Ink4a', 'Gene', '12578', (117, 122))	('downregulation', 'NegReg', (82, 96))	('mice', 'Species', '10090', (70, 74))	('Rb', 'Chemical', 'MESH:D012413', (271, 273))	('Bap1+/-', 'Var', (62, 69))	('mesothelioma', 'Disease', (197, 209))	('Ink4a', 'Gene', (117, 122))	('Rb', 'Chemical', 'MESH:D012413', (100, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (38, 50))
180608	24928783	Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.	('BAP1', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mesothelioma', 'Disease', (196, 208))	('human', 'Species', '9606', (21, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('mutation', 'Var', (87, 95))	('asbestos', 'Chemical', 'MESH:D001194', (151, 159))
180613	24928783	identified a novel protein, BAP1 (BRCA1-associated protein 1), a nuclear-localized deubiquitylase, and intragenic homozygous rearrangements and deletions of BAP1 were found in several lung carcinoma cell lines(8).	('lung carcinoma', 'Disease', 'MESH:D008175', (184, 198))	('lung carcinoma', 'Disease', (184, 198))	('BAP1', 'Gene', (157, 161))	('deletions', 'Var', (144, 153))	('BRCA1-associated protein 1', 'Gene', (34, 60))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('83', '97'))	('found', 'Reg', (167, 172))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('BRCA1-associated protein 1', 'Gene', '104416', (34, 60))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
180615	24928783	Indeed, the high incidence(~25-60%) of somatic BAP1 mutations reported in MM implicates defects of this putative tumor suppressor gene along with frequent alterations of CDKN2A(13, 14), which encodes the tumor suppressors p16(INK4A) and p14(ARF), as well as NF2(15, 16) as the main drivers of MM tumorigenesis identified to date.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('defects', 'NegReg', (88, 95))	('NF2', 'Gene', '18016', (258, 261))	('ARF', 'Disease', 'MESH:D058186', (241, 244))	('CDKN2A', 'Gene', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (296, 301))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('BAP1', 'Gene', (47, 51))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('ARF', 'Disease', (241, 244))	('mutations', 'Var', (52, 61))	('p14', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('NF2', 'Gene', (258, 261))	('p14', 'Gene', '18542', (237, 240))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
180616	24928783	Importantly, in 2011 germline BAP1 mutations were found in two families with multiple MMs (one also having two UMs) as well as in two sporadic cases affected by both MM and UM(11), the first demonstration that a hereditary defect can affect risk of MM.	('BAP1', 'Gene', (30, 34))	('MMs', 'Chemical', 'MESH:D008741', (86, 89))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('found', 'Reg', (50, 55))	('mutations', 'Var', (35, 44))	('affect', 'Reg', (234, 240))
180617	24928783	described germline BAP1 mutations in two families with atypical melanocytic tumors, UM and cutaneous melanoma (CM)(17), and similar findings were reported by others (18).	('melanocytic tumors', 'Disease', 'MESH:D009508', (64, 82))	('melanocytic tumors', 'Disease', (64, 82))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('CM', 'Disease', 'MESH:D009202', (111, 113))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cutaneous melanoma', 'Disease', (91, 109))	('BAP1', 'Gene', (19, 23))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('mutations', 'Var', (24, 33))	('CM', 'Phenotype', 'HP:0012056', (111, 113))
180618	24928783	Collectively, the observations in these high-risk cancer families have led investigators to propose that germline BAP1 mutations cause a novel cancer susceptibility syndrome characterized by a high incidence of MM, UM, CM and probably additional cancers(19, 20).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cause', 'Reg', (129, 134))	('CM', 'Disease', 'MESH:D009202', (219, 221))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancer', 'Disease', (246, 252))	('cancers', 'Disease', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('CM', 'Phenotype', 'HP:0012056', (219, 221))	('UM', 'Phenotype', 'HP:0007716', (215, 217))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
180620	24928783	We have hypothesized that when families with germline BAP1 mutations are exposed to asbestos, MM may represent the predominant cancer observed(11).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('germline', 'Var', (45, 53))	('asbestos', 'Chemical', 'MESH:D001194', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (127, 133))	('BAP1', 'Gene', (54, 58))
180622	24928783	(2012) reported a germline BAP1 mutation in a European family with four MMs, none with any known exposure to asbestos(26).	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('BAP1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('MMs', 'Chemical', 'MESH:D008741', (72, 75))
180623	24928783	Thus, it is possible that exposure to carcinogenic mineral fibers may not be required for development of MM in BAP1 mutation carriers.	('carcinogenic mineral fibers', 'Disease', 'MESH:C537337', (38, 65))	('carriers', 'Reg', (125, 133))	('mutation', 'Var', (116, 124))	('carcinogenic mineral fibers', 'Disease', (38, 65))	('BAP1', 'Gene', (111, 115))
180625	24928783	While conditional, whole-body (except brain) homozygous deletion of Bap1 in adult mice recapitulates features of human myelodysplastic syndrome (MDS)(27), studies of germline heterozygous mutation of Bap1 have not been described to date.	('deletion', 'Var', (56, 64))	('Bap1', 'Gene', (68, 72))	('mice', 'Species', '10090', (82, 86))	('MDS', 'Disease', (145, 148))	('MDS', 'Disease', 'MESH:D009190', (145, 148))	('MDS', 'Phenotype', 'HP:0002863', (145, 148))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (119, 143))	('myelodysplastic syndrome', 'Disease', (119, 143))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (119, 143))	('human', 'Species', '9606', (113, 118))
180627	24928783	While no spontaneous MMs or MDS were seen in unexposed Bap1+/- mice followed for up to 20 months of age, such haploinsufficient mutant mice exhibited a markedly higher incidence and accelerated onset of asbestos-induced MM when compared to wild-type (WT) littermates.	('MMs', 'Chemical', 'MESH:D008741', (21, 24))	('asbestos', 'Chemical', 'MESH:D001194', (203, 211))	('MDS', 'Disease', (28, 31))	('MDS', 'Disease', 'MESH:D009190', (28, 31))	('MDS', 'Phenotype', 'HP:0002863', (28, 31))	('haploinsufficient', 'Disease', (110, 127))	('asbestos-induced', 'Disease', (203, 219))	('mice', 'Species', '10090', (63, 67))	('mutant', 'Var', (128, 134))	('mice', 'Species', '10090', (135, 139))	('accelerated', 'PosReg', (182, 193))	('higher', 'PosReg', (161, 167))	('haploinsufficient', 'Disease', 'MESH:D058495', (110, 127))
180628	24928783	Mechanistically, we also demonstrate that predisposition of Bap1+/- mice to MM may be facilitated, in part, by cooperation between Bap1 and p16(Ink4a)-independent epigenetic inactivation of Rb.	('mice', 'Species', '10090', (68, 72))	('Ink4a', 'Gene', '12578', (144, 149))	('Ink4a', 'Gene', (144, 149))	('epigenetic inactivation', 'Var', (163, 186))	('Rb', 'Chemical', 'MESH:D012413', (190, 192))
180646	24928783	To assess cell proliferation and apoptosis, IHC staining of tumors was performed with antibodies for Ki-67 (Dako)and cleaved caspase 3(Cell Signaling), respectively.	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('Signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('cleaved', 'Var', (117, 124))	('Ki-67', 'Gene', '17345', (101, 106))	('Ki-67', 'Gene', (101, 106))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('10', '28'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
180652	24928783	Primary MM cells were isolated from ascitic fluid and/or peritoneal lavage from Bap1+/- and WT mice as described (30).	('ascitic', 'Disease', 'MESH:D001201', (36, 43))	('mice', 'Species', '10090', (95, 99))	('ascitic', 'Disease', (36, 43))	('Bap1+/-', 'Var', (80, 87))
180669	24928783	Bone marrow smears from the three 18-month-old Bap1+/- mice showed no evidence of MDS or other hematological disease, and no macroscopic and microscopic abnormalities of the uvea, skin, mesothelial tissues, or other organs were observed except for the single SCC.	('hematological disease', 'Disease', (95, 116))	('abnormalities of the uvea', 'Phenotype', 'HP:0000553', (153, 178))	('Bap1+/-', 'Var', (47, 54))	('abnormalities of the uvea', 'Disease', 'MESH:C536494', (153, 178))	('mice', 'Species', '10090', (55, 59))	('hematological disease', 'Disease', 'MESH:D006402', (95, 116))	('abnormalities of the uvea', 'Disease', (153, 178))	('hematological disease', 'Phenotype', 'HP:0001871', (95, 116))	('MDS', 'Phenotype', 'HP:0002863', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (259, 262))	('MDS', 'Disease', (82, 85))	('MDS', 'Disease', 'MESH:D009190', (82, 85))
180673	24928783	Abdominal swelling was observed in Bap1+/- mice as early as 20 weeks after the first injection of asbestos, whereas WT animals did not begin showing this effect until 27 weeks after the initial injection.	('mice', 'Species', '10090', (43, 47))	('Bap1+/-', 'Var', (35, 42))	('Abdominal swelling', 'Disease', 'MESH:D015746', (0, 18))	('Abdominal swelling', 'Phenotype', 'HP:0003270', (0, 18))	('observed', 'Reg', (23, 31))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('Abdominal swelling', 'Disease', (0, 18))
180674	24928783	Eventually, 90% of the asbestos-exposed Bap1+/- mice showed abdominal distention, and ~60% of these were found to have as cites when sacrificed.	('abdominal distention', 'Phenotype', 'HP:0003270', (60, 80))	('Bap1+/-', 'Var', (40, 47))	('mice', 'Species', '10090', (48, 52))	('abdominal distention', 'CPA', (60, 80))	('asbestos', 'Chemical', 'MESH:D001194', (23, 31))
180677	24928783	The Bap1+/- mice were found to succumb to disease earlier than their WT littermates, with a median survival of 43 weeks from the time of the first asbestos injection in Bap1+/- mice versus 55 weeks in WT mice (Fig.	('Bap1+/-', 'Var', (4, 11))	('mice', 'Species', '10090', (12, 16))	('mice', 'Species', '10090', (177, 181))	('asbestos', 'Chemical', 'MESH:D001194', (147, 155))	('mice', 'Species', '10090', (204, 208))	('Bap1+/-', 'Var', (169, 176))
180679	24928783	Other deaths in WT and Bap1+/- mice occurred mainly due to plaque-related organ failure or intestinal obstructions related to fibrosis.	('plaque-related', 'Disease', (59, 73))	('deaths', 'Disease', 'MESH:D003643', (6, 12))	('Bap1+/-', 'Var', (23, 30))	('intestinal obstructions', 'Phenotype', 'HP:0005214', (91, 114))	('fibrosis', 'Disease', 'MESH:D005355', (126, 134))	('fibrosis', 'Disease', (126, 134))	('mice', 'Species', '10090', (31, 35))	('organ failure', 'Disease', (74, 87))	('organ failure', 'Disease', 'MESH:D009102', (74, 87))	('intestinal obstructions', 'Disease', (91, 114))	('deaths', 'Disease', (6, 12))
180682	24928783	Notably, asbestos-induced MMs seen in Bap1+/- mice were consistently larger and more aggressive than those found in WT littermates, often with invasion to the pancreas, liver, and/or intestinal smooth muscle (Suppl.	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('pancreas', 'Disease', (159, 167))	('MMs', 'Chemical', 'MESH:D008741', (26, 29))	('mice', 'Species', '10090', (46, 50))	('Bap1+/-', 'Var', (38, 45))	('pancreas', 'Disease', 'MESH:D010190', (159, 167))	('aggressive', 'CPA', (85, 95))	('more', 'PosReg', (80, 84))
180683	24928783	3); occasional metastasis to the lungs was also observed in the Bap1+/- mice.	('metastasis to the lungs', 'CPA', (15, 38))	('Bap1+/-', 'Var', (64, 71))	('mice', 'Species', '10090', (72, 76))
180684	24928783	Moreover, tumors in Bap1+/- mice were more proliferative based on Ki-67 staining (Suppl.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (28, 32))	('Ki-67', 'Gene', (66, 71))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('more', 'PosReg', (38, 42))	('proliferative', 'CPA', (43, 56))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Bap1+/-', 'Var', (20, 27))	('Ki-67', 'Gene', '17345', (66, 71))
180693	24928783	Intriguingly, aCGH analysis revealed that all three MM cell cultures derived from WT mice had homozygous deletions of the Cdkn2a/Cdkn2b loci, whereas MM cells from two Bap1+/- mice did not (Fig.	('Cdkn2b', 'Gene', (129, 135))	('mice', 'Species', '10090', (85, 89))	('deletions', 'Var', (105, 114))	('Cdkn2a', 'Gene', '12578', (122, 128))	('Cdkn2b', 'Gene', '12579', (129, 135))	('Cdkn2a', 'Gene', (122, 128))	('mice', 'Species', '10090', (176, 180))
180696	24928783	Interestingly, expression of Rb was strikingly decreased in MM cells from Bap1+/- mice, which showed no expression of Bap1 protein, when compared toBap1-expressing MM cells from WT tumors that lacked expression of p16Ink4a(Fig.	('mice', 'Species', '10090', (82, 86))	('WT tumors', 'Disease', 'MESH:C536751', (178, 187))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('p16Ink4a', 'Gene', '12578', (214, 222))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Bap1+/-', 'Var', (74, 81))	('p16Ink4a', 'Gene', (214, 222))	('WT tumors', 'Disease', (178, 187))	('expression', 'MPA', (15, 25))	('Rb', 'Chemical', 'MESH:D012413', (29, 31))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('decreased', 'NegReg', (47, 56))
180698	24928783	Surprisingly, expression of total Rb protein was markedly decreased in tumor cells from Bap1+/- mice.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('Rb protein', 'Protein', (34, 44))	('mice', 'Species', '10090', (96, 100))	('Bap1+/-', 'Var', (88, 95))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
180699	24928783	Quantitative RT-PCR revealed that the mRNA expression levels of Rb1 in MM cells from the Bap1+/- mice were less than half that of tumor cells from WT mice (Fig.	('less', 'NegReg', (107, 111))	('mice', 'Species', '10090', (150, 154))	('Bap1+/-', 'Var', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mice', 'Species', '10090', (97, 101))	('Rb1', 'Gene', (64, 67))	('mRNA expression levels', 'MPA', (38, 60))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Rb1', 'Gene', '19645', (64, 67))	('tumor', 'Disease', (130, 135))
180700	24928783	Intriguingly, expression of Rb1 mRNA and Rb protein was also found to be down regulated in early passage (<=3) normal mesothelial cells isolated from Bap1+/- mice compared to those from WT mice (Fig.	('Bap1+/-', 'Var', (150, 157))	('Rb protein', 'Protein', (41, 51))	('mice', 'Species', '10090', (158, 162))	('mice', 'Species', '10090', (189, 193))	('Rb', 'Chemical', 'MESH:D012413', (41, 43))	('expression', 'MPA', (14, 24))	('down regulated', 'NegReg', (73, 87))	('Rb', 'Chemical', 'MESH:D012413', (28, 30))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('protein', 'Protein', (44, 51))	('Rb1', 'Gene', (28, 31))	('Rb1', 'Gene', '19645', (28, 31))
180702	24928783	Since aCGH analysis did not uncover any DNA copy number changes at theRb1 locus in any of the MM cell cultures tested, we hypothesized that the decreased Rb1 expression was due to aberrant epigenetic modification of the Rb1 gene in MM cells from Bap1+/- mice.	('decreased', 'NegReg', (144, 153))	('Rb1', 'Gene', (70, 73))	('Rb1', 'Gene', '19645', (70, 73))	('expression', 'MPA', (158, 168))	('mice', 'Species', '10090', (254, 258))	('Rb1', 'Gene', (154, 157))	('Rb1', 'Gene', '19645', (154, 157))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('epigenetic modification', 'Var', (189, 212))	('Rb1', 'Gene', (220, 223))	('Rb1', 'Gene', '19645', (220, 223))
180705	24928783	Indeed, we found that treatment of Bap1-null MM cells with 5-Aza-CdRsignificantly increased the expression of Rb (Fig.	('5-Aza', 'Chemical', 'MESH:D001374', (59, 64))	('5-Aza-CdRsignificantly', 'Var', (59, 81))	('expression', 'MPA', (96, 106))	('Rb', 'Chemical', 'MESH:D012413', (110, 112))	('increased', 'PosReg', (82, 91))
180707	24928783	Collectively, these findings suggest that the lower expression of Rb1 in Bap1-null MM cells is due to hypermethylation of theRb1 promoter.	('Rb1', 'Gene', (125, 128))	('Rb1', 'Gene', '19645', (125, 128))	('expression', 'MPA', (52, 62))	('lower', 'NegReg', (46, 51))	('hypermethylation', 'Var', (102, 118))	('Rb1', 'Gene', (66, 69))	('Rb1', 'Gene', '19645', (66, 69))
180709	24928783	Interestingly, we found MM cell cultures from both WT and Bap1+/- mice were sensitive to the E2f inhibitor, but only the cells derived from WT mice were highly sensitive to the Cdk4/6 inhibitor.	('Cdk4/6', 'Gene', (177, 183))	('E2f inhibitor', 'MPA', (93, 106))	('Bap1+/-', 'Var', (58, 65))	('mice', 'Species', '10090', (66, 70))	('Cdk', 'molecular_function', 'GO:0004693', ('177', '180'))	('Cdk4/6', 'Gene', '12567;12571', (177, 183))	('sensitive', 'MPA', (76, 85))	('mice', 'Species', '10090', (143, 147))
180710	24928783	p16(Ink4a)is known to inhibit the activity of a complex composed by cyclin D, Cdk4 and Cdk6, leading to inactivation of Rb by phosphorylation, thereby abolishing binding between Rb and E2f, leading to activation of E2f target genes.	('activity', 'MPA', (34, 42))	('Cdk4', 'Gene', (78, 82))	('Ink4a', 'Gene', '12578', (4, 9))	('cyclin', 'molecular_function', 'GO:0016538', ('68', '74'))	('Ink4a', 'Gene', (4, 9))	('E2f', 'Protein', (185, 188))	('Cdk6', 'Gene', '12571', (87, 91))	('activation', 'PosReg', (201, 211))	('Cdk', 'molecular_function', 'GO:0004693', ('87', '90'))	('inactivation', 'NegReg', (104, 116))	('inhibit', 'NegReg', (22, 29))	('Cdk4', 'Gene', '12567', (78, 82))	('binding', 'Interaction', (162, 169))	('phosphorylation', 'MPA', (126, 141))	('Rb', 'Chemical', 'MESH:D012413', (178, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('abolishing', 'NegReg', (151, 161))	('Cdk6', 'Gene', (87, 91))	('p16', 'Var', (0, 3))	('Rb', 'Chemical', 'MESH:D012413', (120, 122))	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('Cdk', 'molecular_function', 'GO:0004693', ('78', '81'))
180719	24928783	Importantly, MM development was significantly accelerated and more aggressive in the Bap1+/- mice, providing unbiased genetic evidence supporting a fundamental role of Bap1 loss in MM pathogenesis.	('accelerated', 'PosReg', (46, 57))	('Bap1+/-', 'Var', (85, 92))	('Bap1', 'Gene', (168, 172))	('aggressive', 'CPA', (67, 77))	('more', 'PosReg', (62, 66))	('MM development', 'CPA', (13, 27))	('loss', 'NegReg', (173, 177))	('mice', 'Species', '10090', (93, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('184', '196'))
180723	24928783	In our report of human BAP1 families(11), all of the available MM specimens seen in BAP1 mutation carriers were of the epithelial type, although the significance of this finding could not be established due to the relatively small number of cases evaluated.	('human', 'Species', '9606', (17, 22))	('BAP1', 'Gene', (84, 88))	('mutation', 'Var', (89, 97))
180725	24928783	could find no obvious difference in tumor histology among MMs with and without somatic BAP1 mutations (39).	('MMs', 'Chemical', 'MESH:D008741', (58, 61))	('BAP1', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
180726	24928783	Collectively, the experimental findings summarized here indicate that germline Bap1 mutation predisposes to the tumorigenic effects of asbestos.	('predisposes', 'Reg', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Bap1', 'Gene', (79, 83))	('asbestos', 'Chemical', 'MESH:D001194', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('germline', 'Var', (70, 78))	('tumor', 'Disease', (112, 117))	('mutation', 'Var', (84, 92))
180727	24928783	By using an unbiased genetic model system and chronic exposure to asbestos, we have been able to demonstrate that germline haploinsufficiency for Bap1 causes increased susceptibility to asbestos-induced MM formation, which may be facilitated, at least in part, by a p16(Ink4a)-independent mechanism involving epigenetic dysregulation of Rb.	('Ink4a', 'Gene', '12578', (270, 275))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('haploinsufficiency', 'Disease', 'MESH:D058495', (123, 141))	('Ink4a', 'Gene', (270, 275))	('MM formation', 'CPA', (203, 215))	('asbestos', 'Chemical', 'MESH:D001194', (186, 194))	('susceptibility', 'Reg', (168, 182))	('epigenetic dysregulation', 'Var', (309, 333))	('Rb', 'Chemical', 'MESH:D012413', (337, 339))	('Bap1', 'Gene', (146, 150))	('haploinsufficiency', 'Disease', (123, 141))
180728	24928783	Although loss of p16(INK4A) expression, via homozygous deletion of CDKN2A, has long been known to be a frequent finding in human MM(13, 14), a recent integrated genomic analysis of 53 sporadic pleural MMs revealed that 6 of 12 tumors with BAP1 mutations did not exhibit allelic losses of CDKN2A; moreover, 17 of 20 tumors with homozygous losses of CDKN2A did not show point mutations in BAP1(10).	('tumors', 'Disease', (315, 321))	('CDKN2A', 'Gene', (67, 73))	('BAP1', 'Gene', (387, 391))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('human', 'Species', '9606', (123, 128))	('tumors', 'Disease', (227, 233))	('loss', 'NegReg', (9, 13))	('pleural MMs', 'Disease', (193, 204))	('pleural MMs', 'Disease', 'MESH:D010995', (193, 204))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('deletion', 'Var', (55, 63))	('mutations', 'Var', (244, 253))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('BAP1', 'Gene', (239, 243))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
180729	24928783	It is also noteworthy that our earlier aCGH analysis of MMs from two unrelated BAP1 mutation carriers revealed no homozygous losses of CDKN2A, although one of the tumors did exhibit monosomy 9, resulting in heterozygous loss of CDKN2A(11).	('CDKN2A', 'Gene', (135, 141))	('losses', 'NegReg', (125, 131))	('mutation', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CDKN2A', 'MPA', (228, 234))	('BAP1', 'Gene', (79, 83))	('MMs', 'Chemical', 'MESH:D008741', (56, 59))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('loss', 'NegReg', (220, 224))
180732	24928783	Relevant to this possibility, germline heterozygous mutations of other cancer susceptibility genes, such as the tumor suppressor gene VHL connected with hereditary renal cancer, have been shown to alter the mRNA expression profiles of primary cultures of phenotypically normal epithelial cells in a gene-specific manner, and in some instances the expression data confirmed what is known about key tumorigenic pathways affected by biallelic mutations of such tumor suppressor genes (40).	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('cancer', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('458', '474'))	('cancer', 'Disease', (71, 77))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('renal cancer', 'Phenotype', 'HP:0009726', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('458', '474'))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('biallelic mutations', 'Var', (430, 449))	('tumor', 'Disease', (397, 402))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('mutations', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('hereditary renal cancer', 'Disease', 'MESH:D007680', (153, 176))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('VHL', 'Disease', (134, 137))	('alter', 'Reg', (197, 202))	('hereditary renal cancer', 'Disease', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (458, 463))	('mRNA expression profiles', 'MPA', (207, 231))
180733	24928783	In Bap1+/- mice, heterozygous ("one hit") mutation is associated with alteration in the expression of a central node (Rb) in a cellular corridor - the p16(Ink4a)-Rb pathway - that is strongly implicated in MM pathogenesis generally.	('Rb', 'Gene', (118, 120))	('expression', 'MPA', (88, 98))	('Rb', 'Chemical', 'MESH:D012413', (118, 120))	('mice', 'Species', '10090', (11, 15))	('Ink4a', 'Gene', '12578', (155, 160))	('mutation', 'Var', (42, 50))	('Rb', 'Chemical', 'MESH:D012413', (162, 164))	('Ink4a', 'Gene', (155, 160))	('alteration', 'Reg', (70, 80))
180736	24928783	Germane to this possibility, the initial two reports of families with germline BAP1 mutations were paradoxical, with our group reporting two families with multiple (5 and 7) MMs(11), and a second group describing two families with atypical melanocytic neoplasms but no MMs (17), although a follow up study uncovered a single MM in one of the latter families(26).	('MMs', 'Chemical', 'MESH:D008741', (174, 177))	('MMs', 'Chemical', 'MESH:D008741', (269, 272))	('neoplasms', 'Phenotype', 'HP:0002664', (252, 261))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (240, 261))	('BAP1', 'Gene', (79, 83))	('melanocytic neoplasms', 'Disease', (240, 261))	('mutations', 'Var', (84, 93))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (240, 261))
180737	24928783	Rather than representing two dissimilar cancer-related syndromes, it became apparent that germline BAP1 mutations are associated with a spectrum of neoplasms, suggesting that BAP1 has acritical tumor suppressor function in a variety of tissues (41, 42).	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('neoplasms', 'Disease', (148, 157))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('neoplasms', 'Disease', 'MESH:D009369', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Disease', (40, 46))	('acritical tumor', 'Disease', (184, 199))	('tumor suppressor', 'biological_process', 'GO:0051726', ('194', '210'))	('associated', 'Reg', (118, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('acritical tumor', 'Disease', 'MESH:D009369', (184, 199))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('194', '210'))
180740	24928783	Based on our earlier work on two BAP1 families with multiple MMs(11),it appears that the level of asbestos exposure need not be high in BAP1 mutation carriers, as occupational histories on those families did not suggest any obvious exposure, and only modest or trace levels of asbestos were found in their homes.	('BAP1', 'Gene', (136, 140))	('mutation', 'Var', (141, 149))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('asbestos', 'Chemical', 'MESH:D001194', (277, 285))	('MMs', 'Chemical', 'MESH:D008741', (61, 64))
180742	24928783	Drawing parallels to humans, our findings provide experimental support for the idea that BAP1 mutation carriers may be highly susceptible to MM even at modest levels of asbestos exposure that would be considerably less tumorigenic in the general population and, thus, would require close clinical monitoring with the goal of early detection and intervention.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('BAP1', 'Gene', (89, 93))	('tumor', 'Disease', (219, 224))	('susceptible', 'Reg', (126, 137))	('asbestos', 'Chemical', 'MESH:D001194', (169, 177))	('humans', 'Species', '9606', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('mutation', 'Var', (94, 102))
180899	19099560	The role of Simian virus (SV-40) in the pathogenesis of mesothelioma is more controversial; SV-40 was found to contaminate polio vaccines in the 1950s and 60s in the UK, and although it has been suggested that it is a causative factor in the development of mesothelioma, recent studies have found no link.	('mesothelioma', 'Disease', (257, 269))	('mesothelioma', 'Disease', (56, 68))	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('men', 'Species', '9606', (249, 252))	('pathogenesis', 'biological_process', 'GO:0009405', ('40', '52'))	('SV-40', 'Var', (92, 97))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
180912	19099560	Infiltration of the pericardium can result in signs of cardiac tamponade, and mesothelioma can grow along needle tracks and incisions.	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('cardiac tamponade', 'Disease', (55, 72))	('result in', 'Reg', (36, 45))	('Infiltration', 'Var', (0, 12))	('mesothelioma', 'Disease', (78, 90))
180955	19099560	Soluble mesothelin related proteins (SMRP) are serum proteins thought to be released by alternative splicing of the mesothelin protein and thereby preventing adherence to cell membranes.	('mesothelin', 'Gene', '10232', (116, 126))	('mesothelin', 'Gene', (8, 18))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('alternative splicing', 'Var', (88, 108))	('mesothelin', 'Gene', (116, 126))	('Soluble', 'cellular_component', 'GO:0005625', ('0', '7'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('mesothelin', 'Gene', '10232', (8, 18))	('preventing', 'NegReg', (147, 157))	('adherence to cell membranes', 'CPA', (158, 185))
180985	19099560	Despite the possibilities for improved tumour control, however, IMRT still carries a potential risk of fatal pulmonary toxicity in mesothelioma.	('IMRT', 'Var', (64, 68))	('tumour', 'Disease', (39, 45))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (109, 127))	('mesothelioma', 'Disease', (131, 143))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))	('pulmonary toxicity', 'Disease', (109, 127))
180994	19099560	The impact of P/D on overall survival is contentious, with some evidence suggesting that P/D surgery via a VATS approach may provide a survival benefit in patients with advanced disease not suitable for EPP, whilst other studies do not clearly distinguish the benefit of P/D over EPP.	('patients', 'Species', '9606', (155, 163))	('survival', 'MPA', (135, 143))	('benefit', 'PosReg', (144, 151))	('P/D', 'Var', (89, 92))
181183	32751556	The angiogenic activity is flanked by a pivotal role in the promotion of cell migration and metastasis in many tumor types, and the main mediators of this activity seem to be miR-9, miR-105, miR-142-3p, miR-210, miR-19a and H19 lncRNA.	('miR-19a', 'Gene', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('H19', 'Gene', '283120', (224, 227))	('cell migration', 'biological_process', 'GO:0016477', ('73', '87'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('H19', 'Gene', (224, 227))	('metastasis', 'CPA', (92, 102))	('miR-142-3p', 'Var', (191, 201))	('miR-9', 'Var', (175, 180))	('tumor', 'Disease', (111, 116))	('miR-19a', 'Gene', '406979', (212, 219))	('cell migration', 'CPA', (73, 87))	('miR-105', 'Var', (182, 189))	('angiogenic activity', 'CPA', (4, 23))	('promotion', 'PosReg', (60, 69))	('miR-210', 'Gene', (203, 210))	('miR-210', 'Gene', '406992', (203, 210))
181188	32751556	The inhibition of exosome production in TNBC has been deepened through the blocking of ESCRT-independent pathways, or silencing the Rab27, which mediate another exosome-production pathway: in both cases, experimental evidence shows a slowing down of cell proliferation rate and reduction of local growth and metastasis.	('reduction', 'NegReg', (278, 287))	('Rab27', 'Gene', (132, 137))	('men', 'Species', '9606', (210, 213))	('exosome', 'cellular_component', 'GO:0070062', ('161', '168'))	('Rab27', 'Gene', '5873', (132, 137))	('exosome', 'cellular_component', 'GO:0070062', ('18', '25'))	('TNBC', 'Disease', 'None', (40, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('250', '268'))	('TNBC', 'Disease', (40, 44))	('silencing', 'Var', (118, 127))	('exosome-production', 'biological_process', 'GO:0097734', ('161', '179'))	('cell proliferation rate', 'CPA', (250, 273))	('slowing down', 'NegReg', (234, 246))	('exosome production', 'biological_process', 'GO:0097734', ('18', '36'))	('ESCRT-independent pathways', 'Pathway', (87, 113))
181244	32751556	Following this, it was possible to underline several proteins that constitute a sort of molecular "fingerprint" of MPM: the list of potential candidates as mesothelioma biomarkers includes, but is not limited to, Piruvate Kinase, Annexin A1 and A2, Heat Shock Cognate 71, Heat Shock Protein 90, Alpha Enolase, glucose6-phosphate1-dehydrogenase and 5 tubulin isotypes (such as TUBB4A, Q8IWP6 and B3KPS3).	('Heat Shock Protein 90, Alpha Enolase', 'Gene', '2023', (272, 308))	('TUBB4A', 'Gene', '10382', (376, 382))	('mesothelioma', 'Disease', 'MESH:D008654', (156, 168))	('Shock', 'Phenotype', 'HP:0031273', (277, 282))	('Annexin A1', 'Gene', '301', (230, 240))	('glucose6-phosphate1-dehydrogenase', 'Enzyme', (310, 343))	('MPM', 'Chemical', '-', (115, 118))	('glucose', 'Chemical', 'MESH:D005947', (310, 317))	('Q8IWP6', 'Var', (384, 390))	('Shock', 'Phenotype', 'HP:0031273', (254, 259))	('Annexin A1', 'Gene', (230, 240))	('B3KPS3', 'Disease', (395, 401))	('mesothelioma', 'Disease', (156, 168))	('TUBB4A', 'Gene', (376, 382))
181249	32751556	Finally, it has been observed how, through the exosome-mediated expression of CD39 and CD73, MPM can induce the extracellular expression of adenosine that, in turn, behaves as an immunomodulator exerting an anti-inflammatory action by suppressing the T-cell mediated response.	('CD39', 'Gene', (78, 82))	('suppressing', 'NegReg', (235, 246))	('CD73', 'Gene', '4907', (87, 91))	('MPM', 'Chemical', '-', (93, 96))	('CD39', 'Gene', '953', (78, 82))	('CD73', 'Gene', (87, 91))	('T-cell mediated response', 'CPA', (251, 275))	('exosome-mediated', 'biological_process', 'GO:0099156', ('47', '63'))	('extracellular', 'cellular_component', 'GO:0005576', ('112', '125'))	('exosome', 'cellular_component', 'GO:0070062', ('47', '54'))	('adenosine', 'Chemical', 'MESH:D000241', (140, 149))	('MPM', 'Var', (93, 96))	('extracellular expression', 'MPA', (112, 136))	('induce', 'PosReg', (101, 107))
181263	32751556	The trial showed that the progression free-survival (PFS) of patients treated with the compound ADI-PEG20 increased compared to the control group (15.7 months in the ADI-PEG20 group versus 12.1 months of PFS in the control group).	('ADI-PEG20', 'Chemical', 'MESH:C512527', (166, 175))	('PE', 'Phenotype', 'HP:0002202', (170, 172))	('patients', 'Species', '9606', (61, 69))	('increased', 'PosReg', (106, 115))	('ADI-PEG20', 'Var', (96, 105))	('progression free-survival', 'CPA', (26, 51))	('ADI-PEG20', 'Var', (166, 175))	('PE', 'Phenotype', 'HP:0002202', (100, 102))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (96, 105))
181284	28491037	Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization.	('mitotic arrest', 'Disease', (64, 78))	('tubulin', 'CPA', (125, 132))	('depolymerization', 'NegReg', (133, 149))	('mitotic arrest', 'Disease', 'MESH:D006323', (64, 78))	('HPR', 'Gene', '3250', (43, 46))	('sodium 4-carboxymethoxyimino-', 'Chemical', '-', (11, 40))	('multipolar spindle formation', 'CPA', (92, 120))	('sodium 4-carboxymethoxyimino-', 'Var', (11, 40))	('HPR', 'Gene', (43, 46))	('spindle', 'cellular_component', 'GO:0005819', ('103', '110'))	('spindle formation', 'biological_process', 'GO:0051225', ('103', '120'))
181310	28491037	The following antibodies used for immunoblotting were purchased from the indicated suppliers and used according the manufacturer testing conditions: PLAB and pJNK from Santa Cruz Biotechnology (Santa Cruz, CA, USA); cleaved caspase-3 and pEIF2alpha from Cell Signaling (Beverly, MA, USA); and GAPDH, alpha-tubulin, and actin from Sigma-Aldrich.	('JNK', 'Gene', (159, 162))	('cleaved', 'Var', (216, 223))	('caspase-3', 'Gene', '836', (224, 233))	('alpha-tubulin', 'Protein', (300, 313))	('GAPDH', 'Gene', '2597', (293, 298))	('EIF2alpha', 'Gene', '83939', (239, 248))	('JNK', 'Gene', '5599', (159, 162))	('Signaling', 'biological_process', 'GO:0023052', ('259', '268'))	('GAPDH', 'Gene', (293, 298))	('actin', 'Protein', (319, 324))	('EIF2alpha', 'Gene', (239, 248))	('caspase-3', 'Gene', (224, 233))
181335	28491037	The improvement in solubility obtained through the chemical modification of 4-oxo-4-HPR, prompted us to investigate the antitumor activity of this new derivative.	('solubility', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('chemical modification', 'Var', (51, 72))	('HPR', 'Gene', '3250', (84, 87))	('tumor', 'Disease', (124, 129))	('HPR', 'Gene', (84, 87))	('improvement', 'PosReg', (4, 15))
181352	28491037	We next investigated whether the two mechanisms of action of 4-carboxymethoxyimino-(4-HPR) described in A2780 were recapitulated also in other human cancer cells responsive to the retinoid.	('cancer', 'Disease', (149, 155))	('human', 'Species', '9606', (143, 148))	('4-carboxymethoxyimino', 'Chemical', '-', (61, 82))	('retinoid', 'Chemical', 'MESH:D012176', (180, 188))	('HPR', 'Gene', (86, 89))	('A2780', 'CellLine', 'CVCL:0134', (104, 109))	('A2780', 'Var', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HPR', 'Gene', '3250', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
181376	28491037	As a downstream effect, sodium 4-carboxymethoxyimino-(4-HPR) induced the activation of the entire ROS-related apoptotic cascade through the ER stress response (determined by the phosphorylation of EIF2alpha) and the upregulation of pJNK and PLAB, leading to caspase-3 cleavage.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('activation', 'PosReg', (73, 83))	('HPR', 'Gene', '3250', (56, 59))	('JNK', 'Gene', '5599', (233, 236))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('EIF2', 'cellular_component', 'GO:0005850', ('197', '201'))	('sodium 4-carboxymethoxyimino-', 'Chemical', '-', (24, 53))	('caspase-3', 'Gene', '836', (258, 267))	('ROS-related apoptotic cascade', 'Pathway', (98, 127))	('EIF2alpha', 'Gene', '83939', (197, 206))	('sodium 4-carboxymethoxyimino-', 'Var', (24, 53))	('HPR', 'Gene', (56, 59))	('upregulation', 'PosReg', (216, 228))	('ER stress response', 'Pathway', (140, 158))	('ER stress response', 'biological_process', 'GO:0034976', ('140', '158'))	('JNK', 'Gene', (233, 236))	('EIF2alpha', 'Gene', (197, 206))	('caspase-3', 'Gene', (258, 267))
181407	26140217	Genetic testing confirmed a novel and unusual germline mutation in the ubiquitin hydrolase domain of the BAP1 gene (p.Tyr173Cys) and the patient was diagnosed with the BAP1 hereditary cancer predisposition syndrome.	('BAP1', 'Gene', '8314', (168, 172))	('patient', 'Species', '9606', (137, 144))	('hereditary cancer', 'Disease', (173, 190))	('hereditary cancer', 'Disease', 'MESH:D009369', (173, 190))	('BAP1', 'Gene', '8314', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('BAP1', 'Gene', (168, 172))	('p.Tyr173Cys', 'Var', (116, 127))	('ubiquitin', 'molecular_function', 'GO:0031386', ('71', '80'))	('germline mutation in', 'Var', (46, 66))	('p.Tyr173Cys', 'Mutation', 'p.Y173C', (116, 127))	('BAP1', 'Gene', (105, 109))
181408	26140217	The diagnosis of a germline BAP1 mutation may have important implications for both the patient and their families with regards to further genetic testing and active surveillance programs.	('BAP1', 'Gene', '8314', (28, 32))	('patient', 'Species', '9606', (87, 94))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))
181412	26140217	Genetic studies of these families subsequently lead to the discovery of germline mutations in BAP1 and the recognition of a new cancer predisposition syndrome.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BAP1', 'Gene', '8314', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BAP1', 'Gene', (94, 98))	('germline mutations', 'Var', (72, 90))	('cancer', 'Disease', (128, 134))
181439	26140217	Testing for BAP1 mutations by immunohistochemistry showed loss of nuclear BAP1 labeling in the primary biliary tract adenocarcinoma, but nuclear labeling for BAP1 was retained in the malignant mesothelioma (Fig.	('labeling', 'MPA', (79, 87))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (183, 205))	('loss', 'NegReg', (58, 62))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (158, 162))	('nuclear', 'MPA', (66, 73))	('malignant mesothelioma', 'Disease', (183, 205))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (74, 78))	('BAP1', 'Gene', '8314', (74, 78))	('primary biliary tract adenocarcinoma', 'Disease', (95, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (183, 205))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('primary biliary tract adenocarcinoma', 'Disease', 'MESH:D001661', (95, 131))
181441	26140217	Germline DNA sequencing was performed and revealed the patient to carry a germline missense mutation in the catalytic domain (g.52441252A > G, p.Tyr173Cys) located in exon 7 of the BAP1 gene (Fig.	('BAP1', 'Gene', (181, 185))	('g.52441252A > G', 'Mutation', 'g.52441252A>G', (126, 141))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('patient', 'Species', '9606', (55, 62))	('BAP1', 'Gene', '8314', (181, 185))	('g.52441252A > G', 'Var', (126, 141))	('p.Tyr173Cys', 'Mutation', 'p.Y173C', (143, 154))
181447	26140217	Other cancers have been reported in families suffering germline mutations but no direct correlations have yet been established.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))	('germline mutations', 'Var', (55, 73))
181448	26140217	In a review of 76 patients with a BAP1 germline mutation, 53 patients had developed at least one malignancy with 13 developing at least two.	('BAP1', 'Gene', (34, 38))	('germline mutation', 'Var', (39, 56))	('patients', 'Species', '9606', (61, 69))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('patients', 'Species', '9606', (18, 26))	('BAP1', 'Gene', '8314', (34, 38))	('malignancy', 'Disease', (97, 107))
181450	26140217	This study highlights the strong link between germline BAP1 mutations and carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('BAP1', 'Gene', (55, 59))	('carcinogenesis', 'Disease', (74, 88))	('mutations', 'Var', (60, 69))	('BAP1', 'Gene', '8314', (55, 59))
181451	26140217	Here, we reported a case involving an individual with a germline BAP1 mutation who was diagnosed with 3 distinct malignancies in short succession, an event that appears uncommon even for individuals carrying a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (219, 223))	('malignancies', 'Disease', (113, 125))	('BAP1', 'Gene', (65, 69))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('germline', 'Var', (56, 64))	('mutation', 'Var', (70, 78))	('BAP1', 'Gene', '8314', (219, 223))
181455	26140217	BAP1 mutations may result in proteins that lack the nuclear localization sequence, or may affect its deubiquitinase activity.	('affect', 'Reg', (90, 96))	('BAP1', 'Gene', (0, 4))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('101', '124'))	('deubiquitinase activity', 'MPA', (101, 124))	('result in', 'Reg', (19, 28))	('proteins', 'Protein', (29, 37))	('mutations', 'Var', (5, 14))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('101', '124'))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('nuclear localization sequence', 'MPA', (52, 81))	('lack', 'NegReg', (43, 47))	('BAP1', 'Gene', '8314', (0, 4))
181456	26140217	It is not fully known why germline mutations may predispose to the development of certain cancers over others; most likely cell-type specific functions as well as gene-environment interactions play an important role.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('predispose', 'Reg', (49, 59))	('germline mutations', 'Var', (26, 44))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
181457	26140217	The BAP1 germline alteration identified in our patient was a missense mutation at the active site of its ubiquitin hydrolase domain.	('patient', 'Species', '9606', (47, 54))	('BAP1', 'Gene', (4, 8))	('ubiquitin', 'molecular_function', 'GO:0031386', ('105', '114'))	('missense mutation', 'Var', (61, 78))	('BAP1', 'Gene', '8314', (4, 8))
181458	26140217	Similar missense mutations were found in uveal melanoma (p.Ser172Arg) and pleural biphasic mesothelioma (p.Tyr173Ser) tissue.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('p.Tyr173Ser', 'Mutation', 'p.Y173S', (105, 116))	('p.Ser172Arg', 'Var', (57, 68))	('p.Ser172Arg', 'Mutation', 'p.S172R', (57, 68))	('p.Tyr173Ser', 'Var', (105, 116))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('Ser', 'cellular_component', 'GO:0005790', ('113', '116'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('pleural biphasic mesothelioma', 'Disease', (74, 103))	('pleural biphasic mesothelioma', 'Disease', 'MESH:D008654', (74, 103))
181461	26140217	Both N-terminus BAP1 mutations and C-terminus mutations lead to lack of BAP1 nuclear labeling due to either lack of the nuclear localization signal, or to lack of deubiquitinase activity, as autodeubiquition is required for nuclear transport of BAP1 protein.	('deubiquitinase activity', 'MPA', (163, 186))	('localization', 'biological_process', 'GO:0051179', ('128', '140'))	('nuclear labeling', 'MPA', (77, 93))	('BAP1', 'Gene', '8314', (72, 76))	('nuclear localization signal', 'MPA', (120, 147))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('163', '186'))	('lack', 'NegReg', (155, 159))	('BAP1', 'Gene', '8314', (245, 249))	('lack', 'NegReg', (108, 112))	('nuclear transport', 'biological_process', 'GO:0051169', ('224', '241'))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('BAP1', 'Gene', (245, 249))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('163', '186'))	('lack', 'NegReg', (64, 68))	('BAP1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
181462	26140217	This has been confirmed in a comprehensive study showing that all BAP1 abnormalities found in mesothelioma to date are always associated with absence of BAP1 nuclear staining and/or presence of cytoplasmic BAP1 staining.	('BAP1', 'Gene', '8314', (206, 210))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (206, 210))	('BAP1', 'Gene', '8314', (153, 157))	('BAP1', 'Gene', (66, 70))	('abnormalities', 'Var', (71, 84))	('mesothelioma', 'Disease', (94, 106))	('absence', 'NegReg', (142, 149))	('BAP1', 'Gene', (153, 157))
181463	26140217	The complete loss of BAP1 nuclear staining observed in our primary biliary tract adenocarcinoma is likely due to LOH at somatic level, while the mesothelioma tissue seems to have preserved the other BAP1 allele.	('primary biliary tract adenocarcinoma', 'Disease', (59, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('primary biliary tract adenocarcinoma', 'Disease', 'MESH:D001661', (59, 95))	('BAP1', 'Gene', (199, 203))	('BAP1', 'Gene', (21, 25))	('mesothelioma', 'Disease', (145, 157))	('loss', 'NegReg', (13, 17))	('nuclear staining', 'MPA', (26, 42))	('BAP1', 'Gene', '8314', (199, 203))	('LOH', 'Var', (113, 116))	('BAP1', 'Gene', '8314', (21, 25))
181464	26140217	One could argue that the fact that mesothelioma developed even in absence of LOH further confirms the deleteriousness of the Tyr 173 mutation.	('mesothelioma', 'Disease', (35, 47))	('Tyr 173', 'Var', (125, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('Tyr', 'Chemical', 'MESH:D014443', (125, 128))
181466	26140217	Loss of nuclear BAP1 staining on immunohistochemistry was thought to be an accessible and reliable test of BAP1 mutations, including germline and has been used for prognostication in mesothelioma.	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', (107, 111))	('mesothelioma', 'Disease', (183, 195))	('mutations', 'Var', (112, 121))	('BAP1', 'Gene', '8314', (16, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('BAP1', 'Gene', (16, 20))
181468	26140217	With regards to specific cancers, germline BAP1 mutations have been shown to play a role in a small number (3-4 %) of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (118, 133))	('BAP1', 'Gene', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('germline', 'Var', (34, 42))	('BAP1', 'Gene', '8314', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('uveal melanomas', 'Disease', (118, 133))	('uveal melanomas', 'Phenotype', 'HP:0007716', (118, 133))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
181470	26140217	BAP1 mutations have been implicated in metastatic ability.	('BAP1', 'Gene', (0, 4))	('metastatic ability', 'CPA', (39, 57))	('mutations', 'Var', (5, 14))	('implicated', 'Reg', (25, 35))	('BAP1', 'Gene', '8314', (0, 4))
181471	26140217	A germline mutation was found in 4 out of 50 metastatic uveal melanomas and was not identified in a further 50 non-metastatic tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('uveal melanomas', 'Disease', 'MESH:C536494', (56, 71))	('germline mutation', 'Var', (2, 19))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('uveal melanomas', 'Phenotype', 'HP:0007716', (56, 71))	('tumours', 'Disease', (126, 133))	('found', 'Reg', (24, 29))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('uveal melanomas', 'Disease', (56, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
181472	26140217	Sporadic BAP1 mutations have also been found in 84 % of metastasizing uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (70, 85))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('found', 'Reg', (39, 44))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanomas', 'Disease', (70, 85))	('uveal melanomas', 'Phenotype', 'HP:0007716', (70, 85))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
181473	26140217	Loss of BAP1 both germline and sporadic appears to lead to a more aggressive tumour phenotype in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('aggressive tumour', 'Disease', (66, 83))	('BAP1', 'Gene', '8314', (8, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('lead to', 'Reg', (51, 58))	('aggressive tumour', 'Disease', 'MESH:D001523', (66, 83))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
181476	26140217	Both germline and sporadic BAP1 mutations has been shown to play a role in malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (75, 97))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (75, 97))	('BAP1', 'Gene', (27, 31))	('play', 'Reg', (60, 64))	('role', 'Reg', (67, 71))	('mutations', 'Var', (32, 41))	('malignant mesothelioma', 'Disease', (75, 97))	('BAP1', 'Gene', '8314', (27, 31))
181478	26140217	Germline mutations make up much smaller proportion of cancers.	('Germline mutations', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
181479	26140217	A recent study compared the clinical characteristics of 23 mesotheliomas that occurred in carriers of germline BAP1 mutations to 10,556 sporadic mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (59, 72))	('mesotheliomas', 'Disease', (59, 72))	('BAP1', 'Gene', '8314', (111, 115))	('mesotheliomas', 'Disease', 'MESH:D008654', (145, 158))	('mesotheliomas', 'Disease', (145, 158))	('BAP1', 'Gene', (111, 115))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (136, 158))	('mutations', 'Var', (116, 125))
181481	26140217	Tumors that occur in a setting of germline BAP1 mutations are much less aggressive than their somatic counterparts and are associated with a significant improved mean survival of 5 years compared to 1 year with sporadic malignant mesothelioma.	('malignant mesothelioma', 'Disease', (220, 242))	('BAP1', 'Gene', (43, 47))	('aggressive', 'CPA', (72, 82))	('less', 'NegReg', (67, 71))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (220, 242))	('BAP1', 'Gene', '8314', (43, 47))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('improved', 'PosReg', (153, 161))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (220, 242))	('mutations', 'Var', (48, 57))
181484	26140217	Germline mutations also had a higher incidence of peritoneal disease (as in our patient) where in sporadic tumours pleural disease predominates.	('Germline mutations', 'Var', (0, 18))	('peritoneal disease', 'Disease', 'MESH:D010532', (50, 68))	('peritoneal disease', 'Disease', (50, 68))	('sporadic tumours pleural disease', 'Disease', 'MESH:D010997', (98, 130))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('sporadic tumours pleural disease', 'Disease', (98, 130))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('patient', 'Species', '9606', (80, 87))	('pleural disease', 'Phenotype', 'HP:0002103', (115, 130))
181486	26140217	Germline BAP1 mutations have cutaneous manifestations that include basal cell carcinomas, malignant melanoma and the recently described melanocytic-BAP1 mutated atypical intradermal tumour (MBAIT).	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (67, 88))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('BAP1', 'Gene', '8314', (148, 152))	('mutated', 'Var', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('malignant melanoma', 'Phenotype', 'HP:0002861', (90, 108))	('intradermal tumour', 'Disease', 'MESH:D018330', (170, 188))	('basal cell carcinomas', 'Disease', (67, 88))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (67, 88))	('BAP1', 'Gene', '8314', (9, 13))	('BAP1', 'Gene', (148, 152))	('malignant melanoma', 'Disease', 'MESH:D008545', (90, 108))	('intradermal tumour', 'Disease', (170, 188))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('malignant melanoma', 'Disease', (90, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
181491	26140217	Bi-allelic loss of BAP1 in itself along with a BRAF mutation is not sufficient for melanoma formation.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('loss', 'NegReg', (11, 15))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('BAP1', 'Gene', '8314', (19, 23))	('mutation', 'Var', (52, 60))	('BAP1', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('Bi-allelic', 'Var', (0, 10))	('melanoma', 'Disease', (83, 91))
181492	26140217	It has been suggested that MBAITs may be used to screen individuals for germline BAP1 mutations; 19 out of 35 individuals with a BAP1 mutation were found to have one or more lesion.	('mutations', 'Var', (86, 95))	('BAP1', 'Gene', (81, 85))	('mutation', 'Var', (134, 142))	('BAP1', 'Gene', '8314', (129, 133))	('BAP1', 'Gene', (129, 133))	('BAP1', 'Gene', '8314', (81, 85))
181496	26140217	A much smaller component can be attributed to germline BAP1 mutations.	('BAP1', 'Gene', (55, 59))	('germline', 'Var', (46, 54))	('BAP1', 'Gene', '8314', (55, 59))
181498	26140217	Sporadic BAP1 mutations have also been associated with a more aggressive form of cancer however it appears germline mutations may have different consequences.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('BAP1', 'Gene', '8314', (9, 13))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
181500	26140217	Other cancers including meningioma, lung, ovarian, pancreatic and breast cancers have been found in families that harbor BAP1 germline mutations.	('cancers', 'Disease', (73, 80))	('BAP1', 'Gene', '8314', (121, 125))	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('germline', 'Var', (126, 134))	('found', 'Reg', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BAP1', 'Gene', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('meningioma', 'Phenotype', 'HP:0002858', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('meningioma, lung, ovarian, pancreatic and breast cancers', 'Disease', 'MESH:D001943', (24, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
181501	26140217	However it is unclear whether germline BAP1 mutations directly predispose to the development of these tumours.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('predispose', 'Reg', (63, 73))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('BAP1', 'Gene', '8314', (39, 43))	('mutations', 'Var', (44, 53))	('tumours', 'Disease', (102, 109))	('BAP1', 'Gene', (39, 43))
181503	26140217	There are reports of individuals with BAP1 mutations developing primary biliary tract cancers but no definitive predisposition has been attributed.	('developing', 'Reg', (53, 63))	('BAP1', 'Gene', (38, 42))	('primary biliary tract cancer', 'Disease', (64, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (72, 92))	('biliary tract cancers', 'Disease', 'MESH:D001661', (72, 93))	('mutations', 'Var', (43, 52))	('biliary tract cancers', 'Disease', (72, 93))	('primary biliary tract cancer', 'Disease', 'MESH:D001661', (64, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('BAP1', 'Gene', '8314', (38, 42))
181504	26140217	Somatic BAP1 mutations are relatively frequent in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('BAP1', 'Gene', '8314', (8, 12))	('cholangiocarcinoma', 'Disease', (50, 68))	('BAP1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('mutations', 'Var', (13, 22))	('frequent', 'Reg', (38, 46))
181506	26140217	This indicates that secondary sporadic mutations had occurred in the adenocarcinoma, resulting in loss of protein translocation (Fig.	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('protein translocation', 'MPA', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('mutations', 'Var', (39, 48))	('loss', 'NegReg', (98, 102))	('adenocarcinoma', 'Disease', (69, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
181512	26140217	Those who are confirmed to carry a BAP1 mutation will then need appropriate genetic counseling for themselves and their families.	('mutation', 'Var', (40, 48))	('BAP1', 'Gene', '8314', (35, 39))	('BAP1', 'Gene', (35, 39))
181514	26140217	BAP1 mutations have been described in some US and European families with a very high incidence of cancer and they are transmitted in a Mendelian fashion (i.e., about 50 % of offspring inherit the mutation).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BAP1', 'Gene', (0, 4))	('mutation', 'Var', (196, 204))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (98, 104))	('BAP1', 'Gene', '8314', (0, 4))
181515	26140217	So far all of the family members that inherited this mutation have developed one and often several cancers by age 65 (18).	('mutation', 'Var', (53, 61))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('developed', 'Reg', (67, 76))
181516	26140217	Characteristically, when malignancies occur in a setting of germline BAP1 mutations they are less aggressive and patients live significantly longer compared to patients with the same types of tumors occurring in a sporadic setting.	('less', 'NegReg', (93, 97))	('patients', 'Species', '9606', (160, 168))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('BAP1', 'Gene', (69, 73))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('malignancies', 'Disease', (25, 37))	('aggressive', 'CPA', (98, 108))	('longer', 'PosReg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BAP1', 'Gene', '8314', (69, 73))
181574	21447742	Nonetheless, additional engineering of M40 may further increase the kidney clearance rate and improve the contrast.	('M40', 'Gene', (39, 42))	('increase', 'PosReg', (55, 63))	('increase the kidney', 'Phenotype', 'HP:0000105', (55, 74))	('M40', 'Gene', '203068', (39, 42))	('improve', 'PosReg', (94, 101))	('contrast', 'MPA', (106, 114))	('engineering', 'Var', (24, 35))	('kidney clearance', 'MPA', (68, 84))
181582	10584869	Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (20, 42))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('malignant mesothelioma', 'Disease', (196, 218))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (196, 218))	('loss', 'Var', (238, 242))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (20, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('266', '276'))	('tumours', 'Disease', 'MESH:D009369', (179, 186))	('human', 'Species', '9606', (190, 195))	('tumours', 'Disease', (179, 186))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (196, 218))	('malignant mesothelioma', 'Disease', (20, 42))	('Deletions', 'Var', (0, 9))
181583	10584869	Here we further verify the frequency and pattern of deletions at 14q in mesothelioma.	('mesothelioma', 'Disease', (72, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('deletions at', 'Var', (52, 64))
181585	10584869	Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%).	('allelic imbalance', 'Var', (26, 43))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Disease', (95, 102))	('Loss', 'NegReg', (0, 4))	('imbalance', 'Phenotype', 'HP:0002172', (34, 43))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
181586	10584869	Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour.	('Partial deletions', 'Var', (0, 17))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))
181587	10584869	The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours).	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('D14S283', 'Var', (107, 114))	('tumours', 'Disease', (146, 153))	('tumours', 'Disease', (225, 232))	('tumours', 'Disease', 'MESH:D009369', (274, 281))	('D14S972', 'CellLine', 'CVCL:N149', (131, 138))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('D14S284', 'Var', (261, 268))	('tumours', 'Disease', (248, 255))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (121, 128))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('deletions', 'Var', (35, 44))	('D14S77', 'Var', (235, 241))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Disease', 'MESH:D009369', (248, 255))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('D14S972', 'Var', (131, 138))	('tumours', 'Disease', (22, 29))	('D14S258', 'Var', (211, 218))	('tumours', 'Disease', (172, 179))	('S64', 'CellLine', 'CVCL:5770', (162, 165))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('D14S64', 'Var', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', (274, 281))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
181588	10584869	We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma.	('genomic deletions at', 'Var', (33, 53))	('mesothelioma', 'Disease', (102, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))
181590	10584869	This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('tumour', 'Disease', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('deletions', 'Var', (19, 28))
181591	10584869	Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('involved', 'Reg', (143, 151))	('tumours', 'Disease', (23, 30))	('deletions', 'Var', (163, 172))
181593	32992696	AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression Previous studies have shown that AXL is a crucial protein that is activated in mesothelioma to cause growth and invasiveness.	('Inactivation', 'Var', (4, 16))	('activated', 'PosReg', (159, 168))	('p53', 'Gene', '7157', (78, 81))	('Mesothelioma Growth', 'Disease', 'MESH:D008654', (26, 45))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('invasiveness', 'CPA', (205, 217))	('cause', 'PosReg', (188, 193))	('AXL', 'Gene', '558', (0, 3))	('mesothelioma', 'Disease', (172, 184))	('AXL', 'Gene', '558', (126, 129))	('p53', 'Gene', (78, 81))	('Inhibits', 'NegReg', (17, 25))	('AXL', 'Gene', (126, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (172, 184))	('Mesothelioma Growth', 'Disease', (26, 45))	('AXL', 'Gene', (0, 3))	('growth', 'MPA', (194, 200))
181594	32992696	p53 is the tumor suppressor protein that is most frequently inactivated by mutations in human cancers, but these p53 inactivating mutations are not common in mesothelioma.	('p53', 'Gene', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mesothelioma', 'Disease', (158, 170))	('tumor', 'Disease', (11, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('mutations', 'Var', (75, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancers', 'Disease', (94, 101))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
181596	32992696	Specifically, we show that AXL suppresses p53 expression by binding to DNA sequences upstream from the p53 gene, thereby blocking transcription of p53 DNA into RNA.	('p53', 'Gene', (42, 45))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('transcription', 'MPA', (130, 143))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('p53', 'Gene', (103, 106))	('blocking', 'NegReg', (121, 129))	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('transcription', 'biological_process', 'GO:0006351', ('130', '143'))	('p53', 'Var', (147, 150))	('expression', 'Species', '29278', (46, 56))	('suppresses', 'NegReg', (31, 41))	('expression', 'MPA', (46, 56))	('binding', 'Interaction', (60, 67))
181598	32992696	p53 inactivation attenuates the impact of the AXL inhibitor, providing further support for interplay between AXL and p53 in mesothelioma oncogenesis.	('p53', 'Gene', (0, 3))	('inactivation', 'Var', (4, 16))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('attenuates', 'NegReg', (17, 27))	('mesothelioma oncogenesis', 'Disease', 'MESH:D063646', (124, 148))	('interplay', 'Interaction', (91, 100))	('mesothelioma oncogenesis', 'Disease', (124, 148))
181601	32992696	Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mesothelioma', 'Disease', (87, 99))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('tumor', 'Disease', (145, 150))	('Gas6/AXL tyrosine kinase signaling', 'MPA', (32, 66))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('activation', 'PosReg', (18, 28))	('associated', 'Reg', (71, 81))
181602	32992696	p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter.	('p53', 'Gene', (0, 3))	('lung carcinoma', 'Disease', 'MESH:D008175', (15, 29))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('mutants', 'Var', (4, 11))	('binding', 'Interaction', (59, 66))	('acetylating', 'MPA', (71, 82))	('lung carcinoma', 'Disease', (15, 29))	('AXL expression', 'MPA', (41, 55))	('expression', 'Species', '29278', (45, 55))	('upregulate', 'PosReg', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('AXL promoter', 'MPA', (87, 99))
181603	32992696	Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mesothelioma', 'Disease', (40, 52))	('mutations', 'Var', (14, 23))
181606	32992696	AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function.	('p53', 'Protein', (176, 179))	('tumor', 'Disease', (119, 124))	('mutant', 'Var', (45, 51))	('p53', 'Gene', (52, 55))	('expression', 'Species', '29278', (56, 66))	('mesothelioma', 'Disease', (70, 82))	('expression', 'MPA', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('function', 'MPA', (180, 188))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('suppression', 'NegReg', (161, 172))
181610	32992696	AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells.	('AXL', 'Protein', (0, 3))	('reduced', 'NegReg', (31, 38))	('migration', 'CPA', (152, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (39, 51))	('TP53', 'Gene', '7157', (101, 105))	('R428', 'Var', (25, 29))	('R428', 'Chemical', '-', (25, 29))	('silencing', 'NegReg', (191, 200))	('AXL', 'Protein', (187, 190))	('TP53', 'Gene', (101, 105))	('invasion', 'CPA', (83, 91))	('invasive effects', 'CPA', (167, 183))	('antiproliferative', 'CPA', (133, 150))	('inhibition', 'NegReg', (4, 14))	('migration', 'CPA', (68, 77))	('attenuated', 'NegReg', (122, 132))	('mesothelioma', 'Disease', (39, 51))
181619	32992696	For example, AXL regulation of miR-374a and miR-548b conferred drug resistance to EGFR inhibitors such as gefitinib in non-small cell lung cancer (NSCLC), and activated AXL is a prognostic marker and potential therapeutic target in NSCLC.	('miR-374a', 'Var', (31, 39))	('drug resistance', 'biological_process', 'GO:0009315', ('63', '78'))	('drug resistance', 'biological_process', 'GO:0042493', ('63', '78'))	('conferred', 'Reg', (53, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('regulation', 'biological_process', 'GO:0065007', ('17', '27'))	('EGFR', 'Gene', (82, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('miR-548b', 'Var', (44, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('AXL regulation', 'MPA', (13, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('non-small cell lung cancer', 'Disease', (119, 145))	('NSCLC', 'Disease', 'MESH:D002289', (232, 237))	('drug resistance', 'MPA', (63, 78))	('gefitinib', 'Chemical', 'MESH:D000077156', (106, 115))	('NSCLC', 'Disease', (147, 152))	('drug resistance', 'Phenotype', 'HP:0020174', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('NSCLC', 'Disease', (232, 237))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
181623	32992696	Various studies have shown that more than half of human cancers harbor TP53 mutations, and more than 50% of these TP53 mutations are missense mutations which have both gain-of-function and loss-of-function properties.	('cancers', 'Disease', (56, 63))	('TP53', 'Gene', '7157', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('mutations', 'Var', (76, 85))	('TP53', 'Gene', (114, 118))	('loss-of-function', 'NegReg', (189, 205))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TP53', 'Gene', '7157', (114, 118))	('human', 'Species', '9606', (50, 55))	('TP53', 'Gene', (71, 75))	('gain-of-function', 'PosReg', (168, 184))	('mutations', 'Var', (119, 128))	('missense', 'Var', (133, 141))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
181624	32992696	Recent studies in lung cancer showed that the mutated p53 upregulated AXL at both mRNA and protein levels through histone acetylation on the AXL promoter region.	('histone acetylation', 'MPA', (114, 133))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('mutated', 'Var', (46, 53))	('upregulated', 'PosReg', (58, 69))	('p53', 'Gene', (54, 57))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('histone acetylation', 'biological_process', 'GO:0016573', ('114', '133'))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('AXL', 'Enzyme', (70, 73))
181628	32992696	Our recent studies showed that AXL knockdown induced p53 expression, suggesting that regulatory interactions between p53 and AXL are bidirectional.	('expression', 'MPA', (57, 67))	('knockdown', 'Var', (35, 44))	('p53', 'Gene', (53, 56))	('induced', 'Reg', (45, 52))	('expression', 'Species', '29278', (57, 67))
181630	32992696	In the present report, we show that AXL knockdown induces p53 transcription via loss of AXL-mediated repressive effects on the TP53 promoter.	('AXL-mediated repressive effects', 'MPA', (88, 119))	('loss', 'NegReg', (80, 84))	('knockdown', 'Var', (40, 49))	('transcription', 'MPA', (62, 75))	('induces', 'PosReg', (50, 57))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('p53', 'Gene', (58, 61))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
181642	32992696	The AXL shRNA-mediated knockdown resulted in upregulation of p53 and p21 in p53 wild type cell lines, and a mild increase in the expression of p53 and p21 in p53 mutant JMN1B (Figure 2A).	('expression', 'Species', '29278', (129, 139))	('expression', 'MPA', (129, 139))	('p21', 'Gene', '12575', (151, 154))	('p21', 'Gene', (69, 72))	('p53 mutant', 'Var', (158, 168))	('mutant', 'Var', (162, 168))	('p21', 'Gene', '12575', (69, 72))	('p53', 'Protein', (61, 64))	('increase', 'PosReg', (113, 121))	('p53', 'Protein', (143, 146))	('upregulation', 'PosReg', (45, 57))	('JMN1B', 'CellLine', 'CVCL:M006', (169, 174))	('p21', 'Gene', (151, 154))
181646	32992696	The above-mentioned findings indicate that AXL regulates mesothelioma proliferation, in part, by p53 dysregulation.	('mesothelioma', 'Disease', (57, 69))	('p53', 'Gene', (97, 100))	('regulates', 'Reg', (47, 56))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('dysregulation', 'Var', (101, 114))
181651	32992696	MESO507 and sample 7 from mesothelioma cell lines and tumor tissues, respectively, which harbored TP53 point mutation did not show this relationship (Figure S2).	('mesothelioma', 'Disease', (26, 38))	('MESO507', 'Chemical', '-', (0, 7))	('point mutation', 'Var', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mesothelioma', 'Disease', 'MESH:D008654', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Disease', (54, 59))	('TP53', 'Gene', (98, 102))
181656	32992696	As AXL knockdown induced p53 protein expression (Figure 2A), we further analyzed TP53 transcripts after AXL silencing (Figure 5A).	('p53 protein', 'Protein', (25, 36))	('induced', 'Reg', (17, 24))	('expression', 'Species', '29278', (37, 47))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('knockdown', 'Var', (7, 16))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
181658	32992696	qRT-PCR demonstrated that the TP53 transcript was increased after AXL knockdown (Figure 5A).	('TP53', 'Gene', (30, 34))	('knockdown', 'Var', (70, 79))	('AXL', 'Protein', (66, 69))	('increased', 'PosReg', (50, 59))	('TP53', 'Gene', '7157', (30, 34))
181664	32992696	Wound-healing assays in AXL-phosphorylated MESO924 cells demonstrated that AXL inhibition (R428) or AXL shRNA knockdown resulted in greater inhibition of wound closure at 24 h than in control cells treated with DMSO or infected with empty lentiviral vector (Figure 6A,B).	('AXL', 'Gene', (100, 103))	('knockdown', 'Var', (110, 119))	('DMSO', 'Chemical', 'MESH:D004121', (211, 215))	('Wound-healing', 'biological_process', 'GO:0042060', ('0', '13'))	('infected', 'Disease', 'MESH:D007239', (219, 227))	('shRNA', 'Gene', (104, 109))	('infected', 'Disease', (219, 227))	('wound closure at 24 h', 'CPA', (154, 175))	('inhibition', 'NegReg', (79, 89))	('inhibition', 'NegReg', (140, 150))	('AXL', 'Protein', (75, 78))	('MESO924', 'Chemical', '-', (43, 50))	('R428', 'Chemical', '-', (91, 95))
181665	32992696	However, TP53 shRNA-mediated knockdown resulted in complete wound closure as compared to the control cells infected with empty lentiviral vector (Figure 6A,B).	('wound closure', 'CPA', (60, 73))	('knockdown', 'Var', (29, 38))	('infected', 'Disease', 'MESH:D007239', (107, 115))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('infected', 'Disease', (107, 115))
181666	32992696	Cell migration was less inhibited by R428 or AXL shRNA after p53 knockdown than after AXL silencing or inactivation.	('R428', 'Var', (37, 41))	('knockdown', 'Var', (65, 74))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('p53', 'Gene', (61, 64))	('R428', 'Chemical', '-', (37, 41))
181667	32992696	MESO924 cells with p53 knockdown showed similar results to the control cells treated with DMSO or infected with empty lentiviral vector (Figure 6A,B).	('infected', 'Disease', (98, 106))	('knockdown', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('MESO924', 'Chemical', '-', (0, 7))	('infected', 'Disease', 'MESH:D007239', (98, 106))	('DMSO', 'Chemical', 'MESH:D004121', (90, 94))
181668	32992696	Assays were performed in MESO924 to evaluate the effects of AXL inhibition and p53 knockdown on mesothelioma cell invasion.	('MESO924', 'Chemical', '-', (25, 32))	('p53', 'Gene', (79, 82))	('mesothelioma', 'Disease', (96, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('AXL', 'Protein', (60, 63))	('knockdown', 'Var', (83, 92))
181669	32992696	Transwell matrigel assays demonstrated that AXL inhibition (R428) resulted in greater inhibition of invasiveness at 24 h than those of control cells treated with DMSO and infected with empty lentiviral vector (Figure 6C,D), whereas p53 shRNA knockdown increased invasiveness as compared to the control cells infected with empty lentiviral vector (Figure 6C,D).	('invasiveness', 'MPA', (262, 274))	('invasiveness at 24 h', 'CPA', (100, 120))	('p53 shRNA knockdown', 'Var', (232, 251))	('knockdown', 'Var', (242, 251))	('infected', 'Disease', (308, 316))	('infected', 'Disease', 'MESH:D007239', (308, 316))	('AXL', 'MPA', (44, 47))	('infected', 'Disease', (171, 179))	('R428', 'Chemical', '-', (60, 64))	('increased', 'PosReg', (252, 261))	('DMSO', 'Chemical', 'MESH:D004121', (162, 166))	('inhibition', 'NegReg', (48, 58))	('inhibition', 'NegReg', (86, 96))	('infected', 'Disease', 'MESH:D007239', (171, 179))
181670	32992696	Cell invasion was less inhibited by R428 after p53 knockdown.	('R428', 'Chemical', '-', (36, 40))	('Cell invasion', 'CPA', (0, 13))	('knockdown', 'Var', (51, 60))
181671	32992696	MESO924 growth after p53 knockdown was equivalent to that of control cells treated with DMSO and infected with empty lentiviral vector (Figure 6C,D).	('p53', 'Gene', (21, 24))	('DMSO', 'Chemical', 'MESH:D004121', (88, 92))	('infected', 'Disease', 'MESH:D007239', (97, 105))	('infected', 'Disease', (97, 105))	('MESO924', 'Chemical', '-', (0, 7))	('knockdown', 'Var', (25, 34))
181672	32992696	AXL knockdown or kinase inhibition in MESO924 resulted in  30% inhibition of cell viability (Promega CellTiter-Glo assay; Madison, WI, USA) at 3 days after AXL silencing or treatment with R428, compared with the empty vector or DMSO control (Figure 6E,F).	('R428', 'Var', (188, 192))	('DMSO', 'Chemical', 'MESH:D004121', (228, 232))	('AXL', 'Protein', (0, 3))	('MESO924', 'Chemical', '-', (38, 45))	('silencing', 'NegReg', (160, 169))	('inhibition', 'NegReg', (63, 73))	('AXL', 'Protein', (156, 159))	('kinase', 'Var', (17, 23))	('inhibition', 'NegReg', (24, 34))	('knockdown', 'Var', (4, 13))	('R428', 'Chemical', '-', (188, 192))	('cell viability', 'CPA', (77, 91))	('MESO924', 'Gene', (38, 45))
181673	32992696	p53 shRNA-mediated knockdown had little effect on cell viability as compared to the control cells infected with empty lentiviral vector (Figure 6E,F).	('p53', 'Gene', (0, 3))	('knockdown', 'Var', (19, 28))	('infected', 'Disease', 'MESH:D007239', (98, 106))	('infected', 'Disease', (98, 106))
181674	32992696	However, p53 shRNA knockdown decreased the antiproliferative effects of AXL kinase inhibition or AXL knockdown in MESO924, and showed similar results to the control cells treated with DMSO or infected with empty lentiviral vector (Figure 6E,F).	('p53', 'Var', (9, 12))	('shRNA', 'Gene', (13, 18))	('AXL kinase', 'Enzyme', (72, 82))	('inhibition', 'NegReg', (83, 93))	('MESO924', 'Chemical', '-', (114, 121))	('knockdown', 'Var', (19, 28))	('infected', 'Disease', 'MESH:D007239', (192, 200))	('infected', 'Disease', (192, 200))	('decreased', 'NegReg', (29, 38))	('antiproliferative effects', 'MPA', (43, 68))	('DMSO', 'Chemical', 'MESH:D004121', (184, 188))	('knockdown', 'Var', (101, 110))
181678	32992696	Furthermore, inhibition of PI3K/AKT signaling is associated with aberrant MDM2-p53 interaction in mesothelioma.	('MDM2-p53', 'Protein', (74, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('aberrant', 'Var', (65, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('interaction', 'Interaction', (83, 94))	('PI3K/AKT signaling', 'Pathway', (27, 45))	('inhibition', 'NegReg', (13, 23))	('AKT signaling', 'biological_process', 'GO:0043491', ('32', '45'))	('mesothelioma', 'Disease', (98, 110))
181679	32992696	Cotargeting of FAK-p53 and MDM2-p53 interactions exhibited antiproliferative effects in mesothelioma, suggesting that p53 functional inactivation is a key event in mesothelioma development, as genomic TP53 mutations are not frequent in mesothelioma.	('interactions', 'Var', (36, 48))	('mesothelioma', 'Disease', (236, 248))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('mesothelioma', 'Disease', 'MESH:D008654', (236, 248))	('p53', 'Gene', (118, 121))	('mesothelioma', 'Disease', (164, 176))	('TP53', 'Gene', '7157', (201, 205))	('FAK', 'molecular_function', 'GO:0004717', ('15', '18'))	('TP53', 'Gene', (201, 205))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('mesothelioma', 'Disease', (88, 100))
181683	32992696	Further, high AXL expression in mesothelioma is significantly associated with poorer survival (Figure 1 and Figure S1).	('mesothelioma', 'Disease', 'MESH:D008654', (32, 44))	('expression', 'Species', '29278', (18, 28))	('mesothelioma', 'Disease', (32, 44))	('poorer', 'NegReg', (78, 84))	('high', 'Var', (9, 13))
181684	32992696	These findings indicate that high AXL expression identifies a subset of mesotheliomas for which novel therapies are a particularly urgent need.	('high', 'Var', (29, 33))	('expression', 'Species', '29278', (38, 48))	('mesotheliomas', 'Disease', 'MESH:D008654', (72, 85))	('mesotheliomas', 'Disease', (72, 85))
181685	32992696	Previous evidence demonstrated that p53 mutants induce upregulation of AXL transcript via direct binding to AXL promoter, and p53 mutant knockdown reduced acetylation of AXL promoter histones in lung cancer, indicating that p53 regulates AXL transcription.	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('AXL transcript', 'MPA', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('p53', 'Gene', (36, 39))	('lung cancer', 'Disease', (195, 206))	('p53', 'Gene', (126, 129))	('AXL', 'Protein', (108, 111))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('mutants', 'Var', (40, 47))	('binding', 'Interaction', (97, 104))	('transcription', 'biological_process', 'GO:0006351', ('242', '255'))	('acetylation', 'MPA', (155, 166))	('mutant', 'Var', (130, 136))	('reduced', 'NegReg', (147, 154))	('upregulation', 'PosReg', (55, 67))
181689	32992696	However, in our current studies, AXL knockdown resulted in p53 upregulation in three wild-type p53 mesothelioma cell lines (MESO924, MESO296, and MESO428) and one p53 mutant mesothelioma cell line (JMN1B), and overexpression of AXL inhibited p53 expression after cotransfection of AXL and TP53 (wild type) expression constructs in COS-7 cells or transfection with AXL construct alone in the 293T cell line.	('p53', 'Gene', (59, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('knockdown', 'Var', (37, 46))	('MESO428', 'Chemical', '-', (146, 153))	('upregulation', 'PosReg', (63, 75))	('TP53', 'Gene', (289, 293))	('expression', 'Species', '29278', (306, 316))	('COS-7', 'CellLine', 'CVCL:0224', (331, 336))	('overexpression', 'PosReg', (210, 224))	('expression', 'MPA', (246, 256))	('293T', 'CellLine', 'CVCL:0063', (391, 395))	('mesothelioma', 'Disease', (174, 186))	('inhibited', 'NegReg', (232, 241))	('mesothelioma', 'Disease', 'MESH:D008654', (174, 186))	('MESO296', 'Chemical', '-', (133, 140))	('JMN1B', 'CellLine', 'CVCL:M006', (198, 203))	('MESO924', 'Chemical', '-', (124, 131))	('TP53', 'Gene', '7157', (289, 293))	('p53', 'Gene', (242, 245))	('expression', 'Species', '29278', (246, 256))	('expression', 'Species', '29278', (214, 224))	('mesothelioma', 'Disease', (99, 111))
181691	32992696	Thus, we hypothesized that there may be a self-feedback regulatory loop between AXL and p53, namely, p53 negatively regulates transcription and expression of AXL, and AXL negatively regulates transcription and expression of TP53.	('AXL', 'Protein', (158, 161))	('p53', 'Var', (101, 104))	('expression', 'Species', '29278', (144, 154))	('regulates', 'Reg', (116, 125))	('transcription', 'MPA', (126, 139))	('TP53', 'Gene', (224, 228))	('expression', 'Species', '29278', (210, 220))	('expression', 'MPA', (144, 154))	('transcription', 'MPA', (192, 205))	('transcription', 'biological_process', 'GO:0006351', ('126', '139'))	('expression', 'MPA', (210, 220))	('regulates', 'Reg', (182, 191))	('negatively', 'NegReg', (171, 181))	('negatively', 'NegReg', (105, 115))	('TP53', 'Gene', '7157', (224, 228))	('transcription', 'biological_process', 'GO:0006351', ('192', '205'))
181696	32992696	qRT-PCR demonstrated that AXL shRNA knockdown upregulated TP53 transcripts in each of three wild-type TP53 mesothelioma cell lines (MESO924, MESO296, and MESO428), and one TP53-mutant mesothelioma cell line (JMN1B) (Figure 5A).	('MESO296', 'Chemical', '-', (141, 148))	('TP53', 'Gene', (102, 106))	('MESO428', 'Chemical', '-', (154, 161))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', (172, 176))	('MESO924', 'Chemical', '-', (132, 139))	('transcripts', 'MPA', (63, 74))	('mesothelioma', 'Disease', (107, 119))	('knockdown', 'Var', (36, 45))	('TP53', 'Gene', '7157', (102, 106))	('mesothelioma', 'Disease', (184, 196))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('JMN1B', 'CellLine', 'CVCL:M006', (208, 213))	('mesothelioma', 'Disease', 'MESH:D008654', (184, 196))	('upregulated', 'PosReg', (46, 57))
181707	32992696	AXL shRNA knockdown or kinase inhibition with R428 inhibited cell viability, migration, and invasion in MESO924 (Figure 6), which is consistent with our previous findings.	('MESO924', 'Chemical', '-', (104, 111))	('kinase', 'Var', (23, 29))	('invasion in MESO924', 'CPA', (92, 111))	('R428', 'Chemical', '-', (46, 50))	('migration', 'CPA', (77, 86))	('cell viability', 'CPA', (61, 75))	('R428', 'Gene', (46, 50))	('inhibited', 'NegReg', (51, 60))	('knockdown', 'Var', (10, 19))
181711	32992696	Polyclonal goat antibody to AXL (#sc-1096), and monoclonal mouse antibodies to AXL (#sc-166269), p53 (#sc-126), and p21 (#sc-6246) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('#sc-166269', 'Var', (84, 94))	('p21', 'Gene', (116, 119))	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('p21', 'Gene', '12575', (116, 119))	('mouse', 'Species', '10090', (59, 64))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('#sc-126', 'Var', (102, 109))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))
181712	32992696	Anti-rabbit HRP-IgG (#7074) and anti-mouse HRP-IgG ((#7076) were from Cell Signaling Technology (Pudong, Shanghai, China).	('#7074', 'Var', (21, 26))	('(#7076', 'Var', (52, 58))	('mouse', 'Species', '10090', (37, 42))	('Signaling', 'biological_process', 'GO:0023052', ('75', '84'))
181719	32992696	MESO924, MESO257, MESO1401, MESO542, MESO507, and MESO346 cell lines were established from epithelial-type mesotheliomas, MESO296 and MESO647 from mixed-histology mesotheliomas, and MESO188 and MESO428 from a spindle-cell mesothelioma.	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesothelioma', 'Disease', (107, 119))	('MESO647', 'Chemical', '-', (134, 141))	('mesotheliomas', 'Disease', 'MESH:D008654', (163, 176))	('MESO296', 'Chemical', '-', (122, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('MESO428', 'Chemical', '-', (194, 201))	('MESO542', 'Chemical', '-', (28, 35))	('MESO647', 'Var', (134, 141))	('MESO924', 'Chemical', '-', (0, 7))	('spindle', 'cellular_component', 'GO:0005819', ('209', '216'))	('MESO296', 'Var', (122, 129))	('mesothelioma', 'Disease', (222, 234))	('MESO188', 'Chemical', '-', (182, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (222, 234))	('mesotheliomas', 'Disease', (107, 120))	('MESO1401', 'Chemical', '-', (18, 26))	('mesothelioma', 'Disease', (163, 175))	('mesotheliomas', 'Disease', (163, 176))	('spindle-cell', 'Disease', (209, 221))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('MESO507', 'Chemical', '-', (37, 44))
181720	32992696	MESO924, MESO296, MESO428, MESO188, MESO1401, MESO542, MESO346, MESO647, and MESO257 harbor wild-type p53.	('MESO296', 'Var', (9, 16))	('MESO188', 'Var', (27, 34))	('MESO542', 'Var', (46, 53))	('MESO1401', 'Var', (36, 44))	('MESO924', 'Var', (0, 7))	('MESO296', 'Chemical', '-', (9, 16))	('MESO188', 'Chemical', '-', (27, 34))	('MESO647', 'Chemical', '-', (64, 71))	('MESO428', 'Chemical', '-', (18, 25))	('MESO257', 'Var', (77, 84))	('MESO346', 'Var', (55, 62))	('MESO428', 'Var', (18, 25))	('MESO1401', 'Chemical', '-', (36, 44))	('MESO924', 'Chemical', '-', (0, 7))	('MESO542', 'Chemical', '-', (46, 53))	('MESO647', 'Var', (64, 71))
181721	32992696	MESO507 harbored TP53 S241F missense mutation.	('MESO507', 'Chemical', '-', (0, 7))	('S241F', 'Mutation', 'rs28934573', (22, 27))	('S241F missense mutation', 'Var', (22, 45))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
181722	32992696	An additional mesothelioma cell line, JMN1B, was established from an epithelial-type mesothelioma, had been found to contain TP53 G245S missense mutation.	('mesothelioma', 'Disease', (85, 97))	('G245S missense mutation', 'Var', (130, 153))	('TP53', 'Gene', '7157', (125, 129))	('JMN1B', 'CellLine', 'CVCL:M006', (38, 43))	('mesothelioma', 'Disease', (14, 26))	('G245S', 'Mutation', 'rs28934575', (130, 135))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('TP53', 'Gene', (125, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (14, 26))
181731	32992696	Well-validated shRNAs were used for AXL or p53 knockdowns, which had been evaluated in our previous published papers, including mesothelioma, ovarian cancer, and liposarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (162, 173))	('mesothelioma, ovarian cancer', 'Disease', 'MESH:D008654', (128, 156))	('knockdowns', 'Var', (47, 57))	('liposarcoma', 'Phenotype', 'HP:0012034', (162, 173))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('p53', 'Gene', (43, 46))	('liposarcoma', 'Disease', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
181863	26316950	The following variables were collected: age, sex, International Mesothelioma Interest Group (IMIG) stage, histological subtype, Eastern Cooperative Oncology Group (ECOG) performance status, presenting symptoms and signs, weight loss >=5%, leukocytosis defined as WBC count >= 8.7 x 109/L, thrombocytosis defined as platelet count > 400 x 109/L, hemoglobin < 146 x 109/L, and LDH > 500 IU/L.	('thrombocytosis', 'Disease', 'MESH:D013922', (289, 303))	('LDH', 'MPA', (375, 378))	('platelet count', 'MPA', (315, 329))	('leukocytosis', 'Disease', 'MESH:D007964', (239, 251))	('hemoglobin', 'MPA', (345, 355))	('thrombocytosis', 'Disease', (289, 303))	('leukocytosis', 'Phenotype', 'HP:0001974', (239, 251))	('weight loss', 'Disease', 'MESH:D015431', (221, 232))	('> 400 x', 'Var', (330, 337))	('leukocytosis', 'Disease', (239, 251))	('thrombocytosis', 'Phenotype', 'HP:0001894', (289, 303))	('weight loss', 'Disease', (221, 232))	('Oncology', 'Phenotype', 'HP:0002664', (148, 156))	('weight loss', 'Phenotype', 'HP:0001824', (221, 232))
181884	23489943	Many institutional reports have shown that in patients with MPM operative cytoreduction and hyperthermic intraoperative peritoneal chemotherapy (HIPEC) using cisplatin or mitomycin-C is associated with long term survival.	('mitomycin-C', 'Chemical', 'MESH:D016685', (171, 182))	('patients', 'Species', '9606', (46, 54))	('hyperthermic intraoperative peritoneal', 'Disease', 'MESH:D010534', (92, 130))	('hyperthermic intraoperative peritoneal', 'Disease', (92, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))	('MPM', 'Var', (60, 63))
181925	23489943	On univariate analysis male gender, age >= 60 years, high grade histology, CCR >=2, and HIPEC agent (mitomycin C versus cisplatin) were found to be associated with worsened overall survival (Table 3).	('high', 'Var', (53, 57))	('overall survival', 'MPA', (173, 189))	('worsened', 'NegReg', (164, 172))	('CCR', 'molecular_function', 'GO:0043880', ('75', '78'))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('mitomycin C', 'Chemical', 'MESH:D016685', (101, 112))
181941	23489943	Specific inhibitors of these pathways have been shown to inhibit cellular proliferation and MPM xenograft growth in nude mice.	('MPM xenograft growth', 'CPA', (92, 112))	('nude mice', 'Species', '10090', (116, 125))	('inhibit', 'NegReg', (57, 64))	('inhibitors', 'Var', (9, 19))	('cellular proliferation', 'CPA', (65, 87))
181950	23300762	The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat.	('Bim', 'Gene', (84, 87))	('Bim', 'Gene', '10018', (84, 87))	('resistance', 'MPA', (37, 47))	('Noxa', 'Gene', '5366', (126, 130))	('ablated', 'NegReg', (52, 59))	('Noxa', 'Gene', (126, 130))	('vorinostat', 'Chemical', 'MESH:D000077337', (159, 169))	('vorinostat', 'Chemical', 'MESH:D000077337', (15, 25))	('Noxa', 'Gene', '5366', (76, 80))	('Bim', 'Gene', (131, 134))	('knockdown', 'Var', (63, 72))	('Bim', 'Gene', '10018', (131, 134))	('Noxa', 'Gene', (76, 80))
181953	23300762	Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma.	('improve', 'PosReg', (112, 119))	('chemosensitivity', 'CPA', (124, 140))	('mesothelioma', 'Disease', (144, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('manipulation', 'Var', (62, 74))	('core', 'cellular_component', 'GO:0019013', ('82', '86'))
181954	23300762	Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies.	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('bortezomib', 'Chemical', 'MESH:D000069286', (31, 41))	('vorinostat', 'Chemical', 'MESH:D000077337', (16, 26))	('undermine', 'NegReg', (110, 119))	('vorinostat', 'Var', (95, 105))	('bortezomib', 'Chemical', 'MESH:D000069286', (139, 149))	('vorinostat', 'Chemical', 'MESH:D000077337', (95, 105))	('mesothelioma', 'Disease', (81, 93))	('chemoresistance', 'CPA', (120, 135))
181964	23300762	Vorinostat has been shown to induce apoptosis in many in vitro studies of solid tumors, including mesothelioma, largely by unwinding condensed chromatin and allowing transcription of epigenetically silenced genes.	('epigenetically silenced', 'Var', (183, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('condensed chromatin', 'MPA', (133, 152))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('apoptosis', 'Disease', (36, 45))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))	('unwinding', 'Reg', (123, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('chromatin', 'cellular_component', 'GO:0000785', ('143', '152'))	('solid tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('allowing', 'Reg', (157, 165))	('transcription', 'MPA', (166, 179))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('solid tumors', 'Disease', (74, 86))	('mesothelioma', 'Disease', (98, 110))
181993	23300762	The antibody against Bim (#559685) was from BD Pharmingen (San Jose, CA) and the Noxa antibody was from Calbiochem (#OP180).	('Noxa', 'Gene', '5366', (81, 85))	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('antibody', 'cellular_component', 'GO:0042571', ('4', '12'))	('#559685', 'Var', (26, 33))	('Bim', 'Gene', (21, 24))	('Bim', 'Gene', '10018', (21, 24))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019815', ('4', '12'))	('Noxa', 'Gene', (81, 85))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019814', ('4', '12'))	('antibody', 'molecular_function', 'GO:0003823', ('4', '12'))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))
182014	23300762	Primary antibodies for cleaved caspase 3 (1:100, Chemicon; #AB3623) and pan-cytokeratin (1:100, Progen, Heidelberg, Germany; clone GP14) were incubated in a humidified chamber at 4 C overnight.	('caspase 3', 'Gene', '836', (31, 40))	('caspase 3', 'Gene', (31, 40))	('1:100', 'Var', (42, 47))	('1:100', 'Var', (89, 94))
182019	23300762	5 microm paraffin sections were stained using a Bim antibody (#559685BD, Pharmingen, San Jose, CA - 1:200, 2 h, 4 C) and a Noxa antibody (#OP-180, Calbiochem - 1:200, 2 h, 4 C) and visualized with a HRP/DAB Envision plus Kit (#K4010, Dako, Carpinteria, CA).	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('Noxa', 'Gene', '5366', (123, 127))	('antibody', 'cellular_component', 'GO:0042571', ('52', '60'))	('Noxa', 'Gene', (123, 127))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('antibody', 'cellular_component', 'GO:0019815', ('52', '60'))	('#K4010', 'Var', (226, 232))	('Bim', 'Gene', (48, 51))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('antibody', 'cellular_component', 'GO:0019814', ('52', '60'))	('antibody', 'molecular_function', 'GO:0003823', ('52', '60'))	('Bim', 'Gene', '10018', (48, 51))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('#559685BD', 'Var', (62, 71))
182021	23300762	Taqman probes for Noxa (Hs00560402_m1), Bim (Hs01076940_m1), Bmf (Hs00372937_m1) and the control beta glucuronidase (GUSB 4333767T) were from Applied Biosystems (Life Technologies, Carlsbad, CA).	('Bmf', 'Chemical', '-', (61, 64))	('Bim', 'Gene', '10018', (40, 43))	('Hs01076940_m1', 'Var', (45, 58))	('Hs00560402_m1', 'Var', (24, 37))	('GUSB', 'Gene', (117, 121))	('Noxa', 'Gene', '5366', (18, 22))	('Noxa', 'Gene', (18, 22))	('beta glucuronidase', 'Gene', (97, 115))	('GUSB', 'Gene', '2990', (117, 121))	('Bim', 'Gene', (40, 43))	('Hs00372937_m1', 'Var', (66, 79))	('beta glucuronidase', 'Gene', '2990', (97, 115))
182024	23300762	Remarkably, in all four lines, when vorinostat was added in combination with bortezomib, vorinostat effectively abolished the multicellular resistance to bortezomib, as shown by the restoration of apoptosis in the cells in 3D to the same or greater level as that seen in 2D ( Figure 1A-D ).	('bortezomib', 'Chemical', 'MESH:D000069286', (77, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('restoration', 'PosReg', (182, 193))	('apoptosis', 'MPA', (197, 206))	('bortezomib', 'Chemical', 'MESH:D000069286', (154, 164))	('vorinostat', 'Chemical', 'MESH:D000077337', (36, 46))	('multicellular resistance to bortezomib', 'MPA', (126, 164))	('abolished', 'NegReg', (112, 121))	('vorinostat', 'Chemical', 'MESH:D000077337', (89, 99))	('vorinostat', 'Var', (89, 99))
182033	23300762	When used alone, vorinostat had little effect on Noxa protein expression; however, when used in combination with bortezomib, vorinostat significantly increased Noxa expression in both 2D and 3D.	('vorinostat', 'Chemical', 'MESH:D000077337', (17, 27))	('bortezomib', 'Chemical', 'MESH:D000069286', (113, 123))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('vorinostat', 'Var', (125, 135))	('Noxa', 'Gene', '5366', (49, 53))	('vorinostat', 'Chemical', 'MESH:D000077337', (125, 135))	('increased', 'PosReg', (150, 159))	('Noxa', 'Gene', (49, 53))	('Noxa', 'Gene', '5366', (160, 164))	('Noxa', 'Gene', (160, 164))
182060	23300762	Previously, we have reported that the acquired multicellular resistance is mediated by alterations in the Bcl-2 family of proteins, raising the hope that strategies directed to the Bcl-2 family could undermine resistance.	('alterations', 'Var', (87, 98))	('mediated', 'Reg', (75, 83))	('Bcl-2', 'molecular_function', 'GO:0015283', ('181', '186'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('106', '111'))	('Bcl-2', 'Gene', (181, 186))	('Bcl-2', 'Gene', (106, 111))	('Bcl-2', 'Gene', '596', (181, 186))	('Bcl-2', 'Gene', '596', (106, 111))
182064	23300762	Therefore, in this study, we sought means of restoring the upregulation of Noxa in the spheroids and turned to vorinostat, an HDAC inhibitor thought to act via enhanced transcription and expression of epigenetically-silenced genes, many of which are pro-apoptotic.	('Noxa', 'Gene', '5366', (75, 79))	('expression', 'MPA', (187, 197))	('Noxa', 'Gene', (75, 79))	('vorinostat', 'Chemical', 'MESH:D000077337', (111, 121))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('spheroids', 'Chemical', '-', (87, 96))	('upregulation', 'PosReg', (59, 71))	('HDAC', 'Gene', (126, 130))	('enhanced', 'PosReg', (160, 168))	('epigenetically-silenced', 'Var', (201, 224))	('HDAC', 'Gene', '9734', (126, 130))
182080	23300762	This raises the possibility that the resistance of the tumor cells in 3D, which can be localized to the Bcl-2 family, is mediated via epigenetic mechanisms.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Bcl-2', 'molecular_function', 'GO:0015283', ('104', '109'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Bcl-2', 'Gene', (104, 109))	('Bcl-2', 'Gene', '596', (104, 109))	('tumor', 'Disease', (55, 60))	('epigenetic', 'Var', (134, 144))	('mediated', 'Reg', (121, 129))
182083	9628896	OCI-5/GPC3, a Glypican Encoded by a Gene That Is Mutated in the Simpson-Golabi-Behmel Overgrowth Syndrome, Induces Apoptosis in a Cell Line-specific Manner OCI-5/GPC3 is a member of the glypican family.	('GPC3', 'Gene', '2719', (162, 166))	('OCI-5', 'Gene', (0, 5))	('OCI-5', 'Gene', '2719', (156, 161))	('Glypican', 'Gene', (14, 22))	('Induces', 'Reg', (107, 114))	('Simpson-Golabi-Behmel Overgrowth Syndrome', 'Disease', (64, 105))	('Apoptosis', 'CPA', (115, 124))	('glypican', 'Gene', (186, 194))	('Simpson-Golabi-Behmel Overgrowth Syndrome', 'Disease', 'MESH:C537340', (64, 105))	('OCI-5', 'Gene', '2719', (0, 5))	('Glypican', 'Gene', '2817', (14, 22))	('Mutated', 'Var', (49, 56))	('glypican', 'Gene', '2817', (186, 194))	('GPC3', 'Gene', (6, 10))	('GPC3', 'Gene', '2719', (6, 10))	('OCI-5', 'Gene', (156, 161))	('Overgrowth', 'Phenotype', 'HP:0001548', (86, 96))	('Glypican', 'molecular_function', 'GO:0015017', ('14', '22'))	('GPC3', 'Gene', (162, 166))	('glypican', 'molecular_function', 'GO:0015017', ('186', '194'))
182085	9628896	It has recently been shown that the OCI-5/GPC3 gene is mutated in patients with the Simpson-Golabi-Behmel Syndrome (SGBS), an X-linked disorder characterized by pre- and postnatal overgrowth and various visceral and skeletal dysmorphisms.	('OCI-5/GPC3', 'Gene', (36, 46))	('X-linked disorder', 'Disease', 'MESH:D040181', (126, 143))	('mutated', 'Var', (55, 62))	('Simpson-Golabi-Behmel Syndrome', 'Disease', 'MESH:C537340', (84, 114))	('Simpson-Golabi-Behmel Syndrome', 'Disease', (84, 114))	('X-linked disorder', 'Disease', (126, 143))	('visceral and skeletal dysmorphisms', 'Disease', 'None', (203, 237))	('SGBS', 'Gene', '2719', (116, 120))	('pre', 'molecular_function', 'GO:0003904', ('161', '164'))	('SGBS', 'Gene', (116, 120))	('dysmorphisms', 'Disease', 'None', (225, 237))	('overgrowth', 'Phenotype', 'HP:0001548', (180, 190))	('dysmorphisms', 'Disease', (225, 237))	('patients', 'Species', '9606', (66, 74))
182096	9628896	Recently, reported that individuals with SGBS display mutations in the OCI-5/glypican 3 (OCI-5/GPC3) gene.	('glypican', 'molecular_function', 'GO:0015017', ('77', '85'))	('glypican 3', 'Gene', (77, 87))	('mutations', 'Var', (54, 63))	('OCI-5/GPC3', 'Gene', (89, 99))	('glypican 3', 'Gene', '2719', (77, 87))
182103	9628896	Regulatory mutations of dally have a severe impact on the postembryonic development of the nervous system and produce morphological defects in several tissues, including the eyes, antennae, wings, and genitalia.	('defects', 'NegReg', (132, 139))	('mutations', 'Var', (11, 20))	('impact', 'Reg', (44, 50))	('genitalia', 'Disease', (201, 210))	('genitalia', 'Disease', 'MESH:D012734', (201, 210))	('morphological', 'CPA', (118, 131))	('postembryonic development of the nervous system', 'CPA', (58, 105))	('dally', 'Gene', (24, 29))
182109	9628896	After mutation, the AgeI-EcoRI fragment containing the 3' end of the OCI-5 cDNA was removed and replaced by a linker sequence (5'-CCGGAGCTGACTAACTGAATT-3') that contains three stop codons.	('OCI-5', 'Gene', (69, 74))	('mutation', 'Var', (6, 14))	('GAG', 'Chemical', 'MESH:D006025', (133, 136))
182270	30410563	the detection of loss of nuclear staining of BAP1 by IHC combined with the homozygous deletion of p16 detected by in situ hybridization offer a high sensitivity of 92.5% in the differentiation of benign versus malignant mesothelial cell proliferations.	('p16', 'Gene', (98, 101))	('BAP1', 'Gene', (45, 49))	('nuclear staining', 'MPA', (25, 41))	('p16', 'Gene', '1029', (98, 101))	('loss', 'NegReg', (17, 21))	('BAP1', 'Gene', '8314', (45, 49))	('deletion', 'Var', (86, 94))
182294	28031909	Parents are faced with all sorts of other difficult decisions such as how do you tell a child that he or she is affected, and then do you test the other children to see if they carry the triplet repeat or even a mutation.	('mutation', 'Var', (212, 220))	('children', 'Species', '9606', (153, 161))	('test', 'Reg', (138, 142))	('triplet repeat', 'Var', (187, 201))	('carry', 'Reg', (177, 182))
182489	20035722	An epigenetic mechanism for capecitabine resistance in mesothelioma Mesothelioma is an uncommon malignancy whose global incidence continues to rise.	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('mesothelioma', 'Disease', (55, 67))	('capecitabine', 'Chemical', 'MESH:D000069287', (28, 40))	('malignancy', 'Disease', (96, 106))	('mesothelioma Mesothelioma', 'Phenotype', 'HP:0100001', (55, 80))	('Mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('epigenetic', 'Var', (3, 13))	('Mesothelioma', 'Disease', (68, 80))
182496	20035722	One of the four cell lines tested (H290) was methylated for ECGF-1.	('methylated', 'Var', (45, 55))	('ECGF-1', 'Gene', '1890', (60, 66))	('H290', 'CellLine', 'CVCL:A555', (35, 39))	('ECGF-1', 'Gene', (60, 66))
182501	20035722	Patient tumor samples revealed an increased number of methylated CpG sites in ECGF-1 compared to normal pericardium.	('ECGF-1', 'Gene', '1890', (78, 84))	('methylated', 'MPA', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ECGF-1', 'Gene', (78, 84))	('tumor', 'Disease', (8, 13))	('CpG sites', 'Var', (65, 74))	('Patient', 'Species', '9606', (0, 7))
182502	20035722	Methylation of ECGF-1, leads to transcriptional silencing of TP and may explain the lack of any effect of capecitabine, especially when compared to pemetrexed.	('ECGF-1', 'Gene', '1890', (15, 21))	('capecitabine', 'Chemical', 'MESH:D000069287', (106, 118))	('Methylation', 'Var', (0, 11))	('pemetrexed', 'Chemical', 'MESH:D000068437', (148, 158))	('TP', 'Gene', '1890', (61, 63))	('transcriptional', 'MPA', (32, 47))	('ECGF-1', 'Gene', (15, 21))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('silencing', 'NegReg', (48, 57))
182507	20035722	The SV40 DNA tumor virus has been implicated as a risk factor or co-factor in the development of this malignancy though its precise role in the pathogenesis of mesothelioma has yet to be clarified.	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('tumor', 'Disease', (13, 18))	('pathogenesis', 'biological_process', 'GO:0009405', ('144', '156'))	('malignancy', 'Disease', (102, 112))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mesothelioma', 'Disease', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('malignancy', 'Disease', 'MESH:D009369', (102, 112))	('SV40', 'Var', (4, 8))
182527	20035722	We hypothesized that the reason that capecitabine is ineffective in the treatment of mesothelioma as opposed to other anti-folate therapy like pemetrexed and raltitrexed, is through methylation induced transcriptional silencing of TP which is critical to the activation of capecitabine but plays no role in the metabolism or catabolism of other anti-folate agents.	('mesothelioma', 'Disease', (85, 97))	('folate', 'Chemical', 'MESH:D005492', (350, 356))	('folate', 'Chemical', 'MESH:D005492', (123, 129))	('catabolism', 'biological_process', 'GO:0009056', ('325', '335'))	('silencing', 'NegReg', (218, 227))	('ineffective', 'NegReg', (53, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('methylation', 'Var', (182, 193))	('TP', 'Gene', '1890', (231, 233))	('pemetrexed', 'Chemical', 'MESH:D000068437', (143, 153))	('metabolism', 'biological_process', 'GO:0008152', ('311', '321'))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('capecitabine', 'Chemical', 'MESH:D000069287', (37, 49))	('raltitrexed', 'Chemical', 'MESH:C068874', (158, 169))	('capecitabine', 'Chemical', 'MESH:D000069287', (273, 285))
182557	20035722	Real time PCR results confirmed the greater than six-fold increase in TP mRNA in the H290 cell line after treatment with the DNMT inhibitor, 5-aza-CdR, compared to the same cell line that was not treated with the 5-aza-CdR.	('H290', 'CellLine', 'CVCL:A555', (85, 89))	('increase', 'PosReg', (58, 66))	('DNMT', 'Gene', (125, 129))	('5-aza-CdR', 'Chemical', '-', (213, 222))	('5-aza-CdR', 'Chemical', '-', (141, 150))	('5-aza-CdR', 'Var', (141, 150))	('TP', 'Gene', '1890', (70, 72))	('DNMT', 'Gene', '1786', (125, 129))
182561	20035722	Analogous to the results seen in the RNA analysis, there was up-regulation of TP protein expression in H290 cells exposed to 5-aza-CdR compared to those which were not (Figure 2B).	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('H290', 'CellLine', 'CVCL:A555', (103, 107))	('TP', 'Gene', '1890', (78, 80))	('5-aza-CdR', 'Chemical', '-', (125, 134))	('RNA', 'cellular_component', 'GO:0005562', ('37', '40'))	('5-aza-CdR', 'Var', (125, 134))	('up-regulation', 'PosReg', (61, 74))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
182565	20035722	When utilizing 5-FU or pemetrexed, (drugs that do not require processing to target TS directly in order to have cytotoxic effects), we predicted that the exposure to 5-aza-CdR would have no influence on the cytotoxicity relative to those that were not exposed.	('pemetrexed', 'Chemical', 'MESH:D000068437', (23, 33))	('cytotoxicity', 'Disease', 'MESH:D064420', (207, 219))	('5-aza-CdR', 'Chemical', '-', (166, 175))	('5-aza-CdR', 'Var', (166, 175))	('TS', 'Gene', '7298', (83, 85))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))	('cytotoxicity', 'Disease', (207, 219))
182566	20035722	With DFUR, however, which requires TP in order to be converted to the cytotoxic 5-FU (Figure 1), we predicted that the presence of 5-aza-CdR in the methylated H290 cell line would enhance the cytotoxic effect of the drug compared to the methylated cells that were not exposed to the DNMT inhibitor.	('DFUR', 'Chemical', 'MESH:C025034', (5, 9))	('DNMT', 'Gene', '1786', (283, 287))	('cytotoxic effect of the drug', 'CPA', (192, 220))	('DNMT', 'Gene', (283, 287))	('5-aza-CdR', 'Chemical', '-', (131, 140))	('presence', 'Var', (119, 127))	('5-FU', 'Chemical', 'MESH:D005472', (80, 84))	('5-aza-CdR', 'Var', (131, 140))	('H290', 'CellLine', 'CVCL:A555', (159, 163))	('enhance', 'PosReg', (180, 187))	('TP', 'Gene', '1890', (35, 37))
182570	20035722	H1977 showed no difference in DFUR cytotoxicity despite prior exposure to 5-aza-CdR (Figure 3, Panel B. H290 and H1977 5-aza-CdR pretreated and untreated cells were then exposed to varying concentrations of 5-FU (Figure 3, Panels C and D) or pemetrexed (Figure 3 Panels E and F).	('H1977', 'CellLine', 'CVCL:A520', (0, 5))	('5-aza-CdR', 'Chemical', '-', (119, 128))	('H290', 'CellLine', 'CVCL:A555', (104, 108))	('DFUR', 'Chemical', 'MESH:C025034', (30, 34))	('cytotoxicity', 'Disease', (35, 47))	('5-aza-CdR', 'Chemical', '-', (74, 83))	('5-FU', 'Chemical', 'MESH:D005472', (207, 211))	('H1977', 'Var', (113, 118))	('pemetrexed', 'Chemical', 'MESH:D000068437', (242, 252))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))	('H1977', 'CellLine', 'CVCL:A520', (113, 118))
182572	20035722	The methylation analysis revealed an increased number of methylated CpG islands in the tumor samples, averaging 93.45% methylated in the 4 patient samples compared to the pericardial tissue whose clones averaged only a 34.8 % methylated CpG islands in the same gene (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('methylated', 'MPA', (119, 129))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patient', 'Species', '9606', (139, 146))	('methylated', 'Var', (57, 67))
182573	20035722	In this study, we found that promoter methylation of CpG dinucleotides within the ECGF-1 gene (responsible for TP protein expression) led to transcriptional silencing of this gene product in one cell line as well as in patient specimens.	('transcriptional', 'MPA', (141, 156))	('TP', 'Gene', '1890', (111, 113))	('patient', 'Species', '9606', (219, 226))	('ECGF-1', 'Gene', '1890', (82, 88))	('promoter methylation', 'Var', (29, 49))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('silencing', 'NegReg', (157, 166))	('ECGF-1', 'Gene', (82, 88))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (53, 70))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
182577	20035722	The demonstration of hypermethylation of the ECGF-1 gene in tumor relative to pericardial tissue, as demonstrated in the bisulfite sequencing analysis suggests that this finding may be a relevant mechanism of drug resistance.	('hypermethylation', 'Var', (21, 37))	('ECGF-1', 'Gene', (45, 51))	('drug resistance', 'biological_process', 'GO:0042493', ('209', '224'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ECGF-1', 'Gene', '1890', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('bisulfite', 'Chemical', 'MESH:C042345', (121, 130))	('tumor', 'Disease', (60, 65))	('drug resistance', 'biological_process', 'GO:0009315', ('209', '224'))	('drug resistance', 'Phenotype', 'HP:0020174', (209, 224))
182586	20035722	The role of epigenetics in tumor biology has been well established.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('epigenetics', 'Var', (12, 23))
182587	20035722	Recent studies have demonstrated that methylation of the O6MGMT gene leads to enhanced clinical activity of the oral alkylating temozolomide in patients with glioblastoma multiforme.	('methylation', 'Var', (38, 49))	('glioblastoma multiforme', 'Disease', (158, 181))	('patients', 'Species', '9606', (144, 152))	('temozolomide', 'Chemical', 'MESH:D000077204', (128, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (158, 181))	('MGMT', 'molecular_function', 'GO:0003908', ('59', '63'))	('MGMT', 'Gene', (59, 63))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('MGMT', 'Gene', '4255', (59, 63))	('enhanced', 'PosReg', (78, 86))
182588	20035722	In this instance, MGMT enzymatically reverses the DNA damaging activity of temozolomide, therefore, transcriptional silencing of this enzyme adds to the efficacy of the drug.	('MGMT', 'Gene', (18, 22))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('DNA damaging activity of temozolomide', 'MPA', (50, 87))	('MGMT', 'Gene', '4255', (18, 22))	('efficacy', 'MPA', (153, 161))	('transcriptional silencing', 'Var', (100, 125))	('MGMT', 'molecular_function', 'GO:0003908', ('18', '22'))	('temozolomide', 'Chemical', 'MESH:D000077204', (75, 87))
182589	20035722	In contrast, the situation we describe of ECGF-1 methylation would be predicted to lead to reduced activation of the prodrug capecitabine.	('activation of the prodrug capecitabine', 'MPA', (99, 137))	('capecitabine', 'Chemical', 'MESH:D000069287', (125, 137))	('ECGF-1', 'Gene', '1890', (42, 48))	('reduced', 'NegReg', (91, 98))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('methylation', 'Var', (49, 60))	('ECGF-1', 'Gene', (42, 48))
182590	20035722	These modifications can have a tremendous impact on which therapies are active in a malignancy.	('modifications', 'Var', (6, 19))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('impact', 'Reg', (42, 48))	('malignancy', 'Disease', (84, 94))
182591	20035722	If methylation can impart chemo-resistance to agents that have a reasonable to work then demethylation may increase the number of active agents to treat malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (153, 175))	('increase', 'PosReg', (107, 115))	('methylation', 'Var', (3, 14))	('malignant mesothelioma', 'Disease', (153, 175))	('demethylation', 'Var', (89, 102))	('methylation', 'biological_process', 'GO:0032259', ('3', '14'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (153, 175))	('demethylation', 'biological_process', 'GO:0070988', ('89', '102'))
182593	20035722	Thus the significance of epigenetic modification in tumor DNA may affect both tumorigenesis as well as efficacy of treatment agents.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('affect', 'Reg', (66, 72))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('epigenetic modification', 'Var', (25, 48))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
182594	20035722	Further experiments to determine epigenetic alterations in mesothelioma cell lines as well as in primary tumors are needed to further explore the other mechanisms of chemo-resistance as well as explanations of pathogenesis of tumor biology in this malignancy.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mesothelioma', 'Disease', (59, 71))	('epigenetic alterations', 'Var', (33, 55))	('malignancy', 'Disease', 'MESH:D009369', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('malignancy', 'Disease', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('pathogenesis', 'biological_process', 'GO:0009405', ('210', '222'))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (226, 231))
182653	19523217	Because these mice have a mutation in one allele of the Trp53 gene, they are prone to develop cancer.	('Trp53', 'Gene', (56, 61))	('mutation', 'Var', (26, 34))	('develop', 'PosReg', (86, 93))	('mice', 'Species', '10090', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('prone', 'Reg', (77, 82))	('Trp53', 'Gene', '22059', (56, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
182662	19523217	The overall incidence of mesotheliomas was 86% in MWCNT-treated rats while no mesothelioma was found in vehicle- or crocidolite-treated rats.	('rats', 'Species', '10116', (64, 68))	('crocidolite', 'Chemical', 'MESH:D017638', (116, 127))	('rats', 'Species', '10116', (136, 140))	('mesotheliomas', 'Disease', 'MESH:D008654', (25, 38))	('mesotheliomas', 'Disease', (25, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('mesothelioma', 'Disease', (25, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (25, 37))	('MWCNT', 'Chemical', '-', (50, 55))	('MWCNT-treated', 'Var', (50, 63))	('mesothelioma', 'Disease', (78, 90))
182670	19523217	It should be recalled that modification of the surface of asbestos fibres modulates the cell responses.	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('modulates', 'Reg', (74, 83))	('cell responses', 'CPA', (88, 102))	('modification', 'Var', (27, 39))
182678	19523217	In vivo, a mutation of the K-ras oncogene was observed in mice exposed to SWCNTs by inhalation, and chromosomal aberrations were detected in type II pneumocytes after intratracheal deposition of MWCNTs in mice.	('rat', 'Species', '10116', (170, 173))	('mice', 'Species', '10090', (58, 62))	('MWCNTs', 'Chemical', '-', (195, 201))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (100, 123))	('rat', 'Species', '10116', (116, 119))	('mice', 'Species', '10090', (205, 209))	('mutation', 'Var', (11, 19))	('K-ras', 'Gene', (27, 32))	('K-ras', 'Gene', '16653', (27, 32))
182679	19523217	Activation of DNA repair processes and mutagenesis of the adenine phosphoribosyl transferase gene was found in mouse embryonic stem cells.	('adenine phosphoribosyl transferase gene', 'Gene', (58, 97))	('Activation of DNA repair', 'biological_process', 'GO:0045739', ('0', '24'))	('DNA repair processes', 'CPA', (14, 34))	('mouse', 'Species', '10090', (111, 116))	('Activation', 'PosReg', (0, 10))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('mutagenesis', 'Var', (39, 50))	('mutagenesis', 'biological_process', 'GO:0006280', ('39', '50'))
182719	19523217	Loss of heterozygosity was detected as asbestos-induced mutations in a human mesothelioma cell line.	('mesothelioma', 'Disease', (77, 89))	('mutations', 'Var', (56, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('asbestos', 'Chemical', 'MESH:D001194', (39, 47))	('asbestos-induced', 'Disease', (39, 55))	('human', 'Species', '9606', (71, 76))
182728	19523217	MM cells exhibit frequent alterations in tumour suppressor genes found at the INK4 locus, and often the type of alteration is deletions.	('INK4', 'Gene', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('deletions', 'Var', (126, 135))	('rat', 'Species', '10116', (30, 33))	('alterations', 'Reg', (26, 37))	('rat', 'Species', '10116', (116, 119))	('tumour', 'Disease', (41, 47))	('INK4', 'Gene', '1029', (78, 82))
182766	19523217	While not yet definitive, data are now available providing information on the pulmonary and cellular effects of CNTs, which may be compared to those of asbestos fibres.	('pulmonary', 'CPA', (78, 87))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('CNTs', 'Var', (112, 116))
182979	30587874	M199 containing 10% fetal bovine serum (#S1780, Biowest; Nuaille, France) and 1% antibiotic-antimyotic (#15240-062, GIBCO; Grand Island, NY) was used in a humidified incubator with 5% CO2 at 37  C. Cells were used within two months after thawing.	('CO2', 'Chemical', '-', (184, 187))	('bovine', 'Species', '9913', (26, 32))	('#15240-062', 'Var', (104, 114))	('#S1780', 'Var', (40, 46))
182996	30587874	NT50 induced severe fibrosing inflammation in the entire peritoneal cavity, thus changing the liver to a dull-edged round shape (Fig.	('NT50', 'Var', (0, 4))	('NT50', 'Chemical', '-', (0, 4))	('changing', 'Reg', (81, 89))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	('inflammation', 'biological_process', 'GO:0006954', ('30', '42'))	('fibrosing', 'CPA', (20, 29))	('inflammation', 'Disease', (30, 42))
183000	30587874	However, peritoneal fibrosis in the NT50 group was diffuse on the whole peritoneal surface.	('peritoneal fibrosis', 'Phenotype', 'HP:0005200', (9, 28))	('fibrosis', 'Disease', 'MESH:D005355', (20, 28))	('fibrosis', 'Disease', (20, 28))	('NT50', 'Var', (36, 40))	('NT50', 'Chemical', '-', (36, 40))
183025	27705913	It has been shown that all three types of asbestos are the most potent micro-enviromental inducers of MErT by means of an epigenetic process or direct interaction with mesothelial cells.	('epigenetic', 'Var', (122, 132))	('MErT', 'Disease', (102, 106))	('interaction', 'Interaction', (151, 162))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))
183030	27705913	It has been suggested that EMT is a significant morphological feature of malignant mesothelioma, and that aberrant polycomb-group (PcG) protein expression contributes to the pathogenesis of MpM.	('EMT', 'biological_process', 'GO:0001837', ('27', '30'))	('pathogenesis', 'biological_process', 'GO:0009405', ('174', '186'))	('aberrant', 'Var', (106, 114))	('malignant mesothelioma', 'Disease', (73, 95))	('contributes', 'Reg', (155, 166))	('EMT', 'Disease', (27, 30))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (73, 95))	('MpM', 'Disease', (190, 193))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (73, 95))	('polycomb-group', 'Protein', (115, 129))
183032	27705913	E-MpMs may progress toward the undifferentiated high-grade (HG-MpM) variant or a sarcomatous MpM (S-MpM), which is characterised by a change in immunophenotypical make up from the pluripotent OMSK (OCT4, c-MYC SOX2, and KLF4) marker c-MYC to the TWIST and SLUG EMT regulators.	('sarcomatous MpM', 'Disease', (81, 96))	('SOX2', 'Gene', (210, 214))	('c-MYC', 'Gene', (233, 238))	('HG-MpM', 'Gene', (60, 66))	('TWIST', 'Gene', '7291', (246, 251))	('KLF4', 'Gene', '9314', (220, 224))	('EMT', 'biological_process', 'GO:0001837', ('261', '264'))	('sarcomatous MpM', 'Disease', 'MESH:D018316', (81, 96))	('KLF4', 'Gene', (220, 224))	('c-MYC', 'Gene', (204, 209))	('c-MYC', 'Gene', '4609', (233, 238))	('OCT4', 'Gene', (198, 202))	('variant', 'Var', (68, 75))	('TWIST', 'Gene', (246, 251))	('OCT4', 'Gene', '5460', (198, 202))	('OMSK', 'Chemical', '-', (192, 196))	('c-MYC', 'Gene', '4609', (204, 209))	('SOX2', 'Gene', '6657', (210, 214))
183047	27705913	As the observed modulation of c-MYC in E-MPMs and S-MPMs paralleled the level of miRNA 17-5p, we used ISH to investigate miRNA 17-5p expression in two cases of E-MpM (#1 and #11, Table 1) and one of S-MpM (S-MpM3, case #20, Table 1).	('E-MpM', 'Var', (160, 165))	('c-MYC', 'Gene', '4609', (30, 35))	('miRNA 17', 'Gene', '406952', (121, 129))	('miRNA 17', 'Gene', (121, 129))	('miRNA 17', 'Gene', '406952', (81, 89))	('c-MYC', 'Gene', (30, 35))	('miRNA 17', 'Gene', (81, 89))
183053	27705913	To address this issue, we first investigated VEGFR2/MET co-immunoprecipitation in order to explore the hypothesis of VEGFR2 silencing- induced phosphatase-mediated MET up-regulation.	('VEGFR2', 'Gene', '3791', (117, 123))	('silencing-', 'Var', (124, 134))	('VEGFR2', 'Gene', '3791', (45, 51))	('phosphatase', 'molecular_function', 'GO:0016791', ('143', '154'))	('MET', 'MPA', (164, 167))	('VEGFR2', 'Gene', (117, 123))	('VEGFR2', 'Gene', (45, 51))	('regulation', 'biological_process', 'GO:0065007', ('171', '181'))	('up-regulation', 'PosReg', (168, 181))
183086	27705913	Our findings provide evidence that E-MpM is enriched in stemness and plasticity governed by an MErT process.	('stemness', 'Disease', (56, 64))	('plasticity', 'CPA', (69, 79))	('stemness', 'Disease', 'MESH:D020295', (56, 64))	('E-MpM', 'Var', (35, 40))
183092	27705913	The aim of the subsequent surgical specimen-based analyses was to identify the interactions between chromatin-modifying factors, TFs, adhesion molecules and RTKs, and showed that EZH2 was increasingly expressed from E-MpM to HG E-MpM and S-MpM, whereas c-MYC, E-cadherin and VEGFR2 expression was restricted to E-MpMs.	('VEGFR2', 'Gene', '3791', (275, 281))	('EZH2', 'Gene', (179, 183))	('increasingly', 'PosReg', (188, 200))	('E-MpM', 'Var', (216, 221))	('interactions', 'Interaction', (79, 91))	('chromatin', 'cellular_component', 'GO:0000785', ('100', '109'))	('E-cadherin', 'Gene', (260, 270))	('c-MYC', 'Gene', (253, 258))	('E-cadherin', 'Gene', '999', (260, 270))	('VEGFR2', 'Gene', (275, 281))	('cadherin', 'molecular_function', 'GO:0008014', ('262', '270'))	('c-MYC', 'Gene', '4609', (253, 258))
183097	27705913	In the first case, which may correspond to that described as transitional or, more probably HG/undifferentiated MpM, the E-MpM cells retain the immunophenotypical profile but activate c-MYC and EZH2.	('activate', 'PosReg', (175, 183))	('EZH2', 'Protein', (194, 198))	('c-MYC', 'Gene', (184, 189))	('E-MpM', 'Var', (121, 126))	('c-MYC', 'Gene', '4609', (184, 189))
183152	26568187	Microscopically, the tumor was composed of prominent papillo-tubular structures, and immunohistochemically, the spindle to polygonal-shaped tumor cells with nuclear polymorphism were strongly reactive for calretinin.	('tumor', 'Disease', (21, 26))	('nuclear polymorphism', 'Var', (157, 177))	('calretinin', 'Protein', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('spindle', 'cellular_component', 'GO:0005819', ('112', '119'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('reactive', 'Reg', (192, 200))	('tumor', 'Disease', (140, 145))
183195	25393473	Inhibitors for geranlygeranyl transferase I and for RhoA produced morphological changes and disrupted actin fiber structures, both of which were similar to those by ZOL treatments.	('RhoA', 'Gene', (52, 56))	('disrupted', 'NegReg', (92, 101))	('actin', 'MPA', (102, 107))	('RhoA', 'Gene', '387', (52, 56))	('Inhibitors', 'Var', (0, 10))	('ZOL', 'Chemical', 'MESH:D000077211', (165, 168))	('morphological changes', 'CPA', (66, 87))
183240	25393473	NSC23766, an inhibitor of Rac1, which decreased the level of GTP-binding Rac1 without upregulating the whole protein level, did not influence on cell cycle in both MSTO-211H and EHMES-10 cells (Figures 2c and d).	('NSC23766', 'Var', (0, 8))	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('decreased', 'NegReg', (38, 47))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('GTP-binding', 'molecular_function', 'GO:0005525', ('61', '72'))	('Rac1', 'Gene', (26, 30))	('Rac1', 'Gene', '5879', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (164, 173))	('Rac1', 'Gene', '5879', (73, 77))	('EHMES-10', 'CellLine', 'CVCL:M208', (178, 186))	('Rac1', 'Gene', (73, 77))
183245	25393473	We further investigated the effects of inhibitors for geranylgeranylation, GGTI-298 and NE10790, which inhibit geranylgeranyl transferase I and II, respectively (Supplementary Figure S1).	('GGTI', 'Gene', '5229', (75, 79))	('GGTI', 'Gene', (75, 79))	('NE10790', 'Var', (88, 95))	('geranylgeranyl transferase I', 'Enzyme', (111, 139))	('inhibit', 'NegReg', (103, 110))
183246	25393473	GGTI-298 treatments increased unprenylated Rap1A and whole RhoA levels as shown in ZOL-treated cells, but did not influence Rab6 expression (Figure 3a).	('treatments', 'Var', (9, 19))	('increased', 'PosReg', (20, 29))	('Rab6', 'Gene', '5870', (124, 128))	('Rap1A', 'Gene', (43, 48))	('Rap1A', 'Gene', '5906', (43, 48))	('GGTI', 'Gene', '5229', (0, 4))	('GGTI', 'Gene', (0, 4))	('RhoA', 'Gene', (59, 63))	('ZOL', 'Chemical', 'MESH:D000077211', (83, 86))	('Rab6', 'Gene', (124, 128))	('RhoA', 'Gene', '387', (59, 63))
183249	25393473	NE10790 treatments did not influence the levels of unprenylated Rap1A or total RhoA expression, or fractionated RhoA distributions (Figures 3a-c).	('RhoA', 'Gene', '387', (79, 83))	('Rap1A', 'Gene', (64, 69))	('RhoA', 'Gene', (112, 116))	('Rap1A', 'Gene', '5906', (64, 69))	('RhoA', 'Gene', '387', (112, 116))	('NE10790', 'Var', (0, 7))	('RhoA', 'Gene', (79, 83))
183250	25393473	In contrast, NE10790-treated cells showed downregulation of Rab6 translocation to membrane in MSTO-211H and EHMES-10 cells although the expression levels were variable depending on the cells tested.	('Rab6', 'Gene', (60, 64))	('EHMES-10', 'CellLine', 'CVCL:M208', (108, 116))	('membrane', 'cellular_component', 'GO:0016020', ('82', '90'))	('Rab6', 'Gene', '5870', (60, 64))	('NE10790-treated', 'Var', (13, 28))	('downregulation', 'NegReg', (42, 56))	('MSTO-211H', 'CellLine', 'CVCL:1430', (94, 103))
183252	25393473	NE10790 also augmented sub-G1 fractions in MSTO-211H cells but had little effects on cell cycle in EHMES-10 cells (Figure 3e).	('sub-G1 fractions', 'MPA', (23, 39))	('augmented', 'PosReg', (13, 22))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (43, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('NE10790', 'Var', (0, 7))	('EHMES-10', 'CellLine', 'CVCL:M208', (99, 107))
183253	25393473	These data indicated that ungeranylgeranylation of Rho and/or Rab family proteins was responsible for ZOL-induced apoptosis but not for S-phase arrest.	('Rab', 'Gene', '3267', (62, 65))	('ZOL', 'Chemical', 'MESH:D000077211', (102, 105))	('ZOL-induced', 'Disease', (102, 113))	('Rho', 'Protein', (51, 54))	('Rab', 'Gene', (62, 65))	('responsible', 'Reg', (86, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('ungeranylgeranylation', 'Var', (26, 47))	('S-phase', 'biological_process', 'GO:0051320', ('136', '143'))
183254	25393473	We investigated a possible mechanism of apoptosis induction by the inhibitors that increased sub-G1 fractions in MSTO-211H cells, C3 transferase, GGTI-298 and NE10790 (Figure 4a).	('increased', 'PosReg', (83, 92))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (113, 128))	('NE10790', 'Var', (159, 166))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('C3 transferase', 'Enzyme', (130, 144))	('GGTI', 'Gene', '5229', (146, 150))	('GGTI', 'Gene', (146, 150))
183257	25393473	In contrast, NE10790 treatments decreased both phosphorylated Akt and Mcl-1 levels, and induced cleavages of caspase-9, -3 and PARP, all of which changes were the same as those observed in ZOL-treated MSTO-211H cells.	('caspase-9', 'Gene', '842', (109, 118))	('PARP', 'Gene', (127, 131))	('Mcl-1', 'Gene', '4170', (70, 75))	('cleavages', 'MPA', (96, 105))	('Akt', 'Gene', '207', (62, 65))	('MSTO-211H cells', 'CellLine', 'CVCL:1430', (201, 216))	('ZOL', 'Chemical', 'MESH:D000077211', (189, 192))	('caspase-9', 'Gene', (109, 118))	('PARP', 'Gene', '142', (127, 131))	('Mcl-1', 'Gene', (70, 75))	('NE10790', 'Var', (13, 20))	('decreased', 'NegReg', (32, 41))	('Akt', 'Gene', (62, 65))
183281	25393473	We examined the target molecules with supplementary isoprenoids, specific inhibitors and siRNA for small G proteins because ZOL-mediated unprenylation of small G proteins resulted in the loss of functions.	('functions', 'MPA', (195, 204))	('loss', 'NegReg', (187, 191))	('isoprenoids', 'Chemical', 'MESH:D013729', (52, 63))	('unprenylation', 'Var', (137, 150))	('ZOL', 'Chemical', 'MESH:D000077211', (124, 127))
183284	25393473	N-BPs can produce cytotoxic effects, but the precise mechanism remains uncharacterized in particular as for which small G proteins are involved.	('cytotoxic effects', 'CPA', (18, 35))	('N-BPs', 'Chemical', '-', (0, 5))	('N-BPs', 'Var', (0, 5))	('small G proteins', 'Protein', (114, 130))
183287	25393473	Expression patterns of apoptosis-related molecules indicated that NE10790 but not GGTI-298 or C3 transferase activated the same apoptotic pathways that ZOL did.	('GGTI', 'Gene', '5229', (82, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('apoptotic pathways', 'Pathway', (128, 146))	('GGTI', 'Gene', (82, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('ZOL', 'Chemical', 'MESH:D000077211', (152, 155))	('NE10790', 'Var', (66, 73))
183290	25393473	Rab family proteins possess a one- or two-cysteine-containing motif at the C terminal, and NE10790 inhibits geranylgeranylation of only the second of the two-cysteines residues.	('cysteine', 'Chemical', 'MESH:D003545', (158, 166))	('inhibits', 'NegReg', (99, 107))	('cysteine', 'Chemical', 'MESH:D003545', (42, 50))	('geranylgeranylation', 'MPA', (108, 127))	('NE10790', 'Var', (91, 98))	('Rab', 'Gene', '3267', (0, 3))	('Rab', 'Gene', (0, 3))	('cysteines', 'Chemical', 'MESH:D003545', (158, 167))
183291	25393473	The targets of NE10790 are consequently Rab family proteins with two-cysteine-containing motifs such as Rab1, Rab5 and Rab6.	('cysteine', 'Chemical', 'MESH:D003545', (69, 77))	('Rab', 'Gene', '3267', (119, 122))	('Rab1', 'Gene', (104, 108))	('Rab1', 'Gene', '5861', (104, 108))	('Rab', 'Gene', (40, 43))	('Rab5', 'Gene', '5868', (110, 114))	('Rab', 'Gene', '3267', (104, 107))	('Rab6', 'Gene', (119, 123))	('NE10790', 'Var', (15, 22))	('Rab6', 'Gene', '5870', (119, 123))	('Rab', 'Gene', '3267', (110, 113))	('Rab', 'Gene', (119, 122))	('Rab5', 'Gene', (110, 114))	('Rab', 'Gene', '3267', (40, 43))	('Rab', 'Gene', (104, 107))	('Rab', 'Gene', (110, 113))
183298	25393473	The first generation of non-N-BPs, which does not influence prenylation processes of small G proteins, was converted into an ATP analogue similar to ApppI in the structure and achieved apoptosis by reducing mitochondria membrane potentials.	('N-BPs', 'Chemical', '-', (28, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('185', '194'))	('prenylation', 'biological_process', 'GO:0097354', ('60', '71'))	('membrane', 'cellular_component', 'GO:0016020', ('220', '228'))	('apoptosis', 'CPA', (185, 194))	('apoptosis', 'biological_process', 'GO:0097194', ('185', '194'))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('non-N-BPs', 'Var', (24, 33))	('achieved', 'PosReg', (176, 184))	('ApppI', 'Chemical', '-', (149, 154))	('reducing', 'NegReg', (198, 206))	('mitochondria', 'cellular_component', 'GO:0005739', ('207', '219'))	('mitochondria membrane potentials', 'MPA', (207, 239))
183306	25393473	We further investigated whether clodronate, which belongs to the first generation of BPs and produces an ATP analogue, AppCCl2p, similar to ApppI in the structure, induced S-phase arrest in EHMES-10 cells (Supplementary Figure S6).	('AppCCl2p', 'Chemical', '-', (119, 127))	('S-phase arrest', 'CPA', (172, 186))	('ApppI', 'Chemical', '-', (140, 145))	('BPs', 'Chemical', 'MESH:D004164', (85, 88))	('EHMES-10', 'CellLine', 'CVCL:M208', (190, 198))	('induced', 'Reg', (164, 171))	('S-phase', 'biological_process', 'GO:0051320', ('172', '179'))	('clodronate', 'Chemical', 'MESH:D004002', (32, 42))	('ATP', 'Chemical', 'MESH:D000255', (105, 108))	('AppCCl2p', 'Var', (119, 127))
183314	25393473	The GGTI-298-induced alterations were similar to those by ZOL but NE10790 or NSC23766 had no effect on the morphological changes.	('NSC23766', 'Var', (77, 85))	('ZOL', 'Chemical', 'MESH:D000077211', (58, 61))	('GGTI', 'Gene', '5229', (4, 8))	('GGTI', 'Gene', (4, 8))	('NE10790', 'Var', (66, 73))
183349	21913025	Higher degrees of tumor-infiltrating CD3+ in ovarian cancers and intratumoral CD45RO+ cells in colorectal cancer were associated with prolonged survival.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('colorectal cancer', 'Disease', (95, 112))	('tumor', 'Disease', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (70, 75))	('CD3+', 'Var', (37, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('ovarian cancers', 'Phenotype', 'HP:0100615', (45, 60))	('ovarian cancers', 'Disease', (45, 60))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('ovarian cancers', 'Disease', 'MESH:D010051', (45, 60))	('prolonged', 'PosReg', (134, 143))
183352	21913025	Patients with high stromal, chronic inflammatory responses were observed to have improved median overall survival, as compared to patients with low chronic inflammatory responses (19.4 vs. 15.0 months, respectively).	('improved', 'PosReg', (81, 89))	('overall survival', 'MPA', (97, 113))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (130, 138))	('Patients', 'Species', '9606', (0, 8))
183363	21913025	Interestingly, the authors observed higher CD8+ lymphocyte infiltration in patients receiving cisplatin/pemetrexed (currently the most efficacious MPM chemotherapy regimen) versus cisplatin/vinorelbine.	('cisplatin/pemetrexed', 'Var', (94, 114))	('higher', 'PosReg', (36, 42))	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', '925', (43, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('patients', 'Species', '9606', (75, 83))	('vinorelbine', 'Chemical', 'MESH:D000077235', (190, 201))	('pemetrexed', 'Chemical', 'MESH:D000068437', (104, 114))
183375	21913025	CD25, a marker of activation on T lymphocytes, is constitutively expressed by Tregs; the presence of CD4+ CD25+ Tregs has been implied in the inhibition of anti-tumor immunity and has also been associated with worse prognosis in several cancers.	('Tregs', 'Chemical', '-', (78, 83))	('inhibition', 'NegReg', (142, 152))	('Tregs', 'Chemical', '-', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CD25+', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('associated', 'Reg', (194, 204))	('CD4+', 'Var', (101, 105))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('presence', 'Var', (89, 97))
183376	21913025	Depletion of Tregs using intratumoral or intraperitoneally injected anti-CD25 antibody in mice prior to intraperitoneal inoculation with mesothelioma tumor resulted in the restriction of tumor growth and significantly increased median survival from 19 to 33 days.	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (187, 192))	('anti-CD25', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('increased', 'PosReg', (218, 227))	('median survival', 'CPA', (228, 243))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mesothelioma tumor', 'Disease', (137, 155))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', (150, 155))	('restriction', 'NegReg', (172, 183))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (137, 155))	('Tregs', 'Chemical', '-', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (137, 155))	('tumor', 'Disease', (30, 35))
183377	21913025	Flow cytometric analysis of tumor cell suspensions showed that Treg depletion resulted in a large accumulation of intratumoral interferon-gamma (IFN-gamma)-producing CD4+ and CD8+ cytotoxic T cells, which the investigators proposed to be responsible for the observed anti-tumor response.	('tumor', 'Disease', (28, 33))	('interferon-gamma', 'Gene', '3458', (127, 143))	('CD8', 'Gene', '925', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('accumulation', 'PosReg', (98, 110))	('tumor', 'Disease', (272, 277))	('depletion', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('Treg', 'Chemical', '-', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CD8', 'Gene', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (119, 124))	('IFN-gamma', 'Gene', '3458', (145, 154))	('IFN-gamma', 'Gene', (145, 154))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('127', '143'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('interferon-gamma', 'Gene', (127, 143))
183378	21913025	CD4+ cells appeared to be important mediators that lure CD8+ cells into the tumor microenvironment, as depletion of CD4+ cells significantly reduced intratumoral CD8+ cell infiltration by approximately 2.5-fold.	('CD8', 'Gene', '925', (162, 165))	('CD4+', 'Var', (116, 120))	('depletion', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('reduced', 'NegReg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', (162, 165))	('CD8', 'Gene', '925', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (154, 159))
183381	21913025	Treg depletion by anti-CD25 antibody did not improve survival, however, if administered as a monotherapy in established MPM tumors.	('antibody', 'molecular_function', 'GO:0003823', ('28', '36'))	('MPM tumors', 'Disease', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MPM tumors', 'Disease', 'MESH:D009369', (120, 130))	('antibody', 'cellular_component', 'GO:0042571', ('28', '36'))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Treg', 'Chemical', '-', (0, 4))	('antibody', 'cellular_component', 'GO:0019814', ('28', '36'))	('antibody', 'cellular_component', 'GO:0019815', ('28', '36'))	('anti-CD25', 'Var', (18, 27))
183387	21913025	Cyclophosphamide, a chemotherapeutic with established immunostimulatory properties including the ability to selectively deplete Tregs, was found to sensitize MPM tumor cells to TRAIL-mediated apoptosis, suggesting that anti-tumor immune responses provoked by cyclophosphamide depend on increased tumor cell susceptibility, rather than effector cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (162, 167))	('cyclophosphamide', 'Var', (259, 275))	('TRAIL', 'Gene', '8743', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('tumor', 'Disease', (296, 301))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (259, 275))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('MPM tumor', 'Disease', 'MESH:D009369', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('TRAIL', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Tregs', 'Chemical', '-', (128, 133))	('tumor', 'Disease', (224, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('344', '362'))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('sensitize', 'Reg', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('MPM tumor', 'Disease', (158, 167))
183388	21913025	A more recent investigation observed retarded MPM tumor growth when either anti-CD25 antibody or cyclophosphamide was given following cisplatin cycles.	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (97, 113))	('retarded MPM tumor', 'Disease', (37, 55))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('anti-CD25', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('anti-CD25', 'Gene', (75, 84))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('retarded MPM tumor', 'Disease', 'MESH:D009369', (37, 55))
183389	21913025	These data implied that Treg depletion between cisplatin cycles may hinder MPM tumor cell repopulation, potentially improving outcomes.	('depletion', 'Var', (29, 38))	('hinder', 'NegReg', (68, 74))	('MPM tumor', 'Disease', (75, 84))	('improving', 'PosReg', (116, 125))	('outcomes', 'MPA', (126, 134))	('Treg', 'Chemical', '-', (24, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('MPM tumor', 'Disease', 'MESH:D009369', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
183404	21913025	Furthermore, adoptively transferred CD8+ T cells from mice treated with tumor lysate-pulsed DCs retained tumor-specific cytotoxicity when injected into mesothelioma-bearing mice, prolonging survival in mice when given either 1 week before or 2 days after tumor inoculation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('prolonging', 'PosReg', (179, 189))	('mice', 'Species', '10090', (173, 177))	('survival', 'CPA', (190, 198))	('mice', 'Species', '10090', (202, 206))	('cytotoxicity', 'Disease', (120, 132))	('DCs', 'Var', (92, 95))	('mesothelioma', 'Disease', (152, 164))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('tumor', 'Disease', (105, 110))	('mesothelioma', 'Disease', 'MESH:D008654', (152, 164))	('CD8', 'Gene', '925', (36, 39))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mice', 'Species', '10090', (54, 58))	('CD8', 'Gene', (36, 39))
183437	21913025	The anti-CD40 treatment primarily recruited B cells, whereas IL-2 treatment increased CD4+ and CD8+ T-cell infiltration into the MPM tumor microenvironment, as determined by flow cytometry.	('CD8', 'Gene', '925', (95, 98))	('increased', 'PosReg', (76, 85))	('IL-2', 'molecular_function', 'GO:0005134', ('61', '65'))	('MPM tumor', 'Disease', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('anti-CD40', 'Var', (4, 13))	('MPM tumor', 'Disease', 'MESH:D009369', (129, 138))	('CD4+', 'MPA', (86, 90))	('CD8', 'Gene', (95, 98))
183439	21913025	In mice bearing small MPM flank tumors, depletion of both CD4+ and CD8+ cells did not prevent the efficacy of combination IL-2 and anti-CD40 treatment, implying other effector mechanisms may be important in early tumor eradication.	('tumor', 'Disease', (213, 218))	('MPM flank tumors', 'Disease', (22, 38))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('MPM flank tumors', 'Disease', 'MESH:D021501', (22, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (32, 37))	('IL-2', 'molecular_function', 'GO:0005134', ('122', '126'))	('CD8', 'Gene', (67, 70))	('anti-CD40', 'Var', (131, 140))	('CD8', 'Gene', '925', (67, 70))
183443	21913025	Neutrophil infiltration of large tumors was also shown to be required in order to eradicate tumors, as depletion of neutrophils also prevented tumor regression, implying that both CD8+ and neutrophils, together, are required for an effective anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('prevented', 'NegReg', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (33, 38))	('CD8', 'Gene', '925', (180, 183))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('depletion', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('CD8', 'Gene', (180, 183))	('tumors', 'Disease', (33, 39))
183451	21913025	assessed the anti-tumor efficacy of IL-12 by transfecting a murine MPM cell line with IL-12 genes, inducing local IL-12 production within the tumor microenvironment.	('IL-12', 'molecular_function', 'GO:0005143', ('114', '119'))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('genes', 'Var', (92, 97))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (142, 147))	('IL-12', 'Gene', (86, 91))	('murine', 'Species', '10090', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IL-12', 'molecular_function', 'GO:0005143', ('36', '41'))	('IL-12 production', 'biological_process', 'GO:0032615', ('114', '130'))	('IL-12', 'molecular_function', 'GO:0005143', ('86', '91'))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('inducing', 'PosReg', (99, 107))	('local IL-12 production', 'MPA', (108, 130))
183456	21913025	Furthermore, investigations have revealed evidence of cytokine therapy conferring long-term immunity as demonstrated by resistance to tumor re-challenge.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cytokine therapy', 'Var', (54, 70))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
183461	21913025	Importantly, blockade of CCL2/12, in concert with vaccine immunotherapy, induced ~twofold higher expression of the pro-inflammatory molecules CXCL10, ICAM, IL-10, IL-12, IFN-gamma, and TNF-alpha.	('IL-10', 'Gene', '3586', (156, 161))	('IL-10', 'molecular_function', 'GO:0005141', ('156', '161'))	('IL-10', 'Gene', (156, 161))	('IFN-gamma', 'Gene', (170, 179))	('blockade', 'Var', (13, 21))	('IFN-gamma', 'Gene', '3458', (170, 179))	('CCL2/12', 'Gene', (25, 32))	('CCL', 'molecular_function', 'GO:0044101', ('25', '28'))	('CXCL10', 'Gene', (142, 148))	('ICAM', 'MPA', (150, 154))	('IL-12', 'molecular_function', 'GO:0005143', ('163', '168'))	('higher', 'PosReg', (90, 96))	('CXCL10', 'Gene', '3627', (142, 148))	('expression', 'MPA', (97, 107))
183468	21913025	The aforementioned data led the authors to hypothesize that TGF-beta blockade resulted in the polarization of TANs toward the anti-tumor, N1 phenotype.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('polarization', 'MPA', (94, 106))	('blockade', 'Var', (69, 77))	('TANs', 'Chemical', 'MESH:D014216', (110, 114))	('TGF-beta', 'Gene', (60, 68))
183471	21913025	The results of this study imply that following TGF-beta blockade, TANs that exhibit an anti-tumor phenotype (N1 TANs) are recruited into the MPM tumor microenvironment, leading to elaboration of pro-inflammatory cytokines with subsequent activation of intratumoral CD8+ T cells.	('MPM tumor', 'Disease', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CD8', 'Gene', (265, 268))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (145, 150))	('pro-inflammatory cytokines', 'MPA', (195, 221))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('elaboration', 'MPA', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('activation', 'PosReg', (238, 248))	('MPM tumor', 'Disease', 'MESH:D009369', (141, 150))	('CD8', 'Gene', '925', (265, 268))	('blockade', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('TANs', 'Chemical', 'MESH:D014216', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TANs', 'Chemical', 'MESH:D014216', (112, 116))	('tumor', 'Disease', (92, 97))	('TGF-beta', 'Gene', (47, 55))
183478	21913025	The authors hypothesized that systemic anti-CD40 antibody administration, a surrogate for CD4+ T helper cells, increased tumor cell sensitivity to cytotoxic T cells or increased the quality of the CD8+ T-cell response.	('increased', 'PosReg', (168, 177))	('CD8', 'Gene', '925', (197, 200))	('increased', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('anti-CD40', 'Var', (39, 48))	('antibody', 'cellular_component', 'GO:0042571', ('49', '57'))	('tumor', 'Disease', (121, 126))	('antibody', 'molecular_function', 'GO:0003823', ('49', '57'))	('antibody', 'cellular_component', 'GO:0019815', ('49', '57'))	('CD8', 'Gene', (197, 200))	('antibody', 'cellular_component', 'GO:0019814', ('49', '57'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
183566	31842309	Two further adjustments were made to fit with the context of the study: The dose-response model considered for lung cancers is based on the study of Stayner, who observed that the incidence of lung cancer IL is directly proportional to the exposure concentration f [fibers/mL], the duration of the exposure [years], and a multiplicative factor KL, reflecting the carcinogenic potential of the pollutant.	('carcinogenic', 'Disease', 'MESH:D063646', (363, 375))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))	('carcinogenic', 'Disease', (363, 375))	('men', 'Species', '9606', (18, 21))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('lung cancers', 'Disease', (111, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('f [', 'Var', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('lung cancer', 'Disease', (193, 204))	('lung cancers', 'Disease', 'MESH:D008175', (111, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
183619	29212260	We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('reduced', 'NegReg', (195, 202))	('cellular oxygen consumption', 'MPA', (20, 47))	('decreased', 'NegReg', (66, 75))	('cisplatin resistant', 'Var', (79, 98))	('mitochondrial activity', 'MPA', (157, 179))	('reduced', 'NegReg', (149, 156))	('mitochondrial abundance', 'MPA', (203, 226))	('oxygen', 'Chemical', 'MESH:D010100', (29, 35))
183621	29212260	Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls.	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (39, 72))	('stabilization', 'MPA', (149, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('increased', 'PosReg', (94, 103))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))	('HIF1alpha', 'Gene', (138, 147))	('increased', 'PosReg', (39, 48))	('HIF1alpha', 'Gene', '3091', (138, 147))	('hypoxia inducible factor 1-alpha', 'Gene', (104, 136))	('hypoxia inducible factor 1-alpha', 'Gene', '3091', (104, 136))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))	('cisplatin', 'Var', (166, 175))
183626	29212260	Altered metabolism is a hallmark of cancer and while acquired genetic and molecular modifications have enabled cancers to survive the onslaught of various cancer therapies, understanding tumour cell metabolism is becoming increasingly more important.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('tumour', 'Disease', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Disease', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (36, 42))	('modifications', 'Var', (84, 97))	('metabolism', 'biological_process', 'GO:0008152', ('8', '18'))	('metabolism', 'biological_process', 'GO:0008152', ('199', '209'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
183637	29212260	We also looked at reactive oxygen species (ROS) production, as it can be augmented as a result of dysfunctional mitochondria through accumulations of mitochondrial mutations, impairment of oxidative phosphorylation and an imbalance in the expression of antioxidant enzymes.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (18, 41))	('expression', 'MPA', (239, 249))	('augmented', 'PosReg', (73, 82))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (98, 124))	('mitochondria', 'cellular_component', 'GO:0005739', ('112', '124'))	('imbalance', 'Reg', (222, 231))	('accumulations', 'PosReg', (133, 146))	('dysfunctional mitochondria', 'Disease', (98, 124))	('imbalance', 'Phenotype', 'HP:0002172', (222, 231))	('impairment', 'NegReg', (175, 185))	('reactive oxygen species', 'MPA', (18, 41))	('mitochondrial', 'Gene', (150, 163))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('189', '214'))	('mutations', 'Var', (164, 173))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('oxidative phosphorylation', 'MPA', (189, 214))
183638	29212260	In order to confirm the relative cisplatin sensitivities of the H1299 and P31 resistant and their parental counterparts, cells were treated with vehicle (0.9% NaCl) or varying concentrations of cisplatin (50 nmol/L -100 mumol/L) for 72 h and IC50 values were determined using the Alamar Blue viability assay.	('H1299', 'Var', (64, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('NaCl', 'Chemical', 'MESH:D012965', (159, 163))	('H1299', 'CellLine', 'CVCL:0060', (64, 69))	('P31', 'Gene', (74, 77))	('P31', 'Gene', '529', (74, 77))
183639	29212260	As seen in Figure 1, cisplatin decreased the viability of H1299, H1299r, P31 and P31r cells in a dose-dependent manner with the maximum cytotoxic effect being observed at approx.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('viability', 'CPA', (45, 54))	('decreased', 'NegReg', (31, 40))	('H1299', 'CellLine', 'CVCL:0060', (65, 70))	('P31', 'Gene', (73, 76))	('P31', 'Gene', '529', (73, 76))	('P31', 'Gene', (81, 84))	('P31', 'Gene', '529', (81, 84))	('H1299r', 'Var', (65, 71))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))
183644	29212260	Thus the H1299 resistant cells demonstrated a 10-fold greater resistance to cisplatin compared to the parental cells whereas the P31 resistant cells showed a 3-fold resistance to cisplatin compared to the sensitive cells.	('resistance to cisplatin', 'MPA', (62, 85))	('P31', 'Gene', (129, 132))	('P31', 'Gene', '529', (129, 132))	('H1299', 'CellLine', 'CVCL:0060', (9, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('greater', 'PosReg', (54, 61))	('H1299', 'Var', (9, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))
183652	29212260	Figure 2A gives a classic profile of cellular oxygen consumption for cisplatin H1299 and H1299r cells in the presence of inhibitors and uncoupler.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('H1299r', 'Var', (89, 95))	('cellular oxygen consumption', 'MPA', (37, 64))	('H1299', 'CellLine', 'CVCL:0060', (89, 94))	('H1299', 'CellLine', 'CVCL:0060', (79, 84))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))
183654	29212260	OCRs were significantly lower in H1299r cells compared to H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (33, 38))	('lower', 'NegReg', (24, 29))	('OCRs', 'CPA', (0, 4))	('H1299r cells', 'Var', (33, 45))	('OCRs', 'Chemical', '-', (0, 4))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))
183661	29212260	It is also noteworthy that basal oxygen consumption is approximately 2-fold greater in H1299 cells, per unit number of cells, when compared to P31 cells (Figure 2A and 2B).	('H1299', 'CellLine', 'CVCL:0060', (87, 92))	('P31', 'Gene', (143, 146))	('P31', 'Gene', '529', (143, 146))	('greater', 'PosReg', (76, 83))	('H1299', 'Var', (87, 92))	('basal oxygen consumption', 'MPA', (27, 51))	('oxygen', 'Chemical', 'MESH:D010100', (33, 39))
183662	29212260	The ECAR is taken as an index of glycolytic flux, and as expected, oligomycin increased glycolytic flux in H1299r and H1299 cells compared to their respective basal ECAR rates.	('oligomycin', 'Chemical', 'MESH:D009840', (67, 77))	('H1299', 'CellLine', 'CVCL:0060', (107, 112))	('H1299', 'CellLine', 'CVCL:0060', (118, 123))	('glycolytic flux', 'MPA', (88, 103))	('oligomycin', 'Var', (67, 77))	('increased', 'PosReg', (78, 87))
183666	29212260	Interestingly, absolute basal ECARs were similar for both H1299r/H1299 and P31r/P31 cells (~25 mpH/min/20,000 cells - Figure 2C and 2D).	('P31', 'Gene', (80, 83))	('P31', 'Gene', (75, 78))	('P31', 'Gene', '529', (80, 83))	('P31', 'Gene', '529', (75, 78))	('H1299r/H1299', 'Var', (58, 70))	('H1299', 'CellLine', 'CVCL:0060', (65, 70))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))
183668	29212260	Having established that the basal and maximal in situ mitochondrial OCRs were lower in H1299r and P31r cells compared to the equivalent parental counterparts, we set out to determine whether the reduced in situ mitochondrial OCRs were due to reduced mitochondrial numbers in the cisplatin resistant cells.	('H1299r', 'Var', (87, 93))	('P31', 'Gene', '529', (98, 101))	('H1299', 'CellLine', 'CVCL:0060', (87, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (279, 288))	('OCRs', 'Chemical', '-', (225, 229))	('reduced', 'NegReg', (242, 249))	('mitochondrial OCRs', 'MPA', (211, 229))	('OCRs', 'Chemical', '-', (68, 72))	('mitochondrial numbers', 'CPA', (250, 271))	('lower', 'NegReg', (78, 83))	('reduced mitochondrial numbers', 'Phenotype', 'HP:0040013', (242, 271))	('P31', 'Gene', (98, 101))
183670	29212260	There was a significantly greater (~2-fold) citrate synthase activity in the H1299 in comparison to H1299r cells (p<0.01) (Figure 3A).	('citrate synthase activity', 'molecular_function', 'GO:0004108', ('44', '69'))	('citrate synthase', 'Gene', '1431', (44, 60))	('H1299', 'Var', (77, 82))	('H1299', 'CellLine', 'CVCL:0060', (77, 82))	('activity', 'MPA', (61, 69))	('greater', 'PosReg', (26, 33))	('citrate synthase activity', 'molecular_function', 'GO:0036440', ('44', '69'))	('citrate synthase', 'Gene', (44, 60))	('H1299', 'CellLine', 'CVCL:0060', (100, 105))
183675	29212260	These data provide supporting evidence for reduced mitochondrial abundance in cisplatin resistant cells compared to their cisplatin sensitive counterparts.	('cisplatin', 'Var', (78, 87))	('mitochondrial abundance', 'MPA', (51, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('reduced', 'NegReg', (43, 50))
183676	29212260	This is further supported by the mRNA expression data (Table 1) for H1299 with large decreases seen for all four proteins in the resistant cells.	('decreases', 'NegReg', (85, 94))	('mRNA expression', 'MPA', (33, 48))	('H1299', 'Var', (68, 73))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))
183679	29212260	The H1299r cells exhibited a significantly greater (2-fold) degree of ROS production when compared to the H1299 cells (Figure 5A).	('ROS production', 'MPA', (70, 84))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('H1299', 'CellLine', 'CVCL:0060', (106, 111))	('H1299r', 'Var', (4, 10))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))	('greater', 'PosReg', (43, 50))
183686	29212260	The increase in mRNA expression in H1299r was accompanied by a 9% reduction in DNA methylation.	('mRNA expression', 'MPA', (16, 31))	('H1299', 'CellLine', 'CVCL:0060', (35, 40))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('DNA methylation', 'MPA', (79, 94))	('DNA methylation', 'biological_process', 'GO:0006306', ('79', '94'))	('increase', 'PosReg', (4, 12))	('H1299r', 'Var', (35, 41))	('reduction', 'NegReg', (66, 75))
183688	29212260	The mRNA expression data of the studied genes (Table 1) appears to highlight a difference between the two cell lines as most of the selected genes show a reduction with resistance in H1299 but an increase in P31.	('resistance', 'MPA', (169, 179))	('H1299', 'CellLine', 'CVCL:0060', (183, 188))	('reduction', 'NegReg', (154, 163))	('increase', 'PosReg', (196, 204))	('P31', 'Gene', (208, 211))	('H1299', 'Var', (183, 188))	('P31', 'Gene', '529', (208, 211))
183690	29212260	We hypothesize that those genes that changed their expression in the same direction in both H1299 and P31 are more likely to be mechanistically involved in the induction of resistance than those genes that changed in opposite directions (Supplementary Table 1).	('P31', 'Gene', (102, 105))	('resistance', 'Disease', (173, 183))	('H1299', 'Var', (92, 97))	('P31', 'Gene', '529', (102, 105))	('involved', 'Reg', (144, 152))	('H1299', 'CellLine', 'CVCL:0060', (92, 97))	('expression', 'MPA', (51, 61))
183701	29212260	The data for H1299 cells suggests that acquired cisplatin resistance does not result in increased glycolytic flux, but if anything reduces the capacity for an increased glycolytic flux.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('cisplatin resistance', 'Var', (48, 68))	('reduces', 'NegReg', (131, 138))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('glycolytic', 'MPA', (98, 108))	('capacity for an increased glycolytic flux', 'MPA', (143, 184))
183703	29212260	Furthermore, the oxygen consumption not due to oxidative phosphorylation (non-mitochondrial oxygen consumption) is less in H1299r cells compared to H1299 cells, but greater in P31r cells compared to P31 cells.	('less', 'NegReg', (115, 119))	('H1299', 'CellLine', 'CVCL:0060', (148, 153))	('greater', 'PosReg', (165, 172))	('P31', 'Gene', (199, 202))	('oxygen', 'Chemical', 'MESH:D010100', (17, 23))	('P31', 'Gene', '529', (199, 202))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('47', '72'))	('oxygen consumption', 'MPA', (17, 35))	('P31', 'Gene', (176, 179))	('H1299r', 'Var', (123, 129))	('P31', 'Gene', '529', (176, 179))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))
183706	29212260	Furthermore, it is clear that H1299 cells are significantly (~3 fold) more oxidative than P31 cells, yet glycolytic flux is similar in both cell types.	('oxidative', 'MPA', (75, 84))	('H1299', 'Var', (30, 35))	('P31', 'Gene', (90, 93))	('P31', 'Gene', '529', (90, 93))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('glycolytic', 'MPA', (105, 115))	('more', 'PosReg', (70, 74))
183707	29212260	These differences in oxidation between the cell lines could be indicative as to why H1299r cells have a higher (~3 fold) resistance to cisplatin when compared to P31r cells.	('resistance to cisplatin', 'MPA', (121, 144))	('H1299r', 'Var', (84, 90))	('H1299', 'CellLine', 'CVCL:0060', (84, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('P31', 'Gene', (162, 165))	('P31', 'Gene', '529', (162, 165))	('higher', 'PosReg', (104, 110))
183709	29212260	There was approximately a 3-fold reduction in mitochondrial activity in H1299r cells compared to H1299 cells under basal and maximal activity conditions.	('H1299', 'CellLine', 'CVCL:0060', (97, 102))	('reduction', 'NegReg', (33, 42))	('mitochondrial activity', 'MPA', (46, 68))	('H1299r', 'Var', (72, 78))	('H1299', 'CellLine', 'CVCL:0060', (72, 77))
183729	29212260	Deacetylation by SIRT1 supports mitochondrial biogenesis and maintains the sensitivity of PGC1alpha to both the energy and redox balance within the cell.	('PGC1alpha', 'Gene', (90, 99))	('Deacetylation', 'Var', (0, 13))	('SIRT1', 'Gene', '23411', (17, 22))	('PGC1alpha', 'Gene', '10891', (90, 99))	('mitochondrial biogenesis', 'CPA', (32, 56))	('SIRT1', 'Gene', (17, 22))	('sensitivity', 'MPA', (75, 86))
183740	29212260	Selecting the more oxidative H1299 cells for further studies, we were also able to demonstrate that there was greater ROS production in H1299r cells compared to H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (29, 34))	('H1299r', 'Var', (136, 142))	('greater', 'PosReg', (110, 117))	('H1299', 'CellLine', 'CVCL:0060', (161, 166))	('H1299', 'CellLine', 'CVCL:0060', (136, 141))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('ROS production', 'MPA', (118, 132))
183747	29212260	Despite the huge rise in mRNA expression and increased protein expression of AMPKalpha2 seen in H1299r, there is only a slight change in methylation.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('H1299', 'CellLine', 'CVCL:0060', (96, 101))	('increased', 'PosReg', (45, 54))	('AMPKalpha2', 'Gene', '5563', (77, 87))	('mRNA expression', 'MPA', (25, 40))	('protein expression', 'MPA', (55, 73))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('rise', 'PosReg', (17, 21))	('AMPKalpha2', 'Gene', (77, 87))	('H1299r', 'Var', (96, 102))
183749	29212260	The lack of concordant changes in mRNA expression found between the two cell lines suggests different mechanisms of acquiring resistance to cisplatin between the two cell lines which could also account for the fact that H1299r is approximately 3 times more resistant to cisplatin than P31r.	('H1299', 'CellLine', 'CVCL:0060', (220, 225))	('resistant', 'MPA', (257, 266))	('P31', 'Gene', (285, 288))	('resistance', 'MPA', (126, 136))	('P31', 'Gene', '529', (285, 288))	('cisplatin', 'Chemical', 'MESH:D002945', (270, 279))	('H1299r', 'Var', (220, 226))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))
183774	29212260	H1299, H1299r, P31 and P31r cells were plated at 300,000 cells in T25 culture flasks, lysed with Tris-Triton X-100 (0.2% (v/v)) and the protein content was assessed using the BCA assay (below).	('P31', 'Gene', (23, 26))	('Tris-Triton X-100', 'Chemical', '-', (97, 114))	('P31', 'Gene', '529', (23, 26))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('BCA', 'Chemical', 'MESH:C047117', (175, 178))	('H1299', 'CellLine', 'CVCL:0060', (7, 12))	('H1299r', 'Var', (7, 13))	('P31', 'Gene', (15, 18))	('P31', 'Gene', '529', (15, 18))
183781	29212260	The membranes were blocked in Marvel (low fat milk powder, Premier Foods, UK) for 1 h at 21 C, washed with PBS Tween (PBST) and subsequently incubated with antibody for AMPK subunit alpha2 (1:1000), HIF-1alpha (1:500), SIRT1 (1:500), PGC1alpha (1:1000), TFAM (1:500), SIRT3 (1:1000), VDAC1 (1:1000), cytochrome oxidase subunit 4 (1:500), or the loading control gamma-tubulin (1:2000), diluted in 1% PBST at 4 C overnight.	('1:500', 'Var', (260, 265))	('PBS', 'Disease', (399, 402))	('PBS', 'Disease', (107, 110))	('cytochrome', 'molecular_function', 'GO:0045156', ('300', '310'))	('TFAM', 'Gene', (254, 258))	('AMPK subunit alpha2', 'Gene', (169, 188))	('SIRT1', 'Gene', (219, 224))	('antibody', 'molecular_function', 'GO:0003823', ('156', '164'))	('PGC1alpha', 'Gene', '10891', (234, 243))	('PBS', 'Disease', 'MESH:D011535', (118, 121))	('VDAC1', 'Gene', (284, 289))	('AMPK', 'molecular_function', 'GO:0050405', ('169', '173'))	('HIF-1alpha', 'Gene', '3091', (199, 209))	('antibody', 'cellular_component', 'GO:0042571', ('156', '164'))	('VDAC1', 'Gene', '7416', (284, 289))	('cytochrome', 'molecular_function', 'GO:0009458', ('300', '310'))	('cytochrome', 'molecular_function', 'GO:0045153', ('300', '310'))	('AMPK subunit alpha2', 'Gene', '5563', (169, 188))	('AMPK', 'molecular_function', 'GO:0004691', ('169', '173'))	('PBS', 'Disease', (118, 121))	('TFAM', 'Gene', '7019', (254, 258))	('antibody', 'cellular_component', 'GO:0019815', ('156', '164'))	('1:1000', 'Var', (291, 297))	('PGC1alpha', 'Gene', (234, 243))	('cytochrome', 'molecular_function', 'GO:0045157', ('300', '310'))	('cytochrome', 'molecular_function', 'GO:0045154', ('300', '310'))	('HIF-1alpha', 'Gene', (199, 209))	('cytochrome', 'molecular_function', 'GO:0045155', ('300', '310'))	('PBS', 'Disease', 'MESH:D011535', (399, 402))	('PBS', 'Disease', 'MESH:D011535', (107, 110))	('SIRT3', 'Gene', (268, 273))	('SIRT3', 'Gene', '23410', (268, 273))	('1:1000', 'Var', (275, 281))	('cytochrome', 'molecular_function', 'GO:0045158', ('300', '310'))	('SIRT1', 'Gene', '23411', (219, 224))	('AMPK', 'molecular_function', 'GO:0047322', ('169', '173'))	('antibody', 'cellular_component', 'GO:0019814', ('156', '164'))	('1:500', 'Var', (226, 231))
183794	29212185	The level of RHAMM expression was decreased by YAP1/TAZ knockdown, and conversely increased by forced expression of the active form of YAP1, suggesting that RHAMM was regulated by YAP1/TAZ in MPM cells.	('RHAMM', 'Gene', '3161', (157, 162))	('RHAMM', 'Gene', (157, 162))	('RHAMM', 'Gene', '3161', (13, 18))	('level', 'MPA', (4, 9))	('decreased', 'NegReg', (34, 43))	('RHAMM', 'Gene', (13, 18))	('YAP1', 'Gene', (180, 184))	('YAP1', 'Gene', '10413', (180, 184))	('increased', 'PosReg', (82, 91))	('YAP1', 'Gene', (135, 139))	('YAP1', 'Gene', '10413', (135, 139))	('YAP1', 'Gene', '10413', (47, 51))	('knockdown', 'Var', (56, 65))	('YAP1', 'Gene', (47, 51))
183795	29212185	Cell migration and invasion were also decreased by YAP1/TAZ or RHAMM knockdown.	('RHAMM', 'Gene', '3161', (63, 68))	('decreased', 'NegReg', (38, 47))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('invasion', 'CPA', (19, 27))	('RHAMM', 'Gene', (63, 68))	('YAP1', 'Gene', (51, 55))	('YAP1', 'Gene', '10413', (51, 55))	('knockdown', 'Var', (69, 78))
183805	29212185	Recent genome-wide studies have revealed that about 50% of MPMs have mutations in Hippo pathway-related genes, especially in NF2 and LATS2.	('mutations', 'Var', (69, 78))	('LATS2', 'Gene', (133, 138))	('LATS2', 'Gene', '26524', (133, 138))	('MPMs', 'Disease', (59, 63))	('NF2', 'Gene', (125, 128))	('Hippo pathway-related genes', 'Gene', (82, 109))	('NF2', 'Gene', '4771', (125, 128))
183808	29212185	Dysregulation of this pathway has been shown to lead to aberrant stabilization and activation of YAP1/TAZ protein, resulting in tumorigenesis, progression, metastasis, and recurrence, and further causing drug resistance by acquisition of cancer stem cell-like properties.	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('YAP1', 'Gene', (97, 101))	('recurrence', 'CPA', (172, 182))	('activation', 'PosReg', (83, 93))	('causing', 'Reg', (196, 203))	('cancer', 'Disease', (238, 244))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('progression', 'CPA', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('aberrant', 'Var', (56, 64))	('metastasis', 'CPA', (156, 166))	('drug resistance', 'biological_process', 'GO:0009315', ('204', '219'))	('drug resistance', 'biological_process', 'GO:0042493', ('204', '219'))	('tumor', 'Disease', (128, 133))	('drug', 'MPA', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('YAP1', 'Gene', '10413', (97, 101))	('stabilization', 'MPA', (65, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (204, 219))
183809	29212185	It has been reported that inactivation of LATS2, the major kinase of Hippo pathway, is one of the key mechanisms for aberrant activation of YAP1, and confers a proliferation advantage on MPM cells via transcriptional regulation of cell cycle-related genes such as CCND1 and FOXM1.	('YAP1', 'Gene', (140, 144))	('YAP1', 'Gene', '10413', (140, 144))	('inactivation', 'Var', (26, 38))	('CCND1', 'Gene', '595', (264, 269))	('proliferation advantage', 'CPA', (160, 183))	('activation', 'PosReg', (126, 136))	('LATS2', 'Gene', (42, 47))	('FOXM1', 'Gene', '2305', (274, 279))	('LATS2', 'Gene', '26524', (42, 47))	('FOXM1', 'Gene', (274, 279))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('217', '241'))	('CCND1', 'Gene', (264, 269))
183814	29212185	Beside CD44, receptor for hyaluronic acid-mediated motility (RHAMM, also known as HMMR, IHABP or CD168) functions as a HA receptor, and several studies have shown that aberrant expression of RHAMM, which is generally not detected in normal tissues, is involved in cell proliferation, migration, invasion and drug resistance in several tumors including breast, lung, and liver cancers.	('cancers', 'Phenotype', 'HP:0002664', (376, 383))	('liver cancers', 'Phenotype', 'HP:0002896', (370, 383))	('tumors', 'Disease', (335, 341))	('lung', 'Disease', (360, 364))	('HA', 'Chemical', 'MESH:D006820', (119, 121))	('HA', 'Chemical', 'MESH:D006820', (62, 64))	('drug resistance', 'biological_process', 'GO:0042493', ('308', '323'))	('involved in', 'Reg', (252, 263))	('HMMR', 'Gene', (82, 86))	('cell proliferation', 'CPA', (264, 282))	('migration', 'CPA', (284, 293))	('aberrant expression', 'Var', (168, 187))	('CD168', 'Gene', '3161', (97, 102))	('IHABP', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('liver cancers', 'Disease', (370, 383))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (26, 41))	('RHAMM', 'Gene', '3161', (191, 196))	('RHAMM', 'Gene', (191, 196))	('CD44', 'Gene', '960', (7, 11))	('breast', 'Disease', (352, 358))	('CD44', 'Gene', (7, 11))	('CD168', 'Gene', (97, 102))	('IHABP', 'Gene', '3161', (88, 93))	('RHAMM', 'Gene', '3161', (61, 66))	('RHAMM', 'Gene', (61, 66))	('HA', 'Chemical', 'MESH:D006820', (89, 91))	('HMMR', 'Gene', '3161', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('liver cancers', 'Disease', 'MESH:D006528', (370, 383))	('HA', 'Chemical', 'MESH:D006820', (192, 194))	('cell proliferation', 'biological_process', 'GO:0008283', ('264', '282'))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('drug resistance', 'Phenotype', 'HP:0020174', (308, 323))	('drug resistance', 'biological_process', 'GO:0009315', ('308', '323'))
183822	29212185	Among the cell lines tested, Y-MESO-27 has been shown to harbor a homozygous deletion mutation in LATS2 gene, a major kinase of Hippo pathway.	('Y-MESO-27', 'Chemical', '-', (29, 38))	('deletion mutation', 'Var', (77, 94))	('LATS2', 'Gene', (98, 103))	('LATS2', 'Gene', '26524', (98, 103))
183823	29212185	Because LATS2 phosphorylates serine 127 and causes cytoplasmic sequestration of YAP1, failure of phosphorylation at serine 127 in the YAP1 protein causes constitutive translocation to the nucleus and transcription of its target genes.	('YAP1', 'Gene', (134, 138))	('YAP1', 'Gene', '10413', (134, 138))	('LATS2', 'Gene', (8, 13))	('constitutive translocation to the nucleus', 'MPA', (154, 195))	('LATS2', 'Gene', '26524', (8, 13))	('transcription', 'biological_process', 'GO:0006351', ('200', '213'))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('causes', 'Reg', (147, 153))	('nucleus', 'cellular_component', 'GO:0005634', ('188', '195'))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('failure', 'Var', (86, 93))	('YAP1', 'Gene', (80, 84))	('YAP1', 'Gene', '10413', (80, 84))	('transcription', 'MPA', (200, 213))	('serine', 'Chemical', 'MESH:D012694', (29, 35))	('cytoplasmic sequestration', 'MPA', (51, 76))	('serine', 'Chemical', 'MESH:D012694', (116, 122))
183825	29212185	Although Y-MESO-12 and Y-MESO-30, which harbor a homozygous deletion in NF2 gene and a partial deletion in LATS2 gene, respectively, were expected to show YAP1 activation, they had lower levels of RHAMM protein (Figure 1A) and mRNA (Figure 1B) than Y-MESO-27.	('mRNA', 'MPA', (227, 231))	('deletion', 'Var', (60, 68))	('activation', 'PosReg', (160, 170))	('lower', 'NegReg', (181, 186))	('Y-MESO', 'Chemical', '-', (9, 15))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('NF2', 'Gene', (72, 75))	('YAP1', 'Gene', (155, 159))	('YAP1', 'Gene', '10413', (155, 159))	('LATS2', 'Gene', (107, 112))	('LATS2', 'Gene', '26524', (107, 112))	('Y-MESO-27', 'Chemical', '-', (249, 258))	('Y-MESO', 'Chemical', '-', (249, 255))	('NF2', 'Gene', '4771', (72, 75))	('RHAMM', 'Gene', '3161', (197, 202))	('RHAMM', 'Gene', (197, 202))	('Y-MESO', 'Chemical', '-', (23, 29))
183827	29212185	The other cell lines, ACC-MESO-4 and NCI-H28, neither of which harbors mutation in NF2 and LATS2 genes, showed relatively low levels of RHAMM protein (Figure 1A) and mRNA (Figure 1B).	('mRNA', 'MPA', (166, 170))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('RHAMM', 'Gene', (136, 141))	('ACC-MESO-4', 'Chemical', '-', (22, 32))	('LATS2', 'Gene', (91, 96))	('mutation', 'Var', (71, 79))	('NF2', 'Gene', (83, 86))	('LATS2', 'Gene', '26524', (91, 96))	('low', 'NegReg', (122, 125))	('NF2', 'Gene', '4771', (83, 86))	('levels', 'MPA', (126, 132))	('RHAMM', 'Gene', '3161', (136, 141))
183831	29212185	Expression of CTGF and ANKRD1, which are reported to be YAP1/TAZ-regulated genes , was decreased by knockdown of YAP1 or TAZ in the MPM cell lines (Supplementary Figure 1).	('CTGF', 'Gene', '1490', (14, 18))	('knockdown', 'Var', (100, 109))	('CTGF', 'Gene', (14, 18))	('ANKRD1', 'Gene', '27063', (23, 29))	('decreased', 'NegReg', (87, 96))	('Expression', 'MPA', (0, 10))	('ANKRD1', 'Gene', (23, 29))	('YAP1', 'Gene', (56, 60))	('YAP1', 'Gene', '10413', (56, 60))	('YAP1', 'Gene', (113, 117))	('YAP1', 'Gene', '10413', (113, 117))
183832	29212185	Concomitant knockdown of YAP1 and TAZ markedly decreased the expression of RHAMM protein in all of the cell lines tested (Figure 1C).	('RHAMM', 'Gene', '3161', (75, 80))	('YAP1', 'Gene', (25, 29))	('YAP1', 'Gene', '10413', (25, 29))	('knockdown', 'Var', (12, 21))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('expression', 'MPA', (61, 71))	('RHAMM', 'Gene', (75, 80))	('decreased', 'NegReg', (47, 56))
183833	29212185	As judged by the ratio of RHAMM and alpha-tubulin, a decrease of over 90% was achieved by concomitant knockdown.	('alpha-tubulin', 'Gene', '10376', (36, 49))	('RHAMM', 'Gene', (26, 31))	('knockdown', 'Var', (102, 111))	('alpha-tubulin', 'Gene', (36, 49))	('RHAMM', 'Gene', '3161', (26, 31))
183835	29212185	It is interesting to note that almost complete knockdown of RHAMM (Figure 1C) decreased the cell proliferation of Y-MESO-27 cells only about 50% (Supplementary Figure 3C).	('RHAMM', 'Gene', (60, 65))	('cell proliferation of Y-MESO-27 cells', 'CPA', (92, 129))	('Y-MESO-27', 'Chemical', '-', (114, 123))	('knockdown', 'Var', (47, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('decreased', 'NegReg', (78, 87))	('RHAMM', 'Gene', '3161', (60, 65))
183839	29212185	Furthermore, forced expression of hyperactive YAP1 (YAP1-5SA, where 5 phosphorylation sites are mutated to alanine, including the major LATS phosphorylation sites) induced RHAMM mRNA expression in the MPM cell lines (Figure 1E, 1F).	('induced', 'PosReg', (164, 171))	('RHAMM', 'Gene', '3161', (172, 177))	('YAP1', 'Gene', (52, 56))	('YAP1', 'Gene', '10413', (52, 56))	('alanine', 'Chemical', 'MESH:D000409', (107, 114))	('RHAMM', 'Gene', (172, 177))	('hyperactive', 'Var', (34, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('YAP1', 'Gene', (46, 50))	('YAP1', 'Gene', '10413', (46, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('141', '156'))
183842	29212185	Therefore, we first confirmed the effect of YAP1/TAZ knockdown in the MPM cell lines we used.	('YAP1', 'Gene', (44, 48))	('knockdown', 'Var', (53, 62))	('YAP1', 'Gene', '10413', (44, 48))
183843	29212185	Whereas single knockdown of YAP1 or TAZ did not decrease cell proliferation in our system, concomitant knockdown of YAP1 and TAZ decreased cell proliferation significantly (41%, 43%, and 46% decrease in ACC-MESO-4, NCI-H28, and Y-MESO-27, respectively) (Supplementary Figure 3A).	('NCI-H28', 'CPA', (215, 222))	('ACC-MESO-4', 'CPA', (203, 213))	('YAP1', 'Gene', (116, 120))	('YAP1', 'Gene', (28, 32))	('YAP1', 'Gene', '10413', (28, 32))	('Y-MESO-27', 'CPA', (228, 237))	('cell proliferation', 'CPA', (139, 157))	('ACC-MESO-4', 'Chemical', '-', (203, 213))	('decrease', 'NegReg', (191, 199))	('Y-MESO-27', 'Chemical', '-', (228, 237))	('YAP1', 'Gene', '10413', (116, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('TAZ', 'Gene', (125, 128))	('decreased', 'NegReg', (129, 138))	('knockdown', 'Var', (103, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))
183845	29212185	Therefore, we further studied whether knockdown of YAP1/TAZ would affect cell migration and invasion in these cell lines.	('affect', 'Reg', (66, 72))	('cell migration', 'biological_process', 'GO:0016477', ('73', '87'))	('YAP1', 'Gene', (51, 55))	('invasion', 'CPA', (92, 100))	('YAP1', 'Gene', '10413', (51, 55))	('cell migration', 'CPA', (73, 87))	('knockdown', 'Var', (38, 47))
183848	29212185	Single knockdown of YAP1 or TAZ significantly decreased cell migration, and concomitant knockdown showed a more marked effect on cell migration in all of the cell lines tested (Figure 2A).	('YAP1', 'Gene', (20, 24))	('YAP1', 'Gene', '10413', (20, 24))	('cell migration', 'CPA', (56, 70))	('knockdown', 'Var', (88, 97))	('TAZ', 'Gene', (28, 31))	('decreased', 'NegReg', (46, 55))	('cell migration', 'biological_process', 'GO:0016477', ('129', '143'))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))	('cell migration', 'CPA', (129, 143))
183849	29212185	Similarly, the invasion activities of the cell lines tended to be decreased by YAP1, TAZ, or concomitant knockdown, and RHAMM knockdown also suppressed the invasion activity at or under the same levels with the concomitant knockdown, with Y-MESO-27 (a 74% decrease) showing the most apparent effect (Figure 2B).	('RHAMM', 'Gene', (120, 125))	('invasion activities of the cell lines', 'CPA', (15, 52))	('YAP1', 'Gene', (79, 83))	('decreased', 'NegReg', (66, 75))	('YAP1', 'Gene', '10413', (79, 83))	('knockdown', 'Var', (105, 114))	('suppressed', 'NegReg', (141, 151))	('Y-MESO-27', 'Chemical', '-', (239, 248))	('concomitant', 'Var', (93, 104))	('invasion activity', 'CPA', (156, 173))	('RHAMM', 'Gene', '3161', (120, 125))
183854	29212185	Cell invasion was stimulated significantly in ACC-MESO-4 and Y-MESO-27 (Figure 3B).	('ACC-MESO-4', 'Chemical', '-', (46, 56))	('Y-MESO-27', 'Var', (61, 70))	('ACC-MESO-4', 'Var', (46, 56))	('Cell invasion', 'CPA', (0, 13))	('Y-MESO-27', 'Chemical', '-', (61, 70))	('stimulated', 'PosReg', (18, 28))
183856	29212185	RHAMM knockdown without HA treatment decreased cell migration significantly (Figure 2A, 3C).	('RHAMM', 'Gene', (0, 5))	('cell migration', 'biological_process', 'GO:0016477', ('47', '61'))	('HA', 'Chemical', 'MESH:D006820', (24, 26))	('cell migration', 'CPA', (47, 61))	('HA', 'Chemical', 'MESH:D006820', (1, 3))	('knockdown', 'Var', (6, 15))	('decreased', 'NegReg', (37, 46))	('RHAMM', 'Gene', '3161', (0, 5))
183857	29212185	As expected, the increase of cell migration induced by HA was significantly decreased by RHAMM knockdown in all of the cell lines tested (Figure 3C).	('RHAMM', 'Gene', (89, 94))	('cell migration', 'biological_process', 'GO:0016477', ('29', '43'))	('decreased', 'NegReg', (76, 85))	('HA', 'Chemical', 'MESH:D006820', (90, 92))	('knockdown', 'Var', (95, 104))	('HA', 'Chemical', 'MESH:D006820', (55, 57))	('cell migration', 'CPA', (29, 43))	('increase', 'PosReg', (17, 25))	('RHAMM', 'Gene', '3161', (89, 94))
183874	29212185	YAP1/TAZ have various roles in the regulation of homeostasis, and their dysregulation is associated with tumorigenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('associated', 'Reg', (89, 99))	('homeostasis', 'biological_process', 'GO:0042592', ('49', '60'))	('YAP1', 'Gene', (0, 4))	('YAP1', 'Gene', '10413', (0, 4))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('dysregulation', 'Var', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Disease', (123, 129))	('regulation of homeostasis', 'MPA', (35, 60))	('tumor', 'Disease', (105, 110))
183879	29212185	It has been reported that the frequency of LATS2 alterations in MPMs is around 20%.	('LATS2', 'Gene', '26524', (43, 48))	('alterations', 'Var', (49, 60))	('LATS2', 'Gene', (43, 48))	('MPMs', 'Disease', (64, 68))
183882	29212185	RHAMM is expressed at low levels in most normal tissues and up-regulated during wound repair in response to hypoxia and growth factors, hyper-expression of RHAMM being associated with tumor development, progression, and metastasis.	('associated', 'Reg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('RHAMM', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('RHAMM', 'Gene', (156, 161))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('response to hypoxia', 'biological_process', 'GO:0001666', ('96', '115'))	('tumor', 'Disease', (184, 189))	('up-regulated', 'PosReg', (60, 72))	('progression', 'CPA', (203, 214))	('RHAMM', 'Gene', '3161', (156, 161))	('hypoxia', 'Disease', (108, 115))	('RHAMM', 'Gene', '3161', (0, 5))	('hyper-expression', 'Var', (136, 152))	('metastasis', 'CPA', (220, 230))
183884	29212185	Our results indicated that although knockdown of RHAMM decreased cell proliferation significantly (Supplementary Figure 3A), the resulting effects on cell migration (Figure 2A) and invasion (Figure 2B) were more potent in the MPM cell lines we tested.	('RHAMM', 'Gene', '3161', (49, 54))	('RHAMM', 'Gene', (49, 54))	('knockdown', 'Var', (36, 45))	('decreased', 'NegReg', (55, 64))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('cell proliferation', 'CPA', (65, 83))	('invasion', 'CPA', (181, 189))	('cell migration', 'CPA', (150, 164))
183891	29212185	The present results suggest that MPMs harboring LATS2 mutation may show relatively higher frequencies of metastasis to intra-thoracic lymph nodes.	('mutation', 'Var', (54, 62))	('metastasis to intra-thoracic lymph nodes', 'CPA', (105, 145))	('LATS2', 'Gene', (48, 53))	('LATS2', 'Gene', '26524', (48, 53))	('higher', 'PosReg', (83, 89))
183892	29212185	Our study revealed that concomitant knockdown of both YAP1 and TAZ had a greater effect on cell migration and invasion than single knockdown of either (Figure 2).	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('knockdown', 'Var', (36, 45))	('TAZ', 'Gene', (63, 66))	('YAP1', 'Gene', (54, 58))	('cell migration', 'CPA', (91, 105))	('YAP1', 'Gene', '10413', (54, 58))
183894	29212185	Interestingly, the expression level of TAZ protein was increased to a greater degree by single knockdown of YAP1 in ACC-MESO-4 and NCI-H28 cells, which do not harbor LATS2 mutation (Figure 1C).	('ACC-MESO-4', 'Chemical', '-', (116, 126))	('increased', 'PosReg', (55, 64))	('YAP1', 'Gene', (108, 112))	('YAP1', 'Gene', '10413', (108, 112))	('expression level', 'MPA', (19, 35))	('knockdown', 'Var', (95, 104))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('LATS2', 'Gene', (166, 171))	('LATS2', 'Gene', '26524', (166, 171))
183990	28606736	The immunohistochemical profile of mesotheliomas that arise from the tunica vaginalis testis is similar to those that arise from the pleura and is typically positive for calretinin, Wilms tumor antibody (WT1), D2-40, epithelial membrane antigen (EMA), thrombomodulin, and CK7, variably positive for CK5/6, and negative for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20).	('tunica vaginalis testis', 'Disease', 'MESH:D013736', (69, 92))	('carcinoembryonic antigen (CEA', 'Gene', (323, 352))	('mesotheliomas', 'Disease', (35, 48))	('cytokeratin 20', 'Gene', '54474', (358, 372))	('antibody', 'cellular_component', 'GO:0019814', ('194', '202'))	('CK7', 'Gene', (272, 275))	('CK20', 'Gene', (374, 378))	('mesotheliomas', 'Disease', 'MESH:D008654', (35, 48))	('D2-40', 'Var', (210, 215))	('thrombomodulin', 'Protein', (252, 266))	('pleura', 'Disease', 'MESH:D054363', (133, 139))	('Wilms tumor', 'Disease', 'MESH:D009396', (182, 193))	('calretinin', 'Gene', (170, 180))	('membrane', 'cellular_component', 'GO:0016020', ('228', '236'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('CK5/6', 'Gene', '3852', (299, 304))	('carcinoembryonic antigen (CEA)', 'Gene', '1084', (323, 353))	('antibody', 'molecular_function', 'GO:0003823', ('194', '202'))	('CK20', 'Gene', '54474', (374, 378))	('CK7', 'Gene', '3855', (272, 275))	('antibody', 'cellular_component', 'GO:0042571', ('194', '202'))	('positive', 'Reg', (286, 294))	('Wilms tumor', 'Phenotype', 'HP:0002667', (182, 193))	('tunica vaginalis testis', 'Disease', (69, 92))	('positive', 'Reg', (157, 165))	('CK5/6', 'Gene', (299, 304))	('calretinin', 'Gene', '794', (170, 180))	('cytokeratin 20', 'Gene', (358, 372))	('pleura', 'Disease', (133, 139))	('antibody', 'cellular_component', 'GO:0019815', ('194', '202'))	('Wilms tumor', 'Disease', (182, 193))
184007	28874135	In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype.	('greater', 'PosReg', (47, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (101, 121))	('Ad', 'Gene', '8081', (35, 37))	('cytotoxicity', 'Disease', (175, 187))	('p53', 'Gene', (71, 74))	('cytotoxicity', 'Disease', (55, 67))	('mutated', 'Var', (75, 82))	('p53', 'Gene', '7157', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal carcinoma', 'Disease', (101, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (175, 187))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (101, 121))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (196, 199))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
184017	28874135	Consequently, substituting the fiber-knob region can convert the infectivity based on the Ad subtypes.	('substituting', 'Var', (14, 26))	('convert', 'Reg', (53, 60))	('Ad', 'Gene', '8081', (90, 92))	('infectivity', 'MPA', (65, 76))
184026	28874135	Replacement of the fiber-knob region with the Ad35-derived one can widen the target tumor scopes and furthermore produce better cytotoxicity.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('widen', 'PosReg', (67, 72))	('Replacement', 'Var', (0, 11))	('cytotoxicity', 'Disease', (128, 140))	('Ad', 'Gene', '8081', (46, 48))
184030	28874135	Human pancreatic carcinoma, PANC-1 (TKG 0606, p53 genotype: mutated), AsPC-1 (JCRB1454, null), MIA-PaCa-2 (TKG 0227, mutated) and BxPC-3 (JCRB1448, mutated) cells, and human esophageal carcinoma, TE-1 (TGK 0252, mutated at codon 272 Val to Met), TE-2 (TGK 0253, wild-type), TE-10 (TKG 0261, mutated at codon 242 Cys to Tyr), TE-11 (TKG 0262, wild-type), YES-2 (mutated at codon 236 Tyr to Asn), YES-4 (wild-type), YES-5 (mutated at codon 280 Arg to Gly), YES-6 (wild-type) and T.Tn (JCRB 0261, mutated at codon 214 His to Arg and 258 Glu to stop) cells were from Cell Resource Center for Biomedical Research (TKG number; Sendai, Japan), National Institutes of Biomedical Innovation, Health and Nutrition (JCRB number; Tokyo, Japan) or Dr. Yutaka Shimada (YES-2, YES-4, YES-5 and YES-6; Kyoto University, Kyoto, Japan).	('Human', 'Species', '9606', (0, 5))	('242 Cys to Tyr', 'Mutation', 'p.C242Y', (308, 322))	('280 Arg to Gly', 'Mutation', 'p.R280G', (438, 452))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('TGK', 'Gene', '7051', (252, 255))	('YES-2', 'Gene', (354, 359))	('AsPC-1', 'CellLine', 'CVCL:0152', (70, 76))	('258 Glu to stop', 'SUBSTITUTION', 'None', (530, 545))	('TGK', 'Gene', (252, 255))	('human', 'Species', '9606', (168, 173))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (174, 194))	('214 His to Arg', 'Mutation', 'p.H214R', (511, 525))	('p53', 'Gene', '7157', (46, 49))	('272 Val to Met', 'Mutation', 'p.V272M', (229, 243))	('258 Glu to stop', 'Var', (530, 545))	('YES-2', 'Gene', '7526', (354, 359))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (6, 26))	('p53', 'Gene', (46, 49))	('YES-2', 'Gene', (755, 760))	('MIA-PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))	('TGK', 'Gene', '7051', (202, 205))	('TGK', 'Gene', (202, 205))	('BxPC-3', 'CellLine', 'CVCL:0186', (130, 136))	('TE-2', 'Gene', '8260', (246, 250))	('pancreatic carcinoma', 'Disease', (6, 26))	('TE-2', 'Gene', (246, 250))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (174, 194))	('236 Tyr to Asn', 'Mutation', 'p.Y236N', (378, 392))	('PANC-1', 'CellLine', 'CVCL:0480', (28, 34))	('YES-2', 'Gene', '7526', (755, 760))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('esophageal carcinoma', 'Disease', (174, 194))
184031	28874135	HEK293 cells (CRL-1573) and human mesothelioma, NCI-H2452 (CRL-5946, wild-type but truncated p53 protein), NCI-H2052 (CRL-5915, wild-type), NCI-H226 (CRL-5826, wild-type), NCI-H28 (CRL-5820, wild-type) and MSTO-211H (CRL-2081, wild-type) cells, were from ATCC (CRL number; Manassas, VA, USA).	('NCI-H2452', 'CellLine', 'CVCL:1553', (48, 57))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('human', 'Species', '9606', (28, 33))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('mesothelioma', 'Disease', (34, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('CRL-5946', 'Var', (59, 67))	('NCI-H226', 'CellLine', 'CVCL:1544', (140, 148))
184035	28874135	Replication-competent Ad5 or AdF35 in which the E1 gene was activated by an exogenous regulatory element, Ad5/Sur, Ad5/MK, Ad5/COX-2, AdF35/Sur, AdF35/MK and AdF35/COX-2, were prepared by replacing the authentic E1 promoter region with 5' upstream regulatory sequences of the MK (0.6 kb, D10604) the Sur (0.5 kb, U75285), or COX-2 (0.3 kb, U04636) gene.	('Ad', 'Gene', '8081', (106, 108))	('COX-2', 'Gene', (325, 330))	('COX-2', 'Gene', (127, 132))	('Ad', 'Gene', '8081', (134, 136))	('Ad5', 'Gene', '8081', (123, 126))	('Ad', 'Gene', '8081', (158, 160))	('Ad5', 'Gene', (22, 25))	('Ad5', 'Gene', '8081', (115, 118))	('Ad', 'Gene', '8081', (29, 31))	('Ad', 'Gene', '8081', (22, 24))	('COX-2', 'Gene', (164, 169))	('COX-2', 'Gene', '5743', (325, 330))	('COX-2', 'Gene', '5743', (127, 132))	('D10604', 'Var', (288, 294))	('Ad5', 'Gene', '8081', (106, 109))	('Ad5/Sur', 'Gene', '8081;6833', (106, 113))	('Ad5', 'Gene', (123, 126))	('MK', 'Gene', '4192', (119, 121))	('COX-2', 'Gene', '5743', (164, 169))	('MK', 'Gene', '4192', (151, 153))	('Ad', 'Gene', '8081', (123, 125))	('Ad5', 'Gene', (115, 118))	('Ad', 'Gene', '8081', (145, 147))	('Ad', 'Gene', '8081', (115, 117))	('U04636', 'Var', (340, 346))	('Ad5', 'Gene', (106, 109))	('MK', 'Gene', '4192', (276, 278))	('Ad5', 'Gene', '8081', (22, 25))	('Ad5/Sur', 'Gene', (106, 113))
184039	28874135	Cells were stained with either anti-CAR antibody (Ab) (#05-644, Upstate, Charlottesville, VA, USA) followed by fluorescein isothiocyanate (FITC)-conjugated anti-mouse IgG Ab or with FITC-conjugated anti-human CD46 Ab (#555949, BD Pharmingen, San Jose, CA, USA).	('CD46', 'Gene', (209, 213))	('#05-644', 'Var', (55, 62))	('human', 'Species', '9606', (203, 208))	('FITC', 'Chemical', 'MESH:D016650', (139, 143))	('mouse', 'Species', '10090', (161, 166))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('CAR', 'cellular_component', 'GO:0005826', ('36', '39'))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (111, 137))	('CAR', 'Gene', '1525', (36, 39))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('CAR', 'Gene', (36, 39))	('#555949', 'Var', (218, 225))	('FITC', 'Chemical', 'MESH:D016650', (182, 186))	('CD46', 'Gene', '4179', (209, 213))
184044	28874135	The protein was transferred to a nylon filter and was hybridized with Ab against gamma-H2A histone family member X (gamma-H2AX) (#613401, BioLegend, San Diego, CA, USA), p53 (DO-10 MS-187-P, Thermo Fisher Scientific, Fremont, CA, USA), p21 (#2947, Cell Signaling, Danvers, MA, USA) or beta-actin (#4970, Cell Signaling) as a control.	('beta-actin', 'Gene', (285, 295))	('gamma-H2AX', 'Chemical', '-', (116, 126))	('#613401', 'Var', (129, 136))	('Signaling', 'biological_process', 'GO:0023052', ('309', '318'))	('p53', 'Gene', (170, 173))	('p53', 'Gene', '7157', (170, 173))	('#4970', 'Var', (297, 302))	('p21', 'Gene', (236, 239))	('p21', 'Gene', '644914', (236, 239))	('Signaling', 'biological_process', 'GO:0023052', ('253', '262'))	('beta-actin', 'Gene', '728378', (285, 295))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
184082	28874135	The p53 genotype of all the pancreatic carcinoma was either mutated (PANC-1, BxPC-3 and MIA-PaCa-2) or deleted (AsPC-1), and that of all the mesothelioma was wild-type except NCI-H2452 cells which had truncated p53 protein despite the wild-type p53 gene.	('pancreatic carcinoma', 'Disease', (28, 48))	('PANC-1', 'CellLine', 'CVCL:0480', (69, 75))	('protein', 'Protein', (215, 222))	('MIA-PaCa-2', 'CellLine', 'CVCL:0428', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('p53', 'Gene', '7157', (245, 248))	('mutated', 'Var', (60, 67))	('BxPC-3', 'CellLine', 'CVCL:0186', (77, 83))	('p53', 'Gene', (245, 248))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('p53', 'Gene', '7157', (211, 214))	('NCI-H2452', 'CellLine', 'CVCL:1553', (175, 184))	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (211, 214))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (28, 48))	('AsPC-1', 'CellLine', 'CVCL:0152', (112, 118))	('mesothelioma', 'Disease', (141, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('p53', 'Gene', (4, 7))
184084	28874135	We then investigated cytotoxicity of esophageal carcinoma, which included 5 cells with mutated (TE-1, TE-10, YES-2, YES-5 and T.Tn) and 4 cells with wild-type p53 gene (TE-2, TE-11, YES-4 and YES-6).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (37, 57))	('mutated', 'Var', (87, 94))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('cytotoxicity', 'Disease', (21, 33))	('YES-2', 'Gene', (109, 114))	('TE-2', 'Gene', '8260', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('YES-2', 'Gene', '7526', (109, 114))	('TE-2', 'Gene', (169, 173))	('esophageal carcinoma', 'Disease', (37, 57))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (37, 57))
184088	28874135	In contrast, Ad5 vectors did not show the statistical difference (P = 0.21) with those in the wild-type (103.0 +- 39.2, n = 12) and in mutant p53 gene (49.4 +- 20.0, n = 15), but Ad5 tended to be more effective to p53-mutant than the wild-type cells.	('Ad5', 'Gene', '8081', (13, 16))	('p53', 'Gene', (142, 145))	('Ad5', 'Gene', '8081', (179, 182))	('p53', 'Gene', '7157', (142, 145))	('mutant', 'Var', (135, 141))	('Ad5', 'Gene', (13, 16))	('p53', 'Gene', (214, 217))	('p53', 'Gene', '7157', (214, 217))	('Ad5', 'Gene', (179, 182))
184093	28874135	Cells with mutated p53 gene showed various responses, decreased in TE-1, increased in YES-2 and T.Tn, and unchanged p53 in TE-10 cells.	('TE-1', 'CPA', (67, 71))	('increased', 'PosReg', (73, 82))	('YES-2', 'Gene', '7526', (86, 91))	('p53', 'Gene', '7157', (116, 119))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('decreased', 'NegReg', (54, 63))	('T.Tn', 'CPA', (96, 100))	('YES-2', 'Gene', (86, 91))	('mutated', 'Var', (11, 18))	('p53', 'Gene', (116, 119))
184112	28874135	The fiber-knob region of Ad5 and Ad35 is responsible for binding with CAR and CD46 molecules, respectively, and replacement of the Ad5-derived region with the Ad35 region ablated the CAR binding ability and enabled AdF35 bind to CD46 molecules.	('Ad', 'Gene', '8081', (25, 27))	('Ad', 'Gene', '8081', (159, 161))	('CAR', 'Gene', '1525', (183, 186))	('Ad', 'Gene', '8081', (215, 217))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('ablated', 'NegReg', (171, 178))	('CAR', 'cellular_component', 'GO:0005826', ('183', '186'))	('CAR', 'cellular_component', 'GO:0005826', ('70', '73'))	('CAR', 'Gene', (183, 186))	('CD46', 'Gene', (78, 82))	('CD46', 'Gene', (229, 233))	('Ad5', 'Gene', '8081', (131, 134))	('bind', 'Interaction', (221, 225))	('Ad5', 'Gene', '8081', (25, 28))	('Ad', 'Gene', '8081', (131, 133))	('enabled', 'PosReg', (207, 214))	('CAR', 'Gene', '1525', (70, 73))	('CD46', 'Gene', '4179', (229, 233))	('CD46', 'Gene', '4179', (78, 82))	('replacement', 'Var', (112, 123))	('binding', 'molecular_function', 'GO:0005488', ('187', '194'))	('binding', 'Interaction', (57, 64))	('Ad5', 'Gene', (131, 134))	('Ad', 'Gene', '8081', (33, 35))	('CAR', 'Gene', (70, 73))	('Ad5', 'Gene', (25, 28))
184130	28874135	We examined a correlation between the p53 genotype and the cytotoxic activity with esophageal carcinoma and demonstrated that cells with wild-type p53 gene were resistant to Ad replication-induced cytotoxicity compared with those with mutant p53 in particular with the AdF35 vectors.	('Ad', 'Gene', '8081', (174, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (197, 209))	('p53', 'Gene', (242, 245))	('esophageal carcinoma', 'Disease', (83, 103))	('Ad', 'Gene', '8081', (269, 271))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('p53', 'Gene', '7157', (242, 245))	('p53', 'Gene', '7157', (147, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('mutant', 'Var', (235, 241))	('resistant', 'NegReg', (161, 170))	('cytotoxicity', 'Disease', (197, 209))	('p53', 'Gene', (147, 150))
184131	28874135	Previous studies showed that transduction with the wild-type p53 enhanced cytotoxicity produced by replication-competent Ad and that the Ad-mediated cytotoxicity, which was further augmented by co-expressed p53, was independent of the p53 status of target cells.	('cytotoxicity', 'Disease', (149, 161))	('cytotoxicity', 'Disease', (74, 86))	('Ad', 'Gene', '8081', (121, 123))	('enhanced', 'PosReg', (65, 73))	('p53', 'Gene', (207, 210))	('cytotoxicity', 'Disease', 'MESH:D064420', (149, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (74, 86))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', (235, 238))	('p53', 'Gene', '7157', (235, 238))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('transduction', 'Var', (29, 41))	('transduction', 'biological_process', 'GO:0009293', ('29', '41'))	('Ad', 'Gene', '8081', (137, 139))
184132	28874135	Expression of E1A accompanied by the viral replications enhanced expression of p53 and the phosphorylation, which contributed to augmentation of cell death.	('phosphorylation', 'MPA', (91, 106))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('E1A', 'Var', (14, 17))	('cell death', 'biological_process', 'GO:0008219', ('145', '155'))	('expression', 'MPA', (65, 75))	('enhanced', 'PosReg', (56, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('cell death', 'CPA', (145, 155))	('augmentation', 'PosReg', (129, 141))
184133	28874135	In contrast, the E1A-induced phosphorylation of mutated p53, functioned as a dominant-negative form, increased the resistance to cell death, which consequently augmented viral replications and production of viral progenies.	('viral replications', 'CPA', (170, 188))	('mutated', 'Var', (48, 55))	('p53', 'Gene', (56, 59))	('increased', 'PosReg', (101, 110))	('resistance to cell death', 'CPA', (115, 139))	('p53', 'Gene', '7157', (56, 59))	('cell death', 'biological_process', 'GO:0008219', ('129', '139'))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('augmented', 'PosReg', (160, 169))	('phosphorylation', 'MPA', (29, 44))
184146	28874135	We noticed that the mutated p53 esophageal carcinoma tended to decreased p21 expression, and consequently mutated p53 genotype and decreased p21 levels could be relevant to each other regarding the Ad-mediated cytotoxicity.	('p53', 'Gene', (28, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (210, 222))	('p53', 'Gene', (114, 117))	('p21', 'Gene', (73, 76))	('p21', 'Gene', '644914', (73, 76))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (32, 52))	('p21', 'Gene', (141, 144))	('decreased', 'NegReg', (63, 72))	('p21', 'Gene', '644914', (141, 144))	('mutated', 'Var', (20, 27))	('Ad', 'Gene', '8081', (198, 200))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (32, 52))	('mutated', 'Var', (106, 113))	('p53', 'Gene', '7157', (114, 117))	('p53', 'Gene', '7157', (28, 31))	('decreased', 'NegReg', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cytotoxicity', 'Disease', (210, 222))	('esophageal carcinoma', 'Disease', (32, 52))
184152	28874135	Prediction of Ad-mediated cytotoxicity is important from the standpoint of the possible clinical application, and further investigations are required to establish such predictive markers because genetic and epigenetic alterations in target cells are involved in the Ad-mediated cytotoxicity.	('involved', 'Reg', (250, 258))	('cytotoxicity', 'Disease', 'MESH:D064420', (278, 290))	('cytotoxicity', 'Disease', (26, 38))	('epigenetic alterations', 'Var', (207, 229))	('Ad', 'Gene', '8081', (14, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('cytotoxicity', 'Disease', (278, 290))	('Ad', 'Gene', '8081', (266, 268))
184155	28874135	We however demonstrated that the cytotoxicity was greater in p53 mutated than in wild-type esophageal carcinoma cells and perhaps was associated decreased p21 levels.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('cytotoxicity', 'Disease', (33, 45))	('p21', 'Gene', (155, 158))	('p21', 'Gene', '644914', (155, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('decreased', 'NegReg', (145, 154))	('p53', 'Gene', '7157', (61, 64))	('greater', 'PosReg', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('p53', 'Gene', (61, 64))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('mutated', 'Var', (65, 72))
184207	23991003	We calculated standardized mortality ratios (SMR) for lung cancer (including trachea, bronchus, lung cancer and other thoracic neoplasm, corresponding to the ICD-10 of C33, C34, C37 and C38), GI cancer including stomach cancer (C16), esophageal cancer (C15), liver cancer (C22), colorectum cancer (C18, C19 and C20), gallbladder cancer (C23, C24), and pancreas cancer (C25), and NMRD comprising asbestosis (J66), low respiratory tract diseases, emphysema and asthma (J43, Z82), pneumonia (J18), chronic bronchitis, emphysema, COPD and other respiratory diseases (J40-44), and pulmonary tuberculosis (A19).	('asthma', 'Phenotype', 'HP:0002099', (459, 465))	('pulmonary tuberculosis', 'Disease', (576, 598))	('gallbladder cancer', 'Disease', 'MESH:D005706', (317, 335))	('pancreas cancer', 'Disease', 'MESH:D010190', (352, 367))	('stomach cancer', 'Disease', (212, 226))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pulmonary tuberculosis', 'Disease', 'MESH:D014397', (576, 598))	('pancreas cancer', 'Phenotype', 'HP:0002894', (352, 367))	('respiratory tract diseases', 'Disease', (417, 443))	('liver cancer', 'Phenotype', 'HP:0002896', (259, 271))	('bronchitis', 'Phenotype', 'HP:0012387', (503, 513))	('pneumonia', 'Phenotype', 'HP:0002090', (478, 487))	('emphysema', 'Phenotype', 'HP:0002097', (445, 454))	('bronchitis', 'Disease', (503, 513))	('respiratory diseases', 'Disease', 'MESH:D012131', (541, 561))	('asbestosis', 'Disease', (395, 405))	('esophageal cancer', 'Disease', (234, 251))	('pancreas cancer', 'Disease', (352, 367))	('lung cancer', 'Disease', (54, 65))	('thoracic neoplasm', 'Disease', (118, 135))	('liver cancer', 'Disease', (259, 271))	('pneumonia', 'Disease', 'MESH:D011014', (478, 487))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('GI cancer', 'Disease', (192, 201))	('emphysema', 'Phenotype', 'HP:0002097', (515, 524))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('emphysema and asthma', 'Disease', 'MESH:D004646', (445, 465))	('stomach cancer', 'Disease', 'MESH:D013274', (212, 226))	('stomach cancer', 'Phenotype', 'HP:0012126', (212, 226))	('pneumonia', 'Disease', (478, 487))	('gallbladder cancer', 'Disease', (317, 335))	('low respiratory tract diseases', 'Phenotype', 'HP:0002783', (413, 443))	('respiratory diseases', 'Disease', (541, 561))	('J40-44', 'Var', (563, 569))	('emphysema', 'Disease', 'MESH:D004646', (445, 454))	('bronchitis', 'Disease', 'MESH:D001991', (503, 513))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('asbestosis', 'Disease', 'MESH:D001195', (395, 405))	('COPD', 'Disease', 'MESH:D029424', (526, 530))	('GI cancer', 'Disease', 'MESH:D009369', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('GI cancer', 'Phenotype', 'HP:0007378', (192, 201))	('COPD', 'Disease', (526, 530))	('emphysema', 'Disease', 'MESH:D004646', (515, 524))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('chronic bronchitis', 'Phenotype', 'HP:0004469', (495, 513))	('neoplasm', 'Phenotype', 'HP:0002664', (127, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('emphysema', 'Disease', (445, 454))	('lung cancer', 'Disease', (96, 107))	('thoracic neoplasm', 'Disease', 'MESH:D013899', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('respiratory tract diseases', 'Disease', 'MESH:D012140', (417, 443))	('liver cancer', 'Disease', 'MESH:D006528', (259, 271))	('colorectum cancer', 'Disease', 'MESH:D009369', (279, 296))	('pulmonary tuberculosis', 'Phenotype', 'HP:0032262', (576, 598))	('colorectum cancer', 'Disease', (279, 296))	('emphysema', 'Disease', (515, 524))
184212	23991003	However, most of the deaths from cancers centered on the high exposures, based on which we used cut points of approximately 50%, 75% and 85% to categorize the cumulative exposures, namely, <20, >=20, >=100 and >=450 f-y/ml.	('deaths', 'Disease', 'MESH:D003643', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('<20', 'Var', (189, 192))	('cancers', 'Disease', (33, 40))	('>=20', 'Var', (194, 198))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('>=450 f-y/ml', 'Var', (210, 222))	('deaths', 'Disease', (21, 27))	('>=100', 'Var', (200, 205))
184228	23991003	However, significantly increased mortality from lung cancer was seen at the level of >=100 f-y/ml and above, in spite of wide conference intervals.	('>=100 f-y/ml', 'Var', (85, 97))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('increased', 'PosReg', (23, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
184233	23991003	In this study, we followed an asbestos miner cohort from the largest Chinese chrysotile asbestos mine for 26 years, and observed some interesting findings: there were nearly 5- and 3-fold SMRs that expected for lung cancer and nonmalignant respiratory diseases, respectively.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('respiratory diseases', 'Disease', 'MESH:D012131', (240, 260))	('asbestos', 'Chemical', 'MESH:D001194', (30, 38))	('asbestos mine', 'Phenotype', 'HP:0011002', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('respiratory diseases', 'Disease', (240, 260))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('asbestos', 'Chemical', 'MESH:D001194', (88, 96))	('asbestos mine', 'Phenotype', 'HP:0011002', (30, 43))	('SMRs', 'Var', (188, 192))	('chrysotile asbestos', 'Disease', (77, 96))	('chrysotile asbestos', 'Disease', 'MESH:D001195', (77, 96))	('lung cancer', 'Disease', (211, 222))
184245	23991003	Although there was less clear exposure-response gradient in nonsmokers, possibly due to a small number of nonsmokers and deaths in each category, we observed significantly increased mortality from lung cancer at >=100 f-y/ml and >=450 f-y/ml.	('>=100 f-y/ml', 'Var', (212, 224))	('deaths', 'Disease', (121, 127))	('>=450 f-y/ml', 'Var', (229, 241))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('increased', 'PosReg', (172, 181))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('lung cancer', 'Disease', (197, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('deaths', 'Disease', 'MESH:D003643', (121, 127))
184249	23991003	It is not surprising that smoking might have contributed significantly to mortality for lung cancer and nonmalignant respiratory diseases, as indicated by the results that the smokers had 3.7-fold SMR for lung cancer and 2.6-fold SMR for nonmalignant diseases, compared to the nonsmokers.	('lung cancer', 'Disease', (88, 99))	('respiratory diseases', 'Disease', 'MESH:D012131', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('SMR', 'Var', (197, 200))	('malignant disease', 'Disease', 'MESH:D009369', (241, 258))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('respiratory diseases', 'Disease', (117, 137))	('malignant disease', 'Disease', (241, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('lung cancer', 'Disease', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
184300	23136186	Previous strategies designed to improve the cytotoxic activity of PE-based RITs include substitution of the native C-terminal residues of PE, REDLK, with the canonical ER-retention signal KDEL.	('cytotoxic activity', 'MPA', (44, 62))	('D', 'Chemical', 'MESH:D003903', (189, 190))	('substitution', 'Var', (88, 100))	('RITs', 'Chemical', '-', (75, 79))	('PE', 'Chemical', '-', (66, 68))	('retention', 'biological_process', 'GO:0051235', ('171', '180'))	('PE', 'Chemical', '-', (138, 140))	('rat', 'Species', '10116', (11, 14))	('D', 'Chemical', 'MESH:D003903', (144, 145))
184301	23136186	This substitution is known to enhance the cytotoxicity of PE, presumably by improving the efficiency of retrograde transport to the ER from the Golgi, but can increase off-target toxicity in animal models.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('improving', 'PosReg', (76, 85))	('Golgi', 'cellular_component', 'GO:0005794', ('144', '149'))	('transport', 'biological_process', 'GO:0006810', ('115', '124'))	('efficiency', 'MPA', (90, 100))	('substitution', 'Var', (5, 17))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('PE', 'Chemical', '-', (58, 60))	('toxicity', 'Disease', (179, 187))	('retrograde transport to the ER from the Golgi', 'MPA', (104, 149))	('cytotoxicity', 'Disease', (42, 54))	('toxicity', 'Disease', 'MESH:D064420', (46, 54))	('enhance', 'PosReg', (30, 37))	('toxicity', 'Disease', (46, 54))	('increase', 'PosReg', (159, 167))
184305	23136186	We found that the LR mutation did not greatly diminish in vitro activity on cell lines, but greatly reduced off-target toxicity in mice and dramatically enhanced activity on patient CLL cells in vitro.	('toxicity', 'Disease', 'MESH:D064420', (119, 127))	('LR', 'Chemical', '-', (18, 20))	('toxicity', 'Disease', (119, 127))	('patient', 'Species', '9606', (174, 181))	('reduced', 'NegReg', (100, 107))	('activity', 'MPA', (162, 170))	('mutation', 'Var', (21, 29))	('mice', 'Species', '10090', (131, 135))	('enhanced', 'PosReg', (153, 161))
184306	23136186	Additionally, the LR variant eliminates two major mouse B cell epitope groups and antigen processing sites from PE38, helping to reduce its immunogenicity in mice.	('LR', 'Chemical', '-', (18, 20))	('reduce', 'NegReg', (129, 135))	('mice', 'Species', '10090', (158, 162))	('immunogenicity', 'MPA', (140, 154))	('antigen processing', 'biological_process', 'GO:0019882', ('82', '100'))	('variant', 'Var', (21, 28))	('mouse', 'Species', '10090', (50, 55))	('PE', 'Chemical', '-', (112, 114))	('PE38', 'Var', (112, 116))	('mouse', 'Protein', (50, 55))	('eliminates', 'NegReg', (29, 39))
184311	23136186	Due to the modular nature of RITs, the LR variant of PE should, in principle, be applicable to targeting other tumor-associated antigens by exchanging one Fv for another.	('D', 'Chemical', 'MESH:D003903', (0, 1))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('LR', 'Chemical', '-', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('RITs', 'Chemical', '-', (29, 33))	('PE', 'Chemical', '-', (53, 55))	('variant', 'Var', (42, 49))	('exchanging', 'Var', (140, 150))
184313	23136186	CD22, the target of HA22, is expressed exclusively on B cells and associated malignancies, and is a large transmembrane glycoprotein that appears to undergo constitutive clathrin-dependent endocytic recycling.	('transmembrane', 'cellular_component', 'GO:0016021', ('106', '119'))	('endocytic recycling', 'biological_process', 'GO:0032456', ('189', '208'))	('CD22', 'Gene', '933', (0, 4))	('CD22', 'Gene', (0, 4))	('transmembrane', 'cellular_component', 'GO:0044214', ('106', '119'))	('HA22', 'Var', (20, 24))
184317	23136186	In addition to the receptor, it is also possible that removing or adding sequences to a RIT could alter its trafficking, processing, and cytotoxic activity.	('sequences', 'Var', (73, 82))	('alter', 'Reg', (98, 103))	('trafficking', 'MPA', (108, 119))	('RIT', 'Chemical', '-', (88, 91))	('cytotoxic activity', 'CPA', (137, 155))	('removing', 'Var', (54, 62))	('processing', 'MPA', (121, 131))
184361	23136186	A recently designed variant of PE38, called LR (; PE Delta251-273 & Delta285-394), has produced lower immunogenicity and off-target toxicity in mice, and could potentially alleviate these deficits in SS1P.	('SS1P', 'Chemical', 'MESH:C474515', (200, 204))	('potentially', 'NegReg', (160, 171))	('lower', 'MPA', (96, 101))	('mice', 'Species', '10090', (144, 148))	('and off-target', 'CPA', (117, 131))	('PE38', 'Gene', (31, 35))	('PE', 'Chemical', '-', (31, 33))	('LR', 'Chemical', '-', (44, 46))	('toxicity', 'Disease', 'MESH:D064420', (132, 140))	('& Delta285-394', 'Var', (66, 80))	('toxicity', 'Disease', (132, 140))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('produced', 'NegReg', (87, 95))	('PE', 'Chemical', '-', (50, 52))	('D', 'Chemical', 'MESH:D003903', (68, 69))
184363	23136186	1B/C) by replacing the Fv of HA22-LR with the SS1 Fv, and tested it against a panel of eight cell lines that express mesothelin (Fig.	('mesothelin', 'Gene', (117, 127))	('mesothelin', 'Gene', '10232', (117, 127))	('HA22-LR', 'Var', (29, 36))	('LR', 'Chemical', '-', (34, 36))	('tested', 'Reg', (58, 64))	('SS1', 'Gene', '3123', (46, 49))	('1B/C', 'SUBSTITUTION', 'None', (0, 4))	('1B/C', 'Var', (0, 4))	('SS1', 'Gene', (46, 49))
184377	23136186	1B/C) includes a Gly-Gly-Ser linker on the C-terminal end of the 11-residue furin cleavage site, and has enhanced activity relative to SS1-LR on all cell lines tested (Fig.	('Ser', 'Chemical', 'MESH:D012694', (25, 28))	('LR', 'Chemical', '-', (139, 141))	('activity', 'MPA', (114, 122))	('furin', 'Gene', '5045', (76, 81))	('Gly', 'Chemical', 'MESH:D005998', (17, 20))	('Gly', 'Chemical', 'MESH:D005998', (21, 24))	('Ser', 'cellular_component', 'GO:0005790', ('25', '28'))	('Gly-Gly-Ser linker', 'Var', (17, 35))	('furin', 'Gene', (76, 81))	('SS1', 'Gene', '3123', (135, 138))	('1B/C', 'SUBSTITUTION', 'None', (0, 4))	('1B/C', 'Var', (0, 4))	('SS1', 'Gene', (135, 138))	('enhanced', 'PosReg', (105, 113))
184380	23136186	1B/C) nor duplication of the furin cleavage site with additional linker regions (SS1-LR/2xFur; Fig.	('SS1', 'Gene', (81, 84))	('SS1', 'Gene', '3123', (81, 84))	('LR', 'Chemical', '-', (85, 87))	('furin', 'Gene', '5045', (29, 34))	('furin', 'Gene', (29, 34))	('duplication', 'Var', (10, 21))	('1B/C', 'SUBSTITUTION', 'None', (0, 4))	('1B/C', 'Var', (0, 4))
184381	23136186	1B/C) enhanced the cytotoxicity beyond that of SS1-LR/GGS (data not shown).	('SS1', 'Gene', '3123', (47, 50))	('cytotoxicity', 'Disease', (19, 31))	('enhanced', 'PosReg', (6, 14))	('SS1', 'Gene', (47, 50))	('cytotoxicity', 'Disease', 'MESH:D064420', (19, 31))	('1B/C', 'SUBSTITUTION', 'None', (0, 4))	('1B/C', 'Var', (0, 4))	('LR', 'Chemical', '-', (51, 53))
184382	23136186	Thus, by appending a flexible linker to the SS1-LR furin site, we produced a more active RIT.	('active', 'MPA', (82, 88))	('SS1', 'Gene', (44, 47))	('more', 'PosReg', (77, 81))	('furin', 'Gene', '5045', (51, 56))	('furin', 'Gene', (51, 56))	('appending', 'Var', (9, 18))	('RIT', 'Chemical', '-', (89, 92))	('LR', 'Chemical', '-', (48, 50))	('SS1', 'Gene', '3123', (44, 47))
184383	23136186	To confirm the importance of furin cleavage in the intoxication process, we also prepared the mutant SS1-LR/GGS R279G (Fig.	('SS1', 'Gene', (101, 104))	('LR', 'Chemical', '-', (105, 107))	('furin', 'Gene', '5045', (29, 34))	('SS1', 'Gene', '3123', (101, 104))	('furin', 'Gene', (29, 34))	('R279G', 'Var', (112, 117))	('R279G', 'Mutation', 'p.R279G', (112, 117))
184384	23136186	1B/C), which includes a point mutation of Arg to Gly at the site of hydrolysis that prevents furin cleavage.	('Arg', 'Chemical', 'MESH:D001120', (42, 45))	('Arg to Gly', 'Var', (42, 52))	('prevents', 'NegReg', (84, 92))	('furin', 'Gene', '5045', (93, 98))	('furin', 'Gene', (93, 98))	('Gly', 'Chemical', 'MESH:D005998', (49, 52))	('1B/C', 'SUBSTITUTION', 'None', (0, 4))	('1B/C', 'Var', (0, 4))
184391	23136186	Previous research has identified eight point mutations in domain III (D406A, R432G, R467A, R490A, R513A, E548S, Q592A, & K590S) that silence B cell epitopes and dramatically reduce the immunogenicity of PE38 RITs in mice.	('E548S', 'Var', (105, 110))	('D406A', 'Mutation', 'p.D406A', (70, 75))	('the', 'MPA', (181, 184))	('R490A', 'Var', (91, 96))	('D406A', 'Var', (70, 75))	('dramatically', 'NegReg', (161, 173))	('R513A', 'Mutation', 'p.R513A', (98, 103))	('R467A', 'Mutation', 'p.R467A', (84, 89))	('that', 'NegReg', (128, 132))	('PE', 'Chemical', '-', (203, 205))	('mice', 'Species', '10090', (216, 220))	('R432G', 'Var', (77, 82))	('& K590S', 'Var', (119, 126))	('RITs', 'Chemical', '-', (208, 212))	('Q592A', 'Mutation', 'p.Q592A', (112, 117))	('Q592A', 'Var', (112, 117))	('E548S', 'Mutation', 'p.E548S', (105, 110))	('R432G', 'Mutation', 'p.R432G', (77, 82))	('R490A', 'Mutation', 'p.R490A', (91, 96))	('R467A', 'Var', (84, 89))	('K590S', 'Mutation', 'p.K590S', (121, 126))	('silence B', 'Protein', (133, 142))	('R513A', 'Var', (98, 103))
184395	23136186	RIT off-target toxicity in mice is the result of liver damage, which appears to be caused by sequences in domain II that are absent in LR variant RITs.	('LR', 'Chemical', '-', (135, 137))	('RIT', 'Chemical', '-', (146, 149))	('toxicity', 'Disease', 'MESH:D064420', (15, 23))	('mice', 'Species', '10090', (27, 31))	('off-target', 'NegReg', (4, 14))	('sequences', 'Var', (93, 102))	('liver damage', 'Disease', (49, 61))	('liver damage', 'Disease', 'MESH:D056486', (49, 61))	('RITs', 'Chemical', '-', (146, 150))	('RIT', 'Chemical', '-', (0, 3))	('toxicity', 'Disease', (15, 23))	('variant', 'Var', (138, 145))
184398	23136186	RITs engineered to include the LR variant of PE, however, show greatly reduced off-target toxicity in mice.	('mice', 'Species', '10090', (102, 106))	('PE', 'Chemical', '-', (45, 47))	('RITs', 'Chemical', '-', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('reduced', 'NegReg', (71, 78))	('toxicity', 'Disease', (90, 98))	('variant', 'Var', (34, 41))	('LR', 'Chemical', '-', (31, 33))
184405	23136186	Since the absence of domain II in LR-based RITs significantly decreases liver toxicity in mice, we reasoned that it might also diminish lung damage in rats.	('decreases liver', 'Phenotype', 'HP:0001410', (62, 77))	('liver toxicity', 'Disease', 'MESH:D056486', (72, 86))	('diminish lung', 'Phenotype', 'HP:0002089', (127, 140))	('decreases', 'NegReg', (62, 71))	('RITs', 'Chemical', '-', (43, 47))	('liver toxicity', 'Disease', (72, 86))	('rats', 'Species', '10116', (151, 155))	('lung', 'CPA', (136, 140))	('diminish', 'NegReg', (127, 135))	('mice', 'Species', '10090', (90, 94))	('LR', 'Chemical', '-', (34, 36))	('domain II', 'Protein', (21, 30))	('absence', 'Var', (10, 17))
184406	23136186	Using the rat CLS model, we administered a single intravenous injection of D-PBS, SS1P, or SS1-LR/GGS/8M and observed the rats for signs of hydrothorax (Fig.	('SS1', 'Gene', '3123', (82, 85))	('SS1', 'Gene', (91, 94))	('rats', 'Species', '10116', (122, 126))	('SS1', 'Gene', (82, 85))	('CLS', 'Disease', (14, 17))	('LR', 'Chemical', '-', (95, 97))	('CLS', 'Disease', 'MESH:D038921', (14, 17))	('hydrothorax', 'Disease', (140, 151))	('SS1P', 'Chemical', 'MESH:C474515', (82, 86))	('rat', 'Species', '10116', (122, 125))	('D-PBS', 'Chemical', 'MESH:C012939', (75, 80))	('rat', 'Species', '10116', (10, 13))	('SS1', 'Gene', '3123', (91, 94))	('D-PBS', 'Var', (75, 80))
184410	23136186	Lungs from rats treated with D-PBS, SS1P, and SS1-LR/GGS/8M were fixed, sectioned, and stained; those from rats treated with D-PBS or SS1-LR/GGS/8M appeared normal, while those from rats treated with SS1P showed signs of toxicity including thickening of the vessels and fluid accumulation in the perivascular spaces (Fig.	('thickening', 'PosReg', (240, 250))	('rats', 'Species', '10116', (107, 111))	('fluid accumulation', 'Phenotype', 'HP:0000969', (270, 288))	('toxicity', 'Disease', 'MESH:D064420', (221, 229))	('SS1', 'Gene', (46, 49))	('SS1P', 'Chemical', 'MESH:C474515', (36, 40))	('fluid accumulation', 'CPA', (270, 288))	('SS1', 'Gene', (134, 137))	('rats', 'Species', '10116', (11, 15))	('SS1', 'Gene', '3123', (200, 203))	('toxicity', 'Disease', (221, 229))	('SS1', 'Gene', (36, 39))	('SS1', 'Gene', '3123', (46, 49))	('SS1P', 'Chemical', 'MESH:C474515', (200, 204))	('LR', 'Chemical', '-', (138, 140))	('SS1', 'Gene', '3123', (134, 137))	('LR', 'Chemical', '-', (50, 52))	('D-PBS', 'Chemical', 'MESH:C012939', (125, 130))	('D-PBS', 'Chemical', 'MESH:C012939', (29, 34))	('rats', 'Species', '10116', (182, 186))	('D-PBS', 'Var', (125, 130))	('vessels', 'CPA', (258, 265))	('SS1', 'Gene', '3123', (36, 39))	('perivascular spaces', 'Phenotype', 'HP:0012520', (296, 315))	('SS1', 'Gene', (200, 203))
184415	23136186	For comparison, additional groups were treated intravenously on the same schedule with vehicle (0.2% HSA in D-PBS; n=5) or 0.4 mg/kg SS1P (n=4), the maximum tolerated dose of SS1P under this dosing schedule.	('HSA', 'Gene', '213', (101, 104))	('D-PBS', 'Chemical', 'MESH:C012939', (108, 113))	('SS1P', 'Chemical', 'MESH:C474515', (133, 137))	('HSA', 'Gene', (101, 104))	('SS1P', 'Chemical', 'MESH:C474515', (175, 179))	('rat', 'Species', '10116', (161, 164))	('0.4 mg/kg', 'Var', (123, 132))
184458	23136186	This result is consistent with previous observations, and indicates that we have identified and silenced the majority of the human immunogenic epitopes in PE38-based RITs.	('PE', 'Chemical', '-', (155, 157))	('PE38-based', 'Var', (155, 165))	('human', 'Species', '9606', (125, 130))	('RITs', 'Chemical', '-', (166, 170))	('silenced', 'NegReg', (96, 104))
184463	23136186	The early passage mesothelioma patient cells NCI-M-02, NCI-M-03, NCI-M-16, and NCI-M-19 showed clear responses to treatment with SS1P (>75% decrease in viability at the 100 ng/ml dose level).	('SS1P', 'Chemical', 'MESH:C474515', (129, 133))	('NCI-M-19', 'Disease', 'MESH:C566367', (79, 87))	('NCI-M-03', 'CellLine', 'CVCL:D357', (55, 63))	('SS1P', 'Var', (129, 133))	('decrease', 'NegReg', (140, 148))	('NCI-M-19', 'Disease', (79, 87))	('mesothelioma', 'Disease', (18, 30))	('patient', 'Species', '9606', (31, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('NCI-M-16', 'CellLine', 'CVCL:G225', (65, 73))	('viability', 'MPA', (152, 161))
184465	23136186	A similarly increased sensitivity was observed when cells derived from patients with chronic lymphocytic leukemia were treated with HA22-LR.	('chronic lymphocytic leukemia', 'Disease', (85, 113))	('HA22-LR', 'Var', (132, 139))	('patients', 'Species', '9606', (71, 79))	('increased', 'PosReg', (12, 21))	('LR', 'Chemical', '-', (137, 139))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (85, 113))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (85, 113))
184466	23136186	The mechanism of enhanced sensitivity is not clear, but we hypothesize that LR-based RITs are more stable inside the cell than PE38-based RITs because of decreased susceptibility to degradation.	('LR', 'Chemical', '-', (76, 78))	('LR-based', 'Var', (76, 84))	('susceptibility', 'MPA', (164, 178))	('PE', 'Chemical', '-', (127, 129))	('RITs', 'Chemical', '-', (85, 89))	('RITs', 'Chemical', '-', (138, 142))	('degradation', 'biological_process', 'GO:0009056', ('182', '193'))	('degradation', 'MPA', (182, 193))
184500	18728709	For example, the pentaglutamatation of pemetrexed increases its ability to inhibit thymidylate synthase 84-fold.	('pemetrexed', 'Gene', (39, 49))	('inhibit', 'NegReg', (75, 82))	('increases', 'PosReg', (50, 59))	('thymidylate synthase', 'Gene', (83, 103))	('pentaglutamatation', 'Var', (17, 35))	('pemetrexed', 'Chemical', 'MESH:D000068437', (39, 49))	('thymidylate synthase', 'Gene', '7298', (83, 103))
184525	18728709	Patients with both homocysteine and methylmalonic acid in the highest quartile were 15.6 times more likely to suffer severe toxicity than those with normal levels.	('homocysteine', 'Chemical', 'MESH:D006710', (19, 31))	('methylmalonic acid', 'Var', (36, 54))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('Patients', 'Species', '9606', (0, 8))	('suffer', 'MPA', (110, 116))	('toxicity', 'Disease', (124, 132))	('homocysteine', 'Var', (19, 31))	('methylmalonic acid', 'Chemical', 'MESH:D008764', (36, 54))
184531	18728709	Due to limited treatment options and poor outcomes in MPM, significant pressure exists to expand the application of novel therapies to an ever-broader patient population, but overgeneralization increases the risk of poor outcomes.	('MPM', 'Disease', (54, 57))	('MPM', 'Chemical', '-', (54, 57))	('overgeneralization', 'Var', (175, 193))	('patient', 'Species', '9606', (151, 158))
184560	18728709	The median survival of patients treated with cisplatin plus pemetrexed and subsequent PSC was 15.3 months (95% CI 13.3-18.9 months), compared to median survival of 12.2 months (95% CI 9.9-14.2 months) in patients treated with cisplatin and pemetrexed without PSC.	('patients', 'Species', '9606', (204, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('pemetrexed', 'Chemical', 'MESH:D000068437', (60, 70))	('patients', 'Species', '9606', (23, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('pemetrexed', 'Chemical', 'MESH:D000068437', (240, 250))	('PSC', 'Disease', (86, 89))	('cisplatin', 'Var', (45, 54))
184612	27602956	The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA; Plau) levels.	('urokinase-type plasminogen activator', 'Gene', (149, 185))	('rat', 'Species', '10116', (22, 25))	('knockdown', 'Var', (78, 87))	('migration', 'CPA', (19, 28))	('uPA', 'molecular_function', 'GO:0008243', ('187', '190'))	('uPAR', 'molecular_function', 'GO:0030377', ('73', '77'))	('invasion of MM cells', 'CPA', (33, 53))	('suppressed', 'NegReg', (59, 69))	('uPAR', 'Gene', (73, 77))	('Plau', 'Gene', (192, 196))	('increased', 'PosReg', (92, 101))	('urokinase-type plasminogen activator', 'molecular_function', 'GO:0008243', ('149', '185'))	('rat', 'Species', '10116', (11, 14))	('Plau', 'Gene', '5328', (192, 196))	('urokinase-type plasminogen activator', 'Gene', '5328', (149, 185))
184614	27602956	uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity.	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (29, 38))	('uPAR', 'Gene', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('uPAR', 'molecular_function', 'GO:0030377', ('0', '4'))	('cisplatin sensitivity', 'MPA', (115, 136))	('sensitivity to cisplatin', 'MPA', (39, 63))	('decreased', 'NegReg', (105, 114))
184617	27602956	In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.	('uPAR', 'molecular_function', 'GO:0030377', ('84', '88'))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('uPAR', 'molecular_function', 'GO:0030377', ('36', '40'))	('abrogation', 'Var', (89, 99))	('uPAR', 'Gene', (84, 88))
184632	27602956	GSE48298) in rats, both histological subtypes of MM, i.e., the epithelioid (EM) and sarcomatoid (SM) subtypes, showed approximately 6-7-fold increase in uPAR expression compared with scraped normal mesothelial cells (Figure 1A).	('sarcomatoid', 'Disease', 'MESH:C538614', (84, 95))	('rats', 'Species', '10116', (13, 17))	('increase', 'PosReg', (141, 149))	('uPAR expression', 'MPA', (153, 168))	('sarcomatoid', 'Disease', (84, 95))	('uPAR', 'molecular_function', 'GO:0030377', ('153', '157'))	('GSE48298', 'Var', (0, 8))
184642	27602956	In both the EM and SM cell lines, stable uPAR knockdown resulted in significantly suppressed proliferation, as determined by cell counting with the trypan blue exclusion method (Figure 2C).	('knockdown', 'Var', (46, 55))	('proliferation', 'CPA', (93, 106))	('trypan blue', 'Chemical', 'MESH:D014343', (148, 159))	('suppressed', 'NegReg', (82, 92))	('uPAR', 'molecular_function', 'GO:0030377', ('41', '45'))	('rat', 'Species', '10116', (100, 103))
184647	27602956	Moreover, proliferation and invasion of rat MM cells were not significantly inhibited by uPA knockdown (Figure 3H, 3I).	('knockdown', 'Var', (93, 102))	('uPA', 'Gene', (89, 92))	('rat', 'Species', '10116', (40, 43))	('invasion', 'CPA', (28, 36))	('rat', 'Species', '10116', (17, 20))	('uPA', 'molecular_function', 'GO:0008243', ('89', '92'))
184651	27602956	We observed that AKT/mTOR activity was closely associated with uPAR expression, as demonstrated through uPAR knockdown and overexpression in MM cells (Figure 5A, 5B, Supplementary Figure S1G, S1H).	('rat', 'Species', '10116', (90, 93))	('knockdown', 'Var', (109, 118))	('mTOR', 'Gene', (21, 25))	('uPAR', 'molecular_function', 'GO:0030377', ('63', '67'))	('mTOR', 'Gene', '2475', (21, 25))	('uPAR', 'molecular_function', 'GO:0030377', ('104', '108'))
184655	27602956	The tumor growth curves derived from the xenograft experiments indicated that uPAR knockdown significantly impeded MM cell growth in nude mice (Figure 6A).	('tumor', 'Disease', (4, 9))	('uPAR', 'Gene', (78, 82))	('cell growth', 'biological_process', 'GO:0016049', ('118', '129'))	('nude mice', 'Species', '10090', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('uPAR', 'molecular_function', 'GO:0030377', ('78', '82'))	('MM cell growth in nude mice', 'CPA', (115, 142))	('impeded', 'NegReg', (107, 114))	('knockdown', 'Var', (83, 92))
184656	27602956	Moreover, AKT showed decreased activity after uPAR knockdown in MM tumors by immunohistochemistry and Western blot analyses (Figure 6B, 6C, Supplementary Figure S1I).	('activity', 'MPA', (31, 39))	('decreased', 'NegReg', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MM tumors', 'Disease', 'MESH:D009369', (64, 73))	('AKT', 'Pathway', (10, 13))	('MM tumors', 'Disease', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('uPAR', 'molecular_function', 'GO:0030377', ('46', '50'))	('knockdown', 'Var', (51, 60))
184659	27602956	In contrast, uPAR knockdown sensitized both EM and SM cells to CDDP at 24 h (Figure 7A).	('knockdown', 'Var', (18, 27))	('sensitized', 'Reg', (28, 38))	('CDDP', 'Chemical', 'MESH:D002945', (63, 67))	('uPAR', 'molecular_function', 'GO:0030377', ('13', '17'))
184660	27602956	After CDDP treatment (20 muM at 24 h) with uPAR knockdown, the proportion of early/late apoptotic cells increased significantly, whereas uPAR knockdown alone did not induce significant MM cell death (Figure 7B, 7C).	('CDDP', 'Chemical', 'MESH:D002945', (6, 10))	('uPAR', 'molecular_function', 'GO:0030377', ('43', '47'))	('uPAR', 'Gene', (43, 47))	('increased', 'PosReg', (104, 113))	('MM cell death', 'Disease', 'MESH:D003643', (185, 198))	('cell death', 'biological_process', 'GO:0008219', ('188', '198'))	('MM cell death', 'Disease', (185, 198))	('uPAR', 'molecular_function', 'GO:0030377', ('137', '141'))	('knockdown', 'Var', (48, 57))
184661	27602956	Because the AKT signaling pathway and its downstream proteins have been reported to interact with the caspase family to regulate cell apoptosis, we further evaluated the caspase-3 levels to determine whether decreased AKT activity induced by uPAR knockdown was associated with promoted apoptotic activity.	('interact', 'Reg', (84, 92))	('AKT', 'Enzyme', (218, 221))	('AKT signaling', 'biological_process', 'GO:0043491', ('12', '25'))	('caspase-3', 'Gene', (170, 179))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('decreased', 'NegReg', (208, 217))	('promoted', 'PosReg', (277, 285))	('caspase-3', 'Gene', '836', (170, 179))	('signaling pathway', 'biological_process', 'GO:0007165', ('16', '33'))	('AKT signaling pathway', 'Pathway', (12, 33))	('activity', 'MPA', (222, 230))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('knockdown', 'Var', (247, 256))	('uPAR', 'molecular_function', 'GO:0030377', ('242', '246'))	('apoptotic activity', 'CPA', (286, 304))
184662	27602956	Our results revealed that CDDP suppressed the AKT pathway, which was promoted by uPAR knockdown; this suppression led to activation of the apoptotic pathway, as shown by caspase-3 cleavage.	('knockdown', 'Var', (86, 95))	('caspase-3', 'Gene', (170, 179))	('AKT pathway', 'Pathway', (46, 57))	('caspase-3', 'Gene', '836', (170, 179))	('apoptotic pathway', 'Pathway', (139, 156))	('uPAR', 'molecular_function', 'GO:0030377', ('81', '85'))	('suppressed', 'NegReg', (31, 41))	('CDDP', 'Chemical', 'MESH:D002945', (26, 30))	('activation', 'PosReg', (121, 131))
184665	27602956	uPAR overexpression induced resistance to apoptosis after CDDP treatment, whereas a PI3K/AKT inhibitor, LY294002, and a specific AKT inhibitor, Akti-1/2, partially reversed the effect.	('CDDP', 'Chemical', 'MESH:D002945', (58, 62))	('PI3K/AKT', 'Gene', (84, 92))	('LY294002', 'Var', (104, 112))	('resistance', 'CPA', (28, 38))	('overexpression', 'PosReg', (5, 19))	('uPAR', 'molecular_function', 'GO:0030377', ('0', '4'))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('LY294002', 'Chemical', 'MESH:C085911', (104, 112))	('PI3K/AKT', 'Gene', '5293;207', (84, 92))
184673	27602956	Recently, a comprehensive genomic analysis of MM identified recurrent mutations, gene fusions and splicing alterations.	('rat', 'Species', '10116', (111, 114))	('mutations', 'Var', (70, 79))	('splicing alterations', 'Var', (98, 118))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('gene fusions', 'Var', (81, 93))
184682	27602956	Coincidently, uPAR overexpression was mostly reproduced in both rat and human MM cell lines, and with knockdown and overexpression studies in vitro and in vivo, we showed that uPAR is intimately associated with the malignant character of MM cells.	('associated with', 'Reg', (195, 210))	('human', 'Species', '9606', (72, 77))	('uPAR', 'molecular_function', 'GO:0030377', ('14', '18'))	('rat', 'Species', '10116', (64, 67))	('malignant character of MM cells', 'CPA', (215, 246))	('uPAR', 'Var', (176, 180))	('uPAR', 'molecular_function', 'GO:0030377', ('176', '180'))
184684	27602956	Also, some studies have reported that uPAR could activate cellular signaling and increase tumor cell malignancy in the absence of uPA through the binding of vitronectin.	('cellular signaling', 'MPA', (58, 76))	('increase tumor cell malignancy', 'Disease', (81, 111))	('uPA', 'molecular_function', 'GO:0008243', ('130', '133'))	('uPAR', 'molecular_function', 'GO:0030377', ('38', '42'))	('activate', 'PosReg', (49, 57))	('binding', 'molecular_function', 'GO:0005488', ('146', '153'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('vitronectin', 'Gene', '7448', (157, 168))	('increase tumor cell malignancy', 'Disease', 'MESH:D018273', (81, 111))	('uPAR', 'Var', (38, 42))	('vitronectin', 'Gene', (157, 168))	('binding', 'Interaction', (146, 153))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
184685	27602956	Our results confirmed that the suppressed effect of the proliferation and invasion with uPAR knockdown is not related to uPA expression in MM cells.	('knockdown', 'Var', (93, 102))	('uPAR', 'Gene', (88, 92))	('uPA', 'molecular_function', 'GO:0008243', ('121', '124'))	('invasion', 'CPA', (74, 82))	('uPAR', 'molecular_function', 'GO:0030377', ('88', '92'))	('proliferation', 'CPA', (56, 69))	('rat', 'Species', '10116', (63, 66))
184692	27602956	Our results showed that MM cells revealed caspase activation and apoptotic features with cisplatin treatment, which were inhibited by uPAR overexpression and promoted by uPAR knockdown.	('caspase activation', 'biological_process', 'GO:0006919', ('42', '60'))	('uPAR', 'molecular_function', 'GO:0030377', ('134', '138'))	('apoptotic features', 'CPA', (65, 83))	('cisplatin', 'Var', (89, 98))	('activation', 'PosReg', (50, 60))	('uPAR', 'molecular_function', 'GO:0030377', ('170', '174'))	('caspase', 'Protein', (42, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))
184698	27602956	Cleaved uPAR from the MM cell membrane leads to uPAR secretion into the blood flow, and our study was the first to show that MM patients have higher serum uPAR levels compared to those with benign diseases.	('uPAR', 'molecular_function', 'GO:0030377', ('8', '12'))	('uPAR', 'molecular_function', 'GO:0030377', ('155', '159'))	('cell membrane', 'cellular_component', 'GO:0005886', ('25', '38'))	('Cleaved', 'Var', (0, 7))	('uPAR', 'molecular_function', 'GO:0030377', ('48', '52'))	('benign diseases', 'Disease', (190, 205))	('uPAR secretion into the blood flow', 'MPA', (48, 82))	('serum uPAR levels', 'MPA', (149, 166))	('benign diseases', 'Disease', 'MESH:D009369', (190, 205))	('patients', 'Species', '9606', (128, 136))	('secretion', 'biological_process', 'GO:0046903', ('53', '62'))	('higher', 'PosReg', (142, 148))
184700	27602956	Overexpression of uPAR downstream genes, such as AKT and mTOR, in MM tissues is associated with shortened MM patient survival.	('AKT', 'Gene', (49, 52))	('patient', 'Species', '9606', (109, 116))	('uPAR', 'molecular_function', 'GO:0030377', ('18', '22'))	('shortened', 'NegReg', (96, 105))	('mTOR', 'Gene', (57, 61))	('Overexpression', 'Var', (0, 14))	('mTOR', 'Gene', '2475', (57, 61))
184705	27602956	A PI3K inhibitor, LY294002 (129-04861), and vehicle control, dimethyl sulfoxide, were purchased from Wako, Japan.	('PI3', 'Gene', (2, 5))	('PI3K', 'molecular_function', 'GO:0016303', ('2', '6'))	('LY294002', 'Var', (18, 26))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (61, 79))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('PI3', 'Gene', '5266', (2, 5))
184720	27602956	The 4 intensity levels resulted in the following score ranges: 0-300; mild (0-100), moderate (101-200) and strong (201-300).	('201-300', 'Var', (115, 122))	('rat', 'Species', '10116', (88, 91))	('101-200', 'Var', (94, 101))
184752	20307263	PM10 particles also affect susceptible populations, exacerbating existing airways disease and cardiovascular disease, probably via pro-inflammatory effects emanating from the lungs.	('airways disease', 'Disease', 'MESH:D000402', (74, 89))	('airways disease', 'Phenotype', 'HP:0002099', (74, 89))	('exacerbating', 'PosReg', (52, 64))	('airways disease', 'Disease', (74, 89))	('cardiovascular disease', 'Disease', (94, 116))	('man', 'Species', '9606', (157, 160))	('PM10 particles', 'Var', (0, 14))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (94, 116))	('cardiovascular disease', 'Disease', 'MESH:D002318', (94, 116))
184762	20307263	In the seventies Stanton carried out a large number of studies aimed at understanding the role of fibre characteristics in mesothelioma using implantation of fibres in gelatin, directly onto the pleural mesothelial surface.	('pleural', 'Disease', 'MESH:D010995', (195, 202))	('implantation', 'Var', (142, 154))	('pleural', 'Disease', (195, 202))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('fibres', 'Var', (158, 164))	('mesothelioma', 'Disease', (123, 135))
184766	20307263	The mouse peritoneal cavity has been used as a model of direct mesothelial exposure and much greater toxic, inflammatory and granuloma-generating responses were evident in mice that were exposed to high doses of long fibres than was seen with shorter fibres.	('mouse', 'Species', '10090', (4, 9))	('toxic', 'CPA', (101, 106))	('granuloma', 'Phenotype', 'HP:0032252', (125, 134))	('rat', 'Species', '10116', (139, 142))	('granuloma', 'Disease', 'MESH:D006099', (125, 134))	('long fibres', 'Var', (212, 223))	('mice', 'Species', '10090', (172, 176))	('granuloma', 'Disease', (125, 134))
184890	20307263	In a time course, the long nanotubes caused a sustained high level of inflammation at 7 days, which was the same as was present at 1 day.	('inflammation', 'Disease', (70, 82))	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('inflammation', 'biological_process', 'GO:0006954', ('70', '82'))	('long', 'Var', (22, 26))
184943	19671873	PE38 is a truncated form of PE which is missing its binding domain, and can be directed by a ligand to bind, internalize into, and kill target cells by ADP-ribosylation and inactivation of elongation factor 2 and apoptosis.	('bind', 'Interaction', (103, 107))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('PE38', 'Var', (0, 4))	('ADP-ribosylation', 'Var', (152, 168))	('ligand', 'molecular_function', 'GO:0005488', ('93', '99'))	('elongation factor 2', 'Gene', '1938', (189, 208))	('apoptosis', 'CPA', (213, 222))	('elongation factor 2', 'Gene', (189, 208))	('apoptosis', 'biological_process', 'GO:0097194', ('213', '222'))	('inactivation', 'NegReg', (173, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('213', '222'))
184983	19671873	One patient at the 25 ug/Kg/day x10 dose level had grade III proteinuria not associated with symptoms or with a creatinine elevation, resolving several days later with the next 24 hour urine.	('creatinine elevation', 'Phenotype', 'HP:0003259', (112, 132))	('patient', 'Species', '9606', (4, 11))	('proteinuria', 'Disease', (61, 72))	('proteinuria', 'Phenotype', 'HP:0000093', (61, 72))	('creatinine', 'Chemical', 'MESH:D003404', (112, 122))	('proteinuria', 'Disease', 'MESH:D011507', (61, 72))	('x10', 'Var', (32, 35))
184985	19671873	The last patient had baseline pulmonary hypertension and diastolic dysfunction, and with SS1P plus exogenous fluid developed large pleural effusions and respiratory failure, resolving with aggressive diuresis.	('pleural effusions', 'Phenotype', 'HP:0002202', (131, 148))	('diastolic dysfunction', 'Disease', (57, 78))	('diastolic dysfunction', 'Phenotype', 'HP:0025168', (57, 78))	('hypertension', 'Phenotype', 'HP:0000822', (40, 52))	('respiratory failure', 'Disease', (153, 172))	('respiratory failure', 'Disease', 'MESH:D012131', (153, 172))	('diuresis', 'biological_process', 'GO:0035810', ('200', '208'))	('diastolic dysfunction', 'Disease', 'MESH:D054144', (57, 78))	('pleural effusions', 'Disease', (131, 148))	('SS1P', 'Chemical', 'MESH:C474515', (89, 93))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (30, 52))	('pulmonary hypertension', 'Disease', (30, 52))	('patient', 'Species', '9606', (9, 16))	('SS1P', 'Var', (89, 93))	('respiratory failure', 'Phenotype', 'HP:0002878', (153, 172))	('pleural effusions', 'Disease', 'MESH:D010996', (131, 148))	('diuresis', 'biological_process', 'GO:0030146', ('200', '208'))
184997	19671873	She had a 15 x 26 mm hepatic lesion which decreased in size to 10 x 19 mm by C1D29, and to 7 x 16 mm by C1D64.	('to 7', 'Species', '1214577', (88, 92))	('C1D29', 'Var', (77, 82))	('C1D64', 'Var', (104, 109))	('hepatic lesion', 'Disease', (21, 35))	('hepatic lesion', 'Disease', 'MESH:D056486', (21, 35))
185001	19671873	By the end of the infusion of 18 ug/Kg/day x10, the patient's pain had resolved, he regained full range of motion of his arms without pain, and was taken off of narcotics.	('pain', 'Disease', (134, 138))	('x10', 'Var', (43, 46))	('pain', 'Phenotype', 'HP:0012531', (62, 66))	('pain', 'Disease', 'MESH:D010146', (62, 66))	('pain', 'Disease', (62, 66))	('patient', 'Species', '9606', (52, 59))	('pain', 'Phenotype', 'HP:0012531', (134, 138))	('pain', 'Disease', 'MESH:D010146', (134, 138))	('regained', 'PosReg', (84, 92))
185015	19671873	As shown in Table 2, the total dose of SS1P delivered at the MTD, 250 ug/Kg, is slightly higher than that achieved by bolus dosing of 3 doses of SS1P.	('higher', 'PosReg', (89, 95))	('SS1P', 'Chemical', 'MESH:C474515', (145, 149))	('SS1P', 'Var', (39, 43))	('SS1P', 'Chemical', 'MESH:C474515', (39, 43))
185016	19671873	Although immunogenicity of SS1P when given by continuous infusion was slightly lower than that observed by bolus dosing, it represented a major potential limitation in response.	('SS1P', 'Chemical', 'MESH:C474515', (27, 31))	('lower', 'NegReg', (79, 84))	('immunogenicity', 'MPA', (9, 23))	('SS1P', 'Var', (27, 31))
185149	29025836	We observed 24 mesothelin concentrations >=1.5 nM (specificity 95.8%, 95% CI 93.8% to 97.2%) and 34 calretinin concentrations >=1.0 ng/mL (specificity 94.0%, 95% CI 91.7% to 95.7%).	('mesothelin', 'Gene', (15, 25))	('calretinin', 'Gene', (100, 110))	('mesothelin', 'Gene', '10232', (15, 25))	('calretinin', 'Gene', '794', (100, 110))	('to 9', 'Species', '1214577', (171, 175))	('>=1.5', 'Var', (41, 46))	('to 9', 'Species', '1214577', (83, 87))	('>=1.0', 'Var', (126, 131))
185293	28205183	Immunohistochemically, the tumor cells were positive for D2-40, BCL-2, CD99, and p53; they were negative for TTF-1, WT1, calretinin, cytokeratin (CK)5/6, CK7, CK20, HBME-1, CEA, and CD34.	('BCL-2', 'molecular_function', 'GO:0015283', ('64', '69'))	('WT1', 'Gene', (116, 119))	('p53', 'Gene', (81, 84))	('CK7', 'Gene', '3855', (154, 157))	('CD34', 'Gene', '947', (182, 186))	('calretinin', 'Gene', (121, 131))	('WT1', 'Gene', '7490', (116, 119))	('tumor', 'Disease', (27, 32))	('HBME-1', 'CellLine', 'CVCL:U718', (165, 171))	('CK20', 'Gene', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('TTF-1', 'Gene', (109, 114))	('D2-40', 'Var', (57, 62))	('CD99', 'Gene', (71, 75))	('BCL-2', 'Gene', '596', (64, 69))	('BCL-2', 'Gene', (64, 69))	('CK20', 'Gene', '54474', (159, 163))	('calretinin', 'Gene', '794', (121, 131))	('CD99', 'Gene', '4267', (71, 75))	('CD34', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CK7', 'Gene', (154, 157))	('p53', 'Gene', '7157', (81, 84))	('TTF-1', 'Gene', '7270', (109, 114))
185325	28205183	The chromosomal translocation t(X;18)(p11.2;q11.2) has been found in more than 90% of synovial sarcomas, regardless of histologic subtype.	('t(X;18)(p11.2;q11.2', 'Var', (30, 49))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (86, 103))	('found', 'Reg', (60, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('synovial sarcomas', 'Disease', 'MESH:D013584', (86, 103))	('synovial sarcomas', 'Disease', (86, 103))
185385	25588643	As a tumor suppressor, inactivation of p16 by homozygous deletion, promoter methylation, and point mutation has been demonstrated in carcinogenesis.	('p16', 'Gene', (39, 42))	('homozygous', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('point mutation', 'Var', (93, 107))	('carcinogenesis', 'Disease', (133, 147))	('p16', 'Gene', '1029', (39, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('tumor', 'Disease', (5, 10))	('promoter', 'MPA', (67, 75))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('inactivation', 'Var', (23, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))
185386	25588643	A recent study has shown that deletion of p16/CDKN2A is occurs in mesothelioma, but not in benign mesothelial cells, which can be detected by fluorescence in situ hybridization.	('p16', 'Gene', '1029', (42, 45))	('CDKN2A', 'Gene', (46, 52))	('CDKN2A', 'Gene', '1029', (46, 52))	('mesothelioma', 'Disease', (66, 78))	('deletion', 'Var', (30, 38))	('p16', 'Gene', (42, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))
185387	25588643	Aberrant expression of p16 on immunohistochemical staining has been reported in breast and colorectal carcinoma, which exhibit p16 inactivation and poor prognosis.	('Aberrant expression', 'Var', (0, 19))	('p16', 'Gene', (23, 26))	('colorectal carcinoma', 'Disease', (91, 111))	('p16', 'Gene', (127, 130))	('breast', 'Disease', (80, 86))	('inactivation', 'NegReg', (131, 143))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (91, 111))	('p16', 'Gene', '1029', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('p16', 'Gene', '1029', (127, 130))	('reported', 'Reg', (68, 76))
185401	28548074	Notably, SV40 is the only agent inducing malignant transformation of HM in tissue culture, while asbestos itself is not able to induce HM transformation.	('SV40', 'Species', '1891767', (9, 13))	('asbestos', 'Chemical', 'MESH:D001194', (97, 105))	('SV40', 'Var', (9, 13))	('inducing', 'Reg', (32, 40))	('malignant transformation', 'CPA', (41, 65))
185404	28548074	We and others identified germline mutations in the BRCA-associated protein 1 (BAP1) gene, predisposing for a novel cancer syndrome linked to an inherited very high risk of developing mesothelioma, uveal melanoma, and possibly additional cancers.	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('cancer syndrome', 'Disease', (115, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('predisposing', 'Reg', (90, 102))	('BAP1', 'Gene', '8314', (78, 82))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('mesothelioma', 'Disease', (183, 195))	('cancers', 'Disease', (237, 244))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('BAP1', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('BRCA-associated protein 1', 'Gene', (51, 76))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('BRCA-associated protein 1', 'Gene', '8314', (51, 76))	('cancer syndrome', 'Disease', 'MESH:D009369', (115, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('uveal melanoma', 'Disease', (197, 211))	('germline mutations', 'Var', (25, 43))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
185417	28548074	Dysregulated MET signaling and consequent aberrant function in human tumors can occur via: (i) gene amplification and overexpression of HGF or Met, (ii) mutation of the receptor kinase domain and other regions, or (iii) establishment of an autocrine loop.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('overexpression', 'PosReg', (118, 132))	('MET signaling', 'MPA', (13, 26))	('human', 'Species', '9606', (63, 68))	('HGF', 'Gene', (136, 139))	('function', 'MPA', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('Met', 'Gene', (143, 146))	('mutation', 'Var', (153, 161))
185433	28548074	This mechanism eliminates HM with accumulated asbestos-induced mutations, without promoting inflammation, and may be regarded as a strategy to protect against the development of MM.	('mutations', 'Var', (63, 72))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('asbestos', 'Chemical', 'MESH:D001194', (46, 54))	('rat', 'Species', '10116', (133, 136))	('inflammation', 'biological_process', 'GO:0006954', ('92', '104'))	('inflammation', 'Disease', (92, 104))	('eliminates', 'NegReg', (15, 25))
185463	28548074	All these processes are hallmarks of cancer and a large body of evidence indicates that dysregulation of Akt activity plays an important role in human cancer.	('Akt', 'Gene', '207', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (37, 43))	('Akt', 'Gene', (105, 108))	('human', 'Species', '9606', (145, 150))	('activity', 'MPA', (109, 117))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('dysregulation', 'Var', (88, 101))
185469	28548074	In MM multicellular spheroids and MM tumor fragment spheroids, the role of mTOR in mediating survival signals has been assessed in two in vitro clinically relevant three-dimensional settings, suggesting that inhibition of mTOR may provide a valid nontoxic therapy for MM.	('MM tumor', 'Disease', (34, 42))	('MM tumor', 'Disease', 'MESH:D009369', (34, 42))	('mTOR', 'Gene', '2475', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mTOR', 'Gene', (222, 226))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('inhibition', 'Var', (208, 218))
185477	28548074	The miR-34b and miR-34c were found frequently downregulated by aberrant methylation in MM, resulting in the loss of tumor-suppressive p53 function and the acquisition of a malignant phenotype.	('loss', 'NegReg', (108, 112))	('miR-34c', 'Gene', (16, 23))	('p53', 'Gene', '7157', (134, 137))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('malignant phenotype', 'CPA', (172, 191))	('function', 'MPA', (138, 146))	('methylation', 'Var', (72, 83))	('miR-34b', 'Gene', '407041', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('downregulated', 'NegReg', (46, 59))	('miR-34b', 'Gene', (4, 11))	('aberrant methylation', 'Var', (63, 83))	('p53', 'Gene', (134, 137))	('tumor', 'Disease', (116, 121))	('miR-34c', 'Gene', '407042', (16, 23))
185481	28548074	The first generation small molecule Met inhibitor SU11274 has been successfully used to impair proliferation, wound healing and motility of H28 MM cells, by inhibiting Met kinase activity and downstream phosphorylation of Erk1/2 and Akt.	('motility', 'CPA', (128, 136))	('inhibiting', 'NegReg', (157, 167))	('kinase activity', 'molecular_function', 'GO:0016301', ('172', '187'))	('proliferation', 'CPA', (95, 108))	('Erk1/2', 'Gene', (222, 228))	('SU11274', 'Chemical', 'MESH:C478479', (50, 57))	('wound healing', 'CPA', (110, 123))	('rat', 'Species', '10116', (102, 105))	('Akt', 'Gene', (233, 236))	('rat', 'Species', '10116', (14, 17))	('H28 MM', 'CellLine', 'CVCL:4D15', (140, 146))	('Akt', 'Gene', '207', (233, 236))	('Erk1/2', 'Gene', '5595;5594', (222, 228))	('Erk1', 'molecular_function', 'GO:0004707', ('222', '226'))	('impair', 'NegReg', (88, 94))	('Met', 'Enzyme', (168, 171))	('SU11274', 'Var', (50, 57))	('phosphorylation', 'MPA', (203, 218))	('wound healing', 'biological_process', 'GO:0042060', ('110', '123'))	('phosphorylation', 'biological_process', 'GO:0016310', ('203', '218'))
185482	28548074	The second generation small molecule Met inhibitor, PHA665752, has been shown effective in MM, blocking the phosphorylation of Met, Akt, Erk1/2 and p70-S6K, in vitro alone or in combination with rapamycin, revealing that combination targeting of mTOR and Met suppresses Akt pathway activation and more effectively decreases cell growth.	('Akt', 'Gene', '207', (270, 273))	('Erk1/2', 'Gene', (137, 143))	('PHA665752', 'Var', (52, 61))	('rat', 'Species', '10116', (15, 18))	('Erk1', 'molecular_function', 'GO:0004707', ('137', '141'))	('Akt', 'Gene', (132, 135))	('cell growth', 'biological_process', 'GO:0016049', ('324', '335'))	('activation', 'MPA', (282, 292))	('blocking', 'NegReg', (95, 103))	('p70-S6K', 'Gene', '6198', (148, 155))	('decreases', 'NegReg', (314, 323))	('PHA665752', 'Chemical', 'MESH:C480541', (52, 61))	('Akt', 'Gene', '207', (132, 135))	('Erk1/2', 'Gene', '5595;5594', (137, 143))	('cell growth', 'CPA', (324, 335))	('mTOR', 'Gene', (246, 250))	('phosphorylation', 'MPA', (108, 123))	('p70-S6K', 'Gene', (148, 155))	('suppresses', 'NegReg', (259, 269))	('Akt', 'Gene', (270, 273))	('phosphorylation', 'biological_process', 'GO:0016310', ('108', '123'))	('rapamycin', 'Chemical', 'MESH:D020123', (195, 204))	('mTOR', 'Gene', '2475', (246, 250))
185486	28548074	The combination of PHA-665752 Met inhibitor and the EGFR inhibitor, erlotinib, suppressed MM cell growth with an additive effect, as occurred by combinations of rapamycin with different RTK inhibitors.	('MM cell growth', 'CPA', (90, 104))	('cell growth', 'biological_process', 'GO:0016049', ('93', '104'))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('suppressed', 'NegReg', (79, 89))	('PHA-665752', 'Var', (19, 29))	('rapamycin', 'Chemical', 'MESH:D020123', (161, 170))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
185492	28548074	In MM we showed that chondroitin sulphate proteoglycan 4 (CSPG4), belonging to the same family of CD44, is expressed in MM cell and biopsies, and monoclonal antibodies against CSPG4 significantly reduced MM cell motility, migration, invasiveness, and anchorage-independent growth.	('chondroitin sulphate proteoglycan', 'molecular_function', 'GO:0005204', ('21', '54'))	('chondroitin sulphate proteoglycan 4', 'Gene', '1464', (21, 56))	('CSPG4', 'Gene', (176, 181))	('CD44', 'Gene', '960', (98, 102))	('chondroitin sulphate proteoglycan 4', 'Gene', (21, 56))	('invasiveness', 'CPA', (233, 245))	('rat', 'Species', '10116', (225, 228))	('MM cell motility', 'CPA', (204, 220))	('CD44', 'Gene', (98, 102))	('migration', 'CPA', (222, 231))	('anchorage-independent growth', 'CPA', (251, 279))	('cell motility', 'biological_process', 'GO:0048870', ('207', '220'))	('monoclonal antibodies', 'Var', (146, 167))	('CSPG4', 'Gene', (58, 63))	('reduced', 'NegReg', (196, 203))
185493	28548074	CSPG4 antibodies also prevented or inhibited MM xenografts in SCID mice with a significant increase in animal survival.	('MM xenografts', 'CPA', (45, 58))	('animal survival', 'CPA', (103, 118))	('increase', 'PosReg', (91, 99))	('antibodies', 'Var', (6, 16))	('inhibited', 'NegReg', (35, 44))	('SCID', 'Disease', 'MESH:D053632', (62, 66))	('CSPG4', 'Gene', (0, 5))	('SCID', 'Disease', (62, 66))	('mice', 'Species', '10090', (67, 71))	('prevented', 'NegReg', (22, 31))
185496	28548074	However, the common pathways affected and the converging effects obtained with neutralizing antibodies suggest an intriguing role for anti-CSPG4 in antagonizing Met mediated carcinogenesis.	('carcinogenesis', 'Disease', (174, 188))	('carcinogenesis', 'Disease', 'MESH:D063646', (174, 188))	('anti-CSPG4', 'Var', (134, 144))
185498	28548074	In humans, the same tumor types have been shown to contain SV40 DNA and proteins.	('proteins', 'Protein', (72, 80))	('SV40 DNA', 'Var', (59, 67))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('SV40', 'Species', '1891767', (59, 63))	('humans', 'Species', '9606', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
185500	28548074	In vitro and animal experiments show co-carcinogenicity between SV40 and asbestos in HM that are particularly susceptible to SV40 transformation, possibly because in SV40-transformed HM abundant viral DNA persists in episomal form without completing the viral cycle.	('carcinogenic', 'Disease', (40, 52))	('SV40', 'Species', '1891767', (166, 170))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('SV40', 'Var', (125, 129))	('SV40', 'Species', '1891767', (64, 68))	('asbestos', 'Chemical', 'MESH:D001194', (73, 81))	('SV40', 'Species', '1891767', (125, 129))	('carcinogenic', 'Disease', 'MESH:D063646', (40, 52))
185506	28548074	Moreover, we also demonstrated that SV40 infection of HM and astrocytes induced an increase of Met and Notch-1 expression, and this effect was specific because the expression of other tyrosine kinase receptors in HM and astrocytes (e.g., EGFR, PDGFR) were not influenced by SV40 infection.	('increase', 'PosReg', (83, 91))	('SV40', 'Species', '1891767', (36, 40))	('SV40', 'Gene', (36, 40))	('SV40', 'Species', '1891767', (274, 278))	('tyrosine', 'Chemical', 'MESH:D014443', (184, 192))	('expression', 'MPA', (111, 121))	('EGFR', 'Gene', '1956', (238, 242))	('EGFR', 'Gene', (238, 242))	('Notch-1', 'Gene', (103, 110))	('infection', 'Var', (41, 50))	('rat', 'Species', '10116', (25, 28))	('Notch-1', 'Gene', '4851', (103, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))	('Met', 'MPA', (95, 98))
185510	28548074	SV40 activates a HGF/Met autocrine loop, driving accelerated and invasive cell growth, while Notch-1 is transcriptionally induced by SV40 early proteins in infected HM.	('SV40', 'Species', '1891767', (133, 137))	('cell growth', 'biological_process', 'GO:0016049', ('74', '85'))	('accelerated', 'PosReg', (49, 60))	('Notch-1', 'Gene', (93, 100))	('SV40', 'Species', '1891767', (0, 4))	('Notch-1', 'Gene', '4851', (93, 100))	('HGF/Met autocrine loop', 'MPA', (17, 39))	('rat', 'Species', '10116', (55, 58))	('SV40', 'Var', (0, 4))
185511	28548074	In HM and astrocytes, SV40 activates Met and Notch-1, possibly altering the Met-Notch negative feedback, thus facilitating cellular transformation.	('facilitating', 'Reg', (110, 122))	('altering', 'Reg', (63, 71))	('Notch-1', 'Gene', (45, 52))	('SV40', 'Species', '1891767', (22, 26))	('Notch-1', 'Gene', '4851', (45, 52))	('cellular transformation', 'CPA', (123, 146))	('SV40', 'Var', (22, 26))	('Met', 'Gene', (37, 40))	('Met-Notch negative feedback', 'MPA', (76, 103))	('activates', 'PosReg', (27, 36))
185520	28548074	At present, the common link between MM and ccRCC is limited to the fact that both cancers share a relevant percentage of Bap1 mutational loss.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('mutational loss', 'Var', (126, 141))	('Bap1', 'Gene', '8314', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('ccRCC', 'Disease', (43, 48))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('Bap1', 'Gene', (121, 125))
185524	28548074	A large body of evidence reported the association of Met with beta-catenin (Figure 4), followed by Wnt-independent nuclear translocation in human tumor cells.	('association', 'Interaction', (38, 49))	('beta-catenin', 'Gene', (62, 74))	('human', 'Species', '9606', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('Met', 'Var', (53, 56))	('beta-catenin', 'Gene', '1499', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
185570	24885895	It has also been demonstrated that asbestos can induce inflammation, perhaps due to activation of inflammasomes.	('asbestos', 'Var', (35, 43))	('asbestos', 'Chemical', 'MESH:D001194', (35, 43))	('induce', 'PosReg', (48, 54))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('rat', 'Species', '10116', (24, 27))	('inflammation', 'biological_process', 'GO:0006954', ('55', '67'))	('inflammation', 'Disease', (55, 67))
185576	24885895	In addition, knockdown of TXNIP expression by siRNA attenuated crocidolite asbestos-induced activation of the inflammasome.	('attenuated', 'NegReg', (52, 62))	('activation of the inflammasome', 'MPA', (92, 122))	('crocidolite asbestos-induced', 'Disease', (63, 91))	('TXNIP', 'Gene', (26, 31))	('TXNIP', 'Gene', '10628', (26, 31))	('crocidolite asbestos', 'Chemical', 'MESH:D017638', (63, 83))	('knockdown', 'Var', (13, 22))
185597	24885895	Our results indicate that oxidation of Trx1 by crocidolite asbestos results in dissociation of TXNIP and subsequent activation of inflammasomes, as knockdown of TXNIP by siRNA partially reduced crocidolite asbestos-induced inflammasome activation as indicated by a reduction in caspase-1 activation.	('reduction', 'NegReg', (265, 274))	('inflammasome activation', 'MPA', (223, 246))	('crocidolite asbestos', 'Chemical', 'MESH:D017638', (194, 214))	('dissociation', 'MPA', (79, 91))	('caspase-1', 'Gene', (278, 287))	('inflammasomes', 'MPA', (130, 143))	('reduced', 'NegReg', (186, 193))	('TXNIP', 'Gene', '10628', (161, 166))	('TXNIP', 'Gene', '10628', (95, 100))	('activation', 'PosReg', (116, 126))	('crocidolite asbestos', 'Chemical', 'MESH:D017638', (47, 67))	('Trx1', 'Gene', (39, 43))	('TXNIP', 'Gene', (161, 166))	('TXNIP', 'Gene', (95, 100))	('caspase-1', 'Gene', '834', (278, 287))	('Trx1', 'Gene', '7295', (39, 43))	('activation', 'MPA', (288, 298))	('knockdown', 'Var', (148, 157))
185633	24885895	To determine whether modulation of Trx1 protein levels and oxidation state altered cell death in human mesothelial cells, detection of apoptosis was performed using the ApoStain technique as described previously (Shukla et al., 2003).	('modulation', 'Var', (21, 31))	('cell death', 'biological_process', 'GO:0008219', ('83', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('Trx1', 'Gene', '7295', (35, 39))	('Trx1', 'Gene', (35, 39))	('human', 'Species', '9606', (97, 102))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('cell', 'CPA', (83, 87))	('altered', 'Reg', (75, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
185660	24885895	To determine whether inhibition of TR by DNCB would increase asbestos-induced oxidation of Trx1, LP9 cells were pretreated with 10 muM DNCB and exposed to 75 x 106 mum2/cm2 crocidolite asbestos for 8 and 24 h. A lactate dehydrogenase (LDH) assay performed on the medium from exposed cells showed that LDH levels were reduced in cells pretreated with DNCB when compared with cells exposed to asbestos alone (Figure  3A).	('DNCB', 'Var', (350, 354))	('DNCB', 'Chemical', 'MESH:D004137', (135, 139))	('asbestos', 'Chemical', 'MESH:D001194', (61, 69))	('reduced', 'NegReg', (317, 324))	('Trx1', 'Gene', '7295', (91, 95))	('TR', 'Gene', '25824', (35, 37))	('muM', 'Gene', (131, 134))	('DNCB', 'Chemical', 'MESH:D004137', (350, 354))	('muM', 'Gene', '56925', (131, 134))	('asbestos', 'Chemical', 'MESH:D001194', (391, 399))	('DNCB', 'Chemical', 'MESH:D004137', (41, 45))	('LP9', 'CellLine', 'CVCL:E109', (97, 100))	('Trx1', 'Gene', (91, 95))	('crocidolite asbestos', 'Chemical', 'MESH:D017638', (173, 193))	('LDH levels', 'MPA', (301, 311))	('asbestos', 'Chemical', 'MESH:D001194', (185, 193))
185671	24885895	Cells over-expressing Trx1 were found to exhibit a trend of reduced ROS levels compared to the null controls exposed to asbestos (Figure  4C).	('ROS levels', 'MPA', (68, 78))	('ROS', 'Chemical', 'MESH:D017382', (68, 71))	('over-expressing', 'Var', (6, 21))	('reduced', 'NegReg', (60, 67))	('Trx1', 'Gene', (22, 26))	('Trx1', 'Gene', '7295', (22, 26))	('asbestos', 'Chemical', 'MESH:D001194', (120, 128))
185681	24885895	Western blot analysis of the cell medium after exposure to asbestos for 48 h indicated that active caspase 1 levels (caspase1-p20) were reduced after knockdown of TXNIP when compared to siControl transfected cells (Figure  6B).	('asbestos', 'Chemical', 'MESH:D001194', (59, 67))	('caspase 1', 'Gene', '834', (99, 108))	('TXNIP', 'Gene', '10628', (163, 168))	('caspase1', 'Gene', '834', (117, 125))	('p20', 'Gene', '51673', (126, 129))	('TXNIP', 'Gene', (163, 168))	('knockdown', 'Var', (150, 159))	('caspase1', 'Gene', (117, 125))	('reduced', 'NegReg', (136, 143))	('caspase 1', 'Gene', (99, 108))	('p20', 'Gene', (126, 129))
185682	24885895	In mesothelioma cell lines with a stable knockdown of extracellular signal regulated kinase 2 (shERK 2), the expression of TXNIP was found to be down-regulated 4-fold (Figure  6C).	('extracellular signal regulated kinase 2', 'Gene', (54, 93))	('expression', 'MPA', (109, 119))	('mesothelioma', 'Disease', (3, 15))	('down-regulated', 'NegReg', (145, 159))	('extracellular signal regulated kinase 2', 'Gene', '5595', (54, 93))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('TXNIP', 'Gene', '10628', (123, 128))	('knockdown', 'Var', (41, 50))	('extracellular', 'cellular_component', 'GO:0005576', ('54', '67'))	('TXNIP', 'Gene', (123, 128))
185688	24885895	Immunoblotting for Cas-1 p20 in concentrated medium supernatants also confirmed that the inhibitor attenuated activation of the caspase-1 as expected (Figure  6F).	('inhibitor', 'Var', (89, 98))	('caspase-1', 'Gene', (128, 137))	('p20', 'Gene', '51673', (25, 28))	('activation', 'MPA', (110, 120))	('rat', 'Species', '10116', (39, 42))	('Cas', 'cellular_component', 'GO:0005650', ('19', '22'))	('Cas-1', 'Gene', (19, 24))	('p20', 'Gene', (25, 28))	('attenuated', 'NegReg', (99, 109))	('caspase-1', 'Gene', '834', (128, 137))	('Cas-1', 'Gene', '9564', (19, 24))
185700	24885895	We also report that TXNIP is involved in asbestos mediated activation of the inflammasome which may be as a result of the oxidation of Trx1 by asbestos-induced ROS generation.	('asbestos', 'Chemical', 'MESH:D001194', (41, 49))	('oxidation', 'Var', (122, 131))	('inflammasome', 'MPA', (77, 89))	('ROS generation', 'biological_process', 'GO:1903409', ('160', '174'))	('Trx1', 'Gene', (135, 139))	('Trx1', 'Gene', '7295', (135, 139))	('rat', 'Species', '10116', (168, 171))	('ROS', 'Chemical', 'MESH:D017382', (160, 163))	('TXNIP', 'Gene', (20, 25))	('activation', 'PosReg', (59, 69))	('TXNIP', 'Gene', '10628', (20, 25))	('asbestos', 'Chemical', 'MESH:D001194', (143, 151))
185705	24885895	Exogenous thioredoxin as well as endogenously over-expressed Trx has also been shown to increase MnSOD levels in a redox dependent manner .	('Trx', 'Gene', (61, 64))	('MnSOD', 'Gene', '6648', (97, 102))	('thioredoxin', 'molecular_function', 'GO:0030508', ('10', '21'))	('thioredoxin', 'Gene', '7295', (10, 21))	('MnSOD', 'Gene', (97, 102))	('increase', 'PosReg', (88, 96))	('thioredoxin', 'molecular_function', 'GO:0000008', ('10', '21'))	('thioredoxin', 'Gene', (10, 21))	('endogenously over-expressed', 'Var', (33, 60))	('Trx', 'Gene', '7295', (61, 64))
185714	24885895	Oxidation of these structural cysteines can lead to disulfide bond formation between Cys 62 and 69 which has been shown to reduce the use of Trx1 as a substrate for TR .	('lead to', 'Reg', (44, 51))	('disulfide', 'Chemical', 'MESH:D004220', (52, 61))	('rat', 'Species', '10116', (156, 159))	('disulfide bond formation', 'MPA', (52, 76))	('Trx1', 'Gene', '7295', (141, 145))	('Trx1', 'Gene', (141, 145))	('TR', 'Gene', '25824', (165, 167))	('reduce', 'NegReg', (123, 129))	('use', 'MPA', (134, 137))	('Oxidation', 'Var', (0, 9))	('cysteines', 'Chemical', 'MESH:D003545', (30, 39))	('Cys', 'Chemical', 'MESH:D003545', (85, 88))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))
185718	24885895	Other studies have shown that strong oxidants can cause the oxidation of Trx1 producing a mixture of Trx1 monomers, dimers and oligomers with no free sulfhydryl groups .	('Trx1', 'Gene', (73, 77))	('Trx1', 'Gene', '7295', (73, 77))	('dimers', 'MPA', (116, 122))	('Trx1', 'Gene', (101, 105))	('oxidation', 'Var', (60, 69))	('mixture', 'MPA', (90, 97))	('Trx1', 'Gene', '7295', (101, 105))	('monomers', 'MPA', (106, 114))
185720	24885895	Maintenance of the reducing milieu of the cell is also important for cell survival; thus, imbalances in the ratio of cellular antioxidants and oxidants could lead to deleterious or lethal effects on the cell.	('lead to', 'Reg', (158, 165))	('rat', 'Species', '10116', (108, 111))	('imbalances', 'Var', (90, 100))	('imbalances', 'Phenotype', 'HP:0002172', (90, 100))
185723	24885895	In contrast, recent studies have shown that inhibition of TR leads to increases in GSH levels and a reduction of Trx1 and Trx2 by glutaredoxin in the absence of a functional TR enzyme .	('reduction', 'NegReg', (100, 109))	('TR', 'Gene', '25824', (174, 176))	('GSH levels', 'MPA', (83, 93))	('Trx2', 'Gene', '25828', (122, 126))	('glutaredoxin', 'molecular_function', 'GO:0015038', ('130', '142'))	('inhibition', 'Var', (44, 54))	('GSH', 'Chemical', 'MESH:D005978', (83, 86))	('TR', 'Gene', '25824', (58, 60))	('increases', 'PosReg', (70, 79))	('glutaredoxin', 'Gene', '2745', (130, 142))	('Trx2', 'Gene', (122, 126))	('Trx1', 'Gene', (113, 117))	('Trx1', 'Gene', '7295', (113, 117))	('glutaredoxin', 'molecular_function', 'GO:0009487', ('130', '142'))	('glutaredoxin', 'molecular_function', 'GO:0030508', ('130', '142'))	('glutaredoxin', 'Gene', (130, 142))
185732	24885895	This implies that the oxidative stress induced by asbestos exposure is ameliorated by NAC.	('NAC', 'Var', (86, 89))	('rat', 'Species', '10116', (77, 80))	('NAC', 'cellular_component', 'GO:0005854', ('86', '89'))	('oxidative stress', 'MPA', (22, 38))	('asbestos', 'Chemical', 'MESH:D001194', (50, 58))	('NAC', 'Chemical', 'MESH:D000111', (86, 89))	('oxidative stress', 'Phenotype', 'HP:0025464', (22, 38))	('ameliorated', 'PosReg', (71, 82))
185735	24885895	However, this observation needs to be confirmed using siRNA mediated knockdown of caspase-1 in future studies.	('knockdown', 'Var', (69, 78))	('caspase-1', 'Gene', (82, 91))	('caspase-1', 'Gene', '834', (82, 91))
185737	24885895	Assessment of the effects of Trx1 over-expression on asbestos-induced ROS generation revealed that LP9 cells over-expressing Trx1 had lower levels of ROS after asbestos exposure when compared to vector transfected cells.	('lower', 'NegReg', (134, 139))	('over-expressing', 'Var', (109, 124))	('Trx1', 'Gene', (125, 129))	('LP9', 'CellLine', 'CVCL:E109', (99, 102))	('Trx1', 'Gene', '7295', (125, 129))	('Trx1', 'Gene', '7295', (29, 33))	('rat', 'Species', '10116', (78, 81))	('Trx1', 'Gene', (29, 33))	('ROS', 'MPA', (150, 153))	('asbestos', 'Chemical', 'MESH:D001194', (160, 168))	('levels', 'MPA', (140, 146))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('asbestos', 'Chemical', 'MESH:D001194', (53, 61))	('ROS generation', 'biological_process', 'GO:1903409', ('70', '84'))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))
185743	24885895	When TXNIP, the negative regulator of Trx1 reductase activity, was knocked down in LP9 cells, inflammasome activation was reduced.	('knocked', 'Var', (67, 74))	('Trx1', 'Gene', '7295', (38, 42))	('TXNIP', 'Gene', '10628', (5, 10))	('inflammasome activation', 'MPA', (94, 117))	('TXNIP', 'Gene', (5, 10))	('LP9', 'CellLine', 'CVCL:E109', (83, 86))	('reduced', 'NegReg', (122, 129))	('Trx1', 'Gene', (38, 42))
185746	24885895	demonstrated that knockdown of TXNIP by siRNA in beta islet cells reduced activation of the NLRP3 inflammasome.	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (66, 73))	('TXNIP', 'Gene', (31, 36))	('NLRP3', 'Gene', (92, 97))	('NLRP3', 'Gene', '114548', (92, 97))	('TXNIP', 'Gene', '10628', (31, 36))	('rat', 'Species', '10116', (7, 10))	('activation', 'MPA', (74, 84))	('beta islet cells reduced', 'Phenotype', 'HP:0006274', (49, 73))
185763	22645409	Tumor could be clearly visualized with 99mTc-ECG and 68Ga-ECG in mesothelioma-bearing rats.	('99mTc-ECG', 'Var', (39, 48))	('-ECG', 'Chemical', '-', (44, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mesothelioma', 'Disease', (65, 77))	('-ECG', 'Chemical', '-', (57, 61))	('Ga-ECG', 'Chemical', '-', (55, 61))	('68Ga-ECG', 'Var', (53, 61))	('rats', 'Species', '10116', (86, 90))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))
185764	22645409	99mTc-ECG and 68Ga-ECG showed increased uptake in mesothelioma, suggesting they may be useful in diagnosing mesothelioma and also monitoring therapeutic response.	('-ECG', 'Chemical', '-', (5, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('99mTc-ECG', 'Var', (0, 9))	('mesothelioma', 'Disease', (108, 120))	('uptake', 'MPA', (40, 46))	('Ga-ECG', 'Chemical', '-', (16, 22))	('uptake', 'biological_process', 'GO:0098657', ('40', '46'))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('uptake', 'biological_process', 'GO:0098739', ('40', '46'))	('mesothelioma', 'Disease', (50, 62))	('increased', 'PosReg', (30, 39))	('-ECG', 'Chemical', '-', (18, 22))	('68Ga-ECG', 'Var', (14, 22))
185790	22645409	Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor and transforming growth factor-beta which, in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibers.	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('172', '203'))	('release', 'MPA', (85, 92))	('result in', 'Reg', (71, 80))	('induce', 'PosReg', (224, 230))	('rat', 'Species', '10116', (266, 269))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('asbestos', 'Chemical', 'MESH:D001194', (310, 318))	('proliferation', 'CPA', (259, 272))	('rat', 'Species', '10116', (25, 28))	('genetic alterations', 'Var', (13, 32))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('137', '167'))
185827	22645409	In tissue distribution studies, each animal was injected (iv, 10 muCi/rat, 10 mug/rat) with 99mTc-ECG, 68Ga-ECG, and 18F-FDG.	('99mTc-ECG', 'Var', (92, 101))	('68Ga-ECG', 'Var', (103, 111))	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (82, 85))	('mug', 'molecular_function', 'GO:0043739', ('78', '81'))	('Ga-ECG', 'Chemical', '-', (105, 111))	('-ECG', 'Chemical', '-', (107, 111))	('18F-FDG', 'Chemical', '-', (117, 124))	('-ECG', 'Chemical', '-', (97, 101))
185852	22645409	Higher kidney uptake was observed for both 68Ga-ECG and 99mTc-ECG groups, presumable because EC and EC-conjugates may interact with renal tubules in the kidney.	('EC', 'Chemical', '-', (48, 50))	('EC', 'Chemical', '-', (62, 64))	('-ECG', 'Chemical', '-', (61, 65))	('68Ga-ECG', 'Var', (43, 51))	('-ECG', 'Chemical', '-', (47, 51))	('EC', 'Chemical', '-', (100, 102))	('EC', 'Chemical', '-', (93, 95))	('kidney uptake', 'MPA', (7, 20))	('Higher', 'PosReg', (0, 6))	('99mTc-ECG', 'Var', (56, 65))	('interact', 'Reg', (118, 126))	('Higher kidney', 'Phenotype', 'HP:0000105', (0, 13))	('uptake', 'biological_process', 'GO:0098657', ('14', '20'))	('uptake', 'biological_process', 'GO:0098739', ('14', '20'))	('Ga-ECG', 'Chemical', '-', (45, 51))
185853	22645409	Scintigraphic images of rats administered 68Ga-ECG, 99mTc-ECG, and 18F-FDG showed that tumors could be clearly visualized at 0.5-4 hrs (Figures 5-7).	('-ECG', 'Chemical', '-', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('-ECG', 'Chemical', '-', (57, 61))	('18F-FDG', 'Chemical', '-', (67, 74))	('rats', 'Species', '10116', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('Ga-ECG', 'Chemical', '-', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('68Ga-ECG', 'Var', (42, 50))
185854	22645409	Dynamic plot of tumor uptake with 68Ga-ECG and 18F-FDG showed similar transporter pattern (Figure 5).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('uptake', 'biological_process', 'GO:0098739', ('22', '28'))	('18F-FDG', 'Chemical', '-', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Ga-ECG', 'Chemical', '-', (36, 42))	('uptake', 'biological_process', 'GO:0098657', ('22', '28'))	('tumor', 'Disease', (16, 21))	('68Ga-ECG', 'Var', (34, 42))
185857	22645409	Tumor in 99mTc-ECG group showed much higher uptake than 99mTc-EC (control) group at 1 and 2 hrs (Figure 7).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (37, 43))	('-EC', 'Chemical', '-', (61, 64))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('uptake', 'MPA', (44, 50))	('-ECG', 'Chemical', '-', (14, 18))	('-EC', 'Chemical', '-', (14, 17))	('99mTc-ECG', 'Var', (9, 18))
185860	22645409	Cell cycle analysis revealed that 99mTc-ECG was able to transport across the nucleus membrane and involved in proliferation activity in all phases cell cycles.	('proliferation activity', 'CPA', (110, 132))	('rat', 'Species', '10116', (117, 120))	('membrane', 'cellular_component', 'GO:0016020', ('85', '93'))	('nucleus', 'cellular_component', 'GO:0005634', ('77', '84'))	('transport', 'biological_process', 'GO:0006810', ('56', '65'))	('-ECG', 'Chemical', '-', (39, 43))	('99mTc-ECG', 'Var', (34, 43))	('involved in', 'Reg', (98, 109))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('transport across the nucleus membrane', 'MPA', (56, 93))
185872	22645409	Clinical phase 1 and 2 trials revealed that 99mTc-ECG was safe and had favorable radiation dosimetry.	('radiation', 'Disease', 'MESH:D004194', (81, 90))	('-ECG', 'Chemical', '-', (49, 53))	('99mTc-ECG', 'Var', (44, 53))	('radiation', 'Disease', (81, 90))
185877	22645409	From biodistribution (Tables 1-3), tumor/brain count density ratios of 99mTc-ECG and 68Ga-ECG were better than those of FDG.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('99mTc-ECG', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Ga-ECG', 'Chemical', '-', (87, 93))	('tumor', 'Disease', (35, 40))	('rat', 'Species', '10116', (61, 64))	('-ECG', 'Chemical', '-', (89, 93))	('68Ga-ECG', 'Var', (85, 93))	('-ECG', 'Chemical', '-', (76, 80))
185879	22645409	However, tumor/blood count density ratios of 99mTc-ECG and 68Ga-ECG were less than that of FDG.	('-ECG', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('-ECG', 'Chemical', '-', (63, 67))	('99mTc-ECG', 'Var', (45, 54))	('68Ga-ECG', 'Var', (59, 67))	('Ga-ECG', 'Chemical', '-', (61, 67))	('less', 'NegReg', (73, 77))
185883	22645409	68Ga-ECG and 99mTc-ECG showed an increased uptake in mesothelioma in the model tested, indicating that they are feasible to assess tumor volume.	('mesothelioma', 'Disease', 'MESH:D008654', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('uptake', 'MPA', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('99mTc-ECG', 'Var', (13, 22))	('Ga-ECG', 'Chemical', '-', (2, 8))	('tumor', 'Disease', (131, 136))	('increased', 'PosReg', (33, 42))	('-ECG', 'Chemical', '-', (4, 8))	('68Ga-ECG', 'Var', (0, 8))	('uptake', 'biological_process', 'GO:0098657', ('43', '49'))	('uptake', 'biological_process', 'GO:0098739', ('43', '49'))	('-ECG', 'Chemical', '-', (18, 22))	('mesothelioma', 'Disease', (53, 65))
185916	30572031	Short answer: Focal positivity for TTF1 is considered a positive reaction indicating pulmonary adenocarcinoma in the proper clinical context, whereas for p40 the cut-off rate should be positivity in more than 50% of tumor nuclei.	('tumor', 'Disease', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (85, 109))	('p40', 'Gene', '8626', (154, 157))	('p40', 'cellular_component', 'GO:0043514', ('154', '157'))	('Focal positivity', 'Var', (14, 30))	('p40', 'cellular_component', 'GO:0070743', ('154', '157'))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 109))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('TTF1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('p40', 'Gene', (154, 157))	('pulmonary adenocarcinoma', 'Disease', (85, 109))
185919	30572031	Regarding TTF1 immunoreactivity, focal positivity is considered a positive reaction (Figure 2), indicative of adenocarcinoma in the proper clinical context.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('focal positivity', 'Var', (33, 49))	('TTF1', 'Gene', (10, 14))	('adenocarcinoma', 'Disease', (110, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))
185929	30572031	Conversely, double positivity (TTF1 and p40/p63) in the same cell does not define adenosquamous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TTF1', 'Var', (31, 35))	('p63', 'Gene', '8626', (44, 47))	('p40', 'Gene', '8626', (40, 43))	('p40', 'cellular_component', 'GO:0070743', ('40', '43'))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (82, 105))	('adenosquamous carcinoma', 'Disease', (82, 105))	('p40', 'Gene', (40, 43))	('p63', 'Gene', (44, 47))	('p40', 'cellular_component', 'GO:0043514', ('40', '43'))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (87, 105))
185931	30572031	Another challenging situation is the recurrence of EGFR mutated adenocarcinomas following targeted therapy that results in a pure squamous cell carcinoma that may be p40 positive and TTF1 negative while retaining the original EGFR mutation, sometime with an additional T790M mutation.	('negative', 'NegReg', (188, 196))	('EGFR', 'Gene', (51, 55))	('mutated', 'Var', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('squamous cell carcinoma', 'Disease', (130, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('226', '230'))	('T790M', 'Var', (269, 274))	('pure', 'molecular_function', 'GO:0034023', ('125', '129'))	('results in', 'Reg', (112, 122))	('p40', 'Gene', (166, 169))	('EGFR', 'Gene', (226, 230))	('EGFR', 'Gene', '1956', (226, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('EGFR', 'Gene', '1956', (51, 55))	('p40', 'Gene', '8626', (166, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('p40', 'cellular_component', 'GO:0070743', ('166', '169'))	('adenocarcinomas', 'Disease', 'MESH:D000230', (64, 79))	('adenocarcinomas', 'Disease', (64, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('p40', 'cellular_component', 'GO:0043514', ('166', '169'))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))	('T790M', 'Mutation', 'rs121434569', (269, 274))
185933	30572031	A number of different TTF1 clones are commercially available including rabbit and goat polyclonal antibodies, mouse monoclonal antibodies including 8G7G3/1, SPT24, BGX-397A, SMP150 and 5S143 clones, and rabbit monoclonal antibodies including SP141, EP15844, C12-I and G21-G clones.	('EP15844', 'Var', (249, 256))	('rabbit', 'Species', '9986', (71, 77))	('SMP', 'molecular_function', 'GO:0004193', ('174', '177'))	('SPT', 'molecular_function', 'GO:0004760', ('157', '160'))	('SPT', 'molecular_function', 'GO:0004758', ('157', '160'))	('rabbit', 'Species', '9986', (203, 209))	('TTF1', 'Gene', (22, 26))
185936	30572031	Focusing on TTF1 and the distinction between lung adenocarcinoma and squamous cell carcinoma, a review of the current literature revealed that the 8G7G3/1 clone was less sensitive for the detection of lung adenocarcinoma in comparison to the SPT24 clone (Table 3).	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (201, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('SPT', 'molecular_function', 'GO:0004760', ('242', '245'))	('SPT', 'molecular_function', 'GO:0004758', ('242', '245'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('8G7G3/1', 'Var', (147, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('squamous cell carcinoma', 'Disease', (69, 92))	('lung adenocarcinoma', 'Disease', (201, 220))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('less', 'NegReg', (165, 169))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (45, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma', 'Disease', (45, 64))
185937	30572031	However, when referring to TTF1 staining in lung squamous cell carcinoma, the specificity for adenocarcinoma is higher in 8G7G3/1 than SPT24 (Figure 3).	('specificity', 'MPA', (78, 89))	('SPT', 'molecular_function', 'GO:0004758', ('135', '138'))	('higher', 'PosReg', (112, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('8G7G3/1', 'Var', (122, 129))	('SPT', 'molecular_function', 'GO:0004760', ('135', '138'))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (44, 72))	('adenocarcinoma', 'Disease', (94, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
185938	30572031	It is noted that a certain percentage of squamous cell carcinoma are labelled with TTF1, particularly when applying a signal amplification system; the frequency of positivity in squamous cell carcinoma is higher with SPT24.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 201))	('SPT', 'molecular_function', 'GO:0004758', ('217', '220'))	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', (178, 201))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('SPT', 'molecular_function', 'GO:0004760', ('217', '220'))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('SPT24', 'Var', (217, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
185959	30572031	For these reasons, molecular testing is still recommended in the 2015 WHO classification in case of a CK5/6 (-), CK7 (+), TTF1 (-) p40 (-) and mucicarmine (-) NSCC.	('p40', 'Gene', '8626', (131, 134))	('TTF1', 'Gene', (122, 126))	('NSCC', 'Disease', 'MESH:D002289', (159, 163))	('mucicarmine', 'Var', (143, 154))	('NSCC', 'Phenotype', 'HP:0030358', (159, 163))	('mucicarmine', 'Chemical', 'MESH:C029618', (143, 154))	('CK7', 'Gene', (113, 116))	('p40', 'cellular_component', 'GO:0070743', ('131', '134'))	('CK5/6', 'Gene', '3852', (102, 107))	('NSCC', 'Disease', (159, 163))	('p40', 'Gene', (131, 134))	('CK5/6', 'Gene', (102, 107))	('CK7', 'Gene', '3855', (113, 116))	('p40', 'cellular_component', 'GO:0043514', ('131', '134'))
185962	30572031	TTF1 negativity correlates with invasive mucinous adenocarcinoma and solid adenocarcinoma with mucin (Figure 5), with only 10% to 15% of mucinous adenocarcinoma being TTF1 positive.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('TTF1', 'Gene', (0, 4))	('mucin', 'Gene', (95, 100))	('mucinous adenocarcinoma', 'Disease', (137, 160))	('mucin', 'Gene', '100508689', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (137, 160))	('invasive mucinous adenocarcinoma and solid adenocarcinoma', 'Disease', 'MESH:D002288', (32, 89))	('mucin', 'Gene', (137, 142))	('negativity', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('mucinous adenocarcinoma', 'Disease', (41, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (41, 64))	('mucin', 'Gene', (41, 46))	('mucin', 'Gene', '100508689', (95, 100))	('mucin', 'Gene', '100508689', (137, 142))
186017	30572031	Recently, an excellent performance of GATA3 has been reported in this distinction, and 100% sensitivity for sarcomatoid/desmoplastic malignant mesothelioma in particular suggested that lack of GATA3 expression could be used to exclude the diagnosis of sarcomatoid mesothelioma.	('GATA3', 'Gene', '2625', (38, 43))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', (108, 155))	('GATA3', 'Gene', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (133, 155))	('sarcomatoid mesothelioma', 'Disease', 'MESH:D008654', (252, 276))	('lack', 'Var', (185, 189))	('GATA3', 'Gene', '2625', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', 'MESH:C562839', (108, 155))	('GATA3', 'Gene', (38, 43))	('sarcomatoid mesothelioma', 'Disease', (252, 276))
186023	30572031	Molecular testing may support the diagnosis of sarcomatoid carcinoma by identifying alterations typical of non-small cell carcinoma, such as EGFR, KRAS or MET exon 14 splice site mutations, of which the latter are associated with sarcomatoid histology.	('sarcomatoid', 'Disease', (230, 241))	('sarcomatoid carcinoma', 'Disease', (47, 68))	('MET exon 14 splice site mutations', 'Var', (155, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (107, 131))	('sarcomatoid', 'Disease', (47, 58))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (111, 131))	('associated', 'Reg', (214, 224))	('KRAS', 'Gene', (147, 151))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (47, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('EGFR', 'Gene', '1956', (141, 145))	('sarcomatoid', 'Disease', 'MESH:D002292', (230, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (47, 68))	('sarcomatoid', 'Disease', 'MESH:D002292', (47, 58))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (107, 131))	('non-small cell carcinoma', 'Disease', (107, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (230, 251))	('EGFR', 'Gene', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('KRAS', 'Gene', '3845', (147, 151))
186072	30572031	Further, nonspecific labeling with polyclonal Napsin-A in mucinous adenocarcinomas appears to have peculiar supranuclear localization opposed to the pan-cytoplasmic granular staining present with monoclonal Napsin-A, possibly due to cross-reaction with pan-mucin antigen by the polyclonal antibody (Figure 14).	('localization', 'biological_process', 'GO:0051179', ('121', '133'))	('supranuclear', 'MPA', (108, 120))	('mucin', 'Gene', (58, 63))	('mucin', 'Gene', (257, 262))	('Napsin-A', 'Gene', '9476', (46, 54))	('antibody', 'cellular_component', 'GO:0019814', ('289', '297'))	('mucin', 'Gene', '100508689', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('mucin', 'Gene', '100508689', (257, 262))	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (58, 82))	('antibody', 'molecular_function', 'GO:0003823', ('289', '297'))	('antibody', 'cellular_component', 'GO:0042571', ('289', '297'))	('Napsin-A', 'Gene', (207, 215))	('mucinous adenocarcinomas', 'Disease', (58, 82))	('polyclonal', 'Var', (35, 45))	('antibody', 'cellular_component', 'GO:0019815', ('289', '297'))	('Napsin-A', 'Gene', '9476', (207, 215))	('Napsin-A', 'Gene', (46, 54))
186122	30572031	As aberrant TTF1 expression in schwannoma was recently reported, we do not still recognize all of them.	('aberrant', 'Var', (3, 11))	('schwannoma', 'Disease', (31, 41))	('schwannoma', 'Disease', 'MESH:D009442', (31, 41))	('TTF1', 'Gene', (12, 16))	('schwannoma', 'Phenotype', 'HP:0100008', (31, 41))
49167	24989332	Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%).	('toxicities', 'Disease', (14, 24))	('hypotension', 'Disease', 'MESH:D007022', (99, 110))	('back pain', 'Disease', (78, 87))	('back pain', 'Phenotype', 'HP:0003418', (78, 87))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (55, 70))	('hypotension', 'Disease', (99, 110))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (55, 70))	('SS1P', 'Chemical', 'MESH:C474515', (41, 45))	('hypoalbuminemia', 'Disease', (55, 70))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('SS1P', 'Var', (41, 45))	('hypotension', 'Phenotype', 'HP:0002615', (99, 110))	('pain', 'Phenotype', 'HP:0012531', (83, 87))	('back pain', 'Disease', 'MESH:D001416', (78, 87))
186200	24989332	In that group of heavily pretreated patients, SS1P had limited antitumor activity.	('SS1P', 'Chemical', 'MESH:C474515', (46, 50))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SS1P', 'Var', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
186202	24989332	In mice with mesothelin-expressing human tumor xenografts, SS1P had modest antitumor activity by itself; however, when combined with chemotherapy, remarkable synergy was observed.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (41, 46))	('mice', 'Species', '10090', (3, 7))	('human', 'Species', '9606', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('SS1P', 'Chemical', 'MESH:C474515', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('SS1P', 'Var', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
186204	24989332	On the basis of these preclinical data, we designed this study to determine whether a similar synergistic antitumor effect could be observed in patients with MPM by combining SS1P with standard chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (144, 152))	('MPM', 'Disease', (158, 161))	('combining', 'Interaction', (165, 174))	('SS1P', 'Chemical', 'MESH:C474515', (175, 179))	('SS1P', 'Var', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
186218	24989332	The following AEs were considered dose-limiting: nonhematologic AEs of grade >=3 severity that were suspected of a causal relation to SS1P, grade 3 vascular leak syndrome (VLS) (defined as a requirement for fluids >20 mL/kg per hour for at least 30 minutes to treat hypotension), grade 3 hypotension in temporal association with VLS, VLS resulting in symptomatic pulmonary edema requiring supplemental oxygen or a decrease >10% in oxygen saturation, grade >=4 hematologic AEs except lymphopenia lasting >5 days, grade 2 allergic reactions of bronchospasm or urticaria, or any grade >=3 allergic reaction in the presence of premedication.	('hypotension', 'Disease', 'MESH:D007022', (266, 277))	('grade', 'Var', (280, 285))	('VLS', 'Disease', (329, 332))	('lymphopenia', 'Disease', (483, 494))	('hypotension', 'Disease', (288, 299))	('bronchospasm', 'Phenotype', 'HP:0025428', (542, 554))	('hypotension', 'Phenotype', 'HP:0002615', (266, 277))	('SS1P', 'Chemical', 'MESH:C474515', (134, 138))	('lymphopenia', 'Phenotype', 'HP:0001888', (483, 494))	('SS1P', 'Gene', (134, 138))	('allergic reaction', 'Disease', (586, 603))	('allergic reaction', 'Disease', 'MESH:D004342', (520, 537))	('allergic reaction', 'Phenotype', 'HP:0012393', (586, 603))	('hypotension', 'Disease', 'MESH:D007022', (288, 299))	('oxygen saturation', 'MPA', (431, 448))	('urticaria', 'Phenotype', 'HP:0001025', (558, 567))	('VLS', 'Phenotype', 'HP:0030005', (172, 175))	('vascular leak syndrome', 'Disease', (148, 170))	('allergic reactions', 'Phenotype', 'HP:0012393', (520, 538))	('hypotension', 'Phenotype', 'HP:0002615', (288, 299))	('VLS', 'Disease', (334, 337))	('lymphopenia', 'Disease', 'MESH:D008231', (483, 494))	('VLS', 'Phenotype', 'HP:0030005', (329, 332))	('pulmonary edema', 'Disease', 'MESH:D011654', (363, 378))	('allergic reactions of bronchospasm or urticaria', 'Disease', 'MESH:D004342', (520, 567))	('allergic reaction', 'Phenotype', 'HP:0012393', (520, 537))	('pulmonary edema', 'Phenotype', 'HP:0100598', (363, 378))	('men', 'Species', '9606', (198, 201))	('decrease', 'NegReg', (414, 422))	('men', 'Species', '9606', (395, 398))	('vascular leak syndrome', 'Phenotype', 'HP:0030005', (148, 170))	('pulmonary edema', 'Disease', (363, 378))	('hypotension', 'Disease', (266, 277))	('allergic reactions of bronchospasm or urticaria', 'Disease', (520, 567))	('vascular leak syndrome', 'Disease', 'MESH:D019559', (148, 170))	('allergic reaction', 'Disease', 'MESH:D004342', (586, 603))	('VLS', 'Phenotype', 'HP:0030005', (334, 337))	('edema', 'Phenotype', 'HP:0000969', (373, 378))
186255	24989332	One patient who received SS1P 55 mug/kg had grade 3 fatigue, which was considered a DLT.	('mug', 'molecular_function', 'GO:0043739', ('33', '36'))	('fatigue', 'Disease', 'MESH:D005221', (52, 59))	('SS1P 55 mug/kg', 'Var', (25, 39))	('patient', 'Species', '9606', (4, 11))	('fatigue', 'Disease', (52, 59))	('fatigue', 'Phenotype', 'HP:0012378', (52, 59))	('SS1P', 'Chemical', 'MESH:C474515', (25, 29))
186296	24989332	Our results indicate that combining SS1P with pemetrexed and cisplatin is well tolerated and produces no overlapping toxicities.	('pemetrexed', 'Chemical', 'MESH:D000068437', (46, 56))	('toxicities', 'Disease', (117, 127))	('SS1P', 'Var', (36, 40))	('SS1P', 'Chemical', 'MESH:C474515', (36, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('toxicities', 'Disease', 'MESH:D064420', (117, 127))
186299	24989332	The combination of SS1P with cisplatin and pemetrexed resulted in response rates of 60% in all evaluable patients and 77% in patients who received the MTD.	('pemetrexed', 'Chemical', 'MESH:D000068437', (43, 53))	('patients', 'Species', '9606', (105, 113))	('SS1P', 'Chemical', 'MESH:C474515', (19, 23))	('SS1P', 'Var', (19, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('combination', 'Interaction', (4, 15))	('patients', 'Species', '9606', (125, 133))
186385	30240138	discuss the use of a gene expression test to determine the prognosis of patients with mesothelioma using samples taken prior to surgery.16 When comparing their data to an independent cohort, they found that the gene expression score was a significant predictor of survival in both univariate and multivariate analysis.	('gene expression', 'biological_process', 'GO:0010467', ('211', '226'))	('gene expression score', 'Var', (211, 232))	('mesothelioma', 'Disease', (86, 98))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('survival', 'MPA', (264, 272))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('patients', 'Species', '9606', (72, 80))
186399	26678224	Importantly, PLF WBC gene expression of cytokines (IL-1ss, IL-6, TNFalpha, HMGB1 and TGFss1) and cytokine receptors (TNFalphaR1 and TGFssR1) were also downregulated by FLC.	('TNFalphaR1', 'Gene', '21937', (117, 127))	('TNFalpha', 'Gene', (65, 73))	('TNFalpha', 'Gene', '21926', (117, 125))	('FLC', 'Var', (168, 171))	('expression', 'MPA', (26, 36))	('TGFss1', 'Gene', (85, 91))	('PLF WBC', 'Gene', (13, 20))	('IL-6', 'Gene', (59, 63))	('IL-1', 'Gene', (51, 55))	('HMGB1', 'Gene', (75, 80))	('TNFalphaR1', 'Gene', (117, 127))	('TNFalpha', 'Gene', (117, 125))	('downregulated', 'NegReg', (151, 164))	('IL-1', 'molecular_function', 'GO:0005149', ('51', '55'))	('IL-6', 'Gene', '16193', (59, 63))	('TNFalpha', 'Gene', '21926', (65, 73))	('TGFssR1', 'Gene', (132, 139))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('IL-1', 'Gene', '111343', (51, 55))	('IL-6', 'molecular_function', 'GO:0005138', ('59', '63'))	('HMGB1', 'Gene', '15289', (75, 80))
186401	26678224	FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.	('reduces', 'NegReg', (4, 11))	('asbestos', 'Chemical', 'MESH:D001194', (18, 26))	('oxidative stress', 'MPA', (76, 92))	('peritoneal inflammation', 'Disease', (35, 58))	('inflammation', 'biological_process', 'GO:0006954', ('46', '58'))	('peritoneal inflammation', 'Phenotype', 'HP:0002586', (35, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('peritoneal inflammation', 'Disease', 'MESH:D007249', (35, 58))	('FLC', 'Var', (0, 3))
186420	26678224	To begin to test this hypothesis, we first evaluated its effects on acute asbestos-induced peritoneal inflammation in a mouse model (with genetic alterations in the NF2 genes) of accelerated MM development that recapitulates many of the molecular, genetic and cell signaling features of human MM after asbestos injection.	('genetic alterations', 'Var', (138, 157))	('NF2', 'Gene', (165, 168))	('signaling', 'biological_process', 'GO:0023052', ('265', '274'))	('MM development', 'CPA', (191, 205))	('peritoneal inflammation', 'Disease', 'MESH:D007249', (91, 114))	('asbestos', 'Chemical', 'MESH:D001194', (302, 310))	('NF2', 'Gene', '18016', (165, 168))	('accelerated', 'PosReg', (179, 190))	('asbestos', 'Chemical', 'MESH:D001194', (74, 82))	('inflammation', 'biological_process', 'GO:0006954', ('102', '114'))	('human', 'Species', '9606', (287, 292))	('peritoneal inflammation', 'Disease', (91, 114))	('peritoneal inflammation', 'Phenotype', 'HP:0002586', (91, 114))	('mouse', 'Species', '10090', (120, 125))
186452	26678224	We observed a significant increase (P < 0.01) in WBC (Figure 1A) and neutrophil (Figure 1B) concentrations in PLF collected 3 days post asbestos exposure (121 250+-8750 cells/ml compared to a baseline WBC concentration of 40 563+-5120 cells/ml at day 0) that was significantly reduced by day 9 (49 625+-10 375 cells/ml) consistent with a previous report.	('WBC', 'MPA', (49, 52))	('neutrophil', 'MPA', (69, 79))	('increase', 'PosReg', (26, 34))	('asbestos', 'Chemical', 'MESH:D001194', (136, 144))	('121 250+-8750 cells/ml', 'Var', (155, 177))
186463	26678224	Mice-fed FLC diet had statistically significantly (P < 0.0001) less inflammation, with a 58.3% decrease in mean PLF total WBCs (Figure 2B) compared to CTL-fed mice (890 588+-76 957 cells/ml for FLC-fed mice compared to 2 134 000+-220 076 cells/ml for CTL-fed mice).	('decrease', 'NegReg', (95, 103))	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('mice', 'Species', '10090', (202, 206))	('PLF total WBCs', 'MPA', (112, 126))	('mice', 'Species', '10090', (159, 163))	('FLC', 'Var', (9, 12))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('mice', 'Species', '10090', (259, 263))	('inflammation', 'Disease', (68, 80))	('Mice', 'Species', '10090', (0, 4))	('less', 'NegReg', (63, 67))
186499	26678224	The chronic production of the above mentioned mediators of inflammation, caused by asbestos exposure, may be critical for malignant transformation and the formation of MM through the induction of DNA damage, defective cell cycle control mechanisms, prolonged angiogenesis, uncontrollable growth signaling and tissue invasion/metastasis.	('asbestos', 'Chemical', 'MESH:D001194', (83, 91))	('signaling', 'biological_process', 'GO:0023052', ('295', '304'))	('inflammation', 'biological_process', 'GO:0006954', ('59', '71'))	('defective cell cycle control mechanisms', 'Phenotype', 'HP:0011018', (208, 247))	('angiogenesis', 'CPA', (259, 271))	('tissue invasion/metastasis', 'CPA', (309, 335))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('angiogenesis', 'biological_process', 'GO:0001525', ('259', '271'))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('cell cycle control mechanisms', 'CPA', (218, 247))	('defective', 'Var', (208, 217))	('tissue invasion', 'biological_process', 'GO:0001404', ('309', '324'))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))	('cell cycle control', 'biological_process', 'GO:1901987', ('218', '236'))	('lignan', 'Chemical', 'MESH:D017705', (124, 130))
186509	26678224	The SDG in FLC can act as a direct antioxidant.	('SDG', 'Var', (4, 7))	('SDG', 'Chemical', 'MESH:C090142', (4, 7))	('FLC', 'Gene', (11, 14))
186551	26678224	has a pending patent application on BAP1 mutation testing.	('mutation', 'Var', (41, 49))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '104416', (36, 40))
186563	25950487	One of the tumor-suppressor genes frequently mutated in MPM is NF2 and NF2-null cells were shown to be sensitive to growth-inhibitory effects of rapamycin via mechanisms involving PI3K signaling-independent mTORC1 activation.	('PI3', 'Gene', (180, 183))	('NF2', 'Gene', '4771', (63, 66))	('NF2', 'Gene', (71, 74))	('PI3K signaling', 'biological_process', 'GO:0014065', ('180', '194'))	('mutated', 'Var', (45, 52))	('rapamycin', 'Chemical', 'MESH:D020123', (145, 154))	('NF2', 'Gene', (63, 66))	('tumor', 'Disease', (11, 16))	('mTORC1', 'cellular_component', 'GO:0031931', ('207', '213'))	('sensitive to growth-inhibitory effects', 'MPA', (103, 141))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('MPM', 'Gene', (56, 59))	('mTORC1', 'Gene', (207, 213))	('PI3', 'Gene', '5266', (180, 183))	('mTORC1', 'Gene', '382056', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('PI3K', 'molecular_function', 'GO:0016303', ('180', '184'))	('NF2', 'Gene', '4771', (71, 74))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('11', '27'))
186566	25950487	Furthermore, NF2 was also shown to inhibit PI3K activity by binding to PI3K enhancer-L (PIKE-L), which disrupts binding of PIKE-L to PI3K and loss of NF2 in schwannoma was shown to sensitize to PI3K inhibitors.	('PI3', 'Gene', '5266', (43, 46))	('NF2', 'Gene', '4771', (150, 153))	('schwannoma', 'Disease', (157, 167))	('loss', 'Var', (142, 146))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('disrupts', 'NegReg', (103, 111))	('NF2', 'Gene', (150, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('194', '198'))	('PIKE', 'Gene', '116986', (88, 92))	('PI3', 'Gene', '5266', (71, 74))	('binding', 'Interaction', (60, 67))	('NF2', 'Gene', '4771', (13, 16))	('activity', 'MPA', (48, 56))	('schwannoma', 'Disease', 'MESH:D009442', (157, 167))	('PI3', 'Gene', (194, 197))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('PI3', 'Gene', (43, 46))	('PIKE', 'Gene', (123, 127))	('NF2', 'Gene', (13, 16))	('PI3', 'Gene', '5266', (133, 136))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('PI3', 'Gene', (71, 74))	('inhibit', 'NegReg', (35, 42))	('PIKE', 'Gene', '116986', (123, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))	('binding', 'Interaction', (112, 119))	('PIKE', 'Gene', (88, 92))	('schwannoma', 'Phenotype', 'HP:0100008', (157, 167))	('PI3', 'Gene', (133, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('PI3', 'Gene', '5266', (194, 197))
186567	25950487	In a screen on the dual PI3K/mTOR inhibitor NVP-BEZ235, within the Sanger Institute/MGH's 'Genomics of Drug Sensitivity' screening panel, CDKN2A deletion was shown to be associated with increased sensitivity.	('PI3', 'Gene', (24, 27))	('CDKN2A', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (138, 144))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (103, 119))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (44, 54))	('increased', 'PosReg', (186, 195))	('PI3', 'Gene', '5266', (24, 27))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('sensitivity', 'Disease', (196, 207))	('associated', 'Reg', (170, 180))	('deletion', 'Var', (145, 153))
186570	25950487	NVP-BEZ235 and GDC-0980 are small-molecule inhibitors of class I PI3K and mTOR (mTORC1 and mTORC2).	('GDC-0980', 'Chemical', 'MESH:C569670', (15, 23))	('mTORC2', 'cellular_component', 'GO:0031932', ('91', '97'))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('mTORC2', 'Gene', '74343', (91, 97))	('mTORC2', 'Gene', (91, 97))	('mTORC1', 'Gene', '382056', (80, 86))	('PI3', 'Gene', '5266', (65, 68))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (0, 10))	('mTORC1', 'Gene', (80, 86))	('mTORC1', 'cellular_component', 'GO:0031931', ('80', '86'))	('GDC-0980', 'Var', (15, 23))	('PI3', 'Gene', (65, 68))
186575	25950487	We observed that PI3K/mTOR inhibition increases autophagic rate, which constitutes an efficient mechanism of resistance by inducing growth arrest and survival.	('growth arrest', 'Disease', 'MESH:D006323', (132, 145))	('increases', 'PosReg', (38, 47))	('survival', 'CPA', (150, 158))	('growth arrest', 'Phenotype', 'HP:0001510', (132, 145))	('PI3', 'Gene', '5266', (17, 20))	('autophagic rate', 'CPA', (48, 63))	('inhibition', 'Var', (27, 37))	('inducing', 'PosReg', (123, 131))	('PI3', 'Gene', (17, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('growth arrest', 'Disease', (132, 145))
186579	25950487	Cells were treated with increasing doses of either NVP-BEZ235 or GDC-0980, and viability and growth inhibition were assayed by measuring mitochondrial activity at 72 h using an MTT assay.	('NVP-BEZ235', 'Var', (51, 61))	('GDC-0980', 'Gene', (65, 73))	('mitochondrial activity', 'MPA', (137, 159))	('MTT', 'Chemical', 'MESH:C070243', (177, 180))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (51, 61))	('GDC-0980', 'Chemical', 'MESH:C569670', (65, 73))
186580	25950487	The IC50 distribution determined for NVP-BEZ235 showed a difference of about 26-fold between the most sensitive and the most resistant cell lines, whereas GDC-0980 IC50 distribution was more homogenous and showed a maximal difference of 8-fold (Figure 1).	('IC50', 'MPA', (4, 8))	('NVP-BEZ235', 'Var', (37, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (155, 163))	('difference', 'Reg', (57, 67))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (37, 47))
186581	25950487	In order to determine whether the results obtained were suitable to select resistant and sensitive cell lines, we tested whether the percentages of growth and viability for a given concentration of either GDC-0980 or NVP-BEZ235 were normally distributed using the Quantile-Quantile Plot (Q-Q Plot) normality test (Figure 1, Supplementary Figure S1).	('tested', 'Reg', (114, 120))	('GDC-0980', 'Chemical', 'MESH:C569670', (205, 213))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (324, 347))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (217, 227))	('Supplementary Figure S1', 'Disease', (324, 347))	('GDC-0980', 'Var', (205, 213))	('NVP-BEZ235', 'Var', (217, 227))
186585	25950487	The IC50 of 26% of the MPM cell lines treated with NVP-BEZ235 was <100 nM and the IC50 of 68% of MPM cell lines cells treated with GDC-0980 was <500 nM.	('NVP-BEZ235', 'Var', (51, 61))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (51, 61))	('IC50', 'MPA', (4, 8))	('GDC-0980', 'Chemical', 'MESH:C569670', (131, 139))
186591	25950487	S6 phosphorylation did not correlate with 4E-BP1 phosphorylation, and this may be representative on the addiction of cancer cells to aberrant eIF4F heterotrimer-mediated translation, the assembly of which is inhibited by dephosphorylated 4E-BP1.	('aberrant', 'Var', (133, 141))	('translation', 'biological_process', 'GO:0006412', ('170', '181'))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('4E-BP1', 'Gene', (238, 244))	('4E-BP1', 'Gene', '1978', (42, 48))	('eIF4F', 'cellular_component', 'GO:0016281', ('142', '147'))	('phosphorylation', 'biological_process', 'GO:0016310', ('3', '18'))	('4E-BP1', 'Gene', '1978', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('eIF4F', 'Gene', (142, 147))	('eIF4F', 'Gene', '1981', (142, 147))	('cancer', 'Disease', (117, 123))	('4E-BP1', 'Gene', (42, 48))	('heterotrimer-mediated translation', 'MPA', (148, 181))
186595	25950487	Taken together, although there was no correlation between markers of PI3K/mTORC1/2 activity and the cell growth in sensitive and resistant cell lines for both dual PI3K/mTORC1/2 inhibitors, GDC-0980 was more efficient in blocking PI3K/mTORC2 compared with NVP-BEZ235.	('PI3', 'Gene', (69, 72))	('mTORC2', 'Gene', '74343', (235, 241))	('mTORC1', 'Gene', (169, 175))	('mTORC1', 'cellular_component', 'GO:0031931', ('169', '175'))	('mTORC2', 'cellular_component', 'GO:0031932', ('235', '241'))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('PI3', 'Gene', '5266', (230, 233))	('mTORC1', 'Gene', (74, 80))	('mTORC1', 'Gene', '382056', (169, 175))	('mTORC1', 'Gene', '382056', (74, 80))	('PI3', 'Gene', '5266', (164, 167))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (256, 266))	('blocking', 'NegReg', (221, 229))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('PI3', 'Gene', '5266', (69, 72))	('PI3', 'Gene', (230, 233))	('GDC-0980', 'Var', (190, 198))	('mTORC2', 'Gene', (235, 241))	('GDC-0980', 'Chemical', 'MESH:C569670', (190, 198))	('cell growth', 'biological_process', 'GO:0016049', ('100', '111'))	('PI3', 'Gene', (164, 167))	('mTORC1', 'cellular_component', 'GO:0031931', ('74', '80'))	('PI3K', 'molecular_function', 'GO:0016303', ('230', '234'))
186597	25950487	G1 accumulation with 200 nM NVP-BEZ235 and 500 nM GDC-0980 was significantly more pronounced in the sensitive lines than the resistant cell lines; however, no cell death was observed (Figure 2b, Supplementary Figure S2).	('GDC-0980', 'Var', (50, 58))	('cell death', 'biological_process', 'GO:0008219', ('159', '169'))	('GDC-0980', 'Chemical', 'MESH:C569670', (50, 58))	('accumulation', 'PosReg', (3, 15))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (28, 38))
186605	25950487	Consistently with the observations done by others that NVP-BEZ235 induces autophagy in glioma cells and GDC-0980 in pancreatic cancer, we also observed sustained autophagy induction in SPC212 and Mero-82 cells after 72 h of treatment, evidenced by the processing of LC3-I to the autophagosome localized LC3-II form and P62 degradation (Figure 3a).	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('autophagy', 'biological_process', 'GO:0016236', ('74', '83'))	('Mero-82', 'Chemical', '-', (196, 203))	('degradation', 'biological_process', 'GO:0009056', ('323', '334'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('P62', 'Gene', '23636', (319, 322))	('pancreatic cancer', 'Disease', (116, 133))	('autophagy', 'biological_process', 'GO:0016236', ('162', '171'))	('GDC-0980', 'Chemical', 'MESH:C569670', (104, 112))	('autophagy', 'biological_process', 'GO:0006914', ('74', '83'))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('autophagy', 'CPA', (162, 171))	('induces', 'Reg', (66, 73))	('autophagosome', 'cellular_component', 'GO:0005776', ('279', '292'))	('NVP-BEZ235', 'Var', (55, 65))	('autophagy', 'CPA', (74, 83))	('P62', 'Gene', (319, 322))	('SPC', 'molecular_function', 'GO:0009004', ('185', '188'))	('glioma', 'Disease', (87, 93))	('processing', 'MPA', (252, 262))	('SPC212', 'CellLine', 'CVCL:D312', (185, 191))	('autophagy', 'biological_process', 'GO:0006914', ('162', '171'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (55, 65))
186609	25950487	GDC-0980 and NVP-BEZ235 alone or in combination with other chemotherapeutics or radiotherapy have been shown to induce intrinsic apoptosis in a variety of solid and liquid tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('intrinsic apoptosis', 'biological_process', 'GO:0097193', ('119', '138'))	('intrinsic apoptosis', 'CPA', (119, 138))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (13, 23))	('GDC-0980', 'Var', (0, 8))	('GDC-0980', 'Chemical', 'MESH:C569670', (0, 8))	('NVP-BEZ235', 'Var', (13, 23))	('induce', 'PosReg', (112, 118))
186612	25950487	In order to test whether NVP-BEZ235 and GDC-0980 promote survival via autophagy, sensitive and resistant lines were treated with the inhibitors alone or in combination with CQ.	('GDC-0980', 'Gene', (40, 48))	('autophagy', 'biological_process', 'GO:0006914', ('70', '79'))	('autophagy', 'CPA', (70, 79))	('CQ', 'Chemical', 'MESH:D002738', (173, 175))	('GDC-0980', 'Chemical', 'MESH:C569670', (40, 48))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (25, 35))	('promote', 'PosReg', (49, 56))	('autophagy', 'biological_process', 'GO:0016236', ('70', '79'))	('NVP-BEZ235', 'Var', (25, 35))	('survival', 'CPA', (57, 65))
186613	25950487	CQ alone and in combination with GDC-0980 efficiently blocked autophagy after 24 h of treatment, and this effect was maintained after 72 h. GDC-0980 alone increased the autophagic flux in SPC212 and Mero-82 cells at 72 h (Figure 4a).	('SPC212', 'CellLine', 'CVCL:D312', (188, 194))	('Mero-82', 'Chemical', '-', (199, 206))	('autophagic flux', 'CPA', (169, 184))	('SPC', 'molecular_function', 'GO:0009004', ('188', '191'))	('increased', 'PosReg', (155, 164))	('GDC-0980', 'Chemical', 'MESH:C569670', (33, 41))	('GDC-0980', 'Var', (140, 148))	('autophagy', 'biological_process', 'GO:0016236', ('62', '71'))	('GDC-0980', 'Chemical', 'MESH:C569670', (140, 148))	('autophagy', 'biological_process', 'GO:0006914', ('62', '71'))	('CQ', 'Chemical', 'MESH:D002738', (0, 2))
186619	25950487	Silencing of Atg5 resulted in abolition of P62 accumulation after CQ treatment (Figure 5b), thus demonstrating efficient blockade of autophagy.	('Atg5', 'Gene', (13, 17))	('CQ', 'Chemical', 'MESH:D002738', (66, 68))	('abolition', 'NegReg', (30, 39))	('blockade', 'NegReg', (121, 129))	('autophagy', 'biological_process', 'GO:0016236', ('133', '142'))	('P62', 'Gene', (43, 46))	('autophagy', 'biological_process', 'GO:0006914', ('133', '142'))	('Atg5', 'Gene', '9474', (13, 17))	('autophagy', 'CPA', (133, 142))	('Silencing', 'Var', (0, 9))	('P62', 'Gene', '23636', (43, 46))
186620	25950487	Surprisingly, silencing Atg5 gene was associated with significantly impaired cell growth in SPC212 sensitive line and Mero-82 resistant line (Figure 5c), indicating the dependency of the MPM on autophagy.	('silencing', 'Var', (14, 23))	('autophagy', 'biological_process', 'GO:0016236', ('194', '203'))	('Mero-82', 'Chemical', '-', (118, 125))	('Atg5', 'Gene', (24, 28))	('SPC', 'molecular_function', 'GO:0009004', ('92', '95'))	('cell growth', 'CPA', (77, 88))	('autophagy', 'biological_process', 'GO:0006914', ('194', '203'))	('impaired', 'NegReg', (68, 76))	('cell growth', 'biological_process', 'GO:0016049', ('77', '88'))	('SPC212', 'CellLine', 'CVCL:D312', (92, 98))	('Atg5', 'Gene', '9474', (24, 28))
186634	25950487	We observed that GDC-0980 induced activation of ERK in resistant Mero-82 cells but not in sensitive SPC212 cells (Supplementary Figure S8a).	('ERK', 'Gene', (48, 51))	('Mero-82', 'Chemical', '-', (65, 72))	('SPC212', 'CellLine', 'CVCL:D312', (100, 106))	('SPC', 'molecular_function', 'GO:0009004', ('100', '103'))	('GDC-0980', 'Var', (17, 25))	('activation', 'PosReg', (34, 44))	('ERK', 'Gene', '5594', (48, 51))	('GDC-0980', 'Chemical', 'MESH:C569670', (17, 25))	('ERK', 'molecular_function', 'GO:0004707', ('48', '51'))
186637	25950487	U0126 efficiently inhibited ERK induction by CQ and GDC-0980 (Supplementary Figure S8b).	('ERK', 'Gene', (28, 31))	('CQ', 'Chemical', 'MESH:D002738', (45, 47))	('GDC-0980', 'Chemical', 'MESH:C569670', (52, 60))	('U0126', 'Var', (0, 5))	('inhibited', 'NegReg', (18, 27))	('ERK', 'Gene', '5594', (28, 31))	('GDC-0980', 'Var', (52, 60))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))
186638	25950487	However, combination of U0126, GDC-0980 and CQ did not induce cell death (Supplementary Figure S8c).	('U0126', 'Chemical', 'MESH:C113580', (24, 29))	('GDC-0980', 'Var', (31, 39))	('U0126', 'Var', (24, 29))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))	('CQ', 'Chemical', 'MESH:D002738', (44, 46))	('GDC-0980', 'Chemical', 'MESH:C569670', (31, 39))
186651	25950487	Combination of U0126 and GDC-0980 had a slight additive effect on viability, and there was no additional significant effect when CQ was added.	('U0126', 'Var', (15, 20))	('GDC-0980', 'Var', (25, 33))	('viability', 'CPA', (66, 75))	('U0126', 'Chemical', 'MESH:C113580', (15, 20))	('CQ', 'Chemical', 'MESH:D002738', (129, 131))	('GDC-0980', 'Chemical', 'MESH:C569670', (25, 33))
186653	25950487	In this study, we demonstrate that shortcut escape into autophagy is one way to improve therapeutic efficiency of PI3K/mTOR inhibition in MPM.	('PI3', 'Gene', (114, 117))	('autophagy', 'biological_process', 'GO:0016236', ('56', '65'))	('PI3K', 'molecular_function', 'GO:0016303', ('114', '118'))	('autophagy', 'CPA', (56, 65))	('autophagy', 'biological_process', 'GO:0006914', ('56', '65'))	('PI3', 'Gene', '5266', (114, 117))	('inhibition', 'Var', (124, 134))	('improve', 'PosReg', (80, 87))	('MPM', 'Disease', (138, 141))
186655	25950487	For example, breast cancer cell lines resistant to NVP-BEZ235 have increased JAK2/STAT5 activation resulting from IL-8 secretion.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('JAK2', 'Gene', '3717', (77, 81))	('IL-8', 'molecular_function', 'GO:0005153', ('114', '118'))	('IL-8', 'Gene', (114, 118))	('NVP-BEZ235', 'Var', (51, 61))	('JAK2', 'Gene', (77, 81))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('STAT5', 'Gene', '6776', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('IL-8 secretion', 'biological_process', 'GO:0072606', ('114', '128'))	('breast cancer', 'Disease', (13, 26))	('secretion', 'MPA', (119, 128))	('JAK', 'molecular_function', 'GO:0004713', ('77', '80'))	('increased', 'PosReg', (67, 76))	('STAT5', 'Gene', (82, 87))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (51, 61))	('IL-8', 'Gene', '3576', (114, 118))
186656	25950487	Along these lines, combined treatment with GDC-0980 together with a c-Met inhibitor efficiently inhibited mesothelioma tumor growth in vivo.	('mesothelioma tumor', 'Disease', 'MESH:D008654', (106, 124))	('GDC-0980', 'Var', (43, 51))	('c-Met', 'Gene', '4233', (68, 73))	('GDC-0980', 'Chemical', 'MESH:C569670', (43, 51))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (106, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('inhibited', 'NegReg', (96, 105))	('c-Met', 'Gene', (68, 73))	('mesothelioma tumor', 'Disease', (106, 124))
186661	25950487	NVP-BEZ235 was shown to induce upregulation and/or activation of several prosurvival proteins such as RTK, cytosolic kinases, antiapoptotic proteins and transcription factors mostly by cap-independent translation.	('NVP-BEZ235', 'Var', (0, 10))	('RTK', 'MPA', (102, 105))	('translation', 'biological_process', 'GO:0006412', ('201', '212'))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (0, 10))	('cytosolic', 'Enzyme', (107, 116))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('activation', 'PosReg', (51, 61))	('upregulation', 'PosReg', (31, 43))
186662	25950487	Levels of XIAP were upregulated by GDC-0980 in Mero-82 resistant but not in SPC212 sensitive cells.	('SPC212', 'CellLine', 'CVCL:D312', (76, 82))	('upregulated', 'PosReg', (20, 31))	('GDC-0980', 'Var', (35, 43))	('Mero-82', 'Chemical', '-', (47, 54))	('SPC', 'molecular_function', 'GO:0009004', ('76', '79'))	('GDC-0980', 'Chemical', 'MESH:C569670', (35, 43))	('Levels of XIAP', 'MPA', (0, 14))
186665	25950487	Indeed, mTORC2 was more efficiently inhibited by GDC-0980 compared with NVP-BEZ235, resulting in inhibition of AKT activation.	('AKT', 'Gene', '207', (111, 114))	('inhibited', 'NegReg', (36, 45))	('mTORC2', 'Gene', '74343', (8, 14))	('inhibition', 'NegReg', (97, 107))	('GDC-0980', 'Var', (49, 57))	('AKT', 'Gene', (111, 114))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (72, 82))	('mTORC2', 'cellular_component', 'GO:0031932', ('8', '14'))	('GDC-0980', 'Chemical', 'MESH:C569670', (49, 57))	('mTORC2', 'Gene', (8, 14))
186675	25950487	The likelihood of this scenario is suggested by recent data showing that XIAP inhibits TNF- and RIP3-dependent cell death and by our observation that XIAP was not efficiently downregulated upon combined drug treatment in Mero-82 compared with SPC212 cells The results observed were consistent in the 2D and 3D models.	('SPC212', 'CellLine', 'CVCL:D312', (243, 249))	('cell death', 'biological_process', 'GO:0008219', ('111', '121'))	('TNF-', 'Gene', (87, 91))	('Mero-82', 'Chemical', '-', (221, 228))	('RIP3', 'Gene', '11035', (96, 100))	('SPC', 'molecular_function', 'GO:0009004', ('243', '246'))	('RIP3', 'Gene', (96, 100))	('inhibits', 'NegReg', (78, 86))	('XIAP', 'Var', (73, 77))
186680	25950487	Inhibition of cancer cells' intrinsic autophagy by silencing Atg5 decreases B16-F10 tumor growth.	('cancer', 'Disease', (14, 20))	('silencing', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('decreases', 'NegReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('intrinsic autophagy', 'CPA', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', (84, 89))	('Atg5', 'Gene', '9474', (61, 65))	('autophagy', 'biological_process', 'GO:0016236', ('38', '47'))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('Atg5', 'Gene', (61, 65))	('autophagy', 'biological_process', 'GO:0006914', ('38', '47'))
186683	25950487	Knocking out essential autophagy genes in genetically engineered mouse models for cancer have demonstrated a pro-tumorigenic role for autophagy.	('autophagy', 'biological_process', 'GO:0006914', ('134', '143'))	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mouse', 'Species', '10090', (65, 70))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('autophagy', 'biological_process', 'GO:0016236', ('134', '143'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('autophagy', 'biological_process', 'GO:0016236', ('23', '32'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('autophagy', 'CPA', (134, 143))	('Knocking out', 'Var', (0, 12))	('autophagy', 'biological_process', 'GO:0006914', ('23', '32'))
186708	25950487	9452), rabbit-Phospho-4E-BP1 (Thr37/46) (236B4, no.	('236B4', 'Var', (41, 46))	('4E-BP1', 'Gene', '1978', (22, 28))	('4E-BP1', 'Gene', (22, 28))	('rabbit', 'Species', '9986', (7, 13))
186762	25952930	In particular this drug to inhibits the phosphorylation of ERM in their critical sites (Thr567 on ezrin; Thr564 on radixin and Thr558 on moesin).	('Thr567', 'Var', (88, 94))	('inhibits', 'NegReg', (27, 35))	('Thr558', 'Chemical', '-', (127, 133))	('Thr558', 'Var', (127, 133))	('ezrin', 'Gene', (98, 103))	('moesin', 'Gene', '4478', (137, 143))	('ezrin', 'Gene', '7430', (98, 103))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Thr567', 'Chemical', '-', (88, 94))	('moesin', 'Gene', (137, 143))	('Thr564', 'Var', (105, 111))	('phosphorylation', 'MPA', (40, 55))	('Thr564', 'Chemical', '-', (105, 111))	('ERM', 'Protein', (59, 62))
186806	25952930	To further elucidate the role of ERM proteins in MPM cells, we down-regulated the expression of its principal component, ezrin, by transducing H226 and MSTO-H211 with specific siRNA.	('expression', 'MPA', (82, 92))	('H226', 'Var', (143, 147))	('MSTO-H211', 'Gene', (152, 161))	('down-regulated', 'NegReg', (63, 77))	('ezrin', 'Gene', (121, 126))	('ezrin', 'Gene', '7430', (121, 126))	('transducing', 'Reg', (131, 142))
186826	25952930	We quantified ROS production by the use of a specific probe (MitoSOX ), demonstrating by confocal analysis that the percentage of positive cells dramatically increased in sorafenib (31.33 +- 4.3%) and combination-treated cells (55.98 +- 6.1%) in comparison with everolimus- treated cells (19.05 +- 2.7%) and untreated controls (16.22% +- 2.1%).	('increased', 'PosReg', (158, 167))	('ROS', 'Chemical', '-', (14, 17))	('combination-treated', 'Var', (201, 220))	('sorafenib', 'Chemical', 'MESH:D000077157', (171, 180))	('everolimus', 'Chemical', 'MESH:D000068338', (262, 272))
186850	25952930	We further report that the phosphorylation of mTOR is not a consequence of the occurrence of somatic mutations in upstream mediators, e.g., PIK3CA, KRAS, BRAF and EGFR.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('KRAS', 'Gene', (148, 152))	('PIK3CA', 'Gene', (140, 146))	('mutations', 'Var', (101, 110))	('mTOR', 'Gene', '2475', (46, 50))	('BRAF', 'Gene', '673', (154, 158))	('KRAS', 'Gene', '3845', (148, 152))	('mTOR', 'Gene', (46, 50))	('PIK3CA', 'Gene', '5290', (140, 146))	('EGFR', 'Gene', '1956', (163, 167))	('BRAF', 'Gene', (154, 158))	('EGFR', 'Gene', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))
186894	22831987	Inhibition of VEGF signaling decreases proliferation of mesothelioma cell lines in preclinical models.	('Inhibition of VEGF signaling', 'biological_process', 'GO:1900747', ('0', '28'))	('VEGF', 'Gene', '7422', (14, 18))	('mesothelioma', 'Disease', (56, 68))	('proliferation', 'CPA', (39, 52))	('decreases', 'NegReg', (29, 38))	('Inhibition', 'Var', (0, 10))	('VEGF', 'Gene', (14, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
186950	22831987	There was a trend for improved median overall survival in those patients with epithelial histology compared to all other histologies (6.6 vs. 4.4 months, p=0.15).	('improved', 'PosReg', (22, 30))	('overall survival', 'MPA', (38, 54))	('epithelial histology', 'Var', (78, 98))	('patients', 'Species', '9606', (64, 72))
186959	22831987	Inhibition of VEGF signaling decreases nitric oxide production, which causes vasoconstriction, decreased sodium ion renal excretion, and resultant hypertension.	('hypertension', 'Disease', 'MESH:D006973', (147, 159))	('hypertension', 'Disease', (147, 159))	('decreases', 'NegReg', (29, 38))	('hypertension', 'Phenotype', 'HP:0000822', (147, 159))	('causes', 'Reg', (70, 76))	('nitric oxide production', 'MPA', (39, 62))	('decreased', 'NegReg', (95, 104))	('vasoconstriction', 'biological_process', 'GO:0042310', ('77', '93'))	('decreased sodium', 'Phenotype', 'HP:0002902', (95, 111))	('sodium', 'Chemical', 'MESH:D012964', (105, 111))	('Inhibition', 'Var', (0, 10))	('excretion', 'biological_process', 'GO:0007588', ('122', '131'))	('vasoconstriction', 'MPA', (77, 93))	('renal excretion', 'Disease', (116, 131))	('Inhibition of VEGF signaling', 'biological_process', 'GO:1900747', ('0', '28'))	('VEGF', 'Gene', '7422', (14, 18))	('nitric oxide', 'Chemical', 'MESH:D009569', (39, 51))	('renal excretion', 'Disease', 'MESH:D007674', (116, 131))	('VEGF', 'Gene', (14, 18))
186976	25361002	Both PEITC and cisplatin were cytotoxic on MPM cells in a dose dependent manner.	('cytotoxic', 'CPA', (30, 39))	('cisplatin', 'Var', (15, 24))	('PEITC', 'Chemical', 'MESH:C058305', (5, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))
187013	25361002	In the presence of NAC, ROS generation and cell cytotoxicity were decreased, strongly suggesting the causative link between ROS generation and PEITC-induced cell death.	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('ROS generation', 'biological_process', 'GO:1903409', ('24', '38'))	('decreased', 'NegReg', (66, 75))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('NAC', 'cellular_component', 'GO:0005854', ('19', '22'))	('NAC', 'Var', (19, 22))	('PEITC', 'Chemical', 'MESH:C058305', (143, 148))	('cytotoxicity', 'Disease', (48, 60))	('NAC', 'Chemical', '-', (19, 22))	('ROS generation', 'biological_process', 'GO:1903409', ('124', '138'))	('ROS generation', 'CPA', (24, 38))
187014	25361002	As a control, H2O2 was shown to induce apoptosis and ROS production in MPM cells.	('apoptosis', 'CPA', (39, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('ROS', 'Chemical', 'MESH:D017382', (53, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('induce', 'PosReg', (32, 38))	('H2O2', 'Chemical', 'MESH:D006861', (14, 18))	('H2O2', 'Var', (14, 18))	('ROS production', 'MPA', (53, 67))
187023	25361002	As a control, H2O2 induced ROS production and MPM cell death.	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('cell death', 'biological_process', 'GO:0008219', ('50', '60'))	('ROS production', 'MPA', (27, 41))	('MPM cell death', 'CPA', (46, 60))	('H2O2', 'Chemical', 'MESH:D006861', (14, 18))	('H2O2', 'Var', (14, 18))
187028	25361002	While no DNA damage was observed in MPM cells after cisplatin treatment alone, combination of cisplatin with PEITC strongly enhanced P-H2A.X signal.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('P-H2A.X signal', 'MPA', (133, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('enhanced', 'PosReg', (124, 132))	('PEITC', 'Chemical', 'MESH:C058305', (109, 114))	('combination', 'Interaction', (79, 90))	('cisplatin', 'Var', (94, 103))
187038	25361002	For both cell lines, PEITC and cisplatin increase cell death compared to untreated cells.	('cell death', 'CPA', (50, 60))	('cell death', 'biological_process', 'GO:0008219', ('50', '60'))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('PEITC', 'Chemical', 'MESH:C058305', (21, 26))	('cisplatin', 'Var', (31, 40))
187087	25361002	Therefore, we hypothesized that by combining cisplatin with PEITC, both BER and NER pathways would be activated.	('BER', 'biological_process', 'GO:0006284', ('72', '75'))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('activated', 'PosReg', (102, 111))	('PEITC', 'Chemical', 'MESH:C058305', (60, 65))	('NER', 'biological_process', 'GO:0006289', ('80', '83'))	('cisplatin', 'Var', (45, 54))
187094	25361002	These changes lead to a higher level of ROS in malignant cells compared to healthy cells, which contribute to promote oncogenic properties such as generation of resistant cells to conventional therapies but also to sensitize cells to strong oxidative stress.	('oncogenic', 'MPA', (118, 127))	('ROS', 'MPA', (40, 43))	('changes', 'Var', (6, 13))	('oxidative stress', 'Phenotype', 'HP:0025464', (241, 257))	('promote', 'PosReg', (110, 117))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))
187101	25361002	Moreover, although the strongest concentration of PEITC (6muM) combined to cisplatin led to a higher sensitivity of PMC to the combination, we showed that cisplatin combined to PEITC at 4muM was toxic on MPM cells while remaining safe for PMC.	('PEITC', 'Chemical', 'MESH:C058305', (177, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('PEITC', 'Chemical', 'MESH:C058305', (50, 55))	('sensitivity', 'MPA', (101, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('cisplatin', 'Var', (155, 164))
187186	25141917	The most common chromosomal change in human MM is homozygous deletion of the p16INK4A/p14ARF locus which occurs in 50-70% of human mesothelioma samples and in up to 90% of stable MM cell lines.	('p14ARF', 'Gene', '1029', (86, 92))	('human', 'Species', '9606', (38, 43))	('deletion', 'Var', (61, 69))	('p16INK4A', 'Gene', (77, 85))	('human', 'Species', '9606', (125, 130))	('p14ARF', 'Gene', (86, 92))	('mesothelioma', 'Disease', (131, 143))	('p16INK4A', 'Gene', '1029', (77, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (131, 143))
187189	25141917	Homozygous deletion of Cdkn2a/2b along with a co-deletion of Mtap at 5q32 was identified in both the parental and combination resistant II-45 cells (supplementary Figure 3) providing chromosomal evidence for the relevance of these models to the human malignancy.	('Cdkn2a/2b', 'Gene', (23, 32))	('Mtap', 'Gene', (61, 65))	('malignancy', 'Disease', (251, 261))	('Mtap', 'Gene', '4507', (61, 65))	('human', 'Species', '9606', (245, 250))	('deletion', 'Var', (11, 19))	('malignancy', 'Disease', 'MESH:D009369', (251, 261))
187190	25141917	Alterations at Nf2, Tp53, Bap1 or Egfr are also noted in subsets of MM cases.	('Nf2', 'Gene', '25744', (15, 18))	('Tp53', 'Gene', (20, 24))	('Nf2', 'Gene', (15, 18))	('Egfr', 'molecular_function', 'GO:0005006', ('34', '38'))	('Alterations', 'Var', (0, 11))	('Tp53', 'Gene', '24842', (20, 24))	('Bap1', 'Gene', '306257', (26, 30))	('rat', 'Species', '10116', (4, 7))	('Egfr', 'Gene', (34, 38))	('Egfr', 'Gene', '24329', (34, 38))	('Bap1', 'Gene', (26, 30))
187229	25141917	Total neutrophil counts were significantly decreased in rats with gemcitabine resistant and vinorelbine resistant II-45 cells (p < 0.01) while NLR was significantly decreased only in rats with gemcitabine resistant II-45 cells (p < 0.01).	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('rats', 'Species', '10116', (183, 187))	('NLR', 'MPA', (143, 146))	('rats', 'Species', '10116', (56, 60))	('vinorelbine', 'Chemical', 'MESH:D000077235', (92, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (193, 204))	('decreased', 'NegReg', (43, 52))	('gemcitabine', 'Var', (66, 77))
187234	25141917	In addition to our models developing clinically relevant levels of chemo-resistance, they were also found to contain similar gene changes and chromosomal abnormalities as those found in human mesothelioma samples with increased expression of many ABC transporter proteins and homozygous deletion of the p16INK4A/p14ARF locus, thus highlighting the biological and clinical relevance of our models to the human malignancy.	('ABC transporter', 'molecular_function', 'GO:0140359', ('247', '262'))	('malignancy', 'Disease', (409, 419))	('mesothelioma', 'Disease', (192, 204))	('p16INK4A', 'Gene', '1029', (303, 311))	('mesothelioma', 'Disease', 'MESH:D008654', (192, 204))	('malignancy', 'Disease', 'MESH:D009369', (409, 419))	('p14ARF', 'Gene', (312, 318))	('deletion', 'Var', (287, 295))	('increased', 'PosReg', (218, 227))	('chromosomal abnormalities', 'Disease', (142, 167))	('human', 'Species', '9606', (403, 408))	('human', 'Species', '9606', (186, 191))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (142, 167))	('p14ARF', 'Gene', '1029', (312, 318))	('ABC transporter', 'Gene', (247, 262))	('p16INK4A', 'Gene', (303, 311))	('expression', 'MPA', (228, 238))
187238	25141917	who suggested high expression of podoplanin as a prognostic marker of decreased survival in human mesothelioma.	('podoplanin', 'Protein', (33, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (98, 110))	('survival', 'MPA', (80, 88))	('decreased', 'NegReg', (70, 79))	('high', 'Var', (14, 18))	('human', 'Species', '9606', (92, 97))	('mesothelioma', 'Disease', (98, 110))
187300	24743707	Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.	('enhanced', 'PosReg', (106, 114))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('anti-CD26', 'Var', (89, 98))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('patients', 'Species', '9606', (268, 276))
187306	24743707	CD26 is a 110-kDa, type II transmembrane glycoprotein with known dipeptidyl peptidase IV (DPPIV) (DPPIV, EC 3.4.14.5) activity in its extracellular domain and is capable of cleaving N-terminal dipeptides with either L-proline or L-alanine at the penultimate position.	('cleaving N-terminal dipeptides', 'MPA', (173, 203))	('dipeptidyl peptidase IV', 'molecular_function', 'GO:0004274', ('65', '88'))	('L-alanine', 'Var', (229, 238))	('dipeptides', 'Chemical', 'MESH:D004151', (193, 203))	('DPPIV', 'Gene', '1803', (98, 103))	('dipeptidyl peptidase IV', 'Gene', (65, 88))	('L-alanine', 'Chemical', 'MESH:D000409', (229, 238))	('CD26', 'Gene', (0, 4))	('transmembrane', 'cellular_component', 'GO:0044214', ('27', '40'))	('extracellular', 'cellular_component', 'GO:0005576', ('134', '147'))	('L-proline', 'Chemical', 'MESH:D011392', (216, 225))	('DPPIV', 'Gene', (90, 95))	('DPPIV', 'Gene', '1803', (90, 95))	('transmembrane', 'cellular_component', 'GO:0016021', ('27', '40'))	('DPPIV', 'Gene', (98, 103))	('dipeptidyl peptidase IV', 'Gene', '1803', (65, 88))
187309	24743707	Moreover, CD26 itself appears to be a novel therapeutic target, and anti-CD26 monoclonal antibody (mAb) treatment resulted in both in vitro and in vivo anti-tumour activity against several tumour types, including lymphoma and renal cell carcinoma.	('lymphoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (213, 246))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (226, 246))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('anti-CD26', 'Gene', (68, 77))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('anti-CD26', 'Var', (68, 77))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('lymphoma', 'Phenotype', 'HP:0002665', (213, 221))	('tumour', 'Disease', (157, 163))	('tumour', 'Disease', (189, 195))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
187311	24743707	Previously, humanised anti-CD26 antibody inhibited growth of MPM cells and induced long-term survival of tumour-transplanted SCID mice.	('antibody', 'cellular_component', 'GO:0042571', ('32', '40'))	('mice', 'Species', '10090', (130, 134))	('anti-CD26', 'Var', (22, 31))	('growth', 'CPA', (51, 57))	('tumour-transplanted SCID', 'Disease', 'MESH:D053632', (105, 129))	('antibody', 'cellular_component', 'GO:0019815', ('32', '40'))	('long-term survival', 'CPA', (83, 101))	('antibody', 'cellular_component', 'GO:0019814', ('32', '40'))	('induced', 'PosReg', (75, 82))	('antibody', 'molecular_function', 'GO:0003823', ('32', '40'))	('inhibited', 'NegReg', (41, 50))	('human', 'Species', '9606', (12, 17))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour-transplanted SCID', 'Disease', (105, 129))
187314	24743707	More recently, we showed that nuclear localisation of CD26 molecules induced by anti-CD26 mAbs inhibited cell proliferation by modulating POLR2A transcription in MPM cells.	('anti-CD26', 'Var', (80, 89))	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('modulating', 'Reg', (127, 137))	('nuclear localisation', 'MPA', (30, 50))	('anti-CD26', 'Gene', (80, 89))	('POLR2A', 'Gene', (138, 144))	('inhibited', 'NegReg', (95, 104))	('transcription', 'MPA', (145, 158))	('POLR2A', 'Gene', '5430', (138, 144))	('localisation', 'biological_process', 'GO:0051179', ('38', '50'))	('CD26 molecules', 'Protein', (54, 68))	('cell proliferation', 'CPA', (105, 123))
187329	24743707	Two days after transfection of CD26WT, CD26/10Chi or mock plasmids, the cells were selected for G418 (500 mug ml-1) (Sigma-Aldrich, St Louis, MO, USA) resistance for 4 weeks.	('G418', 'Var', (96, 100))	('mug', 'molecular_function', 'GO:0043739', ('106', '109'))	('CD26WT', 'Gene', (31, 37))	('CD26WT', 'Gene', '1803', (31, 37))
187330	24743707	Single clone cells expressing CD26WT (MSTO-CD26WT), CD26/10Chi (MSTO-CD26/10Chi), or mock (MSTO-Mock) were then selected using a standard limiting dilution method.	('MSTO', 'Chemical', '-', (64, 68))	('CD26WT', 'Gene', (30, 36))	('MSTO', 'Chemical', '-', (91, 95))	('MSTO', 'Chemical', '-', (38, 42))	('CD26/10Chi', 'Var', (52, 62))	('CD26WT', 'Gene', (43, 49))	('CD26WT', 'Gene', '1803', (43, 49))	('CD26WT', 'Gene', '1803', (30, 36))
187382	24743707	To define the crucial role of the CD26 cytoplasmic region in regulating migratory, invasive or proliferative activity of MPM cells, we used a mutant construct of CD26 in which its cytoplasmic region was replaced with that of human CD10 (CD26-CD10 chimaeric receptor), which was shown to abrogate CD26-mediated costimulation in T cells.	('CD26-CD10 chimaeric receptor', 'Gene', (237, 265))	('CD26-CD10 chimaeric receptor', 'Gene', '1803', (237, 265))	('CD10', 'molecular_function', 'GO:0004245', ('242', '246'))	('cytoplasmic region', 'cellular_component', 'GO:0099568', ('39', '57'))	('CD10', 'Gene', (242, 246))	('CD10', 'Gene', (231, 235))	('mutant', 'Var', (142, 148))	('CD10', 'molecular_function', 'GO:0004245', ('231', '235'))	('CD10', 'Gene', '4311', (242, 246))	('CD10', 'Gene', '4311', (231, 235))	('human', 'Species', '9606', (225, 230))	('cytoplasmic region', 'cellular_component', 'GO:0099568', ('180', '198'))	('CD26', 'Gene', (162, 166))	('migratory', 'CPA', (72, 81))
187394	24743707	To determine whether these proteins are present in MPM cells, we conducted a conventional western blotting analysis using total cell lysates of MSTO-Mock, MSTO-CD26WT or MSTO-CD26/10Chi.	('MSTO-CD26/10Chi', 'Var', (170, 185))	('MSTO', 'Chemical', '-', (144, 148))	('CD26WT', 'Gene', '1803', (160, 166))	('MSTO', 'Chemical', '-', (155, 159))	('CD26WT', 'Gene', (160, 166))	('MSTO', 'Chemical', '-', (170, 174))
187400	24743707	Expression of CD26 or SSTR4 was determined by western blotting analysis of cell lysates of MSTO-Mock, MSTO-CD26WT or MSTO-CD26/10Chi in the presence of control siRNA or two different sequences of SSTR4-siRNAs (si-1 or si-2) (Supplementary Figure S2A).	('si-1', 'Var', (210, 214))	('MSTO', 'Chemical', '-', (102, 106))	('MSTO', 'Chemical', '-', (91, 95))	('CD26WT', 'Gene', (107, 113))	('CD26WT', 'Gene', '1803', (107, 113))	('si-2', 'Var', (218, 222))	('MSTO', 'Chemical', '-', (117, 121))
187405	24743707	To exclude the possibility of serum-derived SSTR4 agonistic effect, we established various MPM cell lines that have been adapted to the serum-reduced condition, and conducted cell migration, invasion and colony formation assays in the presence or absence of the specific SSTR4 agonist L803087.	('invasion', 'CPA', (191, 199))	('L803087', 'Chemical', 'MESH:C429628', (285, 292))	('formation', 'biological_process', 'GO:0009058', ('211', '220'))	('L803087', 'Var', (285, 292))	('cell migration', 'biological_process', 'GO:0016477', ('175', '189'))	('colony formation assays', 'CPA', (204, 227))	('SSTR4', 'Gene', (271, 276))	('cell migration', 'CPA', (175, 189))
187406	24743707	As shown in Figure 3B, levels of cell migration, invasion and colony formation were observed to be equal among MSTO-Mock, MSTO-CD26WT or MSTO-CD26/10Chi (NS at points of medium alone in panels a-c), suggesting that the influence of serum on these cell lines was minimised by the serum-reduced condition.	('colony formation', 'CPA', (62, 78))	('MSTO', 'Chemical', '-', (137, 141))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('MSTO', 'Chemical', '-', (122, 126))	('CD26WT', 'Gene', (127, 133))	('CD26WT', 'Gene', '1803', (127, 133))	('cell migration', 'biological_process', 'GO:0016477', ('33', '47'))	('invasion', 'CPA', (49, 57))	('MSTO-CD26/10Chi', 'Var', (137, 152))	('MSTO', 'Chemical', '-', (111, 115))	('cell migration', 'CPA', (33, 47))
187409	24743707	Expression of CD26 or SSTR4 was determined by western blotting analysis of cell lysates of JMN or MESO1 cell lines in the presence of control siRNA (csi) or two different sequences of CD26-siRNAs (si-1 or si-2) (Supplementary Figure S2C).	('si-2', 'Var', (205, 209))	('MN', 'CellLine', 'CVCL:U508', (92, 94))	('MES', 'Chemical', 'MESH:C004550', (98, 101))	('si-1', 'Var', (197, 201))
187410	24743707	Following knockdown of endogenous CD26, inhibition of migration, invasion and colony formation of JMN cells by SSTR4 agonist in a serum-reduced condition was observed in a dose-dependent manner of L803087 (P<0.0001, panels a-c of Figure 3C).	('colony formation of JMN cells', 'CPA', (78, 107))	('L803087', 'Chemical', 'MESH:C429628', (197, 204))	('inhibition', 'NegReg', (40, 50))	('migration', 'CPA', (54, 63))	('CD26', 'Gene', (34, 38))	('L803087', 'Var', (197, 204))	('invasion', 'CPA', (65, 73))	('MN', 'CellLine', 'CVCL:U508', (99, 101))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('SSTR4', 'Gene', (111, 116))
187411	24743707	Similarly, following knockdown of endogenous CD26 in MESO1 cells adapted to a serum-reduced condition, inhibition of migration, invasion and colony formation by SSTR4 agonist was also observed in a dose-dependent manner of L803087 (P<0.0001, panels a-c of Figure 3D).	('colony formation', 'CPA', (141, 157))	('L803087', 'Chemical', 'MESH:C429628', (223, 230))	('MES', 'Chemical', 'MESH:C004550', (53, 56))	('migration', 'CPA', (117, 126))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('SSTR4', 'Gene', (161, 166))	('L803087', 'Var', (223, 230))	('CD26', 'Gene', (45, 49))	('invasion', 'CPA', (128, 136))	('inhibition', 'NegReg', (103, 113))
187419	24743707	As further support for this conclusion, we next conducted knockdown experiments using siRNAs against SHP-2 in MSTO-Mock cells.	('siRNAs', 'Var', (86, 92))	('SHP-2', 'Gene', '5781', (101, 106))	('SHP-2', 'Gene', (101, 106))	('MSTO', 'Chemical', '-', (110, 114))
187428	24743707	As shown in Figure 5A, humanised anti-CD26 mAb treatment resulted in increased levels of CD26, SSTR4 and SHP-2 molecules in lipid raft fractions (upper three of right panels) while a non-lipid raft anchored protein, transferrin receptor (TfR), was not aggregated in lipid raft fractions (bottom panels).	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('increased', 'PosReg', (69, 78))	('anti-CD26', 'Gene', (33, 42))	('TfR', 'Gene', '7037', (238, 241))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('lipid', 'Chemical', 'MESH:D008055', (187, 192))	('SHP-2', 'Gene', (105, 110))	('lipid', 'Chemical', 'MESH:D008055', (266, 271))	('anti-CD26', 'Var', (33, 42))	('levels', 'MPA', (79, 85))	('lipid raft', 'cellular_component', 'GO:0045121', ('266', '276'))	('transferrin receptor', 'Gene', '7037', (216, 236))	('lipid raft', 'cellular_component', 'GO:0045121', ('124', '134'))	('human', 'Species', '9606', (23, 28))	('CD26', 'MPA', (89, 93))	('lipid raft', 'cellular_component', 'GO:0045121', ('187', '197'))	('TfR', 'Gene', (238, 241))	('transferrin receptor', 'Gene', (216, 236))	('SHP-2', 'Gene', '5781', (105, 110))	('SSTR4', 'Gene', (95, 100))
187431	24743707	These results suggest that SSTR4 and CD26 are associated in lipid rafts, and that anti-CD26 mAb ligates CD26 to cause the release of SSTR4 from CD26 and the clustering of SSTR4 in lipid rafts, hence providing a platform for signalling events associated with multimerisation of SSTR4 molecules, such as SHP-2 activation.	('clustering', 'MPA', (157, 167))	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('anti-CD26', 'Var', (82, 91))	('SSTR4', 'Gene', (171, 176))	('SHP-2', 'Gene', (302, 307))	('SHP-2', 'Gene', '5781', (302, 307))	('release', 'MPA', (122, 129))	('lipid', 'Chemical', 'MESH:D008055', (180, 185))	('CD26', 'Gene', (104, 108))	('ligates', 'Var', (96, 103))	('signalling', 'biological_process', 'GO:0023052', ('224', '234'))	('CD26', 'MPA', (144, 148))	('SSTR4', 'MPA', (133, 138))
187434	24743707	These results indicate that the effect of humanised anti-CD26 mAb on anti-tumour activity is enhanced by SSTR4-mediated activation of SHP-2, which is induced by lipid raft clustering.	('lipid', 'Chemical', 'MESH:D008055', (161, 166))	('SSTR4-mediated', 'Gene', (105, 119))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('human', 'Species', '9606', (42, 47))	('tumour', 'Disease', (74, 80))	('activation', 'PosReg', (120, 130))	('SHP-2', 'Gene', '5781', (134, 139))	('lipid raft', 'cellular_component', 'GO:0045121', ('161', '171'))	('enhanced', 'PosReg', (93, 101))	('anti-CD26', 'Var', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('SHP-2', 'Gene', (134, 139))
187435	24743707	To further validate our in vitro observations regarding the enhancing effect of humanised anti-CD26 mAb treatment on SSTR4-mediated anti-tumour effect, we conducted in vivo experiments using SCID mice transplanted with MPM cells.	('SCID', 'Disease', 'MESH:D053632', (191, 195))	('mice', 'Species', '10090', (196, 200))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Disease', (137, 143))	('human', 'Species', '9606', (80, 85))	('SCID', 'Disease', (191, 195))	('anti-CD26', 'Var', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
187436	24743707	As shown in Figure 6A and B, humanised anti-CD26 mAb reduced the tumorigenicity of s.c. inoculated JMN (blue line, P<0.0001), while this anti-tumour effect was not observed in mice treated with the SSTR4 agonist L803087 alone (green or yellow lines).	('tumour', 'Disease', (142, 148))	('tumorigenicity', 'CPA', (65, 79))	('anti-CD26', 'Var', (39, 48))	('MN', 'CellLine', 'CVCL:U508', (100, 102))	('reduced', 'NegReg', (53, 60))	('mice', 'Species', '10090', (176, 180))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('L803087', 'Chemical', 'MESH:C429628', (212, 219))	('human', 'Species', '9606', (29, 34))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
187437	24743707	This in vivo anti-tumour effect was enhanced with the combined administration of humanised anti-CD26 mAb and SSTR4 agonist (red line in Figure 6A, P<0.0001, and Figure 6B).	('anti-CD26', 'Var', (91, 100))	('SSTR4', 'Gene', (109, 114))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('combined', 'Interaction', (54, 62))	('enhanced', 'PosReg', (36, 44))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('human', 'Species', '9606', (81, 86))	('tumour', 'Disease', (18, 24))
187438	24743707	As shown in Figure 6C, humanised anti-CD26 mAb reduced the tumorigenicity of i.p.	('anti-CD26', 'Var', (33, 42))	('reduced', 'NegReg', (47, 54))	('human', 'Species', '9606', (23, 28))
187440	24743707	This in vivo anti-tumour effect was enhanced with the combined administration of humanised anti-CD26 mAb and SSTR4 agonist (red line in Figure 6C, P<0.0001).	('anti-CD26', 'Var', (91, 100))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('enhanced', 'PosReg', (36, 44))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('human', 'Species', '9606', (81, 86))	('tumour', 'Disease', (18, 24))
187441	24743707	Taken together with results of the in vitro experiments presented in Figure 5C; Supplementary Figure S4A and B, our work illustrates the potency of the anti-tumour effect of the combination of humanised anti-CD26 mAb and the SSTR4 agonist on CD26-expressing MPM cells.	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('combination', 'Interaction', (178, 189))	('anti-CD26', 'Var', (203, 212))	('tumour', 'Disease', (157, 163))	('human', 'Species', '9606', (193, 198))
187445	24743707	Furthermore, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of humanised anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment.	('enhanced', 'PosReg', (120, 128))	('human', 'Species', '9606', (93, 98))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('anti-CD26', 'Var', (103, 112))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))
187447	24743707	We previously showed that anti-CD26 mAb inhibited growth of MPM cells and induced long-term survival of tumour-transplanted SCID mice.	('tumour-transplanted SCID', 'Disease', 'MESH:D053632', (104, 128))	('long-term survival', 'CPA', (82, 100))	('inhibited', 'NegReg', (40, 49))	('anti-CD26', 'Var', (26, 35))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('growth', 'CPA', (50, 56))	('tumour-transplanted SCID', 'Disease', (104, 128))	('mice', 'Species', '10090', (129, 133))	('induced', 'PosReg', (74, 81))
187457	24743707	Although these anti-tumour effects were blocked by coexpression of CD26, ligation of CD26 molecules by humanised anti-CD26 mAb induced lipid raft aggregation, leading to the activation of the cytostatic signalling molecule SHP-2 via clustering of SSTR4, which provides a platform for signalling events associated with multimerisation of SSTR4 molecules.	('lipid raft aggregation', 'MPA', (135, 157))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('CD26', 'Gene', (85, 89))	('lipid raft', 'cellular_component', 'GO:0045121', ('135', '145'))	('clustering', 'MPA', (233, 243))	('SHP-2', 'Gene', (223, 228))	('signalling', 'biological_process', 'GO:0023052', ('203', '213'))	('human', 'Species', '9606', (103, 108))	('cytostatic signalling molecule', 'MPA', (192, 222))	('anti-CD26', 'Var', (113, 122))	('induced', 'Reg', (127, 134))	('ligation', 'Var', (73, 81))	('signalling', 'biological_process', 'GO:0023052', ('284', '294'))	('SSTR4', 'Gene', (247, 252))	('lipid', 'Chemical', 'MESH:D008055', (135, 140))	('activation', 'PosReg', (174, 184))	('SHP-2', 'Gene', '5781', (223, 228))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
187462	24743707	These data support our previous findings that anti-CD26 mAb treatment induces upregulation of these CDKIs in T cells, renal carcinoma and MPM cells.	('renal carcinoma', 'Disease', (118, 133))	('renal carcinoma', 'Phenotype', 'HP:0005584', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('CDKIs', 'Protein', (100, 105))	('upregulation', 'PosReg', (78, 90))	('renal carcinoma', 'Disease', 'MESH:C538614', (118, 133))	('anti-CD26', 'Var', (46, 55))
187469	24743707	Taken together with the current in vitro observations, these results suggest that a novel therapeutic approach combining anti-CD26 mAb and an SSTR4 agonist may be of clinical benefit in selected patients with MPM, a notion that will be explored in future investigations.	('benefit', 'PosReg', (175, 182))	('clinical', 'Species', '191496', (166, 174))	('MPM', 'Disease', (209, 212))	('patients', 'Species', '9606', (195, 203))	('anti-CD26', 'Var', (121, 130))
187470	24743707	Humanised anti-CD26 mAb induces SSTR4 aggregation in lipid rafts and potentiates its cytostatic and anti-tumour effects.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('Human', 'Species', '9606', (0, 5))	('SSTR4', 'Gene', (32, 37))	('tumour', 'Disease', (105, 111))	('induces', 'Reg', (24, 31))	('anti-CD26', 'Var', (10, 19))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('aggregation in lipid rafts', 'MPA', (38, 64))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('potentiates', 'PosReg', (69, 80))
187471	24743707	As SSTR4 and CD26 are found to coexpress in surgically resected specimens of human MPM, combination therapy using humanised anti-CD26 mAb and an SSTR4 agonist may provide clinical benefits in MPM.	('combination', 'Interaction', (88, 99))	('MPM', 'Disease', (192, 195))	('human', 'Species', '9606', (114, 119))	('clinical', 'Species', '191496', (171, 179))	('anti-CD26', 'Var', (124, 133))	('human', 'Species', '9606', (77, 82))
187608	33490725	They found that OS and cancer-specific survival were higher with SIB if the gross tumor volume based on PET volume was not greater than 205 cc.	('higher', 'PosReg', (53, 59))	('SIB', 'Var', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (82, 87))
187609	33490725	Although PET-based volumes have limited spatial resolution and are unlikely to be feasible for the majority of MPcM, emerging technologies such as 4D-MRI and MRI-guided linear accelerators may be able to provide more precise target delineation and localization, allowing for further dose escalation, as is currently being investigated in locally advanced pancreatic adenocarcinoma (NCT03621644).	('pancreatic adenocarcinoma', 'Disease', (355, 380))	('NCT03621644', 'Var', (382, 393))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (355, 380))	('localization', 'biological_process', 'GO:0051179', ('248', '260'))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (355, 380))
187624	32276524	About 60% of MPM patients carry mutations in the BRCA1 associated protein-1 (BAP1) gene.	('BRCA1 associated protein-1', 'Gene', '8314', (49, 75))	('MPM', 'Disease', (13, 16))	('BRCA1 associated protein-1', 'Gene', (49, 75))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (32, 41))	('MPM', 'Chemical', '-', (13, 16))	('patients', 'Species', '9606', (17, 25))	('BAP1', 'Gene', (77, 81))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
187626	32276524	BAP1 mutational status is clearly associated with the insurgence of MPM, the response to chemotherapy, patient survival, and, when coupled to other DNA repair gene alterations, it has suggested synthetic lethality therapeutic approaches.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('associated', 'Reg', (34, 44))	('BAP1', 'Gene', (0, 4))	('MPM', 'Chemical', '-', (68, 71))	('DNA repair', 'biological_process', 'GO:0006281', ('148', '158'))	('MPM', 'Disease', (68, 71))	('mutational status', 'Var', (5, 22))	('patient', 'Species', '9606', (103, 110))	('BAP1', 'Gene', '8314', (0, 4))
187634	32276524	Recently, PD-L1 expression in malignant mesothelioma has been assessed on tissue microarrays using two different FDA-approved antibodies, and 22% to 27% of cases were positive for PD-L1 (1% cut off).	('malignant mesothelioma', 'Disease', 'MESH:C562839', (30, 52))	('positive', 'Reg', (167, 175))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (30, 52))	('malignant mesothelioma', 'Disease', (30, 52))	('PD-L1', 'Gene', (10, 15))	('expression', 'Species', '29278', (16, 26))	('PD-L1', 'Var', (180, 185))
187635	32276524	PD-L1 is expressed by a substantial proportion of biphasic and sarcomatoid MPM cases, and its positivity above 1% is associated with a significant 10-months reduction in median OS compared to PD-L1 negative tumors.	('biphasic', 'Disease', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcomatoid MPM', 'Disease', 'MESH:C538614', (63, 78))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('reduction', 'NegReg', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('sarcomatoid MPM', 'Disease', (63, 78))	('positivity', 'Var', (94, 104))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('median OS', 'MPA', (170, 179))
187660	32276524	In a murine model of MPM, the abscopal effect can be induced by local RT and enhanced by immune-suppressive CTLA-4 blockade as infiltrated T-cells, both in primary and secondary tumor sites, are predominantly composed by anti-tumor cytotoxic CD8+ T-cells, while immunosuppressive regulatory T-cell (Tregs) are reduced.	('enhanced', 'PosReg', (77, 85))	('tumor', 'Disease', (178, 183))	('CTLA-4', 'Gene', (108, 114))	('MPM', 'Chemical', '-', (21, 24))	('murine', 'Species', '10090', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('MPM', 'Disease', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('abscopal', 'Disease', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CD8', 'Gene', '925', (242, 245))	('blockade', 'Var', (115, 123))	('Tregs', 'Chemical', '-', (299, 304))	('CD8', 'Gene', (242, 245))	('tumor', 'Disease', (226, 231))
187671	32276524	Importantly, its prognostic value is independent of tumor-node-metastasis (TNM) staging in most malignancies, suggesting TLS can induce a systemic, long-lasting anti-tumor response.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (166, 171))	('malignancies', 'Disease', (96, 108))	('TLS', 'Var', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
187677	32276524	Tumor-resident Tregs co-express high levels of CTLA-4, OX-40, and GITR compared to effector T-cells, and in murine models of mesothelioma, the combination of anti-OX-40 and anti-CTLA-4 has a synergistic effect and results into a 20% to 80% increase in tumor regression as compared to single-antibody treatment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GITR', 'Gene', '21936', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('antibody', 'molecular_function', 'GO:0003823', ('291', '299'))	('antibody', 'cellular_component', 'GO:0042571', ('291', '299'))	('OX-40', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('GITR', 'Gene', (66, 70))	('anti-CTLA-4', 'Var', (173, 184))	('OX-40', 'Gene', '22163', (55, 60))	('antibody', 'cellular_component', 'GO:0019815', ('291', '299'))	('murine', 'Species', '10090', (108, 114))	('Tregs', 'Chemical', '-', (15, 20))	('OX-40', 'Gene', (163, 168))	('increase', 'PosReg', (240, 248))	('OX-40', 'Gene', '22163', (163, 168))	('antibody', 'cellular_component', 'GO:0019814', ('291', '299'))	('mesothelioma', 'Disease', (125, 137))	('tumor', 'Disease', (252, 257))	('mesothelioma', 'Disease', 'MESH:D008654', (125, 137))
187705	32276524	Next-generation sequencing applied to tumor cells is a powerful tool to identify and quantify expressed neoantigens as mutations/fusions or as alternative splicing variants.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('splicing', 'biological_process', 'GO:0045292', ('155', '163'))	('mutations/fusions', 'Var', (119, 136))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
187707	32276524	In lung cancer patients, for example, the abundance of alternative splicing variants correlates with the longest OS, suggesting that variants can be displayed and targeted by adaptive immunity.	('longest OS', 'Disease', (105, 115))	('patients', 'Species', '9606', (15, 23))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('alternative splicing variants', 'Var', (55, 84))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
187708	32276524	Altered sequences generated by improper splicing or mutations can be expressed and used to generate human antibodies specific to these moieties.	('mutations', 'Var', (52, 61))	('improper', 'Var', (31, 39))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('human', 'Species', '9606', (100, 105))
187743	32276524	Additionally, treatment with the ICI ipilimumab in combination with anti-TGF-beta and anti-CD25 antibodies of syngeneic MPM in BALB/c mice resulted in (i) disease eradication in all treated animals, (ii) elevated levels of tumor-specific IgG antibodies in cured mice, (iii) failure to regrow tumors in cured mice when re-challenged with the same tumor, and (iv) response abolition in the absence of B-cells, suggesting that antibodies generated upon treatment contribute significantly to the curative effect.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('mice', 'Species', '10090', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('TGF-beta', 'Gene', '21802', (73, 81))	('IgG', 'Protein', (238, 241))	('failure to regrow', 'Phenotype', 'HP:0001508', (274, 291))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('CD25', 'Gene', (91, 95))	('tumors', 'Disease', (292, 298))	('CD25', 'Gene', '16184', (91, 95))	('eradication', 'NegReg', (163, 174))	('antibodies', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Disease', (223, 228))	('TGF-beta', 'Gene', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('ipilimumab', 'Chemical', 'MESH:D000074324', (37, 47))	('IgG antibodies', 'Phenotype', 'HP:0003237', (238, 252))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (292, 297))	('mice', 'Species', '10090', (262, 266))	('absence of B-cells', 'Phenotype', 'HP:0005365', (388, 406))	('mice', 'Species', '10090', (308, 312))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('MPM', 'Chemical', '-', (120, 123))	('tumor', 'Disease', (346, 351))
187769	32156681	More recently, somatic or germline mutations of BAP1 (BRCA1-associated protein 1) gene have been described as predisposing factor for MPM.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('BAP1', 'Gene', '8314', (48, 52))	('germline mutations', 'Var', (26, 44))	('BAP1', 'Gene', (48, 52))	('MPM', 'Disease', 'MESH:C562839', (134, 137))	('MPM', 'Disease', (134, 137))	('BRCA1-associated protein 1', 'Gene', '8314', (54, 80))	('BRCA1-associated protein 1', 'Gene', (54, 80))
187809	32156681	Moving forward from single agent checkpoint blockade, ongoing combination strategies include combination of PD-1/PD-L1 antibodies with chemotherapy, anti CTLA-4, or targeted therapy such as FAK (Focal Adhesion Kinase) or AXL inhibitors and antiangiogenic drugs.	('combination', 'Interaction', (93, 104))	('Focal Adhesion Kinase', 'Gene', '5747', (195, 216))	('FAK', 'Gene', (190, 193))	('FAK', 'Gene', '5747', (190, 193))	('antibodies', 'Var', (119, 129))	('AXL', 'Gene', (221, 224))	('Focal Adhesion', 'cellular_component', 'GO:0005925', ('195', '209'))	('PD-L1', 'Gene', (113, 118))	('CTLA-4', 'Gene', '1493', (154, 160))	('Focal Adhesion Kinase', 'Gene', (195, 216))	('PD-1', 'Gene', (108, 112))	('FAK', 'molecular_function', 'GO:0004717', ('190', '193'))	('PD-1', 'Gene', '5133', (108, 112))	('PD-L1', 'Gene', '29126', (113, 118))	('CTLA-4', 'Gene', (154, 160))	('AXL', 'Gene', '558', (221, 224))
187815	32156681	Furthermore, the genomic landscape is dominated by inactivation of several tumour suppressors genes.	('inactivation', 'Var', (51, 63))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
187816	32156681	In particular, mutations of CDKN2A, BAP1 and NF2 are three of the most frequent genomic alterations detected, for which novel drugs are under investigation.	('NF2', 'Gene', (45, 48))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (36, 40))	('NF2', 'Gene', '4771', (45, 48))	('CDKN2A', 'Gene', (28, 34))	('BAP1', 'Gene', (36, 40))	('CDKN2A', 'Gene', '1029', (28, 34))
187949	29046510	Based on the results of our 13-week inhalation toxicity study, male and female F344 rats, 6-week-old at the commencement of exposure, were exposed to MWNT-7 at concentrations of 0, 0.02, 0.2, and 2 mg/m3 for 6 h/d, 5 d/wk and 104 weeks.	('inhalation toxicity', 'Disease', (36, 55))	('0.02', 'Var', (181, 185))	('MWNT-7', 'Gene', (150, 156))	('rat', 'Species', '10116', (84, 87))	('inhalation toxicity', 'Disease', 'MESH:D058545', (36, 55))	('rat', 'Species', '10116', (167, 170))	('MWNT-7', 'Chemical', '-', (150, 156))	('rats', 'Species', '10116', (84, 88))
187960	29046510	Notably, the MWNT-7-induced bronchiolo-alveolar carcinomas were often accompanied by proliferative fibrous connective tissue, which was not present in the spontaneous bronchiolo-alveolar carcinoma that developed in the control rat.	('rat', 'Species', '10116', (227, 230))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('accompanied', 'Reg', (70, 81))	('alveolar carcinoma', 'Disease', 'MESH:D002282', (39, 57))	('alveolar carcinoma', 'Phenotype', 'HP:0006519', (178, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('alveolar carcinomas', 'Phenotype', 'HP:0006519', (39, 58))	('rat', 'Species', '10116', (92, 95))	('MWNT-7-induced', 'Var', (13, 27))	('alveolar carcinoma', 'Disease', 'MESH:D002282', (178, 196))	('bronchiolo-alveolar carcinomas', 'Disease', (28, 58))	('alveolar carcinoma', 'Disease', (178, 196))	('proliferative', 'CPA', (85, 98))	('MWNT-7', 'Chemical', '-', (13, 19))	('alveolar carcinoma', 'Phenotype', 'HP:0006519', (39, 57))	('bronchiolo-alveolar carcinomas', 'Disease', 'MESH:D002282', (28, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
187974	29046510	This supports the possibility that inhaled MWNT-7 could also be carcinogenic in mice, if the mice are exposed to MWNT-7 for a longer duration.	('carcinogenic', 'Disease', 'MESH:D063646', (64, 76))	('carcinogenic', 'Disease', (64, 76))	('rat', 'Species', '10116', (135, 138))	('MWNT-7', 'Chemical', '-', (43, 49))	('mice', 'Species', '10090', (93, 97))	('MWNT-7', 'Chemical', '-', (113, 119))	('mice', 'Species', '10090', (80, 84))	('MWNT-7', 'Var', (43, 49))
188026	29046510	examined potency of mesothelioma induction by 4 different MWCNT fibers using intraperitoneal injection with 1x109 or 5x109 WHO carbon nanotubes in Wistar rats.	('MWCNT', 'Chemical', '-', (58, 63))	('mesothelioma', 'Disease', (20, 32))	('carbon', 'Chemical', 'MESH:D002244', (127, 133))	('5x109', 'Var', (117, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('Wistar rats', 'Species', '10116', (147, 158))
188112	29046510	In rats, MWNT-7 induced lung carcinomas, but not in mice, although it promoted MCA-initiated lung carcinogenesis.	('MWNT-7', 'Chemical', '-', (9, 15))	('lung carcinomas', 'Disease', (24, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('MCA-initiated lung carcinogenesis', 'Disease', 'MESH:D063646', (79, 112))	('rats', 'Species', '10116', (3, 7))	('mice', 'Species', '10090', (52, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('MCA-initiated lung carcinogenesis', 'Disease', (79, 112))	('MWNT-7', 'Var', (9, 15))	('promoted', 'PosReg', (70, 78))	('lung carcinomas', 'Disease', 'MESH:D008175', (24, 39))
188113	29046510	It is possible that if the mice were exposed to a higher concentration of MWNT-7 or exposed for a longer period of time, MWNT-7 alone may have induced lung carcinomas in the mice.	('MWNT-7', 'Chemical', '-', (121, 127))	('lung carcinomas', 'Disease', (151, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('mice', 'Species', '10090', (174, 178))	('MWNT-7', 'Var', (121, 127))	('mice', 'Species', '10090', (27, 31))	('lung carcinomas', 'Disease', 'MESH:D008175', (151, 166))	('rat', 'Species', '10116', (64, 67))	('induced', 'Reg', (143, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('MWNT-7', 'Chemical', '-', (74, 80))
188114	29046510	Inhalation exposure to MWNT-7 induced lung carcinoma but not pleural mesothelioma in rats, however, MWCNT-N administered by intratracheal instillation induced not only lung carcinoma but also pleural mesothelioma in rats.	('rats', 'Species', '10116', (85, 89))	('MWCNT-N', 'Var', (100, 107))	('pleural mesothelioma', 'Disease', (61, 81))	('rat', 'Species', '10116', (127, 130))	('lung carcinoma', 'Disease', 'MESH:D008175', (168, 182))	('rats', 'Species', '10116', (216, 220))	('rat', 'Species', '10116', (85, 88))	('induced', 'Reg', (151, 158))	('pleural mesothelioma', 'Disease', (192, 212))	('lung carcinoma', 'Disease', 'MESH:D008175', (38, 52))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (61, 81))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('MWNT-7', 'Chemical', '-', (23, 29))	('lung carcinoma', 'Disease', (168, 182))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (192, 212))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (192, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('lung carcinoma', 'Disease', (38, 52))	('rat', 'Species', '10116', (216, 219))	('MWCNT-N', 'Chemical', '-', (100, 107))
188128	29046510	Introduction of large amount of fibers into the lung at the beginning of the experiment also allows for a longer period of time for higher numbers of fibers to be translocated into the pleural cavity and exert a carcinogenic effect on the mesothelium.	('fibers', 'Var', (150, 156))	('pleural', 'Disease', 'MESH:D010995', (185, 192))	('carcinogenic', 'Disease', 'MESH:D063646', (212, 224))	('carcinogenic', 'Disease', (212, 224))	('pleural', 'Disease', (185, 192))	('exert', 'Reg', (204, 209))
188147	29046510	The large MWCNT-N, but not the small MWCNT-N translocated into the pleural cavity, deposited in the parietal pleura, and induced fibrosis and patchy parietal mesothelial cell proliferation.	('patchy parietal mesothelial cell proliferation', 'CPA', (142, 188))	('parietal pleura', 'Disease', (100, 115))	('MWCNT-N', 'Var', (10, 17))	('parietal pleura', 'Disease', 'MESH:D054363', (100, 115))	('MWCNT-N', 'Chemical', '-', (37, 44))	('fibrosis', 'Disease', 'MESH:D005355', (129, 137))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('rat', 'Species', '10116', (182, 185))	('pleural', 'Disease', 'MESH:D010995', (67, 74))	('MWCNT-N', 'Chemical', '-', (10, 17))	('pleural', 'Disease', (67, 74))	('fibrosis', 'Disease', (129, 137))	('induced', 'Reg', (121, 128))
188162	29046510	This agrees with the premise that large amounts of MWCNTs are needed to exert a carcinogenic effect in rodents, and that the number of MWNT-7 fibers that were translocated to the peritoneal cavity, especially when compared to the total area of the serosal surface in the peritoneal cavity, were far below the threshold required to induce a mesothelial hyperplastic response.	('MWCNTs', 'Chemical', '-', (51, 57))	('MWNT-7', 'Chemical', '-', (135, 141))	('translocated', 'Var', (159, 171))	('carcinogenic', 'Disease', 'MESH:D063646', (80, 92))	('MWNT-7', 'Gene', (135, 141))	('carcinogenic', 'Disease', (80, 92))
188221	29046510	reported that MWNT-7 was negative for mutagenicity at the hgprt locus of a mammalian cell line, a CHL/IU derived sub-clone, indicating that MWNT-7 is not a direct DNA mutagen.	('MWNT-7', 'Var', (140, 146))	('MWNT-7', 'Chemical', '-', (14, 20))	('CHL', 'Disease', (98, 101))	('mammalian', 'Species', '9606', (75, 84))	('MWNT-7', 'Chemical', '-', (140, 146))	('CHL', 'Disease', 'MESH:D006689', (98, 101))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))
188229	29046510	report that intratracheal instillation of MWNT-7 in mice increased gpt mutant frequencies, DNA damage by comet assay, and DNA oxidative damage.	('DNA', 'CPA', (91, 94))	('oxidative damage', 'MPA', (126, 142))	('comet assay', 'MPA', (105, 116))	('rat', 'Species', '10116', (15, 18))	('gpt', 'Gene', (67, 70))	('mice', 'Species', '10090', (52, 56))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('mutant', 'Var', (71, 77))	('increased', 'PosReg', (57, 66))	('comet', 'Species', '302767', (105, 110))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('gpt', 'molecular_function', 'GO:0004021', ('67', '70'))	('MWNT-7', 'Chemical', '-', (42, 48))
188239	29046510	In our separate 4-week inhalation study, we found an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in the lungs of rats exposed to MWNT-7 (unpublished data), demonstrating a genotoxic mechanism that could contribute to the development of rat lung carcinogenesis.	('formation', 'MPA', (102, 111))	('MWNT-7', 'Var', (144, 150))	('lung carcinogenesis', 'Disease', (255, 274))	('8-OHdG', 'Chemical', 'MESH:C067134', (94, 100))	('contribute', 'Reg', (218, 228))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (255, 274))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('increase', 'PosReg', (53, 61))	('rats', 'Species', '10116', (128, 132))	('MWNT-7', 'Chemical', '-', (144, 150))	('rat', 'Species', '10116', (178, 181))	('rat', 'Species', '10116', (251, 254))	("8-hydroxy-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (65, 92))	('rat', 'Species', '10116', (11, 14))	('rat', 'Species', '10116', (128, 131))	("8-hydroxy-2'-deoxyguanosine", 'MPA', (65, 92))
188244	29046510	These biopersistent fibers could then lead to phagocytosis, persistent generation of oxidants and cytokines, and chronic inflammation, as discussed above, producing a microenvironment that supports generation of DNA mutations, including the survival and proliferation of cells harboring these mutations, and ultimately leading to development of mesothelioma.	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('DNA', 'Gene', (212, 215))	('rat', 'Species', '10116', (75, 78))	('inflammation', 'Disease', (121, 133))	('mutations', 'Var', (293, 302))	('phagocytosis', 'biological_process', 'GO:0006909', ('46', '58'))	('mesothelioma', 'Disease', (345, 357))	('leading to', 'Reg', (319, 329))	('inflammation', 'biological_process', 'GO:0006954', ('121', '133'))	('lead to', 'Reg', (38, 45))	('rat', 'Species', '10116', (202, 205))	('rat', 'Species', '10116', (261, 264))	('mesothelioma', 'Disease', 'MESH:D008654', (345, 357))	('iron', 'Chemical', 'MESH:D007501', (175, 179))
188254	29046510	In conclusion, MWNT-7 was classified as possibly carcinogenic to humans (Group 2B).	('carcinogenic', 'Disease', 'MESH:D063646', (49, 61))	('carcinogenic', 'Disease', (49, 61))	('MWNT-7', 'Chemical', '-', (15, 21))	('MWNT-7', 'Var', (15, 21))	('humans', 'Species', '9606', (65, 71))
188264	29046510	MeIQx is carcinogenic for the rat liver and is a direct mutagen.	('carcinogenic', 'Disease', (9, 21))	('MeIQx', 'Var', (0, 5))	('rat', 'Species', '10116', (30, 33))	('MeIQx', 'Chemical', 'MESH:C036990', (0, 5))	('carcinogenic', 'Disease', 'MESH:D063646', (9, 21))
188266	29046510	Starting at very low doses, levels of MeIQx-DNA adducts increased, then formation of 8-OHdG, which is a maker of oxidative stress, lacI gene mutations and initiation activity began to increase, and this was followed by the development of glutathione S-transferase placental form (GST-P) positive foci, which is a preneoplastic lesion and a marker of rat hepatocarcinogenicity.	('positive', 'Reg', (287, 295))	('lacI', 'Gene', (131, 135))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (316, 333))	('lacI', 'Gene', '29436', (131, 135))	('mutations', 'Var', (141, 150))	('hepatocarcinogenic', 'Disease', (354, 372))	('increase', 'PosReg', (184, 192))	('8-OHdG', 'Chemical', 'MESH:C067134', (85, 91))	('glutathione S-transferase placental form (GST-P', 'Gene', '24426', (238, 285))	('rat', 'Species', '10116', (350, 353))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('preneoplastic lesion', 'Disease', (313, 333))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('MeIQx', 'Chemical', 'MESH:C036990', (38, 43))	('preneoplastic lesion', 'Disease', 'MESH:D011230', (313, 333))	('hepatocarcinogenic', 'Disease', 'MESH:D008113', (354, 372))	('oxidative stress', 'Phenotype', 'HP:0025464', (113, 129))
188441	22500091	(3) Cleavage of prointerleukin (IL)-1beta to an active form for release to form fibrotic nodules.	('prointerleukin (IL)-1beta', 'Gene', '3553', (16, 41))	('Cleavage', 'Var', (4, 12))	('prointerleukin (IL)-1beta', 'Gene', (16, 41))	('IL)-1', 'molecular_function', 'GO:0005149', ('32', '37'))
188473	22500091	Production of the Th1 type CXCR3 ligand CXCL10/IP10 was also significantly reduced in sublines compared with the original line.	('IP10', 'Gene', (47, 51))	('Th1', 'Gene', (18, 21))	('IP10', 'Gene', '3627', (47, 51))	('CXCL10', 'Gene', '3627', (40, 46))	('CXCL10', 'Gene', (40, 46))	('reduced', 'NegReg', (75, 82))	('ligand', 'molecular_function', 'GO:0005488', ('33', '39'))	('CXCR3', 'Gene', (27, 32))	('sublines', 'Var', (86, 94))	('Th1', 'Gene', '51497', (18, 21))	('CXCR3', 'Gene', '2833', (27, 32))
188496	22500091	In addition, the molecular events regarding carcinogenesis found in mesothelioma cells include (1) homogenous deletion of p16INK4a/p19ARF found in more than 90% of cases, (2) inactivation of neurofibromatosis 2 (NF2)/Merlin found in approximately half of the cases, (3) inactivation of the serine/threonine-protein kinase (LATS2) gene in approximately one-third of mesothelioma cell lines and representinga candidate for a novel tumor suppressor in MM, and (4) transcription factor, Yes-associated protein (YAP) involved in the NF2/Merlin-hippo signaling pathway and constitutively dephosphorylated by LATS, and usually acting as an oncogene to bind with the TEAD transcription factor to enhance the cell cycle and resistance to apoptosis.	('mesothelioma', 'Disease', (68, 80))	('resistance to apoptosis', 'CPA', (715, 738))	('p19ARF', 'Gene', '1029', (131, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (191, 208))	('p19ARF', 'Gene', (131, 137))	('Merlin', 'Gene', (532, 538))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('429', '445'))	('Merlin', 'Gene', '4771', (217, 223))	('enhance', 'PosReg', (688, 695))	('cell cycle', 'biological_process', 'GO:0007049', ('700', '710'))	('Yes-associated protein', 'Gene', (483, 505))	('deletion', 'Var', (110, 118))	('YAP', 'Gene', (507, 510))	('hippo signaling pathway', 'biological_process', 'GO:0035329', ('539', '562'))	('transcription', 'biological_process', 'GO:0006351', ('461', '474'))	('bind', 'Interaction', (645, 649))	('transcription', 'biological_process', 'GO:0006351', ('664', '677'))	('transcription factor', 'molecular_function', 'GO:0000981', ('664', '684'))	('protein', 'cellular_component', 'GO:0003675', ('498', '505'))	('carcinogenesis', 'Disease', (44, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('429', '445'))	('cell cycle', 'CPA', (700, 710))	('NF2', 'Gene', '4771', (212, 215))	('neurofibromatosis 2', 'Gene', (191, 210))	('LATS2', 'Gene', (323, 328))	('LATS2', 'Gene', '26524', (323, 328))	('protein', 'cellular_component', 'GO:0003675', ('307', '314'))	('NF2', 'Gene', (212, 215))	('tumor', 'Disease', (429, 434))	('NF2', 'Gene', '4771', (528, 531))	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('YAP', 'Gene', '10413', (507, 510))	('Merlin', 'Gene', '4771', (532, 538))	('p16INK4a', 'Gene', (122, 130))	('Merlin', 'Gene', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (429, 434))	('mesothelioma', 'Disease', (365, 377))	('NF2', 'Gene', (528, 531))	('inactivation', 'Var', (270, 282))	('Yes-associated protein', 'Gene', '10413', (483, 505))	('transcription factor', 'molecular_function', 'GO:0000981', ('461', '481'))	('mesothelioma', 'Disease', 'MESH:D008654', (365, 377))	('apoptosis', 'biological_process', 'GO:0097194', ('729', '738'))	('p16INK4a', 'Gene', '1029', (122, 130))	('p19', 'cellular_component', 'GO:0070743', ('131', '134'))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))	('apoptosis', 'biological_process', 'GO:0006915', ('729', '738'))	('neurofibromatosis 2', 'Gene', '4771', (191, 210))
188503	32169873	The relapse biopsy had missense mutation in BTN2A1.	('BTN2A1', 'Gene', (44, 50))	('BTN2A1', 'Gene', '11120', (44, 50))	('missense mutation', 'Var', (23, 40))
188532	32169873	The relapse biopsy had missense mutation in BTN2A1 (c.1352G>C).	('c.1352G>C', 'Mutation', 'rs3734543', (52, 61))	('c.1352G>C', 'Var', (52, 61))	('BTN2A1', 'Gene', '11120', (44, 50))	('missense mutation', 'Var', (23, 40))	('BTN2A1', 'Gene', (44, 50))
188586	27129173	Among the new hallmarks identified during the last decade, deregulation of cellular energetics, such as local hyperinsulinism, has also been identified to lead to the development of preneoplastic lesions, while other reports have demonstrated links between glucose metabolism and epigenetic regulator function.	('deregulation', 'Var', (59, 71))	('local hyperinsulinism', 'Disease', 'MESH:D006946', (104, 125))	('lead to', 'Reg', (155, 162))	('glucose metabolism', 'biological_process', 'GO:0006006', ('257', '275'))	('rat', 'Species', '10116', (237, 240))	('cellular energetics', 'MPA', (75, 94))	('local hyperinsulinism', 'Disease', (104, 125))	('preneoplastic lesions', 'CPA', (182, 203))	('glucose', 'Chemical', 'MESH:D005947', (257, 264))
188587	27129173	The last decade has also been characterized by a considerable improvement in our understanding of the consequences of epigenomic disruption on the genesis of cancer.	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epigenomic disruption', 'Var', (118, 139))
188590	27129173	Recent reports have suggested that TET2 could be the major function affected in myeloid disorders and that loss of TET2 catalytic function might promote leukemogenesis.	('myeloid disorders', 'Disease', 'MESH:D007951', (80, 97))	('loss', 'Var', (107, 111))	('TET2', 'Gene', (115, 119))	('leukemogenesis', 'Disease', (153, 167))	('myeloid disorders', 'Disease', (80, 97))	('promote', 'PosReg', (145, 152))	('catalytic function', 'MPA', (120, 138))
188594	27129173	Subsequently, the role of polycomb proteins as epigenetic silencers was shown in preneoplastic states in the pancreas of mice and rats, while other epigenetic alterations were documented during early stages of hepatocarcinogenesis in rats.	('rat', 'Species', '10116', (163, 166))	('polycomb', 'Gene', (26, 34))	('rats', 'Species', '10116', (130, 134))	('rats', 'Species', '10116', (234, 238))	('preneoplastic states', 'CPA', (81, 101))	('pancreas', 'Disease', 'MESH:D010190', (109, 117))	('hepatocarcinogenesis', 'Disease', (210, 230))	('polycomb', 'Gene', '12416', (26, 34))	('epigenetic', 'Var', (47, 57))	('mice', 'Species', '10090', (121, 125))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (234, 237))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (210, 230))	('pancreas', 'Disease', (109, 117))
188611	27129173	Among the preneoplastic cell lines with epithelial morphology, a first subgroup (named subnormal, "Subnl") was identified by the highest expression of c-Myc, a proto-oncogene gene the deregulation of which contributes to deregulated DNA synthesis and genomic instability, and the lowest expression of Igf1, a gene involved in the deregulation of cellular energetics (Figure 4A).	('genomic instability', 'CPA', (251, 270))	('lowest', 'NegReg', (280, 286))	('expression', 'MPA', (137, 147))	('c-Myc', 'Gene', (151, 156))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('231', '244'))	('deregulation', 'Var', (184, 196))	('Igf1', 'Gene', (301, 305))	('deregulated DNA synthesis', 'MPA', (221, 246))	('c-Myc', 'Gene', '24577', (151, 156))	('expression', 'MPA', (287, 297))	('Igf1', 'Gene', '24482', (301, 305))
188619	27129173	Characterization of the four tumor models by immunohistochemical markers revealed that, although the staining was moderate and heterogeneous, all tumor cells exhibited positivity for WT1, a common positive mesothelioma marker (Figure 5A).	('mesothelioma', 'Disease', (206, 218))	('positivity', 'Var', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (146, 151))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('tumor', 'Disease', (29, 34))	('WT1', 'Gene', '24883', (183, 186))	('WT1', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
188622	27129173	The unique structural rearrangement observed in the F3-1 cell line was a der(15)t(1;15)(q?41 ;q2?2), leading to a distal gain of chromosome 1 in 15% of metaphases (Figure S4A, D).	('tap', 'Gene', (154, 157))	('der(15)t(', 'Var', (73, 82))	('gain', 'PosReg', (121, 125))	('tap', 'Gene', '59087', (154, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
188627	27129173	Otherwise, no more metaphases with normal karyotypes were observed and all the chromosomes except chromosomes 7 and 16 were involved in either numerical alterations and/or structural alterations such as translocations and deletions.	('tap', 'Gene', '59087', (21, 24))	('deletions', 'Var', (222, 231))	('rat', 'Species', '10116', (187, 190))	('tap', 'Gene', (21, 24))	('translocations', 'CPA', (203, 217))	('involved', 'Reg', (124, 132))	('rat', 'Species', '10116', (157, 160))
188628	27129173	The major recurrent alteration was deletion of chromosome 5 (82% of all M5-T1 metaphases).	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('tap', 'Gene', '59087', (80, 83))	('deletion', 'Var', (35, 43))	('rat', 'Species', '10116', (24, 27))	('tap', 'Gene', (80, 83))
188638	27129173	Representative images of the M5-T1, F5-T1, F4-T2 and M5-T2 tumors (HPS staining of detailed views in Figure 8A, left column, general views in Figure S6) globally reveal low levels of staining for 5-hmC, which contrasts with the strong nuclear signals observed in the vicinal normal liver tissue (Figure 8A, right column).	('hmC', 'Chemical', 'MESH:C011865', (198, 201))	('F5-T1', 'Var', (36, 41))	('M5-T2 tumors', 'Disease', 'MESH:C535434', (53, 65))	('M5-T2 tumors', 'Disease', (53, 65))	('F4-T2', 'Var', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('staining', 'MPA', (183, 191))	('M5-T1', 'Var', (29, 34))	('HPS', 'Chemical', '-', (67, 70))
188640	27129173	Quantification of the staining intensity for 5-hmC in tumor vs. liver revealed marked differences between the four different tumor types, with M5-T1 exhibiting the highest ratio (Figure 8B).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('M5-T1', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('hmC', 'Chemical', 'MESH:C011865', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rat', 'Species', '10116', (172, 175))	('tumor', 'Disease', (54, 59))
188649	27129173	Investigations on this gene have proven to be a reliable way of separating benign from malignant mesothelial proliferations in tissues, in particular for the sarcomatoid subtype.	('sarcomatoid subtype', 'Disease', 'MESH:C538614', (158, 177))	('Investigations', 'Var', (0, 14))	('sarcomatoid subtype', 'Disease', (158, 177))	('rat', 'Species', '10116', (68, 71))	('rat', 'Species', '10116', (116, 119))
188677	27129173	A recent study confirmed that p16 deletion is a good marker of malignancy, both in pleural and peritoneal mesotheliomas with invasive components.	('peritoneal mesotheliomas', 'Phenotype', 'HP:0100003', (95, 119))	('p16', 'Gene', (30, 33))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('malignancy', 'Disease', (63, 73))	('pleural and peritoneal mesotheliomas', 'Disease', 'MESH:D010997', (83, 119))	('deletion', 'Var', (34, 42))
188679	27129173	The results from our model tend to confirm this fact, as M5-T1 cells exhibited the lowest level of Cdkn2a expression while spectral karyotyping of this cell line revealed a recurrent, large deletion of one rat chromosome 5, including the q32 band, in 82% of metaphases, suggesting at least loss of heterozygosity for Cdkn2a.	('tap', 'Gene', (260, 263))	('deletion', 'Var', (190, 198))	('tap', 'Gene', '59087', (260, 263))	('rat', 'Species', '10116', (206, 209))	('chromosome', 'cellular_component', 'GO:0005694', ('210', '220'))
188690	27129173	The involvement of DNA methylation in EMT has also been documented, hypermethylation of the promoter region being one of the key factors leading to a reduced mRNA expression of Cdh1 during EMT.	('Cdh1', 'Gene', '83502', (177, 181))	('mRNA expression', 'MPA', (158, 173))	('EMT', 'biological_process', 'GO:0001837', ('189', '192'))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('reduced', 'NegReg', (150, 157))	('EMT', 'biological_process', 'GO:0001837', ('38', '41'))	('hypermethylation', 'Var', (68, 84))	('Cdh1', 'Gene', (177, 181))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
188695	27129173	We observed here that the most aggressive MM cell line, M5-T1, showed the lowest expression of TET3, an observation that could be explained by the deletion of the q34-q44 region of chromosome 4, which includes the TET3 gene.	('TET3', 'Gene', (214, 218))	('TET3', 'Gene', '680576', (95, 99))	('lowest', 'NegReg', (74, 80))	('TET3', 'Gene', (95, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('181', '191'))	('deletion', 'Var', (147, 155))	('TET3', 'Gene', '680576', (214, 218))	('expression', 'MPA', (81, 91))
188705	27129173	Finally, evaluation of this biocollection allowed us to suggest that epigenetic alterations, downregulation of TETs and DNMTs and a decrease of 5-hmC in tumor cells are all correlated with the acquisition of an aggressive phenotype, in good agreement with human MM.	('epigenetic alterations', 'Var', (69, 91))	('human', 'Species', '9606', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('rat', 'Species', '10116', (84, 87))	('TETs', 'Chemical', 'MESH:C010349', (111, 115))	('5-hmC', 'MPA', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('DNMT', 'Gene', '1786', (120, 124))	('DNMT', 'Gene', (120, 124))	('TETs', 'Gene', (111, 115))	('downregulation', 'NegReg', (93, 107))	('hmC', 'Chemical', 'MESH:C011865', (146, 149))	('decrease', 'NegReg', (132, 140))
188725	27129173	Antibodies used for immunohistochemical analyses were anti-WT-1 ab15249, anti-calretinin ab16694 and anti-vimentin ab8978 from Abcam, anti ESA/EPCAM (MOC 31) LS-C331328 from LSBio, and anti-5-hmC 39769 (1/200) and anti-5-mC 61255 (1/60) from Active Motif Europe (La Hulpe, Belgium), with an anti-mouse secondary antibody and the N-Histofine Simple Stain Mouse MAX Peroxidase (Nichirei Biosciences, Tokyo, Japan) as the detection reagent.	('Mouse', 'Species', '10090', (354, 359))	('vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('mouse', 'Species', '10090', (296, 301))	('vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('hmC', 'Chemical', 'MESH:C011865', (192, 195))	('antibody', 'cellular_component', 'GO:0042571', ('312', '320'))	('antibody', 'cellular_component', 'GO:0019815', ('312', '320'))	('antibody', 'cellular_component', 'GO:0019814', ('312', '320'))	('5-mC', 'Chemical', '-', (219, 223))	('anti-5-mC 61255', 'Var', (214, 229))	('ab16694', 'Var', (89, 96))	('antibody', 'molecular_function', 'GO:0003823', ('312', '320'))
188741	27129173	Chromosomal gains or structural aberrations had to be detected in at least two metaphases and chromosomal losses in three metaphases to be acknowledged as clonal.	('tap', 'Gene', (81, 84))	('tap', 'Gene', '59087', (124, 127))	('rat', 'Species', '10116', (36, 39))	('tap', 'Gene', '59087', (81, 84))	('chromosomal losses', 'Var', (94, 112))	('tap', 'Gene', (124, 127))	('structural aberrations', 'CPA', (21, 43))
188753	24592197	Moreover, ROS have been shown to cause apoptosis, inflammation, and proliferation.	('cause', 'Reg', (33, 38))	('proliferation', 'CPA', (68, 81))	('apoptosis', 'CPA', (39, 48))	('inflammation', 'Disease', 'MESH:D007249', (50, 62))	('ROS', 'Var', (10, 13))	('inflammation', 'biological_process', 'GO:0006954', ('50', '62'))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('inflammation', 'Disease', (50, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))
188853	15608393	It has been thought that E-cadherin loss or dysfunction, probably resulting from down regulation or mutation of cadherin genes during tumorigenesis, causes loss of cell-to-cell adhesion in carcinoma cell clusters, which leads to increased invasiveness of carcinoma cells.	('invasiveness of carcinoma', 'Disease', (239, 264))	('loss', 'NegReg', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Disease', (255, 264))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('down regulation', 'NegReg', (81, 96))	('loss or dysfunction', 'Disease', 'MESH:D015431', (36, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('loss or dysfunction', 'Disease', (36, 55))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('carcinoma', 'Disease', (189, 198))	('cadherin genes', 'Gene', (112, 126))	('E-cadherin', 'Gene', (25, 35))	('invasiveness of carcinoma', 'Disease', 'MESH:D009361', (239, 264))	('cell-to-cell adhesion', 'CPA', (164, 185))	('E-cadherin', 'Gene', '999', (25, 35))	('tumor', 'Disease', (134, 139))	('carcinoma', 'Disease', 'MESH:D002277', (255, 264))	('cell adhesion', 'biological_process', 'GO:0007155', ('172', '185'))	('increased', 'PosReg', (229, 238))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutation', 'Var', (100, 108))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))
188880	31976036	COMMAND was negative, despite hopes of recapitulating preclinically observed synthetic lethality in the context of NF2 mutation, as well as targeting of the stem cell compartment.	('NF2', 'Gene', (115, 118))	('mutation', 'Var', (119, 127))	('NF2', 'Gene', '4771', (115, 118))
188881	31976036	Merlin is encoded by NF2 which undergoes positive selection in mesothelioma, a gene affected by somatic copy number alterations, fusions and epigenetic suppression.	('NF2', 'Gene', (21, 24))	('mesothelioma', 'Disease', (63, 75))	('NF2', 'Gene', '4771', (21, 24))	('fusions', 'Var', (129, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('Merlin', 'Gene', '4771', (0, 6))	('Merlin', 'Gene', (0, 6))	('epigenetic suppression', 'Var', (141, 163))
188882	31976036	In COMMAND, detection of aberrant Merlin, was therefore determined using immunohistochemistry to minimize false negative stratification that could occur through exclusively genetic screening.	('false', 'biological_process', 'GO:0071877', ('106', '111'))	('aberrant', 'Var', (25, 33))	('Merlin', 'Gene', (34, 40))	('Merlin', 'Gene', '4771', (34, 40))	('false', 'biological_process', 'GO:0071878', ('106', '111'))
188883	31976036	Since the initiation of the COMMAND trial, comprehensive genomic studies have revealed extensive genetic disruption of hippo signaling in mesothelioma involving multiple components of this tumor suppressor pathway.	('tumor', 'Disease', (189, 194))	('genetic disruption', 'Var', (97, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('189', '205'))	('mesothelioma', 'Disease', (138, 150))	('hippo signaling', 'Gene', (119, 134))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('189', '205'))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hippo signaling', 'biological_process', 'GO:0035329', ('119', '134'))
188885	31976036	These genetic alterations involve, in addition to NF2, LATS2 (a positively selected gene), MST1, LATS1, SAV1, and RASSFA1, all capable of phenocopying loss of NF2- summarized in figure 1.	('alterations', 'Var', (14, 25))	('NF2', 'Gene', '4771', (50, 53))	('LATS1', 'Gene', '9113', (97, 102))	('LATS2', 'Gene', (55, 60))	('NF2', 'Gene', (159, 162))	('MST1', 'Gene', '4485', (91, 95))	('NF2', 'Gene', '4771', (159, 162))	('NF2', 'Gene', (50, 53))	('SAV1', 'Gene', '60485', (104, 108))	('MST1', 'Gene', (91, 95))	('loss', 'NegReg', (151, 155))	('SAV1', 'Gene', (104, 108))	('LATS2', 'Gene', '26524', (55, 60))	('LATS1', 'Gene', (97, 102))
188892	31976036	Inhibiting FAK drives a CD8 host response with evidence of reduced Tregs both preclinically and clinically.	('reduced', 'NegReg', (59, 66))	('Inhibiting', 'Var', (0, 10))	('FAK', 'molecular_function', 'GO:0004717', ('11', '14'))	('FAK', 'Gene', (11, 14))	('FAK', 'Gene', '5747', (11, 14))	('CD8', 'Gene', (24, 27))	('CD8', 'Gene', '925', (24, 27))	('Tregs', 'CPA', (67, 72))
189068	30542213	One of the samples without zeolite (080604-04) was from weathered surficial material, and another (080604-05) was a lithic fragment.	('080604-05', 'Var', (99, 108))	('zeolite', 'Chemical', 'MESH:D017641', (27, 34))	('080604-04', 'Var', (36, 45))
189101	28476017	NCI-H28 [H28], ACC-MESO-1 [MESO-1], and ACC-MESO-4 [MESO-4]), and exhibited synergistic effects with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in H28 cells and interferon-gamma in hepatoma cell lines.	('interferon-gamma', 'molecular_function', 'GO:0005133', ('182', '198'))	('interferon-gamma', 'Gene', '3458', (182, 198))	('necrosis', 'biological_process', 'GO:0008220', ('107', '115'))	('ligand', 'molecular_function', 'GO:0005488', ('150', '156'))	('NCI-H28', 'Var', (0, 7))	('necrosis', 'biological_process', 'GO:0070265', ('107', '115'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('101', '122'))	('necrosis', 'biological_process', 'GO:0019835', ('107', '115'))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (101, 156))	('necrosis', 'biological_process', 'GO:0001906', ('107', '115'))	('TRAIL', 'Gene', '8743', (158, 163))	('hepatoma', 'Disease', (202, 210))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('necrosis', 'biological_process', 'GO:0008219', ('107', '115'))	('TRAIL', 'Gene', (158, 163))	('interferon-gamma', 'Gene', (182, 198))	('hepatoma', 'Disease', 'MESH:D006528', (202, 210))
189122	28476017	After 72 h of treatment, the percentage of annexin V-positive cells was 27.3%, 38.7%, and 44.3% in cells treated with pemetrexed, cisplatin, and cSBL, respectively, and 44.8%, 47.3%, and 46.0% in cells treated with pemetrexed + cisplatin, pemetrexed + cSBL, and cisplatin + cSBL, respectively (Figure 3).	('pemetrexed', 'Chemical', 'MESH:D000068437', (118, 128))	('pemetrexed', 'Chemical', 'MESH:D000068437', (215, 225))	('cisplatin', 'Chemical', 'MESH:D002945', (262, 271))	('pemetrexed', 'Chemical', 'MESH:D000068437', (239, 249))	('cisplatin', 'Var', (130, 139))	('cSBL', 'Chemical', '-', (145, 149))	('cSBL', 'Chemical', '-', (274, 278))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('annexin V', 'Gene', '308', (43, 52))	('cSBL', 'Chemical', '-', (252, 256))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('annexin V', 'Gene', (43, 52))	('pemetrexed', 'Var', (118, 128))
189131	28476017	The total number of cells decreased by 10.4%, 14.2%, and 32.7% in cells treated with pemetrexed, cisplatin, and cSBL, respectively, for 72 h compared to control (PBS-treated) cells (Figure 5A).	('pemetrexed', 'Chemical', 'MESH:D000068437', (85, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cSBL', 'Chemical', '-', (112, 116))	('PBS', 'Chemical', 'MESH:D007854', (162, 165))	('decreased', 'NegReg', (26, 35))	('cisplatin', 'Var', (97, 106))
189139	28476017	Cyclin A and B1 levels significantly decreased in cisplatin-treated cells, while p21Waf1/Cip1 levels increased.	('p21Waf1/Cip1', 'Gene', (81, 93))	('Cyclin A', 'Gene', '890', (0, 8))	('increased', 'PosReg', (101, 110))	('p21Waf1/Cip1', 'Gene', '1026', (81, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('Cyclin A', 'Gene', (0, 8))	('cisplatin-treated', 'Var', (50, 67))	('decreased', 'NegReg', (37, 46))
189255	19139719	FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37).	('PAX5', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCLC tumor', 'Disease', 'MESH:D018288', (78, 88))	('SCLC tumor', 'Disease', (78, 88))	('polyploidy', 'Var', (59, 69))
189259	19139719	Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used.	('decreased', 'NegReg', (38, 47))	('SU11274', 'Chemical', 'MESH:C478479', (115, 122))	('SCLC', 'Gene', (65, 69))	('SCLC', 'Gene', '7864', (65, 69))	('PAX5', 'Protein', (19, 23))	('combined', 'Interaction', (93, 101))	('SN38', 'Var', (107, 111))	('Loss', 'NegReg', (0, 4))	('SU11274', 'Var', (115, 122))	('SN38', 'Chemical', 'MESH:D000077146', (107, 111))
189281	19139719	Since enforced expression of PAX5 in neuroblastoma S-type cells confers on them a more oncogenic phenotype and since PAX5 knockdown results in significant loss in cell viability, PAX5 is believed to not only support cancer cell survival but also contribute to metastasis.	('oncogenic', 'CPA', (87, 96))	('loss', 'NegReg', (155, 159))	('contribute', 'Reg', (246, 256))	('neuroblastoma', 'Disease', 'MESH:D009447', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('support', 'PosReg', (208, 215))	('neuroblastoma', 'Disease', (37, 50))	('cell viability', 'CPA', (163, 177))	('knockdown', 'Var', (122, 131))	('PAX5', 'Gene', (117, 121))	('metastasis', 'CPA', (260, 270))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('PAX5', 'Var', (179, 183))	('PAX5', 'Gene', (29, 33))
189294	19139719	The phospho specific (pY1230/1234/1235 anti-c-Met rabbit polyclonal was from Biosource (Carlsbad, CA) and the rabbit polyclonal against Ron-beta and the mouse monoclonal against Topoisomerase 1 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).	('pY1230/1234/1235', 'Var', (22, 38))	('rabbit', 'Species', '9986', (110, 116))	('Ron', 'Gene', '4486', (136, 139))	('Topoisomerase', 'molecular_function', 'GO:0003917', ('178', '191'))	('Ron', 'Gene', (136, 139))	('rabbit', 'Species', '9986', (50, 56))	('mouse', 'Species', '10090', (153, 158))	('c-Met', 'Gene', (44, 49))	('c-Met', 'Gene', '4233', (44, 49))	('Topoisomerase', 'molecular_function', 'GO:0003918', ('178', '191'))
189316	19139719	Further incubation with the appropriate secondary antibodies conjugated with fluorescein (CY3 and CY5) followed.	('CY5', 'Chemical', 'MESH:C085321', (98, 101))	('CY5', 'Var', (98, 101))	('CY3', 'Chemical', '-', (90, 93))	('fluorescein', 'Chemical', 'MESH:D019793', (77, 88))	('CY3', 'Var', (90, 93))
189334	19139719	SU11274 was used to inhibit c-Met at 2.5 microM, whereas SN38 was used at 2.5 nM.	('c-Met', 'Gene', '4233', (28, 33))	('SN38', 'Chemical', 'MESH:D000077146', (57, 61))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('inhibit', 'NegReg', (20, 27))	('c-Met', 'Gene', (28, 33))
189364	19139719	Fifteen (50%) SCLC exhibited increased PAX5 copy number (N3, N4 and/or N5), whereas one (3%) additional small cell carcinoma contained PAX5 tetraploid (N4) and octaploid (N8) cells.	('SCLC', 'Gene', '7864', (14, 18))	('SCLC', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PAX5 tetraploid', 'Var', (135, 150))	('PAX5', 'Protein', (39, 43))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (104, 124))	('carcinoma', 'Disease', (115, 124))	('increased', 'PosReg', (29, 38))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))
189368	19139719	One non-synonymous heterozygous mutation 964G>AG leading to amino acid change A322S in the PAX5 gene was detected in cell line H146.	('964G>AG', 'Mutation', 'c.964G>AG', (41, 48))	('PAX5', 'Gene', (91, 95))	('A322S', 'SUBSTITUTION', 'None', (78, 83))	('A322S', 'Var', (78, 83))	('H146', 'CellLine', 'CVCL:1473', (127, 131))
189378	19139719	To demonstrate the endogenous relationship between PAX5 activity and c-Met protein levels, we knocked down PAX5 in H526 SCLC cells and determined the intracellular levels of c-Met.	('c-Met', 'Gene', (174, 179))	('c-Met', 'Gene', (69, 74))	('c-Met', 'Gene', '4233', (174, 179))	('c-Met', 'Gene', '4233', (69, 74))	('intracellular', 'cellular_component', 'GO:0005622', ('150', '163'))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('H526 SCLC', 'CellLine', 'CVCL:1569', (115, 124))	('PAX5', 'Gene', (107, 111))	('knocked', 'Var', (94, 101))
189389	19139719	In order to test the translational potential of PAX5 as an adjuvant chemotherapeutic target in SCLC therapy, as an initial step, we determined the effects of knockdown of PAX5 in H69 cells, individually and in combination with SU11274 (a specific c-Met inhibitor currently in clinical trials) and SN38 (a potent Topoisomerase 1 inhibitor and the active metabolite of irinotecan); a drug used in the treatment of SCLC.	('SCLC', 'Gene', '7864', (412, 416))	('SCLC', 'Gene', (412, 416))	('c-Met', 'Gene', (247, 252))	('c-Met', 'Gene', '4233', (247, 252))	('Topoisomerase', 'molecular_function', 'GO:0003918', ('312', '325'))	('PAX5', 'Gene', (171, 175))	('SN38', 'Chemical', 'MESH:D000077146', (297, 301))	('H69', 'CellLine', 'CVCL:8121', (179, 182))	('irinotecan', 'Chemical', 'MESH:D000077146', (367, 377))	('Topoisomerase', 'molecular_function', 'GO:0003917', ('312', '325'))	('knockdown', 'Var', (158, 167))	('SU11274', 'Chemical', 'MESH:C478479', (227, 234))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Gene', (95, 99))
189392	19139719	The cell viability in the above knockdown cells further decreased when treated with either SU11274 or SN38, however the loss in viability was significantly higher in those cells treated with the Topo1 inhibitor SN38.	('SU11274', 'Chemical', 'MESH:C478479', (91, 98))	('SN38', 'Var', (102, 106))	('SU11274', 'Var', (91, 98))	('SN38', 'Chemical', 'MESH:D000077146', (211, 215))	('cell viability', 'CPA', (4, 18))	('decreased', 'NegReg', (56, 65))	('SN38', 'Chemical', 'MESH:D000077146', (102, 106))
189393	19139719	Finally, treatment of PAX5 knockdown cells with both SN38 and SU11274 compounds resulted in maximum loss in viability.	('loss', 'NegReg', (100, 104))	('SN38', 'Chemical', 'MESH:D000077146', (53, 57))	('viability', 'CPA', (108, 117))	('SU11274', 'Chemical', 'MESH:C478479', (62, 69))	('SU11274 compounds', 'Var', (62, 79))	('SN38', 'Var', (53, 57))
189429	19139719	In diffuse large B cell lymphomas and lymphoplasmacytoid lymphoma, a sub-type of B-cell non-Hodgkin's lymphoma, frequent translocation of the PAX5 gene to the IgH chain gene locus [t (9; 14) (p13; q32)] was reported most likely due to aberrant somatic hypermutation events.	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (92, 110))	('p13', 'Gene', (192, 195))	('lymphomas', 'Disease', 'MESH:D008223', (24, 33))	("Hodgkin's lymphoma", 'Disease', (92, 110))	('lymphoplasmacytoid lymphoma', 'Disease', (38, 65))	('lymphomas', 'Phenotype', 'HP:0002665', (24, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('translocation', 'Var', (121, 134))	('p13', 'Gene', '440926', (192, 195))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (92, 110))	('IgH', 'Gene', '3492', (159, 162))	('IgH', 'Gene', (159, 162))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (17, 33))	('PAX5', 'Gene', (142, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('lymphoplasmacytoid lymphoma', 'Disease', 'MESH:D008258', (38, 65))	('lymphomas', 'Disease', (24, 33))
189431	19139719	We have used the FISH method that previously identified reproducibly PAX and non-PAX gene rearrangements in other cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('PAX', 'Chemical', '-', (81, 84))	('rearrangements', 'Var', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PAX', 'Chemical', '-', (69, 72))
189438	19139719	The physiological relevance can be appreciated by the fact that knockdown of PAX5 in SCLC cells resulted in a substantial loss in c-Met protein expression, thereby linking directly expression of c-Met to PAX5.	('c-Met', 'Gene', '4233', (195, 200))	('linking', 'Reg', (164, 171))	('PAX5', 'Gene', (77, 81))	('SCLC', 'Gene', '7864', (85, 89))	('knockdown', 'Var', (64, 73))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('c-Met', 'Gene', (130, 135))	('loss', 'NegReg', (122, 126))	('SCLC', 'Gene', (85, 89))	('c-Met', 'Gene', (195, 200))	('c-Met', 'Gene', '4233', (130, 135))
189445	19139719	Since most of the SCLC has mutated p53 that makes it nonfunctional, the above role of PAX5 may not be relevant, however in those tumors that harbor wt p53, depending on the expression, PAX5 (or PAX2 and PAX8) is very likely to interfere with p53 transcription and thereby contribute to the tumor development.	('transcription', 'biological_process', 'GO:0006351', ('246', '259'))	('PAX5', 'Var', (185, 189))	('tumors', 'Disease', (129, 135))	('p53', 'Gene', (35, 38))	('PAX8', 'Gene', (203, 207))	('tumor', 'Disease', (129, 134))	('transcription', 'MPA', (246, 259))	('p53', 'Gene', '7157', (151, 154))	('PAX2', 'Gene', '5076', (194, 198))	('tumor', 'Disease', (290, 295))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('PAX8', 'Gene', '7849', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('contribute', 'Reg', (272, 282))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('interfere', 'NegReg', (227, 236))	('p53', 'Gene', (151, 154))	('mutated', 'Var', (27, 34))	('p53', 'Gene', '7157', (242, 245))	('PAX2', 'Gene', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('SCLC', 'Gene', '7864', (18, 22))	('p53', 'Gene', '7157', (35, 38))	('SCLC', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', (242, 245))
189456	19139719	It is possible that in normal cells, nuclear c-Met binds to PAX5 and acts as a feedback inhibitor of PAX5 transcriptional activity, however in SCLC cells, although the mutated c-Met is translocated into the nucleus in HGF treated cells, its ability to inhibit PAX5 function may be lost and therefore led to the elevated levels of c-Met in SCLC.	('c-Met', 'Gene', '4233', (176, 181))	('HGF', 'Gene', '3082', (218, 221))	('HGF', 'Gene', (218, 221))	('c-Met', 'Gene', (45, 50))	('nucleus', 'cellular_component', 'GO:0005634', ('207', '214'))	('inhibit', 'NegReg', (252, 259))	('c-Met', 'Gene', (330, 335))	('SCLC', 'Gene', '7864', (339, 343))	('SCLC', 'Gene', (339, 343))	('c-Met', 'Gene', (176, 181))	('elevated', 'PosReg', (311, 319))	('mutated', 'Var', (168, 175))	('c-Met', 'Gene', '4233', (45, 50))	('lost', 'NegReg', (281, 285))	('PAX5', 'Gene', (260, 264))	('c-Met', 'Gene', '4233', (330, 335))	('function', 'MPA', (265, 273))	('SCLC', 'Gene', '7864', (143, 147))	('SCLC', 'Gene', (143, 147))
189457	19139719	Abrogation of PAX5 is known to decrease viability of cancer cells thereby suggesting that PAX5 is required for survival and proliferation.	('viability', 'CPA', (40, 49))	('Abrogation', 'Var', (0, 10))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('decrease', 'NegReg', (31, 39))	('PAX5', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
189463	19139719	Loss of PAX5 clearly decreases the viability of SCLC cells, however the decrease is much greater when combined with c-Met or Topo1 inhibitor; and the maximum effect is seen when all the three conditions are combined.	('PAX5', 'Gene', (8, 12))	('SCLC', 'Gene', (48, 52))	('decreases', 'NegReg', (21, 30))	('SCLC', 'Gene', '7864', (48, 52))	('viability', 'CPA', (35, 44))	('Loss', 'Var', (0, 4))	('c-Met', 'Gene', (116, 121))	('c-Met', 'Gene', '4233', (116, 121))
189501	19830019	MPM may however complicate these procedures and develop subcutaneous tumor deposits via needle biopsy tracks, surgical scars, and chest tube tracts.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('develop', 'PosReg', (48, 55))	('MPM', 'Var', (0, 3))	('scars', 'Phenotype', 'HP:0100699', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (56, 74))
189539	32868383	To evaluate ALPPL2 as a potential therapeutic target, we constructed antibody-drug conjugates (ADCs) by conjugating microtubule inhibitors to our anti-ALPPL2 human monoclonal antibody M25 and showed that M25 ADCs potently inhibited tumor cell proliferation in vitro and mesothelioma cell line xenograft growth in vivo.	('M25', 'Var', (204, 207))	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('mesothelioma', 'Disease', 'MESH:D008654', (270, 282))	('antibody', 'cellular_component', 'GO:0019814', ('175', '183'))	('human', 'Species', '9606', (158, 163))	('antibody', 'molecular_function', 'GO:0003823', ('175', '183'))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('inhibited', 'NegReg', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('antibody', 'cellular_component', 'GO:0042571', ('175', '183'))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('cell proliferation', 'biological_process', 'GO:0008283', ('238', '256'))	('mesothelioma', 'Disease', (270, 282))	('tumor', 'Disease', (232, 237))	('microtubule', 'cellular_component', 'GO:0005874', ('116', '127'))	('antibody', 'cellular_component', 'GO:0019815', ('175', '183'))
189597	32868383	In parallel, we produced recombinant M25 human IgG1.	('M25 human', 'Var', (37, 46))	('IgG1', 'Gene', '105243590', (47, 51))	('human', 'Species', '9606', (41, 46))	('IgG1', 'cellular_component', 'GO:0071735', ('47', '51'))	('IgG1', 'Gene', (47, 51))
189599	32868383	As shown in Figure 1D, M25 IgG1 binds specifically to CHO-K1-ALPPL2 but not CHO-K1, further validating that the target for M25 is ALPPL2.	('CHO', 'molecular_function', 'GO:0043848', ('76', '79'))	('CHO-K1', 'CellLine', 'CVCL:0214', (76, 82))	('IgG1', 'Gene', (27, 31))	('sp', 'Gene', '21785', (38, 40))	('IgG1', 'Gene', '105243590', (27, 31))	('CHO-K1', 'CellLine', 'CVCL:0214', (54, 60))	('binds', 'Interaction', (32, 37))	('IgG1', 'cellular_component', 'GO:0071735', ('27', '31'))	('CHO-K1-ALPPL2', 'Var', (54, 67))	('CHO', 'molecular_function', 'GO:0043848', ('54', '57'))
189614	32868383	Importantly, like the parental M25 scFv, none of the high affinity variants bind to the closely related ALPI or the non-tissue specific ALPL (Supplemental Table S3).	('sp', 'Gene', '21785', (127, 129))	('scFv', 'Gene', (35, 39))	('ALPI', 'Gene', '248', (104, 108))	('scFv', 'Gene', '652070', (35, 39))	('ALPI', 'Gene', (104, 108))	('variants', 'Var', (67, 75))
189615	32868383	We thus have created a series of M25 variants with high specificity and a range of affinities, which can meet the demand of developing various types of therapies in the future using different antibody forms, i.e., scFv for chimeric antigen receptor T cell (CAR-T), or IgG for antibody-drug conjugate, or a combination of forms for bispecific.	('sp', 'Gene', '21785', (333, 335))	('M25', 'Gene', (33, 36))	('antibody', 'cellular_component', 'GO:0042571', ('192', '200'))	('antibody', 'cellular_component', 'GO:0042571', ('276', '284'))	('sp', 'Gene', '21785', (56, 58))	('CAR', 'Gene', (257, 260))	('antibody', 'cellular_component', 'GO:0019815', ('192', '200'))	('variants', 'Var', (37, 45))	('antibody', 'cellular_component', 'GO:0019815', ('276', '284'))	('antibody', 'cellular_component', 'GO:0019814', ('192', '200'))	('antibody', 'molecular_function', 'GO:0003823', ('192', '200'))	('scFv', 'Gene', (214, 218))	('antibody', 'cellular_component', 'GO:0019814', ('276', '284'))	('scFv', 'Gene', '652070', (214, 218))	('antibody', 'molecular_function', 'GO:0003823', ('276', '284'))	('CAR', 'Gene', '653108', (257, 260))	('CAR', 'cellular_component', 'GO:0005826', ('257', '260'))
189618	32868383	As shown in Figure 2A, M25 IgG1 showed specific binding to the two mesothelioma cell lines studied, M28 (apparent KD = 0.44 nM) and VAMT-1 (apparent KD = 0.8 nM), but not to any of the normal cell lines studied, including human fibroblast cell line HS27, kidney cell line HK-2, and primary liver cell line HS775Li.	('HS27', 'CellLine', 'CVCL:0E34', (249, 253))	('HK-2', 'CellLine', 'CVCL:0302', (272, 276))	('IgG1', 'Gene', (27, 31))	('HK-2', 'molecular_function', 'GO:0008256', ('272', '276'))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('M25', 'Var', (23, 26))	('IgG1', 'Gene', '105243590', (27, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (67, 79))	('binding', 'Interaction', (48, 55))	('HS775Li', 'CellLine', 'CVCL:S044', (306, 313))	('sp', 'Gene', '21785', (39, 41))	('human', 'Species', '9606', (222, 227))	('IgG1', 'cellular_component', 'GO:0071735', ('27', '31'))	('mesothelioma', 'Disease', (67, 79))
189620	32868383	We studied binding specificity using CHO-K1 cells transfected with plasmids expressing the four genes, and found that M25 IgG1 binds only to ALPPL2 and ALPP but not the closely related ALPI and the tissue non-specific ALPL (Figure 2B).	('sp', 'Gene', '21785', (209, 211))	('ALPI', 'Gene', (185, 189))	('IgG1', 'Gene', '105243590', (122, 126))	('ALPP', 'Gene', '250', (152, 156))	('sp', 'Gene', '21785', (19, 21))	('IgG1', 'cellular_component', 'GO:0071735', ('122', '126'))	('CHO', 'molecular_function', 'GO:0043848', ('37', '40'))	('CHO-K1', 'CellLine', 'CVCL:0214', (37, 43))	('ALPI', 'Gene', '248', (185, 189))	('ALPP', 'Gene', (141, 145))	('binding', 'molecular_function', 'GO:0005488', ('11', '18'))	('M25', 'Var', (118, 121))	('ALPP', 'Gene', (152, 156))	('IgG1', 'Gene', (122, 126))	('ALPP', 'Gene', '250', (141, 145))	('binds', 'Interaction', (127, 132))
189621	32868383	The apparent binding affinities of the M25 IgG1 for ALPPL2 and ALPP are about 0.5 nM on living cells, well suited for therapeutic development.	('IgG1', 'Gene', '105243590', (43, 47))	('binding', 'Interaction', (13, 20))	('M25', 'Var', (39, 42))	('IgG1', 'cellular_component', 'GO:0071735', ('43', '47'))	('ALPP', 'Gene', (63, 67))	('ALPP', 'Gene', (52, 56))	('ALPP', 'Gene', '250', (63, 67))	('IgG1', 'Gene', (43, 47))	('binding', 'molecular_function', 'GO:0005488', ('13', '20'))	('ALPP', 'Gene', '250', (52, 56))
189624	32868383	The result suggests that M25 binds to a conformational epitope within amino acids 55-262 of ALPP.	('ALPP', 'Gene', '250', (92, 96))	('binds', 'Interaction', (29, 34))	('M25', 'Var', (25, 28))	('ALPP', 'Gene', (92, 96))
189627	32868383	The same tissue specificity was also observed for the high affinity variant M25FYIA IgG1 (Supplemental Table S4).	('IgG1', 'Gene', '105243590', (84, 88))	('IgG1', 'cellular_component', 'GO:0071735', ('84', '88'))	('M25FYIA', 'Var', (76, 83))	('IgG1', 'Gene', (84, 88))	('sp', 'Gene', '21785', (16, 18))
189630	32868383	As shown in Figure S4A, M25 IgG1 was internalized by both M28 and VAMT-1 cells at a moderate rate, with clear evidence of internalization occurring between 4-24h.	('IgG1', 'Gene', '105243590', (28, 32))	('IgG1', 'cellular_component', 'GO:0071735', ('28', '32'))	('IgG1', 'Gene', (28, 32))	('M25', 'Var', (24, 27))
189638	32868383	On both M28 and VAMT-1 cells, M25ADCMMAF internalization was detected during the first 4h of incubation (Figure 3C) and continually increased over the 24h incubation period (Supplemental Figure S6).	('internalization', 'MPA', (41, 56))	('M25ADCMMAF', 'Chemical', '-', (30, 40))	('M25ADCMMAF', 'Var', (30, 40))	('increased', 'PosReg', (132, 141))
189639	32868383	In contrast, the MMAE-conjugated ADC showed higher internalization activity with complete internalization of M25ADCMMAE detected during the first 4h of incubation (Figure 3D).	('internalization activity', 'MPA', (51, 75))	('M25ADCMMAE', 'Var', (109, 119))	('higher', 'PosReg', (44, 50))	('internalization', 'MPA', (90, 105))	('M25ADCMMAE', 'Chemical', '-', (109, 119))
189641	32868383	M25ADCMMAF colocalization with LAMP1 was observed in M28 and VAMT-1 mesothelioma cells after 4h of incubation (Figure 3C) and continually increased during the 24h incubation period (Supplemental Figure S6).	('mesothelioma', 'Disease', (68, 80))	('increased', 'PosReg', (138, 147))	('LAMP1', 'Gene', '3916', (31, 36))	('colocalization', 'MPA', (11, 25))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('M25ADCMMAF', 'Chemical', '-', (0, 10))	('LAMP1', 'Gene', (31, 36))	('M25ADCMMAF', 'Var', (0, 10))
189642	32868383	M25ADCMMAE colocalization with LAMP1 was observed in M28 and VAMT-1 cells after 4h of incubation (Figure 3D).	('LAMP1', 'Gene', '3916', (31, 36))	('colocalization', 'MPA', (11, 25))	('M25ADCMMAE', 'Var', (0, 10))	('LAMP1', 'Gene', (31, 36))	('M25ADCMMAE', 'Chemical', '-', (0, 10))
189644	32868383	As shown in Figure 4, anti-ALPPL2 ADCs potently reduced the viability of both mesothelioma cell lines but none of the control cells.	('viability', 'CPA', (60, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('reduced', 'NegReg', (48, 55))	('anti-ALPPL2 ADCs', 'Var', (22, 38))	('mesothelioma', 'Disease', (78, 90))
189645	32868383	The EC50 value was estimated to be 0.48 nM for M25ADCMMAF on M28, and 36 nM on VAMT-1; and 0.3 nM for M25ADCMMAE on M28, and 0.44 nM on VAMT-1.	('M25ADCMMAF', 'Var', (47, 57))	('M25ADCMMAF', 'Chemical', '-', (47, 57))	('M25ADCMMAE', 'Var', (102, 112))	('M25ADCMMAE', 'Chemical', '-', (102, 112))
189646	32868383	No cytotoxic effect was observed on control normal cells for either M25ADCMMAF or M25ADCMMAE.	('M25ADCMMAF', 'Var', (68, 78))	('M25ADCMMAE', 'Var', (82, 92))	('M25ADCMMAE', 'Chemical', '-', (82, 92))	('M25ADCMMAF', 'Chemical', '-', (68, 78))
189648	32868383	To further assess the threshold for effective ADC killing, we transfected HEK293 cells with varying amounts of ALPPL2-expression plasmids, measured antigen density and EC50 value following M25ADCMMAE treatment (Supplemental Figure S7B).	('HEK293', 'CellLine', 'CVCL:0045', (74, 80))	('M25ADCMMAE', 'Chemical', '-', (189, 199))	('EC50 value', 'MPA', (168, 178))	('measured antigen density', 'MPA', (139, 163))	('M25ADCMMAE', 'Var', (189, 199))
189655	32868383	As shown in Figure 5B, tumor growth is inhibited by M25ADCMMAF but not vehicle control or naked antibody.	('M25ADCMMAF', 'Var', (52, 62))	('inhibited', 'NegReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('tumor', 'Disease', (23, 28))	('M25ADCMMAF', 'Chemical', '-', (52, 62))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))
189660	32868383	injected (Q4Dx4) with M25ADCMMAF, CtrlADCMMAF, naked M25 IgG1 or PBS on Study Day 0 at 5 mg/kg.	('IgG1', 'Gene', '105243590', (57, 61))	('M25ADCMMAF', 'Chemical', '-', (22, 32))	('IgG1', 'cellular_component', 'GO:0071735', ('57', '61'))	('M25ADCMMAF', 'Var', (22, 32))	('PBS', 'Chemical', 'MESH:D007854', (65, 68))	('IgG1', 'Gene', (57, 61))
189661	32868383	Tumor growth was inhibited by M25ADCMMAF but not vehicle control (PBS), naked IgG1, or the control ADC (Figure 5C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('M25ADCMMAF', 'Chemical', '-', (30, 40))	('PBS', 'Chemical', 'MESH:D007854', (66, 69))	('inhibited', 'NegReg', (17, 26))	('M25ADCMMAF', 'Var', (30, 40))	('IgG1', 'Gene', (78, 82))	('IgG1', 'cellular_component', 'GO:0071735', ('78', '82'))	('Tumor growth', 'CPA', (0, 12))	('IgG1', 'Gene', '105243590', (78, 82))
189664	32868383	The M25ADCMMAE was able to greatly reduce the size of this large tumor (> 90% reduction) (Figure 5D).	('M25ADCMMAE', 'Chemical', '-', (4, 14))	('tumor', 'Disease', (65, 70))	('reduction', 'NegReg', (78, 87))	('M25ADCMMAE', 'Var', (4, 14))	('reduce', 'NegReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
189669	32868383	Both 3 mg/kg and 5 mg/kg M25ADCMMAE resulted in potent tumor size reduction.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('M25ADCMMAE', 'Var', (25, 35))	('tumor', 'Disease', (55, 60))	('reduction', 'NegReg', (66, 75))	('M25ADCMMAE', 'Chemical', '-', (25, 35))
189671	32868383	CtrlADCMMAE did not have any significant effect on tumor growth (Supplemental Figure S10A for the 5 mg/kg and S10B for the 3 mg/kg cohorts, respectively).	('S10A', 'Var', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('S10B', 'SUBSTITUTION', 'None', (110, 114))	('tumor', 'Disease', (51, 56))	('S10A', 'SUBSTITUTION', 'None', (85, 89))	('sp', 'Gene', '21785', (142, 144))	('S10B', 'Var', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
189672	32868383	No body weight loss was observed in all treatment groups (Supplemental Figure S11A for the 5 mg/kg and S11B for the 3 mg/kg cohorts, respectively).	('S11A', 'SUBSTITUTION', 'None', (78, 82))	('weight loss', 'Phenotype', 'HP:0001824', (8, 19))	('S11B', 'Var', (103, 107))	('weight loss', 'Disease', 'MESH:D015431', (8, 19))	('S11B', 'SUBSTITUTION', 'None', (103, 107))	('sp', 'Gene', '21785', (135, 137))	('weight loss', 'Disease', (8, 19))	('S11A', 'Var', (78, 82))
189677	32868383	The size of M28 tumors (> 500 mm3) was reduced by 90-100% on Day 45 (absolute tumor size shown in Figure 6B with normalized size shown in Figure 6D) while VAMT-1 was not detectable by caliper measurement on Day 51 (absolute tumor size shown in Figure 6B with normalized size shown in Figure 6C).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('M28', 'Var', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Disease', (16, 21))	('reduced', 'NegReg', (39, 46))	('tumor', 'Disease', (78, 83))	('size', 'MPA', (4, 8))	('tumors', 'Disease', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
189691	32868383	To evaluate therapeutic potential of targeting this novel tumor antigen, we constructed M25 ADCs conjugated with either MMAF or MMAE, and showed that M25 ADCs kill both epithelial and sarcomatous mesothelial cell lines in vitro and in mouse xenograft models, with MMAE-based ADC showing higher potency in vivo.	('sarcomatous', 'Disease', 'MESH:D018316', (184, 195))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('M25', 'Var', (150, 153))	('sarcomatous', 'Disease', (184, 195))	('mouse', 'Species', '10090', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor antigen', 'molecular_function', 'GO:0008222', ('58', '71'))
189700	32868383	Indeed, on VAMT-1 cell, M25ADCMMAF is less potent than M25ADCMMAE.	('M25ADCMMAF', 'Var', (24, 34))	('M25ADCMMAE', 'Chemical', '-', (55, 65))	('M25ADCMMAF', 'Chemical', '-', (24, 34))	('less', 'NegReg', (38, 42))
189702	32868383	One explanation for this phenomenon is that the high ALPPL2 antigen density on M28 cell (1.1 million per cell, as opposed to 0.34 million per cell for VAMT-1) enabled uptake of sufficient amount of M25ADCMMAF above a threshold for cell killing, thus blunted the impact of difference in internalization rate between MMAF- and MMAE-conjugated ADCs.	('M25ADCMMAF', 'Chemical', '-', (198, 208))	('uptake', 'MPA', (167, 173))	('M25ADCMMAF', 'Var', (198, 208))	('cell killing', 'biological_process', 'GO:0001906', ('231', '243'))	('uptake', 'biological_process', 'GO:0098657', ('167', '173'))	('uptake', 'biological_process', 'GO:0098739', ('167', '173'))
189713	32868383	We showed that M25 ADCs are effective against both epithelial and sarcomatous mesothelioma cell lines in vitro and in vivo.	('epithelial', 'Disease', (51, 61))	('M25', 'Var', (15, 18))	('sarcomatous mesothelioma', 'Disease', (66, 90))	('sarcomatous mesothelioma', 'Disease', 'MESH:D008654', (66, 90))
189721	30140266	Tumors can express antigens that are rapidly recognized by T cells, where mutations of self-antigens or germline cancer antigens differ sufficiently from normal antigens, or those that are less robustly detected, such as overexpressed self-antigens or differentiation antigens expressed by tissue from which the tumor originates.	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('cancer', 'Disease', (113, 119))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
189738	30140266	Because CD19 is expressed ubiquitously in the B cell lineage, targeting CD19 ablates this cell compartment in patients, though sparing of some plasma cells with long-term humoral immunity is possible.	('CD19', 'Gene', (8, 12))	('CD19', 'Gene', '930', (72, 76))	('ablates', 'NegReg', (77, 84))	('CD19', 'Gene', '930', (8, 12))	('targeting', 'Var', (62, 71))	('CD19', 'Gene', (72, 76))	('patients', 'Species', '9606', (110, 118))
189751	30140266	CAR T cells engineered against ERBB2 given in a high dose to a patient with metastatic colorectal cancer caused multi-organ failure with acute pulmonary toxicity due to antigen expression on lung epithelium.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('acute pulmonary toxicity', 'Disease', (137, 161))	('CAR', 'cellular_component', 'GO:0005826', ('0', '3'))	('acute pulmonary toxicity', 'Disease', 'MESH:D008171', (137, 161))	('colorectal cancer', 'Disease', (87, 104))	('patient', 'Species', '9606', (63, 70))	('multi-organ failure', 'Disease', 'MESH:D009102', (112, 131))	('ERBB2', 'Gene', '2064', (31, 36))	('ERBB2', 'Gene', (31, 36))	('antigen', 'Var', (169, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('multi-organ failure', 'Disease', (112, 131))
189803	30140266	Therefore, maintenance of memory characteristics in vivo through inducible IL-21 expression in CAR T cells, theoretically also supporting memory of endogenous tumor-specific T cells, may greatly improve the longevity of future CAR therapies for long-lasting curative responses.	('memory', 'biological_process', 'GO:0007613', ('26', '32'))	('IL-21', 'molecular_function', 'GO:0001531', ('75', '80'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('inducible', 'Var', (65, 74))	('CAR', 'cellular_component', 'GO:0005826', ('227', '230'))	('improve', 'PosReg', (195, 202))	('tumor', 'Disease', (159, 164))	('CAR', 'cellular_component', 'GO:0005826', ('95', '98'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('memory', 'biological_process', 'GO:0007613', ('138', '144'))
189807	30140266	Collectively, manipulating cytokine production or cytokine signaling has opened new possibilities for generating CARs with desirable traits to bolster their efficacy against tumors and improve immunity of other infiltrating immune cells.	('cytokine production', 'biological_process', 'GO:0001816', ('27', '46'))	('bolster', 'PosReg', (143, 150))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('improve', 'PosReg', (185, 192))	('immunity', 'CPA', (193, 201))	('efficacy', 'MPA', (157, 165))	('manipulating', 'Var', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
189810	30140266	The earliest studies using this approach were with Epstein-Barr virus-specific T cells engineered with a dominant negative mutation of the TGF-beta receptor, which allowed tumor-specific T cells to resist suppression by the tumor-derived TGF-beta.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TGF-beta', 'Gene', '7040', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('mutation', 'Var', (123, 131))	('TGF-beta', 'Gene', '7040', (139, 147))	('TGF-beta', 'Gene', (238, 246))	('tumor', 'Disease', (172, 177))	('Epstein-Barr virus', 'Species', '10376', (51, 69))	('tumor', 'Disease', (224, 229))	('negative', 'NegReg', (114, 122))	('TGF-beta', 'Gene', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
189819	30140266	Dimerization leads to cleavage of caspase 3 and apoptosis of the CAR T cells.	('caspase 3', 'Gene', '836', (34, 43))	('Dimerization', 'Var', (0, 12))	('cleavage', 'MPA', (22, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('CAR', 'cellular_component', 'GO:0005826', ('65', '68'))	('apoptosis', 'CPA', (48, 57))	('caspase 3', 'Gene', (34, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
189821	30140266	As rituximab is widely used clinically, this is a non-toxic and relatively inexpensive method for rapid deletion of CAR T cells in case of severe toxicity.	('CAR T cells', 'Gene', (116, 127))	('CAR', 'cellular_component', 'GO:0005826', ('116', '119'))	('rituximab', 'Chemical', 'MESH:D000069283', (3, 12))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('toxicity', 'Disease', (146, 154))	('deletion', 'Var', (104, 112))
189852	30140266	For a patient in complete remission from CLL after CD19-CAR T therapy, CAR integration into the tumor suppressor gene, TET2, resulted in robust clonal proliferation of CAR T cells with a predominantly CM phenotype.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('CAR', 'cellular_component', 'GO:0005826', ('168', '171'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('clonal proliferation', 'CPA', (144, 164))	('TET2', 'Gene', '54790', (119, 123))	('CAR', 'cellular_component', 'GO:0005826', ('71', '74'))	('patient', 'Species', '9606', (6, 13))	('tumor', 'Disease', (96, 101))	('CAR', 'cellular_component', 'GO:0005826', ('56', '59'))	('integration', 'Var', (75, 86))	('CAR', 'Disease', (168, 171))	('CD19', 'Gene', (51, 55))	('CM', 'Disease', 'MESH:D009202', (201, 203))	('TET2', 'Gene', (119, 123))	('CD19', 'Gene', '930', (51, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('CLL', 'Phenotype', 'HP:0005550', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
189854	30140266	This suggests that epigenetic or genetic manipulation of T cells ex vivo could be a novel approach to control memory differentiation of cells and generate a more therapeutic product before transferring cells into patients.	('memory', 'biological_process', 'GO:0007613', ('110', '116'))	('epigenetic or genetic manipulation', 'Var', (19, 53))	('patients', 'Species', '9606', (213, 221))	('memory differentiation', 'CPA', (110, 132))
189860	30140266	One approach to accomplish this objective includes targeting downstream of the IL-2 pathway during ex vivo expansion through inhibiting subunits of GSK-3beta, AKT, and PI3K (Figure 4).	('IL-2', 'molecular_function', 'GO:0005134', ('79', '83'))	('AKT', 'Gene', (159, 162))	('GSK-3beta', 'Gene', (148, 157))	('GSK-3beta', 'Gene', '2932', (148, 157))	('IL-2', 'Gene', '3558', (79, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('PI3K', 'Var', (168, 172))	('IL-2', 'Gene', (79, 83))	('inhibiting', 'NegReg', (125, 135))	('AKT', 'Gene', '207', (159, 162))	('GSK', 'molecular_function', 'GO:0050321', ('148', '151'))	('subunits', 'Protein', (136, 144))
189861	30140266	GSK-3beta inhibition was shown to bolster Wnt/beta-catenin signaling and maintain the TCM phenotype with ex vivo expansion, thus improving efficacy of infused antitumor CD8+ T cells.	('maintain', 'Reg', (73, 81))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('improving', 'PosReg', (129, 138))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('beta-catenin', 'Gene', (46, 58))	('CM', 'Disease', 'MESH:D009202', (87, 89))	('bolster', 'PosReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('beta-catenin', 'Gene', '1499', (46, 58))	('tumor', 'Disease', (163, 168))	('efficacy', 'CPA', (139, 147))	('inhibition', 'Var', (10, 20))	('GSK-3beta', 'Gene', '2932', (0, 9))	('GSK-3beta', 'Gene', (0, 9))	('CD8', 'Gene', (169, 172))	('CD8', 'Gene', '925', (169, 172))
189862	30140266	Inhibition of AKT (AKT inhibitor VIII) or the p110delta subunit of PI3K (Idelalisib/CAL-101) ex vivo were also two strong approaches to enrich the frequency of TCM cells in infusion products and improve ACT with CAR-engineered cells for leukemia and mesothelioma models, respectively.	('VIII', 'Gene', (33, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('mesothelioma', 'Disease', 'MESH:D008654', (250, 262))	('PI3K', 'Gene', (67, 71))	('CM', 'Disease', 'MESH:D009202', (161, 163))	('CAR', 'cellular_component', 'GO:0005826', ('212', '215'))	('AKT', 'Gene', (14, 17))	('leukemia', 'Disease', (237, 245))	('AKT', 'Gene', '207', (19, 22))	('improve', 'PosReg', (195, 202))	('leukemia', 'Disease', 'MESH:D007938', (237, 245))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('Inhibition', 'Var', (0, 10))	('p110delta', 'Var', (46, 55))	('mesothelioma', 'Disease', (250, 262))	('AKT', 'Gene', (19, 22))	('VIII', 'Gene', '1351', (33, 37))	('AKT', 'Gene', '207', (14, 17))
189863	30140266	However, when directly compared in a transgenic model of melanoma, CAL-101 improved persistence of CD8+KLRG1loCD62Lhi cells in the peripheral blood and significantly enhanced tumor regression compared with AKTi.	('improved', 'PosReg', (75, 83))	('AKT', 'Gene', (206, 209))	('CD8', 'Gene', (99, 102))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('CAL-101', 'Var', (67, 74))	('CD62L', 'Gene', '6402', (110, 115))	('CD62L', 'Gene', (110, 115))	('AKT', 'Gene', '207', (206, 209))	('enhanced', 'PosReg', (166, 174))	('KLRG1', 'Gene', (103, 108))	('tumor', 'Disease', (175, 180))	('CD8', 'Gene', '925', (99, 102))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('KLRG1', 'Gene', '50928', (103, 108))	('transgenic', 'Species', '10090', (37, 47))	('persistence', 'CPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
189864	30140266	CAL-101 has also been shown to improve antitumor efficacy of Th17 cells by enhancing the proportion of TCM cells and reducing Tregs in culture.	('enhancing', 'PosReg', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('reducing', 'NegReg', (117, 125))	('CAL-101', 'Var', (0, 7))	('CM', 'Disease', 'MESH:D009202', (104, 106))	('improve', 'PosReg', (31, 38))	('Tregs in culture', 'CPA', (126, 142))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
189887	30140266	While both Th1 and Th2 have demonstrated some degree of antitumor efficacy in vivo, Th1 cells were shown to induce a CD8+ CTL memory response against antigen rechallenge while Th2 cells did not.	('memory', 'biological_process', 'GO:0007613', ('126', '132'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Th1', 'Var', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('induce', 'PosReg', (108, 114))	('CD8', 'Gene', (117, 120))	('CD8', 'Gene', '925', (117, 120))	('tumor', 'Disease', (60, 65))
189903	30140266	Important to the field of CAR therapies, Th17-polarized human meso-CAR T cells exhibit enhanced immunity against mesothelioma versus Th1-polarized cells after both short and long expansion.	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('immunity', 'CPA', (96, 104))	('CAR', 'cellular_component', 'GO:0005826', ('67', '70'))	('CAR', 'cellular_component', 'GO:0005826', ('26', '29'))	('Th17-polarized', 'Var', (41, 55))	('human', 'Species', '9606', (56, 61))	('enhanced', 'PosReg', (87, 95))	('mesothelioma', 'Disease', (113, 125))
189920	30140266	As memory-like T cells are most effective in mediating long-term responses to solid tumors, new data implicates that modulation of their metabolism to favor catabolic pathways may generate a lymphocyte population with enhanced antitumor functions in vivo.	('solid tumors', 'Disease', (78, 90))	('enhanced', 'PosReg', (218, 226))	('favor', 'PosReg', (151, 156))	('modulation', 'Var', (117, 127))	('catabolic pathways', 'MPA', (157, 175))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('memory', 'biological_process', 'GO:0007613', ('3', '9'))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (84, 89))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('metabolism', 'MPA', (137, 147))	('metabolism', 'biological_process', 'GO:0008152', ('137', '147'))
189921	30140266	For example, in models of autoimmunity, genetic deletion of Glut1 prevented effector T cells from causing pathology in inflammatory bowel disease.	('Glut1', 'Gene', '6513', (60, 65))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (119, 145))	('inflammatory bowel disease', 'Disease', (119, 145))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (119, 145))	('autoimmunity', 'Phenotype', 'HP:0002960', (26, 38))	('prevented', 'NegReg', (66, 75))	('genetic deletion', 'Var', (40, 56))	('autoimmunity', 'Disease', (26, 38))	('Glut1', 'Gene', (60, 65))	('autoimmunity', 'Disease', 'MESH:D001327', (26, 38))
189922	30140266	Inhibition of fatty acid synthesis in T cells limited Th17-induced autoimmunity and promoted a Treg signature, notoriously implicated in promoting tolerance to tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('14', '34'))	('promoted', 'PosReg', (84, 92))	('autoimmunity', 'Phenotype', 'HP:0002960', (67, 79))	('limited', 'NegReg', (46, 53))	('syn', 'Gene', '23336', (25, 28))	('autoimmunity', 'Disease', (67, 79))	('Th17-induced', 'CPA', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Inhibition', 'Var', (0, 10))	('Treg signature', 'CPA', (95, 109))	('tumors', 'Disease', (160, 166))	('syn', 'Gene', (25, 28))	('autoimmunity', 'Disease', 'MESH:D001327', (67, 79))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
189927	30140266	Interestingly, several groups have demonstrated that metabolic manipulation of T cells in vitro can benefit antitumor efficacy of transferred cells in vivo.	('benefit', 'PosReg', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('metabolic manipulation', 'Var', (53, 75))	('manipulation', 'Var', (63, 75))	('tumor', 'Disease', (112, 117))
189928	30140266	Overexpression of glycolytic enzyme phosphoglycerate-mutase 1 limited persistence of transferred CD8+ T cells, while inhibition of glycolysis with 2-deoxyglucose augmented stem memory characteristics like Tcf7 and Lef1 expression, and significantly enhanced survival of tumor-bearing hosts.	('stem memory characteristics', 'CPA', (172, 199))	('Lef1', 'Gene', (214, 218))	('expression', 'MPA', (219, 229))	('Tcf7', 'Gene', '6932', (205, 209))	('Tcf7', 'Gene', (205, 209))	('augmented', 'PosReg', (162, 171))	('survival', 'CPA', (258, 266))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (147, 161))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('Lef1', 'Gene', '51176', (214, 218))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('117', '141'))	('memory', 'biological_process', 'GO:0007613', ('177', '183'))	('CD8', 'Gene', (97, 100))	('inhibition', 'Var', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('enhanced', 'PosReg', (249, 257))	('tumor', 'Disease', (270, 275))	('CD8', 'Gene', '925', (97, 100))
189929	30140266	Inhibition of AKT signaling, discussed previously as a method for reducing T cell differentiation ex vivo, was also shown to decrease glycolytic function and enhance mitochondrial spare respiratory capacity in CD8+ T cells.	('enhance', 'PosReg', (158, 165))	('AKT signaling', 'biological_process', 'GO:0043491', ('14', '27'))	('mitochondrial spare respiratory capacity', 'MPA', (166, 206))	('glycolytic function', 'MPA', (134, 153))	('AKT', 'Gene', (14, 17))	('CD8', 'Gene', (210, 213))	('T cell differentiation', 'biological_process', 'GO:0030217', ('75', '97'))	('Inhibition', 'Var', (0, 10))	('CD8', 'Gene', '925', (210, 213))	('decrease', 'NegReg', (125, 133))	('AKT', 'Gene', '207', (14, 17))
189931	30140266	Similarly, inhibition of the inositol triphosphate receptor, an important second messenger for calcium release from intracellular storage, in CD4+ T cells ex vivo prevented glycolytic initiation due to altered calcium flux, fostered a CM phenotype, and augmented their therapeutic efficacy against established melanoma tumors.	('fostered', 'PosReg', (224, 232))	('CD4', 'Gene', (142, 145))	('melanoma tumors', 'Disease', 'MESH:D008545', (310, 325))	('inhibition', 'Var', (11, 21))	('altered calcium flux', 'MPA', (202, 222))	('CM', 'Disease', 'MESH:D009202', (235, 237))	('calcium', 'Chemical', 'MESH:D002118', (210, 217))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('melanoma tumors', 'Disease', (310, 325))	('glycolytic initiation', 'MPA', (173, 194))	('augmented', 'PosReg', (253, 262))	('intracellular', 'cellular_component', 'GO:0005622', ('116', '129'))	('calcium', 'Chemical', 'MESH:D002118', (95, 102))	('prevented', 'NegReg', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('intracellular storage', 'biological_process', 'GO:0051651', ('116', '137'))	('CD4', 'Gene', '920', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('therapeutic efficacy', 'CPA', (269, 289))
189947	30140266	Strategies to improve efficacy of PD-1 expressing, exhausted CAR T cells or to rejuvenate host tumor-specific exhausted T cells along with CAR therapy are threefold: (1) genetic removal of PD-1 from CAR T cells, (2) combination PD-1 blockade with CAR infusion, or (3) CAR T cell production of PD-1 blockade within the host.	('PD-1', 'Gene', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD-1 blockade within the host', 'Disease', 'MESH:D001929', (293, 322))	('CAR', 'cellular_component', 'GO:0005826', ('199', '202'))	('combination', 'Interaction', (216, 227))	('CAR', 'cellular_component', 'GO:0005826', ('247', '250'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CAR', 'cellular_component', 'GO:0005826', ('61', '64'))	('CAR', 'cellular_component', 'GO:0005826', ('139', '142'))	('CAR', 'cellular_component', 'GO:0005826', ('268', '271'))	('genetic', 'Var', (170, 177))	('PD-1 blockade within the host', 'Disease', (293, 322))	('tumor', 'Disease', (95, 100))
189956	30140266	At the time of writing, clinical trials with such combinations are heavily skewed toward blood cancers (NCT02926833, NCT02706495, and NCT03287817 in DLBCL, NCT03310619 in B cell NHL, and NCT02650999 in DLBCL, follicular lymphoma, and mantle cell lymphoma;  identifiers).	('NCT02926833', 'Var', (104, 115))	('follicular lymphoma', 'Disease', (209, 228))	('blood cancers', 'Phenotype', 'HP:0001909', (89, 102))	('blood cancers', 'Disease', 'MESH:D009369', (89, 102))	('blood cancers', 'Disease', (89, 102))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (234, 254))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mantle cell lymphoma', 'Disease', (234, 254))	('cell lymphoma', 'Phenotype', 'HP:0012191', (241, 254))	('NCT02650999', 'Var', (187, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (246, 254))	('lymphoma', 'Phenotype', 'HP:0002665', (220, 228))	('DLBCL', 'Disease', (202, 207))	('follicular lymphoma', 'Disease', 'MESH:D008224', (209, 228))	('NCT03287817', 'Var', (134, 145))	('NCT02706495', 'Var', (117, 128))	('NCT03310619', 'Var', (156, 167))
189957	30140266	Preliminary results in these hematologic malignancies suggest that PD-1 blockade may enhance CAR T cell persistence and could improve objective responses in patients.	('PD-1', 'Gene', (67, 71))	('CAR', 'cellular_component', 'GO:0005826', ('93', '96'))	('CAR T cell persistence', 'CPA', (93, 115))	('improve', 'PosReg', (126, 133))	('hematologic malignancies', 'Disease', 'MESH:D019337', (29, 53))	('patients', 'Species', '9606', (157, 165))	('hematologic malignancies', 'Disease', (29, 53))	('blockade', 'Var', (72, 80))	('objective responses', 'CPA', (134, 153))	('enhance', 'PosReg', (85, 92))
189959	30140266	Similar results were found in a renal cell carcinoma model where production of antibodies to PD-L1 enhanced CAR T cell function, though the results were less dramatic.	('renal cell carcinoma', 'Disease', (32, 52))	('PD-L1', 'Gene', '29126', (93, 98))	('enhanced CAR T cell function', 'Phenotype', 'HP:0100828', (99, 127))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('CAR', 'cellular_component', 'GO:0005826', ('108', '111'))	('enhanced', 'PosReg', (99, 107))	('antibodies', 'Var', (79, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('CAR T cell function', 'CPA', (108, 127))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('PD-L1', 'Gene', (93, 98))
189975	30140266	We posit that a future CAR T cell armored with (1) a superior targeting system specific to the tumor and tumor tissue, (2) engineering of a highly potent, persistent, and self-renewing T cell subset, and (3) rejuvenation of the endogenous host response through CAR T cell production of monoclonal antibodies against immune checkpoint molecules will bolster the immune attack on the solid tumor to best reduce toxicity and support a long-lived memory response against targeted antigens and personalized neoantigens.	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('solid tumor', 'Disease', (382, 393))	('memory response', 'CPA', (443, 458))	('reduce', 'NegReg', (402, 408))	('monoclonal', 'Var', (286, 296))	('memory', 'biological_process', 'GO:0007613', ('443', '449'))	('tumor', 'Disease', (105, 110))	('solid tumor', 'Disease', 'MESH:D009369', (382, 393))	('toxicity', 'Disease', 'MESH:D064420', (409, 417))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (388, 393))	('bolster', 'PosReg', (349, 356))	('CAR', 'cellular_component', 'GO:0005826', ('23', '26'))	('toxicity', 'Disease', (409, 417))	('CAR', 'cellular_component', 'GO:0005826', ('261', '264'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (388, 393))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
190002	29669604	Accordingly, PD-1 or PD-L1 blockade de-represses T-cell activation, unleashing a clinical immune response with tumour regression.	('clinical', 'MPA', (81, 89))	('PD-1', 'Gene', (13, 17))	('PD-1', 'Gene', '5133', (13, 17))	('de-represses', 'NegReg', (36, 48))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('blockade', 'Var', (27, 35))	('PD-L1', 'Gene', (21, 26))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('T-cell activation', 'biological_process', 'GO:0042110', ('49', '66'))	('tumour', 'Disease', (111, 117))	('T-cell activation', 'CPA', (49, 66))	('unleashing', 'NegReg', (68, 78))	('immune response', 'biological_process', 'GO:0006955', ('90', '105'))
190113	27129163	Additive effects were observed in cells containing wild-type p53 through coordinated attack on MDM2-p53 binding and cyclin D1 by lentivirual shRNA knockdown or small molecule inhibition, as demonstrated by immunoblots and cell viability analyses.	('attack', 'PosReg', (85, 91))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('binding', 'Interaction', (104, 111))	('cyclin D1', 'Gene', '595', (116, 125))	('inhibition', 'NegReg', (175, 185))	('p53', 'Gene', '7157', (100, 103))	('co', 'Chemical', '-', (73, 75))	('cyclin D1', 'Gene', (116, 125))	('co', 'Chemical', '-', (40, 42))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('p53 binding', 'molecular_function', 'GO:0002039', ('100', '111'))	('knockdown', 'Var', (147, 156))	('p53', 'Gene', (100, 103))
190115	27129163	MDM2 and p53 knockdown experiments demonstrated inhibition of cyclin D1 by MDM2 but not p53.	('cyclin D1', 'Gene', (62, 71))	('MDM2', 'Var', (75, 79))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('cyclin D1', 'Gene', '595', (62, 71))	('inhibition', 'NegReg', (48, 58))
190117	27129163	The human homolog of mouse double minute 2 (MDM2) is an oncoprotein overexpressed in different types of malignant cancers, due to gene amplification or the SNP309 polymorphism in the promoter region of MDM2.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('human', 'Species', '9606', (4, 9))	('malignant cancers', 'Disease', 'MESH:D009369', (104, 121))	('co', 'Chemical', '-', (58, 60))	('mouse', 'Species', '10090', (21, 26))	('malignant cancers', 'Disease', (104, 121))	('MDM2', 'Gene', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SNP309 polymorphism in', 'Var', (156, 178))
190123	27129163	Previous reports have confirmed that Nutlin-3 inhibits cell viability in cancer cell lines harboring wild-type p53, with an attenuated effect in cell lines harboring mutant p53, indicating that p53 mutation is a strong negative predictor of response.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('p53', 'Gene', (173, 176))	('Nutlin-3', 'Chemical', 'MESH:C482205', (37, 45))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('p53', 'Gene', '7157', (173, 176))	('inhibits', 'NegReg', (46, 54))	('cell viability', 'CPA', (55, 69))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('mutant', 'Var', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('co', 'Chemical', '-', (22, 24))
190125	27129163	Many MDM2 splicing variants have been described in a variety of malignancies, including ovarian cancer, breast cancer, non-small cell lung cancer, and liposarcoma, revealing the complexity of the MDM2 and p53 feedback loop.	('co', 'Chemical', '-', (158, 160))	('described', 'Reg', (38, 47))	('MDM2', 'Gene', (5, 9))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('splicing', 'biological_process', 'GO:0045292', ('10', '18'))	('variants', 'Var', (19, 27))	('liposarcoma', 'Disease', 'MESH:D008080', (151, 162))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('p53', 'Gene', '7157', (205, 208))	('co', 'Chemical', '-', (178, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('p53', 'Gene', (205, 208))	('ovarian cancer', 'Disease', (88, 102))	('liposarcoma', 'Disease', (151, 162))	('non-small cell lung cancer', 'Disease', (119, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (151, 162))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
190126	27129163	Alternative MDM2 transcripts mainly include MDM2-FL (full length, ~90kDa), MDM2-A (~60 kDa), MDM2-B (~45 kDa), MDM2-C, MDM2-HL1, and MDM2-HL2 (~30 kDa).	('MDM2', 'Gene', (12, 16))	('MDM2-HL2', 'Disease', 'None', (133, 141))	('MDM2-C', 'Disease', 'MESH:C537418', (111, 117))	('MDM2-FL', 'Var', (44, 51))	('MDM2-HL1', 'CellLine', 'CVCL:D272', (119, 127))	('MDM2-HL2', 'Disease', (133, 141))	('MDM2-C', 'Disease', (111, 117))
190127	27129163	A number of variant transcripts may not retain the entire p53 binding site, therefore limiting the response of cancer cells to Nutlin-3.	('variant', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('limiting', 'NegReg', (86, 94))	('Nutlin-3', 'Chemical', 'MESH:C482205', (127, 135))	('p53 binding', 'molecular_function', 'GO:0002039', ('58', '69'))	('response', 'MPA', (99, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
190128	27129163	MDM2 splicing variants are tumorigenic in mouse models and have been associated with tumor progression in breast carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (85, 90))	('breast carcinomas', 'Disease', 'MESH:D001943', (106, 123))	('breast carcinomas', 'Disease', (106, 123))	('mouse', 'Species', '10090', (42, 47))	('tumor', 'Disease', (27, 32))	('splicing', 'biological_process', 'GO:0045292', ('5', '13'))	('breast carcinomas', 'Phenotype', 'HP:0003002', (106, 123))	('associated with', 'Reg', (69, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MDM2', 'Gene', (0, 4))	('splicing variants', 'Var', (5, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
190130	27129163	For example, MDM2-B stimulates the growth of mouse embryo fibroblasts and exerts antiapoptotic effects.	('antiapoptotic effects', 'MPA', (81, 102))	('MDM2-B', 'Var', (13, 19))	('stimulates', 'PosReg', (20, 30))	('growth', 'CPA', (35, 41))	('mouse', 'Species', '10090', (45, 50))
190131	27129163	Notably, expression of MDM2-A and MDM2-B increases the expression levels of cyclin D1, which has an oncogenic role in cancer cells.	('MDM2-B', 'Var', (34, 40))	('cyclin D1', 'Gene', '595', (76, 85))	('cancer', 'Disease', (118, 124))	('co', 'Chemical', '-', (102, 104))	('cyclin D1', 'Gene', (76, 85))	('increases', 'PosReg', (41, 50))	('expression', 'Species', '29278', (55, 65))	('expression', 'Species', '29278', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression levels', 'MPA', (55, 72))	('MDM2-A', 'Var', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cyclin', 'molecular_function', 'GO:0016538', ('76', '82'))
190141	27129163	Due to the observation of cyclin D1 induction after treatment with Nutlin-3, we expected to see additive inhibitory effects on cell viability through coordinated suppression of MDM2-p53 binding and cyclin D1 knockdown or inhibition.	('cyclin D1', 'Gene', '595', (198, 207))	('suppression', 'NegReg', (162, 173))	('knockdown', 'Var', (208, 217))	('inhibition', 'NegReg', (221, 231))	('p53', 'Gene', '7157', (182, 185))	('Nutlin-3', 'Chemical', 'MESH:C482205', (67, 75))	('cyclin D1', 'Gene', (198, 207))	('cyclin', 'molecular_function', 'GO:0016538', ('26', '32'))	('cyclin D1', 'Gene', '595', (26, 35))	('cyclin', 'molecular_function', 'GO:0016538', ('198', '204'))	('cyclin D1', 'Gene', (26, 35))	('p53 binding', 'molecular_function', 'GO:0002039', ('182', '193'))	('binding', 'Interaction', (186, 193))	('co', 'Chemical', '-', (150, 152))	('p53', 'Gene', (182, 185))
190143	27129163	Cell lines with wild-type p53 (MESO924, MESO257, MESO296, MCS170, LPS695, and LMS05) were evaluated after 3 days of cyclin D1 knockdown and 48 hours of Nutlin-3 treatment.	('MCS', 'cellular_component', 'GO:0044232', ('58', '61'))	('MESO924', 'Chemical', '-', (31, 38))	('LPS695', 'Chemical', '-', (66, 72))	('MESO257', 'Chemical', '-', (40, 47))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('p53', 'Gene', (26, 29))	('cyclin D1', 'Gene', '595', (116, 125))	('MCS170', 'Chemical', '-', (58, 64))	('cyclin D1', 'Gene', (116, 125))	('p53', 'Gene', '7157', (26, 29))	('knockdown', 'Var', (126, 135))	('MESO296', 'Chemical', '-', (49, 56))	('Nutlin-3', 'Chemical', 'MESH:C482205', (152, 160))
190145	27129163	Cyclin D1 knockdown resulted in greater than 80% reduction of cyclin D1 and an increase in p27 and cyclin E expression.	('increase', 'PosReg', (79, 87))	('cyclin D1', 'Gene', (62, 71))	('reduction', 'NegReg', (49, 58))	('Cyclin D1', 'Gene', '595', (0, 9))	('cyclin', 'molecular_function', 'GO:0016538', ('99', '105'))	('expression', 'Species', '29278', (108, 118))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('expression', 'MPA', (108, 118))	('Cyclin D1', 'Gene', (0, 9))	('cyclin D1', 'Gene', '595', (62, 71))	('knockdown', 'Var', (10, 19))	('p27', 'Protein', (91, 94))
190146	27129163	The combination of cyclin D1 knockdown and MDM2-p53 inhibition by Nutlin-3 resulted in increased MDM2, p53, p21, p27, and cyclin E expression and reduced phospho-RB, RB, and cyclin A expression to a greater extent than with either intervention alone (Figure 3A and Figure S1).	('cyclin', 'molecular_function', 'GO:0016538', ('174', '180'))	('cyclin D1', 'Gene', '595', (19, 28))	('knockdown', 'Var', (29, 38))	('p21', 'Gene', '1026', (108, 111))	('phospho-RB', 'MPA', (154, 164))	('reduced', 'NegReg', (146, 153))	('MDM2', 'Protein', (97, 101))	('Nutlin-3', 'Chemical', 'MESH:C482205', (66, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))	('cyclin E', 'Protein', (122, 130))	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', '7157', (48, 51))	('expression', 'Species', '29278', (131, 141))	('inhibition', 'NegReg', (52, 62))	('p27', 'Protein', (113, 116))	('p53', 'Gene', (48, 51))	('p53', 'Gene', (103, 106))	('p21', 'Gene', (108, 111))	('co', 'Chemical', '-', (4, 6))	('increased', 'PosReg', (87, 96))	('cyclin D1', 'Gene', (19, 28))	('expression', 'Species', '29278', (183, 193))	('expression', 'MPA', (131, 141))	('cyclin', 'Protein', (174, 180))	('cyclin', 'molecular_function', 'GO:0016538', ('122', '128'))
190148	27129163	Cyclin D1 knockdown in wild-type p53 cancer cell lines (MESO257, MESO296, MESO428, MCF-7, MCS170, LPS695, MESO924, and LMS05) and in mutant p53 JMN1B cells resulted in ~45-55% and ~20% inhibition of cell viability at 3 days after cyclin D1 silencing, respectively, compared to the empty vector control (Figure 3B).	('cyclin', 'molecular_function', 'GO:0016538', ('230', '236'))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Cyclin D1', 'Gene', '595', (0, 9))	('p53', 'Gene', '7157', (33, 36))	('cyclin D1', 'Gene', (230, 239))	('Cyclin D1', 'Gene', (0, 9))	('MESO924', 'Chemical', '-', (106, 113))	('MESO257', 'Chemical', '-', (56, 63))	('MESO296', 'Chemical', '-', (65, 72))	('cell viability', 'CPA', (199, 213))	('MESO428', 'Chemical', '-', (74, 81))	('cyclin D1', 'Gene', '595', (230, 239))	('p53', 'Gene', (33, 36))	('MCS170', 'Chemical', '-', (90, 96))	('LPS695', 'Chemical', '-', (98, 104))	('silencing', 'NegReg', (240, 249))	('cancer', 'Disease', (37, 43))	('co', 'Chemical', '-', (265, 267))	('MCS', 'cellular_component', 'GO:0044232', ('90', '93'))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('inhibition', 'NegReg', (185, 195))	('mutant', 'Var', (133, 139))	('p53', 'Gene', '7157', (140, 143))	('p53', 'Gene', (140, 143))	('co', 'Chemical', '-', (294, 296))
190149	27129163	In addition, cell viability was evaluated after inhibition of cyclin D1 expression by small-molecule inhibitors 4-CPA or CyP (Figure S2), which have been demonstrated to inhibit CCND1 promoter activity and breast cancer cell growth.	('cyclin D1', 'Gene', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('CyP', 'Var', (121, 124))	('inhibit', 'NegReg', (170, 177))	('CCND1', 'Gene', '595', (178, 183))	('inhibition', 'NegReg', (48, 58))	('cell growth', 'biological_process', 'GO:0016049', ('220', '231'))	('expression', 'Species', '29278', (72, 82))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('expression', 'MPA', (72, 82))	('breast cancer', 'Disease', (206, 219))	('4-CPA', 'Chemical', 'MESH:C029716', (112, 117))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('cyclin D1', 'Gene', '595', (62, 71))	('CCND1', 'Gene', (178, 183))
190150	27129163	Treatment with 50 muM CyP resulted in ~50% reduction in viability at day 3 in MESO924, MESO296, and MCS170.	('muM', 'Gene', '56925', (18, 21))	('reduction', 'NegReg', (43, 52))	('CyP', 'Var', (22, 25))	('MCS170', 'Chemical', '-', (100, 106))	('MESO924', 'Chemical', '-', (78, 85))	('muM', 'Gene', (18, 21))	('MCS', 'cellular_component', 'GO:0044232', ('100', '103'))	('viability', 'MPA', (56, 65))	('MESO296', 'Chemical', '-', (87, 94))
190155	27129163	Notably, CCND1 shRNA knockdown or drug inhibition resulted in ~80% or 30-50% reduction in viability in JMN1B cells, respectively (Figure 3B and Figure S2).	('CCND1', 'Gene', (9, 14))	('viability', 'MPA', (90, 99))	('reduction', 'NegReg', (77, 86))	('inhibition', 'NegReg', (39, 49))	('CCND1', 'Gene', '595', (9, 14))	('knockdown', 'Var', (21, 30))
190156	27129163	We investigated cyclin D1 expression in mutant p53 JMN1B after treatment with Nutlin-3 for 48 hours or in three mutant p53 LPS cell lines (LPS141/266, LPS141/239, and LPS510) and wild-type p53 LPS141 cells after TP53 gene expression was stably silenced by lentiviral shRNAs.	('LPS141', 'Chemical', '-', (193, 199))	('mutant', 'Var', (112, 118))	('p53', 'Gene', '7157', (119, 122))	('expression', 'MPA', (26, 36))	('LPS510', 'Chemical', '-', (167, 173))	('cyclin D1', 'Gene', (16, 25))	('LPS141', 'Chemical', '-', (151, 157))	('mutant', 'Var', (40, 46))	('p53', 'Gene', (119, 122))	('p53', 'Gene', '7157', (47, 50))	('TP53', 'Gene', '7157', (212, 216))	('p53', 'Gene', '7157', (189, 192))	('Nutlin-3', 'Chemical', 'MESH:C482205', (78, 86))	('cyclin D1', 'Gene', '595', (16, 25))	('p53', 'Gene', (47, 50))	('expression', 'Species', '29278', (26, 36))	('LPS141', 'Chemical', '-', (139, 145))	('p53', 'Gene', (189, 192))	('JMN1B', 'Gene', (51, 56))	('gene expression', 'biological_process', 'GO:0010467', ('217', '232'))	('cyclin', 'molecular_function', 'GO:0016538', ('16', '22'))	('investigated', 'Reg', (3, 15))	('expression', 'Species', '29278', (222, 232))	('TP53', 'Gene', (212, 216))
190158	27129163	Silencing of p53 induced MDM2-FL and cyclin D1 expression in LPS141/239 and LPS510, however, p53 knockdown had minimal effect on the expression of MDM2-FL and cyclin D1 in LPS141 and LPS141/266 cells (Figure 4B).	('LPS510', 'Chemical', '-', (76, 82))	('Silencing', 'Var', (0, 9))	('expression', 'Species', '29278', (133, 143))	('MDM2-FL', 'Gene', (25, 32))	('cyclin', 'molecular_function', 'GO:0016538', ('37', '43'))	('LPS141', 'Chemical', '-', (183, 189))	('cyclin D1', 'Gene', (159, 168))	('p53', 'Gene', '7157', (13, 16))	('expression', 'MPA', (47, 57))	('cyclin D1', 'Gene', '595', (159, 168))	('p53', 'Gene', '7157', (93, 96))	('LPS141', 'Chemical', '-', (61, 67))	('cyclin D1', 'Gene', (37, 46))	('LPS141', 'Chemical', '-', (172, 178))	('p53', 'Gene', (13, 16))	('cyclin D1', 'Gene', '595', (37, 46))	('p53', 'Gene', (93, 96))	('cyclin', 'molecular_function', 'GO:0016538', ('159', '165'))	('expression', 'Species', '29278', (47, 57))
190161	27129163	MDM2 knockdown increased cyclin D1 and p53 expression in MESO924 (Figure 5A).	('cyclin', 'molecular_function', 'GO:0016538', ('25', '31'))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (15, 24))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('MDM2', 'Gene', (0, 4))	('MESO924', 'Chemical', '-', (57, 64))	('expression', 'Species', '29278', (43, 53))	('cyclin D1', 'Gene', '595', (25, 34))	('expression', 'MPA', (43, 53))	('cyclin D1', 'Gene', (25, 34))
190163	27129163	The MDM2 shRNA1/2 transductions resulted in greater than ~50% knockdown of MDM2-FL, while the MDM2 shRNA2 decreased MDM2-A expression, but MDM2 shRNA1 had minimal effect on MDM2-A expression (Figure 5B).	('MDM2-A', 'MPA', (116, 122))	('transductions', 'Var', (18, 31))	('expression', 'MPA', (123, 133))	('MDM2-FL', 'Gene', (75, 82))	('expression', 'Species', '29278', (180, 190))	('knockdown', 'MPA', (62, 71))	('expression', 'Species', '29278', (123, 133))
190164	27129163	MDM2 shRNA1 knockdown increased p53 and p21 expression in wild-type p53 cell lines, induced p27 expression in MESO428 and JMN1B, and decreased cyclin D1 expression in MESO428 and MCF7, but had no effect on cyclin D1 expression in MESO924, MESO296, and JMN1B (Figure 5B).	('expression', 'MPA', (44, 54))	('p53', 'Gene', '7157', (32, 35))	('increased', 'PosReg', (22, 31))	('expression', 'MPA', (153, 163))	('p21', 'Gene', (40, 43))	('p27', 'Protein', (92, 95))	('MCF7', 'CellLine', 'CVCL:0031', (179, 183))	('cyclin', 'molecular_function', 'GO:0016538', ('206', '212'))	('knockdown', 'Var', (12, 21))	('expression', 'MPA', (96, 106))	('MESO296', 'Chemical', '-', (239, 246))	('p53', 'Gene', (32, 35))	('cyclin', 'molecular_function', 'GO:0016538', ('143', '149'))	('cyclin D1', 'Gene', (143, 152))	('expression', 'Species', '29278', (44, 54))	('decreased', 'NegReg', (133, 142))	('MESO924', 'Chemical', '-', (230, 237))	('cyclin D1', 'Gene', (206, 215))	('MESO428', 'Chemical', '-', (167, 174))	('p21', 'Gene', '1026', (40, 43))	('expression', 'Species', '29278', (153, 163))	('MESO428', 'Chemical', '-', (110, 117))	('cyclin D1', 'Gene', '595', (143, 152))	('MDM2', 'Gene', (0, 4))	('induced', 'PosReg', (84, 91))	('p53', 'Gene', '7157', (68, 71))	('cyclin D1', 'Gene', '595', (206, 215))	('expression', 'Species', '29278', (96, 106))	('expression', 'Species', '29278', (216, 226))	('p53', 'Gene', (68, 71))
190165	27129163	MDM2 shRNA2 induced expression of cyclin D1, p21, and p27 in all cell lines, irrespective of p53 mutation status, but had minimal effect on p53 expression.	('p21', 'Gene', '1026', (45, 48))	('expression', 'Species', '29278', (144, 154))	('expression', 'MPA', (20, 30))	('p21', 'Gene', (45, 48))	('MDM2', 'Var', (0, 4))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('cyclin', 'molecular_function', 'GO:0016538', ('34', '40'))	('cyclin D1', 'Gene', '595', (34, 43))	('p27', 'Protein', (54, 57))	('shRNA2', 'Gene', (5, 11))	('cyclin D1', 'Gene', (34, 43))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('induced', 'Reg', (12, 19))	('expression', 'Species', '29278', (20, 30))
190166	27129163	In addition, cyclin D1 knockdown resulted in induction of p27 (Figure 5B).	('p27', 'Protein', (58, 61))	('induction', 'Reg', (45, 54))	('knockdown', 'Var', (23, 32))	('cyclin', 'molecular_function', 'GO:0016538', ('13', '19'))	('cyclin D1', 'Gene', '595', (13, 22))	('cyclin D1', 'Gene', (13, 22))
190168	27129163	qRT-PCR demonstrated upregulation of CCND1 mRNA in the MDM2-knockdown cells, with minimal increase in TP53 mRNA, compared to the empty vector treatment cells (Figure 5C).	('TP53', 'Gene', (102, 106))	('MDM2-knockdown', 'Var', (55, 69))	('CCND1', 'Gene', (37, 42))	('CCND1', 'Gene', '595', (37, 42))	('MDM2-knockdown', 'Gene', (55, 69))	('upregulation', 'PosReg', (21, 33))	('TP53', 'Gene', '7157', (102, 106))	('co', 'Chemical', '-', (113, 115))
190169	27129163	By contrast, MDM2 and TP53 mRNA expression was relatively unchanged after cyclin D1 knockdown in these cell lines (Figure 5C).	('cyclin', 'molecular_function', 'GO:0016538', ('74', '80'))	('co', 'Chemical', '-', (3, 5))	('cyclin D1', 'Gene', '595', (74, 83))	('knockdown', 'Var', (84, 93))	('MDM2', 'Gene', (13, 17))	('cyclin D1', 'Gene', (74, 83))	('TP53', 'Gene', '7157', (22, 26))	('expression', 'Species', '29278', (32, 42))	('TP53', 'Gene', (22, 26))
190178	27129163	Bortezomib and MG132 treatment resulted in cyclin D1 accumulation and an increase in ubiquitination, accompanied by accumulation of MDM2, p53, p21, and p27 in MESO924.	('p21', 'Gene', (143, 146))	('accumulation', 'PosReg', (116, 128))	('ubiquitination', 'MPA', (85, 99))	('p53', 'Gene', (138, 141))	('increase', 'PosReg', (73, 81))	('MG132', 'Gene', (15, 20))	('MESO924', 'Chemical', '-', (159, 166))	('cyclin D1', 'Gene', '595', (43, 52))	('p53', 'Gene', '7157', (138, 141))	('co', 'Chemical', '-', (103, 105))	('Bortezomib', 'Chemical', 'MESH:D000069286', (0, 10))	('cyclin D1', 'Gene', (43, 52))	('p21', 'Gene', '1026', (143, 146))	('p27', 'Var', (152, 155))	('MG132', 'Chemical', 'MESH:C072553', (15, 20))	('cyclin', 'molecular_function', 'GO:0016538', ('43', '49'))	('MDM2', 'Gene', (132, 136))	('accumulation', 'PosReg', (53, 65))
190187	27129163	Additionally, inhibition of the MDM2-p53 interaction induced cyclin D1 and cyclin E expression (Figure 2, Figure 3A, and Figure S1), which is consistent with published data showing that expression of MDM2-A resulted in induction of cyclin D1 and cyclin E in Hodgkin's lymphoma cells.	('MDM2-A', 'Gene', (200, 206))	('co', 'Chemical', '-', (142, 144))	('expression', 'Species', '29278', (84, 94))	('cyclin D1', 'Gene', (232, 241))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (258, 276))	('cyclin D1', 'Gene', '595', (232, 241))	('expression', 'Species', '29278', (186, 196))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (258, 276))	('cyclin', 'molecular_function', 'GO:0016538', ('232', '238'))	('cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('induced', 'Reg', (53, 60))	('cyclin D1', 'Gene', (61, 70))	('cyclin E', 'Gene', (75, 83))	("Hodgkin's lymphoma", 'Disease', (258, 276))	('p53', 'Gene', '7157', (37, 40))	('expression', 'MPA', (84, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (268, 276))	('interaction', 'Interaction', (41, 52))	('cyclin E', 'MPA', (246, 254))	('induction', 'PosReg', (219, 228))	('cyclin D1', 'Gene', '595', (61, 70))	('p53', 'Gene', (37, 40))	('cyclin', 'molecular_function', 'GO:0016538', ('246', '252'))	('inhibition', 'Var', (14, 24))	('cyclin', 'molecular_function', 'GO:0016538', ('61', '67'))
190189	27129163	Additive effects were obtained through simultaneous MDM2 inhibition and cyclin D1 shRNA knockdown/drug inhibition (Figure 3B and Figure S2), as shown by a decrease in cyclin A expression and reduction of cell viability.	('cyclin D1', 'Gene', (72, 81))	('reduction', 'NegReg', (191, 200))	('expression', 'Species', '29278', (176, 186))	('inhibition', 'NegReg', (57, 67))	('decrease', 'NegReg', (155, 163))	('cyclin', 'molecular_function', 'GO:0016538', ('72', '78'))	('cell viability', 'CPA', (204, 218))	('knockdown/drug', 'Var', (88, 102))	('MDM2', 'Gene', (52, 56))	('cyclin', 'molecular_function', 'GO:0016538', ('167', '173'))	('cyclin D1', 'Gene', '595', (72, 81))	('cyclin A expression', 'MPA', (167, 186))
190193	27129163	p53 knockdown by shRNAs induced expression cyclin D1 and MDM2-FL in mutant p53 LPS510 and LPS141/239, but resulted in no changes in expression in mutant p53 LPS141/266 and wild-type p53 LPS141 cell lines (Figure 4B).	('LPS510', 'Var', (79, 85))	('cyclin D1', 'Gene', '595', (43, 52))	('p53', 'Gene', '7157', (153, 156))	('p53', 'Gene', '7157', (182, 185))	('p53', 'Gene', '7157', (0, 3))	('induced', 'PosReg', (24, 31))	('MDM2-FL', 'Gene', (57, 64))	('p53', 'Gene', (153, 156))	('expression', 'Species', '29278', (132, 142))	('expression', 'MPA', (32, 42))	('p53', 'Gene', (182, 185))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (75, 78))	('LPS141', 'Chemical', '-', (157, 163))	('LPS141', 'Chemical', '-', (186, 192))	('LPS510', 'Chemical', '-', (79, 85))	('cyclin D1', 'Gene', (43, 52))	('p53', 'Gene', (75, 78))	('expression', 'Species', '29278', (32, 42))	('LPS141', 'Chemical', '-', (90, 96))	('cyclin', 'molecular_function', 'GO:0016538', ('43', '49'))	('mutant', 'Var', (68, 74))
190194	27129163	These results indicate that cyclin D1 expression might be inhibited by MDM2 but not p53, and there is no consistent response to p53 knockdown in the cell lines tested.	('expression', 'Species', '29278', (38, 48))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('expression', 'MPA', (38, 48))	('cyclin D1', 'Gene', '595', (28, 37))	('cyclin', 'molecular_function', 'GO:0016538', ('28', '34'))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('inhibited', 'NegReg', (58, 67))	('co', 'Chemical', '-', (105, 107))	('MDM2', 'Var', (71, 75))	('cyclin D1', 'Gene', (28, 37))
190195	27129163	To demonstrate cyclin D1 suppression by MDM2, MDM2 was silenced by siRNA and lentiviral shRNAs (Figure 5A and 5B).	('suppression', 'NegReg', (25, 36))	('cyclin D1', 'Gene', '595', (15, 24))	('cyclin D1', 'Gene', (15, 24))	('MDM2', 'Var', (40, 44))	('cyclin', 'molecular_function', 'GO:0016538', ('15', '21'))
190198	27129163	MDM2 shRNA2 knockdown resulted in upregulation of cyclin D1, without changing p53 expression (Figure 5B).	('expression', 'Species', '29278', (82, 92))	('cyclin D1', 'Gene', '595', (50, 59))	('cyclin D1', 'Gene', (50, 59))	('knockdown', 'Var', (12, 21))	('p53', 'Gene', (78, 81))	('cyclin', 'molecular_function', 'GO:0016538', ('50', '56'))	('shRNA2', 'Gene', (5, 11))	('p53', 'Gene', '7157', (78, 81))	('MDM2 shRNA2', 'Gene', (0, 11))	('upregulation', 'PosReg', (34, 46))
190200	27129163	qRT-PCR showed that MDM2 shRNA2 knockdown increased CCND1 transcript levels, with minimal effect on p53 levels (Figure 5C).	('increased', 'PosReg', (42, 51))	('CCND1', 'Gene', '595', (52, 57))	('p53', 'Gene', (100, 103))	('knockdown', 'Var', (32, 41))	('p53', 'Gene', '7157', (100, 103))	('transcript levels', 'MPA', (58, 75))	('CCND1', 'Gene', (52, 57))
190201	27129163	In addition, MDM2 inhibited CCND1 promoter activity, as shown by luciferase reporter assays (Figure 5D).	('CCND1', 'Gene', (28, 33))	('CCND1', 'Gene', '595', (28, 33))	('inhibited', 'NegReg', (18, 27))	('MDM2', 'Var', (13, 17))
190203	27129163	This finding is in line with increasing evidence that MDM2 promotes tumorigenesis in a p53-independent manner in cells lacking p53, in cells with mutant p53, and in cells expressing MDM2 splice variants lacking a p53-binding domain but possessing transforming activity.	('tumor', 'Disease', (68, 73))	('MDM2', 'Gene', (54, 58))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('p53-binding', 'molecular_function', 'GO:0002039', ('213', '224'))	('lacking', 'NegReg', (203, 210))	('promotes', 'PosReg', (59, 67))	('mutant', 'Var', (146, 152))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p53', 'Gene', (213, 216))	('p53', 'Gene', '7157', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
190208	27129163	Nutlin-3 treatment dramatically decreased the binding of MDM2 and p53, and partially attenuated cyclin D1 binding by MDM2 (Figure 6B).	('cyclin D1', 'Gene', (96, 105))	('MDM2', 'Protein', (57, 61))	('p53', 'Gene', '7157', (66, 69))	('binding', 'Interaction', (106, 113))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('cyclin D1', 'Gene', '595', (96, 105))	('binding', 'molecular_function', 'GO:0005488', ('46', '53'))	('cyclin', 'molecular_function', 'GO:0016538', ('96', '102'))	('MDM2', 'Var', (117, 121))	('Nutlin-3', 'Chemical', 'MESH:C482205', (0, 8))	('binding', 'Interaction', (46, 53))	('attenuated', 'NegReg', (85, 95))	('decreased', 'NegReg', (32, 41))	('p53', 'Gene', (66, 69))
190212	27129163	In the present study, MDM2 knockdown resulted in downregulation (MDM2 shRNA1) and upregulation (MDM2 shRNA2 and MDM2 siRNA) of cyclin D1 (Figure 5B), suggesting that complicated mechanisms may be involved for the different isoform expression of MDM2.	('knockdown', 'Var', (27, 36))	('MDM2', 'Gene', (22, 26))	('cyclin', 'molecular_function', 'GO:0016538', ('127', '133'))	('upregulation', 'PosReg', (82, 94))	('downregulation', 'NegReg', (49, 63))	('cyclin D1', 'Gene', '595', (127, 136))	('expression', 'Species', '29278', (231, 241))	('co', 'Chemical', '-', (166, 168))	('cyclin D1', 'Gene', (127, 136))
190215	27129163	Finally, a multipoint targeted attack on MDM2-p53 interaction and cyclin D1 could potentially maximize the treatment effect of MDM2-p53 inhibitors by blocking the compensatory upregulation of cyclin D1.	('cyclin D1', 'Gene', '595', (66, 75))	('cyclin D1', 'Gene', (66, 75))	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('upregulation', 'PosReg', (176, 188))	('cyclin', 'molecular_function', 'GO:0016538', ('192', '198'))	('p53', 'Gene', (46, 49))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('inhibitors', 'Var', (136, 146))	('co', 'Chemical', '-', (76, 78))	('p53', 'Gene', '7157', (46, 49))	('maximize', 'PosReg', (94, 102))	('co', 'Chemical', '-', (163, 165))	('cyclin D1', 'Gene', '595', (192, 201))	('blocking', 'NegReg', (150, 158))	('cyclin D1', 'Gene', (192, 201))
190223	27129163	MESO924, MESO257, MESO296, and MESO428 have wild-type p53, but JMN1B contains a p53 point mutation (G245S).	('MESO296', 'Chemical', '-', (18, 25))	('MESO257', 'Chemical', '-', (9, 16))	('G245S', 'Var', (100, 105))	('p53', 'Gene', (80, 83))	('co', 'Chemical', '-', (69, 71))	('p53', 'Gene', (54, 57))	('MESO428', 'Chemical', '-', (31, 38))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', '7157', (54, 57))	('MESO924', 'Chemical', '-', (0, 7))	('G245S', 'Mutation', 'rs28934575', (100, 105))
190225	27129163	LPS141, LPS141/266, LPS141/239, LPS695, and LPS510 were developed in the Department of Pathology at Brigham and Women's Hospital.	('LPS141', 'Chemical', '-', (0, 6))	('LPS141', 'Chemical', '-', (20, 26))	('LPS510', 'Var', (44, 50))	('LPS695', 'Var', (32, 38))	('LPS695', 'Chemical', '-', (32, 38))	('LPS510', 'Chemical', '-', (44, 50))	('LPS141/239', 'Var', (20, 30))	('Women', 'Species', '9606', (112, 117))	('LPS141/266', 'Var', (8, 18))	('LPS141', 'Chemical', '-', (8, 14))
190227	27129163	LPS141/266 and LPS141/239 are isogenic sublines of LPS141 which retain the parental MDM2 and CDK4 genomic amplification but have acquired p53 point mutations (G266R and N239D, respectively).	('CDK', 'molecular_function', 'GO:0004693', ('93', '96'))	('p53', 'Gene', (138, 141))	('N239D', 'Mutation', 'rs876660807', (169, 174))	('G266R', 'Var', (159, 164))	('G266R', 'Mutation', 'rs1057519990', (159, 164))	('p53', 'Gene', '7157', (138, 141))	('LPS141', 'Chemical', '-', (15, 21))	('N239D', 'Var', (169, 174))	('LPS141', 'Chemical', '-', (0, 6))	('LPS141', 'Chemical', '-', (51, 57))
190236	27129163	3 mug of primary mouse antibodies against MDM2, p53, and primary rabbit antibodies against cyclin D1 were rocked with the lysates for 2 hours at 4 C. Then, 20 muL of sepharose-protein G/A beads was added and rocked overnight at 4 C, then centrifuged at 10,000 rpm for 2 min at 4 C, after which the sepharose beads were washed 3 times (25 min each) with 750 muL of IP buffer and once with 750muL 10 mM Tris-Cl buffer (pH7.6).	('Tris-Cl', 'Chemical', '-', (401, 408))	('p53', 'Gene', (48, 51))	('rabbit', 'Species', '9986', (65, 71))	('sepharose', 'Chemical', 'MESH:D012685', (166, 175))	('cyclin', 'molecular_function', 'GO:0016538', ('91', '97'))	('mouse', 'Species', '10090', (17, 22))	('p53', 'Gene', '7157', (48, 51))	('mug', 'molecular_function', 'GO:0043739', ('2', '5'))	('MDM2', 'Var', (42, 46))	('cyclin D1', 'Gene', '595', (91, 100))	('sepharose', 'Chemical', 'MESH:D012685', (298, 307))	('cyclin D1', 'Gene', (91, 100))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
190241	27129163	Lentiviruses were produced by cotransfecting pLKO.1puro plasmids containing MDM2, p53 or CCND1 shRNAs, and helper virus packaging plasmids pCMVDeltaR8.91 and pMD.G (at a 10:10:1 ratio) into 293T cells.	('co', 'Chemical', '-', (65, 67))	('293T', 'CellLine', 'CVCL:0063', (190, 194))	('CCND1', 'Gene', (89, 94))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (82, 85))	('co', 'Chemical', '-', (30, 32))	('MDM2', 'Var', (76, 80))	('CCND1', 'Gene', '595', (89, 94))
190244	27129163	Mesothelioma cell lines (MESO924, MESO257, MESO296, MESO428, and JMN1B), LPS cell lines (LPS141, LPS695, LPS141/239, LPS141/266, and LPS510), MCF-7, and MCS170 were maintained in RPMI 1640 with 10% fetal bovine serum (FBS) supplemented with penicillin/streptomycin and 1% (v/v) L-glutamine.	('LPS141', 'Chemical', '-', (105, 111))	('MCF-7', 'CellLine', 'CVCL:0031', (142, 147))	('LPS695', 'Var', (97, 103))	('MESO428', 'Chemical', '-', (52, 59))	('MESO296', 'Chemical', '-', (43, 50))	('streptomycin', 'Chemical', 'MESH:D013307', (252, 264))	('LPS141', 'Chemical', '-', (89, 95))	('FBS', 'Disease', (218, 221))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('MESO924', 'Chemical', '-', (25, 32))	('FBS', 'Disease', 'MESH:D005198', (218, 221))	('MCS', 'cellular_component', 'GO:0044232', ('153', '156'))	('L-glutamine', 'Chemical', 'MESH:D005973', (278, 289))	('LPS141', 'Chemical', '-', (117, 123))	('MCS170', 'Chemical', '-', (153, 159))	('LPS695', 'Chemical', '-', (97, 103))	('RPMI', 'Chemical', '-', (179, 183))	('LPS141/239', 'Var', (105, 115))	('bovine', 'Species', '9913', (204, 210))	('LPS510', 'Chemical', '-', (133, 139))	('penicillin', 'Chemical', 'MESH:D010406', (241, 251))	('MESO257', 'Chemical', '-', (34, 41))
190268	19846892	To address the molecular pathogenesis of environmental carcinogens, we examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer.	('pathogenesis', 'biological_process', 'GO:0009405', ('25', '37'))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('colon', 'Disease', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (86, 92))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('rat', 'Species', '10116', (163, 166))	('alterations', 'Var', (159, 170))	('epigenetic events', 'Var', (191, 208))	('lung', 'Disease', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('human', 'Species', '9606', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('mesothelioma', 'Disease', (141, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
190281	19846892	The pathogenesis of colon cancer is a multi-step process involving activation of oncogenes, loss of tumor suppressor gene function, and dysfunction of DNA repair.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('activation', 'PosReg', (67, 77))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('colon cancer', 'Disease', 'MESH:D015179', (20, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('loss', 'NegReg', (92, 96))	('oncogenes', 'Gene', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DNA repair', 'biological_process', 'GO:0006281', ('151', '161'))	('pathogenesis', 'biological_process', 'GO:0009405', ('4', '16'))	('colon cancer', 'Disease', (20, 32))	('dysfunction', 'Var', (136, 147))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
190282	19846892	Loss of function of the APC tumor suppressor gene or beta-catenin (CTNNB1) gene mutation are early events in the development of colon cancer in humans.	('colon cancer', 'Disease', (128, 140))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('APC tumor', 'Disease', 'MESH:D011125', (24, 33))	('APC tumor', 'Disease', (24, 33))	('CTNNB1', 'Gene', '1499', (67, 73))	('Loss of function', 'NegReg', (0, 16))	('humans', 'Species', '9606', (144, 150))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('CTNNB1', 'Gene', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutation', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
190284	19846892	With loss of function of APC due to mutation, accumuation of beta-catenin occurs, followed by activation of nuclear transcription factors and increases in levels of target proteins such as MYC and cyclin D1.	('APC', 'Gene', (25, 28))	('MYC', 'Gene', (189, 192))	('cyclin D1', 'MPA', (197, 206))	('cyclin', 'molecular_function', 'GO:0016538', ('197', '203'))	('increases', 'PosReg', (142, 151))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('beta-catenin', 'Protein', (61, 73))	('activation', 'PosReg', (94, 104))	('APC', 'Gene', '324', (25, 28))	('MYC', 'Gene', '4609', (189, 192))	('loss of function', 'NegReg', (5, 21))	('levels of target proteins', 'MPA', (155, 180))	('APC', 'cellular_component', 'GO:0005680', ('25', '28'))	('mutation', 'Var', (36, 44))	('nuclear transcription factors', 'MPA', (108, 137))
190285	19846892	However, mutation of the CTNNB1 gene without loss of the APC gene also results in accumulation of ss-catenin protein and increased WNT signaling in a subset of colon cancers.	('WNT', 'Gene', '114487', (131, 134))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('colon cancers', 'Phenotype', 'HP:0003003', (160, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('CTNNB1', 'Gene', '1499', (25, 31))	('accumulation', 'PosReg', (82, 94))	('APC', 'Gene', (57, 60))	('WNT', 'Gene', (131, 134))	('colon cancers', 'Disease', 'MESH:D015179', (160, 173))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('mutation', 'Var', (9, 17))	('colon cancers', 'Disease', (160, 173))	('increased', 'PosReg', (121, 130))	('CTNNB1', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('APC', 'cellular_component', 'GO:0005680', ('57', '60'))	('APC', 'Gene', '324', (57, 60))	('ss-catenin protein', 'Protein', (98, 116))
190286	19846892	The genetic alterations involved in familial adenomatous polyposis (FAP), leading to colorectal cancer, have been well documented and in addition to alterations of the APC gene there are mutations in the KRAS oncogene, p53 tumor suppressor gene (TP53), and TGFB growth regulatory genes.	('APC', 'Gene', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (36, 66))	('rat', 'Species', '10116', (16, 19))	('rat', 'Species', '10116', (153, 156))	('APC', 'cellular_component', 'GO:0005680', ('168', '171'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('223', '239'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor suppressor', 'biological_process', 'GO:0051726', ('223', '239'))	('tumor', 'Disease', (223, 228))	('APC', 'Gene', '324', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('FAP', 'Disease', (68, 71))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (45, 66))	('p53', 'Gene', '7157', (219, 222))	('FAP', 'Disease', 'MESH:C567782', (68, 71))	('colorectal cancer', 'Disease', (85, 102))	('TGFB', 'Gene', (257, 261))	('mutations', 'Var', (187, 196))	('TP53', 'Gene', (246, 250))	('TGFB', 'Gene', '7040', (257, 261))	('p53', 'Gene', (219, 222))	('familial adenomatous polyposis', 'Disease', (36, 66))
190291	19846892	The National Toxicology 2-year carcinogenicity bioassay determined that exposure of B6C3F1 mice to o-nitrotoluene resulted in an increased incidence of cecal carcinomas.	('carcinomas', 'Disease', (158, 168))	('carcinomas', 'Disease', 'MESH:D002277', (158, 168))	('mice', 'Species', '10090', (91, 95))	('o-nitrotoluene', 'Chemical', 'MESH:C029955', (99, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (31, 43))	('o-nitrotoluene', 'Var', (99, 113))	('carcinogenic', 'Disease', (31, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))
190297	19846892	Exon 2 (corresponding with exon 3 in humans) Catnb mutations were present in 100% of carcinomas, and mutations in Tp53 and Kras occurred in a majority of tumors.	('tumors', 'Disease', (154, 160))	('mutations', 'Var', (51, 60))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('humans', 'Species', '9606', (37, 43))	('Catnb', 'Gene', '12387', (45, 50))	('Catnb', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('carcinomas', 'Disease', 'MESH:D002277', (85, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinomas', 'Disease', (85, 95))
190298	19846892	These data showed that genetic alterations in the mouse large intestinal carcinomas resulted in activation of signal transduction (Kras and Catnb) and disruption of cell-cycle control (Tp53, cyclin D1), hallmarks of human colon cancer.	('human', 'Species', '9606', (216, 221))	('activation of signal transduction', 'biological_process', 'GO:0009967', ('96', '129'))	('cell-cycle control', 'biological_process', 'GO:1901987', ('165', '183'))	('colon cancer', 'Disease', (222, 234))	('signal transduction', 'MPA', (110, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('intestinal carcinomas', 'Disease', (62, 83))	('activation', 'PosReg', (96, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (222, 234))	('cyclin', 'molecular_function', 'GO:0016538', ('191', '197'))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('genetic alterations', 'Var', (23, 42))	('rat', 'Species', '10116', (35, 38))	('Catnb', 'Gene', '12387', (140, 145))	('cell-cycle control', 'CPA', (165, 183))	('disruption', 'NegReg', (151, 161))	('intestinal carcinomas', 'Disease', 'MESH:D007414', (62, 83))	('colon cancer', 'Disease', 'MESH:D015179', (222, 234))	('mouse', 'Species', '10090', (50, 55))	('Catnb', 'Gene', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
190299	19846892	Considering that 100% of cecal carcinomas had mutations in the Catnb gene, it is likely that dysregulated expression of beta-catenin protein plays a role in the pathogenesis of these mouse cecal carcinomas, as is the case in human colon cancer.	('carcinomas', 'Disease', (31, 41))	('mouse', 'Species', '10090', (183, 188))	('Catnb', 'Gene', '12387', (63, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (231, 243))	('carcinomas', 'Disease', (195, 205))	('mutations', 'Var', (46, 55))	('pathogenesis', 'biological_process', 'GO:0009405', ('161', '173'))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('Catnb', 'Gene', (63, 68))	('colon cancer', 'Disease', 'MESH:D015179', (231, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('carcinomas', 'Disease', 'MESH:D002277', (31, 41))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('carcinomas', 'Disease', 'MESH:D002277', (195, 205))	('colon cancer', 'Disease', (231, 243))	('human', 'Species', '9606', (225, 230))
190300	19846892	These data correlate with the hypothesis that large intestinal epithelium in the mouse, similar to the case in humans, must acquire multiple mutations for transformation, ultimately culminating in the full malignant phenotype of the adenocarcinoma.	('mutations', 'Var', (141, 150))	('adenocarcinoma', 'Disease', (233, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('culminating in', 'Reg', (182, 196))	('adenocarcinoma', 'Disease', 'MESH:D000230', (233, 247))	('mouse', 'Species', '10090', (81, 86))	('humans', 'Species', '9606', (111, 117))
190301	19846892	The activation of the Kras oncogene provides growth-promoting signals, the loss of Tp53 results in unregulated growth and DNA repair defects, and activation of both Catnb and Kras results in increased cyclin D1 expression.	('cyclin D1 expression', 'MPA', (201, 221))	('DNA repair', 'biological_process', 'GO:0006281', ('122', '132'))	('Tp53', 'Gene', (83, 87))	('Kras', 'Gene', (175, 179))	('cyclin', 'molecular_function', 'GO:0016538', ('201', '207'))	('increased', 'PosReg', (191, 200))	('Catnb', 'Gene', '12387', (165, 170))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('loss', 'Var', (75, 79))	('Catnb', 'Gene', (165, 170))
190302	19846892	The interaction between these various mutations and their impact on signaling pathways ultimately culminates in the full malignant phenotype of cecal carcinomas.	('interaction', 'Interaction', (4, 15))	('signaling pathways', 'Pathway', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('mutations', 'Var', (38, 47))	('carcinomas', 'Disease', (150, 160))	('carcinomas', 'Disease', 'MESH:D002277', (150, 160))	('culminates in', 'Reg', (98, 111))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
190306	19846892	Most lung cancers in humans are non-small-cell lung cancers resulting from genetic and epigenetic damage from chronic exposure to tobacco smoke carcinogens, but the frequency of adenocarcinoma is on the rise in non-smokers.	('lung cancer', 'Phenotype', 'HP:0100526', (5, 16))	('lung cancers', 'Phenotype', 'HP:0100526', (5, 17))	('smoke carcinogens', 'Disease', (138, 155))	('epigenetic damage', 'Var', (87, 104))	('smoke carcinogens', 'Disease', 'MESH:D000074607', (138, 155))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (36, 58))	('tobacco', 'Species', '4097', (130, 137))	('small-cell lung cancer', 'Disease', (36, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('humans', 'Species', '9606', (21, 27))	('resulting from', 'Reg', (60, 74))	('lung cancers', 'Disease', 'MESH:D008175', (47, 59))	('adenocarcinoma', 'Disease', (178, 192))	('lung cancers', 'Disease', (47, 59))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (36, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancers', 'Disease', 'MESH:D008175', (5, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancers', 'Phenotype', 'HP:0100526', (47, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (178, 192))	('lung cancers', 'Disease', (5, 17))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (32, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
190308	19846892	Mouse models have been utilized for studying carcinogenesis of human lung cancers, and are both histologically similar and share many of the major genetic alterations detected in human pulmonary adenocarcinoma, including activation of the KRAS protooncogene and inactivation of the TP53 tumor suppressor gene.	('man', 'Species', '9606', (129, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('man', 'Species', '9606', (65, 68))	('KRAS protooncogene', 'Gene', (239, 257))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', (287, 292))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('287', '303'))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (185, 209))	('carcinogenesis of human lung cancers', 'Disease', (45, 81))	('man', 'Species', '9606', (181, 184))	('carcinogenesis of human lung cancers', 'Disease', 'MESH:D063646', (45, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('287', '303'))	('human', 'Species', '9606', (179, 184))	('pulmonary adenocarcinoma', 'Disease', (185, 209))	('activation', 'PosReg', (221, 231))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (185, 209))	('inactivation', 'Var', (262, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('Mouse', 'Species', '10090', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('lung cancers', 'Phenotype', 'HP:0100526', (69, 81))	('rat', 'Species', '10116', (159, 162))
190309	19846892	Kras mutation is the most common molecular alteration identified in mouse lung adenomas and carcinomas, and occurs in 30-50% of human lung adenocarcinomas.	('mouse', 'Species', '10090', (68, 73))	('lung adenomas and carcinomas', 'Disease', 'MESH:D000236', (74, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (134, 154))	('rat', 'Species', '10116', (47, 50))	('Kras', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('human', 'Species', '9606', (128, 133))	('lung adenocarcinomas', 'Disease', (134, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (134, 154))	('mutation', 'Var', (5, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
190314	19846892	Since certain chemicals often induce specific patterns of activation of Ras oncogenes or inactivation of Tp53 tumor suppressor gene function compared to spontaneous neoplasms in mice, and these genetic mutations are considered important in the pathogenesis of human lung cancer, we evaluated spontaneous and cumene-induced lung neoplasms for mutations in Kras and Tp53 genes, as well as chemical-specific mutations that could function as biomarkers of chemical exposure with potential human health importance.	('lung neoplasms', 'Disease', 'MESH:D008175', (323, 337))	('neoplasm', 'Phenotype', 'HP:0002664', (165, 173))	('mutations', 'Var', (342, 351))	('activation', 'PosReg', (58, 68))	('neoplasms', 'Disease', 'MESH:D009369', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('neoplasms', 'Phenotype', 'HP:0002664', (328, 337))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('human', 'Species', '9606', (485, 490))	('neoplasm', 'Phenotype', 'HP:0002664', (328, 336))	('lung cancer', 'Disease', (266, 277))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('Tp53', 'Gene', (364, 368))	('neoplasms', 'Disease', (165, 174))	('pathogenesis', 'biological_process', 'GO:0009405', ('244', '256'))	('mice', 'Species', '10090', (178, 182))	('Ras', 'Gene', (72, 75))	('lung neoplasms', 'Phenotype', 'HP:0100526', (323, 337))	('Kras', 'Gene', (355, 359))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('human', 'Species', '9606', (260, 265))	('neoplasms', 'Disease', 'MESH:D009369', (328, 337))	('cumene', 'Chemical', 'MESH:C015763', (308, 314))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))	('tumor', 'Disease', (110, 115))	('lung cancer', 'Disease', 'MESH:D008175', (266, 277))	('neoplasms', 'Phenotype', 'HP:0002664', (165, 174))	('neoplasms', 'Disease', (328, 337))	('lung neoplasms', 'Disease', (323, 337))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
190319	19846892	Principal component analysis was able to segregate pulmonary carcinomas induced by cumene into groups with and without Kras mutations.	('mutations', 'Var', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('cumene', 'Chemical', 'MESH:C015763', (83, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('pulmonary carcinomas', 'Disease', (51, 71))	('pulmonary carcinomas', 'Disease', 'MESH:D008175', (51, 71))
190320	19846892	Following this, genes associated with the ERK-MAPK signaling pathway were shown to be significantly upregulated in tumors with Kras mutations, as well as a number of genes associated with tumor malignancy (invasion and metastasis) such as Krt8, Krt18, Lasp1, Sdc1, Ccnd1, and Mmp14, suggesting that cumene-induced carcinomas with Kras mutations have greater malignant potential than those without mutations.	('Sdc1', 'Gene', (259, 263))	('Sdc1', 'Gene', '6382', (259, 263))	('upregulated', 'PosReg', (100, 111))	('mutations', 'Var', (335, 344))	('ERK', 'Gene', '5594', (42, 45))	('Mmp', 'molecular_function', 'GO:0004235', ('276', '279'))	('Mmp14', 'Gene', '4323', (276, 281))	('Lasp1', 'Gene', '3927', (252, 257))	('Mmp14', 'Gene', (276, 281))	('Kras', 'Gene', (127, 131))	('carcinomas', 'Disease', (314, 324))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ERK', 'Gene', (42, 45))	('Ccnd1', 'Gene', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor malignancy', 'Disease', 'MESH:D018198', (188, 204))	('Krt18', 'Gene', '3875', (245, 250))	('tumors', 'Disease', (115, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('malignant potential', 'CPA', (358, 377))	('Kras', 'Gene', (330, 334))	('Krt8', 'Gene', (239, 243))	('ERK', 'molecular_function', 'GO:0004707', ('42', '45'))	('Krt18', 'Gene', (245, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('mutations', 'Var', (132, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (314, 324))	('MAPK signaling', 'biological_process', 'GO:0000165', ('46', '60'))	('carcinomas', 'Disease', 'MESH:D002277', (314, 324))	('tumor malignancy', 'Disease', (188, 204))	('signaling pathway', 'biological_process', 'GO:0007165', ('51', '68'))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('Lasp1', 'Gene', (252, 257))	('cumene', 'Chemical', 'MESH:C015763', (299, 305))	('Ccnd1', 'Gene', '595', (265, 270))	('Krt8', 'Gene', '3856', (239, 243))
190321	19846892	SAFE (significance analysis of function and expression) analysis further showed that carcinomas with Kras mutations had changes in expression of histone deacetylases (HDACs), suggesting histone modification as an epigenetic mechanism of carcinogenesis in cumene-induced lung carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (275, 285))	('carcinomas', 'Disease', 'MESH:D002277', (275, 285))	('lung carcinomas', 'Disease', 'MESH:D008175', (270, 285))	('carcinomas', 'Disease', (275, 285))	('carcinogenesis', 'Disease', 'MESH:D063646', (237, 251))	('histone modification', 'biological_process', 'GO:0016570', ('186', '206'))	('cumene', 'Chemical', 'MESH:C015763', (255, 261))	('changes', 'Reg', (120, 127))	('expression', 'MPA', (131, 141))	('carcinogenesis', 'Disease', (237, 251))	('lung carcinomas', 'Disease', (270, 285))	('mutations', 'Var', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Disease', 'MESH:D002277', (85, 95))	('Kras', 'Gene', (101, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinomas', 'Disease', (85, 95))
190322	19846892	Our gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation and activation of Kras, with activation of the MAPK pathway and dysregulation of a number of genes associated with tumor malignancy.	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('alveolar/bronchiolar carcinomas', 'Disease', (56, 87))	('mice', 'Species', '10090', (106, 110))	('cumene', 'Chemical', 'MESH:C015763', (91, 97))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('mutation', 'Var', (130, 138))	('tumor malignancy', 'Disease', 'MESH:D018198', (254, 270))	('MAPK pathway', 'Pathway', (186, 198))	('Kras', 'Gene', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('alveolar/bronchiolar carcinomas', 'Disease', 'MESH:D002282', (56, 87))	('dysregulation', 'MPA', (203, 216))	('activation', 'PosReg', (143, 153))	('activation', 'PosReg', (168, 178))	('tumor malignancy', 'Disease', (254, 270))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
190323	19846892	In cumene-induced tumors with and without Kras mutation, there was downregulation of a number of tumor suppressor genes (Ptprd, Igsf4a, Fhl1, Pdzd2, Cdkn2d, Cdh5, Loxl1, and Akap12) and genes associated with inhibition of invasion (Reck, Gsn, Lims2, Cav1, and Gpx3).	('Igsf4a', 'Gene', '23705', (128, 134))	('cumene', 'Chemical', 'MESH:C015763', (3, 9))	('Lims2', 'Gene', '55679', (243, 248))	('Cav1', 'Gene', (250, 254))	('Loxl1', 'Gene', (163, 168))	('Gsn', 'Gene', '2934', (238, 241))	('Kras', 'Gene', (42, 46))	('tumors', 'Disease', (18, 24))	('Gsn', 'Gene', (238, 241))	('Ptprd', 'Gene', (121, 126))	('Ptprd', 'Gene', '5789', (121, 126))	('genes', 'Gene', (186, 191))	('Cav1', 'Gene', '857', (250, 254))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (97, 102))	('Akap12', 'Gene', '9590', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Reck', 'Gene', '8434', (232, 236))	('downregulation', 'NegReg', (67, 81))	('Cdkn2d', 'Gene', '1032', (149, 155))	('Cdh5', 'Gene', (157, 161))	('Cdkn2d', 'Gene', (149, 155))	('Pdzd2', 'Gene', (142, 147))	('Fhl1', 'Gene', (136, 140))	('Reck', 'Gene', (232, 236))	('Cdh5', 'Gene', '1003', (157, 161))	('Pdzd2', 'Gene', '23037', (142, 147))	('Igsf4a', 'Gene', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('Gpx3', 'Gene', (260, 264))	('Fhl1', 'Gene', '2273', (136, 140))	('Loxl1', 'Gene', '4016', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutation', 'Var', (47, 55))	('Akap12', 'Gene', (174, 180))	('Lims2', 'Gene', (243, 248))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('Gpx3', 'Gene', '2878', (260, 264))	('tumor suppressor', 'biological_process', 'GO:0051726', ('97', '113'))
190324	19846892	In cumene-induced tumors with Kras mutations, there was decreased expression of additional genes associated with inhibition of cell motility and cell proliferation (Igfbp4, Sod3, Rb1, Cebpd, Vwf, and Dlc1) and genes associated with patient survival (Cyr61and Enpp2).	('cumene', 'Chemical', 'MESH:C015763', (3, 9))	('expression', 'MPA', (66, 76))	('cell motility', 'CPA', (127, 140))	('tumors', 'Disease', (18, 24))	('Cyr61', 'Gene', '3491', (250, 255))	('Igfbp4', 'Gene', (165, 171))	('Enpp2', 'Gene', (259, 264))	('Sod3', 'Gene', '6649', (173, 177))	('Cebpd', 'Gene', '1052', (184, 189))	('Rb1', 'Gene', '5925', (179, 182))	('decreased', 'NegReg', (56, 65))	('Dlc1', 'Gene', '10395', (200, 204))	('Igfbp4', 'Gene', '3487', (165, 171))	('rat', 'Species', '10116', (157, 160))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('Rb', 'Phenotype', 'HP:0009919', (179, 181))	('Sod3', 'molecular_function', 'GO:0004784', ('173', '177'))	('Enpp2', 'Gene', '5168', (259, 264))	('Vwf', 'Gene', '7450', (191, 194))	('Vwf', 'Gene', (191, 194))	('Cebpd', 'Gene', (184, 189))	('Cyr61', 'Gene', (250, 255))	('Dlc1', 'Gene', (200, 204))	('Sod3', 'Gene', (173, 177))	('Rb1', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cell motility', 'biological_process', 'GO:0048870', ('127', '140'))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('Kras', 'Gene', (30, 34))	('inhibition', 'NegReg', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('patient', 'Species', '9606', (232, 239))	('mutations', 'Var', (35, 44))
190326	19846892	Additionally, cluster analysis of genes generally associated with HDAC regulation revealed a stronger association with tumors with Kras mutation.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('association', 'Interaction', (102, 113))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('mutation', 'Var', (136, 144))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Kras', 'Gene', (131, 135))
190327	19846892	These results suggest that in cumene-induced pulmonary tumors in mice, DNA damage and genomic instability leading to Kras and Tp53 dysregulation leads to upregulation of pathways associated with the development of lung cancer in cumene-exposed mice, and that tumors resulting from mutations in Kras possess a gene expression associated with a greater degree of malignancy.	('pulmonary tumors', 'Phenotype', 'HP:0100526', (45, 61))	('mice', 'Species', '10090', (244, 248))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('dysregulation', 'Var', (131, 144))	('pulmonary tumors', 'Disease', (45, 61))	('lung cancer', 'Disease', (214, 225))	('Kras', 'Gene', (294, 298))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('malignancy', 'Disease', 'MESH:D009369', (361, 371))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', (259, 265))	('gene expression', 'biological_process', 'GO:0010467', ('309', '324'))	('Tp53', 'Gene', (126, 130))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('mice', 'Species', '10090', (65, 69))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('malignancy', 'Disease', (361, 371))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('pathways', 'Pathway', (170, 178))	('Kras', 'Gene', (117, 121))	('pulmonary tumors', 'Disease', 'MESH:D008175', (45, 61))	('cumene', 'Chemical', 'MESH:C015763', (229, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cumene', 'Chemical', 'MESH:C015763', (30, 36))	('mutations', 'Var', (281, 290))	('upregulation', 'PosReg', (154, 166))
190334	19846892	The results of mutational analysis revealed that a majority of the AZT-induced tumors contained mutations in Kras (66%) and Tp53 (84%).	('AZT', 'Chemical', 'MESH:D015215', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Kras', 'Gene', (109, 113))	('Tp53', 'Gene', (124, 128))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('contained', 'Reg', (86, 95))	('mutations', 'Var', (96, 105))
190335	19846892	Although the incidence of AZT-induced lung tumors in females was not statistically significantly increased above controls, a majority of these tumors contained the same Kras mutation (61%) as found in male lung tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('lung tumors', 'Disease', 'MESH:D008175', (38, 49))	('lung tumors', 'Disease', 'MESH:D008175', (206, 217))	('tumors', 'Disease', (143, 149))	('lung tumors', 'Phenotype', 'HP:0100526', (38, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('lung tumors', 'Phenotype', 'HP:0100526', (206, 217))	('contained', 'Reg', (150, 159))	('AZT', 'Chemical', 'MESH:D015215', (26, 29))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('lung tumors', 'Disease', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (211, 217))	('male lung tumors', 'Disease', 'MESH:D018567', (201, 217))	('male lung tumors', 'Disease', (201, 217))	('Kras mutation', 'Var', (169, 182))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
190344	19846892	To evaluate the potential human risk from EO, our laboratory examined EO-induced tumors in the lung, harderian gland, and uterus from exposed mice for Kras mutations.	('tumors', 'Disease', (81, 87))	('EO', 'Chemical', 'MESH:D005027', (42, 44))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (156, 165))	('EO', 'Chemical', 'MESH:D005027', (70, 72))	('rat', 'Species', '10116', (54, 57))	('Kras', 'Gene', (151, 155))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (26, 31))
190345	19846892	While this mutation was found in 25% (27/108) of spontaneous lung tumors, 100% (23/23) of EO-induced lung tumors had Kras mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('lung tumors', 'Phenotype', 'HP:0100526', (101, 112))	('EO', 'Chemical', 'MESH:D005027', (90, 92))	('lung tumors', 'Phenotype', 'HP:0100526', (61, 72))	('lung tumors', 'Disease', (61, 72))	('EO-induced', 'Disease', (90, 100))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lung tumors', 'Disease', 'MESH:D008175', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('lung tumors', 'Disease', 'MESH:D008175', (61, 72))	('Kras mutations', 'Var', (117, 131))	('lung tumors', 'Disease', (101, 112))
190346	19846892	The most common mutations were codon 12 G T transversions, which were infrequent in spontaneous tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('codon 12 G T transversions', 'Var', (31, 57))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))
190347	19846892	Kras mutations were also very common in EO-induced harderian gland tumors (18/21, 86%), and infrequent in spontaneous tumors (2/27, 7%).	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('harderian gland tumors', 'Disease', 'MESH:D010871', (51, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('harderian gland tumors', 'Disease', (51, 73))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EO', 'Chemical', 'MESH:D005027', (40, 42))	('Kras', 'Gene', (0, 4))	('common', 'Reg', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
190348	19846892	In EO-induced tumors, codon 13 G C and codon 12 G T transversions were common, but spontaneous tumors did not possess these mutations.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('EO', 'Chemical', 'MESH:D005027', (3, 5))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('codon 13 G C', 'Var', (22, 34))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('codon 12 G T transversions', 'Var', (39, 65))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
190349	19846892	Likewise, in uterine tumors, Kras mutations occurred in a majority (5/6, 83%) of EO-induced uterine carcinomas, and all were codon 13 C T transitions.	('Kras', 'Gene', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinomas', 'Disease', (100, 110))	('carcinomas', 'Disease', 'MESH:D002277', (100, 110))	('occurred', 'Reg', (44, 52))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (92, 110))	('EO', 'Chemical', 'MESH:D005027', (81, 83))	('uterine tumors', 'Phenotype', 'HP:0010784', (13, 27))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
190350	19846892	These data shows that mutations in Kras are very common and an important step in the pathogenesis of EO-induced lung, harderian gland, and uterine tumors in the B6C3F1 mouse.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('mouse', 'Species', '10090', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('pathogenesis', 'biological_process', 'GO:0009405', ('85', '97'))	('uterine tumors', 'Phenotype', 'HP:0010784', (139, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('EO', 'Chemical', 'MESH:D005027', (101, 103))	('mutations', 'Var', (22, 31))	('harderian gland', 'Disease', (118, 133))	('Kras', 'Gene', (35, 39))	('EO-induced lung', 'Disease', (101, 116))
190358	19846892	Mutational analysis indicated that a large proportion of lung tumors induced by these chemicals harbored Kras mutations.	('Kras', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung tumors', 'Disease', (57, 68))	('mutations', 'Var', (110, 119))	('lung tumors', 'Phenotype', 'HP:0100526', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('harbored', 'Reg', (96, 104))	('lung tumors', 'Disease', 'MESH:D008175', (57, 68))
190359	19846892	A majority (34/51, 67%) of lung tumors induced by 1,3-butadiene had codon 13 G C transversions.	('lung tumors', 'Disease', 'MESH:D008175', (27, 38))	('1,3-butadiene', 'Chemical', 'MESH:C031763', (50, 63))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('lung tumors', 'Disease', (27, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('lung tumors', 'Phenotype', 'HP:0100526', (27, 38))	('codon 13 G C transversions', 'Var', (68, 94))
190360	19846892	Likewise, a large proportion (19/25, 76%) of lung tumors arising from chloroprene exposure had Kras mutations, except that mutation profile was different, with half of the tumors harboring codon 61 A T mutations.	('mutations', 'Var', (100, 109))	('chloroprene', 'Chemical', 'MESH:D002737', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('lung tumors', 'Disease', 'MESH:D008175', (45, 56))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Kras', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('lung tumors', 'Disease', (45, 56))	('lung tumors', 'Phenotype', 'HP:0100526', (45, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
190361	19846892	These mutations lead to the formation of guanine and adenine DNA adducts in the lung, and may play critical roles in the development of lung tumors induced by these chemicals.	('lead to', 'Reg', (16, 23))	('roles', 'Reg', (108, 113))	('guanine', 'Chemical', 'MESH:D006147', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('lung tumors', 'Disease', (136, 147))	('formation', 'MPA', (28, 37))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('adenine', 'Chemical', 'MESH:D000225', (53, 60))	('lung tumors', 'Phenotype', 'HP:0100526', (136, 147))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('formation', 'biological_process', 'GO:0009058', ('28', '37'))	('lung tumors', 'Disease', 'MESH:D008175', (136, 147))	('mutations', 'Var', (6, 15))	('play', 'Reg', (94, 98))
190363	19846892	The findings of Kras mutation and wild type allele loss in these mouse lung tumors are similar to molecular alterations in some human lung adenocarcinomas, and suggest that wildtype Kras may act as a tumor suppressor gene.	('tumor', 'Disease', (76, 81))	('rat', 'Species', '10116', (112, 115))	('lung tumors', 'Disease', 'MESH:D008175', (71, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('loss', 'NegReg', (51, 55))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (134, 154))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('lung tumors', 'Phenotype', 'HP:0100526', (71, 82))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (128, 133))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('200', '216'))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (134, 154))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('lung tumors', 'Disease', (71, 82))	('Kras', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('200', '216'))	('lung adenocarcinomas', 'Disease', (134, 154))	('mouse', 'Species', '10090', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutation', 'Var', (21, 29))
190368	19846892	First, alterations in the Tp53 tumor suppressor gene were common.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('alterations', 'Var', (7, 18))	('tumor', 'Disease', (31, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('rat', 'Species', '10116', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
190369	19846892	TP53 mutation is common in human glial tumors, dysfunction of which has been suggested to be an early event in glial tumorigenesis in humans.	('glial tumors', 'Disease', (33, 45))	('human', 'Species', '9606', (134, 139))	('TP53', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (117, 122))	('human', 'Species', '9606', (27, 32))	('humans', 'Species', '9606', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('glial tumors', 'Disease', 'MESH:D005910', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mutation', 'Var', (5, 13))
190370	19846892	There were mis-sense mutations in half (3/6) of malignant gliomas, and in both (2/2) neuroblastomas examined.	('malignant gliomas', 'Disease', (48, 65))	('neuroblastomas', 'Phenotype', 'HP:0003006', (85, 99))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('malignant gliomas', 'Disease', 'MESH:D005910', (48, 65))	('neuroblastomas', 'Disease', 'MESH:D009447', (85, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('mis-sense mutations', 'Var', (11, 30))	('neuroblastomas', 'Disease', (85, 99))
190372	19846892	Most of the Tp53 mutations found in this study were G A transitions, similar to those seen in human glioblastoma, in which up to 67% of tumors have Tp53 mutations, with the majority being G A transitions.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (153, 162))	('Tp53', 'Gene', (148, 152))	('glioblastoma', 'Disease', (100, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('human', 'Species', '9606', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('Tp53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
190377	19846892	Ultraviolet light plays a significant role in the development of SCC, and both UVA and UVB may contribute to skin cancer; both UVA and UVB cause DNA damage, but UVB also causes injury to Langerhans cells, resulting in compromised local immune surveillance.	('causes', 'Reg', (170, 176))	('skin cancer', 'Disease', (109, 120))	('local immune surveillance', 'MPA', (230, 255))	('SCC', 'Gene', (65, 68))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('UVB', 'Var', (161, 164))	('skin cancer', 'Disease', 'MESH:D012878', (109, 120))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('skin cancer', 'Phenotype', 'HP:0008069', (109, 120))	('injury', 'MPA', (177, 183))	('DNA damage', 'MPA', (145, 155))
190382	19846892	A consistent mutation pattern of TP53 has been shown in vivo and in vitro as a result of the direct action of UV light on DNA, rather than photoactivation of the psoraslen treatment, showing a direct involvement of the TP53 gene in human skin tumorigenesis.	('TP53', 'Gene', (219, 223))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('rat', 'Species', '10116', (127, 130))	('TP53', 'Gene', (33, 37))	('human', 'Species', '9606', (232, 237))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('involvement', 'Reg', (200, 211))	('tumor', 'Disease', (243, 248))
190388	19846892	In UVA and 8-MOP treated animals with SCC, 15/17 (88%) had mutation of Tp53, and 93% of those animals had mutation in exon 6 (93%).	('MOP', 'molecular_function', 'GO:0033727', ('13', '16'))	('SCC', 'Gene', (38, 41))	('8-MOP', 'Chemical', 'MESH:D008730', (11, 16))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('SCC', 'Gene', '6317', (38, 41))	('mutation', 'Var', (59, 67))	('Tp53', 'Gene', (71, 75))
190389	19846892	However, Tp53 mutations in SCCs from human patients treated with PUVA predominantly occur in exons 5, 7, and 8.	('SCC', 'Gene', (27, 30))	('patients', 'Species', '9606', (43, 51))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('SCC', 'Gene', '6317', (27, 30))	('Tp53', 'Gene', (9, 13))	('human', 'Species', '9606', (37, 42))	('occur', 'Reg', (84, 89))	('mutations', 'Var', (14, 23))	('PUVA', 'Chemical', '-', (65, 69))
190390	19846892	Additionally, there was no evidence of Hras mutations in either hyperplastic skin lesions or SCCs.	('hyperplastic skin lesions', 'Disease', (64, 89))	('Hras', 'Gene', (39, 43))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('mutations', 'Var', (44, 53))	('SCC', 'Gene', '6317', (93, 96))	('hyperplastic skin lesions', 'Disease', 'MESH:D012871', (64, 89))
190392	19846892	The study described above showed that photoactivated 8-MOP induced an increased incidence of SCCs with a high frequency of Tp53 mutations in HRA/Skh mice that were dosed orally, and given similar UV intensity as would occur in human patients.	('Tp53', 'Gene', (123, 127))	('HRA', 'Disease', (141, 144))	('MOP', 'molecular_function', 'GO:0033727', ('55', '58'))	('mutations', 'Var', (128, 137))	('human', 'Species', '9606', (227, 232))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('HRA', 'Disease', 'MESH:C536482', (141, 144))	('mice', 'Species', '10090', (149, 153))	('patients', 'Species', '9606', (233, 241))	('8-MOP', 'Chemical', 'MESH:D008730', (53, 58))	('SCC', 'Gene', '6317', (93, 96))
190393	19846892	The mutagenic effect of PUVA on the Tp53 tumor suppressor gene may lead to a conformational modification and inactivation of the Tp53 protein, which is considered a critical step in PUVA-induced skin carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('skin carcinogenesis', 'Disease', (195, 214))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('mutagenic', 'Var', (4, 13))	('lead to', 'Reg', (67, 74))	('tumor', 'Disease', (41, 46))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('inactivation', 'MPA', (109, 121))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (195, 214))	('protein', 'Protein', (134, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('Tp53', 'Gene', (129, 133))	('PUVA', 'Chemical', '-', (24, 28))	('PUVA', 'Chemical', '-', (182, 186))	('conformational modification', 'MPA', (77, 104))
190400	19846892	Loss of cyclin dependent kinase function (CDKN2A, CDKN2B), leading to Tp53 and pRB inhibition is well characterized in human malignant mesothelioma, as is overexpression of genes associated with cellular growth and survival (IGF, IGFR, EGFR, FOS, JUN), anti-apoptotic pathways (BCL2), angiogenesis (VEGF, COX2), loss of tumor suppressor genes either through mutation (NF2, WT1), or hypermethylation (APC, CDNK2A, CDNK2B, RASSF1A).	('pRB', 'Gene', '5925', (79, 82))	('IGFR', 'Gene', '3480', (230, 234))	('cellular growth', 'biological_process', 'GO:0016049', ('195', '210'))	('pRB', 'Gene', (79, 82))	('cyclin', 'molecular_function', 'GO:0016538', ('8', '14'))	('hypermethylation', 'Var', (382, 398))	('CDKN2A', 'Gene', (42, 48))	('CDKN2B', 'Gene', '1030', (50, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('236', '240'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (125, 147))	('IGFR', 'Gene', (230, 234))	('cyclin', 'Gene', '18538', (8, 14))	('cyclin', 'Gene', (8, 14))	('tumor', 'Disease', (320, 325))	('Loss', 'NegReg', (0, 4))	('EGFR', 'Gene', '1956', (236, 240))	('mutation', 'Var', (358, 366))	('CDKN2A', 'Gene', '1029', (42, 48))	('angiogenesis', 'CPA', (285, 297))	('RASSF1A', 'Gene', '11186', (421, 428))	('human', 'Species', '9606', (119, 124))	('anti-apoptotic', 'CPA', (253, 267))	('APC', 'Gene', '324', (400, 403))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('BCL2', 'Gene', '596', (278, 282))	('malignant mesothelioma', 'Disease', (125, 147))	('COX2', 'Gene', (305, 309))	('WT1', 'Gene', (373, 376))	('FOS', 'Gene', (242, 245))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (125, 147))	('loss', 'Gene', (312, 316))	('NF2', 'Gene', '4771', (368, 371))	('RASSF1A', 'Gene', (421, 428))	('BCL2', 'molecular_function', 'GO:0015283', ('278', '282'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('320', '336'))	('FOS', 'Gene', '2353', (242, 245))	('angiogenesis', 'biological_process', 'GO:0001525', ('285', '297'))	('APC', 'cellular_component', 'GO:0005680', ('400', '403'))	('inhibition', 'NegReg', (83, 93))	('WT1', 'Gene', '7490', (373, 376))	('CDKN2B', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('NF2', 'Gene', (368, 371))	('VEGF', 'Gene', '7422', (299, 303))	('COX2', 'Gene', '4513', (305, 309))	('tumor suppressor', 'biological_process', 'GO:0051726', ('320', '336'))	('BCL2', 'Gene', (278, 282))	('APC', 'Gene', (400, 403))	('EGFR', 'Gene', (236, 240))	('VEGF', 'Gene', (299, 303))
190403	19846892	Many chemicals in NTP studies have been shown to increase the incidence of mesothelioma in F344 rats, including o-nitrotoluene (o-NT) and bromochloroacetic acid (BCA).	('increase', 'PosReg', (49, 57))	('NTP', 'Chemical', '-', (18, 21))	('o-NT', 'Chemical', 'MESH:C029955', (128, 132))	('BCA', 'Chemical', 'MESH:C099813', (162, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('rats', 'Species', '10116', (96, 100))	('bromochloroacetic acid', 'Chemical', 'MESH:C099813', (138, 160))	('o-nitrotoluene', 'Chemical', 'MESH:C029955', (112, 126))	('mesothelioma', 'Disease', (75, 87))	('bromochloroacetic', 'Var', (138, 155))	('o-nitrotoluene', 'MPA', (112, 126))
190407	19846892	Analysis revealed dysregulation of 169 cancer-related genes, involving numerous biological processes such as cell cycle progression, growth and proliferation, apoptosis, invasion, and metastasis.	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('cancer', 'Disease', (39, 45))	('metastasis', 'CPA', (184, 194))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('dysregulation', 'Var', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cell cycle', 'biological_process', 'GO:0007049', ('109', '119'))	('rat', 'Species', '10116', (151, 154))	('cell cycle progression', 'CPA', (109, 131))	('invasion', 'CPA', (170, 178))	('apoptosis', 'CPA', (159, 168))
190416	19846892	Various genetic alterations have been reported in the development of liver tumors in humans, including alterations in genes involved in growth and proliferation, oncogenes, DNA damage response and cell cycle control genes, genes associated with cell-cell interaction and signal transduction, as well as epigenetic mechanisms.	('oncogenes', 'Gene', (162, 171))	('liver tumor', 'Phenotype', 'HP:0002896', (69, 80))	('alterations', 'Reg', (103, 114))	('cell cycle control', 'biological_process', 'GO:1901987', ('197', '215'))	('liver tumors', 'Disease', 'MESH:D008113', (69, 81))	('alterations', 'Var', (16, 27))	('rat', 'Species', '10116', (154, 157))	('DNA damage response', 'biological_process', 'GO:0006974', ('173', '192'))	('liver tumors', 'Disease', (69, 81))	('humans', 'Species', '9606', (85, 91))	('rat', 'Species', '10116', (107, 110))	('liver tumors', 'Phenotype', 'HP:0002896', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('rat', 'Species', '10116', (20, 23))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('signal transduction', 'biological_process', 'GO:0007165', ('271', '290'))	('cell cycle control genes', 'Gene', (197, 221))
190419	19846892	Furthermore, liver tumors may be associated with mutations in oncogenes such as Hras in spontaneous or chemically-induced mouse models, and increased expression of HRAS, NRAS, and KRAS have been associated with liver tumors and preneoplastic lesions in humans, with associated upregulation of downstream MAP kinase pathway.	('NRAS', 'Gene', (170, 174))	('KRAS', 'Gene', (180, 184))	('liver tumor', 'Phenotype', 'HP:0002896', (211, 222))	('increased', 'PosReg', (140, 149))	('Hras', 'Gene', (80, 84))	('liver tumors', 'Disease', 'MESH:D008113', (13, 25))	('mutations', 'Var', (49, 58))	('liver tumors', 'Phenotype', 'HP:0002896', (13, 25))	('HRAS', 'Gene', (164, 168))	('downstream MAP kinase pathway', 'Pathway', (293, 322))	('humans', 'Species', '9606', (253, 259))	('upregulation', 'PosReg', (277, 289))	('liver tumors', 'Disease', 'MESH:D008113', (211, 223))	('liver tumors', 'Phenotype', 'HP:0002896', (211, 223))	('preneoplastic lesions', 'Disease', (228, 249))	('associated', 'Reg', (195, 205))	('expression', 'MPA', (150, 160))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('liver tumors', 'Disease', (13, 25))	('MAP', 'molecular_function', 'GO:0004239', ('304', '307'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (231, 249))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mouse', 'Species', '10090', (122, 127))	('liver tumors', 'Disease', (211, 223))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('preneoplastic lesions', 'Disease', 'MESH:D011230', (228, 249))	('liver tumor', 'Phenotype', 'HP:0002896', (13, 24))
190420	19846892	Alterations in the WNT signaling pathway are common in chemically-induced liver tumors, including mutations in beta-catenin (Catnb), resulting in translocation of beta-catenin to the nucleus and cyclin D expression.	('liver tumors', 'Disease', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('WNT', 'Gene', '114487', (19, 22))	('nucleus', 'cellular_component', 'GO:0005634', ('183', '190'))	('translocation', 'MPA', (146, 159))	('beta-catenin', 'Protein', (163, 175))	('WNT signaling pathway', 'biological_process', 'GO:0016055', ('19', '40'))	('liver tumor', 'Phenotype', 'HP:0002896', (74, 85))	('WNT', 'Gene', (19, 22))	('Alterations', 'Reg', (0, 11))	('cyclin', 'molecular_function', 'GO:0016538', ('195', '201'))	('Catnb', 'Gene', '12387', (125, 130))	('cyclin', 'Gene', '18538', (195, 201))	('cyclin', 'Gene', (195, 201))	('rat', 'Species', '10116', (4, 7))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('Catnb', 'Gene', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (98, 107))
190421	19846892	Mutations in the beta-catenin gene are frequent and early in the pathogenesis of chemically-induced hepatic tumors in mice, and may be chemical-specific in nature.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pathogenesis', 'biological_process', 'GO:0009405', ('65', '77'))	('hepatic tumors', 'Disease', 'MESH:D056486', (100, 114))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('hepatic tumor', 'Phenotype', 'HP:0002896', (100, 113))	('mice', 'Species', '10090', (118, 122))	('hepatic tumors', 'Disease', (100, 114))	('beta-catenin', 'Gene', (17, 29))
190422	19846892	In the NTP two year bioassay of methyleugenol-induced and oxazepam-induced liver tumors in B6C3F1 mice, there was a 69% and 41% mutation incidence in beta-catenin, respectively.	('oxazepam', 'Chemical', 'MESH:D010076', (58, 66))	('liver tumors', 'Disease', (75, 87))	('liver tumors', 'Phenotype', 'HP:0002896', (75, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('liver tumor', 'Phenotype', 'HP:0002896', (75, 86))	('beta-catenin', 'Protein', (150, 162))	('methyleugenol', 'Chemical', 'MESH:C005223', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutation', 'Var', (128, 136))	('NTP', 'Chemical', '-', (7, 10))	('liver tumors', 'Disease', 'MESH:D008113', (75, 87))	('mice', 'Species', '10090', (98, 102))
190423	19846892	Similarly, following exposure to diethanolamine for two years, B6C3F1 mice developed HCC associated with genetic alterations in the Catnb gene; 32% (11/34) adenomas and carcinomas had mutations in exon 2 of the beta-catenin gene.	('rat', 'Species', '10116', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (156, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('HCC', 'Disease', (85, 88))	('beta-catenin', 'Gene', (211, 223))	('mutations in exon 2', 'Var', (184, 203))	('Catnb', 'Gene', '12387', (132, 137))	('mice', 'Species', '10090', (70, 74))	('Catnb', 'Gene', (132, 137))	('diethanolamine', 'Chemical', 'MESH:C020283', (33, 47))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))
190424	19846892	Similar mutations in exon 3 of the human beta-catenin gene have been frequently reported in human HCA.	('beta-catenin gene', 'Gene', (41, 58))	('HCA', 'Disease', (98, 101))	('human', 'Species', '9606', (35, 40))	('mutations', 'Var', (8, 17))	('reported', 'Reg', (80, 88))	('HCA', 'Phenotype', 'HP:0012028', (98, 101))	('human', 'Species', '9606', (92, 97))
190425	19846892	Like HCA, hepatoblastomas in mice and humans are also associated with high incidences of beta-catenin gene mutation, including downstream activation of WNT signaling.	('WNT', 'Gene', '114487', (152, 155))	('hepatoblastomas', 'Disease', (10, 25))	('HCA', 'Disease', (5, 8))	('HCA', 'Phenotype', 'HP:0012028', (5, 8))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (10, 24))	('hepatoblastomas', 'Disease', 'MESH:D018197', (10, 25))	('WNT', 'Gene', (152, 155))	('beta-catenin', 'Protein', (89, 101))	('humans', 'Species', '9606', (38, 44))	('mice', 'Species', '10090', (29, 33))	('mutation', 'Var', (107, 115))	('activation', 'PosReg', (138, 148))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
190429	19846892	Several genetic and epigenetic alterations have been implicated in the genesis of breast cancer, and in general breast cancer is divided into hereditary and sporadic forms.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer', 'Disease', (112, 125))	('implicated', 'Reg', (53, 63))	('epigenetic alterations', 'Var', (20, 42))	('rat', 'Species', '10116', (35, 38))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
190430	19846892	Hereditary forms account for approximately 5-10% of breast cancers, and are caused predominantly by mutation in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2.	('BRCA1', 'Gene', (167, 172))	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('caused', 'Reg', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA2', 'Gene', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancers', 'Disease', (52, 66))	('mutation', 'Var', (100, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('BRCA2', 'Gene', '675', (177, 182))	('BRCA1', 'Gene', '672', (167, 172))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
190431	19846892	Sporadic or non-hereditary cases of breast cancer are associated with a variety of genetic and epigenetic abnormalities that result in dysregulation of growth pathways (IGF, EGFR, ESR1), cell cycle regulators (CDKN1A, CDKN1B, CDKN2A, CCND1), oncogenes (ERBB2, MYC), tumor suppressor genes (TP53, RB, ATM, CDH1), and chromatin modifiers (BMI1).	('growth pathways', 'Pathway', (152, 167))	('MYC', 'Gene', '4609', (260, 263))	('ESR1', 'Gene', '2099', (180, 184))	('BMI1', 'Gene', '648', (337, 341))	('CDKN2A', 'Gene', (226, 232))	('ESR1', 'Gene', (180, 184))	('CDKN1B', 'Gene', (218, 224))	('CDKN1A', 'Gene', (210, 216))	('TP53', 'Gene', (290, 294))	('tumor', 'Disease', (266, 271))	('CDKN1A', 'Gene', '1026', (210, 216))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('266', '282'))	('EGFR', 'Gene', '1956', (174, 178))	('ERBB2', 'Gene', (253, 258))	('ATM', 'Gene', '472', (300, 303))	('EGFR', 'molecular_function', 'GO:0005006', ('174', '178'))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('abnormalities', 'Var', (106, 119))	('CDKN2A', 'Gene', '1029', (226, 232))	('tumor suppressor', 'biological_process', 'GO:0051726', ('266', '282'))	('CDH1', 'Gene', '999', (305, 309))	('dysregulation', 'MPA', (135, 148))	('ERBB2', 'Gene', '2064', (253, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('CDKN1B', 'Gene', '1027', (218, 224))	('chromatin', 'cellular_component', 'GO:0000785', ('316', '325'))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('MYC', 'Gene', (260, 263))	('BMI1', 'Gene', (337, 341))	('CDH1', 'Gene', (305, 309))	('ATM', 'Gene', (300, 303))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('EGFR', 'Gene', (174, 178))	('breast cancer', 'Disease', (36, 49))	('CCND1', 'Gene', '595', (234, 239))	('CCND1', 'Gene', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cell cycle', 'biological_process', 'GO:0007049', ('187', '197'))
190438	19846892	DNA mutation analysis detected Tp53 mutation in a significant number of spontaneous (7/12, 58%), benzene-induced (8/14, 57%), and ethylene oxide-induced carcinomas (8/12, 67%).	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('mutation', 'Var', (36, 44))	('Tp53', 'Gene', (31, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('carcinomas', 'Disease', 'MESH:D002277', (153, 163))	('carcinomas', 'Disease', (153, 163))	('benzene', 'Chemical', 'MESH:D001554', (97, 104))	('ethylene oxide', 'Chemical', 'MESH:D005027', (130, 144))
190439	19846892	Twenty-six percent (5/19) of spontaneous, 50% (7/14) of benzene-, and 33% (4/12) of ethylene oxide-induced carcinomas had mutations in Hras, and importantly, concurrent Tp53 mutation was observed when Hras mutations were present.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('carcinomas', 'Disease', 'MESH:D002277', (107, 117))	('carcinomas', 'Disease', (107, 117))	('mutations', 'Var', (122, 131))	('ethylene oxide', 'Chemical', 'MESH:D005027', (84, 98))	('Tp53', 'Gene', (169, 173))	('benzene', 'Chemical', 'MESH:D001554', (56, 63))	('Hras', 'Gene', (135, 139))
190440	19846892	Concurrent Tp53 gene mutations were identified in 71% (5/7) of benzene-induced, 75% (3/4) of ethylene oxide-induced, and 40% (2/5) of spontaneous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('Tp53 gene', 'Gene', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('carcinomas', 'Disease', 'MESH:D002277', (146, 156))	('benzene', 'Chemical', 'MESH:D001554', (63, 70))	('ethylene oxide', 'Chemical', 'MESH:D005027', (93, 107))	('identified', 'Reg', (36, 46))	('benzene-induced', 'Disease', (63, 78))	('mutations', 'Var', (21, 30))
190442	19846892	In chemically induced tumors, Hras mutations most commonly involved the second base of codon 61, and in 10/11 tumors resulted in an amino acid change from glutamine to leucine or arginine.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('leucine', 'Chemical', 'MESH:D007930', (168, 175))	('glutamine', 'Chemical', 'MESH:D005973', (155, 164))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('arginine', 'Chemical', 'MESH:D001120', (179, 187))	('Hras', 'Gene', (30, 34))	('glutamine', 'MPA', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('involved', 'Reg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (110, 116))	('amino acid change', 'MPA', (132, 149))	('resulted in', 'Reg', (117, 128))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('arginine', 'MPA', (179, 187))	('tumors', 'Disease', (22, 28))	('mutations', 'Var', (35, 44))
190443	19846892	Mutations in spontaneous tumors however, involved the first base and most often resulted in amino acid changes of glutamine to lysine.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('glutamine to lysine', 'MPA', (114, 133))	('tumors', 'Disease', (25, 31))	('glutamine', 'Chemical', 'MESH:D005973', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('involved', 'Reg', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Mutations', 'Var', (0, 9))	('spontaneous', 'Disease', (13, 24))	('resulted in', 'Reg', (80, 91))	('lysine', 'Chemical', 'MESH:D008239', (127, 133))	('amino acid changes', 'MPA', (92, 110))
190444	19846892	Our results show that although mutations of the Tp53 and Hras genes are relatively common in spontaneous, as well as in chemically induced, mouse mammary carcinomas, the incidence of concurrent Tp53 and Hras mutation is increased in chemically induced tumors.	('mouse', 'Species', '10090', (140, 145))	('mutations', 'Var', (31, 40))	('Hras', 'Gene', (57, 61))	('mutation', 'Var', (208, 216))	('Tp53', 'Gene', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Hras', 'Gene', (203, 207))	('Tp53', 'Gene', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('carcinomas', 'Disease', (154, 164))	('carcinomas', 'Disease', 'MESH:D002277', (154, 164))	('tumors', 'Disease', (252, 258))
190445	19846892	Furthermore, the pattern of mutations in Tp53 and HRas differed between chemically induced and spontaneous mammary carcinomas, suggesting that different mechanisms are involved between these tumors in B6C3F1 mice.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('Tp53', 'Gene', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('mice', 'Species', '10090', (208, 212))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('differed', 'Reg', (55, 63))	('carcinomas', 'Disease', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('HRas', 'Gene', '15461', (50, 54))	('tumors', 'Disease', (191, 197))	('HRas', 'Gene', (50, 54))	('mutations', 'Var', (28, 37))
190446	19846892	Immunohistochemistry may be used to detect the effects of gene mutation on protein expression and/or localization in chemically induced tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gene mutation', 'Var', (58, 71))	('localization', 'biological_process', 'GO:0051179', ('101', '113'))	('protein expression', 'MPA', (75, 93))
190448	19846892	As stated previously, the majority of hepatoblastomas in mice have mutations in the beta-catenin gene.	('hepatoblastomas', 'Disease', (38, 53))	('mice', 'Species', '10090', (57, 61))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (38, 52))	('hepatoblastomas', 'Disease', 'MESH:D018197', (38, 53))	('mutations', 'Var', (67, 76))	('beta-catenin', 'Gene', (84, 96))
190449	19846892	This mutation affects the binding region of GSK3B, resulting in prevention of phosphorylation of beta-catenin and resultant accumulation within the cytoplasm.	('beta-catenin', 'Protein', (97, 109))	('phosphorylation', 'MPA', (78, 93))	('cytoplasm', 'cellular_component', 'GO:0005737', ('148', '157'))	('GSK3B', 'Gene', '2932', (44, 49))	('GSK3B', 'Gene', (44, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('accumulation', 'MPA', (124, 136))	('GSK', 'molecular_function', 'GO:0050321', ('44', '47'))	('affects', 'Reg', (14, 21))	('prevention', 'NegReg', (64, 74))	('binding', 'Interaction', (26, 33))	('mutation', 'Var', (5, 13))
190451	19846892	Since nuclear localization may not be present in all tumors with Catnb mutation in mice, mutation analysis including PCR and sequencing should be used to follow up on the identification of the specific mutation.	('Catnb', 'Gene', '12387', (65, 70))	('mutation', 'Var', (71, 79))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Catnb', 'Gene', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('localization', 'biological_process', 'GO:0051179', ('14', '26'))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
190452	19846892	Several proto-oncogenes are converted to oncogenes through mutation, and induce uncontrolled proliferation through various growth pathways.	('growth pathways', 'CPA', (123, 138))	('uncontrolled proliferation', 'CPA', (80, 106))	('mutation', 'Var', (59, 67))	('induce', 'Reg', (73, 79))	('rat', 'Species', '10116', (100, 103))
190454	19846892	Using immunohistochemistry, the effects of Ras mutation may be detected, such as overexpression of downstream mediators such as MAP kinases and transcription factors that lead to promotion of the cell cycle and cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('211', '229'))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('cell cycle', 'CPA', (196, 206))	('mutation', 'Var', (47, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('196', '206'))	('overexpression', 'PosReg', (81, 95))	('Ras', 'Gene', (43, 46))	('MAP', 'molecular_function', 'GO:0004239', ('128', '131'))	('promotion', 'PosReg', (179, 188))	('rat', 'Species', '10116', (223, 226))	('cell proliferation', 'CPA', (211, 229))
190456	19846892	Loss of expression of a protein product in tumors is often associated with inactivation or deletion mutations in tumor suppressor genes or genes regulating apoptosis.	('inactivation', 'Var', (75, 87))	('tumor', 'Disease', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('protein', 'Protein', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('deletion mutations', 'Var', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Loss of expression', 'NegReg', (0, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('tumors', 'Disease', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
190460	19846892	Mutation of other tumor suppressor genes, such as Cdkn2a or Rb1, may result in decreased or complete absence of protein expression by immunohistochemistry.	('absence', 'NegReg', (101, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('tumor', 'Disease', (18, 23))	('Rb', 'Phenotype', 'HP:0009919', (60, 62))	('Mutation', 'Var', (0, 8))	('Rb1', 'Gene', (60, 63))	('Cdkn2a', 'Gene', (50, 56))	('Cdkn2a', 'Gene', '1029', (50, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('Rb1', 'Gene', '5925', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('protein expression', 'MPA', (112, 130))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
190461	19846892	Rb1 is an important tumor suppressor gene regulating the cell cycle, and mutation or loss causes unchecked cell proliferation.	('Rb1', 'Gene', '5925', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('unchecked cell proliferation', 'CPA', (97, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('rat', 'Species', '10116', (119, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Rb', 'Phenotype', 'HP:0009919', (0, 2))	('causes', 'Reg', (90, 96))	('Rb1', 'Gene', (0, 3))	('loss', 'NegReg', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('mutation', 'Var', (73, 81))	('tumor', 'Disease', (20, 25))
190463	19846892	Mutation in either of these tumor suppressor genes results in decreased or loss of expression of their protein products in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('expression of their protein products', 'MPA', (83, 119))	('tumor', 'Disease', (28, 33))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('loss of', 'NegReg', (75, 82))	('cancer', 'Disease', (123, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
190467	19846892	The genetic mutations that occur in rodent models often follow a distinct progression in the development from benign tumors to malignant cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('benign tumors to malignant cancers', 'Disease', (110, 144))	('benign tumors to malignant cancers', 'Disease', 'MESH:D009369', (110, 144))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('development', 'CPA', (93, 104))
190468	19846892	Chemically induced and transgenic rodent models are frequently used to model preneoplastic and neoplastic lesions that result from genetic alterations in humans, and such models give insight into mechanisms and potential treatment or provide information on current applications of diagnostic modalities for use in human patients.	('human', 'Species', '9606', (154, 159))	('alterations', 'Var', (139, 150))	('neoplastic lesions', 'Disease', 'MESH:D051437', (95, 113))	('neoplastic lesions', 'Disease', (95, 113))	('transgenic', 'Species', '10090', (23, 33))	('humans', 'Species', '9606', (154, 160))	('rat', 'Species', '10116', (143, 146))	('human', 'Species', '9606', (314, 319))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (95, 113))	('patients', 'Species', '9606', (320, 328))
190471	19846892	Mutations in Kras are believed to be an early initiating event in lung carcinogenesis in humans, and mice.	('lung carcinogenesis', 'Disease', (66, 85))	('Kras', 'Gene', (13, 17))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (66, 85))	('Mutations', 'Var', (0, 9))	('mice', 'Species', '10090', (101, 105))	('humans', 'Species', '9606', (89, 95))
190472	19846892	Similarly, in chemically induced rodent liver tumor models as well as human liver tumors, Ras mutation is associated with early events in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Ras', 'Gene', (90, 93))	('associated', 'Reg', (106, 116))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (82, 87))	('liver tumor', 'Disease', 'MESH:D008113', (76, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('liver tumor', 'Phenotype', 'HP:0002896', (40, 51))	('liver tumor', 'Disease', (40, 51))	('tumor', 'Disease', (46, 51))	('human', 'Species', '9606', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('liver tumors', 'Disease', 'MESH:D008113', (76, 88))	('liver tumors', 'Phenotype', 'HP:0002896', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('liver tumor', 'Disease', 'MESH:D008113', (40, 51))	('liver tumors', 'Disease', (76, 88))	('mutation', 'Var', (94, 102))	('liver tumor', 'Phenotype', 'HP:0002896', (76, 87))
190474	19846892	Beta-catenin gene mutation is another important event in mouse and human hepatic tumors that has been shown to be an early initiating event in chemically-induced mouse and rat hepatocellular carcinogenesis.	('hepatic tumor', 'Phenotype', 'HP:0002896', (73, 86))	('Beta-catenin', 'Gene', (0, 12))	('mouse', 'Species', '10090', (162, 167))	('mouse', 'Species', '10090', (57, 62))	('hepatic tumors', 'Disease', 'MESH:D056486', (73, 87))	('hepatocellular carcinogenesis', 'Disease', (176, 205))	('mutation', 'Var', (18, 26))	('rat', 'Species', '10116', (172, 175))	('hepatocellular carcinogenesis', 'Disease', 'MESH:D063646', (176, 205))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('human', 'Species', '9606', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('hepatic tumors', 'Disease', (73, 87))
190476	19846892	Although dysregulation of beta-catenin and WNT signaling most often follows mutation of the APC gene as an initiating event in human colon cancer, mutation of the beta-catenin gene as a primary initiating event also occurs in a subset of colon cancers in humans, as well as a chemically-induced mouse model of large intestinal (cecal) carcinoma.	('beta-catenin', 'MPA', (26, 38))	('mutation', 'Var', (147, 155))	('WNT', 'Gene', '114487', (43, 46))	('colon cancer', 'Disease', (133, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('mutation', 'Var', (76, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (238, 250))	('carcinoma', 'Disease', (335, 344))	('dysregulation', 'MPA', (9, 22))	('human', 'Species', '9606', (255, 260))	('APC', 'Gene', '324', (92, 95))	('colon cancers', 'Phenotype', 'HP:0003003', (238, 251))	('WNT', 'Gene', (43, 46))	('colon cancer', 'Disease', 'MESH:D015179', (238, 250))	('large intestinal', 'Disease', (310, 326))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('human', 'Species', '9606', (127, 132))	('carcinoma', 'Disease', 'MESH:D002277', (335, 344))	('colon cancers', 'Disease', 'MESH:D015179', (238, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('APC', 'Gene', (92, 95))	('colon cancers', 'Disease', (238, 251))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('APC', 'cellular_component', 'GO:0005680', ('92', '95'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('humans', 'Species', '9606', (255, 261))	('mouse', 'Species', '10090', (295, 300))
190477	19846892	In addition, Kras activating mutations have been shown to be an early initiating event in a rat model of chemically induced colon carcinogenesis.	('mutations', 'Var', (29, 38))	('rat', 'Species', '10116', (92, 95))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (124, 144))	('Kras activating', 'Gene', (13, 28))	('colon carcinogenesis', 'Disease', (124, 144))
190478	19846892	Mutations in TP53 are frequently observed in human lung adenocarcinomas, as well as mouse lung tumors, and can act synergistically with Kras mutation in the development of certain cancers in mice and humans.	('TP53', 'Gene', (13, 17))	('observed', 'Reg', (33, 41))	('human', 'Species', '9606', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lung tumors', 'Disease', (90, 101))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('act', 'Reg', (111, 114))	('Mutations', 'Var', (0, 9))	('mouse', 'Species', '10090', (84, 89))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (51, 71))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung tumors', 'Phenotype', 'HP:0100526', (90, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('mice', 'Species', '10090', (191, 195))	('humans', 'Species', '9606', (200, 206))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (51, 71))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('lung tumors', 'Disease', 'MESH:D008175', (90, 101))	('human', 'Species', '9606', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('lung adenocarcinomas', 'Disease', (51, 71))
190479	19846892	Mutation of TP53 occurs late in the course of disease and plays an important role in progression to malignancy in mice, and is associated with a poor prognosis in human patients with non-small cell lung cancer.	('malignancy', 'Disease', 'MESH:D009369', (100, 110))	('patients', 'Species', '9606', (169, 177))	('associated', 'Reg', (127, 137))	('non-small cell lung cancer', 'Disease', (183, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (187, 209))	('Mutation', 'Var', (0, 8))	('malignancy', 'Disease', (100, 110))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (183, 209))	('human', 'Species', '9606', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('mice', 'Species', '10090', (114, 118))	('TP53', 'Gene', (12, 16))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (183, 209))
190480	19846892	In the liver, TP53 mutation is associated with later stages in aflatoxin induced hepatocellular carcinogenesis and advanced stages of tumorigenesis in humans.	('hepatocellular carcinogenesis', 'Disease', 'MESH:D063646', (81, 110))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('aflatoxin', 'Chemical', 'MESH:D000348', (63, 72))	('associated', 'Reg', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('humans', 'Species', '9606', (151, 157))	('hepatocellular carcinogenesis', 'Disease', (81, 110))	('tumor', 'Disease', (134, 139))
190482	19846892	Thus the occurrence of these mutations in the mouse suggests that chemically induced mouse models of carcinogenesis can in many ways model human tumorigenesis.	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('man', 'Species', '9606', (123, 126))	('carcinogenesis', 'Disease', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (29, 38))	('mouse', 'Species', '10090', (46, 51))	('tumor', 'Disease', (145, 150))	('human', 'Species', '9606', (139, 144))	('man', 'Species', '9606', (141, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))
190500	19846892	Using mutation analysis, gene expression studies, immunohistochemistry, and other allied research techniques, we have identified several factors in the rodent models that are responsible for the generation of cancer.	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('mutation', 'Var', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('rat', 'Species', '10116', (199, 202))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
190598	20920331	Although the data above indicate that MWCNT can cause mesothelioma after intraperitoneal instillation, as does asbestos, data are required that MWCNT actually come in contact with the mesothelial cells lining the lung after pulmonary exposure.	('MWCNT', 'Chemical', '-', (38, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('asbestos', 'Chemical', 'MESH:D001194', (111, 119))	('cause', 'Reg', (48, 53))	('mesothelioma', 'Disease', (54, 66))	('MWCNT', 'Chemical', '-', (144, 149))	('MWCNT', 'Var', (38, 43))
190623	20920331	Based on the morphometric analysis, there were substantial number of alveolar epithelial cells penetrations by MWCNT (Figure 5).	('MWCNT', 'Chemical', '-', (111, 116))	('alveolar epithelial cells penetrations', 'CPA', (69, 107))	('rat', 'Species', '10116', (100, 103))	('MWCNT', 'Var', (111, 116))
190641	20920331	The FESEM of Figure 7D (80 mug, 56 days) shows a MWCNT penetrating the mesothelial surface of the visceral pleura, through the mesothelial cell layer with the fiber ending in the alveolar region.	('visceral pleura', 'Disease', (98, 113))	('MWCNT', 'Var', (49, 54))	('MWCNT', 'Chemical', '-', (49, 54))	('rat', 'Species', '10116', (60, 63))	('mug', 'molecular_function', 'GO:0043739', ('27', '30'))	('visceral pleura', 'Disease', 'MESH:D054363', (98, 113))
190753	32301278	We found that both administration of exogenous MTA and stable PRMT5 knock-down, by short hairpin RNAs (shRNAs), selectively reduced the growth of MTAP-deleted MM cells.	('MTA', 'Chemical', 'MESH:C008500', (47, 50))	('reduced', 'NegReg', (124, 131))	('knock-down', 'Var', (68, 78))	('growth', 'MPA', (136, 142))	('MTA', 'Chemical', 'MESH:C008500', (146, 149))	('MTAP-deleted', 'Gene', (146, 158))	('PRMT5', 'Gene', (62, 67))
190760	32301278	Among the most common genetic alterations or deregulated pathways identified in MM, deletions in the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus, inactivation of the retinoblastoma (RB) pathway, mutations in the BRCA1-associated protein 1 (BAP1) and neurofibromatosis type 2 (NF2) genes, and aberrant regulation of phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K)/AKT pathway are all related to MM uncontrolled growth and resistance to treatment-induced cell death.	('cyclin-dependent kinase inhibitor 2A', 'Gene', (101, 137))	('retinoblastoma', 'Phenotype', 'HP:0009919', (174, 188))	('BRCA1-associated protein 1', 'Gene', '8314', (220, 246))	('BAP1', 'Gene', (248, 252))	('regulation', 'biological_process', 'GO:0065007', ('309', '319'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('118', '134'))	('NF2', 'Gene', '4771', (284, 287))	('CDKN2A', 'Gene', '1029', (139, 145))	('inactivation', 'NegReg', (154, 166))	('AKT', 'Gene', '207', (378, 381))	('neurofibromatosis type 2', 'Gene', (258, 282))	('BRCA1-associated protein 1', 'Gene', (220, 246))	('NF2', 'Gene', (284, 287))	('RB', 'Phenotype', 'HP:0009919', (190, 192))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (258, 275))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('101', '134'))	('retinoblastoma (RB', 'Gene', (174, 192))	('AKT', 'Gene', (378, 381))	('cell death', 'biological_process', 'GO:0008219', ('468', '478'))	('related', 'Reg', (398, 405))	('aberrant', 'Var', (300, 308))	('PI3K', 'molecular_function', 'GO:0016303', ('372', '376'))	('neurofibromatosis type 2', 'Gene', '4771', (258, 282))	('mutations', 'Var', (203, 212))	('BAP1', 'Gene', '8314', (248, 252))	('phosphatidylinositol-4,5- bisphosphate 3-kinase', 'Gene', '5290', (323, 370))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (101, 137))	('retinoblastoma (RB)', 'Gene', '5925', (174, 193))	('CDKN2A', 'Gene', (139, 145))	('deletions', 'Var', (84, 93))
190762	32301278	17  The discovery that CDKN2A deletion in cancer cells commonly involves codeletion of adjacent genes opened new perspectives in cancer research with a possible impact also for MM 18  It has indeed observed that the methylthioadenosine phosphorylase (MTAP) gene, encoding a key enzyme in the adenosine and methionine salvage pathway from the substrate 5'-methylthioadenosine (MTA), is frequently codeleted with CDKN2A in different cancer types 19  including MM 20 ,  21  The MTAP gene has been suggested to be a tumour suppressor, the loss of which results in a higher cell invasive potential and poor prognosis for patients with different cancer types.	('methylthioadenosine phosphorylase', 'Gene', (216, 249))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('MTA', 'Chemical', 'MESH:C008500', (251, 254))	('tumour', 'Phenotype', 'HP:0002664', (512, 518))	('cancer', 'Disease', (431, 437))	('cancer', 'Disease', (129, 135))	('CDKN2A', 'Gene', '1029', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (512, 518))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('tumour', 'Disease', (512, 518))	('CDKN2A', 'Gene', '1029', (411, 417))	('patients', 'Species', '9606', (616, 624))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (640, 646))	('higher', 'PosReg', (562, 568))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('MTA', 'Chemical', 'MESH:C008500', (376, 379))	('cancer', 'Disease', 'MESH:D009369', (431, 437))	('methionine salvage pathway', 'biological_process', 'GO:0019509', ('306', '332'))	('adenosine', 'Chemical', 'MESH:D000241', (365, 374))	('methylthioadenosine phosphorylase', 'Gene', '4507', (216, 249))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('deletion', 'Var', (30, 38))	('loss', 'Var', (535, 539))	('MTAP', 'Gene', (475, 479))	('adenosine', 'Chemical', 'MESH:D000241', (292, 301))	('cancer', 'Disease', (640, 646))	('CDKN2A', 'Gene', (23, 29))	('MTA', 'Chemical', 'MESH:C008500', (475, 478))	("5'-methylthioadenosine", 'Chemical', 'MESH:C008500', (352, 374))	('cancer', 'Disease', (42, 48))	('CDKN2A', 'Gene', (411, 417))	('adenosine', 'Chemical', 'MESH:D000241', (226, 235))	('cancer', 'Phenotype', 'HP:0002664', (640, 646))
190779	32301278	Solid tissue was minced into small pieces, 1-3 mm, and then incubated in complete medium supplemented with collagenase type I from Clostridium histolyticum (Thermo Fisher Scientific, Cat #17100017) at 200 U/mL concentration for 1 hour to digest collagen and release tumour cells.	('collagen', 'Protein', (245, 253))	('collagen', 'molecular_function', 'GO:0005202', ('245', '253'))	('tumour', 'Disease', (266, 272))	('Cat', 'molecular_function', 'GO:0004096', ('183', '186'))	('Clostridium histolyticum', 'Species', '1498', (131, 155))	('release', 'MPA', (258, 265))	('digest', 'Var', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('tumour', 'Disease', 'MESH:D009369', (266, 272))
190782	32301278	Qualitative detection of CDKN2A gene (green signal) deletions and the classical satellite III region of chromosome 9 (CEN9) (red signal) were detected by fluorescence in situ hybridization (FISH), using SPEC CDKN2A/CEN 9 Dual Color Probe ZytoLight (ZytoVision GmbH, Bremerhaven, Germany).	('CDKN2A', 'Gene', (208, 214))	('CDKN2A', 'Gene', '1029', (208, 214))	('SPEC', 'molecular_function', 'GO:0004586', ('203', '207'))	('deletions', 'Var', (52, 61))	('CDKN2A', 'Gene', (25, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('CDKN2A', 'Gene', '1029', (25, 31))
190821	32301278	These results support the hypothesis that MTAP-deleted MM cells could be selectively targeted for their susceptibility to PRMT5 inhibition due to the accumulation of its natural inhibitor MTA.	('accumulation', 'PosReg', (150, 162))	('MTA', 'Chemical', 'MESH:C008500', (188, 191))	('MTA', 'Chemical', 'MESH:C008500', (42, 45))	('MTAP-deleted', 'Var', (42, 54))	('MTA', 'MPA', (188, 191))
190827	32301278	To explore at the molecular level the proliferative role of PRMT5 in MTAP-deleted MM cells, we analysed the effect of PRMT5 knock-down on the expression of genes involved in cancer cell growth.	('analysed', 'Reg', (95, 103))	('PRMT5', 'Gene', (118, 123))	('cell growth', 'biological_process', 'GO:0016049', ('181', '192'))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('knock-down', 'Var', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
190828	32301278	We observed that PRMT5 knock-down inhibited the E2F1 growth-promoting signalling, as suggested by the down-regulation of the E2F1-regulated genes  35 ,  36 ,  37 ,  38 ,  39  cyclin A2 (CCNA2), cyclin E1 (CCNE1), enhancer of zeste homolog 2 (EZH2), thymidylate synthase (TS) and E2F1 itself (Figure 5A).	('cyclin', 'molecular_function', 'GO:0016538', ('194', '200'))	('cyclin E1', 'Gene', (194, 203))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('TS', 'Gene', '7298', (271, 273))	('E2F1', 'Gene', (48, 52))	('knock-down', 'Var', (23, 33))	('E2F1-regulated genes', 'Gene', (125, 145))	('CCNE1', 'Gene', (205, 210))	('inhibited', 'NegReg', (34, 43))	('down-regulation', 'NegReg', (102, 117))	('enhancer of zeste homolog 2', 'Gene', '2146', (213, 240))	('CCNE1', 'Gene', '898', (205, 210))	('growth-promoting signalling', 'MPA', (53, 80))	('thymidylate synthase', 'Gene', (249, 269))	('CCNA2', 'Gene', (186, 191))	('thymidylate synthase', 'Gene', '7298', (249, 269))	('cyclin A2', 'Gene', (175, 184))	('PRMT5', 'Gene', (17, 22))	('cyclin E1', 'Gene', '898', (194, 203))	('enhancer of zeste homolog 2', 'Gene', (213, 240))	('signalling', 'biological_process', 'GO:0023052', ('70', '80'))	('cyclin', 'molecular_function', 'GO:0016538', ('175', '181'))	('EZH2', 'Gene', '2146', (242, 246))	('cyclin A2', 'Gene', '890', (175, 184))	('EZH2', 'Gene', (242, 246))	('CCNA2', 'Gene', '890', (186, 191))
190831	32301278	41   Therefore, we investigated the effect of PRMT5 knock-down in the MTAP-negative cells, NCI-H2452, on the expression of EMT markers.	('NCI-H2452', 'CellLine', 'CVCL:1553', (91, 100))	('knock-down', 'Var', (52, 62))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('PRMT5', 'Gene', (46, 51))
190832	32301278	As shown in Figure 6, PRMT5 depletion led to the up-regulation of the epithelial marker, E-cadherin, and the concomitant down-regulation of the mesenchymal markers, N-cadherin, alpha-smooth muscle actin (alpha-SMA) and matrix metallopeptidase 9 (MMP9).	('alpha-SMA', 'Gene', (204, 213))	('alpha-smooth muscle actin', 'Protein', (177, 202))	('PRMT5', 'Gene', (22, 27))	('N-cadherin', 'Gene', (165, 175))	('depletion', 'Var', (28, 37))	('N-cadherin', 'Gene', '1000', (165, 175))	('MMP9', 'Gene', (246, 250))	('MMP9', 'Gene', '4318', (246, 250))	('alpha-SMA', 'Gene', '58', (204, 213))	('matrix metallopeptidase 9', 'Gene', '4318', (219, 244))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('up-regulation', 'PosReg', (49, 62))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('down-regulation', 'NegReg', (121, 136))	('MMP9', 'molecular_function', 'GO:0004229', ('246', '250'))	('matrix metallopeptidase 9', 'Gene', (219, 244))	('cadherin', 'molecular_function', 'GO:0008014', ('167', '175'))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))
190833	32301278	Recent advances in cancer metabolism research have identified molecular defects leading to vulnerabilities, which can be exploited therapeutically 42  These molecular alterations can also represent biomarkers helping move towards personalized medicine.	('defects', 'Var', (72, 79))	('metabolism', 'biological_process', 'GO:0008152', ('26', '36'))	('cancer metabolism', 'Disease', 'MESH:D009369', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('vulnerabilities', 'MPA', (91, 106))	('cancer metabolism', 'Disease', (19, 36))	('leading to', 'Reg', (80, 90))
190835	32301278	Indeed, genomic deletions of tumour suppressor genes can involve adjacent metabolic genes, thus generating a targetable vulnerability 42  PRMT5 dependence is an example of this phenomenon, which has been termed collateral lethality43 Indeed, the passenger deletion of MTAP, resulting from the deletion of the CDKN2A tumour suppressor gene, generates a selective vulnerability to PRMT5 inhibition 24  In the recent years, interest for PRMT5 as a new druggable target for anticancer therapy has increased exponentially and great efforts have been made to discover new and selective PRMT5 inhibitors 44  Among a number of chemical compounds demonstrated to be active in pre-clinical studies, GSK3326595 (NCT02783300), PF-06939999 (NCT03854227), JNJ-64619178 (NCT03573310) and PRT543 (NCT03886831) have entered clinical trials.	('tumour', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (474, 480))	('GSK', 'molecular_function', 'GO:0050321', ('689', '692'))	('deletion', 'Var', (293, 301))	('NCT02783300', 'Var', (701, 712))	('NCT03854227', 'Var', (728, 739))	('pre', 'molecular_function', 'GO:0003904', ('667', '670'))	('MTAP', 'Gene', (268, 272))	('CDKN2A', 'Gene', (309, 315))	('cancer', 'Disease', (474, 480))	('PRT', 'molecular_function', 'GO:0004048', ('773', '776'))	('cancer', 'Phenotype', 'HP:0002664', (474, 480))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('tumour', 'Disease', 'MESH:D009369', (316, 322))	('NCT03886831', 'Var', (781, 792))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('NCT03573310', 'Var', (756, 767))	('CDKN2A', 'Gene', '1029', (309, 315))	('tumour', 'Disease', (316, 322))
190839	32301278	We then analysed the MTAP status and MTA intracellular content in a panel of MM and normal mesothelial cell lines and, in line with what previously reported for other cancer types, 24 ,  25  we found a higher MTA content in MTAP-deleted MM cells and a greater cytotoxic effect of exogenous addition of MTA, the natural inhibitor of PRMT5, in these cells.	('MTA', 'Chemical', 'MESH:C008500', (209, 212))	('MTA', 'Chemical', 'MESH:C008500', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cytotoxic effect', 'CPA', (260, 276))	('MTA', 'Chemical', 'MESH:C008500', (224, 227))	('cancer', 'Disease', (167, 173))	('MTA', 'Chemical', 'MESH:C008500', (302, 305))	('MTAP-deleted', 'Var', (224, 236))	('intracellular', 'cellular_component', 'GO:0005622', ('41', '54'))	('higher', 'PosReg', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('greater', 'PosReg', (252, 259))	('MTA content', 'MPA', (209, 220))	('MTA', 'Chemical', 'MESH:C008500', (37, 40))
190840	32301278	E2F1 has previously been found to exert controversial roles in different human cancers, promoting either proliferation or tumour suppression, depending on the context  50  Although E2F1 has been proposed as a therapeutic target and it is an independent prognostic factor for many cancers, 51 ,  52 ,  53 ,  54  the role of E2F1 in MM has poorly been investigated.	('tumour suppression', 'Disease', (122, 140))	('cancers', 'Disease', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', (280, 287))	('tumour suppression', 'Disease', 'MESH:D009369', (122, 140))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('human', 'Species', '9606', (73, 78))	('proliferation', 'CPA', (105, 118))	('E2F1', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('promoting', 'PosReg', (88, 97))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
190842	32301278	Interestingly, among the E2F1 target genes down-regulated by PRMT5 silencing and involved in cell cycle progression, the EZH2 gene encodes a factor implicated in the epigenetic regulation of gene expression 56  which is a negative prognostic factor and a potential therapeutic target in MM 57   Finally, we identified a subset of EMT markers regulated by PRMT5 in MM, including E-cadherin, N-cadherin, alpha-smooth muscle actin and MMP9, indicating that targeting PRMT5 could hamper this crucial process for cancer progression.	('EZH2', 'Gene', '2146', (121, 125))	('MMP9', 'molecular_function', 'GO:0004229', ('432', '436'))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('177', '206'))	('targeting', 'Var', (454, 463))	('E-cadherin', 'Gene', (378, 388))	('EZH2', 'Gene', (121, 125))	('cancer', 'Disease', (508, 514))	('PRMT5', 'Gene', (464, 469))	('E-cadherin', 'Gene', '999', (378, 388))	('cancer', 'Phenotype', 'HP:0002664', (508, 514))	('EMT', 'biological_process', 'GO:0001837', ('330', '333'))	('cell cycle', 'biological_process', 'GO:0007049', ('93', '103'))	('hamper', 'NegReg', (476, 482))	('MMP9', 'Gene', (432, 436))	('MMP9', 'Gene', '4318', (432, 436))	('cadherin', 'molecular_function', 'GO:0008014', ('380', '388'))	('silencing', 'Var', (67, 76))	('cancer', 'Disease', 'MESH:D009369', (508, 514))	('alpha-smooth muscle actin', 'Protein', (402, 427))	('N-cadherin', 'Gene', (390, 400))	('down-regulated', 'NegReg', (43, 57))	('N-cadherin', 'Gene', '1000', (390, 400))	('cadherin', 'molecular_function', 'GO:0008014', ('392', '400'))
190843	32301278	In agreement with previous studies underlining the potential value of PRMT5 as a therapeutic approach, 58 ,  59 ,  60 ,  61  our results represent a starting point for the evaluation of PRMT5 inhibitors also in MTAP-deleted mesothelioma.	('PRMT5', 'Gene', (186, 191))	('mesothelioma', 'Disease', 'MESH:D008654', (224, 236))	('MTAP-deleted', 'Var', (211, 223))	('mesothelioma', 'Disease', (224, 236))
190853	32276343	MiR-144s are located in the chromosomal region 17q11.2, which is subject to significant damage in many types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('MiR-144s', 'Var', (0, 8))	('chromosomal region', 'cellular_component', 'GO:0098687', ('28', '46'))
190854	32276343	In this review, we assess the involvement of miR-144s in several cancer types by illustrating the possible target genes that are related to each cancer, and we also briefly describe the clinical applications of miR-144s as a diagnostic and prognostic tool in cancers.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('men', 'Species', '9606', (37, 40))	('miR-144s', 'Var', (211, 219))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (259, 265))
190861	32276343	Among several miRNAs assessed, miR-144s seem to have a role in several cancers.	('role', 'Reg', (55, 59))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('miR-144s', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
190863	32276343	The miR-144 hairpin gives rise to the "guide strand" miR-144-5p and the sister "passenger" strand miR-144-3p (Figure 1B).	('miR-144-3p', 'Chemical', '-', (98, 108))	('miR-144', 'Gene', (4, 11))	('miR-144-5p', 'Var', (53, 63))
190879	32276343	In particular, animal studies showed that the deletion of the miR-144 locus in aged mice induces the development of B-cell lymphoma and acute myeloid leukemia.	('deletion', 'Var', (46, 54))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (116, 131))	('induces', 'Reg', (89, 96))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('men', 'Species', '9606', (108, 111))	('miR-144', 'Gene', (62, 69))	('acute myeloid leukemia', 'Disease', (136, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (136, 158))	('B-cell lymphoma', 'Disease', (116, 131))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (116, 131))	('mice', 'Species', '10090', (84, 88))
190887	32276343	Since rLN showed a higher level of miR-144 and a lower number of Foxp3+ cells, the authors hypothesized that both events might cooperate in supporting the proliferation of FL cells.	('Foxp3', 'Gene', (65, 70))	('proliferation', 'CPA', (155, 168))	('miR-144', 'Var', (35, 42))	('lower', 'NegReg', (49, 54))	('Foxp3', 'Gene', '50943', (65, 70))
190901	32276343	Evidence showed that several miRNAs, including miR-144, miR-181a, miR-18a, miR-34c, miR-34a, miR-140, miR-137, miR-148b, and miR-429, which were significantly upregulated in CNS, enhanced the permeability of blood tumor barrier (BTB) and downregulated the expression of junction-related proteins.	('BTB', 'Chemical', '-', (229, 232))	('miR-144', 'Var', (47, 54))	('blood tumor', 'Disease', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('miR-34a', 'Gene', (84, 91))	('expression', 'MPA', (256, 266))	('miR-137', 'Gene', (102, 109))	('miR-34c', 'Gene', '407042', (75, 82))	('miR-18a', 'Gene', (66, 73))	('miR-148b', 'Gene', '442892', (111, 119))	('miR-34c', 'Gene', (75, 82))	('junction-related proteins', 'Protein', (270, 295))	('miR-137', 'Gene', '406928', (102, 109))	('miR-148b', 'Gene', (111, 119))	('miR-34a', 'Gene', '407040', (84, 91))	('miR-429', 'Gene', '554210', (125, 132))	('downregulated', 'NegReg', (238, 251))	('blood tumor', 'Phenotype', 'HP:0004377', (208, 219))	('permeability', 'MPA', (192, 204))	('miR-18a', 'Gene', '406953', (66, 73))	('upregulated', 'PosReg', (159, 170))	('miR-181a', 'Var', (56, 64))	('enhanced', 'PosReg', (179, 187))	('miR-140', 'Gene', (93, 100))	('blood tumor', 'Disease', 'MESH:D007022', (208, 219))	('miR-429', 'Gene', (125, 132))	('miR-140', 'Gene', '406932', (93, 100))
190905	32276343	By using Real-time PCR, luciferase reporter assay, and bioinformatics tools, they also that reported that the deletion of TUG1 via upregulation of miR-144 increased BTB permeability, and down-regulated the expression of the tight junction proteins ZO-1, occludin, and claudin-5.	('down-regulated', 'NegReg', (187, 201))	('ZO-1', 'Gene', '7082', (248, 252))	('upregulation', 'PosReg', (131, 143))	('occludin', 'Gene', (254, 262))	('miR-144', 'Gene', (147, 154))	('expression', 'MPA', (206, 216))	('increased', 'PosReg', (155, 164))	('PC', 'Phenotype', 'HP:0002894', (19, 21))	('TUG1', 'Gene', (122, 126))	('tight junction', 'cellular_component', 'GO:0070160', ('224', '238'))	('TUG1', 'Gene', '55000', (122, 126))	('claudin-5', 'Gene', (268, 277))	('BTB', 'Chemical', '-', (165, 168))	('occludin', 'Gene', '100506658', (254, 262))	('claudin-5', 'Gene', '7122', (268, 277))	('ZO-1', 'Gene', (248, 252))	('deletion', 'Var', (110, 118))	('BTB permeability', 'MPA', (165, 181))
190911	32276343	In 2008, WHO classified seven AML subtypes: 1:AML with recurrent genetic abnormalities and with gene mutations; 2:AML with myelodysplasia-related changes; 3:therapy-related myeloid neoplasms; 4:AML not otherwise specified (NOS); 5:myeloid sarcoma; 6:myeloid proliferations related to the Down syndrome; and, 7:blastic plasmacytoid dendritic cell neoplasms.	('AML', 'Disease', (114, 117))	('AML', 'Disease', 'MESH:D015470', (194, 197))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('AML', 'Phenotype', 'HP:0004808', (114, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (346, 355))	('AML', 'Disease', (194, 197))	('myeloid', 'Disease', (250, 257))	('myeloid neoplasms', 'Disease', (173, 190))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('neoplasm', 'Phenotype', 'HP:0002664', (346, 354))	('blastic', 'CPA', (310, 317))	('myelodysplasia', 'Disease', (123, 137))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (231, 246))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('myeloid sarcoma', 'Disease', (231, 246))	('mutations', 'Var', (101, 110))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (173, 190))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (331, 355))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('Down syndrome', 'Disease', (288, 301))	('AML', 'Disease', (46, 49))	('AML', 'Disease', (30, 33))	('AML', 'Phenotype', 'HP:0004808', (30, 33))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (173, 190))	('OS', 'Phenotype', 'HP:0002669', (224, 226))	('myelodysplasia', 'Phenotype', 'HP:0002863', (123, 137))	('genetic abnormalities', 'Disease', 'MESH:D030342', (65, 86))	('myelodysplasia', 'Disease', 'MESH:D009190', (123, 137))	('genetic abnormalities', 'Disease', (65, 86))	('dendritic cell neoplasms', 'Disease', (331, 355))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('AML', 'Disease', 'MESH:D015470', (114, 117))
190915	32276343	They assessed the expression of miR-144-3p in the BM and peripheral blood of AML patients and healthy controls.	('AML', 'Disease', 'MESH:D015470', (77, 80))	('patients', 'Species', '9606', (81, 89))	('AML', 'Disease', (77, 80))	('miR-144-3p', 'Var', (32, 42))	('miR-144-3p', 'Chemical', '-', (32, 42))	('expression', 'MPA', (18, 28))	('AML', 'Phenotype', 'HP:0004808', (77, 80))
190917	32276343	The result showed that miR-144-3p was significantly higher in both the peripheral blood and BM of AML patients when compared with the controls and in HL-60 cells.	('AML', 'Disease', 'MESH:D015470', (98, 101))	('patients', 'Species', '9606', (102, 110))	('HL-60', 'CellLine', 'CVCL:0002', (150, 155))	('higher', 'PosReg', (52, 58))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('miR-144-3p', 'Chemical', '-', (23, 33))	('AML', 'Disease', (98, 101))	('miR-144-3p', 'Var', (23, 33))
190918	32276343	In this study, the downregulation of miR-144-3p, as an oncogene, via the upregulation of NRF2, reduced cell viability and promoted apoptosis.	('NRF2', 'Gene', (89, 93))	('cell viability', 'CPA', (103, 117))	('reduced', 'NegReg', (95, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('miR-144-3p', 'Var', (37, 47))	('promoted', 'PosReg', (122, 130))	('miR-144-3p', 'Chemical', '-', (37, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('apoptosis', 'CPA', (131, 140))	('NRF2', 'Gene', '4780', (89, 93))	('downregulation', 'NegReg', (19, 33))	('upregulation', 'PosReg', (73, 85))
190921	32276343	Mutations of the FLT3 gene occur in almost 30% of all AML cases, with the internal tandem duplication (ITD) expressing the most common type of FLT3 mutation.	('AML', 'Disease', 'MESH:D015470', (54, 57))	('FLT3', 'Gene', '2322', (143, 147))	('FLT3', 'Gene', '2322', (17, 21))	('Mutations', 'Var', (0, 9))	('AML', 'Phenotype', 'HP:0004808', (54, 57))	('AML', 'Disease', (54, 57))	('FLT3', 'Gene', (143, 147))	('internal tandem duplication', 'Var', (74, 101))	('FLT3', 'Gene', (17, 21))
190922	32276343	FLT3 gene alterations are associated with a form of AML that is known as cytogenetically normal AML (CN-AML).	('AML', 'Disease', (96, 99))	('alterations', 'Var', (10, 21))	('AML', 'Phenotype', 'HP:0004808', (104, 107))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('AML', 'Disease', (104, 107))	('AML', 'Disease', (52, 55))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('AML', 'Disease', 'MESH:D015470', (104, 107))	('FLT3', 'Gene', '2322', (0, 4))	('FLT3', 'Gene', (0, 4))	('associated', 'Reg', (26, 36))	('AML', 'Phenotype', 'HP:0004808', (96, 99))	('AML', 'Disease', 'MESH:D015470', (52, 55))
190925	32276343	They reported the downregulation of miR-144 and upregulation of FLT3, homeobox genes (MEIS1, PBX3, HOXB3) as a possible target of miR-144 in CN-AML.	('AML', 'Phenotype', 'HP:0004808', (144, 147))	('HOXB3', 'Gene', '3213', (99, 104))	('miR-144', 'Var', (130, 137))	('AML', 'Disease', (144, 147))	('HOXB3', 'Gene', (99, 104))	('FLT3', 'Gene', '2322', (64, 68))	('PBX3', 'Gene', (93, 97))	('PBX3', 'Gene', '5090', (93, 97))	('AML', 'Disease', 'MESH:D015470', (144, 147))	('MEIS1', 'Gene', '4211', (86, 91))	('MEIS1', 'Gene', (86, 91))	('FLT3', 'Gene', (64, 68))	('downregulation', 'NegReg', (18, 32))	('miR-144', 'Gene', (36, 43))	('upregulation', 'PosReg', (48, 60))
190929	32276343	The acute myeloid leukemia 1 protein/protein ETO (AML1/ETO; A/E) fusion gene is responsible for 15% of AML cases and 15-26.7% of young patients with EMI.	('patients', 'Species', '9606', (135, 143))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('AML', 'Phenotype', 'HP:0004808', (50, 53))	('AML1', 'Gene', '861', (50, 54))	('AML', 'Disease', (50, 53))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('ETO', 'Gene', '862', (55, 58))	('acute myeloid leukemia', 'Disease', (4, 26))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('AML', 'Disease', (103, 106))	('AML1', 'Gene', (50, 54))	('AML', 'Phenotype', 'HP:0004808', (103, 106))	('ETO', 'Gene', '862', (45, 48))	('fusion', 'Var', (65, 71))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (4, 26))	('responsible', 'Reg', (80, 91))	('ETO', 'Gene', (55, 58))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (4, 26))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (10, 26))	('ETO', 'Gene', (45, 48))
190932	32276343	The patients with high expression of APP were more prone to developing EMI  Acute lymphoblastic leukemia (ALL) is a multi-factorial malignancy with an incidence of over 6000 new cases per year in the United States.	('EMI  Acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (71, 104))	('Acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (76, 104))	('multi-factorial malignancy', 'Disease', 'MESH:D009369', (116, 142))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('Acute lymphoblastic leukemia', 'Disease', (76, 104))	('ALL', 'Phenotype', 'HP:0006721', (106, 109))	('multi-factorial malignancy', 'Disease', (116, 142))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (82, 104))	('patients', 'Species', '9606', (4, 12))	('APP', 'Gene', (37, 40))	('high expression', 'Var', (18, 33))	('Acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (76, 104))
190942	32276343	evaluated the regulatory feedback between the myc and the miR-144/451 clusters in CML.	('CML', 'Phenotype', 'HP:0005506', (82, 85))	('CML', 'Disease', (82, 85))	('myc', 'Gene', (46, 49))	('miR-144/451', 'Var', (58, 69))	('myc', 'Gene', '4609', (46, 49))	('CML', 'Disease', 'MESH:D015464', (82, 85))
190952	32276343	They reported the upregulation of several miRNAs in CLL, including miR-144-5p, miR-144-3p, miR-28-5p, miR-486-5p, and miR-486-3p.	('upregulation', 'PosReg', (18, 30))	('miR-28', 'Gene', (91, 97))	('miR-144-3p', 'Var', (79, 89))	('miR-144-5p', 'Var', (67, 77))	('miR-28', 'Gene', '407020', (91, 97))	('CLL', 'Phenotype', 'HP:0005550', (52, 55))	('miR-486-3p', 'Var', (118, 128))	('miR-486-5p', 'Var', (102, 112))	('miR-144-3p', 'Chemical', '-', (79, 89))
190958	32276343	Furthermore, miR-144 by downregulation of MET signaling reduced GC progression that eventually blocks the activation of the Akt pathway.	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('Akt', 'Gene', (124, 127))	('miR-144', 'Var', (13, 20))	('reduced', 'NegReg', (56, 63))	('MET', 'Gene', (42, 45))	('MET', 'Gene', '4233', (42, 45))	('downregulation', 'NegReg', (24, 38))	('Akt', 'Gene', '207', (124, 127))	('GC', 'Phenotype', 'HP:0012126', (64, 66))
190965	32276343	The results showed that miR-144-3p, miR-134-5p, and miR-451a were deregulated in GC, but using these miRNAs had a moderate diagnostic value.	('miR-144-3p', 'Chemical', '-', (24, 34))	('miR-134', 'Gene', (36, 43))	('miR-134', 'Gene', '406924', (36, 43))	('miR-451a', 'Gene', '574411', (52, 60))	('miR-451a', 'Gene', (52, 60))	('deregulated', 'MPA', (66, 77))	('GC', 'Phenotype', 'HP:0012126', (81, 83))	('miR-144-3p', 'Var', (24, 34))
190972	32276343	C-X C motif chemokine ligand 11 (CXCL11) is another target of miR-144 in CRC.	('C-X C motif chemokine ligand 11', 'Gene', '6373', (0, 31))	('CXCL11', 'Gene', (33, 39))	('CXCL11', 'Gene', '6373', (33, 39))	('C-X C motif chemokine ligand 11', 'Gene', (0, 31))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('miR-144', 'Var', (62, 69))	('ligand', 'molecular_function', 'GO:0005488', ('22', '28'))
190976	32276343	The mTOR is a downstream effector of the PI3K/AKT pathway and it is a target of miR-144 in CRC.	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('PI3K/AKT pathway', 'Pathway', (41, 57))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('miR-144', 'Var', (80, 87))
190983	32276343	demonstrated that miR-144-3p was reduced in PC tissues and PANC-1 cells.	('miR-144-3p', 'Var', (18, 28))	('PC', 'Phenotype', 'HP:0002894', (44, 46))	('miR-144-3p', 'Chemical', '-', (18, 28))	('reduced', 'NegReg', (33, 40))	('PANC-1', 'CellLine', 'CVCL:0480', (59, 65))
190984	32276343	MiR-144-3p expression inhibited cell growth in the S-phase cell-cycle, leading to cell apoptosis in vitro.	('MiR-144-3p expression', 'Var', (0, 21))	('cell growth', 'biological_process', 'GO:0016049', ('32', '43'))	('inhibited', 'NegReg', (22, 31))	('cell-cycle', 'biological_process', 'GO:0007049', ('59', '69'))	('S-phase', 'biological_process', 'GO:0051320', ('51', '58'))	('cell apoptosis', 'CPA', (82, 96))	('leading', 'Reg', (71, 78))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('cell growth in the S-phase cell-cycle', 'CPA', (32, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
190985	32276343	MiR-144-3p regulated proline-rich protein 11 (PRR11 3'-UTR).	('proline-rich protein 11', 'Gene', '55771', (21, 44))	('proline-rich protein 11', 'Gene', (21, 44))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('PRR11', 'Gene', '55771', (46, 51))	('MiR-144-3p', 'Var', (0, 10))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('PRR11', 'Gene', (46, 51))	('PRR', 'molecular_function', 'GO:0038187', ('46', '49'))
190986	32276343	When the PC cells were transfected with miR-144-3p, PRR11 decreased, with the upregulation of p-JNK and p-p38, with a key role in cancer progression impairment.	('men', 'Species', '9606', (155, 158))	('PRR11', 'Gene', '55771', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('JNK', 'molecular_function', 'GO:0004705', ('96', '99'))	('JNK', 'Gene', '5599', (96, 99))	('PC', 'Phenotype', 'HP:0002894', (9, 11))	('PRR', 'molecular_function', 'GO:0038187', ('52', '55'))	('cancer', 'Disease', (130, 136))	('decreased', 'NegReg', (58, 67))	('PRR11', 'Gene', (52, 57))	('p38', 'Gene', '1432', (106, 109))	('upregulation', 'PosReg', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-144-3p', 'Var', (40, 50))	('miR-144-3p', 'Chemical', '-', (40, 50))	('p38', 'Gene', (106, 109))	('JNK', 'Gene', (96, 99))
190988	32276343	So far, miR-144-3p induced cell cycle inhibition and apoptosis in PC cell impairing PRR11.	('apoptosis', 'CPA', (53, 62))	('PRR', 'molecular_function', 'GO:0038187', ('84', '87'))	('cell cycle', 'biological_process', 'GO:0007049', ('27', '37'))	('PRR11', 'Gene', '55771', (84, 89))	('miR-144-3p', 'Var', (8, 18))	('miR-144-3p', 'Chemical', '-', (8, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('PRR11', 'Gene', (84, 89))	('cell cycle inhibition', 'CPA', (27, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('PC', 'Phenotype', 'HP:0002894', (66, 68))
190989	32276343	Additionally, in another in vitro study, the MiR-144-3p results downregulated in vitro evaluations.	('MiR-144-3p', 'Chemical', '-', (45, 55))	('MiR-144-3p', 'Var', (45, 55))	('downregulated', 'NegReg', (64, 77))
190990	32276343	MiR-144-3p overexpression reduces PC cell growth, chemotaxis, and metastasis.	('chemotaxis', 'biological_process', 'GO:0006935', ('50', '60'))	('MiR-144-3p', 'Var', (0, 10))	('PC', 'Phenotype', 'HP:0002894', (34, 36))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('chemotaxis', 'CPA', (50, 60))	('cell growth', 'biological_process', 'GO:0016049', ('37', '48'))	('reduces', 'NegReg', (26, 33))	('overexpression', 'PosReg', (11, 25))	('metastasis', 'CPA', (66, 76))
190991	32276343	demonstrated that MiR-144-3p enhancing could downregulated PC cell migration, proliferation, and invasion by inhibiting the expression of FOSB So far, enhancing miR-144 could provide a new target against PC, even if more studies are warranted.	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('PC', 'Phenotype', 'HP:0002894', (204, 206))	('inhibiting', 'NegReg', (109, 119))	('FOSB', 'Gene', '2354', (138, 142))	('cell migration', 'biological_process', 'GO:0016477', ('62', '76'))	('miR-144', 'Gene', (161, 168))	('enhancing', 'PosReg', (151, 160))	('downregulated', 'NegReg', (45, 58))	('MiR-144-3p', 'Var', (18, 28))	('expression', 'MPA', (124, 134))	('MiR-144-3p', 'Chemical', '-', (18, 28))	('invasion', 'CPA', (97, 105))	('PC', 'Phenotype', 'HP:0002894', (59, 61))	('FOSB', 'Gene', (138, 142))
190996	32276343	MiR-144 triggers Nrf2 mRNA degeneration by targeting the 3'UTR region and it leads to reverse chemoresistance in HCC cell lines.	('reverse chemoresistance', 'CPA', (86, 109))	('Nrf2', 'Gene', '4780', (17, 21))	('Nrf2', 'Gene', (17, 21))	('MiR-144', 'Var', (0, 7))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('mRNA', 'MPA', (22, 26))	('CC', 'Phenotype', 'HP:0002664', (114, 116))	('triggers', 'Reg', (8, 16))
190999	32276343	Another study detected that the levels of miR-141-3p were significantly increased in serum extracellular vehicles (EVs) and liver cancer tissues as compared with serum and the distal liver tissues in HCC patients.	('patients', 'Species', '9606', (204, 212))	('miR-141-3p', 'Chemical', '-', (42, 52))	('increased', 'PosReg', (72, 81))	('extracellular', 'cellular_component', 'GO:0005576', ('91', '104'))	('HCC', 'Phenotype', 'HP:0001402', (200, 203))	('liver cancer', 'Phenotype', 'HP:0002896', (124, 136))	('liver cancer', 'Disease', 'MESH:D006528', (124, 136))	('levels', 'MPA', (32, 38))	('liver cancer', 'Disease', (124, 136))	('EVs', 'Chemical', '-', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('serum extracellular vehicles', 'MPA', (85, 113))	('miR-141-3p', 'Var', (42, 52))	('CC', 'Phenotype', 'HP:0002664', (201, 203))
191001	32276343	MiR-141-3p also leads to invasion and metastasis of HCC by the direct targeting of SMAD4 and SGK3.	('leads to', 'Reg', (16, 24))	('HCC', 'Phenotype', 'HP:0001402', (52, 55))	('MiR-141-3p', 'Var', (0, 10))	('SMAD4', 'Gene', '4089', (83, 88))	('MiR-141-3p', 'Chemical', '-', (0, 10))	('SGK3', 'Gene', (93, 97))	('invasion', 'CPA', (25, 33))	('SGK3', 'Gene', '23678', (93, 97))	('targeting', 'Reg', (70, 79))	('SMAD4', 'Gene', (83, 88))	('CC', 'Phenotype', 'HP:0002664', (53, 55))	('metastasis', 'CPA', (38, 48))	('HCC', 'Disease', (52, 55))
191012	32276343	Additionally, they found the platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1) as one of the targets of miR-144 in CCA.	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('targets', 'Reg', (121, 128))	('PAFAH1B1', 'Gene', (97, 105))	('PAFAH1B1', 'Gene', '5048', (97, 105))	('platelet activating factor acetylhydrolase 1b regulatory subunit 1', 'Gene', '5048', (29, 95))	('CC', 'Phenotype', 'HP:0002664', (143, 145))	('CCA', 'Disease', (143, 146))	('miR-144', 'Var', (132, 139))
191014	32276343	The high expression of miR-144-3p, miR-144-5p, and miR-451 through targeting Myc and P-ERK led to the apoptosis and inhibition of migration, invasion, and proliferation of EC cells.	('invasion', 'CPA', (141, 149))	('ERK', 'Gene', (87, 90))	('Myc', 'Gene', (77, 80))	('miR-451', 'Gene', (51, 58))	('Myc', 'Gene', '4609', (77, 80))	('apoptosis', 'CPA', (102, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('proliferation', 'CPA', (155, 168))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('inhibition', 'NegReg', (116, 126))	('ERK', 'molecular_function', 'GO:0004707', ('87', '90'))	('miR-451', 'Gene', '574411', (51, 58))	('migration', 'CPA', (130, 139))	('miR-144-3p', 'Chemical', '-', (23, 33))	('miR-144-5p', 'Var', (35, 45))	('miR-144-3p', 'Var', (23, 33))	('ERK', 'Gene', '5594', (87, 90))
191024	32276343	displayed that miR-144-3p inhibited the growth and metastasis of tumor cells by targeting mitogen-activated protein kinase 6 (MAPK6).	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('inhibited', 'NegReg', (26, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('miR-144-3p', 'Chemical', '-', (15, 25))	('miR-144-3p', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mitogen-activated protein kinase 6', 'Gene', '5597', (90, 124))	('MAPK6', 'Gene', (126, 131))	('targeting', 'Reg', (80, 89))	('MAPK6', 'Gene', '5597', (126, 131))	('mitogen-activated protein kinase 6', 'Gene', (90, 124))
191027	32276343	The expression of miR-144, miR-93, and miR-382 was reduced in primary ovarian tumors.	('miR-382', 'Gene', (39, 46))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('reduced', 'NegReg', (51, 58))	('primary ovarian tumors', 'Disease', (62, 84))	('miR-93', 'Gene', '407051', (27, 33))	('ovarian tumors', 'Phenotype', 'HP:0100615', (70, 84))	('miR-93', 'Gene', (27, 33))	('expression', 'MPA', (4, 14))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (62, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('miR-144', 'Var', (18, 25))	('miR-382', 'Gene', '494331', (39, 46))
191037	32276343	found that miR-124 and miR-144 directly targeted the 3'UTR of PIM1 and, via its downregulation, led to hypoxia-induced autophagy and increased radiosensitivity of PrC.	('miR-144', 'Var', (23, 30))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (133, 159))	('PIM1', 'Gene', '5292', (62, 66))	('led to', 'Reg', (96, 102))	('autophagy', 'biological_process', 'GO:0006914', ('119', '128'))	('PrC', 'Phenotype', 'HP:0012125', (163, 166))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('miR-124', 'Var', (11, 18))	('PIM1', 'Gene', (62, 66))	('radiosensitivity', 'CPA', (143, 159))	('increased', 'PosReg', (133, 142))	('hypoxia', 'Disease', (103, 110))	('downregulation', 'NegReg', (80, 94))	('autophagy', 'biological_process', 'GO:0016236', ('119', '128'))
191038	32276343	determined that miR-144-3 prevents proliferation and leads to cell death in PrC by targeting CEP55.	('death', 'Disease', 'MESH:D003643', (67, 72))	('death', 'Disease', (67, 72))	('miR-144-3', 'Var', (16, 25))	('proliferation', 'CPA', (35, 48))	('prevents', 'NegReg', (26, 34))	('PrC', 'Phenotype', 'HP:0012125', (76, 79))	('targeting', 'Reg', (83, 92))	('CEP', 'molecular_function', 'GO:0047849', ('93', '96'))	('CEP55', 'Gene', '55165', (93, 98))	('CEP55', 'Gene', (93, 98))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))
191042	32276343	Studies showed that both miR-144-5p and miR-144-3p were significantly downregulated in RCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('downregulated', 'NegReg', (70, 83))	('miR-144-3p', 'Var', (40, 50))	('miR-144-5p', 'Var', (25, 35))	('miR-144-3p', 'Chemical', '-', (40, 50))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
191044	32276343	Furthermore, miR-144-3p leads to the suppression of invasion and migration, by targeting MAP3K8; so far, it can act as a tumor suppressor.	('miR-144-3p', 'Chemical', '-', (13, 23))	('MAP3K', 'molecular_function', 'GO:0004709', ('89', '94'))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('MAP3K8', 'Gene', '1326', (89, 95))	('targeting', 'Reg', (79, 88))	('suppression', 'NegReg', (37, 48))	('MAP3K8', 'Gene', (89, 95))	('miR-144-3p', 'Var', (13, 23))
191045	32276343	showed that the overexpression of miR-144-3p promoted proliferation, metastasis, and sunitinib resistance by targeting AT-rich interactive domain-containing protein 1A (ARID1A) in clear cell renal cell carcinoma (ccRCC).	('targeting', 'Reg', (109, 118))	('AT-rich interactive domain-containing protein 1A', 'Gene', (119, 167))	('proliferation', 'CPA', (54, 67))	('ARID1A', 'Gene', (169, 175))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (180, 211))	('miR-144-3p', 'Chemical', '-', (34, 44))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('promoted', 'PosReg', (45, 53))	('ARID1A', 'Gene', '8289', (169, 175))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))	('metastasis', 'CPA', (69, 79))	('clear cell renal cell carcinoma', 'Disease', (180, 211))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (191, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('RCC', 'Disease', (215, 218))	('CC', 'Phenotype', 'HP:0002664', (216, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('AT-rich interactive domain-containing protein 1A', 'Gene', '8289', (119, 167))	('miR-144-3p', 'Var', (34, 44))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (180, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
191047	32276343	Additionally, in a recent survey, the antitumor roles of miR-451a, miR-144-5p, and miR-144-3p were confirmed in RCC.	('tumor', 'Disease', (42, 47))	('miR-144-5p', 'Var', (67, 77))	('CC', 'Phenotype', 'HP:0002664', (113, 115))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('miR-144-3p', 'Var', (83, 93))	('miR-144-3p', 'Chemical', '-', (83, 93))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('miR-451a', 'Gene', '574411', (57, 65))	('miR-451a', 'Gene', (57, 65))
191048	32276343	The assays determined that miR-144-5p and miR-144-3p significantly reduced the migration and invasion in RCC cells, proposing these miRNAs behaved as tumor suppressor miRNAs in RCC.	('miR-144-3p', 'Var', (42, 52))	('miR-144-3p', 'Chemical', '-', (42, 52))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('150', '166'))	('RCC', 'Disease', (177, 180))	('CC', 'Phenotype', 'HP:0002664', (106, 108))	('CC', 'Phenotype', 'HP:0002664', (178, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('reduced', 'NegReg', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('miR-144-5p', 'Var', (27, 37))	('tumor suppressor', 'biological_process', 'GO:0051726', ('150', '166'))	('tumor', 'Disease', (150, 155))
191049	32276343	Computational analyses recognized a total of 65 possible targets of miR-144-5p in RCC cells.	('miR-144-5p', 'Var', (68, 78))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('CC', 'Phenotype', 'HP:0002664', (83, 85))
191051	32276343	Among them, the expression of SDC3 was directly regulated by miR-144-5p, and its upregulation enhanced RCC cell invasiveness.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('miR-144-5p', 'Var', (61, 71))	('SDC3', 'Gene', (30, 34))	('SDC3', 'Gene', '9672', (30, 34))	('CC', 'Phenotype', 'HP:0002664', (104, 106))	('upregulation enhanced', 'PosReg', (81, 102))	('regulated', 'Reg', (48, 57))	('expression', 'MPA', (16, 26))
191052	32276343	reported a significantly higher level of miR-144-3p in 106 ccRCC plasmas as compared with healthy individuals, suggesting the role of miR-144-3p as a novel and unique plasma biomarker for the diagnosis of ccRCC.	('miR-144-3p', 'Chemical', '-', (41, 51))	('higher', 'PosReg', (25, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('miR-144-3p', 'Chemical', '-', (134, 144))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('CC', 'Phenotype', 'HP:0002664', (62, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('miR-144-3p', 'MPA', (41, 51))	('CC', 'Phenotype', 'HP:0002664', (208, 210))	('miR-144-3p', 'Var', (134, 144))
191059	32276343	found miR-144-5p acts as a tumor suppressor by directly targeting CCNE1/2 in BlC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', (27, 32))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('CCNE1', 'Gene', '898', (66, 71))	('BlC', 'Phenotype', 'HP:0009725', (77, 80))	('targeting', 'Reg', (56, 65))	('CCNE1', 'Gene', (66, 71))	('miR-144-5p', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))
191060	32276343	This study was conducted to evaluate the functional roles of miR-144-3p and miR-144-5p and their modulation of targets in BlC cells.	('miR-144-5p', 'Var', (76, 86))	('miR-144-3p', 'Var', (61, 71))	('BlC', 'Phenotype', 'HP:0009725', (122, 125))	('miR-144-3p', 'Chemical', '-', (61, 71))
191061	32276343	Their results showed that miR-144-5p, via the direct targeting of CCNE1, CCNE2, CDC25A, and PKMYT1, dramatically repressed the cell proliferation of BlC cells.	('PKMYT1', 'Gene', (92, 98))	('cell proliferation of BlC', 'CPA', (127, 152))	('CCNE2', 'Gene', (73, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('BlC', 'Phenotype', 'HP:0009725', (149, 152))	('CDC25A', 'Gene', (80, 86))	('CCNE2', 'Gene', '9134', (73, 78))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('repressed', 'PosReg', (113, 122))	('miR-144-5p', 'Var', (26, 36))	('CCNE1', 'Gene', '898', (66, 71))	('PKMYT1', 'Gene', '9088', (92, 98))	('CC', 'Phenotype', 'HP:0002664', (73, 75))	('CCNE1', 'Gene', (66, 71))	('CDC25A', 'Gene', '993', (80, 86))
191064	32276343	They reported three significant upregulated blood miRNAs (miR-26b-5p, miR-144-5p, and miR-374-5p) in invasive BlC patients when compared with the control group.	('patients', 'Species', '9606', (114, 122))	('BlC', 'Phenotype', 'HP:0009725', (110, 113))	('invasive BlC', 'Disease', (101, 113))	('miR-26b', 'Gene', '407017', (58, 65))	('miR-374-5p', 'Var', (86, 96))	('miR-26b', 'Gene', (58, 65))	('miR-144-5p', 'Var', (70, 80))	('upregulated', 'PosReg', (32, 43))
191068	32276343	The concentrations of miR-144 duplex (miR-144-5p and miR-144-3p) were significantly reduced in squamous NSCLC tissues as compared to healthy adjacent tissues.	('concentrations', 'MPA', (4, 18))	('squamous NSCLC', 'Disease', (95, 109))	('reduced', 'NegReg', (84, 91))	('squamous NSCLC', 'Disease', 'MESH:D002294', (95, 109))	('miR-144-3p', 'Chemical', '-', (53, 63))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('miR-144-3p', 'Var', (53, 63))	('miR-144', 'Protein', (22, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
191069	32276343	It was observed that both miR-144-5p and miR-144-3p had tumor inhibitory effects by targeting several oncogenes in squamous NSCLC including neuronal calcium sensor 1 (NCS1), solute carrier family 44 member 5 (SLC44A5), and myristoylated alanine rich protein kinase C substrate (MARCKS) genes.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-144-3p', 'Var', (41, 51))	('MARCKS', 'Gene', '4082', (278, 284))	('squamous NSCLC', 'Disease', 'MESH:D002294', (115, 129))	('neuronal calcium sensor 1', 'Gene', '23413', (140, 165))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('SLC44A5', 'Gene', '204962', (209, 216))	('myristoylated alanine rich protein kinase C substrate', 'Gene', '4082', (223, 276))	('NCS1', 'Gene', '23413', (167, 171))	('squamous NSCLC', 'Disease', (115, 129))	('miR-144-3p', 'Chemical', '-', (41, 51))	('tumor', 'Disease', (56, 61))	('oncogenes', 'Gene', (102, 111))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('solute carrier family 44 member 5', 'Gene', (174, 207))	('SLC44A5', 'Gene', (209, 216))	('carrier', 'molecular_function', 'GO:0005215', ('181', '188'))	('MARCKS', 'Gene', (278, 284))	('NCS1', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('neuronal calcium sensor 1', 'Gene', (140, 165))	('miR-144-5p', 'Var', (26, 36))	('solute carrier family 44 member 5', 'Gene', '204962', (174, 207))	('targeting', 'Reg', (84, 93))
191075	32276343	They reported lower expression of miR-144-3p in NSCLC tissue when compared with the normal tissue.	('NSCLC', 'Disease', (48, 53))	('expression', 'MPA', (20, 30))	('SCLC', 'Phenotype', 'HP:0030357', (49, 53))	('lower', 'NegReg', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('miR-144-3p', 'Var', (34, 44))	('miR-144-3p', 'Chemical', '-', (34, 44))
191076	32276343	Additionally, miR-144-3p expression was significantly associated with stage, metastasis, and invasion of tumor cells, suggesting that miR-144-3p could function as a potential tumor biomarker in the prognosis prediction for NSCLC and as a potential clinical target in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('NSCLC', 'Disease', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('miR-144-3p', 'Chemical', '-', (14, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('miR-144-3p', 'Var', (134, 144))	('metastasis', 'CPA', (77, 87))	('miR-144-3p', 'Gene', (14, 24))	('tumor', 'Disease', (105, 110))	('associated', 'Reg', (54, 64))	('tumor', 'Disease', (175, 180))	('SCLC', 'Phenotype', 'HP:0030357', (224, 228))	('lung cancer', 'Disease', (267, 278))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('miR-144-3p', 'Chemical', '-', (134, 144))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('stage', 'CPA', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
191084	32276343	The results showed miR-144 with eight other miRNAs, including let-7e, miR-203, miR-340, miR-34a, miR-423, miR-582, miR-7-1, and miR-9 were significantly down-regulated in the tissue samples of mesothelioma patients when compared to normal tissues.	('mesothelioma', 'Disease', (193, 205))	('miR-9', 'Var', (128, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (193, 205))	('miR-423', 'Gene', '494335', (97, 104))	('miR-144', 'Gene', (19, 26))	('miR-582', 'Gene', '693167', (106, 113))	('let-7e', 'Gene', (62, 68))	('miR-340', 'Gene', '442908', (79, 86))	('miR-340', 'Gene', (79, 86))	('miR-7-1', 'Gene', '407043', (115, 122))	('miR-34a', 'Gene', (88, 95))	('miR-203', 'Gene', (70, 77))	('let-7e', 'Gene', '406887', (62, 68))	('miR-582', 'Gene', (106, 113))	('miR-423', 'Gene', (97, 104))	('miR-7-1', 'Gene', (115, 122))	('miR-34a', 'Gene', '407040', (88, 95))	('patients', 'Species', '9606', (206, 214))	('down-regulated', 'NegReg', (153, 167))	('miR-203', 'Gene', '406986', (70, 77))
191089	32276343	Additionally, this study showed that the expression of miR-144 can repress the process of EMT in MCF-7 and MDA-MB-231 cell lines.	('process of EMT', 'CPA', (79, 93))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('miR-144', 'Gene', (55, 62))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))	('repress', 'NegReg', (67, 74))	('expression', 'Var', (41, 51))
191091	32276343	found that miR-144 might function as an oncomiR by an increase in the survival rate of breast cancer cells.	('miR-144', 'Var', (11, 18))	('increase', 'PosReg', (54, 62))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('survival rate', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
191096	32276343	demonstrated that miR-144-3p, by targeting of ETS-1 and insulin receptor substrate 1 (IRS1) in laryngeal squamous cell carcinoma, led to the inhibition of metastasis and invasion of tumor cells.	('IRS1', 'Gene', '3667', (86, 90))	('miR-144-3p', 'Var', (18, 28))	('IRS1', 'Gene', (86, 90))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('ETS-1', 'Gene', (46, 51))	('inhibition', 'NegReg', (141, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Disease', (105, 128))	('metastasis', 'CPA', (155, 165))	('insulin receptor substrate 1', 'Gene', (56, 84))	('insulin', 'molecular_function', 'GO:0016088', ('56', '63'))	('miR-144-3p', 'Chemical', '-', (18, 28))	('targeting', 'NegReg', (33, 42))	('insulin receptor substrate 1', 'Gene', '3667', (56, 84))	('tumor', 'Disease', (182, 187))	('ETS-1', 'Gene', '2113', (46, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
191097	32276343	Moreover, miR-144-3p, by inhibition of E-cadherin, reduces cellular EMT in laryngeal squamous cell carcinoma.	('miR-144-3p', 'Chemical', '-', (10, 20))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('reduces', 'NegReg', (51, 58))	('miR-144-3p', 'Var', (10, 20))	('cellular EMT', 'CPA', (59, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('inhibition', 'NegReg', (25, 35))	('squamous cell carcinoma', 'Disease', (85, 108))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))
191105	32276343	Moreover, miR-144 targets ZEB 1 and ZEB2 and inhibits the invasion of tumor cells, which suggests the role of miR-144 as a tumor suppressor in TC.	('ZEB2', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (123, 128))	('TC', 'Phenotype', 'HP:0002890', (143, 145))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Disease', (70, 75))	('miR-144', 'Gene', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('miR-144', 'Var', (110, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('123', '139'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('ZEB 1', 'Gene', '6935', (26, 31))	('ZEB2', 'Gene', '9839', (36, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('123', '139'))	('ZEB 1', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
191108	32276343	Another in vitro study displayed that miR-144-3p is involved in cell cycle progression and EMT.	('miR-144-3p', 'Chemical', '-', (38, 48))	('EMT', 'CPA', (91, 94))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('involved', 'Reg', (52, 60))	('cell cycle', 'biological_process', 'GO:0007049', ('64', '74'))	('cell cycle progression', 'CPA', (64, 86))	('miR-144-3p', 'Var', (38, 48))
191112	32276343	Several studies verified the downregulation of MiR-144-3p in GBM over non-neoplastic brain tissues.	('downregulation', 'NegReg', (29, 43))	('MiR-144-3p', 'Chemical', '-', (47, 57))	('neoplastic brain', 'Phenotype', 'HP:0030692', (74, 90))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('GBM', 'Disease', (61, 64))	('MiR-144-3p', 'Var', (47, 57))
191113	32276343	MiR-144-3p negatively exerts tumor growth and apoptosis in glioma cells by targeting topoisomerase II alpha (TOP2A).	('apoptosis', 'CPA', (46, 55))	('glioma', 'Disease', (59, 65))	('negatively', 'NegReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('targeting', 'Reg', (75, 84))	('MiR-144-3p', 'Var', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (29, 34))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('85', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('TOP2A', 'Gene', '7153', (109, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('TOP2A', 'Gene', (109, 114))
191115	32276343	indicated that miR-144-3p inhibits metastasis by targeting FZD7.	('FZD7', 'Gene', '8324', (59, 63))	('inhibits', 'NegReg', (26, 34))	('metastasis', 'CPA', (35, 45))	('miR-144-3p', 'Chemical', '-', (15, 25))	('FZD7', 'Gene', (59, 63))	('miR-144-3p', 'Var', (15, 25))	('targeting', 'Reg', (49, 58))
191127	32276343	Additionally, the upregulation of TAGLN, as a target of miR-144, is inversely associated with miR-144 expression Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) are other targets of miR-144 that downregulate them by the upregulation of miR-144, and it has an important role in suppressing the proliferation and invasion.	('ROCK2', 'Gene', '9475', (155, 160))	('upregulation', 'PosReg', (18, 30))	('OC', 'Phenotype', 'HP:0100615', (156, 158))	('TAGLN', 'Gene', '6876', (34, 39))	('ROCK1', 'Gene', '6093', (145, 150))	('upregulation', 'PosReg', (221, 233))	('miR-144', 'Var', (237, 244))	('downregulate', 'NegReg', (196, 208))	('miR-144', 'Gene', (94, 101))	('suppressing', 'NegReg', (278, 289))	('ROCK2', 'Gene', (155, 160))	('TAGLN', 'Gene', (34, 39))	('ROCK1', 'Gene', (145, 150))	('OC', 'Phenotype', 'HP:0100615', (146, 148))
191129	32276343	Mice deficient of miR-144 have shown to undergo impairment in late erythrocyte maturation, which further leads to splenomegaly, mild anemia, and erythroid hyperplasia.	('erythroid hyperplasia', 'Disease', 'MESH:D006965', (145, 166))	('erythroid hyperplasia', 'Phenotype', 'HP:0012132', (145, 166))	('impairment', 'NegReg', (48, 58))	('erythroid hyperplasia', 'Disease', (145, 166))	('late erythrocyte maturation', 'CPA', (62, 89))	('splenomegaly', 'Disease', 'MESH:D013163', (114, 126))	('erythrocyte maturation', 'biological_process', 'GO:0043249', ('67', '89'))	('anemia', 'Disease', (133, 139))	('splenomegaly', 'Phenotype', 'HP:0001744', (114, 126))	('miR-144', 'Gene', (18, 25))	('men', 'Species', '9606', (54, 57))	('Mice', 'Species', '10090', (0, 4))	('anemia', 'Disease', 'MESH:D000740', (133, 139))	('leads to', 'Reg', (105, 113))	('anemia', 'Phenotype', 'HP:0001903', (133, 139))	('splenomegaly', 'Disease', (114, 126))	('deficient', 'Var', (5, 14))
191226	29369779	However, dysregulation of the Eph/ephrin interactions is implicated in cancer contributing to tumour growth, metastasis, and angiogenesis.	('angiogenesis', 'CPA', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('ephrin', 'molecular_function', 'GO:0046875', ('34', '40'))	('cancer', 'Disease', (71, 77))	('implicated', 'Reg', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('metastasis', 'CPA', (109, 119))	('tumour growth', 'Disease', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ephrin', 'molecular_function', 'GO:0005106', ('34', '40'))	('Eph', 'Gene', '2041', (30, 33))	('tumour growth', 'Disease', 'MESH:D006130', (94, 107))	('Eph', 'Gene', (30, 33))	('dysregulation', 'Var', (9, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('125', '137'))
191239	29369779	However, crosstalk between elevated Eph receptors and other oncogenes, such as the ErbB family of receptor tyrosine kinases is thought to result in enhanced cell proliferation and tumorigenesis, presumably independent of ephrin stimulation (reviewed,) (Fig.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ErbB', 'Gene', '1956;2064', (83, 87))	('ephrin', 'molecular_function', 'GO:0046875', ('221', '227'))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cell proliferation', 'CPA', (157, 175))	('crosstalk', 'Var', (9, 18))	('tyrosine', 'Chemical', 'MESH:D014443', (107, 115))	('tumor', 'Disease', (180, 185))	('cell proliferation', 'biological_process', 'GO:0008283', ('157', '175'))	('ephrin', 'molecular_function', 'GO:0005106', ('221', '227'))	('Eph', 'Gene', '2041', (36, 39))	('elevated', 'PosReg', (27, 35))	('enhanced', 'PosReg', (148, 156))	('ErbB', 'Gene', (83, 87))	('Eph', 'Gene', (36, 39))
191247	29369779	The EphB4-ephrinB2 structural analysis suggested that L95 plays a particularly important role in defining ligand selectivity of EphB4.	('EphB4', 'Gene', (128, 133))	('ephrinB2', 'Gene', '1948', (10, 18))	('L95', 'Var', (54, 57))	('ephrinB2', 'Gene', (10, 18))	('ligand', 'molecular_function', 'GO:0005488', ('106', '112'))
191248	29369779	Furthermore, amino acid changes in the EphB4 ligand binding cavity when designed based on comparison with the crystal structure of the more promiscuous EphB2 receptor, yielded EphB4 variants with altered binding affinity for ephrinB2 and TNYL-RAW.	('EphB2', 'Gene', '2048', (152, 157))	('ephrinB2', 'Gene', (225, 233))	('altered', 'Reg', (196, 203))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('variants', 'Var', (182, 190))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('amino acid changes', 'Var', (13, 31))	('binding', 'Interaction', (204, 211))	('EphB4', 'Gene', (176, 181))	('ephrinB2', 'Gene', '1948', (225, 233))	('TNYL-RAW', 'MPA', (238, 246))	('ligand', 'molecular_function', 'GO:0005488', ('45', '51'))	('EphB2', 'Gene', (152, 157))
191249	29369779	Finally, binding studies employing isothermal titration calorimetry with the EphB4 L95R mutant confirmed the importance of this amino acid in conferring high affinity binding to both ephrinB2 and TNYL-RAW.	('ephrinB2', 'Gene', (183, 191))	('EphB4', 'Gene', (77, 82))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('L95R', 'Mutation', 'p.L95R', (83, 87))	('ephrinB2', 'Gene', '1948', (183, 191))	('mutant', 'Var', (88, 94))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('L95R mutant', 'Var', (83, 94))	('TNYL-RAW', 'Protein', (196, 204))	('binding', 'Interaction', (167, 174))
191259	29369779	However, overexpression of EphB4 or that of an inactive mutant EphB4 kinase in esophageal squamous cell carcinoma cells promoted cell growth and migration, suggesting EphB4 promoted cell growth and migration independently of its kinase activity and that repressed tumourigenesis.	('tumour', 'Disease', (264, 270))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('promoted', 'PosReg', (173, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cell growth', 'biological_process', 'GO:0016049', ('182', '193'))	('promoted', 'PosReg', (120, 128))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('EphB4', 'Gene', (63, 68))	('migration', 'CPA', (145, 154))	('cell growth', 'CPA', (129, 140))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('kinase activity', 'molecular_function', 'GO:0016301', ('229', '244'))	('cell growth', 'biological_process', 'GO:0016049', ('129', '140'))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('cell growth', 'CPA', (182, 193))	('EphB4', 'Var', (167, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
191261	29369779	Furthermore, similar to the situation with forward signaling, reverse signaling has also been observed to result in both tumour suppression as well as progression.	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour suppression', 'Disease', (121, 139))	('reverse signaling', 'Var', (62, 79))	('progression', 'CPA', (151, 162))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('tumour suppression', 'Disease', 'OMIM:146850', (121, 139))
191262	29369779	For example, tumour cells expressing dominant negative EphB4 are incapable of forward signaling, but remain able to stimulate ephrinB2 reverse signaling, that in turn promotes cell invasion and proliferation.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('ephrinB2', 'Gene', '1948', (126, 134))	('promotes', 'PosReg', (167, 175))	('stimulate', 'PosReg', (116, 125))	('dominant negative', 'Var', (37, 54))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('proliferation', 'CPA', (194, 207))	('tumour', 'Disease', (13, 19))	('cell invasion', 'CPA', (176, 189))	('ephrinB2', 'Gene', (126, 134))	('reverse signaling', 'MPA', (135, 152))	('EphB4', 'Gene', (55, 60))
191265	29369779	Furthermore, mutations dysregulating Eph function likely also play a role in cancer progression.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Eph', 'Gene', '2041', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (13, 22))	('play', 'Reg', (62, 66))	('Eph', 'Gene', (37, 40))
191268	29369779	Three potentially relevant EphB6 mutations were identified in NSCLC patients (3.8%) that included two point mutations and an in-frame deletion mutation (del915-917).	('NSCLC', 'Disease', (62, 67))	('EphB6', 'Gene', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('del915-917', 'Mutation', 'c.915_917del', (153, 163))	('del915-917', 'Var', (153, 163))
191269	29369779	Furthermore, the del915-917 mutation also increased the metastatic capability of NSCLC cells in an in vivo mouse model suggesting that EphB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer (NSCLC) cells.	('metastasis', 'CPA', (159, 169))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (199, 225))	('del915-917', 'Var', (17, 27))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('promote', 'PosReg', (151, 158))	('non-small cell lung cancer', 'Disease', (199, 225))	('increased', 'PosReg', (42, 51))	('mutations', 'Var', (141, 150))	('NSCLC', 'Disease', (227, 232))	('mouse', 'Species', '10090', (107, 112))	('patients', 'Species', '9606', (185, 193))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('del915-917', 'Mutation', 'c.915_917del', (17, 27))	('EphB6', 'Gene', (135, 140))	('NSCLC', 'Disease', (81, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('metastatic capability', 'CPA', (56, 77))
191271	29369779	While mutations in EphA3 appear to have pro-tumourigenic effects thereby transforming tumour suppressor function of the WT protein in the lung, the functional significance of these alterations in EphA5 is unknown.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('EphA3', 'Gene', (19, 24))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('EphA3', 'Gene', '2042', (19, 24))	('EphA5', 'Gene', (196, 201))	('EphA5', 'Gene', '2044', (196, 201))	('tumour', 'Disease', (86, 92))	('mutations', 'Var', (6, 15))	('transforming', 'PosReg', (73, 85))
191274	29369779	Several non-synonymous mutations in EphB4 have also been identified, in human tumour tissues and cell lines.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('EphB4', 'Gene', (36, 41))	('human', 'Species', '9606', (72, 77))	('non-synonymous mutations', 'Var', (8, 32))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
191275	29369779	Thus, a mutation resulting in an R564K substitution occurring in the intracellular juxtamembrane (JM) domain was detected in one multiple myeloma cell line, and an R889W substitution was detected in one gastric carcinoma tissue sample.	('juxtamembrane', 'cellular_component', 'GO:0005886', ('83', '96'))	('R889W', 'Mutation', 'rs762016655', (164, 169))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (203, 220))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('83', '96'))	('gastric carcinoma', 'Disease', 'MESH:D013274', (203, 220))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('83', '96'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('83', '96'))	('R564K', 'Var', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('multiple myeloma', 'Disease', 'MESH:D009101', (129, 145))	('gastric carcinoma', 'Disease', (203, 220))	('multiple myeloma', 'Phenotype', 'HP:0006775', (129, 145))	('R564K', 'Mutation', 'rs767980355', (33, 38))	('multiple myeloma', 'Disease', (129, 145))
191276	29369779	A detailed genetic analysis of small cell lung cancer (SCLC) also identified several mutations in the ephrin receptor family including EphB4 (Rudin et al, 2012).	('ephrin', 'molecular_function', 'GO:0005106', ('102', '108'))	('small cell lung cancer', 'Disease', 'MESH:D055752', (31, 53))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('small cell lung cancer', 'Disease', (31, 53))	('mutations', 'Var', (85, 94))	('ephrin', 'molecular_function', 'GO:0046875', ('102', '108'))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('EphB4', 'Gene', (135, 140))	('SCLC', 'Disease', (55, 59))	('SCLC', 'Disease', 'MESH:D018288', (55, 59))
191277	29369779	Another comprehensive study by revealed EphB4 can be mutated in lung cancer and that they lead to putative structural alterations as well as increased cellular proliferation and motility.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('EphB4', 'Gene', (40, 45))	('structural', 'MPA', (107, 117))	('increased', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutated', 'Var', (53, 60))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('cellular proliferation', 'CPA', (151, 173))	('motility', 'CPA', (178, 186))
191278	29369779	Notably, the authors detected eight NS EphB4 mutations with one (A230V) in an extracellular linker region, two (A371V and P381S) in the first extracellular fibronectin III repeat, two (W534* and E536K) in the extracellular juxtamembrane domain, two (G723S and A742V) in the tyrosine kinase domain, and one (P881S) in an intracellular linker region just C-terminal to the tyrosine kinase domain.	('P881S', 'Var', (307, 312))	('E536K', 'Var', (195, 200))	('P381S', 'Mutation', 'p.P381S', (122, 127))	('tyrosine', 'Chemical', 'MESH:D014443', (371, 379))	('P881S', 'Mutation', 'p.P881S', (307, 312))	('A371V', 'Mutation', 'rs55720981', (112, 117))	('tyrosine', 'Chemical', 'MESH:D014443', (274, 282))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('223', '236'))	('extracellular', 'cellular_component', 'GO:0005576', ('78', '91'))	('EphB4', 'Gene', (39, 44))	('W534*', 'SUBSTITUTION', 'None', (185, 190))	('A230V', 'Mutation', 'p.A230V', (65, 70))	('A371V', 'Var', (112, 117))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('223', '236'))	('A742V', 'Var', (260, 265))	('W534*', 'Var', (185, 190))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('223', '236'))	('G723S', 'Mutation', 'p.G723S', (250, 255))	('P381S', 'Var', (122, 127))	('mutations', 'Var', (45, 54))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('223', '236'))	('extracellular', 'cellular_component', 'GO:0005576', ('142', '155'))	('A742V', 'Mutation', 'p.A742V', (260, 265))	('intracellular', 'cellular_component', 'GO:0005622', ('320', '333'))	('E536K', 'Mutation', 'p.E536K', (195, 200))	('G723S', 'Var', (250, 255))	('A230V', 'Var', (65, 70))	('extracellular', 'cellular_component', 'GO:0005576', ('209', '222'))
191279	29369779	Three of these (A230V, A371V, and P381S) occurred in adenocarcinoma, one (A742V) occurred in SCC, and four (W534*, E536K, G723S, and P881S) occurred in SCLC.	('A742V', 'Mutation', 'p.A742V', (74, 79))	('SCLC', 'Disease', 'MESH:D018288', (152, 156))	('SCC', 'Gene', (93, 96))	('E536K', 'Var', (115, 120))	('occurred', 'Reg', (41, 49))	('P381S', 'Mutation', 'p.P381S', (34, 39))	('adenocarcinoma', 'Disease', (53, 67))	('A230V', 'Var', (16, 21))	('W534*', 'SUBSTITUTION', 'None', (108, 113))	('SCLC', 'Disease', (152, 156))	('W534*', 'Var', (108, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('A371V', 'Mutation', 'rs55720981', (23, 28))	('P881S', 'Var', (133, 138))	('G723S', 'Mutation', 'p.G723S', (122, 127))	('P381S', 'Var', (34, 39))	('A371V', 'Var', (23, 28))	('P881S', 'Mutation', 'p.P881S', (133, 138))	('A230V', 'Mutation', 'p.A230V', (16, 21))	('SCC', 'Gene', '6317', (93, 96))	('G723S', 'Var', (122, 127))	('E536K', 'Mutation', 'p.E536K', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
191283	29369779	Interestingly, of the 16 sites with EphB4 mutations in adenocarcinoma tissues identified by, 12.5% were located in the kinase domain underscoring the functional implications.	('EphB4', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('adenocarcinoma', 'Disease', (55, 69))	('mutations', 'Var', (42, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))
191284	29369779	Furthermore, a bioinformatics analysis of these mutations revealed that a) they are mutually exclusive from other common RTK variants in lung cancer, b) they correspond to analogous sites of other RTK's variations in cancers, c) they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints, and d) EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells.	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Disease', (408, 419))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('EPHB4', 'Gene', (340, 345))	('EPHB4', 'Gene', '2050', (340, 345))	('lung cancer', 'Phenotype', 'HP:0100526', (408, 419))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('changes', 'Reg', (373, 380))	('mutations', 'Var', (346, 355))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('kinome signature', 'MPA', (388, 404))	('cancers', 'Disease', (217, 224))	('lung cancer', 'Disease', 'MESH:D008175', (408, 419))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
191286	29369779	However, thus far, no non-synonymous EphB4 mutations have been reported in HNSCC or pleural mesothelioma tissues.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (84, 104))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (84, 104))	('EphB4', 'Gene', (37, 42))	('pleural mesothelioma', 'Disease', (84, 104))	('mutations', 'Var', (43, 52))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
191289	29369779	assessed a single-nucleotide polymorphism in EphB4 to determine its effect on protein expression in NSCLC.	('single-nucleotide polymorphism', 'Var', (11, 41))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('EphB4', 'Gene', (45, 50))	('effect', 'Reg', (68, 74))	('protein expression', 'MPA', (78, 96))
191301	29369779	Furthermore, EphB4 siRNA and AS-ODN significantly inhibited tumour cell viability, induced apoptosis, activated caspase-8, and sensitized cells to TRAIL-induced cell death.	('EphB4', 'Var', (13, 18))	('TRAIL', 'Gene', '8743', (147, 152))	('caspase-8', 'Gene', '841', (112, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('sensitized', 'Reg', (127, 137))	('apoptosis', 'CPA', (91, 100))	('cell death', 'biological_process', 'GO:0008219', ('161', '171'))	('activated', 'PosReg', (102, 111))	('tumour', 'Disease', (60, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('TRAIL', 'Gene', (147, 152))	('caspase-8', 'Gene', (112, 121))	('AS-ODN', 'Chemical', 'MESH:D016376', (29, 35))	('induced', 'Reg', (83, 90))	('inhibited', 'NegReg', (50, 59))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
191325	29369779	Knocking down EphB4 initiated caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl.	('bcl-xl', 'Gene', (109, 115))	('Knocking down', 'Var', (0, 13))	('caspase-8', 'Gene', '841', (30, 39))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('bcl-xl', 'Gene', '598', (109, 115))	('EphB4', 'Gene', (14, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('caspase-8', 'Gene', (30, 39))	('down-regulation', 'NegReg', (63, 78))
191326	29369779	EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription.	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('Akt', 'Gene', '207', (60, 63))	('EphB4', 'Gene', (0, 5))	('phosphorylation', 'MPA', (41, 56))	('Akt', 'Gene', (60, 63))	('reduced', 'NegReg', (33, 40))	('down-regulation', 'NegReg', (68, 83))	('knockdown', 'Var', (6, 15))	('matrix metalloproteinase-2', 'Gene', (87, 113))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))	('matrix metalloproteinase-2', 'Gene', '4313', (87, 113))
191327	29369779	In addition, murine tumour xenograft studies showed a marked reduction in tumour growth that was accompanied by a decline in EphB4 protein expression, reduced cell division, apoptosis in tumour tissue, and decreased microvascular density upon EphB4 silencing.	('cell division', 'biological_process', 'GO:0051301', ('159', '172'))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('reduction', 'NegReg', (61, 70))	('apoptosis', 'CPA', (174, 183))	('tumour', 'Disease', (20, 26))	('microvascular density', 'CPA', (216, 237))	('EphB4', 'Gene', (243, 248))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour growth', 'Disease', 'MESH:D006130', (74, 87))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumour', 'Disease', (187, 193))	('murine', 'Species', '10090', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('cell division', 'CPA', (159, 172))	('reduced', 'NegReg', (151, 158))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('tumour', 'Disease', (74, 80))	('decreased', 'NegReg', (206, 215))	('silencing', 'Var', (249, 258))	('tumour growth', 'Disease', (74, 87))	('EphB4', 'Gene', (125, 130))	('decline', 'NegReg', (114, 121))	('protein', 'Protein', (131, 138))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
191335	29369779	This inhibitor was tested in an open-label, multi-institutional Phase II trial to investigate efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations and is currently in a Phase III trial (XL647 versus erlotinib), in patients with stage IIIB-IV NSCLC with progression after first- or second-line chemotherapy.	('patients', 'Species', '9606', (169, 177))	('erlotinib', 'Chemical', 'MESH:D000069347', (285, 294))	('lung cancer', 'Disease', (157, 168))	('men', 'Species', '9606', (131, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('218', '222'))	('NSCLC', 'Disease', 'MESH:D002289', (328, 333))	('EGFR', 'Gene', '1956', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NSCLC', 'Disease', (328, 333))	('EGFR', 'Gene', (218, 222))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('mutations', 'Var', (223, 232))	('patients', 'Species', '9606', (300, 308))
191351	29369779	In contrast, MAb47 targets fibronectin-like domain 2 of both human and murine EphB4 and does not alter EphB4 receptor levels, but inhibits angiogenesis and growth of both EphB4-positive and EphB4-negative tumours in a mouse HNSCC xenograft model.	('EphB4', 'Gene', (78, 83))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('SCC', 'Gene', (226, 229))	('tumours', 'Disease', (205, 212))	('murine', 'Species', '10090', (71, 77))	('angiogenesis', 'CPA', (139, 151))	('SCC', 'Gene', '6317', (226, 229))	('MAb47', 'Var', (13, 18))	('growth', 'CPA', (156, 162))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('mouse', 'Species', '10090', (218, 223))	('human', 'Species', '9606', (61, 66))	('angiogenesis', 'biological_process', 'GO:0001525', ('139', '151'))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('inhibits', 'NegReg', (130, 138))
191352	29369779	Furthermore, a combination of MAb47 and another anti-angiogenesis mAb, bevacizumab, enhances the antitumour activity and induces tumour regression.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('enhances', 'PosReg', (84, 92))	('combination', 'Interaction', (15, 26))	('bevacizumab', 'Chemical', 'MESH:D000068258', (71, 82))	('tumour', 'Disease', (101, 107))	('MAb47', 'Var', (30, 35))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour regression', 'Disease', (129, 146))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('tumour', 'Disease', (129, 135))	('induces', 'PosReg', (121, 128))	('tumour regression', 'Disease', 'MESH:D009365', (129, 146))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
191355	29369779	sEphB4-HSA has full-length human serum albumin fused to the C-terminus of sEphB4 to improve half-life and delivery, and both variants of the protein, sEphB4 alone and sEphB4-HAS, have anti-tumour activities in multiple tumour models.	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('sEphB4', 'Gene', (74, 80))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('human', 'Species', '9606', (27, 32))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('sEphB4', 'Chemical', '-', (150, 156))	('tumour', 'Disease', (219, 225))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('sEphB4', 'Chemical', '-', (0, 6))	('tumour', 'Disease', (189, 195))	('multiple tumour', 'Disease', 'MESH:D009369', (210, 225))	('multiple tumour', 'Disease', (210, 225))	('delivery', 'MPA', (106, 114))	('improve', 'PosReg', (84, 91))	('half-life', 'MPA', (92, 101))	('sEphB4-HSA', 'Chemical', '-', (0, 10))	('sEphB4', 'Chemical', '-', (167, 173))	('sEphB4', 'Chemical', '-', (74, 80))	('variants', 'Var', (125, 133))
191365	29369779	Interestingly, a mutation in EphA3 identified in lung cancer enhances cis interaction with ephrin-A3.	('ephrin-A3', 'Gene', '1944', (91, 100))	('EphA3', 'Gene', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('ephrin', 'molecular_function', 'GO:0046875', ('91', '97'))	('mutation', 'Var', (17, 25))	('cis interaction', 'MPA', (70, 85))	('ephrin', 'molecular_function', 'GO:0005106', ('91', '97'))	('ephrin-A3', 'Gene', (91, 100))	('lung cancer', 'Disease', (49, 60))	('enhances', 'PosReg', (61, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EphA3', 'Gene', '2042', (29, 34))
191366	29369779	Taken together, these tantalizing observations suggest that modulating Eph receptor, more specifically EphB4 activity in cis may be a novel therapeutic approach for upper aerodigestive malignancies.	('Eph', 'Gene', '2041', (103, 106))	('upper aerodigestive malignancies', 'Disease', (165, 197))	('Eph', 'Gene', (103, 106))	('Eph', 'Gene', '2041', (71, 74))	('cis', 'Disease', (121, 124))	('activity', 'MPA', (109, 117))	('modulating', 'Var', (60, 70))	('Eph', 'Gene', (71, 74))	('upper aerodigestive malignancies', 'Disease', 'MESH:D006258', (165, 197))
191375	29369779	In two established SCC xenograft models, CARgpc3 T cells almost completely eliminated the growth of GPC3-positive cells.	('eliminated', 'NegReg', (75, 85))	('SCC', 'Gene', '6317', (19, 22))	('CARgpc3 T', 'Var', (41, 50))	('GPC3', 'Gene', (100, 104))	('SCC', 'Gene', (19, 22))	('growth', 'MPA', (90, 96))	('GPC3', 'Gene', '2719', (100, 104))
191499	23963796	Changes in tumor vasculature initiated by antiangiogenic agents appear to enhance chemotherapy diffusion and delivery, possibly by reducing interstitial pressure and increasing permeability and perfusion.	('interstitial pressure', 'MPA', (140, 161))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('increasing', 'PosReg', (166, 176))	('permeability', 'MPA', (177, 189))	('tumor', 'Disease', (11, 16))	('delivery', 'MPA', (109, 117))	('perfusion', 'MPA', (194, 203))	('antiangiogenic agents', 'Var', (42, 63))	('chemotherapy diffusion', 'MPA', (82, 104))	('reducing', 'NegReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('enhance', 'PosReg', (74, 81))
191543	23963796	The diarrhea was considered by the investigator to be related to sunitinib and pemetrexed, while the neutropenia and fatigue were attributed to all three study treatments.	('fatigue', 'Disease', 'MESH:D005221', (117, 124))	('diarrhea', 'Phenotype', 'HP:0002014', (4, 12))	('sunitinib', 'Var', (65, 74))	('sunitinib', 'Chemical', 'MESH:D000077210', (65, 74))	('diarrhea', 'Disease', (4, 12))	('fatigue', 'Disease', (117, 124))	('neutropenia', 'Disease', (101, 112))	('pemetrexed', 'Chemical', 'MESH:D000068437', (79, 89))	('diarrhea', 'Disease', 'MESH:D003967', (4, 12))	('fatigue', 'Phenotype', 'HP:0012378', (117, 124))	('neutropenia', 'Disease', 'MESH:D009503', (101, 112))	('neutropenia', 'Phenotype', 'HP:0001875', (101, 112))
191569	23963796	Samples from the last 3 patients enrolled in the Schedule 2/1 MTD cohort showed that the geometric mean ratios (triple combination relative to sunitinib alone) for sunitinib Cmax and AUC24 were 1.12 and 1.38, respectively.	('sunitinib', 'Chemical', 'MESH:D000077210', (143, 152))	('sunitinib', 'Gene', (164, 173))	('AUC24', 'Var', (183, 188))	('patients', 'Species', '9606', (24, 32))	('Cmax', 'Var', (174, 178))	('sunitinib', 'Chemical', 'MESH:D000077210', (164, 173))
191679	16232314	In either case, mistaking a carcinoid of the appendix with a goblet cell carcinoid of appendix could result in harm to the patient.	('patient', 'Species', '9606', (123, 130))	('carcinoid', 'Phenotype', 'HP:0100570', (28, 37))	('carcinoid', 'Phenotype', 'HP:0100570', (73, 82))	('mistaking', 'Var', (16, 25))	('result in', 'Reg', (101, 110))
191718	30349644	TG2 knockdown or TG2 inhibitor treatment reduces MCS cell spheroid formation, matrigel invasion, migration and tumor formation.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('MCS cell spheroid formation', 'CPA', (49, 76))	('migration', 'CPA', (97, 106))	('reduces', 'NegReg', (41, 48))	('TG2', 'Gene', '7052', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MCS', 'Chemical', '-', (49, 52))	('reduces MCS', 'Phenotype', 'HP:0025066', (41, 52))	('TG2', 'Gene', '7052', (0, 3))	('matrigel invasion', 'CPA', (78, 95))	('tumor', 'Disease', (111, 116))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))	('TG2', 'Gene', (0, 3))	('TG2', 'Gene', (17, 20))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('MCS', 'cellular_component', 'GO:0044232', ('49', '52'))	('knockdown', 'Var', (4, 13))
191719	30349644	Time to tumor first appearance is doubled in TG2 knockout cells as compared to wild-type.	('doubled', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TG2', 'Gene', '7052', (45, 48))	('tumor', 'Disease', (8, 13))	('knockout', 'Var', (49, 57))	('TG2', 'Gene', (45, 48))
191728	30349644	Our approach, in this context, is to identify proteins that are essential for MCS cell survival and then eliminate or inactivate these proteins to reduce survival.	('MCS', 'cellular_component', 'GO:0044232', ('78', '81'))	('MCS', 'Chemical', '-', (78, 81))	('reduce', 'NegReg', (147, 153))	('eliminate', 'NegReg', (105, 114))	('inactivate', 'Var', (118, 128))
191737	30349644	Elevated TG2 expression is associated with enhanced cancer stem cell survival and resistance to chemotherapy and knockdown of TG2 results in re-sensitization of cancer cells to conventional anti-cancer drugs.	('enhanced', 'PosReg', (43, 51))	('results in', 'Reg', (130, 140))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('TG2', 'Gene', (126, 129))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('resistance', 'CPA', (82, 92))	('sensitization', 'biological_process', 'GO:0046960', ('144', '157'))	('TG2', 'Gene', '7052', (9, 12))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('knockdown', 'Var', (113, 122))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TG2', 'Gene', (9, 12))	('expression', 'MPA', (13, 23))	('TG2', 'Gene', '7052', (126, 129))	('re-sensitization', 'MPA', (141, 157))
191741	30349644	In addition, TG2 knockout or treatment with a TG2-specific inhibitor reduces spheroid formation, matrigel invasion, migration and tumor formation.	('TG2', 'Gene', '7052', (13, 16))	('TG2', 'Gene', (46, 49))	('matrigel invasion', 'CPA', (97, 114))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('reduces', 'NegReg', (69, 76))	('knockout', 'Var', (17, 25))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('spheroid formation', 'CPA', (77, 95))	('TG2', 'Gene', (13, 16))	('migration', 'CPA', (116, 125))	('tumor', 'Disease', (130, 135))	('TG2', 'Gene', '7052', (46, 49))
191749	30349644	Figure 1F, 1G shows that TG2 null cells form reduced numbers of spheroids of smaller size.	('TG2', 'Gene', '7052', (25, 28))	('null', 'Var', (29, 33))	('reduced', 'NegReg', (45, 52))	('TG2', 'Gene', (25, 28))
191760	30349644	TG2 appears to have a role in controlling EMT, as TG2 knockdown reduces fibronectin, Snail and Slug level (Figure 2D).	('TG2', 'Gene', '7052', (50, 53))	('fibronectin', 'Gene', (72, 83))	('knockdown', 'Var', (54, 63))	('Slug', 'Gene', (95, 99))	('TG2', 'Gene', (50, 53))	('Snail', 'Gene', (85, 90))	('Snail', 'Gene', '6615', (85, 90))	('EMT', 'biological_process', 'GO:0001837', ('42', '45'))	('TG2', 'Gene', '7052', (0, 3))	('TG2', 'Gene', (0, 3))	('fibronectin', 'Gene', '2335', (72, 83))	('reduces', 'NegReg', (64, 71))	('Slug', 'Gene', '6591', (95, 99))
191762	30349644	Meso-2 cells were electroporated with control- or TG2-siRNA and knockdown of TG2 was confirmed (Figure 3A).	('TG2', 'Gene', '7052', (50, 53))	('TG2', 'Gene', (77, 80))	('TG2', 'Gene', (50, 53))	('knockdown', 'Var', (64, 73))	('TG2', 'Gene', '7052', (77, 80))
191763	30349644	TG2 knockdown in Meso-2 cells is associated with reduced spheroid formation and spheroid size, as well as, accumulation of debris in the spheroid cultures (Figure 3B) and a reduction in matrigel invasion and wound closure-related migration (Figure 3C, 3D).	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('reduced', 'NegReg', (49, 56))	('reduction', 'NegReg', (173, 182))	('matrigel invasion', 'CPA', (186, 203))	('spheroid size', 'CPA', (80, 93))	('accumulation', 'PosReg', (107, 119))	('TG2', 'Gene', '7052', (0, 3))	('spheroid formation', 'CPA', (57, 75))	('TG2', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('wound closure-related migration', 'CPA', (208, 239))
191767	30349644	In addition, loss of TG2 reduces polycomb protein level (Ezh2, Bmi-1) and activity (H3K27me3) and stem cell marker (Sox-2, Oct-4) level.	('stem cell', 'CPA', (98, 107))	('Oct-4', 'Gene', '5460', (123, 128))	('Ezh2', 'Gene', (57, 61))	('Sox-2', 'Gene', (116, 121))	('Ezh2', 'Gene', '2146', (57, 61))	('Sox-2', 'Gene', '6657', (116, 121))	('reduces', 'NegReg', (25, 32))	('TG2', 'Gene', '7052', (21, 24))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('TG2', 'Gene', (21, 24))	('Bmi-1', 'Gene', '648', (63, 68))	('Bmi-1', 'Gene', (63, 68))	('Oct-4', 'Gene', (123, 128))	('loss', 'Var', (13, 17))	('polycomb protein level', 'MPA', (33, 55))
191775	30349644	Figure 5E provides evidence that TG2 knockdown reduces EMT marker (Fibronectin, Slug, Snail and Twist) levels in tumors, but that other markers are not substantially altered.	('Fibronectin', 'Gene', (67, 78))	('TG2', 'Gene', '7052', (33, 36))	('reduces', 'NegReg', (47, 54))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('knockdown', 'Var', (37, 46))	('Slug', 'Gene', '6591', (80, 84))	('TG2', 'Gene', (33, 36))	('EMT', 'biological_process', 'GO:0001837', ('55', '58'))	('Snail', 'Gene', '6615', (86, 91))	('Snail', 'Gene', (86, 91))	('Slug', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Fibronectin', 'Gene', '2335', (67, 78))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
191778	30349644	We therefore cultured cells from TG2 wild-type and TG2 knockout tumors and monitored TG2 level.	('TG2', 'Gene', '7052', (33, 36))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TG2', 'Gene', '7052', (85, 88))	('TG2', 'Gene', (85, 88))	('TG2', 'Gene', (33, 36))	('TG2', 'Gene', '7052', (51, 54))	('knockout', 'Var', (55, 63))	('monitored', 'Reg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TG2', 'Gene', (51, 54))
191782	30349644	NC9 treatment produces a marked reduction in tumor formation (Figure 5G, 5H) and this is associated with a parallel reduction in stem cell (Sox-2, Oct-4) and EMT (fibronectin, N-cadherin, Slug and Twist) marker levels (Figure 5I).	('cadherin', 'molecular_function', 'GO:0008014', ('178', '186'))	('tumor', 'Disease', (45, 50))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('reduction', 'NegReg', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('Sox-2', 'Gene', (140, 145))	('stem cell', 'CPA', (129, 138))	('Slug', 'Gene', (188, 192))	('N-cadherin', 'Gene', (176, 186))	('Sox-2', 'Gene', '6657', (140, 145))	('N-cadherin', 'Gene', '1000', (176, 186))	('Oct-4', 'Gene', '5460', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('fibronectin', 'Gene', (163, 174))	('treatment', 'Var', (4, 13))	('EMT', 'biological_process', 'GO:0001837', ('158', '161'))	('Oct-4', 'Gene', (147, 152))	('Slug', 'Gene', '6591', (188, 192))	('NC9 treatment', 'Var', (0, 13))	('reduction', 'NegReg', (32, 41))	('fibronectin', 'Gene', '2335', (163, 174))	('EMT', 'CPA', (158, 161))
191797	30349644	Tumors and MCS cells display elevated expression of proteins involved in EMT, including Snail, Slug, N-cadherin and fibronectin, and TG2 knockdown reduces the level of these proteins.	('reduces', 'NegReg', (147, 154))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('elevated', 'PosReg', (29, 37))	('Snail', 'Gene', '6615', (88, 93))	('fibronectin', 'Gene', '2335', (116, 127))	('TG2', 'Gene', (133, 136))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('N-cadherin', 'Gene', (101, 111))	('N-cadherin', 'Gene', '1000', (101, 111))	('level of', 'MPA', (159, 167))	('MCS', 'Chemical', '-', (11, 14))	('Slug', 'Gene', (95, 99))	('proteins', 'Protein', (52, 60))	('Tumors', 'Disease', (0, 6))	('knockdown', 'Var', (137, 146))	('MCS', 'cellular_component', 'GO:0044232', ('11', '14'))	('EMT', 'biological_process', 'GO:0001837', ('73', '76'))	('Snail', 'Gene', (88, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('expression', 'MPA', (38, 48))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Slug', 'Gene', '6591', (95, 99))	('fibronectin', 'Gene', (116, 127))	('TG2', 'Gene', '7052', (133, 136))
191804	30349644	Thus, inhibition of TG2 markedly reduces processes associated with the aggressive MCS cell phenotype that are required for MCS cell survival, and also induces cell death.	('MCS', 'Chemical', '-', (123, 126))	('cell death', 'biological_process', 'GO:0008219', ('159', '169'))	('processes', 'CPA', (41, 50))	('MCS', 'cellular_component', 'GO:0044232', ('123', '126'))	('induces', 'Reg', (151, 158))	('TG2', 'Gene', '7052', (20, 23))	('inhibition', 'Var', (6, 16))	('TG2', 'Gene', (20, 23))	('cell death', 'CPA', (159, 169))	('reduces', 'NegReg', (33, 40))	('MCS', 'Chemical', '-', (82, 85))	('MCS', 'cellular_component', 'GO:0044232', ('82', '85'))
191810	30349644	TG2-positive MCS cell tumors are first detected at week nine post-injection, but tumor appearance is delayed until week eighteen in TG2 knockout MSC cells.	('MCS cell tumors', 'Disease', (13, 28))	('MCS', 'cellular_component', 'GO:0044232', ('13', '16'))	('TG2', 'Gene', (132, 135))	('TG2', 'Gene', '7052', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('MCS cell tumors', 'Disease', 'MESH:C536703', (13, 28))	('TG2', 'Gene', '7052', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('knockout', 'Var', (136, 144))	('TG2', 'Gene', (0, 3))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (81, 86))
191811	30349644	Thus, TG2 knockout doubles the time to first tumor appearance.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('time', 'MPA', (31, 35))	('tumor', 'Disease', (45, 50))	('doubles', 'PosReg', (19, 26))	('TG2', 'Gene', '7052', (6, 9))	('knockout', 'Var', (10, 18))	('TG2', 'Gene', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
191812	30349644	In addition, the TG2 knockdown tumors express reduced levels of stem cell and EMT markers, and display reduced vascularity (i.e., reduced CD31 expression).	('CD31', 'Gene', '5175', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression', 'MPA', (143, 153))	('EMT markers', 'CPA', (78, 89))	('TG2', 'Gene', '7052', (17, 20))	('tumors', 'Disease', (31, 37))	('reduced', 'NegReg', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('reduced', 'NegReg', (46, 53))	('reduced', 'NegReg', (130, 137))	('vascularity', 'CPA', (111, 122))	('TG2', 'Gene', (17, 20))	('levels of', 'MPA', (54, 63))	('knockdown', 'Var', (21, 30))	('CD31', 'Gene', (138, 142))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
191816	30349644	RPMI1640 medium (11875-093), sodium pyruvate, L-glutamine (25030-164), penicillin-streptomycin solution (15140-122) and 0.25% trypsin-EDTA (25200-056) were purchased from Gibco (Grand Island, NY).	('11875-093', 'Var', (17, 26))	('RPMI1640', 'Chemical', '-', (0, 8))	('25030-164', 'Var', (59, 68))	('15140-122', 'Var', (105, 114))	('penicillin', 'Chemical', 'MESH:D010406', (71, 81))	('sodium pyruvate', 'Chemical', '-', (29, 44))	('streptomycin', 'Chemical', 'MESH:D013307', (82, 94))	('L-glutamine', 'Chemical', 'MESH:D005973', (46, 57))	('EDTA', 'Chemical', 'MESH:D004492', (134, 138))
191817	30349644	Antibodies for Ezh2 (612667), fibronectin (610077), N-cadherin (610920), PARP (556494) were obtained from BD transduction laboratories (San Jose, CA).	('556494', 'Var', (79, 85))	('612667', 'Var', (21, 27))	('fibronectin', 'Gene', '2335', (30, 41))	('PARP', 'Gene', '1302', (73, 77))	('610920', 'Var', (64, 70))	('transduction', 'biological_process', 'GO:0009293', ('109', '121'))	('610077', 'Var', (43, 49))	('N-cadherin', 'Gene', (52, 62))	('PARP', 'Gene', (73, 77))	('cadherin', 'molecular_function', 'GO:0008014', ('54', '62'))	('N-cadherin', 'Gene', '1000', (52, 62))	('fibronectin', 'Gene', (30, 41))	('Ezh2', 'Gene', (15, 19))	('Ezh2', 'Gene', '2146', (15, 19))
191819	30349644	Antibodies for Bmi-1 (ab14389), Slug (ab27568), Twist (ab49254), HIF1-alpha (ab113642) and MMP9 (ab38898) were obtained from Abcam (Cambridge, UK).	('Bmi-1', 'Gene', '648', (15, 20))	('MMP9', 'molecular_function', 'GO:0004229', ('91', '95'))	('Bmi-1', 'Gene', (15, 20))	('ab113642', 'Var', (77, 85))	('HIF1-alpha', 'Gene', '3091', (65, 75))	('Slug', 'Gene', '6591', (32, 36))	('ab14389', 'Var', (22, 29))	('MMP9', 'Gene', (91, 95))	('Slug', 'Gene', (32, 36))	('MMP9', 'Gene', '4318', (91, 95))	('HIF1-alpha', 'Gene', (65, 75))
191890	28810922	It showed co-expression of Vimentin, CK7, D2-40, focal PanCK, but it stained negatively for EMA, CEA, EpCAM, usually positive in sarcomatoid carcinoma.	('CEA', 'Gene', '1048', (97, 100))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (129, 150))	('EpCAM', 'Gene', '4072', (102, 107))	('D2-40', 'Var', (42, 47))	('sarcomatoid carcinoma', 'Disease', (129, 150))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (129, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('CEA', 'Gene', (97, 100))	('Vimentin', 'Gene', '7431', (27, 35))	('CK7', 'Gene', (37, 40))	('Vimentin', 'cellular_component', 'GO:0045099', ('27', '35'))	('Vimentin', 'Gene', (27, 35))	('EMA', 'Gene', '4582', (92, 95))	('D2-40', 'Chemical', '-', (42, 47))	('Vimentin', 'cellular_component', 'GO:0045098', ('27', '35'))	('CK7', 'Gene', '3855', (37, 40))	('EpCAM', 'Gene', (102, 107))	('EMA', 'Gene', (92, 95))
191900	28810922	In our case, the presence of sinusoidal vascular channels lacking of red blood cells and containing amorphous Alcian blue positive substance, the marked cellular atypia, the presence of necrosis and numerous atypical mitoses, the high Ki67 expression and the positive immunostaining for CD31 and D2-40 were more consistent with the diagnosis of "epithelioid angiosarcoma with lymphatic differentiation".	('necrosis', 'biological_process', 'GO:0008220', ('186', '194'))	('D2-40', 'Gene', (296, 301))	('necrosis', 'biological_process', 'GO:0001906', ('186', '194'))	('Alcian blue', 'Chemical', 'MESH:D000423', (110, 121))	('necrosis', 'Disease', (186, 194))	('CD31', 'Gene', (287, 291))	('epithelioid angiosarcoma', 'Disease', 'MESH:D006394', (346, 370))	('CD31', 'Gene', '5175', (287, 291))	('expression', 'MPA', (240, 250))	('angiosarcoma', 'Phenotype', 'HP:0200058', (358, 370))	('epithelioid angiosarcoma', 'Phenotype', 'HP:0032060', (346, 370))	('necrosis', 'biological_process', 'GO:0008219', ('186', '194'))	('necrosis', 'biological_process', 'GO:0070265', ('186', '194'))	('epithelioid angiosarcoma', 'Disease', (346, 370))	('D2-40', 'Chemical', '-', (296, 301))	('Ki67', 'Var', (235, 239))	('necrosis', 'biological_process', 'GO:0019835', ('186', '194'))	('necrosis', 'Disease', 'MESH:D009336', (186, 194))
192007	23059782	In order to validate appropriate criteria for progression, it may be more appropriate to identify tumor thickness changes that correspond to meaningful deterioration in other patient-rated outcomes such as dyspnea, pain, and quality of life.	('dyspnea', 'Disease', (206, 213))	('dyspnea', 'Disease', 'MESH:D004417', (206, 213))	('patient', 'Species', '9606', (175, 182))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('pain', 'Phenotype', 'HP:0012531', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('dyspnea', 'Phenotype', 'HP:0002094', (206, 213))	('pain', 'Disease', 'MESH:D010146', (215, 219))	('pain', 'Disease', (215, 219))	('tumor', 'Disease', (98, 103))	('changes', 'Var', (114, 121))
192030	32435497	Particularly, long non-coding RNAs (lncRNAs) represent a versatile and promising group of potential markers, playing a role as oncogenes as well as tumor suppressors, and showing an altered expression in cancer.	('cancer', 'Disease', (204, 210))	('long non-coding RNAs', 'Var', (14, 34))	('altered', 'Reg', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('expression', 'MPA', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
192058	32435497	Here, values of Exp(beta) > 1 indicate a positive and Exp(beta) < 1 indicate a negative association between analyzed factor and GAS5.	('Exp', 'Var', (54, 57))	('GAS5', 'Gene', '60674', (128, 132))	('negative', 'NegReg', (79, 87))	('GAS5', 'Gene', (128, 132))	('GAS', 'molecular_function', 'GO:0034005', ('128', '131'))
192063	32435497	Using the 2-DeltaDeltaCt method to assess different expressions between mesothelioma cell lines and MeT-5A as control revealed an up-regulation of AFAP1-AS1, GAS5, and LOC84856 in at least three of the mesothelioma cell lines.	('GAS5', 'Gene', '60674', (158, 162))	('GAS', 'molecular_function', 'GO:0034005', ('158', '161'))	('mesothelioma', 'Disease', (202, 214))	('AS1', 'Gene', '5729', (153, 156))	('AS1', 'Gene', (153, 156))	('GAS5', 'Gene', (158, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (202, 214))	('mesothelioma', 'Disease', (72, 84))	('AFAP1', 'Gene', (147, 152))	('up-regulation', 'PosReg', (130, 143))	('LOC84856', 'Var', (168, 176))	('AFAP1', 'Gene', '60312', (147, 152))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
192064	32435497	LOC642852 and LOC388796 showed a constant down-regulation in all cell lines, whereas CRNDE and LOC100130776 showed no altered regulation in mesothelioma cell lines.	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('mesothelioma', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('LOC642852', 'Gene', (0, 9))	('CRNDE', 'Gene', '643911', (85, 90))	('CRNDE', 'Gene', (85, 90))	('down-regulation', 'NegReg', (42, 57))	('LOC388796', 'Var', (14, 23))	('LOC642852', 'Gene', '642852', (0, 9))	('LOC100130776', 'Var', (95, 107))
192123	32435497	miR-103a-3p, miR-132-3p, and 126-3p, that were identified in common case-control studies but ultimately failed to detect mesothelioma in prediagnostic samples.	('miR-132-3p', 'Var', (13, 23))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('mesothelioma', 'Disease', (121, 133))	('miR-103a-3p', 'Var', (0, 11))
192226	29337930	documents the propaganda of the asbestos lobby and its contining efforts to disinform ministries, state labor inspectorates and social accident insurance associations, by claiming that any bans or categoric substitution orders on the use of asbestos would represent a substantial risk for the economy, the asbestos industry and many jobs.	('men', 'Species', '9606', (4, 7))	('asbestos', 'Chemical', 'MESH:D001194', (241, 249))	('asbestos', 'Chemical', 'MESH:D001194', (306, 314))	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('asbestos lobby', 'Disease', (32, 46))	('bans', 'Var', (189, 193))	('asbestos lobby', 'Disease', 'MESH:D001195', (32, 46))
192417	26431275	The efficacy was attributed to vaccine-elicited CD8+ T cells that could retain their effector functions once infiltrated into the tumor, reduce myeloid-derived suppressor cells (MDSCs) and CD4+CD25+Foxp3+ regulatory T lymphocytes (Treg) cell populations, and lead to the complete clearance of tumor cells.	('lead to', 'Reg', (259, 266))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('CD4', 'Gene', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('reduce', 'NegReg', (137, 143))	('CD4', 'Gene', '12504', (189, 192))	('tumor', 'Disease', (293, 298))	('Foxp3', 'Gene', '20371', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Foxp3', 'Gene', (198, 203))	('tumor', 'Disease', (130, 135))	('CD8+ T', 'Var', (48, 54))	('myeloid-derived suppressor cells', 'CPA', (144, 176))
192436	26431275	Our previous data indicated that the presence of cytotoxic CD8+ T cells is an important factor responsible for the eradication of AB1-GAG by releasing inflammatory IFN-gamma and TNF-alpha in the vicinity of target cells as well as by initiating TRAIL-directed tumor cell apoptosis.	('tumor', 'Disease', (260, 265))	('TNF-alpha', 'Gene', (178, 187))	('GAG', 'Gene', (134, 137))	('IFN-gamma', 'Gene', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('releasing', 'PosReg', (141, 150))	('IFN-gamma', 'Gene', '15978', (164, 173))	('initiating', 'PosReg', (234, 244))	('TNF-alpha', 'Gene', '21926', (178, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('271', '280'))	('GAG', 'Gene', '155030', (134, 137))	('TRAIL', 'Gene', '22035', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('eradication', 'Var', (115, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('271', '280'))	('TRAIL', 'Gene', (245, 250))
192451	26431275	Therefore, under our experimental conditions cell debris released after AB1-GAG destruction likely induced tumor-specific CD8+ T cell immune responses against WT-AB1.	('GAG', 'Gene', '155030', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('induced', 'Reg', (99, 106))	('tumor', 'Disease', (107, 112))	('destruction', 'Var', (80, 91))	('GAG', 'Gene', (76, 79))	('CD8+ T cell immune responses', 'CPA', (122, 150))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
192475	26431275	By measuring the expression of active caspase-3 and annexin V, we found that M-MDSCs were prone to apoptosis and had a significantly shorter life-span than PMN-MDSCs in vitro (Figure 6B).	('annexin V', 'Gene', '11747', (52, 61))	('shorter', 'NegReg', (133, 140))	('prone', 'Reg', (90, 95))	('M-MDSCs', 'Var', (77, 84))	('annexin V', 'Gene', (52, 61))	('caspase-3', 'Gene', '12367', (38, 47))	('apoptosis', 'CPA', (99, 108))	('life-span', 'CPA', (141, 150))	('PMN', 'biological_process', 'GO:0034727', ('156', '159'))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('caspase-3', 'Gene', (38, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))
192484	26431275	Besides the inverse correlation between the frequency of efficacious PD1-Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo, these functional CD8+ T cells not only kill wild-type mesothelioma in vivo but also lead to apoptosis of the predominant PMN-MDSCs significantly in a dose-dependent manner.	('PMN', 'biological_process', 'GO:0034727', ('254', '257'))	('tumor', 'Disease', (113, 118))	('apoptosis', 'CPA', (225, 234))	('kill', 'PosReg', (172, 176))	('apoptosis', 'biological_process', 'GO:0006915', ('225', '234'))	('lead to', 'Reg', (217, 224))	('Tim3', 'Gene', (73, 77))	('mesothelioma', 'Disease', (187, 199))	('CD8+ T', 'Var', (150, 156))	('Tim3', 'Gene', '171285', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('225', '234'))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))
192486	26431275	Cancer immunotherapy has been hindered by poor CD8+ T cell responses against tumor-specific antigens because tumor cells often evolve to escape immune recognition and develop resistance through mutation or other mechanisms.	('mutation', 'Var', (194, 202))	('poor CD8+ T cell', 'Phenotype', 'HP:0005415', (42, 58))	('immune', 'MPA', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('escape', 'NegReg', (137, 143))	('tumor', 'Disease', (77, 82))	('resistance', 'CPA', (175, 185))	('tumor', 'Disease', (109, 114))
192592	23140511	Local resection of the hydrocele wall is associated with a local recurrence rate of 36%, and hemiscrotectomy is often required for local control, whereas local recurrence after orchidectomy is reported in 10.5 to 11.5% of patients .	('hydrocele', 'Phenotype', 'HP:0000034', (23, 32))	('local', 'CPA', (59, 64))	('patients', 'Species', '9606', (222, 230))	('Local', 'Var', (0, 5))
192678	30990472	The authors identified two mesothelioma-specific ENOX2 protein transcript variants in the serum of asbestos-exposed individuals 4-10 years prior to clinical diagnosis of malignant mesothelioma.	('asbestos', 'Chemical', 'MESH:D001194', (99, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('mesothelioma', 'Disease', (27, 39))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (170, 192))	('malignant mesothelioma', 'Disease', (170, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('ENOX2', 'Gene', (49, 54))	('mesothelioma', 'Disease', (180, 192))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('variants', 'Var', (74, 82))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (170, 192))	('ENOX2', 'Gene', '10495', (49, 54))
192691	30990472	The most discriminating miRNA panel was given by the combination of miR-103a-3p and miR-30e-3p.	('miR-30e-3p', 'Var', (84, 94))	('miR-103a-3p', 'Chemical', '-', (68, 79))	('miR-103a-3p', 'Var', (68, 79))
192764	33050791	We recently observed that mutations resulting from RNA editing due to hydrolytic deamination of adenosine increase during the development of mesothelioma, a rare cancer linked to chronic exposure to asbestos.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('RNA editing', 'biological_process', 'GO:0009451', ('51', '62'))	('RNA editing', 'Gene', (51, 62))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mesothelioma', 'Disease', (141, 153))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('hydrolytic deamination of adenosine', 'MPA', (70, 105))	('increase', 'PosReg', (106, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('adenosine', 'Chemical', 'MESH:D000241', (96, 105))	('asbestos', 'Chemical', 'MESH:D001194', (199, 207))
192770	33050791	We recently observed in an experimental animal model of asbestos-induced mesothelioma development, that asbestos increased the levels of RNA mutations and the most abundant changes were A to G mutations, probably resulting from the hydrolytic deamination of adenosine downstream of adenosine deaminase editing activity (I is detected as G in RNA sequencing).	('adenosine', 'Chemical', 'MESH:D000241', (258, 267))	('adenosine deaminase', 'Gene', (282, 301))	('adenosine', 'Chemical', 'MESH:D000241', (282, 291))	('asbestos', 'Chemical', 'MESH:D001194', (104, 112))	('RNA', 'cellular_component', 'GO:0005562', ('137', '140'))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('mesothelioma development', 'Disease', 'MESH:D008654', (73, 97))	('RNA', 'cellular_component', 'GO:0005562', ('342', '345'))	('RNA', 'Gene', (137, 140))	('adenosine deaminase', 'Gene', '100', (282, 301))	('A to G mutations', 'Var', (186, 202))	('mesothelioma development', 'Disease', (73, 97))	('levels', 'MPA', (127, 133))	('changes', 'Reg', (173, 180))
192776	33050791	RNA editing by ADAR occurs mostly in non-coding regions where inverted repeat sequences are likely to form dsRNA structures, which function as the substrate.	('rat', 'Species', '10116', (152, 155))	('RNA editing', 'biological_process', 'GO:0009451', ('0', '11'))	('inverted repeat sequences', 'Var', (62, 87))	('RNA editing', 'MPA', (0, 11))	('ADAR', 'Gene', (15, 19))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
192782	33050791	Taking into account that 70% of the genome is transcribed and only 2% of the genome encodes for proteins, this may explain the reason why the vast majority of editing sites in human and primates are in inverted repeat SINE (Alu elements in human) and ERV which forms stable dsRNA structures and are largely in non-coding regions of the genome.	('Alu', 'Chemical', '-', (224, 227))	('human', 'Species', '9606', (240, 245))	('sites', 'Var', (167, 172))	('human', 'Species', '9606', (176, 181))	('ERV', 'Gene', (251, 254))
192790	33050791	Analysis of TCGA mesothelioma data revealed that high expression of ADAR2 is associated with worst overall survival, supporting the idea that RNA editing is relevant in mesothelioma as it is in other cancers (reviewed in).	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('worst', 'NegReg', (93, 98))	('mesothelioma', 'Disease', (17, 29))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('RNA editing', 'biological_process', 'GO:0009451', ('142', '153'))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('ADAR2', 'Gene', (68, 73))	('overall survival', 'MPA', (99, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (17, 29))	('high expression', 'Var', (49, 64))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('mesothelioma', 'Disease', (169, 181))
192791	33050791	In addition, decreased expression of ADAR2 has been observed upon Yes-associated protein (YAP) silencing in mesothelioma cells, which resulted in decreased cell growth, providing a possible mechanism behind the TCGA data associating high ADAR2 expression with worst overall survival.	('decreased', 'NegReg', (13, 22))	('cell growth', 'CPA', (156, 167))	('mesothelioma', 'Disease', (108, 120))	('YAP', 'Gene', (90, 93))	('decreased', 'NegReg', (146, 155))	('Yes-associated protein', 'Gene', (66, 88))	('cell growth', 'biological_process', 'GO:0016049', ('156', '167'))	('Yes-associated protein', 'Gene', '10413', (66, 88))	('silencing', 'Var', (95, 104))	('ADAR2', 'Gene', (238, 243))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('YAP', 'Gene', '10413', (90, 93))	('ADAR2', 'Gene', (37, 42))	('expression', 'MPA', (23, 33))
192795	33050791	Furthermore, in a recent study, silencing ADAR2 in one mesothelioma cell line resulted in reduced cell proliferation, invasiveness and motility, while overexpression of ADAR2 with a mutated dsRBD showed the opposite effect, consistent with a dominant negative effect of mutant overexpression.	('rat', 'Species', '10116', (110, 113))	('cell proliferation', 'CPA', (98, 116))	('reduced', 'NegReg', (90, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('mesothelioma', 'Disease', (55, 67))	('invasiveness', 'CPA', (118, 130))	('ADAR2', 'Gene', (42, 47))	('motility', 'CPA', (135, 143))	('silencing', 'Var', (32, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))
192800	33050791	In in vivo mouse models, the function of Adar1 p150-mediated editing is to prevent endogenous dsRNA-dependent activation of innate immune receptors such as mitochondrial antiviral signalling adaptor protein (MAVS) or IFIH1-encoded melanoma differentiation-associated protein 5 (MDA5) (figure 2).	('activation', 'PosReg', (110, 120))	('mouse', 'Species', '10090', (11, 16))	('Adar1 p150', 'Gene', '56417', (41, 51))	('editing', 'Var', (61, 68))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('endogenous', 'MPA', (83, 93))	('MAVS', 'Gene', (208, 212))	('Adar1 p150', 'Gene', (41, 51))	('MAVS', 'Gene', '228607', (208, 212))	('melanoma differentiation-associated protein 5', 'Gene', (231, 276))	('IFIH1', 'Gene', '71586', (217, 222))	('signalling', 'biological_process', 'GO:0023052', ('180', '190'))	('protein', 'cellular_component', 'GO:0003675', ('267', '274'))	('IFIH1', 'Gene', (217, 222))	('melanoma differentiation-associated protein 5', 'Gene', '71586', (231, 276))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
192801	33050791	Indeed, embryonic lethality is rescued in double ADAR1/dsRNA sensor mutants, although mice survive only until birth.	('double ADAR1/dsRNA sensor', 'Gene', (42, 67))	('mice', 'Species', '10090', (86, 90))	('rescued', 'PosReg', (31, 38))	('embryonic lethality', 'Disease', 'MESH:D020964', (8, 27))	('embryonic lethality', 'Disease', (8, 27))	('mutants', 'Var', (68, 75))
192802	33050791	However, mice lacking exons 7-9 rescued by Mavs-/- and Ifih-/- have an intermediate phenotype and live longer compared with Adar1-deficient mice lacking exons 2-13; Mavs-/-.	('mice', 'Species', '10090', (9, 13))	('Mavs-/-', 'Var', (43, 50))	('mice', 'Species', '10090', (140, 144))	('Ifih-/-', 'Var', (55, 62))
192804	33050791	This is consistent with the aberrant activation of innate immune receptors observed in a spectrum of immune disorders, such as systemic lupus erythematosus or Aicardi-Goutieres syndrome, a disease characterized by severe changes in the brain and neurological function, and it has been linked to mutations inducing loss of ADAR function or gain of function in MDA5.	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (127, 155))	('activation', 'PosReg', (37, 47))	('Aicardi-Goutieres syndrome', 'Disease', (159, 185))	('loss', 'NegReg', (314, 318))	('gain of function', 'PosReg', (339, 355))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (127, 155))	('mutations', 'Var', (295, 304))	('MDA5', 'Gene', (359, 363))	('Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (159, 185))	('systemic lupus erythematosus', 'Disease', (127, 155))	('ADAR', 'Gene', (322, 326))
192805	33050791	Mesothelioma is the sixth of 31 cancer types with most prevalent ISG 38 gene signature.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('ISG', 'Var', (65, 68))
192806	33050791	Importantly, in the context of mesothelioma, type 1 IFN signature is linked to both clinical outcome and specific driver mutations.	('mutations', 'Var', (121, 130))	('linked', 'Reg', (69, 75))	('mesothelioma', 'Disease', (31, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('IFN', 'Gene', '3439', (52, 55))	('IFN', 'Gene', (52, 55))
192814	33050791	More recently, targeted Adar1 deletion in neural crest cells also resulted in the death of mice 10 days after birth due to impairment of neural crest cell differentiation to melanocytes.	('mice', 'Species', '10090', (91, 95))	('deletion', 'Var', (30, 38))	('neural crest cell differentiation to melanocytes', 'CPA', (137, 185))	('Adar1', 'Gene', (24, 29))	('impairment', 'NegReg', (123, 133))	('neural crest cell differentiation', 'biological_process', 'GO:0014033', ('137', '170'))
192815	33050791	This may explain why mutations in human ADAR1 are associated with dyschromatosis symmetrica hereditaria, an autosomal dominant hyperpigmentation of the hands and feet occurring in Chinese and Japanese families.	('human', 'Species', '9606', (34, 39))	('dyschromatosis symmetrica hereditaria', 'Disease', 'MESH:C535729', (66, 103))	('dyschromatosis symmetrica hereditaria', 'Disease', (66, 103))	('hyperpigmentation', 'Disease', 'MESH:D017495', (127, 144))	('hyperpigmentation', 'Disease', (127, 144))	('associated', 'Reg', (50, 60))	('ADAR1', 'Gene', (40, 45))	('mutations', 'Var', (21, 30))
192816	33050791	The majority of these disease-associated mutations are single-allele truncations of ADAR1, and the dominant phenotype seems to be due to haploinsufficiency for ADAR1.	('mutations', 'Var', (41, 50))	('haploinsufficiency', 'Disease', 'MESH:D058495', (137, 155))	('due', 'Reg', (130, 133))	('ADAR1', 'Gene', (84, 89))	('ADAR1', 'Gene', (160, 165))	('disease-associated', 'Reg', (22, 40))	('haploinsufficiency', 'Disease', (137, 155))
192819	33050791	The relevance of the z-DNA-binding domain of ADAR1 p150 in the dysregulation of ISG has been recently highlighted by analysis of dsRNA-binding impaired natural variants of this domain (Pro193Ala and Asn173Ser) in the few cases of diseases linked to the loss of an allele of ADAR1 p150 but not ADAR1 p110.	('p150', 'Gene', (51, 55))	('Pro193Ala', 'SUBSTITUTION', 'None', (185, 194))	('p110', 'Gene', '100616443', (299, 303))	('p150', 'Gene', '10036', (51, 55))	('Asn173Ser', 'SUBSTITUTION', 'None', (199, 208))	('Pro193Ala', 'Var', (185, 194))	('p110', 'Gene', (299, 303))	('p150', 'Gene', (280, 284))	('p150', 'Gene', '10036', (280, 284))	('Ser', 'cellular_component', 'GO:0005790', ('205', '208'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('23', '34'))	('dsRNA-binding', 'molecular_function', 'GO:0003725', ('129', '142'))	('Asn173Ser', 'Var', (199, 208))	('ADAR1', 'Gene', (274, 279))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
192824	33050791	Although the phenotype of Adar1-deficient mice can also be due to editing-independent functions, the role of the catalytic function of Adar1 in the phenotype of Adar1-deficient mice has been confirmed in studies using mice with an editing knock-in mutation (E861A), which results in disruption of the catalytic activity.	('E861A', 'Mutation', 'p.E861A', (258, 263))	('catalytic activity', 'MPA', (301, 319))	('disruption', 'NegReg', (283, 293))	('mice', 'Species', '10090', (42, 46))	('E861A', 'Var', (258, 263))	('mice', 'Species', '10090', (218, 222))	('mice', 'Species', '10090', (177, 181))
192827	33050791	While most investigations draw attention to the role of ADAR1 in preventing the activation of type 1 IFN, the observation of abnormal kidney development in Adar1-/-; Mavs-/- but not in Adar1 p150-/-; Mavs-/- indicates a specific role for Adar1 p110 in renal development.	('IFN', 'Gene', (101, 104))	('kidney development', 'biological_process', 'GO:0001822', ('134', '152'))	('p110', 'Gene', (244, 248))	('kidney development', 'CPA', (134, 152))	('Adar1 p150', 'Gene', '56417', (185, 195))	('Adar1 p150', 'Gene', (185, 195))	('Mavs-/-', 'Var', (166, 173))	('abnormal kidney', 'Phenotype', 'HP:0000077', (125, 140))	('IFN', 'Gene', '3439', (101, 104))	('Adar1-/-; Mavs-/-', 'Var', (156, 173))	('p110', 'Gene', '100616443', (244, 248))
192831	33050791	Therefore, nuclear RNA editing of genes expressed during embryo development or genes reactivated in cancer has consequences for both innate immunity and specific innate immunity-independent signalling.	('consequences', 'Reg', (111, 123))	('signalling', 'biological_process', 'GO:0023052', ('190', '200'))	('RNA editing', 'biological_process', 'GO:0009451', ('19', '30'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('innate immunity', 'biological_process', 'GO:0045087', ('133', '148'))	('nuclear RNA', 'Var', (11, 22))	('embryo development', 'biological_process', 'GO:0009790', ('57', '75'))	('innate immunity', 'biological_process', 'GO:0045087', ('162', '177'))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
192837	33050791	The destabilizing of dsRNA structures by ADAR activity suppresses dsRNA-activated signalling to avoid growth arrest due to the activity of the other genes and is therefore considered to act as a negative feedback loop.	('ADAR', 'Gene', (41, 45))	('growth arrest', 'Disease', 'MESH:D006323', (102, 115))	('growth arrest', 'Disease', (102, 115))	('signalling', 'biological_process', 'GO:0023052', ('82', '92'))	('destabilizing', 'NegReg', (4, 17))	('growth arrest', 'Phenotype', 'HP:0001510', (102, 115))	('activity', 'Var', (46, 54))	('suppresses', 'NegReg', (55, 65))	('activity', 'MPA', (127, 135))	('dsRNA-activated signalling', 'MPA', (66, 92))
192838	33050791	dsRNA also increases the activation of IFN-inducible oligoadenylate synthetases (OAS), which produce 2',5'-oligoadenylate activating RNAse L to degrade rRNA, tRNA and Y-RNA.	('dsRNA', 'Var', (0, 5))	('tRNA', 'MPA', (158, 162))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('RNAse L', 'Gene', '6041', (133, 140))	('IFN', 'Gene', (39, 42))	('degrade', 'NegReg', (144, 151))	('IFN', 'Gene', '3439', (39, 42))	('rRNA', 'MPA', (152, 156))	('tRNA', 'molecular_function', 'GO:0030533', ('158', '162'))	('RNAse L', 'Gene', (133, 140))
192845	33050791	Importantly, total (or in some cases partial) rescue has been observed by overexpression of catalytically inactive E912A ADAR1 p150.	('ADAR1', 'Gene', (121, 126))	('E912A', 'Var', (115, 120))	('p150', 'Gene', (127, 131))	('E912A', 'Mutation', 'p.E912A', (115, 120))	('p150', 'Gene', '10036', (127, 131))
192855	33050791	Adar2 deficiency results in early lethality due to seizures, and this can be rescued by a point mutation in Gria2 (Gria R/R mice).	('Gria2', 'Gene', '14800', (108, 113))	('seizures', 'Disease', 'MESH:D012640', (51, 59))	('deficiency', 'Var', (6, 16))	('mice', 'Species', '10090', (124, 128))	('point mutation', 'Var', (90, 104))	('seizures', 'Disease', (51, 59))	('seizures', 'Phenotype', 'HP:0001250', (51, 59))	('Adar2', 'Gene', (0, 5))	('Gria2', 'Gene', (108, 113))
192857	33050791	The crossing of Adar2-/-; Gria2 R/R mice with Adar1 Delta7-9; Mavs-/- mice showed decreased survival and increased activation of type 1 IFN signalling, indicating a previously unexpected, although small, compensatory contribution of Adar2 in the phenotype of Adar1 Delta7-9; Mavs-/-.	('Adar2-/-', 'Var', (16, 24))	('survival', 'CPA', (92, 100))	('Delta7', 'Mutation', 'c.del7', (52, 58))	('Delta7', 'Mutation', 'c.del7', (265, 271))	('IFN', 'Gene', '3439', (136, 139))	('Gria2', 'Gene', (26, 31))	('IFN', 'Gene', (136, 139))	('mice', 'Species', '10090', (70, 74))	('decreased', 'NegReg', (82, 91))	('Gria2', 'Gene', '14800', (26, 31))	('increased activation', 'PosReg', (105, 125))	('mice', 'Species', '10090', (36, 40))	('Delta7-9', 'Var', (52, 60))	('Adar1', 'Gene', (46, 51))	('signalling', 'biological_process', 'GO:0023052', ('140', '150'))
192861	33050791	In addition, editing of rat Adar2 pre-mRNA regulates its alternative splicing with the generation of 47 nt insert that leads to decreased activity.	('Adar2', 'Gene', (28, 33))	('activity', 'MPA', (138, 146))	('regulates', 'Reg', (43, 52))	('rat', 'Species', '10116', (91, 94))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('alternative splicing', 'MPA', (57, 77))	('editing', 'Var', (13, 20))	('decreased', 'NegReg', (128, 137))	('pre', 'molecular_function', 'GO:0003904', ('34', '37'))	('rat', 'Species', '10116', (24, 27))
192862	33050791	Therefore, it is difficult to interpret the observation that Adar2 expression is increased in developing mesothelioma in asbestos exposed mice and that high ADAR2 expression is associated with worst overall survival in mesothelioma patients until additional functional studies are carried out.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('ADAR2', 'Gene', (157, 162))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('mesothelioma', 'Disease', (219, 231))	('patients', 'Species', '9606', (232, 240))	('mice', 'Species', '10090', (138, 142))	('Adar2', 'Gene', (61, 66))	('expression', 'MPA', (163, 173))	('mesothelioma', 'Disease', (105, 117))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))	('expression', 'MPA', (67, 77))	('increased', 'PosReg', (81, 90))	('high', 'Var', (152, 156))
192867	33050791	Editing of AZIN1, which encodes an antizyme inhibitor, generates an amino acid change (Ser367Gly) creating an isoform with increased affinity to antizyme, promoting cell proliferation by reducing antizyme-mediated degradation of ornithine decarboxylase and cyclin D1, and has been associated with hepatocellular carcinoma progression.	('cyclin D1', 'Gene', (257, 266))	('Ser367Gly', 'Var', (87, 96))	('antizyme-mediated degradation', 'MPA', (196, 225))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (297, 321))	('cyclin D1', 'Gene', '595', (257, 266))	('AZIN1', 'Gene', '51582', (11, 16))	('associated with', 'Reg', (281, 296))	('cell proliferation', 'biological_process', 'GO:0008283', ('165', '183'))	('promoting', 'PosReg', (155, 164))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (297, 321))	('increased', 'PosReg', (123, 132))	('Ser367Gly', 'SUBSTITUTION', 'None', (87, 96))	('ornithine decarboxylase', 'Gene', '4953', (229, 252))	('isoform', 'MPA', (110, 117))	('hepatocellular carcinoma', 'Disease', (297, 321))	('affinity', 'Interaction', (133, 141))	('degradation', 'biological_process', 'GO:0009056', ('214', '225'))	('reducing', 'NegReg', (187, 195))	('rat', 'Species', '10116', (59, 62))	('cyclin', 'molecular_function', 'GO:0016538', ('257', '263'))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))	('AZIN1', 'Gene', (11, 16))	('rat', 'Species', '10116', (177, 180))	('cell proliferation', 'CPA', (165, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('ornithine decarboxylase', 'Gene', (229, 252))
192868	33050791	AZIN1 editing is also observed in mesothelioma, where it can be used as readout of RNA editing activity.	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('mesothelioma', 'Disease', (34, 46))	('observed', 'Reg', (22, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('editing', 'Var', (6, 13))	('RNA editing', 'biological_process', 'GO:0009451', ('83', '94'))	('AZIN1', 'Gene', '51582', (0, 5))	('AZIN1', 'Gene', (0, 5))
192869	33050791	Relevant for MPM, where a subset of patients show Hedgehog signalling activation (reviewed in), editing of mRNA encoding for glioma-associated oncogene 1 (GLI-1) results in increased Gli-1 protein stability and maintains tumour initiating cells in leukaemia.	('GLI-1', 'Gene', (155, 160))	('leukaemia', 'Disease', (248, 257))	('glioma-associated oncogene 1', 'Gene', '2735', (125, 153))	('tumour', 'Disease', (221, 227))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('signalling', 'biological_process', 'GO:0023052', ('59', '69'))	('patients', 'Species', '9606', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('increased', 'PosReg', (173, 182))	('editing', 'Var', (96, 103))	('glioma-associated oncogene 1', 'Gene', (125, 153))	('Gli-1', 'Gene', (183, 188))	('leukaemia', 'Disease', 'MESH:D007938', (248, 257))	('GLI-1', 'Gene', '2735', (155, 160))	('Gli-1', 'Gene', '2735', (183, 188))	('tumour', 'Disease', 'MESH:D009369', (221, 227))
192871	33050791	Editing of insulin-like growth factor-binding protein 7 (IGFBP7), a secreted protein associated with apoptosis and senescence, in oesophageal cancer cells, results in an amino acid change protecting the protein from proteolysis.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('insulin-like growth factor-binding', 'molecular_function', 'GO:0005520', ('11', '45'))	('insulin-like growth factor-binding protein 7', 'Gene', '3490', (11, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('proteolysis', 'biological_process', 'GO:0006508', ('216', '227'))	('IGFBP7', 'Gene', (57, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('amino acid change', 'MPA', (170, 187))	('cancer', 'Disease', (142, 148))	('Editing', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('protecting', 'Reg', (188, 198))	('senescence', 'biological_process', 'GO:0010149', ('115', '125'))	('insulin-like growth factor-binding protein 7', 'Gene', (11, 55))	('protein', 'Protein', (203, 210))	('proteolysis', 'MPA', (216, 227))	('insulin-like growth factor-binding protein', 'cellular_component', 'GO:0017052', ('11', '53'))	('IGFBP7', 'Gene', '3490', (57, 63))
192872	33050791	Editing of GABA receptor alpha3 (Gabra3) in breast cancer cells changes an amino acid, thereby reducing its surface expression and decreasing cell migration and invasion, and is accompanied by decreased AKT activation.	('cell migration', 'biological_process', 'GO:0016477', ('142', '156'))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('Editing', 'Var', (0, 7))	('AKT', 'Gene', (203, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('decreasing', 'NegReg', (131, 141))	('activation', 'PosReg', (207, 217))	('changes', 'Reg', (64, 71))	('breast cancer', 'Disease', (44, 57))	('surface expression', 'MPA', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('rat', 'Species', '10116', (150, 153))	('amino acid', 'MPA', (75, 85))	('reducing', 'NegReg', (95, 103))	('AKT', 'Gene', '207', (203, 206))	('decreased', 'NegReg', (193, 202))	('Gabra3', 'Gene', (33, 39))
192875	33050791	Finally, ADAR2 editing of pre-miR-221 and 222 results in decreased levels of mature miR-221 and 222 and decreased growth in glioblastoma cells.	('editing', 'Var', (15, 22))	('pre', 'molecular_function', 'GO:0003904', ('26', '29'))	('growth', 'CPA', (114, 120))	('decreased', 'NegReg', (104, 113))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('ADAR2', 'Gene', (9, 14))	('decreased growth', 'Phenotype', 'HP:0001510', (104, 120))	('decreased', 'NegReg', (57, 66))
192877	33050791	In the context of MPM, which is treated in first-line therapy with cisplatin and antifolates, editing of the 3'-UTR may protect dihydrofolate reductase (DHFR) mRNA from mir-25-3p- and miR-125-3p-induced degradation, leading to resistance to antifolates such as methotrexate and pemetrexed, as it has been recently observed in breast cancer cells.	('breast cancer', 'Disease', (326, 339))	('methotrexate', 'Chemical', 'MESH:D008727', (261, 273))	('leading to', 'Reg', (216, 226))	('miR-125-3p', 'Gene', (184, 194))	('editing', 'Var', (94, 101))	('mir-25-3p', 'Chemical', '-', (169, 178))	('resistance to antifolates', 'MPA', (227, 252))	('DHFR', 'Gene', (153, 157))	('DHFR', 'molecular_function', 'GO:0004146', ('153', '157'))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('degradation', 'MPA', (203, 214))	('dihydrofolate reductase', 'Gene', '1719', (128, 151))	('dihydrofolate reductase', 'Gene', (128, 151))	('DHFR', 'Gene', '1719', (153, 157))	('pemetrexed', 'Chemical', 'MESH:D000068437', (278, 288))	('degradation', 'biological_process', 'GO:0009056', ('203', '214'))	('breast cancer', 'Phenotype', 'HP:0003002', (326, 339))	('miR-125-3p', 'Gene', '100302208', (184, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('breast cancer', 'Disease', 'MESH:D001943', (326, 339))
192879	33050791	This might be important in the context of mesothelioma because NF2 alterations, which are frequent in mesothelioma (reviewed in), result in the activation of FAK and mesothelioma cells are sensitive to FAK inhibitors.	('mesothelioma', 'Disease', (102, 114))	('FAK', 'molecular_function', 'GO:0004717', ('158', '161'))	('rat', 'Species', '10116', (71, 74))	('NF2', 'Gene', (63, 66))	('FAK', 'Gene', '5747', (158, 161))	('mesothelioma', 'Disease', (42, 54))	('alterations', 'Var', (67, 78))	('FAK', 'Gene', '5747', (202, 205))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('FAK', 'Gene', (158, 161))	('activation', 'PosReg', (144, 154))	('NF2', 'Gene', '4771', (63, 66))	('mesothelioma', 'Disease', (166, 178))	('FAK', 'Gene', (202, 205))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('FAK', 'molecular_function', 'GO:0004717', ('202', '205'))
192880	33050791	Adenosine-to-inosine conversion can change the sequence of the mature miRNA (including the critical seed sequence) to block target recognition and also change base pairing and hence can reduce the dsRNA structure to interfere with pri-miRNA processing.	('change', 'Reg', (152, 158))	('base pairing', 'MPA', (159, 171))	('Adenosine-to-inosine', 'Var', (0, 20))	('Adenosine', 'Chemical', 'MESH:D000241', (0, 9))	('miR', 'Gene', '220972', (235, 238))	('base pairing', 'molecular_function', 'GO:0003676', ('159', '171'))	('miR', 'Gene', (235, 238))	('pri-miRNA processing', 'biological_process', 'GO:0031053', ('231', '251'))	('target recognition', 'MPA', (124, 142))	('dsRNA structure', 'MPA', (197, 212))	('block', 'NegReg', (118, 123))	('inosine', 'Chemical', 'MESH:D007288', (13, 20))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('reduce', 'NegReg', (186, 192))	('change', 'Reg', (36, 42))
192881	33050791	For example, editing of hairpin structures in pri-miRNA reduces the production of mature miRNA due to the impairment of their processing by Drosha.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('processing', 'MPA', (126, 136))	('Drosha', 'Gene', (140, 146))	('reduces', 'NegReg', (56, 63))	('editing', 'Var', (13, 20))	('Drosha', 'Gene', '29102', (140, 146))
192882	33050791	RNA editing of pri-miR-142 by ADAR1 and ADAR2 inhibits its processing by Drosha and also facilitates pri-miR-142 degradation.	('Drosha', 'Gene', (73, 79))	('facilitates', 'PosReg', (89, 100))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('ADAR1', 'Var', (30, 35))	('RNA editing', 'biological_process', 'GO:0009451', ('0', '11'))	('inhibits', 'NegReg', (46, 54))	('Drosha', 'Gene', '29102', (73, 79))	('miR-142', 'Gene', '406934', (19, 26))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('miR-142', 'Gene', '406934', (105, 112))	('processing', 'MPA', (59, 69))	('ADAR2', 'Var', (40, 45))	('degradation', 'MPA', (113, 124))	('miR-142', 'Gene', (105, 112))	('miR-142', 'Gene', (19, 26))
192890	33050791	ADAR1-dependent editing of MDM2 3'-UTR facilitates nuclear retention of MDM2 mRNA by competing with Staufen1.	('MDM2', 'Gene', '17246', (27, 31))	('editing', 'Var', (16, 23))	('nuclear retention', 'MPA', (51, 68))	('MDM2', 'Gene', '17246', (72, 76))	('retention', 'biological_process', 'GO:0051235', ('59', '68'))	('MDM2', 'Gene', (27, 31))	('MDM2', 'Gene', (72, 76))	('facilitates', 'PosReg', (39, 50))
192901	33050791	DNA demethylation occurs passively during DNA replication or actively via demethylation by ten-eleven translocations (TETs) enzymes, which catalyse the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine.	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (185, 208))	('5-formylcytosine', 'Chemical', 'MESH:C560973', (210, 226))	('5-carboxylcytosine', 'Chemical', 'MESH:C560974', (231, 249))	('demethylation', 'Var', (74, 87))	('DNA replication', 'biological_process', 'GO:0006260', ('42', '57'))	('5-formylcytosine', 'MPA', (210, 226))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('demethylation', 'biological_process', 'GO:0070988', ('74', '87'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('0', '17'))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (165, 181))
192903	33050791	In summary, ADAR-dependent RNA editing and ADAR expression, via their involvement in regulating type 1 IFN signalling, represent potential biomarkers and targets for mesothelioma immunotherapy for the treatment of mesothelioma, as has been shown for other cancers.	('ADAR', 'Gene', (43, 47))	('RNA editing', 'biological_process', 'GO:0009451', ('27', '38'))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('mesothelioma', 'Disease', 'MESH:D008654', (214, 226))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('cancers', 'Disease', (256, 263))	('ADAR-dependent', 'Var', (12, 26))	('IFN', 'Gene', '3439', (103, 106))	('mesothelioma', 'Disease', (166, 178))	('signalling', 'biological_process', 'GO:0023052', ('107', '117'))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('mesothelioma', 'Disease', (214, 226))	('IFN', 'Gene', (103, 106))
192904	33050791	In addition, by their participation to RNA processing either through editing or by competing with other dsRNA-binding proteins, ADARs are involved in what has been called the 11th hallmark of cancer.	('participation', 'Reg', (22, 35))	('ADARs', 'Gene', (128, 133))	('dsRNA-binding', 'molecular_function', 'GO:0003725', ('104', '117'))	('involved', 'Reg', (138, 146))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('RNA processing', 'biological_process', 'GO:0006396', ('39', '53'))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('editing', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
192922	32326213	8-oxodG, if not fully repaired, can induce G:C to T:A transversions and G:C to A:T transitions, the same kind of damage induced by some asbestos fibers.	('8-oxodG', 'Var', (0, 7))	('induce', 'Reg', (36, 42))	('asbestos', 'Chemical', 'MESH:D001194', (136, 144))	('8-oxodG', 'Chemical', 'MESH:C067134', (0, 7))
192991	32326213	This data has a special value since highly increased amounts of 8-oxo-dG increase the probability of mutagenic G:T-transversions during cell division, which are frequently found in tumor-relevant genes.	('G:T-transversions', 'Var', (111, 128))	('tumor', 'Disease', (181, 186))	('cell division', 'biological_process', 'GO:0051301', ('136', '149'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('increased', 'PosReg', (43, 52))	('mutagenic G:T-transversions', 'Var', (101, 128))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
192994	32326213	Adduct results have a great importance since adducts levels have been associated with higher risks of developing lung cancer.	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('adducts levels', 'Var', (45, 59))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))
193000	32326213	High frequency of micronucleus was also reported in subjects who were diagnosed with pleural plaques due to asbestos exposure.	('micronucleus', 'Var', (18, 30))	('pleural', 'Disease', (85, 92))	('asbestos', 'Chemical', 'MESH:D001194', (108, 116))	('pleural', 'Disease', 'MESH:D010995', (85, 92))	('micronucleus', 'cellular_component', 'GO:0031040', ('18', '30'))
193009	32326213	ROS generated by persistent inflammation and macrophages and neutrophils activation in lung parenchyma can indirectly cause 8-oxodG and other effects such as lipid peroxidation, and subsequently M1dG, in addition to activation of signaling pathways and cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('253', '271'))	('inflammation', 'Disease', (28, 40))	('ROS', 'Var', (0, 3))	('lipid', 'Chemical', 'MESH:D008055', (158, 163))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('signaling pathways', 'Pathway', (230, 248))	('M1dG', 'Chemical', '-', (195, 199))	('inflammation', 'biological_process', 'GO:0006954', ('28', '40'))	('lipid peroxidation', 'MPA', (158, 176))	('8-oxodG', 'Chemical', 'MESH:C067134', (124, 131))	('effects', 'MPA', (142, 149))	('signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('8-oxodG', 'MPA', (124, 131))	('cause', 'Reg', (118, 123))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))
193015	32326213	The generation of oxidative adducts may reflect the concentrations of asbestos fibers that have been accumulated in lung parenchyma, where those fibers can cause chronic inflammation, leading in turn to greater ROS production, which may overwhelm intrinsic anti-oxidant defense.	('cause', 'Reg', (156, 161))	('inflammation', 'biological_process', 'GO:0006954', ('170', '182'))	('inflammation', 'Disease', 'MESH:D007249', (170, 182))	('greater', 'PosReg', (203, 210))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('inflammation', 'Disease', (170, 182))	('fibers', 'Var', (145, 151))	('ROS', 'Chemical', 'MESH:D017382', (211, 214))	('ROS production', 'MPA', (211, 225))
193027	32326213	Instead, educational levels, a parameter that can reflect the socioeconomic status, was found to be a significant risk factor for higher 8-oxodG levels.	('higher', 'PosReg', (130, 136))	('8-oxodG', 'Chemical', 'MESH:C067134', (137, 144))	('8-oxodG levels', 'MPA', (137, 151))	('educational levels', 'Var', (9, 27))
193066	31315884	Among those whose tumors had >= 1% PD-L1 expression, the response rate was 40% and only 8% in those whose tumors did not have PD-L1 expression.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('PD-L1', 'Gene', '29126', (35, 40))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', (18, 24))	('PD-L1', 'Gene', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('PD-L1', 'Gene', '29126', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('expression', 'Var', (41, 51))	('PD-L1', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
193071	31315884	Also, despite the relatively low tumor mutation burden in mesothelioma, chromosomal rearrangements are common in this cancer and may have neoantigenic potential.	('cancer', 'Disease', (118, 124))	('chromosomal rearrangements', 'Var', (72, 98))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mesothelioma', 'Disease', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('tumor', 'Disease', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
193078	31315884	The next wave of clinical trials with immune checkpoint inhibitors is already underway and in a few years we will have insight into (1) whether combined PD-1 and CTLA-4 inhibition improves survival over first line chemotherapy, (2) whether combined chemotherapy and PD-L1 inhibition improves survival over chemotherapy alone, (3) whether PD-(L)1 inhibitors are synergistic with other agents in second or later lines of therapy (4) how neo-adjuvant chemo-immunotherapy affects surgical outcomes, and (5) the role of other immune checkpoints in mesothelioma.	('CTLA-4', 'Gene', '1493', (162, 168))	('improves', 'PosReg', (283, 291))	('mesothelioma', 'Disease', (543, 555))	('CTLA-4', 'Gene', (162, 168))	('PD-L1', 'Gene', (266, 271))	('PD-L1', 'Gene', '29126', (266, 271))	('PD-(L)1', 'Gene', (338, 345))	('mesothelioma', 'Disease', 'MESH:D008654', (543, 555))	('improves', 'PosReg', (180, 188))	('PD-1', 'Gene', (153, 157))	('PD-1', 'Gene', '5133', (153, 157))	('PD-(L)1', 'Gene', '29126', (338, 345))	('inhibition', 'Var', (169, 179))
193093	28170372	The current best practice is serial thoracic computerised tomography (CT) scans reported using the modified RECIST criteria, a technique which only partially allows for the fact that MPM usually grows as a pleural rind as opposed to a spherical mass.	('pleural', 'Disease', 'MESH:D010995', (206, 213))	('pleural', 'Disease', (206, 213))	('MPM', 'Var', (183, 186))
193131	28170372	One study by Yamada et al found patients (n=45) with higher pf SM levels survived significantly longer (dichotomy at 10 nM) at univariate but not multivariate analysis.	('patients', 'Species', '9606', (32, 40))	('longer', 'PosReg', (96, 102))	('pf SM', 'Chemical', '-', (60, 65))	('pf', 'Phenotype', 'HP:0002202', (60, 62))	('survived', 'CPA', (73, 81))	('higher', 'Var', (53, 59))
193149	28170372	Using a cut-off of 350 ng ml-1 (selected using a maximisation of HR model), patients with a low-serum OPN had a median OS of 15 months compared with 5 months in high-serum OPN levels.	('OPN', 'Gene', '6696', (172, 175))	('patients', 'Species', '9606', (76, 84))	('OPN', 'Gene', (172, 175))	('low-serum', 'Var', (92, 101))	('OPN', 'Gene', '6696', (102, 105))	('OS', 'Chemical', '-', (119, 121))	('OPN', 'Gene', (102, 105))
193184	28170372	A 7-year prospective single centre case series of 51 patients with MPM analysed serum pan-VEGF levels and compared them to a non-MPM asbestos-exposed population (n=42).	('VEGF', 'Gene', (90, 94))	('patients', 'Species', '9606', (53, 61))	('VEGF', 'Gene', '7422', (90, 94))	('asbestos', 'Chemical', 'MESH:D001194', (133, 141))	('MPM', 'Var', (67, 70))
193214	28170372	This systematic review identified several studies that correlated high OPN levels with poor prognosis, including within prognostic tools.	('OPN', 'Gene', '6696', (71, 74))	('poor', 'Disease', (87, 91))	('high', 'Var', (66, 70))	('OPN', 'Gene', (71, 74))
193338	30885330	Modulation of hypoxia may increase therapeutic efficacy; therefore, the monitoring of hypoxia in preclinical models may lead to the development of strategies that can be translated to human clinical trials.	('Modulation', 'Var', (0, 10))	('therapeutic', 'MPA', (35, 46))	('lead to', 'Reg', (120, 127))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', (14, 21))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (14, 21))	('human', 'Species', '9606', (184, 189))	('increase', 'PosReg', (26, 34))
193349	30885330	By systematically fine-tuning these CT imaging parameters, the best possible quality of mesothelioma imaging on CT may be achieved, which has implications both for clinical management of patients and for research and development of imaging software tools.	('patients', 'Species', '9606', (187, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('mesothelioma', 'Disease', (88, 100))	('fine-tuning', 'Var', (18, 29))
193370	30885330	The primary tumor was delineated in 30 patients with proven MPM in CT images performed at the time of primary diagnosis.	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('MPM', 'Var', (60, 63))
193391	30885330	The median DSC (range) when comparing deep CNN-predicted tumor segmentations with observer reference segmentations on the test set were 0.776 (0.314-0.938), 0.688 (0.251-0.931), and 0.800 (0.308-0.952) for Observers A, B, and C, respectively.	('0.800', 'Var', (182, 187))	('0.688', 'Var', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
193392	30885330	The median DSC (range) when comparing tumor segmentations obtained from the 2011 Method with observer reference segmentations on the same test set were 0.718 (0-0.938), 0.604 (0-0.902), and 0.709 (0-0.926) for Observers A, B, and C, respectively.	('0.604', 'Var', (169, 174))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('0.718', 'Var', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('0.709', 'Var', (190, 195))
193492	27391069	overexpression of oncogenes, downregulation of onco-suppressor genes, dysregulation of microRNA, or alteration of intracellular Ca2+ homeostasis and of apoptosis.	('downregulation', 'NegReg', (29, 43))	('alteration', 'Reg', (100, 110))	('onco-suppressor genes', 'Gene', (47, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('intracellular', 'cellular_component', 'GO:0005622', ('114', '127'))	('Ca2+', 'Chemical', 'MESH:D000069285', (128, 132))	('microRNA', 'Protein', (87, 95))	('homeostasis', 'biological_process', 'GO:0042592', ('133', '144'))	('dysregulation', 'Var', (70, 83))	('intracellular Ca2+ homeostasis', 'MPA', (114, 144))	('apoptosis', 'CPA', (152, 161))	('oncogenes', 'Gene', (18, 27))
193495	27391069	In this report we show that the P2x7R is expressed by three MPM cell lines established from MPM patients but not by mesothelial cells from healthy subjects (healthy mesothelial cells, HMCs).	('HMCs', 'Gene', (184, 188))	('patients', 'Species', '9606', (96, 104))	('HMCs', 'Gene', '55034', (184, 188))	('P2x7R', 'Var', (32, 37))
193497	27391069	Systemic administration of the selective P2x7R blocker AZ10606120 inhibited in vivo growth of MPM tumors whether implanted subcutaneously (s.c.) or intraperitoneally (i.p.).	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('AZ10606120', 'Var', (55, 65))	('growth', 'CPA', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MPM tumors', 'Disease', (94, 104))	('inhibited', 'NegReg', (66, 75))	('AZ10606120', 'Chemical', 'MESH:C000602458', (55, 65))	('MPM tumors', 'Disease', 'MESH:D009369', (94, 104))
193506	27391069	We and others have shown that the P2x7R supports tumor cell growth both in vitro and in vivo,, affords a proliferative advantage under limiting growth condition and glucose deprivation, facilitates extracellular matrix invasion, and stimulates VEGF secretion.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('supports', 'PosReg', (40, 48))	('extracellular matrix invasion', 'CPA', (198, 227))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('proliferative advantage', 'CPA', (105, 128))	('tumor', 'Disease', (49, 54))	('VEGF', 'Gene', '7422', (244, 248))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('198', '218'))	('secretion', 'biological_process', 'GO:0046903', ('249', '258'))	('stimulates', 'PosReg', (233, 243))	('facilitates', 'PosReg', (186, 197))	('glucose deprivation', 'Disease', 'MESH:D012892', (165, 184))	('P2x7R', 'Var', (34, 39))	('VEGF', 'Gene', (244, 248))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('glucose deprivation', 'Disease', (165, 184))
193510	27391069	Expression of ATP receptors, notably P2x7R, is thought to have profound effects on host-tumor interaction since there is now very solid proof that the tumor microenvironment (TME) is enriched in ATP.	('effects', 'Reg', (72, 79))	('host-tumor', 'Disease', 'MESH:D006086', (83, 93))	('P2x7R', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ATP', 'Chemical', 'MESH:D000255', (195, 198))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('host-tumor', 'Disease', (83, 93))
193511	27391069	In the TME this nucleotide may promote tumor growth (for example via the P2x7R) and at the same time enhance host defenses, because tumor infiltrating immune cells also express P2x7R and other nucleotide/nucleoside receptors.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('P2x7R', 'Var', (177, 182))	('enhance', 'PosReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (132, 137))	('promote', 'PosReg', (31, 38))	('tumor', 'Disease', (39, 44))	('host defenses', 'CPA', (109, 122))
193521	27391069	In all these three models, P2x7R targeting strongly reduced tumor growth.	('reduced', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('P2x7R targeting', 'Var', (27, 42))
193524	27391069	In HMCs P2x7R was virtually absent whether by conventional (Figure 1A) or qRT-PCR (Figure 1B).	('P2x7R', 'Var', (8, 13))	('HMCs', 'Gene', (3, 7))	('HMCs', 'Gene', '55034', (3, 7))
193525	27391069	In MPP89, MSTO-211H and SV40-Tag cells, P2x7R transcript expression was comparable to that of THP-1 cells, a human leukemic cell line known to express this receptor.	('MPP89', 'Var', (3, 8))	('leukemic', 'Disease', (115, 123))	('human', 'Species', '9606', (109, 114))	('leukemic', 'Disease', 'MESH:D007938', (115, 123))	('MPP', 'molecular_function', 'GO:0004240', ('3', '6'))	('THP-1', 'Gene', '2736', (94, 99))	('THP-1', 'Gene', (94, 99))	('SV40', 'Species', '1891767', (24, 28))	('MSTO-211H', 'Chemical', '-', (10, 19))
193538	27391069	At variance from this anticipation, MSTO-211H cells showed a BzATP-stimulated Ca2+ rise 4-5 fold higher than that of MPP89 cells, suggesting that in these latter cells the P2x7R might be in part sequestered intracellularly and thus not fully accessible to BzATP stimulation on the plasma membrane.	('BzATP', 'Chemical', '-', (256, 261))	('BzATP', 'Chemical', '-', (61, 66))	('MSTO-211H', 'Chemical', '-', (36, 45))	('Ca2+ rise', 'MPA', (78, 87))	('MPP', 'molecular_function', 'GO:0004240', ('117', '120'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('281', '296'))	('Ca2+', 'Chemical', 'MESH:D000069285', (78, 82))	('P2x7R', 'Var', (172, 177))
193539	27391069	In the SV40-Tag cells P2x7R stimulation triggered a Ca2+ rise in the 30-40 nM range, about twice the Ca2+ increase measured in IST-MES2 cells (15-20 nM) (Figure 2C).	('Ca2+', 'Chemical', 'MESH:D000069285', (52, 56))	('Ca2+', 'Chemical', 'MESH:D000069285', (101, 105))	('P2x7R stimulation', 'Var', (22, 39))	('Ca2+ rise in the 30-40 nM range', 'MPA', (52, 83))	('SV40', 'Species', '1891767', (7, 11))	('IST-MES2', 'Chemical', '-', (127, 135))
193540	27391069	The Ca2+ rise was almost completely obliterated by AZ10606120, except for a small and transient Ca2+ increase observed in MSTO-211H and SV-40Tag cells (Figure 2B).	('Ca2+', 'Chemical', 'MESH:D000069285', (4, 8))	('SV-40', 'Species', '1891767', (136, 141))	('Ca2+', 'Chemical', 'MESH:D000069285', (96, 100))	('AZ10606120', 'Var', (51, 61))	('AZ10606120', 'Chemical', 'MESH:C000602458', (51, 61))	('MSTO-211H', 'Chemical', '-', (122, 131))	('Ca2+ rise', 'MPA', (4, 13))
193541	27391069	We also analyzed the expression of other P2XRs and P2YRs, but only P2x4R, P2Y2R and P2Y11R were expressed albeit to a very low level (not shown).	('P2x4R', 'Gene', '5025', (67, 72))	('P2x4R', 'Gene', (67, 72))	('P2Y2R', 'Gene', (74, 79))	('P2Y2R', 'Gene', '5029', (74, 79))	('P2Y11R', 'Var', (84, 90))	('P2Y', 'molecular_function', 'GO:0045028', ('74', '77'))	('P2Y', 'molecular_function', 'GO:0045028', ('84', '87'))
193543	27391069	It is worth noting that SV40-Tag cells showed a growth kinetic that was twice as fast as that of the other MPM cell lines.	('SV40-Tag', 'Var', (24, 32))	('growth', 'MPA', (48, 54))	('SV40', 'Species', '1891767', (24, 28))
193544	27391069	As shown in panels 3A-3E, the five different mesothelial cell lines used in this study showed striking morphological differences: HMC were thin, flattened and very large (over 40 mum in diameter and 100 mum in length), with a typical mesothelial shape; SV40-Tag were fibroblast-like and about 40 mum in length.	('SV40-Tag', 'Var', (253, 261))	('SV40', 'Species', '1891767', (253, 257))	('mum', 'Gene', '56925', (203, 206))	('mum', 'Gene', (296, 299))	('mum', 'Gene', '56925', (296, 299))	('mum', 'Gene', '56925', (179, 182))	('mum', 'Gene', (203, 206))	('mum', 'Gene', (179, 182))
193550	27391069	P2XR7 blockade by the highly selective antagonist AZ10606120 or by the less specific covalent blocker oxidized ATP (oxoATP) inhibited proliferation and increased LDH release.	('P2XR7', 'Enzyme', (0, 5))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('AZ10606120', 'Chemical', 'MESH:C000602458', (50, 60))	('oxoATP', 'Chemical', 'MESH:C017199', (116, 122))	('increased', 'PosReg', (152, 161))	('AZ10606120', 'Var', (50, 60))	('ATP', 'Chemical', 'MESH:D000255', (111, 114))	('LDH release', 'MPA', (162, 173))	('proliferation', 'CPA', (134, 147))	('inhibited', 'NegReg', (124, 133))
193551	27391069	MSTO-211H cell proliferation was fully blocked by oxoATP or by AZ10606120, but contrary to the other cell types BzATP showed growth-promoting activity (Figure 4E-4F).	('BzATP', 'Chemical', '-', (112, 117))	('AZ10606120', 'Var', (63, 73))	('AZ10606120', 'Chemical', 'MESH:C000602458', (63, 73))	('growth-promoting activity', 'CPA', (125, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('10', '28'))	('MSTO-211H', 'Gene', (0, 9))	('oxoATP', 'Chemical', 'MESH:C017199', (50, 56))	('MSTO-211H', 'Chemical', '-', (0, 9))
193554	27391069	In this cell type, AZ10606120 caused a severe reduction in cell number in the absence of significant LDH release, suggesting an apoptotic process.	('reduction', 'NegReg', (46, 55))	('AZ10606120', 'Chemical', 'MESH:C000602458', (19, 29))	('cell number', 'CPA', (59, 70))	('apoptotic process', 'biological_process', 'GO:0006915', ('128', '145'))	('LDH release', 'MPA', (101, 112))	('AZ10606120', 'Var', (19, 29))
193555	27391069	MPP89 cell proliferation was fully inhibited by BzATP or by oxoATP, while AZ10606120 had a negligible effect (Figure 4I-4J).	('oxoATP', 'Chemical', 'MESH:C017199', (60, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('6', '24'))	('AZ10606120', 'Chemical', 'MESH:C000602458', (74, 84))	('BzATP', 'Chemical', '-', (48, 53))	('inhibited', 'NegReg', (35, 44))	('AZ10606120', 'Var', (74, 84))	('MPP89', 'Gene', (0, 5))	('MPP', 'molecular_function', 'GO:0004240', ('0', '3'))	('BzATP', 'Var', (48, 53))
193556	27391069	BzATP, oxoATP and AZ10606120 had a small but significant cytotoxic effect in MPP89 cells.	('cytotoxic effect', 'CPA', (57, 73))	('oxoATP', 'Chemical', 'MESH:C017199', (7, 13))	('BzATP', 'Chemical', '-', (0, 5))	('AZ10606120', 'Var', (18, 28))	('MPP', 'molecular_function', 'GO:0004240', ('77', '80'))	('AZ10606120', 'Chemical', 'MESH:C000602458', (18, 28))
193561	27391069	AZ-10606120 or placebo were injected every two d after tumor mass became first detectable (d six from tumor cell inoculation), and tumor mass was assessed by caliper measurement for a total of 20 (MSTO-211H) or 15 (IST-MES2) d. For the MSTO-211H inoculum, initial kinetic of tumor growth (from post-inoculum d 6 to d 10) was due both to the increase in cell number and to the tumor-associated edema (Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('increase', 'PosReg', (341, 349))	('tumor', 'Disease', (275, 280))	('tumor', 'Disease', (376, 381))	('tumor', 'Disease', (131, 136))	('IST-MES2', 'Chemical', '-', (215, 223))	('MSTO-211H', 'Var', (236, 245))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('edema', 'Phenotype', 'HP:0000969', (393, 398))	('MSTO-211H', 'Chemical', '-', (236, 245))	('MSTO-211H', 'Chemical', '-', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('cell number', 'CPA', (353, 364))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('edema', 'Disease', 'MESH:D004487', (393, 398))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('edema', 'Disease', (393, 398))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (55, 60))
193564	27391069	Treatment with AZ10606120 significantly inhibited the kinetic of tumor growth, leading to a 50% reduction of tumor size at the time of excision (Figure 5A-5C), thus confirming the strong growth inhibitory effect observed in vitro.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('inhibited', 'NegReg', (40, 49))	('AZ10606120', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('AZ10606120', 'Chemical', 'MESH:C000602458', (15, 25))	('reduction', 'NegReg', (96, 105))	('tumor', 'Disease', (109, 114))	('kinetic', 'MPA', (54, 61))
193569	27391069	In the animals treated with AZ10606120 tumor regression was significantly accelerated, starting soon after drug administration.	('AZ10606120', 'Var', (28, 38))	('accelerated', 'PosReg', (74, 85))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('AZ10606120', 'Chemical', 'MESH:C000602458', (28, 38))	('tumor', 'Disease', (39, 44))
193581	27391069	However, despite this perturbing factor, AZ10606120-treated mice showed a more localized and fainter luminescence emission whether recorded from a ventral or a dorsal projection, suggesting a reduced diffusion of the tumor cells in the peritoneal cavity.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('fainter', 'NegReg', (93, 100))	('AZ10606120-treated', 'Var', (41, 59))	('diffusion', 'CPA', (200, 209))	('AZ10606120', 'Chemical', 'MESH:C000602458', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mice', 'Species', '10090', (60, 64))	('reduced', 'NegReg', (192, 199))
193585	27391069	Signalling via extracellular ATP has a major role in supporting cell growth and differentiation by activating the P2YRs or P2XRs.	('activating', 'PosReg', (99, 109))	('ATP', 'Chemical', 'MESH:D000255', (29, 32))	('extracellular', 'cellular_component', 'GO:0005576', ('15', '28'))	('supporting cell growth', 'CPA', (53, 75))	('differentiation', 'CPA', (80, 95))	('Signalling', 'biological_process', 'GO:0023052', ('0', '10'))	('P2XRs', 'Var', (123, 128))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('P2YRs', 'Var', (114, 119))
193586	27391069	P2YRs have been traditionally credited with growth-promoting activity, as they are G- protein-coupled, and thus linked to phosphoinositide hydrolysis, Ca2+ mobilization from intracellular stores and activation of the MAPK pathway.	('Ca2+', 'Chemical', 'MESH:D000069285', (151, 155))	('growth-promoting', 'MPA', (44, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('217', '221'))	('intracellular', 'cellular_component', 'GO:0005622', ('174', '187'))	('P2YRs', 'Var', (0, 5))	('linked', 'Reg', (112, 118))	('Ca2+ mobilization from intracellular stores', 'MPA', (151, 194))	('phosphoinositide hydrolysis', 'MPA', (122, 149))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('phosphoinositide', 'Chemical', 'MESH:D010716', (122, 138))	('MAPK pathway', 'Pathway', (217, 229))
193587	27391069	under stimulation by locally-released ATP, the P2x7R promotes a trophic response, without the untoward effects due to indiscriminate large pore opening.	('promotes', 'PosReg', (53, 61))	('ATP', 'Chemical', 'MESH:D000255', (38, 41))	('P2x7R', 'Var', (47, 52))	('pore', 'cellular_component', 'GO:0046930', ('139', '143'))	('trophic response', 'CPA', (64, 80))	('trophic response', 'Phenotype', 'HP:0010834', (64, 80))
193588	27391069	Tonic, low intensity, P2x7R activation stabilizes the mitochondrial network, and increases mitochondrial membrane potential, the Ca2+ content of the mitochondrial matrix and the overall efficiency of the oxidative phosphorylation, with the end result of increasing the total cellular ATP content.	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('91', '113'))	('Ca2+ content', 'MPA', (129, 141))	('P2x7R', 'Var', (22, 27))	('oxidative phosphorylation', 'MPA', (204, 229))	('increasing', 'PosReg', (254, 264))	('mitochondrial matrix', 'cellular_component', 'GO:0005759', ('149', '169'))	('mitochondrial membrane potential', 'MPA', (91, 123))	('mitochondrial network', 'CPA', (54, 75))	('cellular ATP content', 'MPA', (275, 295))	('Ca2+', 'Chemical', 'MESH:D000069285', (129, 133))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('204', '229'))	('stabilizes', 'Reg', (39, 49))	('ATP', 'Chemical', 'MESH:D000255', (284, 287))	('increases', 'PosReg', (81, 90))
193589	27391069	P2x7R expression also stimulates the Warburg effect, increasing glycolytic ATP generation as well as availability of carbon species for anapleurotic processes.	('increasing', 'PosReg', (53, 63))	('stimulates', 'PosReg', (22, 32))	('glycolytic ATP generation', 'MPA', (64, 89))	('carbon', 'Chemical', 'MESH:D002244', (117, 123))	('Warburg', 'MPA', (37, 44))	('P2x7R expression', 'Var', (0, 16))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))	('availability of carbon species', 'MPA', (101, 131))
193590	27391069	Thus, it appears that P2x7R enhances ATP generation via both the mitochondrial and glycolytic pathways, and in addition increases availability of building blocks for synthetic processes.	('ATP', 'Chemical', 'MESH:D000255', (37, 40))	('mitochondrial', 'Pathway', (65, 78))	('availability', 'MPA', (130, 142))	('P2x7R', 'Var', (22, 27))	('glycolytic pathways', 'Pathway', (83, 102))	('ATP generation', 'MPA', (37, 51))	('enhances', 'PosReg', (28, 36))	('increases', 'PosReg', (120, 129))
193591	27391069	Besides fueling energy metabolism, P2x7R also increases invasiveness and metastatic ability of cancer cells.	('P2x7R', 'Var', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('invasiveness', 'CPA', (56, 68))	('cancer', 'Disease', (95, 101))	('increases', 'PosReg', (46, 55))	('metabolism', 'biological_process', 'GO:0008152', ('23', '33'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
193592	27391069	Given these P2x7R activities, it is not surprising that most, although but by no means all, malignant tumors so far tested overexpress P2x7R.	('P2x7R', 'Var', (135, 140))	('malignant tumors', 'Disease', (92, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('overexpress', 'PosReg', (123, 134))	('malignant tumors', 'Disease', 'MESH:D018198', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
193594	27391069	In fact, HMCs kept under conditions of limited nutrient supply have a very slow growth rate over a 72 incubation time, and accordingly express little P2x7R, whether at the protein or mRNA level.	('HMCs', 'Gene', '55034', (9, 13))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('slow', 'NegReg', (75, 79))	('P2x7R', 'Var', (150, 155))	('little', 'NegReg', (143, 149))	('growth', 'MPA', (80, 86))	('slow growth', 'Phenotype', 'HP:0001510', (75, 86))	('HMCs', 'Gene', (9, 13))
193599	27391069	We tested the effect of the highly selective P2x7R drug-like antagonist AZ10606120 in three different in vivo settings: nude/nude mice inoculated s.c. with MSTO-211H or IST-MES2 cells, or i.p.	('nude mice', 'Species', '10090', (125, 134))	('MSTO-211H', 'Chemical', '-', (156, 165))	('AZ10606120', 'Var', (72, 82))	('tested', 'Reg', (3, 9))	('IST-MES2', 'Chemical', '-', (169, 177))	('AZ10606120', 'Chemical', 'MESH:C000602458', (72, 82))
193600	27391069	In both cases we observed a large reduction of tumor growth in the AZ10606120-treated host.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('reduction', 'NegReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AZ10606120-treated', 'Var', (67, 85))	('tumor', 'Disease', (47, 52))	('AZ10606120', 'Chemical', 'MESH:C000602458', (67, 77))
193617	27391069	The P2x7R inhibitor AZ10606120 (Tocris Bioscience, Ellisville, MS, USA) was dissolved as a stock solution of 100 mM in DMSO, and used for all in vitro and in vivo experiments at a final concentration of 300 nM in sterile PBS (EuroClone).	('Tocris Bioscience', 'Disease', (32, 49))	('Tocris Bioscience', 'Disease', 'None', (32, 49))	('DMSO', 'Chemical', 'MESH:D004121', (119, 123))	('AZ10606120', 'Chemical', 'MESH:C000602458', (20, 30))	('PBS', 'Chemical', 'MESH:D007854', (221, 224))	('AZ10606120', 'Var', (20, 30))
193627	27391069	Samples were run in triplicate in an AB StepOne Real Time PCR (Applied Biosystems) with TaqMan Gene Expression Master Mix (Applied Biosystems) using the following TaqMan probes: NM_002562.5 (P2x7R, Life Technologies) and NM_001101.2 (human beta-actin, Applied Biosystems).	('human', 'Species', '9606', (234, 239))	('Mix', 'Gene', (118, 121))	('Gene Expression', 'biological_process', 'GO:0010467', ('95', '110'))	('Mix', 'Gene', '83881', (118, 121))	('NM_002562.5', 'Var', (178, 189))	('NM_001101.2', 'Var', (221, 232))	('beta-actin', 'Gene', '728378', (240, 250))	('beta-actin', 'Gene', (240, 250))
193778	21858171	Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing.	('p21', 'Gene', (171, 174))	('piroxicam', 'Chemical', 'MESH:D010894', (114, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('p21', 'Gene', '1026', (81, 84))	('apoptotic', 'CPA', (18, 27))	('p21', 'Gene', '1026', (171, 174))	('p21', 'Gene', (81, 84))	('silencing', 'Var', (175, 184))
193796	21858171	In particular, NS398 produced a significant reduction of proliferation level in MM cell lines, while celecoxib resulted efficient in inhibiting mesothelioma cell growth.	('NS398', 'Chemical', 'MESH:C080955', (15, 20))	('inhibiting', 'NegReg', (133, 143))	('mesothelioma', 'Disease', (144, 156))	('celecoxib', 'Chemical', 'MESH:D000068579', (101, 110))	('reduction', 'NegReg', (44, 53))	('NS398', 'Var', (15, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('proliferation', 'CPA', (57, 70))	('cell growth', 'biological_process', 'GO:0016049', ('157', '168'))
193803	21858171	We associated apoptosis activation of the combined treatment to p21 expression, since apoptosis enhancement is impared upon silencing of p21.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('silencing', 'Var', (124, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('p21', 'Gene', '1026', (64, 67))	('p21', 'Gene', '1026', (137, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('p21', 'Gene', (64, 67))	('p21', 'Gene', (137, 140))
193819	21858171	We were unable to detect differentially expressed genes upon cisplatin treatment, thus supporting the hypothesis that the cisplatin-induced cytotoxicity might be enhanced by piroxicam through the modulation of specific endogenous effectors as for the previously described HtrA1 - a serine protease that acts as a tumor suppressor-like protein.	('modulation', 'Var', (196, 206))	('tumor', 'Disease', (313, 318))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('piroxicam', 'Chemical', 'MESH:D010894', (174, 183))	('HtrA1', 'Gene', '5654', (272, 277))	('protein', 'cellular_component', 'GO:0003675', ('335', '342'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('313', '329'))	('cytotoxicity', 'Disease', (140, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('313', '329'))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('enhanced', 'PosReg', (162, 170))	('HtrA1', 'Gene', (272, 277))	('cisplatin-induced', 'MPA', (122, 139))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('cytotoxicity', 'Disease', 'MESH:D064420', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
193832	21858171	As shown in Figure 5A, we detected an increase of p53 levels in cisplatin treatment, probably related to the cisplatin-induced cellular stress that acts through nuclear DNA binding, as well as in piroxicam/cisplatin treatment.	('increase', 'PosReg', (38, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('cisplatin', 'Var', (64, 73))	('DNA binding', 'molecular_function', 'GO:0003677', ('169', '180'))	('piroxicam', 'Chemical', 'MESH:D010894', (196, 205))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
193846	21858171	Figure 7 shows that upon p21 silencing, cisplatin single treatment induced apoptosis activation comparable with untreated cells, while we observed a marked decrease in the percentage (70%) of apoptotic cells in combined treatment (Figure 7A).	('p21', 'Gene', (25, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('silencing', 'Var', (29, 38))	('apoptosis', 'CPA', (75, 84))	('activation', 'PosReg', (85, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('decrease', 'NegReg', (156, 164))	('p21', 'Gene', '1026', (25, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
193851	21858171	Microarray analyses revealed that the majority of transcription changes was detected after 24 hours treatment with piroxicam or with piroxicam/cisplatin and that the functional classes most affected by these changes are associated to cancer, cell cycle, cellular growth and proliferation.	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('piroxicam', 'Chemical', 'MESH:D010894', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('changes', 'Var', (208, 215))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('cellular growth', 'biological_process', 'GO:0016049', ('254', '269'))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cellular growth', 'CPA', (254, 269))	('piroxicam', 'Chemical', 'MESH:D010894', (115, 124))	('transcription', 'MPA', (50, 63))	('cell cycle', 'CPA', (242, 252))	('cancer', 'Disease', (234, 240))	('cell cycle', 'biological_process', 'GO:0007049', ('242', '252'))	('proliferation', 'CPA', (274, 287))
193884	21858171	Specifically the presence of differential expression at transcriptional level of p21 upon the P/C combined treatment prompted us to hypothesize a role of p21 in the effects induced by the combined treatment.	('expression', 'MPA', (42, 52))	('p21', 'Gene', '1026', (81, 84))	('p21', 'Gene', '1026', (154, 157))	('p21', 'Gene', (81, 84))	('p21', 'Gene', (154, 157))	('P/C', 'Var', (94, 97))
193885	21858171	Although silencing of p21 impairs the functionality of the P/C combined treatment, reinforcing the idea of an involvement of p21 in the mechanism of action of P/C treatment, p21 transcription changes are not translated at protein level.	('p21', 'Gene', (174, 177))	('impairs', 'NegReg', (26, 33))	('p21', 'Gene', '1026', (125, 128))	('silencing', 'Var', (9, 18))	('p21', 'Gene', '1026', (22, 25))	('transcription', 'biological_process', 'GO:0006351', ('178', '191'))	('p21', 'Gene', (125, 128))	('p21', 'Gene', (22, 25))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('p21', 'Gene', '1026', (174, 177))	('functionality', 'MPA', (38, 51))
193957	19091133	Both agents were reduced on day 8 to 25% in the event of grade 3 leukopenia and/or the thrombopenia between 99 x 109/L and 50 x 109/L.	('leukopenia', 'Disease', 'MESH:D007970', (65, 75))	('leukopenia', 'Disease', (65, 75))	('thrombopenia', 'Disease', 'MESH:D013921', (87, 99))	('50 x 109/L', 'Var', (123, 133))	('leukopenia', 'Phenotype', 'HP:0001882', (65, 75))	('thrombopenia', 'Disease', (87, 99))
194077	29346042	Recent studies suggest that the loss of the BRCA1-associated protein (BAP1) and deletion of p16 seen in mesothelioma but not reactive mesothelial cells could be useful adjuncts for cytologic diagnosis of mesothelioma.	('p16', 'Gene', (92, 95))	('deletion', 'Var', (80, 88))	('loss', 'NegReg', (32, 36))	('BAP1', 'Gene', '8314', (70, 74))	('BRCA1-associated protein', 'Gene', (44, 68))	('mesothelioma', 'Disease', (104, 116))	('BRCA1-associated protein', 'Gene', '8315', (44, 68))	('BAP1', 'Gene', (70, 74))	('p16', 'Gene', '1029', (92, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('mesothelioma', 'Disease', (204, 216))	('mesothelioma', 'Disease', 'MESH:D008654', (204, 216))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
194127	29346042	The frequencies of mutations of TP53, SETD2, and NF2 were different in the four clusters.	('NF2', 'Gene', (49, 52))	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (38, 43))	('NF2', 'Gene', '4771', (49, 52))	('TP53', 'Gene', (32, 36))	('SETD2', 'Gene', (38, 43))
194188	29346042	Modified RECIST did not alter the tumor response classification criteria (the actual numeric values) that separate response categories (partial response, stable disease, and progressive disease); in fact, with the exception of the measurement acquisition approach previously described, modified RECIST implicitly adopted all other aspects of RECIST (and, by extension, the more recent RECIST 1.1).	('modified', 'Var', (286, 294))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
194336	29346042	Survival was shorter for patients with concurrent N1/N2 disease (13 months) than those with only N1 or N2 disease (17 and 16 months, respectively).	('N1/N2 disease', 'Var', (50, 63))	('shorter', 'NegReg', (13, 20))	('Survival', 'MPA', (0, 8))	('patients', 'Species', '9606', (25, 33))
194481	29346042	The first experience with IMRT after EPP showed that the V5, V20, and mean lung dose (MLD) were associated with the development of pneumonitis.	('associated with', 'Reg', (96, 111))	('pneumonitis', 'Disease', (131, 142))	('V20', 'Var', (61, 64))	('MLD', 'Disease', 'MESH:D007966', (86, 89))	('MLD', 'Disease', (86, 89))	('pneumonitis', 'Disease', 'MESH:D011014', (131, 142))
194484	29346042	After lung-sparing P/D and adjuvant tomotherapy, the contralateral lung V5 has been associated with the risk of radiation pneumonitis.	('radiation pneumonitis', 'Disease', 'MESH:D017564', (112, 133))	('associated', 'Reg', (84, 94))	('P/D', 'Var', (19, 22))	('radiation pneumonitis', 'Disease', (112, 133))
194571	32894005	Thus, using cell blocks prepared from the pleural effusion, p16 homozygous deletion was confirmed by p16 fluorescence in situ hybridization because 45% of the tumor cells showed loss of both p16 gene signals.	('p16', 'Gene', (60, 63))	('p16', 'Gene', '1029', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('p16', 'Gene', '1029', (191, 194))	('deletion', 'Var', (75, 83))	('pleural effusion', 'Disease', 'MESH:D010996', (42, 58))	('pleural effusion', 'Phenotype', 'HP:0002202', (42, 58))	('pleural effusion', 'Disease', (42, 58))	('p16', 'Gene', '1029', (60, 63))	('tumor', 'Disease', (159, 164))	('p16', 'Gene', (101, 104))	('p16', 'Gene', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('loss', 'NegReg', (178, 182))
194669	24963429	Resection of the colon and ileum revealed a T3N0 colonic mucinous adenocarcinoma and concurrent diffuse malignant peritoneal mesothelioma.	('T3N0', 'Var', (44, 48))	('peritoneal mesothelioma', 'Disease', (114, 137))	('colonic mucinous adenocarcinoma', 'Disease', (49, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (114, 137))	('colonic mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (49, 80))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (114, 137))
194791	24963429	Changes in tumor suppressor gene and/or oncogene could have field effect involving multiple organs.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('oncogene', 'Gene', (40, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
194793	24963429	Adenomatous polyposis coli (APC) gene has mutation in approximately 80% colon adenocarcinoma.	('Adenomatous polyposis coli', 'Disease', (0, 26))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (0, 26))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (0, 26))	('APC', 'cellular_component', 'GO:0005680', ('28', '31'))	('colon adenocarcinoma', 'Disease', (72, 92))	('APC', 'Phenotype', 'HP:0005227', (28, 31))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (72, 92))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('mutation', 'Var', (42, 50))	('APC', 'Disease', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
194795	24963429	Genetic alteration may have played an important role in tumorigenesis of both tumors in our case.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Genetic alteration', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
194845	24179709	GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells.	('2B4', 'Gene', '51744', (145, 148))	('CD4', 'Gene', '920', (46, 49))	('DNAM-1', 'Gene', '10666', (153, 159))	('2B4', 'Gene', (145, 148))	('CD4', 'Gene', (46, 49))	('GC1008', 'Var', (0, 6))	('expression', 'MPA', (131, 141))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))	('GC1008', 'Chemical', 'MESH:C560928', (0, 6))	('decrease', 'NegReg', (115, 123))	('DNAM-1', 'Gene', (153, 159))
194866	24179709	Although this small number of patients precluded any definitive conclusions about the clinical efficacy and safety of this approach, we were able to obtain serum and peripheral blood mononuclear cells (PBMC) from the majority of these patients before and after receiving the anti-TGFbeta antibody.	('anti-TGFbeta', 'Gene', (275, 287))	('anti-TGFbeta', 'Var', (275, 287))	('antibody', 'cellular_component', 'GO:0019815', ('288', '296'))	('antibody', 'cellular_component', 'GO:0019814', ('288', '296'))	('patients', 'Species', '9606', (235, 243))	('antibody', 'molecular_function', 'GO:0003823', ('288', '296'))	('patients', 'Species', '9606', (30, 38))	('antibody', 'cellular_component', 'GO:0042571', ('288', '296'))
194892	24179709	After treatment with GC1008, TGFbeta levels detected by ELISA markedly decreased (Fig.	('TGFbeta levels detected', 'MPA', (29, 52))	('decreased', 'NegReg', (71, 80))	('GC1008', 'Chemical', 'MESH:C560928', (21, 27))	('GC1008', 'Var', (21, 27))
194913	24179709	The administration of GC1008 did not alter any of these markers, with the exception of a significant decrease in the levels of 2B4 and DNAM1 (Table 2; Table S3).	('GC1008', 'Var', (22, 28))	('2B4', 'Gene', (127, 130))	('rat', 'Species', '10116', (12, 15))	('GC1008', 'Chemical', 'MESH:C560928', (22, 28))	('DNAM1', 'Gene', (135, 140))	('2B4', 'Gene', '51744', (127, 130))	('DNAM1', 'Gene', '10666', (135, 140))	('decrease', 'NegReg', (101, 109))	('levels', 'MPA', (117, 123))
194928	24179709	We also observed one patient who exhibited rapid tumor growth after being given GC1008.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Disease', (49, 54))	('GC1008', 'Var', (80, 86))	('GC1008', 'Chemical', 'MESH:C560928', (80, 86))
194930	24179709	It is conceivable- that in a small minority of tumors- TGFbeta inhibitory pathways are still intact and that removal of these signals by the antibody results in "release of inhibition" with subsequent rapid tumor growth.	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('tumors- TGFbeta', 'Disease', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))	('inhibitory pathways', 'Pathway', (63, 82))	('removal', 'Var', (109, 116))	('tumors- TGFbeta', 'Disease', 'MESH:D009369', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))	('tumor', 'Disease', (47, 52))
194939	24179709	One hypothesis that might explain potential antineoplastic activity of GC1008 is that blockade of TGFbeta would release tumor-induced immunosuppression and induce of anti-tumor immune responses.	('GC1008', 'Chemical', 'MESH:C560928', (71, 77))	('release', 'PosReg', (112, 119))	('TGFbeta', 'Gene', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('induce', 'Reg', (156, 162))	('blockade', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (120, 125))
194941	24179709	Furthermore, at least in vitro, anti-TGFbeta antibodies can upregulate these receptors from patients with chronic viral infection.	('chronic viral infection', 'Disease', (106, 129))	('chronic viral infection', 'Disease', 'MESH:D001102', (106, 129))	('anti-TGFbeta', 'Gene', (32, 44))	('anti-TGFbeta antibodies', 'Var', (32, 55))	('upregulate', 'PosReg', (60, 70))	('patients', 'Species', '9606', (92, 100))	('viral infection', 'biological_process', 'GO:0016032', ('114', '129'))	('antibodies', 'Var', (45, 55))
194949	24179709	Finally, as TGFbeta has been implicated in the formation of Tregs and blockade of TGFbeta in animal models inhibited their formation, we measured the frequency of circulating CD4+ Tregs (marked by expression of FOXP3) in the blood of healthy volunteers and MPM patients before and after treatment with GC1008.	('patients', 'Species', '9606', (261, 269))	('FOXP3', 'Gene', '50943', (211, 216))	('CD4', 'Gene', '920', (175, 178))	('TGFbeta', 'Gene', (82, 89))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))	('circulating CD4+ Tregs', 'Phenotype', 'HP:0030336', (163, 185))	('FOXP3', 'Gene', (211, 216))	('blockade', 'Var', (70, 78))	('inhibited', 'NegReg', (107, 116))	('GC1008', 'Chemical', 'MESH:C560928', (302, 308))	('CD4', 'Gene', (175, 178))	('MPM', 'Chemical', '-', (257, 260))
194961	24179709	Taken together, our data are consistent with the hypothesis that blockade of TGFbeta can lead to local anti-tumor immune responses, in at least a subpopulation of subjects, and that induction of anti-tumor immunity may be associated with increased survival.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('TGFbeta', 'Gene', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('local', 'MPA', (97, 102))	('lead to', 'Reg', (89, 96))	('tumor', 'Disease', (200, 205))	('survival', 'CPA', (248, 256))	('tumor', 'Disease', (108, 113))	('increased', 'PosReg', (238, 247))	('blockade', 'Var', (65, 73))
194966	24179709	GC1008 was generally well tolerated in pretreated MPM patients; however, there was a suggestion that blockade of TGFbeta might support the growth of susceptible premalignant or malignant cells in a minority of subjects.	('blockade', 'Var', (101, 109))	('patients', 'Species', '9606', (54, 62))	('TGFbeta', 'Gene', (113, 120))	('growth', 'CPA', (139, 145))	('rat', 'Species', '10116', (30, 33))	('MPM', 'Chemical', '-', (50, 53))	('support', 'PosReg', (127, 134))	('GC1008', 'Chemical', 'MESH:C560928', (0, 6))
194970	24179709	Importantly, our data do not exclude the possibility that anti-TGFbeta antibodies may be effectively combined with immunotherapeutic regimens that activate cellular immunity (i.e., anticancer vaccines, antibodies specific for CTLA4 or PD-1), resulting in the elicitation of potent antitumor immune responses.	('PD-1', 'Gene', '5133', (235, 239))	('activate', 'PosReg', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('cellular immunity', 'CPA', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('CTLA4', 'Gene', (226, 231))	('tumor', 'Disease', (285, 290))	('antibodies', 'Var', (202, 212))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PD-1', 'Gene', (235, 239))	('CTLA4', 'Gene', '1493', (226, 231))	('cancer', 'Disease', (185, 191))	('elicitation', 'Reg', (259, 270))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
194986	24179709	PF4 is released in significant amounts from platelets as a result of activation and was therefore used as a surrogate marker to assess the quality of samples in which the presence of TGFbeta may be due to platelet degranulation related to sample processing.	('due', 'Reg', (198, 201))	('PF4', 'Gene', (0, 3))	('TGFbeta', 'Gene', (183, 190))	('presence', 'Var', (171, 179))	('PF4', 'Gene', '5196', (0, 3))	('platelet degranulation', 'biological_process', 'GO:0002576', ('205', '227'))
195072	22576592	Our estimate of lifetime cost to the NHI also corroborates with another study using claims data from a single tertiary care medical centre in Taiwan during 1999-2002; the undiscounted average cost up to 10 years for lung cancer was NT$ 448 371 (1US$ = NT$ 33 in 2002), which is equivalent to US$16 703 in 2010.	('lung cancer', 'Disease', (216, 227))	('NT$ 448 371', 'Var', (232, 243))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))
195093	21955916	First somatic mutation of E2F1 in a critical DNA binding residue discovered in well-differentiated papillary mesothelioma of the peritoneum Well differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare variant of epithelial mesothelioma of low malignancy potential, usually found in women with no history of asbestos exposure.	('WDPMP', 'Chemical', '-', (202, 207))	('epithelial mesothelioma of low malignancy', 'Disease', 'MESH:C562839', (230, 271))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('epithelial mesothelioma of low malignancy', 'Disease', (230, 271))	('mutation', 'Var', (14, 22))	('E2F1', 'Gene', '1869', (26, 30))	('asbestos', 'Chemical', 'MESH:D001194', (325, 333))	('E2F1', 'Gene', (26, 30))	('DNA binding', 'molecular_function', 'GO:0003677', ('45', '56'))	('women', 'Species', '9606', (300, 305))	('Well differentiated papillary mesothelioma of the', 'Disease', (140, 189))
195095	21955916	WDPMP exome sequencing reveals the first somatic mutation of E2F1, R166H, to be identified in human cancer.	('WDPMP', 'Chemical', '-', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('R166H', 'Var', (67, 72))	('R166H', 'Mutation', 'rs864622017', (67, 72))	('human', 'Species', '9606', (94, 99))	('cancer', 'Disease', (100, 106))	('E2F1', 'Gene', (61, 65))
195096	21955916	We show that the R166H mutation abrogates E2F1's DNA binding ability and is associated with reduced activation of E2F1 downstream target genes.	('E2F1', 'Gene', (42, 46))	('DNA binding', 'molecular_function', 'GO:0003677', ('49', '60'))	('DNA binding', 'Interaction', (49, 60))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('abrogates', 'NegReg', (32, 41))	('reduced', 'NegReg', (92, 99))	('R166H', 'Mutation', 'rs864622017', (17, 22))	('activation', 'PosReg', (100, 110))	('R166H', 'Var', (17, 22))
195097	21955916	The R166H mutation in E2F1 is shown to have a deleterious effect on its DNA binding ability as well as increasing its stability and subsequent accumulation in R166H mutant cells.	('accumulation', 'PosReg', (143, 155))	('DNA binding', 'molecular_function', 'GO:0003677', ('72', '83'))	('R166H', 'Mutation', 'rs864622017', (159, 164))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('R166H', 'Var', (159, 164))	('DNA binding', 'Interaction', (72, 83))	('increasing', 'PosReg', (103, 113))	('E2F1', 'Gene', (22, 26))	('stability', 'MPA', (118, 127))	('R166H', 'Mutation', 'rs864622017', (4, 9))	('R166H', 'Var', (4, 9))
195098	21955916	Based on the results, two compatible theories can be formed: R166H mutation appears to allow for protein over-expression while minimizing the apoptotic consequence and the R166H mutation may behave similarly to SV40 large T antigen, inhibiting tumor suppressive functions of retinoblastoma protein 1.	('R166H', 'Var', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('protein', 'cellular_component', 'GO:0003675', ('290', '297'))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('tumor', 'Disease', (244, 249))	('inhibiting', 'NegReg', (233, 243))	('apoptotic', 'CPA', (142, 151))	('R166H', 'Mutation', 'rs864622017', (61, 66))	('retinoblastoma', 'Phenotype', 'HP:0009919', (275, 289))	('protein', 'Protein', (97, 104))	('minimizing', 'NegReg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('R166H mutation', 'Var', (61, 75))	('R166H', 'Mutation', 'rs864622017', (172, 177))	('retinoblastoma', 'Disease', 'MESH:D012175', (275, 289))	('retinoblastoma', 'Disease', (275, 289))
195103	21955916	We demonstrate that while this WDPMP tumor does not exhibit any of the chromosomal aberrations and focal deletions commonly associated with asbestos-related mesothelioma, it does exhibit the first reported somatic single nucleotide mutation of E2F1 (E2F transcription factor 1) in cancer, with the mutation affecting one of two evolutionarily conserved arginine residues responsible for motif recognition and DNA binding.	('DNA binding', 'molecular_function', 'GO:0003677', ('409', '420'))	('arginine', 'Chemical', 'MESH:D001120', (353, 361))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('WDPMP', 'Chemical', '-', (31, 36))	('affecting', 'Reg', (307, 316))	('asbestos', 'Chemical', 'MESH:D001194', (140, 148))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('DNA', 'cellular_component', 'GO:0005574', ('409', '412'))	('transcription', 'biological_process', 'GO:0006351', ('254', '267'))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (71, 94))	('E2F1', 'Gene', (244, 248))	('single nucleotide mutation', 'Var', (214, 240))	('E2F transcription factor 1', 'Gene', (250, 276))	('transcription factor', 'molecular_function', 'GO:0000981', ('254', '274'))	('cancer', 'Disease', (281, 287))	('tumor', 'Disease', (37, 42))	('E2F transcription factor 1', 'Gene', '1869', (250, 276))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
195106	21955916	Figure 2 shows the Hilbert plots of the sequenced tumor, tumor-derived cell line and normal blood sample exomes, revealing some systemic capturing biases but no deletion/amplification events, with particular attention paid to known somatic deletions of 3p21, 9p13~21 and 22q associated with loss of RASSF1A (RAS association family 1A), CDKN2A (cyclin-dependent kinase inhibitor 2A) and NF2 (neurofibromin 2) genes, respectively, in malignant mesothelioma.	('malignant mesothelioma', 'Disease', (432, 454))	('RAS association family 1A', 'Gene', (308, 333))	('RASSF1A', 'Gene', (299, 306))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (432, 454))	('loss', 'NegReg', (291, 295))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (344, 380))	('deletions', 'Var', (240, 249))	('neurofibromin 2', 'Gene', '4771', (391, 406))	('CDKN2A', 'Gene', (336, 342))	('neurofibromin 2', 'Gene', (391, 406))	('tumor', 'Disease', (57, 62))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('361', '377'))	('tumor', 'Disease', (50, 55))	('NF2', 'Gene', '4771', (386, 389))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NF2', 'Gene', (386, 389))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (432, 454))	('CDKN2A', 'Gene', '1029', (336, 342))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('344', '377'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('RAS association family 1A', 'Gene', '11186', (308, 333))	('RASSF1A', 'Gene', '11186', (299, 306))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (344, 380))
195109	21955916	Nineteen potential somatic mutations remain and these were validated using Sanger sequencing (Additional file 2); E2F1, PPFIBP2 (liprin beta 2) and TRAF7 (TNF receptor-associated factor 7) were validated to contain true somatic mutations (Additional file 3).	('TRAF7', 'Gene', (148, 153))	('TNF receptor-associated factor 7', 'Gene', (155, 187))	('TNF receptor-associated factor 7', 'Gene', '84231', (155, 187))	('liprin beta 2', 'Gene', '8495', (129, 142))	('TRAF7', 'Gene', '84231', (148, 153))	('liprin beta 2', 'Gene', (129, 142))	('PPFIBP2', 'Gene', (120, 127))	('PPFIBP2', 'Gene', '8495', (120, 127))	('E2F1', 'Var', (114, 118))
195110	21955916	The E2F1 R166H somatic mutation is of particular interest as there is no reported mutation of the E2F1 gene in cancer.	('R166H', 'Mutation', 'rs864622017', (9, 14))	('R166H', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('E2F1', 'Gene', (98, 102))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('E2F1', 'Gene', (4, 8))
195114	21955916	The E2F4 DNA binding structure was used as an adequate representation of its E2F1 counterpart due to the conserved status of the R165-R166 residues across the E2F paralogues (Figure 3, bottom right) as well as the affected residue being a part of the winged-helix DNA-binding motif observed across the whole E2F family of transcription factors.	('R165-R166', 'Var', (129, 138))	('E2F4', 'Gene', '1874', (4, 8))	('DNA binding', 'molecular_function', 'GO:0003677', ('9', '20'))	('DNA', 'cellular_component', 'GO:0005574', ('264', '267'))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('transcription', 'biological_process', 'GO:0006351', ('322', '335'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('264', '275'))	('E2F4', 'Gene', (4, 8))
195115	21955916	The arginine residues of E2F4 and its dimerization partner DP are responsible for DNA binding (Figure 4, top) and the analysis clearly shows R166 as one of four arginine residues contacting the DNA target (Figure 4, bottom).	('E2F4', 'Gene', '1874', (25, 29))	('DNA binding', 'molecular_function', 'GO:0003677', ('82', '93'))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('arginine', 'Chemical', 'MESH:D001120', (161, 169))	('binding', 'Interaction', (86, 93))	('arginine', 'Chemical', 'MESH:D001120', (4, 12))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('R166', 'Var', (141, 145))	('responsible', 'Reg', (66, 77))	('E2F4', 'Gene', (25, 29))
195117	21955916	Figure 5 (top) shows the modeling of the E2F1 mutant and wild-type DNA binding domain; Calculation of individual residue energy using ANOLEA (Atomic Non-Local Environment Assessment) and GROMOS (Groningen Molecular Simulation) indicated that the mutant histidine's predicted position and conformation were still favorable as indicated by the negative energy value (Figure 5, bottom).	('DNA binding', 'molecular_function', 'GO:0003677', ('67', '78'))	('histidine', 'Chemical', 'MESH:D006639', (253, 262))	('mutant', 'Var', (246, 252))	('mutant', 'Var', (46, 52))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('E2F1', 'Gene', (41, 45))
195118	21955916	While there is a difference in the size and charge between the mutant histidine and wild-type arginine residue coupled with a conformational shift at the mutated position, the overall three-dimensional structure of the domain appears minimally affected by the mutation.	('conformational', 'MPA', (126, 140))	('histidine', 'Chemical', 'MESH:D006639', (70, 79))	('mutant', 'Var', (63, 69))	('difference', 'Reg', (17, 27))	('arginine', 'Chemical', 'MESH:D001120', (94, 102))
195119	21955916	In order to conclusively show the effect of the R166H mutation on DNA binding, chromatin immunoprecipitation (ChIP) assays targeting the SIRT1 (sirtuin 1) and APAF1 (apoptotic peptidase activating factor 1) promoters using the MSTO-211H cell line over-expressing E2F1 (wild type and mutant) were performed.	('apoptotic peptidase activating factor 1', 'Gene', '317', (166, 205))	('sirtuin 1', 'Gene', '23411', (144, 153))	('DNA binding', 'molecular_function', 'GO:0003677', ('66', '77'))	('apoptotic peptidase activating factor 1', 'Gene', (166, 205))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('sirtuin 1', 'Gene', (144, 153))	('R166H', 'Mutation', 'rs864622017', (48, 53))	('MSTO-211H', 'CellLine', 'CVCL:1430', (227, 236))	('R166H', 'Var', (48, 53))
195120	21955916	The ChIP result indicates that the R166H mutation has a detrimental effect on E2F1's DNA binding ability.	('R166H', 'Mutation', 'rs864622017', (35, 40))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('R166H', 'Var', (35, 40))	('E2F1', 'Gene', (78, 82))	('DNA binding', 'Interaction', (85, 96))	('DNA binding', 'molecular_function', 'GO:0003677', ('85', '96'))
195121	21955916	To show that the R166H mutant's reduced DNA binding affinity affected the expression of E2F1 target genes, the expression of SIRT1, APAF1 and CCNE1 (cyclin E1) was examined by real-time PCR in MSTO-211H and NCI-H28 cell lines that were transfected with the E2F1 mutant or wild type.	('expression', 'MPA', (74, 84))	('NCI-H28', 'CellLine', 'CVCL:1555', (207, 214))	('R166H', 'Mutation', 'rs864622017', (17, 22))	('MSTO-211H', 'CellLine', 'CVCL:1430', (193, 202))	('cyclin E1', 'Gene', (149, 158))	('affected', 'Reg', (61, 69))	('reduced', 'NegReg', (32, 39))	('DNA binding', 'molecular_function', 'GO:0003677', ('40', '51'))	('CCNE1', 'Gene', '898', (142, 147))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('DNA', 'Protein', (40, 43))	('cyclin', 'molecular_function', 'GO:0016538', ('149', '155'))	('CCNE1', 'Gene', (142, 147))	('R166H', 'Var', (17, 22))	('cyclin E1', 'Gene', '898', (149, 158))
195123	21955916	In particular, levels of SIRT1 and APAF1 expression in MSTO-211H cells observed with E2F1-R166H were significantly lower than those with the E2F1 wild type (P = 0.032 for SIRT1 and P = 0.005 for APAF1).	('APAF1', 'Gene', (35, 40))	('R166H', 'Mutation', 'rs864622017', (90, 95))	('levels', 'MPA', (15, 21))	('lower', 'NegReg', (115, 120))	('E2F1-R166H', 'Var', (85, 95))	('SIRT1', 'MPA', (25, 30))	('MSTO-211H', 'CellLine', 'CVCL:1430', (55, 64))
195126	21955916	Clearly, the levels of expression of the E2F1 wild type and mutant were similar when normalized to EGFP levels (Additional file 4), indicating that the transfection efficiency of E2F1-R166H is not different from that of the wild type.	('transfection', 'CPA', (152, 164))	('E2F1-R166H', 'Var', (179, 189))	('R166H', 'Mutation', 'rs864622017', (184, 189))
195127	21955916	To monitor E2F1 protein stability, we over-expressed the E2F1 wild type and mutant in MSTO-211H cells before treating the cells with 25 mug/ml cyclohexamide to block new protein synthesis in half hour intervals.	('cyclohexamide', 'Chemical', '-', (143, 156))	('over-expressed', 'PosReg', (38, 52))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('mutant', 'Var', (76, 82))	('E2F1', 'Gene', (57, 61))	('mug', 'molecular_function', 'GO:0043739', ('136', '139'))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('protein synthesis', 'biological_process', 'GO:0006412', ('170', '187'))	('block', 'NegReg', (160, 165))	('MSTO-211H', 'CellLine', 'CVCL:1430', (86, 95))
195128	21955916	This result suggests that the mutant protein is more stable and resistant to degradation than the wild type and the increased stability of E2F1-R166H is the cause of its accumulation within cells over-expressing it.	('stability', 'MPA', (126, 135))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('E2F1-R166H', 'Var', (139, 149))	('degradation', 'biological_process', 'GO:0009056', ('77', '88'))	('more', 'PosReg', (48, 52))	('R166H', 'Mutation', 'rs864622017', (144, 149))	('increased', 'PosReg', (116, 125))	('accumulation', 'PosReg', (170, 182))
195130	21955916	Although E2F1-R166H does not show a significant effect on regulating cell proliferation, it is possible that the mutation is advantageous to cancer cells as it does not inhibit cell growth when the mutant is highly expressed in cells.	('E2F1-R166H', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cell growth', 'biological_process', 'GO:0016049', ('177', '188'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('cancer', 'Disease', (141, 147))	('R166H', 'Mutation', 'rs864622017', (14, 19))
195135	21955916	The Y621D mutation in TRAF7 occurs in the WD40 repeat domain, which has been shown to be involved in MEKK3-induced activator protein 1 (AP1) activation.	('activator protein 1', 'Gene', '3726', (115, 134))	('MEKK3', 'molecular_function', 'GO:0004709', ('101', '106'))	('AP1', 'Gene', (136, 139))	('AP1', 'cellular_component', 'GO:0005907', ('136', '139'))	('activator protein 1', 'Gene', (115, 134))	('Y621D', 'Var', (4, 9))	('TRAF7', 'Gene', (22, 27))	('Y621D', 'Mutation', 'p.Y621D', (4, 9))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('MEKK3', 'Gene', '4215', (101, 106))	('MEKK3', 'Gene', (101, 106))	('TRAF7', 'Gene', '84231', (22, 27))	('AP1', 'Gene', '3726', (136, 139))
195136	21955916	Since AP1 in turn controls a large number of cellular processes involved in differentiation, proliferation and apoptosis, this mutation in TRAF7's WD40 repeat domain may de-regulate MEKK3's control over AP1 activation, which may contribute to WDPMP transformation.	('AP1', 'Gene', '3726', (203, 206))	('WDPMP', 'Chemical', '-', (243, 248))	('TRAF7', 'Gene', (139, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('contribute', 'Reg', (229, 239))	('WDPMP', 'Disease', (243, 248))	('AP1', 'Gene', (6, 9))	('mutation', 'Var', (127, 135))	('MEKK3', 'molecular_function', 'GO:0004709', ('182', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('AP1', 'Gene', (203, 206))	('AP1', 'cellular_component', 'GO:0005907', ('203', '206'))	('MEKK3', 'Gene', '4215', (182, 187))	('MEKK3', 'Gene', (182, 187))	('TRAF7', 'Gene', '84231', (139, 144))	('de-regulate', 'NegReg', (170, 181))	('AP1', 'cellular_component', 'GO:0005907', ('6', '9'))	('AP1', 'Gene', '3726', (6, 9))
195139	21955916	However, the Q791H mutation in PPFIBP2 is predicted by Polyphen to be benign and the Catalogue of Somatic Mutations in Cancer (COSMIC) did not show this particular mutation to occur in other cancers; thus, this mutation is likely to be of a passenger variety.	('PPFIBP2', 'Gene', '8495', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('Cancer', 'Disease', (119, 125))	('cancers', 'Disease', (191, 198))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Q791H', 'Var', (13, 18))	('Q791H', 'Mutation', 'p.Q791H', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('PPFIBP2', 'Gene', (31, 38))
195140	21955916	Using various bioinformatics tools, this mutation was identified to mutate an arginine residue into a histidine residue, thus altering a critical evolutionarily conserved DNA contact point responsible for DNA binding and motif recognition.	('binding', 'Interaction', (209, 216))	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('altering', 'Reg', (126, 134))	('DNA binding', 'molecular_function', 'GO:0003677', ('205', '216'))	('histidine', 'Chemical', 'MESH:D006639', (102, 111))	('mutate', 'Var', (68, 74))	('mutation', 'Var', (41, 49))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))
195141	21955916	Since computational modeling is sufficient to pinpoint the mutation's structural location but is inconclusive in showing the mutation's functional effect on DNA binding, we performed a ChIP assay that showed the R166H mutation abrogates E2F1 DNA binding.	('DNA binding', 'molecular_function', 'GO:0003677', ('157', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('R166H', 'Mutation', 'rs864622017', (212, 217))	('DNA binding', 'molecular_function', 'GO:0003677', ('242', '253'))	('R166H', 'Var', (212, 217))	('E2F1', 'Protein', (237, 241))	('abrogates', 'NegReg', (227, 236))
195144	21955916	Our study has also shown that the R166H mutant is much more stable than its wild-type counterpart, enabling massive accumulation within the cell.	('R166H', 'Mutation', 'rs864622017', (34, 39))	('R166H', 'Var', (34, 39))	('accumulation', 'MPA', (116, 128))
195145	21955916	E2F1-/- mice can grow to maturity and reproduce normally but display a predisposition to develop various cancers, indicating the greater importance of the tumor suppressive function of E2F1 compared to its cell cycle gene activation function.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cell cycle', 'biological_process', 'GO:0007049', ('206', '216'))	('tumor', 'Disease', (155, 160))	('E2F1', 'Var', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('develop', 'PosReg', (89, 96))	('mice', 'Species', '10090', (8, 12))
195146	21955916	An alternative but not mutually exclusive explanation is that stable and numerous E2F1-R166H proteins behave functionally like SV40 large T antigens, serving as competitive inhibitors by taking up the lion's share of the binding capacity of retinoblastoma protein 1 (Rb), resulting in unbound wild-type E2F1, which drives the cell cycle.	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('retinoblastoma', 'Disease', 'MESH:D012175', (241, 255))	('retinoblastoma', 'Disease', (241, 255))	('cell cycle', 'biological_process', 'GO:0007049', ('326', '336'))	('unbound wild-type', 'MPA', (285, 302))	('retinoblastoma', 'Phenotype', 'HP:0009919', (241, 255))	('drives', 'Reg', (315, 321))	('lion', 'Species', '9689', (201, 205))	('E2F1-R166H', 'Var', (82, 92))	('binding', 'Interaction', (221, 228))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('cell cycle', 'CPA', (326, 336))	('E2F1', 'Gene', (303, 307))	('R166H', 'Mutation', 'rs864622017', (87, 92))
195147	21955916	While the R166H mutation cripples E2F1's DNA binding ability, its other interaction domains, including the Rb interaction domain, are still active.	('DNA binding', 'Interaction', (41, 52))	('DNA binding', 'molecular_function', 'GO:0003677', ('41', '52'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('E2F1', 'Gene', (34, 38))	('R166H', 'Mutation', 'rs864622017', (10, 15))	('R166H', 'Var', (10, 15))
195148	21955916	The mutant's stability and large quantities will favor its preferential binding to Rb due to its sheer numbers and the heterozygous nature of the mutation in the WDPMP tumor would ensure active copies of wild-type E2F1 were present to drive the cell cycle.	('preferential', 'PosReg', (59, 71))	('tumor', 'Disease', (168, 173))	('WDPMP', 'Chemical', '-', (162, 167))	('binding', 'Interaction', (72, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('245', '255'))	('cell cycle', 'CPA', (245, 255))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutation', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
195149	21955916	created an E2F1-E132 mutant that is artificially mutated in position 132 within E2F1's DNA binding domain and that was demonstrated to have lost its DNA binding capacity, like our R166H mutant; Halaban et al.	('R166H', 'Mutation', 'rs864622017', (180, 185))	('DNA binding', 'molecular_function', 'GO:0003677', ('87', '98'))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('E2F1', 'Gene', (80, 84))	('E2F1-E132', 'Var', (11, 20))	('lost', 'NegReg', (140, 144))	('DNA binding', 'Interaction', (149, 160))	('DNA binding', 'molecular_function', 'GO:0003677', ('149', '160'))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))
195150	21955916	demonstrated that expression of the E2F1-E132 mutant can induce a partially transformed phenotype by conferring growth factor-independent cell cycle progression in mice melanocytes.	('cell cycle', 'biological_process', 'GO:0007049', ('138', '148'))	('growth factor-independent cell cycle progression', 'CPA', (112, 160))	('mice', 'Species', '10090', (164, 168))	('partially transformed phenotype', 'CPA', (66, 97))	('induce', 'PosReg', (57, 63))	('E2F1-E132', 'Var', (36, 45))
195153	21955916	A p16 null cell has already lost its G1/S checkpoint control; thus, introducing another mutation that will cause the same checkpoint loss will not cause noticeable growth differences.	('mutation', 'Var', (88, 96))	('p16', 'Gene', '1029', (2, 5))	('G1/S checkpoint control', 'MPA', (37, 60))	('p16', 'Gene', (2, 5))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('37', '52'))
195156	21955916	On the other hand, E2F1 also plays an important role in the activation of apoptosis pathways, and the R166H mutation, with its abrogated DNA binding, may contribute to the survival of the cancer cell harboring this mutation.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('60', '83'))	('apoptosis pathways', 'Pathway', (74, 92))	('survival', 'CPA', (172, 180))	('contribute', 'Reg', (154, 164))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('60', '83'))	('abrogated', 'NegReg', (127, 136))	('R166H', 'Mutation', 'rs864622017', (102, 107))	('cancer', 'Disease', (188, 194))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('R166H', 'Var', (102, 107))	('DNA binding', 'molecular_function', 'GO:0003677', ('137', '148'))	('DNA binding', 'Interaction', (137, 148))
195157	21955916	It would be worth checking the remaining 28% of MPMs without CDKN2A deletion for possible mutations in E2F1 and other related genes.	('CDKN2A', 'Gene', '1029', (61, 67))	('CDKN2A', 'Gene', (61, 67))	('E2F1', 'Gene', (103, 107))	('deletion', 'Var', (68, 76))
195158	21955916	It is interesting to note that BAP1 (BRCA1 associated protein-1), a nuclear deubiquitinase affecting E2F and Polycomb target genes, was recently shown to be inactivated by somatic mutations in 23% of MPMs, suggesting that the genes within the E2F pathways might play an important role in mesothelioma in general.	('mutations', 'Var', (180, 189))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('BAP1', 'Gene', '8314', (31, 35))	('BRCA1 associated protein-1', 'Gene', '8314', (37, 63))	('MPMs', 'Gene', (200, 204))	('BAP1', 'Gene', (31, 35))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('76', '90'))	('BRCA1 associated protein-1', 'Gene', (37, 63))	('mesothelioma', 'Disease', (288, 300))
195159	21955916	We have performed the first exome sequencing of a WDPMP tumor and a matched control sample and a tumor-derived cell line and discovered the first somatic mutation of E2F1, R166H.	('R166H', 'Var', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('E2F1', 'Gene', (166, 170))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (97, 102))	('WDPMP', 'Chemical', '-', (50, 55))	('R166H', 'Mutation', 'rs864622017', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
195160	21955916	Large accumulation of the mutant protein is observed in over-expression studies and this is due to a great increase in protein stability as shown by a cyclohexamide chase assay.	('protein stability', 'MPA', (119, 136))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('accumulation', 'PosReg', (6, 18))	('increase', 'PosReg', (107, 115))	('cyclohexamide', 'Chemical', '-', (151, 164))	('mutant', 'Var', (26, 32))	('protein', 'Protein', (33, 40))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
195161	21955916	Overall, two compatible theories can explain the observed results: first, E2F1-R166H decreases apoptosis and its abrogated cell cycle role is compensated for by other members of its family; and second, heterozygous E2F1-R166H behaves like SV-40 large T antigen, interfering with the tumor suppressive role of Rb and allowing its wild-type counterpart to drive cell division.	('cell cycle', 'CPA', (123, 133))	('decreases', 'NegReg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('allowing', 'Reg', (316, 324))	('apoptosis', 'CPA', (95, 104))	('interfering', 'NegReg', (262, 273))	('E2F1-R166H', 'Var', (215, 225))	('E2F1-R166H', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('tumor', 'Disease', (283, 288))	('drive cell division', 'CPA', (354, 373))	('R166H', 'Mutation', 'rs864622017', (79, 84))	('cell cycle', 'biological_process', 'GO:0007049', ('123', '133'))	('R166H', 'Mutation', 'rs864622017', (220, 225))	('cell division', 'biological_process', 'GO:0051301', ('360', '373'))
195175	21955916	This pipeline was performed for tumor, normal sample and cell line exomes and only SNVs that had a quality/depth score > 3 and were present in both the tumor and cell line and not in the normal sample were retained; SNVs in this final pool were considered to be candidate somatic mutations.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SNVs', 'Var', (216, 220))	('tumor', 'Disease', (32, 37))
195176	21955916	The validation PCR primers were (where F and R stand for forward and reverse, respectively): E2F1_F, 5' GCAGCCACAGTGGGTATTACT 3'; E2F1_R, 5' GGGGAGAAGTCACGCTATGA 3'; TRAF7_F, 5' GCCTTGCTCAGTGTCTTTGA 3'; TRAF7_R, 5' CATGTTGTCCATACTCCAGACC 3'; PPFIBP2_F, 5' CCCTCGAGCCATTTGTATTT 3'; PPFIBP2_R, 5' CCACAGCAGAAGCTGAAAGA 3'.	('PPFIBP2', 'Gene', (242, 249))	('TRAF7', 'Gene', (166, 171))	('PPFIBP2', 'Gene', '8495', (281, 288))	('TRAF7', 'Gene', '84231', (203, 208))	('TRAF7', 'Gene', '84231', (166, 171))	('E2F1_F', 'Var', (93, 99))	('PPFIBP2', 'Gene', '8495', (242, 249))	('PPFIBP2', 'Gene', (281, 288))	('E2F1_R', 'Var', (130, 136))	('TRAF7', 'Gene', (203, 208))
195179	21955916	Full-length wild-type and mutant E2F1 were amplified using iProof DNA polymerase (Bio-Rad) and E2F1 primers.	('Rad', 'Gene', (86, 89))	('E2F1', 'Gene', (33, 37))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('Rad', 'biological_process', 'GO:1990116', ('86', '89'))	('mutant', 'Var', (26, 32))	('Rad', 'Gene', '6236', (86, 89))
195181	21955916	Plasmids expressing wild-type E2F1 (pcDNA6-E2F1) or mutant E2F1 (pcDNA6-E2F1/R166H) were validated by dideoxy terminator sequencing.	('pcDNA6-E2F1', 'Gene', '1869', (36, 47))	('pcDNA6-E2F1', 'Gene', (36, 47))	('mutant', 'Var', (52, 58))	('R166H', 'Mutation', 'rs864622017', (77, 82))	('pcDNA6-E2F1', 'Gene', '1869', (65, 76))	('pcDNA6-E2F1', 'Gene', (65, 76))	('E2F1', 'Gene', (59, 63))
195197	21955916	MSTO-211H cells were transfected with 4 mug of wild-type E2F1 or E2F1-R166H in a 99-mm dish.	('E2F1', 'Var', (57, 61))	('mug', 'molecular_function', 'GO:0043739', ('40', '43'))	('MSTO-211H', 'CellLine', 'CVCL:1430', (0, 9))	('R166H', 'Mutation', 'rs864622017', (70, 75))	('E2F1-R166H', 'Var', (65, 75))
195200	21955916	Proliferation rates for cells over-expressing wild-type E2F1 and E2F1-R166H were assessed using the colorimetric 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazoluim assay according to the manufacturer's protocol (MTS; Promega).	('3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazoluim', 'Chemical', '-', (113, 198))	('E2F1', 'Var', (56, 60))	('R166H', 'Mutation', 'rs864622017', (70, 75))	('E2F1-R166H', 'Var', (65, 75))
195201	21955916	AP1: activator protein 1; BWA: Burrows-Wheeler Aligner; ChIP: chromatin immunoprecipitation; DP: E2F dimerization partner; E2F1: E2F transcription factor 1; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; MEKK3: mitogen-activated protein kinase kinase kinase 3; MPM: malignant peritoneal mesothelioma; ORF: open reading frame; PPFIBP2: liprin beta 2; Rb: retinoblastoma protein 1; SNP: single nucleotide polymorphism; SNV: single nucleotide variant; TRAF7: TNF receptor-associated factor 7; WDPMP: well differentiated papillary mesothelioma of the peritoneum.	('retinoblastoma', 'Disease', (398, 412))	('malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (310, 343))	('single nucleotide variant', 'Var', (466, 491))	('activator protein 1', 'Gene', '3726', (5, 24))	('AP1', 'Gene', (0, 3))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (206, 246))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (206, 246))	('E2F transcription factor 1', 'Gene', '1869', (129, 155))	('PPFIBP2', 'Gene', (370, 377))	('GAPDH', 'Gene', '2597', (199, 204))	('mitogen-activated protein kinase kinase kinase 3', 'Gene', '4215', (255, 303))	('PPFIBP2', 'Gene', '8495', (370, 377))	('transcription factor', 'molecular_function', 'GO:0000981', ('133', '153'))	('TRAF7', 'Gene', '84231', (493, 498))	('WDPMP', 'Chemical', '-', (534, 539))	('protein', 'cellular_component', 'GO:0003675', ('413', '420'))	('retinoblastoma', 'Disease', 'MESH:D012175', (398, 412))	('chromatin', 'cellular_component', 'GO:0000785', ('62', '71'))	('GAPDH', 'Gene', (199, 204))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('liprin beta 2', 'Gene', (379, 392))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (320, 343))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('activator protein 1', 'Gene', (5, 24))	('MEKK3', 'molecular_function', 'GO:0004709', ('248', '253'))	('AP1', 'cellular_component', 'GO:0005907', ('0', '3'))	('liprin beta 2', 'Gene', '8495', (379, 392))	('TRAF7', 'Gene', (493, 498))	('MEKK3', 'Gene', '4215', (248, 253))	('malignant peritoneal mesothelioma', 'Disease', (310, 343))	('MEKK3', 'Gene', (248, 253))	('E2F transcription factor 1', 'Gene', (129, 155))	('TNF receptor-associated factor 7', 'Gene', (500, 532))	('mitogen-activated protein kinase kinase kinase 3', 'Gene', (255, 303))	('retinoblastoma', 'Phenotype', 'HP:0009919', (398, 412))	('TNF receptor-associated factor 7', 'Gene', '84231', (500, 532))	('AP1', 'Gene', '3726', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('273', '280'))
195202	21955916	CKO participated in the design and interpretation and carried out the initial isolation of mutant E2F1 from the tumor and cell line for downstream studies.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('E2F1', 'Gene', (98, 102))	('tumor', 'Disease', (112, 117))	('mutant', 'Var', (91, 97))
195209	21124760	Our data indicate that ERbeta knockdown in ER positive cells confers a more invasive phenotype, increases anchorage independent proliferation and elevates the constitutive activation of EGFR-coupled signal transduction pathways.	('anchorage independent proliferation', 'CPA', (106, 141))	('signal transduction', 'biological_process', 'GO:0007165', ('199', '218'))	('invasive phenotype', 'CPA', (76, 94))	('constitutive', 'MPA', (159, 171))	('increases', 'PosReg', (96, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('186', '190'))	('elevates', 'PosReg', (146, 154))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (186, 190))	('ERbeta', 'Gene', (23, 29))	('knockdown', 'Var', (30, 39))
195232	21124760	Here we found that ERbeta expression significantly reduced the number and the size of colonies that MSTO-211H cells formed when cultured for 7 days in soft agar.	('reduced', 'NegReg', (51, 58))	('expression', 'Var', (26, 36))	('ERbeta', 'Gene', (19, 25))	('agar', 'Chemical', 'MESH:D000362', (156, 160))	('number', 'CPA', (63, 69))	('MSTO-211H', 'CellLine', 'CVCL:1430', (100, 109))
195235	21124760	Silencing of ERbeta expression in REN cells resulted in increased EGFR, Akt and ERK1/2 phosphorylation without a change in the total abundance of the proteins.	('Akt', 'Gene', '207', (72, 75))	('increased', 'PosReg', (56, 65))	('Akt', 'Gene', (72, 75))	('EGFR', 'Gene', (66, 70))	('REN', 'Gene', '5972', (34, 37))	('EGFR', 'Gene', '1956', (66, 70))	('REN', 'Gene', (34, 37))	('ERbeta', 'Gene', (13, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))	('phosphorylation', 'MPA', (87, 102))	('ERK1', 'molecular_function', 'GO:0004707', ('80', '84'))	('Silencing', 'Var', (0, 9))	('ERK1/2', 'Pathway', (80, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
195237	21124760	2B) revealed that silencing of ERbeta resulted in the loss of contact inhibition by the REN cells, which allowed them to form dense foci rather than a confluent monolayer.	('ERbeta', 'Gene', (31, 37))	('silencing', 'Var', (18, 27))	('contact inhibition', 'biological_process', 'GO:0060242', ('62', '80'))	('loss', 'NegReg', (54, 58))	('REN', 'Gene', (88, 91))	('contact inhibition', 'MPA', (62, 80))	('REN', 'Gene', '5972', (88, 91))
195239	21124760	Suppression of ERbeta resulted in significant remodeling of the actin structure within the REN cells, with a transition from a largely cortical actin polymerization pattern to a highly defined stress fibers organization.	('transition', 'Reg', (109, 119))	('Suppression', 'Var', (0, 11))	('remodeling', 'Reg', (46, 56))	('REN', 'Gene', (91, 94))	('ERbeta', 'Gene', (15, 21))	('actin polymerization', 'biological_process', 'GO:0030041', ('144', '164'))	('REN', 'Gene', '5972', (91, 94))	('actin structure', 'MPA', (64, 79))
195244	21124760	Here we show that the proliferation of REN cells is promoted by EGF treatment; while transfection of REN cells with the ERbeta expression plasmid significantly (p<0.05) inhibited the proliferation rate of these cells both under basal conditions and following EGF exposure (Fig.	('EGF', 'molecular_function', 'GO:0005154', ('64', '67'))	('EGF', 'Gene', (259, 262))	('REN', 'Gene', (101, 104))	('EGF', 'Gene', (64, 67))	('transfection', 'Var', (85, 97))	('proliferation rate', 'CPA', (183, 201))	('REN', 'Gene', (39, 42))	('EGF', 'Gene', '1950', (259, 262))	('EGF', 'Gene', '1950', (64, 67))	('REN', 'Gene', '5972', (101, 104))	('REN', 'Gene', '5972', (39, 42))	('inhibited', 'NegReg', (169, 178))	('EGF', 'molecular_function', 'GO:0005154', ('259', '262'))
195269	21124760	Mutations in EGFR-TK domain have been associated with response in patients with metastatic NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('associated', 'Reg', (38, 48))	('response', 'Disease', (54, 62))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('patients', 'Species', '9606', (66, 74))
195270	21124760	The prevalence of such mutations in mesothelioma is presently unknown but it seems that they are very rare in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('mesothelioma', 'Disease', (110, 122))	('mutations', 'Var', (23, 32))	('mesothelioma', 'Disease', (36, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))
195274	21124760	The silencing of ERbeta expression rendered the cells more sensitive to EGFR antagonism, suggesting that the loss of ERbeta expression resulted in a greater reliance of the cells upon EGFR-coupled signaling pathways to support proliferation.	('reliance', 'MPA', (157, 165))	('ERbeta', 'Gene', (117, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'molecular_function', 'GO:0005006', ('184', '188'))	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', '1956', (184, 188))	('greater', 'PosReg', (149, 156))	('loss', 'NegReg', (109, 113))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('EGFR', 'Gene', (72, 76))	('EGFR', 'Gene', (184, 188))	('ERbeta', 'Gene', (17, 23))	('silencing', 'Var', (4, 13))
195277	21124760	The basal level of phosphorylated EGFR was increased in both cell types upon EGF treatment and this resulted in increased Akt and ERK1/2 phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('EGF', 'Gene', (77, 80))	('EGFR', 'Gene', (34, 38))	('ERK1/2', 'Pathway', (130, 136))	('treatment', 'Var', (81, 90))	('phosphorylation', 'MPA', (137, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGF', 'Gene', '1950', (77, 80))	('Akt', 'Gene', '207', (122, 125))	('EGF', 'Gene', (34, 37))	('increased', 'PosReg', (112, 121))	('EGF', 'molecular_function', 'GO:0005154', ('77', '80'))	('increased', 'PosReg', (43, 52))	('EGF', 'Gene', '1950', (34, 37))	('Akt', 'Gene', (122, 125))	('ERK1', 'molecular_function', 'GO:0004707', ('130', '134'))	('EGFR', 'Gene', '1956', (34, 38))
195286	21124760	The modulation of cell cycle regulating proteins through ERbeta is compatible with rapidly induced signaling and ablation of ERbeta impacts upon the activation but not the expression of multiple signaling intermediates in the MMe cells including Akt and Erk1/2.	('ERbeta', 'Gene', (125, 131))	('impacts', 'Reg', (132, 139))	('Akt', 'Gene', '207', (246, 249))	('Erk1', 'molecular_function', 'GO:0004707', ('254', '258'))	('Erk1/2', 'Gene', (254, 260))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('Akt', 'Gene', (246, 249))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('ablation', 'Var', (113, 121))	('activation', 'MPA', (149, 159))	('cell cycle', 'biological_process', 'GO:0007049', ('18', '28'))	('Erk1/2', 'Gene', '5595;5594', (254, 260))
195295	21124760	The monoclonal antibody specific for Akt and the phosphorylation site-specific polyclonal antibodies for ERK1 (pThr202 and pTyr204), ERK2 (pThr185 and pTyr187) MAP kinases, and Akt (pSer473 and pThr308) were from Cell Signaling Technology (Beverly, MA).	('pThr308', 'Chemical', '-', (194, 201))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('pTyr187', 'Chemical', '-', (151, 158))	('MAP', 'molecular_function', 'GO:0004239', ('160', '163'))	('pTyr187', 'Var', (151, 158))	('pTyr204', 'Chemical', '-', (123, 130))	('Akt', 'Gene', (37, 40))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('ERK1', 'Gene', (105, 109))	('pThr185', 'Chemical', '-', (139, 146))	('pSer473', 'Chemical', '-', (182, 189))	('Akt', 'Gene', '207', (37, 40))	('Akt', 'Gene', (177, 180))	('ERK2', 'Gene', '5594', (133, 137))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('Akt', 'Gene', '207', (177, 180))	('Signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('pThr185', 'Var', (139, 146))	('ERK1', 'Gene', '5595', (105, 109))	('pThr202', 'Var', (111, 118))	('ERK2', 'Gene', (133, 137))	('ERK2', 'molecular_function', 'GO:0004707', ('133', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('ERK1', 'molecular_function', 'GO:0004707', ('105', '109'))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('pSer473', 'Var', (182, 189))
195308	21124760	Cells were extracted with NP-40 lysis buffer (1% NP-40, 150 mM NaCl, 50 mM Tris-HCl pH 8, 5 mM EDTA, 10 mM NaF, 10 mM Na4P2O7, 0.4 mM Na3VO4, 10 microg/ml leupeptin, 4 microg/ml pepstatin and 0.1 Unit/ml aprotinin).	('NP-40', 'Chemical', 'MESH:C010615', (26, 31))	('Na3VO4', 'Chemical', '-', (134, 140))	('NP-40', 'Chemical', 'MESH:C010615', (49, 54))	('lysis', 'biological_process', 'GO:0019835', ('32', '37'))	('pepstatin', 'Chemical', 'MESH:C031375', (178, 187))	('NaCl', 'Chemical', 'MESH:D012965', (63, 67))	('NaF', 'Gene', '3576', (107, 110))	('Tris-HCl', 'Chemical', '-', (75, 83))	('NaF', 'Gene', (107, 110))	('leupeptin', 'Chemical', 'MESH:C032854', (155, 164))	('EDTA', 'Chemical', 'MESH:D004492', (95, 99))	('Na4P2O7', 'Var', (118, 125))	('Na4P2O7', 'Chemical', 'MESH:C107241', (118, 125))
195373	21151527	Most useful markers in our experience from MM are calretinin and D2-40 and negative reaction for CEA, MOC-31, and TTF-1.	('CEA', 'Gene', '1048', (97, 100))	('CEA', 'Gene', (97, 100))	('calretinin', 'Gene', '794', (50, 60))	('TTF-1', 'Gene', (114, 119))	('TTF-1', 'Gene', '7270', (114, 119))	('calretinin', 'Gene', (50, 60))	('MOC-31', 'Gene', (102, 108))	('D2-40', 'Var', (65, 70))
195390	29797583	Also, this route of administration may not result in an adequate local concentration of GM-CSF in the tumors.20 Thus, engineering the viral genome with the gene encoding GM-CSF reduces the risk of toxicities, ensuring desired local levels of GM-CSF to improve the induction of antitumor immunity.	('tumors', 'Disease', (102, 108))	('engineering', 'Var', (118, 129))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('toxicities', 'Disease', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (281, 286))	('toxicities', 'Disease', 'MESH:D064420', (197, 207))	('improve', 'PosReg', (252, 259))
195391	29797583	Ranki et al16, 17 reported the results of a Phase I study (NCT01598129) in which ONCOS-102 (Ad5/3-Delta24-GM-CSF) was well tolerated and induced local and systemic CD8+ T-cell immunity in patients with treatment-refractory and immune-cell poor solid tumors.	('induced', 'PosReg', (137, 144))	('CD8', 'Gene', (164, 167))	('CD8', 'Gene', '925', (164, 167))	('ONCOS-102', 'Chemical', '-', (81, 90))	('patients', 'Species', '9606', (188, 196))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('ONCOS-102', 'Var', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))
195419	29797583	reported a panel of CD4+ and CD8+ T-cell epitopes that could be used to prime antigen-specific T-cells and challenge adoptively transferred T-cells in vivo.	('CD8', 'Gene', '925', (29, 32))	('CD4+', 'Var', (20, 24))	('CD8', 'Gene', (29, 32))
195546	27457872	The role of EPP within multimodality approaches was recently extensively discussed after the publication of the Mesothelioma and Radical Surgery (MARS I) trial which aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy.	('patients', 'Species', '9606', (207, 215))	('EPP', 'Var', (246, 249))	('Mesothelioma', 'Disease', (112, 124))	('Mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('trimodal', 'Chemical', '-', (278, 286))
195565	27457872	The concept of localized intracavitary cisplatin-fibrin chemotherapy after MCR is evaluated in a phase IIa trial to assess safety and toxicity of the treatment (NCT01644994 Influence Meso).	('NCT01644994', 'Var', (161, 172))	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('toxicity', 'Disease', (134, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))
195623	27069474	However, it is accepted that chrysotile can cause lung cancer in humans and malignant mesothelioma in rats.	('lung cancer', 'Disease', (50, 61))	('malignant mesothelioma', 'Disease', (76, 98))	('rats', 'Species', '10116', (102, 106))	('chrysotile', 'Var', (29, 39))	('cause', 'Reg', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (76, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('humans', 'Species', '9606', (65, 71))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (76, 98))
195638	27069474	For MPM, the CT images manifest with diffuse nodules and plaques which tend to envelop the bowel viscera or with a large tumour mass that is usually in the upper abdomen, and there may be discrete nodules scattered throughout the peritoneum.	('bowel viscera', 'Disease', 'MESH:C536351', (91, 104))	('man', 'Species', '9606', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('MPM', 'Var', (4, 7))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('bowel viscera', 'Disease', (91, 104))	('tumour', 'Disease', (121, 127))
195705	22223868	As data have emerged identifying epigenetic regulation via histones as an important mechanism in the development of mesothelioma, HDAC inhibitors have become an appealing therapy to explore for this disease.	('mesothelioma', 'Disease', (116, 128))	('epigenetic', 'Var', (33, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('histones', 'Protein', (59, 67))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))
195715	22223868	In mesothelioma cell lines, Merlin loss activates mTOR complex 1 (mTORC1) signaling, and cells with NF2 mutations are selectively sensitive to drugs targeting mTORC1.	('mTOR', 'Gene', (50, 54))	('activates', 'PosReg', (40, 49))	('mTORC1', 'Gene', (66, 72))	('mTOR', 'Gene', (66, 70))	('mTORC1', 'cellular_component', 'GO:0031931', ('159', '165'))	('mutations', 'Var', (104, 113))	('mesothelioma', 'Disease', (3, 15))	('mTOR', 'Gene', '2475', (50, 54))	('mTORC1', 'Gene', '382056', (66, 72))	('Merlin', 'Gene', (28, 34))	('NF2', 'Gene', '4771', (100, 103))	('mTOR complex', 'cellular_component', 'GO:0038201', ('50', '62'))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('mTORC1', 'Gene', (159, 165))	('NF2', 'Gene', (100, 103))	('mTOR', 'Gene', '2475', (66, 70))	('loss', 'NegReg', (35, 39))	('mTOR', 'Gene', (159, 163))	('mTORC1', 'Gene', '382056', (159, 165))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('mTOR', 'Gene', '2475', (159, 163))	('Merlin', 'Gene', '4771', (28, 34))	('mTORC1', 'cellular_component', 'GO:0031931', ('66', '72'))
195756	22223868	Consequently, several antiangiogenic agents, particularly small molecule VEGFR tyrosine kinase inhibitors, including SU5416, vatalanib, sorafenib, and sunitinib, have been studied in mesothelioma and have shown low levels of activity.	('SU5416', 'Var', (117, 123))	('sunitinib', 'Chemical', 'MESH:D000077210', (151, 160))	('mesothelioma', 'Disease', (183, 195))	('vatalanib', 'Chemical', 'MESH:C404768', (125, 134))	('VEGFR', 'Gene', '3791', (73, 78))	('sorafenib', 'Chemical', 'MESH:D000077157', (136, 145))	('SU5416', 'Chemical', 'MESH:C116890', (117, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('VEGFR', 'Gene', (73, 78))
195871	25093718	In complete conflict, low cholesterol has even been associated with a higher cancer incidence.	('low cholesterol', 'Var', (22, 37))	('cholesterol', 'Chemical', 'MESH:D002784', (26, 37))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('low cholesterol', 'Phenotype', 'HP:0003146', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
196037	23924264	Numerous in vivo studies have already demonstrated that both single-walled (SW)- and multi-walled (MW)-CNTs, when instilled into the lungs of rodents, have the potential to cause inflammation, fibrosis (scarring of the lungs) and granuloma (small nodule) formation, consistent with the pathogenic behaviors of asbestos.	('nodule) formation', 'biological_process', 'GO:0009877', ('247', '264'))	('granuloma', 'Disease', (230, 239))	('scarring', 'Phenotype', 'HP:0100699', (203, 211))	('inflammation', 'biological_process', 'GO:0006954', ('179', '191'))	('asbestos', 'Chemical', 'MESH:D001194', (310, 318))	('inflammation', 'Disease', 'MESH:D007249', (179, 191))	('multi-walled', 'Var', (85, 97))	('granuloma', 'Phenotype', 'HP:0032252', (230, 239))	('fibrosis', 'Disease', 'MESH:D005355', (193, 201))	('fibrosis', 'Disease', (193, 201))	('cause', 'Reg', (173, 178))	('inflammation', 'Disease', (179, 191))	('granuloma', 'Disease', 'MESH:D006099', (230, 239))	('rat', 'Species', '10116', (45, 48))
196057	23924264	Analysis of cell growth characteristics by Cyquant  assay shows that mesothelial cells treated with SWCNT, MWCNT, or asbestos exhibited a significantly higher growth rate than Survanta (vehicle)- or saline-treated controls (Figure 1A).	('higher', 'PosReg', (152, 158))	('MWCNT', 'Var', (107, 112))	('MWCNT', 'Chemical', '-', (107, 112))	('rat', 'Species', '10116', (166, 169))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('saline', 'Chemical', 'MESH:D012965', (199, 205))	('growth rate', 'CPA', (159, 170))	('SWCNT', 'Chemical', '-', (100, 105))	('cell growth', 'biological_process', 'GO:0016049', ('12', '23'))
196062	23924264	These results indicate that high-aspect ratio SWCNT and MWCNT, like asbestos, can induce accelerated cell growth and invasiveness, which are key cancer phenotypes that may contribute to their mesothelioma pathogenicity.	('cancer', 'Disease', (145, 151))	('invasiveness', 'CPA', (117, 129))	('asbestos', 'Chemical', 'MESH:D001194', (68, 76))	('MWCNT', 'Chemical', '-', (56, 61))	('cell growth', 'CPA', (101, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (192, 204))	('rat', 'Species', '10116', (95, 98))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('high-aspect ratio', 'Var', (28, 45))	('cell growth', 'biological_process', 'GO:0016049', ('101', '112'))	('accelerated', 'PosReg', (89, 100))	('SWCNT', 'Chemical', '-', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('mesothelioma', 'Disease', (192, 204))
196081	23924264	Together, these results indicate effective knockdown of MMP-2 expression and enzyme activity in the SWCNT, MWCNT, and asbestos-transformed mesothelial cells.	('MWCNT', 'Chemical', '-', (107, 112))	('enzyme activity', 'molecular_function', 'GO:0003824', ('77', '92'))	('expression', 'MPA', (62, 72))	('knockdown', 'Var', (43, 52))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('MMP-2', 'Gene', (56, 61))	('activity', 'MPA', (84, 92))	('MMP-2', 'molecular_function', 'GO:0004228', ('56', '61'))	('SWCNT', 'Chemical', '-', (100, 105))
196082	23924264	To determine whether MMP-2 plays a role in the aggressive behavior of CNT and asbestos-transformed cells, cell invasion and migration assays of the MMP-2 knockdown and vector-transfected control cells were performed.	('aggressive behavior', 'biological_process', 'GO:0002118', ('47', '66'))	('MMP-2', 'molecular_function', 'GO:0004228', ('148', '153'))	('MMP-2', 'Gene', (148, 153))	('knockdown', 'Var', (154, 163))	('aggressive behavior', 'Phenotype', 'HP:0000718', (47, 66))	('rat', 'Species', '10116', (127, 130))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('MMP-2', 'molecular_function', 'GO:0004228', ('21', '26'))
196083	23924264	Likewise, knocking down of MMP-2 in the CNT and asbestos-transformed cells has an inhibitory effect on the migratory activity of the cells (Figure 6B).	('rat', 'Species', '10116', (110, 113))	('knocking down', 'Var', (10, 23))	('inhibitory effect', 'NegReg', (82, 99))	('asbestos', 'Chemical', 'MESH:D001194', (48, 56))	('migratory activity of the cells', 'CPA', (107, 138))	('MMP-2', 'Gene', (27, 32))	('MMP-2', 'molecular_function', 'GO:0004228', ('27', '32'))
196117	23924264	Inhibition of MMP-2 activity by MMP-2 inhibitors has been reported to suppress local invasiveness of various carcinomas.	('activity', 'MPA', (20, 28))	('MMP-2', 'molecular_function', 'GO:0004228', ('14', '19'))	('invasiveness of various carcinomas', 'Disease', (85, 119))	('Inhibition', 'NegReg', (0, 10))	('suppress', 'NegReg', (70, 78))	('MMP-2', 'molecular_function', 'GO:0004228', ('32', '37'))	('inhibitors', 'Var', (38, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('MMP-2', 'Protein', (14, 19))	('invasiveness of various carcinomas', 'Disease', 'MESH:C566351', (85, 119))	('MMP-2', 'Gene', (32, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))
196118	23924264	Furthermore, elevated MMP-2 levels has been used for prognosis of invasive and metastatic lung cancers and the reduction of cancer cell colonization in the lung of MMP-2 deficient mice than wild-type mice has been reported.	('lung cancers', 'Disease', 'MESH:D008175', (90, 102))	('lung cancers', 'Phenotype', 'HP:0100526', (90, 102))	('reduction of cancer', 'Disease', (111, 130))	('MMP-2', 'molecular_function', 'GO:0004228', ('164', '169'))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('MMP-2', 'Gene', (164, 169))	('reduction of cancer', 'Disease', 'MESH:D009369', (111, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancers', 'Disease', (90, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('invasive', 'Disease', (66, 74))	('mice', 'Species', '10090', (180, 184))	('mice', 'Species', '10090', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('deficient', 'Var', (170, 179))	('MMP-2', 'molecular_function', 'GO:0004228', ('22', '27'))
196126	23924264	Blockade of activated STAT3 by ectopic expression of dominant negative STAT3 suppresses MMP-2 expression and invasiveness of tumor cells, inhibits tumor growth, and prevents metastasis in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('suppresses', 'NegReg', (77, 87))	('inhibits', 'NegReg', (138, 146))	('dominant negative', 'Var', (53, 70))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MMP-2', 'molecular_function', 'GO:0004228', ('88', '93'))	('tumor', 'Disease', (125, 130))	('nude mice', 'Species', '10090', (188, 197))	('prevents', 'NegReg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('STAT3', 'Gene', (71, 76))	('expression', 'MPA', (94, 104))	('MMP-2', 'Gene', (88, 93))	('metastasis', 'CPA', (174, 184))
196148	23924264	Functionally, the MMP-2 knockdown cells showed greatly reduced invasive and migratory properties as compared to their vector-transfected controls (Figure 6).	('MMP-2', 'Gene', (18, 23))	('reduced', 'NegReg', (55, 62))	('rat', 'Species', '10116', (79, 82))	('MMP-2', 'molecular_function', 'GO:0004228', ('18', '23'))	('knockdown', 'Var', (24, 33))
196198	23924264	Volcano plots were constructed using two sample t-tests assuming equal variance (p <= 0.05) with a fold-change screening (>= +- 2-fold) to identify differentially expressed genes (DEGs) for SWCNT and MWCNT compared to dispersant-treated cells, and asbestos compared to control cells.	('asbestos', 'Chemical', 'MESH:D001194', (248, 256))	('MWCNT', 'Var', (200, 205))	('MWCNT', 'Chemical', '-', (200, 205))	('SWCNT', 'Var', (190, 195))	('SWCNT', 'Chemical', '-', (190, 195))
196226	23800084	Tissue blocks were cut into 4-mum slides, deparaffinized in xylene, rehydrated with graded alcohols, and immunostained with the following antibodies: cytokeratin (CK,AE1/AE3, 1:50, DAKO), cytokeratin 5/6 (CK 5/6, 1:200, DAKO), cytokeratin7 (CK7, 1:200, DAKO), Vimentin (1:200, DAKO), CD30 (1:100, DAKO), carcino embryonic antigen (CEA, 1:100, DAKO), alpha-Fetoprofein (AFP, 1:200, DAKO), human chorionic gonadotropin beta (HCG-beta, 1:100, DAKO), thyroid transcription factor 1 (TTF-1, 1:100, DAKO), epithelial membrane antigen (EMA, 1:200, DAKO), Prostate Specific Antigen (PSA,1:100, Santa cruz), CA19-9 (1:100, Santa cruz), CA125 (1:100, Santa cruz), Calretinin (1:100, DAKO),alpha-inhibin (1:100, DAKO), PLAP (1:100, DAKO), CD117 (1:100, DAKO) and Ki67 (1:200, DAKO).	('CEA', 'Gene', (331, 334))	('PSA', 'Gene', '354', (575, 578))	('CEA', 'Gene', '5670', (331, 334))	('EMA', 'Gene', (529, 532))	('Vimentin', 'cellular_component', 'GO:0045099', ('260', '268'))	('cytokeratin 5/6 (CK 5/6', 'Gene', '3852', (188, 211))	('paraffin', 'Chemical', 'MESH:D010232', (44, 52))	('CA125', 'Gene', '94025', (627, 632))	('membrane', 'cellular_component', 'GO:0016020', ('511', '519'))	('Calretinin', 'Gene', '794', (654, 664))	('CK,AE1', 'Gene', '6521', (163, 169))	('CK7', 'Gene', '3855', (241, 244))	('carcino embryonic', 'Disease', (304, 321))	('AFP', 'Gene', (369, 372))	('AFP', 'Gene', '174', (369, 372))	('inhibin', 'molecular_function', 'GO:0016916', ('685', '692'))	('CD117', 'Gene', '3815', (728, 733))	('alpha-Fetoprofein', 'Gene', '174', (350, 367))	('cytokeratin7', 'Gene', '3855', (227, 239))	('Prostate Specific Antigen', 'Gene', '354', (548, 573))	('inhibin', 'molecular_function', 'GO:0005160', ('685', '692'))	('Prostate Specific Antigen', 'Gene', (548, 573))	('carcino embryonic', 'Disease', 'MESH:D009373', (304, 321))	('Vimentin', 'Gene', '7431', (260, 268))	('human', 'Species', '9606', (388, 393))	('transcription factor', 'molecular_function', 'GO:0000981', ('455', '475'))	('Vimentin', 'cellular_component', 'GO:0045098', ('260', '268'))	('CD30', 'Gene', (284, 288))	('TTF-1', 'Gene', '7080', (479, 484))	('CA19-9', 'Chemical', 'MESH:C086528', (599, 605))	('CD117', 'Gene', (728, 733))	('Calretinin', 'Gene', (654, 664))	('PSA', 'Gene', (575, 578))	('Ki67', 'Var', (752, 756))	('TTF-1', 'Gene', (479, 484))	('thyroid transcription factor 1', 'Gene', (447, 477))	('PLAP', 'Gene', (708, 712))	('Vimentin', 'Gene', (260, 268))	('1:100', 'Var', (735, 740))	('transcription', 'biological_process', 'GO:0006351', ('455', '468'))	('alpha-Fetoprofein', 'Gene', (350, 367))	('CA125', 'Gene', (627, 632))	('CD30', 'Gene', '943', (284, 288))	('thyroid transcription factor 1', 'Gene', '7080', (447, 477))	('EMA', 'Gene', '4582', (529, 532))	('CK7', 'Gene', (241, 244))	('cytokeratin7', 'Gene', (227, 239))	('PLAP', 'Gene', '250', (708, 712))
196243	23800084	It was reported that exposure to diethylstilbestrol could cause various degrees of papillary proliferation, hyperplasia of the epithelium and adenocarcinoma of the rete testis in the male mice; while in humans no reports of hyperplasia and adenocarcinoma were attributed to exposure to diethylstilbestrol.	('mice', 'Species', '10090', (188, 192))	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (33, 51))	('hyperplasia and adenocarcinoma', 'Disease', 'MESH:D006965', (224, 254))	('hyperplasia', 'Disease', (108, 119))	('adenocarcinoma of the rete testis', 'Disease', (142, 175))	('hyperplasia', 'Disease', 'MESH:D006965', (224, 235))	('hyperplasia', 'Disease', 'MESH:D006965', (108, 119))	('papillary proliferation', 'CPA', (83, 106))	('humans', 'Species', '9606', (203, 209))	('diethylstilbestrol', 'Var', (33, 51))	('various degrees of papillary proliferation', 'Phenotype', 'HP:0007482', (64, 106))	('adenocarcinoma of the rete testis', 'Disease', 'MESH:D013736', (142, 175))	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (286, 304))	('hyperplasia', 'Disease', (224, 235))
196355	33880588	Previous studies using microarray technology have been able to determine that ONC caused upregulation of activating transcription factor 3 (ATF3), which was important for its antitumor effect of ONC, and that PE5 caused pleiotropic effects, including gene expression changes mainly related to metabolism.	('gene expression changes', 'MPA', (251, 274))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('gene expression', 'biological_process', 'GO:0010467', ('251', '266'))	('ATF3', 'Gene', '467', (140, 144))	('activating transcription factor 3', 'Gene', '467', (105, 138))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('activating transcription factor 3', 'Gene', (105, 138))	('ATF3', 'Gene', (140, 144))	('upregulation', 'PosReg', (89, 101))	('transcription factor', 'molecular_function', 'GO:0000981', ('116', '136'))	('metabolism', 'biological_process', 'GO:0008152', ('293', '303'))	('PE5', 'Var', (209, 212))	('tumor', 'Disease', (179, 184))
196404	33880588	A comparison of the expression profiles in the cSR-A1, cSR-B1, and parental H28 cell lines revealed that 1254 genes (623 upregulated and 631 downregulated) were dysregulated in cSR-A1 cells and 1,225 genes (608 upregulated and 617 downregulated) were dysregulated in cSR-B1 cells compared to H28 cells.	('upregulated', 'PosReg', (211, 222))	('H28', 'Chemical', '-', (76, 79))	('upregulated', 'PosReg', (121, 132))	('downregulated', 'NegReg', (141, 154))	('downregulated', 'NegReg', (231, 244))	('dysregulated', 'Var', (161, 173))	('H28', 'Chemical', '-', (292, 295))
196405	33880588	Interestingly, the GO terms included not only terms related to cancer characteristics, such as cell proliferation (GO:0008284, GO:0008285), adhesion (GO:0007155, GO:0007162), migration (GO:0016477), and apoptosis (GO:0006915), but also several metabolic processes related to lipids (GO:0006869), cellular protein (GO:0044267), and drugs (GO:00171449).	('GO:0008284', 'Var', (115, 125))	('lipids', 'Chemical', 'MESH:D008055', (275, 281))	('apoptosis', 'CPA', (203, 212))	('GO:0007162', 'Var', (162, 172))	('GO:0007155', 'Var', (150, 160))	('adhesion', 'CPA', (140, 148))	('GO:0016477', 'Var', (186, 196))	('cancer', 'Disease', (63, 69))	('cell proliferation', 'CPA', (95, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('GO:0006915', 'Var', (214, 224))	('rat', 'Species', '10116', (178, 181))	('GO:0008285', 'Var', (127, 137))	('rat', 'Species', '10116', (107, 110))	('GO:0006869', 'Var', (283, 293))	('protein', 'cellular_component', 'GO:0003675', ('305', '312'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('migration', 'CPA', (175, 184))	('GO:0044267', 'Var', (314, 324))
196406	33880588	There were several other binding functions, including growth factors [IGF (GO:0005520), FGF (GO:0017134), TGF (GO:0050431), and EGF (GO:0005154)] and other cell membrane molecules such as receptors (GO:0005102), heparin (GO:0005102), and syndecan (GO:0045545).	('syndecan', 'Gene', '6382', (238, 246))	('binding', 'Interaction', (25, 32))	('EGF', 'Gene', '1950', (128, 131))	('cell membrane', 'cellular_component', 'GO:0005886', ('156', '169'))	('GO:0017134', 'Var', (93, 103))	('syndecan', 'molecular_function', 'GO:0015023', ('238', '246'))	('GO:0005154)]', 'Var', (133, 145))	('GO:0005102', 'Var', (221, 231))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))	('heparin', 'Chemical', 'MESH:D006493', (212, 219))	('GO:0005102', 'Var', (199, 209))	('EGF', 'Gene', (128, 131))	('syndecan', 'Gene', (238, 246))	('EGF', 'molecular_function', 'GO:0005154', ('128', '131'))	('GO:0005520', 'Var', (75, 85))
196431	33880588	However, the decrease in the AKR family detected here was also observed in the short-term treatment of PE5; PE5 is known to reduce the expression of AKR1A1, a member of the AKR family.	('PE5', 'Var', (108, 111))	('expression', 'MPA', (135, 145))	('AKR1A1', 'Gene', (149, 155))	('AKR1A1', 'Gene', '10327', (149, 155))	('reduce', 'NegReg', (124, 130))
196450	33880588	Another report showed that under serum starvation conditions, AKT was phosphorylated in Y-MESO-8D but not in Y-MESO-8A.	('AKT', 'Gene', (62, 65))	('Y-MESO-8D', 'Var', (88, 97))	('Y-MESO', 'Chemical', '-', (88, 94))	('Y-MESO', 'Chemical', '-', (109, 115))	('AKT', 'Gene', '207', (62, 65))	('Y-MESO-8A', 'Chemical', '-', (109, 118))
196455	33880588	Indeed, Toyooka and Hayakawa's group has succeeded in developing a novel AKR1B10 inhibitor that suppressed cisplatin resistance in non-small cell lung cancer cells.	('inhibitor', 'Var', (81, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (131, 157))	('AKR1B10', 'Gene', (73, 80))	('cisplatin resistance', 'MPA', (107, 127))	('AKR1B10', 'Gene', '57016', (73, 80))	('suppressed', 'NegReg', (96, 106))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))
196467	33880588	Our previous studies have shown that cSBL had a stronger apoptosis-inducing effect on multidrug resistant K562 leukemia cells that overexpressed ABCB1 than on their parent K562 cells.	('K562', 'CellLine', 'CVCL:0004', (106, 110))	('multidrug resistant', 'Disease', (86, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('apoptosis-inducing', 'CPA', (57, 75))	('overexpressed', 'Var', (131, 144))	('K562', 'CellLine', 'CVCL:0004', (172, 176))	('leukemia', 'Disease', (111, 119))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('leukemia', 'Disease', 'MESH:D007938', (111, 119))	('ABCB1', 'Gene', (145, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
196524	31212997	Finally, we were interested in investigating if variations of circulating miR-625-3p and GAS5 after chemotherapy may have a prognostic value as suggested from our observations above.	('GAS5', 'Gene', '60674', (89, 93))	('variations', 'Var', (48, 58))	('miR-625', 'Gene', '693210', (74, 81))	('GAS5', 'Gene', (89, 93))	('GAS', 'molecular_function', 'GO:0034005', ('89', '92'))	('3p', 'Chemical', '-', (82, 84))	('miR-625', 'Gene', (74, 81))
196540	31212997	Also, considering that changes in levels of GAS5 may predict outcome after chemotherapy and surgery, it may hold potential in guiding treatment decisions.	('GAS5', 'Gene', (44, 48))	('changes', 'Var', (23, 30))	('predict', 'Reg', (53, 60))	('GAS', 'molecular_function', 'GO:0034005', ('44', '47'))	('GAS5', 'Gene', '60674', (44, 48))	('levels', 'MPA', (34, 40))
196551	31212997	IsomiRs with shifts on their 5' end alters the miRNA seed sequence, resulting in changes in target profiles that can target largely non-overlapping groups of mRNAs, however, while the existence of 5' variant of miR-625-3p has already been described in MPM tissue, we found circulating 3' variants in the few clones sequenced.	('alters', 'Reg', (36, 42))	('target profiles', 'MPA', (92, 107))	('miR', 'Gene', (211, 214))	('3p', 'Chemical', '-', (219, 221))	('miR', 'Gene', '220972', (211, 214))	('miR-625', 'Gene', '693210', (211, 218))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('miR', 'Gene', (3, 6))	('changes', 'Reg', (81, 88))	('miR', 'Gene', '220972', (3, 6))	('shifts', 'Var', (13, 19))	('miR-625', 'Gene', (211, 218))
196552	31212997	3' end modifications modulate miRNA processing, stability, argonaute loading and targeting effectiveness.	('miR', 'Gene', '220972', (30, 33))	('targeting', 'MPA', (81, 90))	('miR', 'Gene', (30, 33))	('modifications', 'Var', (7, 20))	('miRNA processing', 'biological_process', 'GO:0035196', ('30', '46'))	('stability', 'MPA', (48, 57))	('argonaute', 'Protein', (59, 68))	('modulate', 'Reg', (21, 29))
196603	30306051	Immunohistochemical analysis showed no expression of K20; proliferation rate of Ki67 was 10%; calretinin, CK7 and vimentin were expressed (Fig.	('vimentin', 'Protein', (114, 122))	('K20', 'Gene', (53, 56))	('K20', 'Gene', '54474', (53, 56))	('vimentin', 'cellular_component', 'GO:0045098', ('114', '122'))	('calretinin', 'Gene', (94, 104))	('CK7', 'Gene', (106, 109))	('Ki67', 'Var', (80, 84))	('calretinin', 'Gene', '794', (94, 104))	('vimentin', 'cellular_component', 'GO:0045099', ('114', '122'))	('CK7', 'Gene', '3855', (106, 109))
196661	28159921	ROS generation is supposed to cause DNA damage that rapidly results in the phosphorylation of the histone H2A variant (H2AX) at Ser 139 (gamma-H2AX).	('H2AX', 'Gene', '15270', (143, 147))	('ROS', 'Var', (0, 3))	('gamma-H2AX', 'Gene', '15270', (137, 147))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('ROS generation', 'biological_process', 'GO:1903409', ('0', '14'))	('results in', 'Reg', (60, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('Ser', 'Chemical', 'MESH:D012694', (128, 131))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('H2AX', 'Gene', (119, 123))	('gamma-H2AX', 'Gene', (137, 147))	('Ser', 'cellular_component', 'GO:0005790', ('128', '131'))	('H2AX', 'Gene', (143, 147))	('phosphorylation', 'MPA', (75, 90))	('H2AX', 'Gene', '15270', (119, 123))
196663	28159921	Reactive oxygen species (ROS) are the main intracellular signal transducers sustaining autophagy whose activation can be revealed by the conversion of LC3-I in LC3-II.	('autophagy', 'CPA', (87, 96))	('conversion', 'Var', (137, 147))	('intracellular', 'cellular_component', 'GO:0005622', ('43', '56'))	('autophagy', 'biological_process', 'GO:0016236', ('87', '96'))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('autophagy', 'biological_process', 'GO:0006914', ('87', '96'))	('activation', 'PosReg', (103, 113))	('LC3-I', 'Gene', (151, 156))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))
196674	28159921	In addition, CUR increased p53 expression compared to DMSO treatment in MM-F1 (p=0.012), MM-B1 (p=0.028), and H-Meso-1 (p=0.005) cells (Figure 4, Panel A).	('increased', 'PosReg', (17, 26))	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))	('Meso-1', 'Gene', '21407', (112, 118))	('Meso-1', 'Gene', (112, 118))	('CUR', 'Var', (13, 16))	('expression', 'MPA', (31, 41))	('p53', 'Protein', (27, 30))
196685	28159921	Z-VAD-FMK was able to significantly reduce CUR-mediated apoptosis in MM-F1 and #40a cells and abolish it in MM-B1 and H-Meso-1 cell lines (Table 3, Figure 5).	('Z-VAD-FMK', 'Var', (0, 9))	('reduce', 'NegReg', (36, 42))	('abolish', 'NegReg', (94, 101))	('CUR-mediated apoptosis', 'CPA', (43, 65))	('Meso-1', 'Gene', '21407', (120, 126))	('Meso-1', 'Gene', (120, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (0, 9))
196704	28159921	To evaluate the in vivo antitumor effects of CUR, C57BL/6 mice (6 mice per group) were intraperitoneally inoculated with 1x106 #40a cells.	('tumor', 'Disease', (28, 33))	('mice', 'Species', '10090', (66, 70))	('mice', 'Species', '10090', (58, 62))	('1x106 #40a', 'Var', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
196734	28159921	Apoptosis can be also activated by oxidative stress-induced DNA damage, which activates p53 and different signal transducers such as p38, ERK and JNK.	('ERK', 'Gene', (138, 141))	('ERK', 'Gene', '26413', (138, 141))	('p38', 'Var', (133, 136))	('oxidative stress', 'Phenotype', 'HP:0025464', (35, 51))	('activates', 'PosReg', (78, 87))	('p53', 'Gene', (88, 91))	('Apoptosis', 'CPA', (0, 9))	('ERK', 'molecular_function', 'GO:0004707', ('138', '141'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('JNK', 'molecular_function', 'GO:0004705', ('146', '149'))
196737	28159921	Indeed, Z-VAD-FMK was able to significantly reduce and in MM-B1 and H-Meso-1 cell lines abolish the CUR-mediated MM cells apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('Z-VAD-FMK', 'Var', (8, 17))	('CUR-mediated MM cells apoptosis', 'CPA', (100, 131))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (8, 17))	('Meso-1', 'Gene', '21407', (70, 76))	('abolish', 'NegReg', (88, 95))	('Meso-1', 'Gene', (70, 76))
196746	28159921	CUR-mediated apoptosis was dependent on JNK and p38 activation in colon cancer cell lines.	('JNK', 'molecular_function', 'GO:0004705', ('40', '43'))	('colon cancer', 'Disease', (66, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('apoptosis', 'CPA', (13, 22))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('JNK', 'MPA', (40, 43))	('p38', 'Var', (48, 51))	('activation', 'PosReg', (52, 62))
196747	28159921	Moreover, it has been reported that JNK activation stimulates the autophagy by interfering with Bcl-2/Beclin interaction and that the pharmacological inhibition of JNK causes accumulation of p62 and reduces the LC3II/LC3I ratio flux and activates caspase 3.	('JNK', 'molecular_function', 'GO:0004705', ('164', '167'))	('interfering', 'NegReg', (79, 90))	('autophagy', 'biological_process', 'GO:0016236', ('66', '75'))	('stimulates', 'PosReg', (51, 61))	('activates', 'PosReg', (237, 246))	('Bcl-2/Beclin interaction', 'MPA', (96, 120))	('Bcl-2', 'molecular_function', 'GO:0015283', ('96', '101'))	('autophagy', 'biological_process', 'GO:0006914', ('66', '75'))	('JNK', 'Gene', (164, 167))	('accumulation', 'PosReg', (175, 187))	('reduces', 'NegReg', (199, 206))	('inhibition', 'Var', (150, 160))	('JNK', 'Gene', (36, 39))	('JNK', 'molecular_function', 'GO:0004705', ('36', '39'))	('caspase 3', 'Pathway', (247, 256))	('autophagy', 'CPA', (66, 75))	('LC3II/LC3I ratio flux', 'MPA', (211, 232))	('p62', 'Gene', (191, 194))	('p62', 'Gene', '18412', (191, 194))
196748	28159921	In particular, p54 JNK phosphorylation may support cell survival during cellular stress, while viral infections such as Kaposi sarcoma-associated herpes virus infections are able to inhibit p54 JNK phosphorylation, thus inhibiting autophagy and reducing cell survival.	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (120, 134))	('support', 'PosReg', (43, 50))	('inhibiting', 'NegReg', (220, 230))	('inhibit', 'NegReg', (182, 189))	('infections', 'Disease', 'MESH:D007239', (159, 169))	('autophagy', 'biological_process', 'GO:0006914', ('231', '240'))	('p54 JNK', 'Var', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('infections', 'Disease', (159, 169))	('viral infections', 'Disease', 'MESH:D001102', (95, 111))	('Kaposi sarcoma', 'Disease', (120, 134))	('cell survival', 'CPA', (51, 64))	('reducing', 'NegReg', (245, 253))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (120, 134))	('viral infections', 'Disease', (95, 111))	('cell survival', 'CPA', (254, 267))	('infections', 'Disease', 'MESH:D007239', (101, 111))	('p54', 'Protein', (190, 193))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('infections', 'Disease', (101, 111))	('JNK', 'molecular_function', 'GO:0004705', ('19', '22'))	('autophagy', 'biological_process', 'GO:0016236', ('231', '240'))	('autophagy', 'CPA', (231, 240))	('JNK', 'molecular_function', 'GO:0004705', ('194', '197'))
196840	32823952	YB-1 Knockdown Inhibits the Proliferation of Mesothelioma Cells through Multiple Mechanisms Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein that has been shown to regulate proliferation, invasion and metastasis in a variety of cancer types.	('invasion', 'CPA', (203, 211))	('Knockdown', 'Var', (5, 14))	('Y-box binding protein-1', 'Gene', (92, 115))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('YB-1', 'Gene', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('regulate', 'Reg', (179, 187))	('YB-1', 'Gene', '4904', (0, 4))	('Mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('Inhibits', 'NegReg', (15, 23))	('Mesothelioma', 'Disease', (45, 57))	('rat', 'Species', '10116', (195, 198))	('rat', 'Species', '10116', (35, 38))	('YB-1', 'Gene', (117, 121))	('Y-box binding protein-1', 'Gene', '4904', (92, 115))	('YB-1', 'Gene', '4904', (117, 121))	('cancer', 'Disease', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('metastasis', 'CPA', (216, 226))
196841	32823952	We previously demonstrated that YB-1 is overexpressed in mesothelioma cells and its knockdown significantly reduces tumour cell proliferation, migration, and invasion.	('YB-1', 'Gene', (32, 36))	('mesothelioma', 'Disease', (57, 69))	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('rat', 'Species', '10116', (135, 138))	('rat', 'Species', '10116', (146, 149))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('knockdown', 'Var', (84, 93))	('tumour', 'Disease', (116, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('reduces', 'NegReg', (108, 115))	('rat', 'Species', '10116', (21, 24))	('invasion', 'CPA', (158, 166))	('migration', 'CPA', (143, 152))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
196842	32823952	Here, we utilised an unbiased RNA-seq approach to characterise the changes to gene expression caused by loss of YB-1 knockdown in three mesothelioma cell lines (MSTO-211H, VMC23 and REN cells).	('mesothelioma', 'Disease', (136, 148))	('changes', 'Reg', (67, 74))	('loss', 'Var', (104, 108))	('REN', 'Gene', '5972', (182, 185))	('gene expression', 'MPA', (78, 93))	('YB-1', 'Gene', (112, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (136, 148))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('MSTO-211H', 'Chemical', '-', (161, 170))	('REN', 'Gene', (182, 185))
196845	32823952	In conclusion, this data indicates that YB-1 knockdown affects a core set of genes in mesothelioma cells.	('mesothelioma', 'Disease', (86, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('core set of genes', 'MPA', (65, 82))	('core', 'cellular_component', 'GO:0019013', ('65', '69'))	('affects', 'Reg', (55, 62))	('knockdown', 'Var', (45, 54))	('YB-1', 'Gene', (40, 44))
196846	32823952	Loss of YB-1 causes a cascade of events that leads to reduced mesothelioma proliferation, dependent on the underlying functionality of the STAT3/p53-pathways and the genetic landscape of the cell.	('YB-1', 'Gene', (8, 12))	('STAT3', 'Gene', '6774', (139, 144))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('mesothelioma', 'Disease', (62, 74))	('STAT3', 'Gene', (139, 144))	('reduced', 'NegReg', (54, 61))	('rat', 'Species', '10116', (82, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('Loss', 'Var', (0, 4))
196860	32823952	Furthermore, siRNA-mediated knockdown of YB-1 inhibited the proliferation, migration and invasion in 3 out of 4 MPM cell lines.	('rat', 'Species', '10116', (67, 70))	('YB-1', 'Gene', (41, 45))	('invasion', 'CPA', (89, 97))	('rat', 'Species', '10116', (78, 81))	('knockdown', 'Var', (28, 37))	('migration', 'CPA', (75, 84))	('inhibited', 'NegReg', (46, 55))
196862	32823952	Mutations of YB-1 are rare in MPM and other cancers (<1%), however, overexpression is strongly associated with poor prognosis.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('MPM', 'Disease', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('YB-1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
196869	32823952	YB-1 stimulates the pro-survival mTOR/STAT3 signalling pathway and its knockdown results in reduced STAT3 phosphorylation and MCL-1 expression.	('signalling pathway', 'biological_process', 'GO:0007165', ('44', '62'))	('STAT3', 'Gene', (100, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('stimulates', 'PosReg', (5, 15))	('pro-survival', 'biological_process', 'GO:0043066', ('20', '32'))	('mTOR', 'Gene', '2475', (33, 37))	('knockdown', 'Var', (71, 80))	('YB-1', 'Gene', (0, 4))	('mTOR', 'Gene', (33, 37))	('STAT3', 'Gene', '6774', (38, 43))	('reduced', 'NegReg', (92, 99))	('STAT3', 'Gene', '6774', (100, 105))	('expression', 'MPA', (132, 142))	('MCL-1', 'Gene', '4170', (126, 131))	('STAT3', 'Gene', (38, 43))	('MCL-1', 'Gene', (126, 131))
196873	32823952	To determine how YB-1 controls proliferation in MPM, we utilised next-generation RNA-sequencing (RNA-seq) to characterise the gene expression changes induced by loss of YB-1 in three MPM cell lines.	('YB-1', 'Gene', (169, 173))	('rat', 'Species', '10116', (74, 77))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('rat', 'Species', '10116', (38, 41))	('loss', 'Var', (161, 165))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))
196875	32823952	Notably, the p53-pathway appeared as a key central node of difference, with increased enrichment of p53-dependent gene changes correlating with cell death and/or G1 arrest while loss of p53-dependent pathways correlated with a lack of cell cycle arrest, culminating in a defective mitosis.	('lack', 'NegReg', (227, 231))	('mitosis', 'biological_process', 'GO:0000278', ('281', '288'))	('p53', 'Gene', (186, 189))	('defective mitosis', 'Disease', (271, 288))	('increased', 'PosReg', (76, 85))	('arrest', 'Disease', (165, 171))	('cell death', 'CPA', (144, 154))	('arrest', 'Disease', 'MESH:D006323', (246, 252))	('p53', 'Gene', '7157', (13, 16))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('loss', 'NegReg', (178, 182))	('p53', 'Gene', '7157', (100, 103))	('defective mitosis', 'Disease', 'MESH:D000014', (271, 288))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (100, 103))	('arrest', 'Disease', 'MESH:D006323', (165, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (235, 252))	('changes', 'Var', (119, 126))	('p53', 'Gene', '7157', (186, 189))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('235', '252'))	('arrest', 'Disease', (246, 252))
196877	32823952	We previously demonstrated that YB-1 knockdown can inhibit the proliferation of MPM cells in a panel of 4 cell lines.	('YB-1', 'Gene', (32, 36))	('proliferation', 'CPA', (63, 76))	('rat', 'Species', '10116', (70, 73))	('knockdown', 'Var', (37, 46))	('rat', 'Species', '10116', (21, 24))	('inhibit', 'NegReg', (51, 58))
196880	32823952	We previously demonstrated that MSTO-211H, REN and VMC23 overexpress between 2.5 to 4.5-fold more YB-1 mRNA compared to non-malignant mesothelial cells and that knockdown of YB-1 inhibits VMC23 cell proliferation.	('inhibits', 'NegReg', (179, 187))	('cell proliferation', 'biological_process', 'GO:0008283', ('194', '212'))	('YB-1', 'Gene', (98, 102))	('MSTO-211H', 'Chemical', '-', (32, 41))	('REN', 'Gene', '5972', (43, 46))	('rat', 'Species', '10116', (21, 24))	('REN', 'Gene', (43, 46))	('knockdown', 'Var', (161, 170))	('VMC23 cell proliferation', 'CPA', (188, 212))	('rat', 'Species', '10116', (206, 209))	('more', 'PosReg', (93, 97))	('overexpress', 'PosReg', (57, 68))	('mRNA', 'MPA', (103, 107))
196881	32823952	Consistent with the above data, the proliferation of all cell lines to YB-1 knockdown was also significantly reduced by 40-60% in response to siYB-1 #1, and to a lesser extent (10-50%) with siYB-1 #2, across all 3 lines (Figure S1C).	('YB-1', 'Gene', (71, 75))	('knockdown', 'Var', (76, 85))	('rat', 'Species', '10116', (43, 46))	('reduced', 'NegReg', (109, 116))	('proliferation', 'CPA', (36, 49))	('siYB-1 #1', 'Var', (142, 151))
196884	32823952	Two-way hierarchical clustering indicated that gene changes in MSTO-211H and VMC23 were more similar than in REN (Figure 1A), suggesting that MSTO-211H and VMC23 respond to YB-1 siRNA differently to REN.	('MSTO-211H', 'Chemical', '-', (142, 151))	('MSTO-211H', 'Var', (142, 151))	('REN', 'Gene', '5972', (199, 202))	('REN', 'Gene', '5972', (109, 112))	('REN', 'Gene', (109, 112))	('REN', 'Gene', (199, 202))	('MSTO-211H', 'Chemical', '-', (63, 72))	('VMC23', 'Gene', (156, 161))
196887	32823952	The above data suggested that knockdown of YB-1 inhibited MPM proliferation by deregulating gene expression of key cell cycle and growth-related pathways.	('YB-1', 'Gene', (43, 47))	('gene expression', 'MPA', (92, 107))	('deregulating', 'Reg', (79, 91))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('inhibited', 'NegReg', (48, 57))	('MPM proliferation', 'CPA', (58, 75))	('cell cycle', 'biological_process', 'GO:0007049', ('115', '125'))	('knockdown', 'Var', (30, 39))	('rat', 'Species', '10116', (69, 72))	('growth-related pathways', 'Pathway', (130, 153))
196889	32823952	MSTO-211H cells were significantly enriched and upregulated for G2/M checkpoint signalling, while the transcriptional activating STAT3 pathway, was significantly downregulated (Figure 2B).	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('64', '79'))	('G2/M checkpoint signalling', 'Pathway', (64, 90))	('STAT3', 'Gene', '6774', (129, 134))	('STAT3', 'Gene', (129, 134))	('downregulated', 'NegReg', (162, 175))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('upregulated', 'PosReg', (48, 59))	('MSTO-211H', 'Var', (0, 9))	('MSTO-211H', 'Chemical', '-', (0, 9))
196892	32823952	Taken together, these data suggest that YB-1 knockdown induces both common and unique gene expression changes in each cell line, including several pathways that are known to regulate cell migration, proliferation and cell survival.	('proliferation', 'CPA', (199, 212))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('cell migration', 'biological_process', 'GO:0016477', ('183', '197'))	('rat', 'Species', '10116', (191, 194))	('regulate', 'Reg', (174, 182))	('cell migration', 'CPA', (183, 197))	('changes', 'Reg', (102, 109))	('gene expression', 'MPA', (86, 101))	('rat', 'Species', '10116', (206, 209))	('knockdown', 'Var', (45, 54))	('YB-1', 'Gene', (40, 44))
196903	32823952	Specifically, significant enrichment of active upstream p53-dependent pathways was seen in MSTO-211H, a weak activation seen in VMC23, while robust downregulation of p53-dependent pathways was seen in REN cells (Figure 3C).	('REN', 'Gene', (201, 204))	('p53', 'Gene', (56, 59))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('p53', 'Gene', '7157', (56, 59))	('MSTO-211H', 'Chemical', '-', (91, 100))	('REN', 'Gene', '5972', (201, 204))	('active', 'PosReg', (40, 46))	('MSTO-211H', 'Var', (91, 100))	('downregulation', 'NegReg', (148, 162))
196910	32823952	Specifically, MSTO-211H cells are predicted to arrest in G1 or G2/M and undergo cell death, which correlates with a strong p53-dependent pathway response.	('arrest', 'Disease', (47, 53))	('cell death', 'biological_process', 'GO:0008219', ('80', '90'))	('MSTO-211H', 'Var', (14, 23))	('G2/M', 'CPA', (63, 67))	('arrest', 'Disease', 'MESH:D006323', (47, 53))	('p53', 'Gene', (123, 126))	('cell death', 'CPA', (80, 90))	('p53', 'Gene', '7157', (123, 126))	('MSTO-211H', 'Chemical', '-', (14, 23))
196912	32823952	The above upstream pathway analysis implicated p53-dependent pathways as a potential determinant regulating the response to YB-1 knockdown.	('p53', 'Gene', (47, 50))	('YB-1', 'Gene', (124, 128))	('p53', 'Gene', '7157', (47, 50))	('knockdown', 'Var', (129, 138))
196915	32823952	Interestingly, analysis of the raw expression and log fold-changes for TP53 were significantly increased in only MSTO-211H cells following YB-1 knockdown, while both VMC23 and REN cells saw a significant decrease in TP53 (Figure 4B,C).	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', '7157', (71, 75))	('YB-1', 'Gene', (139, 143))	('REN', 'Gene', (176, 179))	('increased', 'PosReg', (95, 104))	('expression', 'MPA', (35, 45))	('MSTO-211H', 'Chemical', '-', (113, 122))	('knockdown', 'Var', (144, 153))	('REN', 'Gene', '5972', (176, 179))	('TP53', 'Gene', '7157', (216, 220))	('TP53', 'Gene', (71, 75))
196918	32823952	In contrast, REN cells expressed far lower basal levels of CDKN1A compared to MSTO-211H (~12 fold less) and VMC23 (~9 fold less), and these levels decreased further upon YB-1 knockdown, albeit not significantly.	('CDKN1A', 'Gene', '1026', (59, 65))	('decreased', 'NegReg', (147, 156))	('less', 'NegReg', (98, 102))	('MSTO-211H', 'Chemical', '-', (78, 87))	('REN', 'Gene', (13, 16))	('knockdown', 'Var', (175, 184))	('lower', 'NegReg', (37, 42))	('CDKN1A', 'Gene', (59, 65))	('YB-1', 'Gene', (170, 174))	('REN', 'Gene', '5972', (13, 16))
196919	32823952	CDKN2A, which encodes the CDK4 inhibitor p16 and the MDM2 inhibitor p14arf, is frequently deleted in MPM.	('p14arf', 'Gene', (68, 74))	('CDKN2A', 'Gene', '1029', (0, 6))	('MDM2', 'Gene', '4193', (53, 57))	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('MDM2', 'Gene', (53, 57))	('deleted', 'Var', (90, 97))	('p16', 'Gene', (41, 44))	('p14arf', 'Gene', '1029', (68, 74))	('CDK4', 'Gene', (26, 30))	('CDK4', 'Gene', '1019', (26, 30))	('CDKN2A', 'Gene', (0, 6))	('p16', 'Gene', '1029', (41, 44))
196926	32823952	One potential explanation for the variable changes in p53 signalling could be due to potential mutations in TP53, which occur in ~15% of MPM tumour samples.	('signalling', 'biological_process', 'GO:0023052', ('58', '68'))	('TP53', 'Gene', '7157', (108, 112))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('TP53', 'Gene', (108, 112))	('changes', 'Reg', (43, 50))	('p53', 'Gene', (54, 57))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('mutations', 'Var', (95, 104))	('p53', 'Gene', '7157', (54, 57))	('tumour', 'Disease', (141, 147))
196927	32823952	MSTO-211H have previously been annotated as wild-type for p53, however, the status of REN and VMC23 cells has not yet been published.	('REN', 'Gene', '5972', (86, 89))	('MSTO-211H', 'Var', (0, 9))	('MSTO-211H', 'Chemical', '-', (0, 9))	('p53', 'Gene', (58, 61))	('REN', 'Gene', (86, 89))	('p53', 'Gene', '7157', (58, 61))
196928	32823952	We therefore utilised our RNA-seq data and performed alignment and SNV variant calling for the TP53 gene in each cell line and cross-referenced this with the IARC TP53 (version R20) database.	('variant', 'Var', (71, 78))	('TP53', 'Gene', '7157', (163, 167))	('TP53', 'Gene', (163, 167))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
196929	32823952	Interestingly, we identified two variants in exon 4 in MSTO-211H (c.215C>G, and c.348T>C), which resulted in the common P72R missense polymorphism and a silent mutation at S116S (Figure 4D, Table S3).	('c.348T>C', 'Var', (80, 88))	('c.348T>C', 'Mutation', 'rs369789011', (80, 88))	('c.215C>G', 'Var', (66, 74))	('MSTO-211H', 'Chemical', '-', (55, 64))	('P72R', 'Mutation', 'rs1042522', (120, 124))	('S116S', 'Mutation', 'rs376611439', (172, 177))	('MSTO-211H', 'Gene', (55, 64))	('P72R missense', 'Var', (120, 133))	('c.215C>G', 'Mutation', 'rs1042522', (66, 74))
196930	32823952	VMC23, also contained the missense P72R polymorphism, along with three other silent mutations (A63, G187, R196).	('R196', 'Var', (106, 110))	('P72R', 'Mutation', 'rs1042522', (35, 39))	('A63', 'Var', (95, 98))	('G187', 'Var', (100, 104))	('missense P72R', 'Var', (26, 39))
196931	32823952	In contrast, REN cells did not carry the P72R mutation, but did carry two polymorphisms in exon 11 (c.314G>A, c.409C>A) of unknown significance, along with 22 intronic SNVs mostly in intron 1, the majority of which are validated polymorphisms with no known clinical significance (Table S3).	('c.314G>A', 'Mutation', 'c.314G>A', (100, 108))	('c.409C>A', 'Mutation', 'c.409C>A', (110, 118))	('P72R', 'Mutation', 'rs1042522', (41, 45))	('c.409C>A', 'Var', (110, 118))	('REN', 'Gene', (13, 16))	('c.314G>A', 'Var', (100, 108))	('REN', 'Gene', '5972', (13, 16))
196932	32823952	Consequently, based on these data, it is likely that all three cell lines express wild-type p53, with MSTO-211H and VMC23 both containing the P72R polymorphism.	('P72R', 'Var', (142, 146))	('p53', 'Gene', (92, 95))	('MSTO-211H', 'Chemical', '-', (102, 111))	('P72R', 'Mutation', 'rs1042522', (142, 146))	('p53', 'Gene', '7157', (92, 95))
196934	32823952	In correlation with the RNA-seq data (Figure 4B), p21 levels significantly increased in MSTO-211H cells following YB-1#1 knockdown (Figure 4E), which corresponded with a reduction in MDM2 levels and an increase in a lower molecular weight band, while total p53 levels did not significantly change.	('knockdown', 'Var', (121, 130))	('reduction', 'NegReg', (170, 179))	('p53', 'Gene', '7157', (257, 260))	('lower molecular weight band', 'MPA', (216, 243))	('YB-1#1', 'Gene', (114, 120))	('p21', 'Gene', '1026', (50, 53))	('MSTO-211H', 'Chemical', '-', (88, 97))	('p53', 'Gene', (257, 260))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))	('MDM2', 'Gene', '4193', (183, 187))	('p21', 'Gene', (50, 53))	('increased', 'PosReg', (75, 84))	('increase', 'PosReg', (202, 210))	('MDM2', 'Gene', (183, 187))
196936	32823952	Finally, REN cells had much lower levels of p21 protein, which reduced further upon YB-1 depletion (Figure 4E), similar to the RNA-seq data.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('YB-1', 'Gene', (84, 88))	('reduced', 'NegReg', (63, 70))	('depletion', 'Var', (89, 98))	('REN', 'Gene', (9, 12))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('p21', 'Gene', '1026', (44, 47))	('p21', 'Gene', (44, 47))	('REN', 'Gene', '5972', (9, 12))
196940	32823952	However, in MSTO-211H cells, increased expression of IGFBP3 potentially primes cells for apoptosis, while loss of IGFBP3 combined with increased SIRT1 may protect VMC23 cells from death.	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('SIRT1', 'Gene', (145, 150))	('IGFBP3', 'Gene', '3486', (114, 120))	('cells', 'CPA', (79, 84))	('increased expression of IGFBP3', 'Phenotype', 'HP:0030269', (29, 59))	('apoptosis', 'CPA', (89, 98))	('MSTO-211H', 'Chemical', '-', (12, 21))	('IGFBP3', 'Gene', (114, 120))	('primes', 'Reg', (72, 78))	('increased', 'PosReg', (29, 38))	('IGFBP3', 'Gene', (53, 59))	('expression', 'MPA', (39, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('SIRT1', 'Gene', '23411', (145, 150))	('loss', 'Var', (106, 110))	('IGFBP3', 'Gene', '3486', (53, 59))
196948	32823952	MSTO-211H cells had a significant increase in late apoptotic cells and a decrease in viable cells (An-/PI-) after YB-1 knockdown (Figure 6A), confirming the enrichment of cell death signals seen by RNA-seq in Figure 3A.	('YB-1', 'Gene', (114, 118))	('late apoptotic cells', 'CPA', (46, 66))	('cell death', 'biological_process', 'GO:0008219', ('171', '181'))	('decrease', 'NegReg', (73, 81))	('knockdown', 'Var', (119, 128))	('MSTO-211H', 'Chemical', '-', (0, 9))	('increase', 'PosReg', (34, 42))	('viable cells', 'CPA', (85, 97))	('MSTO-211H', 'Var', (0, 9))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))
196949	32823952	In VMC23, there was no significant increase in apoptotic or necrotic cells, nor a decrease of viable cells in response to YB-1 siRNA transfection compared to the control transfected group (Figure 6A).	('transfection', 'Var', (133, 145))	('apoptotic', 'CPA', (47, 56))	('necrotic', 'Disease', 'MESH:D009336', (60, 68))	('decrease', 'NegReg', (82, 90))	('VMC23', 'Gene', (3, 8))	('YB-1', 'Gene', (122, 126))	('necrotic', 'Disease', (60, 68))
196952	32823952	Taken together these results confirm the above RNA-seq data that predicted higher rates of cell death in MSTO-211H and REN compared to VMC23 cells.	('REN', 'Gene', '5972', (119, 122))	('cell death', 'CPA', (91, 101))	('cell death', 'biological_process', 'GO:0008219', ('91', '101'))	('rat', 'Species', '10116', (82, 85))	('MSTO-211H', 'Chemical', '-', (105, 114))	('REN', 'Gene', (119, 122))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('MSTO-211H', 'Var', (105, 114))
196954	32823952	Concordant with TALI  and RNA-seq results, YB-1 silencing induced a significant increase in the sub-G0 (dead cell) population for MSTO-211H and REN cells, compared to control, but not for VMC23 (Figure 6B).	('silencing', 'Var', (48, 57))	('YB-1', 'Gene', (43, 47))	('increase', 'PosReg', (80, 88))	('REN', 'Gene', '5972', (144, 147))	('MSTO-211H', 'Chemical', '-', (130, 139))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('REN', 'Gene', (144, 147))
196957	32823952	These data indicate that all three cell lines were likely delayed in G0/G1 at 96 h after YB-1 knockdown, supporting the RNA-seq and p53/p21 data for VMC23 and MSTO-211H cells, however, this does not explain the predicted G2/M arrest in REN cells.	('knockdown', 'Var', (94, 103))	('p21', 'Gene', (136, 139))	('MSTO-211H', 'Chemical', '-', (159, 168))	('REN', 'Gene', (236, 239))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('RNA', 'cellular_component', 'GO:0005562', ('120', '123'))	('YB-1', 'Gene', (89, 93))	('M arrest', 'Disease', 'MESH:D006323', (224, 232))	('p21', 'Gene', '1026', (136, 139))	('REN', 'Gene', '5972', (236, 239))	('M arrest', 'Disease', (224, 232))
196961	32823952	These observations were confirmed by quantifying the total number of divisions each cell performed, with the average number of divisions significantly reduced from 2 to 1 in MSTO-211H and VMC23, and from 3 down to 1 in REN cells after YB-1 knockdown (Figure 7B).	('reduced', 'NegReg', (151, 158))	('YB-1', 'Gene', (235, 239))	('REN', 'Gene', '5972', (219, 222))	('knockdown', 'Var', (240, 249))	('MSTO-211H', 'Chemical', '-', (174, 183))	('REN', 'Gene', (219, 222))
196966	32823952	YB-1 knockdown significantly reduced cells undergoing a normal cell cycle by 38%, 42% and 56% in MSTO-211H, VMC23 and REN cells, respectively (Figure 8B).	('cells undergoing a normal cell cycle', 'CPA', (37, 73))	('MSTO-211H', 'Chemical', '-', (97, 106))	('REN', 'Gene', (118, 121))	('knockdown', 'Var', (5, 14))	('cell cycle', 'biological_process', 'GO:0007049', ('63', '73'))	('YB-1', 'Gene', (0, 4))	('reduced', 'NegReg', (29, 36))	('REN', 'Gene', '5972', (118, 121))
196973	32823952	Over-expression of YB-1 has long been associated with driving cancer proliferation, migration and invasion in a number of cancer types, including breast, colon, lung and MPM.	('lung', 'Disease', (161, 165))	('YB-1', 'Gene', (19, 23))	('colon', 'Disease', (154, 159))	('associated', 'Reg', (38, 48))	('rat', 'Species', '10116', (76, 79))	('MPM', 'Disease', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('invasion', 'CPA', (98, 106))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('migration', 'CPA', (84, 93))	('breast', 'Disease', (146, 152))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Over-expression', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rat', 'Species', '10116', (87, 90))
196974	32823952	Conversely, knockdown/out of YB-1 has been shown to block the proliferation and migration of a variety of cancer cell types including MPM.	('rat', 'Species', '10116', (83, 86))	('YB-1', 'Gene', (29, 33))	('block', 'NegReg', (52, 57))	('proliferation', 'CPA', (62, 75))	('knockdown/out', 'Var', (12, 25))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('MPM', 'Disease', (134, 137))	('rat', 'Species', '10116', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
196975	32823952	However, over-expression has also been shown to reverse AKT-induced oncogenesis, while in non-cancerous H9C2 cells (rat cardiomyocytes), loss of YB-1 promotes cellular proliferation.	('cellular proliferation', 'CPA', (159, 181))	('oncogenesis', 'CPA', (68, 79))	('H9C2', 'CellLine', 'CVCL:0286', (104, 108))	('promotes', 'PosReg', (150, 158))	('AKT', 'Gene', (56, 59))	('AKT', 'Gene', '24185', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rat', 'Species', '10116', (116, 119))	('rat', 'Species', '10116', (175, 178))	('oncogenesis', 'biological_process', 'GO:0007048', ('68', '79'))	('loss', 'Var', (137, 141))	('YB-1', 'Gene', (145, 149))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
196977	32823952	In support, our data demonstrated that while loss of YB-1 blocked the proliferation of 3 MPM cell lines, the phenotypic mechanisms for this reduced proliferation were unique to each cell line.	('proliferation', 'CPA', (148, 161))	('rat', 'Species', '10116', (77, 80))	('YB-1', 'Gene', (53, 57))	('rat', 'Species', '10116', (28, 31))	('proliferation', 'CPA', (70, 83))	('blocked', 'NegReg', (58, 65))	('rat', 'Species', '10116', (155, 158))	('loss', 'Var', (45, 49))	('reduced', 'NegReg', (140, 147))
196979	32823952	Analysis of the gene expression changes found that similar to previous reports, loss of YB-1 resulted in the downregulation of genes that control DNA replication, mitosis and cell migration.	('rat', 'Species', '10116', (183, 186))	('downregulation', 'NegReg', (109, 123))	('mitosis', 'biological_process', 'GO:0000278', ('163', '170'))	('YB-1', 'Gene', (88, 92))	('DNA replication', 'biological_process', 'GO:0006260', ('146', '161'))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('loss', 'Var', (80, 84))	('cell migration', 'biological_process', 'GO:0016477', ('175', '189'))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('DNA', 'MPA', (146, 149))	('cell migration', 'CPA', (175, 189))	('mitosis', 'CPA', (163, 170))
196988	32823952	Consequently, loss of YB-1 has been shown to increase p53 activity and induce p53-dependent apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('loss', 'Var', (14, 18))	('activity', 'MPA', (58, 66))	('YB-1', 'Gene', (22, 26))	('p53', 'Gene', (54, 57))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (54, 57))	('induce', 'PosReg', (71, 77))	('p53', 'Gene', '7157', (78, 81))	('increase', 'PosReg', (45, 53))
196989	32823952	Our results correlated partially with these previous observations, with YB-1 knockdown in MSTO-211H cells significantly increasing p53 mRNA levels, which subsequently resulted in increased p21 mRNA and protein.	('p21', 'Gene', '1026', (189, 192))	('p21', 'Gene', (189, 192))	('increasing', 'PosReg', (120, 130))	('MSTO-211H', 'Chemical', '-', (90, 99))	('p53', 'Gene', (131, 134))	('knockdown', 'Var', (77, 86))	('p53', 'Gene', '7157', (131, 134))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('increased', 'PosReg', (179, 188))	('YB-1', 'Gene', (72, 76))
196991	32823952	Consequently, the presence of R72 in MSTO-211H may explain the predisposition for apoptosis in these cells.	('presence', 'Var', (18, 26))	('R72', 'Var', (30, 33))	('apoptosis', 'CPA', (82, 91))	('MSTO-211H', 'Chemical', '-', (37, 46))	('MSTO-211H', 'Gene', (37, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))
196992	32823952	However, neither REN nor VMC23 cells followed the same pattern, with p53 mRNA levels and activity decreasing, as noted by the failure to induce p21 levels, suggesting that loss of YB-1 was not sufficient to drive p53 activity in these two cell lines.	('YB-1', 'Gene', (180, 184))	('activity', 'MPA', (217, 225))	('p53', 'Gene', (69, 72))	('mRNA levels', 'MPA', (73, 84))	('loss', 'Var', (172, 176))	('decreasing', 'NegReg', (98, 108))	('p21', 'Gene', (144, 147))	('REN', 'Gene', '5972', (17, 20))	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (213, 216))	('p53', 'Gene', '7157', (213, 216))	('REN', 'Gene', (17, 20))	('p21', 'Gene', '1026', (144, 147))	('activity', 'MPA', (89, 97))
196994	32823952	Similarly, the P72R polymorphism, which is present in VMC23 but not REN cells, also does not explain the lack of cell death seen in VMC23 cells, or the reduced cell cycle arrest observed in REN cells.	('P72R', 'Mutation', 'rs1042522', (15, 19))	('REN', 'Gene', '5972', (68, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (160, 177))	('P72R', 'Var', (15, 19))	('REN', 'Gene', (190, 193))	('reduced', 'NegReg', (152, 159))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('160', '177'))	('cell death', 'biological_process', 'GO:0008219', ('113', '123'))	('REN', 'Gene', (68, 71))	('arrest', 'Disease', 'MESH:D006323', (171, 177))	('arrest', 'Disease', (171, 177))	('REN', 'Gene', '5972', (190, 193))
196995	32823952	Clearly, other factors beyond p53 itself, must also impact the response to YB-1 knockdown.	('knockdown', 'Var', (80, 89))	('YB-1', 'Gene', (75, 79))	('impact', 'Reg', (52, 58))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('response', 'MPA', (63, 71))
196998	32823952	Notably, in contrast to a previous report in glioma cells, we saw a significant increase rather than decrease in MDM2 mRNA following YB-1 knockdown in both MSTO-211H and VMC23 cells, while REN cells showed no significant change.	('knockdown', 'Var', (138, 147))	('MDM2', 'Gene', '4193', (113, 117))	('MSTO-211H', 'Chemical', '-', (156, 165))	('MDM2', 'Gene', (113, 117))	('YB-1', 'Gene', (133, 137))	('increase', 'PosReg', (80, 88))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('REN', 'Gene', '5972', (189, 192))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('rat', 'Species', '10116', (89, 92))	('decrease', 'NegReg', (101, 109))	('glioma', 'Disease', (45, 51))	('REN', 'Gene', (189, 192))
197001	32823952	YB-1 has been shown to regulate alternative splicing of MDM2 transcripts, with knockdown of YB-1 promoting exon skipping resulting in less stable MDM2 protein, potentially explaining the reduced MDM2 in MSTO-211H cells.	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))	('MDM2', 'Gene', '4193', (56, 60))	('YB-1', 'Gene', (92, 96))	('protein', 'Protein', (151, 158))	('promoting', 'PosReg', (97, 106))	('MDM2', 'Gene', '4193', (195, 199))	('MDM2', 'Gene', (195, 199))	('exon', 'MPA', (107, 111))	('less', 'NegReg', (134, 138))	('MDM2', 'Gene', '4193', (146, 150))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('MDM2', 'Gene', (146, 150))	('knockdown', 'Var', (79, 88))	('MDM2', 'Gene', (56, 60))	('MSTO-211H', 'Chemical', '-', (203, 212))
197003	32823952	REN cells were unique and characterised by a failure to upregulate p53, with both mRNA and protein decreasing after YB-1 knockdown, indicating that REN cells, despite likely containing wild-type p53, are unable to upregulate p21 expression.	('knockdown', 'Var', (121, 130))	('p53', 'Gene', (195, 198))	('p53', 'Gene', '7157', (195, 198))	('REN', 'Gene', (148, 151))	('REN', 'Gene', '5972', (0, 3))	('decreasing', 'NegReg', (99, 109))	('p21', 'Gene', '1026', (225, 228))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('p21', 'Gene', (225, 228))	('REN', 'Gene', (0, 3))	('REN', 'Gene', '5972', (148, 151))	('expression', 'MPA', (229, 239))
197004	32823952	This likely explains why these cells were unable to sustain stable G1 or G2 arrests after YB-1 knockdown.	('arrest', 'Disease', 'MESH:D006323', (76, 82))	('knockdown', 'Var', (95, 104))	('YB-1', 'Gene', (90, 94))	('arrest', 'Disease', (76, 82))
197007	32823952	Notably, over-expression or loss of YB-1 has been previously shown to disrupt the mitotic spindle and cause cytokinesis defects.	('cytokinesis', 'biological_process', 'GO:0000910', ('108', '119'))	('YB-1', 'Gene', (36, 40))	('loss', 'Var', (28, 32))	('cause', 'Reg', (102, 107))	('disrupt', 'NegReg', (70, 77))	('cytokinesis defects', 'Disease', 'MESH:D000014', (108, 127))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('82', '97'))	('over-expression', 'PosReg', (9, 24))	('cytokinesis defects', 'Disease', (108, 127))
197009	32823952	This was most likely an indirect consequence due to the loss of E2F and FOXM1 driven S/G2 transcriptional activity seen across all three cell lines, particularly as E2F1 is transcriptionally upregulated by YB-1.	('upregulated', 'PosReg', (191, 202))	('FOXM1', 'Gene', (72, 77))	('loss', 'NegReg', (56, 60))	('transcriptional activity', 'MPA', (90, 114))	('E2F1', 'Var', (165, 169))	('S/G2', 'Var', (85, 89))	('S/G2', 'SUBSTITUTION', 'None', (85, 89))	('E2F', 'Var', (64, 67))	('FOXM1', 'Gene', '2305', (72, 77))
197020	32823952	Single Nucleotide Variations (SNVs) were identified using SNV caller Freebayes (v1.3.1) and annotated using Bcftools (v1.9) with database NCBI dbSNP (v146).	('Single Nucleotide Variations', 'Var', (0, 28))	('v1.9', 'Gene', (118, 122))	('v1.3', 'Gene', (80, 84))	('v1.9', 'Gene', '28811', (118, 122))	('v1.3', 'Gene', '28816', (80, 84))
197026	32823952	Immunodetection was performed using specific antibodies (monoclonal rabbit anti-YB-1 (ab12148, Abcam; 1:1000), rabbit monoclonal anti-p53 (2527S, Cell Signaling Technology, Danvers, MA, USA; 1:1000), monoclonal rabbit anti-p21 (2947S, Cell Signaling Technology; 1:1000), and mouse anti-MDM2 (ab16895, Abcam, Cambridge, UK; 1:200) and Bio-Rad Clarity (Hercules, CA, USA) enhanced chemiluminescence (ECL).	('MDM2', 'Gene', (286, 290))	('p21', 'Gene', '1026', (223, 226))	('Rad', 'Gene', '6236', (338, 341))	('Signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('enhanced', 'PosReg', (370, 378))	('p53', 'Gene', '7157', (134, 137))	('Rad', 'Gene', (338, 341))	('ab16895', 'Var', (292, 299))	('p21', 'Gene', (223, 226))	('Rad', 'biological_process', 'GO:1990116', ('338', '341'))	('chemiluminescence', 'MPA', (379, 396))	('p53', 'Gene', (134, 137))	('Signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('MDM2', 'Gene', '4193', (286, 290))
197028	32823952	beta-actin (antibody A2228, Sigma Aldrich, St. Louis, MO, USA; 1:1000) or GAPDH (G9545, Sigma Aldrich, 1:5000) served as loading controls.	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('GAPDH', 'Gene', '2597', (74, 79))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('GAPDH', 'Gene', (74, 79))	('G9545', 'Var', (81, 86))
197039	32823952	In summary, we have demonstrated through RNA-seq that knockdown of YB-1 in MPM cells drives a large number of gene expression changes, many of which have not previously been reported.	('gene expression changes', 'MPA', (110, 133))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('knockdown', 'Var', (54, 63))	('YB-1', 'Gene', (67, 71))	('rat', 'Species', '10116', (27, 30))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
197041	32823952	Loss of YB-1 drove the downregulation of a core set of common key genes involved in cell cycle and migration, which, combined with the overall functionality of the STAT3 and p53 pathways, determined if cells were able to initiate a stable cell cycle arrest, trigger apoptosis or fail to arrest and progress through an aberrant mitosis.	('downregulation', 'NegReg', (23, 37))	('arrest', 'Disease', 'MESH:D006323', (287, 293))	('aberrant mitosis', 'Disease', (318, 334))	('mitosis', 'biological_process', 'GO:0000278', ('327', '334'))	('p53', 'Gene', '7157', (174, 177))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (239, 256))	('cell cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('trigger', 'Reg', (258, 265))	('rat', 'Species', '10116', (102, 105))	('p53', 'Gene', (174, 177))	('arrest', 'Disease', (250, 256))	('STAT3', 'Gene', (164, 169))	('YB-1', 'Gene', (8, 12))	('apoptosis', 'CPA', (266, 275))	('STAT3', 'Gene', '6774', (164, 169))	('arrest', 'Disease', (287, 293))	('Loss', 'Var', (0, 4))	('core', 'cellular_component', 'GO:0019013', ('43', '47'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('239', '256'))	('aberrant mitosis', 'Disease', 'MESH:D002869', (318, 334))	('arrest', 'Disease', 'MESH:D006323', (250, 256))	('apoptosis', 'biological_process', 'GO:0097194', ('266', '275'))	('apoptosis', 'biological_process', 'GO:0006915', ('266', '275'))
197170	31419989	In addition, the presence of PARP cleavage confirmed activation of apoptosis.	('apoptosis', 'CPA', (67, 76))	('PARP', 'Gene', '142', (29, 33))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('53', '76'))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('53', '76'))	('es', 'Chemical', 'MESH:D004540', (19, 21))	('presence', 'Var', (17, 25))	('PARP', 'Gene', (29, 33))
197228	30871186	Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi).	('Multiple Cancer', 'Disease', 'MESH:D009369', (78, 93))	('PARP', 'Gene', '142', (292, 296))	('homologous recombination', 'biological_process', 'GO:0035825', ('114', '138'))	('BRCA', 'Gene', (175, 179))	('mutations', 'Var', (180, 189))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('HRR', 'biological_process', 'GO:0000724', ('151', '154'))	('Homologous Recombination', 'biological_process', 'GO:0035825', ('27', '51'))	('DNA repair', 'biological_process', 'GO:0006281', ('139', '149'))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('DNA Repair', 'biological_process', 'GO:0006281', ('52', '62'))	('PARP', 'Gene', (292, 296))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('platinum', 'Chemical', 'MESH:D010984', (226, 234))	('poly(ADP-ribose) polymerase', 'Gene', '142', (252, 279))	('Multiple Cancer', 'Disease', (78, 93))	('poly(ADP-ribose) polymerase', 'Gene', (252, 279))	('BRCA', 'Gene', '672', (175, 179))
197236	30871186	Tumour-specific defects in the DNA damage response (DDR) are common across the spectrum of tumour types and are exploitable, provided that they can be reliably identified.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('defects', 'Var', (16, 23))	('DNA damage response', 'MPA', (31, 50))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('DNA damage response', 'biological_process', 'GO:0006974', ('31', '50'))
197238	30871186	Dysfunction in a DDR pathway promotes the genomic instability that leads to cancer formation, but also determines the sensitivity to novel therapies targeting a compensatory DDR function by "synthetic lethality" as well as conventional DNA damaging chemotherapy and radiotherapy.	('leads to', 'Reg', (67, 75))	('Dysfunction', 'Var', (0, 11))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('genomic instability', 'MPA', (42, 61))	('DDR', 'Enzyme', (17, 20))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('promotes', 'PosReg', (29, 37))
197239	30871186	The classic demonstration of synthetic lethality is the role of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancers in which homologous recombination DNA repair (HRR) is defective (HRD), particularly in breast and ovarian cancers associated with germline BRCA1 and BRCA2 mutations.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (209, 235))	('cancers', 'Disease', (114, 121))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('DNA repair', 'biological_process', 'GO:0006281', ('156', '166'))	('BRCA2', 'Gene', (271, 276))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('mutations', 'Var', (277, 286))	('associated', 'Reg', (236, 246))	('HRR', 'biological_process', 'GO:0000724', ('168', '171'))	('PARP', 'Gene', '142', (104, 108))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('HRD', 'Disease', (187, 190))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Disease', (228, 235))	('BRCA2', 'Gene', '675', (271, 276))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('homologous recombination', 'biological_process', 'GO:0035825', ('131', '155'))	('PARP', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('HRD', 'Disease', 'None', (187, 190))	('poly(ADP-ribose) polymerase', 'Gene', '142', (64, 91))	('poly(ADP-ribose) polymerase', 'Gene', (64, 91))	('BRCA1', 'Gene', '672', (261, 266))	('ovarian cancers', 'Phenotype', 'HP:0100615', (220, 235))	('BRCA1', 'Gene', (261, 266))
197242	30871186	BRCA 1/2 (germline and somatic) mutations are only seen in up to 20% of high-grade serous ovarian cancer, but our own group was the first to identify a substantially higher fraction (~55%) of tumours with HRD using a functional assay, which was later confirmed with molecular analysis by The Cancer Genome Atlas (TCGA).	('serous ovarian cancer', 'Disease', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HRD', 'Disease', (205, 208))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('BRCA 1/2', 'Gene', '672;675', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (83, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('Cancer', 'Phenotype', 'HP:0002664', (292, 298))	('mutations', 'Var', (32, 41))	('Cancer Genome Atlas', 'Disease', (292, 311))	('tumours', 'Disease', (192, 199))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (292, 311))	('BRCA 1/2', 'Gene', (0, 8))	('HRD', 'Disease', 'None', (205, 208))
197244	30871186	Various genomic screens are currently being used to identify HRD ovarian cancer without pathogenic BRCA mutation, such as the loss of heterozygosity (LOH) and the mutational analysis of key HRR genes.	('loss of heterozygosity', 'Var', (126, 148))	('BRCA', 'Gene', (99, 103))	('HRR', 'biological_process', 'GO:0000724', ('190', '193'))	('mutational', 'Var', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('HRD ovarian cancer', 'Disease', 'MESH:D010051', (61, 79))	('HRD ovarian cancer', 'Disease', (61, 79))	('HRR genes', 'Gene', (190, 199))	('BRCA', 'Gene', '672', (99, 103))
197249	30871186	Pancreatic cancer is of particular interest, with a rising incidence, a disproportionate number of cancer deaths, and recognition that at least a proportion of pancreatic cancer is associated with germline BRCA mutations.	('associated', 'Reg', (181, 191))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (160, 177))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA', 'Gene', (206, 210))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('cancer deaths', 'Disease', (99, 112))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('pancreatic cancer', 'Disease', 'MESH:D010190', (160, 177))	('pancreatic cancer', 'Disease', (160, 177))	('cancer deaths', 'Disease', 'MESH:D003643', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('germline', 'Var', (197, 205))	('BRCA', 'Gene', '672', (206, 210))
197256	30871186	Samples PA025 (HB cancer) and PA026 (upper GI cancer) were excluded from analysis due to failure to increase gammaH2AX foci, indicating that they had failed to replicate during the exposure period to generate collapsed replication forks.	('upper GI cancer', 'Disease', (37, 52))	('upper GI cancer', 'Disease', 'MESH:D009369', (37, 52))	('HB cancer', 'Disease', (15, 24))	('gammaH2AX', 'Chemical', '-', (109, 118))	('PA', 'Chemical', '-', (8, 10))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('PA', 'Chemical', '-', (30, 32))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HB cancer', 'Disease', 'MESH:D009369', (15, 24))	('PA026', 'Var', (30, 35))	('gammaH2AX', 'Gene', (109, 118))
197284	30871186	The functional characterisation of patient primary cultures for HRR status is shown to be predictive of sensitivity ex vivo to PARPi and clinically to platinum sensitivity in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('PARP', 'Gene', (127, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('HRR status', 'Var', (64, 74))	('platinum', 'CPA', (151, 159))	('patient', 'Species', '9606', (35, 42))	('sensitivity', 'MPA', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('PARP', 'Gene', '142', (127, 131))	('ovarian cancer', 'Disease', (175, 189))	('HRR', 'biological_process', 'GO:0000724', ('64', '67'))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))
197291	30871186	loss of 53BP1 or DNA-PKcs restores HRR in BRCA-mutated cells).	('loss', 'Var', (0, 4))	('HRR', 'MPA', (35, 38))	('53BP1', 'Gene', '7158', (8, 13))	('BRCA', 'Gene', '672', (42, 46))	('BRCA', 'Gene', (42, 46))	('restores', 'PosReg', (26, 34))	('DNA-PKcs', 'Gene', '5591', (17, 25))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('HRR', 'biological_process', 'GO:0000724', ('35', '38'))	('53BP1', 'Gene', (8, 13))	('DNA-PKcs', 'Gene', (17, 25))
197292	30871186	The epigenetic silencing of BRCA1 accounted for 11% of the HRR defects reported in the TCGA ovarian cancer analysis, but was not investigated by Riaz et al., who undertook whole-exome sequencing rather than the more sensitive whole genome analysis, offering further potential explanations for the apparent lower incidence of HRD in this dataset.	('BRCA1', 'Gene', '672', (28, 33))	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('epigenetic silencing', 'Var', (4, 24))	('ovarian cancer', 'Disease', (92, 106))	('HRR', 'MPA', (59, 62))	('BRCA1', 'Gene', (28, 33))	('HRD', 'Disease', (325, 328))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('HRR', 'biological_process', 'GO:0000724', ('59', '62'))	('HRD', 'Disease', 'None', (325, 328))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))
197296	30871186	There is also a desire to test the efficacy of PARPi in patients without germline BRCA mutations, with several studies in ovarian cancer aiming to further define this subpopulation.	('PARP', 'Gene', (47, 51))	('patients', 'Species', '9606', (56, 64))	('BRCA', 'Gene', (82, 86))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('ovarian cancer', 'Disease', (122, 136))	('PARP', 'Gene', '142', (47, 51))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('BRCA', 'Gene', '672', (82, 86))	('mutations', 'Var', (87, 96))
197298	30871186	PARPi are currently in clinical trials in pancreatic cancer patients with BRCA mutations, but there are also over 200 ongoing trials of PARPi in various other cancer types, which are not restricted to BRCA mutated cancer; some have had promising results.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('mutations', 'Var', (79, 88))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (214, 220))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('BRCA', 'Gene', '672', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('BRCA', 'Gene', '672', (74, 78))	('cancer', 'Disease', (53, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA', 'Gene', (201, 205))	('PARP', 'Gene', '142', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('PARP', 'Gene', '142', (0, 4))	('BRCA', 'Gene', (74, 78))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('pancreatic cancer', 'Disease', (42, 59))	('PARP', 'Gene', (136, 140))	('PARP', 'Gene', (0, 4))
197299	30871186	Our previous studies in malignant pleural effusions and the pilot data presented here indicate that HRR dysfunction is prevalent in a broad range of cancers, such that limiting trials to patients/tumours with germline or somatic BRCA mutations is likely to underrepresent the number who may benefit from PARPi therapy.	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('BRCA', 'Gene', (229, 233))	('patients', 'Species', '9606', (187, 195))	('pleural effusion', 'Phenotype', 'HP:0002202', (34, 50))	('PARP', 'Gene', '142', (304, 308))	('prevalent', 'Reg', (119, 128))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('PARP', 'Gene', (304, 308))	('cancers', 'Disease', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('malignant pleural effusions', 'Disease', (24, 51))	('HRR', 'biological_process', 'GO:0000724', ('100', '103'))	('tumours', 'Disease', (196, 203))	('mutations', 'Var', (234, 243))	('HRR dysfunction', 'Disease', (100, 115))	('HRR dysfunction', 'Disease', 'MESH:D006331', (100, 115))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('pleural effusions', 'Phenotype', 'HP:0002202', (34, 51))	('BRCA', 'Gene', '672', (229, 233))	('malignant pleural effusions', 'Disease', 'MESH:D016066', (24, 51))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
197346	30871186	The accumulation of gammaH2AX foci was used as a pharmacodynamic biomarker of PARP inhibition in one of the earliest clinical trials.	('gammaH2AX', 'Var', (20, 29))	('PARP', 'Gene', (78, 82))	('gammaH2AX', 'Chemical', '-', (20, 29))	('PARP', 'Gene', '142', (78, 82))
197348	30871186	The mean number of foci in treated cells was divided by the mean number of foci in control cells to calculate the fold induction of gammaH2AX and RAD51 for each sample.	('RAD', 'biological_process', 'GO:1990116', ('146', '149'))	('gammaH2AX', 'Chemical', '-', (132, 141))	('gammaH2AX', 'Var', (132, 141))	('RAD51', 'Gene', (146, 151))	('RAD51', 'Gene', '5888', (146, 151))
197353	30871186	Samples PA006, PA007, PA009, PA010, PA012, PA014, PA017, PA021, and PA022 were re-established from cryopreserved cells that had been frozen at the first or second passage of culture, and were treated with 0 to 30 microM of rucaparib for 48 h before replacing it with drug-free medium and incubated until untreated controls were just subconfluent.	('PA014', 'Var', (43, 48))	('PA012', 'Var', (36, 41))	('PA017', 'Var', (50, 55))	('PA006', 'Var', (8, 13))	('PA007', 'Var', (15, 20))	('PA', 'Chemical', '-', (29, 31))	('PA', 'Chemical', '-', (8, 10))	('PA', 'Chemical', '-', (68, 70))	('PA', 'Chemical', '-', (43, 45))	('PA', 'Chemical', '-', (57, 59))	('PA', 'Chemical', '-', (50, 52))	('rucaparib', 'Chemical', 'MESH:C531549', (223, 232))	('PA010', 'Var', (29, 34))	('PA', 'Chemical', '-', (15, 17))	('PA', 'Chemical', '-', (36, 38))	('PA', 'Chemical', '-', (22, 24))	('PA009', 'Var', (22, 27))
197476	23989951	Previous analysis of these data has shown that the risk of death with mesothelioma was greatest among insulation workers compared with the other occupations, as expected.	('death', 'Disease', 'MESH:D003643', (59, 64))	('death', 'Disease', (59, 64))	('mesothelioma', 'Disease', (70, 82))	('insulation workers', 'Var', (102, 120))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))
197505	23989951	Occupation is probably the strongest indicator of intensity of asbestos exposure and has the most consistent association with latency in the literature, but this study found no evidence that insulation workers had shorter latencies than other asbestos workers.	('asbestos', 'Chemical', 'MESH:D001194', (63, 71))	('insulation', 'Var', (191, 201))	('asbestos', 'Chemical', 'MESH:D001194', (243, 251))	('shorter', 'NegReg', (214, 221))	('latencies', 'MPA', (222, 231))
197509	16909142	Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes.	('ICD-10', 'Var', (59, 65))	('mesothelioma', 'Disease', (151, 163))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
197556	16909142	Similarly, the proportion of deaths attributed to specific accidental poisoning codes (E866.4 in ICD-9 and X49 in ICD-10) appears fairly constant between 4 and 7%.	('poisoning', 'Disease', (70, 79))	('E866.4', 'Var', (87, 93))	('poisoning', 'Disease', 'MESH:D011041', (70, 79))	('X49', 'Var', (107, 110))	('death', 'Disease', 'MESH:D003643', (29, 34))	('death', 'Disease', (29, 34))
197558	16909142	If such coding patterns are followed internationally and use of these codes is not extensively employed for other conditions - in Scotland 81% (79/97) of underlying cause of deaths encoded E8664, 1981-1999 and 65% (36/55) of deaths encoded X49, 2000-2003 were listed as mesotheliomas in the cancer registry - 86% (83/97) and 69% (47/68), respectively based on Scottish mortality data with supplemental mesothelioma code use - they may represent an additional way to identify mesothelioma deaths, beyond ICD-9 code 163 and ICD-10 C45, within epidemiological studies in the future.	('mesothelioma deaths', 'Disease', 'MESH:D008654', (475, 494))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('mesothelioma', 'Disease', (402, 414))	('death', 'Disease', 'MESH:D003643', (488, 493))	('death', 'Disease', 'MESH:D003643', (225, 230))	('mesothelioma', 'Disease', 'MESH:D008654', (402, 414))	('death', 'Disease', (174, 179))	('mesothelioma deaths', 'Disease', (475, 494))	('mesothelioma', 'Disease', (270, 282))	('mesotheliomas', 'Disease', (270, 283))	('mesothelioma', 'Disease', 'MESH:D008654', (270, 282))	('cancer', 'Disease', (291, 297))	('death', 'Disease', (488, 493))	('mesotheliomas', 'Disease', 'MESH:D008654', (270, 283))	('death', 'Disease', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('death', 'Disease', 'MESH:D003643', (174, 179))	('E8664', 'Var', (189, 194))	('mesothelioma', 'Disease', (475, 487))	('mesothelioma', 'Disease', 'MESH:D008654', (475, 487))
197566	33466653	Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model.	('upregulation', 'PosReg', (103, 115))	('anti PD-L1', 'Var', (203, 213))	('cytokine secretion', 'biological_process', 'GO:0050663', ('33', '51'))	('cJ mesothelioma', 'Disease', (295, 310))	('cJ mesothelioma', 'Disease', 'MESH:D008654', (295, 310))	('mouse', 'Species', '10090', (311, 316))
197567	33466653	PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.	('survival benefit', 'CPA', (124, 140))	('monotherapy', 'Var', (6, 17))	('delayed', 'NegReg', (87, 94))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
197577	33466653	For example, a significant improvement of progression-free survival (and higher overall response rates were observed in patients with non-small cell lung carcinoma (NSCLC) treated with anti PD-1 (pembrolizumab) plus chemotherapy.	('improvement', 'PosReg', (27, 38))	('non-small cell lung carcinoma', 'Disease', (134, 163))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('anti', 'Var', (185, 189))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (138, 163))	('patients', 'Species', '9606', (120, 128))	('PD-1', 'Gene', (190, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (134, 163))	('pembrolizumab', 'Chemical', 'MESH:C582435', (196, 209))	('NSCLC', 'Disease', (165, 170))	('higher', 'PosReg', (73, 79))
197584	33466653	MPM cells of the epithelioid (NCI-H2818, NCI-H2795) and sarcomatoid (NCI-H2731) subtypes were placed in co-cultures with peripheral blood mononuclear cells (PBMC) from healthy donors.	('NCI-H2795', 'CellLine', 'CVCL:U996', (41, 50))	('sarcomatoid', 'Disease', (56, 67))	('NCI-H2731', 'CellLine', 'CVCL:U995', (69, 78))	('NCI-H2731', 'Var', (69, 78))	('sarcomatoid', 'Disease', 'MESH:C538614', (56, 67))
197589	33466653	The highest concentration of IL-5 was observed with the combined treatment of anti PD-1 and anti TIM-3 for two of our cell lines (NCI-H2795 and NCI-H2731), and for the combination of anti PD-L1 with anti LAG-3 for the NCI-H2818 cell line (Figure 4).	('NCI-H2731', 'CellLine', 'CVCL:U995', (144, 153))	('combined', 'Interaction', (56, 64))	('TIM-3', 'Gene', (97, 102))	('anti', 'Var', (183, 187))	('PD-1', 'Gene', (83, 87))	('PD-L1', 'Gene', (188, 193))	('concentration', 'MPA', (12, 25))	('IL-5', 'molecular_function', 'GO:0005137', ('29', '33'))	('anti', 'Var', (78, 82))	('NCI-H2795', 'CellLine', 'CVCL:U996', (130, 139))
197598	33466653	Considering the significant upregulation of PD-L1 on healthy donor PBMC after co-culture with MPM tumor cells, we chose the combination of anti PD-L1 with anti TIM-3 for further in vivo investigation in the AB1-HA BALB/cJ mesothelioma mouse model.	('upregulation', 'PosReg', (28, 40))	('cJ mesothelioma', 'Disease', 'MESH:D008654', (219, 234))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mouse', 'Species', '10090', (235, 240))	('PD-L1', 'Gene', (144, 149))	('tumor', 'Disease', (98, 103))	('anti', 'Var', (139, 143))	('cJ mesothelioma', 'Disease', (219, 234))
197600	33466653	Mice were treated with anti PD-L1, anti TIM-3, or anti LAG-3 as monotherapies or with the combination of anti PD-L1 + anti TIM-3, or anti PD-L1 + anti LAG-3.	('anti PD-L1', 'Var', (133, 143))	('anti PD-L1', 'Var', (105, 115))	('Mice', 'Species', '10090', (0, 4))
197602	33466653	We observed a delay in tumor growth for anti PD-L1 and anti PD-L1 + anti LAG-3 treatment when compared to our PBS control group, though not statistically significant (Figure 8A).	('anti PD-L1', 'Var', (40, 50))	('PBS', 'Chemical', '-', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('delay', 'NegReg', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
197611	33466653	Overexpression of ICs has already been described in several cancer types, and results in suppression of immune cell activity.	('immune cell activity', 'CPA', (104, 124))	('ICs', 'Gene', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('Overexpression', 'Var', (0, 14))	('suppression', 'NegReg', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
197618	33466653	Surprisingly, although LAG-3 expression was absent on our murine MPM cells, and the expression on human PBMC remained steady before and after co-culture, the combination with PD-L1 also showed a significant survival benefit in vivo (p = 0.003).	('combination', 'Var', (158, 169))	('survival benefit', 'CPA', (207, 223))	('PD-L1', 'Var', (175, 180))	('murine', 'Species', '10090', (58, 64))	('human', 'Species', '9606', (98, 103))
197619	33466653	This can be explained by the high percentage of PD-L1+ and LAG-3+ TILs that we observed after harvesting the tumor and spleen.	('LAG-3+', 'Var', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('PD-L1+', 'Var', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
197620	33466653	Remarkably, while only very low percentages of PD-L1+ and LAG-3+ CD8+ effector T cells were found in the spleen, very high percentages of PD-L1+ and LAG-3+ TILs were found.	('CD8', 'Gene', (65, 68))	('PD-L1+', 'Var', (138, 144))	('CD8', 'Gene', '925', (65, 68))
197624	33466653	looked at PD-1 expression on T cells in bronchoalveolar lavage fluids (BALF) and blood samples (PB) of NSCLC patients, and observed a significantly higher proportion of CD8+ and CD4+ cells with PD-1 expression in the BALF when compared with the PB.	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Disease', (103, 108))	('PD-1', 'Gene', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('expression', 'Var', (199, 209))	('CD8', 'Gene', (169, 172))	('CD8', 'Gene', '925', (169, 172))	('higher', 'PosReg', (148, 154))	('PD-1', 'Gene', (194, 198))
197626	33466653	They found that both the frequency and the level of expression of PD-1 were significantly higher on CD4 and CD8 TILs compared with T cells in normal tissues and peripheral blood in the same patients and healthy donors.	('CD4', 'Var', (100, 103))	('patients', 'Species', '9606', (190, 198))	('expression', 'MPA', (52, 62))	('PD-1', 'Gene', (66, 70))	('CD8', 'Gene', (108, 111))	('CD8', 'Gene', '925', (108, 111))	('higher', 'PosReg', (90, 96))
197631	33466653	We are the first to report in vivo data on the combination of anti PD-L1 with TIM-3 or LAG-3 blockade in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('PD-L1', 'Gene', (67, 72))	('anti', 'Var', (62, 66))	('combination', 'Interaction', (47, 58))	('mesothelioma', 'Disease', (105, 117))
197653	33466653	The following anti mouse Abs were included: CD45.1-APC Cy7 (clone A20), CD8-FITC (clone 53-6.7), CD4-PercP-Cy5 (clone RM4-5), CD3-PE (clone 17A2), PD-1-BV42 (clone 29F.1A12), PD-L1-APC (clone 10F.9G2), TIM-3-BV785 (clone RMT3-23), and LAG-3-PeCy7 (clone C9B7W).	('clone 10F.9G2', 'Var', (186, 199))	('PD-L1-APC', 'Disease', 'MESH:D010300', (175, 184))	('APC', 'cellular_component', 'GO:0005680', ('51', '54'))	('CD3', 'Gene', (126, 129))	('PD-L1-APC', 'Disease', (175, 184))	('CD3', 'Gene', '12503', (126, 129))	('CD45', 'Gene', '19264', (44, 48))	('CD45', 'Gene', (44, 48))	('CD8', 'Gene', (72, 75))	('mouse', 'Species', '10090', (19, 24))	('APC', 'cellular_component', 'GO:0005680', ('181', '184'))	('CD8', 'Gene', '925', (72, 75))
197769	30862609	Whole-exome sequencing revealed a total of 121 somatic variants in the T1 and 429 in the T2 tumor sample (Fig.	('revealed', 'Reg', (23, 31))	('variants', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
197770	30862609	Four and eight known protein-coding cancer-relevant mutations were identified in T1 and T2, respectively (Table 1).	('mutations', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
197774	30862609	The stop-gained (LATS1 p.Trp879Ter), and frame-shift (LATS2 p.Val901SerfsTer43) mutations are situated in the kinase domains, likely causing loss of protein functions.	('p.Trp879Ter', 'Mutation', 'rs1408705745', (23, 34))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('loss', 'NegReg', (141, 145))	('Ter', 'cellular_component', 'GO:0097047', ('31', '34'))	('protein', 'Protein', (149, 156))	('p.Val901Ser', 'SUBSTITUTION', 'None', (60, 71))	('LATS1', 'Gene', (17, 22))	('p.Val901Ser', 'Var', (60, 71))	('LATS1', 'Gene', '9113', (17, 22))
197775	30862609	MECOM (MDS1 and EVI-1 complex locus) was also mutated in both samples (AF 0.34 and 0.19).	('mutated', 'Var', (46, 53))	('MECOM', 'Gene', (0, 5))	('MECOM', 'Gene', '2122', (0, 5))	('MDS1 and EVI-1 complex locus', 'Gene', '2122', (7, 35))	('AF', 'Disease', 'MESH:D001281', (71, 73))
197777	30862609	GATA3 (GATA binding protein 3) and EPHA3 (ephrin receptor A3) were mutated only in T2.	('GATA3', 'Gene', '2625', (0, 5))	('EPHA3', 'Gene', '2042', (35, 40))	('GATA binding protein 3', 'Gene', '2625', (7, 29))	('ephrin receptor A3', 'Gene', '2042', (42, 60))	('mutated', 'Var', (67, 74))	('ephrin', 'molecular_function', 'GO:0046875', ('42', '48'))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('EPHA3', 'Gene', (35, 40))	('GATA3', 'Gene', (0, 5))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))	('GATA binding protein 3', 'Gene', (7, 29))	('ephrin receptor A3', 'Gene', (42, 60))	('ephrin', 'molecular_function', 'GO:0005106', ('42', '48'))
197779	30862609	The EPHA3 gene, encoding a receptor tyrosine kinase, carried a stop-gained mutation in the ligand-binding domain, causing loss of protein function.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('EPHA3', 'Gene', '2042', (4, 9))	('ligand', 'molecular_function', 'GO:0005488', ('91', '97'))	('EPHA3', 'Gene', (4, 9))	('protein function', 'MPA', (130, 146))	('mutation in', 'Var', (75, 86))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('loss', 'NegReg', (122, 126))
197791	30862609	In addition, increased activity of pathways concerning cell adhesion and cytoskeleton organization may indicate altered cell plasticity and motility, which might be related to the mutated GATA3 and EPHA3.	('cell adhesion', 'biological_process', 'GO:0007155', ('55', '68'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('73', '85'))	('motility', 'CPA', (140, 148))	('GATA3', 'Gene', '2625', (188, 193))	('cell plasticity', 'CPA', (120, 135))	('cytoskeleton organization', 'biological_process', 'GO:0007010', ('73', '98'))	('mutated', 'Var', (180, 187))	('cell adhesion', 'CPA', (55, 68))	('pathways', 'Pathway', (35, 43))	('EPHA3', 'Gene', '2042', (198, 203))	('activity', 'MPA', (23, 31))	('GATA3', 'Gene', (188, 193))	('altered', 'Reg', (112, 119))	('increased', 'PosReg', (13, 22))	('EPHA3', 'Gene', (198, 203))
197796	30862609	Loss-of-function mutations in tumor suppressors LATS1/2 together with LOH of both genes would leave the tumor cells with only one copy of LATS1/2, the majority harboring the mutations.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('LATS1/2', 'Gene', '9113;26524', (138, 145))	('tumor', 'Disease', (104, 109))	('LATS1/2', 'Gene', '9113;26524', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('LATS1/2', 'Gene', (138, 145))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('LATS1/2', 'Gene', (48, 55))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
197798	30862609	Loss of functional LATS1/2 will activate transcriptional coactivators (YAP/TAZ) to promote cell migration, proliferation, and survival (Fig.	('TAZ', 'Gene', (75, 78))	('LATS1/2', 'Gene', (19, 26))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('survival', 'CPA', (126, 134))	('cell migration', 'CPA', (91, 105))	('activate', 'PosReg', (32, 40))	('Loss of functional', 'Var', (0, 18))	('LATS1/2', 'Gene', '9113;26524', (19, 26))	('promote', 'PosReg', (83, 90))	('transcriptional', 'MPA', (41, 56))	('TAZ', 'Gene', '6901', (75, 78))
197799	30862609	The homozygous loss of tumor suppressors BAP1 and PBRM1, found in both tumor samples may also contribute to cancer progression, because defective chromatin remodeling and HR repair over time will give rise to genomic instability and increased mutation rate, consistent with the findings in our study.	('chromatin remodeling', 'CPA', (146, 166))	('PBRM1', 'Gene', '55193', (50, 55))	('BAP1', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('PBRM1', 'Gene', (50, 55))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('146', '166'))	('give rise to', 'Reg', (196, 208))	('mutation rate', 'MPA', (243, 256))	('increased', 'PosReg', (233, 242))	('genomic', 'MPA', (209, 216))	('chromatin', 'cellular_component', 'GO:0000785', ('146', '155'))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (71, 76))	('cancer', 'Disease', (108, 114))	('BAP1', 'Gene', '8314', (41, 45))	('defective', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('contribute', 'Reg', (94, 104))
197800	30862609	Taken together, LATS1/2 mutations and loss of BAP1 and PBRM1 are likely genomic drivers of the disease.	('BAP1', 'Gene', '8314', (46, 50))	('LATS1/2', 'Gene', '9113;26524', (16, 23))	('PBRM1', 'Gene', '55193', (55, 60))	('BAP1', 'Gene', (46, 50))	('PBRM1', 'Gene', (55, 60))	('mutations', 'Var', (24, 33))	('LATS1/2', 'Gene', (16, 23))	('loss', 'Gene', (38, 42))
197804	30862609	The majority of mesothelioma patients harbor BAP1 alterations with heterozygous loss being detected in about 30%-60% of cases, whereas homozygous deletion seem to be a rare event in peritoneal mesothelioma and infrequent also in pleural mesothelioma (which is far more extensively studied).	('mesothelioma', 'Disease', 'MESH:D008654', (16, 28))	('patients', 'Species', '9606', (29, 37))	('BAP1', 'Gene', (45, 49))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (182, 205))	('pleural mesothelioma', 'Disease', (229, 249))	('mesothelioma', 'Disease', (237, 249))	('alterations', 'Var', (50, 61))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (182, 205))	('peritoneal mesothelioma', 'Disease', (182, 205))	('mesothelioma', 'Disease', (193, 205))	('mesothelioma', 'Disease', (16, 28))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))	('BAP1', 'Gene', '8314', (45, 49))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (229, 249))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (229, 249))	('mesothelioma', 'Disease', 'MESH:D008654', (193, 205))
197805	30862609	However, biallelic inactivation of BAP1, which also includes heterozygous deletion combined with an inactivating mutation, seems to be a more common occurrence, and often correlates with loss of BAP1 expression assessed by immunohistochemistry.	('BAP1', 'Gene', (195, 199))	('loss', 'NegReg', (187, 191))	('deletion', 'Var', (74, 82))	('BAP1', 'Gene', '8314', (35, 39))	('biallelic inactivation', 'Var', (9, 31))	('BAP1', 'Gene', (35, 39))	('expression', 'MPA', (200, 210))	('BAP1', 'Gene', '8314', (195, 199))
197809	30862609	Complete deletion of PBRM1 alone or in combination with BAP1 in this case could therefore represent a distinct genotype that could be hypothesized to confer increased sensitivity to DNA damaging agents.	('sensitivity', 'MPA', (167, 178))	('BAP1', 'Gene', '8314', (56, 60))	('PBRM1', 'Gene', (21, 26))	('PBRM1', 'Gene', '55193', (21, 26))	('BAP1', 'Gene', (56, 60))	('increased', 'PosReg', (157, 166))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('Complete deletion', 'Var', (0, 17))
197817	30862609	A functional dependency of EZH2 activity has been described for PBRM1 and BAP1 aberrations in tumors and cell lines, respectively.	('aberrations', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('BAP1', 'Gene', '8314', (74, 78))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('BAP1', 'Gene', (74, 78))
197822	30862609	Immune check-point inhibition is being explored in pleural mesothelioma (NCT03048474, NCT02716272), but in our case the evidence to support such treatment is not conclusive.	('NCT03048474', 'Var', (73, 84))	('NCT02716272', 'Var', (86, 97))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (51, 71))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (51, 71))	('pleural mesothelioma', 'Disease', (51, 71))
197835	30862609	We applied a bioinformatics pipeline to detect acquired single nucleotide variants and short insertions and deletions in the two tumor samples.	('single nucleotide variants', 'Var', (56, 82))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('insertions', 'Var', (93, 103))	('deletions', 'Var', (108, 117))	('tumor', 'Disease', (129, 134))
197842	30862609	The variants were subsequently annotated using an in-house developed cancer predisposition report tool .	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('variants', 'Var', (4, 12))
197895	31190990	Analysis for BAP1 mutation can also be helpful in assessing newly diagnosed patients.	('BAP1', 'Gene', '8314', (13, 17))	('patients', 'Species', '9606', (76, 84))	('BAP1', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))
197907	31190990	Stage I disease included T1N0M0, stage II included T2-3N0M0, and stage III included T4N0M0 and N1 or M1 disease.	('T4N0M0', 'Var', (84, 90))	('M1 disease', 'Disease', (101, 111))	('T2-3N0M0', 'Var', (51, 59))	('M1 disease', 'Disease', 'MESH:D015470', (101, 111))	('T1N0M0', 'Var', (25, 31))
197961	31190990	When comparing survival with cisplatin or mitomycin perfusion, we demonstrated a statistically significant OS benefit at 1, 2, and 3 years in patients perfused with cisplatin (80% vs 47%, 80% vs 47%, and 80% vs 42%, respectively).	('OS', 'Chemical', '-', (107, 109))	('benefit', 'PosReg', (110, 117))	('cisplatin', 'Var', (165, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('patients', 'Species', '9606', (142, 150))	('mitomycin', 'Chemical', 'MESH:D016685', (42, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))
197969	31190990	Using tumor DNA to identify actionable genetic mutations for use in adjuvant treatment is an emerging strategy in precision oncology.	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('oncology', 'Phenotype', 'HP:0002664', (124, 132))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('men', 'Species', '9606', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
197973	31190990	Moreover, they identified a specific genetic mutation in one patient which conferred susceptibility to a non-standard treatment and further confirmed its effectiveness in tumor regression.	('susceptibility', 'Reg', (85, 99))	('patient', 'Species', '9606', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('genetic mutation', 'Var', (37, 53))	('men', 'Species', '9606', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
198012	31190990	Alexander and colleagues had similar findings, showing that patients with a CC of 2 or 3 had nearly twice the risk of death compared to those with a CC of 0 or 1 (HR 1.81, p=0.02).	('patients', 'Species', '9606', (60, 68))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))	('CC of 2', 'Var', (76, 83))
198037	30301262	Delays or errors in diagnosis hinder treatment intervention that can subsequently adversely affect the patients' survival and quality-of-life (QoL); therefore, accurate diagnosis is essential for prognostic and therapeutic purposes.	('survival', 'CPA', (113, 121))	('quality-of-life', 'CPA', (126, 141))	('hinder', 'NegReg', (30, 36))	('errors', 'Var', (10, 16))	('affect', 'Reg', (92, 98))	('patients', 'Species', '9606', (103, 111))	('treatment intervention', 'CPA', (37, 59))
198046	30301262	The most commonly reported mutations are identified in genes such as NF2, BAP1, TP53, NRAS, and EGFR.	('mutations', 'Var', (27, 36))	('NRAS', 'Gene', (86, 90))	('NF2', 'Gene', (69, 72))	('EGFR', 'Gene', (96, 100))	('TP53', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (74, 78))
198048	30301262	Among the three, CDKN2A represents the highest number of homozygous deletions in MPM-patient tumors.	('patient', 'Species', '9606', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('deletions', 'Var', (68, 77))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('CDKN2A', 'Gene', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('CDKN2A', 'Gene', '1029', (17, 23))	('MPM-patient', 'Disease', (81, 92))
198050	30301262	Molecular intertumor heterogeneity, including a diversity of mutation, epigenetic, expression, and microscopic (phenotypic) changes may cause inefficacy of the treatment regimens.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cause', 'Reg', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('epigenetic', 'Var', (71, 81))	('tumor', 'Disease', (15, 20))
198052	30301262	For example, the determination of p16 (CDKN2A) homozygous deletion using Fluorescence In Situ Hybridization (FISH) and identification of BRCA1-associated protein 1 (BAP1) loss by IHC are particularly useful to differentiate mesothelial hyperplasia (MH) from MPM.	('hyperplasia', 'Disease', 'MESH:D006965', (236, 247))	('CDKN2A', 'Gene', (39, 45))	('BAP1', 'Gene', (165, 169))	('CDKN2A', 'Gene', '1029', (39, 45))	('hyperplasia', 'Disease', (236, 247))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('deletion', 'Var', (58, 66))	('loss', 'NegReg', (171, 175))	('BAP1', 'Gene', '8314', (165, 169))
198071	30301262	Many studies have reported that loss of BAP1 protein expression is due to genetic mutation or DNA methylation in the genomic region.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('loss', 'NegReg', (32, 36))	('protein', 'Protein', (45, 52))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('genetic mutation', 'Var', (74, 90))	('BAP1', 'Gene', '8314', (40, 44))	('expression', 'MPA', (53, 63))	('BAP1', 'Gene', (40, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('94', '109'))
198072	30301262	To better understand the mechanism causing BAP1 loss in MPM, we performed genomic Sanger sequencing of the genetic regions spanning exon 6 and 7, where the majority of mutations reside, as reported in the literature.	('loss', 'NegReg', (48, 52))	('MPM', 'Disease', (56, 59))	('BAP1', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (43, 47))	('mutations', 'Var', (168, 177))
198075	30301262	Results obtained from ddPCR analysis confirm BAP1 deletion (Figure 3) in MPM samples that correlate with the loss of BAP1 protein expression observed using IHC analysis (Figure 1).	('protein', 'Protein', (122, 129))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('deletion', 'Var', (50, 58))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (117, 121))	('loss', 'NegReg', (109, 113))	('BAP1', 'Gene', (117, 121))	('BAP1', 'Gene', '8314', (45, 49))
198076	30301262	Loss of CDKN2A is a common event in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('CDKN2A', 'Gene', (8, 14))	('CDKN2A', 'Gene', '1029', (8, 14))	('mesothelioma', 'Disease', (36, 48))	('Loss', 'Var', (0, 4))
198078	30301262	To assess the potential of detecting copy number loss of CDKN2A in MPM samples using ddPCR, we performed CNV ddPCR analysis in MPM tissues and their matched primary cell lines.	('loss', 'NegReg', (49, 53))	('copy number', 'Var', (37, 48))	('CDKN2A', 'Gene', '1029', (57, 63))	('CDKN2A', 'Gene', (57, 63))
198082	30301262	Seven percent (one out of 14) of samples showed the retention of both alleles, and the majority of cases (93%: 13 out of 14) showed deletion of the CDKN2A genomic region.	('deletion', 'Var', (132, 140))	('CDKN2A', 'Gene', '1029', (148, 154))	('CDKN2A', 'Gene', (148, 154))	('retention', 'biological_process', 'GO:0051235', ('52', '61'))
198089	30301262	CDKN2A genomic loss had 96.4% of sensitivity and 100% specificity for MPM detection.	('MPM', 'Disease', (70, 73))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))	('genomic loss', 'Var', (7, 19))
198091	30301262	Results from SPSS indicated there was 93.3% sensitivity and 63.6% specificity when combining the protein expression and genomic deletion of BAP1 as a marker for MPM.	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('genomic deletion', 'Var', (120, 136))	('BAP1', 'Gene', (140, 144))	('MPM', 'Disease', (161, 164))	('BAP1', 'Gene', '8314', (140, 144))
198113	30301262	Results indicated that BAP1 expression loss and CDKN2A homozygous deletion were present in 27 (67.5%) and 17 (42.5%) MPM cases, respectively.	('BAP1', 'Gene', (23, 27))	('expression', 'MPA', (28, 38))	('BAP1', 'Gene', '8314', (23, 27))	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('loss', 'NegReg', (39, 43))	('MPM', 'Disease', (117, 120))	('deletion', 'Var', (66, 74))
198116	30301262	Our results indicate that CNV analysis of tumor and matched cell-line samples were concurrent and both indicated CDKN2A deletion.	('tumor', 'Disease', (42, 47))	('CDKN2A', 'Gene', (113, 119))	('deletion', 'Var', (120, 128))	('CDKN2A', 'Gene', '1029', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('indicated', 'Reg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
198117	30301262	BAP1 loss in MPM is attributed to multiple mechanisms including mutation, DNA methylation, or copy number loss.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (0, 4))	('copy number loss', 'Var', (94, 110))	('MPM', 'Disease', (13, 16))	('DNA methylation', 'Var', (74, 89))	('loss', 'NegReg', (5, 9))	('DNA methylation', 'biological_process', 'GO:0006306', ('74', '89'))	('BAP1', 'Gene', '8314', (0, 4))
198121	30301262	This highlights the stability of CDKN2A and BAP1 genomic deletion in MPM tumors and suggests identification of CNV could offer a potential alternative in MPM diagnostic testing.	('CDKN2A', 'Gene', (33, 39))	('CDKN2A', 'Gene', '1029', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('genomic deletion', 'Var', (49, 65))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MPM tumors', 'Disease', (69, 79))	('BAP1', 'Gene', '8314', (44, 48))	('MPM tumors', 'Disease', 'MESH:D009369', (69, 79))	('BAP1', 'Gene', (44, 48))
198134	30301262	Each FISH assay included normal lung-tissue sections as a negative control, and sections of mesothelioma previously identified as carrying p16 deletion as a positive control.	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('p16', 'Gene', (139, 142))	('mesothelioma', 'Disease', (92, 104))	('deletion', 'Var', (143, 151))
198142	30301262	The sensitivity and specificity of BAP1 and CDKN2A deletion were performed using the crosstabs function of in the descriptive statistics of SPSS.	('CDKN2A', 'Gene', (44, 50))	('BAP1', 'Gene', '8314', (35, 39))	('CDKN2A', 'Gene', '1029', (44, 50))	('BAP1', 'Gene', (35, 39))	('deletion', 'Var', (51, 59))
198143	30301262	Loss of BAP1 and CDKN2A are important diagnostic biomarkers in MPM.	('BAP1', 'Gene', '8314', (8, 12))	('CDKN2A', 'Gene', (17, 23))	('CDKN2A', 'Gene', '1029', (17, 23))	('BAP1', 'Gene', (8, 12))	('MPM', 'Disease', (63, 66))	('Loss', 'Var', (0, 4))
198144	30301262	This study demonstrated the feasibility of genomic deletion as an appropriate biomarker for MPM detection that is consistent in both MPM tumor tissue and matched MPM cell lines.	('genomic deletion', 'Var', (43, 59))	('MPM', 'Disease', (92, 95))	('MPM tumor', 'Disease', (133, 142))	('MPM tumor', 'Disease', 'MESH:D009369', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
198303	29621151	In addition, aberrant focal expression of cytokeratin has been reported in other tumours including angiosarcomas, epithelioid hemangioendotheliomas, epithelioid leiomyosarcomas and meningiomas, undifferentiated pleomorphic sarcomas, rhabdomyosarcomas, malignant rhabdoid tumours and peripheral nerve sheath tumours, clear cell sarcomas, plasmacytomas, diffuse large B-cell lymphomas, anaplastic large cell lymphomas and melanomas.	('anaplastic large cell lymphomas', 'Phenotype', 'HP:0012193', (384, 415))	('lymphomas', 'Disease', 'MESH:D008223', (373, 382))	('tumours', 'Disease', 'MESH:D009369', (307, 314))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (233, 250))	('sarcomas', 'Phenotype', 'HP:0100242', (223, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('lymphomas', 'Disease', (406, 415))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (161, 176))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (194, 231))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (149, 176))	('undifferentiated pleomorphic sarcomas', 'Disease', (194, 231))	('rhabdomyosarcomas', 'Disease', (233, 250))	('peripheral nerve sheath tumours', 'Disease', 'MESH:D010524', (283, 314))	('tumours', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('lymphomas', 'Phenotype', 'HP:0002665', (373, 382))	('epithelioid hemangioendotheliomas', 'Disease', (114, 147))	('angiosarcomas', 'Phenotype', 'HP:0200058', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (307, 313))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (233, 250))	('meningiomas', 'Disease', (181, 192))	('tumours', 'Disease', (271, 278))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (114, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (233, 249))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (406, 414))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('angiosarcomas', 'Disease', (99, 112))	('melanoma', 'Phenotype', 'HP:0002861', (420, 428))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (114, 147))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (242, 250))	('tumours', 'Phenotype', 'HP:0002664', (271, 278))	('lymphoma', 'Phenotype', 'HP:0002665', (373, 381))	('meningiomas', 'Phenotype', 'HP:0002858', (181, 192))	('plasmacytomas', 'Disease', (337, 350))	('peripheral nerve sheath tumours', 'Disease', (283, 314))	('tumours', 'Disease', 'MESH:D009369', (271, 278))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (161, 175))	('lymphomas', 'Disease', (373, 382))	('plasmacytomas', 'Phenotype', 'HP:0011857', (337, 350))	('aberrant', 'Var', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('melanomas', 'Disease', 'MESH:D008545', (420, 429))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (316, 335))	('lymphomas', 'Disease', 'MESH:D008223', (406, 415))	('epithelioid leiomyosarcomas', 'Disease', (149, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (366, 382))	('malignant rhabdoid tumours', 'Disease', 'MESH:C563738', (252, 278))	('melanomas', 'Phenotype', 'HP:0002861', (420, 429))	('lymphomas', 'Phenotype', 'HP:0002665', (406, 415))	('melanomas', 'Disease', (420, 429))	('malignant rhabdoid tumours', 'Disease', (252, 278))	('cytokeratin', 'Gene', (42, 53))	('tumours', 'Disease', (307, 314))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (327, 335))	('angiosarcomas', 'Disease', 'MESH:D006394', (99, 112))	('tumours', 'Phenotype', 'HP:0002664', (307, 314))	('clear cell sarcomas', 'Disease', (316, 335))	('meningiomas', 'Disease', 'MESH:D008577', (181, 192))
198357	29621151	In men, the useful markers for MPM are Calretinin, WT1 (nuclear reactivity) and D2-40.	('WT1', 'Gene', '7490', (51, 54))	('D2-40', 'Var', (80, 85))	('Calretinin', 'Gene', (39, 49))	('WT1', 'Gene', (51, 54))	('MPM', 'Disease', (31, 34))	('Calretinin', 'Gene', '794', (39, 49))	('men', 'Species', '9606', (3, 6))
198358	29621151	Finally, the useful markers for a non-serous carcinoma are: B72.3, MOC31, BG8 and Ber-EP4.	('serous carcinoma', 'Disease', 'MESH:D018284', (38, 54))	('BG8', 'CellLine', 'CVCL:M614', (74, 77))	('Ber', 'biological_process', 'GO:0006284', ('82', '85'))	('BG8', 'Gene', (74, 77))	('serous carcinoma', 'Disease', (38, 54))	('MOC31', 'Var', (67, 72))	('B72.3', 'Var', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
198367	29621151	CDX2 expression may be decreased in right-sided or proximally located colon carcinomas, in poorly differentiated colorectal carcinomas as well as in colorectal carcinomas with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).	('expression', 'MPA', (5, 15))	('dMMR', 'Chemical', '-', (246, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('colorectal carcinomas', 'Disease', (149, 170))	('mismatch repair', 'Var', (219, 234))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (149, 170))	('microsatellite instability-high', 'Var', (176, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('decreased', 'NegReg', (23, 32))	('CDX2', 'Gene', '1045', (0, 4))	('colorectal carcinomas', 'Disease', (113, 134))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (113, 134))	('MSI-H', 'Disease', (209, 214))	('CDX2', 'Gene', (0, 4))	('colon carcinomas', 'Disease', (70, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('colon carcinomas', 'Disease', 'MESH:D015179', (70, 86))	('mismatch repair', 'biological_process', 'GO:0006298', ('219', '234'))	('MSI-H', 'Disease', 'MESH:D000848', (209, 214))
198383	29621151	CK34betaE12 is expressed in approximately 60% of urachal adenocarcinomas and in only 10% of colorectal adenocarcinomas (Figure 5).	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('urachal adenocarcinomas', 'Disease', 'MESH:C536474', (49, 72))	('CK34betaE12', 'Var', (0, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('urachal adenocarcinoma', 'Phenotype', 'HP:0012618', (49, 71))	('colorectal adenocarcinomas', 'Disease', (92, 118))	('urachal adenocarcinomas', 'Phenotype', 'HP:0012618', (49, 72))	('urachal adenocarcinomas', 'Disease', (49, 72))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
198384	29621151	Loss of membrane localization and aberrant nuclear E-cadherin expression is often associated with aggressive progression of certain carcinomas, including primary urachal adenocarcinoma.	('associated with', 'Reg', (82, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('urachal adenocarcinoma', 'Disease', (162, 184))	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('aberrant', 'Var', (34, 42))	('urachal adenocarcinoma', 'Phenotype', 'HP:0012618', (162, 184))	('localization', 'biological_process', 'GO:0051179', ('17', '29'))	('expression', 'MPA', (62, 72))	('membrane', 'cellular_component', 'GO:0016020', ('8', '16'))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('Loss', 'NegReg', (0, 4))	('carcinomas', 'Disease', (132, 142))	('carcinomas', 'Disease', 'MESH:D002277', (132, 142))	('membrane localization', 'MPA', (8, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('urachal adenocarcinoma', 'Disease', 'MESH:C536474', (162, 184))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
198397	29621151	This oncogenic pathway results from the loss of function of the dMMR genes, most often of sporadic origin (80% of cases) by somatic inactivation of the MLH1 gene (hypermethylation of the MLH1 gene promoter), more rarely with genetic harbouring of a deleterious germline mutation in one of the four MMR genes associated with the Lynch syndrome.	('MLH1', 'Gene', (152, 156))	('dMMR', 'Gene', (64, 68))	('dMMR', 'Chemical', '-', (64, 68))	('MLH1', 'Gene', '4292', (152, 156))	('MMR', 'biological_process', 'GO:0006298', ('298', '301'))	('inactivation', 'Var', (132, 144))	('Lynch syndrome', 'Disease', (328, 342))	('Lynch syndrome', 'Disease', 'MESH:D003123', (328, 342))	('loss of function', 'NegReg', (40, 56))	('MLH1', 'Gene', '4292', (187, 191))	('MLH1', 'Gene', (187, 191))
198398	29621151	BRAF gene mutations in MSI-H colorectal cancers are associated with sporadic forms and can be used to rule out the Lynch syndrome.	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (23, 47))	('Lynch syndrome', 'Disease', (115, 129))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('MSI-H colorectal cancers', 'Disease', (23, 47))	('Lynch syndrome', 'Disease', 'MESH:D003123', (115, 129))	('associated', 'Reg', (52, 62))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
198400	29621151	It is important to identify the colorectal origin of a metastatic neoplasm to propose the most appropriate therapy and to initiate molecular testing guiding this treatment: RAS mutations (KRAS and NRAS mutations on exons 2, 3 and 4) for the use of EGFR inhibitors, BRAF mutations on exon 15 for therapeutic intensification and dMMR testing for immunotherapy.	('EGFR', 'Gene', '1956', (248, 252))	('neoplasm', 'Disease', (66, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('248', '252'))	('BRAF', 'Gene', '673', (265, 269))	('mutations', 'Var', (177, 186))	('EGFR', 'Gene', (248, 252))	('mutations', 'Var', (270, 279))	('NRAS', 'Gene', (197, 201))	('neoplasm', 'Disease', 'MESH:D009369', (66, 74))	('KRAS', 'Gene', (188, 192))	('RAS', 'Gene', (173, 176))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('NRAS', 'Gene', '4893', (197, 201))	('dMMR', 'Chemical', '-', (327, 331))	('KRAS', 'Gene', '3845', (188, 192))	('men', 'Species', '9606', (167, 170))	('BRAF', 'Gene', (265, 269))
198414	29621151	A KRAS mutation was found in 56% of mucinous adenocarcinomas, while the mutational status correlated neither with the architectural pattern nor with survival of patients.	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (36, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mucinous adenocarcinomas', 'Disease', (36, 60))	('KRAS', 'Gene', (2, 6))	('patients', 'Species', '9606', (161, 169))	('mutation', 'Var', (7, 15))	('found', 'Reg', (20, 25))	('KRAS', 'Gene', '3845', (2, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))
198422	29621151	NUT midline carcinomas are very aggressive tumours harbouring rearrangements in the NUT gene that can be detected by IHC using an anti-NUT-specific monoclonal antibody.	('NUT', 'Gene', (84, 87))	('NUT midline carcinomas are very aggressive tumours', 'Disease', 'MESH:D000326', (0, 50))	('midline', 'cellular_component', 'GO:0031430', ('4', '11'))	('antibody', 'cellular_component', 'GO:0019814', ('159', '167'))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('rearrangements', 'Var', (62, 76))	('men', 'Species', '9606', (71, 74))	('antibody', 'molecular_function', 'GO:0003823', ('159', '167'))	('antibody', 'cellular_component', 'GO:0042571', ('159', '167'))	('NUT midline carcinomas are very aggressive tumours', 'Disease', (0, 50))	('NUT', 'Gene', (0, 3))	('NUT', 'Gene', '256646', (0, 3))	('NUT', 'Gene', '256646', (135, 138))	('NUT', 'Gene', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('antibody', 'cellular_component', 'GO:0019815', ('159', '167'))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('NUT', 'Gene', '256646', (84, 87))
198434	29621151	A panel of four markers, associating positivity for Maspin A (mammary serine protease inhibitor), S100P (placental S100 protein), IMP-3 (insulin-like growth factor II messenger RNA binding protein-3) and negativity for pVHL (von Hippel-Lindau tumour suppressor), has 100% sensitivity and specificity for distinguishing high grade dysplasia or malignancy from reactive atypia within the biliary-pancreatic system.	('dysplasia', 'Disease', (330, 339))	('malignancy', 'Disease', (343, 353))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (225, 249))	('dysplasia', 'Disease', 'MESH:D004476', (330, 339))	('atypia within the biliary-pancreatic system', 'Disease', 'MESH:D001929', (368, 411))	('IMP-3', 'Gene', (130, 135))	('atypia within the biliary-pancreatic system', 'Disease', (368, 411))	('positivity', 'Var', (37, 47))	('S100', 'Gene', (115, 119))	('Maspin A', 'Gene', (52, 60))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('S100', 'Gene', '6271', (115, 119))	('S100', 'Gene', (98, 102))	('IMP', 'cellular_component', 'GO:0042720', ('130', '133'))	('S100', 'Gene', '6271', (98, 102))	('IMP', 'molecular_function', 'GO:0004244', ('130', '133'))	('RNA', 'cellular_component', 'GO:0005562', ('177', '180'))	('pVHL', 'Gene', '7428', (219, 223))	('pVHL', 'Gene', (219, 223))	('S100P', 'Gene', '6286', (98, 103))	('von Hippel-Lindau tumour', 'Disease', (225, 249))	('malignancy', 'Disease', 'MESH:D009369', (343, 353))	('S100P', 'Gene', (98, 103))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('137', '163'))	('RNA binding', 'molecular_function', 'GO:0003723', ('177', '188'))	('IMP-3', 'Gene', '55272', (130, 135))
198438	29621151	Finally, activating mutations in the KRAS oncogene are likely the single most common genetic abnormality in pancreatic cancer, present in ~90-95% of cases.	('activating mutations', 'Var', (9, 29))	('genetic abnormality', 'Disease', 'MESH:D030342', (85, 104))	('genetic abnormality', 'Disease', (85, 104))	('pancreatic cancer', 'Disease', (108, 125))	('KRAS', 'Gene', (37, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('KRAS', 'Gene', '3845', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
198439	29621151	Despite the low specificity, a KRAS gene mutation could provide additional diagnostic criteria.	('mutation', 'Var', (41, 49))	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '3845', (31, 35))
198453	29621151	Other markers, described as highly specific of a prostate origin, can also be used alone or in combination to determine a prostate origin, such as P501S (prostein), PSAM (prostate-specific antigen membrane) and NKX3.1.	('PSA', 'Gene', (165, 168))	('NKX3.1', 'Gene', '4824', (211, 217))	('PSA', 'Gene', '354', (165, 168))	('P501S', 'Mutation', 'p.P501S', (147, 152))	('P501S', 'Var', (147, 152))	('NKX3.1', 'Gene', (211, 217))	('membrane', 'cellular_component', 'GO:0016020', ('197', '205'))
198495	29621151	IHC may provide an efficient screening tool for "druggable" genomic alterations by taking advantage of a growing list of available mutation-specific antibodies (i.e., ALK rearrangements, D5F3 and 5A4 clones; ROS1 rearrangements, clone D4D6; BRAF V600E mutation, clone VE1; EGFR exon 19 E746_A750del, 6B6 clone; EGFR exon 21 L858R mutation, 43B2 clone).	('A750del', 'Mutation', 'c.750delA', (291, 298))	('EGFR', 'Gene', (273, 277))	('E746_A750del', 'Var', (286, 298))	('BRAF', 'Gene', (241, 245))	('L858R', 'Var', (324, 329))	('EGFR', 'molecular_function', 'GO:0005006', ('271', '275'))	('EGFR', 'Gene', (311, 315))	('ROS1', 'Gene', '6098', (208, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('309', '313'))	('EGFR', 'Gene', '1956', (273, 277))	('men', 'Species', '9606', (222, 225))	('ALK', 'Gene', '238', (167, 170))	('V600E', 'Mutation', 'rs113488022', (246, 251))	('ALK', 'Gene', (167, 170))	('men', 'Species', '9606', (180, 183))	('L858R', 'Mutation', 'rs121434568', (324, 329))	('EGFR', 'Gene', '1956', (311, 315))	('BRAF', 'Gene', '673', (241, 245))	('ROS1', 'Gene', (208, 212))
198500	29621151	Aberrant or unexpected antigen expression should be considered as a source of a diagnostic pitfall in the evaluation of undifferentiated tumours.	('Aberrant', 'Var', (0, 8))	('undifferentiated tumours', 'Disease', 'MESH:D002277', (120, 144))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('undifferentiated tumours', 'Disease', (120, 144))	('antigen', 'Protein', (23, 30))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
198518	29621151	On the other hand, CD34 is almost always negative in both components and a positive CD34 rules out the diagnosis of synovial sarcoma.	('CD34', 'Gene', '947', (19, 23))	('CD34', 'Gene', '947', (84, 88))	('positive', 'Var', (75, 83))	('CD34', 'Gene', (19, 23))	('synovial sarcoma', 'Disease', (116, 132))	('CD34', 'Gene', (84, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('synovial sarcoma', 'Disease', 'MESH:D013584', (116, 132))
198519	29621151	More than 95% of synovial sarcomas are characterized by a recurrent, tumour-specific translocation t(X;18)(p11;q11), that can be detected by FISH in looking for the rearrangement in the SS18 (SYT) gene.	('tumour', 'Disease', (69, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('SS18', 'Gene', (186, 190))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('t(X;18)(p11;q11', 'Var', (99, 114))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (17, 34))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('SS18', 'Gene', '6760', (186, 190))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('synovial sarcomas', 'Disease', 'MESH:D013584', (17, 34))	('synovial sarcomas', 'Disease', (17, 34))	('men', 'Species', '9606', (174, 177))
198529	29621151	About half of soft tissue myoepitheliomas show specific translocations involving the EWSR1 gene with variable partners such as the POU5F1, PBXI and ZNF444 genes.	('POU5F1', 'Gene', (131, 137))	('EWSR1', 'Gene', '2130', (85, 90))	('POU5F1', 'Gene', '5460', (131, 137))	('myoepitheliomas', 'Disease', (26, 41))	('myoepitheliomas', 'Disease', 'MESH:D009208', (26, 41))	('EWSR1', 'Gene', (85, 90))	('translocations', 'Var', (56, 70))
198530	29621151	These translocations can be detected by FISH by identifying a rearrangement in the EWSR1 gene.	('men', 'Species', '9606', (71, 74))	('rearrangement', 'Var', (62, 75))	('EWSR1', 'Gene', '2130', (83, 88))	('EWSR1', 'Gene', (83, 88))
198535	29621151	The search for the SS18 gene rearrangement gives a reliable diagnosis: the presence of a SS18 gene rearrangement in synovial sarcomas and the absence in MPNSTs.	('men', 'Species', '9606', (38, 41))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (116, 133))	('rearrangement', 'Var', (99, 112))	('SS18', 'Gene', (19, 23))	('SS18', 'Gene', '6760', (89, 93))	('men', 'Species', '9606', (108, 111))	('synovial sarcomas', 'Disease', 'MESH:D013584', (116, 133))	('synovial sarcomas', 'Disease', (116, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('presence', 'Var', (75, 83))	('SS18', 'Gene', (89, 93))	('SS18', 'Gene', '6760', (19, 23))
198562	28560410	Furthermore, XML184 and XMD8-92 treatment impaired invasion and tumor sphere formation ability of H290 mesothelioma cells.	('sph', 'Gene', (70, 73))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('tumor', 'Disease', (64, 69))	('XMD8-92', 'Chemical', 'MESH:C568790', (24, 31))	('mesothelioma', 'Disease', (103, 115))	('sph', 'Gene', '253970', (70, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('invasion', 'CPA', (51, 59))	('XMD8-92', 'Var', (24, 31))	('H290', 'CellLine', 'CVCL:A555', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('impaired', 'NegReg', (42, 50))
198629	28560410	Our results showed that moderate to strong staining for MET was detected in 67.1% of the analyzed mesothelioma tumor samples but in only 12.5% of the normal pleural tissues.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MET', 'Var', (56, 59))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (98, 116))	('detected', 'Reg', (64, 72))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (98, 116))	('ate ', 'Gene', (29, 33))	('ate ', 'Gene', '472', (29, 33))	('mesothelioma tumor', 'Disease', (98, 116))
198631	28560410	Four of the tested mesothelioma cell lines H290, H513, H28 and 211H showed strong positive staining for MET, whereas MS-1, H2052 and normal mesothelial cell line LP9 showed negative staining for MET, indicating a lack of expression (Fig.	('H290', 'CellLine', 'CVCL:A555', (43, 47))	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('MET', 'Var', (104, 107))	('H513', 'CellLine', 'CVCL:A570', (49, 53))	('LP9', 'CellLine', 'CVCL:E109', (162, 165))	('mesothelioma', 'Disease', (19, 31))
198653	28560410	5, the OS times with high DCLK1 staining is significantly shorter than those with low DCLK1 staining (0-1) (24 vs. 21, P=0.0235), which indicated DCLK1 level is a potential indicator of OS survival of MPM patients.	('MPM', 'Disease', (201, 204))	('shorter', 'NegReg', (58, 65))	('patients', 'Species', '9606', (205, 213))	('DCLK1', 'Gene', (26, 31))	('high', 'Var', (21, 25))	('DCLK1', 'Gene', (86, 91))	('DCLK1', 'Gene', '9201', (26, 31))	('DCLK1', 'Gene', (146, 151))	('is a', 'Gene', (158, 162))	('OS times', 'CPA', (7, 15))	('DCLK1', 'Gene', '9201', (86, 91))	('is a', 'Gene', '312', (158, 162))	('DCLK1', 'Gene', '9201', (146, 151))
198655	28560410	A higher dose of XL184 and XMD8-92 resulted in lower viability of the mesothelioma cell lines.	('lower', 'NegReg', (47, 52))	('XMD8-92', 'Chemical', 'MESH:C568790', (27, 34))	('XL184', 'Chemical', 'MESH:C558660', (17, 22))	('XL184', 'Var', (17, 22))	('mesothelioma', 'Disease', (70, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('XMD8-92', 'Var', (27, 34))	('viability', 'CPA', (53, 62))
198658	28560410	In contrast, XL184 had minimal inhibitory effects on the viability of the normal human mesothelial cell line LP9.	('LP9', 'CellLine', 'CVCL:E109', (109, 112))	('XL184', 'Var', (13, 18))	('XL184', 'Chemical', 'MESH:C558660', (13, 18))	('ntr', 'Gene', '4923', (5, 8))	('human', 'Species', '9606', (81, 86))	('ntr', 'Gene', (5, 8))
198659	28560410	Three cell lines (H290, H513 and H28) stained positive with anti-ERK5 antibody, which also showed relative high sensitivity to the ERK5 inhibitor XMD8-92.	('antibody', 'cellular_component', 'GO:0042571', ('70', '78'))	('ERK', 'molecular_function', 'GO:0004707', ('65', '68'))	('ERK', 'molecular_function', 'GO:0004707', ('131', '134'))	('H513', 'CellLine', 'CVCL:A570', (24, 28))	('H290', 'CellLine', 'CVCL:A555', (18, 22))	('antibody', 'cellular_component', 'GO:0019815', ('70', '78'))	('antibody', 'cellular_component', 'GO:0019814', ('70', '78'))	('XMD8-92', 'Chemical', 'MESH:C568790', (146, 153))	('positive', 'Reg', (46, 54))	('antibody', 'molecular_function', 'GO:0003823', ('70', '78'))	('anti-ERK5', 'Var', (60, 69))
198661	28560410	We found that phosphor-MET, phospho-ERK5 and DCLK1 protein level decreased after treatment with XL184 (Fig.	('ERK', 'molecular_function', 'GO:0004707', ('36', '39'))	('sph', 'Gene', '253970', (17, 20))	('decreased', 'NegReg', (65, 74))	('sph', 'Gene', '253970', (31, 34))	('DCLK1', 'Gene', (45, 50))	('XL184', 'Var', (96, 101))	('sph', 'Gene', (17, 20))	('DCLK1', 'Gene', '9201', (45, 50))	('XL184', 'Chemical', 'MESH:C558660', (96, 101))	('sph', 'Gene', (31, 34))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
198667	28560410	The use of specific inhibitors, XL184 and XMD8-92, one targeting MET signaling and the other targeting ERK5, decreased the mRNA levels and protein levels of DCLK1 in human mesothelioma cells, suggesting that DCLK1 lies downstream of both MET and ERK5 signaling.	('XL184', 'Var', (32, 37))	('ERK', 'molecular_function', 'GO:0004707', ('246', '249'))	('DCLK1', 'Gene', '9201', (208, 213))	('protein levels', 'MPA', (139, 153))	('DCLK1', 'Gene', (157, 162))	('ERK5, ', 'Gene', '5598', (103, 109))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('human', 'Species', '9606', (166, 171))	('XMD8-92', 'Chemical', 'MESH:C568790', (42, 49))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('mesothelioma', 'Disease', (172, 184))	('DCLK1', 'Gene', '9201', (157, 162))	('mesothelioma', 'Disease', 'MESH:D008654', (172, 184))	('XMD8-92', 'Var', (42, 49))	('DCLK1', 'Gene', (208, 213))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('XL184', 'Chemical', 'MESH:C558660', (32, 37))
198673	28560410	The cell viability of H2052 was not affected by 1.0 microM XL184 and 1.0 microM XMD8-92 treatment for 20 h compared to cells treated with 0.1% DMSO.	('croM', 'Gene', '1604', (75, 79))	('cell viability', 'CPA', (4, 18))	('XL184', 'Var', (59, 64))	('DMSO', 'Chemical', 'MESH:D004121', (143, 147))	('XL184', 'Chemical', 'MESH:C558660', (59, 64))	('H2052', 'Var', (22, 27))	('XMD8-92', 'Chemical', 'MESH:C568790', (80, 87))	('croM', 'Gene', (54, 58))	('croM', 'Gene', '1604', (54, 58))	('croM', 'Gene', (75, 79))
198683	28560410	Deregulated activity of MET can lead to many different cancers.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('lead to', 'Reg', (32, 39))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('MET', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
198690	28560410	XL184, which also affects the VEGF receptor 2, and has significant inhibitory activity against numerous solid tumors including melanoma, non-small cell lung cancer, breast cancer, liver cancer, ovarian cancer, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('XL184', 'Var', (0, 5))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (137, 163))	('numerous solid tumors', 'Disease', 'MESH:D009369', (95, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('liver cancer', 'Phenotype', 'HP:0002896', (180, 192))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('liver cancer', 'Disease', (180, 192))	('VEGF receptor 2', 'Protein', (30, 45))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('ovarian cancer', 'Disease', (194, 208))	('breast cancer', 'Disease', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (214, 229))	('prostate cancer', 'Phenotype', 'HP:0012125', (214, 229))	('non-small cell lung cancer', 'Disease', (137, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('prostate cancer', 'Disease', (214, 229))	('XL184', 'Chemical', 'MESH:C558660', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('inhibitory activity', 'MPA', (67, 86))	('affects', 'Reg', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('numerous solid tumors', 'Disease', (95, 116))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('liver cancer', 'Disease', 'MESH:D006528', (180, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (194, 208))
198692	28560410	Interestingly, four analyzed human mesothelioma cell lines (H290, H513, H28 and 211H) which had high expression of MET showed relative high sensitivity (IC50, H290-1.27 microM; H513-1.54 microM; H28-0.62 microM; 211H-0.46 microM) to the MET inhibitor XL184.	('croM', 'Gene', '1604', (171, 175))	('croM', 'Gene', (206, 210))	('croM', 'Gene', (224, 228))	('H290-1.27', 'Var', (159, 168))	('mesothelioma', 'Disease', (35, 47))	('croM', 'Gene', (189, 193))	('croM', 'Gene', '1604', (224, 228))	('croM', 'Gene', '1604', (189, 193))	('croM', 'Gene', '1604', (206, 210))	('XL184', 'Chemical', 'MESH:C558660', (251, 256))	('H513', 'CellLine', 'CVCL:A570', (66, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('H290-1.27', 'CellLine', 'CVCL:A555', (159, 168))	('human', 'Species', '9606', (29, 34))	('H290', 'CellLine', 'CVCL:A555', (159, 163))	('H290', 'CellLine', 'CVCL:A555', (60, 64))	('H513', 'CellLine', 'CVCL:A570', (177, 181))	('croM', 'Gene', (171, 175))
198696	28560410	Furthermore, XL184 significantly inhibited the invasion and tumorsphere formation ability of H290.	('XL184', 'Var', (13, 18))	('XL184', 'Chemical', 'MESH:C558660', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('H290', 'CellLine', 'CVCL:A555', (93, 97))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('tumorsphere formation ability', 'CPA', (60, 89))	('inhibited', 'NegReg', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
198701	28560410	In a mouse model, ERK5 knockdown increases tumor epithelialization and suppresses intravascular invasion by reducing the generation of circulating tumor cells (CTCs) and the formation of lung metastases in human breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('ntr', 'Gene', (83, 86))	('lung metastases', 'Disease', 'MESH:D009362', (187, 202))	('tumor', 'Disease', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('tumor', 'Disease', (147, 152))	('breast cancer', 'Disease', (212, 225))	('lung metastases', 'Disease', (187, 202))	('increases tumor', 'Disease', 'MESH:D009369', (33, 48))	('ERK', 'molecular_function', 'GO:0004707', ('18', '21'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mouse', 'Species', '10090', (5, 10))	('ERK5', 'Gene', (18, 22))	('ntr', 'Gene', '4923', (83, 86))	('suppresses', 'NegReg', (71, 81))	('human', 'Species', '9606', (206, 211))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('reducing', 'NegReg', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('increases tumor', 'Disease', (33, 48))	('knockdown', 'Var', (23, 32))
198709	28560410	Like XL184, XMD8-92 significantly inhibited the invasion and tumorsphere formation ability of H290.	('tumorsphere formation ability', 'CPA', (61, 90))	('XL184', 'Chemical', 'MESH:C558660', (5, 10))	('XMD8-92', 'Var', (12, 19))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('H290', 'CellLine', 'CVCL:A555', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('XMD8-92', 'Chemical', 'MESH:C568790', (12, 19))	('XL184', 'Var', (5, 10))
198720	28560410	Constitutive activation of ERK5 in various malignant mesothelioma cell lines could be a consequence of activated MET.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (43, 65))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('malignant mesothelioma', 'Disease', (43, 65))	('activation', 'PosReg', (13, 23))	('MET', 'Var', (113, 116))	('ERK5', 'Protein', (27, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (43, 65))
198726	28560410	We found that XMD8-92 not only decreased the protein levels of phospho-ERK5, but also decreased the protein levels of DCLK1 in mesothelioma cells (Fig.	('protein levels', 'MPA', (45, 59))	('mesothelioma', 'Disease', (127, 139))	('DCLK1', 'Gene', '9201', (118, 123))	('decreased', 'NegReg', (31, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('sph', 'Gene', '253970', (66, 69))	('decreased', 'NegReg', (86, 95))	('XMD8-92', 'Chemical', 'MESH:C568790', (14, 21))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('ERK5, ', 'Gene', '5598', (71, 77))	('sph', 'Gene', (66, 69))	('DCLK1', 'Gene', (118, 123))	('XMD8-92', 'Var', (14, 21))	('protein levels', 'MPA', (100, 114))
198850	26396196	where rs1 and rs2 are two positive constants.	('rs1', 'Gene', '6247', (6, 9))	('rs1', 'Gene', (6, 9))	('rs2', 'DBSNP_MENTION', 'None', (14, 17))	('rs2', 'Var', (14, 17))
198853	26396196	According to the experimental data from several studies, elevating cIP3 mainly changes the mean and the maximum (mu and ri,max) of the bell-shaped curve of ccyt dependence.	('bell-shaped curve', 'MPA', (135, 152))	('elevating', 'Var', (57, 66))	('cIP3', 'Gene', '11340', (67, 71))	('ccyt dependence', 'MPA', (156, 171))	('ccyt', 'Chemical', '-', (156, 160))	('changes', 'Reg', (79, 86))	('cIP3', 'Gene', (67, 71))	('mean', 'MPA', (91, 95))
198854	26396196	Nevertheless, based on the experimental data presented, elevating cIP3 also has an effect on the loading of the ER.	('effect', 'Reg', (83, 89))	('cIP3', 'Gene', (66, 70))	('loading', 'MPA', (97, 104))	('elevating', 'Var', (56, 65))	('cIP3', 'Gene', '11340', (66, 70))
198906	26396196	Briefly, after serum readministration, the addition of CGP-37157 (50 mum), a nonspecific blocker of the mitochondrial Na+/Ca2+ exchanger, had no effect on the patterns of Ca2+ oscillations in either ccyt or cmito (data not shown).	('mito', 'Species', '262676', (104, 108))	('CGP-37157', 'Var', (55, 64))	('Ca2+ oscillations', 'MPA', (171, 188))	('Na+/Ca2+ exchanger', 'Gene', '6546', (118, 136))	('ccyt', 'Chemical', '-', (199, 203))	('mito', 'Species', '262676', (208, 212))	('rat', 'Species', '10116', (31, 34))	('Na+/Ca2+ exchanger', 'Gene', (118, 136))	('exchanger', 'molecular_function', 'GO:0015297', ('127', '136'))	('CGP', 'Chemical', '-', (55, 58))
198907	26396196	However, some cells pretreated with CGP-37157 for 30 min displayed stairlike increases in cmito (Fig.	('mito', 'Species', '262676', (91, 95))	('CGP', 'Chemical', '-', (36, 39))	('increases', 'PosReg', (77, 86))	('CGP-37157', 'Var', (36, 45))
198911	26396196	Pretreatment of cells with 10 mum Ru-360 reduced the average oscillation frequency (approximately a 30% decrease during each time segment) and the initial mitochondrial Ca2+ uptake (Fig.	('reduced', 'NegReg', (41, 48))	('mito', 'Species', '262676', (155, 159))	('mitochondrial Ca2+ uptake', 'MPA', (155, 180))	('Ru-360', 'Var', (34, 40))	('decrease', 'NegReg', (104, 112))	('Ru-360', 'Chemical', 'MESH:C112020', (34, 40))	('uptake', 'biological_process', 'GO:0098657', ('174', '180'))	('uptake', 'biological_process', 'GO:0098739', ('174', '180'))
198912	26396196	However, it is currently still unclear whether in intact cells Ru-360 acts uniquely by the inhibition of the mitochondrial Ca2+ uptake or additionally by the inhibition of the extracellular Ca2+ influx.	('Ru-360', 'Chemical', 'MESH:C112020', (63, 69))	('mito', 'Species', '262676', (109, 113))	('inhibition', 'NegReg', (91, 101))	('extracellular Ca2+ influx', 'MPA', (176, 201))	('uptake', 'biological_process', 'GO:0098739', ('128', '134'))	('uptake', 'biological_process', 'GO:0098657', ('128', '134'))	('mitochondrial Ca2+ uptake', 'MPA', (109, 134))	('inhibition', 'NegReg', (158, 168))	('Ru-360', 'Var', (63, 69))	('extracellular', 'cellular_component', 'GO:0005576', ('176', '189'))
198929	26396196	In addition, CCCP also decreased the basal level in ccyt (both at 100 and 10 mum), signifying that also the plasma membrane potential was affected.	('CCCP', 'Chemical', 'MESH:D002258', (13, 17))	('plasma membrane', 'cellular_component', 'GO:0005886', ('108', '123'))	('ccyt', 'MPA', (52, 56))	('ccyt', 'Chemical', '-', (52, 56))	('affected', 'Reg', (138, 146))	('CCCP', 'Var', (13, 17))	('decreased', 'NegReg', (23, 32))	('basal level', 'MPA', (37, 48))
198938	26396196	Shortly after the collapse of DeltaPsi induced by CCCP, an immediate fall in ATP levels was observed (Fig.	('ATP levels', 'MPA', (77, 87))	('fall', 'NegReg', (69, 73))	('DeltaPsi', 'MPA', (30, 38))	('fall', 'Phenotype', 'HP:0002527', (69, 73))	('CCCP', 'Chemical', 'MESH:D002258', (50, 54))	('CCCP', 'Var', (50, 54))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))
198939	26396196	Overall, our findings indicate that the oscillation stop induced by the protonophore CCCP is not exclusively the result of the decreased mitochondrial Ca2+ uptake but also mediated via CCCP-induced changes in plasmalemmal Ca2+ influx and decreased ATP production.	('CCCP', 'Chemical', 'MESH:D002258', (85, 89))	('uptake', 'biological_process', 'GO:0098657', ('156', '162'))	('decreased', 'NegReg', (127, 136))	('changes', 'Reg', (198, 205))	('uptake', 'biological_process', 'GO:0098739', ('156', '162'))	('CCCP', 'Chemical', 'MESH:D002258', (185, 189))	('ATP production', 'MPA', (248, 262))	('ATP', 'Chemical', 'MESH:D000255', (248, 251))	('mito', 'Species', '262676', (137, 141))	('decreased', 'NegReg', (238, 247))	('mitochondrial Ca2+ uptake', 'MPA', (137, 162))	('plasmalemmal Ca2+ influx', 'MPA', (209, 233))	('CCCP-induced', 'Var', (185, 197))	('CCCP', 'Gene', (85, 89))
198956	26396196	In some cases, La3+ treatment caused a final longer lasting Ca2+ spike (Fig.	('La3+', 'Chemical', '-', (15, 19))	('Ca2+ spike', 'MPA', (60, 70))	('La3+', 'Var', (15, 19))
198961	26396196	Based on previous findings that human mesothelioma in vivo, mesothelioma cells in vitro, and reactive mesothelial cells express calretinin, we hypothesized that prMC also might express this protein and that its presence might affect the Ca2+ oscillations.	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('mesothelioma', 'Disease', (38, 50))	('calretinin', 'Gene', '794', (128, 138))	('calretinin', 'Gene', (128, 138))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('presence', 'Var', (211, 219))	('prMC', 'Chemical', '-', (161, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (38, 50))	('Ca2+ oscillations', 'MPA', (237, 254))	('human', 'Species', '9606', (32, 37))	('affect', 'Reg', (226, 232))	('mesothelioma', 'Disease', (60, 72))
198998	26396196	Ca2+ transients in ccyt were previously reported to evoke an increase in cmito, activating both cytoplasmic and mitochondrial enzymes.	('cytoplasmic', 'Enzyme', (96, 107))	('cmito', 'MPA', (73, 78))	('mitochondrial', 'Enzyme', (112, 125))	('mito', 'Species', '262676', (74, 78))	('Ca2+ transients', 'Var', (0, 15))	('ccyt', 'Gene', (19, 23))	('mito', 'Species', '262676', (112, 116))	('activating', 'PosReg', (80, 90))	('increase', 'PosReg', (61, 69))	('ccyt', 'Chemical', '-', (19, 23))
199013	26396196	A similar phenomenon is also observed in our model; the total cellular Ca2+ content (ccyt + cER + cmito) determines the response to the La3+ insulation; blocking of the Ca2+ influx and efflux results in an oscillation stop that can either occur after a final Ca2+ spike or directly after La3+ addition, i.e.	('oscillation stop', 'MPA', (206, 222))	('Ca2+ influx', 'MPA', (169, 180))	('ccyt', 'Chemical', '-', (85, 89))	('efflux', 'biological_process', 'GO:0140115', ('185', '191'))	('efflux', 'biological_process', 'GO:0140352', ('185', '191'))	('results in', 'Reg', (192, 202))	('efflux', 'MPA', (185, 191))	('mito', 'Species', '262676', (99, 103))	('La3+', 'Chemical', '-', (288, 292))	('La3+', 'Chemical', '-', (136, 140))	('blocking', 'Var', (153, 161))
199019	26396196	One has to keep in mind that CCCP also results in the collapse of the plasma membrane potential, which subsequently reduces the plasmalemmal Ca2+ influx.	('collapse of the plasma membrane potential', 'MPA', (54, 95))	('reduces', 'NegReg', (116, 123))	('plasmalemmal Ca2+ influx', 'MPA', (128, 152))	('results in', 'Reg', (39, 49))	('plasma membrane', 'cellular_component', 'GO:0005886', ('70', '85'))	('CCCP', 'Var', (29, 33))	('CCCP', 'Chemical', 'MESH:D002258', (29, 33))
199047	26396196	Moreover, down-regulation of calretinin by lentiviral infection induces apoptosis in mesothelioma cell lines in vitro via an intrinsic mitochondrion-mediated pathway.	('mesothelioma', 'Disease', (85, 97))	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('mito', 'Species', '262676', (135, 139))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('calretinin', 'Gene', (29, 39))	('lentiviral', 'Var', (43, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('intrinsic mitochondrion-mediated pathway', 'Pathway', (125, 165))	('apoptosis', 'CPA', (72, 81))	('mitochondrion', 'cellular_component', 'GO:0005739', ('135', '148'))	('down-regulation', 'NegReg', (10, 25))	('calretinin', 'Gene', '794', (29, 39))
199073	25774992	A mouse model reported that PD-L1 is highly expressed in the tumor cells and within tumor stroma and PD-L1 blockade results in T cell activation.	('tumor stroma', 'Disease', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('T cell activation', 'biological_process', 'GO:0042110', ('127', '144'))	('activation', 'PosReg', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('T cell', 'CPA', (127, 133))	('tumor', 'Disease', (84, 89))	('tumor stroma', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mouse', 'Species', '10090', (2, 7))	('PD-L1', 'Gene', (28, 33))	('blockade', 'Var', (107, 115))	('tumor', 'Disease', (61, 66))	('PD-L1', 'Gene', (101, 106))
199089	25774992	The antibodies used for tumor-infiltrating lymphocytes (TILs) were anti-human CD4 (clone BC/1F6;Abcam) and anti-human CD8 (clone 4B11;Novocastra).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CD4', 'Gene', '920', (78, 81))	('tumor', 'Disease', (24, 29))	('TIL', 'Gene', '7096', (56, 59))	('human', 'Species', '9606', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('anti-human', 'Var', (107, 117))	('CD8', 'Gene', (118, 121))	('CD4', 'Gene', (78, 81))	('TIL', 'Gene', (56, 59))	('CD8', 'Gene', '925', (118, 121))	('human', 'Species', '9606', (112, 117))	('anti-human', 'Var', (67, 77))
199121	25774992	Patients with PD-L1 positive expression presented shorter survival than PD-L1 negative patients (Fig.	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (50, 57))	('PD-L1', 'Gene', (14, 19))	('patients', 'Species', '9606', (87, 95))	('positive expression', 'Var', (20, 39))	('survival', 'MPA', (58, 66))
199122	25774992	Median survival for PD-L1 positive patients was 4.8 months and 16.3 months for PD-L1 negative patients (p = 0.012).	('positive', 'Var', (26, 34))	('PD-L1', 'Gene', (20, 25))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (35, 43))
199125	25774992	Median survival for patients with weak, moderate and strong PD-L1 staining was 6.1, 5.2 and 2.6 months respectively (p = 0.9).	('staining', 'Var', (66, 74))	('patients', 'Species', '9606', (20, 28))	('PD-L1', 'Protein', (60, 65))
199144	25774992	The clinical trial with MPDL3280A suggests that tumor-expressed membrane PD-L1 and immune infiltrate cell correlates with response to anti-PD-1 therapy.	('tumor', 'Disease', (48, 53))	('MPDL3280A', 'Var', (24, 33))	('membrane', 'cellular_component', 'GO:0016020', ('64', '72'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
199162	25774992	In a tumor model of mesothelioma they reported PD-L1 is ubiquitously expressed in the tumor stroma, and that PD-L1 blockade results in T cell activation  In summary, this is the first report measuring PD-L1 protein levels in MPM with the E1L3N antibody.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('antibody', 'cellular_component', 'GO:0019814', ('244', '252'))	('antibody', 'cellular_component', 'GO:0019815', ('244', '252'))	('mesothelioma', 'Disease', (20, 32))	('T cell activation', 'biological_process', 'GO:0042110', ('135', '152'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (86, 91))	('antibody', 'molecular_function', 'GO:0003823', ('244', '252'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('tumor stroma', 'Disease', 'MESH:D009369', (86, 98))	('tumor', 'Disease', (5, 10))	('antibody', 'cellular_component', 'GO:0042571', ('244', '252'))	('tumor stroma', 'Disease', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('PD-L1', 'MPA', (201, 206))	('E1L3N', 'Var', (238, 243))
199166	32545767	Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas.	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (194, 217))	('mutations', 'Var', (90, 99))	('SH2D2A', 'Gene', (122, 128))	('FBXO10', 'Gene', (114, 120))	('CDH5', 'Gene', (130, 134))	('ATM', 'Gene', '472', (109, 112))	('EHD1', 'Gene', '10938', (103, 107))	('TP73', 'Gene', '7161', (148, 152))	('MAGED1', 'Gene', '9500', (136, 142))	('FBXO10', 'Gene', '26267', (114, 120))	('WDPM', 'Disease', (163, 167))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (194, 217))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (194, 216))	('TP73', 'Gene', (148, 152))	('ATM', 'Gene', (109, 112))	('CDH5', 'Gene', '1003', (130, 134))	('malignant mesotheliomas', 'Disease', (194, 217))	('EHD1', 'Gene', (103, 107))	('MAGED1', 'Gene', (136, 142))
199167	32545767	Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas.	('malignant mesotheliomas', 'Disease', (136, 159))	('WDPM', 'Disease', (26, 30))	('C > A transversion substitution mutations', 'Var', (57, 98))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (136, 159))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (136, 158))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (136, 159))
199174	32545767	Genome-wide sequencing analyses of malignant mesotheliomas have revealed frequently observed genomic aberrations such as loss of function mutation and/or copy number alterations/deletion of BAP1, SETD2, CDKN2A, and NF2.	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (35, 58))	('BAP1', 'Gene', '8314', (190, 194))	('copy number alterations/deletion', 'Var', (154, 186))	('malignant mesotheliomas', 'Disease', (35, 58))	('CDKN2A', 'Gene', (203, 209))	('NF2', 'Gene', (215, 218))	('BAP1', 'Gene', (190, 194))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (35, 58))	('loss of function', 'NegReg', (121, 137))	('mutation', 'Var', (138, 146))	('CDKN2A', 'Gene', '1029', (203, 209))	('SETD2', 'Gene', '29072', (196, 201))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (35, 57))	('SETD2', 'Gene', (196, 201))	('NF2', 'Gene', '4771', (215, 218))
199175	32545767	Case studies have reported WDPMs with somatic mutation of E2F1, heterozygous loss of NF2, and germline BAP1 mutation, which if correct would suggest that they may be variants of malignant mesothelioma.	('BAP1', 'Gene', '8314', (103, 107))	('WDPMs', 'Disease', (27, 32))	('NF2', 'Gene', '4771', (85, 88))	('BAP1', 'Gene', (103, 107))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (178, 200))	('malignant mesothelioma', 'Disease', (178, 200))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (178, 200))	('mutation', 'Var', (108, 116))	('NF2', 'Gene', (85, 88))	('E2F1', 'Gene', '1869', (58, 62))	('E2F1', 'Gene', (58, 62))
199177	32545767	performed genomic profiling of 10 WDPMs and found that they harbored TRAF7 or CDC42 mutually exclusive missense mutations.	('TRAF7', 'Gene', '84231', (69, 74))	('missense mutations', 'Var', (103, 121))	('CDC42', 'Gene', '998', (78, 83))	('TRAF7', 'Gene', (69, 74))	('CDC42', 'Gene', (78, 83))
199181	32545767	Two genes:FBXO10 and SH2D2A:were mutated in all five WDPM cases, again displaying consistent mutational patterns (Figure 2C).	('WDPM', 'Disease', (53, 57))	('FBXO10', 'Gene', (10, 16))	('FBXO10', 'Gene', '26267', (10, 16))	('mutated', 'Var', (33, 40))	('SH2D2A', 'Gene', (21, 27))
199183	32545767	The variant allele frequency (VAF) of EHD1 was in the range 29-43%, indicating its likely clonal origin (given that the tumor cellularity of the WDPM tissues were estimated to be about 50%) (Figure S1).	('EHD1', 'Gene', (38, 42))	('AF', 'Disease', 'MESH:D001281', (31, 33))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('variant', 'Var', (4, 11))	('tumor', 'Disease', (120, 125))	('EHD1', 'Gene', '10938', (38, 42))
199184	32545767	Notably, we identified missense mutation in DNA-damage response gene ATM in four cases (Figure 2C,E).	('ATM', 'Gene', '472', (69, 72))	('DNA-damage response', 'biological_process', 'GO:0006974', ('44', '63'))	('missense mutation', 'Var', (23, 40))	('ATM', 'Gene', (69, 72))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))
199187	32545767	The gene encoding cadherin 5 (CDH5) harbored CDH5D714E mutations in its C-terminus cadherin protein domain in four cases (Figure 2C,F).	('mutations', 'Var', (55, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('CDH5', 'Gene', (30, 34))	('CDH5', 'Gene', '1003', (30, 34))	('CDH5', 'Gene', (45, 49))	('CDH5', 'Gene', '1003', (45, 49))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('cadherin 5', 'Gene', '1003', (18, 28))	('cadherin 5', 'Gene', (18, 28))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
199194	32545767	Furthermore, we also identified mutations in MAGED1 and TP73 in each of the four WDPM cases (Figure 2C).	('TP73', 'Gene', '7161', (56, 60))	('TP73', 'Gene', (56, 60))	('MAGED1', 'Gene', (45, 51))	('mutations', 'Var', (32, 41))	('MAGED1', 'Gene', '9500', (45, 51))
199196	32545767	Notably, we found copy number gain of SETDB2 and LAST2 and copy number loss of SMARCA4 and TRAF7 in WDPM-02.	('SETDB2', 'Gene', '83852', (38, 44))	('SMARCA4', 'Gene', (79, 86))	('LAST2', 'Gene', (49, 54))	('TRAF7', 'Gene', (91, 96))	('copy number', 'Var', (59, 70))	('SMARCA4', 'Gene', '6597', (79, 86))	('TRAF7', 'Gene', '84231', (91, 96))	('copy number', 'Var', (18, 29))	('gain', 'PosReg', (30, 34))	('SETDB2', 'Gene', (38, 44))
199197	32545767	We also found copy number loss of cancer genes such as CCNE1, MAF, MAFB, MYC, ZNF479, and MGMT and copy number gain of FOXA2, CDH10, and GPC5 in at least two WDPM cases.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('FOXA2', 'Gene', (119, 124))	('MGMT', 'Gene', '4255', (90, 94))	('MAF', 'Gene', (62, 65))	('MGMT', 'molecular_function', 'GO:0003908', ('90', '94'))	('number loss of cancer', 'Disease', 'MESH:D007680', (19, 40))	('FOXA2', 'Gene', '3170', (119, 124))	('CCNE1', 'Gene', (55, 60))	('MAF', 'Gene', '4094', (62, 65))	('CDH10', 'Gene', (126, 131))	('MYC', 'Gene', (73, 76))	('MAFB', 'Gene', '9935', (67, 71))	('ZNF479', 'Gene', '90827', (78, 84))	('CCNE1', 'Gene', '898', (55, 60))	('MAF', 'Gene', (67, 70))	('GPC5', 'Gene', '2262', (137, 141))	('MAFB', 'Gene', (67, 71))	('MGMT', 'Gene', (90, 94))	('number loss of cancer', 'Disease', (19, 40))	('gain', 'PosReg', (111, 115))	('MAF', 'Gene', '4094', (67, 70))	('MYC', 'Gene', '4609', (73, 76))	('CDH10', 'Gene', '1008', (126, 131))	('copy number', 'Var', (99, 110))	('ZNF479', 'Gene', (78, 84))	('GPC5', 'Gene', (137, 141))
199198	32545767	Our analysis revealed that WDPM mutations target different signaling pathways often dysregulated in cancer (Figure 3 and Table S5) such as pathways in cancer, focal adhesion, Vascular endothelial growth factor (VEGF) signaling, Janus kinases - signal transducer and activator of transcription (JAK-STAT) signaling, Wnt signaling, P53 signaling, apoptosis, etc.	('P53 signaling', 'Pathway', (330, 343))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('175', '209'))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('VEGF', 'Gene', (211, 215))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('focal adhesion', 'cellular_component', 'GO:0005925', ('159', '173'))	('transcription', 'biological_process', 'GO:0006351', ('279', '292'))	('VEGF) signaling', 'biological_process', 'GO:0038084', ('211', '226'))	('signaling', 'biological_process', 'GO:0023052', ('334', '343'))	('mutations', 'Var', (32, 41))	('Vascular endothelial growth factor', 'Gene', '493845', (175, 209))	('cancer', 'Disease', (151, 157))	('Vascular endothelial growth factor', 'Gene', (175, 209))	('apoptosis', 'CPA', (345, 354))	('WDPM', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('signaling', 'biological_process', 'GO:0023052', ('304', '313'))	('cancer', 'Disease', (100, 106))	('JAK', 'molecular_function', 'GO:0004713', ('294', '297'))	('VEGF', 'Gene', '493845', (211, 215))	('Wnt signaling', 'Pathway', (315, 328))	('apoptosis', 'biological_process', 'GO:0097194', ('345', '354'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('apoptosis', 'biological_process', 'GO:0006915', ('345', '354'))	('signaling pathways', 'Pathway', (59, 77))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('signaling', 'biological_process', 'GO:0023052', ('319', '328'))
199199	32545767	We found CDH5 mutations target cell adhesion and the leukocyte migration pathway, EHD1 mutations target endocytosis, SH2D2A mutations target the VEGF signaling pathway, ATM mutations target apoptosis and P53 signaling pathways, and TP73 targets the neurotrophin signaling and P53 signaling pathways.	('leukocyte migration pathway', 'Pathway', (53, 80))	('VEGF signaling', 'biological_process', 'GO:0038084', ('145', '159'))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('target', 'Reg', (134, 140))	('TP73', 'Gene', (232, 236))	('mutations', 'Var', (87, 96))	('P53 signaling pathways', 'Pathway', (204, 226))	('VEGF', 'Gene', '493845', (145, 149))	('CDH5', 'Gene', (9, 13))	('signaling pathway', 'biological_process', 'GO:0007165', ('150', '167'))	('P53 signaling pathways', 'Pathway', (276, 298))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('apoptosis', 'Pathway', (190, 199))	('mutations', 'Var', (14, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('EHD1', 'Gene', (82, 86))	('VEGF', 'Gene', (145, 149))	('ATM', 'Gene', '472', (169, 172))	('mutations', 'Var', (173, 182))	('SH2D2A', 'Gene', (117, 123))	('neurotrophin', 'Gene', '627', (249, 261))	('cell adhesion', 'MPA', (31, 44))	('neurotrophin', 'molecular_function', 'GO:0005163', ('249', '261'))	('leukocyte migration', 'biological_process', 'GO:0050900', ('53', '72'))	('neurotrophin', 'molecular_function', 'GO:0005165', ('249', '261'))	('mutations', 'Var', (124, 133))	('CDH5', 'Gene', '1003', (9, 13))	('cell adhesion', 'biological_process', 'GO:0007155', ('31', '44'))	('signaling', 'biological_process', 'GO:0023052', ('280', '289'))	('target', 'Reg', (24, 30))	('EHD1', 'Gene', '10938', (82, 86))	('neurotrophin', 'Gene', (249, 261))	('TP73', 'Gene', '7161', (232, 236))	('endocytosis', 'MPA', (104, 115))	('ATM', 'Gene', (169, 172))	('endocytosis', 'biological_process', 'GO:0006897', ('104', '115'))	('target', 'Reg', (183, 189))	('signaling', 'biological_process', 'GO:0023052', ('262', '271'))
199202	32545767	We first assessed the pattern of mutations in WDPM and peritoneal mesothelioma cases.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (55, 78))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (55, 78))	('mutations', 'Var', (33, 42))	('WDPM', 'Gene', (46, 50))	('peritoneal mesothelioma', 'Disease', (55, 78))
199203	32545767	Intriguingly, we observed that WDPM has a strong enrichment of C > A transversion substitution mutation (Figure 2A,B), whereas, peritoneal mesothelioma has strong enrichment of C > T transition substitution mutation (Figure S4).	('peritoneal mesothelioma', 'Disease', (128, 151))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (128, 151))	('C > A transversion substitution mutation', 'Var', (63, 103))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (128, 151))	('WDPM', 'Disease', (31, 35))	('C > T transition substitution', 'Var', (177, 206))
199205	32545767	Notably, we found WDPM specific mutations in EHD1, FBXO10, CHD5, MAGED1, ATM, and TP73 genes that were absent in peritoneal mesothelioma (Figure 4A).	('ATM', 'Gene', (73, 76))	('EHD1', 'Gene', (45, 49))	('FBXO10', 'Gene', (51, 57))	('ATM', 'Gene', '472', (73, 76))	('MAGED1', 'Gene', '9500', (65, 71))	('peritoneal mesothelioma', 'Disease', (113, 136))	('FBXO10', 'Gene', '26267', (51, 57))	('mutations', 'Var', (32, 41))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (113, 136))	('TP73', 'Gene', '7161', (82, 86))	('TP73', 'Gene', (82, 86))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (113, 136))	('CHD5', 'Gene', (59, 63))	('EHD1', 'Gene', '10938', (45, 49))	('CHD5', 'Gene', '26038', (59, 63))	('MAGED1', 'Gene', (65, 71))
199206	32545767	Although mutations in EHD1 and ATM genes were each observed in peritoneal mesothelioma, we did not find the WDPM-specific EHD1D147A, EHD1A465D, and ATMK2303R mutations in these cases.	('EHD1', 'Gene', (122, 126))	('ATM', 'Gene', '472', (31, 34))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (63, 86))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (63, 86))	('mutations', 'Var', (9, 18))	('ATM', 'Gene', '472', (148, 151))	('EHD1', 'Gene', '10938', (133, 137))	('EHD1', 'Gene', '10938', (22, 26))	('EHD1', 'Gene', '10938', (122, 126))	('observed', 'Reg', (51, 59))	('ATM', 'Gene', (31, 34))	('peritoneal mesothelioma', 'Disease', (63, 86))	('EHD1', 'Gene', (133, 137))	('EHD1', 'Gene', (22, 26))	('ATM', 'Gene', (148, 151))
199207	32545767	Interestingly, in WDPM, we did not find any of the mutations in BAP1, SETD2, TP53, NF2, CDKN2A, and LAST1/2 frequently observed in malignant mesotheliomas (Figure 4A).	('CDKN2A', 'Gene', (88, 94))	('mutations', 'Var', (51, 60))	('NF2', 'Gene', (83, 86))	('CDKN2A', 'Gene', '1029', (88, 94))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (131, 154))	('observed', 'Reg', (119, 127))	('malignant mesotheliomas', 'Disease', (131, 154))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (131, 154))	('SETD2', 'Gene', '29072', (70, 75))	('NF2', 'Gene', '4771', (83, 86))	('BAP1', 'Gene', '8314', (64, 68))	('SETD2', 'Gene', (70, 75))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (131, 153))	('BAP1', 'Gene', (64, 68))
199208	32545767	We also did not find mutations in TRAF7 or CDC42 in WDPM, however, TRAF7 mutations were observed in several peritoneal mesothelioma cases.	('CDC42', 'Gene', (43, 48))	('peritoneal mesothelioma', 'Disease', (108, 131))	('CDC42', 'Gene', '998', (43, 48))	('TRAF7', 'Gene', '84231', (34, 39))	('observed', 'Reg', (88, 96))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (108, 131))	('TRAF7', 'Gene', (67, 72))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (108, 131))	('TRAF7', 'Gene', (34, 39))	('TRAF7', 'Gene', '84231', (67, 72))	('mutations', 'Var', (73, 82))
199211	32545767	TRAF copy number loss was observed in one WDPM case, whereas, several peritoneal mesothelioma cases harbored TRAF7 copy number alteration.	('copy number', 'Var', (5, 16))	('TRAF7', 'Gene', '84231', (109, 114))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (70, 93))	('copy number alteration', 'Var', (115, 137))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (70, 93))	('TRAF7', 'Gene', (109, 114))	('AF', 'Disease', 'MESH:D001281', (2, 4))	('AF', 'Disease', 'MESH:D001281', (111, 113))	('loss', 'NegReg', (17, 21))	('peritoneal mesothelioma', 'Disease', (70, 93))
199215	32545767	Indeed, our most important finding is the lack of alterations involving BAP1, SETD2, NF2, CDKN2A, PBRM1, and SMARCC1 genes consistently mutated or deleted in malignant mesotheliomas.	('PBRM1', 'Gene', (98, 103))	('CDKN2A', 'Gene', '1029', (90, 96))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (158, 181))	('deleted', 'Var', (147, 154))	('SETD2', 'Gene', '29072', (78, 83))	('NF2', 'Gene', '4771', (85, 88))	('BAP1', 'Gene', '8314', (72, 76))	('malignant mesotheliomas', 'Disease', (158, 181))	('SMARCC1', 'Gene', (109, 116))	('PBRM1', 'Gene', '55193', (98, 103))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (158, 181))	('SETD2', 'Gene', (78, 83))	('SMARCC1', 'Gene', '6599', (109, 116))	('BAP1', 'Gene', (72, 76))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (158, 180))	('mutated', 'Var', (136, 143))	('CDKN2A', 'Gene', (90, 96))	('NF2', 'Gene', (85, 88))
199216	32545767	The WDPMs harbored distinct mutations in EHD1, FBXO10, CHD5, MAGED1, ATM, and TP73 genes either in all five or at least four out of five WDPM cases.	('CHD5', 'Gene', '26038', (55, 59))	('ATM', 'Gene', '472', (69, 72))	('EHD1', 'Gene', (41, 45))	('MAGED1', 'Gene', (61, 67))	('MAGED1', 'Gene', '9500', (61, 67))	('FBXO10', 'Gene', (47, 53))	('TP73', 'Gene', '7161', (78, 82))	('TP73', 'Gene', (78, 82))	('ATM', 'Gene', (69, 72))	('FBXO10', 'Gene', '26267', (47, 53))	('mutations', 'Var', (28, 37))	('EHD1', 'Gene', '10938', (41, 45))	('CHD5', 'Gene', (55, 59))
199219	32545767	Mutations and copy number changes in CDH5 have been previously reported in mesotheliomas but are uncommon events and were not present in any of our reference mesothelioma datasets (Figure 3).	('reported', 'Reg', (63, 71))	('mesothelioma', 'Disease', (158, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('CDH5', 'Gene', (37, 41))	('CDH5', 'Gene', '1003', (37, 41))	('Mutations', 'Var', (0, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('mesotheliomas', 'Disease', 'MESH:D008654', (75, 88))	('mesotheliomas', 'Disease', (75, 88))	('mesothelioma', 'Disease', (75, 87))	('copy number changes', 'Var', (14, 33))
199225	32545767	Mutations in FBXO10, SH2D2A, and TP73 has not been reported in any malignant mesotheliomas.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (67, 89))	('FBXO10', 'Gene', '26267', (13, 19))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (67, 90))	('Mutations', 'Var', (0, 9))	('SH2D2A', 'Gene', (21, 27))	('TP73', 'Gene', (33, 37))	('TP73', 'Gene', '7161', (33, 37))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (67, 90))	('FBXO10', 'Gene', (13, 19))	('malignant mesotheliomas', 'Disease', (67, 90))
199227	32545767	Copy number loss of BAP1, SETD2, PBRM1, and SMARCC1 is often observed in peritoneal mesothelioma.	('PBRM1', 'Gene', '55193', (33, 38))	('peritoneal mesothelioma', 'Disease', 'MESH:D010534', (73, 96))	('SMARCC1', 'Gene', (44, 51))	('BAP1', 'Gene', (20, 24))	('SETD2', 'Gene', '29072', (26, 31))	('SMARCC1', 'Gene', '6599', (44, 51))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (73, 96))	('SETD2', 'Gene', (26, 31))	('observed', 'Reg', (61, 69))	('peritoneal mesothelioma', 'Disease', (73, 96))	('BAP1', 'Gene', '8314', (20, 24))	('PBRM1', 'Gene', (33, 38))	('Copy number loss', 'Var', (0, 16))
199228	32545767	Copy number loss of BAP1, CDKN2A/B, LAST1/2, and NF2 is frequently found in pleural mesothelioma.	('pleural mesothelioma', 'Disease', (76, 96))	('CDKN2A', 'Gene', (26, 32))	('BAP1', 'Gene', (20, 24))	('NF2', 'Gene', (49, 52))	('CDKN2A', 'Gene', '1029', (26, 32))	('found', 'Reg', (67, 72))	('NF2', 'Gene', '4771', (49, 52))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (76, 96))	('BAP1', 'Gene', '8314', (20, 24))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (76, 96))	('Copy number loss', 'Var', (0, 16))
199231	32545767	Alterations in TRAF7 have also been reported in malignant mesotheliomas.	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (48, 71))	('TRAF7', 'Gene', (15, 20))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (48, 70))	('Alterations', 'Var', (0, 11))	('malignant mesotheliomas', 'Disease', (48, 71))	('reported', 'Reg', (36, 44))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (48, 71))	('TRAF7', 'Gene', '84231', (15, 20))
199236	32545767	We note that, despite high sequencing depth, no mutations in ATM (which was examined in the UCSF500 panel) were reported by Stevers et al., whereas we identified consistent ATMK2303R mutations in 4 out of 5 WDPM cases (Figure S5C).	('mutations', 'Var', (183, 192))	('ATM', 'Gene', '472', (173, 176))	('ATM', 'Gene', (61, 64))	('WDPM', 'Disease', (207, 211))	('ATM', 'Gene', '472', (61, 64))	('ATM', 'Gene', (173, 176))
199237	32545767	We did identify a few low confidence TRAF7 mutations, but these did not pass our mutation filtering criteria (see Table S6 and Appendix A for detailed information).	('mutations', 'Var', (43, 52))	('TRAF7', 'Gene', '84231', (37, 42))	('TRAF7', 'Gene', (37, 42))
199246	32545767	Non-silent exonic variants including non-synonymous single nucleotide variations (SNVs), stop-codon gain SNVs, stop-codon loss SNVs, splice site SNVs, and frameshift In-Dels in coding regions were retained if they were supported by more than 50 reads.	('loss SNVs', 'Disease', (122, 131))	('gain', 'PosReg', (100, 104))	('frameshift In-Dels', 'Var', (155, 173))	('stop-codon', 'MPA', (111, 121))	('loss SNVs', 'Disease', 'MESH:D014786', (122, 131))	('stop-codon', 'MPA', (89, 99))
199258	32545767	Mutations in gene CDC42 and TRAF7 reported Stevers et al.	('TRAF7', 'Gene', '84231', (28, 33))	('CDC42', 'Gene', '998', (18, 23))	('CDC42', 'Gene', (18, 23))	('Mutations', 'Var', (0, 9))	('TRAF7', 'Gene', (28, 33))
199263	32545767	reported two unique mutations in CDC42 and six unique mutations in TRAF7.	('TRAF7', 'Gene', (67, 72))	('CDC42', 'Gene', '998', (33, 38))	('TRAF7', 'Gene', '84231', (67, 72))	('mutations', 'Var', (20, 29))	('CDC42', 'Gene', (33, 38))
199264	32545767	We identified three unique very low confidence mutations in the TRAF7 gene, one in WDPM-03 and two in WDPM-01 (Supplementary Table S6).	('TRAF7', 'Gene', (64, 69))	('WDPM-01', 'CellLine', 'CVCL:9726', (102, 109))	('TRAF7', 'Gene', '84231', (64, 69))	('mutations', 'Var', (47, 56))
199267	32545767	Given that the tumor cellularity of the WDPM tissues was estimated to be about 50%, the TRAF mutations mentioned above were deemed very low confidence and hence did not pass our mutation filtering criteria.	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('AF', 'Disease', 'MESH:D001281', (90, 92))	('tumor', 'Disease', (15, 20))
199268	32545767	The rest of the CDC42 and TRAF7 mutated regions reported by Stevers et al.	('mutated', 'Var', (32, 39))	('TRAF7', 'Gene', (26, 31))	('CDC42', 'Gene', '998', (16, 21))	('CDC42', 'Gene', (16, 21))	('TRAF7', 'Gene', '84231', (26, 31))
199271	30060470	To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma.	('human', 'Species', '9606', (34, 39))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (40, 62))	('malignant mesothelioma', 'Disease', (269, 291))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('human', 'Species', '9606', (263, 268))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (40, 62))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (269, 291))	('mice', 'Species', '10090', (155, 159))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('malignant mesothelioma', 'Disease', (40, 62))	('mutations', 'Var', (171, 180))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (269, 291))	('tumour', 'Disease', (184, 190))
199304	30060470	Gene fusions and splice alterations were also described mostly in NF2, BAP1 and SETD2 genes.	('NF2', 'Gene', (66, 69))	('SETD2', 'Gene', (80, 85))	('Gene fusions', 'Var', (0, 12))	('SETD2', 'Gene', '235626', (80, 85))	('NF2', 'Gene', '18016', (66, 69))	('BAP1', 'Gene', (71, 75))	('splice alterations', 'Var', (17, 35))
199305	30060470	So far, no recurrent oncogene was found altered in MM, but an oncogenic hotspot mutation was reported in the promoter of TERT in 15% MPM.	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '21752', (121, 125))	('mutation', 'Var', (80, 88))
199306	30060470	However amplification of oncogenes such as PDGFRB, MYC or VEGFR could play a role in mesothelial neoplastic transformation.	('play', 'Reg', (70, 74))	('MYC', 'Gene', '17869', (51, 54))	('amplification', 'Var', (8, 21))	('MYC', 'Gene', (51, 54))	('mesothelial neoplastic', 'Disease', (85, 107))	('role', 'Reg', (77, 81))	('VEGFR', 'Gene', (58, 63))	('PDGFRB', 'Gene', '18596', (43, 49))	('PDGFRB', 'Gene', (43, 49))
199310	30060470	Hippo and PI3K/AKT/mTOR are deregulated either because of the mutation in critical genes of the pathway and/or inappropriate activation of members of the pathway.	('activation', 'PosReg', (125, 135))	('AKT', 'Gene', '11651', (15, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('10', '14'))	('Hippo', 'Pathway', (0, 5))	('mTOR', 'Gene', (19, 23))	('mutation', 'Var', (62, 70))	('AKT', 'Gene', (15, 18))	('mTOR', 'Gene', '56717', (19, 23))	('deregulated', 'PosReg', (28, 39))
199320	30060470	These mutations result in the alteration of several signal pathways such as Hippo, mTOR, histone methylation, RNA helicase and p53 pathways.	('signal pathways', 'Pathway', (52, 67))	('mTOR', 'Gene', (83, 87))	('mTOR', 'Gene', '56717', (83, 87))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('histone methylation', 'biological_process', 'GO:0016571', ('89', '108'))	('histone', 'Protein', (89, 96))	('p53', 'Gene', '22059', (127, 130))	('alteration', 'Reg', (30, 40))	('RNA', 'Protein', (110, 113))	('Hippo', 'Pathway', (76, 81))	('mutations', 'Var', (6, 15))	('p53', 'Gene', (127, 130))
199321	30060470	Hippo pathway was altered in all molecular subtypes, mTOR more in biphasic-S. Histone methylation and BAP1 alteration were more frequent in epithelioid MPM.	('BAP1', 'Gene', (102, 106))	('Histone methylation', 'biological_process', 'GO:0016571', ('78', '97'))	('epithelioid MPM', 'Disease', (140, 155))	('mTOR', 'Gene', '56717', (53, 57))	('altered', 'Reg', (18, 25))	('methylation', 'Var', (86, 97))	('Hippo pathway', 'Pathway', (0, 13))	('mTOR', 'Gene', (53, 57))	('alteration', 'Var', (107, 117))	('frequent', 'Reg', (128, 136))
199355	30060470	In all but one cell line, recurrent genomic changes included homozygous (Hom) loss of Cdkn2a (this gene encodes two proteins, p16Ink4a and p19Arf) and deletion in Lats2 and Setd2, but no mutation in Bap1 or Nf2.	('Cdkn2a', 'Gene', (86, 92))	('p19Arf', 'Gene', '12578', (139, 145))	('Bap1', 'Gene', (199, 203))	('Nf2', 'Gene', '18016', (207, 210))	('p19Arf', 'Gene', (139, 145))	('Lats2', 'Gene', (163, 168))	('Setd2', 'Gene', (173, 178))	('p16Ink4a', 'Gene', '12578', (126, 134))	('Lats2', 'Gene', '50523', (163, 168))	('loss', 'NegReg', (78, 82))	('Setd2', 'Gene', '235626', (173, 178))	('deletion', 'Var', (151, 159))	('p19', 'cellular_component', 'GO:0070743', ('139', '142'))	('Cdkn2a', 'Gene', '12578', (86, 92))	('p16Ink4a', 'Gene', (126, 134))	('Bap1', 'Gene', '104416', (199, 203))	('Nf2', 'Gene', (207, 210))
199357	30060470	Several pathways were affected by mutations such as Wnt, Hedgehog, Notch, mTOR, MAPK and p53 pathways, but not Hippo.	('affected', 'Reg', (22, 30))	('MAPK', 'Pathway', (80, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('mTOR', 'Gene', (74, 78))	('p53', 'Gene', (89, 92))	('mTOR', 'Gene', '56717', (74, 78))	('Hedgehog', 'Gene', (57, 65))	('p53', 'Gene', '22059', (89, 92))	('Wnt', 'Gene', (52, 55))	('mutations', 'Var', (34, 43))	('Notch', 'Gene', (67, 72))
199359	30060470	Moreover, mesotheliomas arose in the absence of alteration of Bap1 and Nf2, as in HMM, consistent with a role of other pathways affected by the genes mutated at low frequency, or epigenetic mechanism.	('Nf2', 'Gene', (71, 74))	('Bap1', 'Gene', '104416', (62, 66))	('mesotheliomas', 'Disease', 'MESH:D008654', (10, 23))	('mesotheliomas', 'Disease', (10, 23))	('Nf2', 'Gene', '18016', (71, 74))	('Bap1', 'Gene', (62, 66))	('HMM', 'Disease', (82, 85))	('alteration', 'Var', (48, 58))
199360	30060470	An epigenetic mechanism of inactivation of Cdkn2a locus was suggested to be an initial step of MuMM induction, leading later to allelic deletion of Arf, in WT mice exposed to CNT by intrapleural instillation.	('Cdkn2a', 'Gene', '12578', (43, 49))	('Arf', 'Gene', (148, 151))	('Cdkn2a', 'Gene', (43, 49))	('deletion', 'Var', (136, 144))	('mice', 'Species', '10090', (159, 163))
199362	30060470	GEM in Rb, Tsc1 and Pten were also generated despite the absence of mutation in HMM.	('GEM', 'Chemical', '-', (0, 3))	('absence', 'NegReg', (57, 64))	('mutation', 'Var', (68, 76))	('Rb', 'Chemical', 'MESH:D012413', (7, 9))	('Pten', 'Gene', (20, 24))	('Tsc1', 'Gene', (11, 15))	('Pten', 'Gene', '19211', (20, 24))	('HMM', 'Gene', (80, 83))	('Tsc1', 'Gene', '64930', (11, 15))
199365	30060470	injected AdCre in the pleural cavity of mice carrying conditional mutant alleles in Nf2, Cdkn2a, Trp53 or Rb, and Htz Ink4a mutant.	('Ink4a', 'Gene', (118, 123))	('Nf2', 'Gene', (84, 87))	('mutant', 'Var', (66, 72))	('Trp53', 'Gene', (97, 102))	('mutant', 'Var', (124, 130))	('Rb', 'Chemical', 'MESH:D012413', (106, 108))	('Cdkn2a', 'Gene', '12578', (89, 95))	('Nf2', 'Gene', '18016', (84, 87))	('Cdkn2a', 'Gene', (89, 95))	('Ink4a', 'Gene', '12578', (118, 123))	('mice', 'Species', '10090', (40, 44))	('Trp53', 'Gene', '22059', (97, 102))
199366	30060470	The highest rate of thoracic MuMM was observed in double mutants Nf2 and Cdkn2a, Trp53 or Rb and triple mutants Nf2, Trp53 and Ink4a.	('Cdkn2a', 'Gene', '12578', (73, 79))	('Cdkn2a', 'Gene', (73, 79))	('Nf2', 'Gene', (112, 115))	('Trp53', 'Gene', (117, 122))	('Ink4a', 'Gene', '12578', (127, 132))	('Trp53', 'Gene', '22059', (81, 86))	('thoracic MuMM', 'CPA', (20, 33))	('Nf2', 'Gene', (65, 68))	('Rb', 'Chemical', 'MESH:D012413', (90, 92))	('Ink4a', 'Gene', (127, 132))	('Trp53', 'Gene', '22059', (117, 122))	('Nf2', 'Gene', '18016', (112, 115))	('Trp53', 'Gene', (81, 86))	('Nf2', 'Gene', '18016', (65, 68))	('double mutants', 'Var', (50, 64))
199367	30060470	Mutations in Cdkn2a, Ink4a or Trp53 were the most pejorative in term of MuMM incidence.	('Trp53', 'Gene', '22059', (30, 35))	('Ink4a', 'Gene', '12578', (21, 26))	('Cdkn2a', 'Gene', '12578', (13, 19))	('Mutations', 'Var', (0, 9))	('Cdkn2a', 'Gene', (13, 19))	('Ink4a', 'Gene', (21, 26))	('MuMM', 'Disease', (72, 76))	('Trp53', 'Gene', (30, 35))
199368	30060470	Rb inactivation induces the lowest incidence of MuMM.	('Rb', 'Chemical', 'MESH:D012413', (0, 2))	('MuMM', 'Disease', (48, 52))	('inactivation', 'Var', (3, 15))
199369	30060470	Hom Nf2 enhanced tumours rate in Rb mutants.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('Nf2', 'Gene', (4, 7))	('enhanced', 'PosReg', (8, 16))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('mutants', 'Var', (36, 43))	('Nf2', 'Gene', '18016', (4, 7))	('Rb', 'Chemical', 'MESH:D012413', (33, 35))
199371	30060470	injected AdCre in the peritoneal cavity or in the bladder, in conditional mutants Trp53 and Tsc1.	('Trp53', 'Gene', '22059', (82, 87))	('Tsc1', 'Gene', (92, 96))	('Tsc1', 'Gene', '64930', (92, 96))	('Trp53', 'Gene', (82, 87))	('mutants', 'Var', (74, 81))
199372	30060470	High rate of MuMM was found in double Hom Trp53/Tsc1 mutants, but none in Htz/Hom mutants.	('MuMM', 'Disease', (13, 17))	('Trp53', 'Gene', (42, 47))	('Trp53', 'Gene', '22059', (42, 47))	('mutants', 'Var', (53, 60))	('double Hom', 'Var', (31, 41))	('Tsc1', 'Gene', (48, 52))	('Tsc1', 'Gene', '64930', (48, 52))
199375	30060470	Three types of Htz Bap1 mutants were generated in mice, one was knockout in exons 6 and 7 of Bap1, and the two others with point mutations identical to germline mutations found in two human families (W and L, respectively) with a BAP1 cancer syndrome presenting mesothelioma in several family members.	('mutants', 'Var', (24, 31))	('mesothelioma', 'Disease', (262, 274))	('Bap1', 'Gene', '104416', (93, 97))	('cancer syndrome', 'Disease', 'MESH:D009369', (235, 250))	('cancer syndrome', 'Disease', (235, 250))	('Bap1', 'Gene', (93, 97))	('Bap1', 'Gene', '104416', (19, 23))	('human', 'Species', '9606', (184, 189))	('mice', 'Species', '10090', (50, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (262, 274))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Bap1', 'Gene', (19, 23))
199376	30060470	Htz germline mutations in BAP1 predispose to a range of benign and malignant tumours, including mesothelioma.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('BAP1', 'Gene', (26, 30))	('malignant tumours', 'Disease', 'MESH:D009369', (67, 84))	('predispose', 'Reg', (31, 41))	('mesothelioma', 'Disease', (96, 108))	('benign and', 'Disease', (56, 66))	('malignant tumours', 'Disease', (67, 84))	('germline mutations', 'Var', (4, 22))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
199378	30060470	The tumour type with the highest incidence was ovarian sex cord stromal tumours, 38 of 60 (63%) in Bap1 mutant mice.	('Bap1', 'Gene', (99, 103))	('sex cord stromal tumours', 'Phenotype', 'HP:0031918', (55, 79))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('ovarian sex cord stromal tumours', 'Disease', (47, 79))	('ovarian sex cord stromal tumours', 'Disease', 'MESH:D018312', (47, 79))	('mutant', 'Var', (104, 110))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('mice', 'Species', '10090', (111, 115))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (4, 10))	('Bap1', 'Gene', '104416', (99, 103))	('tumour', 'Disease', (72, 78))
199380	30060470	However, Htz Trp53 in association with Htz or Hom Tcs1 did not induce MM, contrary to its association with Nf2, but consistent with a bona fine role of Nf2 in MM.	('Hom', 'Var', (46, 49))	('Tcs1', 'Gene', '21752', (50, 54))	('Nf2', 'Gene', '18016', (152, 155))	('Nf2', 'Gene', '18016', (107, 110))	('induce', 'Reg', (63, 69))	('Htz', 'Var', (9, 12))	('Trp53', 'Gene', '22059', (13, 18))	('Tcs1', 'Gene', (50, 54))	('association', 'Interaction', (22, 33))	('Nf2', 'Gene', (107, 110))	('Nf2', 'Gene', (152, 155))	('Trp53', 'Gene', (13, 18))
199381	30060470	Results also showed that Bap1 Htz mutations are not sufficient to induce MuMM.	('Bap1', 'Gene', (25, 29))	('induce', 'Reg', (66, 72))	('MuMM', 'Disease', (73, 77))	('Bap1', 'Gene', '104416', (25, 29))	('mutations', 'Var', (34, 43))
199383	30060470	Despite the different genetic background of mice, these studies underline several key genes for MM, consistent with findings in HMM, and that MM can develop with a variety TGS mutations, and likely with more than one TSG.	('mutations', 'Var', (176, 185))	('TGS', 'biological_process', 'GO:0006342', ('172', '175'))	('TSG', 'Gene', '65960', (217, 220))	('develop', 'Reg', (149, 156))	('TGS mutations', 'Var', (172, 185))	('mice', 'Species', '10090', (44, 48))	('TSG', 'Gene', (217, 220))
199391	30060470	Inactivation of Asc in GEM non-significantly reduced the percentage of mice with MuMM, but the disease-free survival was significantly lowered.	('mice', 'Species', '10090', (71, 75))	('Asc', 'Gene', (16, 19))	('reduced', 'NegReg', (45, 52))	('disease-free survival', 'CPA', (95, 116))	('MuMM', 'Disease', (81, 85))	('Asc', 'Gene', '20905', (16, 19))	('GEM', 'Chemical', '-', (23, 26))	('Inactivation', 'Var', (0, 12))	('lowered', 'NegReg', (135, 142))
199397	30060470	Inactivation of Cdkn2a and Cdkn2b was predominant, and resulted from biallelic deletions.	('Cdkn2a', 'Gene', '12578', (16, 22))	('Cdkn2b', 'Gene', (27, 33))	('resulted from', 'Reg', (55, 68))	('Cdkn2a', 'Gene', (16, 22))	('Cdkn2b', 'Gene', '12579', (27, 33))	('Inactivation', 'Var', (0, 12))
199398	30060470	Otherwise, co-deletion of Cdkn2a (Ink4a and Arf) and Cdkn2b was predominant.	('co-deletion', 'Var', (11, 22))	('Cdkn2b', 'Gene', '12579', (53, 59))	('Cdkn2a', 'Gene', '12578', (26, 32))	('Ink4a', 'Gene', '12578', (34, 39))	('Cdkn2a', 'Gene', (26, 32))	('Ink4a', 'Gene', (34, 39))	('Cdkn2b', 'Gene', (53, 59))
199399	30060470	Rates of Trp53 mutations were less frequent, about 20% as in HMM.	('HMM', 'Disease', (61, 64))	('mutations', 'Var', (15, 24))	('Trp53', 'Gene', '22059', (9, 14))	('Trp53', 'Gene', (9, 14))
199400	30060470	Two cell lines with alteration of Trp53 were Cdkn2a (Ink4a and Arf) and Cdkn2b WT, suggesting two different pathways of carcinogenesis.	('Trp53', 'Gene', (34, 39))	('Ink4a', 'Gene', (53, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('alteration', 'Var', (20, 30))	('carcinogenesis', 'Disease', (120, 134))	('Trp53', 'Gene', '22059', (34, 39))	('Cdkn2b', 'Gene', (72, 78))	('Cdkn2a', 'Gene', '12578', (45, 51))	('Cdkn2b', 'Gene', '12579', (72, 78))	('Ink4a', 'Gene', '12578', (53, 58))	('Cdkn2a', 'Gene', (45, 51))
199402	30060470	reported biallelic inactivation of Arf in all cell lines from Htz Arf mice, in 3/7 from WT mice, and no deletion of Ink4a or Ink4b (Cdkn2b) in all but one cell line from these mice, and no loss of p53 protein.	('mice', 'Species', '10090', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('Ink4a', 'Gene', (116, 121))	('Cdkn2b', 'Gene', '12579', (132, 138))	('Ink4b', 'Gene', (125, 130))	('mice', 'Species', '10090', (176, 180))	('p53', 'Gene', (197, 200))	('mice', 'Species', '10090', (70, 74))	('Cdkn2b', 'Gene', (132, 138))	('inactivation', 'NegReg', (19, 31))	('p53', 'Gene', '22059', (197, 200))	('Arf', 'Gene', (35, 38))	('Ink4b', 'Gene', '12579', (125, 130))	('deletion', 'Var', (104, 112))	('Ink4a', 'Gene', '12578', (116, 121))
199405	30060470	Accordingly, in Htz Cdkn2a (Ink4a and Arf) mice, a biallelic loss of both Ink4a and Arf was observed, with protein loss of p16Ink4a and p19ARF, and in Htz Ink4a mice, there was a biallelic inactivation of Ink4a, loss of p16Ink4a or p53, and frequent loss p15Inkba and p19Arf, but one cell line from Htz Ink4a mice expressed p19Arf but did not express p53.	('p19Arf', 'Gene', '12578', (268, 274))	('p19', 'cellular_component', 'GO:0070743', ('136', '139'))	('Ink4a', 'Gene', '12578', (28, 33))	('Ink4a', 'Gene', (205, 210))	('p19ARF', 'Gene', '12578', (136, 142))	('Cdkn2a', 'Gene', '12578', (20, 26))	('p53', 'Gene', (232, 235))	('Ink4a', 'Gene', (28, 33))	('Ink4a', 'Gene', '12578', (155, 160))	('Ink4a', 'Gene', '12578', (74, 79))	('loss', 'NegReg', (61, 65))	('Ink4a', 'Gene', (155, 160))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('Ink4a', 'Gene', (74, 79))	('p53', 'Gene', (351, 354))	('p19Arf', 'Gene', (324, 330))	('loss', 'NegReg', (115, 119))	('loss', 'NegReg', (250, 254))	('Cdkn2a', 'Gene', (20, 26))	('p16Ink4a', 'Gene', (220, 228))	('p19ARF', 'Gene', (136, 142))	('mice', 'Species', '10090', (43, 47))	('mice', 'Species', '10090', (161, 165))	('p19', 'cellular_component', 'GO:0070743', ('324', '327'))	('p19Arf', 'Gene', (268, 274))	('Ink4a', 'Gene', '12578', (223, 228))	('p16Ink4a', 'Gene', '12578', (220, 228))	('p53', 'Gene', '22059', (232, 235))	('Ink4a', 'Gene', '12578', (303, 308))	('p16Ink4a', 'Gene', (123, 131))	('Ink4a', 'Gene', (223, 228))	('Ink4a', 'Gene', (303, 308))	('p15Inkba', 'Var', (255, 263))	('Ink4a', 'Gene', '12578', (126, 131))	('p19Arf', 'Gene', '12578', (324, 330))	('p53', 'Gene', '22059', (351, 354))	('p19', 'cellular_component', 'GO:0070743', ('268', '271'))	('p16Ink4a', 'Gene', '12578', (123, 131))	('inactivation', 'NegReg', (189, 201))	('mice', 'Species', '10090', (309, 313))	('Ink4a', 'Gene', (126, 131))	('Ink4a', 'Gene', '12578', (205, 210))
199410	30060470	Rb protein was down regulated in cells from Htz Bap1 mice due to aberrant epigenetic of the Rb promoter, suggesting a role of Bap1 on Rb expression.	('Bap1', 'Gene', '104416', (48, 52))	('Bap1', 'Gene', (126, 130))	('Rb', 'Chemical', 'MESH:D012413', (92, 94))	('mice', 'Species', '10090', (53, 57))	('Rb', 'Chemical', 'MESH:D012413', (134, 136))	('Rb protein', 'Protein', (0, 10))	('Bap1', 'Gene', (48, 52))	('Bap1', 'Gene', '104416', (126, 130))	('epigenetic', 'Var', (74, 84))	('Rb', 'Chemical', 'MESH:D012413', (0, 2))	('down regulated', 'NegReg', (15, 29))	('protein', 'cellular_component', 'GO:0003675', ('3', '10'))	('aberrant epigenetic', 'Var', (65, 84))
199418	30060470	MuMM were developed in mice harbouring Htz and Hom inactivation of TSG, or Hom and Hom inactivation.	('TSG', 'Gene', (67, 70))	('inactivation', 'Var', (51, 63))	('inactivation', 'Var', (87, 99))	('TSG', 'Gene', '65960', (67, 70))	('mice', 'Species', '10090', (23, 27))
199421	30060470	In mice, the median survival in animals was about more than one year, except in Hom Nf2/Trp53 and Hom Nf2/Trp53/Ink4a.	('Nf2', 'Gene', (84, 87))	('Ink4a', 'Gene', (112, 117))	('Trp53', 'Gene', '22059', (88, 93))	('Nf2', 'Gene', (102, 105))	('Trp53', 'Gene', '22059', (106, 111))	('mice', 'Species', '10090', (3, 7))	('Hom', 'Var', (98, 101))	('Nf2', 'Gene', '18016', (84, 87))	('Nf2', 'Gene', '18016', (102, 105))	('Trp53', 'Gene', (88, 93))	('Trp53', 'Gene', (106, 111))	('Ink4a', 'Gene', '12578', (112, 117))
199427	30060470	Investigations of spontaneous MM in GEM harbouring co-mutations in TSG showed that two genes, Cdkn2a and Trp53 are predominant for MM development, as biallelic inactivation generates the highest rate of MM.	('Cdkn2a', 'Gene', (94, 100))	('Trp53', 'Gene', '22059', (105, 110))	('TSG', 'Gene', (67, 70))	('Trp53', 'Gene', (105, 110))	('GEM', 'Chemical', '-', (36, 39))	('biallelic inactivation', 'Var', (150, 172))	('TSG', 'Gene', '65960', (67, 70))	('Cdkn2a', 'Gene', '12578', (94, 100))
199428	30060470	This is found despite the biallelic inactivation of Nf2, suggesting a cooperative but not predominant role of this gene.	('Nf2', 'Gene', (52, 55))	('Nf2', 'Gene', '18016', (52, 55))	('biallelic inactivation', 'Var', (26, 48))
199431	30060470	Among genes encoded at the Ink4 locus (Ink4a, Ink4b and Arf), Trp53 biallelic inactivation is an alternative mechanism to carcinogenesis via genes inactivated at the Ink4 locus.	('Ink4a', 'Gene', (39, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('Trp53', 'Gene', (62, 67))	('Ink4b', 'Gene', (46, 51))	('carcinogenesis', 'Disease', (122, 136))	('Ink4', 'Gene', (166, 170))	('Ink4b', 'Gene', '12579', (46, 51))	('Trp53', 'Gene', '22059', (62, 67))	('Ink4a', 'Gene', '12578', (39, 44))	('biallelic inactivation', 'Var', (68, 90))
199432	30060470	Of note, TP53 mutations are found in 11% of HMM (Cosmic database v85, ).	('HMM', 'Disease', (44, 47))	('TP53', 'Gene', '22059', (9, 13))	('TP53', 'Gene', (9, 13))	('found', 'Reg', (28, 33))	('mutations', 'Var', (14, 23))
199434	30060470	Independently of the inactivation of TSG already known to be involved in MM, mutations in genes involved in other regulatory pathways act as complementary mechanism accounting for mesothelial carcinogenesis.	('TSG', 'Gene', '65960', (37, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('TSG', 'Gene', (37, 40))	('carcinogenesis', 'Disease', (192, 206))	('mutations', 'Var', (77, 86))
199437	30060470	The diversity of mutated genes, the complex combination of altered genes, and the variety of associated deregulated pathways, lead to the heterogeneity of the tumour molecular profiles and is in agreement with the inter-tumour heterogeneity observed in HMM.	('tumour', 'Disease', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('tumour', 'Disease', 'MESH:D009369', (220, 226))	('lead to', 'Reg', (126, 133))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('tumour', 'Disease', (220, 226))	('mutated', 'Var', (17, 24))
199441	30060470	reported that epigenetic inactivation of Ink4a, although enhancing the malignancy, does not contribute to the development of pleural MuMM in Htz Nf2/Trp53, in agreement with the evidence of deletions of this gene demonstrated in several studies.	('Nf2', 'Gene', '18016', (145, 148))	('enhancing', 'PosReg', (57, 66))	('Ink4a', 'Gene', '12578', (41, 46))	('Trp53', 'Gene', (149, 154))	('epigenetic inactivation', 'Var', (14, 37))	('pleural MuMM', 'Disease', (125, 137))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))	('pleural MuMM', 'Disease', 'MESH:D010995', (125, 137))	('Nf2', 'Gene', (145, 148))	('malignancy', 'Disease', (71, 81))	('Ink4a', 'Gene', (41, 46))	('Trp53', 'Gene', '22059', (149, 154))
199442	30060470	Nevertheless, hypermethylation of Cdkn2a locus preceding allelic Arf deletion was suggested to be a mesothelial carcinogenesis step in pleura of mice exposed to CNT.	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('Arf', 'Gene', (65, 68))	('carcinogenesis', 'Disease', (112, 126))	('Cdkn2a', 'Gene', '12578', (34, 40))	('mice', 'Species', '10090', (145, 149))	('Cdkn2a', 'Gene', (34, 40))	('deletion', 'Var', (69, 77))	('hypermethylation', 'MPA', (14, 30))
199487	27908590	Noteworthy is that the removal of both random effects in the Poisson linear predictor severely worsens fits (e.g.	('worsens', 'NegReg', (95, 102))	('fits', 'Disease', (103, 107))	('fits', 'Disease', 'MESH:D012640', (103, 107))	('removal', 'Var', (23, 30))
199509	26730811	Reducing the minimal structure required to transcribe shRNA and the presence of the 4'-thiomodification synergistically function to abrogate innate immune response induced by dsDNA.	('abrogate', 'NegReg', (132, 140))	('dsDNA', 'Disease', (175, 180))	("4'-thio", 'Chemical', '-', (84, 91))	('presence', 'Var', (68, 76))	('innate immune', 'MPA', (141, 154))	('innate immune response', 'biological_process', 'GO:0045087', ('141', '163'))
199537	26730811	All iReds containing each modification pattern reduced pGL3 Fluc gene expression in a dose-dependent manner, similar to pDNA and synthetic shRNA (Figure 3).	('pGL3', 'Gene', (55, 59))	('modification', 'Var', (26, 38))	('pGL', 'molecular_function', 'GO:0004598', ('55', '58'))	('pGL3', 'Gene', '6391', (55, 59))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('expression', 'MPA', (70, 80))	('reduced', 'NegReg', (47, 54))
199541	26730811	To ensure that this termination in RNA polymerase III-dependent transcription was conserved even in case of 4'-thioDNA in the iRed, we prepared another series of iReds with a poly(U) stretch in the middle of the shRNA coding regions, which targeted pGL3 Fluc (Supplementary Figure S4).	('pGL3', 'Gene', (249, 253))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('pGL', 'molecular_function', 'GO:0004598', ('249', '252'))	('pGL3', 'Gene', '6391', (249, 253))	('poly(U) stretch', 'Var', (175, 190))	("4'-thioDNA", 'Chemical', '-', (108, 118))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
199558	26730811	We therefore conclude that the downsizing and 4'-thiomodification synergized to abrogate the innate immune response to pDNA.	('innate immune response', 'biological_process', 'GO:0045087', ('93', '115'))	("4'-thiomodification", 'Var', (46, 65))	('abrogate', 'NegReg', (80, 88))	("4'-thio", 'Chemical', '-', (46, 53))	('innate', 'CPA', (93, 99))
199580	26730811	The toll-like receptor 9 (TLR9) plays a critical role in immune stimulation triggered by dsDNA that harbors CpG motifs.	('CpG motifs', 'Var', (108, 118))	('toll-like receptor 9', 'Gene', '81897', (4, 24))	('toll-like receptor 9', 'Gene', (4, 24))	('TLR9', 'Gene', (26, 30))	('dsDNA', 'Disease', (89, 94))	('immune stimulation', 'MPA', (57, 75))	('TLR9', 'Gene', '81897', (26, 30))
199582	26730811	The conformational changes in the sugar ring caused by the substitution of O4' with sulfur may result in the loss of recognition of the iRed-4'-thioDNA through the interaction of TLR9 with the phosphate backbone.	('interaction', 'Interaction', (164, 175))	('recognition', 'MPA', (117, 128))	('conformational changes', 'MPA', (4, 26))	('sugar', 'Chemical', 'MESH:D000073893', (34, 39))	('loss', 'NegReg', (109, 113))	('TLR9', 'Gene', (179, 183))	('phosphate', 'Chemical', 'MESH:D010710', (193, 202))	('substitution', 'Var', (59, 71))	("4'-thioDNA", 'Chemical', '-', (141, 151))	('TLR9', 'Gene', '81897', (179, 183))	('sulfur', 'Chemical', 'MESH:D013455', (84, 90))
199872	26938529	We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 microM) 4-h prior to asbestos exposure.	('LGM2605', 'Chemical', '-', (104, 111))	('mitigate', 'MPA', (44, 52))	('LGM2605', 'Var', (104, 111))	('LGM2605', 'Chemical', '-', (33, 40))	('asbestos', 'Chemical', 'MESH:D001194', (53, 61))	('asbestos', 'Chemical', 'MESH:D001194', (137, 145))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))
199875	26938529	Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment.	('expression', 'MPA', (116, 126))	('Nrf2', 'Gene', (92, 96))	('enhanced', 'PosReg', (192, 200))	('activation', 'PosReg', (97, 107))	('LGM2605', 'Chemical', '-', (204, 211))	('HO-1', 'Gene', '15368', (160, 164))	('HO-1', 'Gene', (160, 164))	('cell protective defenses', 'CPA', (49, 73))	('Nqo1', 'Gene', (169, 173))	('Nqo1', 'Gene', '18104', (169, 173))	('LGM2605', 'Var', (204, 211))	('Nqo1', 'molecular_function', 'GO:0003955', ('169', '173'))	('Nrf2', 'Gene', '18024', (92, 96))	('asbestos', 'Chemical', 'MESH:D001194', (25, 33))
199898	26938529	Our objectives were: (1) to characterize the antioxidant response in murine peritoneal macrophages following asbestos exposure; (2) to evaluate the ability of LGM2605 to interfere with asbestos-induced ROS generation and oxidative cell damage in macrophages; and (3) to determine the potential molecular mechanisms through which LGM2605 exerts antioxidant effects following asbestos exposure.	('interfere', 'NegReg', (170, 179))	('LGM2605', 'Chemical', '-', (159, 166))	('asbestos', 'Chemical', 'MESH:D001194', (374, 382))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('oxidative cell damage', 'MPA', (221, 242))	('LGM2605', 'Chemical', '-', (329, 336))	('LGM2605', 'Var', (329, 336))	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('ROS generation', 'biological_process', 'GO:1903409', ('202', '216'))	('antioxidant effects', 'MPA', (344, 363))	('murine', 'Species', '10090', (69, 75))	('LGM2605', 'Gene', (159, 166))	('asbestos', 'Chemical', 'MESH:D001194', (185, 193))
199906	26938529	Treatment with 50 microM LGM2605 led to a significant 43% reduction in ROS relative to untreated macrophages and was selected as the optimal treatment dose for evaluating the preventive properties of LGM2605 in attenuating the deleterious effects of asbestos exposure.	('LGM2605', 'Var', (25, 32))	('ROS', 'MPA', (71, 74))	('LGM2605', 'Chemical', '-', (200, 207))	('LGM2605', 'Var', (200, 207))	('asbestos', 'Chemical', 'MESH:D001194', (250, 258))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('LGM2605', 'Chemical', '-', (25, 32))	('reduction', 'NegReg', (58, 67))
199934	26938529	However, pretreatment with 50 microM LGM2605 led to significant (p < 0.0001) activation of Nrf2 signaling at baseline prior to asbestos exposure that remained elevated through the 12-h of observation (elevated 2.81-fold from control, non-asbestos exposed macrophages).	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('Nrf2', 'Gene', (91, 95))	('activation', 'PosReg', (77, 87))	('asbestos', 'Chemical', 'MESH:D001194', (238, 246))	('LGM2605', 'Var', (37, 44))	('LGM2605', 'Chemical', '-', (37, 44))	('asbestos', 'Chemical', 'MESH:D001194', (127, 135))	('elevated', 'PosReg', (159, 167))	('Nrf2', 'Gene', '18024', (91, 95))
199938	26938529	Importantly, although mRNA levels of HO-1 and NQO1 were significantly elevated above control after 8 and 24-h of asbestos exposure, treatment with LGM2605 further boosted antioxidant gene expression above asbestos-only exposure (Figure 6b,c) by an additional 28%-31% and 25%-26%, respectively.	('elevated', 'PosReg', (70, 78))	('antioxidant gene expression', 'MPA', (171, 198))	('NQO1', 'Gene', (46, 50))	('NQO1', 'molecular_function', 'GO:0003955', ('46', '50'))	('gene expression', 'biological_process', 'GO:0010467', ('183', '198'))	('HO-1', 'Gene', '15368', (37, 41))	('asbestos', 'Chemical', 'MESH:D001194', (205, 213))	('boosted', 'PosReg', (163, 170))	('HO-1', 'Gene', (37, 41))	('mRNA levels', 'MPA', (22, 33))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('LGM2605', 'Chemical', '-', (147, 154))	('NQO1', 'Gene', '18104', (46, 50))	('LGM2605', 'Var', (147, 154))
199940	26938529	Importantly, treatment of macrophages with LGM2605-alone led to a robust increase in the expression of both HO-1 and Nqo1 prior to asbestos exposure (2.45 +- 0.11 and 9.94 +- 0.49 fold change from control, respectively).	('HO-1', 'Gene', (108, 112))	('expression', 'MPA', (89, 99))	('increase', 'PosReg', (73, 81))	('Nqo1', 'molecular_function', 'GO:0003955', ('117', '121'))	('Nqo1', 'Gene', (117, 121))	('Nqo1', 'Gene', '18104', (117, 121))	('asbestos', 'Chemical', 'MESH:D001194', (131, 139))	('LGM2605', 'Chemical', '-', (43, 50))	('LGM2605-alone', 'Var', (43, 56))	('HO-1', 'Gene', '15368', (108, 112))
199941	26938529	Although protein levels of HO-1 (Figure 7a,b) and Nqo1 (Figure 7a,c) were significantly elevated above control after 8 and 24-h of exposure, macrophages treated with LGM2605 displayed a further increase in both antioxidant enzymes by 39%-40% and 60%-79%, respectively.	('LGM2605', 'Chemical', '-', (166, 173))	('Nqo1', 'molecular_function', 'GO:0003955', ('50', '54'))	('protein levels', 'MPA', (9, 23))	('elevated', 'PosReg', (88, 96))	('increase', 'PosReg', (194, 202))	('LGM2605', 'Var', (166, 173))	('Nqo1', 'Gene', (50, 54))	('Nqo1', 'Gene', '18104', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('antioxidant', 'Enzyme', (211, 222))	('HO-1', 'Gene', '15368', (27, 31))	('HO-1', 'Gene', (27, 31))
199945	26938529	We determined decreased levels of MDA and 8-isoP with LGM2605 treatment, indicative of decreased asbestos-induced oxidative stress.	('decreased', 'NegReg', (14, 23))	('decreased', 'NegReg', (87, 96))	('8-isoP', 'Chemical', 'MESH:C075750', (42, 48))	('asbestos', 'Chemical', 'MESH:D001194', (97, 105))	('MDA', 'MPA', (34, 37))	('LGM2605', 'Chemical', '-', (54, 61))	('LGM2605', 'Var', (54, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (114, 130))	('asbestos-induced oxidative stress', 'MPA', (97, 130))	('8-isoP', 'MPA', (42, 48))	('MDA', 'Chemical', 'MESH:D008315', (34, 37))
199946	26938529	Importantly, while asbestos exposure activates Nrf2 signaling and the expression of phase II antioxidant enzymes, LGM2605 further enhances levels of key antioxidant enzymes involved in the detoxification of reactive oxygen species.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('LGM2605', 'Chemical', '-', (114, 121))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (207, 230))	('Nrf2', 'Gene', (47, 51))	('enhances', 'PosReg', (130, 138))	('activates', 'PosReg', (37, 46))	('expression', 'MPA', (70, 80))	('LGM2605', 'Var', (114, 121))	('detoxification', 'biological_process', 'GO:0098754', ('189', '203'))	('levels of key antioxidant enzymes', 'MPA', (139, 172))	('asbestos', 'Chemical', 'MESH:D001194', (19, 27))	('Nrf2', 'Gene', '18024', (47, 51))
200043	26938529	LGM2605 reduced asbestos-induced ROS generation, cytotoxicity, and markers of oxidative stress in murine peritoneal macrophages and may impede the asbestos-induced oxidative signaling cascade on the way to malignancy.	('ROS generation', 'biological_process', 'GO:1903409', ('33', '47'))	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('LGM2605', 'Var', (0, 7))	('asbestos', 'Chemical', 'MESH:D001194', (147, 155))	('malignancy', 'Disease', (206, 216))	('signaling cascade', 'biological_process', 'GO:0007165', ('174', '191'))	('murine', 'Species', '10090', (98, 104))	('reduced', 'NegReg', (8, 15))	('cytotoxicity', 'Disease', (49, 61))	('impede', 'NegReg', (136, 142))	('asbestos', 'Chemical', 'MESH:D001194', (16, 24))	('LGM2605', 'Chemical', '-', (0, 7))	('asbestos-induced oxidative signaling cascade', 'Pathway', (147, 191))	('ROS generation', 'MPA', (33, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))
200124	22541196	The survival for the 20 epithelial N2 patients was statistically significantly different (p = 0.02) from the 11 epithelial patients with N0-1 disease (Figure 8).	('N0-1 disease', 'Disease', (137, 149))	('N0-1 disease', 'Disease', 'MESH:C536594', (137, 149))	('different', 'Reg', (79, 88))	('epithelial N2', 'Var', (24, 37))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (38, 46))
200150	22541196	PDT did not appear to have a positive impact on local control, but may have played a role in extending survival for a duration well beyond what would commonly be expected for recurrence after surgery in this cohort of patients.	('PDT', 'Var', (0, 3))	('extending', 'PosReg', (93, 102))	('survival', 'MPA', (103, 111))	('patients', 'Species', '9606', (218, 226))
200157	32236606	In the present study, the effects of three DUB inhibitors, PR-619, RA-9 and LDN-91946, on a non-small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('PR-619', 'Chemical', 'MESH:C570894', (59, 65))	('RA-9', 'Gene', '474229', (67, 71))	('non-small cell lung cancer', 'Disease', (92, 118))	('mesothelioma', 'Disease', (142, 154))	('H2373', 'CellLine', 'CVCL:A533', (166, 171))	('LDN-91946', 'Chemical', '-', (76, 85))	('RA-9', 'Gene', (67, 71))	('LDN-91946', 'Var', (76, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
200158	32236606	PR-619 significantly inhibited cell adhesion and the proliferation of both cell lines.	('PR-619', 'Var', (0, 6))	('cell adhesion', 'biological_process', 'GO:0007155', ('31', '44'))	('cell adhesion', 'CPA', (31, 44))	('proliferation', 'CPA', (53, 66))	('inhibited', 'NegReg', (21, 30))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))
200172	32236606	In each case, Zn2+ polarizes a water molecule, which then performs a nucleophilic attack on an isopeptide bond.	('Zn2+', 'Chemical', '-', (14, 18))	('polarizes', 'MPA', (19, 28))	('water', 'Chemical', 'MESH:D014867', (31, 36))	('nucleophilic attack', 'MPA', (69, 88))	('Zn2+', 'Var', (14, 18))
200179	32236606	In contrast to the two previously described compounds, LDN-91946 is a specific inhibitor of ubiquitin C-terminal hydrolase-L1 (UCH-L1), binding to the complex of the enzyme and the substrate.	('ubiquitin C-terminal hydrolase-L1', 'Gene', '7345', (92, 125))	('ubiquitin C-terminal hydrolase-L1', 'Gene', (92, 125))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('ubiquitin C-terminal hydrolase', 'molecular_function', 'GO:0036459', ('92', '122'))	('complex', 'Interaction', (151, 158))	('UCH-L1', 'Gene', '7345', (127, 133))	('LDN-91946', 'Chemical', '-', (55, 64))	('LDN-91946', 'Var', (55, 64))	('UCH-L1', 'Gene', (127, 133))	('binding', 'Interaction', (136, 143))
200181	32236606	The data of the present study indicated that while LDN-91946 and RA-9 attenuated the proliferation of both lung cancer and mesothelioma cell lines, they had no effect on their migration.	('RA-9', 'Gene', (65, 69))	('attenuated', 'NegReg', (70, 80))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('LDN-91946', 'Chemical', '-', (51, 60))	('LDN-91946', 'Var', (51, 60))	('lung cancer', 'Disease', (107, 118))	('RA-9', 'Gene', '474229', (65, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('proliferation', 'CPA', (85, 98))	('mesothelioma', 'Disease', (123, 135))
200182	32236606	By contrast, PR-619 attenuated both the proliferation and migration of the mesothelioma cell line.	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('PR-619', 'Chemical', 'MESH:C570894', (13, 19))	('PR-619', 'Var', (13, 19))	('proliferation', 'CPA', (40, 53))	('mesothelioma', 'Disease', (75, 87))	('attenuated', 'NegReg', (20, 30))
200183	32236606	PR-619 also inhibited the proliferation of the lung cancer cell line; surprisingly, however, PR-619 augments the migration of lung cancer cells.	('inhibited', 'NegReg', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('PR-619', 'Var', (93, 99))	('PR-619', 'Chemical', 'MESH:C570894', (93, 99))	('augments', 'NegReg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('migration', 'CPA', (113, 122))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))	('proliferation', 'CPA', (26, 39))
200192	32236606	Cells were treated either with PR-619, RA-9 and LDN-91946, or dimethyl sulfoxide (DMSO), control.	('RA-9', 'Gene', '474229', (39, 43))	('DMSO', 'Chemical', 'MESH:D004121', (82, 86))	('LDN-91946', 'Var', (48, 57))	('LDN-91946', 'Chemical', '-', (48, 57))	('RA-9', 'Gene', (39, 43))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (62, 80))	('PR-619', 'Chemical', 'MESH:C570894', (31, 37))
200196	32236606	Cell lines were treated with LD91946 (10 microM), RA9 (5 microM) and PR619 (10 microM) for 24 h, followed by lysing with RIPA buffer.	('PR', 'Chemical', 'MESH:D011221', (69, 71))	('LD91946', 'Var', (29, 36))	('RA9', 'Gene', '474229', (50, 53))	('PR619', 'Var', (69, 74))	('RIPA buffer', 'Chemical', '-', (121, 132))	('RA9', 'Gene', (50, 53))
200200	32236606	The effect of PR-619, RA-9 and LDN-91946 (Fig.	('PR-619', 'Chemical', 'MESH:C570894', (14, 20))	('RA-9', 'Gene', '474229', (22, 26))	('LDN-91946', 'Chemical', '-', (31, 40))	('LDN-91946', 'Var', (31, 40))	('RA-9', 'Gene', (22, 26))
200203	32236606	While LDN-91946 and PR-619 attenuated the proliferation of the lung cancer cell line (A549), RA-9 failed to inhibit the proliferation of this cell line.	('attenuated', 'NegReg', (27, 37))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('RA-9', 'Gene', '474229', (93, 97))	('proliferation', 'CPA', (42, 55))	('LDN-91946', 'Var', (6, 15))	('RA-9', 'Gene', (93, 97))	('LDN-91946', 'Chemical', '-', (6, 15))	('lung cancer', 'Disease', (63, 74))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('PR-619', 'Chemical', 'MESH:C570894', (20, 26))	('PR-619', 'Var', (20, 26))
200204	32236606	On the other hand, while PR-619 and RA-9 impeded the proliferation of the mesothelioma cells (H2373), LDN-91946 did not.	('RA-9', 'Gene', '474229', (36, 40))	('PR-619', 'Var', (25, 31))	('LDN-91946', 'Chemical', '-', (102, 111))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('RA-9', 'Gene', (36, 40))	('H2373', 'CellLine', 'CVCL:A533', (94, 99))	('impeded', 'NegReg', (41, 48))	('mesothelioma', 'Disease', (74, 86))	('PR-619', 'Chemical', 'MESH:C570894', (25, 31))
200205	32236606	Furthermore, Tukey's post hoc test indicated significant differences in adhesion and proliferation, as compared with the DMSO control, when treating the A549 cells with LDN-91946 or PR-619, and when treating the H2373 cells with PR-169 or RA-9 (Table I).	('differences', 'Reg', (57, 68))	('H2373', 'CellLine', 'CVCL:A533', (212, 217))	('RA-9', 'Gene', '474229', (239, 243))	('adhesion', 'CPA', (72, 80))	('LDN-91946', 'Chemical', '-', (169, 178))	('PR', 'Chemical', 'MESH:D011221', (229, 231))	('A549', 'CellLine', 'CVCL:0023', (153, 157))	('RA-9', 'Gene', (239, 243))	('LDN-91946', 'Var', (169, 178))	('PR', 'Chemical', 'MESH:D011221', (182, 184))	('DMSO', 'Chemical', 'MESH:D004121', (121, 125))	('proliferation', 'CPA', (85, 98))	('PR-619', 'Chemical', 'MESH:C570894', (182, 188))
200208	32236606	These experiments establish potent single agent activity of both LDN91946 and PR-619 in the models in the present study.	('LDN91946', 'Var', (65, 73))	('PR-619', 'Gene', (78, 84))	('PR-619', 'Chemical', 'MESH:C570894', (78, 84))
200210	32236606	Representative data of the replicated measurements of the A549 and H2373 cells treated with DMSO, PR-619, or LDN-91946 are shown on Fig.	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('LDN-91946', 'Chemical', '-', (109, 118))	('LDN-91946', 'Var', (109, 118))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('PR-619', 'Chemical', 'MESH:C570894', (98, 104))	('H2373', 'CellLine', 'CVCL:A533', (67, 72))	('PR-619', 'Var', (98, 104))
200212	32236606	Notably, while LDN-91946 and RA-9 had no detectable effect on THE migration in either cell line, PR-619 significantly attenuated the migration of the mesothelioma cell line (H2373), but increased the migration rate of the lung cancer cell line (A549).	('migration rate', 'CPA', (200, 214))	('mesothelioma', 'Disease', (150, 162))	('RA-9', 'Gene', '474229', (29, 33))	('lung cancer', 'Disease', (222, 233))	('H2373', 'CellLine', 'CVCL:A533', (174, 179))	('PR-619', 'Chemical', 'MESH:C570894', (97, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('increased', 'PosReg', (186, 195))	('PR-619', 'Var', (97, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (150, 162))	('RA-9', 'Gene', (29, 33))	('A549', 'CellLine', 'CVCL:0023', (245, 249))	('attenuated', 'NegReg', (118, 128))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('LDN-91946', 'Chemical', '-', (15, 24))
200213	32236606	To the best of our knowledge, the effects of LDN-91946, PR-619 and RA-9 on the motility of cell lines have not yet been reported.	('PR-619', 'Chemical', 'MESH:C570894', (56, 62))	('RA-9', 'Gene', '474229', (67, 71))	('LDN-91946', 'Chemical', '-', (45, 54))	('LDN-91946', 'Var', (45, 54))	('RA-9', 'Gene', (67, 71))
200218	32236606	Compared to the DMSO control, a statistically significant difference was found in the presence of LDN-91946 (increase), RA-9 (increase) and PR-619 (decrease).	('LDN-91946', 'Chemical', '-', (98, 107))	('PR-619', 'Chemical', 'MESH:C570894', (140, 146))	('LDN-91946', 'Gene', (98, 107))	('DMSO', 'Chemical', 'MESH:D004121', (16, 20))	('increase', 'PosReg', (109, 117))	('RA-9', 'Gene', '474229', (120, 124))	('RA-9', 'Gene', (120, 124))	('PR-619', 'Var', (140, 146))	('increase', 'PosReg', (126, 134))
200219	32236606	P85A is involved in numerous pathways, including the mTOR and PI3K-Akt signaling pathways as found in the KEGG pathway database (KEGG, 21).	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('P85A', 'Mutation', 'p.P85A', (0, 4))	('Akt', 'Gene', (67, 70))	('mTOR', 'Gene', (53, 57))	('P85A', 'Var', (0, 4))	('mTOR', 'Gene', '2475', (53, 57))	('involved', 'Reg', (8, 16))	('Akt signaling', 'biological_process', 'GO:0043491', ('67', '80'))	('Akt', 'Gene', '207', (67, 70))
200220	32236606	Similarly, for the A549 cells, >20 peptides were affected, which were involved in 'Pathways in cancer' (hsa05200), including the PI3K-Akt signaling pathway (hsa04151) and the Ras signaling pathway (hsa04014), among others.	('Akt signaling', 'biological_process', 'GO:0043491', ('134', '147'))	('signaling pathway', 'biological_process', 'GO:0007165', ('138', '155'))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('signaling pathway', 'biological_process', 'GO:0007165', ('179', '196'))	('Akt', 'Gene', '207', (134, 137))	('hsa05200', 'Var', (104, 112))	('cancer', 'Disease', (95, 101))	('peptides', 'Protein', (35, 43))	('affected', 'Reg', (49, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('Ras signaling pathway', 'Pathway', (175, 196))	("'Pathways", 'Pathway', (82, 91))	('involved', 'Reg', (70, 78))	('hsa04151', 'Var', (157, 165))	('hsa04014', 'Var', (198, 206))	('Akt', 'Gene', (134, 137))
200222	32236606	LDN-91946, being a specific DUB inhibitor, unsurprisingly did not result an easily measurable change in the context of the whole cell ubiquitin levels, making it difficult to determine whether the impact on proliferation in A549 was an on-target effect using this method.	('LDN-91946', 'Chemical', '-', (0, 9))	('LDN-91946', 'Var', (0, 9))	('A549', 'CellLine', 'CVCL:0023', (224, 228))	('ubiquitin', 'molecular_function', 'GO:0031386', ('134', '143'))	('proliferation', 'MPA', (207, 220))
200225	32236606	In conclusion, the findings of the present study demonstrate that while PR-619 acts as a proliferation-inhibitor for both cell lines and exerts a significant effect on overall ubiquitin levels, it affects cell motility quite differently, which points to a need for detailed investigations into the role of ubiquitination in these two important processes (Fig.	('cell motility', 'biological_process', 'GO:0048870', ('205', '218'))	('PR-619', 'Chemical', 'MESH:C570894', (72, 78))	('ubiquitin levels', 'MPA', (176, 192))	('affects', 'Reg', (197, 204))	('PR-619', 'Var', (72, 78))	('ubiquitin', 'molecular_function', 'GO:0031386', ('176', '185'))	('cell motility', 'CPA', (205, 218))	('effect', 'Reg', (158, 164))
200233	32236606	The highly selective effect of altered phosphorylation on P85A in the mesothelioma cell line, versus a much larger number of proteins in the same (PI3K) pathway in the lung cancer cell line, after the application of the same drugs, emphasizes the subtleties with which proliferation and migration are coordinated.	('altered', 'Reg', (31, 38))	('phosphorylation', 'MPA', (39, 54))	('P85A', 'Mutation', 'p.P85A', (58, 62))	('lung cancer', 'Disease', (168, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('mesothelioma', 'Disease', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('P85A', 'Var', (58, 62))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))
200247	31783660	ONC affected the total viability and the proliferation rate of both A375P and A375DR cell subpopulations in a dose-dependent manner and also induced apoptotic cell death.	('apoptotic cell death', 'CPA', (149, 169))	('proliferation rate', 'CPA', (41, 59))	('affected', 'Reg', (4, 12))	('A375', 'CellLine', 'CVCL:0132', (68, 72))	('A375', 'CellLine', 'CVCL:0132', (78, 82))	('induced', 'Reg', (141, 148))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('149', '169'))	('A375DR', 'Var', (78, 84))
200249	31783660	Notably, it induced apoptosis and inhibited colony formation and invasiveness more extensively in A375DR than in A375P cells.	('A375', 'CellLine', 'CVCL:0132', (98, 102))	('colony formation', 'CPA', (44, 60))	('inhibited', 'NegReg', (34, 43))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0097194', ('20', '29'))	('apoptosis', 'CPA', (20, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('20', '29'))	('A375', 'CellLine', 'CVCL:0132', (113, 117))	('invasiveness', 'CPA', (65, 77))	('induced', 'Reg', (12, 19))	('A375DR', 'Var', (98, 104))
200275	31783660	In malignant mesothelioma, ONC inhibits Tumor Necrosis Factor-alpha (TNFalpha)-elicited NF-kappaB nuclear translocation and reduces MMP9 activity, as well as cell invasiveness.	('inhibits', 'NegReg', (31, 39))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (3, 25))	('NF-kappaB', 'Gene', (88, 97))	('Tumor Necrosis Factor-alpha', 'Gene', '7124', (40, 67))	('TNFalpha', 'Gene', '7124', (69, 77))	('NF-kappaB', 'Gene', '4790', (88, 97))	('Tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Necrosis', 'biological_process', 'GO:0019835', ('46', '54'))	('MMP9', 'Gene', '4318', (132, 136))	('MMP9', 'Gene', (132, 136))	('Necrosis', 'biological_process', 'GO:0008220', ('46', '54'))	('TNFalpha', 'Gene', (69, 77))	('Necrosis', 'biological_process', 'GO:0001906', ('46', '54'))	('cell invasiveness', 'CPA', (158, 175))	('Necrosis', 'biological_process', 'GO:0070265', ('46', '54'))	('MMP9', 'molecular_function', 'GO:0004229', ('132', '136'))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (3, 25))	('Tumor Necrosis Factor-alpha', 'Gene', (40, 67))	('Tumor Necrosis Factor', 'molecular_function', 'GO:0005164', ('40', '61'))	('reduces', 'NegReg', (124, 131))	('Necrosis', 'biological_process', 'GO:0008219', ('46', '54'))	('ONC', 'Var', (27, 30))	('malignant mesothelioma', 'Disease', (3, 25))
200291	31783660	No statistically significant differences in the sensitivity to ONC emerged within the two cell subpopulations, although the mean viability reduction of A375DR cells was lower than that of parental ones for each concentration tested (Figure 1b).	('reduction', 'NegReg', (139, 148))	('A375', 'CellLine', 'CVCL:0132', (152, 156))	('A375DR', 'Var', (152, 158))	('viability', 'CPA', (129, 138))	('lower', 'NegReg', (169, 174))
200292	31783660	To evaluate the specificity of ONC activity against melanoma cells, we also measured the sensitivity of normal human epidermal melanocytes (NHEM) to this RNase variant.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('variant', 'Var', (160, 167))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('human', 'Species', '9606', (111, 116))
200293	31783660	By the crystal violet assay, we found no reduction in cell viability either at 0.5 or 1 microM ONC concentration (Figure 1b, cyan dots; NHEM versus A375P, p = 0.00004 and p = 0.00002 for 0.5 and 1 microM ONC, respectively).	('A375P', 'Var', (148, 153))	('A375', 'CellLine', 'CVCL:0132', (148, 152))	('crystal violet', 'Chemical', 'MESH:D005840', (7, 21))	('cell viability', 'CPA', (54, 68))	('NHEM', 'Var', (136, 140))
200295	31783660	We performed a 5-Br-2'-deoxyuridine (BrdU) incorporation assay to identify whether in both cell subpopulations the viability reduction elicited by ONC might depend on the cell proliferation rate or, instead, on a cell mass decrease consequent to cell death.	('reduction', 'NegReg', (125, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('171', '189'))	('cell death', 'biological_process', 'GO:0008219', ('246', '256'))	('BrdU', 'Chemical', '-', (37, 41))	('ONC', 'Var', (147, 150))	('decrease', 'NegReg', (223, 231))	('viability', 'CPA', (115, 124))	("5-Br-2'-deoxyuridine", 'Chemical', '-', (15, 35))	('cell mass', 'CPA', (213, 222))
200300	31783660	Although not visible in Figure 2, we underline that also ONC-free A375DR cells appeared to be about 50-70% less proliferating, as a function of time, than ONC-free A375P cells.	('less', 'NegReg', (107, 111))	('A375', 'CellLine', 'CVCL:0132', (164, 168))	('A375', 'CellLine', 'CVCL:0132', (66, 70))	('A375DR', 'Var', (66, 72))	('proliferating', 'CPA', (112, 125))
200301	31783660	In the end, these data indicate that ONC decreases the proliferation rate of both A375P and A375DR cells, although this reduction is more evident in A375P, probably because these cells display a higher replication rate than the A375DR subpopulation.	('A375', 'CellLine', 'CVCL:0132', (82, 86))	('decreases', 'NegReg', (41, 50))	('higher', 'PosReg', (195, 201))	('proliferation rate', 'CPA', (55, 73))	('A375P', 'Var', (149, 154))	('A375', 'CellLine', 'CVCL:0132', (149, 153))	('A375', 'CellLine', 'CVCL:0132', (228, 232))	('A375', 'CellLine', 'CVCL:0132', (92, 96))	('A375DR', 'Var', (92, 98))
200310	31783660	Instead, either A375P or A375DR cells treated with 1 microM ONC showed a significantly decreased nuclear p65 level (Figure 3a,c; p = 0.04 and p = 0.008, for A375P and A375DR, respectively).	('A375', 'CellLine', 'CVCL:0132', (157, 161))	('A375DR', 'Var', (25, 31))	('A375', 'CellLine', 'CVCL:0132', (25, 29))	('p65', 'Gene', (105, 108))	('decreased', 'NegReg', (87, 96))	('p65', 'Gene', '5970', (105, 108))	('A375P', 'Var', (16, 21))	('A375DR', 'Var', (167, 173))	('A375P', 'Var', (157, 162))	('A375', 'CellLine', 'CVCL:0132', (16, 20))	('A375', 'CellLine', 'CVCL:0132', (167, 171))
200314	31783660	Indeed, the detected p-IKK level was higher in ONC-free A375DR than in A375P cells (p = 0.008), while ONC decreased its amount especially in A375DR cells (Figure 3a,c; p = 0.04 and p = 0.001, for A375P and A375DR, respectively).	('A375', 'CellLine', 'CVCL:0132', (196, 200))	('A375', 'CellLine', 'CVCL:0132', (206, 210))	('higher', 'PosReg', (37, 43))	('p-IKK level', 'MPA', (21, 32))	('A375DR', 'Var', (56, 62))	('A375', 'CellLine', 'CVCL:0132', (141, 145))	('A375', 'CellLine', 'CVCL:0132', (56, 60))	('IKK', 'molecular_function', 'GO:0008384', ('23', '26'))	('A375', 'CellLine', 'CVCL:0132', (71, 75))
200316	31783660	A375DR cells display a lower BrdU incorporation level than their BRAFi-sensitive A375P counterpart.	('A375DR', 'Var', (0, 6))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('BrdU incorporation level', 'MPA', (29, 53))	('BRAF', 'Gene', '673', (65, 69))	('BrdU', 'Chemical', '-', (29, 33))	('BRAF', 'Gene', (65, 69))	('A375', 'CellLine', 'CVCL:0132', (81, 85))	('lower', 'NegReg', (23, 28))
200319	31783660	These results demonstrate that A375DR cells display a higher gene expression level of both CD133 and NANOG markers of undifferentiation and embryonic stem cells than A375P ones.	('A375DR', 'Var', (31, 37))	('higher', 'PosReg', (54, 60))	('A375', 'CellLine', 'CVCL:0132', (31, 35))	('NANOG', 'Gene', '79923', (101, 106))	('A375', 'CellLine', 'CVCL:0132', (166, 170))	('CD133', 'Gene', (91, 96))	('CD133', 'Gene', '8842', (91, 96))	('NANOG', 'Gene', (101, 106))	('gene expression level', 'MPA', (61, 82))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
200321	31783660	Representative WB experiments showing a higher expression level of N-cadherin and nuclear beta-catenin in ONC-free A375DR than in ONC-free A375P cell subpopulations are reported in Figure 4b.	('higher', 'PosReg', (40, 46))	('beta-catenin', 'Gene', (90, 102))	('A375DR', 'Var', (115, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('A375', 'CellLine', 'CVCL:0132', (115, 119))	('expression level', 'MPA', (47, 63))	('beta-catenin', 'Gene', '1499', (90, 102))	('N-cadherin', 'Gene', (67, 77))	('A375', 'CellLine', 'CVCL:0132', (139, 143))	('N-cadherin', 'Gene', '1000', (67, 77))
200330	31783660	Importantly, this ability was suppressed by ONC to a greater extent in A375DR than in A375P cells.	('suppressed', 'NegReg', (30, 40))	('A375', 'CellLine', 'CVCL:0132', (71, 75))	('A375DR', 'Var', (71, 77))	('A375', 'CellLine', 'CVCL:0132', (86, 90))
200331	31783660	A wound-healing assay was performed to measure the cell migration ability of both A375P and A375DR subpopulations in the presence or absence of ONC.	('A375', 'CellLine', 'CVCL:0132', (82, 86))	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('cell migration', 'CPA', (51, 65))	('wound-healing', 'biological_process', 'GO:0042060', ('2', '15'))	('A375', 'CellLine', 'CVCL:0132', (92, 96))	('A375DR', 'Var', (92, 98))	('A375P', 'Var', (82, 87))
200332	31783660	Notably, the time necessary to close the wound was different: In particular, A375DR cells migrated and proliferated more slowly than the A375P counterpart.	('proliferated', 'CPA', (103, 115))	('slowly', 'NegReg', (121, 127))	('A375', 'CellLine', 'CVCL:0132', (77, 81))	('A375DR', 'Var', (77, 83))	('A375', 'CellLine', 'CVCL:0132', (137, 141))
200333	31783660	Indeed, 1 microM ONC remarkably reduced the migration rate either of A375P or of A375DR cells, as is visible in Figure 6a,b, respectively.	('A375P', 'Var', (69, 74))	('A375', 'CellLine', 'CVCL:0132', (69, 73))	('reduced', 'NegReg', (32, 39))	('migration rate', 'CPA', (44, 58))	('A375DR', 'Var', (81, 87))	('A375', 'CellLine', 'CVCL:0132', (81, 85))
200337	31783660	Then, the invading cells were stained and analyzed after 48 h: Both subpopulations invaded the Matrigel, and ONC-free A375DR cells showed only a small and not significant increase in their invasion potential with respect to the ONC-free A375P subpopulation.	('ONC-free', 'Var', (109, 117))	('A375', 'CellLine', 'CVCL:0132', (237, 241))	('invaded the Matrigel', 'CPA', (83, 103))	('A375', 'CellLine', 'CVCL:0132', (118, 122))
200340	31783660	The results shown in Figure 8a,b demonstrate that ONC decreases MMP2 activity at a similar and remarkable extent either in A375P or in A375DR cells (p = 0.001 and p = 0.0006 for A375P and A375DR, respectively).	('A375P', 'Var', (178, 183))	('A375P', 'Var', (123, 128))	('MMP2', 'Gene', '4313', (64, 68))	('A375', 'CellLine', 'CVCL:0132', (178, 182))	('A375DR', 'Var', (135, 141))	('decreases', 'NegReg', (54, 63))	('MMP2', 'molecular_function', 'GO:0004228', ('64', '68'))	('A375', 'CellLine', 'CVCL:0132', (135, 139))	('A375', 'CellLine', 'CVCL:0132', (188, 192))	('MMP2', 'Gene', (64, 68))	('A375', 'CellLine', 'CVCL:0132', (123, 127))
200341	31783660	Targeted therapy against melanoma performed with dabrafenib or vemurafenib BRAFi in patients that harbor BRAF mutations is initially effective but subsequently fails because alternative tumor-growth-inducing pathways are activated.	('dabrafenib', 'Chemical', 'MESH:C561627', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('activated', 'PosReg', (221, 230))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (84, 92))	('vemurafenib', 'Chemical', 'MESH:D000077484', (63, 74))	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('BRAF', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))
200347	31783660	In addition, A375DR cells display both higher CD133 and NANOG gene and protein expression levels than A375P ones (Figure 4a).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('A375DR', 'Var', (13, 19))	('A375', 'CellLine', 'CVCL:0132', (102, 106))	('higher', 'PosReg', (39, 45))	('CD133', 'Gene', (46, 51))	('CD133', 'Gene', '8842', (46, 51))	('NANOG', 'Gene', '79923', (56, 61))	('NANOG', 'Gene', (56, 61))	('A375', 'CellLine', 'CVCL:0132', (13, 17))
200353	31783660	Indeed, A375DR cells are less proliferative than A375P, as shown by the BrdU incorporation assay (Figure 2).	('A375', 'CellLine', 'CVCL:0132', (49, 53))	('A375DR', 'Var', (8, 14))	('BrdU', 'Chemical', '-', (72, 76))	('less', 'NegReg', (25, 29))	('A375', 'CellLine', 'CVCL:0132', (8, 12))	('proliferative', 'CPA', (30, 43))
200357	31783660	Importantly, although we found no statistically significant differences in the reduction of the total cell viability within the two ONC-treated A375 subpopulations, the high expression level of cleaved PARP1 found in A375DR cells indicates that ONC elicits a massive apoptotic cell death in this subpopulation.	('PARP1', 'Gene', '142', (202, 207))	('A375', 'CellLine', 'CVCL:0132', (144, 148))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('267', '287'))	('ONC', 'Var', (245, 248))	('PARP1', 'Gene', (202, 207))	('apoptotic cell death', 'CPA', (267, 287))	('A375', 'CellLine', 'CVCL:0132', (217, 221))	('expression level', 'MPA', (174, 190))
200359	31783660	It is worth noting that a significant difference in the expression of cleaved PARP1 is also detectable between the ONC-free samples of the two cell subpopulations.	('PARP1', 'Gene', '142', (78, 83))	('expression', 'MPA', (56, 66))	('PARP1', 'Gene', (78, 83))	('cleaved', 'Var', (70, 77))
200360	31783660	Therefore, A375DR control cells should be more prone to undergoing apoptotic cell death than A375P, while our results suggest that this unusual propensity is greatly strengthened by ONC.	('A375DR', 'Var', (11, 17))	('A375', 'CellLine', 'CVCL:0132', (11, 15))	('A375', 'CellLine', 'CVCL:0132', (93, 97))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('67', '87'))	('undergoing apoptotic cell death', 'CPA', (56, 87))
200362	31783660	The molecular mechanisms underlying ONC cytotoxicity are linked to its ribonucleolytic activity, since enzymatically inactive variants of this RNase are not cytotoxic.	('ONC cytotoxicity', 'Disease', 'MESH:D064420', (36, 52))	('ribonucleolytic activity', 'MPA', (71, 95))	('ONC cytotoxicity', 'Disease', (36, 52))	('variants', 'Var', (126, 134))
200371	31783660	However, the 1 microM ONC incubation reduced the migration of either A375P or A375DR cells, as compared to each relative ONC-free control.	('A375P', 'Var', (69, 74))	('A375', 'CellLine', 'CVCL:0132', (69, 73))	('migration', 'CPA', (49, 58))	('A375', 'CellLine', 'CVCL:0132', (78, 82))	('reduced', 'NegReg', (37, 44))	('A375DR', 'Var', (78, 84))
200372	31783660	As regards the invasion assay, no significant differences were found between the two ONC-free A375P and A375DR counterparts in the ability to cross the Matrigel, in line with data reported by Fratangelo et al.. On the contrary, 1 microM ONC induced a 33% significant reduction of the invasion capability in A375DR cells in comparison with its ONC-free control.	('A375', 'CellLine', 'CVCL:0132', (104, 108))	('A375', 'CellLine', 'CVCL:0132', (307, 311))	('invasion capability', 'CPA', (284, 303))	('reduction', 'NegReg', (267, 276))	('A375', 'CellLine', 'CVCL:0132', (94, 98))	('ONC', 'Var', (237, 240))
200381	31783660	In conclusion, besides its intrinsic cytostatic/cytotoxic effects exerted on parental A375 melanoma cells, ONC significantly enhances its antitumor efficacy by triggering apoptosis in cells that were pre-treated with other drugs.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('enhances', 'PosReg', (125, 133))	('triggering', 'Reg', (160, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('tumor', 'Disease', (142, 147))	('apoptosis', 'CPA', (171, 180))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('A375', 'CellLine', 'CVCL:0132', (86, 90))	('pre', 'molecular_function', 'GO:0003904', ('200', '203'))	('ONC', 'Var', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
200396	31783660	Both A375P and A375DR subpopulations were mycoplasma tested (negative) every three months.	('A375DR', 'Var', (15, 21))	('A375', 'CellLine', 'CVCL:0132', (15, 19))	('A375P', 'Var', (5, 10))	('A375', 'CellLine', 'CVCL:0132', (5, 9))
200432	31783660	Membranes were blocked at RT with TBST buffer (10 mM Tris-HCl pH 7.5, 100 mM NaCl, and 0.1% Tween 20 containing 5% bovine albumin serum (BSA, Serva Electrophoresis GmbH, Heidelberg, Germany) for 1 h. Then, they were incubated overnight on a shaker, at 4  C, with a 5% BSA solution containing the primary antibodies for: Cleaved PARP1 (#5625, 1:2000), p65 NF-kappaB (#8242S, 1:1000), p-IKKalpha/beta (Ser176/180) (#2697S, 1:1000), pERK1/2 (#4370S, 1:1000) (Cell Signaling Technology, Danvers, CO, USA), beta-catenin (GTX101435, 1:5000), N-cadherin (GTX127345, 1:3000), NANOG (GTX100863, 1:3000), CD133 (GTX100567, 1:5000) (Genetex, San Antonio, TX, USA), and beta-tubulin (T8328, 1:2000; Sigma-Aldrich, Milan, Italy).	('TBST buffer', 'Chemical', '-', (34, 45))	('beta-catenin', 'Gene', (502, 514))	('beta-catenin', 'Gene', '1499', (502, 514))	('Tris-HCl', 'Chemical', '-', (53, 61))	('PARP1', 'Gene', (328, 333))	('N-cadherin', 'Gene', (536, 546))	('NANOG', 'Gene', '79923', (568, 573))	('ERK1/2', 'Gene', '5595;5594', (431, 437))	('ERK1/2', 'Gene', (431, 437))	('NANOG', 'Gene', (568, 573))	('Ser', 'cellular_component', 'GO:0005790', ('400', '403'))	('N-cadherin', 'Gene', '1000', (536, 546))	('CD133', 'Gene', (595, 600))	('IKKalpha/beta', 'Gene', '1147', (385, 398))	('CD133', 'Gene', '8842', (595, 600))	('NF-kappaB', 'Gene', (355, 364))	('p65', 'Gene', (351, 354))	('GTX100863', 'Var', (575, 584))	('Signaling', 'biological_process', 'GO:0023052', ('461', '470'))	('NF-kappaB', 'Gene', '4790', (355, 364))	('PARP1', 'Gene', '142', (328, 333))	('IKKalpha/beta', 'Gene', (385, 398))	('GTX127345', 'Var', (548, 557))	('p65', 'Gene', '5970', (351, 354))	('cadherin', 'molecular_function', 'GO:0008014', ('538', '546'))	('beta-tubulin', 'Protein', (658, 670))	('GTX101435', 'Var', (516, 525))
200594	26156019	We determined that this characteristic was associated with resistance to apoptotic stimuli and that correction of intracellular Ca2+ signaling resulted in the rescue of efficient apoptotic responses.	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('intracellular', 'cellular_component', 'GO:0005622', ('114', '127'))	('Ca2', 'Gene', (128, 131))	('correction', 'Var', (100, 110))	('apoptotic responses', 'CPA', (179, 198))	('Ca2', 'Gene', '760', (128, 131))
200604	26156019	In particular, perturbations in Ca2+ homeostasis and alterations in the principal pumps and channels responsible for appropriate Ca2+ handling have been found in cancers of different histotypes.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('perturbations', 'Var', (15, 28))	('cancers', 'Disease', (162, 169))	('principal pumps', 'MPA', (72, 87))	('Ca2', 'Gene', '760', (32, 35))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('Ca2', 'Gene', '760', (129, 132))	('alterations', 'Reg', (53, 64))	('Ca2', 'Gene', (32, 35))	('homeostasis', 'biological_process', 'GO:0042592', ('37', '48'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Ca2', 'Gene', (129, 132))
200607	26156019	Moreover, mutations and alterations in the expression of many oncogenes and tumor suppressor genes, which are involved in the control of both apoptosis and Ca2+ handling, have been identified in mesothelioma specimens and are considered responsible for MPM onset/progression.	('identified', 'Reg', (181, 191))	('mesothelioma', 'Disease', (195, 207))	('alterations', 'Var', (24, 35))	('oncogenes', 'Gene', (62, 71))	('Ca2', 'Gene', '760', (156, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('MPM', 'Disease', (253, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('Ca2', 'Gene', (156, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('responsible', 'Reg', (237, 248))	('mutations', 'Var', (10, 19))	('expression', 'MPA', (43, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
200608	26156019	Collectively, these data suggest the importance of crosstalk between the dysregulation of Ca2+ homeostasis, apoptosis and cancer progression.	('homeostasis', 'biological_process', 'GO:0042592', ('95', '106'))	('Ca2', 'Gene', (90, 93))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('dysregulation', 'Var', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Ca2', 'Gene', '760', (90, 93))	('apoptosis', 'CPA', (108, 117))
200610	26156019	In this study, MPM-specimens exhibited a global reduction in Ca2+ physiology.	('Ca2', 'Gene', '760', (61, 64))	('reduction', 'NegReg', (48, 57))	('MPM-specimens', 'Var', (15, 28))	('Ca2', 'Gene', (61, 64))
200619	26156019	In MPM cells, the [Ca2+]c increases were significantly smaller than those in control cells (Figure 1C-1D).	('Ca2', 'Gene', (19, 22))	('MPM', 'Var', (3, 6))	('smaller', 'NegReg', (55, 62))	('Ca2', 'Gene', '760', (19, 22))
200638	26156019	Indeed, MPP89 cells displayed a significant reduction in their ability to take up Ca2+ into the cytosolic compartment compared with HMC.	('MPP', 'molecular_function', 'GO:0004240', ('8', '11'))	('Ca2', 'Gene', '760', (82, 85))	('reduction', 'NegReg', (44, 53))	('MPP89', 'Var', (8, 13))	('Ca2', 'Gene', (82, 85))
200639	26156019	In accordance with these data, the basal [Ca2+]i was markedly lower in the MPM cells compared with the control cells (Figure 1G-1H).	('MPM', 'Var', (75, 78))	('Ca2', 'Gene', (42, 45))	('1H', 'Chemical', '-', (128, 130))	('lower', 'NegReg', (62, 67))	('Ca2', 'Gene', '760', (42, 45))
200656	26156019	As expected, we found that apoptotic activity was strongly induced in HMCs treated with menadione, but not in MPM cells, where the ability of the oxidative agent to induce apoptosis was abrogated (Figure 3A-3B and Supplementary Figure S3A-3B).	('menadione', 'Var', (88, 97))	('HMCs', 'Gene', '55034', (70, 74))	('menadione', 'Chemical', 'MESH:D024483', (88, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('172', '181'))	('induced', 'Reg', (59, 66))	('HMCs', 'Gene', (70, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('172', '181'))	('apoptotic activity', 'CPA', (27, 45))
200657	26156019	We found that treatment with H2O2 and C2 did not activate the apoptotic program in mesothelioma cells (Supplementary Figure S3C).	('H2O2', 'Chemical', 'MESH:D006861', (29, 33))	('H2O2', 'Var', (29, 33))	('apoptotic program', 'biological_process', 'GO:0006915', ('62', '79'))	('apoptotic program', 'CPA', (62, 79))	('mesothelioma', 'Disease', (83, 95))	('C2', 'Gene', '717', (38, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))
200679	26156019	After 5 days of incubation in [Ca2+] or NaV, the growth capacity of the cells was affected (Figure 5A): a crystal violet cell proliferation assay indicated that the mesothelioma cells were less proliferative in the presence of high external [Ca2+] or NaV.	('Ca2', 'Gene', '760', (242, 245))	('mesothelioma', 'Disease', (165, 177))	('Ca2', 'Gene', (31, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('crystal violet', 'Chemical', 'MESH:D005840', (106, 120))	('Ca2', 'Gene', (242, 245))	('NaV', 'Var', (251, 254))	('NaV', 'Chemical', '-', (40, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('less', 'NegReg', (189, 193))	('Ca2', 'Gene', '760', (31, 34))	('NaV', 'Chemical', '-', (251, 254))
200680	26156019	The inhibition of ATP2Bs promoted by NaV and the high external [Ca2+] should increase the [Ca2+]i levels and, in turn, [Ca2+]m uptake.	('Ca2', 'Gene', (120, 123))	('Ca2', 'Gene', '760', (91, 94))	('ATP2Bs', 'Gene', (18, 24))	('NaV', 'Chemical', '-', (37, 40))	('Ca2', 'Gene', '760', (120, 123))	('Ca2', 'Gene', '760', (64, 67))	('increase', 'PosReg', (77, 85))	('high', 'Var', (49, 53))	('Ca2', 'Gene', (91, 94))	('Ca2', 'Gene', (64, 67))	('inhibition', 'NegReg', (4, 14))	('uptake', 'biological_process', 'GO:0098657', ('127', '133'))	('uptake', 'biological_process', 'GO:0098739', ('127', '133'))
200687	26156019	Thus, to rule out the possibility that we were observing spurious effects, we evaluated the impact of silencing ATP2B4 on mitochondrial Ca2+ uptake and the apoptotic process using RNA interference (RNAi).	('RNAi', 'biological_process', 'GO:0016246', ('198', '202'))	('ATP2B4', 'Gene', (112, 118))	('RNA', 'cellular_component', 'GO:0005562', ('180', '183'))	('apoptotic process', 'biological_process', 'GO:0006915', ('156', '173'))	('Ca2', 'Gene', '760', (136, 139))	('uptake', 'biological_process', 'GO:0098657', ('141', '147'))	('RNA interference', 'biological_process', 'GO:0016246', ('180', '196'))	('uptake', 'biological_process', 'GO:0098739', ('141', '147'))	('apoptotic', 'CPA', (156, 165))	('silencing', 'Var', (102, 111))	('ATP2B4', 'Gene', '493', (112, 118))	('Ca2', 'Gene', (136, 139))
200688	26156019	Silencing ATP2B4 in MPM cells expressing a mtAEQ restores the [Ca2+]m uptake (Supplementary Figure S4A).	('Ca2', 'Gene', (63, 66))	('ATP2B4', 'Gene', '493', (10, 16))	('mtAEQ', 'Chemical', '-', (43, 48))	('uptake', 'biological_process', 'GO:0098657', ('70', '76'))	('restores', 'PosReg', (49, 57))	('uptake', 'biological_process', 'GO:0098739', ('70', '76'))	('Silencing', 'Var', (0, 9))	('ATP2B4', 'Gene', (10, 16))	('Ca2', 'Gene', '760', (63, 66))
200697	26156019	Next, we explored whether the modulation of MCU activity could modulate apoptotic cell death via regulation of [Ca2+]m uptake in normal and MPM cells.	('MCU', 'Gene', '90550', (44, 47))	('uptake', 'biological_process', 'GO:0098657', ('119', '125'))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('uptake', 'biological_process', 'GO:0098739', ('119', '125'))	('Ca2', 'Gene', '760', (112, 115))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('72', '92'))	('MCU', 'Gene', (44, 47))	('modulate', 'Reg', (63, 71))	('Ca2', 'Gene', (112, 115))	('modulation', 'Var', (30, 40))	('apoptotic cell death', 'CPA', (72, 92))
200700	26156019	Furthermore, silencing MCU induced a marked reduction in the apoptotic machinery and in the sensitivity to pro-apoptotic stimuli (Figure 5H).	('MCU', 'Gene', '90550', (23, 26))	('apoptotic machinery', 'CPA', (61, 80))	('sensitivity to pro-apoptotic stimuli', 'MPA', (92, 128))	('reduction', 'NegReg', (44, 53))	('MCU', 'Gene', (23, 26))	('silencing', 'Var', (13, 22))
200710	26156019	We found that similar to the mesothelioma cell lines, the primary mesothelioma short-term cultures were less proliferative in the presence of high external [Ca2+] or NaV after 5 days of incubation (Figure 6A).	('Ca2', 'Gene', (157, 160))	('primary mesothelioma', 'Phenotype', 'HP:0100001', (58, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('NaV', 'Var', (166, 169))	('NaV', 'Chemical', '-', (166, 169))	('mesothelioma', 'Disease', (66, 78))	('proliferative', 'CPA', (109, 122))	('Ca2', 'Gene', '760', (157, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('mesothelioma', 'Disease', (29, 41))	('less', 'NegReg', (104, 108))
200712	26156019	Similar results were obtained after ATP2B4 silencing.	('silencing', 'Var', (43, 52))	('ATP2B4', 'Gene', (36, 42))	('ATP2B4', 'Gene', '493', (36, 42))
200714	26156019	We also evaluated the effects of ATP2B4 silencing in modulating the apoptotic response.	('ATP2B4', 'Gene', (33, 39))	('apoptotic response', 'CPA', (68, 86))	('ATP2B4', 'Gene', '493', (33, 39))	('silencing', 'Var', (40, 49))	('modulating', 'Reg', (53, 63))
200716	26156019	As result, the silencing of ATP2B4 promoted reactivation of the apoptotic machinery and sensitized mesothelioma cells to apoptotic stimuli (Figure 6D-6E).	('ATP2B4', 'Gene', '493', (28, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (99, 111))	('apoptotic machinery', 'Pathway', (64, 83))	('silencing', 'Var', (15, 24))	('reactivation', 'MPA', (44, 56))	('sensitized', 'Reg', (88, 98))	('promoted', 'PosReg', (35, 43))	('ATP2B4', 'Gene', (28, 34))	('mesothelioma', 'Disease', (99, 111))
200723	26156019	As expected, silencing of MCU reduces the ability of mitochondria to take up Ca2+ (Supplementary Figure S4D) and the MCU protein levels (Figure 6J).	('mitochondria', 'MPA', (53, 65))	('mitochondria', 'cellular_component', 'GO:0005739', ('53', '65'))	('Ca2', 'Gene', '760', (77, 80))	('MCU', 'Gene', (26, 29))	('MCU', 'Gene', (117, 120))	('ability', 'MPA', (42, 49))	('MCU', 'Gene', '90550', (117, 120))	('Ca2', 'Gene', (77, 80))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('MCU', 'Gene', '90550', (26, 29))	('reduces', 'NegReg', (30, 37))	('silencing', 'Var', (13, 22))
200747	26156019	Consistent with this, silencing PMCA by RNA interference or NaV treatment restores the Ca2+ homeostasis and rescues the sensitivity of mesothelioma to apoptotic stimuli.	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('sensitivity', 'MPA', (120, 131))	('Ca2', 'Gene', '760', (87, 90))	('RNA interference', 'MPA', (40, 56))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('RNA interference', 'biological_process', 'GO:0016246', ('40', '56'))	('restores', 'PosReg', (74, 82))	('rescues', 'PosReg', (108, 115))	('Ca2', 'Gene', (87, 90))	('PMCA', 'Gene', (32, 36))	('silencing', 'Var', (22, 31))	('mesothelioma', 'Disease', (135, 147))	('NaV', 'Chemical', '-', (60, 63))	('homeostasis', 'biological_process', 'GO:0042592', ('92', '103'))
200754	26156019	For example, MCU silencing attenuates [Ca2+]m, and reduced [Ca2+]m levels suppress cell death in a variety of cancerous cell lines, including those derived from the cervix, central nervous system and lymph tissues.	('cell death', 'biological_process', 'GO:0008219', ('83', '93'))	('reduced', 'NegReg', (51, 58))	('MCU', 'Gene', '90550', (13, 16))	('cancerous', 'Disease', (110, 119))	('Ca2', 'Gene', '760', (60, 63))	('attenuates', 'NegReg', (27, 37))	('Ca2', 'Gene', '760', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('suppress', 'NegReg', (74, 82))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('Ca2', 'Gene', (60, 63))	('cell death', 'CPA', (83, 93))	('Ca2', 'Gene', (39, 42))	('silencing', 'Var', (17, 26))	('MCU', 'Gene', (13, 16))
200758	26156019	The results reported in Figure 5F and 6F support this hypothesis and show that MPM samples display an overall reduction in MCU expression.	('MCU', 'Gene', (123, 126))	('MPM', 'Var', (79, 82))	('MCU', 'Gene', '90550', (123, 126))	('reduction', 'NegReg', (110, 119))
200760	26156019	Interestingly, one of the most recent advances in cancer research is the demonstration that microRNAs (miRs) cause a variety of human disorders, particularly cancer, and regulate the expression of genes encoding key regulatory molecules of Ca2+ signaling.	('genes', 'Gene', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Ca2', 'Gene', (240, 243))	('cause', 'Reg', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('microRNAs', 'Var', (92, 101))	('human disorders', 'Disease', (128, 143))	('cancer', 'Disease', (158, 164))	('signaling', 'biological_process', 'GO:0023052', ('245', '254'))	('miR', 'Gene', '220972', (103, 106))	('expression', 'MPA', (183, 193))	('miR', 'Gene', (103, 106))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Ca2', 'Gene', '760', (240, 243))	('regulate', 'Reg', (170, 178))
200764	26156019	Preliminary results (data not shown) suggest that inhibition of miR-25 may modulate apoptotic cell death via the enhancement of [Ca2+]m uptake.	('miR-25', 'Gene', '407014', (64, 70))	('apoptotic cell death', 'CPA', (84, 104))	('inhibition', 'Var', (50, 60))	('Ca2', 'Gene', '760', (129, 132))	('miR-25', 'Gene', (64, 70))	('modulate', 'Reg', (75, 83))	('enhancement', 'PosReg', (113, 124))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('84', '104'))	('Ca2', 'Gene', (129, 132))	('uptake', 'biological_process', 'GO:0098657', ('136', '142'))	('uptake', 'biological_process', 'GO:0098739', ('136', '142'))
200802	26156019	The aequorin luminescence data were calibrated offline into [Ca2+] values using a computer algorithm based on the Ca2+ response curve of wild-type and mutant aequorins.	('mutant', 'Var', (151, 157))	('Ca2', 'Gene', (114, 117))	('Ca2', 'Gene', '760', (61, 64))	('Ca2', 'Gene', '760', (114, 117))	('Ca2', 'Gene', (61, 64))
200807	26156019	Non-specific binding sites were saturated by incubating the membranes with TBS-Tween 20 (0.05%) supplemented with 5% nonfat powdered milk for 1 h. Next, the membranes were incubated overnight with primary antibodies, and the binding was assessed using appropriate HRP-labeled secondary antibodies [Life Technologies, A16104 (goat anti-rabbit) and A24512 (goat anti-mouse)] plus a chemiluminescent substrate (Thermo Scientific, 34080).	('binding', 'molecular_function', 'GO:0005488', ('225', '232'))	('goat', 'Species', '9925', (325, 329))	('mouse', 'Species', '10090', (365, 370))	('A24512', 'Var', (347, 353))	('rabbit', 'Species', '9986', (335, 341))	('binding', 'Interaction', (225, 232))	('binding', 'molecular_function', 'GO:0005488', ('13', '20'))	('goat', 'Species', '9925', (355, 359))	('A16104', 'Var', (317, 323))	('TBS-Tween 20', 'Chemical', '-', (75, 87))
200912	24807157	Poor performance status (PS), nonepithelioid histology, male sex, low hemoglobin, high platelet count, high white blood cell count, and high lactate dehydrogenase were found to be poor prognostic indicators in mesothelioma, and subsequently validated.	('mesothelioma', 'Disease', (210, 222))	('high', 'Var', (136, 140))	('high platelet count', 'Phenotype', 'HP:0001894', (82, 101))	('mesothelioma', 'Disease', 'MESH:D008654', (210, 222))	('high lactate dehydrogenase', 'Phenotype', 'HP:0025435', (136, 162))	('low', 'Var', (66, 69))	('low hemoglobin', 'Phenotype', 'HP:0001903', (66, 80))	('high white blood cell count', 'Phenotype', 'HP:0001974', (103, 130))
200929	24807157	Lack of adjuvant therapy, along with the presence of asbestos exposure, weight loss, and chest pain, as well as low hemoglobin, high platelet count, and high white blood count, was found to be associated with a worse prognosis independent of the CORE variables.	('high platelet count', 'Phenotype', 'HP:0001894', (128, 147))	('weight loss', 'Disease', 'MESH:D015431', (72, 83))	('low hemoglobin', 'Phenotype', 'HP:0001903', (112, 126))	('low', 'NegReg', (112, 115))	('chest pain', 'Disease', 'MESH:D002637', (89, 99))	('high white blood count', 'Phenotype', 'HP:0001974', (153, 175))	('chest pain', 'Disease', (89, 99))	('weight loss', 'Disease', (72, 83))	('pain', 'Phenotype', 'HP:0012531', (95, 99))	('weight loss', 'Phenotype', 'HP:0001824', (72, 83))	('asbestos', 'Chemical', 'MESH:D001194', (53, 61))	('high', 'Var', (128, 132))	('chest pain', 'Phenotype', 'HP:0100749', (89, 99))	('high white', 'Var', (153, 163))
200957	25026211	Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('oncogenicity', 'CPA', (132, 144))	('missense mutations', 'Var', (60, 78))	('tumor', 'Disease', (46, 51))	('deficient tumor', 'Disease', 'MESH:D009369', (155, 170))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('deficient tumor', 'Disease', (155, 170))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('tumor', 'Disease', (165, 170))
200958	25026211	Analysis of clinical samples confirms that this pathway operates in NF2 mutant tumors.	('mutant', 'Var', (72, 78))	('NF2', 'Gene', '4771', (68, 71))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('NF2', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
200968	25026211	Since mammalian Merlin can inhibit YAP and TEAD-dependent transcription and deletion of Yap suppresses liver overgrowth and tumorigenesis in mice carrying a conditional ablation of Nf2, it has been proposed that Merlin suppresses tumorigenesis by activating the Hippo pathway.	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('activating', 'PosReg', (247, 257))	('tumor', 'Disease', (124, 129))	('mice', 'Species', '10090', (141, 145))	('mammalian', 'Species', '9606', (6, 15))	('Nf2', 'Gene', '18016', (181, 184))	('Yap', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('YAP', 'MPA', (35, 38))	('overgrowth', 'Phenotype', 'HP:0001548', (109, 119))	('TEAD', 'Gene', '32536', (43, 47))	('TEAD', 'Gene', (43, 47))	('Hippo', 'Gene', (262, 267))	('Hippo', 'Gene', '37247', (262, 267))	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('liver overgrowth', 'Disease', (103, 119))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('inhibit', 'NegReg', (27, 34))	('deletion', 'Var', (76, 84))	('suppresses', 'NegReg', (92, 102))	('liver overgrowth', 'Disease', 'MESH:D017093', (103, 119))	('Yap', 'Gene', '10413', (88, 91))	('suppresses', 'NegReg', (219, 229))	('Nf2', 'Gene', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
200975	25026211	To examine if CRL4DCAF1 inactivates the Hippo signaling pathway, we examined NF2 mutant mesothelioma and Schwannoma cells.	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('40', '63'))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('NF2', 'Gene', '4771', (77, 80))	('Schwannoma', 'Disease', 'MESH:D009442', (105, 115))	('Hippo', 'Gene', '37247', (40, 45))	('NF2', 'Gene', (77, 80))	('Schwannoma', 'Phenotype', 'HP:0100008', (105, 115))	('mutant', 'Var', (81, 87))	('Schwannoma', 'Disease', (105, 115))	('mesothelioma', 'Disease', (88, 100))	('inactivates', 'NegReg', (24, 35))	('Hippo', 'Gene', (40, 45))
200978	25026211	In agreement with this hypothesis, depletion of DCAF1 induced phosphorylation of YAP and suppressed expression of the YAP target genes CTGF (Figures 1B and S1B), BIRC5 and CYR61 (Figure S1B).	('YAP', 'Protein', (81, 84))	('BIRC5', 'Gene', (162, 167))	('CYR61', 'Gene', '3491', (172, 177))	('induced', 'Reg', (54, 61))	('DCAF1', 'Gene', (48, 53))	('suppressed', 'NegReg', (89, 99))	('phosphorylation', 'MPA', (62, 77))	('CTGF', 'Gene', '1490', (135, 139))	('expression', 'MPA', (100, 110))	('CTGF', 'Gene', (135, 139))	('CYR61', 'Gene', (172, 177))	('depletion', 'Var', (35, 44))	('BIRC5', 'Gene', '332', (162, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
200980	25026211	These results indicate that CRL4DCAF1 is necessary for activation of Yap in NF2 mutant mesothelioma cells.	('mutant', 'Var', (80, 86))	('Yap', 'Gene', (69, 72))	('NF2', 'Gene', (76, 79))	('mesothelioma', 'Disease', (87, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('Yap', 'Gene', '10413', (69, 72))	('NF2', 'Gene', '4771', (76, 79))
200982	25026211	In response to re-expression of Merlin, these cells undergo proliferation arrest and are no longer tumorigenic.	('tumor', 'Disease', (99, 104))	('re-expression', 'Var', (15, 28))	('Merlin', 'Protein', (32, 38))	('proliferation arrest', 'Disease', (60, 80))	('proliferation arrest', 'Disease', 'MESH:D006323', (60, 80))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
200983	25026211	Strikingly, whereas YAP/TAZ accumulated almost exclusively in the nuclei of these cells even if they were confluent, silencing of DCAF1 provoked almost complete YAP/TAZ extrusion to the cytoplasm in most cells (Figure 1C; data not shown).	('cytoplasm', 'cellular_component', 'GO:0005737', ('186', '195'))	('silencing', 'Var', (117, 126))	('TAZ', 'Gene', '6901', (165, 168))	('TAZ', 'Gene', (165, 168))	('TAZ', 'Gene', (24, 27))	('TAZ', 'Gene', '6901', (24, 27))	('DCAF1', 'Gene', (130, 135))
200984	25026211	Moreover, silencing of DCAF1 inhibited transcription from a TEAD-dependent reporter, although not as completely as overexpression of Merlin or dominant negative TEAD (Figure 1D).	('inhibited', 'NegReg', (29, 38))	('TEAD', 'Gene', '32536', (60, 64))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('TEAD', 'Gene', '32536', (161, 165))	('TEAD', 'Gene', (60, 64))	('TEAD', 'Gene', (161, 165))	('DCAF1', 'Gene', (23, 28))	('silencing', 'Var', (10, 19))
200985	25026211	Finally, in agreement with prior DNA microarray analyses, overexpression of DCAF1 increased, and silencing of DCAF1 decreased, the expression of YAP target genes in FC1801 cells (Figure S1G).	('silencing', 'Var', (97, 106))	('FC1801', 'CellLine', 'CVCL:1W22', (165, 171))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('DCAF1', 'Gene', (76, 81))	('DCAF1', 'Gene', (110, 115))	('expression', 'MPA', (131, 141))	('overexpression', 'PosReg', (58, 72))	('increased', 'PosReg', (82, 91))	('decreased', 'NegReg', (116, 125))
200986	25026211	Thus, de-repression of CRL4DCAF1 activates YAP and induces TEAD-dependent transcription in NF2 mutant tumor cells.	('de-repression', 'Var', (6, 19))	('TEAD', 'Gene', '32536', (59, 63))	('activates', 'PosReg', (33, 42))	('induces', 'Reg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('CRL4DCAF1', 'Gene', (23, 32))	('YAP', 'MPA', (43, 46))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('NF2', 'Gene', (91, 94))	('mutant', 'Var', (95, 101))	('TEAD', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('NF2', 'Gene', '4771', (91, 94))
200987	25026211	Unexpectedly, neither expression of Merlin nor silencing of DCAF1 increased phosphorylation of the activation loop of MST1 or MST2 (Figures S1H and S1I).	('MST2', 'Gene', (126, 130))	('increased', 'PosReg', (66, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('MST1', 'Gene', '4485', (118, 122))	('S1I', 'Mutation', 'p.S1I', (148, 151))	('MST2', 'Gene', '6788', (126, 130))	('MST1', 'Gene', (118, 122))	('phosphorylation', 'MPA', (76, 91))	('silencing', 'Var', (47, 56))	('DCAF1', 'Gene', (60, 65))
200989	25026211	Rather, these manipulations decreased this phosphorylation (Figures S1H and S1I), presumably by activating the negative feedback loops that restrain flux through the Hippo pathway.	('decreased', 'NegReg', (28, 37))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('activating', 'Reg', (96, 106))	('flux', 'MPA', (149, 153))	('S1I', 'Mutation', 'p.S1I', (76, 79))	('negative feedback loops', 'MPA', (111, 134))	('Hippo', 'Gene', (166, 171))	('restrain', 'NegReg', (140, 148))	('manipulations', 'Var', (14, 27))	('Hippo', 'Gene', '37247', (166, 171))
200991	25026211	To corroborate this hypothesis, we examined if simultaneous depletion of MST1 and MST2 decreased phosphorylation of YAP in Merlin re-expressing or DCAF1-silenced Meso-33 cells.	('MST1', 'Gene', (73, 77))	('decreased', 'NegReg', (87, 96))	('MST2', 'Gene', '6788', (82, 86))	('YAP', 'Protein', (116, 119))	('depletion', 'Var', (60, 69))	('phosphorylation', 'MPA', (97, 112))	('MST1', 'Gene', '4485', (73, 77))	('MST2', 'Gene', (82, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
200993	25026211	Additional experiments revealed that silencing of Sav1 enhances TEAD-dependent transcription in Meso-33 cells, suggesting that the canonical Hippo pathway operates in these cells.	('Sav1', 'Gene', (50, 54))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('TEAD', 'Gene', '32536', (64, 68))	('silencing', 'Var', (37, 46))	('TEAD', 'Gene', (64, 68))	('Sav1', 'Gene', '60485', (50, 54))	('Hippo', 'Gene', (141, 146))	('enhances', 'PosReg', (55, 63))	('Hippo', 'Gene', '37247', (141, 146))
200995	25026211	As anticipated, silencing of DCAF1 and re-expression of Merlin failed to induce phosphorylation of YAP at Ser 127 in cells depleted of Lats1 and 2 (Figure S1K and S1L).	('Ser', 'Chemical', 'MESH:D012694', (106, 109))	('Lats1 and 2', 'Gene', '8140;7462', (135, 146))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('Ser', 'cellular_component', 'GO:0005790', ('106', '109'))	('silencing', 'Var', (16, 25))	('phosphorylation', 'MPA', (80, 95))	('DCAF1', 'Gene', (29, 34))	('Merlin', 'Gene', (56, 62))	('S1L', 'Mutation', 'p.S1L', (163, 166))
200996	25026211	These findings indicate that the loss of Merlin and ensuing de-repression of CRL4DCAF1 activate YAP independently of decreased flux through the core Hippo kinase cassette.	('de-repression', 'Var', (60, 73))	('decreased', 'NegReg', (117, 126))	('YAP', 'Disease', (96, 99))	('Hippo kinase', 'Gene', '37247', (149, 161))	('Merlin', 'Protein', (41, 47))	('CRL4DCAF1', 'Gene', (77, 86))	('activate', 'PosReg', (87, 95))	('loss', 'Var', (33, 37))	('Hippo kinase', 'Gene', (149, 161))	('core', 'cellular_component', 'GO:0019013', ('144', '148'))
200997	25026211	Motivated by the above findings, we examined the hypothesis that CRL4DCAF1 inhibits Lats1 and 2 by promoting their ubiquitylation.	('Lats1 and 2', 'Gene', '8140;7462', (84, 95))	('ubiquitylation', 'MPA', (115, 129))	('CRL4DCAF1', 'Var', (65, 74))	('promoting', 'PosReg', (99, 108))	('inhibits', 'NegReg', (75, 83))
201002	25026211	Since the C-terminal fragment of DCAF1 contains the WD40 domain, which is involved in substrate recruitment, we hypothesized that CRL4DCAF1 recruits Lats1 and 2 in order to direct their ubiquitylation.	('direct', 'PosReg', (173, 179))	('CRL4DCAF1', 'Var', (130, 139))	('ubiquitylation', 'MPA', (186, 200))	('DCAF1', 'Gene', (33, 38))	('Lats1 and 2', 'Gene', '8140;7462', (149, 160))
201005	25026211	Lower amounts of ubiquitylated Lats1 were recovered in the absence of MG132 (Li and Giancotti, unpublished results), in consonance with the hypothesis that poly-ubiquitylation targets Lats1 for degradation through the proteasome.	('targets', 'Reg', (176, 183))	('Lats1', 'Gene', (184, 189))	('Lats1', 'Gene', (31, 36))	('degradation', 'biological_process', 'GO:0009056', ('194', '205'))	('MG132', 'Chemical', 'MESH:C072553', (70, 75))	('MG132', 'Var', (70, 75))	('poly-ubiquitylation', 'Var', (156, 175))	('degradation', 'MPA', (194, 205))	('Lats1', 'Gene', '9113', (31, 36))	('Lats1', 'Gene', '9113', (184, 189))	('proteasome', 'molecular_function', 'GO:0004299', ('218', '228'))	('proteasome', 'cellular_component', 'GO:0000502', ('218', '228'))
201008	25026211	K R substitution of residue 830 did not reduce poly-ubiquitylation of Lats1 (Figure S2D), pointing to compensatory ubiquitylation of additional lysine residues.	('Lats1', 'Gene', (70, 75))	('poly-ubiquitylation', 'MPA', (47, 66))	('substitution', 'Var', (4, 16))	('Lats1', 'Gene', '9113', (70, 75))	('ubiquitylation', 'MPA', (115, 129))	('lysine', 'Chemical', 'MESH:D008239', (144, 150))
201009	25026211	In contrast, Lats2 was ubiquitylated at 4 sites (K383, K527, K633, K968) (Figure 2E, Table S1).	('Lats2', 'Gene', (13, 18))	('K383', 'Var', (49, 53))	('K968', 'Var', (67, 71))	('Lats2', 'Gene', '26524', (13, 18))	('K633', 'Var', (61, 65))	('K527', 'Var', (55, 59))
201010	25026211	Simultaneous K R substitutions at these residues did not reduce oligo-ubiquitylation of Lats2, again pointing to compensatory ubiquitylation of additional lysine residues (Figure S2E).	('lysine', 'Chemical', 'MESH:D008239', (155, 161))	('Lats2', 'Gene', '26524', (88, 93))	('ubiquitylation', 'MPA', (126, 140))	('oligo-ubiquitylation', 'MPA', (64, 84))	('lysine residues', 'MPA', (155, 170))	('compensatory', 'MPA', (113, 125))	('Lats2', 'Gene', (88, 93))	('substitutions', 'Var', (17, 30))
201013	25026211	Moreover, whereas treatment with MG132 increased the level of poly-ubiquitylation of Lats1 in control 293T cells, it failed to produce this effect in DCAF1-depleted cells, indicating that CRL4DCAF1 is required for efficient poly-ubiquitylation of Lats1 (Figure S3A).	('293T', 'CellLine', 'CVCL:0063', (102, 106))	('poly-ubiquitylation', 'MPA', (62, 81))	('Lats1', 'Gene', '9113', (85, 90))	('Lats1', 'Gene', '9113', (247, 252))	('increased', 'PosReg', (39, 48))	('MG132', 'Chemical', 'MESH:C072553', (33, 38))	('Lats1', 'Gene', (85, 90))	('MG132', 'Var', (33, 38))	('Lats1', 'Gene', (247, 252))
201016	25026211	Since we had noticed that re-expression of Merlin and silencing of DCAF1 increase the steady-state levels of Lats1 in NF2 mutant cells (Figures S1H and S1I), we examined if expression of DCAF1 causes the opposite effect.	('increase', 'PosReg', (73, 81))	('Lats1', 'Gene', '9113', (109, 114))	('silencing', 'Var', (54, 63))	('NF2', 'Gene', (118, 121))	('S1I', 'Mutation', 'p.S1I', (152, 155))	('mutant', 'Var', (122, 128))	('DCAF1', 'Gene', (67, 72))	('Lats1', 'Gene', (109, 114))	('NF2', 'Gene', '4771', (118, 121))
201018	25026211	Furthermore, cycloheximide chase experiments demonstrated that silencing of DCAF1 prolongs the half-life of Lats1 in Meso-33 cells by more than 2 fold, indicating that CRL4DCAF1 promotes degradation of Lats1 (Figure 3C and 3D).	('Lats1', 'Gene', (202, 207))	('degradation', 'MPA', (187, 198))	('promotes', 'PosReg', (178, 186))	('prolongs', 'PosReg', (82, 90))	('Lats1', 'Gene', (108, 113))	('DCAF1', 'Gene', (76, 81))	('Lats1', 'Gene', '9113', (202, 207))	('Lats1', 'Gene', '9113', (108, 113))	('degradation', 'biological_process', 'GO:0009056', ('187', '198'))	('CRL4DCAF1', 'Var', (168, 177))	('half-life', 'MPA', (95, 104))	('silencing', 'Var', (63, 72))	('cycloheximide', 'Chemical', 'MESH:D003513', (13, 26))
201019	25026211	Since K830 lies within the kinase domain, poly-ubiquitylation of Lats1 may inhibit kinase activity by interfering with binding of ATP or recruitment of substrates.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('interfering', 'NegReg', (102, 113))	('recruitment of substrates', 'MPA', (137, 162))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('inhibit', 'NegReg', (75, 82))	('kinase activity', 'MPA', (83, 98))	('Lats1', 'Gene', '9113', (65, 70))	('K830', 'Var', (6, 10))	('ATP', 'Protein', (130, 133))	('kinase activity', 'molecular_function', 'GO:0016301', ('83', '98'))	('poly-ubiquitylation', 'Var', (42, 61))	('Lats1', 'Gene', (65, 70))	('binding', 'Interaction', (119, 126))
201022	25026211	An in vitro kinase assay indicated that ubiquitylated Lats1 possesses a severely diminished ability to phosphorylate GST-YAP at serine 127 as compared to total Lats1 (Figure S3C, bottom).	('diminished', 'NegReg', (81, 91))	('Lats1', 'Gene', '9113', (160, 165))	('ubiquitylated', 'Var', (40, 53))	('ability', 'MPA', (92, 99))	('Lats1', 'Gene', '9113', (54, 59))	('Lats1', 'Gene', (160, 165))	('serine', 'Chemical', 'MESH:D012694', (128, 134))	('phosphorylate', 'MPA', (103, 116))	('Lats1', 'Gene', (54, 59))
201023	25026211	These results suggest that poly-ubiquitylation inhibits Lats1 by blocking its kinase activity and by promoting its degradation.	('poly-ubiquitylation', 'Var', (27, 46))	('blocking', 'NegReg', (65, 73))	('degradation', 'biological_process', 'GO:0009056', ('115', '126'))	('Lats1', 'Gene', (56, 61))	('promoting', 'PosReg', (101, 110))	('degradation', 'MPA', (115, 126))	('kinase activity', 'MPA', (78, 93))	('Lats1', 'Gene', '9113', (56, 61))	('kinase activity', 'molecular_function', 'GO:0016301', ('78', '93'))	('inhibits', 'NegReg', (47, 55))
201030	25026211	In agreement with the model that mono- and oligo-ubiquitylation modify protein function without affecting protein stability, silencing of DCAF1 did not increase the steady-state levels of Lats2 (Figure S3G).	('protein function', 'MPA', (71, 87))	('Lats2', 'Gene', (188, 193))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('silencing', 'Var', (125, 134))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('DCAF1', 'Gene', (138, 143))	('modify', 'Reg', (64, 70))	('Lats2', 'Gene', '26524', (188, 193))
201031	25026211	Interestingly, Lats2 is ubiquitylated at K968 within the kinase domain, at K633 near the binding site for the co-activator Mob1/Mats, and at K527 near the PPXY motif involved in binding to YAP, suggesting that oligo-ubiquitylated Lats2 may exhibit reduced ability to phosphorylate YAP/TAZ in vivo.	('ability', 'MPA', (256, 263))	('at K527', 'Var', (138, 145))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('Lats2', 'Gene', '26524', (15, 20))	('Mob1', 'Gene', '55233', (123, 127))	('TAZ', 'Gene', '6901', (285, 288))	('Mob1', 'Gene', (123, 127))	('Lats2', 'Gene', (15, 20))	('K633', 'Var', (75, 79))	('TAZ', 'Gene', (285, 288))	('Lats2', 'Gene', '26524', (230, 235))	('binding', 'molecular_function', 'GO:0005488', ('178', '185'))	('Lats2', 'Gene', (230, 235))
201033	25026211	Immunoblotting with anti-P-YAP revealed that de-ubiquitylated Lats2 possesses a greatly increased ability to phosphorylate GST-YAP at Ser 127 as compared to total Lats2 (Fig.	('Lats2', 'Gene', '26524', (163, 168))	('Ser', 'Chemical', 'MESH:D012694', (134, 137))	('de-ubiquitylated', 'Var', (45, 61))	('Lats2', 'Gene', (62, 67))	('ability', 'MPA', (98, 105))	('phosphorylate', 'MPA', (109, 122))	('Lats2', 'Gene', (163, 168))	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('increased', 'PosReg', (88, 97))	('Lats2', 'Gene', '26524', (62, 67))
201036	25026211	Intriguingly, patient-derived mutants of Merlin lacking the coiled-coil and C-terminal segments bind to DCAF1 but fail to suppress CRL4DCAF1, suggesting that these latter segments are also required for inhibition of ligase activity.	('bind', 'Reg', (96, 100))	('inhibition of ligase activity', 'biological_process', 'GO:0051352', ('202', '231'))	('DCAF1', 'Gene', (104, 109))	('patient', 'Species', '9606', (14, 21))	('lacking', 'NegReg', (48, 55))	('coiled-coil', 'MPA', (60, 71))	('mutants', 'Var', (30, 37))	('Merlin', 'Gene', (41, 47))	('ligase activity', 'molecular_function', 'GO:0016874', ('216', '231'))
201045	25026211	Whereas alanine permutation of each residue or combinations of two or three residues within this motif inhibited nuclear accumulation of Merlin partially, simultaneous alanine substitution of all four residues (24-27A) blocked this process completely (Figures 4A and 4B).	('alanine', 'Chemical', 'MESH:D000409', (168, 175))	('alanine permutation', 'Var', (8, 27))	('Merlin', 'Protein', (137, 143))	('alanine substitution', 'Var', (168, 188))	('nuclear accumulation', 'MPA', (113, 133))	('inhibited', 'NegReg', (103, 112))	('alanine', 'Chemical', 'MESH:D000409', (8, 15))
201046	25026211	A mutant form of Merlin lacking the VRIV sequence (Delta24-27) did not accumulate in the nucleus even if Crm1-dependent nuclear export was blocked with Leptomycin B, confirming that this motif acts as a non-canonical nuclear localization sequence (Figure 4C).	('Crm1', 'Gene', '7514', (105, 109))	('nucleus', 'cellular_component', 'GO:0005634', ('89', '96'))	('nuclear export', 'biological_process', 'GO:0051168', ('120', '134'))	('Leptomycin B', 'Chemical', 'MESH:C038753', (152, 164))	('Crm1', 'Gene', (105, 109))	('localization', 'biological_process', 'GO:0051179', ('225', '237'))	('Delta24-27', 'Var', (51, 61))
201047	25026211	Functional analysis revealed that re-expression of Merlin Delta24-27 or Merlin 24-27A does not induce phosphorylation of YAP or inhibit cell proliferation and soft agar growth in Meso-33 cells (Figures 4D-F and S4E).	('inhibit', 'NegReg', (128, 135))	('Merlin 24-27A', 'Var', (72, 85))	('agar', 'Chemical', 'MESH:D000362', (164, 168))	('Delta24-27', 'Var', (58, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('Merlin', 'Gene', (51, 57))	('cell proliferation', 'CPA', (136, 154))
201053	25026211	In agreement with the observation that Meso-33 cells do not express E-cadherin nor assemble adherens junctions, we did not detect endogenous Lats1 at cell junctions or at the cell cortex in these cells (Figure 5C), suggesting that de-regulated CRL4DCAF1 does not target Lats1 at the cell cortex in NF2 mutant cells.	('cell cortex', 'cellular_component', 'GO:0005938', ('283', '294'))	('Lats1', 'Gene', (141, 146))	('Lats1', 'Gene', '9113', (270, 275))	('NF2', 'Gene', '4771', (298, 301))	('mutant', 'Var', (302, 308))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('Lats1', 'Gene', (270, 275))	('Lats1', 'Gene', '9113', (141, 146))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))	('NF2', 'Gene', (298, 301))	('cell cortex', 'cellular_component', 'GO:0005938', ('175', '186'))
201060	25026211	Irrespective of the mechanism involved, the predominant accumulation of CRL4DCAF1 and activated Lats in the nucleus is consistent with the hypothesis that CRL4DCAF1 binds to Lats and inhibits it in the nucleus.	('nucleus', 'cellular_component', 'GO:0005634', ('108', '115'))	('Lats', 'Gene', (174, 178))	('inhibits', 'NegReg', (183, 191))	('Lats', 'Gene', '43651', (96, 100))	('Lats', 'Gene', '43651', (174, 178))	('Lats', 'Gene', (96, 100))	('CRL4DCAF1', 'Var', (155, 164))	('binds', 'Interaction', (165, 170))	('nucleus', 'cellular_component', 'GO:0005634', ('202', '209'))
201061	25026211	Having noted that Lats1 partially localizes to the cell cortex in normal but not NF2 mutant cells (Figure 5B, C), we asked if re-expression of Merlin modifies the subcellular localization of Lats1 in NF2 mutant cells.	('NF2', 'Gene', '4771', (200, 203))	('NF2', 'Gene', '4771', (81, 84))	('Lats1', 'Gene', '9113', (191, 196))	('cell cortex', 'cellular_component', 'GO:0005938', ('51', '62'))	('Lats1', 'Gene', '9113', (18, 23))	('mutant', 'Var', (204, 210))	('Lats1', 'Gene', (191, 196))	('NF2', 'Gene', (200, 203))	('NF2', 'Gene', (81, 84))	('mutant', 'Var', (85, 91))	('localization', 'biological_process', 'GO:0051179', ('175', '187'))	('Lats1', 'Gene', (18, 23))
201066	25026211	To investigate the functional relevance of the interaction of Merlin with Lats1, we tested four patient-derived missense mutants, which fail to accumulate in the nucleus (L46R, L64P, L141P, and A211D), and one that enters into the nucleus but does not bind to DCAF1 (E270G).	('A211D', 'Var', (194, 199))	('E270G', 'Mutation', 'p.E270G', (267, 272))	('L141P', 'Mutation', 'p.L141P', (183, 188))	('A211D', 'Mutation', 'p.A211D', (194, 199))	('E270G', 'Var', (267, 272))	('patient', 'Species', '9606', (96, 103))	('nucleus', 'cellular_component', 'GO:0005634', ('162', '169'))	('L64P', 'Var', (177, 181))	('L46R', 'Mutation', 'p.L46R', (171, 175))	('Lats1', 'Gene', (74, 79))	('L64P', 'Mutation', 'p.L64P', (177, 181))	('nucleus', 'cellular_component', 'GO:0005634', ('231', '238'))	('L141P', 'Var', (183, 188))	('Lats1', 'Gene', '9113', (74, 79))	('L46R', 'Var', (171, 175))
201068	25026211	In addition, whereas all nuclear-defective and patient-derived mutants of Merlin failed to associate with DCAF1 in this assay, none of them exhibited reduced ability to interact with Lats1 (Figures 5E and 5F).	('patient', 'Species', '9606', (47, 54))	('associate', 'Interaction', (91, 100))	('mutants', 'Var', (63, 70))	('Merlin', 'Gene', (74, 80))	('failed', 'NegReg', (81, 87))	('Lats1', 'Gene', (183, 188))	('ability', 'MPA', (158, 165))	('interact', 'Interaction', (169, 177))	('reduced', 'NegReg', (150, 157))	('Lats1', 'Gene', '9113', (183, 188))
201070	25026211	In agreement with these results, none of the patient-derived mutants exhibited reduced ability to recruit Lats1 to lamellipodia and membrane ruffles upon transient overexpression in Meso-33 cells (Figure S5E).	('membrane', 'cellular_component', 'GO:0016020', ('132', '140'))	('Lats1', 'Gene', '9113', (106, 111))	('recruit', 'Interaction', (98, 105))	('patient', 'Species', '9606', (45, 52))	('overexpression', 'PosReg', (164, 178))	('Lats1', 'Gene', (106, 111))	('mutants', 'Var', (61, 68))
201073	25026211	As previously shown, depletion of DCAF1 caused a profound proliferation arrest in Meso-33 cells (Figure 6A).	('DCAF1', 'Gene', (34, 39))	('proliferation arrest', 'Disease', (58, 78))	('depletion', 'Var', (21, 30))	('proliferation arrest', 'Disease', 'MESH:D006323', (58, 78))
201076	25026211	Next, we tested if simultaneous depletion of Lats1 and 2 rescues the tumorigenic potential of DCAF1-silenced NF2 mutant cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('NF2', 'Gene', '4771', (109, 112))	('rescues', 'PosReg', (57, 64))	('tumor', 'Disease', (69, 74))	('Lats1 and 2', 'Gene', '8140;7462', (45, 56))	('NF2', 'Gene', (109, 112))	('mutant', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
201077	25026211	Simultaneous silencing of Lats1 and 2 largely reversed the proliferation arrest induced by depletion of DCAF1 in Meso-33 cells (Figure 6D).	('depletion', 'Var', (91, 100))	('Lats1 and 2', 'Gene', '8140;7462', (26, 37))	('DCAF1', 'Gene', (104, 109))	('proliferation arrest', 'Disease', (59, 79))	('proliferation arrest', 'Disease', 'MESH:D006323', (59, 79))	('silencing', 'Var', (13, 22))
201078	25026211	Furthermore, silencing of Lats1/2 enabled DCAF1-depleted Meso-33 cells to grow in soft agar as efficiently as those expressing DCAF1 (Figures 6E and 6F).	('agar', 'Chemical', 'MESH:D000362', (87, 91))	('Lats1/2', 'Gene', (26, 33))	('DCAF1-depleted', 'Gene', (42, 56))	('silencing', 'Var', (13, 22))	('grow', 'CPA', (74, 78))
201080	25026211	Finally, we examined if silencing of Lats1/2 rescues the tumorigenic ability of DCAF1-depleted FC-1801 cells.	('rescues', 'PosReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Lats1/2', 'Gene', (37, 44))	('FC-1801', 'CellLine', 'CVCL:1W22', (95, 102))	('tumor', 'Disease', (57, 62))	('silencing', 'Var', (24, 33))
201081	25026211	Intriguingly, silencing of Lats1/2 rescued the ability of DCAF1-depleted Schwannoma cells to form tumors to a very large extent (Figures 6G and S6B).	('silencing', 'Var', (14, 23))	('Schwannoma', 'Disease', 'MESH:D009442', (73, 83))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ability', 'MPA', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('Schwannoma', 'Phenotype', 'HP:0100008', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('rescued', 'PosReg', (35, 42))	('Schwannoma', 'Disease', (73, 83))	('DCAF1-depleted', 'Gene', (58, 72))	('Lats1/2', 'Gene', (27, 34))
201082	25026211	We consider this effect specific, because silencing of Lats1/2 alone did not increase tumor growth (Figures 6G and S6B).	('silencing', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Lats1/2', 'Gene', (55, 62))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
201083	25026211	Taken together, these findings indicate that de-repression of CRL4DCAF1 promotes tumorigenesis of NF2 mutant cells by inactivating Lats1/2 and, hence, activating YAP.	('mutant', 'Var', (102, 108))	('inactivating', 'NegReg', (118, 130))	('YAP', 'MPA', (162, 165))	('CRL4DCAF1', 'Gene', (62, 71))	('NF2', 'Gene', (98, 101))	('NF2', 'Gene', '4771', (98, 101))	('activating', 'PosReg', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('de-repression', 'Var', (45, 58))	('promotes', 'PosReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('Lats1/2', 'Protein', (131, 138))
201085	25026211	Immunoblotting revealed that the NF2 mutant lines exhibited severely diminished levels of Lats1, but not Lats2, as compared to NF2 wild type lines (Figures 7A and S7A).	('NF2', 'Gene', '4771', (33, 36))	('NF2', 'Gene', (127, 130))	('Lats1', 'Gene', (90, 95))	('NF2', 'Gene', '4771', (127, 130))	('Lats2', 'Gene', '26524', (105, 110))	('mutant', 'Var', (37, 43))	('Lats2', 'Gene', (105, 110))	('NF2', 'Gene', (33, 36))	('diminished', 'NegReg', (69, 79))	('Lats1', 'Gene', '9113', (90, 95))
201086	25026211	In addition, all except one of the NF2 mutant cell lines displayed decreased phosphorylation of YAP, and 4 out of 7 lines displayed increased expression of the YAP target gene CTGF (Figures 7A and S7A).	('phosphorylation', 'MPA', (77, 92))	('NF2', 'Gene', (35, 38))	('CTGF', 'Gene', '1490', (176, 180))	('CTGF', 'Gene', (176, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('YAP', 'Protein', (96, 99))	('increased', 'PosReg', (132, 141))	('NF2', 'Gene', '4771', (35, 38))	('mutant', 'Var', (39, 45))	('expression', 'MPA', (142, 152))	('decreased', 'NegReg', (67, 76))
201088	25026211	To examine if loss of NF2 induces YAP-dependent oncogenic gene expression in clinical samples, we generated a gene expression signature reflective of CRL4DCAF1-dependent YAP activity.	('induces', 'Reg', (26, 33))	('NF2', 'Gene', '4771', (22, 25))	('loss', 'Var', (14, 18))	('NF2', 'Gene', (22, 25))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
201089	25026211	Since only simultaneous depletion of YAP and TAZ induced Meso-33 cells to undergo a proliferation arrest as profound as that induced by depletion of DCAF1 (Figures 7B and S7B), we used DNA microarray analysis to compare the effect of inactivation of CRL4DCAF1 and simultaneous inactivation of YAP and TAZ on gene expression.	('TAZ', 'Gene', (301, 304))	('proliferation arrest', 'Disease', (84, 104))	('gene expression', 'biological_process', 'GO:0010467', ('308', '323'))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('inactivation', 'Var', (234, 246))	('proliferation arrest', 'Disease', 'MESH:D006323', (84, 104))	('TAZ', 'Gene', '6901', (45, 48))	('TAZ', 'Gene', (45, 48))	('TAZ', 'Gene', '6901', (301, 304))
201091	25026211	Notably, silencing of DCAF1 suppressed the expression of a large fraction of YAP/TAZ target genes (~39%) (Figures 7C, 7D, and S7C; Table S2).	('TAZ', 'Gene', (81, 84))	('silencing', 'Var', (9, 18))	('expression', 'MPA', (43, 53))	('suppressed', 'NegReg', (28, 38))	('DCAF1', 'Gene', (22, 27))	('TAZ', 'Gene', '6901', (81, 84))
201092	25026211	In addition, silencing of DCAF1 enhanced the expression of a somewhat smaller fraction of the genes repressed by YAP/TAZ (~8%), including some TGF-beta target genes (Figures 7C, 7D, and S7D; Table S3 and S5).	('TGF-beta', 'Gene', '7039', (143, 151))	('TGF-beta', 'Gene', (143, 151))	('expression', 'MPA', (45, 55))	('enhanced', 'PosReg', (32, 40))	('TAZ', 'Gene', '6901', (117, 120))	('TAZ', 'Gene', (117, 120))	('DCAF1', 'Gene', (26, 31))	('silencing', 'Var', (13, 22))
201093	25026211	These results indicate that CRL4DCAF1 controls a large fraction of the transcriptional output of YAP in NF2 mutant cells.	('transcriptional output', 'MPA', (71, 93))	('NF2', 'Gene', (104, 107))	('mutant', 'Var', (108, 114))	('NF2', 'Gene', '4771', (104, 107))
201094	25026211	We next examined the gene expression profiles of 53 human mesotheliomas, 39 of which harbored mutation or genomic loss at the NF2 locus.	('mesotheliomas', 'Disease', 'MESH:D008654', (58, 71))	('mesotheliomas', 'Disease', (58, 71))	('loss', 'NegReg', (114, 118))	('human', 'Species', '9606', (52, 57))	('NF2', 'Gene', '4771', (126, 129))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('mutation', 'Var', (94, 102))	('NF2', 'Gene', (126, 129))
201095	25026211	Unsupervised hierarchical clustering strongly suggested that the NF2 mutant mesotheliomas were endowed with a largely distinct gene expression program (Figure S7E).	('NF2', 'Gene', (65, 68))	('mutant', 'Var', (69, 75))	('mesotheliomas', 'Disease', 'MESH:D008654', (76, 89))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('NF2', 'Gene', '4771', (65, 68))	('mesotheliomas', 'Disease', (76, 89))
201096	25026211	Gene set enrichment analysis (GSEA) revealed that CRL4DCAF1-activated genes were highly enriched in NF2 mutant mesotheliomas as compared to the remaining mesotheliomas (Figure 7E).	('NF2', 'Gene', (100, 103))	('mutant', 'Var', (104, 110))	('mesotheliomas', 'Disease', 'MESH:D008654', (111, 124))	('mesotheliomas', 'Disease', (111, 124))	('NF2', 'Gene', '4771', (100, 103))	('mesotheliomas', 'Disease', 'MESH:D008654', (154, 167))	('GSEA', 'Chemical', '-', (30, 34))	('mesotheliomas', 'Disease', (154, 167))
201098	25026211	These results indicate that CRL4DCAF1 controls YAP/TAZ-dependent gene expression in NF2 mutant mesotheliomas.	('NF2', 'Gene', '4771', (84, 87))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('TAZ', 'Gene', '6901', (51, 54))	('mutant', 'Var', (88, 94))	('NF2', 'Gene', (84, 87))	('TAZ', 'Gene', (51, 54))	('mesotheliomas', 'Disease', 'MESH:D008654', (95, 108))	('mesotheliomas', 'Disease', (95, 108))
201101	25026211	Interestingly, re-expression of Merlin and silencing of DCAF1 induced a similar level of phosphorylation of YAP in these cells (Figure 7F), suggesting that CRL4DCAF1 controls the output of the Hippo pathway also in freshly explanted, patient-derived NF2 mutant Schwannoma cells.	('NF2', 'Gene', '4771', (250, 253))	('Schwannoma', 'Phenotype', 'HP:0100008', (261, 271))	('phosphorylation', 'MPA', (89, 104))	('Hippo', 'Gene', '37247', (193, 198))	('Schwannoma', 'Disease', (261, 271))	('output', 'MPA', (179, 185))	('DCAF1', 'Gene', (56, 61))	('silencing', 'Var', (43, 52))	('patient', 'Species', '9606', (234, 241))	('NF2', 'Gene', (250, 253))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('mutant', 'Var', (254, 260))	('Schwannoma', 'Disease', 'MESH:D009442', (261, 271))	('Hippo', 'Gene', (193, 198))
201102	25026211	We then examined activation of YAP in 40 human meningioma and vestibular schwannoma samples classified as NF2 mutant or not by using targeted genomic sequencing and immunoblotting with anti-Merlin (Figure S7 and Table S6).	('meningioma', 'Disease', (47, 57))	('meningioma', 'Phenotype', 'HP:0002858', (47, 57))	('mutant', 'Var', (110, 116))	('vestibular schwannoma', 'Disease', 'MESH:D009464', (62, 83))	('human', 'Species', '9606', (41, 46))	('vestibular schwannoma', 'Disease', (62, 83))	('NF2', 'Gene', '4771', (106, 109))	('meningioma', 'Disease', 'MESH:D008577', (47, 57))	('activation', 'PosReg', (17, 27))	('vestibular schwannoma', 'Phenotype', 'HP:0009588', (62, 83))	('NF2', 'Gene', (106, 109))	('schwannoma', 'Phenotype', 'HP:0100008', (73, 83))
201103	25026211	Immunoblotting tumor lysates with anti-p- YAP antibodies indicated that the level of phosphorylation of YAP was significantly lower in NF2 mutant tumors as compared to that of other tumors (Figures 7G and S7F).	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('lower', 'NegReg', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('phosphorylation', 'MPA', (85, 100))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutant', 'Var', (139, 145))	('Immunoblotting tumor', 'Disease', 'MESH:D009369', (0, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))	('level', 'MPA', (76, 81))	('NF2', 'Gene', (135, 138))	('Immunoblotting tumor', 'Disease', (0, 20))	('tumors', 'Disease', (146, 152))	('NF2', 'Gene', '4771', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
201106	25026211	In addition, we noted weak to absent cytoplasmic staining of tumor cells for P-YAP in 12/23 (52%) and moderate to strong staining in 11/23 (48%) samples (Figure 7H and Table S6).	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('P-YAP', 'Var', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('absent', 'NegReg', (30, 36))	('staining', 'MPA', (121, 129))	('tumor', 'Disease', (61, 66))	('cytoplasmic staining', 'MPA', (37, 57))
201107	25026211	There was a strong positive correlation of nuclear YAP staining and weak or absent cytoplasmic P-YAP staining in tumors with low Merlin expression (p=0.001 for YAP and p=0.001 for phospho-YAP, Mann-Whitney U test), indicating that loss of Merlin causes activation of YAP via reduced phosphorylation and increased accumulation in the nucleus.	('accumulation in the nucleus', 'MPA', (313, 340))	('reduced', 'NegReg', (275, 282))	('YAP', 'Disease', (267, 270))	('increased', 'PosReg', (303, 312))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('phosphorylation', 'biological_process', 'GO:0016310', ('283', '298'))	('Merlin', 'Gene', (239, 245))	('loss', 'Var', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('phosphorylation', 'MPA', (283, 298))	('nucleus', 'cellular_component', 'GO:0005634', ('333', '340'))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
201108	25026211	These clinical findings corroborate the hypothesis that CRL4DCAF1 inhibits Lats and hence activates YAP in NF2 mutant tumors.	('activates', 'PosReg', (90, 99))	('mutant', 'Var', (111, 117))	('inhibits', 'NegReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('NF2', 'Gene', (107, 110))	('Lats', 'Gene', (75, 79))	('Lats', 'Gene', '43651', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('NF2', 'Gene', '4771', (107, 110))	('tumors', 'Disease', (118, 124))	('YAP', 'MPA', (100, 103))	('CRL4DCAF1', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
201109	25026211	Our results reveal that de-repressed CRL4DCAF1 functions in the nucleus of NF2 mutant cells to promote activation of YAP.	('NF2', 'Gene', '4771', (75, 78))	('YAP', 'MPA', (117, 120))	('promote', 'PosReg', (95, 102))	('mutant', 'Var', (79, 85))	('nucleus', 'cellular_component', 'GO:0005634', ('64', '71'))	('activation', 'MPA', (103, 113))	('CRL4DCAF1', 'Gene', (37, 46))	('NF2', 'Gene', (75, 78))
201112	25026211	As a consequence, active YAP and TAZ accumulate in the nucleus and function redundantly to support the oncogenic potential of NF2 mutant cells.	('TAZ', 'Gene', '6901', (33, 36))	('TAZ', 'Gene', (33, 36))	('NF2', 'Gene', '4771', (126, 129))	('oncogenic potential', 'CPA', (103, 122))	('accumulate', 'PosReg', (37, 47))	('mutant', 'Var', (130, 136))	('nucleus', 'cellular_component', 'GO:0005634', ('55', '62'))	('NF2', 'Gene', (126, 129))
201118	25026211	We observed that re-expression of Merlin induces phosphorylation and inactivation of YAP in NF2 mutant cells without increasing the levels of activation of MST1/2 or Lats1.	('inactivation', 'MPA', (69, 81))	('MST1/2', 'Gene', (156, 162))	('mutant', 'Var', (96, 102))	('Lats1', 'Gene', (166, 171))	('NF2', 'Gene', '4771', (92, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('phosphorylation', 'MPA', (49, 64))	('Lats1', 'Gene', '9113', (166, 171))	('YAP', 'Gene', (85, 88))	('MST1/2', 'Gene', '4485;6788', (156, 162))	('NF2', 'Gene', (92, 95))
201122	25026211	The results of our biochemical studies suggest that CRL4DCAF1 employs distinct mechanisms to inhibit Lats1 and 2.	('inhibit', 'NegReg', (93, 100))	('CRL4DCAF1', 'Var', (52, 61))	('Lats1 and 2', 'Gene', '8140;7462', (101, 112))
201124	25026211	In contrast, Lats 2 is oligo-ubiquitylated at multiple sites, including at lysines in the kinase domain, near the Mob1-binding site, and near the PPXY motif required for interaction with YAP.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('lysines', 'Var', (75, 82))	('Lats 2', 'Gene', (13, 19))	('Mob1', 'Gene', '55233', (114, 118))	('Lats 2', 'Gene', '26524', (13, 19))	('Mob1', 'Gene', (114, 118))	('lysines', 'Chemical', 'MESH:D008239', (75, 82))	('interaction', 'Interaction', (170, 181))
201125	25026211	Presumably as a result of these multiple modifications, Lats2 becomes inactive.	('Lats2', 'Gene', (56, 61))	('modifications', 'Var', (41, 54))	('Lats2', 'Gene', '26524', (56, 61))
201126	25026211	Future studies will be required to determine the impact of each one of these modifications on the kinase activity of Lats2 and its interaction with substrates or necessary cofactors.	('Lats2', 'Gene', (117, 122))	('kinase activity', 'molecular_function', 'GO:0016301', ('98', '113'))	('kinase activity', 'MPA', (98, 113))	('interaction', 'Interaction', (131, 142))	('Lats2', 'Gene', '26524', (117, 122))	('modifications', 'Var', (77, 90))
201127	25026211	Notably, both Lats1 and Lats2 possess an N-terminal UBA domain, suggesting the possibility that an intramolecular association of this domain with a C-terminal ubiquitylated sequence motif may contribute to maintain the two kinases in an inactive state in NF2 mutant tumor cells.	('NF2', 'Gene', (255, 258))	('Lats1', 'Gene', (14, 19))	('Lats2', 'Gene', (24, 29))	('NF2', 'Gene', '4771', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('mutant', 'Var', (259, 265))	('UBA', 'Chemical', '-', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('Lats1', 'Gene', '9113', (14, 19))	('Lats2', 'Gene', '26524', (24, 29))	('tumor', 'Disease', (266, 271))
201128	25026211	To examine the relevance of CRL4DCAF1-mediated inhibition of Lats1/2 in NF2 loss-driven oncogenesis, we reconstituted NF2 mutant cells with wild type and mutant forms of Merlin.	('loss-driven', 'NegReg', (76, 87))	('NF2', 'Gene', (118, 121))	('NF2', 'Gene', (72, 75))	('NF2', 'Gene', '4771', (118, 121))	('oncogenesis', 'biological_process', 'GO:0007048', ('88', '99'))	('NF2', 'Gene', '4771', (72, 75))	('mutant', 'Var', (122, 128))	('mutant', 'Var', (154, 160))
201129	25026211	Deletion or alanine substitution of a short nuclear localization sequence prevented Merlin from interacting with CRL4DCAF1 and from suppressing activation of YAP and cell proliferation.	('activation', 'MPA', (144, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('166', '184'))	('Deletion', 'Var', (0, 8))	('alanine', 'Chemical', 'MESH:D000409', (12, 19))	('alanine substitution', 'Var', (12, 32))	('cell proliferation', 'CPA', (166, 184))	('localization', 'biological_process', 'GO:0051179', ('52', '64'))	('suppressing', 'NegReg', (132, 143))	('CRL4DCAF1', 'Gene', (113, 122))	('interacting', 'Interaction', (96, 107))	('prevented', 'NegReg', (74, 83))	('Merlin', 'Gene', (84, 90))
201131	25026211	Furthermore, analysis of a large panel of patient-derived missense mutants of Merlin, which do not combine with CRL4DCAF1 as a result of their inability to enter into the nucleus and/or to bind to the Merlin-binding segment of DCAF1, revealed that all of them exhibit a severely reduced capacity to inhibit activation of YAP and cell proliferation.	('inhibit', 'NegReg', (299, 306))	('cell proliferation', 'biological_process', 'GO:0008283', ('329', '347'))	('activation', 'CPA', (307, 317))	('missense mutants', 'Var', (58, 74))	('reduced', 'NegReg', (279, 286))	('cell proliferation', 'CPA', (329, 347))	('nucleus', 'cellular_component', 'GO:0005634', ('171', '178'))	('DCAF1', 'Gene', (227, 232))	('Merlin', 'Gene', (78, 84))	('patient', 'Species', '9606', (42, 49))	('bind', 'Interaction', (189, 193))	('binding', 'molecular_function', 'GO:0005488', ('208', '215'))
201132	25026211	Finally, in vitro and in vivo genetic epistasis experiments demonstrated that YAP and TAZ are necessary to maintain the oncogenicity of NF2 mutant tumor cells, and that simultaneous inactivation of Lats1 and 2 rescues the oncogenicity of DCAF1-depleted NF2 mutant tumor cells.	('mutant', 'Var', (257, 263))	('NF2', 'Gene', '4771', (136, 139))	('tumor', 'Disease', (147, 152))	('NF2', 'Gene', (136, 139))	('NF2', 'Gene', '4771', (253, 256))	('tumor', 'Disease', (264, 269))	('oncogenicity', 'CPA', (222, 234))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('NF2', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('Lats1 and 2', 'Gene', '8140;7462', (198, 209))	('oncogenicity', 'MPA', (120, 132))	('rescues', 'PosReg', (210, 217))	('mutant', 'Var', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inactivation', 'Var', (182, 194))	('TAZ', 'Gene', '6901', (86, 89))	('TAZ', 'Gene', (86, 89))
201135	25026211	Consistently, overexpressed tagged forms of Lats 1 and 2 accumulate predominantly in the cytosol or at centrosomes, respectively, whereas a mutant form of YAP that cannot be phosphorylated by Lats accumulates in the nucleus and promotes TEAD-dependent transcription and oncogenesis.	('promotes', 'PosReg', (228, 236))	('oncogenesis', 'CPA', (270, 281))	('accumulates', 'PosReg', (197, 208))	('Lats', 'Gene', '43651', (44, 48))	('transcription', 'biological_process', 'GO:0006351', ('252', '265'))	('Lats', 'Gene', (44, 48))	('mutant', 'Var', (140, 146))	('Lats', 'Gene', '43651', (192, 196))	('oncogenesis', 'biological_process', 'GO:0007048', ('270', '281'))	('Lats', 'Gene', (192, 196))	('Lats 1 and 2', 'Gene', '8140;7462', (44, 56))	('TEAD', 'Gene', '32536', (237, 241))	('cytosol', 'cellular_component', 'GO:0005829', ('89', '96'))	('nucleus', 'cellular_component', 'GO:0005634', ('216', '223'))	('TEAD', 'Gene', (237, 241))
201143	25026211	However, in contrast to the results of a more limited but similar analysis, we found that mutations that abolish the tumor suppressor function of Merlin do not interfere with its ability to bind to Lats1 and recruit it to the cell cortex.	('Merlin', 'Gene', (146, 152))	('Lats1', 'Gene', '9113', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (90, 99))	('cell cortex', 'cellular_component', 'GO:0005938', ('226', '237'))	('bind', 'Interaction', (190, 194))	('tumor', 'Disease', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('Lats1', 'Gene', (198, 203))	('abolish', 'NegReg', (105, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
201145	25026211	In fact, Drosophila Merlin contains a Glycine residue at the position corresponding to E270 in human Merlin, a substitution that is predicted to abolish interaction with DCAF1.	('human', 'Species', '9606', (95, 100))	('abolish', 'NegReg', (145, 152))	('Merlin', 'Gene', (101, 107))	('interaction', 'Interaction', (153, 164))	('Glycine', 'Chemical', 'MESH:D005998', (38, 45))	('E270', 'Var', (87, 91))	('DCAF1', 'Protein', (170, 175))	('Drosophila', 'Species', '7227', (9, 19))
201149	25026211	Inactivation of NF2 eliminates the clamp, causing deregulated YAP/TEAD dependent transcription of pro-survival and mitogenic genes.	('NF2', 'Gene', '4771', (16, 19))	('TEAD', 'Gene', (66, 70))	('mitogenic genes', 'Gene', (115, 130))	('eliminates', 'NegReg', (20, 30))	('NF2', 'Gene', (16, 19))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('clamp', 'MPA', (35, 40))	('TEAD', 'Gene', '32536', (66, 70))	('pro-survival', 'biological_process', 'GO:0043066', ('98', '110'))	('Inactivation', 'Var', (0, 12))
201150	25026211	It remains to be examined if this clamp on the activation of YAP operates also during development to limit stem cell self-renewal, organ size, and cell fate specification, as it is anticipated from the known physiological function of YAP and its deregulation following inactivation of NF2 during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('NF2', 'Gene', (285, 288))	('deregulation', 'MPA', (246, 258))	('cell fate specification', 'CPA', (147, 170))	('stem cell self-renewal', 'CPA', (107, 129))	('YAP', 'Gene', (61, 64))	('tumor', 'Disease', (296, 301))	('NF2', 'Gene', '4771', (285, 288))	('inactivation', 'Var', (269, 281))	('limit', 'NegReg', (101, 106))	('cell fate specification', 'biological_process', 'GO:0001708', ('147', '170'))	('organ size', 'CPA', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
201152	25026211	First, genetic manipulation indicated that re-expression of Merlin and silencing of DCAF1 inhibit activation of YAP and cell proliferation in primary schwannoma cells from NF2 patients.	('YAP', 'Protein', (112, 115))	('inhibit', 'NegReg', (90, 97))	('NF2', 'Gene', (172, 175))	('Merlin', 'Protein', (60, 66))	('cell proliferation', 'CPA', (120, 138))	('patients', 'Species', '9606', (176, 184))	('schwannoma', 'Disease', 'MESH:D009442', (150, 160))	('NF2', 'Gene', '4771', (172, 175))	('schwannoma', 'Phenotype', 'HP:0100008', (150, 160))	('silencing', 'Var', (71, 80))	('DCAF1', 'Gene', (84, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('activation', 'MPA', (98, 108))	('schwannoma', 'Disease', (150, 160))
201154	25026211	Third, analysis of a panel of human mesothelioma lines indicated that deletion of NF2 correlates with reduced levels of Lats1 protein and increased activation of YAP.	('deletion', 'Var', (70, 78))	('human', 'Species', '9606', (30, 35))	('mesothelioma', 'Disease', 'MESH:D008654', (36, 48))	('NF2', 'Gene', '4771', (82, 85))	('Lats1', 'Gene', '9113', (120, 125))	('levels', 'MPA', (110, 116))	('YAP', 'CPA', (162, 165))	('increased activation', 'PosReg', (138, 158))	('Lats1', 'Gene', (120, 125))	('mesothelioma', 'Disease', (36, 48))	('NF2', 'Gene', (82, 85))	('reduced', 'NegReg', (102, 109))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))
201155	25026211	Finally, GSEA demonstrated that the gene expression program regulated by CRL4DCAF1 through activation of YAP/TAZ is highly enriched in NF2 mutant mesotheliomas as compared to those lacking NF2 alterations.	('NF2', 'Gene', (189, 192))	('TAZ', 'Gene', '6901', (109, 112))	('CRL4DCAF1', 'Gene', (73, 82))	('TAZ', 'Gene', (109, 112))	('GSEA', 'Chemical', '-', (9, 13))	('activation', 'PosReg', (91, 101))	('mesotheliomas', 'Disease', (146, 159))	('mesotheliomas', 'Disease', 'MESH:D008654', (146, 159))	('mutant', 'Var', (139, 145))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))	('NF2', 'Gene', (135, 138))	('NF2', 'Gene', '4771', (189, 192))	('NF2', 'Gene', '4771', (135, 138))
201156	25026211	We note that simultaneous depletion of Lats1 and 2 did not completely rescue the ability of DCAF1-silenced NF2 mutant cells to overproliferate in vitro and in vivo, suggesting that CRL4DCAF1 may have additional substrates that contribute to its pro-oncogenic function.	('mutant', 'Var', (111, 117))	('overproliferate', 'MPA', (127, 142))	('NF2', 'Gene', (107, 110))	('Lats1 and 2', 'Gene', '8140;7462', (39, 50))	('CRL4DCAF1', 'Var', (181, 190))	('NF2', 'Gene', '4771', (107, 110))
201159	25026211	We suggest that, since CRL4DCAF1 may promote oncogenesis through multiple mechanisms, CRL4DCAF1 inhibitors may display enhanced efficacy in NF2 mutant tumors as compared to drugs that interfere with the interaction of YAP with TEAD.	('TEAD', 'Gene', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('oncogenesis', 'biological_process', 'GO:0007048', ('45', '56'))	('CRL4DCAF1', 'Gene', (86, 95))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('oncogenesis', 'CPA', (45, 56))	('NF2', 'Gene', '4771', (140, 143))	('TEAD', 'Gene', '32536', (227, 231))	('mutant', 'Var', (144, 150))	('enhanced', 'PosReg', (119, 127))	('NF2', 'Gene', (140, 143))
201168	25026211	De-regulated CRL4DCAF1 induces activation of YAP in NF2 mutant tumor cells CRL4DCAF1 promotes ubiquitin-mediated proteasomal degradation of Lats1 CRL4DCAF1-mediated oligo-ubiquitylation inhibits the kinase activity of Lats2 CRL4DCAF1 activates Yap-dependent oncogenic gene expression In spite of significant advances, the mechanism by which Merlin/NF2 suppresses tumorigenesis has remained incompletely understood.	('kinase activity', 'molecular_function', 'GO:0016301', ('199', '214'))	('degradation', 'biological_process', 'GO:0009056', ('125', '136'))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('NF2', 'Gene', '4771', (348, 351))	('Yap', 'Gene', '10413', (244, 247))	('Lats1', 'Gene', '9113', (140, 145))	('mutant', 'Var', (56, 62))	('NF2', 'Gene', (348, 351))	('Lats1', 'Gene', (140, 145))	('tumor', 'Disease', (63, 68))	('ubiquitin', 'molecular_function', 'GO:0031386', ('94', '103'))	('gene expression', 'biological_process', 'GO:0010467', ('268', '283'))	('Yap', 'Gene', (244, 247))	('ubiquitin-mediated', 'MPA', (94, 112))	('Lats2', 'Gene', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('NF2', 'Gene', '4771', (52, 55))	('tumor', 'Disease', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('Lats2', 'Gene', '26524', (218, 223))	('NF2', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
201170	25026211	Analysis of clinical samples indicates that this signaling mechanism operates in NF2 mutant tumors.	('NF2', 'Gene', '4771', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('NF2', 'Gene', (81, 84))	('mutant', 'Var', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
201195	19662092	Moreover cytogenetic studies have shown that mesotheliomas have highly complex and variable chromosomal aberrations, and only few common important features have been identified, as the deletion of 9p21 including the CDKN2A gene.	('variable chromosomal aberrations', 'Phenotype', 'HP:0040012', (83, 115))	('mesotheliomas', 'Disease', 'MESH:D008654', (45, 58))	('mesotheliomas', 'Disease', (45, 58))	('9p21', 'Gene', (197, 201))	('CDKN2A', 'Gene', (216, 222))	('deletion', 'Var', (185, 193))	('CDKN2A', 'Gene', '1029', (216, 222))
201240	19662092	Importantly there were more down-regulated than overexpressed genes in tumour versus parietal tissue corresponding with the recent findings of more chromosomal losses than gains in mesothelioma.	('mesothelioma', 'Disease', (181, 193))	('tumour versus parietal', 'Disease', 'MESH:D006086', (71, 93))	('down-regulated', 'NegReg', (28, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (181, 193))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('chromosomal losses', 'Var', (148, 166))	('tumour versus parietal', 'Disease', (71, 93))
201262	19662092	CDKN2A (cyclin-dependent kinase inhibitor 2A) encoding the p16ink4a that inhibits pRb phosphorylation is almost always deleted in mesothelioma, resulting in normal but non-functional pRB expression, was not differentially expressed.	('cyclin-dependent kinase inhibitor 2A', 'Gene', (8, 44))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (8, 44))	('mesothelioma', 'Disease', (130, 142))	('non-functional', 'NegReg', (168, 182))	('pRb', 'Gene', '5925', (82, 85))	('pRB', 'Gene', '5925', (183, 186))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('25', '41'))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('pRb', 'Gene', (82, 85))	('p16ink4a', 'Gene', '1029', (59, 67))	('pRB', 'Gene', (183, 186))	('CDKN2A', 'Gene', (0, 6))	('expression', 'MPA', (187, 197))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('8', '41'))	('p16ink4a', 'Gene', (59, 67))	('deleted', 'Var', (119, 126))	('CDKN2A', 'Gene', '1029', (0, 6))
201268	19662092	MCM3 is overexpressed in multiple malignancies, regarded a more sensitive tumour marker than Ki67, and 90% of mice injected with MCM3 transfected cells developed epithelial tumours within 6 weeks.	('Ki67', 'Gene', (93, 97))	('tumour', 'Disease', (173, 179))	('epithelial tumours', 'Disease', 'MESH:D000077216', (162, 180))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('developed', 'PosReg', (152, 161))	('tumour', 'Disease', (74, 80))	('mice', 'Species', '10090', (110, 114))	('Ki67', 'Gene', '17345', (93, 97))	('MCM3', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('epithelial tumours', 'Disease', (162, 180))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('multiple malignancies', 'Disease', 'MESH:D009369', (25, 46))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('transfected', 'Var', (134, 145))	('multiple malignancies', 'Disease', (25, 46))
201274	19662092	Inhibition of CDK7 by gambogic acid induced irreversible arrest of G2/M phase in gastric cancer cells, and is thus a putative treatment target.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CDK7', 'Gene', '1022', (14, 18))	('arrest', 'CPA', (57, 63))	('M phase', 'biological_process', 'GO:0000279', ('70', '77'))	('G2/M phase', 'CPA', (67, 77))	('gambogic acid', 'Chemical', 'MESH:C052659', (22, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('Inhibition', 'Var', (0, 10))	('CDK7', 'Gene', (14, 18))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
201286	19662092	The negative regulators of the cell cycle PER (period) and CRY (cryptochrome) genes, and their protein expression are downregulated in breast and lung cancer tissue when compared with matched normal tissue, as was found here, and methylation rather than mutation of these genes confer to this phenotype.	('cell cycle PER (period', 'Gene', (31, 53))	('methylation', 'biological_process', 'GO:0032259', ('230', '241'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('31', '41'))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('negative', 'NegReg', (4, 12))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('breast and lung cancer', 'Disease', 'MESH:D001943', (135, 157))	('methylation', 'Var', (230, 241))	('CRY (cryptochrome) genes', 'Gene', (59, 83))	('downregulated', 'NegReg', (118, 131))	('protein', 'Protein', (95, 102))
201290	19662092	Conversely, BMAL1 knockout conferred cyclohosphamide sensitivity and CRY knockout conferred cyclophosphamide resistance, showing that circadian genes are important in drug resistance as well.	('drug resistance', 'biological_process', 'GO:0042493', ('167', '182'))	('drug resistance', 'biological_process', 'GO:0009315', ('167', '182'))	('BMAL1', 'Gene', (12, 17))	('conferred', 'Reg', (27, 36))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('cyclohosphamide', 'Chemical', '-', (37, 52))	('conferred', 'Reg', (82, 91))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (92, 108))	('cyclophosphamide resistance', 'MPA', (92, 119))	('cyclohosphamide sensitivity', 'MPA', (37, 64))	('knockout', 'Var', (18, 26))
201291	19662092	High mRNA levels in breast cancer of the positive regulator TIMELESS has been significantly associated with shorter relapse-free survival and recently been regarded as a promising marker of tamoxifen resistance in women with estrogen receptor alpha-positive breast tumors.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('shorter', 'NegReg', (108, 115))	('tamoxifen', 'Chemical', 'MESH:D013629', (190, 199))	('High', 'Var', (0, 4))	('women', 'Species', '9606', (214, 219))	('estrogen receptor alpha', 'Gene', '2099', (225, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('TIMELESS', 'Gene', '8914', (60, 68))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('relapse-free survival', 'CPA', (116, 137))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('breast tumors', 'Disease', 'MESH:D001943', (258, 271))	('breast tumors', 'Disease', (258, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('estrogen receptor alpha', 'Gene', (225, 248))	('TIMELESS', 'Gene', (60, 68))	('breast tumors', 'Phenotype', 'HP:0100013', (258, 271))	('mRNA levels', 'MPA', (5, 16))
201313	19662092	Loss of the tumour suppressor TGFBR2 expression is seen in many cancers with microsatellite instability and deleted in large-cell lung carcinoma.	('Loss of the tumour', 'Disease', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('TGFBR2', 'Gene', '7048', (30, 36))	('lung carcinoma', 'Disease', 'MESH:D008175', (130, 144))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('lung carcinoma', 'Disease', (130, 144))	('microsatellite instability', 'Var', (77, 103))	('cancers', 'Disease', (64, 71))	('Loss of the tumour', 'Disease', 'MESH:D009369', (0, 18))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('expression', 'MPA', (37, 47))	('TGFBR2', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
201318	19662092	Finally, mutation and dysfunction of the detoxifier GSTM1 is related to high risk of head and neck and lung cancer in smokers.	('mutation', 'Var', (9, 17))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('neck', 'cellular_component', 'GO:0044326', ('94', '98'))	('related', 'Reg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('GSTM1', 'Gene', '2944', (52, 57))	('dysfunction', 'Var', (22, 33))	('GSTM1', 'Gene', (52, 57))
201368	31670317	Baicalin (C21H18O11) is the major active component of Skullcap (Huang-Qin, a medicinal plant), an important traditional Chinese medicinal herb, which can be distilled from the root.	('C21H18O11', 'Var', (10, 19))	('Qin', 'Gene', (70, 73))	('C21H18O11', 'Chemical', 'MESH:C090732', (10, 19))	('Baicalin', 'Chemical', 'MESH:C038044', (0, 8))	('Qin', 'Gene', '2290', (70, 73))
201372	31670317	Furthermore, as an inhibitor of the aryl hydrocarbon receptor (AhR), baicalin is considered an effective drug for the treatment of cancers induced by aberrant activation of AhR.	('activation', 'PosReg', (159, 169))	('AhR', 'Gene', '196', (63, 66))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('aberrant', 'Var', (150, 158))	('AhR', 'Gene', (173, 176))	('baicalin', 'Chemical', 'MESH:C038044', (69, 77))	('AhR', 'Gene', '196', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('aryl hydrocarbon receptor', 'Gene', '196', (36, 61))	('aryl hydrocarbon receptor', 'Gene', (36, 61))	('AhR', 'Gene', (63, 66))
201379	31670317	Monoclonal antibodies to p-EGFR (Tyr1068), p-AKT (AKT1/2/3) (S473), p-MAPK (MAPK1/2) (T202/Y204), and p-S6 (S235/236) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('EGFR', 'Gene', (27, 31))	('S473', 'Chemical', 'MESH:C015765', (61, 65))	('AKT', 'Gene', '207', (50, 53))	('MAPK1/2', 'Gene', '6300;5594', (76, 83))	('p-S6', 'Gene', '338413', (102, 106))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('AKT1/2/3', 'Gene', (50, 58))	('MAPK', 'Gene', (76, 80))	('Tyr1068', 'Var', (33, 40))	('p-S6', 'Gene', (102, 106))	('T202/Y204', 'Var', (86, 95))	('AKT', 'Gene', (45, 48))	('MAPK', 'Gene', '6300', (70, 74))	('EGFR', 'Gene', '1956', (27, 31))	('AKT1/2/3', 'Gene', '207;208;10000', (50, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('AKT', 'Gene', (50, 53))	('MAPK', 'Gene', '6300', (76, 80))	('MAPK1/2', 'Gene', (76, 83))	('AKT', 'Gene', '207', (45, 48))	('S235', 'Chemical', 'MESH:C056056', (108, 112))	('Signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('MAPK', 'Gene', (70, 74))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('S473', 'Var', (61, 65))	('Tyr1068', 'Chemical', 'MESH:C056418', (33, 40))
201409	31670317	The results showed that treatment of MESO924 with baicalin was associated with a reduction in the G1 peak (80.63% for DMSO versus 64.94% for 50 muM baicalin and 57.01% for 100 muM baicalin) and an increase in the S peak (10.81% for DMSO, 24.89% for 50 muM baicalin, and 32.85% for 100 muM baicalin) when compared to the control group (Figure 1B).	('increase', 'PosReg', (197, 205))	('DMSO', 'Chemical', 'MESH:D004121', (232, 236))	('baicalin', 'Chemical', 'MESH:C038044', (256, 264))	('MESO924', 'Var', (37, 44))	('muM', 'Gene', '56925', (176, 179))	('G1 peak', 'MPA', (98, 105))	('muM', 'Gene', (176, 179))	('muM', 'Gene', '56925', (144, 147))	('DMSO', 'Chemical', 'MESH:D004121', (118, 122))	('muM', 'Gene', '56925', (285, 288))	('baicalin', 'Chemical', 'MESH:C038044', (180, 188))	('muM', 'Gene', (144, 147))	('muM', 'Gene', '56925', (252, 255))	('baicalin', 'Chemical', 'MESH:C038044', (148, 156))	('muM', 'Gene', (285, 288))	('reduction', 'NegReg', (81, 90))	('muM', 'Gene', (252, 255))	('MESO924', 'CellLine', 'CVCL:N715', (37, 44))	('baicalin', 'Chemical', 'MESH:C038044', (289, 297))	('S peak', 'MPA', (213, 219))	('baicalin', 'Chemical', 'MESH:C038044', (50, 58))
201427	31670317	The PI3K/AKT/mTOR pathway was inactivated by a small-molecule inhibitor, LY294002.	('LY294002', 'Var', (73, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PI3K/AKT', 'Gene', '5293;207', (4, 12))	('PI3K/AKT', 'Gene', (4, 12))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('inactivated', 'NegReg', (30, 41))	('LY294002', 'Chemical', 'MESH:C085911', (73, 81))
201429	31670317	Treatment of MESO924 cells with 10 muM LY294002 resulted in a ~25% decrease of cell viability at day 2.	('muM', 'Gene', '56925', (35, 38))	('decrease', 'NegReg', (67, 75))	('LY294002', 'Chemical', 'MESH:C085911', (39, 47))	('muM', 'Gene', (35, 38))	('cell viability at day 2', 'CPA', (79, 102))	('MESO924', 'CellLine', 'CVCL:N715', (13, 20))	('LY294002', 'Var', (39, 47))
201430	31670317	Interestingly, combined treatment with baicalin and LY294002 achieved a greater inhibition of the cell proliferation in a dose-dependent manner than that with either intervention alone (Figure 5).	('cell proliferation', 'CPA', (98, 116))	('inhibition', 'NegReg', (80, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('LY294002', 'Var', (52, 60))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))	('baicalin', 'Chemical', 'MESH:C038044', (39, 47))
201436	31670317	Incubation of MESO924 with doxorubicin (2.5 muM), cisplatin (5 muM), and pemetrexed (0.1 muM) for 48 h resulted in ~40%, ~30%, and ~25% decrease of proliferation in MESO924 cells, respectively.	('MESO924', 'CellLine', 'CVCL:N715', (14, 21))	('muM', 'Gene', (44, 47))	('muM', 'Gene', (89, 92))	('muM', 'Gene', '56925', (63, 66))	('proliferation', 'CPA', (148, 161))	('decrease', 'NegReg', (136, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('muM', 'Gene', (63, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (27, 38))	('muM', 'Gene', '56925', (44, 47))	('muM', 'Gene', '56925', (89, 92))	('MESO924', 'CellLine', 'CVCL:N715', (165, 172))	('cisplatin', 'Var', (50, 59))
201453	31670317	Interestingly, the treatment of MESO924 cells with the PI3K/AKT/mTOR inhibitor LY294002 augmented the anti-proliferation effects induced by baicalin, consistent with the observation that the PI3K/AKT/mTOR signaling pathway exerts essential roles in the growth of MESO.	('MESO', 'Disease', (32, 36))	('MESO', 'Disease', (263, 267))	('augmented', 'PosReg', (88, 97))	('PI3K/AKT', 'Gene', '5293;207', (191, 199))	('mTOR', 'Gene', (200, 204))	('MESO924', 'CellLine', 'CVCL:N715', (32, 39))	('mTOR', 'Gene', (64, 68))	('signaling pathway', 'biological_process', 'GO:0007165', ('205', '222'))	('PI3K/AKT', 'Gene', '5293;207', (55, 63))	('LY294002', 'Var', (79, 87))	('mTOR', 'Gene', '2475', (200, 204))	('anti-proliferation', 'CPA', (102, 120))	('PI3K', 'molecular_function', 'GO:0016303', ('191', '195'))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('mTOR', 'Gene', '2475', (64, 68))	('PI3K/AKT', 'Gene', (191, 199))	('baicalin', 'Chemical', 'MESH:C038044', (140, 148))	('MESO', 'Disease', 'MESH:D008654', (32, 36))	('MESO', 'Disease', 'MESH:D008654', (263, 267))	('LY294002', 'Chemical', 'MESH:C085911', (79, 87))	('PI3K/AKT', 'Gene', (55, 63))
201478	31670317	Blockage of the PI3K/AKT signaling pathway by a small molecule, LY294002, augmented the inhibition of proliferation induced by baicalin.	('PI3K/AKT', 'Gene', '5293;207', (16, 24))	('baicalin', 'Chemical', 'MESH:C038044', (127, 135))	('AKT signaling', 'biological_process', 'GO:0043491', ('21', '34'))	('LY294002', 'Chemical', 'MESH:C085911', (64, 72))	('inhibition', 'NegReg', (88, 98))	('signaling pathway', 'biological_process', 'GO:0007165', ('25', '42'))	('PI3K/AKT', 'Gene', (16, 24))	('LY294002', 'Var', (64, 72))	('proliferation', 'CPA', (102, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))	('Blockage', 'NegReg', (0, 8))
201480	31323388	Brief Report: Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers.	('BAP1', 'Gene', '8314', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('mutations', 'Var', (132, 141))	('Mutations', 'Var', (112, 121))	('BAP1', 'Gene', (107, 111))	('influence', 'Reg', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
201481	31323388	Germline mutations in BRCA associated protein-1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma (UM), but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown.	('Germline mutations', 'Var', (0, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('mesothelioma', 'Disease', (102, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('uveal melanoma', 'Disease', (141, 155))	('atypical spitz nevi', 'Phenotype', 'HP:0001062', (116, 135))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (225, 229))	('BAP1', 'Gene', '8314', (49, 53))	('atypical spitz nevi', 'Disease', (116, 135))	('associated', 'Reg', (59, 69))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('BAP1', 'Gene', (225, 229))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('patient', 'Species', '9606', (170, 177))
201484	31323388	We tested screening criteria developed to identify patients with a possible germline BAP1 mutation.	('mutation', 'Var', (90, 98))	('BAP1', 'Gene', (85, 89))	('patients', 'Species', '9606', (51, 59))	('BAP1', 'Gene', '8314', (85, 89))
201485	31323388	Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria.	('mutations', 'Var', (46, 55))	('BAP1', 'Gene', (41, 45))	('Pathogenic', 'Reg', (0, 10))	('patients', 'Species', '9606', (132, 140))	('pathogenic', 'Reg', (21, 31))	('BAP1', 'Gene', '8314', (41, 45))
201486	31323388	Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation.	('mutation', 'Var', (115, 123))	('BAP1', 'Gene', '8314', (110, 114))	('patients', 'Species', '9606', (8, 16))	('BAP1', 'Gene', (110, 114))
201487	31323388	The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1).	('patients', 'Species', '9606', (56, 64))	('pathogenic', 'Reg', (18, 28))	('BAP1', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('mesothelioma', 'Disease', (70, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('BAP1', 'Gene', '8314', (38, 42))
201488	31323388	Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma.	('mesothelioma', 'Disease', (165, 177))	('patients', 'Species', '9606', (151, 159))	('BAP1', 'Gene', '8314', (77, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('low', 'NegReg', (141, 144))	('alterations', 'Var', (82, 93))	('BAP1', 'Gene', (77, 81))
201493	31323388	In 2011, alterations in BRCA-associated protein 1 (BAP1) were identified as common oncogenic drivers in malignant pleural mesothelioma (MPM).	('BRCA-associated protein 1', 'Gene', '8314', (24, 49))	('BAP1', 'Gene', (51, 55))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('BRCA-associated protein 1', 'Gene', (24, 49))	('alterations', 'Var', (9, 20))	('malignant pleural mesothelioma', 'Disease', (104, 134))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (104, 134))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (114, 134))	('BAP1', 'Gene', '8314', (51, 55))
201494	31323388	Germline BAP1 mutations are also found in atypical Spitz nevi, uveal melanoma (UM), and a wide range of other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cancers', 'Disease', (110, 117))	('atypical Spitz nevi', 'Phenotype', 'HP:0001062', (42, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('BAP1', 'Gene', '8314', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('found in', 'Reg', (33, 41))	('nevi', 'Phenotype', 'HP:0003764', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
201495	31323388	Pathogenic BAP1 alterations typically decrease or eliminate expression of the tumor suppressor and ubiquitin hydrolase protein, BAP1.	('expression', 'MPA', (60, 70))	('ubiquitin', 'molecular_function', 'GO:0031386', ('99', '108'))	('BAP1', 'Gene', '8314', (11, 15))	('BAP1', 'Gene', '8314', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('eliminate', 'NegReg', (50, 59))	('alterations', 'Var', (16, 27))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decrease', 'NegReg', (38, 46))	('BAP1', 'Gene', (11, 15))	('BAP1', 'Gene', (128, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
201496	31323388	BAP1 tumor predisposition syndrome (BAP1-TPDS) is characterized by increased cancer risk in individuals with inherited BAP1 mutations.	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BAP1', 'Gene', '8314', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('BAP1', 'Gene', '8314', (119, 123))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (119, 123))
201497	31323388	A recent review analyzed the history of cancer in families with germline BAP1 mutations and started to refine the phenotypes associated with these alterations.	('BAP1', 'Gene', '8314', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('germline', 'Var', (64, 72))
201498	31323388	The prevalence of germline BAP1 alterations in unselected patients with metastatic UM ranges from 2 to 8%.	('metastatic UM', 'Disease', (72, 85))	('BAP1', 'Gene', (27, 31))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('alterations', 'Var', (32, 43))	('patients', 'Species', '9606', (58, 66))	('BAP1', 'Gene', '8314', (27, 31))
201501	31323388	BAP1 mutation status offers an easy way to identify patients at an increased risk of developing mesothelioma and other cancers and provides prognostic insight into management of these cases.	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', (96, 108))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))	('patients', 'Species', '9606', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
201502	31323388	Cancer screening recommendations, based on a retrospective analysis of familial clusters, have been proposed for individuals with a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', (141, 145))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutation', 'Var', (146, 154))
201504	31323388	Therefore, we developed and began to validate screening criteria to identify and determine the incidence of germline BAP1 mutations in patients with BAP1-associated diseases.	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', '8314', (149, 153))	('BAP1', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('BAP1', 'Gene', (149, 153))
201507	31323388	All patients receiving clinical care at MSK between March 2013 and October 2016 for disorders associated with germline BAP1 mutations (mesothelioma, UM, and choroidal nevus (CN)) were eligible and offered enrollment in this prospective clinical trial .	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('mutations', 'Var', (124, 133))	('choroidal nevus', 'Disease', (157, 172))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('nevus', 'Phenotype', 'HP:0003764', (167, 172))	('MSK', 'Gene', '150094', (40, 43))	('MSK', 'Gene', (40, 43))	('BAP1', 'Gene', '8314', (119, 123))	('mesothelioma', 'Disease', (135, 147))	('choroidal nevus', 'Phenotype', 'HP:0025314', (157, 172))	('patients', 'Species', '9606', (4, 12))	('BAP1', 'Gene', (119, 123))
201510	31323388	Germline DNA was extracted from blood samples, sequenced using a 410-gene next-generation sequencing assay (MSK-IMPACT; MSK-Integrated Mutation Profiling of Actionable Cancer Targets), and BAP1 alterations called as previously described.	('BAP1', 'Gene', '8314', (189, 193))	('MSK', 'Gene', '150094', (108, 111))	('MSK', 'Gene', (108, 111))	('BAP1', 'Gene', (189, 193))	('Cancer', 'Disease', (168, 174))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('alterations', 'Var', (194, 205))	('Cancer', 'Disease', 'MESH:D009369', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))	('MSK', 'Gene', '150094', (120, 123))	('MSK', 'Gene', (120, 123))
201512	31323388	Individuals matching screening criteria developed to identify potential carriers of pathogenic germline BAP1 mutations were offered additional genetic counseling and non-anonymous genetic testing.	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (109, 118))
201514	31323388	Relatives of patients with a pathogenic BAP1 mutation were invited to participate in a family expansion phase of the study that is beyond the scope of this manuscript.	('pathogenic', 'Reg', (29, 39))	('patients', 'Species', '9606', (13, 21))	('BAP1', 'Gene', '8314', (40, 44))	('mutation', 'Var', (45, 53))	('BAP1', 'Gene', (40, 44))
201515	31323388	The prevalence of deleterious BAP1 mutations was estimated as the proportion of all tested specimens that were positive for any pathogenic or likely pathogenic BAP1 alteration and calculated separately for various patient groups.	('patient', 'Species', '9606', (214, 221))	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', '8314', (160, 164))	('positive', 'Reg', (111, 119))	('BAP1', 'Gene', (160, 164))	('BAP1', 'Gene', '8314', (30, 34))	('mutations', 'Var', (35, 44))
201516	31323388	Patient demographics and disease characteristics were compared between patients with and without BAP1 mutations by the Fisher's exact test and Wilcoxon rank-sum test for categorical variables and continuous variables, respectively.	('BAP1', 'Gene', '8314', (97, 101))	('patients', 'Species', '9606', (71, 79))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('Patient', 'Species', '9606', (0, 7))
201517	31323388	The Fisher's exact test was also used to determine whether the screening criteria enriched for pathogenic BAP1 mutations by chance.	('mutations', 'Var', (111, 120))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', (106, 110))
201521	31323388	Ten of the 180 (5.6%) patient samples had a germline BAP1 mutation, with 5 of these mutations considered pathogenic or likely pathogenic (Supplemental Table 1).	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('patient', 'Species', '9606', (22, 29))	('BAP1', 'Gene', (53, 57))
201522	31323388	BAP1 alterations included point mutations and frame shifts but not copy number variations.	('point mutations', 'Var', (26, 41))	('BAP1', 'Gene', (0, 4))	('frame shifts', 'Var', (46, 58))	('alterations', 'Reg', (5, 16))	('BAP1', 'Gene', '8314', (0, 4))
201523	31323388	Several patients without germline BAP1 mutations had characteristics suggestive of a heritable disorder: three patients had mesothelioma and a family history of mesothelioma, another patient had a personal history of both MPM and UM, and several other patients had a personal or family history that was suspicious for a germline mutation.	('patient', 'Species', '9606', (252, 259))	('mesothelioma', 'Disease', (161, 173))	('BAP1', 'Gene', (34, 38))	('patients', 'Species', '9606', (252, 260))	('mesothelioma', 'Disease', (124, 136))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (111, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('patient', 'Species', '9606', (183, 190))	('patient', 'Species', '9606', (8, 15))	('patient', 'Species', '9606', (111, 118))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (34, 38))	('patients', 'Species', '9606', (8, 16))
201524	31323388	Pathogenic BAP1 mutations (depicted in a mutation diagram in Supplementary Fig.	('BAP1', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('BAP1', 'Gene', '8314', (11, 15))	('Pathogenic', 'Reg', (0, 10))
201526	31323388	The prevalence of germline BAP1 mutations in the cohort of unselected patients with mesothelioma was 4.4%.	('patients', 'Species', '9606', (70, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (84, 96))	('BAP1', 'Gene', '8314', (27, 31))
201527	31323388	Notably, all of the patients with pathogenic BAP1 alterations were positively identified by our screening criteria.	('BAP1', 'Gene', (45, 49))	('alterations', 'Var', (50, 61))	('patients', 'Species', '9606', (20, 28))	('pathogenic', 'Reg', (34, 44))	('BAP1', 'Gene', '8314', (45, 49))
201528	31323388	We examined the demographics and disease characteristics of patients with MPM with or without a germline BAP1 mutation (Table 3).	('MPM', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (105, 109))	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (110, 118))	('BAP1', 'Gene', (105, 109))
201529	31323388	Patients with a germline BAP1 mutation were more likely to be diagnosed with stage IV disease and tended to be younger at diagnosis than patients without a germline BAP1 mutation.	('germline', 'Var', (16, 24))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', (165, 169))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (137, 145))	('stage IV disease', 'Disease', 'MESH:D058625', (77, 93))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (25, 29))	('stage IV disease', 'Disease', (77, 93))	('BAP1', 'Gene', '8314', (165, 169))
201530	31323388	Despite having more advanced disease, patients with MPM and a germline BAP1 mutation had improved overall survival compared to patients without a germline BAP1 mutation, though this was not statistically significant (Supplementary Fig.	('improved', 'PosReg', (89, 97))	('BAP1', 'Gene', '8314', (155, 159))	('germline', 'Var', (62, 70))	('BAP1', 'Gene', (155, 159))	('BAP1', 'Gene', '8314', (71, 75))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (38, 46))	('overall survival', 'MPA', (98, 114))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))	('MPM', 'Disease', (52, 55))
201531	31323388	Early identification of patients with germline BAP1 mutations is important because of the unique disease courses and characteristics observed in cancers with this alteration.	('cancers', 'Disease', (145, 152))	('mutations', 'Var', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('BAP1', 'Gene', '8314', (47, 51))	('patients', 'Species', '9606', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('BAP1', 'Gene', (47, 51))
201533	31323388	Our cohort of patients with MPM and a germline BAP1 mutation, compared to patients without a germline BAP1 mutation, were more often diagnosed at an advanced disease stage, and tended to be younger at diagnosis and have better overall survival.	('BAP1', 'Gene', (102, 106))	('patients', 'Species', '9606', (74, 82))	('overall', 'MPA', (227, 234))	('better', 'PosReg', (220, 226))	('BAP1', 'Gene', '8314', (47, 51))	('mutation', 'Var', (52, 60))	('BAP1', 'Gene', '8314', (102, 106))	('patients', 'Species', '9606', (14, 22))	('BAP1', 'Gene', (47, 51))
201534	31323388	Improved survival in patients with mesothelioma and germline BAP1 mutations has been observed previously.	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('survival', 'MPA', (9, 17))	('mesothelioma', 'Disease', (35, 47))	('patients', 'Species', '9606', (21, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('germline', 'Var', (52, 60))	('BAP1', 'Gene', '8314', (61, 65))	('Improved', 'PosReg', (0, 8))
201535	31323388	Importantly, our screening criteria identified all patients in the cohort with heritable BAP1 mutations, reducing the proportion of suspected carriers to 60% of the total population.	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (51, 59))	('reducing', 'NegReg', (105, 113))	('BAP1', 'Gene', '8314', (89, 93))
201538	31323388	In our cohort of 113 analyzed samples from patients with mesothelioma (2 samples were lost due to technical issues), we identified 5 pathogenic BAP1 variants.	('mesothelioma', 'Disease', (57, 69))	('patients', 'Species', '9606', (43, 51))	('BAP1', 'Gene', (144, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('pathogenic', 'Reg', (133, 143))	('variants', 'Var', (149, 157))	('BAP1', 'Gene', '8314', (144, 148))
201539	31323388	The majority (80%) of patients with deleterious BAP1 variants had MPM, with only one pathogenic variant identified in patients with MPeM.	('BAP1', 'Gene', '8314', (48, 52))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', (48, 52))	('MPM', 'Disease', (66, 69))	('patients', 'Species', '9606', (118, 126))	('variants', 'Var', (53, 61))
201548	31323388	There were numerous patients in our cohort with personal or family histories suspicious for a predisposition to cancer that did not have a germline BAP1 mutation.	('cancer', 'Disease', (112, 118))	('BAP1', 'Gene', '8314', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('BAP1', 'Gene', (148, 152))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (153, 161))
201567	30545133	CR's binding targets include the pore-forming alpha1 subunit of the Ca2+ channel CaV2.1, the mutant form of huntingtin (mHtt) in neurons and cytoskeletal elements such as cytokeratins and alpha-tubulin in WiDr colon cancer cells.	('colon cancer', 'Disease', (210, 222))	('huntingtin', 'Gene', (108, 118))	('rat', 'Species', '10116', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mHtt', 'Gene', (120, 124))	('CR', 'Gene', '794', (0, 2))	('colon cancer', 'Phenotype', 'HP:0003003', (210, 222))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('mutant', 'Var', (93, 99))	('CaV2.1', 'Gene', (81, 87))	('CaV2.1', 'Gene', '773', (81, 87))	('huntingtin', 'Gene', '3064', (108, 118))	('colon cancer', 'Disease', 'MESH:D015179', (210, 222))	('pore', 'cellular_component', 'GO:0046930', ('33', '37'))	('Ca2+', 'Chemical', 'MESH:D000069285', (68, 72))
201604	30545133	In CB-expressing cells the viability was strongly decreased, suggesting that CB may possibly compete with CR with respect to particular functions of CR implicated in cell proliferation/survival (e.g., interaction with FAK and/or septin 7; see below Figure 3).	('septin 7', 'Gene', (229, 237))	('FAK', 'Gene', '5747', (218, 221))	('CR', 'Gene', '794', (106, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('166', '184'))	('FAK', 'Gene', (218, 221))	('interaction', 'Interaction', (201, 212))	('viability', 'CPA', (27, 36))	('decreased', 'NegReg', (50, 59))	('septin 7', 'Gene', '989', (229, 237))	('CR', 'Gene', '794', (149, 151))	('rat', 'Species', '10116', (178, 181))	('CB-expressing', 'Var', (3, 16))	('FAK', 'molecular_function', 'GO:0004717', ('218', '221'))
201638	30545133	However, due to the significantly lower concentrations of Ca2+-binding sites that were present in the different PV clones tested ( 20-40-fold lower than the CB and CR clones, Figure 1B), we cannot unambiguously conclude that the increased survival observed in SPC111-CB clones is specifically mediated by the Ca2+ sensor function of CB.	('survival', 'CPA', (239, 247))	('CR', 'Gene', '794', (164, 166))	('SPC', 'molecular_function', 'GO:0009004', ('260', '263'))	('Ca2+', 'Chemical', 'MESH:D000069285', (309, 313))	('lower', 'NegReg', (34, 39))	('Ca2+', 'Chemical', 'MESH:D000069285', (58, 62))	('increased', 'PosReg', (229, 238))	('rat', 'Species', '10116', (47, 50))	('concentrations', 'MPA', (40, 54))	('SPC111-CB', 'CellLine', 'CVCL:D311', (260, 269))	('SPC111-CB', 'Var', (260, 269))	('PV', 'Gene', '5816', (112, 114))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
201675	29719805	We present the case of 79-year-old male smoker with no documented history of asbestos exposure, who was found to have MPM after presenting with dyspnea and subsequently found to have recurrent hydro-pneumothorax.	('pneumothorax', 'Phenotype', 'HP:0002107', (199, 211))	('dyspnea', 'Phenotype', 'HP:0002094', (144, 151))	('MPM', 'Var', (118, 121))	('hydro-pneumothorax', 'Disease', (193, 211))	('asbestos', 'Chemical', 'MESH:D001194', (77, 85))	('dyspnea', 'Disease', (144, 151))	('dyspnea', 'Disease', 'MESH:D004417', (144, 151))
201694	29719805	Additionally, the elevated coincidence between tobacco use (more-so than documented asbestos exposure) and hydro-pneumothorax gives rise to the question of whether or not concomitant tobacco use predispose to MPM variants in which hydro-pneumothorax are present, predispose to more severe cases, or to a more invasive nature of the cancerous tissue.	('hydro-pneumothorax', 'Disease', (231, 249))	('pneumothorax', 'Phenotype', 'HP:0002107', (237, 249))	('variants', 'Var', (213, 221))	('tobacco', 'Species', '4097', (47, 54))	('predispose', 'Reg', (263, 273))	('cancerous', 'Disease', (332, 341))	('pneumothorax', 'Phenotype', 'HP:0002107', (113, 125))	('tobacco', 'Species', '4097', (183, 190))	('MPM', 'Gene', (209, 212))	('cancerous', 'Disease', 'MESH:D009369', (332, 341))
201698	28212571	However, 3-methyladenine (3MA) and NH4Cl increased cytotoxicity in Tan I treated H28 cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('increased', 'PosReg', (41, 50))	('NH4Cl', 'Var', (35, 40))	('NH4Cl', 'Chemical', 'MESH:D000643', (35, 40))	('3-methyladenine', 'Chemical', 'MESH:C025946', (9, 24))	('Tan I', 'Chemical', 'MESH:C021751', (67, 72))	('3MA', 'Chemical', 'MESH:C025946', (26, 29))	('cytotoxicity', 'Disease', (51, 63))	('4Cl', 'molecular_function', 'GO:0016207', ('37', '40'))
201699	28212571	Furthermore, autophagy flux was enhanced in Tan I-treated H28 cells transfected by RFP-GFP-LC3 constructs, with colocalization of GFP-LC3 punctae with LAMP1 or Lysotracker.	('LC3', 'Gene', '84557', (134, 137))	('LC3', 'Gene', (134, 137))	('LAMP1', 'Gene', '3916', (151, 156))	('constructs', 'Var', (95, 105))	('RFP', 'Gene', (83, 86))	('autophagy', 'biological_process', 'GO:0016236', ('13', '22'))	('autophagy flux', 'CPA', (13, 27))	('Tan I', 'Chemical', 'MESH:C021751', (44, 49))	('LC3', 'Gene', '84557', (91, 94))	('enhanced', 'PosReg', (32, 40))	('autophagy', 'biological_process', 'GO:0006914', ('13', '22'))	('RFP', 'Gene', '2358', (83, 86))	('LC3', 'Gene', (91, 94))	('LAMP1', 'Gene', (151, 156))
201701	28212571	Notably, Tan I upregulated CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring protein-1 (IRE1) and p-c-Jun N-terminal kinase (p-JNK), but silencing of IRE1 or p62 and JNK inhibitor SP600125 blocked the LC3II accumulation in Tan I-treated H28 cells.	('upregulated', 'PosReg', (15, 26))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('LC3', 'Gene', (228, 231))	('IRE1', 'Gene', (177, 181))	('CHOP', 'Gene', '1649', (78, 82))	('Tan I', 'Chemical', 'MESH:C021751', (250, 255))	('JNK', 'molecular_function', 'GO:0004705', ('154', '157'))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('p-c-Jun N-terminal kinase', 'MPA', (125, 150))	('enhancer-binding', 'molecular_function', 'GO:0035326', ('33', '49'))	('JNK', 'molecular_function', 'GO:0004705', ('193', '196'))	('silencing', 'Var', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('Tan I', 'Chemical', 'MESH:C021751', (9, 14))	('CCAAT-enhancer-binding protein homologous protein', 'Gene', '1649', (27, 76))	('CCAAT-enhancer-binding protein homologous protein', 'Gene', (27, 76))	('JNK', 'Gene', (154, 157))	('CHOP', 'Gene', (78, 82))	('IRE1', 'Gene', '2081', (115, 119))	('LC3', 'Gene', '84557', (228, 231))	('JNK', 'Gene', '5599', (154, 157))	('inositol-requiring protein-1', 'Gene', (85, 113))	('JNK', 'Gene', (193, 196))	('p62', 'Gene', '8878', (185, 188))	('JNK', 'Gene', '5599', (193, 196))	('p62', 'Gene', (185, 188))	('IRE1', 'Gene', '2081', (177, 181))	('IRE1', 'Gene', (115, 119))	('inositol-requiring protein-1', 'Gene', '2081', (85, 113))	('SP600125', 'Chemical', 'MESH:C432165', (207, 215))
201726	28212571	In contrast, after transfection with the GFP-fused LC3II plasmid, the immunofluorescence showed that the number of GFP-LC3II green punctae (Figure 2C), LC3II protein expression (Figure 2D) and cytotoxicity (Figure 2E) by Tan I were increased by NH4Cl compared to untreated control (Figure 2C and 2D).	('Tan I', 'Chemical', 'MESH:C021751', (221, 226))	('LC3', 'Gene', (119, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (193, 205))	('LC3', 'Gene', '84557', (51, 54))	('LC3', 'Gene', (51, 54))	('4Cl', 'molecular_function', 'GO:0016207', ('247', '250'))	('expression', 'MPA', (166, 176))	('NH4Cl', 'Var', (245, 250))	('LC3', 'Gene', '84557', (152, 155))	('NH4Cl', 'Chemical', 'MESH:D000643', (245, 250))	('LC3', 'Gene', (152, 155))	('increased', 'PosReg', (232, 241))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('LC3', 'Gene', '84557', (119, 122))	('cytotoxicity', 'Disease', (193, 205))
201737	28212571	To investigate whether p62/SQSTM1 interacts with LC3II after transfection with the different Myc tagged-p62/SQSTM1 deletion constructs in H28 cells, their effects on the protein expression of LC3II and p62 were comparatively examined.	('p62', 'Gene', (23, 26))	('deletion', 'Var', (115, 123))	('LC3', 'Gene', '84557', (192, 195))	('SQSTM1', 'Gene', (108, 114))	('LC3', 'Gene', (192, 195))	('LC3', 'Gene', '84557', (49, 52))	('SQSTM1', 'Gene', '8878', (108, 114))	('p62', 'Gene', '8878', (202, 205))	('p62', 'Gene', (202, 205))	('p62', 'Gene', '8878', (104, 107))	('p62', 'Gene', (104, 107))	('LC3', 'Gene', (49, 52))	('Myc', 'Gene', '4609', (93, 96))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('Myc', 'Gene', (93, 96))	('p62', 'Gene', '8878', (23, 26))	('SQSTM1', 'Gene', (27, 33))	('SQSTM1', 'Gene', '8878', (27, 33))
201743	28212571	However, inhibition of p-JNK by the JNK inhibitor SP600125 suppressed the autophagic ability of Tan I to activate the expression of p62/SQSTM1 and LC3II in H28 cells (Figure 5D).	('JNK', 'Gene', '5599', (25, 28))	('SQSTM1', 'Gene', '8878', (136, 142))	('SP600125', 'Var', (50, 58))	('p62', 'Gene', '8878', (132, 135))	('p62', 'Gene', (132, 135))	('autophagic ability', 'CPA', (74, 92))	('activate', 'PosReg', (105, 113))	('LC3', 'Gene', (147, 150))	('JNK', 'molecular_function', 'GO:0004705', ('36', '39'))	('JNK', 'Gene', (36, 39))	('JNK', 'molecular_function', 'GO:0004705', ('25', '28'))	('JNK', 'Gene', '5599', (36, 39))	('Tan I', 'Chemical', 'MESH:C021751', (96, 101))	('expression', 'MPA', (118, 128))	('SP600125', 'Chemical', 'MESH:C432165', (50, 58))	('SQSTM1', 'Gene', (136, 142))	('suppressed', 'NegReg', (59, 69))	('JNK', 'Gene', (25, 28))	('LC3', 'Gene', '84557', (147, 150))
201746	28212571	As shown in Figure 6A, IRE1 depletion attenuated the expression of p62/SQSTM1 and LC3II to subsequently reduce the expression of procaspase 3 in Tan I-treated H28 cells compared to the untreated control.	('LC3', 'Gene', (82, 85))	('attenuated', 'NegReg', (38, 48))	('procaspase 3', 'Gene', (129, 141))	('SQSTM1', 'Gene', (71, 77))	('SQSTM1', 'Gene', '8878', (71, 77))	('depletion', 'Var', (28, 37))	('expression', 'MPA', (115, 125))	('IRE1', 'Gene', '2081', (23, 27))	('reduce', 'NegReg', (104, 110))	('p62', 'Gene', '8878', (67, 70))	('expression', 'MPA', (53, 63))	('p62', 'Gene', (67, 70))	('Tan I', 'Chemical', 'MESH:C021751', (145, 150))	('LC3', 'Gene', '84557', (82, 85))	('IRE1', 'Gene', (23, 27))	('procaspase 3', 'Gene', '836', (129, 141))
201748	28212571	However, silencing of IRE1 or ATG5 increased the cytotoxicity by Tan I, but not depletion of p62 and Beclin 1 in H28 cells (Figure 6C).	('ATG5', 'Gene', (30, 34))	('increased', 'PosReg', (35, 44))	('silencing', 'Var', (9, 18))	('Beclin 1', 'Gene', (101, 109))	('p62', 'Gene', '8878', (93, 96))	('cytotoxicity', 'Disease', (49, 61))	('Beclin 1', 'Gene', '8678', (101, 109))	('p62', 'Gene', (93, 96))	('Tan I', 'Chemical', 'MESH:C021751', (65, 70))	('IRE1', 'Gene', '2081', (22, 26))	('ATG5', 'Gene', '9474', (30, 34))	('IRE1', 'Gene', (22, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))
201750	28212571	Furthermore, our data were supported by protein-protein interactions (PPI) suggested by GeneCards dataset, since PPI binding scores are 0.926 between ATG5 and LC3II, 0.999 between p62/SQSTM1 and LC3II and 0.643 between ATG5 and IRE1 (Figure 6F).	('PPI', 'biological_process', 'GO:0060134', ('70', '73'))	('ATG5', 'Gene', (219, 223))	('LC3', 'Gene', '84557', (195, 198))	('SQSTM1', 'Gene', '8878', (184, 190))	('0.999', 'Var', (166, 171))	('protein-protein', 'Protein', (40, 55))	('LC3', 'Gene', '84557', (159, 162))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('p62', 'Gene', '8878', (180, 183))	('IRE1', 'Gene', '2081', (228, 232))	('p62', 'Gene', (180, 183))	('ATG5', 'Gene', '9474', (150, 154))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('LC3', 'Gene', (195, 198))	('IRE1', 'Gene', (228, 232))	('ATG5', 'Gene', '9474', (219, 223))	('SQSTM1', 'Gene', (184, 190))	('ATG5', 'Gene', (150, 154))	('LC3', 'Gene', (159, 162))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('PPI', 'biological_process', 'GO:0060134', ('113', '116'))
201766	28212571	Interestingly, IRE1 depletion in Tan I-treated H28 cells decreased the expression of p62/SQSTM1 and LC3II through direct binding between IRE1 and p62/SQSTM1 by IP Western blotting and the colocalization of p62 with endogenous IRE1 detected by immunofluorescence, implying the direct interaction of p62/SQSTM1 with IRE1 by Tan I, which was supported by GeneCards dataset.	('p62', 'Gene', '8878', (206, 209))	('Tan I', 'Chemical', 'MESH:C021751', (322, 327))	('p62', 'Gene', (206, 209))	('IRE1', 'Gene', '2081', (15, 19))	('SQSTM1', 'Gene', (150, 156))	('depletion', 'Var', (20, 29))	('SQSTM1', 'Gene', '8878', (89, 95))	('decreased', 'NegReg', (57, 66))	('p62', 'Gene', '8878', (85, 88))	('p62', 'Gene', (85, 88))	('SQSTM1', 'Gene', '8878', (302, 308))	('LC3', 'Gene', (100, 103))	('IRE1', 'Gene', (15, 19))	('IRE1', 'Gene', '2081', (226, 230))	('SQSTM1', 'Gene', '8878', (150, 156))	('p62', 'Gene', '8878', (298, 301))	('expression', 'MPA', (71, 81))	('Tan I', 'Chemical', 'MESH:C021751', (33, 38))	('p62', 'Gene', (298, 301))	('p62', 'Gene', '8878', (146, 149))	('IRE1', 'Gene', '2081', (314, 318))	('IRE1', 'Gene', '2081', (137, 141))	('p62', 'Gene', (146, 149))	('binding', 'Interaction', (121, 128))	('IRE1', 'Gene', (226, 230))	('LC3', 'Gene', '84557', (100, 103))	('SQSTM1', 'Gene', (89, 95))	('IRE1', 'Gene', (314, 318))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('SQSTM1', 'Gene', (302, 308))	('IRE1', 'Gene', (137, 141))
201767	28212571	Consistently, silencing of p62 decreased the activated expression of LC3 II, but not IRE1 in Tan I-treated H28 cells, indicating that IRE-1 is an upstream of p62.	('silencing', 'Var', (14, 23))	('p62', 'Gene', (158, 161))	('p62', 'Gene', '8878', (27, 30))	('LC3', 'Gene', '84557', (69, 72))	('activated expression', 'MPA', (45, 65))	('p62', 'Gene', (27, 30))	('decreased', 'NegReg', (31, 40))	('LC3', 'Gene', (69, 72))	('IRE-1', 'Gene', (134, 139))	('Tan I', 'Chemical', 'MESH:C021751', (93, 98))	('IRE1', 'Gene', '2081', (85, 89))	('IRE-1', 'Gene', '2081', (134, 139))	('p62', 'Gene', '8878', (158, 161))	('IRE1', 'Gene', (85, 89))
201768	28212571	Furthermore, inhibition of p-JNK by using JNK inhibitor SP600125 decreased the ability of Tan I to activate p62/SQSTM1, LC3II and IRE1 in H28 cells, implying that p-JNK activates the signaling of p62 or IRE1 through the autophagy process, which was supported by the previous report that resveratrol-mediated JNK activation increased the expression of p62/SQSTM1 protein and mRNA levels.	('IRE1', 'Gene', (130, 134))	('JNK', 'Gene', (42, 45))	('JNK', 'Gene', '5599', (42, 45))	('LC3', 'Gene', (120, 123))	('increased', 'PosReg', (323, 332))	('decreased', 'NegReg', (65, 74))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('protein', 'cellular_component', 'GO:0003675', ('362', '369'))	('mRNA levels', 'MPA', (374, 385))	('SQSTM1', 'Gene', '8878', (112, 118))	('resveratrol', 'Chemical', 'MESH:D000077185', (287, 298))	('SP600125', 'Chemical', 'MESH:C432165', (56, 64))	('JNK', 'molecular_function', 'GO:0004705', ('308', '311'))	('SQSTM1', 'Gene', (355, 361))	('p62', 'Gene', '8878', (196, 199))	('p62', 'Gene', (196, 199))	('p62', 'Gene', '8878', (108, 111))	('JNK', 'Gene', (308, 311))	('p62', 'Gene', (108, 111))	('autophagy', 'biological_process', 'GO:0016236', ('220', '229'))	('JNK', 'Gene', '5599', (308, 311))	('JNK', 'Gene', (165, 168))	('IRE1', 'Gene', '2081', (203, 207))	('Tan I', 'Chemical', 'MESH:C021751', (90, 95))	('LC3', 'Gene', '84557', (120, 123))	('SQSTM1', 'Gene', '8878', (355, 361))	('JNK', 'Gene', '5599', (165, 168))	('JNK', 'Gene', (29, 32))	('JNK', 'Gene', '5599', (29, 32))	('JNK', 'molecular_function', 'GO:0004705', ('42', '45'))	('IRE1', 'Gene', '2081', (130, 134))	('autophagy', 'biological_process', 'GO:0006914', ('220', '229'))	('SP600125', 'Var', (56, 64))	('IRE1', 'Gene', (203, 207))	('JNK', 'molecular_function', 'GO:0004705', ('165', '168'))	('SQSTM1', 'Gene', (112, 118))	('p62', 'Gene', '8878', (351, 354))	('expression', 'MPA', (337, 347))	('p62', 'Gene', (351, 354))	('JNK', 'molecular_function', 'GO:0004705', ('29', '32'))
201772	28212571	The JNK inhibitor SP600125 and 3MA were obtained from CALBIOCHEM (LL20119) and Santa Cruz (5142-23-4), respectively.	('SP600125', 'Var', (18, 26))	('3MA', 'Chemical', 'MESH:C025946', (31, 34))	('JNK', 'molecular_function', 'GO:0004705', ('4', '7'))	('JNK', 'Gene', (4, 7))	('SP600125', 'Chemical', 'MESH:C432165', (18, 26))	('JNK', 'Gene', '5599', (4, 7))
201861	26912149	The reasons for exclusion were extraperitoneal or liver metastases (n = 10), disease considered to be unresectable upon imaging (n = 7) with poor performance status (ECOG 2 or 3), CC-score of 2 during the laparotomy (n = 2), and short bowel syndrome (n = 1).	('CC-score of 2', 'Var', (180, 193))	('extraperitoneal', 'CPA', (31, 46))	('liver metastases', 'Disease', (50, 66))	('short bowel syndrome', 'Disease', (229, 249))	('short bowel', 'Phenotype', 'HP:0030889', (229, 240))	('short bowel syndrome', 'Disease', 'MESH:D012778', (229, 249))	('liver metastases', 'Disease', 'MESH:D009362', (50, 66))
201941	18795165	The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies.	('cause', 'Reg', (77, 82))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('SWCNTs', 'Chemical', '-', (66, 72))	('SWCNTs', 'Var', (66, 72))	('oxidative stress', 'Phenotype', 'HP:0025464', (201, 217))	('cellular responses', 'CPA', (103, 121))	('activation', 'PosReg', (151, 161))	('molecular signaling', 'MPA', (165, 184))
201961	18795165	Exposure to crocidolite is well documented to cause mesothelioma in humans and animals, and cellular studies using mesothelial cells are reported to mimic important biologic responses involved in mesothelioma development.	('crocidolite', 'Var', (12, 23))	('mesothelioma', 'Disease', (196, 208))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('mesothelioma', 'Disease', (52, 64))	('crocidolite', 'Chemical', 'MESH:D017638', (12, 23))	('humans', 'Species', '9606', (68, 74))	('cause', 'Reg', (46, 51))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
201994	18795165	In the presence of 150 mug/mL SWCNTs for 90 min, the fluorescence for O2 - and H2O2 were increased in both NM and MM cells.	('O2', 'Chemical', '-', (70, 72))	('SWCNTs', 'Chemical', '-', (30, 36))	('O2', 'Chemical', '-', (81, 83))	('mug', 'molecular_function', 'GO:0043739', ('23', '26'))	('increased', 'PosReg', (89, 98))	('fluorescence for O2 -', 'MPA', (53, 74))	('H2O2', 'Chemical', 'MESH:D006861', (79, 83))	('H2O2', 'Var', (79, 83))
201996	18795165	Fluorescence for O2 - and H2O2 was significantly greater with crocidolite than with SWCNTs in both cell types (Figure 1).	('greater', 'PosReg', (49, 56))	('crocidolite', 'Chemical', 'MESH:D017638', (62, 73))	('O2', 'Chemical', '-', (17, 19))	('H2O2', 'Chemical', 'MESH:D006861', (26, 30))	('H2O2', 'Var', (26, 30))	('crocidolite', 'Disease', (62, 73))	('SWCNTs', 'Chemical', '-', (84, 90))	('Fluorescence', 'MPA', (0, 12))	('O2', 'Chemical', '-', (28, 30))
202013	18795165	Coincubation of MM cells with SWCNTs (25 mug/cm2) and catalase (100 U/mL), SOD (100 U/mL), or deferoxamine (1 mM; an iron chelator) for 24 hr resulted in a 35%, 30%, and 32% decrease in DNA damage, respectively.	('SOD', 'Gene', '6647', (75, 78))	('DNA damage', 'MPA', (186, 196))	('SWCNTs', 'Chemical', '-', (30, 36))	('decrease', 'NegReg', (174, 182))	('mug', 'molecular_function', 'GO:0043739', ('41', '44'))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('25 mug/cm2', 'Var', (38, 48))	('SOD', 'Gene', (75, 78))	('catalase', 'Gene', (54, 62))	('deferoxamine', 'Chemical', 'MESH:D003676', (94, 106))	('100 U/mL', 'Var', (80, 88))	('100 U/mL', 'Var', (64, 72))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('catalase', 'Gene', '847', (54, 62))	('SOD', 'molecular_function', 'GO:0004784', ('75', '78'))
202040	18795165	Several studies have shown that occupational and environmental exposures to particulate matter with mean diameters of < 10 mum or nanoparticles with a size dimension < 100 nm are associated with respiratory diseases, including cancer.	('respiratory diseases', 'Disease', 'MESH:D012131', (195, 215))	('associated', 'Reg', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('iron', 'Chemical', 'MESH:D007501', (52, 56))	('respiratory diseases', 'Disease', (195, 215))	('nanoparticles', 'Var', (130, 143))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
202045	18795165	These studies are further justified by a recent report on the induction of mesothelioma in p53+/-mice by multiwall carbon nanotubes.	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('mice', 'Species', '10090', (97, 101))	('carbon', 'Chemical', 'MESH:D002244', (115, 121))	('p53', 'Gene', (91, 94))	('multiwall', 'Var', (105, 114))	('mesothelioma', 'Disease', (75, 87))	('p53', 'Gene', '22060', (91, 94))
202074	18795165	ROS in the absence of anti-oxidant protection can directly interact or modify cellular proteins, lipids, and DNA, which in turn may alter cellular functions and predispose the cells to impaired apoptosis and abnormal cell growth.	('ROS', 'Var', (0, 3))	('interact', 'Interaction', (59, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('194', '203'))	('DNA', 'MPA', (109, 112))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('modify', 'Reg', (71, 77))	('lipids', 'Protein', (97, 103))	('cellular proteins', 'Protein', (78, 95))	('lipids', 'Chemical', 'MESH:D008055', (97, 103))	('cellular functions', 'MPA', (138, 156))	('cell growth', 'biological_process', 'GO:0016049', ('217', '228'))	('impaired apoptosis', 'CPA', (185, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('194', '203'))	('predispose', 'Reg', (161, 171))	('alter', 'Reg', (132, 137))
202079	18795165	As a result of the DNA double-strand breaks, the histone H2AX protein can be distinguished from other histones by a unique carboxy-terminal sequence that is rapidly phosphorylated at the fourth residue (Ser139) in response to DNA damage.	('histone H2AX', 'Gene', (49, 61))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('DNA', 'Var', (19, 22))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('Ser139', 'Chemical', '-', (203, 209))	('Ser', 'cellular_component', 'GO:0005790', ('203', '206'))	('histone H2AX', 'Gene', '3014', (49, 61))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
202088	18795165	A growing body of evidence suggests that EGF, platelet-derived growth factor, and the insulin signal transduction pathway mediated by PI-3Ks play important roles in the activation of Akt.	('insulin signal transduction pathway', 'Pathway', (86, 121))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('46', '76'))	('PI-3Ks', 'Var', (134, 140))	('activation', 'PosReg', (169, 179))	('Akt', 'Gene', (183, 186))	('EGF', 'molecular_function', 'GO:0005154', ('41', '44'))	('insulin', 'molecular_function', 'GO:0016088', ('86', '93'))	('EGF', 'Gene', (41, 44))	('signal transduction', 'biological_process', 'GO:0007165', ('94', '113'))	('Akt', 'Gene', '207', (183, 186))	('EGF', 'Gene', '1950', (41, 44))
202090	18795165	The PI-3K phosphorylated membrane phospholipid products induce the activation of Akt.	('PI-3K', 'molecular_function', 'GO:0016303', ('4', '9'))	('Akt', 'Gene', '207', (81, 84))	('activation', 'PosReg', (67, 77))	('PI-3K', 'Var', (4, 9))	('phospholipid', 'Chemical', 'MESH:D010743', (34, 46))	('Akt', 'Gene', (81, 84))	('membrane', 'cellular_component', 'GO:0016020', ('25', '33'))
202108	18795165	In human mesotheliomas, deletions of the Cdkn2a/Arf and Cdkn2b gene loci associated with hypermethylation are reported to be common at the NF2 gene locus.	('NF2', 'Gene', '4771', (139, 142))	('Cdkn2a', 'Gene', '1029', (41, 47))	('human', 'Species', '9606', (3, 8))	('Cdkn2b', 'Gene', '1030', (56, 62))	('Cdkn2b', 'Gene', (56, 62))	('mesotheliomas', 'Disease', 'MESH:D008654', (9, 22))	('deletions', 'Var', (24, 33))	('associated', 'Reg', (73, 83))	('mesotheliomas', 'Disease', (9, 22))	('NF2', 'Gene', (139, 142))	('Cdkn2a', 'Gene', (41, 47))
202124	33608377	In addition, CD40 can re-educate macrophages to destroy tumor stroma.	('tumor stroma', 'Disease', 'MESH:D009369', (56, 68))	('CD40', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor stroma', 'Disease', (56, 68))
202127	33608377	In this study, the maximum tolerated dose (MTD) of rhuCD40L was based on transient grades 3/4 elevations in serum liver transaminases, and liver function test abnormalities have since been identified as a class effect of CD40 agonists.	('serum liver transaminases', 'MPA', (108, 133))	('abnormalities', 'Var', (159, 172))	('rhuCD40L', 'Gene', (51, 59))	('rhuCD40L', 'Chemical', '-', (51, 59))	('liver function test', 'MPA', (139, 158))	('elevations', 'PosReg', (94, 104))
202131	33608377	Consequently, alternate delivery methods of CD40 agonists have been employed, including subcutaneous and intratumoral administration of anti-CD40 antibodies or adenoviral vectors expressing CD40 ligand.	('ligand', 'molecular_function', 'GO:0005488', ('195', '201'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('anti-CD40', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
202147	33608377	ABBV-428 was administered at nine dose levels (0.01, 0.03, 0.1, 0.2, 0.4, 0.8, 1.6, 2.4, and 3.6 mg/kg every 2 weeks) in patients with advanced solid tumors who had progression on or intolerance to standard therapies.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('0.03', 'Var', (53, 57))	('0.01', 'Var', (47, 51))	('ABBV-428', 'Chemical', '-', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('0.4', 'Var', (69, 72))	('0.2', 'Var', (64, 67))	('patients', 'Species', '9606', (121, 129))	('0.1', 'Var', (59, 62))
202153	33608377	Eligible patients were aged >=18 years, with an advanced solid tumor, who had progression on or intolerance to standard therapies known to provide clinical benefit; had an Eastern Cooperative Oncology Group performance status of 0-2; had adequate bone marrow (absolute neutrophil count >=1500/mm3, platelets >=100x109/L, hemoglobin >=9.0 g/dL), renal (creatinine clearance >=50 mL/min), hepatic (total bilirubin <=1.5xupper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase <=2.5xULN), and coagulation function; and had measurable disease per Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST V.1.1) in the dose expansion arm.	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (9, 17))	('bilirubin', 'Chemical', 'MESH:D001663', (402, 411))	('Oncology', 'Phenotype', 'HP:0002664', (192, 200))	('Tumors', 'Phenotype', 'HP:0002664', (610, 616))	('Tumor', 'Phenotype', 'HP:0002664', (610, 615))	('coagulation', 'biological_process', 'GO:0050817', ('519', '530'))	('alanine aminotransferase', 'Gene', (478, 502))	('>=100x109/L', 'Var', (308, 319))	('creatinine', 'Chemical', 'MESH:D003404', (352, 362))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('alanine aminotransferase', 'Gene', '2875', (478, 502))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Tumors', 'Disease', (610, 616))	('Tumors', 'Disease', 'MESH:D009369', (610, 616))
202169	33608377	For dose escalation, patients were treated at one of nine ABBV-428 dose levels: 0.01 mg/kg (n=2), 0.03 mg/kg (n=2), 0.1 mg/kg (n=6), 0.2 mg/kg (n=6), 0.4 mg/kg (n=5), 0.8 mg/kg (n=4), 1.6 mg/kg (n=3), 2.4 mg/kg (n=3), and 3.6 mg/kg (n=6).	('patients', 'Species', '9606', (21, 29))	('0.03 mg/kg', 'Var', (98, 108))	('0.01 mg/kg', 'Var', (80, 90))	('ABBV-428', 'Chemical', '-', (58, 66))
202185	33608377	For the 3.6 mg/kg RP2D of ABBV-428 in cycle 1, the median Tmax was 0.25 hours after end of infusion, and the geometric mean Cmax and AUClast were 48.5 microg/mL and 717 microg hour/mL, respectively, and the estimated t1/2 was 13.9 hours.	('RP2D', 'Var', (18, 22))	('ABBV-428', 'Gene', (26, 34))	('ABBV-428', 'Chemical', '-', (26, 34))
202228	33608377	Similarly, peripheral B-cell CD40 receptor occupancy was used as a pharmacodynamic readout in this study; however, the lack of changes in cytokine secretion and intratumoral pharmacodynamic biomarkers (eg, CD8+ T-cells, PD-L1+ cells, and immune-related gene expression) indicates that ABBV-428 did not induce an effective antitumor immune response at the doses tested in this study.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('ABBV-428', 'Var', (285, 293))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Disease', (166, 171))	('PD-L1+', 'Gene', (220, 226))	('CD8', 'Gene', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('ABBV-428', 'Chemical', '-', (285, 293))	('CD8', 'Gene', '925', (206, 209))	('immune response', 'biological_process', 'GO:0006955', ('332', '347'))	('cytokine secretion', 'biological_process', 'GO:0050663', ('138', '156'))	('tumor', 'Disease', (326, 331))	('gene expression', 'biological_process', 'GO:0010467', ('253', '268'))	('cytokine secretion', 'MPA', (138, 156))	('PD-L1+', 'Gene', '29126', (220, 226))
202373	22353806	Patients received LD 40 mg m-2 in 60 min and cisplatin 60 mg m-2 in a 3-h infusion on day 1 of every 21 days cycle, patients were treated for a maximum of six cycles and all patients received antiemetic therapy with ondansetron, dexamethasone, and aprepitant.	('LD 40', 'Var', (18, 23))	('LD', 'Chemical', 'MESH:C506643', (18, 20))	('ondansetron', 'Chemical', 'MESH:D017294', (216, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (174, 182))	('Patients', 'Species', '9606', (0, 8))	('cisplatin', 'Var', (45, 54))	('dexamethasone', 'Chemical', 'MESH:D003907', (229, 242))
202532	33741915	Personalised treatments are lacking for MPM, however recent insights into the inter-patient genomic heterogeneity of this cancer have revealed frequent somatic alterations involving the cancer genes BAP1, NF2 and CDKN2A.	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('BAP1', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CDKN2A', 'Gene', (213, 219))	('alterations', 'Var', (160, 171))	('NF2', 'Gene', (205, 208))	('patient', 'Species', '9606', (84, 91))	('CDKN2A', 'Gene', '1029', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BAP1', 'Gene', '8314', (199, 203))	('cancer', 'Disease', (186, 192))	('NF2', 'Gene', '4771', (205, 208))
202546	33741915	The nucleotide transition C T was the most common clonal and subclonal base substitution, resulting from deamination of 5-methylcytosine (supplementary fig.	('nucleotide transition C T', 'Var', (4, 29))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (120, 136))	('deamination of 5-methylcytosine', 'MPA', (105, 136))
202547	33741915	Mutational signatures inferred using deconstructSigs showed clonal enrichment of clock-like, base excision repair deficiency and single base substitution signatures SBS16, SBS19, SBS32 and SBS39, reflecting underlying mutagenesis mechanisms involved in early MPM evolution (supplementary fig.	('SBS39', 'Var', (189, 194))	('base excision repair', 'biological_process', 'GO:0006284', ('93', '113'))	('deficiency', 'Disease', (114, 124))	('SBS32', 'Var', (179, 184))	('SBS16', 'Var', (165, 170))	('deficiency', 'Disease', 'MESH:D007153', (114, 124))	('mutagenesis', 'biological_process', 'GO:0006280', ('218', '229'))	('base excision repair', 'MPA', (93, 113))	('SBS19', 'Var', (172, 177))
202551	33741915	In contrast, subclonal positive selection was only associated with NF2 (14%).	('NF2', 'Gene', (67, 70))	('NF2', 'Gene', '4771', (67, 70))	('subclonal positive selection', 'Var', (13, 41))
202552	33741915	The majority of driver mutations were predicted as deleterious, loss of function events and were enriched in tumour suppressor genes (supplementary fig.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('loss of function', 'NegReg', (64, 80))	('tumour', 'Disease', (109, 115))	('mutations', 'Var', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
202557	33741915	The presence of circulating tumour DNA was significantly associated with NF2 mutation (p = 0.015 Fig.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('mutation', 'Var', (77, 85))	('NF2', 'Gene', (73, 76))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('tumour', 'Disease', (28, 34))	('NF2', 'Gene', '4771', (73, 76))	('associated', 'Reg', (57, 67))
202558	33741915	Secondary tumour suppressor hits leading to bi-allelic inactivation of drivers by either mutation and/or copy number loss were more common during early evolution.	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('mutation', 'Var', (89, 97))	('copy number loss', 'Var', (105, 121))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))	('bi-allelic inactivation', 'Var', (44, 67))
202562	33741915	Subclonal bi-allelic inactivation commonly involved BAP1 and the Hippo pathway genes NF2 (MED34) and LATS1 (MED3), (supplementary fig.	('LATS1', 'Gene', '9113', (101, 106))	('bi-allelic inactivation', 'Var', (10, 33))	('NF2', 'Gene', '4771', (85, 88))	('BAP1', 'Gene', '8314', (52, 56))	('MED3', 'Gene', (108, 112))	('LATS1', 'Gene', (101, 106))	('MED3', 'Gene', (90, 94))	('MED3', 'Gene', '9442', (108, 112))	('MED3', 'Gene', '9442', (90, 94))	('BAP1', 'Gene', (52, 56))	('NF2', 'Gene', (85, 88))	('involved', 'Reg', (43, 51))
202564	33741915	Subclonal NF2 copy number loss was observed at the time of radiological progression, and this coincided with both a higher burden of copy number alterations and chemoresistant MPM, suggesting late stage subclonal expansion, and Hippo pathway inactivation coincident with clinically more aggressive growth and drug resistance (Fig.	('NF2', 'Gene', (10, 13))	('copy number alterations', 'Var', (133, 156))	('Hippo pathway', 'Pathway', (228, 241))	('drug resistance', 'Phenotype', 'HP:0020174', (309, 324))	('inactivation', 'NegReg', (242, 254))	('NF2', 'Gene', '4771', (10, 13))	('more', 'PosReg', (282, 286))	('loss', 'NegReg', (26, 30))	('drug resistance', 'biological_process', 'GO:0009315', ('309', '324'))	('copy number', 'Var', (14, 25))	('drug resistance', 'biological_process', 'GO:0042493', ('309', '324'))
202568	33741915	The most frequent was -22q (NF2) in 82% of MPMs, followed by 9p21.3 (CDKN2A and MTAP), and 3p21.3 (BAP1), (supplementary fig.	('BAP1', 'Gene', (99, 103))	('MPMs', 'Disease', (43, 47))	('CDKN2A', 'Gene', '1029', (69, 75))	('MTAP', 'Gene', (80, 84))	('NF2', 'Gene', (28, 31))	('MTAP', 'Gene', '4507', (80, 84))	('NF2', 'Gene', '4771', (28, 31))	('BAP1', 'Gene', '8314', (99, 103))	('3p21.3', 'Var', (91, 97))	('CDKN2A', 'Gene', (69, 75))	('9p21.3', 'Var', (61, 67))
202569	33741915	Clonal NF2 deletion was present in the cell line MED85 and this was associated with constitutive nuclear translocation of YAP, compared with MED96 which harboured wild-type NF2 (Fig.	('NF2', 'Gene', (7, 10))	('YAP', 'Gene', (122, 125))	('associated with', 'Reg', (68, 83))	('constitutive nuclear translocation', 'MPA', (84, 118))	('NF2', 'Gene', (173, 176))	('NF2', 'Gene', '4771', (7, 10))	('YAP', 'Gene', '10413', (122, 125))	('deletion', 'Var', (11, 19))	('NF2', 'Gene', '4771', (173, 176))
202571	33741915	Copy-neutral loss of heterozygosity (CN LOH also referred to as uniparental disomy) involving duplication of an allele with concurrent loss of the other allele, occurred in 12 patients of which 11 events were restricted to chromosome 9 (supplementary fig.	('patients', 'Species', '9606', (176, 184))	('uniparental disomy', 'Disease', 'MESH:D024182', (64, 82))	('duplication', 'Var', (94, 105))	('loss', 'NegReg', (13, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('223', '233'))	('uniparental disomy', 'Disease', (64, 82))
202576	33741915	One MPM (MED109) exhibited no driver single nucleotide variants (SNVs) or INDELs, had more copy number gains than losses, and had clonal deletions involving multiple drivers CDKN2A and NF2.	('NF2', 'Gene', (185, 188))	('copy number', 'MPA', (91, 102))	('CDKN2A', 'Gene', (174, 180))	('NF2', 'Gene', '4771', (185, 188))	('CDKN2A', 'Gene', '1029', (174, 180))	('single nucleotide', 'Var', (37, 54))	('gains', 'PosReg', (103, 108))
202577	33741915	In addition, this patient also had deletion of ID3 (1p36.12), and a region spanning 14q11-14q32 harbouring the genes CCNB1IP1 (14q11.2), BAZ1A, NKX2-1 (14q13), MAX, RAD51B (14q23-24), DICER1, and BCL1B as well as -22q encompassing LZTR1, ZNRF3, MYH9, APOBEC3B, MRTFA, PATZ1, EP300 and CHEK2 (supplementary fig.	('MYH9', 'Gene', (245, 249))	('APOBEC', 'cellular_component', 'GO:0030895', ('251', '257'))	('CHEK2', 'Gene', '11200', (285, 290))	('APOBEC3B', 'Gene', '9582', (251, 259))	('LZTR1', 'Gene', (231, 236))	('EP300', 'Gene', '2033', (275, 280))	('patient', 'Species', '9606', (18, 25))	('BAZ1A', 'Gene', (137, 142))	('ZNRF3', 'Gene', '84133', (238, 243))	('RAD51B', 'Gene', '5890', (165, 171))	('MRTFA', 'Gene', '57591', (261, 266))	('ZNRF3', 'Gene', (238, 243))	('ID3', 'Gene', '3399', (47, 50))	('NKX2-1', 'Gene', '7080', (144, 150))	('LZTR1', 'Gene', '8216', (231, 236))	('DICER1', 'Gene', '23405', (184, 190))	('RAD', 'biological_process', 'GO:1990116', ('165', '168'))	('EP300', 'Gene', (275, 280))	('BAZ1A', 'Gene', '11177', (137, 142))	('NKX2-1', 'Gene', (144, 150))	('DICER1', 'Gene', (184, 190))	('APOBEC3B', 'Gene', (251, 259))	('MRTFA', 'Gene', (261, 266))	('PATZ1', 'Gene', '23598', (268, 273))	('deletion', 'Var', (35, 43))	('CCNB1IP1', 'Gene', (117, 125))	('ID3', 'Gene', (47, 50))	('RAD51B', 'Gene', (165, 171))	('CCNB1IP1', 'Gene', '57820', (117, 125))	('CHEK2', 'Gene', (285, 290))	('PATZ1', 'Gene', (268, 273))	('MYH9', 'Gene', '4627', (245, 249))
202578	33741915	Notably the largest cluster C5, which exhibited the largest number of repeated early clonal transitions, and featured frequent FBXW7 mutation (supplementary fig.	('FBXW7', 'Gene', (127, 132))	('mutation', 'Var', (133, 141))	('FBXW7', 'Gene', '55294', (127, 132))
202583	33741915	A consistent feature across the evolutionary clusters was the timing of hippo pathway inactivation signified by either loss of 22q or NF2 mutation.	('inactivation', 'NegReg', (86, 98))	('NF2', 'Gene', '4771', (134, 137))	('mutation', 'Var', (138, 146))	('NF2', 'Gene', (134, 137))	('hippo pathway', 'Pathway', (72, 85))	('22q', 'Protein', (127, 130))	('loss', 'NegReg', (119, 123))
202590	33741915	MPMs harbouring high clonal copy number burden exhibited greater systemic inflammation reflected by Neutrophil:lymphocyte and platelet:lymphocyte ratios (Fig.	('greater', 'PosReg', (57, 64))	('high clonal copy number burden', 'Var', (16, 46))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('inflammation', 'biological_process', 'GO:0006954', ('74', '86'))
202596	33741915	BAP1 mutation or 3p21 loss was predominantly heterozygous, with evidence of clonal and subclonal second hits leading to its complete inactivation.	('BAP1', 'Gene', (0, 4))	('3p21', 'Gene', (17, 21))	('loss', 'NegReg', (22, 26))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
202599	33741915	We reported a clonal BAP1 mutation rate of 36%, similar to that reported in the TCGA.	('CGA', 'Gene', '1113', (81, 84))	('mutation', 'Var', (26, 34))	('BAP1', 'Gene', (21, 25))	('CGA', 'Gene', (81, 84))	('BAP1', 'Gene', '8314', (21, 25))
202600	33741915	However, minute deletions revealed by single region high density comparative genomic hybridisation array, combined with next-generation sequencing implicates a generally higher rate of BAP1 somatic alterations in MPM.	('higher', 'PosReg', (170, 176))	('BAP1', 'Gene', (185, 189))	('MPM', 'MPA', (213, 216))	('minute deletions', 'Var', (9, 25))	('alterations', 'Var', (198, 209))	('BAP1', 'Gene', '8314', (185, 189))
202603	33741915	Its inactivation upregulates the prosurvival BCL2 family member, MCL1 leading to resistance to antimicrotubule agents such as vinorelbine, which has demonstrated useful clinical efficacy in relapsed MPM.	('BCL2', 'Gene', '596', (45, 49))	('inactivation', 'Var', (4, 16))	('relapsed MPM', 'Disease', (190, 202))	('BCL2', 'Gene', (45, 49))	('BCL2', 'molecular_function', 'GO:0015283', ('45', '49'))	('upregulates', 'PosReg', (17, 28))	('MCL1', 'Gene', (65, 69))	('MCL1', 'Gene', '4170', (65, 69))	('vinorelbine', 'Chemical', 'MESH:D000077235', (126, 137))	('resistance to antimicrotubule agents', 'MPA', (81, 117))
202605	33741915	NF2 mutation was positively selected during both early and late evolution.	('NF2', 'Gene', (0, 3))	('mutation', 'Var', (4, 12))	('NF2', 'Gene', '4771', (0, 3))
202608	33741915	Clonal homozygous deletion of CDKN2A was identified in approximately a third of the MEDUSA22 cohort.	('CDKN2A', 'Gene', '1029', (30, 36))	('CDKN2A', 'Gene', (30, 36))	('deletion', 'Var', (18, 26))
202609	33741915	Loss of 9p21.3 carries CDKN2A leading to loss of p16ink4a and derepression of cyclin-dependent kinases 4 and 6 which may serve as a therapeutic target.	('cyclin', 'molecular_function', 'GO:0016538', ('78', '84'))	('p16ink4a', 'Gene', (49, 57))	('CDKN2A', 'Gene', (23, 29))	('Loss of 9p21.3', 'Var', (0, 14))	('cyclin-dependent', 'Enzyme', (78, 94))	('loss', 'NegReg', (41, 45))	('CDKN2A', 'Gene', '1029', (23, 29))	('p16ink4a', 'Gene', '1029', (49, 57))	('derepression', 'PosReg', (62, 74))
202610	33741915	MTAP deletion has been reported to confer sensitivity to inhibition of PRMT5 or deprivation of its substrate s-adenosylmethionine via inhibition of MAT2A, both currently clinical drug development targets with potential in MPM.	('deletion', 'Var', (5, 13))	('PRMT5', 'Gene', (71, 76))	('sensitivity', 'MPA', (42, 53))	('inhibition', 'NegReg', (57, 67))	('PRMT5', 'Gene', '10419', (71, 76))	('inhibition', 'NegReg', (134, 144))	('MTAP', 'Gene', (0, 4))	('MAT', 'molecular_function', 'GO:0004314', ('148', '151'))	('MAT2A', 'Gene', '4144', (148, 153))	('s-adenosylmethionine', 'Chemical', 'MESH:D012436', (109, 129))	('MAT2A', 'Gene', (148, 153))	('MTAP', 'Gene', '4507', (0, 4))	('deprivation of', 'MPA', (80, 94))
202636	33741915	Briefly, VarScan2 somatic (v2.3) were used to do somatic variants calling between tumour and matched normal samples based on the output from SAMtools mpileup (1.0).	('tumour', 'Disease', (82, 88))	('variants', 'Var', (57, 65))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))
202639	33741915	Main databases used in future filtering or downstream analysis are as follows: SIFT, PolyPhen and MutationTaster scores used to predict the deleteriousness of mutations; Alternative allele frequencies in populations reported by large scale sequencing projects 1000 Human Genome(1000G), Exome Aggregation Consortium(ExAC) and exome sequencing project(ESP); Other databases including dbSNP, COSMIC, GO and KEGG.	('mutations', 'Var', (159, 168))	('ESP', 'Gene', (350, 353))	('ESP', 'Gene', '148713', (350, 353))	('Human', 'Species', '9606', (265, 270))
202646	33741915	Beside, as the majority of ubiquitous mutations are likely clonal, their VAFs (after correcting for copy number) should reflect the tumour purity, says the maximum peak of variant allele fraction distribution should equal to one half of the purity.	('tumour', 'Disease', (132, 138))	('VAFs', 'Disease', 'None', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('mutations', 'Var', (38, 47))	('VAFs', 'Disease', (73, 77))
202666	33741915	All non-silent variants were compared with a potential driver genes list (n = 26), curated from previous pleural mesothelioma analyses.	('variants', 'Var', (15, 23))	('pleural mesothelioma', 'Disease', (105, 125))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (105, 125))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (105, 125))
202676	33741915	In this analysis, neoantigens were defined as 8-11-mer peptides resulted from somatic SNVs or InDels which lead to amino-acid changes and, binding affinity score between remodelled peptide and respective patient's HLA class-I molecules was <500 nM.	('InDels', 'Var', (94, 100))	('binding affinity', 'Interaction', (139, 155))	('amino-acid', 'MPA', (115, 125))	('changes', 'Var', (126, 133))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('patient', 'Species', '9606', (204, 211))
202679	33741915	Epitope prediction was performed based on the selected prediction algorithms, after which, sequencing-based information was integrated to enable filtering of neoantigen candidates (Normal Coverage >=5X, Normal VAF <=2%, Tumour Coverage >=10X, Tumour VAF >=10%).	('Tumour VAF', 'Disease', (243, 253))	('Tumour', 'Phenotype', 'HP:0002664', (243, 249))	('Normal Coverage', 'Var', (181, 196))	('Tumour', 'Phenotype', 'HP:0002664', (220, 226))	('Tumour VAF', 'Disease', 'MESH:D009369', (243, 253))
202696	33741915	Cells were resuspended in phosphate-buffered saline (10209252, Oxoid) with 0.5% of bovine serum albumin (A7030, Sigma-Aldrich) and aliquoted 1 x 105 per tube.	('phosphate-buffered saline', 'Chemical', '-', (26, 51))	('A7030', 'Var', (105, 110))	('serum albumin', 'Gene', '213', (90, 103))	('serum albumin', 'Gene', (90, 103))
202736	32326079	In vivo NIR-PIT led to significant reduction in both tumor volume and luciferase activity in a flank model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group).	('luciferase activity', 'molecular_function', 'GO:0047077', ('70', '89'))	('NZ-1-IR700', 'Chemical', '-', (139, 149))	('luciferase', 'Enzyme', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('luciferase activity', 'molecular_function', 'GO:0045289', ('70', '89'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('70', '89'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NIR-PIT', 'Chemical', '-', (118, 125))	('luciferase activity', 'molecular_function', 'GO:0050248', ('70', '89'))	('NIR-PIT', 'Chemical', '-', (8, 15))	('luciferase activity', 'molecular_function', 'GO:0050397', ('70', '89'))	('tumor', 'Disease', (53, 58))	('activity', 'MPA', (81, 89))	('NIR-PIT', 'Var', (8, 15))	('reduction', 'NegReg', (35, 44))
202737	32326079	The PDPN-targeted NIR-PIT resulted in a significant antitumor effect in an MPM orthotopic mouse model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('mouse', 'Species', '10090', (90, 95))	('MPM', 'Chemical', '-', (75, 78))	('NIR-PIT', 'Chemical', '-', (18, 25))	('NZ-1-IR700', 'Chemical', '-', (134, 144))	('NIR-PIT', 'Chemical', '-', (113, 120))	('NIR-PIT', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
202795	32326079	One hundred thousand cells were seeded on 12 well plates and incubated with NZ-1-IR700 at 10 mug/mL for 12 h at 37  C. After the medium was replaced with PBS, the cells were irradiated with an NIR-light-emitting diode, which emitted light at 670-710 nm wavelength (L690-66-60, Ushio-Epitex, Kyoto, Japan).	('NZ-1-IR700', 'Chemical', '-', (76, 86))	('NZ-1-IR700', 'Var', (76, 86))	('PBS', 'Chemical', 'MESH:D007854', (154, 157))	('Ushio-Epitex', 'Disease', (277, 289))	('Kyoto', 'Disease', (291, 296))	('mug', 'molecular_function', 'GO:0043739', ('93', '96'))	('L690-66-60', 'Var', (265, 275))
202796	32326079	The cytotoxic effects of NIR-PIT with NZ-1-IR700 were determined by luciferase activity and flow cytometry with PI staining.	('NZ-1-IR700', 'Var', (38, 48))	('NIR-PIT', 'Chemical', '-', (25, 32))	('luciferase activity', 'molecular_function', 'GO:0047077', ('68', '87'))	('luciferase', 'Enzyme', (68, 78))	('luciferase activity', 'molecular_function', 'GO:0045289', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('68', '87'))	('NZ-1-IR700', 'Chemical', '-', (38, 48))	('luciferase activity', 'molecular_function', 'GO:0050397', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('68', '87'))
202803	32326079	To examine the distribution of NZ-1-IR700 in vivo, we prepared a xenograft tumor mouse model of MSTO-211H-PDPN-luc-GFP in the right dorsum.	('MSTO-211H', 'Chemical', '-', (96, 105))	('NZ-1-IR700', 'Chemical', '-', (31, 41))	('MSTO-211H-PDPN-luc-GFP', 'Var', (96, 118))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mouse', 'Species', '10090', (81, 86))	('tumor', 'Disease', (75, 80))
202817	32326079	The mice with tumors on both dorsal sides were injected with 100 mug of NZ-1-IR700 on day 13, and larger tumors were irradiated with NIR-light at 50 J/cm2 on day 14 and 100 J/cm2 on day 15.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mice', 'Species', '10090', (4, 8))	('mug', 'molecular_function', 'GO:0043739', ('65', '68'))	('NZ-1-IR700', 'Var', (72, 82))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('NZ-1-IR700', 'Chemical', '-', (72, 82))
202826	32326079	Blocking of signals on MSTO-211H-PDPN with the addition of excess NZ-1 was confirmed (Figure 2c), suggesting that NZ-1-IR700 bound specifically on PDPN.	('NZ-1-IR700', 'Var', (114, 124))	('bound', 'Interaction', (125, 130))	('MSTO-211H', 'Chemical', '-', (23, 32))	('NZ-1-IR700', 'Chemical', '-', (114, 124))
202829	32326079	To evaluate PDPN expression in a variety of MPM cell lines, IR700 fluorescence signals were detected with NZ-1-IR700 on ACC-MESO-1, ACC-MESO-4, Y-MESO-9, Y-MESO-12, and Y-MESO-14 (Japanese MPM cell lines) and MSTO-211H, NCI-H28, NCI-H226, NCI-H290, NCI-H2052, NCI-H2373, and NCI-H2452 (Caucasian MPM cell lines) using a flow cytometer.	('NCI-H226', 'CellLine', 'CVCL:1544', (229, 237))	('ACC', 'Gene', (132, 135))	('MPM', 'Chemical', '-', (189, 192))	('NCI-H2452', 'CellLine', 'CVCL:1553', (275, 284))	('MPM', 'Chemical', '-', (44, 47))	('PDPN', 'Gene', (12, 16))	('NCI-H28', 'CellLine', 'CVCL:1555', (220, 227))	('NZ-1-IR700', 'Chemical', '-', (106, 116))	('MPM', 'Chemical', '-', (296, 299))	('Y-MESO-14', 'Chemical', '-', (169, 178))	('NCI-H290', 'CellLine', 'CVCL:A555', (239, 247))	('ACC', 'Gene', '31', (120, 123))	('Y-MESO-12', 'Chemical', '-', (154, 163))	('MSTO-211H', 'Chemical', '-', (209, 218))	('ACC', 'Gene', (120, 123))	('NCI-H2052', 'CellLine', 'CVCL:1518', (249, 258))	('NCI-H2373', 'CellLine', 'CVCL:A533', (260, 269))	('ACC', 'Gene', '31', (132, 135))	('NZ-1-IR700', 'Var', (106, 116))
202835	32326079	Time-lapse imaging of MSTO-211H-PDPN-luc-GFP showed acute morphological changes and an increase in fluorescence of PI staining within 30 min (Supplementary Materials Video S1).	('MSTO-211H', 'Chemical', '-', (22, 31))	('increase', 'PosReg', (87, 95))	('fluorescence of', 'MPA', (99, 114))	('MSTO-211H-PDPN-luc-GFP', 'Var', (22, 44))
202838	32326079	These data showed that NIR-PIT with NZ-1-IR700 could selectively destroy PDPN-expressing cancer cells without damaging nontarget cells.	('destroy', 'NegReg', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('NZ-1-IR700', 'Chemical', '-', (36, 46))	('cancer', 'Disease', (89, 95))	('NZ-1-IR700', 'Var', (36, 46))	('NIR-PIT', 'Chemical', '-', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
202839	32326079	To quantitate in vitro NIR-PIT with NZ-1-IR700, we examined luciferase activity and PI staining with flow cytometry for various MPM cell lines (H2373-luc, MSTO-211H-PDPN-luc-GFP, ACC-MESO-1, Y-MESO-9, NCI-H28, and NCI-H226).	('luciferase activity', 'molecular_function', 'GO:0050248', ('60', '79'))	('MSTO-211H', 'Chemical', '-', (155, 164))	('MPM', 'Chemical', '-', (128, 131))	('luciferase activity', 'molecular_function', 'GO:0050397', ('60', '79'))	('ACC', 'Gene', (179, 182))	('H2373-luc', 'Var', (144, 153))	('NCI-H226', 'CellLine', 'CVCL:1544', (214, 222))	('luciferase activity', 'molecular_function', 'GO:0047077', ('60', '79'))	('NZ-1-IR700', 'Chemical', '-', (36, 46))	('ACC', 'Gene', '31', (179, 182))	('NCI-H28', 'CellLine', 'CVCL:1555', (201, 208))	('NIR-PIT', 'Chemical', '-', (23, 30))	('luciferase activity', 'molecular_function', 'GO:0045289', ('60', '79'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('60', '79'))
202842	32326079	No significant cytotoxicity was observed with NIR-light exposure alone or NZ-1-IR700 alone in either luciferase activity or PI staining (Figure 3d).	('cytotoxicity', 'Disease', (15, 27))	('luciferase', 'Enzyme', (101, 111))	('luciferase activity', 'molecular_function', 'GO:0047077', ('101', '120'))	('NZ-1-IR700', 'Chemical', '-', (74, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (15, 27))	('NZ-1-IR700', 'Var', (74, 84))	('luciferase activity', 'molecular_function', 'GO:0045289', ('101', '120'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('101', '120'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('101', '120'))	('activity', 'MPA', (112, 120))	('luciferase activity', 'molecular_function', 'GO:0050248', ('101', '120'))
202843	32326079	Collectively, these studies confirmed that NIR-PIT with NZ-1-IR700 can cause necrotic cell death, universally for MPM cancer cells with PDPN expression.	('NZ-1-IR700', 'Chemical', '-', (56, 66))	('cancer', 'Disease', (118, 124))	('MPM', 'Chemical', '-', (114, 117))	('cause', 'Reg', (71, 76))	('NZ-1-IR700', 'Var', (56, 66))	('NIR-PIT', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('necrotic cell death', 'biological_process', 'GO:0070265', ('77', '96'))	('necrotic cell death', 'Disease', 'MESH:D003643', (77, 96))	('necrotic cell death', 'Disease', (77, 96))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('NIR-PIT', 'Chemical', '-', (43, 50))
202844	32326079	After injection of NZ-1-IR700 into the subcutaneous flank model, IR700 fluorescence was observed on the whole mouse body and gradually accumulated at the tumor site 2 h after the injection (Figure 4a).	('accumulated', 'PosReg', (135, 146))	('mouse', 'Species', '10090', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('NZ-1-IR700', 'Chemical', '-', (19, 29))	('NZ-1-IR700', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('IR700', 'Var', (65, 70))	('tumor', 'Disease', (154, 159))
202850	32326079	The BLI showed that luminescence inside the treated tumor disappeared 1 day after NIR-PIT (* p < 0.05 versus no NIR-light irradiation tumor (control; NZ-1-IR700 iv only), t-test), indicating that the antitumor effect was strong.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('NIR-PIT', 'Var', (82, 89))	('tumor', 'Disease', (52, 57))	('luminescence', 'MPA', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('disappeared', 'NegReg', (58, 69))	('tumor', 'Disease', (204, 209))	('NZ-1-IR700', 'Chemical', '-', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('NIR-PIT', 'Chemical', '-', (82, 89))	('tumor', 'Disease', (134, 139))
202853	32326079	Therefore, PDPN-targeted NIR-PIT with NZ-1-IR700 demonstrated a significant antitumor effect on the subcutaneous flank tumor model.	('flank tumor', 'Disease', 'MESH:D021501', (113, 124))	('NZ-1-IR700', 'Var', (38, 48))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('rat', 'Species', '10116', (56, 59))	('NIR-PIT', 'Chemical', '-', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('subcutaneous flank tumor', 'Phenotype', 'HP:0001482', (100, 124))	('tumor', 'Disease', (80, 85))	('flank tumor', 'Disease', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('NZ-1-IR700', 'Chemical', '-', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
202857	32326079	These data suggested that MPM pleural disseminated orthotopic models were successfully established and that intravenous injection of NZ-1-IR700 could reach and accumulate on the disseminated tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('NZ-1-IR700', 'Chemical', '-', (133, 143))	('MPM', 'Chemical', '-', (26, 29))	('accumulate', 'PosReg', (160, 170))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('NZ-1-IR700', 'Var', (133, 143))
202861	32326079	Collectively, these data suggested that NIR-PIT caused significant antitumor effects even in the MPM pleural disseminated orthotopic model, and the therapy was feasible.	('NIR-PIT', 'Var', (40, 47))	('MPM', 'Chemical', '-', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('NIR-PIT', 'Chemical', '-', (40, 47))	('tumor', 'Disease', (71, 76))
202891	32326079	NZ-12 is applicable for RIT and radiolabeled NZ-12 enhances the antitumor effect.	('tumor', 'Disease', (68, 73))	('NZ-12', 'Chemical', '-', (0, 5))	('NZ-12', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('NZ-12', 'Chemical', '-', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhances', 'PosReg', (51, 59))	('radiolabeled', 'Var', (32, 44))
203002	30594195	As to other occupational carcinogens, the observed excess of lung cancer among autogenous welders (SMR = 171) may be explained by exposure to welding fumes containing polycyclic aromatic hydrocarbons because of work in confined spaces -such as oil tankers- and is unlikely to be explained by a higher proportion of smokers among welders than in the reference population.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (167, 199))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('polycyclic', 'Var', (167, 177))
203039	30441807	Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced.	('SS1P', 'Var', (62, 66))	('tumor', 'Disease', (85, 90))	('mesothelioma', 'Disease', (30, 42))	('patients', 'Species', '9606', (43, 51))	('mesothelioma', 'Disease', 'MESH:D008654', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SS1P', 'Chemical', 'MESH:C474515', (62, 66))
203043	30441807	We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner.	('increased', 'PosReg', (19, 28))	('SS1P', 'Chemical', 'MESH:C474515', (14, 18))	('release of ATP', 'MPA', (33, 47))	('SS1P', 'Var', (14, 18))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))
203044	30441807	In addition, SS1P induced calreticulin expression on the surface of AE17M cells.	('calreticulin', 'Gene', (26, 38))	('SS1P', 'Chemical', 'MESH:C474515', (13, 17))	('SS1P', 'Var', (13, 17))	('expression', 'MPA', (39, 49))	('induced', 'Reg', (18, 25))	('calreticulin', 'Gene', '12317', (26, 38))
203045	30441807	These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sensitize', 'Reg', (74, 83))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('SS1P', 'Chemical', 'MESH:C474515', (27, 31))	('tumors', 'Disease', (84, 90))	('SS1P', 'Var', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('promotes', 'PosReg', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('immunogenic cell death', 'CPA', (41, 63))
203046	30441807	In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy.	('intra-tumoral', 'Disease', (68, 81))	('combination', 'Interaction', (36, 47))	('mouse', 'Species', '10090', (3, 8))	('regressions', 'CPA', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (124, 128))	('survival benefit', 'CPA', (170, 186))	('SS1P', 'Chemical', 'MESH:C474515', (82, 86))	('anti-CTLA-4', 'Var', (51, 62))	('intra-tumoral', 'Disease', 'MESH:D009369', (68, 81))	('anti-CTLA-4', 'Gene', (51, 62))
203059	30441807	In our lab, we develop immunotoxins that use truncated Pseudomonas exotoxin A (PE) as their payload fused to an antibody fragment that targets a tumor antigen.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('antibody', 'cellular_component', 'GO:0019814', ('112', '120'))	('truncated', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('tumor', 'Disease', (145, 150))	('Pseudomonas', 'Species', '287', (55, 66))	('tumor antigen', 'molecular_function', 'GO:0008222', ('145', '158'))	('antibody', 'cellular_component', 'GO:0042571', ('112', '120'))	('antibody', 'cellular_component', 'GO:0019815', ('112', '120'))
203071	30441807	We suspect that the direct cytotoxic effect of SS1P was accompanied by the induction of anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('SS1P', 'Chemical', 'MESH:C474515', (47, 51))	('SS1P', 'Var', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
203078	30441807	SS1P was more cytotoxic than LMB-100.	('SS1P', 'Var', (0, 4))	('cytotoxic', 'CPA', (14, 23))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))
203080	30441807	Extracellular ATP promotes dendritic cell activation and is considered a marker of immunogenic cell death.	('dendritic cell activation', 'CPA', (27, 52))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('promotes', 'PosReg', (18, 26))	('Extracellular', 'Var', (0, 13))	('Extracellular', 'cellular_component', 'GO:0005576', ('0', '13'))	('cell activation', 'biological_process', 'GO:0001775', ('37', '52'))	('cell death', 'biological_process', 'GO:0008219', ('95', '105'))
203083	30441807	This indicates that SS1P induces ATP secretion and that the intensity of ATP secretion is dose-dependent.	('ATP', 'Chemical', 'MESH:D000255', (33, 36))	('ATP secretion', 'MPA', (33, 46))	('induces', 'Reg', (25, 32))	('secretion', 'biological_process', 'GO:0046903', ('37', '46'))	('ATP', 'Chemical', 'MESH:D000255', (73, 76))	('SS1P', 'Chemical', 'MESH:C474515', (20, 24))	('secretion', 'biological_process', 'GO:0046903', ('77', '86'))	('SS1P', 'Var', (20, 24))
203099	30441807	In particular, in cells that were treated with SS1P, the percentage of dead cells increased from 31% at 21 h to 51% at 24 h indicating that cells were actively dying (Figure 3D).	('SS1P', 'Var', (47, 51))	('SS1P', 'Chemical', 'MESH:C474515', (47, 51))	('increased', 'PosReg', (82, 91))
203100	30441807	These results indicate that SS1P causes calreticulin to be translocated to the surface of AE17M cells in a similar manner to oxaliplatin.	('SS1P', 'Var', (28, 32))	('translocated', 'MPA', (59, 71))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (125, 136))	('calreticulin', 'Gene', '12317', (40, 52))	('SS1P', 'Chemical', 'MESH:C474515', (28, 32))	('calreticulin', 'Gene', (40, 52))
203110	30441807	SS1P (10 microg) every four days had a significant reduction in tumor size on days 12, 14, and 16, compared to mice injected with the vehicle alone (p < 0.01).	('reduction', 'NegReg', (51, 60))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (111, 115))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('SS1P', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
203112	30441807	Based on the findings that SS1P enhances markers of immunogenic cell death, we hypothesize that SS1P will render tumors more sensitive to the activity of anti-CTLA-4.	('enhances', 'PosReg', (32, 40))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))	('activity', 'MPA', (142, 150))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('more', 'PosReg', (120, 124))	('SS1P', 'Chemical', 'MESH:C474515', (27, 31))	('markers of immunogenic cell death', 'MPA', (41, 74))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SS1P', 'Var', (27, 31))	('SS1P', 'Chemical', 'MESH:C474515', (96, 100))	('sensitive', 'MPA', (125, 134))	('SS1P', 'Var', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
203121	30441807	anti-CTLA-4, the tumor growth rate was decreased in 3/8 mice and lead to tumor eradication in two mice (Figure 5B).	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('anti-CTLA-4', 'Var', (0, 11))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('anti-CTLA-4', 'Gene', (0, 11))	('decreased', 'NegReg', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mice', 'Species', '10090', (98, 102))
203123	30441807	SS1P, tumor growth delay was noted in all mice and tumors were completely eradicated in seven out of the eight mice (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', (51, 56))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('SS1P', 'Chemical', 'MESH:C474515', (0, 4))	('growth delay', 'Phenotype', 'HP:0001510', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SS1P', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
203126	30441807	A significant survival benefit was noted in mice treated with SS1P and anti-CTLA-4 compared to the control groups (p < 0.05).	('SS1P', 'Var', (62, 66))	('survival', 'CPA', (14, 22))	('benefit', 'PosReg', (23, 30))	('anti-CTLA-4', 'Var', (71, 82))	('mice', 'Species', '10090', (44, 48))	('SS1P', 'Chemical', 'MESH:C474515', (62, 66))
203134	30441807	This result is in accordance with our previous report of a synergy between anti-CTLA-4 and locally injected anti-mesothelin immunotoxins found in the 66C14-M murine tumor model.	('anti-CTLA-4', 'Gene', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('murine', 'Species', '10090', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('anti-CTLA-4', 'Var', (75, 86))	('tumor', 'Disease', (165, 170))
203135	30441807	We found a significant increase in the number of cells that present calreticulin on their membrane and an increase in ATP secretion after exposure to cytotoxic levels of SS1P.	('ATP secretion', 'MPA', (118, 131))	('SS1P', 'Chemical', 'MESH:C474515', (170, 174))	('calreticulin', 'Gene', '12317', (68, 80))	('SS1P', 'Var', (170, 174))	('secretion', 'biological_process', 'GO:0046903', ('122', '131'))	('increase', 'PosReg', (23, 31))	('increase', 'PosReg', (106, 114))	('ATP', 'Chemical', 'MESH:D000255', (118, 121))	('calreticulin', 'Gene', (68, 80))	('membrane', 'cellular_component', 'GO:0016020', ('90', '98'))
203139	30441807	We found that in response to SS1P or LMB-100, ATP is released from dying AE17M cells.	('LMB-100', 'Gene', (37, 44))	('ATP', 'MPA', (46, 49))	('SS1P', 'Chemical', 'MESH:C474515', (29, 33))	('SS1P', 'Var', (29, 33))	('ATP', 'Chemical', 'MESH:D000255', (46, 49))
203144	30441807	Besides inducing immunogenic cell death in cancer cells, immunogenic chemotherapies, such as doxorubicin and oxaliplatin, are myelosuppressive and can induce leukopenia.	('oxaliplatin', 'Var', (109, 120))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('induce', 'Reg', (151, 157))	('cancer', 'Disease', (43, 49))	('leukopenia', 'Phenotype', 'HP:0001882', (158, 168))	('inducing', 'Reg', (8, 16))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))	('cell death', 'biological_process', 'GO:0008219', ('29', '39'))	('leukopenia', 'Disease', 'MESH:D007970', (158, 168))	('leukopenia', 'Disease', (158, 168))
203148	30441807	They found that locally delivered 8H9scFv-PE38 reduced the size of tumors, caused tumor necrosis and prolonged the survival of rats from 24 to 43 days.	('H9', 'CellLine', 'CVCL:1240', (35, 37))	('necrosis', 'biological_process', 'GO:0008220', ('88', '96'))	('rats', 'Species', '10116', (127, 131))	('8H9scFv-PE38', 'Var', (34, 46))	('tumor necrosis', 'Disease', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('necrosis', 'biological_process', 'GO:0001906', ('88', '96'))	('necrosis', 'biological_process', 'GO:0008219', ('88', '96'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('prolonged', 'PosReg', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'CPA', (115, 123))	('tumor necrosis', 'Disease', 'MESH:D009336', (82, 96))	('tumors', 'Disease', (67, 73))	('reduced', 'NegReg', (47, 54))	('necrosis', 'biological_process', 'GO:0070265', ('88', '96'))	('necrosis', 'biological_process', 'GO:0019835', ('88', '96'))
203160	30441807	immunotoxin sensitizes tumors to the therapeutic effect of anti-CTLA-4.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('anti-CTLA-4', 'Var', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
203164	30441807	VB4-845 in cutaneous metastases resulted in the partial or complete regression in many of the injected tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('VB4-845', 'Var', (0, 7))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('regression', 'NegReg', (68, 78))	('metastases', 'Disease', (21, 31))
203197	29651248	Additionally, a recent set of case reports suggests that inhalation of polyacrylate/nanosilica could in part be associated with inflammation and fibrosis of the pleura of factory workers.	('polyacrylate/nanosilica', 'Var', (71, 94))	('fibrosis of the pleura', 'Disease', 'MESH:D005355', (145, 167))	('inflammation', 'Disease', (128, 140))	('pleura of factory workers', 'Phenotype', 'HP:0002102', (161, 186))	('associated', 'Reg', (112, 122))	('inflammation', 'biological_process', 'GO:0006954', ('128', '140'))	('polyacrylate', 'Chemical', '-', (71, 83))	('fibrosis of the pleura', 'Disease', (145, 167))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
203202	29651248	At an organism level, a number of fibrous shaped nanotubes are related with features of chronic inflammation and MWCNT-7 is the only type to consistently inflict mesothelioma.	('MWCNT-7', 'Chemical', '-', (113, 120))	('chronic inflammation', 'Disease', (88, 108))	('chronic inflammation', 'Disease', 'MESH:D007249', (88, 108))	('MWCNT-7', 'Var', (113, 120))	('mesothelioma', 'Disease', (162, 174))	('inflammation', 'biological_process', 'GO:0006954', ('96', '108'))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))	('inflict', 'Reg', (154, 161))
203275	29651248	The key functional role of MMP-2 in CNT induced aggressive phenotypes was revealed with knockdown of MMP-2 by short-hairpin RNA plasmid, which reduced invasion (60-90%) and migration of MeT5A cells (Lohcharoenkal et al.,).	('rat', 'Species', '10116', (176, 179))	('MMP-2', 'Gene', '4313', (101, 106))	('MMP-2', 'Gene', (27, 32))	('MMP-2', 'molecular_function', 'GO:0004228', ('101', '106'))	('migration', 'CPA', (173, 182))	('knockdown', 'Var', (88, 97))	('invasion', 'CPA', (151, 159))	('MMP-2', 'Gene', (101, 106))	('MMP-2', 'molecular_function', 'GO:0004228', ('27', '32'))	('MMP-2', 'Gene', '4313', (27, 32))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))	('reduced', 'NegReg', (143, 150))
203285	29651248	Subsequently, Annexin 1 was validated to contribute in cell migration, as siRNA knockdown significantly reduced the migratory potential of transfected MeT5A cells in a wound healing assay (Ju et al.,).	('siRNA', 'Gene', (74, 79))	('knockdown', 'Var', (80, 89))	('cell migration', 'biological_process', 'GO:0016477', ('55', '69'))	('reduced', 'NegReg', (104, 111))	('wound healing', 'biological_process', 'GO:0042060', ('168', '181'))	('rat', 'Species', '10116', (119, 122))	('Annexin 1', 'Gene', (14, 23))	('rat', 'Species', '10116', (63, 66))	('Annexin 1', 'Gene', '301', (14, 23))
203291	29651248	The pronounced response to nanotube-protein conjugates was driven by cellular transferrin receptor 1, given that knockdown by a specific inhibitor reduced uptake (by 20%) and cellular ferrous content.	('uptake', 'MPA', (155, 161))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('uptake', 'biological_process', 'GO:0098657', ('155', '161'))	('knockdown', 'Var', (113, 122))	('cellular', 'CPA', (175, 183))	('transferrin', 'Gene', '7018', (78, 89))	('uptake', 'biological_process', 'GO:0098739', ('155', '161'))	('transferrin', 'Gene', (78, 89))	('reduced', 'NegReg', (147, 154))
203310	29651248	were one of the first groups to study the role of length in nanotube associated respiratory morbidity following exposure though the airways.	('respiratory morbidity', 'Disease', (80, 101))	('rat', 'Species', '10116', (85, 88))	('nanotube', 'Var', (60, 68))
203333	29651248	If considered together, inflammation and direct genotoxic effects of CNTs may inflict DNA damage particularly in constituent cells of hyperplasic lesions, which more readily accumulate mutations by virtue of their increased proliferation and survival.	('inflict', 'Reg', (78, 85))	('inflammation', 'biological_process', 'GO:0006954', ('24', '36'))	('rat', 'Species', '10116', (231, 234))	('increased', 'PosReg', (214, 223))	('hyperplasic lesions', 'Disease', (134, 153))	('inflammation', 'Disease', 'MESH:D007249', (24, 36))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('mutations', 'Var', (185, 194))	('hyperplasic lesions', 'Disease', 'MESH:D051437', (134, 153))	('survival', 'CPA', (242, 250))	('DNA damage', 'MPA', (86, 96))	('inflammation', 'Disease', (24, 36))
203366	29651248	After 4 weeks, 50 nm CNT induced severe peritonitis, fibrosis and mesothelal proliferation whereas 145 nm and tangled CNT treated rats only showed a mild fibrotic reaction at the deposition site.	('fibrosis', 'Disease', 'MESH:D005355', (53, 61))	('rats', 'Species', '10116', (130, 134))	('peritonitis', 'Disease', (40, 51))	('rat', 'Species', '10116', (84, 87))	('peritonitis', 'Phenotype', 'HP:0002586', (40, 51))	('mesothelal proliferation', 'CPA', (66, 90))	('rat', 'Species', '10116', (130, 133))	('50 nm', 'Var', (15, 20))	('fibrosis', 'Disease', (53, 61))	('peritonitis', 'Disease', 'MESH:D010534', (40, 51))
203369	29651248	Remarkably, MWCNT associated malignancies were predominantly of the sarcomatoid type (86%), which is indicative of their highly aggressive nature, and displayed homozygous CDKN2A/2B tumor suppressor gene deletions, a typical molecular abberration of asbestos induced mosothelioma.	('asbestos induced mosothelioma', 'Disease', (250, 279))	('malignancies', 'Disease', (29, 41))	('CDKN2A/2', 'Gene', '1029', (172, 180))	('tumor', 'Disease', (182, 187))	('sarcomatoid type', 'Disease', 'MESH:C538614', (68, 84))	('asbestos induced mosothelioma', 'Disease', 'MESH:D001195', (250, 279))	('sarcomatoid type', 'Disease', (68, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('182', '198'))	('CDKN2A/2', 'Gene', (172, 180))	('MWCNT', 'Chemical', '-', (12, 17))	('malignancies', 'Disease', 'MESH:D009369', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('deletions', 'Var', (204, 213))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('182', '198'))	('rat', 'Species', '10116', (240, 243))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
203421	29651248	At the moment, only MWCNT-7 is consistently shown to induce mesothelioma whereas other classes of fibrous shaped CNT as well as silver and nickel nanowires are associated with pathological features of inflammation in rodent animal studies.	('inflammation', 'Disease', 'MESH:D007249', (201, 213))	('inflammation', 'biological_process', 'GO:0006954', ('201', '213'))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('inflammation', 'Disease', (201, 213))	('silver', 'Chemical', 'MESH:D012834', (128, 134))	('MWCNT-7', 'Chemical', '-', (20, 27))	('nickel', 'Chemical', 'MESH:D009532', (139, 145))	('MWCNT-7', 'Var', (20, 27))	('mesothelioma', 'Disease', (60, 72))	('induce', 'PosReg', (53, 59))	('associated', 'Reg', (160, 170))
203472	28361465	Peptide mapping methodology shows that up to 70 individual lysine residues are partially modified by linker-payload to an average level of about 4% with a range from 25% to <1%.	('modified', 'Reg', (89, 97))	('lysine', 'Protein', (59, 65))	('lysine', 'Chemical', 'MESH:D008239', (59, 65))	('to 7', 'Species', '1214577', (42, 46))	('linker-payload', 'Var', (101, 115))
203576	28361465	ADCs that have shown promising activity in solid tumors in early phase clinical trials, but that have not yet advanced into pivotal trials, also show most benefit in patients whose tumors express the highest levels of target antigen; for example, lifatuzumab vedotin which targets NaPi2b, and SAR566658 which targets the CA6 antigen of mucin-1.	('solid tumors', 'Disease', (43, 55))	('CA6', 'Gene', (321, 324))	('SAR566658', 'Var', (293, 302))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('lifatuzumab', 'Chemical', '-', (247, 258))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('lifatuzumab', 'Var', (247, 258))	('patients', 'Species', '9606', (166, 174))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('solid tumors', 'Disease', 'MESH:D009369', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('CA6', 'Gene', '765', (321, 324))
203585	28361465	Not only do such ADCs induce immunogenic cell death, but the ADC-mediated tumor accumulation of a potent microtubule agent appears to activate intra-tumor dendritic cells, inducing uptake of antigens and the migration of antigen-loaded dendritic cells to lymph nodes where they can trigger activation of T-cells which may be directed towards tumor-associated antigens.	('inducing', 'PosReg', (172, 180))	('activate', 'PosReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (74, 79))	('microtubule', 'cellular_component', 'GO:0005874', ('105', '116'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('T-cells', 'CPA', (304, 311))	('uptake', 'biological_process', 'GO:0098657', ('181', '187'))	('tumor', 'Disease', (342, 347))	('intra-tumor', 'Disease', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('uptake', 'biological_process', 'GO:0098739', ('181', '187'))	('ADC-mediated', 'Var', (61, 73))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('intra-tumor', 'Disease', 'MESH:D009369', (143, 154))	('migration', 'CPA', (208, 217))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('uptake', 'MPA', (181, 187))	('antigens', 'Protein', (191, 199))
203600	27343465	As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles.	('doubled', 'PosReg', (81, 88))	('PTX-eNPs', 'Chemical', '-', (138, 146))	('PTX', 'Chemical', '-', (138, 141))	('mesothelioma', 'Disease', (58, 70))	('survival', 'CPA', (21, 29))	('PTX', 'Chemical', '-', (204, 207))	('PTX-eNPs', 'Var', (138, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('PTX', 'Chemical', '-', (182, 185))
203651	27343465	Mice received an intraperitoneal (IP) injection of 5 x 106 MSTO-211H or MSTO-211H-Luc cells yielding established tumors within 7-10 days of xenografting.	('MSTO-211H', 'Chemical', '-', (72, 81))	('tumors', 'Disease', (113, 119))	('MSTO-211H', 'Var', (59, 68))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Mice', 'Species', '10090', (0, 4))	('MSTO-211H', 'Chemical', '-', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MSTO-211H-Luc', 'Var', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
203709	27343465	However, the tumor concentration of PTX was significantly higher in PTX-eNP treated mice than in either PTX-PLGA-NP or PTX treated mice (116.0 +- 66.9 mug/g vs. 25.4 +- 28.2 mug/g and 0.37 +- 0.27 mug/g, both P < 0.05; Fig.	('tumor', 'Disease', (13, 18))	('PTX-eNP', 'Var', (68, 75))	('PTX', 'Chemical', '-', (104, 107))	('PTX-eNP', 'Chemical', '-', (68, 75))	('PTX', 'Chemical', '-', (36, 39))	('mug', 'molecular_function', 'GO:0043739', ('174', '177'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mug', 'molecular_function', 'GO:0043739', ('151', '154'))	('higher', 'PosReg', (58, 64))	('mice', 'Species', '10090', (131, 135))	('PTX', 'Chemical', '-', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PTX', 'Chemical', '-', (119, 122))	('mice', 'Species', '10090', (84, 88))	('mug', 'molecular_function', 'GO:0043739', ('197', '200'))
203711	27343465	The % of the total injected dose of PTX remaining in the tumor tissue three days after treatment followed a similar trend with 20 +- 6% for PTX-eNPs vs. 6 +- 7% for PTX-PLGA-eNPs and 0.1 +- 0.1% for PTX.	('PTX', 'Chemical', '-', (165, 168))	('PTX', 'Chemical', '-', (199, 202))	('PTX-eNPs', 'Var', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PTX', 'Chemical', '-', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('PTX-eNPs', 'Chemical', '-', (140, 148))	('PTX', 'Chemical', '-', (140, 143))
203712	27343465	In a second study, PTX concentration within the tumor, peritoneal fluid, and plasma was determined over a 7-day time-course for animals receiving PTX-eNPs or PTX (10 mg/kg PTX for both treatment groups).	('PTX', 'Chemical', '-', (172, 175))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (55, 71))	('tumor', 'Disease', (48, 53))	('PTX-eNPs', 'Var', (146, 154))	('PTX-eNPs', 'Chemical', '-', (146, 154))	('PTX', 'Chemical', '-', (146, 149))	('PTX', 'Chemical', '-', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('PTX', 'Chemical', '-', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
203713	27343465	PTX concentrations within the tumor were significantly higher (4- to over 100-fold) in PTX-eNP treated animals compared to standard PTX treated animals at all time points from 1 hr to 7 days (P < 0.001, Fig.	('PTX', 'Chemical', '-', (0, 3))	('PTX-eNP treated', 'Var', (87, 102))	('to 7', 'Species', '1214577', (181, 185))	('PTX', 'Chemical', '-', (87, 90))	('PTX', 'Chemical', '-', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('higher', 'PosReg', (55, 61))	('PTX-eNP', 'Chemical', '-', (87, 94))	('PTX concentrations', 'MPA', (0, 18))	('tumor', 'Disease', (30, 35))
203717	27343465	Mice with established intraperitoneal mesothelioma xenografts were treated with four weekly doses of PTX (10 mg/kg/dose) formulated as: PTX-eNPs (experimental), PTX-PLGA-NPs (generic NP control), PTX (clinical formulation control) as well as the respective unloaded particle or vehicle controls (i.e., eNPs, PLGA-NPs), or saline (tumor growth control).	('PTX', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (27, 50))	('tumor', 'Disease', (330, 335))	('PTX-PLGA-NPs', 'Var', (161, 173))	('intraperitoneal mesothelioma xenografts', 'Disease', 'MESH:D008654', (22, 61))	('PTX', 'Chemical', '-', (101, 104))	('intraperitoneal mesothelioma', 'Phenotype', 'HP:0100003', (22, 50))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('Mice', 'Species', '10090', (0, 4))	('PTX-eNPs', 'Chemical', '-', (136, 144))	('PTX', 'Chemical', '-', (161, 164))	('saline', 'Chemical', 'MESH:D012965', (322, 328))	('PTX', 'Chemical', '-', (196, 199))	('intraperitoneal mesothelioma xenografts', 'Disease', (22, 61))
203727	27343465	Doubling the number of treatments resulted in a significantly increased median overall survival of 103 days for the PTX-eNP group vs essentially unchanged survival in the PTX group at 49 days (P < 0.01) (Fig.	('PTX', 'Chemical', '-', (116, 119))	('increased', 'PosReg', (62, 71))	('PTX-eNP', 'Var', (116, 123))	('PTX-eNP', 'Chemical', '-', (116, 123))	('PTX', 'Chemical', '-', (171, 174))
203781	27343465	We therefore employed a second, standard strategy, co-treating the cells with particles and bafilomycin:bafilomycin is a V-ATPase inhibitor and thereby prevents acidification of lysosomes and, subsequently, the merging of lysosomes with autophagosomes resulting in the accumulation of autophagosomes (i.e., inhibition of autophagic degradation and flux).	('prevents', 'NegReg', (152, 160))	('acidification', 'MPA', (161, 174))	('bafilomycin', 'Var', (104, 115))	('V-ATPase', 'cellular_component', 'GO:0000219', ('121', '129'))	('inhibition', 'NegReg', (307, 317))	('bafilomycin', 'Chemical', '-', (104, 115))	('accumulation', 'PosReg', (269, 281))	('autophagic degradation', 'CPA', (321, 343))	('autophagosomes', 'CPA', (285, 299))	('V-ATPase', 'cellular_component', 'GO:0008245', ('121', '129'))	('degradation', 'biological_process', 'GO:0009056', ('332', '343'))	('bafilomycin', 'Chemical', '-', (92, 103))	('acidification', 'biological_process', 'GO:0045851', ('161', '174'))
203783	27343465	This trend suggests that PLGA-NPs and neNPs do not inhibit autophagic degradation because co-treatment with bafilomycin leads to a further increase in LC3-II (indicating an accumulation of autophagosomes mainly due to the latter inhibition of autophagic degradation by bafilomycin and not by PLGA-NPs/neNPs).	('LC3', 'Gene', '84557', (151, 154))	('LC3', 'Gene', (151, 154))	('bafilomycin', 'Var', (108, 119))	('degradation', 'biological_process', 'GO:0009056', ('70', '81'))	('autophagosomes', 'CPA', (189, 203))	('inhibition', 'NegReg', (229, 239))	('bafilomycin', 'Chemical', '-', (269, 280))	('increase', 'PosReg', (139, 147))	('bafilomycin', 'Chemical', '-', (108, 119))	('accumulation', 'PosReg', (173, 185))	('autophagic degradation', 'CPA', (243, 265))	('degradation', 'biological_process', 'GO:0009056', ('254', '265'))
203799	27343465	Given the higher and more prolonged intratumoral drug concentrations noted when PTX was delivered via PTX-eNPs compared to PTX in Cremophor EL, we hypothesized that PTX-eNPs would lead to improved efficacy and thus prolong survival in a murine model of human intraperitoneal mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('PTX', 'Chemical', '-', (80, 83))	('survival', 'CPA', (223, 231))	('murine', 'Species', '10090', (237, 243))	('PTX', 'Chemical', '-', (102, 105))	('PTX', 'Chemical', '-', (165, 168))	('prolong', 'PosReg', (215, 222))	('PTX-eNPs', 'Var', (165, 173))	('PTX', 'Chemical', '-', (123, 126))	('PTX-eNPs', 'Chemical', '-', (102, 110))	('human', 'Species', '9606', (253, 258))	('improved', 'PosReg', (188, 196))	('peritoneal mesothelioma', 'Disease', (264, 287))	('PTX-eNPs', 'Chemical', '-', (165, 173))	('tumor', 'Disease', (41, 46))	('Cremophor EL', 'Chemical', 'MESH:C000515', (130, 142))	('peritoneal mesothelioma', 'Disease', 'MESH:D008654', (264, 287))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('efficacy', 'MPA', (197, 205))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (264, 287))	('intraperitoneal mesothelioma', 'Phenotype', 'HP:0100003', (259, 287))
203805	27343465	This resulted in a significantly longer median overall survival following treatment with PTX-eNPs (72 days) vs. PTX and PTX-PLGA-NPs (46 and 43 days, respectively; P < 0.05).	('PTX-eNPs', 'Chemical', '-', (89, 97))	('PTX-eNPs', 'Var', (89, 97))	('PTX', 'Chemical', '-', (89, 92))	('overall survival', 'MPA', (47, 63))	('PTX', 'Chemical', '-', (112, 115))	('PTX', 'Chemical', '-', (120, 123))	('longer', 'PosReg', (33, 39))
203817	27343465	Given the importance of both concentration and duration of exposure to the effectiveness of PTX, the multiple order-of-magnitude increase in tumoral concentration maintained over a prolonged timeframe as described above is certainly one of the reasons for the significantly improved overall survival with PTX-eNPs as compared to PTX.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PTX-eNPs', 'Var', (305, 313))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('PTX', 'Chemical', '-', (305, 308))	('increase', 'PosReg', (129, 137))	('overall survival', 'MPA', (283, 299))	('PTX', 'Chemical', '-', (92, 95))	('improved', 'PosReg', (274, 282))	('PTX-eNPs', 'Chemical', '-', (305, 313))	('PTX', 'Chemical', '-', (329, 332))
203853	27045023	One peptide, called "regulatory subunit I anchoring disruptor" (RIAD), displaced PKA from lipid rafts and ultimately diminished phosphorylation of Y505 on Lck, leading to upregulated T-cell signaling.	('T-cell signaling', 'MPA', (183, 199))	('Y505', 'Var', (147, 151))	('RIAD', 'Disease', (64, 68))	('upregulated', 'PosReg', (171, 182))	('RIAD', 'Disease', 'None', (64, 68))	('Lck', 'Protein', (155, 158))	('diminished', 'NegReg', (117, 127))	('phosphorylation', 'MPA', (128, 143))	('lipid', 'Chemical', 'MESH:D008055', (90, 95))
203856	27045023	Given the key role of PKA signaling in the inhibition of T-cell function in tumors and our ability to genetically manipulate T cells for adoptive transfer, we hypothesized that cloning the RISR-RIAD transgene (referred to as RIAD henceforth) into T cells also expressing a CAR would enhance their function within the tumor microenvironment and result in superior tumoricidal ability as compared to CAR T cells alone.	('RIAD', 'Disease', (194, 198))	('RIAD', 'Disease', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('RIAD henceforth', 'Disease', (225, 240))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('enhance', 'PosReg', (283, 290))	('CAR', 'cellular_component', 'GO:0005826', ('273', '276'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('RIAD', 'Disease', 'None', (225, 229))	('RIAD', 'Disease', 'None', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('PKA', 'cellular_component', 'GO:0005952', ('22', '25'))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('tumor', 'Disease', (317, 322))	('PKA', 'molecular_function', 'GO:0004691', ('22', '25'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('CAR', 'cellular_component', 'GO:0005826', ('398', '401'))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('cloning', 'Var', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('RIAD henceforth', 'Disease', 'None', (225, 240))	('inhibition of T-cell function', 'Phenotype', 'HP:0005435', (43, 72))	('function', 'MPA', (297, 305))	('superior', 'PosReg', (354, 362))
203871	27045023	The following conjugated antibodies for flow cytometric analysis of murine cells were purchased from Biolegend: CD8 (#100762), CD4 (#100406), IFNgamma (#505825), IL2 (#503808), and anti-GFP (#338008).	('CD8', 'Gene', (112, 115))	('IL2', 'molecular_function', 'GO:0005134', ('162', '165'))	('#503808', 'Var', (167, 174))	('#100406', 'Var', (132, 139))	('CD8', 'Gene', '925', (112, 115))	('murine', 'Species', '10090', (68, 74))	('#100762', 'Var', (117, 124))	('#338008', 'Var', (191, 198))	('#505825', 'Var', (152, 159))
203872	27045023	For human cells, the following were purchased from Biolegend: FOXP3 (#320106); BD Biosciences: CD45 (#555483), CD8 (#555367), IL2 (#340448), CD69 (#555530), IFNgamma (#562016), and TNFalpha (#340511); and R&D Biosystems: human mesothelin (FAB32652P).	('#555483', 'Var', (101, 108))	('human', 'Species', '9606', (4, 9))	('FOXP3', 'Gene', (62, 67))	('IL2', 'molecular_function', 'GO:0005134', ('126', '129'))	('TNFalpha', 'Gene', (181, 189))	('CD69', 'Gene', '969', (141, 145))	('#340448', 'Var', (131, 138))	('#340511', 'Var', (191, 198))	('FOXP3', 'Gene', '50943', (62, 67))	('#555530', 'Var', (147, 154))	('CD69', 'Gene', (141, 145))	('#555367', 'Var', (116, 123))	('TNFalpha', 'Gene', '7124', (181, 189))	('human', 'Species', '9606', (221, 226))	('#320106', 'Var', (69, 76))	('CD8', 'Gene', (111, 114))	('#562016', 'Var', (167, 174))	('CD8', 'Gene', '925', (111, 114))
203911	27045023	2A, left panel), mesoCAR-RIAD T cells showed some evidence of basal activation with increased phosphorylation of LckY394 (an activated form of Lck) and Akt compared with mesoCAR T cells.	('CAR-RIAD', 'Disease', (21, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('LckY394', 'Var', (113, 120))	('CAR-RIAD', 'Disease', 'MESH:D056733', (21, 29))	('Akt', 'Pathway', (152, 155))	('activation', 'PosReg', (68, 78))	('basal', 'MPA', (62, 67))	('increased', 'PosReg', (84, 93))	('phosphorylation', 'MPA', (94, 109))
203919	27045023	PKA regulates T-cell signaling by phosphorylating the kinase Csk at S364, which leads to phosphorylation of the key TCR proximal signaling molecule, Lck, at Y505, a change that inhibits the activity of Lck.	('T-cell signaling', 'MPA', (14, 30))	('phosphorylation', 'MPA', (89, 104))	('PKA', 'molecular_function', 'GO:0004691', ('0', '3'))	('signaling molecule', 'molecular_function', 'GO:0048018', ('129', '147'))	('at Y505', 'Var', (154, 161))	('PKA', 'cellular_component', 'GO:0005952', ('0', '3'))	('activity', 'MPA', (190, 198))	('Csk', 'Gene', '12988', (61, 64))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('regulates', 'Reg', (4, 13))	('TCR', 'cellular_component', 'GO:0042101', ('116', '119'))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('TCR', 'Gene', (116, 119))	('TCR', 'biological_process', 'GO:0006283', ('116', '119'))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('Csk', 'Gene', (61, 64))	('TCR', 'Gene', '328483', (116, 119))
203922	27045023	To compare the ability of mesoCAR-RIAD T cells versus mesoCAR T cells to control tumor burden, we used two tumor models that have produce more PGE2 compared to normal lung or liver tissue (Supplemental Fig.	('PGE2', 'Chemical', 'MESH:D015232', (143, 147))	('CAR-RIAD', 'Disease', (30, 38))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CAR-RIAD', 'Disease', 'MESH:D056733', (30, 38))	('PGE2', 'Var', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (81, 86))
203953	27045023	Although adoptive T cell therapy using chimeric antigen receptors (CARs) for cancer has shown great promise in the treatment of blood-borne malignancies, their application in the treatment in solid tumors has not yet been as successful.	('blood-borne malignancies', 'Disease', (128, 152))	('solid tumors', 'Disease', (192, 204))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('solid tumors', 'Disease', 'MESH:D009369', (192, 204))	('chimeric', 'Var', (39, 47))	('blood-borne malignancies', 'Disease', 'MESH:D009369', (128, 152))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
203959	27045023	In this study, we demonstrated the importance of adenosine and PGE2 in CAR dysfunction by showing that the presence of either agent during coculture of CAR T cells with tumor cells results in a decrease in tumor cell killing.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('presence', 'Var', (107, 115))	('adenosine', 'Chemical', 'MESH:D000241', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('PGE2', 'Chemical', 'MESH:D015232', (63, 67))	('tumor', 'Disease', (206, 211))	('cell killing', 'biological_process', 'GO:0001906', ('212', '224'))	('CAR', 'cellular_component', 'GO:0005826', ('71', '74'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('CAR dysfunction', 'Disease', (71, 86))	('CAR', 'cellular_component', 'GO:0005826', ('152', '155'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('decrease', 'NegReg', (194, 202))
203962	27045023	Consistent with our proposed mechanism, we saw a decrease in the baseline phosphorylation of Csk at S364 and reduced phosphorylation of Lck at Y505 in the CAR-RIAD cells.	('baseline phosphorylation', 'MPA', (65, 89))	('CAR', 'cellular_component', 'GO:0005826', ('155', '158'))	('CAR-RIAD', 'Disease', (155, 163))	('Lck', 'Protein', (136, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('Csk', 'Gene', (93, 96))	('at S364', 'Var', (97, 104))	('decrease', 'NegReg', (49, 57))	('phosphorylation', 'MPA', (117, 132))	('CAR-RIAD', 'Disease', 'MESH:D056733', (155, 163))	('reduced', 'NegReg', (109, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('Csk', 'Gene', '12988', (93, 96))
203988	27045023	This observation fits with our data showing that inhibition of PKA by RIAD augmented T cell migration and adhesion in vitro and T cell migration in vivo.	('T cell migration', 'CPA', (85, 101))	('RIAD', 'Disease', 'None', (70, 74))	('T cell migration', 'biological_process', 'GO:0072678', ('128', '144'))	('fits', 'Disease', (17, 21))	('T cell migration', 'biological_process', 'GO:0072678', ('85', '101'))	('PKA', 'Gene', (63, 66))	('PKA', 'molecular_function', 'GO:0004691', ('63', '66'))	('T cell migration', 'CPA', (128, 144))	('PKA', 'cellular_component', 'GO:0005952', ('63', '66'))	('fits', 'Disease', 'MESH:D012640', (17, 21))	('inhibition', 'Var', (49, 59))	('adhesion', 'CPA', (106, 114))	('RIAD', 'Disease', (70, 74))	('augmented', 'PosReg', (75, 84))
204074	24240684	In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence.	('OCT4', 'Gene', (37, 41))	('reintroduction', 'Var', (19, 33))	('replicative senescence', 'biological_process', 'GO:0090399', ('117', '139'))	('OCT4', 'Gene', '5460', (37, 41))
204082	24240684	MicroRNAs (miRs) are short (17-22 nucleotides) noncoding RNAs that regulate gene expression by inhibiting protein translation, through base-pairing mediated interaction with the 3'UTR of target mRNAs.	('protein translation', 'biological_process', 'GO:0006412', ('106', '125'))	('inhibiting', 'NegReg', (95, 105))	('interaction', 'Interaction', (157, 168))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('protein translation', 'MPA', (106, 125))	('gene expression', 'MPA', (76, 91))	('base-pairing', 'Var', (135, 147))	('base-pairing', 'molecular_function', 'GO:0003676', ('135', '147'))	('expression', 'Species', '29278', (81, 91))
204097	24240684	Additionally, transfection of mimic-145 into MSTO-211H cells strongly reduced tumor engraftment in vivo.	('reduced', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('transfection', 'Var', (14, 26))	('mimic-145', 'Gene', (30, 39))	('tumor', 'Disease', (78, 83))
204137	24240684	SA-beta-galactosidase staining (at pH 6) of both MSTO-211H and NCI-H2052 cells transfected with ctrl or mimic-145 revealed strong staining in most of the cells expressing mimic-145, with no or little staining observed in the control cells at 5 days after transfection (Fig.	('mimic-145', 'Var', (171, 180))	('staining', 'MPA', (130, 138))	('beta-galactosidase', 'Gene', '2720', (3, 21))	('NCI-H2052 cells', 'CellLine', 'CVCL:1518', (63, 78))	('beta-galactosidase', 'Gene', (3, 21))
204139	24240684	This revealed a significant reduction of both lamin B1 and AcH3K9 and induction of the p21 proteins in both mesothelioma cell lines transfected with mimic-145 (as compared to ctrl-transfected cells)(Fig.	('p21', 'Gene', '1026', (87, 90))	('lamin B1', 'Gene', (46, 54))	('mesothelioma', 'Disease', (108, 120))	('AcH3K9', 'Protein', (59, 65))	('p21', 'Gene', (87, 90))	('induction', 'PosReg', (70, 79))	('mesothelioma', 'Disease', 'MESH:D008654', (108, 120))	('mimic-145', 'Var', (149, 158))	('lamin B1', 'Gene', '4001', (46, 54))	('reduction', 'NegReg', (28, 37))
204142	24240684	Altogether, these observations support the idea that mir-145 expression induces senescence in MPM cells and that induction of replicative senescence may mediate the anti-clonogenic effects of mimic-145 transfection.	('mir-145', 'Gene', '406937', (53, 60))	('induces', 'Reg', (72, 79))	('expression', 'Var', (61, 71))	('replicative senescence', 'biological_process', 'GO:0090399', ('126', '148'))	('senescence', 'MPA', (80, 90))	('expression', 'Species', '29278', (61, 71))	('senescence', 'biological_process', 'GO:0010149', ('80', '90'))	('mir-145', 'Gene', (53, 60))	('anti-clonogenic effects', 'CPA', (165, 188))
204149	24240684	Additionally, such effect was specific for mir-145, since it was abolished in cells transfected with a mutant 3'UTR construct unable to bind to mir-145 (Fig 3A).	('mir-145', 'Gene', (43, 50))	('mutant', 'Var', (103, 109))	('mir-145', 'Gene', (144, 151))	('mir-145', 'Gene', '406937', (43, 50))	('bind', 'Interaction', (136, 140))	('mir-145', 'Gene', '406937', (144, 151))	('unable', 'NegReg', (126, 132))
204158	24240684	Western blotting analysis of lysates derived from control- and mimic-145 transfected cells revealed in fact significantly lower levels of ZEB1 protein in both mimic-145 treated MSTO-211H and NCI-H2052 cells (Suppl.	('lower', 'NegReg', (122, 127))	('NCI-H2052 cells', 'CellLine', 'CVCL:1518', (191, 206))	('ZEB1 protein', 'Protein', (138, 150))	('levels', 'MPA', (128, 134))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('mimic-145', 'Var', (159, 168))
204160	24240684	This revealed that mimic-145 transfection strongly reduced the number of OCT4-positive cells (8.94% +- 2.2 vs 1.94 +- 0.8% for ctrl- and mimic-145 transfected cells, respectively) (Fig.	('OCT4', 'Gene', '5460', (73, 77))	('reduced', 'NegReg', (51, 58))	('OCT4', 'Gene', (73, 77))	('mimic-145', 'Gene', (19, 28))	('transfection', 'Var', (29, 41))
204168	24240684	To correlate the anti-cancer effects of mimic-145 with its activity toward the OCT4 gene product, we hypothesized that mimic-145 may antagonize the increase of OCT4 induced by pemetrexed treatment.	('activity', 'MPA', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('OCT4', 'Gene', '5460', (160, 164))	('cancer', 'Disease', (22, 28))	('OCT4', 'Gene', (160, 164))	('mimic-145', 'Var', (119, 128))	('mimic-145', 'Gene', (40, 49))	('antagonize', 'NegReg', (133, 143))	('pemetrexed', 'Chemical', 'MESH:D000068437', (176, 186))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('OCT4', 'Gene', '5460', (79, 83))	('OCT4', 'Gene', (79, 83))
204179	24240684	Further, we evaluated the effect of OCT4 overexpression on the extent of cell senescence induced by the expression of mimic-145 (Fig.	('OCT4', 'Gene', '5460', (36, 40))	('expression', 'Species', '29278', (45, 55))	('expression', 'Species', '29278', (104, 114))	('OCT4', 'Gene', (36, 40))	('senescence', 'biological_process', 'GO:0010149', ('78', '88'))	('mimic-145', 'Var', (118, 127))
204188	24240684	This revealed a dramatic change in the methylation status of the CpG islands in the cells treated with 5'AZA (Suppl.	("5'AZA (Suppl", 'Chemical', '-', (103, 115))	("5'AZA", 'Var', (103, 108))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('change', 'Reg', (25, 31))	('methylation status', 'MPA', (39, 57))	('CpG', 'Protein', (65, 68))
204196	24240684	Notably, some of the microRNAs identified in this study have been found by others and already shown to possess the power to discriminate between lung adenocarcinoma and mesothelioma tissues (mir-141, mir-200c, mir-193).	('mir-200c', 'Gene', (200, 208))	('mir-141', 'Gene', '406933', (191, 198))	('mir-141', 'Gene', (191, 198))	('mir-200c', 'Gene', '406985', (200, 208))	('lung adenocarcinoma and mesothelioma', 'Disease', 'MESH:D000077192', (145, 181))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('mir-193', 'Var', (210, 217))
204197	24240684	On the other hand, some other microRNAs (mir-145, mir-204, mir-486-5p, mir-1287) have not been described yet for mesothelioma, to the best of our knowledge.	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('mir-145', 'Gene', (41, 48))	('mesothelioma', 'Disease', (113, 125))	('mir-486-5p', 'Var', (59, 69))	('mir-204', 'Gene', '406987', (50, 57))	('mir-145', 'Gene', '406937', (41, 48))	('mir-204', 'Gene', (50, 57))	('mir-1287', 'Var', (71, 79))
204199	24240684	We provide evidence here that hypermethylation of mir-145 regulatory region is responsible for the low levels of this microRNA in both malignant mesothelial tissues and mesothelioma cell lines.	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('mir-145', 'Gene', '406937', (50, 57))	('mesothelioma', 'Disease', (169, 181))	('mir-145', 'Gene', (50, 57))	('hypermethylation', 'Var', (30, 46))
204203	24240684	Indeed, proliferation, clonal growth and migration of MPM cells are readily reduced by the transfection of "mimic" compounds and in vivo tumorigenicity is reduced as well.	('transfection', 'Var', (91, 103))	('migration', 'CPA', (41, 50))	('tumor', 'Disease', (137, 142))	('reduced', 'NegReg', (155, 162))	('clonal growth', 'CPA', (23, 36))	('proliferation', 'CPA', (8, 21))	('reduced', 'NegReg', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
204208	24240684	In fact, add-back of OCT4 into mimic-145 treated MPM cells at least partially restores the clonogenicity of the cells, while reducing significantly the number of senescent cells.	('restores', 'PosReg', (78, 86))	('add-back', 'Var', (9, 17))	('clonogenicity of the cells', 'CPA', (91, 117))	('reducing', 'NegReg', (125, 133))	('OCT4', 'Gene', '5460', (21, 25))	('OCT4', 'Gene', (21, 25))
204209	24240684	These observations agree with the data from Beltran et al., showing that lentiviral expression of OCT4 in human mammary epithelial cells (HMECs) can "bypass" the spontaneous senescence occurring in those primary cultures after few passages.	('human', 'Species', '9606', (106, 111))	('spontaneous senescence', 'MPA', (162, 184))	('expression', 'Species', '29278', (84, 94))	('OCT4', 'Gene', '5460', (98, 102))	('OCT4', 'Gene', (98, 102))	('senescence', 'biological_process', 'GO:0010149', ('172', '182'))	('lentiviral expression', 'Var', (73, 94))
204259	24240684	The cells were subjected to immunofluorescence staining with Oct-3/4 Prediluted Monoclonal Antibody (PM 313 AA, BIOCARE Medical, Concord, CA 94520 USA) for 2 h at room temperature.	('PM', 'Var', (101, 103))	('Oct-3/4', 'Gene', '5460', (61, 68))	('Oct-3/4', 'Gene', (61, 68))
204275	25823924	Elimination of Snail restored p53 expression.	('Elimination', 'Var', (0, 11))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('Snail', 'Gene', '6615', (15, 20))	('Snail', 'Gene', (15, 20))
204294	25823924	Finally, we revealed that inhibition of Snail-p53 interaction could restore the tumor suppressive role of p53 in MPM cell line.	('p53', 'Gene', '7157', (106, 109))	('Snail', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('restore', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Snail', 'Gene', '6615', (40, 45))	('p53', 'Gene', (46, 49))	('inhibition', 'Var', (26, 36))	('tumor', 'Disease', (80, 85))	('p53', 'Gene', '7157', (46, 49))	('interaction', 'Interaction', (50, 61))	('p53', 'Gene', (106, 109))
204311	25823924	Thus, PD98059 or U0126 did not show obvious growth suppression effect on MPM cell lines (Supplementary Figure 1B and 1C).	('U0126', 'Chemical', 'MESH:C113580', (17, 22))	('Supplementary Figure 1B', 'Disease', (89, 112))	('PD98059', 'Var', (6, 13))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (89, 112))	('PD98059', 'Chemical', 'MESH:C093973', (6, 13))	('U0126', 'Var', (17, 22))
204331	25823924	For example, RKIP was reduced in p53 null H1299 and mutated H23.	('null H1299', 'Var', (37, 47))	('mutated', 'Var', (52, 59))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('RKIP', 'Gene', '5037', (13, 17))	('reduced', 'NegReg', (22, 29))	('RKIP', 'Gene', (13, 17))	('H1299', 'CellLine', 'CVCL:0060', (42, 47))	('H23', 'Gene', (60, 63))
204332	25823924	Instead, transfection of RKIP could increase p53 expression as dosage-dependent manner (Figure 3B).	('p53', 'Gene', (45, 48))	('RKIP', 'Gene', (25, 29))	('p53', 'Gene', '7157', (45, 48))	('increase', 'PosReg', (36, 44))	('RKIP', 'Gene', '5037', (25, 29))	('transfection', 'Var', (9, 21))
204341	25823924	In fact, H28 and H2452 are different pathological types (sarcomatoid vs epithelial MPM).	('H28', 'Var', (9, 12))	('sarcomatoid', 'Disease', (57, 68))	('H2452', 'Var', (17, 22))	('H2452', 'Chemical', '-', (17, 22))	('sarcomatoid', 'Disease', 'MESH:C538614', (57, 68))
204356	25823924	Consistently with p53 induction, cell viability was also decreased by GN25 in H28 and A549 (Figure 4I).	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('GN25', 'Chemical', '-', (70, 74))	('GN25', 'Var', (70, 74))	('cell viability', 'CPA', (33, 47))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('decreased', 'NegReg', (57, 66))
204357	25823924	Although we observed partial reduction of cell viability in H2452 by GN25, it seems to be not related with p53 (Figure 4I).	('GN25', 'Chemical', '-', (69, 73))	('cell viability', 'CPA', (42, 56))	('GN25', 'Var', (69, 73))	('H2452', 'Var', (60, 65))	('p53', 'Gene', (107, 110))	('reduction', 'NegReg', (29, 38))	('p53', 'Gene', '7157', (107, 110))	('H2452', 'Chemical', '-', (60, 65))
204369	25823924	In addition, p53 reduction (Figure 5C) and p-Erk induction by silica and Snail (Supplementary Figure S4C) were abolished by NF2 transfection.	('Erk', 'molecular_function', 'GO:0004707', ('45', '48'))	('Erk', 'Gene', (45, 48))	('NF2', 'Gene', (124, 127))	('Erk', 'Gene', '5594', (45, 48))	('Snail', 'Gene', (73, 78))	('induction', 'MPA', (49, 58))	('abolished', 'NegReg', (111, 120))	('transfection', 'Var', (128, 140))	('p53', 'Gene', (13, 16))	('NF2', 'Gene', '4771', (124, 127))	('Snail', 'Gene', '6615', (73, 78))	('reduction', 'NegReg', (17, 26))	('p53', 'Gene', '7157', (13, 16))	('silica', 'Chemical', 'MESH:D012822', (62, 68))
204374	25823924	Moreover, transfection of NF2 into H28 could induce p53 expression in nucleus (Figure 5G).	('NF2', 'Gene', '4771', (26, 29))	('induce', 'PosReg', (45, 51))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('nucleus', 'cellular_component', 'GO:0005634', ('70', '77'))	('expression', 'MPA', (56, 66))	('transfection', 'Var', (10, 22))	('NF2', 'Gene', (26, 29))
204378	25823924	Consistently with our GST-pull down results, interaction between NF2 and Snail was increased by silica-treatment, whereas RKIP-NF2 binding was reduced (Figure 6C).	('NF2', 'Gene', (127, 130))	('increased', 'PosReg', (83, 92))	('NF2', 'Gene', (65, 68))	('silica', 'Chemical', 'MESH:D012822', (96, 102))	('interaction', 'Interaction', (45, 56))	('NF2', 'Gene', '4771', (127, 130))	('Snail', 'Gene', '6615', (73, 78))	('NF2', 'Gene', '4771', (65, 68))	('silica-treatment', 'Var', (96, 112))	('binding', 'Interaction', (131, 138))	('binding', 'molecular_function', 'GO:0005488', ('131', '138'))	('RKIP', 'Gene', '5037', (122, 126))	('RKIP', 'Gene', (122, 126))	('Snail', 'Gene', (73, 78))
204405	25823924	Although we also observed the reduction of cell viability in H2452 by GN25 (Figure 4I), it would be resulted from p53 independent mechanism.	('GN25', 'Chemical', '-', (70, 74))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('H2452', 'Var', (61, 66))	('reduction', 'NegReg', (30, 39))	('GN25', 'Gene', (70, 74))	('H2452', 'Chemical', '-', (61, 66))	('cell viability', 'CPA', (43, 57))
204411	25823924	Indeed, we could observe the increase of cell size by NF2 transfection (Figure 5G) that is one of important feature of Hippo pathway.	('NF2', 'Gene', '4771', (54, 57))	('increase', 'PosReg', (29, 37))	('cell size', 'CPA', (41, 50))	('transfection', 'Var', (58, 70))	('NF2', 'Gene', (54, 57))
204419	25823924	Our results are consistent with previous hypothesis that cytotoxic stresses (in our case, silica or asbestos) provide selective pressure and resistant clones against this pressure by genetic or non-genetic signaling alternation (RKIP reduced or NF2 mutated cells) would be founder of cancer.	('NF2', 'Gene', '4771', (245, 248))	('asbestos', 'Chemical', 'MESH:D001194', (100, 108))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('silica', 'Chemical', 'MESH:D012822', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('RKIP', 'Gene', '5037', (229, 233))	('NF2', 'Gene', (245, 248))	('RKIP', 'Gene', (229, 233))	('mutated', 'Var', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))
204439	25823924	The following antibodies were used in this study: HA (sc-7392), His (sc-8036), GFP (sc-9996), GST (sc-138), RKIP (sc-5426), SNAIL (sc-28199), p53 (sc-126), NF2 (sc-331), beta-catenin (sc-7963), Actin (se-1616) and E-cadherin (sc-8426) were purchased from Santa Cruz biotechnology (Santa Cruz, CA, USA).	('SNAIL', 'Gene', '6615', (124, 129))	('SNAIL', 'Gene', (124, 129))	('se-1616', 'Var', (201, 208))	('RKIP', 'Gene', '5037', (108, 112))	('p53', 'Gene', (142, 145))	('E-cadherin', 'Gene', (214, 224))	('RKIP', 'Gene', (108, 112))	('E-cadherin', 'Gene', '999', (214, 224))	('p53', 'Gene', '7157', (142, 145))	('beta-catenin', 'Gene', (170, 182))	('NF2', 'Gene', (156, 159))	('cadherin', 'molecular_function', 'GO:0008014', ('216', '224'))	('sc-7963', 'Var', (184, 191))	('sc-8426', 'Var', (226, 233))	('beta-catenin', 'Gene', '1499', (170, 182))	('NF2', 'Gene', '4771', (156, 159))
204440	25823924	Anti-HER2/Neu (MAB3782) and anti-FLAG (F3165) was obtained from Millipore (Billerica, MA, USA) and Sigma Aldrich (St, Louis, Mo, USA), respectively.	('HER2/Neu', 'Gene', (5, 13))	('MAB3782', 'Var', (15, 22))	('HER2/Neu', 'Gene', '2064', (5, 13))
204490	24146039	As a control for the RT-PCR, beta-actin mRNA was amplified using the following beta-actin-specific primers: sense, 5'-CCGCGAGAAG ATGACCCAGA-3' and antisense, 5'-CAGGAGGAGCAATG ATCTTG-3'.	('C', 'Chemical', 'MESH:D002244', (121, 122))	('beta-actin', 'Gene', '728378', (29, 39))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('beta-actin', 'Gene', (29, 39))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('beta-actin', 'Gene', '728378', (79, 89))	('beta-actin', 'Gene', (79, 89))	('C', 'Chemical', 'MESH:D002244', (25, 26))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('C', 'Chemical', 'MESH:D002244', (161, 162))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('antisense', 'Var', (147, 156))	('C', 'Chemical', 'MESH:D002244', (178, 179))
204555	24146039	In the present study, C-ERC/mesothelin positivity was detected in 5 of 6 gastric cancer cell lines (83.3%).	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('detected', 'Reg', (54, 62))	('ERC', 'cellular_component', 'GO:0055037', ('24', '27'))	('C-ERC/mesothelin', 'Gene', (22, 38))	('positivity', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (73, 87))	('C-ERC/mesothelin', 'Gene', '10232', (22, 38))
204612	32664372	The following gene expression assays were obtained from the Thermo Fisher Scientific: POU5F1 (Hs00999632_g1), NANOG (Hs04260366_g1), SOX2 (Hs01053049_s1), KRT5 (Hs00361185_m1), WT1 (Hs01103751_m1), PI3KCA (Hs00907957_m1), PIK3CD (Hs00192399_m1), AKT1 (Hs00178289_m1), AKT2 (Hs01086102_m1), AKT3 (Hs00987350_m1), BCL2 (Hs00608023_m1) and RPLP0 (Hs00420895_gH).	('RPLP0', 'Gene', '6175', (337, 342))	('AKT2', 'Gene', (268, 272))	('BCL2', 'molecular_function', 'GO:0015283', ('312', '316'))	('PIK3CD', 'Gene', (222, 228))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('AKT3', 'Gene', '10000', (290, 294))	('BCL2', 'Gene', '596', (312, 316))	('WT1', 'Gene', (177, 180))	('POU5F1', 'Gene', '5460', (86, 92))	('Hs00907957_m1', 'Var', (206, 219))	('KRT5', 'Gene', '3852', (155, 159))	('AKT3', 'Gene', (290, 294))	('Hs00192399_m1', 'Var', (230, 243))	('WT1', 'Gene', '7490', (177, 180))	('Hs00987350_m1', 'Var', (296, 309))	('BCL2', 'Gene', (312, 316))	('Hs00178289_m1', 'Var', (252, 265))	('RPLP0', 'Gene', (337, 342))	('KRT5', 'Gene', (155, 159))	('Hs01086102_m1', 'Var', (274, 287))	('PIK3CD', 'Gene', '5293', (222, 228))	('POU5F1', 'Gene', (86, 92))	('AKT2', 'Gene', '208', (268, 272))	('Hs01053049_s1', 'Var', (139, 152))	('NANOG', 'Gene', '79923', (110, 115))	('Hs01103751_m1', 'Var', (182, 195))	('Hs00608023_m1', 'Var', (318, 331))	('NANOG', 'Gene', (110, 115))
204632	32664372	The mesothelioma samples used for testing OCT4, NANOG and SOX2 expression were also used for investigating the expression of phosphorylated (activated) PI3K (Tyr607; p-PI3K), phosphorylated/activated AKT (Ser473; p-AKT) and BCL2 (Figure 2).	('Ser473;', 'Var', (205, 212))	('BCL2', 'Gene', '596', (224, 228))	('AKT', 'Gene', '207', (200, 203))	('mesothelioma', 'Disease', (4, 16))	('Tyr607', 'Chemical', '-', (158, 164))	('AKT', 'Gene', '207', (215, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('NANOG', 'Gene', '79923', (48, 53))	('Ser473', 'Chemical', '-', (205, 211))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('BCL2', 'Gene', (224, 228))	('AKT', 'Gene', (200, 203))	('mesothelioma', 'Disease', 'MESH:D008654', (4, 16))	('Tyr607; p-PI3K', 'Var', (158, 172))	('AKT', 'Gene', (215, 218))	('NANOG', 'Gene', (48, 53))	('Ser', 'cellular_component', 'GO:0005790', ('205', '208'))	('BCL2', 'molecular_function', 'GO:0015283', ('224', '228'))
204633	32664372	p-PI3K protein was expressed in mesothelium and mesothelioma to the similar extent according to the Im index.	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('PI3K', 'molecular_function', 'GO:0016303', ('2', '6'))	('mesothelioma', 'Disease', (48, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('p-PI3K', 'Var', (0, 6))
204636	32664372	Analysis of the expression of p-PI3K and p-AKT showed no differences among different histological subtypes of mesothelioma.	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('AKT', 'Gene', '207', (43, 46))	('mesothelioma', 'Disease', (110, 122))	('p-PI3K', 'Var', (30, 36))	('AKT', 'Gene', (43, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))
204655	32664372	However, upon addition of antimycin A, a potent stimulator of ROS production at the respiratory chain complex III, Mero-14 cells responded with a dose-dependent raise in ROS generation that increased eight fold at 10 muM antimycin A.	('antimycin A', 'Var', (221, 232))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('respiratory chain complex III', 'cellular_component', 'GO:0045276', ('84', '113'))	('increased', 'PosReg', (190, 199))	('Mero-14', 'Chemical', '-', (115, 122))	('respiratory chain complex III', 'cellular_component', 'GO:0045275', ('84', '113'))	('ROS generation', 'biological_process', 'GO:1903409', ('170', '184'))	('raise', 'PosReg', (161, 166))	('ROS generation', 'MPA', (170, 184))	('antimycin A', 'Chemical', 'MESH:D000968', (221, 232))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('antimycin A', 'Chemical', 'MESH:D000968', (26, 37))
204696	32664372	Similarly, a study also showed that upon phosphorylation of OCT4 by AKT, OCT4 dissociated from AKT1 promotor, stimulating its expression.	('OCT4', 'Gene', (73, 77))	('expression', 'MPA', (126, 136))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('AKT', 'Gene', '207', (95, 98))	('OCT4', 'Protein', (60, 64))	('AKT', 'Gene', '207', (68, 71))	('AKT', 'Gene', (95, 98))	('stimulating', 'PosReg', (110, 121))	('phosphorylation', 'Var', (41, 56))	('AKT', 'Gene', (68, 71))
204702	32664372	Although it would be intuitive that, due to its anti-apoptotic activity, low BCL2 expression would suppress cancer, studies show controversial results.	('anti-apoptotic', 'MPA', (48, 62))	('BCL2', 'Gene', (77, 81))	('BCL2', 'molecular_function', 'GO:0015283', ('77', '81'))	('expression', 'MPA', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('suppress', 'NegReg', (99, 107))	('BCL2', 'Gene', '596', (77, 81))	('low', 'Var', (73, 76))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
204703	32664372	Some correlate high BCL2 expression with poor survival, while other indicate good prognosis of mesothelioma patients with high BLC2 expression.	('high', 'Var', (15, 19))	('BCL2', 'Gene', '596', (20, 24))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('expression', 'MPA', (25, 35))	('BCL2', 'Gene', (20, 24))	('patients', 'Species', '9606', (108, 116))	('BCL2', 'molecular_function', 'GO:0015283', ('20', '24'))	('mesothelioma', 'Disease', (95, 107))
204726	32664372	Proton pumping by respiratory chain complexes is less opposed by lower DeltaPsim, which improves coupled electron flux across respiratory chain.	('improves', 'PosReg', (88, 96))	('DeltaPsim', 'Disease', (71, 80))	('lower', 'Var', (65, 70))	('respiratory chain', 'cellular_component', 'GO:0070469', ('126', '143'))	('Proton pumping', 'MPA', (0, 14))	('DeltaPsim', 'Disease', 'None', (71, 80))	('respiratory chain', 'cellular_component', 'GO:0070469', ('18', '35'))	('coupled electron flux across respiratory chain', 'MPA', (97, 143))
204730	32664372	One of our key findings is that mitochondrial ROS induces NANOG protein expression in mesothelioma, which emphasizes the key role of mitochondria in the maintenance of undifferentiated state of human mesothelioma cells.	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('NANOG', 'Gene', '79923', (58, 63))	('mitochondria', 'cellular_component', 'GO:0005739', ('133', '145'))	('mesothelioma', 'Disease', (86, 98))	('NANOG', 'Gene', (58, 63))	('human', 'Species', '9606', (194, 199))	('mitochondrial', 'Var', (32, 45))	('mesothelioma', 'Disease', (200, 212))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('induces', 'Reg', (50, 57))
204733	32664372	Others have shown that H2O2 can upregulate POU5F1, NANOG and SOX2 in mesothelioma line.	('upregulate', 'PosReg', (32, 42))	('POU5F1', 'Gene', '5460', (43, 49))	('POU5F1', 'Gene', (43, 49))	('mesothelioma', 'Disease', (69, 81))	('H2O2', 'Var', (23, 27))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('NANOG', 'Gene', '79923', (51, 56))	('NANOG', 'Gene', (51, 56))	('SOX2', 'Gene', (61, 65))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))
204734	32664372	However, their experiment relied on non-physiological, exogenous application of H2O2, while we stimulated endogenous mitochondrial ROS formation, which corresponds better to conditions occurring in the tumor.	('endogenous', 'MPA', (106, 116))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('H2O2', 'Var', (80, 84))	('tumor', 'Disease', (202, 207))	('stimulated', 'PosReg', (95, 105))	('ROS formation', 'biological_process', 'GO:1903409', ('131', '144'))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
204738	32664372	It has been shown in various types of cancer cell lines that ROS can activate HIF-1alpha, which induced the expression of pluripotency factors.	('ROS', 'Var', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('activate', 'PosReg', (69, 77))	('HIF-1alpha', 'Gene', '3091', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('induced', 'Reg', (96, 103))	('expression of pluripotency factors', 'MPA', (108, 142))	('cancer', 'Disease', (38, 44))	('HIF-1alpha', 'Gene', (78, 88))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
204826	30651858	FAB32652A; 1:100; R&D Systems, Inc.) for 30 min at room temperature and then washed 3 times with PBS.	('PBS', 'Disease', 'MESH:D011535', (97, 100))	('PBS', 'Disease', (97, 100))	('FAB32652A', 'Var', (0, 9))	('rat', 'Species', '10116', (61, 64))
204852	30651858	Similarly, recombinant CHO-K1-MSLN exhibited abundant MSLN expression, where 93.1% CHO-K1-MSLN cells overexpressed MSLN, and 6.9% of them carried low content of MSLN (Fig.	('MSLN', 'Gene', (54, 58))	('MSLN', 'Var', (115, 119))	('CHO', 'molecular_function', 'GO:0043848', ('23', '26'))	('CHO-K1-MSLN', 'CellLine', 'CVCL:0214', (23, 34))	('expression', 'MPA', (59, 69))	('CHO', 'molecular_function', 'GO:0043848', ('83', '86'))	('CHO-K1-MSLN', 'CellLine', 'CVCL:0214', (83, 94))
204854	30651858	When the E:T ratio reached 0.5:1, the antitumor effect of CAR-T cells was significantly higher than control T cells (P<0.05; Fig.	('higher', 'PosReg', (88, 94))	('CAR-T', 'Var', (58, 63))	('tumor', 'Disease', (42, 47))	('CAR', 'cellular_component', 'GO:0005826', ('58', '61'))	('rat', 'Species', '10116', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
204861	30651858	The difference in growth rate of tumor size was significant at PG-D31 (P=0.03), whereas subsequently, both groups gradually synchronized in tumor growth rate without continuous injection (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (33, 38))	('rat', 'Species', '10116', (25, 28))	('PG-D31', 'Var', (63, 69))	('tumor', 'Disease', (140, 145))
204869	30651858	DC cells could recognize tumor antigens and CIK cells secrete cytotoxic factors, and combination of DC and CIK was demonstrated to improve efficacy of chemotherapy, mitigate side effects and prolong life expectancy of patients.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('life expectancy', 'CPA', (199, 214))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Disease', (25, 30))	('prolong', 'PosReg', (191, 198))	('side effects', 'CPA', (174, 186))	('rat', 'Species', '10116', (122, 125))	('efficacy', 'CPA', (139, 147))	('improve', 'PosReg', (131, 138))	('chemotherapy', 'CPA', (151, 163))	('mitigate', 'NegReg', (165, 173))	('combination', 'Var', (85, 96))
204885	30651858	Recently, treatment of B cell malignancies achieved a breaking advancement with CAR-T cell therapy: Multiple clinical trials have revealed that CAR-T cells targeting CD19 could treat refractory lymphoma with response rates over 50%, and in myeloma, CAR-T cells engineered to target CD19+ demonstrated efficacy in eradicating the disease.	('lymphoma', 'Disease', 'MESH:D008223', (194, 202))	('CD19', 'Gene', (166, 170))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('CAR', 'cellular_component', 'GO:0005826', ('249', '252'))	('CD19', 'Gene', '930', (166, 170))	('myeloma', 'Disease', 'MESH:D009101', (240, 247))	('CAR', 'cellular_component', 'GO:0005826', ('80', '83'))	('rat', 'Species', '10116', (295, 298))	('breaking advancement', 'Phenotype', 'HP:0001061', (54, 74))	('CAR', 'cellular_component', 'GO:0005826', ('144', '147'))	('lymphoma', 'Disease', (194, 202))	('CD19', 'Gene', (282, 286))	('myeloma', 'Disease', (240, 247))	('rat', 'Species', '10116', (217, 220))	('targeting', 'Var', (156, 165))	('CD19', 'Gene', '930', (282, 286))
204886	30651858	Other target antigens include tumor-associated glycoprotein 72 for metastatic colorectal cancer, folate receptor-alpha for ovarian cancer, L1-cell adhesion molecule for metastatic neuroblastoma, and CD22 for ALL, in which 5 targets have entered phase 2 trials: GD2 (NCT02765243), CD22 (NCT03196830), CD20 (NCT03196830), CD30 (NCT03196830) and carcinoembryonic antigen (NCT01723306).	('cell adhesion', 'biological_process', 'GO:0007155', ('142', '155'))	('NCT01723306', 'Var', (369, 380))	('NCT03196830', 'Var', (306, 317))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('CD20', 'Gene', '931', (300, 304))	('CD22', 'Gene', '933', (280, 284))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ALL', 'Phenotype', 'HP:0006721', (208, 211))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('142', '164'))	('CD30', 'Gene', (320, 324))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('CD22', 'Gene', (199, 203))	('NCT02765243', 'Var', (266, 277))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ovarian cancer', 'Disease', (123, 137))	('carcinoembryonic', 'Disease', (343, 359))	('colorectal cancer', 'Disease', (78, 95))	('neuroblastoma', 'Disease', (180, 193))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('CD30', 'Gene', '943', (320, 324))	('neuroblastoma', 'Phenotype', 'HP:0003006', (180, 193))	('CD22', 'Gene', '933', (199, 203))	('neuroblastoma', 'Disease', 'MESH:D009447', (180, 193))	('NCT03196830', 'Var', (326, 337))	('carcinoembryonic', 'Disease', 'None', (343, 359))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('NCT03196830', 'Var', (286, 297))	('CD20', 'Gene', (300, 304))	('tumor', 'Disease', (30, 35))	('CD22', 'Gene', (280, 284))
204906	30651858	Results suggested that MSLN CAR-T cells have more potent cytotoxicity than T cells, yet this advantageous effect was due to the cumulative influence of MSLN targeting T cells and the targetability of MSLN antigen.	('CAR', 'cellular_component', 'GO:0005826', ('28', '31'))	('cytotoxicity', 'Disease', (57, 69))	('MSLN', 'Var', (23, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))
204907	30651858	This finding is primarily sufficient to support the conclusion that MSLN CAR-T cells are superior than T cells in killing MSLN expressing tumors.	('MSLN', 'Var', (68, 72))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('CAR', 'cellular_component', 'GO:0005826', ('73', '76'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
204970	30533375	In the present case, the patient had high levels of HA (>80,000 ng/mL), CYFRA (466.9 ng/mL) and TPA (7636 U/L), and normal CEA levels in the pleural fluid.	('466.9', 'Var', (79, 84))	('pleural fluid', 'Phenotype', 'HP:0002202', (141, 154))	('HA', 'Chemical', 'MESH:D006820', (52, 54))	('TPA', 'Gene', '5327', (96, 99))	('pleural', 'Disease', 'MESH:D010995', (141, 148))	('pleural', 'Disease', (141, 148))	('CEA', 'Gene', (123, 126))	('patient', 'Species', '9606', (25, 32))	('TPA', 'molecular_function', 'GO:0031299', ('96', '99'))	('CEA', 'Gene', '1084', (123, 126))	('CYFRA', 'MPA', (72, 77))	('7636 U/L', 'Var', (101, 109))	('TPA', 'Gene', (96, 99))
205069	21769693	In an analysis of 57 patients who received neoadjuvant chemotherapy, presence of necrosis was a predictor of shorter OS (P = 0.034, data not shown), although this significance was not observed in the study cohort of chemo-naive patients.	('necrosis', 'biological_process', 'GO:0008219', ('81', '89'))	('presence', 'Var', (69, 77))	('OS', 'Chemical', '-', (117, 119))	('necrosis', 'biological_process', 'GO:0019835', ('81', '89'))	('necrosis', 'biological_process', 'GO:0008220', ('81', '89'))	('necrosis', 'biological_process', 'GO:0070265', ('81', '89'))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('necrosis', 'biological_process', 'GO:0001906', ('81', '89'))	('patients', 'Species', '9606', (228, 236))	('patients', 'Species', '9606', (21, 29))	('necrosis', 'Disease', (81, 89))	('shorter', 'Disease', (109, 116))
205074	21769693	Again, a much shorter median OS was observed in the high NLR group (n = 22, 10.2 months) compared to the low NLR group (n = 54, 18.9 months), although this did not reach statistical significance (P = 0.34).	('shorter', 'NegReg', (14, 21))	('OS', 'Chemical', '-', (29, 31))	('high NLR', 'Var', (52, 60))
205089	21769693	One such approach was demonstrated in a recent preclinical work by Fridlender et al., who has shown that blockade of chemokine CCL2 augments CD8 + T cell response.	('CCL2', 'Gene', (127, 131))	('blockade', 'Var', (105, 113))	('men', 'Species', '9606', (135, 138))	('CCL2', 'Gene', '6347', (127, 131))	('CCL', 'molecular_function', 'GO:0044101', ('127', '130'))	('CD8', 'Gene', (141, 144))	('CD8', 'Gene', '925', (141, 144))	('augments', 'NegReg', (132, 140))
205244	26765459	Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.	('BAP1', 'Gene', '8314', (11, 15))	('reported', 'Reg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('BAP1', 'Gene', (11, 15))	('inactivation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', (84, 115))	('tumor', 'Disease', (61, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
205255	26765459	That is, germline BAP1 mutation is associated with a newly recognized autosomal-dominant hereditary cancer syndrome, (OMIM #6143), characterized by uveal melanoma, mesothelioma, cutaneous melanocytic lesions, renal cell carcinoma, basal cell carcinoma, and intrahepatic cholangiocarcinoma (ICC); while biallelic inactivations including somatic mutations or deletions have also been reported in a range of tumors including uveal melanoma, mesothelioma, cutaneous melanocytic neoplasms, and clear cell renal carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 229))	('mesothelioma', 'Disease', (164, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('autosomal-dominant hereditary cancer syndrome', 'Disease', (70, 115))	('BAP1', 'Gene', (18, 22))	('uveal melanoma', 'Disease', (148, 162))	('basal cell carcinoma', 'Disease', (231, 251))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('clear cell renal carcinoma', 'Disease', (489, 515))	('germline', 'Var', (9, 17))	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (178, 207))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (462, 483))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (257, 288))	('tumors', 'Disease', 'MESH:D009369', (405, 411))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('intrahepatic cholangiocarcinoma', 'Disease', (257, 288))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (489, 515))	('melanoma', 'Phenotype', 'HP:0002861', (428, 436))	('cutaneous melanocytic neoplasms', 'Disease', (452, 483))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mesothelioma', 'Disease', (438, 450))	('renal cell carcinoma', 'Disease', (209, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (422, 436))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))	('uveal melanoma', 'Disease', (422, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (506, 515))	('mesothelioma', 'Disease', 'MESH:D008654', (438, 450))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (270, 288))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (231, 251))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (70, 115))	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (452, 483))	('tumors', 'Phenotype', 'HP:0002664', (405, 411))	('uveal melanoma', 'Phenotype', 'HP:0007716', (422, 436))	('BAP1', 'Gene', '8314', (18, 22))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (489, 515))	('mutation', 'Var', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('associated', 'Reg', (35, 45))	('deletions', 'Var', (357, 366))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('renal carcinoma', 'Phenotype', 'HP:0005584', (500, 515))	('cutaneous melanocytic lesions', 'Disease', (178, 207))	('neoplasms', 'Phenotype', 'HP:0002664', (474, 483))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (231, 251))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('tumors', 'Disease', (405, 411))
205262	26765459	It has recently been suggested that germline BAP1 mutations predispose to intrahepatic cholangiocarcinoma and somatic biallelic inactivating BAP1 mutations have been reported in up to 25% of intrahepatic cholangiocarcinomas (ICC).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (204, 222))	('intrahepatic cholangiocarcinomas', 'Disease', (191, 223))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (50, 59))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (191, 223))	('reported', 'Reg', (166, 174))	('BAP1', 'Gene', (141, 145))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 222))	('predispose', 'Reg', (60, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('biallelic inactivating', 'Var', (118, 140))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('BAP1', 'Gene', '8314', (45, 49))	('intrahepatic cholangiocarcinoma', 'Disease', (74, 105))
205282	26765459	BAP1 IHC positive ICCs demonstrated worse median survival, 24.87 months (95% CI, 18.73-31.01 months), compared with BAP1 IHC negative cases, 40.80 months (95% CI, 28.14-53.46 months), but this did not reach statistical significance (P = 0.059).	('BAP1', 'Gene', (116, 120))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', '8314', (116, 120))	('positive', 'Var', (9, 17))
205293	26765459	Although our study was not intended or designed to assess the sensitivity and specificity of BAP1 IHC for BAP1 mutation, our incidence of negative staining for BAP1 is very similar to the rate of inactivating mutations reported by Jiao et al (25%) and Chan-On et al (22.2%), suggesting that loss of IHC staining for BAP1 is likely to correlate strongly with BAP1 mutation in ICC as it has been proven to do in mesothelioma and uveal melanoma.	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', '8314', (358, 362))	('BAP1', 'Gene', (106, 110))	('mutation', 'Var', (363, 371))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('BAP1', 'Gene', '8314', (316, 320))	('BAP1', 'Gene', '8314', (160, 164))	('BAP1', 'Gene', (358, 362))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', (316, 320))	('BAP1', 'Gene', (160, 164))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (410, 441))
205299	26765459	Presumably this indicates that pathways other than those associated with BAP1 mutation are more lethal in mesothelioma but less lethal that BAP1 associated pathways in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('BAP1', 'Gene', '8314', (73, 77))	('mesothelioma', 'Disease', (106, 118))	('mutation', 'Var', (78, 86))	('BAP1', 'Gene', (140, 144))	('BAP1', 'Gene', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BAP1', 'Gene', '8314', (140, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
205308	26765459	It has been suggested that ICC may be a component of the hereditary cancer syndrome associated with germline BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (114, 123))	('BAP1', 'Gene', '8314', (109, 113))	('component of the hereditary cancer syndrome', 'Disease', (40, 83))	('associated', 'Reg', (84, 94))	('BAP1', 'Gene', (109, 113))	('ICC', 'Disease', (27, 30))	('component of the hereditary cancer syndrome', 'Disease', 'MESH:D009386', (40, 83))
205309	26765459	Therefore, it is possible that IHC for BAP1 may play a role in triaging formal genetic testing for germline BAP1 mutation in patients presenting with cholangiocarcinoma.	('patients', 'Species', '9606', (125, 133))	('mutation', 'Var', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('BAP1', 'Gene', '8314', (108, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', (150, 168))	('BAP1', 'Gene', (39, 43))
205310	26765459	That is, if a tumor shows positive staining for BAP1 then germline BAP1 mutation can be considered unlikely, whereas if a tumor shows negative staining for BAP1 then BAP1 mutation is not excluded and formal counselling and genetic testing may be warranted in patients considered at high risk for hereditary disease for example due to onset at a young age or a family history of BAP1-associated malignancy such as mesothelioma, uveal melanoma, or cholangiocarcinoma.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', '8314', (166, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('malignancy', 'Disease', 'MESH:D009369', (394, 404))	('patients', 'Species', '9606', (259, 267))	('BAP1', 'Gene', '8314', (156, 160))	('BAP1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mesothelioma', 'Disease', (413, 425))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (446, 464))	('BAP1', 'Gene', (166, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (413, 425))	('BAP1', 'Gene', '8314', (378, 382))	('malignancy', 'Disease', (394, 404))	('hereditary disease', 'Disease', (296, 314))	('cholangiocarcinoma', 'Disease', (446, 464))	('hereditary disease', 'Disease', 'MESH:D030342', (296, 314))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (446, 464))	('BAP1', 'Gene', '8314', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('tumor', 'Disease', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (455, 464))	('BAP1', 'Gene', (378, 382))	('uveal melanoma', 'Disease', 'MESH:C536494', (427, 441))	('uveal melanoma', 'Disease', (427, 441))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', (67, 71))
205311	26765459	The incidence of germline BAP1 mutations in cholangiocarcinoma is not currently known; however, the incidence of germline BAP1 mutations in malignancies such as mesothelioma and metastasising uveal melanoma has been estimated at 1 to 2% or less.	('BAP1', 'Gene', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('mesothelioma', 'Disease', (161, 173))	('BAP1', 'Gene', (122, 126))	('uveal melanoma', 'Disease', (192, 206))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('malignancies', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (127, 136))	('cholangiocarcinoma', 'Disease', (44, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))
205312	26765459	It is likely that the rate of germline BAP1 mutations to be lower in cholangiocarcinoma than that found in mesothelioma and uveal melanoma, given that somatic mutations resulting in BAP1 loss occur in approximately half of mesotheliomas and in up to 84% of uveal melanomas, which is higher than the rate of BAP1 loss so far reported in cholangiocarcinoma.	('loss', 'NegReg', (187, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (336, 354))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('cholangiocarcinoma', 'Disease', (69, 87))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Disease', (336, 354))	('uveal melanomas', 'Disease', 'MESH:C536494', (257, 272))	('lower', 'NegReg', (60, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (336, 354))	('BAP1', 'Gene', '8314', (182, 186))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (107, 138))	('BAP1', 'Gene', '8314', (307, 311))	('mesotheliomas', 'Disease', (223, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BAP1', 'Gene', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (257, 271))	('mesotheliomas', 'Disease', 'MESH:D008654', (223, 236))	('BAP1', 'Gene', (182, 186))	('uveal melanomas', 'Disease', (257, 272))	('uveal melanomas', 'Phenotype', 'HP:0007716', (257, 272))	('BAP1', 'Gene', (307, 311))	('melanomas', 'Phenotype', 'HP:0002861', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))
205313	26765459	Given that real rate of germline BAP1 mutations is likely to be less than 1%, it is reasonable that formal genetic testing for BAP1 mutation be reserved for those patients who are considered high-risk based on family and personal history and demonstrate loss of BAP1 expression by IHC.	('loss', 'NegReg', (254, 258))	('BAP1', 'Gene', '8314', (262, 266))	('BAP1', 'Gene', (127, 131))	('patients', 'Species', '9606', (163, 171))	('BAP1', 'Gene', (262, 266))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', '8314', (127, 131))	('mutation', 'Var', (132, 140))	('expression', 'MPA', (267, 277))
205324	25980578	Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma.	('tumor growth delay', 'Disease', 'MESH:D006130', (190, 208))	('mesothelioma', 'Disease', (89, 101))	('mesothelioma', 'Disease', (251, 263))	('T cells increased', 'Phenotype', 'HP:0100828', (44, 61))	('tumor growth delay', 'Disease', (190, 208))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('rat', 'Species', '10116', (129, 132))	('blockade', 'Var', (140, 148))	('CTLA-4', 'Gene', '12477', (171, 177))	('growth delay', 'Phenotype', 'HP:0001510', (196, 208))	('murine', 'Species', '10090', (82, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (251, 263))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('CTLA-4', 'Gene', '12477', (34, 40))	('CTLA-4', 'Gene', (171, 177))	('abscopal effects', 'MPA', (62, 78))	('CTLA-4', 'Gene', (34, 40))	('murine', 'Species', '10090', (244, 250))
205329	25980578	LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells.	('more', 'PosReg', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('T cell infiltration', 'CPA', (21, 40))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('LRT', 'Var', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('rat', 'Species', '10116', (34, 37))
205330	25980578	Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated.	('blockade', 'Var', (101, 109))	('CTLA-4', 'Gene', '12477', (94, 100))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('CTLA-4', 'Gene', (94, 100))	('CD8', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD8', 'Gene', '925', (117, 120))
205337	25980578	Radiotherapy can induce direct cancer cell death while also producing a systemic anti-tumor effect in the non-irradiated field, which has been referred to as the abscopal effect.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('systemic', 'MPA', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (86, 91))	('Radiotherapy', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cell death', 'biological_process', 'GO:0008219', ('38', '48'))
205364	25980578	The growth of tumors on the right flank of mice injected with 5Gy or 15Gy irradiated cells was significantly slower than that of the non-radiated group.	('mice', 'Species', '10090', (43, 47))	('slower', 'NegReg', (109, 115))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('5Gy', 'Var', (62, 65))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
205365	25980578	On the counterlateral site, injection of non-radiated cells led to tumors that grew significantly more slowly in mice receiving cells radiated with 5Gy or 15Gy on the right side.	('5Gy', 'Var', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('slowly', 'NegReg', (103, 109))	('mice', 'Species', '10090', (113, 117))	('tumors', 'Disease', (67, 73))
205377	25980578	RT-PCR results demonstrated that LRT combined with anti-CTLA-4 antibody resulted in upregulation of the immune-associated genes such as IFN-gamma and its inducible protein perforin IP-10, cytolytic enzymes perforin and granzyme B, inducible costimulation molecule ICOS, DC maturation markers CD80 and CD86.	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('CD86', 'Gene', '12524', (301, 305))	('rat', 'Species', '10116', (22, 25))	('ICOS', 'Gene', '54167', (264, 268))	('rat', 'Species', '10116', (277, 280))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('ICOS', 'Gene', (264, 268))	('antibody', 'Var', (63, 71))	('CD80', 'Gene', '12519', (292, 296))	('IP-10', 'Gene', (181, 186))	('CD86', 'Gene', (301, 305))	('CTLA-4', 'Gene', (56, 62))	('upregulation', 'PosReg', (84, 96))	('IP-10', 'Gene', '15945', (181, 186))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))	('granzyme B', 'Gene', (219, 229))	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('IFN-gamma', 'Gene', '15978', (136, 145))	('CD80', 'Gene', (292, 296))	('granzyme B', 'Gene', '14939', (219, 229))	('cytolytic', 'MPA', (188, 197))	('IFN-gamma', 'Gene', (136, 145))	('CTLA-4', 'Gene', '12477', (56, 62))
205419	25980578	Interestingly, LRT resulted in an increase of tumor-infiltrating Tregs, while CTLA-4 blockade gave rise to reversal of Tregs in both tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('LRT', 'Var', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CTLA-4', 'Gene', '12477', (78, 84))	('increase', 'PosReg', (34, 42))	('tumor', 'Disease', (133, 138))	('rat', 'Species', '10116', (58, 61))	('CTLA-4', 'Gene', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
205709	30518402	In the CD4+ T cell population, there was a statistically significant larger proportion of PE T cells that expressed PD-1 (p = 0.004), Tim-3 (p = 0.004) and LAG-3 (p = 0.004) compared to peripheral blood (Fig.	('PD-1', 'Gene', (116, 120))	('LAG-3', 'Gene', (156, 161))	('CD4+', 'Var', (7, 11))	('Tim-3', 'Gene', (134, 139))	('PE', 'Phenotype', 'HP:0002202', (90, 92))	('Tim-3', 'Gene', '84868', (134, 139))
205712	30518402	We examined the T cell repertoire by sequencing the TCRbeta chain in T cells from PE and matched peripheral blood.	('TCRbeta', 'Gene', '6962', (52, 59))	('PE', 'Phenotype', 'HP:0002202', (82, 84))	('sequencing', 'Var', (37, 47))	('TCRbeta', 'Gene', (52, 59))
205730	30518402	We observed a more restricted TCR repertoire in effusion CD4+PD-1+ T cells compared to CD4+ T cells, similar to previous studies studying PD-1+ TILs.	('TCR', 'Gene', '6962', (30, 33))	('CD4+PD-1+ T', 'Var', (57, 68))	('effusion', 'Disease', 'MESH:D010996', (48, 56))	('TCR', 'cellular_component', 'GO:0042101', ('30', '33'))	('TCR', 'Gene', (30, 33))	('effusion', 'Disease', (48, 56))	('TCR', 'biological_process', 'GO:0006283', ('30', '33'))
205741	28470935	We found decreased phospho-YAP to YAP protein ratio and consistently increased GTIIC reporter activity in 211H, H2052 and H290 compared to LP9.	('YAP', 'Gene', (27, 30))	('H290', 'CellLine', 'CVCL:A555', (122, 126))	('YAP', 'Gene', (34, 37))	('increased', 'PosReg', (69, 78))	('211H', 'Chemical', '-', (106, 110))	('H2052', 'CellLine', 'CVCL:1518', (112, 117))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('H2052', 'Var', (112, 117))	('LP9', 'Chemical', 'MESH:C110575', (139, 142))	('decreased', 'NegReg', (9, 18))	('YAP', 'Gene', '10413', (34, 37))	('YAP', 'Gene', '10413', (27, 30))	('H290', 'Var', (122, 126))	('GTIIC reporter activity', 'MPA', (79, 102))
205749	28470935	Inhibition of ROCK2 decreased GTIIC reporter activity in H2052 and 211H suggesting that Rho/ROCK signaling also contributed to YAP activation in mesothelioma cells.	('YAP', 'Gene', (127, 130))	('activation', 'PosReg', (131, 141))	('decreased', 'NegReg', (20, 29))	('GTIIC reporter activity', 'MPA', (30, 53))	('mesothelioma', 'Disease', (145, 157))	('YAP', 'Gene', '10413', (127, 130))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('ROCK2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('ROCK2', 'Gene', '9475', (14, 19))	('H2052', 'CellLine', 'CVCL:1518', (57, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))	('211H', 'Chemical', '-', (67, 71))
205755	28470935	The Hippo (also known as the Salvador-Warts-Hippo) tumour suppressor pathway is a crucial regulator of organ growth, tissue regeneration and cell proliferation, and dysregulation of this pathway leads to tissue overgrowth and tumourigenesis 5.	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('organ growth', 'biological_process', 'GO:0035265', ('103', '115'))	('leads to', 'Reg', (195, 203))	('dysregulation', 'Var', (165, 178))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('Salvador', 'Gene', '252554', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('Salvador', 'Gene', (29, 37))	('tissue overgrowth', 'CPA', (204, 221))	('tumour', 'Disease', (226, 232))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('overgrowth', 'Phenotype', 'HP:0001548', (211, 221))	('tumour', 'Disease', (51, 57))	('Warts', 'Phenotype', 'HP:0200043', (38, 43))	('tissue regeneration', 'biological_process', 'GO:0042246', ('117', '136'))
205757	28470935	Recent studies suggest that the elevated YAP activity due to genetic inactivation of the Hippo pathway components may be associated with poor prognosis of patients with mesothelioma 9.	('YAP', 'Gene', (41, 44))	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('elevated', 'PosReg', (32, 40))	('genetic inactivation', 'Var', (61, 81))	('Hippo pathway', 'Pathway', (89, 102))	('mesothelioma', 'Disease', (169, 181))	('patients', 'Species', '9606', (155, 163))	('YAP', 'Gene', '10413', (41, 44))
205758	28470935	The NF2 gene, which encodes the Merlin tumour suppressor protein, shows the highest frequency of inactivating mutation in the Hippo pathway of mesothelioma 10:nearly 50% of mesothelioma tumours according to one study 11.	('mesothelioma', 'Disease', 'MESH:D008654', (173, 185))	('Merlin', 'Gene', (32, 38))	('mesothelioma tumours', 'Disease', (173, 193))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('tumour', 'Disease', (186, 192))	('mesothelioma', 'Disease', (143, 155))	('Merlin', 'Gene', '4771', (32, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('NF2', 'Gene', '4771', (4, 7))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (173, 193))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('NF2', 'Gene', (4, 7))	('tumour', 'Disease', (39, 45))	('inactivating mutation', 'Var', (97, 118))	('mesothelioma', 'Disease', (173, 185))
205759	28470935	In addition, genetic inactivation status of LATS2, SAV1 and RASSF has been identified in several mesothelioma cell lines and clinical samples 12, 13.	('clinical samples', 'Species', '191496', (125, 141))	('LATS2', 'Gene', (44, 49))	('LATS2', 'Gene', '26524', (44, 49))	('SAV1', 'Gene', '60485', (51, 55))	('mesothelioma', 'Disease', (97, 109))	('genetic inactivation status', 'Var', (13, 40))	('SAV1', 'Gene', (51, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('RASSF', 'Gene', (60, 65))
205760	28470935	Deletion of these molecules caused by genetic inactivation leads to constitutive YAP activation and induces the oncogenic transformation in cooperation with distinct transcription factors such as TEAD family members (TEAD1-4) 14, 15, 16, 17.	('oncogenic transformation', 'CPA', (112, 136))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))	('YAP', 'Gene', '10413', (81, 84))	('activation', 'PosReg', (85, 95))	('induces', 'Reg', (100, 107))	('YAP', 'Gene', (81, 84))	('Deletion', 'Var', (0, 8))
205762	28470935	Dysfunction of the Hippo pathway caused by such complicated factors eventually leads to dramatic increases in cell proliferation and metastasis that are largely dependent on YAP in mesothelioma.	('YAP', 'Gene', (174, 177))	('Hippo pathway', 'Pathway', (19, 32))	('Dysfunction', 'Var', (0, 11))	('mesothelioma', 'Disease', (181, 193))	('increases', 'PosReg', (97, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('110', '128'))	('mesothelioma', 'Disease', 'MESH:D008654', (181, 193))	('YAP', 'Gene', '10413', (174, 177))	('cell proliferation', 'CPA', (110, 128))	('metastasis', 'CPA', (133, 143))
205796	28470935	To investigate YAP activation in mesothelioma cell lines, we analysed the phosphorylation status phospho-YAP (Ser127) and total amount of YAP in 211H, H2052, H2452, H290 and MS-1 cells and in a normal mesothelial cell line, LP9, by Western blotting.	('211H', 'Chemical', '-', (145, 149))	('H2052', 'Var', (151, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('LP9', 'Chemical', 'MESH:C110575', (224, 227))	('YAP', 'Gene', '10413', (105, 108))	('H290', 'CellLine', 'CVCL:A555', (165, 169))	('H2052', 'CellLine', 'CVCL:1518', (151, 156))	('YAP', 'Gene', '10413', (15, 18))	('YAP', 'Gene', (138, 141))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('YAP', 'Gene', (15, 18))	('YAP', 'Gene', (105, 108))	('Ser127', 'Chemical', '-', (110, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('mesothelioma', 'Disease', (33, 45))	('YAP', 'Gene', '10413', (138, 141))
205803	28470935	Of the five cell lines tested, three showed high sensitivity to verteporfin treatment: the IC50 of verteporfin was 418.1 nM in 211H cells, 689.3 nM in H2052 cells and 788.6 nM in H290 cells.	('211H', 'Chemical', '-', (127, 131))	('689.3 nM', 'Var', (139, 147))	('H290', 'CellLine', 'CVCL:A555', (179, 183))	('H2052', 'CellLine', 'CVCL:1518', (151, 156))	('verteporfin', 'Chemical', 'MESH:D000077362', (99, 110))	('verteporfin', 'Chemical', 'MESH:D000077362', (64, 75))	('418.1 nM', 'Var', (115, 123))
205804	28470935	In contrast, the IC50 of verteporfin was much higher in MS-1 (2027 nM), H2452 cells (3485 nM) and LP9 (3915 nM).	('higher', 'PosReg', (46, 52))	('2027 nM', 'Var', (62, 69))	('LP9', 'Chemical', 'MESH:C110575', (98, 101))	('verteporfin', 'Chemical', 'MESH:D000077362', (25, 36))	('IC50', 'MPA', (17, 21))	('3915 nM', 'Var', (103, 110))	('3485 nM', 'Var', (85, 92))
205806	28470935	We chose H2052, H290 and 211H for further analysis due to their known genetic mutations of Hippo pathway components, and high YAP and reporter activity level.	('Hippo', 'Gene', (91, 96))	('YAP', 'Gene', (126, 129))	('211H', 'Chemical', '-', (25, 29))	('H2052', 'CellLine', 'CVCL:1518', (9, 14))	('mutations', 'Var', (78, 87))	('YAP', 'Gene', '10413', (126, 129))	('H290', 'CellLine', 'CVCL:A555', (16, 20))
205815	28470935	As shown in Figure S1A, when proteasome degradation was inhibited by MG132, YAP protein level was increased compared to that for verteporfin treatment alone at 8 and 24 hrs time-points in all three cell lines.	('YAP', 'Gene', '10413', (76, 79))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('proteasome degradation', 'MPA', (29, 51))	('MG132', 'Chemical', 'MESH:C072553', (69, 74))	('YAP', 'Gene', (76, 79))	('MG132', 'Var', (69, 74))	('verteporfin', 'Chemical', 'MESH:D000077362', (129, 140))	('proteasome degradation', 'biological_process', 'GO:1903009', ('29', '51'))	('increased', 'PosReg', (98, 107))	('proteasome', 'molecular_function', 'GO:0004299', ('29', '39'))	('proteasome', 'cellular_component', 'GO:0000502', ('29', '39'))	('inhibited', 'NegReg', (56, 65))
205833	28470935	The invasion assay indicated that knockdown of YAP significantly reduced the invasion ability of H90 and H2052, respectively to 26.2% and 56.7% compared to cells treated with control siRNA (Fig.	('invasion ability', 'CPA', (77, 93))	('reduced', 'NegReg', (65, 72))	('H90', 'CellLine', 'CVCL:1B47', (97, 100))	('YAP', 'Gene', '10413', (47, 50))	('knockdown', 'Var', (34, 43))	('YAP', 'Gene', (47, 50))	('H2052', 'CellLine', 'CVCL:1518', (105, 110))
205853	28470935	ROCK1 siRNA also significantly down-regulated GTIIC reported activity in H2052, but not in 211H.	('211H', 'Chemical', '-', (91, 95))	('H2052', 'Var', (73, 78))	('ROCK1', 'Gene', '6093', (0, 5))	('ROCK1', 'Gene', (0, 5))	('GTIIC reported activity', 'MPA', (46, 69))	('down-regulated', 'NegReg', (31, 45))	('H2052', 'CellLine', 'CVCL:1518', (73, 78))
205854	28470935	Additionally treating mesothelioma cells with GSK269962A, a selective inhibitor of Rho-Kinase, largely decreased GTIIC reporter activity in both H2052 and 211H, and this suppression effect of GSK269962A on YAP activity was dose-dependent (Fig.	('YAP', 'Gene', (206, 209))	('mesothelioma', 'Disease', (22, 34))	('GSK269962A', 'Var', (192, 202))	('mesothelioma', 'Disease', 'MESH:D008654', (22, 34))	('decreased', 'NegReg', (103, 112))	('GTIIC reporter activity', 'MPA', (113, 136))	('H2052', 'CellLine', 'CVCL:1518', (145, 150))	('GSK269962A', 'Chemical', 'MESH:C516969', (46, 56))	('GSK269962A', 'Chemical', 'MESH:C516969', (192, 202))	('YAP', 'Gene', '10413', (206, 209))	('211H', 'Chemical', '-', (155, 159))	('GSK269962A', 'Var', (46, 56))	('GSK', 'molecular_function', 'GO:0050321', ('192', '195'))	('GSK', 'molecular_function', 'GO:0050321', ('46', '49'))
205855	28470935	More importantly, GSK269962A treatment decreased cell viability of 211H, H290, H2052, MS-1, H2452 and LP9 in a dose-dependent manner as well (Fig.	('GSK269962A', 'Chemical', 'MESH:C516969', (18, 28))	('H2052', 'CellLine', 'CVCL:1518', (79, 84))	('cell viability', 'CPA', (49, 63))	('H290', 'CellLine', 'CVCL:A555', (73, 77))	('GSK269962A', 'Var', (18, 28))	('GSK', 'molecular_function', 'GO:0050321', ('18', '21'))	('LP9', 'Chemical', 'MESH:C110575', (102, 105))	('decreased', 'NegReg', (39, 48))	('211H', 'Chemical', '-', (67, 71))
205856	28470935	Collectively, these findings indicate that activation of RhoA/ROCK signaling contributes to YAP hyperactivity in pleural mesothelioma and inhibitors of RhoA/ROCK could be used to suppress YAP activity and thereby decrease cell viability of mesothelioma cells.	('activation', 'PosReg', (43, 53))	('RhoA', 'Gene', '387', (152, 156))	('decrease', 'NegReg', (213, 221))	('RhoA', 'Gene', '387', (57, 61))	('YAP', 'Gene', (188, 191))	('mesothelioma', 'Disease', (240, 252))	('mesothelioma', 'Disease', (121, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('mesothelioma', 'Disease', 'MESH:D008654', (121, 133))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('YAP', 'Gene', (92, 95))	('hyperactivity in pleural mesothelioma', 'Disease', 'MESH:D008654', (96, 133))	('YAP', 'Gene', '10413', (188, 191))	('hyperactivity', 'Phenotype', 'HP:0000752', (96, 109))	('RhoA', 'Gene', (152, 156))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (113, 133))	('YAP', 'Gene', '10413', (92, 95))	('RhoA', 'Gene', (57, 61))	('suppress', 'NegReg', (179, 187))	('hyperactivity in pleural mesothelioma', 'Disease', (96, 133))	('inhibitors', 'Var', (138, 148))
205857	28470935	Nearly 75% of mesothelioma tumours contain genetic inactivation status of NF2 or downstream components of the Hippo pathway, which negatively regulates YAP activity 25, 26.	('YAP', 'Gene', '10413', (152, 155))	('mesothelioma tumours', 'Disease', (14, 34))	('NF2', 'Gene', '4771', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('genetic inactivation status', 'Var', (43, 70))	('negatively regulates', 'NegReg', (131, 151))	('YAP', 'Gene', (152, 155))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('mesothelioma tumours', 'Disease', 'MESH:D008654', (14, 34))	('NF2', 'Gene', (74, 77))
205858	28470935	This finding suggests that mesothelioma mostly relies on dysregulation of the Hippo pathway for tumour activity 27.	('mesothelioma', 'Disease', (27, 39))	('dysregulation', 'Var', (57, 70))	('Hippo pathway', 'Pathway', (78, 91))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (96, 102))
205859	28470935	The frequent mutations present in the Hippo pathway components indicate the feasibility of targeting this pathway for mesothelioma therapy.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('mutations', 'Var', (13, 22))	('mesothelioma', 'Disease', (118, 130))	('Hippo', 'Gene', (38, 43))
205865	28470935	Importantly, all of these three cell lines reportedly contain genetic inactivation status of the Hippo pathway components: H290 with NF2 homozygous deletion, 211H with LATS2 deletion, and H2052 with both NF2 mutation and LAST2 deletion 19.	('deletion', 'Var', (148, 156))	('mutation', 'Var', (208, 216))	('NF2', 'Gene', '4771', (204, 207))	('H2052', 'CellLine', 'CVCL:1518', (188, 193))	('NF2', 'Gene', '4771', (133, 136))	('211H', 'Chemical', '-', (158, 162))	('deletion', 'Var', (174, 182))	('NF2', 'Gene', (204, 207))	('LATS2', 'Gene', (168, 173))	('LATS2', 'Gene', '26524', (168, 173))	('NF2', 'Gene', (133, 136))	('Hippo pathway', 'Pathway', (97, 110))	('H290', 'CellLine', 'CVCL:A555', (123, 127))
205866	28470935	The results of our study support that these mutations lead to aberrant YAP activation and elevated transcriptional activity of the Hippo pathway in several mesothelioma cell lines.	('transcriptional activity', 'MPA', (99, 123))	('elevated', 'PosReg', (90, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (156, 168))	('YAP', 'Gene', '10413', (71, 74))	('activation', 'PosReg', (75, 85))	('YAP', 'Gene', (71, 74))	('mutations', 'Var', (44, 53))	('mesothelioma', 'Disease', (156, 168))	('Hippo pathway', 'Pathway', (131, 144))
205871	28470935	Our data indicate that YAP is a potential therapeutic target in mesothelioma and deprivation of YAP could suppress tumour progression in mesothelioma.	('YAP', 'Gene', (96, 99))	('YAP', 'Gene', '10413', (23, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('deprivation', 'Var', (81, 92))	('YAP', 'Gene', '10413', (96, 99))	('YAP', 'Gene', (23, 26))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('suppress', 'NegReg', (106, 114))	('tumour', 'Disease', (115, 121))	('mesothelioma', 'Disease', (64, 76))	('mesothelioma', 'Disease', (137, 149))
205884	28470935	The high sensitivity of 211H, H2052 and H290 may be due to their aberrant YAP activation, elevated transcriptional activity and known mutations of the Hippo pathway components.	('transcriptional activity', 'MPA', (99, 123))	('elevated', 'PosReg', (90, 98))	('YAP', 'Gene', '10413', (74, 77))	('211H', 'Chemical', '-', (24, 28))	('H2052', 'Var', (30, 35))	('H290', 'Var', (40, 44))	('activation', 'PosReg', (78, 88))	('YAP', 'Gene', (74, 77))	('H290', 'CellLine', 'CVCL:A555', (40, 44))	('H2052', 'CellLine', 'CVCL:1518', (30, 35))
205885	28470935	In other words, the mesothelioma cells with aberrant YAP activation due to the Hippo pathway dysfunction were extremely sensitive to verteporfin treatment (Figs 1D and 8).	('mesothelioma', 'Disease', (20, 32))	('activation', 'PosReg', (57, 67))	('YAP', 'Gene', '10413', (53, 56))	('verteporfin', 'Chemical', 'MESH:D000077362', (133, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (20, 32))	('dysfunction', 'Var', (93, 104))	('Hippo pathway', 'Pathway', (79, 92))	('YAP', 'Gene', (53, 56))
205886	28470935	This provides potential approaches to select patients likely to benefit from verteporfin by checking Hippo pathway components mutations contributing aberrant YAP activation.	('verteporfin', 'Chemical', 'MESH:D000077362', (77, 88))	('Hippo', 'Gene', (101, 106))	('YAP', 'Gene', '10413', (158, 161))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (126, 135))	('YAP', 'Gene', (158, 161))
205896	28470935	This finding indicated that YAP inhibition may suppress tumour progression through the suppression of cancer stem cells in mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibition', 'Var', (32, 42))	('suppression', 'NegReg', (87, 98))	('YAP', 'Gene', (28, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('suppress', 'NegReg', (47, 55))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('YAP', 'Gene', '10413', (28, 31))	('tumour', 'Disease', (56, 62))	('mesothelioma', 'Disease', (123, 135))
205902	28470935	Inhibition of RhoA/ROCK signaling by siRNAs or inhibitors decreased YAP transcriptional activity.	('RhoA', 'Gene', '387', (14, 18))	('inhibitors', 'Var', (47, 57))	('decreased', 'NegReg', (58, 67))	('YAP', 'Gene', '10413', (68, 71))	('YAP', 'Gene', (68, 71))	('RhoA', 'Gene', (14, 18))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
205903	28470935	Interestingly, in H2052, LATS2 is mutated and LATS1 is wild-type; in 211H cells, both LATS1 and LATS2 are mutated.	('LATS2', 'Gene', '26524', (25, 30))	('H2052', 'CellLine', 'CVCL:1518', (18, 23))	('LATS1', 'Gene', '9113', (46, 51))	('211H', 'Chemical', '-', (69, 73))	('LATS2', 'Gene', (96, 101))	('LATS2', 'Gene', '26524', (96, 101))	('LATS2', 'Gene', (25, 30))	('LATS1', 'Gene', (86, 91))	('LATS1', 'Gene', '9113', (86, 91))	('LATS1', 'Gene', (46, 51))	('H2052', 'Var', (18, 23))	('mutated', 'Var', (106, 113))
205904	28470935	These mutations in LATS1/2 resulted in partial or total inactive regulation of YAP through LATS1/2 in these cells.	('LATS1/2', 'Gene', (91, 98))	('LATS1/2', 'Gene', (19, 26))	('YAP', 'Gene', (79, 82))	('inactive regulation', 'MPA', (56, 75))	('YAP', 'Gene', '10413', (79, 82))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('LATS1/2', 'Gene', '9113;26524', (91, 98))	('LATS1/2', 'Gene', '9113;26524', (19, 26))	('mutations', 'Var', (6, 15))
205914	28470935	However, when the tumour suppressors NF2, LATS1/2, SAV1, RASSF are inactivated due to genetic mutation, fusion or deletion 13, YAP can translocate and accumulate in the nucleus and interact with transcription factor TEAD and initiate the gene transcription involved in anti-apoptosis and proliferation, for example, that of CTGF and AREG.	('YAP', 'Gene', (127, 130))	('transcription', 'biological_process', 'GO:0006351', ('195', '208'))	('accumulate', 'PosReg', (151, 161))	('SAV1', 'Gene', '60485', (51, 55))	('CTGF', 'Gene', (324, 328))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('269', '283'))	('interact', 'Interaction', (181, 189))	('transcription', 'biological_process', 'GO:0006351', ('243', '256'))	('deletion 13', 'Var', (114, 125))	('YAP', 'Gene', '10413', (127, 130))	('SAV1', 'Gene', (51, 55))	('AREG', 'Gene', '374', (333, 337))	('translocate', 'MPA', (135, 146))	('NF2', 'Gene', '4771', (37, 40))	('LATS1/2', 'Gene', '9113;26524', (42, 49))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('fusion', 'Var', (104, 110))	('LATS1/2', 'Gene', (42, 49))	('NF2', 'Gene', (37, 40))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('nucleus', 'cellular_component', 'GO:0005634', ('169', '176'))	('tumour', 'Disease', (18, 24))	('initiate', 'PosReg', (225, 233))	('CTGF', 'Gene', '1490', (324, 328))	('transcription factor', 'molecular_function', 'GO:0000981', ('195', '215'))	('gene transcription', 'MPA', (238, 256))	('AREG', 'Gene', (333, 337))	('genetic mutation', 'Var', (86, 102))
205918	28470935	In summary, mesothelioma shows frequent YAP activation due to genetic inactivation of the Hippo pathway components.	('YAP', 'Gene', '10413', (40, 43))	('activation', 'PosReg', (44, 54))	('mesothelioma', 'Disease', (12, 24))	('genetic inactivation', 'Var', (62, 82))	('YAP', 'Gene', (40, 43))	('Hippo pathway', 'Pathway', (90, 103))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))
205927	28536345	In pre-clinical models of different thoracic cancers, it has been found that these viruses can induce immunogenic cell death, increase the number of immune mediators brought into the tumor microenvironment and broaden the neoantigen-specific T cell response.	('neoantigen-specific T cell response', 'CPA', (222, 257))	('broaden', 'PosReg', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('thoracic cancers', 'Disease', 'MESH:D009369', (36, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('thoracic cancers', 'Disease', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('immunogenic cell death', 'CPA', (102, 124))	('viruses', 'Var', (83, 90))	('number of immune mediators brought', 'MPA', (139, 173))	('tumor', 'Disease', (183, 188))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cell death', 'biological_process', 'GO:0008219', ('114', '124'))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('increase', 'PosReg', (126, 134))	('induce', 'Reg', (95, 101))
205933	28536345	Immunotherapy, using anti-programmed death 1 (anti-PD1) antibodies, has recently been approved by the Food and Drug Administration (FDA) for NSCLC based on a statistically significant improvement in survival compared to standard chemotherapy.	('PD1', 'Gene', (51, 54))	('PD1', 'Gene', '5133', (51, 54))	('SCLC', 'Phenotype', 'HP:0030357', (142, 146))	('improvement', 'PosReg', (184, 195))	('NSCLC', 'Disease', (141, 146))	('antibodies', 'Var', (56, 66))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('anti-programmed', 'Var', (21, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('survival', 'MPA', (199, 207))
205934	28536345	For SCLC and MM, data has been presented to suggest that anti-PD1 antibodies may be as effective as chemotherapy for these diseases as well.	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('antibodies', 'Var', (66, 76))	('PD1', 'Gene', (62, 65))	('PD1', 'Gene', '5133', (62, 65))	('SCLC', 'Gene', '7864', (4, 8))	('SCLC', 'Gene', (4, 8))
205995	28536345	The presence of numerous mutations increases the likelihood of recognition by tumor-specific T cells.	('mutations', 'Var', (25, 34))	('increases', 'PosReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
205999	28536345	This data reveals a potential mechanism by which viral oncolysis can increase the chance of immune recognition by a tumor-specific T cell and lead to antitumor immune responses.	('viral oncolysis', 'Var', (49, 64))	('increase', 'PosReg', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('immune recognition', 'CPA', (92, 110))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (116, 121))	('lead to', 'Reg', (142, 149))	('tumor', 'Disease', (154, 159))
206008	28536345	Intratumoral VSV expressing IFNbeta (VSV-IFNbeta) results in a profound change in the tumor microenvironment of murine lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('VSV-IFNbeta', 'Disease', 'None', (37, 48))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('murine', 'Species', '10090', (112, 118))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('VSV', 'Var', (13, 16))	('VSV', 'Species', '11276', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('VSV', 'Species', '11276', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('change', 'Reg', (72, 78))	('tumor', 'Disease', (5, 10))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('VSV-IFNbeta', 'Disease', (37, 48))
206026	28536345	While anti-PD1 antibodies have demonstrated improvement in outcomes for patients with thoracic malignancies, the response rate remains low.	('PD1', 'Gene', (11, 14))	('thoracic malignancies', 'Disease', 'MESH:D009369', (86, 107))	('thoracic malignancies', 'Disease', (86, 107))	('improvement', 'PosReg', (44, 55))	('PD1', 'Gene', '5133', (11, 14))	('antibodies', 'Var', (15, 25))	('patients', 'Species', '9606', (72, 80))
206030	28536345	The promise of this approach has already been published with adenovirus in the NSCLC model and several groups are actively pursuing this approach for clinical translation.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('translation', 'biological_process', 'GO:0006412', ('159', '170'))	('SCLC', 'Phenotype', 'HP:0030357', (80, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('adenovirus', 'Var', (61, 71))	('NSCLC', 'Disease', (79, 84))
206188	27141352	To make the new virus vvDD-CXCL11, CV-1 cells were infected with vSC20 at multiplicity of infection (MOI) of 0.1 and then transfected with the shuttle plasmid.	('CXCL11', 'Gene', '56066', (27, 33))	('infection', 'Disease', (90, 99))	('CXCL11', 'Gene', (27, 33))	('infection', 'Disease', 'MESH:D007239', (90, 99))	('CV-1', 'CellLine', 'CVCL:0229', (35, 39))	('vSC20', 'Var', (65, 70))
206196	27141352	into mice to deplete CD8+ T cells, CD4+ T cells or neutralize circulating IFNgamma.	('IFNgamma', 'Gene', (74, 82))	('CD4', 'Gene', (35, 38))	('IFNgamma', 'Gene', '15978', (74, 82))	('CD8', 'Gene', (21, 24))	('CD4', 'Gene', '12504', (35, 38))	('CD8', 'Gene', '925', (21, 24))	('neutralize', 'Var', (51, 61))	('deplete', 'NegReg', (13, 20))	('mice', 'Species', '10090', (5, 9))
206258	26525147	The internalized cells may remain alive for some time, but will eventually be digested by specific enzymes within a cannibalistic vacuole; the inhibition or down regulation of these enzymes seems to affect the phagocytic activity of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('vacuole', 'cellular_component', 'GO:0005773', ('130', '137'))	('tumor', 'Disease', (233, 238))	('inhibition', 'Var', (143, 153))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('down regulation', 'NegReg', (157, 172))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('affect', 'Reg', (199, 205))
206349	25100651	Previous studies report the median length of hospital stay of between 4 and 6 days for inpatient talc pleurodesis, which for patients with a high LENT score would represent a substantial proportion of their remaining life, given their median survival in this study of only 44 days.	('patient', 'Species', '9606', (89, 96))	('talc pleurodesis', 'Disease', 'None', (97, 113))	('talc pleurodesis', 'Disease', (97, 113))	('patient', 'Species', '9606', (125, 132))	('high', 'Var', (141, 145))	('patients', 'Species', '9606', (125, 133))
206493	23272646	On the basis of these clinical examinations, the tumor was diagnosed as being T3N0M0 stage III MPM according to the Union for International Cancer Control guidelines.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('T3N0M0', 'Var', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', (49, 54))
206572	23108223	Small metastases and some non-solid adenocarcinomas were predominantly hypointense on diffusion-weighted images with high b values.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('adenocarcinomas', 'Disease', 'MESH:D000230', (36, 51))	('hypointense', 'Var', (71, 82))	('metastases', 'Disease', (6, 16))	('adenocarcinomas', 'Disease', (36, 51))
206751	30022998	For instance, recent genomic profiling of mesotheliomas shows that mutations in the BAP1 gene render its protein product inactive, and are correlated with MM and uveal melanoma incidence.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('mesotheliomas', 'Disease', 'MESH:D008654', (42, 55))	('mesotheliomas', 'Disease', (42, 55))	('correlated', 'Reg', (139, 149))	('BAP1', 'Gene', '8314', (84, 88))	('mutations', 'Var', (67, 76))	('protein product inactive', 'MPA', (105, 129))	('BAP1', 'Gene', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))
206761	30022998	Interestingly, some studies showed that SV40 rendered animals more susceptible to asbestos-related carcinogenesis, while asbestos was also reported to promote SV40 infection of cells.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('SV40', 'Species', '1891767', (159, 163))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('SV40 infection', 'Disease', 'MESH:D007239', (159, 173))	('SV40', 'Species', '1891767', (40, 44))	('SV40', 'Var', (40, 44))	('SV40 infection', 'Disease', (159, 173))	('carcinogenesis', 'Disease', (99, 113))	('asbestos-related', 'Disease', (82, 98))	('more', 'PosReg', (62, 66))	('promote', 'PosReg', (151, 158))	('asbestos', 'Chemical', 'MESH:D001194', (82, 90))	('susceptible', 'MPA', (67, 78))
206766	30022998	Combined genomics studies further showed that MM tumors have frequent hypermethylations or deletions at the Cdkn2a/Arf and Cdkn2b gene loci.	('Cdkn2a', 'Gene', (108, 114))	('hypermethylations', 'Var', (70, 87))	('Cdkn2b', 'Gene', (123, 129))	('MM tumors', 'Disease', (46, 55))	('deletions', 'Var', (91, 100))	('MM tumors', 'Disease', 'MESH:D009369', (46, 55))	('Cdkn2a', 'Gene', '1029', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Cdkn2b', 'Gene', '1030', (123, 129))
206769	30022998	Common chromosomal abnormalities, such as deletions, of chromosomes 1, 3, 4, 9, 11, 14 and 22, have been identified in patient-derived cell lines of MM.	('patient', 'Species', '9606', (119, 126))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (7, 32))	('deletions', 'Var', (42, 51))	('chromosomal abnormalities', 'Disease', (7, 32))
206776	30022998	Among these four cell lines, Nf2 was found to be mutated only in ACC-MESO-1.	('MESO-1', 'Gene', '21407', (69, 75))	('mutated', 'Var', (49, 56))	('MESO-1', 'Gene', (69, 75))	('Nf2', 'Gene', (29, 32))
206778	30022998	In another study, homozygous deletions of p16INK4A and inactivation of the p14ARF gene were found in all four cell lines.	('p16INK4A', 'Gene', '1029', (42, 50))	('p14ARF', 'Gene', (75, 81))	('p16INK4A', 'Gene', (42, 50))	('p14ARF', 'Gene', '1029', (75, 81))	('deletions', 'Var', (29, 38))
206848	28884088	The concern for toxicity of wild-type viruses led to the first recombinant viruses being engineered as replication-incompetent strains, with the goal of delivering gene therapy but not necessarily propagation of viral infection.	('toxicity', 'Disease', 'MESH:D064420', (16, 24))	('toxicity', 'Disease', (16, 24))	('viral infection', 'Disease', (212, 227))	('gene', 'Var', (164, 168))	('viral infection', 'biological_process', 'GO:0016032', ('212', '227'))	('viral infection', 'Disease', 'MESH:D001102', (212, 227))
206853	28884088	Gene therapy with replication-incompetent viruses has a bystander effect that also may amplify cell death in the local tumor environment, although to a lesser extent than actively replicating viruses.	('tumor', 'Disease', (119, 124))	('amplify', 'PosReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Gene therapy', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cell death', 'biological_process', 'GO:0008219', ('95', '105'))
206857	28884088	A third method of antitumor efficacy is insertion of transgenes into the viral genome, so-called "armed" viruses.	('insertion', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('transgenes', 'Var', (53, 63))
206858	28884088	An early model of transgene insertion is the HSV thymidine kinase gene, which metabolizes ganciclovir into a toxic byproduct.	('HSV thymidine kinase gene', 'Gene', (45, 70))	('insertion', 'Var', (28, 37))	('ganciclovir', 'Chemical', 'MESH:D015774', (90, 101))
206859	28884088	Cells infected with a virus carrying this gene are rapidly lysed in the presence of ganciclovir.	('infect', 'Disease', 'MESH:D007239', (6, 12))	('gene', 'Var', (42, 46))	('ganciclovir', 'Chemical', 'MESH:D015774', (84, 95))	('infect', 'Disease', (6, 12))
206874	28884088	This illustrates how cellular changes defining malignancy, such as resistance to apoptosis and loss of p53, often overlap with virally induced cellular changes.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('resistance to apoptosis', 'CPA', (67, 90))	('rat', 'Species', '10116', (11, 14))	('malignancy', 'Disease', 'MESH:D009369', (47, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('malignancy', 'Disease', (47, 57))	('loss', 'Var', (95, 99))
206877	28884088	A dysfunctional PKR pathway enhances reovirus replication, and defects in the type 1 IFN response potentiate the replication of vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV).	('potentiate', 'PosReg', (98, 108))	('PKR', 'Gene', (16, 19))	('IFN', 'Gene', '3439', (85, 88))	('NDV', 'Species', '11176', (190, 193))	('replication', 'MPA', (113, 124))	('dysfunctional', 'Var', (2, 15))	('defects', 'Var', (63, 70))	('IFN', 'Gene', (85, 88))	('stomatitis', 'Phenotype', 'HP:0010280', (138, 148))	('PKR', 'Gene', '5610', (16, 19))	('reovirus', 'Species', '10891', (37, 45))	('vesicular stomatitis virus (VSV) and Newcastle disease virus', 'Disease', 'MESH:D054243', (128, 188))	('enhances', 'PosReg', (28, 36))	('reovirus', 'Protein', (37, 45))
206879	28884088	Gene deletions can remove viral genes necessary for replication in normal tissue but not required for replication in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Gene deletions', 'Var', (0, 14))
206881	28884088	Deletion of these viral genes restores the ability of healthy cells to prevent viral replication, while cancer cells already deficient in the antiviral pathway remain susceptible.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('viral replication', 'biological_process', 'GO:0019079', ('79', '96'))	('viral replication', 'biological_process', 'GO:0019058', ('79', '96'))	('ability', 'MPA', (43, 50))	('restores', 'PosReg', (30, 38))	('prevent viral replication', 'MPA', (71, 96))	('viral replication', 'biological_process', 'GO:0008166', ('79', '96'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('Deletion', 'Var', (0, 8))
206882	28884088	HSV-1 modified for deletion of the ICP34.5 gene is such an example.	('HSV-1', 'Species', '10298', (0, 5))	('deletion', 'Var', (19, 27))	('ICP34.5', 'Gene', (35, 42))
206897	28884088	The move to immune-competent models was accompanied by suppression of the immune response, such as dampening T cell response through gene deletions or administering cyclophosphamide prior to viral administration.	('gene deletions', 'Var', (133, 147))	('rat', 'Species', '10116', (205, 208))	('T cell', 'MPA', (109, 115))	('dampening T cell response', 'Phenotype', 'HP:0005419', (99, 124))	('dampening', 'NegReg', (99, 108))	('dampening T cell', 'Phenotype', 'HP:0005403', (99, 115))	('immune response', 'biological_process', 'GO:0006955', ('74', '89'))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (165, 181))
206899	28884088	Viral genetic engineering now includes modifications to boost immune antitumor activity, often through insertion of cytokine genes.	('boost', 'PosReg', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('insertion', 'Var', (103, 112))	('tumor', 'Disease', (73, 78))	('cytokine genes', 'Gene', (116, 130))
206902	28884088	The HSV-1 protein ICP47 decreases antigen presentation on infected cells, and deletion of this gene augments antitumor effects.	('decreases', 'NegReg', (24, 33))	('tumor', 'Disease', (113, 118))	('antigen presentation', 'MPA', (34, 54))	('augments', 'NegReg', (100, 108))	('deletion', 'Var', (78, 86))	('infect', 'Disease', 'MESH:D007239', (58, 64))	('antigen presentation', 'biological_process', 'GO:0019882', ('34', '54'))	('decreases antigen presentation on infected cells', 'Phenotype', 'HP:0041048', (24, 72))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('HSV-1', 'Species', '10298', (4, 9))	('ICP47', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('infect', 'Disease', (58, 64))
206921	28884088	Two viral modifications for molecular imaging are insertion of the gene encoding green fluorescent protein (GFP) or the human sodium iodide symporter (hNIS) protein.	('human', 'Species', '9606', (120, 125))	('sodium iodide', 'Chemical', 'MESH:D012974', (126, 139))	('hNIS', 'Gene', (151, 155))	('hNIS', 'Gene', '6528', (151, 155))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('insertion', 'Var', (50, 59))
206924	28884088	This is illustrated by T-VEC, an HSV-1 with three separate modifications:deletion of gene ICP34.5 to attenuate neurovirulence, deletion of ICP47 to increase antigen presentation on infected cells, and insertion of the gene for GM-CSF to attract antigen-presenting cells.	('increase', 'PosReg', (148, 156))	('ICP47', 'Gene', (139, 144))	('antigen presentation', 'MPA', (157, 177))	('neurovirulence', 'MPA', (111, 125))	('HSV-1', 'Species', '10298', (33, 38))	('ICP34.5', 'Gene', (90, 97))	('rat', 'Species', '10116', (54, 57))	('infect', 'Disease', 'MESH:D007239', (181, 187))	('deletion', 'Var', (127, 135))	('attenuate', 'NegReg', (101, 110))	('deletion', 'Var', (73, 81))	('antigen presentation', 'biological_process', 'GO:0019882', ('157', '177'))	('infect', 'Disease', (181, 187))	('rat', 'Species', '10116', (14, 17))
206946	28884088	In several murine experiments, IT injection of an adenovirus with insertion of the IFNgamma gene resulted in tumor regression and a CD8+ T cell-mediated response.	('adenovirus', 'Species', '28285', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('insertion', 'Var', (66, 75))	('IFNgamma', 'Gene', (83, 91))	('CD8', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('murine', 'Species', '10090', (11, 17))	('CD8', 'Gene', '925', (132, 135))	('IFNgamma', 'Gene', '3458', (83, 91))	('tumor', 'Disease', (109, 114))
206951	28884088	In vivo studies with murine models have used a number of CRAd modifications:promoters linked to E1 gene expression, viral capsid alterations, and insertion of GFP for viral imaging.	('rat', 'Species', '10116', (133, 136))	('CRAd', 'Gene', (57, 61))	('viral capsid', 'cellular_component', 'GO:0019028', ('116', '128'))	('CRAd', 'Gene', '19683', (57, 61))	('insertion', 'Var', (146, 155))	('murine', 'Species', '10090', (21, 27))	('E1 gene', 'Gene', (96, 103))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))
206953	28884088	This was co-administered with a replication-incompetent adenovirus with insertion of the heparanase gene to improve viral penetration through the dense extracellular matrix.	('viral penetration', 'CPA', (116, 133))	('heparanase gene', 'Gene', (89, 104))	('viral penetration', 'biological_process', 'GO:0046718', ('116', '133'))	('rat', 'Species', '10116', (127, 130))	('improve', 'PosReg', (108, 115))	('insertion', 'Var', (72, 81))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('152', '172'))	('adenovirus', 'Species', '28285', (56, 66))
206958	28884088	Seventeen patients had evidence of IT gene transfer on repeat pleural biopsy, although this was limited to the outermost tumor layers.	('gene transfer', 'Var', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
206987	28884088	This natural tropism for neuronal tissue led to early studies on brain tumors and also necessitates viral gene deletions to attenuate neurotoxicity in all oncolytic experiments using HSV-1.	('tropism', 'biological_process', 'GO:0009606', ('13', '20'))	('HSV-1', 'Species', '10298', (183, 188))	('neurotoxicity', 'Disease', 'MESH:D020258', (134, 147))	('brain tumors', 'Disease', 'MESH:D001932', (65, 77))	('attenuate', 'NegReg', (124, 133))	('brain tumors', 'Phenotype', 'HP:0030692', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('deletions', 'Var', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('neurotoxicity', 'Disease', (134, 147))	('brain tumors', 'Disease', (65, 77))
206993	28884088	Fourteen days later, the mice were given HSV-1716 by intraperitoneal injection, resulting in decreased tumor burden and increased survival compared to controls.	('decreased tumor', 'Disease', 'MESH:D009369', (93, 108))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('survival', 'CPA', (130, 138))	('HSV-1716', 'Var', (41, 49))	('decreased tumor', 'Disease', (93, 108))	('increased', 'PosReg', (120, 129))	('HSV-1', 'Species', '10298', (41, 46))
206995	28884088	Another preclinical study evaluated three different replication-competent, oncolytic herpesviruses: G207, NV1020, and NV1066.	('NV1066', 'Var', (118, 124))	('herpesvirus', 'Species', '39059', (85, 96))	('G207', 'Var', (100, 104))	('NV1020', 'Var', (106, 112))
206998	28884088	A murine model of MPM treated with NV1066 decreased tumor burden and increased survival.	('MPM', 'Chemical', '-', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('increased', 'PosReg', (69, 78))	('murine', 'Species', '10090', (2, 8))	('survival', 'CPA', (79, 87))	('decreased tumor', 'Disease', 'MESH:D009369', (42, 57))	('NV1066', 'Var', (35, 41))	('decreased tumor', 'Disease', (42, 57))	('MPM', 'Disease', (18, 21))
206999	28884088	The first study evaluated viral replication and cytotoxicity in 10 human MPM cell lines infected with NV1066 with or without cisplatin.	('viral replication', 'biological_process', 'GO:0008166', ('26', '43'))	('MPM', 'Chemical', '-', (73, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('infect', 'Disease', (88, 94))	('NV1066', 'Var', (102, 108))	('viral replication', 'biological_process', 'GO:0019079', ('26', '43'))	('viral replication', 'biological_process', 'GO:0019058', ('26', '43'))	('cytotoxicity', 'Disease', (48, 60))	('infect', 'Disease', 'MESH:D007239', (88, 94))	('human', 'Species', '9606', (67, 72))
207000	28884088	The combination proved synergistic, at least partly attributable to cisplatin-induced DNA damage upregulating the protein GADD34 that in turn potentiates replication and cytotoxicity of the mutant HSV-1.	('cytotoxicity', 'Disease', (170, 182))	('potentiates', 'PosReg', (142, 153))	('HSV-1', 'Gene', (197, 202))	('GADD34', 'Gene', '23645', (122, 128))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('mutant', 'Var', (190, 196))	('HSV-1', 'Species', '10298', (197, 202))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('upregulating', 'PosReg', (97, 109))	('GADD34', 'Gene', (122, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
207001	28884088	The second study combined NV1066 and radiation therapy in multiple human MPM cell lines and found synergistic or additive effects depending on the cell line, based on the same mechanism of GADD34 upregulation.	('MPM', 'Chemical', '-', (73, 76))	('NV1066', 'Var', (26, 32))	('GADD34', 'Gene', (189, 195))	('upregulation', 'PosReg', (196, 208))	('human', 'Species', '9606', (67, 72))	('GADD34', 'Gene', '23645', (189, 195))
207006	28884088	An enveloped, double-stranded DNA virus in the poxvirus family, vaccinia virus has a large ~190 kb genome that facilitates insertion and deletion modifications to improve oncolytic efficacy.	('oncolytic efficacy', 'CPA', (171, 189))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('insertion', 'Var', (123, 132))	('vaccinia virus', 'Species', '10245', (64, 78))	('facilitates', 'PosReg', (111, 122))	('improve', 'PosReg', (163, 170))	('deletion modifications', 'Var', (137, 159))
207015	28884088	The replication-competent vaccinia virus GLV-1h68 has deletions of the hemagglutinin and thymidine kinase genes for attenuation and insertion of three transgenes including GFP for viral imaging.	('attenuation', 'NegReg', (116, 127))	('deletions', 'Var', (54, 63))	('vaccinia virus GLV-1h68', 'Species', '502057', (26, 49))	('hemagglutinin', 'Gene', (71, 84))
207018	28884088	The GLV-1h153 virus, a modification of the parent virus GLV-1h68 by insertion of the hNIS gene, proved similarly effective for in vitro and murine models with the addition of radioiodine-based imaging for viral infection.	('hNIS', 'Gene', (85, 89))	('hNIS', 'Gene', '6528', (85, 89))	('viral infection', 'biological_process', 'GO:0016032', ('205', '220'))	('insertion', 'Var', (68, 77))	('murine', 'Species', '10090', (140, 146))	('viral infection', 'Disease', 'MESH:D001102', (205, 220))	('GLV-1h68', 'Species', '502057', (56, 64))	('radioiodine', 'Chemical', 'MESH:C000614965', (175, 186))	('viral infection', 'Disease', (205, 220))
207020	28884088	An oncolytic strain with deletions in thymidine kinase and vaccinia growth factor genes for tumor selectivity was used, the double-deleted vaccinia virus (vvDD).	('vaccinia virus', 'Species', '10245', (139, 153))	('vaccinia', 'Species', '10245', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('deletions', 'Var', (25, 34))	('tumor', 'Disease', (92, 97))	('vaccinia', 'Species', '10245', (139, 147))
207022	28884088	A small pilot study published in 2000 used a vaccinia virus with insertion of the IL-2 gene into the thymidine kinase gene region, a replication-competent virus with tumor cell selectivity.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('IL-2', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('IL-2', 'molecular_function', 'GO:0005134', ('82', '86'))	('insertion', 'Var', (65, 74))	('vaccinia virus', 'Species', '10245', (45, 59))	('IL-2', 'Gene', '3558', (82, 86))
207039	28884088	Li and colleagues used a murine model of mesothelioma to study Edmonston strain MV with insertion of the IFNbeta and NIS genes (MV-mIFNbeta-NIS).	('mIFNbeta', 'Chemical', '-', (131, 139))	('insertion', 'Var', (88, 97))	('NIS', 'Gene', '6528', (140, 143))	('mesothelioma', 'Disease', (41, 53))	('MV', 'Species', '11234', (80, 82))	('MV', 'Species', '11234', (128, 130))	('NIS', 'Gene', '6528', (117, 120))	('NIS', 'Gene', (140, 143))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('murine', 'Species', '10090', (25, 31))	('NIS', 'Gene', (117, 120))
207042	28884088	Tumors injected with MV-mIFNbeta had increased immune cell infiltration and decreased angiogenesis compared to tumors injected with the parent MV without mIFNbeta expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('increased', 'PosReg', (37, 46))	('mIFNbeta', 'Chemical', '-', (154, 162))	('MV', 'Species', '11234', (143, 145))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('Tumors', 'Disease', (0, 6))	('mIFNbeta', 'Chemical', '-', (24, 32))	('MV', 'Species', '11234', (21, 23))	('immune cell infiltration', 'CPA', (47, 71))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('angiogenesis', 'CPA', (86, 98))	('angiogenesis', 'biological_process', 'GO:0001525', ('86', '98'))	('MV-mIFNbeta', 'Var', (21, 32))	('decreased', 'NegReg', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('rat', 'Species', '10116', (65, 68))
207053	28884088	A phase I trial using the attenuated Edmonston strain with insertion of the NIS gene (MV-NIS) is currently enrolling patients with MPM confined to a single pleural cavity.	('MPM', 'Disease', (131, 134))	('NIS', 'Gene', (76, 79))	('MV', 'Species', '11234', (86, 88))	('MPM', 'Chemical', '-', (131, 134))	('insertion', 'Var', (59, 68))	('NIS', 'Gene', (89, 92))	('NIS', 'Gene', '6528', (76, 79))	('patients', 'Species', '9606', (117, 125))	('NIS', 'Gene', '6528', (89, 92))
207101	28761723	These cases demonstrate significant sustained clinical benefit of phosphoinositide 3-kinase-mammalian target of rapamycin (PI3K-mTOR) inhibition in peritoneal cases without PIK3CA mutations or phosphatase and tensin homologue (PTEN) loss.	('phosphatase', 'molecular_function', 'GO:0016791', ('193', '204'))	('PIK3CA', 'Gene', '5290', (173, 179))	('mTOR', 'Gene', (128, 132))	('PTEN', 'Gene', (227, 231))	('mutations', 'Var', (180, 189))	('mammalian target of rapamycin', 'Gene', '2475', (92, 121))	('mammalian target of rapamycin', 'Gene', (92, 121))	('PTEN', 'Gene', '5728', (227, 231))	('mTOR', 'Gene', '2475', (128, 132))	('phosphoinositide 3-kinase', 'Gene', '5290', (66, 91))	('inhibition', 'NegReg', (134, 144))	('phosphoinositide 3-kinase', 'Gene', (66, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('peritoneal', 'Disease', (148, 158))	('loss', 'NegReg', (233, 237))	('PIK3CA', 'Gene', (173, 179))
207157	28761723	Notably, no assays to assess NF2 have been undertaken, this would be interesting to know as mutations can occur in up to half of mesothelioma cases and could account for sensitivity to PI3K-mTOR pathway blockade.	('occur', 'Reg', (106, 111))	('NF2', 'Gene', '4771', (29, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('mTOR', 'Gene', '2475', (190, 194))	('mTOR', 'Gene', (190, 194))	('mutations', 'Var', (92, 101))	('NF2', 'Gene', (29, 32))	('mesothelioma', 'Disease', (129, 141))
207158	28761723	Another molecular change that would be interesting to assess is the BRCA-associated protein 1 (BAP1), a tumour suppressor, in which somatic mutations occur up to 60% in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (169, 181))	('BAP1', 'Gene', (95, 99))	('BRCA-associated protein 1', 'Gene', (68, 93))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('BAP1', 'Gene', '8314', (95, 99))	('mesothelioma', 'Disease', (169, 181))	('mutations', 'Var', (140, 149))	('BRCA-associated protein 1', 'Gene', '8314', (68, 93))	('tumour', 'Disease', (104, 110))
207161	28761723	Targeting the loss of function of tumour suppressors PTEN and NF2 is pharmacologically challenging, and new efforts are needed through inhibition of synthetic lethal targets or other approaches such as targeting ubiquitin-mediated destruction or epigenetic gene silencing.	('ubiquitin', 'molecular_function', 'GO:0031386', ('212', '221'))	('ubiquitin-mediated', 'MPA', (212, 230))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('NF2', 'Gene', '4771', (62, 65))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('gene silencing', 'biological_process', 'GO:0016458', ('257', '271'))	('loss of function', 'NegReg', (14, 30))	('tumour', 'Disease', (34, 40))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('NF2', 'Gene', (62, 65))	('epigenetic gene silencing', 'Var', (246, 271))
207223	27886205	NO36 CM stimulated similar levels of AP production in LO68 cells compared with OM and OM + NO36 CM (Fig.	('LO68', 'Chemical', '-', (54, 58))	('NO36 CM', 'Var', (0, 7))	('AP production', 'MPA', (37, 50))
207232	27886205	DEX treatment did not enhance bone formation in AE5 or AB1 MM tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('bone formation', 'biological_process', 'GO:0001503', ('30', '44'))	('AE5', 'Gene', '25832', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('bone formation', 'CPA', (30, 44))	('AB1', 'Var', (55, 58))	('MM tumors', 'Disease', (59, 68))	('AE5', 'Gene', (48, 51))	('DEX', 'Chemical', 'MESH:D003907', (0, 3))	('MM tumors', 'Disease', 'MESH:D009369', (59, 68))
207249	27886205	NO36-CM induced AP expression in LO68 cells but did not induce formation of mineralized nodules, suggesting that other factors may be required to drive mineralization.	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('AP expression', 'MPA', (16, 29))	('LO68', 'Chemical', '-', (33, 37))	('mineralization', 'biological_process', 'GO:0110148', ('152', '166'))	('NO36-CM', 'Var', (0, 7))
207256	27886205	DEX treatment did not induce bone formation in either cell line, however tumor growth was significantly increased in DEX treated AE5 cells with evidence of dermal invasion and abundant collagen.	('dermal invasion', 'CPA', (156, 171))	('DEX', 'Chemical', 'MESH:D003907', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('AE5', 'Gene', (129, 132))	('increased', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DEX', 'Chemical', 'MESH:D003907', (0, 3))	('collagen', 'molecular_function', 'GO:0005202', ('185', '193'))	('collagen', 'CPA', (185, 193))	('tumor', 'Disease', (73, 78))	('DEX', 'Var', (117, 120))	('bone formation', 'biological_process', 'GO:0001503', ('29', '43'))	('AE5', 'Gene', '25832', (129, 132))
207282	27886205	Approximately, 2 x 106 AB1 and 3.5 x 106 AE5 syngeneic cells were injected subcutaneously into the right flank of either BALB/C (AB1) or C57BL/6 (AE5) mice respectively and tumor growth monitored by taking perpendicular measurements using microcalipers.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('AE5', 'Gene', '25832', (41, 44))	('mice', 'Species', '10090', (151, 155))	('AE5', 'Gene', (41, 44))	('AE5', 'Gene', '25832', (146, 149))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('AE5', 'Gene', (146, 149))	('C57BL/6', 'Var', (137, 144))
207290	26140232	Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen A key to improving cancer immunotherapy will be the identification of tumor-specific "neoantigens" that arise from mutations and augment the resultant host immune response.	('augment', 'PosReg', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('immune response', 'biological_process', 'GO:0006955', ('238', '253'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (199, 208))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('human', 'Species', '9606', (67, 72))	('tumor', 'Disease', (154, 159))
207297	26140232	Although it has been known for many years that tumors express a large number of mutated proteins that could potentially elicit strong immune responses, the difficulty of detecting these antigens and quantifying their specific antitumor reactivity has meant that few such neoantigens have been identified.	('tumor', 'Disease', (230, 235))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('elicit', 'Reg', (120, 126))	('mutated', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('proteins', 'Protein', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))
207299	26140232	NGS of tumors, identification of non-synonymous mutations, and in silico epitope prediction have successfully been used to identify tumor neoantigens in several mouse cancers, including spontaneous melanoma and methylcholanthrene (MCA)-induced sarcoma, and in some human cancers, including melanoma, cholangiocarcinoma, ovarian cancer, and chronic lymphocytic leukemia in a variety of treatment settings.	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('human', 'Species', '9606', (265, 270))	('melanoma', 'Disease', 'MESH:D008545', (290, 298))	('tumor', 'Disease', (132, 137))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('cancers', 'Disease', (271, 278))	('ovarian cancer', 'Disease', 'MESH:D010051', (320, 334))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('sarcoma', 'Disease', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('tumors', 'Disease', (7, 13))	('melanoma', 'Disease', (198, 206))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('ovarian cancer', 'Disease', (320, 334))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (340, 368))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('chronic lymphocytic leukemia', 'Disease', (340, 368))	('melanoma', 'Disease', (290, 298))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('ovarian cancer', 'Phenotype', 'HP:0100615', (320, 334))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (300, 318))	('mouse', 'Species', '10090', (161, 166))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (340, 368))	('tumor', 'Disease', (7, 12))	('cholangiocarcinoma', 'Disease', (300, 318))	('leukemia', 'Phenotype', 'HP:0001909', (360, 368))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (300, 318))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
207309	26140232	To increase the probability of identifying mutations that were expressed by the cancer, we used RNAseq.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))
207315	26140232	All mice generated a CD8+ T-cell response that was restricted to the mutant peptides in pool B only (Fig.	('CD8+ T-cell response', 'MPA', (21, 41))	('mice', 'Species', '10090', (4, 8))	('mutant', 'Var', (69, 75))
207316	26140232	Deconvolution of pool B revealed that the immune response was directed against only one of the 5 peptides, mutated Uqcrc2, with a median of 0.17 (interquartile range [IQR], 0-1.42) spot-forming units (SFU)/105 cells against the wild-type peptide detected in 9 mice, which was significantly less than the 14.38 (IQR 9.32-29.42) SFU/105 cells demonstrated against the mutant peptide (P < 0.01) Fig.	('mice', 'Species', '10090', (260, 264))	('Uqcrc2', 'Gene', '67003', (115, 121))	('immune response', 'biological_process', 'GO:0006955', ('42', '57'))	('mutated', 'Var', (107, 114))	('Uqcrc2', 'Gene', (115, 121))	('mutant', 'Var', (366, 372))
207319	26140232	Although the total number of SFU/105 cells was lower in the spleen than in the dLN, there was still a significantly greater response against the mutant Uqcrc2 peptide (4.5 [IQR 0.34-7.5] SFU/105 cells) compared to the wild-type peptide (0.34 [IQR 0-1.12] SFU/105 cells; P < 0.05) in this compartment Fig.	('greater', 'PosReg', (116, 123))	('mutant', 'Var', (145, 151))	('Uqcrc2', 'Gene', '67003', (152, 158))	('Uqcrc2', 'Gene', (152, 158))	('response', 'MPA', (124, 132))
207322	26140232	The median response to the mutant Uqcrc2 peptide was 15.38 (IQR 4.90-58.50) SFU/105 cells, which is in the range of that seen with the HA CL4 peptide (5.04 [IQR 0.40-63.17] SFU/105 cells) Fig.	('Uqcrc2', 'Gene', '67003', (34, 40))	('Uqcrc2', 'Gene', (34, 40))	('mutant', 'Var', (27, 33))
207324	26140232	3C, whereas a second animal (mouse 1) had a significantly stronger response to the mutant Uqcrc2 peptide than to the HA peptide Fig.	('response to', 'MPA', (67, 78))	('Uqcrc2', 'Gene', '67003', (90, 96))	('mutant', 'Var', (83, 89))	('Uqcrc2', 'Gene', (90, 96))	('stronger', 'PosReg', (58, 66))	('mouse', 'Species', '10090', (29, 34))
207337	26140232	Our data from this study of an asbestos-induced tumor, mesothelioma, in mice suggest that the number of mutations is similar to that seen in human mesothelioma (unpublished data).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mesothelioma', 'Disease', (147, 159))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (48, 53))	('mesothelioma', 'Disease', (55, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('human', 'Species', '9606', (141, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('asbestos', 'Chemical', 'MESH:D001194', (31, 39))
207340	26140232	Although this molecule is involved in cellular respiration and its mutation might affect the altered glycolysis that is common in tumor biology, we do not yet know whether this mutation has any non-immunologic relevance in this model.	('mutation', 'Var', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('glycolysis', 'biological_process', 'GO:0006096', ('101', '111'))	('altered glycolysis', 'MPA', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cellular respiration', 'biological_process', 'GO:0045333', ('38', '58'))	('tumor', 'Disease', (130, 135))	('affect', 'Reg', (82, 88))
207364	26140232	Matched sequences were analyzed using NetMHCpan 2.8 algorithm and the potential class I binding affinity to murine MHC class I haplotype of H-2 Dd, H-2 Kd and H-2 Ld were determined.	('H-2 Dd', 'Var', (140, 146))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('H-2 Kd', 'Gene', (148, 154))	('H-2 Kd', 'Gene', '14972', (148, 154))	('binding', 'Interaction', (88, 95))	('murine', 'Species', '10090', (108, 114))
207392	25502863	In vivo, tumor xenograft studies showed that amatuximab plus chemotherapy led to a greater reduction in the growth of mesothelin-expressing tumors than either amatuximab or chemotherapy alone.	('tumors', 'Disease', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (9, 14))	('reduction', 'NegReg', (91, 100))	('amatuximab', 'Chemical', 'MESH:C526187', (159, 169))	('amatuximab', 'Chemical', 'MESH:C526187', (45, 55))	('amatuximab', 'Var', (45, 55))	('growth', 'MPA', (108, 114))	('tumor', 'Disease', (140, 145))
207412	25502863	Other key inclusion criteria were as follows: age of 20-79 years; a life expectancy of 12 weeks or more; Eastern Cooperative Oncology Group performance score of 0 or 1; adequate organ function [hemoglobin >=9.0 g/dL; neutrophil count >=1.5 x 103/muL; white blood cell count 3.0-12.0 x 103/muL; platelet count >=10 x 104/muL; aspartate transaminase (AST) <=5 x upper limit of normal (ULN); alanine transaminase (ALT) <=5 x ULN; alkaline phosphatase <=5 x ULN; total bilirubin <=2.0 mg/dL; serum creatinine <=2.0 mg/dL].	('phosphatase', 'molecular_function', 'GO:0016791', ('436', '447'))	('AST', 'Gene', '26503', (349, 352))	('serum creatinine', 'MPA', (488, 504))	('>=9.0', 'Var', (205, 210))	('total bilirubin', 'MPA', (459, 474))	('aspartate transaminase', 'Gene', '26503', (325, 347))	('ALT', 'molecular_function', 'GO:0004021', ('411', '414'))	('aspartate transaminase', 'Gene', (325, 347))	('alkaline phosphatase', 'MPA', (427, 447))	('Oncology', 'Phenotype', 'HP:0002664', (125, 133))	('alanine transaminase', 'MPA', (389, 409))	('AST', 'Gene', (349, 352))
207546	23082261	Pathology reported mesothelioma with malignant cells positive by immunohistochemistry to calretinin and D240, and negative for CEA and MOC31 (Figures 1, 2, 3, 4, and 5).	('mesothelioma', 'Disease', 'MESH:D008654', (19, 31))	('calretinin', 'Gene', '794', (89, 99))	('CEA', 'Gene', (127, 130))	('D240', 'Var', (104, 108))	('calretinin', 'Gene', (89, 99))	('mesothelioma', 'Disease', (19, 31))	('CEA', 'Gene', '1084', (127, 130))
207642	31832406	However, we observed no increase in the amount of ascites following KM-CART, during GEM therapy, or until 4 mo before death.	('KM-CART', 'Chemical', '-', (68, 75))	('ascites', 'Disease', 'MESH:D001201', (50, 57))	('KM-CART', 'Var', (68, 75))	('GEM', 'Chemical', 'MESH:C056507', (84, 87))	('ascites', 'Phenotype', 'HP:0001541', (50, 57))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))	('ascites', 'Disease', (50, 57))
207666	28288645	Secondly, genetic knockdown of MSLN significantly reduced anchorage-independent cell growth, tumor sphere formation, cell adhesion, migration and invasion in vitro, as well as tumor formation and metastasis in vivo.	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cell adhesion', 'biological_process', 'GO:0007155', ('117', '130'))	('anchorage-independent cell growth', 'CPA', (58, 91))	('cell adhesion', 'CPA', (117, 130))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (93, 98))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('reduced', 'NegReg', (50, 57))	('formation', 'biological_process', 'GO:0009058', ('182', '191'))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('MSLN', 'Gene', (31, 35))	('metastasis', 'CPA', (196, 206))	('invasion', 'CPA', (146, 154))
207683	28288645	In lung cancer, accumulating evidence indicates that high expression of MSLN is correlated with poor patient's overall prognosis and relapse-free survival.	('lung cancer', 'Disease', (3, 14))	('MSLN', 'Gene', (72, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('relapse-free survival', 'CPA', (133, 154))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patient', 'Species', '9606', (101, 108))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('high expression', 'Var', (53, 68))
207725	28288645	Mice (6/group) were subcutaneously injected with 1 x 106 cells of H460 or H2052 with shMSLN stable knockdown or shRNA control cells suspended in 100 mul of ExtraCel  hydrogel (Advanced BioMatrix, San Diego, CA, USA).	('shMSLN', 'Gene', (85, 91))	('H460', 'CellLine', 'CVCL:0459', (66, 70))	('knockdown', 'Var', (99, 108))	('Mice', 'Species', '10090', (0, 4))	('H2052', 'CellLine', 'CVCL:1518', (74, 79))
207739	28288645	Figure 2b shows that the MSLN knockdown (shMSLN) clones exhibited a slower rate of proliferation than their vector (shC) controls in both H460 and H2052 cell lines.	('slower', 'NegReg', (68, 74))	('H2052', 'CellLine', 'CVCL:1518', (147, 152))	('MSLN knockdown', 'Var', (25, 39))	('H460', 'CellLine', 'CVCL:0459', (138, 142))
207740	28288645	Soft agar colony formation assay indicated that the shMSLN cells formed substantially smaller and fewer colonies than the control shC cells (Fig.	('shMSLN', 'Var', (52, 58))	('smaller', 'NegReg', (86, 93))	('colonies', 'CPA', (104, 112))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('fewer', 'NegReg', (98, 103))	('agar', 'Chemical', 'MESH:D000362', (5, 9))
207741	28288645	Likewise, shMSLN cells formed smaller and fewer of tumor spheres than control cells (Fig.	('fewer', 'NegReg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('shMSLN', 'Var', (10, 16))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
207746	28288645	This result implies that MSLN knockdown cells are more epithelial-like and likely to localize in the primary tumor as compared to control cells which are more mobile and likely to metastasize to other tissues.	('more', 'PosReg', (50, 54))	('MSLN knockdown', 'Var', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('knockdown', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
207747	28288645	Experiments to assess the motility of MSLN knockdown cells using Transwell  assays showed that the shMSLN cells were indeed less migratory and less invasive through extracellular matrix than the control shC cells (Fig.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('165', '185'))	('migratory', 'CPA', (129, 138))	('less', 'NegReg', (143, 147))	('invasive through extracellular matrix', 'CPA', (148, 185))	('shMSLN', 'Var', (99, 105))	('less', 'NegReg', (124, 128))	('men', 'Species', '9606', (6, 9))
207751	28288645	To verify the in vitro observations, we conducted in vivo experiments assessing the effects of MSLN knockdown on tumor formation and metastasis using a xenograft mouse model.	('tumor', 'Disease', (113, 118))	('knockdown', 'Var', (100, 109))	('mouse', 'Species', '10090', (162, 167))	('MSLN', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('men', 'Species', '9606', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
207755	28288645	The metastatic nodules were observed in the liver and lungs of all mice in the shC group, whereas only one in six mice in the shMSLN group developed such nodules.	('shC', 'Var', (79, 82))	('metastatic nodules', 'CPA', (4, 22))	('mice', 'Species', '10090', (67, 71))	('mice', 'Species', '10090', (114, 118))
207758	28288645	Tumor area analysis of the tissue sections revealed a substantial reduction in liver and lung tumors in the shMSLN group compared to the shC group (Fig.	('lung tumor', 'Phenotype', 'HP:0100526', (89, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('liver and lung tumors', 'Disease', 'MESH:D008175', (79, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('shMSLN', 'Var', (108, 114))	('lung tumors', 'Phenotype', 'HP:0100526', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('reduction', 'NegReg', (66, 75))
207767	28288645	The pathway specific PCR results were verified by Western blotting, which confirmed that MSLN knockdown upregulated the epithelial markers (E-cadherin and caveolin-2) and downregulated stem cell/EMT markers (twist, snail, slug, and ABCG2) (Fig.	('knockdown', 'Var', (94, 103))	('twist', 'Gene', '7291', (208, 213))	('stem cell/EMT markers', 'CPA', (185, 206))	('slug', 'Gene', (222, 226))	('E-cadherin', 'Gene', (140, 150))	('snail', 'Gene', (215, 220))	('E-cadherin', 'Gene', '999', (140, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('ABCG2', 'Gene', (232, 237))	('ABCG2', 'Gene', '9429', (232, 237))	('epithelial', 'MPA', (120, 130))	('EMT', 'biological_process', 'GO:0001837', ('195', '198'))	('caveolin-2', 'Gene', '858', (155, 165))	('caveolin-2', 'Gene', (155, 165))	('upregulated', 'PosReg', (104, 115))	('slug', 'Gene', '6591', (222, 226))	('snail', 'Gene', '6615', (215, 220))	('twist', 'Gene', (208, 213))	('downregulated', 'NegReg', (171, 184))	('MSLN', 'Gene', (89, 93))
207769	28288645	Flow cytometric analysis of ALDH activity by Aldefluor  assay revealed that knockdown of MSLN significantly reduced the ALDH activity of lung carcinoma (H460) and mesothelioma (H2052) cells (Fig.	('knockdown', 'Var', (76, 85))	('ALDH', 'molecular_function', 'GO:0004030', ('28', '32'))	('reduced', 'NegReg', (108, 115))	('ALDH activity', 'MPA', (120, 133))	('mesothelioma', 'Disease', (163, 175))	('ALDH', 'molecular_function', 'GO:0004030', ('120', '124'))	('lung carcinoma', 'Disease', (137, 151))	('MSLN', 'Gene', (89, 93))	('lung carcinoma', 'Disease', 'MESH:D008175', (137, 151))	('H2052', 'CellLine', 'CVCL:1518', (177, 182))	('H460', 'CellLine', 'CVCL:0459', (153, 157))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('Aldefluor', 'Chemical', '-', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
207770	28288645	Furthermore, analysis of ALDH activity-high and ALDH activity-low cells after flow cytometry sorting showed that the ALDH high cells expressed a higher level of MSLN and were more resistant to anoikis (detachment-induced cell death) as compared to the ALDH low cells (Fig.	('MSLN', 'MPA', (161, 165))	('death', 'Disease', 'MESH:D003643', (226, 231))	('death', 'Disease', (226, 231))	('resistant', 'CPA', (180, 189))	('high', 'Var', (122, 126))	('ALDH', 'molecular_function', 'GO:0004030', ('25', '29'))	('men', 'Species', '9606', (208, 211))	('anoikis', 'biological_process', 'GO:0043276', ('193', '200'))	('ALDH', 'molecular_function', 'GO:0004030', ('48', '52'))	('detachment-induced cell death', 'biological_process', 'GO:0043276', ('202', '231'))	('ALDH', 'molecular_function', 'GO:0004030', ('117', '121'))	('ALDH', 'molecular_function', 'GO:0004030', ('252', '256'))	('ALDH', 'Gene', (117, 121))	('higher', 'PosReg', (145, 151))
207783	28288645	Our study showed for the first time that MSLN regulates EMT, and possibly CTCs and CSCs, which may be responsible for tumorigenesis and metastasis.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('EMT', 'CPA', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('tumor', 'Disease', (118, 123))	('MSLN', 'Var', (41, 45))	('CTCs', 'CPA', (74, 78))	('CSCs', 'CPA', (83, 87))	('regulates', 'Reg', (46, 55))
207789	28288645	In mesothelioma cells, we present that knockdown of MSLN reversed the EMT to MET phenotype and significantly reduced CSC markers and ALDH activity, which may contribute to the observed reduction in tumorigenicity and metastasis of the knockdown cells.	('CSC markers', 'MPA', (117, 128))	('ALDH', 'Protein', (133, 137))	('activity', 'MPA', (138, 146))	('knockdown', 'Var', (39, 48))	('mesothelioma', 'Disease', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('EMT', 'biological_process', 'GO:0001837', ('70', '73'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ALDH', 'molecular_function', 'GO:0004030', ('133', '137'))	('reduced', 'NegReg', (109, 116))	('MSLN', 'Gene', (52, 56))	('reduction', 'NegReg', (185, 194))	('EMT to MET phenotype', 'CPA', (70, 90))	('tumor', 'Disease', (198, 203))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('metastasis', 'CPA', (217, 227))
207790	28288645	For example, knockdown of MSLN promoted the epithelial phenotype by up-regulating E-cadherin, cytokeratins, claudins, occludin, IL1RN, MITF, MSTIR, and NUDT, and by downregulating transcription factors such as Twist, Snail1, as well as fibronectin, ILK, EGFR, and WNT11 (Fig.	('occludin', 'Gene', (118, 126))	('IL1', 'molecular_function', 'GO:0005149', ('128', '131'))	('epithelial phenotype', 'CPA', (44, 64))	('cytokeratins', 'Protein', (94, 106))	('promoted', 'PosReg', (31, 39))	('up-regulating', 'PosReg', (68, 81))	('knockdown', 'Var', (13, 22))	('downregulating', 'NegReg', (165, 179))	('MITF', 'Gene', '4286', (135, 139))	('ILK', 'Gene', (249, 252))	('ILK', 'Gene', '3611', (249, 252))	('fibronectin', 'Gene', (236, 247))	('Snail1', 'Gene', '6615', (217, 223))	('Twist', 'Gene', (210, 215))	('MITF', 'Gene', (135, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('254', '258'))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('EGFR', 'Gene', (254, 258))	('claudins', 'Protein', (108, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('WNT11', 'Gene', (264, 269))	('E-cadherin', 'Gene', (82, 92))	('Snail1', 'Gene', (217, 223))	('E-cadherin', 'Gene', '999', (82, 92))	('WNT11', 'Gene', '7481', (264, 269))	('IL1RN', 'Gene', (128, 133))	('occludin', 'Gene', '100506658', (118, 126))	('fibronectin', 'Gene', '2335', (236, 247))	('MSLN', 'Gene', (26, 30))	('Twist', 'Gene', '7291', (210, 215))	('IL1RN', 'Gene', '3557', (128, 133))	('EGFR', 'Gene', '1956', (254, 258))
207806	28288645	Such knockdown also resulted in a reduction of EMT and CSC markers and a parallel decrease in tumor growth and metastasis in animals.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('EMT', 'biological_process', 'GO:0001837', ('47', '50'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('decrease', 'NegReg', (82, 90))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', (94, 99))	('reduction', 'NegReg', (34, 43))	('EMT', 'MPA', (47, 50))
207815	27384677	Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors.	('GPER', 'Gene', '2852', (87, 91))	('knocking-down', 'Var', (106, 119))	('DDR1', 'Gene', '780', (17, 21))	('GPER', 'Gene', (87, 91))	('expression', 'MPA', (124, 134))	('IGF-IR', 'Gene', (76, 82))	('DDR1', 'Gene', (17, 21))	('IGF-IR', 'Gene', '3480', (76, 82))
207825	27384677	Moreover, a dysregulated IGF system has been shown to be implicated in various chronic diseases, such as pulmonary fibrosis.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (105, 123))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (105, 123))	('implicated', 'Reg', (57, 67))	('dysregulated', 'Var', (12, 24))	('IGF', 'Pathway', (25, 28))	('pulmonary fibrosis', 'Disease', (105, 123))	('chronic diseases', 'Disease', 'MESH:D002908', (79, 95))	('chronic diseases', 'Disease', (79, 95))
207846	27384677	Moreover, we ascertained that these responses to IGF-I occurred through IGF-IR, as the induction of GPER mRNA (data not shown) and protein levels (Figure 2C-2E) was abolished by knocking-down IGF-IR expression.	('abolished', 'NegReg', (165, 174))	('protein levels', 'MPA', (131, 145))	('GPER', 'Gene', '2852', (100, 104))	('IGF-IR', 'Gene', (192, 198))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('GPER', 'Gene', (100, 104))	('IGF-IR', 'Gene', '3480', (192, 198))	('IGF-IR', 'Gene', (72, 78))	('knocking-down', 'Var', (178, 191))	('IGF-IR', 'Gene', '3480', (72, 78))
207852	27384677	Next, we determined that this action of IGF-I involves not only the IGF-IR but also GPER, as the silencing of each of these receptors prevented gene changes (Figure 4A-4H).	('silencing', 'Var', (97, 106))	('gene changes', 'MPA', (144, 156))	('IGF-IR', 'Gene', (68, 74))	('IGF-IR', 'Gene', '3480', (68, 74))	('GPER', 'Gene', '2852', (84, 88))	('GPER', 'Gene', (84, 88))
207853	27384677	In accordance with these observations, the IGF-I transactivation of CTGF (Figure 4I) and EGR1 (Figure 4J) promoters required both IGF-IR and GPER, as demonstrated by knocking down the expression of these receptors.	('IGF-IR', 'Gene', (130, 136))	('transactivation', 'biological_process', 'GO:2000144', ('49', '64'))	('EGR1', 'Gene', '1958', (89, 93))	('GPER', 'Gene', '2852', (141, 145))	('IGF-IR', 'Gene', '3480', (130, 136))	('knocking', 'Var', (166, 174))	('CTGF', 'Gene', '1490', (68, 72))	('rat', 'Species', '10116', (157, 160))	('expression', 'MPA', (184, 194))	('CTGF', 'Gene', (68, 72))	('GPER', 'Gene', (141, 145))	('EGR1', 'Gene', (89, 93))
207859	27384677	Then, we assessed that these DDR1 target genes are also stimulated by IGF-I (Figure 6A-6B) and that this response was inhibited by DDR1 IN (Figure 6C-6D) as well as by silencing IGF-IR (Figure 6E-6F) or GPER (Figure 6G-6H).	('inhibited', 'NegReg', (118, 127))	('silencing', 'Var', (168, 177))	('DDR1', 'Gene', '780', (131, 135))	('GPER', 'Gene', '2852', (203, 207))	('DDR1', 'Gene', '780', (29, 33))	('DDR1', 'Gene', (131, 135))	('DDR1', 'Gene', (29, 33))	('IGF-IR', 'Gene', (178, 184))	('GPER', 'Gene', (203, 207))	('IGF-IR', 'Gene', '3480', (178, 184))	('stimulated', 'PosReg', (56, 66))	('IGF-I', 'Gene', (70, 75))
207866	27384677	Moreover, we ascertained that the chemotactic motility induced by IGF-I requires also IGF-IR and GPER as the aforementioned effect was prevented silencing the expression of these receptors (Videos 7-12).	('silencing', 'Var', (145, 154))	('GPER', 'Gene', '2852', (97, 101))	('IGF-IR', 'Gene', (86, 92))	('GPER', 'Gene', (97, 101))	('IGF-IR', 'Gene', '3480', (86, 92))	('IGF-I', 'Gene', (66, 71))	('chemotactic motility', 'CPA', (34, 54))
207868	27384677	Likewise, we determined that IST-MES1 and A549 cell migration induced by both IGF-I and COL1 is abolished using DDR1 IN (Figure 9A), whereas the silencing of IGF-IR or GPER abolished cell migration triggered by IGF-I, as determined by Boyden chamber assay (Figure 9B).	('COL1', 'Gene', (88, 92))	('cell migration', 'biological_process', 'GO:0016477', ('47', '61'))	('IGF-IR', 'Gene', (158, 164))	('silencing', 'Var', (145, 154))	('abolished', 'NegReg', (96, 105))	('rat', 'Species', '10116', (191, 194))	('GPER', 'Gene', '2852', (168, 172))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('IGF-IR', 'Gene', '3480', (158, 164))	('cell migration', 'CPA', (183, 197))	('DDR1', 'Gene', '780', (112, 116))	('DDR1', 'Gene', (112, 116))	('GPER', 'Gene', (168, 172))	('A549 cell migration', 'CPA', (42, 61))	('cell migration', 'biological_process', 'GO:0016477', ('183', '197'))	('rat', 'Species', '10116', (55, 58))
207918	27384677	The plasmid DN/cfos, which encodes a c-fos mutant that heterodimerizes with c-fos dimerization partners but does not allow DNA biding, was a kind gift from Dr C Vinson (NIH, Bethesda, MD, USA).	('c-fos', 'Gene', (37, 42))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('c-fos', 'Gene', '2353', (76, 81))	('mutant', 'Var', (43, 49))	('c-fos', 'Gene', '2353', (37, 42))	('c-fos', 'Gene', (76, 81))
207971	26161391	In accord with the impaired cytotoxicity, YT-CB5 showed decreases in cell surface expression of NKG2D and 2B4, whereas NKG2A and CD94 showed no changes in expression.	('CD94', 'Gene', '3824', (129, 133))	('NKG2A', 'Gene', (119, 124))	('YT-CB5', 'Chemical', '-', (42, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('CD94', 'Gene', (129, 133))	('decreases', 'NegReg', (56, 65))	('NKG2D and 2B4', 'Gene', '22914', (96, 109))	('cell surface', 'cellular_component', 'GO:0009986', ('69', '81'))	('YT-CB5', 'Var', (42, 48))	('cytotoxicity', 'Disease', (28, 40))	('NKG2A', 'Gene', '3821', (119, 124))	('cell surface expression', 'MPA', (69, 92))
207987	26161391	In accord with this finding, an individual with high cytotoxicity showed a high level of phosphor-ERK1/2 following stimulation with antibodies to NKp46 or NKG2D, whereas another with low cytotoxicity showed a low level of phosphorylation of ERK1/2.	('antibodies', 'Var', (132, 142))	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('ERK1/2', 'Gene', (241, 247))	('ERK1/2', 'Gene', '5595;5594', (241, 247))	('ERK1', 'molecular_function', 'GO:0004707', ('98', '102'))	('cytotoxicity', 'Disease', (53, 65))	('NKp46', 'Gene', '9437', (146, 151))	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('NKG2D', 'Gene', '22914', (155, 160))	('ERK1/2', 'Gene', (98, 104))	('NKG2D', 'Gene', (155, 160))	('ERK1', 'molecular_function', 'GO:0004707', ('241', '245'))	('cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('222', '237'))	('NKp46', 'Gene', (146, 151))	('cytotoxicity', 'Disease', (187, 199))	('stimulation', 'PosReg', (115, 126))
208064	24468420	Cholesterol depletion has been shown to diminish signaling normally associated with lipid raft formation.	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('diminish', 'NegReg', (40, 48))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('signaling', 'MPA', (49, 58))	('lipid raft formation', 'biological_process', 'GO:0001765', ('84', '104'))	('Cholesterol depletion', 'Var', (0, 21))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('lipid raft', 'cellular_component', 'GO:0045121', ('84', '94'))
208085	24468420	While several chemical compounds/agents have been shown to inhibit or suppress exosome secretion, we elected not to add this additional step due to unknown or non-specific effects of such compounds (such as amiloride, DMA, or inhibitors of Na+/H+ or Na+/Ca2+ transporters) on TnT formation and other cellular pathways.	('suppress', 'NegReg', (70, 78))	('exosome secretion', 'MPA', (79, 96))	('formation', 'biological_process', 'GO:0009058', ('280', '289'))	('amiloride', 'Chemical', 'MESH:D000584', (207, 216))	('TnT formation', 'MPA', (276, 289))	('inhibitors', 'Var', (226, 236))	('inhibit', 'NegReg', (59, 66))	('TnT', 'Chemical', '-', (276, 279))	('exosome', 'cellular_component', 'GO:0070062', ('79', '86'))	('DMA', 'Chemical', 'MESH:C405765', (218, 221))	('secretion', 'biological_process', 'GO:0046903', ('87', '96'))
208087	24468420	Increased glycolysis is a well-established property of proliferating and metastatic cancer cells and the low pH has been demonstrated to increase exosome release in mesothelioma.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('low', 'Var', (105, 108))	('mesothelioma', 'Disease', (165, 177))	('cancer', 'Disease', (84, 90))	('exosome', 'cellular_component', 'GO:0070062', ('146', '153'))	('increase', 'PosReg', (137, 145))	('Increased', 'PosReg', (0, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('exosome release', 'MPA', (146, 161))	('glycolysis', 'biological_process', 'GO:0006096', ('10', '20'))	('glycolysis', 'MPA', (10, 20))
208136	24468420	The ratios of CTCF/area between TnT-forming and non-TnT forming cells were as follows: 1.48 for VAMT, 2.06 for H2052, 1.76 for MSTO-211H, and 1.82 for Met5A.	('CTCF', 'Gene', (14, 18))	('H2052', 'Var', (111, 116))	('VAMT', 'Chemical', '-', (96, 100))	('CTCF', 'Gene', '10664', (14, 18))	('TnT', 'Chemical', '-', (52, 55))	('TnT', 'Chemical', '-', (32, 35))	('MSTO-211H', 'Chemical', '-', (127, 136))
208156	24468420	Indeed, acidic pH has been reported to enhance the invasive potential of cancer cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('acidic', 'Var', (8, 14))	('enhance', 'PosReg', (39, 46))
208162	24468420	It was recently reported that disruption of F-actin polymerization in hepatocarcinoma and ovarian cancer cells led to significantly decreased release of cellular microparticles (MPs) from these cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('actin polymerization', 'biological_process', 'GO:0030041', ('46', '66'))	('disruption', 'Var', (30, 40))	('hepatocarcinoma and ovarian cancer', 'Disease', 'MESH:D010051', (70, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('F-actin', 'cellular_component', 'GO:0031941', ('44', '51'))	('decreased', 'NegReg', (132, 141))	('F-actin polymerization', 'Protein', (44, 66))
208235	24987442	Mutations in BRAF, RET, TRK, RAS and PAX8/PPARgamma are found in 70% of follicular thyroid cancers.	('PAX8', 'Gene', (37, 41))	('PAX8', 'Gene', '7849', (37, 41))	('PPARgamma', 'Gene', (42, 51))	('RET', 'Gene', (19, 22))	('BRAF', 'Gene', '673', (13, 17))	('follicular thyroid cancers', 'Disease', 'MESH:C572845', (72, 98))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('RAS', 'Gene', (29, 32))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('found', 'Reg', (56, 61))	('follicular thyroid cancers', 'Disease', (72, 98))	('follicular thyroid cancers', 'Phenotype', 'HP:0006731', (72, 98))	('TRK', 'Gene', (24, 27))	('PPARgamma', 'Gene', '5468', (42, 51))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('RET', 'Gene', '5979', (19, 22))	('TRK', 'Gene', '4914', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
208237	24987442	BRAF is commonly mutated in melanomas, Langerhans cell histiocytosis, a subset of colonic tumors and rare lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (106, 126))	('histiocytosis', 'Phenotype', 'HP:0100727', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('melanomas', 'Disease', (28, 37))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))	('colonic tumors', 'Disease', 'MESH:D015179', (82, 96))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('colonic tumors', 'Disease', (82, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('lung adenocarcinomas', 'Disease', (106, 126))	('Langerhans cell histiocytosis', 'Disease', (39, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('BRAF', 'Gene', (0, 4))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (106, 126))	('mutated', 'Var', (17, 24))
208238	24987442	Of importance, many metastases including mesothelioma would test negative for these mutations.	('mesothelioma', 'Disease', (41, 53))	('mutations', 'Var', (84, 93))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('metastases', 'Disease', (20, 30))	('metastases', 'Disease', 'MESH:D009362', (20, 30))
208246	21269462	Recently, it has been suggested that the expression of estrogen receptor beta in malignant mesothelioma leads to tumor suppression and a better prognosis.	('tumor', 'Disease', (113, 118))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (81, 103))	('better', 'PosReg', (137, 143))	('estrogen receptor beta', 'Gene', '2100', (55, 77))	('estrogen receptor beta', 'Gene', (55, 77))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (81, 103))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('malignant mesothelioma', 'Disease', (81, 103))	('expression', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
208297	21269462	These authors have also suggested that manipulation of ERbeta receptors may offer a new mode of therapy for this type of cancer.	('ERbeta', 'Gene', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('manipulation', 'Var', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('ERbeta', 'Gene', '2100', (55, 61))	('cancer', 'Disease', (121, 127))
208298	21269462	Our studies have also shown that the expression of ERbeta in peritoneal mesothelioma offers a better prognosis (unpublished data).	('expression', 'Var', (37, 47))	('ERbeta', 'Gene', (51, 57))	('mesothelioma', 'Disease', (72, 84))	('ERbeta', 'Gene', '2100', (51, 57))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (61, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))
208313	20043850	Alternative splicing of pre-mRNA is a post-transcriptional process that occurs in approximately 70% or more of all human genes presumably to increase the diversity of the transcriptome and proteome.	('pre', 'molecular_function', 'GO:0003904', ('24', '27'))	('increase', 'PosReg', (141, 149))	('diversity', 'MPA', (154, 163))	('human', 'Species', '9606', (115, 120))	('Alternative splicing', 'Var', (0, 20))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
208315	20043850	In some cases, specific alternative splicing variants have been proposed as potential clinical markers for cancer diagnosis and prognosis as well as function in the role of therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('alternative splicing variants', 'Var', (24, 53))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
208338	20043850	We arbitrarily weighted our list towards exon junctions over-expressed in MPM tumor because we found more highly expressed exon junctions in MPM (76) than in normal lung (32) and sought to increase our chances of identifying potentially diagnostic alternatively spliced transcripts.	('highly expressed', 'PosReg', (106, 122))	('exon junctions', 'MPA', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('MPM', 'Disease', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MPM', 'Var', (141, 144))	('tumor', 'Disease', (78, 83))
208366	20043850	Several of the other genes that appeared to exhibit differentially expressed splice variants in the present study have also been implicated in cancer and would be worthy of further study.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('splice variants', 'Var', (77, 92))
208405	19738457	Inactivating mutations in the TNX gene are the genetic cause of some cases of the Ehlers-Danlos syndrome.	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (82, 104))	('TNX', 'Gene', (30, 33))	('Ehlers-Danlos syndrome', 'Disease', (82, 104))	('Inactivating mutations', 'Var', (0, 22))	('TNX', 'Gene', '7146', (30, 33))	('cause', 'Reg', (55, 60))
208417	19738457	Primers for TNXB (NM_019105) were located at exon 4-5.	('TNXB', 'Gene', (12, 16))	('TNXB', 'Gene', '7148', (12, 16))	('NM_019105', 'Var', (18, 27))
208453	19738457	Statistical analysis showed significant difference in tenascin-X expression (p<0.001) between MM and carcinomas using different groupings of the latter (all MM vs. all carcinomas grouped together, MM vs. OC/PPC, and MM vs. OC/PPC, breast carcinomas, lung carcinomas, GI-tract carcinomas and non-ovarian gynecological carcinomas).	('MM vs. OC/PPC', 'Var', (216, 229))	('carcinomas', 'Disease', (317, 327))	('carcinomas', 'Disease', (276, 286))	('breast carcinomas', 'Disease', 'MESH:D001943', (231, 248))	('breast carcinomas', 'Disease', (231, 248))	('carcinomas', 'Disease', 'MESH:D002277', (168, 178))	('GI-tract carcinomas and non-ovarian gynecological carcinomas', 'Disease', 'MESH:D005833', (267, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('carcinomas', 'Disease', 'MESH:D002277', (255, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinomas', 'Phenotype', 'HP:0030731', (238, 248))	('carcinomas', 'Disease', 'MESH:D002277', (238, 248))	('carcinomas', 'Disease', (101, 111))	('tenascin-X', 'cellular_component', 'GO:0090733', ('54', '64'))	('breast carcinomas', 'Phenotype', 'HP:0003002', (231, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tenascin-X', 'Gene', (54, 64))	('carcinomas', 'Disease', 'MESH:D002277', (317, 327))	('breast carcinoma', 'Phenotype', 'HP:0003002', (231, 247))	('MM vs.', 'Var', (197, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('carcinomas', 'Disease', 'MESH:D002277', (276, 286))	('tenascin-X', 'Gene', '7148', (54, 64))	('carcinomas', 'Disease', (168, 178))	('lung carcinomas', 'Disease', 'MESH:D008175', (250, 265))	('ovarian gynecological carcinomas', 'Phenotype', 'HP:0100615', (295, 327))	('carcinomas', 'Disease', (255, 265))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('carcinomas', 'Disease', 'MESH:D002277', (101, 111))	('lung carcinomas', 'Disease', (250, 265))	('carcinomas', 'Disease', (238, 248))
208467	19738457	B72.3 staining was highly specific for carcinoma in effusions, with a sensitivity that was much higher for OC/PPC than for breast carcinoma.	('OC/PPC', 'Disease', (107, 113))	('breast carcinoma', 'Disease', (123, 139))	('carcinoma', 'Disease', 'MESH:D002277', (39, 48))	('breast carcinoma', 'Disease', 'MESH:D001943', (123, 139))	('carcinoma', 'Disease', 'MESH:D002277', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('breast carcinoma', 'Phenotype', 'HP:0003002', (123, 139))	('carcinoma', 'Disease', (39, 48))	('higher', 'PosReg', (96, 102))	('carcinoma', 'Disease', (130, 139))	('B72.3', 'Var', (0, 5))
208491	31263571	High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer.	('pathogenic', 'Reg', (18, 28))	('cancer', 'Disease', (112, 118))	('variants', 'Var', (38, 46))	('type of cancer', 'Disease', (241, 255))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('homologous recombination', 'biological_process', 'GO:0035825', ('54', '78'))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('type of cancer', 'Disease', 'MESH:D009369', (241, 255))
208493	31263571	We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing.	('variants', 'Var', (41, 49))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
208495	31263571	These variants were identified in 17.8% of the patients and within a wide range of cancer types.	('variants', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
208496	31263571	In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants.	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('urothelial cancer', 'Disease', 'MESH:D014523', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ovarian cancer', 'Disease', (43, 57))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('urothelial cancer', 'Disease', (76, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (51, 57))	('cervical cancer', 'Disease', (59, 74))	('cervical cancer', 'Disease', 'MESH:D002583', (59, 74))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (68, 74))	('variants', 'Var', (173, 181))	('mesothelioma', 'Disease', (29, 41))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
208497	31263571	Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines.	('patients', 'Species', '9606', (149, 157))	('BRCA2', 'Gene', '675', (21, 26))	('BRCA1', 'Gene', '672', (11, 16))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BRCA1', 'Gene', (11, 16))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BRCA2', 'Gene', (21, 26))
208500	31263571	The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers.	('patients', 'Species', '9606', (115, 123))	('pathogenic', 'Reg', (43, 53))	('homologous recombination', 'biological_process', 'GO:0035825', ('79', '103'))	('germline variants', 'Var', (54, 71))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('solid cancers', 'Disease', (138, 151))	('homologous recombination pathway', 'Pathway', (79, 111))	('solid cancers', 'Disease', 'MESH:D009369', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
208506	31263571	In particular, pathogenic variants in the two high penetrance genes BRCA1 and BRCA2, known to predispose to breast and ovarian cancer, are frequently observed.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('BRCA1', 'Gene', (68, 73))	('predispose', 'Reg', (94, 104))	('pathogenic', 'Reg', (15, 25))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (108, 133))	('BRCA2', 'Gene', (78, 83))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1', 'Gene', '672', (68, 73))	('variants', 'Var', (26, 34))
208507	31263571	Thus, 72% of women carrying a BRCA1 mutation and 69% with a BRCA2 mutation will develop breast cancer by the age of 80, while up to 44% with a BRCA1 mutation and 17% with a BRCA2 mutation will develop ovarian cancer.	('BRCA1', 'Gene', (30, 35))	('breast cancer', 'Disease', (88, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('BRCA2', 'Gene', '675', (60, 65))	('develop', 'PosReg', (80, 87))	('mutation', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA2', 'Gene', (173, 178))	('ovarian cancer', 'Disease', (201, 215))	('women', 'Species', '9606', (13, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('develop', 'Reg', (193, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('BRCA1', 'Gene', '672', (143, 148))	('BRCA1', 'Gene', (143, 148))	('BRCA2', 'Gene', (60, 65))	('BRCA2', 'Gene', '675', (173, 178))	('BRCA1', 'Gene', '672', (30, 35))	('mutation', 'Var', (149, 157))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('mutation', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
208508	31263571	Mutations in BRCA1 and BRCA2 however also increase the risk of other cancers, including pancreatic, fallopian tube, and peritoneal cancer.	('BRCA1', 'Gene', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('fallopian tube', 'Disease', (100, 114))	('pancreatic', 'Disease', 'MESH:D010195', (88, 98))	('BRCA2', 'Gene', (23, 28))	('fallopian tube', 'Disease', 'MESH:D005184', (100, 114))	('Mutations', 'Var', (0, 9))	('pancreatic', 'Disease', (88, 98))	('BRCA2', 'Gene', '675', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('increase', 'Reg', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA1', 'Gene', '672', (13, 18))
208509	31263571	Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are also at increased risk of breast and prostate cancer.	('BRCA2', 'Gene', (9, 14))	('BRCA1', 'Gene', '672', (49, 54))	('mutations', 'Var', (15, 24))	('BRCA2', 'Gene', '675', (9, 14))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (96, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('BRCA1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Men', 'Species', '9606', (0, 3))
208511	31263571	The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC) and APC mutations are found in individuals with familial adenomatous polyposis (FAP).	('hereditary nonpolyposis colorectal cancer', 'Disease', (79, 120))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (186, 207))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mismatch repair', 'biological_process', 'GO:0006298', ('4', '19'))	('MMR', 'Gene', (21, 24))	('HNPCC', 'Disease', 'None', (122, 127))	('HNPCC', 'Disease', (122, 127))	('familial adenomatous polyposis', 'Disease', (177, 207))	('MMR', 'biological_process', 'GO:0006298', ('21', '24'))	('APC', 'Disease', 'MESH:D011125', (133, 136))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (177, 207))	('APC', 'Disease', (133, 136))	('MSH2', 'Gene', (38, 42))	('associated', 'Reg', (63, 73))	('MSH6', 'Gene', (44, 48))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (79, 120))	('APC', 'cellular_component', 'GO:0005680', ('133', '136'))	('PMS2', 'Gene', '5395', (54, 58))	('MSH6', 'Gene', '2956', (44, 48))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (79, 120))	('MSH2', 'Gene', '4436', (38, 42))	('HNPCC', 'Phenotype', 'HP:0006716', (122, 127))	('FAP', 'Disease', (209, 212))	('MLH1', 'Gene', (32, 36))	('FAP', 'Disease', 'MESH:C567782', (209, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('mutations', 'Var', (137, 146))	('PMS2', 'Gene', (54, 58))	('MLH1', 'Gene', '4292', (32, 36))
208512	31263571	Mutations in TP53, PTEN, CDH1, CHEK2, ATM, RAD51D, PALB2, and FANCM have been associated with increased risk of breast cancer or prostate cancer, although with varying penetrance.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('TP53', 'Gene', (13, 17))	('breast cancer', 'Disease', (112, 125))	('CHEK2', 'Gene', '11200', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('FANCM', 'Gene', '57697', (62, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('ATM', 'Gene', '472', (38, 41))	('FANCM', 'Gene', (62, 67))	('PTEN', 'Gene', (19, 23))	('prostate cancer', 'Disease', (129, 144))	('Mutations', 'Var', (0, 9))	('RAD51D', 'Gene', (43, 49))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('associated', 'Reg', (78, 88))	('CDH1', 'Gene', '999', (25, 29))	('PTEN', 'Gene', '5728', (19, 23))	('ATM', 'Gene', (38, 41))	('CDH1', 'Gene', (25, 29))	('PALB2', 'Gene', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('RAD', 'biological_process', 'GO:1990116', ('43', '46'))	('CHEK2', 'Gene', (31, 36))	('RAD51D', 'Gene', '5892', (43, 49))	('PALB2', 'Gene', '79728', (51, 56))
208513	31263571	In particular loss-of-function germline variants in PALB2 increase the risk of breast cancer before 40 years of age eight times and heterozygous mutations within the FANCM gene were recently demonstrated to be associated with familial breast cancer, in particular for early-onset or triple-negative breast cancer.	('FANCM', 'Gene', '57697', (166, 171))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('germline variants', 'Var', (31, 48))	('breast cancer', 'Disease', (79, 92))	('FANCM', 'Gene', (166, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (299, 312))	('familial breast cancer', 'Disease', 'MESH:D001943', (226, 248))	('familial breast cancer', 'Disease', (226, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('breast cancer', 'Disease', 'MESH:D001943', (299, 312))	('early-onset', 'Disease', (268, 279))	('breast cancer', 'Disease', (299, 312))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('PALB2', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('heterozygous mutations', 'Var', (132, 154))	('PALB2', 'Gene', '79728', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('loss-of-function', 'NegReg', (14, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
208514	31263571	Furthermore, bi-allelic inherited germline variants in ataxia telangiectasia mutated (ATM) result in the multisystem disorder ataxia telangiectasia syndrome, which manifests with progressive neurological disease and an increased predisposition to lymphoid, gastric, breast, central nervous system, and skin cancer, as well as other cancers.	('ATM', 'Gene', '472', (86, 89))	('gastric', 'Disease', (257, 264))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('ataxia telangiectasia', 'Disease', (55, 76))	('neurological disease', 'Disease', (191, 211))	('multisystem disorder', 'Disease', (105, 125))	('multisystem disorder', 'Disease', 'MESH:D004194', (105, 125))	('result in', 'Reg', (91, 100))	('central nervous system', 'Disease', (274, 296))	('skin cancer', 'Disease', (302, 313))	('ATM', 'Gene', (86, 89))	('breast', 'Disease', (266, 272))	('telangiectasia', 'Phenotype', 'HP:0001009', (62, 76))	('germline variants', 'Var', (34, 51))	('lymphoid', 'Disease', (247, 255))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (55, 76))	('ataxia telangiectasia syndrome', 'Disease', (126, 156))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('skin cancer', 'Phenotype', 'HP:0008069', (302, 313))	('neurological disease', 'Phenotype', 'HP:0000707', (191, 211))	('cancers', 'Disease', (332, 339))	('telangiectasia', 'Phenotype', 'HP:0001009', (133, 147))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (126, 147))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('ataxia', 'Phenotype', 'HP:0001251', (126, 132))	('neurological disease', 'Disease', 'MESH:D019636', (191, 211))	('ataxia telangiectasia syndrome', 'Disease', 'MESH:D001260', (126, 156))	('progressive neurological disease', 'Phenotype', 'HP:0002344', (179, 211))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('ataxia', 'Phenotype', 'HP:0001251', (55, 61))	('skin cancer', 'Disease', 'MESH:D012878', (302, 313))
208515	31263571	Studies have shown a moderate increased risk of breast cancer in heterozygote carriers of pathogenic ATM variants.	('ATM', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('ATM', 'Gene', '472', (101, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('variants', 'Var', (105, 113))
208516	31263571	Studies on germline ataxia-telangiectasia and Rad3-related (ATR) mutations with respect to cancer susceptibility have mainly been inconsistent or inconclusive.	('ataxia-telangiectasia and Rad3-related', 'Gene', '545', (20, 58))	('ATR', 'Gene', '545', (60, 63))	('ATR', 'Gene', (60, 63))	('ataxia', 'Phenotype', 'HP:0001251', (20, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Rad', 'biological_process', 'GO:1990116', ('46', '49'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('telangiectasia', 'Phenotype', 'HP:0001009', (27, 41))	('mutations', 'Var', (65, 74))
208517	31263571	Thus, the role of ATR variants for cancer susceptibility remains unclear.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('ATR', 'Gene', '545', (18, 21))	('ATR', 'Gene', (18, 21))	('variants', 'Var', (22, 30))	('cancer', 'Disease', (35, 41))
208518	31263571	Most of the known cancer susceptibility genes are involved in maintenance of genomic integrity, safeguarding DNA from mutations that ultimately could lead to malignancy.	('lead to', 'Reg', (150, 157))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('malignancy', 'Disease', (158, 168))	('malignancy', 'Disease', 'MESH:D009369', (158, 168))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
208519	31263571	BRCA1 and BRCA2 proteins are key players in the molecular events following double-stranded DNA damage and homologous recombination (HR), while ATM, ATR, CHK1, CHK2, and Tumor suppressor p53 proteins are all central players in sensing and orchestrating the checkpoint signaling from double strand breaks (DSBs) to DNA repair.	('DNA', 'cellular_component', 'GO:0005574', ('313', '316'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('p53', 'Gene', (186, 189))	('CHK1', 'Gene', (153, 157))	('homologous recombination', 'biological_process', 'GO:0035825', ('106', '130'))	('BRCA2', 'Gene', '675', (10, 15))	('ATM', 'Gene', (143, 146))	('BRCA1', 'Gene', '672', (0, 5))	('CHK2', 'Gene', (159, 163))	('ATR', 'Gene', (148, 151))	('CHK1', 'Gene', '1111', (153, 157))	('BRCA1', 'Gene', (0, 5))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('169', '185'))	('DNA repair', 'biological_process', 'GO:0006281', ('313', '323'))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('169', '185'))	('double-stranded', 'Var', (75, 90))	('CHK2', 'Gene', '11200', (159, 163))	('p53', 'Gene', '7157', (186, 189))	('Tumor', 'Phenotype', 'HP:0002664', (169, 174))	('signaling', 'biological_process', 'GO:0023052', ('267', '276'))	('BRCA2', 'Gene', (10, 15))	('ATM', 'Gene', '472', (143, 146))	('ATR', 'Gene', '545', (148, 151))
208520	31263571	In contrary, the MMR system recognizes and repairs DNA errors from mismatched nucleotides with MSH proteins being key players in recognizing and initiating the MMR repair process.	('DNA', 'Var', (51, 54))	('MMR', 'biological_process', 'GO:0006298', ('160', '163'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('MMR', 'biological_process', 'GO:0006298', ('17', '20'))	('MSH', 'Gene', (95, 98))	('MSH', 'Gene', '4488', (95, 98))	('mismatched', 'Var', (67, 77))
208521	31263571	In case of BRCA1 or BRCA2, mutations improve responsiveness to platinum-based chemotherapy, as well as poly(ADP-ribose) polymerase inhibitor (PARPi) treatment.	('mutations', 'Var', (27, 36))	('BRCA2', 'Gene', '675', (20, 25))	('PARP', 'Gene', '142', (142, 146))	('improve', 'PosReg', (37, 44))	('BRCA1', 'Gene', '672', (11, 16))	('BRCA1', 'Gene', (11, 16))	('PARP', 'Gene', (142, 146))	('BRCA2', 'Gene', (20, 25))	('platinum', 'Chemical', 'MESH:D010984', (63, 71))	('responsiveness to platinum-based chemotherapy', 'MPA', (45, 90))
208522	31263571	In particular, PARPi treatment of patients with ovarian and breast cancer carrying germline BRCA1/2 mutations has shown an exceptional increase in response rate and progression-free survival, illustrating the first clinical proof for the concept of synthetic lethality.	('mutations', 'Var', (100, 109))	('progression-free survival', 'CPA', (165, 190))	('BRCA1/2', 'Gene', '672;675', (92, 99))	('increase', 'PosReg', (135, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('PARP', 'Gene', '142', (15, 19))	('response rate', 'CPA', (147, 160))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (48, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (34, 42))	('BRCA1/2', 'Gene', (92, 99))	('PARP', 'Gene', (15, 19))
208523	31263571	These results have led to clinical approval of PARPi in ovarian cancer, and in January 2018, also for the treatment of germline BRCA1/2 mutated metastatic breast cancers, thereby becoming the first targeted therapy for patients with breast cancer carrying BRCA1/2 mutations.	('PARP', 'Gene', (47, 51))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('BRCA1/2', 'Gene', (256, 263))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('BRCA1/2', 'Gene', (128, 135))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('BRCA1/2', 'Gene', '672;675', (256, 263))	('patients', 'Species', '9606', (219, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('BRCA1/2', 'Gene', '672;675', (128, 135))	('mutated', 'Var', (136, 143))	('ovarian cancer', 'Disease', (56, 70))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('PARP', 'Gene', '142', (47, 51))	('breast cancer', 'Disease', (233, 246))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
208524	31263571	In addition, prostate cancers with somatic or germline variants in DNA-repair genes including BRCA2 and ATM displayed a high response rate to PARPi treatment.	('PARP', 'Gene', '142', (142, 146))	('BRCA2', 'Gene', (94, 99))	('ATM', 'Gene', '472', (104, 107))	('prostate cancers', 'Phenotype', 'HP:0012125', (13, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('DNA-repair', 'biological_process', 'GO:0006281', ('67', '77'))	('germline variants', 'Var', (46, 63))	('prostate cancers', 'Disease', (13, 29))	('DNA-repair genes', 'Gene', (67, 83))	('BRCA2', 'Gene', '675', (94, 99))	('PARP', 'Gene', (142, 146))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('ATM', 'Gene', (104, 107))	('prostate cancers', 'Disease', 'MESH:D011471', (13, 29))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))
208526	31263571	We investigated a cohort of 636 advanced cancer patients for pathogenic germline variants to gain insights into possible new associations between germline variants, cancer types and molecular pathways.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('associations', 'Interaction', (125, 137))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (48, 56))	('variants', 'Var', (81, 89))
208529	31263571	Out of these patients, 17.8% (n = 113) were shown to have a pathogenic or likely pathogenic (hereafter collectively referred to as pathogenic) germline variant in at least one of the 168 cancer-associated genes tested (Supplementary Table 1; excluding heterozygous variants in genes known to have a recessive inheritance pattern) (Table 1).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('variant', 'Var', (152, 159))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (13, 21))	('pathogenic', 'Reg', (81, 91))	('pathogenic', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
208531	31263571	In addition, 16 patients were heterozygous for pathogenic variants in genes known to have a recessive pattern of inheritance, i.e., the colorectal cancer (CRC) predisposition genes MUTYH and NTHL1 (Supplementary Table 3).	('NTHL1', 'Gene', (191, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('NTHL1', 'Gene', '4913', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('variants', 'Var', (58, 66))	('MUTYH', 'Gene', (181, 186))	('colorectal cancer', 'Disease', (136, 153))	('patients', 'Species', '9606', (16, 24))	('MUTYH', 'Gene', '4595', (181, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))
208533	31263571	Fifteen pathogenic variants were identified in BRCA2 and CHEK2, while seven pathogenic variants were identified in BRCA1, thus, about one third of the pathogenic variants were identified in these three genes (Fig.	('pathogenic', 'Reg', (8, 18))	('BRCA1', 'Gene', '672', (115, 120))	('BRCA2', 'Gene', (47, 52))	('BRCA1', 'Gene', (115, 120))	('CHEK2', 'Gene', '11200', (57, 62))	('BRCA2', 'Gene', '675', (47, 52))	('variants', 'Var', (19, 27))	('CHEK2', 'Gene', (57, 62))
208534	31263571	The CHEK2 variant c.1100del, p.Thr367Metfs*15, which has an allele frequency of 0.2% in non-Finish Europeans (GnomAD) and is known to have reduced penetrance was e.g., observed in 12 patients (1.9%).	('CHEK2', 'Gene', (4, 9))	('p.Thr367Metfs*15', 'FRAMESHIFT', 'None', (29, 45))	('c.1100del', 'Mutation', 'c.1100del', (18, 27))	('p.Thr367Metfs*15', 'Var', (29, 45))	('c.1100del', 'Var', (18, 27))	('CHEK2', 'Gene', '11200', (4, 9))	('patients', 'Species', '9606', (183, 191))
208535	31263571	Pathogenic variants were associated with every tumor type found in at least 10 individuals, except in the case of patients suffering from small cell lung cancer (SCLC) (Fig.	('SCLC', 'Disease', 'MESH:D018288', (162, 166))	('associated', 'Reg', (25, 35))	('variants', 'Var', (11, 19))	('SCLC', 'Phenotype', 'HP:0030357', (162, 166))	('small cell lung cancer', 'Disease', (138, 160))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (138, 160))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (47, 52))	('SCLC', 'Disease', (162, 166))	('small cell lung cancer', 'Disease', 'MESH:D055752', (138, 160))
208537	31263571	The incidence of patients with germline pathogenic variants ranged from 58% in malignant mesothelioma, 30% in ovarian cancer, 28% in cervical cancer, 25% in cancer of unknown primary origin and 25% in urothelial cancer, and down to 5% in gastric cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('ovarian cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', (238, 252))	('variants', 'Var', (51, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('malignant mesothelioma', 'Disease', (79, 101))	('urothelial cancer', 'Disease', 'MESH:D014523', (201, 218))	('cancer', 'Disease', (246, 252))	('cervical cancer', 'Disease', 'MESH:D002583', (133, 148))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (79, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('cervical cancer', 'Disease', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('urothelial cancer', 'Disease', (201, 218))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (212, 218))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Disease', (157, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (79, 101))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
208538	31263571	Genes encoding proteins within the HR pathways, including BRCA1, BRCA2, and genes in the Fanconi anemia pathway, generally harbored more pathogenic germline variants (52%) than genes within other pathways such as DNA damage checkpoint control (22%), nucleotide excision repair (7%), MMR (3%) and other pathways (16%) (Fig.	('BRCA2', 'Gene', '675', (65, 70))	('MMR', 'biological_process', 'GO:0006298', ('283', '286'))	('BRCA1', 'Gene', (58, 63))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (89, 103))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('213', '234'))	('anemia', 'Phenotype', 'HP:0001903', (97, 103))	('Fanconi anemia', 'Disease', (89, 103))	('Fanconi anemia', 'Disease', 'MESH:D005199', (89, 103))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('BRCA2', 'Gene', (65, 70))	('pathogenic', 'Reg', (137, 147))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('250', '276'))	('BRCA1', 'Gene', '672', (58, 63))	('variants', 'Var', (157, 165))
208539	31263571	However, looking into the different tumor types, particularly pancreatic cancer, mesothelioma and ovarian cancer show a tendency for enrichment of pathogenic variants in genes within the HR pathway with 70-85% of the identified variants located within these genes; although the number of included patients within these cancer types is limited (Fig.	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('tumor', 'Disease', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (73, 79))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('patients', 'Species', '9606', (297, 305))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('variants', 'Var', (158, 166))	('mesothelioma and ovarian cancer', 'Disease', 'MESH:D010051', (81, 112))	('variants', 'Var', (228, 236))
208540	31263571	Interestingly, more than half of the possible pathogenic variants identified in patients with mesothelioma were located within genes of the Fanconi anemia pathway (FANCA, FANCC, FANCD2, and FANCM).	('Fanconi anemia', 'Disease', 'MESH:D005199', (140, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('patients', 'Species', '9606', (80, 88))	('variants', 'Var', (57, 65))	('FANCC', 'Gene', '2176', (171, 176))	('FANCM', 'Gene', '57697', (190, 195))	('FANCC', 'Gene', (171, 176))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (140, 154))	('FANCM', 'Gene', (190, 195))	('anemia', 'Phenotype', 'HP:0001903', (148, 154))	('Fanconi anemia', 'Disease', (140, 154))	('FANCA', 'Gene', '2175', (164, 169))	('mesothelioma', 'Disease', (94, 106))	('FANCD2', 'Gene', '2177', (178, 184))	('FANCA', 'Gene', (164, 169))	('FANCD2', 'Gene', (178, 184))
208541	31263571	Furthermore, remarkably, only a single pathogenic variant (MLH1 p.Pro648Ser) within the MMR genes was identified in patients with CRC (Fig.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('MMR', 'biological_process', 'GO:0006298', ('88', '91'))	('p.Pro648Ser', 'Mutation', 'rs63750899', (64, 75))	('patients', 'Species', '9606', (116, 124))	('MLH1', 'Gene', '4292', (59, 63))	('MMR', 'Gene', (88, 91))	('MLH1', 'Gene', (59, 63))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('p.Pro648Ser', 'Var', (64, 75))
208543	31263571	When analyzing each of the pathogenic germline variants in the tumor sample from the same patient, allele frequencies above 65% were observed, indicating LOH of these genomic regions.	('tumor', 'Disease', (63, 68))	('variants', 'Var', (47, 55))	('LOH', 'NegReg', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patient', 'Species', '9606', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
208546	31263571	On the contrary, chromosomal instability may give rise to LOH of genes that are not causal for the cancer, showing the results should be interpreted with caution.	('chromosomal instability', 'Phenotype', 'HP:0040012', (17, 40))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('LOH', 'NegReg', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('chromosomal instability', 'Var', (17, 40))
208547	31263571	Using the cut-off value of 65% allele frequency, 19% of the overall identified pathogenic germline variants showed LOH in tumor samples (Fig.	('LOH', 'NegReg', (115, 118))	('variants', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
208551	31263571	Focusing on the germline variants identified within genes involved in HR, most variants showing LOH were in agreement with known genotype-phenotype correlation as indicted by the observation of BRCA1/2 variants in breast, ovarian and prostate tumor samples and BAP1 variants in uveal melanoma (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (278, 292))	('uveal melanoma', 'Disease', (278, 292))	('variants', 'Var', (202, 210))	('ovarian and prostate tumor', 'Disease', 'MESH:D010051', (222, 248))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('variants', 'Var', (79, 87))	('BAP1', 'Gene', (261, 265))	('variants', 'Var', (266, 274))	('BRCA1/2', 'Gene', (194, 201))	('uveal melanoma', 'Disease', 'MESH:C536494', (278, 292))	('BRCA1/2', 'Gene', '672;675', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('prostate tumor', 'Phenotype', 'HP:0100787', (234, 248))
208552	31263571	For example, a BRCA2 nonsense variant (p.Lys944Ter) and a FANCM nonsense variant (p.Arg486Ter) displayed LOH in the tumor samples of two patient with CRC, as well as LOH of a NBN missense variant (p.Ile171Val) in the tumor sample of a patient with NSCLC previously suggested to increase the risk of developing NSCLC.	('patient', 'Species', '9606', (137, 144))	('NSCLC', 'Disease', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('p.Lys944Ter', 'Var', (39, 50))	('NBN', 'Gene', (175, 178))	('tumor', 'Disease', (217, 222))	('BRCA2', 'Gene', (15, 20))	('SCLC', 'Phenotype', 'HP:0030357', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('p.Ile171Val', 'Var', (197, 208))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('p.Ile171Val', 'Mutation', 'rs61754966', (197, 208))	('Ter', 'cellular_component', 'GO:0097047', ('90', '93'))	('BRCA2', 'Gene', '675', (15, 20))	('FANCM', 'Gene', '57697', (58, 63))	('p.Arg486Ter', 'Mutation', 'rs1011870043', (82, 93))	('Ter', 'cellular_component', 'GO:0097047', ('47', '50'))	('CRC', 'Phenotype', 'HP:0003003', (150, 153))	('patient', 'Species', '9606', (235, 242))	('SCLC', 'Phenotype', 'HP:0030357', (311, 315))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('NSCLC', 'Disease', (248, 253))	('FANCM', 'Gene', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (310, 315))	('p.Lys944Ter', 'Mutation', 'rs80358533', (39, 50))	('p.Arg486Ter', 'Var', (82, 93))	('NBN', 'Gene', '4683', (175, 178))	('tumor', 'Disease', (116, 121))
208553	31263571	In addition, a WRN nonsense variant (p.Arg369Ter) showed a high allele frequency (>85%) in the tumor sample of a patient with pancreatic cancer in line with previous suggestions that loss-of-function variants within WRN might be associated with an increased predisposition to pancreatic cancer.	('patient', 'Species', '9606', (113, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('WRN', 'Gene', (15, 18))	('WRN', 'Gene', '7486', (15, 18))	('p.Arg369Ter', 'Var', (37, 48))	('pancreatic cancer', 'Disease', (276, 293))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.Arg369Ter', 'Mutation', 'rs17847577', (37, 48))	('pancreatic cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('loss-of-function', 'NegReg', (183, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (276, 293))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('WRN', 'Gene', (216, 219))	('WRN', 'Gene', '7486', (216, 219))	('tumor', 'Disease', (95, 100))	('Ter', 'cellular_component', 'GO:0097047', ('45', '48'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (276, 293))	('tumor', 'Disease', 'MESH:D009369', (95, 100))
208554	31263571	Of note, the LOH in tumor tissue detected by NGS was confirmed by SNParray.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('NGS', 'Var', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
208558	31263571	A second hit in BRCA2 was also observed in a patient with ovarian cancer, however, further analysis revealed that the germline variant, c.7069_7070del, p.Leu2357Valfs*2, and the somatic variant, c.7065del, p.Glu2355Aspfs*12, were located on the same allele, thus, the somatic variant would be expected to restore the interrupted reading frame (resulting in p.Glu2355_Phe2356delinsAsp) reversing the pathogenicity of the germline variant.	('p.Glu2355Aspfs*12', 'Var', (206, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('interrupted', 'MPA', (317, 328))	('c.7069_7070del', 'Mutation', 'c.7069_7070del', (136, 150))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('c.7069_7070del', 'Var', (136, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('BRCA2', 'Gene', (16, 21))	('p.Glu2355_Phe2356delinsAsp', 'Var', (357, 383))	('patient', 'Species', '9606', (45, 52))	('p.Glu2355Aspfs*12', 'FRAMESHIFT', 'None', (206, 223))	('p.Glu2355_Phe2356delinsAsp', 'Mutation', 'p.E2355,2356F,D', (357, 383))	('p.Leu2357Valfs*2', 'Var', (152, 168))	('BRCA2', 'Gene', '675', (16, 21))	('p.Leu2357Valfs*2', 'FRAMESHIFT', 'None', (152, 168))	('ovarian cancer', 'Disease', (58, 72))	('c.7065del', 'Mutation', 'c.7065del', (195, 204))
208559	31263571	This paradoxical phenomenon of a restoring mechanism has previously been described for BRCA variants in platinum resistant ovarian cancer.	('platinum', 'Chemical', 'MESH:D010984', (104, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('BRCA', 'Gene', '672', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA', 'Gene', (87, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('ovarian cancer', 'Disease', (123, 137))	('variants', 'Var', (92, 100))
208561	31263571	Furthermore, a patient with urothelial cancer and a pathogenic germline variant in BRCA2 was found to have two second hits.	('patient', 'Species', '9606', (15, 22))	('BRCA2', 'Gene', '675', (83, 88))	('urothelial cancer', 'Disease', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('urothelial cancer', 'Disease', 'MESH:D014523', (28, 45))	('BRCA2', 'Gene', (83, 88))	('germline variant', 'Var', (63, 79))
208562	31263571	The two somatic variants, c.517-1G>A and c.631+3A>G, were located on opposite alleles, however, it was not possible to determine the allelic location of the germline variants in the other cases (Fig.	('c.631+3A>G', 'Mutation', 'rs397507840', (41, 51))	('c.631+3A>G', 'Var', (41, 51))	('c.517-1G>A', 'Mutation', 'rs81002849', (26, 36))	('c.517-1G>A', 'Var', (26, 36))
208563	31263571	Furthermore, we examined the occurrence of somatic pathogenic variants in genes associated with HR repair and DSB repair and characterized the gene expression profiles of 534 tumors from the patients.	('tumors', 'Disease', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('patients', 'Species', '9606', (191, 199))	('variants', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('gene expression', 'biological_process', 'GO:0010467', ('143', '158'))
208565	31263571	In total, 57 tumors exhibited mutations in the HR pathway and more than half of these mutations were found in BAP1 and BRCA2.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BAP1', 'Gene', (110, 114))	('BRCA2', 'Gene', (119, 124))	('mutations', 'Var', (30, 39))	('HR pathway', 'Pathway', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BRCA2', 'Gene', '675', (119, 124))
208566	31263571	Seven of the mutations occurred in tumors from patients carrying pathogenic germline variants.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('patients', 'Species', '9606', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('occurred', 'Reg', (23, 31))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (13, 22))
208569	31263571	79% (15 out of 19) of the tumors with LOH or a concurrent somatic mutation were predicted to have HRD and 37% (7) of these were predicted to be PARPi sensitive (Fig.	('HRD', 'Disease', 'None', (98, 101))	('PARP', 'Gene', (144, 148))	('HRD', 'Disease', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutation', 'Var', (66, 74))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PARP', 'Gene', '142', (144, 148))	('tumors', 'Disease', (26, 32))
208570	31263571	Taken together, we infer that co-occurrence of germline and somatic variants in the HR pathway may play a role in cancer development and treatment response.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('germline', 'Var', (47, 55))	('HR pathway', 'Pathway', (84, 94))	('treatment response', 'CPA', (137, 155))	('play', 'Reg', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('role', 'Reg', (106, 110))	('cancer', 'Disease', (114, 120))
208571	31263571	Overall, pathogenic BRCA1 and BRCA2 germline variants were observed in patients with expected malignancies such as breast, ovarian, prostate and pancreatic cancer, a large proportion of which showed loss of the wild-type allele in the tumor sample (Fig.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('pathogenic', 'Reg', (9, 19))	('BRCA1', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('patients', 'Species', '9606', (71, 79))	('pancreatic cancer', 'Disease', (145, 162))	('variants', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('breast, ovarian, prostate', 'Disease', 'MESH:D010051', (115, 140))	('malignancies', 'Disease', 'MESH:D009369', (94, 106))	('tumor', 'Disease', (235, 240))	('BRCA2', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BRCA1', 'Gene', '672', (20, 25))	('malignancies', 'Disease', (94, 106))	('BRCA2', 'Gene', '675', (30, 35))
208572	31263571	BRCA1/2 germline variants were also observed in patients with other more atypical cancer types such as salivary adenoid cystic carcinoma, bile duct cancer, endometrial cancer, mesothelioma, esophageal cancer and urothelial cancer, however, without a clear loss of the wild-type allele in the tumor sample (Supplementary Table 4).	('cancer', 'Disease', (201, 207))	('urothelial cancer', 'Disease', (212, 229))	('salivary adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (103, 136))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('variants', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('mesothelioma', 'Disease', (176, 188))	('endometrial cancer', 'Phenotype', 'HP:0012114', (156, 174))	('BRCA1/2', 'Gene', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (176, 188))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('observed', 'Reg', (36, 44))	('salivary adenoid cystic carcinoma', 'Disease', (103, 136))	('bile duct cancer', 'Phenotype', 'HP:0030153', (138, 154))	('bile duct cancer', 'Disease', (138, 154))	('endometrial cancer', 'Disease', (156, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('bile duct cancer', 'Disease', 'MESH:D001650', (138, 154))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('endometrial cancer', 'Disease', 'MESH:D016889', (156, 174))	('cancer', 'Disease', (148, 154))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('tumor', 'Disease', (292, 297))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('esophageal cancer', 'Disease', (190, 207))	('urothelial cancer', 'Disease', 'MESH:D014523', (212, 229))	('patients', 'Species', '9606', (48, 56))
208573	31263571	Pathogenic BRCA1 and BRCA2 variants were identified in 7% of the investigated patients with breast cancer.	('variants', 'Var', (27, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('BRCA2', 'Gene', '675', (21, 26))	('breast cancer', 'Disease', (92, 105))	('BRCA1', 'Gene', '672', (11, 16))	('Pathogenic', 'Reg', (0, 10))	('patients', 'Species', '9606', (78, 86))	('BRCA1', 'Gene', (11, 16))	('BRCA2', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
208574	31263571	In addition, this patient group harbored pathogenic germline variants in other genes previously known or suggested to be associated with breast cancer to a varying extent, including ATR, CDH1, CHEK1, CHEK2, ERCC2, FAN1, SEC23B, and SMAD9.	('ATR', 'Gene', (182, 185))	('CDH1', 'Gene', '999', (187, 191))	('patient', 'Species', '9606', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('CHEK1', 'Gene', (193, 198))	('SEC23B', 'Gene', (220, 226))	('germline variants', 'Var', (52, 69))	('SEC23B', 'Gene', '10483', (220, 226))	('CDH1', 'Gene', (187, 191))	('CHEK2', 'Gene', (200, 205))	('ERCC2', 'Gene', (207, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('SMAD9', 'Gene', (232, 237))	('ATR', 'Gene', '545', (182, 185))	('CHEK2', 'Gene', '11200', (200, 205))	('ERCC2', 'Gene', '2068', (207, 212))	('FAN1', 'Gene', (214, 218))	('pathogenic', 'Reg', (41, 51))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('SMAD9', 'Gene', '4093', (232, 237))	('associated', 'Reg', (121, 131))	('FAN1', 'Gene', '22909', (214, 218))	('CHEK1', 'Gene', '1111', (193, 198))
208575	31263571	However, with the exception of a single patient carrying the moderately penetrant CHEK2 variant, c.1100del, p.Thr367Metfs*15, none of these variants had indications of LOH in the breast tumor samples.	('patient', 'Species', '9606', (40, 47))	('breast tumor', 'Disease', (179, 191))	('p.Thr367Metfs*15', 'Var', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('breast tumor', 'Phenotype', 'HP:0100013', (179, 191))	('c.1100del', 'Var', (97, 106))	('c.1100del', 'Mutation', 'c.1100del', (97, 106))	('CHEK2', 'Gene', '11200', (82, 87))	('breast tumor', 'Disease', 'MESH:D001943', (179, 191))	('p.Thr367Metfs*15', 'FRAMESHIFT', 'None', (108, 124))	('CHEK2', 'Gene', (82, 87))
208576	31263571	To further evaluate whether variants played a role in the cancer etiology of each case, all pathogenic variants were categorized into three groups based on their clinical significance and thus potential causality (Supplementary Table 4).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('variants', 'Var', (28, 36))	('variants', 'Var', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
208577	31263571	Group 1 includes likely causal variants, representing genes known to be associated with an increased risk of the given cancer type, e.g.	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('variants', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
208579	31263571	This group also includes variants with a reduced penetrance, e.g., the CHEK2 c.1100del variant in breast cancer.	('c.1100del', 'Mutation', 'c.1100del', (77, 86))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('CHEK2', 'Gene', '11200', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('c.1100del', 'Var', (77, 86))	('CHEK2', 'Gene', (71, 76))
208580	31263571	About one fourth of the variants falls into this category and are thus likely to be causative and a primary diagnostic finding relevant to the cancer type.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('falls', 'Reg', (33, 38))	('variants', 'Var', (24, 32))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('falls', 'Phenotype', 'HP:0002527', (33, 38))
208581	31263571	Group 2, constituting about 20% of the variants, represents interesting findings that show new possible associations between a gene and a given cancer type but with limited or no previously known predisposition.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('variants', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
208582	31263571	This group also includes variants with a high tumor allele frequency or genes/gene-families overrepresented in a given cancer type in our data set, e.g.	('variants', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
208585	31263571	based on lacking expression of the variant in the tumor sample, or where lack of evidence from the literature in a given cancer type makes the causality inconclusive.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('variant', 'Var', (35, 42))	('cancer', 'Disease', (121, 127))	('tumor', 'Disease', (50, 55))
208591	31263571	Potential actionable treatment targets were identified in 25 patients (4%) and included PARPi for patients with a pathogenic BRCA1/2 variant (n = 21) and immunotherapy for patients harboring a pathogenic variant within the MMR genes (n = 4).	('MMR', 'Gene', (223, 226))	('MMR', 'biological_process', 'GO:0006298', ('223', '226'))	('BRCA1/2', 'Gene', (125, 132))	('PARP', 'Gene', '142', (88, 92))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (98, 106))	('BRCA1/2', 'Gene', '672;675', (125, 132))	('variant', 'Var', (133, 140))	('patients', 'Species', '9606', (172, 180))	('PARP', 'Gene', (88, 92))
208594	31263571	Current results from germline studies of The Cancer Genome Atlas or datasets derived from routine clinical tumor sequencing for allocation of cancer patients to early clinical trials have indicated that variants in cancer susceptibility genes may be more frequent in atypical cancer forms than anticipated.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (215, 221))	('tumor', 'Disease', (107, 112))	('variants', 'Var', (203, 211))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('frequent', 'Reg', (255, 263))	('Cancer Genome Atlas', 'Disease', (45, 64))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (142, 148))
208595	31263571	We analyzed the presence of germline variants in consecutive patients with advanced cancer from the CoPPO study that comprise patients with exhausted treatment options and observed a prevalence of pathogenic germline variants in ~18% among the patients.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('variants', 'Var', (217, 225))	('pathogenic', 'Reg', (197, 207))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (244, 252))
208596	31263571	As mentioned, studies have reported pathogenic germline variants in various cancer populations.	('germline variants', 'Var', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pathogenic', 'Reg', (36, 46))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
208597	31263571	that discovered pathogenic variants in 19.7% of advanced cancer patients.	('variants', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Disease', (57, 63))	('pathogenic', 'Reg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
208599	31263571	reports a larger number of variants within APC and the MMR genes.	('APC', 'Disease', 'MESH:D011125', (43, 46))	('variants', 'Var', (27, 35))	('APC', 'Disease', (43, 46))	('MMR', 'biological_process', 'GO:0006298', ('55', '58'))	('APC', 'cellular_component', 'GO:0005680', ('43', '46'))	('MMR', 'Gene', (55, 58))
208600	31263571	did not include any of the genes in the Fanconi anemia pathway, where we observed a relatively large proportion of pathogenic variants, while our study did not include heterozygous variants in MUTYH in the overall frequency of identified germline variants in contrast to Mandelker et al.	('MUTYH', 'Gene', '4595', (193, 198))	('variants', 'Var', (126, 134))	('anemia', 'Phenotype', 'HP:0001903', (48, 54))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (40, 54))	('Fanconi anemia', 'Disease', (40, 54))	('Fanconi anemia', 'Disease', 'MESH:D005199', (40, 54))	('MUTYH', 'Gene', (193, 198))
208604	31263571	Germline variants in mesothelioma have previously been reported with a frequency of 10-12% in patients.	('mesothelioma', 'Disease', (21, 33))	('Germline variants', 'Var', (0, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('patients', 'Species', '9606', (94, 102))
208605	31263571	In concordance with previous studies, the majority of the mutated genes were involved in HR (BAP1, BRCA2, FANCA, FANCC, FANCD2, and FANCM) and a single gene was involved in nucleotide excision repair (XPC).	('XPC', 'Gene', (201, 204))	('involved', 'Reg', (77, 85))	('FANCM', 'Gene', '57697', (132, 137))	('FANCC', 'Gene', '2176', (113, 118))	('FANCC', 'Gene', (113, 118))	('XPC', 'Gene', '7508', (201, 204))	('FANCA', 'Gene', '2175', (106, 111))	('FANCD2', 'Gene', '2177', (120, 126))	('BRCA2', 'Gene', (99, 104))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('173', '199'))	('FANCA', 'Gene', (106, 111))	('FANCD2', 'Gene', (120, 126))	('FANCM', 'Gene', (132, 137))	('BRCA2', 'Gene', '675', (99, 104))	('mutated genes', 'Var', (58, 71))
208608	31263571	The high frequency of pathogenic germline variants in mesothelioma indicates that this group of patients should be offered mutation screening on a routine basis:especially if they have a family history of mesothelioma or other cancer types associated with mutations in HR genes.	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('mesothelioma', 'Disease', (205, 217))	('cancer', 'Disease', (227, 233))	('mutations', 'Var', (256, 265))	('patients', 'Species', '9606', (96, 104))	('mesothelioma', 'Disease', (54, 66))
208610	31263571	CRC was the predominant cancer type and 19% of the patients exhibited a pathogenic germline variant.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('patients', 'Species', '9606', (51, 59))	('CRC', 'Disease', (0, 3))	('germline variant', 'Var', (83, 99))	('pathogenic', 'Reg', (72, 82))
208612	31263571	Neither did we identify pathogenic variants in the APC gene that predispose to FAP, nor did we observe homozygous or compound heterozygous germline variants in the recessive CRC predisposition genes MUTYH and NTHL1.	('CRC', 'Phenotype', 'HP:0003003', (174, 177))	('APC', 'cellular_component', 'GO:0005680', ('51', '54'))	('FAP', 'Disease', (79, 82))	('predispose', 'Reg', (65, 75))	('variants', 'Var', (35, 43))	('NTHL1', 'Gene', (209, 214))	('MUTYH', 'Gene', (199, 204))	('MUTYH', 'Gene', '4595', (199, 204))	('NTHL1', 'Gene', '4913', (209, 214))	('FAP', 'Disease', 'MESH:C567782', (79, 82))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))
208616	31263571	Obviously, patients with de novo MMR mutations could be represented in our study, but a number of studies have indicated that Lynch de novo mutation are relatively rare compared to e.g., APC related polyposis and it is estimated that only 1-3% of all HNPCC cases are caused by MMR de novo mutations.	('HNPCC', 'Disease', 'None', (251, 256))	('HNPCC', 'Disease', (251, 256))	('mutations', 'Var', (289, 298))	('caused by', 'Reg', (267, 276))	('APC', 'cellular_component', 'GO:0005680', ('187', '190'))	('polyposis', 'Disease', (199, 208))	('HNPCC', 'Phenotype', 'HP:0006716', (251, 256))	('MMR', 'biological_process', 'GO:0006298', ('277', '280'))	('MMR', 'Gene', (277, 280))	('APC', 'Disease', 'MESH:D011125', (187, 190))	('patients', 'Species', '9606', (11, 19))	('APC', 'Disease', (187, 190))	('polyposis', 'Disease', 'MESH:D011125', (199, 208))	('MMR', 'biological_process', 'GO:0006298', ('33', '36'))
208618	31263571	We speculate that the selection of patients in our cohort with advanced cancer displaying a drug-resistant phenotype might be enriched for either germline or somatic variants within specific pathways such as the HR pathway.	('HR pathway', 'Pathway', (212, 222))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('variants', 'Var', (166, 174))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
208621	31263571	The occurrence of pathogenic germline variants in patients with advanced cancer raises the question of whether genetic testing should become part of the clinical routine for a group of patients.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pathogenic', 'Reg', (18, 28))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (185, 193))	('germline', 'Var', (29, 37))
208622	31263571	In this context it is important to distinguish between pathogenic variations in the well-established actionable genes such as BRCA1 and BRCA2 and novel candidate genes such as FANCM and BLM.	('FANCM', 'Gene', '57697', (176, 181))	('BRCA1', 'Gene', (126, 131))	('FANCM', 'Gene', (176, 181))	('BLM', 'Gene', (186, 189))	('variations', 'Var', (66, 76))	('BRCA2', 'Gene', (136, 141))	('BRCA1', 'Gene', '672', (126, 131))	('BLM', 'Gene', '641', (186, 189))	('BRCA2', 'Gene', '675', (136, 141))
208623	31263571	Of note, we could classify about haft of the variants as having either likely or possible clinical significance for the cancer; however, with the caution that further validation is needed to confirm these potential causalities, including pedigree of affected families and functional studies of variants.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (45, 53))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
208625	31263571	Obviously, we could decide to selectively screen a small panel of actionable cancer genes, but we risk that patients or healthy carriers exhibiting pathogenic variants in emerging factors may wrongly be excluded from targeted treatment or pre-symptomatic screening programs.	('variants', 'Var', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (108, 116))	('pre', 'molecular_function', 'GO:0003904', ('239', '242'))
208627	31263571	In conclusion, our study of patients with advanced solid cancers showed a high frequency of germline variants, especially in the HR pathway.	('solid cancers', 'Disease', 'MESH:D009369', (51, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('germline variants', 'Var', (92, 109))	('solid cancers', 'Disease', (51, 64))	('HR pathway', 'Pathway', (129, 139))	('patients', 'Species', '9606', (28, 36))
208628	31263571	This implies that testing for selected germline variants in precision oncology may contribute to the improved treatment of cancer patients.	('treatment', 'CPA', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('improved', 'PosReg', (101, 109))	('patients', 'Species', '9606', (130, 138))	('cancer', 'Disease', (123, 129))	('germline variants', 'Var', (39, 56))	('oncology', 'Phenotype', 'HP:0002664', (70, 78))	('contribute', 'Reg', (83, 93))
208635	31263571	Variant files were filtered so all the variants: (1) were covered by at least 10 reads, (2) had variant score higher or equal to 20, (3) were within the genes of interest using a list of 168 cancer-associated genes (Supplementary Table 1).	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('variant score', 'Var', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('variants', 'Var', (39, 47))
208639	31263571	All variants identified after IVA processing were divided into subgroups based on the classification provided by IVA.	('variants', 'Var', (4, 12))	('IVA', 'Disease', 'MESH:C538167', (113, 116))	('IVA', 'Disease', 'MESH:C538167', (30, 33))	('IVA', 'Disease', (113, 116))	('IVA', 'Disease', (30, 33))
208641	31263571	Furthermore, variants within BRCA1 and BRCA2 and within the MMR genes (MLH1, MSH2, MSH6, and PMS2) classified as uncertain by IVA were manually classified using the same procedure as well as the guidelines provided by ENIGMA and InSiGHT, respectively.	('MSH6', 'Gene', (83, 87))	('variants', 'Var', (13, 21))	('MLH1', 'Gene', '4292', (71, 75))	('IVA', 'Disease', (126, 129))	('MLH1', 'Gene', (71, 75))	('BRCA2', 'Gene', (39, 44))	('MSH2', 'Gene', '4436', (77, 81))	('PMS2', 'Gene', (93, 97))	('BRCA1', 'Gene', '672', (29, 34))	('MMR', 'biological_process', 'GO:0006298', ('60', '63'))	('MSH6', 'Gene', '2956', (83, 87))	('IVA', 'Disease', 'MESH:C538167', (126, 129))	('BRCA2', 'Gene', '675', (39, 44))	('PMS2', 'Gene', '5395', (93, 97))	('BRCA1', 'Gene', (29, 34))	('MSH2', 'Gene', (77, 81))
208689	28817672	Mesothelioma incidence and resident data were further divided into age groups using 5-year units (0-4, 5-9, 10-14, 15-19, 20-24, 25-29, 30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, 85+ years of age).	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))	('30-34', 'Var', (136, 141))	('35-39', 'Var', (143, 148))
208777	28817672	In addition, SV40 in contaminated polio vaccines, and germline BAP1 mutations have been associated with malignant mesothelioma.	('contaminated polio', 'Phenotype', 'HP:0020090', (21, 39))	('BAP1', 'Gene', (63, 67))	('malignant mesothelioma', 'Disease', (104, 126))	('mutations', 'Var', (68, 77))	('SV40', 'Var', (13, 17))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (104, 126))	('associated', 'Reg', (88, 98))	('BAP1', 'Gene', '8314', (63, 67))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (104, 126))
208778	28817672	In South Korea, a study utilizing data from the malignant mesothelioma surveillance system failed to confirm that SV40 was associated with the development of mesothelioma.	('associated with', 'Reg', (123, 138))	('mesothelioma', 'Disease', (58, 70))	('mesothelioma', 'Disease', (158, 170))	('SV40', 'Var', (114, 118))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (48, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('men', 'Species', '9606', (150, 153))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (48, 70))	('malignant mesothelioma', 'Disease', (48, 70))
208779	28817672	However, the SV40 test was performed in only some of the patients; thus, the results of this previous study alone cannot be said to indicate that SV40 is unassociated with malignant mesothelioma in South Korea.	('malignant mesothelioma', 'Disease', (172, 194))	('SV40', 'Var', (146, 150))	('patients', 'Species', '9606', (57, 65))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (172, 194))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (172, 194))
208780	28817672	Germline BAP1 mutations also can increase the incidence of mesothelioma; however, the BAP1 test is not generally performed, and studies on BAP1 mutations have not yet been conducted in South Korea.	('mesothelioma', 'Disease', (59, 71))	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', '8314', (139, 143))	('BAP1', 'Gene', '8314', (9, 13))	('increase', 'PosReg', (33, 41))	('BAP1', 'Gene', (86, 90))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('BAP1', 'Gene', (139, 143))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
208782	28817672	Further studies are needed regarding the potential associations between malignant mesothelioma and SV40 exposure and BAP1 mutations.	('malignant mesothelioma', 'Disease', (72, 94))	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', (117, 121))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (72, 94))	('mutations', 'Var', (122, 131))	('SV40', 'Gene', (99, 103))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (72, 94))
208843	26039812	It has been clearly established in multiple models that asbestos fiber inhalation can lead to neoplastic diseases such as MM and lung cancer, as well as pulmonary fibrosis.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (153, 171))	('asbestos', 'Chemical', 'MESH:D001194', (56, 64))	('neoplastic diseases', 'Disease', 'MESH:D009386', (94, 113))	('pulmonary fibrosis', 'Disease', (153, 171))	('asbestos', 'Protein', (56, 64))	('neoplastic diseases', 'Disease', (94, 113))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('lead to', 'Reg', (86, 93))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('inhalation', 'Var', (71, 81))
208860	26039812	After adjustments for asbestos exposure and latency time, patients with plaques had a significantly elevated risk of mesothelioma.	('plaques', 'Var', (72, 79))	('mesothelioma', 'Disease', (117, 129))	('men', 'Species', '9606', (12, 15))	('asbestos', 'Chemical', 'MESH:D001194', (22, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('patients', 'Species', '9606', (58, 66))
208873	26039812	Furthermore, some studies have shown that the cyclin-dependent kinase inhibitor 4a (P16INK4a) and ARF tumor suppressor (p14ARF) genes are frequently inactivated in mesothelioma and approximately 50% of MM cases contain missense or nonsense mutations in the neurofibromin type 2 gene.	('ARF tumor', 'Disease', (98, 107))	('missense', 'Var', (219, 227))	('p14ARF', 'Gene', (120, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('mesothelioma', 'Disease', (164, 176))	('inactivated', 'NegReg', (149, 160))	('P16INK4a', 'Gene', '1029', (84, 92))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('63', '79'))	('p14ARF', 'Gene', '1029', (120, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('ARF tumor', 'Disease', 'MESH:D009369', (98, 107))	('nonsense mutations', 'Var', (231, 249))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('contain', 'Reg', (211, 218))	('P16INK4a', 'Gene', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('46', '79'))	('neurofibromin type 2', 'Gene', (257, 277))
208875	26039812	In addition, within the last few years, germ line and sporadic mutations of the tumor suppressor, breast cancer susceptibility (BRCA)-1 associated protein-1 (BAP-1) gene, which expresses a deubiquitinating enzyme, appear to predispose patients to DNA damage after environmental stress.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('predispose', 'Reg', (224, 234))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DNA damage', 'Disease', (247, 257))	('patients', 'Species', '9606', (235, 243))	('tumor', 'Disease', (80, 85))	('BAP-1', 'Gene', '8314', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('189', '212'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('breast cancer susceptibility (BRCA)-1 associated protein-1', 'Gene', '8314', (98, 156))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('BAP-1', 'Gene', (158, 163))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
208879	26039812	Furthermore, genetic studies indicate that polymorphisms in genes within the NRLP3 family can both predispose and protect against fibrosis following asbestos exposure.	('polymorphisms', 'Var', (43, 56))	('protect', 'Reg', (114, 121))	('fibrosis', 'Disease', (130, 138))	('fibrosis', 'Disease', 'MESH:D005355', (130, 138))	('asbestos', 'Chemical', 'MESH:D001194', (149, 157))	('NRLP3', 'Gene', (77, 82))	('predispose', 'Reg', (99, 109))
208910	26039812	During oxidative stress, ROS can cause oxidative damage to dGuo to form 8-oxo-dGuo in DNA and the trinucleotide pool.	('cause', 'Reg', (33, 38))	('trinucleotide', 'Chemical', '-', (98, 111))	('ROS', 'Var', (25, 28))	('dGuo', 'Chemical', '-', (78, 82))	('8-oxo-dGuo', 'Chemical', 'MESH:C067134', (72, 82))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('oxidative stress', 'Phenotype', 'HP:0025464', (7, 23))	('dGuo', 'Chemical', '-', (59, 63))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('oxidative damage', 'MPA', (39, 55))
209012	26039812	Specifically, activation of the NF-kappaB signaling pathway and release of tumor necrosis factor-alpha (TNFalpha) are downstream consequences of HMGB1 activity.	('necrosis', 'biological_process', 'GO:0008219', ('81', '89'))	('activation', 'PosReg', (14, 24))	('necrosis', 'biological_process', 'GO:0019835', ('81', '89'))	('tumor necrosis factor-alpha', 'Gene', '7124', (75, 102))	('necrosis', 'biological_process', 'GO:0008220', ('81', '89'))	('TNFalpha', 'Gene', (104, 112))	('activity', 'Var', (151, 159))	('NF-kappaB signaling pathway', 'Pathway', (32, 59))	('release of', 'MPA', (64, 74))	('necrosis', 'biological_process', 'GO:0001906', ('81', '89'))	('signaling pathway', 'biological_process', 'GO:0007165', ('42', '59'))	('HMGB1', 'Gene', (145, 150))	('TNFalpha', 'Gene', '7124', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor necrosis factor-alpha', 'Gene', (75, 102))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('75', '96'))	('necrosis', 'biological_process', 'GO:0070265', ('81', '89'))
209021	26039812	Typically upregulated after phagocytosis of fibers by macrophages, generation of TNFalpha may induce further binding of particles, thus exacerbating the effects of asbestos exposure.	('TNFalpha', 'Gene', (81, 89))	('asbestos', 'Chemical', 'MESH:D001194', (164, 172))	('generation', 'Var', (67, 77))	('rat', 'Species', '10116', (71, 74))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('TNFalpha', 'Gene', '7124', (81, 89))	('phagocytosis', 'biological_process', 'GO:0006909', ('28', '40'))	('induce', 'Reg', (94, 100))	('upregulated', 'PosReg', (10, 21))	('particles', 'Protein', (120, 129))	('binding', 'Interaction', (109, 116))	('exacerbating', 'PosReg', (136, 148))
209063	26039812	Papers of special note have been highlighted as either:   of interest    of considerable interest Asbestos exposure is now known to cause lung cancer and mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('mesothelioma', 'Disease', (154, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('Asbestos exposure', 'Var', (98, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (154, 166))	('Asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('lung cancer', 'Disease', (138, 149))	('exposure', 'Var', (107, 115))	('cause', 'Reg', (132, 137))
209197	23484132	A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world.	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (79, 101))	('Malignant Mesothelioma', 'Disease', 'MESH:C562839', (37, 59))	('occupational asbestos', 'Disease', (123, 144))	('Malignant Mesothelioma', 'Disease', (37, 59))	('Gene Medicine', 'Var', (65, 78))	('patient', 'Species', '9606', (200, 207))	('occupational asbestos', 'Disease', 'MESH:D009784', (123, 144))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (79, 101))	('Malignant mesothelioma', 'Disease', (79, 101))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (37, 59))
209207	23484132	Interestingly, there is also an arousing concern about a widespread usage of nanosized particles for medical and industrial purposes, which may predispose to mesothelioma developments.	('nanosized', 'Var', (77, 86))	('mesothelioma', 'Disease', (158, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('arousing concern', 'Phenotype', 'HP:0000741', (32, 48))	('predispose', 'Reg', (144, 154))
209225	23484132	Inhibition of angiogenesis produced antitumor responses and decreased pleural effusion, and therefore targeting angiogenesis was clinically examined for the therapeutic efficacy.	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('decreased pleural effusion', 'Disease', (60, 86))	('Inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('0', '26'))	('pleural effusion', 'Phenotype', 'HP:0002202', (70, 86))	('Inhibition', 'Var', (0, 10))	('angiogenesis', 'CPA', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('decreased pleural effusion', 'Disease', 'MESH:D010996', (60, 86))
209226	23484132	A phase II study, however, demonstrated that antibody for VEGF, bevacizumab, with chemotherapy failed to prolong the progression free survival compared with the chemotherapy alone.	('VEGF', 'Gene', (58, 62))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('VEGF', 'Gene', '7422', (58, 62))	('bevacizumab', 'Chemical', 'MESH:D000068258', (64, 75))	('progression free survival', 'CPA', (117, 142))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('antibody', 'Var', (45, 53))
209227	23484132	Taking these results together, molecular target medicine, as a single agent, could produce only a limited success, and no survival benefits have been observed even in a combination with other anticancer agents.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('molecular', 'Var', (31, 40))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))
209232	23484132	The NF2  gene-encoded protein, merlin, regulates several signal cascades, and the defect constitutively activates Yes-associated protein transcriptional coactivator.	('Yes-associated', 'MPA', (114, 128))	('regulates', 'Reg', (39, 48))	('activates', 'PosReg', (104, 113))	('signal cascades', 'MPA', (57, 72))	('merlin', 'Gene', (31, 37))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('NF2', 'Gene', '4771', (4, 7))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('defect', 'Var', (82, 88))	('merlin', 'Gene', '4771', (31, 37))	('NF2', 'Gene', (4, 7))
209234	23484132	Deficient BAP1 is not specific to mesothelioma and is rather more often linked with other cancer types, and the biological significance is currently unknown.	('Deficient', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BAP1', 'Gene', (10, 14))	('linked', 'Reg', (72, 78))	('mesothelioma', 'Disease', (34, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('BAP1', 'Gene', '8314', (10, 14))
209238	23484132	Lack of p16 leads to the enhanced activities of cyclin-dependent kinase 4 and 6 and induces the phosphorylation of pRb.	('cyclin-dependent kinase 4', 'Gene', '1019', (48, 73))	('enhanced', 'PosReg', (25, 33))	('p16', 'Gene', '1029', (8, 11))	('cyclin-dependent kinase 4', 'Gene', (48, 73))	('pRb', 'Gene', '5925', (115, 118))	('Lack', 'Var', (0, 4))	('phosphorylation', 'MPA', (96, 111))	('pRb', 'Gene', (115, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('cyclin', 'molecular_function', 'GO:0016538', ('48', '54'))	('p16', 'Gene', (8, 11))	('activities', 'MPA', (34, 44))	('induces', 'Reg', (84, 91))
209239	23484132	Loss of p21 induction due to the p53 deficiency does not suppress cyclin-dependent kinase 2 activities and favors pRb phosphorylation as well, which promotes cell cycle progression.	('pRb', 'Gene', '5925', (114, 117))	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('pRb', 'Gene', (114, 117))	('cell cycle progression', 'CPA', (158, 180))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('p21', 'Gene', (8, 11))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('activities', 'MPA', (92, 102))	('cyclin-dependent kinase 2', 'Gene', '1017', (66, 91))	('p21', 'Gene', '644914', (8, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('promotes', 'PosReg', (149, 157))	('deficiency', 'Var', (37, 47))	('favors', 'PosReg', (107, 113))	('cyclin-dependent kinase 2', 'Gene', (66, 91))
209243	23484132	Interestingly, Ad-16 produced greater antitumor effects than Ad-p14, and a combinatory use of Ad-p14 and Ad-p16 did not achieve better therapeutic effects than monotherapy with individual Ad.	('Ad-16', 'Var', (15, 20))	('tumor', 'Disease', (42, 47))	('p16', 'Gene', '1029', (108, 111))	('p14', 'Gene', '1029', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p14', 'Gene', (97, 100))	('p16', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('p14', 'Gene', '1029', (97, 100))	('p14', 'Gene', (64, 67))
209249	23484132	Ad-p53 transduction not only produced apoptotic tumor cell death but synergistic cytotoxicity with the first-line anticancer agents, cisplatin, and pemetrexed.	('p53', 'Gene', '7157', (3, 6))	('cancer', 'Disease', (118, 124))	('tumor', 'Disease', (48, 53))	('cytotoxicity', 'Disease', (81, 93))	('transduction', 'biological_process', 'GO:0009293', ('7', '19'))	('transduction', 'Var', (7, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cell death', 'biological_process', 'GO:0008219', ('54', '64'))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('p53', 'Gene', (3, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('pemetrexed', 'Chemical', 'MESH:D000068437', (148, 158))
209251	23484132	These data collectively indicate that the reactivation of the defective p53 pathways is a promising direction of gene therapy for mesothelioma.	('mesothelioma', 'Disease', (130, 142))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (72, 75))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('defective', 'Var', (62, 71))
209256	23484132	The HGF/c-Met pathways have a crucial role in the invasion of tumors and in metastasis, and previous studies in fact demonstrated that the inhibition of the pathway suppressed tumor infiltration into neighboring tissues.	('metastasis', 'CPA', (76, 86))	('inhibition', 'Var', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('HGF', 'Gene', (4, 7))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('c-Met', 'Gene', (8, 13))	('suppressed', 'NegReg', (165, 175))	('HGF', 'Gene', '3082', (4, 7))	('c-Met', 'Gene', '4233', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
209280	23484132	Ad infection promptly induces E1A, one of the immediate early gene products, and E1A subsequently induces p53 expression in the host cells.	('p53', 'Gene', '7157', (106, 109))	('E1A', 'Gene', (30, 33))	('E1A', 'Var', (81, 84))	('induces', 'Reg', (98, 105))	('p53', 'Gene', (106, 109))	('induces', 'Reg', (22, 29))
209285	23484132	The defective Ads, thus, have two mechanisms to achieve antitumor effects through augmenting the p53 pathways and viral replication.	('p53', 'Gene', (97, 100))	('viral replication', 'biological_process', 'GO:0008166', ('114', '131'))	('defective', 'Var', (4, 13))	('p53', 'Gene', '7157', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('viral replication', 'CPA', (114, 131))	('viral replication', 'biological_process', 'GO:0019079', ('114', '131'))	('augmenting', 'NegReg', (82, 92))	('tumor', 'Disease', (60, 65))	('viral replication', 'biological_process', 'GO:0019058', ('114', '131'))
209293	23484132	These studies showed the transgene expression in mesothelioma but also revealed that the viral spread was limited only around the injection sites or in a surface region even with good amounts of Ad used.	('mesothelioma', 'Disease', (49, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (49, 61))	('transgene', 'Var', (25, 34))
209314	23484132	An exact mechanism about the verapamil-mediated enhancement of antitumor effects remains unclear, but the inhibition of calcium influx may augment Ad releases and improve the spread into the vicinity.	('calcium influx', 'MPA', (120, 134))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('augment', 'PosReg', (139, 146))	('inhibition', 'Var', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('spread into the vicinity', 'CPA', (175, 199))	('verapamil', 'Chemical', 'MESH:D014700', (29, 38))	('calcium', 'Chemical', 'MESH:D002118', (120, 127))	('tumor', 'Disease', (67, 72))	('improve', 'PosReg', (163, 170))	('Ad releases', 'CPA', (147, 158))
209318	23484132	Moreover, the decoy inhibited collagen formation around the tumors.	('collagen', 'molecular_function', 'GO:0005202', ('30', '38'))	('collagen formation', 'biological_process', 'GO:0032964', ('30', '48'))	('tumors', 'Disease', (60, 66))	('inhibited', 'NegReg', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('decoy', 'Var', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
209477	18310086	However, there is a rapidly emerging literature that describes inactivation of a diverse array of tumor suppressor genes (TSGs) via promoter DNA CpG methylation in MPM, although the etiology of these alterations remains unclear.	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('TSG', 'Gene', '57045', (122, 125))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('tumor', 'Disease', (98, 103))	('inactivation', 'NegReg', (63, 75))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('promoter', 'MPA', (132, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'Var', (149, 160))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('TSG', 'Gene', (122, 125))	('MPM', 'Gene', (164, 167))
209480	18310086	We observed significantly higher lung asbestos body burden if any of these cell cycle genes were methylated (P < 0.02), and there was a significant trend of increasing asbestos body counts as the number of methylated cell cycle pathway genes increased from 0 to 1 to >1 (P < 0.005).	('lung asbestos body', 'Disease', 'MESH:D001195', (33, 51))	('cell cycle', 'biological_process', 'GO:0007049', ('217', '227'))	('asbestos', 'Chemical', 'MESH:D001194', (168, 176))	('higher', 'PosReg', (26, 32))	('lung asbestos body', 'Disease', (33, 51))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('methylated', 'Var', (206, 216))	('increasing', 'PosReg', (157, 167))	('asbestos body', 'Phenotype', 'HP:0011002', (38, 51))	('cell cycle genes', 'Gene', (75, 91))	('asbestos body', 'Phenotype', 'HP:0011002', (168, 181))	('asbestos body counts', 'MPA', (168, 188))	('methylated', 'Var', (97, 107))	('cell cycle pathway genes', 'Gene', (217, 241))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))
209491	18310086	Phagocytosis of fibers by macrophages and oxidoreduction reactions on fiber surfaces are known to generate genotoxic reactive oxygen species that are capable of inducing DNA damage and leading to genetic alterations in MPM.	('inducing', 'Reg', (161, 169))	('MPM', 'Gene', (219, 222))	('DNA damage', 'MPA', (170, 180))	('Phagocytosis', 'biological_process', 'GO:0006909', ('0', '12'))	('leading to', 'Reg', (185, 195))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (117, 140))	('genetic alterations', 'Var', (196, 215))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
209492	18310086	In addition to genetic alterations, the rapidly emerging literature indicates that epigenetic tumor suppressor gene (TSG) silencing via promoter methylation occurs in MPM.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('epigenetic', 'Var', (83, 93))	('TSG', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('TSG', 'Gene', '57045', (117, 120))	('MPM', 'Disease', (167, 170))	('silencing', 'NegReg', (122, 131))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('promoter', 'MPA', (136, 144))
209493	18310086	Methylation of cytosines in the context of promoter CpG islands of TSGs is a well-established mechanism of stable gene silencing in human cancers.	('TSG', 'Gene', (67, 70))	('Methylation', 'Var', (0, 11))	('cytosines', 'Chemical', 'MESH:D003596', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('TSG', 'Gene', '57045', (67, 70))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('gene silencing', 'biological_process', 'GO:0016458', ('114', '128'))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
209494	18310086	However, the precise mechanisms underlying the induction of TSG methylation and the factors that influence tumor-specific methylation profiles are incompletely understood.	('methylation', 'Var', (64, 75))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('TSG', 'Gene', (60, 63))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TSG', 'Gene', '57045', (60, 63))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))
209506	18310086	These genes were chosen as both a part of a larger pathway-based group of genes studied in our laboratory:in this and other types of human cancers:and because they are generally considered among the most important cell cycle control TSGs known to be inactivated via methylation in cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('methylation', 'Var', (266, 277))	('TSG', 'Gene', '57045', (233, 236))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cell cycle control', 'biological_process', 'GO:1901987', ('214', '232'))	('methylation', 'biological_process', 'GO:0032259', ('266', '277'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (281, 287))	('cancers', 'Disease', (139, 146))	('TSG', 'Gene', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('human', 'Species', '9606', (133, 138))	('inactivated', 'NegReg', (250, 261))	('cancer', 'Disease', (139, 145))
209507	18310086	We examined whether methylation of specific genes, methylation at any of these loci or methylation of an increasing number of genes was associated with asbestos exposure, patient demographic variables or tumor histology.	('associated', 'Reg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('patient', 'Species', '9606', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('tumor', 'Disease', (204, 209))	('methylation', 'Var', (51, 62))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))
209521	18310086	Univariate tests for association between methylation at each of the cell cycle genes and patient demographic, tumor characteristic and exposure variables were carried out with the appropriate statistical tests using SAS analysis software.	('patient', 'Species', '9606', (89, 96))	('association', 'Interaction', (21, 32))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('methylation', 'Var', (41, 52))	('cell cycle genes', 'Gene', (68, 84))	('cell cycle', 'biological_process', 'GO:0007049', ('68', '78'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
209522	18310086	Similarly, tests for association between methylation at zero, one or greater than one gene, and patient demographic, tumor characteristic and exposure variables also were performed.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('patient', 'Species', '9606', (96, 103))	('methylation', 'Var', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
209530	18310086	The prevalence of methylation among the cell cycle control genes varied; RASSF1 was methylated in 33% (n = 22) of cases, APPBP1 in 20% (n = 14), CDKN2A in 13% (n = 9), APC and CCND2 in 9% (n = 6) and finally CDKN2B was methylated in 4% (n = 3) of cases (Figure 1).	('RASSF1', 'Gene', (73, 79))	('CDKN2B', 'Gene', '1030', (208, 214))	('APPBP1', 'Gene', '8883', (121, 127))	('APC', 'cellular_component', 'GO:0005680', ('168', '171'))	('n = 14', 'Gene', (136, 142))	('CCND2', 'Gene', (176, 181))	('CDKN2A', 'Gene', (145, 151))	('CCND2', 'Gene', '894', (176, 181))	('cell cycle control', 'biological_process', 'GO:1901987', ('40', '58'))	('methylated', 'Var', (84, 94))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('CDKN2A', 'Gene', '1029', (145, 151))	('APPBP1', 'Gene', (121, 127))	('n = 14', 'Gene', '8636', (136, 142))	('CDKN2B', 'Gene', (208, 214))	('APC', 'Disease', 'MESH:D011125', (168, 171))	('APC', 'Disease', (168, 171))	('methylation', 'Var', (18, 29))	('RASSF1', 'Gene', '11186', (73, 79))
209531	18310086	We found no significant associations between patient gender or tumor histology and methylation at any of the six individual loci examined.	('tumor', 'Disease', (63, 68))	('patient', 'Species', '9606', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('methylation', 'Var', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
209532	18310086	However, patients with RASSF1 methylation were significantly older (65 +- 6.6 years) than patients without RASSF1 methylation (61 +- 9.5 years) (P < 0.05).	('RASSF1', 'Gene', (107, 113))	('patients', 'Species', '9606', (9, 17))	('methylation', 'Var', (30, 41))	('RASSF1', 'Gene', '11186', (23, 29))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('RASSF1', 'Gene', '11186', (107, 113))	('RASSF1', 'Gene', (23, 29))	('patients', 'Species', '9606', (90, 98))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))
209533	18310086	We observed a similar relationship between methylation of CCND2 and older age (methylated, 69 +- 8.2 years; unmethylated, 61 +- 8.9 years) (P < 0.05).	('methylation', 'Var', (43, 54))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('CCND2', 'Gene', (58, 63))	('CCND2', 'Gene', '894', (58, 63))
209534	18310086	We then asked whether this relationship with age was a more general phenomenon and found that methylation at any (one or more gene) of the six TSGs was significantly associated with increased age (methylated, 64 +- 8.1 years; unmethylated, 58 +- 9.4 years) (P < 0.01).	('TSG', 'Gene', '57045', (143, 146))	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('TSG', 'Gene', (143, 146))	('methylation', 'Var', (94, 105))	('associated', 'Reg', (166, 176))
209536	18310086	While we found no significant associations between methylation at any one of the six genes and self-reported asbestos exposure, cases with RASSF1 methylation had significantly higher asbestos body counts (mean count = 698) compared with cases without RASSF1 methylation (mean count = 409) (P < 0.01, Wilcoxon test).	('asbestos body counts', 'CPA', (183, 203))	('RASSF1', 'Gene', (139, 145))	('asbestos', 'Chemical', 'MESH:D001194', (183, 191))	('RASSF1', 'Gene', '11186', (251, 257))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('methylation', 'biological_process', 'GO:0032259', ('258', '269'))	('higher', 'PosReg', (176, 182))	('RASSF1', 'Gene', '11186', (139, 145))	('methylation', 'Var', (146, 157))	('asbestos body', 'Phenotype', 'HP:0011002', (183, 196))	('RASSF1', 'Gene', (251, 257))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
209537	18310086	Similarly, there was no significant relationship between methylation of any cell cycle gene (comparing samples with no genes methylated to those with any genes methylated) and self-reported asbestos exposure.	('methylation', 'Var', (57, 68))	('asbestos', 'Chemical', 'MESH:D001194', (190, 198))	('methylated', 'Var', (125, 135))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('cell cycle gene', 'Gene', (76, 91))
209541	18310086	Figure 2 shows that log transformed asbestos body counts are significantly correlated with the number of cell cycle control genes methylated (linear regression F-test, P < 0.005).	('asbestos body', 'Phenotype', 'HP:0011002', (36, 49))	('asbestos', 'Chemical', 'MESH:D001194', (36, 44))	('cell cycle control', 'biological_process', 'GO:1901987', ('105', '123'))	('cell cycle control genes', 'Gene', (105, 129))	('methylated', 'Var', (130, 140))
209543	18310086	We evaluated promoter hypermethylation of six cell cycle control and progression pathway genes in an incident case series of 70 MPMs examining whether methylation of specific genes, methylation of any of these loci or methylation of an increasing number of genes was associated with patient demographic variables, tumor histology or asbestos exposure.	('asbestos', 'Chemical', 'MESH:D001194', (333, 341))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('methylation', 'biological_process', 'GO:0032259', ('218', '229'))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('methylation', 'Var', (151, 162))	('methylation', 'Var', (182, 193))	('tumor', 'Disease', (314, 319))	('cell cycle control', 'biological_process', 'GO:1901987', ('46', '64'))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('cell cycle control', 'Gene', (46, 64))	('associated', 'Reg', (267, 277))	('patient', 'Species', '9606', (283, 290))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
209545	18310086	Further, these genes are known to be subject to inactivation by promoter hypermethylation in cancer and are recognized as important in cell cycle control and progression.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('promoter hypermethylation', 'Var', (64, 89))	('inactivation', 'NegReg', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cell cycle control', 'biological_process', 'GO:1901987', ('135', '153'))
209546	18310086	Methylation of RASSF1 has been observed in 32% of MPM (n = 66) and previously significantly associated with SV40 exposure.	('RASSF1', 'Gene', '11186', (15, 21))	('MPM', 'Disease', (50, 53))	('Methylation', 'Var', (0, 11))	('RASSF1', 'Gene', (15, 21))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('observed', 'Reg', (31, 39))	('associated', 'Reg', (92, 102))
209547	18310086	We observed essentially the same prevalence of RASSF1 methylation among our cases (33%), and we also found that RASSF1 methylation was significantly associated with increased asbestos body count.	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))	('RASSF1', 'Gene', '11186', (112, 118))	('asbestos body', 'CPA', (175, 188))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('RASSF1', 'Gene', '11186', (47, 53))	('methylation', 'Var', (54, 65))	('methylation', 'Var', (119, 130))	('asbestos body', 'Phenotype', 'HP:0011002', (175, 188))	('RASSF1', 'Gene', (47, 53))	('associated', 'Reg', (149, 159))	('RASSF1', 'Gene', (112, 118))	('increased', 'PosReg', (165, 174))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))
209548	18310086	Furthermore, significant, independent associations between older patient age and methylation of CCND2 and RASSF1 were observed.	('CCND2', 'Gene', '894', (96, 101))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('associations', 'Interaction', (38, 50))	('RASSF1', 'Gene', '11186', (106, 112))	('patient', 'Species', '9606', (65, 72))	('RASSF1', 'Gene', (106, 112))	('CCND2', 'Gene', (96, 101))
209554	18310086	In our data, tumors with methylation have significantly higher asbestos exposure, using the asbestos body counts as a quantitative measure of burden.	('asbestos', 'Chemical', 'MESH:D001194', (63, 71))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('asbestos body', 'Phenotype', 'HP:0011002', (92, 105))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('asbestos exposure', 'MPA', (63, 80))	('methylation', 'Var', (25, 36))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('asbestos', 'Chemical', 'MESH:D001194', (92, 100))	('higher', 'PosReg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
209562	18310086	Repeated passaging of cells in tissue culture, similar to the process of aging, is associated with the induction of TSG silencing by promoter methylation.	('TSG', 'Gene', '57045', (116, 119))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('silencing', 'NegReg', (120, 129))	('promoter methylation', 'Var', (133, 153))	('TSG', 'Gene', (116, 119))	('aging', 'biological_process', 'GO:0007568', ('73', '78'))
209563	18310086	The known decades-long latency of MPM then suggests that there is ample time for appreciable fields of clonally altered cells to accumulate, perhaps leading to malignancy through a combination of acquired genetic and epigenetic alterations enhanced by repeated mitotic selection.	('malignancy', 'Disease', (160, 170))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('leading to', 'Reg', (149, 159))	('epigenetic', 'Var', (217, 227))
209565	18310086	While these mechanisms of clonal selection for epigenetic silencing are consistent with our data, it does not necessarily imply any direct asbestos fiber interaction with the histone/DNA methylation machinery, but instead that the chronic inflammation response and/or accelerated tumor growth related to asbestos burden may select for cells capable of continued proliferation.	('accelerated', 'PosReg', (268, 279))	('epigenetic silencing', 'Var', (47, 67))	('chronic inflammation', 'Disease', (231, 251))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('inflammation', 'biological_process', 'GO:0006954', ('239', '251'))	('chronic inflammation', 'Disease', 'MESH:D007249', (231, 251))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('asbestos', 'Chemical', 'MESH:D001194', (139, 147))	('asbestos', 'Chemical', 'MESH:D001194', (304, 312))	('tumor', 'Disease', (280, 285))	('DNA methylation', 'biological_process', 'GO:0006306', ('183', '198'))
209567	18310086	Our data, using a quantitative measure of asbestos exposure, demonstrate that epigenetic gene inactivation is a crucial and novel mechanism for asbestos action in the genesis of this rapidly fatal cancer.	('epigenetic gene inactivation', 'Var', (78, 106))	('asbestos', 'Chemical', 'MESH:D001194', (144, 152))	('asbestos', 'Chemical', 'MESH:D001194', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
209629	25756396	Considering a division at the median TGV of 1800, in the chemotherapy group, patients with a baseline TGV>=1800 had a significantly shorter median survival of 266 (IQR 180-479) days compared with 456 (IQR 266-653) days in patients with TGV <1800 (HR 3.00; 95% CI: 1.53-5.88; chi2=13.53; d.f.=1; P=0.001).	('median survival', 'MPA', (140, 155))	('TGV', 'Chemical', '-', (236, 239))	('TGV', 'Chemical', '-', (37, 40))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (77, 85))	('shorter', 'NegReg', (132, 139))	('TGV', 'Chemical', '-', (102, 105))	('TGV>=1800', 'Var', (102, 111))
209665	25756396	There was nearly 7 months greater median survival in the low baseline NLR patients when considering the chemotherapy group.	('median survival', 'MPA', (34, 49))	('patients', 'Species', '9606', (74, 82))	('low', 'Var', (57, 60))	('NLR', 'Gene', (70, 73))	('greater', 'PosReg', (26, 33))